MCL-1 inhibitors

Abstract

To provide compounds and pharmaceutical compositions that may be used in methods of treating cancer.SOLUTION: In some embodiments, a pharmaceutical composition comprises a compound according to Formula (I), or a tautomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, a method of inhibiting MCL-1 in a patient comprises administering a compound according to Formula (I), or a tautomer or pharmaceutically acceptable salt thereof, to the patient.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 hereby incorporated by reference in their entirety.

[0002] This application generally relates to certain compounds that inhibit MCL - 1, pharmaceutical compositions containing such compounds, the use of such compounds for treating cancer, and methods of making such compounds.

Background Art

[0003] Apoptosis (programmed cell death) is a process for eliminating unwanted or potentially dangerous cells from an organism. Avoidance of apoptosis is very important for tumorigenesis and the sustained growth of tumors. 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. The overexpression of MCL - 1 prevents cancer cells from undergoing apoptosis. Studies have 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 Problems

[0004] The above need is 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)

Chemical Formula

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

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

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

[0009] Unless the context otherwise requires, throughout the specification and claims, the word "comprise", and variations such as "comprises" and "comprising", are to be construed in an open, inclusive sense, i.e., "including, but not limited to".

[0010] The prefix "C u~v " or "(C u ~C v )" etc. indicates that the subsequent 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 1 to 6 carbon atoms.

[0011] A dash ("-") not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -C(O)NH2 is attached via a carbon atom. Dashes at the beginning or end of a chemical group are for convenience, and the chemical groups may be depicted with or without one or more dashes without losing their normal meaning. Unless chemically or structurally necessary, the order in which chemical groups are described or named does not indicate or imply directionality.

[0012] As shown below, a wavy line on a chemical group, e.g.,

Chemical Structure

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

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

[0015] As used herein, "alkyl" is a straight-chain or branched monovalent saturated hydrocarbon. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)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 (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 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, but are not limited to, ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0017] "Alkoxy", as used herein, refers to the formula -OR A (wherein R A 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 a fused ring system, wherein 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 include heteroaryl in any way or overlap with it. 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 definition does not exclude further substituents on the aryl group. For example, as used herein, an aryl group of "A-aryl-B" is a diradical, and an aryl group of "A-B-aryl" is a monoradical, but further substituents may be present on each aryl group.

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

[0021] "Cycloalkyl" refers to a saturated or partially saturated cyclic alkyl group 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] As used herein, the term "haloalkyl" refers to alkyl as defined herein, wherein 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 hydrogen atoms of the alkyl are replaced by halo substituents 1~6 alkyl. 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 by a heteroatom group, the same or different. The term "heteroalkyl" includes non-branched or branched saturated chains having carbon, and heteroatoms selected from nitrogen, sulfur, phosphorus and oxygen. The heteroatoms within "heteroalkyl" may be oxidized, for example -N(O)-, -S(O)-, -S(O)2-. Examples of heteroalkyl groups include -OCH3, -CH2OCH3, -SCH3, -CH2SCH3, -NRCH3, and -CH2NRCH3 (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 within "heteroaryl" may be oxidized, for example, -N(O)-, -S(O)-, -S(O)2-. This term includes fused ring systems where one or more of the fused rings are fully or partially unsaturated. The classification of monoradical or diradical indicates whether the heteroaryl group terminates in a chain (monoradical) or is within a chain (diradical). The above definition does not exclude additional substituents on the heteroaryl group. For example, a heteroaryl group of "A-heteroaryl-B" is a diradical, and a heteroaryl group of "A-B-heteroaryl" is a monoradical, but additional substituents may be present on each heteroaryl group. Heteroaryl includes, but is not overlapping with, aryl as previously defined. Non-limiting examples of heteroaryl groups include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4(l,4)]diox 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 , such as, but not limited to, 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)-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 an -O-heteroaryl group.

[0027] The terms "heterocyclyl", "heterocyclic", or "heterocyclic ring" 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 within "heterocyclyl" may be oxidized, for example, -N(O)-, -S(O)-, -S(O)2-. Heterocyclyl may be a single ring or multiple rings, and the multiple rings may be fused, bridged, or spiro. Any non-aromatic ring containing at least one heteroatom is considered heterocyclyl regardless of the bond (i.e., it can be bonded through 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 -CN group.

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

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

[0031] "Isomers" are different compounds having 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 mirror images of each other and cannot be superimposed. 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 are not mirror images of each other.

[0035] As used herein, "treatment" or "treating" is a procedure for obtaining a beneficial or desirable result. For the purposes of the present disclosure, beneficial or desirable results include, but are not limited to, the reduction of symptoms associated with a disease or condition and / or a decrease in the degree of symptoms. In one embodiment, "treatment" or "treating" includes one or more of a) inhibition of a disease or condition (e.g., reduction of one or more symptoms resulting from the disease or condition and / or a decrease in the degree of the disease or condition), b) slowing or halting the onset of one or more symptoms associated with the disease or condition (e.g., stabilization of the disease or condition, delay in the worsening or progression of the disease or condition), and c) alleviating the disease or condition, e.g., causing regression of clinical symptoms, ameliorating the medical condition, delaying the progression of the disease, improving the quality of life, and / or extending survival.

[0036] As used herein, "prevention" or "preventing" refers to a regimen that protects against the development of a disease or disorder so that the clinical symptoms of the disease or disorder do not occur. Thus, "prevention" relates to treating a subject before signs of the disease are detectable in the subject. The subject may be an individual at risk of developing a disease or disorder, e.g., an individual having one or more risk factors known to be associated with the onset or occurrence of the disease or disorder.

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

[0038] As used herein, "co - administration" includes administering a compound disclosed herein in a unit dosage amount before or after administering one or more additional therapeutic agents in a unit dosage amount, for example, including administering the compound disclosed herein within seconds, minutes, or hours of administering one or more additional therapeutic agents. For example, in some embodiments, after a unit dosage of a compound of the present disclosure is first administered, within seconds or minutes, a unit dosage of one or more additional therapeutic agents is administered. Alternatively, in other embodiments, after a unit dosage of one or more additional therapeutic agents is first administered, within seconds or minutes, a unit dosage of a compound of the present disclosure is administered. In some embodiments, after a unit dosage of a compound of the present disclosure is first administered, after several hours (e.g., 1 - 12 hours) have elapsed, a unit dosage of one or more additional therapeutic agents is administered. In other embodiments, after a unit dosage of one or more additional therapeutic agents is first administered, after several hours (e.g., 1 - 12 hours) have elapsed, a unit dosage of a compound of the present disclosure is administered.

[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 suitable for use in the manufacture of pharmaceuticals for animals or humans.

[0040] The compounds described herein can be prepared and / or formulated as pharmaceutically acceptable salts. Pharmaceutically acceptable salts are non-toxic salts of the free base form of the compound that possess the desired pharmacological activity of the 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 compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methylsulfonate, propylsulfonate, besylate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, γ-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 Wiliams and Wilkins, Philadelphia, Pa., 2006.

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

[0042] "Stereoisomers" refer to compounds that are made up of the same atoms bonded by the same bonds but have different three-dimensional structures that cannot be interchanged. The present disclosure contemplates various stereoisomers and mixtures thereof, and includes "enantiomers", which refer to two stereoisomers having molecules that are mirror images that cannot be superimposed on each other.

[0043] "Tautomers" refer to the transfer of a proton from one atom of a molecule to another atom of the same molecule. The present disclosure includes tautomers of any of the foregoing compounds.

[0044] "Solvates" are 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 a 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 relates to a compound of formula (I) [Chemical formula] wherein [wherein, [Chemical formula] is a single bond or a double bond, and 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 optionally substituted with 1 to 5 R 10 groups, 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 optionally substituted with 1 to 5 R 10 groups, R 3 and R 4 are independently hydrogen, C 1~6 alkyl, -OR 7 C 1~6 heteroalkyl, -NR 8 R 9 NR 8 C(O)R 9 -NR 8 C(O)OR 9 C 6~10 aryl, C 3~10Cycloalkyl, 5- to 10-membered heteroaryl, 3- to 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 optionally substituted with 1 to 5 R 10 groups 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 optionally substituted with 1 to 5 R 10 groups R 6 is hydrogen or halo each R 7 is independently hydrogen, C 1~6 alkyl, C 3~10 cycloalkyl, C 1~6 heteroalkyl, 3- to 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- to 12-membered heterocyclyl, C 6~10Aryl, and 5- to 10-membered heteroaryl are optionally substituted with 1 to 5 Rs 10 and each R and R 8 and R 9 are independently hydrogen, C 1~6 alkyl, C 3~10 cycloalkyl, C 1~6 heteroalkyl, 3- to 12-membered heterocyclyl, C 6~10 aryl or 5- to 10-membered heteroaryl, or R 8 and R 9 together with the atom to which they are attached form a 3- to 12-membered heterocycle, said C 1~6 alkyl, C 3~10 cycloalkyl, C 1~6 heteroalkyl, 3- to 12-membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl are optionally substituted with 1 to 5 Rs 10 and each R is independently C 10 alkyl, C 1~6 cycloalkyl, C 3~10 heteroalkyl, 3- to 12-membered heterocyclyl, C 1~6 aryl, 5- to 10-membered heteroaryl, halo, oxo, -OR 6~10 , -C(O)R a , -C(O)OR a , -C(O)NR a R a , -OC(O)NR b R a , -NR b R a , -NR b , -NR a C(O)R b , -NR a C(O)OR b , -S(O) q R a , -S(O)2NR a R b , -NR a S(O)2R b , -N3, -CN or -NO2, or two Rs 10The base forms a fused, spiro or bridged C 3~10 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 heterocyclic ring, and 5- to 10-membered heteroaryl are optionally substituted with 1 to 5 R 20 groups, each R a and R b is independently hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 3~10 cycloalkyl, C 1~6 heteroalkyl, 3- to 12-membered heterocyclyl, C 6~10 aryl, 5- to 10-membered heteroaryl, or R a and R b together with the atom 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- to 12-membered heterocyclyl, C 6~10 aryl, 5- to 10-membered heteroaryl are optionally substituted with 1 to 5 R 20 groups, each R 20 is independently C 1~6 alkyl, C 3~10 cycloalkyl, C 1~6 heteroalkyl, 3- to 12-membered heterocyclyl, C6-C 10 aryl, 5- to 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)2, -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 pharmaceutically acceptable salt thereof is provided.

[0047] In some embodiments, the present disclosure provides a compound of formula (Ia)

Chemical formula

[0048] In some embodiments, the present disclosure provides a compound of formula (II)

Chemical formula

Chemical formula

[0049] In some embodiments, the present disclosure provides a compound of formula (II) according to formula (IIa)

Chemical formula

[0050] In some embodiments, the present disclosure R 2 is hydrogen or C 1~3 alkyl, R 3 is hydrogen or C 1~3 alkyl, R 4 is hydrogen, R 5 is C 1~3 alkyl, said C 1~3 alkyl is optionally substituted with a 5- to 6-membered heterocyclyl, a compound of formula (I), formula (Ia), formula (II) or formula (IIa), or a tautomer or pharmaceutically acceptable salt thereof is provided.

[0051] In some embodiments, the present disclosure R 2 is hydrogen, methyl, or ethyl, R 3 is hydrogen or methyl, R 4 is hydrogen, R5 is hydrogen, methyl,

Chemical formula

[0052] In some embodiments, the present disclosure R 2 is hydrogen, R 3 is C 1~3 alkyl, providing a compound 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 R 2 is C 1~3 alkyl, R 3 is hydrogen, providing a compound 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 R 2 is hydrogen, R 3 is hydrogen, providing a compound 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 R 2 is C 1~3 alkyl, R 3 is C 1~3 alkyl, Provide a compound of formula (I), formula (Ia), formula (II) or formula (IIa), or a pharmaceutically acceptable salt thereof.

[0056] In some embodiments, the present disclosure relates to a compound of formula (III)

Chemical formula

Chemical formula

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

[0058] In some embodiments, the present disclosure provides a compound of formula (IIIb) [Chemical formula] or a pharmaceutically acceptable salt thereof according to [wherein R 1 is C 1~6 alkyl, C 3~10 cycloalkyl, C 6~10 aryl, 5- to 10-membered heteroaryl, -NHC 1~6 alkyl, -NHC 1~6 haloalkyl, 4- to 6-membered heterocyclyl, C 3~6 cycloalkyl, -NHC 3~10 cycloalkyl, or -NH(4- to 6-membered heterocyclyl), and each C 1 of R 1~6 alkyl and -NHC 1~6 alkyl is independently optionally substituted with 1 to 3 substituents selected independently from hydroxyl, C 1~6 alkoxy, 5- to 10-membered heteroaryl, C 3~6 cycloalkyl, phenyl, or -O-(4- to 10-membered heterocyclyl), and each 5- to 10-membered heteroaryl, C 3~6 cycloalkyl, phenyl, and -O-(4- to 10-membered heterocyclyl) is independently halo, C1~6 alkyl, and C 1~6 optionally substituted with 1 to 4 substituents independently selected from haloalkyl, R 1 each C of 6~10 aryl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 substituents independently selected from halo, hydroxyl, -CN, C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 heteroalkyl, 4- to 6-membered heterocyclyl, and C 3~6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from R 1 each 4- to 6-membered heterocyclyl, C 3~6 cycloalkyl, -NHC 3~10 cycloalkyl, and -NH(4- to 6-membered heterocyclyl) are optionally substituted with 1 to 3 substituents independently selected from 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 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from each C 6~10 aryl, 5- to 10-membered heteroaryl, 4- to 6-membered heterocyclyl, and C 3~6 cycloalkyl is independently optionally substituted with 1 to 3 substituents selected from halo, C 1~4 alkyl, and C 1~4 haloalkyl, optionally substituted with 1 to 3 substituents independently selected from each R 2 , R 3 , R 4 , and R 5 is independently hydrogen or C 1~6 alkyl, and R 6 is hydrogen or halo], provided that

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

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

[0061] In some embodiments, the present disclosure provides a compound of formula (IV) [Chemical formula] or a pharmaceutically acceptable salt thereof [wherein R 1 is C 3~10 cycloalkyl, 3- to 12-membered heterocyclyl, C 6~10 aryl, or 5- to 10-membered heteroaryl, and R 1 is independently optionally substituted with 1 to 4 R 10 s, and each R 10 is independently selected from halo, hydroxyl, -CN, C 1~6 alkyl, C 1~6 heteroalkyl, C 3~10 cycloalkyl, and 3- to 12-membered heterocyclyl, and R 10 of C 1~6 alkyl, C 1~6 heteroalkyl, C 3~10Cycloalkyl and 3- to 12-membered heterocyclyl are each independently optionally substituted with 1 to 4 substituents selected independently from halo, C 1~4 alkyl, C 1~4 haloalkyl, and C 1~4 heteroalkyl, R 2 is hydrogen, C 1~6 alkyl, or C 1~6 heteroalkyl, R 2 's C 1~6 alkyl and C 1~6 heteroalkyl are each independently optionally substituted with 1 to 3 substituents selected independently from halo, oxo, and hydroxyl, R 3 and R 4 are each independently hydrogen, C 1~6 alkyl, C 1~6 heteroalkyl, -OR 7 , or -SO2R 7 . R 3 and R 4 's C 1~6 alkyl and C 1~6 heteroalkyl are each independently optionally substituted with 1 to 3 substituents selected independently from halo, oxo, C 3~6 cycloalkyl, 4- to 6-membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, C 3~6 cycloalkyl, 4- to 6-membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl are each independently optionally substituted with 1 to 3 substituents selected independently from halo, C 1~4 alkyl, and C 1~4 heteroalkyl, R 5 is hydrogen, C 1~6 alkyl, or C 1~6 heteroalkyl, R 5 's C 1~6 alkyl and C 1~6 heteroalkyl are halo, oxo, C3~6 Optionally substituted with 1 to 3 substituents independently selected from cycloalkyl and 4- to 6-membered heterocyclyl, R 7 is independently hydrogen, C 1~6 alkyl, C 1~6 heteroalkyl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6~10 aryl, or 5- to 10-membered heteroaryl, R 7 's C 1~6 alkyl, C 1~6 heteroalkyl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl are optionally substituted with 1 to 4 substituents independently selected from halo, oxo, C 1~4 alkyl, C 1~4 haloalkyl, and C 1~4 heteroalkyl.]] is provided.

[0062] In some embodiments, the present disclosure relates to a compound of formula (IVa)

Chemical formula

[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 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 R 2 is hydrogen.

[0065] 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 R 2 is C 1~3 alkyl.

[0066] 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 R 2 is methyl.

[0067] 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 R 3 is C 1~3 alkyl.

[0068] 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 R 3A compound of formula (I), formula (Ia), formula (II), formula (IIa), formula (III), formula (IIIa) or formula (IIIb) wherein R is methyl, or a tautomer or pharmaceutically acceptable salt thereof.

[0069] 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) wherein R 4 is hydrogen, or a tautomer or pharmaceutically acceptable salt thereof.

[0070] 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) wherein R 5 is C 1~3 alkyl, or a tautomer or pharmaceutically acceptable salt thereof.

[0071] 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) wherein R 5 is methyl, or a tautomer or pharmaceutically acceptable salt thereof.

[0072] 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) wherein R 6 is Cl, or a tautomer or pharmaceutically acceptable salt thereof.

[0073] 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) wherein -C(O)R 1 is

Chemical formula

Chemical formula

[0074] In some embodiments, the present disclosure provides that R 1 is

Chem.

[0075] In some embodiments, the present disclosure provides that R 1 is

Chem.

Chem.

[0076] In some embodiments, the present disclosure provides that R 1 is

Chem.

[0077] In some embodiments, the present disclosure provides that R 1 is one or two R 10Compounds of formula (II), formula (IIa), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV) or formula (IVa), which are 3- to 12-membered heterocyclyl or 5- to 10-membered heteroaryl optionally substituted as required, or pharmaceutically acceptable salts thereof, are provided.

[0078] In some embodiments, the present disclosure provides that R 1 is

Chemical formula

[0079] In some embodiments, R 1 is optionally substituted with one or two R 10 as required

Chemical formula

Chemical formula

Chemical formula

[0080] In some embodiments, R 1 is [Chemical formula] is. In some embodiments, R 1 is [Chemical formula] is.

[0081] In some embodiments, the present disclosure provides 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) wherein R 2 is hydrogen or C 1~3 alkyl, or a pharmaceutically acceptable salt thereof. In some embodiments, R 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 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) wherein R 3 is hydrogen or C 1~3 alkyl, or a pharmaceutically acceptable salt thereof. In some embodiments, R 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 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) wherein R 4 is hydrogen, C 1~3 alkyl, or C 1~3Provided are 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) that are alkoxyl, or a pharmaceutically acceptable salt thereof. In some embodiments, R 4 is selected from hydrogen, methyl, and -OCH3. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -OCH3. In some embodiments, R 4 is methyl.

[0084] In some embodiments, the present disclosure provides 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) wherein R 2 and R 4 are hydrogen and R 3 is methyl, or a pharmaceutically acceptable salt thereof. In some embodiments, R 2 and R 3 are methyl and R 4 is hydrogen. In some embodiments, R 2 is hydrogen, R 3 is methyl, and R 4 is -OCH3.

[0085] In some embodiments, the present disclosure provides compounds of formula (I), formula (Ia), formula (II), formula (IIa), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId) or formula (IV) wherein R 5 is hydrogen or C 1~3 alkyl, or a pharmaceutically acceptable salt thereof. In some embodiments, R 5 is methyl. In some embodiments, R 5 is hydrogen.

[0086] In some embodiments, the present disclosure provides compounds selected from Examples 1 to 464.

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

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

[0089] In some embodiments, the present disclosure

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0090] In some embodiments, the present disclosure

Chemical formula

[0091] In some embodiments, the present disclosure [Chemistry] [Chemistry] [Chemistry] provide a compound selected from

[0092] In some embodiments, isotopically labeled forms of the compounds of formula (I), formula (Ia), formula (II), or formula (IIa) are provided herein. In some embodiments, isotopically labeled forms of the 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 the structures depicted by the formulas given herein, except that one or more atoms are replaced by an isotope having a selected atomic mass or mass number. Isotopically labeled compounds have the structures depicted by the formulas given 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 the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 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 are included, but are not limited thereto. Various isotopically labeled compounds of the present disclosure, such as 3 H, 13 C and 14 C, etc., compounds incorporated with radioisotopes are within the scope of the present disclosure. Such isotopically labeled compounds can be useful in metabolic studies, reaction rate 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 the treatment of patients. Such isotopically labeled analogs of the compounds of the present disclosure can also improve pharmacokinetic and / or pharmacodynamic properties over the unlabeled form of the same compound, and thus can be useful in the treatment of the diseases disclosed herein. Such isotopically labeled forms or analogs of the compounds herein are within the scope of the present disclosure. Those skilled in the art can prepare and use such isotopically labeled forms according to procedures for isotopically labeling a compound or an aspect of a compound to arrive at the isotopic or radiolabeled analogs of the compounds disclosed herein.

[0093] The compounds disclosed herein can contain one or more chiral centers and, accordingly, can give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)- with respect to absolute stereochemistry or, for amino acids, as (D)- or (L)-. This disclosure is meant to encompass 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 a chiral synthon or chiral reagent or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from an appropriate optically pure precursor or resolution of a racemate (or racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). Similarly, all tautomeric forms are also intended to be encompassed.

[0094] In certain embodiments, the disclosure provides a pharmaceutical composition comprising a compound of the 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] A pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, can be prepared using one or more pharmaceutically acceptable excipients selected in accordance with conventional pharmaceutical practice. "Pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent, or emulsifying agent approved by the U.S. Food and Drug Administration as acceptable for use in humans or domestic animals.

[0096] In certain embodiments, the pharmaceutical composition is provided as a solid oral dosage form, such as a solid dosage form including a tablet. The tablet can contain excipients including a glidant, a filler, a binder, and the like. The aqueous composition can be prepared in a sterile form and can generally be made isotonic if delivery by means other than oral administration is contemplated. All compositions can contain excipients, as needed, 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, and the like.

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

[0098] The 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 of the compounds disclosed herein, or pharmaceutically acceptable salts thereof, together with pharmaceutically acceptable excipients and optionally other therapeutic agents. The pharmaceutical compositions containing the active ingredient may be in any form suitable for the intended method of administration. When used 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 manufacturing pharmaceutical compositions, and such compositions can contain one or more excipients including sweetening agents, flavoring agents, coloring agents and preservatives to provide a palatable preparation. Tablets containing the active ingredient as a mixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets 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; binding agents such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricants such as magnesium stearate, stearic acid or talc. Tablets may not be coated or may be coated by known techniques including microencapsulation to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, time delay materials such as glyceryl monostearate or glyceryl distearate can be used alone or in combination with waxes.

[0100] The amount of active ingredient that can be combined with the inert ingredients to produce a dosage form can vary depending on the intended subject of treatment and the particular method of administration. For example, in some embodiments, a dosage form for oral administration to humans can contain from about 1 to 1000 mg of active material, formulated with a suitable 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 a method of inhibiting MCL-1. In some embodiments, the present disclosure provides a method 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 of treating or preventing cancer. In certain embodiments, the present disclosure provides a method of 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, kidney 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, intravaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural), among others.

[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 for a longer period. In one variant form, the compound is administered on a daily or intermittent schedule over the lifetime of the individual.

[0105] The dosage or dosing frequency of the compounds of the present disclosure can be adjusted over the course of treatment based on the judgment of the physician administering it.

[0106] The therapeutically effective amount of the compounds 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 for example from about 0.001 mg / kg (body weight) per day to about 1 mg / kg (body weight) per day, or for example from about 0.01 mg / kg (body weight) per day to about 1 mg / kg (body weight) per day, or for example from about 0.05 mg / kg (body weight) per day to about 0.5 mg / kg (body weight) per day, or for example from about 0.3 μg to about 30 mg per day, or for example 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 at any dosage of the compounds of the present disclosure (e.g., 1 mg to 1000 mg of the compound). The therapeutically effective amount of a compound of formula (I), formula (Ia), formula (II) or formula (IIa), or a tautomer or pharmaceutically acceptable salt thereof, can 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 for example from about 0.1 mg per dose to about 100 mg per dose, or for example from about 1 mg per dose to about 100 mg per dose, or for example 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) can be 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) can be 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 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 for example from about 0.1 mg per dose to about 100 mg per dose, or for example from about 1 mg per dose to about 100 mg per dose, or for example 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 once every 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 16 hours, or once every 24 hours. The single dose can also be administered once every 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or once every 7 days. The single dose can also be administered once every 1 week, 2 weeks, 3 weeks, or once every 4 weeks. In certain embodiments, the single dose can be administered once a week. The single dose can also be administered once a month. In some embodiments, the compounds disclosed herein are administered once a day by the methods disclosed herein. In some embodiments, the compounds disclosed herein are administered twice a day by the methods disclosed herein.

[0110] The dosing frequency of the compounds disclosed herein is determined by the needs of the individual patient and can be, for example, once or twice a day or more times a day. Administration of the compound is continued as long as necessary to treat the cancer. For example, the compounds disclosed herein can be administered to a human having cancer over a period of 20 days to 180 days, or for example, over a period of 20 days to 90 days, or for example, over a period of 30 days to 60 days.

[0111] Administration can be intermittent, and for several days or a longer period, the patient receives a daily dose of the compounds disclosed herein, and then for several days or a longer period, the patient does not receive a daily dose of the compound. For example, the patient can receive a dose of the compound every 2 days or three times a week. Again, as a non-limiting example, the patient can receive a dose of the compound daily over a period of 1 to 14 days, and then for a period of 7 to 21 days the patient does not receive a dose of the compound, and then over a subsequent period (e.g., 1 to 14 days), the patient again receives a daily dose of the compound. The alternation between the period of administering the compound and the period of not administering the compound thereafter can be repeated as clinically necessary to treat the patient. Combination therapy

[0112] Also provided is a method 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 that coexists with or is exacerbated or induced by cancer, such as an allergic disorder and / or an autoimmune disease and / or an inflammatory disease, and / or an acute inflammatory reaction, 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, in combination, if desired, with a further agent (e.g., a second, third, fourth or fifth active agent) useful in treating cancer, an allergic disorder and / or an autoimmune disease and / or an inflammatory disease that results from or coexists with cancer, and / or an acute inflammatory reaction. Treatment with the second, third, fourth or fifth active agent can be carried out before, simultaneously with or after 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 anti-tumor or anti-cancer therapeutic 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, 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 aforementioned chemotherapeutic agents. Anti-tumor agents for radiotherapy can also be used alone or in combination with chemotherapeutic agents.

[0114] 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), or tautomers or pharmaceutically acceptable salts thereof, can be useful as chemical sensitizers and, thus, can be useful in combination with other chemotherapeutic agents, particularly agents that induce apoptosis. Thus, 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 an 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, sufficient to increase the sensitivity of 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 (camptothecin 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 biological agents (e.g., antibodies, e.g., anti-CD20 antibody, IDEC8, immunotoxins, and cytokines).

[0116] In some embodiments, the 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), or tautomers or pharmaceutically acceptable salts thereof, are used in combination with Rituxan® (rituximab) and / or other agents that act by selectively depleting CD20+ B cells.

[0117] Also 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, but are not limited to, NSAIDs, non-specific and COX-2 specific cyclooxygenase enzyme inhibitors, gold compounds, corticosteroids, methotrexate, tumor necrosis factor receptor (TNF) receptor antagonists, immunosuppressive drugs, and methotrexate. Examples of NSAIDs include, but are not limited to, ibuprofen, flurbiprofen, naproxen and naproxen sodium, diclofenac, the combination of diclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal, piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen, nabumetone sodium, sulfasalazine, tolmetin sodium, and hydroxychloroquine. Examples of NSAIDs also include COX-2 specific inhibitors (i.e., compounds that inhibit COX-2 with an IC

[0118] that is at least 1 / 50 of the IC 50 for COX-1), such as celecoxib, valdecoxib, lumiracoxib, etoricoxib and / or rofecoxib. 50

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

[0120] The anti-inflammatory agent may be a corticosteroid. For example, the corticosteroid can be selected from cortisone, dexamethasone, methylprednisolone, prednisolone, sodium prednisolone phosphate, and prednisone. In some embodiments, the anti-inflammatory therapeutic agent is a gold compound, such as sodium aurothiomalate 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, 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 anti-inflammatory compound that is an anti-C5 monoclonal antibody (e.g., eculizumab or pexelizumab), a TNF antagonist, such as etanercept, or infliximab, an anti-TNF alpha monoclonal antibody.

[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 that is an immunosuppressive drug compound, such as methotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine, or mycophenolate mofetil.

[0123] In other embodiments, the 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), or tautomers or pharmaceutically acceptable salts thereof, are used, for example, 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 pharmaceutically acceptable salts thereof.

Chemical formula

[0124] Compounds A, B and C are disclosed in WO2015 / 017460 and WO2015 / 100217. Further examples of PI3K inhibitors include, but are not limited to, 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, LY294002, LY3023414, MLN1117, OXY111A, PA799, PX-866, RG7604, Ligosatib, RP5090, Taselisib, TG100115, TGR-1202, TGX221, WX-037, X-339, X-414, XL147 (SAR245408), XL499, XL756, Wortmannin, ZSTK474, and the compounds described in 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, can 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, cerdulatinib (PRT-062607), entospletinib, fostamatinib (R788), HMPL-523, NVP-QAB 205 AA, R112, R343, tamatinib (R406), and those described in U.S. 8450321 (Gilead Connecticut) and U.S. 2015 / 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 TKI include, but are not limited to, afatinib, ARQ-087, asp5878, AZD3759, AZD4547, bosutinib, brigatinib, cabozantinib, cediranib, clenolanib, dacomitinib, dasatinib, dovitinib, E-6201, erdafitinib, erlotinib, gefitinib, gilteritinib (ASP-2215), FP-1039, HM61713, icotinib, imatinib, KX2-391 (Src), lapatinib, lestaurtinib, midostaurin, nintedanib, ODM-203, osimertinib (AZD-9291), ponatinib, poziotinib, quizartinib, radotinib, rociletinib, sulfatinib (HMPL-012), sunitinib, and TH-4000.

[0127] In yet 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 a substance that binds to lysyl oxidase-like 2 (LOXL), including one or more inhibitors of LOXL, or a humanized monoclonal antibody (mAb) having an immunoglobulin IgG4 isotype that targets, for example, 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, lefitimimod, lirentelimod, 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 the treatment of cancer in combination with a BTK (Bruton's tyrosine kinase) inhibitor. 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, is useful in the treatment of cancer in combination with a BET inhibitor. 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 for the treatment of cancer in combination with a TBK (Tank-binding kinase) inhibitor. An example of such a TBK inhibitor is the 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 for the treatment of cancer in combination with an OX40 inhibitor. An example of such an OX40 inhibitor is the compound disclosed in U.S. 8,450,460, the entire content of which is 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 for the treatment of cancer in combination with a JAK-1 inhibitor. An example of such a JAK-1 inhibitor is the 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 for the treatment of cancer in combination with an indoleamine-pyrrole-2,3-dioxygenase (IDO) inhibitor. An example of such an IDO inhibitor is the compound disclosed in WO2016 / 186967. In one embodiment, a compound of formula (I), formula (Ia), formula (II), or formula (IIa) is useful for the treatment of cancer in combination with an IDO1 inhibitor including, but not limited to, BLV-0801, epacadostat, F-001287, GBV-1012, GBV-1028, GDC-0919, indoximod, NKTR-218, NLG-919-based vaccine, PF-06840003, pyranonaphthoquinone derivative (SN-35837), resminostat, SBLK-200802, and shIDO-ST.

[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 for the treatment of cancer in combination with a mitogen-activated protein kinase (MEK) inhibitor. 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 andrographolide, 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 for 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 Company), US2011-0287011 (Oncomed Pharmaceuticals), WO2013 / 027802 (Chugai Pharmaceutical Co., Ltd.), 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, can 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, givinostat, mocetinostat, panobinostat, pracinostat, xenoSTAT (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 in the treatment of cancer in combination with standard care in the treatment of each cancer. One of ordinary skill in the art is aware of the standard care in a particular cancer treatment area or at a given date with respect to a given cancer.

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

[0145] In one embodiment, there is provided a kit comprising a pharmaceutical composition comprising a compound of formula (I), formula (Ia), formula (II) or formula (IIa), or a tautomer or pharmaceutically acceptable salt thereof, and at least one additional anti-cancer agent, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. In one embodiment, there is provided a kit comprising 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, and 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 for use in the treatment of cancer. In one embodiment, the instructions for use in the kit are directed to the use of the pharmaceutical composition for the treatment of hematological malignancies, multiple myeloma, breast cancer, colorectal cancer, skin cancer, melanoma, ovarian cancer, kidney 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 treatments, such as chemotherapy, radiation therapy, immunotherapy, surgery, or combinations thereof, the method comprising administering or co-administering to the subject 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. Accordingly, one or more 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), or a tautomer or pharmaceutically acceptable salt thereof, can be administered before, during, or after the administration of chemotherapy, radiation therapy, immunotherapy, surgery or combinations 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 treatment with chemotherapy, 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 chemotherapy).

[0148] In one embodiment, the subject 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 fludarabine, rituximab, obinutuzumab, alkylating agents, alemtuzumab, and other chemotherapy treatments such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone); R-CHOP (rituximab-CHOP); hyper-CVAD (multi-fraction cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine); R-hyper-CVAD (rituximab-hyper-CVAD); FCM (fludarabine, cyclophosphamide, mitoxantrone); R-FCM (rituximab, fludarabine, cyclophosphamide, mitoxantrone); bortezomib and rituximab; temsirolimus and rituximab; temsirolimus and Velcade®; iodine-131 tositumomab (Bexxar®) and CHOP; CVP (cyclophosphamide, vincristine, prednisone); R-CVP (rituximab-CVP); ICE (ifosfamide, carboplatin, etoposide); R-ICE (rituximab-ICE); FCR (fludarabine, cyclophosphamide, rituximab); FR (fludarabine, rituximab); and D.T.PACE (dexamethasone, thalidomide, cisplatin, Adriamycin®, cyclophosphamide, etoposide).

[0149] Other examples of chemotherapy treatments (including standard or experimental chemotherapy) are described below. Further, the treatment of certain lymphomas is reviewed in Cheson, B.D., Leonard, J.P., "Monoclonal Antibody Therapy for B-Cell Non-Hodgkin's Lymphoma" The New England Journal of Medicine 2008, 359(6), p. 613-626, and Wierda, W.G., "Current and Investigational Therapies for Patients with CLL" Hematology 2006, p. 285-294. The lymphoma incidence patterns in the United States are profiled in Morton, L.M., 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 antibody, anti-CD20 antibody, anti-MN-14 antibody, anti-TRAIL, anti-TRAIL DR4 and DR5 antibodies, anti-CD74 antibody,apolizumab, bevacizumab, CHIR-12.12, epratuzumab (hLL2 - anti-CD22 humanized antibody), galiximab, ha20, ibritumomab tiuxetan, lumiliximab, miratumumab, ofatumumab, PRO131921, SGN-40, WT-1 analog peptide vaccine, WT1 126-134 peptide vaccine, tositumomab, autologous human tumor-derived HSPPC-96, and belzutifan. Further 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, albosidib, antineoplaston AS2-1, antineoplaston A10, antithymocyte globulin, amifostine trihydrate, aminocamptothecin, arsenic trioxide, beta-aretin, 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, fostamatinib 10, doxorubicin (Adriamycin®, adriblastine), 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 (Genasense) obatoclax (GX15-070), oblimersen, octreotide acetate, omega-3 fatty acids, oxaliplatin, paclitaxel, PD0332991, pegylated liposomal doxorubicin hydrochloride, pegfilgrastim, pentostatin (Pentstatin) (Nipent), perifosine, prednisolone, prednisone, R-roscovitine (Seliciclib, 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 (CCI-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), hyper-CVAD (multi-fraction cyclophosphamide, vincristine, doxorubicin, dexamethasone,Methotrexate, cytarabine), ICE (ifosfamide, carboplatin and etoposide), MCP (mitoxantrone, chlorambucil, and prednisone), R-CHOP (rituximab and CHOP), R-CVP (rituximab and CVP), R-FCM (rituximab and FCM), R-ICE (rituximab-ICE), and R-MCP (rituximab-MCP) are included.

[0152] In some embodiments, the cancer is melanoma. Agents suitable for use in combination with the compounds described herein include dacarbazine (DTIC) (optionally in combination with other chemotherapeutic agents such as carmustine (BCNU) and cisplatin), the "Dartmouth regimen" (consisting of DTIC, BCNU, cisplatin and tamoxifen), the combination of cisplatin, vinblastine and DTIC, temozolomide or YERVOY™, but are not limited thereto. 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 compounds described herein can also be used in combination with vaccine therapy in the treatment of melanoma. Anti-melanoma vaccines are somewhat similar in some respects to anti-viral vaccines used to prevent diseases caused by viruses such as polio, measles, and mumps. Weakened melanoma cells or parts of melanoma cells called antigens can be injected into a patient to stimulate the body's immune system to destroy melanoma cells.

[0154] Melanomas localized to the arm or leg can also be treated with a combination of agents comprising one or more of the compounds described herein, for example using the hyperthermic isolated limb perfusion technique. This treatment protocol temporarily isolates the circulation of the limb involved from the rest of the body, injects a high dose of chemotherapy into the supplying artery of the limb, and thus provides a high dose to the tumor area without exposing the internal organs to these doses which would otherwise risk severe side effects. Typically, the fluid is warmed to 102° - 104°F. Melphalan is the drug most commonly used in this chemotherapy procedure. This can be given in combination with another agent called tumor necrosis factor (TNF) and, if desired, 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] The therapeutic treatment can complement or be combined with either stem cell transplantation or any of the aforementioned treatments using the treatment. An example of a modified approach is radioimmunotherapy, in which monoclonal antibodies are combined with radioisotope particles such as indium In111, yttrium Y90, iodine I - 131. Examples of combination therapies include, but are not limited to, iodine - 131 tositumomab (Bexxar®), yttrium - 90 ibritumomab tiuxetan (Zevalin®), Bexxar® and CHOP.

[0156] Other therapeutic procedures useful in combination with a treatment using a compound of formula (I), (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV) or (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, peripheral blood stem cell transplantation treated in vitro, cord blood transplantation, immunoenzymatic techniques, pharmacological research, low LET cobalt-60 gamma ray therapy, bleomycin, conventional surgery, radiotherapy, 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), (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV) or (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 the 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 immunomodulators, such as immunostimulants or immunosuppressants. In certain other embodiments, the immunomodulator is an agent that can alter 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 immunomodulator 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, the immunomodulator includes agents that can alter the function of mediators in cytokine-mediated signaling pathways.

[0160] In some embodiments, one or more additional therapies or anti-cancer agents are gene therapy or cell therapy for cancer. Gene therapy and cell therapy for cancer include insertion of a normal gene into cancer cells to replace a mutated or modified gene; gene modification to stop expression of a mutated gene; genetic techniques to directly kill cancer cells; injection of immune cells designed to replace a substantial portion of a patient's own immune system or to activate the patient's own immune system (T cells or natural killer cells) to kill cancer cells or to find and kill cancer cells in order to enhance the immune response against cancer cells; genetic techniques to modify cell activity to further alter the endogenous immune responsiveness to cancer. Non-limiting examples include Algenpantucel-L (2 pancreatic cell lines), Sipuleucel-T, SGT-53 liposomal nano-delivery of the 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 (WO2016090190), 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 exploit a mechanism known as T cell exhaustion, which results from chronic exposure to antigens and is characterized by upregulation of inhibitory receptors, to disrupt the immune system. These inhibitory receptors act as immune checkpoints to prevent an uncontrolled immune response.

[0162] PD-1 and 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), lymphocyte activation gene-3 (Lag-3; CD223), etc., are often referred to as checkpoint regulators. Checkpoint regulators act as molecular determinants that influence whether the progression of the cell cycle and other intracellular signaling processes should proceed based on extracellular information.

[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 co-stimulatory receptors. These surface proteins are typically members of either the TNF receptor or B7 superfamily. Agonist antibodies against activating co-stimulatory molecules and blocking antibodies against negative co-stimulatory 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 co-stimulatory receptors, including CD28, CTLA-4, inducible co-stimulator (ICOS), and BTLA, which are members of the immunoglobulin superfamily. PD-1 is highly expressed on activated T cells and B cells. PD-1 expression can also be detected at various levels on memory T cell subsets. Two ligands specific for PD-1, programmed death-ligand 1 (PD-L1, also known as B7-H1 or CD274) and PD-L2 (also known as B7-DC or CD273), have been identified. 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 and expression on antigen-presenting cells (APCs) and dendritic cells (DCs) The interaction of its ligands, PD-L1 and PD-L2, transmits negative regulatory stimuli to down-modulate the activated T cell immune response. Blockade of PD-1 suppresses this negative signal and amplifies the T cell response. Numerous studies have shown that the cancer microenvironment manipulates the PD-L1 / PD-1 signaling pathway and that induction of PD-L1 expression is associated with inhibition of the immune response against cancer, thus enabling cancer progression and metastasis. The PD-L1 / PD-1 signaling pathway has become the main mechanism of cancer immune evasion for several reasons. This pathway is involved in the negative control of the immune response of activated T effector cells found in the periphery. PD-L1 is upregulated in the cancer microenvironment, while at the same time, PD-1 is also upregulated on activated tumor-infiltrating T cells, thus potentially enhancing the vicious cycle of inhibition. This pathway is also intricately involved in both innate and adaptive immune control through bidirectional signaling. These factors make the PD-1 / PD-L1 complex the central point where cancer can manipulate the immune response and promote its own progression.

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

[0166] The treatment enhances the anti-tumor function of CD8+ T cells, increases the ratio of CD8+ T cells to Foxp3+ regulatory T cells, and inhibits the inhibitory function of regulatory T cells. TIM-3 has been identified as another important inhibitory receptor expressed by exhausted CD8+ T cells. In mouse models of cancer, it has been shown that the most dysfunctional tumor-infiltrating CD8+ T cells actually co-express PD-1 and LAG-3. LAG-3 is another recently identified inhibitory receptor that acts to limit effector T cell function and enhance the inhibitory activity of regulatory T cells. In recent years, in mice, it has been revealed that PD-1 and LAG-3 are widely co-expressed by tumor-infiltrating T cells, and that the combination of blockade of PD-1 and LAG-3 elicits a potent synergistic anti-tumor immune response in mouse models of cancer.

[0167] Accordingly, 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, for treating or preventing 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, an MPDL3280A (atezolizumab) antibody, a MEDI-4736 antibody, an 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 the immune response against tumors. Lirilumab is an antagonist against the KIR receptor, 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 glucocorticoid-induced 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, the compound of formula (I), or a tautomer or pharmaceutically acceptable salt thereof, is used in combination with IMP321, lirilumab and / or BMS986016.

[0169] Anti-PD-1 antibodies that can be used in the compositions and methods described herein include nivolumab / MDX-11, a fully human IgG(1gG)4 anti-PD-1 monoclonal antibody 06 / BMS-936558 / ONO1152, pidilizumab (MDV9300 / CT-011), a humanized IgG1 monoclonal antibody, pembrolizumab (MK-3475 / pembrolizumab / lanbrolizumab), a humanized monoclonal IgG4 antibody, durvalumab (MEDI-4736), and atezolizumab, but are not limited thereto. Anti-PD-L1 antibodies that can be used in the compositions and methods described herein include avelumab, BMS-936559, a fully human IgG4 antibody, atezolizumab (MPDL3280A / RG-7446), a human monoclonal antibody, MEDI4736, MSB0010718C, and MDX1105-01, but are not limited thereto.

[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 nivolumab, pembrolizumab, and / or pidilizumab, which are anti-PD-1 antibodies. In one embodiment, anti-PD-L1 antibodies 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, are BMS-936559, atezolizumab, or avelumab. In one embodiment, the immunomodulatory agent 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. In the compositions and methods described herein, additional antibodies 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 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 that is secreted mainly by macrophages but also by various other cell types including lymphoid cells, mast cells, endothelial cells, cardiomyocytes, adipose tissue, fibroblasts, and nerve tissue. TNF-α is also known as an endotoxin-inducing factor, cachectin, and differentiation-inducing factor in serum. 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, shows inducible expression, and competes with HSV glycoprotein D for the receptor HVEM, which is expressed by T lymphocytes), and some of their most important cytokines have been involved in the initiation of systemic inflammation, tumor lysis, apoptosis, and acute-phase reactions, among other physiological processes.

[0172] When the above therapeutic agents are used in combination with the compounds disclosed herein, they can be used, for example, in the 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 can 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 can be combined in a single formulation or kit when appropriate. For example, tablets, capsules or liquid formulations can be combined with other tablets, capsules or liquid formulations in a formulation or regimen of a single fixed dose or combined doses. Other combinations can also be administered 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 means known in the art, including chromatographic means such as high performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography and ion exchange chromatography. Any suitable stationary phase, including normal and reverse phases as well as ion resins, can be used. Most typically, the disclosed compounds are purified via silica gel and / or alumina chromatography.

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

Chemical formula

[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, and then treating the mixture 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 an aqueous solution of NaOH, KOH, or LiOH, at an elevated temperature, preferably 60 °C, overnight, in a suitable solvent, such as MeOH, EtOH, or THF. The mixture is cooled, acidified using a suitable acidifying agent, such as HCl, concentrated, filtered, and the resulting solid carboxylic acid is dissolved in a suitable solvent, such as CH2Cl2 or 1,2-dichloroethane. A suitable acid chloride forming agent, such as thionyl chloride or oxalyl chloride, can be added to 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 it 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 CH2Cl2 or 1,2-dichloroethane, under a N2 atmosphere, adding a suitable organic base, such as trimethylamine or diisopropylethylamine, and then adding a solution of Intermediate F in a suitable solvent, such as CH2Cl2 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, and then 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 CH2Cl2 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 Intermediate I-1 or I-2 with a Hoveyda Grubbs second generation catalyst at an elevated temperature, preferably 60 °C, in a suitable solvent, such as CH2Cl2 or 1,2-dichloroethane. 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)

Chemical Formula

[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 CH2Cl2 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 overnight at rt. After concentration and purification by silica gel chromatography, the mixture of Boc-protected diastereomers can be treated with a Hoveyda Grubbs second generation catalyst at an elevated temperature, preferably 60 °C, in a suitable solvent, such as CH2Cl2 or 1,2-dichloroethane. 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 and EDCI and an organic base. Scheme 3: Preparation of Optically Pure Compounds of Formula (I)

[0186] J-1 and J-2 can also be prepared by acylating intermediate H, macrocyclizing intermediate I with Hoveyda Grubbs second-generation catalyst, and then separating by either silica gel column chromatography or chiral HPLC.

Chemical formula

Chemical formula

[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 CH2Cl2 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 CH2Cl2 or 1,2-dichloroethane, at an elevated temperature, preferably 60 °C. After concentrating the reaction mixture and purifying the residue by preparative HPLC, an appropriate acylating agent, such as an acid chloride and an organic base, or a carboxylic acid and 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 obtain J-1 or J-2. Scheme 5: Preparation of Optically Pure Compound of Formula (I)

[0189] Intermediates L-1 and L-2 can be Boc-protected, macrocyclized with the Hoveyda Grubbs second-generation catalyst, and then separated by either silica gel column chromatography or chiral HPLC, and then acylated to provide J-1 and J-2, respectively.

Chemical Structure

Chemical Structure

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

Chemical Structure

[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 obtained 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, and then separated by either silica gel column chromatography or chiral HPLC.

Chemical Structure

Chem.

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

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

Chem.

Chem.

[0195] Alternatively, O-2 can be prepared by treating L-2 with diphenyl carbonate and then with a suitable alcohol.

[0196] Alternatively, the two stereoisomers can be separated by treating the diastereomer mixture L with diphenyl carbonate and then with an alcohol suitable as a nucleophile or a substituted chloroformate under ice-bath cooling, followed by separation by either silica gel column chromatography or chiral HPLC to obtain O-2 (Scheme 12).

Chem.

Examples

[0197] Exemplary chemical entities of the present disclosure are provided in the following specific examples. Those skilled in the art will recognize that the starting materials can be appropriately selected such that the ultimately desired substituents are maintained through the reaction scheme, with or without appropriate protection as appropriate, to give the desired product. Alternatively, it may be necessary or desirable to use a suitable group that is maintained through the reaction scheme and can be appropriately replaced with the ultimately desired substituent. Further, those skilled in the art will recognize that the transformations shown in the schemes below can be carried out 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 the compounds may be combined and then carried forward to the next synthetic step.

[0199] In the description of the following examples, specific embodiments are described. These embodiments are described in sufficient detail so that those skilled in the art can practice a particular embodiment of the present disclosure. Other embodiments can be utilized and logical and other changes can be made without departing from the scope of the present disclosure. Accordingly, the following description is not intended to limit the scope of the present disclosure. (Example 1) [Chemical formula]

[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): 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 (prepared according to the procedure described in International Patent Application No. WO2016 / 033486) (1.02 g, 2.18 mmol) in THF (10 mL), sodium hydride (60% in mineral oil, 183.1 mg, 4.57 mmol) was added in an ice bath, followed by 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 H2O and extracted with CH2Cl2. The organic layer was concentrated and purified by silica gel column (EtOAc / hexane = 2 / 3) to obtain 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 C

[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): To a stirred solution 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 (707.0 mg, 1.4 mmol) in DMF (8 mL) was added sodium hydride (60% in mineral oil, 88.0 mg, 2.2 mmol) 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 H2O and extracted with CH2Cl2. 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 C

[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 at 60 °C overnight in 2N aqueous NaOH (3 mL) and MeOH (8 mL). After cooling, the mixture was acidified with HCl and concentrated. The resulting solid was treated with CH2Cl2 and filtered. The filtrate was concentrated, and 174.5 mg (0.36 mmol) was dissolved in CH2Cl2 (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 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 by silica gel column (EtOAc / hexane = 1 / 4) to give (2R,3S)-N-(tert-butyldimethylsilyl)-3-methylhex-5-ene-2-sulfonamide. 11H 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-en-2-sulfonimidamide (1-5): Under N2 atmosphere, trimethylamine (0.43 mL, 3.087 mmol) was added to a stirred suspension of Ph3PCl2 (754.33 mg, 2.264 mmol) in CH2Cl2 (4.0 mL). The mixture was stirred at room temperature for 10 minutes and then cooled to 0 °C, and a solution of (2R,3S)-N-(tert-butyldimethylsilyl)-3-methylhex-5-en-2-sulfonamide (600.00 mg, 2.058 mmol) in CH2Cl2 (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 obtain (2R,3S)-N'-(tert-butyldimethylsilyl)-3-methylhex-5-en-2-sulfonimidamide (1-5). 1 1H 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)-l6-sulfanilylidene)-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): 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 (181.00 mg, 0.362 mmol) in acetonitrile (2.0 mL) was added pyridazine (0.03 mL, 0.362 mmol) in 2 mL of acetonitrile, followed by (2R,3S)-N’-(tert-butyldimethylsilyl)-3-methylhex-5-en-2-sulfonimidamide (126.00 mg, 0.434 mmol) in an acetonitrile solution (2.0 mL). 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)-l6-sulfanilylidene)-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. 11H NMR (400 MHz, chloroform-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 alculated value for ClN3O4S: 640.3; measured value: 640.3.

[0206] It should be noted that there seems to be a small error in the original text where "C 35 H 46 " is an incomplete expression. The above translation is based on the best understanding of the overall context.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)-l6-sulfanilylidene)-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 CH2Cl2 (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 5μm 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 afford 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 (11.0 mg, 0.016 mmol) from Step 7 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 h. After concentration, the residue was purified by preparative HPLC to afford Example 1. 1 1H 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 C 36 H 46 ClN3O5S: 668.3; Found: 668.3. (Example 2)

Chemical Structure

[0208] Example 2 was synthesized in the same manner as Example 1 (Step 8), using diastereomers 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 C18H24ClN3O5S: 668.3; Found: 668.3. (Examples 3 and 4) [Chemical Structure]

[0209] Step 1: Preparation of N'-(tert-butyldimethylsilyl)penta-4-ene-1-sulfonimidamide: N'-(tert-butyldimethylsilyl)penta-4-ene-1-sulfonimidamide was prepared in the same manner as in Example 1 (Steps 4 and 5), using penta-4-ene-1-sulfonamide instead of (2R,3S)-3-methylhex-5-ene-2-sulfonamide). 1 H NMR (400 MHz, chloro form-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)(penta-4-en-1-yl)-l6-sulfaniliden)-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)penta-4-en-1-sulfonimidamide 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 similar manner to Example 1 (Step 6) to obtain the title compound.

[0211] Step 3: Preparation of (S)-6’-Chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-N-((R)-oxo(penta-4-en-1-yl)(propionamido)-l6-sulfanilidene)-3’,4,4’,5-tetrahydro-2H,2’H-spiro[benzo[b][1,4]oxazepine-3,1’-naphthalene]-7-carboxamide: To a stirred solution of (3S)-N-(amino(oxo)(penta-4-en-1-yl)-l6-sulfanilidene)-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) in CH2Cl2 (5.0 mL), triethylamine (0.02 mL, 0.162 mmol) was added in an ice bath, followed by 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(penta-4-en-1-yl)(propionamido)-l6-sulfanilidene)-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(penta-4-en-1-yl)(propionamido)-l6-sulfanilidene)-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 second-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 obtain 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 value of ClN3O5S: 640.2; Measured value: 640.2) was obtained. (Examples 5 and 6)

Chemical formula

[0213] 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)penta-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)penta-4-en-1-ylsulfonimidoyl)carbamate: To a stirred solution of (3S)-N-(amino(oxo)(penta-4-en-1-yl)-l6-sulfanilidene)-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 CH2Cl2 (5.0 mL), triethylamine (0.02 mL, 0.105 mmol) was added 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, and 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)penta-4-en-1-ylsulfonimidoyl)carbamate was obtained from the more polar fraction, 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)penta-4-en-1-ylsulfonimidoyl)carbamate was obtained from the less polar fraction.

[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)penta-4-en-1-ylsulfonimidoyl)carbamate (14 mg, 0.02 mmol) and Hoveyda Grubbs second-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 obtain 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)penta-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:

Chemical Structure

[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)penta-4-en-1-ylsulfonimidoyl)carbamate: To a stirred solution of (3S)-N-(amino(oxo)(penta-4-en-1-yl)-l6-sulfanilylidene)-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) in CH2Cl2 (5.0 mL), 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)penta-4-en-1-ylsulfonimidoyl)carbamate as a mixture of diastereomers.

[0217] Steps 2 and 3: The mixture of diastereomeric Boc-protected product (112.0 mg, 0.157 mmol) from Method 2 Step 1 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 h. 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: [Chemical formula]

[0218] Step 1: Preparation of (S)-4-nitrophenyl (1-phenylethyl) carbonate (5-3-1): A mixture of (1S)-1-(4-biphenylyl)ethanol (8.7 g, 71.2 mmol) was dissolved in MeTHF (90 mL) and cooled to 0 °C. Pyridine (7.1 mL) was added to this cold stirred solution. Then, a solution of 4-nitro-phenyl-chloroformate (14.4 g, 71.2 mmol) in MeTHF (60.0 mL) was 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 h. TLC indicated that (1S)-1-(4-biphenylyl)ethanol was consumed but 4-nitro-phenyl-chloroformate still remained. Additional (1S)-1-(4-biphenylyl)ethanol (2.6 g, 21.3 mmol) and pyridine (1.0 mL) were added and stirring was continued overnight. The reaction mixture was then washed with 1 N 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 / hexane). 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)penta-4-en-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 minutes, after which a solution of (4-nitrophenyl)[(1S)-1-phenylethyl] carbonate in THF (60 mL) was slowly added dropwise. The resulting mixture was stirred at -50 °C for 15 minutes and then switched to an ice bath and stirred at 0 °C for 3 hours. The reaction was quenched with ice and extracted with EtOAc (1×). The organic layer was washed with 1 N NaOH (3×), brine (1×), dried over sodium sulfate, filtered, concentrated, and purified by normal phase chromatography (silica gel, 0 - 20% EtOAc / hexanes). The purification was repeated, the desired fractions were combined, and concentrated to give a mixture of diastereomers (5-3-2) and (5-3-3). Subsequently, the mixture of diastereomers was separated into single diastereomers by chiral SFC. Chirality as shown in (5-3-2) was assigned to the first elution peak, and chirality as shown in (5-3-3) was assigned to the second elution peak. 1 H NMR (400 MHz, chloroform-d), for the 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 minutes. The reaction was then concentrated and purified by normal phase chromatography (silica gel, 0 - 80% EtOAc / hexane) 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 was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (152 mg, 0.98 mmol), followed by 4-(dimethylamino)pyridine (120 mg, 0.98 mmol). After stirring for 5 minutes, a solution of Intermediate (5-3-3A) (159 mg, 0.54 mmol) in DCM (3 mL) was added. The resulting mixture was removed from the cooling bath and stirred at room temperature overnight. The reaction was further diluted with DCM (30 mL) and washed with 1N 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 / hexane) to afford 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: After sparging the solution intermediate 5-3-4 in DCE (10 mL) with nitrogen for 5 minutes, Hoveyda-Grubbs 2nd generation catalyst (7 mg, 0.011 mmol) was added. The newly formed mixture was further degassed for 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 2.0N NH3)) to give Example 5 (first elution peak: LCMS-ESI+(m / z): [M+H]+ calculated: 584.2; found: 583.4); and the carbamate-protected macrocyclic intermediate 5-3-5 (second elution 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 this cold solution. The resulting mixture was stirred at 0 °C for 2 minutes and then at room temperature for 1 hour. The reaction was cooled back to 0 °C and basified to pH ~8 with 1N NaOH. The mixture was extracted with DCM (2×). The combined organic layers were washed with brine (1×), dried over sodium sulfate, filtered, concentrated, and purified by Combiflash (silica gel, 0 - 100% EtOAc / hexane) 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 to 6) using Intermediate 5-3-3 instead of Intermediate 5-3-2. (Examples 7 and 8)

Chemical Structure

[0225] Example 7 and Example 8 were prepared in the same manner as Example 3 and Example 4, using 2-methoxyacetyl chloride instead of propionyl chloride.

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

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

Chemical Structure

[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 CH2Cl2 (5.0 mL) was added triethylamine (0.004 mL, 0.027 mmol) in an ice bath, followed by 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 Calculated [M+H]+ for C 34 H 42 ClN3O6S: 656.2; Found: 656.2) and Example 10 (less polar fraction). (Examples 11 and 12)

Chemical Structure

[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 CH2Cl2 (4.0 mL) was added triethylamine (0.006 mL, 0.046 mmol) in an ice bath, followed by propionyl chloride (3.41 mg, 0.037 mmol). The resulting mixture was stirred at room temperature for 2 h. After concentration, the residue was purified by preparative HPLC to give Example 11 (more polar fraction) (LCMS-ESI+(m / z): C 34 H 44 ClN3O5S calculated [M+H]+: 642.3; found: 642.2) and Example 12 (less polar fraction) (LCMS-ESI+(m / z): C 34 H 44 ClN3O5S calculated [M+H]+: 642.3; found: 642.3). (Examples 13 and 14)

Chemical Structure

[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 CH2Cl2 (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 h. After concentration, the residue was purified by preparative HPLC, followed by preparative TLC (5% MeOH / CH2Cl2) to give Example 13 (more polar fraction) (LCMS-ESI+(m / z): C 34H 43 (Calculated value of [M+H]+ for ClN4O5S: 655.3; measured value: 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 of ClN4O5S: 655.3; the measured value: 655.2 was obtained. (Example 15)

Chemical Structure

[0232] To a stirred solution of 3-(dimethylamino)propionic acid hydrochloride (3.94 mg, 0.026 mmol) in CH2Cl2 (3 mL) were added Et3N (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 value of [M+H]+ for ClN4O5S: 683.3; measured value: 683.3. (Examples 16 and 17)

Chemical Structure

[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) was added Pd / C (10 wt%, 0.36 mg, 0.03 mmol). The resulting mixture was stirred under H2 at room temperature for 1.5 h. 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 Example 11 and Example 12 to give Example 16 (less polar fraction) (LCMS-ESI+(m / z): C 34 H 45 N3O5S calculated [M+H]+: 607.8; found: 608.3) and Example 17 (more polar fraction) (LCMS-ESI+(m / z): C 34 H 45 N3O5S calculated [M+H]+: 607.8; found: 608.4. (Example 18)

Chemical Structure

[0235] To a stirred solution of 3-methoxypropionic acid (2.3 mg, 0.022 mmol) in CH2Cl2 (2 mL) were 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 h 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 = 15.0, 11.0 Hz, 1H), 2.80 - 2.71 (m, 5H), 2.43 - 2.28 (m, 4H), 2.11 - 1.69 (m, 8H), 1.42 - 1.36 (m, 1H). LCMS-ESI+ (m / z): [M+H]+ C 35 H 44 Calculated value of C 35 H 44 ClN3O6S: 670.3; Measured value: 670.4. (Example 19)

Chemical formula

[0236] To a stirred solution of Example 5 (8.5 mg, 0.015 mmol) in CH2Cl2 (2.0 mL), triethylamine (0.003 mL, 0.022 mmol) was added in an ice bath, followed by addition of 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 / CH2Cl2) to obtain Example 19. LCMS-ESI+ (m / z): C 35 H 45 Calculated value of [M+H]+ of C 35 H 45 ClN4O5S: 669.3; Measured value: 691.3. (Example 20)

Chemical formula

[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 C 37 H 42 ClN5O5S: 704.3; found: 704.4. (Example 21)

Chemical Structure

[0238] To a stirred solution of Example 5 (10.0 mg, 0.017 mmol) in CH2Cl2 (2.0 mL) was added triethylamine (0.004 mL, 0.026 mmol) in an ice bath, followed by the addition of 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 C 36 H 44 ClN3O5S: 666.3; found: 666.3. (Example 22)

Chemical Structure

[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 1H 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 value of ClN5O5S: 720.3; Measured value: 720.4. (Example 23)

Chemical Structure

[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 value of [M+H]+ for ClF3N3O5S: 694.2; Measured value: 694.4. (Example 24)

Chemical Structure

[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 C H ClN3O6S: 668.3; Found: 668.6. (Example 25)

Chemical formula

[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 C H ClN3O5S: 626.2; Found: 626.4. (Example 26)

Chemical formula

[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 C H ClN3O5S: 668.3; Found: 668.4. (Example 27)

Chemical formula

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

Chemical Structure

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

Chemical Structure

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

Chemical Structure

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

Chemical Structure

[0248] Example 31 was synthesized in the same manner as Example 21, using cyclobutanecarbonyl chloride instead of cyclopropylacetyl chloride. 1 H NMR (400 MHz, methanol-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 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 value of HClN3O5S: 666.3; Measured value: 666.4. (Example 32)

Chemical Structure

[0249] Example 32 was synthesized in the same manner as Example 19, using 1-isocyanato-1-(trifluoromethyl)cyclopropane in place of isopropyl isocyanate. 1 1H 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 1H 42 Calculated for C18H21ClF3N4O5S: 735.3; Found: 735.3. (Example 33)

Chemical Structure

[0250] Example 33 was synthesized in the same manner as Example 18, using 2-butynoic acid in place of 3-methoxypropionic acid. LCMS-ESI+(m / z):C 35 1H 40 Calculated for C16H17ClN3O5S [M+H]+: 650.2; Found: 650.3. (Example 34)

Chemical Structure

[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 C (Example 37)

Chemical Structure

[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 Calculated for C Calculated value: 735.3; Observed value: 735.3. (Example 38)

Chem.

[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-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 HClN5O5S calculated value: 718.3; measured value: 718.3. 38 H 44 ClN5O5S calculated value: 718.3; measured value: 718.3. (Example 39)

Chem.

[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, methanol -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 ClN5O5S calculated: 706.3; found: 706.3. (Example 40)

Chemical Structure

[0257] Example 40 was synthesized in the same manner as Example 18, using 3-pyridinepropionic acid instead of 3-methoxypropionic acid.1 1H 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 C H ClN4O5S: 717.3; Found: 717.4. (Example 41)

Chemical Structure

[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 1H NMR (400 MHz, methanol Ru-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, J = 7.0 Hz, 2H), 2.87 - 2.77 (m, 3H), 2.54 - 1.80 (m, 10H), 1.47 - 1.41 (m, 1H). LCMS-ESI+ (m / z): [M+H]+ C 39 H 45 Calculated value of ClN4O5S: 717.3; Measured value: 717.3. (Example 42)

Chemical formula

[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 value of [M+H]+ of ClN6O5S: 707.3; Measured value: 707.3. (Example 43)

Chemical formula

[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 [M+H]+ calculated 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, MeOH 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 value for ClN5O5S: 718.3; Measured Value: 719.4. (Example 45)

Chemical Structure

[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 value for C21H28ClN5O5S: 734.4; Measured value: 734.4. (Example 46)

Chemical Structure

[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 1H 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 alculated for ClN6O5S: 721.3; found: 721.3. (Example 47)

Chemical Structure

[0264] Example 47 was synthesized in the same manner as Example 18, using 2-pyridinepropanoic acid instead of 3-methoxypropionic acid. 1 1H 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 alculated for C 38 H 46 ClN4O5S: 717.3; found: 717.5. (Example 48)

Chemical formula

[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 in place of 3-methoxypropanoic acid and Example 5. LCMS-ESI+(m / z): Calculated for C 38 H 46 ClN5O5S [M+H]+: 720.3; found: 720.0. 38 H 46 alculated for C 38 H 46 ClN5O5S [M+H]+: 720.3; found: 720.0. (Example 49)

Chemical formula

[0266] Step 1: To a stirred solution of (3S)-N-(amino((2R,3S)-3-methylhex-5-en-2-yl)(oxo)-l6-sulfanilidene)-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 (309.00 mg, 0.483 mmol) in CH2Cl2 (15.0 mL), triethylamine (0.14 mL, 0.965 mmol) was added in an ice bath, followed by the addition of 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 mixture of diastereomers 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 of C H (Example 50)

Chemical formula

[0269] Example 50 was synthesized in the procedure described in Example 49 (Steps 2 and 3) using Intermediate 49-2 instead of Intermediate 49-1. LCMS-ESI+(m / z): C 40 H 50 Calculated value of [M+H]+ for C (Example 51)

Chemical formula

[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. 11H 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 alculated for ClN5O5S: 720.3; found: 720.0. (Example 52) [Chemical Structure]

[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): Calculated [M+H]+ for C 41 H 46 lN5O5S: 756.4; found: 756.2. (Example 53) [Chemical Structure]

[0272] It should be noted that there may be some inaccuracies in the chemical formula and related content in the original text, and the translation is mainly based on the literal meaning. In actual patent translation, more in-depth chemical knowledge and accuracy verification are often required. 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, methanol -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 ClN5O5S calculated value: 718.3; measured value: 718.1. (Example 54)

Chemical formula

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

Chemical formula

[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)

Chemical Structure

[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 C 38 H 46 ClN5O5S: 720.3; Found: 720.1. (Example 57)

Chemical Structure

[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, methanol-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 37 H 43 Calculated for C 37 H 43 ClN4O6S: 707.3; Found: 707.1. (Example 58)

Chemical Structure

[0277] Example 58 was synthesized in the same manner as Example 18 using 3-(1,2-oxazol-3-yl)propanoic acid instead of 3-methoxypropanoic 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 value for C19H24ClN4O6S: 707.3; Measured value: 707.0. (Example 59)

Chemical Structure

[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. 1H 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 alculated for C19H24ClN5O5S: 720.3; found: 720.1. (Example 60)

Chemical Structure

[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 value of [M+H]+ for ClN5O6S: 722.3; Measured value: 722.1. (Example 61)

Chemical formula

[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, 2H), 2.85 - 2.75 (m, 3H), 2.52 - 1.78 (m, 13H), 1.45 (t, J = 12.8 Hz, 1H). LCMS-ESI+ (m / z): [M+H]+ C 38 H 46 Calculated value of ClN5O5S: 720.3; Measured value: 720.1. (Examples 62 and 63)

Chemical formula

[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 were added pyridine (1.0 g, 8.5 mmol) and acetic anhydride (1.3 g, 8.5 mmol). The mixture was stirred at room temperature for 48 h, and then the solvent was evaporated. 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 gr, 3.6 mmol) in CH2Cl2 was cooled to 0 °C. To this mixture was added dropwise SOCl2 (2 mL) with vigorous stirring. The mixture was stirred at 0 °C and slowly warmed to room temperature. After the reaction was complete, it was evaporated to remove the 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 was added a racemic mixture of (S)-N'-(tert-butyldimethylsilyl)penta-4-ene-1-sulfonimidamide and (R)-N'-(tert-butyldimethylsilyl)penta-4-ene-1-sulfonimidamide (99 mg, 0.38 mmol). 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% for 30 min to give a diastereomeric mixture of intermediate IV.

[0284] Step 4: A mixture of sulfonimide amide intermediate IV (150 mg, 0.23 mmol), propionyl chloride (26 mg, 0.29 mmol), and triethylamine (0.29 mmol) was stirred in CH2Cl2 at room temperature for 1 hour. The reaction mixture was evaporated under reduced pressure, dissolved in DMF, and purified by reverse-phase chromatography, acetonitrile - water 50 - 90% for 30 minutes to obtain 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 hour. 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 minutes to obtain 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% - 90% for 30 minutes to obtain 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 Calculated for C 33 H 40 ClN3O5S: 626.2; Found: 626.2.

[0288] Example 63: 1 H NMR (400 MHz, chloroform-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 of C H (Examples 64 and 65) [Chemical formula]

[0289] Step 1: Preparation of (R)-N-(tert-butyldimethylsilyl)hepta-6-en-3-sulfonamide: To a stirred solution of (R)-hepta-6-en-3-sulfonamide (prepared according to the procedure in International Publication No. WO17 / 147410, 1.5 g, 9.2 mmol) in THF, Et3N (1.8 g, 18.3 mmol) was added in an ice bath, followed by tert-butyldimethylsilyl chloride (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)hepta-6-en-3-sulfonamide.

[0290] Step 2: Preparation of (3R)-N'-(tert-butyldimethylsilyl)hepta-6-ene-3-sulfonimidamide: Under a nitrogen atmosphere, triethylamine (1.2 g, 12.6 mmol) was added to a stirred suspension of Ph3PCl2 (4.2 g, 12.6 mmol) in CH2Cl2. The mixture was stirred at room temperature for 10 minutes and then cooled to 0 °C, and a solution of (R)-N-(tert-butyldimethylsilyl)hepta-6-ene-3-sulfonamide (2.2 g, 7.9 mmol) in CH2Cl2 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 and then at room temperature for 24 hours. The precipitate was filtered off and washed with CH2Cl2. The filtrate was concentrated and purified by normal-phase chromatography (hexane:EtOAc = 7:3) to give (3R)-N'-(tert-butyldimethylsilyl)hepta-6-ene-3-sulfonimidamide. 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)hepta-6-ene-3-sulfonimidamide in place of N'-(tert-butyldimethylsilyl)penta-4-ene-1-sulfonimidamide.

[0292] Example 64 (more polar fraction): 11H NMR (400 MHz, chloroform-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 alculated for C H ClN3O5S: 668.2; found: 668.3.

[0293] Example 65 (less polar fraction): 1 1H NMR (400 MHz, chloroform-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 value of ClN3O5S: 668.2; Measured value: 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 CH2Cl2 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 obtain Intermediate 66-1.

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

Chemical formula

[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% - 90% for 30 minutes) to obtain 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, and the mixture was stirred for 10 minutes. 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 obtain 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 at 50 °C for 1 hour. The mixture was evaporated under reduced pressure to obtain 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 CH2Cl2 (2 mL) and TFA (1 mL) and stirred at room temperature for 1 hour. The mixture was dissolved in ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was concentrated and purified by reverse-phase chromatography with acetonitrile-water 50% - 90% for 30 minutes to obtain 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 CH2Cl2 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 with acetonitrile-water 50 - 90% for 30 minutes to obtain Example 66. 1H 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 C 39 H 51 ClN4O6S: 739.3; Found: 739.5. (Example 67) [Chemical Structure]

[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 C 39 H 51 ClN4O6S: 739.3; Found: 739.5. (Example 68)

Chemical Structure

[0302] Example 68 was synthesized in the same manner as Example 67 using Intermediate 67-4 (the 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 C 40 H 54 ClN5O5S: 752.3; Found: 752.4. (Example 69)

[0303] Step 1: N'-(tert-butyldimethylsilyl)hexa-5-ene-1-sulfonimidamide was prepared in the same manner as in Example 1 (Steps 4 and 5) using hexa-5-ene-1-sulfonamide instead of (2R,3S)-3-methylhexa-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). [Chemical formula]

[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 (200 mg, 0.40 mmol, from Step 3 of Example 1) and pyridazine (32 mg, 0.40 mmol) in acetonitrile stirred at room temperature for 5 minutes was added N’-(tert-butyldimethylsilyl)hexa-5-en-1-sulfonimidamide 70-1 (121 mg, 0.44 mmol). 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: A mixture of diastereomer mixture 69-2 (160 mg, 0.25 mmol), propionyl chloride (28 mg, 0.30 mmol), and triethylamine (0.56 mmol) was stirred in CH2Cl2 at room temperature for 1 hour. 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 minutes to give 69-3 as a mixture of diastereoisomers.

[0306] Step 4: Preparation of Example 69: To a microwave vial were added intermediate 69-3 (25 mg, 0.037 mmol) and Hoveyda-Grubbs II (2.2 mg, 0.004 mmol). The vial was sealed, purged with argon, and then 1,2-DCE was added. The microwave vial was heated to 60 °C for 1 hour. 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 minutes to give Example 69 (the 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 C 35 H 44 ClN3O5S: 654.4; Found: 654.2. (Examples 70 and 71)

Chemical Structure

[0307] Examples 71 and 72 were synthesized in the same manner as Examples 3 and 4 using (3R)-N'-(tert-butyldimethylsilyl)hepta-6-en-3-sulfonimidamide (Steps 1 of Examples 64 and 65) 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 Calculated for ClN5O5S: 748.2; Found: 748.3.

[0309] Example 71: 1 1H NMR (400 MHz, chloroform-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 C 1 H 40 ClN5O5S: 748.2; Found: 748.3. (Example 72)

Chemical Structure

[0310] Example 72 was synthesized in the same manner as Example 18, using (S)-3-hydroxy-3-phenylpropanoic acid in place 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 value of ClN3O6S: 732.2; Measured value: 732.0. (Example 73)

Chemical Structure

[0311] To a solution of Example 5 (12 mg, 0.021 mmol) and diisopropylethylamine (0.041 mmol) in 3 mL of dichloromethane, a solution of thiomorpholine-4-carbonyl chloride 1,1-dioxide (8 mg, 0.041 mmol) in 1 mL of dichloromethane was added dropwise, and the mixture was stirred and refluxed for 16 hours. LC / MS indicated the completion of the reaction. The solvent was evaporated under reduced pressure, and the residue was dissolved in 3 mL of methanol and purified using HPLC to obtain 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 value of ClN4O7S2: 745.25; Measured value: 745.96. (Example 74)

Chemical Structure

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

Chemical formula

[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 stirred at room temperature for an additional 1 hour. LC / MS indicated completion of the reaction. The solvent was evaporated under reduced pressure, and the residue was dissolved in 3 mL of methanol and purified using HPLC to obtain 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 (dd, J = 15.0, 10.7 Hz, 1H), 2.93 - 2.60 (m, 3H), 2.58 - 2.15 (m, 3H), 2.15 - 1.64 (m, 6H), 1.52 - 1.17 (m, 2H). LCMS-ESI+ (m / z): [M+H]+ C 37 H 45 Calculated value for ClN6O5S: 721.29; Measured value: 721.91. (Example 76) [Chemistry]

[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 C (Example 77) [Chemistry]

[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 C (Example 78) [Chemistry]

[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 C (Example 79) [Chemistry]

[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 C21H28ClN5O5S: 718.28; Found: 719.76. (Example 80) [Chemical formula]

[0318] Example 80 was synthesized in the same manner as Example 76 using pyrazin-2-ylmethanamine. 11H 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 C 37 H 43 ClN6O5S: 719.27; Found: 719.71. (Example 81) [Chemical Structure]

[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 ClN3O5S calculated value: 680.29; measured value: 680.98. (Example 82)

Chemical Structure

[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 value of [M+H]+ of ClN3O5S: 709.32; measured value: 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 MgSO4, the solvent was removed, and the crude product was used without further purification.

Chemical formula

[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 1N NaOH was added and the reaction was stirred at room temperature for 3 hours. Methanol was removed under reduced pressure and the aqueous solution was acidified to pH 4 using concentrated HCl. The precipitate formed was collected by filtration, washed with water, and air-dried to obtain 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 1H 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 alculated for C19H28ClN5O5S: 732.29; found: 732.00.

[0325] Example 84 (More Polar Fraction): 1 1H 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, It should be noted that there seems to be an error in the original text where "Calculated for C19H28ClN5O5S: 732.29; found: 732.00." was wrongly split into two parts in the original text. The corrected translation above combines it as one sentence. Also, in the part "LCMS-ESI+ (m / z): [M+H]+ C", it seems incomplete in the original text, but the translation is presented as accurately as possible based on the given content.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 732.29; Measured value: 732.06. (Example 85)

Chemical Structure

[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, methyl 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 value of ClN5O5S: 720.29; Measured value: 720.97. (Example 86)

Chemical Structure

[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 value of [M+H]+ of ClN5O5S: 742.28; Measured value: 742.10. (Example 87)

Chemical Structure

[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-methoxypropanoic acid. LCMS-ESI+(m / z): C 41 H 45 Calculated [M+H]+ for ClF3N3O5S: 784.2793; found: 784.392. (Example 88)

Chemical Structure

[0329] Example 88 was synthesized in the same manner as Example 18, using 3-(furan-2-yl)propanoic acid instead of 3-methoxypropanoic acid. 1 H NMR (400 MHz, chloroform-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 = 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 H 38 H 44Calculated value of ClN3O6S: 706.2712; Measured value: 706.305. (Example 89)

Chemical formula

[0330] Step 1: Sodium hydride (70 mg, 3 mmol) was dissolved in THF (6 mL), then cooled to 0 °C, then ethyl 2-(dimethoxyphosphoryl)acetate (650 mg, 3 mmol) was added to the mixture and stirred for 20 minutes. Then, 1,3-dimethyl-1H-pyrazole-5-carbaldehyde (300 mg, 2.417 mmol) was added to the reaction, and the reaction was warmed to room temperature for 30 minutes. After the reaction was completed as determined by TLC, the contents were diluted with ethyl acetate and aqueous ammonium chloride solution, then the organic layer was dehydrated with MgSO4, filtered, and concentrated. Then, the crude reaction mixture was purified by silica gel chromatography in 2 / 1 hexane ethyl acetate to obtain ethyl (E)-3-(1,3-dimethyl-1H-pyrazol-5-yl)acrylate (405 mg). LCMS-ESI+(m / z): C 10 H 14 Calculated value of N2O2: 195.113; Measured value: 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). Then, palladium on carbon was added, the reaction was stirred, the contents were purged, and evacuated with nitrogen. Then, hydrogen gas from a balloon was added and the reaction was stirred for 3 hours. LCMS showed complete conversion to the hydrogenated product. Then, the contents were filtered through a frit funnel and diluted with ethyl acetate. The palladium frit was moistened with water. The contents were concentrated and the product was used in the next step without further purification to obtain ethyl 3-(1,3-dimethyl-1H-pyrazol-5-yl)propanoate. LCMS-ESI+(m / z): C 10 H 17Calculated value of [M+H] for N2O2: 197.129; Measured value: 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), and then sodium hydroxide (412 mg, 10 mmol) was added. The reaction mixture was then stirred for 1 hour. LCMS showed complete conversion. The reaction mixture was diluted with DCM and then acidified to pH ~4 with 1N HCl. The organic layer was then dried over MgSO4 and concentrated to afford 3-(1,3-dimethyl-1H-pyrazol-5-yl)propanoic acid. LCMS-ESI+(m / z): C8H 13 Calculated value of [M+H] for N2O2: 169.0972; Measured value: 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 C 39 H 45 ClN5O5S: 734.3137; Measured value: 734.400. (Example 90)

Chemical Structure

[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 Cl2N3O5S calculated value of [M+H]: 750.253; Measured value: 750.976. 39 H 45 Calculated value of [M+H] for C 39 H 45 Cl2N3O5S: 750.253; Measured value: 750.976. (Example 91)

Chemical Structure

[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, 2H), 2.45 - 2.23 (m, 4H), 2.09 - 1.99 (m, 2H), 1.94 (q, J = 9.6 Hz, 4H), 1.88 - 1.64 (m, 4H), 1.27 (d, J = 9.8 Hz, 2H). LCMS-ESI+ (m / z): [M+H] C 37 H 43 Calculated for C18H22ClN4O5S2: 723.2436; Found: 723.971. (Example 92)

Chemical Structure

[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). Then Dess-Martin periodinane (2.2 g, 5 mmol) was added. The reaction mixture was stirred for 45 minutes. Then LCMS indicated completion of the reaction, and the contents were diluted with aqueous sodium bicarbonate solution, and then the organic layer was dried over MgSO4, then filtered and concentrated. The crude material was purified by silica gel chromatography in 1 / 1 hexane / ethyl acetate to give 1-(2,2,2-trifluoroethyl)-1H-pyrazole-5-carbaldehyde. LCMS-ESI+ (m / z): Calculated for [M+H] of C6H5F3N2O: 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-methoxypropanoic 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 for C21H28ClN5O5S2: 788.2855; Found: 788.261. (Example 93)

Chemical Structure

[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 C 38 H 45 ClN4O5S2: 737.2593; found: 737.220. (Example 94)

Chemical Structure

[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 C 35 H 41 ClF3N3O5S: 708.248; found: 708.865. (Example 95)

Chemical Structure

[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 -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 alculated for ClF3N3O5S: 722.264; found: 722.274. (Example 96)

Chemical formula

[0342] Example 96 was synthesized in the same manner as Example 18, using 2-phenoxyacetic acid instead of 3-methoxypropionic acid. 11H 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, 2.8 Hz, 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 C21H28ClN3O6S: 718.271; Found: 718.109. (Example 97)

Chemical Structure

[0343] Example 97 was synthesized in the same manner as Example 18 using 3-phenylpropanoic acid instead of 3-methoxypropionic acid. 1 1H 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 of C H (Example 98) [Chemical Structure]

[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 value of [M+H] of C (Example 99) [Chemical Structure]

[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. 11H 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 alculated value for ClN4O5S2: 737.295; found value: 737.040. (Example 100)

Chemical Structure

[0346] Step 1: 1-Methyl-1H-pyrazol-5-ol (250 mg, 3 mmol) was placed in a round-bottom flask, and then potassium carbonate (387 mg, 3 mmol) was added. Then, THF (5 mL) was added. Ethyl bromoacetate (547 mg, 3 mmol) was added, and then the reaction mixture 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 dehydrated over MgSO4, filtered, and concentrated to obtain 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 diluted in THF (2 mL), water (1 mL), and ethanol (1 mL), and then sodium hydroxide (115 mg, 2.88 mmol) was added. The reaction mixture was stirred for 2 hours, then diluted with sec-butanol and 1N HCl to pH ~4, the organic layer was dehydrated over MgSO4, filtered, and concentrated to obtain 2-((1-methyl-1H-pyrazol-5-yl)oxy)acetic acid. LCMS-ESI+ (m / z): calculated for C6H8N2O3 [M+H]: 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 1H 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, 3H), 2.46 (d, J = 7.2 Hz, 2H), 2.34 - 2.18 (m, 2H), 2.01 - 1.91 (m, 5H), 1.84 - 1.70 (m, 3H), 1.57 - 1.39 (m, 2H). LCMS-ESI+ (m / z): [M+H] C 37 H 44 Calculated for C19H26ClN5O6S: 722.277; Found: 722.907. (Example 101)

Chemical Structure

[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 C20H25ClN4O5S2: 737.2953; Found: 737.894. (Example 102)

Chemical Structure

[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 in the same manner as 3-(1,3-dimethyl-1H-pyrazol-5-yl)propanoic acid in Example 89 from 5-methyl-1,3,4-thiadiazole-2-carbaldehyde). 1 H NMR (400 MHz, chloro form-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 alculated 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 in the same manner as 3-(1,3-dimethyl-1H-pyrazol-5-yl)propanoic acid in Example 89 from 5-methyl-1,3,4-thiadiazole-2-carbaldehyde). 1 H NMR (400 MHz, chloroform-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 (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 alculated value for C21H28ClN5O5S: 734.314; measured value: 734.132.

Chemical Structure

Chemical Structure

[0352] Example 104 was synthesized in the same manner as Example 18, using 1-ethyl-1H-pyrazole-4-carboxylic acid in place 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 for HClN5O5S: 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 in place 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 value of ClN3O7S: 726.29; Measured value: 726.22.

Chemical Structure

Chemical Structure

[0354] Step 1: N'-(tert-butyldimethylsilyl)hexa-5-en-1-sulfonimidamide was prepared in the same manner as in Example 1 (Steps 4 and 5), using (S)-2-methylpenta-4-en-1-sulfonamide instead of (2R,3S)-3-methylhexa-5-en-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-methylpenta-4-ene-1-sulfonimidamide (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 hexane).

[0356] Step 3: Preparation of Intermediate 106-3: To a stirred solution of Intermediate 106-2 (1.54 g, 2.46 mmol) in CH2Cl2 (15 mL) was added triethylamine (0.69 mL, 4.92 mmol) in an ice bath, followed by 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. The fractions were concentrated, dissolved in EtOAc, washed with 1% HCl solution, and then with saturated aqueous NaHCO3. The organic phase was dried over MgSO4, filtered, concentrated, and the residue was purified again by silica gel column to give the desired product.

[0357] Step 4: Preparation of Intermediate 106-4: The reaction mixture of Intermediate 106-3 (330 mg, 0.45 mmol) and Hoveyda-Grubbs 2nd 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. 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 diastereomer 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 C H (Example 107)

Chemical Structure

[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 value for C H ClN4O5S: 695.3 (M+H);

Chemical Structure

[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. 11H NMR (400 MHz, methanol-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 alculated for C19H21ClN3O7S: 754.4; found: 754.2. (Example 109) Method 1

Chemical Structure

[0361] Step 1: (4S)-5-[S-amino-N-[tert-butyl(dimethyl)silyl]sulfonimidoyl]-4-methyl-penta-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 minutes. The mixture was stirred and left for 15 minutes. At the same time, (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 became a very dark color (green). After 15 minutes, the reaction was warmed to 0 °C (ice bath). The reaction became yellow during warming. After 1 hour, TLC (20% ethyl acetate / hexanes visualized with KMnO4 staining) indicated that 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 × 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-methylpenta-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 minutes 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 pressure and the residue was subjected to flash chromatography (0 - 65% ethyl acetate / hexane on a 120 g gold Teledyne ISCO column with solid loading). An evaporative light scattering detector (ELSD) was used for peak detection along with UV. The fractions containing the product were combined and the solvent was removed under reduced pressure to give ((2S)-2-methylpenta-4-en-1-ylsulfonimidoyl)carbamate as a mixture of diastereomers at sulfur. The solid was subjected to chiral SFC separation using ethanol as a co-solvent on a ChiralPak IC column. Alternatively, methanol was used as a co-solvent on a ChiralPak AD-H column. The fractions containing the same diastereomers were combined and the solvent was removed under reduced pressure to give (S)-1-phenylethyl ((2S)-2-methylpenta-4-en-1-ylsulfonimidoyl)carbamate as two diastereomers.

[0363] The first eluting diasteromer (109-1-2, 15% ethanol co- solvent) had a retention time (Rt) of 3.05 minutes on ChiralPak IC using the co-solvent and the absolute stereochemistry was 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 using 15% ethanol cosolvent, 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 stirred at 60 °C overnight in 2N aqueous NaOH (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 Calculated [M+H]+ for CClNO4: 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 (the first eluted 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: TFA (25 mL) was added to a solution of Intermediate 109-1-5 (12.7 g, 16.4 mmol) in DCM (130 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 obtain 109-1-6, which was used further without purification.

[0368] Step 5: 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 to a solution of Intermediate 109-1-6 (10 g, 15.97 mmol) in DCM. The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with 1N HCl (aqueous solution) and brine. The organic phase was separated, dried over MgSO4, filtered, concentrated, and purified by silica gel column chromatography (0 - 100% EtOAc / hexane) to obtain Intermediate 109-1-7.

[0369] Step 6: Intermediate 109-1-7 (1 g, 1.38 mmol) and Hoveyda-Grubbs II (258.13 mg, 0.41 mmol) in 1,2-dichloroethane (400 mL) were 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 (SiO2, 0 - 70% EtOAc / hexane) to obtain 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 Calculated value for ClN3O4S: 598.2; Measured value: 598.1. Method 2

Chemical Structure

[0370] Step 1: To a solution of intermediate 109-1-3 (1.1 g, 3.54 mmol, the second eluted diastereomer from Example 109 - Method 1 - Step 2) in DCM (50 mL) at 0 °C was added triethylamine (1.48 mL, 10.63 mmol) and trifluoroacetic anhydride (1 mL, 7.08 mmol). 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 / hexane) 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) were added 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). 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, concentrated, and the residue was purified by silica gel column chromatography (0 - 100% EtOAc / hexane) 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) were 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 / hexane) 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 H2O (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 MgSO4, filtered, concentrated, and purified by silica gel column chromatography (0 - 70% EtOAc / hexane) 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 was added n-butyllithium (1.6 M in hexane, 1.87 mL). The resulting mixture was stirred at -40 °C for 20 minutes. 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 hours. 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 by silica gel column (0 - 20% EtOAc / hexane). Two diastereomers were separated.

Chemical Structure

[0376] The first eluted 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 eluted 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 was slowly added tetrabutylammonium fluoride (1.0 M THF, 0.14 mL). 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

Chemical formula

[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 in place 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 minutes. The mixture was stirred and left for 15 minutes. At the same time, (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 minutes. The reaction was initially yellow but became a very dark color (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 / hexane visualized by KMnO4 staining) indicated that 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 to give crude [(1S)-1-phenylethyl] N-[N-[tert-butyl(dimethyl)silyl]-S-[(1R,2S)-1,2-dimethylpenta-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 hour 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 pressure and the residue was subjected to flash chromatography (0 - 65% EtOAc / hexane on a 120 g gold isco column with solid loading). ELSD was used for peak detection together with UV. The fractions containing the product were combined and the solvent was removed under reduced pressure to obtain [(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] The first eluting diastereomer (110-1-2, RT = 2.37 min on ChiralPak IC using 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 eluted diastereomer (110-1-3, Rt = 3.92 min on ChiralPak IC using 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 to 6), using Intermediate 110-1-2 in place 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 value of HClN3O4S: 612.26; Measured value: 612.06. Method 2:

Chemical Structure

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

[0386] Step 2: To a stirred mixture of dichloromethane / trifluoroacetic acid (3 / 1) (200 mL), Intermediate 110-2-1 (4.2 g, 9.98 mmol) was added. The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. Then, 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. The residue thus obtained was purified by normal-phase chromatography (SiO2, 1:2 Hex:EtOAc) to obtain Intermediate 110-2-2. 1H NMR (400 MHz, chloro Form - 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 minutes. 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 NaHCO3, 1N aqueous HCl, and brine. The organic layer was dried over Mg2SO4 and the solvent was removed under reduced pressure to give a crude residue, which was subjected to column chromatography (SiO2, 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 hours. Further catalyst was added (196 mg, 0.32 mmol) and the mixture was stirred at 60 °C for 24 hours. 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, then dissolved in DCM. Water was added, and then the mixture was 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% hexane / 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 was added dropwise n-butyllithium (1.6 M in hexanes, 4.6 mL, 7.40 mmol) over 5 minutes. The mixture was stirred and left 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 became a very dark color (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 staining) indicated completion of the reaction. 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). The ELSD active fractions were assayed by silica gel TLC (3:1 hexanes:ethyl acetate, KMnO4 staining) and the diastereomer products were co-eluted with 70 - 100% dichloromethane. The crude product mixture was redissolved in hexanes and purified again by flash column chromatography (silica gel, 0 - 20% ethyl acetate in hexanes, ELSD detector). The ELSD active fractions were assayed by silica gel TLC (3:1 hexanes:ethyl acetate, KMnO4 staining). The first eluting peak (110-3-1, absolute stereochemistry tentatively assigned as shown) eluted with 10% ethyl acetate while the later eluting peak (110-3-2, absolute stereochemistry tentatively assigned as shown) eluted with 15% ethyl acetate. [Chemical formula]

[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 minutes 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 pressure and the residue was subjected to flash chromatography (0 - 50% EtOAc / hexane, 80 g of silica gel). ELSD was used for peak detection along with UV. The fractions containing the product 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:

Chemical formula

[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 in place 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)

Chemical formula

[0395] To a mixture of Example 109 (10 mg, 0.0167 mmol) in DCM (0.6 mL), ACN (1.7 mL) was added at room temperature. Then, 4-dimethylaminopyridine (10.2 mg, 0.0836 mmol) and diphenyl carbonate (28.6 mg, 0.134 mmol) were added to the mixture and stirred at room temperature. After 5 hours, pyrimidin-2-amine (12.7 mg, 0.134 mmol) was added and the reaction was heated at 60 °C for 5 hours and then left at 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 H2O. 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 alculated for ClN6O5S: 719.2; found: 719.5. (Example 112)

Chemical Structure

[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, 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 / 0.1% TFA in H2O 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 ClN5O5S calculated: 692.2; found: 691.973. (Example 114) [Chemistry]

[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 value for ClN5O7S: 754.29 (M+H); Measured value: 753.97 (M+H). (Example 115) [Chemistry]

[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 value of ClFN4O5S: 699.27 (M+H); Measured value: 698.73 (M+H). (Example 116)

Chemical Structure

[0400] Example 116 was synthesized in the same manner as Example 75 using Example 109 and (1R,2S)-2-fluorocyclopropanamine. 11H 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 C 36 H 44 ClFN4O5S: 699.27 (M+H); Found: 698.65 (M+H). (Example 117) [Chemical Structure Diagram]

[0401] Example 117 was prepared in the same manner as Example 75 using (1S,2R)-2-methylcyclopropane-1-amine hydrochloride, triethylamine, and Example 109. 1H NMR (400 MHz, methanol-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 for C H (Example 118)

Chemical Structure

[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 powdered potassium hydroxide (KOH (solid); 0.231 g; 4.12 mmol). The heterogeneous slurry was stirred for 50 minutes, after which iodomethane (MeI; 0.048 mL; 0.109 g; 0.773 mmol) was added. After stirring the mixture at ambient temperature for 4 hours, the reaction mixture was diluted with 10 mL each of CH2Cl2 and 1N HCl (aqueous solution). The biphasic mixture was stirred for at least 10 minutes, 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 H2O and dried over anhydrous Na2SO4. 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-d6) 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, Methanol-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 Calculated for Cl2N4O5S: 739.24; Found: 739.75 (M+H). (Example 119)

Chemical Structure

[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 alculated for ClF2N5O5S: 742.26; found 742.13. (Example 120) [Chemical formula]

[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 value of ClN5O6S: 750.30; Measured value 750.08. (Example 121) [Chemical formula]

[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, acetonitrile -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). 1919F NMR (376 MHz, acetonitrile-d3) δ -77.38. LCMS-ESI+ (m / z): [M+H]+ C 41 H 48 Calculated for C 41 H 48 ClN3O6S: 746.3; Found: 746.0. (Example 122)

Chemical Structure

[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, acetonitrile -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 alculated for ClN3O6S: 746.3; found: 746.0. (Example 123)

Chemical Structure

[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, acet onitrile-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 alculated for ClN5O5S: 734.3; found: 733.8. (Example 124)

Chemical Structure

[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 C 19 HClN3O7S: 754.3; Found: 753.9. (Example 125)

Chemical Structure

[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 -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 of ClN3O6S: 736.3; Measured value: 736.12. (Example 126)

Chemical Structure

[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, methyl 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 C (Example 127)

Chemical Structure

[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 C 38 H 48 ClN3O6S: 710.3 (M+H); Found: 710.1 (M+H). (Example 128)

Chemical Structure

[0413] Example 128 was synthesized in the same manner as Example 18 using trans-3-methoxycyclobutanecarboxylic acid and Example 109. 11H NMR (400 MHz, methanol-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 = 13.9 Hz, 2H), 2.02 - 1.67 (m, 6H), 1.45 (t, J = 12.5 Hz, 1H), 1.14 (d, J = 6.9 Hz, 3H). LCMS-ESI+: C 38 H 48 alculated value for C18H19ClN3O6S: 710.3 (M+H); found: 710.1 (M+H). (Example 129) [Chemical Structure]

[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 ClN6O5S calculated value: 761.3 (M+H); measured value: 760.8 (M+H). (Example 130)

Chemical Structure

[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 = 6.2 Hz, 3H), 1.88 - 1.69 (m, 3H), 1.46 (t, J = 7.3 Hz, 4H), 1.31 (s, 1H), 1.14 (d, J = 6.5 Hz, 3H). LCMS-ESI+: C 39 H 47 Calculation of value: 719.3 (M+H); found: 718.8 (M+H). (Example 131)

Chemical Structure

[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 alculated value for ClN4O6S: 725.3 (M+H); measured value: 724.8 (M+H). (Example 132)

Chemical formula

[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 for C 36 H 47 ClN4O6S: 699.3 (M+H); Found: 698.6 (M+H). (Example 133)

Chemical Structure

[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 alculated value of ClFN3O7S: 772.3 (M+H); measured value: 772.2 (M+H). (Example 134) [Chemical formula]

[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 Calculated for C 38 H 46 ClN5O5S: 720.3 (M+H); Found: 719.0 (M+H). (Example 135)

Chemical Structure

[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. Then, a solution of methyl 3-bromopropanoate (13.17 g, 0.079 mol) was added dropwise and the temperature was raised to room temperature. The reaction mixture was stirred at this temperature for 48 hours. Then, water was 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 purification by normal-phase chromatography (silica gel column, 0 - 80% EtOAc / hexane) gave methyl 3-(2-formyl-1H-pyrrol-1-yl)propanoate.

[0421] Step 2: Preparation of methyl 3H-pyrrolidine-6-carboxylate: NaOMe (2.62 g, 12.14 mmol) was added to a solution of methyl 3-(2-formyl-1H-pyrrol-1-yl)propanoate (2.0 g, 11.04 mmol) in MeOH (20 mL). The reaction mixture was stirred at 45 °C for 48 hours. Then, water was 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 purification by normal-phase chromatography (silica gel column, 0 - 80% EtOAc / hexane) gave 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) was added 2N LiOH (1 mL), and the reaction mixture was stirred at room temperature for 3 h. To the reaction mixture was added 2N HCl (1 mL), and it 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 alculated for C 40 H 45 ClN4O5S: 729.26; found: 729.30. (Example 136) [Chemical Structure]

[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 then the mixture was stirred for 5 hours. The mixture was filtered through silica and concentrated. Then, 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 obtain 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 in 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 for ClN4O5S: 731.30; Found: 731.22. (Example 137)

Chemical Structure

[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, J = 9.2 Hz, 3H), 1.72 - 1.55 (m, 4H), 1.41 (t, J = 12.8 Hz, 1H), 1.28 (s, 2H), 1.01 (d, J = 6.2 Hz, 3H). LCMS-ESI+ (m / z): [M+H]+ C 41 H 49 Calculated for C H ClN4O6S: 761.29; Found: 761.22. (Example 138)

Chemical Structure

[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 alculated for ClN5O5S: 720.29; found: 720.23. (Example 139)

Chemical Structure

[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; Measured value: 747.04. (Example 140)

Chemical Structure

[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 mixture was removed from the cooling bath and stirred overnight at ambient temperature. The reaction mixture was then concentrated by removing DCM, diluted with DMF (1 mL), filtered, and purified by Gilson reverse-phase preparative HPLC (60 - 100% ACN / H2O containing 0.1% TFA) to afford Example 140. 1H NMR (400 MHz, methanol-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): calculated [M+H]+ C HClN3O6S: 710.3; found: 710.1. 38 H 48 ClN3O6S calculated value: 710.3; found value: 710.1. (Example 141)

Chemical Structure

[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, me thanol-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): calculated [M+H] C 41 H 50 ClN5O5S: 760.3; found: 760.1. (Example 142) [Chemical formula]

[0432] Example 142 was synthesized in the same manner as Example 140 using 3-(1-methylpyrazol-4-yl)propanoic acid in place of 3-hydroxy-3-methyl-cyclobutanecarboxylic acid, and DMF (1.0 mL) was also added as a co-solvent for this reaction. 1H NMR (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 value of measured value: 734.07. (Example 143)

Chemical Structure

[0433] Example 143 was synthesized in the same manner as Example 140 using isochroman-3-carboxylic acid in place of 3-hydroxy-3-methyl-cyclobutanecarboxylic acid. The earlier eluting peak from reverse-phase preparative HPLC was arbitrarily assigned as "R" without determining the actual stereochemistry. 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 ClN3O6S calculated: 758.37; found: 758.07. (Example 144)

Chemical formula

[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). The resulting mixture was stirred at room temperature for 2 hours, after which the reaction was concentrated by removing DCM. The resulting residue was redissolved in EtOAc (30 mL) and washed with 1N HCl (15 mL). The aqueous layer was extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with saturated NaHCO3 (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 (12 g silica gel, 2.0N NH3 in 0 - 10% DCM / 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 value for ClN4O5S: 681.28; Measured value: 680.81. (Example 145)

Chemical Structure

[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) at 0 °C over 2 minutes, and the resulting mixture was warmed to room temperature. After 4.5 hours, 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 minutes, the reaction mixture was heated to 100 °C. After 23 hours, the resulting mixture was cooled to room temperature, and diethyl ether (400 mL) and saturated aqueous ammonium chloride solution (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 hexane) to give 145-1.

[0436] Step 2: An aqueous lithium hydroxide solution (2.0 M, 11.0 mL, 22 mmol) was added via syringe at room temperature 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). After 1 hour, the resulting mixture was heated to 70 °C. After 3.5 hours, the resulting mixture was cooled to room temperature, and aqueous hydrochloric acid solution (2.0 M, 20 mL) and ethyl acetate (100 mL) were sequentially added. 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 sequentially washed with aqueous hydrochloric acid solution (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 hexane) to obtain 145-2.

[0437] Step 3: A mixture of an aqueous sodium chlorite solution (2.0 M, 469 mL, 0.94 mmol) and sodium dihydrogen phosphate monohydrate (120 mg, 0.868 mmol) was added via syringe at room temperature 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). After 16.5 hours, aqueous hydrochloric acid solution (2.0 M, 20 mL) and ethyl acetate (100 mL) were sequentially added. 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 obtain 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 ClN4O6S calculated value: 759.3 (M+H); measured value: 759.0 (M+H). (Example 146)

Chemical Structure

[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 HClN4O5S2: 723.248; Found: 723.221. (Example 147)

Chemical Structure

[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 HClN4O5S: 705.288; Found: 705.295. (Example 148)

Chemical formula

[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...

Claims

【Claim 1】 The invention described in this specification.

Images