Substituted thiophene fused cyclohexanone derivatives, compositions comprising same and their use as medicaments

Abstract

A compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof is provided. Also provided is a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable carrier, diluent or excipient. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition containing the same can be used for treating or preventing diseases to which an ASIC inhibitor is applied. In some embodiments, the compound or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition comprising the same, the compound can be used for treating or preventing pain, arthritis, stroke, epilepsy, anxiety disorder, post-traumatic stress disorder (PTSD), depression, multiple sclerosis, Alzheimer's disease, gastroesophageal reflux disease, cancer, migraine, cough or acute lung injury. (I).

Description

Priority application

[0001] This application claims priority to U.S. Provisional Application No. 63 / 491,473, filed March 21, 2023, which is incorporated herein by reference. Technical Field

[0002] This technical field generally relates to compounds, compositions, and their use in treating diseases and conditions suitable for inhibiting acid-sensitive ion channels (also known as "ASICs"). For example, this application relates to substituted thiophene-fused cyclohexanone derivatives, pharmaceutical compositions comprising them, and their use as ASIC inhibitors. Background Technology

[0003] Since their discovery in 1997, acid-sensitive ion channels (ASICs) have become increasingly important for the health of neurons and other non-neuronal cells. ASICs play a crucial role in mediating pain sensation, and their activity can contribute to conditions such as stroke, inflammation, arthritis, cancer, and migraines.

[0004] ASIC for Na + Ions (and other cations) are permeable, activated by low extracellular pH, and widely expressed in the central nervous system (CNS) and peripheral nervous system (PNS). ASICs are formed by the assembly of homo and heterotrimers of subunits, including ASIC1a, ASIC1b, ASIC2a, ASIC2b, and ASIC3. ASIC1a is expressed in both the PNS and CNS, while ASIC1b is expressed in the PNS.

[0005] Tissue damage and inflammation can lead to acidosis, and acidification is considered a significant factor in related pain. Literature suggests that ASIC inhibitors may alleviate pain in a variety of clinical conditions. Furthermore, due to their different mechanisms of action, ASIC antagonists may offer a new treatment option for patients who cannot benefit from current analgesics or tolerate their adverse side effects.

[0006] Therefore, developing novel small molecule inhibitors for ASIC is crucial for providing further useful therapeutic agents for treating ASIC-related diseases or conditions such as pain. Summary of the Invention

[0007] According to one aspect, this application relates to a compound having formula (I), (I) Or its pharmaceutically acceptable salt, solvate, or prodrug, in: R a It is -NH2, -NH-OH, -OH, -NHRb or -NR c R d ; R b is C1-C6alkyl, C3-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl, wherein C1-C6alkyl is optionally substituted with 1 to 3 halogen, 1 to 3 -OH, -OC1-C3alkyl, -COOH, or cyclopropyl optionally substituted with -OH, wherein C3-C6cycloalkyl is optionally substituted with -CN; R c and R d together with the nitrogen to which they are attached form a 4-membered heterocycloalkyl, wherein the 4-membered heterocycloalkyl is optionally substituted with at least one of -OH and C1-C3alkyl; denotes one of the following residues A0to A 12

[0008] or ; wherein: R is H, C1-C6alkyl, or phenyl; R 1 and R 2 are each independently -CN, C6-C 10 aryl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, 4- to 14- membered heterocycloalkyl, 5- to 10-membered heteroaryl, -C(O)NH2, -C(O)NHR 5 , -C(O) R 6 , or -C(O)OR 5 , wherein each C1-C6alkyl is optionally substituted with 1 to 3 R 7 substituents, each C6-C 10 aryl is optionally substituted with 1 to 3 R 8 substituents, each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R 22 substituents, with the proviso that when R a is -OH, denotes A0, and R 1 is then R 2 in residue A0is different from ; each R 5 is independently C1-C6alkyl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R 9 substituents; each R 6 is independently C3-C6cycloalkyl, 4- to 6-membered heterocycloalkyl, or C6-C​10 aryl; each R 7 independently -OH, -C(O)R 11 , C3-C6cycloalkyl, -CN, C6-C 10 aryl, halogen, -C(O)OH, 5- to 10-membered heteroaryl, -NH(C(O)OC1-C6alkyl), -N(C1-C4alkyl)(C(O)OC1-C6alkyl), 4- to 6-membered heterocycloalkyl, -NH(C(O)C1-C6alkyl), -OR 20 , -SC1-C6alkyl, -NH2, -NH(C1-C4alkyl), or -N(C1-C4alkyl)2, wherein each C3-C6cycloalkyl is optionally substituted with 1 to 3 R 12 substituents, each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R 13 substituents, each 4- to 6-membered heterocycloalkyl is optionally substituted with C1-C4alkyl or oxo; each R 8 independently halogen, C1-C6alkyl, -OC1-C6alkyl, C3-C6cycloalkyl, or 5- to 10-membered heteroaryl, wherein each -OC1-C6alkyl is optionally substituted with -OC1-C4alkyl, and each 5- to 10-membered heteroaryl is optionally substituted with C1-C4alkyl; each R 22 independently C1-C6alkyl optionally substituted with phenyl; each R 9 independently -OH, -C(O)R 15 , C3-C6cycloalkyl, -CN, C6-C 10 aryl, halogen, -C(O)OH, 4- to 6-membered heterocycloalkyl, -NH(C(O)C1-C6alkyl), -OC1-C6alkyl, -SC1-C6alkyl, -NH2, -NH(C1-C4alkyl), or -N(C1-C4alkyl)2, wherein each 4- to 6-membered heterocycloalkyl is optionally substituted with C1-C4alkyl, and each -OC1-C6alkyl is optionally substituted with -OC1-C4alkyl; each R 11 independently -NH2, -NH(C1-C4alkyl), -N(C1-C4alkyl)2, or 4- to 6-membered heterocycloalkyl; each R 20 independently C1-C6alkyl or 5- to 10-membered heteroaryl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R 14 substituents, and each 5- to 10-membered heteroaryl is optionally substituted with -OH or -NH(cyclopropyl); each R 12independently C1-C4 alkyl, -SC1-C4 alkyl, -Ph, -OC1-C4 alkyl, or -SPh, wherein each C1-C4 alkyl is optionally substituted with -OH; each R 13 is independently halogen, C1-C4 alkyl, C3-C6 cycloalkyl, -OH, -OC1-C6 alkyl, -SC1-C6 alkyl, -S(O)2C1-C6 alkyl, -NH2, -NH(C1-C4 alkyl), or -N(C1-C4 alkyl)2, wherein each -OC1-C6 alkyl, -SC1-C6 alkyl, -S(O)2C1-C6 alkyl, -NH(C1-C4 alkyl), and -N(C1-C4 alkyl)2is optionally substituted with 1 to 3 R 9 substituents; each R 14 is independently halogen, -OC1-C4 alkyl, or C3-C6 cycloalkyl; each R 15 is independently -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, or 4- to 6- membered heterocycloalkyl; R 4 is C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 aryl, 7- to 10-membered partially unsaturated heterocyclyl, or 5- to 10-membered heteroaryl, wherein C1-C6 alkyl and C3-C8 cycloalkyl are optionally substituted with 1 to 3 R 9 substituents, C6-C 10 aryl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 R 10 substituents, with the proviso that: (i) when R a is -OH, -NH2, or , and represents A2, then R 4 in residue A2is different from -CH3; and (ii) when R a is -NH2and represents A3, then R 4 in residue A3is different from -C(CH3)3; each R 10 is independently C1-C4 alkyl, halogen, -OC1-C6 alkyl, -NH2, -NH(C1-C4 alkyl), or -N(C1-C4 alkyl)2, wherein each C1-C4 alkyl is optionally substituted with 1 to 3 halogens; R 2a is C1-C6 alkyl, C3-C8 cycloalkyl, or C6-C 10 aryl, wherein C1-C6 alkyl and C3-C8 cycloalkyl are optionally substituted with 1 to 3 R 9 substituents, C6-C10 aryl is optionally substituted with 1 to 3 R 10 substituents; R 1a and R 2b each independently -CN, C6-C 10 aryl, C1-C6alkyl, C3-C8cycloalkyl, -C(O)NH2, -C(O)NHR 5 or -C(O)OC1-C6alkyl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R 16 substituents, each C6-C 10 aryl is optionally substituted with 1 to 3 R 17 substituents; each R 16 independently -OH, -C(O)NH2, -C(O)NH(C1-C4alkyl), C3-C6cycloalkyl, -CN, C6-C 10 aryl, halogen, -C(O)OH, 5- to 10-membered heteroaryl, -NH(C(O)OC1-C6alkyl), 4- to 6-membered heterocycloalkyl, -NH(C(O)C1-C6alkyl), or -OC1-C4alkyl(OC1-C4alkyl), wherein each C3-C6cycloalkyl is optionally substituted with 1 to 3 R 18 substituents, each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R 21 substituents, each 4- to 6-membered heterocycloalkyl is optionally substituted with C1-C4alkyl; each R 17 independently halogen, C1-C6alkyl, -OC1-C6alkyl, or 5- to 10-membered heteroaryl, wherein each 5- to 10-membered heteroaryl is optionally substituted with C1-C4alkyl; each R 18 independently C1-C4alkyl, -SC1-C4alkyl, -Ph, or -OC1-C4alkyl; each R 21 independently halogen or C1-C4alkyl; R 4a is C1-C6alkyl or C3-C8cycloalkyl, wherein each C1-C6alkyl and C3-C8cycloalkyl is optionally substituted with 1 to 3 R 19 substituents; each R 19 independently halogen, -OH, -OC1-C4alkyl, -SC1-C4alkyl, -NH2, -NH(C1-C4alkyl), or -N(C1-C4alkyl)2; R 1b and R 2ctogether with the carbon atom to which they are attached form a C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, 8- to 14-membered partially unsaturated heterocyclyl, or 8- to 14-membered partially unsaturated carbocyclyl, wherein the C3-C8cycloalkyl is optionally substituted with 1 to 3 R 9 substituted with 1 to 3 R R 2d and R 4b together with the carbon atom to which they are attached form a C3-C8cycloalkyl or 4- to 14-membered heterocycloalkyl, wherein the C3-C8cycloalkyl is optionally substituted with 1 to 3 R 19 substituted with 1 to 3 R R 1c and R 3 together with the carbon atom to which they are attached form a C3-C8cycloalkyl or 4- to 14-membered heterocycloalkyl, wherein the C3-C8cycloalkyl is optionally substituted with 1 to 3 R 19 substituted with 1 to 3 R

[0009] In some embodiments, the compound of Formula (I) can be a compound of Formula (la), (la’), (lb), (lb’), (lc), (lc’), (Id), (Id’), (le), (le’), (If), (If’), or (lg) as described herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0010] In some embodiments, the compound of Formula (I) can be a compound of Table 1 of the specification, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0011] Another aspect relates to a pharmaceutical composition comprising: a compound as defined herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and a pharmaceutically acceptable carrier, diluent, or excipient.

[0012] Another aspect relates to the use of a compound as defined herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in the preparation of a pharmaceutical composition for the treatment or prevention of a disease for which an ASIC inhibitor is indicated. This aspect also relates to a compound as defined herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for use in the treatment or prevention of a disease for which an ASIC inhibitor is indicated. Similarly, this aspect relates to a method of treating or preventing a disease for which an ASIC inhibitor is indicated, comprising administering to a patient in need thereof a compound as defined herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In one embodiment, the ASIC inhibitor is an ASIC la or ASIC lb inhibitor.

[0013] Another aspect relates to the use of a compound as defined herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in the preparation of a pharmaceutical composition for the treatment or prevention of a disease selected from the group consisting of pain, arthritis, stroke, epilepsy, anxiety, post-traumatic stress disorder (PTSD), depression, multiple sclerosis, Alzheimer's disease, gastroesophageal reflux disease, cancer, migraine, cough, and acute lung injury. This aspect also relates to a compound as defined herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for use in the treatment or prevention of a disease selected from the group consisting of pain, arthritis, stroke, epilepsy, anxiety, post-traumatic stress disorder (PTSD), depression, multiple sclerosis, Alzheimer's disease, gastroesophageal reflux disease, cancer, migraine, cough, and acute lung injury. Similarly, this aspect relates to a method of treating or preventing a disease selected from the group consisting of pain, arthritis, stroke, epilepsy, anxiety, post-traumatic stress disorder (PTSD), depression, multiple sclerosis, Alzheimer's disease, gastroesophageal reflux disease, cancer, migraine, cough, and acute lung injury, comprising administering to a patient in need thereof a compound as defined herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In one embodiment, the disease is pain, e.g., inflammatory pain or neuropathic pain. In one embodiment, the disease is inflammatory pain. In another embodiment, the disease is neuropathic pain. BRIEF DESCRIPTION OF DRAWINGS

[0014] Figure 1 Dose-dependent anti-nociceptive effects of compound 61 (A, B) and compound 63 (C, D) and naproxen (E, F) as a positive control in the rat carrageenan model are shown (upper left and lower left panels: thermal hyperalgesia response; upper right and lower right panels: mechanical hyperalgesia response). Compound 61 responses are from pooled results of two independent studies. Data are presented as mean ± SEM. *p < 0.05, **p < 0.01, ***p < 0.001.

[0015] Figure 2Dose-dependent antinociceptive effects of compound 61 in a rat chronic constriction injury (CCI) model are shown (thermal hyperalgesia (A); and mechanical hyperalgesia (B)). Data are expressed as mean ± SEM. *p < 0.05, **p < 0.01, ***p < 0.001.

[0016] Figure 3 Dose-dependent antinociceptive effects of compound 63 in a rat CCI model assessing thermal hyperalgesia are shown. Data are expressed as mean ± SEM. *p < 0.05, **p < 0.01, ***p < 0.001.

[0017] DETAILED DESCRIPTION General Definitions All technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this technology belongs unless clearly indicated otherwise. The meanings of certain terms and phrases in this specification are provided below for convenience.

[0018] The definitions of terms in the publications, patents, and patent applications incorporated herein by reference, if any, are to be construed in a manner consistent with the definition of those terms in this specification. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0019] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. It will be noted that, as used in this specification, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. For example, a reference to "a compound" is a reference to one or more compounds. In addition, it should be noted that the term "or" is generally employed in its sense including "and / or" unless the content clearly dictates otherwise. It is further emphasized that the terms "comprise," "comprises," "comprising," "include," "includes," "including," "have," "has," "having," or variants thereof are to be construed as being inclusive (i.e., open-ended) and not exclusive.

[0020] The term "about" means within an acceptable limit of error for the particular value as determined by one of ordinary skill in the art to which that value pertains, which varies from instrument to instrument, and from context to context. For example, "about" can mean within one standard deviation, or beyond one standard deviation, depending on convention. Alternatively, "about" can mean within 20%, preferably within 10%, more preferably within 5%, and most preferably within 1% of the given value. Furthermore, especially when referring to biological systems or processes, the term can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold. When particular values are described in the application and claims, "about" should be assumed to mean within an acceptable limit of error for that particular value, unless otherwise stated.

[0021] Compounds The present application relates to novel compounds of general formula (I) (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R a and will be defined in detail below.

[0022] Accordingly, the compounds described in the present application include those represented by the chemical structure of formula I, with reference to any applicable embodiments described below, as well as exemplary compounds such as compounds 4, 8, 9, 14-39, 47-54, 59, 60a, 60b, 61-72, 75, 81-84, 89, 91, 97, 101, 108, 109, 119-136, 138-150, 154, 155, 163, 168-170, 173-175, 178-181, 183, 189-195, 197-202, 211-216, 219, 221, 227-232, 237, 238, 239, 245-251, 253, 254, 255, 257, 258, 263, 264, 271, 272, 273, 278-281, 287, 288, 290, 291, 297, 298, 305, 306, 313, 314, 321, 322, 330, 331, 337-349, 352-358, 360, 362, 371, 378, 391-393, 394a, 394b, 395a, 395b, 396, 397, 401-403, 406-408, 412-414, 416, 418, 422, 427-431, 433, 434, 445-454, 462-466, 468-476, 478-483, 486, 488, 489, 492, 495-498, 511-515, 520, 523, 524, or 534 of Table 1, and pharmaceutically acceptable salts, solvates and prodrugs thereof, as applicable. Compounds can be identified by their chemical structure or chemical name. In the event of a conflict between the chemical structure and the chemical name, the chemical structure controls.

[0023] Unless otherwise indicated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the present description unless it is otherwise indicated. Unless otherwise specified, all tautomeric forms of the compounds are within the scope of the present description. Additionally, unless otherwise specified, the structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or replacement of a carbon by a13C- or14C-enriched carbon are within the scope of this description. Such compounds are useful in metabolic studies, as probes in biological assays, or as therapeutic agents. 13 C or 14 C enriched carbons, are within the scope of this description. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to the present description.

[0024] Definitions for certain functional groups and chemical terms are provided herein.

[0025] Chemical structures herein are drawn according to conventional standards known in the art. Thus, if an atom (such as a carbon atom) appears to have an unsatisfied valence, it is assumed to be bonded to a hydrogen atom (unless otherwise specified) even when the hydrogen atom is not explicitly shown. A hydrogen atom should be implied to be present unless otherwise stated.

[0026] The number of carbon atoms in a hydrocarbyl substituent can be denoted by the prefix "Cx-Cy-", wherein x is the minimum and y is the maximum number of carbon atoms in the substituent. When referring to "x to y membered" heterocyclyl groups (e.g., heterocycloalkyl, partially unsaturated heterocyclyl groups, or heteroaryl groups), x and y define the minimum and maximum number of atoms in the ring group, respectively, including both carbon and heteroatoms. x -C y The term "heteroatom" refers to one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon, more particularly one or more of oxygen, sulfur, or nitrogen.

[0027] The term "halogen" as used herein means an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I).

[0028] The term "heteroatom" refers to one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon, more particularly one or more of oxygen, sulfur, or nitrogen.

[0029] The term "alkyl" as used herein means a saturated straight (linear) or branched chain hydrocarbon group. In some embodiments, the alkyl group can contain from 1 to 6 carbon atoms, although alkyl groups with more than 6 carbon atoms are also contemplated. For example, a "C1-C6alkyl" group contains from 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, neopentyl, n-hexyl, heptyl, octyl, and the like.

[0030] As used herein, the term "alkenyl" refers to straight or branched chain hydrocarbon groups containing one or more double bonds. In some embodiments, alkenyl groups can contain 2 to 6 carbon atoms, although alkenyl groups with more than 6 carbon atoms are also contemplated. For example, "C2-C6alkenyl" contains 2 to 6 carbon atoms. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, pentenyl, 1 -methyl-2-buten-1 -yl, hexenyl, and the like.

[0031] As used herein, the term "alkynyl" refers to straight or branched chain hydrocarbon groups containing one or more triple bonds. In some embodiments, alkynyl groups can contain 2 to 6 carbon atoms, although alkynyl groups with more than 6 carbon atoms are also contemplated. For example, "C2-C6alkynyl" contains 2 to 6 carbon atoms. Alkynyl groups include, but are not limited to, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

[0032] The term "cycloalkyl," used alone or as part of a larger moiety, refers to a group including saturated carbon rings in monocyclic or polycyclic ring systems, including spiro (sharing one atom), fused (sharing at least one bond), or bridged (sharing two or more bonds) carbon ring systems, having three to fifteen ring members. In some embodiments, cycloalkyl groups can contain 3 to 8 carbon atoms. For example, "C3-C8cycloalkyl" contains 3 to 8 carbon atoms in the ring. Examples of cycloalkyl groups can include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[4.2.0]octyl, norbornyl, and the like.

[0033] As used herein, the term "aryl" refers to a monocyclic or bicyclic or tricyclic fused ring system in which the ring system is carbocyclic and completely aromatic. In some embodiments, aryl groups can contain 6 to 14 carbon atoms, for example 6 to 10 carbon atoms. For example, "C6-C10aryl" contains 6 to 10 carbon atoms in the aromatic ring system. In certain embodiments, "aryl" refers to aromatic ring systems including, but not limited to, phenyl, naphthyl, azulenyl, anthracenyl, and the like. 10 As used herein, the term "aryl" refers to a monocyclic or bicyclic or tricyclic fused ring system in which the ring system is carbocyclic and completely aromatic. In some embodiments, aryl groups can contain 6 to 14 carbon atoms, for example 6 to 10 carbon atoms. For example, "C6-C10aryl" contains 6 to 10 carbon atoms in the aromatic ring system. In certain embodiments, "aryl" refers to aromatic ring systems including, but not limited to, phenyl, naphthyl, azulenyl, anthracenyl, and the like.

[0034] As used herein, the term "heterocyclic group" refers to a chemically stable, saturated, partially unsaturated, or fully aromatic monocyclic or polycyclic ring system, including spiro (sharing one atom), fused (sharing at least one bond), or bridged (sharing two or more bonds) carbon ring systems, including at least one heteroatom as described above. Heterocyclic groups can be heterocycloalkyl, heteroaryl, or partially unsaturated heterocyclic groups as defined herein.

[0035] The term "heterocycloalkyl," used alone or as part of a larger moiety, refers to a saturated cyclic group containing at least one heteroatom as defined herein, which can include a single ring or two or more rings. In some embodiments, a heterocycloalkyl group can include 3 to 14 ring atoms, although heterocycloalkyl groups having more than 14 ring atoms are also contemplated. In some embodiments, a heterocycloalkyl group can contain, for example, 4 to 14 ring atoms, or 4 to 6 ring atoms or 3 to 6 ring atoms. For example, a "3 to 14 membered heterocycloalkyl" contains 3 to 14 atoms by counting the total number of carbon and heteroatoms in the saturated heterocyclic portion. In some embodiments, a heterocycloalkyl group can contain 1 to 4 heteroatoms. Heterocycloalkyl groups can include, but are not limited to, oxiranyl, aziridinyl, oxetanyl, tetrahydropyranyl (oxanyl), tetrahydrofuranyl (oxolanyl), pyrrolidinyl (azolidinyl), piperidinyl, dioxanyl, morpholinyl, thietanyl, azetidinyl, diazetidinyl, oxathiolanyl, oxepanyl, azocanyl (octahydroazocinyl), thiepanyl, azocanyl (octahydroazocinyl), 1,3-dioxolanyl, pyrazolidinyl, imidazolidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiophenyl, tetrahydrodithiophenyl, thiomorpholinyl, thioxazolidinyl, homopiperidinyl, thiepanyl, dithianyl, dithiolanyl, 3-azabicyclo[3,1,0]hexyl, 3-azabicyclo[4,1,0]heptyl, quinuclidinyl, decahydroquinolinyl, octahydroindolyl, and the like. A heterocycloalkyl group can be attached to its pendant group at any heteroatom or carbon atom, resulting in a chemically stable structure.

[0036] The term "heteroaryl," used alone or as part of a larger moiety, refers to an all- aromatic ring group containing at least one heteroatom as defined herein, which can include a single ring or two or more condensed rings. In some embodiments, a heteroaryl group can include 5 to 10 ring atoms, although heteroaryls with more than 10 ring atoms are also contemplated. In some embodiments, a heteroaryl group can contain one to four heteroatoms. Heteroaryl groups can include, but are not limited to, thienyl, furanyl (furyl), pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, benzofuranyl, dibenzofuranyl, benzimidazolyl, benzothiazolyl, benzothienyl (benzothiophenyl), benzoxazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, furopyridinyl, indolyl, indazolyl, isoindolyl, indolizinyl, purinyl, quinolinyl (quinolyl), isoquinolinyl (isoquinolyl), acridinyl, cinnolinyl, quinazolinyl, naphthyridinyl, carbazolyl, phenanthridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and pteridinyl. A heteroaryl group can be attached to its side group at any heteroatom or carbon atom, forming a chemically stable structure.

[0037] As used herein, the term "partially unsaturated heterocyclyl" refers to a carbocyclic ring system that includes at least one double bond between ring atoms but is not fully aromatic and includes at least one heteroatom. "Partially unsaturated heterocyclyl" is intended to encompass ring systems that can be monocyclic, bicyclic or tricyclic and have one or more unsaturation sites. In some embodiments, a partially unsaturated heterocyclyl can include a polycyclic ring system in which at least one ring is aromatic and at least one other ring is not aromatic. For example, a partially unsaturated heterocyclyl can include an aryl group fused to a heterocycloalkyl group, a heteroaryl group fused to a cycloalkyl group, or a heteroaryl group fused to a heterocycloalkyl group, where each of the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups can be monocyclic or bicyclic in itself. In some embodiments, a partially unsaturated heterocyclyl can contain 7 to 14 carbon atoms, such as 7 to 10 carbon atoms or 8 to 14 carbon atoms. For example, a "7 to 10 membered partially unsaturated heterocyclyl" contains 7 to 10 atoms by counting the total number of carbon atoms and heteroatoms in the heterocyclic portion. In some embodiments, a partially unsaturated heterocyclyl can contain 1 to 4 heteroatoms. A partially unsaturated heterocyclyl can be attached to its side groups at any heteroatom or carbon atom, resulting in a chemically stable structure. Non-limiting examples of partially unsaturated heterocyclyl groups include pyrazolinyl, imidazolinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2H-pyranyl, 4H-pyranyl, dihydropyranyl, dihydrothiophenyl, dihydrofuryl, quinolizinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, 1,3-benzodioxolanyl, chromanyl, chromenyl, indolinyl, quinolonyl, isoquinolonyl, oxazepinyl, diazepinyl, thiazepinyl, phthalazinyl, quinoxalinyl, pyrido[2,3-b]-1,4-oxazin-3(4H)-one, 、 、 When used to refer to a ring atom of a heterocyclyl group, the term "nitrogen" includes the case of a substituted nitrogen. For example, in a saturated or partially unsaturated ring containing 1 to 3 heteroatoms selected from oxygen, sulfur, and nitrogen, a nitrogen atom can be represented as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR° (as in N-substituted pyrrolidinyl).

[0038] As used herein, the term "partially unsaturated carbocyclic group" refers to a carbocyclic ring system that includes at least one double bond between ring atoms but is not fully aromatic. A "partially unsaturated carbocyclic group" is intended to encompass ring systems that contain only carbon atoms in the ring, the ring is monocyclic, bicyclic or tricyclic and has one or more points of unsaturation. In some embodiments, a partially unsaturated carbocyclic group can include a polycyclic ring system in which at least one ring is aromatic and at least one other ring is not aromatic. For example, a partially unsaturated heterocyclic group can include an aryl group fused to a cycloalkyl group, where each of the aryl and cycloalkyl groups can be monocyclic or bicyclic by itself. In some embodiments, a partially unsaturated carbocyclic group can contain 7 to 14 carbon atoms, such as 7 to 10 carbon atoms or 8 to 14 carbon atoms. For example, an "8 to 14 membered partially unsaturated carbocyclic group" contains 8 to 14 carbon atoms in the ring portion. A partially unsaturated carbocyclic group can be attached at any carbon atom, thereby forming a chemically stable structure. Non-limiting examples of partially unsaturated carbocyclic groups include .

[0039] As described herein, the various chemical groups present in the compounds of the present disclosure, such as any of the groups defined above, can be optionally substituted. In general, the term "substituted" means that one or more hydrogen atoms of the designated moiety are replaced by a suitable substituent. Unless otherwise indicated, a substituted chemical group can have a suitable substituent at each substitutable position of the group, and when more than one position can be substituted on any given structure, the substituent on each position can be the same or different. Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term "chemically stable" as used herein means a compound that does not undergo substantial modification while subjected to the conditions allowed for its production, detection, in certain embodiments, conditions allowed for its recovery, purification, and for use for one or more purposes disclosed herein.

[0040] In some particular embodiments, when any chemical group is substituted, it can be substituted by the independent substitution of one, two, or three or more hydrogen atoms with a substituent including, but not limited to, halogen (i.e., -F, -CI, -Br, -I), -OH, -CO2H, alkoxy (e.g., methoxy, ethoxy, or propoxy), -OCHF2, -OCH2CHF2, -OCH2CF3, -OCH2CH2OCH3, protected alkoxy, alkyl as defined above (e.g., methyl, ethyl, propyl, or -C(CH3)3), aryl as defined above (e.g., phenyl), cycloalkyl as defined above (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), oxo (=0), thioxo (=S), (=0), oxime (=N-OH), C1-C3alkoxyoxime (=N-OC1-C3alkyl), -NO2, -CN, -NH2, -NHMe, -NHEt, -N(Me)2, -NHCOMe, -NH(COO t Bu), -N(Et)(COO t Bus), protected amino, -CH2OH, -COOH, -COOMe, -COOEt, -COOEt, -CONH2, -CONHMe, -CONHEt, -CF3, -CHF2, -CH2F, -Si(Me), -OSi(Me)2( t Bu), -SMe, -SO2NH(CH2)3OH, -SO2Me, -SO2Ph, -SPh, pyrazolyl, pyrrolyl, pyridinyl, piperidinyl, triazolyl, tetrazolyl, morpholinyl, isoxazolyl, oxazolyl, thiazolyl, imidazolyl, benzothiazolyl, benzimidazolyl, 、

[0041] .

[0042] The phrase "pharmaceutically acceptable salt" means those salts of the compounds of the present specification that are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. Salts can be prepared in situ during the final isolation and purification of the compounds of the present specification, or separately by reacting the free base function of a compound with a suitable organic or inorganic acid (acid addition salt), or by reacting the acid function with a suitable organic or inorganic base (base addition salt). Examples of pharmaceutically acceptable salts include, but are not limited to, non-toxic acid addition salts or salts of base addition salts that are not biologically or otherwise undesirable. Acid addition salts include the salts of mineral acids (hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric) and the salts of organic acids (acetic, maleic, tartaric, citric, succinic, or malonic acid) or amino acids, or formed using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pantothenate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative base addition salt forms include alkali or alkaline earth salts, such as sodium, lithium, potassium, calcium, and magnesium, and other salts with amines.

[0043] The term "solvate" refers to a physical association between one or more solvent molecules and a compound of the present application. This physical association can occur intramolecularly or intermolecularly. In certain instances the solvate can be isolated. The term "solvate" encompasses both solution-phase and isolatable solvates. Exemplary solvates include, but are not limited to, hydrates, hemi-hydrates, ethanolates, hemi-ethanolates, n-propanolates, isopropanolates, 1-butanolates, 2-butanolates, and solvates of other physiologically acceptable solvents. The compounds described herein also encompass all solvate forms thereof and mixtures thereof.

[0044] The term "prodrug", as used herein, refers to those prodrugs of the compounds of the present specification which are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and effective for their intended therapeutic purpose. A "prodrug", as used herein, is intended to mean a compound that is convertible, in vivo, by metabolic means (e.g., hydrolysis) to any of the compounds of the general formula described herein. A variety of forms of prodrugs are known to those skilled in the art.

[0045] The compounds of the present application can be prepared by conventional chemical synthesis, for example, as illustrated in the general schemes provided below and in Examples 1 to 260. It will be appreciated by those skilled in the art that further methods of synthesizing the compounds of the general formulae herein will be readily apparent to those of ordinary skill in the art. Also, the various synthetic steps can be performed in an alternate sequence or order, and / or equivalent steps can be performed to those described herein. In addition, the solvents, temperatures, reaction durations, etc. described herein are chosen to be illustrative only and those of ordinary skill in the art will recognize that variations in reaction conditions can produce the desired products of the present specification. Synthetic chemistry transformations and / or protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known to those skilled in the art. The synthesized compounds can be isolated from the reaction mixture and further purified by column chromatography, high pressure liquid chromatography, or recrystallization, and the like standard methods.

[0046] The compounds described herein can be modified by the addition of various functional groups via synthetic means described herein to enhance their selective biological properties. Such modifications are well known in the art and include those that increase bio-penetrability into a particular biological system (e.g., blood, lymphatic system, central nervous system), increase oral bioavailability, improve solubility for administration by injection, alter metabolism, and alter rate of excretion.

[0047] Accordingly, in some embodiments, the present disclosure provides a compound of Formula (I), (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R a is -NH2, -NH-OH, -OH, -NHR b or -NR c R d ; R b is C1-C6 alkyl, C3-C6 cycloalkyl, or 3- to 6-membered heterocycloalkyl, wherein C1-C6 alkyl is optionally substituted with 1 to 3 halogen, 1 to 3 -OH, -OC1-C3 alkyl, -COOH, or cyclopropyl optionally substituted with -OH, wherein C3-C6 cycloalkyl is optionally substituted with -CN; R c and R d form a 4-membered heterocycloalkyl with the nitrogen to which they are attached, wherein the 4-membered heterocycloalkyl is optionally substituted with at least one of -OH and C1-C3 alkyl; denotes one of the following residues A0to A 12

[0048] or ; wherein: R is H, C1-C6 alkyl, or phenyl; R 1 and R 2 are each independently -CN, C6-C 10 aryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 14- membered heterocycloalkyl, 5- to 10-membered heteroaryl, -C(O)NH2, -C(O)NHR 5 , -C(O)R 6 , or -C(O)OR 5 , wherein each C1-C6 alkyl is optionally substituted with 1 to 3 R 7 substituents, each C6-C 10 aryl is optionally substituted with 1 to 3 R 8 substituents, each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R 22 substituents, with the proviso that when R a is -OH, denotes A0, and R 1 is then R 2 in residue A0is different from ; each R 5 is independently C1-C6 alkyl, wherein each C1-C6 alkyl is optionally substituted with 1 to 3 R 9 substituents; each R 6 is independently C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, or C6-C 10 aryl; each R 7 is independently -OH, -C(O)R 11 , C3-C6 cycloalkyl, -CN, C6-C 10 ​aryl, halogen, -C(0)OH, 5- to 10-membered heteroaryl, -NH(C(0)OCi-C6alkyl), -N(Ci-C4alkyl)(C(0)OCi-C6alkyl), 4- to 6-membered heterocycloalkyl, -NH(C(0)Ci-C6alkyl), -OR 20 , -SCi-C6alkyl, -NH2, -NH(Ci-C4alkyl), or -N(Ci-C4alkyl)2, wherein each C3-C6cycloalkyl is optionally substituted with 1 to 3 R 12 substituents, each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R 13 substituents, each 4- to 6-membered heterocycloalkyl is optionally substituted with Ci-C4alkyl or oxo; each R 8 is independently halogen, Ci-C6alkyl, -OCi-C6alkyl, C3-C6cycloalkyl, or 5- to 10-membered heteroaryl, wherein each -OCi-C6alkyl is optionally substituted with -OCi-C4alkyl, and each 5- to 10-membered heteroaryl is optionally substituted with Ci-C4alkyl; each R 22 is independently Ci-C6alkyl optionally substituted with phenyl; each R 9 is independently -OH, -C(0)R 15 , C3-C6cycloalkyl, -CN, C6-C 10 aryl, halogen, -C(0)OH, 4- to 6-membered heterocycloalkyl, -NH(C(0)Ci-C6alkyl), -OCi-C6alkyl, -SCi-C6alkyl, -NH2, -NH(Ci-C4alkyl), or -N(Ci-C4alkyl)2, wherein each 4- to 6-membered heterocycloalkyl is optionally substituted with Ci-C4alkyl, and each -OCi-C6alkyl is optionally substituted with -OCi-C4alkyl; each R 11 is independently -NH2, -NH(Ci-C4alkyl), -N(Ci-C4alkyl)2, or 4- to 6-membered heterocycloalkyl; each R 20 is independently Ci-C6alkyl or 5- to 10-membered heteroaryl, wherein each Ci-C6alkyl is optionally substituted with 1 to 3 R 14 substituents, and each 5- to 10-membered heteroaryl is optionally substituted with -OH or -NH(cyclopropyl); each R 12 is independently Ci-C4alkyl, -SCi-C4alkyl, -Ph, -OCi-C4alkyl, or -SPh, wherein each Ci-C4alkyl is optionally substituted with -OH; each R 13independently halogen, C1-C4alkyl, C3-C6cycloalkyl, -OH, -OC1-C6alkyl, -SC1-C6alkyl, -S(O)2C1-C6alkyl, -NH2, -NH(C1-C4alkyl), or -N(C1-C4alkyl)2, wherein each -OC1-C6alkyl, -SC1-C6alkyl, -S(O)2C1-C6alkyl, -NH(C1-C4alkyl), and -N(C1-C4alkyl)2is optionally substituted with one to three R 9 substituted with one to three R each R 14 is independently halogen, -OC1-C4alkyl, or C3-C6cycloalkyl; each R 15 is independently -NH2, -NH(C1-C4alkyl), -N(C1-C4alkyl)2, or 4- to 6- membered heterocycloalkyl; R 4 is C1-C6alkyl, C3-C8cycloalkyl, C6-C 10 aryl, 7- to 10-membered partially unsaturated heterocyclyl, or 5- to 10-membered heteroaryl, wherein C1-C6alkyl and C3-C8cycloalkyl are optionally substituted with one to three R 9 substituted, C6-C 10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one to three R 10 substituted, with the proviso that: (i) when R a is -OH, -NH2, or , and represents A2, then R 4 in residue A2is different from -CH3; and (ii) when R a is -NH2and represents A3, then R 4 in residue A3is different from -C(CH3)3; each R 10 is independently C1-C4alkyl, halogen, -OC1-C6alkyl, -NH2, -NH(C1-C4alkyl), or -N(C1-C4alkyl)2, wherein each C1-C4alkyl is optionally substituted with one to three halogens; R 2a is C1-C6alkyl, C3-C8cycloalkyl, or C6-C 10 aryl, wherein C1-C6alkyl and C3-C8cycloalkyl are optionally substituted with one to three R 9 substituted, C6-C 10 aryl is optionally substituted with one to three R 10 substituted; R 1a and R 2b each independently -CN, C6-C10 aryl, C1-C6alkyl, C3-C8cycloalkyl, -C(O)NH2, -C(O)NHR 5 or -C(O)OC1-C6alkyl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R 16 substituted, each C6-C 10 aryl is optionally substituted with 1 to 3 R 17 substituted; each R 16 is independently -OH, -C(O)NH2, -C(O)NH(C1-C4alkyl), C3-C6cycloalkyl, -CN, C6-C 10 aryl, halo, -C(O)OH, 5- to 10-membered heteroaryl, -NH(C(O)OC1-C6alkyl), 4- to 6-membered heterocycloalkyl, -NH(C(O)C1-C6alkyl), or -OC1-C4alkyl(OC1-C4alkyl), wherein each C3-C6cycloalkyl is optionally substituted with 1 to 3 R 18 substituted, each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R 21 substituted, each 4- to 6-membered heterocycloalkyl is optionally substituted with C1-C4alkyl; each R 17 is independently halo, C1-C6alkyl, -OC1-C6alkyl, or 5- to 10-membered heteroaryl, wherein each 5- to 10-membered heteroaryl is optionally substituted with C1-C4alkyl; each R 18 is independently C1-C4alkyl, -SC1-C4alkyl, -Ph, or -OC1-C4alkyl; each R 21 is independently halo or C1-C4alkyl; R 4a is C1-C6alkyl or C3-C8cycloalkyl, wherein each C1-C6alkyl and C3-C8cycloalkyl is optionally substituted with 1 to 3 R 19 substituted; each R 19 is independently halo, -OH, -OC1-C4alkyl, -SC1-C4alkyl, -NH2, -NH(C1-C4alkyl), or -N(C1-C4alkyl)2; R 1b and R 2c together with the carbon atom to which they are attached form a C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, 8- to 14-membered partially unsaturated heterocyclic group, or 8- to 14-membered partially unsaturated carbocyclic group, wherein the C3-C8cycloalkyl is optionally substituted with 1 to 3 R 9Substituent substitution, wherein a 4- to 14-membered heterocyclic alkyl group, an 8- to 14-membered partially unsaturated heterocyclic group, or an 8- to 14-membered partially unsaturated carbocyclic group is optionally substituted with an oxo (=O), an oxime (=N-OH), a C1-C3 alkoxy oxime (=N-OC1-C3 alkyl), or one to three substituents independently selected from -OH and -CF3; R 2d and R 4b Together with the carbon atoms they are attached to, they form C3-C8 cycloalkyl or 4- to 14-membered heterocycloalkyl, wherein the C3-C8 cycloalkyl is optionally surrounded by 1 to 3 R atoms. 19 Substituent substitution; R 1c and R 3 Together with the carbon atoms they are attached to, they form C3-C8 cycloalkyl or 4- to 14-membered heterocycloalkyl, wherein the C3-C8 cycloalkyl is optionally surrounded by 1 to 3 R atoms. 19 Substituent substitution.

[0049] In some embodiments, the compound of formula (I) is such that: (i) when R a It is -OH. Let A0 be an integer, and R be an integer. 1 yes When, then R in residue A0 2 Unlike (ii) When R a It is -OH and When A2 is represented, then R in residue A2 4 Unlike -CH3 and -CH2CH3; (iii) when R a It is -NH2, and When A2 is represented, then R in residue A2 4 Unlike -CH3; and (iv) when R a It is -NH2 and When A3 is represented, then the R in residue A3 4 Unlike -C(CH3)3.

[0050] In some embodiments, the compound of formula (I) is such that: (i) when R a It is -OH. Let A0 be an integer, and R be an integer. 1 yes When, then R in residue A0 2 Unlike (ii) When R a It is -OH and When A2 is represented, then R in residue A2 4 Unlike -CH3 and -CH2CH3; (iii) when R aIt is -NH2, and When A2 is represented, then R in residue A2 4 Unlike -CH3; (iv) when R a yes ,and When A2 is represented, then R in residue A2 4 Unlike -CH3; and (v) when R a It is -NH2 and When A3 is represented, then the R in residue A3 4 Unlike -C(CH3)3.

[0051] In other embodiments, the compound of formula (I) is such that: (i) when R a It is -OH. Let A0 be an integer, and R be an integer. 1 yes When, then R in residue A0 2 Unlike (ii) When R a It is -OH and When A2 is represented, then R in residue A2 4 Unlike alkyl groups; (iii) when R a It is -NH2 and When representing A2, R in residue A2 4 Unlike -CH3; and (iv) when R a It is -NH2 and When A3 is represented, then the R in residue A3 4 Unlike -C(CH3)3.

[0052] In other embodiments, the compound of formula (I) is such that: (i) when R a It is -OH. Let A0 be an integer, and R be an integer. 1 yes When, then R in residue A0 2 Unlike (ii) When R a It is -OH and When A2 is represented, then R in residue A2 4 Unlike alkyl groups; (iii) when R a It is -NH2, and When A2 is represented, then R in residue A2 4 Unlike -CH3; (iv) when R a yes and When A2 is represented, then R in residue A2 4 Unlike -CH3; and (v) when Ra is -NH2and represents A3, then R in residue A3 is 4 different from -C(CH3)3.

[0053] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is such that R is H.

[0054] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is such that R a is -NHR b and R b represents C1-C6 alkyl, C3-C6 cycloalkyl, or 3- to 6-membered heterocycloalkyl, wherein C1-C6 alkyl is optionally substituted with 1 to 3 halogen, 1 to 3 -OH, -OC1-C3 alkyl, -COOH, or cyclopropyl optionally substituted with -OH, wherein C3-C6 cycloalkyl is optionally substituted with -CN.

[0055] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is such that R a is -NHR b , and R b represents:

[0056] .

[0057] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is such that R a is -NHR b and R b represents: .

[0058] In some embodiments, R a is -NHR b and R b represents .

[0059] In other embodiments, R a is -NR c R d , R c and R d form a 4-membered heterocycloalkyl with the nitrogen to which they are attached, wherein the 4-membered heterocycloalkyl is optionally substituted with at least one of -OH and C1-C3 alkyl.

[0060] In other embodiments, R a is .

[0061] In other embodiments, R a is .

[0062] In other embodiments, R a is -OH In other embodiments, R a is NH2.

[0063] In other embodiments, R a is -NH-OH.

[0064] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, can be in the form of a racemate or any enantiomer thereof.

[0065] In some embodiments, the compound of formula (I) can have the following structure (la), (la'), (lb), (lb'), (lc), (lc'), (Id), (Id'), (le), (le'), (If), (If'), or (lg):

[0066]

[0067]

[0068] , wherein R 1 , R 2 , R 3 , R 4 , R 1a , R 1b , R 1c , R 2a , R 2b , R 2c , R 2d , R 4a , R 4b , R and R a are as defined herein.

[0069] Compounds of formula (Ia) and (Ia') In some embodiments, the compound is of formula (la) or (la'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0070]

[0071] group R, R a , R 1and R 2 may be as defined above for general formula (I).

[0072] In some embodiments, the compound is a compound of formula (Ia), or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0073]

[0074] the group R a , R 1 and R 2 may be as defined above for general formula (I).

[0075] In some embodiments, R 1 and R 2 may independently represent -CN, C6-C 10 aryl, C1-C6alkyl, C2-C6alkynyl, C3-C8cycloalkyl, 5- to 10-membered heteroaryl, -C(O)NH2, -C(O)NHR 5 , -C(O)R 6 or -C(O)OR 5 , wherein each C1-C6alkyl is optionally substituted with 1 to 3 R 7 substituents, each C6-C 10 aryl is optionally substituted with 1 to 3 R 8 substituents, each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R 22 substituents, and R 5 , R 6 , R 7 , R 8 and R 22 are as defined herein.

[0076] In some embodiments, R 1 and R 2 are independently -CN, C6-C 10 aryl, C1-C6alkyl, C2-C6alkynyl, C3-C8cycloalkyl, 5- to 10-membered heteroaryl, or -C(O)NH2, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R 7 substituents, each C6-C 10 aryl is optionally substituted with 1 to 3 R 8 substituents, each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R 22 substituents, and R 7 , R 8 and R 22 are as defined herein.

[0077] In further embodiments, R 1 and R2 may independently represent -CN, phenyl, C1-C4alkyl, C2-C4alkynyl, C3-C6cycloalkyl, 5-membered heteroaryl, or -C(O)NH2, wherein each C1-C4alkyl is optionally substituted with 1 or 2 R 7 substituents, each phenyl is optionally substituted with 1 or 2 halo, and each 5-membered heteroaryl is optionally substituted with 1 or 2 -CH3.

[0078] According to some embodiments, R 1 and R 2 independently represent -CN, C6-C 10 aryl, C1-C6alkyl, C3-C8cycloalkyl, or -C(O)NH2, wherein each C1-C6alkyl is optionally substituted with 1 to 2 R 7 substituents as defined herein.

[0079] In some embodiments, when R 1 and / or R 2 represent -C(O)NHR 5 or -C(O)OR 5 , each R 5 may be C1-C6alkyl. In other embodiments, when R 1 and / or R 2 represent -C(O)R 6 , each R 6 may be 4 to 6 membered heterocycloalkyl.

[0080] In some embodiments, when R 1 and / or R 2 represent C1-C6alkyl substituted with 1 to 3 R 7 substituents, then each R 7 may independently represent -OH, -C(O)R 11 , C3-C6cycloalkyl, -CN, C6-C 10 aryl, halo, -C(O)OH, 5 to 10 membered heteroaryl, -NH(C(O)OC1-C6alkyl), -N(C1-C4alkyl)(C(O)OC1-C6alkyl), -NH(C(O)C1-C6alkyl), 4 to 6 membered heterocycloalkyl, -OR 20 , -SC1-C6alkyl, -NH2, or -N(C1-C4alkyl)2, wherein each C3-C6cycloalkyl is optionally substituted with 1 to 3 R 12 substituents, each 5 to 10 membered heteroaryl is optionally substituted with 1 to 3 R 13 substituents, and each 4 to 6 membered heterocycloalkyl is optionally substituted with C1-C4alkyl or oxo.

[0081] In some embodiments, R 7Can be used independently to represent -OH, -C(O)R 11 -OR 20 C3-C6 cycloalkyl, -CN, C6-C 10 aryl, halogen, -C(O)OH or 5 to 10 heteroaryl, wherein each C3-C6 cycloalkyl group is optionally surrounded by 1 to 3 R groups. 12 Substituents, each of 5 to 10 heteroaryl groups, are optionally replaced by 1 to 3 R groups. 13 Substituent substitution.

[0082] In a further embodiment, R 7 It can independently represent -OH, -C(O)NH2, and -OR. 20 C3-C6 cycloalkyl, -CN, phenyl, halogen, -C(O)OH or 5-membered heteroaryl, wherein each C3-C6 cycloalkyl group is optionally substituted with -CH3.

[0083] In other embodiments, R 7 It can independently represent -OH, -C(O)NH2, C3-C6 cycloalkyl, -CN, C6-C 10 Aryl, halogen, or 5- to 8-membered heteroaryl, wherein each C3-C6 cycloalkyl group is optionally substituted with 1 to 2 C1-C4 alkyl groups, and each 5- to 8-membered heteroaryl group is optionally substituted with 1 to 2 R groups. 13 Substituent substitution.

[0084] In some implementations, the above-mentioned R 11 Substituents can independently represent -NH2, -NH (C1-C4 alkyl), or 4- to 6-membered heterocyclic alkyl groups. In some specific embodiments, R 11 It can represent -NH2.

[0085] In some implementations, the above-mentioned R 12 The substituents can independently represent C1-C4 alkyl, -SC1-C4 alkyl, -Ph, -OC1-C4 alkyl, or -SPh, wherein each C1-C4 alkyl group is optionally substituted with -OH. In some specific embodiments, R 12 It is a C1-C4 alkyl group.

[0086] In some implementations, the above-mentioned R 13 Substituents can independently represent halogens, C1-C4 alkyl groups, or C3-C6 cycloalkyl groups. In some specific embodiments, R 13 It is independently a halogen or a C1-C4 alkyl group.

[0087] In some implementations, the above-mentioned R 14 Substituents can independently represent halogens, -OC1-C4 alkyl groups, or C3-C6 cycloalkyl groups. In some specific embodiments, R 14is halogen.

[0088] In some embodiments, R 20 substituted, each C1-C6alkyl is optionally substituted with 1 to 3 instances of R 14 substituted, each 5- to 10-membered heteroaryl is optionally substituted with -OH or -NH(cyclopropyl). In some specific embodiments, R 20 is C1-C6alkyl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 instances of R 14 substituted. In further embodiments, R 20 is C1-C6alkyl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 instances of halogen. In some embodiments, R 20 is 5- to 10-membered heteroaryl substituted with -OH or -NH(cyclopropyl). In some embodiments, R 20 is 5- to 10-membered heteroaryl substituted with -OH. In other embodiments, R 20 is 5- or 6-membered heteroaryl substituted with -OH.

[0089] In some embodiments, R 22 substituted, each C1-C4alkyl is optionally substituted with 1 to 3 instances of R

[0090] In some embodiments, when R 1 and / or R 2 represents C6-C 8 aryl substituted with 1 to 3 instances of R 10 substituted, each R 8 may independently represent halogen, C1-C6alkyl, or -OC1-C6alkyl, wherein each -OC1-C6alkyl is optionally substituted with -OC1-C4alkyl. In some specific embodiments, R 8 is halogen. In some embodiments, when R 1 and / or R 2 represents 5- to 10-membered heteroaryl substituted with 1 to 3 instances of R 22 substituted, each R 22 may independently represent C1-C6alkyl optionally substituted with phenyl. In some embodiments, R 22 is C1-C2alkyl substituted with phenyl.

[0091] In some embodiments, R 1 and R 2 are each independently -CN, C6-C 10aryl, C1-C6alkyl, C2-C6alkynyl, C3-C8cycloalkyl, 5- to 10-membered heteroaryl, -C(O)NH2, -C(O)NHR 5 , -C(O)R 6 , or -C(O)OR 5 , wherein each C1-C6alkyl is optionally substituted with 1 to 3 R 7 substituents, each C6-C 10 aryl is optionally substituted with 1 to 3 R 8 substituents, each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R 22 substituents, each R 5 is independently C1-C6alkyl; each R 6 is independently 4- to 6-membered heterocycloalkyl; each R 7 is independently -OH, -C(O)R 11 , C3-C6cycloalkyl, -CN, C6-C 10 aryl, halogen, -C(O)OH, 5- to 10-membered heteroaryl, -NH(C(O)OC1-C6alkyl), -N(C1-C4alkyl)(C(O)OC1-C6alkyl), 4- to 6-membered heterocycloalkyl, -NH(C(O)C1-C6alkyl), -OR 20 , -SC1-C6alkyl, -NH2, or -N(C1-C4alkyl)2, wherein each C3-C6cycloalkyl is optionally substituted with 1 to 3 R 12 substituents, each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R 13 substituents, and each 4- to 6-membered heterocycloalkyl is optionally substituted with C1-C4alkyl or oxo; each R 8 is independently halogen, C1-C6alkyl, or -OC1-C6alkyl, wherein each -OC1-C6alkyl is optionally substituted with -OC1-C4alkyl; each R 22 is independently C1-C6alkyl optionally substituted with phenyl; each R 11 is independently -NH2, -NH(C1-C4alkyl), or 4- to 6-membered heterocycloalkyl; each R 20 is independently C1-C6alkyl or 5- to 10-membered heteroaryl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R 14 substituents, and each 5- to 10-membered heteroaryl is optionally substituted with -OH or -NH(cyclopropyl); each R 12independently -OH, -C(O)R each R 13 is independently halogen, -OC1-C4alkyl, or C3-C6cycloalkyl. each R 14 is independently halogen, -OC1-C4alkyl, or C3-C6cycloalkyl.

[0092] in some embodiments, R 1 and R 2 is independently -CN, C6-C 10 aryl, C1-C6alkyl, C2-C6alkynyl, C3-C8cycloalkyl, 5- to 10-membered heteroaryl, or -C(O)NH2, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R 7 substituents, each C6-C 10 aryl is optionally substituted with 1 to 3 R 8 substituents, each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R 22 substituents, each R 7 is independently -OH, -C(O)R 11 , C3-C6cycloalkyl, -CN, C6-C 10 aryl, halogen, -C(O)OH, 5- to 10-membered heteroaryl, -NH(C(O)OC1-C6alkyl), -N(C1-C4alkyl)(C(O)OC1-C6alkyl), -NH(C(O)C1-C6alkyl), 4- to 6-membered heterocycloalkyl, -OR 20 , -SC1-C6alkyl, -NH2, or -N(C1-C4alkyl)2, wherein each C3-C6cycloalkyl is optionally substituted with 1 to 3 R 12 substituents, each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R 13 substituents, each 4- to 6-membered heterocycloalkyl is optionally substituted with C1-C4alkyl or oxo; each R 8 is independently halogen, C1-C6alkyl, or -OC1-C6alkyl, wherein each -OC1-C6alkyl is optionally substituted with -OC1-C4alkyl; each R 11 is independently -NH2, -NH(C1-C4alkyl), or 4- to 6-membered heterocycloalkyl. each R 20 is independently C1-C6alkyl or 5- to 10-membered heteroaryl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R 14each 5- or 6-membered heteroaryl is optionally substituted with 1 to 3 Rsubstituents, each Rsubstituent is -OH, -NH2, -SCi-C4alkyl, -Ph, -OCi-C4alkyl, or -SPh, wherein each Ci-C4alkyl is optionally substituted with -OH; each R 12 is independently Ci-C4alkyl, -SCi-C4alkyl, -Ph, -OCi-C4alkyl, or -SPh, wherein each Ci-C4alkyl is optionally substituted with -OH; each R 13 is independently halogen, Ci-C4alkyl, or C3-C6cycloalkyl; each R 14 is independently halogen, -OCi-C4alkyl, or C3-C6cycloalkyl; each R 22 is independently Ci-C4alkyl.

[0093] In some embodiments, R 1 and R 2 are independently -CN, C6-C 10 aryl, Ci-C6alkyl, C2-C6alkynyl, C3-C8cycloalkyl, 5- to 10-membered heteroaryl, or -C(O)NH2, wherein each Ci-C6alkyl is optionally substituted with 1 to 3 R 7 substituents, each C6-C 10 aryl is optionally substituted with 1 to 3 R 8 substituents, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R 22 substituents, each R 7 is independently -OH, -C(O)R 11 , -OR 20 , C3-C6cycloalkyl, -CN, C6-C 10 aryl, halogen, -C(O)OH, or 5- to 10-membered heteroaryl, wherein each C3-C6cycloalkyl is optionally substituted with 1 to 3 R 12 substituents, each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R 13 substituents; each R 8 is halogen; each R 11 is -NH2; each R 20 is Ci-C6alkyl or 5- or 6-membered heteroaryl, wherein each Ci-C6alkyl is optionally substituted with 1 to 3 R 14 substituents, each 5- or 6-membered heteroaryl is optionally substituted with -OH or -NH(cyclopropyl); each R 12 is Ci-C4alkyl; each R 13 is independently halogen or Ci-C4alkyl; each R14 is halogen; each R 22 independently is C1-C4 alkyl.

[0094] In some embodiments, R 1 and R 2 independently represent -CN, phenyl, C1-C4 alkyl, C2-C4 alkynyl, C3-C6 cycloalkyl, 5-membered heteroaryl, or -C(O)NH2, wherein each C1-C4 alkyl is optionally substituted with 1 or 2 R 7 substituents, each phenyl is optionally substituted with 1 or 2 halogen, each 5-membered heteroaryl is optionally substituted with 1 or 2 -CH3, each R 7 independently is -OH, -C(O)NH2, -OR 20 , C3-C6 cycloalkyl, -CN, phenyl, halogen, -C(O)OH, or 5-membered heteroaryl, wherein each C3-C6 cycloalkyl is optionally substituted with -CH3; each R 20 is C1-C6 alkyl or 5 or 6 membered heteroaryl, wherein each C1-C6 alkyl is optionally substituted with 1 to 3 halogen, each 5 or 6 membered heteroaryl is optionally substituted with -OH.

[0095] In some embodiments, R 1 and R 2 independently represent -CN, C6-C 10 aryl, C1-C6 alkyl, C3-C8 cycloalkyl, 5-membered heteroaryl, or -C(O)NH2, wherein each C1-C6 alkyl is optionally substituted with 1 to 2 R 7 substituents; each R 7 independently is -OH, -C(O)NH2, C3-C6 cycloalkyl, -CN, C6-C 10 aryl, halogen, or 5 to 8 membered heteroaryl, wherein each C3-C6 cycloalkyl is optionally substituted with 1 to 2 C1-C4 alkyl, each 5 to 8 membered heteroaryl is optionally substituted with 1 to 2 R 13 substituents; and each R 13 independently is halogen or C1-C4 alkyl.

[0096] In some embodiments, R 1 and R 2 may be the same or different and can represent:

[0097]

[0098] .

[0099] In some embodiments, R 1 and R 2 may be the same or different and can represent:

[0100]

[0101]

[0102] .

[0103] In some embodiments, R 1 and R 2 may be the same or different and can represent:

[0104]

[0105]

[0106] .

[0107] In some embodiments, R 1 and R 2 may be the same or different and can represent:

[0108]

[0109]

[0110] .

[0111] In some embodiments, R 1 and R 2 may be the same or different and can represent:

[0112]

[0113]

[0114] or .

[0115] In some embodiments, R 1 and R 2 may be the same or different and can represent:

[0116]

[0117]

[0118] or .

[0119] In some embodiments, R 1 and R 2 may be the same or different and can represent:

[0120]

[0121] .

[0122] In some embodiments, R 1 and R 2 may be the same or different and can represent:

[0123]

[0124] .

[0125] In some embodiments, R 1 and R 2 may be the same or different and can represent:

[0126]

[0127] .

[0128] In some embodiments, R 1 and R 2 may be the same or different and can represent:

[0129]

[0130] .

[0131] In some embodiments, R 1 and R 2 may be the same or different and can represent:

[0132] In some specific embodiments, R 1 and R 2In another particular embodiment, R 1 and one of R 2 is -CN. Other embodiments include a compound of Formula (Ia) or (Ia'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 1 and one of R 2 is .

[0133] Compounds of formula (Ib) and (Ib') In some embodiments, the compound is a compound of Formula (Ib) or (Ib'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0134]

[0135] The groups R, R a and R 4 may be as defined above for general Formula (I).

[0136] In some embodiments, the compound is a compound of Formula (Ib), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0137]

[0138] The groups R a and R 4 may be as defined above for general Formula (I).

[0139] In some embodiments, R 4 may represent C1-C6 alkyl, C6-C 10 aryl, 7- to 10-membered partially unsaturated heterocyclyl, or 5- to 10-membered heteroaryl, wherein C1-C6 alkyl is optionally substituted with 1 to 3 R 9 substituents, C6-C 10 aryl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 R 10 substituents, wherein R 9 and R 10 are as defined herein.

[0140] In some embodiments, R 4 may represent C1-C6 alkyl, C6-C 10 aryl, 7- to 10-membered partially unsaturated heterocyclyl, or 5- to 10-membered heteroaryl, wherein C6-C 10 aryl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 R 10 substituents, wherein R 10 substituents are as defined herein.

[0141] In some embodiments, R4 It can represent C1-C4 alkyl, phenyl, 9-membered partially unsaturated heterocyclic group or 5- to 6-membered heteroaryl, wherein the phenyl and 5- to 6-membered heteroaryl are optionally surrounded by 1 or 2 R groups. 10 Substituent substitution, where R 10 Substituents are as defined in this article.

[0142] In some implementations, R 10 The substituents may independently represent C1-C4 alkyl, halogen, -OC1-C6 alkyl, -NH2, -NH(C1-C4 alkyl)2 or -N(C1-C4 alkyl)2, wherein each C1-C4 alkyl group is optionally substituted with 1 to 3 halogens.

[0143] In other embodiments, R 10 Substituents may independently represent C1-C4 alkyl, halogen, -OC1-C6 alkyl or -N(C1-C4 alkyl)2, wherein each C1-C4 alkyl may optionally be substituted with 1 to 3 halogens.

[0144] In a further embodiment, R 10 Substituents can be independently represented as -CF3, halogen, -OCH3, or -N(CH3)2.

[0145] In some implementations, R 4 It is a C1-C6 alkyl, C6-C 10 aryl, 7- to 10-membered partially unsaturated heterocyclic groups, or 5- to 10-membered heteroaryl, wherein C6-C 10 Aryl and 5 to 10 heteroaryl groups are optionally bounded by 1 to 3 R groups. 10 Substituent substitution, Each R 10 Independently, it is a C1-C4 alkyl, halogen, -OC1-C6 alkyl, -NH2, -NH(C1-C4 alkyl)2 or -N(C1-C4 alkyl)2, wherein each C1-C4 alkyl is optionally substituted with 1 to 3 halogens.

[0146] In some implementations, R 4 It is a C1-C6 alkyl, C6-C 10 aryl, 7- to 10-membered partially unsaturated heterocyclic groups, or 5- to 10-membered heteroaryl, wherein C6-C 10 Aryl and 5 to 10 heteroaryl groups are optionally bounded by 1 to 3 R groups. 10 Substituent substitution, Each R 10 Independently, it is a C1-C4 alkyl, halogen, -OC1-C6 alkyl or -N(C1-C4 alkyl)2, wherein each C1-C4 alkyl is optionally substituted with 1 to 3 halogens.

[0147] In some implementations, R4 is C1-C4 alkyl, phenyl, a 9-membered partially unsaturated heterocyclic group, or a 5- to 6-membered heteroaryl group, wherein phenyl and 5- to 6-membered heteroaryl are optionally substituted with 1 or 2 R 10 substituents, each R 10 is independently -CF3, halogen, -OCH3, or -N(CH3)2.

[0148] Specific R 4 Examples of R

[0149] .

[0150] Compounds of formula (Ic) and (Ic') In some embodiments, the compound is a compound of Formula (Ic) or (Ic), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0151]

[0152] The groups R, R a and R 2a may be as defined above for general Formula (I).

[0153] In some embodiments, the compound is a compound of Formula (Ic), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0154]

[0155] The groups R a and R 2a may be as defined above for general Formula (I).

[0156] In some embodiments, R 2a may represent C1-C6 alkyl or C6-C 10 aryl, wherein C1-C6 alkyl is optionally substituted with 1 to 3 R 9 substituents, C6-C 10 aryl is optionally substituted with 1 to 3 R 10 substituents, R 9 and R 10 are as defined herein.

[0157] In some embodiments, R 2a may represent C1-C6 alkyl or C6-C 10 aryl, wherein C1-C6 alkyl is optionally substituted with 1 to 3 halogen.

[0158] In some embodiments, R 2aIt is a C1-C6 alkyl group, such as a C1-C4 alkyl group or preferably an ethyl group.

[0159] Compounds of formula (Id) and (Id') In some embodiments, the compound is a compound of formula (Id) or (Id'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0160]

[0161] Groups R, R a R 1a R 2b and R 4a It can be defined as above for general formula (I).

[0162] In some embodiments, the compound is a compound of formula (Id), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0163]

[0164] Group R a R 1a R 2b and R 4a It can be defined as above for general formula (I).

[0165] In some implementations, R 1a and R 2b It can independently represent -CN, C6-C 10 aryl, C1-C6 alkyl, C3-C8 cycloalkyl or -C(O)NH2, wherein each C1-C6 alkyl group is optionally surrounded by one or two R groups as defined herein. 16 Substituent substitution.

[0166] In some implementations, R 1a and R 2b It can be represented independently as -CN or C6-C. 10 Aryl.

[0167] In some implementations, R 4a It can represent C1-C6 alkyl groups.

[0168] In some implementations, the substituent R 16 It can independently represent -OH, -C(O)NH2, C3-C6 cycloalkyl, -CN, C6-C 10 Aryl, halogen, or 5- to 8-membered heteroaryl groups, wherein each C3-C6 cycloalkyl group is optionally substituted with 1 to 2 C1-C4 alkyl groups, and each 5- to 10-membered heteroaryl group is optionally substituted with 1 to 2 R groups as defined herein. 21 Substituent substitution.

[0169] In some embodiments, each R 21 may independently represent halogen or C1-C4 alkyl.

[0170] In some embodiments, R 1a and R 2b are independently -CN, C6-C 10 aryl, C1-C6 alkyl, C3-C8 cycloalkyl, or -C(O)NH2, wherein each C1-C6 alkyl is optionally substituted with 1 to 2 R 16 substituents; each R 16 is independently -OH, -C(O)NH2, C3-C6 cycloalkyl, -CN, C6-C 10 aryl, halogen, or 5- to 8-membered heteroaryl, wherein each C3-C6 cycloalkyl is optionally substituted with 1 to 2 C1-C4 alkyl, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 2 R 21 substituents; each R 21 is independently halogen or C1-C4 alkyl.

[0171] Compounds of formula (Ie) and (Ie') In some embodiments, the compound is a compound of Formula (Ie) or (Ie’), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0172]

[0173] groups R, R a , R 1b , and R 2c may be as defined above for general Formula (I).

[0174] In some embodiments, the compound is of Formula (Ie), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0175]

[0176] groups R a , R 1b , and R 2c may be as defined above for general Formula (I).

[0177] In some embodiments, R 1b and R 2cmay form together with the carbon atom to which they are attached a C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, 8- to 14-membered partially unsaturated heterocyclyl or 8- to 14-membered partially unsaturated carbocyclyl, wherein each 4- to 14-membered heterocycloalkyl, 8- to 14-membered partially unsaturated heterocyclyl or 8- to 14-membered partially unsaturated carbocyclyl is optionally substituted with oxo (=0), oxime (=N-OH), methoxyoxime (=N-OMe), or 1 to 3 substituents independently selected from -OH and -CF3.

[0178] In some embodiments, R 1b and R 2c may form together with the carbon atom to which they are attached a C3-C8cycloalkyl or 8- to 10-membered partially unsaturated carbocyclyl, wherein the 8- to 10-membered partially unsaturated carbocyclyl is optionally substituted with oxo (=0), oxime (=N-OH), methoxyoxime (=N-OCH3) or 1 to 2 substituents independently selected from -OH and -CF3.

[0179] In some embodiments, R 1b and R 2c may form together with the carbon atom to which they are attached a C4-C6cycloalkyl or a group selected from wherein the dotted line indicates that the cyclohexanone unit of the compound of formula (Ie) or (Ie') carries the moiety R 1b and R 2c .

[0180] In some embodiments, R 1b and R 2c may form together with the carbon atom to which they are attached a cyclopentyl group, or a group selected from wherein the dotted line indicates that the cyclohexanone unit of the compound of formula (Ie) or (Ie') carries the moiety R 1b and R 2c .

[0181] In some embodiments, R 1b and R 2c may form together with the carbon atom to which they are attached a group selected from wherein the dotted line indicates that the cyclohexanone unit of the compound of formula (Ie) or (Ie') carries the moiety R 1b and R 2c .

[0182] In some embodiments, R 1b and R 2c may form together with the carbon atom to which they are attached a cyclopentyl group.

[0183] Compounds of formula (If) and (If') In some embodiments, the compound is a compound of Formula (If) or (If), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0184]

[0185] The groups R, R a , R 2d , and R 4b may be as defined above for general Formula (I).

[0186] In some embodiments, the compound is a compound of Formula (If), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0187]

[0188] The groups R a , R 2d , and R 4b may be as defined above for general Formula (I).

[0189] In some embodiments, R 2d and R 4b may be taken together with the carbon atom to which they are attached to form a C3-C8 cycloalkyl, wherein each C3-C8 cycloalkyl is optionally substituted with 1 to 3 R 19 substituents as defined herein.

[0190] In some embodiments, R 2d and R 4b may be taken together with the carbon atom to which they are attached to form a C3-C8 cycloalkyl.

[0191] In some embodiments, R 2d and R 4b may be taken together with the carbon atom to which they are attached to form a cyclohexyl.

[0192] Compounds of formula (Ig) In some embodiments, the compound is a compound of Formula (Ig), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0193]

[0194] The groups R a , R 1c , and R 3 may be as defined above for general Formula (I).

[0195] In some embodiments, R 1c and R3 may form, together with the carbon atom to which they are attached, a C3-C8cycloalkyl group, wherein each C3-C8cycloalkyl is optionally substituted with 1 to 3 R 19 substituted.

[0196] In some embodiments, R 1c and R 3 may form, together with the carbon atom to which they are attached, a C3-C8cycloalkyl group.

[0197] In some embodiments, R 1c and R 3 may form, together with the carbon atom to which they are attached, a cyclohexyl group.

[0198] In some embodiments, the compound of Formula (I) described herein can be selected from compounds 4, 8, 9, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 47, 48, 49, 50, 51, 52, 53, 54, 59, 60a, 60b, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 75, 81, 82, 83, 84, 89, 91, 97, 101, 108, 109, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 154, 155, 163, 168, 169, 170, 173, 174, 175, 178, 179, 180, 181, 183, 189, 190, 191, 192, 193, 194, 195, 197, 198, 199, 200, 201, 202, 211, 212, 213, 214, 215, 216, 219, 221, 227, 228, 229, 230, 231, 232, 237, 238, 239, 245, 246, 247, 248, 249, 250, 251, 253, 254, 255, 257, 258, 263, 264, 271, 272, 273, 278, 279, 280, 281, 287, 288, 290, 291, 297, 298, 305, 306, 313, 314, 321, 322, 330, 331, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 352, 353, 354, 355, 356, 357, 358, 360, 362, 371, 378, 391, 392, 393, 394a, 394b, 395a, 395b, 396, 397, 401, 402, 403, 406, 407, 408, 412, 413, 414, 416, 418, 422, 427, 428, 429, 430, 431, 433, 434, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 462, 463, 464, 465, 466, 468, 469, 470, 471, 472, 473, 474, 475, 476, 478, 479, 480, 481, 482, 483, 486 of Table 1, below.488, 489, 492, 495, 496, 497, 498, 511, 512, 513, 514, 515, 520, 523, 524, and 534, or can be any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0199] Table 1

[0200] In some embodiments, the compound of Formula (I) described herein is Compound 4, 9, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 47, 48, 49, 50, 51, 52, 53, 54, 59, 60a, 60b, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 75, 81, 82, 83, 84, 89, 91, 97, 101, 109, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 155, 163, 168, 169, 170, 173, 174, 175, 179, 180, 181, 183, 189, 191, 192, 193, 194, 195, 197, 198, 199, 200, 201, 202, 211, 212, 213, 214, 215, 216, 219, 221, 228, 229, 230, 231, 232, 237, 238, 239, 246, 247, 248, 249, 250, 251, 253, 254, 255, 258, 263, 264, 271, 272, 273, 278, 279, 280, 281, 287, 288, 291, 297, 298, 305, 306, 313, 314, 321, 322, 331, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 352, 353, 354, 355, 356, 357, or 358 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0201] In some embodiments, the compound of Formula (I) described herein is Compound 4, 9, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 47, 48, 49, 50, 51, 52, 53, 54, 59, 60b, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 75, 81, 82, 83, 84, 89, 91, 97, 101, 109, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 138, 139, 140, 141, 143, 144, 145, 146, 147, 148, 149, 150, 155, 163, 168, 169, 170, 173, 174, 175, 179, 180, 181, 183, 189, 191, 192, 193, 194, 195, 198, 199, 200, 201, 202, 211, 212, 213, 214, 215, 216, 219, 228, 230, 231, 232, 237, 238, 239, 246, 247, 248, 249, 250, 251, 253, 254, 255, 258, 263, 264, 271, 272, 273, 278, 279, 280, 281, 287, 288, 291, 297, 298, 305, 306, 313, 314, 321, 322, 331, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 352, 353, 354, 355, 356, 357, or 358 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0202] In some embodiments, the compound of Formula (I) described herein is Compound 4, 9, 15, 16, 17, 18, 19, 20, 21, 22, 24, 25, 26, 27, 29, 30, 31, 32, 33, 34, 36, 37, 38, 39, 47, 48, 49, 50, 51, 52, 53, 54, 59, 60b, 61, 62, 63, 64, 65, 66, 67, 68, 71, 72, 75, 81, 82, 83, 84, 89, 91, 97, 101, 109, 119, 120, 121, 122, 123, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 138, 139, 140, 141, 143, 144, 145, 146, 147, 148, 149, 150, 155, 163, 168, 169, 170, 173, 174, 175, 179, 180, 181, 183, 189, 191, 192, 194, 195, 198, 199, 201, 202, 212, 213, 214, 215, 216, 228, 230, 231, 232, 237, 238, 239, 246, 248, 249, 250, 251, 253, 254, 255, 258, 263, 264, 271, 272, 273, 278, 279, 280, 281, 287, 288, 291, 297, 298, 305, 306, 313, 314, 321, 322, 331, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 352, 353, 354, 355, 356, 357, or 358 of Table 1, or any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0203] In some embodiments, the compound of Formula (I) described herein is Compound 4, 9, 15, 16, 17, 18, 19, 20, 21, 22, 24, 25, 26, 27, 29, 30, 31, 32, 33, 34, 36, 37, 38, 39, 47, 48, 49, 50, 51, 52, 53, 54, 59, 60b, 61, 62, 63, 64, 65, 66, 67, 68, 71, 72, 75, 81, 82, 83, 84, 89, 91, 97, 101, 109, 119, 120, 121, 122, 123, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 138, 139, 140, 141, 143, 144, 145, 146, 147, 148, 149, 150, 155, 163, 168, 169, 170, 173, 174, 175, 179, 180, 181, 183, 189, 191, 192, 194, 195, 198, 199, 201, 202, 212, 213, 214, 215, 216, 228, 230, 231, 232, 237, 238, 239, 245, 246, 248, 249, 250, 251, 253, 254, 255, 258, 263, 264, 271, 272, 273, 278, 279, 280, 281, 287, 288, 291, 297, 298, 305, 306, 313, 314, 321, 322, 331, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 352, 353, 354, 355, 356, 357, 358, 391, 392, 393, 394a, 394b, 395a, 395b, 396, 397, 401, 402, 403, 406, 407, 408, 413, 414, 416, 418, 422, 427, 428, 429, 430, 431, 434, 445, 446, 447, 448, 449, 450, 451, 453, 454, 462, 463, 464, 465, 466, 468, 470, 472, 474, 475, 476, 478, 479, 480, 481, 482, 486, 489, 492, 495, 496, 498, 511, 512, 513, 514, 515, 520, or 524 of Table 1, or any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0204] In some embodiments, the compound of Formula (I) described herein is Compound 4, 15, 16, 17, 20, 24, 25, 26, 27, 29, 30, 31, 32, 33, 34, 36, 37, 47, 48, 49, 50, 51, 52, 53, 54, 59, 60b, 61, 62, 63, 64, 65, 66, 67, 71, 72, 75, 81, 82, 83, 84, 89, 91, 97, 101, 109, 119, 120, 121, 122, 123, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 138, 139, 140, 141, 143, 144, 145, 146, 147, 148, 149, 150, 155, 163, 168, 169, 170, 173, 174, 175, 179, 180, 181, 183, 191, 192, 194, 195, 198, 199, 201, 202, 212, 213, 214, 215, 216, 228, 230, 231, 232, 237, 238, 239, 246, 248, 250, 251, 253, 254, 255, 258, 263, 264, 271, 272, 273, 278, 279, 280, 281, 287, 288, 291, 298, 305, 306, 313, 314, 321, 322, 331, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 352, 353, 354, 355, 356, 357, 358, 391, 392, 393, 394a, 394b, 395a, 395b, 396, 397, 401, 402, 403, 406, 407, 408, 413, 414, 416, 418, 422, 428, 429, 430, 431, 434, 445, 446, 447, 448, 449, 450, 451, 453, 454, 462, 463, 464, 465, 466, 468, 470, 472, 474, 475, 476, 479, 480, 481, 482, 486, 489, 495, 496, 498, 511, 512, 513, 514, 515, 520, or 524 of Table 1, or any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0205] In some embodiments, the compound of Formula (I) described herein is Compound 4, 15, 16, 20, 25, 26, 29, 30, 31, 32, 33, 34, 37, 47, 48, 49, 50, 51, 52, 54, 59, 60b, 61, 62, 63, 64, 65, 72, 75, 82, 83, 84, 89, 91, 97, 101, 109, 119, 121, 123, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 138, 139, 140, 141, 143, 144, 145, 146, 147, 148, 149, 150, 155, 163, 168, 169, 170, 173, 174, 175, 179, 180, 181, 183, 191, 192, 194, 195, 201, 212, 213, 214, 215, 216, 230, 231, 232, 238, 239, 246, 248, 250, 251, 253, 254, 255, 258, 263, 264, 271, 272, 273, 278, 279, 280, 281, 288, 291, 298, 305, 306, 313, 314, 321, 322, 331, 338, 339, 340, 341, 342, 343, 344, 345, 346, 352, 353, 354, 355, 356, 358, 391, 392, 393, 394a, 394b, 395a, 395b, 396, 397, 401, 402, 403, 406, 407, 408, 413, 414, 416, 418, 422, 428, 429, 430, 431, 434, 445, 446, 447, 448, 449, 450, 451, 453, 454, 462, 463, 464, 465, 466, 468, 470, 472, 474, 475, 476, 479, 480, 481, 482, 486, 489, 495, 496, 498, 511, 512, 513, 514, 515, 520, or 524 of Table 1, or any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0206] In some embodiments, the compound of Formula (I) described herein is Compound 4, 15, 16, 20, 25, 26, 29, 30, 31, 32, 33, 34, 37, 47, 48, 49, 50, 51, 52, 54, 59, 60b, 61, 62, 63, 64, 65, 72, 75, 82, 83, 84, 89, 91, 97, 101, 109, 119, 121, 123, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 138, 139, 140, 141, 143, 144, 145, 146, 147, 148, 149, 150, 155, 163, 168, 169, 170, 173, 174, 175, 179, 180, 181, 183, 191, 192, 194, 195, 201, 212, 213, 214, 215, 216, 230, 231, 232, 238, 239, 245, 246, 248, 250, 251, 253, 254, 255, 258, 263, 264, 271, 272, 273, 278, 279, 280, 281, 288, 291, 298, 305, 306, 313, 314, 321, 322, 331, 338, 339, 340, 341, 342, 343, 344, 345, 346, 352, 353, 354, 355, 356, 358, 391, 392, 393, 394a, 394b, 395a, 395b, 396, 397, 402, 403, 407, 408, 413, 414, 416, 418, 422, 428, 429, 430, 431, 434, 445, 446, 447, 448, 449, 450, 451, 453, 454, 462, 463, 464, 465, 466, 468, 472, 475, 476, 479, 480, 481, 482, 486, 489, 495, 496, 498, 511, 512, 514, 515, 520, or 524 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0207] In some embodiments, the compound of Formula (I) described herein is Compound 4, 15, 25, 32, 33, 47, 48, 49, 50, 52, 54, 59, 60b, 61, 62, 63, 72, 75, 82, 83, 89, 97, 101, 109, 119, 121, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 138, 139, 140, 141, 143, 144, 145, 146, 147, 148, 149, 150, 163, 169, 170, 174, 179, 181, 183, 191, 192, 194, 195, 212, 213, 214, 215, 230, 231, 232, 238, 239, 246, 248, 250, 251, 253, 254, 255, 258, 263, 264, 272, 273, 278, 279, 280, 281, 288, 291, 298, 305, 306, 313, 314, 321, 322, 331, 338, 339, 340, 341, 342, 343, 344, 345, 353, 355, 356, 358, 391, 392, 393, 394a, 394b, 395a, 395b, 396, 397, 402, 403, 407, 408, 413, 418, 422, 428, 429, 430, 431, 434, 445, 446, 447, 448, 449, 450, 451, 454, 463, 464, 465, 466, 472, 475, 476, 479, 481, 486, 489, 495, 498, 512, 514, 515, 520, or 524 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0208] In some embodiments, the compound of Formula (I) described herein is Compound 15, 25, 32, 48, 49, 50, 52, 54, 59, 60b, 61, 62, 63, 72, 75, 82, 83, 97, 101, 109, 119, 127, 128, 129, 130, 135, 136, 140, 141, 143, 144, 145, 146, 147, 148, 149, 150, 163, 169, 170, 174, 179, 181, 183, 191, 192, 194, 195, 212, 213, 215, 230, 231, 232, 238, 239, 246, 248, 250, 251, 254, 255, 258, 263, 272, 273, 279, 281, 288, 291, 306, 313, 314, 321, 322, 331, 338, 339, 340, 341, 342, 343, 344, 345, 353, 355, 356, 358, 391, 392, 393, 394a, 394b, 395a, 395b, 396, 397, 402, 403, 407, 408, 413, 418, 422, 428, 429, 430, 431, 434, 445, 446, 447, 448, 449, 450, 451, 454, 463, 464, 465, 466, 472, 475, 476, 479, 481, 486, 489, 495, 498, 512, 514, 515, 520, or 524 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0209] In some embodiments, the compound of Formula (I) described herein is Compound 15, 25, 32, 48, 49, 50, 52, 54, 59, 60b, 61, 62, 63, 72, 75, 82, 83, 97, 101, 109, 119, 127, 128, 129, 130, 135, 136, 140, 141, 143, 144, 145, 146, 147, 148, 149, 150, 163, 169, 170, 174, 179, 181, 183, 191, 192, 194, 195, 212, 213, 215, 230, 231, 232, 238, 239, 246, 248, 250, 251, 254, 255, 258, 263, 272, 273, 279, 281, 288, 291, 306, 313, 314, 321, 322, 331, 338, 339, 340, 341, 342, 343, 344, 345, 353, 355, 356, 358, 391, 392, 393, 394a, 394b, 395a, 395b, 396, 397, 402, 403, 407, 418, 428, 430, 431, 434, 445, 446, 447, 448, 449, 450, 454, 463, 464, 465, 466, 476, 489, 512, 514, 515, or 524 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0210] In some embodiments, the compound of Formula (I) described herein is Compound 48, 50, 54, 60b, 61, 63, 72, 75, 83, 97, 101, 109, 127, 135, 140, 141, 143, 144, 145, 146, 147, 149, 163, 169, 170, 174, 179, 181, 191, 194, 195, 212, 215, 230, 231, 232, 238, 246, 248, 250, 251, 255, 258, 272, 273, 279, 281, 291, 306, 314, 321, 322, 331, 338, 339, 340, 341, 342, 345, 353, 355, 356, 391, 393, 395a, 395b, 397, 402, 428, 430, 431, 434, 446, 447, 448, 450, 463, 464, 465, 466, 489, 512, 514, 515, or 524 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0211] In some embodiments, the compound of Formula (I) described herein is Compound 48, 50, 54, 60b, 61, 63, 75, 83, 97, 101, 127, 135, 140, 141, 143, 144, 146, 147, 149, 163, 170, 174, 181, 191, 195, 215, 230, 231, 232, 238, 246, 248, 250, 251, 255, 258, 272, 273, 279, 281, 306, 314, 322, 338, 339, 340, 345, 353, 355, 356, 391, 393, 397, 402, 428, 430, 431, 434, 446, 447, 450, 463, 465, 466, 489, 512, 514, 515, or 524 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0212] In some embodiments, the compound of Formula (I) described herein is Compound 54, 61, 63, 75, 140, 143, 146, 174, 215, 230, 250, 251, 273, 306, 322, 430, 446, 463, or 512 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is Compound 61, 63, 75, 143, 146, 174, 230, 250, 273, 306, 446, or 512 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0213] In some embodiments, the compound of Formula (I) described herein is Compound 4 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is Compound 33 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is Compound 47 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is Compound 89 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is Compound 121 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is Compound 131 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is Compound 132 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is Compound 133 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is Compound 134 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is Compound 138 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is Compound 139 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is Compound 214 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is Compound 253 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is Compound 264 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is Compound 278 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is Compound 280 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is Compound 298 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is Compound 305 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof.In some embodiments, the compound of Formula (I) described herein is compound 408 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 413 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 422 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 429 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 451 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 472 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 475 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 479 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 481 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 486 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 495 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 498 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 520 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0214] In some embodiments, the compound of Formula (I) described herein is compound 15 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 25 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 32 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 49 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 52 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 59 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 62 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 72 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 82 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 109 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 119 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 128 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 129 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 130 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 136 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 145 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 148 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 150 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof.In some embodiments, the compound of Formula (I) described herein is compound 169 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 179 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 183 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 192 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 194 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 212 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 213 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 239 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 254, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 263, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 288, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 291 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 313 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 321 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 331, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 341, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 342 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 343 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof.In some embodiments, the compound of Formula (I) described herein is compound 344 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 358 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 392 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 394a of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 394b of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 395a of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 395b of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 396 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 403 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 407, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 418 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 445 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 448 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 449 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 454 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 464 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 476 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0215] In some embodiments, the compound of Formula (I) described herein is compound 48 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 50 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 54 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 60b of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 61 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 63 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 75 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 83 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 97 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 101 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 127 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 135 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 140 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 141 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 143 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 144 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 146 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 147 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof.In some embodiments, the compound of Formula (I) described herein is compound 149 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 163 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 170 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 174 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 181, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 191 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 195 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 215 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 230 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 231 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 232 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 238 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 246 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 248 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 250 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 251 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 255 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 258 of Table 1 above, or any pharmaceutically acceptable salt, solvate, or prodrug thereof.In some embodiments, a compound of Formula (I) described herein is compound 272 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, a compound of Formula (I) described herein is compound 273 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, a compound of Formula (I) described herein is compound 279 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, a compound of Formula (I) described herein is compound 281 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, a compound of Formula (I) described herein is compound 306 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, a compound of Formula (I) described herein is compound 314 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, a compound of Formula (I) described herein is compound 322 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, a compound of Formula (I) described herein is compound 338 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, a compound of Formula (I) described herein is compound 339 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, a compound of Formula (I) described herein is compound 340, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, a compound of Formula (I) described herein is compound 345 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, a compound of Formula (I) described herein is compound 353 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, a compound of Formula (I) described herein is compound 355 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, a compound of Formula (I) described herein is compound 356 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, a compound of Formula (I) described herein is compound 391 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, a compound of Formula (I) described herein is compound 393 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, a compound of Formula (I) described herein is compound 397 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, a compound of Formula (I) described herein is compound 402 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.In some embodiments, the compound of Formula (I) described herein is compound 428 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 430 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 431 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 434 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 446 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 447 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 450 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 463 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 465 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 466 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 489 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 512 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 514 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 515 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) described herein is compound 524 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0216] Methods, Uses, Formulations, and Administration The substituted thiophene-fused cyclohexanone compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, are useful in the treatment or prevention of diseases for which an inhibitor of ASICs is indicated. Accordingly, in some embodiments, a compound of Formula (I) can be formulated into a pharmaceutical composition comprising an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0217] Accordingly, in some embodiments, the present specification provides a method of treating or preventing a disease for which an inhibitor of ASICs is indicated, comprising administering to a patient or subject identified as in need thereof at least one compound of Formula (I), as defined herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0218] It is well within the abilities and knowledge of those skilled in the art to identify those patients in need of treatment for the diseases described above. The medical arts recognize certain methods for identifying patients at risk of developing a disease state that can be treated by the methods of the present application, such as family history, and the presence of risk factors in the subject patient that correlate with development of the disease state. Those skilled in the art can readily identify such candidate patients through the use of, for example, clinical trials, physical examinations, and medical history / family history.

[0219] As used herein, the term "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by a researcher, clinician, or other caregiver. Furthermore, the term "therapeutically effective amount" means any amount of a compound that, when administered to a subject in need thereof, will cure, heal, prevent, or ameliorate a disease, condition, or side effect or will reduce the rate of disease or condition progression compared to that subject not receiving the amount. The term also includes within its scope amounts effective to enhance normal physiological function.

[0220] As used herein, the term "treatment" refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment can be undertaken after the manifestation of one or more symptoms. In other embodiments, treatment can be undertaken in the absence of symptoms. For example, treatment can be undertaken in susceptible individuals prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other predisposing factors). Treatment can also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

[0221] The term "patient" or "subject" as used herein generally refers to a mammal. Thus, a subject refers to, for example, a dog, cat, horse, cow, pig, guinea pig, and the like. Preferably, the subject is a human. When the subject is a human, the subject can be a patient or a healthy human.

[0222] The terms "pharmaceutically acceptable carrier, diluent, or excipient" and their equivalents refer to non-toxic carriers, diluents, and excipients that do not impair the pharmacological activity of the compound in which they are formulated. Pharmaceutically acceptable carriers, diluents, or excipients that can be used in the compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering substances such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts, or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and lanolin.

[0223] The term “ASIC inhibitor” as used in this article refers to compounds that inhibit acid-sensitive ion channels such as acid-sensitive ion channel 1a (ASIC1a) or acid-sensitive ion channel 1b (ASIC1b).

[0224] In some embodiments, diseases or conditions that can be treated using compounds of formula (I) described herein or their pharmaceutically acceptable salts, solvates or prodrugs may include pain, arthritis, stroke, epilepsy, anxiety, post-traumatic stress disorder (PTSD), depression, multiple sclerosis, Alzheimer's disease, gastroesophageal reflux disease, cancer, migraine, cough and acute lung injury.

[0225] In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition comprising thereof, may be used to treat or prevent a disease, wherein the disease is pain. In some embodiments, pain may include acute pain or chronic pain. In some embodiments, pain may include nociceptive pain, inflammatory pain, neuropathic pain, idiopathic pain, musculoskeletal pain, visceral pain, or abdominal pain. In some embodiments, pain may include inflammatory pain or neuropathic pain. In some embodiments, pain may include inflammatory pain. In other embodiments, pain may include neuropathic pain.

[0226] In some embodiments, the pain may include pain associated with rheumatic diseases. In other embodiments, the pain may include arthritis pain. In some embodiments, the pain may include osteoarthritis pain, rheumatoid arthritis pain, ankylosing spondylitis pain, gouty arthritis pain, psoriatic arthritis pain, juvenile arthritis pain, juvenile rheumatoid arthritis pain, bursitis pain, tendinitis pain, tenosynovitis pain, periarthritis pain, or polymyalgia rheumatica pain.

[0227] In certain embodiments, the pain can include osteoarthritis inflammatory pain or osteoarthritis neuropathic pain. In some embodiments, the pain can include hip osteoarthritis pain, knee osteoarthritis pain, spinal osteoarthritis pain, shoulder osteoarthritis pain, hand osteoarthritis pain, finger osteoarthritis pain, thumb osteoarthritis pain, foot osteoarthritis pain, or toe osteoarthritis pain. In certain embodiments, the pain can include rheumatoid arthritis inflammatory pain or rheumatoid arthritis neuropathic pain. In certain embodiments, the pain can include shoulder bursitis pain or hip bursitis pain. In some embodiments, the pain can include shoulder tendonitis pain, elbow tendonitis pain, hip tendonitis pain, wrist tendonitis pain, knee tendonitis pain, or heel tendonitis pain. In certain embodiments, the pain can include shoulder periarthritis pain or hip periarthritis pain.

[0228] In some embodiments, the pain can include pain associated with musculoskeletal injury and / or soft tissue injury, including pain associated with sprains, strains, swelling, or stiffness. In certain embodiments, the pain can include pain associated with musculoskeletal injury and / or soft tissue injury of the back, shoulder, or ankle. In certain embodiments, the pain can include myofascial pain syndrome. In other embodiments, the pain can include exercise-induced pain, repetitive motion injury pain, or fracture-induced pain. In other embodiments, the pain can include temporomandibular joint disorder pain.

[0229] In certain embodiments, the pain can include ocular pain. In certain embodiments, the pain can include postoperative pain following cataract surgery, postoperative pain following refractive surgery, ocular pain from non-penetrating injury, ocular pain from foreign body sensation, ocular burning or stinging, uveitis pain, iritis pain, retinopathy pain, or optic neuritis pain.

[0230] In some embodiments, the pain can include dental pain. In certain embodiments, the pain can include tooth pain or postoperative pain following dental surgery, including pain following tooth extraction.

[0231] In certain embodiments, the pain can include postoperative pain. In some embodiments, the pain can include postoperative pain following minor surgery, postoperative pain following general surgery, postoperative pain following orthopedic surgery, postoperative pain following bunionectomy, postoperative pain following herniorrhaphy, postoperative pain following hernioplasty, postoperative pain following arthroplasty, including postoperative pain following knee joint replacement or hip joint replacement, postoperative pain following gynecological surgery, postoperative pain following cesarean section, postoperative pain following abdominoplasty, postoperative pain following laminectomy, postoperative pain following hemorrhoidectomy, or postoperative pain following thoracotomy.

[0232] In certain embodiments, the pain can include menstrual cramp pain, episiotomy pain, endometriosis pain, or postpartum pain, including postpartum spasm pain.

[0233] In certain embodiments, the pain can include pain from the common cold, pain from the flu, sore throat, sinus pain, including sinusitis pain, immunization pain, ear pain, fever pain, body pain, muscle pain, bone pain, joint pain, back pain, or neck pain.

[0234] In certain embodiments, the pain can include neuropathic pain. In some embodiments, the pain can include trigeminal neuralgia, post-herpetic neuralgia, occipital neuralgia, post-surgical neuralgia, pudendal neuralgia, diabetic neuropathy, glossopharyngeal neuralgia, intercostal neuralgia, or drug therapy-induced neuropathic pain, including cancer chemotherapy-induced neuropathic pain or antiretroviral therapy-induced neuropathic pain.

[0235] In certain embodiments, the pain can include nerve injury pain, peripheral nerve injury pain, nerve compression pain, nerve avulsion injury pain, nerve entrapment injury pain, radiculopathy pain, brachial plexus injury pain, burning mouth syndrome pain, complex regional pain syndrome type 1, complex regional pain syndrome type 2, neuroma pain, Morton's neuroma pain, spinal cord injury pain, spinal cord compression pain, radicular pain, sciatica pain, spinal stenosis pain, cervical spine injury pain, brain injury pain, or post-stroke pain.

[0236] In some embodiments, the pain can include neuropathic pain. In certain embodiments, the pain can include peripheral neuropathic pain, polyneuropathic pain, mononeuropathic pain, multiple mononeuropathic pain, proximal neuropathic pain, sensory neuropathic pain, small-fiber sensory neuropathic pain, idiopathic neuropathic pain, or distal sensory polyneuropathic pain. In certain embodiments, the pain can include diabetic neuropathic pain. In some embodiments, the pain can include diabetic peripheral neuropathic pain, diabetic polyneuropathic pain, diabetic proximal neuropathic pain, or diabetic mononeuropathic pain. In certain embodiments, the pain can include autoimmune disease neuropathic pain. In some embodiments, the pain can include Sjogren's syndrome neuropathic pain, Guillain-Barre syndrome neuropathic pain, chronic inflammatory demyelinating polyneuropathy neuropathic pain, or vasculitic neuropathic pain. In some embodiments, the pain can include multiple sclerosis neuropathic pain. In certain embodiments, the pain can include carpal tunnel syndrome pain. In certain embodiments, the pain can include neuropathic pain associated with a bacterial infection or neuropathic pain associated with a viral infection. In some embodiments, the pain can include Lyme disease neuropathic pain, Epstein-Barr virus neuropathic pain, hepatitis B virus neuropathic pain, hepatitis C virus neuropathic pain, leprosy neuropathic pain, diphtheria neuropathic pain, or human immunodeficiency virus (HIV) neuropathic pain, including HIV distal symmetric polyneuropathy. In certain embodiments, the pain can include hereditary neuropathic pain. In some embodiments, the pain can include Charcot-Marie-Tooth disease neuropathic pain or hereditary neuropathic (HNPP) pain with pressure palsy. In certain embodiments, the pain can include neuropathic pain caused by a malignant tumor, neuropathic pain caused by a benign tumor, or paraneoplastic neuropathic pain. In some embodiments, the pain can include myeloma neuropathic pain, lymphoma neuropathic pain, or amyloid neuropathic pain. In certain embodiments, the pain can include hepatopathy neuropathic pain, uremia neuropathic pain, connective tissue disease neuropathic pain, and hypothyroidism neuropathic pain, alcohol use neuropathic pain, or vitamin deficiency neuropathic pain. In some embodiments, the pain can include vitamin B deficiency neuropathic pain, including vitamin Bl, niacin, vitamin B6, or vitamin B 12 deficiency neuropathic pain, or vitamin E deficiency neuropathic pain. In certain embodiments, the pain can include toxic substance exposure neuropathic pain, including neuropathic pain following lead exposure or neuropathic pain following mercury exposure. In certain embodiments, the pain can include antiretroviral therapy-induced neuropathic pain or neurotoxic drug-induced neuropathic pain.In certain embodiments, the pain can include chemotherapy-induced neuropathic pain, including platinum-based antineoplastic drug-induced neuropathic pain or chemotherapy-induced peripheral neuropathy (CIPN) pain, radiation therapy-induced pain, including radiation therapy-induced neuropathic pain, cancer-targeted therapy-induced neuropathic pain, or immunotherapy-induced neuropathic pain. In some embodiments, the pain can include central neuropathic pain. In certain embodiments, the pain can include central post-stroke pain, central neuropathic pain associated with spinal cord injury, central neuropathic pain associated with brain injury, or central neuropathic pain associated with multiple sclerosis.

[0237] In certain embodiments, the pain can include cancer pain. In some embodiments, the pain can include bone cancer pain, breakthrough pain, cancer neuropathic pain, including neuropathy caused by tumor compression of nerves. In some embodiments, the pain can include mucositis pain, stomatitis pain, or post-mastectomy pain syndrome (PMPS).

[0238] In certain embodiments, the pain can include post-amputation pain. In some embodiments, the pain can include phantom pain, phantom limb pain, or residual limb pain.

[0239] In some embodiments, the pain can include headache, migraine, including migraine pain with aura, migraine pain without aura, tension headache, or cluster headache.

[0240] In certain embodiments, the pain can include Paget’s disease pain. In other embodiments, the pain can include pain associated with fibromyalgia. In certain embodiments, the pain can include pain associated with lupus, including lupus-associated inflammatory pain and lupus-associated neuropathic pain. In some embodiments, the pain can include gastrointestinal motility disorder pain, irritable bowel syndrome pain, Crohn’s disease pain, ulcer-associated pain, or ulcerative colitis pain. In other embodiments, the pain can include incontinence pain or interstitial cystitis pain. In certain embodiments, the pain can include shingles pain. In certain embodiments, the pain can include pain caused by angina. In certain embodiments, the pain can include pain from animal bites or stings, or pain caused by burns, including pain caused by first, second, or third degree burns.

[0241] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition comprising the same, can be used to treat or prevent arthritis, including rheumatoid arthritis (Xu, Y. et al., 2021).

[0242] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition comprising the same, can be used to treat or prevent stroke (Chassagnon, I. R. et al., 2017; Qi, X. et al., 2022).

[0243] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition comprising the same, can be used to treat or prevent epilepsy (Cheng, Y. et al., 2021).

[0244] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition comprising the same, can be used to treat or prevent anxiety (Cittaro, D. et al., 2016; Battaglia, M. et al., 2019; Yellepeddi, V. et al., 2020).

[0245] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition comprising the same, can be used to treat or prevent post-traumatic stress disorder (PTSD) (Wemmie, J. A. et al., 2004).

[0246] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition comprising the same, can be used to treat or prevent depression (Coryell, M. W. et al., 2009; Mango, D. et al., 2019).

[0247] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition comprising the same, can be used to treat or prevent multiple sclerosis (Vergo S. et al., 2011; Wei W. et al., 2021).

[0248] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition comprising the same, can be used to treat or prevent Alzheimer’s disease (Mango, D. et al., 2023).

[0249] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition comprising the same, can be used to treat or prevent gastroesophageal reflux disease (Han, X. et al., 2022).

[0250] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition comprising the same, can be used to treat or prevent cancer. In certain embodiments, the cancer can include a glioma, such as a glioblastoma multiforme (Sheng, Y. et al., 2021), hepatocellular carcinoma (HCC) (Zhang, Y. et al., 2022), gastric cancer (Zhang, Q. et al., 2017; Chen, X. et al., 2018), pancreatic cancer (Zhu, L. et al., 2021), lung cancer (Wu, Y. et al., 2017), breast cancer (Gupta, S. C. et al., 2016; Yang, C. et al., 2020), skin cancer including melanoma (Bychkov, M. L. et al., 2021), prostate cancer (Chen, B. et al., 2016), or chronic myelogenous leukemia (Bychkov, M. L. et al., 2020).

[0251] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition comprising the same, can be used to treat or prevent migraine (Holland, P. R. et al., 2012; Karsan, N. et al., 2018).

[0252] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition comprising the same, can be used to treat or prevent cough (Reznikov, L. R. et al., 2016).

[0253] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition comprising the same, can be used to treat or prevent acute lung injury (Liu, Y. et al., 2023).

[0254] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition comprising the same, can be used to treat or prevent itch (Papalampropoulou-Tsiridou, M. et al., 2022; Jung, M. et al., 2023).

[0255] In some embodiments, a therapeutically effective amount of a compound as defined herein can be administered to a patient or subject alone or in admixture with a pharmaceutically acceptable carrier, diluent, or excipient.

[0256] The compositions described herein can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenterally" as used herein includes subcutaneous, intravenous, intramuscular, intra-articulate, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Other modes of administration include intradermal or transdermal administration.

[0257] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, baby oil, olive oil, castor oil and sesame seed oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.

[0258] Injectable preparations, such as sterile injectable aqueous or oleaginous suspensions, can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, such as, for example, a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0259] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0260] In order to prolong the effect of the provided compounds, it is often desirable to slow their absorption from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution which, in turn, can depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the particular polymer employed, the rate of compound release can be controlled.

[0261] Other examples of biodegradable polymers include poly(orthoesters) and poly(anhydrides). Storage of injectable formulations is also achieved by encapsulating compounds in liposomes or microemulsions that are compatible with body tissues.

[0262] Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing the compounds of this specification with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or suppository wax, which is solid at ambient temperature but liquid at body temperature, and thus melts and releases the active compound in the rectal or vaginal cavity.

[0263] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or fillers, such as starch, lactose, sucrose, glucose, mannitol, and silicate; b) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone (PVP), sucrose, and gum arabic; c) humectants, such as glycerin; d) disintegrants, such as agar, calcium carbonate, potato or cassava starch, alginic acid, certain silicates, and sodium carbonate; e) solution blockers, such as paraffin; f) absorption enhancers, such as quaternary ammonium compounds; g) wetting agents, such as hexadecyl alcohol and glyceryl monostearate; h) absorbents, such as kaolin and bentonite; and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain buffers.

[0264] Similar types of solid compositions can also be used as fillers in soft-filled and hard-filled gelatin capsules, using excipients such as lactose or toffee and high molecular weight polyethylene glycol. Solid dosage forms of tablets, sugar-coated tablets, capsules, pills, and granules can be prepared using coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation field. They may optionally contain emulsifiers and may also have compositions that release only the active ingredient, or preferentially release the active ingredient in a portion of the intestine, optionally in a delayed manner. Examples of usable encapsulation compositions include polymeric substances and waxes. Similar types of solid compositions can also be used as fillers in soft-filled and hard-filled gelatin capsules, using excipients such as lactose or toffee and high molecular weight polyethylene glycol.

[0265] The provided compounds may also be in microencapsulated form, containing one or more excipients as described above. Solid dosage forms of tablets, sugar-coated tablets, capsules, pills, and granules can be prepared using coatings and shells, such as enteric coatings, release-controlled coatings, and other coatings well known in the field of pharmaceutical formulations. In such solid dosage forms, the active compound may be mixed with at least one inert diluent (e.g., sucrose, lactose, or starch). Conventionally, such dosage forms may also contain substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also contain buffers. They may optionally contain emulsifiers and may also have compositions that release only the active ingredient, or preferentially release the active ingredient in a portion of the intestine, optionally releasing the active ingredient in a delayed manner. Examples of usable encapsulation compositions include polymers and waxes.

[0266] Dosage forms for topical or transdermal application of the compounds of this invention include ointments, pastes, creams, emulsions, gels, powders, solutions, sprays, inhalers, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers. Ophthalmic preparations, ear drops, and eye drops are also considered within the scope of this specification. Furthermore, the use of transdermal patches is considered, offering the additional advantage of controlled delivery of the compound to the body. This dosage form can be prepared by dissolving or dispensing the compound into a suitable medium. Absorption enhancers may also be used to increase the flux of the compound through the skin. The rate can be controlled by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or gel.

[0267] The pharmaceutically acceptable compositions described herein can also be administered via nasal aerosol or inhalation. Such compositions are prepared using techniques well-known in the pharmaceutical formulation field, and can be formulated as saline solutions using benzyl alcohol or other suitable preservatives, bioavailability enhancers, fluorocarbons, and / or other conventional solubilizers or dispersants.

[0268] The pharmaceutically acceptable compositions provided herein can be formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of this disclosure are administered without food. In other embodiments, the pharmaceutically acceptable compositions of this disclosure are administered with food.

[0269] The amount of the provided compound that can bind with the carrier material to form a composition in a single dosage form will vary depending on the patient to be treated and the specific route of administration. The provided compositions can be formulated as inhibitors that can be administered to patients receiving these compositions at a dose of 0.01-100 mg / kg body weight / day.

[0270] It should also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including age, weight, general health condition, sex, diet, timing of administration, excretion rate, drug combination, the judgment of the treating physician, and the severity of the specific disease being treated. The amount of compounds provided in the composition will also depend on the specific compounds in the composition.

[0271] The compounds or compositions described herein may be administered in any amount and via any route of administration to effectively treat or reduce the severity of the disease or illness described herein. The exact amount required varies from subject to subject, depending on the subject’s type, age and general condition, severity of infection, specific agent, route of administration, etc. The compounds provided are preferably formulated in unit dosage forms to facilitate administration and uniform dosage. As used herein, “unit dosage form” refers to a physically discrete unit of pharmaceutical preparation suitable for a patient to be treated. However, it should be understood that the total daily dosage of the compounds and compositions disclosed herein will be determined by the attending physician within reasonable medical judgment. The specific effective dose level for any particular patient or organism will depend on a variety of factors, including the disease being treated and its severity; the activity of the specific compound used; the specific composition employed; the patient’s age, weight, general health condition, sex, and diet; the timing, route of administration, and excretion rate of the specific compound used; the duration of treatment; drugs used in combination with or concurrently with the specific compound used; and similar factors well known in the medical field.

[0272] The pharmaceutically acceptable compositions of this disclosure can be administered to humans and other animals orally, rectally, parenterally, intracerebrospinally, vaginally, intraperitoneally, topically (e.g., by powder, ointment, or drops), orally, as an oral or nasal spray, depending on the severity of the infection being treated. In some embodiments, the provided compounds can be administered orally or parenterally at dose levels of about 0.01 mg / kg to about 50 mg / kg, preferably about 1 mg / kg to about 25 mg / kg of subject body weight per day, once or more daily to achieve the desired therapeutic effect.

[0273] Once the subject's condition improves, a maintenance dose of the compound or composition described in this instruction manual may be administered, if necessary. Subsequently, the dosage, frequency of administration, or both may be reduced to a level that maintains the improved condition, depending on the degree of symptom relief. Treatment should be discontinued when the expected degree of symptom relief is achieved. However, if a relapse occurs, the subject may require long-term intermittent treatment.

[0274] However, it should be understood that the total daily dosage of the compounds and compositions described in this instruction manual will be determined by the attending physician within the bounds of reasonable medical judgment. The specific effective inhibitory dose for any particular patient will depend on a variety of factors, including the disease being treated and its severity; the activity of the specific compound used; the specific composition employed; the patient's age, weight, general health condition, sex, and diet; the timing, route of administration, and excretion rate of the specific compound used; the duration of treatment; drugs used in combination with or concurrently with the specific compound used; and similar factors well-known in the medical field.

[0275] The total daily inhibitory dose of the compound of this specification administered to a subject in a single dose or multiple doses may be, for example, from 0.01 to 50 mg / kg body weight or more typically from 0.1 to 25 mg / kg body weight. A single-dose composition may contain such an amount or approximation thereof to constitute a daily dose. In one embodiment, a treatment regimen according to this specification comprises administering about 10 mg to about 1000 mg of the compound of this specification daily in single or multiple doses to a patient requiring such treatment.

[0276] Examples General methods Compound Preparation All reagent-grade chemicals and anhydrous solvents were purchased commercially and used directly without further purification unless otherwise specified. Product names were determined using the naming tool built into ChemDraw (PerkinElmer) software. When the preparation methods of compounds mentioned in this document refer to previous examples or intermediates, parameters such as reaction time, reagent equivalents, temperature, post-treatment, and purification techniques may differ slightly from those in the examples described.

[0277] Purification Chromatographic separation was performed on the following instruments: The Teledyne ISCO CombiFlash rapid chromatography system uses pre-packaged SiO2 or C 18 column.

[0278] Teledyne ISCO ACCQPrep high-pressure preparative liquid chromatography system; column: Gemini 5 um C18110 Å, 150×30 mm.

[0279] Biotage Isolera rapid chromatography system, using pre-packaged SiO2 or C 18 column.

[0280] Waters Mass Trigger semi-preparative HPLC; column: Gemini 5 um NX-C18 110 Å, 100×30 mm.

[0281] Chiral separation is performed on the following instruments: Mettler Toledo Berger Minigram supercritical fluid chromatography; column: ChiralPak IG, 20×250 mm or ChiralPak IG, 10×250 mm.

[0282] Waters ACQUITY UPC2 supercritical fluid chromatography; column: ChiralPak IG, 10×250 mm.

[0283] Analytical Methods LC-MS was performed on the following instruments: Waters UPLC-MS; Column: Acquity UPLC, CSH C18, 1.7 μm, 2.1 × 30 mm; Method: 5% to 95% CH3CN in water (containing 0.1% (v / v) formic acid) over 2 minutes; or 5% to 95% CH3CN in 10 mM ammonium bicarbonate over 2 minutes.

[0284] Agilent HPLC-MS; Column: Kinetex EVO C18 100 Å 2.6 μm, 50 × 3 mm; Method: 10% to 95% CH3CN (containing 0.1% (v / v) formic acid) in water (containing 0.1% (v / v) formic acid) solution over 4.5 min.

[0285] Agilent UPLC-MS; Column: Kinetex EVOC18 100 Å 1.7 μm, 50 x 3 mm; Method: Solutions of CH3CN (containing 0.1% (v / v) formic acid) in water (containing 0.1% (v / v) formic acid) from 5% to 95% in 3 minutes.

[0286] Analytical SFC was performed on the following instruments: Waters ACQUITY UPC2; columns: ChiralPak IG 4.6×250 mm or ChiralPak IC 4.6×150 mm.

[0287] Nuclear magnetic resonance (NMR) spectroscopy analysis was performed using a Varian NMR (AS 400) 400 MHz spectrometer equipped with an Inova interface. In all cases, the NMR data were consistent with the proposed structure. Characteristic chemical shifts (δ) were expressed in parts per million (ppm), and peak labels were indicated using conventional abbreviations: e.g., s for singlet, d for doublet, t for triplet, q for quartet, dd for double doublet, dt for double triplet, etc.

[0288] Abbreviations 9-BBN9-boronibiricum[3.3.1]nonane δ chemical shift Å Acetyl group Bn benzyl Boc tert-butyloxycarbonyl bs “Broad Single Peak” Bu Butyl Calcd values d double peak DAST diethylaminosulfuric acid dd double double peak dt double triple peak DCM dichloromethane DDQ2,3-Dichloro-5,6-dicyano-1,4-benzoquinone DIBALH (Diisobutylaluminum hydride) DIPEA N,N -Diisopropylethylamine DMAP 4-Dimethylaminopyridine DMF N,N-dimethylformamide DMP Dys-Martin Oxidant DMPU N,N′-dimethylpropaneurea DMSO (dimethyl sulfoxide) Dppf1,1'-bis(diphenylphosphine)ferrocene EA (ethyl acetate) ee enantiomer excess Et Ethyl EtOH (ethanol) eq equivalent g gram HATU benzotriazole tetramethylurea hexafluorophosphate Hz Hertz HPLC (High Performance Liquid Chromatography) i- Pr isopropyl J Coupling constant L rise LC-MS (Liquid Chromatography-Mass Spectrometry) LDA diisopropylaminolithium LHMDS Bis(trimethylsilyl)aminolithium M Moore's m multiplet mCPBA m-chloroperoxybenzoic acid Me methyl MeOH methanol mg MHz min minutes mL mm mmol millimole mol MS mass spectrometry N normal NBS N - Bromosuccinimide PCC pyridine chlorochromate pH Ph phenyl PPh3 triphenylphosphine ppm (parts per million) PyBOP Benzotriazole-1-yl-oxytripyrrolidinyl hexafluorophosphate q quadruple peak RT room temperature rt retention time NMR (Nuclear Magnetic Resonance) s singlet Saturated SFC Supercritical Fluid Chromatography sxt Six-peak t Uncle triple peak tt triple triple peak t- Bu tert-butyl TMS Trimethylsilyl TFA (trifluoroacetic acid) THF Tetrahydrofuran Ts Toluenesulfonyl uL microliter umol micromolar v / v volume / volume ° degree % percentage Example 1 2-Amino-7-oxo-5-(2-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrobenzo[ b ]Thiophene-3-carboxamide (4) Scheme 1 Step 1. 2-(3-oxo-5-(2-(trifluoromethyl)phenyl)cyclohexylidene)propanedinitrile (2) A solution of malononitrile (100 mg, 1.51 mmol, recrystallized from EtOH), triethylamine (253 μL, 1.82 mmol), and 5-(2-(trifluoromethyl)phenyl)cyclohexane-1,3-dione (1,396 mg, 1.51 mmol) in EtOH (1.30 mL) was stirred at 80°C for 2 hours. Then, 62 mg malononitrile (0.94 mmol) and 250 μL triethylamine (1.82 mmol) were added, and the mixture was stirred at 80°C for 16 hours. The mixture was then cooled to room temperature and concentrated to dryness. Crude product 2 was used unpurified for step 2. LC-MS: rt = 1.94 min, MS: 304.1 (calcd), 305.1 (M+H) + (Measured value).

[0289] Step 2. 2-Amino-7-oxo-5-(2-(trifluoromethyl)phenyl)-4,5,6,7- tetrahydrobenzo[ b ]thiophene-3-carboxylic acid nitrile (3) A mixture of sulfur (50.9 mg, 198 μmol), diethylamine (157 μL, 1.52 mmol), and compound 2 (461 mg, 1.52 mmol, assuming the quantitative yield in step 1) in EtOH (2.00 mL) was stirred at 80°C for 16 hours. The mixture was then cooled to room temperature and concentrated by rotary evaporation. The residue was purified by rapid column chromatography (elution gradient of 40% to 100% hexane solution of EA) to give title compound 3 (220 mg, 43% yield in two steps) as a light brown solid. LC-MS: rt = 1.73 min, MS: 336.1 (calcd), 337.0 (M+H) + (Measured value).

[0290] Step 3. 2-Amino-7-oxo-5-(2-(trifluoromethyl)phenyl)-4,5,6,7- tetrahydrobenzo[ b ]thiophene-3-carboxylic acid formamide (4) A 30% aqueous hydrogen peroxide solution (0.33 mL) was added to a suspension of compound 3 (41.1 mg, 122 μmol) and potassium carbonate (33.8 mg, 244 μmol) in DMSO (1.64 mL). The mixture was stirred at room temperature for 2 hours, and then partitioned between EA and water (20 mL each). The layers were separated, and the aqueous phase was extracted with another 20 mL of EA. The combined organic matter was washed with brine (20 mL), dried over Na2SO4, filtered, concentrated, and dried under vacuum to give title compound 4 (36.7 mg, 85% yield) as a pale yellow solid.

[0291] 1 H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.06 (s, 2H), 7.90 (d, J = 8.0 Hz,1H), 7.76-7.68 (m, 2H), 7.49 (t, J = 7.7 Hz, 1H), 6.96 (bs, 2H), 3.73-3.58(m, 1H), 3.40-3.29 (m, 1H), 3.07-2.90 (m, 2H), 2.36 (dd, J = 16.3, 3.8 Hz, 1H). 19 F NMR: 376 MHz, DMSO-d6, δ (ppm): ‒57.5 (s). LC-MS: rt = 1.40 min, MS: 354.1 (calcd), 355.1 (M+H + (Measured value).

[0292] Example 2 2-Amino- N -Cyclopropyl-6-ethyl-7-oxo-4,5,6,7-tetrahydrobenzo[ b ]Thiophene-3-carboxamide (9) Scheme 2

[0293] Step 1. Ethyl 2-cyano-2-(4-ethyl-3-oxocyclohexylidene)acetate (6) 4-Ethylcyclohexane-1,3-dione (5,150 mg, 910 μmol) Synlett.A mixture of 2012, 1199-1204), triethylamine (380 μL, 2.73 mmol), and ethyl 2-cyanoacetate (145 μL, 1.36 mmol) in EtOH (784 μL) was stirred at 80°C for 16 hours. Then, 100 μL of ethyl 2-cyanoacetate (0.94 mmol) and 130 μL of triethylamine (0.93 mmol) were added, and the resulting mixture was stirred at 80°C for another 24 hours. The mixture was then cooled to room temperature and concentrated to dryness. Crude product 6 was used for step 2 without purification. LC-MS: rt = 1.73 min, MS: 235.1 (calcd), 236.1 (M+H) + (Measured value).

[0294] Step 2. 2-Amino-6-ethyl-7-oxo-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxylic acid ethyl ester (7) A mixture of crude product 6 (214 mg, 910 μmol; assuming the quantitative yield in step 1), sulfur (30.6 mg, 119 μmol), and diethylamine (94.1 μL, 910 μmmol) in EtOH (910 μL) was stirred at 80°C for 2 hours. The mixture was then cooled to room temperature and concentrated to dryness. The residue was purified by rapid column chromatography (elution gradient of 5% to 50% hexane solution of EA) to give title compound 7 (135.2 mg, 52% yield in two steps) as a yellow solid. LC-MS: rt = 1.77 min, MS: 267.1 (calcd), 268.1 (M+H) + (Measured value).

[0295] Step 3. 2-Amino-6-ethyl-7-oxo-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxylic acid (8) Lithium hydroxide monohydrate (68.0 mg, 1.62 mmol) was added to a suspension of 7 (86.6 mg, 324 μmol) in a mixture of MeOH (4.86 mL) and H₂O (1.62 mL). The resulting mixture was stirred under reflux for 2 hours, then cooled to room temperature, diluted with water (20 mL), and washed with EA (20 mL). The organic phase was discarded, and the aqueous phase was acidified to pH 2–3 with 3N HCl and extracted with EA (3 x 20 mL). The combined organic matter was washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated to give title compound 8 (60.5 mg, 78% yield) as a white solid. The crude product was used unpurified for step 4. (Characteristics are shown in Table 6) Step 4. 2-Amino- N - cyclopropyl-6-ethyl-7-oxo-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxamide (9) Add to 8 (60.5 mg, 253 μmol) of DMF (3.16 mL) solution N,N-Diisopropylethylamine (132 μL, 758 μmol), cyclopropylamine (19.3 μL, 278 μmol), and HATU (115 mg, 303 μmol). The resulting mixture was stirred at room temperature for 16 hours. The mixture was then diluted with saturated NH4Cl aqueous solution (30 mL) and extracted with EA (3 × 20 mL). The combined organics were washed with ice-cold brine (40 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was first purified by rapid column chromatography (eluent gradient of 1% to 10% MeOH in DCM solution) and then recrystallized from hot EA to give title compound 9 as a white solid (16.4 mg, 23% yield).

[0296] 1 H NMR: 400 MHz, DMSO-d6, δ (ppm): 7.68 (d, J = 5.7 Hz, 2H), 7.34 (d, J = 3.8 Hz, 1H), 2.86 (dt, J = 17.3, 5.2 Hz, 1H), 2.76 (ddt, J = 19.0, 7.1,4.2 Hz, 2H), 2.20 (ddt, J = 9.4, 7.8, 4.7 Hz, 1H), 2.06 (dq, J = 13.2, 5.0Hz, 1H), 1.82-1.67 (m, 2H), 1.50-1.33 (m, 1H), 0.90 (t, J = 7.4 Hz, 3H), 0.66(td, J = 7.0, 4.6 Hz, 2H), 0.57-0.47 (m, 2H). LC-MS: rt = 1.26 min, MS: 278.1(calcd), 279.1 (M+H + (Measured value).

[0297] Example 3 2-Amino-6-(2-chlorophenyl)-6-cyano-7-oxo-4,5,6,7-tetrahydrobenzo[ b ]Thiophene-3-carboxamide (15) Scheme 3

[0298] Step 1. 2-((Di-tert-butyi)carbonyl)amino)-7-oxo-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxylic acid ethyl ester ester (11) Ethyl 2-amino-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (10, 2.26 g, 9.25 mmol) was added to a suspension of 2-amino-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (10, 2.26 g, 9.25 mmol) in DCM (58.2 mL) along with triethylamine (2.85 mL, 20.4 mmol), 4-dimethylaminopyridine (228 mg, 1.85 mmol), and di-tert-butyl dicarbonate (4.44 g, 20.4 mmol). The resulting solution was stirred under reflux for 4 hours. The mixture was then cooled to room temperature, diluted with DCM (50 mL), and washed successively with 1N HCl, water, and brine (70 mL each). The organic phase was dried over Na₂SO₄, filtered, and concentrated. The residue was purified by rapid column chromatography (elution gradient of 10% to 60% hexane solution of EA) to give title compound 11 (3.42 g, 84% yield) as a pale orange solid. LC-MS: rt = 1.78 min, MS: 439.2 (calcd), 462.2 (M+Na + (Measured value).

[0299] Step 2. 2-((Di-tert-butyi)carbonyl)amino)-6-cyano-7-oxo-4,5,6,7- tetrahydrobenzo[d]thiophene-3-carboxylic acid b ]thiophene- 3-ethyl formate (12) Under Ar conditions, 11 (2.29 g, 5.22 mmol) of anhydrous THF (16 mL) solution was added to an LDA solution (10.4 mL, 1 M in THF / hexane, 10.4 mmol) cooled to -78°C. The resulting mixture was stirred at -78°C for 15 min, and then TsCN (975 mg, 5.22 mmol) of anhydrous THF (16 mL) solution was added dropwise. The mixture was stirred at -78°C for 20 min, and then stirred from -78°C to room temperature for 4 h. Subsequently, the mixture was quenched with a saturated aqueous NH4Cl solution (200 mL) and extracted with DCM (2 x 200 mL). The combined organic compounds were dried over Na2SO4, filtered and concentrated, and the residue was purified by rapid column chromatography (elution gradient of 5% to 50% EA in hexane solution) to give title compound 12 (1.13 g, 46% yield) as a pale yellow solid. LC-MS:rt = 1.73 min, MS: 464.2 (calcd), 487.2 (M+Na + (Measured value).

[0300] Step 3. 2-((tert-butoxycarbonyl)amino)-6-(2-chlorophenyl)-6-cyano-7-oxo-4,5,6,7- tetrahydrobenzene and b ] ethyl thiophene-3-carboxylate (13) Under Ar, to the device containing t- Add 12 (200 mg, 431 μmol) of anhydrous DMF (1.3 mL) to a flame-dried microwave-safe vial containing BuOK (57.5 mg, 512 μmol) and anhydrous DMF (860 μL). Stir the resulting mixture at 0°C for 35 minutes, then add dropwise 188 mg, 431 μmol of iodonium di(2-chlorophenyl)tetrafluoroborate (iodonium salt). J. Am. Chem. Soc. An anhydrous DMF solution (430 μL) of 2016, 13183-13186 was added, and the mixture was stirred at room temperature for 2.5 hours. Then, more iodonium di(2-chlorophenyl)tetrafluoroborate (40 mg, 92 μmol dissolved in 500 μL of anhydrous DMF) was added, and the mixture was stirred at room temperature for 16 hours. The mixture was then diluted with water (2 mL) and acidified to pH 6-7 with 1N HCl. 10 mL of water was added, and the product was extracted with EA (3 x 20 mL). The combined organic matter was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was dissolved in heptane and concentrated several times by rotary evaporation to remove residual DMF. The resulting solid was purified by rapid column chromatography (elution gradient of 0% to 50% EA in hexane solution) to give a pale yellow solid, title compound 13 (40 mg, 20% yield). LC-MS: rt = 2.06 min, MS: 474.1 (calcd), 475.1 (M+H + (Measured value).

[0301] Step 4. 2-Amino-6-(2-chlorophenyl)-6-cyano-7-oxo-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxylic acid methyl ester acid (14) At 0°C, TFA (2.26 mL, 29.6 mmol) was added dropwise to a solution of 13 (40.0 mg, 84.2 μmol) in DCM (4.6 mL). The resulting mixture was stirred at 0°C for 1 hour and then concentrated to dryness to give a crude intermediate (33 mg) as a brown solid, which was dissolved in MeOH (10 mL). A solution of lithium hydroxide monohydrate (17.4 mg, 414 μmol) in water (10 mL) was added to the solution, and the mixture was stirred under reflux for 1 hour. The mixture was then cooled to room temperature and concentrated to dryness. The residue was washed with EA (10 mL), acidified to pH 1-2 with 1 N HCl, and extracted with EA (3 × 10 mL). The combined organic matter was dried over Na₂SO₄, filtered, and concentrated to give a title compound 14 (26.9 mg, 94% yield) as a brown solid. The crude product was used for step 5 without further purification. (Characteristics are shown in Table 6) Step 5. 2-Amino-6-(2-chlorophenyl)-6-cyano-7-oxo-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxylic acid methyl ester amide (15) Add to the suspension of 14 (19.9 mg, 57.4 μmol) in CHCl3 (398 μL)N,N - Diisopropylethylamine (30.0 μL, 172 μmol), a saturated NH3 solution in CHCl3 (0.3 mL) (prepared internally), and HATU (24.0 mg, 63.1 μmol). The mixture was stirred at room temperature. After stirring for 5 hours, 24 mg of HATU (63.1 μmol) and 0.5 mL of a saturated NH3 solution in CHCl3 were added. The mixture was stirred for 16 hours, then 25 mg of HATU (65.7 μmol) and 0.6 mL of a saturated NH3 solution in CHCl3 were added, and stirring continued for 4.5 hours. The mixture was then diluted with 5 mL of water and 5 mL of CHCl3. The layers were separated, and the aqueous phase was extracted with CHCl3 (2 × 5 mL). The combined organic compounds were dried over Na2SO4, filtered and concentrated, and the residue was purified by reversed-phase rapid column chromatography (elution buffer gradient of 0% to 100% CH3CN H2O solution containing 0.1% (v / v) formic acid) to give title compound 15 as a white solid (6.2 mg, 31% yield).

[0302] 1 H NMR: 400 MHz, CD3OD, δ (ppm): 7.73-7.68 (m, 1H), 7.50-7.45 (m, 1H), 7.45-7.40 (m, 2H), 3.29-3.11 (m, 3H), 2.48-2.41 (m, 1H). LC-MS: rt = 1.15min, MS: 345.0 (calcd), 346.0 (M+H + (Measured value).

[0303] Example 4-27 Compounds 16-34 (Examples 4-22) were synthesized using appropriately substituted diketones as starting materials, following the synthetic steps of compound 4 described above (Example 1, Scheme 1). Compounds 35 and 36 (Examples 23 and 24) were synthesized in a similar manner following the synthetic steps of compound 8 described above (Scheme 2). Compounds 37-39 (Examples 25-27) were synthesized in a similar manner following the synthetic steps of compound 9 described above (Scheme 2). The characterization of compounds 16-39 (Examples 4-27) is provided in Table 2.

[0304] Table 2. Characterization of compounds 16-39 (Examples 4-27)

[0305] Example 28 2-Amino-6-cyano-6-(cyclobutylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[ b ]Thiophene-3-carboxylic acid (47) and Example 29 2-Amino-6-cyano-6-(cyclobutylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[ b Thiophene-3-carboxamide (48) Scheme 4

[0306] Step 1. 8-(cyclobutylmethyl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (41) Under Ar conditions, a solution of LDA (2.69 mL, 1 M in THF / hexane, 2.69 mmol) in anhydrous THF (3.60 mL) was added to a flame-dried round-bottom flask. The solution was cooled to -78°C, and 1,4-dioxaspiro[4.5]decane-8-carboxynitrile (40, 265 μL, 1.79 mmol) was added. The mixture was stirred at -78°C for 30 min, and then (bromomethyl)cyclobutane (202 μL, 1.79 mmol) was added. The reaction vessel was removed from the acetone / dry ice bath, and the solution was stirred at room temperature for 64 h. The mixture was then partitioned between EA and water (15 mL each), the layers were separated, and the aqueous phase was extracted with EA (2 × 15 mL). The combined organics were dried over Na2SO4, filtered, and concentrated to give an orange oily crude title compound 41, which was unpurified and uncharacterized for use in step 2.

[0307] Step 2. 1-(cyclobutylmethyl)-4-oxocyclohexane-1-carbonitrile (42) A solution of 41 (422 mg, 1.79 mmol, assuming the quantitative yield in step 1) in acetone (25.3 mL) was treated with 2 N HCl (4.59 mL, 9.19 mmol), and the resulting mixture was stirred at 40°C for 64 hours. The mixture was then cooled to room temperature, concentrated by rotary evaporation to remove acetone, and the aqueous residue was extracted with EA (3 x 30 mL). The combined organic matter was dried over Na₂SO₄, filtered, and concentrated to give a crude title compound 42 as a brown solid, which was not purified or characterized and used in step 3.

[0308] Step 3. 2-Amino-6-cyano-6-(cyclobutylmethyl)-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxylic acid ethyl ester ester (43) A suspension of ethyl 2-cyanoacetate (210 μL, 1.97 mmol), morpholine (172 μL, 1.95 mmol), sulfur (63 mg, 247 μmol), and 42 (342 mg, 1.79 mmol, assuming the quantitative yield in step 2) in EtOH (1.8 mL) was stirred at 60°C for 16 h. The mixture was cooled to room temperature and then concentrated by rotary evaporation, partitioning the residue between EA and water (20 mL each). The organic phase was dried over Na₂SO₄, filtered, and concentrated. The residue was purified by rapid column chromatography (elution gradient of 0% to 50% hexane solution of EA) to give the title compound 43 (353 mg, 62% yield in three steps) as a pale yellow solid. LC-MS: rt = 1.74 min, MS: 318.1 (calcd), 319.1 (M+H) + (Measured value).

[0309] Step 4. 2-Acetylamino-6-cyano-6-(cyclobutylmethyl)-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxylic acid methyl ester ethyl formate (44) The suspension of 43 (227 mg, 713 μol) in acetic acid (4.09 mL) was treated with acetic anhydride (80.9 μL, 856 μol), and the resulting mixture was stirred at 70°C for 3 hours. The mixture was then cooled to room temperature and concentrated to dryness. The residue was diluted with DCM (10 mL), washed successively with saturated aqueous NaHCO3 solution, water, and brine (10 mL each), dried over Na2SO4, filtered, and concentrated to give a yellow solid, title compound 44 (227 mg, 88% yield). LC-MS: rt = 1.79 min, MS: 360.2 (calcd), 361.1 (M+H2O). + (Measured value).

[0310] Step 5. 2-Acetylamino-6-cyano-6-(cyclobutylmethyl)-7-oxo-4,5,6,7- tetrahydrobenzo[d]thiazole b ] Step 6. 2-Acetylamino-6-cyano-6-(cyclobutylmethyl)-7-oxo-4,5,6,7- tetrahydrobenzo[d]thiazole-3-carboxylic acid ethyl phen-3-formate (45) Cerium sulfate (1.81 g, 5.44 mmol) was added to a suspension of 44 (227 mg, 630 μmol) in acetic acid (2.1 mL) and water (6.3 mL). The mixture was sonicated for 1 min and then stirred at room temperature for 88 h. Subsequently, the mixture was diluted with water and EA (30 mL each), sonicated for 3 min, and transferred to a separatory funnel. The layers were separated, and the organic phase was washed successively with 1 N NaOH and brine (30 mL each), dried over Na2SO4, filtered, and concentrated to give a yellow gelatinous title compound 45 (175.1 mg, 74% yield), which was unpurified and used in step 6. LC-MS: rt = 1.71 min, MS: 374.1 (calcd), 375.2 (M+H + (Measured value).

[0311] Step 6. 2-Amino-6-cyano-6-(cyclobutylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxylic acid ethyl formate (46) A solution of 45 (170 mg, 454 μmol) in toluene (744 μL) was treated with pyrrolidine (559 μL, 6.81 mmol) and stirred at room temperature for 1 hour. The mixture was then concentrated by rotary evaporation, and the residue was purified by rapid column chromatography (elution gradient of 0% to 50% hexane solution of EA) to give a white solid, title compound 46 (118.1 mg, 78% yield). LC-MS: rt = 1.63 min, MS: 332.1 (calcd), 333.1 (M+H) + (Measured value).

[0312] Step 7. 2-Amino-6-cyano-6-(cyclobutylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxylic acid formic acid (47) A solution of lithium hydroxide monohydrate (66.9 mg, 1.59 mmol) in water (38.4 mL) was added to a solution of 46 (100 mg, 261 μmol) in MeOH (38.4 mL). The mixture was stirred under reflux for 16 hours, then cooled to room temperature and concentrated by rotary evaporation to remove most of the MeOH. The aqueous residue was washed with EA (2 × 25 mL), acidified to pH 1-2 with 3 N HCl, and extracted with EA (3 × 25 mL). The organic matter was dried over Na₂SO₄, filtered, and concentrated to give a white solid, title compound 47 (78.2 mg, 81% yield).

[0313] 1 H NMR: 400 MHz, DMSO-d6, δ (ppm): 12.75 (bs, 1H), 8.48 (bs, 2H), 3.08-3.02 (m, 2H), 2.55-2.42 (m, 1H), 2.43-2.29 (m, 1H), 2.27-2.16 (m, 1H), 2.13-1.96 (m, 3H), 1.93-1.61 (m, 5H). LC-MS: rt = 1.32 min, MS: 304.1(calcd), 305.1 (M+H + (Measured value).

[0314] Step 8. 2-Amino-6-cyano-6-(cyclobutylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxylic acid formamide (48) To 47 (38.3 mg, 126 μmol), a saturated NH3 solution in chloroform (780 μL) (prepared internally), ammonium chloride (135 mg, 2.52 mmol), and N,N- HATU (73.2 mg, 189 μmol) was added to a suspension of diisopropylethylamine (43.8 μL, 252 μmol) in DMF (1.39 mL). The resulting mixture was stirred at room temperature for 16 hours, then diluted with saturated NH4Cl aqueous solution (20 mL) and extracted with EA (3 × 10 mL). The combined organic matter was washed with ice-cold brine (2 × 15 mL), dried over Na2SO4, filtered, and concentrated. The residue was first purified by reversed-phase rapid column chromatography (elution gradient of 0% to 100% CH3CN in H2O solution containing 0.1% (v / v) formic acid), and then by semi-preparative HPLC-MS (elution gradient of 25% to 100% CH3CN in 10 mM ammonium bicarbonate solution) to give the title compound 48 (14.5 mg, 38%) as a white solid.

[0315] 1 H NMR (400 MHz, CD3OD): δ 3.16-3.08 (m, 2H), 2.65-2.57 (m, 1H), 2.47(ddd, J = 13.3, 7.7, 5.4 Hz, 1H), 2.30 (ddd, J = 13.7, 6.0, 5.0 Hz, 1H), 2.20-2.10 (m, 3H), 2.00-1.90 (m, 2H), 1.87-1.74 (m, 3H). LC-MS: rt = 1.15min, MS: 303.1 (calcd), 304.1 (M+H) + (Measured value).

[0316] Example 30 2-Amino-6-cyano-6-(cyclopentylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[ b ]Thiophene-3-carboxylic acid (49) and Example 31 2-Amino-6-cyano-6-(cyclopentylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[ b Thiophene-3-carboxamide (50) Scheme 5

[0317] 2-amino-6-cyano-6-(cyclopentylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxylic acid (49) Compound 49 (Example 30) was synthesized in a manner similar to that of compound 47 (Example 28, Scheme 4) by using 1,4-dioxane[4.5]decane-8-carboxylonitrile (40) as the starting material and replacing (bromomethyl)cyclopentane with (bromomethyl)cyclobutane in the first step.

[0318] 1 H NMR: 400 MHz, DMSO-d6, δ (ppm): 12.75 (bs, 1H), 8.48 (bs, 2H), 3.13-3.00 (m, 2H), 2.48-2.38 (m, 1H), 2.29 (dt, J = 13.5, 5.2 Hz, 1H), 2.04-1.76 (m, 5H), 1.63-1.37 (m, 4H), 1.25-1.05 (m, 2H). LC-MS: rt = 1.41 min, MS:318.1 (calcd), 319.1 (M+H) + (Measured value).

[0319] 2-amino-6-cyano-6-(cyclopentylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxamide (50) To 49 (40.0 mg, 126 μmol), a saturated NH3 solution in chloroform (741 μL) (prepared internally), ammonium chloride (134 mg, 2.51 mmol), and N,N HATU (73.1 mg, 188 μmol) was added to a suspension of diisopropylethylamine (43.8 μL, 252 μmol) in DMF (1.39 mL). The resulting mixture was stirred at room temperature for 16 hours, and then 40 μL of HATU was added. N,N The mixture was prepared by stirring diisopropylethylamine (230 μmol), 550 μL of saturated NH3 solution in chloroform, and 65 mg of HATU (167 μmol) at 40°C for 24 hours. Subsequently, the mixture was partitioned between saturated NH4Cl aqueous solution and EA (20 mL each), the layers were separated, the organic phase was washed with ice-cold brine (2 × 15 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by reversed-phase rapid column chromatography (elution buffer gradient of 0% to 100% CH3CN in H2O solution containing 0.1% (v / v) formic acid) to give the title compound 50 (14.5 mg, 36%) as a white solid.

[0320] 1 H NMR: 400 MHz, CD3OD, δ (ppm): 3.25-3.05 (m, 2H), 2.54 (ddd, J=13.4, 7.9, 5.4 Hz, 1H), 2.38 (ddd, J = 13.7, 5.9, 5.0 Hz, 1H), 2.12 (dd, J =13.5, 6.7 Hz, 1H), 2.07-1.85 (m, 4H), 1.73-1.51 (m, 4H), 1.26-1.18 (m, 2H).LC-MS: rt = 1.25 min, MS: 317.1 (calcd), 318.0 (M+H + (Measured value).

[0321] Example 32 2-Amino-6-cyano-6-(cyclohexylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[ b ]Thiophene-3-carboxylic acid (51) and Example 33 2-Amino-6-cyano-6-(cyclohexylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[ b ]Thiophene-3-carboxamide (52) Scheme 6

[0322] 2-amino-6-cyano-6-(cyclohexylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxylic acid (51) Compound 51 (Example 32) was synthesized in a manner similar to that of compound 47 (Example 28, Scheme 4) by using 1,4-dioxane[4.5]decane-8-carboxylon (40) as the starting material and replacing (bromomethyl)cyclohexane with (bromomethyl)cyclobutane in the first step.

[0323] 1 H NMR: 400 MHz, DMSO-d6, δ (ppm): 12.69 (bs, 1H), 8.48 (bs, 2H), 3.12-2.97 (m, 2H), 2.47-2.36 (m, 1H), 2.27 (dt, J LC-MS: rt = 1.49 min, MS: 332.1 (calcd), 333.0 (M+H + (Measured value).

[0324] 2-amino-6-cyano-6-(cyclohexylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxamide (52) Add PyBOP (56.5 mg, 108 μmol) to a DMF (798 μL) solution containing 51 (24.0 mg, 72.2 μmol). N,N - Diisopropylethylamine (40.0 μL, 230 μmol) and ammonium chloride (38.6 mg, 722 μmol). The resulting mixture was stirred at room temperature for 80 minutes, then diluted with saturated NH4Cl aqueous solution (5 mL) and extracted with EA (3 × 5 mL). The combined organic matter was washed with ice-cold brine (2 × 10 mL), dried over Na2SO4, filtered and concentrated, and the residue was purified by rapid column chromatography (elution gradient of 10% to 100% EA in hexane solution) to give title compound 52 as an orange solid (13.6 mg, 57% yield).

[0325] 1 H NMR: 400 MHz, CD3OD, δ (ppm): 3.18-3.09 (m, 2H), 2.51 (ddd, J =13.3, 7.5, 5.6 Hz, 1H), 2.36 (dt, J LC-MS: rt = 1.34min, MS: 331.1 (calcd), 332.2 (M+H + (Measured value).

[0326] Example 34 2-Amino-6-cyano-6-(cyclopropylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[ b ]Thiophene-3-carboxylic acid (53) and Example 35 2-Amino-6-cyano-6-(cyclopropylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[ b ]Thiophene-3-carboxamide (54) Scheme 7

[0327] 2-amino-6-cyano-6-(cyclopropylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxylic acid (53) Compound 53 (Example 34) was synthesized in a manner similar to that of compound 47 (Example 28, Scheme 4) by using 1,4-dioxane[4.5]decane-8-carboxylon (40) as the starting material and (bromomethyl)cyclopropane instead of (bromomethyl)cyclobutane in the first step.

[0328] 1 H NMR: 400 MHz, CD3OD, δ (ppm): 3.23-3.19 (m, 2H), 2.54-2.50 (m, 1H), 2.42-2.39 (m, 1H), 1.89 (dd, J = 14.27, 7.15 Hz, 1H), 1.78 (dd, J = 14.26,6.72 Hz, 1H), 0.91-0.87 (m, 1H), 0.57-0.53 (m, 2H), 0.22-0.19 (m, 2H). LC-MS:rt = 1.18 min, MS: 290.1 ​​(calcd), 291.0 (M+H) + (Measured value).

[0329] 2-amino-6-cyano-6-(cyclopropylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxamide (54) HATU (52.4 mg, 0.138 mmol) was added to the suspension of 53 (36.4 mg, 0.125 mmol) in CHCl3 (871 μL). N,N -Diisopropylethylamine (65.5 μL, 0.376 mmol). The mixture was stirred at room temperature for 20 min, and saturated NH3 solution in CHCl3 (0.8 mL) (prepared internally) and NH4Cl (6.71 mg, 0.125 mmol) were added. The reaction mixture was stirred for 16 h and partitioned between EA and saturated NaHCO3 aqueous solution. The layers were separated, the organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid column chromatography (elution gradient of 20% to 100% EA in hexane solution) to give title compound 54 as a white solid (20.0 mg, 55% yield).

[0330] 1 H NMR: 400 MHz, CD3OD, δ (ppm): 3.13 (t, J = 6.03 Hz, 2H), 2.60-2.53(m, 1H), 2.48-2.42 (m, 1H), 1.93 (dd,J = 14.28, 7.11 Hz, 1H), 1.80 (dd, J =14.28, 6.79 Hz, 1H), 0.94-0.84 (m, 1H), 0.58-0.55 (m, 2H), 0.24-0.20 (m, 2H).LC-MS: rt = 1.02 min, MS: 289.1 (calcd), 290.1 ​​(M+H) + (Measured value).

[0331] Example 36 2-Amino-6-cyano-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b Thiophene-3-carboxylic acid (59) Scheme 8

[0332] Step 1. 2-Amino-6-cyano-6-phenyl-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxylic acid ethyl ester (56) Morpholine (2.60 mL, 30.1 mmol) and sulfur (969 mg, 3.78 mmol) were added to a solution of 4-oxo-1-phenylcyclohexane-1-carboxynitrile (55) (6.00 g, 30.1 mmol) and ethyl 2-cyanoacetate (2.91 mL, 27.4 mmol) in EtOH (48.0 mL). The reaction mixture was stirred at 60°C for 16 hours. The mixture was cooled to room temperature, and a white precipitate appeared. The solid was collected by filtration, washed with EtOH, and dried under vacuum to give the title compound 56 (8.15 g, 91% yield) as a white solid. LC-MS: rt = 1.55 min, MS: 326.1 (calcd), 327.0 (M+H) + (Measured value).

[0333] Step 2. 2-Acetylamino-6-cyano-6-phenyl-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxylic acid ethyl ester (57) Acetic anhydride (2.83 mL, 30.0 mmol) was added to a solution of acetic acid (143 mL) containing 56 (8.15 g, 25.0 mmol). The mixture was stirred at 60°C for 1 day, then cooled to room temperature and concentrated to dryness. The residue was partitioned between DCM and water. The layers were separated, and the organic phase was washed with saturated aqueous NaHCO3 solution, water, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated to give a white solid, title compound 57 (9.0 g, 98% yield). LC-MS: rt = 1.61 min, MS: 368.1 (calcd), 369.1 (M+H2O). + (Measured value).

[0334] Step 3. 2-Acetylamino-6-cyano-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxylic acid ethyl formate (58) Cerium sulfate (70.1 g, 211 mmol) was added to a solution of acetic acid (66 mL) and water (66 mL) containing 57 (9.00 g, 24.4 mmol). The mixture was sonicated until homogeneous and stirred at room temperature for 24 hours. The suspension was partitioned between EA and water. The layers were separated, and the organic phase was washed with NaOH 1N, water, and brine. The organic layer was then dried over Na2SO4, filtered, and concentrated to give a white solid, title compound 58 (9.10 g, 97% yield). LC-MS: rt = 1.56 min, MS: 382.1 (calcd), 383.1 (M+H) + (Measured value).

[0335] Step 4. 2-Amino-6-cyano-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxylic acid (59) A solution of lithium hydroxide monohydrate (2.20 g, 52.4 mmol) in water (1.26 L) was added to a suspension of 58 (4.00 g, 10.44 mmol) in MeOH (1.26 L). The reaction mixture was stirred under reflux for 2 hours and then cooled to room temperature. The mixture was diluted with water and concentrated to remove most of the organic solvent, and then washed with EA. The aqueous layer was acidified by slow addition of HCl 3N and extracted with EA. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by grinding with a DCM / pentane mixture to give title compound 59 (2.54 g, 78% yield) as a gray solid.

[0336] 1 H NMR: 400 MHz, CD3OD, δ (ppm): 7.43-7.31 (m, 5H), 3.27-3.23 (m, 1H), 2.88-2.73 (m, 2H), 2.71-2.61 (m, 1H). LC-MS: rt = 1.23 min, MS: 312.1(calcd), 313.1 (M+H) + (Measured value).

[0337] Example 37 ( R )-2-amino-6-cyano-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b Thiophene-3-carboxylic acid (60a) ( S )-2-amino-6-cyano-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ bThiophene-3-carboxylic acid (60b) Scheme 9

[0338] Racemic compound 59 (86.0 mg) was subjected to SFC chiral separation (isocratic in CO2 35% MeOH) to give a pale pink solid enantiomer-enriched compound 60a (33.1 mg, 38% separation yield) and a white solid 60b (35.4 mg, 41% separation yield) (absolute configuration was determined based on the analytical crystal structure of enantiomer 60a).

[0339] 60a: 1 ¹H NMR: Same as racemic mixture (59). LC-MS: rt = 1.23 min, MS: 312.1 (calcd), 313.1 (M+H) + (Measured values). Analytical SFC (IG column with a gradient of 5-60% MeOH aqueous solution (95-40% CO2)): rt = 3.84 min, ee. = 99.9%.

[0340] 60b: 1 ¹H NMR: Same as racemic mixture (59). LC-MS: rt = 1.23 min, MS: 312.1 (calcd), 313.1 (M+H) + (Measured values). Analytical SFC (IG column with a gradient of 5-60% MeOH aqueous solution (95-40% CO2)): rt = 4.76 min, ee. = 97.6%.

[0341] Example 38 2-Amino-6-cyano-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b ]Thiophene-3-carboxamide (61) and Example 39 2-Amino-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b Thiophene-3,6-dicarboxamide (62) Scheme 10

[0342] Step 1. 2-Amino-6-cyano-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxamide (61) Add HATU (4.73 g, 12.2 mmol) to a DMF (90.0 mL) solution containing 59 g (2.54 g, 8.13 mmol) andN,N - Diisopropylethylamine (2.83 mL, 16.4 mmol) was added, and the mixture was stirred at room temperature for 20 minutes. Then, ammonium chloride (8.74 g, 163 mmol), an NH3 solution in THF (45.0 mL, 18.0 mmol, 0.4 M), and a saturated NH3 solution in chloroform (45.0 mL) (prepared internally) were added to the mixture. The reaction mixture was stirred at room temperature for 16 hours and partitioned between EA and a saturated aqueous solution of NaHCO3. The layers were separated, the organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid column chromatography (elution gradient of 20% to 100% EA in hexane solution) followed by reversed-phase rapid column chromatography (elution gradient of 0% to 100% CH3CN in H2O solution containing 0.1% (v / v) formic acid) to give title compound 61 as a white solid (1.20 g, 47% yield).

[0343] 1 H NMR: 400 MHz, CD3OD, δ (ppm): 7.41-7.36 (m, 5H), 3.17-3.11 (m, 1H), 2.87-2.77 (m, 2H), 2.74-2.66 (m, 1H). LC-MS: rt = 1.04 min, MS: 311.1(calcd), 312.0 (M+H) + (Measured value).

[0344] Step 2. 2-Amino-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3,6-dicarboxylic acid diamide (62) ) A 30% aqueous hydrogen peroxide solution (170 μL) was added to a suspension of 61 (13.2 mg, 42.4 μmol) and potassium carbonate (11.7 mg, 84.8 μmol) in DMSO (569 μL). The mixture was stirred at room temperature for 3 hours, and then partitioned between EA and water (5 mL each). The layers were separated, the organic phase was washed with 5 mL of water, and the combined aqueous phase was extracted with EA (2 x 3 mL). The combined organic phase was washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by reversed-phase rapid column chromatography (elution buffer gradient of 0% to 70% CH3CN in H2O solution, containing 0.1% (v / v) formic acid) to give title compound 62 (3.6 mg, 28% yield) as a white solid.

[0345] 1 H NMR: 400 MHz, CD3OD, δ (ppm): 7.41-7.25 (m, 5H), 3.05 (dt, J=16.8, 4.2 Hz, 1H), 2.78-2.59 (m, 3H). LC-MS: rt = 0.86 min, MS: 329.1(calcd), 329.9 (M+H + (Measured value).

[0346] Example 40 ( S )-2-amino-6-cyano-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b ]Thiophene-3-carboxamide (63) and Example 41 ( R )-2-amino-6-cyano-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b Thiophene-3-carboxamide (64) Scheme 11

[0347] Racemic compound 61 (96.5 mg) was subjected to SFC chiral separation (isocratic: CH3CN / EtOH 1:1 in CO2 at 45%) to give enantiomerically enriched compound 63 (29.0 mg, 30% separation yield) and enantiomerically enriched compound 64 (29.0 mg, 30% separation yield) as white solids (absolute configuration was determined based on the analytical crystal structure of enantiomer 64).

[0348] 63: 1 ¹H NMR: Same as racemic mixture (61). LC-MS: rt = 1.04 min, MS: 311.1 (calcd), 312.0 (M+H) + (Measured values). Analytical SFC (IG column with 5-60% ACN / EtOH (95-40% CO2) gradient): rt = 4.71 min, ee = >99.9%.

[0349] 64: 1 ¹H NMR: Same as racemic mixture (61). LC-MS: rt = 1.04 min, MS: 311.1 (calcd), 312.0 (M+H) + (Measured values). SCF analysis (IG column with 5-60% ACN / EtOH (95-40% CO2) gradient): rt = 4.09 min, ee = >99.9%.

[0350] Examples 42-49 Compound 59 (Example 36, Scheme 8) was used instead of Compound 8 as the starting material, and cyclobutylamine, cyclopentylamine, 3-aminooxetane, 3-aminotetrahydrofuran, 4-aminotetrahydropyran, 2,2,2-trifluoroethylamine, and 2,2-difluoroethane-1-amine were used instead of cyclopropylamine, respectively, to synthesize Compounds 65-71 (Examples 42-48) in a manner similar to that used to synthesize Compound 9 (Example 2, Scheme 2). Compound 72 (Example 49) was obtained in the same manner using Compound 53 (Example 34, Scheme 7) as the starting material. The characterization of Compounds 65-72 (Examples 42-49) is provided in Table 3.

[0351] Table 3. Characterization of compounds 65-72 (Examples 42-49)

[0352] Example 50 2-Amino-6-cyano-6-isobutyl-7-oxo-4,5,6,7-tetrahydrobenzo[ b ]Thiophene-3-carboxamide (75) Scheme 12

[0353] Step 1. 1-isobutyl-4-oxocyclohexane-1-carbonitrile (73) At -78°C, LDA (2.39 mL, 1 M in THF / hexane, 2.39 mmol) was added dropwise to a THF (3.0 mL) solution of 1,4-dioxane[4.5]decane-8-carboxynitrile (40, 221 μL, 1.50 mmol, Scheme 4). After 30 minutes, 1-bromo-2-methylpropane (164 μL, 1.50 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 72 hours. The reaction mixture was then partitioned between hexane and water. The layers were separated, and the aqueous phase was extracted with EA. The combined organic layers were combined, dried over Na2SO4, filtered, and concentrated. The dried residue was dissolved in acetone (19.7 mL), and HCl 3N (4.98 mL, 15.0 mmol) was slowly added. The mixture was stirred for 16 hours and then concentrated to remove the organic solvent by slow addition of a saturated NaHCO3 solution. The remaining aqueous solution was extracted with EA, the organic layer was dried over Na2SO4, filtered, and concentrated to dryness to give title compound 73 (141 mg, 52% yield in two steps). LC-MS: rt = 1.45 min, MS: 179.1 (calcd), 180.0 (M+H) + (Measured value).

[0354] Step 2. 2-Amino-6-cyano-6-isobutyl-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxamide (74) Morpholine (67.6 μL, 0.784 mmol) and sulfur (25.2 mg, 98.3 μmol) were added to a solution of 73 (141 mg, 0.784 mmol) and cyanoacetamide (59.9 mg, 0.713 mmol) in EtOH (713 μL). The reaction mixture was stirred at 60°C for 19 hours, cooled to room temperature, and concentrated to dryness. The residue was partitioned between EA and water. The layers were separated, the organic phase was dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid column chromatography (elution gradient of 0% to 100% EA in hexane) to give a beige solid, title compound 74 (115 mg, 58% yield). LC-MS: rt = 1.49 min, MS: 277.1 (calcd), 277.9 (M+H) + (Measured value).

[0355] Step 3. 2-Amino-6-cyano-6-isobutyl-7-oxo-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxamide (75) Selenium dioxide (12.0 mg, 0.108 mmol) was added to a solution of 74 (30 mg, 0.108 mmol) in DMSO (643 μL). The reaction mixture was stirred at room temperature for 12 hours, and then partitioned between brine and EA. The layers were separated, the organic phase was dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid column chromatography (eluent gradient of 0% to 10% MeOH in DCM solution) and subsequent semi-preparative HPLC-MS (35% to 100% MeOH in 10 mM ammonium formate solution, pH 3.8) to give title compound 75 (3.20 mg, 10% yield) as a white solid.

[0356] 1 H NMR: 400 MHz, CD3OD, δ (ppm): 3.19-3.09 (m, 2H), 2.51 (ddd, J =13.71, 7.59, 5.42 Hz, 1H), 2.36 (dt, J = 13.65, 5.45 Hz, 1H), 1.97-1.85 (m,2H), 1.80-1.75 (m, 1H), 1.03 (d, J = 6.05 Hz, 6 H). LC-MS: rt = 1.11 min, MS: 291.1 (calcd), 292.1 (M+H + (Measured value).

[0357] Example 51 2-Amino-6-(cyanomethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b ]Thiophene-3-carboxylic acid (81) and Example 52 2-Amino-6-(cyanomethyl)- N -Cyclopropyl-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b ]Thiophene-3-carboxamide (82) Scheme 13

[0358] Step 1. 2-Amino-6-(cyanomethyl)-6-phenyl-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxylic acid ethyl ester (77) 2-(4-oxo-1-phenylcyclohexyl)acetonitrile (76) Bioorg. Med. Chem. Lett. Morpholine (285 μL, 3.31 mmol) and sulfur (106 mg, 0.415 mmol) were added to a solution of ethyl 2-cyanoacetate (705 mg, 3.31 mmol) and EtOH (3.01 mL). The mixture was stirred at 60 °C for 16 h and then cooled to room temperature, forming a white precipitate. The solid was collected by filtration, washed with EtOH, and dried under vacuum to give a white solid of title compound 77 (682 mg, 67% yield). LC-MS: rt = 1.55 min, MS: 340.1 (calcd), 341.1 (M+H) + (Measured value).

[0359] Step 2. 2-Acetylamino-6-(cyanomethyl)-6-phenyl-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxylic acid ethyl formate (78) Acetic anhydride (227 μL, 2.40 mmol) was added to a solution of acetic acid (11.5 mL) containing 77 (682 mg, 2.00 mmol). The mixture was stirred at 60°C for 24 hours, then cooled to room temperature and concentrated to dryness. The residue was partitioned between DCM and water. The layers were separated, and the organic phase was washed with saturated aqueous NaHCO3 solution, water, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated to give a white solid, title compound 78 (766 mg, >99% yield). LC-MS: rt = 1.61 min, MS: 382.1 (calcd), 383.1 (M+H2O). + (Measured value).

[0360] Step 3. 2-Acetylamino-6-(cyanomethyl)-7-oxo-6-phenyl-4,5,6,7- tetrahydrobenzo[d]thiophene-3-carboxylic acid b ]thiophene- 3-ethyl formate (79) Cerium sulfate (5.75 g, 17.3 mmol) was added to a solution of 78 (766 mg, 2.00 mmol) in acetic acid (6.73 mL) and water (6.73 mL). The suspension was sonicated until homogeneous, stirred at room temperature for 1 day, and then partitioned between EA and water. The layers were separated, and the organic phase was washed with 1 N NaOH, water, and brine. The organic layer was dried over Na₂SO₄, filtered, and concentrated to give a white solid, title compound 79 (794 mg, >99% yield). LC-MS: rt = 1.47 min, MS: 396.1 (calcd), 397.1 (M+H₂O). + (Measured value).

[0361] Step 4. 2-Amino-6-(cyanomethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxylic acid methyl ester ethyl formate (80) Pyrrolidine (2.46 mL, 30.0 mmol) was added to a suspension of 79 (793 mg, 2.00 mmol) in toluene (3.28 mL). After stirring for a few minutes, the suspension became a solution. The reaction mixture was stirred at 80°C for 1 hour, then cooled to room temperature and concentrated. The residue was purified by rapid column chromatography (elution gradient of 0% to 100% EA in hexane) to give the title compound 80 (408 mg, 57% yield) as a white solid. LC-MS: rt = 1.43 min, MS: 354.1 (calcd), 355.0 (M+H) + (Measured value).

[0362] Step 5. 2-Amino-6-(cyanomethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxylic acid methyl ester acid (81) A solution of lithium hydroxide monohydrate (242 mg, 5.76 mmol) in water (139 mL) was added to a suspension of 80 (408 mg, 1.15 mmol) in MeOH (139 mL). The reaction mixture was stirred under reflux for 16 hours and then cooled to room temperature. The mixture was diluted with water and concentrated to remove most of the organic solvent, and then washed with EA. The aqueous layer was collected, acidified by slow addition of 2N HCl, and extracted with EA. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid column chromatography (eluent gradient of 0% to 10% in DCM solution of MeOH) to give a white solid, title compound 81 (376 mg, >99% yield).

[0363] 1 H NMR: 400 MHz, CD3OD, δ (ppm): 7.34-7.27 (m, 5H), 3.35-3.30 (m, 1H), 3.01 (d, J= 16.71 Hz, 1H), 2.89 (d, J = 16.71 Hz, 1H), 2.77-2.74 (m, 1H), 2.49-2.45 (m, 2H). LC-MS: rt = 1.16 min, MS: 326.1 (calcd), 327.0 (M+H + (Measured value).

[0364] Step 6. 2-Amino-6-(cyanomethyl)- 1,3-benzoxazin-4-ol N - cyclopropyl-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo b ] thiophene-3-carboxamide (82)​ HATU (359 mg, 0.944 mmol) was added to the suspension of 81 (154 mg, 0.472 mmol) in THF (5.90 mL). N,N -Diisopropylethylamine (164 μL, 0.944 mmol). The mixture was stirred at room temperature for 20 min, and then cyclopropylamine (327 μL, 4.72 mmol) was added. The reaction mixture was stirred for another 16 h, and then partitioned between EA and saturated NH4Cl aqueous solution. The layers were separated, the organic phase was collected, washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid column chromatography (elution gradient of 20% to 100% EA in hexane solution) and subsequent reversed-phase rapid column chromatography (elution gradient of 0% to 100% CH3CN in H2O solution containing 0.1% (v / v) formic acid) to give title compound 82 as a white solid (46.5 mg, 27% yield).

[0365] 1 H NMR: 400 MHz, CD3OD, δ (ppm): 7.35-7.27 (m, 5H), 3.00 (d, J = 16.70Hz, 1H), 2.89 (d, J = 16.71 Hz, 1H), 2.82-2.78 (m, 1H), 2.77-2.74 (m, 1H), 2.69-2.64 (m, 2H), 2.49-2.42 (m, 1H), 0.72-0.67 (m, 2H), 0.54-0.48 (m, 2H).LC-MS: rt = 1.20 min, MS: 365.1 (calcd), 366.1 (M+H + (Measured value).

[0366] Example 53 2-Amino-6-(cyanomethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b ]Thiophene-3-carboxamide (83) and Example 54 2-Amino-6-(2-amino-2-oxoethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b Thiophene-3-carboxamide (84) Scheme 14

[0367] Step 1. 2-Amino-6-(cyanomethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxylic acid methyl ester Step 2. 2-Amino-6-(cyanomethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxylic acid Step 3. amide (83) The suspension of 81 (50.0 mg, 0.153 mmol) in anhydrous DMF (1.69 mL) was saturated with gaseous NH3. Then, PyBOP (120 mg, 0.230 mmol) and N,N -Diisopropylethylamine (53.4 μL, 0.306 mmol): The reaction mixture was stirred at room temperature for 16 hours. The mixture was then partitioned between EA and a saturated aqueous NH4Cl solution. The layers were separated, and the aqueous phase was extracted with EA. The combined organic matter was dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid column chromatography (eluent gradient of 20% to 100% EA in hexane solution) followed by reversed-phase rapid column chromatography (eluent gradient of 0% to 100% CH3CN in H2O solution containing 0.1% (v / v) formic acid) to give title compound 83 (47.0 mg, 94% yield) as a white solid.

[0368] 1 H NMR: 400 MHz, CD3OD, δ (ppm): 7.39-7.29 (m, 5H), 3.02-2.95 (m, 2H), 2.90 (d, J = 16.72 Hz, 1H), 2.80 (ddd, J = 13.55, 4.09, 2.50 Hz, 1H), 2.67(ddd, J = 17.32, 11.78, 4.10 Hz, 1H), 2.49 (ddd, J = 13.53, 11.79, 4.45 Hz,1H). LC-MS: rt = 1.01 min, MS: 325.1 (calcd), 326.0 (M+H + (Measured value).

[0369] Step 2. 2-Amino-6-(2-amino-2-oxoethyl)-7-oxo-6-phenyl-4,5,6,7- tetrahydrobenzo[d]oxazole-3-carboxylic acid b ] thiophene-3-carboxamide (84) The suspension of 83 (47.0 mg, 0.144 mmol) in concentrated sulfuric acid (470 μL) was stirred at room temperature for 72 hours, then poured onto crushed ice. The resulting mixture was alkalized with 4N NaOH solution. The solution was extracted with DCM. The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid column chromatography (eluent gradient of 0% to 10% MeOH in DCM solution, followed by 100% isopropanol) to give the title compound 84 (17.5 mg, 35% yield) as a white solid.

[0370] 1 H NMR: 400 MHz, CD3OD, δ (ppm): 7.32-7.27 (m, 4H), 7.23-7.19 (m, 1H), 2.99 (d, J = 14.78 Hz, 1H), 2.92-2.87 (m, 1H), 2.78-2.71 (m, 1H), 2.65 (d, J = 14.76 Hz, 2H), 2.60-5.50 (m, 1H). LC-MS: rt = 0.84 min, MS: 343.1 (calcd), 344.1 (M+H + (Measured value).

[0371] Example 55 2-Amino-6-(2-hydroxyethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b Thiophene-3-carboxylic acid (89) Scheme 15

[0372] Step 1. 2-Amino-6-(2-hydroxyethyl)-6-phenyl-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxylic acid ethyl ester (86) To 4-(2-hydroxyethyl)-4-phenylcyclohexane-1-one (85) Bioorg. Med. Chem. Lett.Morpholine (3.50 mL, 40.1 mmol) and sulfur (1.29 g, 5.03 mmol) were added to a solution of ethyl 2-cyanoacetate (7.95 g, 36.4 mmol) and ethyl 2-cyanoacetate (4.26 mL, 40.1 mmol) in EtOH (36.4 mL). The reaction mixture was stirred at 60°C for 16 hours and then cooled to room temperature, resulting in a white precipitate. The solid was collected by filtration, washed with EtOH, and dried under vacuum to give a white solid, title compound 86 (9.40 g, 72% yield). LC-MS: rt = 1.41 min, MS: 345.1 (calcd), 346.1 (M+H) + (Measured value).

[0373] Step 2. 2-Acetylamino-6-(2-hydroxyethyl)-6-phenyl-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxylic acid ethyl formate (87) Acetic anhydride (2.73 mL, 28.8 mmol) was added to a solution of 86 (8.30 g, 24.0 mmol) in 138 mL of acetic acid. The mixture was stirred at 60°C for 2 hours, then cooled to room temperature and concentrated to dryness to give a brown oily title compound 87, which was used directly in the next step. LC-MS: rt = 1.78 min, MS: 387.2 (calcd), 388.2 (M+H) + (Measured value).

[0374] Step 3. 2-Acetylamino-6-(2-hydroxyethyl)-7-oxo-6-phenyl-4,5,6,7- tetrahydrobenzo[ b ]thiophene- 3-ethyl formate (88) Cerium sulfate (69.0 g, 208 mmol) was added to a solution of acetic acid (160 mL), water (160 mL), and dioxane (160 mL) for 87 (24.0 mmol). The mixture was sonicated until homogeneous, stirred at room temperature for 24 hours, and partitioned between EA and water. The layers were separated, and the organic phase was washed with NaOH 1N, water, and brine. The organic layer was then dried over Na2SO4, filtered, and concentrated to give title compound 88 (9.60 g, 91% yield) as an orange solid. LC-MS: rt = 1.56 min, MS: 401.1 (calcd), 402.1 (M+H) + (Measured value).

[0375] Step 4. 2-Amino-6-(2-hydroxyethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxylic acid methyl ester acid (89) A solution of lithium hydroxide monohydrate (6.86 g, 163.4 mmol) in water (1.11 L) was added to a suspension of 88 (9.60 g, 24.1 mmol) in MeOH (1.11 L). The reaction mixture was stirred at 55°C for 24 hours and then cooled to room temperature. The cooled mixture was diluted with water and concentrated to remove most of the organic solvent, and then washed with EA. The aqueous layer was collected, acidified by slow addition of HCl 2N, and extracted with EA. The organic extract was dried over Na2SO4, filtered, and concentrated to give title compound 89 (7.0 g, 88% yield) as an orange solid.

[0376] 1 H NMR: 400 MHz, CD3OD, δ (ppm): 7.29-7.16 (m, 5H), 3.53-3.38 (m, 2H), 3.20-3.12 (m, 1H), 2.61-2.53 (dt, J = 13.63, 3.48 Hz, 1H), 2.44 (ddd, J =18.55, 11.61, 4.01 Hz, 1H), 2.34-2.23 (m, 1H), 2.15-2.03 (m, 2H). LC-MS: rt =1.04 min, MS: 331.1 (calcd), 332.0 (M+H + (Measured value).

[0377] Example 56 2-Amino-7-oxo-5-propyl-4,5,6,7-tetrahydrobenzo[ b ]Thiophene-3-carboxamide (91) Scheme 16

[0378] Compound 90 (277 mg, 1.18 mmol, synthesized in a manner similar to compound 3 in Scheme 1, using 5-propyl-1,3-cyclohexanedione instead of 5-(2-(trifluoromethyl)phenyl)cyclohexane-1,3-dione as the starting material) was dissolved in 98% H₂SO₄ (2.5 mL), and the mixture was stirred at room temperature for 24 hours. The reaction mixture was then slowly poured into an ice-cold aqueous solution of K₂CO₃, diluted with water, and extracted with EA (partial product precipitated; collected by filtration and combined with the remaining crude product). The organic layer was dried over Na₂SO₄, filtered, and concentrated. The residue was purified by rapid column chromatography (elution gradient of 50% to 100% EA in hexane solution) to give title compound 91 (144 mg, 48% yield) as a white solid.

[0379] 1 H NMR: 400 MHz, DMSO-d6, δ (ppm): 7.97 (s, 2H), 6.96 (bs, 2H), 2.99-2.95 (m, 1H), 2.67-2.57 (m, 1H), 2.38-2.32 (m, 1H), 2.19-2.07 (2H, m), 1.36(bs, 4H), 0.88 (bs, 3H). LC-MS: rt = 2.30 min, MS: 252.1 (calcd), 253.1 (M+H + (Measured value).

[0380] Example 57 2-Amino-6-(2,2-difluoroethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b ]Thiophene-3-carboxamide (97) Scheme 17

[0381] Step 1. 2-(8-phenyl-1,4-dioxaspiro[4.5]dec-8-yl)acetaldehyde (93) At -78°C, 2-(8-phenyl-1,4-dioxaspiro[4.5]decane-8-yl)acetonitrile (92) (1.0 g, 3.89 mmol) was reacted with acetonitrile (92) (1.0 g, 3.89 mmol). Bioorg Med. Chem LettDIBALH (3.92 mL, 25% in toluene, 5.83 mmol) was added dropwise to anhydrous toluene (24.5 mL) solution (p. 21, p. 405, 2011). The reaction mixture was stirred at -78°C for 2 hours, then carefully quenched with MeOH and saturated NH4Cl solution. The mixture was then allowed to reach room temperature, diluted with Et2O, and filtered through a diatomaceous earth mat. The layers were separated, and the organic phase was concentrated. The residue was dissolved in THF (15.0 mL) and 1N HCl (3.89 mL, 3.89 mmol) was added. The mixture was stirred at room temperature for 15 minutes, then quenched with saturated NaHCO3 solution and extracted with Et2O. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid column chromatography (elution gradient of 5% to 100% hexane solution of EA) to give colorless oily title compound 93 (605 mg, 60% yield), which was not characterized and used directly in the next step.

[0382] Step 2. 8-(2,2-difluoroethyl)-8-phenyl-1,4-dioxaspiro[4.5]decane (94) At 0°C, DAST (0.19 mL, 1.54 mmol) was added to a solution of 93 (200 mg, 0.77 mmol) in anhydrous DCM (9.5 mL). The reaction mixture was stirred at room temperature for 1 hour, then quenched with saturated NaHCO3 solution and extracted with DCM. The organic layer was dried over Na2SO4, filtered, and concentrated to give a colorless oily title compound 94 (213 mg, 98% yield), which was not characterized and used directly in the next step.

[0383] Step 3. 4-(2,2-difluoroethyl)-4-phenylcyclohexan-1-one (95) To a solution of 94 (213 mg, 0.75 mmol) in acetone (10.5 mL), HCl 2N (1.89 mL, 3.77 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. The mixture was then concentrated to remove the organic solvent by slowly adding a saturated NaHCO3 solution. The residue was extracted with EA, the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to dryness to give a colorless oily title compound 95 (169 mg, 94% yield), which was not characterized and used directly in the next step.

[0384] Step 4. 2-Amino-6-(2,2-difluoroethyl)-6-phenyl-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxylic acid methyl ester amine (96) Morpholine (0.068 mL, 0.78 mmol) and sulfur (25 mg, 0.098 mmol) were added to a solution of 95 (169 mg, 0.709 mmol) and cyanoacetamide (66 mg, 0.78 mmol) in EtOH (0.7 mL). The reaction mixture was stirred at 60°C for 16 hours, then cooled to room temperature and concentrated to dryness. The residue was partitioned between water and EA. The layers were separated, the organic phase was dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid column chromatography (elution gradient of 50% to 100% EA in hexane) to give title compound 96 (93 mg, 39% yield). LC-MS: rt = 1.39 min, MS: 336.1 (calcd), 337.1 (M+H) + (Measured value).

[0385] Step 5. 2-Amino-6-(2,2-difluoroethyl)-7-oxo-6-phenyl-4,5,6,7- tetrahydrobenzo[ b ]thiophene-3-carboxylic acid 3-formamide (97) At 0°C, a solution of DDQ (82 mg, 0.36 mmol) in THF (0.4 mL) was added dropwise to a mixture of 96 (40 mg, 0.119 mmol) in THF (0.4 mL) and water (0.08 mL). The reaction mixture was stirred at 0°C for 30 min, then quenched with saturated NaHCO3 solution and extracted with EA. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid column chromatography (elution gradient of 50% to 100% EA in hexane solution) to give title compound 97 (3 mg, 7% yield) as a pale yellow solid.

[0386] 1 H NMR: 400 MHz, CDCl3, δ (ppm): 7.37-7.27 (m, 5H), 7.04 (s, 2H), 5.80(tt, J = 56.4, 4.6, 1H), 5.32 (s, 2H), 2.97-2.92 (m, 1H), 2.83-2.78 (m, 1H), 2.65-2.57 (m, 1H), 2.53-2.42 (m, 3H). 19 F NMR: 376 MHz, CDCl3, δ (ppm): ‒110.4(ddt, J = 287.8, 56.1, 18.0 Hz, 1F), ‒111.5 (ddt, J= 287.8, 56.5, 16.3 Hz,1F). LC-MS: rt = 1.25 min, MS: 350.1 (calcd), 351.0 (M+H + (Measured value).

[0387] Example 58 2-Amino-6-cyano-6-isopropyl-7-oxo-4,5,6,7-tetrahydrobenzo[ b Thiophene-3-carboxamide (101) Scheme 18

[0388] Step 1. 8-isopropyl-1,4-dioxaspiro[4.5]decane-8-carbonitrile (98) At 0°C, LHMDS (6.88 mL, 1 M in THF, 6.88 mmol) was added dropwise to an anhydrous THF (12.0 mL) solution of 1,4-dioxane[4.5]decane-8-carboxynitrile (40, Scheme 4) (1.0 g, 5.98 mmol). The reaction mixture was stirred at 0°C for 1 hour, followed by the addition of 2-iodopropane (0.597 mL, 5.98 mmol). The reaction mixture was then allowed to slowly reach room temperature and stirred for 16 hours. The reaction mixture was then quenched with water and extracted with EA. The organic layer was dried over Na2SO4, filtered, and concentrated to dryness to give a brown solid, title compound 98, which was used directly for the next step. LC-MS: rt = 3.05 min, MS: 209.1 (calcd), 210.1 (M+H + (Measured value).

[0389] Step 2. 1-isopropyl-4-oxocyclohexane-1-carbonitrile (99) HCl 2N (23.9 mL, 47.8 mmol) was added to a solution of acetone (80 mL) at 98 (5.98 mmol), and the reaction mixture was stirred at room temperature for 2 days. The mixture was then concentrated to remove the organic solvent by slowly adding a saturated NaHCO3 solution. The residue was extracted with EA, the organic layer was dried over Na2SO4, filtered, and concentrated to dryness to give title compound 99 (445 mg, 45% yield in two steps). LC-MS: rt = 2.35 min, MS: 165.2 (calcd), 166.1 (M+H2O). + (Measured value).

[0390] Step 3. 2-Amino-6-cyano-6-isopropyl-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxamide (100) Morpholine (0.24 mL, 2.69 mmol) and sulfur (87 mg, 0.338 mmol) were added to a solution of 99 (445 mg, 2.69 mmol) and cyanoacetamide (206 mg, 2.45 mmol) in EtOH (4.9 mL). The reaction mixture was stirred at 60°C for 16 hours, resulting in a large precipitate. The solid was collected by filtration to give the title compound 100 (477 mg, 74% yield) as a white solid. LC-MS: rt = 2.60 min, MS: 263.1 (calcd), 264.1 (M+H+, determined).

[0391] Step 4. 2-Amino-6-cyano-6-isopropyl-7-oxo-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxamide (101) Selenium dioxide (42 mg, 0.38 mmol) was added to a 2.25 mL solution of DMSO (100 mg, 0.38 mmol). The reaction mixture was stirred at room temperature for 16 hours, then partitioned between brine and EA to concentrate the organic layer. The residue was purified by rapid column chromatography (DCM solution with an eluent gradient of 0.5% to 10% MeOH) and then further purified by semi-preparative HPLC-MS (10 mM ammonium bicarbonate solution with an eluent gradient of 30% to 100% MeOH) to give title compound 101 (5.0 mg, 5% yield) as a white solid.

[0392] 1 H NMR: 400 MHz, CD3OD, δ (ppm): 3.18 (ddd, J = 17.9, 8.2, 5.1 Hz,1H), 3.06 (dt, J = 17.9, 5.4 Hz, 1H), 2.50-2.39 (m, 3H), 1.12-1.08 (m, 6H).LC-MS: rt = 0.97 min, MS: 277.1 (calcd), 278.1 (M+H + (Measured value).

[0393] Example 59 2-Amino-6-(hydroxymethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b Thiophene-3-carboxamide (109) Scheme 19

[0394] Step 1. 4-(((tert-butyldimethylsilyl)oxy)methyl)-4-phenylcyclohexan-1-one (103) To 4-(hydroxymethyl)-4-phenylcyclohexane-1-one (102) ( Bioorg. Med. Chem. Lett. To a solution of anhydrous DMF (40 mL) containing 890 mg (4.36 mmol), tert-butyldimethylchlorosilane (737 mg, 4.79 mmol) and imidazole (653 mg, 9.59 mmol) were added. The resulting mixture was stirred at room temperature for 16 hours, then diluted with water (30 mL) and extracted with EA (70 mL). The organic phase was dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid column chromatography (elution gradient of 0% to 20% EA in hexane) to give the title compound 103 (1.20 g, 86% yield) as a white solid, which was not characterized and used directly in the next step.

[0395] Step 2. 2-amino-6-(((tert-butyldimethylsilyl)oxy)methyl)-6-phenyl-4,5,6,7- tetrahydrobenzene and b ] ethyl thiophene-3-carboxylate (104) A suspension of 103 (1.20 g, 3.77 mmol), morpholine (330 μL, 3.77 mmol), thiosulfate (121 mg, 473 μmol), and ethyl 2-cyanoacetate (364 μL, 3.42 mmol) in EtOH (6.01 mL) was stirred at 60°C for 16 hours. The mixture was then cooled to room temperature and concentrated. The residue was purified by rapid column chromatography (elution gradient of 0% to 100% EA in hexane) to give the title compound 104 (1.49 g, 97% yield) as a white solid. LC-MS: rt = 2.34 min, MS: 445.2 (calcd), 446.2 (M+H) + (Measured value).

[0396] Step 3. 2-((tert-butoxycarbonyl)amino)-6-(((tert-butyldimethylsilyl)oxy)methyl)-6- phenyl- hexanoic acid (109) 4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxylic acid ethyl ester (105) At 0°C, a solution of di-tert-butyl dicarbonate (802 mg, 3.68 mmol) in DCM was added dropwise to a solution of 104 (1.49 g, 3.34 mmol), DMAP (41.7 mg, 334 μmol), and triethylamine (699 μL, 5.01 mmol) in 66.8 mL of DCM. The resulting mixture was stirred at room temperature for 16 hours and then quenched with a saturated aqueous NH4Cl solution. The layers were separated, and the aqueous phase was extracted with DCM. The combined organic matter was dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid column chromatography (elution gradient of 0% to 100% EA in hexane) to give the title compound 105 (1.66 g, 91% yield) as an off-white solid. LC-MS: rt = 2.63 min, MS: 545.3 (calcd), 546.0 (M+H) + (Measured value).

[0397] Step 4. 2-((tert-butoxy carbonyl)amino)-6-(((tert-butyldimethylsilyl ) oxy ) methyl)-7-oxo- 6-phenyl-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxylic acid ethyl ester (106) A suspension of pyridinium chlorochromate (4.50 g, 20.9 mmol), diatomaceous earth (1.50 g), and 105 (1.50 g, 2.75 mmol) in anhydrous benzene (40.7 mL) was stirred at 80°C for 4 hours. The mixture was then cooled to room temperature, filtered through a diatomaceous earth pad, and the solid residue was washed with CHCl3. The filtrate was concentrated, and the residue was purified by rapid column chromatography (elution gradient of 0% to 30% hexane solution of EA) to give the title compound 106 (395 mg, 26% yield) as a white solid. LC-MS: rt = 2.52 min, MS: 559.2 (calcd), 560.2 (M+H) + (Measured value).

[0398] Step 5. 2-((tert-butoxy carbonyl)amino)-6-(((tert-butyldimethyl silyl ) oxy ) methyl)-7-oxo- 6-phenyl-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxylic acid (107) A solution of NaOH (136 mg, 3.39 mmol) in water (20.0 mL) was added to a solution of 106 (380 mg, 679 μmol) in EtOH (20.0 mL). The resulting mixture was sonicated for 1 min and then vigorously stirred at room temperature for 68 h. Subsequently, the mixture was diluted with water (15 mL) and extracted with EA (3 × 30 mL). The combined organic matter was dried over Na₂SO₄, filtered, and concentrated. The residue was purified by rapid column chromatography (elution gradient of 0% to 50% EA in hexane, then 0% to 30% MeOH in DCM) to give the title compound 107 (264 mg, 73% yield) as a white solid. LC-MS: rt = 1.60 min, MS: 531.2 (calcd), 532.1 (M+H) + (Measured value).

[0399] Step 6. 2-Amino-6-(hydroxymethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxylic acid (108) Trifluoroacetic acid (5.99 mL, 78.2 mmol) was added dropwise to a 30.0 mL solution of DCM containing 107 (260 mg, 489 μmol) at 0°C. The mixture was stirred at 0°C for 2 hours, then the reaction vessel was removed from the ice bath and stirring was continued at room temperature for another 2 hours. The mixture was then concentrated, the residue was dissolved in DCM and concentrated three times, and then purified by rapid column chromatography (eluent gradient of 0% to 13% MeOH in DCM solution) to give the title compound 108 (80 mg, 52% yield) as a pale yellow solid. (Characteristics are shown in Table 6) Step 7. 2-Amino-6-(hydroxymethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxylic acidN,N Add dropwise to a suspension of 108 (54.0 mg, 170 μmol), ammonium chloride (182 mg, 3.40 mmol), and HATU (97.0 mg, 255 μmol) in DMF (4.00 mL). Scheme 20 -Diisopropylethylamine (59.3 μL, 340 μmol). The mixture was stirred at room temperature for 16 hours, then 97 mg of HATU (255 μmol) was added and stirring was continued for 1 hour. The mixture was diluted with saturated NH4Cl aqueous solution and extracted with EA (3 × 20 mL). The combined organic compounds were washed successively with brine (3 × 20 mL) and 0.05 N HCl aqueous solution, and then concentrated. The residue was purified by rapid column chromatography (eluent gradient of 0% to 15% MeOH in DCM solution) and then again by reversed-phase rapid column chromatography (eluent gradient of 10% to 100% CH3CN in H2O solution containing 0.1% (v / v) formic acid) to give the title compound 109 (17.2 mg, 32% yield) as a white solid.

[0400] 1 H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.06 (s, 2H) 7.32-7.27 (m, 4H),7.23-7.20 (m 1H), 6.88 (bs, 2H), 4.77 (t, J = 5.5 Hz, 1H), 3.92 (dd, J =10.4, 5.6 Hz, 1H), 3.35-3.32 (m, 1H), 2.89-2.84 (m, 1H), 2.73-2.67 (m, 1H), 2.50-2.48 (m, 1H, partially overlapping with solvent signal). LC-MS: rt = 0.88 min, MS: 316.1 (calcd), 317.0 (M+H) + (Measured value).

[0401] Examples 60-67 Intermediate compound 111 1-Benzyl-4-oxocyclohexane-1-carboxynitrile (111) Step 1. 8-benzyl-l,4-dioxaspiro[4.5]decane-8-carbonitrile (110)

[0402] Step 2. l-benzyl-4-oxocyclohexane-l-carbonitrile (111) At -78°C, LDA (6.58 mL, 1 M in THF / hexane, 6.58 mmol) was added dropwise to 40 (Scheme 4) (1.0 g, 5.98 mmol) of anhydrous THF (24.0 mL). The reaction mixture was stirred at -78°C for 45 min, followed by the dropwise addition of benzyl bromide (0.870 mL, 7.18 mmol). The reaction mixture was allowed to reach room temperature and stirred for 2.5 h. The reaction mixture was then quenched with water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid column chromatography (elution gradient of 0% to 30% EA in hexane) to give title compound 110 (1.22 g, 79% yield) as a white solid, which was not characterized and used directly in the next step.

[0403] Scheme 21 To a solution of 110 (1.21 g, 4.70 mmol) in acetone (63 mL), HCl 2N (11.8 mL, 23.5 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. The organic solvent was then removed by slowly adding a saturated NaHCO3 solution to neutralize the mixture and concentrating. The residue was extracted with EA, the organic layer was dried over Na2SO4, filtered, and concentrated to dryness to give title compound 111 (1.00 g, >99% yield). LC-MS: rt = 2.93 min, MS: 213.1 (calcd), 214.1 (M+H2O). + (Measured value).

[0404] Intermediate compound 115 2-(8-(cyclopropylmethyl)-1,4-dioxaspiro[4.5]decane-8-yl)ethane-1-ol (115) Step 1. 8-(cyclopropylmethyl)-l,4-dioxaspiro[4.5]decane-8-carbaldehyde (113)

[0405] ACS Med. Chem. Lett At -78°C, diisobutylaluminum hydride (25% in toluene; 121 mL, 180.0 mmol) was added dropwise to 8-(cyclopropylmethyl)-1,4-dioxane[4.5]decane-8-carboxynitrile (112) (24.3 g, 110 mmol) Step 2. 8-(cyclopropylmethyl)-8-vinyl-l,4-dioxaspiro[4.5]decane (114)The resulting mixture was stirred at -78°C for 2 hours in anhydrous toluene (600 mL) solution of .2010, 350-354. The reaction mixture was then quenched with methanol (15 mL) at -78°C and partitioned between saturated NH4Cl aqueous solution (200 mL) and diethyl ether (300 mL). The mixture was allowed to slowly reach room temperature, and saturated aqueous solution of Rochelle salt (1 L) was added. The layers were separated, the organic phase was washed with brine (2 × 200 mL), dried over Na2SO4, filtered, and concentrated. The residue was dissolved in THF (400 mL) and treated with 2N HCl aqueous solution (27.5 mL, 54.9 mmol). The mixture was stirred at room temperature for 1 hour, then quenched with saturated NaHCO3 aqueous solution and concentrated to remove the organic solvent. The aqueous residue was extracted with diethyl ether, the organic matter was dried with Na2SO4, filtered and concentrated to give colorless oily title compound 113 (24.6 g, >99% yield), which was not characterized and used directly in the next step.

[0406] Step 3. 2-(8-(cyclopropylmethyl)-l,4-dioxaspiro[4.5]decane-8-yl)ethan-l-ol (115) At 60°C, methyltriphenylphosphonium bromide (2.23 g, 6.24 mmol) was added in four portions over 30 minutes to a 1 M L HMDS solution diluted with 55.0 mL of anhydrous THF (10 mL, 10.0 mmol). After the last addition, the reaction mixture was stirred at 60°C for 1 hour. Then, 113 (700 mg, 3.12 mmol) of anhydrous THF (10.0 mL) was added dropwise, and the reaction mixture was stirred at 60°C for another 30 minutes. The mixture was then cooled to room temperature, quenched with 40 mL of saturated NH4Cl solution, and extracted twice with EA (2 x 50 mL). The combined organic compounds were dried with Na2SO4, filtered and concentrated, and the residue was purified by rapid column chromatography (elution gradient of 0% to 30% hexane solution of Et2O) to give colorless oily title compound 114 (527 mg, 76% yield). It was not characterized and was used directly in the next step.

[0407] Scheme 22 At 0°C, 9-BBN (9.35 mL, 0.5 M in THF, 4.68 mmol) was added dropwise to a solution of 114 (520 mg, 2.34 mmol) in 12 mL of anhydrous THF. The reaction mixture was stirred at room temperature for 2.5 h, then cooled again to 0°C, and water (42 μL, 2.34 mmol), NaOH 1 N (7.0 mL, 7.0 mmol), and 30% H2O2 (12 mL) were added. The reaction mixture was stirred at 0°C for 10 min, then at room temperature for 16 h. The mixture was then diluted with EA and water. The layers were separated, the organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid column chromatography (eluent gradient of 30% to 100% EA in hexane) to give a colorless oily title compound 115 (479 mg, 85% yield), which was not characterized and used directly in the synthesis of the relevant examples.

[0408] Intermediate compound 118 2-(8-(cyclopropylmethyl)-1,4-dioxaspiro[4.5]decane-8-yl)acetonitrile (118) Step 1. (8-(cyclopropylmethyl)-l,4-dioxaspiro[4.5]decane-8-yl)methanol (116) Step 2. (8-(cyclopropylmethyl)-l,4-dioxaspiro[4.5]decane-8-yl)methyl 4- methylbenzenesulfonate Sodium borohydride (816 mg, 21.1 mmol) was added to a solution of 113 (Scheme 21) (3.16 g, 14.1 mmol) in 86.8 mL of MeOH at 0°C. The resulting solution was stirred at room temperature for 1 hour, and then the reaction mixture was quenched with a saturated aqueous solution of NH4Cl (30 mL). The mixture was diluted with EA (30 mL), the layers were separated, and the aqueous layer was extracted with EA (30 mL). The combined organic compounds were washed with 0.2 N HCl (50 mL) and brine, dried over Na2SO4, filtered, and concentrated to give a colorless oily title compound 116 (2.95 g, 93% yield), which was not characterized and used directly in the next step.

[0409] Step 3. 2-(8-(cyclopropylmethyl)-l,4-dioxaspiro[4.5]decane-8-yl)acetonitrile (118) (117) To a solution of 116 (2.70 g, 11.9 mmol) in pyridine (51.9 mL), p-toluenesulfonyl chloride (7.96 g, 41.8 mmol) was added, and the resulting mixture was stirred at room temperature for 16 hours. The mixture was then diluted with EA and water (30 mL each), and the layers were separated. The aqueous phase was extracted with EA (30 mL), and the combined organic matter was washed with water (30 mL) and brine (2 × 30 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was diluted with heptane and concentrated to dryness, then purified by rapid column chromatography (elution gradient of 0% to 40% EA in hexane solution) to give a colorless oily title compound 117 (3.65 g, 80% yield). LC-MS: rt = 1.78 min. MS: 380.2 (calcd), 381.3 (M+H₂O). + (Measured value).

[0410] Scheme 23 Sodium cyanide (1.41 g, 28.8 mmol) was added to a solution of 117 (3.65 g, 9.59 mmol) in DMSO (57.1 mL), and the resulting mixture was stirred at 60°C for 96 hours. The mixture was cooled to room temperature and diluted with a saturated aqueous solution of NaHCO3 (50 mL). The mixture was then diluted with EA (50 mL) and water (40 mL), and the layers were separated. The aqueous phase was extracted with EA (2 × 50 mL). The combined organic compounds were washed with water (2 × 30 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to give a yellow oily title compound 118 (2.5 g, 72% yield), which was not characterized and was used directly in the synthesis of the relevant examples.

[0411] Compounds 119-126 Compounds 119-123 (Examples 60-64) were synthesized in a manner similar to that of compound 81 (Example 51, Scheme 13) by using 4-methyl-4-phenylcyclohexane-1-one, compound 111 (Scheme 20), compound 73 (Scheme 12), compound 95 (Scheme 17), and compound 99 (Scheme 18) instead of 2-(4-oxo-1-phenylcyclohexyl)acetonitrile (76) as starting materials. Compounds 124-126 (Examples 65-67) were synthesized in a manner similar to that of compound 47 (Example 28, Scheme 4) by using compound 115 (Scheme 21), compound 116 (Scheme 22), and compound 118 (Scheme 22) instead of compound 41 as starting materials. Characterization of compounds 119-126 (Examples 60-67) is provided in Table 4.

[0412] Table 4. Characterization of compounds 119-126 (Examples 60-67)

[0413] Examples 68-77 Compounds 127-133 (Examples 68-74) were synthesized in a manner similar to that of compound 82 (Example 52, Scheme 13) by using compounds 119-125 (Examples 60-66, Table 4) instead of compound 81 as starting materials. Compounds 134-135 (Examples 75-76) were synthesized in a manner similar to that of compound 9 (Example 2, Scheme 2) by using compounds 126 (Example 67, Table 4) and 89 (Example 55, Scheme 15) instead of compound 8 as starting materials. Compound 136 (Example 77) was synthesized in a manner similar to that of compound 82 (Example 52, Scheme 13) by using compound 108 (Scheme 19) instead of compound 81 as starting material. Characterization of compounds 127-136 (Examples 68-77) is provided in Table 5.

[0414] Table 5. Characterization of compounds 127-136 (Examples 68-77)

[0415] Example 78 2-Amino-6-(2-cyanoethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b ]Thiophene-3-carboxylic acid (138) and Example 79 2-Amino-6-(3-amino-3-oxopropyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b Thiophene-3-carboxylic acid (139) Bioorg Med. Chem

[0416] To 137 (1.0 g, 2.71 mmol, with 3-(4-oxo-1-phenylcyclohexyl)propionitrile ( Lett. Scheme 2421, p.405, 2011) Instead of 2-(4-oxo-1-phenylcyclohexyl)acetonitrile (76) as the starting material, a solution of lithium hydroxide monohydrate (569 mg, 13.6 mmol) in water (330 mL) was added to a MeOH (330 mL) solution. The reaction mixture was stirred at 80°C for 16 hours and then cooled to room temperature. The mixture was concentrated to remove most of the organic solvent. The aqueous layer was acidified by slow addition of HCl 1N and extracted with EA. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid column chromatography (eluent gradient of 0% to 30% in DCM solution of MeOH) to give title compound 138 (648 mg, 70% yield) and title compound 139 as yellow solids. The latter was purified again by semi-preparative HPLC-MS (10 mM ammonium bicarbonate solution with an eluent gradient of 15% to 100% MeOH) to give a white solid (142 mg, 15% yield).

[0417] 138: 1 H NMR: 400 MHz, DMSO-d6, δ (ppm): 12.51 (bs, 1H), 8.28 (s, 2H),7.36-7.32 (m, 2H), 7.27-7.24 (m, 3H), 3.15-3.09 (m, 1H), 2.60-2.55 (m, 1H),2.48-2.42 (m, 1H), 2.38-2.30 (m, 1H), 2.26-2.18 (m, 2H), 2.12-2.07 (m, 2H).LC-MS: rt = 1.23 min, MS: 340.1 (calcd), 341.1 (M+H + (Measured value).

[0418] 139: 1 H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.30 (bs, 2H), 7.33-7.26 (m,4H), 7.23-7.19 (m, 1H), 7.18 (s, 1H), 6.62 (s, 1H), 3.20-3.15 (m, 2H), 2.45-2.37 (m, 1H), 2.16-2.07 (m, 1H), 2.00-1.91 (m, 4H). LC-MS: rt = 0.98 min, MS:358.1 (calcd), 359.1 (M+H+ (Measured value).

[0419] Example 80 2-Amino-6-(2-cyanoethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b Thiophene-3-carboxamide (140) N,N

[0420] HATU (855 mg, 2.20 mmol) was added to a suspension of 138 (500 mg, 1.47 mmol) and ammonium chloride (1.57 g, 29.4 mmol) in anhydrous DMF (16.2 mL). Scheme 25 -Diisopropylethylamine (0.512 mL, 2.94 mmol). Then, a saturated NH3 solution (8.7 mL) in CHCl3 (prepared internally) and a 0.4 M NH3 solution (9.2 mL) in THF were added dropwise, and the reaction mixture was stirred at room temperature for 16 hours. Afterward, the reaction mixture was quenched with saturated NH4Cl solution and extracted with EA. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by reversed-phase rapid column chromatography (elution gradient of 0% to 100% CH3CN in H2O solution containing 0.1% (v / v) formic acid) to give the title compound 140 as a white solid (419 mg, 84% yield).

[0421] 1 H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.13 (s, 2H), 7.37-7.24 (m, 5H), 6.88 (bs, 2H), 2.91-2.84 (m, 1H), 2.68-2.56 (m, 2H), 2.46-2.42 (m, 1H), 2.25-2.17 (m, 2H), 2.13-2.07 (m, 2H). LC-MS: rt = 1.10 min, MS: 339.1 (calcd),340.1 (M+H + (Measured value).

[0422] Example 81 2-Amino-6-(2-cyanoethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b Thiophene-3-carboxamide (141)

[0423] Compound 141 (Example 81) was synthesized in a manner similar to that of Compound 62 (Example 39, Scheme 10) using Compound 140 (Example 80, Scheme 24) instead of Compound 61 as the starting material.

[0424] 1 H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.08 (s, 2H), 7.35-7.21 (m, 5H), 7.17 (s, 1H), 6.87 (bs, 2H), 6.63 (s, 1H), 2.91-2.84 (m, 1H), 2.73-2.65 (m, 1H), 2.55-2.53 (m, 1H), 2.20-2.12 (m, 1H), 2.02-1.90 (m, 4H). LC-MS: rt =0.88 min, MS: 357.1 (calcd), 358.2 (M+H + (Measured value).

[0425] Example 82 ( S )-2-amino-6-(3-amino-3-oxopropyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b ]Thiophene-3-carboxamide (142) and Example 83 ( R )-2-amino-6-(3-amino-3-oxopropyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b Thiophene-3-carboxamide (143) Scheme 26

[0426] 100.3 mg of racemic compound 141 was subjected to SFC chiral separation to yield enantiomerically enriched title compound 142 (29.9 mg, 30% separation yield) and title compound 143 (26.2 mg, 26% separation yield) as white solids. The absolute configurations of compounds 142 and 143 were determined based on a well-defined analogy with the absolute configurations of crystalline compounds within the same or similar series.

[0427] 142: 1 ¹H NMR: Same as racemic mixture (141). LC-MS: rt = 0.88 min, MS: 357.1 (calcd), 358.2 (M+H). +(Measured values). Analytical SFC (IC column, using a gradient of 5-60% MeOH + 10mM AmFor (95-40% CO2)): rt = 5.80 min, ee. = 99.76%.

[0428] 143: 1 ¹H NMR: Same as racemic mixture (141). LC-MS: rt = 0.88 min, MS: 357.1 (calcd), 358.2 (M+H). + (Measured values). Analytical SFC (IC column, using a 5-60% MeOH + 10mM AmFor (95-40% CO2) gradient): rt = 6.45 min, ee. = 97.82%.

[0429] Example 84 2-Amino-6-(2-cyanoethyl)- N -Cyclopropyl-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b ]Thiophene-3-carboxamide (144) and Example 85 2-Amino-6-(3-Amino-3-oxopropyl)- N -Cyclopropyl-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b Thiophene-3-carboxamide (145) Scheme 27

[0430] Compound 144 (Example 84) was synthesized in a manner similar to that of compound 82 (Example 52, Scheme 13) using compound 138 (Example 78, Scheme 23) instead of compound 81 as the starting material.

[0431] 1 H NMR: 400 MHz, DMSO-d6, δ (ppm): 7.87 (s, 2H), 7.37-7.25 (m, 6H), 2.74-2.52 (m, 4H), 2.48-2.41 (m, 1H), 2.24-2.07 (m, 4H), 0.64-0.57 (m, 2H),0.50-0.43 (m, 2H). LC-MS: rt = 1.27 min, MS: 379.1 (calcd), 380.2 (M+H + (Measured value).

[0432] 30% hydrogen peroxide (0.09 mL) was added to a suspension of 144 (35 mg, 0.092 mmol) and K2CO3 (26 mg, 0.18 mmol) in MeOH (1.8 mL) and water (0.6 mL). The reaction mixture was stirred vigorously at room temperature for 2 days. Then, more 30% hydrogen peroxide (0.19 mL) was added, and the reaction mixture was stirred vigorously at room temperature for another 24 hours. The mixture was then concentrated to remove the organic solvent, and the residue was extracted with EA. The organic layer was dried over NaSO4, filtered, and concentrated to give a white solid, title compound 145 (17 mg, 46% yield).

[0433] 1 H NMR: 400 MHz, DMSO-d6, δ (ppm): 7.81 (s, 2H), 7.35-7.21 (m, 6H), 7.17 (bs, 1H), 6.63 (bs, 1H), 2.77-2.59 (m, 3H), 2.50-2.48 (m, 1H), 2.16-2.08(m, 1H), 2.01-1.90 (m, 4H), 0.64-0.58 (m, 2H), 0.50-0.45 (m, 2H). LC-MS: rt =1.05 min, MS: 397.2 (calcd), 398.3 (M+H + (Measured value).

[0434] Example 86 2-Amino-6-methyl-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b Thiophene-3-carboxamide (146) N,N

[0435] Compound 119 (Table 4) (50 mg, 0.17 mmol) was dissolved in 17 mL of 0.4 M NH3 THF solution, and HATU (126 mg, 0.33 mmol) was added to the mixture. Scheme 28-Diisopropylethylamine (0.058 mL, 0.33 mmol). The reaction mixture was then stirred at room temperature for 16 hours. Afterwards, the reaction mixture was quenched with saturated NH4Cl solution and extracted with EA. The organic layer was washed with water and brine, dried over NaSO4, filtered, and concentrated. The residue was purified by rapid column chromatography (elution gradient of 40% to 100% EA in hexane solution) and then further purified by semi-preparative HPLC-MS (elution gradient of 35% to 100% acetonitrile in 10 mM ammonium bicarbonate solution) to give the title compound 146 as a white solid (22 mg, 44% yield).

[0436] 1 H NMR: 400 MHz, CD3OD, δ (ppm): 7.32-7.28 (m, 4H), 7.24-7.19 (m, 1H), 2.95-2.89 (m, 1H), 2.68-2.58 (m, 2H), 2.28-2.21 (m, 1H), 1.48 (s, 3H). LC-MS:rt = 1.13, MS: 300.1 (calcd), 301.1 (M+H + (Measured value).

[0437] Example 87 2-Amino-6-benzyl-6-cyano-7-oxo-4,5,6,7-tetrahydrobenzo[ b Thiophene-3-carboxamide (147) N,N

[0438] Add HATU (87 mg, 0.230 mmol) to a suspension of 120 (Table 4) (50 mg, 0.153 mmol) and ammonium chloride (164 mg, 3.06 mmol) in anhydrous THF (2.0 mL). Scheme 29 -Diisopropylethylamine (0.053 mL, 0.306 mmol). Subsequently, a saturated NH3 solution (0.25 mL) in CHCl3 (prepared internally) was added dropwise, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then quenched with a saturated NH4Cl solution and extracted with EA. The organic layer was dried over NaSO4, filtered, and concentrated. The residue was purified by reversed-phase rapid column chromatography (elution gradient of 0% to 100% CH3CN in H2O solution containing 0.1% (v / v) formic acid) to give the title compound 147 as a white solid (35 mg, 70% yield).

[0439] 1H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.34 (bs, 2H), 7.40-7.30 (m, 5H), 7.13 (bs, 2H), 3.25-3.16 (m, 2H), 3.10-2.98 (m, 2H), 2.23-2.16 (m, 1H), 2.11-2.04 (m, 1H). LC-MS: rt = 1.15 min, MS: 325.1 (calcd), 326.1 (M+H + (Measured value).

[0440] Example 88 2-Amino-6-(cyclopropylmethyl)-6-(2-hydroxyethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[ b Thiophene-3-carboxamide (148)

[0441] Compound 148 (Example 88) was synthesized in a manner similar to that of Compound 140 (Example 80, Scheme 24) by using Compound 124 (Table 4) instead of Compound 138 as the starting material.

[0442] 1 H NMR: 400 MHz, CD3OD, δ (ppm): 3.67-3.56 (m, 2H), 3.03 (t, J = 6.1Hz, 2H), 2.28 (dt, J = 13.8, 5.9 Hz, 1H), 2.17-2.10 (m, 1H), 2.05 (ddd, J =13.7, 8.9, 6.1 Hz, 1H), 1.85 (ddd, J = 13.7, 8.9, 6.2 Hz, 1H), 1.74 (dd, J =14.1, 6.1 Hz, 1H), 1.41 (dd, J = 14.2, 7.2 Hz, 1H), 0.74-0.64 (m, 1H), 0.50-0.42 (m, 2H), 0.11-0.00 (m, 2H). LC-MS: rt = 0.92 min, MS: 308.1 (calcd), 309.2 (M+H) + (Measured value).

[0443] Example 89 2-Amino-6-(cyclopropylmethyl)-6-(hydroxymethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[ b Thiophene-3-carboxamide (149)

[0444] Compound 149 (Example 89) was synthesized in a manner similar to that of compound 140 (Example 80, Scheme 24) by using compound 125 (Table 4) instead of compound 138 as the starting material.

[0445] 1 H NMR: 400 MHz, DMSO-d6, δ (ppm): 7.97 (s, 2H), 6.92 (bs, 2H), 4.54(t, J = 5.4 Hz, 1H), 3.71 (dd, J = 10.5, 5.5 Hz, 1H), 3.39 (dd, J = 10.5, 5.3Hz, 1H), 3.03-2.87 (m, 2H), 2.17-2.10 (m, 1H), 2.07-2.01 (m, 1H), 1.54 (dd, J = 14.0, 6.5 Hz, 1H), 1.32 (dd, J LC-MS: rt = 0.88min, MS: 294.1 (calcd), 295.0 (M+H + (Measured value).

[0446] Example 90 2-Amino-6-(cyanomethyl)-6-(cyclopropylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[ b Thiophene-3-carboxamide (150)

[0447] Compound 150 (Example 90) was synthesized in a manner similar to that of compound 109 (Example 59, Scheme 19) by using compound 126 (Table 4) instead of compound 108 as the starting material.

[0448] 1 H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.06 (s, 2H), 6.97 (bs, 2H), 3.16-3.03 (m, 1H), 2.99-2.81 (m, 3H), 2.16-2.02 (m, 2H), 1.60-1.44 (m, 2H), 0.66-0.57 (m, 1H), 0.47-0.35 (m, 2H), 0.13-0.07 (m, 1H), ‒0.01 - ‒0.07 (m, 1H).LC-MS: rt = 0.94 min. MS: 303.1 (calcd), 304.0 (M+H + (Measured value).

[0449] Example 91 2-Amino-7-oxo-4,7-dihydro-5H-spiro[benzo[] b [Thiophene-6,1'-cyclopentane]-3-carboxamide (155) Ester (153)

[0450] Step 1. 2-Amino-4,7-dihydro-5H-spiro[benzo[ b ]thiophene-6,1 '-cyclopentane]-3-carboxylic acid ethyl ester (152) Morpholine (0.126 mL, 1.44 mmol) and sulfur (46 mg, 0.18 mmol) were added to a solution of spiro[4.5]decane-8-one (151) (199 mg, 1.31 mmol) and ethyl 2-cyanoacetate (0.139 mL, 1.31 mol) in EtOH (1.3 mL). The reaction mixture was stirred at 60°C for 16 hours, then cooled to room temperature and concentrated to dryness. The residue was purified by rapid column chromatography to give title compound 152 (270 mg, 74% yield). LC-MS: rt = 1.98 min, MS: 279.1 (calcd), 280.1 (M+H) + (Measured value).

[0451] Step 2. 2-Amino-7-oxo-4,7-dihydro-5H-spiro[benzo[ b ]thiophene-6, 1 '-cyclopentan e]-3-carboxylic acid ethyl ester N,N At 0°C, a solution of DDQ (81 mg, 0.358 mmol) in THF (1.0 mL) was added dropwise to a mixture of 152 (100 mg, 0.358 mmol) in THF (1.2 mL) and water (0.2 mL), and the reaction mixture was stirred at 0°C for 30 min. The reaction mixture was then quenched with saturated NaHCO3 solution and extracted with EA. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid column chromatography to give title compound 153 (15 mg, 14% yield). LC-MS: rt = 1.63 min, MS: 293.1 (calcd), 294.1 (M+H2O). + (Measured value).

[0452] Step 3. 2-Amino-7-oxo-4,7-dihydro-5H-spiro[benzo[ b ]thiophene-6,1 '-cyclopentane]-3-carboxylic acid (154) A solution of lithium hydroxide monohydrate (7 mg, 0.283 mmol) in water (1.1 mL) was added to a solution of 153 (15 mg, 0.051 mmol) in MeOH (1.1 mL). The reaction mixture was stirred under reflux for 16 hours and then cooled to room temperature. The mixture was diluted with water and concentrated to remove most of the organic solvent. The aqueous layer was acidified by slow addition of HCl 1N and extracted with EA. The organic layer was dried over Na2SO4, filtered, and concentrated to give the title compound 154 (6 mg, 44% yield) as a white solid. (Characteristics are shown in Table 6) Step 4. 2-Amino-7-oxo-4,7-dihydro-5H-spiro[benzo[ b ]thiophene-6,1 '-cyclopentane]-3-carboxamide (155) Compound 154 (6 mg, 0.023 mmol) was dissolved in 1.5 mL of 0.4 M NH3 solution in THF, and HATU (17 mg, 0.045 mmol) was added to the mixture. Scheme 30 -Diisopropylethylamine (0.008 mL, 0.045 mol). The reaction mixture was then stirred at room temperature for 16 hours. The reaction mixture was then quenched with saturated NH4Cl solution and extracted with EA. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid column chromatography to give the title compound 155 (3.7 mg, 62% yield) as a white solid.

[0453] 1 H NMR: 400 MHz, CD3OD, δ (ppm): 2.99 (t, J = 6.0 Hz, 2H), 2.06 (t, J= 6.0 Hz, 2H), 2.03-1.97 (m, 2H), 1.79-1.68 (m, 4H), 1.62-1.56 (m, 2H). LC-MS: rt = 1.07 min, MS: 264.1 (calcd), 265.1 (MH + (Measured value).

[0454] Example 92 2-Amino-6-(3-hydroxypropyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b Thiophene-3-carboxamide (163) Step 1. 3-(8-phenyl-l,4-dioxaspiro[4.5]decane-8-yl)propanoic acid (157)

[0455] Bioorg Med. Chem Lett To 3-(8-phenyl-1,4-dioxaspiro[4.5]decane-8-yl)propionitrile (156) (2.30 g, 8.48 mmol) Step 2. Methyl 3-(8-phenyl-l,4-dioxaspiro[4.5]decane-8-yl)propanoate (158) Potassium hydroxide (3.80 g, 67.8 mmol) and water (0.030 mL, 1.70 mmol) were added to a 40.0 mL solution of ethylene glycol (p. 405, 2011). The reaction mixture was stirred at 170°C for 16 hours, then cooled to room temperature and diluted with water and DCM. The layers were separated by acidifying the aqueous phase with HCl 2N by slow addition and extraction with DCM. The organic layer was dried over MgSO4, filtered, and concentrated to give the title compound 157 (2.03 g, 82% yield) as a brown solid. LC-MS: rt = 0.84 min, MS: 290.2 (calcd), 289.2 ([MH]). - (Measured value).

[0456] Step 3. 3-(8-phenyl-l,4-dioxaspiro[4.5]decane-8-yl)propan-l-ol (159) At 0°C, potassium carbonate (1.86 g, 13.4 mmol) and methyl iodide (0.418 mL, 6.72 mmol) were added to a solution of 157 (1.30 g, 4.48 mmol) in 10.0 mL of anhydrous DMF. The reaction mixture was stirred at room temperature for 16 hours, then diluted with water and extracted with Et₂O. The organic layer was washed with brine, dried over MgSO₄, filtered, and concentrated to give the title compound 158 (1.35 g, 99% yield) in an oily form. LC-MS: rt = 1.53 min, MS: 304.2 (calcd), 305.2 (M+H₂O). + (Measured value).

[0457] Step 4. 4-(3-hydroxypropyl)-4-phenylcyclohexan-l-one (160) At 0°C, a solution of 158 (865 mg, 2.84 mmol) in anhydrous THF (7.0 mL) was added dropwise to a solution of lithium aluminum hydride (6.25 mL, 1 M in THF, 6.25 mmol). The reaction mixture was stirred at 0°C for 1 hour, then carefully quenched at 0°C with MeOH and water. The mixture was then diluted with EA and a saturated Rochelle salt solution and stirred at room temperature for 30 minutes. The layers were separated, and the aqueous phase was extracted with EA. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid column chromatography (elution gradient of 0% to 70% EA in hexane) to give the title compound 159 (760 mg, 97% yield) as a yellow oil. LC-MS: rt = 1.28 min, MS: 276.2 (calcd), 277.2 (M+H) + (Measured value).

[0458] Step 5. 4-(3-((tert-butyldimethylsilyl)oxy)propyl)-4-phenylcyclohexan-l-one (161) To a solution of acetone (18.0 mL) containing 159 g (368 mg, 1.33 mmol), HCl 2N (3.33 mL, 6.66 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. The organic solvent was then removed by slowly adding a saturated aqueous solution of NaHCO3 and concentrating. The residue was extracted with EA, the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to dryness to give a yellow oily title compound 160 (289 mg, 94% yield), which was not characterized and used directly in the next step.

[0459] Step 6. 2-amino-6-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-phenyl-4,5,6,7- tetrahydro To a solution of 160 (196 mg, 0.84 mmol) of anhydrous DMF (4.2 mL), tert-butyldimethylchlorosilane (162 mg, 1.08 mmol) and imidazole (144 mg, 2.11 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours, then diluted with water and EA. The layers were separated, the organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid column chromatography (elution gradient of 0% to 30% EA in hexane) to give a pale yellow oily title compound 161 (259 mg, 89% yield), which was not characterized and used directly in the next step.

[0460] Amide (163) benzo[ b ]thiophene-3-carboxamide (162) To a solution of 161 (259 mg, 0.747 mmol) and cyanoacetamide (57 mg, 0.679 mmol) in EtOH (1.4 mL), morpholine (0.065 mL, 0.747 mmol) and sulfur (24 mg, 0.093 mmol) were added. The reaction mixture was stirred at 60°C for 16 hours, cooled to room temperature, and concentrated to dryness. The residue was purified by rapid column chromatography (DCM solution with an eluent gradient of 0% to 10% MeOH) to give title compound 162 (200 mg, 60% yield). LC-MS: rt = 2.07 min, MS: 444.2 (calcd), 445.3 (M+H) + (Measured value).

[0461] Step 7. 2-Amino-6-(3-hydroxypropyl)-7-oxo-6-phenyl-4,5,6,7- tetrahydrobenzo[d]thiophene-3-carboxylic acid b ]thiophene-3-carboxylic acid methyl ester Scheme 31 At 0°C, a solution of DDQ (306 mg, 1.35 mmol) in THF (1.25 mL) was added dropwise to a mixture of 162 (200 mg, 0.450 mmol) in THF (1.5 mL) and water (0.25 mL). The reaction mixture was allowed to slowly reach room temperature and stirred for 16 hours. The mixture was then quenched with saturated NaHCO3 solution and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid column chromatography (eluent gradient of 2% to 10% in DCM solution of MeOH) and then further purified by semi-preparative HPLC-MS (eluent gradient of 30% to 100% in 10 mM ammonium bicarbonate solution of MeOH) to give the title compound 163 (10 mg, 6% yield) as a white solid.

[0462] 1 H NMR: 400 MHz, CD3OD, δ (ppm): 7.34-7.28 (m, 4H), 7.23-7.19 (m, 1H), 3.54-3.43 (m, 2H), 2.96 (ddd, J LC-MS: rt = 0.96 min, MS: 344.1 (calcd), 345.1 (M+H + (Measured value).

[0463] Example 93 2-Amino-6-(3-hydroxypropyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b ]Thiophene-3-carboxylic acid (168) and Example 94 2-Amino- N -Cyclopropyl-6-(3-hydroxypropyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b Thiophene-3-carboxamide (169) Ethyl formate (165)

[0464] Step 1. 2-Amino-6-(3-hydroxypropyl)-6-phenyl-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxylic acid ethyl ester (164) Morpholine (0.120 mL, 1.37 mol) and sulfur (44 mg, 0.172 mmol) were added to a solution of 160 (Scheme 30) (289 mg, 1.24 mmol) and ethyl 2-cyanoacetate (0.149 mL, 1.37 mmol) in EtOH (10.0 mL). The reaction mixture was stirred at 60°C for 24 hours, then cooled to room temperature and concentrated to dryness. The residue was partitioned between EA and water. The layers were separated, and the aqueous phase was extracted with EA. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid column chromatography (elution gradient of 0% to 50% EA in hexane) to give the title compound 164 (336 mg, 75% yield) as a white solid. LC-MS: rt = 1.53 min, MS: 359.2 (calcd), 360.2 (M+H) + (Measured value).

[0465] Step 2. 2-Acetylamino-6-(3-acetyloxypropyl)-6-phenyl-4,5,6,7- tetrahydrobenzo[ b ] thiophene-3-carboxylic acid Ethyl thiophene-3-carboxylate (166) To a suspension of 164 (336 mg, 0.935 mmol) in anhydrous DCM (3.0 mL), acetic anhydride (0.265 mL, 2.80 mmol) and acetic acid (0.054 mL, 0.935 mmol) were added. The reaction mixture was stirred at room temperature for 4 days, then diluted with DCM and washed with saturated NaHCO3 solution, water, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid column chromatography (elution gradient from 0% to 50% hexane solution of EA) to give the title compound 165 (208 mg, 50% yield) as a white solid. LC-MS: rt = 1.53 min, MS: 359.2 (calcd), 360.2 (M+H) + (Measured value).

[0466] Step 3. 2-Acetylamino-6-(3-acetyloxypropyl)-7-oxo-6-phenyl-4,5,6,7- tetrahydrobenzo[d]oxazole-1 -carboxylic acid ethyl ester b ] 3-ethyl formate (167) Intermediate 165 (208 mg, 0.469 mmol) and cerium sulfate (1.35 g, 4.05 mmol) were added to a 1:1:1 mixture of acetic acid / water / dioxane (15 mL). The flask was sonicated to homogenize the suspension, and the reaction mixture was vigorously stirred at room temperature for 16 hours. The mixture was then diluted with water and extracted with EA. The organic layer was washed with NaOH 1N, water, and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid column chromatography (elution buffer gradient of 0% to 45% EA in hexane) to give the title compound 166 (122 mg, 57% yield) as a white solid. LC-MS: rt = 1.73 min, MS: 457.2 (calcd), 458.3 (M+H) + (Measured value).

[0467] Step 4. 6-(3-Acetyloxypropyl)-2-amino-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b ]thiophene- Acid (168) To a solution of 166 (122 mg, 0.267 mmol) in toluene (0.5 mL), pyrrolidine (0.35 mL, 4.26 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The mixture was then diluted with brine and extracted with EA. The organic layer was dried over Na₂SO₄, filtered, and concentrated to give a deep orange oily title compound 167, which was used directly in the next step. LC-MS: rt = 1.64 min, MS: 415.2 (calcd), 416.3 (M+H₂O). + (Measured value).

[0468] Step 5. 2-Amino-6-(3-hydroxypropyl)-7-oxo-6-phenyl-4,5,6,7- tetrahydrobenzo[d]thiophene-3-carboxylic acid b ]thiophene-3-carboxylic acid methyl ester Thiophene-3-carboxamide A solution of lithium hydroxide monohydrate (162 mg, 3.86 mmol) in water (2.0 mL) was added to a solution of 167 (0.267 mmol) of MeOH (4.0 mL). The reaction mixture was stirred at 60°C for 3 days and then cooled to room temperature. The mixture was concentrated to remove most of the organic solvent. The aqueous layer was acidified by slow addition of HCl 1N and extracted with EA. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid column chromatography (elution gradient of 50% to 100% EA in hexane) to give a yellow solid, title compound 168 (70 mg, 76% yield in two steps).

[0469] 1 H NMR: 400 MHz, CD3OD, δ (ppm): 7.32-7.28 (m, 4H), 7.23-7.18 (m, 1H), 3.53-3.43 (m, 2H), 3.26-3.19 (m, 1H), 2.60-2.51 (m, 2H), 2.35-2.27 (m, 1H), 1.98-1.83 (m, 2H), 1.55-1.44 (m, 2H). LC-MS: rt = 1.09 min, MS: 345.1(calcd), 346.0 (M+H + (Measured value).

[0470] Step 6. 2-amino- N - cyclopropyl-6-(3-hydroxypropyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b ] N,N (169) Add HATU (119 mg, 0.313 mmol) to anhydrous DMF (1.95 mL) solution of 168 (54 mg, 0.156 mmol). Scheme 32 -Diisopropylethylamine (0.082 mL, 0.469 mmol) and cyclopropylamine (0.012 mL, 0.172 mmol). The reaction mixture was then stirred at room temperature for 16 hours. The reaction mixture was then diluted with EA and washed with saturated NaHCO3 solution and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid column chromatography (elution gradient of 30% to 100% EA in hexane solution) to give the title compound 169 (46 mg, 77% yield) as a white solid.

[0471] 1 H NMR: 400 MHz, CD3OD, δ (ppm): 7.33-7.26 (m, 4H), 7.21-7.17 (m, 1H), 3.52-3.42 (m, 2H), 2.81 (ddd, J = 17.3, 4.4, 3.3 Hz, 1H), 2.70-2.62 (m, 2H), 2.58 (dt, J = 13.9, 3.7 Hz, 1H), 2.31 (ddd, J LC-MS: rt = 1.13 min, MS: 384.1 (calcd), 385.1 (M+H +(Measured value).

[0472] Example 95 2-Amino-6-cyano- N -Cyclopropyl-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b Thiophene-3-carboxamide (170) N,N

[0473] At 0°C, PyBOP (3.73 g, 7.15 mmol) was added to 59 (Example 36, Scheme 8) (2.03 g, 6.50 mmol) of anhydrous DMF (72 mL). Scheme 33 -Diisopropylethylamine (2.26 mL, 13.0 mmol) and cyclopropylamine (2.25 mL, 32.5 mmol). The reaction mixture was then stirred at room temperature for 16 hours. Afterward, the reaction mixture was quenched with saturated NH4Cl solution and extracted with EA. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid column chromatography (eluent gradient of 40% to 100% EA in hexane solution) followed by reversed-phase rapid column chromatography (eluent gradient of 10% to 100% CH3CN in H2O solution containing 0.1% (v / v) formic acid) to give the title compound 170 (1.48 g, 65% yield) as a white solid.

[0474] 1 H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.16 (s, 2H), 7.61-7.59 (m, 1H), 7.47-7.38 (m, 5H), 3.04-2.97 (m, 1H), 2.80-2.70 (m, 3H), 2.64-2.57 (m, 1H), 0.68-0.60 (m, 2H), 0.54-0.48 (m, 2H). LC-MS: rt = 1.25 min, MS: 351.1(calcd), 352.2 (M+H + (Measured value).

[0475] Example 96 2-Amino-6-cyano-6-((1-methylcyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydrobenzo[ b Thiophene-3-carboxamide (174) Intermediate compound 172 8-((1-methylcyclopropyl)methyl)-1,4-dioxaspiro[4.5]decane-8-carboxylonitrile (172) Step 1. 8-(2-methylallyl)-l,4-dioxaspiro[4.5]decane-8-carbonitrile (171)

[0476] Step 2. 8-((l-methylcyclopropyl)methyl)-l,4-dioxaspiro[4.5]decane-8-carbonitrile (172) At -78°C, LDA (6.67 mL, 1 M in THF / hexane, 6.67 mmol) was added dropwise to a solution of 1,4-dioxaspiro[4.5]decane-8-carboxynitrile (40, Scheme 4) (0.696 mL, 4.44 mmol) in 10 mL of anhydrous THF. The reaction mixture was stirred at -78°C for 30 min, and then a solution of 3-bromo-2-methylpropene (0.448 mL, 4.44 mmol) in 10 mL of anhydrous THF was added dropwise. The reaction mixture was then allowed to reach room temperature and stirred for 3 days. The reaction mixture was then quenched with saturated NH4Cl solution and extracted with EA. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid column chromatography (elution gradient of 0% to 50% EA in hexane solution) to give a colorless oily title compound 171 (753 mg, 77% yield), which was not characterized and used directly for the next step.

[0477] Scheme 34 At -10°C, diethylzinc (5.87 mL, 1 M in hexane, 5.87 mmol) and diiodomethane (0.946 mL, 11.7 mmol) were added to anhydrous DCM (29 mL) solution of 171 (650 mg, 2.94 mmol). The reaction mixture was stirred at -10°C for 30 min, then allowed to reach room temperature and stirred for 3 days. The reaction mixture was then quenched with saturated NH4Cl solution, and the layers were separated. The organic phase was dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid column chromatography (elution gradient of 0% to 50% EA in hexane solution) to give a colorless oily title compound 172 (233 mg, 34% yield), which was not characterized and was used directly in the synthesis of the relevant examples.

[0478] 2-Amino-6-cyano-6-((1-methylcyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydrobenzo[ b Thiophene-3-carboxamide (174) N,N

[0479] HATU (88 mg, 0.227 mmol) was added to a suspension of 173 (characterization shown in Table 6) (using compound 172 (scheme 33) instead of compound 41 as the starting material, synthesized in a manner similar to compound 47 (scheme 4)) (46 mg, 0.151 mmol) and ammonium chloride (162 mg, 3.02 mmol) in anhydrous DMF (2.0 mL). Scheme 35 -Diisopropylethylamine (0.053 mL, 0.302 mmol). Then, a CHCl3 solution (0.9 mL) saturated with NH3 (prepared internally) and a THF solution of 0.4 M NH3 (0.9 mL) were added dropwise, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then quenched with saturated NH4Cl solution and extracted with EA. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by reversed-phase rapid column chromatography (elution gradient of 0% to 100% CH3CN in H2O solution containing 0.1% (v / v) formic acid) to give the title compound 174 as a white solid (26 mg, 57% yield).

[0480] 1 H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.24 (s, 2H), 7.09 (bs, 2H), 3.15-3.01 (m, 2H), 2.46-2.43 (m, 1H), 2.39-2.32 (m, 1H), 1.88 (s, 2H), 1.12 (s,3H), 0.46-0.38 (m, 1H), 0.32-0.24 (m, 3H). LC-MS: rt = 1.12 min, MS: 303.1(calcd), 304.1 (M+H + (Measured value).

[0481] Example 97 2-Amino- N 3 -Cyclopropyl-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b Thiophene-3,6-dicarboxamide (175)

[0482] Compound 175 (Example 97) was synthesized in a manner similar to that of Compound 145 (Example 85, Scheme 26) using Compound 170 (Example 95, Scheme 32) instead of Compound 144 as the starting material.

[0483] 1H NMR: 400 MHz, CD3OD, δ (ppm): 7.35-7.33 (m, 4H), 7.32-7.28 (m, 1H), 2.92 (dt, J = 17.1, 4.8 Hz, 1H), 2.73-2.68 (m, 3H), 2.58 (ddd, J = 17.1, 7.9,5.5 Hz, 1H), 0.76-0.71 (m, 2H), 0.57-0.53 (m, 2H). LC-MS: rt = 1.02 min, MS:369.1 (calcd), 370.2 (M+H + (Measured value).

[0484] Example 98 2-Amino-6-(but-3-yn-1-yl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b Thiophene-3-carboxamide (179) Intermediate compound 177 8-(but-3-yn-1-yl)-8-phenyl-1,4-dioxaspiro[4.5]decane (177) Step 1. 3-(8-phenyl-l,4-dioxaspiro[4.5]decane-8-yl)propanal

[0485] Bioorg Med. Chem Lett (176) At -78°C, 3-(8-phenyl-1,4-dioxaspiro[4.5]decane-8-yl)propionitrile (156, Scheme 30) (1.40 g, 5.16 mmol) was reacted with 3-(8-phenyl-1,4-dioxaspiro[4.5]decane-8-yl)propionitrile (156, Scheme 30) (1.40 g, 5 ​ DIBALH (4.16 mL, 25% toluene solution, 6.19 mmol) was added dropwise to anhydrous toluene (33 mL) solution (p. 21, p. 405, 2011). The reaction mixture was stirred at -78°C for 5 min and then quenched with saturated NH4Cl solution. The mixture was then allowed to reach room temperature, and HCl 2N (2.58 mL, 5.16 mmol) was added. The mixture was extracted with Et2O, the organic layer was washed with saturated NaHCO3 solution and brine, dried with Na2SO4, filtered and concentrated to give a colorless oily title compound 176, which was not characterized and used directly in the next step.

[0486] Step 2. 8-(but-3-yn-1-yl)-8-phenyl-1,4-dioxaspiro[4.5]decane (177) At 0°C, carbon tetrabromide (2.22 g, 6.71 mmol) was added to an anhydrous DCM (32 mL) solution of triphenylphosphine (3.59 g, 13.4 mmol). The reaction mixture was stirred at room temperature for 30 min, then cooled again to 0°C, and an anhydrous DCM (8 mL) solution of 176 g (5.16 mmol) was added. The reaction mixture was stirred at 0°C for 30 min. The reaction mixture was then diluted with hexane, filtered through a diatomaceous earth mat, and concentrated. The residue was diluted with hexane, filtered through a diatomaceous earth mat, and concentrated again. The residue was dissolved in anhydrous THF (23 mL), and the solution was cooled to -78°C. Then, n-butyllithium (4.13 mL, 2.5 M in hexane, 10.3 mmol) was added dropwise, and the reaction mixture was stirred at -78°C for 1 h. The reaction mixture was then quenched with saturated NH4Cl solution and extracted with EA. The organic layer was washed with brine, dried with Na2SO4, filtered, and concentrated. The residue was purified by rapid column chromatography (elution gradient of 0% to 50% hexane solution of EA) to give a white solid title compound 177 (734 mg, two-step yield 53%), which was not characterized and was used directly in the synthesis of the relevant examples.

[0487] 2-Amino-6-(but-3-yn-1-yl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b Thiophene-3-carboxamide (179) Scheme 36

[0488] A 2.7 mL solution of anhydrous DMF containing 178 (characterization shown in Table 6) (synthesized in a manner similar to compound 47 (Scheme 4) using compound 177 (Scheme 35) instead of compound 41 as the starting material) (83 mg, 0.25 mmol) was saturated with bubbling NH3 from a balloon. Then PyBOP (191 mg, 0.37 mmol) and N,N -Diisopropylethylamine (0.085 mL, 0.49 mmol) was used, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then quenched with saturated NH₄Cl solution and extracted with EA. The organic layer was dried over Na₂SO₄, filtered, and concentrated. The residue was purified by rapid column chromatography (elution gradient of 40% to 100% EA in hexane) to give the title compound 179 (50 mg, 60% yield) as a white solid.

[0489] 1 H NMR: 400 MHz, CDCl3, δ (ppm): 7.34-7.23 (m, 5H), 6.99 (s, 2H), 5.29 (s, 2H), 2.96-2.88 (m, 1H), 2.68-2.56 (m, 2H), 2.47-2.40 (m, 1H), 2.35-2.26(m, 1H), 2.23-2.11 (m, 2H), 2.09-2.01 (m, 1H), 1.91 (t, J = 2.5 Hz, 1H). LC-MS: rt = 1.24 min, MS: 338.1 (calcd), 339.1 (M+H + (Measured value).

[0490] Example 99 6-(2-(1H-1,2,3-triazol-5-yl)ethyl)-2-amino-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b Thiophene-3-carboxylic acid (180) Scheme 37

[0491] Copper(II) sulfate pentahydrate (30 mg, 0.12 mmol) and sodium ascorbate (24 mg, 0.12 mmol) were added to a suspension of 178 (Protocol 36) (20 mg, 0.059 mmol) in DMF (0.6 mL) and water (0.3 mL). The flask was evacuated and backfilled with nitrogen, and then trimethylsilazine (0.06 mL, 0.47 mmol) was added. The reaction mixture was stirred at room temperature for 10 min. The mixture was then purified by reversed-phase rapid column chromatography (elution gradient of 10% to 100% CH3CN in H2O solution containing 0.1% (v / v) formic acid) to give title compound 180 as a white solid (16 mg, 71% yield).

[0492] 1 H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.26 (s, 2H), 7.49 (bs, 1H), 7.35-7.31 (m, 4H), 7.26-7.21 (m, 1H), 3.17-3.12 (m, 1H), 2.67-2.63 (m, 1H), 2.50-2.41 (m, 3H), 2.33-2.23 (m, 1H), 2.11-2.07 (m, 2H). LC-MS: rt = 1.11 min, MS: 382.1 (calcd), 383.2 (M+H + (Measured value).

[0493] Example 100 6-(2-(1H-1,2,3-triazol-5-yl)ethyl)-2-amino-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b Thiophene-3-carboxamide (181) Scheme 38

[0494] To a suspension of 179 (Scheme 36) (25 mg, 0.074 mmol) in DMF (0.8 mL) and water (0.4 mL), copper(II) sulfate pentahydrate (37 mg, 0.148 mmol) and sodium ascorbate (29 mg, 0.148 mmol) were added. The flask was evacuated and backfilled with nitrogen, and then trimethylsilazine (0.078 mL, 0.591 mmol) was added. The reaction mixture was stirred at room temperature for 10 min. The reaction mixture was then quenched with saturated NH4Cl solution and extracted with EA. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid column chromatography (eluent gradient of 0% to 20% MeOH in DCM solution) to give title compound 181 as a white solid (13 mg, 46% yield).

[0495] 1 H NMR: 400 MHz, CD3OD, δ (ppm): 7.52 (bs, 1H), 7.37-7.31 (m, 4H), 7.26-7.22 (m, 1H), 3.02-2.98 (m, 1H), 2.85-2.57 (m, 4H), 2.48-2.41 (m, 1H), 2.30-2.16 (m, 2H). LC-MS: rt = 0.98 min, MS: 381.1 (calcd), 382.2 (M+H +(Measured value).

[0496] Example 101 2-Amino-6-(2-(3-bromoisoxazol-5-yl)ethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b Thiophene-3-carboxamide (183) Scheme 39

[0497] Step 1. (4-(2-amino-3-aminomethyl-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b ]thiophene-6-yl)phenyl)dimethyl-lambda;4-sulfanylidenecarbamate (Compound 1) Step 1. 8-(but-3-yn-1-yl)-8-phenyl-1,4-dioxaspiro[4.5]decane (182) Under N2, hydroxylamine hydrochloride (24.6 mg, 355 μmol) was added to a solution of copper sulfate pentahydrate (88.5 mg, 355 μmol) and 28% ammonium hydroxide aqueous solution (177 μL, 1.32 mmol) cooled to 0°C in 1 mL of water. The mixture was stirred for 10 minutes, and then 179 (Scheme 36) (30.0 mg, 88.6 μmol) of ethanol (3 mL) was added in one batch. The resulting mixture was stirred for 5 minutes, then stopped and allowed to stand for another 5 minutes. The precipitate was filtered off and washed successively with water (5 × 5 mL), EtOH (5 × 6 mL), and Et2O (5 × 5 mL). The precipitate was then dried under vacuum overnight to give a deep yellow solid, title compound 182 (30 mg, 84% yield), which was not characterized and used directly in the next step.

[0498] Step 2. 2-amino-6-(2-(3-bromoisoxazol-5-yl)ethyl)-7-oxo-6-phenyl-4,5,6,7- tetrahydrobenzo[d]oxazole benzo[ b ]thiophene-3-carboxamide (183) Add 1,1-dibromoformaldehyde oxime (18.2 mg, 89.8 μmol) to the suspension of 182 (30.0 mg, 74.8 μmol) in DCE (1 mL), and incubate the resulting mixture at 45 °C. o The mixture was stirred at C for 4 hours. The mixture was then cooled to room temperature and purified by rapid column chromatography (eluent gradient of 0% to 100% EA in hexane solution) and subsequent reversed-phase rapid column chromatography (eluent gradient of 5% to 100% CH3CN in H2O solution containing 0.1% (v / v) formic acid) to give the title compound 183 (2.6 mg, 7.5%) as a pale yellow solid.

[0499] 1 H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.10 (s, 2H), 7.35-7.30 (m, 4H), 7.27-7.21 (m, 1H), 6.85 (bs, 2H); 6.53 (s, 1H), 2.91-2.81 (m, 1H), 2.78-2.63(m, 2H), 2.63-2.54 (m, 2H), 2.33-2.19 (m, 1H), 2.16-2.09 (m, 2H). LC-MS: rt =1.39 min, MS: 459.0 and 461.0 (calcd), 460.0 and 462.0 (M+H + (Measured value).

[0500] Example 102 2-Amino-6-(2-cyanoethyl)-6-(cyclopropylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[ b Thiophene-3-carboxylic acid (189) Example 103 2-Amino-6-(3-amino-3-oxopropyl)-6-(cyclopropylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[ b Thiophene-3-carboxamide (191) Example 104 2-Amino-6-(2-cyanoethyl)- N -Cyclopropyl-6-(cyclopropylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[ b Thiophene-3-carboxamide (192) Scheme 40

[0501] Step 1. 3-(8-(cyclopropylmethyl)-1,4-dioxaspiro[4.5]decan-8-yl)acrylonitrile (184) At 0°C, diethylcyanomethylphosphonate (8.65 mL, 53.5 mmol) was slowly added to a mixture of sodium hydride (2.14 g, 53.5 mmol) and DMPU (11.3 mL, 93.6 mmol) in anhydrous THF (40 mL). The mixture was stirred at 0°C for 1 hour, then a solution of 113 (Scheme 21) (10.0 g, 44.6 mmol) in anhydrous THF (65 mL) was added dropwise, and the reaction mixture was stirred at room temperature for 24 hours. The mixture was partitioned between water and EA (200 mL each). The layers were separated, the organic phase was washed with brine (150 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (eluent mixture of 50% Et2O in hexane) to give a colorless oily title compound 184 (10.0 g, 91% yield), which was not characterized and used directly in the next step.

[0502] Step 2. 3-(8-(cyclopropylmethyl)-1,4-dioxaspiro[4.5]decan-8-yl)propanenitrile (185) A suspension of 184 (10.0 g, 40.4 mmol) and Pd / C 10% (215 mg) in EA (189 mL) and EtOH (246 mL) was stirred at room temperature for 24 hours under a hydrogen atmosphere (balloon). The mixture was then filtered, and the filtrate was concentrated to give a colorless, oily title compound 185 (9.90 g, 98% yield), which was not purified and characterized for use in step 4.

[0503] Step 3. 3-(1-(cyclopropylmethyl)-4-oxocyclohexyl)propanenitrile (186) A 2N HCl aqueous solution (186 mL, 372 mmol) was added to a solution of acetone (460 mL) containing 185 g (9.30 g, 37.3 mmol). The resulting mixture was stirred at 40°C for 24 hours, then quenched with a saturated NaHCO3 aqueous solution (200 mL) and concentrated to remove the organic solvent. The residue was extracted with EA (2 × 250 mL). The combined organic matter was washed with brine, dried over Na2SO4, filtered, and concentrated to give a colorless oily title compound 186 (6.90 g, 90% yield), which was not purified or characterized and was used in step 5.

[0504] Step 4. 2-Amino-6-(2-cyanoethyl)-6-(cyclopropylmethyl)-4,5,6,7- tetrahydrobenzo[ b ]thiophene- 3-carboxylic acid ethyl ester (187) A suspension of 186 (6.10 g, 29.7 mmol), morpholine (2.82 mL, 32.7 mmol), sulfur (1.05 g, 4.10 mmol), and ethyl 2-cyanoacetate (3.16 mL, 29.7 mmol) in EtOH (52 mL) was stirred at 60°C for 16 hours. The mixture was then cooled to room temperature, diluted with brine (100 mL), and extracted with EA (3 × 100 mL). The combined organics were dried over Na₂SO₄, filtered, and concentrated. The residue was purified by rapid column chromatography (elution gradient of 0% to 70% EA in hexane) to give the title compound 187 (4.10 g, 42% yield) as a deep yellow oil. LC-MS: rt = 1.71 min, MS: 332.2 (calcd), 333.1 (M+H) + (Measured value).

[0505] Step 5. 2-acetylamino-6-(2-cyanoethyl)-6-(cyclopropylmethyl)-7-oxo-4,5,6,7- tetrahydrobenzo[d]oxazole and b ] ethyl thiophene-3-carboxylate (188) A mixture of 187 (4.10 g, 12.3 mmol) and acetic anhydride (1.40 mL, 14.8 mmol) in acetic acid (71 mL) was stirred at 70°C for 2 hours. The mixture was cooled to room temperature and concentrated to approximately 50 mL. The mixture was then diluted with water (50 mL) and dioxane (50 mL), and cerium sulfate (37.3 g, 107 mmol) was added. The reaction mixture was stirred at room temperature for 24 hours. A yellow solid was then filtered off, washed with EA (150 mL), and the filtrate was diluted with brine. The layers were separated, and the aqueous phase was extracted with EA (150 mL). The combined organic matter was washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated to give an orange oily title compound 188 (4.20 g, 88% yield). LC-MS: rt = 1.63 min, MS: 388.2 (calcd), 389.3 (M+H₂O). + (Measured value).

[0506] Step 6a. 2-amino-6-(2-cyanoethyl)-6-(cyclopropylmethyl)-7-oxo-4,5,6,7- tetrahydrobenzo[d]oxazole [ b ] thiophene-3-carboxylic acid (189) and 2-amino-6-(3-amino-3-oxopropyl)-6- (cyclopropylmethyl)-7-oxo-4,5,​ 6,7-tetrahydrobenzo[ b ]thiophene-3-carboxylic acid (190) A solution of lithium hydroxide monohydrate (109 mg, 2.60 mmol) in water (63 mL) was added to a solution of 188 (202 mg, 0.52 mmol) in methanol (63 mL). The mixture was stirred at 80°C for 16 hours, then cooled to room temperature and concentrated by rotary evaporation to remove most of the organic solvent. The aqueous residues were washed with EA, and the layers were separated. The aqueous layer was acidified by slow addition of 1N HCl and extracted with EA (3 x 40 mL). The organics were dried over Na2SO4, filtered, and concentrated to give a mixture of title compounds 189 and 190. The crude product was purified by rapid column chromatography (eluent gradient of 0% to 35% MeOH in DCM solution) to give 189 (111 mg, 67% yield) and 190 (40.0 mg, 23% yield). 24 mg of 189 was further purified by semi-preparative HPLC-MS (elution gradient of 20% to 100% MeOH in 10 mM ammonium bicarbonate solution) to obtain 14.8 mg of off-white solid high-purity substance.

[0507] 189 1 H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.32 (bs, 2H), 3.09-3.03 (m,1H), 2.94-2.87 (m, 1H), 2.43-2.31 (m, 2H), 2.07-1.93 (m, 3H), 1.84-1.74 (m,1H), 1.54 (dd, J = 14.2, 6.3 Hz, 1H), 1.30 (dd, J LC-MS of 189: rt = 1.22 min, MS: 318.1 (calcd), 319.1 (M+H + (Measured value).

[0508] (For the characterization of 190, see Table 6) Step 7. 2-amino-6-(3-amino-3-oxopropyl)-6-(cyclopropylmethyl)-7-oxo-4,5,6,7- tetrahydrobenzo[d]oxazole hydrobenzo[ b ]thiophene-3-carboxamide (191) Add ammonium chloride (127 mg, 2.38 mmol), HATU (69.2 mg, 178 μmol), and [other ingredients] to a 1.26 mL solution of anhydrous DMF at a concentration of 190 (40.0 mg, 119 μmol). N,N-Diisopropylethylamine (41.4 μL, 238 μmol). The resulting mixture was stirred at room temperature for 16 hours and then concentrated. The residue was purified by reversed-phase column chromatography (elution buffer gradient of 0% to 100% CH3CN in H2O solution containing 0.1% (v / v) formic acid) to give title compound 191 as a white solid (15.8 mg, 40% yield).

[0509] 1 H NMR: 400 MHz, DMSO-d6, δ (ppm): 7.97 (s, 2H), 7.20 (s, 1H), 6.92(bs, 2H), 6.64 (s, 1H), 2.98-2.90 (m, 2H), 2.12-2.04 (m, 1H), 2.00-1.87 (m,3H), 1.84-1.71 (m, 2H), 1.57 (dd, J = 14.1, 6.3 Hz, 1H), 1.27 (dd, J LC-MS: rt = 0.88 min, MS: 335.1 (calcd), 336.0 (M+H + (Measured value).

[0510] Step 6b. 2-amino-6-(2-cyanoethyl)- 4,5,6,7-tetrahydro-4,4-dimethyl-2H- inden-7-ol N - cyclopropyl-6-(cyclopropylmethyl)-7-oxo-4,5,6,7- tetrahydrobenzo[ b ]thiophene-3-carboxamide (192) A solution of lithium hydroxide monohydrate (3.10 g, 73.8 mmol) in water (500 mL) was added to a solution of 188 (4.20 g, 10.8 mmol) in MeOH (500 mL). The mixture was stirred at 55°C for 16 hours, then cooled to room temperature and concentrated by rotary evaporation to remove most of the organic solvent. The aqueous residue was washed with DCM, and the layers were separated. The aqueous layer was acidified by slow addition of 1 N HCl and extracted with EA (3 x 100 mL). The organic matter was dried over Na₂SO₄, filtered, and concentrated. The residue was dissolved in anhydrous THF (90 mL), and HATU (7.17 g, 18.8 mmol) was added. N,N-Diisopropylethylamine (3.28 mL, 18.8 mmol) and cyclopropylamine (6.53 mL, 94.2 mmol). The reaction mixture was stirred at room temperature for 3 hours, then diluted with brine (50 mL) and extracted with EA (3 × 100 mL). The combined organic compounds were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid column chromatography (elution gradient of 0% to 100% EA in hexane) to give the title compound 192 as a yellow solid (1.86 g, 45% yield in two steps).

[0511] 1 H NMR: 400 MHz, DMSO-d6, δ (ppm): 7.73 (s, 2H), 7.31 (d, J = 3.8 Hz,1H), 2.93-2.82 (m, 1H), 2.81-2.77 (m, 1H), 2.77-2.67 (m, 1H), 2.38-2.32 (m,2H), 2.02-1.98 (m, 2H), 1.94-1.86 (m, 1H), 1.84-1.76 (m, 1H), 1.54 (dd, J =14.2, 6.3 Hz, 1H), 1.29 (dd, J = 14.1, 7.0 Hz, 1H), 0.66-0.60 (m, 2H), 0.60-0.52 (m, 1H), 0.51-0.46 (m, 2H), 0.37-0.35 (m, 2H), 0.04 - ‒0.01 (m, 1H), ‒0.04 - ‒0.1 (m, 1H). LC-MS: rt = 1.25 min, MS: 357.2 (calcd), 358.1 (M+H+, measured value).

[0512] Example 105 ( S )-2-amino-6-(2-cyanoethyl)- N -Cyclopropyl-6-(cyclopropylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[ b ]Thiophene-3-carboxamide (193) and Example 106 ( R )-2-amino-6-(2-cyanoethyl)- N -Cyclopropyl-6-(cyclopropylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[ bThiophene-3-carboxamide (194) Scheme 41

[0513] Racemic compound 192 (Scheme 40) (1.14 g) was subjected to SFC chiral separation (isocratic: 1:1 methanol in 50% CO2) to give an orange solid enantiomer-enriched compound 193 (468.9 mg, 41% separation yield) and an off-white solid enantiomer-enriched compound 194 (424.5 mg, 37% separation yield) (absolute configuration was determined based on the resolved crystal structure of enantiomer 194).

[0514] 193: 1 ¹H NMR: Same as racemic mixture (192). LC-MS: rt = 1.27 min, MS: 357.2 (calcd), 358.2 (M+H). + (Measured values). Analytical SFC (IG column, using a gradient of 5-60% methanol in aqueous solution (95-40% CO2)): rt = 5.44 min, ee = >99.9%.

[0515] 194: 1 ¹H NMR: Same as racemic mixture (192). LC-MS: rt = 1.27 min, MS: 357.2 (calcd), 358.2 (M+H). + (Measured values). Analytical SFC (IG column, using a gradient of 5-60% methanol in aqueous solution (95-40% CO2)): rt = 6.49 min, ee. = 99.4%.

[0516] Example 107 2-Amino-6-(2-cyanoethyl)-6-(cyclopropylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[ b Thiophene-3-carboxamide (195)

[0517] Compound 195 (Example 107) was synthesized in a manner similar to that of compound 109 (Example 59, Scheme 19) by using compound 189 (Scheme 40) instead of compound 108 as the starting material.

[0518] 1 H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.01 (s, 2H), 6.94 (bs, 2H), 3.05-2.89 (m, 2H), 2.44-2.32 (m, 2H), 2.08-2.02 (m, 2H), 1.99-1.92 (m, 1H), 1.86-1.79 (m, 1H), 1.55 (dd, J = 14.2, 6.4 Hz, 1H), 1.35 (dd, J LC-MS: rt = 1.07 min. 317.1 (calcd), 318.2 (M+H + (Measured value).

[0519] Example 108 2-Amino-6-(2-Amino-2-oxoethyl)- N -Cyclopropyl-6-(cyclopropylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[ b Thiophene-3-carboxamide (198) Intermediate compound 196 2-(8-(cyclopropylmethyl)-1,4-dioxaspiro[4.5]decane-8-yl)acetamide (196) Scheme 42

[0520] Add potassium hydroxide (1.55 g, 27.7 mmol) and water (1 mL) to a solution of 118 (Scheme 22) (814 mg, 3.46 mmol) in ethylene glycol (18.3 mL). Stir the resulting mixture at 170°C for 24 hours, then add more potassium hydroxide (1.55 g, 27.7 mmol) and water (1 mL), and stir the reaction mixture at 170°C for another 24 hours. Cool the mixture to room temperature, dilute with water (50 mL), and extract with EA (2 × 50 mL). Acidify the aqueous layer by adding HCl 2N and extract with EA (3 × 50 mL). Wash the combined organic matter with water (50 mL) and brine (50 mL), dry with Na2SO4, filter, and concentrate. The residue was purified by rapid column chromatography (elution gradient of 0% to 100% hexane solution of EA, followed by 0% to 20% DCM solution of MeOH) to give title compound 196 (320 mg, 37% yield) as a white solid. It was not characterized and was used directly in the synthesis of the relevant examples.

[0521] 2-Amino-6-(2-Amino-2-oxoethyl)- N -Cyclopropyl-6-(cyclopropylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[ b Thiophene-3-carboxamide (198) Scheme 43

[0522] Compound 197 (characterization shown in Table 6) (synthesized using compound 196 (Scheme 42) instead of compound 41 as the starting material, in a manner similar to compound 47 (Example 28, Scheme 4)) (70.0 mg, 217 μmol) was dissolved in DMF (1 mL). HATU (248 mg, 651 μmol), cyclopropylamine (150 μL, 2.17 mmol), and... N,N -Diisopropylethylamine (113 μL, 651 μmol) was used to stir the resulting mixture at room temperature for 1 hour. The crude mixture was then purified directly by reversed-phase column chromatography (elution buffer gradient of 5% to 100% CH3CN in H2O solution containing 0.1% (v / v) formic acid) to give the title compound 198 as a pale yellow solid (19.2 mg, 24% yield).

[0523] 1 H NMR: 400 MHz, DMSO-d6, δ (ppm): 7.68 (s, 2H), 7.29 (s, 1H), 7.15 (s, 1H), 6.67 (s, 1H), 2.96-2.85 (m, 1H), 2.75-2.70 (m, 2H), 2.56 (d, J =14.81 Hz, 1H), 2.36-2.28 (m, 1H), 2.24 (d, J = 14.80 Hz, 1H), 2.06-2.00 (m,1H), 1.65 (dd, J = 14.02, 6.34 Hz, 1H), 1.30 (dd, J = 14.00, 7.00 Hz, 1H),0.68-0.61 (m, 3H), 0.53-0.49 (m, 2H), 0.38-0.36 (m, 2H), 0.08-0.02 (m, 1H), ‒0.06 - ‒0.13 (m, 1H). LC-MS: rt = 1.00 min. MS: 361.1 (calcd), 362.2 (M+H + (Measured value).

[0524] Example 109 2-Amino-6-(2-amino-2-oxoethyl)-6-(cyclopropylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[ b Thiophene-3-carboxamide (199)

[0525] Compound 199 (Example 109) was synthesized in a manner similar to that of compound 109 (Example 59, Scheme 19) by using compound 197 instead of compound 108 as the starting material.

[0526] 1 H NMR: 400 MHz, DMSO-d6, δ (ppm): 7.92 (s, 2H), 7.13 (s, 1H), 6.88 (bs, 1H), 6.65 (s, 1H), 3.00-2.90 (m, 1H), 2.88-2.81 (m, 1H), 2.53 (d, J =14.81 Hz, 1H), 2.35-2.27 (m, 1H), 2.24 (d, J= 14.81 Hz, 1H), 2.06-2.00 (m,1H), 1.62-1.56 (m, 1H), 1.33-1.28 (m, 1H), 0.62-0.55 (m, 1H), 0.38-0.30 (m,2H), 0.07-0.02 (m, 1H), ‒0.08 - ‒0.14 (m, 1H). LC-MS: rt = 0.83 min. MS:321.1 (calcd), 322.2 (M+H + (Measured value).

[0527] Example 110 2-Amino-6-carbamoyl-6-(cyclopropylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[ b Thiophene-3-carboxylic acid (200) Scheme 44

[0528] To a mixture of 53 (Scheme 7) (100 mg, 344 μmol) in methanol (4.39 mL) and water (1.41 mL), 30% aqueous hydrogen peroxide solution (352 μL, 3.44 mmol) and potassium hydroxide (199 mg, 3.55 mmol) were added, and the reaction mixture was stirred at room temperature for 24 hours. The mixture was diluted with water (5 mL) and concentrated to remove the organic solvent. The aqueous residue was washed with EA (10 mL), acidified to pH 1, and extracted with EA (3 × 10 mL). The organics were dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid column chromatography (eluent gradient of 0% to 30% in DCM solution of MeOH) and then purified again by reversed-phase column chromatography (eluent gradient of 5% to 100% in H2O solution of CH3CN containing 0.1% (v / v) formic acid) to give title compound 200 (7 mg, 6% yield) as a yellow solid.

[0529] 1 H NMR: 400 MHz, DMSO-d6, δ (ppm): 2.50 (bs, 1H), 8.29 (bs, 2H), 7.05 (s, 1H), 6.77 (s, 1H), 3.08-3.01 (m, 1H), 2.92-2.83 (m, 1H), 2.47-2.44 (m,1H), 2.14-2.06 (m, 1H), 1.76 (dd, J= 13.99, 6.23 Hz, 1H), 1.65 (dd, J =13.99, 6.23 Hz, 1H), 0.63-0.56 (m, 1H), 0.39-0.35 (m, 2H), 0.05 - ‒0.01 (m,2H). LC-MS: rt = 0.99 min. MS: 308.1 (calcd), 309.0 (M+H) + (Measured value).

[0530] Example 111 2-Amino-6-(cyclopropylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[ b Thiophene-3,6-dicarboxamide (201)

[0531] Compound 201 (Example 111) was synthesized in a manner similar to that of compound 109 (Example 59, Scheme 19) by using compound 200 instead of compound 108 as the starting material.

[0532] 1 H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.12 (s, 2H), 7.06 (s, 1H), 6.94 (bs, 1H), 6.77 (s, 1H), 3.07-2.97 (m, 1H), 2.90-2.83 (m, 1H), 2.49-2.44 (m, 1H), 2.16-2.08 (m, 1H), 1.79-1.66 (m, 2H), 0.64-0.57 (m, 1H), 0.38-0.34 (m,2H), 0.08-0.03 (m, 2H). LC-MS: rt = 0.89 min. MS: 307.1 (calcd), 308.0 (M+H + (Measured value).

[0533] Example 112 2-Amino- N 3 -Cyclopropyl-6-(cyclopropylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[ b Thiophene-3,6-dicarboxamide (202) Scheme 45

[0534] At room temperature, lithium hydroxide monohydrate (19.6 mg, 467 μol) was added to a solution of compound 72 (Table 3) (77.0 mg, 234 μol) in a mixture of MeOH (10.1 mL) and water (10.1 mL). The reaction mixture was cooled to 0°C, and 30% H2O2 (145 μL) was added. The mixture was stirred at 0°C for 1 hour, then more 30% H2O2 (145 μL) was added, and the reaction mixture was stirred at room temperature for another 2.5 hours, then at 40°C for another 45 minutes. The mixture was then cooled to 0°C and diluted with brine (10 mL) and EA (10 mL). The layers were separated, and the aqueous phase was extracted with EA (3 × 10 mL). The combined organics were dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid column chromatography (elution gradient of 0% to 100% hexane solution of EA) to give the title compound 202 as a white solid (13.2 mg, 16% yield).

[0535] 1 H NMR: 400 MHz, DMSO-d6, δ (ppm): 7.84 (s, 2H), 7.40 (d, J = 3.86 Hz,1H), 7.05 (s, 1H), 6.74 (s, 1H), 2.98-2.90 (m, 1H), 2.75-2.68 (m, 2H), 2.46-2.41 (m, 1H), 2.12-2.04 (m, 1H), 1.78-1.73 (m, 1H), 1.68-1.63 (m, 1H), 0.66-0.55 (m, 3H), 0.53-0.48 (m, 2H), 0.37-0.34 (m, 2H), 0.05-0.02 (m, 2H). LC-MS:rt = 1.05 min. MS: 347.1 (calcd), 348.1 (M+H + (Measured value).

[0536] Example 113 2-Amino-6-(cyclopropylmethyl)-6-(3-hydroxypropyl)-7-oxo-4,5,6,7-tetrahydrobenzo[ b Thiophene-3-carboxylic acid (211) Scheme 46

[0537] Step 1. 3-(8-(cyclopropylmethyl)-1,4-dioxaspiro[4.5]decan-8-yl)propanoic acid (203) Potassium hydroxide (3.85 g, 68.7 mmol) and water (31.0 μL, 1.72 mmol) were added to a solution of 185 (Protocol 40) (2.14 g, 8.58 mmol) in ethylene glycol (45.5 mL). The resulting mixture was stirred at 170 °C for 24 hours. The mixture was cooled to room temperature, diluted with water (50 mL), and washed with DCM (2 × 50 mL). The aqueous phase was acidified to pH 2 by adding 2N HCl and extracted with DCM (3 × 10 mL). The organics were dried over MgSO4, filtered, and concentrated to give a red oily title compound 203, which was used directly in step 2 without purification and characterization.

[0538] Step 2. 3-(8-(cyclopropylmethyl)-1,4-dioxaspiro[4.5]decan-8-yl)propan-1-ol (204) At 0°C, lithium aluminum hydride (9.55 mL, 2 M in THF, 19.1 mmol) was added dropwise to a solution of 203 (8.58 mmol) in anhydrous THF (54 mL). The resulting mixture was stirred at 0°C for 1 hour, allowed to reach room temperature, and stirred for 16 hours. A saturated Rochelle salt aqueous solution (30 mL) was added dropwise, and the mixture was diluted with EA (50 mL), stirred at room temperature for 30 minutes, and filtered through a diatomaceous earth mat. The layers were separated, and the aqueous phase was extracted with EA (2 × 50 mL). The combined organic matter was dried over MgSO4, filtered, and concentrated to give a yellow oily title compound 204 (2.07 g, 95% yield in two steps), which was unpurified and uncharacterized for use in step 3.

[0539] Step 3. 4-(cyclopropylmethyl)-4-(3-hydroxypropyl)cyclohexan-1-one (205) To a solution of 204 (2.07 g, 8.14 mmol) in acetone (125 mL), 2N HCl aqueous solution (22.9 mL, 45.7 mmol) was added, and the resulting mixture was stirred at room temperature for 70 hours. The mixture was then neutralized with saturated NaHCO3 aqueous solution (50 mL) and concentrated to remove the organic solvent. The residue was then partitioned between EA (50 mL) and water (40 mL), the layers separated, the organic phase dried over Na2SO4, filtered, and concentrated. The residue was dissolved in DCM (30 mL), insoluble impurities were filtered off, and the residue was washed with DCM (50 mL). The filtrate and washings were combined and concentrated to give a thick, pale yellow oily title compound 205 (1.53 g, 89% yield), which was unpurified and uncharacterized for use in step 4.

[0540] Step 4. 3-(1-(cyclopropylmethyl)-4-oxocyclohexyl)propyl acetate (206) At 0°C, acetic anhydride (1.65 mL, 17.5 mmol) and pyridine (1.77 mL, 21.8 mmol) were added to anhydrous DCM (15.9 mL) solution of 205 (1.53 g, 7.27 mmol). The reaction mixture was brought to room temperature and stirred for 19 hours. The mixture was then diluted with DCM (40 mL) and washed with 1N HCl (40 mL). The organic phase was dried over Na2SO4, filtered, and concentrated to give a yellow oily title compound 206 (1.80 g, 98% yield), which was unpurified and uncharacterized for use in step 5.

[0541] Step 5. 6-(3-acetyloxypropyl)-2-amino-6-(cyclopropylmethyl)-4,5,6,7- tetrahydrobenzo[d]thiazole b ] Step 6. 6-(3-acetyloxypropyl)-2-amino-6-(cyclopropylmethyl)-4,5,6,7- tetrahydrobenzo[d]thiazole thiophene-3-carboxylic acid ethyl ester (207) A suspension of sulfur (253 mg, 984 μmol), 206 (1.80 g, 7.13 mmol), morpholine (677 μL, 7.85 mmol), and ethyl 2-cyanoacetate (759 μL, 7.13 mmol) in EtOH (12.5 mL) was stirred at 60°C for 16 hours. The mixture was cooled to room temperature, diluted with brine (20 mL), and extracted with EA (3 × 20 mL). The combined organic compounds were dried over Na₂SO₄, filtered, and concentrated. The residue was purified by rapid column chromatography (elution gradient of 0% to 35% EA in hexane) to give the title compound 207 (2.25 g, 83% yield) as a yellow oil. LC-MS: rt = 1.90 min, MS: 379.2 (calcd), 380.2 (M+H) + (Measured value).

[0542] Step 6. 2-Acetylamino-6-(3-acetyloxypropyl)-6-(cyclopropylmethyl)-4,5,6,7- tetrahydrobenzo[d]imidazole-1 -carboxylic acid ethyl ester b ] thiophene-3-carboxylic acid ethyl ester (208) At 0°C, acetic anhydride (1.34 mL, 14.2 mmol) and pyridine (1.44 mL, 17.8 mmol) were added to an anhydrous DCM solution of 207 (2.25 g, 5.93 mmol) in 12.9 mL. The reaction mixture was brought to room temperature and stirred for 16 hours. The mixture was then diluted with DCM (20 mL) and washed with 1N HCl (40 mL). The organic phase was dried over Na2SO4, filtered, and concentrated to give a yellow oily title compound 208 (2.50 g, >99% yield), which was unpurified and uncharacterized for use in step 7. LC-MS: rt = 1.96 min, MS: 421.2 (calcd), 422.2 (M+H) + (Measured value).

[0543] Step 7. 2-acetylamino-6-(3-acetyloxypropyl)-6-(cyclopropylmethyl)-7-oxo-4,5,6,7- tetrahydrobenzo[d]oxazole benzo[ b ] thiophene-3-carboxylic acid ethyl ester (209) To a solution of 208 (2.50 g, 5.93 mmol) in dioxane (27.1 mL), acetic acid (27.1 mL), cerium sulfate (17.0 g, 51.2 mmol), and water (12.9 mL) were added. The resulting mixture was stirred at room temperature for 16 hours, then the solid was filtered off and washed with EA (100 mL). The filtrate and washes were combined, diluted with water (50 mL), and the layers were separated. The aqueous phase was extracted with EA (2 × 50 mL). The combined organic matter was dried over Na₂SO₄, filtered, and concentrated to give solid title compound 209 (2.50 g, 97% yield), which was used in step 8. LC-MS: rt = 1.76 min, MS: 435.2 (calcd), 436.3 (M+H + (Measured value).

[0544] Step 8. 6-(3-acetyloxypropyl)-2-amino-6-(cyclopropylmethyl)-7-oxo-4,5,6,7- tetrahydrobenzo[d]oxazole [ b ] ethyl thiophene-3-carboxylate (210)​ Pyrrolidine (7.30 mL, 88.9 mmol) was added to a solution of 209 g (2.50 g, 5.74 mmol) in toluene (9.71 mL). The resulting mixture was stirred at room temperature for 1 hour, then diluted with EA (40 mL) and brine (40 mL). The layers were separated, and the aqueous phase was extracted with EA (2 × 40 mL). The combined organic matter was dried over Na₂SO₄, filtered, and concentrated to give a dark oily title compound 210 (2.26 g, >99% yield), which was used in step 9 without purification. LC-MS: rt = 1.68 min, MS: 393.2 (calcd), 394.3 (M+H₂O). + (Measured value).

[0545] Step 9. 2-Amino-6-(cyclopropylmethyl)-6-(3-hydroxypropyl)-7-oxo-4,5,6,7- tetrahydrobenzo[d]oxazepine-3-carboxylic acid b ] thiophene-3-carboxylic acid (211) A solution of lithium hydroxide monohydrate (1.24 g, 29.6 mmol) in water (100 mL) was added to a solution of 210 (2.26 g, 5.74 mmol) in MeOH (100 mL). The resulting mixture was stirred at 80°C for 4 hours and then concentrated to remove most of the organic solvent. The aqueous residue was washed with EA (40 mL), then acidified to pH 4 by slow addition of 1N HCl aqueous solution, and extracted with EA (2 × 70 mL). The combined organic matter was dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid column chromatography (eluent gradient of 0% to 15% in DCM solution of MeOH) to give the title compound 211 (1.07 g, 58% yield) as a light brown solid.

[0546] 1H NMR: 400 MHz, DMSO-d6, δ (ppm): 12.44 (s, 1H), 8.17 (s, 2H), 4.32(t, J = 5.1 Hz, 1H), 3.34-3.29 (m, 2H, partially overlapping with water signals), 3.01-2.83 (m, 2H), 2.14-2.04 (m, 1H), 1.98-1.88 (m, 1H), 1.65-1.52 (m, 2H), 1.52-1.41 (m, 1H), 1.38-1.27 (m, 2H), 1.22 (dd, J = 14.1, 7.4 Hz, 1H), 0.61-0.50 (m, 1H), 0.40-0.30 (m, 2H), 0.02 - ‒0.01 (m, 2H). LC-MS: rt = 1.11 min. MS: 323.1 (calcd), 324.1 (M+H) + (Measured value).

[0547] Example 114 2-Amino-6-(cyclopropylmethyl)-6-(3-hydroxypropyl)-7-oxo-4,5,6,7-tetrahydrobenzo[ b Thiophene-3-carboxamide (212)

[0548] Compound 212 (Example 114) was synthesized in a manner similar to that of compound 109 (Example 59, Scheme 19) by using compound 211 (Scheme 46) instead of compound 108 as the starting material.

[0549] 1 H NMR: 400 MHz, DMSO-d6, δ (ppm): 7.96 (s, 2H), 6.90 (bs, 1H), 4.33(t, J = 5.2 Hz, 1H), 3.36-3.30 (m, 2H, partially overlapping with water signals), 2.93 (t, J= 6.0Hz, 2H), 2.12-2.06 (m, 1H), 1.98-1.91 (m, 1H), 1.62-1.46 (m, 3H), 1.39-1.23(m, 3H), 0.61-0.54 (m, 1H), 0.38-0.33 (m, 2H), 0.06-0.00 (m, 1H), ‒0.02 - ‒0.08 (m, 1H). LC-MS: rt = 0.97 min. MS: 322.1 (calcd), 323.2 (M+H + (Measured value).

[0550] Example 115 2-Amino- N -Cyclopropyl-6-(cyclopropylmethyl)-6-(3-hydroxypropyl)-7-oxo-4,5,6,7-tetrahydrobenzo[ b Thiophene-3-carboxamide (213)

[0551] Compound 213 (Example 115) was synthesized in a manner similar to that of compound 82 (Example 52, Scheme 13) by using compound 211 (Scheme 46) instead of compound 81 as the starting material.

[0552] 1 H NMR: 400 MHz, DMSO-d6, δ (ppm): 7.68 (bs, 2H), 7.31 (d, J = 3.8 Hz, 1H), 4.33 (t, J = 5.2 Hz, 1H), 3.35-3.27 (m, 2H, partially overlapping with water signals), 2.83 (t, J = 6.0 Hz, 2H), 2.75-2.70 (m, 1H), 2.07-2.02 (m, 1H), 1.93-1.88 (m, 1H), 1.63-1.50 (m, 3H), 1.35-1.23 (m, 3H), 0.67-0.62 (m, 2H), 0.59-0.54 (m, 1H), 0.52-0.49 (m, 2H), 0.38-0.33 (m, 2H), 0.03 - ‒0.02 (m, 1H), ‒0.02 - ‒0.09 (m,1H). LC-MS: rt = 1.15 min. MS: 362.2 (calcd), 363.2 (M+H+ (Measured value).

[0553] Example 116 2-Amino-6-cyano- N -Isopropyl-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b Thiophene-3-carboxamide (214) Scheme 47

[0554] Isopropylamine (55.0 μL, 640 μL), HATU (124 mg, 320 μL), and [other active ingredients] were added to an anhydrous DMF (1.58 mL) solution of compound 59 (Example 36, Scheme 8) (50.0 mg, 160 μL). N,N -Diisopropylethylamine (55.8 μL, 320 μmmol). The resulting mixture was stirred at room temperature for 30 minutes and then diluted with EA (5 mL) and water (5 mL). The layers were separated, and the aqueous phase was extracted with EA (5 mL). The combined organics were washed with brine (2 × 10 mL) and concentrated. The residues were purified by rapid column chromatography (eluent gradient of 0% to 100% EA in hexane solution) and then purified again by reversed-phase column chromatography (eluent gradient of 0% to 100% CH3CN in H2O solution containing 0.1% (v / v) formic acid) to give the title compound 214 (16.2 mg, 29% yield) as a white solid.

[0555] 1 H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.11 (bs, 1H), 7.47-7.36 (m, 6H), 4.03-3.95 (m, 1H), 3.10-3.02 (m, 1H), 2.81-2.70 (m, 2H), 2.67-2.59 (m, 1H), 1.11 (dd, J = 6.58, 3.79 Hz, 6H). LC-MS: rt = 1.33 min. MS: 353.1 (calcd), 354.1 (M+H + (Measured value).

[0556] Example 117 2-Amino-6-(2-hydroxyethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b Thiophene-3-carboxamide (215)

[0557] Compound 215 (Example 117) was synthesized in a manner similar to that of compound 61 (Example 38, Scheme 10) by using compound 89 (Scheme 15) instead of compound 59 as the starting material.

[0558] 1 H NMR: 400 MHz, CD3OD, δ (ppm): 7.30-7.25 (m, 4H), 7.21-7.17 (m, 1H), 3.51-3.38 (m, 2H), 2.95-2.87 (m, 1H), 2.63-2.60 (m, 2H), 2.38-2.29 (m, 1H), 2.15-2.06 (m, 2H). LC-MS: rt = 0.90 min, MS: 330.1 (calcd), 331.2 (M+H + (Measured value).

[0559] Example 118 2-Amino-6-cyano- N -Hydroxy-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b Thiophene-3-carboxamide (216) Scheme 48

[0560] At 0℃, N,N Diisopropylethylamine (26.8 μL, 154 μmol) was added to an anhydrous DMF solution (4.20 mL) of 2-amino-6-cyano-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (59, Scheme 8) (40.0 mg, 128 μmol) and HATU (49.7 mg, 128 μmol). The reaction mixture was stirred at 0 °C for 1 hour. In a separate reaction vessel, an anhydrous DMF solution (1.00 mL) of hydroxylamine (5.23 mg, 154 μmol) was added... N,N- Diisopropylethylamine (68.3 μL, 384 μmol) was added, and the resulting mixture was stirred for 5 minutes or until the hydroxylamine was completely dissolved. The resulting solution was then added to the reaction mixture and stirred at room temperature for 2.5 hours, followed by dilution with brine (5 mL) and EA (5 mL). The layers were separated, and the aqueous phase was extracted with EA (2 × 10 mL). The combined organic phases were washed with water (10 mL) and HCl 1N (2 × 10 mL), dried over NaSO4, filtered, and concentrated. The residue was purified by reversed-phase rapid column chromatography (eluent gradient of 5% to 100% CH3CN in H2O solution containing 0.1% (v / v) formic acid), then purified a second time by reversed-phase rapid column chromatography (eluent gradient of 5% to 100% CH3CN in 10mM ammonium bicarbonate solution), and then purified a third time by reversed-phase rapid column chromatography (eluent gradient of 5% to 100% CH3CN in H2O solution containing 0.1% (v / v) formic acid) to give the title compound 216 (8.1 mg, 19% yield) as a white solid.

[0561] 1 H NMR: 400 MHz, DMSO-d6, δ (ppm): 9.21 (bs, 1H), 8.29-8.05 (m, 2H), 7.48-7.31 (m, 5H), 3.05-2.94 (m, 1H), 2.80-2.71 (m, 2H), 2.68-2.56 (m, 1H).LC-MS: rt = 0.78 min. MS: 327.1 (calcd), 328.1 (M+H + (Measured value).

[0562] Example 119 2-Amino-6-ethyl-4-oxo-4,5,6,7-tetrahydrobenzo[ b Thiophene-3-carboxamide (219) Scheme 49

[0563] Step 1. 2-Amino-6-ethyl-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxamide (218) Morpholine (0.474 mL, 5.50 mmol) and sulfur (177 mg, 0.69 mmol) were added to a solution of 4-ethylcyclohexane-1-one (217) (0.776 mL, 5.50 mmol) and cyanoacetamide (420 mg, 5.00 mmol) in EtOH (5 mL). The reaction mixture was stirred at 60 °C for 19 hours, cooled to room temperature, and concentrated to dryness. The residue was purified by rapid column chromatography (eluting with DCM solution of MeOH at a gradient of 0 to 10%) to give the title compound 218 (658 mg, 59% yield) as a light orange solid. LC-MS: rt = 1.43 min, MS: 224.1 (calcd), 225.1 (M+H) + (Measured value).

[0564] Step 2. 2-Amino-6-ethyl-4-oxo-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxamide (219) Compound 218 (50.0 mg, 0.223 mmol) was dissolved in DMSO (5 mL), and O2 was bubbled through the mixture for 4 days. The mixture was then purified directly by rapid column chromatography (elution gradient of 0% to 100% EA in hexane, washed with 90:10 DCM / MeOH). Fractions containing the desired compound were combined and diluted with EA and water. The aqueous layer was extracted with EA. The combined organic layers were washed with brine, dried over NaSO4, filtered, and concentrated. Recrystallization from EA yielded the title compound 219 (16.0 mg, 30% yield) as a yellow solid.

[0565] 1 H NMR: 400 MHz, DMSO-d6, δ (ppm): 9.47 (s, 1H), 7.88 (s, 2H), 6.83 (s, 1H), 2.95 (dd, J = 16.85, 4.44 Hz, 1H), 2.56-2.50 (m, 2H), 2.35 (dd, J =16.26, 11.90 Hz, 1H), 2.12-1.98 (m, 1H), 1.38 (p, J = 7.23 Hz, 2H), 0.88 (t, J = 7.41 Hz, 3H). LC-MS: rt = 1.31 min, MS: 238.1 (calcd), 239.1 (M+H + (Measured value).

[0566] Example 120 2-Amino-4-oxo-4,7-dihydro-5H-spiro[benzo[] b [Thiophene-6,1'-cyclopentane]-3-carboxamide (221) Scheme 50

[0567] Step 1. 2-Amino-4,7-dihydro-5H-spiro[benzo[ b ]thiophene-6,1 '-cyclopentane]-3-carboxamide (220) Morpholine (0.056 mL, 0.654 mmol) and sulfur (21.1 mg, 0.082 mmol) were added to a solution of spiro[4.5]decane-8-one (151, Scheme 29) (99.6 mg, 0.654 mmol) and cyanoacetamide (50.0 mg, 0.595 mmol) in EtOH (0.595 mL). The reaction mixture was stirred at 60°C for 19 hours, then cooled to room temperature and concentrated to dryness. The residue was first purified by rapid column chromatography (eluent gradient of 0 to 10% MeOH in DCM solution) and then by reversed-phase rapid column chromatography (eluent gradient of 10 to 100% CH3CN in H2O solution containing 0.1% (v / v) formic acid) to give title compound 220 (77.0 mg, 50% yield) as a white solid. LC-MS: rt = 1.73 min, MS: 250.1 (calcd), 251.1 (M+H + (Measured value).

[0568] Step 2. 2-Amino-4-oxo-4,7-dihydro-5H-spiro[benzo[ b ]thiophene-6,1 '-cyclopentane]-3-carboxamide (221) 220 (10.0 mg, 0.040 mmol) and Oxone ® A mixture of potassium persulfate complex salt (6.72 mg, 0.04 mmol) in DMSO (0.896 mL) was stirred at room temperature for 72 hours. The mixture was then diluted with EA and water, and the aqueous layer was extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was first purified by rapid column chromatography (DCM solution with an eluent gradient of 0% to 10% MeOH) and then by semi-preparative HPLC-MS (10 mM ammonium formate solution with an eluent gradient of 30% to 100% ACN) to give title compound 221 as a white solid (1.10 mg, 10% yield).

[0569] 1 H NMR: 400 MHz, CD3OD, δ (ppm): 2.86 (s, 2H), 2.59 (s, 2H), 1.74-1.67(m, 4H), 1.63-1.47 (m, 4H). LC-MS: rt = 1.55 min, MS: 264.1 (calcd), 265.1 (M+H + (Measured value).

[0570] Example 121 2-Amino-6-(2-Amino-2-oxoethyl)- N -Cyclopropyl-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[ b Thiophene-3-carboxamide (228) Scheme 51

[0571] Step 1. 2-(8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl)acetic acid (222) Powdered potassium hydroxide (48.8 g, 799.0 mmol) was added to 2-(8-phenyl-1,4-dioxaspiro[4.5]decane-8-yl)acetonitrile (92, Scheme 17) (25.7 g, 99.9 mmol) Bioorg Med. Chem Lett The solution of the title compound 222 (21, p. 405, 2011) in ethylene glycol (524 mL) and water (12.9 mL) was stirred at 170°C for 16 hours. The mixture was then cooled to room temperature, diluted with water (250 mL), and washed with DCM (250 mL). The organic layer was discarded. The aqueous layer was acidified with 2N HCl and extracted with DCM (2 x 250 mL). These organic phases were combined, dried over Na2SO4, filtered, and concentrated to give a light orange solid, title compound 222 (24.8 g, 90% yield), which was not characterized and used directly in the next step.

[0572] Step 2. 2-(4-oxo-1-phenylcyclohexyl)acetic acid (223) To a solution of 222 (2.83 g, 10.2 mmol) in acetone (127 mL), 2N HCl (51.2 mL, 102 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. The organic solvent was then removed by slowly adding a saturated aqueous solution of NaHCO3 and concentrating. The residue was extracted with EA, the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to dryness to give a yellow oily title compound 223 (2.38 g, 96% yield), which was not characterized and used directly in the next step.

[0573] Step 3. 2-(2-amino-3-(ethoxycarbonyl)-6-phenyl-4,5,6,7-tetrahydrobenzo[ b ]thiophen-6-yl) acetic acid (224) Morpholine (1.97 mL, 22.5 mmol) and sulfur (363 mg, 1.41 mmol) were added to a solution of 223 (2.38 g, 10.2 mmol) and ethyl 2-cyanoacetate (1.20 mL, 11.3 mmol) in EtOH (10.2 mL). The reaction mixture was stirred at 60°C for 16 hours, then cooled to room temperature and concentrated to dryness. The residue was partitioned between water and EA. The layers were separated, the organic phase was dried over Na₂SO₄, filtered, and concentrated. The residue was ground in MeOH to give a beige solid, title compound 224 (2.44 g, 66% yield). LC-MS: rt = 1.42 min, MS: 359.1 (calcd), 360.0 (M+H₂O). + (Measured value).

[0574] Step 4. 2-Amino-6-(2-amino-2-oxoethyl)-6-phenyl-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxylic acid carboxylic acid ethyl ester (225) Compound 224 (400 mg, 1.11 mmol) was dissolved i...

Claims

1. A compound of Formula (I), (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R a is -NH2, -NH-OH, -OH, -NHR b or -NR c R d ; R b is C1-C6alkyl, C3-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl, wherein C1-C6alkyl is optionally substituted with 1 to 3 halogen, 1 to 3 -OH, -OC1-C3alkyl, -COOH, or cyclopropyl optionally substituted with -OH, wherein C3-C6cycloalkyl is optionally substituted with -CN; R c and R d form a 4-membered heterocycloalkyl with the nitrogen to which they are attached, wherein the 4-membered heterocycloalkyl is optionally substituted with at least one of -OH and C1-C3 alkyl; denotes one of the following residues A0to A 12 one of the following residues or ; wherein: R is H, C1-C6 alkyl, or phenyl; R 1 and R 2 are independently -CN, C6-C 10 aryl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, 5- to 10-membered heteroaryl, -C(O)NH2, -C(O)NHR 5 , -C(O)R 6 , or -C(O)OR 5 , wherein each C1-C6alkyl is optionally substituted with 1 to 3 R 7 substituents, each C6-C 10 aryl is optionally substituted with 1 to 3 R 8 substituents, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R 22 substituents, with the proviso that when R a is -OH, represents A0, and R 1 is then R 2 in the residue A0is different from ; each R is independently C1-C6alkyl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R 5 independently C1-C6alkyl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R 9 substituents; each R is independently C3-C6cycloalkyl, 4- to 6-membered heterocycloalkyl, or C6-C10aryl; 6 independently C3-C6cycloalkyl, 4- to 6-membered heterocycloalkyl, or C6-C10aryl; 10 aryl; each R 7 is independently -OH, -C(O)R 11 , C3-C6cycloalkyl, -CN, C6-C 10 aryl, halogen, -C(O)OH, 5- to 10-membered heteroaryl, -NH(C(O)OC1-C6alkyl), -N(C1-C4alkyl)(C(O)OC1-C6alkyl), 4- to 6-membered heterocycloalkyl, -NH(C(O)C1-C6alkyl), -OR 20 , -SC1-C6alkyl, -NH2, -NH(C1-C4alkyl), or -N(C1-C4alkyl)2, wherein each C3-C6cycloalkyl is optionally substituted with 1 to 3 R 12 substituents, each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R 13 substituents, and each 4- to 6-membered heterocycloalkyl is optionally substituted with C1-C4alkyl or oxo; Each R 8 It is independently a halogen, a C1-C6 alkyl, a -OC1-C6 alkyl, a C3-C6 cycloalkyl or a 5- to 10-membered heteroaryl, wherein each -OC1-C6 alkyl is optionally substituted with a -OC1-C4 alkyl, and each 5- to 10-membered heteroaryl is optionally substituted with a C1-C4 alkyl. Each R 22 Independently, it is a C1-C6 alkyl group optionally substituted with a phenyl group; each R is independently -OH, -C(O)R 9 is independently -OH, -C(O)R 15 , C3-C6cycloalkyl, -CN, C6-C 10 aryl, halogen, -C(O)OH, 4- to 6-membered heterocycloalkyl, -NH(C(O)C1-C6alkyl), -OC1-C6alkyl, -SC1-C6alkyl, -NH2, -NH(C1-C4alkyl), or -N(C1-C4alkyl)2, wherein each 4- to 6-membered heterocycloalkyl is optionally substituted with C1-C4alkyl, and each -OC1-C6alkyl is optionally substituted with -OC1-C4alkyl; Each R 11 Independently, it is -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2 or a 4- to 6-membered heterocyclic alkyl group; each R is independently H, C1-C6alkyl, or 5- to 10-membered heteroaryl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R 20 independently C1-C6alkyl or 5- to 10-membered heteroaryl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R 14 substituted, each 5- to 10-membered heteroaryl is optionally substituted with -OH or -NH(cyclopropyl); Each R 12 It is independently C1-C4 alkyl, -SC1-C4 alkyl, -Ph, -OC1-C4 alkyl or -SPh, wherein each C1-C4 alkyl is optionally substituted with -OH; Each R 13 Independently, it is a halogen, C1-C4 alkyl, C3-C6 cycloalkyl, -OH, -OC1-C6 alkyl, -SC1-C6 alkyl, -S(O)2C1-C6 alkyl, -NH2, -NH(C1-C4 alkyl)2, or -N(C1-C4 alkyl)2, wherein each of -OC1-C6 alkyl, -SC1-C6 alkyl, -S(O)2C1-C6 alkyl, -NH(C1-C4 alkyl)2 is optionally surrounded by 1 to 3 R 9 Substituent substitution; Each R 14 It can be independently a halogen, -OC1-C4 alkyl, or C3-C6 cycloalkyl; Each R 15 Independently, it is -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2 or a 4- to 6-membered heterocyclic alkyl group; R 4 is C1-C6alkyl, C3-C8cycloalkyl, C6-C 10 aryl, 7- to 10-membered partially unsaturated heterocyclyl, or 5- to 10-membered heteroaryl, wherein C1-C6alkyl and C3-C8cycloalkyl are optionally substituted with 1 to 3 R 9 substituents, C6-C 10 aryl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 R 10 substituents, with the proviso that: (i) when R a is -OH, -NH2, or and represents A2, then R 4 in residue A2 is different from -CH3; and (ii) when R a is -NH2and represents A3, then R 4 in residue A3 is different from -C(CH3)3; Each R 10 Independently, it is a C1-C4 alkyl, halogen, -OC1-C6 alkyl, -NH2, -NH(C1-C4 alkyl)2 or -N(C1-C4 alkyl)2, wherein each C1-C4 alkyl is optionally substituted with 1 to 3 halogens; R 2a is C1-C6alkyl, C3-C8cycloalkyl or C6-C 10 aryl, wherein C1-C6alkyl and C3-C8cycloalkyl are optionally substituted with 1 to 3 R 9 substituents, C6-C 10 aryl is optionally substituted with 1 to 3 R 10 substituents; R 1a and R 2b are independently -CN, C6-C 10 aryl, C1-C6alkyl, C3-C8cycloalkyl, -C(O)NH2, -C(O)NHR 5 or -C(O)OC1-C6alkyl, wherein each C1-C6alkyl is optionally substituted with one to three R 16 substituents, each C6-C 10 aryl is optionally substituted with one to three R 17 substituents; Each R 16 Independently -OH, -C(O)NH2, -C(O)NH (C1-C4 alkyl), C3-C6 cycloalkyl, -CN, C6-C 10 Aryl, halogen, -C(O)OH, 5 to 10-membered heteroaryl, -NH(C(O)OC1-C6 alkyl), 4 to 6-membered heterocyclic alkyl, -NH(C(O)C1-C6 alkyl) or -OC1-C4 alkyl (OC1-C4 alkyl), wherein each C3-C6 cycloalkyl group is optionally surrounded by 1 to 3 R 18 Substituents, each of 5 to 10 heteroaryl groups, are optionally replaced by 1 to 3 R groups. 21 Substituents are used, with each of the 4 to 6-membered heterocyclic alkyl groups optionally replaced by C1-C4 alkyl groups; Each R 17 It is independently a halogen, a C1-C6 alkyl, an -OC1-C6 alkyl or a 5 to 10 heteroaryl group, wherein each 5 to 10 heteroaryl group is optionally substituted with a C1-C4 alkyl group; Each R 18 Independently, it is a C1-C4 alkyl, -SC1-C4 alkyl, -Ph, or -OC1-C4 alkyl; each R is independently halogen or C1-C4alkyl; 21 independently halogen or C1-C4alkyl; R 4a is C1-C6alkyl or C3-C8cycloalkyl, wherein each C1-C6alkyl and C3-C8cycloalkyl is optionally substituted with 1 to 3 R 19 substituents; Each R 19 It can be independently a halogen, -OH, -OC1-C4 alkyl, -SC1-C4 alkyl, -NH2, -NH(C1-C4 alkyl) or -N(C1-C4 alkyl)2; R 1b and R 2c together with the carbon atom to which they are attached form a C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, 8- to 14-membered partially unsaturated heterocyclyl, or 8- to 14-membered partially unsaturated carbocyclyl, wherein the C3-C8cycloalkyl is optionally substituted with 1 to 3 R 9 substituents, wherein the 4- to 14-membered heterocycloalkyl, 8- to 14-membered partially unsaturated heterocyclyl, or 8- to 14-membered partially unsaturated carbocyclyl is optionally substituted with oxo (=0), oxime (=N-OH), C1-C3alkoxyoxime (=N-OC1-C3alkyl), or 1 to 3 substituents independently selected from -OH and -CF3; R 2d and R 4b together with the carbon atom to which they are attached form a C3-C8cycloalkyl or 4- to 14-membered heterocycloalkyl, wherein C3-C8cycloalkyl is optionally substituted with 1 to 3 R 19 substituents; and R 1c and R 3 together with the carbon atom to which they are attached form a C3-C8cycloalkyl or 4- to 14-membered heterocycloalkyl, wherein C3-C8cycloalkyl is optionally substituted with 1 to 3 R 19 substituents.

2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R is H.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the compound is represented by Formula (la) or (la’): (Ia') wherein R 1 , R 2 , R and R a are as defined in claim 1 or 2.

4. The compound of claim 3, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the compound is represented by Formula (la): (Ia) wherein R 1 , R 2 and R a are as defined in claim 1.

5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 1 and R 2 are independently -CN, C6-C 10 aryl, C1-C6alkyl, C2-C6alkynyl, C3-C8cycloalkyl, 5- to 10-membered heteroaryl, -C(O)NH2, -C(O)NHR 5 , -C(O)R 6 , or -C(O)OR 5 , wherein each C1-C6alkyl is optionally substituted with 1 to 3 R 7 substituents, each C6-C 10 aryl is optionally substituted with 1 to 3 R 8 substituents, each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R 22 substituents, R 5 , R 6 , R 7 , R 8 , and R 22 are as defined in claim 1.

6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 1 and R 2 are independently -CN, C6-C 10 aryl, C1-C6 alkyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 5- to 10-membered heteroaryl, -C(O)NH2, -C(O)NHR 5 , -C(O)R 6 , or -C(O)OR 5 , wherein each C1-C6 alkyl is optionally substituted with 1 to 3 R 7 substituents, each C6-C 10 aryl is optionally substituted with 1 to 3 R 8 substituents, each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R 22 substituents, and wherein: Each R 5 Independently, it is a C1-C6 alkyl group; Each R 6 Independently, it is a 4- to 6-membered heterocyclic alkyl group; each R 7 is independently -OH, -C(O)R 11 , C3-C6cycloalkyl, -CN, C6-C 10 aryl, halogen, -C(O)OH, 5- to 10-membered heteroaryl, -NH(C(O)OC1-C6alkyl), -N(C1-C4alkyl)(C(O)OC1-C6alkyl), 4- to 6-membered heterocycloalkyl, -NH(C(O)C1-C6alkyl), -OR 20 , -SC1-C6alkyl, -NH2, or -N(C1-C4alkyl)2, wherein each C3-C6cycloalkyl is optionally substituted with 1 to 3 R 12 substituents, each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R 13 substituents, and each 4- to 6-membered heterocycloalkyl is optionally substituted with C1-C4alkyl or oxo; Each R 8 It is independently a halogen, a C1-C6 alkyl or an -OC1-C6 alkyl, wherein each -OC1-C6 alkyl is optionally substituted with an -OC1-C4 alkyl; Each R 22 Independently, it is a C1-C6 alkyl group optionally substituted with a phenyl group; Each R 11 Independently -NH2, -NH (C1-C4 alkyl) or 4 to 6-membered heterocyclic alkyl; each R is independently H, C1-C6alkyl, or 5- to 10-membered heteroaryl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R 20 independently C1-C6alkyl or 5- to 10-membered heteroaryl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R 14 substituted, each 5- to 10-membered heteroaryl is optionally substituted with -OH or -NH(cyclopropyl); Each R 12 It is independently C1-C4 alkyl, -SC1-C4 alkyl, -Ph, -OC1-C4 alkyl or -SPh, wherein each C1-C4 alkyl is optionally substituted with -OH; Each R 13 It can be independently a halogen, a C1-C4 alkyl group, or a C3-C6 cycloalkyl group; Each R 14 It can be halogen, -OC1-C4 alkyl or C3-C6 cycloalkyl independently.

7. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 1 and R 2 are independently -CN, C6-C 10 aryl, C1-C6alkyl, C2-C6alkynyl, C3-C8cycloalkyl, 5- to 10-membered heteroaryl, or -C(O)NH2, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R 7 substituents, each C6-C 10 aryl is optionally substituted with 1 to 3 R 8 substituents, each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R 22 substituents, R 7 , R 8 , and R 22 are as defined in claim 1.

8. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 1 and R 2 are independently -CN, C6-C 10 aryl, C1-C6 alkyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 5- to 10-membered heteroaryl, or -C(O)NH2, wherein each C1-C6 alkyl is optionally substituted with 1 to 3 R 7 substituents, each C6-C 10 aryl is optionally substituted with 1 to 3 R 8 substituents, each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R 22 substituents, and wherein: each R 7 is independently -OH, -C(O)R 11 , C3-C6cycloalkyl, -CN, C6-C 10 aryl, halogen, -C(O)OH, 5- to 10-membered heteroaryl, -NH(C(O)OC1-C6alkyl), -N(C1-C4alkyl)(C(O)OC1-C6alkyl), -NH(C(O)C1-C6alkyl), 4- to 6-membered heterocycloalkyl, -OR 20 , -SC1-C6alkyl, -NH2, or -N(C1-C4alkyl)2, wherein each C3-C6cycloalkyl is optionally substituted with 1 to 3 R 12 substituents, each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R 13 substituents, and each 4- to 6-membered heterocycloalkyl is optionally substituted with C1-C4alkyl or oxo; Each R 8 It is independently a halogen, a C1-C6 alkyl or an -OC1-C6 alkyl, wherein each -OC1-C6 alkyl is optionally substituted with an -OC1-C4 alkyl; Each R 11 Independently -NH2, -NH (C1-C4 alkyl) or 4 to 6-membered heterocyclic alkyl; each R is independently H, C1-C6alkyl, or 5- to 10-membered heteroaryl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R 20 independently C1-C6alkyl or 5- to 10-membered heteroaryl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R 14 substituted, each 5- to 10-membered heteroaryl is optionally substituted with -OH or -NH(cyclopropyl); Each R 12 It is independently C1-C4 alkyl, -SC1-C4 alkyl, -Ph, -OC1-C4 alkyl or -SPh, wherein each C1-C4 alkyl is optionally substituted with -OH; Each R 13 It can be independently a halogen, a C1-C4 alkyl group, or a C3-C6 cycloalkyl group; Each R 14 Independently halogenated, -OC1-C4 alkyl, or C3-C6 cycloalkyl; and Each R 22 It is independently a C1-C4 alkyl group.

9. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 1 and R 2 are independently -CN, C6-C 10 aryl, C1-C6 alkyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 5- to 10-membered heteroaryl, or -C(O)NH2, wherein each C1-C6 alkyl is optionally substituted with 1 to 3 R 7 substituents, each C6-C 10 aryl is optionally substituted with 1 to 3 R 8 substituents, each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R 22 substituents, and wherein: each R 7 is independently -OH, -C(O)R 11 , -OR 20 , C3-C6cycloalkyl, -CN, C6-C 10 aryl, halogen, -C(O)OH, or 5- to 10-membered heteroaryl, wherein each C3-C6cycloalkyl is optionally substituted with 1 to 3 R 12 substituents, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R 13 substituents; Each R 8 It is halogen; Each R 11 yes - NH2; Each R 20 It is a C1-C6 alkyl or a 5- or 6-membered heteroaryl group, wherein each C1-C6 alkyl group is optionally surrounded by 1 to 3 R groups. 14 Substituents are substituted, with each of the 5 or 6 heteroaryl groups optionally replaced by -OH or -NH (cyclopropyl); Each R 12 It is a C1-C4 alkyl group; each R is independently halogen or C1-C4alkyl; 13 independently halogen or C1-C4alkyl; Each R 14 It is halogen; Each R 22 It is independently a C1-C4 alkyl group.

10. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 1 and R 2 are independently -CN, phenyl, C1-C4 alkyl, C2-C4 alkynyl, C3-C6 cycloalkyl, 5-membered heteroaryl, or -C(O)NH2, wherein each C1-C4 alkyl is optionally substituted with 1 or 2 R 7 substituents, each phenyl is optionally substituted with 1 or 2 halogens, and each 5-membered heteroaryl is optionally substituted with 1 or 2 -CH3. each R is independently -OH, -C(O)NH2, -OR 7 is independently -OH, -C(O)NH2, -OR 20 , C3-C6cycloalkyl, -CN, phenyl, halogen, -C(O)OH, or 5-membered heteroaryl, wherein each C3-C6cycloalkyl is optionally substituted with -CH3; each R is independently H, C1-C6alkyl, or 5- or 6-membered heteroaryl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 halogens, and each 5- or 6-membered heteroaryl is optionally substituted with -OH. 20 each R is independently H, C1-C6alkyl, or 5- or 6-membered heteroaryl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 halogens, and each 5- or 6-membered heteroaryl 11. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 1 and R 2 independently represent: 。 12. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 1 and R 2 independently represent: 。 13. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 1 and R 2 independently represent: 。 14. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 1 and R 2 independently represent: 。 15. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 1 and R 2 are independently -CN, C6-C 10 aryl, C1-C6 alkyl, C3-C8 cycloalkyl, 5-membered heteroaryl, or -C(O)NH2, wherein each C1-C6 alkyl is optionally substituted with 1 to 2 R 7 substituents; Each R 7 Independently -OH, -C(O)NH2, C3-C6 cycloalkyl, -CN, C6-C 10 Aryl, halogen, or 5- to 8-membered heteroaryl, wherein each C3-C6 cycloalkyl group is optionally substituted with 1 to 2 C1-C4 alkyl groups, and each 5- to 8-membered heteroaryl group is optionally substituted with 1 to 2 R groups. 13 Substituent substitution; each R is independently halogen or C1-C4alkyl. 13 independently halogen or C1-C4alkyl.

16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 1 and R 2 are different.

17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein one of R 1 and R 2 is -CN.

18. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 1 and one of R 2 is .

19. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the compound is represented by Formula (lb) or (lb’): (Ib) (Ib’) wherein R 4 , R and R a as defined in claim 1 or 2.

20. The compound of claim 19, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the compound is represented by Formula (lb): (Ib) wherein R 4 and R a as defined in claim 1.

21. The compound of any one of claims 1, 2, 19, and 20, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 4 is Ci-C6alkyl, C6-C 10 aryl, 7- to 10-membered partially unsaturated heterocyclyl, or 5- to 10-membered heteroaryl, wherein Ci-C6alkyl is optionally substituted with 1 to 3 R 9 substituents, C6-C 10 aryl, and 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R 10 substituents, wherein R 9 and R 10 are as defined in claim 1.

22. The compound of any one of claims 1, 2, 19, and 20, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 4 is Ci-C6alkyl, C6-C 10 aryl, 7- to 10-membered partially unsaturated heterocyclyl, or 5- to 10-membered heteroaryl, wherein C6-C 10 aryl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 R 10 substituents, and wherein: each R 10 independently C1-C4alkyl, halogen, -OC1-C6alkyl, -NH2, -NH(C1-C4alkyl), or -N(C1-C4alkyl)2, wherein each C1-C4alkyl is optionally substituted with 1 to 3 halogens.

23. The compound of any one of claims 1, 2, 19, and 20, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 4 is Ci-C6alkyl, C6-C 10 aryl, 7- to 10-membered partially unsaturated heterocyclyl, or 5- to 10-membered heteroaryl, wherein C6-C 10 aryl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 R 10 substituents, and wherein: Each R 10 Independently, it is a C1-C4 alkyl, halogen, -OC1-C6 alkyl or -N(C1-C4 alkyl)2, wherein each C1-C4 alkyl is optionally substituted with 1 to 3 halogens.

24. The compound of any one of claims 1, 2, 19, and 20, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 4 is C1-C4 alkyl, phenyl, 9-membered partially unsaturated heterocyclic group, or 5- to 6- membered heteroaryl, wherein phenyl and 5- to 6-membered heteroaryl are optionally substituted with 1 or 2 R 10 substituents, and wherein: Each R 10 It can be -CF3, halogen, -OCH3 or -N(CH3)2 independently.

25. The compound of any one of claims 1, 2, 19, and 20, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 4 represents: 。 26. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the compound is represented by Formula (lc) or (lc’): (Ic) (Ic') wherein R 2a , R and R a as defined in claim 1 or 2.

27. The compound of claim 26, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the compound is represented by Formula (lc): (Ic) wherein R 2a and R a as defined in claim 1.

28. The compound of any one of claims 1, 2, 26, and 27, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 2a is Ci-C6alkyl or C6-C 10 aryl, wherein Ci-C6alkyl is optionally substituted with 1 to 3 R 9 substituents, C6-C 10 aryl is optionally substituted with 1 to 3 R 10 substituents, R 9 and R 10 are as defined in claim 1.

29. The compound of any one of claims 1, 2, 26, and 27, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 2a is Ci-C6alkyl or C6-C 10 aryl, wherein Ci-C6alkyl is optionally substituted with 1 to 3 halogen.

30. The compound of any one of claims 1, 2, 26, and 27, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 2a is Ci-C6alkyl.

31. The compound of any one of claims 1, 2, 26, and 27, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 2a is C1-C4alkyl.

32. The compound of any one of claims 1, 2, 26, and 27, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 2a is ethyl.

33. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the compound is represented by Formula (Id) or (Id’): (Id) (Id') wherein R 1a , R 2b , R 4a , R and R a are as defined in claim 1 or 2.

34. The compound of claim 33, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the compound is represented by Formula (Id): (Id) wherein R 1a , R 2b , R 4a and R a are as defined in claim 1.

35. The compound of any one of claims 1, 2, 33, and 34, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 1a and R 2b are independently -CN, C6-C 10 aryl, C1-C6 alkyl, C3-C8 cycloalkyl, or -C(O)NH2, wherein each C1-C6 alkyl is optionally substituted with 1 to 2 R 16 substituents. Each R 16 Independently -OH, -C(O)NH2, C3-C6 cycloalkyl, -CN, C6-C 10 Aryl, halogen, or 5- to 8-membered heteroaryl groups, wherein each C3-C6 cycloalkyl group is optionally substituted with 1 to 2 C1-C4 alkyl groups, and each 5- to 10-membered heteroaryl group is optionally substituted with 1 to 2 R groups. 21 Substituent substitution; each R is independently halogen or C1-C4alkyl. 21 independently halogen or C1-C4alkyl.

36. The compound of any one of claims 1, 2, 33, and 34, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 1a and R 2b are independently -CN or C6-C 10 aryl.

37. The compound of any one of claims 1, 2, 33, 34, 35, and 36, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 4a is C1-C6alkyl.

38. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the compound is represented by Formula (le) or (le’): (Ie) (Ie') wherein R, R a , R 1b and R 2c are as defined in claim 1 or 2.

39. The compound of claim 38, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the compound is represented by Formula (le): (Ie) wherein R a , R 1b and R 2c are as defined in claim 1.

40. The compound of any one of claims 1, 2, 38, and 39, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 1b and R 2c together with the carbon atom to which they are attached form a C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, 8- to 14-membered partially unsaturated heterocyclyl, or 8- to 14-membered partially unsaturated carbocyclyl, wherein each 4- to 14-membered heterocycloalkyl, 8- to 14-membered partially unsaturated heterocyclyl, or 8- to 14-membered partially unsaturated carbocyclyl is optionally substituted with oxo (=0), oxime (=N-OH), C1-C3alkoxyoxime (=N-OC1-C3alkyl), or 1 to 3 substituents independently selected from -OH and -CF3.

41. The compound of any one of claims 1, 2, 38, and 39, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 1b and R 2c together with the carbon atom to which they are attached form a C3-C8cycloalkyl or 8- to 10-membered partially unsaturated carbocyclyl, wherein the 8- to 10-membered partially unsaturated carbocyclyl is optionally substituted with oxo (=0), oxime (=N-OH), methoxime (=N-OCH3), or 1 to 2 substituents independently selected from -OH and -CF3.

42. The compound of any one of claims 1, 2, 38, and 39, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 1b and R 2c together with the carbon atom to which they are attached form C4-C6cycloalkyl or a group selected from: wherein the dotted line indicates that the cyclohexanone unit of the compound of formula (Ie) or (Ie') carries R 1b and the moiety R 2c .

43. The compound of any one of claims 1, 2, 38, and 39, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 1b and R 2c together with the carbon atom to which they are attached form a cyclopentyl group or a group selected from the group consisting of wherein the dotted line indicates that the cyclohexanone unit of the compound of formula (Ie) or (Ie') carries R 1b and the moiety R 2c .

44. The compound of any one of claims 1, 2, 38, and 39, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 1b and R 2c together with the carbon atom to which they are attached form a group selected from the group consisting of wherein the dotted line indicates that the cyclohexanone unit of the compound of formula (Ie) or (Ie') carries R 1b and the moiety R 2c .

45. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the compound is represented by Formula (If) or (If’): (If) (If’) wherein R, R a , R 4b and R 2d are as defined in claim 1 or 2.

46. The compound of claim 45, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the compound is represented by Formula (If): (if) wherein R a , R 4b and R 2d are as defined in claim 1.

47. The compound of any one of claims 1, 2, 45, and 46, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 2d and R 4b together with the carbon atom to which they are attached form a C3-C8cycloalkyl, wherein each C3-C8cycloalkyl is optionally substituted with 1 to 3 R 19 substituents as defined in claim 1.

48. The compound of any one of claims 1, 2, 45, and 46, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 2d and R 4b together with the carbon atom to which they are attached form C3-C8cycloalkyl.

49. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the compound is represented by Formula (lg): (Ig) wherein R a , R 1c and R 3 are as defined in claim 1.

50. The compound of any one of claims 1, 2, and 49, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 1c and R 3 together with the carbon atom to which they are attached form a C3-C8cycloalkyl, wherein each C3-C8cycloalkyl is optionally substituted with 1 to 3 R 19 substituents as defined in claim 1.

51. The compound of any one of claims 1, 2, and 49, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R 1c and R 3 together with the carbon atom to which they are attached form C3-C8cycloalkyl.

52. The compound of any one of claims 1-51, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R a is -NHR b , R b represents: 。 53. The compound of any one of claims 1-52, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R a is -NHR b , R b represents: 。 54. The compound of any one of claims 1-53, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R a is -NHR b , R b represents .

55. The compound of any one of claims 1-51, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R a is .

56. The compound of any one of claims 1-51 and 55, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R a is .

57. The compound of any one of claims 1-51, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R a is -OH.

58. The compound of any one of claims 1-51, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R a is NH2.

59. The compound of any one of claims 1-51, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R a is -NH-OH.

60. The compound of any one of claims 1-59, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the compound is in the form of a racemate or any enantiomer thereof.

61. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, which is compound 4, 8, 9, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 47, 48, 49, 50, 51, 52, 53, 54, 59, 60a, 60b, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 75, 81, 82, 83, 84, 89, 91, 97, 101, 108, 109, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 154, 155, 163, 168, 169, 170, 173, 174, 175, 178, 179, 180, 181, 183, 189, 190, 191, 192, 193, 194, 195, 197, 198, 199, 200, 201, 202, 211, 212, 213, 214, 215, 216, 219, 221, 227, 228, 229, 230, 231, 232, 237, 238, 239, 245, 246, 247, 248, 249, 250, 251, 253, 254, 255, 257, 258, 263, 264, 271, 272, 273, 278, 279, 280, 281, 287, 288, 290, 291, 297, 298, 305, 306, 313, 314, 321, 322, 330, 331, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 352, 353, 354, 355, 356, 357, 358, 360, 362, 371, 378, 391, 392, 393, 394a, 394b, 395a, 395b, 396, 397, 401, 402, 403, 406, 407, 408, 412, 413, 414, 416, 418, 422, 427, 428, 429, 430, 431, 433, 434, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 462, 463, 464, 465, 466, 468, 469, 470, 471, 472, 473, 474, 475, 476, 478, 479, of Table 1 of the specification, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.480, 481, 482, 483, 486, 488, 489, 492, 495, 496, 497, 498, 511, 512, 513, 514, 515, 520, 523, 524, or 534.

62. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, which is compound 4, 15, 16, 17, 20, 24, 25, 26, 27, 29, 30, 31, 32, 33, 34, 36, 37, 47, 48, 49, 50, 51, 52, 53, 54, 59, 60b, 61, 62, 63, 64, 65, 66, 67, 71, 72, 75, 81, 82, 83, 84, 89, 91, 97, 101, 109, 119, 120, 121, 122, 123, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 138, 139, 140, 141, 143, 144, 145, 146, 147, 148, 149, 150, 155, 163, 168, 169, 170, 173, 174, 175, 179, 180, 181, 183, 191, 192, 194, 195, 198, 199, 201, 202, 212, 213, 214, 215, 216, 228, 230, 231, 232, 237, 238, 239, 246, 248, 250, 251, 253, 254, 255, 258, 263, 264, 271, 272, 273, 278, 279, 280, 281, 287, 288, 291, 298, 305, 306, 313, 314, 321, 322, 331, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 352, 353, 354, 355, 356, 357, 358, 391, 392, 393, 394a, 394b, 395a, 395b, 396, 397, 401, 402, 403, 406, 407, 408, 413, 414, 416, 418, 422, 428, 429, 430, 431, 434, 445, 446, 447, 448, 449, 450, 451, 453, 454, 462, 463, 464, 465, 466, 468, 470, 472, 474, 475, 476, 479, 480, 481, 482, 486, 489, 495, 496, 498, 511, 512, 513, 514, 515, 520, or 524 of the Table 1 of the specification.

63. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, which is compound 4, 15, 25, 32, 33, 47, 48, 49, 50, 52, 54, 59, 60b, 61, 62, 63, 72, 75, 82, 83, 89, 97, 101, 109, 119, 121, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 138, 139, 140, 141, 143, 144, 145, 146, 147, 148, 149, 150, 163, 169, 170, 174, 179, 181, 183, 191, 192, 194, 195, 212, 213, 214, 215, 230, 231, 232, 238, 239, 246, 248, 250, 251, 253, 254, 255, 258, 263, 264, 272, 273, 278, 279, 280, 281, 288, 291, 298, 305, 306, 313, 314, 321, 322, 331, 338, 339, 340, 341, 342, 343, 344, 345, 353, 355, 356, 358, 391, 392, 393, 394a, 394b, 395a, 395b, 396, 397, 402, 403, 407, 408, 413, 418, 422, 428, 429, 430, 431, 434, 445, 446, 447, 448, 449, 450, 451, 454, 463, 464, 465, 466, 472, 475, 476, 479, 481, 486, 489, 495, 498, 512, 514, 515, 520, or 524 of Table 1 of the specification.

64. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, which is compound 48, 50, 54, 60b, 61, 63, 72, 75, 83, 97, 101, 109, 127, 135, 140, 141, 143, 144, 145, 146, 147, 149, 163, 169, 170, 174, 179, 181, 191, 194, 195, 212, 215, 230, 231, 232, 238, 246, 248, 250, 251, 255, 258, 272, 273, 279, 281, 291, 306, 314, 321, 322, 331, 338, 339, 340, 341, 342, 345, 353, 355, 356, 391, 393, 395a, 395b, 397, 402, 428, 430, 431, 434, 446, 447, 448, 450, 463, 464, 465, 466, 489, 512, 514, 515, or 524 of Table 1 of the specification.

65. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, which is compound 54, 61, 63, 75, 140, 143, 146, 174, 215, 230, 250, 251, 273, 306, 322, 430, 446, 463, or 512 of Table 1 of the specification.

66. A pharmaceutical composition comprising: A compound according to any one of claims 1 to 65, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and a pharmaceutically acceptable carrier, diluent, or excipient.

67. Use of a compound as defined in any one of claims 1 to 65, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for the manufacture of a pharmaceutical composition for the treatment or prevention of a disease for which an ASIC inhibitor is indicated.

68. The use of claim 67, wherein the ASIC inhibitor is an ASIC la inhibitor or an ASIC lb inhibitor.

69. The use of claim 67 or 68, wherein the ASIC inhibitor is an ASIC la inhibitor.

70. The use of claim 67 or 68, wherein the ASIC inhibitor is an ASIC lb inhibitor.

71. Use of a compound as defined in any one of claims 1 to 65, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for the manufacture of a pharmaceutical composition for the treatment or prevention of a disease selected from the group consisting of pain, arthritis, stroke, epilepsy, anxiety, post-traumatic stress disorder (PTSD), depression, multiple sclerosis, Alzheimer's disease, gastroesophageal reflux disease, cancer, migraine, cough, and acute lung injury.

72. The use of any one of claims 67 to 71, wherein the disease is pain.

73. The use of any one of claims 67 to 72, wherein the disease is inflammatory pain or neuropathic pain.

74. The use of any one of claims 67 to 72, wherein the disease is inflammatory pain.

75. The use of any one of claims 67 to 72, wherein the disease is neuropathic pain.

76. A method for the treatment or prevention of a disease for which an ASIC inhibitor is indicated, comprising administering to a patient in need thereof a compound as defined in any one of claims 1 to 65, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

77. The method of claim 76, wherein the ASIC inhibitor is an ASIC la inhibitor or an ASIC lb inhibitor.

78. The method of claim 76 or 77, wherein the ASIC inhibitor is an ASIC la inhibitor.

79. The method of claim 76 or 77, wherein the ASIC inhibitor is an ASIC lb inhibitor.

80. A method for the treatment or prevention of a disease selected from the group consisting of pain, arthritis, stroke, epilepsy, anxiety, post-traumatic stress disorder (PTSD), depression, multiple sclerosis, Alzheimer's disease, gastroesophageal reflux disease, cancer, migraine, cough and acute lung injury, comprising administering to a patient in need thereof a compound as defined in any one of claims 1 to 65, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

81. The method of any one of claims 76 to 80, wherein the disease is pain.

82. The method of any one of claims 76 to 81, wherein the disease is inflammatory pain or neuropathic pain.

83. The method of any one of claims 76 to 81, wherein the disease is inflammatory pain.

84. The method of any one of claims 76 to 81, wherein the disease is neuropathic pain.

85. A compound as defined in any one of claims 1 to 65, or a pharmaceutically acceptable salt, solvate or prodrug thereof, for use in the treatment or prevention of a disease for which an ASIC inhibitor is indicated.

86. The compound for use of claim 85, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein the ASIC inhibitor is an ASIC la inhibitor or an ASIC lb inhibitor.

87. The compound for use of claim 85 or 86, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein the ASIC inhibitor is an ASIC la inhibitor.

88. The compound for use of claim 85 or 86, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein the ASIC inhibitor is an ASIC lb inhibitor.

89. A compound as defined in any one of claims 1 to 65, or a pharmaceutically acceptable salt, solvate or prodrug thereof, for use in the treatment or prevention of a disease selected from the group consisting of pain, arthritis, stroke, epilepsy, anxiety, post-traumatic stress disorder (PTSD), depression, multiple sclerosis, Alzheimer's disease, gastroesophageal reflux disease, cancer, migraine, cough and acute lung injury.

90. The compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for use according to any one of claims 85-89, wherein the disease is pain.

91. The compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for use according to any one of claims 85-90, wherein the disease is inflammatory pain or neuropathic pain.

92. The compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for use according to any one of claims 85-90, wherein the disease is inflammatory pain.

93. The compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for use according to any one of claims 85-90, wherein the disease is neuropathic pain.

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