NK3 modulator and its usage

Abstract

This disclosure relates to compounds useful as modulators of neurokinin receptor 3 (NK3) for the treatment of disease or disorder.

Description

[Technical Field]

[0001] cross reference This application claims the interests of U.S. Provisional Application No. 63 / 545,395 filed on 24 October 2023, U.S. Provisional Application No. 63 / 541,107 filed on 28 September 2023, and U.S. Provisional Application No. 63 / 460,109 filed on 18 April 2023, each of which is incorporated herein by reference in whole. [Background technology]

[0002] Migraine is a painful, debilitating neurological condition of the trigeminal vascular system with a high prevalence in the general population, affecting approximately 15% of individuals and being the second leading cause of physical disability worldwide. Migraine is characterized by recurrent, pulsating headache attacks of moderate to severe intensity, which can last 4 to 72 hours and involve sensitivity to motor, visual, auditory, and other sensory inputs.

[0003] While multiple classes of oral medications are approved for the treatment of migraines, many currently used are associated with serious side effects, leading to frequent discontinuation and class switching along with poor outcomes. Antibody therapies and small molecules targeting CGRP receptors have been reported to have fewer side effects, but less than one-third of migraine patients respond to these treatments. Therefore, there is a great need for novel therapies to treat migraines and other disorders of the trigeminal vascular system, such as cluster headaches, medication-induced headaches, and trigeminal neuralgia.

[0004] A novel class of neurokinin receptor 3 (NK3) antagonists, which may be useful in the treatment of migraines and other disorders of the trigeminal vascular system, are described herein. [Overview of the project]

[0005] In certain embodiments, neurokinin receptor 3 (NK3) (also known as tachykinin receptor 3) modulators useful for the treatment of a disease or disorder are described herein. In some embodiments, the NK3 modulator is an NK3 antagonist. In some embodiments, the disease or disorder is a neurokinin receptor 3 (NK3)-dependent disease or disorder. In some embodiments, the disease or disorder is selected from the group consisting of migraine, drug abuse headache, cluster headache, tension headache, trigeminal neuralgia, and orofacial pain.

[0006] In one aspect, a compound of formula (I),

[0007] [Chemical formula] or a pharmaceutically acceptable salt or solvate thereof is described herein, wherein, Z is a divalent group selected from -S-, -N=C(R 10 , 12 )-, -C(R 5 )=N-, or -C(R 5 )=C(R 5 )-, R 1 is pyrazole, and the pyrazole is optionally substituted with 1 to 3 groups independently selected from R 6 , R 2 is C1-C 10 alkyl, C1-C 10 heteroalkyl, -C(=O)OR 7 , -C(=O)N(R 8 )(R 7 ), -N(R 8 )(R 7 ), -C(=NR 9 )N(R 8 )(R 7 ), -N(R 7 )C(=NR 9 )N(R 8 )(R 7 ), C6-C 10 aryl, 5- to 10-membered heteroaryl, C3-C 12A cycloalkyl or a 3- to 15-membered heterocycloalkyl, where aryl and heteroaryl are optional, R 10 Substituted with 1 to 4 groups independently selected from, alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl groups are optional, oxo and R 10 It is replaced by 1 to 4 elements independently selected from, R 3 These are halogens, cyanos, -C(=O)OH, -C(=O)O(C1-C6 alkyl), C1-C6 alkyl, C1-C6 alkenyl, -O(C1-C6 alkyl), C3-C6 cycloalkyl, or C1-C6 haloalkyl. R 4 Each of these is independently hydrogen, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C6 haloalkyl, or -O-(C1-C6 haloalkyl), L is a bond, a C1-C2 alkylene or a C3-C6 cycloalkylene, wherein the alkylene or cycloalkylene is optionally substituted with one or two -OH groups. R 5 Each of these is independently hydrogen, cyano, halogen, C1-C6 alkyl, -O(C1-C6 alkyl), C3-C6 cycloalkyl, C1-C6 haloalkyl, or -O(C1-C6 haloalkyl), R 6 These are, independently, halogen, hydroxy, cyano, amino, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C3-C6 cycloalkyl, and -CH2-(C 3-6 Cycloalkyl), -O-(C 3-6 Selected from the group consisting of cycloalkyl, C1-C6 haloalkyl, and -O(C1-C6 haloalkyl), R 6 If it is bonded to a nitrogen atom, it is C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C3-C6 cycloalkyl, -CH2-(C 3-6Selected from the group consisting of cycloalkyl and C1-C6 haloalkyl groups, R 7 Each of these is independently hydrogen or a C1-C6 alkyl group, and the alkyl group is optionally substituted with 1-2 hydroxyl groups. R 8 is hydrogen, C1-C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Alkenyl, C1-C 10 Alkinyl, C3-C 12 Cycloalkyl, 3-15 member heterocycloalkyl, C6-C 10 It is an aryl or a 5-10 member heteroaryl, and the aryl and heteroaryl are optional, R 11 Substituted with 1 to 6 groups independently selected from, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl groups are optional, oxo and R 11 It is replaced by 1 to 6 groups independently selected from, Alternatively, one R bonded to the same nitrogen atom 7 and one R 8 These combine to form oxo and R 11 Forms a 3-15 member heterocycloalkyl group that is optionally substituted with 1-6 groups independently selected from the above, R 9 is hydrogen, -C(O)OR 12 ,-C(O)N(R 12 )2, -S(O)2R 12 -S(O)2N(R 12 )2, or C1-C6 alkyl, R 10 These are independently hydroxy, amino, cyano, fluoro, and -C(=O)OR. 12 -C(=O)N(R 12)2, C1-C4 alkyl, C1-C4 haloalkyl, -O(C1-C6 alkyl), -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C3-C6 cycloalkyl, where the alkyl, haloalkyl, or cycloalkyl is optional, and hydroxy, amino, cyano, fluoro, -C(=O)OR 12 , and -C(=O)N(R 12 ) Replaced by 1-2 elements selected from 2, R 11 These are, independently, halogen, hydroxy, amino, cyano, and -S(=O)2(R) 13 ), -N(R 12 )S(=O)2(R 13 ), -S(=O)(R 13 ), -N(R 12 )S(=O)(R 13 ), -C(=O)R 13 , -N(R 12 )C(=O)R 13 , C1-C6 alkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-10 member heterocycloalkyl, C6-C 10 Selected from the group consisting of aryls and 5-10 member heteroaryls, aryls and heteroaryls are R 14 Optionally substituted with 1 to 4 groups independently selected from, with alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, and heterocycloalkyl groups being optional, as well as oxo and R 14 It is replaced by 1 to 4 elements independently selected from, Alternatively, two R atoms bonded to the same carbon or nitrogen atom 11 These combine to form a C3-C6 cycloalkyl or a 3-6 member heterocycloalkyl, and the cycloalkyl and heterocycloalkyl are oxo and R 14 It is optionally replaced by 1 to 4 bases independently selected from, R 12 Each of these is independently hydrogen or a C1-C6 alkyl group. R 13 Each of these is independently a hydroxyl, amino, C1-C6 alkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 haloalkyl, C3-C6 cycloalkyl, or a 3- to 6-membered heterocycloalkyl. R 14 These are independently cyano, amino, hydroxy, and -C(=O)OR 12 -C(=O)N(R 12 )2, C1-C6 alkyl, -O(C1-C6 alkyl), -NR 12 The alkyl group is (C1-C6 alkyl), aryl, heteroaryl, C3-C6 cycloalkyl, or a 3- to 6-membered heterocycloalkyl, and each alkyl group is optionally substituted with 1 to 2 hydroxyl groups.

[0008] In some embodiments, the compound (for example, the compound of formula (I)) is of formula (IIa)

[0009] [ka] It has the structure of, or a pharmaceutically acceptable salt or solvate thereof.

[0010] In some embodiments, the compound (e.g., the compound of formula (I)) is of formula (IIb)

[0011] [ka] It has the structure of, or a pharmaceutically acceptable salt or solvate thereof.

[0012] In some embodiments, the compound (e.g., the compound of formula (I)) is of formula (IIc)

[0013] [ka] It has the structure of, or a pharmaceutically acceptable salt or solvate thereof.

[0014] In some embodiments, the compound (e.g., the compound of formula (I)) is of formula (IId)

[0015] [ka] It has the structure of, or a pharmaceutically acceptable salt or solvate thereof.

[0016] In some embodiments, the compound (e.g., the compound of formula (I)) is the compound of formula (III)

[0017] [ka] It has the structure of, or a pharmaceutically acceptable salt or solvate thereof.

[0018] In some embodiments, the compound (e.g., the compound of formula (I)) is of formula (IVa)

[0019] [ka] It has the structure of, or a pharmaceutically acceptable salt or solvate thereof.

[0020] In some embodiments, the compound (e.g., the compound of formula (I)) is of formula (VIa)

[0021] [ka] It has the structure of, or a pharmaceutically acceptable salt or solvate thereof.

[0022] In some embodiments, the compound (for example, the compound of formula (I)) is of formula (VIIa)

[0023] [ka] It has the structure of, or a pharmaceutically acceptable salt or solvate thereof.

[0024] Pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient are also described herein. In some embodiments, the pharmaceutical composition is formulated for administration to mammals by intravenous, subcutaneous, oral, inhalation, nasal, transdermal, or ophthalmic administration. In some embodiments, the pharmaceutical composition is formulated for administration to mammals by oral administration. In some embodiments, the pharmaceutical composition is in the form of a tablet, pill, capsule, liquid, suspension, gel, dispersant, liquid, emulsion, ointment, or lotion. In some embodiments, the pharmaceutical composition is in the form of a tablet, pill, or capsule.

[0025] This specification also describes methods for treating diseases or conditions in mammals that would benefit from the modulation of neurokinin receptor 3 activity, the methods comprising the step of administering the compounds described herein, or pharmaceutically acceptable salts or solvates thereof, to a mammal in need of treatment. In some embodiments, the compounds described herein, or pharmaceutically acceptable salts or solvates thereof, are administered orally. In some embodiments, the disease or condition is migraine, drug abuse headache, cluster headache, generalized headache, trigeminal neuralgia, orofacial pain, or a combination thereof. In some embodiments, the disease or condition is migraine, drug abuse headache, cluster headache, generalized headache, or a combination thereof. In some embodiments, the disease or condition is migraine.

[0026] Further embodiments exist in which, in any of the above-described embodiments, an effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered (a) systemically to a mammal, and / or (b) orally to a mammal, and / or (c) intravenously to a mammal, and / or (d) by inhalation, and / or (e) by nasal administration, and / or (f) by injection to a mammal, and / or (g) topically to a mammal, and / or (h) by ocular administration, and / or (i) rectally to a mammal, and / or (j) non-systemically or topically to a mammal.

[0027] In any of the embodiments described above, further embodiments include a single dose of an effective amount of the compound administered once daily to a mammal, or further embodiments include the administration of the compound multiple times over a day to a mammal. In some embodiments, the compound is administered in a continuous dosing schedule. In some embodiments, the compound is administered in a continuous daily dosing schedule.

[0028] In any of the embodiments disclosed herein, the mammal is a human.

[0029] In some embodiments, the compounds provided herein are administered orally to humans.

[0030] A product is provided which includes packaging material, a compound of formula (I) in the packaging material, or a pharmaceutically acceptable salt or solvate thereof, and a label indicating that the compound or composition, or a pharmaceutically acceptable salt, tautomer, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof is used to modulate the neurokinin receptor 3 protein, or to treat, prevent or improve one or more symptoms of a disease or illness that would benefit from the modulation of neurokinin receptor 3.

[0031] Other purposes, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description. However, since various changes and modifications within the spirit and scope of this disclosure will become apparent to those skilled in the art from this detailed description, it should be understood that the detailed description and specific examples are given only as illustrations, although they illustrate specific embodiments.

[0032] Built-in by reference All publications, patents, and patent applications referenced herein are incorporated herein by reference to the same extent as individual publications, patents, or patent applications are incorporated herein by reference specifically and individually. [Modes for carrying out the invention]

[0033] Neurokinin receptor 3 (NK3) (also known as tachykinin receptor 3) is encoded by the TACR3 gene (also referred to herein as the NK3 gene). Compounds of formula (I) detailed herein are NK3 modulators. In some embodiments, compounds of formula (I) detailed herein are NK3 antagonists. In some embodiments, compounds of formula (I) may be used to treat headache disorders and diseases such as cluster headaches and migraines. This disclosure demonstrates the efficacy of compounds of formula (I) acting as NK3 modulators in well-known in vitro models.

[0034] Specific terms Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art in which the present invention pertains. All patents and publications referenced herein are incorporated by reference.

[0035] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural references unless the context otherwise explicitly indicates otherwise. Thus, for example, a reference to “drug” includes multiple such drugs, and a reference to “cell” includes one or more cells (or more cells) and their equivalents known to those skilled in the art, etc. Where a range is used herein with respect to physical properties such as molecular weight, or chemical properties such as chemical formula, it is intended to include all combinations and partial combinations of the range and any particular embodiment within it.

[0036] The term "about" when referring to a number or range of numbers means that the number or range being referred to is an approximation within experimental variation (or statistical experimental error), and therefore the number or range may vary, in some cases, from 1% to 15% of the explicitly stated number or range.

[0037] "Comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude, in other specific embodiments, from "consisting of" or "essentially consisting of" any composition of matter, composition, method, or process described herein.

[0038] As used herein and in the appended claims, unless otherwise specified, the following terms have the meanings set forth below.

[0039] When used herein, C1-C x C1-C2, C1-C3...C1-C xThis includes. As just one example, a group designated as "C1-C4" indicates that there are 1 to 4 carbon atoms in that part, i.e., a group containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. Therefore, as just one example, "C1-C4 alkyl" indicates that there are 1 to 4 carbon atoms in the alkyl group, i.e., the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl.

[0040] "Alkyl" refers to an optionally substituted linear or optionally substituted branched saturated hydrocarbon monoradical having 1 to about 10 carbon atoms, or more preferably 1 to 6 carbon atoms, and the sp of the alkyl residue. 3 - The hybridized carbon is attached to the rest of the molecule by a single bond. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, as well as long alkyl groups such as heptyl and octyl. Wherever it appears herein, numerical ranges such as “C1-C6 alkyl” mean that an alkyl group consists of one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms, or six carbon atoms; however, this definition also includes instances where the term “alkyl” does not specify a numerical range. In some embodiments, alkyl groups are C1-C 10It is alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, or C1 alkyl. Unless otherwise defined herein, an alkyl group may have the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilyl, -OR a , -SR a , -OC(O)R a , -OC(O)-OR f , -N(R a )2, -N + (R a )3, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR f , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R f (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t R f (t is 1 or 2), and -S(O) t N(R a )2 (t is 1 or 2) and is optionally substituted as described below by one or more of these, where R a are each independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, and R f are each independently alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl.

[0041] "Alkenyl" refers to an optionally substituted linear or optionally substituted branched hydrocarbon monoradical having one or more carbon-carbon double bonds and 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms, where the sp of the alkenyl residue 2 - Hybridize carbon or sp 3 - The hybridizing carbon is attached to the rest of the molecule by a single bond. The group may be in either a cis or trans configuration with respect to the double bond and should be understood to include both isomers. Examples, but not limited to, include ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl (-C(CH3)=CH2), butenyl, 1,3-butadienyl, etc. Wherever it appears herein, numerical ranges such as "C2-C6 alkenyl" mean that the alkenyl group may consist of two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms, or six carbon atoms, but this definition also includes the appearance of the term "alkenyl" where a numerical range is not explicitly stated. In some embodiments, the alkenyl is C2-C 10 Alkenyl, C2-C9 alkenyl, C2-C8 alkenyl, C2-C7 alkenyl, C2-C6 alkenyl, C2-C5 alkenyl, C2-C4 alkenyl, C2-C3 alkenyl, or C2 alkenyl. Unless otherwise specified herein, the alkenyl group may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. Unless otherwise specified herein, the alkenyl group may be substituted with the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oxymo, trimethylsilanyl, -OR a , -SR a -OC(O)-R f , -OC(O)-OR f , -N(R a )2, -N + (R a )3, -C(O)R a , -C(O)OR a,-C(O)N(R a )2, -N(R a )C(O)OR f -OC(O)-N(R a )2, -N(R a )C(O)R f , -N(R a )S(O) t R f (t is 1 or 2), -S(O) t Ure a (t is 1 or 2), -S(O) t R f (t is 1 or 2), and -S(O) t N(R a )2(t is 1 or 2) is optionally replaced by one or more of the following, where R a Each of these is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, and R f Each of these is independently an alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl.

[0042] "Alkynyl" refers to an optionally substituted linear or optionally substituted branched hydrocarbon monoradical having one or more carbon-carbon triple bonds and 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms, where the sp-hybridized carbon or sp of the alkynyl residue. 3 -The hybridized carbon is bonded to the rest of the molecule by a single bond. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, and 1,3-butadiinyl. Wherever it appears herein, numerical ranges such as "C2-C6 alkynyl" mean that the alkynyl group may consist of two, three, four, five, or six carbon atoms, but this definition also includes instances where the term "alkynyl" does not specify a numerical range. In some embodiments, the alkynyl is C2-C10 Alkynyl, C2-C9 alkynyl, C2-C8 alkynyl, C2-C7 alkynyl, C2-C6 alkynyl, C2-C5 alkynyl, C2-C4 alkynyl, C2-C3 alkynyl, or C2 alkynyl. Unless otherwise specified herein, the alkynyl group is substituted with the following: halo, cyano, nitro, oxo, thioxo, imino, oxymo, trimethylsilanyl, -OR a , -SR a ,-OC(O)R a , -OC(O)-OR f , -N(R a )2, -N + (R a )3, -C(O)R a , -C(O)OR a ,-C(O)N(R a )2, -N(R a )C(O)OR f -OC(O)-N(R a )2, -N(R a )C(O)R f , -N(R a )S(O) t R f (t is 1 or 2), -S(O) t Ure a (t is 1 or 2), -S(O) t R f (t is 1 or 2), and -S(O) t N(R a )2(t is 1 or 2) is optionally replaced by one or more of the following, where R a Each of these is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, and R f Each of these is independently an alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl.

[0043] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain consisting only of carbon and hydrogen, unsaturated, and having 1 to 12 carbon atoms, with the rest of the molecule bonded to a radical group, such as methylene, ethylene, propylene, and n-butylene. The alkylene chain is bonded to the rest of the molecule via single bonds and to the radical group via single bonds. The bonding sites of the alkylene chain to the rest of the molecule and the radical group are via one carbon in the alkylene chain, or any two carbons in the chain. Unless otherwise specified herein, alkylene groups are substituents: halo, cyano, nitro, oxo, thioxo, imino, oxymo, trimethylsilanyl, -OR a , -SR a ,-OC(O)R a , -OC(O)-OR f , -N(R a )2, -N + (R a )3, -C(O)R a , -C(O)OR a ,-C(O)N(R a )2, -N(R a )C(O)OR f -OC(O)-N(R a )2, -N(R a )C(O)R f , -N(R a )S(O) t R f (t is 1 or 2), -S(O) t Ure a (t is 1 or 2), -S(O) t R f (t is 1 or 2), and -S(O) t N(R a )2(t is 1 or 2) is optionally replaced by one or more of the following, where R a Each of these is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, and R fEach of these is independently an alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl.

[0044] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain consisting only of carbon and hydrogen, containing at least one carbon-carbon double bond, and having 2 to 12 carbon atoms, with the rest of the molecule bonded to a radical group. Alkenylene chains are bonded to the rest of the molecule via single bonds and to the radical group via single bonds. Unless otherwise specified herein, alkenylene groups include the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oxymo, trimethylsilanyl, -OR a , -SR a -OC(O)-R f , -OC(O)-OR f , -N(R a )2, -N + (R a )3, -C(O)R a , -C(O)OR a ,-C(O)N(R a )2, -N(R a )C(O)OR f -OC(O)-N(R a )2, -N(R a )C(O)R f , -N(R a )S(O) t R f (t is 1 or 2), -S(O) t Ure a (t is 1 or 2), -S(O) t R f (t is 1 or 2), and -S(O) t N(R a )2(t is 1 or 2) is optionally replaced by one or more of the following, where R a Each of these is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, and R fEach of these is independently an alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl.

[0045] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain consisting only of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having 2 to 12 carbon atoms, with the rest of the molecule bonded to a radical group. Alkynylene chains are bonded to the rest of the molecule via single bonds and to the radical group via single bonds. Unless otherwise specified herein, the alkynylene group is a substituent of the following: halo, cyano, nitro, oxo, thioxo, imino, oxymo, trimethylsilanyl, -OR a , -SR a ,-OC(O)R a , -OC(O)-OR f , -N(R a )2, -N + (R a )3, -C(O)R a , -C(O)OR a ,-C(O)N(R a )2, -N(R a )C(O)OR f -OC(O)-N(R a )2, -N(R a )C(O)R f , -N(R a )S(O) t R f (t is 1 or 2), -S(O) t Ure a (t is 1 or 2), -S(O) t R f (t is 1 or 2), and -S(O) t N(R a )2(t is 1 or 2) is optionally replaced by one or more of the following, where R a Each of these is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, and R fEach of these is independently an alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl.

[0046] "Alkoxy" or "alkoxyl" refers to a radical bonded via an oxygen atom of the formula -O-alkyl, where alkyl is the alkyl chain defined above.

[0047] "Aminoalkyl" refers to the alkyl radical defined above that is substituted by one or more amino radicals as defined above, such as aminomethyl, 1-aminoethyl, 2-aminoethyl, 2-aminopropyl, 3-aminopropyl, 1,2-diaminoethyl, 2,3-diaminopropyl, and 2,3,4,5,6-pentaaminohexyl.

[0048] The term "aromatic" refers to a planar ring having a delocalized p-electron system containing 4n+2p electrons (where n is an integer). The term "aromatic" includes both carbocyclic aryl ("aryl," e.g., phenyl) and heterocyclic aryl (or "heteroaryl" or "heteroaromatic") groups (e.g., pyridine). This term includes monocyclic or fused polycyclic (i.e., rings sharing adjacent carbon atom pairs) groups.

[0049] "Aryl" refers to a radical arising from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. Unless otherwise specified, an aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon atoms (i.e., 6 to 18 carbon atoms), where at least one of the rings in the ring system is completely unsaturated (i.e., this includes a cyclic delocalized (4n+2)π-electron system according to Hückel's theory). Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indan, indene, tetralin, and naphthalene. In some embodiments, aryl is C6-C 10It is an aryl. In one embodiment, the aryl is phenyl or naphthyl. In some embodiments, the aryl is phenyl. In some embodiments, the aryl is phenyl, naphthyl, indanyl, indenyl, or tetrahydronaphthyl. Unless otherwise specified herein, the term "aryl" or the prefix "ar-" (as in "aralkyl," etc.) means alkyl, alkenyl, alkynyl, halo, haloalkyl, cyano, nitro, aryl, aralkyl, aralkenyl, aralquinyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -R b -OR a ,-R b -SR a ,-R b -OC(O)-R a ,-R b -OC(O)-OR f ,-R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -N + (R a )3, -R b -C(O)R a ,-R b -C(O)OR a ,-R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR f ,-R b -N(R a )C(O)R a ,-R b -N(R a )S(O) t R f (t is 1 or 2), -R b -S(O) t Ure a (t is 1 or 2), -R b -S(O) t R f(t is 1 or 2), and -R b -S(O) t N(R a ) means that it contains an aryl radical which is optionally substituted by one or more substituents independently selected from 2(t is 1 or 2) as described below, where R a Each of these is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, and R f R is independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, b Each of these is independently a directly bonded, or linear or branched alkylene or alkenylene chain, and R c These are linear or branched alkylene or alkenylene chains.

[0050] "Arylene" refers to a divalent radical derived from an "aryl" group, as described above, which binds the rest of the molecule to a radical group. Arylene is bonded to the rest of the molecule by a single bond and to the radical group by a single bond. In some embodiments, arylene is phenylene. Unless otherwise specified herein, the arylene group is optionally substituted for the aryl group as described above.

[0051] "Cycloalkyl" refers to a stable, partially or fully saturated, monocyclic or polycyclic carbon ring, which may include condensed (when condensed with an aryl or heteroaryl ring, the cycloalkyl is bonded by non-aromatic ring atoms) ring systems, bridging ring systems, and / or spiro ring systems. Typical cycloalkyls include, but are not limited to, those with 3 to 15 carbon atoms (C3-C3). 15 Cycloalkyl), 3-10 carbon atoms (C3-C 10Examples include cycloalkyls having 3 to 8 carbon atoms (C3-C8 cycloalkyl), 3 to 6 carbon atoms (C3-C6 cycloalkyl), 3 to 5 carbon atoms (C3-C5 cycloalkyl), or 3 to 4 carbon atoms (C3-C4 cycloalkyl). In some embodiments, the cycloalkyl is a 3- to 6-membered cycloalkyl. In some embodiments, the cycloalkyl is a 5- to 6-membered cycloalkyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl or carbocyclic compounds include, for example, adamantyl, norbornyl, dekalinyl, bicyclo[1.1.1]pentyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, etc. Unless otherwise specified herein, the term "cycloalkyl" includes alkyl, alkenyl, alkynyl, halo, haloalkyl, cyano, nitro, aryl, aralkyl, aralkenyl, aralquinyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -R b -OR a ,-R b -SR a ,-R b -OC(O)-R a ,-R b -OC(O)-OR f ,-R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -N + (R a )3, -R b -C(O)R a ,-R b -C(O)OR a ,-R b -C(O)N(R a )2, -Rb -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR f ,-R b -N(R a )C(O)R a ,-R b -N(R a )S(O) t R f (t is 1 or 2), -R b -S(O) t Ure a (t is 1 or 2), -R b -S(O) t R f (t is 1 or 2), and -R b -S(O) t N(R a ) means that it comprises a cycloalkyl radical which is optionally substituted by one or more substituents independently selected from 2(t is 1 or 2) as described below, where R a Each of these is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, and R f R is independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, b Each of these is independently a directly bonded, or linear or branched alkylene or alkenylene chain, and R c These are linear or branched alkylene or alkenylene chains.

[0052] "Cycloalkylene" refers to a divalent radical derived from a "cycloalkyl" group, as described above, which binds the rest of the molecule to a radical group. Cycloalkylene is bonded to the rest of the molecule by a single bond and to the radical group by a single bond. Unless otherwise specified herein, the cycloalkylene group is optionally substituted for the cycloalkyl group as described above.

[0053] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodine. In some embodiments, the halogen is fluoro or chloro. In some embodiments, the halogen is fluoro.

[0054] "Haloalkyl" refers to the alkyl radicals defined above that are substituted by one or more halo radicals, such as trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl.

[0055] "Fluoroalkyl" refers to an alkyl radical defined above that is substituted by one or more fluoro radicals defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, and 1-fluoromethyl-2-fluoroethyl.

[0056] "Haloalkoxy" or "haloalkoxyl" refers to an alkoxyl radical as defined above, which is substituted by one or more halo radicals as defined above.

[0057] "Fluoroalkoxy" or "fluoroalkoxyl" refers to an alkoxy radical defined above that is substituted by one or more of the fluoro radicals defined above, such as trifluoromethoxy, difluoromethoxy, and fluoromethoxy.

[0058] "Hydroxyalkyl" refers to an alkyl radical defined above that is substituted by one or more hydroxyl radicals defined above, such as hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1,2-dihydroxyethyl, 2,3-dihydroxypropyl, and 2,3,4,5,6-pentahydroxyhexyl.

[0059] "Heterocycloalkyl" refers to a stable, 3-24 membered, partially or fully saturated ring radical comprising 2-23 carbon atoms and 1-8 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Unless otherwise specified herein, heterocycloalkyl radicals may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include condensed ring systems (when condensed with an aryl or heteroaryl ring, the heterocycloalkyl is bonded via a non-aromatic ring atom), bridging ring systems, and / or spiro-ring systems, and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized, and the nitrogen atom may be optionally quaternized. In some embodiments, the heterocycloalkyl is a 3-8 membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-6 membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5-6 membered heterocycloalkyl. Examples of such heterocycloalkyl radicals include, but are not limited to, azilidinyl, azetidinyl, dioxolanil, thienyl[1,3]dithianil, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperadinyl, and 4-piperidinyl. Examples include pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianil, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term "heterocycloalkyl" also includes, but is not limited to, all cyclic forms of carbohydrates, including monosaccharides, disaccharides, and oligosaccharides. More preferably, heterocycloalkyls have 2 to 10 carbon atoms in the ring.When referring to the number of carbon atoms in a heterocycloalkyl, note that the number of carbon atoms in a heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) that make up the heterocycloalkyl (i.e., the skeletal atoms of the heterocycloalkyl ring). Unless otherwise specified herein, the term "heterocycloalkyl" includes alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, aryl, aralkyl, aralkenyl, aralquinyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -R. b -OR a ,-R b -SR a ,-R b -OC(O)-R a ,-R b -OC(O)-OR f ,-R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -N + (R a )3, -R b -C(O)R a ,-R b -C(O)OR a ,-R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR f ,-R b -N(R a )C(O)R a ,-R b -N(R a )S(O) t R f (t is 1 or 2), -R b -S(O) t Ure a (t is 1 or 2), -R b -S(O) t R f (t is 1 or 2), and -Rb -S(O) t N(R a This means that it includes a heterocycloalkyl radical defined above, which is optionally substituted by one or more substituents selected from )2 (where t is 1 or 2), where R a Each of these is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, and R f R is independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, b Each of these is independently a directly bonded, or linear or branched alkylene or alkenylene chain, and R c These are linear or branched alkylene or alkenylene chains.

[0060] An "N-heterocycloalkyl" refers to a heterocycloalkyl radical as defined above, containing at least one nitrogen atom, and the bonding site between the heterocycloalkyl radical and the rest of the molecule is via the nitrogen atom in the heterocycloalkyl radical. N-heterocycloalkyl radicals are optionally substituted for heterocycloalkyl radicals as described above.

[0061] "C-heterocycloalkyl" refers to the heterocycloalkyl radical defined above, and the bond site of the heterocycloalkyl radical to the rest of the molecule is via the carbon atom in the heterocycloalkyl radical. The C-heterocycloalkyl radical can be optionally substituted for the heterocycloalkyl radical as described above.

[0062] "Hypercycloalkylene" refers to a divalent radical derived from a "heterocycloalkyl" group, as described above, which binds the rest of the molecule to a radical group. Heterocycloalkylenes are bound to the rest of the molecule by single bonds and to the radical group by single bonds. Unless otherwise specified herein, heterocycloalkyl groups are optionally substituted for heterocycloalkyl groups as described above.

[0063] The term "heteroaryl" refers to radicals derived from 5- to 18-membered aromatic ring radicals containing 1 to 17 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl radicals are monocyclic, bicyclic, tricyclic, or tetracyclic ring systems in which at least one of the rings in the ring system is completely unsaturated, i.e., contains a cyclic delocalized (4n+2)π-electron system according to Hückel's theory. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a monocyclic heteroaryl, or a monocyclic 5- or 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6,5-condensed bicyclic heteroaryl. Exemplary examples of heteroaryl groups include monocyclic and bicyclic heteroaryls. Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and flazanil. Bicyclic heteroaryls include indolidinyl, indolyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, prinyl, quinolidinyl, quinolinyl, isoquinolinyl, sinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthylidinyl, and pteridinyl. In some embodiments, the heteroaryl ring contains 0 to 4 nitrogen atoms. In some embodiments, the heteroaryl ring contains 1 to 4 nitrogen atoms. In some embodiments, the heteroaryl ring contains 0 to 4 N atoms, 0 to 1 O atom, and 0 to 1 S atom. In some embodiments, the heteroaryl ring contains 1 to 4 N atoms, 0 to 1 O atom, and 0 to 1 S atom. In some embodiments, the heteroaryl is a C1-C9 heteroaryl. In some embodiments, the monocyclic heteroaryl is a C1-C5 heteroaryl. In some embodiments, the monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl.In some embodiments, the bicyclic heteroaryl is a C6-C9 heteroaryl. The heteroatoms in the heteroaryl radical are optionally oxidized. The carbon atoms in the heteroaryl are optionally oxidized. Two non-limiting examples of heteroaryl radicals that are oxidized and encompassed by the term heteroaryl are pyridone and pyridine N-oxide. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is bonded to the rest of the molecule via any atom of the ring. Unless otherwise specified herein, the term "heteroaryl" includes alkyl, alkenyl, alkynyl, halo, haloalkyl, oxo, thioxo, cyano, nitro, aryl, aralkyl, aralkenyl, aralquinyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -R. b -OR a ,-R b -SR a ,-R b -OC(O)-R a ,-R b -OC(O)-OR f ,-R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -N + (R a )3, -R b -C(O)R a ,-R b -C(O)OR a ,-R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR f ,-R b -N(R a )C(O)R a ,-R b -N(R a )S(O) t R f (t is 1 or 2), -R b -S(O)t Ure a (t is 1 or 2), -R b -S(O) t R f (t is 1 or 2), and -R b -S(O) t N(R a This means that it includes a heteroaryl radical defined above, which is optionally substituted by one or more substituents selected from )2 (where t is 1 or 2), where R a Each of these is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, and R f R is independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, b Each of these is independently a directly bonded, or linear or branched alkylene or alkenylene chain, and R c These are linear or branched alkylene or alkenylene chains.

[0064] "Heteroarylene" refers to a divalent radical derived from a "heteroaryl" group, as described above, which binds the rest of the molecule to a radical group. Heteroarylenes are bonded to the rest of the molecule by single bonds and to the radical group by single bonds. Unless otherwise specified herein, heteroarylene groups are optionally substituted for heteroaryl groups as described above.

[0065] The terms “optional” or “optionally” mean that the events or circumstances described below may or may not occur, and that this description includes examples in which such events or circumstances occur and examples in which they do not. For example, “optionally substituted alkyl” means “alkyl” or “substituted alkyl” as defined above. Furthermore, an optionally substituted group may be unsubstituted (e.g., -CH2CH3), completely substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted at a level between complete and monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). It will be understood by those skilled in the art that, with respect to any group containing one or more substituents, such group is not intended to introduce any sterically impractical and / or synthetically unfeasible substitution or substitution pattern (for example, a substituted alkyl group is defined as one which may optionally contain a substituted cycloalkyl group, and such cycloalkyl group may optionally contain an infinite number of substituted alkyl groups).

[0066] The terms "salt" or "pharmaceutically acceptable salt" refer to salts derived from various organic and inorganic counterions known in the art. Pharmacopoecitable acid addition salts can be formed from inorganic and organic acids. Pharmacopoecitable base addition salts can be formed from inorganic and organic bases.

[0067] The term "pharmaceutically acceptable" is used herein to mean such compounds, materials, compositions, and / or dosage forms that, within the bounds of sound medical judgment, are suitable for contact use with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and are balanced by a reasonable benefit-risk ratio.

[0068] As used herein, the terms “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” mean a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be “acceptable” in the sense that it is compatible with the other components of the formulation and is not harmful to the patient.

[0069] The term “prevent” is recognized in the art and, when used in relation to conditions such as headaches, is well understood in the art, and includes the administration of a composition that reduces the frequency of symptoms of a medical condition in a subject compared to a subject not administered the composition, or delays the onset thereof. Thus, prevention of headaches includes, for example, reducing the number of patients suffering from headaches in a group of patients receiving preventive treatment compared to an untreated control group. Prevention of headache conditions further includes, for example, reducing the number of diagnoses of headache conditions in a treated group versus an untreated control group, and / or delaying the onset of symptoms of headache conditions in a treated group versus an untreated control group.

[0070] As used herein, the term “therapeutic dose” means the amount of a compound sufficient to treat a disease or illness when administered to a patient for that purpose. The “therapeutic dose” varies depending on the compound, the disease, its severity, and the age, weight, adsorption, distribution, metabolism, and excretion of the patient being treated.

[0071] As used herein, “treatment” or “treating” refers to an approach to obtain beneficial or desired results, including but not limited to therapeutic benefits, with respect to a disease, disorder, or medical condition. In certain embodiments, treatment or treating includes administering the compounds or compositions described herein to a subject. Therapeutic benefits may include the eradication or improvement of the underlying disease being treated.

[0072] As used herein, “modulate” means a change in the activity or expression of a target protein / gene in the presence of a composition compared to comparable conditions in the absence of the composition. As used herein, the term “modulate” may be upmodulation (e.g., activation or stimulation) or downmodulation (e.g., inhibition or repression). For example, modulation may result in a cellular-level change in the target protein or a change in the expression of a target gene, protein stability, enzymatic modification of the target protein (e.g., phosphorylation), binding properties (e.g., binding to a target transcriptional regulatory element), or any other biological, functional, or immunological properties of the target protein. Changes in activity may result from, for example, an increase or decrease in the expression of a target gene, the stability or translation efficiency of the mRNA encoding the target protein, or from other changes in the biological activity of a target protein transcription factor (e.g., regulation of the expression of a target protein-responsive gene). The mechanism of action of a target gene / protein modulator may be direct, for example, through binding to the target protein or the gene encoding the target protein. The changes may also be indirect, for example, through binding to and / or modification (e.g., enzymatically) of another molecule that modulates the target gene / protein (e.g., a kinase that specifically phosphorylates the target protein).

[0073] As used herein, the terms “administer,” “administered,” “dosage,” or “for administration” refer to the process of giving (i.e., administering) a pharmaceutical composition to a subject or subject receiving the pharmaceutical composition. The pharmaceutical compositions described herein can be administered topically by a variety of methods. For example, intramuscular, intradermal, subcutaneous, intrathecal, intraperitoneal, topical (percutaneous), intravenous infusion, and implantation (e.g., polymer implants or sustained-release devices such as mini osmotic pumps) can all be appropriate routes of administration.

[0074] The terms “subject,” “individual,” and “patient” may be used interchangeably and refer to humans as well as non-human mammals (e.g., non-human primates, dogs, horses, cats, pigs, cattle, ungulates, rabbits, rodents, etc.). In various embodiments, the subject may be a human being (e.g., an adult male, an adult female, adolescent male, an adolescent female, a boy, or a girl) under the care of a physician or other healthcare professional in a hospital, either as an outpatient or in other clinical settings. In certain embodiments, the subject may not be under the care or prescription of a physician or other healthcare professional.

[0075] As used herein, the phrase “subjects requiring ~” refers to subjects suffering from, or at risk of suffering from, a pathology that should be treated prophylactically or therapeutically with the therapeutic proteins described herein, such as those listed below.

[0076] As used herein, the term "specificity" refers to the ability of a protein-binding domain, in particular an immunoglobulin or immunoglobulin fragment, such as a nanobody, to preferentially bind to one antigen over a different antigen, and does not necessarily imply high affinity.

[0077] As used herein, the term "agonism" refers to the activation of a receptor or enzyme by a modulator or agonist to produce a biological response.

[0078] As used herein, the term "agonist" refers to a modulator that binds to a receptor or target enzyme and activates the receptor or enzyme to produce a biological response. For example, an "NK3 agonist" is a modulator of NK3 activity of approximately 100 μM or less as measured by an inositol phosphate accumulation assay. 50 It can be used to refer to compounds exhibiting [the characteristic]. In some embodiments, the term "agonist" includes full agonists or partial agonists.

[0079] The term "full agonist" refers to a modulator that activates a receptor or target enzyme by binding to it in the maximum response that an agonist can induce at that enzyme.

[0080] The term "partial agonist" refers to a modulator that binds to and activates a receptor or target enzyme, but exhibits partial efficacy, i.e., less than the maximum response, compared to a full agonist.

[0081] The term "positive allosteric modulator" refers to a modulator that binds to a site different from the orthosteric binding site and enhances or amplifies the effect of the agonist.

[0082] As used herein, the term "antagonism" refers to the inactivation of a receptor or target enzyme by a modulator or antagonist. Receptor antagonism occurs, for example, when a molecule binds to a receptor or target enzyme and prevents it from producing activity.

[0083] As used herein, the terms “antagonist” or “neutral antagonist” refer to modulators that bind to a receptor or target enzyme and block the biological response. For example, NK3 antagonists, when measured by FLIPR calcium assay, have ICs for NK3 activity of approximately 1 μM, 2 μM, 3 μM, 4 μM, 5 μM, 6 μM, 7 μM, 8 μM, 9 μM, or less than 10 μM. 50 It can be used to refer to compounds that exhibit the following characteristics. In some embodiments, NK3 antagonists have an IC50 for NK3 activity less than about 10 μM when measured by a FLIPR calcium assay. 50 It can be used to refer to compounds that exhibit the following characteristics. In some embodiments, NK3 antagonists have an IC50 for NK3 activity less than about 1 μM when measured by a FLIPR calcium assay. 50This can be used to refer to compounds that exhibit this characteristic. An antagonist is inactive in the absence of an agonist or inverse agonist, but can block the activity of either without causing any change in biological response.

[0084] The term "inverse agonist" refers to a modulator that binds to the same receptor or target enzyme as an agonist, but induces a pharmacological response opposite to that of the agonist, i.e., a reduction in the biological response.

[0085] The term "negative allosteric modulator" refers to a modulator that binds to a site different from the orthosteric binding site, reducing or attenuating the effect of the agonist.

[0086] When used herein, "EC 50 " is intended to refer to the concentration of a substance (e.g., a compound or drug) required for 50% activation or enhancement of a biological process. In some examples, EC 50 EC refers to the concentration of the agonist that elicits an intermediate response between baseline and maximum response in an in vitro assay. In some embodiments used herein, EC 50 'EC' refers to the concentration of an agonist (e.g., an NK3 agonist) required for 50% activation of the receptor or target enzyme (e.g., NK3). Similarly, in some embodiments used herein, 'EC' refers to the concentration of an agonist (e.g., an NK3 agonist) required for 50% activation of the receptor or target enzyme (e.g., NK3). 70 " refers to the concentration of an agonist (e.g., an NK3 agonist) required for 70% activation of a receptor or target enzyme (e.g., NK3).

[0087] When used herein, "IC 50 "IC" is intended to refer to the concentration of a substance (e.g., a compound or drug) required to inhibit a biological process by 50%. For example, IC 50 This refers to the maximum half-capacity (50%) inhibitory concentration (IC) of a substance determined by an appropriate assay. In some examples, IC 50IC is determined in an in vitro assay system. In some embodiments used herein, IC 50 This refers to the concentration of a modulator (e.g., an NK3 antagonist) required for 50% inhibition of a receptor or target enzyme (e.g., NK3).

[0088] The terms “subject,” “individual,” and “patient” are used interchangeably. These terms encompass mammals. Examples of mammals include, but are not limited to, classes of mammals: humans, non-human primates such as chimpanzees, as well as other apes and monkey species, domesticated animals such as cattle, horses, sheep, goats, and pigs, pet animals such as rabbits, dogs, and cats, and any member of laboratory animals such as rats, mice, and guinea pigs. In some embodiments, the subject or mammal is human.

[0089] NK3 modulator In some embodiments, the compounds described herein, or their pharmaceutically acceptable salts or solvates, are therapeutic agents. In some embodiments, the compounds described herein, or their pharmaceutically acceptable salts or solvates, are NK3 modulators. In some embodiments, the compounds described herein, or their pharmaceutically acceptable salts or solvates, modulate the activity of the NK3 protein. In some embodiments, the compounds described herein, or their pharmaceutically acceptable salts or solvates, are NK3 antagonists.

[0090] The methods of this disclosure involve the administration of compounds described herein, or pharmaceutically acceptable salts or solvates thereof, that can modulate the activity of the NK3 protein. In some embodiments, at therapeutically effective concentrations, the compounds described herein, or pharmaceutically acceptable salts or solvates thereof, modulate the NK3 protein activity by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 99%, or about 100% compared to the NK3 protein activity at standard time.

[0091] NK3 signaling has distinct functions in the central nervous system (CNS), and its regulation of KNDy (kisspeptin, NKB, dinorphin) neurons in the hypothalamus modulates gonadotropin-releasing hormone (GnRH), which ultimately controls pulsatile pituitary secretion of LH. Uenoyama, Y., Nagae, M., Tsuchida, H., Inoue, N. & Tsukamura, H., Role of KNDy Neurons Expressing Kisspeptin, Neurokinin B, and Dynorphin A as a GnRH Pulse Generator Controlling Mammalian Reproduction.12 See FRONT.ENDOCRINOL.724632(2021); Depypere, H., Lademacher, C., Siddiqui, E. & Fraser, GLFezolinetant in the treatment of vasomotor symptoms associated with menopause, 30 EXPERT OPIN.INVESTIG.DRUGS 681-694(2021) (hereinafter "Depypere 2021"). To avoid undesirable side effects associated with affecting the secretion of these gonadotropins, in some embodiments, the compounds described herein, or their pharmaceutically acceptable salts or solvates, selectively modulate NK3 in peripheral tissues more selectively than NK3 in the CNS.

[0092] In some embodiments, administration of the compounds described herein, or pharmaceutically acceptable salts or solvates thereof, selectively modulates the activity of the NK3 protein in peripheral tissues compared to the central nervous system. In some embodiments, administration of the compounds described herein, or pharmaceutically acceptable salts or solvates thereof, does not cause one or more pharmacological effects related to NK3 modulation in the CNS. In some embodiments, administration of the compounds described herein, or pharmaceutically acceptable salts or solvates thereof, does not cause one or more pharmacological effects selected from thermoregulatory dysfunction, bone density, paresthesia, thrombophlebitis, and changes in gonadotropin levels (e.g., luteinizing hormone).

[0093] In some embodiments, the compounds described herein, or their pharmaceutically acceptable salts or solvates, are limited to peripheral tissues. In some embodiments, the compounds described herein, or their pharmaceutically acceptable salts or solvates, are limited to the peripheral nervous system. In some embodiments, the compounds described herein, or their pharmaceutically acceptable salts or solvates, do not substantially cross the blood-brain barrier. In some embodiments, administration of the compounds described herein, or pharmaceutically acceptable salts or solvates thereof, results in a plasma concentration to brain tissue concentration ratio in a subject of, for example, at least about 2:1, at least about 3:1, at least about 4:1, at least about 5:1, at least about 10:1, at least about 15:1, at least about 20:1, at least about 25:1, at least about 50:1, at least about 75:1, at least about 100:1, at least about 150:1, at least about 200:1, at least about 250:1, at least about 300:1, at least about 350:1, at least about 400:1, at least about 450:1, at least about 500:1, or at least about 1000:1. In some embodiments, administration of the compounds described herein, or pharmaceutically acceptable salts or solvates thereof, results in a plasma concentration to brain tissue concentration ratio in a subject of at least about 10:1. In further embodiments, administration of the compounds described herein, or a pharmaceutically acceptable salt or solvate thereof, results in a plasma concentration-to-brain tissue concentration ratio of at least about 50:1 in the subject. In further embodiments, administration of the compounds described herein, or a pharmaceutically acceptable salt or solvate thereof, results in a plasma concentration-to-brain tissue concentration ratio of at least about 100:1 in the subject.

[0094] In some embodiments, administration of the compounds described herein, or pharmaceutically acceptable salts or solvates thereof, results in plasma concentration to brain tissue concentration ratios in subjects of, for example, about 2:1 to about 1000:1, about 2:1 to about 500:1, about 2:1 to about 250:1, about 2:1 to about 100:1, about 2:1 to about 75:1, about 2:1 to about 50:1, about 2:1 to about 25:1, about 2:1 to about 20:1, about 2:1 to about 15:1, about 2:1 to about 10:1, about 2:1 to about 5:1, about 2:1 to about 4:1, or about 2:1 to about 3:1. In some embodiments, administration of the compounds described herein, or pharmaceutically acceptable salts or solvates thereof, results in plasma concentration to brain tissue concentration ratios in subjects of, for example, about 4:1 to about 1000:1, about 4:1 to about 500:1, about 4:1 to about 250:1, about 4:1 to about 100:1, about 4:1 to about 75:1, about 4:1 to about 50:1, about 4:1 to about 25:1, about 4:1 to about 20:1, about 4:1 to about 15:1, about 4:1 to about 10:1, or about 4:1 to about 5:1. In some embodiments, administration of the compounds described herein, or pharmaceutically acceptable salts or solvates thereof, results in plasma-to-brain tissue concentration ratios in subjects of, for example, about 10:1 to about 1000:1, about 10:1 to about 500:1, about 10:1 to about 250:1, about 10:1 to about 100:1, about 10:1 to about 75:1, about 10:1 to about 50:1, about 10:1 to about 25:1, about 10:1 to about 20:1, or about 10:1 to about 15:1. In some embodiments, administration of the compounds described herein, or pharmaceutically acceptable salts or solvates thereof, results in plasma-to-brain tissue concentration ratios in subjects of, for example, about 2:1 to about 20:1.

[0095] In some cases, P-glycoprotein (P-gp) at the blood-brain barrier (BBB) ​​is an efflux transporter that functions to actively pump small molecule compounds from brain tissue into the bloodstream. In some cases, in vitro P-gp substrate evaluation is used to predict the in vivo relevance of P-gp-mediated efflux at the BBB. In some cases, central nervous system (CNS) drugs are not substrates of P-gp (efflux ratio < 2), but peripherally restricted compounds are P-gp substrates (efflux ratio ≥ 2). In some embodiments, the compounds described herein, or their pharmaceutically acceptable salts or solvates, have efflux ratios of at least 2, at least 3, at least 4, at least 5, at least 10, at least 15, at least 20, at least 25, at least 30, or more, as measured by P-gp substrate evaluation tests.

[0096] In some embodiments, the compounds described herein, or their pharmaceutically acceptable salts or solvates, are peripherally restricted NK3 modulators. In some embodiments, the compounds described herein, or their pharmaceutically acceptable salts or solvates, are peripherally restricted NK3 modulators (e.g., not accumulating to clinically significant concentrations in the brain). In some embodiments, the use of peripherally restricted NK3 modulators minimizes or avoids undesirable side effects associated with NK3 modulation in the CNS (e.g., changes in gonadotropin levels such as LH). Such side effects include impaired thermoregulation, changes in bone density, paresthesia, thrombophlebitis, and changes in one or more gonadotropin levels. In some embodiments, administration of the NK3 modulators disclosed herein is free from one or more of the following side effects: changes in bone density, paresthesia, thrombophlebitis, infertility, changes in libido, menstrual cycle abnormalities (e.g., delayed or blocked ovulation), changes in testosterone levels, testicular atrophy, and changes in gonadotropin levels (e.g., luteinizing hormone). In some embodiments, administration of the compounds described herein, or their pharmaceutically acceptable salts or solvates, does not lower LH levels in the subject.

[0097] In some embodiments, administration of the compounds described herein, or pharmaceutically acceptable salts or solvates thereof, does not reduce luteinizing hormone in a subject at a therapeutically effective dose. In some embodiments, administration of a therapeutically effective dose of the compounds described herein, or pharmaceutically acceptable salts or solvates thereof, reduces luteinizing hormone in a subject by, for example, less than 1%, less than 2%, less than 3%, less than 4%, less than 5%, less than 6%, less than 7%, less than 8%, less than 9%, less than 10%, less than 11%, less than 12%, less than 13%, less than 14%, less than 15%, less than 20%, less than 25%, less than 30%, less than 35%, less than 40%, less than 45%, or less than 50%. In some embodiments, administration of a therapeutically effective amount of the compound described herein, or a pharmaceutically acceptable salt or solvate thereof, reduces the concentration of luteinizing hormone in a sample obtained from a subject by, for example, less than 1%, less than 2%, less than 3%, less than 4%, less than 5%, less than 6%, less than 7%, less than 8%, less than 9%, less than 10%, less than 11%, less than 12%, less than 13%, less than 14%, less than 15%, less than 20%, less than 25%, less than 30%, less than 35%, less than 40%, less than 45%, or less than 50%. In some embodiments, administration of the compounds described herein, or pharmaceutically acceptable salts or solvates thereof, at therapeutic levels reduces luteinizing hormone in a subject by less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, or less than about 0.5%. In some embodiments, the sample includes, for example, blood, plasma, urine, mucus, or saliva. The examples described above are merely illustrative and are not intended to limit the scope of this disclosure.

[0098] In some embodiments, the compounds described herein (e.g., compounds of formula (I)) bind selectively to NK3 rather than to NK2. In some embodiments, the compounds described herein (e.g., compounds of formula (I)) bind selectively to NK3 rather than to NK1. In some embodiments, the compounds described herein (e.g., compounds of formula (I)) bind selectively to NK3 rather than to NK1 and NK2. In some embodiments, the compounds described herein (e.g., compounds of formula (I)) bind selectively to NK3 rather than to NK2 ​​with at least 2 times, at least 3 times, at least 5 times, at least 10 times, at least 25 times, at least 50 times, at least 100 times, or more than 100 times the selectivity of NK3 compared to NK2. In some embodiments, the compounds described herein (e.g., compounds of formula (I)) bind selectively to NK3 rather than to NK1 with at least 2 times, at least 3 times, at least 5 times, at least 10 times, at least 25 times, at least 50 times, at least 100 times, or more than 100 times the selectivity of NK3 compared to NK1. In some embodiments, the compounds described herein (e.g., the compounds of formula (I)) bind to NK3 more selectively than both NK1 and NK2, with a selectivity of at least 2 times, at least 3 times, at least 5 times, at least 10 times, at least 25 times, at least 50 times, at least 100 times, or more than 100 times for NK3 than for both NK1 and NK2.

[0099] In some embodiments, the compounds described herein (e.g., compounds of formula (I)) selectively modulate NK3 activity rather than NK2 activity. In some embodiments, the compounds described herein (e.g., compounds of formula (I)) selectively inhibit NK3 activity rather than NK1 activity. In some embodiments, the compounds described herein (e.g., compounds of formula (I)) selectively inhibit NK3 activity rather than both NK1 and NK2 activity. In some embodiments, the compounds described herein (e.g., compounds of formula (I)) selectively inhibit NK3 activity rather than NK2 activity. In some embodiments, the compounds described herein (e.g., compounds of formula (I)) selectively modulate NK3 activity rather than NK1 activity. In some embodiments, NK2 is neurokinin receptor 2. In some embodiments, NK1 is neurokinin receptor 1. In some embodiments, the compounds described herein (e.g., compounds of formula (I)) selectively inhibit the activity of NK3 by at least 2 times, at least 3 times, at least 5 times, at least 10 times, at least 25 times, at least 50 times, at least 100 times, or more than 100 times compared to the activity of NK2. In some embodiments, the compounds described herein (e.g., compounds of formula (I)) selectively inhibit the activity of NK3 by at least 2 times, at least 3 times, at least 5 times, at least 10 times, at least 25 times, at least 50 times, at least 100 times, or more than 100 times compared to the activity of NK2. In some embodiments, the compounds described herein (e.g., compounds of formula (I)) selectively inhibit the activity of NK3 by at least 2 times, at least 3 times, at least 5 times, at least 10 times, at least 25 times, at least 50 times, at least 100 times, or more than 100 times compared to the activity of both NK1 and NK2.

[0100] Treatment of headache disorders This specification provides a method for treating a disease or illness in which treatment is required, the method comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound described herein, or a pharmaceutically acceptable salt or solvate thereof, modulates the activity of the NK3 protein in the subject requiring treatment. In some embodiments, the disease or illness is a headache disorder. In some embodiments, the disease or illness is selected from migraine, drug abuse headache, cluster headache, generalized headache, tension headache, caffeine headache, hormonal headache, persistent hemiplegia (hemicrania continua), hypertensive headache, rebound headache, post-traumatic headache, exertional headache, spinal headache, thunderclap headache, icepick headache, trigeminal neuralgia, orofacial pain (e.g., chronic orofacial pain), or two or more combinations of these diseases or illnesses. Non-limiting examples of such combinations include migraine and generalized headache, generalized headache and trigeminal neuralgia, and cluster headache and orofacial pain. In some embodiments, the disease or illness is selected from the group consisting of migraine, medication-induced headache, cluster headache, generalized headache, trigeminal neuralgia, and orofacial pain. In further embodiments, the disease or illness is migraine. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0101] In some embodiments, the compounds described herein, or pharmaceutically acceptable salts or solvates thereof, are used in the preparation of pharmaceuticals for the prevention or treatment of diseases or illnesses. In some embodiments, the compounds described herein, or pharmaceutically acceptable salts or solvates thereof, are used in the preparation of pharmaceuticals for the prevention or treatment of headache disorders. In some embodiments, the compounds described herein, or pharmaceutically acceptable salts or solvates thereof, are used in the preparation of pharmaceuticals for the prevention or treatment of migraines, drug abuse headaches, cluster headaches, generalized headaches, tension headaches, caffeine headaches, hormonal headaches, persistent hemiparesis, hypertensive headaches, rebound headaches, post-traumatic headaches, exertional headaches, spinal headaches, thunderclap headaches, icepick headaches, trigeminal neuralgia, orofacial pain, or a combination of two or more of these diseases or illnesses.

[0102] In some embodiments, compounds of formula (I) for use in treating or preventing diseases or illnesses are described herein. In some embodiments, compounds of formula (I) for use in treating or preventing headache disorders are described herein. In some embodiments, the disclosure provides compounds of formula (I) for use in treating or preventing diseases or illnesses selected from the group consisting of migraine, medication-induced headache, cluster headache, generalized headache, trigeminal neuralgia, and orofacial pain.

[0103] In some embodiments, compositions comprising the compounds described herein, or pharmaceutically acceptable salts or solvates thereof, and at least one pharmaceutically acceptable excipient are administered for prophylactic and / or therapeutic purposes. In some embodiments, the compounds described herein, or pharmaceutically acceptable salts or solvates thereof, are administered to patients already suffering from a headache disorder in an amount sufficient to cure or at least partially cessate one or more symptoms of the headache disorder. The effective amount for this use depends on the severity and course of the disease or illness, previous treatments, the patient's health status, weight, and response to the drug, as well as the judgment of the treating physician.

[0104] In some embodiments, administration of the compounds described herein, or pharmaceutically acceptable salts or solvates thereof, results in the cessation or reduction of one or more symptoms of headache disorders. In some embodiments, administration of the compounds described herein, or pharmaceutically acceptable salts or solvates thereof, results in the cessation or reduction of one or more symptoms of a disorder or illness selected from migraine, drug abuse headache, cluster headache, generalized headache, trigeminal neuralgia, and orofacial pain. In some embodiments, administration of the compounds described herein, or pharmaceutically acceptable salts or solvates thereof, results in the cessation or reduction of one or more symptoms selected from pain, sensitivity to light, sensitivity to sound, sensitivity to smell, aura, nausea, vomiting, excitement, dizziness, confusion, muscle rigidity, muscle spasms, swelling, numbness, scalp tenderness, and nasal congestion. In some embodiments, administration of the compounds described herein, or pharmaceutically acceptable salts or solvates thereof, results in the cessation or reduction of one or more symptoms selected from pain, sensitivity to light, sensitivity to sound, nausea, and vomiting. In some embodiments, administration of the compounds described herein, or pharmaceutically acceptable salts or solvates thereof, results in the cessation or reduction of pain (e.g., pain associated with headache disorders). In some embodiments, administration of the compounds described herein, or pharmaceutically acceptable salts or solvates thereof, results in relief from pain.

[0105] In prophylactic applications, compositions comprising the compounds described herein, or pharmaceutically acceptable salts or solvates thereof, and at least one pharmaceutically acceptable excipient are administered to patients who are susceptible to or otherwise at risk of a disorder or disease (e.g., headache disorder). Such amounts are defined as “a prophylactically effective amount or dose.” In this application, the exact amount will also vary depending on the patient’s health condition, weight, etc. When used in a patient, the effective amount for this application will depend on the disease, disorder, or the severity and course of the disease, previous treatments, the patient’s health condition and response to the drug, and the judgment of the treating physician.

[0106] The compounds described herein, or their pharmaceutically acceptable salts or solvates, may be administered to subjects using different routes of administration, including oral, mucosal, topical, dermal, inhalation, intravenous, subcutaneous, intradermal, intramuscular, intra-articular, perineurial, intraventricular, intraperitoneal, intranasal, and intraocular.

[0107] compound In a particular embodiment, the compound of formula (I),

[0108] [ka] Or a pharmaceutically acceptable salt or solvate thereof is disclosed herein, in formula, Z is -S-, -N=C(R 5 )-,-C(R 5 )=N-, or -C(R 5 )=C(R 5 )- is a divalent group selected from, R 1 is a pyrazole, and the pyrazole is optionally selected, R 6 It is replaced by 1 to 3 groups independently selected from, R 2 C1-C 10 Alkyl, C1-C 10 Heteroalkyl, -C(=O)OR 7 -C(=O)N(R8 )(R 7 ), -N(R 8 )(R 7 ), -C(=NR 9 )N(R 8 )(R 7 ), -N(R 7 )C(=NR 9 )N(R 8 )(R 7 ), C6-C 10 Aryl, 5-10 member heteroaryl, C3-C 12 A cycloalkyl or a 3- to 15-membered heterocycloalkyl, where aryl and heteroaryl are optional, R 10 Substituted with 1 to 4 groups independently selected from, alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl groups are optional, oxo and R 10 It is replaced by 1 to 4 elements independently selected from, R 3 These are halogens, cyanos, -C(=O)OH, -C(=O)O(C1-C6 alkyl), C1-C6 alkyl, C1-C6 alkenyl, -O(C1-C6 alkyl), C3-C6 cycloalkyl, or C1-C6 haloalkyl. R 4 Each of these is independently hydrogen, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C6 haloalkyl, or -O-(C1-C6 haloalkyl), L is a bond, a C1-C2 alkylene or a C3-C6 cycloalkylene, wherein the alkylene or cycloalkylene is optionally substituted with one or two -OH groups. R 5 Each of these is independently hydrogen, cyano, halogen, C1-C6 alkyl, -O(C1-C6 alkyl), C3-C6 cycloalkyl, C1-C6 haloalkyl, or -O(C1-C6 haloalkyl), R 6These are, independently, halogen, hydroxy, cyano, amino, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C3-C6 cycloalkyl, and -CH2-(C 3-6 Cycloalkyl), -O-(C 3-6 Selected from the group consisting of cycloalkyl, C1-C6 haloalkyl, and -O(C1-C6 haloalkyl), R 6 If it is bonded to a nitrogen atom, it is C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C3-C6 cycloalkyl, -CH2-(C 3-6 Selected from the group consisting of cycloalkyl and C1-C6 haloalkyl groups, R 7 Each of these is independently hydrogen or a C1-C6 alkyl group, and the alkyl group is optionally substituted with 1-2 hydroxyl groups. R 8 is hydrogen, C1-C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Alkenyl, C1-C 10 Alkinyl, C3-C 12 Cycloalkyl, 3-15 member heterocycloalkyl, C6-C 10 It is an aryl or a 5-10 member heteroaryl, and the aryl and heteroaryl are optional, R 11 Substituted with 1 to 6 groups independently selected from, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl groups are optional, oxo and R 11 It is replaced by 1 to 6 groups independently selected from, Alternatively, one R bonded to the same nitrogen atom 7 and one R 8 These combine to form oxo and R 11 Forms a 3-15 member heterocycloalkyl group that is optionally substituted with 1-6 groups independently selected from the above, R 9is hydrogen, -C(O)OR 12 ,-C(O)N(R 12 )2, -S(O)2R 12 -S(O)2N(R 12 )2, or C1-C6 alkyl, R 10 These are independently hydroxy, amino, cyano, fluoro, and -C(=O)OR. 12 -C(=O)N(R 12 )2, C1-C4 alkyl, C1-C4 haloalkyl, -O(C1-C6 alkyl), -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C3-C6 cycloalkyl, where the alkyl, haloalkyl, or cycloalkyl is optional, and hydroxy, amino, cyano, fluoro, -C(=O)OR 12 , and -C(=O)N(R 12 ) Replaced by 1-2 elements selected from 2, R 11 These are, independently, halogen, hydroxy, amino, cyano, and -S(=O)2(R) 13 ), -N(R 12 )S(=O)2(R 13 ), -S(=O)(R 13 ), -N(R 12 )S(=O)(R 13 ), -C(=O)R 13 , -N(R 12 )C(=O)R 13 , C1-C6 alkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-10 member heterocycloalkyl, C6-C 10 Selected from the group consisting of aryls and 5-10 member heteroaryls, aryls and heteroaryls are R 14 Optionally substituted with 1 to 4 groups independently selected from, with alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, and heterocycloalkyl groups being optional, as well as oxo and R 14 It is replaced by 1 to 4 elements independently selected from, Alternatively, two R atoms bonded to the same carbon or nitrogen atom 11 These combine to form a C3-C6 cycloalkyl or a 3-6 member heterocycloalkyl, and the cycloalkyl and heterocycloalkyl are oxo and R 14 It is optionally replaced by 1 to 4 bases independently selected from, R 12 Each of these is independently hydrogen or a C1-C6 alkyl group. R 13 Each of these is independently a hydroxyl, amino, C1-C6 alkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 haloalkyl, C3-C6 cycloalkyl, or a 3- to 6-membered heterocycloalkyl. R 14 These are independently cyano, amino, hydroxy, and -C(=O)OR 12 -C(=O)N(R 12 )2, C1-C6 alkyl, -O(C1-C6 alkyl), -NR 12 The alkyl group is (C1-C6 alkyl), aryl, heteroaryl, C3-C6 cycloalkyl, or a 3- to 6-membered heterocycloalkyl, and each alkyl group is optionally substituted with 1 to 2 hydroxyl groups.

[0109] For any and all embodiments, the substituent is selected from a subset of the enumerated alternatives. For example, in some embodiments of the compound of formula (I), or its pharmaceutically acceptable salt or solvate, Z is -S-, -N=C(R 5 )-,-C(R 5 )=N-, or -C(R 5 )=C(R 5 A divalent group selected from )-. In some embodiments, Z is -S- or -C(R 5 )=C(R 5 )-. In some embodiments, Z is -N=C(R 5 )- or -C(R 5 )=N-. In some embodiments, Z is -S-. In some embodiments, Z is -C(R5 )=C(R 5 )-. In some embodiments, Z is -C(R 5 ) = N-. In some embodiments, Z is -N = C(R 5 )-is.

[0110] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salt or solvate, Z is a divalent group selected from -S-, -N=CH-, -CH=N-, or -CH=CH-. In some embodiments, Z is -S- or -CH=CH-. In some embodiments, Z is -N=CH- or -CH=N-. In some embodiments, Z is -S-. In some embodiments, Z is -CH=CH-. In some embodiments, Z is -CH=N-. In some embodiments, Z is -N=CH-.

[0111] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salt or solvate, R 3 R is a halogen, cyano, -C(=O)OH, C1-C6 alkyl, C1-C6 alkenyl, -O(C1-C6 alkyl), C3-C6 cycloalkyl, or C1-C6 haloalkyl. In some embodiments, R 3 is a halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl. In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salt or solvate, R 3 R is a fluoro, chloro, cyano, -C(=O)OH, C1-C6 alkyl, C1-C6 alkenyl, -O(C1-C6 alkyl), C3-C6 cycloalkyl, or C1-C6 haloalkyl compound. In some embodiments of the compound of formula (I) or its pharmaceutically acceptable salt or solvate, R 3R is a fluoro, chloro, cyano, -C(=O)OH, C1-C4 alkyl, C1-C4 alkenyl, -O(C1-C4 alkyl), C3-C4 cycloalkyl, or C1-C4 haloalkyl. In some embodiments, R 3 R is fluoro, chloro, cyano, methyl, ethyl, vinyl, -OMe, -C(=O)OH, trifluoromethyl, difluoromethyl, or cyclopropyl. In some embodiments, R 3 These are chloro, cyano, methyl, or ethyl compounds.

[0112] In some embodiments, the compound (for example, the compound of formula (I)) is of formula (IIa)

[0113] [ka] It has the structure of, or a pharmaceutically acceptable salt or solvate thereof.

[0114] In some embodiments, the compound (e.g., the compound of formula (I)) is of formula (IIb)

[0115] [ka] It has the structure of, or a pharmaceutically acceptable salt or solvate thereof.

[0116] In some embodiments, the compound (e.g., the compound of formula (I)) is of formula (IIc)

[0117] [ka] It has the structure of, or a pharmaceutically acceptable salt or solvate thereof.

[0118] In some embodiments, the compound (e.g., the compound of formula (I)) is of formula (IId)

[0119] [ka] It has the structure of, or a pharmaceutically acceptable salt or solvate thereof.

[0120] In some embodiments of compounds of formula (IIa), formula (IIb), formula (IIc), or formula (IId), or pharmaceutically acceptable salts or solvates thereof, R 3 R is a halogen, cyano, -C(=O)OH, C1-C6 alkyl, C1-C6 alkenyl, -O(C1-C6 alkyl), C3-C6 cycloalkyl, or C1-C6 haloalkyl. In some embodiments, R 3 is a halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl. In some embodiments, R 3 R is a fluoro, chloro, cyano, -C(=O)OH, C1-C6 alkyl, C1-C6 alkenyl, -O(C1-C6 alkyl), C3-C6 cycloalkyl, or C1-C6 haloalkyl. In some embodiments, R 3 R is a fluoro, chloro, cyano, -C(=O)OH, C1-C4 alkyl, C1-C4 alkenyl, -O(C1-C4 alkyl), C3-C4 cycloalkyl, or C1-C4 haloalkyl. In some embodiments, R 3 R is fluoro, chloro, cyano, methyl, ethyl, vinyl, -OMe, -C(=O)OH, trifluoromethyl, difluoromethyl, or cyclopropyl. In some embodiments, R 3 These are chloro, cyano, methyl, or ethyl compounds.

[0121] In some embodiments of compounds of formula (I), formula (IIa), formula (IIb), formula (IIc), or formula (IId), or pharmaceutically acceptable salts or solvates thereof, L is a bond, a C1-C2 alkylene, or a C3-C6 cycloalkylene, wherein the alkylene or cycloalkylene is optionally substituted with one or two -OH groups. In some embodiments, L is a bond or a C1-C2 alkylene. In some embodiments, L is a bond, a C1-C2 alkylene, or a C3-C4 cycloalkylene. In some embodiments, L is a bond or a C1 alkylene. In some embodiments, L is a bond. In some embodiments, L is methylene. In some embodiments, L is ethylene. In some embodiments, L is cyclopropylene. In some embodiments, L is cyclobutylene.

[0122] In some embodiments of the compounds of formula (I), formula (IIa), formula (IIb), formula (IIc), or formula (IId), or their pharmaceutically acceptable salts or solvates, L is optionally substituted with one or two -OH groups. In some embodiments, L is unsubstituted. In some embodiments, L is substituted with one or two -OH groups. In some embodiments, L is substituted with one -OH group.

[0123] In some embodiments of compounds of formula (I), formula (IIa), formula (IIb), formula (IIc), or formula (IId), or pharmaceutically acceptable salts or solvates thereof, -LR 2 is -C(=O)OR 7 Or -C(=O)NR 7 R 8 In some embodiments, -LR 2 is -C(=O)OR 7 In some embodiments, -LR 2 is -C(=O)N(R 8 )(R 7) is. In some embodiments, -C(=O)N(R 8 )(R 7 ) is structure

[0124] [ka] It is depicted as having -R 2 is -C(=O)OR 7 Or -C(=O)NR 7 R 8 In some embodiments, -R 2 is -C(=O)OR 7 In some embodiments, -R 2 is -C(=O)N(R 8 )(R 7 )

[0125] In some embodiments of compounds of formula (I), formula (IIa), formula (IIb), formula (IIc), or formula (IId), or pharmaceutically acceptable salts or solvates thereof, R 2 C1-C 10 Alkyl, C1-C 10 Heteroalkyl, -C(=O)OR 7 -C(=O)N(R 8 )(R 7 ), -N(R 8 )(R 7 ), -C(=NR 9 )N(R 8 )(R 7 ), -N(R 7 )C(=NR 9 )N(R 8 )(R 7 ), C6-C 10 Aryl, 5-10 member heteroaryl, C3-C 12 A cycloalkyl or a 3- to 15-membered heterocycloalkyl, where aryl and heteroaryl are optional, R 10 Substituted with 1 to 4 groups independently selected from, alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl groups are optional, oxo and R 10It is replaced by 1 to 4 groups independently selected from R. In some embodiments, R 2 is -C(=O)OR 7 -C(=O)N(R 8 )(R 7 ), -N(R 8 )(R 7 ), -C(=NR 9 )N(R 8 )(R 7 ), or -N(R 7 )C(=NR 9 )N(R 8 )(R 7 ) is. In some embodiments, R 2 is -C(=O)OR 7 -C(=O)N(R 8 )(R 7 ), or -C(=NR 9 )N(R 8 )(R 7 ) is. In some embodiments, R 2 is -C(=O)OR 7 In some embodiments, R 2 is -C(=O)N(R 8 )(R 7 ) is. In some embodiments, R 2 is -C(=NR 9 )N(R 8 )(R 7 ) is. In some embodiments, R 2 is -C(=NR 9 )N(R 8 )(R 7 ) is. In some embodiments, R 2 is -N(R 8 )(R 7 ) is. In some embodiments, R 2 C1-C 10 Alkyl, C1-C 10 Heteroalkyl, C6-C 10 Aryl, 5-10 member heteroaryl, C3-C 12 It is a cycloalkyl or a 3- to 15-membered heterocycloalkyl. In some embodiments, R 2C1-C6 alkyl, C1-C6 heteroalkyl, phenyl, 5-12 member heteroaryl, C3-C 10 It is a cycloalkyl or a 3- to 12-membered heterocycloalkyl. In some embodiments, R 2 C1-C 10 Alkyl, C1-C 10 Heteroalkyl, C6-C 10 Aryl, 5-10 member heteroaryl, C3-C 12 It is a cycloalkyl or a 3- to 15-membered heterocycloalkyl. In some embodiments, R 2 is a 5-10 member heteroaryl or a 3-15 member heterocycloalkyl. In some embodiments, R 2 R is a 5-6 member heteroaryl or a 3-8 member heterocycloalkyl. In some embodiments, R 2 R is a 5-10 member heteroaryl. In some embodiments, R 2 R is a 5-6 member heteroaryl. In some embodiments, R 2 R is a 3- to 15-membered heterocycloalkyl. In some embodiments, R 2 R is a 3- to 8-membered heterocycloalkyl. In some embodiments, R 2 It is a 3- to 6-membered heterocycloalkyl group.

[0126] In some embodiments of compounds of formula (I), formula (IIa), formula (IIb), formula (IIc), or formula (IId), or pharmaceutically acceptable salts or solvates thereof, R 2 R 10 It is optionally replaced by 1 to 4 groups independently selected from. In some embodiments, R 2 R 10 It is optionally replaced by 1 to 3 bases independently selected from. In some embodiments, R 2 R 10 It is optionally replaced by one or two bases independently selected from. In some embodiments, R 2 R 10It is optionally replaced by one of the bases selected from. In some embodiments, R 2 R 10 It is replaced by 1 to 4 groups independently selected from R. In some embodiments, R 2 R 10 It is replaced by 1 to 3 groups independently selected from R. In some embodiments, R 2 R 10 It is replaced by one or two groups independently selected from R. In some embodiments, R 2 R 10 It is replaced by one group selected from. In some embodiments, R 2 R 10 It is replaced by two groups independently selected from R. In some embodiments, R 2 R 10 It is replaced by three groups independently selected from R. In some embodiments, R 2 R 10 It is replaced by four groups independently selected from R. In some embodiments, R 2 is non-substitutable. In some embodiments, R 2 , oxo and R 10 It is optionally replaced by 1 to 4 groups independently selected from. In some embodiments, R 2 , oxo and R 10 It is optionally replaced by 1 to 3 bases independently selected from. In some embodiments, R 2 , oxo and R 10 R may be optionally replaced by one or two bases independently selected from the others. In some embodiments, R 2 , oxo and R 10 It is optionally replaced by one base selected from. In some embodiments, R 2 , oxo and R 10 It is replaced by 1 to 4 groups independently selected from R. In some embodiments, R 2 , oxo and R 10 It is replaced by 1 to 3 groups independently selected from R. In some embodiments, R2 , oxo and R 10 It is replaced by one or two groups independently selected from R. In some embodiments, R 2 , oxo and R 10 It is replaced by one base selected from. In some embodiments, R 2 , oxo and R 10 It is replaced by two groups independently selected from R. In some embodiments, R 2 , oxo and R 10 It is replaced by three groups independently selected from R. In some embodiments, R 2 , oxo and R 10 It is replaced by four elements independently selected from it.

[0127] In some embodiments of compounds of formula (I), formula (IIa), formula (IIb), formula (IIc), or formula (IId), or pharmaceutically acceptable salts or solvates thereof, R 10 These are independently hydroxy, amino, cyano, fluoro, and -C(=O)OR. 12 -C(=O)N(R 12 )2, C1-C4 alkyl, C1-C4 haloalkyl, -O(C1-C6 alkyl), -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C3-C6 cycloalkyl, where the alkyl, haloalkyl, or cycloalkyl is optional, and hydroxy, amino, cyano, fluoro, -C(=O)OR 12 , and -C(=O)N(R 12 ) is replaced by one or two groups selected from 2. In some embodiments, R 10 Each of these is independently selected from hydroxy, amino, cyano, fluoro, -C(=O)OH, -C(=O)NH2, C1-C4 alkyl, C1-C4 haloalkyl, and C3-C6 cycloalkyl, and the alkyl, haloalkyl, or cycloalkyl is optionally substituted with one or two groups selected from hydroxy, amino, cyano, fluoro, -C(=O)OH, and -C(=O)NH2. In some embodiments, R 10Each of these is independently selected from hydroxy, amino, cyano, fluoro, -C(=O)OH, -C(=O)NH2, C1-C4 alkyl, C1-C4 haloalkyl, and C3-C4 cycloalkyl. In some embodiments, R 10 Each of these is independently selected from hydroxy, amino, cyano, fluoro, -C(=O)OH, -C(=O)NH2, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, -OMe, -OEt, trifluoromethyl, and difluoromethyl. In some embodiments, R 10 Each of these is independently selected from hydroxy, amino, cyano, fluoro, -C(=O)OH, -C(=O)NH2, methyl, ethyl, cyclopropyl, cyclobutyl, and -OMe. In some embodiments, R 10 Each of these is independently selected from hydroxy, fluoro, -C(=O)OH, -C(=O)NH2, methyl, cyclobutyl, and -OMe. In some embodiments, R 10 Each is independently selected from hydroxy, -C(=O)OH, methyl, and cyclobutyl. In some embodiments, R 10 Each of these is hydroxyl. In some embodiments, R 10 Each of these is methyl. In some embodiments, R 10 Each of these is -C(=O)OH. In some embodiments, R 10 These are cyclobutyl compounds.

[0128] In some embodiments of compounds of formula (I), formula (IIa), formula (IIb), formula (IIc), or formula (IId), or pharmaceutically acceptable salts or solvates thereof, R 10 Each of these is optionally substituted with one or two groups selected from hydroxy, amino, cyano, fluoro, -C(=O)OH, and -C(=O)NH2. In some embodiments, R 10Each of these is optionally substituted with one group selected from hydroxy, amino, cyano, fluoro, -C(=O)OH, and -C(=O)NH2. In some embodiments, R 10 Each of these is optionally substituted with one or two groups selected from hydroxy, fluoro, and -C(=O)OH. In some embodiments, R 10 Each of these is optionally substituted with one or two groups selected from hydroxyl and -C(=O)OH. In some embodiments, R 10 Each of these is non-substitutable. In some embodiments, at least one R 10 is non-substitutable. In some embodiments, at least one R 10 It has been replaced.

[0129] In some embodiments of compounds of formula (I), formula (IIa), formula (IIb), formula (IIc), or formula (IId), or pharmaceutically acceptable salts or solvates thereof, -LR 2 is -C(=O)OR 7 Or -C(=O)NR 7 R 8 And, R 3 These are halogens, cyanos, C1-C6 alkyls, C3-C6 cycloalkyls, or C1-C6 fluoroalkyls. R 4 Each is independently either hydrogen or halogen, R 5 Each is independently either hydrogen or halogen, R 6 These are, independently, halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, and -CH2-(C 3-6 Selected from the group consisting of cycloalkyl and C1-C6 haloalkyl, R 6 If it is bonded to a nitrogen atom, it is independently C1-C6 alkyl, C3-C6 cycloalkyl, -CH2-(C 3-6 It is a cycloalkyl or C1-C6 haloalkyl, R7 is hydrogen or C 1-6 It is alkyl, R 8 C1-C 10 Alkyl, C1-C 10 Heteroalkyl, C3-C 12 Cycloalkyl, or 3-15 member heterocycloalkyl, alkyl, cycloalkyl, and heterocycloalkyl are oxo and R 11 It is optionally replaced by 1 to 6 bases independently selected from, Alternatively, one R bonded to the same nitrogen atom 7 and one R 8 These combine to form oxo and R 11 Forms a 3-15 member heterocycloalkyl group that is optionally substituted with 1-6 groups independently selected from the above, R 11 These are, independently, halogen, hydroxy, amino, cyano, and -S(=O)2(R) 13 ), -N(R 12 )S(=O)2(R 13 ), -S(=O)(R 13 ), -N(R 12 )S(=O)(R 13 ), -C(=O)R 13 , -N(R 12 )C(=O)R 13 The group consists of C1-C6 alkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-10 member heterocycloalkyl, and 5-10 member heteroaryl, and the heteroaryl is optional. 14 Substituted with 1 to 4 groups independently selected from, alkyl, haloalkyl, cycloalkyl, and heterocycloalkyl groups are optional, oxo and R 14 It is replaced by 1 to 4 elements independently selected from, Alternatively, two R atoms bonded to the same carbon or nitrogen atom 11These combine to form a C3-C6 cycloalkyl or a 3-6 member heterocycloalkyl, and the cycloalkyl and heterocycloalkyl are oxo and R 14 It is optionally replaced by 1 to 4 bases independently selected from, R 12 Each of these is independently hydrogen or a C1-C6 alkyl group. R 13 Each of these is independently hydroxy, amino, C1-C6 alkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or C1-C6 haloalkyl. R 14 These are independently cyano, amino, hydroxy, and -C(=O)OR 12 -C(=O)N(R 12 )2, C1-C6 alkyl, -O(C1-C6 alkyl), or -NR 12 The (C1-C6 alkyl) group is one of several alkyl groups, each optionally substituted with one or two hydroxyl groups.

[0130] In some embodiments, the compound (e.g., the compound of formula (I)) is the compound of formula (III)

[0131] [ka] It has the structure of, or a pharmaceutically acceptable salt or solvate thereof.

[0132] In some embodiments of the compound of formula (III), or its pharmaceutically acceptable salt or solvate, Z is -S-, -N=C(R 5 )-,-C(R 5 )=N-, or -C(R 5 )=C(R 5 A divalent group selected from )-. In some embodiments, Z is -S- or -C(R 5 )=C(R 5 )-. In some embodiments, Z is -N=C(R 5 )- or -C(R 5)=N-. In some embodiments, Z is -S-. In some embodiments, Z is -C(R 5 )=C(R 5 )-. In some embodiments, Z is -C(R 5 ) = N-. In some embodiments, Z is -N = C(R 5 )-is.

[0133] In some embodiments, the compound (e.g., the compound of formula (I)) is of formula (IIIa)

[0134] [ka] It has the structure of, or a pharmaceutically acceptable salt or solvate thereof.

[0135] In some embodiments, the compound (e.g., the compound of formula (I)) is of formula (IIIb)

[0136] [ka] It has the structure of, or a pharmaceutically acceptable salt or solvate thereof.

[0137] In some embodiments, the compound (e.g., the compound of formula (I)) is of formula (IIIc)

[0138] [ka] It has the structure of, or a pharmaceutically acceptable salt or solvate thereof.

[0139] In some embodiments, the compound (e.g., the compound of formula (I)) is of formula (IIId)

[0140] [ka] It has the structure of, or a pharmaceutically acceptable salt or solvate thereof.

[0141] In some embodiments of compounds of formula (III), formula (IIIa), formula (IIIb), formula (IIIc), or formula (IIId), or pharmaceutically acceptable salts or solvates thereof, R 3 R is a halogen, cyano, -C(=O)OH, C1-C6 alkyl, C1-C6 alkenyl, -O(C1-C6 alkyl), C3-C6 cycloalkyl, or C1-C6 haloalkyl. In some embodiments, R 3 R is a fluoro, chloro, cyano, -C(=O)OH, C1-C6 alkyl, C1-C6 alkenyl, -O(C1-C6 alkyl), C3-C6 cycloalkyl, or C1-C6 haloalkyl. In some embodiments, R 3 R is a fluoro, chloro, cyano, -C(=O)OH, C1-C4 alkyl, C1-C4 alkenyl, -O(C1-C4 alkyl), C3-C4 cycloalkyl, or C1-C4 haloalkyl. In some embodiments, R 3 is a halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl. In some embodiments, R 3 R is fluoro, chloro, cyano, methyl, ethyl, vinyl, -OMe, -C(=O)OH, trifluoromethyl, difluoromethyl, or cyclopropyl. In some embodiments, R 3 is chloro, cyano, methyl, or ethyl. In some embodiments, R 3 is chloro or cyano. In some embodiments, R 3 is chloro. In some embodiments, R 3 It is cyano.

[0142] In some embodiments of compounds of formula (I), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), or formula (IIId), or pharmaceutically acceptable salts or solvates thereof, R 5Each of these is independently hydrogen, cyano, halogen, C1-C6 alkyl, -O(C1-C6 alkyl), C3-C6 cycloalkyl, C1-C6 haloalkyl, or -O(C1-C6 haloalkyl). In some embodiments, R 5 Each of these is independently hydrogen, cyano, halogen, C1-C6 alkyl, -O(C1-C6 alkyl), C3-C6 cycloalkyl, or C1-C6 haloalkyl. In some embodiments, R 5 Each of these is independently hydrogen, cyano, halogen, C1-C4 alkyl, -O(C1-C4 alkyl), C3-C4 cycloalkyl, or C1-C4 haloalkyl. In some embodiments, R 5 Each of these is independently hydrogen, cyano, halogen, methyl, ethyl, propyl, isopropyl, -OMe, -OEt, cyclopropyl, cyclobutyl, trifluoromethyl, or difluoromethyl. In some embodiments, R 5 Each of these is independently hydrogen, cyano, fluoro, chloro, methyl, -OMe, cyclopropyl, trifluoromethyl, or difluoromethyl. In some embodiments, R 5 Each is independently hydrogen or fluoro. In some embodiments, R 5 Each of these is hydrogen. In some embodiments, R 5 Each of these is fluoro. In some embodiments, R 5 Each of these is independently either hydrogen or a halogen.

[0143] In some embodiments of compounds of formula (I), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), or formula (IIId), or pharmaceutically acceptable salts or solvates thereof, R 4 Each of these is independently hydrogen, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C6 haloalkyl, or -O-(C1-C6 haloalkyl). In some embodiments, R 4Each of these is independently hydrogen, halogen, C1-C4 alkyl, -O-C1-C4 alkyl, C1-C4 haloalkyl, or -O-(C1-C4 haloalkyl). In some embodiments, R 4 Each is independently hydrogen, halogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, trifluoroethyl, -O-(trifluoromethyl), -O-(difluoromethyl), -O-(trifluoroethyl), -OMe, or -OEt. In some embodiments, R 4 Each of these is independently hydrogen, fluoro, chloro, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, -O-(trifluoromethyl), -OMe, or -OEt. In some embodiments, R 4 Each is independently hydrogen, fluoro, trifluoromethyl, methyl, or -OMe. In some embodiments, R 4 Each of these is independently hydrogen, fluoro, or methyl. In some embodiments, one R 4 R is fluoro, methyl, or -OMe, and the other R is 4 Each of these is hydrogen. In some embodiments, R 4 Each of these is hydrogen. In some embodiments, R 4 Each of these is independently either hydrogen or a halogen.

[0144] In some embodiments, a compound (e.g., a compound of formula (I)) is a compound of formula (IV)

[0145] [ka] It has the structure of, or a pharmaceutically acceptable salt or solvate thereof.

[0146] In some embodiments of the compound of formula (IV), or its pharmaceutically acceptable salt or solvate, Z is -S-, -N=C(R 5 )-,-C(R 5 )=N-, or -C(R5 )=C(R 5 A divalent group selected from )-. In some embodiments, Z is -S- or -C(R 5 )=C(R 5 )-. In some embodiments, Z is -N=C(R 5 )- or -C(R 5 )=N-. In some embodiments, Z is -S-. In some embodiments, Z is -C(R 5 )=C(R 5 )-. In some embodiments, Z is -C(R 5 ) = N-. In some embodiments, Z is -N = C(R 5 )-is.

[0147] In some embodiments of the compound of formula (IV), or its pharmaceutically acceptable salt or solvate, Z is a divalent group selected from -S-, -N=CH-, -CH=N-, or -CH=CH-. In some embodiments, Z is -S- or -CH=CH-. In some embodiments, Z is -N=CH- or -CH=N-. In some embodiments, Z is -S-. In some embodiments, Z is -CH=CH-. In some embodiments, Z is -CH=N-. In some embodiments, Z is -N=CH-.

[0148] In some embodiments, the compound (e.g., the compound of formula (I)) is of formula (IVa)

[0149] [ka] It has the structure of, or a pharmaceutically acceptable salt or solvate thereof.

[0150] In some embodiments, the compound (e.g., the compound of formula (I)) is of formula (IVb)

[0151] [ka] It has the structure of, or a pharmaceutically acceptable salt or solvate thereof.

[0152] In some embodiments, the compound (e.g., the compound of formula (I)) is of formula (IVc)

[0153] [ka] It has the structure of, or a pharmaceutically acceptable salt or solvate thereof.

[0154] In some embodiments, the compound (e.g., the compound of formula (I)) is of formula (IVd)

[0155] [ka] It has the structure of, or a pharmaceutically acceptable salt or solvate thereof.

[0156] In some embodiments of compounds of formula (IV), formula (IVa), formula (IVb), formula (IVc), or formula (IVd), or pharmaceutically acceptable salts or solvates thereof, R 3 R is a halogen, cyano, -C(=O)OH, C1-C6 alkyl, C1-C6 alkenyl, -O(C1-C6 alkyl), C3-C6 cycloalkyl, or C1-C6 haloalkyl. In some embodiments, R 3 R is a fluoro, chloro, cyano, -C(=O)OH, C1-C6 alkyl, C1-C6 alkenyl, -O(C1-C6 alkyl), C3-C6 cycloalkyl, or C1-C6 haloalkyl. In some embodiments, R 3 R is a fluoro, chloro, cyano, -C(=O)OH, C1-C4 alkyl, C1-C4 alkenyl, -O(C1-C4 alkyl), C3-C4 cycloalkyl, or C1-C4 haloalkyl. In some embodiments, R 3is a halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl. In some embodiments, R 3 R is fluoro, chloro, cyano, methyl, ethyl, vinyl, -OMe, -C(=O)OH, trifluoromethyl, difluoromethyl, or cyclopropyl. In some embodiments, R 3 These are chloro, cyano, methyl, or ethyl compounds.

[0157] In some embodiments of compounds of formula (IV), formula (IVa), formula (IVb), formula (IVc), or formula (IVd), or pharmaceutically acceptable salts or solvates thereof, R 5 Each of these is independently hydrogen, cyano, halogen, C1-C6 alkyl, -O(C1-C6 alkyl), C3-C6 cycloalkyl, C1-C6 haloalkyl, or -O(C1-C6 haloalkyl). In some embodiments, R 5 Each of these is independently hydrogen, cyano, halogen, C1-C6 alkyl, -O(C1-C6 alkyl), C3-C6 cycloalkyl, or C1-C6 haloalkyl. In some embodiments, R 5 Each of these is independently hydrogen, cyano, halogen, C1-C4 alkyl, -O(C1-C4 alkyl), C3-C4 cycloalkyl, or C1-C4 haloalkyl. In some embodiments, R 5 Each of these is independently hydrogen, cyano, halogen, methyl, ethyl, propyl, isopropyl, -OMe, -OEt, cyclopropyl, cyclobutyl, trifluoromethyl, or difluoromethyl. In some embodiments, R 5 Each of these is independently hydrogen, cyano, fluoro, chloro, methyl, -OMe, cyclopropyl, trifluoromethyl, or difluoromethyl. In some embodiments, R 5 Each is independently hydrogen or fluoro. In some embodiments, R 5 Each of these is hydrogen. In some embodiments, R 5 Each of these is independently either hydrogen or a halogen.

[0158] In compounds of formula (I), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), formula (IVa), formula (IVb), formula (IVc), or formula (IVd), or in pharmaceutically acceptable salts or solvates thereof, R 1 is a pyrazole, and the pyrazole is optionally selected, R 6 It is replaced by 1 to 3 groups independently selected from R. In some embodiments, R 1 It is a pyrazole.

[0159] In compounds of formula (I), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), formula (IVa), formula (IVb), formula (IVc), or formula (IVd), or in pharmaceutically acceptable salts or solvates thereof, R 1 R 6 It is optionally replaced by 1 to 3 bases independently selected from. In some embodiments, R 1 R 6 It is optionally replaced by one or two bases independently selected from. In some embodiments, R 1 is non-substitutable. In some embodiments, R 1 R 6 It is replaced by one group selected from. In some embodiments, R 1 R 6 It is replaced by two groups independently selected from R. In some embodiments, R 1 R 6 It is replaced by one or two elements selected independently of it.

[0160] In compounds of formula (I), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), formula (IVa), formula (IVb), formula (IVc), or formula (IVd), or in pharmaceutically acceptable salts or solvates thereof, R 1 This is one to three R compounds independently selected from the group consisting of methyl, ethyl, cyano, fluoro, chloro, -OMe, cyclopropyl, -CH2-cyclopropyl, trifluoromethyl, and difluoromethyl. 6 The base is optionally replaced, R 6 If bonded to a nitrogen atom, it is selected from the group consisting of methyl, ethyl, cyclopropyl, -CH2-cyclopropyl, trifluoromethyl, trifluoroethyl, and difluoromethyl. In some embodiments, R 1 This is one to two R compounds independently selected from the group consisting of methyl, cyano, fluoro, chloro, -OMe, cyclopropyl, -CH2-cyclopropyl, and difluoromethyl. 6 The base is optionally replaced, R 6 If it is bonded to a nitrogen atom, it is methyl, cyclopropyl, or -CH2-cyclopropyl.

[0161] In compounds of formula (I), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), formula (IVa), formula (IVb), formula (IVc), or formula (IVd), or in pharmaceutically acceptable salts or solvates thereof, R 1 teeth,

[0162] [ka] In some embodiments, R 1 teeth

[0163] [ka] In some embodiments, R 1 teeth

[0164] [ka] In some embodiments, R 1 teeth

[0165] [ka] And R 6 Each of these is independently fluoro, chloro, cyano, cyclopropyl, -CH2-cyclopropyl, or methyl, and R 6 If it is bonded to a nitrogen atom, it is methyl, cyclopropyl, or -CH2-cyclopropyl. In some embodiments, R 1 teeth

[0166] [ka] And R 6 Each of these is independently fluoro, chloro, cyano, or methyl, and R 6 If it is bonded to a nitrogen atom, it is methyl. In some embodiments, R 1 teeth

[0167] [ka] In some embodiments, R 1 teeth

[0168] [ka] And R 6 R is fluoro, chloro, cyano, cyclopropyl, -CH2-cyclopropyl, or methyl. In some embodiments, R 1 teeth

[0169] [ka] And R 6 is fluoro, chloro, cyano, or methyl. In some embodiments, R 1 teeth

[0170] [ka] In some embodiments, R 1 teeth

[0171] [ka] And R 6 R is methyl, cyclopropyl, or -CH2-cyclopropyl. In some embodiments, R 1 teeth

[0172] [ka] In some embodiments, R 1 teeth

[0173] [ka] In some embodiments, R 1 teeth

[0174] [ka] In some embodiments, R 1 teeth

[0175] [ka] In some embodiments, R 1 teeth

[0176] [ka] In some embodiments, R 1 teeth

[0177] [ka] In some embodiments, R 1 teeth

[0178] [ka] That is the case.

[0179] In some embodiments, the compound (for example, the compound of formula (I)) is of formula (VI)

[0180] [ka] It has the structure of, or a pharmaceutically acceptable salt or solvate thereof.

[0181] In some embodiments, a compound (e.g., a compound of formula (I)) is a compound of formula (VII)

[0182] [ka] It has the structure of, or a pharmaceutically acceptable salt or solvate thereof.

[0183] In some embodiments of compounds of formula (VI) or formula (VII), or pharmaceutically acceptable salts or solvates thereof, R 3 R is a halogen, cyano, -C(=O)OH, C1-C6 alkyl, C1-C6 alkenyl, -O(C1-C6 alkyl), C3-C6 cycloalkyl, or C1-C6 haloalkyl. In some embodiments, R 3R is a fluoro, chloro, cyano, -C(=O)OH, C1-C6 alkyl, C1-C6 alkenyl, -O(C1-C6 alkyl), C3-C6 cycloalkyl, or C1-C6 haloalkyl. In some embodiments, R 3 R is a fluoro, chloro, cyano, -C(=O)OH, C1-C4 alkyl, C1-C4 alkenyl, -O(C1-C4 alkyl), C3-C4 cycloalkyl, or C1-C4 haloalkyl. In some embodiments, R 3 is a halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl. In some embodiments, R 3 R is fluoro, chloro, cyano, methyl, ethyl, vinyl, -OMe, -C(=O)OH, trifluoromethyl, difluoromethyl, or cyclopropyl. In some embodiments, R 3 These are chloro, cyano, methyl, or ethyl compounds.

[0184] In some embodiments of compounds of formula (VI) or formula (VII), or pharmaceutically acceptable salts or solvates thereof, R 5 Each of these is independently hydrogen, cyano, halogen, C1-C6 alkyl, -O(C1-C6 alkyl), C3-C6 cycloalkyl, C1-C6 haloalkyl, or -O(C1-C6 haloalkyl). In some embodiments, R 5 Each of these is independently hydrogen, cyano, halogen, C1-C6 alkyl, -O(C1-C6 alkyl), C3-C6 cycloalkyl, or C1-C6 haloalkyl. In some embodiments, R 5 Each of these is independently hydrogen, cyano, halogen, C1-C4 alkyl, -O(C1-C4 alkyl), C3-C4 cycloalkyl, or C1-C4 haloalkyl. In some embodiments, R 5 Each of these is independently hydrogen, cyano, halogen, methyl, ethyl, propyl, isopropyl, -OMe, -OEt, cyclopropyl, cyclobutyl, trifluoromethyl, or difluoromethyl. In some embodiments, R5 Each of these is independently hydrogen, cyano, fluoro, chloro, methyl, -OMe, cyclopropyl, trifluoromethyl, or difluoromethyl. In some embodiments, R 5 Each is independently hydrogen or fluoro. In some embodiments, R 5 Each of these is hydrogen.

[0185] In some embodiments of compounds of formula (VI) or formula (VII), or pharmaceutically acceptable salts or solvates thereof, R 4 Each of these is independently hydrogen, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C6 haloalkyl, or -O-(C1-C6 haloalkyl). In some embodiments, R 4 Each of these is independently hydrogen, halogen, C1-C4 alkyl, -O-C1-C4 alkyl, C1-C4 haloalkyl, or -O-(C1-C4 haloalkyl). In some embodiments, R 4 Each is independently hydrogen, halogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, trifluoroethyl, -O-(trifluoromethyl), -O-(difluoromethyl), -O-(trifluoroethyl), -OMe, or -OEt. In some embodiments, R 4 Each of these is independently hydrogen, fluoro, chloro, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, -O-(trifluoromethyl), -OMe, or -OEt. In some embodiments, R 4 Each is independently hydrogen, fluoro, trifluoromethyl, methyl, or -OMe. In some embodiments, R 4 Each of these is independently hydrogen, fluoro, or methyl. In some embodiments, one R 4 R is fluoro, methyl, or -OMe, and the other R is 4 Each of these is hydrogen. In some embodiments, R 4 Each of these is hydrogen. In some embodiments, R4 is independently hydrogen or halogen, respectively.

[0186] In some embodiments of the compound of formula (VI) or formula (VII), or a pharmaceutically acceptable salt or solvate thereof, R 3 is halogen, cyano, or C1-C6 alkyl, R 4 is independently hydrogen or halogen, respectively, R 5 is independently hydrogen or halogen, respectively, R 6 is independently selected from the group consisting of halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, -CH2-(C 3-6 cycloalkyl), and C1-C6 haloalkyl, R 7 is hydrogen or C 1-6 alkyl, R 8 is C1-C 10 alkyl, C1-C 10 heteroalkyl, C3-C 12 cycloalkyl, or 3- to 15-membered heterocycloalkyl, and the alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with 1 to 6 groups independently selected from oxo and R 11 ; or, one R bonded to the same nitrogen atom and one R 7 together form a 3- to 15-membered heterocycloalkyl optionally substituted with 1 to 6 groups independently selected from oxo and R 8 ; and 11 11 11 R 11 is independently halogen, hydroxy, amino, cyano, -S(=O)2(R 13 ), -N(R 12 )S(=O)2(R 13 ), -S(=O)(R 13 ), -N(R 12 )S(=O)(R 13 ), -C(=O)R13 , -N(R 12 )C(=O)R 13 , C1-C6 alkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein heteroaryl is optionally substituted with 1 to 4 groups independently selected from R 14 , and alkyl, haloalkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with oxo and 1 to 4 groups independently selected from R 14 , alternatively, two Rs bonded to the same carbon or nitrogen atom are taken together to form C3-C6 cycloalkyl or 3- to 6-membered heterocycloalkyl, and the cycloalkyl and heterocycloalkyl are optionally substituted with 1 to 4 groups independently selected from oxo and R 11 , 14 , R 12 is independently hydrogen or C1-C6 alkyl, R 13 is independently hydroxy, amino, C1-C6 alkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or C1-C6 haloalkyl, R 14 is independently cyano, amino, hydroxy, -C(=O)OR 12 , -C(=O)N(R 12 )2, C1-C6 alkyl, -O(C1-C6 alkyl), or -NR 12 (C1-C6 alkyl), and the alkyls are each optionally substituted with 1 to 2 hydroxy groups.

[0187] In some embodiments, the compound (e.g., a compound of formula (I)) is of formula (VIa)

[0188]

Chemical formula

[0189] In some embodiments, the compound (for example, the compound of formula (I)) is of formula (VIIa)

[0190] [ka] Having the structure of, or a pharmaceutically acceptable salt or solvate thereof, R 3 These are halogens, cyanos, -C(=O)OH, -C(=O)O(C1-C6 alkyl), C1-C6 alkyl, C1-C6 alkenyl, -O(C1-C6 alkyl), C3-C6 cycloalkyl, or C1-C6 haloalkyl. R 5 Each of these is independently hydrogen, cyano, halogen, C1-C6 alkyl, -O(C1-C6 alkyl), C3-C6 cycloalkyl, C1-C6 haloalkyl, or -O(C1-C6 haloalkyl), R 6 These include halogen, hydroxy, cyano, amino, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C3-C6 cycloalkyl, and -CH2-(C 3-6 Cycloalkyl), -O-(C 3-6selected from the group consisting of cycloalkyl), C1-C6 haloalkyl, and -O(C1-C6 haloalkyl), R 7 is hydrogen or C1-C6 alkyl, and the alkyl is optionally substituted with 1 to 2 hydroxy groups, R 8 is hydrogen, C1-C 10 alkyl, C1-C 10 heteroalkyl, C1-C 10 alkenyl, C1-C 10 alkynyl, C3-C 12 cycloalkyl, 3- to 15-member heterocycloalkyl, C6-C 10 aryl, or 5- to 10-member heteroaryl, aryl and heteroaryl are optionally substituted with 1 to 6 groups independently selected from R 11 alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with oxo and 1 to 6 groups independently selected from R 11 and, alternatively, one R 7 and one R 8 bonded to the same nitrogen atom are combined to form a 3- to 15-member heterocycloalkyl optionally substituted with oxo and 1 to 6 groups independently selected from R 11 and, R 11 are each independently halogen, hydroxy, amino, cyano, -S(=O)2(R 13 ), -N(R 12 )S(=O)2(R 13 ), -S(=O)(R 13 ), -N(R 12 )S(=O)(R 13 ), -C(=O)R 13 ), -N(R 12 )C(=O)R 13, C1-C6 alkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-10 member heterocycloalkyl, C6-C 10 Selected from the group consisting of aryls and 5-10 member heteroaryls, aryls and heteroaryls are R 14 Optionally substituted with 1 to 4 groups independently selected from, with alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, and heterocycloalkyl groups being optional, as well as oxo and R 14 It is replaced by 1 to 4 elements independently selected from, Alternatively, two R atoms bonded to the same carbon or nitrogen atom 11 These combine to form a C3-C6 cycloalkyl or a 3-6 member heterocycloalkyl, and the cycloalkyl and heterocycloalkyl are oxo and R 14 It is optionally replaced by 1 to 4 bases independently selected from, R 12 Each of these is independently hydrogen or a C1-C6 alkyl group. R 13 Each of these is independently a hydroxyl, amino, C1-C6 alkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 haloalkyl, C3-C6 cycloalkyl, or a 3- to 6-membered heterocycloalkyl. R 14 These are independently cyano, amino, hydroxy, and -C(=O)OR 12 -C(=O)N(R 12 )2, C1-C6 alkyl, -O(C1-C6 alkyl), -NR 12 The alkyl group is (C1-C6 alkyl), aryl, heteroaryl, C3-C6 cycloalkyl, or a 3- to 6-membered heterocycloalkyl, and each alkyl group is optionally substituted with 1 to 2 hydroxyl groups.

[0191] In some embodiments of compounds of formula (VI), formula (VII), formula (VIa), or formula (VIIa), or pharmaceutically acceptable salts or solvates thereof, R 3 R is a halogen, cyano, -C(=O)OH, C1-C6 alkyl, C1-C6 alkenyl, -O(C1-C6 alkyl), C3-C6 cycloalkyl, or C1-C6 haloalkyl. In some embodiments, R 3 R is a fluoro, chloro, cyano, -C(=O)OH, C1-C6 alkyl, C1-C6 alkenyl, -O(C1-C6 alkyl), C3-C6 cycloalkyl, or C1-C6 haloalkyl. In some embodiments, R 3 R is a fluoro, chloro, cyano, -C(=O)OH, C1-C4 alkyl, C1-C4 alkenyl, -O(C1-C4 alkyl), C3-C4 cycloalkyl, or C1-C4 haloalkyl. In some embodiments, R 3 is a halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl. In some embodiments, R 3 R is fluoro, chloro, cyano, methyl, ethyl, vinyl, -OMe, -C(=O)OH, trifluoromethyl, difluoromethyl, or cyclopropyl. In some embodiments, R 3 These are chloro, cyano, methyl, or ethyl compounds.

[0192] In some embodiments of compounds of formula (VI), formula (VII), formula (VIa), or formula (VIIa), or pharmaceutically acceptable salts or solvates thereof, R 5 Each of these is independently hydrogen, cyano, halogen, C1-C6 alkyl, -O(C1-C6 alkyl), C3-C6 cycloalkyl, C1-C6 haloalkyl, or -O(C1-C6 haloalkyl). In some embodiments, R 5 Each of these is independently hydrogen, cyano, halogen, C1-C6 alkyl, -O(C1-C6 alkyl), C3-C6 cycloalkyl, or C1-C6 haloalkyl. In some embodiments, R 5Each of these is independently hydrogen, cyano, halogen, C1-C4 alkyl, -O(C1-C4 alkyl), C3-C4 cycloalkyl, or C1-C4 haloalkyl. In some embodiments, R 5 Each of these is independently hydrogen, cyano, halogen, methyl, ethyl, propyl, isopropyl, -OMe, -OEt, cyclopropyl, cyclobutyl, trifluoromethyl, or difluoromethyl. In some embodiments, R 5 Each of these is independently hydrogen, cyano, fluoro, chloro, methyl, -OMe, cyclopropyl, trifluoromethyl, or difluoromethyl. In some embodiments, R 5 Each is independently hydrogen or fluoro. In some embodiments, R 5 Each is independently hydrogen or halogen. In some embodiments, R 5 Each of these is hydrogen.

[0193] In some embodiments of compounds of formula (I), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), formula (IVa), formula (IVb), formula (IVc), formula (IVd), formula (VI), formula (VIa), or formula (VIIa), or pharmaceutically acceptable salts or solvates thereof, R 3 R is a halogen, cyano, -C(=O)OH, -C(=O)O(C1-C6 alkyl), C1-C6 alkyl, C1-C6 alkenyl, -O(C1-C6 alkyl), C3-C6 cycloalkyl, or C1-C6 haloalkyl. In some embodiments, R 3 is a halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl. In some embodiments, R 3 is a halogen, cyano, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, R 3 is a halogen, cyano, or C1-C6 alkyl. In some embodiments, R 3R is chloro, fluoro, cyano, -C(=O)OH, -C(=O)O(C1-C6 alkyl), C1-C6 alkyl, C1-C6 alkenyl, -O(C1-C6 alkyl), C3-C6 cycloalkyl, or C1-C6 haloalkyl. In some embodiments, R 3 R is a halogen, cyano, -C(=O)OH, -C(=O)O(C1-C4 alkyl), C1-C4 alkyl, C1-C4 alkenyl, -O(C1-C4 alkyl), C3-C4 cycloalkyl, or C1-C4 haloalkyl. In some embodiments, R 3 R is a chloro, fluoro, cyano, -C(=O)OH, C1-C4 alkyl, C1-C4 alkenyl, -O(C1-C4 alkyl), C3-C4 cycloalkyl, or C1-C4 haloalkyl. In some embodiments, R 3 R is fluoro, chloro, cyano, methyl, ethyl, vinyl, -OMe, -C(=O)OH, trifluoromethyl, difluoromethyl, or cyclopropyl. In some embodiments, R 3 is chloro, cyano, methyl, or ethyl. In some embodiments, R 3 is chloro. In some embodiments, R 3 is cyano. In some embodiments, R 3 is methyl. In some embodiments, R 3 is ethyl. In some embodiments, R 3 It is vinyl. In some embodiments, R 3 is -OMe. In some embodiments, R 3 It is cyclopropyl.

[0194] In some embodiments of compounds of formula (I), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), formula (IVa), formula (IVb), formula (IVc), formula (IVd), formula (VI), formula (VIa), formula (VII), or formula (VIIa), or pharmaceutically acceptable salts or solvates thereof, R6 These are, independently, halogen, hydroxy, cyano, amino, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C3-C6 cycloalkyl, and -CH2-(C 3-6 Cycloalkyl), -O-(C 3-6 Selected from the group consisting of cycloalkyl, C1-C6 haloalkyl, and -O(C1-C6 haloalkyl), R 6 If it is bonded to a nitrogen atom, it is C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C3-C6 cycloalkyl, -CH2-(C 3-6 Selected from the group consisting of cycloalkyl and C1-C6 haloalkyl. In some embodiments, R 6 These are, independently, halogen, hydroxy, cyano, amino, C1-C6 alkyl, C1-C6 hydroxyalkyl, -O(C1-C6 alkyl), C3-C6 cycloalkyl, and -CH2-(C 3-6 Selected from the group consisting of cycloalkyl, C1-C6 haloalkyl, and -O(C1-C6 haloalkyl), R 6 If it is bonded to a nitrogen atom, it is C1-C6 alkyl, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, -CH2-(C 3-6 Selected from the group consisting of cycloalkyl and C1-C6 haloalkyl. In some embodiments, R 6 These are, independently, halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, and -CH2-(C 3-6 Selected from the group consisting of cycloalkyl and C1-C6 haloalkyl, R 6 If it is bonded to a nitrogen atom, it is a C1-C6 alkyl, C3-C6 cycloalkyl, -CH2-(C 3-6 Selected from the group consisting of cycloalkyl and C1-C6 haloalkyl groups.

[0195] In some embodiments of compounds of formula (I), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), formula (IVa), formula (IVb), formula (IVc), formula (IVd), formula (VI), formula (VIa), formula (VII), or formula (VIIa), or pharmaceutically acceptable salts or solvates thereof, R 6 Each of these is independently selected from the group consisting of halogen, hydroxyl, cyano, C1-C4 alkyl, -O(C1-C4 alkyl), -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C3-C4 cycloalkyl, C1-C4 haloalkyl, and -O(C1-C4 haloalkyl), R 6 If bonded to a nitrogen atom, it is selected from the group consisting of C1-C4 alkyl, C3-C4 cycloalkyl, and C1-C4 haloalkyl. In some embodiments, R 6 Each of these is independently selected from the group consisting of halogen, hydroxyl, cyano, C1-C4 alkyl, -O(C1-C4 alkyl), C3-C4 cycloalkyl, and C1-C4 haloalkyl, R 6 If bonded to a nitrogen atom, it is selected from the group consisting of C1-C4 alkyl, C3-C4 cycloalkyl, and C1-C4 haloalkyl. In some embodiments, R 6 These are, independently, halogen, cyano, and C. 1-6 Alkyl, C 1-6 Fluoroalkyl, C 3-6 Cycloalkyl, or -CH2-(C 3-6 It is a cycloalkyl, and R 6 If it is bonded to a nitrogen atom, then it is C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 3-6 Cycloalkyl, or -CH2-(C 3-6 It is a cycloalkyl. In some embodiments, R 6 Each is independently selected from the group consisting of methyl, ethyl, cyano, fluoro, chloro, -OMe, trifluoromethyl, and difluoromethyl, R 6When bonded to a nitrogen atom, R is selected from the group consisting of methyl, ethyl, trifluoromethyl, and difluoromethyl. In some embodiments, R 6 Each of these is independently fluoro, chloro, cyano, cyclopropyl, -CH2-cyclopropyl, or methyl, and R 6 If bonded to a nitrogen atom, it is methyl, cyclopropyl, or -CH2-cyclopropyl. In some embodiments, R 6 Each is independently selected from the group consisting of methyl, cyano, fluoro, -OMe, and difluoromethyl, R 6 If it is bonded to a nitrogen atom, it is methyl. In some embodiments, R 6 Each of these is methyl. In some embodiments, R 6 These are methyl or fluoro, respectively, and R 6 If it is bonded to a nitrogen atom, it is methyl. In some embodiments, R 6 Each of these is fluoro. In some embodiments, R 6 These are each chloroforms.

[0196] In some embodiments of compounds of formula (I), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), formula (IVa), formula (IVb), formula (IVc), formula (IVd), formula (VI), formula (VIa), formula (VII), or formula (VIIa), or pharmaceutically acceptable salts or solvates thereof, R 7 Each is independently hydrogen or a C1-C6 alkyl group. In some embodiments, R 7 Each is independently hydrogen or a C1-C6 alkyl group, and the alkyl group is optionally substituted with 1-2 hydroxyl groups, R 8 is hydrogen, C1-C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Alkenyl, C1-C 10 Alkinyl, C3-C12 Cycloalkyl, 3-15 member heterocycloalkyl, C6-C 10 It is an aryl or a 5-10 member heteroaryl, and the aryl and heteroaryl are optional, R 11 Substituted with 1 to 6 groups independently selected from, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl groups are optional, oxo and R 11 Substituted by 1 to 6 groups independently selected from the same nitrogen atom, or by one R bonded to the same nitrogen atom. 7 and one R 8 These combine to form oxo and R 11 A 3- to 15-membered heterocycloalkyl group is formed by optionally substituting 1 to 6 groups independently selected from the group. In some embodiments, R 7 Each of these is hydrogen. In some embodiments, at least one R 7 is hydrogen. In some embodiments, one R 7 is hydrogen. In some embodiments, R 7 Each of these is a C1-C6 alkyl group, and the alkyl group is optionally substituted with 1-2 hydroxyl groups. In some embodiments, at least one R 7 is a C1-C6 alkyl group, and the alkyl group is optionally substituted with 1-2 hydroxyl groups. In some embodiments, R 7 Each of these is a C1-C4 alkyl group. In some embodiments, at least one R 7 is a C1-C4 alkyl group. In some embodiments, R 7 Each of these is a C1-C4 alkyl group, and the alkyl group is optionally substituted with one hydroxyl group. In some embodiments, at least one R 7 is a C1-C4 alkyl group, and the alkyl group is optionally substituted with 1-2 hydroxyl groups. In some embodiments, at least one R 7 is methyl. In some embodiments, at least one R 7It is 2-hydroxyethyl. In some embodiments, one R 7 is methyl. In some embodiments, one R 7 It is 2-hydroxyethyl.

[0197] In some embodiments of compounds of formula (I), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), formula (IVa), formula (IVb), formula (IVc), formula (IVd), formula (VI), formula (VIa), formula (VII), or formula (VIIa), or pharmaceutically acceptable salts or solvates thereof, R 8 is hydrogen, C1-C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Alkenyl, C1-C 10 Alkinyl, C3-C 12 Cycloalkyl, 3-15 member heterocycloalkyl, C6-C 10 It is an aryl or a 5-10 member heteroaryl, and the aryl and heteroaryl are optional, R 11 Substituted with 1 to 6 groups independently selected from, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl groups are optional, oxo and R 11 It is replaced by 1 to 6 groups independently selected from R. In some embodiments, R 8 is hydrogen, C1-C 10 Alkyl, C1-C 10 Heteroalkyl, C3-C 12 Cycloalkyl, 3-15 member heterocycloalkyl, C6-C 10 It is an aryl or a 5- to 10-membered heteroaryl. In some embodiments, R 8 is hydrogen, C1-C 10 Alkyl, C1-C 10 Heteroalkyl, C3-C 12 It is a cycloalkyl or a 3- to 15-membered heterocycloalkyl. In some embodiments, R 8 C1-C10 Alkyl, C1-C 10 Heteroalkyl, C3-C 12 Cycloalkyl, or 3-15 member heterocycloalkyl, and alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl are oxo and R 11 It is optionally replaced by 1 to 6 groups independently selected from. In some embodiments, R 8 is hydrogen, C1-C 10 Alkyl, C3-C 12 It is a cycloalkyl or a 3- to 15-membered heterocycloalkyl. In some embodiments, R 8 C1-C 10 Alkyl, C3-C 12 A cycloalkyl or a 3- to 15-membered heterocycloalkyl, wherein alkyl, cycloalkyl, or heterocycloalkyl are oxo and R 11 It is optionally replaced by 1 to 6 groups independently selected from. In some embodiments, R 8 These are hydrogen, C1-C6 alkyl, and C3-C 10 It is a cycloalkyl or a 3- to 12-membered heterocycloalkyl. In some embodiments, R 8 C1-C6 alkyl, C3-C 10 A cycloalkyl or a 3- to 12-membered heterocycloalkyl, wherein alkyl, cycloalkyl, or heterocycloalkyl are oxo and R 11 It is optionally replaced by 1 to 6 groups independently selected from. In some embodiments, R 8 is hydrogen or a C1-C6 alkyl group. In some embodiments, R 8 C1-C 10 It is heteroalkyl. In some embodiments, R 8 C1-C 10 It is alkyl. In some embodiments, R 8 is a C1-C6 alkyl group. In some embodiments, R 8 C3-C 12It is a cycloalkyl or a 3- to 15-membered heterocycloalkyl. In some embodiments, R 8 C3-C 12 A cycloalkyl or a 3-15 member heterocycloalkyl, where the cycloalkyl or heterocycloalkyl is oxo and R 11 It is optionally replaced by 1 to 6 groups independently selected from. In some embodiments, R 8 C3-C 12 It is cycloalkyl. In some embodiments, R 8 R is a 3- to 15-membered heterocycloalkyl. In some embodiments, R 8 C3-C 10 It is a cycloalkyl or a 3- to 12-membered heterocycloalkyl. In some embodiments, R 8 C3-C 10 A cycloalkyl or a 3- to 12-membered heterocycloalkyl, where the cycloalkyl or heterocycloalkyl is oxo and R 11 It is optionally replaced by 1 to 6 groups independently selected from. In some embodiments, R 8 C3-C 10 It is cycloalkyl. In some embodiments, R 8 C3-C 10 It is a cycloalkyl, and cycloalkyl is oxo and R 11 It is optionally replaced by 1 to 6 groups independently selected from. In some embodiments, R 8 R is a 3- to 12-membered heterocycloalkyl. In some embodiments, R 8 These are 3-12 member heterocycloalkyls, and heterocycloalkyls are oxo and R 11 It is optionally replaced by 1 to 6 groups independently selected from. In some embodiments, R 8 C1-C 10 Alkyl, monocyclic C3-C 12 Cycloalkyl, condensed bicyclic C5-C 12 Cycloalkyl, cross-linked bicyclic C5-C 12 Cycloalkyl, spirocyclic, bicyclic C5-C12 These are cycloalkyl groups, monocyclic 3-15 member heterocycloalkyl groups, condensed bicyclic 5-15 member heterocycloalkyl groups, cross-linked bicyclic 5-15 member heterocycloalkyl groups, or spirocyclic bicyclic 5-15 member heterocycloalkyl groups. In some embodiments, R 8 This is a single-ring C3-C 10 Cycloalkyl, condensed bicyclic C5-C 10 Cycloalkyl, cross-linked bicyclic C5-C 10 Cycloalkyl, spirocyclic, bicyclic C5-C 10 These are cycloalkyl groups, monocyclic 3-12 member heterocycloalkyl groups, condensed bicyclic 5-12 member heterocycloalkyl groups, cross-linked bicyclic 5-12 member heterocycloalkyl groups, or spirocyclic bicyclic 5-12 member heterocycloalkyl groups. In some embodiments, R 8 This is a single-ring C3-C 10 Cycloalkyl, condensed bicyclic C5-C 10 Cycloalkyl, cross-linked bicyclic C5-C 10 Cycloalkyl, spirocyclic, bicyclic C5-C 10 The cycloalkyl group is a monocyclic 3-12 member heterocycloalkyl group, a condensed bicyclic 5-12 member heterocycloalkyl group, a cross-linked bicyclic 5-12 member heterocycloalkyl group, or a spirocyclic bicyclic 5-12 member heterocycloalkyl group, and the cycloalkyl group or heterocycloalkyl group is oxo and R 11 It is optionally replaced by 1 to 6 groups independently selected from. In some embodiments, R 8 C1-C 10 Alkyl, monocyclic C3-C 10 Cycloalkyl, condensed bicyclic C5-C 10 Cycloalkyl, cross-linked bicyclic C5-C 10 Cycloalkyl, spirocyclic, bicyclic C5-C 10 These are cycloalkyl groups, monocyclic 3-12 member heterocycloalkyl groups, condensed bicyclic 5-12 member heterocycloalkyl groups, cross-linked bicyclic 5-12 member heterocycloalkyl groups, or spirocyclic bicyclic 5-12 member heterocycloalkyl groups. In some embodiments, R 8 This is a single-ring C3-C 10Cycloalkyl, condensed bicyclic C5-C 10 Cycloalkyl, cross-linked bicyclic C5-C 10 Cycloalkyl, spirocyclic, bicyclic C5-C 10 These are cycloalkyl groups, monocyclic 3-12 member heterocycloalkyl groups, condensed bicyclic 5-12 member heterocycloalkyl groups, cross-linked bicyclic 5-12 member heterocycloalkyl groups, or spirocyclic bicyclic 5-12 member heterocycloalkyl groups. In some embodiments, R 8 It is a single ring C3-C 10 It is cycloalkyl. In some embodiments, R 8 R is a monocyclic 5-12 member heterocycloalkyl. In some embodiments, R 8 R is a monocyclic C3-C6 cycloalkyl. In some embodiments, R 8 R is a monocyclic 5-6 member heterocycloalkyl. In some embodiments, R 8 This is a condensed biringular C5-C 12 Cycloalkyl, cross-linked bicyclic C5-C 12 Cycloalkyl, spirocyclic, bicyclic C5-C 12 These are cycloalkyl groups, condensed bicyclic 5-15 member heterocycloalkyl groups, cross-linked bicyclic 5-15 member heterocycloalkyl groups, or spirocyclic bicyclic 5-15 member heterocycloalkyl groups. In some embodiments, R 8 This is a condensed biringular C5-C 10 Cycloalkyl, cross-linked bicyclic C5-C 10 Cycloalkyl, spirocyclic, bicyclic C5-C 10 These are cycloalkyl groups, condensed bicyclic 5-12 member heterocycloalkyl groups, cross-linked bicyclic 5-12 member heterocycloalkyl groups, or spirocyclic bicyclic 5-12 member heterocycloalkyl groups. In some embodiments, R 8 This is a condensed biringular C5-C 10 Cycloalkyl, cross-linked bicyclic C5-C 10 Cycloalkyl, spirocyclic, bicyclic C5-C 10The cycloalkyl group is a condensed bicyclic 5-12 member heterocycloalkyl group, a cross-linked bicyclic 5-12 member heterocycloalkyl group, or a spirocyclic bicyclic 5-12 member heterocycloalkyl group, and the cycloalkyl group or heterocycloalkyl group is oxo and R 11 It is optionally replaced by 1 to 6 groups independently selected from. In some embodiments, R 8 This is a condensed biringular C5-C 12 Cycloalkyl, cross-linked bicyclic C5-C 12 The molecules are cycloalkyl, condensed bicyclic 5-15 member heterocycloalkyl, or crosslinked bicyclic 5-15 member heterocycloalkyl. In some embodiments, R 8 This is a condensed biringular C5-C 12 Cycloalkyl, cross-linked bicyclic C5-C 12 The cycloalkyl group is a condensed bicyclic 5-15 member heterocycloalkyl group, or a cross-linked bicyclic 5-15 member heterocycloalkyl group, and the cycloalkyl group or heterocycloalkyl group is oxo and R 11 It is optionally replaced by 1 to 6 groups independently selected from. In some embodiments, R 8 This is a condensed biringular C5-C 10 Cycloalkyl, cross-linked bicyclic C5-C 10 Cycloalkyl, condensed bicyclic 5-12 member heterocycloalkyl, or cross-linked bicyclic 5-12 member hetero It is cycloalkyl. In some embodiments, R 8 This is a condensed biringular C5-C 10 Cycloalkyl, cross-linked bicyclic C5-C 10 The cycloalkyl group is a condensed bicyclic 5-12 member heterocycloalkyl group, or a cross-linked bicyclic 5-12 member heterocycloalkyl group, and the cycloalkyl group or heterocycloalkyl group is oxo and R 11 It is optionally replaced by 1 to 6 groups independently selected from. In some embodiments, R 8 This is a spiro-ring bi-ring C5-C 12 It is a cycloalkyl or a 5-15 membered heterocycloalkyl with a spirocyclic or bicyclic structure. In some embodiments, R 8This is a spiro-ring bi-ring C5-C 10 It is a cycloalkyl or a spirocyclic bicyclic heterocycloalkyl with 5 to 12 members. In some embodiments, R 8 This is a spiro-ring bi-ring C5-C 10 A cycloalkyl or a spirocyclic bicyclic heterocycloalkyl with 5 to 12 members, where the cycloalkyl or heterocycloalkyl is oxo and R 11 It is optionally replaced by 1 to 6 groups independently selected from. In some embodiments, R 8 It is methyl.

[0198] In some embodiments of compounds of formula (I), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), formula (IVa), formula (IVb), formula (IVc), formula (IVd), formula (VI), formula (VIa), formula (VII), or formula (VIIa), or pharmaceutically acceptable salts or solvates thereof, R 8 , oxo and R 11 It is optionally replaced by 1 to 6 groups independently selected from. In some embodiments, R 8 is, R 11 It is optionally replaced by 1 to 6 groups independently selected from. In some embodiments, R 8 , oxo and R 11 It is optionally replaced by 1 to 4 bases independently selected from. In some embodiments, R 8 is, R 11 It is optionally replaced by 1 to 4 bases independently selected from. In some embodiments, R 8 , oxo and R 11 It is optionally replaced by one or two bases independently selected from. In some embodiments, R 8 is, R 11 It is optionally replaced by one or two bases independently selected from. In some embodiments, R 8 is non-substitutable. In some embodiments, R 8, oxo and R 11 It is replaced by at least one group selected from. In some embodiments, R 8 is, R 11 It is replaced by at least one group selected from. In some embodiments, R 8 , oxo and R 11 It is replaced by 1 to 6 groups independently selected from R. In some embodiments, R 8 is, R 11 It is replaced by 1 to 6 groups independently selected from R. In some embodiments, R 8 , oxo and R 11 It is replaced by 1 to 4 groups independently selected from R. In some embodiments, R 8 is, R 11 It is replaced by 1 to 4 groups independently selected from R. In some embodiments, R 8 , oxo and R 11 It is replaced by one or two groups independently selected from R. In some embodiments, R 8 is, R 11 It is replaced by one or two elements selected independently of it.

[0199] In some embodiments of compounds of formula (I), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), formula (IVa), formula (IVb), formula (IVc), formula (IVd), formula (VI), formula (VIa), formula (VII), or formula (VIIa), or pharmaceutically acceptable salts or solvates thereof, one R bonded to the same nitrogen atom 7 and one R 8 These are integrated into oxo and R 11 Forms a 3- to 15-membered heterocycloalkyl group optionally substituted with 1 to 6 groups independently selected from the group. In some embodiments, one R bonded to the same nitrogen atom 7 and one R 8 These combine to form oxo and R 11Forms a 3- to 12-membered heterocycloalkyl group optionally substituted with 1 to 6 groups independently selected from the group. In some embodiments, one R bonded to the same nitrogen atom 7 and one R 8 These combine to form oxo and R 11 Forms a 3- to 12-membered heterocycloalkyl group optionally substituted with 1 to 4 groups independently selected from the group. In some embodiments, one R bonded to the same nitrogen atom 7 and one R 8 These combine to form oxo and R 11 Forms a 3- to 12-membered heterocycloalkyl group optionally substituted with 1-2 groups independently selected from the group. In some embodiments, one R bonded to the same nitrogen atom 7 and one R 8 These combine to form a condensed bicyclic 5-15 member heterocycloalkyl, a bridging bicyclic 5-15 member heterocycloalkyl, or a spirocyclic bicyclic 5-15 member heterocycloalkyl. In some embodiments, one R bonded to the same nitrogen atom 7 and one R 8 These combine to form a condensed bicyclic 5-12 member heterocycloalkyl, a bridging bicyclic 5-12 member heterocycloalkyl, or a spirocyclic bicyclic 5-12 member heterocycloalkyl. In some embodiments, one R bonded to the same nitrogen atom 7 and one R 8 These combine to form a condensed bicyclic 5-12 member heterocycloalkyl, a cross-linked bicyclic 5-12 member heterocycloalkyl, or a spirocyclic bicyclic 5-12 member heterocycloalkyl, and the heterocycloalkyl is oxo and R 11 It is optionally substituted with 1 to 6 groups independently selected from the nitrogen atom. In some embodiments, one R bonded to the same nitrogen atom 7 and one R 8 These combine to form a bridging bicyclic 5-15 member heterocycloalkyl or a spirocyclic bicyclic 5-15 member heterocycloalkyl. In some embodiments, one R bonded to the same nitrogen atom 7and one R 8 These combine to form a crosslinked bicyclic 5-15 member heterocycloalkyl or a spirocyclic bicyclic 5-15 member heterocycloalkyl, and the heterocycloalkyl is oxo and R 11 It is optionally substituted with 1 to 6 groups independently selected from the nitrogen atom. In some embodiments, one R bonded to the same nitrogen atom 7 and one R 8 These combine to form a bridging bicyclic 5-12 member heterocycloalkyl or a spirocyclic bicyclic 5-12 member heterocycloalkyl. In some embodiments, one R bonded to the same nitrogen atom 7 and one R 8 These combine to form a crosslinked bicyclic 5-12 member heterocycloalkyl or a spirocyclic bicyclic 5-12 member heterocycloalkyl, and the heterocycloalkyl is oxo and R 11 It is optionally substituted with 1 to 6 groups independently selected from the nitrogen atom. In some embodiments, one R bonded to the same nitrogen atom 7 and one R 8 These combine to form a condensed bicyclic 5-15 member heterocycloalkyl group. In some embodiments, one R bonded to the same nitrogen atom 7 and one R 8 These combine to form a condensed bicyclic 5-12 member heterocycloalkyl group. In some embodiments, one R bonded to the same nitrogen atom 7 and one R 8 These combine to form a condensed bicyclic 5-12 member heterocycloalkyl, and the heterocycloalkyl is composed of oxo and R 11 It is optionally substituted with 1 to 6 groups independently selected from the nitrogen atom. In some embodiments, one R bonded to the same nitrogen atom 7 and one R 8 These combine to form a bridged bicyclic 5-15 member heterocycloalkyl group. In some embodiments, one R bonded to the same nitrogen atom 7 and one R 8These combine to form a bridged bicyclic 5-12 member heterocycloalkyl group. In some embodiments, one R bonded to the same nitrogen atom 7 and one R 8 These combine to form a crosslinked bicyclic 5-12 member heterocycloalkyl group, and the heterocycloalkyl group consists of oxo and R 11 It is optionally substituted with 1 to 6 groups independently selected from the nitrogen atom. In some embodiments, one R bonded to the same nitrogen atom 7 and one R 8 These combine to form a spirocyclic bicyclic 5-15 member heterocycloalkyl group. In some embodiments, one R bonded to the same nitrogen atom 7 and one R 8 These combine to form a spirocyclic bicyclic 5-12 member heterocycloalkyl group. In some embodiments, one R bonded to the same nitrogen atom 7 and one R 8 These combine to form a spirocyclic bicyclic 5-12 member heterocycloalkyl group, and the heterocycloalkyl group consists of oxo and R 11 It is optionally substituted with 1 to 6 groups independently selected from the above. In some embodiments, R bonded to the same nitrogen atom 7 and one R 8 These combine to form a 5-7 member heterocycloalkyl group. In some embodiments, R bonded to the same nitrogen atom 7 and one R 8 These combine to form a 5-7 member heterocycloalkyl group, and the heterocycloalkyl group consists of oxo and R 11 It is optionally substituted with 1 to 6 groups independently selected from the above. In some embodiments, R bonded to the same nitrogen atom 7 and one R 8 These combine to form a diazepane ring. In some embodiments, R bonded to the same nitrogen atom 7 and one R 8 These combine to form a morpholine ring. In some embodiments, R bonded to the same nitrogen atom 7 and one R8 These combine to form a piperidine ring. In some embodiments, R bonded to the same nitrogen atom 7 and one R 8 These combine to form a piperazine ring. In some embodiments, R bonded to the same nitrogen atom 7 and one R 8 These combine to form a pyrrolidine ring. In some embodiments, R bonded to the same nitrogen atom 7 and one R 8 These combine to form an azetidine ring. In some embodiments, R bonded to the same nitrogen atom 7 and one R 8 These combine to form an imidazolidine ring. In some embodiments, R bonded to the same nitrogen atom 7 and one R 8 These combine to form an unsubstituted heterocycloalkyl group. In some embodiments, R bonded to the same nitrogen atom 7 and one R 8 These combine to form oxo and R 11 It forms heterocycloalkyl groups substituted with 1 to 4 groups independently selected from the above. In some embodiments, R bonded to the same nitrogen atom 7 and one R 8 These combine to form oxo and R 11 It forms a heterocycloalkyl group substituted with 1-2 groups independently selected from the original group.

[0200] In some embodiments of compounds of formula (I), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), formula (IVa), formula (IVb), formula (IVc), formula (IVd), formula (VI), formula (VIa), formula (VII), or formula (VIIa), or pharmaceutically acceptable salts or solvates thereof, R 11 These are, independently, halogen, hydroxy, amino, cyano, and -S(=O)2(R) 13 ), -N(R 12)S(=O)2(R 13 ), -S(=O)(R 13 ), -N(R 12 )S(=O)(R 13 ), -C(=O)R 13 , -N(R 12 )C(=O)R 13 , C1-C6 alkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-10 member heterocycloalkyl, C6-C 10 Selected from the group consisting of aryls and 5-10 member heteroaryls, where aryls and heteroaryls are R 14 Optionally substituted with 1 to 4 groups independently selected from, with alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, and heterocycloalkyl groups being optional, as well as oxo and R 14 Substituted by 1 to 4 groups independently selected from the same carbon or nitrogen atom, or by two R groups bonded to the same carbon or nitrogen atom. 11 These combine to form a C3-C6 cycloalkyl or a 3-6 member heterocycloalkyl, and the cycloalkyl and heterocycloalkyl are oxo and R 14 It is optionally replaced by 1 to 4 bases independently selected from. In some embodiments, R 11 These are, independently, halogen, hydroxy, amino, cyano, and -S(=O)2(R) 13 ), -N(R 12 )S(=O)2(R 13 ), -S(=O)(R 13 ), -N(R 12 )S(=O)(R 13 ), -C(=O)R 13 , -N(R 12 )C(=O)R 13Selected from the group consisting of C1-C6 alkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-10 member heterocycloalkyl, C6 aryl, and 5-6 member heteroaryl, where aryl and heteroaryl are R 14 Optionally substituted with 1 to 4 groups independently selected from, alkyl, haloalkyl, cycloalkyl, and heterocycloalkyl groups, oxo and R 14 Optionally substituted with 1 to 4 groups independently selected from the original, or with two R groups bonded to the same carbon or nitrogen atom. 11 These combine to form a C3-C6 cycloalkyl or a 3-6 member heterocycloalkyl, and the cycloalkyl and heterocycloalkyl are oxo and R 14 It is optionally replaced by 1 to 4 bases independently selected from. In some embodiments, R 11 These are, independently, halogen, hydroxy, amino, cyano, and -S(=O)2(R) 13 ), -N(R 12 )S(=O)2(R 13 ), -S(=O)(R 13 ), -N(R 12 )S(=O)(R 13 ), -C(=O)R 13 , -N(R 12 )C(=O)R 13 The group is selected from C1-C6 alkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-10 member heterocycloalkyl, and 5-10 member heteroaryl, and the heteroaryl is R 14 Optionally substituted with 1 to 4 groups independently selected from, alkyl, haloalkyl, cycloalkyl, and heterocycloalkyl groups, oxo and R 14 Optionally substituted with 1 to 4 groups independently selected from the original, or with two R groups bonded to the same carbon or nitrogen atom. 11These combine to form a C3-C6 cycloalkyl or a 3-6 member heterocycloalkyl, and the cycloalkyl and heterocycloalkyl are oxo and R 14 It is optionally replaced by 1 to 4 bases independently selected from. In some embodiments, R 11 These are, independently, halogen, hydroxyl, amino, and -S(=O)2(R) 13 ), -N(R 12 )S(=O)2(R 13 ), -S(=O)(R 13 ), -N(R 12 )S(=O)(R 13 ), -N(R 12 )C(=O)R 13 The group is selected from C1-C6 alkyl, -O(C1-C6 alkyl), C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-10 member heterocycloalkyl, and 5-6 member heteroaryl, and the heteroaryl is R 14 Optionally substituted with 1 to 4 groups independently selected from, alkyl, haloalkyl, cycloalkyl, and heterocycloalkyl groups, oxo and R 14 Optionally substituted with 1 to 4 groups independently selected from the original, or with two R groups bonded to the same carbon or nitrogen atom. 11 These combine to form a C3-C6 cycloalkyl or a 3-6 member heterocycloalkyl, and the cycloalkyl and heterocycloalkyl are oxo and R 14 It is optionally replaced by 1 to 4 bases independently selected from. In some embodiments, R 11 These are independently fluoro, hydroxy, amino, and -S(=O)2(R) 13 ), -N(R 12 )S(=O)2(R 13 ), -S(=O)(R 13 ), -N(R 12 )S(=O)(R 13 ), -N(R 12 )C(=O)R 13The group is selected from C1-C4 alkyl, -O(C1-C4 alkyl), C1-C4 haloalkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, and 5-6 member heteroaryl, and the heteroaryl is R 14 Optionally substituted with 1 to 4 groups independently selected from, alkyl, haloalkyl, cycloalkyl, and heterocycloalkyl groups, oxo and R 14 Optionally substituted with 1 to 4 groups independently selected from the original, or with two R groups bonded to the same carbon or nitrogen atom. 11 These combine to form a C3-C4 cycloalkyl or a 3-4 member heterocycloalkyl, and the cycloalkyl and heterocycloalkyl are oxo and R 14 It is optionally replaced by 1 to 4 bases independently selected from. In some embodiments, R 11 These are independently fluoro, hydroxy, amino, and -S(=O)2(R) 13 ), -N(R 12 )S(=O)2(R 13 ), -S(=O)(R 13 ), -N(R 12 )S(=O)(R 13 ), -N(R 12 )C(=O)R 13 The group is selected from C1-C4 alkyl, -O(C1-C4 alkyl), C1-C4 haloalkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, and 5-6 member heteroaryl, and the heteroaryl is R 14 Optionally substituted with 1 to 4 groups independently selected from, alkyl, haloalkyl, cycloalkyl, and heterocycloalkyl groups, oxo and R 14 Optionally substituted with 1-2 groups independently selected from the original, or with two R groups bonded to the same carbon or nitrogen atom. 11 These combine to form a C3-C4 cycloalkyl or a 3-4 member heterocycloalkyl, and the cycloalkyl and heterocycloalkyl are oxo and R 14 It is optionally replaced by one or two bases independently selected from. In some embodiments, R11 These are independently fluoro, hydroxy, amino, and -S(=O)2(R) 13 ), -N(R 12 )S(=O)2(R 13 ), -S(=O)(R 13 ), -N(R 12 )S(=O)(R 13 ), -N(R 12 )C(=O)R 13 Selected from the group consisting of C1-C4 alkyl, -O(C1-C4 alkyl), C1-C4 haloalkyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, and 5-6 membered heteroaryl, or two R groups bonded to the same carbon or nitrogen atom. 11 These combine to form a C3-C4 cycloalkyl or a 3-4 member heterocycloalkyl. In some embodiments, R 11 These are independently fluoro, hydroxy, amino, and -S(=O)2(R) 13 ), -N(R 12 )S(=O)2(R 13 ), -S(=O)(R 13 ), -N(R 12 )S(=O)(R 13 ), -N(R 12 )C(=O)R 13 The group is selected from the group consisting of C1-C4 alkyl, -O(C1-C4 alkyl), C1-C4 haloalkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, and 5-6 member heteroaryl.

[0201] In some embodiments of compounds of formula (I), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), formula (IVa), formula (IVb), formula (IVc), formula (IVd), formula (VI), formula (VIa), formula (VII), or formula (VIIa), or pharmaceutically acceptable salts or solvates thereof, R 11 These are, independently, halogen, hydroxy, amino, cyano, and -S(=O)2(R) 13 ), -N(R 12)S(=O)2(R 13 ), -S(=O)(R 13 ), -N(R 12 )S(=O)(R 13 ), -C(=O)R 13 , -N(R 12 )C(=O)R 13 The group is selected from C1-C6 alkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-10 member heterocycloalkyl, and 5-10 member heteroaryl, and the heteroaryl is R 14 Optionally substituted with 1 to 4 groups independently selected from, alkyl, haloalkyl, cycloalkyl, and heterocycloalkyl groups, oxo and R 14 Substituted by 1 to 4 groups independently selected from the same carbon or nitrogen atom, or by two R groups bonded to the same carbon or nitrogen atom. 11 These combine to form a C3-C6 cycloalkyl or a 3-6 member heterocycloalkyl, and the cycloalkyl and heterocycloalkyl are oxo and R 14 It is optionally replaced by 1 to 4 bases that are independently selected.

[0202] In some embodiments of compounds of formula (I), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), formula (IVa), formula (IVb), formula (IVc), formula (IVd), formula (VI), formula (VIa), formula (VII), or formula (VIIa), or pharmaceutically acceptable salts or solvates thereof, R 9 is hydrogen, -C(O)OR 12 ,-C(O)N(R 12 )2, -S(O)2R 12 -S(O)2N(R 12 )2, or C1-C6 alkyl. In some embodiments, R 9 is hydrogen, -C(O)N(R 12 )2, -S(O)2R 12 -S(O)2N(R 12)2, or C1-C6 alkyl. In some embodiments, R 9 is hydrogen. In some embodiments, R 9 is a C1-C6 alkyl group. In some embodiments, R 9 is a C1-C4 alkyl group. In some embodiments, R 9 is methyl. In some embodiments, R 9 is -C(O)N(R 12 )2, -S(O)2R 12 , or -S(O)2N(R 12 )2. In some embodiments, R 9 is -C(O)N(R 12 )2. In some embodiments, R 9 is -S(O)2R 12 In some embodiments, R 9 is -S(O)2N(R 12 )2.

[0203] In some embodiments of compounds of formula (I), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), formula (IVa), formula (IVb), formula (IVc), formula (IVd), formula (VI), formula (VIa), formula (VII), or formula (VIIa), or pharmaceutically acceptable salts or solvates thereof, R 12 Each is independently hydrogen or a C1-C6 alkyl group. In some embodiments, R 12 Each of these is hydrogen. In some embodiments, at least one R 12 is hydrogen. In some embodiments, one R 12 is hydrogen. In some embodiments, R 12 Each of these is a C1-C6 alkyl group. In some embodiments, at least one R 12 is a C1-C6 alkyl group. In some embodiments, one R 12 is a C1-C6 alkyl group. In some embodiments, R12 Each of these is a C1-C4 alkyl group. In some embodiments, at least one R 12 is a C1-C4 alkyl group. In some embodiments, one R 12 is a C1-C4 alkyl group. In some embodiments, R 12 Each of these is methyl. In some embodiments, at least one R 12 is methyl. In some embodiments, one R 12 It is methyl.

[0204] In some embodiments of compounds of formula (I), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), formula (IVa), formula (IVb), formula (IVc), formula (IVd), formula (VI), formula (VIa), formula (VII), or formula (VIIa), or pharmaceutically acceptable salts or solvates thereof, R 13 Each of these is independently a hydroxyl, amino, C1-C6 alkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 haloalkyl, C3-C6 cycloalkyl, or a 3- to 6-membered heterocycloalkyl. In some embodiments, R 13 Each of these is independently a hydroxyl, amino, C1-C6 alkyl, -O(C1-C6 alkyl), C3-C6 cycloalkyl, or 3- to 6-membered heterocycloalkyl. In some embodiments, R 13 Each of these is independently a hydroxyl, amino, C1-C4 alkyl, -O(C1-C4 alkyl), C3-C4 cycloalkyl, or 3-4 membered heterocycloalkyl. In some embodiments, R 13 Each of these is independently hydroxy, amino, methyl, ethyl, -OMe, -OEt, or cyclopropyl. In some embodiments, R 13 Each is independently hydroxy, amino, methyl, ethyl, or -OMe. In some embodiments, R 13Each of these is independently hydroxy, amino, or methyl. In some embodiments, at least one R 13 is hydroxyl. In some embodiments, at least one R 13 is an amino acid. In some embodiments, at least one R 13 is methyl. In some embodiments, at least one R 13 is -OMe. In some embodiments, one R 13 is hydroxyl. In some embodiments, one R 13 is an amino acid. In some embodiments, one R 13 is methyl. In some embodiments, one R 13 It is -OMe.

[0205] In some embodiments of compounds of formula (I), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), formula (IVa), formula (IVb), formula (IVc), formula (IVd), formula (VI), formula (VIa), formula (VII), or formula (VIIa), or pharmaceutically acceptable salts or solvates thereof, R 13 Each of these is independently hydroxy, amino, C1-C6 alkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or C1-C6 haloalkyl.

[0206] In some embodiments of compounds of formula (I), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), formula (IVa), formula (IVb), formula (IVc), formula (IVd), formula (VI), formula (VIa), formula (VII), or formula (VIIa), or pharmaceutically acceptable salts or solvates thereof, R 14 The existence of each is independent of cyano, amino, hydroxy, and -C(=O)OR 12 -C(=O)N(R 12)2, C1-C6 alkyl, -O(C1-C6 alkyl), -NR 12 The alkyl groups are (C1-C6 alkyl), aryl, heteroaryl, C3-C6 cycloalkyl, or 3- to 6-membered heterocycloalkyl, where each alkyl group is optionally substituted with 1 to 2 hydroxyl groups.

[0207] In some embodiments of compounds of formula (I), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), formula (IVa), formula (IVb), formula (IVc), formula (IVd), formula (VI), formula (VIa), formula (VII), or formula (VIIa), or pharmaceutically acceptable salts or solvates thereof, R 14 These are independently cyano, amino, hydroxy, and -C(=O)OR 12 -C(=O)N(R 12 )2, C1-C6 alkyl, -O(C1-C6 alkyl), -NR 12 The alkyl groups are (C1-C6 alkyl), aryl, heteroaryl, C3-C6 cycloalkyl, or 3- to 6-membered heterocycloalkyl, where each alkyl group is optionally substituted with 1 to 2 hydroxyl groups. In some embodiments, R 14 These are, independently, amino, hydroxy, and -C(=O)OR. 12 -C(=O)N(R 12 )2, C1-C6 alkyl, -O(C1-C6 alkyl), 5-6 member heteroaryl, C3-C6 cycloalkyl, or 3-6 member heterocycloalkyl, where each alkyl is optionally substituted with 1-2 hydroxyl groups. In some embodiments, R 14 Each of these is independently an amino, hydroxy, -C(=O)OH, -C(=O)NH2, C1-C6 alkyl, -O(C1-C6 alkyl), 5-6 member heteroaryl, C3-C6 cycloalkyl, or 3-6 member heterocycloalkyl, where each alkyl is optionally substituted with 1-2 hydroxyl groups. In some embodiments, R 14Each of these is independently amino, hydroxy, -C(=O)OH, -C(=O)NH2, C1-C4 alkyl, -O(C1-C4 alkyl), 5-membered heteroaryl, C3-C6 cycloalkyl, or 3- to 6-membered heterocycloalkyl, where each alkyl is optionally substituted with 1 to 2 hydroxyl groups. In some embodiments, R 14 Each of these is independently an amino, hydroxy, -C(=O)OH, -C(=O)NH2, C1-C4 alkyl, -O(C1-C4 alkyl), or a 5-membered heteroaryl, where each alkyl is optionally substituted with 1-2 hydroxyl groups. In some embodiments, at least one R 14 is an amino acid. In some embodiments, at least one R 14 is hydroxyl. In some embodiments, at least one R 14 is methyl. In some embodiments, at least one R 14 is a C1-C4 alkyl group. In some embodiments, at least one R 14 is methyl. In some embodiments, at least one R 14 is a C1-C4 alkyl group substituted with 1-2 hydroxyl groups. In some embodiments, at least one R 14 is -C(=O)OR 12 In some embodiments, at least one R 14 is -C(=O)N(R 12 )2. In some embodiments, at least one R 14 is -C(=O)OH. In some embodiments, at least one R 14 is -C(=O)NH2. In some embodiments, at least one R 14 is -O(C1-C4 alkyl). In some embodiments, at least one R 14 It is -OMe.

[0208] In some embodiments of compounds of formula (I), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), formula (IVa), formula (IVb), formula (IVc), formula (IVd), formula (VI), formula (VIa), formula (VII), or formula (VIIa), or pharmaceutically acceptable salts or solvates thereof, R 11 These are, independently, halogen, hydroxy, amino, cyano, and -S(=O)2(R) 13 ), -N(R 12 )S(=O)2(R 13 ), -S(=O)(R 13 ), -N(R 12 )S(=O)(R 13 ), -C(=O)R 13 , -N(R 12 )C(=O)R 13 Selected from the group consisting of C1-C6 alkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-10 member heterocycloalkyl, C6 aryl, and 5-6 member heteroaryl, where aryl and heteroaryl are R 14 Optionally substituted with 1 to 4 groups independently selected from, alkyl, haloalkyl, cycloalkyl, and heterocycloalkyl groups, oxo and R 14 Substituted by 1 to 4 groups independently selected from the same carbon or nitrogen atom, or by two R groups bonded to the same carbon or nitrogen atom. 11 These combine to form a C3-C6 cycloalkyl or a 3-6 member heterocycloalkyl, and the cycloalkyl and heterocycloalkyl are oxo and R 14 It is optionally replaced by 1 to 4 elements independently selected from R 14 The existence of each is independent of cyano, amino, hydroxy, and -C(=O)OR 12 -C(=O)N(R 12 )2, C1-C6 alkyl, -O(C1-C6 alkyl), -NR 12The alkyl groups are (C1-C6 alkyl), aryl, heteroaryl, C3-C6 cycloalkyl, or 3- to 6-membered heterocycloalkyl, where each alkyl group is optionally substituted with 1 to 2 hydroxyl groups.

[0209] In some embodiments of compounds of formula (I), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), formula (IVa), formula (IVb), formula (IVc), formula (IVd), formula (VI), formula (VIa), formula (VII), or formula (VIIa), or pharmaceutically acceptable salts or solvates thereof, R 11 These are, independently, halogen, hydroxy, amino, cyano, and -S(=O)2(R) 13 ), -N(R 12 )S(=O)2(R 13 ), -S(=O)(R 13 ), -N(R 12 )S(=O)(R 13 ), -C(=O)R 13 , -N(R 12 )C(=O)R 13 Selected from the group consisting of C1-C6 alkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-10 member heterocycloalkyl, C6 aryl, and 5-6 member heteroaryl, where aryl and heteroaryl are R 14 Optionally substituted with 1 to 4 groups independently selected from, alkyl, haloalkyl, cycloalkyl, and heterocycloalkyl groups, oxo and R 14 Substituted by 1 to 4 groups independently selected from the same carbon or nitrogen atom, or by two R groups bonded to the same carbon or nitrogen atom. 11 These combine to form a C3-C6 cycloalkyl or a 3-6 member heterocycloalkyl, and the cycloalkyl and heterocycloalkyl are oxo and R 14 It is optionally replaced by 1 to 4 elements independently selected from R 14The existence of each is independent of cyano, amino, hydroxy, and -C(=O)OR 12 -C(=O)N(R 12 )2, C1-C6 alkyl, -O(C1-C6 alkyl), -NR 12 The alkyl groups are (C1-C6 alkyl), aryl, heteroaryl, C3-C6 cycloalkyl, or 3- to 6-membered heterocycloalkyl, where each alkyl group is optionally substituted with 1 to 2 hydroxyl groups.

[0210] In some embodiments of compounds of formula (I), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), formula (IVa), formula (IVb), formula (IVc), formula (IVd), formula (VI), formula (VIa), formula (VII), or formula (VIIa), or pharmaceutically acceptable salts or solvates thereof, -LR 2 teeth,

[0211] [ka]

[0212] [ka]

[0213] [ka]

[0214] [ka]

[0215] [ka]

[0216] [ka]

[0217] [ka]

[0218] [ka]

[0219] [ka]

[0220] [ka] That is the case.

[0221] In some embodiments of compounds of formula (I), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), formula (IVa), formula (IVb), formula (IVc), formula (IVd), formula (VI), formula (VIa), formula (VII), or formula (VIIa), or pharmaceutically acceptable salts or solvates thereof, -LR 2 teeth,

[0222] [ka]

[0223] [ka] In some embodiments, -LR 2 teeth,

[0224] [ka] In some embodiments, -LR 2 teeth,

[0225] [ka] In some embodiments, -LR 2 teeth,

[0226] [ka] In some embodiments, -LR 2 teeth,

[0227] [ka] That is the case.

[0228] In some embodiments of compounds of formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), formula (IVa), formula (IVb), formula (IVc), formula (IVd), formula (VI), formula (VIa), formula (VII), or formula (VIIa), or pharmaceutically acceptable salts or solvates thereof,

[0229] [ka] teeth,

[0230] [ka]

[0231] [ka]

[0232] [ka]

[0233] [ka]

[0234] [ka]

[0235] [ka]

[0236] [ka]

[0237] [ka]

[0238] [ka] That is the case.

[0239] In some embodiments of compounds of formula (I), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), formula (IVa), formula (IVb), formula (IVc), formula (IVd), formula (VI), formula (VIa), formula (VII), or formula (VIIa), or pharmaceutically acceptable salts or solvates thereof, -LR 2 teeth,

[0240] [ka]

[0241] [ka]

[0242] [ka]

[0243] [ka] That is the case.

[0244] In some embodiments of compounds of formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), formula (IVa), formula (IVb), formula (IVc), formula (IVd), formula (VI), formula (VIa), formula (VII), or formula (VIIa), or pharmaceutically acceptable salts or solvates thereof,

[0245] [ka] teeth,

[0246] [ka]

[0247] [ka]

[0248] [ka]

[0249] [ka] That is the case.

[0250] In some embodiments of compounds of formula (I), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), formula (IVa), formula (IVb), formula (IVc), formula (IVd), formula (VI), formula (VIa), formula (VII), or formula (VIIa), or pharmaceutically acceptable salts or solvates thereof, -LR2 は、

[0251]

change

[0252]

change

[0253]

change

[0254]

change

[0255]

change

[0256]

change

[0257]

change

[0258]

change

[0259]

change

[0260]

change

[0261] [ka] That is the case.

[0262] In some embodiments of compounds of formula (I), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), formula (IVa), formula (IVb), formula (IVc), formula (IVd), formula (VI), formula (VIa), formula (VII), or formula (VIIa), or pharmaceutically acceptable salts or solvates thereof, -LR 2 teeth,

[0263] [ka]

[0264] [ka]

[0265] [ka]

[0266] [ka] That is the case.

[0267] In some embodiments of compounds of formula (I), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), formula (IVa), formula (IVb), formula (IVc), formula (IVd), formula (VI), formula (VIa), formula (VII), or formula (VIIa), or pharmaceutically acceptable salts or solvates thereof,

[0268] [ka] teeth,

[0269] [ka]

[0270] [ka]

[0271] [ka]

[0272] [ka] That is the case.

[0273] Any combination of the above groups is contemplated herein for various variables. Throughout the specification, the groups and their substituents are selected by those skilled in the art to provide stable moieties and compounds.

[0274] In some embodiments, the compound is a compound prepared or described in the examples provided herein. In some embodiments, the compound is a compound listed in Table 1.

[0275] Further forms of compounds Furthermore, in some embodiments, the compounds described herein exist as "geometric isomers." In some embodiments, the compounds described herein have one or more double bonds. The compounds presented in the present invention include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, and their corresponding mixtures. In some situations, the compounds exist as tautomers.

[0276] A "tautomer" refers to a molecule in which a proton shift from one atom to another atom of the same molecule is possible. In certain embodiments, the compounds presented herein exist as tautomers. A chemical equilibrium of tautomers exists under conditions where tautomerization is possible. The exact ratio of tautomers depends on several factors, including physical conditions, temperature, solvent, and pH. Some examples of tautomer equilibrium include:

[0277] [ka] It includes.

[0278] Depending on the context, the compounds described herein may have one or more chiral centers, each center existing in either the (R) or (S) configuration. The compounds described herein include all diastereomer, enantiomer, and epimer forms, as well as corresponding mixtures thereof. In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers derived from a single preparation step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as optically pure enantiomers by chiral chromatographic resolution of a racemic mixture. In some embodiments, the compounds described herein are prepared as individual stereoisomers of the compound by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomer compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred (e.g., crystalline diastereomer salts). In some embodiments, diastereomers possess characteristic physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.) and are separated by utilizing these differences. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably by separation / resolution techniques based on differences in solubility. In some embodiments, the optically pure enantiomers are recovered together with a resolving agent by any practical means that does not result in racemization.

[0279] The term "positional isomer" refers to structural isomers around a central ring, such as ortho-isomers, meta-isomers, and para-isomers, around a benzene ring.

[0280] The methods and formulations described herein involve the use of N-oxides (where appropriate), crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of the compounds described herein, as well as active metabolites of these compounds having the same type of activity.

[0281] "Pharmacologically acceptable salts" include both acid addition salts and base addition salts. A pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass any and all pharmaceutically acceptable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0282] A "pharmaceutically acceptable acid addition salt" refers to a salt formed using an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, or phosphorous acid, which retains the biological efficacy and properties of the free base and is not biologically or otherwise undesirable. Salts formed with organic acids, such as aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkanes, hydroxyalkanoates, alkanedionic acids, aromatic acids, and aliphatic and aromatic sulfonic acids, are also included, such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Therefore, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrophosphates, dihydrophosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, suberinate succinate, sebacinate, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, maleates, tartrates, and methanesulfonates. Salts of amino acids such as alginates, glucons, and galacturons are also considered (see, for example, Berge SM et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt.

[0283] A "pharmaceutically acceptable base addition salt" refers to a salt that retains the biological efficacy and properties of a free acid, and is not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to a free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines (e.g., alkali metals and alkaline earth metals or organic amines). Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Examples of salts derived from organic bases include, but are not limited to, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as salts of isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydravamin, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, and polyamine resins. See Berge et al. above.

[0284] The term "prodrug" in some embodiments refers to a compound that is converted to the active compound described herein under physiological conditions or by solvolysis. Therefore, the term prodrug refers to a precursor of a pharmaceutically acceptable active compound. Prodrugs are typically inactive when administered to a subject but are converted to the active compound in vivo, for example, by hydrolysis. Prodrug compounds often offer advantages in mammalian solubility, histocompatibility, or delayed release (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7 9, 21 24 (Elsevier, Amsterdam)).

[0285] A discussion of prodrugs is provided in Higuchi, T., et al., “Pro drugs as Novel Delivery Systems,” ACSSymposium Series, Vol.14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

[0286] The term “prodrug” further means that such a prodrug includes any covalent carrier that releases the active compound in vivo when administered to a mammalian subject. Prodrugs of active compounds described herein are prepared by modifying functional groups present in the active compound so that the modification is cleaved either in a routine operation or in vivo to become the parental active compound. Prodrugs include compounds in which a hydroxy, amino, carboxy, or mercapto group is bonded to any group that is cleaved to form a free hydroxy, free amino, free carboxy, or free mercapto group, respectively, when the prodrug of the active compound is administered to a mammalian subject. Examples of prodrugs include, but are not limited to, acetic acid, formic acid, and benzoic acid derivatives of alcohol or amine functional groups in the active compound.

[0287] A “pharmaceutically acceptable solvate” refers to a composition of a substance in a solvent-added form. In some embodiments, the solvate is formed during a process using a pharmaceutically acceptable solvent, such as water or ethanol, comprising a stoichiometric or non-stoichiometric amount of solvent. A “hydrate” is formed when the solvent is water, or an alkoxide is formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein may optionally exist in both solvated and non-solvated forms.

[0288] The compounds disclosed herein, in some embodiments, are in different enriched isotopic forms, for example, 2 H, 3 H, 11 C, 13 C, and / or 14 It is used concentrated with a C content. In some embodiments, the compound is deuterated at at least one position. Such deuterated forms can be prepared by the procedures described in U.S. Patents 5,846,514 and 6,334,997. As described in U.S. Patents 5,846,514 and 6,334,997, deuteration can improve metabolic stability and / or efficacy and thus increase the duration of action of the drug.

[0289] Unless otherwise specified, the structures shown herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, hydrogen substitution with deuterium or tritium, or 13 C or 14 Apart from carbon substitution with carbon-enriched carbon, compounds having this structure are within the scope of this disclosure.

[0290] The compounds of this disclosure optionally contain unnatural proportions of atomic isotopes in one or more atoms constituting such compounds. For example, the compounds may contain, for example, deuterium (2 H), tritium ( 3 H), Iodine-125( 125 I), or carbon-14 ( 14 It can be labeled with isotopes such as C). 2 H, 3 H, 11 C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 17 O, 18 O, 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, 125 All isotopic substitutions with I are intended. All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0291] In certain embodiments, the compounds disclosed herein are 1 Some or all of the H atoms 2The deuterium-substituted compounds are substituted with hydrogen atoms. Methods for synthesizing deuterium-containing compounds are known in the art. In some embodiments, deuterium-substituted compounds are synthesized using various methods as described in Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21, and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0292] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0293] In certain embodiments, the compounds described herein, or their pharmaceutically acceptable salts, solvates, stereoisomers, or prodrugs, are substantially pure in that they contain, for example, less than 5%, less than 1%, or less than 0.1% of other small organic molecules, such as contaminating intermediates or by-products generated in one or more steps of the synthesis method.

[0294] Preparation of compounds The compounds described herein are synthesized using standard synthetic techniques or by methods known in the art in combination with the methods described herein.

[0295] Unless otherwise specified, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology will be employed.

[0296] The compounds are prepared using standard organic chemistry techniques, such as those described in March's Advanced Organic Chemistry, 6th Edition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein may be employed, including changes in solvent, reaction temperature, reaction time, and different chemical reagents and other reaction conditions.

[0297] In some embodiments, the compounds described herein are prepared as outlined in the examples.

[0298] Pharmaceutical composition In some embodiments, the disclosure provides a pharmaceutical composition comprising a compound of formula (I) and at least one pharmaceutically acceptable excipient.

[0299] The compound of formula (I) can be formulated into any suitable pharmaceutical formulation. The pharmaceutical formulations of this disclosure typically comprise an active ingredient (e.g., the compound of formula (I)) and one or more pharmaceutically acceptable excipients or carriers, including, but not limited to, inert solid diluents and fillers, diluents, sterile aqueous solutions, and various organic solvents, penetration enhancers, antioxidants, solubilizers, and adjuvants. The preparation of such pharmaceutical compositions is well known in the art. For example, Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw See Hill, 2003; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remington's Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999).

[0300] The amount of therapeutic agent disclosed herein depends on the mammal being treated, the severity of the disorder or disease, the rate of administration, the nature of the therapeutic protein, and the discretion of the prescribing physician.

[0301] Preferred embodiments of the present invention have been shown and described herein, but it will be apparent to those skilled in the art that such embodiments are provided only as examples. Those skilled in the art will be able to conceive of many variations, alterations, and substitutions without departing from the present invention. It should be understood that various alternative forms of the embodiments of the present invention described herein may be employed when carrying out the present invention. The following claims define the scope of the present invention, and the methods and structures within these claims, as well as their equivalents, are intended to be encompassed by these claims.

[0302] Combination therapy In certain embodiments, it is appropriate to administer at least one of the compounds described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, in combination with one or more other therapeutic agents (e.g., additional therapeutic agents). In some embodiments, the compounds described herein, or a pharmaceutically acceptable salt or solvate thereof, are administered in combination with one or more other therapeutic agents (e.g., additional therapeutic agents) used to treat migraines. In some embodiments, one or more other therapeutic agents (e.g., additional therapeutic agents) are: beta-blockers, e.g., propranolol, nadolol, timolol, metoprolol, and atenolol; antidepressants, e.g., amitriptyline and venlafaxine; anticonvulsants, e.g., valproate and topiramate; phenothiazine antiemetics, e.g., prochlorperazine; non-phenothiazine antiemetics, e.g., metoclopramide; nonsteroidal anti-inflammatory drugs (NSAIDS), e.g., aspirin, ibuprofen, and naproxen; acetaminophen; caffeine; ergot (ergo) ts), e.g., ergotamine and dihydroergotamine (DHE); ditans, e.g., rasmiditan; triptans, e.g., alumotriptan, eletriptan, fluvatriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan; calcitonin gene-related peptide (CGRP) receptor antagonists, e.g., uvrogepant, rimegepant, atogepant, and zabegepant; CGRP antibodies, e.g., erenumab, fremanezumab, galcanezumab, and eptinezumab; and combinations thereof.

[0303] Non-limiting embodiment Some non-limiting embodiments of this disclosure are listed below. Embodiment 1. Formula (I)

[0304] [ka] A compound of, or a pharmaceutically acceptable salt or solvate thereof, wherein, Z is -S-, -N=C(R 5 )-,-C(R 5 )=N-, or -C(R 5 )=C(R 5 )- is a divalent group selected from, R 1 is a pyrazole, and the pyrazole is optionally selected, R 6 It is replaced by 1 to 3 groups independently selected from, R 2 C1-C 10 Alkyl, C1-C 10 Heteroalkyl, -C(=O)OR 7 -C(=O)N(R 8 )(R 7 ), -N(R 8 )(R 7 ), -C(=NR 9 )N(R 8 )(R 7 ), -N(R 7 )C(=NR 9 )N(R 8 )(R 7 ), C6-C 10 Aryl, 5-10 member heteroaryl, C3-C 12 A cycloalkyl or a 3- to 15-membered heterocycloalkyl, where aryl and heteroaryl are optional, R 10 Substituted with 1 to 4 groups independently selected from, alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl groups are optional, oxo and R 10 It is replaced by 1 to 4 elements independently selected from, R 3 These are halogens, cyanos, -C(=O)OH, -C(=O)O(C1-C6 alkyl), C1-C6 alkyl, C1-C6 alkenyl, -O(C1-C6 alkyl), C3-C6 cycloalkyl, or C1-C6 haloalkyl. R 4 Each of these is independently hydrogen, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C6 haloalkyl, or -O-(C1-C6 haloalkyl), L is a bond, a C1-C2 alkylene or a C3-C6 cycloalkylene, wherein the alkylene or cycloalkylene is optionally substituted with one or two -OH groups. R 5 Each of these is independently hydrogen, cyano, halogen, C1-C6 alkyl, -O(C1-C6 alkyl), C3-C6 cycloalkyl, C1-C6 haloalkyl, or -O(C1-C6 haloalkyl), R 6 These are, independently, halogen, hydroxy, cyano, amino, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C3-C6 cycloalkyl, and -CH2-(C 3-6 Cycloalkyl), -O-(C 3-6 Selected from the group consisting of cycloalkyl, C1-C6 haloalkyl, and -O(C1-C6 haloalkyl), R 6 If it is bonded to a nitrogen atom, it is C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C3-C6 cycloalkyl, -CH2-(C 3-6 Selected from the group consisting of cycloalkyl and C1-C6 haloalkyl groups, R 7 Each of these is independently hydrogen or a C1-C6 alkyl group, and the alkyl group is optionally substituted with 1-2 hydroxyl groups. R 8 is hydrogen, C1-C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Alkenyl, C1-C 10 Alkinyl, C3-C 12 Cycloalkyl, 3-15 member heterocycloalkyl, C6-C 10 It is an aryl or a 5-10 member heteroaryl, and the aryl and heteroaryl are optional, R 11Substituted with 1 to 6 groups independently selected from, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl groups are optional, oxo and R 11 It is replaced by 1 to 6 groups independently selected from, Alternatively, one R bonded to the same nitrogen atom 7 and one R 8 These combine to form oxo and R 11 Forms a 3-15 member heterocycloalkyl group that is optionally substituted with 1-6 groups independently selected from the above, R 9 is hydrogen, -C(O)OR 12 ,-C(O)N(R 12 )2, -S(O)2R 12 -S(O)2N(R 12 )2, or C1-C6 alkyl, R 10 These are independently hydroxy, amino, cyano, fluoro, and -C(=O)OR. 12 -C(=O)N(R 12 )2, C1-C4 alkyl, C1-C4 haloalkyl, -O(C1-C6 alkyl), -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C3-C6 cycloalkyl, where the alkyl, haloalkyl, or cycloalkyl is optional, and hydroxy, amino, cyano, fluoro, -C(=O)OR 12 , and -C(=O)N(R 12 ) Replaced by 1-2 elements selected from 2, R 11 These are, independently, halogen, hydroxy, amino, cyano, and -S(=O)2(R) 13 ), -N(R 12 )S(=O)2(R 13 ), -S(=O)(R 13 ), -N(R 12 )S(=O)(R 13 ), -C(=O)R 13 , -N(R 12 )C(=O)R 13, C1-C6 alkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-10 member heterocycloalkyl, C6-C 10 Selected from the group consisting of aryls and 5-10 member heteroaryls, aryls and heteroaryls are R 14 Optionally substituted with 1 to 4 groups independently selected from, with alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, and heterocycloalkyl groups being optional, as well as oxo and R 14 It is replaced by 1 to 4 elements independently selected from, Alternatively, two R atoms bonded to the same carbon or nitrogen atom 11 These combine to form a C3-C6 cycloalkyl or a 3-6 member heterocycloalkyl, and the cycloalkyl and heterocycloalkyl are oxo and R 14 It is optionally replaced by 1 to 4 bases independently selected from, R 12 Each of these is independently hydrogen or a C1-C6 alkyl group. R 13 Each of these is independently a hydroxyl, amino, C1-C6 alkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 haloalkyl, C3-C6 cycloalkyl, or a 3- to 6-membered heterocycloalkyl. R 14 These are independently cyano, amino, hydroxy, and -C(=O)OR 12 -C(=O)N(R 12 )2, C1-C6 alkyl, -O(C1-C6 alkyl), -NR 12 Compounds, or pharmaceutically acceptable salts or solvates thereof, that are (C1-C6 alkyl), aryl, heteroaryl, C3-C6 cycloalkyl, or 3- to 6-membered heterocycloalkyl, where each alkyl is optionally substituted with 1 to 2 hydroxyl groups. Embodiment 2.R 3The compound described in Embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, is fluoro, chloro, cyano, methyl, ethyl, vinyl, -OMe, -C(=O)OH, trifluoromethyl, difluoromethyl, or cyclopropyl. Embodiment 3.R 3 The compound described in Embodiment 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein is chloro, cyano, methyl, or ethyl. Embodiment 4. One R 4 R is fluoro, methyl, or -OMe, and the other R is 4 The compound according to any one of Embodiments 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, wherein each of the three elements is hydrogen. Embodiment 5.R 4 The compound according to any one of Embodiments 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, wherein each of the three elements is hydrogen. Embodiment 6.Z is -C(R 5 )=C(R 5 A compound according to any one of Embodiments 1 to 5, which is - or -S-, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 7. Formula (IIa)

[0305] [ka] A compound according to Embodiment 6 having the structure, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 8. Formula (IIb)

[0306] [ka] A compound according to Embodiment 6 having the structure, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 9.Z is -N=C(R 5 )- or -C(R 5 A compound according to any one of Embodiments 1 to 5, or a pharmaceutically acceptable salt or solvate thereof, wherein )=N-. Embodiment 10. Formula (IIc)

[0307] [ka] A compound according to Embodiment 9 having the structure, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 11. Formula (IId)

[0308] [ka] A compound according to Embodiment 9 having the structure, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 12.L is a compound according to any one of Embodiments 1 to 11, or a pharmaceutically acceptable salt or solvate thereof, which is a bond or C1 alkylene. Embodiment 13.R 2 is -C(O)(OR 7 A compound according to any one of Embodiments 1 to 12, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 14.R 2 The compound described in any one of Embodiments 1 to 12, or a pharmaceutically acceptable salt or solvate thereof, is a 5-10 member heteroaryl or a 3-15 member heterocycloalkyl. Embodiment 15.R 2 The compound described in any one of Embodiments 1 to 12, or a pharmaceutically acceptable salt or solvate thereof, is a 5-6 member heteroaryl or a 3-8 member heterocycloalkyl. Embodiment 16. Formula (III)

[0309] [ka] A compound according to Embodiment 1 having the structure, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 17. Formula (IVa)

[0310] [ka] A compound according to Embodiment 16 having the structure, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 18.R 1 This is one to three R compounds independently selected from the group consisting of methyl, ethyl, cyano, fluoro, chloro, -OMe, trifluoromethyl, and difluoromethyl. 6 Replaced by any choice in the base, R 6 If bonded to a nitrogen atom, it is a compound according to any one of Embodiments 1 to 17, or a pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of methyl, ethyl, trifluoromethyl, trifluoroethyl, and difluoromethyl. Embodiment 19.R 1 teeth,

[0311] [ka] The compound described in any one of Embodiments 1 to 18, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 20.R 1 This is one to two R independently selected from the group consisting of methyl, cyano, fluoro, chloro, -OMe, and difluoromethyl. 6 Replaced by any choice in the base, R 6 If bonded to a nitrogen atom, it is methyl, the compound according to any one of Embodiments 1 to 19, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 21.R 1 teeth,

[0312] [ka] And, R 6 Each of these is independently fluoro, chloro, cyano, or methyl, and R 6The compound described in Embodiment 19, or a pharmaceutically acceptable salt or solvate thereof, wherein if bonded to a nitrogen atom, it is methyl. Embodiment 22.R 1 teeth,

[0313] [ka] And, R 6 The compounds described in Embodiment 19, or pharmaceutically acceptable salts or solvates thereof, wherein each is independently fluoro, chloro, cyano, or methyl. Embodiment 23. Formula (VIa)

[0314] [ka] The structure of the compound described in Embodiment 1, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 24. Formula (VIIa)

[0315] [ka] A compound according to Embodiment 1 having the structure, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 25.R 5 A compound according to any one of Embodiments 1 to 24, or a pharmaceutically acceptable salt or solvate thereof, wherein each is independently hydrogen or fluoro. Embodiment 26.R 5 A compound according to any one of Embodiments 1 to 25, or a pharmaceutically acceptable salt or solvate thereof, wherein each of the elements is hydrogen. Embodiment 27.R 7 The compound described in any one of Embodiments 1 to 13 or 16 to 26, or a pharmaceutically acceptable salt or solvate thereof, wherein is hydrogen. Embodiment 28.R 8 C1-C 10 Alkyl, C1-C 10Heteroalkyl, C3-C 12 A compound according to any one of Embodiments 1 to 12 or 16 to 27, which is a cycloalkyl or a 3- to 15-membered heterocycloalkyl, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 29.R 8 C1-C 10 Alkyl, C3-C 12 A compound according to Embodiment 28, which is a cycloalkyl or a 3- to 15-membered heterocycloalkyl, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 30.R 8 C3-C 10 A compound according to Embodiment 28 or 29, which is a cycloalkyl or a 3- to 12-membered heterocycloalkyl, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 31.R 8 This is a single-ring C3-C 10 Cycloalkyl, condensed bicyclic C5-C 10 Cycloalkyl, cross-linked bicyclic C5-C 10 Cycloalkyl, spirocyclic, bicyclic C5-C 10 A compound according to any one of Embodiments 28 to 30, which is a cycloalkyl, a monocyclic 3- to 12-membered heterocycloalkyl, a condensed bicyclic 5- to 12-membered heterocycloalkyl, a cross-linked bicyclic 5- to 12-membered heterocycloalkyl, or a spirocyclic bicyclic 5- to 12-membered heterocycloalkyl, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 32.R 8 This is a condensed biringular C5-C 10 Cycloalkyl, cross-linked bicyclic C5-C 10 Cycloalkyl, spirocyclic, bicyclic C5-C 10 A compound according to any one of Embodiments 28 to 31, which is a cycloalkyl, a condensed bicyclic 5-12 member heterocycloalkyl, a cross-linked bicyclic 5-12 member heterocycloalkyl, or a spirocyclic bicyclic 5-12 member heterocycloalkyl, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 33.R 8 This is a spiro-ring bi-ring C5-C 10A compound according to any one of embodiments 28 to 32, which is a cycloalkyl or a 5-12 membered spirocyclic bicyclic heterocycloalkyl, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 34. One R bonded to the same nitrogen atom 7 and one R 8 These combine to form oxo and R 11 A compound according to any one of Embodiments 1 to 12 or 16 to 26, or a pharmaceutically acceptable salt or solvate thereof, forming a 3 to 15-membered heterocycloalkyl group optionally substituted with 1 to 6 groups independently selected from the above. Embodiment 35. One R bonded to the same nitrogen atom 7 and one R 8 The compound according to Embodiment 34, or a pharmaceutically acceptable salt or solvate thereof, wherein these elements together form a condensed bicyclic 5-12 member heterocycloalkyl, a cross-linked bicyclic 5-12 member heterocycloalkyl, or a spirocyclic bicyclic 5-12 member heterocycloalkyl. Embodiment 36. One R bonded to the same nitrogen atom 7 and one R 8 The compound according to Embodiment 34 or 35, or a pharmaceutically acceptable salt or solvate thereof, wherein the compounds together form a crosslinked bicyclic 5-12 membered heterocycloalkyl group, or a spirocyclic bicyclic 5-12 membered heterocycloalkyl group. Embodiment 37. One R bonded to the same nitrogen atom 7 and one R 8 A compound according to any one of embodiments 34 to 36, or a pharmaceutically acceptable salt or solvate thereof, wherein the compounds together form a spirocyclic bicyclic 5-12 membered heterocycloalkyl group. Embodiment 38.R 11 These are, independently, halogen, hydroxy, amino, cyano, and -S(=O)2(R) 13 ), -N(R 12 )S(=O)2(R 13 ), -S(=O)(R 13 ), -N(R 12 )S(=O)(R 13), -C(=O)R 13 , -N(R 12 )C(=O)R 13 Selected from the group consisting of C1-C6 alkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-10 member heterocycloalkyl, C6 aryl, and 5-6 member heteroaryl, where aryl and heteroaryl are R 14 Optionally substituted with 1 to 4 groups independently selected from, alkyl, haloalkyl, cycloalkyl, and heterocycloalkyl groups, oxo and R 14 It is replaced by 1 to 4 elements independently selected from, Alternatively, two R atoms bonded to the same carbon or nitrogen atom 11 These combine to form a C3-C6 cycloalkyl or a 3-6 member heterocycloalkyl, and the cycloalkyl and heterocycloalkyl are oxo and R 14 It is optionally replaced by 1 to 4 bases independently selected from, and also, R 14 The existence of each is independent of cyano, amino, hydroxy, and -C(=O)OR 12 -C(=O)N(R 12 )2, C1-C6 alkyl, -O(C1-C6 alkyl), -NR 12 A compound according to any one of Embodiments 1 to 12 or 16 to 37, or a pharmaceutically acceptable salt or solvate thereof, which is a (C1-C6 alkyl), aryl, heteroaryl, C3-C6 cycloalkyl, or 3- to 6-membered heterocycloalkyl, where each alkyl is optionally substituted with 1 to 2 hydroxyl groups. Embodiment 39.R 11 These are independently fluoro, hydroxy, amino, and -S(=O)2(R) 13 ), -N(R 12 )S(=O)2(R 13 ), -S(=O)(R 13 ), -N(R 12 )S(=O)(R 13 ), -C(=O)R 13, -N(R 12 )C(=O)R 13 Selected from the group consisting of C1-C6 alkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-10 member heterocycloalkyl, phenyl, and 5-6 member heteroaryl, where phenyl and heteroaryl are R 14 Optionally substituted with 1 to 4 groups independently selected from, alkyl, haloalkyl, cycloalkyl, and heterocycloalkyl groups, oxo and R 14 The compound according to Embodiment 38, or a pharmaceutically acceptable salt or solvate thereof, is substituted with 1 to 4 groups independently selected from the above. Embodiment 40.

[0316] [ka]

[0317] [ka]

[0318] [ka]

[0319] [ka]

[0320] [ka]

[0321] [ka]

[0322] [ka]

[0323] [ka]

[0324] [ka]

[0325] [ka]

[0326] [ka] A compound according to any one of Embodiments 1 to 11, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 41.-LR 2 teeth,

[0327] [ka]

[0328] [ka]

[0329] [ka] The compound described in any one of Embodiments 1 to 11, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 42. Compounds listed in Table 1, or pharmaceutically acceptable salts or solvates thereof. Embodiment 43. A pharmaceutical composition comprising a compound described in any one of Embodiments 1 to 42, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient. Embodiment 44. A method for treating a disease or disorder in a subject requiring treatment, comprising the step of administering to the subject a therapeutically effective amount of a compound described in any one of Embodiments 1 to 42, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition described in Embodiment 43. Embodiment 45. The method according to Embodiment 44, wherein the disease or disorder is a neurokinin receptor 3 (NK3)-dependent disease or disorder. Embodiment 46. The method according to Embodiment 44 or 45, wherein the disease or disorder is selected from the group consisting of migraine, medication-induced headache, cluster headache, generalized headache, trigeminal neuralgia, orofacial pain, and combinations thereof. Embodiment 47. The method according to any one of Embodiments 44 to 46, wherein the disease or disorder is selected from the group consisting of migraine, medication-induced headache, cluster headache, generalized headache, and combinations thereof. Embodiment 48. The method according to any one of Embodiments 44 to 47, wherein the disease or disorder is migraine. Embodiment 49. The method according to any one of Embodiments 44 to 48, further comprising the step of administering an additional therapeutically effective amount of the therapeutic agent. Embodiment 50. Formula (I)

[0330] [ka] A compound of, or a pharmaceutically acceptable salt or solvate thereof, wherein, Z is -S-, -N=C(R 5 )-,-C(R 5 )=N-, or -C(R 5 )=C(R 5 )- is a divalent group selected from, R 1 is a pyrazole, and the pyrazole is optionally selected, R 6 It is replaced by 1 to 3 groups independently selected from, R 2 C1-C 10 Alkyl, C1-C 10 Heteroalkyl, -C(=O)OR 7-C(=O)N(R 8 )(R 7 ), -N(R 8 )(R 7 ), -C(=NR 9 )N(R 8 )(R 7 ), -N(R 7 )C(=NR 9 )N(R 8 )(R 7 ), C6-C 10 Aryl, 5-10 member heteroaryl, C3-C 12 A cycloalkyl or a 3- to 15-membered heterocycloalkyl, where aryl and heteroaryl are optional, R 10 Substituted with 1 to 4 groups independently selected from, alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl groups are optional, oxo and R 10 It is replaced by 1 to 4 elements independently selected from, R 3 These are halogens, cyanos, -C(=O)OH, -C(=O)O(C1-C6 alkyl), C1-C6 alkyl, C1-C6 alkenyl, -O(C1-C6 alkyl), C3-C6 cycloalkyl, or C1-C6 haloalkyl. R 4 Each of these is independently hydrogen, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C6 haloalkyl, or -O-(C1-C6 haloalkyl), L is a bond, a C1-C2 alkylene or a C3-C6 cycloalkylene, wherein the alkylene or cycloalkylene is optionally substituted with one or two -OH groups. R 5 Each of these is independently hydrogen, cyano, halogen, C1-C6 alkyl, -O(C1-C6 alkyl), C3-C6 cycloalkyl, C1-C6 haloalkyl, or -O(C1-C6 haloalkyl), R 6These are, independently, halogen, hydroxy, cyano, amino, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C3-C6 cycloalkyl, and -CH2-(C 3-6 Cycloalkyl), -O-(C 3-6 Selected from the group consisting of cycloalkyl, C1-C6 haloalkyl, and -O(C1-C6 haloalkyl), R 6 If it is bonded to a nitrogen atom, it is C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C3-C6 cycloalkyl, -CH2-(C 3-6 Selected from the group consisting of cycloalkyl and C1-C6 haloalkyl groups, R 7 Each of these is independently hydrogen or a C1-C6 alkyl group, and the alkyl group is optionally substituted with 1-2 hydroxyl groups. R 8 is hydrogen, C1-C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Alkenyl, C1-C 10 Alkinyl, C3-C 12 Cycloalkyl, 3-15 member heterocycloalkyl, C6-C 10 It is an aryl or a 5-10 member heteroaryl, and the aryl and heteroaryl are optional, R 11 Substituted with 1 to 6 groups independently selected from, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl groups are optional, oxo and R 11 It is replaced by 1 to 6 groups independently selected from, Alternatively, one R bonded to the same nitrogen atom 7 and one R 8 These combine to form oxo and R 11 Forms a 3-15 member heterocycloalkyl group that is optionally substituted with 1-6 groups independently selected from the above, R 9is hydrogen, -C(O)OR 12 ,-C(O)N(R 12 )2, -S(O)2R 12 -S(O)2N(R 12 )2, or C1-C6 alkyl, R 10 These are independently hydroxy, amino, cyano, fluoro, and -C(=O)OR. 12 -C(=O)N(R 12 )2, C1-C4 alkyl, C1-C4 haloalkyl, -O(C1-C6 alkyl), -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C3-C6 cycloalkyl, where the alkyl, haloalkyl, or cycloalkyl is optional, and hydroxy, amino, cyano, fluoro, -C(=O)OR 12 , and -C(=O)N(R 12 ) Replaced by 1-2 elements selected from 2, R 11 These are, independently, halogen, hydroxy, amino, cyano, and -S(=O)2(R) 13 ), -N(R 12 )S(=O)2(R 13 ), -S(=O)(R 13 ), -N(R 12 )S(=O)(R 13 ), -C(=O)R 13 , -N(R 12 )C(=O)R 13 , C1-C6 alkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-10 member heterocycloalkyl, C6-C 10 Selected from the group consisting of aryls and 5-10 member heteroaryls, aryls and heteroaryls are R 14 Optionally substituted with 1 to 4 groups independently selected from, with alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, and heterocycloalkyl groups being optional, as well as oxo and R 14 It is replaced by 1 to 4 elements independently selected from, Alternatively, two R atoms bonded to the same carbon or nitrogen atom 11 These combine to form a C3-C6 cycloalkyl or a 3-6 member heterocycloalkyl, and the cycloalkyl and heterocycloalkyl are oxo and R 14 It is optionally replaced by 1 to 4 bases independently selected from, R 12 Each of these is independently hydrogen or a C1-C6 alkyl group. R 13 Each of these is independently a hydroxyl, amino, C1-C6 alkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 haloalkyl, C3-C6 cycloalkyl, or a 3- to 6-membered heterocycloalkyl. R 14 These are independently cyano, amino, hydroxy, and -C(=O)OR 12 -C(=O)N(R 12 )2, C1-C6 alkyl, -O(C1-C6 alkyl), -NR 12 Compounds, or pharmaceutically acceptable salts or solvates thereof, that are (C1-C6 alkyl), aryl, heteroaryl, C3-C6 cycloalkyl, or 3- to 6-membered heterocycloalkyl, where each alkyl is optionally substituted with 1 to 2 hydroxyl groups. Embodiment 51.R 3 The compound described in Embodiment 50, or a pharmaceutically acceptable salt or solvate thereof, is a halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl. Embodiment 52.R 3 The compound described in Embodiment 50, or a pharmaceutically acceptable salt or solvate thereof, is fluoro, chloro, cyano, methyl, ethyl, vinyl, -OMe, -C(=O)OH, trifluoromethyl, difluoromethyl, or cyclopropyl. Embodiment 53.R 3 The compound described in any one of Embodiments 50 to 52, or a pharmaceutically acceptable salt or solvate thereof, wherein is chloro, cyano, methyl, or ethyl. Embodiment 54.R 4 The compounds described in any one of Embodiments 50 to 53, or pharmaceutically acceptable salts or solvates thereof, wherein each is independently hydrogen, fluoro, or methyl. Embodiment 55.R 4 The compounds described in any one of embodiments 50 to 53, or pharmaceutically acceptable salts or solvates thereof, wherein each of the elements is hydrogen. Embodiment 56.Z is -C(R 5 )=C(R 5 A compound according to any one of embodiments 50 to 55, or a pharmaceutically acceptable salt or solvate thereof, which is - or -S-. Embodiment 57. Formula (IIa)

[0331] [ka] A compound according to Embodiment 56 having the structure, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 58. Formula (IIb)

[0332] [ka] A compound according to Embodiment 56 having the structure, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 59.Z is -N=C(R 5 )- or -C(R 5 A compound according to any one of embodiments 50 to 55, or a pharmaceutically acceptable salt or solvate thereof, wherein )=N-. Embodiment 60. Formula (IIc)

[0333] [ka] A compound according to Embodiment 59 having the structure, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 61. Formula (IId)

[0334] [ka] A compound according to Embodiment 59 having the structure, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 62.L is a compound according to any one of Embodiments 50 to 61, or a pharmaceutically acceptable salt or solvate thereof, which is a bond or C1 alkylene. Embodiment 63.R 2 is -C(O)(OR 7 ) or -C(O)N(R 8 )(R 7 A compound according to any one of embodiments 50 to 62, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 64.R 2 The compound according to any one of Embodiments 50 to 62, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is a 5-10 member heteroaryl or a 3-15 member heterocycloalkyl. Embodiment 65.R 2 The compound according to any one of embodiments 50 to 62, or a pharmaceutically acceptable salt or solvate thereof, is a 5-6 member heteroaryl or a 3-8 member heterocycloalkyl. Embodiment 66. Formula (III)

[0335] [ka] A compound according to any one of embodiments 50 to 56 having the structure, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 67. Formula (IVa)

[0336] [ka] A compound according to Embodiment 66 having the structure, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 68.R 1This is one to three R compounds independently selected from the group consisting of methyl, ethyl, cyano, fluoro, chloro, -OMe, cyclopropyl, -CH2-cyclopropyl, trifluoromethyl, and difluoromethyl. 6 Replaced by any choice in the base, R 6 If bonded to a nitrogen atom, it is a compound according to any one of Embodiments 50 to 67, selected from the group consisting of methyl, ethyl, cyclopropyl, -CH2-cyclopropyl, trifluoromethyl, trifluoroethyl, and difluoromethyl, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 69.R 1 teeth,

[0337] [ka] The compound described in any one of embodiments 50 to 68, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 70.R 1 This is one to two R compounds independently selected from the group consisting of methyl, cyano, fluoro, chloro, -OMe, cyclopropyl, -CH2-cyclopropyl, and difluoromethyl. 6 Replaced by any choice in the base, R 6 If bonded to a nitrogen atom, it is methyl, cyclopropyl, or -CH2-cyclopropyl, the compound according to any one of Embodiments 50 to 69, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 71.R 1 teeth,

[0338] [ka] And, R 6 Each of these is independently fluoro, chloro, cyano, cyclopropyl, -CH2-cyclopropyl, or methyl, and R 6If bonded to a nitrogen atom, it is methyl, cyclopropyl, or -CH2-cyclopropyl, the compound according to Embodiment 69, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 72.R 1 teeth,

[0339] [ka] And, R 6 The compound described in Embodiment 69, or a pharmaceutically acceptable salt or solvate thereof, wherein is independently fluoro, chloro, cyano, cyclopropyl, -CH2-cyclopropyl, or methyl. Embodiment 73.R 1 teeth,

[0340] [ka] And, R 6 The compound described in Embodiment 69, or a pharmaceutically acceptable salt or solvate thereof, is methyl, cyclopropyl, or -CH2-cyclopropyl. Embodiment 74. Formula (VIa)

[0341] [ka] A compound according to any one of embodiments 50 to 53 having the structure, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 75. Formula (VIIa)

[0342] [ka] A compound according to any one of embodiments 50 to 53 having the structure, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 76.R 6 These are, independently, halogen, cyano, and C. 1-6 Alkyl, C1-6 Fluoroalkyl, C 3-6 Cycloalkyl, or -CH2-(C 3-6 It is a cycloalkyl, and R 6 If it is bonded to a nitrogen atom, then it is C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 3-6 Cycloalkyl, or -CH2-(C 3-6 A compound according to Embodiment 74 or 75, or a pharmaceutically acceptable salt or solvate thereof, which is a cycloalkyl compound. Embodiment 77.R 6 Each of these is independently fluoro, chloro, cyano, cyclopropyl, -CH2-cyclopropyl, or methyl, and R 6 If bonded to a nitrogen atom, it is methyl, cyclopropyl, or -CH2-cyclopropyl, the compound according to Embodiment 74 or 75, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 78.R 5 A compound according to any one of embodiments 50 to 77, or a pharmaceutically acceptable salt or solvate thereof, wherein each is independently hydrogen or fluoro. Embodiment 79.R 5 The compounds described in Embodiment 78, or pharmaceutically acceptable salts or solvates thereof, wherein each of these is hydrogen. Embodiment 80.R 7 Each of the compounds described in any one of Embodiments 50-63 or 66-79, or a pharmaceutically acceptable salt or solvate thereof, wherein each is independently hydrogen or a C1-C6 alkyl group. Embodiment 81.R 8 C1-C 10 Alkyl, C1-C 10 Heteroalkyl, C3-C 12 Cycloalkyl, or 3-15 member heterocycloalkyl, and alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl are oxo and R 11A compound according to any one of embodiments 50-63 or 66-80, or a pharmaceutically acceptable salt or solvate thereof, optionally substituted with 1 to 6 groups independently selected from the above. Embodiment 82.R 8 C1-C 10 Alkyl, C3-C 12 A cycloalkyl or a 3- to 15-membered heterocycloalkyl, wherein alkyl, cycloalkyl, or heterocycloalkyl are oxo and R 11 The compound according to Embodiment 81, or a pharmaceutically acceptable salt or solvate thereof, optionally substituted with 1 to 6 groups independently selected from the above. Embodiment 83.R 8 C3-C 10 A cycloalkyl or a 3- to 12-membered heterocycloalkyl, where the cycloalkyl or heterocycloalkyl is oxo and R 11 The compound according to Embodiment 81 or 82, or a pharmaceutically acceptable salt or solvate thereof, optionally substituted with 1 to 6 groups independently selected from the above. Embodiment 84.R 8 This is a single-ring C3-C 10 Cycloalkyl, condensed bicyclic C5-C 10 Cycloalkyl, cross-linked bicyclic C5-C 10 Cycloalkyl, spirocyclic, bicyclic C5-C 10 The cycloalkyl group is a monocyclic 3-12 member heterocycloalkyl group, a condensed bicyclic 5-12 member heterocycloalkyl group, a cross-linked bicyclic 5-12 member heterocycloalkyl group, or a spirocyclic bicyclic 5-12 member heterocycloalkyl group, and the cycloalkyl group or heterocycloalkyl group is oxo and R 11 A compound according to any one of embodiments 81 to 83, or a pharmaceutically acceptable salt or solvate thereof, optionally substituted with 1 to 6 groups independently selected from the above. Embodiment 85.R 8 This is a condensed biringular C5-C 10 Cycloalkyl, cross-linked bicyclic C5-C 10 Cycloalkyl, spirocyclic, bicyclic C5-C 10The cycloalkyl group is a condensed bicyclic 5-12 member heterocycloalkyl group, a cross-linked bicyclic 5-12 member heterocycloalkyl group, or a spirocyclic bicyclic 5-12 member heterocycloalkyl group, and the cycloalkyl group or heterocycloalkyl group is oxo and R 11 A compound according to any one of embodiments 81 to 84, or a pharmaceutically acceptable salt or solvate thereof, optionally substituted with 1 to 6 groups independently selected from the above. Embodiment 86.R 8 This is a spiro-ring bi-ring C5-C 10 A cycloalkyl or a spirocyclic bicyclic heterocycloalkyl with 5 to 12 members, where the cycloalkyl or heterocycloalkyl is oxo and R 11 A compound according to any one of embodiments 81 to 85, or a pharmaceutically acceptable salt or solvate thereof, optionally substituted with 1 to 6 groups independently selected from the above. Embodiment 87. One R bonded to the same nitrogen atom 7 and one R 8 These combine to form oxo and R 11 A compound according to any one of embodiments 50-62 or 66-79, or a pharmaceutically acceptable salt or solvate thereof, forming a 3- to 15-membered heterocycloalkyl group optionally substituted with 1-6 groups independently selected from the above. Embodiment 88. One R bonded to the same nitrogen atom 7 and one R 8 These combine to form a condensed bicyclic 5-12 member heterocycloalkyl, a cross-linked bicyclic 5-12 member heterocycloalkyl, or a spirocyclic bicyclic 5-12 member heterocycloalkyl, and the heterocycloalkyl is oxo and R 11 The compound according to Embodiment 87, or a pharmaceutically acceptable salt or solvate thereof, optionally substituted with 1 to 6 groups independently selected from the above. Embodiment 89. One R bonded to the same nitrogen atom 7 and one R 8These combine to form a crosslinked bicyclic 5-12 member heterocycloalkyl or a spirocyclic bicyclic 5-12 member heterocycloalkyl, and the heterocycloalkyl is oxo and R 11 The compound according to Embodiment 87 or 88, or a pharmaceutically acceptable salt or solvate thereof, optionally substituted with 1 to 6 groups independently selected from the above. Embodiment 90. One R bonded to the same nitrogen atom 7 and one R 8 These combine to form a spirocyclic bicyclic 5-12 member heterocycloalkyl group, and the heterocycloalkyl group consists of oxo and R 11 A compound according to any one of embodiments 87 to 89, or a pharmaceutically acceptable salt or solvate thereof, optionally substituted with 1 to 6 groups independently selected from the above. Embodiment 91.R 11 These are, independently, halogen, hydroxy, amino, cyano, and -S(=O)2(R) 13 ), -N(R 12 )S(=O)2(R 13 ), -S(=O)(R 13 ), -N(R 12 )S(=O)(R 13 ), -C(=O)R 13 , -N(R 12 )C(=O)R 13 Selected from the group consisting of C1-C6 alkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-10 member heterocycloalkyl, C6 aryl, and 5-6 member heteroaryl, where aryl and heteroaryl are R 14 Optionally substituted with 1 to 4 groups independently selected from, alkyl, haloalkyl, cycloalkyl, and heterocycloalkyl groups, oxo and R 14 It is replaced by 1 to 4 elements independently selected from, Alternatively, two R atoms bonded to the same carbon or nitrogen atom 11These combine to form a C3-C6 cycloalkyl or a 3-6 member heterocycloalkyl, and the cycloalkyl and heterocycloalkyl are oxo and R 14 It is optionally replaced by 1 to 4 bases independently selected from, and also, R 14 The existence of each is independent of cyano, amino, hydroxy, and -C(=O)OR 12 -C(=O)N(R 12 )2, C1-C6 alkyl, -O(C1-C6 alkyl), -NR 12 A compound according to any one of Embodiments 50-62 or 66-90, or a pharmaceutically acceptable salt or solvate thereof, which is a (C1-C6 alkyl), aryl, heteroaryl, C3-C6 cycloalkyl, or 3- to 6-membered heterocycloalkyl, where each alkyl is optionally substituted with 1-2 hydroxyl groups. Embodiment 92.R 11 These are independently fluoro, hydroxy, amino, and -S(=O)2(R) 13 ), -N(R 12 )S(=O)2(R 13 ), -S(=O)(R 13 ), -N(R 12 )S(=O)(R 13 ), -C(=O)R 13 , -N(R 12 )C(=O)R 13 Selected from the group consisting of C1-C6 alkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-10 member heterocycloalkyl, phenyl, and 5-6 member heteroaryl, where phenyl and heteroaryl are R 14 Optionally substituted with 1 to 4 groups independently selected from, alkyl, haloalkyl, cycloalkyl, and heterocycloalkyl groups, oxo and R 14 A compound according to Embodiment 91, or a pharmaceutically acceptable salt or solvate thereof, substituted with 1 to 4 groups independently selected from the above. Embodiment 93.R 11These are, independently, halogen, hydroxy, amino, cyano, and -S(=O)2(R) 13 ), -N(R 12 )S(=O)2(R 13 ), -S(=O)(R 13 ), -N(R 12 )S(=O)(R 13 ), -C(=O)R 13 , -N(R 12 )C(=O)R 13 The group consists of C1-C6 alkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-10 member heterocycloalkyl, and 5-10 member heteroaryl, and the heteroaryl is optional. 14 Substituted with 1 to 4 groups independently selected from, alkyl, haloalkyl, cycloalkyl, and heterocycloalkyl groups are optional, oxo and R 14 It is replaced by 1 to 4 elements independently selected from, Alternatively, two R atoms bonded to the same carbon or nitrogen atom 11 These combine to form a C3-C6 cycloalkyl or a 3-6 member heterocycloalkyl, and the cycloalkyl and heterocycloalkyl are oxo and R 14 It is optionally replaced by 1 to 4 bases independently selected from, R 12 Each of these is independently hydrogen or a C1-C6 alkyl group. R 13 Each of these is independently hydroxy, amino, C1-C6 alkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or C1-C6 haloalkyl. R 14 These are independently cyano, amino, hydroxy, and -C(=O)OR 12 -C(=O)N(R 12 )2, C1-C6 alkyl, -O(C1-C6 alkyl), or -NR 12A compound according to any one of Embodiments 50-62 or 66-90, or a pharmaceutically acceptable salt or solvate thereof, wherein the (C1-C6 alkyl) group is optionally substituted with one or two hydroxyl groups. Embodiment 94.

[0343] [ka] teeth,

[0344] [ka]

[0345] [ka]

[0346] [ka]

[0347] [ka] The compound described in any one of embodiments 66-67 or 74-77, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 95.-LR 2 teeth,

[0348] [ka]

[0349] [ka]

[0350] [ka]

[0351] [ka] The compound described in any one of embodiments 50 to 61, or a pharmaceutically acceptable salt or solvate thereof. Embodiment 96. The compound is one of the compounds described in Embodiment 50, or a pharmaceutically acceptable salt or solvate thereof, which is one of the compounds shown in Table 1. Embodiment 97. A pharmaceutical composition comprising a compound according to any one of Embodiments 50 or 96, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient. Embodiment 98. A method for treating a disease or disorder in a subject requiring treatment, comprising the step of administering to the subject a therapeutically effective amount of a compound described in any one of Embodiments 50 to 96, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition described in Embodiment 97. Embodiment 99. The method according to Embodiment 98, wherein the disease or disorder is a neurokinin receptor 3 (NK3)-dependent disease or disorder. Embodiment 100. The method according to Embodiment 98 or 99, wherein the disease or disorder is selected from the group consisting of migraine, drug abuse headache, cluster headache, generalized headache, trigeminal neuralgia, orofacial pain, and combinations thereof. Embodiment 101. The method according to any one of Embodiments 98 to 100, wherein the disease or disorder is selected from the group consisting of migraine, medication-induced headache, cluster headache, generalized headache, and combinations thereof. Embodiment 102. The method according to any one of Embodiments 98 to 101, wherein the disease or disorder is migraine. Embodiment 103. The method according to any one of Embodiments 98 to 102, further comprising the step of administering an additional therapeutically effective amount of the therapeutic agent. Embodiment 104. Additional therapeutic agents include: beta-blockers, e.g., propranolol, nadolol, timolol, metoprolol, and atenolol; antidepressants, e.g., amitriptyline and venlafaxine; anticonvulsants, e.g., valproate and topiramate; phenothiazine antiemetics, e.g., prochlorperazine; non-phenothiazine antiemetics, e.g., metoclopramide; nonsteroidal anti-inflammatory drugs (NSAIDS), e.g., aspirin, ibuprofen, and naproxen; acetaminophen; caffeine; ergots, e.g., ergotamine. The method according to Embodiment 103, selected from: rin and dihydroergotamine (DHE); ditans, e.g., rasmiditan; triptans, e.g., alumotriptan, eletriptan, fluvatriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan; calcitonin gene-related peptide (CGRP) receptor antagonists, e.g., uvrogepant, rimegepant, atogepant, and zabegepant; CGRP antibodies, e.g., erenumab, fremanezumab, galcanezumab, and eptinezumab; and combinations thereof. [Examples]

[0352] The following embodiments are illustrative and do not limit the scope of this disclosure.

[0353] List of abbreviations As used above, and throughout this description of the present invention, unless otherwise specified, the following abbreviations shall be understood to have the following meanings: NK3 Neurokinin Receptor 3 NKB Neurokinin B FLIPR Fluorescence Imaging Plate Reader eq equivalent g, mg, μg: grams, milligrams, micrograms h, hr(s) time(s) min(s) minutes(s) LCMS (Liquid Chromatography Mass Spectrometry) mL / μl / nL milliliter / microliter / nanol mol / mmol / μmol mole / millimole / micromol N normality, equivalent concentration M molar concentration NMR nuclear magnetic resonance psi (pounds per square inch) RFU (Relative Fluorescence Unit) Acetyl AcOH or HOAc acetic acid OAc Acetate ACN or MeCN acetonitrile Boc tert-butyloxycarbonyl BPD Bis (Pinacolato) Diboron cataCXium A Pd G2 Chloro[(di(1-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) CMPI 2-chloro-N-methylpyridinium iodide Cy Cyclohexyl (Cy)3P-Pg-G3 or Pcy3-Pg-G3 [(tricyclohexylphosphine)-2-(2'-aminobiphenyl)]palladium(II) methanesulfonate DAST Diethylaminosulfur Trifluoride DCE Dichloroethane DCM Dichloromethane DIEA N,N-diisopropylethylamine DME (Dimethoxyethane) DMF (N,N-dimethylformamide) DMP Des-Martin Periodinaan DMSO (Dimethyl Sulfoxide) dppf 1,1'-bis(diphenylphosphin)ferrocene EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Me methyl MeNH2 methylamine, methaneamine MeOH methanol Et ethyl EtOH Ethanol hydroxy,EA ethyl acetate EtMgBr Ethyl Magnesium Bromide iPr isopropyl, 2-propyl iPrOH, IPA Isopropyl alcohol, isopropanol, 2-propanol t-Butyl HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate MTBE methyl tert-butyl ether NBS N-bromosuccinimide NCS N-chlorosuccinimide NMM (N-methylmorpholine) NMO N-methylmorpholine N-oxide Oxone potassium peroxymonosulfate PE (Petroleum Ether) Py Pyridine SEMCl 2-(trimethylsilyl)ethoxymethylchloride TBD Triazabicyclodecene,1,5,7-Triazabicyclo[4.4.0]deca-5-ene Tf Trifluoromethanesulfonyl TfOH Trifluoromethanesulfonic acid TFA (Trifluoroacetic Acid) THF (Tetrahydrofuran) TMS (trimethylsilyl) TBS tert-butyldimethylsilyl Ts tosyl, p-toluenesulfonyl TsOH,PTSA Tosylic Acid, p-Toluene Sulfonic Acid

[0354] I. Chemical synthesis Unless otherwise noted, reagents and solvents were used as they were obtained from commercial suppliers. Anhydrous solvents and oven-dried glassware were used for synthetic transformations sensitive to moisture and / or oxygen. Yields were not optimized. Reaction times were approximate and not optimized. Column chromatography and thin-layer chromatography (TLC) were performed on silica gel unless otherwise noted.

[0355] Example 1: Methyl 2-(2-bromophenyl)imidazo[1,2-a]pyridine-7-carboxylate (1-1)

[0356] [ka]

[0357] Step 1: Methyl 2-(2-bromophenyl)imidazo[1,2-a]pyridine-7-carboxylate (1-1): To a solution of methyl 2-aminoisonicotinate (0.87 g, 5.7 mmol, 1 equivalent) in i-PrOH (10 mL), 2-bromo-1-(2-bromophenyl)ethane-1-one (1.6 g, 5.7 mmol, 1 equivalent) and Na2CO3 (0.61 g, 5.7 mmol, 1 equivalent) were added. The mixture was stirred at 100°C for 4 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®, 40 g SepaFlash® silica flash column, eluate with a 0-15% ethyl acetate / petroleum ether gradient at 100 mL / min) to obtain 1-1 (1.1 g, yield 58%) as a yellow solid. LCMS: (ES + )m / z(M+H) + =333.1. 1 H NMR(400MHz,CDCl3)δ=8.32(s,2H)8.03-8.18(m,2H)7.62(d,J=8.0Hz,1H)7.32-7.43(m,2H)7.11-7.18(m,1H)3.90(s,3H).

[0358] Example 2: 3-Chloro-2-(2-(1,3-dimethyl-1H-pyrazole-4-yl)phenyl)-N-((3R,3aR,6R,6aR)-6-hydroxyhexahydrofluoro[3,2-b]furan-3-yl)imidazo[1,2-a]pyridine-7-carboxamide (Compound 7)

[0359] [ka]

[0360] Step 1: To a solution of methyl 2-(2-(1,3-dimethyl-1H-pyrazole-4-yl)phenyl)imidazo[1,2-a]pyridine-7-carboxylate (7-1):dioxane (250 mL) containing 1-1 (27 g, 0.81 mol, 1 equivalent) and 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (27 g, 0.12 mol, 1.5 equivalents), (Cy)3P-Pd-G3 (6.0 g, 8.1 mol, 0.1 equivalent) and Cs2CO3 (80 g, 0.24 mol, 3 equivalents) were added. The mixture was stirred under N2 at 115°C for 12 hours. The reaction mixture was filtered to remove insoluble matter. The filter liquor was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®, 120g SepaFlash® silica flash column, eluate with a 0-100% ethyl acetate / petroleum ether gradient at 100 mL / min, PE / EA=1 / 1, Rf=0.1) to obtain 7-1 (27g, 94% yield) as a brown solid. LCMS: (ES + )m / z(M+H) + =347.1. 1 H NMR(400MHz,CDCl3)δ ppm 1.92(s,3H)3.91(s,3H)3.96(s,3H)7.05(s,1H)7.27(d,J=3.76Hz,2H)7.31-7.40(m,2H)7.47( td,J=7.58,1.38Hz,1H)7.96(dd,J=7.08,0.68Hz,1H)8.22(dd,J=7.82,1.18Hz,1H)8.35(s,1H)

[0361] Step 2: To a solution of methyl 3-chloro-2-(2-(1,3-dimethyl-1H-pyrazole-4-yl)phenyl)imidazo[1,2-a]pyridine-7-carboxylate (7-2): 27 g, 78 mmol, 1 equivalent of 7-1 in DMF (250 mL), NCS (12 g, 93 mmol, 1.2 equivalents) was added. The mixture was stirred at 60°C for 1 hour. The reaction mixture was diluted with H2O (100 mL) and extracted with EA (100 mL x 3). The combined organic layers were washed with saturated sodium chloride aqueous solution (100 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 120g SepaFlash® silica flash column, eluate with a 0-100% ethyl acetate / petroleum ether gradient at 100 mL / min, PE / EA=0 / 1, Rf=0.4) to obtain 7-2 (15g, 38 mmol, 97% purity) as a yellow solid. LCMS: (ES + )m / z(M+H) + =381.2. 1 H NMR(400MHz,CD3OD)δ ppm 1.90(s,3H),3.69(s,3H),3.98(s,3H),7.22(s,1H),7.46(dd,J=16.70,7.68Hz, 2H),7.51-7.56(m,1H),7.57-7.62(m,2H),8.25(s,1H),8.32(d,J=7.26Hz,1H).

[0362] Step 3: 3-Chloro-2-(2-(1,3-dimethyl-1H-pyrazole-4-yl)phenyl)imidazo[1,2-a]pyridine-7-carboxylic acid (7-3): To a solution of 7-2 (14 g, 37 mmol, 1 equivalent) in THF (60 mL) and H2O (60 mL), LiOH·H2O (3.1 g, 74 mmol, 2 equivalents) was added. The mixture was stirred at 25°C for 1 hour. The reaction mixture was adjusted to pH=5 with 2N HCl. The reaction mixture was then filtered, and the filtered cake was dried under vacuum. The crude product was purified by recrystallization from H2O (50 mL) at 25°C to obtain 7-3 (15 g, 32 mmol, yield 88%, 2HCl) as a yellow solid. LCMS: (ES+ )m / z(M+H) + =367.0. 1 H NMR(400MHz,CD3OD)δ ppm 1.91(s,3H),3.69(s,3H),7.22(s,1H),7.41-7.50(m,2H),7.53(d,J=7.52H z,1H),7.60(dd,J=6.50,5.12Hz,2H),8.25(s,1H),8.30(d,J=7.14Hz,1H).

[0363] Step 4: 3-Chloro-2-(2-(1,3-dimethyl-1H-pyrazole-4-yl)phenyl)-N-((3R,3aR,6R,6aR)-6-hydroxyhexahydrofl[3,2-b]furan-3-yl)imidazo[1,2-a]pyridine-7-carboxamide (Compound 7): To a solution of (3R,3aR,6R,6aR)-6-aminohexahydrofl[3,2-b]furan-3-ol (2 g, 14 mmol, 1 equivalent) and 7-3 (5.9 g, 14 mmol, 1 equivalent), HATU (6.3 g, 16 mmol, 1.2 equivalents) and DIEA (7.1 g, 55 mmol, 9.6 mL, 4 equivalents) were added. The mixture was stirred at 25°C for 1 hour. The reaction mixture was diluted with H2O (100 mL) and extracted with EA (100 mL x 3). The combined organic layer was washed with saturated brine (100 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by reverse-phase HPLC (column: Phenomenex luna C18 (250 × 70 mm, 10 μm), mobile phase: [water (0.1% NH4HCO3)-ACN], gradient: 17%~47% B over 20 minutes) to obtain compound 7 (2.5 g, yield 35%) as an off-white solid. LCMS: (ES + )m / z(MH) + =494.1. 1H NMR(400MHz,CD3OD)δ ppm 1.88(s,3H)3.64-3.68(m,1H)3.69(s,3H)3.73-3.81(m,1H)3.96(dd,J=8.88,6.12Hz,1H)4.16-4.24(m,1H)4.29-4.37(m,1H)4.59(t,J= 4.64Hz,1H)4.62-4.70(m,2H)7.23(s,1H)7.40-7.44(m,1H)7.45-7.55(m,3H)7.59(d,J=7.50Hz,1H)8.10(s,1H)8.30(d,J=7.14Hz,1H).

[0364] Example 3: 3-Chloro-2-(2-(1,3-dimethyl-1H-pyrazole-4-yl)-4-fluorophenyl)-N-((3R,3aR,6R,6aR)-6-hydroxyhexahydrofluoro[3,2-b]furan-3-yl)imidazo[1,2-a]pyridine-7-carboxamide (Compound 16)

[0365] [ka]

[0366] Step 1: 2-Bromo-1-(2-bromo-4-fluorophenyl)ethan-1-one (16-1): To a solution of 1-(2-bromo-4-fluorophenyl)ethanone (5.0 g, 23 mmol, 1.0 equivalent) in ACN (100 mL), TsOH.H2O (5.3 g, 28 mmol, 1.2 equivalents) and NBS (4.5 g, 25 mmol, 1.1 equivalents) were added. The mixture was stirred at 50°C for 12 hours. The reaction mixture was diluted with H2O (100 mL) and extracted with ELISA (100 mL x 3). The combined organic layers were washed with saturated brine (100 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to obtain 16-1 (6.3 g, 18 mmol, yield 79%, purity 85%) as a colorless oil. 1H NMR(400MHz,CD3OD)δ=7.75-7.70(m,1H),7.56-7.52(m,1H),7.28-7.23(m,1H),4.61(s,2H).

[0367] Step 2: Methyl 2-(2-bromo-4-fluorophenyl)imidazo[1,2-a]pyridine-7-carboxylate (16-2): To a solution of 16-1 (2.0 g, 6.8 mmol, 1.0 equivalent) and methyl 2-aminoisonicotinate (1.1 g, 7.4 mmol, 1.1 equivalents) in DMF (20 mL), KHCO3 (0.74 g, 7.4 mmol, 1.1 equivalents) was added. The mixture was stirred at 100°C for 12 hours. The reaction mixture was diluted with H2O (100 mL) and extracted with SiO (100 mL x 3). The combined organic layers were washed with saturated brine (100 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0~3 / 1) to obtain 16-2 (1.2 g, 3.2 mmol, yield 47%, purity 92%) as a yellow solid. LCMS:(ES + )m / z(M+H) + =350.7

[0368] Step 3: To a solution of methyl 2-(2-(1,3-dimethyl-1H-pyrazole-4-yl)-4-fluorophenyl)imidazo[1,2-a]pyridine-7-carboxylate (16-3):dioxane (15 mL) containing 16-2 (1.2 g, 3.4 mmol, 1.0 equivalent) and 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.0 g, 4.5 mmol, 1.3 equivalents), Cs2CO3 (3.4 g, 10 mmol, 3.0 equivalents) and (Cy)3P Pd G3 (0.25 g, 0.34 mmol, 0.10 equivalents) was added. The mixture was degassed, purged three times with N2, and stirred at 115°C for 5 hours under an N2 atmosphere. The reaction mixture was diluted with H2O (100 mL) and extracted with RINKAN (100 mL x 3). The combined organic layer was washed with saturated brine (100 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0~1 / 3) to obtain 16-3 (1.2 g, 2.8 mmol, yield 82%, purity 85%) as a yellow oil. LCMS:(ES + )m / z(M+H) + =365.0.

[0369] Step 4: Methyl 3-chloro-2-(2-(1,3-dimethyl-1H-pyrazole-4-yl)-4-fluorophenyl)imidazo[1,2-a]pyridine-7-carboxylate (16-4): To a solution of 16-3 (1.2 g, 3.3 mmol, 1.0 equivalent) in DMF (20 mL), NCS (0.44 g, 3.3 mmol, 1.0 equivalent) was added. The mixture was stirred at 40°C for 2 hours. The reaction mixture was diluted with H2O (100 mL) and extracted with ELISA (100 mL x 3). The combined organic layers were washed with saturated brine (100 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 16-4 (1.3 g, crude) as a yellow oil. LCMS: (ES + )m / z(M+H) + =399.1.

[0370] Step 5: To a solution of 16-4 (1.3 g, 3.3 mmol, 1.0 equivalent) in 3-chloro-2-(2-(1,3-dimethyl-1H-pyrazole-4-yl)-4-fluorophenyl)imidazo[1,2-a]pyridine-7-carboxylic acid (16-5): LiOH,H2O (0.69 g, 16 mmol, 5.0 equivalent) was added to MeOH (5.0 mL), H2O (5.0 mL), and THF (5.0 mL). The mixture was stirred at 25°C for 2 hours. The reaction mixture was adjusted to pH 4 by adding 1N HCl. The reaction mixture was diluted with H2O (100 mL) and extracted with ELISA (100 mL x 3). The combined organic layers were washed with saturated brine (100 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by reverse-phase HPLC (0.1% FA conditions) (330g Flash Column Welch Ultimate XB_C18 20-40μm; 120A, 100mL / min, H2O + ACN, 5-35%, 20 min; 35%, 5 min, Biotage Prime) to obtain 16-5 (0.60g, 1.6 mmol, yield 48%, purity 100%) as a yellow solid. LCMS: (ES + )m / z(M+H) + =384.9.

[0371] Step 6: 3-Chloro-2-(2-(1,3-dimethyl-1H-pyrazole-4-yl)-4-fluorophenyl)-N-((3R,3aR,6R,6aR)-6-hydroxyhexahydrofluoro[3,2-b]furan-3-yl)imidazo[1,2-a]pyridine-7-carboxamide (compound 16): To a solution of 16-5 (0.15 g, 0.39 mmol, 1.0 equivalent) in DMF (2 mL), HATU (0.30 g, 0.78 mmol, 2.0 equivalents) and DIEA (0.25 g, 2.0 mmol, 0.34 mL, 5.0 equivalents) were added. The mixture was stirred at 25°C for 10 minutes. Subsequently, (3R,3aR,6R,6aR)-6-aminohexahydroflu[3,2-b]furan-3-ol (62 mg, 0.43 mmol, 1.1 equivalents) was added to the mixture, and the mixture was stirred at 25°C for 30 minutes. The reaction mixture was diluted with H2O (30 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (50 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by reverse-phase HPLC (neutral conditions) (40g Flash Column Welch Ultimate XB_C18 20-40μm; 120A, 100mL / min, H2O + ACN, 5-45% 20 min; 45% 5 min, Biotage Prime) to obtain compound 16 (0.12g, 0.23 mmol, yield 58%, purity 97%) as a white solid. LCMS: (ES + )m / z(M+H) + =512.2. 1 H NMR(400MHz,CD3OD)δ=8.31(d,J=7.2Hz,1H),8.10(s,1H),7.64-7.57(m,1H),7.53-7.47(m,1H),7.27(s,1H),7.25-7.17(m,2H),4.69-4.62(m,2H) ),4.59(t,J=4.8Hz,1H),4.37-4.30(m,1H),4.23-4.16(m,1H),3.98-3.9 3(m,1H),3.80-3.74(m,1H),3.69(s,3H),3.68-3.65(m,1H),1.89(s,3H).

[0372] Example 4: 2-(2-(1,3-dimethyl-1H-pyrazole-4-yl)-6-fluorophenyl)-N-((3R,3aR,6R,6aR)-6-hydroxyhexahydrofluoro[3,2-b]furan-3-yl)-3-methylimidazo[1,2-a]pyridine-7-carboxamide (Compound 17)

[0373] [ka]

[0374] Step 1: To a solution of methyl 2-aminopyridine-4-carboxylate (2.0 g, 13 mmol, 1.0 equivalent) and 2-bromo-6-fluorobenzaldehyde (2.7 g, 13 mmol, 1.0 equivalent) in methyl 2-(2-bromo-6-fluorophenyl)-3-methylimidazo[1,2-a]pyridine-7-carboxylate (17-1): methyl 2-aminopyridine-4-carboxylate (2.0 g, 13 mmol, 1.0 equivalent) and 2-bromo-6-fluorobenzaldehyde (2.7 g, 13 mmol, 1.0 equivalent) in 1-nitroethane (22 g, 0.29 mol, 21 mL, 22 equivalents), FeCl3 (0.21 g, 1.3 mmol, 76 μL, 0.1 equivalent) was added. The mixture was stirred in air at 100°C for 12 hours. The reaction mixture was diluted with H2O (50 mL) and extracted with siRNA (100 mL x 3). The combined organic layers were washed with saturated brine (80 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 20g SepaFlash® silica flash column, eluate with a 0-25% ethyl acetate / petroleum ether gradient at 100 mL / min, PE / EA=1 / 1, Rf=0.59) to obtain 17-1 (2.2 g, yield 44%) as a yellow solid. LCMS: (ES + )m / z(M+H) + =364.6. 1 H NMR(400MHz,CDCl3)δ=2.29-2.39(m,3H)3.90(s,3H)7.04-7.14(m,1H)7.14-7.31(m,1H)7.35-7.55(m,2H)7.79-7.96(m,1H)8.33(s,1H).

[0375] Step 2: A mixture of methyl 2-(2-(1,3-dimethyl-1H-pyrazole-4-yl)-6-fluorophenyl)-3-methylimidazo[1,2-a]pyridine-7-carboxylate (17-2):dioxane (8 mL) containing 17-1 (0.5 g, 1.4 mmol, 1.0 equivalent), 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (0.61 g, 2.8 mmol, 2.0 equivalent), (Cy)3P Pd G3 (0.10 g, 0.14 mmol, 0.1 equivalent), and Cs2CO3 (1.4 g, 4.1 mmol, 3.0 equivalent) was degassed and purged three times with N2. The mixture was stirred at 115°C for 12 hours under an N2 atmosphere. The residue was obtained by concentrating the mixture. The residue was purified by flash silica gel chromatography (ISCO®, 12g SepaFlash® silica flash column, eluate with a 0-80% ethyl acetate / petroleum ether gradient at 100 mL / min, PE / EA=1 / 1, Rf=0.1) to obtain 17-2 (0.4g, yield 74%, purity 97%) as a yellow oil. LCMS: (ES + )m / z(M+H) + =379.2. 1 H NMR(400MHz,CDCl3)δ=2.03-2.05(m,3H)2.09-2.17(m,3H)3.62-3.71(m,3H)3.89-4.07(m ,3H)6.90-7.04(m,1H)7.07-7.24(m,2H)7.34-7.54(m,2H)7.80-7.86(m,1H)8.36(s,1H).

[0376] Step 3: 2-(2-(1,3-dimethyl-1H-pyrazole-4-yl)-6-fluorophenyl)-3-methylimidazo[1,2-a]pyridine-7-carboxylic acid (17-3): To a solution of 17-2 (0.4 g, 1.1 mmol, 1.0 equivalent) in THF (1.5 mL) and H2O (1.5 mL), LiOH.H2O (0.13 g, 3.2 mmol, 3.0 equivalent) was added. The mixture was stirred at 25°C for 2 hours. 2 M HCl was added to the reaction mixture to pH=5, and the mixture was concentrated under reduced pressure to obtain 17-3 (0.5 g, crude) as a yellow oil. LCMS: (ES +)m / z(M+H) + =365.1.

[0377] Step 4: 2-(2-(1,3-dimethyl-1H-pyrazole-4-yl)-6-fluorophenyl)-N-((3R,3aR,6R,6aR)-6-hydroxyhexahydrofluoro[3,2-b]furan-3-yl)-3-methylimidazo[1,2-a]pyridine-7-carboxamide (compound 17): 17-3 (0.15 g, 0.3) in DMF (2 mL) solution To a solution of (4 mmol, 1.0 equivalent) and (3R,3aR,6R,6aR)-3-amino-2,3,3a,5,6,6a-hexahydroflu[3,2-b]furan-6-ol (69 mg, 0.38 mmol, 1.1 equivalents), HATU (0.26 g, 0.69 mmol, 2.0 equivalents) and DIEA (0.22 g, 1.7 mmol, 5.0 equivalents) were added. The mixture was stirred at 25°C for 1 hour. The mixture was concentrated to obtain a residue. The residue was purified by preparative HPLC (column: Waters xbridge xbridge 150 × 25 mm × 10 μm, mobile phase: [water (0.1% NH4HCO3)-ACN], B%: 16%~46%, 10 min) to obtain compound 17 (0.1 g, yield 59%) as a white solid. LCMS:(ES + )m / z(M+H) + =492.3. 1 H NMR(400MHz,CD3OD)δ=1.85-2.02(m,3H)2.12-2.26(m,3H)3.51-3.66(m,3H)3 .66-3.73(m,1H)3.73-3.82(m,1H)3.91-4.04(m,1H)4.11-4.28(m,1H)4.28-4. 42(m,1H)4.51-4.61(m,1H)4.62-4.74(m,2H)7.05-7.15(m,1H)7.15-7.30(m,2 H)7.33-7.45(m,1H)7.46-7.60(m,1H)8.01-8.13(m,1H)8.22(d,J=8.0Hz,1H).

[0378] Example 5: 3-Chloro-2-(2-(1,3-dimethyl-1H-pyrazole-4-yl)-3-fluorophenyl)-N-((3R,3aR,6R,6aR)-6-hydroxyhexahydrofluoro[3,2-b]furan-3-yl)imidazo[1,2-a]pyridine-7-carboxamide (Compound 18)

[0379] [ka]

[0380] Step 1: 2-Bromo-1-(2-bromo-3-fluorophenyl)ethan-1-one (18-1): To a solution of 1-(2-bromo-3-fluorophenyl)ethanone (0.50 g, 2.3 mmol, 1.0 equivalent) in ACN (5 mL), NBS (0.49 g, 2.8 mmol, 1.2 equivalents) and TsOH (0.60 g, 3.5 mmol, 1.5 equivalents) were added at 0°C. The mixture was stirred at 60°C for 2 hours. The reaction mixture was quenched by adding water (50 mL), then diluted with ethyl acetate (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with saturated brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1:0 to 30:1) to obtain 18-1 (0.56 g, 1.6 mmol, yield 70%, purity 85%) as a yellow oil. 1 H NMR(400MHz, CDCl3)δ=7.41-7.30(m,1H),7.25-7.10(m,2H),4.40(s,2H).

[0381] Step 2: Methyl 2-(2-bromo-3-fluorophenyl)imidazo[1,2-a]pyridine-7-carboxylate (18-2): To a solution of 18-1 (0.30 g, 0.86 mmol, 1.0 equivalent) and methyl 2-aminoisonicotinate (0.13 g, 0.86 mmol, 1.0 equivalent) in DMF (5 mL), KHCO3 (86 mg, 0.86 mmol, 1.0 equivalent) was added. The mixture was stirred at 100°C for 3 hours. The reaction mixture was quenched by adding water (50 mL), then diluted with ethyl acetate (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with saturated brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1:0~5:1) to obtain 18-2 (0.30 g, 0.69 mmol, yield 80%, purity 80%) as a yellow oil. LCMS:(ES + )m / z(M+H) + =350.9. 1 H NMR(400MHz,CDCl3)δ=8.43(s,1H),8.25-8.20(m,1H),8.00-7.90(m,1H),7.50-7.45(m,1H),7.45-7.35(m,1H),7.25-7.15(m,2H),3.99(s,3H).

[0382] Step 3: To a solution of methyl 2-(2-(1,3-dimethyl-1H-pyrazole-4-yl)-3-fluorophenyl)imidazo[1,2-a]pyridine-7-carboxylate (18-3):dioxane (5 mL) containing 18-2 (0.30 g, 0.69 mmol, 1.0 equivalent) and 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.23 g, 1.0 mmol, 1.5 equivalents), Cs2CO3 (0.67 g, 2.1 mmol, 3.0 equivalents) and (Cy)3P-Pd G3 (51 mg, 69 μmol, 0.1 equivalent) was added. The mixture was degassed, purged three times with N2, and then stirred at 115°C under N2 for 5 hours. The reaction mixture was quenched by adding water (50 mL), then diluted with ethyl acetate (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with saturated brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1:0~0:1) to obtain 18-3 (0.20 g, 0.54 mmol, yield 78%, purity 98%) as a yellow oil. LCMS:(ES + )m / z(M+H) + =365.1.

[0383] Step 4: Methyl 3-chloro-2-(2-(1,3-dimethyl-1H-pyrazole-4-yl)-3-fluorophenyl)imidazo[1,2-a]pyridine-7-carboxylate (18-4): To a solution of 18-3 (0.18 g, 0.49 mmol, 1.0 equivalent) in DMF (2 mL), NCS (66 mg, 0.49 mmol, 1.0 equivalent) was added at 0°C. The mixture was stirred at 40°C for 1 hour. The reaction mixture was quenched by adding water (30 mL), then diluted with ethyl acetate (30 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic layer was washed with saturated brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 18-4 (0.18 g, crude) as a yellow oil. LCMS: (ES + )m / z(M+H) + =399.1.

[0384] Step 5: 3-Chloro-2-(2-(1,3-dimethyl-1H-pyrazole-4-yl)-3-fluorophenyl)imidazo[1,2-a]pyridine-7-carboxylic acid (18-5): To a solution of 18-4 (0.18 g, 0.45 mmol, 1.0 equivalent) in i-PrOH (0.5 mL), THF (0.5 mL), and H2O (0.5 mL), LiOH.H2O (47 mg, 1.1 mmol, 2.5 equivalents) was added. The mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (0.1% FA conditions) to obtain 18-5 (0.17 g, 0.39 mmol, yield 86%, purity 98%, FA) as a yellow solid. LCMS: (ES + )m / z(M+H) + =385.0. 1 H NMR(400MHz,CDCl3)δ=8.47(s,1H),8.10-8.00(m,1H),7.65-7.55(m,1H),7.50 -7.40(m,2H),7.35-7.25(m,1H),7.25-7.20(m,1H),3.81(s,3H),1.98(s,3H).

[0385] Step 6: 3-Chloro-2-(2-(1,3-dimethyl-1H-pyrazole-4-yl)-3-fluorophenyl)-N-((3R,3aR,6R,6aR)-6-hydroxyhexahydrofluoro[3,2-b]furan-3-yl)imidazo[1,2-a]pyridine-7-carboxamide (compound 18): To a solution of 18-5 (0.15 g, 0.39 mmol, 1.0 equivalent) in DMF (2 mL), HATU (0.30 g, 0.78 mmol, 2.0 equivalents) and DIEA (0.15 g, 1.2 mmol, 3.0 equivalents) were added. The mixture was stirred at 25°C for 0.2 hours. Subsequently, (3R,3aR,6R,6aR)-6-aminohexahydroflu[3,2-b]furan-3-ol (57 mg, 0.39 mmol, 1.0 equivalent) was added to the solution, and the mixture was stirred at 25°C for 0.8 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 × 25 mm × 10 μm, mobile phase: [water (FA)-ACN], gradient: 18%~48%B over 11 minutes) to obtain compound 18 (62 mg, yield 29%, purity 99%, FA) as a white solid. LCMS: (ES + )m / z(M+H) + =512.1. 1 H NMR(400MHz,CD3OD)δ=8.31(d,J=7.2Hz,1H),8.10(s,1H),7.55-7.47(m,2 H),7.45-7.40(m,1H),7.37-7.29(m,1H),7.26(s,1H),4.70-4.63(m,2H), 4.59(d,J=4.8Hz,1H),4.33(q,J=5.2Hz,1H),4.25-4.15(m,1H),4.00-3.9 0(m,1H),3.80-3.75(m,1H),3.69(s,3H),3.67-3.62(m,1H),1.91(s,3H).

[0386] Example 6: 3-Chloro-2-(2-(1,3-dimethyl-1H-pyrazole-4-yl)-4,6-difluorophenyl)-N-((3R,3aR,6R,6aR)-6-hydroxyhexahydrofluoro[3,2-b]furan-3-yl)imidazo[1,2-a]pyridine-7-carboxamide (Compound 787)

[0387] [ka]

[0388] Step 1: 1-(2-bromo-4,6-difluorophenyl)ethane-1-one (19-1): A solution of 1-bromo-3,5-difluoro-2-iodobenzene (50 g, 0.16 mol, 1 equivalent) in THF (50 mL) was degassed, purged three times with N2, then cooled to -78°C, and i-PrMgCl (2 M in THF, 94 mL, 1.2 equivalents) was added dropwise. The mixture was stirred for 2 hours. Then the temperature was raised to -60°C, and CuCl (11 g, 0.11 mol, 2.6 mL, 0.7 equivalents) was added. The solution was heated to -40°C over 1 hour, and then acetyl chloride (15 g, 0.19 mol, 13 mL, 1.2 equivalents) was added dropwise under an N2 atmosphere. After heating to 25°C, the solution was heated to 50°C for 0.5 hours. The reaction mixture was quenched at 0°C by adding saturated NH4Cl aqueous solution (200 mL), and then extracted with EA (200 mL x 3). The combined organic layer was washed with saturated sodium chloride aqueous solution (50 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 330 g SepaFlash® silica flash column, eluate with a 0-5% ethyl acetate / petroleum ether gradient at 100 mL / min) to obtain 19-1 (31 g, yield 84%) as a yellow oil.

[0389] Step 2: 2-Bromo-1-(2-bromo-4,6-difluorophenyl)ethane-1-one (19-2): A solution of 19-1 (25 g, 0.11 mol, 1 equivalent) in ACN (250 mL) was degassed, purged three times with N2, and then NBS (28 g, 0.16 mol, 1.5 equivalents) and TsOH·H2O (30 g, 0.16 mol, 1.5 equivalents) were added at 0°C. The mixture was stirred at 80°C for 12 hours. The mixture was diluted with H2O (300 mL) and extracted with EA (200 mL x 3). The combined organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 120g SepaFlash® silica flash column, eluate with a 0-5% ethyl acetate / petroleum ether gradient at 100 mL / min) to obtain 19-2 (33g, 75% yield) as a yellow oil. 1 H NMR(400MHz, CDCl3)δ=7.26-7.16(m,1H),6.98-6.84(m,1H),4.35(s,2H).

[0390] [ka]

[0391] Step 3: To a solution of methyl 2-(2-bromo-4,6-difluorophenyl)imidazo[1,2-a]pyridine-7-carboxylate (19-3): 19-2 (33 g, 0.11 mol, 1 equivalent) and methyl 2-aminoisonicotinate (24 g, 0.16 mol, 1.5 equivalents) in i-PrOH (200 mL), NaHCO3 (8.8 g, 0.11 mol, 4.1 mL, 1 equivalent) was added. The mixture was degassed and purged three times with N2. The mixture was stirred at 100°C for 12 hours. The mixture was diluted with H2O (300 mL) and extracted with EA (200 mL x 3). The combined organic layers were washed with saturated sodium chloride aqueous solution (100 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 120g SepaFlash® silica flash column, eluate with a 0-30% ethyl acetate / petroleum ether gradient at 100 mL / min) to obtain 19-3 (35g, yield 82%) as a yellow solid. LCMS: (ES + )m / z(M+H) + =366.8. 1 H NMR(400MHz,CDCl3)δ=8.42(s,1H),8.21(d,J=6.8Hz,1H),7.84(s,1H),7.47(dd,J =1.6,7.2Hz,1H),7.31(td,J=2.1,7.9Hz,1H),6.95(dt,J=2,8Hz,1H),3.98(s,3H).

[0392] Step 4: Methyl 2-(2-(1,3-dimethyl-1H-pyrazole-4-yl)-4,6-difluorophenyl)imidazo[1,2-a]pyridine-7-carboxylate (19-4): The solution of 19-3 (35 g, 0.1 mol, 1 equivalent) and 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (42 g, 0.2 mol, 2 equivalents) in 300 mL of dioxane was degassed and purged three times with N2. To the mixture, Cs2CO3 (62 g, 0.19 mol, 2 equivalents) and [2-(2-aminophenyl)phenyl]-methylsulfonyloxypalladium, dichloromethane, and tricyclohexylphosphan (3.50 g, 4.8 mmol, 0.1 equivalent) were added under an N2 atmosphere. The mixture was stirred at 110°C for 12 hours. The mixture was diluted with H2O (500 mL) and extracted with EA (300 mL x 3). The combined organic layers were washed with saturated sodium chloride aqueous solution (200 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 330 g SepaFlash® silica flash column, eluate with a 0-70% ethyl acetate / petroleum ether gradient at 100 mL / min) to obtain 19-4 (16 g, yield 43%) as a yellow solid. LCMS: (ES + )m / z(M+H) + =382.9.

[0393] [ka]

[0394] Step 5: Methyl 3-chloro-2-(2-(1,3-dimethyl-1H-pyrazole-4-yl)-4,6-difluorophenyl)imidazo[1,2-a]pyridine-7-carboxylate (19-5): To a solution of 19-4 (16 g, 42 mmol, 1 equivalent) in ACN (200 mL), NCS (6.2 g, 46 mmol, 1.1 equivalents) was added at 0°C. The mixture was stirred at 55°C for 12 hours. The mixture was diluted with H2O (500 mL) and extracted with EA (300 mL x 3). The combined organic layers were washed with saturated sodium chloride aqueous solution (200 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 330g SepaFlash® silica flash column, eluate with a 0-60% ethyl acetate / petroleum ether gradient at 100 mL / min) to obtain 19-5 (16.6 g, 95% yield) as a yellow solid. LCMS: (ES + )m / z(M+H) + =416.9. 1 H NMR(400MHz,CD3OD)δ=8.35(d,J=7.2Hz,1H),8.25(s,1H),7.61(dd,J=1.6,7.2 Hz,1H),7.18(s,1H),7.16-7.06(m,2H),3.98(s,3H),3.64(s,3H),2.00(s,3H).

[0395] Step 6: 3-Chloro-2-(2-(1,3-dimethyl-1H-pyrazole-4-yl)-4,6-difluorophenyl)imidazo[1,2-a]pyridine-7-carboxylic acid (19-6): To a solution of 19-5 (17 g, 40 mmol, 1 equivalent) in THF (80 mL) and H2O (80 mL), LiOH·H2O (3.3 g, 80 mmol, 2 equivalents) was added at 0°C. The mixture was stirred at 25°C for 2 hours. The mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by reverse-phase HPLC (Santai Technologies SepaFlash® cartridge 184.4 × 26.7 mm × 40~60 μm, mobile phase: [A: water (0.1% FA), B: ACN], B%: 45%~50%, 20 min) to obtain 19-6 (12 g, yield 67%) as a white solid. LCMS: (ES + )m / z(M+H) + =403. 1 H NMR (400MHz,METHANOL-d4)δ=8.33(d,J=7.2Hz,1H),8.24(s,1H),7.61(dd,J=1.6,7.2Hz,1H),7.18(s,1H),7.15-7.06(m,2H),3.64(s,3H),2.01(s,3H).

[0396] Step 7: 3-Chloro-2-(2-(1,3-dimethyl-1H-pyrazole-4-yl)-4,6-difluorophenyl)-N-((3R,3aR,6R,6aR)-6-hydroxyhexahydrofluoro[3,2-b]furan-3-yl)imidazo[1,2-a]pyridine-7-carboxamide (compound 787): To a solution of 19-6 (3 g, 7.5 mmol, 1 equivalent) in DMAC (30 mL), HATU (5.7 g, 15 mmol, 2 equivalents) and DIPEA (3.9 g, 30 mmol, 5.2 mL, 4 equivalents) were added at 0°C. The mixture was stirred at 25°C for 0.5 hours, after which (3R,3aR,6R,6aR)-6-aminohexahydroflu[3,2-b]furan-3-ol (1.4 g, 9.7 mmol, 1.3 equivalents) was added. The mixture was stirred at 25°C for 12 hours. The mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250 × 50 mm × 10 μm, mobile phase: [A: water (0.1% FA), B: ACN], B%: 25%~53%, 18 min) to obtain compound 787 (1.9 g, yield 44%) as a white solid. LCMS: (ES + )m / z(M+H) + =530.1. 1 H NMR(400MHz,METHANOL-d4)δ=8.35(d,J=7.2Hz,1H),8.10(s,1H),7.52(dd,J=1.6,7.2Hz,1H),7.18(s,1H),7.16-7.05(m,2H),4.70-4.61(m,2) H),4.59(t,J=4.8Hz,1H),4.37-4.29(m,1H),4.24-4.15(m,1H),3.95(dd,J=6,8.8Hz,1H),3.81-3.73(m,1H),3.70-3.60(m,4H),1.99(s,3H).

[0397] Example 7: 3-Chloro-2-(2-(3-chloro-1H-pyrazole-4-yl)-4,6-difluorophenyl)-N-(1-methyl-2-oxabicyclo[2.1.1]hexane-4-yl)imidazo[1,2-a]pyridine-7-carboxamide (compound 788)

[0398] [ka]

[0399] Step 1: 3-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (20-1): To a solution of 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5.0 g, 22 mmol, 1.0 equivalent) in DCM (50 mL), DIEA (8.5 g, 66 mmol, 11.0 mL, 3.0 equivalents) and SEMCl (5.5 g, 33 mmol, 5.8 mL, 1.5 equivalents) were added. The mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with H2O (100 mL) and extracted with EA (100 mL x 2). The combined organic layers were washed with saturated brine (150 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 80 g SepaFlash® silica flash column, eluate with a 0-10% ethyl acetate / petroleum ether gradient at 100 mL / min) to obtain 20-1 (6.0 g, yield 76%) as a yellow oil. 1 H NMR(400MHz,CD3OD)δ=7.97(s,1H),5.37(s,2H),3.64-3.59(t,J=7.6Hz,2H),1.34(s,12H),0.90(t,J=7.6Hz,2H),0.00(s,9H).

[0400] Step 2: A solution of methyl 2-(2-(3-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-yl)-4,6-difluorophenyl)imidazo[1,2-a]pyridine-7-carboxylate (20-2):dioxane (50 mL) containing 19-3 (4.7 g, 13 mmol, 1.0 equivalent), 20-1 (6.0 g, 17 mmol, 1.3 equivalents), and Cs2CO3 (13.0 g, 38 mmol, 3.0 equivalents) was degassed and purged three times with N2. Then, PCy3-Pd-G3 (0.9 mg, 1.3 mmol, 0.1 equivalents) was added to the reaction mixture under an N2 atmosphere. The mixture was stirred at 110°C for 2 hours. The reaction mixture was diluted with H2O (50 mL) and extracted with EA (50 mL x 3). The combined organic layers were washed with saturated brine (50 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 80 g SepaFlash® silica flash column, eluate with a 20-30% ethyl acetate / petroleum ether gradient at 100 mL / min) to obtain 20-2 (4.9 g, yield 74%) as a yellow oil. 1 H NMR(400MHz,CD3OD)δ=8.55(d,J=7.2Hz,1H),8.23(s,1H),8.04(s,1H),7.52(d,J=7.2Hz,1H),7.39(s,1H) ),7.24-7.20(m,2H),5.46(s,2H),4.02(s,3H),3.58(t,J=7.6Hz,2H),0.88(t,J=7.6Hz,2H),0.00(s,9H).

[0401] Step 3: Methyl 3-chloro-2-(2-(3-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-yl)-4,6-difluorophenyl)imidazo[1,2-a]pyridine-7-carboxylate (20-3): To a solution of 20-2 (4.9 g, 9.4 mmol, 1.0 equivalent) in ACN (49 mL), NCS (1.5 g, 11 mmol, 1.2 equivalents) was added. The mixture was stirred at 45°C for 12 hours. The reaction mixture was diluted with H2O (50 mL) and extracted with EA (50 mL x 3). The combined organic layers were washed with saturated brine (60 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 40g SepaFlash® silica flash column, eluate with a 15-15% ethyl acetate / petroleum ether gradient at 100 mL / min) to obtain 20-3 (3.6 g, yield 66%) as a yellow oil. LCMS: (ES + )m / z(M+H) + =553.1. 1 H NMR(400MHz,CD3OD)δ=8.44(d,J=7.2Hz,1H),8.30(s,1H),7.68(d,J=7.2Hz,1H),7.56(s,1H),7.32 -7.28(m,2H),5.45(s,2H),4.04(s,3H),3.55(t,J=7.6Hz,2H),0.86(t,J=7.6Hz,2H),0.00(s,9H).

[0402] Step 4: Methyl 3-chloro-2-(2-(3-chloro-1H-pyrazole-4-yl)-4,6-difluorophenyl)imidazo[1,2-a]pyridine-7-carboxylate (20-4): To a solution of 20-3 (3.6 g, 6.3 mmol, 1.0 equivalent) in DCM (36 mL), TFA (0.5 mol, 36 mL, 77.0 equivalents) was added. The mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain 20-4 (2.6 g, crude) as a yellow oil.

[0403] Step 5: 3-Chloro-2-(2-(3-chloro-1H-pyrazole-4-yl)-4,6-difluorophenyl)imidazo[1,2-a]pyridine-7-carboxylic acid (20-5): To a solution of 20-4 (2.6 g, 6.1 mmol, 1.0 equivalent) in THF (26 mL) and H2O (26 mL), LiOH·H2O (2.6 g, 61 mmol, 10.0 equivalent) was added. The mixture was stirred at 25°C for 0.5 hours. The pH of the mixture was adjusted to 5 by adding 1 N aqueous HCl. The reaction mixture was filtered, and the residue was concentrated under reduced pressure to obtain the crude product. The crude product was kneaded with MTBE (30 mL) at 25°C for 10 minutes to obtain 2-5 (1.3 g, yield 52%) as a white solid. LCMS: (ES + )m / z(M+H) + =409.1. 1 H NMR(400MHz,CD3OD)δ=8.36(d,J=7.2Hz,1H),8.24(s,1H),7.62(d,J=7.2Hz,1H),7.34(s,1H),7.26-7.14(m,2H).

[0404] Step 6: To a solution of 20-5 (1.0 g, 2.0 mmol, 1.0 equivalent) of 3-chloro-2-(2-(3-chloro-1H-pyrazole-4-yl)-4,6-difluorophenyl)-N-(1-methyl-2-oxabicyclo[2.1.1]hexane-4-yl)imidazo[1,2-a]pyridine-7-carboxamide (compound 788):ACN (10 mL), HATU (1.5 g, 3.9 mmol, 2.0 equivalent) and DIEA (0.7 g, 5.9 mmol, 1.0 mL, 3.0 equivalent) were added. The mixture was stirred at 25°C for 0.5 hours. Then, 1-methyl-2-oxabicyclo[2.1.1]hexane-4-amine hydrochloride (0.4 g, 2.4 mmol, 1.2 equivalents) was added. The mixture was stirred at 25°C for 11.5 hours. The reaction mixture was quenched by adding H2O (50 mL), and then extracted with EA (80 mL x 3). The combined organic layer was washed with saturated brine (80 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 250 × 50 mm × 10 μm, mobile phase: [A: water (0.5% NH4HCO3), B: ACN], B%: 27%~57%, 10 min) to obtain compound 788 (0.31 g, yield 33%) as a white solid. LCMS: (ES + )m / z(M+H) + =504.1. 1 H NMR(400MHz,CD3OD)δ=8.37-8.36(d,J=7.2Hz,1H),8.07(s,1H),7.52-7.50(dd,J=7.2,1.6Hz,1H) ,7.35(s,1H),7.24-7.15(m,2H),3.91(s,2H),2.11-2.06(m,2H),2.03-1.98(m,2H),1.46(s,3H).

[0405] Example 8: 3-Chloro-N-(3-cyanobicyclo[1.1.1]pentan-1-yl)-2-(2,4-difluoro-6-(3-fluoro-1H-pyrazole-4-yl)phenyl)imidazo[1,2-a]pyridine-7-carboxamide (compound 789)

[0406] [ka]

[0407] Step 1: 3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole(21-1): To a solution of 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5 g, 24 mmol, 1 equivalent) in DCM (50 mL), DIEA (9.1 g, 71 mmol, 12 mL, 3 equivalents) and SEM-Cl (5.9 g, 35 mmol, 6.3 mL, 1.5 equivalents) were added at 0°C. The mixture was stirred under N2 at 25°C for 12 hours. The mixture was diluted with H2O (50 mL) and extracted with EA (50 mL x 3). The combined organic layers were washed with saturated brine (50 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 40 g SepaFlash® silica flash column, eluate with a 0-20% ethyl acetate / petroleum ether gradient at 100 mL / min) to obtain 21-1 (6 g, 70% yield) as a yellow oil. 1 H NMR(400MHz, CDCl3)δ=7.70-7.61(m,1H),5.37-5.25(m,2H),3.66-3.59(m,2H),0.93(br t,J=8.4Hz,2H),0.00(s,9H).

[0408] Step 2: Methyl 2-(2,4-difluoro-6-(3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-yl)phenyl)imidazo[1,2-a]pyridine-7-carboxylate (21-2): To a solution of 19-3 (5g, 0.14mol, 1 equivalent) and 21-1 (6g, 0.18mol, 1.3 equivalents) in 50mL of dioxane, Cs2CO3 (13g, 0.41mol, 3 equivalents) and Cy3P-Pd-G3 (885.43mg, 1.4 mmol, 0.1 equivalents) were added under N2. The mixture was stirred under N2 at 100°C for 4 hours. The mixture was diluted with H2O (60mL) and extracted with EA (60mL x 3). The combined organic layers were washed with saturated brine (50 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 40 g SepaFlash® silica flash column, eluate with a 0-40% ethyl acetate / petroleum ether gradient at 100 mL / min) to obtain 21-2 (6 g, 74% yield) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ=8.30(s,1H),8.14(d,J=7.1Hz,1H),7.69(s,1H),7.43(d,J=7.2Hz,1H),7.07(d,J=9.2Hz,1H),6.96(d,J=2.4Hz,1H),6.89(br t,J=9.2Hz,1H),5.27-5.10(m,2H),3.96(s,3H),3.60-3.45(m,2H),0.88(t,J=8.0Hz,2H),-0.02--0.05(m,9H).

[0409] Step 3: Methyl 3-chloro-2-(2,4-difluoro-6-(3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-yl)phenyl)imidazo[1,2-a]pyridine-7-carboxylate (21-3): To a solution of 21-2 (7 g, 0.14 mol, 1 equivalent) in ACN (60 mL), NCS (2.1 g, 0.15 mol, 1.1 equivalents) was added at 0°C. The mixture was stirred under N2 at 50°C for 12 hours. The mixture was diluted with H2O (60 mL) and extracted with EA (50 mL x 3). The combined organic layers were washed with saturated brine (50 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 40g SepaFlash® silica flash column, eluate with a 0-10% ethyl acetate / petroleum ether gradient at 100 mL / min) to obtain 21-3 (4g, 60% yield) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ=8.34(s,1H),8.10(d,J=7.2Hz,1H),7.58(dd,J1=1.6Hz,J2=7.2Hz,1H),7.10(br d,J=8.4Hz,1H),6.93(dt,J1=2.4Hz,J2=8.8Hz,1H),6.86(d,J=2.8Hz,1H),5.27-5. 08(m,2H),3.99(s,3H),3.64-3.47(m,2H),0.96-0.83(m,2H),-0.02~-0.04(m,9H).

[0410] Step 4: Methyl 3-chloro-2-(2,4-difluoro-6-(3-fluoro-1H-pyrazole-4-yl)phenyl)imidazo[1,2-a]pyridine-7-carboxylate (21-4): To a solution of 21-3 (4 g, 7.5 mmol, 1 equivalent) in DCM (10 mL), TFA (14 g, 0.12 mol, 10 mL, 16 equivalents) was added at 0°C. The mixture was stirred at 25°C for 1 hour. The mixture was diluted with H2O (50 mL) and extracted with EA (60 mL x 3). The combined organic layers were washed with saturated brine (50 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 21-4 (1.8 g, yield 56%) as a yellow oil. LCMS: (ES + )m / z(M+H) + =406.9.

[0411] Step 5: 3-Chloro-2-(2,4-difluoro-6-(3-fluoro-1H-pyrazole-4-yl)phenyl)imidazo[1,2-a]pyridine-7-carboxylic acid (21-5): To a solution of 21-4 (1.8 g, 4.4 mmol, 1 equivalent) in MeOH (8 mL) and H2O (8 mL), LiOH·H2O (0.55 g, 0.13 mol, 3 equivalents) was added at 0°C. The mixture was stirred at 25°C for 1 hour. The residue was obtained by concentrating the reaction mixture under vacuum. The crude product was purified by reverse-phase HPLC (80g Flash Column Agela Flash Spherical C8 20-35μm; 100A: flow rate 65mL / min, mobile phase: (A): H2O (0.1% NH4HCO3), B: ACN), gradient B%: 15-30%, 40 min) to obtain 21-5 (1.0g, yield 55%) as a white solid. LCMS: (ES + )m / z(M+H) + =393.0. 1 H NMR(400MHz,CD3OD)δ=8.30(d,J=7.2Hz,1H),8.19(s,1H),7.68(d,J=7.2Hz,1H),7.24(br d,J=9.6Hz,1H),7.11(dt,J1=2.4Hz,J2=9.2Hz,1H),7.01(d,J=1.6Hz,1H).

[0412] Step 6: To a solution of 21-5 (0.5 g, 1.3 mmol, 1 equivalent) of 3-chloro-N-(3-cyanobicyclo[1.1.1]pentan-1-yl)-2-(2,4-difluoro-6-(3-fluoro-1H-pyrazole-4-yl)phenyl)imidazo[1,2-a]pyridine-7-carboxamide (compound 789): DIEA (0.5 g, 3.8 mmol, 0.66 mL, 3 equivalents) and CMPI (0.65 g, 2.5 mmol, 2 equivalents) were added at 0°C. The mixture was stirred at 0°C for 0.5 hours. Then, 3-aminobicyclo[1.1.1]pentan-1-carbonitrile (0.21 g, 1.9 mmol, 1.5 equivalents) was added at 0°C. The mixture was stirred at 25°C for 11.5 hours. The mixture was diluted with H2O (60 mL) and extracted with EA (50 mL x 3). The combined organic layer was washed with saturated brine (50 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by reverse-phase HPLC (80 g Flash Column Agela Flash Spherical C8 20-35 μm; 100A: flow rate 65 mL / min, mobile phase (A: H2O (0.1% NH4HCO3), B: ACN), gradient B%: 30-60%, 10 min) to obtain compound 789 (0.22 g, yield 35%) as a white solid. LCMS: (ES + )m / z(M+H) + =483.0. 1 H NMR(400MHz,CD3OD)δ=8.40(d,J=7.2Hz,1H),8.06(s,1H),7.51(d,J=7.2Hz,1H),7.24(br d,J=4.0Hz,1H),7.17-7.07(m,2H),2.66(s,6H).

[0413] Example 9: 3-Chloro-2-(2,4-difluoro-6-(3-fluoro-1H-pyrazole-4-yl)phenyl)-N-(1-methyl-2-oxabicyclo[2.1.1]hexane-4-yl)imidazo[1,2-a]pyridine-7-carboxamide (compound 790)

[0414] [ka]

[0415] Step 1: To a solution of 21-5 (0.35 g, 0.89 mmol, 1.0 equivalent) of 3-chloro-2-(2,4-difluoro-6-(3-fluoro-1H-pyrazole-4-yl)phenyl)-N-(1-methyl-2-oxabicyclo[2.1.1]hexane-4-yl)imidazo[1,2-a]pyridine-7-carboxamide (compound 790):ACN (4.0 mL), DIEA (0.35 g, 2.7 mmol, 0.47 μL, 3.0 equivalents) and HATU (0.51 g, 1.3 mmol, 1.5 equivalents) were added dropwise. The mixture was stirred at 25°C for 30 minutes, after which 1-methyl-2-oxabicyclo[2.1.1]hexane-4-amine hydrochloride (0.15 g, 0.98 mmol, 1.1 equivalents) was added. The resulting mixture was stirred at 25°C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge 150×25mm×5um, mobile phase: [water (0.1%NH3·H2O), B:ACN], B%:26%~56%, 12 min) to obtain compound 790 (0.16g, yield 36%) as a white solid. LCMS: (ES + )m / z(M+H) + =488.1. 1 H NMR(400MHz,CD3OD)δ=8.41(d,J=7.2Hz,1H),8.10(s,1H),7.54(d,J=7.2Hz,1H),7.23(dd,J=1.6,8.2H z,1H),7.15(s,1H),7.14-7.09(m,1H),3.91(s,2H),2.13-2.05(m,2H),2.05-1.97(m,2H),1.47(s,3H).

[0416] Example 10: 3-Chloro-2-(2-fluoro-6-(3-fluoro-1-methyl-1H-pyrazole-4-yl)phenyl)-N-((1s,3s)-3-hydroxy-3-methylcyclobutyl)imidazo[1,2-a]pyridine-7-carboxamide (Compound 791)

[0417] [ka]

[0418] Step 1: 2-Bromo-1-(2-bromo-6-fluorophenyl)ethane-1-one (22-1): To a solution of 1-(2-bromo-6-fluorophenyl)ethane-1-one (20 g, 92 mmol, 1 equivalent) in ACN (200 mL), NBS (20 g, 0.11 mmol, 1.2 equivalents) and TsOH (24 g, 0.14 mol, 1.5 equivalents) were added at 0°C. The mixture was stirred at 60°C for 12 hours. The reaction mixture was diluted with H2O (300 mL) and extracted with EA (200 mL x 3). The combined organic layers were washed with saturated brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 220g SepaFlash® silica flash column, eluate with a 0-5% ethyl acetate / petroleum ether gradient at 100 mL / min) to obtain 22-1 (33g, 79% yield) as a yellow oil. 1 H NMR(400MHz, CDCl3)δ=7.45(d,J=8.0Hz,1H),7.32(dt,J=6.0,8.4Hz,1H),7.17-7.11(m,1H),4.39(s,2H).

[0419] Step 2: Methyl 2-(2-bromo-6-fluorophenyl)imidazo[1,2-a]pyridine-7-carboxylate (22-2): To a solution of 22-1 (33 g, 73.60 mmol, 1 equivalent) and methyl 2-aminoisonicotinate (13 g, 88 mmol, 1.2 equivalents) in toluene (300 mL), NaHCO3 (7.8 g, 88 mmol, 1 equivalent) was added. The mixture was stirred at 110 °C for 12 hours. The reaction mixture was diluted with H2O (400 mL) and extracted with EA (300 mL x 3). The combined organic layers were washed with saturated brine (300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 330g SepaFlash® silica flash column, eluate with a 0-50% ethyl acetate / petroleum ether gradient at 100 mL / min) to obtain 22-2 (16 g, 60% yield) as a yellow solid. LCMS: (ES + )m / z(M+H) + =349.8. 1 H NMR(400MHz,CDCl3)δ=8.57(d,J=7.2Hz,1H),8.28(s,1H),8.16(s,1H),7.59(d,J=8.0Hz,1H ),7.49(dd,J=1.6,7.2Hz,1H),7.40(dt,J=6.0,8.4Hz,1H),7.32-7.19(m,1H),3.98(s,3H).

[0420] [ka]

[0421] Step 3: 3-Fluoro-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(22-3): A mixture of 4-bromo-3-fluoro-1-methyl-1H-pyrazole (1.0 g, 5.6 mmol, 1 equivalent) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolan (3.1 g, 17 mmol, 3.4 mL, 3 equivalents) in THF (10 mL) was degassed, purged three times with N2, and then n-BuLi (2.5 M in n-hexane, 3.4 mL, 1.5 equivalents) was added dropwise at -78°C under an N2 atmosphere. The mixture was stirred under an N2 atmosphere for 1 hour at -78°C and 2 hours at 25°C. The reaction mixture was quenched by adding saturated NH4Cl aqueous solution (20 mL) and extracted with EA (20 mL x 3). The combined organic layer was washed with saturated brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, eluate with a 0-20% ethyl acetate / petroleum ether gradient at 50 mL / min) to obtain 22-3 (0.5 g, yield 33%) as a yellow solid. LCMS: (ES + )m / z(M+H) + =227.1. 1 H NMR(400MHz, CDCl3)δ=7.44(d,J=1.6Hz,1H),3.76(s,3H),1.32(s,12H).

[0422] Step 4: To a solution of 22-3 (0.5 g, 1.9 mmol, 1.2 equivalents) and 22-2 (0.55 g, 1.6 mmol, 1 equivalent) in methyl 2-(2-fluoro-6-(3-fluoro-1-methyl-1H-pyrazole-4-yl)phenyl)imidazo[1,2-a]pyridine-7-carboxylate (22-4):dioxane (10 mL), Cs2CO3 (1.5 g, 4.7 mmol, 3 equivalents) and Cy3P Pd G3 (0.10 g, 0.16 mmol, 0.1 equivalent) were added. The reaction mixture was degassed, purged three times with N2, and then stirred at 110°C for 12 hours. The reaction mixture was diluted with H2O (20 mL) and extracted with EA (20 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 12 g SepaFlash® silica flash column, eluate with a 0-50% ethyl acetate / petroleum ether gradient at 50 mL / min) to obtain 22-4 (0.4 g, yield 62%) as a yellow solid. LCMS: (ES + )m / z(M+H) + =369.0. 1 H NMR(400MHz,CD3OD)δ=8.51(d,J=7.2Hz,1H),8.21(s,1H),7.99(s,1H),7.53-7.43(m,2H),7.34(br d,J=8.0Hz,1H),7.20(br s,2H),3.97(s,3H),3.63(s,3H).

[0423] [ka]

[0424] Step 5: To a solution of methyl 3-chloro-2-(2-fluoro-6-(3-fluoro-1-methyl-1H-pyrazole-4-yl)phenyl)imidazo[1,2-a]pyridine-7-carboxylate (22-5):0.3 mg, 0.81 mmol, 1 equivalent of 22-4 in ACN (1 mL), NCS (0.13 mg, 0.98 mmol, 1.2 equivalents) was added at 0°C. The mixture was stirred at 25°C for 12 hours. The reaction mixture was diluted with H2O (20 mL) and extracted with EA (20 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 20g SepaFlash® silica flash column, eluate with a 0-50% ethyl acetate / petroleum ether gradient at 50 mL / min) to obtain 22-5 (0.3 g, 91% yield) as a yellow oil. 1 H NMR(400MHz,CD3OD)δ=8.42(d,J=7.2Hz,1H),8.27(s,1H),7.73-7.62(m,1H),7.61(s,1H),7.40(br d,J=7.6Hz,1H),7.28-7.20(m,1H),7.17(s,1H),3.99(s,3H),3.61(s,3H).

[0425] Step 6: 3-Chloro-2-(2-fluoro-6-(3-fluoro-1-methyl-1H-pyrazole-4-yl)phenyl)imidazo[1,2-a]pyridine-7-carboxylic acid (22-6): To a solution of 22-5 (0.3 g, 0.74 mmol, 1 equivalent) in THF (3 mL) and H2O (1.5 mL), LiOH·H2O (93 mg, 2.2 mmol, 3 equivalents) was added at 25°C. The mixture was stirred at 25°C for 2 hours. The reaction mixture was adjusted to pH=7 with 2N aqueous HCl. The reaction mixture was filtered and concentrated under reduced pressure to obtain 22-6 (0.3 g, crude) as a yellow solid.

[0426] Step 7: To a solution of 22-6 (0.15 g, 0.36 mmol, 1 equivalent) of 3-chloro-2-(2-fluoro-6-(3-fluoro-1-methyl-1H-pyrazole-4-yl)phenyl)-N-((1s,3s)-3-hydroxy-3-methylcyclobutyl)imidazo[1,2-a]pyridine-7-carboxamide (compound 791): HATU (0.22 g, 0.58 mmol, 1.5 equivalents), DIEA (0.25 g, 1.9 mmol, 0.34 mL, 5 equivalents), and (1s,3s)-3-amino-1-methylcyclobutan-1-ol hydrochloride (78 mg, 0.57 mmol, 1.5 equivalents) in ACN (1.5 mL) and DMF (1.5 mL), HATU (0.22 g, 0.58 mmol, 1.5 equivalents), DIEA (0.25 g, 1.9 mmol, 0.34 mL, 5 equivalents), and (1s,3s)-3-amino-1-methylcyclobutan-1-ol hydrochloride (78 mg, 0.57 mmol, 1.5 equivalents) were added at 25°C. The mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into H2O (40 mL) and extracted with EA (40 mL x 3). The reaction mixture was adjusted to pH 7 with 2N aqueous HCl. The reaction mixture was filtered and concentrated under vacuum to obtain the residue. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150 × 25 mm × 5 μm, mobile phase: [A: water (0.1% FA), B: ACN], B%: 20%~40%, 15 min) to obtain compound 791 (87 mg, yield 40%) as a white solid. LCMS: (ES + )m / z(M+H) + =472.1. 1 H NMR(400MHz,CD3OD)δ=8.39(d,J=7.2Hz,1H),8.08(s,1H),7.62-7.49(m,2H),7.39(d,J=7.6Hz,1H),7.23(t,J=8.8Hz, 1H),7.16(d,J=1.6Hz,1H),4.10(quin,J=8.0Hz,1H),3.60(s,3H),2.59-2.43(m,2H),2.25-2.09(m,2H),1.40(s,3H).

[0427] Example 11: 3-chloro-2-(2-fluoro-6-(3-fluoro-1-methyl-1H-pyrazole-4-yl)phenyl)-N-(1-(hydroxymethyl)-2-oxabicyclo[2.2.1]heptan-4-yl)imidazo[1,2-a]pyridine-7-carboxamide, first eluted enantiomer, and 3-chloro-2-(2-fluoro-6-(3-fluoro-1-methyl-1H-pyrazole-4-yl)phenyl)-N-(1-(hydroxymethyl)-2-oxabicyclo[2.2.1]heptan-4-yl)imidazo[1,2-a]pyridine-7-carboxamide, second eluted enantiomer (compound 920)

[0428] [ka]

[0429] Step 1: To a solution of 3-chloro-2-(2-fluoro-6-(3-fluoro-1-methyl-1H-pyrazole-4-yl)phenyl)-N-(1-(hydroxymethyl)-2-oxabicyclo[2.2.1]heptan-4-yl)imidazo[1,2-a]pyridine-7-carboxamide (23-1): EDCI (0.27 g, 0.47 mmol, 1 equivalent, HCl salt) in pyridine (4 mL) was mixed with (4-amino-2-oxabicyclo[2.2.1]heptan-1-yl)methanol (92.90 mg, 0.52 mmol, 1.1 equivalents, HCl salt). The mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with water (10 mL) and then extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, eluate of 30-50% ethyl acetate / dichloromethane gradient at 80 mL / min) and preparative HPLC (column: Santai Technologies SepaFlash® cartridge 184 × 21.4 mm, 40-60 μm, mobile phase: [A: water (0.1% FA), B: ACN], B%: 30-40%) to obtain 23-1 (0.14 g, yield 50%) as a yellow oil. LCMS: (ES + )m / z(M+H) + =514.1.

[0430] Step 2: 3-chloro-2-(2-fluoro-6-(3-fluoro-1-methyl-1H-pyrazole-4-yl)phenyl)-N-(1-(hydroxymethyl)-2-oxabicyclo[2.2.1]heptan-4-yl)imidazo[1,2-a]pyridine-7-carboxamide, first eluted enantiomer, and 3-chloro-2-(2-fluoro-6-(3-fluoro-1-methyl-1H -Pyrazole-4-yl)phenyl)-N-(1-(hydroxymethyl)-2-oxabicyclo[2.2.1]heptan-4-yl)imidazo[1,2-a]pyridine-7-carboxamide, the second eluted enantiomer (compound 920):23-1 was purified by SFC (column: Phenomenex-cellulose-2 (250 mm × 30 mm, 10 μm), mobile phase: [CO2-MeOH (0.1% NH3·H2O)], B%: 55%, homogeneous concentration elution mode) to obtain compound 920 (45.86 mg, yield 32%) as an off-white solid. LCMS: (ES + )m / z(M+H) + =514.2. 1 H NMR(400MHz,CD3OD)δ 9.21(s,1H),8.20(s,1H),7.58-7.52(m,3H),7.41-7.39(d,J=8.0Hz,1H),6.96-6.95(d,J=4.0Hz,2H),6 .94-6.86(m,1H),2.99(s,3H),2.74-2.71(m,2H),2.69(s,3H),2.1(s,3H),0.92-0.88(t,J=7.6Hz,3H).

[0431] Example 12: Trans-3-chloro-2-(2-fluoro-6-(3-fluoro-1-methyl-1H-pyrazole-4-yl)phenyl)-N-(6-hydroxyspiro[3,3]heptan-2-yl)imidazo[1,2-a]pyridine-7-carboxamide (compound 921)

[0432] [ka]

[0433] Step 1: 3-Chloro-2-(2-fluoro-6-(3-fluoro-1-methyl-1H-pyrazole-4-yl)phenyl)-N-(6-hydroxyspiro[3.3]heptan-2-yl)imidazo[1,2-a]pyridine-7-carboxamide (24-1): To a solution of 22-6 (0.20 g, 0.51 mmol, 1 equivalent) and 6-aminospiro[3.3]heptan-2-ol (78.52 mg, 0.62 mmol, 1.2 equivalents) in pyridine (3 mL), EDCI (0.30 g, 1.54 mmol, 3 equivalents) was added. The mixture was stirred at 25°C for 12 hours. The reaction mixture was diluted with water (10 mL) and then extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 12 g SepaFlash® silica flash column, eluate with an 80-100% ethyl acetate / petroleum ether gradient at 50 mL / min) to obtain 24-1 (170 mg, yield 62%) as a yellow solid. LCMS: (ES + )m / z(M+H) + =498.0.

[0434] Step 2: Trans-3-chloro-2-(2-fluoro-6-(3-fluoro-1-methyl-1H-pyrazole-4-yl)phenyl)-N-(6-hydroxyspiro[3,3]heptan-2-yl)imidazo[1,2-a]pyridine-7-carboxamide (compound 921):24-1 (0.17 g, 0.34 mmol, 1 equivalent) was purified by SFC (column: DAIEL CHIRALPAK AD (250 mm × 30 mm, 10 μm), mobile phase: [A: CO2, B: i-PrOH], B%: 40%, homogeneous concentration elution mode) to obtain compound 921 (22.9 mg, yield 13%) as a white solid. LCMS: (ES + )m / z(M+H) + =498.2. 1H NMR(400MHz,DMSO)δ=8.83-8.31(d,J=7.2Hz,1H),8.46-8.44(d,J=7.2Hz,1H),8.18 (s,1H),7.65-7.56(m,1H),7.52-7.51(d,J=7.2Hz,1H),7.38-7.36(d,J=8.0Hz,1H) ,7.33-7.31(m,1H),5.12-4.70(m,1H),4.45-4.21(m,1H),4.07-3.88(m,1H),3.58( s,3H),2.43-2.27(m,2H),2.26-2.15(m,2H),2.14-1.99(m,2H),1.91-1.73(m,2H).

[0435] Example 13: 33-Chloro-2-(2,4-difluoro-6-(3-fluoro-1-methyl-1H-pyrazole-4-yl)phenyl)-N-((1s,3s)-3-hydroxy-3-(hydroxymethyl)cyclobutyl)imidazo[1,2-a]pyridine-7-carboxamide (compound 922)

[0436] [ka]

[0437] Step 1: Benzyl (3-hydroxy-3-(hydroxymethyl)cyclobutyl) carbamate (25-1): To a solution of benzyl (3-methylenecyclobutyl) carbamate (3 g, 13.81 mmol, 1 equivalent) in ACN (30 mL) and H2O (10 mL), N-methylmorpholine N-oxide (7.28 g, 62.14 mmol, 4.5 equivalents) and potassium dioxide (dioxo)osmium dihydrate (0.51 g, 1.38 mmol, 0.1 equivalent) were added at 0°C. The mixture was stirred at 25°C for 12 hours. The reaction mixture was poured into saturated Na2SO3 aqueous solution (100 mL) and then extracted with EA (100 mL x 3). The combined organic layers were washed with saturated brine (100 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain 3-1 (3.4 g, crude) as a yellow solid. 1H NMR(400MHz,DMSO)δ=7.52-7.41(m,1H),7.40-7.28(m,5H),4.99(s,2H),4.87-4.70(m,1H),4.63-4.61(td,J=14.8,5.6Hz,1H), 4.12-3.51(m,1H),3.24-3.22(dd,J=19.2,5.2Hz,2H),2.38-2.29(m,1H),2.06-1.93(m,2H),1.84-1.82(dt,J=8.8,2.4Hz,1H).

[0438] Step 2: Benzyl ((1s,3s)-3-hydroxy-3-(hydroxymethyl)cyclobutyl) carbamate (25-2A) and benzyl ((1r,3r)-3-hydroxy-3-(hydroxymethyl)cyclobutyl) carbamate (25-2B): 25-1 (3.4g, 13.53 mmol, 1 equivalent) was separated by SFC (column: DAIEL CHIRALCEL OX (250mm × 30mm, 10um), mobile phase: [A: CO2, B: MeOH (0.1% NH3·H2O)], B%: 25%, homogeneous concentration elution mode) to obtain 25-2A (1.29g, yield 38%, RT=1.369 min) and 25-2B (1.28g, yield 38%, RT=1.530 min) as yellow solids. 25-2A: 1 H NMR(400MHz,DMSO)δ=7.49-7.47(d,J=7.2Hz,1H),7.40-7.22(m,5H),4.98(s,2H),4.82(s,1H),4.63 (s,1H),3.60-3.45(m,1H),3.25(s,2H),2.40-2.28(m,2H),1.83-1.81(dt,J=9.2,2.4Hz,2H).25-2B: 1 H NMR(400MHz,DMSO)δ=7.49-7.47(d,J=7.2Hz,1H),7.40-7.22(m,5H),4.98(s,2H),4.82(s,1H),4 .63(s,1H),3.60-3.45(m,1H),3.25(s,2H),2.40-2.28(m,2H),1.83-1.81(dt,J=9.2,2.4Hz,2H).

[0439] Step 3: (1s,3s)-3-amino-1-(hydroxymethyl)cyclobutanol (25-3A): A mixture of 25-2A (1.8g, 7.16 mmol, 1 equivalent) in MeOH (10 mL) and THF (10 mL) was degassed, purged three times with H2, and then Pd / C (0.76 g, 0.72 mmol, purity 10%, 0.1 equivalent) was added. The mixture was degassed, purged three more times with H2, and then stirred at 25°C for 12 hours under H2 (15 psi). The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 25-3A (800 mg, crude) as a yellow oil. 1 H NMR(400MHz,CD3OD)δ=3.43(s,2H),2.99-2.92(m,1H),2.50-2.48(ddd,J=10.0,7.2,2.8Hz,2H),1.84-1.68(m,2H).

[0440] [ka]

[0441] Step 4: A mixture of methyl 2-(2,4-difluoro-6-(3-fluoro-1-methyl-1H-pyrazole-4-yl)phenyl)imidazo[1,2-a]pyridine-7-carboxylate (25-4):dioxane (70 mL) containing 19-3 (7 g, 19.07 mmol, 1 equivalent), 22-3 (10.77 g, 47.67 mmol, 2.5 equivalents), Cs2CO3 (18.64 g, 57.20 mmol, 3 equivalents), and PCy3Pd G3 (1.40 g, 1.91 mmol, 0.1 equivalents) was degassed and purged three times with N2. The mixture was stirred at 115°C for 12 hours under an N2 atmosphere. The reaction mixture was filtered. The filtrate was diluted with water (100 mL) and then extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 120 g SepaFlash® silica flash column, eluate with a 30-70% ethyl acetate / petroleum ether gradient at 100 mL / min) to obtain 25-4 (4.8 g, yield 65%) as a yellow solid. 1 H NMR(400MHz,CD3OD)δ=8.52(d,J=7.2Hz,1H),8.21(s,1H),8.00(s,1H),7.47(dd,J=1.6 ,7.2Hz,1H),7.20-7.13(m,2H),7.08(dt,J=2.4,9.2Hz,1H),3.97(s,3H),3.62(s,3H).

[0442] Step 5: To a solution of methyl 3-chloro-2-(2,4-difluoro-6-(3-fluoro-1-methyl-1H-pyrazole-4-yl)phenyl)imidazo[1,2-a]pyridine-7-carboxylate (25-5): 25-4 (4.8 g, 12.42 mmol, 1 equivalent) in ACN (50 mL), NCS (1.99 g, 14.91 mmol, 1.2 equivalents) was added at 0°C. The mixture was stirred at 60°C for 6 hours. The reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 120g SepaFlash® silica flash column, eluate with a 30-50% ethyl acetate / petroleum ether gradient at 100 mL / min) to obtain 25-5 (3.8 g, 70% yield) as a yellow solid. LCMS: (ES + )m / z(M+H) + =421.1. 1 H NMR(400MHz,CD3OD)δ=8.43(d,J=7.2Hz,1H),8.27(s,1H),7.65(d,J=7.2Hz,1 H),7.24-7.16(m,2H),7.12(dt,J=2.4,9.2Hz,1H),3.98(s,3H),3.61(s,3H).

[0443] Step 6: 3-Chloro-2-(2,4-difluoro-6-(3-fluoro-1-methyl-1H-pyrazole-4-yl)phenyl)imidazo[1,2-a]pyridine-7-carboxylic acid (25-6): To a solution of 25-5 (3.8 g, 9.03 mmol, 1 equivalent) in THF (40 mL) and H2O (8 mL), LiOH·H2O (1.14 g, 27.09 mmol, 3 equivalents) was added. The mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under vacuum to remove THF, and then diluted with H2O (20 mL). To precipitate the desired acid, the aqueous phase was adjusted to pH 4 by adding 2N aqueous HCl at 0°C. The mixture was filtered, and the filter cake was dried under reduced pressure to obtain 25-6 (2.85 g, yield 76%) as a yellow solid. 1H NMR(400MHz,CD3OD)δ=8.40(d,J=7.2Hz,1H),8.26(s,1H),7.66(d,J=7.2Hz, 1H),7.21(d,J=10.0Hz,1H),7.16(s,1H),7.12(t,J=9.2Hz,1H),3.61(s,3H).

[0444] Step 7: To a solution of 3-chloro-2-(2,4-difluoro-6-(3-fluoro-1-methyl-1H-pyrazole-4-yl)phenyl)-N-((1s,3s)-3-hydroxy-3-(hydroxymethyl)cyclobutyl)imidazo[1,2-a]pyridine-7-carboxamide (compound 922):25-6 (80 mg, 0.19 mmol, 1 equivalent) and (1s,3s)-3-amino-1-(hydroxymethyl)cyclobutan-1-ol 25-3A (34.56 mg, 0.29 mmol, 1.5 equivalents) in pyridine (1 mL), EDCI (0.11 g, 0.59 mmol, 3 equivalents) was added. The mixture was stirred at 25°C for 2 hours. The reaction mixture was filtered, and the filtrate was separated and purified by HPLC (column: CDO2-Waters Xbridge BEH C18 150×25×10 μm, mobile phase: [A: water (0.05% NH4HCO3), B: ACN], B%: 20%~50%, 10 min) to obtain compound 922 (68.19 mg, yield 67%) as a white solid. LCMS: (ES + )m / z(M+H) + =506.2. 1 H NMR(400MHz,CD3OD)δ=8.41-8.39(dd,J=0.8,7.2Hz,1H),8.17-8.02(m,1H),7.56-7.54(dd,J=1.6,7.2Hz,1H),7.25-7.15(m,2H),7.14-7 .09(dt,J=2.4,9.2Hz,1H),4.12-4.08(t,J=8Hz,1H),3.60(s,3H),3.55(s,2H),2.68-2.63(ddd,J=2.8,7.6,10Hz,2H),2.18-2.10(m,2H).

[0445] Example 14: 3-Chloro-2-(2,4-difluoro-6-(3-fluoro-1-methyl-1H-pyrazole-4-yl)phenyl)-N-((1r,3r)-3-hydroxy-3-(hydroxymethyl)cyclobutyl)imidazo[1,2-a]pyridine-7-carboxamide (compound 923)

[0446] [ka]

[0447] Step 1: (1r,3r)-3-amino-1-(hydroxymethyl)cyclobutan-1-ol (26-1): A mixture of benzyl ((1s,3s)-3-hydroxy-3-(hydroxymethyl)cyclobutyl) carbamate 25-2B (1.8 g, 7.16 mmol, 1 equivalent) in MeOH (10 mL) and THF (10 mL) was degassed, purged three times with H2, and then Pd / C (0.76 g, 0.72 mmol, purity 10%, 0.1 equivalent) was added. The mixture was degassed, purged three more times with H2, and then stirred at 25°C for 12 hours under H2 (15 psi). The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 26-1 (800 mg, crude) as a yellow oil.

[0448] Step 2: 3-Chloro-2-(2,4-difluoro-6-(3-fluoro-1-methyl-1H-pyrazole-4-yl)phenyl)-N-((1r,3r)-3-hydroxy-3-(hydroxymethyl)cyclobutyl)imidazo[1,2-a]pyridine-7-carboxamide (compound 923): To a solution of 25-6 (0.10 g, 0.25 mmol, 1 equivalent) and 26-1 (43.20 mg, 0.37 mmol, 1.5 equivalents) in pyridine (1 mL), EDCI (141.39 mg, 0.74 mmol, 3 equivalents) was added. The mixture was stirred at 25°C for 2 hours. The reaction mixture was filtered. The residue was obtained by concentrating the filtrate under vacuum. The residue was purified by preparative HPLC (column: CDO2-Waters Xbridge BEH C18 150×25×10 μm, mobile phase: [A: water (0.05% NH4HCO3), B: ACN], B%: 20%~50%, 10 min) to obtain compound 923 (61.9 mg, yield 49%) as a white solid. LCMS: (ES + )m / z(M+H) + =506.2. 1 H NMR(400MHz,CD3OD)δ=8.40-8.39(d,J=7.2Hz,1H),8.08(s,1H),7.55-7.53(dd,J=1.6,7.2Hz,1H),7.26-7.15(m,2H),7.13 -7.08(dt,J=2.4,9.2Hz,1H),4.71-4.63(q,J=7.6Hz,1H),3.60(s,3H),3.49(s,2H),2.42-2.35(m,2H),2.34-2.27(m,2H).

[0449] Example 15: 3-Chloro-2-(2-fluoro-6-(3-fluoro-1-methyl-1H-pyrazole-4-yl)phenyl)-N-((3S,6R)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)imidazo[1,2-a]pyridine-7-carboxamide (compound 924)

[0450] [ka]

[0451] Step 1: Tert-butyl(S)-(1-hydroxyhexa-5-en-2-yl)carbamate (27-1): To a cold (-10°C) solution of (S)-2-((tert-butoxycarbonyl)amino)hexa-5-enoic acid (2 g, 8.72 mmol, 1 equivalent) in DME (10 mL), NMM (882.33 mg, 8.72 mmol, 1 equivalent) and isopropylcarbonochloride (1.19 g, 8.71 mmol, 1.14 mL, 1 equivalent) were added. After stirring for 30 minutes, the precipitated N-methylmorpholine hydrochloride was removed by filtration. Then, a solution of NaBH4 (570 mg, 15.07 mmol, 1.73 equivalents) in H2O (5 mL) was added to the filtrate all at once under an N2 atmosphere. The mixture was stirred at -10°C for 30 minutes. The reaction mixture was quenched under N2 at 0°C by adding saturated NH4Cl aqueous solution (20 mL), and then extracted with ethyl acetate (30 mL x 3). The combined organic layer was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 27-1 (1.4 g, yield 75%) as a colorless oil. LCMS:(ES + )m / z(M-56+H)+=160.2. 1 H NMR(400MHz,CDCl3)δ=5.82(tdd,J=6.6,10.2,17.0Hz,1H),5.12-4.93(m,2H),4.74-4.50(m, 1H),3.78-3.62(m,3H),2.23-2.09(m,2H),1.70-1.60(m,1H),1.58-1.51(m,1H),1.46(s,9H).

[0452] Step 2: Tert-butyl((2S)-1-hydroxy-4-(oxiran-2-yl)butan-2-yl)carbamate (27-2): To a solution of 27-1 (1 g, 4.64 mmol, 1 equivalent) in H2O (30 mL) and DCE (40 mL), phosphate buffer (1 M in H2O, 32 mL, 6.89 equivalents) and m-CPBA (3 g, 14.78 mmol, 85% purity, 3.18 equivalents) were added. The reaction mixture was stirred at 25°C for 12 hours. Upon completion, the mixture was quenched by adding saturated Na2SO3 aqueous solution (100 mL) and then extracted with DCM (50 mL x 3). The combined organic layer was washed with saturated brine (30 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 40g SepaFlash® silica flash column, eluate with a 50-80% EA / PE gradient at 50 mL / min) to obtain 5-2 (0.8 g, 75% yield) as a colorless oil. 1 H NMR(400MHz,CDCl3)δ=4.85-4.55(m,1H),3.76-3.66(m,2H),3.63-3.56(m,1H),2.95(br d,J=2.8Hz,1H),2.78(q,J=4.0Hz,1H),2.56-2.46(m,1H),1.79-1.60(m,4H),1.46(s,9H).

[0453] Step 3: Tert-butyl((3S,6R)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)carbamate (27-3): To a solution of 27-2 (804 mg, 3.48 mmol, 1 equivalent) in DCM (10 mL), [rac-(1R,4S)-7,7-dimethyl-2-oxo-norbornan-1-yl]methanesulfonic acid (80.75 mg, 0.35 mmol, 0.1 equivalent) was added. The mixture was stirred at 25°C for 3 hours. The reaction mixture was adjusted to pH 7 with saturated NaHCO3 aqueous solution (20 mL), and then extracted with ethyl acetate (30...

Claims

1. Equation (I) 【Chemistry 1】 A compound of, or a pharmaceutically acceptable salt or solvate thereof, wherein, Z is -S-, -N=C(R ５ )-,-C(R ５ ) = N-, or -C(R ５ ) = C(R ５ ) - a divalent group selected from, R １ is a pyrazole, and the pyrazole is optionally selected, R ６ It is replaced by 1 to 3 groups independently selected from, R ２ is C １ -C １０ alkyl, C １ -C １０ heteroalkyl, -C(=O)OR ７ , -C(=O)N(R ８ )(R ７ ), -N(R ８ )(R ７ ), -C(=NR ９ )N(R ８ )(R ７ ), -N(R ７ )C(=NR ９ )N(R ８ )(R ７ ), C ６ -C １０ aryl, 5- to 10-membered heteroaryl, C ３ -C １２ cycloalkyl, or 3- to 15-membered heterocycloalkyl, wherein aryl and heteroaryl are optionally substituted with 1 to 4 groups independently selected from R １０ , and alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with oxo and 1 to 4 groups independently selected from R １０ , R ３ These are halogen, cyano, -C(=O)OH, -C(=O)O(C １ -C ６ Alkyl), C １ -C ６ Alkyl, C １ -C ６ Alkenyl, -O(C) １ -C ６ Alkyl), C ３ -C ６ Cycloalkyl, or C １ -C ６ It is a haloalkyl, R ４ These are, independently, hydrogen, halogen, and C. １ -C ６ Alkyl, -O-C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, or -O-(C １ -C ６ (Haloalkyl) L is bond, C １ -C ２ Alkylene or C ３ -C ６ It is a cycloalkylene, and the alkylene or cycloalkylene is optionally substituted with one or two -OH groups. R ５ These are, independently, hydrogen, cyano, halogen, and C. １ -C ６ Alkyl, -O(C) １ -C ６ Alkyl), C ３ -C ６ Cycloalkyl, C １ -C ６ Haloalkyl, or -O(C) １ -C ６ (Haloalkyl) R ６ These are, independently, halogen, hydroxy, cyano, amino, and C. １ -C ６ Alkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, -O(C) １ -C ６ Alkyl), -NH(C １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ , C ３ -C ６ Cycloalkyl, -CH ２ - (C ３－６ Cycloalkyl), -O-(C ３－６ Cycloalkyl), C １ -C ６ Haloalkyl and -O(C) １ -C ６ Selected from the group consisting of haloalkyls, R ６ When it is bonded to a nitrogen atom, it is C １ -C ６ alkyl, C １ -C ６ hydroxyalkyl, C １ -C ６ aminoalkyl, C ３ -C ６ cycloalkyl, -CH ２ -(C ３－６ cycloalkyl), and C １ -C ６ selected from the group consisting of haloalkyl, R ７ Each of them independently represents hydrogen or C １ -C ６ It is an alkyl group, and the alkyl group is optionally substituted with one or two hydroxyl groups. R ８ is hydrogen, C １ -C １０ Alkyl, C １ -C １０ Heteroalkyl, C １ -C １０ Alkenil, C １ -C １０ Alkinyl, C ３ -C １２ Cycloalkyl, 3-15 member heterocycloalkyl, C ６ -C １０ It is an aryl or a 5- to 10-membered heteroaryl, and the aryl and heteroaryl are optional, R １１ Substituted with 1 to 6 groups independently selected from, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl groups are optional, oxo and R １１ Substituted by 1 to 6 groups independently selected from, Alternatively, one R bonded to the same nitrogen atom ７ and one R ８ These combine to form oxo and R １１ They form a 3- to 15-membered heterocycloalkyl group, optionally substituted with 1 to 6 groups independently selected from the above. R ９ is hydrogen, -C(O)OR １２ , -C(O)N(R １２ ) ２ , -S(O) ２ R １２ , -S(O) ２ N(R) １２ ) ２ , or C １ -C ６ It is alkyl, R １０ These are independently hydroxy, amino, cyano, fluoro, and -C(=O)OR １２ , -C(=O)N(R １２ ) ２ , C １ -C ４ Alkyl, C １ -C ４ Haloalkyl, -O(C) １ -C ６ Alkyl), -NH(C １ -C ４ Alkyl), -N(C １ -C ４ Alkyl) ２ , C ３ -C ６ Selected from cycloalkyls, wherein the alkyl, haloalkyl, or cycloalkyl is optional, and hydroxy, amino, cyano, fluoro, -C(=O)OR １２ , and -C(=O)N(R １２ ) ２ Substituted with one or two groups selected from, R １１ These are, independently, halogen, hydroxyl, amino, cyano, and -S (=O). ２ (R １３ ), -N(R １２ )S (=O) ２ (R １３ ), -S(=O)(R １３ ), -N(R １２ )S (=O) (R １３ ), -C(=O)R １３ , -N(R １２ )C(=O)R １３ , C １ -C ６ Alkyl, -O(C) １ -C ６ Alkyl), -NH(C １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ , C １ -C ６ Haloalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C ８ Cycloalkyl, 3-10 member heterocycloalkyl, C ６ -C １０ Selected from the group consisting of aryls and 5- to 10-membered heteroaryls, aryls and heteroaryls are R １４ Optionally substituted with 1 to 4 groups independently selected from, with alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, and heterocycloalkyl groups being optional, as well as oxo and R １４ Substituted by 1 to 4 groups independently selected from, Alternatively, two R atoms bonded to the same carbon or nitrogen atom １１ They become one, C ３ -C ６ They form cycloalkyl or 3-6 member heterocycloalkyl groups, and the cycloalkyl and heterocycloalkyl groups are oxo and R １４ It is optionally replaced by 1 to 4 elements that are independently selected from, R １２ Each of them independently represents hydrogen or C １ -C ６ It is alkyl, R １３ These are independently hydroxy, amino, and C. １ -C ６ Alkyl, -O(C) １ -C ６ Alkyl), -NH(C １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ , C １ -C ６ Haloalkyl, C ３ -C ６ It is a cycloalkyl or a 3- to 6-membered heterocycloalkyl, R １４ These are independently cyano, amino, hydroxy, and -C(=O)OR １２ , -C(=O)N(R １２ ) ２ , C １ -C ６ Alkyl, -O(C) １ -C ６ Alkyl), -NR １２ (C １ -C ６ Alkyl), aryl, heteroaryl, C ３ -C ６ A compound, or a pharmaceutically acceptable salt or solvate thereof, that is a cycloalkyl or a 3- to 6-membered heterocycloalkyl, where each alkyl group is optionally substituted with one or two hydroxyl groups.

2. R ３ These are halogen, cyano, and C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, or C １ -C ６ A compound according to claim 1, which is a haloalkyl compound, or a pharmaceutically acceptable salt or solvate thereof.

3. R ３ The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein is fluoro, chloro, cyano, methyl, ethyl, vinyl, -OMe, -C(=O)OH, trifluoromethyl, difluoromethyl, or cyclopropyl.

4. R ３ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, wherein is chloro, cyano, methyl, or ethyl.

5. R ４ The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate thereof, wherein each is independently hydrogen, fluoro, or methyl.

6. R ４ The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate thereof, wherein each of the atoms is hydrogen.

7. Z is -C(R ５ ) = C(R ５ A compound according to any one of claims 1 to 6, which is - or -S-, or a pharmaceutically acceptable salt or solvate thereof.

8. Formula (IIa) 【Chemistry 2】 A compound according to claim 7 having the structure, or a pharmaceutically acceptable salt or solvate thereof.

9. Equation (IIb) 【Transformation 3】 A compound according to claim 7 having the structure, or a pharmaceutically acceptable salt or solvate thereof.

10. Z is -N = C(R ５ ) - or - C (R ５ The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or solvate thereof, wherein ) = N-.

11. Formula (IIc) 【Chemistry 4】 A compound according to claim 10 having the structure, or a pharmaceutically acceptable salt or solvate thereof.

12. Equation (IId) 【Transformation 5】 A compound according to claim 10 having the structure, or a pharmaceutically acceptable salt or solvate thereof.

13. L is a combination or C １ A compound according to any one of claims 1 to 12, which is an alkylene, or a pharmaceutically acceptable salt or solvate thereof.

14. R ２ is -C(O)(OR ７ ) or -C(O)N(R ８ ) (Caution ７ The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt or solvate thereof.

15. R ２ The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt or solvate thereof, wherein is a 5- to 10-membered heteroaryl or a 3- to 15-membered heterocycloalkyl.

16. R ２ The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt or solvate thereof, wherein is a 5-6 member heteroaryl or a 3-8 member heterocycloalkyl.

17. Formula (III) 【Transformation 6】 A compound according to any one of claims 1 to 7 having the structure, or a pharmaceutically acceptable salt or solvate thereof.

18. Formula (IVa) 【Transformation 7】 A compound according to claim 17 having the structure, or a pharmaceutically acceptable salt or solvate thereof.

19. R １ These are methyl, ethyl, cyano, fluoro, chloro, -OMe, cyclopropyl, and -CH ２ - One to three R molecules independently selected from the group consisting of cyclopropyl, trifluoromethyl, and difluoromethyl ６ The base is optionally replaced, R ６ When bonded to a nitrogen atom, it is methyl, ethyl, cyclopropyl, -CH ２ - A compound according to any one of claims 1 to 18, selected from the group consisting of cyclopropyl, trifluoromethyl, trifluoroethyl, and difluoromethyl, or a pharmaceutically acceptable salt or solvate thereof.

20. R １ teeth, 【Transformation 8】 The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt or solvate thereof.

21. R １ These are methyl, cyano, fluoro, chloro, -OMe, cyclopropyl, -CH ２ - One or two R independently selected from the group consisting of cyclopropyl and difluoromethyl ６ The base is optionally replaced, R ６ If it is bonded to a nitrogen atom, it is methyl, cyclopropyl, or -CH ２ - A compound according to any one of claims 1 to 20, which is cyclopropyl, or a pharmaceutically acceptable salt or solvate thereof.

22. R １ teeth, 【Chemistry 9】 And R ６ These are independently fluoro, chloro, cyano, cyclopropyl, and -CH2. ２ -Cyclopropyl or methyl, R ６ If it is bonded to a nitrogen atom, it is methyl, cyclopropyl, or -CH ２ - The compound according to claim 20, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is cyclopropyl.

23. R １ teeth, 【Chemistry 10】 And R ６ These are independently fluoro, chloro, cyano, cyclopropyl, and -CH ２ - The compound according to claim 20, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is cyclopropyl or methyl.

24. R １ teeth, 【Chemistry 11】 And R ６ is methyl, cyclopropyl, or -CH ２ - The compound according to claim 20, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is cyclopropyl.

25. Formula (VIa) 【Chemistry 12】 A compound according to any one of claims 1 to 4 having the structure, or a pharmaceutically acceptable salt or solvate thereof.

26. Formula (VIIa) 【Chemistry 13】 A compound according to any one of claims 1 to 4 having the structure, or a pharmaceutically acceptable salt or solvate thereof.

27. R ６ These are, independently, halogen, cyano, and C. １－６ Alkyl, C １－６ Fluoroalkyl, C ３－６ Cycloalkyl, or -CH ２ - (C ３－６ It is a cycloalkyl, and R ６ If it is bonded to a nitrogen atom, then it is C １－６ Alkyl, C １－６ Fluoroalkyl, C ３－６ Cycloalkyl, or -CH ２ - (C ３－６ The compound according to claim 25 or 26, or a pharmaceutically acceptable salt or solvate thereof, which is a cycloalkyl compound.

28. R ６ These are independently fluoro, chloro, cyano, cyclopropyl, and -CH2. ２ -Cyclopropyl or methyl, R ６ If it is bonded to a nitrogen atom, it is methyl, cyclopropyl, or -CH ２ - The compound according to claim 24 or 25, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is cyclopropyl.

29. R ５ A compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt or solvate thereof, wherein each is independently hydrogen or fluoro.

30. R ５ The compound according to claim 28, or a pharmaceutically acceptable salt or solvate thereof, wherein each of the atoms is hydrogen.

31. R ７ Each of them independently represents hydrogen or C １ -C ６ A compound according to any one of claims 1 to 14 or 17 to 30, which is alkyl, or a pharmaceutically acceptable salt or solvate thereof.

32. R ８ C １ -C １０ Alkyl, C １ -C １０ Heteroalkyl, C ３ -C １２ A cycloalkyl or a 3- to 15-membered heterocycloalkyl, wherein alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is oxo and R １１ A compound according to any one of claims 1 to 14 or 17 to 31, or a pharmaceutically acceptable salt or solvate thereof, optionally substituted with 1 to 6 groups independently selected from the compound.

33. R ８ C １ -C １０ Alkyl, C ３ -C １２ A cycloalkyl or a 3- to 15-membered heterocycloalkyl, wherein the alkyl, cycloalkyl, or heterocycloalkyl is oxo and R １１ The compound according to claim 32, or a pharmaceutically acceptable salt or solvate thereof, optionally substituted with 1 to 6 groups independently selected from the compound.

34. R ８ C ３ -C １０ A cycloalkyl or a 3- to 12-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is oxo and R １１ The compound according to claim 32 or 33, or a pharmaceutically acceptable salt or solvate thereof, optionally substituted with 1 to 6 groups independently selected from the compound.

35. R ８ This is a single ring C ３ -C １０ Cycloalkyl, condensed bicyclic C ５ -C １０ Cycloalkyl, cross-linked bicyclic C ５ -C １０ Cycloalkyl, spirocyclic, bicyclic C ５ -C １０ The cycloalkyl group is a monocyclic 3-12 member heterocycloalkyl group, a condensed bicyclic 5-12 member heterocycloalkyl group, a cross-linked bicyclic 5-12 member heterocycloalkyl group, or a spirocyclic bicyclic 5-12 member heterocycloalkyl group, and the cycloalkyl group or heterocycloalkyl group is oxo and R １１ The compound according to any one of claims 32 to 34, or a pharmaceutically acceptable salt or solvate thereof, optionally substituted with 1 to 6 groups independently selected from the compound.

36. R ８ This is a condensed biringular C ５ -C １０ Cycloalkyl, cross-linked bicyclic C ５ -C １０ Cycloalkyl, spirocyclic, bicyclic C ５ -C １０ The cycloalkyl group is a condensed bicyclic 5-12 member heterocycloalkyl group, a cross-linked bicyclic 5-12 member heterocycloalkyl group, or a spirocyclic bicyclic 5-12 member heterocycloalkyl group, and the cycloalkyl group or heterocycloalkyl group is oxo and R １１ The compound according to any one of claims 32 to 35, or a pharmaceutically acceptable salt or solvate thereof, optionally substituted with 1 to 6 groups independently selected from the compound.

37. R ８ This is a spirocyclic bicyclic C ５ -C １０ A cycloalkyl or a 5-12 membered heterocycloalkyl with a spirocyclic or bicyclic structure, wherein the cycloalkyl or heterocycloalkyl is oxo and R １１ The compound according to any one of claims 31 to 35, or a pharmaceutically acceptable salt or solvate thereof, optionally substituted with 1 to 6 groups independently selected from the compound.

38. One R bonded to the same nitrogen atom ７ and one R ８ These combine to form oxo and R １１ A compound according to any one of claims 1 to 13 or 17 to 30, or a pharmaceutically acceptable salt or solvate thereof, which forms a 3 to 15-membered heterocycloalkyl group optionally substituted with 1 to 6 groups independently selected from the above.

39. One R bonded to the same nitrogen atom ７ and one R ８ These combine to form a condensed bicyclic 5-12 member heterocycloalkyl, a crosslinked bicyclic 5-12 member heterocycloalkyl, or a spirocyclic bicyclic 5-12 member heterocycloalkyl, and the heterocycloalkyl is oxo and R １１ The compound according to claim 38, or a pharmaceutically acceptable salt or solvate thereof, optionally substituted with 1 to 6 groups independently selected from the compound.

40. One R bonded to the same nitrogen atom ７ and one R ８ These combine to form a crosslinked bicyclic 5-12 member heterocycloalkyl or a spirocyclic bicyclic 5-12 member heterocycloalkyl, and the heterocycloalkyl is oxo and R １１ The compound according to claim 38 or 39, or a pharmaceutically acceptable salt or solvate thereof, optionally substituted with 1 to 6 groups independently selected from the compound.

41. One R bonded to the same nitrogen atom ７ and one R ８ These combine to form a spirocyclic bicyclic 5-12 member heterocycloalkyl group, and the heterocycloalkyl group consists of oxo and R １１ The compound according to any one of claims 38 to 40, or a pharmaceutically acceptable salt or solvate thereof, optionally substituted with 1 to 6 groups independently selected from the compound.

42. R １１ These are, independently, halogen, hydroxyl, amino, cyano, and -S (=O). ２ (R １３ ), -N(R １２ )S (=O) ２ (R １３ ), -S(=O)(R １３ ), -N(R １２ )S (=O) (R １３ ), -C(=O)R １３ , -N(R １２ )C(=O)R １３ , C １ -C ６ Alkyl, -O(C) １ -C ６ Alkyl), -NH(C １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ , C １ -C ６ Haloalkyl, C ３ -C ８ Cycloalkyl, 3-10 member heterocycloalkyl, C ６ Selected from the group consisting of aryls and 5-6 member heteroaryls, aryls and heteroaryls are R １４ Optionally substituted with 1 to 4 groups independently selected from, alkyl, haloalkyl, cycloalkyl, and heterocycloalkyl groups, oxo and R １４ Substituted by 1 to 4 groups independently selected from, Alternatively, two R atoms bonded to the same carbon or nitrogen atom １１ They become one, C ３ -C ６ They form cycloalkyl or 3-6 member heterocycloalkyl groups, and the cycloalkyl and heterocycloalkyl groups are oxo and R １４ It is optionally replaced by 1 to 4 elements independently selected from, and also, R １４ The existence of each is independent of cyano, amino, hydroxy, and -C(=O)OR １２ , -C(=O)N(R １２ ) ２ , C １ -C ６ Alkyl, -O(C) １ -C ６ Alkyl), -NR １２ (C １ -C ６ Alkyl), aryl, heteroaryl, C ３ -C ６ A compound according to any one of claims 1 to 13 or 17 to 41, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is a cycloalkyl or a 3- to 6-membered heterocycloalkyl, each alkyl group optionally substituted with 1 to 2 hydroxyl groups.

43. R １１ These are independently fluoro, hydroxy, amino, and -S (=O) ２ (R １３ ), -N(R １２ )S (=O) ２ (R １３ ), -S(=O)(R １３ ), -N(R １２ )S (=O) (R １３ ), -C(=O)R １３ , -N(R １２ )C(=O)R １３ , C １ -C ６ Alkyl, -O(C) １ -C ６ Alkyl), -NH(C １ -C ６ Alkyl), C １ -C ６ Haloalkyl, C ３ -C ８ Selected from the group consisting of cycloalkyls, 3-10 membered heterocycloalkyls, phenyls, and 5-6 membered heteroaryls, where phenyl and heteroaryls are R １４ Optionally substituted with 1 to 4 groups independently selected from, alkyl, haloalkyl, cycloalkyl, and heterocycloalkyl groups, oxo and R １４ The compound according to claim 42, or a pharmaceutically acceptable salt or solvate thereof, substituted with one to four groups independently selected from the above.

44. R １１ These are, independently, halogen, hydroxyl, amino, cyano, and -S (=O). ２ (R １３ ), -N(R １２ )S (=O) ２ (R １３ ), -S(=O)(R １３ ), -N(R １２ )S (=O) (R １３ ), -C(=O)R １３ , -N(R １２ )C(=O)R １３ , C １ -C ６ Alkyl, -O(C) １ -C ６ Alkyl), -NH(C １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ , C １ -C ６ Haloalkyl, C ３ -C ８ Selected from the group consisting of cycloalkyls, 3-10 membered heterocycloalkyls, and 5-10 membered heteroaryls, the heteroaryl is optional, R １４ Substituted with 1 to 4 groups independently selected from, alkyl, haloalkyl, cycloalkyl, and heterocycloalkyl groups are optional, oxo and R １４ Substituted by 1 to 4 groups independently selected from, Alternatively, two R atoms bonded to the same carbon or nitrogen atom １１ They become one, C ３ -C ６ They form cycloalkyl or 3-6 member heterocycloalkyl groups, and the cycloalkyl and heterocycloalkyl groups are oxo and R １４ It is optionally replaced by 1 to 4 elements that are independently selected from, R １２ Each of them independently represents hydrogen or C １ -C ６ It is alkyl, R １３ These are independently hydroxy, amino, and C. １ -C ６ Alkyl, -O(C) １ -C ６ Alkyl), -NH(C １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ , or C １ -C ６ It is a haloalkyl, R １４ These are independently cyano, amino, hydroxy, and -C(=O)OR １２ , -C(=O)N(R １２ ) ２ , C １ -C ６ Alkyl, -O(C) １ -C ６ Alkyl), or -NR １２ (C １ -C ６ A compound according to any one of claims 1 to 13 or 17 to 41, or a pharmaceutically acceptable salt or solvate thereof, wherein each alkyl group is optionally substituted with one or two hydroxyl groups. 【Request Item 45】 【Chemistry 14】 teeth, 【Chemistry 15-1】 【Chemistry 15-2】 【Chemistry 15-3】 【Chemistry 15-4】 The compound according to any one of claims 17-18 or 25-28, or a pharmaceutically acceptable salt or solvate thereof.

46. -L-R ２ teeth, 【Chemistry 16-1】 【Chemistry 16-2】 【Chemistry 16-3】 【Chemistry 16-4】 The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt or solvate thereof.

47. The aforementioned compounds are shown in the following table. Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, which is the compound shown in [reference], or a pharmaceutically acceptable salt or solvate thereof.

48. A pharmaceutical composition comprising a compound according to any one of claims 1 to 47, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

49. A method for treating a disease or disorder in a subject requiring treatment, comprising the step of administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 47, a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 48.

50. The method according to claim 49, wherein the disease or disorder is a neurokinin receptor 3 (NK3)-dependent disease or disorder.

51. The method according to claim 49 or 50, wherein the disease or disorder is selected from the group consisting of migraine, drug abuse headache, cluster headache, generalized headache, trigeminal neuralgia, orofacial pain, and combinations thereof.

52. The method according to any one of claims 49 to 51, wherein the disease or disorder is selected from the group consisting of migraine, medication-induced headache, cluster headache, generalized headache, and combinations thereof.

53. The method according to any one of claims 49 to 52, wherein the disease or disorder is a migraine.

54. The method according to any one of claims 49 to 53, further comprising the step of administering an additional therapeutically effective amount of the therapeutic agent.

55. The additional therapeutic agents include beta-blockers, e.g., propranolol, nadolol, timolol, metoprolol, and atenolol; antidepressants, e.g., amitriptyline and venlafaxine; anticonvulsants, e.g., valproate and topiramate; phenothiazine antiemetics, e.g., prochlorperazine; non-phenothiazine antiemetics, e.g., metoclopramide; nonsteroidal anti-inflammatory drugs (NSAIDs), e.g., aspirin, ibuprofen, and naproxen; acetaminophen; caffeine; ergotamine, e.g., ergotamine and The method according to claim 54, selected from dihydroergotamine (DHE), ditans, e.g., rasmiditan, triptans, e.g., alumotriptan, eletriptan, fluvatriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan, calcitonin gene-related peptide (CGRP) receptor antagonists, e.g., uvrogepant, rimegepant, atogepant, and zabegepant, CGRP antibodies, e.g., erenumab, fremanezumab, galcanezumab, and eptinezumab, and combinations thereof.

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