Compounds, compositions, and methods

Abstract

This disclosure generally relates to small molecule modulators of ion channels and their use as therapeutic agents. This specification provides compounds useful in treating and / or preventing diseases at least partially involving transmembrane protein 175 (TMEM175), such as the development of various neurodegenerative and central nervous system (CNS) disorders, e.g., Parkinson's disease (PD) and REM sleep behavior disorder (RBD), or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs of such compounds.

Description

[Technical Field]

[0001] Cross-reference of related applications This application asserts the interests under Section 119(e) of U.S. Provisional Application No. 63 / 591,960, filed on 20 October 2023, which is incorporated herein by reference in its entirety.

[0002] Technical field This disclosure provides low-molecular-weight modulators of ion channels and their use as therapeutic agents. [Background technology]

[0003] Transmembrane protein 175 (TMEM175) is a lysosomal potassium ion channel that regulates lysosomal membrane potential and pH stability in neurons. TMEM175 is associated with the development of various neurodegenerative and central nervous system (CNS) disorders, including Parkinson's disease (PD).

[0004] Parkinsonism is a term encompassing several conditions, including Parkinson's disease (PD) and other conditions with similar symptoms, such as bradykinesia, rigidity, and gait disturbances. Most people with parkinsonism have idiopathic PD, also known as Parkinson's disease. Idiopathic means that the cause is unknown. The most common symptoms of idiopathic Parkinson's disease are tremor, rigidity, and bradykinesia. The exact cause of PD is unknown, but a combination of genetic and environmental factors is thought to be the etiology of this disease. Drugs approved for the treatment of Parkinson's disease (PD) include dopamine replacement therapy (levodopa / carbidopa), dopamine agonists (pramipexole, ropinirole, rotigotine, apomorphine), catechol-O-methyltransferase (COMT) inhibitors (entacapone, levodopa / carbidopa / entacapone, tolcapone, opicapon), monoamine oxidase B (MAO-B) inhibitors (selegiline hydrochloride, rasagiline, safinamide), amantadine, anticholinergics (trihexyphenidyl, benztropine mesylate), acetylcholinesterase inhibitors (rivastigmine), and serotonin 5-HT. 2A Examples include receptor agonists (pimavanserin) and imaging dopamine transporters (ioflupane I-123).

[0005] There is a need for new therapies aimed at mitigating or delaying disease progression and postponing late-stage motor complications in Parkinson's disease (PD) and other neurodegenerative and central nervous system disorders. [Overview of the project] [Means for solving the problem]

[0006] This specification provides compounds useful for treating and / or preventing diseases that are at least partially related to transmembrane protein 175 (TMEM175), such as the development of various neurodegenerative and central nervous system (CNS) disorders, including Parkinson's disease (PD) and REM sleep behavior disorder (RBD), or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs of such compounds.

[0007] In some embodiments, compounds that modulate the activity of transmembrane protein 175 (TMEM175) are provided.

[0008] In another embodiment, a pharmaceutical composition is provided comprising a compound described herein, or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a mixture of stereoisomers, or a prodrug, and a pharmaceutically acceptable carrier.

[0009] Another embodiment provides a method for treating a disease or condition in which at least partially transmembrane protein 175 (TMEM175) is involved, comprising administering an effective amount of a pharmaceutical composition comprising one of the compounds described herein, or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a mixture of stereoisomers, or a prodrug.

[0010] Another embodiment provides a method for treating a disease or condition relating at least partially to the regulation of transmembrane protein 175 (TMEM175), comprising administering an effective amount of a pharmaceutical composition comprising one of the compounds described herein, or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a mixture of stereoisomers, or a prodrug, and a pharmaceutically acceptable carrier, to a subject in need thereof.

[0011] This disclosure also provides compositions comprising pharmaceutical compositions, kits comprising the compound, and methods for using (or administering) and producing the compound. This disclosure further provides the compound or a composition thereof for use in methods of treating diseases, disorders, or conditions related at least partially to transmembrane protein 175 (TMEM175). Furthermore, this disclosure provides the use of the compound or a composition thereof in the manufacture of pharmaceuticals for the treatment of diseases, disorders, or conditions related at least partially to transmembrane protein 175 (TMEM175).

[0012] In certain embodiments, the disease, disorder, or condition is a neurodegenerative disease, a central nervous system (CNS) disorder, cancer, an inflammatory disease, or a lysosomal storage disorder. [Modes for carrying out the invention]

[0013] The following description outlines exemplary embodiments of the Technology. However, it should be recognized that such descriptions are not intended to limit the scope of the Disclosure, but rather to provide a description of exemplary embodiments.

[0014] definition When used herein, the following terms, phrases, and symbols are generally intended to have the meanings set forth below, unless otherwise indicated in the context in which they are used.

[0015] A dash ("-") without a space between two letters or symbols is used to indicate the bonding point of a substituent. For example, -C(O)NH2 is bonded via a carbon atom. Dashes at the beginning or end of a chemical group are for convenience only, and chemical groups may be represented with or without one or more dashes without losing their usual meaning. Dashed or wavy lines drawn through lines in a structure indicate specific bonding points of a group. Unless chemically or structurally required, the order in which chemical groups are described or named does not indicate or suggest orientation or stereoselectivity.

[0016] Prefix “C” u-v " means that the following group has u to v carbon atoms. For example, "C 1-6 The term "alkyl" means that an alkyl group has 1 to 6 carbon atoms.

[0017] References to values ​​or parameters “approximately” in this specification include (and are described) embodiments relating to the value or parameter itself. In certain embodiments, the term “approximately” includes ±10% of the indicated amount. In other embodiments, the term “approximately” includes ±5% of the indicated amount. In certain other embodiments, the term “approximately” includes ±1% of the indicated amount. Also, the term “approximately X” includes the description of “X.” Furthermore, the singular forms “a” and “the” include plural references unless explicitly indicated otherwise in the context. Thus, for example, a reference to “compound” includes multiple such compounds, and a reference to “assay” includes one or more assays and their equivalents well known to those skilled in the art.

[0018] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C 1-20 Alkyl), having 1 to 12 carbon atoms (i.e., C 1-12 Alkyl), having 1 to 8 carbon atoms (i.e., C 1-8 Alkyl), having 1 to 6 carbon atoms (i.e., C 1-6 Alkyl) or having 1 to 4 carbon atoms (i.e., C 1-4 Alkyl). Examples of alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbon atoms is given a chemical name or identified by a molecular formula, all isomers at that number of carbon atoms may be included. For example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3), and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0019] Certain alternative chemical names that are commonly used may also be employed. For example, divalent groups such as a divalent "alkyl" group, a divalent "aryl" group, and a divalent heteroaryl group may also be referred to as an "alkylene" group or "alkylenyl" group (e.g., methylenyl, ethylenyl, and propylenyl), an "arylene" group or "arylenyl" group (e.g., phenylenyl or naphthylenyl, or quinolinyl in the case of heteroarylene), respectively. Further, unless explicitly stated otherwise, when a combination of groups is referred to herein as a moiety, for example, arylalkyl or aralkyl, the last-mentioned group contains the atom by which the moiety is attached to the rest of the molecule.

[0020] "Alkenyl" contains at least one (e.g., 1 to 3, or 1) carbon-carbon double bond, and has 2 to 20 carbon atoms (i.e., C 2-20 alkenyl), has 2 to 12 carbon atoms (i.e., C 2-12 alkenyl), has 2 to 8 carbon atoms (i.e., C 2-8 alkenyl), has 2 to 6 carbon atoms (i.e., C 2-6 alkenyl), or has 2 to 4 carbon atoms (i.e., C 2-4 alkenyl) refers to an alkyl group. Examples of the alkenyl group include, for example, ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0021] "Alkynyl" contains at least one (e.g., 1 to 3, or 1) carbon-carbon triple bond, and has 2 to 20 carbon atoms (i.e., C 2-20 alkynyl), has 2 to 12 carbon atoms (i.e., C 2-12 alkynyl), has 2 to 8 carbon atoms (i.e., C 2-8 alkynyl), has 2 to 6 carbon atoms (i.e., C 2-6 alkynyl), or has 2 to 4 carbon atoms (i.e., C 2-4Alkynyl refers to an alkyl group. The term "alkynyl" also includes groups having one triple bond and one double bond.

[0022] "Alkoxy" refers to the group "alkyl-O-". Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0023] "Alkoxyalkyl" refers to the group "alkyl-O-alkyl".

[0024] "Alkylthio" refers to the group "alkyl-S-". "Alkylsulfinyl" refers to the group "alkyl-S(O)-". "Alkylsulfonyl" refers to the group "alkyl-S(O)2-". "Alkylsulfonylalkyl" refers to -alkyl-S(O)2-alkyl.

[0025] "Acyl" refers to the base -C(O)R y And R y , where is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein. Examples of acyls include, for example, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, and benzoyl.

[0026] "Amide" refers to the group -C(O)NR y R z The "C-amide" group and the -NR group refer to the "C-amide" group and the -NR group. y C(O)R z Both of the "N-amide" groups that refer to R y and R zHowever, independently, these are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein, or R y and R z However, together they form a cycloalkyl or heterocycline, each of which may be optionally substituted as defined herein.

[0027] "Amino" is the base-NR y R z And R y and R z However, these are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0028] "Amidino" means -C(NR y )(NR z 2) and R y and R z However, these are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0029] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings including a condensed system (e.g., bicyclic or tricyclic). As used herein, aryl has 6 to 20 ring carbon atoms (i.e., C 6-20 (aryl), having 6 to 12 ring carbon atoms (i.e., C 6-12 (aryl), or having 6 to 10 ring carbon atoms (i.e., C 6-10Aryl groups. Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl. However, aryl groups do not include, or overlap with, heteroaryl groups, which are described below. When one or more aryl groups are fused with a heteroaryl group, the resulting ring system is heteroaryl regardless of the bonding site. When one or more aryl groups are fused with a heterocyclyl group, the resulting ring system is heterocyclyl regardless of the bonding site. When one or more aryl groups are fused with a cycloalkyl group, the resulting ring system is cycloalkyl regardless of the bonding site.

[0030] "Arylalkyl" or "aralkyl" refers to the group "aryl-alkyl-".

[0031] "Carbamoyl" is the base -OC(O)NR y R z The "O-carbamoyl" group and the -NR group refer to these groups. y C(O)OR z Both of the "N-carbamoyl" groups that refer to R y and R z However, these are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0032] "Carboxyl ester" or "ester" refers to -OC(O)R x and -C(O)OR x Both are, R x This refers to alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl compounds, each of which may be optionally substituted as defined herein.

[0033] A "cyanoalkyl" refers to an alkyl group as defined above, in which one or more (for example, one or two) hydrogen atoms are replaced by a cyano(-CN) group.

[0034] "Cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings, including condensed, cross-linked, and spiro-ring systems. The term "cycloalkyl" is defined as a cycloalkenyl group (i.e., a cyclic group having at least one double bond) and at least one sp 3 This includes carbocyclic fused ring systems having carbon atoms (i.e., at least one non-aromatic ring). As used herein, cycloalkyls have 3 to 20 ring carbon atoms (i.e., C 3-20 Cycloalkyl), having 3 to 12 ring carbon atoms (i.e., C 3-12 Cycloalkyl), having 3 to 12 ring carbon atoms (i.e., C 3-12 Cycloalkyl), having 3 to 10 ring carbon atoms (i.e., C 3-10 Cycloalkyl), having 3 to 8 ring carbon atoms (i.e., C 3-8 Cycloalkyl, or having 3 to 6 ring carbon atoms (i.e., C 3-6 (Cycloalkyl). Examples of monocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic groups include bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbornyl, dekalinyl, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Furthermore, the term cycloalkyl is intended to encompass any non-aromatic ring that can be condensed to an aryl ring, regardless of its bonding to the remainder of the molecule. Moreover, cycloalkyl also includes "spirocycloalkyl," such as spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl, in the case where there are two substitution positions on the same carbon atom.

[0035] "Cycloalkylalkyl" refers to the group "cycloalkyl-alkyl-".

[0036] "Imino" is the base C(NR y )R zAnd R y and R z Each of these independently refers to hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0037] "Imide" refers to the group -C(O)NR y C(O)R z And R y and R z Each of these independently refers to hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0038] "Halogen" or "halo" refers to atoms that occupy Group VIIA of the periodic table, such as fluoro, chloro, bromo, or iodine.

[0039] A "haloalkyl" refers to an unbranched or branched alkyl group as defined above, in which one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by halogens. For example, if a residue is replaced by two or more halogens, it may be referred to by using a prefix corresponding to the number of halogenated moieties bonded. Dihaloalkyls and trihaloalkyls refer to alkyl groups substituted with two ("di") or three ("tri") halo groups, but these do not necessarily have to be the same halogens. Examples of haloalkyls include trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl.

[0040] A "haloalkoxy" refers to an alkoxy group as defined above, in which one or more (for example, 1 to 6 or 1 to 3) hydrogen atoms are replaced by halogens.

[0041] A "haloalkoxyalkyl" refers to an alkoxyalkyl group as defined above, in which one or more (for example, 1 to 6 or 1 to 3) hydrogen atoms are replaced by halogens.

[0042] A "hydroxyalkyl" is an alkyl group as defined above, in which one or more (for example, 1 to 6 or 1 to 3) hydrogen atoms are replaced by a hydroxyl group.

[0043] A "heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms), excluding one or more terminal carbon atoms, are independently replaced by the same or different heteroatomic groups, provided that the bonding sites to the rest of the molecule are via carbon atoms. The term "heteroalkyl" includes unbranched or branched saturated chains containing carbon and heteroatoms. For example, one, two, or three carbon atoms may be independently replaced by the same or different heteroatomic groups. Examples of heteroatomic groups include -NR y -, -O-, -S-, -S(O)-, -S(O)2-, etc., R y The elements are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein. Examples of heteroalkyl groups include, for example, ethers (e.g., -CH2OCH3, -CH(CH3)OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, etc.), thioethers (e.g., -CH2SCH3, -CH(CH3)SCH3, -CH2CH2SCH3, -CH2CH2SCH2CH2CH3, etc.), sulfones (e.g., -CH2S(O)2CH3, -CH(CH3)S(O)2CH3, -CH2CH2S(O)2CH3, -CH2CH2S(O)2CH3, etc.), and amines (e.g., -CH2NR y CH3, -CH(CH3)NR y CH3, -CH2CH2NRy CH3, -CH2CH2NR y CH2 CH2NR y CH3 and others, R y Examples include hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein. As used herein, a heteroalkyl comprises 2 to 10 carbon atoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0044] "Heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings containing one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl has 1 to 20 ring carbon atoms (i.e., C 1-20 Heteroaryl), having 3 to 12 ring carbon atoms (i.e., C 3-12 Heteroaryl) or having 3 to 8 ring carbon atoms (i.e., C 3-8A heteroaryl ring having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom, each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom, each independently having 1 to 10-membered ring systems, 5 to 7-membered ring systems, or 5 to 6-membered ring systems, each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom, each independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, for example, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, sinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl Examples include isoxazolyl, naphthilidinyl, oxadiazolyl, oxazolyl, 1-oxidepyridinyl, 1-oxidepyrimidinyl, 1-oxidepyradinyl, 1-oxidepyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyridinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, thiophenyl (i.e., thienyl), triazolyl, tetrazolyl, and triazinyl. Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, in which the heteroaryl can be bonded via one of the rings of the fused system. Any aromatic ring having one or more fused rings containing at least one heteroatom is considered a heteroaryl, regardless of its bond to the rest of the molecule (i.e., via any one of the fused rings).A heteroaryl does not include or overlap with an aryl as defined above.

[0045] "Heteroarylalkyl" refers to the group "heteroaryl-alkyl-".

[0046] A "heterocyclyl" refers to a saturated or partially unsaturated cyclic alkyl group containing one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclyl" includes heterocycloalkenyl groups (i.e., heterocyclyl groups having at least one double bond), bridged heterocyclyl groups, condensed heterocyclyl groups, and spiro-heterocyclyl groups. A heterocyclyl may be a single ring or multiple rings, where the multiple rings may be condensed, bridged, or spiro, and contain one or more (e.g., 1 to 3) oxo (=O) or N-oxide (-O) atoms. - ) may include a portion. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of the bonding (i.e., bonding via carbon atoms or heteroatoms). Furthermore, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which may be condensed into a cycloalkyl, aryl, or heteroaryl ring, regardless of bonding to the rest of the molecule. As used herein, a heterocyclyl has 2 to 20 ring carbon atoms (i.e., C 2-20 Heterocyclyls have 2 to 12 ring carbon atoms (i.e., C 2-12 Heterocyclyls have 2 to 10 ring carbon atoms (i.e., C 2-10 Heterocyclyls have 2 to 8 ring carbon atoms (i.e., C 2-8 Heterocyclyls have 3 to 12 ring carbon atoms (i.e., C 3-12 Heterocyclyls have 3 to 8 ring carbon atoms (i.e., C 3-8 Heterocyclyls have 3 to 6 ring carbon atoms (i.e., C 3-6The heterocyclyl group has 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom, independently selected from nitrogen, sulfur, or oxygen. Examples of heterocyclyl groups include, for example, azetidinyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxynyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanoyl, imidazolinyl, imidazolidinyl, indolinyl, indolidinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolinyl Examples include lyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxylanil, oxetanyl, phenothiazinyl, phenoxadinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tetrahydropyranyl, trithianil, tetrahydroquinolinyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. The term "heterocyclyl" also includes "spiroheterocyclyl" when there are two substitution positions on the same carbon atom. Examples of spiro-heterocyclyl rings include, for example, bicyclic and tricyclic ring systems such as oxabicyclo[2.2.2]octanyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of condensed heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, in which the heterocyclyl can be linked via one of the rings of the condensation system.

[0047] "Heterocyclylalkyl" refers to the group "heterocyclyl-alkyl-".

[0048] "Oxime" refers to the group -CR y (=NOH), wherein R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0049] "Sulfonyl" refers to the group -S(O)₂R y , wherein R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein. Examples of sulfonyl include methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0050] "Sulfinyl" refers to the group -S(O)R y , wherein R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein. Examples of sulfinyl include methylsulfinyl, ethylsulfinyl, phenylsulfinyl, and toluenesulfinyl.

[0051] "Sulfonamido" refers to the groups -SO₂NR y R z and -NR y SO₂R z , wherein R y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0052] "Optional" or "optionally" means that the event or situation described thereafter may or may not occur, and that the description includes both cases in which the event or situation occurs and cases in which it does not. The term "optionally substituted" means that any one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms on a specified atom or group may or may not be replaced by non-hydrogen parts.

[0053] As used herein, the term "substituted" means any of the above groups (i.e., alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, and / or heteroalkyl) in which at least one (e.g., 1 to 5 or 1 to 3) hydrogen atoms is substituted, but is not limited to alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amide, amino, amidino, aryl, aralkyl, azide, carbamoyl, carboxyl, car Ruboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanidino, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -NHNH2, =NNH2, imino, imide, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, -S(O)OH, -S(O)2OH, sulfonamide, thiol, thioxo, N-oxide, or -Si(R y )3 is replaced by a bond to a non-hydrogen atom, and each R y However, it means that independently, it is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl.

[0054] In certain embodiments, "substituted" refers to any of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups described above, in which one or more (for example, 1 to 5 or 1 to 3) hydrogen atoms are replaced by deuterium, halo, cyano, nitro, azido, oxo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR g R h , -NR g C(O)R h , -NR g C(O)NR g R h , -NR g C(O)OR h , -NR g S(O) 1-2 R h , -C(O)R g , -C(O)OR g , -OC(O)OR g , -OC(O)R g , -C(O)NR g R h , -OC(O)NR g R h , -OR g , -SR g , -S(O)R g , -S(O)2R g , -OS(O) 1-2 R g , -S(O) 1-2 OR g , -NR g S(O) 1-2 NR g R h , =NSO2R g , =NOR g , -S(O) 1-2 NR g R h , -SF5, -SCF3, or -OCF3, independently. In certain embodiments, "substituted" also refers to any of the groups described above, in which one or more (for example, 1 to 5 or 1 to 3) hydrogen atoms are replaced by -C(O)R g , -C(O)OR g , -C(O)NR g Rh ,-CH2SO2R g , or -CH2SO2NR g R h It means that it has been replaced by R. g and R h These are the same or different and independently of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and / or heteroarylalkyl. In certain embodiments, “substituted” is also any of the above groups in which one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are replaced by a bond to amino, cyano, hydroxy, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, and / or heteroarylalkyl, or R g and R h and R i This means that two of these atoms, together with the atoms to which they are bonded, form a heterocyclyl ring that is optionally substituted with oxo, halo, or alkyl (optionally substituted with oxo, halo, amino, hydroxy, or alkoxy).

[0055] Polymers or similar amorphous structures obtained by adding an infinite number of further substituents to a substituent (e.g., a substituted aryl having a substituted alkyl, which itself is substituted with a substituted aryl group and further substituted with a substituted heteroalkyl group) are not intended to be included herein. Unless otherwise specified, the maximum number of consecutive substitutions in the compounds described herein is three. For example, consecutive substitution of a substituted aryl group containing two other substituted aryl groups is limited to ((substituted aryl)substituted aryl)substituted aryl. Similarly, the above definitions are intended to exclude unacceptable substitution patterns (e.g., a methyl group substituted with five fluorine atoms, or a heteroaryl group having two adjacent oxygen ring atoms). Such unacceptable substitution patterns are well known to those skilled in the art. When used to modify a chemical group, the term “substituted” may describe other chemical groups as defined herein.

[0056] In certain embodiments, as used herein, the phrase "one or more" refers to one to five. In certain embodiments, as used herein, the phrase "one or more" refers to one to three.

[0057] Any compound or structure presented herein is also intended to represent both an unlabeled and an isotopically labeled form of the compound. These forms of a compound may also be referred to as “isotope-enriched analogues.” An isotopically labeled compound has the structure described herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphoric acid, fluorine, chlorine, and iodine, for example, respectively. 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32P, 35 S, 18 F, 36 Cl, 123 I, and 125 I is an example. Various isotope-labeled compounds of this disclosure, for example, 3 H and 14 These compounds incorporate radioactive isotopes such as 13C. Such isotope-labeled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or in radiotherapy for patients.

[0058] The term “isotope-enriched analog” includes “deuterated analogs” of compounds described herein, in which one or more hydrogen atoms, such as hydrogen on a carbon atom, are replaced by deuterium. Such compounds exhibit increased resistance to metabolism and are therefore useful for extending the half-life of any compound when administered to mammals, particularly humans. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by using starting materials in which one or more hydrogen atoms are replaced by deuterium.

[0059] The deuterium-labeled or substituted therapeutic compounds of this disclosure may have improved DMPK (drug metabolism and pharmacokinetic) properties with respect to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes such as deuterium may result in certain therapeutic benefits arising from higher metabolic stability, such as extended in vivo half-life, reduced required dosage, and / or improved therapeutic index. 18 F, 3 H, or 1114C-labeled compounds may be useful in PET, SPECT, or other imaging studies. The isotope-labeled compounds and their prodrugs of this disclosure can generally be prepared by performing the procedures and preparations disclosed in the scheme or examples and described below, by substituting non-isotope labeling reagents with readily available isotope labeling reagents. In this context, deuterium is understood to be a substituent in the compounds described herein.

[0060] The concentrations of such heavier isotopes, particularly deuterium, can be defined by the isotopic enrichment factor. In the compounds of this disclosure, atoms not specifically designated as a particular isotope are intended to represent any stable isotope of that atom. Unless otherwise specified, where a position is specifically designated as "H" or "hydrogen," that position is understood to have hydrogen in its naturally occurring isotopic composition. Thus, in the compounds of this disclosure, an atom specifically designated as deuterium (D) is intended to represent deuterium.

[0061] In many cases, the compounds of this disclosure can form acidic salts and / or basic salts in the presence of amino and / or carboxyl groups, or similar groups.

[0062] Also provided herein are pharmaceutically acceptable salts, isotopically enriched analogs, deuterated analogs, stereoisomers, mixtures of stereoisomers, and prodrugs of the compounds described herein. "pharmaceutically acceptable" or "physiologically acceptable" means compounds, salts, compositions, dosage forms, and other materials useful in the preparation of pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0063] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological efficacy and properties of the given compound and is not biologically or otherwise undesirable. Examples of "pharmaceutically acceptable salts" or "physiologically acceptable salts" include salts with inorganic acids and salts with organic acids. In addition, if the compounds described herein are obtained as acid addition salts, the free base can be obtained by making a solution of its salt basic. Conversely, if the product is a free base, the addition salt, in particular a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, following conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art will recognize the various synthetic methods available for preparing non-toxic, pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic or organic acids. Examples of salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of salts derived from organic acids include acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvate, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic or organic bases. Examples of salts derived from inorganic bases include sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts.Salts derived from organic bases include primary, secondary, and tertiary amines, such as alkylamines (i.e., NH2(alkyl)), dialkylamines (i.e., HN(alkyl)2), trialkylamines (i.e., N(alkyl)3), substituted alkylamines (i.e., NH2(substituted alkyl)), di(substituted alkyl)amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl)amines (i.e., N(substituted alkyl)3), alkenylamines (i.e., NH2(alkenyl)), dialkenylamines (i.e., HN(alkenyl)2), trialkenylamines (i.e., N(alkenyl)3), substituted alkenylamines (i.e., NH2(substituted alkenyl)), and di(substituted alkenyl)amines (i.e., HN(substituted Examples of suitable amines include, but are not limited to, salts of alkenyl 2), tri(substituted alkenyl)amines (i.e., N(substituted alkenyl)3, mono-, di-, or tri-cycloalkylamines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di-, or tri-allylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), or mixed amines. Specific examples of suitable amines, though not exhaustive, include isopropylamine, trimethylamine, diethylamine, tri(iso-propyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, and N-ethylpiperidine.

[0064] Some compounds exist as tautomers. Tautomers exist in equilibrium with each other. For example, amide-containing compounds may exist in equilibrium with imido acid tautomers. Regardless of whether the tautomers are shown and regardless of the nature of the equilibrium between the tautomers, it is understood by those skilled in the art that a compound contains both amide tautomers and imido acid tautomers. Therefore, amide-containing compounds are understood to contain their imido acid tautomers. Similarly, imido acid-containing compounds are understood to contain their amide tautomers.

[0065] The compounds of this disclosure or their pharmaceutically acceptable salts contain chiral centers and can therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms, which can be defined in terms of absolute stereochemistry as (R)- or (S)-, or with respect to amino acids as (D)- or (L)-. This disclosure is intended to include all such conceivable isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or separated using prior art, e.g., chromatography and / or fractional recrystallization. Prior art for the preparation / isolation of individual enantiomers includes chiral synthesis from suitable optically pure precursors, or separation of racemates (or racemates of salts or derivatives) using, for example, chiral high-pressure liquid chromatography (HPLC). If a compound described herein contains an olefin double bond or other geometrically asymmetric center, unless otherwise specified, the compound is intended to include both E and Z geometric isomers.

[0066] A "stereoisomer" refers to a compound that has the same atoms bonded together by the same bonds but possesses different, non-interchangeable three-dimensional structures. This disclosure intends various stereoisomers or mixtures thereof and includes "enantiomers," which refer to two stereoisomers that are mirror images of each other and whose molecules cannot overlap.

[0067] A "diastereomer" is a stereoisomer that has at least two asymmetric atoms but is not a mirror image of one another.

[0068] The relative centers of compounds described herein are indicated graphically using the “thick bond” type (bold or parallel lines), and absolute stereochemistry is indicated using the wedge bond type (bold or parallel lines).

[0069] "Prodrug" means any compound that, when administered to a mammalian subject, releases an active parent drug in vivo according to the structure described herein. Prodrugs of the compounds described herein can be prepared by modifying functional groups present in the compounds described herein so that the modifications can be cleaved in vivo to release the parent compound. Prodrugs can be prepared by routine operations or by modifying functional groups present in the compounds so that the modifications can be cleaved in vivo to become the parent compound. Prodrugs include compounds described herein in which a hydroxy, amino, carboxyl, or sulfhydryl group in the compounds described herein is bound to any group that can be cleaved in vivo to regenerate a free hydroxy, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, esters of the hydroxyl functional groups in the compounds described herein (e.g., acetates, formates, and benzoate derivatives), amides, guanidines, and cacarbamates (e.g., N,N-dimethylaminocarbonyl). The preparation, selection, and use of prodrugs are described in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the ACS Symposium Series; “Design of Prodrugs,” ed. H. Bundgaard, Elsevier, 1985; and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which is incorporated herein by reference in whole.

[0070] compound This specification provides compounds that modulate the activity of the ion channel TMEM175. In certain embodiments, the compound of formula I: [ka] Alternatively, a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, tautomers, or isotopically enriched analog is provided, in the formula, n is 1, 2, or 3; m is 0, 1, 2, 3, or 4, where n+m is 1, 2, 3, 4, or 5; p is 0, 1, 2, 3, 4, or 5; X is NH, N(C 1-6 It is alkyl, O, or S; X 1 CR 1 or N; X 2 CR 2 or N; X 3 CR 3 or N; X 4 CR 4 or N; Y 1 and Y 2 These are, independently, O, S, or NR c and; R 1 , R 2 , R 3 , and R 4 These are, independently, hydrogen, halo, cyano, and C. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, aryl, C3- 10 Cycloalkyl, heterocyclyl, heteroaryl, -C(NH)NH(OH), -C(NH)NH2, -C(O)NR a R b -C(O)NR a -NR a R b -C(O)NH(C 1-6 Alkylene)-NR a R b , -C(O)OR a , -NR a R b -NO2, -OR a -OC(O)R a , -SRa ,-S(O)R a -S(O)2R a -S(O)2NR a R b , or -S(O)3H, and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl independently has 1 to 5 Z 1 It is optionally replaced by; Or R 1 and R 2 , R 2 and R 3 , or R 3 and R 4 Along with the atoms bonded to them, 1 to 5 Z 1 They form optionally substituted 5-6 member cycloalkyl, heterocyclyl, aryl, or heteroaryl groups; R 5 These are hydrogen, halo, cyano, and C. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, aryl, C3- 10 Cycloalkyl, heterocyclyl, heteroaryl, -C(NH)NH(OH), -C(NH)NH2, -C(O)NR a R b -C(O)NR a -NR a R b -C(O)NH(C 1-6 Alkylene)-NR a R b , -C(O)OR a , -NR a R b -NO2, -OR a -OC(O)R a , -SR a ,-S(O)R a -S(O)2R a -S(O)2NR a R b , or -S(O)3H, and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl independently has 1 to 5 Z 1 It is optionally replaced by; R6a and R 6b These are, independently, Halo, Cyano, and C. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, aryl, C 3-10 Cycloalkyl, heterocyclyl, heteroaryl, -C(NH)NH(OH), -C(NH)NH2, -C(O)NR a R b -C(O)NR a -NR a R b -C(O)NH(C 1-6 Alkyl)-NR a R b , -C(O)R a , -C(O)OR a , -NR a R b -NO2, -OR a -OC(O)R a , -SR a ,-S(O)R a -S(O)2R a -S(O)2NR a R b , or -S(O)3H, and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl independently has 1 to 5 Z 1 It is optionally replaced by; or R 6a is hydrogen, and R 6b These are -CH3, -CF3, -OCF3, or C 3-10 It is cycloalkyl; or R 6a and R 6b Each of them, along with the atoms bonded to them, has 1 to 5 Z 1 C arbitrarily substituted with 3-6 Forming cycloalkyl or 3-6 membered heterocyclines; Each R 6c These are independently: halo, cyano, and C. 1-3 Alkyl, or C 1-3 It is a haloalkyl; or Two R's 6cEach of them, along with the atoms bonded to them, has 1 to 5 Z 1 Forms optionally substituted 3-6 membered spiro, condensed, or crosslinked cycloalkyl or 3-6 membered spiro, condensed, or crosslinked heterocyclyl; R 6a is hydrogen, and R 6b and one R 6c Each of them, along with the atoms bonded to them, has 1 to 5 Z 1 Forms optionally substituted 3-6 member condensates, or cross-linked cycloalkyls or 3-6 member condensates, or cross-linked heterocyclines; R 7 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, aryl, C 3-10 These are cycloalkyl, heterocyclyl, or heteroaryl compounds, where each independently comprises 1 to 5 Zs. 1 It is optionally replaced by; R 8 C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, aryl, C 3-10 These are cycloalkyl, heterocyclyl, or heteroaryl compounds, where each independently comprises 1 to 5 Zs. 2 It is optionally replaced by; Alternatively, R 7 and R 8 These atoms bond together with the carbon atoms they are attached to to form C3-6 cycloalkyl or heterocyclines, where each independently has 1 to 5 Z atoms. 1 It is optionally replaced by; Each R a and R b These are, independently, hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 They are cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each C 1-6 Alkyl, C 2-6 Alkenil, C 2-6Alkinyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl compounds are independently classified into 1 to 5 Z groups. 1b It is optionally replaced by; Each R c These are, independently, hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 They are cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl compounds are independently classified into 1 to 5 Z groups. 1b It is optionally replaced by; each Z 1 These are independently: halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 12 )2, -OR 12 , -SR 12 , -C(O)R 12 , -C(O)OR 12 ,-S(O)R 12 -S(O)2R 12 ,-C(O)N(R 12 )2, -NR 12 C(O)R 12 , -NR 12 S(O)R 12 , -NR 12 S(O)2R 12 ,-S(O)N(R 12 )2, -S(O)2N(R 12 )2, -NR 12 C(O)N(R 12 )2, -NR 12 S(O)N(R 12 )2, -NR 12 S(O)2N(R 12 )2, -OC(O)N(R 12)2, or -NR 12 C(O)OR 12 And each C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl compounds are independently classified into 1 to 5 Z groups. 1a It is optionally replaced by; each Z 2 These are independently: halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, -N(R 12 )2, -OR 12 , -SR 12 , -C(O)R 12 , -C(O)OR 12 ,-S(O)R 12 , -S(O)2R 12 ,-C(O)N(R 12 )2, -NR 12 C(O)R 12 , -NR 12 S(O)R 12 , -NR 12 S(O)2R 12 ,-S(O)N(R 12 )2, -S(O)2N(R 12 )2, -NR 12 C(O)N(R 12 )2, -NR 12 S(O)N(R 12 )2, -NR 12 S(O)2N(R 12 )2, -OC(O)N(R 12 )2, or -NR 12 C(O)OR 12 And each C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10Cycloalkyl, or heterocyclyl, is independently classified as halo, cyano, -OH, -SH, -NH2, or -NH-C. 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Optionally substituted with 1 to 5 substituents independently selected from the haloalkoxy; Each R 12 These are, independently, hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 They are cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl compounds are independently classified into 1 to 5 Z groups. 1b It is optionally replaced by; each Z 1a These are independently: halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 13 )2, -OR 13 , -SR 13 , -C(O)R 13 , -C(O)OR 13 ,-S(O)R 13 -S(O)2R 13 ,-C(O)N(R 13 )2, -NR 13 C(O)R 13 , -NR 13 S(O)R 13 , -NR 13 S(O)2R 13 ,-S(O)N(R 13 )2, -S(O)2N(R 13 )2, -NR 13 C(O)N(R 13 )2, -NR13 S(O)N(R 13 )2, -NR 13 S(O)2N(R 13 )2, -OC(O)N(R 13 )2, or -NR 13 C(O)OR 13 And here, each C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl compounds are independently classified into 1 to 5 Z groups. 1b It is optionally replaced by; Each R 13 These are, independently, hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 They are cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl compounds are independently classified into 1 to 5 Z groups. 1b It is optionally replaced by; each Z 1b These are independently: halo, cyano, -OH, -SH, -NH2, -NO2, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -L 1 -C 1-6 Alkyl, -L 1 -C 2-6 Alkenyl, -L 1 -C 2-6 Alkinyl, -L 1 -C 1-6 Haloalkyl, -L 1 -C 3-10 Cycloalkyl, -L 1 -heterocyclyl, -L 1 -aryl or -L-heteroaryl; Each L 1 These are independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, and -N(C 1-6 Alkyl)-,-N(C 2-6 Alkenyl)-, -N(C 2-6 Alkinyl)-, -N(C 1-6 Haloalkyl)-,-N(C) 3-10 Cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 Alkyl)-,-C(O)N(C 2-6 Alkenyl)-,-C(O)N(C 2-6 Alkinyl)-,-C(O)N(C 1-6 Haloalkyl)-,-C(O)N(C 3-10 These are cycloalkyl)-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, or -S(O)2NH-; Here, Z 1b and L 1 Each C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, and heteroaryl compounds can also be independently composed of 1 to 5 halo, cyano, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 It may be optionally substituted with a cycloalkyl, heterocyclyl, aryl, or heteroaryl compound.

[0071] In a particular embodiment, the compound of formula I: [ka] Alternatively, a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, tautomers, or isotopically enriched analog is provided, in the formula, n is 1, 2, or 3; m is 0, 1, 2, 3, or 4, where n+m is 1, 2, 3, 4, or 5; p is 0, 1, 2, 3, 4, or 5; X is NH, N(C 1-6 It is alkyl, O, or S; X 1 CR 1 or N; X 2 CR 2 or N; X 3 CR 3 or N; X 4 CR 4 or N; Y 1 and Y 2 These are, independently, O, S, or NR c and; R 1 , R 2 , R 3 , and R 4 These are, independently, hydrogen, halo, cyano, and C. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, aryl, C3- 10 Cycloalkyl, heterocyclyl, heteroaryl, -C(NH)NH(OH), -C(NH)NH2, -C(O)NR a R b -C(O)NR a -NR a R b -C(O)NH(C 1-6 Alkylene)-NR a R b , -C(O)OR a , -NR a R b -NO2, -OR a -OC(O)R a, -SR a ,-S(O)R a -S(O)2R a -S(O)2NR a R b , or -S(O)3H, and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl independently has 1 to 5 Z 1 It is optionally replaced by; Or R 1 and R 2 , R 2 and R 3 , or R 3 and R 4 Along with the atoms bonded to them, 1 to 5 Z 1 They form optionally substituted 5-6 member cycloalkyl, heterocyclyl, aryl, or heteroaryl groups; R 5 These are hydrogen, halo, cyano, and C. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, aryl, C3- 10 Cycloalkyl, heterocyclyl, heteroaryl, -C(NH)NH(OH), -C(NH)NH2, -C(O)NR a R b -C(O)NR a -NR a R b -C(O)NH(C 1-6 Alkylene)-NR a R b , -C(O)OR a , -NR a R b -NO2, -OR a -OC(O)R a , -SR a ,-S(O)R a -S(O)2R a -S(O)2NR a R b , or -S(O)3H, and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl independently has 1 to 5 Z 1 It is optionally replaced by; R 6a and R 6b These are, independently, Halo, Cyano, and C. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, aryl, C 3-10 Cycloalkyl, heterocyclyl, heteroaryl, -C(NH)NH(OH), -C(NH)NH2, -C(O)NR a R b -C(O)NR a -NR a R b -C(O)NH(C 1-6 Alkyl)-NR a R b , -C(O)R a , -C(O)OR a , -NR a R b -NO2, -OR a -OC(O)R a , -SR a ,-S(O)R a -S(O)2R a -S(O)2NR a R b , or -S(O)3H, and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl independently has 1 to 5 Z 1 It is optionally replaced by; or R 6a is hydrogen, and R 6b These are -CH3, -CF3, -OCF3, or C 3-10 It is cycloalkyl; or R 6a and R 6b Each of them, along with the atoms bonded to them, has 1 to 5 Z 1 C arbitrarily substituted with 3-6 Forming cycloalkyl or 3-6 membered heterocyclines; Each R 6c These are independently: halo, cyano, and C. 1-3 Alkyl, or C 1-3 It is a haloalkyl; or Two R's 6cEach of them, along with the atoms bonded to them, has 1 to 5 Z 1 Forms optionally substituted 3-6 membered spiro, condensed, or crosslinked cycloalkyl or 3-6 membered spiro, condensed, or crosslinked heterocyclyl; R 6a is hydrogen, and R 6b and one R 6c Each of them, along with the atoms bonded to them, has 1 to 5 Z 1 Forms optionally substituted 3-6 member condensates, or cross-linked cycloalkyls or 3-6 member condensates, or cross-linked heterocyclines; R 7 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, aryl, C 3-10 These are cycloalkyl, heterocyclyl, or heteroaryl compounds, where each independently comprises 1 to 5 Zs. 1 It is optionally replaced by; R 8 C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, aryl, C 3-10 These are cycloalkyl, heterocyclyl, or heteroaryl compounds, where each independently comprises 1 to 5 Zs. 2 It is optionally replaced by; Alternatively, R 7 and R 8 These atoms bond together with the carbon atoms they are attached to to form C3-6 cycloalkyl or heterocyclines, where each independently has 1 to 5 Z atoms. 1 It is optionally replaced by; Each R a and R b These are, independently, hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 They are cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each C 1-6 Alkyl, C 2-6 Alkenil, C 2-6Alkinyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl compounds are independently classified into 1 to 5 Z groups. 1b It is optionally replaced by; Each R c These are, independently, hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 They are cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl compounds are independently classified into 1 to 5 Z groups. 1b It is optionally replaced by; each Z 1 These are independently: halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 12 )2, -OR 12 , -SR 12 , -C(O)R 12 , -C(O)OR 12 ,-S(O)R 12 -S(O)2R 12 ,-C(O)N(R 12 )2, -NR 12 C(O)R 12 , -NR 12 S(O)R 12 , -NR 12 S(O)2R 12 ,-S(O)N(R 12 )2, -S(O)2N(R 12 )2, -NR 12 C(O)N(R 12 )2, -NR 12 S(O)N(R 12 )2, -NR 12 S(O)2N(R 12 )2, -OC(O)N(R 12)2, or -NR 12 C(O)OR 12 And each C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl compounds are independently classified into 1 to 5 Z groups. 1a It is optionally replaced by; each Z 2 These are independently: halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, -N(R 12 )2, -OR 12 , -SR 12 , -C(O)R 12 , -C(O)OR 12 ,-S(O)R 12 -S(O)2R 12 ,-C(O)N(R 12 )2, -NR 12 C(O)R 12 , -NR 12 S(O)R 12 , -NR 12 S(O)2R 12 ,-S(O)N(R 12 )2, -S(O)2N(R 12 )2, -NR 12 C(O)N(R 12 )2, -NR 12 S(O)N(R 12 )2, -NR 12 S(O)2N(R 12 )2, -OC(O)N(R 12 )2, or -NR 12 C(O)OR 12 And each C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10Cycloalkyl, or heterocyclyl, is independently classified as halo, cyano, -OH, -SH, -NH2, or -NH-C. 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Optionally substituted with 1 to 5 substituents independently selected from the haloalkoxy; Each R 12 These are, independently, hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 They are cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl compounds are independently classified into 1 to 5 Z groups. 1b It is optionally replaced by; each Z 1a These are independently: halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 13 )2, -OR 13 , -SR 13 , -C(O)R 13 , -C(O)OR 13 ,-S(O)R 13 -S(O)2R 13 ,-C(O)N(R 13 )2, -NR 13 C(O)R 13 , -NR 13 S(O)R 13 , -NR 13 S(O)2R 13 ,-S(O)N(R 13 )2, -S(O)2N(R 13 )2, -NR 13 C(O)N(R 13 )2, -NR13 S(O)N(R 13 )2, -NR 13 S(O)2N(R 13 )2, -OC(O)N(R 13 )2, or -NR 13 C(O)OR 13 And here, each C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl compounds are independently classified into 1 to 5 Z groups. 1b It is optionally replaced by; Each R 13 These are, independently, hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 They are cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl compounds are independently classified into 1 to 5 Z groups. 1b It is optionally replaced by; each Z 1b These are independently: halo, cyano, -OH, -SH, -NH2, -NO2, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -L 1 -C 1-6 Alkyl, -L 1 -C 2-6 Alkenyl, -L 1 -C 2-6 Alkinyl, -L 1 -C 1-6 Haloalkyl, -L 1 -C 3-10 Cycloalkyl, -L 1 -heterocyclyl, -L 1 -aryl or -L-heteroaryl; Each L 1 These are independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, and -N(C 1-6 Alkyl)-,-N(C 2-6 Alkenyl)-, -N(C 2-6 Alkinyl)-, -N(C 1-6 Haloalkyl)-,-N(C) 3-10 Cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 Alkyl)-,-C(O)N(C 2-6 Alkenyl)-,-C(O)N(C 2-6 Alkinyl)-,-C(O)N(C 1-6 Haloalkyl)-,-C(O)N(C 3-10 These are cycloalkyl)-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, or -S(O)2NH-; Here, Z 1b and L 1 Each C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, and heteroaryl compounds can also be independently composed of 1 to 5 halo, cyano, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 Optionally substituted with cycloalkyl, heterocyclyl, aryl, or heteroaryl; however, (a)Y 1 and Y 2 Both are O; R 7 However, hydrogen or unsubstituted C1-3 Alkyl; R 8 However, C is arbitrarily substituted. 1-4 If it is an alkyl or unsubstituted phenyl, part [ka] teeth, [ka] Not its stereoisomer or mixture of stereoisomers; (b)Y 1 and Y 2 Both are O; R 7 However, it is hydrogen; R 8 However, if it is a methyl atom substituted with either an optionally substituted phenyl or an optionally substituted 5- or 6-membered heteroaryl, then part [ka] teeth, [ka] Not; (c)Y 1 and Y 2 Both are O; n+m is 3; R 6a However, it is hydrogen; R 6b However, if it is -CH3, part [ka] is not 1H-indole-2-yl or 3,5-dimethyl-1H-indole-2-yl; and (d) The compound is not one of the following: (R)-4-[(1H-indole-2-ylcarbonyl)amino]-δ-oxo-8-azaspiro[4.5]decane-8-pentanoic acid (CAS 137822-87-8); N-[(1S,2S)-1-[(3,3-difluoro-1-pyrrolidinyl)carbonyl]-2-methylbutyl]-benzo[b]thiophene-2-carboxamide (CAS928403-03-6); N-[(1S,2S)-1-[[(2S)-2-cyano-4,4-difluoro-1-pyrrolidinyl]carbonyl]-2-methylbutyl]-benzo[b]thiophene-2-carboxamide, (CAS928353-89-3); or N-[(1R)-1-[(4-methoxyphenyl)methyl]-2-[3-(1-methylethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]deca-8-yl]-2-oxoethyl]-1H-indole-2-carboxamide (CAS1219969-86-4)

[0072] In some embodiments, Y 1 is O, S, or NR c In some embodiments, Y 1 In some embodiments, Y 1 In some embodiments, Y 1 , NR c That is the case.

[0073] In some embodiments, Y 2 is O, S, or NR c In some embodiments, Y 2 In some embodiments, Y 2 In some embodiments, Y 2 , NR c That is the case.

[0074] In some embodiments, Y 1 O is Y 2 It is O.

[0075] In some embodiments, X is NH, N(C 1-6 X is alkyl), O, or S. In some embodiments, X is NH. In some embodiments, X is N(C) 1-6 It is alkyl. In some embodiments, X is O. In some embodiments, X is S.

[0076] In some embodiments, X is NH or S. In some embodiments, X is NH.

[0077] In some embodiments, X 1 , X 2 , X 3 , and X 4 At least one of them is N.

[0078] In some embodiments, X 1 , X 2 , X 3 , and X 4 One of them is N.

[0079] In some embodiments, X 3 and X 4 One of them is N, and X 1 CR 1 X 2 CR 2 That is the case.

[0080] In some embodiments, X 1 In some embodiments, X 1 N is X 2 CR 2 X 3 CR 3 X 4 CR 4 That is the case.

[0081] In some embodiments, X 2 In some embodiments, X 2 N is X 1 CR 1 X 3 CR 3 X 4 CR 4 That is the case.

[0082] In some embodiments, X 3 In some embodiments, X 3 N is X1 is CR 1 , and X 2 is CR 2 , and X 4 is CR 4 .

[0083] In some embodiments, X 4 is N. In some embodiments, X 4 is N, and X 1 is CR 1 , and X 2 is CR 2 , and X 3 is CR 3 .

[0084] In some embodiments, X 3 is N, and X 4 is N. In some embodiments, X 3 is N, and X 4 is N, and X 1 is CR 1 , and X 2 is CR 2 .

[0085] In some embodiments, X 1 is CR 1 , and X 2 is CR 2 , and X 3 is CR 3 , and X 4 is CR 4 .

[0086] In some embodiments, the moiety [Formula] is [Formula] .

[0087] In some embodiments, R 1 , R 2 , R3 , and R 4 These are, independently, hydrogen, halo, cyano, and C. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, aryl, C3- 10 Cycloalkyl, heterocyclyl, heteroaryl, -C(NH)NH(OH), -C(NH)NH2, -C(O)NR a R b -C(O)NR a -NR a R b -C(O)NH(C 1-6 Alkylene)-NR a R b , -C(O)OR a , -NR a R b -NO2, -OR a -OC(O)R a , -SR a ,-S(O)R a -S(O)2R a -S(O)2NR a R b , or -S(O)3H, and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl independently has 1 to 5 Z 1 It can be arbitrarily replaced with.

[0088] In some embodiments, X 1 However, CR 1 X 2 However, CR 2 If R 1 and R 2 Along with the atoms bonded to them, 1 to 5 Z 1 The optionally substituted 5-6 member cycloalkyl, heterocyclyl, aryl, or heteroaryl groups are formed.

[0089] In some embodiments, X 2 However, CR 2 X 3 However, CR 3 If R 2 and R3 together with the atoms bonded to them, form a 5-6 membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, which is optionally substituted with 1 to 5 Z 1 .

[0090] In some embodiments, X 3 is CR 3 , and X 4 is CR 4 , then R 3 and R 4 , together with the atoms bonded to them, form a 5-6 membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, which is optionally substituted with 1 to 5 Z 1 .

[0091] In some embodiments, R 1 , R 2 , R 3 , and R 4 , if present, are each independently hydrogen, halo, cyano, C 1-6 alkyl, aryl, C 3-10 cycloalkyl, heteroaryl, -OR a , wherein R a is C 1-6 alkyl or C 3-10 cycloalkyl, and each alkyl, cycloalkyl, aryl, or heteroaryl is independently optionally substituted with 1 to 5 Z 1 .

[0092] In some embodiments, R 1 is hydrogen, halo, cyano, C 1-6 alkyl, aryl, C 3-10 cycloalkyl, heteroaryl, -OR a , wherein R a is C 1-6 alkyl or C 3-10 cycloalkyl, and each alkyl, cycloalkyl, aryl, or heteroaryl is independently optionally substituted with 1 to 5 Z 1 .

[0093] In some embodiments, R 1 These are hydrogen, halo, or cyano.

[0094] In some embodiments, R 1 It is hydrogen.

[0095] In some embodiments, R 1 is a halo. In some embodiments, R 1 is chloro. In some embodiments, R 1 It is fluoro.

[0096] In some embodiments, R 1 It is cyano.

[0097] In some embodiments, R 2 These are hydrogen, halo, cyano, and C. 1-6 Alkyl, aryl, C 3-10 Cycloalkyl, heteroaryl, -OR a And here, R a C 1-6 Alkyl or C 3-10 It is a cycloalkyl, and each alkyl, cycloalkyl, aryl, or heteroaryl independently has 1 to 5 Z 1 It can be arbitrarily replaced with.

[0098] In some embodiments, R 2 It is hydrogen.

[0099] In some embodiments, R 2 is a halo. In some embodiments, R 2 is chloro. In some embodiments, R 2 is bromo. In some embodiments, R 2 is fluoro. In some embodiments, R 2 It is iodine.

[0100] In some embodiments, R 2 It is cyano.

[0101] In some embodiments, R 2 These are 1 to 5 Z 1 C arbitrarily substituted with 1-6 It is alkyl. In some embodiments, R 2 is methyl. In some embodiments, R 2 C is replaced by 1 to 3 halos. 1-6 It is alkyl. In some embodiments, R 2 is trifluoromethyl. In some embodiments, R 2 R is difluoromethyl. In some embodiments, 2 This is -CF2CH3.

[0102] In some embodiments, R 2 is unsubstituted C 1-6 It is alkyl. In some embodiments, R 2 is ethyl. In some embodiments, R 2 It is methyl.

[0103] In some embodiments, R 2 C 3-10 It is cycloalkyl. In some embodiments, R 2 It is cyclopropyl.

[0104] In some embodiments, R 2 is -OR a And here, R a C 1-6 Alkyl or C 3-10 It is a cycloalkyl group, and each alkyl or cycloalkyl group is optionally substituted with 1 to 3 halo, cyano, hydroxy, or aryl groups. In some embodiments, R 2 is methoxy. In some embodiments, R 2 is ethoxy. In some embodiments, R 2 is cyclopropoxy. In some embodiments, R 2 It is -OCF3.

[0105] In some embodiments, R 2 is an arrow. In some embodiments, R 2 It is phenyl.

[0106] In some embodiments, R 2 is a heteroaryl compound. In some embodiments, R 2 R is a 5-6 member heteroaryl compound containing one or two nitrogen atoms. In some embodiments, R 2 It is pyrazole-1-yl.

[0107] In some embodiments, R 3 These are hydrogen, halo, cyano, and C. 1-6 Alkyl, aryl, C 3-10 Cycloalkyl, heteroaryl, -OR a Each alkyl, cycloalkyl, aryl, or heteroaryl group independently has 1 to 5 Z 1 It can be arbitrarily replaced with.

[0108] In some embodiments, R 3 These are hydrogen, halo, cyano, and C. 1-6 Alkyl, or -OR a And here, R a C 1-6 Alkyl or C 3-10 It is a cycloalkyl group, and each alkyl or cycloalkyl group independently has 1 to 5 Z 1 It can be arbitrarily replaced with.

[0109] In some embodiments, R 3 It is hydrogen.

[0110] In some embodiments, R 3 is a halo. In some embodiments, R 3 is chloro. In some embodiments, R 3 It is fluoro.

[0111] In some embodiments, R 3It is cyano.

[0112] In some embodiments, R 3 is unsubstituted C 1-6 It is alkyl. In some embodiments, R 3 It is methyl.

[0113] In some embodiments, R 3 is -OR a And here, R a C is optionally substituted with 1 to 3 halo, cyano, hydroxy, or aryl atoms. 1-6 It is alkyl. In some embodiments, R 3 It is methoxy. In some embodiments, it is benzyloxy.

[0114] In some embodiments, R 4 These are hydrogen, halo, cyano, and C. 1-6 Alkyl, aryl, C 3-10 Cycloalkyl, heteroaryl, -OR a And here, R a C 1-6 Alkyl or C 3-10 It is a cycloalkyl, and each alkyl, cycloalkyl, aryl, or heteroaryl independently has 1 to 5 Z 1 It can be arbitrarily replaced with.

[0115] In some embodiments, R 4 is hydrogen, halo, cyano, or -OR a And here, R a C 1-6 Alkyl or C 3-10 It is a cycloalkyl group, and each alkyl or cycloalkyl group independently has 1 to 5 Z 1 It can be arbitrarily replaced with.

[0116] In some embodiments, R 4 It is hydrogen.

[0117] In some embodiments, R 4is a halo. In some embodiments, R 4 is chloro. In some embodiments, R 4 It is fluoro.

[0118] In some embodiments, R 4 It is cyano.

[0119] In some embodiments, R 4 is -OR a And here, R a C 1-6 Alkyl or C 3-10 It is a cycloalkyl group, and each alkyl or cycloalkyl group is optionally substituted with 1 to 3 halo, cyano, hydroxy, or aryl groups. In some embodiments, R 4 is methoxy. In some embodiments, R 4 It is cyclopropoxy.

[0120] In some embodiments, R 1 , R 2 , R 3 , and R 4 If present, each is independently hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, methoxy, ethoxy, phenyl, benzyloxy, trifluoromethyl, difluoromethyl, cyclopropoxy, or pyrazole-1-yl.

[0121] In some embodiments, R 1 , R 2 , R 3 , and R 4 If present, these are, independently, hydrogen, fluoro, chloro, bromo, iodo, cyano, methyl, ethyl, cyclopropyl, methoxy, ethoxy, -OCF3, phenyl, benzyloxy, trifluoromethyl, difluoromethyl, -CF2CH3, cyclopropoxy, or pyrazole-1-yl.

[0122] In some embodiments, n is 1, 2, or 3. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0123] In some embodiments, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0124] In some embodiments, n is 1 and m is 0. In some embodiments, n is 1 and m is 1. In some embodiments, n is 1 and m is 2. In some embodiments, n is 1 and m is 3. In some embodiments, n is 1 and m is 4. In some embodiments, n is 2 and m is 0. In some embodiments, n is 2 and m is 1. In some embodiments, n is 2 and m is 2. In some embodiments, n is 2 and m is 3. In some embodiments, n is 3 and m is 0. In some embodiments, n is 3 and m is 1. In some embodiments, n is 3 and m is 2.

[0125] In some embodiments, n is 1 and m is 1. In some embodiments, n is 2 and m is 1.

[0126] In some embodiments, n=m is 1, 2, 3, 4, or 5. In some embodiments, n+m is 1. In some embodiments, n+m is 2. In some embodiments, n+m is 3. In some embodiments, n+m is 4. In some embodiments, n+m is 5.

[0127] In some embodiments, n+m is 2 or 3. In some embodiments, n+m is 2. In some embodiments, n+m is 3.

[0128] In some embodiments, R 6a and R 6b Along with the atoms bonded to them, 1 to 5 Z 1 C arbitrarily substituted with 3-6 It forms a cycloalkyl group.

[0129] In some embodiments, R 6a and R 6b These are C atoms that are optionally substituted with 1 to 5 fluorocarbons, along with the atoms bonded to them. 3-6 It forms a cycloalkyl group.

[0130] In some embodiments, R 6a and R 6b Along with the atoms bonded to them, 1-2 Z 1 This forms optionally substituted cyclopropyl. In some embodiments, R 6a and R 6b Along with the atoms bonded to them, 1-2 Z 1 Forms optionally substituted cyclobutyl. In a particular embodiment, R 6a and R 6b Together with the carbon atoms bonded to them, they form 1-2 Z 1 It forms a cyclopentyl which is optionally substituted.

[0131] In some embodiments, R 6a and R 6b These, together with the atoms bonded to them, form an unsubstituted cyclopropyl. In some embodiments, R 6a and R 6b These, together with the atoms bonded to them, form a cyclopropyl substituted with one or two fluoroions. In some embodiments, R 6a and R 6bThese, along with the atoms bonded to them, form cyclobutyl molecules optionally substituted with one or two fluorocarbons.

[0132] In some embodiments, R 6a and one R 6c Along with the atoms bonded to them, 1 to 5 Z 1 This forms an optionally substituted 3- to 6-membered condensed cycloalkyl group.

[0133] In some embodiments, R 6a and one R 6c Along with the atoms bonded to them, 1-2 Z 1 The optionally substituted condensed cyclopropyl is formed. In some embodiments, R 6a and one R 6c These, along with the atoms bonded to them, form condensed cyclopropyls optionally substituted with one or two fluorocarbons.

[0134] In some embodiments, R 6a is hydrogen, and R 6b These are -CH3, -CF3, -OCF3, or C 3-10 It is cycloalkyl. In some embodiments, R 6a is hydrogen, and R 6b is -CH3. In some embodiments, R 6a is hydrogen, and R 6b is -CF3. In some embodiments, R 6a is hydrogen, and R 6b is -OCF3. In some embodiments, R 6a is hydrogen, and R 6b It is cyclopropyl.

[0135] In some embodiments, p is 0, 1, 2, 3, 4, or 5. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 4. In some embodiments, p is 5.

[0136] In some embodiments, [ka] teeth, [ka] That is the case.

[0137] In some embodiments, R 5 These are hydrogen, halo, cyano, and C. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, aryl, C3- 10 Cycloalkyl, heterocyclyl, heteroaryl, -C(NH)NH(OH), -C(NH)NH2, -C(O)NR a R b -C(O)NR a -NR a R b -C(O)NH(C 1-6 Alkylene)-NR a R b , -C(O)OR a , -NR a R b -NO2, -OR a -OC(O)R a , -SR a ,-S(O)R a -S(O)2R a -S(O)2NR a R b , or -S(O)3H, and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl independently has 1 to 5 Z 1It can be arbitrarily replaced with.

[0138] In some embodiments, R 5 These are hydrogen, halo, cyano, and C. 1-6 Alkyl, C3- 10 A cycloalkyl, heterocyclyl, or heteroaryl, where each alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl independently has 1 to 5 Z 1 It can be arbitrarily replaced with.

[0139] In some embodiments, R 5 is a halo. In some embodiments, R 5 It is fluoro.

[0140] In some embodiments, R 5 C 1-6 It is alkyl. In some embodiments, R 5 It is methyl.

[0141] In some embodiments, R 5 It is hydrogen.

[0142] In some embodiments, R 7 and R 8 These atoms bond together with the carbon atoms they are attached to to form C3-6 cycloalkyl or heterocyclines, where each independently has 1 to 5 Z atoms. 1 It is optionally replaced by R. In some embodiments, 7 and R 8 They bond together with the carbon atoms they are bonded to, forming 1 to 5 Z 1 This forms a C3-6 cycloalkyl group that is optionally substituted. In some embodiments, R 7 and R 8 They bond together with the carbon atoms they are bonded to, forming 1 to 5 Z 1 It forms a spiroheterocyril with arbitrary substitutions.

[0143] In a particular embodiment, R 7is hydrogen, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, aryl, C 3-10 It is a cycloalkyl, heterocyclyl, or heteroaryl, and each C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, aryl, C 3-10 Cycloalkyl, heterocyclyl, or heteroaryl compounds independently have 1 to 5 Z 1 It can be arbitrarily replaced with.

[0144] In a particular embodiment, R 7 It is hydrogen.

[0145] In a particular embodiment, R 8 C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, aryl, C 3-10 These are cycloalkyl, heterocyclyl, or heteroaryl compounds, where each independently comprises 1 to 5 Zs. 1 It can be arbitrarily replaced with.

[0146] In a particular embodiment, R 8 These are 1 to 5 Z 1 C arbitrarily substituted with 1-6 It is alkyl.

[0147] In a particular embodiment, R 8 C 1-6 It is alkyl. In certain embodiments, R 8 is methyl or ethyl. In certain embodiments, R 8 It is methyl.

[0148] In a particular embodiment, R 7 is hydrogen, and R 8 These are 1 to 5 Z 1 C arbitrarily substituted with 1-6 It is alkyl. In certain embodiments, R 7 is hydrogen, and R 8C 1-6 It is alkyl. In certain embodiments, R 7 is hydrogen, and R 8 is methyl or ethyl. In certain embodiments, R 7 is hydrogen, and R 8 It is methyl.

[0149] In a specific method of operation, each R a and R b These are independently hydrogen, hydroxyl, and C 1-6 Alkyl, phenyl, or benzyl, where alkyl, phenyl, and benzyl are halo, cyano, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl and C 1-6 It is optionally substituted with one or more substituents independently selected from the group consisting of haloalkoxys.

[0150] In a specific method of operation, each R c These are, independently, hydrogen and C 1-6 Alkyl, phenyl, or benzyl, where alkyl, phenyl, and benzyl are halo, cyano, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl and C 1-6 It is optionally substituted with one or more substituents independently selected from the group consisting of haloalkoxys.

[0151] In some embodiments, compounds of formula IA: [ka] Alternatively, a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, tautomer, or isotopically enriched analog is provided, where each X 1 , X 2 , X 3 , X 4 , R 6a , R 6b , m, n, p, R6c , R 7 , and R 8 Each of these is independent and as defined herein.

[0152] In some embodiments, X 1 , X 2 , X 3 , and X 4 At least one of them is N.

[0153] In some embodiments, X 1 , X 2 , X 3 , and X 4 One of them is N.

[0154] In some embodiments, X 3 and X 4 One of them is N, and X 1 CR 1 X 2 CR 2 That is the case.

[0155] In some embodiments, X 3 N is X 4 N is X 1 CR 1 X 2 CR 2 That is the case.

[0156] In some embodiments, X 3 N is X 1 CR 1 X 2 CR 2 X 4 CR 4 That is the case.

[0157] In some embodiments, X 4 N is X 1 CR 1 X 2 CR 2 X 3 CR 3That is the case.

[0158] In some embodiments, X 1 N is X 2 CR 2 X 3 CR 3 X 4 CR 4 That is the case.

[0159] In some embodiments, X 1 CR 1 X 2 CR 2 X 3 CR 3 X 4 CR 4 That is the case.

[0160] In some embodiments, [ka] teeth, [ka] That is the case.

[0161] In some embodiments, [ka] teeth, [ka] That is the case.

[0162] In a particular embodiment, R 7 is hydrogen, and R 8 These are 1 to 5 Z 1 C arbitrarily substituted with 1-6 It is alkyl. In certain embodiments, R 7 is hydrogen, and R 8 C 1-6 It is alkyl. In certain embodiments, R 7is hydrogen, and R 8 is methyl or ethyl. In certain embodiments, R 7 is hydrogen, and R 8 It is methyl.

[0163] In some embodiments, n+m is 2 or 3. In some embodiments, n+m is 2. In some embodiments, n+m is 3.

[0164] In some embodiments, R 6b is hydrogen, and R 6a and R 6c Along with the atoms bonded to them, 1 to 5 Z 1 They form optionally substituted 3-6 member condensed cycloalkyl groups; or R 6a is hydrogen, and R 6b These are -CH3, -CF3, -OCF3, or C 3-10 It is cycloalkyl; or R 6a and R 6b Along with the atoms bonded to them, 1 to 5 Z 1 C arbitrarily substituted with 3-6 It forms a cycloalkyl group.

[0165] In some embodiments, p is 1; R 6b is hydrogen; R 6a and R6 c Along with the atoms bonded to them, 1 to 5 Z 1 This forms an optionally substituted 3- to 6-membered condensed cycloalkyl group.

[0166] In some embodiments, p is 1; R 6b is hydrogen; R 6a and one R 6c These, along with the atoms bonded to them, form condensed cyclopropyls optionally substituted with 1 to 5 fluorocarbons.

[0167] In some embodiments, p is 0; R 6a is hydrogen; R 6b These are -CH3, -CF3, -OCF3, or C 3-10 It is a cycloalkyl group.

[0168] In some embodiments, p is 0; R 6a is hydrogen; R 6b It is -CH3, -CF3, -OCF3, or cyclopropyl.

[0169] In some embodiments, p is 0, and R 6a and R 6b Along with the atoms bonded to them, 1 to 5 Z 1 C arbitrarily substituted with 3-6 It forms a cycloalkyl group.

[0170] In some embodiments, p is 0, and R 6a and R 6b These are C atoms that are optionally substituted with 1 to 5 fluorocarbons, along with the atoms bonded to them. 3-6 It forms a cycloalkyl group.

[0171] In some embodiments, [ka] teeth, [ka] That is the case.

[0172] In some embodiments, [ka] teeth, [ka] That is the case.

[0173] In some embodiments, n is either 1 or 2; m is 0, 1, or 2, where n+m is 2 or 3; X 1 CR 1 or N; X 2 CR 2 or N; X 3 CR 3 or N; X 4 CR 4 or N; R 7 is hydrogen; R 8 These are 1 to 5 Z 1 C arbitrarily substituted with 1-6 It is alkyl; p is either 0 or 1; R 6b is hydrogen, and R 6a and R 6c Along with the atoms bonded to them, 1 to 5 Z 1 They form optionally substituted 3-6 member condensed cycloalkyl groups; or R 6a is hydrogen, and R 6b These are -CH3, -CF3, -OCF3, or C 3-10 It is cycloalkyl; or R 6a and R 6b Along with the atoms bonded to them, 1 to 5 Z 1 C arbitrarily substituted with 3-6 It forms a cycloalkyl group.

[0174] In some embodiments, n is either 1 or 2; m is 0, 1, or 2, where n+m is 2 or 3; X 1 CR1 or N; X 2 CR 2 or N; X 3 CR 3 or N; X 4 CR 4 or N; R 7 is hydrogen; R 8 C 1-6 It is alkyl; p is either 0 or 1; R 6b is hydrogen, and R 6a and R 6c Together with the atoms bonded to them, they form 3-6 membered condensed cycloalkyl groups optionally substituted with 1-5 fluorocarbons; or R 6a is hydrogen, and R 6b These are -CH3, -CF3, -OCF3, or C 3-10 It is cycloalkyl; or R 6a and R 6b These are C atoms that are optionally substituted with 1 to 5 fluorocarbons, along with the atoms bonded to them. 3-6 It forms a cycloalkyl group.

[0175] In some embodiments, compounds of formula IB: [ka] Alternatively, a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, tautomer, or isotopically enriched analog is provided, where X 3 , X 4 , R 6a , R 6b , m, and R 8 Each of these is independent and as defined herein.

[0176] In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, X 3 In some embodiments, X 4 In some embodiments, X 3 CR 3 In some embodiments, X 4 CR 4 That is the case.

[0177] In some embodiments, compounds of formula IC: [ka] Alternatively, a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, tautomer, or isotopically enriched analog is provided, where X 3 , X 4 , R 6a , R 6b , n, and R 8 Each of these is independent and as defined herein.

[0178] In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2.

[0179] In some embodiments, X 3 and X 4 One of them is N.

[0180] In some embodiments, X 3 N is X 4 It is N.

[0181] In some embodiments, X 3 N is X 4 CR 4 That is the case.

[0182] In some embodiments, X 3 CR 3 X 4 It is N.

[0183] In some embodiments, X 3 CR 3 X 4 CR 4 That is the case.

[0184] In some embodiments, [ka] teeth, [ka] That is the case.

[0185] In a particular embodiment, R 8 These are 1 to 5 Z 1 C arbitrarily substituted with 1-6 It is alkyl. In certain embodiments, R 8 C 1-6 It is alkyl. In certain embodiments, R 8 is methyl or ethyl. In certain embodiments, R 8 It is methyl.

[0186] In some embodiments, R 6a is hydrogen, and R 6b These are -CH3, -CF3, -OCF3, or C 3-10 It is a cycloalkyl group.

[0187] In some embodiments, R 6a is hydrogen, and R 6b It is -CH3, -CF3, -OCF3, or cyclopropyl.

[0188] In some embodiments, R 6a and R 6b Along with the atoms bonded to them, 1 to 5 Z 1 C arbitrarily substituted with 3-6 It forms a cycloalkyl group.

[0189] In some embodiments, R 6a and R 6b These are C atoms that are optionally substituted with 1 to 5 fluorocarbons, along with the atoms bonded to them. 3-6 It forms a cycloalkyl group.

[0190] In some embodiments, [ka] teeth, [ka] That is the case.

[0191] In some embodiments, [ka] teeth, [ka] That is the case.

[0192] In some embodiments, n is 1 or 2; X 3 CR 3 or N; X 4 CR 4 or N; R 8 These are 1 to 5 Z 1 C arbitrarily substituted with 1-6 It is alkyl; R 6a is hydrogen, and R 6b These are -CH3, -CF3, -OCF3, or C 3-10 It is cycloalkyl; or, R 6a and R 6b Along with the atoms bonded to them, 1 to 5 Z 1 C arbitrarily substituted with 3-6 It forms a cycloalkyl group.

[0193] In some embodiments, n is 1 or 2; X 3 CR 3 or N; X 4 CR 4 or N; R 8 C 1-6 It is alkyl; R 6a is hydrogen, and R 6b is -CH3, -CF3, -OCF3, or cyclopropyl; or R 6a and R 6b These are C atoms that are optionally substituted with 1 to 5 fluorocarbons, along with the atoms bonded to them. 3-6 It forms a cycloalkyl group.

[0194] In some embodiments, the compound of formula II: [ka] Alternatively, a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, tautomer, or isotopically enriched analog is provided, where X 1 , X 2 , X 3 , X 4 , R 6a , R 6b , and R 8 Each of these is independent and as defined herein.

[0195] In some embodiments, X 1 , X 2 , X 3 , and X 4 At least one of them is N.

[0196] In some embodiments, X 1 , X 2 , X 3 , and X 4 One of them is N.

[0197] In some embodiments, X 3and X 4 One of them is N, and X 1 CR 1 X 2 CR 2 That is the case.

[0198] In some embodiments, X 3 N is X 1 CR 1 X 2 CR 2 X 4 CR 4 That is the case.

[0199] In some embodiments, X 1 CR 1 X 2 CR 2 X 3 CR 3 X 4 CR 4 That is the case.

[0200] In some embodiments, [ka] teeth, [ka] That is the case.

[0201] In a particular embodiment, R 8 These are 1 to 5 Z 1 C arbitrarily substituted with 1-6 It is alkyl. In certain embodiments, R 8 C 1-6 It is alkyl. In certain embodiments, R 8 is methyl or ethyl. In certain embodiments, R 8 It is methyl.

[0202] In some embodiments, R 6a is hydrogen, and R 6b -CF3, -OCF3, or C3-10 These are cycloalkyl compounds (for example, cyclopropyl compounds).

[0203] In some embodiments, R 6a and R 6b Along with the atoms bonded to them, 1 to 5 Z 1 C arbitrarily substituted with 3-6 It forms a cycloalkyl group.

[0204] In some embodiments, R 6a and R 6b These are C atoms that are optionally substituted with 1 to 5 fluorocarbons, along with the atoms bonded to them. 3-6 It forms a cycloalkyl group.

[0205] In some embodiments, [ka] teeth, [ka] That is the case.

[0206] In some embodiments, [ka] teeth, [ka] That is the case.

[0207] In some embodiments, X 1 CR 1 or N; X 2 CR 2 or N; X 3 CR 3 or N; X 4 CR 4 or N; R8 These are 1 to 5 Z 1 C arbitrarily substituted with 1-6 It is alkyl; R 6a is hydrogen, and R 6b -CF3, -OCF3, or C 3-10 It is cycloalkyl; or R 6a and R 6b Along with the atoms bonded to them, 1 to 5 Z 1 C arbitrarily substituted with 3-6 It forms a cycloalkyl group.

[0208] In some embodiments, X 1 CR 1 or N; X 2 CR 2 or N; X 3 CR 3 or N; X 4 CR 4 or N; R 8 C 1-6 It is alkyl; R 6a is hydrogen, and R 6b is -CF3, -OCF3, or cyclopropyl; or R 6a and R 6b These are C atoms that are optionally substituted with 1 to 5 fluorocarbons, along with the atoms bonded to them. 3-6 It forms a cycloalkyl group.

[0209] In some embodiments, the compound of formula IIA: [ka] Alternatively, a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, tautomers, or isotopically enriched analog is provided, where R 1 , R 2 , R3 , R 4 , R 6a , R 6b , and R 8 Each of these is independent and as defined herein.

[0210] In some embodiments, the compound of formula IIB: [ka] Alternatively, a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, tautomers, or isotopically enriched analog is provided, where R 1 , R 2 , R 4 , R 6a , R 6b , and R 8 Each of these is independent and as defined herein.

[0211] In some embodiments, the compound of formula III: [ka] Alternatively, a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, tautomer, or isotopically enriched analog is provided, where X 1 , X 2 , X 3 , X 4 , R 6a , R 6b , and R 8 Each of these is independent and as defined herein.

[0212] In some embodiments, X 1 , X 2 , X 3 , and X 4 At least one of them is N.

[0213] In some embodiments, X 1 , X 2 , X 3 , and X 4 One of them is N.

[0214] In some embodiments, X 3 and X 4 One of them is N, and X 1 CR 1 X 2 CR 2 That is the case.

[0215] In some embodiments, X 3 N is X 4 N is X 1 CR 1 X 2 CR 2 That is the case.

[0216] In some embodiments, X 3 N is X 1 CR 1 X 2 CR 2 X 4 CR 4 That is the case.

[0217] In some embodiments, X 4 N is X 1 CR 1 X 2 CR 2 X 3 CR 3 That is the case.

[0218] In some embodiments, X 1 N is X 2 CR 2 X 3 CR 3 X 4 CR 4 That is the case.

[0219] In some embodiments, X 1 CR 1 X 2 CR 2 X 3 CR 3 X4 CR 4 That is the case.

[0220] In some embodiments, [ka] teeth, [ka] That is the case.

[0221] In some embodiments, [ka] teeth, [ka] That is the case.

[0222] In some embodiments, R 6a is hydrogen, and R 6b This is either -CH3 or -OCF3.

[0223] In some embodiments, R 6a and R 6b Along with the atoms bonded to them, 1 to 5 Z 1 C arbitrarily substituted with 3-6 It forms a cycloalkyl group.

[0224] In some embodiments, R 6a and R 6b These are C atoms that are optionally substituted with 1 to 5 fluorocarbons, along with the atoms bonded to them. 3-6 It forms a cycloalkyl group.

[0225] In some embodiments, [ka] teeth, [ka] That is the case.

[0226] In some embodiments, [ka] teeth, [ka] That is the case.

[0227] In some embodiments, X 1 CR 1 or N; X 2 CR 2 or N; X 3 CR 3 or N; X 4 CR 4 or N; R 8 These are 1 to 5 Z 1 C arbitrarily substituted with 1-6 It is alkyl; R 6a is hydrogen, and R 6b is -CH3 or -OCF3; or R 6a and R 6b Along with the atoms bonded to them, 1 to 5 Z 1 C arbitrarily substituted with 3-6 It forms a cycloalkyl group.

[0228] In some embodiments, X 1 CR 1 or N; X 2 CR 2 or N; X 3 CR 3 or N; X 4 CR 4 or N; R 8 C 1-6 It is alkyl; R 6a is hydrogen, and R 6b is -CH3 or -OCF3; or R 6a and R 6b These are C atoms that are optionally substituted with 1 to 5 fluorocarbons, along with the atoms bonded to them. 3-6 It forms a cycloalkyl group.

[0229] In some embodiments, the compound of formula IIIA: [ka] Alternatively, a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, tautomers, or isotopically enriched analog is provided, where R 1 , R 2 , R 3 , R 4 , R 6a , R 6b , and R 8 Each of these is independent and as defined herein.

[0230] In some embodiments, the compound of formula IIIB: [ka] Alternatively, a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, tautomers, or isotopically enriched analog is provided, where R 1 , R 2 , R 4 , R 6a , R 6b , and R 8 Each of these is independent and as defined herein.

[0231] In certain embodiments, compounds selected from Table 1, or pharmaceutically acceptable salts thereof, stereoisomers, mixtures of stereoisomers, tautomers, or isotopically enriched analogs are provided. [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]

[0232] In certain embodiments, compounds selected from Table 2, or pharmaceutically acceptable salts thereof, stereoisomers, mixtures of stereoisomers, tautomers, or isotopically enriched analogs are provided. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] Table 2-7 Table 2-8 Table 2-9 Table 2-10 Table 2-11 Table 2-12 Table 2-13 Table 2-14 Table 2-15 Table 2-16 Table 2-17 Table 2-18 Table 2-19

[0233] Treatment methods and uses "Treatment" or "treating" means an approach to obtain a beneficial or desired outcome, including a clinical outcome. Beneficial or desired clinical outcomes may include one or more of the following: a) inhibiting the disease or condition (e.g., reducing one or more symptoms resulting from the disease or condition, and / or reducing the severity of the disease or condition); b) delaying or cessating the onset of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying the spread of the disease or condition (e.g., metastasis)); and / or c) alleviating the disease, i.e., causing a regression of clinical symptoms (e.g., alleviating the disease state, causing partial or total remission of the disease or condition, enhancing the effects of another drug, slowing the progression of the disease, improving quality of life, and / or extending survival).

[0234] "Prevention" or "prevention" means any treatment of a disease or condition that prevents the development of clinical symptoms of the disease or condition. In some embodiments, the compound may be administered to subjects (including humans) who are at risk of developing a disease or condition, or who have a family history of such a disease or condition.

[0235] "Subject" refers to an animal, such as a mammal (including a human), that has been or will be the subject of treatment, observation, or experimentation. The methods described herein may be useful for the treatment and / or veterinary use of humans. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human.

[0236] The terms “therapeutic effective dose” or “effective dose” for any compound, or any pharmaceutically acceptable salt thereof, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog described herein, mean an amount sufficient to, when administered to a subject, have a therapeutic effect and produce a therapeutic benefit, such as symptom relief or slowing of disease progression. For example, a therapeutic effective dose may be an amount sufficient to reduce the symptoms of any disease or condition described herein. The therapeutic effective dose may vary depending on the subject and disease or condition being treated, the subject’s weight and age, the severity of the disease or condition, and the mode of administration, which can be readily determined by a person skilled in the art.

[0237] The methods described herein may be applied to cell populations in vivo or in vitro. “In vivo” means within a living organism, as in animals or humans. In this regard, the methods described herein may be used therapeutically in organisms. “In vitro” means outside a living organism. Examples of in vitro cell populations include in vitro cell cultures and biological samples, including liquid or tissue samples taken from organisms. Such samples can be obtained by methods well known in the art. Exemplary biological liquid samples include blood, cerebrospinal fluid, urine, and saliva. In this regard, the compounds and compositions described herein may be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein may be used in vitro to determine the optimal schedule and / or dosage of the compounds disclosed for a given indication, cell type, organism, and other parameters. Information gathered from such use may be used experimentally or in a clinic to establish protocols for in vivo treatment. Other possible in vitro uses of the compounds and compositions described herein may be described below or will be apparent to those skilled in the art. The selected compounds may be further characterized to test for safety or tolerable dosage in human or non-human subjects. Such characteristics can be tested using methods commonly known to those skilled in the art.

[0238] In certain embodiments, compounds, or pharmaceutically acceptable salts thereof, stereoisomers, mixtures of stereoisomers, tautomers, or isotopically enriched analogs thereof that modulate the activity of TMEM175 are provided.

[0239] In the specific methods, uses, and compositions provided herein, the compound is a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, tautomer, or isotope-enriched analog thereof, in the formula, n is 1, 2, or 3; m is 0, 1, 2, 3, or 4, where n+m is 1, 2, 3, 4, or 5; p is 0, 1, 2, 3, 4, or 5; X is NH, N(C 1-6 It is alkyl, O, or S; X 1 CR 1 or N; X 2 CR 2 or N; X 3 CR 3 or N; X 4 CR 4 or N; Y 1 and Y 2 These are, independently, O, S, or NR c and; R 1 , R 2 , R 3 , and R 4 These are, independently, hydrogen, halo, cyano, and C. 1-6 Alkyl, C 2-6 Alkenil, C 2-6Alkinyl, aryl, C3- 10 Cycloalkyl, heterocyclyl, heteroaryl, -C(NH)NH(OH), -C(NH)NH2, -C(O)NR a R b -C(O)NR a -NR a R b -C(O)NH(C 1-6 Alkylene)-NR a R b , -C(O)OR a , -NR a R b -NO2, -OR a -OC(O)R a , -SR a ,-S(O)R a -S(O)2R a -S(O)2NR a R b , or -S(O)3H, and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl independently has 1 to 5 Z 1 It is optionally replaced by; Or R 1 and R 2 , R 2 and R 3 , or R 3 and R 4 Along with the atoms bonded to them, 1 to 5 Z 1 They form optionally substituted 5-6 member cycloalkyl, heterocyclyl, aryl, or heteroaryl groups; R 5 These are hydrogen, halo, cyano, and C. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, aryl, C3- 10 Cycloalkyl, heterocyclyl, heteroaryl, -C(NH)NH(OH), -C(NH)NH2, -C(O)NR a R b -C(O)NR a -NR a R b -C(O)NH(C 1-6 Alkylene)-NR aR b , -C(O)OR a , -NR a R b -NO2, -OR a -OC(O)R a , -SR a ,-S(O)R a -S(O)2R a -S(O)2NR a R b , or -S(O)3H, and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl independently has 1 to 5 Z 1 It is optionally replaced by; R 6a and R 6b These are, independently, Halo, Cyano, and C. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, aryl, C 3-10 Cycloalkyl, heterocyclyl, heteroaryl, -C(NH)NH(OH), -C(NH)NH2, -C(O)NR a R b -C(O)NR a -NR a R b -C(O)NH(C 1-6 Alkyl)-NR a R b , -C(O)R a , -C(O)OR a , -NR a R b -NO2, -OR a -OC(O)R a , -SR a ,-S(O)R a -S(O)2R a -S(O)2NR a R b , or -S(O)3H, and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl independently has 1 to 5 Z 1 It is optionally replaced by; or R 6a is hydrogen, and R 6bThese are -CH3, -CF3, -OCF3, or C 3-10 It is cycloalkyl; or R 6a and R 6b Each of them, along with the atoms bonded to them, has 1 to 5 Z 1 C arbitrarily substituted with 3-6 Forming cycloalkyl or 3-6 membered heterocyclines; Each R 6c These are independently: halo, cyano, and C. 1-3 Alkyl, or C 1-3 It is a haloalkyl; or Two R's 6c Each of them, along with the atoms bonded to them, has 1 to 5 Z 1 Forms optionally substituted 3-6 membered spiro, condensed, or crosslinked cycloalkyl or 3-6 membered spiro, condensed, or crosslinked heterocyclyl; R 6a is hydrogen, and R 6b and one R 6c Each of them, along with the atoms bonded to them, has 1 to 5 Z 1 Forms optionally substituted 3-6 member condensates, or cross-linked cycloalkyls or 3-6 member condensates, or cross-linked heterocyclines; R 7 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, aryl, C 3-10 They are cycloalkyl, heterocyclyl, or heteroaryl compounds, each independently comprising 1 to 5 Zs. 1 It is optionally replaced by; R 8 C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, aryl, C 3-10 These are cycloalkyl, heterocyclyl, or heteroaryl compounds, where each independently comprises 1 to 5 Zs. 2 It is optionally replaced by; Alternatively, R 7 and R 8These atoms bond together with the carbon atoms they are attached to to form C3-6 cycloalkyl or heterocyclines, where each independently has 1 to 5 Z atoms. 1 It is optionally replaced by; Each R a and R b These are, independently, hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 They are cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl compounds are independently classified into 1 to 5 Z groups. 1b It is optionally replaced by; Each R c These are, independently, hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 They are cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl compounds are independently classified into 1 to 5 Z groups. 1b It is optionally replaced by; each Z 1 These are independently: halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 12 )2, -OR 12 , -SR 12 , -C(O)R 12 , -C(O)OR 12 ,-S(O)R 12 -S(O)2R 12 ,-C(O)N(R12 )2, -NR 12 C(O)R 12 , -NR 12 S(O)R 12 , -NR 12 S(O)2R 12 ,-S(O)N(R 12 )2, -S(O)2N(R 12 )2, -NR 12 C(O)N(R 12 )2, -NR 12 S(O)N(R 12 )2, -NR 12 S(O)2N(R 12 )2, -OC(O)N(R 12 )2, or -NR 12 C(O)OR 12 And each C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl compounds are independently classified into 1 to 5 Z groups. 1a It is optionally replaced by; each Z 2 These are independently: halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, -N(R 12 )2, -OR 12 , -SR 12 , -C(O)R 12 , -C(O)OR 12 ,-S(O)R 12 -S(O)2R 12 ,-C(O)N(R 12 )2, -NR 12 C(O)R 12 , -NR 12 S(O)R 12 , -NR 12 S(O)2R 12 ,-S(O)N(R 12 )2, -S(O)2N(R 12 )2, -NR12 C(O)N(R 12 )2, -NR 12 S(O)N(R 12 )2, -NR 12 S(O)2N(R 12 )2, -OC(O)N(R 12 )2, or -NR 12 C(O)OR 12 And each C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, or heterocyclyl, is independently classified as halo, cyano, -OH, -SH, -NH2, or -NH-C. 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Optionally substituted with 1 to 5 substituents independently selected from the haloalkoxy; Each R 12 These are, independently, hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 They are cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl compounds are independently classified into 1 to 5 Z groups. 1b It is optionally replaced by; each Z 1a These are independently: halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 13 )2, -OR 13 , -SR 13 , -C(O)R 13 , -C(O)OR13 ,-S(O)R 13 -S(O)2R 13 ,-C(O)N(R 13 )2, -NR 13 C(O)R 13 , -NR 13 S(O)R 13 , -NR 13 S(O)2R 13 ,-S(O)N(R 13 )2, -S(O)2N(R 13 )2, -NR 13 C(O)N(R 13 )2, -NR 13 S(O)N(R 13 )2, -NR 13 S(O)2N(R 13 )2, -OC(O)N(R 13 )2, or -NR 13 C(O)OR 13 And here, each C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl compounds are independently classified into 1 to 5 Z groups. 1b It is optionally replaced by; Each R 13 These are, independently, hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 They are cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl compounds are independently classified into 1 to 5 Z groups. 1b It is optionally replaced by; each Z 1b These are independently: halo, cyano, -OH, -SH, -NH2, -NO2, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10Cycloalkyl, heterocyclyl, aryl, heteroaryl, -L 1 -C 1-6 Alkyl, -L 1 -C 2-6 Alkenyl, -L 1 -C 2-6 Alkinyl, -L 1 -C 1-6 Haloalkyl, -L 1 -C 3-10 Cycloalkyl, -L 1 -heterocyclyl, -L 1 -aryl or -L-heteroaryl; Each L 1 These are independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, and -N(C 1-6 Alkyl)-,-N(C 2-6 Alkenyl)-, -N(C 2-6 Alkinyl)-, -N(C 1-6 Haloalkyl)-,-N(C) 3-10 Cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 Alkyl)-,-C(O)N(C 2-6 Alkenyl)-,-C(O)N(C 2-6 Alkinyl)-,-C(O)N(C 1-6 Haloalkyl)-,-C(O)N(C 3-10 These are cycloalkyl)-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, or -S(O)2NH-; Here, Z 1b and L 1 Each C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, and heteroaryl compounds can also be independently composed of 1 to 5 halo, cyano, -OH, -SH, -NH2, -NO2, -SF5, C1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 It may be optionally substituted with a cycloalkyl, heterocyclyl, aryl, or heteroaryl compound.

[0240] In a particular embodiment, Y 1 and Y 2 Both are O; R 7 However, hydrogen or unsubstituted C 1-3 Alkyl; R 8 However, C is arbitrarily substituted. 1-4 If it is an alkyl or unsubstituted phenyl, part [ka] teeth, [ka] It is neither a stereoisomer nor a mixture of stereoisomers thereof.

[0241] In a particular embodiment, Y 1 and Y 2 Both are O; R 7 However, it is hydrogen; R 8 However, if it is a methyl atom substituted with either an optionally substituted phenyl or an optionally substituted 5- or 6-membered heteroaryl, then part [ka] teeth, [ka] isn't it.

[0242] In a particular embodiment, Y 1 and Y 2 Both are O; n+m is 3; R 6a However, it is hydrogen; R 6bbut, -If it is CH3, part [ka] It is not 1H-indole-2-yl or 3,5-dimethyl-1H-indole-2-yl.

[0243] In certain embodiments, the compound is not the following: (R)-4-[(1H-indole-2-ylcarbonyl)amino]-δ-oxo-8-azaspiro[4.5]decane-8-pentanoic acid (CAS137822-87-8); N-[(1S,2S)-1-[(3,3-difluoro-1-pyrrolidinyl)carbonyl]-2-methylbutyl]-benzo[b]thiophene-2-carboxamide (CAS928403-03-6); N-[(1S,2S)-1-[[(2S)-2-cyano-4,4-difluoro-1-pyrrolidinyl]carbonyl]-2-methylbutyl]-benzo[b]thiophene-2-carboxamide, (CAS928353-89-3); or N-[(1R)-1-[(4-methoxyphenyl)methyl]-2-[3-(1-methylethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]deca-8-yl]-2-oxoethyl]-1H-indole-2-carboxamide (CAS1219969-86-4)

[0244] In certain embodiments, a method is provided for inhibiting the activity of TMEM175, comprising administering an effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a tautomer, or a mixture of stereoisomers thereof, to a subject requiring such inhibition. Inhibition may be performed in vitro or in vivo.

[0245] In certain embodiments, compounds disclosed herein, or pharmaceutically acceptable salts thereof, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs are provided for use in modulating TMEM175 activity (e.g., in vitro or in vivo).

[0246] In certain embodiments, the disclosure provides the use of the compounds disclosed herein, or pharmaceutically acceptable salts thereof, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs in the manufacture of pharmaceuticals for modulating TMEM175 activity (e.g., in vitro or in vivo).

[0247] In another aspect, the Disclosure relates to a method for treating a disease or condition at least partially related to TMEM175 by a pharmaceutical composition comprising a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a mixture of stereoisomers, or a prodrug and one or more excipients described herein. In particular, the Disclosure provides a method for preventing or treating a disorder related to TMEM175 in a mammal, comprising the step of administering to the mammal a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a mixture of stereoisomers, or a prodrug.

[0248] In some embodiments, diseases or conditions to which TMEM175 is at least partially involved include neurodegenerative diseases, e.g., central nervous system (CNS) disorders, e.g., Parkinson's disease (PD), parkinsonism, Alzheimer's disease (AD), dementia (including Lewy body dementia and vascular dementia), amyotrophic lateral sclerosis (ALS), age-related memory impairment, mild cognitive impairment (e.g., including the transition from mild cognitive impairment to Alzheimer's disease), argyrophilic granule disease, lysosomal disorders, corticobasal degeneration, progressive supranuclear palsy, hereditary frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), drug addiction-related withdrawal symptoms / relapse, L-dopa-induced dyskinesia, Huntington's disease (HD), and HIV-related dementia (HAD).

[0249] In certain embodiments, the treatment is for various neurodegenerative and central nervous system (CNS) disorders, such as Parkinson's disease (PD) and REM sleep behavior disorder (RBD).

[0250] In some embodiments, diseases or conditions to which TMEM175 is at least partially involved include Niemann-Pick disease type C, Gaucher disease, Fabry disease, Krabbe disease, Pompe disease, Tay-Sachs disease, Batten disease, Sandhoff disease, Schindler disease types I and II, metachromatic leukodystrophy (MLD), mucopolysaccharidosis (MPS), and lysosomal disorders such as mucolipidosis types I, II / III, and IV.

[0251] In some embodiments, the disease or condition to which TMEM175 is at least partially involved is an ischemic disease of an organ including, but not limited to, the brain, heart, kidneys, and liver. In some embodiments, the disease is Crohn's disease.

[0252] In some embodiments, the disease or condition is cancer. In some embodiments, the cancer is glioma, thyroid cancer, colorectal cancer, head and neck cancer, gastric cancer, liver cancer, pancreatic cancer, kidney cancer, urothelial carcinoma, prostate cancer, testicular cancer, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, or melanoma. In some embodiments, the disease or condition is cancer selected from the group consisting of kidney cancer, breast cancer, prostate cancer, hematological cancer, papillary carcinoma, lung cancer, acute myeloid leukemia, and multiple myeloma.

[0253] Combination therapy In one embodiment, the compounds disclosed herein may be used in combination with one or more additional therapeutic agents that are used and / or developed to treat diseases or conditions related to TMEM175 in at least part.

[0254] In one embodiment, the compounds disclosed herein may be used in combination with one or more additional therapeutic agents used and / or developed for the treatment of Parkinson's disease (PD).

[0255] In some embodiments, one or more additional therapeutic agents include dopamine replacement therapy (levodopa / carbidopa), dopamine agonists (pramipexole, ropinirole, rotigotine, apomorphine), catechol-O-methyltransferase (COMT) inhibitors (entacapone, levodopa / carbidopa / entacapone, tolcapone, opicapone), monoamine oxidase B (MAO-B) inhibitors (selegiline hydrochloride, rasagiline, safinamide), amantadine, anticholinergics (trihexyphenidyl, benztropine mesylate), acetylcholinesterase inhibitors (rivastigmine), and serotonin 5-HT. 2A It may also be a receptor agonist (pimavanserin) or an imaging dopamine transporter (ioflupane I-123).

[0256] kit This specification also provides kits comprising the compounds of the Disclosure, or pharmaceutically acceptable salts thereof, tautomers, stereoisomers, mixtures of stereoisomers, prodrugs, or deuterated analogs, and suitable packaging. In one embodiment, the kit further includes instructions for use. In one embodiment, the kit includes the compounds of the Disclosure, or pharmaceutically acceptable salts thereof, tautomers, stereoisomers, mixtures of stereoisomers, prodrugs, or deuterated analogs, and labels and / or instructions for the use of the compounds in the treatment of symptoms including diseases or conditions described herein.

[0257] This specification also provides products comprising the compounds described herein, or pharmaceutically acceptable salts, tautomers, stereoisomers, mixtures of stereoisomers, prodrugs, or deuterated analogs thereof, in appropriate containers. The containers may be vials, jars, ampoules, pre-filled syringes, and intravenous bags.

[0258] Pharmaceutical composition and dosage form The compounds provided herein are typically administered in the form of pharmaceutical compositions. Accordingly, pharmaceutical compositions comprising one or more of the compounds described herein, or their pharmaceutically acceptable salts, tautomers, stereoisomers, mixtures of stereoisomers, prodrugs, or deuterated analogs, as well as one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants, and excipients, are also provided herein. Suitable pharmaceutically acceptable vehicles include, for example, inert solid diluents and expanders, diluents including sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants. Such compositions are prepared by methods well known in the pharmaceutical field. See, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (GSBanker & CTRhodes, Eds.).

[0259] The pharmaceutical composition may be administered as a single dose or in repeated doses. The pharmaceutical composition may be administered in various ways, including, for example, rectally, buccally, intranasally, and transdermally. In certain embodiments, the pharmaceutical composition may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0260] One mode of administration is parenteral, for example, by injection. Forms into which the pharmaceutical compositions described herein may be incorporated for administration by injection include, for example, aqueous or oily suspensions, or emulsions with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles.

[0261] Oral administration may be another route for administering the compounds described herein. Administration may be, for example, by capsule or enteric-coated tablet. When producing a pharmaceutical composition comprising at least one of the compounds described herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, the active ingredient is usually diluted with an excipient and / or encapsulated in a carrier, which may be in the form of a capsule, sachet, paper, or other container. When the excipient functions as a diluent, it may be in the form of a solid, semi-solid, or liquid substance acting as a vehicle, carrier, or medium for the active ingredient. Thus, the composition may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid or in a liquid medium), for example, ointments, soft and hard gelatin capsules, sterile injection solutions, and sterile packaging powders containing up to 10% by weight of the active compound.

[0262] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, arginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulation may further contain lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methyl benzoate and propyl hydroxybenzoate; sweeteners; and flavoring agents.

[0263] A composition comprising at least one compound described herein, or a pharmaceutically acceptable salt thereof, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, can be formulated to rapidly release, sustainedly release, or delayed release the active ingredient after administration to a subject using procedures known in the art. Controlled-release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled-release systems are shown in U.S. Patents 3,845,770, 4,326,525, 4,902,514, and 5,616,345. Another formulation for use in the manner disclosed herein is the use of a transdermal delivery device ("patch"). Such transdermal patches may be used to deliver continuous or discontinuous infusions of the compounds described herein in controlled amounts. The configuration and use of transdermal patches for delivering pharmaceuticals are well known in the art. See, for example, U.S. Patent Nos. 5,023,252, 4,992,445, and 5,001,139. ​​Such patches may be configured for continuous, pulsed, or on-demand delivery of pharmaceuticals.

[0264] To prepare solid compositions such as tablets, the main active ingredient may be mixed with pharmaceutically acceptable excipients to form a solid pre-formulation composition comprising a homogeneous mixture of the compound described herein, or a pharmaceutically acceptable salt thereof, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog. When these pre-formulation compositions are referred to as homogeneous, the active ingredient may be evenly dispersed throughout the composition so that the composition can be easily divided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0265] Tablets or pills of the compounds described herein may be formulated to provide a dosage form that offers the benefit of long-term action, or to be coated to protect from the acidic conditions of the stomach, or otherwise. For example, a tablet or pill may contain an internally administered component and an externally administered component, the latter in the form of an envelope covering the former. The two components may be separated by an enteric layer that functions to withstand breakdown in the stomach, allowing the internal component to pass through unchanged into the duodenum or to delay its release. A variety of materials can be used for such enteric layers or coatings, and such materials include many polymer acids, as well as mixtures of polymer acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0266] Compositions for inhalation or inhalation may include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein. In some embodiments, compositions are administered orally or via nasal respiratory routes for topical or systemic effects. In other embodiments, compositions in pharmaceutically acceptable solvents may be sprayed using an inert gas. The sprayed solution may be inhaled directly from a spraying device, or the spraying device may be attached to a facial mask tent or intermittent positive airway pressure (CPAP) device. In one embodiment, the solution, suspension, or powder composition may be administered orally or nasally from a device that delivers the formulation in a suitable manner.

[0267] The amount of compound in a pharmaceutical composition or formulation can be varied within the entire range used by those skilled in the art. Generally, a formulation will contain, in weight percent (W%), about 0.01 to 99.99 Wt% of the compound of this disclosure, based on the entire formulation, together with one or more suitable pharmaceutically acceptable excipients. In one embodiment, the compound is present at a level of about 1 to 80 Wt%. Typical pharmaceutical formulations are described below.

[0268] Formulation Example 1 - Tablet Formulation The following ingredients are tightly mixed and compressed to form a single-scored tablet. [Table 4]

[0269] Formulation Example 2 - Capsule Formulation The following ingredients are tightly mixed and filled into hard-shell gelatin capsules. [Table 5]

[0270] Formulation Example 3 - Suspension Formulation The following ingredients are mixed to form a suspension for oral administration. [Table 6]

[0271] Formulation example 4 - Injectable formulation The following ingredients are mixed to form an injectable formulation. [Table 7]

[0272] Formula Example 5 - Suppository Formula A suppository weighing 2.5 g in total is prepared by mixing the compound of this disclosure with Witepsol® H-15 (saturated plant fatty acid triglyceride; Riches-Nelson, Inc., New York), and has the following components. [Table 8]

[0273] dosage The specific dose level of the compounds of this application for any particular subject will depend on a variety of factors, including the activity of the specific compound used, age, body weight, overall health, sex, diet, timing of administration, route of administration, and excretion rate, drug combinations, and the severity of the specific disease of the subject being treated. For example, the dosage may be expressed as milligrams (mg / kg) of the compound described herein per kilogram of body weight of the subject. Doses of approximately 0.1 to 150 mg / kg may be appropriate. In some embodiments, approximately 0.1 to 100 mg / kg may be appropriate. In other embodiments, doses of 0.5 to 60 mg / kg may be appropriate. Normalizing according to the body weight of the subject is particularly useful when adjusting dosages across a wide range of subject sizes, such as when using drugs in both children and adults, or when converting effective dosages in non-human subjects such as dogs to dosages suitable for human subjects.

[0274] The compound or composition of the present application may be administered once, twice, three times, or four times daily using any suitable format described above. The administration or treatment of the compound may also be continued over several days; for example, treatment would generally last at least 7, 14, or 28 days for one treatment cycle. Treatment cycles are well-known in cancer chemotherapy and are often alternated with rest periods of approximately 1 to 28 days, generally about 7 or 14 days. In other embodiments, treatment cycles may also be continuous.

[0275] Compound Synthesis The compounds may be prepared using the methods disclosed herein and their routine modifications, which will be apparent from the disclosure herein and from methods well known in the art. In addition to the teachings herein, conventional and well known synthetic methods may be used. The synthesis of typical compounds described herein may be achieved as described in the examples below. Where available, reagents can be commercially purchased, for example, from Sigma Aldrich or other chemical manufacturers.

[0276] Typical process conditions (i.e., reaction temperature, time, reactant ratio, solvent, pressure, etc.) are provided, but other process conditions are also acceptable unless otherwise specified. Optimal reaction conditions may vary depending on the specific reactants or solvent used, but such conditions can be determined by those skilled in the art through optimization procedures.

[0277] Furthermore, conventional protecting groups ("PGs") may be necessary to prevent certain functional groups from undergoing undesirable reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting specific functional groups, are well known in the art. For example, numerous protecting groups are described in Wuts, PGM, Greene, TW, & Greene, TW (2006). Greene's protective groups in organic synthesis. Hoboken, NJ, Wiley-Interscience, and the literature cited in that document. For example, silyl ethers (including trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), tri-isopropylsilyloxymethyl (TOM), and triisopropylsilyl (TIPS) ethers) are suitable protecting groups for alcohols such as hydroxyls, which can be removed by acids or fluoride ions such as NaF, TBAF (tetra-n-butylammonium fluoride), HF-Py, or HF-NEt3. Other protecting groups for alcohols include acetyl, which can be removed by an acid or base; benzoyl, which can be removed by an acid or base; benzyl, which can be removed by hydrogenation; methoxyethoxymethyl ether, which can be removed by an acid; dimethoxytrityl, which can be removed by an acid; methoxymethyl ether, which can be removed by an acid; tetrahydropyranyl or tetrahydrofuranyl, which can be removed by an acid; and trityl, which can be removed by an acid.Examples of amine protecting groups include carbobenzyloxy, which is removed by hydrolysis; p-methoxybenzylcarbonyl, which is removed by hydrolysis; tert-butyloxycarbonyl, which is removed by concentrated strong acids (such as HCl or CF3COOH) or by heating to over approximately 80°C; 9-fluorenylmethyloxycarbonyl, which is removed by bases such as piperidine; acetyl, which is removed by treatment with a base; benzoyl, which is removed by treatment with a base; benzyl, which is removed by hydrolysis; and amines removed by acid and gentle heating. Examples include carbamate groups, p-methoxybenzyl removed by hydrocracking, 3,4-dimethoxybenzyl removed by hydrocracking, p-methoxyphenyl removed by cerium(IV) ammonium nitrate, tosyl removed by concentrated acid (such as HBr or H2SO4) and a strong reducing agent (sodium or sodium naphthalenide in liquid ammonia), troc (trichloroethyl chloroformate) removed by Zn insertion in the presence of acetic acid, and sulfonamides (Nosyl & Nps) removed by samarium iodide or tributyltin hydride.

[0278] Furthermore, the compounds of this disclosure may contain one or more chiral centers. Therefore, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as a concentrated mixture of stereoisomers. All such stereoisomers (and concentrated mixtures) are included within the scope of this disclosure unless otherwise specified. Pure stereoisomers (or concentrated mixtures) can be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated, for example, using chiral column chromatography, chiral decomposition agents, etc.

[0279] The starting materials for the following reactions are either commonly known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), and Emka-Chemce or Sigma (St. Louis, Missouri, USA). Others can be prepared by following the procedures or obvious modifications thereof described in standard reference books, such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5th Edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0280] General synthesis Typical embodiments of the compounds described herein can be synthesized using the general reaction scheme described below. It will be apparent from the description herein that the general scheme can be modified by substituting the starting materials with other materials having similar structures, and correspondingly different products can be obtained. The description of the synthesis follows to provide numerous examples of how the starting materials may be modified to provide the corresponding products. Given a desired product with defined substituents, the required starting materials can generally be determined by scrutiny. Starting materials are typically obtained from commercial suppliers or synthesized using publicly available methods. When synthesizing compounds that are embodiments described herein, scrutiny of the structure of the compound to be synthesized reveals the identity of each substituent. Generally, considering the examples herein, a simple process of scrutiny reveals the identity of the starting materials required for the final product. Generally, the compounds described herein are usually stable and isolateable at room temperature and atmospheric pressure.

[0281] Scheme I shows a general method that can be used for the synthesis of the compounds described herein, where n, m, Y 1 , Y 2 , X, X 1 , X 2 , X 3 , X 4 , R 5 , R 6a , R 6b , R 6c , R 7 , and R 8 Each of these is independently as defined herein, where LG is a leaving group (e.g., hydroxyl, alkoxyl, halo, etc.).

[0282] Scheme I [ka] In Scheme I, the compound of Formula I can be prepared by contacting compound I-4 with compound II-1 by coupling under appropriate reaction conditions, followed by any functionalization or deprotection as needed. The reaction may be carried out in aqueous solution or in an inert solvent such as acetonitrile or dichloromethane. The reaction may proceed at room temperature or high temperature. The reaction conditions may be acidic or basic. Alternatively, the reaction may be carried out in the presence of a coupling accelerator, such as chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate. After each reaction is complete, each intermediate or final compound can be recovered by conventional techniques, such as neutralization, extraction, precipitation, chromatography, or filtration, and optionally purified.

[0283] Further derivatization of the compounds obtained by the steps outlined in Scheme I, or any intermediate, yields additional compounds of formula I. It should be understood that any compound or intermediate shown in Scheme I can be prepared using conventional methods or purchased from commercial suppliers. In addition, any intermediate or any product obtained by the methods outlined in Scheme I can be derivatized in any step to obtain a variety of compounds of formula I. In specific embodiments, the various substituents of the compound or intermediate used in Scheme I are as defined for formula I.

[0284] For example, compound I-4 can be prepared according to Scheme II below, following the same procedure as described in Scheme I, where n, m, p, and Y are represented in the formula. 1 , R 6a , R 6b , R 6c , R 7 , and R 8 Each of these is independently defined as herein, where PG is a protecting group (e.g., tert-butyloxycarbonyl) and LG is a leaving group (e.g., hydroxy, alkoxy, halo, etc.).

[0285] Scheme II [ka] In Scheme II, the compounds of formula I-3 can be prepared by contacting amine I-1 with compound I-2 under appropriate reaction conditions, followed by any functionalization or deprotection as needed. The reaction may be carried out in aqueous solution or in an inert solvent such as acetonitrile or dichloromethane. The reaction may proceed at room temperature or high temperature. The reaction conditions may be acidic or basic. Alternatively, the reaction may be carried out in the presence of a coupling accelerator, such as chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate. Compound I-4 can then be prepared by removing the protecting group under appropriate cleavage conditions to produce compound I-4 as either a free amine or a salt (e.g., hydrochloride). The reaction conditions for deprotection will depend on the properties of the protecting group. For example, tert-butyloxycarbonyl can be removed under acidic conditions (e.g., in the presence of HCl).

[0286] Once each reaction is complete, each intermediate or final compound can be recovered and optionally purified using conventional techniques such as neutralization, extraction, precipitation, chromatography, and filtration.

[0287] In a particular embodiment, a process for obtaining a compound of formula I, wherein the compound of formula I-4: [ka] Compound of formula II-1: [ka] The process is provided which includes contact under conditions sufficient to obtain the compound of formula I, where n, m, Y 1 , Y 2 , X, X 1 , X 2 , X 3 , X 4 , R 5 , R 6a , R6b , R 6c , R 7 , and R 8 Each of these is independently as defined herein, and LG is a leaving group.

[0288] In certain embodiments, LG is a halo. In certain embodiments, LG is -OH. [Examples]

[0289] The following embodiments are included to demonstrate specific embodiments of the Disclosure. Those skilled in the art will understand that the techniques disclosed in the following embodiments are representative of techniques that function well in carrying out the Disclosure and can therefore be considered to constitute a particular form for carrying it out. However, those skilled in the art will understand that many modifications can be made to the specific embodiments disclosed in light of the Disclosure without departing from the spirit and scope of the Disclosure, and that similar or comparable results can be obtained.

[0290] General experimental methods All solvents used were commercially available and were used without further purification. Typically, the reaction was carried out using anhydrous solvents under an inert nitrogen atmosphere.

[0291] NMR spectroscopy: Bruker Avance III with a BBFO 300 MHz probe operating at 300 MHz, or one of the following instruments: Bruker Avance 400 instrument with probe DUAL 400 MHz S1, or probe 6 S1 400 MHz 5mm. 1 H- 13 Using a Bruker Avance 400 instrument equipped with a C ID, a Bruker Avance III 400 instrument with a NanoBay equipped with a Broadband BBFO 5 mm direct probe, and a Bruker Mercury Plus 400 NMR spectrometer equipped with a Bruker 400 BBO probe operating at 400 MHz, 1Nuclear magnetic resonance (NMR) spectroscopy was performed. All deuterated solvents typically contained 0.03%–0.05% v / v tetramethylsilane, which was used as a reference signal. 1 H and 13 (Setting δ to 0.00 in both C and C). In some cases, using a Bruker Advance 400 instrument operating at 400 MHz, and using the solvents listed, at room temperature unless otherwise specified. 1 ¹H nuclear magnetic resonance (NMR) spectroscopy was performed. In all cases, the NMR data were consistent with the proposed structure. Characteristic chemical shifts (δ) are shown in parts per million using conventional abbreviations for major peaks: e.g., s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), dt (triplet of doublets), and br (broad).

[0292] Thin-layer chromatography: When thin-layer chromatography (TLC) is used, it refers to silica gel TLC using silica gel F254 (Merck) plates, where Rf is the distance the compound traveled on the TLC plate divided by the distance the solvent traveled. Column chromatography was performed on silica gel cartridges using an automated flash chromatography system, or on C18 cartridges in the case of reverse-phase chromatography. Alternatively, thin-layer chromatography (TLC) was performed using Alugram® (Silica gel 60 F254) from Mancherey-Nagel, typically with UV used to visualize the spots. In some cases, additional visualization methods were also used. In these cases, the TLC plates were treated with iodine (produced by adding approximately 1 g of I2 to 10 g of silica gel and mixing thoroughly), ninhydrin (commercially available from Aldrich), or Magic Stain (25 g of (NH4)6Mo7O 24 The compound was visualized by developing a color using 0.4H2O (produced by completely mixing 450 mL of water containing 5 g of (NH4)2Ce(IV)(NO3)6) with 50 mL of concentrated H2SO4).

[0293] Liquid chromatography-mass spectrometry and HPLC analysis: HPLC analysis was performed using a Shimadzu 20AB HPLC system equipped with a photodiode array detector and a Luna-C18(2) 2.0 × 50 mm, 5 μm column, at a flow rate of 1.2 mL / min, with gradient mobile phase A (MPA, H2O + 0.037% (v / v) TFA): mobile phase B (MPB, ACN + 0.018% (v / v) TFA) (0.01 min, 10% MPB; 4 min, 80% MPB; 4.9 min, 80% MPB; 4.92 min, 10% MPB; 5.5 min, 10% MPB). LC-MS was detected at 220 and 254 mm, or using evaporative light scattering (ELSD) detection and positive electrospray ionization (MS). Semi-preparative HPLC was performed under either acidic or neutral conditions. Acidic: Luna C18 100×30mm, 5μm; MPA: HCl / H2O=0.04%, or formic acid / H2O=0.2% (v / v); MPB: ACN. Neutral: Waters Xbridge 150×25mm, 5μm; MPA: H2O containing 10mM NH4HCO3; MPB: ACN. Gradient for both conditions: at a flow rate of 20 mL / min, 10% MPB to 80% MPB over 12 minutes, then 100% MPB over 2 minutes, 10% MPB over 2 minutes, UV detector. SFC analysis was performed using a Thar analytical SFC system equipped with a UV / Vis detector and a series of chiral columns including AD, AS-H, OJ, OD, AY, and IC, all 4.6 × 100 mm, 3 μm in diameter, at a flow rate of 4 mL / min, with gradient solvent mobile phase A (MPA, CO2): mobile phase B (MPB, MeOH + 0.05% (v / v) IPAm) (0.01 min, 10% MPB; 3 min, 40% MPB; 3.5 min, 40% MPB; 3.56-5 min, 10% MPB).SFC preparative sampling was performed using a Thar 80 preparative SFC system equipped with a UV / Vis detector and a series of chiral preparative columns containing AD-H, AS-H, OJ-H, OD-H, AY-H, and IC-H, each measuring 30 × 250 mm, 5 μm, at a flow rate of 65 mL / min, with gradient solvent mobile phase A (MPA, CO2): mobile phase B (MPB, MeOH + 0.1% (v / v) NH3H2O) (0.01 min, 10% MPB; 5 min, 40% MPB; 6 min, 40% MPB; 6.1~10 min, 10% MPB). LC-MS data were also collected using a UPLC-MS Acquity® system coupled with a Waters single quadrupole mass spectrometer equipped with a PDA detector and operating alternately in positive and negative electrospray ionization modes. The column used was Cortecs UPLC C18, 1.6 μm, 2.1 × 50 mm. A linear gradient was applied, starting with 95% A (A: 0.1% formic acid / water) and ending with 95% B (B: 0.1% formic acid / MeCN) for 2.0 minutes, for a total run time of 2.5 minutes. The column temperature was 40°C and the flow rate was 0.8 mL / min.

[0294] List of abbreviations and acronyms [Table 9]

[0295] Intermediate 1a [ka] (R)-tert-butyl N-[2-(6-azaspiro[2.5]octan-6-yl)-1-methyl-2-oxo-ethyl]carbamate: A solution of 1-methylimidazole (1.08 mL, 13.5 mmol), (R)-2-(tert-butoxycarbonylamino)propanoic acid (640 mg, 3.39 mmol), and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (1.32 g, 4.75 mmol) in MeCN (13.2 mL) was mixed with 6-azaspiro[2.5]octane (376 mg, 3.38 mmol). The reaction mixture was stirred for 4 hours. The reaction mixture was diluted with H2O (10 mL) and extracted with ELISA (3 × 15 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was used directly. LCMS: m / z = 283.3 [M+H] + .

[0296] A mixture of (R)-2-amino-1-(6-azaspiro[2.5]octan-6-yl)propan-1-one hydrochloride:(R)-tert-butyl N-[2-(6-azaspiro[2.5]octan-6-yl)-1-methyl-2-oxo-ethyl]carbamate (400 mg, 1.41 mmol) and 4M HCl (1.14 mL, 4.57 mmol) in dioxane was stirred for 6 hours. The mixture was concentrated under reduced pressure and used directly.

[0297] Intermediate 2a [ka] Benzyl 1,1-difluoro-5-azaspiro[2.4]heptane-5-carboxylate: Benzyl carbonochloride (221 mg, 1.30 mmol) was added to a mixture of 1,1-difluoro-5-azaspiro[2.4]heptane hydrochloride (200 mg, 1.18 mmol) and triethylamine (477 mg, 4.72 mmol) in DCM (4 mL) at 0°C. The mixture was stirred at 20°C for 1 hour. The mixture was poured into H2O (3 mL) and extracted with DCM (3 × 5 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. The mixture was further purified by chiral SFC (Daicel Chiralpak AD (250mm × 50mm, 10μm particle size), mobile phase: A: CO2-MeOH, B: 0.1% NH3-H2O in i-PrOH, gradient: B% = 15% isocratic, detection wavelength: 220nm, flow rate: 3.4mL / min, column temperature: 35℃, system back pressure: 125bar) to obtain the following:

[0298] Benzyl(r)-1,1-difluoro-5-azaspiro[2.4]heptane-5-carboxylate (first eluted isomer): LC-MS: m / z = 268.2 [M + H] + and

[0299] Benzyl(s)-1,1-difluoro-5-azaspiro[2,4]heptane-5-carboxylate (second eluted isomer): LC-MS: m / z = 268.2 [M + H] + The indicated "*" stereocenter represents a single, unknown stereoisomer with unknown stereochemistry.

[0300] (r)-1,1-difluoro-5-azaspiro[2.4]heptane hydrochloride: To a solution of benzyl(r)-1,1-difluoro-5-azaspiro[2.4]heptane-5-carboxylate (first eluting isomer) (1.0 g, 3.74 mmol) in MeOH (20 mL), Pd / C (200 mg, 10%) was added. The suspension was degassed and purged three times with H2. The mixture was stirred under H2 (15 psi) for 2 hours. The mixture was filtered through a Celite pad and added to a solution of HCl / MeOH (40 mmol, 4 M, 10 mL). The combined mixture was concentrated under reduced pressure to obtain a residue, which was used directly.

[0301] (R)-tert-butyl(1-((r)-1,1-difluoro-5-azaspiro[2.4]heptan-5-yl)-1-oxobutan-2-yl)carbamate: SiO2 (2 mL) contained a solution of (r)-1,1-difluoro-5-azaspiro[2.4]heptane hydrochloride (120 mg, 0.71 mmol) and 2-((tert-butoxycarbonyl)amino)butanoic acid (158 mg, 0.78 mmol). Propylphosphonic anhydride (900 mg, 1.42 mmol, 50% in SiO2) and DIEA (366 mg, 2.83 mmol). The mixture was stirred for 16 hours. The reaction mixture was diluted with H2O (2 mL) and extracted with SiO2 (3 × 3 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z = 319.4 [M + H] + .

[0302] A solution of (R)-tert-butyl(1-((r)-1,1-difluoro-5-azaspiro[2.4]heptan-5-yl)-1-oxobutan-2-yl) carbamate (70 mg, 0.22 mmol) in (R)-2-amino-1-((r)-1,1-difluoro-5-azaspiro[2.4]heptan-5-yl)-1-oxobutan-2-yl) carbamate (70 mg, 0.22 mmol) in HCl / SiO2 (4.0 mmol, 4 M, 1 mL) was stirred for 1 hour. The mixture was concentrated under reduced pressure to obtain the residue, which was used directly. LCMS: m / z = 219.1 [M + H]+ .

[0303] Intermediate 3a [ka] (2R)-2-amino-1-(1,1-difluoro-5-azaspiro[2.4]heptan-5-yl)propan-1-one was prepared as a single unknown stereoisomer using (2R)-((tert-butoxycarbonyl)amino)propanoic acid according to the method described for intermediate 2a.

[0304] Step 1 N-[(2R)-1-(6-azapiro[2,5]octan-6-yl)-1-oxopropane-2-yl]-3-chloro-7H-pyrrolo[2,3-c]pyridazine-6-carboxamide(9) [ka] A mixture of 4-bromo-6-chloropyridazine-3-amine (500 mg, 2.40 mmol) and 2-oxopropanoic acid (422 mg, 4.80 mmol) in 3-chloro-7H-pyrrolo[2,3-c]pyridazine-6-carboxylic acid:DMF (10 mL) was mixed with Pd(OAc)2 (108 mg, 0.48 mmol) and DABCO (538 mg, 4.80 mmol). The mixture was stirred at 110°C for 4 hours. The mixture was adjusted to pH=4 with 1 M HCl and extracted with siRNA (3 × 10 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was used directly. LCMS: m / z = 197.9, 200.0 [M+H] +

[0305] A mixture of (R)-2-amino-1-(6-azaspiro[2.5]octan-6-yl)propan-1-one hydrochloride (554 mg, 2.53 mmol) and 3-chloro-7H-pyrrolo[2,3-c]pyridazine-6-carboxylic acid (500 mg, 2.53 mmol) in N-[(2R)-1-(6-azaspiro[2.5]octan-6-yl)propan-1-one hydrochloride (554 mg, 2.53 mmol) and 3-chloro-7H-pyrrolo[2,3-c]pyridazine-6-carboxylic acid (500 mg, 2.53 mmol) was added to N-[(2R)-1-(6-azaspiro[2.5]octan-6-yl)propan-1-one hydrochloride (554 mg, 2.53 mmol) and 3-chloro-7H-pyrrolo[2,3-c]pyridazine-6-carboxylic acid (500 mg, 2.53 mmol) in-1-oxopropan-2-yl]-3-chloro-7H-pyrrolo[2,3-c]pyridazine-6-carb (10 mL) (1.31 g, 10.12 mmol, 1.76 mL) and propylphosphonic anhydride (2.74 g, 3.80 mmol, 50% in N-[(2R)-1-(6-azaspiro[ The mixture was poured into H2O (10 mL) and extracted with siRNA (3 × 5 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z = 362.0, 363.9 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 8.05 (s, 1H), 7.19 (s, 1H), 5.14 (q, J = 7.2 Hz, 1H), 3.81-3.52 (m, 4H), 1.67-1.57 (m, 1H), 1.52-1.28 (m, 6H), 0.41 (d, J = 2.0 Hz, 4H).

[0306] Step 2 N-[(2R)-1-(6-azaspiro[2.5]octan-6-yl)-1-oxopropan-2-yl]-5-(difluoromethyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide(24) [ka] A mixture of 4-methyl-5-nitropicoline aldehyde and 2,4-dimethyl-5-nitropyridine (1.0 g, 6.57 mmol) in 1,4-dioxane (10 mL) was mixed with SeO2 (875 mg, 7.89 mmol). The reaction mixture was stirred at 110°C for 12 hours. The reaction mixture was diluted with H2O (10 mL) and extracted with siRNA (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. LCMS: m / z = 167.0 [M+H] + .

[0307] 2-(difluoromethyl)-4-methyl-5-nitropyridine: DAST (582 mg, 3.61 mmol) was added to a mixture of 4-methyl-5-nitropicolinaldehyde (300 mg, 1.81 mmol) in DCM (3 mL) at 0°C. The mixture was stirred for 1 hour. The mixture was adjusted to pH 7-8 with saturated NaHCO3 aqueous solution and extracted with Â15 (3 × 5 mL) ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z = 189.1 [M+H] + .

[0308] A mixture of ethyl 5-(difluoromethyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate and 2-(difluoromethyl)-4-methyl-5-nitropyridine (230 mg, 1.22 mmol) in diethyl oxalate (3 mL) was mixed with DBU (465 mg, 3.06 mmol). The mixture was stirred for 12 hours. The mixture was concentrated under reduced pressure and resuspended in AcOH (3 mL). Fe (137 mg, 2.45 mmol) was added to the reaction mixture at 60°C. The reaction mixture was stirred at 70°C for 2 hours. The reaction mixture was adjusted to pH 7-8 with saturated NaHCO3 aqueous solution, filtered, and the filtrate was extracted with RINKAN (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z = 241.0 [M+H] + .

[0309] 5-(difluoromethyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid: A mixture of 5-(difluoromethyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (250 mg, 1.04 mmol) in THF (2 mL) and H2O (1 mL) was mixed with LiOH-H2O (87 mg, 2.08 mmol). The reaction mixture was stirred for 2 hours. The mixture was adjusted to pH 4-5 with 2 M HCl, extracted with DCM / MeOH (3 × 5 mL, v / v = 10:1), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was used directly. LCMS: m / z = 213.2 [M+H] + .

[0310] DIEA (122 mg, 0.94 mmol) and propylphosphonic anhydride (255 mg, 0.35 mmol, 50% in ethyl The reaction mixture was diluted with H2O (5 mL) and extracted with ₹ (3 × 5 mL). The combined organic layer was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 377.2 [M + H] + . 1H NMR (400MHz, CDCl3): δ 10.57-10.22 (m, 1H), 8.96 (s, 1H), 7.93 (s, 2H), 7.07 (s, 1H), 6.83 (t, J = 56 Hz, 1H), 5.16-5.09 (m, 1H), 3.86-3.46 (m, 4H), 1.58-1.29 (m, 7H), 0.43 (s, 4H).

[0311] Step 3 N-[(2R)-1-(6-azaspiro[2,5]octan-6-yl)-1-oxopropan-2-yl]-5-chloro-4-fluoro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide(18) [ka] To a solution of 5-bromo-2-chloro-3-fluoropyridine (5.0 g, 23.8 mmol) and tert-butyl carbamate (3.06 g, 26.2 mmol) in 100 mL of tert-butyl(6-chloro-5-fluoropyridine-3-yl)carbamate: Cs2CO3 (7.74 g, 23.8 mmol), Xantphos (825 mg, 1.43 mmol), and Pd2(dba)3 (653 mg, 0.71 mmol) were added. The mixture was stirred at 85°C for 14 hours. The reaction mixture was poured into H2O (50 mL) and extracted with 150 mL (3 × 50 mL) of ethyl acetate. The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LC-MS: m / z = 247.1, 249.0 [M+H] + .

[0312] tert-butyl(6-chloro-5-fluoro-4-iodopyridine-3-yl)carbamate: To a solution of tert-butyl(6-chloro-5-fluoropyridine-3-yl)carbamate (1.5 g, 6.08 mmol) and tetramethylethylenediamine (1.41 g, 12.2 mmol, 1.84 mL) in THF (15 mL) at -78 °C, n-BuLi (15.2 mmol, 2.5 M in n-heptane, 6.08 mL) was added. The mixture was stirred at -78 °C for 0.5 hours, and then I2 (2.32 g, 9.12 mmol) in THF (5 mL) was added. The mixture was stirred at 25 °C for 2 hours. The reaction mixture was poured into a saturated NH4Cl (20 mL) aqueous solution and extracted with ₹ (3 × 15 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z = 372.9, 374.9 [M+H] + .

[0313] 6-Chloro-5-fluoro-4-iodopyridine-3-amine: To a solution of tert-butyl(6-chloro-5-fluoro-4-iodopyridine-3-yl)carbamate (1.76 g, 4.72 mmol) in 15 mL of DCM at 0°C, TFA (4.61 g, 40.4 mmol, 3 mL) was added. The mixture was stirred at 25°C for 2 hours. The reaction mixture was adjusted to pH=8 with saturated NaHCO3 aqueous solution, diluted with H2O (10 mL), and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was used directly. LCMS: m / z = 272.9, 274.9 [M+H] + .

[0314] To a solution of 6-chloro-5-fluoro-4-iodopyridine-3-amine (200 mg, 0.73 mmol) and 2-oxopropanoic acid (129 mg, 1.47 mmol) in 5-chloro-4-fluoro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid:DMF (3 mL), DABCO (165 mg, 1.47 mmol) and Pd(OAc)2 (32.9 mg, 0.15 mmol) were added. The mixture was stirred at 110°C for 4 hours. The reaction mixture was adjusted to pH 4-5 with 2 M HCl, diluted with H2O (5 mL), and extracted with Âx (3 × 5 mL). The combined organic layers were washed with 10 mL (2 × 5 mL) brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was used directly. LCMS: m / z = 215.1, 216.9 [M+H] + .

[0315] To a solution of N-[(2R)-1-(6-azaspiro[2.5]octan-6-yl)-1-oxopropan-2-yl]-5-chloro-4-fluoro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide: siRNA (3 mL) and DMF (1 mL) containing 5-chloro-4-fluoro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (150 mg, 0.70 mmol) and (R)-2-amino-1-(6-azaspiro[2.5]octan-6-yl)propan-1-one hydrochloride (183 mg, 0.84 mmol), DIEA (452 ​​mg, 3.50 mmol) and propylphosphonic anhydride (756 mg, 1.05 mmol, 50% in siRNA) were added. The mixture was stirred at 25°C for 12 hours. The reaction mixture was poured into H2O (5 mL) and extracted with HCl (3 × 3 mL). The combined organic layer was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 379.1, 381.1 [M+H] + . 1H NMR (400 MHz, CDCl3): δ 10.98 (br s, 1H), 8.48-8.35 (m, 2H), 7.08 (s, 1H), 5.24-5.11 (m, 1H), 3.89-3.77 (m, 1H), 3.73-3.57 (m, 3H), 1.62-1.40 (m, 7H), 0.43 (s, 4H).

[0316] Step 4 5-Chloro-N-[(2R)-1-[(3r)-2,2-difluoro-5-azaspiro[2,4]heptan-5-yl]-1-oxobutan-2-yl]-1H-pyrrolo[2,3-c]pyridine-2-carboxamide(10) [ka] To a solution of 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (42 mg, 0.22 mmol) and (e)-2-amino-1-((r)-1,1-difluoro-5-azaspiro[2.4]heptan-5-yl)butan-1-one hydrochloride (50 mg, 0.20 mmol) in siRNA (2 mL), DIEA (101 mg, 0.79 mmol) and propylphosphonic anhydride (212 mg, 0.29 mmol, 50% in siRNA) were added. The mixture was stirred for 12 hours. The reaction mixture was poured into H2O (3 mL) and extracted with siRNA (3 × 3 mL). The combined organic matter was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 397.1, 399.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 10.27-10.05 (m, 1H), 8.68-8.56 (m, 1H), 7.90-7.62 (m, 1H), 7.59-7.48 (m, 1H), 6.90 (br d, J = 1.6 Hz, 1H), 4.99-4.82 (m, 1H), 4.11-3.90 (m, 1H), 3.83-3.55 (m, 3H), 2.27-1.78 (m, 4H), 1.53-1.43 (m, 2H), 1.13-0.99 (m, 3H).

[0317] The following compounds shown in Table 1 were produced or can be produced by the same procedure as described above. [Table 10-1] [Table 10-2] [Table 10-3] [Table 10-4] [Table 10-5] [Table 10-6] [Table 10-7] [Table 10-8] [Table 10-9] [Table 10-10]

[0318] Step 5 5-Chloro-N-[(1-[2,2-difluoro-5-azaspiro[2,4]heptan-5-yl]-1-oxobutan-2-yl]-4-fluoro-1H-indole-2-carboxamide(88) [ka] To a solution of (R)-2-amino-1-((r)-1,1-difluoro-5-azaspiro[2.4]heptan-5-yl)butan-1-one hydrochloride (45 mg, 0.18 mmol, intermediate 2a) in DMF (2 mL), 5-chloro-4-fluoro-1H-indole-2-carboxylic acid (30 mg, 0.14 mmol), DIEA (91 mg, 0.7 mmol), and T4P (152 mg, 0.21 mmol, 50% purity in ethyl acetate) were added. The mixture was stirred for 16 hours. The residue was diluted with H2O (3 mL) and extracted with ethyl acetate (3 × 2 mL). The combined organic layers were washed with brine (3 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 414.1, 416.1 [M+H] + . 1 HNMR (400 MHz, CDCl3): δ 10.20-9.55 (m, 1H), 8.08-7.79 (m, 1H), 7.23-7.16 (m, 1H), 7.13-7.03 (m, 2H), 5.00- 4.80 (m, 1H), 4.16-3.54 (m, 4H), 2.31-1.80 (m, 4H), 1.53-1.30 (m, 2H), 1.05 (dt, J = 2.4, 7.2 Hz, 3H).

[0319] Step 6 N-[1-[2,2-difluoro-5-azapiro[2,4]heptan-5-yl]-1-oxobutan-2-yl]-4,6-difluoro-1H-indole-2-carboxamide(90) [ka] To a solution of 4,6-difluoro-1H-indole-2-carboxylic acid (30 mg, 0.15 mmol) in DMF (1 mL), (R)-2-amino-1-((r)-1,1-difluoro-5-azaspiro[2.4]heptan-5-yl)butan-1-one hydrochloride (39 mg, 0.15 mmol, intermediate 2a), T4P (165 mg, 0.23 mmol, 50% purity in ethyl acetate), and DIEA (79 mg, 0.61 mmol) were added. The mixture was stirred for 12 hours. The reaction mixture was poured into H2O (5 mL) and extracted with ethyl acetate (3 × 3 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 398.2 [M+H] + . 1 HNMR (400 MHz, CDCl3): δ 9.69-9.49 (m, 1H), 7.49-7.30 (m, 1H), 7.04 (s, 1H), 6.94-6.85 (m, 1H), 6.64 (dt, J = 2.0, 10.0 Hz, 1H), 4.99-4.84 (m, 1H), 4.10-3.94 (m, 1H), 3.84-3.54 (m, 3H), 2.29-1.89 (m, 3H), 1.81 (td, J = 7.2, 14.4 Hz, 1H), 1.52-1.39 (m, 2H), 1.03 (dt, J = 4.0, 7.2 Hz, 3H).

[0320] Step 7 N-[1-(6-azaspiro[2,5]octan-6-yl)-1-oxopropan-2-yl]-5-methoxy-1H-pyrrolo[2,3-c]pyridine-2-carboxamide(96) [ka] A mixture of (R)-2-amino-1-(6-azaspiro[2.5]octan-6-yl)propan-1-one hydrochloride (57 mg, 0.26 mmol, intermediate 1a) and 5-methoxy-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (50 mg, 0.26 mmol) in 1 mL of ethyl acetate was mixed with T4P (281 mg, 0.39 mmol, 50% purity in ethyl acetate) and DIEA (168 mg, 1.30 mmol). The mixture was stirred for 16 hours. The mixture was poured into water (3 mL) and extracted with ethyl acetate (3 × 1 mL). The combined organic layer was washed with brine (1 mL), dried over anhydrous sodium 2 SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 357.2 [M+H] + . 1 HNMR (400 MHz, CDCl3):δ 9.84-9.66 (m, 1H), 8.59 (s, 1H), 7.78 (br d, J = 4.8 Hz, 1H), 6.97 (s, 1H), 6.87 (s, 1H), 5.13-5.06 (m, 1H), 4.00 (s, 3H), 3.80-3.74 (m, 1H), 3.70-3.56 (m, 3H), 1.59-1.43 (m, 7H), 0.42 (s, 4H).

[0321] Step 8 N-[1-(6-azapiro[2,5]octan-6-yl)-1-oxopropan-2-yl]-5-methoxy-1H-pyrrolo[2,3-c]pyridine-2-carboxamide(89) [ka] To a solution of 5,6-difluoro-1H-indole-2-carboxylic acid (46 mg, 0.24 mmol) and (R)-2-amino-1-((r)-1,1-difluoro-5-azaspiro[2.4]heptan-5-yl)butan-1-one hydrochloride (50 mg, 0.20 mmol, intermediate 2a) in 1 mL of ethyl acetate, DIEA (76 mg, 0.59 mmol) and T4P (212 mg, 0.30 mmol, 50% purity in ethyl acetate) were added at 0°C. The mixture was stirred at 20°C for 4 hours. The reaction mixture was poured into H2O (2 mL) and extracted with ethyl acetate (3 × 2 mL). The combined organic layer was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 398.2 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 9.87-9.72 (m, 1H), 7.49-7.31 (m, 1H), 7.42-7.31 (m, 1H), 7.21-7.13 (m, 1H), 6.93 (s, 1H), 4.98-4.85 (m, 1H), 4.14-3.90 (m, 1H), 3.88-3.50 (m, 3H), 2.29-1.90 (m, 3H), 1.87-1.73 (m, 1H), 1.52-1.39 (m, 2H), 1.08-1.00 (m, 3H).

[0322] The following compounds shown in Table 1 were produced or can be produced by the same procedure as described above. [Table 11-1] [Table 11-2] [Table 11-3] [Table 11-4] [Table 11-5] [Table 11-6]

[0323] Compound Biological Assays Materials and methods Generation and maintenance of stable human TMEM175 cell lines: HEK293 cells were transduced with a lentivirus containing a tetracycline-dependent inducible expression construct of wild-type human TMEM175 tagged with green fluorescent protein (GFP). The cells were placed under antibiotic selectivity (0.6 mg / mL G418 (Gibco) and 1 μg / mL puromycin (Gibco)) to establish a stable pool. Single-cell clones were isolated from this pool by limiting dilution and then grown. Final clones were selected based on the intensity of their GFP signal and TMEM175 cell surface expression, evaluated by biotinylation-based Western blotting. During pharmacological experiments, the final clones were maintained in a growth medium consisting of Dulbecco's modified Eagle agar (Gibco) supplemented with 10% tetracycline-free fetal bovine serum (Clontech), 2 mM Ultraglutamine-1 (Lonza), 0.6 mg / mL G418 (Gibco), and 1 μg / mL puromycin (Gibco).

[0324] A FLIPR potassium assay kit (R8222) containing a thallium-sensitive fluorescent dye was obtained from Molecular Devices and prepared for use with the dye loading solution according to the manufacturer's instructions.

[0325] Thallium-influx-based FLIPR assay for evaluating the pharmacology of TMEM175: TMEM175 is a potassium and thallium-permeable ion channel that exhibits leak-like properties, i.e., the channel is open in the absence of external stimuli, allowing cations to flow through it. The main component of this assay is the application of extracellular thallium while simultaneously measuring the fluorescence of a thallium-sensitive dye loaded into cells overexpressing human wild-type TMEM175. The cellular response to thallium is measured in the presence or absence of the test compound to identify and characterize modulators of TMEM175-dependent thallium conductance.

[0326] The day before the assay, human TMEM175-GFP-expressing cells were seeded at a density of 20,000 cells / well in growth medium containing 0.5 μg / mL of doxycycline (Sigma) to induce TMEM175 expression in 384-well black-walled, transparent-bottomed poly-D-lysine-coated plates (Corning). The cell plates were placed in a humidified incubator at 5% CO2 and 37°C for 24 hours.

[0327] On the day of the assay, the cell plates were removed from the incubator and equilibrated at room temperature (approximately 23-25°C) for 1 hour. After removing the growth medium from the plates by centrifugation, the cells were incubated in the dye loading solution (20 μL / well) of the FLIPR potassium assay kit at room temperature (approximately 23-25°C) for 1 hour.

[0328] The objective of the pharmacological experiment was to evaluate the ability of the test compound to modulate the signal induced by 1 mM thallium. (Note: This thallium concentration was measured in the assay via EC2. 20(It was previously determined to be close to [the specified value]). To enable these experiments, 384-well thallium solution plates were prepared in chloride-free Tyrode buffer with 90 mM thallium in column 1 and 3 mM thallium in columns 2-24, yielding final concentrations of 30 mM and 1 mM in the assay plates, respectively. In each assay plate, column 1 (i.e., final 30 mM thallium without the test compound) was the HI control condition, and column 24 (i.e., final 1 mM thallium without the test compound) was the LO control condition.

[0329] Compound titration plates were prepared on the day of the experiment. Test compounds solubilized in 100% DMSO at 10 mM, 880 μM, and 1.7 μM were added to Echo acoustic dispenser-compatible plates (Beckman Coulter). Next, compound titration plates were prepared by dispensing appropriate amounts of DMSO-solubilized compounds, pure DMSO (normalized to 3% of all wells, resulting in a final concentration of 1% in the assay plate), and chloride-free Tyrode buffer into 384-well polypropylene plates. Each compound titration plate contained a maximum of 16 compounds, with one unique compound in each row. Each compound was titrated from 300 μM to 143 pM (concentrations of 22 at well positions 2 to 23 in each row) to obtain final test concentrations of 100 μM to 47.7 pM in the assay plate.

[0330] For the pharmacological experiment, cell plates and compound titration plates were placed on the deck of a Bravo liquid handler. The Bravo transferred 10 μL / well of compound-containing solution to the cell plates, and after equilibrating the plates at room temperature (approximately 23-25°C) for 5 minutes, transferred them to the deck of a Fluorometric Imaging Plate Reader (FLIPR; Molecular Devices). At this point, the thallium solution plates were also transferred to the FLIPR. Baseline fluorescence signals were measured from the cell plates for 30 seconds at excitation wavelengths of 470-495 nm and emission wavelengths of 515-575 nm, after which thallium solution (15 μL / well) was applied to the cells using the liquid processing head of the FLIPR. Fluorescence signals were measured for a further 240 seconds (total recording time 270 seconds). The cell response, after subtracting background, was calculated as the AUC for 30-270 seconds. The average cellular AUC response in the HI control well (i.e., column 1 containing 30 mM thallium) was used to define the maximum response, and the average AUC response in the LO control well (i.e., column 24 containing 1 mM thallium) was used to define the minimum response. Cellular responses in all other wells were expressed as a percentage of the assay window defined by HI-LO. These percentage values ​​were plotted as a function of the test compound concentration (e.g., in GraphPad Prism), and the data were plotted against the EC of each compound. 50 (Efficacy) value and E max It was described using a four-parameter logistic function that allows for the estimation of (effectiveness) values.

[0331] The activity of the test compound is shown in Table 3 below: +++=EC 50 <10μM;++=EC 50 10-15 μM; += EC 50 >15μM. [Table 3-1] [Table 3-2]

[0332] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which this disclosure pertains.

[0333] The disclosures described herein as examples are perfectly functional without any elements(s) or limitations(s) not specifically disclosed herein. That is, terms such as “comprising,” “including,” and “containing” should be read broadly and non-restrictively. Furthermore, the terms and expressions used herein are for illustrative purposes only, not limitation, and the use of such terms and expressions is not intended to exclude any equivalents of the features or parts thereof shown or described, and it is recognized that various modifications are possible within the scope of this disclosure.

[0334] Therefore, although this disclosure is specifically disclosed by particular embodiments and optional features, it should be understood that modifications, improvements, and variations of the disclosure disclosed and embodied herein may be used by those skilled in the art, and such modifications, improvements, and variations shall be deemed to be within the scope of the disclosure. The materials, methods, and examples provided herein are representative of particular embodiments and are illustrative, and are not intended to be limitations on the scope of the disclosure.

[0335] This disclosure is described extensively and comprehensively in this specification. Each of the narrower species and sub-concepts included within the comprehensive disclosure also forms part of this disclosure. This includes the comprehensive description of this disclosure with any conditions or negative limitations that exclude any subject matter from its genus, regardless of whether the excluded material is specifically described herein.

[0336] Furthermore, where any feature or aspect of the present disclosure is described in terms of a group of Markushes, a person skilled in the art will understand that the present disclosure also describes any individual element or subgroup of any element of that group of Markushes.

[0337] All publications, patent applications, patents, and other references referred to herein are expressly invoked by reference in whole to the same extent as each of them is invoked by reference individually. In the event of any conflict, including definitions, this specification shall prevail.

[0338] While this disclosure has been described in relation to the embodiments described above, it should be understood that the foregoing description and examples are illustrative and not intended to limit the scope of this disclosure. Other aspects, advantages, and modifications within the scope of this disclosure will be obvious to those skilled in the art to which this disclosure belongs.

Claims

1. Compound of formula I: 【Transformation 70】 or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, tautomer, or isotope-enriched analog thereof, wherein, n is 1, 2, or 3; m is 0, 1, 2, 3, or 4, where n+m is 1, 2, 3, 4, or 5; p is 0, 1, 2, 3, 4, or 5; X is NH, N(C １－６ Alkyl), O, or S; X １ CR １ or N; X ２ CR ２ or N; X ３ CR ３ or N; X ４ is CR ４ or N; Y １ and Y ２ These are, independently, O, S, or NR ｃ And; R １ , R ２ , R ３ , and R ４ These are, independently, hydrogen, halo, cyano, and C. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, aryl, C ３ - １０ Cycloalkyl, heterocyclyl, heteroaryl, -C(NH)NH(OH), -C(NH)NH ２ , -C(O)NR ａ R ｂ , -C(O)NR ａ -NR ａ R ｂ , -C(O)NH(C １－６ Alkylene)-NR ａ R ｂ , -C(O)OR ａ , -NR ａ R ｂ , -NO ２ , -OR ａ , -OC(O)R ａ ,-SR ａ , -S(O)R ａ , -S(O) ２ R ａ , -S(O) ２ NR ａ R ｂ , or -S(O) ３ H is present, and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl independently has 1 to 5 Z １ It is arbitrarily replaced by; Or R １ and R ２ , R ２ and R ３ , or R ３ and R ４ Together with the atoms bonded to them, 1 to 5 Z １ They form optionally substituted 5-6 member cycloalkyl, heterocyclyl, aryl, or heteroaryl groups; R ５ These are hydrogen, halo, cyano, and C. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, aryl, C ３ - １０ Cycloalkyl, heterocyclyl, heteroaryl, -C(NH)NH(OH), -C(NH)NH ２ , -C(O)NR ａ R ｂ , -C(O)NR ａ -NR ａ R ｂ , -C(O)NH(C １－６ Alkylene)-NR ａ R ｂ , -C(O)OR ａ , -NR ａ R ｂ , -NO ２ , -OR ａ , -OC(O)R ａ ,-SR ａ , -S(O)R ａ , -S(O) ２ R ａ , -S(O) ２ NR ａ R ｂ , or -S(O) ３ H is present, and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl independently has 1 to 5 Z １ It is arbitrarily replaced by; R ６ａ and R ６ｂ each independently are halo, cyano, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, aryl, C ３－１０ cycloalkyl, heterocyclyl, heteroaryl, -C(NH)NH(OH), -C(NH)NH ２ , -C(O)NR ａ R ｂ , -C(O)NR ａ -NR ａ R ｂ , -C(O)NH(C １－６ alkyl)-NR ａ R ｂ , -C(O)R ａ , -C(O)OR ａ , -NR ａ R ｂ , -NO ２ , -OR ａ , -OC(O)R ａ , -SR ａ , -S(O)R ａ , -S(O) ２ R ａ , -S(O) ２ NR ａ R ｂ , or -S(O) ３ H, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with 1 to 5 Z １ ; or R ６ａ is hydrogen, and R ６ｂ is, -CH ３ , -CF ３ , -OCF ３ , or C ３－１０ It is cycloalkyl; or R ６ａ and R ６ｂ Each of them, along with the atoms bonded to them, has 1 to 5 Z １ C arbitrarily substituted with ３－６ Forming cycloalkyl or 3-6 membered heterocyclines; Each R ６ｃ These are independently: Halo, Cyano, C １－３ Alkyl, or C １－３ It is a haloalkyl; or Two R's ６ｃ Each of them, along with the atoms bonded to them, has 1 to 5 Z １ Forms optionally substituted 3- to 6-membered spiro, condensed, or crosslinked cycloalkyl or 3- to 6-membered spiro, condensed, or crosslinked heterocyclyl; R ６ａ is hydrogen, and R ６ｂ and one R ６ｃ Each of them, along with the atoms bonded to them, has 1 to 5 Z １ Forms optionally substituted 3-6 member condensates, or cross-linked cycloalkyls or 3-6 member condensates, or cross-linked heterocyclines; R ７ is hydrogen, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, aryl, C ３－１０ A cycloalkyl, heterocyclyl, or heteroaryl, where each independently comprises 1 to 5 Z １ It is arbitrarily replaced by; R ８ C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, aryl, C ３－１０ A cycloalkyl, heterocyclyl, or heteroaryl, where each independently comprises 1 to 5 Z ２ It is arbitrarily replaced by; Alternatively, R ７ and R ８ It bonds together with the carbon atoms that are bonded to them, C ３ - ６ They form cycloalkyl or heterocyclines, each independently comprising 1 to 5 Z １ It is arbitrarily replaced by; Each R ａ and R ｂ These are, independently, hydrogen, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１０ The compounds are cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, or heteroaryl molecules independently have 1 to 5 Z １ｂ It is arbitrarily replaced by; Each R ｃ These are, independently, hydrogen, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１０ The compounds are cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, or heteroaryl molecules independently have 1 to 5 Z １ｂ It is arbitrarily replaced by; Each Z １ These are independently: halo, cyano, -NO ２ , C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R) １２ ) ２ , -OR １２ ,-SR １２ , -C(O)R １２ , -C(O)OR １２ , -S(O)R １２ , -S(O) ２ R １２ , -C(O)N(R １２ ) ２ , -NR １２ C(O)R １２ , -NR １２ S(O)R １２ , -NR １２ S(O) ２ R １２ , -S(O)N(R １２ ) ２ , -S(O) ２ N(R) １２ ) ２ , -NR １２ C(O)N(R) １２ ) ２ , -NR １２ S(O)N(R) １２ ) ２ , -NR １２ S(O) ２ N(R) １２ ) ２ , -OC(O)N(R １２ ) ２ , or -NR １２ C(O)OR １２ And each C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, or heteroaryl molecules independently have 1 to 5 Z １ａ It is arbitrarily replaced by; Each Z ２ These are independently: halo, cyano, -NO ２ , C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, heterocyclyl, -N(R １２ ) ２ , -OR １２ ,-SR １２ , -C(O)R １２ , -C(O)OR １２ , -S(O)R １２ , -S(O) ２ R １２ , -C(O)N(R １２ ) ２ , -NR １２ C(O)R １２ , -NR １２ S(O)R １２ , -NR １２ S(O) ２ R １２ , -S(O)N(R １２ ) ２ , -S(O) ２ N(R) １２ ) ２ , -NR １２ C(O)N(R) １２ ) ２ , -NR １２ S(O)N(R) １２ ) ２ , -NR １２ S(O) ２ N(R) １２ ) ２ , -OC(O)N(R １２ ) ２ , or -NR １２ C(O)OR １２ And each C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyls, or heterocyclyls, are independently halo, cyano, -OH, -SH, and -NH. ２ , -NH-C １－６ Alkyl, -N(C) １－６ Alkyl) ２ , C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl and C １－６ Optionally substituted with 1 to 5 substituents independently selected from the haloalkoxy; Each R １２ These are, independently, hydrogen, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１０ The compounds are cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, or heteroaryl molecules independently have 1 to 5 Z １ｂ It is arbitrarily replaced by; Each Z １ａ These are independently: halo, cyano, -NO ２ , C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R) １３ ) ２ , -OR １３ ,-SR １３ , -C(O)R １３ , -C(O)OR １３ , -S(O)R １３ , -S(O) ２ R １３ , -C(O)N(R １３ ) ２ , -NR １３ C(O)R １３ , -NR １３ S(O)R １３ , -NR １３ S(O) ２ R １３ , -S(O)N(R １３ ) ２ , -S(O) ２ N(R) １３ ) ２ , -NR １３ C(O)N(R) １３ ) ２ , -NR １３ S(O)N(R) １３ ) ２ , -NR １３ S(O) ２ N(R) １３ ) ２ , -OC(O)N(R １３ ) ２ , or -NR １３ C(O)OR １３ And here, each C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, or heteroaryl molecules independently have 1 to 5 Z １ｂ It is arbitrarily replaced by; Each R １３ These are, independently, hydrogen, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１０ The compounds are cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, or heteroaryl molecules independently have 1 to 5 Z １ｂ It is arbitrarily replaced by; Each Z １ｂ These are independently: halo, cyano, -OH, -SH, -NH ２ , -NO ２ , C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, heteroaryl, -L １ -C １－６ Alkyl, -L １ -C ２－６ Alkenyl, -L １ -C ２－６ Alkinyl, -L １ -C １－６ Haloalkyl, -L １ -C ３－１０ Cycloalkyl, -L １ -heterocyclyl, -L １ -aryl or -L-heteroaryl; Each L １ These are independently -O-, -NH-, -S-, -S(O)-, and -S(O) ２ -, -N(C １－６ Alkyl)-,-N(C ２－６ Alkenyl)-,-N(C) ２－６ Alkinyl)-,-N(C) １－６ Haloalkyl)-,-N(C) ３－１０ Cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C １－６ Alkyl)-,-C(O)N(C ２－６ Alkenyl)-,-C(O)N(C ２－６ Alkinyl)-,-C(O)N(C １－６ Haloalkyl)-,-C(O)N(C ３－１０ Cycloalkyl)-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, or -S(O) ２ It is NH-; Here, Z １ｂ and L １ Each C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, and heteroaryl compounds may also independently contain 1 to 5 halo, cyano, -OH, -SH, and -NH compounds. ２ , -NO ２ , -SF ５ , C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, C ３－１０ Optionally substituted with cycloalkyl, heterocyclyl, aryl, or heteroaryl; however, (a) Y １ and Y ２ Both are O; R ７ However, hydrogen or unsubstituted C １－３ It is alkyl; R ８ However, C is arbitrarily substituted. １－４ If it is an alkyl or unsubstituted phenyl, the portion 【Chemistry 71】 teeth, 【Chemistry 72】 Not its stereoisomer or mixture of stereoisomers; (b) Y １ and Y ２ Both are O; R ７ However, it is hydrogen; R ８ However, if the methyl is substituted with either an optionally substituted phenyl or an optionally substituted 5- or 6-membered heteroaryl, then the portion 【Transformation 73】 teeth, 【Chemistry 74】 Rather; (c) Y １ and Y ２ Both are O; n+m is 3; R ６ａ However, it is hydrogen; R ６ｂ However, -CH ３ If so, the part 【Chemistry 75】 is not 1H-indole-2-yl or 3,5-dimethyl-1H-indole-2-yl; and (d) The compound is not the following: (R)-4-[(1H-indole-2-ylcarbonyl)amino]-δ-oxo-8-azaspiro[4.5]decane-8-pentanoic acid (CAS137822-87-8); N-[(1S,2S)-1-[(3,3-difluoro-1-pyrrolidinyl)carbonyl]-2-methylbutyl]-benzo[b]thiophene-2-carboxamide (CAS928403-03-6); N-[(1S,2S)-1-[[(2S)-2-cyano-4,4-difluoro-1-pyrrolidinyl]carbonyl]-2-methylbutyl]-benzo[b]thiophene-2-carboxamide (CAS928353-89-3); or N-[(1R)-1-[(4-methoxyphenyl)methyl]-2-[3-(1-methylethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]deca-8-yl]-2-oxoethyl]-1H-indole-2-carboxamide (CAS1219969-86-4)

2. Y １ The compound according to claim 1, wherein is O.

3. Y ２ The compound according to claim 1 or 2, wherein is O.

4. The compound according to any one of claims 1 to 3, wherein X is NH.

5. X １ , X ２ , X ３ , and X ４ The compound according to any one of claims 1 to 4, wherein at least one of the elements is N.

6. X ３ The compound according to any one of claims 1 to 4, wherein is N.

7. X ４ The compound according to any one of claims 1 to 4, wherein is N.

8. X １ CR １ X ２ CR ２ X ３ CR ３ X ４ CR ４ The compound according to any one of claims 1 to 4.

9. The aforementioned part 【Transformation 76】 teeth, Chemical Formula 77 The compound according to any one of claims 1 to 4.

10. R １ , R ２ , R ３ , and R ４ If present, they are independently hydrogen, halo, cyano, and C. １－６ Alkyl, aryl, C ３－１０ Cycloalkyl, heteroaryl, -OR ａ And here, R ａ C １－６ Alkyl or C ３－１０ It is a cycloalkyl group, and each alkyl, cycloalkyl, aryl, or heteroaryl group independently has 1 to 5 Z １ The compound according to any one of claims 1 to 9, which is optionally substituted with

11. R １ The compound according to any one of claims 1 to 10, wherein is hydrogen, halo, or cyano.

12. R ２ These are hydrogen, halo, cyano, and C. １－６ Alkyl, C ３－１０ Cycloalkyl, -OR ａ , aryl, or heteroaryl, where R ａ C １－６ Alkyl or C ３－１０ It is a cycloalkyl group, and each alkyl, cycloalkyl, aryl, or heteroaryl group independently has 1 to 5 Z １ The compound according to any one of claims 1 to 10, which is optionally substituted with

13. R ３ These are hydrogen, halo, cyano, and C. １－６ Alkyl, or -OR ａ And here, R ａ C １－６ Alkyl or C ３－１０ It is a cycloalkyl group, and each alkyl or cycloalkyl group independently has 1 to 5 Z １ The compound according to any one of claims 1 to 10, which is optionally substituted with

14. R ４ is hydrogen, halo, cyano, or -OR ａ And here, R ａ C １－６ Alkyl or C ３－１０ It is a cycloalkyl group, and each alkyl or cycloalkyl group independently has 1 to 5 Z １ The compound according to any one of claims 1 to 10, which is optionally substituted with

15. R １ , R ２ , R ３ , and R ４ If present, each independently contains hydrogen, fluoro, chloro, bromo, iodine, cyano, methyl, ethyl, cyclopropyl, methoxy, ethoxy, and -OCF. ３ phenyl, benzyloxy, trifluoromethyl, difluoromethyl, -CF ２ CH ３ The compound according to any one of claims 1 to 10, wherein the compound is cyclopropoxy or pyrazole-1-yl.

16. The compound according to any one of claims 1 to 15, wherein n+m is 2 or 3.

17. R ６ａ and R ６ｂ Together with the atoms bonded to them, 1 to 5 Z １ C arbitrarily substituted with ３－６ A compound according to any one of claims 1 to 16, which forms a cycloalkyl group.

18. R ６ａ and one R ６ｃ Together with the atoms bonded to them, 1 to 5 Z １ The compound according to any one of claims 1 to 16, wherein it forms a 3- to 6-membered condensed cycloalkyl group to which the members are optionally substituted.

19. Z １ The compound according to claim 17 or claim 18, wherein the compound is fluoro.

20. R ６ａ is hydrogen, and R ６ｂ is, -CH ３ , -CF ３ , -OCF ３ , or C ３－１０ A compound according to any one of claims 1 to 16, wherein it is a cycloalkyl compound.

21. The aforementioned part 【Transformation 78】 teeth, 【Transformation 79】 The compound according to any one of claims 1 to 16.

22. R ５ The compound according to any one of claims 1 to 21, wherein is H.

23. R ７ The compound according to any one of claims 1 to 21, wherein is hydrogen.

24. R ８ C １ - ６ A compound according to any one of claims 1 to 23, wherein it is alkyl.

25. R ８ The compound according to any one of claims 1 to 24, wherein is methyl or ethyl.

26. Formula II: 【Chemistry 80】 The compound according to claim 1, or represented by a pharmaceutically acceptable salt thereof, a stereoisomer, a mixture of stereoisomers, a tautomer, or an isotopically enriched analog.

27. Formula IIA: 【Chemistry 81】 The compound according to claim 26, or represented by a pharmaceutically acceptable salt thereof, a stereoisomer, a mixture of stereoisomers, a tautomer, or an isotopically enriched analog.

28. Formula IIB: 【Chemistry 82】 The compound according to claim 26, or represented by a pharmaceutically acceptable salt thereof, a stereoisomer, a mixture of stereoisomers, a tautomer, or an isotopically enriched analog.

29. Formula III: 【Chemistry 83】 The compound according to claim 1, or represented by a pharmaceutically acceptable salt thereof, a stereoisomer, a mixture of stereoisomers, a tautomer, or an isotopically enriched analog.

30. Formula IIIA: 【Chemical 84】 The compound according to claim 29, or represented by a pharmaceutically acceptable salt thereof, a stereoisomer, a mixture of stereoisomers, a tautomer, or an isotopically enriched analog.

31. Formula IIIB: 【Chemical 85】 The compound according to claim 29, or represented by a pharmaceutically acceptable salt thereof, a stereoisomer, a mixture of stereoisomers, a tautomer, or an isotopically enriched analog.

32. A compound according to claim 1, selected from Table 1 or Table 2, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, tautomer, or isotopically enriched analog thereof.

33. A pharmaceutical composition comprising a compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a mixture of stereoisomers, and a pharmaceutically acceptable excipient.

34. A method for treating a disease or condition in which TMEM175 is at least partially involved, comprising administering an effective amount of the pharmaceutical composition according to claim 33 to a subject in need thereof.

35. The method according to claim 34, wherein the disease or condition is a neurodegenerative disease.

36. The method according to claim 35, wherein the neurodegenerative disease is Parkinson's disease or dementia.

37. The method according to claim 34, wherein the disease or condition is a central nervous system (CNS) disorder.

38. The method according to claim 35, wherein the CNS disorder is Alzheimer's disease or L-dopa-induced dyskinesia.

39. The method according to claim 34, wherein the disease or condition is a cancer selected from the group consisting of kidney cancer, breast cancer, prostate cancer, hematological cancer, papillary carcinoma, lung cancer, acute myeloid leukemia, and multiple myeloma.

40. The method according to claim 34, wherein the disease or condition is an inflammatory disease.

41. The method according to claim 40, wherein the inflammatory disease is Leigh's disease, Crohn's disease, inflammatory bowel disease, ulcerative colitis, amyotrophic lateral sclerosis, rheumatoid arthritis, or ankylosing spondylitis.

42. The method according to claim 34, wherein the disease or condition is a lysosomal storage disorder.

43. The method according to claim 42, wherein the lysosomal storage disorder is Niemann-Pick disease type C, Gaucher disease, Fabry disease, Krabbe disease, Pompe disease, Tay-Sachs disease, Batten disease, Sandhoff disease, Schindler disease types I and II, metachromatic leukodystrophy (MLD), mucopolysaccharidosis (MPS), or mucolipidosis types I, II / III and IV.

44. A method for improving cognitive memory, comprising administering a therapeutically effective amount of the pharmaceutical composition described in claim 33 to a subject in need thereof.

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