Compounds, compositions and methods

Abstract

The present disclosure relates generally to small molecule modulators of NLR family pyrin domain containing 3 (NLRP3) or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers or prodrugs thereof, methods for making them and intermediates thereof, and methods of use thereof.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 047,811, filed on 2 July 2020 under Section 119(e) of the U.S. Patent Act, which is incorporated herein by reference in its entirety.

[0002] This disclosure generally relates to small molecule modulators of NLR family pyrine domain 3 (NLRP3) and their use as therapeutic agents. [Background technology]

[0003] Inhibiting NLRP3 activation has been shown to produce potent therapeutic effects in animal models of inflammatory diseases. NLRP3 modulators, particularly inhibitors, have broad therapeutic potential in autoinflammatory and chronic inflammatory diseases where better treatment options are needed or where appropriate treatments are lacking. While therapies targeting NLRP3-dependent cytokines are already approved for therapeutic use, they have significant drawbacks compared to direct NLRP3 antagonists. There remains a strong demand for the discovery and clinical development of molecules that antagonize NLRP3. [Overview of the project] [Means for solving the problem]

[0004] Provided herein are compounds, pharmaceutically acceptable salts thereof, isotopic enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs that are useful, at least in part, for the treatment and / or prevention of diseases mediated by NLRP3. [Modes for carrying out the invention]

[0005] In some embodiments, the provided compounds modulate the activity of NLRP3. In some embodiments, the compounds inhibit the activation of NLRP3.

[0006] In another embodiment, the provided pharmaceutical composition comprises a compound described herein, or a pharmaceutically acceptable salt thereof, an isotope-enriched analog, a stereoisomer, a mixture of stereoisomers, or a prodrug, and a pharmaceutically acceptable carrier.

[0007] In another embodiment, the provided method is for treating a disease or condition mediated at least in part by NLRP3, and comprises administering an effective amount of a pharmaceutical composition comprising one of the compounds described herein, or a pharmaceutically acceptable salt thereof, an isotopic enriched analog, a stereoisomer, a mixture of stereoisomers, or a prodrug.

[0008] In another embodiment, the provided method is for treating a disease or condition mediated at least in part by TNF-α, comprising administering an effective amount of a pharmaceutical composition comprising one of the compounds described herein, or a pharmaceutically acceptable salt thereof, an isotopic enriched analog, a stereoisomer, a mixture of stereoisomers, or a prodrug. In some embodiments, the administration is made to a subject resistant to treatment with anti-TNF-α agents. In some embodiments, the disease is a disease or condition of the intestines. In some embodiments, the disease or condition is inflammatory bowel disease, Crohn's disease, or ulcerative colitis.

[0009] This disclosure also provides compositions comprising pharmaceutical compositions; kits comprising compounds, or pharmaceutically acceptable salts thereof, isotopic enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs; methods for the use (or administration) and manufacture of compounds, or pharmaceutically acceptable salts thereof, isotopic enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs, and intermediates thereof.

[0010] The disclosure further provides a compound, or a pharmaceutically acceptable salt thereof, isotope-enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, or composition thereof, for use in methods of treating diseases, disorders, or conditions mediated at least in part by NLRP3.

[0011] Furthermore, this disclosure provides the use of a compound, or a pharmaceutically acceptable salt thereof, isotope-enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, or a composition thereof, in the manufacture of a pharmaceutical product for the treatment of a disease, disorder, or condition mediated at least in part by NLRP3.

[0012] The descriptions herein illustrate exemplary embodiments of the technology. However, it should be noted that such descriptions are not intended to limit the scope of the disclosure and are provided solely for illustrative purposes.

[0013] 1.Definition When used herein, the following words, phrases, and symbols are intended to have the meanings set forth below in general, unless otherwise indicated in the context in which they are used.

[0014] A dash ("-") that is not 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 before or after chemical groups are for convenience, and chemical groups may be represented with or without dashes without losing their usual meaning. Dashed or dashed lines drawn through lines in the structure indicate specific bonding points of a group. Unless chemically or structurally necessary, the order of notation or naming of chemical groups does not indicate or imply directionality or stereochemistry.

[0015] "C u-v The prefix "C" indicates that the following group has u to v carbon atoms. For example, "C 1-6The term "alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

[0016] In this specification, references to values ​​or parameters marked with “approximately” include (and are described) embodiments relating to the value or parameter itself. In certain embodiments, the term “approximately” includes ±10% of the stated amount. In other embodiments, the term “approximately” includes ±5% of the stated amount. In certain other embodiments, the term “approximately” includes ±1% of the stated amount. Also, the term “about X” includes the description of “X.” Furthermore, the singular “a” and “the” include multiple references unless otherwise explicitly indicated by 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 known to those skilled in the art.

[0017] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl refers to a chain with 1 to 20 carbon atoms (i.e., C 1-20 Alkyl), 1 to 12 carbon atoms (i.e., C 1-12 Alkyl), 1 to 8 carbon atoms (i.e., C 1-8 Alkyl), 1 to 6 carbon atoms (i.e., C 1-6 Alkyl) or 1 to 4 carbon atoms (i.e., C 1-4It has an alkyl group. 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 represented by a chemical name or identified by a molecular formula, all positional isomers having that number of carbon atoms may be included. Thus, 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).

[0018] Certain alternative chemical names that are commonly used may also be used. For example, divalent groups such as a divalent "alkyl" group, a divalent "aryl" group, and a divalent heteroaryl group are also referred to as an "alkylene" group or an "alkylenyl" group (e.g., methylenyl, ethylenyl, propylenyl), an "arylene" group or an "arylenyl" group (e.g., phenylenyl or naphthylenyl, or in the case of heteroarylene, quinolinyl). Also, unless explicitly stated otherwise, in this specification, when a combination of groups is referred to as one part, for example, as arylalkyl or aralkyl, the last-mentioned group contains the atom to which that part is attached to the rest of the molecule.

[0019] "Alkenyl" contains at least one (e.g., 1 to 3 or one) carbon-carbon double bond and has 2 to 20 carbon atoms (i.e., C 2-20 alkenyl), 2 to 12 carbon atoms (i.e., C 2-12 alkenyl), 2 to 8 carbon atoms (i.e., C 2-8 alkenyl), 2 to 6 carbon atoms (i.e., C 2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C 2-4This refers to an alkyl group having an alkenyl group. Examples of alkenyl groups include ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0020] "Alkynnyl" contains at least one (e.g., 1-3 or 1) carbon-carbon triple bond and 2-20 carbon atoms (i.e., C 2-20 Alkynyl), 2 to 12 carbon atoms (i.e., C 2-12 Alkynyl), 2 to 8 carbon atoms (i.e., C 2-8 Alkynyl), 2-6 carbon atoms (i.e., C 2-6 Alkynyl) or 2-4 carbon atoms (i.e., C 2-4 The term "alkynyl" refers to an alkyl group having an alkynyl bond. The term "alkynyl" also includes groups having one triple bond and one double bond.

[0021] "Alkoxy" refers to the "alkyl-O-" group. 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.

[0022] "Alkoxyalkyl" refers to the "alkyl-O-alkyl" group.

[0023] "Alkylthio" refers to the "alkyl-S-" group. "Alkylsulfinyl" refers to the "alkyl-S(O)-" group. "Alkylsulfonyl" refers to the "alkyl-S(O)2-" group. "Alkylsulfonylalkyl" refers to the -alkyl-S(O)2-alkyl group.

[0024] "Ashiru" is -C(O)R y It refers to the base, and in the formula, R yis 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.

[0025] "Amide" is -C(O)NR y R z The group referred to is the "C-amide" group, and -NR y C(O)R z The term "N-amide" refers to both groups, and in the formula, R y and R z R is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein, or y and R z These together form a cycloalkyl or heterocycline, each of which may be optionally substituted as defined herein.

[0026] "Amino" is -NR y R z It refers to the base, and in the formula, R y and R z These are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0027] "Amidino" is -C(NR y )(NR z 2) refers to, in the formula, R y and R zThese are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0028] "Aryl" refers to an aromatic carbocyclic group having a monocyclic (e.g., monocyclic) or polycyclic (e.g., bicyclic or tricyclic) system including a condensed system. As used herein, aryl refers to a ring carbon atom (i.e., C) with 6 to 20 carbon atoms. 6-20 aryl), 6-12 carbocyclic atoms (i.e., C 6-12 aryl), or 6 to 10 carbon ring atoms (i.e., C 6-10 It has an aryl group. Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthuryl. However, aryl does not include or overlap with any heteroaryl as defined below. When one or more aryl groups are fused with a heteroaryl, the resulting ring system is a heteroaryl. When one or more aryl groups are fused with a heterocyclyl, the resulting ring system is a heterocyclyl. When one or more aryl groups are fused with a cycloalkyl, the resulting ring system is a cycloalkyl.

[0029] "Arylalkyl" or "aralkyl" refers to the "aryl-alkyl-" group.

[0030] "Carbamoyl" is -OC(O)NR y R z The group referred to is the "O-carbamoyl" group, and -NR y C(O)OR z The term "N-carbamoyl" refers to both groups, and in the formula, R y and R z These are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0031] "Carboxyl ester" or "ester" is -OC(O)R x and -C(O)OR x It refers to both, and in the formula, R x is an alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0032] "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.

[0033] "Cycloalkyl" refers to saturated or partially unsaturated cyclic alkyl groups having monocyclic or polycyclic structures including condensed, cross-linked, and spirocyclic systems. The term "cycloalkyl" refers to 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), 3 to 14 ring carbon atoms (i.e., C 3-12 Cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3-12 Cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3-10 Cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3-8 Cycloalkyl, or a ring of 3-6 carbon atoms (i.e., C 3-6They have cycloalkyl groups. Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, 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 condense to an aryl ring regardless of its bonding to the rest of the molecule. Moreover, cycloalkyl also includes "spirocycloalkyl" when there are two substitution positions on the same carbon atom, such as spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl.

[0034] "Cycloalkylalkyl" refers to the "cycloalkyl-alkyl-" group.

[0035] "Imino" is -C(NR y )R z It refers to the base, and in the formula, R y and R z Each of these is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

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

[0037] "Halogen" or "halo" refers to atoms belonging to Group VIIA of the periodic table, such as fluoro, chloro, bromo, or iodine.

[0038] A "haloalkyl" refers to an unbranched or branched alkyl group as defined above, in which one or more (e.g., 1-6 or 1-3) hydrogen atoms are replaced by halogens. For example, if a residue is substituted with more than one halogen, 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, where the halo groups may, but do not necessarily, be the same halogen. Examples of haloalkyls include, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl.

[0039] A "haloalkoxy" refers to an alkoxy group as defined above, in which one or more hydrogen atoms (for example, 1 to 6 or 1 to 3) are replaced by halogens.

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

[0041] "Hydroxyalkyl" refers to an alkyl group as defined above, in which one or more hydrogen atoms (for example, 1 to 6 or 1 to 3) are replaced by hydroxyl groups.

[0042] A "heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and any bonded hydrogen atoms), excluding any terminal carbon atoms, are independently replaced by the same or different heteroatomic groups, with the bonding sites to the rest of the molecule being via carbon atoms. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon atoms and heteroatoms. For example, one, two, or three carbon atoms may be independently replaced by the same or different heteroatomic groups. Heteroatomic groups include -NRy -, -O-, -S-, -S(O)-, -S(O)2-, etc. are included, but are not limited to these, and in the formula, 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, -CH2CH2SCH2CH2SCH3, 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, -CH2CH2NR y CH3, -CH2CH2NR y CH2 CH2NR y CH3 etc (in the formula, 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, or 2 to 4 heteroatoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0043] "Heteroaryl" refers to an aromatic group having a monocyclic, polycyclic, or multiple fused rings containing one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl refers to a ring with 1 to 20 ring carbon atoms (i.e., C 1-20 Heteroaryl), 3 to 12 ring carbon atoms (i.e., C 3-12 Heteroaryls), or 3 to 8 ring carbon atoms (i.e., C3-8 The heteroaryl comprises a heteroaryl and 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, oxygen, and sulfur. In certain cases, the heteroaryl comprises a 5 to 10-membered ring system, a 5 to 7-membered ring system, or a 5 to 6-membered ring system, each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom, independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, for example, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, 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, isoindo Examples of fused heteroaryl rings include lyl, isoquinolyl, 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, triazolyl, tetrazolyl, and triazinyl. Examples of condensed 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. Here, heteroaryls can be bonded via any of the rings in the condensed system. Any aromatic ring having one or more condensed 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 condensed rings). Heteroaryls do not encompass or overlap with the aryls defined above.

[0044] "Heteroarylalkyl" refers to the "heteroaryl-alkyl-" group.

[0045] 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 spiroheterocyclyl groups. Heterocyclyls can be monocyclic or polycyclic, where the polycyclic may be condensed, bridged, or spiro, and contain one or more (e.g., 1-3) 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 bonding (i.e., it can be bonded via carbon atoms or heteroatoms). Furthermore, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom that can condense into an aryl ring or heteroaryl ring regardless of bonding to the rest of the molecule. As used herein, a heterocyclyl is a ring containing 2 to 20 ring carbon atoms (i.e., C) 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, independently selected from nitrogen, sulfur, or oxygen. 2-20 Heterocyclines), 2 to 12 ring carbon atoms (i.e., C 2-12 Heterocycline), 2 to 10 ring carbon atoms (i.e., C 2-10 Heterocyclyl), 2-8 ring carbon atoms (i.e., C 2-8 Heterocyclines), 3 to 12 ring carbon atoms (i.e., C 3-12 Heterocyclyl), 3-8 ring carbon atoms (i.e., C 3-8 Heterocyclines), or ring carbon atoms with 3-6 atoms (i.e., C 3-6It has a heterocyclyl group. Examples of heterocyclyl groups include, for example, azetidinyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxynyl, benzopyranonyl, benzofuranonyl, dioxalanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolidinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydro Examples include soindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxylanil, oxetanil, phenothiazinyl, phenoxadinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tetrahydropyranyl, trithianil, tetrahydroquinolinyl, thiophenyl (i.e., thienyl), thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. The term "heterocyclyl" also includes "spiroheterocyclyls," which have two substitution positions on the same carbon atom. Examples of spiroheterocyclyl rings include 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. Here, the heterocyclyl can be linked via any of the rings in the condensation system.

[0046] "Heterocyclylalkyl" refers to the "heterocyclyl-alkyl-" group.

[0047] "Oxime" is -CR y (=NOH) refers to the group, and in the formula, Ry is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0048] "Sulfonyl" refers to a -S(O)2R y group, where 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 are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0049] "Sulfinyl" refers to a -S(O)R y group, where 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 are methylsulfinyl, ethylsulfinyl, phenylsulfinyl, and toluenesulfinyl.

[0050] "Sulfonamide" refers to a -SO2NR y R z group and a -NR y SO2R z group, where 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.

[0051] "Optional" or "by optional choice" means that the event or state described below 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 occur. The term "substituted by optional choice" means that any one or more hydrogen atoms (e.g., 1-5 or 1-3) on the specified atom or group may or may not be replaced by non-hydrogen parts.

[0052] As used herein, the term "substituted" means that at least one (e.g., 1-5 or 1-3) hydrogen atoms are substituted, but is not limited to alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amide, amino, amidino, aryl, aralkyl, azide, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanadino, 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(in the formula, each R y This means any of the above groups (i.e., alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heteroaryl, and / or heteroalkyl) that are independently replaced by a bond to a non-hydrogen atom such as hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, and / or heteroalkyl.

[0053] In certain embodiments, "substituted" means that one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are independently 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, and includes any of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups. In certain embodiments, "substituted" also means that one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are -C(O)R g 、 -C(O)OR g 、 -C(O)NR g R h-CH2SO2R g , or -CH2SO2NR g R h It means any of the above bases that are replaced by R. g and R h These are the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and / or heteroarylalkyl. In certain embodiments, "substituted" also means that one or more (e.g., 1-5 or 1-3) 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 Two of these groups, together with the atom to which they are bonded, form an oxo, halo, or optionally substituted heterocyclyl ring with an alkyl group optionally substituted with an oxo, halo, amino, hydroxy, or alkoxy group.

[0054] Polymers or similar infinite structures achieved by defining substituents with an unlimited number of further substituents (e.g., a substituted aryl group having a substituted alkyl group, the substituted alkyl group itself being substituted with a substituted aryl group, and the substituted aryl group being further substituted with a substituted heteroalkyl group) are not intended to be included herein. Unless otherwise specified, the maximum number of substitutions in a series of compounds described herein is three. For example, a series of substitutions of an aryl group substituted with two other substituted aryl groups is limited to ((substituted aryl)substituted aryl)substituted aryl. Similarly, the above definitions are not intended to include 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.

[0055] In certain embodiments, as used herein, the phrase "one or more" refers to 1 to 5. In certain embodiments, as used herein, the phrase "one or more" refers to 1 to 3.

[0056] Any compound or structure given herein is also intended to represent both an unlabeled and an isotope-labeled form of that compound. These forms of a compound may also be referred to as “isotope-enriched analogs.” An isotope-labeled compound has the structure described herein except that one or more atoms are replaced by atoms having the mass or mass number of a selected atom. Examples of isotopes that can be incorporated into the compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, 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,32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I is one example. The various isotope-labeled compounds of this disclosure include, 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 radiation therapy for patients.

[0057] The term “isotope-enriched analog” includes “deuterated analogs” of the compounds described herein, in which one or more hydrogen atoms, such as hydrogen on a carbon atom, are replaced by deuterium. Such compounds are useful for extending the half-life of any compound because they increase metabolic tolerance 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 employing starting materials in which one or more hydrogen atoms are replaced by deuterium.

[0058] The deuterium-labeled or substituted therapeutic compounds of this disclosure may have improved DMPK (drug metabolism and pharmacokinetic) properties related to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes such as deuterium may result in several therapeutic benefits, such as improved metabolic stability, e.g., increased in vivo half-life, reduced dose requirement, and / or improved therapeutic index. For PET or SPECT or other imaging studies, 18 F, 3 H, 1114C-labeled compounds may be useful. The isotope-labeled compounds and their prodrugs of this disclosure can generally be prepared by performing the procedures disclosed in the schemes or examples and preparation methods described below, and by replacing the non-isotopically labeled reagents with readily available isotopely labeled reagents. In this context, deuterium is understood to be a substituent of the compounds described herein.

[0059] The concentration of such heavy isotopes, particularly deuterium, can be defined by the isotopic enrichment factor. In the compounds of this disclosure, any atom for which a specific isotope is not specifically designated is meant to represent any stable isotope of that atom. Unless otherwise indicated, where a position is specifically designated as "H" or "hydrogen," it is understood that the position has hydrogen in its isotopic composition at its natural abundance. Thus, in the compounds of this disclosure, any atom specifically designated as deuterium (D) is meant to represent deuterium.

[0060] In many cases, the compounds of this disclosure can form acidic salts and / or basic salts due to the presence of an amino group and / or a carboxyl group or a similar group.

[0061] Also provided herein are pharmaceutically acceptable salts, isotopic enriched analogs, deuterated analogs, stereoisomers, mixtures of stereoisomers, and prodrugs of the compounds described herein. "pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials useful for preparing pharmaceutical compositions suitable for veterinary use in animals or humans.

[0062] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effects and properties of the given compound and is not biologically or otherwise undesirable. "pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, 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 basifying a solution of the acidic salt. 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 that can be used to prepare pharmaceutically acceptable, non-toxic addition salts. pharmaceutically acceptable acid addition salts can be prepared from inorganic or organic acids. Salts derived from inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Salts derived from organic acids include, for example, 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. Salts derived from inorganic bases include, but are not limited to, salts of sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium.Salts derived from organic bases include 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)), di(substituted alkenyl)amines (i.e., HN(substituted alkenyl)2), and tri(substituted This includes, but is not limited to, salts of primary, secondary, and tertiary amines such as lukenylamines (i.e., N(substituted alkenyl)3, mono, di, or tricycloalkylamines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono, di, or triarylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), or mixed amines. Specific examples of preferred amines, though not exhaustive, include isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylamineethanol, piperazine, piperidine, morpholine, and N-ethylpiperidine.

[0063] Some compounds exist as tautomers. Tautomers exist in equilibrium with each other. For example, an amide-containing compound may exist in equilibrium with an imido acid tautomer. Regardless of which tautomer is shown, and regardless of the nature of the equilibrium between the tautomers, it is understood by those skilled in the art that a compound may contain both an amide tautomer and an imido acid tautomer. Therefore, it is understood that an amide-containing compound may contain its imido acid tautomer. Similarly, it is understood that an imido acid-containing compound may contain its amide tautomer.

[0064] The compounds of this disclosure, or their pharmaceutically acceptable salts, contain a chiral center and thus may give rise to enantiomers, diastereomers, and other stereoisomers that can even be defined from the viewpoint of absolute stereochemistry as (R)- or (S)-, or in the case of amino acids, (D)- or (L)-. This disclosure means to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or they can be resolved using prior art, e.g., chromatography and / or fractional crystallization. Prior art for preparing / isolating individual enantiomers includes chiral synthesis from suitable optically pure precursors, or resolution of racemics (or racemics of salts or derivatives) using, for example, chiral high-performance 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.

[0065] A "stereoisomer" refers to a compound that consists of the same atoms bonded together by the same bonds but has different three-dimensional structures that are not interchangeable. This disclosure intends to include various stereoisomers or mixtures thereof and includes "enantiomers," which refer to two stereoisomers that are mirror images of each other and whose molecules cannot be superimposed.

[0066] A "diastereomer" is a stereoisomer that has at least two chiral atoms but is not a mirror image of one another.

[0067] The relative centers of the compounds described herein are graphically represented using a "thick bond" style (thick or parallel lines), and absolute stereochemistry is represented using wedge-shaped bonds (thick or parallel lines).

[0068] "Prodrug" means any compound that, when administered to a mammalian subject, releases in vivo an active parent drug in the structure described herein. Prodrugs of the compounds described herein are prepared by modifying a functional group present in the compounds described herein, such modification is capable of being cleaved in vivo to release the parent compound. Prodrugs can be prepared by modifying a functional group present in the compound, either by conventional manipulation or in vivo, such that the modification is cleaved to form the parent compound. Prodrugs include compounds described herein in which a hydroxyl group, amino group, carboxyl group, or sulfhydryl group in the compounds described herein is bonded to any group that can be cleaved in vivo to regenerate a free hydroxyl group, amino group, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, esters of the hydroxyl functional group of the compounds described herein (e.g., acetic acid, formic acid, and benzoic acid derivatives), amides, guanidines, and carbamates (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 ACSSymposium 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.

[0069] 2.Compound Provided herein are compounds that are modulators of NLRP3. In certain embodiments, the compound of formula I is provided: [ka] or a pharmaceutically acceptable salt thereof, isotope-enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, in which, A 1 , A 2 , A 3 , A 4 , and A 5 Each of these is independently N or CR 1 And, X is N or CR 5 And, Y 1 and Y 2 Each of them is independently either O or S, Each R 1 These are independently hydrogen, halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2, -OR 11 , -C(O)R 11 , -C(O)OR 11 , -S(O) 0-2 R 11 , -NR 11 S(O) 0-2 -R 11 , -S(O) 0-2 N(R 11 )2, -NR 11 S(O) 0-2 N(R 11 )2, -NR 11 C(O)N(R 11 )2, -C(O)N(R 11 )2, -NR 11 C(O)R 11 ,-OC(O)N(R 11 )2, or -NR 11 C(O)OR 11 And here, each C 1-6 Alkyl, C 2-6 Alkenil, C2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl compounds are independently classified into 1 to 5 Z groups. 1 Replaced by arbitrary selection, any two adjacent R 1 The group is bonded to C 3-10 A cycloalkyl ring, a heterocyclyl ring, an aryl ring, or a heteroaryl ring can be formed, where C 3-10 A cycloalkyl ring, heterocyclyl ring, aryl ring, or heteroaryl ring can independently have 1 to 5 Z 1 This may be further replaced by optional selection. R 2 -C(R 6 )2R 10 , -OR 9 , -N(R 6 )(R 9 ), -SR 9 ,-S(O)R 9 -S(O)2R 9 ,-OC(O)N(R 6 )(R 9 ), -NR 6 C(O)OR 9 , -NR 6 C(O)R 9 , C 3-10 A cycloalkyl, heterocyclyl, or halo, where C 3-10 Cycloalkyl or heterocyclyl molecules independently have 1 to 5 Z 1 Replaced by optional selection, R 3 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl, where C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl compounds can independently have 1 to 5 Z 1 Replaced by optional selection, R 4 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl, where C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl compounds can independently have 1 to 5 Z 1 Replaced by optional selection, Or, R 3 and R 4 These combine to form a heterocyclyl ring or heteroaryl ring, where the heterocyclyl ring or heteroaryl ring independently comprises 1 to 5 Z 1 This may be further replaced by optional selection. R 5 is hydrogen, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 It is a cycloalkyl or heterocyclyl, where C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, or heterocyclyl, independently has 1 to 5 Z 1Replaced by optional selection, Each R 6 These are independently hydrogen, halo, cyano, hydroxy, and 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 2-6 Heteroalkyl, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl, R 7 These are hydrogen, halo, cyano, hydroxy, and 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 2-6 Heteroalkyl, C 3-10 It is a cycloalkyl or heterocycline. R 8 These are hydrogen, halo, cyano, hydroxy, and 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 2-6 Heteroalkyl, C 3-10 It is a cycloalkyl or heterocycline. Or, R 7 and R 8 They combine to form C 3-10 It forms a cycloalkyl ring or a heterocyclyl ring, where C 3-10 A cycloalkyl ring or heterocyclyl ring can independently contain 1 to 5 Z 1a This may be further replaced by optional selection. R 9 C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C2-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl, where C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl compounds can independently have 1 to 5 Z 1 Replaced by optional selection, or R 10 is hydrogen, halo, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl, where C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl compounds can independently have 1 to 5 Z 1 Replaced by optional selection, each Z 1 These are independently halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2, -OR 11 , -C(O)R 11, -C(O)OR 11 , -S(O) 0-2 R 11 , -NR 11 S(O) 0-2 -R 11 , -S(O) 0-2 N(R 11 )2, -NR 11 S(O) 0-2 N(R 11 )2, -NR 11 C(O)N(R 11 )2, -C(O)N(R 11 )2, -NR 11 C(O)R 11 ,-OC(O)N(R 11 )2, or -NR 11 C(O)OR 11 And here, each C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl compounds are independently classified into 1 to 5 Z groups. 1a Replaced by optional selection, Each R 11 These are, independently, hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-10 A cycloalkyl, heterocyclyl, aryl, or heteroaryl, where R 11 Each C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl compounds are independently classified into 1 to 5 Z groups. 1a Replaced by optional selection, each Z 1aThese are independently hydroxy, halo, cyano, hydroxy, -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 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 12 )2, -OR 12 , -C(O)R 12 , -C(O)OR 12 , -S(O) 0-2 R 12 , -NR 12 S(O) 0-2 -R 12 , -S(O) 0-2 N(R 12 )2, -NR 12 S(O) 0-2 N(R 12 )2, -NR 12 C(O)N(R 12 )2, -C(O)N(R 12 )2, -NR 12 C(O)R 12 ,-OC(O)N(R 12 )2, or -NR 12 C(O)OR 12 And here, each 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 Cycloalkyl, heterocyclyl, aryl, or heteroaryl compounds are independently classified into 1 to 5 Z groups. 1b Replaced by optional selection, Each R 12 These are, independently, hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-10A cycloalkyl, heterocyclyl, aryl, or heteroaryl, where R 12 Each C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl compounds are independently classified into 1 to 5 Z groups. 1b Replaced by optional selection, each Z 1b These are independently halo, cyano, hydroxy, -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 2-6 Heteroalkyl, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -LC 1-6 Alkyl, -LC 2-6 Alkenyl, -LC 2-6 Alkinyl, -LC 1-6 Haloalkyl, -LC 3-10 It is a cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl, Each L is independently -O-, -NH-, -S-, -S(O)-, -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 1-6Haloalkyl)-,-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 each C of L 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 Cycloalkyl, heterocyclyl, aryl, and heteroaryl compounds are independently 1 to 5 hydroxy, halo, cyano, hydroxy, -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 is optionally substituted with a cycloalkyl, heterocyclyl, aryl, or heteroaryl compound.

[0070] In certain embodiments, the compound is not N-(4-bromophenyl)-2-[3-methyl-6-oxo-4-phenylpyridazin-1(6H)-yl]acetamide, N-(4-bromophenyl)-5-[(3-methoxyphenyl)methyl]-3-methyl-6-oxo-4-phenyl-1(6H)-pyridazinacetamide, 4-[[2-[4-(2-acetyl-5-chlorophenyl)-3-methoxy-6-oxo-1(6H)-pyridazinyl]-4-methyl-1-oxopentyl]amino]benzoic acid 1,1-dimethylethyl ester, or 4-[[2-[4-(2-acetyl-5-chlorophenyl)-3-methoxy-6-oxo-1(6H)-pyridazinyl]-4-methyl-1-oxopentyl]amino]benzoic acid.

[0071] In a particular embodiment, Y1 In a particular embodiment, Y 1 S is.

[0072] In a particular embodiment, Y 2 In a particular embodiment, Y 2 S is.

[0073] In a particular embodiment, Y 1 is O, Y 2 is O. In a particular embodiment, Y 1 is O, Y 2 S is.

[0074] In a particular embodiment, Y 1 S is Y 2 is O. In a particular embodiment, Y 1 S is Y 2 S is.

[0075] In a particular embodiment, the compound of formula IA is provided: [ka] or a pharmaceutically acceptable salt thereof, isotope-enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, in which, A 1 , A 2 , A 3 , A 4 , and A 5 Each of these is independently N or CR 1 And, X is N or CR 5 And, Each R 1 These are independently hydrogen, halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-10Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2, -OR 11 , -C(O)R 11 , -C(O)OR 11 , -S(O) 0-2 R 11 , -NR 11 S(O) 0-2 -R 11 , -S(O) 0-2 N(R 11 )2, -NR 11 S(O) 0-2 N(R 11 )2, -NR 11 C(O)N(R 11 )2, -C(O)N(R 11 )2, -NR 11 C(O)R 11 ,-OC(O)N(R 11 )2, or -NR 11 C(O)OR 11 And here, any two adjacent R 1 The group is bonded to C 3-10 It can form a cycloalkyl ring, a heterocyclyl ring, an aryl ring, or a heteroaryl ring. R 2 -C(R 6 )2R 10 , -OR 9 , -N(R 6 )(R 9 ), -SR 9 ,-S(O)R 9 -S(O)2R 9 ,-OC(O)N(R 6 )(R 9 ), -NR 6 C(O)OR 9 , -NR 6 C(O)R 9 , C 3-10 It is a cycloalkyl, heterocyclyl, or halo, R 3 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C2-6 Heteroalkyl, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl compound. R 4 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl compound. Or, R 3 and R 4 These combine to form a heterocyclyl ring or heteroaryl ring, R 5 is hydrogen, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6ハロ Alkoxy, C 3-10 It is a cycloalkyl or heterocyclyl, Each R 6 These are independently hydrogen, halo, cyano, hydroxy, and 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 2-6 Heteroalkyl, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl, R 7 These are hydrogen, halo, cyano, hydroxy, and 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 2-6 Heteroalkyl, C 3-10 It is a cycloalkyl or heterocycline. R 8These are hydrogen, halo, cyano, hydroxy, and 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 2-6 Heteroalkyl, C 3-10 It is a cycloalkyl or heterocycline. Or, R 7 and R 8 They combine to form C 3-10 Forming a cycloalkyl ring or a heterocyclyl ring, R 9 C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl compound, or R 10 is hydrogen, halo, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl compound. Each R 11 These are, independently, hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl, Here, each alkyl substituent listed above—alkenyl, alkynyl, haloalkyl, heteroalkyl, alkoxy, haloalkoxycycloalkyl, heterocyclyl, aryl, and heteroaryl—can be substituted independently and of any choice.

[0076] In a particular embodiment, the compound of formula IA is provided: [ka] or a pharmaceutically acceptable salt thereof, isotope-enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, in which, A 1 , A 2 , A 3 , A 4 , and A 5 Each of these is independently N or CR 1 And, X is N or CR 5 And, Each R 1 These are independently hydrogen, halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2, -OR 11 , -C(O)R 11 , -C(O)OR 11 , -S(O) 0-2 R 11 , -NR 11 S(O) 0-2 -R 11 , -S(O) 0-2 N(R 11 )2, -NR 11 S(O) 0-2 N(R 11 )2, -NR 11 C(O)N(R 11 )2, -C(O)N(R 11 )2, -NR11 C(O)R 11 ,-OC(O)N(R 11 )2, or -NR 11 C(O)OR 11 And here, each C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl compounds are independently classified into 1 to 5 Z groups. 1 Replaced by arbitrary selection, any two adjacent R 1 The group is bonded to C 3-10 A cycloalkyl ring, a heterocyclyl ring, an aryl ring, or a heteroaryl ring can be formed, where C 3-10 A cycloalkyl ring, heterocyclyl ring, aryl ring, or heteroaryl ring can independently have 1 to 5 Z 1 This may be further replaced by optional selection. R 2 -C(R 6 )2R 10 , -OR 9 , -N(R 6 )(R 9 ), -SR 9 ,-S(O)R 9 -S(O)2R 9 ,-OC(O)N(R 6 )(R 9 ), -NR 6 C(O)OR 9 , -NR 6 C(O)R 9 , C 3-10 A cycloalkyl, heterocyclyl, or halo, where C 3-10 Cycloalkyl or heterocyclyl molecules independently have 1 to 5 Z 1 Replaced by optional selection, R 3 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 1-6Alkoxy, C 2-6 Heteroalkyl, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl, where C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl compounds can independently have 1 to 5 Z 1 Replaced by optional selection, R 4 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl, where C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl compounds can independently have 1 to 5 Z 1 Replaced by optional selection, Or, R 3 and R 4 These combine to form a heterocyclyl ring or heteroaryl ring, where the heterocyclyl ring or heteroaryl ring independently comprises 1 to 5 Z 1 This may be further replaced by optional selection. R 5 is hydrogen, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10It is a cycloalkyl or heterocyclyl, where C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, or heterocyclyl, independently has 1 to 5 Z 1 Replaced by optional selection, Each R 6 These are independently hydrogen, halo, cyano, hydroxy, and 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 2-6 Heteroalkyl, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl, R 7 These are hydrogen, halo, cyano, hydroxy, and 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 2-6 Heteroalkyl, C 3-10 It is a cycloalkyl or heterocycline. R 8 These are hydrogen, halo, cyano, hydroxy, and 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 2-6 Heteroalkyl, C 3-10 It is a cycloalkyl or heterocycline. Or, R 7 and R 8 They combine to form C 3-10 It forms a cycloalkyl ring or a heterocyclyl ring, where C 3-10A cycloalkyl ring or heterocyclyl ring can independently contain 1 to 5 Z 1a This may be further replaced by optional selection. R 9 C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl, where C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl compounds can independently have 1 to 5 Z 1 Replaced by optional selection, or R 10 is hydrogen, halo, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl, where C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl compounds can independently have 1 to 5 Z 1 Replaced by optional selection, each Z 1 These are independently halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2, -OR 11 , -C(O)R 11 , -C(O)OR 11 , -S(O) 0-2 R 11 , -NR 11 S(O) 0-2 -R 11 , -S(O) 0-2 N(R 11 )2, -NR 11 S(O) 0-2 N(R 11 )2, -NR 11 C(O)N(R 11 )2, -C(O)N(R 11 )2, -NR 11 C(O)R 11 ,-OC(O)N(R 11 )2, or -NR 11 C(O)OR 11 And here, each C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl compounds are independently classified into 1 to 5 Z groups. 1a Replaced by optional selection, Each R 11 These are, independently, hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-10 A cycloalkyl, heterocyclyl, aryl, or heteroaryl, where R 11 Each C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl compounds are independently classified into 1 to 5 Z groups. 1a Replaced by optional selection, each Z 1a These are independently hydroxy, halo, cyano, hydroxy, -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 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 12 )2, -OR 12 , -C(O)R 12 , -C(O)OR 12 , -S(O) 0-2 R 12 , -NR 12 S(O) 0-2 -R 12 , -S(O) 0-2 N(R 12 )2, -NR 12 S(O) 0-2 N(R 12 )2, -NR 12 C(O)N(R 12 )2, -C(O)N(R 12 )2, -NR 12 C(O)R 12 ,-OC(O)N(R 12 )2, or -NR 12 C(O)OR 12 And here, each 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 Cycloalkyl, heterocyclyl, aryl, or heteroaryl compounds are independently classified into 1 to 5 Z groups. 1b Replaced by optional selection, Each R12 is, independently, hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 2-6 heteroalkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each C of R 12 alkyl, C 1-6 alkenyl, C 2-6 alkynyl, C 2-6 haloalkyl, C 1-6 heteroalkyl, C 2-6 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with 1 to 5 Z 3-10 and each Z 1b is independently halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C alkyl, C 1b alkenyl, C 1-6 alkynyl, C 2-6 haloalkyl, C 2-6 alkoxy, C 1-6 heteroalkyl, C 1-6 haloalkoxy, C 2-6 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C 1-6 alkyl, -L-C 3-10 alkenyl, -L-C 1-6 alkynyl, -L-C 2-6 haloalkyl, -L-C 2-6 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl, and 1-6 each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C​​​​​​​​​​​​​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 each C of L 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 Cycloalkyl, heterocyclyl, aryl, and heteroaryl compounds are independently 1 to 5 hydroxy, halo, cyano, hydroxy, -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 is optionally substituted with a cycloalkyl, heterocyclyl, aryl, or heteroaryl compound.

[0077] In certain embodiments, the compound is not N-(4-bromophenyl)-2-[3-methyl-6-oxo-4-phenylpyridazine-1(6H)-yl]acetamide: [ka]

[0078] In certain embodiments, the compound is not N-(4-bromophenyl)-5-[(3-methoxyphenyl)methyl]-3-methyl-6-oxo-4-phenyl-1(6H)-pyridazineacetamide: [ka]

[0079] In certain embodiments, the compound is not 4-[[2-[4-(2-acetyl-5-chlorophenyl)-3-methoxy-6-oxo-1(6H)-pyridazinyl]-4-methyl-1-oxopentyl]amino]-benzoate 1,1-dimethylethyl ester: [ka]

[0080] In certain embodiments, the compound is not 4-[[2-[4-(2-acetyl-5-chlorophenyl)-3-methoxy-6-oxo-1(6H)-pyridazinyl]-4-methyl-1-oxopentyl]amino]benzoic acid: [ka]

[0081] In a particular embodiment, A 1 , A 2 , A 3 , A 4 , and A 5 Each of them independently, CR 1 That is the case.

[0082] In a particular embodiment, A 1 , A 2 , A 3 , A 4 , and A 5 One of them is N, and the remaining A 1 , A 2 , A 3 , A 4 , and A 5 CR is independent. 1is. In certain embodiments, A 1 is N, and the remaining A 2 A 3 A 4 and A 5 are independently CR 1 In certain embodiments, A 2 is N, and the remaining A 1 A 3 A 4 and A 5 are independently CR 1 In certain embodiments, A 3 is N, and the remaining A 1 A 2 A 4 and A 5 are independently CR 1 is.

[0083] In certain embodiments, two of A 1 A 2 A 3 A<​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​These are independently hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, or C 3-10 It is a cycloalkyl, where C 3-10 Cycloalkyl groups independently have 1 to 5 Z 1 It may be further replaced by any choice, or any two adjacent R 1 The groups can bond to form an aryl ring or a heteroaryl ring. In a particular embodiment, each R 1 These are independently hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, or C 3-10 It is a cycloalkyl, where C 3-10 The cycloalkyl group may be independently and optionally further substituted with 1 to 5 halos, or with any two adjacent R groups. 1 The groups can bond to form an aryl ring or a heteroaryl ring. In a particular embodiment, each R 1 These are independently hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, or C 1-6 It is a haloalkyl group.

[0088] In a particular embodiment, each R 1 R is independently hydrogen, fluoro, chloro, cyano, -CH3, -OCH3, -OCH2CH3, -CF3, cyclopropyl, 2,2-difluorocyclopropyl, or cyclobutyl. In certain embodiments, each R 1 These are independently hydrogen, fluoro, chloro, cyano, -CH3, -OCH3, or -CF3.

[0089] In a particular embodiment, each R 1 is independently hydrogen, or any two adjacent R 1 The groups can bond to form an aryl ring or a heteroaryl ring. In a particular embodiment, each R1 is independently hydrogen, or any two adjacent R 1 The groups can bond to form an aryl ring. In a particular embodiment, each R 1 is independently hydrogen, or any two adjacent R 1 The groups can bond to form a phenyl ring. In a particular embodiment, each R 1 is independently hydrogen, or any two adjacent R 1 The groups can bond to form a heteroaryl ring. In a particular embodiment, each R 1 is independently hydrogen, or any two adjacent R 1 The groups can bond to form a pyridyl ring.

[0090] In a particular embodiment, at least one R 1 It is something other than hydrogen.

[0091] In a particular embodiment, A 1 , A 2 , A 3 , A 4 , and A 5 Each of them independently, CR 1 And here, at least one R 1 is something other than hydrogen. In a particular embodiment, A 1 , A 2 , A 3 , A 4 , and A 5 Each of them independently, CR 1 And here, at least two R 1 is something other than hydrogen. In a particular embodiment, A 1 , A 2 , A 3 , A 4 , and A 5 Each of them independently, CR 1 And at least two R 1 It is, independently, a halo.

[0092] In a particular embodiment, R 2 -C(R 6 )2R 10 , -OR 9 , C 3-10 It is a cycloalkyl or halo, where C 3-10 Cycloalkyl groups independently have 1 to 5 Z 1 It is optionally replaced by R. In a particular embodiment, 2 -C(R 6 )2R 10 , -OR 9 , C 3-10 It is a cycloalkyl or halo, where C 3-10 The cycloalkyl group is independently and optionally substituted with 1 to 5 halos. In a particular embodiment, R 2 -C(R 6 )2R 10 , -OR 9 , C 3-10 It is a cycloalkyl or halo, where C 3-10 The cycloalkyl group is independently and optionally substituted with 1 to 5 halos, and at least one R 6 is hydrogen, and R 10 Hello, C 1-6 Alkyl, or C 1-6 It is a haloalkyl, R 9 C 1-6 It is alkyl.

[0093] In a particular embodiment, R 2 -C(R 6 )2R 10 OR 9 In a particular embodiment, R 2 -C(R 6 )2R 10 In a particular embodiment, R 2 is -OR 9 In a particular embodiment, R 2 C 3-10 It is a cycloalkyl, where C 3-10The cycloalkyl group is independently and optionally substituted with 1 to 5 halos. In a particular embodiment, R 2 is a halo. In a particular embodiment, R 2 It is isopropyl.

[0094] In a particular embodiment, R 3 C 3-10 It is a cycloalkyl, heterocyclyl, or heteroaryl, where C 3-10 Cycloalkyl, heterocyclyl, or heteroaryl compounds can independently have 1 to 5 Z values. 1 It is replaced by an optional choice.

[0095] In a particular embodiment, R 3 C 3-10 It is a cycloalkyl, heterocyclyl, or heteroaryl, where C 3-10 Cycloalkyl, heterocyclyl, or heteroaryl compounds independently contain 1 to 5 halo, hydroxy, C 1-6 Alkyl, or C 3-10 It is optionally substituted with a cycloalkyl group.

[0096] In a particular embodiment, R 3 is 5-fluoropyrimidine-4-yl, 1-cyclobutylpiperidine-3-yl, 1-ethylpiperidine-3-yl, 1-cyclopropylpiperidine-3-yl, 3-fluoropyridine-2-yl, 5-fluoropyrimidine-2-yl, 3,5-difluoropyridine-2-yl, or 3-hydroxy-3-methylcyclobutyl. In certain embodiments, R 3 These are 5-fluoropyrimidine-4-yl, 1-cyclobutylpiperidine-3-yl, or 3-hydroxy-3-methylcyclobutyl.

[0097] In a particular embodiment, R 4 It is hydrogen.

[0098] In a particular embodiment, R 2 -C(R6 )2R 10 And at least one R 6 is hydrogen. In a particular embodiment, R 2 -C(R 6 )2R 10 And one R 6 It is hydrogen.

[0099] In a particular embodiment, R 2 -C(R 6 )2R 10 And R 10 Hello, C 1-6 Alkyl, or C 1-6 It is a haloalkyl. In a particular embodiment, R 2 -C(R 6 )2R 10 And R 10 C 1-6 It is alkyl. In a particular embodiment, R 2 -C(R 6 )2R 10 And at least one R 6 is hydrogen, and R 10 C 1-6 It is alkyl.

[0100] In a particular embodiment, R 2 is -OR 9 And R 9 C 1-6 It is alkyl. In a particular embodiment, R 2 is -OR 9 And R 9 C 1-2 It is alkyl.

[0101] In a particular embodiment, R 7 and R 8 It combines to form C 3-10 Forms a cycloalkyl group. In a particular embodiment, R 7 is hydrogen. In a particular embodiment, R 8 is hydrogen. In a particular embodiment, R 7 and R8 is either hydrogen or R 7 and R 8 They combine to form C 3-10 It forms a cycloalkyl group.

[0102] In a particular embodiment, each Z 1 These are independently halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2, -OR 11 , -C(O)R 11 , -C(O)OR 11 , -S(O) 0-2 R 11 , -NR 11 S(O) 0-2 -R 11 , -S(O) 0-2 N(R 11 )2, -NR 11 S(O) 0-2 N(R 11 )2, -NR 11 C(O)N(R 11 )2, -C(O)N(R 11 )2, -NR 11 C(O)R 11 ,-OC(O)N(R 11 )2, or -NR 11 C(O)OR 11 That is the case.

[0103] In a particular embodiment, each Z 1 These are independently halo, cyano, hydroxy, and C. 1-6 Alkyl, or C 3-10 It is a cycloalkyl group.

[0104] In a particular embodiment, each R 11 These are, independently, hydrogen and C 1-6 Alkyl, C 2-6Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl compound.

[0105] In a particular embodiment, each R 11 These are, independently, hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-10 They are cycloalkyl, heterocyclyl, aryl, or heteroaryl. In a particular embodiment, each R 11 These are, independently, hydrogen or C 1-6 It is alkyl. In a particular embodiment, each R 11 It is hydrogen.

[0106] In a particular embodiment, each R 12 These are, independently, hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl compound.

[0107] In a particular embodiment, each R 12 These are, independently, hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-10 They are cycloalkyl, heterocyclyl, aryl, or heteroaryl. In a particular embodiment, each R 12 These are, independently, hydrogen or C 1-6 It is alkyl. In a particular embodiment, each R 12 It is hydrogen.

[0108] In a particular embodiment, A 1 , A2 , A 3 , A 4 , and A 5 Each of them independently, CR 1 And each R 1 These are independently hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, or C 3-10 It is either a cycloalkyl group or any two adjacent R groups. 1 The groups bond to form an aryl ring or heteroaryl ring, and X is CR 5 And R 2 -C(R 6 )2R 10 , -OR 9 , C 3-10 It is a cycloalkyl or halo, where C 3-10 Cycloalkyl groups independently have 1 to 5 Z 1 Replaced by optional selection in R 3 C 3-10 It is a cycloalkyl, heterocyclyl, or heteroaryl, where C 3-10 Cycloalkyl, heterocyclyl, or heteroaryl compounds independently contain 1 to 5 halo, hydroxy, C 1-6 Alkyl, or C 3-10 Optionally substituted with a cycloalkyl group, R 4 is hydrogen, and R 5 is hydrogen, C 1-6 Alkyl, or C 1-6 It is a haloalkyl and has at least one R 6 is hydrogen, and R 7 and R 8 is either hydrogen or R 7 and R 8 They combine to form C 3-10 Forming a cycloalkyl group, R 9 C 1-6 It is alkyl, R 10 Hello, C 1-6 Alkyl, or C 1-6 It is a haloalkyl group.

[0109] In a particular embodiment, A 1 , A 2 , A 3 , A 4 , and A 5 One of them is N, and the remaining A 1 , A 2 , A 3 , A 4 , and A 5 CR is independent. 1 And each R 1 These are independently hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, or C 3-10 It is either a cycloalkyl group or any two adjacent R groups. 1 The groups bond to form an aryl ring or heteroaryl ring, and X is CR 5 And R 2 -C(R 6 )2R 10 , -OR 9 , C 3-10 It is a cycloalkyl or halo, where C 3-10 Cycloalkyl groups independently have 1 to 5 Z 1 Replaced by optional selection in R 3 C 3-10 It is a cycloalkyl, heterocyclyl, or heteroaryl, where C 3-10 Cycloalkyl, heterocyclyl, or heteroaryl compounds independently contain 1 to 5 halo, hydroxy, C 1-6 Alkyl, or C 3-10 Optionally substituted with a cycloalkyl group, R 4 is hydrogen, and R 5 is hydrogen, C 1-6 Alkyl, or C 1-6 It is a haloalkyl and has at least one R 6 is hydrogen, and R 7 and R 8 is either hydrogen or R 7 and R 8 They combine to form C 3-10 Forming a cycloalkyl group, R 9 C 1-6It is alkyl, R 10 Hello, C 1-6 Alkyl, or C 1-6 It is a haloalkyl group.

[0110] In a particular embodiment, A 1 , A 2 , A 3 , A 4 , and A 5 Two of them are N, and the remaining A 1 , A 2 , A 3 , A 4 , and A 5 CR is independent. 1 And each R 1 These are independently hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, or C 3-10 It is either a cycloalkyl group or any two adjacent R groups. 1 The groups bond to form an aryl ring or heteroaryl ring, and X is CR 5 And R 2 -C(R 6 )2R 10 , -OR 9 , C 3-10 It is a cycloalkyl or halo, where C 3-10 Cycloalkyl groups independently have 1 to 5 Z 1 Replaced by optional selection in R 3 C 3-10 It is a cycloalkyl, heterocyclyl, or heteroaryl, where C 3-10 Cycloalkyl, heterocyclyl, or heteroaryl compounds independently contain 1 to 5 halo, hydroxy, C 1-6 Alkyl, or C 3-10 Optionally substituted with a cycloalkyl group, R 4 is hydrogen, and R 5 is hydrogen, C 1-6 Alkyl, or C 1-6 It is a haloalkyl and has at least one R 6 is hydrogen, and R 7 and R8 is hydrogen, and R 9 C 1-6 It is alkyl, R 10 Hello, C 1-6 Alkyl, or C 1-6 It is a haloalkyl group.

[0111] In a particular embodiment, A 1 , A 2 , A 3 , A 4 , and A 5 Each of them independently, CR 1 And each R 1 These are independently hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, or C 3-10 It is either a cycloalkyl group or any two adjacent R groups. 1 The groups bond to form an aryl ring or heteroaryl ring, where X is N and R 2 -C(R 6 )2R 10 , -OR 9 , C 3-10 It is a cycloalkyl or halo, where C 3-10 Cycloalkyl groups independently have 1 to 5 Z 1 Replaced by optional selection in R 3 C 3-10 It is a cycloalkyl, heterocyclyl, or heteroaryl, where C 3-10 Cycloalkyl, heterocyclyl, or heteroaryl compounds independently contain 1 to 5 halo, hydroxy, C 1-6 Alkyl, or C 3-10 Optionally substituted with a cycloalkyl group, R 4 is hydrogen and at least one R 6 is hydrogen, and R 7 and R 8 is either hydrogen or R 7 and R 8 They combine to form C 3-10 Forming a cycloalkyl group, R 9 C 1-6It is alkyl, R 10 Hello, C 1-6 Alkyl, or C 1-6 It is a haloalkyl group.

[0112] In a particular embodiment, A 1 , A 2 , A 3 , A 4 , and A 5 One of them is N, and the remaining A 1 , A 2 , A 3 , A 4 , and A 5 CR is independent. 1 And each R 1 These are independently hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, or C 3-10 It is either a cycloalkyl group or any two adjacent R groups. 1 The groups bond to form an aryl ring or heteroaryl ring, where X is N and R 2 -C(R 6 )2R 10 , -OR 9 , C 3-10 It is a cycloalkyl or halo, where C 3-10 Cycloalkyl groups independently have 1 to 5 Z 1 Replaced by optional selection in R 3 C 3-10 It is a cycloalkyl, heterocyclyl, or heteroaryl, where C 3-10 Cycloalkyl, heterocyclyl, or heteroaryl compounds independently contain 1 to 5 halo, hydroxy, C 1-6 Alkyl, or C 3-10 Optionally substituted with a cycloalkyl group, R 4 is hydrogen and at least one R 6 is hydrogen, and R 7 and R 8 is either hydrogen or R 7 and R 8 They combine to form C 3-10Forming a cycloalkyl group, R 9 C 1-6 It is alkyl, R 10 Hello, C 1-6 Alkyl, or C 1-6 It is a haloalkyl group.

[0113] In a particular embodiment, A 1 , A 2 , A 3 , A 4 , and A 5 Two of them are N, and the remaining A 1 , A 2 , A 3 , A 4 , and A 5 CR is independent. 1 And each R 1 These are independently hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, or C 3-10 It is either a cycloalkyl group or any two adjacent R groups. 1 The groups bond to form an aryl ring or heteroaryl ring, where X is N and R 2 -C(R 6 )2R 10 , -OR 9 , C 3-10 It is a cycloalkyl or halo, where C 3-10 Cycloalkyl groups independently have 1 to 5 Z 1 Replaced by optional selection in R 3 C 3-10 It is a cycloalkyl, heterocyclyl, or heteroaryl, where C 3-10 Cycloalkyl, heterocyclyl, or heteroaryl compounds independently contain 1 to 5 halo, hydroxy, C 1-6 Alkyl, or C 3-10 Optionally substituted with a cycloalkyl group, R 4 is hydrogen and at least one R 6 is hydrogen, and R 7 and R 8 is either hydrogen or R 7and R 8 They combine to form C 3-10 Forming a cycloalkyl group, R 9 C 1-6 It is alkyl, R 10 Hello, C 1-6 Alkyl, or C 1-6 It is a haloalkyl group.

[0114] In a particular embodiment, A 1 , A 2 , A 3 , A 4 , and A 5 Each of them independently, CR 1 And each R 1 These are independently hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, or C 1-6 It is a haloalkyl, and X is CR 5 And R 2 -C(R 6 )2R 10 OR 9 And R 3 C 3-10 It is a cycloalkyl, heterocyclyl, or heteroaryl, where C 3-10 Cycloalkyl, heterocyclyl, or heteroaryl compounds independently contain 1 to 5 halo, hydroxy, C 1-6 Alkyl, or C 3-10 Optionally substituted with a cycloalkyl group, R 4 is hydrogen, and R 5 is hydrogen and at least one R 6 is hydrogen, and R 7 and R 8 is hydrogen, and R 9 C 1-6 It is alkyl, R 10 C 1-6 It is alkyl.

[0115] In a particular embodiment, A 1 , A 2 , A 3 , A 4 , and A 5Each of them independently, CR 1 And X is CR 5 And R 1 R is independently hydrogen, fluoro, chloro, cyano, -CH3, -OCH3, or -CF3, 2 -C(R 6 )2R 10 OR 9 And R 3 C 3-10 It is a cycloalkyl, heterocyclyl, or heteroaryl, where C 3-10 Cycloalkyl, heterocyclyl, or heteroaryl compounds independently contain 1 to 5 halo, hydroxy, C 1-6 Alkyl, or C 3-10 Optionally substituted with a cycloalkyl group, R 4 is hydrogen, and R 5 is hydrogen and at least one R 6 is hydrogen, and R 7 and R 8 is hydrogen, and R 9 C 1-6 It is alkyl, R 10 C 1-6 It is alkyl.

[0116] In a particular embodiment, A 1 , A 2 , A 3 , A 4 , and A 5 One of them is N, and the remaining A 1 , A 2 , A 3 , A 4 , and A 5 CR is independent. 1 And each R 1 These are independently hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, or C 1-6 It is a haloalkyl, and X is CR 5 And R 2 -C(R 6 )2R 10 OR 9 And R3 C 3-10 It is a cycloalkyl, heterocyclyl, or heteroaryl, where C 3-10 Cycloalkyl, heterocyclyl, or heteroaryl compounds independently contain 1 to 5 halo, hydroxy, C 1-6 Alkyl, or C 3-10 Optionally substituted with a cycloalkyl group, R 4 is hydrogen, and R 5 is hydrogen and at least one R 6 is hydrogen, and R 7 and R 8 is hydrogen, and R 9 C 1-6 It is alkyl, R 10 C 1-6 It is alkyl.

[0117] In a particular embodiment, A 1 , A 2 , A 3 , A 4 , and A 5 One of them is N, and the remaining A 1 , A 2 , A 3 , A 4 , and A 5 CR is independent. 1 And X is CR 5 And R 1 R is independently hydrogen, fluoro, chloro, cyano, -CH3, -OCH3, or -CF3, 2 -C(R 6 )2R 10 OR 9 And R 3 C 3-10 It is a cycloalkyl, heterocyclyl, or heteroaryl, where C 3-10 Cycloalkyl, heterocyclyl, or heteroaryl compounds independently contain 1 to 5 halo, hydroxy, C 1-6 Alkyl, or C 3-10 Optionally substituted with a cycloalkyl group, R 4 is hydrogen, and R 5 is hydrogen and at least one R6 is hydrogen, and R 7 and R 8 is hydrogen, and R 9 C 1-6 It is alkyl, R 10 C 1-6 It is alkyl.

[0118] In a particular embodiment, A 1 , A 2 , A 3 , A 4 , and A 5 Two of them are N, and the remaining A 1 , A 2 , A 3 , A 4 , and A 5 CR is independent. 1 And each R 1 These are independently hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, or C 1-6 It is a haloalkyl, and X is CR 5 And R 1 R is independently hydrogen, fluoro, chloro, cyano, -CH3, -OCH3, or -CF3, 2 -C(R 6 )2R 10 OR 9 And R 3 C 3-10 It is a cycloalkyl, heterocyclyl, or heteroaryl, where C 3-10 Cycloalkyl, heterocyclyl, or heteroaryl compounds independently contain 1 to 5 halo, hydroxy, C 1-6 Alkyl, or C 3-10 Optionally substituted with a cycloalkyl group, R 4 is hydrogen, and R 5 is hydrogen and at least one R 6 is hydrogen, and R 7 and R 8 is hydrogen, and R 9 C 1-6 It is alkyl, R 10 C 1-6 It is alkyl.

[0119] In a particular embodiment, A 1 , A 2 , A 3 , A 4 , and A 5 Two of them are N, and the remaining A 1 , A 2 , A 3 , A 4 , and A 5 CR is independent. 1 And X is CR 5 And R 1 R is independently hydrogen, fluoro, chloro, cyano, -CH3, -OCH3, or -CF3, 2 -C(R 6 )2R 10 OR 9 And R 3 C 3-10 It is a cycloalkyl, heterocyclyl, or heteroaryl, where C 3-10 Cycloalkyl, heterocyclyl, or heteroaryl compounds independently contain 1 to 5 halo, hydroxy, C 1-6 Alkyl, or C 3-10 Optionally substituted with a cycloalkyl group, R 4 is hydrogen, and R 5 is hydrogen and at least one R 6 is hydrogen, and R 7 and R 8 is hydrogen, and R 9 C 1-6 It is alkyl, R 10 C 1-6 It is alkyl.

[0120] In a particular embodiment, A 1 , A 2 , A 3 , A 4 , and A 5 Each of them independently, CR 1 And each R 1 These are independently hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6Alkoxy, or C 1-6 It is a haloalkyl, where X is N and R 2 -C(R 6 )2R 10 OR 9 And R 3 C 3-10 It is a cycloalkyl, heterocyclyl, or heteroaryl, where C 3-10 Cycloalkyl, heterocyclyl, or heteroaryl compounds independently contain 1 to 5 halo, hydroxy, C 1-6 Alkyl, or C 3-10 Optionally substituted with a cycloalkyl group, R 4 is hydrogen and at least one R 6 is hydrogen, and R 7 and R 8 is hydrogen, and R 9 C 1-6 It is alkyl, R 10 C 1-6 It is alkyl.

[0121] In a particular embodiment, A 1 , A 2 , A 3 , A 4 , and A 5 Each of them independently, CR 1 X is N, and R 1 R is independently hydrogen, fluoro, chloro, cyano, -CH3, -OCH3, or -CF3, 2 -C(R 6 )2R 10 OR 9 And R 3 C 3-10 It is a cycloalkyl, heterocyclyl, or heteroaryl, where C 3-10 Cycloalkyl, heterocyclyl, or heteroaryl compounds independently contain 1 to 5 halo, hydroxy, C 1-6 Alkyl, or C 3-10 Optionally substituted with a cycloalkyl group, R 4 is hydrogen and at least one R 6 is hydrogen, and R7 and R 8 is hydrogen, and R 9 C 1-6 It is alkyl, R 10 C 1-6 It is alkyl.

[0122] In a particular embodiment, A 1 , A 2 , A 3 , A 4 , and A 5 One of them is N, and the remaining A 1 , A 2 , A 3 , A 4 , and A 5 CR is independent. 1 And each R 1 These are independently hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, or C 1-6 It is a haloalkyl, where X is N and R 2 -C(R 6 )2R 10 OR 9 And R 3 C 3-10 It is a cycloalkyl, heterocyclyl, or heteroaryl, where C 3-10 Cycloalkyl, heterocyclyl, or heteroaryl compounds independently contain 1 to 5 halo, hydroxy, C 1-6 Alkyl, or C 3-10 Optionally substituted with a cycloalkyl group, R 4 is hydrogen and at least one R 6 is hydrogen, and R 7 and R 8 is hydrogen, and R 9 C 1-6 It is alkyl, R 10 C 1-6 It is alkyl.

[0123] In a particular embodiment, A 1 , A 2 , A 3 , A 4 , and A5 One of them is N, and the remaining A 1 , A 2 , A 3 , A 4 , and A 5 CR is independent. 1 X is N, and R 1 R is independently hydrogen, fluoro, chloro, cyano, -CH3, -OCH3, or -CF3, 2 -C(R 6 )2R 10 OR 9 And R 3 C 3-10 It is a cycloalkyl, heterocyclyl, or heteroaryl, where C 3-10 Cycloalkyl, heterocyclyl, or heteroaryl compounds independently contain 1 to 5 halo, hydroxy, C 1-6 Alkyl, or C 3-10 Optionally substituted with a cycloalkyl group, R 4 is hydrogen and at least one R 6 is hydrogen, and R 7 and R 8 is hydrogen, and R 9 C 1-6 It is alkyl, R 10 C 1-6 It is alkyl.

[0124] In a particular embodiment, A 1 , A 2 , A 3 , A 4 , and A 5 Two of them are N, and the remaining A 1 , A 2 , A 3 , A 4 , and A 5 CR is independent. 1 And each R 1 These are independently hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, or C 1-6 It is a haloalkyl, where X is N and R 2 -C(R 6)2R 10 OR 9 And R 3 C 3-10 It is a cycloalkyl, heterocyclyl, or heteroaryl, where C 3-10 Cycloalkyl, heterocyclyl, or heteroaryl compounds independently contain 1 to 5 halo, hydroxy, C 1-6 Alkyl, or C 3-10 Optionally substituted with a cycloalkyl group, R 4 is hydrogen and at least one R 6 is hydrogen, and R 7 and R 8 is hydrogen, and R 9 C 1-6 It is alkyl, R 10 C 1-6 It is alkyl.

[0125] In a particular embodiment, A 1 , A 2 , A 3 , A 4 , and A 5 Two of them are N, and the remaining A 1 , A 2 , A 3 , A 4 , and A 5 CR is independent. 1 X is N, and R 1 R is independently hydrogen, fluoro, chloro, cyano, -CH3, -OCH3, or -CF3, 2 -C(R 6 )2R 10 OR 9 And R 3 C 3-10 It is a cycloalkyl, heterocyclyl, or heteroaryl, where C 3-10 Cycloalkyl, heterocyclyl, or heteroaryl compounds independently contain 1 to 5 halo, hydroxy, C 1-6 Alkyl, or C 3-10 Optionally substituted with a cycloalkyl group, R 4 is hydrogen and at least one R 6is hydrogen, and R 7 and R 8 is hydrogen, and R 9 C 1-6 It is alkyl, R 10 C 1-6 It is alkyl.

[0126] In certain embodiments, the provided compounds are selected from Table 1, or pharmaceutically acceptable salts thereof, isotope-enriched analogs, prodrugs, stereoisomers, or mixtures of stereoisomers. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

[0127] In certain embodiments, the provided compounds are selected from Table 2, or pharmaceutically acceptable salts thereof, isotope-enriched analogs, prodrugs, stereoisomers, or mixtures of stereoisomers. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6]

[0128] 3. Method "Treatment" or "treating" is an approach to obtain beneficial or desirable outcomes, including clinical outcomes. Beneficial or desirable clinical outcomes may include one or more of the following: a) suppression of the disease or condition (e.g., reduction of one or more symptoms resulting from the disease or condition, and / or reduction of the severity of the disease or condition); b) slowing or preventing the onset of one or more clinical symptoms associated with the disease or condition (e.g., stabilization of the disease or condition, prevention or delay of worsening or progression of the disease or condition, and / or prevention or delay of the expansion of the disease or condition (e.g., migration)); and / or c) relief of the disease, i.e., the occurrence of regression of clinical symptoms (e.g., improvement of the disease state, provision of partial or total remission of the disease or condition, enhancement of the effect of another drug, delay of disease progression, improvement of quality of life, and / or extension of survival).

[0129] "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 or have a family history of the disease or condition.

[0130] "Subject" refers to an animal, such as a mammal (including humans), that has been or is the subject of treatment, observation, or experimentation. The methods described herein may be useful for therapies and / or veterinary uses in humans. In some embodiments, the subject is a mammal. In certain embodiments, the subject is a human.

[0131] The terms “therapeutically effective dose” or “effective dose” of any compound or pharmaceutically acceptable salt, isotope-enriched analog, stereoisomer, mixture of stereoisomers, or prodrug described herein mean an amount sufficient to effectively provide a therapeutic benefit, such as symptom relief or delay of disease progression, when administered to a subject. For example, a therapeutically effective dose may be an amount sufficient to reduce the symptoms of the disease or condition described herein. The therapeutically effective dose may vary depending on the subject, as well as the disease or condition being treated, the subject’s weight and age, the severity of the disease or condition, and the mode of administration, and can be readily determined by a person skilled in the art.

[0132] The methods described herein may be applied to cell populations in vivo or ex vivo. “In vivo” means within a living organism, such as inside an animal or human. In this context, the methods described herein may be used therapeutically on an organism. “Ex vivo” means outside a living organism. Examples of ex vivo cell populations include in vitro cell cultures and biological samples, including bodily fluids or tissue samples obtained from organisms. Such samples can be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. In this context, 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 ex vivo to determine the optimal administration schedule and / or dosage of the compounds disclosed herein for a given indication, cell type, organism, and other parameters. Information obtained from such use may be used experimentally or clinically to establish protocols in in vivo therapy. Other ex vivo uses in which the compounds and compositions described herein may be suitable are described below or will be apparent to those skilled in the art. The selected compounds may be further characterized to test their safety or tolerable dose in human or non-human subjects. Such properties may be tested using methods commonly known to those skilled in the art.

[0133] In certain embodiments, compounds, or pharmaceutically acceptable salts thereof, isotope-enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs are provided that modulate the activity of NLR family pyrine domain-containing 3 (NLRP3). In certain embodiments, the compounds, or pharmaceutically acceptable salts thereof, isotope-enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs provided herein inhibit the activity of NLRP3.

[0134] NLR proteins are involved in the immune system, helping to initiate and regulate the immune system's response to injury, toxins, or microbial invasion. NLRP3 (also known as cryopyrin, NALP3, LRR and PYD domain-containing protein 3) is a protein encoded by the NLRP3 gene (also known as CIAS1). When activated, the NLRP3 molecule, along with other proteins, assembles into the inflammasome. Activation of NLRP3 due to cellular stress triggers inflammasome activation and downstream proteolytic events, which include the formation and subsequent secretion of active pro-inflammatory cytokines such as interleukin (IL)-1β and IL-18. Among other cytokines, IL-1β and IL-18 are known as mediators of inflammation, e.g., inflammation of the arterial wall, atherosclerosis, and the aging process.

[0135] In certain embodiments, a method is provided for inhibiting inflammasome (e.g., NLRP3 inflammasome) activity, comprising contacting cells with an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, an isotope-enriched analog, a stereoisomer, a mixture of stereoisomers, or a prodrug. Inhibition may be in vitro or in vivo.

[0136] In certain embodiments, the provided compounds, or pharmaceutically acceptable salts thereof, isotope-enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs, are used for use in inhibiting inflammasome (e.g., NLRP3 inflammasome) activity (e.g., in vitro or in vivo).

[0137] In certain embodiments, the disclosure provides the use of the compounds disclosed herein, or pharmaceutically acceptable salts thereof, isotopic enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs in the manufacture of pharmaceuticals that inhibit inflammasome (e.g., NLRP3 inflammasome) activity (e.g., in vitro or in vivo).

[0138] Chronic inflammatory responses are associated with various types of cancer. During malignant transformation or cancer therapy, inflammasomes can be activated in response to specific signals, and IL-Iβ expression is elevated in various cancers (e.g., breast cancer, prostate cancer, colon cancer, lung cancer, head and neck cancer, melanoma, etc.). Patients with IL-Iβ-producing tumors generally have a poor prognosis.

[0139] In certain embodiments, a method for treating a disease or condition mediated at least in part by NLRP3, comprising administering an effective amount of one of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, an isotopic enriched analog, a stereoisomer, a mixture of stereoisomers, or a prodrug, to a subject in need thereof.

[0140] In certain embodiments, the provided method is for treating a disease or condition selected from autoinflammatory disorders, autoimmune disorders, neurodegenerative diseases or cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt thereof, isotope-enriched analog, stereoisomer, mixture of stereoisomers, or prodrug.

[0141] In certain embodiments, provided are compounds disclosed herein, or pharmaceutically acceptable salts thereof, isotope-enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs for use in treating autoinflammatory disorders, autoimmune disorders, neurodegenerative diseases, or cancer in subjects requiring such treatment.

[0142] In certain embodiments, the Disclosure provides the use of the compounds disclosed herein, or pharmaceutically acceptable salts thereof, isotope-enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs in the manufacture of pharmaceuticals for treating or preventing autoinflammatory disorders, autoimmune disorders, neurodegenerative diseases, or cancer in subjects in need thereof.

[0143] In certain embodiments, the provided method is for treating inflammation, autoimmune diseases, cancer, infections, central nervous system disorders, metabolic diseases, cardiovascular diseases, respiratory diseases, liver diseases, kidney diseases, eye diseases, skin diseases, lymphatic conditions, mental disorders, graft-versus-host diseases, allodynia, or any disease in which an individual has been determined to have germline or somatic non-silent mutations in NLRP3, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt thereof, isotope-enriched analog, stereoisomer, mixture of stereoisomers, or prodrug.

[0144] In certain embodiments, a disease or condition may be a disease or condition of the immune system, cardiovascular system, endocrine system, gastrointestinal tract, renal system, hepatic system, metabolic system, respiratory system, or central nervous system, and may be cancer or other malignant tumors, and / or may be caused by or related to a pathogen. These general embodiments, defined according to a broad classification of diseases, disorders, and conditions, are understood to be non-exclusive.

[0145] In certain embodiments, the disease or condition includes inflammation resulting from inflammatory disorders, such as inflammation resulting from autoinflammatory diseases, inflammation resulting from symptoms of non-inflammatory disorders, inflammation resulting from infection, or inflammation secondary to trauma, injury, or autoimmunity; acute disseminated encephalitis, Addison's disease, ankylosing spondylitis, antiphospholipid syndrome (APS), antisynthesis syndrome, aplastic anemia, autoimmune adrenal dysregulation, autoimmune hepatitis, autoimmune oophoritis, autoimmune polyglandular endocrine insufficiency, autoimmune thyroiditis, celiac disease, Crohn's disease, type 1 diabetes (T1D), and Goodpasture disease. Multiple sclerosis (MS), including multiple sclerosis syndromes such as Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, idiopathic thrombocytopenic purpura, Kawasaki disease, lupus erythematosus including systemic lupus erythematosus (SLE), multiple sclerosis including primary progressive multiple sclerosis (PPMS), secondary progressive multiple sclerosis (SPMS), and relapsing-remitting multiple sclerosis (RRMS), myasthenia gravis, opsoclonus-myoclonus syndrome (OMS), optic neuritis, oudrythyroiditis, pemphigus, pernicious anemia, polyarthritis, primary biliary cirrhosis, rheumatoid arthritis (RA), psoriatic arthritis, juvenile idiopathic arthritis, or steatosis. Autoimmune diseases such as Luther's disease, refractory gouty arthritis, Reiter's syndrome, Sjögren's syndrome, systemic connective tissue disorders including systemic sclerosis, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, alopecia generalis, Behçet's disease, Chagas disease, autonomic neuropathy, endometriosis, hidradenitis suppurativa (HS), interstitial cystitis, neurogenic myotonia, psoriasis, sarcoidosis, scleroderma, ulcerative colitis, Schnitzler syndrome, macrophage activation syndrome, Blau syndrome, vitiligo or vulvodysia, and other autoimmune diseases; lung cancer, pancreatic cancer, gastric cancer, myelodysplastic syndrome, acute lymphoblastic leukemia (AL). Leukemia including L) and acute myeloid leukemia (AML), adrenal cancer, anal cancer, basal squamous cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer, brain and spinal cord tumors, breast cancer, cervical cancer, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), colorectal cancer, endometrial cancer, esophageal cancer, Ewing family tumors, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), gestational trophoblastic disease, glioma, Hodgkin lymphoma, Kaposi's sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, liver cancer, pulmonary carcinoid tumors, lymphoma including cutaneous T-cell lymphoma, malignant mesothelioma,Cancers including melanoma, Merkel cell carcinoma, multiple myeloma, nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral and oropharyngeal cancer, osteosarcoma, ovarian cancer, penile cancer, pituitary tumor, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, gastric cancer, testicular cancer, thymic cancer, thyroid cancer including undifferentiated thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstorm macroglobulinemia and Wilms tumor; viral infections (e.g., influenza virus, human immunodeficiency virus). Viruses (HIV), alpha viruses (such as chikungunya fever and Ross River virus), flaviviruses (such as dengue virus and Zika virus), herpesviruses (such as Epstein-Barr virus, cytomegalovirus, varicella-zoster virus, and KSHV), poxviruses (vaccinia virus (such as modified vaccinia virus Ankara) and myxoma virus), adenoviruses (such as adenovirus 5), or papillomaviruses), bacterial infections (e.g., Staphylococcus) aureus, Helicobacter pylori, Bacillusanthracis, Bordatella pertussis, Burkholderia pseudomallei, Corynebacterium diptheriae, Clostridium tetani, Clostridium botulinum, Streptococcus pneumoniae, Streptococcus pyogenes, Listeria monocytogenes, Hemophilus influenzae, Pasteurella multicida, Shigella dysenteriae, Mycobacterium tuberculosis, Mycobacterium leprae, Mycoplasma pneumoniae, Mycoplasma hominis, Neisseria meningitidis, Neisseria gonorrhoeae, Rickettsia rickettsii, Legionella pneumophila, Klebsiella pneumoniae, Pseudomonas aeruginosa,Infections including those caused by Propionibacterium acnes, Treponema pallidum, Chlamydia trachomatis, Vibrio cholerae, Salmonella typhimurium, Salmonella typhi, Borrelia burgdorferi, or Yersinia pestis), fungal infections (e.g., Candida or Aspergillus species), protozoan infections (e.g., Plasmodium, Babesia, Giardia, Entamoeba, Leishmania, or Trypanosomes), helminthic infections (e.g., schistosomiasis, nematodes, tapeworms, or trematodes), and prion infections; Parkinson's disease, Alzheimer's disease, dementia, and motor neuron diseases. Central nervous system diseases such as Huntington's disease, cerebral malaria, brain injury due to pneumococcal meningitis, intracranial aneurysms, traumatic brain injury, and amyotrophic lateral sclerosis; metabolic diseases such as type 2 diabetes mellitus (T2D), atherosclerosis, obesity, gout, and pseudogout; hypertension, ischemia, reperfusion injury including post-MI ischemia-reperfusion injury, stroke including ischemic stroke, transient ischemic attack, myocardial infarction including recurrent myocardial infarction, heart failure including congestive heart failure and heart failure with preserved ejection fraction, and embolism. Cardiovascular diseases such as aneurysms including abdominal aortic aneurysm, and pericarditis including Dressler syndrome; respiratory diseases including chronic obstructive pulmonary disease (COPD), asthma including allergic asthma and steroid-resistant asthma, asbestos disease, silicosis, nanoparticle-induced inflammation, cystic fibrosis and idiopathic pulmonary fibrosis; non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) (including advanced fibrosis stages F3 and F4); alcoholic fatty liver disease ( Liver diseases including AFLD and alcoholic steatohepatitis (ASH); kidney diseases including chronic kidney disease, oxalate nephropathy, nephrocalcinosis, glomerulonephritis, and diabetic nephropathy; ophthalmic diseases including ocular epithelium, age-related macular degeneration (AMD) (dry and wet), uveitis, corneal infections, diabetic retinopathy, optic neuropathy, dry eye, and glaucoma; dermatitis such as contact dermatitis and atopic dermatitis, contact hypersensitivity, sunburn, skin lesions, hidradenitis suppurativa (HS), and other cystic skin diseases.This includes skin diseases such as acne clusters; lymphatic conditions such as lymphangitis and Castleman disease; mental disorders such as depression and mental stress; graft-versus-host diseases; allodynia, including mechanical allodynia; and any disease in which an individual has been determined to have germline or somatic non-silent mutations in NLRP3.

[0146] In certain embodiments, the disease, disorder, or condition is cryopyrin-associated periodic syndrome (CAPS), Macklewells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), familial Mediterranean fever (FMF), neonatal onset multiorgan inflammatory disease (NOMID), tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), hyperimmuneglobulin D deficiency syndrome / periodic fever syndrome (HIDS), or interleukin-1 receptor antagonist deficiency. These include autoinflammatory diseases such as DIRA, Majeed's syndrome, septic arthritis, pyoderma gangrenosum, and acne syndrome (PAPA), adult Still's disease (AOSD), A20 haploinsufficiency (HA20), granulomatous arteritis (PGA), PLCG2-related antibody deficiency / immunodeficiency (PLAID), PLCG2-related autoinflammatory disease / antibody deficiency / immunodeficiency (APLAID), or sideroblastic anemia / B-cell immunodeficiency, periodic fever / developmental delay (SIFD).

[0147] In certain embodiments, the provided method is for treating a disease or condition selected from autoinflammatory disorders and / or autoimmune disorders selected from cryopyrin-associated periodic syndromes (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS)), Macklewells syndrome (MWS), chronic infantile neurocutaneous arthritis (CINCA) syndrome, neonatal onset multi-organ inflammatory disease (NOMID), familial Mediterranean fever and non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes mellitus, and multiple sclerosis, as well as neuroinflammation resulting from protein misfolding disorders (e.g., prion diseases), comprising administering to a subject in need thereof a therapeutically effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt thereof, isotope-enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0148] In certain embodiments, the following are provided: cryopyrin-associated periodic syndromes (CAPS), Macklewells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal multi-organ inflammatory disease (NOMID), familial Mediterranean fever (FMF), suppurative arthritis, pyoderma gangrenosum, and acne syndrome (PAPA), hyperimmuneglobulin D emia and periodic fever syndromes (HIDS), tumor necrosis factor (TNF) receptor-associated periodic syndromes (TRAPS), systemic juvenile idiopathic arthritis, adult Still's disease (AOSD), A method for treating a disease or condition selected from relapsing polychondritis, Schnitzler syndrome, Sweet's syndrome, Behçet's disease, antisynthesis syndrome, interleukin-1 receptor antagonist deficiency (DIRA), and A20 haploinsufficiency (HA20), comprising administering to a subject in need thereof a therapeutically effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt thereof, isotope-enriched analog, stereoisomer, mixture of stereoisomers, or prodrug.

[0149] In certain embodiments, the provided method is for treating a disease or condition selected from Alzheimer's disease, atherosclerosis, asthma, allergic airway inflammation, cryopyrin-associated periodic syndromes, gout, inflammatory bowel disease and related disorders, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hypertension, myocardial infarction, multiple sclerosis, experimental autoimmune encephalitis, oxalate-induced nephropathy, excessive inflammation after influenza infection, graft-versus-host disease, stroke, silicosis, type 1 diabetes mellitus, obesity-induced inflammation or insulin resistance, rheumatoid arthritis, myelodysplastic syndrome, contact hypersensitivity, arthritis caused by chikungunya virus, or traumatic brain injury, comprising administering to a subject in need thereof a therapeutically effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt thereof, isotope-enriched analog, stereoisomer, mixture of stereoisomers, or prodrug.

[0150] In certain embodiments, what is provided is a method for treating a disease or condition mediated at least in part by TNF-α. In certain embodiments, the disease or condition is resistant to treatment with anti-TNF-α agents. In some embodiments, the disease is a disease or condition of the intestines. In some embodiments, the disease or condition is inflammatory bowel disease, Crohn's disease, or ulcerative colitis. In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts, isotopic enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs are administered in combination with an anti-TNF-α agent. In some embodiments, the anti-TNF-α agent is infliximab, etanercept, certolizumab pegol, golimumab, or adalimumab.

[0151] In certain embodiments, the disease or condition is an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer.

[0152] In certain embodiments, the disease or condition is an autoinflammatory disorder and / or an autoimmune disorder.

[0153] In a particular embodiment, the disease or condition is a neurodegenerative disease.

[0154] In certain embodiments, the disease or condition is Parkinson's disease or Alzheimer's disease.

[0155] In a particular embodiment, the provided method for treating cancer comprises administering to a subject in need of such treatment an effective amount of one of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, an isotope-enriched analog, a stereoisomer, a mixture of stereoisomers, or a prodrug thereof.

[0156] In certain embodiments, the cancer is metastatic cancer, gastrointestinal cancer, skin cancer, non-small cell lung cancer, or colorectal adenocarcinoma.

[0157] In certain embodiments, provided are compounds disclosed herein, or pharmaceutically acceptable salts thereof, isotope-enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs for use in treating neurodegenerative diseases (e.g., Parkinson's disease or Alzheimer's disease) in subjects requiring such treatment.

[0158] In certain embodiments, what is provided is a compound disclosed herein, or a pharmaceutically acceptable salt thereof, isotope-enriched analog, stereoisomer, mixture of stereoisomers, or prodrug for use in treating cancer in a subject that requires it.

[0159] In certain embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, isotope-enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs, may be administered alone as monotherapy or in addition to one or more other substances and / or treatments. Such combination therapy can be achieved by administering the individual components of the treatment simultaneously, sequentially, or separately.

[0160] For example, the administration of an adjuvant may enhance the therapeutic effect (i.e., an adjuvant alone provides only minimal therapeutic benefit, but when combined with another therapeutic agent, it improves the overall therapeutic benefit to the individual). Alternatively, for illustrative purposes only, the benefit experienced by an individual may be increased by administering the compounds disclosed herein, or their pharmaceutically acceptable salts, isotope-enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs, together with another therapeutic agent (including a treatment regimen) that similarly provides therapeutic benefit.

[0161] Other embodiments include the use of the compounds of this disclosure in therapeutic settings.

[0162] 4. Kit This specification also provides kits comprising the compounds of the Disclosure, or pharmaceutically acceptable salts thereof, isotopic-enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs, and suitable packaging. In certain embodiments, the kit further includes instructions for use. In one embodiment, the kit includes the compounds of the Disclosure, or pharmaceutically acceptable salts thereof, isotopic-enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs, and labels and / or instructions relating to the use of the compounds in the treatment of indications, including diseases or conditions described herein.

[0163] Furthermore, this specification provides for products containing the compounds described herein or their pharmaceutically acceptable salts, isotopic enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs in appropriate containers. The containers may be vials, jars, ampoules, pre-filled syringes, or intravenous bags.

[0164] 5. Pharmaceutical composition and dosage form The compounds provided herein are typically administered in the form of pharmaceutical compositions. Therefore, also provided herein are pharmaceutical compositions comprising one or more of the compounds described herein, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants, and excipients. Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers, and adjuvants. Such compositions are prepared in manner 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.).

[0165] The pharmaceutical composition may be administered as a single dose or in multiple 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.

[0166] One mode of administration is parenteral, for example, by injection. Forms into which the pharmaceutical compositions described herein can 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.

[0167] Oral administration may be another route of administration of the compounds described herein. Administration may be, for example, by capsules or enteric-coated tablets. In the preparation of a pharmaceutical composition comprising at least one of the compounds described herein or a pharmaceutically acceptable salt, isotopic enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, the active ingredient is usually diluted with an excipient and / or placed in a carrier, which may be in the form of capsules, sachets, paper, or other containers. If the excipient functions as a diluent, it may be in the form of a solid, semi-solid, or liquid material and functions 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 (solid or liquid media), for example, ointments, soft and hard gelatin capsules, sterile injections, and sterile packaged powders containing up to 10% by weight of the active compound.

[0168] Some examples of suitable excipients include, for example, lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, 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; humectants; emulsifiers and suspending agents; preservatives such as methyl and propyl hydroxybenzoates; sweeteners; and flavoring and odor-modifying agents.

[0169] Compositions comprising at least one compound described herein or a pharmaceutically acceptable salt thereof, isotope-enriched analog, stereoisomer, mixture of stereoisomers, or prodrug can be formulated to provide rapid sustained or delayed release of the active ingredient after administration to a subject by employing procedures known in the art. Controlled-release drug delivery systems for oral administration include an osmotic pump system and a dissolution system comprising a polymer-coated reservoir or drug-polymer matrix formulation. Another formulation for use in the manner disclosed herein utilizes a transdermal delivery device ("patch"). Such transdermal patches may be used to inject controlled amounts of the compounds described herein continuously or discontinuously. The preparation and use of transdermal patches for drug delivery are well known in the art. Such patches can be prepared for continuous pulsed or on-demand delivery of the drug.

[0170] To prepare solid compositions such as tablets, the main active ingredient may be mixed with a pharmaceutically acceptable excipient to form a solid pre-formulation composition containing the compound described herein or a pharmaceutically acceptable salt thereof, isotopic enriched analog, stereoisomer, mixture of stereoisomers, or homogeneous mixture of prodrugs. When these pre-formulation compositions are referred to as homogeneous, the active ingredient is uniformly dispersed throughout the composition, thereby allowing the composition to be easily divided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0171] Tablets or pills of the compounds described herein may be coated or otherwise prepared to provide a dosage form that offers the benefit of long-term action or to protect from the acidic conditions of the stomach. For example, a tablet or pill may contain an inner and an outer dosing component, the latter in the form of a coating covering the former. The two components may be separated by an enteric coating, which functions to withstand disintegration in the stomach and allow the inner component to pass intact to the duodenum or be released with delayed release. Various materials may be used for such enteric coatings or coatings, and such materials include several polymer acids, as well as mixtures of polymer acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0172] Compositions for inhalation or inhalation may include solutions and suspensions in pharmaceutically acceptable aqueous solvents 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 nasally via respiratory routes for topical or systemic effects. In other embodiments, compositions in pharmaceutically acceptable solvents can 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 tent-type face mask or an intermittent positive pressure respirator. The solution, suspension, or powder composition may preferably be administered orally or nasally from a device that delivers the formulation in a suitable manner.

[0173] 6. Administration The specific dose level of the compounds of this application for any particular subject depends on a variety of factors, including the activity of the specific compound employed, age, body weight, overall health status, sex, diet, timing of administration, route of administration, and excretion rate, drug combinations, and the severity of the particular disease of the subject receiving treatment. For example, the dose can be expressed as the number of milligrams of the compound described herein per kilogram of the subject's body weight (mg / kg). A dose of about 0.1 to 150 mg / kg may be appropriate. In some embodiments, a dose of about 0.1 to 100 mg / kg may be appropriate. In other embodiments, a dose of 0.5 to 60 mg / kg may be appropriate. In some embodiments, a dose of about 0.0001 to about 100 mg per kg of body weight, about 0.001 to about 50 mg of the compound per kg of body weight, or about 0.01 to about 10 mg of the compound per kg of body weight per day may be appropriate. Normalization by subject weight is particularly useful when adjusting doses between subjects of vastly different sizes, such as when using drugs in both human children and adults, or when converting effective doses for non-human subjects like dogs to doses suitable for human subjects.

[0174] 7. Synthesis of Compounds The compounds can be prepared using the methods disclosed herein and commonly used variations thereof, as will be apparent from the disclosure herein and methods well known in the art. In addition to the teachings herein, conventionally known synthetic methods may be used. The synthesis of typical compounds described herein can be achieved as described in the following examples. Reagents and starting materials, if available, can be commercially purchased, for example, from Sigma Aldrich or other chemical suppliers.

[0175] Typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are provided, but please understand that other process conditions may also be used 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 using standard optimization methods.

[0176] 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 references cited in that literature. For example, protecting groups for alcohols such as hydroxyls include silyl ethers (including trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), triisopropylsilyloxymethyl (TOM), and triisopropylsilyl (TIPS) ethers), 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 (removed by acid or base), benzoyl (removed by acid or base), benzyl (removed by hydrogenation), methoxyethoxymethyl ether (removed by acid), dimethoxytrityl (removed by acid), methoxymethyl ether (removed by acid), tetrahydropyranyl or tetrahydrofuranyl (removed by acid), and trityl (removed by acid).Examples of amine protecting groups include carbo-benzyloxy, p-methoxybenzylcarbonyl, p-methoxybenzylcarbonyl, p-butyloxycarbonyl, p-butyloxycarbonyl, p-butyloxycarbonyl, p-butyloxycarbonyl, p-fluorobenzyl, p-hydroxybenzoyl, p-methoxybenzyl, p-methoxybenzyl, p-hydroxybenzoyl, p-hydroxybenzoyl, p-hydroxybenzoyl, p-hydroxybenzoyl, p-hydroxybenzoyl, p-hydroxybenzoyl, p-hydroxybenzoyl, p-hydroxybenzoyl, p-hydroxybenzoyl, p-hydroxybenzoyl, p-hydroxybenzoyl, p-hydroxybenzoyl, p-hydroxyphenyl, p-methoxyphenyl, p-methoxyphenyl, p-hydroxybenzoyl (& Nps) are listed as examples.

[0177] Furthermore, the compounds of this disclosure may contain one or more chiral centers. Therefore, if desired, such compounds may be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as concentrated mixtures of stereoisomers. All such stereoisomers (and concentrated mixtures) are included within the scope of this disclosure unless otherwise specified. Pure stereoisomers (or concentrated mixtures) may be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds may be separated, for example, using chiral column chromatography, chiral resolving agents, etc.

[0178] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious variations thereof. For example, many of the starting materials are commercially available from companies such as Aldrich Chemical Co (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce, or Sigma (St. Louis, Missouri, USA). Other preparations can be made by following the procedures or obvious variations 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).

[0179] General synthesis methods Scheme I illustrates a general method that can be used for the synthesis of the compounds described herein, X, Y 1 , Y 2 , A 1 ~A 5 , R 2 , R 3 , R 4 , R 7 , and R 8 Each of these is independently as defined herein, and each R 50 Independently, C 1-6 Alkyl or two R 50These atoms, together with the atoms to which they are bonded, form a ring, and each LG is a leaving group (e.g., a halo). It should be understood that various compounds of formula I can be provided by derivatizing one or more of compounds I-1, I-3, and I-5, or any product obtained by the processes outlined in scheme I. [ka]

[0180] In Scheme I, compound I-3 is obtained by coupling compound I-1 and compound I-2, and compound I-5 is obtained by reacting this with appropriately substituted amine I-4 under amide bond formation reaction conditions. Alternatively, compound I-5 can be prepared from compound I-1 by coupling with compound I-6. Compound I of formula I is provided by contacting compound I-5 with appropriately substituted compound I-7 under standard metal catalyst coupling conditions.

[0181] Alternatively, as shown in Scheme II, compound II-1 can be obtained by first coupling compound I-1 and compound I-7 under standard metal catalyst coupling conditions, and then coupling this compound with compound I-2, and then either I-4 or compound I-6, under the same reaction conditions as described above, to provide the compound of formula I. [ka]

[0182] Suitable starting materials and reagents can be purchased or prepared by methods known to those skilled in the art. Each intermediate or final compound can be recovered at the end of each reaction by conventional techniques such as neutralization, extraction, precipitation, chromatography, and filtration, and optionally purified.

[0183] In some embodiments, the various substituents of compounds I-1, I-2, I-3, I-4, I-5, I-6, I-7, and II-1 used in schemes I and II are as defined for formula I. However, derivatization of compounds I-1, I-2, I-3, I-4, I-5, I-6, I-7, and II-1 provides a variety of compounds of formula I.

[0184] For example, R 2 Starting from compound II-1, which is a halo, R is formed through the exchange of functional groups. 2 Derivatization can be carried out to obtain various starting materials for use in the above scheme (see, for example, Scheme III). Such methods are known to those skilled in the art. [ka]

[0185] In a particular embodiment, the provided process for preparing a compound of formula I is a process comprising contacting a compound of formula I-5 with a compound of formula I-7 under conditions suitable for giving a compound of formula I.

[0186] In a particular embodiment, a process for preparing a compound of formula I is provided, which includes: Contacting the compound of formula I-3 with the compound of formula I-4 under conditions suitable for giving the compound of formula I-5; and Contact the compound of formula I-5 with the compound of formula I-7 under conditions suitable for giving the compound of formula I.

[0187] In a particular embodiment, a process for preparing a compound of formula I is provided, which includes: Contacting the compound of formula I-1 with the compound of formula I-2 under conditions suitable for giving the compound of formula I-3; Contacting the compound of formula I-3 with the compound of formula I-4 under conditions suitable for giving the compound of formula I-5; and Contact the compound of formula I-5 with the compound of formula I-7 under conditions suitable for giving the compound of formula I.

[0188] In a particular embodiment, a process for preparing a compound of formula I is provided, which includes: Contacting the compound of formula I-1 with the compound of formula I-6 under conditions suitable for giving the compound of formula I-5; and Contact the compound of formula I-5 with the compound of formula I-7 under conditions suitable for giving the compound of formula I.

[0189] In a particular embodiment, the provided process is for preparing a compound of formula I, comprising contacting a compound of formula II-1 with a compound of formula I-6 under conditions suitable for giving a compound of formula I.

[0190] In a particular embodiment, a process for preparing a compound of formula I is provided, which includes: Contacting the compound of formula II-1 with the compound of formula I-2 under conditions suitable for giving the compound of formula II-2; and The compound of formula II-2 is brought into contact with the compound of formula I-4 under conditions suitable for giving the compound of formula I.

[0191] In a particular embodiment, a process for preparing a compound of formula I is provided, which includes: Contacting the compound of formula I-1 with the compound of formula I-7 under conditions suitable for giving the compound of formula II-1; and Contact the compound of formula II-1 with the compound of formula I-6 under conditions suitable for giving the compound of formula I.

[0192] In a particular embodiment, a process for preparing a compound of formula I is provided, which includes: Contacting the compound of formula I-1 with the compound of formula I-7 under conditions suitable for giving the compound of formula II-1; Contacting the compound of formula II-1 with the compound of formula I-2 under conditions suitable for giving the compound of formula II-2; and The compound of formula II-2 is brought into contact with the compound of formula I-4 under conditions suitable for giving the compound of formula I. [Examples]

[0193] The following embodiments are included to illustrate specific embodiments of the present disclosure. Those skilled in the art will understand that the techniques disclosed in the following embodiments represent techniques that function well in carrying out the present invention and can therefore be considered to constitute specific forms of its implementation. However, those skilled in the art will understand that, in light of the present disclosure, many modifications can be made to the specific embodiments disclosed without departing from the spirit and scope of the present invention, and still equivalent or similar results can be obtained.

[0194] General experimental methods All solvents used were commercially available and were used without further purification. The reaction was typically carried out using anhydrous solvents under an inert atmosphere of nitrogen.

[0195] NMR spectroscopy: 1 H nuclear magnetic resonance (NMR) spectroscopy is performed using either a Bruker Avance III with a BBFO 300 MHz probe operating at 300 MHz, or one of the following instruments: a Bruker Avance 400 instrument with a DUAL 400 MHz S1 probe, or a 6 S1 400 MHz 5 mm probe. 1 H- 13The experiments were performed using a Bruker Avance 400 instrument with CID, a Bruker Avance III 400 instrument with Nanobay and Broadband BBFO 5mm direct probe, and a Bruker Mercury Plus 400 NMR spectrometer with a Bruker400BBO probe operating at 400 MHz. 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). In certain cases, 1 Nuclear magnetic resonance (NMR) spectroscopy was performed using a Bruker Advance 400 instrument operating at 400 MHz with the specified solvent at near room temperature, unless otherwise specified. In all cases, the NMR data were consistent with the proposed structure. Characteristic chemical shifts (δ) are given in parts per million using conventional abbreviations to specify the major peaks: e.g., s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets; br, broad.

[0196] 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 travels on the TLC plate divided by the distance the solvent travels. Column chromatography was performed on silica gel cartridges using an automated flash chromatography system, and reverse-phase chromatography was performed on C18 cartridges. Alternatively, thin-layer chromatography (TLC) was performed on Mancherey-Nagel's Alugram® (silica gel 60 F254), with UV typically used for spot visualization. In some cases, additional visualization methods were also employed. In these cases, the TLC plates were prepared by adding iodine (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 24The compound was visualized by developing a solution (prepared by thoroughly mixing 0.4H2O and 5g of (NH4)2Ce(IV)(NO3)6 in 450mL of water and 50mL of concentrated H2SO4).

[0197] 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, with a gradient solvent of 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) at a flow rate of 1.2 mL / min. LC-MS was performed using detection at 220 nm and 254 nm, 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 150×25, 5μm; MPA: 10mM NH4HCO3 / H2O; MPB: ACN. Gradient under both conditions: From 10% MPB to 80% MPB at a flow rate of 20mL / min for 12 minutes, then 100% MPB for 2 minutes, 10% MPB for 2 minutes, UV detector. SFC analysis was performed using a Thar analysis SFC system equipped with a UV / Vis detector and a series of chiral columns including AD, AS-H, OJ, OD, AY, and IC, as well as 4.6 × 100 mm and 3 μm columns. The analysis was carried out using a gradient solvent of 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) at a flow rate of 4 mL / min. SFC preparative sampling was performed using a Thar80 preparative SFC system equipped with a UV / Vis detector and a series of chiral preparative columns including AD-H, AS-H, OJ-H, OD-H, AY-H, and IC-H, and 30×250 mm, 5 μm columns. A gradient solvent of 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) was used at a flow rate of 65 mL / min.Furthermore, LC-MS data was acquired using a UPLC-MS Acquity® system coupled to 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 2.0 minute 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), with a total runtime of 2.5 minutes. The column temperature was 40°C and the flow rate was 0.8 mL / min.

[0198] Intermediate 1 [ka] To a solution of 2-chloro-N-(cis-3-hydroxy-3-methylcyclobutyl)acetamide:cis-3-amino-1-methylcyclobutanol HCl (1.1 g, 7.99 mmol) in DCM (15 mL), DMF (2 mL) and N-methylmorpholine (2.43 g, 24.0 mmol) were added. A solution of 2-chloroacetyl chloride (903 mg, 7.99 mmol) in DCM (2 mL) was added dropwise to the reaction mixture at -78°C. The reaction mixture was stirred at 20°C for 2 hours. The reaction mixture was then concentrated under reduced pressure. The crude residue was purified by silica gel chromatography. 1 H NMR (400 MHz, CDCl3): δ 6.81 (br s, 1H), 4.10-3.96 (m, 3H), 2.59-2.48 (m, 2H), 2.14-2.04 (m, 2H), 1.39 (s, 3H).

[0199] Intermediate 2 [ka] 2-(3,4-dichloro-6-oxopyridazine-1(6H)-yl)methyl acetate:5,6-dichloropyridazine-3(2H)-one (40 g, 242 mmol) and 2-bromomethyl acetate (37.8 g, 247 mmol) were dissolved in DMF (500 mL) and Cs2CO3 (79 g, 242 mmol) was added. The reaction mixture was stirred at 15°C for 1 hour. The reaction mixture was poured into water (2000 mL) and extracted with siRNA (3 × 700 mL). The combined organic layers were washed with brine (700 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure to obtain a residue, which was used directly without further purification. 1 H NMR (400 MHz, CDCl3): δ 7.13 (s, 1H), 4.83 (s, 2H), 3.79 (s, 3H).

[0200] 2-(3-chloro-4-methoxy-6-oxopyridazine-1(6H)-yl)methyl acetate: A solution of 2-(3,4-dichloro-6-oxopyridazine-1(6H)-yl)methyl acetate (58 g, 245 mmol) in MeOH (300 mL) was mixed with MeONa (5 M in MeOH, 53.8 mL) at 0°C. The reaction mixture was stirred at 15°C for 1 hour. The reaction mixture was poured into saturated NH4Cl (300 mL) and concentrated under reduced pressure. The remaining aqueous solution was extracted with ₹ (3 × 200 mL). The combined organic matter was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was tritulated with MTBE (500 mL) and then filtered to obtain the desired product. 1 H NMR (400 MHz, CDCl3): δ 6.22 (s, 1H), 4.81 (s, 2H), 3.90 (s, 3H), 3.78 (s, 3H).

[0201] 2-(4-methoxy-6-oxo-3-(propa-1-en-2-yl)pyridazin-1(6H)-yl)methyl acetate: A mixture of 2-(3-chloro-4-methoxy-6-oxopyridazin-1(6H)-yl)methyl acetate (47.6 g, 205 mmol), 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (51.5 g, 307 mmol), and Cs2CO3 (133 g, 409 mmol) in 1,4-dioxane (600 mL) and H2O (150 mL) was mixed with Pd(dppf)Cl2 (7.49 g, 10.2 mmol). The reaction mixture was stirred at 110 °C for 16 hours. The reaction mixture was quenched with water (1000 mL) and extracted with DCM (3 × 400 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography. LCMS: m / z = 239.2 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 6.18 (s, 1H), 5.64 (dd, J = 0.8, 1.5 Hz, 1H), 5.41 (quin, J = 1.6 Hz, 1H), 4.85 (s, 2H), 3.84 (s, 3H), 3.77 (s, 3H), 2.08 - 2.00 (m, 3H).

[0202] 2-(3-isopropyl-4-methoxy-6-oxopyridazine-1(6H)-yl)methyl acetate: 2-(4-methoxy-6-oxo-3-(propa-1-en-2-yl)pyridazine-1(6H)-yl)methyl acetate (15 g, 63.0 mmol) was dissolved in MeOH (150 mL) and Pd (5 g, 10 wt% carbon-supported) was added. The suspension was degassed under vacuum and purged three times with H2. The reaction mixture was stirred at 30°C for 2 hours under an H2 atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was used directly. LCMS: m / z = 241.2 [M+H] + . 1H NMR (400 MHz, CDCl3): δ 6.13 (s, 1H), 4.93-4.72 (m, 2H), 3.82 (s, 3H), 3.77 (s, 3H), 3.13 (spt, J = 6.8 Hz, 1H), 1.18 (d, J = 6.8 Hz, 6H).

[0203] 2-(4-bromo-3-isopropyl-6-oxopyridazine-1(6H)-yl)methyl acetate: 2-(3-isopropyl-4-methoxy-6-oxopyridazine-1(6H)-yl)methyl acetate (18.8 g, 78.3 mmol) was dissolved in 1,4-dioxane (200 mL) and POBr3 (44.9 g, 157 mmol) was added. The reaction mixture was stirred at 110 °C for 1 hour. The reaction mixture was poured into ice water (300 mL) and extracted with DCM (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography. LCMS: m / z = 289.1, 291.1 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 7.27 (s, 1H), 4.85 (s, 2H), 3.79 (s, 3H), 3.27 (spt, J = 6.8 Hz, 1H), 1.24 (d, J = 6.8 Hz, 6H).

[0204] Intermediate 3 [ka] 2-(4-bromo-3-isopropyl-6-oxopyridazin-1(6H)-yl)acetic acid: LiOH·H2O (1.68 g, 40.1 mmol) was added to a solution of methyl 2-(4-bromo-3-isopropyl-6-oxopyridazin-1-yl)acetic acid (5.8 g, 20.1 mmol) in THF (60 mL) and H2O (15 mL). The reaction mixture was stirred at 20°C for 1 hour. The reaction mixture was poured into H2O (100 mL) and washed with MTBE (3 × 40 mL). Then, aqueous HCl (2N) solution was added to the aqueous layer to adjust the pH to 3, and the mixture was extracted with siRNA (3 × 40 mL). The combined siRNA layers were washed with brine (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue, which was used directly. LCMS: m / z = 275.2, 277.2 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 9.40 (br s, 1H), 7.35 (s, 1H), 4.89 (s, 2H), 3.27 (m, 1H), 1.24 (d, J = 6.8 Hz, 6H).

[0205] 2-(4-bromo-3-isopropyl-6-oxopyridazine-1(6H)-yl)-N-(cis-3-hydroxy-3-methylcyclobutyl)acetamide:2-(4-bromo-3-isopropyl-6-oxopyridazine-1(6H)-yl)acetic acid (2.0 g, 7.27 mmol) was dissolved in DMF (30 mL) and HATU (4.15 g, 10.9 mmol) and DIPEA (3.76 g, 29.1 mmol) were added. The reaction mixture was stirred at 20°C for 0.5 hours, and then cis-3-amino-1-methylcyclobutanol HCl salt (1.65 g, 11.96 mmol) was added. The resulting reaction mixture was stirred at 20°C for 1 hour. The reaction mixture was quenched with water (150 mL) and extracted with ELISA (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by reverse-phase HPLC. LCMS: m / z = 358.1, 360.1 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 7.29 (s, 1H), 6.60 (br d, J = 7.2 Hz, 1H), 4.74 (s, 2H), 3.98 (m, 1H), 3.22-3.20 (m, 1H), 3.28 (m, 1H), 2.57-2.46 (m, 2H), 2.09-1.96 (m, 2H), 1.37 (s, 3H), 1.25 (d, J = 6.8 Hz, 6H).

[0206] Intermediate 4 [ka] 2-(4-bromo-3-isopropyl-6-oxopyridazine-1(6H)-yl)-N-(5-fluoropyrimidine-4-yl)acetamide: AlMe3 (2M in toluene, 15.6 mL) was added to a solution of methyl 2-(4-bromo-3-isopropyl-6-oxopyridazine-1-yl)acetate (3.0 g, 10.4 mmol) and 5-fluoropyrimidine-4-amine (3.5 g, 31.1 mmol) in toluene (50 mL) and THF (50 mL). The reaction mixture was stirred at 110°C for 12 hours. The reaction mixture was diluted with water (120 mL) and extracted with ethyl acetate (3 × 40 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography and reverse-phase preparative HPLC. LCMS: m / z = 370.0, 372.0 [M+H] + .

[0207] Intermediate 5 [ka] (R)-2-(4-bromo-3-isopropyl-6-oxopyridazine-1(6H)-yl)-N-(1-ethylpiperidine-3-yl)acetamide: (R)-1-ethylpiperidine-3-amine hydrochloride (563 mg, 2.80 mmol), DIPEA (1.32 g, 10.2 mmol), and HATU (1.94 g, 5.09 mmol) were added to a solution of (R)-2-(4-bromo-3-isopropyl-6-oxopyridazine-1(6H)-yl)acetic acid (700 mg, 2.54 mmol) in DMF (8 mL). The reaction mixture was stirred at 20°C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by reverse-phase preparative HPLC. LCMS: m / z = 385.0, 387.0 [M+H] + .

[0208] Example 1 N-(cis-3-hydroxy-3-methylcyclobutyl)-2-(3-isopropyl-6-oxo-4-phenylpyridazine-1(6H)-yl)acetamide [ka] 6-Chloro-5-phenylpyridazine-3(2H)-one: A mixture of 5,6-dichloropyridazine-3(2H)-one (500 mg, 3.03 mmol), phenylboronic acid (296 mg, 2.42 mmol), and K2CO3 (838 mg, 6.06 mmol) in H2O (1 mL) and 1,4-dioxane (10 mL) was mixed with Pd(dppf)Cl2 (222 mg, 0.30 mmol). The reaction mixture was stirred at 100 °C for 3 hours. The reaction mixture was filtered. The filtrate was poured into H2O (20 mL) and extracted with  (3 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by preparative TLC. LCMS: m / z = 207.0 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 12.49 (br s, 1H), 7.63-7.41 (m, 5H), 6.98 (s, 1H).

[0209] 5-phenyl-6-(propa-1-en-2-yl)pyridazine-3(2H)-one: To a solution of 6-chloro-5-phenylpyridazine-3(2H)-one (220 mg, 1.06 mmol) and 4,4,5,5-tetramethyl-2-(propa-1-en-2-yl)-1,3,2-dioxaborolane (267 mg, 1.59 mmol) in 1,4-dioxane (5 mL) and H2O (0.5 mL), Pd(dppf)Cl2 (78 mg, 0.11 mmol) and K2CO3 (293 mg, 2.12 mmol) were added. The reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was filtered. The filtrate was poured into H2O (10 mL) and extracted with Â(3 × 5 mL). The combined organic layers were washed with brine (2 × 5 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by preparative TLC. LC-MS: m / z = 213.1 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 7.46-7.33 (m, 5H), 6.87 (s, 1H), 5.23-5.17 (m, 1H), 4.96 (s, 1H), 1.80 (s, 3H).

[0210] 6-Isopropyl-5-phenylpyridazine-3(2H)-one: A solution of 5-phenyl-6-(propa-1-en-2-yl)pyridazine-3(2H)-one (150 mg, 0.71 mmol) in MeOH (10 mL) was mixed with Pd (70 mg, 10 wt% carbon-supported). The suspension was degassed under vacuum and purged three times with H2. The reaction mixture was stirred at 15°C under H2 (15 psi) for 2 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure, and the residue was used directly. LCMS: m / z = 215.1 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 7.51-7.43 (m, 3H), 7.32-7.26 (m, 2H), 6.77 (s, 1H), 3.04-2.95 (m, 1H), 1.10 (d, J = 6.8 Hz, 6H).

[0211] N-(cis-3-hydroxy-3-methylcyclobutyl)-2-(3-isopropyl-6-oxo-4-phenylpyridazine-1(6H)-yl)acetamide:6-isopropyl-5-phenylpyridazine-3(2H)-one (40 mg, 0.19 mmol) and 2-chloro-N-(cis-3-hydroxy-3-methylcyclobutyl)acetamide (33 mg, 0.19 mmol) were dissolved in CH3CN (2 mL) and Cs2CO3 (91 mg, 0.28 mmol) was added. The reaction mixture was stirred at 90 °C for 1 hour. The reaction mixture was filtered. The filtrate was poured into H2O (10 mL) and extracted with  (3 × 5 mL). The combined organic layers were washed with brine (2 × 5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by reverse-phase HPLC. LCMS: m / z = 356.2 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 7.55-7.40 (m, 3H), 7.32-7.26 (m, 2H), 7.08 (br d, J = 7.2 Hz, 1H), 6.77 (s, 1H), 4.85 (s, 2H), 4.18-3.91 (m, 1H), 3.06-2.95 (m, 1H), 2.89 (s, 1H), 2.55-2.49 (m, 2H), 2.07 (br t, J = 10 Hz, 2H), 1.36 (s, 3H), 1.10 (d, J = 6.4 Hz, 6H).

[0212] Example 2 The following compounds were prepared, or can be prepared, by the same procedure as described above. [Table 3]

[0213] Example 3 2-(3-ethyl-6-oxo-4-phenylpyridazine-1(6H)-yl)-N-(cis-3-hydroxy-3-methylcyclobutyl)acetamide [ka] 5-phenyl-6-vinylpyridazine-3(2H)-one: A solution of 6-chloro-5-phenylpyridazine-3(2H)-one (230 mg, 1.11 mmol) and potassium trifluoro(vinyl) borate (1.49 g, 11.13 mmol) in 1,4-dioxane (10 mL) and H2O (1 mL) was mixed with Pd(dppf)Cl2 (81 mg, 0.11 mmol) and Cs2CO3 (725 mg, 2.23 mmol). The reaction mixture was stirred at 100 °C for 3 hours. The reaction mixture was filtered. The filtrate was poured into H2O (10 mL) and extracted with  (3 × 5 mL). The combined organic layers were washed with brine (2 × 5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by preparative TLC. LCMS: m / z = 199.1 [M+H] + .

[0214] 6-ethyl-5-phenylpyridazine-3(2H)-one:5-phenyl-6-vinylpyridazine-3(2H)-one (130 mg, 0.66 mmol) was dissolved in MeOH (10 mL) and Pd (70 mg, 10 wt% carbon-supported) was added. The suspension was degassed under vacuum and purged three times with H2. The reaction mixture was stirred at 15°C for 2 hours under an H2 atmosphere (15 psi). The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the residue, which was used directly. LCMS: m / z = 201.1 [M+H] + . 1 H NMR (400 MHz, DMSO): δ 12.93 (br s, 1H), 7.49-7.45 (m, 3H), 7.43-7.39 (m, 2H), 6.62 (s, 1H), 2.48-2.44 (m, 2H), 0.95 (t, J = 7.6 Hz, 3H).

[0215] 2-(3-ethyl-6-oxo-4-phenylpyridazin-1(6H)-yl)-N-(cis-3-hydroxy-3-methylcyclobutyl)acetamide:6-ethyl-5-phenylpyridazin-3(2H)-one (50 mg, 0.25 mmol) and 2-chloro-N-(cis-3-hydroxy-3-methylcyclobutyl)acetamide (45 mg, 0.25 mmol) were dissolved in CH3CN (3 mL) and Cs2CO3 (122 mg, 0.37 mmol) was added. The reaction mixture was stirred at 90°C for 1 hour. The reaction mixture was poured into H2O (10 mL) and extracted with  (3 × 5 mL). The combined organic layer was washed with brine (2 × 5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by reverse-phase HPLC. LCMS: m / z = 342.2 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 7.56-7.42 (m, 3H), 7.31 (m, 2H), 6.90 (br d, J = 7.6 Hz, 1H), 6.80 (s, 1H), 4.84 (s, 2H), 4.13-3.84 (m, 1H), 2.65-2.47 (m, 4H), 2.41 (br s, 1H), 2.08 (br t, J = 10.4 Hz, 2H), 1.38 (s, 3H), 1.07 (t, J = 7.6 Hz, 3H).

[0216] Example 4 2-(4-(2-chlorophenyl)-3-isopropyl-6-oxopyridazine-1(6H)-yl)-N-(cis-3-hydroxy-3-methylcyclobutyl)acetamide [ka] 2-(4-(2-chlorophenyl)-3-isopropyl-6-oxopyridazine-1(6H)-yl)acetic acid: A solution of methyl 2-(4-bromo-3-isopropyl-6-oxopyridazine-1(6H)-yl)acetate (100 mg, 0.35 mmol) and (2-chlorophenyl)boronic acid (59 mg, 0.38 mmol) in 1,4-dioxane (2 mL) and H2O (0.5 mL) was mixed with Pd(dppf)Cl2 (13 mg, 0.017 mmol) and Cs2CO3 (225 mg, 0.69 mmol). The reaction mixture was stirred at 100°C for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water (5 mL) and washed with MTBE (2 × 3 mL). Then, aqueous HCl (3N) solution was added to the aqueous phase to adjust the pH to 3. The aqueous phase was extracted with  (2 × 3 mL). The combined organic matter was washed with brine (5 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure to obtain a residue, which was used directly as a mixture (1:1 molar ratio) of methyl 2-(4-(2-chlorophenyl)-3-isopropyl-6-oxopyridazine-1(6H)-yl)acetate and 2-(4-bromo-3-isopropyl-6-oxopyridazine-1(6H)-yl)acetic acid.

[0217] A mixture of methyl 2-(4-(2-chlorophenyl)-3-isopropyl-6-oxopyridazin-1(6H)-yl)-N-(cis-3-hydroxy-3-methylcyclobutyl)acetamide:DMF (3 mL) and methyl 2-(4-(2-chlorophenyl)-3-isopropyl-6-oxopyridazin-1(6H)-yl)acetate and 2-(4-bromo-3-isopropyl-6-oxopyridazin-1(6H)-yl)acetic acid (100 mg, 1:1 molar ratio) and cis-3-amino-1-methyl-cyclobutanol HCl salt (47 mg, 0.34 mmol) was prepared by adding DIPEA (121 mg, 0.94 mmol) and HATU (178 mg, 0.47 mmol). The reaction mixture was stirred at 20°C for 1 hour. The reaction mixture was diluted with water (5 mL) and extracted with ELISA (2 × 3 mL). The combined organic compounds were washed with brine (3 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by preparative TLC and then further purified by reverse-phase HPLC. LCMS: m / z = 390.0 [M+H] + . 1 H-NMR (400 MHz, CDCl3): δ 7.53-7.49 (m, 1H), 7.46-7.36 (m, 2H), 7.25 (m, 1H), 6.79-6.77 (m, 2H), 4.96-4.74 (m, 2H), 4.06-3.96 (m, 1H), 2.75-2.62 (m, 1H), 2.59-2.49 (m, 2H), 2.12-1.97 (m, 3H), 1.39 (s, 3H), 1.20 (d, J = 6.8 Hz, 3H), 1.00 (d, J = 6.8 Hz, 3H).

[0218] Examples 5-6 The following compounds can be manufactured or produced by the same procedure as described above. [Table 4]

[0219] Example 7 N-(cis-3-hydroxy-3-methylcyclobutyl)-2-(3-isopropyl-4-(3-methoxyphenyl)-6-oxopyridazine-1(6H)-yl)acetamide [ka] A mixture of 2-(4-bromo-3-isopropyl-6-oxopyridazine-1(6H)-yl)-N-(cis-3-hydroxy-3-methylcyclobutyl)acetamide (80 mg, 0.22 mmol) and (3-methoxyphenyl)boronic acid (41 mg, 0.27 mmol) in 1,4-dioxane (2 mL) and H2O (0.5 mL) was mixed with K2CO3 (62 mg, 0.44 mmol) and Pd(dppf)Cl2 (16 mg, 0.022 mmol). The reaction mixture was stirred at 100°C for 2 hours. The reaction mixture was poured into water (10 mL) and extracted with siRNA (3 × 5 mL). The combined organic matter was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by reverse-phase HPLC. LCMS: m / z = 386.1 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 7.39 (m, 1H), 7.00 (m, 1H), 6.88 (m, 1H), 6.84-6.76 (m, 3H), 4.83 (s, 2H), 4.01 (m, 1H), 3.86 (s, 3H), 3.10-2.95 (m, 1H), 2.63-2.42 (m, 2H), 2.13-1.99 (m, 3H), 1.39 (s, 3H), 1.12 (d, J = 7.2 Hz, 6H).

[0220] Examples 8-16 The following compounds can be manufactured or produced by the same procedure as described above. [Table 5-1] [Table 5-2] [Table 5-3]

[0221] Example 17 N-(cis-3-hydroxy-3-methylcyclobutyl)-2-(3-isopropyl-6-oxo-4-(pyridine-2-yl)pyridazine-1(6H)-yl)acetamide [ka] Pd(PPh3)2Cl2 (20 mg, 0.03 mmol) was added to a solution of 2-(4-bromo-3-isopropyl-6-oxopyridazine-1(6H)-yl)-N-(cis-3-hydroxy-3-methylcyclobutyl)acetamide (100 mg, 0.30 mmol) and tributyl(2-pyridyl) stannan (154 mg, 0.42 mmol) in DMF (2 mL). The reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was poured into water (15 mL) and extracted with  (3 × 5 mL). The combined organic matter was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by reverse-phase HPLC. LCMS: m / z = 357.1 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 8.72-8.71 (m, 1H), 7.87-7.83 (m, 1H), 7.44-7.38 (m, 2H), 6.93-6.91 (br d, J = 7.6 Hz, 1H), 6.89 (s, 1H), 4.85 (s, 2H), 4.03-3.97 (m, 1H), 3.31-3.25 (m, 1H), 2.63 (s, 1H), 2.54-2.49 (m, 2H), 2.07-2.02 (m, 2H), 1.36 (s, 3H), 1.12 (d, J = 6.8 Hz, 6H).

[0222] Example 18 2-(3-chloro-6-oxo-4-phenylpyridazine-1(6H)-yl)-N-(cis-3-hydroxy-3-methylcyclobutyl)acetamide [ka] A mixture of 6-chloro-5-phenylpyridazine-3(2H)-one (50 mg, 0.24 mmol) and Cs2CO3 (118 mg, 0.36 mmol) in CH3CN (1 mL) was mixed with 2-chloro-N-(cis-3-hydroxy-3-methylcyclobutyl)acetamide (45 mg, 0.25 mmol). The reaction mixture was stirred at 90°C for 1 hour. The reaction mixture was concentrated. The crude residue was purified by reverse-phase HPLC. LCMS: m / z = 348.1 [M+H] + . 1 H-NMR (400 MHz, CDCl3): δ 7.53-7.48 (m, 3H), 7.47-7.41 (m, 2H), 6.96 (s, 1H), 6.50 (br d, J = 6.8 Hz, 1H), 4.79 (s, 2H), 4.16-3.96 (m, 1H), 2.76-2.46 (m, 2H), 2.20 (br s, 1H), 2.17-1.91 (m, 2H), 1.39 (s, 3H).

[0223] Example 19 N-(cis-3-hydroxy-3-methylcyclobutyl)-2-(3-methoxy-6-oxo-4-phenylpyridazine-1(6H)-yl)acetamide [ka] A solution of 2-(3-chloro-6-oxo-4-phenylpyridazine-1(6H)-yl)-N-(cis-3-hydroxy-3-methylcyclobutyl)acetamide (50 mg, 0.14 mmol) in MeOH (1 mL) was mixed with a solution of NaOMe (0.06 mL, 5 M in MeOH). The reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was filtered, and the filtrate was directly purified by reverse-phase HPLC. LCMS: m / z = 344.2 [M+H] + . 1H-NMR (400 MHz, CDCl3): δ 7.57-7.52 (m, 2H), 7.49-7.45 (m, 3H), 6.97 (s, 1H), 6.84 (br d, J = 6.8 Hz, 1H), 4.72 (s, 2H), 4.07-3.94 (m, 1H), 3.89 (s, 3H), 2.60-2.48 (m, 2H), 2.14-2.01 (m, 3H), 1.38 (s, 3H).

[0224] Example 20 N-(cis-3-hydroxy-3-methylcyclobutyl)-2-(6-isopropyl-3-oxo-5-phenyl-1,2,4-triazine-2(3H)-yl)acetamide [ka] 3-methyl-1-phenylbutan-1,2-dione: A solution of 3-methyl-1-phenylbutan-2-one (500 mg, 3.08 mmol) in 1,4-dioxane (10 mL) was mixed with SeO2 (684 mg, 6.16 mmol). The reaction mixture was stirred at 100 °C for 15 hours. The reaction mixture was poured into water (30 mL) and extracted with ELISA (3 × 10 mL). The combined organic matter was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography. 1 H NMR (400 MHz, CDCl3): δ 7.97-7.91 (m, 2H), 7.69-7.62 (m, 1H), 7.55-7.48 (m, 2H), 3.36 (m, 1H), 1.21 (d, J = 7.2 Hz, 6H).

[0225] To a solution of 6-isopropyl-5-phenyl-1,2,4-triazine-3(2H)-one:3-methyl-1-phenylbutan-1,2-dione (100 mg, 0.57 mmol) in AcOH (1 mL), N-aminourea HCl (69 mg, 0.62 mmol) and NaOAc (51 mg, 0.62 mmol) were added. The reaction mixture was stirred at 120°C for 15 hours. The reaction mixture was poured into water (8 mL) and extracted with  (3 × 5 mL). The combined organic matter was washed with brine (5 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain a residue, which was used directly. 1 H NMR (400 MHz, CDCl3): δ 12.07 (br s, 1H), 7.65-7.59 (m, 2H), 7.58-7.48 (m, 3H), 3.28 (m, 1H), 1.17 (d, J = 7.2 Hz, 6H).

[0226] N-(cis-3-hydroxy-3-methylcyclobutyl)-2-(6-isopropyl-3-oxo-5-phenyl-1,2,4-triazine-2(3H)-yl)acetamide:6-isopropyl-5-phenyl-1,2,4-triazine-3(2H)-one (80 mg, 0.37 mmol) and 2-chloro-N-(cis-3-hydroxy-3-methylcyclobutyl)acetamide (66 mg, 0.37 mmol) were dissolved in DMF (2 mL) and Cs2CO3 (145 mg, 0.45 mmol) was added. The reaction mixture was stirred at 90°C for 1 hour. The reaction mixture was filtered, and the filtrate was directly purified by reverse-phase HPLC. LCMS: m / z = 357.1 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 7.64-7.45 (m, 6H), 4.84 (s, 2H), 4.00 (m, 1H), 3.43 (br s, 1H), 3.24 (m, 1H), 2.47 (m, 2H), 2.13-2.06 (m, 2H), 1.32 (s, 3H), 1.15 (d, J = 7.2 Hz, 6H).

[0227] Examples 21-28 The following compounds can be manufactured or produced by the same procedure as described above. [Table 6-1] [Table 6-2] [Table 6-3]

[0228] Example 29 N-[(3R)-1-ethylpiperidine-3-yl]-2-(4-naphthalene-1-yl-6-oxo-3-propane-2-ylpyridazine-1-yl)acetamide [ka] A mixture of 2-(4-bromo-3-isopropyl-6-oxopyridazin-1-yl)-N-[rac-(3R)-1-ethyl-3-piperidyl]acetamide (18 mg, 0.05 mmol) and 1-naphthylboronic acid (16 mg, 0.09 mmol) in 1,4-dioxane (1 mL) was mixed with K2CO3 (62 mg, 0.44 mmol) and Pd(PPh3)4 (11 mg, 0.01 mmol) in water (0.14 mL). The reaction mixture was stirred at 80°C for 20 hours. The reaction mixture was poured into water (10 mL) and extracted with ELISA (3 × 5 mL). The combined organic matter was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by reverse-phase HPLC. LCMS: m / z = 433.9 [M+H] + . 1H NMR (400 MHz, CDCl3): δ 7.93 (dd, J = 7.7, 6.4 Hz, 2H), 7.56-7.52 (m, 2H), 7.50-7.46 (m, 2H), 7.34 (dt, J = 7.0, 1.2 Hz, 1H), 7.06 (s, 1H), 6.86 (d, J = 0.4 Hz, 1H), 4.99-4.87 (m, 2H), 4.21-4.17 (m, 1H), 2.72-2.60 (m, 2H), 2.57-2.43 (m, 4H), 2.27-2.20 (m, 1H), 1.86-1.53 ​​(m, 4H), 1.10-1.06 (m, 3H), 1.04-0.96 (m, 6H).

[0229] Examples 30-32 The following compounds can be prepared, or manufactured, using appropriate reagents and following the same procedures as described above. [Table 7] Example 33 N-(5-fluoropyrimidine-4-yl)-2-(4-isoquinoline-8-yl-6-oxo-3-propane-2-ylpyridazine-1-yl)acetamide [ka] A mixture of 2-(4-bromo-3-isopropyl-6-oxopyridazin-1-yl)-N-(5-fluoropyrimidine-4-yl)acetamide (39 mg, 0.11 mmol) and 8-isoquinolylboronic acid (36 mg, 0.21 mmol) in 1,4-dioxane (1.5 mL) was mixed with K2CO3 (58 mg, 0.42 mmol) and Pd(PPh3)4 (18 mg, 0.15 mmol) in water (0.13 mL). The reaction mixture was stirred at 80°C for 20 hours. The reaction mixture was poured into water (10 mL) and extracted with Â(3 × 5 mL) ethyl acetate. The combined organic matter was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by reverse-phase HPLC. LCMS: m / z = 419.6 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 9.21 (s, 1H), 9.03 (s, 1H), 8.79 (d, J = 2.1 Hz, 1H), 8.64 (d, J = 5.8 Hz, 1H), 8.52 (d, J = 2.4 Hz, 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.87-7.81 (m, 2H), 7.53 (dd, J = 7.0, 0.9 Hz, 1H), 6.95 (s, 1H), 5.60-5.39 (m, 2H), 2.56-2.49 (m, 1H), 1.04 (dd, J = 14.3, 6.8 Hz, 6H).

[0230] Example 34 2-(3-ethoxy-6-oxo-4-phenylpyridazine-1(6H)-yl)-N-(cis-3-hydroxy-3-methylcyclobutyl)acetamide [ka] A mixture of NaH (14 mg, 0.35 mmol, 60% purity) in EtOH (1 mL) was stirred at 20°C for 15 minutes. 2-(3-chloro-6-oxo-4-phenylpyridazine-1(6H)-yl)-N-(cis-3-hydroxy-3-methylcyclobutyl)acetamide (40 mg, 0.11 mmol) was added to this solution, and the reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was concentrated under reduced pressure and purified directly by reverse-phase preparative HPLC. LCMS: m / z = 358.2 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 7.60-7.53 (m, 2H), 7.47 (m, 3H), 6.96 (s, 1H), 6.94-6.84 (m, 1H), 4.70 (s, 2H), 4.27 (m, 2H), 4.05-3.91 (m, 1H), 2.60-2.45 (m, 2H), 2.17-1.99 (m, 2H), 1.42-1.26 (m, 6H).

[0231] Example 35 2-[5-ethyl-4-(3-fluorophenyl)-6-oxo-3-propane-2-ylpyridazine-1-yl]-N-(5-fluoropyrimidine-4-yl)acetamide [ka] To a solution of methyl 2-(3,4-dichloro-6-oxopyridazine-1(6H)-yl)acetic acid (20 g, 59.1 mmol, purity 70%) in 1,4-dioxane (200 mL) and water (40 mL), (3-fluorophenyl)boronic acid (12.4 g, 88.6 mmol), Na2CO3 (12.5 g, 118 mmol), and Pd(PPh3)4 (3.4 g, 2.9 mmol) were added. The mixture was stirred at 100°C for 16 hours. The mixture was poured into water (200 mL) and the pH was adjusted to 9 with NaHCO3. The mixture was extracted with ELISA (150 mL). The aqueous phase was adjusted to pH=5 with HCl (3M) aqueous solution and extracted with RINKAN (3 × 70 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude residue was used directly. LCMS: m / z = 283.1, 285.1 [M+H] + .

[0232] 2-(4-(3-fluorophenyl)-6-oxo-3-(propa-1-en-2-yl)pyridazin-1(6H)-yl)acetic acid: To a solution of 2-(3-chloro-4-(3-fluorophenyl)-6-oxopyridazin-1(6H)-yl)acetic acid (16 g, 56 mmol) in 1,4-dioxane (160 mL) and water (40 mL), 4,4,5,5-tetramethyl-2-(propa-1-en-2-yl)-1,3,2-dioxaborolane (47 g, 283 mmol), Cs2CO3 (74 g, 226 mmol), and Pd(dppf)Cl2 (4.2 g, 5.7 mmol) were added. The mixture was stirred at 110°C for 16 hours. The mixture was poured into water (200 mL) and extracted with ELISA (150 mL). The aqueous phase was adjusted to pH=5 with HCl (3M) aqueous solution and extracted with siRNA (3 × 70 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure. The crude residue was used directly. LCMS: m / z = 289.2 [M+H] + .

[0233] 2-(4-(3-fluorophenyl)-6-oxo-3-(propa-1-en-2-yl)pyridazin-1(6H)-yl)methyl acetate: (diazomethyl)trimethylsilane (2M in n-hexane, 55.5mL) was added at 0°C to a solution of 2-(4-(3-fluorophenyl)-6-oxo-3-(propa-1-en-2-yl)pyridazin-1(6H)-yl)acetic acid (16g, 55 mmol) in MeCN (160mL). The mixture was stirred at 25°C for 16 hours. The mixture was added to AcOH to adjust the pH to 6. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography. LCMS: m / z = 303.3 [M+H] + .

[0234] 2-(4-(3-fluorophenyl)-3-isopropyl-6-oxopyridazine-1(6H)-yl)methyl acetate: 2-(4-(3-fluorophenyl)-6-oxo-3-(propa-1-en-2-yl)pyridazine-1(6H)-yl)methyl acetate (10 g, 33 mmol) was dissolved in ELISA (70 mL) and Pd / C (2 g, 10% purity) was added. The mixture was stirred at 20°C under H2 (15 psi) for 2 hours. The mixture was filtered and concentrated under reduced pressure. The crude residue was used directly. LCMS: m / z = 305.1 [M+H] + .

[0235] 2-(5-ethyl-4-(3-fluorophenyl)-3-isopropyl-6-oxopyridazine-1(6H)-yl)methyl acetate: To a solution of 2-(4-(3-fluorophenyl)-3-isopropyl-6-oxopyridazine-1(6H)-yl)methyl acetate (500 mg, 1.64 mmol) and propionic acid (6 g, 82 mmol) in water (5 mL) and MeCN (5 mL), (NH4)2S2O8 (936 mg, 4.10 mmol) and AgNO3 (557 mg, 3.28 mmol) was added. The mixture was stirred at 20°C for 16 hours. Then, the mixture was stirred at 50°C for a further 4 hours. The reaction mixture was diluted with water (10 mL) and extracted with RINKAN (3 × 8 mL). The combined organic matter was washed with brine (8 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel chromatography. LCMS: m / z = 333.2 [M+H] + .

[0236] 2-[5-ethyl-4-(3-fluorophenyl)-6-oxo-3-propan-2-ylpyridazin-1-yl]-N-(5-fluoropyrimidine-4-yl)acetamide: To a solution of methyl 2-(5-ethyl-4-(3-fluorophenyl)-3-isopropyl-6-oxopyridazin-1(6H)-yl)acetate (190 mg, 0.57 mmol) and 5-fluoropyrimidine-4-amine (194 mg, 1.71 mmol) in toluene (2 mL) and THF (2 mL), AlMe3 (2 M, 0.86 mL) was added all at once at 20 °C. The mixture was stirred at 110 °C for 4 hours. The reaction mixture was poured into cold H2O (8 mL) and extracted with ELISA (3 × 5 mL). The combined organic matter was dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by reverse-phase preparative HPLC. LCMS: m / z = 414.2 [M+H] + . 1H NMR (400 MHz, CDCl3): δ 9.40 (br s, 1H), 8.80 (s, 1H), 8.50 (d, J = 2.0 Hz, 1H), 7.53-7.43 (m, 1H), 7.21-7.12 (m, 1H), 6.97 (br d, J = 7.6 Hz, 1H), 6.91 (br d, J = 8.8 Hz, 1H), 5.34 (s, 2H), 2.59 (m, 1H), 2.37 (m, 2H), 1.11-1.01 (m, 9H).

[0237] Example 36 2-[4-(3-fluorophenyl)-5-methyl-6-oxo-3-propane-2-ylpyridazine-1-yl]-N-(5-fluoropyrimidine-4-yl)acetamide [ka] 2-(4-(3-fluorophenyl)-3-isopropyl-5-methyl-6-oxopyridazine-1(6H)-yl)methyl acetate (500 mg, 1.64 mmol) and AcOH (4.93 g, 82.2 mmol) were dissolved in water (5 mL) and MeCN (5 mL). Ammonia; sulfooxysulfate (937 mg, 4.11 mmol) and AgNO3 (558 mg, 3.29 mmol) were added. The reaction mixture was stirred at 20 °C for 16 hours. The reaction mixture was poured into brine (30 mL) and extracted with RINKAN (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography. LCMS: m / z = 319.1 [M+H] + .

[0238] 2-[4-(3-fluorophenyl)-5-methyl-6-oxo-3-propan-2-ylpyridazin-1-yl]-N-(5-fluoropyrimidine-4-yl)acetamide: methyl 2-(4-(3-fluorophenyl)-3-isopropyl-5-methyl-6-oxopyridazin-1(6H)-yl)acetate (110 mg, 0.34 mmol) and 5-fluoropyrimidine-4-amine (117 mg, 1.04 mmol) were dissolved in toluene (5 mL) and AlMe3 (2 M in toluene, 0.5 mL, 1.04 mmol) was added. The reaction mixture was stirred at 80°C for 3 hours. The reaction mixture was poured into saturated NH4Cl aqueous solution (10 mL) and extracted with RINKAN (3 × 5 mL). The combined organic layer was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 400.1 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 9.14 (s, 1H), 8.79 (s, 1H), 8.51 (s, 1H), 7.62-7.41 (m, 1H), 7.16 (t, J = 8.4 Hz, 1H), 6.96 (d, J = 7.6 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 5.37 (s, 2H), 2.65 (m, 1H), 1.96 (s, 3H), 1.08 (t, J = 6.8 Hz, 6H).

[0239] Example 37 2-[5-(difluoromethyl)-4-(3-fluorophenyl)-6-oxo-3-propane-2-ylpyridazine-1-yl]-N-(5-fluoropyrimidine-4-yl)acetamide [ka] To a solution of methyl 2-(5-(difluoromethyl)-4-(3-fluorophenyl)-3-isopropyl-6-oxopyridazine-1(6H)-yl)acetate (1.0 g, 3.29 mmol) and 2,2-difluoroacetic acid (442 mg, 4.60 mmol) in water (6 mL) and MeCN (1.5 mL), TFA (75 mg, 0.66 mmol) and AgNO3 (112 mg, 0.66 mmol) in water (2 mL) were added at 55°C. Ammonia; sulfooxysulfate (1.2 g, 5.26 mmol) in water (6 mL) was added to this mixture. The reaction mixture was stirred at 70°C for 1 hour. The reaction mixture was poured into cold water (10 mL) and extracted with SiO2 (3 × 8 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography. 1 H NMR (400 MHz, CDCl3): δ 7.48 (td, J = 8.0, 5.6 Hz, 1H), 7.17-7.23 (m, 1H), 7.05 (d, J = 7.6 Hz, 1H), 6.97-7.02 (m, 1H), 5.98 (t, J = 53.2 Hz, 1H), 5.01 (s, 2H), 3.85 (s, 3H), 2.64-2.73 (m, 1H), 1.08 (dd, J = 10.4, 6.8 Hz, 6H).

[0240] 2-[5-(difluoromethyl)-4-(3-fluorophenyl)-6-oxo-3-propan-2-ylpyridazin-1-yl]-N-(5-fluoropyrimidine-4-yl)acetamide: AlMe3 (2M in toluene, 0.42 mL) was added to a solution of methyl 2-(5-(difluoromethyl)-4-(3-fluorophenyl)-3-isopropyl-6-oxopyridazin-1(6H)-yl)acetate (100 mg, 0.28 mmol) and 5-fluoropyrimidine-4-amine (96 mg, 0.85 mmol) in toluene (1 mL) and THF (0.5 mL). The reaction mixture was stirred at 110°C for 5 hours. The reaction mixture was diluted with water (5 mL) and extracted with ELISA (3 × 5 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 436.2 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 8.78 (d, J = 2.0 Hz, 1H), 8.53 (m, 2H), 7.44-7.52 (m, 1H), 7.20 (td, J = 8.4, 1.6 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 7.00 (br d, J = 8.8 Hz, 1H), 6.87 (t, J = 53.2 Hz, 1H), 5.53 (s, 2H), 2.64-2.73 (m, 1H), 1.09 (dd, J = 9.6, 6.8 Hz, 6H).

[0241] Example 38 2-[4-(3,5-difluorophenyl)-5-methyl-6-oxo-3-propane-2-ylpyridazine-1-yl]-N-(5-fluoropyrimidine-4-yl)acetamide [ka] A mixture of 2-(4-(3,5-difluorophenyl)-3-isopropyl-5-methyl-6-oxopyridazine-1(6H)-yl)methyl acetate (300 mg, 0.93 mmol), AcOH (2.79 g, 46.54 mmol), (NH4)2S2O8 (531 mg, 2.33 mmol), and AgNO3 (316 mg, 1.86 mmol) in water (3 mL) and MeCN (3 mL) was stirred at 20°C for 16 hours. The reaction mixture was poured into brine (8 mL) and the mixture was extracted with RINKAN (3 × 3 mL). The combined organic matter was washed with brine (8 mL), dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel chromatography. LCMS: m / z = 337.2 [M+H] + .

[0242] 2-[4-(3,5-difluorophenyl)-5-methyl-6-oxo-3-propan-2-ylpyridazin-1-yl]-N-(5-fluoropyrimidine-4-yl)acetamide: To a solution of methyl 2-(4-(3,5-difluorophenyl)-3-isopropyl-5-methyl-6-oxopyridazin-1(6H)-yl)acetate (60 mg, 0.18 mmol) in toluene (1 mL) and THF (1 mL), 5-fluoropyrimidine-4-amine (61 mg, 0.54 mmol) and AlMe3 (2 M, 0.54 mmol, 0.27 mL in toluene) were added under N2 conditions. The mixture was stirred at 110°C for 3 hours. The mixture was diluted with water (3 mL) and extracted with ELISA (3 × 1 mL). The combined organic compounds were washed with brine (3 mL), dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by reverse-phase preparative HPLC. LCMS: m / z = 418.1 [M+H] + . 1H NMR (400 MHz, CDCl3): δ 8.78 (d, J = 1.6 Hz, 1H), 8.51 (d, J = 2.4 Hz, 1H), 6.96-6.87 (m, 1H), 6.77-6.70 (m, 2H), 5.39 (s, 2H), 2.66-2.58 (m, 1H), 1.97 (s, 3H), 1.10 (d, J = 6.8 Hz, 6H).

[0243] Example 39 N-[(3R)-1-cyclopropylpiperidine-3-yl]-2-[4-(3-fluorophenyl)-6-oxo-3-propane-2-ylpyridazine-1-yl]acetamide [ka] (R)-tert-butyl=3-(2-(4-bromo-3-isopropyl-6-oxopyridazine-1(6H)-yl)acetamide)piperidine-1-carboxylate: 0.7 g, 2.54 mmol) and tert-butyl=(3R)-3-aminopiperidine-1-carboxylate (559 mg, 2.8 mmol) were added to a mixture of 2-(4-bromo-3-isopropyl-6-oxopyridazine-1-yl)acetic acid (0.7 g, 2.54 mmol) and tert-butyl=(3R)-3-aminopiperidine-1-carboxylate (559 mg, 2.8 mmol) in 7 mL of (R)-tert-butyl=3-(2-(4-bromo-3-isopropyl-6-oxopyridazine-1-yl)acetamide)piperidine-1-carboxylate: 1.3 g, 10.2 mmol and T3P (3.02 mL, 5.1 mmol, 50% purity in ethyl) at 0°C. The mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl (3 × 8 mL). The combined organic matter was washed with brine (8 mL), dried over anhydrous sodium 2 SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z = 357.1, 359.1 [M-99] +

[0244] A mixture of (R)-tert-butyl=3-(2-(4-(3-fluorophenyl)-3-isopropyl-6-oxopyridazine-1(6H)-yl)acetamide)piperidine-1-carboxylate (300 mg, 0.65 mmol) and (3-fluorophenyl)boronic acid (110 mg, 0.78 mmol) in 1,4-dioxane (3 mL) and water (0.5 mL) was mixed with Cs2CO3 (427 mg, 1.3 mmol) and Pd(dppf)Cl2 (48 mg, 0.065 mmol). The mixture was stirred at 100°C for 3 hours. The residue was diluted with water (10 mL) and extracted with ₹ (3 × 5 mL). The combined organic matter was washed with brine (8 mL), dried over anhydrous sodium ₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z = 373.2 [M-99] + .

[0245] (R)-2-(4-(3-fluorophenyl)-3-isopropyl-6-oxopyridazine-1(6H)-yl)-N-(piperidine-3-yl)acetamideHCl salt: (R)-tert-butyl=3-(2-(4-(3-fluorophenyl)-3-isopropyl-6-oxopyridazine-1(6H)-yl)acetamide)piperidine-1-carboxylate (370 mg, 0.78 mmol) was mixed in HCl (4 M in HCl, 5 mL) and stirred for 2 hours. The mixture was concentrated under reduced pressure, and the residue was used directly. LCMS: m / z = 373.1 [M+H] + .

[0246] Et3N (19.8 mg, 0.19 mmol) was added to a solution of N-[(3R)-1-cyclopropylpiperidine-3-yl]-2-[4-(3-fluorophenyl)-6-oxo-3-propane-2-ylpyridazine-1-yl]acetamide:(R)-2-(4-(3-fluorophenyl)-3-isopropyl-6-oxopyridazine-1(6H)-yl)-N-(piperidine-3-yl)acetamide HCl (40 mg, 0.1 mmol) in MeOH (2.5 mL). The reaction mixture was stirred at 20°C for 0.5 hours, followed by the addition of AcOH (0.5 mL), (1-ethoxycyclopropoxy)-trimethyl-silane (34.1 mg, 0.19 mmol), MgSO4 (23.6 mg, 0.19 mmol), and NaBH3CN (12.3 mg, 0.19 mmol). The reaction mixture was stirred at 60°C for a further 12 hours. The mixture was filtered and purified by reverse-phase preparative HPLC. LCMS: m / z = 413.2 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 7.46 (m, 1H), 7.18 (dt, J = 2.0, 8.4 Hz, 1H), 7.09 (d, J = 7.6 Hz, 1H), 7.04 (m, 1H), 6.77 (s, 1H), 6.52 (br d, J = 6.6 Hz, 1H), 4.83 (d, J = 2.4 Hz, 2H), 4.06 (br s, 1H), 3.02-2.93 (m, 1H), 2.73-2.71 (m, 1H), 2.57 (br s, 2H), 2.35-2.33 (m, 1H), 1.64-1.45 (m, 4H), 1.11 (t, J = 6.2 Hz, 6H), 0.48-0.38 (m, 2H), 0.33-0.24 (m, 1H), 0.19-0.09 (m, 1H).

[0247] Example 40 2-[3-Cyclobutyl-4-(3-Fluorophenyl)-6-Oxopyridazine-1-yl]-N-[(3R)-1-Ethylpiperidine-3-yl]acetamide [ka] To a solution of methyl 2-(3,4-dichloro-6-oxopyridazine-1(6H)-yl)acetic acid (20 g, 59.1 mmol) in 1,4-dioxane (200 mL) and water (40 mL), (3-fluorophenyl)boronic acid (12.4 g, 88.6 mmol), Na2CO3 (12.5 g, 118 mmol), and Pd(PPh3)4 (3.4 g, 2.9 mmol) were added. The mixture was stirred at 100°C for 16 hours. The mixture was poured into water (200 mL) and the pH was adjusted to 9 with NaHCO3. The mixture was extracted with HCl (150 mL). The aqueous phase was adjusted to 5 pH with HCl (3 M) aqueous solution and extracted with HCl (3 × 70 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude residue was used directly. LCMS: m / z = 283.1, 285.1 [M+H] +.

[0248] 2-(3-chloro-4-(3-fluorophenyl)-6-oxopyridazine-1(6H)-yl)methyl acetate: Diazomethyl(trimethyl)silane (2M 7.08mL in n-hexane) was added at 0°C to a solution of 2-(3-chloro-4-(3-fluorophenyl)-6-oxopyridazine-1(6H)-yl)acetic acid (2.0g, 7.08 mmol) in MeCN (30mL). The mixture was stirred at 20°C for 16 hours. The mixture was quenched with aqueous NH4Cl solution (60mL) and extracted with ELISA (3×20mL). The combined organic matter was washed with brine (20mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z = 297.2, 299.2 [M+H] +.

[0249] 2-(3-cyclobutyl-4-(3-fluorophenyl)-6-oxopyridazine-1(6H)-yl)acetic acid: To a solution of cyclobutyl zinc(II) bromide (0.5 M in THF, 10.1 mL) in 1,4-dioxane (5 mL), Pd(dppf)Cl2 (74 mg, 0.1 mmol) and methyl 2-(3-chloro-4-(3-fluorophenyl)-6-oxopyridazine-1(6H)-yl)acetate were added. The mixture was stirred at 80°C for 16 hours. The reaction mixture was diluted with water (2 mL) and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 303.3 [M+H] +.

[0250] 2-[3-cyclobutyl-4-(3-fluorophenyl)-6-oxopyridazine-1-yl]-N-[(3R)-1-ethylpiperidine-3-yl]acetamide:2-(3-cyclobutyl-4-(3-fluorophenyl)-6-oxopyridazine-1(6H)-yl)acetic acid (20 mg, 0.07 mmol) and (R)-1-ethylpiperidine-3-amine hydrochloride (16 mg, 0.10 mmol) were dissolved in DMF (2 mL), to which DIPEA (26 mg, 0.20 mmol) and HATU (50 mg, 0.13 mmol) were added. The mixture was stirred at 20 °C for 3 hours. The reaction mixture was directly purified by reverse-phase preparative HPLC. LCMS: m / z = 413.1 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 7.43 (td, J = 8.0, 5.6 Hz, 1H), 7.16 (td, J = 8.4, 2.4 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.96 (br d, J = 9.2 Hz, 1H), 6.82 (br s, 1H), 6.76 (s, 1H), 4.82-4.93 (m, 2H), 4.11-4.13 (m, 1H), 3.42 (m, 1H), 2.33-2.65 (m, 5H), 2.16-2.31 (m, 3H), 1.89-2.06 (m, 5H), 1.64-1.78 (m, 3H), 1.03 (t, J = 7.2 Hz, 3H).

[0251] Example 41 2-[4-(3-fluorophenyl)-6-oxo-3-propane-2-ylpyridazine-1-yl]-N-(3-fluoropyridine-2-yl)acetamide [ka] 2-[4-(3-fluorophenyl)-6-oxo-3-propane-2-ylpyridazin-1-yl]-N-(3-fluoropyridine-2-yl)acetamide: A mixture of methyl 2-(4-(3-fluorophenyl)-3-isopropyl-6-oxopyridazin-1(6H)-yl)acetate (100 mg, 0.33 mmol) and 3-fluoropyridine-2-amine (48 mg, 0.43 mmol) in toluene (3 mL) was mixed with AlMe3 (2 M, 0.49 mL in toluene). The mixture was stirred at 100°C under N2 for 3 hours. The reaction mixture was diluted with water (10 mL) and extracted with RINKAN (3 × 5 mL). The combined organic matter was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by reverse-phase preparative HPLC. LCMS: m / z = 385.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.66 (br s, 1H), 8.22 (br d, J = 4.4 Hz, 1H), 7.52-7.39 (m, 2H), 7.21-7.15 (m, 1H), 7.14-7.06 (m, 2H), 7.03 (br d, J = 8.8 Hz, 1H), 6.82 (s, 1H), 5.33 (br s, 2H), 2.97 (m, 1H), 1.13 (d, J = 6.8 Hz, 6H).

[0252] Example 42 2-[4-(3,5-difluorophenyl)-6-oxo-3-propane-2-ylpyridazine-1-yl]-N-(5-fluoropyrimidine-4-yl)acetamide [ka] 2-(4-(3,5-difluorophenyl)-3-isopropyl-6-oxopyridazine-1(6H)-yl)methyl acetate: A mixture of 2-(4-bromo-3-isopropyl-6-oxopyridazine-1(6H)-yl)methyl acetate (880 mg, 1.52 mmol), (3,5-difluorophenyl)boronic acid (200 mg, 1.27 mmol), and CsF (577 mg, 3.80 mmol) in water (2.5 mL) and THF (5 mL) was mixed with Pd(dppf)Cl2 (93 mg, 0.13 mmol). The mixture was stirred at 100 °C for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with Â(3 × 5 mL). The combined organic matter was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography. LCMS: m / z = 323.2 [M+H] + .

[0253] 2-[4-(3,5-difluorophenyl)-6-oxo-3-propan-2-ylpyridazin-1-yl]-N-(5-fluoropyrimidine-4-yl)acetamide: A mixture of methyl 2-(4-(3,5-difluorophenyl)-3-isopropyl-6-oxopyridazin-1(6H)-yl)acetate (100 mg, 0.31 mmol) and 5-fluoropyrimidine-4-amine (105 mg, 0.93 mmol) in toluene (2 mL) and THF (2 mL) was dropwise added with AlMe3 (2 M in toluene, 0.5 mL) under N2 at 20°C. The mixture was stirred at 110°C for 3 hours. The reaction mixture was poured into H2O (10 mL) at 0°C and extracted with ELISA (4 × 5 mL). The combined organic compounds were washed with brine (2 × 10 mL), dried over Na₂SO₄, filtered, concentrated under reduced pressure, and purified by reverse-phase preparative HPLC. LCMS: m / z = 404.0 [M+H] + . 1H NMR (400 MHz, CDCl3): δ 9.03 (br s, 1H), 8.77 (d, J = 1.6 Hz, 1H), 8.51 (d, J = 2.0 Hz, 1H), 6.98-6.90 (m, 1H), 6.89-6.80 (m, 3H), 5.43 (s, 2H), 2.98-2.90 (m, 1H), 1.13 (d, J = 6.8 Hz, 6H).

[0254] Example 43 2-[4-(3,5-difluorophenyl)-3-isopropyl-6-oxopyridazine-1-yl]-N-pyrimidine-2-ylacetamide [ka] 2-[4-(3,5-difluorophenyl)-3-isopropyl-6-oxopyridazin-1-yl]-N-pyrimidine-2-ylacetamide: AlMe3 (2M in toluene, 0.37mL) was added to a solution of methyl 2-(4-(3,5-difluorophenyl)-3-isopropyl-6-oxopyridazin-1(6H)-yl)acetate (80mg, 0.25 mmol) and pyrimidine-2-amine (71mg, 0.74 mmol) in toluene (2mL) and THF (2mL). The mixture was stirred at 100°C for 8 hours. The reaction mixture was poured into ice-cold water (5mL) and extracted with RINKAN (3×5mL). The combined organic matter was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by reverse-phase preparative HPLC. LCMS: m / z = 386.1 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 9.52 (br s, 1H), 8.66 (d, J = 4.8 Hz, 2H), 7.05 (t, J = 4.8 Hz, 1H), 6.93 (tt, J = 8.8, 2.4 Hz, 1H), 6.89-6.84 (m, 2H), 6.80 (s, 1H), 5.52 (s, 2H), 2.98-2.88 (m, 1H), 1.13 (d, J = 6.8 Hz, 6H).

[0255] Example 44 2-[4-(3,5-difluorophenyl)-6-oxo-3-propane-2-ylpyridazine-1-yl]-N-(5-fluoropyrimidine-2-yl)acetamide [ka] 2-[4-(3,5-difluorophenyl)-3-isopropyl-6-oxopyridazin-1-yl]-N-pyrimidine-2-ylacetamide: AlMe3 (2M in toluene, 0.47 mL) was added to a solution of methyl 2-(4-(3,5-difluorophenyl)-3-isopropyl-6-oxopyridazin-1(6H)-yl)acetate (100 mg, 0.31 mmol) and 5-fluoropyrimidine-2-amine (105 mg, 0.93 mmol) in toluene (1.5 mL) and THF (1.0 mL). The mixture was stirred at 100°C for 3 hours. The reaction mixture was poured into ice-cold water (5 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic matter was dried over anhydrous sodium 2 SO4, filtered, concentrated under reduced pressure, and purified by reverse-phase preparative HPLC. LCMS: m / z = 404.0 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 9.37 (br s, 1H), 8.51 (s, 2H), 6.93 (tt, J = 8.8, 2.4 Hz, 1H), 6.86 (br d, J = 5.4 Hz, 2H), 6.81 (s, 1H), 5.41 (s, 2H), 3.00-2.85 (m, 1H), 1.13 (d, J = 6.8 Hz, 6H).

[0256] Example 45 2-[4-(3,5-difluorophenyl)-6-oxo-3-propane-2-ylpyridazine-1-yl]-N-(3,5-difluoropyridine-2-yl)acetamide [ka] 2-[4-(3,5-difluorophenyl)-3-isopropyl-6-oxopyridazin-1-yl]-N-pyrimidine-2-ylacetamide: 2-(4-(3,5-difluorophenyl)-3-isopropyl-6-oxopyridazin-1(6H)-yl)methyl acetate (100 mg, 0.31 mmol) and 3,5-difluoropyridine-2-amine (48 mg, 0.37 mmol) were dissolved in toluene (3 mL) and AlMe3 (2 M, 0.2 mL in toluene) was added. The mixture was stirred at 80°C for 2 hours. The reaction mixture was diluted with ice-cold water (5 mL) and extracted with ELISA (3 × 5 mL). The combined organic matter was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by reverse-phase preparative HPLC. LCMS: m / z = 421.1 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 9.12 (br s, 1H), 8.12 (d, J = 1.6 Hz, 1H), 7.27 (s, 1H), 7.25-6.92 (m, 1H), 6.87-6.78 (m, 3H), 5.27 (br s, 2H), 2.98-2.88 (m, 1H), 1.12 (d, J = 6.8 Hz, 6H).

[0257] Example 46 2-[4-(3-chloro-5-fluorophenyl)-6-oxo-3-propane-2-ylpyridazine-1-yl]-N-(5-fluoropyrimidine-4-yl)acetamide [ka] 2-(4-(3-chloro-5-fluorophenyl)-3-isopropyl-6-oxopyridazine-1(6H)-yl)methyl acetate (200 mg, 0.69 mmol), (3-chloro-5-fluorophenyl)boronic acid (133 mg, 0.76 mmol), and CsF (315 mg, 2.08 mmol) were dissolved in THF (2.0 mL) and water (1.0 mL), to which Pd(dppf)Cl2 (51 mg, 0.07 mmol) was added. The mixture was stirred at 110 °C for 12 hours. The reaction mixture was quenched with water (10 mL) and extracted with Â(3 × 4 mL). The combined organic compounds were washed with brine (4 mL), dried over anhydrous Na₂SO₄, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography. LCMS: m / z = 339.1, 341.1 [M+H] + .

[0258] 2-[4-(3-chloro-5-fluorophenyl)-6-oxo-3-propan-2-ylpyridazine-1-yl]-N-(5-fluoropyrimidine-4-yl)acetamide: 2-(4-(3-chloro-5-fluorophenyl)-3-isopropyl-6-oxopyridazine-1(6H)-yl)methyl acetate (100 mg, 0.3 mmol) and 5-fluoropyrimidine-4-amine (50.1 mg, 0.44 mmol) were dissolved in toluene (3.0 mL) and AlMe3 (2 M in toluene, 0.45 mL) was added. The mixture was stirred at 50°C for 3 hours. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic matter was washed with brine (5 mL), dried over anhydrous sodium 2 SO4, filtered, concentrated under reduced pressure, and purified by reverse-phase preparative HPLC. LCMS: m / z = 420.1, 422.1 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 8.91 (br s, 1H), 8.78 (d, J = 2.0 Hz, 1H), 8.51 (d, J = 2.4 Hz, 1H), 7.22 (td, J = 2.0, 8.4 Hz, 1H), 7.12 (s, 1H), 6.96 (dd, J = 1.2, 8.4 Hz, 1H), 6.82 (s, 1H), 5.43 (s, 2H), 2.98-2.89 (m, 1H), 1.14 (d, J = 6.8 Hz, 6H).

[0259] Example 47 2-[4-[3-(2,2-difluorocyclopropyl)-5-fluorophenyl]-6-oxo-3-propane-2-ylpyridazine-1-yl]-N-(5-fluoropyrimidine-4-yl)acetamide [ka] 1-Bromo-3-fluoro-5-vinylbenzene: t-BuOK (2.87 g, 25.6 mmol) was added to a solution of methyl(triphenyl)phosphonium bromide (12.3 g, 34.5 mmol) in THF (125 mL). The reaction mixture was stirred at 20°C for 1 hour. The reaction mixture was cooled to 0°C. Then, a solution of 3-bromo-5-fluorobenzaldehyde (5.0 g, 24.6 mmol) in THF (50 mL) was added dropwise. The reaction mixture was stirred at 20°C for a further 12 hours. The reaction mixture was cooled to 0°C, diluted with saturated NH4Cl aqueous solution (100 mL), and extracted with petroleum ether (3 × 50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography.

[0260] 1-Bromo-3-(2,2-difluorocyclopropyl)-5-fluorobenzene:1-bromo-3-fluoro-5-vinylbenzene (50 mg, 0.25 mmol) was dissolved in CH3CN (2.0 mL) and TMSCF3 (354 mg, 2.49 mmol) and NaI (7 mg, 0.05 mmol) were added. The reaction mixture was stirred at 110 °C for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with MTBE (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue, which was used directly.

[0261] Pd(dppf)Cl2·CH2Cl2 (20 mg, 0.02 mmol) was added to a solution of 2-(3-(2,2-difluorocyclopropyl)-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane:4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (30 mg, 0.12 mmol), 1-bromo-3-(2,2-difluorocyclopropyl)-5-fluorobenzene (20 mg, 0.08 mmol), and KOAc (23 mg, 0.24 mmol) in 1,4-dioxane (2 mL). The reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue, which was used directly. LCMS: m / z = 299.2 [M+H] +.

[0262] 2-(4-(3-(2,2-difluorocyclopropyl)-5-fluorophenyl)-3-isopropyl-6-oxopyridazine-1(6H)-yl)methyl acetate: A mixture of 2-(3-(2,2-difluorocyclopropyl)-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (100 mg, 0.11 mmol), 2-(4-bromo-3-isopropyl-6-oxopyridazine-1(6H)-yl)methyl acetate (42 mg, 0.14 mmol), and CsF (49 mg, 0.32 mmol) in water (1.0 mL) and THF (2.0 mL) was mixed with Pd(dppf)Cl2 (8 mg, 0.01 mmol). The reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with ELISA (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography. LCMS: m / z = 381.2 [M+H] +.

[0263] AlMe3 (2M in toluene, 0.039mL) was added dropwise to a mixture of methyl 2-(4-(3-(2,2-difluorocyclopropyl)-5-fluorophenyl)-3-isopropyl-6-oxopyridazine-1(6H)-yl)acetamide (10 mg, 0.03 mmol) and 5-fluoropyrimidine-4-amine (9 mg, 0.09 mmol) in toluene (1.0 mL) and THF (1.0 mL). The reaction mixture was stirred at 110°C for 3 hours. The reaction mixture was cooled to 0°C, diluted with water (10 mL), and extracted with ELISA (4 × 5 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 462.1 [M+H] + . 1H NMR (400 MHz, CDCl3): δ 9.02 (br s, 1H), 8.78 (d, J = 1.6 Hz, 1H), 8.51 (d, J = 2.4 Hz, 1H), 7.05 (br d, J = 9.2 Hz, 1H), 6.99-6.89 (m, 2H), 6.83 (s, 1H), 5.41 (s, 2H), 2.94 (m, 1H), 2.83-2.75 (m, 1H), 2.01-1.88 (m, 1H), 1.75-1.68 (m, 1H), 1.12 (d, J = 6.8 Hz, 6H).

[0264] Example 48 2-[3-cyclopropyl-4-(3,5-difluorophenyl)-6-oxopyridazine-1-yl]-N-(5-fluoropyrimidine-4-yl)acetamide [ka] 2-(3-chloro-4-(3,5-difluorophenyl)-6-oxopyridazine-1(6H)-yl)methyl acetate (600 mg, 2.53 mmol), (3,5-difluorophenyl)boronic acid (400 mg, 2.53 mmol), and CsF (1.15 g, 7.59 mmol) were added to a mixture of 2-(3-chloro-4-(3,5-difluorophenyl)-6-oxopyridazine-1-yl)methyl acetate (600 mg, 2.53 mmol), (3,5-difluorophenyl)boronic acid (400 mg, 2.53 mmol), and CsF (1.15 g, 7.59 mmol) in 1,4-dioxane (6.0 mL). Pd(dppf)Cl2 (93 mg, 0.13 mmol) was added. The reaction mixture was stirred at 100 °C for 12 hours. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium 2 SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography. LCMS: m / z = 315.1, 317.1 [M+H] + .

[0265] Pd(dppf)Cl2 (12 mg, 0.016 mmol) was added to a mixture of methyl 2-(3-chloro-4-(3,5-difluorophenyl)-6-oxopyridazine-1(6H)-yl)acetate (100 mg, 0.32 mmol), cyclopropylboronic acid (136 mg, 1.59 mmol), and CsF (144.82 mg, 0.953 mmol) in 2-(6-bromo-4-isopropyl-1-oxophthalazine-2(1H)-yl)-N-(5-fluoropyrimidine-4-yl)propane:1,4-dioxane (5.0 mL). The reaction mixture was stirred at 80°C for 3 hours. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium 2 SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography. LCMS: m / z = 321.2 [M+H] + .

[0266] 2-[3-cyclopropyl-4-(3,5-difluorophenyl)-6-oxopyridazine-1-yl]-N-(5-fluoropyrimidine-4-yl)acetamide: A mixture of 2-(6-bromo-4-isopropyl-1-oxophthalazine-2(1H)-yl)-N-(5-fluoropyrimidine-4-yl)propanamide (130 mg, 0.41 mmol) and 5-fluoropyrimidine-4-amine (92 mg, 0.81 mmol) in toluene (5.0 mL) was mixed with AlMe3 (2 M in toluene, 0.30 mL). The reaction mixture was stirred at 80°C for 5 hours. The reaction mixture was diluted with water (10 mL) and filtered. The filtrate was extracted with ELISA (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 402.1 [M+H] + . 1H NMR (400 MHz, CDCl3): δ 8.88 (br s, 1H), 8.77 (d, J = 1.6 Hz, 1H), 8.51 (d, J = 2.4 Hz, 1H), 7.02 (br d, J = 5.6 Hz, 2H), 6.98-6.91 (m, 1H), 6.87 (s, 1H), 5.36 (s, 2H), 1.69-1.66 (m, 1H), 1.10-1.04 (m, 2H), 0.95-0.88 (m, 2H).

[0267] Example 49 2-[3-(2,2-difluorocyclopropyl)-4-(3,5-difluorophenyl)-6-oxopyridazine-1-yl]-N-(5-fluoropyrimidine-4-yl)acetamide [ka] To a solution of 2-(4-(3,5-difluorophenyl)-6-oxo-3-vinylpyridazin-1(6H)-yl)methyl acetate (2.0 g, 6.36 mmol) in 1,4-dioxane (100 mL), potassium vinyltrifluoroborate (8.51 g, 63.6 mmol), CsF (2.90 g, 19.1 mmol), and Pd(dppf)Cl2 (465 mg, 0.64 mmol) were added. The reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography. 1 H NMR (400 MHz, CDCl3): δ 6.89-6.99 (m, 3H), 6.84 (s, 1H), 6.36 (dd, J = 17.2, 10.8 Hz, 1H), 6.02 (dd, J = 17.2, 1.2 Hz, 1H), 5.41 (dd, J = 10.8, 1.2 Hz, 1H), 4.98 (s, 2H), 3.83 (s, 3H).

[0268] 2-(3-(2,2-difluorocyclopropyl)-4-(3,5-difluorophenyl)-6-oxopyridazine-1(6H)-yl)methyl acetate (100 mg, 0.33 mmol) and NaI (10 mg, 0.07 mmol) were dissolved in THF (1.0 mL) to which TMSCF3 (929 mg, 6.53 mmol) was added dropwise. The reaction mixture was stirred at 65 °C for 16 hours. Five batches of ongoing reactions were carried out in parallel and combined for workup. The combined reaction mixture was diluted with water (5 mL) and extracted with RINKAN (3 × 10 mL). The combined organic layer was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography.

[0269] 2-[3-(2,2-difluorocyclopropyl)-4-(3,5-difluorophenyl)-6-oxopyridazin-1-yl]-N-(5-fluoropyrimidine-4-yl)acetamide: AlMe3 (2M in toluene, 0.28 mL) was added to a solution of methyl 2-(3-(2,2-difluorocyclopropyl)-4-(3,5-difluorophenyl)-6-oxopyridazin-1(6H)-yl)acetate (100 mg, 0.28 mmol) and 5-fluoropyrimidine-4-amine (25.39 mg, 0.22 mmol) in toluene (1.0 mL) and THF (3.0 mL). The reaction mixture was stirred at 90°C for 3 hours. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (2 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium 2 SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 438.1 [M+H] + . 1H NMR (400 MHz, CDCl3): δ 8.77 (d, J = 2.0 Hz, 1H), 8.49-8.63 (m, 2H), 6.92-7.01 (m, 4H), 5.62 (d, J = 16.4 Hz, 1H), 5.35 (d, J = 16.4 Hz, 1H), 2.44 (m, 1H), 2.22-2.34 (m, 1H), 1.69-1.77 (m, 1H).

[0270] Example 50 2-[4-(3,5-difluorophenyl)-6-oxo-3-(2,2,2-trifluoroethyl)pyridazin-1-yl]-N-(5-fluoropyrimidine-4-yl)acetamide [ka] 2-(4-(3,5-difluorophenyl)-3-formyl-6-oxopyridazine-1(6H)-yl)methyl acetate: A solution of 2-(4-(3,5-difluorophenyl)-6-oxo-3-vinylpyridazine-1(6H)-yl)methyl acetate (1.45 g, 4.73 mmol) in DCM (20 mL) at -78 °C was bubbling with ozone for 0.5 hours, followed by the addition of Me2S (3.97 g, 63.9 mmol). The reaction mixture was heated and stirred at 20 °C for 15.5 hours. The reaction mixture was diluted with water (20 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue, which was used directly. LCMS: m / z = 309.1 [M+H] +.

[0271] 2-(4-(3,5-difluorophenyl)-6-oxo-3-(2,2,2-trifluoro-1-hydroxyethyl)pyridazin-1(6H)-yl)methyl acetate: To a solution of 2-(4-(3,5-difluorophenyl)-3-formyl-6-oxopyridazin-1(6H)-yl)methyl acetate (1.40 g, 4.54 mmol) in THF (30 mL) at 0°C, TMSCF3 (3.23 g, 22.7 mmol) and TBAF (1 M in THF, 0.45 mmol) were added. The reaction mixture was stirred at 20°C for 2 hours, followed by the addition of TBAF (1 M in THF, 9.08 mmol). The reaction mixture was stirred at 20°C for a further 4 hours. The reaction mixture was diluted with water (30 mL) and extracted with ELISA (3 × 10 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography. LCMS: m / z = 379.1 [M+H] +.

[0272] 2-(3-(1-chloro-2,2,2-trifluoroethyl)-4-(3,5-difluorophenyl)-6-oxopyridazine-1(6H)-yl)methyl acetate: A mixture of 2-(4-(3,5-difluorophenyl)-6-oxo-3-(2,2,2-trifluoro-1-hydroxyethyl)pyridazine-1(6H)-yl)methyl acetate (250 mg, 0.66 mmol) in pyridine (105 mg, 1.32 mmol) at 0°C was mixed with SOCl2 (87 mg, 0.73 mmol) and DMF (5 mg, 0.66 mmol). The reaction mixture was stirred at 50°C for 2 hours. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 × 2 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium 2 SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography. LCMS: m / z = 397.1, 399.1 [M+H] +.

[0273] 2-(4-(3,5-difluorophenyl)-6-oxo-3-(2,2,2-trifluoroethyl)pyridazin-1(6H)-yl)methyl acetate (100 mg, 0.25 mmol) was dissolved in ELISA (5.0 mL) and Pd / C (20 mg, 10% purity) was added. The reaction mixture was stirred at 20°C under an H2 atmosphere (15 psi) for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the residue, which was used directly. LCMS: m / z = 363.1 [M+H] + .

[0274] 2-[4-(3,5-difluorophenyl)-6-oxo-3-(2,2,2-trifluoroethyl)pyridazin-1-yl]-N-(5-fluoropyrimidine-4-yl)acetamide: To a solution of methyl 2-(4-(3,5-difluorophenyl)-6-oxo-3-(2,2,2-trifluoroethyl)pyridazin-1(6H)-yl)acetate (40 mg, 0.11 mmol) in toluene (1.0 mL) and THF (1.0 mL), 5-fluoropyrimidine-4-amine (18 mg, 0.17 mmol) and AlMe3 (2 M, 0.17 mL in toluene) were added. The reaction mixture was stirred at 100°C for 3 hours. The reaction mixture was diluted with water (2 mL) and extracted with ethyl acetate (3 × 1 mL). The combined organic layers were washed with brine, dried over anhydrous sodium 2 SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 444.1 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 8.77 (d, J = 2.0 Hz, 1H), 8.53 (d, J = 2.4 Hz, 1H), 8.43 (br s, 1H), 6.98 (tt, J = 2.4, 8.8 Hz, 1H), 6.90 (s, 1H), 6.89-6.83 (m, 2H), 5.58 (s, 2H), 3.42 (q, J = 9.6 Hz, 2H).

[0275] Example 51 1-[4-(3,5-difluorophenyl)-3-isopropyl-6-oxopyridazine-1-yl]-N-pyrimidine-2-ylcyclopropanecarboxamide [ka] 1-(4-(3,5-difluorophenyl)-3-isopropyl-6-oxopyridazine-1(6H)-yl)cyclopropane-carboxylate methyl:5-(3,5-difluorophenyl)-6-isopropylpyridazine-3(2H)-one (180 mg, 0.72 mmol) and 2,4-dibromobutyrate methyl (206 mg, 0.79 mmol) were dissolved in DMF (4.5 mL) and Cs2CO3 (937 mg, 2.88 mmol) was added. The reaction mixture was stirred at 45°C for 2 hours. The reaction mixture was diluted with water (30 mL) and extracted with Â(3 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by preparative TLC. LCMS: m / z = 349.0 [M+H] + .

[0276] AlMe3 (2M in toluene, 0.11mL) was added to a solution of methyl 1-(4-(3,5-difluorophenyl)-3-isopropyl-6-oxopyridazin-1-yl)-N-pyrimidine-2-yl-cyclopropanecarboxamide: 1-(4-(3,5-difluorophenyl)-3-isopropyl-6-oxopyridazin-1(6H)-yl)cyclopropanecarboxylate (80 mg, 0.23 mmol) and pyrimidine-2-amine (44 mg, 0.46 mmol) in THF (1.0 mL) and toluene (1.0 mL). The reaction mixture was stirred at 70°C for 12 hours. The reaction mixture was diluted with water (5 mL) and extracted with ELISA (3 × 5 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 412.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6): δ 9.97 (br. s, 1H), 8.70 (d, J = 4.8 Hz, 2H), 7.41 (t, J = 9.6 Hz, 1H), 7.24 (m, 3H), 6.86 (s, 1H), 2.96-2.89 (m, 1H), 1.87-1.83 (m, 2H), 1.45-1.39 (m, 2H), 1.06 (d, J = 6.8 Hz, 6H).

[0277] Example 52 2-[3-ethyl-4-(3-fluorophenyl)-5-methyl-6-oxopyridazine-1-yl]-N-(5-fluoropyrimidine-4-yl)acetamide [ka] 2-(4-(3-fluorophenyl)-6-oxo-3-vinylpyridazin-1(6H)-yl)methyl acetate: 2-(3-chloro-4-(3-fluorophenyl)-6-oxopyridazin-1(6H)-yl)methyl acetate (300 mg, 1.01 mmol) and potassium vinyltrifluoroborate (1.35 g, 10.11 mmol) were dissolved in 1,4-dioxane (10 mL) and CsF (307 mg, 2.02 mmol) and Pd(dppf)Cl2 (74 mg, 0.1 mmol) were added. The reaction mixture was stirred at 100 °C for 3 hours. The reaction mixture was diluted with water (10 mL) and extracted with Â(3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography.

[0278] 2-(3-ethyl-4-(3-fluorophenyl)-6-oxopyridazine-1(6H)-yl)methyl acetate: 2-(4-(3-fluorophenyl)-6-oxo-3-vinylpyridazine-1(6H)-yl)methyl acetate (280 mg, 0.98 mmol) was dissolved in 10 mL of ELISA, to which Pd / C (100 mg, 10% purity) was added. The mixture was degassed under vacuum and purged with H2. The reaction mixture was stirred at 20°C under an H2 atmosphere (15 psi) for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue, which was used directly.

[0279] 2-(3-ethyl-4-(3-fluorophenyl)-5-methyl-6-oxopyridazine-1(6H)-yl)methyl acetate (140 mg, 0.48 mmol) and AcOH (1.45 g, 24.1 mmol) in a solution of 2-(3-ethyl-4-(3-fluorophenyl)-6-oxopyridazine-1(6H)-yl)methyl acetate (140 mg, 0.48 mmol) and AcOH (1.45 g, 24.1 mmol) were added to ammonia; hydrogen sulfoxysulfate (275 mg, 1.21 mmol) and AgNO3 (164 mg, 0.96 mmol). The reaction mixture was stirred at 20°C for 16 hours, then stirred at 50°C for a further 4 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography. LCMS: m / z = 305.1 [M+H] + .

[0280] AlMe3 (2M in toluene, 0.50 mL) was added to a solution of methyl 2-(3-ethyl-4-(3-fluorophenyl)-5-methyl-6-oxopyridazin-1-yl)acetamide (100 mg, 0.33 mmol) and 5-fluoropyrimidine-4-amine (37 mg, 0.33 mmol) in THF (1.0 mL) and toluene (1.0 mL). The reaction mixture was stirred at 90°C for 3 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl phosphate (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 386.1 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 9.25-8.92 (m, 1H), 8.86-8.72 (m, 1H), 8.50 (br s, 1H), 7.52-7.45 (m, 1H), 7.16 (dt, J = 2.0, 8.4 Hz, 1H), 6.96 (d, J = 7.6 Hz, 1H), 6.90 (br d, J = 8.4 Hz, 1H), 5.41 (s, 2H), 2.36 (q, J = 7.6 Hz, 2H), 1.98 (s, 3H), 1.08-1.02 (t, J = 8.0 Hz, 3H).

[0281] Example 53 2-[3-(difluoromethyl)-4-(3,5-difluorophenyl)-6-oxopyridazine-1-yl]-N-(5-fluoropyrimidine-2-yl)acetamide [ka] A solution of 2-(3-(difluoromethyl)-4-(3,5-difluorophenyl)-6-oxopyridazine-1(6H)-yl)methyl acetate (1.30 g, 4.22 mmol) in BAST (13.1 g, 59.4 mmol) was stirred at 20°C for 12 hours. The reaction mixture was poured into ice-cold saturated NaHCO3 aqueous solution (50 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography. 1 H NMR (400 MHz, CDCl3): δ 6.98-6.94 (m, 3H), 6.90 (s, 1H), 6.42 (t, J = 53.6 Hz, 1H), 4.96 (s, 2H), 3.84 (s, 3H).

[0282] 2-[3-(difluoromethyl)-4-(3,5-difluorophenyl)-6-oxopyridazine-1-yl]-N-(5-fluoropyrimidine-2-yl)acetamide: A mixture of 5-fluoropyrimidine-2-amine (205 mg, 1.82 mmol) and 2-(3-(difluoromethyl)-4-(3,5-difluorophenyl)-6-oxopyridazine-1(6H)-yl)methyl acetate (200 mg, 0.61 mmol) in toluene (5.0 mL) was mixed with trimethyl-(4-trimethylalmanuidyl-1,4-diazoniabicyclo[2.2.2]octan-1-yl)almanuiid (139 mg, 0.55 mmol). The reaction mixture was stirred at 60°C for 12 hours. The reaction mixture was cooled to 0°C, diluted with water (10 mL), and extracted with ELISA (4 × 5 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude residue was purified by preparative TLC and subsequently by preparative SFC. LC-MS: m / z = 412.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6): δ 11.22 (s, 1H), 8.79 (s, 2H), 7.49-7.40 (m, 1H), 7.30 (br d, J = 6.0 Hz, 2H), 7.13 (s, 1H), 6.89 (t, J = 53.2 Hz, 1H), 5.21 (s, 2H).

[0283] Example 54 2-[4-(5-fluoropyridin-3-yl)-6-oxo-3-propane-2-ylpyridazine-1-yl]-N-(5-fluoropyrimidine-2-yl)acetamide [ka] 2-(4-(5-fluoropyridine-3-yl)-3-isopropyl-6-oxopyridazine-1(6H)-yl)methyl acetate (200 mg, 0.69 mmol) was dissolved in 1,4-dioxane (2.0 mL) and (5-fluoropyridine-3-yl)boronic acid (292 mg, 2.08 mmol), CsF (315 mg, 2.08 mmol), and Pd(dppf)Cl2 (51 mg, 0.07 mmol) were added. The reaction mixture was stirred at 90°C for 4 hours. The reaction mixture was diluted with water (5 mL) and extracted with Â(3 × 2 mL). The combined organic layers were washed with brine (3 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography. LCMS: m / z = 306.1 [M+H] + .

[0284] 2-[4-(5-fluoropyridine-3-yl)-6-oxo-3-propan-2-ylpyridazin-1-yl]-N-(5-fluoropyrimidine-2-yl)acetamide: To a solution of methyl 2-(4-(5-fluoropyridine-3-yl)-3-isopropyl-6-oxopyridazin-1(6H)-yl)acetate (100 mg, 0.33 mmol) in toluene (1.0 mL) and THF (0.5 mL), 5-fluoropyrimidine-2-amine (111 mg, 0.98 mmol) and AlMe3 (2 M in toluene, 0.49 mL) were added. The reaction mixture was stirred at 90°C for 6 hours. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 × 2 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium 2 SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 387.1 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 9.08 (br s, 1H), 8.61 (d, J = 2.8 Hz, 1H), 8.51 (s, 2H), 8.44 (s, 1H), 7.42 (td, J = 2.4, 8.4 Hz, 1H), 6.85 (s, 1H), 5.42 (br s, 2H), 2.93-2.84 (m, 1H), 1.14 (d, J = 6.8 Hz, 6H).

[0285] Example 55 2-[4-(3,5-difluorophenyl)-3-(1-fluoropropan-2-yl)-6-oxopyridazine-1-yl]-N-(5-fluoropyrimidine-2-yl)acetamide [ka] 2-(4-(3,5-difluorophenyl)-6-oxo-3-(propa-1-en-2-yl)pyridazin-1(6H)-yl)methyl acetate (5.0 g, 15.9 mmol) and 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (26.7 g, 158.9 mmol) were dissolved in 1,4-dioxane (100 mL) and CsF (7.24 g, 47.7 mmol) and Pd(dppf)Cl2 (1.16 g, 1.59 mmol) were added. The reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was filtered. The filtrate was diluted with water (150 mL) and extracted with ₹ (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium ₂SO₄, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography. LCMS: m / z = 321.0 [M+H] + .

[0286] 2-(4-(3,5-difluorophenyl)-3-(1-hydroxypropan-2-yl)-6-oxopyridazine-1(6H)-yl)methyl acetate: 1.80 g, 5.62 mmol of 2-[4-(3,5-difluorophenyl)-3-isopropenyl-6-oxopyridazine-1-yl]methyl acetate (30 mL) was dissolved in DCM (30 mL) and 9-BBN (0.5 Min THF, 39.3 mL) was added. The reaction mixture was stirred at 50 °C for 64 hours. The reaction mixture was diluted with water (60 mL) and the pH was adjusted to 8 by adding saturated Na2CO3 aqueous solution. The reaction mixture was then cooled to 0 °C, followed by the addition of H2O2 (2.55 g, 22.48 mmol, 36% purity). The reaction mixture was stirred at 15 °C for 1 hour. The reaction mixture was quenched with saturated Na2S2O3 aqueous solution (20 mL) and extracted with RINKAN (3 × 20 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by reverse-phase HPLC. LCMS: m / z = 339.0 [M+H] + .

[0287] 2-(4-(3,5-difluorophenyl)-3-(1-fluoropropan-2-yl)-6-oxopyridazine-1(6H)-yl)methyl acetate: A solution of 2-(4-(3,5-difluorophenyl)-3-(1-hydroxypropan-2-yl)-6-oxopyridazine-1(6H)-yl)methyl acetate (300 mg, 0.887 mmol) in DCM (3 mL) at 0°C was added to a solution of BAST (1.96 g, 8.87 mmol, 1.94 mL). The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was cooled to 0°C, diluted with DCM (5 mL), and quenched with saturated NaHCO3 aqueous solution (10 mL). The resulting mixture was extracted with Depositphotos (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography. LCMS: m / z = 341.0 [M+H] + .

[0288] 2-[4-(3,5-difluorophenyl)-3-(1-fluoropropan-2-yl)-6-oxopyridazine-1-yl]-N-(5-fluoropyrimidine-2-yl)acetamide: Trimethyl-(4-trimethylalmanuidyl-1,4-diazoniabicyclo[2.2.2]octan-1-yl)almanuiid (75 mg, 0.29 mmol) was added to a solution of 2-(4-(3,5-difluorophenyl)-3-(1-fluoropropan-2-yl)-6-oxopyridazine-1(6H)-yl)methyl acetate (100 mg, 0.294 mmol) and 5-fluoropyrimidine-2-amine (37 mg, 0.32 mmol) in DCE (3.0 mL). The reaction mixture was stirred at 80°C for 24 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 422.0 [M+H] + . 1H NMR (400 MHz, CDCl3): δ 9.13-8.84 (m, 1H), 8.62-8.45 (m, 2H), 7.04-6.79 (m, 4H), 5.58-5.24 (m, 2H), 4.74-4.30 (m, 2H), 3.33-3.09 (m, 1H), 1.13 (dd, J = 1.2, 6.8 Hz, 3H).

[0289] Example 56 2-[3-Cyclobutyl-4-(3,5-difluorophenyl)-6-oxopyridazine-1-yl]-N-(5-fluoropyrimidine-2-yl)acetamide [ka] 1-Cyclobutyl-2-(3,5-difluorophenyl)ethanone: 1-Cyclobutylethanone (1.02 g, 10.4 mmol) was added to a mixture of 1-bromo-3,5-difluorobenzene (1.0 g, 5.18 mmol), (5-diphenylphosphanyl-9,9-dimethyl-xanthene-4-yl)-diphenylphosphan (60 mg, 0.11 mmol), Pd2(dba)3 (48 mg, 0.05 mmol), and t-BuONa (598 mg, 6.22 mmol) in THF (15 mL). The reaction mixture was stirred at 50°C for 7 hours. The reaction mixture was diluted with water (10 mL) and extracted with Â(3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography.

[0290] (Z)-Ethyl=4-cyclobutyl-3-(3,5-difluorophenyl)-4-oxobuta-2-enoate: Et3N (3.64 g, 35.9 mmol) was added to a mixture of 1-cyclobutyl-2-(3,5-difluorophenyl)ethanone (1.0 g, 4.76 mmol) and 2-oxoethyl acetate (971 mg, 4.76 mmol) in toluene (10 mL). The reaction mixture was stirred at 20 °C for 12 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium 2 SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography.

[0291] A mixture of ethyl=(Z)-4-cyclobutyl-3-(3,5-difluorophenyl)-4-oxobuta-2-enoate (900 mg, 3.06 mmol) in 6-cyclobutyl-5-(3,5-difluorophenyl)pyridazine-3(2H)-one:EtOH (5.0 mL) was mixed with NH2NH2·H2O (1.56 g, 30.6 mmol). The reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with ELISA (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography. LCMS: m / z = 263.0 [M+H] + .

[0292] A mixture of 6-cyclobutyl-5-(3,5-difluorophenyl)pyridazin-3(2H)-one (40 mg, 0.15 mmol) and 2-bromomethyl acetate (35 mg, 0.23 mmol) in 2-(3-cyclobutyl-4-(3,5-difluorophenyl)-6-oxopyridazin-1(6H)-yl)methyl acetate:DMF (1.0 mL) was mixed with Cs2CO3 (76 mg, 0.23 mmol). The reaction mixture was stirred at 20°C for 1 hour. The reaction mixture was diluted with water (10 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 crude residue was purified by preparative TLC. LCMS: m / z = 335.0 [M+H] + .

[0293] AlMe3 (2.0 M in toluene, 0.2 mL) was added to a mixture of methyl 2-(3-cyclobutyl-4-(3,5-difluorophenyl)-6-oxopyridazine-1(6H)-yl)acetate (40 mg, 0.12 mmol) and 5-fluoropyrimidine-2-amine (41 mg, 0.36 mmol) in 2-[3-cyclobutyl-4-(3,5-difluorophenyl)-6-oxopyridazine-1(6H)-yl)acetamide:DCE (1.0 mL). The reaction mixture was stirred at 80°C for 1 hour. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 416.0 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 9.22 (br s, 1H), 8.52 (s, 2H), 6.92 (br t, J = 8.8 Hz, 1H), 6.86-6.78 (m, 3H), 5.43 (br s, 2H), 3.41 (quin, J = 8.4 Hz, 1H), 2.37-2.19 (m, 2H), 2.06-1.70 (m, 4H).

[0294] Example 57 2-[4-(3,5-difluorophenyl)-3-methoxy-6-oxopyridazine-1-yl]-N-(5-fluoropyrimidine-2-yl)acetamide [ka] A mixture of methyl 2-(3-chloro-4-(3,5-difluorophenyl)-6-oxopyridazine-1(6H)-yl)acetate (500 mg, 1.59 mmol) in methyl 2-(4-(3,5-difluorophenyl)-3-methoxy-6-oxopyridazine-1(6H)-yl)acetate (500 mg, 1.59 mmol) in methyl 2-(4-(3,5-difluorophenyl)-6-oxopyridazine-1(6H)-yl)acetate (10 mL) was mixed with NaOMe (129 mg, 2.38 mmol). The reaction mixture was stirred at 35°C for 12 hours. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 311.2 [M+H] +.

[0295] Trimethyl-(4-trimethylalmanuidyl-1,4-diazoniabicyclo[2.2.2]octan-1-yl)almanoid (54 mg, 0.21 mmol) was added to a mixture of methyl 2-(4-(3,5-difluorophenyl)-3-methoxy-6-oxopyridazine-1(6H)-yl)acetate (50 mg, 0.16 mmol) and 5-fluoropyrimidine-2-amine (37 mg, 0.32 mmol) in 2-[4-(3,5-difluorophenyl)-3-methoxy-6-oxopyridazine-1(6H)-yl)acetamide:DCE (1.0 mL). The reaction mixture was stirred at 80°C for 12 hours. The reaction mixture was diluted with water (10 mL) and extracted with ELISA (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by reverse-phase preparative HPLC, followed by preparative SFC. LCMS: m / z = 392.0 [M+H] + . 1H NMR (400 MHz, CDCl3): δ 9.11 (br s, 1H), 8.50 (s, 2H), 7.16-7.04 (m, 2H), 7.01 (s, 1H), 6.93 (tt, J = 2.4, 8.8 Hz, 1H), 5.26 (br s, 2H), 3.89 (s, 3H).

[0296] Biological Example 1 Biochemical assay of compounds The compounds provided herein were tested using the following assays. Cell culture media containing RPMI1640 medium (89%), FBS (10%), Pen / Strep (1%), and 2-mercaptoethanol (0.05 mM) were used. The frozen medium consisted of 90% FBS and 10% DMSO. THP-1 cells were removed from liquid nitrogen and thawed in a 37°C water bath until the ice disappeared. The cells were then added to 9 mL of warmed cell culture medium and centrifuged at 1000 rpm for 5 minutes. The supernatant was discarded and the cells were resuspended in fresh cell culture medium. The THP-1 cells were then divided and cultured in cell culture medium, and subculturised every 2-3 days (5 × 10⁶ cells). 5 Cells / mL were passaged every two days, 3 × 10 5 Cells / mL are passed every 3 days. Cell density is 5 × 10⁻⁶. 5 ~1.5×10 6 The cells were maintained at a concentration of 100 live cells / mL.

[0297] To freeze the cells, resuspend them in fresh freezing medium and reduce the cell density to 3 × 10⁶. 6 ~10×10 6 The cell concentration was adjusted to cells / mL. The cell suspension was aliquoted into 1 mL portions per vial, and the vials were transferred to a -80°C freezer. After 1 day at -80°C, the cell vials were transferred to a liquid nitrogen freezer for storage.

[0298] Instructions for a 96-well format plate PBST solution was prepared by mixing 3600 mL of water, 400 mL of 10X PBS, and 4 mL of Tween® 20. IFN-γ solution was reconstituted with 100 μL of water to obtain a 1 mg / mL solution, which was then diluted with 0.1% BSA to obtain a 100 μg / mL solution. The IFN-γ solution was stored at -20°C. LPS was reconstituted with 1 mL of PBS solution to obtain a 1 mg / mL stock solution, which was further diluted to 50 ng / mL with serum-free medium. The LPS solution was stored at 4°C.

[0299] Day 1: Differentiation of THP-1 cells by IFN-γ 1.0 × 10 in the cell culture medium 6 A suspension containing 1 THP-1 cells / mL was mixed with IFN-γ (final concentration: 25 ng / mL). 100 μL of this suspension was dispensed into each well of a desired 96-well plate. The 96-well plate was then incubated at 37°C for 24 hours under a humidified atmosphere of 5% CO2.

[0300] Day 2: LPS induction and IL-1β detection kit LPS-induced IFN-γ treatment was completed, and the supernatant was discarded by hand. 100 μL of 1X LPS solution (50 ng / mL) in serum-free medium was added. The plate was incubated at 37°C in a humidified atmosphere of 5% CO2 for 4 hours. The sample compound was dissolved in DMSO, and the compound solution was dispensed into the wells using a Tecan D300e digital dispenser. The final concentration of DMSO in each well was 0.5%. The plate was then incubated at 37°C for 1 hour in a humidified atmosphere of 5% CO2. 20 μL of 6X ATP solution was added (final concentration per well: 5 mM), and the plate was incubated at 37°C for 1 hour in a humidified atmosphere of 5% CO2. The supernatant was then collected and analyzed using an IL-Iβ detection kit. If necessary, the test sample can be stored at -20°C until analysis.

[0301] Compound Dilution: Source plates of compound solutions (20 μL of a 10 mM solution of each compound was supplied to the designated wells and stored in a nitrogen cabinet until testing).

[0302] ELISA plate coating: The capture antibody (mAb Mt175) was diluted to a concentration of 2 μg / mL in PBS, and then used to coat the ELISA plate (SIGMA-P6366) overnight at 4°C.

[0303] Day 3: IL-1β detected The antibody coating was discarded, and the plate was washed four times with PBST. The plate was blocked by adding 25 μL / well of blocking buffer (LiCor-927-40000) containing 0.1% Tween® 20, and then incubated at room temperature for 1 hour. The blocking buffer was then discarded, and the plate was washed four times with PBST.

[0304] One hour before adding the test sample, the sample plate was thawed at room temperature, centrifuged at 1000 rpm for 1 minute, and shaken for 30 seconds. 25 μL / well of the test sample was transferred to the ELISA plate, and the plate was incubated at room temperature for 2 hours.

[0305] The test samples were discarded, and the ELISA plates were washed four times with PBST. Then, 0.5 μg / mL (1:1000) mAb7P10-biotin in blocking buffer was added to the ELISA plates at a rate of 15 μL / well, and incubated at room temperature for 1 hour.

[0306] The antibody was discarded, and the ELISA plate was washed four times with PBST. Then, streptavidin-HRP diluted 1:1000 with blocking buffer was added to the ELISA plate at a rate of 15 μL / well, and incubated at room temperature for 1 hour.

[0307] The streptavidin-HRP was discarded, and the plate was washed four times with PBST. Then, 25 μL / well of the HRP substrate was added to the ELISA plate. The plate was incubated at room temperature for 1-2 minutes, during which time the solution turned blue. Next, 25 μL / well of the liquid stop solution was added to the plate, and the solution turned yellow. The plate was then read at 450 nm using a microplate reader. The inhibition rate (%) was calculated as follows: % inhibition rate = (treated sample - high control) / (low control - high control) × 100

[0308] The activity of the tested compounds is shown in Table 3 below:+++=IC 50 <10μM;++=IC 50 10-15 μM; += IC 50 >15μM. [Table 8]

[0309] Assay procedure for IL-1β secretion in a 384-well plate PMA was dissolved in DMSO to prepare a 5 mg / mL stock solution, which was stored at -20°C in 10 μl aliquots for single use. PMA was added to normal growth medium. LPS was diluted in 1 mL of aqueous solution to obtain a 1 mg / mL stock solution, which was stored at -20°C in 15 μl aliquots for single use. Nigericin was diluted to 5 mg / mL (6.7 mM) with ice-cold 100% ethanol and stored at -20°C in 75 μL aliquots for single use. The serum-free medium contained RPMI1640 medium (99%), Pen / Strep (1%), and 2-mercaptoethanol (0.05 mM). The two control conditions used to quantify and normalize the dose-response curves of the test compounds were as follows: high control = 25 ng / mL LPS, 5 μM nigericin, 0.5% DMSO; low control = 25 ng / mL LPS, 0.5% DMSO.

[0310] Day 1: Differentiation by PMA Dilute THP-1 cells to 1.0 × 10⁶ 6 A suspension was obtained at a concentration of cells / mL, and the total volume of suspension required to prepare the desired number of assay plates was prepared. PMA (final concentration 5 ng / mL) was added to the growth medium, and the cells were incubated at 37°C for 40 hours in a humidified atmosphere of 5% CO2.

[0311] Day 3: Sequential stimulation with LPS and nigericin for plating. All culture medium was carefully aspirated from each culture flask. The cells were carefully washed with 1x DPBS. The cells were then rapidly digested with trypsin LE at 23°C for 5 minutes and immediately resuspended in cell growth medium. After resuspending, the cells were centrifuged at 1000 rpm for 3 minutes, and the supernatant was discarded. The cells were resuspended in DPBS and centrifuged again at 1000 rpm for 5 minutes. The supernatant was discarded, and the cell pellet was resuspended in serum-free medium supplemented with LPS (final concentration 25 ng / mL), making it possible to dispense 30K THP-1 cells in 45 μL of medium into each well of a 384-well PDL-coated plate. The 384-well plate was then incubated at 37°C for 2 hours under a humidified atmosphere of 5% CO2. Subsequently, the test compounds were dispensed by Tecan over the desired concentration range. All wells were normalized to a final concentration of 0.5% DMSO. The plate was then incubated at 37°C for 1 hour under a humidified atmosphere of 5% CO2. Subsequently, 5 μL of 5 mg / mL nigericin stock solution was added to each appropriate well, and the plate was centrifuged at 1000 rpm for 30 seconds. The plate was immediately returned to an incubator at 37°C under a humidified atmosphere of 5% CO2 for 2 hours. After this, 35 μL / well supernatant was collected, transferred to a v-bottom plate, and centrifuged at 1000 rpm for 1 minute. These supernatant aliquots were analyzed using the IL-Iβ detection kit as described below. If necessary, the test samples may also be rapidly frozen and stored at -80°C until analysis.

[0312] IL-1β detection To prepare each ELISA plate, the capture antibody (mAb Mt175) was diluted to a final concentration of 2 μg / mL in PBS, and then 20 μL of this solution was added to each well of the ELISA plate. Each plate was incubated overnight at 4°C. The next day, the capture antibody solution was removed and discarded. Each ELISA plate was washed four times with PBST, followed by the addition of 25 μL / well of blocking buffer (Licor-927-40010) supplemented with 0.1% Tween® 20. Each ELISA plate was then incubated at 23°C for 1 hour. After this, the blocking buffer was removed and discarded. Each ELISA plate was washed four times with PBST. During this time, a v-bottom plate containing the supernatant aliquots obtained from the assay run was centrifuged at 300 g for 5 minutes, and then the supernatant sample was transferred to each ELISA plate at 15 μL / well. Each ELISA plate was then incubated at 23°C for 2 hours. After this, the supernatant sample was removed and discarded. Each ELISA plate was washed four times with PBST. 0.5 μg / mL of mAb 7P10-biotin (diluted 1:1000 with blocking buffer) was added to each ELISA plate at a rate of 15 μL / well. Each ELISA plate was then incubated at 23°C for 1 hour. Afterward, the antibody solution was removed and discarded. Each ELISA plate was washed four times with PBST. Streptavidin-HRP (diluted 1:2000 with blocking buffer) was added to each ELISA plate at a rate of 20 μL / well. Each ELISA plate was then incubated at 23°C for 1 hour. Afterward, the buffer was removed and discarded. Each ELISA plate was washed four times with PBST. HRP substrate was added to each ELISA plate at a rate of 20 μL / well. Each ELISA plate was then incubated at 23°C for 2 minutes. Afterward, 40 μL / well of stop solution was added to each ELISA plate. Each ELISA plate was centrifuged at 1200 rpm for 30 seconds.

[0313] Next, the plate was read at 450 nm using a microplate reader. The inhibition rate (%) was calculated as follows: % inhibition rate = (treated sample - high control) / (low control - high control) × 100

[0314] The activity of the tested compounds is shown in Table 4 below. [Table 9]

[0315] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which this disclosure pertains.

[0316] The disclosures described herein as exemplary may be suitably implemented even without any one or more elements or limitations not specifically disclosed herein. Therefore, terms such as “comprising,” “including,” and “containing” should be interpreted broadly and without limitation. Furthermore, the terms and expressions used herein are for illustrative purposes only and not to limit. While the use of such terms and expressions is not intended to exclude any equivalents of the features or parts thereof shown and described, it is acknowledged that various modifications are possible within the scope of this disclosure.

[0317] All publications, patent applications, patents, and other references referred to herein are expressedly invoked by reference in whole, as are each individually invoked by reference. In the event of any conflict, including definitions, this specification shall prevail.

[0318] 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 the invention. Other aspects, advantages and modifications within the scope of this disclosure will be apparent to those skilled in the art to whom this disclosure relates. The present invention provides, for example, the following items: (Item 1) Compounds of formula I:

change

Claims

1. Compounds of formula IA: 【Chemistry 51】 or a pharmaceutically acceptable salt thereof, isotope-enriched analog, stereoisomer, or mixture of stereoisomers, wherein, A １ A ２ A ３ A ４ , and A ５ Each of these independently corresponds to N or CR １ And, X is CR ５ And, Each R １ is, independently, hydrogen, halo, cyano, hydroxy, -SH, -NH ２ , -NO ２ , -SF ５ , C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ２－６ heteroalkyl, C ３－１０ cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R １１ ), -OR ２ , -C(O)R １１ , -C(O)OR １１ , -S(O) １１ R ０－２ , -NR １１ S(O) １１ -R ０－２ , -S(O) １１ N(R ０－２ ), -NR １１ S(O) ２ N(R １１ ), -NR ０－２ S(O) １１ N(R ２ , -NR １１ C(O)N(R １１ ), -C(O)N(R ２ ), -NR １１ C(O)R ２ , -OC(O)N(R １１ ), or -NR １１ C(O)OR １１ ), where each C ２ alkyl, C １１ alkenyl, C １１ alkynyl, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ２－６ heteroalkyl, C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl is, independently, optionally substituted with 1 to 5 Z １ , and any two adjacent R １ groups are joined to form C ３－１０ A cycloalkyl ring, a heterocyclyl ring, an aryl ring, or a heteroaryl ring can be formed, where C ３－１０ A cycloalkyl ring, heterocyclyl ring, aryl ring, or heteroaryl ring independently contains 1 to 5 Z １ This may be further replaced by optional selection. R ２ is -C(R ６ ) ２ R １０ , -OR ９ , -N(R ６ ) (Caution ９ ), -SR ９ , -S(O)R ９ , -S(O) ２ R ９ , -OC(O)N(R ６ ) (Caution ９ ), -NR ６ C(O)OR ９ , -NR ６ C(O)R ９ , C ３－１０ A cycloalkyl, heterocyclyl, or halo, where C ３－１０ Cycloalkyl or heterocyclyl molecules independently contain 1 to 5 Z １ Replaced by optional selection, R ３ C ３－１０ The C is a cycloalkyl, heterocyclyl, or heteroaryl compound, where C ３－１０ Cycloalkyl, heterocyclyl, or heteroaryl molecules independently contain 1 to 5 Zs. １ Replaced by optional selection, R ４ It is hydrogen, R ５ is hydrogen, halo, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkoxy, C １－６ haloalkoxy, C ３－１０ cycloalkyl, or heterocyclyl, where the C １－６ alkyl, C １－６ haloalkyl, C １－６ alkoxy, C １－６ haloalkoxy, C ３－１０ cycloalkyl, or heterocyclyl is independently optionally substituted with 1 to 5 Z １ and Each R ６ is, independently, hydrogen, halo, cyano, hydroxy, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C １－６ alkoxy, C １－６ haloalkoxy, C ２－６ heteroalkyl, C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl, and R ７ It is hydrogen, R ８ It is hydrogen, R ９ C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ２－６ Heteroalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, C ３－１０ The C is a cycloalkyl, heterocyclyl, aryl, or heteroaryl, where C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ２－６ Heteroalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, C ３－１０ Cycloalkyl, heterocyclyl, aryl, or heteroaryl groups independently have 1 to 5 Z groups. １ Replaced by optional selection, or R １０ is hydrogen, halo, hydroxyl, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ２－６ Heteroalkyl, C ３－１０ The C is a cycloalkyl, heterocyclyl, aryl, or heteroaryl, where C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ２－６ Heteroalkyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, or heteroaryl groups independently have 1 to 5 Z groups. １ Replaced by optional selection, Each Z １ is, independently, halo, cyano, hydroxy, -SH, -NH ２ , -NO ２ , -SF ５ , C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ２－６ heteroalkyl, C ３－１０ cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R １１ ), -OR ２ , -C(O)R １１ , -C(O)OR １１ , -S(O) ０－２ R １１ , -NR １１ S(O) ０－２ -R １１ , -S(O) ０－２ N(R １１ ), -NR<D ２ S(O) １１ N(R ０－２ ), -NR １１ S(O) ２ N(R １１ ), -NR １１ C(O)N(R ２ ), -C(O)N(R １１ ), -NR ２ C(O)R<D １１ , -OC(O)N(R １１ ), -NR １１ [[ID=6⑧]]C(O)OR ２ ), or -NR １１ C(O)OR １１ , where each C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ２－６ heteroalkyl, C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl is, independently, optionally substituted with 1 to 5 Z １ａ s,​​ Each R １１ These are, independently, hydrogen, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ２－６ Heteroalkyl, C ３－１０ A cycloalkyl, heterocyclyl, aryl, or heteroaryl, where R １１ Each C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ２－６ Heteroalkyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, or heteroaryl molecules independently have 1 to 5 Z １ａ Replaced by optional selection, Each Z １ａ is, independently, hydroxy, halo, cyano, hydroxy, -SH, -NH ２ , -NO ２ , -SF ５ , C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C １－６ alkoxy, C １－６ haloalkoxy, C ３－１０ cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R １２ ), ２ , -OR １２ , -C(O)R １２ , -C(O)OR １２ , -S(O) ０－２ R １２ , -NR １２ S(O) ０－２ -R １２ , -S(O) ０－２ N(R １２ ), ２ , -NR １２ S(O) ０－２ N(R １２ ), ２ , -NR １２ C(O)N(R １２ ), ２ , -C(O)N(R １２ ), ２ , -NR １２ C(O)R １２ , -OC(O)N(R １２ ), ２ , or -NR １２ C(O)OR １２ wherein each C １－６ alkyl, C ２－６ [[ID=A]]alkenyl, C ２－６ alkynyl, C １－６ s haloalkyl, C １－６ alkoxy, C １－６ haloalkoxy C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with 1 to 5 Z １ｂ and Each R １２ These are, independently, hydrogen, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ２－６ Heteroalkyl, C ３－１０ A cycloalkyl, heterocyclyl, aryl, or heteroaryl, where R １２ Each C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ２－６ Heteroalkyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, or heteroaryl molecules independently have 1 to 5 Z １ｂ Replaced by optional selection, Each Z １ｂ These are independently halo, cyano, hydroxy, -SH, and -NH 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 ２－６ Heteroalkyl, C １－６ Haloalkoxy, C ３－１０ Cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C １－６ Alkyl, -L-C ２－６ Alkenyl, -L-C ２－６ Alkinyl, -L-C １－６ Haloalkyl, -L-C ３－１０ It is a cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl, Each L is independently -O-, -NH-, -S-, -S(O)-, -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 each C of L 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 Cycloalkyl, heterocyclyl, aryl, and heteroaryl molecules independently contain 1 to 5 hydroxy, halo, cyano, hydroxy, -SH, and -NH groups. 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 Compounds of formula IA, or pharmaceutically acceptable salts thereof, isotope-enriched analogs, stereoisomers, or mixtures of stereoisomers, optionally further substituted with cycloalkyl, heterocyclyl, aryl, or heteroaryl groups.

2. A １ A ２ A ３ A ４ , and A ５ Each of them independently, CR １ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, isotope-enriched analog, stereoisomer, or mixture of stereoisomers.

3. A １ A ２ A ３ A ４ , and A ５ One of them is N, and the remaining A １ A ２ A ３ A ４ , and A ５ CR became independent １ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, isotope-enriched analog, stereoisomer, or mixture of stereoisomers.

4. A １ A ２ A ３ A ４ , and A ５ Two of them are N, and the remaining A １ A ２ A ３ A ４ , and A ５ CR became independent １ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, isotope-enriched analog, stereoisomer, or mixture of stereoisomers.

5. R ５ is hydrogen, C １－６ Alkyl, or C １－６ A compound according to any one of claims 1 to 4, which is a haloalkyl compound, or a pharmaceutically acceptable salt thereof, isotope-enriched analog, stereoisomer, or mixture of stereoisomers.

6. Each R １ However, independently, hydrogen, halo, cyano, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, or C ３－１０ It is either a cycloalkyl group or any two adjacent R groups. １ A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, isotope-enriched analog, stereoisomer, or mixture of stereoisomers, wherein a group can be bonded to form an aryl ring or a heteroaryl ring.

7. Each R １ However, independently, hydrogen, fluoro, chloro, cyano, -CH ３ , -OCH ３ , -OCH ２ CH ３ , -CF ３ A compound according to any one of claims 1 to 6, which is cyclopropyl, 2,2-difluorocyclopropyl, or cyclobutyl, or a pharmaceutically acceptable salt thereof, isotope-enriched analog, stereoisomer, or mixture of stereoisomers.

8. R ２ However, -C(R ６ ) ２ R １０ , -OR ９ , C ３－１０ A cycloalkyl or halo, where C ３－１０ Cycloalkyl groups independently have 1 to 5 Z １ A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, isotope-enriched analog, stereoisomer, or mixture of stereoisomers, which is optionally substituted therefor.

9. R ３ However, C ３－１０ The C is a cycloalkyl, heterocyclyl, or heteroaryl, where C ３－１０ Cycloalkyl, heterocyclyl, or heteroaryl compounds independently contain 1 to 5 halo, hydroxy, C １－６ Alkyl, or C ３－１０ A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, isotope-enriched analog, stereoisomer, or mixture of stereoisomers, optionally substituted with a cycloalkyl group.

10. R ３ The compound according to any one of claims 1 to 9, wherein the compound is 5-fluoropyrimidine-4-yl, 1-cyclobutylpiperidine-3-yl, 1-ethylpiperidine-3-yl, 1-cyclopropylpiperidine-3-yl, 3-fluoropyridine-2-yl, 5-fluoropyrimidine-2-yl, 3,5-difluoropyridine-2-yl, or 3-hydroxy-3-methylcyclobutyl, or a pharmaceutically acceptable salt thereof, isotope-enriched analog, stereoisomer, or mixture of stereoisomers.

11. R ２ ga-C(R ６ ) ２ R １０ And at least one R ６ A compound according to any one of claims 1 to 10, wherein the compound is hydrogen, or a pharmaceutically acceptable salt thereof, isotope-enriched analog, stereoisomer, or mixture of stereoisomers thereof.

12. R ２ ga-C(R ６ ) ２ R １０ And R １０ Hello, C １－６ Alkyl, or C １－６ A compound according to any one of claims 1 to 11, which is a haloalkyl compound, or a pharmaceutically acceptable salt thereof, isotope-enriched analog, stereoisomer, or mixture of stereoisomers thereof.

13. R ２ ga- OR ９ And R ９ C １－６ A compound according to any one of claims 1 to 10, which is alkyl, or a pharmaceutically acceptable salt thereof, isotope-enriched analog, stereoisomer, or mixture of stereoisomers.

14. A １ A ２ A ３ A ４ , and A ５ Each of them independently, CR １ And, Each R １ However, independently, hydrogen, halo, cyano, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, or C ３－１０ It is either a cycloalkyl group or any two adjacent R groups. １ The groups can bond to form an aryl ring or a heteroaryl ring. R ２ However, -C(R ６ ) ２ R １０ , -OR ９ , C ３－１０ A cycloalkyl or halo, where C ３－１０ Cycloalkyl groups independently have 1 to 5 Z １ Replaced by optional selection, R ３ However, C ３－１０ The C is a cycloalkyl, heterocyclyl, or heteroaryl, where C ３－１０ Cycloalkyl, heterocyclyl, or heteroaryl compounds independently contain 1 to 5 halo, hydroxy, C １－６ Alkyl, or C ３－１０ Optionally substituted with cycloalkyl groups, R ５ However, hydrogen, C １－６ Alkyl, or C １－６ It is a haloalkyl, at least one R ６ However, it is hydrogen, R ９ However, C １－６ It is alkyl, R １０ But, hello, C １－６ Alkyl, or C １－６ It is a haloalkyl, The compound described in claim 1, or a pharmaceutically acceptable salt thereof, isotope-enriched analog, stereoisomer, or mixture of stereoisomers thereof.

15. A １ A ２ A ３ A ４ , and A ５ One of them is N, and the remaining A １ A ２ A ３ A ４ , and A ５ However, CR became independent. １ And, Each R １ However, independently, hydrogen, halo, cyano, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, or C ３－１０ It is either a cycloalkyl group or any two adjacent R groups. １ The groups can bond to form an aryl ring or a heteroaryl ring. R ２ However, -C(R ６ ) ２ R １０ , -OR ９ , C ３－１０ A cycloalkyl or halo, where C ３－１０ Cycloalkyl groups independently have 1 to 5 Z １ Replaced by optional selection, R ３ However, C ３－１０ The C is a cycloalkyl, heterocyclyl, or heteroaryl, where C ３－１０ Cycloalkyl, heterocyclyl, or heteroaryl compounds independently contain 1 to 5 halo, hydroxy, C １－６ Alkyl, or C ３－１０ Optionally substituted with cycloalkyl groups, R ５ However, hydrogen, C １－６ Alkyl, or C １－６ It is a haloalkyl, at least one R ６ However, it is hydrogen, R ９ However, C １－６ It is alkyl, R １０ But, hello, C １－６ Alkyl, or C １－６ It is a haloalkyl, The compound described in claim 1, or a pharmaceutically acceptable salt thereof, isotope-enriched analog, stereoisomer, or mixture of stereoisomers thereof.

16. A １ A ２ A ３ A ４ , and A ５ Two of them are N, and the remaining A １ A ２ A ３ A ４ , and A ５ However, CR became independent. １ And, Each R １ However, independently, hydrogen, halo, cyano, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, or C ３－１０ It is either a cycloalkyl group or any two adjacent R groups. １ The groups can bond to form an aryl ring or a heteroaryl ring. R ２ However, -C(R ６ ) ２ R １０ , -OR ９ , C ３－１０ A cycloalkyl or halo, where C ３－１０ Cycloalkyl groups independently have 1 to 5 Z １ Replaced by optional selection, R ３ However, C ３－１０ The C is a cycloalkyl, heterocyclyl, or heteroaryl, where C ３－１０ Cycloalkyl, heterocyclyl, or heteroaryl compounds independently contain 1 to 5 halo, hydroxy, C １－６ Alkyl, or C ３－１０ Optionally substituted with cycloalkyl groups, R ５ However, hydrogen, C １－６ Alkyl, or C １－６ It is a haloalkyl, at least one R ６ However, it is hydrogen, R ９ However, C １－６ It is alkyl, R １０ But, hello, C １－６ Alkyl, or C １－６ It is a haloalkyl, The compound described in claim 1, or a pharmaceutically acceptable salt thereof, isotope-enriched analog, stereoisomer, or mixture of stereoisomers thereof.

17. Compounds of the following formula 【Chemistry 52】 【Chemistry 53】 【Chemistry 54】 【Transformation 55】 【Transformation 56】 【Chemistry 57】 【Transformation 58】 【Chemistry 59】 【Transformation 60】 A compound selected from or a pharmaceutically acceptable salt thereof, isotope-enriched analog, stereoisomer, or mixture of stereoisomers.

18. Compound of the following formula 【Chemistry 61】 【Transformation 62】 【Transformation 63】 【Chemistry 64】 【Transformation 65】 【Chemical Formula 66】 【Transformation 67】 【Transformation 68】 【Transformation 69】 【Transformation 70】 【Chemistry 71】 【Chemistry 72】 A compound selected from or a pharmaceutically acceptable salt thereof, isotope-enriched analog, stereoisomer, or mixture of stereoisomers.

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, a stereoisomer, or a mixture of stereoisomers thereof, and a pharmaceutically acceptable carrier.

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