Compounds, Compositions, and Methods

Abstract

The present disclosure generally relates to the small molecule modulator of NLR family pyrin domain containing 3 (NLRP3), or its pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomer, or prodrug, its intermediate, and its method of use.In another embodiment, a pharmaceutical composition is provided that comprises the compound described herein, or its pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomer, or prodrug, and a pharmaceutically acceptable carrier.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 63 / 325,577, filed March 30, 2022, and U.S. Provisional Application No. 63 / 346,203, filed May 26, 2022, the contents of which are incorporated by reference in their entireties.

[0002] The present disclosure relates generally to small molecule modulators of NLR family pyrin domain-containing 3 (NLRP3) and their use as therapeutic agents. [Background technology]

[0003] Inhibition of NLRP3 activation has been shown to have potent therapeutic effects in animal models of inflammatory diseases. NLRP3 modulators, particularly inhibitors, have broad therapeutic potential in a variety of autoinflammatory and chronic inflammatory diseases that require better treatment options or lack adequate treatments. While therapies targeting NLRP3-dependent cytokines have already been approved for therapeutic use, they suffer from significant drawbacks compared to direct NLRP3 antagonists. There remains a strong need for the discovery and clinical development of molecules that antagonize NLRP3. Summary of the Invention

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

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

[0006] In another embodiment, a pharmaceutical composition is provided comprising a compound described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, and a pharmaceutically acceptable carrier.

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

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

[0009] The disclosure also provides compositions, including pharmaceutical compositions; kits, including the compounds, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof; methods of using (or administering) and preparing the compounds, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, and intermediates thereof.

[0010] The present disclosure further provides a compound, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a composition thereof, for use in a method of treating a disease, disorder, or condition mediated at least in part by NLRP3.

[0011] Further, the present disclosure provides the use of a compound, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a composition thereof, in the manufacture of a medicament for the treatment of a disease, disorder, or condition mediated at least in part by NLRP3.

[0012] The description herein illustrates exemplary embodiments of the present technology, however, it should be recognized that such description is not intended to limit the scope of the present disclosure, but is instead provided as a description of exemplary embodiments.

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

[0014] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment of a substituent. For example, -C(O)NH2 is attached through the carbon atom. Dashes before or after a chemical group are for convenience; a chemical group may be represented with one or more dashes or without any dashes without loss of ordinary meaning. A wavy or dashed line drawn through a line in a structure indicates a particular point of attachment of a group. No directionality or stereochemistry is indicated or implied by the order of writing or naming chemical groups unless chemically or structurally required.

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

[0016] As used herein, reference to a value or parameter with "about" includes (and describes) embodiments that are directed to that value or parameter itself. In certain embodiments, the term "about" includes ±10% of the stated amount. In other embodiments, the term "about" includes ±5% of the stated amount. In certain other embodiments, the term "about" includes ±1% of the stated amount. Also, the term "about X" includes a reference to "X." Additionally, the singular forms "a" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds, and reference to "an assay" includes a reference to one or more assays and equivalents thereof known to those of skill in the art.

[0017] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl refers to an alkyl group having 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 1-4alkyl). 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 designated by a chemical name or identified by a molecular formula, all positional isomers having that number of carbon atoms can 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 commonly used alternative chemical names may be used. For example, divalent groups such as divalent "alkyl" groups, divalent "aryl" groups, and divalent heteroaryl groups are also referred to as "alkylene" or "alkylenyl" groups (e.g., methylenyl, ethylenyl, and propylenyl), "arylene" or "arylenyl" groups (e.g., phenylenyl or naphthylenyl, or, in the case of heteroarylene, quinolinyl), respectively. Also, unless expressly indicated otherwise, when a combination of groups is referred to herein as a single moiety, for example, arylalkyl or aralkyl, the last-mentioned group contains the atom that connects the moiety to the remainder of the molecule.

[0019] "Alkenyl" refers to an alkyl group containing at least one (e.g., 1 to 3, or 1) carbon-carbon double bond and having 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 2-4Examples of alkenyl groups include ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

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

[0021] "Alkoxy" refers to the group "alkyl-O-". Examples of alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0022] "Alkylthio" refers to the group "alkyl-S-". "Alkylsulfinyl" refers to the group "alkyl-S(O)-". "Alkylsulfonyl" refers to the group "alkyl-S(O)2-". "Alkylsulfonylalkyl" refers to -alkyl-S(O)2-alkyl.

[0023] "Acyl" is the group -C(O)R y In the formula, R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which can be optionally substituted as defined herein. Examples of acyls include, for example, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0024] An "amide" is the group -C(O)NR y R z refers to the "C-amido" group and the group -NR y C(O)R z "N-amido" refers to both a hydroxyl group and a hydroxyl group, y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein, or R y and R z taken together form a cycloalkyl or heterocyclyl, each of which may be optionally substituted as defined herein.

[0025] "Amino" is the group -NR y R z In the formula, R y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which can be optionally substituted as defined herein.

[0026] "Amidino" is -C(NR y )(NR z 2), where R y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which can be optionally substituted as defined herein.

[0027] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused systems. As used herein, aryl refers to an aromatic carbocyclic group having 6 to 20 ring carbon atoms (i.e., C 6-20aryl), 6 to 12 carbon ring atoms (i.e., C 6-12 aryl), or 6 to 10 carbon ring atoms (i.e., C 6-10 aryl). Examples of aryl groups include, for example, phenyl, naphthyl, fluorenyl, and anthryl. However, aryl does not encompass or overlap with any heteroaryl, as defined below. When one or more aryl groups and heteroaryls are fused, the resulting ring system is a heteroaryl, regardless of the point of attachment. When one or more aryl groups and heterocyclyls are fused, the resulting ring system is a heterocyclyl, regardless of the point of attachment. When one or more aryl groups and cycloalkyls are fused, the resulting ring system is a cycloalkyl, regardless of the point of attachment.

[0028] "Arylalkyl" or "aralkyl" refers to the group "aryl-alkyl-".

[0029] "Carbamoyl" is the group -OC(O)NR y R z refers to the "O-carbamoyl" group and the group -NR y C(O)OR z "N-carbamoyl" refers to both a hydroxyl group and a hydroxyl group, y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which can be optionally substituted as defined herein.

[0030] "Carboxyl ester" or "ester" is -OC(O)R x and -C(O)OR x In the formula, R x is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which can be optionally substituted as defined herein.

[0031] "Cyanoalkyl" refers to an alkyl group, as defined above, in which one or more (eg, 1 or 2) hydrogen atoms are replaced with a cyano (-CN) group.

[0032] "Cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings, including fused, bridged, and spiro ring 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 As used herein, cycloalkyl includes carbocyclic fused ring systems having 3 to 20 ring carbon atoms (i.e., at least one non-aromatic ring). 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 3 to 6 ring carbon atoms (i.e., C 3-6 cycloalkyl). 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, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Furthermore, the term cycloalkyl is intended to encompass any non-aromatic ring that may be fused to an aryl ring, regardless of attachment to the rest of the molecule. Furthermore, 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.

[0033] "Cycloalkylalkyl" refers to the group "cycloalkyl-alkyl-".

[0034] "Imino" is the group -C(NR y )R z In the formula, R y and R z is each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which can be optionally substituted as defined herein.

[0035] "Imide" is the group -C(O)NR y C(O)R z In the formula, R y and R z is each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which can be optionally substituted as defined herein.

[0036] "Halogen" or "halo" refers to an atom in Group VIIA of the periodic table, such as fluoro, chloro, bromo, or iodo.

[0037] "Haloalkyl" refers to an unbranched or branched alkyl group, as defined above, in which one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms have been replaced with halogen. For example, if a residue is substituted with more than one halogen, it can be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two ("di") or three ("tri") halo groups, where the halo groups can be, but are not necessarily, the same halogen. Examples of haloalkyl include, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0038] "Haloalkoxy" refers to an alkoxy group, as defined above, in which one or more (eg, 1 to 6 or 1 to 3) hydrogen atoms are replaced with halogen.

[0039] "Hydroxyalkyl" refers to an alkyl group, as defined above, in which one or more (eg, 1 to 6 or 1 to 3) hydrogen atoms are replaced with hydroxy groups.

[0040] "Heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms), excluding any terminal carbon atom(s), are each independently replaced with the same or different heteroatom groups, provided that the point of attachment to the remainder of the molecule is through a carbon atom. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon atoms and heteroatoms. By way of example, one, two, or three carbon atoms can be independently replaced with the same or different heteroatom groups. Heteroatom groups include -NR y -, -O-, -S-, -S(O)-, -S(O)2-, and the like, wherein R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which can be optionally substituted as defined herein. Examples of heteroalkyl groups include, for example, ethers (e.g., -CHOCH, -CH(CH)OCH, -CHCHOCH, -CHCHOCH, -CHCHOCHCHOCH, etc.), thioethers (e.g., -CHSCH, -CH(CH)SCH, -CHCHSCH, -CHCHSCHCHSCH, etc.), sulfones (e.g., -CHS(O)CH, -CH(CH)S(O)CH, -CHCHS(O)CH, -CHCHS(O)CHCHOCH, etc.), and amines (e.g., -CHNR y CH3, -CH(CH3)NR y CH3, -CH2CH2NR y CH3, -CH2CH2NR y CH2CH2NR yCH3, etc.), wherein R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which can be optionally substituted as defined herein. As used herein, heteroalkyl includes 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.

[0041] "Heteroaryl" refers to an aromatic group having a single ring or multiple fused rings containing one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl refers to an aromatic group having 1 to 20 ring carbon atoms (i.e., C 1-20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C 3-12 heteroaryl), or 3 to 8 ring carbon atoms (i.e., C 3-8Heteroaryl) 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, heteroaryl includes 5- to 10-membered, 5- to 7-membered, or 5- to 6-membered ring systems, each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom 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, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, and isoquinolyl. , isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, thiophenyl (i.e., thienyl), triazolyl, tetrazolyl, and triazinyl. Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, where the heteroaryl may be attached via any ring of the fused system. Any aromatic ring having single or multiple fused rings containing at least one heteroatom is considered heteroaryl, regardless of attachment to the rest of the molecule (i.e., via any one of the fused rings).Heteroaryl does not encompass or overlap with aryl as defined above.

[0042] "Heteroarylalkyl" refers to the group "heteroaryl-alkyl-".

[0043] "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, fused heterocyclyl groups, and spiroheterocyclyl groups. A heterocyclyl can be monocyclic or polycyclic, where the polycyclic ring can be fused, bridged, or spiro, and can contain one or more (e.g., 1 to 3) oxo (=O) or N-oxide (-O) groups. - ) moiety. Any non-aromatic ring containing at least one heteroatom, regardless of attachment, is considered heterocyclyl (i.e., it can be attached via a carbon atom or a heteroatom). Additionally, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom that can be fused to a cycloalkyl, aryl ring, or heteroaryl ring, regardless of attachment to the rest of the molecule. As used herein, heterocyclyl refers to a ring having 2 to 20 ring carbon atoms (i.e., C 2-20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C 2-12 heterocyclyl), 2 to 10 ring carbon atoms (i.e., C 2-10 heterocyclyl), 2 to 8 ring carbon atoms (i.e., C 2-8 heterocyclyl), 3 to 12 ring carbon atoms (i.e., C 3-12 heterocyclyl), 3 to 8 ring carbon atoms (i.e., C 3-8 heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C 3-6Heterocyclyl) has 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur, or oxygen. Examples of heterocyclyl groups include, for example, azetidinyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxalanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindoline, and the like.

[0033] Examples of heterocyclyl include aryl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tetrahydropyranyl, trithianyl, tetrahydroquinolinyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. The term "heterocyclyl" also includes "spiroheterocyclyl" in which there are two substitution positions on the same carbon atom. Examples of spiroheterocyclyl rings include bicyclic and tricyclic ring systems such as, for example, 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 fused 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, where the heterocyclyl can be attached via either ring of the fused system.

[0044] "Heterocyclylalkyl" refers to the group "heterocyclyl-alkyl-".

[0045] "Oxime" is a group -CR y (=NOH), where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which can be optionally substituted as defined herein.

[0046] "Sulfonyl" refers to the group -S(O)R y In the formula, R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which can be optionally substituted as defined herein. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0047] "Sulfinyl" is the group -S(O)R y In the formula, R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which can be optionally substituted as defined herein. Examples of sulfinyl are methylsulfinyl, ethylsulfinyl, phenylsulfinyl, and toluenesulfinyl.

[0048] "Sulfonamide" is a group -SO2NR y R z and -NR y SO2R z In the formula, R y and R z is each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which can be optionally substituted as defined herein.

[0049] "Optional" or "optionally" means that the described event or condition may or may not occur, and that the description includes cases where the event or condition occurs and cases where it does not occur. Also, the term "optionally substituted" refers to any one or more (e.g., 1-5 or 1-3) hydrogen atoms on a specified atom or group that may or may not be replaced with a non-hydrogen moiety.

[0050] As used herein, the term "substituted" means that at least one (e.g., 1 to 5 or 1 to 3) hydrogen atom has been replaced with, but is not limited to, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl, aralkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanadino, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -NHNH, =NNH, imino, imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanato, -S(O)OH, -S(O)OH, sulfonamide, thiol, thioxo, N-oxide, or -Si(R y )3(in the formula, each R y means any of the above groups (i.e., alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, and / or heteroalkyl), replaced by a bond to a non-hydrogen atom, such as, independently, hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl.

[0051] In certain embodiments, "substituted" means that one or more (e.g., 1-5 or 1-3) hydrogen atoms are independently replaced with 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. In certain embodiments, "substituted" also refers to one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms being replaced with -C(O)R g , -C(O)OR g , -C(O)NR g R h, -CH2SO2R g , or -CH2SO2NR g R h In the above, R g and R h are the same or different and are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and / or heteroarylalkyl. In certain embodiments, "substituted" also refers to any of the above groups in which one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are replaced by a bond to amino, cyano, hydroxy, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, and / or heteroarylalkyl, or R g and R h and R i two of these, together with the atoms to which they are attached, form a heterocyclyl ring optionally substituted with oxo, halo, or alkyl optionally substituted with oxo, halo, amino, hydroxy, or alkoxy.

[0052] It is not intended herein to encompass polymers or similar infinite structures that can be reached by defining a substituent with an unlimited number of additional substituents (e.g., a substituted aryl having a substituted alkyl, which is itself substituted with a substituted aryl group, which is further substituted with a substituted heteroalkyl group, etc.). Unless otherwise stated, the maximum number of series of substitutions for the compounds described herein is three. For example, the 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 definition is not intended to include impermissible substitution patterns (e.g., a methyl substituted with five fluorines or a heteroaryl group with two adjacent oxygen ring atoms). Such impermissible 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 defined herein.

[0053] 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.

[0054] Any compound or structure provided herein is also intended to represent unlabeled and isotopically labeled forms of the compound. These forms of the compound may also be referred to as "isotopically enriched analogs." Isotopically labeled compounds have the structure depicted herein, except that one or more atoms are replaced by an atom having the mass or mass number of a selected atom. Examples of isotopes that can be incorporated into the disclosed compounds include, 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, 18F, 36 Cl, 123 I, and 125 Included are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as I. Various isotopically labeled compounds of the present disclosure, e.g., 3 H and 14 and those into which a radioactive isotope, such as C, has been incorporated. Such isotopically labeled compounds may be useful in detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including metabolism studies, reaction kinetic studies, drug or substrate tissue distribution assays, or in radiation treatment of patients.

[0055] The term "isotopically enriched analog" includes "deuterated analogs" of the compounds described herein, in which one or more hydrogen atoms, such as hydrogen atoms on a carbon atom, are replaced by deuterium. Such compounds are useful for increasing the half-life of any compound when administered to mammals, particularly humans, due to their increased resistance to metabolism. 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 have been replaced by deuterium.

[0056] Deuterium-labeled or substituted therapeutic compounds of the present 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 confer several therapeutic advantages resulting from increased metabolic stability, e.g., increased in vivo half-life, reduced dosage requirements, and / or improved therapeutic index. 18 F, 3 H, 11C-labeled compounds can be useful for PET or SPECT or other imaging diagnostic studies. The isotopically labeled compounds of the present disclosure and their prodrugs can generally be prepared by carrying out the procedures disclosed in the schemes or examples and preparation methods described below, substituting readily available isotopically labeled reagents for non-isotopically labeled reagents. In this context, it is understood that deuterium is considered a substituent of the compounds described herein.

[0057] The concentration of such a heavy isotope, specifically deuterium, can be defined by the isotopic enrichment factor. In the compounds of the present disclosure, any atom without a specific isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen," it is understood that the position has hydrogen at its natural abundance isotopic composition. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is meant to represent deuterium.

[0058] In many cases, the compounds of the present disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0059] Also provided are pharmaceutically acceptable salts, isotopically enriched analogs, deuterated analogs, stereoisomers, mixtures of stereoisomers, and prodrugs of the compounds described herein. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials useful in the preparation of pharmaceutical compositions suitable for animal or human pharmaceutical use.

[0060] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness 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 a compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly 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 according to conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art will recognize 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, phosphoric acid, and the like. Salts derived from organic acids include, for example, acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, 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, salicylic acid, and the like. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic or organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts.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), tri(substituted alkenyl)amines

[0033] Suitable amines include, but are not limited to, salts of primary, secondary, and tertiary amines such as (a)-(substituted alkenyl)amines (i.e., N(substituted alkenyl)s, mono-, di-, or tricycloalkylamines (i.e., NH(cycloalkyl), HN(cycloalkyl), N(cycloalkyl)s), mono-, di-, or triarylamines (i.e., NH(aryl), HN(aryl), N(aryl)s), or mixed amines. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(iso-propyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylamineethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0061] Some compounds exist as tautomers. Tautomers are in equilibrium with each other. For example, an amide-containing compound may exist in equilibrium with an imidic acid tautomer. Regardless of which tautomer is shown and regardless of the nature of the equilibrium between the tautomers, those skilled in the art will understand that the compound includes both the amide tautomer and the imidic acid tautomer. Thus, an amide-containing compound is understood to include its imidic acid tautomer. Similarly, an imidic acid-containing compound is understood to include its amide tautomer.

[0062] The compounds of the present disclosure, or pharmaceutically acceptable salts thereof, contain asymmetric centers and can therefore give rise to enantiomers, diastereomers, and other stereoisomers that can be defined in terms of absolute stereochemistry as (R)- or (S)-, or, in the case of amino acids, (D)- or (L)-. The present disclosure is meant 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 resolved using conventional techniques, such as chromatography and / or fractional crystallization. Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high-performance liquid chromatography (HPLC). When compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless specified otherwise, the compounds are intended to include both E and Z geometric isomers.

[0063] "Stereoisomer" refers to a compound consisting of the same atoms joined by the same bonds but having different, incompatible three-dimensional structures. The present disclosure contemplates various stereoisomers, or mixtures thereof, and includes "enantiomers," which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0064] "Diastereomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0065] Relative centers of compounds depicted herein are shown diagrammatically using a "bold bond" style (bold or parallel lines), and absolute stereochemistry is depicted using a wedge bond (bold or parallel lines).

[0066] "Prodrug" refers to any compound that releases an active parent drug according to the structures described herein in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds described herein are prepared by modifying functional groups present in the compounds described herein such that the modifications can be cleaved in vivo to release the parent compound. Prodrugs can be prepared by modifying functional groups present in the compounds such that the modifications are cleaved to the parent compound, either by routine manipulation or in vivo. Prodrugs include compounds described herein in which a hydroxy, amino, carboxyl, or sulfhydryl group in the compounds described herein is bonded to any group that can be cleaved in vivo to regenerate the free hydroxy, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, esters (e.g., acetate, formate, and benzoate derivatives), amides, guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl), and the like, of the hydroxy functional groups of the compounds described herein. The preparation, selection, and use of prodrugs are discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the ACS Symposium Series; "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which is incorporated herein by reference in its entirety.

[0067] 2.Compound Provided herein are compounds that are modulators of NLRP3. In certain embodiments, the compound is of formula I: [ka] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein: X is C(X 1 ), NR 16 , S(O)2, or S(O)(NR 18 ) and Y is C(Y 1 ), O, NR 17 , S(O)2, or S(O)(NR 19 ) and Z is CR 8 or N, X 1 But, O, NR 18 , or S, Y 1 But, O, NR 19 , or S, A 1 , A 2 , A 3 , and A 4 are each independently N, CH, or CR 1 However, A 1 , A 2 , A 3 , and A 4 At least one of the 1 provided that: Each R 1 However, independently, halo, cyano, -NO2, -SF5, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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(R11 )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 each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl independently represents 1 to 8 Z 1 optionally substituted with Any two adjacent R 1 together with the atoms to which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl ring, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl independently contains 1 to 8 Z 1 optionally substituted with R 2 But C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -NO2, -SF5, -OR 11 , -N(R 11 )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 )2, -NR 11 S(O) 0-2 N(R 11 )2, -NR 11 C(O)N(R 11 )2, -NR 11 C(O)OR 11 , -NR 11C(O)R 11 , -OC(O)R 11 , -OC(O)N(R 11 )2, -C(O)N(R 11 )2, halo, or cyano, wherein 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 1 to 8 Z 1 optionally substituted with R 3 But hydrogen, halo, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 1 to 8 Z 1 or R 2 and R 3 Together, C 3-10 forming a cycloalkyl or heterocyclyl ring, wherein the C 3-10 cycloalkyl or heterocyclyl is 1 to 8 Z 1 optionally substituted with R 4 But hydrogen, halo, -NO2, cyano, hydroxy, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, 5- to 6-membered heteroaryl, -OR 14 , -N(R 14 )2, or -S(O) 0-2 R 14 where C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl may be selected from the group consisting of 1 to 5 halo, hydroxy, -SH, -NH2, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 optionally substituted with haloalkyl; R 5 But hydrogen, halo, -NO2, cyano, hydroxy, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, 5- to 6-membered heteroaryl, -OR 14 , -N(R 14 )2, or -S(O) 0-2 R 14 where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl may be selected from the group consisting of 1 to 5 halo, hydroxy, -SH, -NH2, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 optionally substituted with haloalkyl, or R 4 and R 5 taken together form a heterocyclyl or heteroaryl, wherein the heterocyclyl or heteroaryl is selected from the group consisting of 1 to 5 halo, hydroxy, -SH, -NH, -NO, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 optionally substituted with haloalkyl; R 6 But hydrogen, halo, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C3-10 cycloalkyl, or heterocyclyl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-10 The cycloalkyl or heterocyclyl may further comprise 1 to 5 Z 1b may be optionally substituted with R 7 But hydrogen, halo, cyano, hydroxy, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-10 cycloalkyl, or heterocyclyl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-10 The cycloalkyl or heterocyclyl may further comprise 1 to 5 Z 1b or or R 6 and R 7 combine to form C 3-10 forming a cycloalkyl or heterocyclyl ring, wherein the C 3-10 The cycloalkyl or heterocyclyl ring may further comprise 1 to 5 Z 1b may be optionally substituted with R 8 But hydrogen, halo, cyano, C 1-6 Alkyl or C 1-6 is haloalkyl, R 9 and R 10 are each independently hydrogen, halo, cyano, C 1-6 Alkyl, or C 1-6 haloalkyl, and each C 1-6 Alkyl or C 1-6 haloalkyl, independently, 1 to 5 Z1 or R 9 and R 10 Together, C 3-10 forming a cycloalkyl or heterocyclyl ring, wherein the C 3-10 cycloalkyl or heterocyclyl is 1 to 8 Z 1 optionally substituted with each Z 1 However, independently, halo, cyano, -NO2, -SF5, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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 each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl independently selected from 1 to 5 Z 1a optionally substituted with Each R 11 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C1-6 Haloalkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl independently selected from 1 to 5 Z 1a optionally substituted with R 12 But hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 1 to 8 Z 1 optionally substituted with each Z 1a are independently hydroxy, halo, cyano, -NO2, -SF5, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 13 )2, -OR 13 , -C(O)R 13 , -C(O)OR 13 , -S(O) 0-2 R 13 , -NR 13 S(O) 0-2 R 13 , -S(O) 0-2 N(R 13 )2, -NR 13 S(O) 0-2 N(R 13 )2, -NR 13 C(O)N(R 13 )2, -C(O)N(R 13 )2, -NR13 C(O)R 13 , -OC(O)N(R 13 )2, or -NR 13 C(O)OR 13 and each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl independently selected from 1 to 5 Z 1b optionally substituted with Each R 13 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl independently selected from 1 to 5 Z 1b optionally substituted with Each R 14 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, and each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl may be selected from the group consisting of 1 to 5 halo, hydroxy, -SH, -NH2, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 optionally substituted with haloalkyl; R 16 But hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl independently selected from 1 to 5 Z 1b optionally substituted with R 17 But hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl independently selected from 1 to 5 Z 1b optionally substituted with R 18 But hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl independently selected from 1 to 5 Z 1b optionally substituted with R 19 But hydrogen, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl independently selected from 1 to 5 Z 1b optionally substituted with each Z 1b are independently halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -LC 1-6 Alkyl, -LC 2-6 Alkenyl, -LC 2-6 Alkynyl, -LC 1-6 Haloalkyl, -LC 3-10 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 alkynyl)-, -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 alkynyl)-, -C(O)N(C 1-6 haloalkyl)-, -C(O)N(C3-10 -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)NH-; Z 1b and each C of L 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may further independently be selected from the group consisting of 1 to 5 hydroxy, halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, 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 Provided are compounds, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, that are optionally substituted with cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0068] In certain embodiments, X is C(X 1 In certain embodiments, X is NR 16 In certain embodiments, X is S(O).

[0069] In certain embodiments, Y is C(X 1 In certain embodiments, Y is O. In certain embodiments, Y is NR 16 In certain embodiments, Y is S(O).

[0070] In certain embodiments, Z is CR 8 In certain embodiments, Z is N.

[0071] In certain embodiments, the compound of formula IA: [ka] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein: X 1 is O or S, Y 1 is O or S, A 1 , A 2 , A 3 , and A 4 are each independently N, CH, or CR 1 However, A 1 , A 2 , A 3 , and A 4 At least one of the 1 provided that: Each R 1 However, independently, halo, cyano, -NO2, -SF5, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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 -NR11 C(O)OR 11 and each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl independently represents 1 to 8 Z 1 optionally substituted with Any two adjacent R 1 together with the atoms to which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl ring, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl independently contains 1 to 8 Z 1 optionally substituted with R 2 But C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -NO2, -SF5, -OR 11 , -N(R 11 )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 )2, -NR 11 S(O) 0-2 N(R 11 )2, -NR 11 C(O)N(R 11 )2, -NR 11 C(O)OR 11 , -NR 11 C(O)R 11 , -OC(O)R 11 , -OC(O)N(R 11 )2, -C(O)N(R 11 )2, halo, or cyano, wherein 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 1 to 8 Z 1 optionally substituted with R 3 But hydrogen, halo, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 1 to 8 Z 1 or R 2 and R 3 Together, C 3-10 forming a cycloalkyl or heterocyclyl ring, wherein the C 3-10 cycloalkyl or heterocyclyl is 1 to 8 Z 1 optionally substituted with R 4 But hydrogen, halo, -NO2, cyano, hydroxy, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, 5- to 6-membered heteroaryl, -OR 14 , -N(R 14 )2, or -S(O) 0-2 R 14 where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl may be selected from the group consisting of 1 to 5 halo, hydroxy, -SH, -NH2, -NO2, C 1-6 Alkyl, C 1-6Alkoxy or C 1-6 optionally substituted with haloalkyl; R 5 But hydrogen, halo, -NO2, cyano, hydroxy, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, 5- to 6-membered heteroaryl, -OR 14 , -N(R 14 )2, or -S(O) 0-2 R 14 where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl may be selected from the group consisting of 1 to 5 halo, hydroxy, -SH, -NH2, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 optionally substituted with haloalkyl, or R 4 and R 5 taken together form a heterocyclyl or heteroaryl, wherein the heterocyclyl or heteroaryl is selected from the group consisting of 1 to 5 halo, hydroxy, -SH, -NH, -NO, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 optionally substituted with haloalkyl; R 6 But hydrogen, halo, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-10 cycloalkyl, or heterocyclyl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C3-10 The cycloalkyl or heterocyclyl may further comprise 1 to 5 Z 1b may be optionally substituted with R 7 But hydrogen, halo, cyano, hydroxy, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-10 cycloalkyl, or heterocyclyl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-10 The cycloalkyl or heterocyclyl may further comprise 1 to 5 Z 1b or or R 6 and R 7 combine to form C 3-10 forming a cycloalkyl or heterocyclyl ring, wherein the C 3-10 The cycloalkyl or heterocyclyl ring may further comprise 1 to 5 Z 1b may be optionally substituted with R 9 and R 10 are each independently hydrogen, halo, cyano, C 1-6 Alkyl or C 1-6 haloalkyl, and each C 1-6 Alkyl or C 1-6 haloalkyl, independently, 1 to 5 Z 1 or R 9 and R 10 Together, C 3-10 forming a cycloalkyl or heterocyclyl ring, wherein the C 3-10 cycloalkyl or heterocyclyl is 1 to 8 Z 1 optionally substituted with each Z 1However, independently, halo, cyano, -NO2, -SF5, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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 each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl independently selected from 1 to 5 Z 1a optionally substituted with Each R 11 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl independently selected from 1 to 5 Z1a optionally substituted with R 12 But hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 1 to 8 Z 1 optionally substituted with each Z 1a are independently hydroxy, halo, cyano, -NO2, -SF5, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 13 )2, -OR 13 , -C(O)R 13 , -C(O)OR 13 , -S(O) 0-2 R 13 , -NR 13 S(O) 0-2 R 13 , -S(O) 0-2 N(R 13 )2, -NR 13 S(O) 0-2 N(R 13 )2, -NR 13 C(O)N(R 13 )2, -C(O)N(R 13 )2, -NR 13 C(O)R 13 , -OC(O)N(R 13 )2, or -NR 13 C(O)OR 13 and each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl independently selected from 1 to 5 Z1b optionally substituted with Each R 13 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl independently selected from 1 to 5 Z 1b optionally substituted with Each R 14 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, and each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl may be selected from the group consisting of 1 to 5 halo, hydroxy, -SH, -NH2, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 optionally substituted with haloalkyl; each Z 1b are independently halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -LC 1-6 Alkyl, -LC 2-6Alkenyl, -LC 2-6 Alkynyl, -LC 1-6 Haloalkyl, -LC 3-10 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 alkynyl)-, -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 alkynyl)-, -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)NH-; Z 1b and each C of L 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may further independently be selected from the group consisting of 1 to 5 hydroxy, halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, 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 3-10Provided are compounds, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, that are optionally substituted with cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0072] In certain embodiments, the compound of formula IB: [ka] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein: X 1 is O or S, Y 1 is O or S, A 1 , A 2 , A 3 , and A 4 are each independently N, CH, or CR 1 However, A 1 , A 2 , A 3 , and A 4 At least one of the 1 provided that: Each R 1 However, independently, halo, cyano, -NO2, -SF5, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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, -NR11 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 each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl independently represents 1 to 8 Z 1 optionally substituted with Any two adjacent R 1 together with the atoms to which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl ring, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl independently contains 1 to 8 Z 1 optionally substituted with R 2 But C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -NO2, -SF5, -OR 11 , -N(R 11 )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 )2, -NR 11 S(O) 0-2 N(R 11 )2, -NR 11 C(O)N(R 11 )2, -NR 11 C(O)OR 11 , -NR 11 C(O)R 11, -OC(O)R 11 , -OC(O)N(R 11 )2, -C(O)N(R 11 )2, halo, or cyano, wherein 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 1 to 8 Z 1 optionally substituted with R 3 But hydrogen, halo, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 1 to 8 Z 1 or R 2 and R 3 Together, C 3-10 forming a cycloalkyl or heterocyclyl ring, wherein the C 3-10 cycloalkyl or heterocyclyl is 1 to 8 Z 1 optionally substituted with R 4 But hydrogen, halo, -NO2, cyano, hydroxy, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, 5- to 6-membered heteroaryl, -OR 14 , -N(R 14 )2, or -S(O) 0-2 R 14 where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl may be selected from the group consisting of 1 to 5 halo, hydroxy, -SH, -NH2, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 optionally substituted with haloalkyl; R 5 But hydrogen, halo, -NO2, cyano, hydroxy, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, 5- to 6-membered heteroaryl, -OR 14 , -N(R 14 )2, or -S(O) 0-2 R 14 where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl may be selected from the group consisting of 1 to 5 halo, hydroxy, -SH, -NH2, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 optionally substituted with haloalkyl, or R 4 and R 5 taken together form a heterocyclyl or heteroaryl, wherein the heterocyclyl or heteroaryl is selected from the group consisting of 1 to 5 halo, hydroxy, -SH, -NH, -NO, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 optionally substituted with haloalkyl; R 6 But hydrogen, halo, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-10cycloalkyl, or heterocyclyl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-10 The cycloalkyl or heterocyclyl may further comprise 1 to 5 Z 1b may be optionally substituted with R 7 But hydrogen, halo, cyano, hydroxy, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-10 cycloalkyl, or heterocyclyl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-10 The cycloalkyl or heterocyclyl may further comprise 1 to 5 Z 1b or or R 6 and R 7 combine to form C 3-10 forming a cycloalkyl or heterocyclyl ring, wherein the C 3-10 The cycloalkyl or heterocyclyl ring may further comprise 1 to 5 Z 1b may be optionally substituted with R 8 But hydrogen, halo, cyano, C 1-6 Alkyl or C 1-6 is haloalkyl, R 9 and R 10 are each independently hydrogen, halo, cyano, C 1-6 Alkyl, or C 1-6 haloalkyl, and each C 1-6 Alkyl or C 1-6 haloalkyl, independently, 1 to 5 Z 1or R 9 and R 10 Together, C 3-10 forming a cycloalkyl or heterocyclyl ring, wherein the C 3-10 cycloalkyl or heterocyclyl is 1 to 8 Z 1 optionally substituted with each Z 1 However, independently, halo, cyano, -NO2, -SF5, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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 each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl independently selected from 1 to 5 Z 1a optionally substituted with Each R 11 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6Haloalkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl independently selected from 1 to 5 Z 1a optionally substituted with R 12 But hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 1 to 8 Z 1 optionally substituted with each Z 1a are independently hydroxy, halo, cyano, -NO2, -SF5, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 13 )2, -OR 13 , -C(O)R 13 , -C(O)OR 13 , -S(O) 0-2 R 13 , -NR 13 S(O) 0-2 R 13 , -S(O) 0-2 N(R 13 )2, -NR 13 S(O) 0-2 N(R 13 )2, -NR 13 C(O)N(R 13 )2, -C(O)N(R 13 )2, -NR 13 C(O)R13 , -OC(O)N(R 13 )2, or -NR 13 C(O)OR 13 and each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl independently selected from 1 to 5 Z 1b optionally substituted with Each R 13 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl independently selected from 1 to 5 Z 1b optionally substituted with Each R 14 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, and each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl may be selected from the group consisting of 1 to 5 halo, hydroxy, -SH, -NH2, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 optionally substituted with haloalkyl; each Z 1bare independently halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -LC 1-6 Alkyl, -LC 2-6 Alkenyl, -LC 2-6 Alkynyl, -LC 1-6 Haloalkyl, -LC 3-10 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 alkynyl)-, -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 alkynyl)-, -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)NH-; Z 1b and each C of L 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10The cycloalkyl, heterocyclyl, aryl, or heteroaryl may further independently be selected from the group consisting of 1 to 5 hydroxy, halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, 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 Provided are compounds, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, that are optionally substituted with cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0073] In certain embodiments, A 2 , A 3 , and A 4 are each independently N, CH, or CR 1 and A 1 is CR 1 is.

[0074] In certain embodiments, A 1 , A 3 , and A 4 are each independently N, CH, or CR 1 and A 2 is CR 1 is.

[0075] In certain embodiments, A 1 , A 2 , and A 4 are each independently N, CH, or CR 1 and A 3 is CR 1 is.

[0076] In certain embodiments, A 1 , A 2 , and A 3 are each independently N, CH, or CR 1 and A 4 is CR1 is.

[0077] In certain embodiments, A 1 , A 2 , A 3 , and A 4 At least one of is N.

[0078] In certain embodiments, A 1 , A 2 , A 3 , and A 4 are each independently CH or CR 1 is.

[0079] In certain embodiments, A 2 , A 3 , and A 4 are each independently CH or CR 1 and A 1 is CR 1 is.

[0080] In certain embodiments, A 1 , A 3 , and A 4 are each independently CH or CR 1 and A 2 is CR 1 is.

[0081] In certain embodiments, A 1 , A 2 , and A 4 are each independently CH or CR 1 and A 3 is CR 1 is.

[0082] In certain embodiments, A 1 , A 2 , and A 3 are each independently CH or CR 1 and A 4 is CR 1 is.

[0083] In certain embodiments, the compound represented by formula IC: [ka] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , R 10 , and R 12 are each independently as defined herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0084] In certain embodiments, R 12 is hydrogen or C 1-6 In certain embodiments, R 12 is hydrogen or methyl. In certain embodiments, R 12 is hydrogen. In certain embodiments, R 12 is C 1-6 In certain embodiments, R 12 is methyl.

[0085] In certain embodiments, R 9 is hydrogen or C 1-6 In certain embodiments, R 9 is hydrogen or methyl, and R 10 is hydrogen. In certain embodiments, R 9 is hydrogen. In certain embodiments, R 10 is hydrogen. In certain embodiments, R 9 and R 10 is hydrogen. In certain embodiments, R 9 is methyl and R 10is hydrogen.

[0086] In certain embodiments, compounds represented by formula II: [ka] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 12 are each independently as defined herein; The compound, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, is provided wherein p is 1, 2, 3, or 4.

[0087] In certain embodiments, the compound represented by formula III: [ka] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 12 are each independently as defined herein; The compound, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, is provided wherein p is 1, 2, 3, or 4.

[0088] In certain embodiments, the compound represented by formula IV: [ka] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 12 are each independently as defined herein; The compound, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, is provided wherein p is 1, 2, 3, or 4.

[0089] In certain embodiments, compounds represented by formula V: [ka] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 12 are each independently as defined herein; The compound, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, is provided wherein p is 1, 2, 3, or 4.

[0090] In certain embodiments, the compound represented by formula VI: [ka] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 12 are each independently as defined herein; The compound, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, is provided wherein p is 1, 2, 3, or 4.

[0091] In certain embodiments, R 6 is hydrogen, halo, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-10 cycloalkyl, or heterocyclyl. In certain embodiments, R 6 is hydrogen.

[0092] In certain embodiments, R 7 is hydrogen, halo, cyano, hydroxy, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-10 cycloalkyl, or heterocyclyl. In certain embodiments, R 7 is hydrogen.

[0093] In certain embodiments, R 6 and R 7 is hydrogen.

[0094] In certain embodiments, R 6 and R 7is combined with C 3-10 Forms a cycloalkyl.

[0095] In certain embodiments, R 8 is hydrogen, halo, C 1-6 Alkyl, or C 1-6 In certain embodiments, R 8 is hydrogen or halo. In certain embodiments, R 8 is hydrogen or fluoro.

[0096] In certain embodiments, R 12 is hydrogen and R 6 is hydrogen and R 7 is hydrogen.

[0097] In certain embodiments, the compound represented by formula VII: [ka] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein: R 1 , R 2 , R 3 , R 4 , and R 5 are each independently as defined herein; The compound, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, is provided wherein p is 1, 2, 3, or 4.

[0098] In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 1 or 2. In certain embodiments, p is 3. In certain embodiments, p is 4.

[0099] In certain embodiments, each R 1are independently halo, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-10 cycloalkyl, or heterocyclyl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, and C 3-10 Cycloalkyl independently represents 1 to 8 Z 1 or any two adjacent R 1 together with the atoms to which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl ring.

[0100] In certain embodiments, each R 1 are independently fluoro, bromo, chloro, iodo, cyano, ethyl, vinyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, methoxy, fluoromethoxy, difluoromethoxy, cyclopropyl, cyclobutyl, cyclopropylmethyl, oxetan-3-yl, 2,2-difluorocycloprop-1-yl, 1-cyanocyclopropyl, 1-methylcyclopropyl, 1-fluoro-2-(trifluoromethyl)cyclopropyl, ethynyl, 1-fluorovinyl, 1-fluorocyclopropyl, 2-fluorocyclopropyl, or 1,2-difluorocyclopropyl, or two adjacent R 1 together with the atoms to which they are attached to form thiophene.

[0101] In certain embodiments, each R 1 are independently halo, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, or C 3-10cycloalkyl, wherein the C 2-6 Alkenyl or C 3-10 Cycloalkyl independently represents 1 to 8 Z 1 In certain embodiments, each R 1 are independently halo, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, or C 3-10 cycloalkyl, wherein the C 3-10 Cycloalkyl independently represents 1 to 8 Z 1 In certain embodiments, each R 1 are independently halo, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, or C 3-10 cycloalkyl, wherein the C 2-6 Alkenyl or C 3-10 Cycloalkyl independently represents 1 to 8 Z 1 and optionally substituted with, each independently, halo, cyano, and C 1-6 alkyl.

[0102] In certain embodiments, each R 1 are independently halo, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Haloalkyl, or C 3-10 In certain embodiments, each R 1 are independently halo, cyano, C 1-6 Haloalkoxy, C 1-6 Haloalkyl, or C 3-10 In certain embodiments, each R 1 are independently halo, cyano, C1-6 Alkyl, C 1-6 Alkoxy, or C 1-6 In certain embodiments, each R 1 are independently halo or C 1-6 It is alkyl.

[0103] In certain embodiments, each R 1 is independently fluoro, bromo, chloro, iodo, cyano, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, methoxy, fluoromethoxy, difluoromethoxy, cyclopropyl, cyclobutyl, 2,2-difluorocycloprop-1-yl, 1-cyanocyclopropyl, and 1-methylcyclopropyl, ethynyl, 1-fluorovinyl, 1-fluorocyclopropyl, or 1,2-difluorocyclopropyl. 1 are independently fluoro, bromo, chloro, iodo, cyano, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, methoxy, fluoromethoxy, difluoromethoxy, cyclopropyl, cyclobutyl, 2,2-difluorocycloprop-1-yl, 1-cyanocyclopropyl, and 1-methylcyclopropyl. 1 is independently fluoro, bromo, —CH, —OCHF, —CF, or cyclopropyl. 1 is independently fluoro, bromo, or —CH. In certain embodiments, each R 1 is independently halo. In certain embodiments, each R 1 is independently bromo. In certain embodiments, each R 1 are independently halo or -CF3.

[0104] In certain embodiments, p is 1 and each R 1 are independently halo, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, or C 1-6In certain embodiments, p is 2 and each R 1 are independently halo, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, or C 1-6 In certain embodiments, p is 1 or 2, and each R 1 are independently halo, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, or C 1-6 It is haloalkyl.

[0105] In certain embodiments, R 2 and R 3 Together, C 3-10 forming a cycloalkyl or heterocyclyl ring, where C 3-10 The cycloalkyl or heterocyclyl independently has 1 to 8 Z 1 In certain embodiments, R 2 and R 3 together, 1 to 8 Z 1 C optionally substituted with 3-10 In certain embodiments, R 2 and R 3 Together, halo, cyano, C 1-6 Alkyl, or C 1-6 C optionally substituted with haloalkyl 3-10 In certain embodiments, R 2 and R 3 Let's get together, Hello, C 1-6 Alkyl, or C 1-6 C optionally substituted with haloalkyl 3-10 In certain embodiments, R 2 and R 3 together form C optionally substituted with fluoro, methyl, or trifluoromethyl. 3-10 In certain embodiments, R 2 and R 3Together, C 1-6 C optionally substituted with alkyl 3-10 In certain embodiments, R 2 and R 3 together form a C optionally substituted with methyl 3-10 In certain embodiments, R 2 and R 3 together, 1 to 8 Z 1 In certain embodiments, R 2 and R 3 Together, C 3-10 In certain embodiments, R 2 and R 3 together, the unsubstituted C 3-10 In certain embodiments, R 2 and R 3 taken together form an unsubstituted cyclopropyl ring. In certain embodiments, R 2 and R 3 taken together form an unsubstituted heterocyclyl ring.

[0106] In certain embodiments, R 2 is C 1-6 Alkyl, C 1-6 Haloalkyl, or -OR 11 where R 11 is 1 to 5 Z 1a C optionally substituted with 1-6 In certain embodiments, R 2 is C 1-6 Alkyl or C 1-6 haloalkyl, and R 3 is hydrogen or C 1-6 In certain embodiments, R 2 is C 1-6 Alkyl or C 1-6 In certain embodiments, R 2 is C1-6 In certain embodiments, R 2 is methyl or ethyl.

[0107] In certain embodiments, R 2 is -C(R 24 )2R 25 and each R 24 and R 25 are independently hydrogen, halo, C 1-4 Alkyl, or C 1-4 In certain embodiments, R 2 is -C(R 24 )2R 25 and each R 24 are independently hydrogen, halo, C 1-4 Alkyl, or C 1-4 haloalkyl, and R 25 is hydrogen.

[0108] In certain embodiments, R 3 is hydrogen, C 1-6 Alkyl, or C 1-6 In certain embodiments, R 3 is hydrogen or C 1-6 In certain embodiments, R 3 is C 1-6 In certain embodiments, R 3 is hydrogen or methyl. In certain embodiments, R 3 is hydrogen. In certain embodiments, R 3 is methyl.

[0109] In certain embodiments, R 2 is C 1-6 alkyl, and R 3 is hydrogen, or C 1-6 alkyl, or R 2 and R 3 Together, C 1-6 C optionally substituted with alkyl 3-10In certain embodiments, R 2 and R 3 is C 1-6 It is alkyl.

[0110] In certain embodiments, the compound represented by formula VIII: [ka] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein q is 0, 1, 2, 3, or 4; and Z 1 , R 1 , R 4 , and R 5 are each independently as defined herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0111] In certain embodiments, the compound represented by formula IX: [ka] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein q is 0, 1, 2, 3, or 4; and Z 1 , R 1 , R 4 , and R 5 are each independently as defined herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0112] In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is 3. In certain embodiments, q is 4. In certain embodiments, each Z 1 are independently halo, cyano, C1-6 Alkyl, or C 1-6 In certain embodiments, q is 1 or 2, and each Z 1 are independently halo, cyano, C 1-6 Alkyl, or C 1-6 It is haloalkyl.

[0113] In certain embodiments, each R 1 are independently halo, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, or C 1-6 haloalkyl, q is 1 or 2, and each Z 1 are independently halo, cyano, C 1-6 Alkyl, or C 1-6 It is haloalkyl.

[0114] In certain embodiments, the compound represented by formula VIIIA: [ka] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein R 1 , R 4 , and R 5 are each independently as defined herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0115] In certain embodiments, R 1 Halo, Cyano, C 1-6 Alkyl, C 1-6 Alkoxy, or C 1-6 In certain embodiments, R 1 is halo. In certain embodiments, R 1 is bromo. In certain embodiments, R 1 is -CF3.

[0116] In certain embodiments, the compound represented by formula IXA: [ka] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein R 1 , R 4 , and R 5 are each independently as defined herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0117] In certain embodiments, each R 1 are independently halo, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, or C 1-6 In certain embodiments, each R 1 is independently fluoro, chloro, bromo, —CH, or —CF. In certain embodiments, each R 1 is independently fluoro, bromo, —CH, or —CF. In certain embodiments, each R 1 is independently halo. In certain embodiments, each R 1 is independently bromo. In certain embodiments, each R 1 are independently halo or -CF3.

[0118] In certain embodiments, R 5 is hydrogen or C 1-6 In certain embodiments, R 5 is hydrogen or —CF. In certain embodiments, R 5 is hydrogen. In certain embodiments, R 5 is C 1-6 In certain embodiments, R 5 is -CF3.

[0119] In certain embodiments, R 4 is hydrogen.

[0120] In certain embodiments, R 4 is hydrogen and R 5 is hydrogen or C 1-6 In certain embodiments, R 4 is hydrogen and R 5 is hydrogen or —CF. In certain embodiments, R 4 is hydrogen and R 5 is hydrogen. In certain embodiments, R 4 is hydrogen and R 5 is C 1-6 In certain embodiments, R 4 is hydrogen and R 5 is -CF3.

[0121] In certain embodiments, each Z 1a are, independently, halos.

[0122] In certain embodiments, each Z 1 are independently halo, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, or -C(O)OR 11 is.

[0123] In certain embodiments, each R 11 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 It is cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0124] In certain embodiments, each R 11 are independently hydrogen or C 1-6In certain embodiments, each R 11 is hydrogen.

[0125] In certain embodiments, R 12 is hydrogen or C 1-6 In certain embodiments, R 12 is hydrogen.

[0126] In certain embodiments, each R 13 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl. In certain embodiments, each R 13 are independently hydrogen or C 1-6 It is alkyl.

[0127] In certain embodiments, each R 14 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, or C 3-6 In certain embodiments, each R 14 are independently hydrogen or C 1-6 In certain embodiments, each R 14 is hydrogen.

[0128] In certain embodiments, a compound selected from Table 1, or a pharmaceutically acceptable salt, isotopically enriched analog, prodrug, stereoisomer, or mixture of stereoisomers thereof is provided. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12]

[0129] In certain embodiments, a compound selected from Table 2, or a pharmaceutically acceptable salt, isotopically enriched analog, prodrug, stereoisomer, or mixture of stereoisomers thereof, is provided. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9]

[0130] 3. Method "Treatment" or "treating" is an approach to obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can 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 lessening 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., stabilizing the disease or condition, preventing or slowing the worsening or progression of the disease or condition, and / or preventing or slowing the spread (e.g., metastasis) of the disease or condition); and / or c) palliation of the disease, i.e., causing regression of clinical symptoms (e.g., improving the disease state, providing partial or total remission of the disease or condition, enhancing the effect of another drug, slowing the progression of the disease, improving quality of life, and / or prolonging survival).

[0131] "Prevention" or "preventing" means any treatment of a disease or condition that keeps the clinical symptoms of the disease or condition from developing. The compounds, in some embodiments, can be administered to subjects (including humans) at risk or with a family history of the disease or condition.

[0132] "Subject" refers to an animal, such as a mammal (including a human), that has been the object or subject of treatment, observation, or experiment. The methods described herein may be useful for human therapy and / or veterinary applications. In some embodiments, the subject is a mammal. In certain embodiments, the subject is a human.

[0133] The term "therapeutically effective amount" or "effective amount" of a compound described herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof means an amount sufficient to effectively treat a subject that provides a therapeutic benefit, such as alleviating symptoms or delaying disease progression, when administered to the subject. For example, a therapeutically effective amount can be an amount sufficient to reduce the symptoms of a disease or condition described herein. A therapeutically effective amount can vary depending on the subject and 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 one of ordinary skill in the art.

[0134] The methods described herein may be applied to in vivo or ex vivo cell populations. "In vivo" means inside a living individual, such as inside an animal or human. In this context, the methods described herein may be used therapeutically on an individual. "Ex vivo" means outside a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples, including bodily fluid or tissue samples obtained from an individual. Such samples may 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 optimal dosing schedules and / or dosages of the disclosed compounds for a given indication, cell type, individual, and other parameters. Information obtained from such use may be used experimentally or clinically to design in vivo treatment protocols. Other ex vivo uses for which the compounds and compositions described herein may be suitable are described below or will be apparent to those skilled in the art. Compounds may be further characterized to test for safety or tolerated doses in human or non-human subjects. Such properties may be tested using methods commonly known to those skilled in the art.

[0135] In certain embodiments, provided herein is a compound, or its pharmaceutically acceptable salt, isotope-enriched analog, stereoisomer, stereoisomer mixture or prodrug, that regulates the activity of NLR family pyrin domain-containing 3 (NLRP3).In certain embodiments, provided herein is a compound, or its pharmaceutically acceptable salt, isotope-enriched analog, stereoisomer, stereoisomer mixture or prodrug, that inhibits the activity of NLRP3.

[0136] NLR proteins are involved in the immune system and help initiate and regulate the immune system's response to injury, toxins, or microbial invasion. NLRP3 (also known as cryopyrin, NALP3, and LRR- and PYD-domain-containing protein 3) is a protein encoded by the NLRP3 gene (also known as CIAS1). Upon activation, NLRP3 molecules assemble into inflammasomes along with other proteins. Activation of NLRP3 by cellular stress leads to inflammasome activation and downstream proteolytic events, including the formation and subsequent secretion of active pro-inflammatory cytokines such as interleukin (IL)-1β and IL-18. IL-1β and IL-18, among other cytokines, are known mediators of inflammation, e.g., inflammation of the arterial wall, atherosclerosis, and the aging process.

[0137] In certain embodiments, a method for inhibiting inflammasome (e.g., NLRP3 inflammasome) activity is provided, comprising contacting a cell with an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof. Inhibition can be in vitro or in vivo.

[0138] In certain embodiments, provided are compounds disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, for use in inhibiting inflammasome (e.g., NLRP3 inflammasome) activity (e.g., in vitro or in vivo).

[0139] In certain embodiments, the present disclosure provides the use of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, in the manufacture of a medicament for inhibiting (e.g., in vitro or in vivo) inflammasome (e.g., NLRP3 inflammasome) activity.

[0140] 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. IL-Iβ expression is elevated in various cancers (e.g., breast cancer, prostate cancer, colon cancer, lung cancer, head and neck cancer, melanoma, etc.), and patients with IL-Iβ-producing tumors generally have a poor prognosis.

[0141] In certain embodiments, a method for treating a disease or condition mediated at least in part by NLRP3, comprising administering to a subject in need thereof an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0142] In certain embodiments, provided are methods for treating a disease or condition selected from an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0143] In certain embodiments, provided are compounds disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, for use in treating an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer in a subject in need thereof.

[0144] In certain embodiments, the present disclosure provides for the use of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, in the manufacture of a medicament for treating or preventing an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer in a subject in need thereof.

[0145] In certain embodiments, methods are provided for treating inflammation, autoimmune diseases, cancer, infectious diseases, central nervous system diseases, metabolic diseases, cardiovascular diseases, respiratory diseases, liver diseases, kidney diseases, eye diseases, skin diseases, lymphatic conditions, psychiatric disorders, graft-versus-host disease, allodynia, and any disease in which an individual has been determined to have a germline or somatic non-silent mutation in NLRP3, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0146] In certain embodiments, the disease or condition may be a disease or condition of the immune system, cardiovascular system, endocrine system, gastrointestinal tract, renal system, liver system, metabolic system, respiratory system, central nervous system, may be cancer or other malignancy, and / or may be caused by or associated with a pathogen. It is understood that these general embodiments, defined according to broad classifications of diseases, disorders, and conditions, are not mutually exclusive.

[0147] In certain embodiments, the disease or condition is an inflammatory disorder, e.g., inflammation including inflammation resulting from an autoinflammatory disease, inflammation occurring as a symptom of a non-inflammatory disorder, inflammation resulting from an infection, or inflammation secondary to trauma, injury, or autoimmunity; acute disseminated encephalitis, Addison's disease, ankylosing spondylitis, antiphospholipid syndrome (APS), antisynthetase syndrome, aplastic anemia, autoimmune adrenalitis, autoimmune hepatitis, autoimmune oophoritis, autoimmune polyendocrine deficiency, autoimmune thyroiditis, celiac disease, Crohn's disease, type 1 diabetes (T1D), Goodpasture's disease, syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, idiopathic thrombocytopenic purpura, Kawasaki disease, lupus erythematosus including systemic lupus erythematosus (SLE), multiple sclerosis (MS) 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, ordinal thyroiditis, pemphigus, pernicious anemia, polyarthritis, primary biliary cirrhosis, rheumatoid arthritis (RA), psoriatic arthritis, juvenile idiopathic arthritis or steatohepatitis Autoimmune diseases such as leukemia, refractory gouty arthritis, Reiter's syndrome, Sjögren's syndrome, systemic connective tissue disorder systemic sclerosis, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, alopecia universalis, Behçet's disease, Chagas' disease, autonomic neuropathy, endometriosis, hidradenitis suppurativa (HS), interstitial cystitis, neuromyotonia, psoriasis, sarcoidosis, scleroderma, ulcerative colitis, Schnitzler's syndrome, macrophage activation syndrome, Blau's syndrome, vitiligo, or vulvodynia; lung cancer, pancreatic cancer, gastric cancer, myelodysplastic syndrome, acute lymphoblastic leukemia (A) Leukemia including acute myeloid leukemia (AML), adrenal cancer, anal cancer, basal squamous cell carcinoma, bile duct cancer, 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's family of tumors, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), gestational trophoblastic disease, glioma, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, liver cancer, lung carcinoid tumors, lymphomas including cutaneous T-cell lymphoma, malignant mesothelioma,Cancers including melanoma skin cancer, Merkel cell skin cancer, multiple myeloma, cancer of the nasal cavity and paranasal sinuses, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oral and oropharyngeal cancer, osteosarcoma, ovarian cancer, penile cancer, pituitary tumors, 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 anaplastic thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom's macroglobulinemia, and Wilms' tumor; viral infections (e.g., influenza virus, human immunodeficiency virus, Infections caused by whole viruses (e.g., HIV), alphaviruses (e.g., chikungunya and Ross River viruses), flaviviruses (e.g., dengue and Zika viruses), herpesviruses (e.g., Epstein-Barr virus, cytomegalovirus, varicella-zoster virus, and KSHV), poxviruses (e.g., vaccinia virus (e.g., modified vaccinia virus Ankara) and myxoma virus), adenoviruses (e.g., adenovirus 5), or papillomaviruses), bacterial infections (e.g., Staphylococcus aureus, Helicobacter pylori, Bacillus anthracis, 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,Infectious diseases, 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., caused by Candida or Aspergillus species), protozoal infections (e.g., caused by Plasmodium, Babesia, Giardia, Entamoeba, Leishmania or Trypanosomes), helminth infections (e.g., caused by schistosomes, nematodes, cestodes or flukes) and prion infections; Parkinson's disease, Alzheimer's disease, dementia, motor neuron disease Central nervous system diseases such as Huntington's disease, cerebral malaria, brain injury due to pneumococcal meningitis, intracranial aneurysm, traumatic brain injury, and amyotrophic lateral sclerosis; metabolic diseases such as type 2 diabetes (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 aneurysms, and pericarditis, including Dressler's syndrome; respiratory diseases including chronic obstructive pulmonary disease (COPD), asthma, including allergic asthma and steroid-resistant asthma, asbestosis, 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 (AF) liver disease, including LD, and alcoholic steatohepatitis (ASH); kidney disease, including chronic kidney disease, oxalate nephropathy, nephrocalcinosis, glomerulonephritis, and diabetic nephropathy; ophthalmological diseases, including those of the 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;and acne conglobata; lymphatic conditions such as lymphangitis and Castleman's disease; psychiatric disorders such as depression and psychological stress; graft-versus-host disease; allodynia, including mechanical allodynia; and any disease in which an individual is determined to have a germline or somatic non-silent mutation in NLRP3.

[0148] In certain embodiments, the disease, disorder, or condition is selected from the group consisting of cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), familial Mediterranean fever (FMF), neonatal-onset multisystem inflammatory disease (NOMID), tumor necrosis factor (TNF) receptor-associated periodic syndromes (TRAPS), hyperimmunoglobulin Demia and periodic fever syndrome (HIDS), interleukin-1 receptor antagonist deficiency, and urinary tract infections. These include autoinflammatory diseases such as Diabetes Infectious Disease (DIRA), Majeed syndrome, Septic Arthritis, Pyoderma Gangrenosum, and Acne Syndrome (PAPA), Adult Onset Still's Disease (AOSD), A20 Haploinsufficiency (HA20), Childhood Granulomatous Arteritis (PGA), PLCG2-Associated Antibody Deficiency and Immune Dysfunction (PLAID), PLCG2-Associated Autoinflammatory Antibody Deficiency and Immune Dysfunction (APLAID), or B-cell immunodeficiency, sideroblastic anemia with periodic fever and developmental delay (SIFD).

[0149] In certain embodiments, provided are methods for treating a disease or condition selected from cryopyrin-associated autoinflammatory syndromes (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS)), Muckle-Wells syndrome (MWS), chronic infantile neurological, cutaneous, and articular (CINCA) syndrome, neonatal-onset multisystem inflammatory disease (NOMID), familial Mediterranean fever, and an autoinflammatory and / or autoimmune disorder selected from 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, and multiple sclerosis, and neuroinflammation occurring in protein misfolding diseases (e.g., prion diseases), comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0150] In certain embodiments, the present invention is directed to a disease caused by cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), familial Mediterranean fever (FMF), septic arthritis, pyoderma gangrenosum, and acne syndrome (PAPA), hyperimmunoglobulin D-related periodic fever syndrome (HIDS), tumor necrosis factor (TNF) receptor-associated periodic syndromes (TRAPS), systemic juvenile idiopathic arthritis, adult-onset Still's disease (AOSD), relapsing multiple myeloma, and myeloma. Methods are provided for treating a disease or condition selected from chondritis, Schnitzler's syndrome, Sweet's syndrome, Behcet's disease, antisynthetase syndrome, interleukin-1 receptor antagonist deficiency (DIRA), and A20 haploinsufficiency (HA20), comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0151] In certain embodiments, provided are methods 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, hyperinflammation after influenza infection, graft-versus-host disease, stroke, silicosis, type 1 diabetes, obesity-induced inflammation or insulin resistance, rheumatoid arthritis, myelodysplastic syndrome, contact hypersensitivity, chikungunya virus-induced joint inflammation, or traumatic brain injury, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0152] In certain embodiments, methods are provided for treating diseases or conditions mediated at least in part by TNF-α. In certain embodiments, the disease or condition is resistant to treatment with an anti-TNF-α agent. In some embodiments, the disease is an intestinal disease or condition. In some embodiments, the disease or condition is inflammatory bowel disease, Crohn's disease, or ulcerative colitis. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, is 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.

[0153] In certain embodiments, the disease or condition is an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer.

[0154] In certain embodiments, the disease or condition is an autoinflammatory and / or autoimmune disorder.

[0155] In certain embodiments, the disease or condition is a neurodegenerative disease.

[0156] In certain embodiments, the disease or condition is Parkinson's disease or Alzheimer's disease.

[0157] In certain embodiments, methods are provided for treating cancer, comprising administering to a subject in need thereof an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0158] In certain embodiments, the cancer is metastatic cancer, gastrointestinal cancer, skin cancer, non-small cell lung cancer, or colon adenocarcinoma.

[0159] In certain embodiments, provided are compounds disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, for use in treating a neurodegenerative disease (e.g., Parkinson's disease or Alzheimer's disease) in a subject in need thereof.

[0160] In certain embodiments, provided are compounds disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, for use in treating cancer in a subject in need thereof.

[0161] In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, can be administered alone as monotherapy or in addition to one or more other substances and / or treatments. Such combination treatment can be achieved by simultaneous, sequential, or separate administration of the individual components of the treatment.

[0162] For example, administration of an adjuvant may enhance the therapeutic effect (i.e., an adjuvant alone may provide minimal therapeutic benefit, but when combined with another therapeutic agent, enhances the overall therapeutic benefit to the individual). Alternatively, by way of example only, the benefit experienced by an individual may be increased by administering a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, with another therapeutic agent (including treatment regimen) that also has a therapeutic benefit.

[0163] Other embodiments include the use of the disclosed compounds in therapy.

[0164] 4. Kit Also provided herein are kits comprising a compound of the present disclosure, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, and suitable packaging. In certain embodiments, the kit further comprises instructions for use. In one aspect, the kit comprises a compound of the present disclosure, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, and a label and / or instructions for using the compound in the treatment of an indication, including a disease or condition described herein.

[0165] Also provided herein is an article of manufacture comprising a compound described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, in a suitable container, which may be a vial, jar, ampoule, pre-filled syringe, or intravenous bag.

[0166] 5. Pharmaceutical Compositions and Modes of Administration The compounds provided herein are usually administered in the form of pharmaceutical compositions. Thus, pharmaceutical compositions containing one or more of the compounds described herein, or their pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or prodrugs, and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants, and excipients are also provided herein. 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 a manner well known in the pharmaceutical arts. See, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985), and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (GS Banker & CT Rhodes, Eds.).

[0167] The pharmaceutical composition may be administered in a single dose or multiple doses. The pharmaceutical composition may be administered in a variety of ways, including, for example, rectally, bucally, intranasally, and transdermally. In certain embodiments, the pharmaceutical composition may be administered by intraarterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0168] 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.

[0169] Oral administration may be another route of administration for the compounds described herein. Administration may be, for example, via capsules or enteric-coated tablets. In preparing pharmaceutical compositions containing at least one compound described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, the active ingredient is usually diluted with an excipient and / or placed within a carrier, which may be in the form of a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it may be in the form of a solid, semi-solid, or liquid material and serves as a vehicle, carrier, or medium for the active ingredient. Thus, the composition may be in the form of a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (solid or liquid medium), for example, an ointment containing up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0170] 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 additionally contain lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl and propylhydroxybenzoates; sweeteners; and flavoring agents.

[0171] Compositions containing at least one compound described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, can be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a subject by using procedures known in the art. Controlled-release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Another formulation for use in the methods disclosed herein utilizes transdermal delivery devices ("patches"). Such transdermal patches can be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts. The construction and use of transdermal patches for drug delivery is well known in the art. Such patches can be constructed for continuous, pulsatile, or on-demand delivery of drugs.

[0172] To prepare solid compositions such as tablets, the primary active ingredient can be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof. When these preformulation compositions are referred to as homogeneous, the active ingredient is dispersed evenly throughout the composition, which allows the composition to be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0173] Tablets or pills of the compounds described herein can be coated or otherwise compounded to provide a dosage form offering the advantage of prolonged action or to protect against the acidic conditions of the stomach. For example, tablets or pills can comprise an inner dosage component and an outer dosage component, the latter being in the form of a coating over the former. The two components can be separated by an enteric layer, which serves to resist disintegration in the stomach and allow the inner component to pass intact into the duodenum or be released later. A variety of materials can be used for such enteric layers or coatings, including several polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0174] Compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein. In some embodiments, compositions are administered by the oral or nasal respiratory route for local or systemic effect. In other embodiments, compositions in pharmaceutically acceptable solvents can be nebulized using inert gases. Nebulized solutions can be inhaled directly from the nebulizing device, or the nebulizing device can be attached to a tent-like face mask or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0175] 6. Administration The specific dosage level of the compounds of the present application for any particular subject will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health, sex, diet, timing, route of administration, and rate of excretion, drug combinations, and the severity of the particular disease in the subject receiving therapy. For example, dosages can be expressed as milligrams of a compound described herein per kilogram of subject body weight (mg / kg). Doses of about 0.1 to 150 mg / kg may be appropriate. In some embodiments, doses of about 0.1 to 100 mg / kg may be appropriate. In other embodiments, doses of 0.5 to 60 mg / kg may be appropriate. In some embodiments, doses of about 0.0001 to about 100 mg / kg of compound per day, about 0.001 to about 50 mg / kg of compound per day, or about 0.01 to about 10 mg / kg of compound per day may be appropriate. Normalization by subject weight is particularly useful when adjusting doses between subjects of widely differing sizes, such as occurs when using a drug in both human children and adults, or when converting an effective dose in a non-human subject, such as a dog, to a dose suitable for human subjects.

[0176] 7. Compound Synthesis The compounds can be prepared using the methods disclosed herein, as well as routine variations thereof that become apparent in light of the disclosure herein and methods well known in the art. Conventional and well-known synthetic methods can be used in addition to the teachings herein. The synthesis of exemplary compounds described herein can be achieved as described in the following examples. Where available, reagents and starting materials can be purchased commercially, for example, from Sigma Aldrich or other chemical suppliers.

[0177] It will be understood that although typical process conditions (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are given, other process conditions can be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art from routine optimization procedures.

[0178] Additionally, conventional protecting groups ("PG") may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting particular functional groups, are well known in the art. Numerous protecting groups are described, for example, in Wuts, PGM, Greene, TW, & Greene, TW (2006). Greene's Protective Groups in Organic Synthesis. Hoboken, NJ, Wiley-Interscience, and references cited therein. For example, protecting groups for alcohols such as hydroxy include silyl ethers (including trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), triisopropylsilyloxymethyl (TOM), and triisopropylsilyl (TIPS) ethers), which can be removed by acid or fluoride ions, such as NaF, TBAF (tetra-n-butylammonium fluoride), HF-Py, or HF-NEt. Other protecting groups for alcohols include acetyl, which is removed by acid or base, benzoyl, which is removed by acid or base, benzyl, which is removed by hydrogenation, methoxyethoxymethyl ether, which is removed by acid, dimethoxytrityl, methoxymethyl ether, which is removed by acid, tetrahydropyranyl or tetrahydrofuranyl, which is removed by acid, and trityl, which is removed by acid.Examples of protecting groups for amines include carboxybenzyloxy, which is removed by hydrogenolysis; p-methoxybenzylcarbonyl, which is removed by hydrogenolysis; tert-butyloxycarbonyl, which is removed by concentrated strong acid (such as HCl or CF3COOH) or heating above about 80°C; 9-fluorenylmethyloxycarbonyl, which is removed by a base such as piperidine; acetyl, which is removed by treatment with base; benzoyl, which is removed by treatment with base; benzyl, which is removed by hydrogenolysis; carbamate groups, which are removed by acid and mild heating; p-methoxybenzyl, which is removed by hydrogenolysis; 3,4-dimethoxybenzyl, which is removed by hydrogenolysis; p-methoxyphenyl, which is removed by cerium(IV) ammonium nitrate; tosyl, which is removed by concentrated acid (such as HBr or H2SO4) and a strong reducing agent (sodium or sodium naphthalenide in liquid ammonia); & Nps).

[0179] Furthermore, compounds of the present disclosure may contain one or more chiral centers. Thus, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as enriched mixtures of stereoisomers. All such stereoisomers (and enriched mixtures) are included within the scope of the present disclosure, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) can be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated, for example, using chiral column chromatography, chiral resolvents, and the like.

[0180] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chem or Sigma (St. Louis, Missouri, USA). Others can be prepared by procedures described in standard reference texts 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), or obvious modifications thereof. [Example]

[0181] The following examples are included to demonstrate specific embodiments of the present disclosure. It will be understood by those skilled in the art that the techniques disclosed in the examples that follow represent techniques that work well in the practice of the invention and, as such, can be considered to constitute specific modes of its practice. However, those skilled in the art should, in light of the present disclosure, understand that many changes can be made in the specific embodiments disclosed and still obtain equivalent or similar results without departing from the spirit and scope of the invention.

[0182] General Experimental Methods All solvents used were commercially available and were used without further purification. Reactions were typically carried out using anhydrous solvents under an inert atmosphere of nitrogen.

[0183] NMR spectroscopy: 1 H nuclear magnetic resonance (NMR) spectroscopy was performed on a Bruker Avance III equipped with a BBFO 300MHz probe operating at 300MHz or one of the following instruments: a Bruker Avance 400 instrument equipped with probe DUAL 400MHz S1, probe 6 S1 400MHz 5mm 1 H- 13 The NMR studies were carried out using a Bruker Avance 400 instrument equipped with a C ID, a Bruker Avance III 400 instrument equipped with a nanobay probe Broadband BBFO 5mm Direct, and a Bruker Mercury Plus 400 NMR spectrometer equipped with a Bruker 400BBO 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 C and δ are both set to 0.00). In a particular case, 1 H nuclear magnetic resonance (NMR) spectroscopy was performed using a Bruker Advance 400 instrument operating at 400 MHz with the indicated solvents at near room temperature unless otherwise noted. In all cases, the NMR data were consistent with the proposed structures. Characteristic chemical shifts (δ) are given in parts per million using conventional abbreviations to designate major peaks: e.g., s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets; br, broad.

[0184] Thin-layer chromatography: When thin-layer chromatography (TLC) is used, it refers to silica gel TLC using silica gel F254 (Merck) plates, with Rf being the distance traveled by the compound on the TLC plate divided by the distance traveled by the solvent. Column chromatography was performed on silica gel cartridges using an automated flash chromatography system, or on C18 cartridges for reverse-phase chromatography. Alternatively, thin-layer chromatography (TLC) was performed on Mancherey-Nagel Alugram® (silica gel 60 F254), with UV typically used for spot visualization. In some cases, additional visualization methods were also employed. In these cases, TLC plates were stained with iodine (generated by adding approximately 1 g of I2 to 10 g of silica gel and mixing well), ninhydrin (commercially available from Aldrich), or Magic Stain (25 g of (NH4)6Mo7O 24 The compounds were visualized by development with 4H2O (generated by thoroughly mixing 5 g of (NH4)2Ce(IV)(NO3)6 in 450 mL of water and 50 mL of concentrated H2SO4).

[0185] Liquid chromatography-mass spectrometry and HPLC analysis: HPLC analysis was performed on a Shimadzu 20AB HPLC system equipped with a photodiode array detector and a Luna-C18(2) 2.0 × 50 mm, 5 μm column using a gradient of mobile phase A (MPA, HO + 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. LCMS was performed with detection at 220 nm and 254 nm or with 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 x 30 mm, 5 μm; MPA: HCl / H2O = 0.04% or formic acid / H2O = 0.2% (v / v); MPB: ACN. Neutral: Waters Xbridge 150 x 25, 5 μm; MPA: 10 mM NH4HCO3 / H2O; MPB: ACN. Gradient for both conditions: 10% MPB to 80% MPB at a flow rate of 20 mL / min for 12 min, then 100% MPB for 2 min, then 10% MPB for 2 min, UV detector. SFC analysis was performed on a Thar analytical SFC system equipped with a UV / Vis detector and a series of chiral columns, including AD, AS-H, OJ, OD, AY, and IC, 4.6 × 100 mm, 3 μm columns, 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 analysis was performed on 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, 30 × 250 mm, 5 μm columns, using a gradient 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) at a flow rate of 65 mL / min.LC-MS data were also acquired using a UPLC-MS Acquity™ system coupled to a Waters single quadrupole mass spectrometer equipped with a PDA detector and operated alternately in positive and negative electrospray ionization modes. The column used was a 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), for a total run time of 2.5 minutes. The column temperature was 40°C, and the flow rate was 0.8 mL / min.

[0186] Intermediates 1 and 2 (2's,4r)-6-Bromo-2'-fluorospiro[2,3-dihydroisoquinoline-4,1'-cyclopropan]-1-one and (2'r,4r)-6-Bromo-2'-fluorospiro[2,3-dihydroisoquinoline-4,1'-cyclopropan]-1-one [ka] Methyl 4-bromo-2-iodobenzoate: To a solution of 4-bromo-2-iodobenzoic acid (10.0 g, 30.6 mmol) in MeOH (100 mL) was added concentrated H2SO4 (15 g, 153 mmol) at 0 °C. The reaction mixture was stirred at 80 °C for 5 h. The reaction mixture was poured into water (300 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (3 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude residue that was used directly. 1 H NMR (400 MHz, CDCl3): δ 8.18(s,1H),7.70(d,J=8.4 Hz,1H),7.55(dd,J=0.8,8.0 Hz,1H),3.93(s,3H).

[0187] Methyl 4-bromo-2-vinylbenzoate: To a mixture of methyl 4-bromo-2-iodobenzoate (6.0 g, 17.6 mmol), potassium vinyltrifluoroborate (2.4 g, 17.6 mmol), and CsF (8.0 g, 52.8 mmol) in 1,4-dioxane (100 mL) was added Pd(dppf)Cl (1.3 g, 1.76 mmol). The reaction mixture was stirred at 90 °C for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. 1 H NMR(400 MHz,CDCl3): δ 7.77(d,J=8.4 Hz,1H),7.72(d,J=2.0 Hz,1H),7.49-7.37(m,2H),5.66(d,J=17.2 Hz,1H),5.41(d,J=10.8 Hz,1H),3.90(s,3H).

[0188] Methyl 4-bromo-2-(1-cyanovinyl)benzoate: To a mixture of CuO (345 mg, 2.41 mmol), 6,6'-dimethyl-2,2'-bipyridine (444 mg, 2.41 mmol), and Selectfluor (6.4 g, 18 mmol) in acetone (20 mL) and water (10 mL) was added methyl 4-bromo-2-vinylbenzoate (2.9 g, 12 mmol) and TMSCN (2.4 g, 24.1 mmol). The reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was poured into aqueous NaHCO (1 M, 30 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. 1 H NMR (400 MHz, CDCl3): δ 7.89(d,J=8.4 Hz,1H),7.65(dd,J=2.0,8.4 Hz,1H),7.51(d,J=1.6 Hz,1H),6.24(s,1H),6.01(s,1H),3.96(s,3H).

[0189] Methyl 4-bromo-2-((1r,2r)-1-cyano-2-fluorocyclopropyl)benzoate and methyl 4-bromo-2-((1r,2s)-1-cyano-2-fluorocyclopropyl)benzoate: To a solution of 4-bromo-2-(1-cyanovinyl)benzoate (800 mg, 3.01 mmol) in THF (30 mL) was added (fluoromethyl)(phenyl)(2,3,4,5-tetramethylphenyl)sulfonium tetrafluoroborate (2.3 g, 6.0 mmol) and NaH (1.2 g, 30.1 mmol, 60% purity in mineral oil) at 0 °C. The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title products as a 3:2 mixture. LCMS: m / z=298.0, 300.0 [M+H] + .

[0190] (2's,4r)-6-Bromo-2'-fluorospiro[2,3-dihydroisoquinolin-4,1'-cyclopropan]-1-one and (2'r,4r)-6-Bromo-2'-fluorospiro[2,3-dihydroisoquinolin-4,1'-cyclopropan]-1-one: To a solution of methyl 4-bromo-2-((1r,2r)-1-cyano-2-fluorocyclopropyl)benzoate and methyl 4-bromo-2-((1r,2s)-1-cyano-2-fluorocyclopropyl)benzoate (0.92 g, 3.09 mmol, 3:2 mixture) and dichlorocobalt (401 mg, 3.09 mmol) in MeOH (10 mL) was added NaBH (350 mg, 9.26 mmol) at 0 °C. The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was poured into saturated aqueous NH4Cl (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give:

[0191] (2's,4r)-6-Bromo-2'-fluorospiro[2,3-dihydroisoquinoline-4,1'-cyclopropan]-1-one (Int. 1): 1 H NMR(400 MHz,CDCl3): δ 8.02(d,J=8.4 Hz,1H),7.52(dd,J=2.0,8.4 Hz,1H),6.85(d,J=2.0 Hz,1H),6.12(br s,1H),4.70-4.50(m,1H),3.87(d,J=12.4 Hz,1H),3.51(dd,J=4.4,12.8 Hz,1H),1.62-1.54(m,1H),1.42-1.24(m,1H).

[0192] (2'r,4r)-6-Bromo-2'-fluorospiro[2,3-dihydroisoquinoline-4,1'-cyclopropan]-1-one (Int.2): 1 H NMR(400 MHz,CDCl3): δ 8.02(d,J=8.4 Hz,1H),7.55(dd,J=2.0,8.4 Hz,1H),7.28(d,J=2.0 Hz,1H),6.56(br s,1H),4.81-4.59(m,1H),3.78(dd,J=7.6,12.4 Hz,1H),2.74(dd,J=4.4,12.8 Hz,1H),1.83-1.73(m,1H),1.21-1.15(m,1H).

[0193] Intermediate 3 Methyl 2-[(2's,4r)-6-bromo-2'-fluoro-1-oxospiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]acetate [ka] To a solution of (2's,4r)-6-bromo-2'-fluorospiro[2,3-dihydroisoquinolin-4,1'-cyclopropan]-1-one (200 mg, 0.74 mmol, Int. 1) in DMF (2.0 mL) was added NaH (45 mg, 1.11 mmol, 60% purity in mineral oil) at 0 °C. The reaction mixture was stirred at 20 °C for 0.5 h, followed by the addition of methyl 2-bromoacetate (227 mg, 1.48 mmol). The reaction mixture was stirred at 20 °C for 3 h. The reaction mixture was poured into a mixture of saturated aqueous NH4Cl and ice water (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z = 342.0, 344.0 [M+H] + . 1 H NMR(400 MHz,CDCl3): δ 8.03(d,J=4.4 Hz,1H),7.51(d,J=8.4 Hz,1H),6.83(s,1H),4.73-4.54(m,2H),4.13-4.08(m,1H),4.03-3.94( m,1H),3.77(s,3H),3.44(m,1H),1.63-1.55(m,1H),1.44-1.33(m,1H).

[0194] Intermediates 4 and 5 Methyl 2-((1R,2S)-6'-bromo-2-fluoro-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetate and Methyl 2-((1S,2R)-6'-bromo-2-fluoro-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetate [ka] Methyl 2-[(2's,4r)-6-bromo-2'-fluoro-1-oxospiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]acetate (Int. 3) could be further separated by chiral SFC (column: Daicel Chiralpak AD (250 mm x 30 mm, 10 μm particle size), mobile phase: A: CO, B: 0.1% NHOH in i-PrOH; gradient: 38% B isocratic; flow rate: 64 g / min; detection wavelength: 220 nm; column temperature: 40°C, system back pressure: 100 bar) to give:

[0195] Methyl 2-((1R,2S)-6'-bromo-2-fluoro-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetate (first eluting isomer, Int.4): 1 H NMR(400 MHz,CDCl3): δ 8.02(d,J=8.0 Hz,1H),7.51(dd,J=1.6,8.4 Hz,1H),6.83(d,J=1.6 Hz,1H),4.73-4.54(m,2H),4.10(dd,J=2.0,12.4 Hz,1H),4.00(d,J=17.2 Hz,1H),3.77(s,3H),3.44(d,J=12.4 Hz,1H),1.60-1.57(m,1H),1.44-1.33(m,1H).

[0196] Methyl 2-((1S,2R)-6'-bromo-2-fluoro-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetate (second eluting isomer, Int. 5): 1 H NMR(400 MHz,CDCl3): δ 8.02(d,J=8.0 Hz,1H),7.51(dd,J=1.6,8.4 Hz,1H),6.83(d,J=1.6 Hz,1H),4.73-4.54(m,2H),4.10(dd,J=2.0,12.4 Hz,1H),4.00(d,J=17.2 Hz,1H),3.77(s,3H),3.44(d,J=12.4 Hz,1H),1.60-1.57(m,1H),1.44-1.33(m,1H).

[0197] Intermediate 6 2-((1S,2R)-6'-Bromo-2-fluoro-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetic acid [ka] To a solution of methyl 2-((1S,2R)-6'-bromo-2-fluoro-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetate (150 mg, 0.44 mmol, Int. 5) in THF (2.0 mL) and water (2.0 mL) was added LiOH·HO (46 mg, 1.10 mmol). The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was diluted with water (5 mL), extracted with MTBE (3 mL), and the organics were discarded. The aqueous portion was adjusted to pH = 3 by the addition of aqueous HCl (3 M) and extracted with EtOAc (3 × 2 mL). The combined organics were washed with brine (5 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue that was used directly. LCMS: m / z = 328.0, 330.0 [M+H] + .

[0198] Intermediate 7 2-((1S,2R)-2-fluoro-6'-(1-fluorocyclopropyl)-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetic acid [ka] tert-Butyl 2-((1S,2R)-6'-bromo-2-fluoro-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetate: To a solution of 2-((1S,2R)-6'-bromo-2-fluoro-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetic acid (1.25 g, 3.81 mmol, Int. 6) in DCM (20 mL) was added DMAP (465 mg, 3.81 mmol), DCC (865 mg, 4.19 mmol), and t-BuOH (424 mg, 5.71 mmol) at 0°C. The mixture was stirred at 20°C for 16 h. The mixture was filtered, and the filtrate was washed with saturated aqueous Na2CO3 (3 x 200 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography. 1 H NMR(400 MHz,CDCl3): δ 8.03(d,J=8.0 Hz,1H),7.50(dd,J=2.0,8.4 Hz,1H),6.82(d,J=2.0 Hz,1H),4.73-4.51(m,2H),4.07(dd,J=1.6,12.4 Hz,1H),3.85(d,J=17.2 Hz,1H),3.43(d,J=12.4 Hz,1H),1.58-1.54(m,1H),1.48(s,9H),1.44-1.33(m,1H).

[0199] tert-Butyl 2-((1S,2R)-2-fluoro-1'-oxo-6'-vinyl-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetate: To a solution of tert-butyl 2-((1S,2R)-6'-bromo-2-fluoro-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetate (500 mg, 1.30 mmol), potassium trifluoro(vinyl)borate (436 mg, 3.25 mmol) in 1,4-dioxane (10 mL) was added CsF (593 mg, 3.90 mmol) and Pd(dppf)Cl (95 mg, 0.13 mmol). The mixture was stirred at 90 °C for 3 h. The reaction mixture was poured into H2O (20 mL) and extracted with EtOAc (4 x 15 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and purified by silica gel column chromatography. LCMS: m / z = 276.2 [M-tBu+H] + . 1 H NMR(400 MHz,CDCl3): δ 8.13(d,J=8.0 Hz,1H),7.41(dd,J=1.6,8.0 Hz,1H),6.75-6.68(m,1H),6.66(d,J=1.6 Hz,1H),5.82(d,J=17.6 Hz,1H),5.37(d,J=11.2 Hz,1H),4.75-4.53(m,2H),4.07(dd,J=2.0,12.8 Hz,1H),3.87(d,J=17.2 Hz,1H),3.44(d,J=12.8 Hz,1H),1.64-1.60(m,1H),1.48(s,9H),1.42-1.31(m,1H).

[0200] tert-Butyl 2-((1S,2R)-2-fluoro-1'-oxo-6'-(2-bromo-1-fluoroethyl)-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetate: To a solution of tert-butyl 2-((1S,2R)-2-fluoro-1'-oxo-6'-vinyl-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetate (1.04 g, 3.14 mmol) in DCM (20 mL) was added NBS (614 mg, 3.45 mmol) and triethylamine tris(hydrogen fluoride) (759 mg, 4.71 mmol) at 0° C. The mixture was stirred at 0° C. for 15 min and then at 20° C. for 16 h. The mixture was poured into H2O (10 mL) and extracted with DCM (3 x 10 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and purified by silica gel column chromatography. LCMS: m / z = 374.0, 376.0 [M-tBu+H] + . 1 H NMR(400 MHz,CDCl3): δ 8.20(d,J=8.0 Hz,1H),7.31(br d,J=8.0 Hz,1H),6.70(s,1H),5.73-5.55(m,1H),4.75-4.52(m,2H),4.15-4.04(m,1H),3.87(dd,J=4.8,17.2 Hz,1H),3.68-3.57(m,2H),3.46(dd,J=6.4,12.8 Hz,1H),1.66-1.59(m,1H),1.49(s,9H),1.45-1.35(m,1H).

[0201] tert-Butyl 2-((1S,2R)-2-fluoro-1'-oxo-6'-(1-fluorovinyl)-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetate: To a solution of tert-butyl 2-((1S,2R)-2-fluoro-1'-oxo-6'-(2-bromo-1-fluoroethyl)-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetate (1.07 g, 2.49 mmol) in DMSO (20 mL) was added DBU (568 mg, 3.73 mmol). The mixture was stirred at 60 °C for 1 h. The reaction mixture was poured into HO (100 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and purified by silica gel column chromatography. LCMS: m / z=294.1 [Mt-Bu+H] + . 1 H NMR(400 MHz,CDCl3): δ 8.27(d,J=8.0 Hz,1H),7.64(d,J=8.0 Hz,1H),6.93(s,1H),5.23(dd,J=3.6,49.2 Hz,1H),5.07(dd,J=3.6,17.6 Hz,1H),4.87-4.62(m,2H),4.26-4.11(m,1H),4.02-3.91(m,1H),3.64-3.50(m,1H),1.74-1.67(m,1H),1.58(s,9H),1.54-1.44(m,1H).

[0202] tert-Butyl 2-((1S,2R)-2-fluoro-1'-oxo-6'-(2,2-dichloro-1-fluorocyclopropyl)-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetate: To a solution of tert-butyl 2-((1S,2R)-2-fluoro-1'-oxo-6'-(1-fluorovinyl)-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetate (650 mg, 1.86 mmol) in CHCl3 (15 mL) was added benzyltriethylammonium chloride (17 mg, 0.07 mmol) at 0°C, followed by the dropwise addition of aqueous NaOH (4.47 g, 55.8 mmol, 50 wt%). The mixture was stirred at 0°C for 0.5 h. The mixture was then stirred at 20° C. for 3 hours. The reaction mixture was poured into ice-cold H2O (20 mL) and extracted with DCM (2×10 mL). The combined organic layers were washed with aqueous HCl (20 mL, 0.1 M), saturated aqueous NaHCO3 (20 mL), and brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z=375.9, 377.0, 377.9 [M- t-Bu +H] + . 1 H NMR(400 MHz,CDCl3): δ 8.22(d,J=8.0 Hz,1H),7.40-7.31(m,1H),6.89-6.81(m,1H),4.76-4.56(m,2H),4.18-4.05(m,1H),3.87(dd,J=3.2,17.2 Hz,1H),3.52-3.42(m,1H),2.36-2.19(m,2H),1.70-1.62(m,1H),1.49(s,9H),1.46-1.36(m,1H).

[0203] tert-Butyl 2-((1S,2R)-2-fluoro-1'-oxo-6'-(1-fluorocyclopropyl)-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetate: To a solution of tert-butyl 2-((1S,2R)-2-fluoro-1'-oxo-6'-(2,2-dichloro-1-fluorocyclopropyl)-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetate (100 mg, 0.23 mmol) in tri-n-butyl-tin hydride (660 mg, 2.27 mmol) was added AIBN (3.80 mg, 0.023 mmol). The mixture was stirred at 160°C for 3 hours. The reaction mixture was poured into saturated aqueous KF (20 mL). The mixture was stirred at 20° C. for 1 hour and extracted with EtOAc (4×10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography. LCMS: m / z=308.1 [M-tBu+H] + . 1 H NMR(400 MHz,CDCl3): δ 8.13(dd,J=0.8,8.0 Hz,1H),6.99(d,J=8.0 Hz,1H),6.71(d,J=1.6 Hz,1H),4.77-4.53(m,2H),4.08(dd,J=2.0,12.8 Hz,1H),3.87(d,J=17.6 Hz,1H),3.45(d,J=12.6 Hz,1H),1.59-1.51(m,2H),1.48(s,9H),1.43-1.32(m,2H),1.14-1.09(m,2H).

[0204] 2-((1S,2R)-2-Fluoro-1'-oxo-6'-(1-fluorocyclopropyl)-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetic acid: To a solution of tert-butyl 2-((1S,2R)-2-fluoro-1'-oxo-6'-(1-fluorocyclopropyl)-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetate (190 mg, 0.52 mmol) in DCM (4.0 mL) was added formic acid (1.0 mL). The mixture was stirred at 40° C. for 12 hours. The mixture was concentrated under reduced pressure to give a residue that was used directly. LCMS: m / z=306.2 [M−H] - .

[0205] Intermediate 8 Methyl 2-((1S,2R)-2-fluoro-1'-oxo-6'-(1-fluorocyclopropyl)-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetate [ka] To a solution of 2-((1S,2R)-2-fluoro-1'-oxo-6'-(1-fluorocyclopropyl)-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetic acid (77 mg, 0.25 mmol, Int. 7) in DMF (2.0 mL) was added K2CO3 (52 mg, 0.38 mmol) and MeI (43 mg, 0.3 mmol). The mixture was stirred at 20 °C for 2 h. The reaction mixture was poured into HO (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography. LCMS: m / z = 322.1 [M+H] + .

[0206] Intermediate 9 (Fluoromethyl)(phenyl)(2,3,4,5-tetramethylphenyl)sulfonium tetrafluoroborate [ka] ((Fluoromethyl)sulfinyl)benzene: To a suspension of SelectFluor (463.5 g, 1.31 mol) in MeCN (1500 mL) was added a solution of methyl(phenyl)sulfane (130.0 g, 1.05 mol) in MeCN (150 mL) over 10 min at 0 °C. EtN (132.4 g, 1.31 mol) was then added to the mixture at 0 °C. The reaction mixture was warmed to 20 °C and stirred for 16 h. The two batches above were run in parallel and combined for workup. The combined batches were diluted with water (1000 mL) and extracted with DCM (3 × 500 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude residue was then dissolved in MeOH (2000 mL), diluted with water (200 mL), and cooled to 0 °C. NBS (372.6 g, 2.09 mol) was added carefully and the mixture was stirred at 15 °C for 16 h. The reaction mixture was diluted with 10% Na2SO3 solution (200 mL), followed by saturated aqueous NaHCO3 solution until pH = 7. Methanol was removed under reduced pressure and the remaining aqueous phase was extracted with DCM (3 x 500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue that was used directly.

[0207] (Fluoromethyl)(phenyl)(2,3,4,5-tetramethylphenyl)sulfonium tetrafluoroborate: To a solution of ((fluoromethyl)sulfinyl)benzene (10.0 g, 63.2 mmol) in diisopropyl ether (100 mL) was added 1,2,3,4-tetramethylbenzene (7.64 g, 56.9 mmol) and TfO (17.8 g, 63.2 mmol) at -10 °C. The reaction mixture was warmed to 20 °C and stirred for 1 h. The reaction mixture was filtered, and the resulting solid was dissolved in DCM (200 mL) and washed with aqueous NaBF (1 M, 6 × 200 mL). The organic phase was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was triturated with MTBE at 20 °C for 30 min, then filtered to give the desired product. LCMS: m / z = 275.2 [M+H] + .

[0208] Intermediate 10 Methyl 4-bromo-2-(1-cyanovinyl)-3-fluorobenzoate [ka] Methyl 2-amino-4-bromo-3-fluorobenzoate: To a solution of 2-amino-4-bromo-3-fluorobenzoic acid (40.0 g, 170 mmol) in DCM (500 mL) and MeOH (500 mL) was added TMSCHN (2 M in n-hexane, 427 mL, 854 mmol) at 0 °C. The mixture was stirred at 15 °C for 16 h, cooled to 0 °C, and TMSCHN (2 M in hexane, 171 mL) was added. The mixture was stirred at 15 °C for an additional 16 h. The mixture was quenched by the addition of saturated aqueous NH Cl (500 mL) and HO (500 mL). The mixture was concentrated under reduced pressure to remove the organic solvent. The white precipitate was filtered and dried under reduced pressure. The filter cake was then suspended in n-hexane (300 mL), stirred for 10 min, filtered, and dried under reduced pressure to give a residue that was used directly. LCMS: m / z=247.9, 249.9 [M+H] + .

[0209] Methyl 4-bromo-3-fluoro-2-iodobenzoate: To a solution of methyl 2-amino-4-bromo-3-fluorobenzoate (42.0 g, 170 mmol) in a mixture of concentrated HSO (420 mL) and MeCN (420 mL) was added a solution of NaNO (14 g, 203 mmol) in HO (60 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h, followed by the addition of a solution of KI (56 g, 338 mmol) in HO (60 mL). The mixture was stirred at 15 °C for 15 h. The mixture was cooled to 0 °C, diluted with saturated aqueous NaSO (1000 mL), and extracted with MTBE (4 × 500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous NaSO, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography.

[0210] Methyl 4-bromo-3-fluoro-2-vinylbenzoate: To a solution of methyl 4-bromo-3-fluoro-2-iodobenzoate (12.0 g, 33.0 mmol) and potassium trifluoro(vinyl)boron hydride (5.6 g, 41.7 mmol) in 1,4-dioxane (300 mL) was added CsF (20.3 g, 133.7 mmol) and Pd(dppf)Cl (4.89 g, 6.69 mmol). The mixture was stirred at 100 °C for 16 hours. The mixture was filtered, and the filtrate was diluted with water (1000 mL) and extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography. 1 H NMR (400 MHz, CDCl3): δ 7.56-7.47(m,2H),7.01(dd,J=11.6,18 Hz,1H),5.81-5.72(m,1H),5.66(td,J=1.2,12.8 Hz,1H),3.90(s,3H).

[0211] Methyl 4-bromo-2-(1-cyanovinyl)-3-fluoro-benzoate: To a solution of 6,6'-dimethyl-2,2'-bipyridine (711 mg, 3.86 mmol), CuO (2.76 g, 19.3 mmol), and SelectFluor (10.3 g, 29.0 mmol) in acetone (60 mL) and water (30 mL) was added a solution of methyl 4-bromo-3-fluoro-2-vinyl-benzoate (5.0 g, 19.3 mmol) in acetone (5 mL) and TMSCN (3.83 g, 38.6 mmol, 4.83 mL) at 0 °C. The mixture was stirred at 20 °C for 16 h. The mixture was quenched with HO (100 mL) and extracted with EtOAc (5 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and purified by silica gel column chromatography. LCMS: m / z=283.9, 285.9 [M+H] + .

[0212] Intermediates 11 and 12 Methyl 4-bromo-3-fluoro-2-[(1s,2r)-1-cyano-2-fluoro-cyclopropyl]benzoate and Methyl 4-bromo-3-fluoro-2-[(1s,2s)-1-cyano-2-fluoro-cyclopropyl]benzoate [ka] To a solution of methyl 4-bromo-2-(1-cyanovinyl)-3-fluoro-benzoate (6.0 g, 21.1 mmol, Int. 10) and (fluoromethyl)(phenyl)(2,3,4,5-tetramethylphenyl)sulfonium tetrafluoroborate (11.5 g, 31.7 mmol) in THF (80 mL) was added NaH (3.38 g, 84.5 mmol, 60% purity) at 0 °C. The mixture was stirred at 20 °C for 1 h. The mixture was cooled to 0 °C, diluted with saturated aqueous NH Cl (150 mL), and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na SO , filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give:

[0213] Methyl 4-bromo-3-fluoro-2-[(1s,2r)-1-cyano-2-fluoro-cyclopropyl]benzoate (Int.11): 1 H NMR (400 MHz, CDCl3): δ 7.73-7.66(m,2H),4.83-4.63(m,1H),4.03(s,3H),2.39-2.28(m,1H),1.67-1.57(m,1H).

[0214] Methyl 4-bromo-3-fluoro-2-[(1s,2s)-1-cyano-2-fluoro-cyclopropyl]benzoate (Int.12): 1 H NMR (400 MHz, CDCl3): δ 7.74-7.67(m,2H),5.29-5.06(m,1H),3.99(s,3H),2.37-2.29(m,1H),1.78-1.67(m,1H).

[0215] Intermediate 13 (2's,4r)-6-Bromo-2',5-difluorospiro[2,3-dihydroisoquinoline-4,1'-cyclopropan]-1-one [ka] To a solution of methyl 4-bromo-3-fluoro-2-[(1s,2r)-1-cyano-2-fluoro-cyclopropyl]benzoate (5.8 g, 18.3 mmol, Int. 11) and CoCl (9.5 g, 73.4 mmol) in MeOH (180 mL) and HO (4.5 mL) was added NaBH (2.78 g, 73.4 mmol) at 0 °C. The mixture was stirred at 20 °C for 2 h. Then, additional NaBH (694 mg, 18.3 mmol) was added to the solution. The mixture was stirred for an additional 1 h. The mixture was quenched with saturated aqueous NH Cl (200 mL) at 0 °C and extracted with EtOAc (3 × 60 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na SO , filtered, concentrated under reduced pressure, and purified by silica gel column chromatography. LCMS: m / z=287.9, 289.9 [M+H] + .

[0216] Intermediates 14 and 15 Methyl 2-[(2's,4r)-6-bromo-2',5-difluoro-1-oxo-spiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]acetate [ka] To a solution of (2's,4r)-6-bromo-2',5-difluorospiro[2,3-dihydroisoquinolin-4,1'-cyclopropan]-1-one (31.0 g, 107 mmol, Int. 13) and NaI (1.61 g, 10.8 mmol) in DMF (350 mL) was added CsCO (70 g, 215 mmol) and methyl 2-bromoacetate (19.7 g, 129 mmol) at 0 °C. The mixture was stirred at 20 °C for 16 h. The reaction mixture was quenched at 0 °C by the addition of aqueous HCl (1 M, 700 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (3 × 350 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. The mixture was further purified by chiral SFC (column: Daicel Chiralpak IG (250 mm x 50 mm, 10 μm particle size); mobile phase: A: CO and B: MeOH; gradient: 35% B isocratic; flow rate: 200 g / min; detection wavelength: 220 nm; column temperature: 40 °C; system back pressure: 100 bar) to give:

[0217] Methyl 2-[(2's,4r)-6-bromo-2',5-difluoro-1-oxo-spiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]acetate (first eluting isomer, Int.14): LCMS: m / z=359.9, 361.9 [M+H] + . 1 H NMR(400 MHz,CDCl3): δ 7.87(dd,J=1.0,8.4 Hz,1H),7.54(dd,J=6.4,8.4 Hz,1H),5.44-5.23(m,1H),4.60(d,J=17.6 Hz,1H),4.12-4.00(m,1H),3.81-3.77(m,4H),3.62(d,J=12.8 Hz,1H),1.93-1.87(m,1H),1.54-1.41(m,1H).

[0218] Methyl 2-[(2's,4r)-6-bromo-2',5-difluoro-1-oxo-spiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]acetate (second eluting isomer, Int. 15): LCMS: m / z = 359.9, 361.9 [M+H] + . 1 H NMR(400 MHz,CDCl3): δ 7.87(dd,J=0.8,8.4 Hz,1H),7.54(dd,J=6.4,8.4 Hz,1H),5.46-5.23(m,1H),4.60(d,J=17.6 Hz,1H),4.08(d,J=17.6 Hz,1H),3.81(d,J=2.6 Hz,1H),3.78(s,3H),3.63(d,J=12.9 Hz,1H),1.93-1.87(m,1H),1.55-1.40(m,1H).

[0219] Intermediate 16 Methyl 2-[(2's,4r)-6-cyclopropyl-2',5-difluoro-1-oxo-spiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]acetate [ka] To a solution of methyl 2-[(2's,4r)-6-bromo-2',5-difluoro-1-oxo-spiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]acetate (50 mg, 0.14 mmol, Int. 15) and potassium cyclopropyltrifluoroborate (62 mg, 0.42 mmol) in 1,4-dioxane (1.0 mL) and HO (0.1 mL) was added CsF (63 mg, 0.42 mmol) and Pd(dppf)Cl (10 mg, 0.014 mmol). The mixture was stirred at 100 °C for 16 h. The reaction mixture was quenched with HO (6 mL) and extracted with EtOAc (3 × 2 mL). The combined organic layers were washed with brine (3 mL), dried over anhydrous NaSO, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography. LCMS: m / z=322.0 [M+H] + .

[0220] Intermediate 17 2-[(2's,4r)-6-Cyclopropyl-2',5-difluoro-1-oxo-spiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]acetic acid [ka] To a solution of methyl 2-[(2's,4r)-6-cyclopropyl-2',5-difluoro-1-oxo-spiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]acetate (260 mg, 0.81 mmol, Int. 16) in THF (3.0 mL) and HO (3.0 mL) was added LiOH·HO (85 mg, 2.02 mmol). The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was diluted with HO (10 mL) and washed with MTBE (4 mL). The aqueous phase was then adjusted to pH = 3 by the addition of aqueous HCl (3 M). The aqueous portion was then extracted with EtOAc (3 × 3 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue that was used directly. LCMS: m / z = 308.1 [M+H] + .

[0221] Intermediate 18 Methyl 2-[(2's,4r)-2',5-difluoro-6-iodo-1-oxo-spiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]acetate [ka] To a solution of methyl 2-[(2's,4r)-6-bromo-2',5-difluoro-1-oxo-spiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]acetate (300 mg, 0.83 mmol, Int. 15) in toluene (5.0 mL) was added CuI (32 mg, 0.17 mmol), N1,N2-dimethylcyclohexane-1,2-diamine (47 mg, 0.33 mmol), and NaI (499 mg, 3.33 mmol). The reaction mixture was stirred at 130 °C for 32 h. The reaction mixture was then cooled to ambient temperature, poured into HO (5 mL), and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography. LCMS: m / z=407.9 [M+H] + .

[0222] Intermediate 19 2-[(2's,4r)-2',5-Difluoro-6-iodo-1-oxo-spiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]acetic acid [ka] To a solution of methyl 2-[(2's,4r)-2',5-difluoro-6-iodo-1-oxo-spiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]acetate (145 mg, 0.35 mmol, Int. 18) in THF (2.0 mL) and water (0.5 mL), LiOH·HO (30 mg, 0.71 mmol) was added. The reaction mixture was stirred at 20° C. for 2 h. The reaction mixture was poured into ice-cold water (10 mL) and the aqueous phase was adjusted to pH=3 by adding aqueous HCl (4 M). The aqueous portion was then extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (20 mL) and concentrated under reduced pressure to give a residue that was used directly. LCMS: m / z=394.0 [M+H] + .

[0223] Intermediate 20 Methyl 2-(6-iodo-1-oxo-4-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)acetate [ka] 2-(3-Bromophenyl)-1,1,1-trifluoro-3-nitropropan-2-ol: To a mixture of nitromethane (116 g, 1.90 mol) in THF (400 mL), 1-(3-bromophenyl)-2,2,2-trifluoro-ethanone (40 g, 158 mmol) and EtN (48 g, 474 mmol) were added at 0 °C. The mixture was stirred at 20 °C for 12 h. The reaction mixture was diluted with HO (100 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography.

[0224] 1-Bromo-3-(3,3,3-trifluoro-1-nitroprop-1-en-2-yl)benzene: To a mixture of 2-(3-bromophenyl)-1,1,1-trifluoro-3-nitro-propan-2-ol (108 g, 343 mmol) in toluene (1000 mL) was added SOCl (61.0 g, 516 mmol) and pyridine (54.0 g, 687 mmol) at 0 °C. The mixture was stirred at 20 °C for 12 h. The reaction mixture was diluted with HO (100 mL) and extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography.

[0225] 2-(3-Bromophenyl)-3,3,3-trifluoropropan-1-amine: To a mixture of 1-bromo-3-(3,3,3-trifluoro-1-nitroprop-1-en-2-yl)benzene (26.0 g, 88.0 mmol) in MeOH (300 mL) was added concentrated HCl (84 mL, 878 mmol) and zinc metal (29.0 g, 439 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hour. The mixture was filtered and concentrated under reduced pressure to give a residue that was used directly. LCMS: m / z=268.0, 270.0 [M+H] + .

[0226] Methyl 2-(((2-(3-bromophenyl)-3,3,3-trifluoropropyl)carbamoyl)oxy)benzoate: A mixture of 2-(3-bromophenyl)-3,3,3-trifluoro-propan-1-amine (41.5 g, 155 mmol) and methyl 2-(2-methoxycarbonylphenoxy)carbonyloxybenzoate (76.7 g, 232 mmol) in THF (430 mL) was stirred at 25° C. for 12 hours. The mixture was concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC.

[0227] 6-Bromo-4-(trifluoromethyl)-3,4-dihydroisoquinolin-1(2H)-one: To a mixture of methyl 2-[[2-(3-bromophenyl)-3,3,3-trifluoro-propyl]carbamoyloxy]benzoate (30 g, 67 mmol) in DCM (300 mL) was added TfOH (150 mL, 1.70 mol) at 0 °C. The mixture was stirred at 20 °C for 12 h. The reaction mixture was diluted with HO (200 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z = 293.9, 295.9 [M+H] + .

[0228] 6-Iodo-4-(trifluoromethyl)-3,4-dihydroisoquinolin-1(2H)-one: To a solution of 6-bromo-4-(trifluoromethyl)-3,4-dihydroisoquinolin-1(2H)-one (2.00 g, 6.80 mmol) in 1,4-dioxane (50 mL) was added NaI (10.2 g, 68.0 mmol), N1,N2-dimethylcyclohexane-1,2-diamine (484 mg, 3.40 mmol), and CuI (1.30 g, 6.80 mmol). The mixture was stirred at 140 °C for 5 h. The reaction mixture was filtered, washed with EtOAc (3 × 20 mL), and concentrated under reduced pressure. The residue was poured into HO (100 mL) and then extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z=341.9 [M+H] + .

[0229] Methyl 2-(6-iodo-1-oxo-4-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)acetate (Int. 20): To 6-iodo-4-(trifluoromethyl)-3,4-dihydroisoquinolin-1(2H)-one (2.0 g, 5.86 mmol) and methyl 2-iodoacetate (1.29 g, 6.45 mmol) in DMF (20 mL) was added CsCO (4.01 g, 12.3 mmol) at 20 °C. The mixture was stirred at 20 °C for 2 h. The reaction mixture was poured into HO (700 mL) and then extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z=414.0 [M+H] + .

[0230] Intermediates 20a and 20b Methyl 2-(6-iodo-1-oxo-4-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)acetate [ka] Methyl 2-(6-iodo-1-oxo-4-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)acetate (Int. 20) was further separated by chiral SFC (Column: Daicel Chiralpak IG (250 mm x 50 mm, 10 μm particle size); Mobile phase: A: CO, B: 0.1% NHOH in i-PrOH; Gradient: 55% B isocratic; Flow rate: 3.4 mL / min; Detection wavelength: 220 nm; Column temperature: 35°C; System back pressure: 2000 psi) to give:

[0231] Methyl 2-(6-iodo-1-oxo-4-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)acetate (first eluting isomer, Int. 20a): 1 H NMR(400 MHz,CDCl3): δ 7.89(s,2H),7.75(s,1H),4.80(d,J=17.2 Hz,1H),4.18(br dd,J=4.4,13.6 Hz,1H),3.91(d,J=17.2 Hz,1H),3.77(s,3H),3.74(dd,J=2.4,13.6 Hz,1H),3.62-3.50(m,1H).

[0232] Methyl 2-(6-iodo-1-oxo-4-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)acetate (second eluting isomer, Int. 20b): 1 H NMR(400 MHz,CDCl3): δ 7.89(s,2H),7.75(s,1H),4.80(d,J=17.6 Hz,1H),4.18(br dd,J=4.4,13.6 Hz,1H),3.91(d,J=17.2 Hz,1H),3.77(s,3H),3.74(dd,J=2.4,13.6 Hz,1H),3.62-3.50(m,1H).

[0233] Intermediate 21 Methyl 2-(6-iodo-1-oxo-4-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)acetate [ka] To a solution of methyl 2-(6-iodo-1-oxo-4-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)acetate (1 g, 2.42 mmol, Int. 20) in THF (15 mL) and HO (5 mL) was added LiOH·HO (406 mg, 9.68 mmol). The mixture was stirred for 20 min. The reaction mixture was diluted with water (5 mL) and washed with MTBE (10 mL). The aqueous phase was adjusted to pH = 2 with aqueous HCl (3 M), and the mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue that was used directly. LCMS: m / z = 399.9.

[0234] Intermediate 22 Methyl 2-(1-cyanovinyl)-3-fluoro-4-(trifluoromethyl)benzoate [ka] Methyl 2,3-difluoro-4-(trifluoromethyl)benzoate: To a solution of 2,3-difluoro-4-(trifluoromethyl)benzoic acid (50.0 g, 221 mmol) in DMF (700 mL) was added KCO (61.1 g, 442 mmol) and MeI (34.5 g, 243 mmol). The reaction mixture was stirred at 20 °C for 4 hours. The reaction mixture was diluted with water (300 mL), filtered, and the filtrate was extracted with EtOAc (3 × 200 mL). The combined organics were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue that was used directly.

[0235] Methyl 2-(1-cyano-2-methoxy-2-oxoethyl)-3-fluoro-4-(trifluoromethyl)benzoate: To a solution of methyl 2,3-difluoro-4-(trifluoromethyl)benzoate (36.5 g, 152 mmol) and methyl 2-cyanoacetate (18.1 g, 182.4 mmol) in DMF (370 mL) was added KCO (42.0 g, 304 mmol). The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was poured into ice-cold water (300 mL), adjusted to pH = 3 by addition of aqueous HCl (3 M), and extracted with EtOAc (3 x 500 mL). The combined organics were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue that was used directly. LCMS: m / z = 320.0 [M+H] + .

[0236] Methyl 2-(cyanomethyl)-3-fluoro-4-(trifluoromethyl)benzoate: To a solution of methyl 2-(1-cyano-2-methoxy-2-oxoethyl)-3-fluoro-4-(trifluoromethyl)benzoate (48.0 g, 150 mmol) in DMSO (420 mL) was added a solution of NaCl (11.4 g, 195 mmol) in HO (60 mL). The reaction mixture was stirred at 120 °C for 12 h. The reaction mixture was diluted with water (1000 mL) and extracted with EtOAc (3 × 300 mL). The combined organics were washed with brine (3 × 100 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z = 262.1 [M+H] + .

[0237] Methyl 2-(1-cyanovinyl)-3-fluoro-4-(trifluoromethyl)benzoate (Int. 22): To a solution of methyl 2-(cyanomethyl)-3-fluoro-4-(trifluoromethyl)benzoate (5.0 g, 19.1 mmol) and N,N,N',N'-tetramethylmethanediamine (2.9 g, 28.7 mmol) in DMSO (50 mL) was added AcO (6.5 g, 63.2 mmol). The reaction mixture was stirred at 20 °C for 4 h. The reaction mixture was diluted with HO (200 mL), filtered, and the filtrate was extracted with EtOAc (3 × 50 mL). The combined organics were washed with saturated aqueous NaHCO (3 × 100 mL), brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. 1 H NMR (400 MHz, CDCl3): δ 7.90(d,J=8.4 Hz,1H),7.81-7.72(m,1H),6.48(s,1H),6.07(d,J=0.8 Hz,1H),3.98(s,3H).

[0238] Intermediate 23 (2's,4r)-2',5-Difluoro-6-(trifluoromethyl)spiro[2,3-dihydroisoquinoline-4,1'-cyclopropan]-1-one [ka] Methyl 2-((1r,2s)-1-cyano-2-fluorocyclopropyl)-3-fluoro-4-(trifluoromethyl)benzoate and methyl 2-((1r,2r)-1-cyano-2-fluorocyclopropyl)-3-fluoro-4-(trifluoromethyl)benzoate: To a solution of methyl 2-(1-cyanovinyl)-3-fluoro-4-(trifluoromethyl)benzoate (678 mg, 2.48 mmol) and (4-chlorophenyl)(fluoromethyl)(2,3,4,5-tetramethylphenyl)sulfonium tetrafluoroborate (1.08 g, 2.73 mmol) in MeCN (5.0 mL) was added NaH (129 mg, 3.23 mmol, 60% purity) at 0 °C. The reaction mixture was stirred at 10 °C for 2 h. The reaction mixture was diluted with HO (15 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title product as a 2:5 mixture. LCMS: m / z=306.0 [M+H] + .

[0239] (2's,4r)-2',5-Difluoro-6-(trifluoromethyl)spiro[2,3-dihydroisoquinolin-4,1'-cyclopropan]-1-one (Int. 23): To a mixture of methyl 2-((1r,2s)-1-cyano-2-fluorocyclopropyl)-3-fluoro-4-(trifluoromethyl)benzoate and methyl 2-((1r,2r)-1-cyano-2-fluorocyclopropyl)-3-fluoro-4-(trifluoromethyl)benzoate (340 mg, 1.11 mmol, 2:5 mixture) and CoCl (145 mg, 1.11 mmol) in MeOH (3.0 mL) was added NaBH (211 mg, 5.57 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 4 h. The reaction mixture was cooled to 0° C., diluted with saturated aqueous NH4Cl (20 mL), and extracted with EtOAc (4×15 mL). The combined organic layers were washed with brine (3×10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z=278.1 [M+H] + .

[0240] Intermediate 24 Methyl 2-[(2's,4r)-2'-fluoro-1-oxo-6-(trifluoromethyl)spiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]acetate [ka] To a solution of (2's,4r)-2',5-difluoro-6-(trifluoromethyl)spiro[2,3-dihydroisoquinolin-4,1'-cyclopropan]-1-one (70 mg, 0.25 mmol) in DMF (2.0 mL) was added NaI (25 mg, 0.17 mmol), CsCO (165 mg, 0.50 mmol), and methyl 2-bromoacetate (58 mg, 0.37 mmol). The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was cooled to 0 °C, diluted with HO (10 mL), and extracted with EtOAc (4 × 15 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z = 350.1 [M+H] + .

[0241] Intermediate 25 Methyl 2-(2,2,5'-trifluoro-1'-oxo-6'-(trifluoromethyl)-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetate [ka] Methyl 2-(1-cyano-2,2-difluorocyclopropyl)-3-fluoro-4-(trifluoromethyl)benzoate: To a solution of methyl 2-(1-cyanovinyl)-3-fluoro-4-(trifluoromethyl)benzoate (1.00 g, 3.66 mmol) in 1,4-dioxane (7.0 mL) was added (2-bromo-2,2-difluoroacetyl)oxysodium (2.16 g, 10.98 mmol). The reaction mixture was stirred at 150° C. for 20 minutes under microwave irradiation. The reaction mixture was cooled to 0° C., diluted with HO (10 mL), and extracted with EtOAc (3×15 mL). The combined organics were washed with brine (25 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC.

[0242] 2,2,5'-Trifluoro-6'-(trifluoromethyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-1'-one: To a solution of methyl 2-(1-cyano-2,2-difluoro-cyclopropyl)-3-fluoro-4-(trifluoromethyl)benzoate (200 mg, 0.62 mmol) in MeOH (4.0 mL) was added dichlorocobalt (80 mg, 0.62 mmol) and NaBH (70 mg, 1.86 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h and then at 20 °C for an additional 12 h. The reaction mixture was quenched by the addition of saturated aqueous NH Cl (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na SO , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography.

[0243] Methyl 2-(2,2,5'-trifluoro-1'-oxo-6'-(trifluoromethyl)-1'H-spiro[cyclopropane-1,4'-isoquinolin]-2'(3'H)-yl)acetate (Int 25): To a solution of 2,2,5'-trifluoro-6'-(trifluoromethyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-1'-one (320 mg, 1.08 mmol) in DMF (7.0 mL) was added NaI (106 mg, 0.70 mmol), CsCO (706 mg, 2.17 mmol), and methyl 2-bromoacetate (249 mg, 1.63 mmol). The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was cooled to 0° C., diluted with H2O (30 mL), and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z=368.1 [M+H] + .

[0244] Intermediate 26 Methyl 2-(6'-bromo-2,2-difluoro-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetate [ka] Methyl 4-bromo-2-(1-cyano-2,2-difluorocyclopropyl)benzoate: A solution of methyl 4-bromo-2-(1-cyanovinyl)benzoate (1.00 g, 3.76 mmol) and sodium 2-bromo-2,2-difluoro-acetate (2.22 g, 11.27 mmol) in 1,4-dioxane (6.0 mL) was heated at 150 °C for 20 min under microwave irradiation. The reaction mixture was poured into H2O (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organics were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with MTBE to give a residue that was used directly. LCMS: m / z = 316.0, 318.0 [M+H] + .

[0245] 6'-Bromo-2,2-difluoro-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-1'-one: To a solution of methyl 4-bromo-2-(1-cyano-2,2-difluorocyclopropyl)benzoate (11.2 g, 35.4 mmol), ZnCl (9.7 g, 70.9 mmol), and CoCl·6H O (11.0 g, 46.1 mmol) in MeOH (150 mL) was added NaBH (6.7 g, 177.2 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was cooled to 0 °C, diluted with saturated aqueous NH Cl (100 mL), and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over anhydrous Na SO , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z = 288.0, 290.0 [M+H] + .

[0246] Methyl 2-(6'-bromo-2,2-difluoro-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinolin]-2'(3'H)-yl)acetate (Int. 26): To a solution of 6'-bromo-2,2-difluoro-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-1'-one (380 mg, 1.32 mmol) in DMF (8.0 mL) was added NaI (129 mg, 0.86 mmol), CsCO (860 mg, 2.64 mmol), and methyl 2-bromoacetate (303 mg, 1.98 mmol). The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with HO (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layer was washed with brine (5 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z=359.9, 361.9 [M+H] + .

[0247] Intermediate 27 2-(6'-bromo-2,2-difluoro-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetic acid: [ka] To a solution of methyl 2-(6'-bromo-2,2-difluoro-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetate (180 mg, 0.50 mmol) in THF (2.0 mL) and HO (0.4 mL) was added LiOH·HO (42 mg, 0.01 mmol). The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with HO (5 mL) and washed with MTBE (2 × 10 mL). The aqueous portion was then acidified to pH = 4 by the addition of aqueous HCl, followed by extraction with EtOAc (3 × 10 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue that was used directly. LCMS: m / z = 346.0, 348.0 [M+H] + .

[0248] Intermediate 28 Methyl 2-(2,2-difluoro-6'-(1-fluorocyclopropyl)-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetate: [ka] Methyl 2-(2,2-difluoro-1'-oxo-6'-vinyl-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetate: To a solution of methyl 2-(6'-bromo-2,2-difluoro-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetate (6.00 g, 16.7 mmol) in 1,4-dioxane (200 mL) was added potassium vinyltrifluoroborate (6.69 g, 50.0 mmol), CsF (7.59 g, 50.0 mmol), and Pd(dppf)Cl (1.22 g, 1.67 mmol). The reaction mixture was stirred at 90 °C for 16 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organics were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z = 308.1 [M+H] + .

[0249] Methyl 2-(2,2-difluoro-6'-(1-fluoro-2-iodoethyl)-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetate: To a solution of 2-(2,2-difluoro-1'-oxo-6'-vinyl-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetate (4.8 g, 15.6 mmol) in DCM (100 mL) was added NIS (7.0 g, 31.2 mmol) at 0°C. The reaction mixture was stirred for 30 minutes, after which N,N-diethylethanamine; trihydrofluoride (12.6 g, 78.1 mmol) was added. The reaction was then stirred at 20°C for an additional 16 hours. The reaction mixture was poured into brine (30 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z = 454.0 [M + H] + .

[0250] Methyl 2-(2,2-difluoro-6'-(1-fluorovinyl)-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetate: To a solution of methyl 2-(2,2-difluoro-6'-(1-fluoro-2-iodoethyl)-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetate (4.75 g, 10.5 mmol) in DMSO (50 mL) was added DBU (2.39 g, 15.72 mmol). The reaction mixture was stirred at 60°C for 1 hour. The reaction mixture was poured into brine (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. LCMS: m / z=326.1 [M+H] + .

[0251] Methyl 2-(2,2-difluoro-6'-(1-fluorocyclopropyl)-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetate (Int. 28): To a solution of ZnEt (2 M in n-hexane, 7.69 mL) was added a solution of TFA (1.75 g, 15.4 mmol) in DCM (1.0 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min, after which CHCl (4.12 g, 15.4 mmol) was added. The mixture was stirred at 0° C. for an additional 20 minutes, after which a solution of methyl 2-(2,2-difluoro-6′-(1-fluorovinyl)-1′-oxo-1′H-spiro[cyclopropane-1,4′-isoquinoline]-2′(3′H)-yl)acetate (500 mg, 1.54 mmol) in DCM (5.0 mL) was added. The reaction mixture was then warmed to 20° C. and stirred for an additional 3 hours. The reaction mixture was then warmed to 40° C. and stirred for an additional 16 hours. The reaction mixture was filtered, and the filtrate was poured into saturated aqueous NH4Cl (5 mL) and extracted with DCM (3×5 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography. LCMS: m / z=340.1 [M+H] + .

[0252] Intermediate 29 2-(2,2-difluoro-6'-(1-fluorocyclopropyl)-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetic acid [ka] To a solution of methyl 2-(2,2-difluoro-6'-(1-fluorocyclopropyl)-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetate (350 mg, 1.03 mmol) in THF (4.0 mL) and HO (4.0 mL) was added LiOH·HO (87 mg, 2.06 mmol). The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with HO (10 mL) and washed with MTBE (10 mL). The aqueous portion was then acidified to pH = 3 by the addition of aqueous HCl (3 M) and then extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue that was used directly. LCMS: m / z = 326.1 [M+H] + .

[0253] Intermediate 30 Methyl 2-(6'-cyclopropyl-2,2-difluoro-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetate [ka] To a solution of potassium cyclopropyltrifluoroborate (1.03 g, 6.94 mmol) and methyl 2-(6-bromo-1',1'-difluoro-1-oxo-spiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl)acetate (500 mg, 1.39 mmol) in toluene (5.0 mL) and HO (0.5 mL), bis(1-adamantyl)-butyl-phosphane (100 mg, 0.28 mmol), Pd(OAc) (31 mg, 0.14 mmol), and CsCO (905 mg, 2.78 mmol) were added. The reaction mixture was stirred at 100 °C for 3 h. The reaction mixture was diluted with water (10 mL) and extracted with MTBE (3 × 3 mL). The combined organic layers were washed with brine (3 × 5 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z=322.1 [M+H] + .

[0254] Intermediate 31 2-(6'-cyclopropyl-2,2-difluoro-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetic acid [ka] To a solution of methyl 2-(6-cyclopropyl-1',1'-difluoro-1-oxo-spiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl)acetate (275 mg, 0.86 mmol) in THF (4.0 mL) and HO (1.0 mL) was added LiOH·HO (72 mg, 1.71 mmol). The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with ice-cold HO (10 mL), acidified to pH = 3 by addition of aqueous HCl (4 M), and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue that was used directly. LCMS: m / z = 308.1 [M+H] + .

[0255] Intermediate 32 Methyl 2-[6-bromo-1',1',5-trifluoro-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]acetate [ka] Methyl 4-bromo-2-(1-cyano-2,2-difluorocyclopropyl)-3-fluorobenzoate: To a solution of methyl 4-bromo-2-(1-cyanovinyl)-3-fluorobenzoate (450 mg, 1.58 mmol, Int. 10) in 1,4-dioxane (2.0 mL) was added sodium 2-chloro-2,2-difluoroacetate (725 mg, 4.75 mmol). The mixture was stirred at 150 °C under microwave irradiation for 20 minutes. The reaction mixture was poured into HO (20 mL) and extracted with EtOAc (4 × 15 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous NaSO, filtered, concentrated under reduced pressure, and purified by reverse-phase preparative HPLC. LCMS: m / z = 333.9, 335.9 [M+H] + .

[0256] 6'-Bromo-2,2,5'-trifluoro-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-1'-one: To a mixture of methyl 4-bromo-2-(1-cyano-2,2-difluorocyclopropyl)-3-fluorobenzoate (600 mg, 1.80 mmol) and CoCl (233 mg, 1.80 mmol) in MeOH (12 mL) and HO (1.2 mL) was added NaBH (204 mg, 5.39 mmol) at -10 °C. The mixture was stirred at 0 °C for 1 h and then at -10 °C for an additional 4 h. The reaction mixture was diluted with saturated aqueous NH Cl (20 mL) and extracted with EtOAc (4 × 15 mL). The combined organic layers were washed with brine (2×10 mL), dried over anhydrous NaSO, filtered, concentrated under reduced pressure and purified by silica gel column chromatography. LCMS: m / z=306.0, 308.0 [M+H] + .

[0257] Methyl 2-[6-bromo-1',1',5-trifluoro-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]acetate (Int. 32): To a solution of methyl 2-bromoacetate (82 mg, 0.54 mmol) in DMF (1.5 mL) was added 6'-bromo-2,2,5'-trifluoro-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-1'-one (110 mg, 0.36 mmol), CsCO (234 mg, 0.72 mmol), and NaI (27 mg, 0.18 mmol). The mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with HO (10 mL) at 0 °C and extracted with EtOAc (4 × 5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and purified by silica gel column chromatography. LCMS: m / z=378.0, 380.0 [M+H] + .

[0258] Intermediate 33 2-[6-Bromo-1',1',5-trifluoro-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]acetic acid [ka] To a solution of methyl 2-[6-bromo-1',1',5-trifluoro-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]acetate (115 mg, 0.30 mmol) in THF (3.0 mL) and HO (0.6 mL) was added LiOH·HO (26 mg, 0.61 mmol). The mixture was stirred at 20 °C for 1 h. The reaction mixture was poured into HO (10 mL) and washed with MTBE (3 × 5 mL). The aqueous layer was adjusted to pH = 3 with aqueous HCl (3 M) at 0 °C and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue that was used directly. LCMS: m / z = 361.9, 363.9 [M−H] - .

[0259] Intermediate 34 Methyl 2-(6'-cyclopropyl-2,2,5'-trifluoro-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetate [ka] To a solution of methyl 2-(6'-bromo-2,2,5'-trifluoro-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetate (2.7 g, 7.14 mmol) in toluene (40 mL) and HO (4 mL) was added potassium cyclopropyltrifluoroborate (3.17 g, 21.42 mmol), CsCO (4.65 g, 14.3 mmol), bis(1-adamantyl)-butyl-phosphane (512 mg, 1.43 mmol), and Pd(OAc) (160 mg, 0.71 mmol). The mixture was stirred at 100 °C for 6 h. The mixture was diluted with water (40 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z=340.1 [M+H] + . 1 H NMR(400MHz,CDCl3): δ 7.89(d,J=8.0 Hz,1H),6.90(t,J=7.2 Hz,1H),4.78-4.86(m,1H),4.30-4.43(m,1H),3.84(d,J=17.6 Hz,1H),3.75-3.78(m,3H),2.88-3.07(m,2H),2.07-2.17(m,1H),1.45-1.56(m,1H),1.01-1.13(m,2H),0.70-0.86(m,2H).

[0260] Intermediate 35 Methyl 2-(2,2-difluoro-1'-oxo-6'-(trifluoromethyl)-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetate [ka] Methyl 4-(trifluoromethyl)-2-vinylbenzoate: To a solution of methyl 2-bromo-4-(trifluoromethyl)benzoate (100 g, 353 mmol) in 1,4-dioxane (2000 mL) was added potassium vinyltrifluoroborate (52 g, 388 mmol), CsF (161 g, 1.06 mol), and Pd(dppf)Cl (12.9 g, 17.7 mmol). The mixture was stirred at 90 °C for 6 h. The mixture was diluted with HO (2000 mL) and extracted with EtOAc (3 × 700 mL). The combined organic layers were washed with brine (1500 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography.

[0261] Methyl 2-(1-cyanovinyl)-4-(trifluoromethyl)benzoate: To a solution of CuO (31.0 g, 217 mmol), 6,6'-dimethyl-2,2'-bipyridine (8.0 g, 43 mmol), and SelectFluor (115 g, 325 mmol) in acetone (1 L) and HO (500 mL) was added methyl 4-(trifluoromethyl)-2-vinylbenzoate (50 g, 217 mmol) and TMSCN (64.6 g, 652 mmol) dropwise. The mixture was stirred at 20 °C for 20 h. The mixture was poured into saturated aqueous NaHCO (200 mL) and HO (800 mL). The mixture was filtered, and the filtrate was extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with brine (600 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z=256.0 [M+H] + .

[0262] Methyl 2-(1-cyano-2,2-difluorocyclopropyl)-4-(trifluoromethyl)benzoate: A solution of methyl 2-(1-cyanovinyl)-4-(trifluoromethyl)benzoate (1.00 g, 3.92 mmol) and sodium 2-bromo-2,2-difluoroacetate (2.31 g, 11.8 mmol) in 1,4-dioxane (6.0 mL) was heated at 150 °C for 20 min under microwave irradiation. The reaction mixture was poured into HO (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC.

[0263] 2,2-Difluoro-6'-(trifluoromethyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-1'-one: To a solution of methyl 2-(1-cyano-2,2-difluoro-cyclopropyl)-4-(trifluoromethyl)benzoate (1.00 g, 3.28 mmol) in MeOH (10 mL) was added CoCl2·6H2O (1.01 g, 4.26 mmol) and NaBH4 (620 mg, 16.4 mmol) at 0 °C. The reaction mixture was stirred at 20 °C for 12 h. The reaction mixture was cooled to 0 °C, diluted with saturated aqueous NH4Cl (30 mL), and extracted with EtOAc (3 × 30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. 1 H NMR(400 MHz,CDCl3): δ 8.31(d,J=8.0 Hz,1H),7.72(d,J=8.4 Hz,1H),7.33(s,1H),6.34(br s,1H),3.92-3.87(m,1H),3.50-3.46(m,1H),2.17-2.14(m,1H),1.75-1.71(m,1H)

[0264] Methyl 2-(2,2-difluoro-1'-oxo-6'-(trifluoromethyl)-1'H-spiro[cyclopropane-1,4'-isoquinolin]-2'(3'H)-yl)acetate (Int. 35): To a solution of 2,2-difluoro-6'-(trifluoromethyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-1'-one (400 mg, 1.44 mmol) in DMF (10 mL) was added NaI (141 mg, 0.94 mmol), CsCO (941 mg, 2.89 mmol), and methyl 2-bromoacetate (331 mg, 2.16 mmol). The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with HO (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. 1 H NMR(400 MHz,CDCl3): δ 8.32(d,J=8.0 Hz,1H),7.71(dd,J=0.8,8.0 Hz,1H),7.32(s,1H),4.79(d,J=17.2 Hz,1H),4.18-4.10(m,1H),3.98(d,J=17.2 Hz,1H),3.78(s,3H),3.40(dd,J=1.2,12.8 Hz,1H),2.17-2.12(m,1H),1.80-1.75(m,1H).

[0265] Intermediate 36 Methyl 2-(6-bromo-1-oxo-spiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl)acetate [ka] Methyl 4-bromo-2-(cyanomethyl)benzoate: A solution of NaCN (8.4 g, 170 mmol) in HO (40 mL) was added dropwise to a solution of methyl 4-bromo-2-(bromomethyl)benzoate (35 g, 114 mmol) in DMSO (500 mL) at 0 °C. The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was poured into HO (1.5 L) and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (3 × 200 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. 1 H NMR (400 MHz, CDCl3): δ 7.93(d,J=8.4 Hz,1H),7.73(d,J=2.0 Hz,1H),7.57(dd,J=2.0,8.8 Hz,1H),4.20(s,2H),3.92(s,3H).

[0266] Methyl 4-bromo-2-(1-cyanocyclopropyl)benzoate: Methyl 4-bromo-2-(cyanomethyl)benzoate (9.0 g, 35.4 mmol) was added to a solution of NaH (3.26 g, 81.5 mmol, 60% purity) in DMSO (90 mL). The reaction mixture was stirred at 20 °C for 1 h, and then 1-bromo-2-chloroethane (8.13 g, 56.7 mmol) was added. The resulting mixture was stirred at 20 °C for an additional 8 h. The reaction mixture was cooled to 0 °C, diluted with saturated aqueous NH Cl (200 mL), and extracted with EtOAc (4 × 50 mL). The combined organic layers were washed with brine (3 × 30 mL), dried over anhydrous Na SO , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z = 280.0, 282.0 [M+H] + .

[0267] 6-Bromospiro[2,3-dihydroisoquinolin-4,1'-cyclopropan]-1-one: To a mixture of methyl 4-bromo-2-(1-cyanocyclopropyl)benzoate (2.50 g, 8.92 mmol) and dichlorocobalt (2.32 g, 17.9 mmol) in MeOH (40 mL) was added NaBH (1.70 g, 44.9 mmol) at 0 °C. The reaction mixture was stirred at 20 °C for 3 h. The reaction mixture was cooled to 0 °C, poured into saturated aqueous NH Cl (50 mL), and extracted with DCM (4 × 15 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na SO , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z = 252.0, 254.0 [M+H] + .

[0268] Methyl 2-(6-bromo-1-oxo-spiro[3H-isoquinoline-4,1′-cyclopropan]-2-yl)acetate (Int. 36): To a solution of 6-bromospiro[2,3-dihydroisoquinolin-4,1′-cyclopropan]-1-one (2.30 g, 9.12 mmol) in DMF (30 mL) was added NaH (401 mg, 10.0 mmol, 60% purity) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 h, after which methyl 2-bromoacetate (2.09 g, 13.7 mmol) was added. The reaction mixture was then stirred at 20° C. for an additional 2 h. The reaction mixture was cooled to 0° C., diluted with saturated aqueous NH4Cl (50 mL), and extracted with EtOAc (4×20 mL). The combined organic layers were washed with brine (3×15 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z=324.0, 326.0 [M+H] + . 1 H NMR(400 MHz,CDCl3): δ 7.98(d,J=8.4 Hz,1H),7.44(dd,J=2.0,8.4 Hz,1H),6.99(d,J=2.0 Hz,1H),4.33(s,2H),3.76(s,3H),3.45(s,2H),1.14-1.09(m,2H),1.08-1.03(m,2H).

[0269] Intermediate 37 Methyl 2-[(2's,4r)-6-chloro-2',5-difluoro-1-oxo-spiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]acetate [ka] Methyl 2-[(2's,4r)-6-((diphenylmethylene)amino)-2',5-difluoro-1-oxo-spiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]acetate: Methyl 2-[(2's,4r)-6-bromo-2',5-difluoro-1-oxo-spiro[3H-isoquinoline- To a solution of 4,1'-cyclopropan-2-yl acetate (650 mg, 1.80 mmol, Int. 15) and diphenylmethanimine (654 mg, 3.61 mmol) was added Pd(dba) (165 mg, 0.18 mmol), XPhos (172 mg, 0.36 mmol), and CsCO (1.18 g, 3.61 mmol). The mixture was stirred at 90 °C for 16 h. The mixture was quenched with HO (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography.

[0270] Methyl 2-[(2's,4r)-6-amino-2',5-difluoro-1-oxo-spiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]acetate: A solution of methyl 2-[(2's,4r)-6-((diphenylmethylene)amino)-2',5-difluoro-1-oxo-spiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]acetate (700 mg, 1.52 mmol), hydroxylamine hydrochloride (211 mg, 3.04 mmol), and NaOAc (374 mg, 4.56 mmol) in MeOH (10 mL) was stirred for 16 h at 20 °C. The mixture was quenched with HO (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography.

[0271] Methyl 2-[(2's,4r)-6-chloro-2',5-difluoro-1-oxo-spiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]acetate: To a mixture of CuCl (100 mg, 1.01 mmol) in MeCN (5 mL) was added a solution of tert-butyl nitrite (94 mg, 0.91 mmol) and methyl 2-[(2's,4r)-6-amino-2',5-difluoro-1-oxo-spiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]acetate (150 mg, 0.51 mmol) in MeCN (1.0 mL). The reaction was stirred at 60 °C for 5 h. The mixture was quenched with HO (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. 1H NMR(400 MHz,CDCl3): δ 7.86(dd,J=1.2,8.4 Hz,1H),7.31(dd,J=7.2,8.4 Hz,1H),5.38-5.13(m,1H),4.53(d,J=17.2 Hz,1H),4.00(d,J=17.2 Hz,1H),3.75-3.68(m,4H),3.55(d,J=12.8 Hz,1H),1.87-1.80(m,1H),1.47-1.36(m,1H).

[0272] Intermediate 38 Methyl 2-(6-bromo-5-fluoro-1-oxospiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl)acetate [ka] 4-Bromo-2-(1-cyanocyclopropyl)-3-fluorobenzoic acid: To a solution of 4-bromo-2,3-difluorobenzoic acid (40 g, 169 mmol) in THF (700 mL) was added cyclopropanecarbonitrile (34 g, 506 mmol). The reaction mixture was cooled to -40 °C, followed by the addition of KHMDS (438.8 mL, 1 M in THF). The reaction mixture was stirred at 20 °C for 1 h, diluted with water (500 mL), and extracted with EtOAc (2 × 100 mL). The aqueous phase was adjusted to pH = 3 with aqueous HCl (3 N) and extracted with EtOAc (3 × 200 mL). The combined organics were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a solid that was used directly. LCMS: m / z = 284.0, 285.9 [M+H] + .

[0273] Methyl 4-bromo-2-(1-cyanocyclopropyl)-3-fluorobenzoate: To a solution of 4-bromo-2-(1-cyanocyclopropyl)-3-fluorobenzoic acid (46 g, 162 mmol) in DMF (500 mL) was added K2CO3 (34 g, 243 mmol) at 0 °C. To the mixture was added MeI (23 g, 162 mmol). The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was poured into ice-cold water (500 mL), filtered, and the filter cake was washed with petroleum ether (2 × 100 mL). The filtrate was concentrated under reduced pressure to give a solid, which was used directly. LCMS: m / z = 298.1, 300.0 [M+H]+.

[0274] 6-Bromo-5-fluoro-spiro[2,3-dihydroisoquinolin-4,1'-cyclopropan]-1-one: To a solution of methyl 4-bromo-2-(1-cyanocyclopropyl)-3-fluorobenzoate (42 g, 141 mmol) in MeOH (600 mL) and water (20 mL) was added dichlorocobalt (73 g, 563 mmol) and NaBH (27.0 g, 704 mmol) at 0 °C. The reaction mixture was stirred at 20 °C for 4 h. The reaction mixture was poured into saturated aqueous NH Cl (600 mL), diluted with water (300 mL), and extracted with EtOAc (3 × 200 mL). The combined organics were dried over anhydrous Na SO , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography. LCMS: m / z = 270.0, 272.0 [M+H].

[0275] Methyl 2-(6-bromo-5-fluoro-1-oxospiro[3H-isoquinoline-4,1′-cyclopropan]-2-yl)acetate: To a solution of 6-bromo-5-fluoro-spiro[2,3-dihydroisoquinolin-4,1′-cyclopropan]-1-one (9.3 g, 34.4 mmol) in DMF (100 mL) was added NaH (2.1 g, 51.6 mmol, 60% purity) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 h. To the reaction mixture was added methyl 2-bromoacetate (11 g, 68.9 mmol, 6.50 mL) at 0° C. The reaction mixture was stirred at 20° C. for 16 h. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl (50 mL) and ice-cold water (300 mL) and extracted with EtOAc (3×80 mL). The combined organics were washed with brine (200 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, and the resulting product was slurried with MTBE:PE (2:1, 5 mL) at 25 °C to give a solid that was filtered and dried under reduced pressure. LCMS: m / z = 342.0, 344.0 [M+H] + .

[0276] Intermediate 39 Methyl 2-[(2's,4r)-2'-fluoro-1-oxo-6-(trifluoromethyl)spiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]acetate [ka] Methyl 4-(trifluoromethyl)-2-vinylbenzoate: To a solution of methyl 2-bromo-4-(trifluoromethyl)benzoate (100 g, 353 mmol) in 1,4-dioxane (2000 mL) was added potassium vinyltrifluoroborate (52 g, 388 mmol), CsF (161 g, 1.06 mol), and Pd(dppf)Cl (12.9 g, 17.7 mmol). The mixture was stirred at 90 °C for 6 h. The mixture was diluted with HO (2000 mL) and extracted with EtOAc (3 × 700 mL). The combined organic layers were washed with brine (1500 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography.

[0277] Methyl 2-(1-cyanovinyl)-4-(trifluoromethyl)benzoate: To a solution of CuO (31.0 g, 217 mmol), 6,6'-dimethyl-2,2'-bipyridine (8.0 g, 43 mmol), and SelectFluor (115 g, 325 mmol) in acetone (1 L) and HO (500 mL) was added methyl 4-(trifluoromethyl)-2-vinylbenzoate (50 g, 217 mmol) and TMSCN (64.6 g, 652 mmol) dropwise. The mixture was stirred at 20 °C for 20 h. The mixture was poured into saturated aqueous NaHCO (200 mL) and HO (800 mL). The mixture was filtered, and the filtrate was extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with brine (600 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z=256.0 [M+H]+.

[0278] Methyl 2-[(1r,2s)-1-cyano-2-fluoro-cyclopropyl]-4-(trifluoromethyl)benzoate and methyl 2-[(1s,2s)-1-cyano-2-fluoro-cyclopropyl]-4-(trifluoromethyl)benzoate: To a solution of methyl 2-(1-cyanovinyl)-4-(trifluoromethyl)benzoate (11.0 g, 43.1 mmol) in THF (200 mL) was added (fluoromethyl)(phenyl)(2,3,4,5-tetramethylphenyl)sulfonium tetrafluoroborate (31.0 g, 86 mmol) and NaH (6.9 g, 172 mmol, 60% purity) at 0 °C. The mixture was stirred at 20 °C for 1 h. The reaction mixture was poured into HO (30 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z=288.0 [M+H].

[0279] (2's,4r)-2'-Fluoro-6-(trifluoromethyl)spiro[2,3-dihydroisoquinolin-4,1'-cyclopropan]-1-one and (2's,4s)-2'-Fluoro-6-(trifluoromethyl)spiro[2,3-dihydroisoquinolin-4,1'-cyclopropan]-1-one: To a solution of methyl 2-[(1r,2s)-1-cyano-2-fluorocyclopropyl]-4-(trifluoromethyl)benzoate and methyl 2-[(1s,2s)-1-cyano-2-fluorocyclopropyl]-4-(trifluoromethyl)benzoate (12.0 g, 41.0 mmol) in MeOH (120 mL) was added Raney-Ni (5.0 g, 58.0 mmol). The mixture was stirred under H2 (30 psi) at 20 °C for 1 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give:

[0280] (2's,4r)-2'-Fluoro-6-(trifluoromethyl)spiro[2,3-dihydroisoquinolin-4,1'-cyclopropan]-1-one: LCMS: m / z = 260.0 [M+H]. 1H NMR (400 MHz, CDCl): δ 8.27 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.04 (br s, 1H), 6.95 (s, 1H), 4.75-4.52 (m, 1H), 3.91 (d, J = 12.8 Hz, 1H), 3.58 (dd, J = 4.4, 13.2 Hz, 1H), 1.61-1.72 (m, 1H), 1.47-1.36 (m, 1H);

[0281] (2's,4')-2'-Fluoro-6-(trifluoromethyl)spiro[2,3-dihydroisoquinolin-4,1'-cyclopropan]-1-one: LCMS: m / z = 260.0 [M+H]. 1H NMR (400 MHz, CDCl): δ 8.27 (d, J = 8.4 Hz, 1H), 7.67 (dd, J = 0.8, 8.0 Hz, 1H), 7.48 (br s, 1H), 7.37 (s, 1H), 4.89-4.62 (m, 1H), 3.81 (dd, J = 7.6, 12.8 Hz, 1H), 2.81 (dd, J = 4.8, 13.2 Hz, 1H), 1.93-1.79 (m, 1H), 1.25-1.18 (m, 1H).

[0282] Methyl 2-[(2's,4r)-2'-fluoro-1-oxo-6-(trifluoromethyl)spiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]acetate: To a solution of (2's,4r)-2'-fluoro-6-(trifluoromethyl)spiro[2,3-dihydroisoquinolin-4,1'-cyclopropan]-1-one (2.4 g, 9.3 mmol) in DMF (30 mL) was added NaH (560 mg, 13.9 mmol, 60% purity) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. To the mixture was added methyl 2-bromoacetate (2.83 g, 18.5 mmol) at 0 °C. The mixture was stirred at 20 °C for 2 h. The mixture was poured into saturated aqueous NH4Cl (30 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z=332.2 [M+H] + .

[0283] Intermediate 40 2-[(2's,4r)-2'-Fluoro-1-oxo-6-(trifluoromethyl)spiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]acetic acid [ka] To a solution of methyl 2-[(2's,4r)-2'-fluoro-1-oxo-6-(trifluoromethyl)spiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]acetate (150 mg, 0.45 mmol) in THF (2.0 mL) and HO (2.0 mL) was added LiOH·HO (47 mg, 1.1 mmol). The mixture was stirred at 20 °C for 2 h. The mixture was diluted with HO (3 mL) and extracted with MTBE (2 mL). The aqueous phase was adjusted to pH = 3 by the addition of aqueous HCl (3 M). The mixture was extracted with EtOAc (3 × 2 mL). The combined organic layers were washed with brine (3 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude residue, which was used directly. LCMS: m / z = 317.9 [M+H] + .

[0284] Intermediate 41 6-(Trifluoromethyl)spiro[2,3-dihydroisoquinoline-4,1'-cyclopropan]-1-one [ka] 2-(1-Cyanocyclopropyl)-4-(trifluoromethyl)benzoic acid: To a solution of 2-fluoro-4-(trifluoromethyl)benzoic acid (2.00 g, 9.61 mmol) and cyclopropanecarbonitrile (1.93 g, 28.8 mmol) in THF (20 mL) was added KHMDS (25.0 mL, 1 M in THF) dropwise at −40° C. The reaction mixture was slowly warmed to 20° C. and then stirred at this temperature for 1 h. The reaction mixture was then heated to 70° C. and stirred for an additional 2 h. The reaction mixture was poured into HO (20 mL) and washed with EtOAc (50 mL). The aqueous layer was then adjusted to pH 3–4 by the addition of aqueous HCl (3N). The aqueous portion was then extracted with EtOAc (3×20 mL). The combined organics were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC.

[0285] Methyl 2-(1-cyanocyclopropyl)-4-(trifluoromethyl)benzoate: To a solution of 2-(1-cyanocyclopropyl)-4-(trifluoromethyl)benzoic acid (0.50 g, 1.96 mmol) in THF (10 mL) was added TMSCHN (3.92 mmol, 2 M in n-hexane) at 0 °C. The reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was quenched by the addition of AcOH (2 mL), and the resulting mixture was extracted with EtOAc (20 mL). The organic layer was washed with saturated aqueous NaHCO (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography.

[0286] 6-(Trifluoromethyl)spiro[2,3-dihydroisoquinolin-4,1'-cyclopropan]-1-one: To a mixture of methyl 2-(1-cyanocyclopropyl)-4-(trifluoromethyl)benzoate (0.30 g, 1.11 mmol) and dichlorocobalt (289 mg, 2.23 mmol) in MeOH (5 mL) and THF (2 mL) was added NaBH (211 mg, 5.57 mmol) at 0 °C. The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was cooled to 0 °C, quenched by the addition of saturated aqueous NH Cl (10 mL), and extracted with EtOAc (3 × 10 mL). The organics were combined, dried over anhydrous Na SO , filtered, and concentrated under reduced pressure to give a residue that was used directly. LCMS: m / z = 242.1 [M+H]

[0287] Methyl 2-[1-oxo-6-(trifluoromethyl)spiro[3H-isoquinolin-4,1′-cyclopropan]-2-yl]acetate: To a solution of 6-(trifluoromethyl)spiro[2,3-dihydroisoquinolin-4,1′-cyclopropan]-1-one (0.20 g, 0.83 mmol) in DMF (5.0 mL) was added NaH (36 mg, 0.91 mmol, 60% purity in mineral oil) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 h, followed by the addition of methyl 2-bromoacetate (190 mg, 1.24 mmol). The reaction mixture was stirred at 20° C. for an additional 2 h. The reaction mixture was quenched by the addition of water (5 mL) and extracted with EtOAc (3×5 mL). The organics were combined, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. 1 H NMR (400 MHz, CDCl3): δ 8.23(d,J=8.0 Hz,1H),7.55(d,J=8.0 Hz,1H),7.08(s,1H),4.35(s,2H),3.76(s,3H),3.48(s,2H),1.21-1.06(m,4H).

[0288] Intermediate 42 3-Amino-1-cyclopropylcyclobutanol [ka] tert-Butyl (3-cyclopropyl-3-hydroxycyclobutyl)carbamate: To a solution of bromo(cyclopropyl)magnesium (1 M in THF, 13.50 mL) in THF (15 mL) was added a solution of tert-butyl N-(3-oxocyclobutyl)carbamate (1.00 g, 5.40 mmol) in THF (15 mL) at −60° C. The mixture was stirred at −60° C. for 1 hour. The mixture was quenched with saturated aqueous NH4Cl (30 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (3 × 30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. 1 H NMR(400MHz,CDCl3): δ 3.74-3.59(m,1H),3.04-2.91(m,1H),2.48-2.33(m,2H),1.95-1.81(m,2 H),1.44(s,9H),1.13-1.08(m,1H),0.54-0.50(m,2H),0.34-0.31(m,2H).

[0289] 3-Amino-1-cyclopropylcyclobutanol HCl salt: A solution of tert-butyl (3-cyclopropyl-3-hydroxycyclobutyl)carbamate (1.00 g, 4.40 mmol) in HCl (4 M in MeOH, 10 mL) was stirred for 1 hour at 20° C. The mixture was concentrated under reduced pressure to give a residue that was used directly.

[0290] Intermediate 43 2-(6-Bromo-1-oxo-spiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl)acetamide [ka] 2-(6-Bromo-1-oxo-spiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl)acetic acid: To a solution of methyl 2-(6-bromo-1-oxo-spiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl)acetate (330 mg, 1.02 mmol) in THF (5 mL) was added a solution of LiOH (2.04 mL, 1 M in HO). The reaction mixture was stirred at 20 °C for 3 h. The reaction mixture was adjusted to pH 4 using 1 N aqueous HCl and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue that was used directly. LCMS: m / z = 310.3, 312.3 [M+H].

[0291] 2-(6-Bromo-1-oxo-spiro[3H-isoquinoline-4,1′-cyclopropan]-2-yl)acetamide: To a solution of 2-(6-bromo-1-oxo-spiro[3H-isoquinoline-4,1′-cyclopropan]-2-yl)acetic acid (2.0 g, 6.45 mmol), NHCl (690 mg, 12.90 mmol), and HOBt (1.05 g, 7.74 mmol) in DCM (20 mL) was added EDCI (1.48 g, 7.74 mmol) and DIPEA (1.67 g, 12.90 mmol). The mixture was stirred at 20° C. for 16 h. The mixture was added to HO (30 mL) and extracted with DCM (3×20 mL). The combined organics were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was triturated with MTBE at 25° C. for 30 min to give a residue that was used directly. LCMS: m / z=309.0, 311.0 [M+H] + .

[0292] Intermediate 44 6-Bromo-5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine [ka] 5-Fluoro-1H-pyrazolo[3,4-b]pyridine 7-oxide: To a solution of 5-fluoro-1H-pyrazolo[3,4-b]pyridine (3.0 g, 21.9 mmol) in EtOAc (30 mL) was added m-CPBA (5.55 g, 27.4 mmol, 85% purity) at 0 °C. The mixture was stirred at 20 °C for 12 h. The mixture was filtered. The filter cake was washed with EtOAc (2 × 3 mL). The filter cake was dried under reduced pressure to give a residue that was used directly. LCMS: m / z = 154.0 [M+H]+.

[0293] 6-Bromo-5-fluoro-1H-pyrazolo[3,4-b]pyridine: To a solution of 5-fluoro-1H-pyrazolo[3,4-b]pyridine 7-oxide (2.70 g, 17.6 mmol) in CHCl (100 mL) was added POBr (7.58 g, 26.4 mmol) at 0 °C. The mixture was stirred at 60 °C for 2 h. The mixture was diluted with HO (20 mL) and extracted with DCM (3 × 7 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z = 215.9, 217.9 [M+H] + .

[0294] 6-Bromo-5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine: To a solution of 6-bromo-5-fluoro-1H-pyrazolo[3,4-b]pyridine (1.16 g, 5.37 mmol) in 1,4-dioxane (15 mL) was added 3,4-dihydro-2H-pyran (903 mg, 10.7 mmol) and p-TsOH (93 mg, 0.54 mmol) at 20 °C. The mixture was stirred at 80 °C for 2 h. The mixture was diluted with HO (15 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z = 299.7, 301.6 [M+H] + .

[0295] Example 1 2-[(2'R,4S)-2'-fluoro-6-(1-fluorocyclopropyl)-1-oxospiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]-N-(5-(trifluoromethyl)pyrimidin-2-yl)acetamide (1) [ka] To a solution of 5-(trifluoromethyl)pyrimidin-2-amine (40 mg, 0.24 mmol) in THF (2.0 mL) was added LiHMDS (1 M in THF, 0.24 mL) at 0° C. The reaction mixture was stirred at 0° C. for 3 hours. Separately, to a solution of 2-((1S,2R)-2-fluoro-1′-oxo-6′-(1-fluorocyclopropyl)-1′H-spiro[cyclopropane-1,4′-isoquinoline]-2′(3′H)-yl)acetic acid (50 mg, 0.16 mmol, Int. 7) in THF (2.0 mL) was added CDI (53 mg, 0.33 mmol). This mixture was stirred at 15° C. for 3 hours and then added to the first mixture at 0° C. The combined reaction mixture was stirred at 0° C. for an additional hour, then at 15° C. for an additional hour. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 453.1 [M+H] + . 1 H NMR(400 MHz,DMSO-d6): δ 11.30(s,1H),9.10(d,J=0.4 Hz,2H),7.93(d,J=8.0 Hz,1H),7.31(dd,J=1.6,8.0 Hz,1H),6.69(d,J=1.2 Hz,1H),5.17-4.94(m,1H),4.84(d,J=17.2 Hz,1H),4.40(d,J=17.2 Hz,1H),3.93(dd,J=2.0,12.8 Hz,1H),3.56(d,J=13.2 Hz,1H),1.78-1.67(m,1H),1.59-1.40(m,3H),1.33-1.21(m,2H).

[0296] Example 2 2-[(2'R,4S)-2'-fluoro-6-(1-fluorocyclopropyl)-1-oxospiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]-N-(5-methylpyrimidin-2-yl)acetamide (2) [ka] To a mixture of methyl 2-((1S,2R)-2-fluoro-1'-oxo-6'-(1-fluorocyclopropyl)-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetate (30 mg, 0.09 mmol, Int. 8), 5-methylpyrimidin-2-amine (20 mg, 0.19 mmol) in DCE (1.0 mL) was added AlMe3 (1 M in n-heptane, 0.28 mL). The mixture was stirred at 60 °C for 6 h. The reaction mixture was poured into ice-cold HO (15 mL) and extracted with EtOAc (4 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 399.1 [M+H] + . 1 H NMR(400 MHz,CDCl3): δ 8.92(br s,1H),8.44(s,2H),8.16(d,J=8.0 Hz,1H),7.00(d,J=8.0 Hz,1H),6.72(d,J=1.2 Hz,1H),5.03(br s,1H),4.79-4.54(m,1H),4.44(br d,J=17.2 Hz,1H),4.18(dd,J=1.6,12.8 Hz,1H),3.55(d,J=12.8 Hz,1H),2.27(s,3H),1.71-1.51(m,3H),1.46-1.32(m,1H),1.18-1.07(m,2H).

[0297] Example 3 2-[(2'R,4S)-2'-fluoro-6-(1-fluorocyclopropyl)-1-oxospiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]-N-(5-cyanopyrimidin-2-yl)acetamide (3) [ka] To a solution of 5-cyanopyrimidin-2-amine (18 mg, 0.15 mmol) in THF (2.0 mL) was added LiHMDS (1 M in THF, 0.15 mL) at 0° C. The reaction mixture was stirred at 0° C. for 3 hours. Separately, to a solution of 2-((1S,2R)-2-fluoro-1′-oxo-6′-(1-fluorocyclopropyl)-1′H-spiro[cyclopropane-1,4′-isoquinoline]-2′(3′H)-yl)acetic acid (30 mg, 0.10 mmol, Int. 7) in THF (1.0 mL) was added CDI (32 mg, 0.20 mmol). This mixture was stirred at 15° C. for 3 hours and then added to the first mixture at 0° C. The combined reaction mixture was stirred at 0° C. for an additional hour, then at 15° C. for an additional hour. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 410.1 [M+H] + . 1 H NMR(400 MHz,DMSO-d6): δ 11.39(s,1H),9.13(s,2H),7.92(d,J=8.0 Hz,1H),7.30(dd,J=1.6,8.4 Hz,1H),6.69(d,J=1.2 Hz,1H),5.20-4.93(m,1H),4.82(d,J=17.6 Hz,1H),4.39(d,J=17.6 Hz,1H),3.92(dd,J=1.6,12.8 Hz,1H),3.56(d,J=13.2 Hz,1H),1.76-1.69(m,1H),1.61-1.41(m,3H),1.31-1.23(m,2H).

[0298] Example 4 N-(3-cis-hydroxy-3-methylcyclobutyl)-2-[(2'R,4S)-2'-fluoro-6-(1-fluorocyclopropyl)-1-oxospiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]acetamide (4) [ka] To a solution of 2-((1S,2R)-2-fluoro-1'-oxo-6'-(1-fluorocyclopropyl)-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetic acid (30 mg, 0.10 mmol, Int. 7) in DMF (1.5 mL) was added 3-cis-amino-1-methylcyclobutanol HCl salt (27 mg, 0.19 mmol), DIPEA (63 mg, 0.49 mmol), HOBt (20 mg, 0.15 mmol), and EDCI (28 mg, 0.15 mmol). The mixture was stirred at 20 °C for 12 h. The reaction mixture was poured into HO (10 mL) and extracted with EtOAc (4 × 5 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC. LCMS: m / z=391.1 [M+H] + . 1 H NMR(400 MHz,CDCl3): δ 8.12(d,J=8.0 Hz,1H),7.02(d,J=8.0 Hz,1H),6.73(s,1H),6.54(br d,J=7.2 Hz,1H),4.71-4.48(m,1H),4.39(d,J=16.0 Hz,1H),4.13-3.92(m,3H),3.47(d,J=12.8 Hz,1H),2.57-2.45(m,2H),2.11(br s,1H),2.07-1.97(m,2H),1.78-1.68(m,1H),1.60-1.52(m,2H),1.43-1.29(m,4H),1.17-1.06(m,2H).

[0299] Example 5 N-(3-cis-hydroxy-3-methylcyclobutyl)-2-[(2's,4r)-2',5-difluoro-6-iodo-1-oxospiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]acetamide (5) [ka] To a solution of 2-[(2's,4r)-2',5-difluoro-6-iodo-1-oxospiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]acetic acid (140 mg, 0.36 mmol, Int. 18) in DMF (1.5 mL) was added 3-cis-amino-1-methylcyclobutanol HCl salt (98 mg, 0.71 mmol), DIPEA (230 mg, 1.78 mmol), HOBt (72 mg, 0.53 mmol), and EDCI (102 mg, 0.53 mmol). The mixture was stirred at 20 °C for 12 h. The reaction mixture was poured into HO (3 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. LCMS: m / z=477.0 [M+H] + . 1 H NMR(400 MHz,CDCl3): δ 7.81-7.75(m,1H),7.73-7.68(m,1H),6.48(br d,J=7.2 Hz,1H),5.34-5.08(m,1H),4.17(s,2H),4.05-3.95(m,1H),3.90(dd,J=2.4,13.2 Hz,1H),3.55(d,J=13.2 Hz,1H),2.51(ddd,J=3.2,8.0,10.4 Hz,2H),2.18(s,1H),2.07-1.97(m,3H),1.51-1.39(m,1H),1.37(s,3H).

[0300] Example 6 N-(3-cis-hydroxy-3-methylcyclobutyl)-2-[(2's,4r)-2',5-difluoro-6-cyclopropyl-1-oxospiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]acetamide (6) [ka] To a solution of 2-[(2's,4r)-6-cyclopropyl-2',5-difluoro-1-oxo-spiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]acetic acid (50 mg, 0.16 mmol, Int. 17) in DMF (1.0 mL) was added 3-cis-amino-1-methylcyclobutanol HCl salt (45 mg, 0.33 mmol), DIPEA (110 mg, 0.82 mmol), HOBt (33 mg, 0.25 mmol), and EDCI (47 mg, 0.25 mmol). The mixture was stirred at 20 °C for 12 h. The reaction mixture was poured into HO (5 mL) and extracted with EtOAc (3 × 2 mL). The combined organic layers were washed with brine (3 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. LCMS: m / z=391.1 [M+H] + . 1 H NMR(400 MHz,CDCl3): δ 7.85(d,J=8.0 Hz,1H),6.83(t,J=7.6 Hz,1H),6.62(br d,J=7.2 Hz,1H),5.37-5.13(m,1H),4.27-4.08(m,2H),4.04-3.91(m,1H),3.87(dd,J=13.2,2.4 Hz,1H),3.53(d,J=12.8 Hz,1H),2.56-2.44(m,2H),2.32(s,1H),2.12-1.95(m,4H),1.41-1.36(m,4H),1.10-1.02(m,2H),0.80-0.72(m,2H).

[0301] Example 7 N-(5-chloropyrimidin-2-yl)-2-(6-iodo-1-oxo-4-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)acetamide (7) [ka] To a solution of a single isomer of methyl 2-(6-iodo-1-oxo-4-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)acetate (100 mg, 0.24 mmol, Int. 20b) in DCE (2.0 mL) was added 5-chloropyrimidin-2-amine (38 mg, 0.30 mmol) and AlMe (1 M in n-heptane, 0.37 mL). The reaction mixture was stirred at 90 °C for 1.5 h. The reaction mixture was cooled to ambient temperature, diluted with water (6 mL), and extracted with EtOAc (3 × 6 mL). The combined organic layers were washed with brine (6 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC to afford the title compound as a single unassigned enantiomer. LCMS: m / z = 510.9, 512.9 [M+H] + . 1 H NMR(400 MHz,CDCl3): δ 8.61(br s,1H),8.55(s,2H),7.93-7.90(m,2H),7.76(s,1H),5.20-5.14(m,1H),4.33(d,J=16.8 Hz,1H),4.28(br dd,J=4.4,13.6 Hz,1H),3.84(dd,J=4.0,13.6 Hz,1H),3.62-3.56(m,1H).

[0302] Examples 8 and 9 2-(6-iodo-1-oxo-4-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)-N-(5-methylpyrimidin-2-yl)acetamide (8) and 2-(6-methyl-1-oxo-4-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)-N-(5-methylpyrimidin-2-yl)acetamide (9) [ka] To a solution of a single isomer of methyl 2-(6-iodo-1-oxo-4-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)acetate (100 mg, 0.24 mol, Int. 20b) in DCE (1.0 mL) was added 5-methylpyrimidin-2-amine (32 mg, 0.30 mmol) and AlMe (1 M in n-heptane, 0.37 mL). The reaction mixture was stirred at 90° C. for 2 h. The reaction mixture was cooled to ambient temperature, diluted with water (6 mL), and extracted with EtOAc (3×6 mL). The combined organic layers were washed with brine (6 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to afford the title compound as a single unassigned enantiomer. The residue was purified by reverse-phase preparative HPLC to give:

[0303] 2-(6-iodo-1-oxo-4-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)-N-(5-methylpyrimidin-2-yl)acetamide (8): LCMS: m / z=490.9 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 8.63(br s,1H),8.45(s,2H),7.94(m,2H),7.77(s,1H),5.32-5.26(m,1H),4.38(d,J=17.2 Hz,1H),4.31(br dd,J=4.0,13.6 Hz,1H),3.84(dd,J=2.0,14.0 Hz,1H),3.64-3.56(m,1H),2.23(s,3H).

[0304] 2-(6-methyl-1-oxo-4-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)-N-(5-methylpyrimidin-2-yl)acetamide (9): LCMS: m / z=379.1 [M+H] + . 1H NMR(400 MHz,CDCl3): δ 8.62(br s,1H),8.43(s,2H),8.11(d,J=8.0 Hz,1H),7.34(br d,J=8.0 Hz,1H),7.17(s,1H),5.22-5.09(m,1H),4.36(d,J=16.8 Hz,1H),4.25(br dd,J=4.8,13.6 Hz,1H),3.85(br d,J=12.8 Hz,1H),3.61-3.54(m,1H),2.44(s,3H),2.28(s,3H).

[0305] Examples 10 and 11 N-(3-cis-hydroxy-3-methylcyclobutyl)-2-(6-iodo-1-oxo-4-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)acetamide (10 and 11) [ka] To a solution of 2-(6-iodo-1-oxo-4-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)acetic acid (150 mg, 0.38 mmol, Int. 21) in DMF (2.0 mL) was added 3-cis-amino-1-methylcyclobutanol HCl salt (103 mg, 0.76 mmol), DIPEA (242 mg, 1.88 mmol), HOBt (76 mg, 0.56 mmol), and EDCI (108 mg, 0.56 mmol). The mixture was stirred at 20 °C for 12 h. The reaction mixture was poured into HO (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC and further purified by chiral SFC (column: REGIS(s,s)WHELK-O1 (250 mm x 30 mm x 10 μm particle size); mobile phase: A: CO B: 0.1% NH OH in EtOH; gradient: B%: 40% isocratic; flow rate: 70 g / min; detection wavelength: 220 nm; column temperature: 35° C., system back pressure: 120 bar) to give:

[0306] N-(3-cis-hydroxy-3-methylcyclobutyl)-2-(6-iodo-1-oxo-4-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)acetamide (first eluting isomer, 10): LCMS: m / z=483.0 [M+H] + .

[0307] N-(3-cis-hydroxy-3-methylcyclobutyl)-2-(6-iodo-1-oxo-4-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)acetamide (second eluting isomer, 11): LCMS: m / z=482.9 [M+H] + .

[0308] Examples 12 and 13 2-[(2's,4r)-2',5-difluoro-1-oxo-6-(trifluoromethyl)spiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]-N-(5-chloropyrimidin-2-yl)acetamide (12 and 13) [ka] To a solution of methyl 2-[(2's,4r)-2'-fluoro-1-oxo-6-(trifluoromethyl)spiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]acetate (70 mg, 0.20 mmol, Int. 24) in DCE (2.0 mL) was added 5-chloropyrimidin-2-amine (31 mg, 0.24 mmol) and AlMe (1 M in n-heptane, 0.30 mL). The reaction mixture was stirred at 60 °C for 16 h. The reaction mixture was cooled to 0 °C, diluted with HO (10 mL), and extracted with EtOAc (4 × 15 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC and further purified by chiral SFC (Column: Chiralpak IG-3 (50 mm x 4.6 mm x 3 μm particle size); Mobile phase: A: CO B: 0.1% i-PrNH in i-PrOH; Gradient: B%: 50% isocratic; Flow rate: 3.4 mL / min; Detection wavelength: 220 nm; Column temperature: 35° C., System back pressure: 1800 psi) to give:

[0309] 2-[(2's,4r)-2',5-difluoro-1-oxo-6-(trifluoromethyl)spiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]-N-(5-chloropyrimidin-2-yl)acetamide (first eluting isomer, 12): LCMS: m / z = 447.0, 449.0 [M+H] + . 1 H NMR(400 MHz,CDCl3): δ 8.70(br s,1H),8.56(br s,2H),8.12(d,J=8.0 Hz,1H),7.62-7.57(m,1H),5.45-5.26(m,1H),5.07(br d,J=16.4 Hz,1H),4.54(br d,J=17.2 Hz,1H),3.96(dd,J=2.8,13.2 Hz,1H),3.70(d,J=13.2 Hz,1H),2.03(td,J=7.6,11.6 Hz,1H),1.61-1.50(m,1H).

[0310] 2-[(2's,4r)-2',5-difluoro-1-oxo-6-(trifluoromethyl)spiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]-N-(5-chloropyrimidin-2-yl)acetamide (second eluting isomer, 13): LCMS: m / z = 447.0, 449.0 [M+H] + . 1 H NMR(400 MHz,CDCl3): δ 8.74(br s,1H),8.56(br s,2H),8.11(d,J=8.4 Hz,1H),7.62(t,J=7.2 Hz,1H),5.45-5.27(m,1H),5.07(br d,J=16.8 Hz,1H),4.54(br d,J=17.2 Hz,1H),3.94(dd,J=2.0,13.2 Hz,1H),3.70(d,J=12.8 Hz,1H),2.03(td,J=6.8,11.2 Hz,1H),1.59-1.51(m,1H).

[0311] Examples 14 and 15 N-(5-chloropyrimidin-2-yl)-2-[1',1',5-trifluoro-6-(trifluoromethyl)-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]acetamide (14 and 15) [ka] To a solution of methyl 2-(2,2,5'-trifluoro-1'-oxo-6'-(trifluoromethyl)-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetate (120 mg, 0.33 mmol) in DCE (2.0 mL) were added 5-chloropyrimidin-2-amine (51 mg, 0.39 mmol) and AlMe (1 M in n-heptane, 0.49 mL). The reaction mixture was stirred at 90 °C for 2 h. The reaction mixture was diluted with HO (12 mL) and extracted with EtOAc (3 × 12 mL). The combined organic layers were washed with brine (12 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC and further purified by chiral SFC (Column: REGIS(s,s)WHELK-O1 (250 mm x 30 mm x 10 μm particle size); Mobile phase: A: CO B: 0.1% NH OH in i-PrOH; Gradient: B%: 32% isocratic; Flow rate: 70 g / min; Detection wavelength: 220 nm; Column temperature: 35° C., System back pressure: 120 bar) to give:

[0312] N-(5-chloropyrimidin-2-yl)-2-[1',1',5-trifluoro-6-(trifluoromethyl)-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]acetamide (first eluting isomer, 14): LCMS: m / z = 465.0, 467.0 [M+H] + . 1 H NMR(400 MHz,CDCl3): δ 8.55(s,2H),8.54-8.47(m,1H),8.13(d,J=8.0 Hz,1H),7.70(t,J=7.3 Hz,1H),5.41-5.26(m,1H),4.50(dd,J=6.4,12.8 Hz,1H),4.28(d,J=17.6 Hz,1H),3.12(br d,J=13.2 Hz,1H),3.04-2.92(m,1H),1.72-1.61(m,1H).

[0313] N-(5-chloropyrimidin-2-yl)-2-[1',1',5-trifluoro-6-(trifluoromethyl)-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]acetamide (second eluting isomer, 15): LCMS: m / z = 465.0, 467.0 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 8.64(br s,1H),8.56(s,2H),8.13(d,J=8.4 Hz,1H),7.73-7.66(m,1H),5.42-5.25(m,1H),4.50(dd,J=6.8,13.2 Hz,1H),4.28(d,J=17.2 Hz,1H),3.16-3.07(m,1H),3.04-2.93(m,1H),1.72-1.61(m,1H).

[0314] Examples 16 and 17 N-(5-chloropyrimidin-2-yl)-2-[6-bromo-1',1'-difluoro-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]acetamide (16 and 17) [ka] N-(5-chloropyrimidin-2-yl)-2-[6-bromo-1',1'-difluoro-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]acetamide: To a mixture of 5-chloropyrimidin-2-amine (72 mg, 0.56 mmol) in toluene (4.0 mL) was added AlMe (1 M in n-heptane, 0.56 mL). The reaction mixture was stirred at 25 °C for 50 minutes, and then a solution of methyl 2-(6'-bromo-2,2-difluoro-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinolin]-2'(3'H)-yl)acetate (100 mg, 0.28 mmol) in toluene (1.0 mL) was added. The reaction mixture was then stirred at 90 °C for 2 hours. The reaction mixture was diluted with water (4 mL) and extracted with EtOAc (3 × 2 mL). The combined organics were washed with brine (3 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC and further purified by chiral SFC (column: Chiralpak AD-3 (50 mm × 4.6 mm × 3 μm particle size); mobile phase: A: CO, B: 0.1% i-PrNH in EtOH; gradient: B%: 50% isocratic; flow rate: 4 mL / min; detection wavelength: 220 nm; column temperature: 35 °C, system back pressure: 1800 psi) to give:

[0315] N-(5-chloropyrimidin-2-yl)-2-[6-bromo-1',1'-difluoro-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]acetamide (first eluting isomer, 16): LCMS: m / z = 456.9, 458.9, 460.9 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 8.89(br s,1H),8.58(s,2H),8.09(d,J=8.4 Hz,1H),7.63(dd,J=1.6,8.4 Hz,1H),7.25(s,1H),5.21-5.16(m,1H),4.37(br d,J=16.8 Hz,1H),4.24(dd,J=5.6,12.8 Hz,1H),3.46(d,J=12.4 Hz,1H),2.13-2.09(m,1H),1.79-1.73(m,1H).

[0316] N-(5-chloropyrimidin-2-yl)-2-[6-bromo-1',1'-difluoro-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]acetamide (second eluting isomer, 17): LCMS: m / z = 456.9, 458.9, 460.9 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 9.02(br s,1H),8.59(s,2H),8.10(d,J=8.4 Hz,1H),7.62(br d,J=8.4 Hz,1H),7.25(s,1H),5.22-5.17(m,1H),4.38(br d,J=17.2 Hz,1H),4.24(br dd,J=5.2,12.8 Hz,1H),3.46(br d,J=12.8 Hz,1H),2.15-2.09(m,1H),1.79-1.71(m,1H).

[0317] Examples 18 and 19 N-(5-methylpyrimidin-2-yl)-2-[6-bromo-1',1'-difluoro-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]acetamide (18 and 19) [ka] To a solution of methyl 2-(6'-bromo-2,2-difluoro-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetate (100 mg, 0.28 mmol) and 5-methylpyrimidin-2-amine (91 mg, 0.83 mmol) in DCE (2.0 mL) was added AlMe (1 M in n-heptane, 0.80 mL). The reaction mixture was stirred at 60 °C for 4 h. The reaction mixture was cooled to 0 °C, diluted with water (8 mL), and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC and further purified by chiral SFC (Column: REGIS(s,s)WHELK-O1 (250 mm x 30 mm x 10 μm particle size); Mobile phase: A: CO B: 0.1% NH OH in EtOH; Gradient: B%: 50% isocratic; Flow rate: 70 g / min; Detection wavelength: 220 nm; Column temperature: 35° C., System back pressure: 120 bar) to give:

[0318] N-(5-methylpyrimidin-2-yl)-2-[6-bromo-1',1'-difluoro-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]acetamide (first eluting isomer, 18): LCMS: m / z = 436.9, 438.9 [M+H] + . 1 H NMR(400 MHz,CDCl3): δ 9.34(br s,1H),8.46(s,2H),8.07(d,J=8.2 Hz,1H),7.57(dd,J=1.8,8.2 Hz,1H),7.23(d,J=1.6 Hz,1H),5.30(br d,J=14.8 Hz,1H),4.38(br d,J=17.2 Hz,1H),4.19(dd,J=5.2,12.8 Hz,1H),3.42(d,J=12.8 Hz,1H),2.28(s,3H),2.09-2.05(m,1H),1.75-1.71(m,1H).

[0319] N-(5-methylpyrimidin-2-yl)-2-[6-bromo-1',1'-difluoro-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]acetamide (second eluting isomer, 19): LCMS: m / z = 436.9, 438.9 [M+H] + . 1 H NMR(400 MHz,CDCl3): δ 9.20(s,1H),8.45(s,2H),8.07(d,J=8.4 Hz,1H),7.57(dd,J=1.6,8.4 Hz,1H),7.23(d,J=1.2 Hz,1H),5.29(br d,J=16.4 Hz,1H),4.38(br d,J=17.2 Hz,1H),4.19(dd,J=5.4,12.8 Hz,1H),3.42(d,J=13.2 Hz,1H),2.28(s,3H),2.09-2.04(m,1H),1.75-1.71(m,1H).

[0320] Examples 20 and 21 N-(3-cis-hydroxy-3-methylcyclobutyl)-2-[6-bromo-1',1'-difluoro-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]acetamide (20 and 21) [ka] To a solution of 2-(6-bromo-1',1'-difluoro-1-oxo-spiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl)acetic acid (100 mg, 0.29 mmol) in DMF (1.0 mL) was added 3-cis-amino-1-methylcyclobutanol HCl salt (101 mg, 0.58 mmol), HOBt (59 mg, 0.44 mmol), DIPEA (187 mg, 1.44 mmol), and EDCI (83 mg, 0.44 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was poured into HO (3 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC and further separated by chiral SFC (column: REGIS(s,s)WHELK-O1 (250 mm x 30 mm x 10 μm particle size); mobile phase: A:CO B:i-PrOH (0.1% i-PrNH, v / v); gradient: B%: 33% isocratic; flow rate: 3.4 mL / min; detection wavelength: 220 nm; column temperature: 35°C, system back pressure: 2000 psi) to give:

[0321] N-(3-cis-hydroxy-3-methylcyclobutyl)-2-[6-bromo-1',1'-difluoro-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]acetamide (first eluting isomer, 20): LCMS: m / z = 429.0, 430.9 [M+H] + . 1 H NMR(400 MHz,CDCl3): δ 8.03(d,J=8.4 Hz,1H),7.59(dd,J=2.0,8.4 Hz,1H),7.21(d,J=1.2 Hz,1H),6.49(br d,J=7.2 Hz,1H),4.18(s,2H),4.07(dd,J=6.0,13.2 Hz,1H),4.01-3.94(m,1H),3.41(dd,J=1.2,13.2 Hz,1H),2.56-2.48(m,2H),2.18-2.09(m,2H),2.07-1.99(m,2H),1.72-1.70(m,1H),1.37(s,3H).

[0322] N-(3-cis-hydroxy-3-methylcyclobutyl)-2-[6-bromo-1',1'-difluoro-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]acetamide (second eluting isomer, 21): LCMS: m / z = 429.0, 430.9 [M+H] + . 1 H NMR(400 MHz,CDCl3): δ 8.03(d,J=8.4 Hz,1H),7.60(dd,J=2.0,8.4 Hz,1H),7.21(d,J=1.6 Hz,1H),6.48(br d,J=7.2 Hz,1H),4.18(s,2H),4.07(dd,J=6.0,12.8 Hz,1H),4.01-3.93(m,1H),3.41(dd,J=1.6,13.2 Hz,1H),2.57-2.48(m,2H),2.16-2.08(m,2H),2.07-1.99(m,2H),1.72-1.70(m,1H),1.37(s,3H).

[0323] Examples 22 and 23 N-(3-cis-hydroxy-3-methylcyclobutyl)-2-[1',1'-difluoro-6-(1-fluorocyclopropyl)-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]acetamide (22 and 23) [ka] To a solution of 2-(2,2-difluoro-6'-(1-fluorocyclopropyl)-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetic acid (100 mg, 0.30 mmol) and 3-cis-amino-1-methylcyclobutanol HCl salt (47 mg, 0.46 mmol) in DMF (1.0 mL) was added HOBt (62 mg, 0.46 mmol), DIPEA (119 mg, 0.90 mmol), and EDCI (88 mg, 0.46 mmol). The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was cooled to 0 °C, poured into HO (5 mL), and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC and further purified by chiral SFC (Column: REGIS(s,s)WHELK-O1 (250 mm x 30 mm x 10 μm particle size); Mobile phase: A: CO B: 0.1% NH OH in EtOH; Gradient: B%: 30% isocratic; Flow rate: 65 g / min; Detection wavelength: 220 nm; Column temperature: 35° C., System back pressure: 100 bar) to give:

[0324] N-(3-cis-hydroxy-3-methylcyclobutyl)-2-[1',1'-difluoro-6-(1-fluorocyclopropyl)-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]acetamide (first eluting isomer, 22): LCMS: m / z=409.1 [M+H] + . 1 H NMR(400 MHz,CDCl3): δ 8.14(d,J=8.0 Hz,1H),7.12(d,J=8.0 Hz,1H),7.04(s,1H),6.54(br d,J=7.2 Hz,1H),4.29-4.12(m,2H),4.08(dd,J=6.0,12.8 Hz,1H),3.98(d,J=8.0 Hz,1H),3.46-3.34(m,1H),2.57-2.45(m,2H),2.25-2.11(m,2H),2.04-2.02(m,2H),1.74-1.53(m,3H),1.37(s,3H),1.20-1.10(m,2H).

[0325] N-(3-cis-hydroxy-3-methylcyclobutyl)-2-[1',1'-difluoro-6-(1-fluorocyclopropyl)-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]acetamide (second eluting isomer, 23): LCMS: m / z=409.1 [M+H] + . 1 H NMR(400 MHz,CDCl3): δ 8.14(d,J=8.0 Hz,1H),7.12(d,J=8.4 Hz,1H),7.04(s,1H),6.54(br d,J=7.2 Hz,1H),4.29-4.12(m,2H),4.08(dd,J=6.0,12.8 Hz,1H),3.98(d,J=8.0 Hz,1H),3.40(d,J=12.8 Hz,1H),2.57-2.46(m,2H),2.25-2.11(m,2H),2.08-1.98(m,2H),1.79-1.49(m,3H),1.37(s,3H),1.16-1.11(m,2H).

[0326] Examples 24 and 25 N-(5-methylpyrimidin-2-yl)-2-[1',1'-difluoro-6-(1-fluorocyclopropyl)-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]acetamide (24 and 25) [ka] To a solution of 5-methylpyrimidin-2-amine (39 mg, 0.35 mmol) in DCE (0.5 mL) was added AlMe (1 M in n-heptane, 0.44 mL). The reaction mixture was stirred at 20 °C for 0.5 h, and then a solution of methyl 2-(2,2-difluoro-6'-(1-fluorocyclopropyl)-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetate (100 mg, 294.72 μmol) in DCE (1.0 mL) was added. The reaction mixture was stirred at 70 °C for an additional 4 h. The reaction mixture was diluted with HO (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC and further purified by chiral SFC (column: REGIS(s,s)WHELK-O1 (250 mm x 30 mm x 10 μm particle size); mobile phase: A: CO B: 0.1% NH OH in EtOH; gradient: B%: 37% isocratic; flow rate: 70 g / min; detection wavelength: 220 nm; column temperature: 35° C., system back pressure: 120 bar) to give:

[0327] N-(5-methylpyrimidin-2-yl)-2-[1',1'-difluoro-6-(1-fluorocyclopropyl)-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]acetamide (first eluting isomer, 24): LCMS: m / z=417.1 [M+H] + . 1 H NMR(400 MHz,CDCl3): δ 8.54(br s,1H),8.43(s,2H),8.18(d,J=8.4 Hz,1H),7.12(d,J=8.4 Hz,1H),7.06(s,1H),5.29-5.10(m,1H),4.34(br d,J=17.2 Hz,1H),4.21(br dd,J=5.6,12.8 Hz,1H),3.42(br d,J=13.2 Hz,1H),2.28(s,3H),2.17-2.14(m,1H),1.77-1.65(m,1H),1.64-1.59(m,1H),1.58(br s,1H),1.20-1.08(m,2H).

[0328] N-(5-methylpyrimidin-2-yl)-2-[1',1'-difluoro-6-(1-fluorocyclopropyl)-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]acetamide (second eluting isomer, 25): LCMS: m / z=417.1 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 8.54(br s,1H),8.43(s,2H),8.19(d,J=7.6 Hz,1H),7.12(d,J=8.0 Hz,1H),7.06(s,1H),5.31-5.08(m,1H),4.34(br d,J=16.8 Hz,1H),4.21(dd,J=6.0,12.8 Hz,1H),3.43(d,J=12.4 Hz,1H),2.28(s,3H),2.21-2.10(m,1H),1.72-1.56(m,3H),1.19-1.11(m,2H).

[0329] Examples 26 and 27 N-(5-fluoropyrimidin-2-yl)-2-[1',1'-difluoro-6-(1-fluorocyclopropyl)-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]acetamide (26 and 27) [ka] To a solution of 2-(2,2-difluoro-6'-(1-fluorocyclopropyl)-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetic acid (0.16 g, 0.49 mmol) in pyridine (4.0 mL) was added 5-fluoropyrimidin-2-amine (111 mg, 0.98 mmol) and EDCI (189 mg, 0.98 mmol). The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with HO (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC and further purified by chiral SFC (Column: REGIS(s,s) WHELK-O1 (250 mm x 30 mm x 10 μm particle size); Mobile phase: A: CO B: 0.1% NH OH in EtOH; Gradient: B%: 33% isocratic; Flow rate: 70 g / min; Detection wavelength: 220 nm; Column temperature: 35° C., System back pressure: 120 bar) to give:

[0330] N-(5-fluoropyrimidin-2-yl)-2-[1',1'-difluoro-6-(1-fluorocyclopropyl)-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]acetamide (first eluting isomer, 26): LCMS: m / z=421.1 [M+H] + . 1 H NMR(400 MHz,CDCl3): δ 8.76(br s,1H),8.48(s,2H),8.19(d,J=8.0 Hz,1H),7.12(d,J=8.0 Hz,1H),7.06(s,1H),5.14-4.98(m,1H),4.31(d,J=16.4 Hz,1H),4.21(dd,J=6.0,12.8 Hz,1H),3.44(d,J=13.2 Hz,1H),2.21-2.15(m,1H),1.71-1.63(m,1H),1.65-1.57(m,2H),1.19-1.10(m,2H).

[0331] N-(5-fluoropyrimidin-2-yl)-2-[1',1'-difluoro-6-(1-fluorocyclopropyl)-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]acetamide (second eluting isomer, 27): LCMS: m / z=421.1 [M+H] + . 1 H NMR(400 MHz,CDCl3): δ 8.76(br s,1H),8.48(s,2H),8.19(d,J=8.0 Hz,1H),7.12(d,J=8.0 Hz,1H),7.06(s,1H),5.14-4.98(m,1H),4.31(d,J=16.4 Hz,1H),4.21(dd,J=6.0,12.8 Hz,1H),3.44(d,J=13.2 Hz,1H),2.19-2.16(m,1H),1.72-1.69(m,1H),1.65-1.57(m,2H),1.19-1.10(m,2H).

[0332] Examples 28 and 29 N-(5-fluoropyrimidin-2-yl)-2-[6-cyclopropyl-1',1'-difluoro-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]acetamide (28 and 29) [ka] To a solution of 2-(6'-cyclopropyl-2,2-difluoro-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetic acid (50 mg, 0.16 mmol) in pyridine (2.0 mL) were added 5-fluoropyrimidin-2-amine (37 mg, 0.32 mmol) and EDCI (94 mg, 0.48 mmol). The reaction mixture was stirred at 20 °C for 2 hours. The reaction mixture was diluted with HO (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC and further purified by chiral SFC (Column: REGIS(s,s)WHELK-O1 (250 mm x 30 mm x 10 μm particle size); Mobile phase: A: CO B: 0.1% NH OH in EtOH; Gradient: B%: 50% isocratic; Flow rate: 70 g / min; Detection wavelength: 220 nm; Column temperature: 35° C., System back pressure: 120 bar) to give:

[0333] N-(5-fluoropyrimidin-2-yl)-2-[6-cyclopropyl-1',1'-difluoro-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]acetamide (first eluting isomer, 28): LCMS: m / z=403.1 [M+H] + . 1 H NMR(400 MHz,DMSO-d6): δ 10.95(s,1H),8.76(s,2H),7.82(d,J=8.0 Hz,1H),7.12(d,J=7.6 Hz,1H),7.01(s,1H),4.83(br d,J=17.2 Hz,1H),4.17(br d,J=17.2 Hz,1H),4.10(br dd,J=6.8,12.8 Hz,1H),3.34(br d,J=13.2 Hz,1H),2.73-2.62(m,1H),2.05-1.95(m,1H),1.94-1.84(m,1H),1.09-0.98(m,2H),0.87-0.72(m,2H).

[0334] N-(5-fluoropyrimidin-2-yl)-2-[6-cyclopropyl-1',1'-difluoro-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]acetamide (second eluting isomer, 29): LCMS: m / z=403.1 [M+H] + . 1 H NMR(400 MHz,DMSO-d6): δ 10.95(br s,1H),8.76(s,2H),7.82(d,J=8.0 Hz,1H),7.12(dd,J=1.2,8.0 Hz,1H),7.01(s,1H),4.83(br d,J=17.2 Hz,1H),4.17(br d,J=17.2 Hz,1H),4.10(br dd,J=6.8,13.2 Hz,1H),3.36(s,1H),2.73-2.63(m,1H),2.04-1.95(m,1H),1.94-1.84(m,1H),1.08-0.98(m,2H),0.87-0.73(m,2H).

[0335] Examples 30 and 31 N-([1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-[6-bromo-1',1',5-trifluoro-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]acetamide (30 and 31) [ka] To a solution of 2-[6-bromo-1',1',5-trifluoro-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]acetic acid (300 mg, 0.82 mmol) and [1,2,4]triazolo[1,5-a]pyridin-2-amine (221 mg, 1.65 mmol) in pyridine (6.0 mL) was added EDCI (315 mg, 1.65 mmol). The reaction mixture was stirred at 20 °C for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC and further purified by chiral SFC (Column: Chiralcel OD-3 (50 mm x 4.6 mm x 3 μm particle size); Mobile phase: A: CO B: 0.1% i-PrNH in MeOH; Gradient: B%: 40% isocratic; Flow rate: 3.4 mL / min; Detection wavelength: 220 nm; Column temperature: 35° C., System back pressure: 1800 psi) to give:

[0336] N-([1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-[6-bromo-1',1',5-trifluoro-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]acetamide (first eluting isomer, 30): LCMS: m / z = 480.0, 482.0 [M+H] + . 1 H NMR(400 MHz,CDCl3): δ 9.75(br s,1H),8.57(br d,J=6.4 Hz,1H),7.93(d,J=8.4 Hz,1H),7.74-7.60(m,2H),7.57-7.52(m,1H),7.04-7.00(m,1H),5.12 -3.84(m,3H),3.36-3.09(m,1H),3.04-2.84(m,1H),1.71-1.54(m,1H).

[0337] N-([1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-[6-bromo-1',1',5-trifluoro-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]acetamide (second eluting isomer, 31): LCMS: m / z = 480.0, 482.0 [M+H] + . 1 H NMR(400 MHz,CDCl3): δ 9.70(br s,1H),8.57(br d,J=6.8 Hz,1H),7.93(d,J=8.0 Hz,1H),7.73-7.61(m,2H),7.56-7.53(m,1H),7.03-7.00(m,1H),5.24 -3.71(m,3H),3.28-3.08(m,1H),2.96-2.91(m,1H),1.67-1.57(m,1H).

[0338] Examples 32 and 33 N-(5-methylpyrimidin-2-yl)-2-[6-bromo-1',1',5-trifluoro-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]acetamide (32 and 33) [ka] To a solution of methyl 2-(6'-bromo-2,2,5'-trifluoro-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetate (20 mg, 0.05 mmol) and 5-methylpyrimidin-2-amine (17 mg, 0.15 mmol) in DCE (1.0 mL) was added AlMe (1 M in n-heptane, 0.15 mL). The reaction mixture was stirred at 60 °C for 4 h. The reaction mixture was cooled to 0 °C, diluted with water (8 mL), and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC and further purified by chiral SFC (column: REGIS(s,s)WHELK-O1 (250 mm x 30 mm x 10 μm particle size); mobile phase: A: CO B: 0.1% NH OH in i-PrOH; gradient: B%: 50% isocratic; flow rate: 70 g / min; detection wavelength: 220 nm; column temperature: 35° C., system back pressure: 120 bar) to give:

[0339] N-(5-methylpyrimidin-2-yl)-2-[6-bromo-1',1',5-trifluoro-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]acetamide (first eluting isomer, 32): LCMS: m / z = 455.0, 456.9 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 8.69(br s,1H),8.43(s,2H),7.92(d,J=8.4 Hz,1H),7.73-7.57(m,1H),5.39(br s,1H),4.48(dd,J=6.8,19.6 Hz,1H),4.27(br d,J=17.2 Hz,1H),3.09(br d,J=12.8 Hz,1H),2.98-2.88(m,1H),2.28(s,3H),1.63(br s,1H).

[0340] N-(5-methylpyrimidin-2-yl)-2-[6-bromo-1',1',5-trifluoro-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]acetamide (second eluting isomer, 33): LCMS: m / z = 454.9, 456.9 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 8.73(br s,1H),8.43(s,2H),7.92(d,J=8.4 Hz,1H),7.63(dd,J=6.4,8.4 Hz,1H),5.48-5.24(m,1H),4.48(dd,J=6.8,13.2 Hz,1H),4.35-4.22(m,1H),3.09(br d,J=12.8 Hz,1H),2.99-2.87(m,1H),2.28(s,3H),1.59-1.55(m,1H).

[0341] Examples 34 and 35 N-(5-chloropyrimidin-2-yl)-2-[6-cyclopropyl-1',1',5-trifluoro-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]acetamide (34 and 35) [ka] To a mixture of 5-chloropyrimidin-2-amine (229 mg, 1.77 mmol) in DCE (6.0 mL) was added AlMe (1 M in n-heptane, 1.77 mL). The reaction mixture was stirred at 25 °C for 50 minutes, and then a solution of methyl 2-(6'-cyclopropyl-2,2,5'-trifluoro-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetate (300 mg, 0.88 mmol) in DCE (3.0 mL) was added. The reaction mixture was stirred at 80 °C for 5 hours, then heated to 100 °C and stirred for 5 hours. The mixture was diluted with water (20 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC and further purified by chiral SFC (Column: Chiralpak AD (250 mm x 30 mm x 10 μm particle size); Mobile phase: A: CO B: 0.1% NH OH in EtOH. Gradient: B%: 50% isocratic; Flow rate: 3.4 mL / min; Detection wavelength: 220 nm; Column temperature: 35° C., System back pressure: 1800 psi) to give:

[0342] N-(5-chloropyrimidin-2-yl)-2-[6-cyclopropyl-1',1',5-trifluoro-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]acetamide (first eluting isomer, 34): LCMS: m / z = 437.0, 439.0 [M+H] + . 1 H NMR(400 MHz,CDCl3): δ 11.04(s,1H),8.78(s,2H),7.72(d,J=8.0 Hz,1H),7.08(t,J=7.6 Hz,1H),4.87(br d,J=17.2 Hz,1H),4.24(br dd,J=7.2,13.6 Hz,1H),4.17(br d,J=17.2 Hz,1H),3.25(br d,J=13.6 Hz,1H),2.84(br t,J=10.4 Hz,1H),2.14-2.04(m,1H),2.04-1.93(m,1H),1.06-1.03(m,2H),0.89-0.71(m,2H).

[0343] N-(5-chloropyrimidin-2-yl)-2-[6-cyclopropyl-1',1',5-trifluoro-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]acetamide (second eluting isomer, 35): LCMS: m / z = 437.0, 439.0 [M+H] + . 1 H NMR(400 MHz,CDCl3): δ 11.04(s,1H),8.78(s,2H),7.72(d,J=8.0 Hz,1H),7.08(t,J=7.6 Hz,1H),4.87(br d,J=17.2 Hz,1H),4.24(br dd,J=7.2,13.2 Hz,1H),4.17(br d,J=17.2 Hz,1H),3.25(br d,J=13.2 Hz,1H),2.84(br t,J=10.4 Hz,1H),2.14-2.04(m,1H),2.04-1.93(m,1H),1.06-1.03(m,2H),0.89-0.71(m,2H).

[0344] Examples 36 and 37 N-(5-methylpyrimidin-2-yl)-2-[6-cyclopropyl-1',1',5-trifluoro-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]acetamide (36 and 37) [ka] To a mixture of 5-methylpyrimidin-2-amine (128 mg, 1.18 mmol) in DCE (5.0 mL) was added AlMe (1 M in n-heptane, 1.18 mL). The reaction mixture was stirred at 25 °C for 60 min, and then a solution of methyl 2-(6'-cyclopropyl-2,2,5'-trifluoro-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetate (200 mg, 0.59 mmol) in DCE (1.0 mL) was added. The reaction mixture was stirred at 80 °C for an additional 5 h. The mixture was diluted with water (30 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC and further purified by chiral SFC (Column: REGIS(s,s)WHELK-O1 (100 mm x 4.6 mm x 3 μm particle size); Mobile phase: A: CO B: 0.1% i-PrNH in EtOH; Gradient: B%: 40% isocratic; Flow rate: 4 mL / min; Detection wavelength: 220 nm; Column temperature: 35° C., System back pressure: 1800 psi) to give:

[0345] N-(5-methylpyrimidin-2-yl)-2-[6-cyclopropyl-1',1',5-trifluoro-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]acetamide (first eluting isomer, 36): LCMS: m / z=417.1 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 8.62(br s,1H),8.43(s,2H),7.92(d,J=8.0 Hz,1H),6.91(t,J=7.2 Hz,1H),5.35-5.12(m,1H),4.43(br dd,J=7.2,13.2 Hz,1H),4.25(br d,J=16.8 Hz,1H),3.09(br d,J=12.4 Hz,1H),3.02-2.91(m,1H),2.28(s,3H),2.16-2.07(m,1H),1.27(br d,J=2.8 Hz,1H),1.07(br d,J=8.4 Hz,2H),0.83-0.73(m,2H).

[0346] N-(5-methylpyrimidin-2-yl)-2-[6-cyclopropyl-1',1',5-trifluoro-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]acetamide (second eluting isomer, 37): LCMS: m / z=417.1 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 8.69(br s,1H),8.43(s,2H),7.92(d,J=8.0 Hz,1H),6.90(t,J=7.2 Hz,1H),5.36-5.10(m,1H),4.43(br dd,J=7.2,13.2 Hz,1H),4.25(br d,J=17.6 Hz,1H),3.09(br d,J=12.4 Hz,1H),2.97(br t,J=10.4 Hz,1H),2.28(s,3H),2.18-2.05(m,1H),1.26(br d,J=7.2 Hz,1H),1.11-1.01(m,2H),0.85-0.71(m,2H).

[0347] Examples 38 and 39 N-(5-chloropyrimidin-2-yl)-2-[1',1'-difluoro-6-(trifluoromethyl)-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]acetamide (38 and 39) [ka] To a mixture of 5-chloropyrimidin-2-amine (223 mg, 1.72 mmol) in DCE (1.0 mL) was added AlMe (1 M in n-heptane, 1.72 mL). The reaction mixture was stirred at 25 °C for 30 minutes, and then a solution of methyl 2-(2,2-difluoro-1'-oxo-6'-(trifluoromethyl)-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetate (200 mg, 0.57 mmol) in DCE (1.0 mL) was added. The reaction mixture was stirred at 90 °C for an additional 12 hours. The mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over anhydrous Na SO , filtered, and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC and further purified by chiral SFC (Column: Phenomenex Cellulose-2 (250 mm x 30 mm x 10 μm particle size); Mobile phase: A: CO B: 0.1% NH OH in EtOH; Gradient: B%: 35% isocratic; Flow rate: 65 g / min; Detection wavelength: 220 nm; Column temperature: 35° C., System back pressure: 120 bar) to give:

[0348] N-(5-chloropyrimidin-2-yl)-2-[1',1'-difluoro-6-(trifluoromethyl)-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]acetamide (first eluting isomer, 38): LCMS: m / z = 447.1, 449.0 [M+H] + . 1 H NMR(400 MHz,CDCl3): δ 8.55(s,2H),8.52(br s,1H),8.34(d,J=8.0 Hz,1H),7.71(d,J=8.4 Hz,1H),7.33(s,1H),5.31-5.16(m,1H),4.37(d,J=17.2 Hz,1H),4.23(dd,J=5.6,12.8 Hz,1H),3.46(d,J=12.8 Hz,1H),2.21-2.16(m,1H),1.81-1.77(m,1H).

[0349] N-(5-chloropyrimidin-2-yl)-2-[1',1'-difluoro-6-(trifluoromethyl)-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]acetamide (second eluting isomer, 39): LCMS: m / z = 447.0, 449.0 [M+H] + . 1 H NMR(400 MHz,CDCl3): δ 8.55(s,2H),8.54-8.48(m,1H),8.34(d,J=8.0 Hz,1H),7.71(d,J=8.4 Hz,1H),7.33(s,1H),5.34-5.15(m,1H),4.37(d,J=17.2 Hz,1H),4.23(dd,J=5.6,12.8 Hz,1H),3.46(d,J=13.6 Hz,1H),2.19-2.15(m,1H),1.81-1.77(m,1H).

[0350] Examples 40 and 41 N-(5-fluoropyrimidin-2-yl)-2-[1',1'-difluoro-6-(trifluoromethyl)-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]acetamide (40 and 41) [ka] To a mixture of 5-fluoropyrimidin-2-amine (233 mg, 2.06 mmol) in DCE (3.0 mL) was added AlMe (1 M in n-heptane, 2.29 mL). After the reaction mixture was stirred at 25 °C for 30 minutes, a solution of methyl 2-(2,2-difluoro-1'-oxo-6'-(trifluoromethyl)-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetate (400 mg, 1.15 mmol) in DCE (5.0 mL) was added. The reaction mixture was stirred at 85 °C for an additional 3 hours. The mixture was diluted with water (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (3 × 3 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC and further purified by chiral SFC (column: REGIS(s,s)WHELK-O1 (250 mm x 30 mm x 5 μm particle size); mobile phase: A: CO B: 0.1% NH OH in i-PrOH; gradient: B%: 30% to 50% in 15 min; flow rate: 3.4 mL / min; detection wavelength: 220 nm; column temperature: 35°C, system back pressure: 1800 psi) to give:

[0351] N-(5-fluoropyrimidin-2-yl)-2-[1',1'-difluoro-6-(trifluoromethyl)-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]acetamide (first eluting isomer, 40): LCMS: m / z=431.0 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 8.59(br s,1H),8.49(s,2H),8.34(d,J=8.4 Hz,1H),7.71(d,J=8.0 Hz,1H),7.33(s,1H),5.33-5.10(m,1H),4.35(br d,J=17.2 Hz,1H),4.24(dd,J=5.2,12.4 Hz,1H),3.47(d,J=13.2 Hz,1H),2.21-2.14(m,1H),1.83-1.76(m,1H).

[0352] N-(5-fluoropyrimidin-2-yl)-2-[1',1'-difluoro-6-(trifluoromethyl)-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]acetamide (second eluting isomer, 41): LCMS: m / z = 431.0 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 8.57(br s,1H),8.48(s,2H),8.34(d,J=8.0 Hz,1H),7.71(br d,J=8.0 Hz,1H),7.33(s,1H),5.33-5.11(m,1H),4.35(br d,J=17.2 Hz,1H),4.24(br dd,J=5.2,12.8 Hz,1H),3.47(br d,J=12.8 Hz,1H),2.21-2.14(m,1H),1.83-1.76(m,1H).

[0353] Example 42 2-(6-Bromo-1-oxo-spiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl)-N-(1H-pyrazolo[3,4-d]pyrimidin-6-yl)acetamide (42) [ka] To a solution of methyl 2-(6-bromo-1-oxo-spiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl)acetate (100 mg, 0.31 mmol) and 1H-pyrazolo[3,4-d]pyrimidin-6-amine (63 mg, 0.46 mmol) in DCE (1.0 mL) was added AlMe (1 M in n-heptane, 0.92 mmol). The reaction mixture was stirred at 90 °C for 3 h. The reaction mixture was diluted with HO (5 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 427.1, 429.1 [M+H] + . 1H NMR(400 MHz,DMSO-d6): δ 13.79(br s,1H),10.91(s,1H),9.18(s,1H),8.24(s,1H),7.82(d,J=8.4 Hz,1H),7.53(dd,J=1.6,8.4 Hz,1H),7.27(d,J=1.6 Hz,1H),4.61(s,2H),3.51(s,2H),1.19-1.14(m,2H),1.09-1.03(m,2H).

[0354] Example 43 2-[(2's,4r)-6-chloro-2',5-difluoro-1-oxospiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]-N-(5-chloropyrimidin-2-yl)acetamide (43) [ka] To a solution of 5-chloropyrimidin-2-amine (62 mg, 0.45 mmol) in DCE (5.0 mL) was added AlMe (1 M in n-heptane, 0.29 mL). The mixture was stirred for 0.5 h, and then methyl 2-[(2's,4r)-6-chloro-2',5-difluoro-1-oxo-spiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]acetate (30 mg, 0.09 mmol) was added. The mixture was stirred at 60 °C for an additional 5 h. The mixture was quenched with HO (10 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. LCMS:m / z=413.0,415.0,417.0[M+H] + . 1 H NMR (400 MHz, CDCl3): δ 11.02(br s,1H),8.78(s,2H),7.85-7.73(m,1H),7.61(dd,J=7.0,8.4 Hz,1H),5.67-5.41(m,1H),4.72(d,J=17.2 Hz,1H),4.40(d,J=17.2 Hz,1H),3.87-3.61(m,2H),1.89-1.79(m,1H),1.73-1.61(m,1H).

[0355] Example 44 2-[(2's,4r)-6-chloro-2',5-difluoro-1-oxospiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]-N-(5-methylpyrimidin-2-yl)acetamide (44) [ka] To a solution of methyl 2-[(2's,4r)-6-chloro-2',5-difluoro-1-oxo-spiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]acetate (40 mg, 0.13 mmol) in DCE (3.0 mL) was added 5-methylpyrimidin-2-amine (69 mg, 0.63 mmol) and AlMe (1 M in n-heptane, 0.38 mL). The mixture was stirred at 60 °C for 4 h. The mixture was quenched with HO (5 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 392.9, 395.0 [M+H] + . 1 H NMR(400 MHz,CDCl3): δ 10.72(s,1H),8.51(s,2H),7.80(d,J=8.6 Hz,1H),7.66-7.56(m,1H),5.69-5.42(m,1H),4.73(br d,J=17.2 Hz,1H),4.40(br d,J=17.2 Hz,1H),3.83-3.76(m,1H),3.71-3.64(m,1H),2.22(s,3H),1.89-1.78(m,1H),1.74-1.61(m,1H).

[0356] Example 45 2-[(2's,4r)-6-chloro-2',5-difluoro-1-oxospiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]-N-(1H-pyrazolo[3,4-d]pyrimidin-6-yl)acetamide (45) [ka] To a solution of 1H-pyrazolo[3,4-d]pyrimidin-6-amine (21 mg, 0.16 mmol) in toluene (1.0 mL) was added methyl 2-[(2's,4r)-6-chloro-2',5-difluoro-1-oxo-spiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]acetate (20 mg, 0.06 mmol) and AlMe3 (1 M in n-heptane, 0.19 mL). The mixture was stirred at 90 °C for 4 h. The mixture was quenched with HO (10 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 419.0, 421.0 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 9.07(s,1H),8.14(s,1H),7.98(d,J=8.4 Hz,1H),7.48-7.35(m,1H),5.51-5.14(m,2H),4.83-4.69(m,1H),4.02-3.66(m,2H),2.04-1.94(m,1H),0.93-0.78(m,1H).

[0357] Example 46 2-(6-bromo-5-fluoro-1-oxospiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl)-N-(1H-pyrazolo[3,4-d]pyrimidin-6-yl)acetamide (46) [ka] To a solution of methyl 2-(6-bromo-5-fluoro-1-oxospiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl)acetate (100 mg, 0.29 mmol) in DCE (1.5 mL) was added 1H-pyrazolo[3,4-d]pyrimidin-6-amine (59 mg, 0.44 mmol) and AlMe (1 M in n-heptane, 0.88 mL). The mixture was stirred at 90 °C for 3 h. The mixture was diluted with HO (10 mL) and extracted with EtOAc (3 × 3 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 445.0, 447.0 [M+H] + . 1 H NMR(400 MHz,DMSO-d6): δ 13.73(br s,1H),10.93(br s,1H),9.18(s,1H),8.24(s,1H),7.59-7.81(m,2H),4.61(s,2H),3.48(s,2H),1.44-1.52(m,2H),1.04-1.15(m,2H).

[0358] Examples 47 and 48 2-[(2's,4r)-2'-Fluoro-1-oxo-6-(trifluoromethyl)spiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]-N-(1H-pyrazolo[3,4-d]pyrimidin-6-yl)acetamide (47 and 48) [ka] To a solution of methyl 2-[(2's,4r)-2'-fluoro-1-oxo-6-(trifluoromethyl)spiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]acetate (200 mg, 0.61 mmol) and 1H-pyrazolo[3,4-d]pyrimidin-6-amine (122 mg, 0.91 mmol) in DCE (2.0 mL) was added AlMe (1 M in n-heptane, 1.81 mL). The reaction mixture was stirred at 90 °C for 5 h. The reaction mixture was diluted with HO (5 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase preparative HPLC and further purified by chiral SFC (column: REGIS(s,s)WHELK-O1 (250 mm x 30 mm, 10 μm particle size); mobile phase: A:CO B:i-PrOH; gradient: B%:50% isocratic; flow rate: 70 g / min; detection wavelength: 220 nm; column temperature: 35°C; system back pressure: 1800 psi) to give:

[0359] 2-[(2's,4r)-2'-fluoro-1-oxo-6-(trifluoromethyl)spiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]-N-(1H-pyrazolo[3,4-d]pyrimidin-6-yl)acetamide (first eluting isomer) (47): LCMS: m / z = 435.1 [M+H] + . 1 H NMR(400 MHz,CDCl3): δ 12.48(br s,1H),11.35(br s,1H),9.10(s,1H),8.34(d,J=8.0 Hz,1H),8.13(s,1H),7.67(d,J=8.0 Hz,1H),6.98(s,1H),5.54(br d,J=18.0 Hz,1H),4.83(br d,J=18.0 Hz,1H),4.80-4.58(m,1H),4.31(dd,J=1.6,12.4 Hz,1H),3.60(d,J=12.8 Hz,1H),1.77-1.68(m,1H),1.53-1.42(m,1H).

[0360] 2-[(2's,4r)-2'-fluoro-1-oxo-6-(trifluoromethyl)spiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]-N-(1H-pyrazolo[3,4-d]pyrimidin-6-yl)acetamide (second eluting isomer) (48): LCMS: m / z = 435.1 [M+H] + . 1 H NMR(400 MHz,CDCl3): δ 12.57(br s,1H),11.43(br s,1H),9.10(s,1H),8.34(d,J=8.0 Hz,1H),8.13(s,1H),7.66(br d,J=8.0 Hz,1H),6.98(s,1H),5.55(br d,J=17.6 Hz,1H),4.83(br d,J=18.0 Hz,1H),4.79-4.58(m,1H),4.31(br d,J=12.8 Hz,1H),3.60(br d,J=12.8 Hz,1H),1.79-1.67(m,1H),1.54-1.41(m,1H).

[0361] Examples 49 and 50 2-[(2's,4r)-2'-fluoro-1-oxo-6-(trifluoromethyl)spiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]-N-([1,2,4]triazolo[1,5-a]pyridin-2-yl)acetamide (49 and 50) [ka] To a solution of 2-[(2's,4r)-2'-fluoro-1-oxo-6-(trifluoromethyl)spiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]acetic acid (150 mg, 0.15 mmol) in pyridine (6.0 mL) was added [1,2,4]triazolo[1,5-a]pyridin-2-amine (127 mg, 0.31 mmol) and EDCI (181 mg, 0.32 mmol). The reaction mixture was stirred at 23°C for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC and further purified by chiral SFC (Column: REGIS(s,s)WHELK-O1 (250 mm x 30 mm, 5 μm particle size); Mobile phase: A: CO B: 0.1% i-PrNH in EtOH; Gradient: B%: 47% isocratic; Flow rate: 3.4 mL / min; Detection wavelength: 220 nm; Column temperature: 35°C, System back pressure: 1800 psi) to give:

[0362] 2-[(2's,4r)-2'-fluoro-1-oxo-6-(trifluoromethyl)spiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]-N-([1,2,4]triazolo[1,5-a]pyridin-2-yl)acetamide (first eluting isomer) (49): LCMS: m / z = 434.0 [M+H] + . 1 H NMR(400 MHz,DMSO-d6): δ11.07(br s,1H),8.85(d,J=6.8 Hz,1H),8.13(d,J=8.0 Hz,1H),7.75(d,J=8.0 Hz,1H),7.72-7.68(m,1H),7.67-7.62(m,1H),7.38(s,1H),7.13(dt,J=1.2,6.8 Hz,1H),5.28-5.05(m,1H),4.88-4.59(m,1H),4.48-4.19(m,1H),3.99(dd,J=1.2,12.8 Hz,1H),3.65(d,J=13.2 Hz,1H),1.87-1.82(m,1H),1.64-1.53(m,1H).

[0363] 2-[(2's,4r)-2'-Fluoro-1-oxo-6-(trifluoromethyl)spiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]-N-([1,2,4]triazolo[1,5-a]pyridin-2-yl)acetamide (second eluting isomer) (50): LCMS: m / z = 434.0 [M+H] + . 1 H NMR(400 MHz,DMSO-d6): δ 11.07(br s,1H),8.85(d,J=6.8 Hz,1H),8.13(d,J=8.0 Hz,1H),7.76(br d,J=8.0 Hz,1H),7.72-7.68(m,1H),7.67-7.61(m,1H),7.38(s,1H),7.14(t,J=6.8 Hz,1H),5.32-5.02(m,1H),4.90-4.24(m,2H),3.99(br d,J=12.8 Hz,1H),3.65(br d,J=12.8 Hz,1H),1.90-1.79(m,1H),1.65-1.52(m,1H).

[0364] Example 51 2-[1-oxo-6-(trifluoromethyl)spiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]-N-(1H-pyrazolo[3,4-d]pyrimidin-6-yl)acetamide (51) [ka] To a solution of 6-(trifluoromethyl)spiro[2,3-dihydroisoquinolin-4,1'-cyclopropan]-1-one (50 mg, 0.16 mmol) and 1H-pyrazolo[3,4-d]pyrimidin-6-amine (32 mg, 0.24 mmol) in DCE (2.0 mL) was added AlMe (1 M in n-heptane, 0.24 mL) at 15 °C. The reaction mixture was stirred at 60 °C for 4 h. The reaction mixture was cooled to 0 °C, diluted with HO (8 mL), and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 417.1 [M+H] + .1 H NMR(400 MHz,DMSO-d6): δ 13.56(br s,1H),10.93(br s,1H),9.18(s,1H),8.24(s,1H),8.10(d,J=8.0 Hz,1H),7.69(d,J=8.0 Hz,1H),7.38(s,1H),4.65(s,2H),3.56(s,2H),1.26-1.22(m,2H),1.13-1.09(m,2H).

[0365] Examples 52 and 53 2-[1',1'-difluoro-1-oxo-6-(trifluoromethyl)spiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]-N-(3-cis-hydroxy-3-methylcyclobutyl)acetamide (52 and 53) [ka] 2-(2,2-Difluoro-1'-oxo-6'-(trifluoromethyl)-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetic acid: To a solution of methyl 2-(2,2-difluoro-1'-oxo-6'-(trifluoromethyl)-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetate (200 mg, 0.57 mmol) in THF (2.0 mL) and HO (2.0 mL) was added LiOH·HO (48 mg, 1.15 mmol). The reaction mixture was stirred for 2 h. The reaction mixture was diluted with HO (20 mL) and washed with MTBE (20 mL). The aqueous layer was adjusted to pH = 3 with aqueous HCl (3 M) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give a residue which was used directly.

[0366] 2-[1',1'-Difluoro-1-oxo-6-(trifluoromethyl)spiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]-N-(3-cis-hydroxy-3-methylcyclobutyl)acetamide: To a solution of 2-(2,2-difluoro-1'-oxo-6'-(trifluoromethyl)-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetic acid (130 mg, 0.39 mmol) and 3-cis-amino-1-methylcyclobutanol HCl salt (80 mg, 0.58 mmol) in DMF (5.0 mL) was added DIPEA (150 mg, 1.16 mmol), HOBt (78 mg, 0.58 mmol), and EDCI (112 mg, 0.58 mmol). The reaction mixture was stirred at 23 °C for 2 hours. The reaction mixture was cooled to 0 °C, diluted with HO (5 mL), and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC and further purified by chiral SFC (column: REGIS(s,s)WHELK-O1 (250 mm × 30 mm, 5 μm particle size); mobile phase: A: CO B: 0.1% NH OH in i-PrOH; gradient: B%: 25% isocratic; flow rate: 70 g / min; detection wavelength: 220 nm; column temperature: 35 °C, system back pressure: 1800 psi) to give:

[0367] 2-[1',1'-difluoro-1-oxo-6-(trifluoromethyl)spiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]-N-(3-cis-hydroxy-3-methylcyclobutyl)acetamide (first eluting isomer) (52): LCMS: m / z = 419.1 [M+H] + . 1H NMR(400 MHz,CDCl3): δ 8.29(d,J=8.0 Hz,1H),7.71(d,J=8.0 Hz,1H),7.31(s,1H),6.53(br d,J=7.2 Hz,1H),4.29-4.26(m,1H),4.20-4.09(m,2H),3.99-3.95(m,1H),3.46(dd,J=0.8,13.2 Hz,1H),2.53-2.51(m,2H),2.23-2.18(m,2H),2.04(br t,J=9.6 Hz,2H),1.78-1.77(m,1H),1.37(s,3H).

[0368] 2-[1',1'-difluoro-1-oxo-6-(trifluoromethyl)spiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl]-N-(3-cis-hydroxy-3-methylcyclobutyl)acetamide (second eluting isomer) (53): LCMS: m / z = 419.1 [M+H] + . 1 H NMR(400 MHz,CDCl3): δ 8.29(d,J=8.0 Hz,1H),7.71(d,J=8.0 Hz,1H),7.31(s,1H),6.53(br d,J=7.2 Hz,1H),4.33-4.25(m,1H),4.16-4.12(m,2H),4.03-3.95(m,1H),3.46(dd,J=0.8,13.2 Hz,1H),2.53-2.51(m,2H),2.30(br s,1H),2.21-2.18(m,1H),2.06-2.01(m,2H),1.80-1.77(m,1H),1.37(s,3H).

[0369] Example 54 2-[(2'R,4S)-6-Bromo-2'-fluoro-1-oxospiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl]-N-(1H-pyrazolo[3,4-d]pyrimidin-6-yl)acetamide (54) [ka] To a solution of methyl 2-((1S,2R)-6'-bromo-2-fluoro-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetate (50 mg, 0.15 mmol, Int. 5) and 1H-pyrazolo[3,4-d]pyrimidin-6-amine (30 mg, 0.22 mmol) in DCE (1.0 mL) was added AlMe (1 M in n-heptane, 0.46 mL). The reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was diluted with HO (3 mL) and extracted with EtOAc (3 × 1 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 445.0, 447.0 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 12.28(br s,1H),11.04(br s,1H),9.08(s,1H),8.25-7.98(m,2H),7.54(dd,J=1.8,8.4 Hz,1H),6.88(d,J=1.6 Hz,1H),5.43(d,J=18.0 Hz,1H),4.93-4.47(m,2H),4.26(dd,J=1.4,12.6 Hz,1H),3.56(d,J=12.8 Hz,1H),1.68-1.61(m,1H),1.49-1.36(m,1H).

[0370] Example 55 2-(6-Bromo-1-oxospiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl)-N-(9H-purin-2-yl)acetamide (55) [ka] To a solution of methyl 2-(6-bromo-1-oxo-spiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl)acetate (100 mg, 0.31 mmol) and 9H-purin-2-amine (62 mg, 0.46 mmol) in DCE (2.0 mL) was added AlMe (1 M in n-heptane, 0.6 mL). The reaction was sealed and heated at 120 °C for 3 h. The reaction mixture was cooled to 23 °C, diluted with HO (5 mL), and extracted with EtOAc (3 × 3 mL). The combined organic layers were washed with brine (3 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 427.0, 429.0 [M+H] + . 1 H NMR(400 MHz,DMSO-d6): δ 10.62(br s,1H),8.91(s,1H),8.40(s,1H),7.82(d,J=8.4 Hz,1H),7.52(dd,J=1.6,8.3 Hz,1H),7.26(d,J=2.0 Hz,1H),4.58(br s,2H),3.51(s,2H),1.21-1.11(m,2H),1.09-1.01(m,2H).

[0371] Examples 56 and 57 2-(6-Bromo-1-oxospiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl)-N-(3-cyclopropyl-3-hydroxycyclobutyl)acetamide (56 and 57) [ka] To a solution of 3-amino-1-cyclopropylcyclobutanol HCl salt (211 mg, 1.29 mmol) and 2-(6-bromo-1-oxo-spiro[3H-isoquinoline-4,1′-cyclopropan]-2-yl)acetic acid (200 mg, 0.65 mmol) in DMF (2.0 mL) was added EDCI (186 mg, 0.97 mmol), HOBt (130 mg, 0.97 mmol), and DIPEA (416 mg, 3.22 mmol). The reaction mixture was stirred at 23° C. for 16 h. The reaction mixture was quenched with HO (2 mL) and extracted with EtOAc (3×2 mL). The combined organic layers were washed with brine (3×2 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC and further purified by chiral SFC (column Phenomenex-Cellulose-2 (250 mm x 30 mm, 5 μm particle size); mobile phase: A: CO B: 0.1% NH OH in MeOH; gradient: B%: 50% isocratic; flow rate: 70 mL / min; detection wavelength: 220 nm; column temperature: 35°C, system back pressure: 1800 psi) to give:

[0372] 2-(6-Bromo-1-oxospiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl)-N-(3-cyclopropyl-3-hydroxycyclobutyl)acetamide (first eluting isomer) (56): LCMS: m / z = 419.1, 421.1 [M+H] + . 1 H NMR(400 MHz,CDCl3): δ 7.98(d,J=8.2 Hz,1H),7.47(dd,J=1.8,8.3 Hz,1H),7.00(d,J=1.8 Hz,1H),6.54(br d,J=6.8 Hz,1H),4.14(s,2H),3.97-3.84(m,1H),3.46(s,2H),2.50-2.35(m,2H),1.98-1.90 (m,2H),1.16-1.08(m,3H),1.06-1.01(m,2H),0.57-0.44(m,2H),0.34-0.32(m,2H).

[0373] 2-(6-Bromo-1-oxospiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl)-N-(3-cyclopropyl-3-hydroxycyclobutyl)acetamide (second eluting isomer) (57): LCMS: m / z = 419.1, 421.1 [M+H] + . 1 H NMR(400 MHz,CDCl3): δ 7.98(d,J=8.4 Hz,1H),7.47(dd,J=1.8,8.4 Hz,1H),7.01(d,J=1.8 Hz,1H),6.53-6.38(m,1H),4.58-4.44(m,1H),4.13(s,2H),3.47(s,2H),2.38-2.27 (m,2H),1.89-1.77(m,2H),1.18-0.97(m,5H),0.53-0.40(m,2H),0.27-0.24(m,2H).

[0374] Example 58 2-(6-Bromo-1-oxospiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl)-N-[3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]acetamide (58) [ka] 6-Chloro-1-(tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidine: To a solution of 6-chloro-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidine (0.60 g, 2.70 mmol) and 3,4-dihydro-2H-pyran (453 mg, 5.39 mmol) in 1,4-dioxane (10 mL) was added p-TsOH·HO (512 mg, 2.70 mmol). The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was cooled to 0 °C, diluted with HO (10 mL), and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography.

[0375] 2-(6'-Bromo-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)-N-(1-(tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)acetamide: 6-chloro-1-(tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)acetamide in 1,4-dioxane (20 mL) To a solution of 2-(6-bromo-1-oxo-spiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl)acetamide (201 mg, 0.65 mmol), CsCO (531 mg, 1.63 mmol), Xantphos (113 mg, 0.2 mmol), and Pd(OAc) (30 mg, 0.13 mmol) were added. The reaction mixture was stirred at 70 °C for 3 h. The reaction mixture was poured into HO (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organics were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography.

[0376] 2-(6'-Bromo-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)-N-(3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)acetamide: To a solution of 2-(6'-bromo-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)-N-(1-(tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)acetamide (100 mg, 0.17 mmol) in DCM (10 mL) was added TFA (5.0 mL). The reaction mixture was stirred at 23 °C for 4 h. The reaction mixture was poured into saturated aqueous NaHCO3 (10 mL) and extracted with DCM (3 x 10 mL). The combined organics were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 495.0, 497.0 [M+H] + . 1H NMR(400 MHz,DMSO-d6): δ 14.55(br s,1H),11.11(s,1H),9.29(s,1H),7.82(d,J=8.4 Hz,1H),7.53(dd,J=1.6,8.4 Hz,1H),7.27(d,J=1.6 Hz,1H),4.61(s,2H),3.51(s,2H),1.21-1.14(m,2H),1.10-0.98(m,2H).

[0377] Example 59 2-(6-Bromo-1-oxospiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl)-N-[5-fluoro-1H-pyrazolo[3,4-b]pyridin-6-yl]acetamide (59) [ka] 2-(6'-Bromo-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)-N-(5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)acetamide: 2-(6-Bromo-1-oxo-spiro[3H-isoquinoline-4,1'-cyclopropane]-2 in THF (4.0 mL) To a solution of 6-bromo-5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine (146 mg, 0.49 mmol), CsCO (211 mg, 0.65 mmol), XPhos (15 mg, 0.03 mmol), and Pd(dba) (30 mg, 0.03 mmol) were added. The reaction mixture was stirred at 50 °C for 12 h. The reaction mixture was diluted with HO (10 mL) and extracted with EtOAc (3 × 3 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z = 528.0, 529.8 [M+H] + .

[0378] 2-(6-Bromo-1-oxospiro[3H-isoquinoline-4,1'-cyclopropane]-2-yl)-N-[5-fluoro-1H-pyrazolo[3,4-b]pyridin-6-yl]acetamide: To a solution of 2-(6'-bromo-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)-N-(5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)acetamide (50 mg, 0.09 mmol) in DCM (1.0 mL) was added TFA (770 mg, 6.75 mmol). The mixture was stirred at 23 °C for 1 hour. The mixture was diluted with saturated aqueous NaHCO (10 mL) and extracted with EtOAc (3 x 3 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. LCMS: m / z=444.0, 446.0 [M+H] + . 1 H NMR(400 MHz,CDCl3): δ 9.03(br s,1H),8.10-7.94(m,2H),7.77(d,J=9.6 Hz,1H),7.48(dd,J=8.4,2.0 Hz,1H),7.04-6.99(m,1H),4.62(s,2H),3.58(s,2H),1.17-1.12(m,2H),1.12-1.06(m,2H).

[0379] Example 60 Methyl 3-[[2-(6-bromo-1-oxospiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl)acetyl]amino]bicyclo[1.1.1]pentane-1-carboxylate (60) [ka] To a solution of 2-(6-bromo-1-oxo-spiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl)acetic acid (70 mg, 0.23 mmol) in DMF (2.0 mL) was added methyl 3-aminobicyclo[1.1.1]pentane-1-carboxylate hydrochloride (100 mg, 0.56 mmol), DIPEA (145 mg, 1.13 mmol), HOBt (49 mg, 0.36 mmol), and EDCI (69 mg, 0.36 mmol). The mixture was stirred at 23 °C for 2 h. The mixture was diluted with HO (10 mL) and extracted with EtOAc (3 × 3 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z = 433.0, 435.0 [M+H] + . 1 H NMR(400 MHz,CDCl3): δ 7.97(d,J=8.0 Hz,1H),7.47(dd,J=1.6,8.4 Hz,1H),7.01(d,J=2.0 Hz,1H),6.73(s,1H),4.11(s,2H),3.69(s,3H),3.46(s,2H),2.36(s,6H),1.16-1.09(m,2H),1.06-0.99(m,2H).

[0380] Example 61 N-(3H-Benzotriazol-5-yl)-2-(6-bromo-5-fluoro-1-oxospiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl)acetamide (61) [ka] To a solution of methyl 2-(6-bromo-5-fluoro-1-oxospiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl)acetate (50 mg, 0.15 mmol) in DCE (1.0 mL) was added 1H-benzo[d][1,2,3]triazol-6-amine (29 mg, 0.22 mmol) and AlMe (1 M in n-heptane, 0.24 mL). The mixture was stirred at 90 °C for 2 h. The mixture was quenched with HO (10 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 444.0 446.0 [M+H] + . 1 H NMR(400 MHz,DMSO-d6): δ 10.44(s,1H),8.31(s,1H),7.91(br d,J=7.8 Hz,1H),7.80-7.63(m,2H),7.39(br d,J=9.4 Hz,1H),4.38(s,2H),3.52(s,2H),1.61-1.45(m,2H),1.15-1.11(m,2H).

[0381] Example 62 2-(6-Bromo-5-fluoro-1-oxospiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl)-N-(9H-purin-2-yl)acetamide (62) [ka] To a solution of methyl 2-(6-bromo-5-fluoro-1-oxospiro[3H-isoquinoline-4,1'-cyclopropan]-2-yl)acetate (50 mg, 0.15 mmol) and 9H-purin-2-amine (30 mg, 0.22 mmol) in DCE (2.0 mL) was added AlMe (1 M in n-heptane, 0.3 mL). The reaction was sealed and heated at 120 °C for 3 h. The reaction mixture was cooled to 0 °C, diluted with HO (5 mL), and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 445.0, 447.0 [M+H] + . 1 H NMR(400 MHz,DMSO-d6): δ 10.72(s,1H),8.95(s,1H),8.45(s,1H),7.74-7.63(m,2H),4.58(br s,2H),3.47(s,2H),1.50-1.44(m,2H),1.12-1.09(m,2H).

[0382] Example 63 2-(6-Bromo-1',1'-difluoro-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl)-N-(1H-pyrazolo[3,4-d]pyrimidin-6-yl)acetamide (63) [ka] To a solution of methyl 2-(6'-bromo-2,2-difluoro-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetate (70 mg, 0.19 mmol) and 1H-pyrazolo[3,4-d]pyrimidin-6-amine (52 mg, 0.38 mmol) in DCE (2.0 mL) was added AlMe (1 M in n-heptane, 0.58 mL). The reaction mixture was stirred at 90 °C for 2 h. The reaction mixture was quenched with HO (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 463.0, 465.0 [M+H] + . 1 H NMR(400 MHz,DMSO-d6): δ 13.77(br s,1H),10.94(s,1H),9.18(s,1H),8.24(s,1H),7.89(d,J=8.4 Hz,1H),7.70(dd,J=1.6,8.4 Hz,1H),7.63(s,1H),5.00-4.30(m,2H),4.16(dd,J=6.8,13.2 Hz,1H),3.41(d,J=13.2 Hz,1H),2.86-2.76(m,1H),2.02-1.92(m,1H).

[0383] Examples 64 and 65 2-(6-Bromo-1',1'-difluoro-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl)-N-(1H-pyrazolo[3,4-d]pyrimidin-6-yl)acetamide (64 and 65) [ka] 2-(6-bromo-1′,1′-difluoro-1-oxospiro[3H-isoquinoline-4,2′-cyclopropan]-2-yl)-N-(1H-pyrazolo[3,4-d]pyrimidin-6-yl)acetamide (Example 62) could be further separated by chiral SFC (Column: DAICEL ChiralPak IG (250 mm×30 mm, 10 μm particle size); Mobile phase: A: CO; B: 0.1% i-PrNH in i-PrOH; Gradient: B%: 55% isocratic; Flow rate: 80 mL / min; Detection wavelength: 220 nm; Column temperature: 35° C., System back pressure: 100 bar) to give:

[0384] 2-(6-Bromo-1',1'-difluoro-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl)-N-(1H-pyrazolo[3,4-d]pyrimidin-6-yl)acetamide (first eluting isomer) (64): LCMS: m / z = 463.0, 465.0 [M+H] + . 1 H NMR(400 MHz,DMSO-d6): δ 13.80(br s,1H),10.94(s,1H),9.18(s,1H),8.23(s,1H),7.89(d,J=8.4 Hz,1H),7.70(dd,J=1.6,8.4 Hz,1H),7.63(s,1H),5.03-4.24(m,2H),4.16(dd,J=6.8,13.2 Hz,1H),3.41(br d,J=13.2 Hz,1H),2.87-2.75(m,1H),2.04-1.90(m,1H).

[0385] 2-(6-Bromo-1',1'-difluoro-1-oxospiro[3H-isoquinoline-4,2'-cyclopropan]-2-yl)-N-(1H-pyrazolo[3,4-d]pyrimidin-6-yl)acetamide (second eluting isomer) (65): LCMS: m / z = 463.0, 465.0 [M+H] + . 1H NMR(400 MHz,DMSO-d6): δ 13.77(br s,1H),10.93(s,1H),9.18(s,1H),8.24(s,1H),7.89(d,J=8.4 Hz,1H),7.70(dd,J=1.6,8.4 Hz,1H),7.63(s,1H),5.01-4.28(m,2H),4.16(dd,J=6.8,13.2 Hz,1H),3.41(br d,J=13.2 Hz,1H),2.88-2.75(m,1H),2.05-1.90(m,1H).

[0386] Biological Example 1 Biochemical assay of compounds THP-1 cell culture procedure The compounds provided herein were tested in the following assay. Cell culture medium containing RPMI 1640 medium (89%), FBS (10%), Pen / Strep (1%), and 2-mercaptoethanol (0.05 mM) was utilized. The freezing medium consisted of 90% FBS and 10% DMSO. THP-1 cells were removed from liquid nitrogen and placed in a 37°C water bath to thaw until all traces of 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. THP-1 cells were then split, cultured in cell culture medium, and passaged every 2–3 days. The cell density was adjusted to 5 × 10 5 ~1.5×10 6 Maintain viable cells / mL between 0.01 and 0.1.

[0387] For freezing, resuspend the cells in fresh freezing medium to a cell density of 5 x 10 6 The cell suspension was adjusted to 100 cells / mL. The cell suspension was dispensed into 1 mL aliquots 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.

[0388] Assay procedure for IL-1β secretion in 384-well plates PMA was dissolved in DMSO to make a 5 mg / mL stock solution and stored at -20°C in 10 μL aliquots for single use. PMA was added to normal growth medium. LPS was diluted with 1 mL of water to obtain a 1 mg / mL stock solution and 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. Serum-free medium contained RPMI 1640 medium (99%), Pen / Strep (1%), and 2-mercaptoethanol (0.05 mM). Two control conditions were used to quantify and normalize dose-response curves of test compounds: high control = 25 ng / mL LPS, 5 μM nigericin, 0.5% DMSO; low control = 25 ng / mL LPS, 0.5% DMSO.

[0389] Day 1: PMA-induced differentiation Dilute THP-1 cells to 1.0 x 10 6 The total volume of suspension was adjusted to obtain the desired number of assay plates, yielding a concentration of 100 cells / mL. PMA (5 ng / mL final concentration) was added to the growth medium, and the cells were incubated at 37°C in a humidified atmosphere of 5% CO for 40 hours.

[0390] Day 3: Plating with sequential stimulation of LPS and nigericin All media was carefully aspirated from each culture flask. The cells were carefully washed with 1x DPBS. The cells were then briefly digested with trypsin-LE at 23°C for 5 minutes and immediately resuspended in cell growth media. After resuspension, 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 media supplemented with LPS (final concentration 25 ng / mL), allowing 30K THP-1 cells in 45 μL of media to be dispensed into each well of a 384-well PDL-coated plate. The 384-well plate was then incubated at 37°C in a humidified atmosphere with 5% CO2 for 2 hours. Test compounds spanning the desired concentration range were then dispensed by Tecan. All wells were normalized to a final concentration of 0.5% DMSO. The plate was then incubated at 37°C in a humidified atmosphere with 5% CO2 for 1 hour. Five microliters of a 5 mg / mL nigericin stock solution was then added to each of the appropriate wells, and the plates were centrifuged at 1000 rpm for 30 seconds. The plates were immediately returned to a 37°C incubator in a humidified atmosphere of 5% CO2 for 2 hours. After this, 35 μL / well of supernatant was collected, transferred to a v-bottom plate, and centrifuged at 1000 rpm for 1 minute. Aliquots of these supernatants were analyzed using the IL-Iβ detection kit as described below. If necessary, test samples can also be flash frozen and stored at -80°C until analysis.

[0391] 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 following 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 for 1 hour at 23°C. After this, the blocking buffer was removed and discarded. Each ELISA plate was washed four times with PBST. During this time, the v-bottom plates containing the supernatant aliquots from the assay runs were centrifuged at 300 g for 5 minutes, after which 15 μL / well of the supernatant samples were transferred to each ELISA plate. Each ELISA plate was then incubated for 2 hours at 23°C. After this, the supernatant samples were removed and discarded. Each ELISA plate was washed four times with PBST. 15 μL / well of 0.5 μg / mL mAb 7P10-biotin (diluted 1:1000 in blocking buffer) was added to each ELISA plate. Each ELISA plate was then incubated at 23°C for 1 hour. After this, the antibody solution was removed and discarded. Each ELISA plate was washed four times with PBST. 20 μL / well of streptavidin-HRP (diluted 1:2000 in blocking buffer) was added to each ELISA plate. Each ELISA plate was then incubated at 23°C for 1 hour. After this, the buffer was removed and discarded. Each ELISA plate was washed four times with PBST. 20 μL / well of HRP substrate was added to each ELISA plate. Each ELISA plate was then incubated at 23°C for 2 minutes. After this, 40 μL / well of stop solution was added to each ELISA plate. Each ELISA plate was centrifuged at 1200 rpm for 30 seconds.

[0392] The plates were then read at 450 nm in a microplate reader. The percent inhibition was calculated as follows: % Inhibition = (treated sample - high control) / (low control - high control) x 100

[0393] The activity of the test compounds is shown in Table 3 below as follows: +++=IC 50 <1 μM; ++=IC 50 1–10 μM; += IC 50 >10 μM. [Table 3-1] [Table 3-2]

[0394] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0395] The embodiments illustratively described herein may suitably be practiced in the absence of any element(s) or limitation(ies) not specifically disclosed herein. Thus, for example, terms such as "comprising," "including," and "containing" should be read expansively and without limitation. Furthermore, the terms and phrases employed herein are used as terms of description and not of limitation, and no attempt is made in the use of such terms and phrases to exclude any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the claimed embodiments.

[0396] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety, as if each were individually incorporated by reference. In case of conflict, the present specification, including definitions, will control.

[0397] While the present disclosure has been described in connection with the above embodiments, it should be understood that the foregoing description and examples are intended to be illustrative, and not limiting, of the scope of the invention. Other aspects, advantages, and modifications within the scope of the present disclosure will be apparent to those skilled in the art to which this disclosure pertains.

Claims

1. 2. A compound selected from the following: or a pharma- ceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof: 【Table 1A-1】 【Table 1A-2】 【Table 1A-3】 【Table 1A-4】 【Table 1A-5】 【Table 1A-6】 【Table 1A-7】 【Table 1A-8】 【Table 1A-9】 【Table 1A-10】 【Table 1A-11】 【Table 1A-12】

2. 2. A compound selected from the following: or a pharma- ceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof: 【Table 4-1】 【Table 4-2】 【Table 4-3】 【Table 4-4】 【Table 4-5】 【Table 4-6】 【Table 4-7】 【Table 4-8】

3. A compound of formula I, 【Chemistry 99】 or a pharma- ceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein: X is C(X １ ), N.R. １６ , S(O) ２ , or S(O)(NR １８ ) and Y is C(Y １ ), O., N.R. １７ , S(O) ２ , or S(O)(NR １９ ) and Z is CR ８ or N, X １ But, O, NR １８ or S, Y １ But, O, NR １９ or S, A １ , A ２ , A ３ , and A ４ are each independently N, CH, or CR １ However, A １ , A ２ , A ３ , and A ４ At least one of the following is CR １ Provided that, Each R １ are independently halo, cyano, -NO ２ , -SF ５ , C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 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 each C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, or heteroaryl are independently selected from 1 to 8 Z １ or any two adjacent R １ together with the atoms to which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl ring, wherein said cycloalkyl, heterocyclyl, aryl, or heteroaryl are independently selected from 1 to 8 Z １ and optionally substituted with R ２ But, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, heteroaryl, -NO ２ , -SF ５ , -OR １１ , -N(R １１ ) 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 ) ２ , -NR １１ S (O) ０－２ N (R １１ ) ２ , -NR １１ C(O)N(R １１ ) ２ , -NR １１ C(O)OR １１ , -NR １１ C(O)R １１ , -OC(O)R １１ , -OC(O)N(R １１ ) ２ , -C(O)N(R １１ ) ２ , halo, or cyano, １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from 1 to 8 Z １ and optionally substituted with R ３ is hydrogen, halo, cyano, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from 1 to 8 Z １ or R ２ and R ３ Together, C ３－１０ Forms a cycloalkyl or heterocyclyl ring, wherein said C ３－１０ Cycloalkyl or heterocyclyl is 1 to 8 Z １ and optionally substituted with R ４ is hydrogen, halo, -NO ２ , cyano, hydroxy, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, 5- to 6-membered heteroaryl, -OR １４ , -N(R １４ ) ２ , or -S(O) ０－２ R １４ wherein said C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl is selected from the group consisting of 1 to 5 halo, hydroxy, -SH, -NH ２ , -NO ２ , C １－６ Alkyl, C １－６ Alkoxy or C １－６ optionally substituted with haloalkyl; R ５ is hydrogen, halo, -NO ２ , cyano, hydroxy, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, 5- to 6-membered heteroaryl, -OR １４ , -N(R １４ ) ２ , or -S(O) ０－２ R １４ wherein said C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl is selected from the group consisting of 1 to 5 halo, hydroxy, -SH, -NH ２ , -NO ２ , C １－６ Alkyl, C １－６ Alkoxy or C １－６ optionally substituted with haloalkyl, or R ４ and R ５ taken together form a heterocyclyl or heteroaryl, wherein said heterocyclyl or heteroaryl is selected from 1 to 5 halo, hydroxy, -SH, -NH ２ , -NO ２ , C １－６ Alkyl, C １－６ Alkoxy or C １－６ optionally substituted with haloalkyl; R ６ is hydrogen, halo, cyano, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ２－６ Heteroalkyl, C ３－１０ cycloalkyl, or heterocyclyl, １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ２－６ Heteroalkyl, C ３－１０ The cycloalkyl or heterocyclyl may further comprise 1 to 5 Z １ｂ may be optionally substituted with R ７ is hydrogen, halo, cyano, hydroxy, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ２－６ Heteroalkyl, C ３－１０ cycloalkyl, or heterocyclyl, １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ２－６ Heteroalkyl, C ３－１０ The cycloalkyl or heterocyclyl may further comprise 1 to 5 Z １ｂ or Or R ６ and R ７ is bonded to C ３－１０ Forms a cycloalkyl or heterocyclyl ring, wherein said C ３－１０ The cycloalkyl or heterocyclyl ring may further comprise 1 to 5 Z １ｂ may be optionally substituted with R ８ is hydrogen, halo, cyano, C １－６ Alkyl or C １－６ is haloalkyl, R ９ and R １０ each independently represents hydrogen, halo, cyano, C １－６ Alkyl or C １－６ haloalkyl, each C １－６ Alkyl or C １－６ haloalkyl is independently 1 to 5 Z １ or R ９ and R １０ Together, C ３－１０ Forms a cycloalkyl or heterocyclyl ring, wherein said C ３－１０ Cycloalkyl or heterocyclyl is 1 to 8 Z １ and optionally substituted with Each Z １ are independently halo, cyano, -NO ２ , -SF ５ , C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 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 each C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, or heteroaryl are independently selected from 1 to 5 Z １ａ and optionally substituted with Each R １１ are independently hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl, each C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, or heteroaryl are independently selected from 1 to 5 Z １ａ and optionally substituted with R １２ is hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from 1 to 8 Z １ and optionally substituted with Each Z １ａ are independently hydroxy, halo, cyano, -NO ２ , -SF ５ , C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R １３ ) ２ , -OR １３ , -C(O)R １３ , -C(O)OR １３ , -S(O) ０－２ R １３ , -NR １３ S (O) ０－２ R １３ , -S(O) ０－２ N (R １３ ) ２ , -NR １３ S (O) ０－２ N (R １３ ) ２ , -NR １３ C(O)N(R １３ ) ２ , -C(O)N(R １３ ) ２ , -NR １３ C(O)R １３ , -OC(O)N(R １３ ) ２ , or -NR １３ C(O)OR １３ and each C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, or heteroaryl are independently selected from 1 to 5 Z １ｂ and optionally substituted with Each R １３ are independently hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl, each C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, or heteroaryl are independently selected from 1 to 5 Z １ｂ and optionally substituted with Each R １４ are independently hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－６ cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, each C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl may be selected from the group consisting of 1-5 halo, hydroxy, -SH, -NH ２ , -NO ２ , C １－６ Alkyl, C １－６ Alkoxy or C １－６ optionally substituted with haloalkyl; R １６ is hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl, each C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, or heteroaryl are independently selected from 1 to 5 Z １ｂ and optionally substituted with R １７ is hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl, each C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, or heteroaryl are independently selected from 1 to 5 Z １ｂ and optionally substituted with R １８ is hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl, each C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, or heteroaryl are independently selected from 1 to 5 Z １ｂ and optionally substituted with R １９ is hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl, each C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, or heteroaryl are independently selected from 1 to 5 Z １ｂ and optionally substituted with Each Z １ｂ are 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 ３－１０ Cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C １－６ Alkyl, -L-C ２－６ Alkenyl, -L-C ２－６ Alkynyl, -L-C １－６ Haloalkyl, -L-C ３－１０ 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 alkynyl)-, -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 alkynyl)-, -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 NH-, Z １ｂ and each C of L １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, or heteroaryl may further independently be selected from 1 to 5 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 The compound, or a pharma- ceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, optionally substituted with cycloalkyl, heterocyclyl, aryl, or heteroaryl.

4. 4. The compound of claim 3, represented by formula IC, or a pharma- ceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof. 【Chemistry 100】

5. R ９ and R １０ The compound according to claim 3 or 4, wherein is hydrogen.

6. R １２ is hydrogen, R ６ is hydrogen, R ７ The compound according to any one of claims 3 to 5, wherein is hydrogen.

7. Represented by formula VII: 【Chemistry 101】 4. The compound of claim 3, wherein p is 1, 2, 3, or 4.

8. Represented by formula VIII: 【Chemistry 102】 4. The compound of claim 3, or a pharma- ceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein q is 0, 1, 2, 3, or 4.

9. 4. The compound of claim 3 represented by formula VIIIA, or a pharma- ceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof. 【Chemistry 103】

10. R １ But, halo, cyano, C １－６ Alkyl, C １－６ Alkoxy, or C １－６ The compound according to any one of claims 3 to 9, which is haloalkyl.

11. R １ The compound according to any one of claims 3 to 10, wherein is halo.

12. R ４ The compound according to any one of claims 3 to 11, wherein is hydrogen.

13. R ５ is hydrogen or C １－６ The compound according to any one of claims 3 to 12, which is haloalkyl.

14. R ５ is hydrogen or -CF ３ The compound according to any one of claims 3 to 13,

15. 15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof, and a pharma- ceutically acceptable carrier.

16. A method for treating a disease or condition mediated at least in part by NLRP3, comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition of claim 15.

17. 17. The method of claim 16, wherein the disease or condition is Alzheimer's disease, atherosclerosis, asthma, allergic airway inflammation, cryopyrin-associated periodic syndrome, gout, inflammatory bowel disease and related disorders, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), hypertension, myocardial infarction, multiple sclerosis, experimental autoimmune encephalitis, oxalate-induced nephropathy, hyperinflammation after influenza infection, graft-versus-host disease, stroke, silicosis, type 1 diabetes, obesity-induced inflammation or insulin resistance, rheumatoid arthritis, myelodysplastic syndrome, contact hypersensitivity, chikungunya virus-induced joint inflammation, or traumatic brain injury.

18. 17. The method of claim 16, wherein the disease is nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH).

19. 17. The method of claim 16, wherein the disease is Alzheimer's disease.

20. 15. Use of a compound according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof, for treating a disease or condition mediated at least in part by NLRP3.

21. 21. The use of claim 20, wherein the disease or condition is Alzheimer's disease, atherosclerosis, asthma, allergic airway inflammation, cryopyrin-associated periodic syndrome, 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, hyperinflammation after influenza infection, graft-versus-host disease, stroke, silicosis, type 1 diabetes, obesity-induced inflammation or insulin resistance, rheumatoid arthritis, myelodysplastic syndrome, contact hypersensitivity, chikungunya virus-induced joint inflammation, or traumatic brain injury.

22. 15. A compound according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof, for use in therapy.

23. 15. A compound according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof, for use in the treatment of Alzheimer's disease.

24. 15. A compound according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof, for use in treating non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).

25. 15. Use of a compound according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof, for the manufacture of a medicament for treating neurodegenerative diseases, treating Alzheimer's disease, atherosclerosis, asthma, allergic airway inflammation, cryopyrin-associated periodic syndrome, 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, hyperinflammation following influenza infection, graft versus host disease, stroke, silicosis, type 1 diabetes, obesity-induced inflammation or insulin resistance, rheumatoid arthritis, myelodysplastic syndrome, contact hypersensitivity, joint inflammation caused by chikungunya virus, or traumatic brain injury.

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