Compounds, compositions and methods

Abstract

The present disclosure relates generally to small molecule modulators comprising the NLR family Pyrin domain 3 (NLRP3), or pharmaceutically acceptable salts, isotope enriched analogs, stereoisomers, stereoisomer mixtures, or prodrugs thereof; processes for their preparation and intermediates; and methods of use thereof.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 325,577 filed on March 30, 2022 and U.S. Provisional Application No. 63 / 346,203 filed on May 26, 2022 under 35 U.S.C. §119(e), the contents of which are hereby incorporated by reference in their entirety. Technical Field

[0003] The present disclosure generally relates to small molecule modulators of NLR family Pyrin domain containing 3 (NLRP3), and their use as therapeutic agents. Background Art

[0004] In animal models of inflammatory diseases, inhibition of NLRP3 activation has been shown to produce potent therapeutic effects. NLRP3 modulators, especially inhibitors, have broad therapeutic potential in a wide variety of autoinflammatory and chronic inflammatory diseases that require better treatment options or do not yet have appropriate therapies. Therapies targeting NLRP3-dependent cytokines have been approved for therapeutic use; however, the therapies have significant disadvantages relative to direct NLRP3 antagonists. The industry is still in urgent need of discovering and clinically developing molecules that antagonize NLRP3. Summary of the invention

[0005] Provided herein are compounds or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof that are useful for treating and / or preventing diseases mediated at least in part by NLRP3.

[0006] In some embodiments, compounds that modulate the activity of NLRP3 are provided. In some embodiments, the compound inhibits the activation of NLRP3.

[0007] In another embodiment, a pharmaceutical composition is provided, comprising a compound as described herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof and a pharmaceutically acceptable carrier.

[0008] In another embodiment, a method for treating a disease or condition mediated at least in part by NLRP3 is provided, the method comprising administering an effective amount of a pharmaceutical composition comprising a compound as described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0009] In another embodiment, a method for treating a disease or disorder mediated at least in part by TNF-α is provided, the method comprising administering an effective amount of a pharmaceutical composition comprising a compound as described herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomer mixture, or prodrug thereof. In some embodiments, administration is to a subject resistant to treatment with an anti-TNF-α agent. In some embodiments, the disease is an intestinal disease or disorder. In some embodiments, the disease or disorder is inflammatory bowel disease, Crohn's disease, or ulcerative colitis.

[0010] The present disclosure also provides compositions, including pharmaceutical compositions; kits comprising a compound or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof; methods of using (or administering) and preparing the compound or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof; and intermediates thereof.

[0011] 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.

[0012] In addition, 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 combination thereof, for the manufacture of a medicament for treating a disease, disorder or condition mediated at least in part by NLRP3.

[0013] The description herein sets forth exemplary embodiments of the present technology. However, it should be recognized that this description is not intended as a limitation on the scope of the present disclosure, but is provided as an illustration of exemplary embodiments.

[0014] 1. Definition

[0015] As used in this specification, the following words, phrases and symbols are generally intended to have the meanings as set forth below, unless otherwise indicated by the context in which they are used.

[0016] A dash ("-") that is not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -C(O)NH2 is attached via a carbon atom. Dashes at the front or end of a chemical group are for convenience; a chemical group may be drawn with or without one or more dashes without losing its ordinary meaning. Wavy or dotted lines drawn along a straight line in a structure indicate a designated point of attachment for a group. Unless chemically or structurally required, the order in which chemical groups are written or named does not indicate or imply any directionality or stereochemistry.

[0017] The prefix "C u-v " indicates that the following group has u to v carbon atoms. For example, "C 1-6 "Alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

[0018] Mentioning "about" a numerical value or parameter in this article includes (and describes) embodiments about the numerical value or parameter itself. In certain embodiments, the term "about" includes an indication of ±10%. In other embodiments, the term "about" includes an indication of ±5%. In certain other embodiments, the term "about" includes an indication of ±1%. The term "about X" also includes an explanation of "X". Unless the context clearly indicates otherwise, the singular forms "a", "an" and "the" also include plural indicators. Therefore, for example, reference to "compound" includes a plurality of such compounds, and reference to "assay" includes reference to one or more assays known to those skilled in the art and their equivalents.

[0019] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, an alkyl group has 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 1-4 Alkyl). Examples of alkyl 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 particular number of carbons is named by a chemical name or identified by a molecular formula, all positional isomers having that number of carbons are contemplated; 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).

[0020] Certain commonly used alternative chemical names may be used. For example, divalent groups such as divalent "alkyl", divalent "aryl", divalent heteroaryl, etc. may also be referred to as "alkylene" or "alkylenyl" (e.g., methylene, ethylene, and propylene), "arylene" or "arylenyl" (e.g., phenylene or naphthylene, or heteroarylene quinolyl), respectively. Likewise, unless otherwise expressly indicated, when a combination of groups is referred to herein as a moiety (e.g., arylalkyl or aralkyl), the last-mentioned group contains the atoms that connect the moiety to the rest of the molecule.

[0021] "Alkenyl" refers to a group containing at least one (e.g., 1-3 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 2-4 Examples of the alkenyl group include, for example, ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0022] "Alkynyl" refers to a group containing at least one (e.g., 1-3 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 those groups having one triple bond and one double bond.

[0023] “Alkoxy” refers to the group “alkyl-O—.” Examples of alkoxy include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

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

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

[0026] "Acylamide" refers to a "C-acylamide" (which refers to the group -C(O)NR y R z ) and "N-amido" (which refers to the group -NR y C(O)R z ) Both, where R 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 Together they form a cycloalkyl or heterocyclyl; each of which may be optionally substituted as defined herein.

[0027] "Amino" refers to the group -NR y R z , where R 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.

[0028] "Carbamimidyl" refers to -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 may be optionally substituted as defined herein.

[0029] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic) including fused systems. As used herein, an aryl group has 6 to 20 ring carbon atoms (i.e., C 6-20 Aryl), 6 to 12 carbon ring atoms (i.e. C 6-12 Aryl) or 6 to 10 carbon ring atoms (i.e. C 6-10 The term "aryl" refers to a group which is fused to a heteroaryl group. The term "aryl" refers to a group which is fused to a heterocyclyl group. The term "aryl" refers to a group which is fused to a cycloalkyl group. The term "aryl" refers to a group which is fused to a cycloalkyl group. The term "aryl" refers to a group which is fused to a cycloalkyl group. The term "aryl" refers to a group which is fused to a heterocyclyl group. The term "aryl" refers to a group which is fused to a cycloalkyl group. The term "aryl" refers to a group which is fused to a cycloalkyl group.

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

[0031] "Carbamyl" refers to "O-carbamyl" (which refers to the group -OC(O)NR y R z ) and "N-carbamyl" (which refers to the group -NR y C(O)OR z ) Both, where R 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.

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

[0033] "Cyanoalkyl" refers to an alkyl group as defined above in which one or more (eg, 1 or 2) hydrogen atoms are replaced by a cyano group (-CN).

[0034] "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" includes cycloalkenyl groups (i.e., cyclic groups having at least one double bond) and cycloalkenyl groups having at least one sp 3 As used herein, a cycloalkyl group has 3 to 20 ring carbon atoms (i.e., C 3-20 Cycloalkyl), 3 to 14 ring carbon atoms (i.e., C 3-12 Cycloalkyl), 3 to 12 ring carbon atoms (i.e. C 3-12 Cycloalkyl), 3 to 10 ring carbon atoms (i.e. C 3-10 Cycloalkyl), 3 to 8 ring carbon atoms (i.e. C 3-8 Cycloalkyl) or 3 to 6 ring carbon atoms (i.e. C 3-6Cycloalkyl). 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, etc. In addition, the term cycloalkyl is intended to encompass any non-aromatic ring that may be fused to an aryl ring, regardless of the connection to the rest of the molecule. In addition, when there are two substitution positions on the same carbon atom, cycloalkyl also includes "spirocycloalkyl", such as spiral [2.5] octanyl, spiral [4.5] decyl or spiral [5.5] undecyl.

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

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

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

[0038] "Halogen" or "halo" refers to an atom occupying Group VIIA of the periodic table, such as fluorine, chlorine, bromine or iodine.

[0039] "Haloalkyl" refers to an unbranched or branched alkyl group as defined above, in which one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by halogen. For example, if the residue is substituted by 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 groups substituted by two ("di") or three ("tri") halogen groups, which may be (but 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, etc.

[0040] "Haloalkoxy" refers to an alkoxy group as defined above wherein one or more (eg, 1 to 6 or 1 to 3) of the hydrogen atoms are replaced by a halogen.

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

[0042] "Heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms), excluding any terminal carbon atoms, are each independently replaced by the same or different heteroatom groups, provided that the point of attachment to the rest of the molecule is through a carbon atom. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon and heteroatoms. For example, 1, 2, or 3 carbon atoms may be independently replaced by the same or different heteroatom groups. Heteroatom groups include, but are not limited to, -NR y -, -O-, -S-, -S(O)-, -S(O)2-, etc., where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted as defined herein. Examples of heteroalkyl include, for example, ethers (e.g., -CH2OCH3, -CH(CH3)OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, etc.), thioethers (e.g., -CH2SCH3, -CH(CH3)SCH3, -CH2CH2SCH3, -CH2CH2SCH2CH2SCH3, etc.), sulfones (e.g., -CH2S(O)2CH3, -CH(CH3)S(O)2CH3, -CH2CH2S(O)2CH3, -CH2CH2S(O)2CH2CH2OCH3, etc.) and amines (e.g., -CH2NR y CH3, -CH(CH3)NR y CH3, -CH2CH2NR y CH3, -CH2CH2NR y CH2CH2NR y CH3, etc., where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may 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 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0043] "Heteroaryl" refers to an aromatic group having a single ring or multiple fused rings, wherein one or more ring heteroatoms are independently selected from nitrogen, oxygen and sulfur. As used herein, a heteroaryl group includes 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 carbon ring atoms (i.e. C 3-8In some cases, the heteroaryl group includes a 5-10 membered ring system, a 5-7 membered ring system, or a 5-6 membered ring system, each of which independently has 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom, and the ring heteroatoms are independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, for example, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl / benzothiophenyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxopyridinyl, 1-oxopyrimidinyl, 1-oxopyrazinyl, 1-oxopyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolyl, quinuclidine, isoquinolyl, thiazolyl, thiadiazolyl, thiophenyl (i.e., thienyl), triazolyl, tetrazolyl, and triazinyl. Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolyl, isoquinolyl, 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 one of the rings of the fused system. Any aromatic ring containing at least one heteroatom, with single or multiple fused rings, is considered a heteroaryl, regardless of attachment to the rest of the molecule (i.e., attachment via any of the fused rings). Heteroaryl does not encompass or overlap with aryl as defined above.

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

[0045] "Heterocyclyl" refers to a saturated or partially unsaturated cyclic alkyl group, wherein one or more ring heteroatoms are independently selected from nitrogen, oxygen and sulfur. The term "heterocyclyl" includes heterocycloalkenyl (i.e., a heterocyclyl having at least one double bond), bridged heterocyclyl, fused heterocyclyl and spiro heterocyclyl. The heterocyclyl group may be a single ring or multiple rings, wherein multiple rings may be fused, bridged or spiro-connected, and may contain one or more (e.g., 1 to 3) oxo (=O) or N-oxide (-O -) moiety. Non-aromatic rings containing at least one heteroatom are considered heterocyclic groups regardless of attachment (i.e., attachment via a carbon atom or a heteroatom). In addition, the term heterocyclic group is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring may be fused to a cycloalkyl, aryl, or heteroaryl ring, regardless of attachment to the rest of the molecule. As used herein, a heterocyclic group has from 2 to 20 ring carbon atoms (i.e., C 2-20 heterocyclic group), 2 to 12 ring carbon atoms (i.e., C 2-12 heterocyclic group), 2 to 10 ring carbon atoms (i.e., C 2-10 heterocyclic group), 2 to 8 ring carbon atoms (i.e., C 2-8 heterocyclic group), 3 to 12 ring carbon atoms (i.e., C 3-12 heterocyclic group), 3 to 8 ring carbon atoms (i.e., C 3-8 heterocyclic group) or 3 to 6 ring carbon atoms (i.e. C 3-6 heterocyclic radical); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms or 1 ring heteroatom, the ring heteroatoms being independently selected from nitrogen, sulfur or oxygen. Examples of heterocyclic radicals include, for example, azetidinyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxazoline, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolyl, indolizinyl, isoindolyl, isothiazolidinyl, isoxazolidine 1,1-dioxo- ... Examples of spiroheterocyclyl rings include, for example, bicyclic and tricyclic ring systems such as oxabicyclo[2.2.2]octanyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of 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, wherein the heterocyclyl may be attached via either ring of the fused system.

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

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

[0048] "Sulfonyl" refers to the group -S(O)2R y , where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted as defined herein. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl and toluenesulfonyl.

[0049] "Sulfinyl" refers to the group -S(O)R y , where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted as defined herein. Examples of sulfinyl are methylsulfinyl, ethylsulfinyl, phenylsulfinyl and toluenesulfinyl.

[0050] "Sulfonamide" refers to the group -SO2NR y R z and-NR y S02R z , where R y and R z Each is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted as defined herein.

[0051] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes instances where the event or circumstance occurs and instances where the event or circumstance does not occur. Similarly, the term "optionally substituted" means that any one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms on the designated atom or group may or may not be replaced by a moiety other than hydrogen.

[0052] The term "substituted" as used herein refers to any of the above groups (i.e., alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl and / or heteroalkyl) in which at least one (e.g., 1 to 5 or 1 to 3) hydrogen atom is replaced by a bond to a non-hydrogen atom, such as, but not limited to, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl, aralkyl, azido, carbamoyl, carboxyl alkyl, -S(O)OH, -S(O)OH, sulfonamide, thiol, thioxo, N-oxide, or -Si(R)2. y )3, where each R y and R is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl.

[0053] In certain embodiments, "substituted" includes any of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are independently replaced by deuterium, halo, cyano, nitro, azido, oxo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR g R h 、-NR g C(O)R h 、-NR g C(O)NR g R h 、-NR g C(O)OR h 、-NR g S(O) 1-2 R h 、-C(O)R g 、-C(O)OR g 、-OC(O)OR g 、-OC(O)R g 、-C(O)NR g R h 、-OC(O)NR g R h 、-OR g 、-SR g 、-S(O)R g 、-S(O)2R g 、-OS(O) 1-2R 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 In certain embodiments, "substituted" also means any of the above groups, wherein one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are replaced by -C(O)R g 、-C(O)OR g 、-C(O)NR g R h 、-CH2SO2R g or -CH2SO2NR g R h In the previous text, R g With R h R is the same or different and is independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, sulfanyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and / or heteroarylalkyl. In certain embodiments, "substituted" also means any of the above groups, wherein one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are replaced by a bond connected to an amino, cyano, hydroxyl, imino, nitro, oxo, sulfo, halo, alkyl, alkoxy, alkylamino, sulfanyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl and / or heteroarylalkyl; or R g and R h and R i The two of the are taken together with the atoms to which they are attached to form a heterocyclyl ring optionally substituted with oxo, halo, or alkyl optionally substituted with oxo, halo, amino, hydroxy, or alkoxy.

[0054] It is not intended herein to include polymers or similar indefinite structures obtained by defining substituents with infinitely additional other substituents (e.g., substituted aryl with substituted alkyl, which is itself substituted by substituted aryl, which is further substituted by substituted heteroalkyl, etc.). Unless otherwise noted, the maximum number of consecutive substitutions in the compounds described herein is 3. For example, the consecutive substitution of substituted aryl by two other substituted aryl groups is limited to aryl substituted by ((substituted aryl) substituted aryl). Similarly, the above definition is not intended to include unauthorized substitution patterns (e.g., methyl substituted by 5 fluorines or heteroaryl with two adjacent oxygen ring atoms). Such unauthorized substitution patterns are well known to those skilled in the art. When used to modify a chemical group, the term "substituted" can describe other chemical groups defined herein.

[0055] In certain embodiments, as used herein, the phrase "one or more" refers to one to five. In certain embodiments, as used herein, the phrase "one or more" refers to one to three.

[0056] Any compound or structure given herein is also intended to represent unlabeled forms of the compound as well as isotopically labeled forms. These forms of the compound may also be referred to as "isotopically enriched analogs." Isotopically labeled compounds have structures depicted herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that may be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, e.g., 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 36 Cl, 123 I and 125 I. Various isotope-labeled compounds of the present disclosure, such as radioactive isotopes such as 3 H and 14 Such isotopically labeled compounds are useful in metabolic studies, reaction kinetic studies, detection or imaging techniques (e.g., positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays), or radiotherapy of patients.

[0057] The term "isotopically enriched analogs" includes "deuterated analogs" of the compounds described herein, in which one or more hydrogens are replaced by deuterium, such as hydrogens on carbon atoms. Such compounds exhibit increased resistance to metabolism when administered to mammals (particularly humans), and can therefore be used to extend the half-life of any compound. For example, see Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sci. 5(12): 524-527 (1984). Such compounds are synthesized by methods well known in the art, for example by using starting materials in which one or more hydrogens are replaced by deuterium.

[0058] The therapeutic compounds of the present disclosure labeled or substituted with deuterium may have improved DMPK (drug metabolism and pharmacokinetics) properties related to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may provide certain therapeutic advantages due to greater metabolic stability, such as extended half-life in vivo, reduced dosage requirements and / or improved therapeutic index. 18 F. 3 H. 11 C-labeled compounds can be used for PET or SPECT or other imaging studies. Isotope-labeled compounds and prodrugs thereof disclosed herein can generally be prepared by implementing the procedures disclosed in the schemes or in the examples and preparations described below by substituting readily available isotope-labeled reagents for non-isotope-labeled reagents. It should be understood that deuterium is considered a substituent in the compounds described herein in this context.

[0059] The concentration of this heavier isotope, specifically deuterium, can be defined by an isotopic enrichment factor. In the compounds of the present disclosure, any atom not explicitly designated as a particular isotope is intended to represent any stable isotope of the atom. Unless otherwise indicated, when a position is explicitly designated as "H" or "hydrogen", the position is understood to be hydrogen with its natural abundance isotopic composition. Therefore, in the compounds of the present disclosure, any atom explicitly designated as deuterium (D) is intended to represent deuterium.

[0060] 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.

[0061] Pharmaceutically acceptable salts, isotopically enriched analogs, deuterated analogs, stereoisomers, stereoisomer mixtures, and prodrugs of the compounds described herein are also provided. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials that can be used to prepare pharmaceutical compositions suitable for veterinary or human medical use.

[0062] 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 formed with inorganic acids and salts formed with organic acids. In addition, if the compound described herein is obtained in the form of an acid addition salt, the free base can be obtained by alkalizing a solution of the acid salt. On the contrary, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be produced according to conventional procedures for preparing acid addition salts from basic compounds by dissolving the free base in a suitable organic solvent and treating the solution with an acid. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable 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, etc. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic bases or organic bases. Salts derived from inorganic bases include, by way of example only, sodium salts, potassium salts, lithium salts, aluminum salts, ammonium salts, calcium salts, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines such as alkylamines (i.e., NH2(alkyl)), dialkylamines (i.e., HN(alkyl)2), trialkylamines (i.e., N(alkyl)3), substituted alkylamines (i.e., NH2(substituted alkyl)), di(substituted alkyl)amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl)amines (i.e., N(substituted alkyl)3), alkenylamines (i.e., NH2(alkenyl)), dienylamines (i.e., HN(alkenyl)2), trialenylamines (i.e., N(alkenyl)3), substituted alkenylamines (i.e., NH2(substituted alkenyl)), di(substituted alkyl)amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl)amines (i.e., N(alkenyl)3), (Substituted alkenyl)amine (i.e. HN(substituted alkenyl)2), tri(substituted alkenyl)amine (i.e. N(substituted alkenyl)3, mono-, di- or tri-cycloalkylamine (i.e. NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di- or tri-arylamine (i.e. NH2(aryl), HN(aryl)2, N(aryl)3) or mixed amines, etc. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, etc.

[0063] Some compounds exist in tautomer forms. Tautomers are in equilibrium with each other. For example, compounds containing amides can exist in equilibrium with imidic acid tautomers. No matter what kind of tautomer is shown and no matter how the equilibrium properties between tautomers are, it will be understood by those of ordinary skill in the art that compounds contain both amides and imidic acid tautomers. Therefore, compounds containing amides are understood to include their imidic acid tautomers. Similarly, compounds containing imidic acid are understood to include their amide tautomers.

[0064] The compounds of the present disclosure, or their pharmaceutically acceptable salts, include asymmetric centers and may give rise to enantiomers, diastereomers, and other stereoisomeric forms, which may be defined in terms of absolute stereochemistry as (R)- or (S)-, or as (D)- or (L)- for amino acids. The present disclosure is intended to include all such possible isomers, as well as racemic and optically pure forms thereof. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques (e.g., chromatography and / or fractional crystallization). Conventional techniques for preparing / separating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, the compounds are intended to include both E and Z geometric isomers.

[0065] "Stereoisomers" refer to compounds made up of the same atoms bonded by the same bonds but with different three-dimensional structures (not interchangeable). The present disclosure contemplates various stereoisomers or mixtures thereof, and includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of each other.

[0066] "Diastereomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror images of each other.

[0067] Relative centers of compounds as drawn herein are indicated graphically using "thick bond" style (bold or parallel lines), and absolute stereochemistry is drawn using wedge-shaped bonds (thick or parallel lines).

[0068] "Prodrug" means any compound that releases an active parent drug according to the structure described herein in vivo when the 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 in such a manner 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 described herein in such a manner that the modifications are cleaved into the parent compound in routine manipulation or in vivo. Prodrugs include compounds described herein, wherein the hydroxyl, amino, carboxyl or sulfhydryl groups in the compounds described herein are bonded to any group that can be cleaved in vivo to regenerate free hydroxyl, amino or sulfhydryl groups, respectively. Examples of prodrugs include, but are not limited to, esters (e.g., acetate, formate and benzoate derivatives) of hydroxyl functional groups in the compounds described herein, amides, guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl), and the like. The preparation, selection, and use of prodrugs are discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Volume 14 of the ACSSymposium Series; "Design of Prodrugs," edited by H. Bundgaard, Elsevier, 1985; and Bioreversible Carriers in Drug Design, edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which is hereby incorporated by reference in its entirety.

[0069] 2. Compounds

[0070] Provided herein are compounds that are NLRP3 modulators. In certain embodiments, a compound of formula I is provided:

[0071]

[0072] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, wherein:

[0073] X is C(X 1 ), NR 16 , S(O)2 or S(O)(NR 18 );

[0074] Y is C(Y 1 ), O, NR 17 , S(O)2 or S(O)(NR 19 );

[0075] Z is CR 8 or N;

[0076] X 1 O, NR 18 or S;

[0077] Y 1 O, NR 19 or S;

[0078] A 1 , A 2 , A 3 and A 4 are independently N, CH or CR 1 ; The condition is A 1 , A 2 , A 3 and A 4 At least one of them is CR 1 ;

[0079] Each R 1 are independently halogen, 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 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to eight Z 1 replace; or

[0080] Any two adjacent R 1 Together with the atoms to which they are attached, they form a cycloalkyl, heterocyclyl, aryl or heteroaryl ring; wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to eight Z 1 replace;

[0081] R 2 C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, 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 the C 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 1-6 haloalkyl, the C 3-10 The cycloalkyl, the heterocyclyl, the aryl or the heteroaryl is optionally substituted by one to eight Z 1 replace;

[0082] R 3 is hydrogen, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the C 1-6Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 3-10 The cycloalkyl, the heterocyclyl, the aryl or the heteroaryl is optionally substituted by one to eight Z 1 replace; or

[0083] R 2 and R 3 Together they form C 3-10 Cycloalkyl or heterocyclyl ring; wherein the C 3-10 The cycloalkyl or heterocyclyl group is optionally substituted by one to eight Z 1 replace;

[0084] R 4 For hydrogen, halogen, -NO2, cyano, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, -OR 14 、-N(R 14 )2 or -S(O) 0-2 R 14 wherein said C 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 3-6 The cycloalkyl, the 3-6 membered heterocyclyl, the phenyl or the 5-6 membered heteroaryl are optionally substituted by one to five halogen, hydroxyl, -SH, -NH2, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 haloalkyl substitution;

[0085] R 5 For hydrogen, halogen, -NO2, cyano, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, -OR 14 、-N(R 14 )2 or -S(O) 0-2 R 14 wherein said C 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 3-6 The cycloalkyl, the 3-6 membered heterocyclyl, the phenyl or the 5-6 membered heteroaryl are optionally substituted by one to five halogen, hydroxyl, -SH, -NH2, -NO2, C 1-6 Alkyl, C1-6 Alkoxy or C 1-6 haloalkyl substitution; or

[0086] R 4 and R 5 together to form a heterocyclic group or a heteroaryl group, wherein the heterocyclic group or the heteroaryl group is optionally substituted by one to five halogen groups, hydroxyl groups, -SH, -NH2, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 haloalkyl substitution;

[0087] R 6 is hydrogen, halogen, 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 heterocyclic group; wherein the C 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 1-6 haloalkyl, the C 2-6 Heteroalkyl, the C 3-10 The cycloalkyl group or the heterocyclic group may be further optionally substituted by one to five Z 1b replace;

[0088] R 7 is hydrogen, halogen, cyano, hydroxyl, 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 heterocyclic group; wherein the C 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 1-6 haloalkyl, the C 2-6 Heteroalkyl, the C 3-10 The cycloalkyl group or the heterocyclic group may be further optionally substituted by one to five Z 1b replace;

[0089] or R 6 and R 7 C 3-10 Cycloalkyl or heterocyclyl ring; wherein the C 3-10 The cycloalkyl or heterocyclyl ring may be further optionally substituted by one to five Z 1b replace;

[0090] R8 is hydrogen, halogen, cyano, C 1-6 Alkyl or C 1-6 Haloalkyl;

[0091] R 9 and R 10 are independently hydrogen, halogen, cyano, C 1-6 Alkyl or C 1-6 A haloalkyl group, wherein each C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted by one to five Z 1 replace; or

[0092] R 9 and R 10 Together they form C 3-10 Cycloalkyl or heterocyclyl ring; wherein the C 3-10 The cycloalkyl group or the heterocyclic group is optionally substituted by one to eight Z 1 replace;

[0093] Each Z 1 are independently halogen, 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 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10Cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to five Z 1a replace;

[0094] 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; wherein 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 is independently optionally substituted by one to five Z 1a replace;

[0095] R 12 For 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, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 3-10 The cycloalkyl, the heterocyclyl, the aryl or the heteroaryl is optionally substituted by one to eight Z 1 replace;

[0096] Each Z 1a are independently hydroxyl, halogen, 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- 2R 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 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to five Z 1b replace;

[0097] 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; wherein 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 is independently optionally substituted by one to five Z 1b replace;

[0098] 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, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; wherein each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl are optionally substituted with one to five halogen, hydroxyl, -SH, -NH2, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 haloalkyl substitution;

[0099] R 16 For hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10Cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein 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 is independently optionally substituted by one to five Z 1b replace;

[0100] R 17 For 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; wherein 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 is independently optionally substituted by one to five Z 1b replace;

[0101] R 18 For 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; wherein 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 is independently optionally substituted by one to five Z 1b replace;

[0102] R 19 For 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; wherein 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 is independently optionally substituted by one to five Z 1b replace;

[0103] Each Z 1bare independently halogen, cyano, hydroxyl, -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; and

[0104] 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)2NH-;

[0105] Where 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 and heteroaryl are further independently optionally substituted by one to five hydroxyl, halo, cyano, hydroxyl, -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, C3-10 The cycloalkyl, heterocyclyl, aryl or heteroaryl groups are substituted.

[0106] In certain embodiments, X is C(X 1 In certain embodiments, X is NR 16 In certain embodiments, X is S(O)2.

[0107] 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)2.

[0108] In certain embodiments, Z is CR 8 In certain embodiments, Z is N.

[0109] In certain embodiments, a compound of Formula IA is provided:

[0110]

[0111] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, wherein:

[0112] X 1 O or S;

[0113] Y 1 O or S;

[0114] A 1 , A 2 , A 3 and A 4 are independently N, CH or CR 1 ; The condition is A 1 , A 2 , A 3 and A 4 At least one of them is CR 1 ;

[0115] Each R 1 are independently halogen, 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 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to eight Z 1 replace; or

[0116] Any two adjacent R 1 Together with the atoms to which they are attached, they form a cycloalkyl, heterocyclyl, aryl or heteroaryl ring; wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to eight Z 1 replace;

[0117] R 2 C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, 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)OR11 、-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 the C 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 1-6 haloalkyl, the C 3-10 The cycloalkyl, the heterocyclyl, the aryl or the heteroaryl is optionally substituted by one to eight Z 1 replace;

[0118] R 3 is hydrogen, halogen, 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, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 3-10 The cycloalkyl, the heterocyclyl, the aryl or the heteroaryl is optionally substituted by one to eight Z 1 replace; or

[0119] R 2 and R 3 Together they form C 3-10 Cycloalkyl or heterocyclyl ring; wherein the C 3-10 The cycloalkyl or heterocyclyl group is optionally substituted by one to eight Z 1 replace;

[0120] R 4 For hydrogen, halogen, -NO2, cyano, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, -OR 14 、-N(R 14 )2 or -S(O) 0-2 R 14 wherein said C 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 3-6 The cycloalkyl, the 3-6 membered heterocyclyl, the phenyl or the 5-6 membered heteroaryl are optionally substituted by one to five halogen, hydroxyl, -SH, -NH2, -NO2, C1-6 Alkyl, C 1-6 Alkoxy or C 1-6 haloalkyl substitution;

[0121] R 5 For hydrogen, halogen, -NO2, cyano, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, -OR 14 、-N(R 14 )2 or -S(O) 0-2 R 14 wherein said C 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 3-6 The cycloalkyl, the 3-6 membered heterocyclyl, the phenyl or the 5-6 membered heteroaryl are optionally substituted by one to five halogen, hydroxyl, -SH, -NH2, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 haloalkyl substitution; or

[0122] R 4 and R 5 together to form a heterocyclic group or a heteroaryl group, wherein the heterocyclic group or the heteroaryl group is optionally substituted by one to five halogen groups, hydroxyl groups, -SH, -NH2, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 haloalkyl substitution;

[0123] R 6 is hydrogen, halogen, 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 heterocyclic group; wherein the C 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 1-6 haloalkyl, the C 2-6 Heteroalkyl, the C 3-10 The cycloalkyl group or the heterocyclic group may be further optionally substituted by one to five Z 1b replace;

[0124] R 7 is hydrogen, halogen, cyano, hydroxyl, C 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-10 Cycloalkyl or heterocyclic group; wherein the C 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 1-6 haloalkyl, the C 2-6 Heteroalkyl, the C 3-10 The cycloalkyl group or the heterocyclic group may be further optionally substituted by one to five Z 1b replace;

[0125] or R 6 and R 7 C 3-10 Cycloalkyl or heterocyclyl ring; wherein the C 3-10 The cycloalkyl or heterocyclyl ring may be further optionally substituted by one to five Z 1b replace;

[0126] R 9 and R 10 are independently hydrogen, halogen, cyano, C 1-6 Alkyl or C 1-6 A haloalkyl group, wherein each C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted by one to five Z 1 replace; or

[0127] R 9 and R 10 Together they form C 3-10 Cycloalkyl or heterocyclyl ring; wherein the C 3-10 The cycloalkyl group or the heterocyclic group is optionally substituted by one to eight Z 1 replace;

[0128] Each Z 1 are independently halogen, 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 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to five Z 1a replace;

[0129] 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; wherein 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 is independently optionally substituted by one to five Z 1a replace;

[0130] R 12 For 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, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 3-10 The cycloalkyl, the heterocyclyl, the aryl or the heteroaryl is optionally substituted by one to eight Z 1 replace;

[0131] Each Z 1a are independently hydroxyl, halogen, cyano, -NO2, -SF5, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-10 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- 2R 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 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to five Z 1b replace;

[0132] 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; wherein 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 is independently optionally substituted by one to five Z 1b replace;

[0133] 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, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; wherein each C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl are optionally substituted with one to five halogen, hydroxyl, -SH, -NH2, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 haloalkyl substitution;

[0134] Each Z 1b are independently halogen, cyano, hydroxyl, -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; and

[0135] 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)2NH-;

[0136] Where Z 1b and each C of L 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl and heteroaryl are further independently optionally substituted by one to five hydroxyl, halo, cyano, hydroxyl, -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 The cycloalkyl, heterocyclyl, aryl or heteroaryl groups are substituted.

[0137] In certain embodiments, a compound of Formula IB is provided:

[0138]

[0139] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, wherein:

[0140] X 1 O or S;

[0141] Y 1 O or S;

[0142] A 1 , A 2 , A 3 and A 4 are independently N, CH or CR 1 ; The condition is A 1 , A 2 , A 3 and A 4 At least one of them is CR 1 ;

[0143] Each R 1 are independently halogen, 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 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to eight Z 1 replace; or

[0144] Any two adjacent R 1 Together with the atoms to which they are attached, they form a cycloalkyl, heterocyclyl, aryl or heteroaryl ring; wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to eight Z 1 replace;

[0145] R 2 C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, 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)R11 、-OC(O)N(R 11 )2、-C(O)N(R 11 ) 2, halo or cyano; wherein the C 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 1-6 haloalkyl, the C 3-10 The cycloalkyl, the heterocyclyl, the aryl or the heteroaryl is optionally substituted by one to eight Z 1 replace;

[0146] R 3 is hydrogen, halogen, 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, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 3-10 The cycloalkyl, the heterocyclyl, the aryl or the heteroaryl is optionally substituted by one to eight Z 1 replace; or

[0147] R 2 and R 3 Together they form C 3-10 Cycloalkyl or heterocyclyl ring; wherein the C 3-10 The cycloalkyl or heterocyclyl group is optionally substituted by one to eight Z 1 replace;

[0148] R 4 For hydrogen, halogen, -NO2, cyano, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, -OR 14 、-N(R 14 )2 or -S(O) 0-2 R 14 wherein said C 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 3-6 The cycloalkyl, the 3-6 membered heterocyclyl, the phenyl or the 5-6 membered heteroaryl are optionally substituted by one to five halogen, hydroxyl, -SH, -NH2, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 haloalkyl substitution;

[0149] R 5 For hydrogen, halogen, -NO2, cyano, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, -OR 14 、-N(R 14 )2 or -S(O) 0-2 R 14 wherein said C 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 3-6 The cycloalkyl, the 3-6 membered heterocyclyl, the phenyl or the 5-6 membered heteroaryl are optionally substituted by one to five halogen, hydroxyl, -SH, -NH2, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 haloalkyl substitution; or

[0150] R 4 and R 5 together to form a heterocyclic group or a heteroaryl group, wherein the heterocyclic group or the heteroaryl group is optionally substituted by one to five halogen groups, hydroxyl groups, -SH, -NH2, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 haloalkyl substitution;

[0151] R 6 is hydrogen, halogen, 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 heterocyclic group; wherein the C 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 1-6 haloalkyl, the C 2-6 Heteroalkyl, the C 3-10 The cycloalkyl group or the heterocyclic group may be further optionally substituted by one to five Z 1b replace;

[0152] R 7 is hydrogen, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C2-6 Heteroalkyl, C 3-10 Cycloalkyl or heterocyclic group; wherein the C 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 1-6 haloalkyl, the C 2-6 Heteroalkyl, the C 3-10 The cycloalkyl group or the heterocyclic group may be further optionally substituted by one to five Z 1b replace;

[0153] or R 6 and R 7 C 3-10 Cycloalkyl or heterocyclyl ring; wherein the C 3-10 The cycloalkyl or heterocyclyl ring may be further optionally substituted by one to five Z 1b replace;

[0154] R 8 is hydrogen, halogen, cyano, C 1-6 Alkyl or C 1-6 Haloalkyl;

[0155] R 9 and R 10 are independently hydrogen, halogen, cyano, C 1-6 Alkyl or C 1-6 A haloalkyl group, wherein each C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted by one to five Z 1 replace; or

[0156] R 9 and R 10 Together they form C 3-10 Cycloalkyl or heterocyclyl ring; wherein the C 3-10 The cycloalkyl group or the heterocyclic group is optionally substituted by one to eight Z 1 replace;

[0157] Each Z 1 are independently halogen, 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 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to five Z 1a replace;

[0158] 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; wherein 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 is independently optionally substituted by one to five Z 1a replace;

[0159] R 12 For 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, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 3-10 The cycloalkyl, the heterocyclyl, the aryl or the heteroaryl is optionally substituted by one to eight Z 1 replace;

[0160] Each Z 1a are independently hydroxyl, halogen, cyano, -NO2, -SF5, C 1-6 Alkyl, C 2-6Alkenyl, 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- 2R 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 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to five Z 1b replace;

[0161] 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; wherein 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 is independently optionally substituted by one to five Z 1b replace;

[0162] Each R 14 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6Cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; wherein each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl are optionally substituted with one to five halogen, hydroxyl, -SH, -NH2, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 haloalkyl substitution;

[0163] Each Z 1b are independently halogen, cyano, hydroxyl, -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; and

[0164] 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)2NH-;

[0165] Where Z 1band 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 and heteroaryl are further independently optionally substituted by one to five hydroxyl, halo, cyano, hydroxyl, -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 The cycloalkyl, heterocyclyl, aryl or heteroaryl groups are substituted.

[0166] In certain embodiments, A 2 , A 3 and A 4 are independently N, CH or CR 1 ; and A 1 CR 1 .

[0167] In certain embodiments, A 1 , A 3 and A 4 are independently N, CH or CR 1 ; and A 2 CR 1 .

[0168] In certain embodiments, A 1 , A 2 and A 4 are independently N, CH or CR 1 ; and A 3 CR 1 .

[0169] In certain embodiments, A 1 , A 2 and A 3 are independently N, CH or CR 1 ; and A 4 CR 1 .

[0170] In certain embodiments, A 1 , A 2 , A 3 and A 4 At least one of them is N.

[0171] In certain embodiments, A 1 , A2 , A 3 and A 4 Each independently is CH or CR 1 .

[0172] In certain embodiments, A 2 , A 3 and A 4 Each independently is CH or CR 1 ; and A 1 CR 1 .

[0173] In certain embodiments, A 1 , A 3 and A 4 Each independently is CH or CR 1 ; and A 2 CR 1 .

[0174] In certain embodiments, A 1 , A 2 and A 4 Each independently is CH or CR 1 ; and A 3 CR 1 .

[0175] In certain embodiments, A 1 , A 2 and A 3 Each independently is CH or CR 1 ; and A 4 CR 1 .

[0176] In certain embodiments, a compound represented by Formula IC is provided:

[0177]

[0178] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomer mixture 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 Each is independently as defined herein.

[0179] In certain embodiments, R 12 is hydrogen or C 1-6In certain embodiments, R 12 is hydrogen or methyl. In certain embodiments, R 12 In certain embodiments, R 12 C 1-6 In certain embodiments, R 12 It is methyl.

[0180] In certain embodiments, R 9 is hydrogen or C 1-6 In certain embodiments, R 9 is hydrogen or methyl, and R 10 In certain embodiments, R 9 In certain embodiments, R 10 In certain embodiments, R 9 and R 10 In certain embodiments, R 9 is methyl and R 10 For hydrogen.

[0181] In certain embodiments, a compound represented by Formula II is provided:

[0182]

[0183] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, wherein:

[0184] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 12 each independently as defined herein; and

[0185] p is 1, 2, 3 or 4.

[0186] In certain embodiments, a compound represented by Formula III is provided:

[0187]

[0188] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, wherein:

[0189] R 1 , R 2 , R 3 , R 4 , R 5 , R6 , R 7 and R 12 each independently as defined herein; and

[0190] p is 1, 2, 3 or 4.

[0191] In certain embodiments, a compound represented by Formula IV is provided:

[0192]

[0193] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, wherein:

[0194] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 12 each independently as defined herein; and

[0195] p is 1, 2, 3 or 4.

[0196] In certain embodiments, a compound represented by Formula V is provided:

[0197]

[0198] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, wherein:

[0199] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 12 each independently as defined herein; and

[0200] p is 1, 2, 3 or 4.

[0201] In certain embodiments, a compound represented by Formula VI is provided:

[0202]

[0203] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, wherein:

[0204] R 1 , R2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 12 each independently as defined herein; and

[0205] p is 1, 2, 3 or 4.

[0206] In certain embodiments, R 6 is hydrogen, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-10 In certain embodiments, R 6 For hydrogen.

[0207] In certain embodiments, R 7 is hydrogen, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 2-6 Heteroalkyl, C 3-10 In certain embodiments, R 7 For hydrogen.

[0208] In certain embodiments, R 6 and R 7 For hydrogen.

[0209] In certain embodiments, R 6 and R 7 C 3-10 Cycloalkyl.

[0210] In certain embodiments, R 8 is hydrogen, halogen, C 1-6 Alkyl or C 1-6 In certain embodiments, R 8 In certain embodiments, R 8 is hydrogen or fluorine.

[0211] In certain embodiments, R 12 is hydrogen; R 6 is hydrogen; and R 7 For hydrogen.

[0212] In certain embodiments, a compound represented by Formula VII is provided:

[0213]

[0214] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, wherein:

[0215] R 1 , R 2 , R 3 , R 4 and R 5 each independently as defined herein; and

[0216] p is 1, 2, 3 or 4.

[0217] 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.

[0218] 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, C 3-10 Cycloalkyl or heterocyclic group, wherein the C 1-6 Alkyl, the C 2-6 The alkenyl group and the C 3-10 Cycloalkyl is optionally substituted by one to eight Z independently 1 Replace; or any two adjacent R 1 Together with the atoms to which they are attached they form a cycloalkyl, heterocyclyl, aryl or heteroaryl ring.

[0219] In certain embodiments, each R 1 R is independently fluorine, bromine, chlorine, iodine, cyano, ethyl, vinyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, methoxy, fluoromethoxy, difluoromethoxy, cyclopropyl, cyclobutyl, cyclopropylmethyl, oxetan-3-yl, 2,2-difluorocyclopropyl-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 it is attached it forms thiophene.

[0220] In certain embodiments, each R 1 are independently halo, cyano, C 1-6 Alkyl, C2-6 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 the C 3-10 Cycloalkyl is optionally substituted by one to eight Z independently 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 is optionally substituted by one to eight Z independently 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 the C 3-10 Cycloalkyl is optionally substituted by one to eight Z independently 1 substituted, wherein each is independently selected from halo, cyano and C 1-6 alkyl.

[0221] 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, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 In certain embodiments, each R 1 are independently halogen or C 1-6 alkyl.

[0222] In certain embodiments, each R 1 R is independently fluorine, bromine, chlorine, iodine, cyano, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, methoxy, fluoromethoxy, difluoromethoxy, cyclopropyl, cyclobutyl, 2,2-difluorocyclopropyl-1-yl, 1-cyanocyclopropyl and 1-methylcyclopropyl, ethynyl, 1-fluorovinyl, 1-fluorocyclopropyl or 1,2-difluorocyclopropyl. 1 R is independently fluoro, bromo, chloro, iodo, cyano, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, methoxy, fluoromethoxy, difluoromethoxy, cyclopropyl, cyclobutyl, 2,2-difluorocyclopropyl-1-yl, 1-cyanocyclopropyl, and 1-methylcyclopropyl. 1 is independently fluorine, bromine, -CH3, -OCHF2, -CF3 or cyclopropyl. In certain embodiments, each R 1 is independently fluorine, bromine or -CH3. In certain embodiments, each R 1 In certain embodiments, each R 1 is independently bromine. In certain embodiments, each R 1 are independently halo or -CF3.

[0223] In certain embodiments, p is 1; and each R 1 are independently halo, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 In 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 Halogenated alkyl.

[0224] In certain embodiments, R 2 and R 3 Together they form C 3-10 Cycloalkyl or heterocyclyl ring; wherein the C 3-10 The cycloalkyl or heterocyclic group is independently optionally substituted by one to eight Z 1 In certain embodiments, R 2 and R 3 Together they form C 3-10 Cycloalkyl ring, which is optionally substituted by one to eight Z1 In certain embodiments, R 2 and R 3 Together they form C 3-10 Cycloalkyl, which is optionally substituted with halo, cyano, C 1-6 Alkyl or C 1-6 In certain embodiments, R 2 and R 3 Together they form C 3-10 Cycloalkyl, which is optionally substituted with halogen, C 1-6 Alkyl or C 1-6 In certain embodiments, R 2 and R 3 Together they form C 3-10 Cycloalkyl, which is optionally substituted with fluorine, methyl or trifluoromethyl. 2 and R 3 Together they form C 3-10 A cycloalkyl ring, which is optionally substituted by C 1-6 In certain embodiments, R 2 and R 3 Together they form C 3-10 In certain embodiments, R 2 and R 3 together to form a heterocyclyl ring, which is optionally substituted by one to eight Z 1 In certain embodiments, R 2 and R 3 Together they form C 3-10 In certain embodiments, R 2 and R 3 Together they form the unsubstituted C 3-10 In certain embodiments, R 2 and R 3 Together they form an unsubstituted cyclopropyl ring. In certain embodiments, R 2 and R 3 Together they form an unsubstituted heterocyclyl ring.

[0225] In certain embodiments, R 2 C 1-6 Alkyl, C 1-6 Haloalkyl or -OR 11 , where R 11 is optionally replaced by one to five Z 1a Substituted C 1-6 In certain embodiments, R 2 C 1-6 Alkyl or C 1-6 haloalkyl, and R3 is hydrogen or C 1-6 In certain embodiments, R 2 C 1-6 Alkyl or C 1-6 In certain embodiments, R 2 C 1-6 In certain embodiments, R 2 It is methyl or ethyl.

[0226] In certain embodiments, R 2 -C(R 24 )2R 25 ; Each R 24 and R 25 are independently hydrogen, halogen, C 1-4 Alkyl or C 1-4 In certain embodiments, R 2 -C(R 24 )2R 25 ; Each R 24 are independently hydrogen, halogen, C 1-4 Alkyl or C 1-4 haloalkyl, and R 25 For hydrogen.

[0227] In certain embodiments, R 3 For 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 C 1-6 In certain embodiments, R 3 is hydrogen or methyl. In certain embodiments, R 3 In certain embodiments, R 3 It is methyl.

[0228] In certain embodiments, R 2 C 1-6 Alkyl; R 3 is hydrogen or C 1-6 Alkyl; or R 2 and R 3 Together they form C 3-10 A cycloalkyl ring, which is optionally substituted by C 1-6 In certain embodiments, R 2 and R 3 C 1-6 alkyl.

[0229] In certain embodiments, a compound represented by Formula VIII is provided:

[0230]

[0231] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomer mixture or prodrug thereof, wherein q is 0, 1, 2, 3 or 4; and Z 1 , R 1 , R 4 and R 5 Each is independently as defined herein.

[0232] In certain embodiments, a compound represented by Formula IX is provided:

[0233]

[0234] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomer mixture or prodrug thereof, wherein q is 0, 1, 2, 3 or 4; and Z 1 , R 1 , R 4 and R 5 Each is independently as defined herein.

[0235] 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, C 1-6 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 Halogenated alkyl.

[0236] 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 Halogenated alkyl.

[0237] In certain embodiments, a compound represented by Formula VIIIA is provided:

[0238]

[0239] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomer mixture or prodrug thereof, wherein R 1 , R 4 and R 5 Each is independently as defined herein.

[0240] In certain embodiments, R 1 For halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 In certain embodiments, R 1 In certain embodiments, R 1 In certain embodiments, R 1 It is -CF3.

[0241] In certain embodiments, a compound represented by Formula IXA is provided:

[0242]

[0243] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomer mixture or prodrug thereof, wherein R 1 , R 4 and R 5 Each is independently as defined herein.

[0244] 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 fluorine, chlorine, bromine, -CH3 or -CF3. In certain embodiments, each R 1 is independently fluorine, bromine, -CH3 or -CF3. In certain embodiments, each R 1 In certain embodiments, each R 1 is independently bromine. In certain embodiments, each R 1 are independently halo or -CF3.

[0245] In certain embodiments, R 5 is hydrogen or C 1-6 In certain embodiments, R 5 is hydrogen or -CF3. In certain embodiments, R 5 In certain embodiments, R 5 C 1-6 In certain embodiments, R 5It is -CF3.

[0246] In certain embodiments, R 4 For hydrogen.

[0247] 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 -CF3. In certain embodiments, R 4 is hydrogen; and R 5 In certain embodiments, R 4 is hydrogen; and R 5 C 1-6 In certain embodiments, R 4 is hydrogen; and R 5 It is -CF3.

[0248] In certain embodiments, each Z 1a are independently halo.

[0249] In certain embodiments, each Z 1 are independently halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl or -C(O)OR 11 .

[0250] 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 Cycloalkyl, heterocyclyl, aryl or heteroaryl.

[0251] In certain embodiments, each R 11 are independently hydrogen or C 1-6 In certain embodiments, each R 11 For hydrogen.

[0252] In certain embodiments, R 12 is hydrogen or C 1-6 In certain embodiments, R 12 For hydrogen.

[0253] In certain embodiments, each R 13 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 In certain embodiments, each R 13 are independently hydrogen or C 1-6 alkyl.

[0254] 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 For hydrogen.

[0255] In certain embodiments, provided is a compound selected from Table 1 or a pharmaceutically acceptable salt, isotopically enriched analog, prodrug, stereoisomer, or stereoisomer mixture thereof:

[0256] Table 1

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267] In certain embodiments, provided is a compound selected from Table 2 or a pharmaceutically acceptable salt, isotopically enriched analog, prodrug, stereoisomer, or stereoisomer mixture thereof:

[0268] Table 2

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278] 3. Methods

[0279] "Treatment" or "treating" is a method of obtaining beneficial or desired results (including clinical results). Beneficial or desired clinical results may include one or more of the following: a) inhibiting a disease or disorder (e.g., reducing one or more symptoms produced by the disease or disorder, and / or reducing the extent of the disease or disorder); b) slowing or preventing the development of one or more clinical symptoms associated with the disease or disorder (e.g., stabilizing the disease or disorder, preventing or delaying the deterioration or progression of the disease or disorder, and / or preventing or delaying the spread of the disease or disorder (e.g., metastasis); and / or c) alleviating the disease, i.e., resolving clinical symptoms (e.g., improving the disease state, causing partial or complete regression of the disease or disorder, enhancing the effect of another agent, delaying disease progression, improving quality of life, and / or prolonging survival).

[0280] "Prevention" or "preventing" means any treatment of a disease or disorder so that clinical symptoms of the disease or disorder do not develop. In some embodiments, the compound can be administered to a subject (including humans) who is at risk for the disease or disorder or has a family history of the disease or disorder.

[0281] "Subject" refers to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation, or experiment. The methods described herein can be used in human therapy and / or veterinary applications. In some embodiments, the subject is a mammal. In certain embodiments, the subject is a human.

[0282] 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 achieve treatment to provide a therapeutic benefit (e.g., improve symptoms or slow disease progression) when administered to a subject. For example, a therapeutically effective amount may be an amount sufficient to reduce the symptoms of a disease or disorder as described herein. A therapeutically effective amount may vary depending on the subject and the disease or disorder being treated, the subject's weight and age, the severity of the disease or disorder, and the mode of administration, which factors can be readily determined by one of ordinary skill in the art.

[0283] The methods described herein can be applied to cell populations in vivo or in vitro. "In vivo" means in a living individual, such as in an animal or human body. In this context, the methods described herein can be used therapeutically in an individual. "Ex vivo" means outside a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples, including fluid or tissue samples obtained from an individual. Such samples can be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. In this context, the compounds and compositions described herein can be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein can be used in vitro to determine the optimal schedule and / or dosing for administering the compounds of the present disclosure for a given indication, cell type, individual, and other parameters. The information collected from such use can be used for experimental purposes or in a clinic to set up a regimen for in vivo treatment. Other ex vivo uses to which the compounds and compositions described herein can be applied are described below or will become apparent to those skilled in the art. The compounds can be further characterized to examine safety or tolerable doses in human or non-human subjects. Such properties can be examined using methods generally known to those skilled in the art.

[0284] In certain embodiments, compounds or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, stereoisomer mixtures or prodrugs thereof that modulate the activity of NLR family Pyrin domain 3 (NLRP3) are provided. In certain embodiments, compounds or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, stereoisomer mixtures or prodrugs provided herein inhibit the activation of NLRP3.

[0285] NLR proteins are involved in the immune system, helping to initiate and regulate the immune system's response to injury, toxins, or microbial invasion. NLRP3 (also known as cryptopyrin, NALP3, LRR, and PYD domain-containing protein 3) is a protein encoded by the NLRP3 gene (also known as CIAS1). Once activated, NLRP3 molecules assemble into inflammasomes with other proteins. Activation of NLRP3 by cellular stress leads to inflammasome activation and downstream proteolytic events, including the formation of active proinflammatory cytokines such as interleukin (IL) -1β and IL-18, which are then secreted. Among other cytokines, IL-1β and IL-18 are known mediators of inflammation, such as arterial wall inflammation, atherosclerosis, and the aging process.

[0286] In certain embodiments, a method of inhibiting the activity of an inflammasome (e.g., an NLRP3 inflammasome) is provided, the method comprising contacting a cell with an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt, an isotopically enriched analog, a stereoisomer, a stereoisomer mixture, or a prodrug thereof. The inhibition may be in vitro or in vivo.

[0287] In certain embodiments, provided are compounds as disclosed herein, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, for use in inhibiting inflammasome (e.g., NLRP3 inflammasome) activity (e.g., in vitro or in vivo).

[0288] In certain embodiments, the present disclosure provides the use of a compound as disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, for the manufacture of a medicament for inhibiting the activity of an inflammasome (e.g., NLRP3 inflammasome) (e.g., in vitro or in vivo).

[0289] Chronic inflammatory responses are associated with various types of cancer. During malignant transformation or cancer therapy, inflammasomes can be activated in response to certain signals; and IL-1β expression is elevated in a variety of cancers (e.g., breast cancer, prostate cancer, colon cancer, lung cancer, head and neck cancer, melanoma, etc.), where patients with IL-1β-producing tumors generally have a worse prognosis.

[0290] In certain embodiments, a method for treating a disease or condition mediated at least in part by NLRP3 is provided, the method 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.

[0291] In certain embodiments, a method for treating a disease or condition selected from an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer is provided, the method 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.

[0292] In certain embodiments, provided are compounds as disclosed herein, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, for use in treating an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer in a subject in need thereof.

[0293] In certain embodiments, the present disclosure provides the use of a compound as disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, for 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.

[0294] In certain embodiments, a method for treating inflammation, autoimmune diseases, cancer, infection, central nervous system diseases, metabolic diseases, cardiovascular diseases, respiratory diseases, liver diseases, kidney diseases, eye diseases, skin diseases, lymphatic diseases, psychological disorders, graft-versus-host disease, hyperalgesia, and any disease in which an individual has been determined to carry a germline or somatic non-silent NLRP3 mutation is provided, the method 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, stereoisomer mixture, or prodrug thereof.

[0295] In certain embodiments, the disease or disorder can be a disease or disorder of the immune system, cardiovascular system, endocrine system, gastrointestinal tract, renal system, liver system, metabolic system, respiratory system, central nervous system, can be cancer or other malignancies, and / or can be caused by or associated with a pathogen. It should be understood that these general embodiments defined according to the broad categories of diseases, disorders and illnesses are not mutually exclusive.

[0296] In certain embodiments, the disease or disorder comprises inflammation, including inflammation due to an inflammatory disorder (e.g., an autoinflammatory disease), inflammation that occurs as a symptom of a non-inflammatory disorder, inflammation due to infection, or inflammation secondary to trauma, injury, or autoimmunity; autoimmune diseases, such as acute disseminated encephalitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome (APS), antisynthetase syndrome, aplastic anemia, autoimmune adrenalitis, autoimmune hepatitis, autoimmune oophoritis, autoimmune polyglandular failure, autoimmune thyroiditis, celiac disease, Crohn's disease, type 1 diabetes (T1D), Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease), idiopathic thrombocytopenic purpura, Kawasaki's 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, Ord's thyroiditis, pemphigus, pernicious anemia, polyarthritis, primary biliary cirrhosis, rheumatoid arthritis (RA), psoriatic arthritis, juvenile idiopathic arthritis or Still's disease, refractory gouty arthritis, Reiter's syndrome, Sjögren's syndrome ( syndrome), systemic sclerosis (systemic connective tissue disorder), Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, alopecia universalis, Behcet's disease disease, Chagas' disease, dysautonomia, endometriosis, hidradenitis suppurativa (HS), interstitial cystitis, neuromyotonia, psoriasis, sarcoidosis, scleroderma, ulcerative colitis, Schnitzler syndrome, macrophage activation syndrome, Blau syndrome, vitiligo, or vulvodynia; cancer, including lung cancer, pancreatic cancer, gastric cancer, myelodysplastic syndrome, leukemia (including acute lymphocytic leukemia (ALL) and acute myeloid leukemia (AML)), adrenal cancer, anal cancer, basal cell and squamous cell skin cancer, 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 family of tumors (including leukemia, ... tumors), eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), gestational trophoblastic disease, gliomas, Hodgkin lymphoma, Kaposi sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, liver cancer, lung carcinoid tumors, lymphomas (including cutaneous T-cell lymphoma), malignant mesothelioma, melanoma skin cancer, Merkel cell (Merkel cell) cell) skin cancer, multiple myeloma, nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cavity 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, stomach cancer, testicular cancer, thymic cancer, thyroid cancer (including anaplastic thyroid cancer), uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom macroglobulinemia, and Wilms tumor; infections, including viral infections (e.g., from influenza virus, human immunodeficiency virus (HIV), alphaviruses (e.g., Chikungunya virus and Ross River virus), flaviviruses (e.g., Dengue virus and Zika virus), herpes viruses (e.g., Epstein-Barr virus), Barr Virus), cytomegalovirus, varicella-zoster virus, and KSHV), poxviruses (e.g., vaccinia virus (Modified vaccinia virus Ankara strain)Ankara) and myxoma virus), adenovirus (e.g., adenovirus 5) or papillomavirus), bacterial infection (e.g., from 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 dysenteriae), Mycobacterium tuberculosis, Mycobacterium leprae, Mycoplasma pneumoniae, Mycoplasma hominis, Neisseria meningitidis, Neisseria gonorrhoeae, Rickettsia rickettsii, Legionella pneumophila, Klebsiella pneumoniae, Pseudomonas aeruginosa, Propionibacterium acnes, Treponema pallidum, Chlamydia trachomatis, Vibrio cholerae cholerae), Salmonella typhimurium, Salmonella typhi, Borrelia burgdorferi, or Yersinia pestispestis), fungal infections (e.g. from Candida or Aspergillus), protozoan infections (e.g. from Plasmodium, Babesia, Giardia, Entamoeba, Leishmania or Trypanosome), helminthic infections (e.g. from schistosoma, roundworms, tapeworms or flukes) and prion infections; central nervous system diseases, such as Parkinson's disease, Alzheimer's disease, dementia, motor neuron disease, Huntington's disease disease), cerebral malaria, brain injury from pneumococcal meningitis, intracranial aneurysms, traumatic brain injury, and amyotrophic lateral sclerosis; metabolic diseases, such as type 2 diabetes (T2D), atherosclerosis, obesity, gout, and pseudogout; cardiovascular diseases, such as hypertension, ischemia, reperfusion injury (including ischemic reperfusion injury after MI), 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), embolism, aneurysms (including abdominal aortic aneurysm), and pericarditis (including Dressler's syndrome). syndrome); respiratory diseases, including chronic obstructive pulmonary disease (COPD), asthma (e.g., allergic asthma and steroid-resistant asthma), asbestosis, silicosis, nanoparticle-induced inflammation, cystic fibrosis, and idiopathic pulmonary fibrosis; liver diseases, including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), including advanced fibrosis stages F3 and F4; alcoholic fatty liver disease (AFLD) and alcoholic steatohepatitis (ASH); kidney diseases, including chronic kidney disease, oxalate nephropathy, and renal Calcium deposition diseases, glomerulonephritis, and diabetic nephropathy; eye diseases, including those of the ocular epithelium, age-related macular degeneration (AMD) (dry and wet), uveitis, corneal infection, diabetic retinopathy, optic nerve damage, dry eye, and glaucoma; skin diseases, including dermatitis (e.g., contact dermatitis and atopic dermatitis), contact allergies, sunburn, skin lesions, hidradenitis suppurativa (HS), other cyst-causing skin diseases, and acne conglobata; lymphatic disorders, such as lymphangitis and Castleman's disease; psychological disorders, such as depression and psychological stress; graft-versus-host disease; allodynia, including mechanical allodynia; and any disease in which an individual has been determined to carry a germline or somatic non-silent NLRP3 mutation.

[0297] In certain embodiments, the disease, disorder or condition is an autoinflammatory disease, such as cryptopyrin-associated periodic syndrome (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 syndrome (TRAPS), hyperimmunoglobulinemia and periodic fever syndrome (HIDS), interleukin-1 receptor antagonist deficiency (DIRA), Majeed syndrome, pyogenic arthritis, pyoderma gangrenosum and acne syndrome (PAPA), adult-onset Still's disease (ADSD), and inflammatory bowel disease. Still's disease (AOSD), A20 haploinsufficiency (HA20), pediatric granulomatous arthritis (PGA), PLCG2-related antibody deficiency and immune dysregulation (PLAID), PLCG2-related autoinflammation, antibody deficiency and immune dysregulation (APLAID), or sideroblastic anemia with B-cell immunodeficiency, periodic fevers and developmental delay (SIFD).

[0298] In certain embodiments, a method for treating a disease or condition selected from an autoinflammatory disorder and / or an autoimmune disorder selected from cryptopyrin-associated autoinflammatory syndrome (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS)), Muir-Wei syndrome (MWS), chronic infantile neurocutaneous and articular (CINCA) syndrome, neonatal-onset multisystem inflammatory disease (NOMID), familial Mediterranean fever and non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, and multiple sclerosis, as well as neuroinflammation occurring in protein misfolding diseases (e.g., prion diseases), is provided, 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, stereoisomer mixture, or prodrug thereof.

[0299] In certain embodiments, a method for treating a disease or condition selected from the group consisting of: cryptopyrin-associated periodic syndrome (CAPS), Muller-Weiss syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), familial Mediterranean fever (FMF), suppurative arthritis, pyoderma gangrenosum, and acne syndrome (PAPA); hyperimmunoglobulinemia and periodic fever syndrome (HIDS), tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), systemic juvenile idiopathic arthritis, adult-onset Still's disease (AOSD), relapsing polychondritis, Stickler syndrome, Sweet's syndrome (Sweet's syndrome, Behcet's disease, antisynthetase syndrome, interleukin-1 receptor antagonist deficiency (DIRA) and A20 haploinsufficiency (HA20), the method 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.

[0300] In certain embodiments, a method for treating a disease or condition selected from the group consisting of Alzheimer's disease, atherosclerosis, asthma, allergic airway inflammation, cryptopyrin-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, excessive inflammation following influenza infection, graft-versus-host disease, stroke, silicosis, type 1 diabetes, obesity-induced inflammation or insulin resistance, rheumatoid arthritis, myelodysplastic syndrome, contact allergy, chikungunya virus-induced joint inflammation, or traumatic brain injury is provided, the method 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, stereoisomer mixture, or prodrug thereof.

[0301] In certain embodiments, a method for treating a disease or disorder mediated at least in part by TNF-α is provided. In certain embodiments, the disease or disorder is resistant to treatment with an anti-TNF-α agent. In some embodiments, the disease is an intestinal disease or disorder. In some embodiments, the disease or disorder is inflammatory bowel disease, Crohn's disease, or ulcerative colitis. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, isotopically enriched analogs, stereoisomers, stereoisomer mixtures, or prodrugs thereof, are administered in combination with an anti-TNF-α agent. In some embodiments, the anti-TNF-α agent is infliximab, etanercept, certolizumab pegol, golimumab, or adalimumab.

[0302] In certain embodiments, the disease or condition is an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer.

[0303] In certain embodiments, the disease or disorder is an autoinflammatory disorder and / or an autoimmune disorder.

[0304] In certain embodiments, the disease or disorder is a neurodegenerative disease.

[0305] In certain embodiments, the disease or disorder is Parkinson's disease or Alzheimer's disease.

[0306] In certain embodiments, a method for treating cancer is provided, 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.

[0307] In certain embodiments, the cancer is metastatic cancer, gastrointestinal cancer, skin cancer, non-small cell lung cancer, or colorectal adenocarcinoma.

[0308] In certain embodiments, provided are compounds as disclosed herein, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, for use in treating a neurodegenerative disease (e.g., Parkinson's disease or Alzheimer's disease) in a subject in need thereof.

[0309] In certain embodiments, provided are compounds as disclosed herein, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, for use in treating cancer in a subject in need thereof.

[0310] In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, stereoisomer mixtures, or prodrugs thereof, may be administered alone as a monotherapy or may be administered in combination with one or more other substances and / or treatments. Such combined therapy may be achieved by simultaneous, sequential, or separate administration of the individual components of the treatment.

[0311] For example, the effectiveness of a treatment may be enhanced by administering an adjuvant (i.e., an adjuvant by itself may have only minimal therapeutic benefit, but in combination 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 as disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, with another therapeutic agent (which also includes a therapeutic regimen) that also has a therapeutic benefit.

[0312] Other embodiments include the use of the compounds disclosed herein in therapy.

[0313] 4. Medicine Box

[0314] Also provided herein is a medicine kit, which includes a compound of the present disclosure or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a mixture of stereoisomers, or a prodrug and suitable packaging. In certain embodiments, the medicine kit also includes instructions for use. On the one hand, the medicine kit includes a compound of the present disclosure or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a mixture of stereoisomers, or a prodrug, and a label and / or instructions for using the compound to treat an indication (including a disease or disorder described herein).

[0315] Also provided herein are articles of manufacture comprising a compound described herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomer mixture, or prodrug thereof in a suitable container. The container may be a vial, can, ampoule, preloaded syringe, or intravenous bag.

[0316] 5. Pharmaceutical composition and mode of administration

[0317] The compounds provided herein are usually administered in the form of pharmaceutical compositions. Therefore, pharmaceutical compositions are also provided herein, which contain one or more compounds described herein or pharmaceutically acceptable salts, stereoisomers, stereoisomer mixtures or prodrugs thereof and one or more pharmaceutically acceptable vehicles, the vehicle being selected from carriers, adjuvants and excipients. Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents (including sterile aqueous solutions and various organic solvents), penetration enhancers, solubilizers and adjuvants. Such compositions are prepared in a manner well known in the medical field. For example, see Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th edition (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd edition (GS Banker and CT Rhodes, ed.).

[0318] The pharmaceutical composition can be administered in a single dose or multiple doses. The pharmaceutical composition can be administered by various methods (including, for example, rectal, buccal, intranasal and transdermal routes). In certain embodiments, the pharmaceutical composition can be administered by intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical or inhaled form.

[0319] One mode of administration is parenteral, for example by injection. Forms that can be incorporated into the pharmaceutical compositions described herein for administration by injection include aqueous or oily suspensions or emulsions containing, for example, sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions and similar pharmaceutical vehicles.

[0320] Oral administration may be another route of administration for the compounds described herein. It may be administered, for example, via capsules or enteric-coated tablets. When preparing a pharmaceutical composition comprising at least one compound described herein or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a mixture of stereoisomers, or a prodrug, the active ingredient is typically diluted with an excipient and / or encapsulated in a carrier so that it may be in the form of a capsule, a sachet, paper, or other container. When an excipient is used as a diluent, it may be in the form of a solid, semisolid, or liquid material that serves as a vehicle, carrier, or medium for the active ingredient. Thus, the composition may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid form or in a liquid medium), ointments containing, for example, up to 10% by weight of active compounds, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0321] Some examples of suitable excipients include, for example, lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulation may additionally include lubricants, such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives, such as methyl and propyl hydroxybenzoates; sweeteners; and flavoring agents.

[0322] Compositions including at least one compound described herein or its pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomer mixture or prodrug can be prepared by using procedures known in the art, so as to provide rapid, continuous or delayed release of active ingredients after administration to a subject. 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 preparation used in the methods disclosed herein uses a transdermal delivery device ("patch"). Such transdermal patches can be used to provide continuous or discontinuous infusion of compounds described herein in controlled amounts. The construction and use of transdermal patches for delivering pharmaceutical agents are well known in the art. Such patches can be constructed for continuous, pulsed or on-demand delivery of pharmaceutical agents.

[0323] For preparing solid compositions (e.g., tablets), the principal active ingredient may 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, stereoisomer mixture, or prodrug thereof. When referring to these preformulation compositions as being homogeneous, the active ingredient may be evenly dispersed throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0324] The tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form that provides an advantage of prolonged action, or to protect against the acidic conditions of the stomach. For example, a tablet or pill may include an inner dosage component and an outer dosage component, the latter being in the form of a coating on the former. The two components may be separated by an enteric layer that resists disintegration in the stomach and allows the inner component to pass intact into the duodenum or to be delayed release. A variety of materials may be used for such enteric layers or coatings, including a variety of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0325] Compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein. In some embodiments, the composition is administered by oral or nasal respiratory route to obtain local or systemic effects. In other embodiments, the composition in a pharmaceutically acceptable solvent may be atomized by the use of an inert gas. The atomized solution may be inhaled directly from the atomizing device, or the atomizing device may be attached to a mask curtain or an intermittent positive pressure breathing machine. Solutions, suspensions, or powder compositions may be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0326] 6. Administration

[0327] The specific dosage level of the compound of the present application for any particular subject will depend on a variety of factors, including the activity of the specific compound used, the age, weight, general health, sex, diet, administration time, route of administration and excretion rate, drug combination and the severity of a specific disease of the subject undergoing therapy. For example, the dosage can be expressed as milligrams (mg / kg) of the compound described herein per kilogram of subject body weight. The dosage between about 0.1mg / kg and 150mg / kg may be appropriate. In some embodiments, about 0.1mg / kg to 100mg / kg may be appropriate. In other embodiments, the dosage between 0.5mg / kg and 60mg / kg may be appropriate. In some embodiments, the dosage of about 0.0001 to about 100mg / kg body weight / day, about 0.001 to about 50mg compound / kg body weight or about 0.01 to about 10mg compound / kg body weight may be appropriate. Normalization to the subject's body weight is particularly useful when adjusting a dose between subjects of widely different sizes, such as occurs when using a drug in children and adults or when converting an effective dose in a non-human subject (e.g., a dog) to a dose suitable for a human subject.

[0328] 7. Synthesis of compounds

[0329] Compounds can be prepared using methods disclosed herein and conventional modifications thereof, which will be apparent in view of the disclosure herein and methods well known in the art. In addition to the teachings herein, conventional and well-known synthetic methods can also be used. The synthesis of the typical compounds described herein can be completed as described in the following examples. If applicable, reagents and starting materials can be purchased from, for example, Sigma Aldrich or other chemical suppliers.

[0330] It should be understood that if typical process conditions (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are given, other process conditions may also be used unless otherwise stated. Optimal reaction conditions may vary with the specific reactants or solvents used, but such conditions can be determined by those skilled in the art through routine optimization procedures.

[0331] In addition, conventional protecting groups ("PG") may be required to prevent certain functional groups from experiencing undesirable reactions. Suitable protecting groups for various functional groups and suitable conditions for protecting and deprotecting specific functional groups are well known in the art. For example, various protecting groups are described in the following documents: Wuts, PGM, Greene, TW and Greene, TW (2006). Greene's protective groups in organic synthesis. Hoboken, NJ, Wiley-Interscience, and references cited therein. For example, the protecting group of alcohol (such as hydroxyl) includes silyl ether (including trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), tri-isopropylsilyloxymethyl (TOM) and triisopropylsilyl (TIPS) ether), which can be removed by acid or fluoride ion (such as NaF, TBAF (tetra-n-butylammonium fluoride), HF-Py or HF-NEt3). Other protecting groups for alcohols include acetyl, removed by acid or base; benzoyl, removed by acid or base; benzyl, removed by hydrogenation; methoxyethoxymethyl ether, removed by acid; dimethoxytrityl, removed by acid; methoxymethyl ether, removed by acid; tetrahydropyranyl or tetrahydrofuranyl, removed by acid; and trityl, removed by acid. Examples of protecting groups for amines include benzyloxycarbonyl, which is removed by hydrolysis; p-methoxybenzylcarbonyl, which is removed by hydrolysis; tert-butyloxycarbonyl, which is removed by concentrated strong acid (e.g., HCl or CF3COOH) or by heating to greater than about 80°C; 9-fluorenylmethyloxycarbonyl, which is removed by base (e.g., piperidine); acetyl, which is removed by treatment with base; benzoyl, which is removed by treatment with base; benzyl, which is removed by hydrolysis; carbamate, which is removed by acid and mild heating; p-methoxybenzyl, which is removed by hydrolysis; 3,4-dimethoxybenzyl, which is removed by hydrolysis; p-methoxyphenyl, which is removed by ammonium cerium (IV) nitrate; tosyl, which is removed by concentrated acid (e.g., HBr or H2SO4) and a strong reducing agent (sodium in liquid ammonia or sodium naphthyl); troc (trichloroethyl chloroformate), which is removed by Zn insertion in the presence of acetic acid; and sulfonamides (Nosyl and Nps), which are removed by samarium iodide or tributyltin hydride.

[0332] In addition, the compounds of the present disclosure may contain one or more chiral centers. Therefore, when necessary, such compounds can be prepared or separated as pure stereoisomers, that is, individual enantiomers or diastereomers or mixtures enriched in stereoisomers. Unless otherwise indicated, all such stereoisomers (and enriched mixtures) are included in the scope of the present disclosure. Pure stereoisomers (or enriched mixtures) can be prepared using, for example, optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, etc.

[0333] 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 starting materials can be obtained from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA). Other starting materials can be prepared by procedures described in, for example, the following standard reference texts: Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), or obvious modifications thereof; Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplements (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). Example

[0334] The following examples are included to show specific embodiments of the present disclosure. It will be appreciated by those skilled in the art that the techniques disclosed in the following examples represent techniques that work well in the practice of the present disclosure, and thus can be considered to constitute specific modes of practice of the present disclosure. However, it will be appreciated by those skilled in the art in view of the present disclosure that various changes can be made to the disclosed specific embodiments without departing from the spirit and scope of the present disclosure and still obtaining the same or similar results.

[0335] General experimental methods

[0336] All solvents used were commercially available and used without further purification. Reactions were generally carried out using anhydrous solvents under an inert nitrogen atmosphere.

[0337] NMR spectroscopy: performed using a Bruker Avance III or one of the following instruments equipped with a BBFO 300 MHz probe operating at 300 MHz 1 H nuclear magnetic resonance (NMR) spectroscopy: Bruker Avance 400 instrument equipped with probe DUAL 400 MHz S1, equipped with probe 6S1 400 MHz 5 mm 1 H- 13 Bruker Avance 400 instrument for C ID, Bruker Avance III 400 instrument with nanobay equipped with Broadband BBFO 5 mm direct probe, Bruker Mercury Plus 400 NMR spectrometer equipped with Bruker 400BBO probe operating at 400 MHz. All deuterated solvents typically contained 0.03% to 0.05% v / v tetramethylsilane, which was used as a reference signal (for 1 H and 13 C was set at δ 0.00). In some cases, unless otherwise stated, the solvents were used at approximately room temperature using a Bruker Advance 400 instrument operating at 400 MHz. 1 H nuclear magnetic resonance (NMR) spectroscopy. 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 for the major peak names: for example, s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets; br, broad.

[0338] Thin layer chromatography: Where thin layer chromatography (TLC) has been used, it refers to silica gel TLC using silica gel F254 (Merck) plates, with Rf being the distance travelled by the compound on the TLC plate divided by the distance travelled by the solvent. Column chromatography is performed using an automated flash chromatography system on silica gel cartridges or on a C18 column in the case of reverse phase chromatography. Alternatively, on a HPLC-MS / MS column from Mancherey-Nagel. Thin layer chromatography (TLC) was performed on 100 μl (silica gel 60 F254) and UV was usually used to visualize the spots. Other visualization methods were also used in some cases. In these cases, 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 (generated by mixing 25 g of (NH4)6Mo7O 24 .4H2O, 5g (NH4)2Ce(IV)(NO3)6 were mixed thoroughly in 450mL water and 50mL concentrated H2SO4) and the TLC plate was developed to visualize the compound.

[0339] Liquid chromatography-mass spectrometry and HPLC analysis: HPLC analysis was performed on a Shimadzu 20AB HPLC system with a photodiode array detector and Luna-C18 (2) 2.0×50 mm (5 μm column) at a flow rate of 1.2 mL / min using a gradient solvent mobile phase A (MPA, H2O+0.037% (v / v) TFA): mobile phase B (MPB, ACN+0.018% (v / v) TFA) (0.01 min, 10% MPB; 4 min, 80% MPB; 4,9 min, 80% MPB; 4.92 min, 10% MPB; 5.5 min, 10% MPB). LCMS was detected at 220 nm and 254 nm or using evaporative light scattering (ELSD) detection and positive electrospray ionization (MS). Semi-preparative HPLC was performed under acidic or neutral conditions. Acidic: Luna C18 100×30mm, 5μm; MPA: HCl / H2O=0.04% or formic acid / H2O=0.2% (v / v); MPB: ACN. Neutral: Waters Xbridge 150×25, 5μm; MPA: 10mM NH4HCO3 in H2O; MPB: ACN. Gradient of two conditions: 10% MPB to 80% MPB over 12min, flow rate of 20mL / min, then 100% MPB over 2min, 10% MPB over 2min, UV detector. SFC analysis was carried out on a Thar analytical SFC system 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) with a flow rate of 4 mL / min and a gradient solvent mobile phase A (MPA, CO2): mobile phase B (MPB, MeOH+0.05% (v / v) IPAm) (0.01 min, 10% MPB; 3 min, 40% MPB; 3.5 min, 40% MPB; 3.56-5 min, 10% MPB). Preparative SFC was performed on a Thar 80 preparative SFC system 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) at a flow rate of 65 mL / min using a gradient solvent mobile phase A (MPA, CO2): mobile phase B (MPB, MeOH+0.1% (v / v) NH3H2O) (0.01 min, 10% MPB; 5 min, 40% MPB; 6 min, 40% MPB; 6.1-10 min, 10% MPB). UPLC-MS Acquity TMLC-MS data were collected by a system equipped with a PDA detector and coupled to a Waters single quadrupole mass spectrometer operating in alternating positive and negative electrospray ionization mode. The column used was a Cortecs UPLC C18, 1.6 μm, 2.1×50 mm. A linear gradient was applied, starting with 95% A (A: 0.1% formic acid / water) and ending with 95% B (B: 0.1% formic acid / MeCN) over 2.0 min, with a total run time of 2.5 min. The column temperature was 40° C. and the flow rate was 0.8 mL / min.

[0340] Intermediates 1 and 2

[0341] (2's,4r)-6-bromo-2'-fluorospiro[2,3-dihydroisoquinolin-4,1'-cyclopropane]-1-one and (2'r,4r)-6-bromo

[0342] -2'-Fluorospiro[2,3-dihydroisoquinolin-4,1'-cyclopropane]-1-one

[0343]

[0344] Methyl 4-bromo-2-iodobenzoate: To a solution of 4-bromo-2-iodo-benzoic 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 which was used directly. 1 HNMR (400MHz, CDCl3): δ8.18 (s, 1H), 7.70 (d, J = 8.4Hz, 1H), 7.55 (dd, J = 0.8, 8.0Hz, 1H), 3.93 (s, 3H).

[0345] Methyl 4-bromo-2-vinylbenzoate: To a mixture of methyl 4-bromo-2-iodo-benzoate (6.0 g, 17.6 mmol), potassium vinyl trifluoroborate (2.4 g, 17.6 mmol) and CsF (8.0 g, 52.8 mmol) in 1,4-dioxane (100 mL) was added Pd(dppf)Cl2 (1.3 g, 1.76 mmol). The reaction mixture was stirred at 90 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. 1H NMR (400MHz, CDCl3): δ7.77 (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).

[0346] 4-Bromo-2-(1-cyanovinyl)benzoic acid methyl ester: To a mixture of Cu2O (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 4-bromo-2-vinyl-benzoic acid methyl ester (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 a NaHCO3 aqueous solution (1 M, 30 mL) and extracted with EtOAc (3×30 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. 1 H NMR (400MHz, CDCl3): δ7.89 (d, J = 8.4Hz, 1H), 7.65 (dd, J = 2.0, 8.4Hz, 1H), 7.51 (d, J = 1.6Hz, 1H), 6.24 (s, 1H), 6.01 (s, 1H), 3.96 (s, 3H).

[0347] 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 methyl 4-bromo-2-(1-cyanovinyl)benzoate (800 mg, 3.01 mmol) in THF (30 mL) was added tetrafluoroborate (fluoromethyl)(phenyl)(2,3,4,5-tetramethylphenyl)sulfonium (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 Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title product as a 3:2 mixture. LCMS: m / z=298.0, 300.0 [M+H] + .

[0348] (2's,4r)-6-bromo-2'-fluorospiro[2,3-dihydroisoquinolin-4,1'-cyclopropane]-1-one and (2'r,4r)-6-bromo-2'-fluorospiro[2,3-dihydroisoquinolin-4,1'-cyclopropane]-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 NaBH4 (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 NH4Cl aqueous solution (20 mL) and extracted with EtOAc (3×20 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 silica gel column chromatography to give:

[0349] (2's,4r)-6-Bromo-2'-fluorospiro[2,3-dihydroisoquinolin-4,1'-cyclopropane]-1-one (Int.1): 1 H NMR (400MHz, CDCl3): δ8.02(d,J=8.4Hz,1H),7.52(dd,J=2.0,8.4Hz,1H),6.85(d,J=2.0Hz,1H),6.12(br s,1H),4.70-4.50(m,1H),3.87(d,J=12.4Hz,1H),3.51(dd,J=4.4,12.8Hz,1H),1.62-1.54(m,1H),1.42-1.24(m,1H).

[0350] (2'r,4r)-6-Bromo-2'-fluorospiro[2,3-dihydroisoquinolin-4,1'-cyclopropane]-1-one (Int.2): 1 H NMR (400MHz, CDCl3): δ8.02(d,J=8.4Hz,1H),7.55(dd,J=2.0,8.4Hz,1H),7.28(d,J=2.0Hz,1H),6.56(br s,1H),4.81-4.59(m,1H),3.78(dd,J=7.6,12.4Hz,1H),2.74(dd,J=4.4,12.8Hz,1H),1.83-1.73(m,1H),1.21-1.15(m,1H).

[0351] Intermediate 3

[0352] Methyl 2-[(2's,4r)-6-bromo-2'-fluoro-1-oxospiro[3H-isoquinolin-4,1'-cyclopropane]-2-yl]acetate

[0353]

[0354] To a solution of (2's,4r)-6-bromo-2'-fluorospiro[2,3-dihydroisoquinolin-4,1'-cyclopropane]-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 (400MHz, CDCl3): δ8.03(d,J=4.4Hz,1H),7.51(d,J=8.4Hz,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).

[0355] Intermediates 4 and 5

[0356] 2-((1R,2S)-6'-bromo-2-fluoro-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinolin]-2'(3'H)-yl)acetate and 2-((1S,2R)-6'-bromo-2-fluoro-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinolin]-2'(3'H)-yl)acetate

[0357]

[0358] Methyl 2-[(2's,4r)-6-bromo-2'-fluoro-1-oxospiro[3H-isoquinoline-4,1'-cyclopropane]-2-yl]acetate (Int.3) can be further separated by chiral SFC (column: Daicel Chiralpak AD (250 mm×30 mm, 10 μm particle size); mobile phase: A: CO2, B: 0.1% NH4OH / 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:

[0359] Methyl 2-((1R,2S)-6'-bromo-2-fluoro-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinolinyl]-2'(3'H)-yl)acetate (first eluting isomer, Int.4): 1 H NMR (400MHz, CDCl3): δ8.02(d,J=8.0Hz,1H),7.51(dd,J=1.6,8.4Hz,1H),6.83(d,J=1.6Hz,1H),4.73-4.54(m,2H),4.10( dd,J=2.0,12.4Hz,1H),4.00(d,J=17.2Hz,1H),3.77(s,3H),3.44(d,J=12.4Hz,1H),1.60-1.57(m,1H),1.44-1.33(m,1H).

[0360] Methyl 2-((1S,2R)-6'-bromo-2-fluoro-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinolinyl]-2'(3'H)-yl)acetate (second eluting isomer, Int.5): 1 H NMR (400MHz, CDCl3): δ8.02(d,J=8.0Hz,1H),7.51(dd,J=1.6,8.4Hz,1H),6.83(d,J=1.6Hz,1H),4.73-4.54(m,2H),4.10( dd,J=2.0,12.4Hz,1H),4.00(d,J=17.2Hz,1H),3.77(s,3H),3.44(d,J=12.4Hz,1H),1.60-1.57(m,1H),1.44-1.33(m,1H).

[0361] Intermediate 6

[0362] 2-((1S,2R)-6'-bromo-2-fluoro-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinolinyl]-2'(3'H)-yl)acetic acid

[0363]

[0364] 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.H2O (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 was adjusted to pH = 3 by adding aqueous HCl (3 M) and extracted with EtOAc (3 x 2 mL). The combined organics were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue that was used directly. LCMS: m / z = 328.0, 330.0 [M+H] + .

[0365] Intermediate 7

[0366] 2-((1S,2R)-2-Fluoro-6'-(1-fluorocyclopropyl)-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinolinyl]-2'(3'H)-yl)acetic acid

[0367]

[0368] Tert-butyl 2-((1S,2R)-6'-bromo-2-fluoro-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinolin]-2'(3'H)-yl)acetate: To a solution of 2-((1S,2R)-6'-bromo-2-fluoro-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinolin]-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 solution (3×200 mL). The combined organic layers were washed with brine (2×20 mL), dried over anhydrous Na 2 SO 4 , filtered, concentrated under reduced pressure, and purified by silica gel column chromatography. 1HNMR (400MHz, CDCl3): δ8.03(d,J=8.0Hz,1H),7.50(dd,J=2.0,8.4Hz,1H),6.82(d,J=2.0Hz,1H),4.73-4.51(m,2H),4.07( dd,J=1.6,12.4Hz,1H),3.85(d,J=17.2Hz,1H),3.43(d,J=12.4Hz,1H),1.58-1.54(m,1H),1.48(s,9H),1.44-1.33(m,1H).

[0369] Tert-butyl 2-((1S,2R)-2-fluoro-1'-oxo-6'-vinyl-1'H-spiro[cyclopropane-1,4'-isoquinolin]-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'-isoquinolin]-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)Cl2 (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 (4×15 mL). The combined organic layers were washed with brine (2×10 mL), dried over anhydrous Na 2 SO 4 , filtered, concentrated under reduced pressure, and purified by silica gel column chromatography. LCMS: m / z=276.2 [M-tBu+H] + . 1 H NMR (400MHz, CDCl3): δ8.13(d,J=8.0Hz,1H),7.41(dd,J=1.6,8.0Hz,1H),6.7 5-6.68(m,1H),6.66(d,J=1.6Hz,1H),5.82(d,J=17.6Hz,1H),5.37(d,J=11.2 Hz,1H),4.75-4.53(m,2H),4.07(dd,J=2.0,12.8Hz,1H),3.87(d,J=17.2Hz,1 H), 3.44 (d, J = 12.8Hz, 1H), 1.64-1.60 (m, 1H), 1.48 (s, 9H), 1.42-1.31 (m, 1H).

[0370] Tert-butyl 2-((1S,2R)-2-fluoro-1'-oxo-6'-(2-bromo-1-fluoroethyl)-1'H-spiro[cyclopropane-1,4'-isoquinolin]-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'-isoquinolin]-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 tri(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 (3×10 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 (400MHz, CDCl3): δ8.20 (d, J = 8.0Hz, 1H), 7.31 (br d,J=8.0Hz,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=6.4,12.8Hz,1H),1.66-1.59(m,1H),1.49(s,9H),1.45-1.35(m,1H).

[0371] Tert-butyl 2-((1S,2R)-2-fluoro-1'-oxo-6'-(1-fluorovinyl)-1'H-spiro[cyclopropane-1,4'-isoquinolin]-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'-isoquinolin]-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 H2O (100 mL) and extracted with EtOAc (3×20 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] + . 1H NMR (400MHz, CDCl3): δ8.27(d,J=8.0Hz,1H),7.64(d,J=8.0Hz,1H),6.93(s,1H),5.23(dd,J=3.6,49.2Hz,1H),5.07(dd,J=3.6,17.6H z,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).

[0372] Tert-butyl 2-((1S,2R)-2-fluoro-1'-oxo-6'-(2,2-dichloro-1-fluorocyclopropyl)-1'H-spiro[cyclopropane-1,4'-isoquinolin]-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'-isoquinolin]-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 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 h. 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 [Mt-Bu+H] + . 1 H NMR (400MHz, CDCl3): δ8.22(d,J=8.0Hz,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=3.2,17.2Hz,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).

[0373] Tert-butyl 2-((1S,2R)-2-fluoro-1'-oxo-6'-(1-fluorocyclopropyl)-1'H-spiro[cyclopropane-1,4'-isoquinolin]-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'-isoquinolin]-2'(3'H)-yl)acetate (100 mg, 0.23 mmol) in tri-n-butyltin hydride (660 mg, 2.27 mmol) was added AIBN (3.80 mg, 0.023 mmol). The mixture was stirred at 160 °C for 3 h. The reaction mixture was poured into saturated aqueous KF solution (20 mL). The mixture was stirred at 20°C for 1 h and extracted with EtOAc (4×10 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 preparative silica gel thin layer chromatography. LCMS: m / z=308.1 [M-tBu+H] + . 1 H NMR (400MHz, CDCl3): δ8.13(dd,J=0.8,8.0Hz,1H),6.99(d,J=8.0Hz,1H),6.71(d,J=1.6Hz,1H),4.77-4.53(m,2H),4.08(dd,J=2.0 ,12.8Hz,1H),3.87(d,J=17.6Hz,1H),3.45(d,J=12.6Hz,1H),1.59-1.51(m,2H),1.48(s,9H),1.43-1.32(m,2H),1.14-1.09(m,2H).

[0374] 2-((1S,2R)-2-fluoro-1'-oxo-6'-(1-fluorocyclopropyl)-1'H-spiro[cyclopropane-1,4'-isoquinolin]-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'-isoquinolin]-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 h. The mixture was concentrated under reduced pressure to give a residue that was used directly. LCMS: m / z = 306.2 [MH] - .

[0375] Intermediate 8

[0376] 2-((1S,2R)-2-fluoro-1'-oxo-6'-(1-fluorocyclopropyl)-1'H-spiro[cyclopropane-1,4'-isoquinolinyl]-2'(3'H)-yl)acetate

[0377]

[0378] To a solution of 2-((1S,2R)-2-fluoro-1'-oxo-6'-(1-fluorocyclopropyl)-1'H-spiro[cyclopropane-1,4'-isoquinolin]-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 H2O (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] + .

[0379] Intermediate 9

[0380] (Fluoromethyl)(phenyl)(2,3,4,5-tetramethylphenyl)sulfonium tetrafluoroborate

[0381]

[0382] ((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) at 0 °C over 10 min. Et3N (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. Two batches of the above were run in parallel and combined for work-up. The combined batch was diluted with water (1000 mL) and extracted with DCM (3×500 mL). The combined organic layers were dried over anhydrous Na2SO4, 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 carefully added, and the mixture was stirred at 15 ° C for 16 h. The reaction mixture was diluted with 10% Na2SO3 solution (200 mL), followed by dilution with saturated NaHCO3 aqueous solution until pH = 7. Methanol was removed under reduced pressure, and the remaining aqueous phase was extracted with DCM (3×500 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.

[0383] Tetrafluoroborate (fluoromethyl) (phenyl) (2,3,4,5-tetramethylphenyl) sulfonium: 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 Tf2O (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 NaBF4 aqueous solution (1 M, 6×200 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was wet-triturated with MTBE at 20 °C for 30 min and then filtered to give the desired product. LCMS: m / z=275.2 [M+H] + .

[0384] Intermediate 10

[0385] 4-Bromo-2-(1-cyanovinyl)-3-fluoro-benzoic acid methyl ester

[0386]

[0387] Methyl 2-amino-4-bromo-3-fluorobenzoate: TMSCHN2 (2M in n-hexane, 427mL, 854mmol) was added to a solution of 2-amino-4-bromo-3-fluoro-benzoic acid (40.0g, 170mmol) in DCM (500mL) and MeOH (500mL) at 0°C. The mixture was stirred at 15°C for 16h, cooled to 0°C, and TMSCHN2 (2M in hexane, 171mL) was added. The mixture was stirred for another 16h at 15°C. The mixture was quenched by adding saturated NH4Cl aqueous solution (500mL) and H2O (500mL). 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 (300mL), stirred for 10min, filtered and dried under reduced pressure to give a residue that was used directly. LCMS: m / z = 247.9, 249.9 [M+H] + .

[0388] Methyl 4-bromo-3-fluoro-2-iodobenzoate: To a solution of methyl 2-amino-4-bromo-3-fluoro-benzoate (42.0 g, 170 mmol) in a mixture of concentrated H2SO4 (420 mL) and MeCN (420 mL) at 0°C was added a solution of NaNO2 (14 g, 203 mmol) in H2O (60 mL). The mixture was stirred at 0°C for 1 h, followed by the addition of a solution of KI (56 g, 338 mmol) in H2O (60 mL). The mixture was stirred at 15°C for 15 h. The mixture was cooled to 0°C, diluted with saturated aqueous Na2S2O3 solution (1000 mL), and extracted with MTBE (4×500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography.

[0389] Methyl 4-bromo-3-fluoro-2-vinylbenzoate: CsF (20.3 g, 133.7 mmol) and Pd(dppf)Cl2 (4.89 g, 6.69 mmol) were added to a solution of methyl 4-bromo-3-fluoro-2-iodo-benzoate (12.0 g, 33.0 mmol) and potassium hydride:trifluoro(vinyl)boron (5.6 g, 41.7 mmol) in 1,4-dioxane (300 mL). The mixture was stirred at 100 °C for 16 h. 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 Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography. 1H NMR (400MHz, CDCl3): δ7.56-7.47(m,2H),7.01(dd,J=11.6,18Hz,1H),5.81-5.72(m,1H),5.66(td,J=1.2,12.8Hz,1H),3.90(s,3H).

[0390] 4-Bromo-2-(1-cyanovinyl)-3-fluoro-benzoic acid methyl ester: To a solution of 6,6'-dimethyl-2,2'-bipyridine (711 mg, 3.86 mmol), Cu2O (2.76 g, 19.3 mmol) and SelectFluor (10.3 g, 29.0 mmol) in acetone (60 mL) and water (30 mL) at 0°C was added a solution of 4-bromo-3-fluoro-2-vinyl-benzoic acid methyl ester (5.0 g, 19.3 mmol) in acetone (5 mL) and TMSCN (3.83 g, 38.6 mmol, 4.83 mL). The mixture was stirred at 20°C for 16 h. The mixture was quenched with H2O (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] + .

[0391] Intermediates 11 and 12

[0392] 4-Bromo-3-fluoro-2-[(1s,2r)-1-cyano-2-fluoro-cyclopropyl]benzoic acid methyl ester and 4-Bromo-3-fluoro

[0393] -2-[(1s,2s)-1-cyano-2-fluoro-cyclopropyl]benzoic acid methyl ester

[0394]

[0395] To a solution of 4-bromo-2-(1-cyanovinyl)-3-fluoro-benzoic acid methyl ester (6.0 g, 21.1 mmol, Int. 10) and tetrafluoroboric acid (fluoromethyl) (phenyl) (2,3,4,5-tetramethylphenyl) sulfonium (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 NH4Cl solution (150 mL), and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give:

[0396] Methyl 4-bromo-3-fluoro-2-[(1s,2r)-1-cyano-2-fluoro-cyclopropyl]benzoate (Int.11): 1 HNMR (400MHz, CDCl3): δ7.73-7.66(m,2H), 4.83-4.63(m,1H), 4.03(s,3H), 2.39-2.28(m,1H), 1.67-1.57(m,1H).

[0397] Methyl 4-bromo-3-fluoro-2-[(1s,2s)-1-cyano-2-fluoro-cyclopropyl]benzoate (Int.12): 1 HNMR (400MHz, CDCl3): δ7.74-7.67(m,2H),5.29-5.06(m,1H),3.99(s,3H),2.37-2.29(m,1H),1.78-1.67(m,1H).

[0398] Intermediate 13

[0399] (2's,4r)-6-Bromo-2',5-difluorospiro[2,3-dihydroisoquinolin-4,1'-cyclopropane]-1-one

[0400]

[0401] 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 CoCl2 (9.5 g, 73.4 mmol) in MeOH (180 mL) and H2O (4.5 mL) was added NaBH4 (2.78 g, 73.4 mmol) at 0°C. The mixture was stirred at 20°C for 2 h. Then NaBH4 (694 mg, 18.3 mmol) was added to the solution. The mixture was stirred for another 1 h. The mixture was quenched by saturated NH4Cl aqueous solution (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 Na2SO4, filtered, concentrated under reduced pressure and purified by silica gel column chromatography. LCMS: m / z = 287.9, 289.9 [M+H] + .

[0402] Intermediates 14 and 15

[0403] 2-[(2's,4r)-6-bromo-2',5-difluoro-1-oxo-spiro[3H-isoquinolin-4,1'-cyclopropane]-2-yl]acetic acid methyl ester

[0404]

[0405] To a solution of (2's,4r)-6-bromo-2',5-difluorospiro[2,3-dihydroisoquinoline-4,1'-cyclopropane]-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 by addition of aqueous HCl (1 M, 700 mL) at 0°C 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×50 mm, 10 μm particle size); mobile phase: A: CO 2 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:

[0406] 2-[(2's,4r)-6-bromo-2',5-difluoro-1-oxo-spiro[3H-isoquinolin-4,1'-cyclopropane]-2-yl]acetic acid methyl ester (first eluting isomer, Int.14): LCMS: m / z=359.9,361.9 [M+H] + . 1 H NMR (400MHz, CDCl3): δ7.87(dd,J=1.0,8.4Hz,1H),7.54(dd,J=6.4,8.4Hz,1H),5.44-5.23(m,1H),4.60(d,J=1 7.6Hz,1H),4.12-4.00(m,1H),3.81-3.77(m,4H),3.62(d,J=12.8Hz,1H),1.93-1.87(m,1H),1.54-1.41(m,1H).

[0407] 2-[(2's,4r)-6-bromo-2',5-difluoro-1-oxo-spiro[3H-isoquinolin-4,1'-cyclopropane]-2-yl]acetic acid methyl ester (second eluting isomer, Int.15): LCMS: m / z=359.9,361.9 [M+H] + . 1H NMR (400MHz, CDCl3): δ7.87(dd,J=0.8,8.4Hz,1H),7.54(dd,J=6.4,8.4Hz,1H),5.46-5.23(m,1H),4.60(d,J=17.6Hz,1H) ,4.08(d,J=17.6Hz,1H),3.81(d,J=2.6Hz,1H),3.78(s,3H),3.63(d,J=12.9Hz,1H),1.93-1.87(m,1H),1.55-1.40(m,1H).

[0408] Intermediate 16

[0409] 2-[(2's,4r)-6-cyclopropyl-2',5-difluoro-1-oxo-spiro[3H-isoquinoline-4,1'-cyclopropane]-2-

[0410] methyl acetate

[0411]

[0412] To a solution of methyl 2-[(2's,4r)-6-bromo-2',5-difluoro-1-oxo-spiro[3H-isoquinoline-4,1'-cyclopropane]-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 H2O (0.1 mL) was added CsF (63 mg, 0.42 mmol) and Pd(dppf)Cl2 (10 mg, 0.014 mmol). The mixture was stirred at 100 °C for 16 h. The reaction mixture was quenched with H2O (6 mL) and extracted with EtOAc (3×2 mL). The combined organic layers were washed with brine (3 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography. LCMS: m / z = 322.0 [M+H] + .

[0413] Intermediate 17

[0414] 2-[(2's,4r)-6-cyclopropyl-2',5-difluoro-1-oxo-spiro[3H-isoquinoline-4,1'-cyclopropane]-2-

[0415] acetic acid

[0416]

[0417] To a solution of methyl 2-[(2's,4r)-6-cyclopropyl-2',5-difluoro-1-oxo-spiro[3H-isoquinoline-4,1'-cyclopropane]-2-yl]acetate (260 mg, 0.81 mmol, Int. 16) in THF (3.0 mL) and H2O (3.0 mL) was added LiOH·H2O (85 mg, 2.02 mmol). The reaction mixture was stirred at 20°C for 1 h. The reaction mixture was diluted with H2O (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 was then extracted with EtOAc (3×3 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue that was used directly. LCMS: m / z = 308.1 [M+H] + .

[0418] Intermediate 18

[0419] 2-[(2's,4r)-2',5-difluoro-6-iodo-1-oxo-spiro[3H-isoquinolin-4,1'-cyclopropane]-2-yl]acetic acid methyl ester

[0420]

[0421] To a solution of methyl 2-[(2's,4r)-6-bromo-2',5-difluoro-1-oxo-spiro[3H-isoquinoline-4,1'-cyclopropane]-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 H2O (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] + .

[0422] Intermediate 19

[0423] 2-[(2's,4r)-2',5-difluoro-6-iodo-1-oxo-spiro[3H-isoquinolin-4,1'-cyclopropane]-2-yl]acetic acid

[0424]

[0425] To a solution of methyl 2-[(2's,4r)-2',5-difluoro-6-iodo-1-oxo-spiro[3H-isoquinoline-4,1'-cyclopropane]-2-yl]acetate (145 mg, 0.35 mmol, Int. 18) in THF (2.0 mL) and water (0.5 mL) was added LiOH HO (30 mg, 0.71 mmol). 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 was then extracted with EtOAc (3 x 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] + .

[0426] Intermediate 20

[0427] Methyl 2-(6-iodo-1-oxo-4-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)acetate

[0428]

[0429] 2-(3-Bromophenyl)-1,1,1-trifluoro-3-nitropropan-2-ol: 1-(3-bromophenyl)-2,2,2-trifluoro-ethanone (40 g, 158 mmol) and Et3N (48 g, 474 mmol) were added to a mixture of nitromethane (116 g, 1.90 mol) in THF (400 mL) at 0 °C. The mixture was stirred at 20 °C for 12 h. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography.

[0430] 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 SOCl2 (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 H2O (100 mL) and extracted with EtOAc (3×25 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography.

[0431] 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 h. 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] + .

[0432] 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 h. The mixture was concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC.

[0433] 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 H2O (200 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z=293.9, 295.9 [M+H] + .

[0434] 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) and 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 H2O (100 mL) and then extracted with EtOAc (3×40 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z=341.9 [M+H] + .

[0435] 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 Cs2CO3 (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 H2O (700 mL) and then extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z=414.0 [M+H] + .

[0436] Intermediates 20a and 20b

[0437] Methyl 2-(6-iodo-1-oxo-4-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)acetate

[0438]

[0439] 2-(6-iodo-1-oxo-4-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)acetic acid methyl ester (Int. 20) was further separated by chiral SFC (column: Daicel Chiralpak IG (250 mm×50 mm, 10 μm particle size); mobile phase: A: CO2, B: 0.1% NH4OH / 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:

[0440] Methyl 2-(6-iodo-1-oxo-4-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)acetate (first eluting isomer, Int. 20a): 1 H NMR (400MHz, CDCl3): δ7.89 (s, 2H), 7.75 (s, 1H), 4.80 (d, J = 17.2Hz, 1H), 4.18 (br dd,J=4.4,13.6Hz,1H),3.91(d,J=17.2Hz,1H),3.77(s,3H),3.74(dd,J=2.4,13.6Hz,1H),3.62-3.50(m,1H).

[0441] Methyl 2-(6-iodo-1-oxo-4-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)acetate (second eluting isomer, Int. 20b): 1 H NMR (400MHz, CDCl3): δ7.89 (s, 2H), 7.75 (s, 1H), 4.80 (d, J = 17.6Hz, 1H), 4.18 (br dd,J=4.4,13.6Hz,1H),3.91(d,J=17.2Hz,1H),3.77(s,3H),3.74(dd,J=2.4,13.6Hz,1H),3.62-3.50(m,1H).

[0442] Intermediate 21

[0443] Methyl 2-(6-iodo-1-oxo-4-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)acetate

[0444]

[0445] 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 H2O (5 mL) was added LiOH·H2O (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 Na2SO4, filtered and concentrated under reduced pressure to give a residue that was used directly. LCMS: m / z=399.9.

[0446] Intermediate 22

[0447] Methyl 2-(1-cyanovinyl)-3-fluoro-4-(trifluoromethyl)benzoate

[0448]

[0449] 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 K2CO3 (61.1 g, 442 mmol) and MeI (34.5 g, 243 mmol). The reaction mixture was stirred at 20 °C for 4 h. 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 Na2SO4, filtered and concentrated under reduced pressure to give a residue that was used directly.

[0450] 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 K2CO3 (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), pH = 3 was adjusted by adding aqueous HCl (3 M), and extracted with EtOAc (3×500 mL). The combined organics were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue that was used directly. LCMS: m / z = 320.0 [M+H] + .

[0451] Methyl 2-(cyanomethyl)-3-fluoro-4-(trifluoromethyl)benzoate: To a solution of methyl 2-(1-cyano-2-methoxy-2-oxo-ethyl)-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 H2O (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 Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z=262.1[M+H] + .

[0452] 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 x 50 mL). The combined organics were washed with saturated aqueous NaHCO3 (3 x 100 mL), brine (100 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): δ7.90 (d, J = 8.4Hz, 1H), 7.81-7.72 (m, 1H), 6.48 (s, 1H), 6.07 (d, J = 0.8Hz, 1H), 3.98 (s, 3H).

[0453] Intermediate 23

[0454] (2's,4r)-2',5-difluoro-6-(trifluoromethyl)spiro[2,3-dihydroisoquinolin-4,1'-cyclopropane]-1-one

[0455]

[0456] 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 H2O (15 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 to give the title product as a 2:5 mixture. LCMS: m / z=306.0 [M+H] + .

[0457] (2's,4r)-2',5-difluoro-6-(trifluoromethyl)spiro[2,3-dihydroisoquinolin-4,1'-cyclopropane]-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 CoCl2 (145 mg, 1.11 mmol) in MeOH (3.0 mL) was added NaBH4 (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 solution (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] + .

[0458] Intermediate 24

[0459] 2-[(2's,4r)-2'-fluoro-1-oxo-6-(trifluoromethyl)spiro[3H-isoquinolin-4,1'-cyclopropane]-2-yl]

[0460] Methyl acetate

[0461]

[0462] To a solution of (2's,4r)-2',5-difluoro-6-(trifluoromethyl)spiro[2,3-dihydroisoquinolin-4,1'-cyclopropane]-1-one (70 mg, 0.25 mmol) in DMF (2.0 mL) was added NaI (25 mg, 0.17 mmol), Cs2CO3 (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 H2O (10 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=350.1 [M+H] + .

[0463] Intermediate 25

[0464] 2-(2,2,5'-trifluoro-1'-oxo-6'-(trifluoromethyl)-1'H-spiro[cyclopropane-1,4'-isoquinolinyl]-2'(3'H)-yl)acetate

[0465]

[0466] 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 sodium (2-bromo-2,2-difluoro-acetyl)oxy (2.16 g, 10.98 mmol). The reaction mixture was stirred at 150 ° C for 20 min under microwave irradiation. The reaction mixture was cooled to 0 ° C, diluted with H2O (10 mL), and extracted with EtOAc (3×15 mL). The combined organics were washed with brine (25 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC.

[0467] 2,2,5'-Trifluoro-6'-(trifluoromethyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-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) at 0°C was added dichlorocobalt (80 mg, 0.62 mmol) and NaBH4 (70 mg, 1.86 mmol). The reaction mixture was stirred at 0°C for 1 h, and then stirred at 20°C for another 12 h. The reaction mixture was quenched by adding saturated NH4Cl aqueous solution (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.

[0468] 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), Cs2CO3 (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 x 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] + .

[0469] Intermediate 26

[0470] 2-(6'-bromo-2,2-difluoro-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinolinyl]-2'(3'H)-yl)acetic acid methyl ester

[0471]

[0472] 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 (3×50 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] + .

[0473] 6'-Bromo-2,2-difluoro-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-1'-one: To a solution of methyl 4-bromo-2-(1-cyano-2,2-difluorocyclopropyl)benzoate (11.2 g, 35.4 mmol), ZnCl2 (9.7 g, 70.9 mmol) and CoCl2·6H2O (11.0 g, 46.1 mmol) in MeOH (150 mL) was added NaBH4 (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 NH4Cl solution (100 mL), and extracted with EtOAc (3×50 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=288.0,290.0[M+H] + .

[0474] Methyl 2-(6'-bromo-2,2-difluoro-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-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'-isoquinoline]-1'-one (380 mg, 1.32 mmol) in DMF (8.0 mL) was added NaI (129 mg, 0.86 mmol), Cs2CO3 (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 H2O (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=359.9, 361.9 [M+H]+ .

[0475] Intermediate 27

[0476] 2-(6'-bromo-2,2-difluoro-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinolinyl]-2'(3'H)-yl)acetic acid:

[0477]

[0478] 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 H2O (0.4 mL) was added LiOH·H2O (42 mg, 0.01 mmol). The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with H2O (5 mL) and washed with MTBE (2×10 mL). The aqueous was then acidified to pH=4 by the addition of aqueous HCl and then extracted with EtOAc (3×10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue that was used directly. LCMS: m / z=346.0,348.0 [M+H] + .

[0479] Intermediate 28

[0480] 2-(2,2-difluoro-6'-(1-fluorocyclopropyl)-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetic acid methyl ester:

[0481]

[0482] Methyl 2-(2,2-difluoro-1'-oxo-6'-vinyl-1'H-spiro[cyclopropane-1,4'-isoquinolin]-2'(3'H)-yl)acetate: To a solution of methyl 2-(6'-bromo-2,2-difluoro-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinolin]-2'(3'H)-yl)acetate (6.00 g, 16.7 mmol) in 1,4-dioxane (200 mL) was added potassium vinyl trifluoroborate (6.69 g, 50.0 mmol), CsF (7.59 g, 50.0 mmol) and Pd(dppf)Cl2 (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 (3×20 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] + .

[0483] Methyl 2-(2,2-difluoro-6'-(1-fluoro-2-iodoethyl)-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinolin]-2'(3'H)-yl)acetate: To a solution of methyl 2-(2,2-difluoro-1'-oxo-6'-vinyl-1'H-spiro[cyclopropane-1,4'-isoquinolin]-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 min and then N,N-diethylethylamine; trihydrofluoride (12.6 g, 78.1 mmol) was added. The reaction was then stirred at 20 °C for another 16 h. 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] + .

[0484] 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 h. 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] + .

[0485] Methyl 2-(2,2-difluoro-6'-(1-fluorocyclopropyl)-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinolin]-2'(3'H)-yl)acetate (Int. 28): To a solution of ZnEt2 (2M 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, then CH2I2 (4.12 g, 15.4 mmol) was added. The mixture was stirred at 0 ° C for another 20 min, and then 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 another 3 h. The reaction mixture was then warmed to 40 ° C and stirred for another 16 h. The reaction mixture was filtered, and the filtrate was poured into saturated NH4Cl aqueous solution (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] + .

[0486] Intermediate 29

[0487] 2-(2,2-difluoro-6'-(1-fluorocyclopropyl)-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinolinyl]-2'(3'H)-yl)acetic acid

[0488]

[0489] 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 H2O (4.0 mL) was added LiOH·H2O (87 mg, 2.06 mmol). The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with H2O (10 mL) and washed with MTBE (10 mL). The aqueous was then acidified to pH = 3 by the addition of aqueous HCl (3 M) and then extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue that was used directly. LCMS: m / z = 326.1 [M+H] + .

[0490] Intermediate 30

[0491] 2-(6'-cyclopropyl-2,2-difluoro-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinolinyl]-2'(3'H)-yl)acetate

[0492]

[0493] 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'-cyclopropane]-2-yl)acetate (500 mg, 1.39 mmol) in toluene (5.0 mL) and H2O (0.5 mL) was added bis(1-adamantyl)-butyl-phosphane (100 mg, 0.28 mmol), Pd(OAc)2 (31 mg, 0.14 mmol) and Cs2CO3 (905 mg, 2.78 mmol). 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 Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z=322.1[M+H] + .

[0494] Intermediate 31

[0495] 2-(6'-cyclopropyl-2,2-difluoro-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinolinyl]-2'(3'H)-yl)acetic acid

[0496]

[0497] To a solution of methyl 2-(6-cyclopropyl-1',1'-difluoro-1-oxo-spiro[3H-isoquinoline-4,2'-cyclopropane]-2-yl)acetate (275 mg, 0.86 mmol) in THF (4.0 mL) and H2O (1.0 mL) was added LiOH·H2O (72 mg, 1.71 mmol). The reaction mixture was stirred at 20°C for 2 h. The reaction mixture was diluted with ice-cold H2O (10 mL), acidified to pH=3 by adding aqueous HCl (4 M), and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue that was used directly. LCMS: m / z=308.1 [M+H] + .

[0498] Intermediate 32

[0499] Methyl 2-[6-bromo-1',1',5-trifluoro-1-oxospiro[3H-isoquinolin-4,2'-cyclopropane]-2-yl]acetate

[0500]

[0501] 4-bromo-2-(1-cyano-2,2-difluorocyclopropyl)-3-fluorobenzoic acid methyl ester: To a solution of 4-bromo-2-(1-cyanovinyl)-3-fluorobenzoic acid methyl ester (450 mg, 1.58 mmol, Int. 10) in 1,4-dioxane (2.0 mL) was added 2-chloro-2,2-difluoroacetic acid sodium (725 mg, 4.75 mmol). The mixture was stirred at 150 ° C for 20 min under microwave irradiation. The reaction mixture was poured into H2O (20 mL) and extracted with EtOAc (4×15 mL). The combined organic layers were washed with brine (2×10 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and purified by reverse phase preparative HPLC. LCMS: m / z=333.9,335.9 [M+H] + .

[0502] 6'-Bromo-2,2,5'-trifluoro-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-1'-one: To a mixture of methyl 4-bromo-2-(1-cyano-2,2-difluorocyclopropyl)-3-fluorobenzoate (600 mg, 1.80 mmol) and CoCl2 (233 mg, 1.80 mmol) in MeOH (12 mL) and H2O (1.2 mL) was added NaBH4 (204 mg, 5.39 mmol) at -10°C. The mixture was stirred at 0°C for 1 h and then stirred at -10°C for another 4 h. The reaction mixture was diluted with saturated aqueous NH4Cl solution (20 mL) and extracted with EtOAc (4×15 mL). The combined organic layers were washed with brine (2×10 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography. LCMS: m / z=306.0,308.0[M+H] + .

[0503] Methyl 2-[6-bromo-1',1',5-trifluoro-1-oxospiro[3H-isoquinolin-4,2'-cyclopropane]-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), Cs2CO3 (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 H2O (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] + .

[0504] Intermediate 33

[0505] 2-[6-Bromo-1',1',5-trifluoro-1-oxospiro[3H-isoquinolin-4,2'-cyclopropane]-2-yl]acetic acid

[0506]

[0507] To a solution of methyl 2-[6-bromo-1',1',5-trifluoro-1-oxospiro[3H-isoquinoline-4,2'-cyclopropane]-2-yl]acetate (115 mg, 0.30 mmol) in THF (3.0 mL) and H2O (0.6 mL) was added LiOH·H2O (26 mg, 0.61 mmol). The mixture was stirred at 20°C for 1 h. The reaction mixture was poured into H2O (10 mL) and washed with MTBE (3×5 mL). The aqueous layer was adjusted to pH=3 at 0°C using aqueous HCl (3 M) 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 to give a residue that was used directly. LCMS: m / z=361.9,363.9 [MH] - .

[0508] Intermediate 34

[0509] 2-(6'-cyclopropyl-2,2,5'-trifluoro-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-

[0510] Methyl acetate

[0511]

[0512] To a solution of methyl 2-(6'-bromo-2,2,5'-trifluoro-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinolin]-2'(3'H)-yl)acetate (2.7 g, 7.14 mmol) in toluene (40 mL) and H2O (4 mL) was added potassium cyclopropyltrifluoroborate (3.17 g, 21.42 mmol), Cs2CO3 (4.65 g, 14.3 mmol), bis(1-adamantyl)-butyl-phosphane (512 mg, 1.43 mmol) and Pd(OAc)2 (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 Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z=340.1 [M+H] + . 1H NMR (400MHz, CDCl3): δ7.89(d,J=8.0Hz,1H),6.90(t,J=7.2Hz,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).

[0513] Intermediate 35

[0514] 2-(2,2-difluoro-1'-oxo-6'-(trifluoromethyl)-1'H-spiro[cyclopropane-1,4'-isoquinolinyl]-2'(3'H)-yl)acetate

[0515]

[0516] 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 vinyl trifluoroborate (52 g, 388 mmol), CsF (161 g, 1.06 mol) and Pd(dppf)Cl2 (12.9 g, 17.7 mmol). The mixture was stirred at 90 °C for 6 h. The mixture was diluted with H2O (2000 mL) and extracted with EtOAc (3×700 mL). The combined organic layers were washed with brine (1500 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography.

[0517] 2-(1-cyanovinyl)-4-(trifluoromethyl)benzoic acid methyl ester: To a solution of Cu2O (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 H2O (500 mL) was added dropwise 4-(trifluoromethyl)-2-vinylbenzoic acid methyl ester (50 g, 217 mmol) and TMSCN (64.6 g, 652 mmol). The mixture was stirred at 20 °C for 20 h. The mixture was poured into a saturated NaHCO3 aqueous solution (200 mL) and H2O (800 mL). The mixture was filtered and the filtrate was extracted with EtOAc (3×300 mL). The combined organic layer was washed with brine (600 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z=256.0 [M+H] + .

[0518] 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 H2O (10 mL) and extracted with EtOAc (3×10 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.

[0519] 2,2-Difluoro-6'-(trifluoromethyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-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 solution (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. 1H NMR (400MHz, CDCl3): δ8.31(d,J=8.0Hz,1H),7.72(d,J=8.4Hz,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)

[0520] 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), Cs2CO3 (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 H2O (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 (400MHz, CDCl3): δ8.32(d,J=8.0Hz,1H),7.71(dd,J=0.8,8.0Hz,1H),7.32(s,1H),4.79(d,J=17.2Hz,1H),4.18- 4.10(m,1H),3.98(d,J=17.2Hz,1H),3.78(s,3H),3.40(dd,J=1.2,12.8Hz,1H),2.17-2.12(m,1H),1.80-1.75(m,1H).

[0521] Intermediate 36

[0522] 2-(6-Bromo-1-oxo-spiro[3H-isoquinolin-4,1'-cyclopropane]-2-yl)acetic acid methyl ester

[0523]

[0524] Methyl 4-bromo-2-(cyanomethyl)benzoate: A solution of NaCN (8.4 g, 170 mmol) in H2O (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 H2O (1.5 L) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (3×200 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): δ7.93 (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).

[0525] 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 another 8 h. The reaction mixture was cooled to 0 ° C, diluted with saturated aqueous NH4Cl solution (200 mL), and extracted with EtOAc (4×50 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. LCMS: m / z=280.0,282.0[M+H] + .

[0526] 6-Bromospiro[2,3-dihydroisoquinolin-4,1'-cyclopropane]-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 NaBH4 (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, diluted with saturated aqueous NH4Cl solution (50 mL), and extracted with DCM (4×15 mL). The combined organic layers were washed with 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=252.0, 254.0 [M+H] + .

[0527] Methyl 2-(6-bromo-1-oxo-spiro[3H-isoquinoline-4,1'-cyclopropane]-2-yl)acetate (Int. 36): To a solution of 6-bromospiro[2,3-dihydroisoquinoline-4,1'-cyclopropane]-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, and then methyl 2-bromoacetate (2.09 g, 13.7 mmol) was added. The reaction mixture was then stirred at 20°C for another 2 h. The reaction mixture was cooled to 0°C, diluted with saturated aqueous NH4Cl solution (50 mL), and extracted with EtOAc (4×20 mL). The combined organic layers were washed with brine (3×15 mL), dried over anhydrous Na2SO4, 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 (400MHz, CDCl3): δ7.98 (d, J = 8.4Hz, 1H), 7.44 (dd, J = 2.0, 8.4Hz, 1H), 6.99 (d, J = 2. 0Hz,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).

[0528] Intermediate 37

[0529] 2-[(2's,4r)-6-chloro-2',5-difluoro-1-oxo-spiro[3H-isoquinolin-4,1'-cyclopropane]-2-yl]acetic acid methyl ester

[0530]

[0531] Methyl 2-[(2's,4r)-6-((diphenylmethylene)amino)-2',5-difluoro-1-oxo-spiro[3H-isoquinolin-4,1'-cyclopropane]-2-yl]acetate: To a solution of methyl 2-[(2's,4r)-6-bromo-2',5-difluoro-1-oxo-spiro[3H-isoquinolin-4,1'-cyclopropane]-2-yl]acetate (650 mg, 1.80 mmol, Int. 15) and diphenylmethanimine (654 mg, 3.61 mmol) in 1,4-dioxane (10 mL) was added Pd2(dba)3 (165 mg, 0.18 mmol), XPhos (172 mg, 0.36 mmol) and Cs2CO3 (1.18 g, 3.61 mmol). The mixture was stirred at 90 °C for 16 h. The mixture was quenched with H2O (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.

[0532] Methyl 2-[(2's,4r)-6-amino-2',5-difluoro-1-oxo-spiro[3H-isoquinolin-4,1'-cyclopropane]-2-yl]acetate: A solution of methyl 2-[(2's,4r)-6-((diphenylmethylene)amino)-2',5-difluoro-1-oxo-spiro[3H-isoquinolin-4,1'-cyclopropane]-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 at 20 °C for 16 h. The mixture was quenched with H2O (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.

[0533] Methyl 2-[(2's,4r)-6-chloro-2',5-difluoro-1-oxo-spiro[3H-isoquinolin-4,1'-cyclopropane]-2-yl]acetate: To a mixture of CuCl (100 mg, 1.01 mmol) in MeCN (5 mL) was added tert-butyl nitrite (94 mg, 0.91 mmol) and a solution of methyl 2-[(2's,4r)-6-amino-2',5-difluoro-1-oxo-spiro[3H-isoquinolin-4,1'-cyclopropane]-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 H2O (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. 1 H NMR (400MHz, CDCl3): δ7.86 (dd, J=1.2, 8.4Hz, 1H), 7.31 (dd, J=7.2, 8.4Hz, 1H), 5.38-5.13 (m, 1H), 4.53 (d, J=17. 2Hz, 1H), 4.00 (d, J = 17.2Hz, 1H), 3.75-3.68 (m, 4H), 3.55 (d, J = 12.8Hz, 1H), 1.87-1.80 (m, 1H), 1.47-1.36 (m, 1H).

[0534] Intermediate 38

[0535] Methyl 2-(6-bromo-5-fluoro-1-oxospiro[3H-isoquinolin-4,1'-cyclopropane]-2-yl)acetate

[0536]

[0537] 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 cyclopropanenitrile (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 x 100 mL). The aqueous phase was adjusted to pH = 3 with aqueous HCl (3N) and extracted with EtOAc (3 x 200 mL). The combined organics were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a solid that was used directly. LCMS: m / z = 284.0, 285.9 [M+H] + .

[0538] 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. MeI (23 g, 162 mmol) was added to the mixture. 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 used directly. LCMS: m / z=298.1, 300.0 [M+H]+.

[0539] 6-Bromo-5-fluoro-spiro[2,3-dihydroisoquinolin-4,1'-cyclopropane]-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 NaBH4 (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 NH4Cl solution (600 mL), diluted with water (300 mL), and extracted with EtOAc (3×200 mL). The combined organics were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography. LCMS: m / z=270.0, 272.0 [M+H]+.

[0540] Methyl 2-(6-bromo-5-fluoro-1-oxospiro[3H-isoquinolin-4,1'-cyclopropane]-2-yl)acetate: To a solution of 6-bromo-5-fluoro-spiro[2,3-dihydroisoquinolin-4,1'-cyclopropane]-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. Methyl 2-bromoacetate (11 g, 68.9 mmol, 6.50 mL) was added to the reaction mixture 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 solution (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 Na2SO4, 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] + .

[0541] Intermediate 39

[0542] 2-[(2's,4r)-2'-fluoro-1-oxo-6-(trifluoromethyl)spiro[3H-isoquinolin-4,1'-cyclopropane]-2-yl]

[0543] Methyl acetate

[0544]

[0545] 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 vinyl trifluoroborate (52 g, 388 mmol), CsF (161 g, 1.06 mol) and Pd(dppf)Cl2 (12.9 g, 17.7 mmol). The mixture was stirred at 90 °C for 6 h. The mixture was diluted with H2O (2000 mL) and extracted with EtOAc (3×700 mL). The combined organic layers were washed with brine (1500 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography.

[0546] 2-(1-cyanovinyl)-4-(trifluoromethyl)benzoic acid methyl ester: To a solution of Cu2O (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 H2O (500 mL) was added dropwise 4-(trifluoromethyl)-2-vinylbenzoic acid methyl ester (50 g, 217 mmol) and TMSCN (64.6 g, 652 mmol). The mixture was stirred at 20 °C for 20 h. The mixture was poured into a saturated NaHCO3 aqueous solution (200 mL) and H2O (800 mL). The mixture was filtered and the filtrate was extracted with EtOAc (3×300 mL). The combined organic layer was washed with brine (600 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z = 256.0 [M+H] +.

[0547] 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) at 0°C was added tetrafluoroborate (fluoromethyl)(phenyl)(2,3,4,5-tetramethylphenyl)sulfonium (31.0 g, 86 mmol) and NaH (6.9 g, 172 mmol, 60% purity). The mixture was stirred at 20°C for 1 h. The reaction mixture was poured into H2O (30 mL) and extracted with EtOAc (3×10 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=288.0 [M+H]+.

[0548] (2's,4r)-2'-Fluoro-6-(trifluoromethyl)spiro[2,3-dihydroisoquinolin-4,1'-cyclopropane]-1-one and (2's,4s)-2'-Fluoro-6-(trifluoromethyl)spiro[2,3-dihydroisoquinolin-4,1'-cyclopropane]-1-one: To a solution of 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 (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:

[0549] (2's, 4r)-2'-fluoro-6-(trifluoromethyl)spiro[2,3-dihydroisoquinolin-4,1'-cyclopropane]-1-one: LCMS: m / z=260.0 [M+H]+. 1H NMR (400MHz, CDCl3): δ8.27 (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);

[0550] (2's, 4s)-2'-fluoro-6-(trifluoromethyl)spiro[2,3-dihydroisoquinolin-4,1'-cyclopropane]-1-one: LCMS: m / z=260.0 [M+H]+. 1H NMR (400 MHz, CDCl3): δ8.27 (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).

[0551] Methyl 2-[(2's,4r)-2'-fluoro-1-oxo-6-(trifluoromethyl)spiro[3H-isoquinolin-4,1'-cyclopropane]-2-yl]acetate: To a solution of (2's,4r)-2'-fluoro-6-(trifluoromethyl)spiro[2,3-dihydroisoquinolin-4,1'-cyclopropane]-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. Methyl 2-bromoacetate (2.83 g, 18.5 mmol) was added to the mixture 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 Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z=332.2 [M+H] + .

[0552] Intermediate 40

[0553] 2-[(2's,4r)-2'-fluoro-1-oxo-6-(trifluoromethyl)spiro[3H-isoquinolin-4,1'-cyclopropane]-2-yl]

[0554] Acetic acid

[0555]

[0556] To a solution of methyl 2-[(2's,4r)-2'-fluoro-1-oxo-6-(trifluoromethyl)spiro[3H-isoquinoline-4,1'-cyclopropane]-2-yl]acetate (150 mg, 0.45 mmol) in THF (2.0 mL) and H2O (2.0 mL) was added LiOH·H2O (47 mg, 1.1 mmol). The mixture was stirred at 20°C for 2 h. The mixture was diluted with H2O (3 mL) and extracted with MTBE (2 mL). The aqueous phase was adjusted to pH=3 by adding 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 Na2SO4, filtered and concentrated under reduced pressure to give a crude residue that was used directly. LCMS: m / z=317.9 [M+H] + .

[0557] Intermediate 41

[0558] 6-(Trifluoromethyl)spiro[2,3-dihydroisoquinolin-4,1'-cyclopropane]-1-one

[0559]

[0560] 2-(1-Cyanocyclopropyl)-4-(trifluoromethyl)benzoic acid: KHMDS (25.0 mL, 1 M in THF) was added dropwise to a solution of 2-fluoro-4-(trifluoromethyl)benzoic acid (2.00 g, 9.61 mmol) and cyclopropanenitrile (1.93 g, 28.8 mmol) in THF (20 mL) 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 another 2 h. The reaction mixture was poured into H2O (20 mL) and washed with EtOAc (50 mL). The aqueous layer was then adjusted to pH = 3-4 by adding aqueous HCl (3N). The aqueous was then extracted with EtOAc (3×20 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC.

[0561] Methyl 2-(1-cyanocyclopropyl)-4-(trifluoromethyl)benzoate: TMSCHN2 (3.92mmol, 2M in n-hexane) was added to a solution of 2-(1-cyanocyclopropyl)-4-(trifluoromethyl)benzoic acid (0.50g, 1.96mmol) in THF (10mL) at 0°C. The reaction mixture was stirred at 20°C for 16h. The reaction mixture was quenched by adding AcOH (2mL), and the resulting mixture was extracted with EtOAc (20mL). The organic layer was washed with saturated NaHCO3 aqueous solution (10mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography.

[0562] 6-(Trifluoromethyl)spiro[2,3-dihydroisoquinolin-4,1'-cyclopropane]-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 NaBH4 (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 NH4Cl (10 mL), and extracted with EtOAc (3×10 mL). The organics were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue that was used directly. LCMS: m / z=242.1 [M+H]+

[0563] Methyl 2-[1-oxo-6-(trifluoromethyl)spiro[3H-isoquinolin-4,1'-cyclopropane]-2-yl]acetate: To a solution of 6-(trifluoromethyl)spiro[2,3-dihydroisoquinolin-4,1'-cyclopropane]-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 another 2 h. The reaction mixture was quenched by the addition of water (5 mL) and extracted with EtOAc (3 x 5 mL). The organics were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. 1 H NMR (400MHz, CDCl3): δ8.23(d,J=8.0Hz,1H),7.55(d,J=8.0Hz,1H),7.08(s,1H),4.35(s,2H),3.76(s,3H),3.48(s,2H),1.21-1.06(m,4H).

[0564] Intermediate 42

[0565] 3-Amino-1-cyclopropylcyclobutanol

[0566]

[0567] Tert-butyl (3-cyclopropyl-3-hydroxycyclobutyl)carbamate: To a solution of bromo(cyclopropyl)magnesium (1M 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 h. The mixture was quenched with saturated aqueous NH4Cl solution (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): δ3.74-3.59(m,1H),3.04-2.91(m,1H),2.48-2.33(m,2H),1.95 -1.81(m,2H),1.44(s,9H),1.13-1.08(m,1H),0.54-0.50(m,2H),0.34-0.31(m,2H).

[0568] 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 h at 20° C. The mixture was concentrated under reduced pressure to provide a residue that was used directly.

[0569] Intermediate 43

[0570] 2-(6-Bromo-1-oxo-spiro[3H-isoquinolin-4,1'-cyclopropane]-2-yl)acetamide

[0571]

[0572] 2-(6-Bromo-1-oxo-spiro[3H-isoquinolin-4,1'-cyclopropane]-2-yl)acetic acid: To a solution of methyl 2-(6-bromo-1-oxo-spiro[3H-isoquinolin-4,1'-cyclopropane]-2-yl)acetate (330 mg, 1.02 mmol) in THF (5 mL) was added LiOH solution (2.04 mL, 1 M in H2O). The reaction mixture was stirred at 20 °C for 3 h. The reaction mixture was adjusted to pH 4 using 1N aqueous HCl and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue that was used directly. LCMS: m / z = 310.3, 312.3 [M+H]+.

[0573] 2-(6-Bromo-1-oxo-spiro[3H-isoquinolin-4,1'-cyclopropane]-2-yl)acetamide: To a solution of 2-(6-bromo-1-oxo-spiro[3H-isoquinolin-4,1'-cyclopropane]-2-yl)acetamide (2.0 g, 6.45 mmol), NH4Cl (690 mg, 12.90 mmol), 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 H2O (30 mL) and extracted with DCM (3 x 20 mL). The combined organics were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was triturated with MTBE at 25°C for 30 min to give a residue which was used directly. LCMS: m / z = 309.0, 311.0 [M+H] + .

[0574] Intermediate 44

[0575] 6-Bromo-5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine

[0576]

[0577] 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]+.

[0578] 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 CHCl3 (100 mL) was added POBr3 (7.58 g, 26.4 mmol) at 0°C. The mixture was stirred at 60°C for 2 h. The mixture was diluted with H2O (20 mL) and extracted with DCM (3×7 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. LCMS: m / z=215.9, 217.9 [M+H] + .

[0579] 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 H2O (15 mL) and extracted with EtOAc (3×5 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. LCMS: m / z=299.7, 301.6 [M+H] + .

[0580] Example 1

[0581] 2-[(2'R,4S)-2'-Fluoro-6-(1-fluorocyclopropyl)-1-oxospiro[3H-isoquinoline-4,1'-cyclopropane]-2-

[0582] ]-N-(5-(trifluoromethyl)pyrimidin-2-yl)acetamide (1)

[0583]

[0584] 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 h. 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 h, and then added to the initial mixture at 0°C. The combined reaction mixture was stirred at 0°C for another 1 h, and then at 15°C for another 1 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3×10 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 (400MHz, DMSO-d6): δ11.30(s,1H),9.10(d,J=0.4Hz,2H),7.93(d,J=8.0H z,1H),7.31(dd,J=1.6,8.0Hz,1H),6.69(d,J=1.2Hz,1H),5.17-4.94(m,1H),4 .84(d,J=17.2Hz,1H),4.40(d,J=17.2Hz,1H),3.93(dd,J=2.0,12.8Hz,1H),3. 56(d,J=13.2Hz,1H),1.78-1.67(m,1H),1.59-1.40(m,3H),1.33-1.21(m,2H).

[0585] Example 2

[0586] 2-[(2'R,4S)-2'-Fluoro-6-(1-fluorocyclopropyl)-1-oxospiro[3H-isoquinoline-4,1'-cyclopropane]-2-

[0587] [Methyl]-N-(5-methylpyrimidin-2-yl)acetamide (2)

[0588]

[0589] To a mixture of methyl 2-((1S,2R)-2-fluoro-1'-oxo-6'-(1-fluorocyclopropyl)-1'H-spiro[cyclopropane-1,4'-isoquinolin]-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 H2O (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 (400MHz, CDCl3): δ8.92(br s,1H),8.44(s,2H),8.16(d,J=8.0Hz,1H),7.00(d,J=8.0Hz,1H),6.72(d,J=1.2Hz,1H),5.03(br s,1H),4.79-4.54(m,1H),4.44(br d,J=17.2Hz,1H),4.18(dd,J=1.6,12.8Hz,1H),3.55(d,J=12.8Hz,1H),2.27(s,3H),1.71-1.51(m,3H),1.46-1.32(m,1H),1.18-1.07(m,2H).

[0590] Example 3

[0591] 2-[(2'R,4S)-2'-Fluoro-6-(1-fluorocyclopropyl)-1-oxospiro[3H-isoquinoline-4,1'-cyclopropane]-2-

[0592] [5-[[(5-cyanopyrimidin-2-yl)acetamide]]-N-(5-cyanopyrimidin-2-yl)acetamide (3)

[0593]

[0594] To a solution of 5-cyanopyrimidine-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 h. 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 h, and then added to the initial mixture at 0°C. The combined reaction mixture was stirred at 0°C for another 1 h, and then at 15°C for another 1 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3×10 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 (400MHz, DMSO-d6): δ11.39(s,1H),9.13(s,2H),7.92(d,J=8.0Hz,1H), 7.30(dd,J=1.6,8.4Hz,1H),6.69(d,J=1.2Hz,1H),5.20-4.93(m,1H),4.82( d,J=17.6Hz,1H),4.39(d,J=17.6Hz,1H),3.92(dd,J=1.6,12.8Hz,1H),3.56 (d,J=13.2Hz,1H),1.76-1.69(m,1H),1.61-1.41(m,3H),1.31-1.23(m,2H).

[0595] Example 4

[0596] N-(3-cis-hydroxy-3-methylcyclobutyl)-2-[(2'R,4S)-2'-fluoro-6-(1-fluorocyclopropyl)-1-oxospiro[3H-isoquinolin-4,1'-cyclopropane]-2-yl]acetamide (4)

[0597]

[0598] To a solution of 2-((1S,2R)-2-fluoro-1'-oxo-6'-(1-fluorocyclopropyl)-1'H-spiro[cyclopropane-1,4'-isoquinolin]-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 H2O (10 mL) and extracted with EtOAc (4×5 mL). The combined organic layers were washed with brine (2×10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC. LCMS: m / z=391.1[M+H] + . 1 H NMR (400MHz, CDCl3): δ8.12(d,J=8.0Hz,1H),7.02(d,J=8.0Hz,1H),6.73(s,1H),6.54(br d,J=7.2Hz,1H),4.71-4.48(m,1H),4.39(d,J=16.0Hz,1H),4.13-3.92(m,3H),3.47(d,J=12.8Hz,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).

[0599] Example 5

[0600] N-(3-cis-hydroxy-3-methylcyclobutyl)-2-[(2's,4r)-2',5-difluoro-6-iodo-1-oxospiro]

[0601] [3H-Isoquinolin-4,1'-cyclopropane]-2-yl]acetamide (5)

[0602]

[0603] To a solution of 2-[(2's,4r)-2',5-difluoro-6-iodo-1-oxospiro[3H-isoquinolin-4,1'-cyclopropane]-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 H2O (3 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 reverse phase preparative HPLC. LCMS: m / z = 477.0 [M+H] + . 1 H NMR (400MHz, CDCl3): δ7.81-7.75(m,1H),7.73-7.68(m,1H),6.48(br d,J=7.2Hz,1H),5.34-5.08(m,1H),4.17(s,2H),4.05-3.95(m,1H),3.90(dd,J=2.4,13.2Hz,1H),3.55(d,J=13 .2Hz,1H),2.51(ddd,J=3.2,8.0,10.4Hz,2H),2.18(s,1H),2.07-1.97(m,3H),1.51-1.39(m,1H),1.37(s,3H).

[0604] Example 6

[0605] N-(3-cis-hydroxy-3-methylcyclobutyl)-2-[(2's,4r)-2',5-difluoro-6-cyclopropyl-1-oxospiro[3H-isoquinolin-4,1'-cyclopropane]-2-yl]acetamide (6)

[0606]

[0607] To a solution of 2-[(2's,4r)-6-cyclopropyl-2',5-difluoro-1-oxo-spiro[3H-isoquinolin-4,1'-cyclopropane]-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 H2O (5 mL) and extracted with EtOAc (3×2 mL). The combined organic layers were washed with brine (3 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC. LCMS: m / z=391.1[M+H] + . 1 H NMR (400MHz, CDCl3): δ7.85 (d, J = 8.0Hz, 1H), 6.83 (t, J = 7.6Hz, 1H), 6.62 (br d,J=7.2Hz,1H),5.37-5.13(m,1H),4.27-4.08(m,2H),4.04-3.91(m,1H),3.87(dd,J=13.2,2.4Hz,1H),3.53(d,J=12. 8Hz,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).

[0608] Example 7

[0609] N-(5-chloropyrimidin-2-yl)-2-(6-iodo-1-oxo-4-(trifluoromethyl)-3,4-dihydroisoquinoline

[0610] -2(1H)-methyl)acetamide (7)

[0611]

[0612] 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 AlMe3 (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 Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC to give the title compound as a single unassigned enantiomer. LCMS: m / z=510.9, 512.9 [M+H] + . 1 H NMR (400MHz, CDCl3): δ8.61(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=16.8Hz,1H),4.28(br dd,J=4.4,13.6Hz,1H), 3.84(dd,J=4.0,13.6Hz,1H), 3.62-3.56(m,1H).

[0613] Examples 8 and 9

[0614] 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

[0615] -2(1H)-yl)-N-(5-methylpyrimidin-2-yl)acetamide (9)

[0616]

[0617] 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 AlMe3 (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 Na2SO4, filtered and concentrated under reduced pressure to give the title compound as a single unassigned enantiomer. The residue was purified by reverse phase preparative HPLC to give:

[0618] 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 (400MHz, CDCl3): δ8.63(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=17.2Hz,1H),4.31(br dd,J=4.0,13.6Hz,1H),3.84(dd,J=2.0,14.0Hz,1H),3.64-3.56(m,1H),2.23(s,3H).

[0619] 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] + . 1 H NMR (400MHz, CDCl3): δ8.62(br s,1H),8.43(s,2H),8.11(d,J=8.0Hz,1H),7.34(br d,J=8.0Hz,1H),7.17(s,1H),5.22-5.09(m,1H),4.36(d,J=16.8Hz,1H),4.25(br dd,J=4.8,13.6Hz,1H),3.85(br d,J=12.8Hz,1H),3.61-3.54(m,1H),2.44(s,3H),2.28(s,3H).

[0620] Examples 10 and 11

[0621] N-(3-cis-hydroxy-3-methylcyclobutyl)-2-(6-iodo-1-oxo-4-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)acetamide (10 and 11)

[0622]

[0623] 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 H2O (5 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 reverse phase preparative HPLC and further purified by chiral SFC (column: REGIS (s,s) WHELK-O1 (250 mm×30 mm×10 μm particle size); mobile phase: A: CO2 B: 0.1% NH4OH / 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:

[0624] 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] + .

[0625] 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] + .

[0626] Examples 12 and 13

[0627] 2-[(2's,4r)-2',5-difluoro-1-oxo-6-(trifluoromethyl)spiro[3H-isoquinoline-4,1'-cyclopropane

[0628] [alkyl]-2-yl]-N-(5-chloropyrimidin-2-yl)acetamide (12 and 13)

[0629]

[0630] To a solution of methyl 2-[(2's,4r)-2'-fluoro-1-oxo-6-(trifluoromethyl)spiro[3H-isoquinolin-4,1'-cyclopropane]-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 AlMe3 (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 H2O (10 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 reverse phase preparative HPLC and further purified by chiral SFC (column: Chiralpak IG-3 (50 mm×4.6 mm×3 μm particle size); mobile phase: A: CO2 B: 0.1% i-PrNH2 / 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:

[0631] 2-[(2's, 4r)-2',5-difluoro-1-oxo-6-(trifluoromethyl)spiro[3H-isoquinolin-4,1'-cyclopropane]-2-yl]-N-(5-chloropyrimidin-2-yl)acetamide (first eluting isomer, 12): LCMS: m / z=447.0, 449.0 [M+H] + . 1 HNMR (400MHz, CDCl3): δ8.70(br s,1H),8.56(br s,2H),8.12(d,J=8.0Hz,1H),7.62-7.57(m,1H),5.45-5.26(m,1H),5.07(br d,J=16.4Hz,1H),4.54(br d,J=17.2Hz,1H),3.96(dd,J=2.8,13.2Hz,1H),3.70(d,J=13.2Hz,1H),2.03(td,J=7.6,11.6Hz,1H),1.61-1.50(m,1H).

[0632] 2-[(2's, 4r)-2',5-difluoro-1-oxo-6-(trifluoromethyl)spiro[3H-isoquinolin-4,1'-cyclopropane]-2-yl]-N-(5-chloropyrimidin-2-yl)acetamide (second eluting isomer, 13): LCMS: m / z=447.0, 449.0 [M+H] + . 1 HNMR (400MHz, CDCl3): δ8.74(br s,1H),8.56(br s,2H),8.11(d,J=8.4Hz,1H),7.62(t,J=7.2Hz,1H),5.45-5.27(m,1H),5.07(br d,J=16.8Hz,1H),4.54(br d,J=17.2Hz,1H),3.94(dd,J=2.0,13.2Hz,1H),3.70(d,J=12.8Hz,1H),2.03(td,J=6.8,11.2Hz,1H),1.59-1.51(m,1H).

[0633] Examples 14 and 15

[0634] N-(5-chloropyrimidin-2-yl)-2-[1',1',5-trifluoro-6-(trifluoromethyl)-1-oxospiro[3H-isoquinoline

[0635] -4,2'-cyclopropane]-2-yl]acetamide (14 and 15)

[0636]

[0637] 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) was added 5-chloropyrimidin-2-amine (51 mg, 0.39 mmol) and AlMe3 (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 H2O (12 mL) and extracted with EtOAc (3×12 mL). The combined organic layers were washed with brine (12 mL), dried over anhydrous Na2SO4, 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×10 μm particle size); mobile phase: A: CO2 B: 0.1% NH4OH / 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:

[0638] N-(5-chloropyrimidin-2-yl)-2-[1',1',5-trifluoro-6-(trifluoromethyl)-1-oxospiro[3H-isoquinolin-4,2'-cyclopropane]-2-yl]acetamide (first eluting isomer, 14): LCMS: m / z=465.0, 467.0 [M+H] + . 1 H NMR (400MHz, CDCl3): δ8.55(s,2H),8.54-8.47(m,1H),8.13(d,J=8.0Hz,1H),7.70(t,J=7. 3Hz,1H),5.41-5.26(m,1H),4.50(dd,J=6.4,12.8Hz,1H),4.28(d,J=17.6Hz,1H),3.12(br d,J=13.2Hz,1H),3.04-2.92(m,1H),1.72-1.61(m,1H).

[0639] N-(5-chloropyrimidin-2-yl)-2-[1',1',5-trifluoro-6-(trifluoromethyl)-1-oxospiro[3H-isoquinolin-4,2'-cyclopropane]-2-yl]acetamide (second eluting isomer, 15): LCMS: m / z=465.0, 467.0 [M+H] + . 1 H NMR(400MHz, CDCl3): δ8.64(br s,1H),8.56(s,2H),8.13(d,J=8.4Hz,1H),7.73-7.66(m,1H),5.42-5.25(m,1H),4.50(dd,J=6. 8,13.2Hz,1H),4.28(d,J=17.2Hz,1H),3.16-3.07(m,1H),3.04-2.93(m,1H),1.72-1.61(m,1H).

[0640] Examples 16 and 17

[0641] N-(5-chloropyrimidin-2-yl)-2-[6-bromo-1',1'-difluoro-1-oxospiro[3H-isoquinolin-4,2'-cyclopropane]-2-yl]acetamide (16 and 17)

[0642]

[0643] N-(5-chloropyrimidin-2-yl)-2-[6-bromo-1',1'-difluoro-1-oxospiro[3H-isoquinolin-4,2'-cyclopropane]-2-yl]acetamide: To a mixture of 5-chloropyrimidin-2-amine (72 mg, 0.56 mmol) in toluene (4.0 mL) was added AlMe3 (1 M in n-heptane, 0.56 mL). The reaction mixture was stirred at 25 °C for 50 min, 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 h. The reaction mixture was diluted with water (4 mL) and extracted with EtOAc (3 x 2 mL). The combined organics were washed with brine (3 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC and further purified by chiral SFC (column: Chiralpak AD-3 (50 mm×4.6 mm×3 μm particle size); mobile phase: A: CO2 B: 0.1% i-PrNH2 / 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:

[0644] N-(5-chloropyrimidin-2-yl)-2-[6-bromo-1',1'-difluoro-1-oxospiro[3H-isoquinolin-4,2'-cyclopropane]-2-yl]acetamide (first eluting isomer, 16): LCMS: m / z=456.9, 458.9, 460.9 [M+H] + . 1 H NMR (400MHz, CDCl3): δ8.89(br s,1H),8.58(s,2H),8.09(d,J=8.4Hz,1H),7.63(dd,J=1.6,8.4Hz,1H),7.25(s,1H),5.21-5.16(m,1H),4.37(br d,J=16.8Hz,1H),4.24(dd,J=5.6,12.8Hz,1H),3.46(d,J=12.4Hz,1H),2.13-2.09(m,1H),1.79-1.73(m,1H).

[0645] N-(5-chloropyrimidin-2-yl)-2-[6-bromo-1',1'-difluoro-1-oxospiro[3H-isoquinolin-4,2'-cyclopropane]-2-yl]acetamide (second eluting isomer, 17): LCMS: m / z=456.9, 458.9, 460.9 [M+H] + .1 H NMR (400MHz, CDCl3): δ9.02(br s,1H),8.59(s,2H),8.10(d,J=8.4Hz,1H),7.62(br d,J=8.4Hz,1H),7.25(s,1H),5.22-5.17(m,1H),4.38(br d,J=17.2Hz,1H),4.24(br dd,J=5.2,12.8Hz,1H),3.46(br d,J=12.8Hz,1H),2.15-2.09(m,1H),1.79-1.71(m,1H).

[0646] Examples 18 and 19

[0647] N-(5-methylpyrimidin-2-yl)-2-[6-bromo-1',1'-difluoro-1-oxospiro[3H-isoquinolin-4,2'-cyclopropane]-2-yl]acetamide (18 and 19)

[0648]

[0649] To 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) and 5-methylpyrimidin-2-amine (91 mg, 0.83 mmol) in DCE (2.0 mL) was added AlMe3 (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 Na2SO4, 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×10 μm particle size); mobile phase: A: CO2 B: 0.1% NH4OH / 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:

[0650] N-(5-methylpyrimidin-2-yl)-2-[6-bromo-1',1'-difluoro-1-oxospiro[3H-isoquinolin-4,2'-cyclopropane]-2-yl]acetamide (first eluting isomer, 18): LCMS: m / z=436.9, 438.9 [M+H] + . 1H NMR (400MHz, CDCl3): δ9.34(br s,1H),8.46(s,2H),8.07(d,J=8.2Hz,1H),7.57(dd,J=1.8,8.2Hz,1H),7.23(d,J=1.6Hz,1H),5.30(br d,J=14.8Hz,1H),4.38(br d,J=17.2Hz,1H),4.19(dd,J=5.2,12.8Hz,1H),3.42(d,J=12.8Hz,1H),2.28(s,3H),2.09-2.05(m,1H),1.75-1.71(m,1H).

[0651] N-(5-methylpyrimidin-2-yl)-2-[6-bromo-1',1'-difluoro-1-oxospiro[3H-isoquinolin-4,2'-cyclopropane]-2-yl]acetamide (second eluting isomer, 19): LCMS: m / z=436.9, 438.9 [M+H] + . 1 H NMR (400MHz, CDCl3): δ9.20 (s, 1H), 8.45 (s, 2H), 8.07 (d, J = 8.4Hz, 1H), 7.57 (dd, J = 1.6, 8.4Hz, 1H), 7.23 (d, J = 1.2Hz, 1H), 5.29 (br d,J=16.4Hz,1H),4.38(br d,J=17.2Hz,1H),4.19(dd,J=5.4,12.8Hz,1H),3.42(d,J=13.2Hz,1H),2.28(s,3H),2.09-2.04(m,1H),1.75-1.71(m,1H).

[0652] Examples 20 and 21

[0653] N-(3-cis-hydroxy-3-methylcyclobutyl)-2-[6-bromo-1',1'-difluoro-1-oxospiro[3H-isoquinolin-4,2'-cyclopropane]-2-yl]acetamide (20 and 21)

[0654]

[0655] To a solution of 2-(6-bromo-1',1'-difluoro-1-oxo-spiro[3H-isoquinolin-4,2'-cyclopropane]-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 H2O (3 mL) and extracted with EtOAc (3×5 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 and further purified by chiral SFC (column: REGIS (s, s) WHELK-O1 (250 mm×30 mm×10 μm particle size); mobile phase: A: CO2 B: i-PrOH (0.1% i-PrNH2, 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:

[0656] N-(3-cis-hydroxy-3-methylcyclobutyl)-2-[6-bromo-1',1'-difluoro-1-oxospiro[3H-isoquinolin-4,2'-cyclopropane]-2-yl]acetamide (first eluting isomer, 20): LCMS: m / z=429.0, 430.9 [M+H] + . 1 H NMR (400MHz, CDCl3): δ8.03(d,J=8.4Hz,1H),7.59(dd,J=2.0,8.4Hz,1H),7.21(d,J=1.2Hz,1H),6.49(br d,J=7.2Hz,1H),4.18(s,2H),4.07(dd,J=6.0,13.2Hz,1H),4.01-3.94(m,1H),3.41(dd,J=1.2,13. 2Hz,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).

[0657] N-(3-cis-hydroxy-3-methylcyclobutyl)-2-[6-bromo-1',1'-difluoro-1-oxospiro[3H-isoquinolin-4,2'-cyclopropane]-2-yl]acetamide (second eluting isomer, 21): LCMS: m / z=429.0, 430.9 [M+H] + . 1H NMR (400MHz, CDCl3): δ8.03(d,J=8.4Hz,1H),7.60(dd,J=2.0,8.4Hz,1H),7.21(d,J=1.6Hz,1H),6.48(br d,J=7.2Hz,1H),4.18(s,2H),4.07(dd,J=6.0,12.8Hz,1H),4.01-3.93(m,1H),3.41(dd,J=1.6,13. 2Hz,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).

[0658] Examples 22 and 23

[0659] N-(3-cis-hydroxy-3-methylcyclobutyl)-2-[1',1'-difluoro-6-(1-fluorocyclopropyl)-1-oxospiro

[0660] [3H-isoquinolin-4,2'-cyclopropane]-2-yl]acetamide (22 and 23)

[0661]

[0662] To a solution of 2-(2,2-difluoro-6'-(1-fluorocyclopropyl)-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinolin]-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 H2O (5 mL), and extracted with EtOAc (3×5 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 and further purified by chiral SFC (column: REGIS (s,s) WHELK-O1 (250 mm×30 mm×10 μm particle size); mobile phase: A: CO2 B: 0.1% NH4OH / 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:

[0663] N-(3-cis-hydroxy-3-methylcyclobutyl)-2-[1',1'-difluoro-6-(1-fluorocyclopropyl)-1-oxospiro[3H-isoquinolin-4,2'-cyclopropane]-2-yl]acetamide (first eluting isomer, 22): LCMS: m / z=409.1 [M+H] + . 1 H NMR (400MHz, CDCl3): δ8.14(d,J=8.0Hz,1H),7.12(d,J=8.0Hz,1H),7.04(s,1H),6.54(br d,J=7.2Hz,1H),4.29-4.12(m,2H),4.08(dd,J=6.0,12.8Hz,1H),3.98(d,J=8.0Hz,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).

[0664] N-(3-cis-hydroxy-3-methylcyclobutyl)-2-[1',1'-difluoro-6-(1-fluorocyclopropyl)-1-oxospiro[3H-isoquinolin-4,2'-cyclopropane]-2-yl]acetamide (second eluting isomer, 23): LCMS: m / z=409.1 [M+H] + . 1 H NMR (400MHz, CDCl3): δ8.14(d,J=8.0Hz,1H),7.12(d,J=8.4Hz,1H),7.04(s,1H),6.54(br d,J=7.2Hz,1H),4.29-4.12(m,2H),4.08(dd,J=6.0,12.8Hz,1H),3.98(d,J=8.0Hz,1H),3.40(d,J=12.8Hz,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).

[0665] Examples 24 and 25

[0666] N-(5-methylpyrimidin-2-yl)-2-[1',1'-difluoro-6-(1-fluorocyclopropyl)-1-oxospiro[3H-isoquinolin-4,2'-cyclopropane]-2-yl]acetamide (24 and 25)

[0667]

[0668] To a solution of 5-methylpyrimidin-2-amine (39 mg, 0.35 mmol) in DCE (0.5 mL) was added AlMe3 (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 another 4 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3×10 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 and further purified by chiral SFC (column: REGIS (s,s) WHELK-O1 (250 mm×30 mm×10 μm particle size); mobile phase: A: CO2 B: 0.1% NH4OH / 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:

[0669] N-(5-methylpyrimidin-2-yl)-2-[1',1'-difluoro-6-(1-fluorocyclopropyl)-1-oxospiro[3H-isoquinolin-4,2'-cyclopropane]-2-yl]acetamide (first eluting isomer, 24): LCMS: m / z=417.1 [M+H] + . 1 H NMR (400MHz, CDCl3): δ8.54(br s,1H),8.43(s,2H),8.18(d,J=8.4Hz,1H),7.12(d,J=8.4Hz,1H),7.06(s,1H),5.29-5.10(m,1H),4.34(br d,J=17.2Hz,1H),4.21(br dd,J=5.6,12.8Hz,1H),3.42(br d,J=13.2Hz,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).

[0670] N-(5-methylpyrimidin-2-yl)-2-[1',1'-difluoro-6-(1-fluorocyclopropyl)-1-oxospiro[3H-isoquinolin-4,2'-cyclopropane]-2-yl]acetamide (second eluting isomer, 25): LCMS: m / z=417.1 [M+H] + .1 H NMR (400MHz, CDCl3): δ8.54(br s,1H),8.43(s,2H),8.19(d,J=7.6Hz,1H),7.12(d,J=8.0Hz,1H),7.06(s,1H),5.31-5.08(m,1H),4.34(br d,J=16.8Hz,1H),4.21(dd,J=6.0,12.8Hz,1H),3.43(d,J=12.4Hz,1H),2.28(s,3H),2.21-2.10(m,1H),1.72-1.56(m,3H),1.19-1.11(m,2H).

[0671] Examples 26 and 27

[0672] N-(5-fluoropyrimidin-2-yl)-2-[1',1'-difluoro-6-(1-fluorocyclopropyl)-1-oxospiro[3H-isoquinoline

[0673] -4,2'-cyclopropane]-2-yl]acetamide (26 and 27)

[0674]

[0675] To a solution of 2-(2,2-difluoro-6'-(1-fluorocyclopropyl)-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinolin]-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 H2O (5 mL) and extracted with EtOAc (3×5 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 and further purified by chiral SFC (column: REGIS (s,s) WHELK-O1 (250 mm×30 mm×10 μm particle size); mobile phase: A: CO2 B: 0.1% NH4OH / 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:

[0676] N-(5-fluoropyrimidin-2-yl)-2-[1',1'-difluoro-6-(1-fluorocyclopropyl)-1-oxospiro[3H-isoquinolin-4,2'-cyclopropane]-2-yl]acetamide (first eluting isomer, 26): LCMS: m / z=421.1 [M+H] + . 1H NMR (400MHz, CDCl3): δ8.76 (br s,1H),8.48(s,2H),8.19(d,J=8.0Hz,1H),7.12(d,J=8.0Hz,1H),7.06(s,1H),5.14-4.98(m,1H),4.31(d,J=16.4Hz,1H),4.2 1(dd,J=6.0,12.8Hz,1H),3.44(d,J=13.2Hz,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).

[0677] N-(5-fluoropyrimidin-2-yl)-2-[1',1'-difluoro-6-(1-fluorocyclopropyl)-1-oxospiro[3H-isoquinolin-4,2'-cyclopropane]-2-yl]acetamide (second eluting isomer, 27): LCMS: m / z=421.1 [M+H] + . 1 H NMR (400MHz, CDCl3): δ8.76 (br s,1H),8.48(s,2H),8.19(d,J=8.0Hz,1H),7.12(d,J=8.0Hz,1H),7.06(s,1H),5.14-4.98(m,1H),4.31(d,J=16.4Hz,1H),4.2 1(dd,J=6.0,12.8Hz,1H),3.44(d,J=13.2Hz,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).

[0678] Examples 28 and 29

[0679] N-(5-fluoropyrimidin-2-yl)-2-[6-cyclopropyl-1',1'-difluoro-1-oxospiro[3H-isoquinoline-4,2'-

[0680] Cyclopropane-2-yl]acetamide (28 and 29)

[0681]

[0682] 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) was 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 h. The reaction mixture was diluted with H2O (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 reverse phase preparative HPLC and further purified by chiral SFC (column: REGIS (s,s) WHELK-O1 (250 mm×30 mm×10 μm particle size); mobile phase: A: CO2 B: 0.1% NH4OH / 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:

[0683] N-(5-fluoropyrimidin-2-yl)-2-[6-cyclopropyl-1',1'-difluoro-1-oxospiro[3H-isoquinolin-4,2'-cyclopropane]-2-yl]acetamide (first eluting isomer, 28): LCMS: m / z=403.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ10.95(s,1H),8.76(s,2H),7.82(d,J=8.0Hz,1H),7.12(d,J=7.6Hz,1H),7.01(s,1H),4.83(br d,J=17.2Hz,1H),4.17(br d,J=17.2Hz,1H),4.10(br dd,J=6.8,12.8Hz,1H),3.34(br d,J=13.2Hz,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).

[0684] N-(5-fluoropyrimidin-2-yl)-2-[6-cyclopropyl-1',1'-difluoro-1-oxospiro[3H-isoquinolin-4,2'-cyclopropane]-2-yl]acetamide (second eluting isomer, 29): LCMS: m / z=403.1 [M+H] + . 1H NMR (400MHz, DMSO-d6): δ10.95(br s,1H),8.76(s,2H),7.82(d,J=8.0Hz,1H),7.12(dd,J=1.2,8.0Hz,1H),7.01(s,1H),4.83(br d,J=17.2Hz,1H),4.17(br d,J=17.2Hz,1H),4.10(br dd,J=6.8,13.2Hz,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).

[0685] Examples 30 and 31

[0686] N-([1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-[6-bromo-1',1',5-trifluoro-1-oxospiro[3H-

[0687] Isoquinolin-4,2'-cyclopropane-2-yl]acetamide (30 and 31)

[0688]

[0689] To a solution of 2-[6-bromo-1',1',5-trifluoro-1-oxospiro[3H-isoquinolin-4,2'-cyclopropane]-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 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 5 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 and further purified by chiral SFC (column: Chiralcel OD-3 (50 mm×4.6 mm×3 μm particle size); mobile phase: A: CO2 B: 0.1% i-PrNH2 / 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:

[0690] N-([1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-[6-bromo-1',1',5-trifluoro-1-oxospiro[3H-isoquinolin-4,2'-cyclopropane]-2-yl]acetamide (first eluting isomer, 30): LCMS: m / z=480.0, 482.0 [M+H] + . 1 H NMR (400MHz, CDCl3): δ9.75(br s,1H),8.57(br d,J=6.4Hz,1H),7.93(d,J=8.4Hz,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).

[0691] N-([1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-[6-bromo-1',1',5-trifluoro-1-oxospiro[3H-isoquinolin-4,2'-cyclopropane]-2-yl]acetamide (second eluting isomer, 31): LCMS: m / z=480.0, 482.0 [M+H] + . 1 H NMR(400MHz, CDCl3): δ9.70(br s,1H),8.57(br d,J=6.8Hz,1H),7.93(d,J=8.0Hz,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).

[0692] Examples 32 and 33

[0693] N-(5-methylpyrimidin-2-yl)-2-[6-bromo-1',1',5-trifluoro-1-oxospiro[3H-isoquinolin-4,2'-cyclopropane]-2-yl]acetamide (32 and 33)

[0694]

[0695] To a solution of methyl 2-(6'-bromo-2,2,5'-trifluoro-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinolin]-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 AlMe3 (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 Na2SO4, 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×10 μm particle size); mobile phase: A: CO2 B: 0.1% NH4OH / 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:

[0696] N-(5-methylpyrimidin-2-yl)-2-[6-bromo-1',1',5-trifluoro-1-oxospiro[3H-isoquinolin-4,2'-cyclopropane]-2-yl]acetamide (first eluting isomer, 32): LCMS: m / z=455.0, 456.9 [M+H] + . 1 H NMR (400MHz, CDCl3): δ8.69(br s,1H),8.43(s,2H),7.92(d,J=8.4Hz,1H),7.73-7.57(m,1H),5.39(brs,1H),4.48(dd,J=6.8,19.6Hz,1H),4.27(br d,J=17.2Hz,1H),3.09(br d,J=12.8Hz,1H),2.98-2.88(m,1H),2.28(s,3H),1.63(br s,1H).

[0697] N-(5-methylpyrimidin-2-yl)-2-[6-bromo-1',1',5-trifluoro-1-oxospiro[3H-isoquinolin-4,2'-cyclopropane]-2-yl]acetamide (second eluting isomer, 33): LCMS: m / z=454.9, 456.9 [M+H] + . 1H NMR (400MHz, CDCl3): δ8.73 (br s,1H),8.43(s,2H),7.92(d,J=8.4Hz,1H),7.63(dd,J=6.4,8.4Hz,1H),5. 48-5.24(m,1H),4.48(dd,J=6.8,13.2Hz,1H),4.35-4.22(m,1H),3.09(br d,J=12.8Hz,1H),2.99-2.87(m,1H),2.28(s,3H),1.59-1.55(m,1H).

[0698] Examples 34 and 35

[0699] N-(5-chloropyrimidin-2-yl)-2-[6-cyclopropyl-1',1',5-trifluoro-1-oxospiro[3H-isoquinoline-4,2'-

[0700] Cyclopropane-2-yl]acetamide (34 and 35)

[0701]

[0702] To a mixture of 5-chloropyrimidine-2-amine (229 mg, 1.77 mmol) in DCE (6.0 mL) was added AlMe3 (1 M in n-heptane, 1.77 mL). The reaction mixture was stirred at 25 ° C for 50 min, and then a solution of 2-(6'-cyclopropyl-2,2,5'-trifluoro-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)acetic acid methyl ester (300 mg, 0.88 mmol) in DCE (3.0 mL) was added. The reaction mixture was stirred at 80 ° C for 5 h, and then heated to 100 ° C and stirred for 5 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (3×10 mL). The combined organic layer was washed with brine (3 mL), dried over anhydrous Na2SO4, 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×30 mm×10 μm particle size); mobile phase: A: CO2 B: 0.1% NH4OH / 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:

[0703] N-(5-chloropyrimidin-2-yl)-2-[6-cyclopropyl-1',1',5-trifluoro-1-oxospiro[3H-isoquinolin-4,2'-cyclopropane]-2-yl]acetamide (first eluting isomer, 34): LCMS: m / z=437.0, 439.0 [M+H] + . 1 H NMR (400MHz, CDCl3): δ11.04(s,1H),8.78(s,2H),7.72(d,J=8.0Hz,1H),7.08(t,J=7.6Hz,1H),4.87(br d,J=17.2Hz,1H),4.24(br dd,J=7.2,13.6Hz,1H),4.17(br d,J=17.2Hz,1H),3.25(br d,J=13.6Hz,1H),2.84(br t,J=10.4Hz,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).

[0704] N-(5-chloropyrimidin-2-yl)-2-[6-cyclopropyl-1',1',5-trifluoro-1-oxospiro[3H-isoquinolin-4,2'-cyclopropane]-2-yl]acetamide (second eluting isomer, 35): LCMS: m / z=437.0, 439.0 [M+H] + . 1 H NMR (400MHz, CDCl3): δ11.04(s,1H),8.78(s,2H),7.72(d,J=8.0Hz,1H),7.08(t,J=7.6Hz,1H),4.87(br d,J=17.2Hz,1H),4.24(br dd,J=7.2,13.2Hz,1H),4.17(br d,J=17.2Hz,1H),3.25(br d,J=13.2Hz,1H),2.84(br t,J=10.4Hz,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).

[0705] Examples 36 and 37

[0706] N-(5-methylpyrimidin-2-yl)-2-[6-cyclopropyl-1',1',5-trifluoro-1-oxospiro[3H-isoquinoline

[0707] -4,2'-cyclopropane]-2-yl]acetamide (36 and 37)

[0708]

[0709] To a mixture of 5-methylpyrimidine-2-amine (128 mg, 1.18 mmol) in DCE (5.0 mL) was added AlMe3 (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 another 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 Na2SO4, 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: CO2 B: 0.1% i-PrNH2 / 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:

[0710] N-(5-methylpyrimidin-2-yl)-2-[6-cyclopropyl-1',1',5-trifluoro-1-oxospiro[3H-isoquinolin-4,2'-cyclopropane]-2-yl]acetamide (first eluting isomer, 36): LCMS: m / z=417.1 [M+H] + . 1 H NMR (400MHz, CDCl3): δ8.62(br s,1H),8.43(s,2H),7.92(d,J=8.0Hz,1H),6.91(t,J=7.2Hz,1H),5.35-5.12(m,1H),4.43(br dd,J=7.2,13.2Hz,1H),4.25(br d,J=16.8Hz,1H),3.09(brd,J=12.4Hz,1H),3.02-2.91(m,1H),2.28(s,3H),2.16-2.07(m,1H),1.27(br d,J=2.8Hz,1H),1.07(br d,J=8.4Hz,2H),0.83-0.73(m,2H).

[0711] N-(5-methylpyrimidin-2-yl)-2-[6-cyclopropyl-1',1',5-trifluoro-1-oxospiro[3H-isoquinolin-4,2'-cyclopropane]-2-yl]acetamide (second eluting isomer, 37): LCMS: m / z=417.1 [M+H] + . 1 H NMR (400MHz, CDCl3): δ8.69(br s,1H),8.43(s,2H),7.92(d,J=8.0Hz,1H),6.90(t,J=7.2Hz,1H),5.36-5.10(m,1H),4.43(br dd,J=7.2,13.2Hz,1H),4.25(br d,J=17.6Hz,1H),3.09(brd,J=12.4Hz,1H),2.97(br t,J=10.4Hz,1H),2.28(s,3H),2.18-2.05(m,1H),1.26(br d,J=7.2Hz,1H),1.11-1.01(m,2H),0.85-0.71(m,2H).

[0712] Examples 38 and 39

[0713] N-(5-chloropyrimidin-2-yl)-2-[1',1'-difluoro-6-(trifluoromethyl)-1-oxospiro[3H-isoquinoline

[0714] -4,2'-cyclopropane]-2-yl]acetamide (38 and 39)

[0715]

[0716] To a mixture of 5-chloropyrimidin-2-amine (223 mg, 1.72 mmol) in DCE (1.0 mL) was added AlMe3 (1 M in n-heptane, 1.72 mL). The reaction mixture was stirred at 25 °C for 30 min, 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 another 12 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (3×10 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 and further purified by chiral SFC (column: Phenomenex Cellulose-2 (250 mm×30 mm×10 μm particle size); mobile phase: A: CO2 B: 0.1% NH4OH / 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:

[0717] N-(5-chloropyrimidin-2-yl)-2-[1',1'-difluoro-6-(trifluoromethyl)-1-oxospiro[3H-isoquinolin-4,2'-cyclopropane]-2-yl]acetamide (first eluting isomer, 38): LCMS: m / z=447.1, 449.0 [M+H] + . 1 H NMR (400MHz, CDCl3): δ8.55(s,2H),8.52(br s,1H),8.34(d,J=8.0Hz,1H),7.71(d,J=8.4Hz,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).

[0718] N-(5-chloropyrimidin-2-yl)-2-[1',1'-difluoro-6-(trifluoromethyl)-1-oxospiro[3H-isoquinolin-4,2'-cyclopropane]-2-yl]acetamide (second eluting isomer, 39): LCMS: m / z=447.0, 449.0 [M+H] + . 1H NMR (400MHz, CDCl3): δ8.55(s,2H),8.54-8.48(m,1H),8.34(d,J=8.0Hz,1H),7.71(d,J=8.4Hz,1H),7.33(s,1H),5.34-5.15 (m,1H),4.37(d,J=17.2Hz,1H),4.23(dd,J=5.6,12.8Hz,1H),3.46(d,J=13.6Hz,1H),2.19-2.15(m,1H),1.81-1.77(m,1H).

[0719] Examples 40 and 41

[0720] N-(5-fluoropyrimidin-2-yl)-2-[1',1'-difluoro-6-(trifluoromethyl)-1-oxospiro[3H-isoquinoline

[0721] -4,2'-cyclopropane]-2-yl]acetamide (40 and 41)

[0722]

[0723] To a mixture of 5-fluoropyrimidine-2-amine (233 mg, 2.06 mmol) in DCE (3.0 mL) was added AlMe3 (1 M in n-heptane, 2.29 mL). The reaction mixture was stirred at 25 °C for 30 min, 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 (400 mg, 1.15 mmol) in DCE (5.0 mL) was added. The reaction mixture was stirred at 85 °C for another 3 h. 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 Na2SO4, 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: CO2 B: 0.1% NH4OH / i-PrOH; gradient: B%: 30% to 50%, 15 min; flow rate: 3.4 mL / min; detection wavelength: 220 nm; column temperature: 35°C; system back pressure: 1800 psi) to give:

[0724] N-(5-fluoropyrimidin-2-yl)-2-[1',1'-difluoro-6-(trifluoromethyl)-1-oxospiro[3H-isoquinolin-4,2'-cyclopropane]-2-yl]acetamide (first eluting isomer, 40): LCMS: m / z=431.0 [M+H]+ . 1 H NMR (400MHz, CDCl3): δ8.59(br s,1H),8.49(s,2H),8.34(d,J=8.4Hz,1H),7.71(d,J=8.0Hz,1H),7.33(s,1H),5.33-5.10(m,1H),4.35(br d,J=17.2Hz,1H),4.24(dd,J=5.2,12.4Hz,1H),3.47(d,J=13.2Hz,1H),2.21-2.14(m,1H),1.83-1.76(m,1H).

[0725] N-(5-fluoropyrimidin-2-yl)-2-[1',1'-difluoro-6-(trifluoromethyl)-1-oxospiro[3H-isoquinolin-4,2'-cyclopropane]-2-yl]acetamide (second eluting isomer, 41): LCMS: m / z=431.0 [M+H] + . 1 H NMR (400MHz, CDCl3): δ8.57(br s,1H),8.48(s,2H),8.34(d,J=8.0Hz,1H),7.71(br d,J=8.0Hz,1H),7.33(s,1H),5.33-5.11(m,1H),4.35(br d,J=17.2Hz,1H),4.24(br dd,J=5.2,12.8Hz,1H),3.47(br d,J=12.8Hz,1H),2.21-2.14(m,1H),1.83-1.76(m,1H).

[0726] Embodiment 42

[0727] 2-(6-Bromo-1-oxo-spiro[3H-isoquinolin-4,1'-cyclopropane]-2-yl)-N-(1H-pyrazolo[3,4-d]

[0728] Pyrimidin-6-yl)acetamide (42)

[0729]

[0730] To a solution of methyl 2-(6-bromo-1-oxo-spiro[3H-isoquinolin-4,1'-cyclopropane]-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 AlMe3 (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 H2O (5 mL) and extracted with EtOAc (3×10 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=427.1, 429.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ13.79(br s,1H),10.91(s,1H),9.18(s,1H),8.24(s,1H),7.82(d,J=8.4Hz,1H),7.53(dd,J=1.6,8.4Hz ,1H),7.27(d,J=1.6Hz,1H),4.61(s,2H),3.51(s,2H),1.19-1.14(m,2H),1.09-1.03(m,2H).

[0731] Embodiment 43

[0732] 2-[(2's,4r)-6-chloro-2',5-difluoro-1-oxospiro[3H-isoquinoline-4,1'-cyclopropane]-2-

[0733]

[43] -N-(5-chloropyrimidin-2-yl)acetamide

[0734]

[0735] To a solution of 5-chloropyrimidin-2-amine (62 mg, 0.45 mmol) in DCE (5.0 mL) was added AlMe3 (1 M in n-heptane, 0.29 mL). The mixture was stirred for 0.5 h, and then 2-[(2's, 4r)-6-chloro-2',5-difluoro-1-oxo-spiro[3H-isoquinoline-4,1'-cyclopropane]-2-yl]acetic acid methyl ester (30 mg, 0.09 mmol) was added. The mixture was stirred at 60 ° C for another 5 h. The mixture was quenched with H2O (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=413.0, 415.0, 417.0 [M+H] + .1 H NMR(400MHz, CDCl3): δ11.02(br s,1H),8.78(s,2H),7.85-7.73(m,1H),7.61(dd,J=7.0,8.4Hz,1H),5.67-5.41(m,1H),4.72(d, J=17.2Hz,1H),4.40(d,J=17.2Hz,1H),3.87-3.61(m,2H),1.89-1.79(m,1H),1.73-1.61(m,1H).

[0736] Embodiment 44

[0737] 2-[(2's,4r)-6-chloro-2',5-difluoro-1-oxospiro[3H-isoquinoline-4,1'-cyclopropane]-2-

[0738]

[44] -N-(5-methylpyrimidin-2-yl)acetamide

[0739]

[0740] To a solution of methyl 2-[(2's,4r)-6-chloro-2',5-difluoro-1-oxo-spiro[3H-isoquinolin-4,1'-cyclopropane]-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 AlMe3 (1 M in n-heptane, 0.38 mL). The mixture was stirred at 60 °C for 4 h. The mixture was quenched with H2O (5 mL) and extracted with DCM (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 reverse phase preparative HPLC. LCMS: m / z=392.9,395.0 [M+H] + . 1 H NMR (400MHz, CDCl3): δ10.72(s,1H),8.51(s,2H),7.80(d,J=8.6Hz,1H),7.66-7.56(m,1H),5.69-5.42(m,1H),4.73(br d,J=17.2Hz,1H),4.40(br d,J=17.2Hz,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).

[0741] Embodiment 45

[0742] 2-[(2's,4r)-6-chloro-2',5-difluoro-1-oxospiro[3H-isoquinoline-4,1'-cyclopropane]-2-

[0743] [3,4-d]pyrimidin-6-yl]-N-(1H-pyrazolo[3,4-d]pyrimidin-6-yl)acetamide (45)

[0744]

[0745] 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-isoquinolin-4,1'-cyclopropane]-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 H2O (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 (400MHz, CDCl3): δ9.07 (s, 1H), 8.14 (s, 1H), 7.98 (d, J = 8.4Hz, 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).

[0746] Embodiment 46

[0747] 2-(6-bromo-5-fluoro-1-oxospiro[3H-isoquinolin-4,1'-cyclopropane]-2-yl)-N-(1H-pyrazolo

[0748] [3,4-d]pyrimidin-6-yl)acetamide (46)

[0749]

[0750] To a solution of methyl 2-(6-bromo-5-fluoro-1-oxospiro[3H-isoquinolin-4,1'-cyclopropane]-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 AlMe3 (1 M in n-heptane, 0.88 mL). The mixture was stirred at 90 °C for 3 h. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (3×3 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 reverse phase preparative HPLC. LCMS: m / z=445.0,447.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ13.73(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).

[0751] Examples 47 and 48

[0752] 2-[(2's,4r)-2'-fluoro-1-oxo-6-(trifluoromethyl)spiro[3H-isoquinoline-4,1'-cyclopropane]-2-

[0753] 1H-pyrazolo[3,4-d]pyrimidin-6-yl]acetamide (47 and 48)

[0754]

[0755] To a solution of methyl 2-[(2's,4r)-2'-fluoro-1-oxo-6-(trifluoromethyl)spiro[3H-isoquinolin-4,1'-cyclopropane]-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 AlMe3 (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 H2O (5 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were dried over anhydrous Na2SO4, 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×30 mm, 10 μm particle size); mobile phase: A: CO2 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:

[0756] 2-[(2's,4r)-2'-fluoro-1-oxo-6-(trifluoromethyl)spiro[3H-isoquinolin-4,1'-cyclopropane]-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 (400MHz, CDCl3): δ12.48(br s,1H),11.35(br s,1H),9.10(s,1H),8.34(d,J=8.0Hz,1H),8.13(s,1H),7.67(d,J=8.0Hz,1H),6.98(s,1H),5.54(br d,J=18.0Hz,1H),4.83(br d,J=18.0Hz,1H),4.80-4.58(m,1H),4.31(dd,J=1.6,12.4Hz,1H),3.60(d,J=12.8Hz,1H),1.77-1.68(m,1H),1.53-1.42(m,1H).

[0757] 2-[(2's,4r)-2'-fluoro-1-oxo-6-(trifluoromethyl)spiro[3H-isoquinolin-4,1'-cyclopropane]-2-yl]-N-(1H-pyrazolo[3,4-d]pyrimidin-6-yl)acetamide (second eluting isomer) (48): LCMS: m / z=435.1 [M+H] + . 1H NMR (400MHz, CDCl3): δ12.57(br s,1H),11.43(br s,1H),9.10(s,1H),8.34(d,J=8.0Hz,1H),8.13(s,1H),7.66(br d,J=8.0Hz,1H),6.98(s,1H),5.55(br d,J=17.6Hz,1H),4.83(br d,J=18.0Hz,1H),4.79-4.58(m,1H),4.31(br d, J=12.8Hz, 1H), 3.60 (brd, J=12.8Hz, 1H), 1.79-1.67 (m, 1H), 1.54-1.41 (m, 1H).

[0758] Examples 49 and 50

[0759] 2-[(2's,4r)-2'-fluoro-1-oxo-6-(trifluoromethyl)spiro[3H-isoquinoline-4,1'-cyclopropane]-2-

[0760] [1,2,4]triazolo[1,5-a]pyridin-2-yl]acetamide (49 and 50)

[0761]

[0762] To a solution of 2-[(2's,4r)-2'-fluoro-1-oxo-6-(trifluoromethyl)spiro[3H-isoquinolin-4,1'-cyclopropane]-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 h. 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×30 mm, 5 μm particle size); mobile phase: A: CO2 B: 0.1% i-PrNH2 / 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:

[0763] 2-[(2's,4r)-2'-fluoro-1-oxo-6-(trifluoromethyl)spiro[3H-isoquinolin-4,1'-cyclopropane]-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 (400MHz, DMSO-d6): δ11.07(br s,1H),8.85(d,J=6.8Hz,1H),8.13(d,J=8.0Hz,1H),7.75(d,J=8.0Hz,1H), 7.72-7.68(m,1H),7.67-7.62(m,1H),7.38(s,1H),7.13(dt,J=1.2,6.8Hz,1 H),5.28-5.05(m,1H),4.88-4.59(m,1H),4.48-4.19(m,1H),3.99(dd,J=1.2 ,12.8Hz,1H),3.65(d,J=13.2Hz,1H),1.87-1.82(m,1H),1.64-1.53(m,1H).

[0764] 2-[(2's,4r)-2'-fluoro-1-oxo-6-(trifluoromethyl)spiro[3H-isoquinolin-4,1'-cyclopropane]-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 (400MHz, DMSO-d6): δ11.07(br s,1H),8.85(d,J=6.8Hz,1H),8.13(d,J=8.0Hz,1H),7.76(br d,J=8.0Hz,1H),7.72-7.68(m,1H),7.67-7.61(m,1H),7.38(s,1H),7.14(t,J=6.8Hz,1H),5.32-5.02(m,1H),4.90-4.24(m,2H),3.99(br d,J=12.8Hz,1H),3.65(br d,J=12.8Hz,1H),1.90-1.79(m,1H),1.65-1.52(m,1H).

[0765] Embodiment 51

[0766] 2-[1-Oxo-6-(trifluoromethyl)spiro[3H-isoquinolin-4,1'-cyclopropane]-2-yl]-N-(1H-pyrazolo[3,4-d]pyrimidin-6-yl)acetamide (51)

[0767]

[0768] To a solution of 6-(trifluoromethyl)spiro[2,3-dihydroisoquinolin-4,1'-cyclopropane]-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 AlMe3 (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 H2O (8 mL), and extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, 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 (400MHz, DMSO-d6): δ13.56(br s,1H),10.93(br s,1H),9.18(s,1H),8.24(s,1H),8.10(d,J=8.0Hz,1H),7.69(d,J=8.0Hz,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).

[0769] Examples 52 and 53

[0770] 2-[1',1'-difluoro-1-oxo-6-(trifluoromethyl)spiro[3H-isoquinoline-4,2'-cyclopropane]-2-

[0771] [3-(4-(4-hydroxy-3-methylcyclobutyl)acetamide]-N-(3-cis-hydroxy-3-methylcyclobutyl)acetamide (52 and 53)

[0772]

[0773] 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 H2O (2.0 mL) was added LiOH·H2O (48 mg, 1.15 mmol). The reaction mixture was stirred for 2 h. The reaction mixture was diluted with H2O (20 mL) and washed with MTBE (20 mL). The aqueous layer was adjusted to pH = 3 using 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 2 SO 4 , filtered and concentrated under reduced pressure to give a residue which was used directly.

[0774] 2-[1',1'-difluoro-1-oxo-6-(trifluoromethyl)spiro[3H-isoquinolin-4,2'-cyclopropane]-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'-isoquinolin]-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 h. The reaction mixture was cooled to 0°C, diluted with H2O (5 mL), and extracted with EtOAc (3×5 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 and further purified by chiral SFC (column: REGIS (s, s) WHELK-O1 (250 mm×30 mm, 5 μm particle size); mobile phase: A: CO2 B: 0.1% NH4OH / 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:

[0775] 2-[1',1'-difluoro-1-oxo-6-(trifluoromethyl)spiro[3H-isoquinolin-4,2'-cyclopropane]-2-yl]-N-(3-cis-hydroxy-3-methylcyclobutyl)acetamide (first eluting isomer) (52): LCMS: m / z=419.1 [M+H] + . 1 HNMR (400MHz, CDCl3): δ8.29(d,J=8.0Hz,1H),7.71(d,J=8.0Hz,1H),7.31(s,1H),6.53(brd,J=7.2Hz,1H),4.29-4.26(m ,1H),4.20-4.09(m,2H),3.99-3.95(m,1H),3.46(dd,J=0.8,13.2Hz,1H),2.53-2.51(m,2H),2.23-2.18(m,2H),2.04(br t,J=9.6Hz,2H),1.78-1.77(m,1H),1.37(s,3H).

[0776] 2-[1',1'-difluoro-1-oxo-6-(trifluoromethyl)spiro[3H-isoquinolin-4,2'-cyclopropane]-2-yl]-N-(3-cis-hydroxy-3-methylcyclobutyl)acetamide (second eluting isomer) (53): LCMS: m / z=419.1 [M+H] + . 1 HNMR (400MHz, CDCl3): δ8.29(d,J=8.0Hz,1H),7.71(d,J=8.0Hz,1H),7.31(s,1H),6.53(brd,J=7.2Hz,1H),4.3 3-4.25(m,1H),4.16-4.12(m,2H),4.03-3.95(m,1H),3.46(dd,J=0.8,13.2Hz,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).

[0777] Embodiment 54

[0778] 2-[(2'R,4S)-6-bromo-2'-fluoro-1-oxospiro[3H-isoquinoline-4,1'-cyclopropane]-2-

[0779] [3,4-d]pyrimidin-6-yl]-N-(1H-pyrazolo[3,4-d]pyrimidin-6-yl)acetamide (54)

[0780]

[0781] To a solution of methyl 2-((1S,2R)-6'-bromo-2-fluoro-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinolin]-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 AlMe3 (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 H2O (3 mL) and extracted with EtOAc (3×1 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=445.0,447.0 [M+H] + . 1 H NMR (400MHz, CDCl3): δ12.28(br s,1H),11.04(br s,1H),9.08(s,1H),8.25-7.98(m,2H),7.54(dd,J=1.8,8.4Hz,1H),6.88(d,J=1.6Hz,1H),5.43(d,J=18.0Hz,1H ),4.93-4.47(m,2H),4.26(dd,J=1.4,12.6Hz,1H),3.56(d,J=12.8Hz,1H),1.68-1.61(m,1H),1.49-1.36(m,1H).

[0782] Embodiment 55

[0783] 2-(6-Bromo-1-oxospiro[3H-isoquinolin-4,1'-cyclopropane]-2-yl)-N-(9H-purin-2-yl)acetamide (55)

[0784]

[0785] To a solution of methyl 2-(6-bromo-1-oxo-spiro[3H-isoquinolin-4,1'-cyclopropane]-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 AlMe3 (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 H2O (5 mL), and extracted with EtOAc (3×3 mL). The combined organic layers were washed with brine (3 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC. LCMS: m / z=427.0,429.0 [M+H]+ . 1 H NMR (400MHz, DMSO-d6): δ10.62(br s,1H),8.91(s,1H),8.40(s,1H),7.82(d,J=8.4Hz,1H),7.52(dd,J=1.6,8.3Hz,1H),7.26(d,J=2.0Hz,1H),4.58(br s,2H),3.51(s,2H),1.21-1.11(m,2H),1.09-1.01(m,2H).

[0786] Examples 56 and 57

[0787] 2-(6-Bromo-1-oxospiro[3H-isoquinolin-4,1'-cyclopropane]-2-yl)-N-(3-cyclopropyl-3-hydroxycyclobutyl)acetamide (56 and 57)

[0788]

[0789] To a solution of 3-amino-1-cyclopropylcyclobutanol HCl salt (211 mg, 1.29 mmol) and 2-(6-bromo-1-oxo-spiro[3H-isoquinolin-4,1'-cyclopropane]-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 H2O (2 mL) and extracted with EtOAc (3×2 mL). The combined organic layers were washed with brine (3×2 mL), dried over anhydrous Na2SO4, 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×30 mm, 5 μm particle size); mobile phase: A: CO2 B: 0.1% NH4OH / 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:

[0790] 2-(6-Bromo-1-oxospiro[3H-isoquinolin-4,1'-cyclopropane]-2-yl)-N-(3-cyclopropyl-3-hydroxycyclobutyl)acetamide (first eluting isomer) (56): LCMS: m / z=419.1, 421.1 [M+H] + . 1H NMR (400MHz, CDCl3): δ7.98(d,J=8.2Hz,1H),7.47(dd,J=1.8,8.3Hz,1H),7.00(d,J=1.8Hz,1H),6.54(br d,J=6.8Hz,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).

[0791] 2-(6-Bromo-1-oxospiro[3H-isoquinolin-4,1'-cyclopropane]-2-yl)-N-(3-cyclopropyl-3-hydroxycyclobutyl)acetamide (second eluting isomer) (57): LCMS: m / z=419.1, 421.1 [M+H] + . 1 H NMR (400MHz, CDCl3): δ7.98(d,J=8.4Hz,1H),7.47(dd,J=1.8,8.4Hz,1H),7.01(d,J=1.8Hz,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).

[0792] Embodiment 58

[0793] 2-(6-Bromo-1-oxospiro[3H-isoquinolin-4,1'-cyclopropane]-2-yl)-N-[3-(trifluoromethyl)-1H-

[0794] Pyrazolo[3,4-d]pyrimidin-6-yl]acetamide(58)

[0795]

[0796] 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 H2O (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 H2O (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 chromatography.

[0797] 2-(6'-bromo-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinolin]-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]pyrimidine (0.20 g, 0. To a solution of 2-(6-bromo-1-oxo-spiro[3H-isoquinolin-4,1'-cyclopropane]-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) was added at 70 °C for 3 h. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography.

[0798] 2-(6'-Bromo-l'-oxo-l'H-spiro[cyclopropane-l,4'-isoquinoline]-2'(3'H)-yl)-N-(3-(trifluoromethyl)-lH-pyrazolo[3,4-d]pyrimidin-6-yl)acetamide: To a solution of 2-(6'-bromo-l'-oxo-l'H-spiro[cyclopropane-l,4'-isoquinoline]-2'(3'H)-yl)-N-(l-(tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-lH-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 solution (10 mL) and extracted with DCM (3×10 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] + . 1 H NMR (400MHz, DMSO-d6): δ14.55(br s,1H),11.11(s,1H),9.29(s,1H),7.82(d,J=8.4Hz,1H),7.53(dd,J=1.6,8.4Hz,1H), 7.27(d,J=1.6Hz,1H),4.61(s,2H),3.51(s,2H),1.21-1.14(m,2H),1.10-0.98(m,2H).

[0799] Embodiment 59

[0800] 2-(6-Bromo-1-oxospiro[3H-isoquinolin-4,1'-cyclopropane]-2-yl)-N-[5-fluoro-1H-pyrazolo

[0801] [3,4-b]pyridin-6-yl]acetamide (59)

[0802]

[0803] 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-yl)acetamide (100 mg, 0.32 mmol) was added. l) 6-bromo-5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine (146 mg, 0.49 mmol), Cs2CO3 (211 mg, 0.65 mmol), XPhos (15 mg, 0.03 mmol) and Pd2(dba)3 (30 mg, 0.03 mmol) were added to a solution in THF (4.0 mL). The reaction mixture was stirred at 50 °C for 12 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3×3 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. LCMS: m / z=528.0, 529.8 [M+H] + .

[0804] 2-(6-Bromo-1-oxospiro[3H-isoquinolin-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'-isoquinolin]-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 h. The mixture was diluted with saturated aqueous NaHCO3 (10 mL) and extracted with EtOAc (3 x 3 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 reverse phase preparative HPLC. LCMS: m / z = 444.0, 446.0 [M+H] + . 1H NMR (400MHz, CDCl3): δ9.03 (br s,1H),8.10-7.94(m,2H),7.77(d,J=9.6Hz,1H),7.48(dd,J=8.4,2.0Hz,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).

[0805] Embodiment 60

[0806] 3-[[2-(6-bromo-1-oxospiro[3H-isoquinolin-4,1'-cyclopropane]-2-yl)acetyl]amino]bicyclo

[0807] [1.1.1] Methyl pentane-1-carboxylate (60)

[0808]

[0809] To a solution of 2-(6-bromo-1-oxo-spiro[3H-isoquinolin-4,1'-cyclopropane]-2-yl)acetic acid (70 mg, 0.23 mmol) in DMF (2.0 mL) was added 3-aminobicyclo[1.1.1]pentane-1-carboxylic acid methyl ester 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 H2O (10 mL) and extracted with EtOAc (3×3 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=433.0,435.0[M+H] + . 1 H NMR (400MHz, CDCl3): δ7.97(d,J=8.0Hz,1H),7.47(dd,J=1.6,8.4Hz,1H),7.01(d,J=2.0Hz,1H),6.7 3(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).

[0810] Embodiment 61

[0811] N-(3H-Benzotriazol-5-yl)-2-(6-bromo-5-fluoro-1-oxospiro[3H-isoquinolin-4,1'-cyclopropane]-2-yl)acetamide (61)

[0812]

[0813] To a solution of methyl 2-(6-bromo-5-fluoro-1-oxospiro[3H-isoquinolin-4,1'-cyclopropane]-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 AlMe3 (1 M in n-heptane, 0.24 mL). The mixture was stirred at 90 °C for 2 h. The mixture was quenched with H2O (10 mL) and extracted with DCM (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 reverse phase preparative HPLC. LCMS: m / z=444.0 446.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ10.44(s,1H),8.31(s,1H),7.91(br d,J=7.8Hz,1H),7.80-7.63(m,2H),7.39(br d,J=9.4Hz,1H),4.38(s,2H),3.52(s,2H),1.61-1.45(m,2H),1.15-1.11(m,2H).

[0814] Embodiment 62

[0815] 2-(6-bromo-5-fluoro-1-oxospiro[3H-isoquinolin-4,1'-cyclopropane]-2-yl)-N-(9H-purine-2-

[0816] 4-(2-Methyl)acetamide(62)

[0817]

[0818] To a solution of methyl 2-(6-bromo-5-fluoro-1-oxospiro[3H-isoquinolin-4,1'-cyclopropane]-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 AlMe3 (1 M in n-heptane, 0.3 mL). The reaction was sealed and heated to 120°C for 3 h. The reaction mixture was cooled to 0°C, diluted with H2O (5 mL), and extracted with EtOAc (3×5 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=445.0,447.0 [M+H] + .1 H NMR (400MHz, DMSO-d6): δ10.72(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).

[0819] Embodiment 63

[0820] 2-(6-Bromo-1',1'-difluoro-1-oxospiro[3H-isoquinolin-4,2'-cyclopropane]-2-yl)-N-(1H-pyrazolo[3,4-d]pyrimidin-6-yl)acetamide (63)

[0821]

[0822] To a solution of methyl 2-(6'-bromo-2,2-difluoro-1'-oxo-1'H-spiro[cyclopropane-1,4'-isoquinolin]-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 AlMe3 (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 H2O (5 mL) and extracted with EtOAc (3×5 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=463.0,465.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ13.77(br s,1H),10.94(s,1H),9.18(s,1H),8.24(s,1H),7.89(d,J=8.4Hz,1H),7.70(dd,J=1.6,8.4Hz,1H),7.63(s,1H) ,5.00-4.30(m,2H),4.16(dd,J=6.8,13.2Hz,1H),3.41(d,J=13.2Hz,1H),2.86-2.76(m,1H),2.02-1.92(m,1H).

[0823] Examples 64 and 65

[0824] 2-(6-Bromo-1',1'-difluoro-1-oxospiro[3H-isoquinolin-4,2'-cyclopropane]-2-yl)-N-(1H-pyrazolo[3,4-d]pyrimidin-6-yl)acetamide (64 and 65)

[0825]

[0826] 2-(6-Bromo-1',1'-difluoro-1-oxospiro[3H-isoquinoline-4,2'-cyclopropane]-2-yl)-N-(1H-pyrazolo[3,4-d]pyrimidin-6-yl)acetamide (Example 62) can be further separated by chiral SFC (column: DAICEL ChiralPak IG (250 mm×30 mm, 10 μm particle size); mobile phase: A: CO2 B: 0.1% i-PrNH2 / 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:

[0827] 2-(6-Bromo-1',1'-difluoro-1-oxospiro[3H-isoquinolin-4,2'-cyclopropane]-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 (400MHz, DMSO-d6): δ13.80 (br s,1H),10.94(s,1H),9.18(s,1H),8.23(s,1H),7.89(d,J=8.4Hz,1H),7.70(dd,J=1. 6,8.4Hz,1H),7.63(s,1H),5.03-4.24(m,2H),4.16(dd,J=6.8,13.2Hz,1H),3.41(br d,J=13.2Hz,1H),2.87-2.75(m,1H),2.04-1.90(m,1H).

[0828] 2-(6-Bromo-1',1'-difluoro-1-oxospiro[3H-isoquinolin-4,2'-cyclopropane]-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 (400MHz, DMSO-d6): δ13.77(br s,1H),10.93(s,1H),9.18(s,1H),8.24(s,1H),7.89(d,J=8.4Hz,1H),7.70(dd,J=1. 6,8.4Hz,1H),7.63(s,1H),5.01-4.28(m,2H),4.16(dd,J=6.8,13.2Hz,1H),3.41(br d,J=13.2Hz,1H),2.88-2.75(m,1H),2.05-1.90(m,1H).

[0829] Biological Example 1

[0830] Biochemical assays of compounds

[0831] Procedure for culturing THP-1 cells

[0832] Compounds as provided herein were tested in the following assays. The cell culture medium used contained RPMI 1640 culture medium (89%), FBS (10%), penicillin / streptomycin (1%) and 2-mercaptoethanol (0.05 mM). The freezing medium consisted of 90% FBS and 10% DMSO. THP-1 cells were taken out of liquid nitrogen and placed in a 37°C water bath to thaw until the ice signs disappeared. The cells were then added to 9 mL of warm cell culture medium and centrifuged at 1000 rpm for 5 minutes. The supernatant was discarded and the cells were resuspended in a new cell culture medium. The THP-1 cells were then divided into several portions and cultured in a cell culture medium, and passaged every 2-3 days, with a cell density maintained between 5 × 10 5 viable cells / mL and 1.5×10 6 viable cells / mL.

[0833] For freezing, resuspend the cells in fresh freezing medium and adjust the cell density to 5 × 10 6 The cell suspension was divided into aliquots of 1 mL per vial and the vials were transferred to a -80°C freezer. After one day at -80°C, the cell vials were transferred to a liquid nitrogen freezer for storage.

[0834] Procedure for IL-1β secretion assay in 384-well plates

[0835] PMA is dissolved in DMSO to make a stock solution of 5mg / ml, and is stored at -20°C with 10 μl aliquots for single use. PMA is added to normal growth medium. LPS is diluted with 1mL aqueous solution to provide a 1mg / mL stock solution, and is stored at -20°C with 15 μL aliquots for single use. Nigericin is diluted to 5mg / ml (6.7mM) in ice-cold 100% ethanol, and is stored at -20°C with 75 μL aliquots for single use. Serum-free medium contains RPMI 1640 culture medium (99%), penicillin / streptomycin (1%) and 2-mercaptoethanol (0.05mM). The two control conditions used to define and normalize the test compound dose-response curves were as follows: High Control = 25 ng / mL LPS, 5 μM nigericin, 0.5% DMSO, Low Control = 25 ng / mL LPS, 0.5% DMSO.

[0836] Day 1: Differentiation using PMA

[0837] Dilute THP-1 cells to provide a concentration of 1.0 × 10 6 The growth medium was supplemented with PMA (5 ng / mL final concentration) and the cells were incubated at 37°C in a humidified atmosphere of 5% CO2 for 40 h.

[0838] Day 3: Sequential plating with LPS and nigericin stimulation

[0839] Carefully aspirate all culture medium from each culture bottle. Wash cells carefully with 1×DPBS. Then the cells were briefly digested with trypsin LE for 5 minutes at 23°C, and immediately resuspended in cell growth medium. After resuspension, the cells were centrifuged at 1000rpm for 3 minutes, and the supernatant was discarded. The cells were resuspended in DPBS, and centrifuged again at 1000rpm for 5 minutes. The supernatant was discarded, and the cell pellet was resuspended in a serum-free medium supplemented with LPS (25ng / mL final concentration) so that 30K THP-1 cells were distributed to each well of 384-well PDL coated plates in 45 μL culture medium. Then 384-well plates were incubated at 37°C for 2h in a humid atmosphere of 5% CO2. After this period, test compounds were distributed across the desired concentration range by Tecan, and all wells were normalized relative to a final 0.5% DMSO concentration. Then the plate was incubated at 37°C for 1h in a humid atmosphere of 5% CO2. After this period, 5 μL of 5 mg / mL nigericin stock solution was added to each appropriate well, and the plate was centrifuged at 1000 rpm for 30 seconds. The plate was then reintroduced into a 37°C incubator under a 5% CO2 humidified atmosphere and kept for 2 h. Thereafter, 35 μL / well of supernatant was collected and transferred to a v-bottom plate and centrifuged at 1000 rpm for 1 minute. These supernatant aliquots were analyzed using an IL-Iβ detection kit as described below. If desired, the test sample can be quickly frozen and stored at -80°C until analysis.

[0840] IL-1β detection

[0841] To prepare each ELISA plate, the capture antibody (mAb Mt175) was diluted with PBS to a final concentration of 2 μg / mL, and then 20 μL of this solution was added to each well of the ELISA plate. Each plate was incubated overnight at 4°C. The next day, the capture antibody solution was removed and discarded. Each ELISA plate was washed 4 times with PBST, followed by addition of 25 μL / well blocking buffer (Licor-927-40010) supplemented with 0.1% Tween 20. Each ELISA plate was then incubated for 1 hour at 23°C. Thereafter, the blocking buffer was removed and discarded. Each ELISA plate was washed 4 times with PBST. During this period, a v-shaped bottom plate containing aliquots of supernatant from the assay was centrifuged at 300g for 5 minutes, and then 15 μL / well supernatant samples were transferred to each ELISA plate. Each ELISA plate was then incubated for 2h at 23°C. Thereafter, the supernatant samples were removed and discarded. Each ELISA plate was washed 4 times with PBST. 15 μL / well of 0.5 μg / mL mAb7P10-biotin (1:1000 diluted in blocking buffer) was added to each ELISA plate. Each ELISA plate was then incubated at 23°C for 1 hour. Thereafter, the antibody solution was removed and discarded. Each ELISA plate was washed 4 times with PBST. 20 μL / well of streptavidin-HRP (1:2000 diluted in blocking buffer) was added to each ELISA plate. Each ELISA plate was then incubated at 23°C for 1 hour. Thereafter, the buffer was removed and discarded. Each ELISA plate was washed 4 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. Thereafter, 40 μL / well of stop solution was added to each ELISA plate. Each ELISA plate was centrifuged at 1200rpm for 30 seconds.

[0842] The plate was then read at 450 nm in a microplate reader. The percent inhibition was calculated as follows:

[0843] Inhibition rate % = (treated sample - high control) / (low control - high control) × 100

[0844] The activities of the test compounds are provided in Table 3 below as follows: +++ = IC 50 <1 μM; ++ = IC 50 1-10 μM; + = IC 50 >10μM.

[0845] Table 3

[0846]

[0847]

[0848] Unless defined otherwise, 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.

[0849] The embodiments described herein in an illustrative manner may be suitably practiced in the absence of any one or more elements, one or more limitations not expressly disclosed herein. Thus, for example, the terms "comprising," "including," "containing," and the like are to be understood broadly and without limitation. In addition, the terms and expressions employed herein are used as illustrative rather than limiting terms, and it is not intended to exclude any equivalents of the features shown and described or portions thereof by the use of such terms and expressions, but it should be appreciated that various modifications may exist within the scope of the claimed embodiments.

[0850] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety to the same extent as if each were individually incorporated by reference. In the event of a conflict, the present specification, including definitions, will control.

[0851] It should be understood that although the present disclosure has been described in conjunction with the above embodiments, the foregoing description and examples are intended to illustrate rather than limit the scope of the present disclosure. Other aspects, advantages and modifications within the scope of the present disclosure will be apparent to those skilled in the art to which the present disclosure belongs.

Claims

1. A compound or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomer mixture or prodrug thereof selected from:

2. A compound or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomer mixture or prodrug thereof selected from:

3. A compound of formula I: 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 ); Y is C(Y 1 ), O, NR 17 , S(O)2 or S(O)(NR 19 ); Z is CR 8 or N; X 1 O, NR 18 or S; Y 1 O, NR 19 or S; A 1 , A 2 , A 3 and A 4 are independently N, CH or CR 1 ; The condition is A 1 , A 2 , A 3 and A 4 At least one of them is CR 1 ; Each R 1 are independently halogen, 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- 2N(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 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to eight Z 1 Replace; or any two adjacent R 1 Together with the atoms to which they are attached, they form a cycloalkyl, heterocyclyl, aryl or heteroaryl ring; wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to eight Z 1 replace; R 2 C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, 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 the C 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 1-6 haloalkyl, the C 3-10 The cycloalkyl, the heterocyclyl, the aryl or the heteroaryl is optionally substituted by one to eight Z 1 replace; R 3 is hydrogen, halogen, 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, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 3-10 The cycloalkyl, the heterocyclyl, the aryl or the heteroaryl is optionally substituted by one to eight Z 1 replace; or R 2 and R 3 Together they form C 3-10 Cycloalkyl or heterocyclyl ring; wherein the C 3-10 The cycloalkyl or heterocyclyl group is optionally substituted by one to eight Z 1 replace; R 4 For hydrogen, halogen, -NO2, cyano, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, -OR 14 、-N(R 14 )2 or -S(O) 0-2 R 14 wherein said C 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 3-6 The cycloalkyl, the 3-6 membered heterocyclyl, the phenyl or the 5-6 membered heteroaryl are optionally substituted by one to five halogen, hydroxyl, -SH, -NH2, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Haloalkyl substitution; R 5 For hydrogen, halogen, -NO2, cyano, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, -OR 14 、-N(R 14 )2 or -S(O) 0-2 R 14 wherein said C 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 3-6 The cycloalkyl, the 3-6 membered heterocyclyl, the phenyl or the 5-6 membered heteroaryl are optionally substituted by one to five halogen, hydroxyl, -SH, -NH2, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 haloalkyl substitution; or R 4 and R 5 together to form a heterocyclic group or a heteroaryl group, wherein the heterocyclic group or the heteroaryl group is optionally substituted by one to five halogen groups, hydroxyl groups, -SH, -NH2, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Haloalkyl substitution; R 6 is hydrogen, halogen, 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 heterocyclic group; wherein the C 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 1-6 haloalkyl, the C 2-6 Heteroalkyl, the C 3-10 The cycloalkyl group or the heterocyclic group may be further optionally substituted by one to five Z 1b replace; R 7 is hydrogen, halogen, cyano, hydroxyl, 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 heterocyclic group; wherein the C 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 1-6 haloalkyl, the C 2-6 Heteroalkyl, the C 3-10 The cycloalkyl group or the heterocyclic group may be further optionally substituted by one to five Z 1b replace; or R 6 and R 7 C 3-10 Cycloalkyl or heterocyclyl ring; wherein the C 3-10 The cycloalkyl or heterocyclyl ring may be further optionally substituted by one to five Z 1b replace; R 8 is hydrogen, halogen, cyano, C 1-6 Alkyl or C 1-6 Haloalkyl; R 9 and R 10 are independently hydrogen, halogen, cyano, C 1-6 Alkyl or C 1-6 A haloalkyl group, wherein each C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted by one to five Z 1 replace; or R 9 and R 10 Together they form C 3-10 Cycloalkyl or heterocyclyl ring; wherein the C 3-10 The cycloalkyl group or the heterocyclic group is optionally substituted by one to eight Z 1 replace; Each Z 1 are independently halogen, 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- 2N(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 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to five Z 1a replace; 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; wherein 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 is independently optionally substituted by one to five Z 1a replace; R 12 For 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, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 3-10 The cycloalkyl, the heterocyclyl, the aryl or the heteroaryl is optionally substituted by one to eight Z 1 replace; Each Z 1a are independently hydroxyl, halogen, 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 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to five Z 1b replace; 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; wherein 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 is independently optionally substituted by one to five Z 1b replace; 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, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; wherein each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl are optionally substituted with one to five halogen, hydroxyl, -SH, -NH2, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Haloalkyl substitution; R 16 For 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; wherein 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 is independently optionally substituted by one to five Z 1b replace; R 17 For 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; wherein 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 is independently optionally substituted by one to five Z 1b replace; R 18 For 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; wherein 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 is independently optionally substituted by one to five Z 1b replace; R 19 For 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; wherein 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 is independently optionally substituted by one to five Z 1b replace; Each Z 1b are independently halogen, cyano, hydroxyl, -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; and 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)2NH-; Where 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 and heteroaryl are further independently optionally substituted by one to five hydroxyl, halo, cyano, hydroxyl, -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 The cycloalkyl, heterocyclyl, aryl or heteroaryl groups are substituted.

4. The compound of claim 3 or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomer mixture or prodrug thereof, which is represented by Formula IC:

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

6. A compound as described in any one of claims 3 to 5, wherein R 12 is hydrogen; R 6 is hydrogen; and R 7 For hydrogen.

7. The compound of claim 3, which is represented by formula VII: Where p is 1, 2, 3 or 4.

8. The compound of claim 3 or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomer mixture or prodrug thereof, which is represented by Formula VIII: Where q is 0, 1, 2, 3 or 4.

9. The compound of claim 3 or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomer mixture or prodrug thereof, which is represented by Formula VIIIA:

10. A compound as described in any one of claims 3 to 9, wherein R 1 For halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkyl.

11. A compound as described in any one of claims 3 to 10, wherein R 1 It is a halogen group.

12. A compound as described in any one of claims 3 to 11, wherein R 4 For hydrogen.

13. A compound as described in any one of claims 3 to 12, wherein R 5 is hydrogen or C 1-6 Halogenated alkyl.

14. A compound as described in any one of claims 3 to 13, wherein R 5 It is hydrogen or -CF3.

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

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

17. The method of claim 16, wherein the disease or condition is Alzheimer's disease, atherosclerosis, asthma, allergic airway inflammation, cryptopyrin-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, excessive inflammation following influenza infection, graft-versus-host disease, stroke, silicosis, type 1 diabetes, obesity-induced inflammation or insulin resistance, rheumatoid arthritis, myelodysplastic syndrome, contact allergy, chikungunya virus-induced joint inflammation, or traumatic brain injury.

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

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

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

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

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

23. A compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or prodrug thereof for use in treating Alzheimer's disease.

24. A compound according to any one of claims 1 to 14 or a pharmaceutically 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. Use of a compound as described in any one of claims 1 to 14, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof, for the manufacture of a medicament for the treatment of a neurodegenerative disease, Alzheimer's disease, atherosclerosis, asthma, allergic airway inflammation, cryptopyrin-associated periodic syndrome, gout, inflammatory bowel disease and related conditions, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hypertension, myocardial infarction, multiple sclerosis, experimental autoimmune encephalitis, oxalate-induced nephropathy, excessive inflammation following influenza infection, graft-versus-host disease, stroke, silicosis, type 1 diabetes, obesity-induced inflammation or insulin resistance, rheumatoid arthritis, myelodysplastic syndrome, contact allergy, chikungunya virus-induced joint inflammation, or traumatic brain injury.

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