Compounds, Compositions, and Methods

Abstract

The present disclosure generally relates to small molecule modulators of NLR family pyrin domain containing 3 (NL-RP3), or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers or prodrugs thereof, methods for their manufacture and intermediates, and methods of their use.

Description

[0001] Cross - Reference to Related Applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 066,074, filed Aug. 14, 2020, and U.S. Provisional Application No. 63 / 151,600, filed Feb. 19, 2021, under 35 U.S.C. § 119(e), each of which is incorporated herein by reference in its 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] Inhibition of NLRP3 activation has been shown to produce effective therapeutic effects in animal models of inflammatory diseases. Modulators of NLRP3, particularly inhibitors, have broad therapeutic potential in a wide variety of auto - inflammatory and chronic inflammatory diseases where better treatment options are needed or where no appropriate therapy exists. Therapies targeting NLRP3 - dependent cytokines have been approved for medical use; however, they have significant disadvantages relative to direct NLRP3 antagonists. There remains strong motivation for the discovery and clinical development of molecules that antagonize NLRP3. Summary of the Invention

[0005] Compounds or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof that can be used to treat and / or prevent diseases mediated at least in part by NLRP3 are provided herein.

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

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

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

[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 or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers or prodrug thereof as described herein. In some embodiments, the administration is to a subject resistant to treatment with an anti-TNF-α agent. In some embodiments, the disease is an intestinal disease or 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 the compound or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers or prodrug thereof, methods of using (or administering) and preparing the compound or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers or prodrug thereof, and intermediates thereof.

[0011] The present disclosure also provides a compound or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers or prodrug thereof or a composition thereof for use in a method for treating a disease, condition or disorder mediated at least in part by NLRP3.

[0012] Furthermore, the present disclosure provides the use of a compound or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers or prodrug thereof or a composition thereof for the manufacture of a medicament for treating a disease, condition or disorder mediated at least in part by NLRP3.

[0013] The description herein describes exemplary embodiments of the technology of the present invention. However, it should be understood that this description is not intended to limit the scope of the present disclosure, but is instead provided as a description of exemplary embodiments.

[0014] 1. Definitions

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

[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 the carbon atom. Dashes at the front or end of a chemical group are for convenience purposes; a chemical group may be depicted with or without one or more dashes without losing its ordinary meaning. A wavy or dashed line depicted as passing through a line in a structure indicates a specified point of attachment between groups. Unless otherwise required chemically or structurally, the order in which chemical groups are written or presented does not indicate or imply 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 has 1 to 6 carbon atoms.

[0018] References herein to “about” a value or parameter include (and describe) embodiments that inherently relate to the value or parameter. In certain embodiments, the term “about” includes an indication of the amount ±10%. In other embodiments, the term “about” includes an indication of the amount ±5%. In certain other embodiments, the term “about” includes the indicated amount ±1%. Additionally, the term “about X” includes the description of “X”. Further, unless the context clearly dictates otherwise, the singular forms “a” and “the” include plural referents. Thus, for example, a reference to “a compound” includes a plurality of such compounds and a reference to “an assay” includes a reference to one or more assays known to those of ordinary skill in the art and their equivalents.

[0019] “Alkyl” refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C 1-20 alkyl), 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 specific number of carbons is named by chemical name or identified by molecular formula, all positional isomers having that number of carbons may be encompassed; 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 common 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 quinolinyl of heteroarylene), respectively. In addition, unless otherwise indicated, when a combination of groups is referred to herein as a moiety (e.g., arylalkyl or aralkyl), the last-mentioned group contains the atom through which the moiety is attached to the rest of the molecule.

[0021] "Alkenyl" refers to an alkyl 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 alkenyl). Examples of alkenyl include, for example, vinyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0022] "Alkynyl" refers to an alkyl 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 alkynyl). The term "alkynyl" also includes 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-pentyloxy, n-hexyloxy, and 1,2-dimethylbutoxy.

[0024] "Alkoxyalkyl" refers to the group "alkyl - O - alkyl".

[0025] "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.

[0026] "Acyl" means the group -C(O)R y , where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl or heteroaryl; each of which may optionally be substituted as defined herein. Examples of acyl include, for example, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl and benzoyl.

[0027] "Acylamino" means the "C-acylamino" group referring to the group -C(O)NR y R z and the "N-acylamino" group referring to -NR y C(O)R z , where R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl or heteroaryl; each of which may optionally be substituted as defined herein, or R y and R z together form cycloalkyl or heterocycloalkyl; each of which may optionally be substituted as defined herein.

[0028] "Amino" means the group -NR y R z , where R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl or heteroaryl; each of which may optionally be substituted as defined herein.

[0029] "Formamido" means -C(NR y )(NR z 2), where R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl or heteroaryl; each of which may optionally be substituted as defined herein.

[0030] "Aryl" means an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic) including a fused system. As used herein, aryl has 6 to 20 ring carbon atoms (i.e., C 6-20 aryl), 6 to 12 carbocyclic atoms (i.e., C 6-12 aryl) or 6 to 10 carbocyclic atoms (i.e., C 6-10aryl). Examples of aryl include, for example, phenyl, naphthyl, fluorenyl, and anthracenyl. However, aryl in no way encompasses or overlaps with heteroaryl as defined below. If one or more aryl groups are fused to a heteroaryl group, the resulting ring system is heteroaryl, regardless of the point of attachment. If one or more aryl groups are fused to a heterocyclic group, the resulting ring system is a heterocyclic group, regardless of the point of attachment. If one or more aryl groups are fused to a cycloalkyl group, the resulting ring system is a cycloalkyl group, regardless of the point of attachment.

[0031] "Arylalkyl" or "aralkyl" refers to the group "aryl-alkyl-".

[0032] "Carbamoyl" refers to both "O-carbamoyl" represented by the group -O-C(O)NR y R z and "N-carbamoyl" represented by the group -NR y C(O)OR z wherein R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted as defined herein.

[0033] "Carboxylate ester" or "ester" refers to both -OC(O)R x and -C(O)OR x wherein R x is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted as defined herein.

[0034] "Cyanoalkyl" refers to an alkyl group in which one or more (e.g., 1 or 2) of the hydrogen atoms as defined above are replaced by a cyano group (-CN).

[0035] "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., ring groups having at least one double bond) and carbocyclic fused ring systems having at least one sp 3 carbon atom (i.e., at least one non-aromatic ring). As used herein, cycloalkyl has 3 to 20 ring carbon atoms (i.e., C 3-20 cycloalkyl), 3 to 14 ring carbon atoms (i.e., C 3-14 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]heptyl, bicyclo[2.2.2]octyl, adamantyl, norbornyl, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, and the like. In addition, the term cycloalkyl is intended to encompass any non-aromatic ring that can be fused to an aromatic ring, regardless of the connection to the rest of the molecule. Furthermore, when there are two substituents on the same carbon atom, cycloalkyl also includes "spirocycloalkyl", such as spiro[2.5]octyl, spiro[4.5]decyl, or spiro[5.5]undecyl.

[0036] "Cycloalkylalkyl" means the group "cycloalkyl-alkyl-".

[0037] "Imino" means the group -C(NR y )R z , where R y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted as defined herein.

[0038] "Imido" means the group -C(O)NR y C(O)R z , where R y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted as defined herein.

[0039] "Halogen" or "halo group" means an atom occupying Group VIIA of the periodic table, such as fluorine, chlorine, bromine, or iodine.

[0040] "Haloalkyl" means a straight-chain or branched alkyl 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, in the case where the residue is substituted by more than one halogen, it may be referred to by using a prefix corresponding to the number of the attached halogen moieties. Dihaloalkyl and trihaloalkyl mean an alkyl substituted by two ("di") or three ("tri") halo groups, which may (but need not) be the same halogen. Examples of haloalkyl include, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0041] "Haloalkoxy" means an alkoxy as defined above, in which one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by halogen.

[0042] "Halogenated alkoxyalkyl" means alkoxyalkyl as defined herein, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by halogen.

[0043] "Hydroxyalkyl" means alkyl as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by hydroxy groups.

[0044] "Heteroalkyl" means an alkyl in which one or more of the 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 remainder of the molecule is via a carbon atom. The term "heteroalkyl" includes straight or branched saturated chains having carbon and heteroatoms. By way of 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, heterocycloalkyl, aryl, heteroalkyl, or heteroaryl; each of which may optionally be 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, heterocycloalkyl, aryl, heteroalkyl, or heteroaryl; each of which may optionally be 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.

[0045] "Heteroaryl" means an aromatic group having a single ring, multiple rings, or multiple fused rings, wherein one or more ring heteroatoms are independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl includes 1 to 20 ring carbon atoms (i.e., C 1-20heteroaryl), 3 to 12 ring carbon atoms (i.e., C 3-12 heteroaryl) or 3 to 8 carbocyclic atoms (i.e., C 3-8 heteroaryl); and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms or 1 ring heteroatom independently selected from nitrogen, oxygen and sulfur. In certain cases, the heteroaryl includes a 5- to 10-membered ring system, a 5- to 7-membered ring system or a 5- to 6-membered ring system, each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms or 1 ring heteroatom independently selected from nitrogen, oxygen and sulfur. Examples of heteroaryl include, for example, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothienyl / benzothiophen yl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxo-pyridinyl, 1-oxo-pyrimidinyl, 1-oxo-pyrazinyl, 1-oxo-pyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl and triazinyl. Examples of fused heteroaromatic rings include (but are not limited to) benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thienyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl and imidazo[1,5-a]pyridinyl, wherein the heteroaryl may be attached via any one of the rings of the fused system. Any aromatic ring having a single ring or multiple fused rings and containing at least one heteroatom is considered a heteroaryl, regardless of the connection to the rest of the molecule (i.e., via any one of the fused rings). Heteroaryl does not encompass aryl as defined above or overlap therewith.

[0046] "Heteroaralkyl" means the group "heteroaryl-alkyl-".

[0047] "Heterocyclic group" means a saturated or partially unsaturated cyclic alkyl group having one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur. The term "heterocyclic group" includes heterocyclic alkenyl (i.e., a heterocyclic group having at least one double bond), bridged heterocyclic group, fused heterocyclic group and spiro heterocyclic group. The heterocyclic group may be monocyclic or polycyclic, wherein the polycyclic may be a fused ring, a bridged ring or a spiro ring, and the heterocyclic group may contain one or more (e.g., 1 to 3) oxo groups (=O) or N-oxides (-O -) moiety. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclic group, regardless of the attachment (i.e., it can be attached via a carbon atom or a heteroatom). In addition, the term heterocyclic group is intended to cover any non-aromatic ring containing at least one heteroatom, which ring can be fused to a cycloalkyl, aryl, or heteroaryl ring, regardless of the attachment to the rest of the molecule. As used herein, a heterocyclic group has 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 group); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms or 1 ring heteroatom independently selected from nitrogen, sulfur or oxygen. Examples of heterocyclic groups include, for example, azetidinyl, azepinyl, benzodioxolyl, benz[b][1,4]dioxazinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxenyl, benzopyrone, benzofuranone, dioxolanyl, dihydropyranyl, hydropyranyl, thieno[1,3]dithianyl, decahydroisoquinolinyl, furanone, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidinone, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, trithianyl, tetrahydroquinolinyl, thiophenyl (i.e., thienyl), thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl and 1,1-dioxo-thiomorpholinyl. When there are two positions for substitution on the same carbon atom, the term "heterocyclic group" also includes "spiroheterocyclic group". Examples of spiro-heterocyclic rings include bicyclic and tricyclic systems such as oxabicyclo[2.2.2]octyl, 2-oxa-7-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.4]octyl and 6-oxa-1-azaspiro[3.3]heptyl. Examples of fused heterocyclic 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 heterocyclic group can be attached via any one of the rings of the fused system.

[0048] "Heterocyclic alkyl" means the group "heterocyclic - alkyl -".

[0049] "Oxime" means the group - CR y (=NOH), where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl or heteroaryl; each of which may optionally be substituted as defined herein.

[0050] "Sulfonyl" means the group - S(O)2R y where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl or heteroaryl; each of the groups may optionally be substituted as defined herein. Examples of sulfonyl groups are methylsulfonyl, ethylsulfonyl, phenylsulfonyl and toluenesulfonyl.

[0051] "Sulfinyl" means the group - S(O)R y where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl or heteroaryl; each of the groups may optionally be substituted as defined herein. Examples of sulfinyl groups are methylsulfinyl, ethylsulfinyl, phenylsulfinyl and toluenesulfinyl.

[0052] "Sulfonamido" means the groups - SO2NR y R z and - NR y SO2R z where R y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl or heteroaryl; each of which may optionally be substituted as defined herein.

[0053] The term "optional" or "optionally" means that the subsequent described event or situation may or may not occur, and the description includes the situation where the event or situation occurs and the situation where the event or situation does not occur. In addition, the term "optionally substituted" means that any one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms on the specified atom or group may or may not be replaced by a moiety other than hydrogen.

[0054] As used herein, the term "substituted" means any of the above groups (i.e., alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclic, heteroaryl, and / or heteroalkyl) in which at least one (e.g., 1 to 5 or 1 to 3) hydrogen atoms is replaced by a bond attached to a non-hydrogen atom, such as (but not limited to) alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, acylamino, amino, amidino, aryl, aralkyl, azido, carbamoyl, carboxy, carboxyester, cyano, cycloalkyl, cycloalkylalkyl, guanadino, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl, -NHNH2, =NNH2, imino, imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, -S(O)OH, -S(O)2OH, sulfonamido, thiol, thiono, N-oxide or -Si(R y )3, where each R y is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl or heterocyclic.

[0055] In certain embodiments, "substituted" includes any of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl groups in which one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are independently replaced by the following groups: deuterium, halo, cyano, nitro, azido, oxo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -NR g R h , -NR g C(O)R h , -NR g C(O)NR g R h , -NR g C(O)OR h , -NR g S(O) 1-2 R h , -C(O)R g , -C(O)OR g , -OC(O)OR g , -OC(O)R g , -C(O)NR g R h , -OC(O)NR g R h , -OR g , -SR g , -S(O)R g , -S(O)2R g , -OS(O)1-2 R g 、-S(O) 1-2 OR g 、-NR g S(O) 1-2 NR g R h , =NSO2R g , =NOR g 、-S(O) 1-2 NR g R h In certain embodiments, "substituted" also means any of the above groups, wherein one or more (eg, 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 foregoing, R g and 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 to: amino, cyano, hydroxyl, imino, nitro, oxo, thioketo, halo, alkyl, alkoxy, alkylamino, sulfanyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl and / or heteroarylalkyl, or R g and R h The two of them together with the atoms to which they are attached form a heterocyclyl ring which is optionally substituted with oxo, halo, or alkyl which is optionally substituted with oxo, halo, amino, hydroxy or alkoxy.

[0056] Polymers or similar indefinite structures obtained by defining substituents with an indefinitely appended other substituent (e.g., a substituted aryl having a substituted alkyl, the substituted alkyl itself being substituted by a substituted aryl, the substituted aryl being further substituted by a substituted heteroalkyl, etc.) are not intended to be included herein. Unless otherwise indicated, the maximum number of consecutive substitutions in the compounds described herein is three. For example, consecutive substitution of a substituted aryl with two other substituted aryls is limited to ((substituted aryl)-substituted aryl)-substituted aryl. Similarly, the above definition is not intended to include non-permitted substitution patterns (e.g., a methyl substituted with five fluorines or a heteroaryl having two adjacent oxygen ring atoms). Such non-permitted substitution patterns are well known to those skilled in the art. When used to modify a chemical group, the term "substituted" may describe other chemical groups as defined herein.

[0057] In certain embodiments, as used herein, the phrase "one or more" means one to five. In certain embodiments, as used herein, the phrase "one or more" means one to three.

[0058] Any compound or structure given herein is also intended to represent both the unlabeled form and the isotopically labeled form of the compound. These forms of the compound may also be referred to as "isotope-enriched analogs". An isotopically labeled compound has the structure depicted herein except that one or more atoms are replaced by atoms 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, such as, respectively 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I. Various isotopically labeled compounds of the present disclosure, such as those incorporating, for example 3 H and 14 C radioactive isotopes. Such isotopically labeled compounds may be useful in metabolic studies, reaction kinetics studies, detection or imaging techniques (e.g., positron emission tomography (PET) or single photon emission computed tomography (SPECT), including determination of drug or substrate tissue distribution) or for radioactive treatment of patients.

[0059] The term "isotopically enriched analog" includes "deuterated analogs" of the compounds described herein, in which one or more hydrogens, such as hydrogens on a carbon atom, are replaced by deuterium. Such compounds exhibit increased metabolic resistance and can thus be used to increase the half-life of any compound when administered to a mammal, particularly a human. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sci. 5(12):524-527(1984). Such compounds are synthesized by means well known in the art, for example by using starting materials in which one or more hydrogens have been replaced by deuterium.

[0060] The deuterium-labeled or substituted therapeutic compounds of the present disclosure can have improved DMPK (drug metabolism and pharmacokinetics) properties, which are related to absorption, distribution, metabolism, and excretion (ADME). Substitution with a heavier isotope such as deuterium can result in certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life, reduced dose requirements, and / or improved therapeutic index. 18 F, 3 H, 11 F, H, C-labeled compounds are suitable for PET or SPECT or other imaging studies. The isotopically labeled compounds and their prodrugs of the present disclosure can generally be prepared by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents by following the procedures disclosed in the examples and preparation methods described in the schemes or below. It should be understood that in this context, deuterium is considered a substituent of the compounds described herein.

[0061] The concentration of such heavier isotopes (specifically deuterium) can be defined by an isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is intended to represent any stable isotope of said atom. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen", it should be understood that the hydrogen at that position has its natural abundance isotopic composition. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is intended to represent deuterium.

[0062] In many cases, the compounds of the present disclosure are capable of forming acid salts and / or base salts by virtue of the presence of an amino and / or carboxyl group or groups similar thereto.

[0063] Pharmaceutically acceptable salts, isotopically enriched analogs, deuterated analogs, stereoisomers, mixtures of stereoisomers, and prodrugs of the compounds described herein are also provided. "Pharmaceutically acceptable" or "physiologically acceptable" means that a compound, salt, composition, dosage form, and other substances can be used to prepare a pharmaceutical composition suitable for veterinary or human medical use.

[0064] The "pharmaceutically acceptable salts" of a given compound refer to salts that retain the biological effectiveness and properties of the given compound and are 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. Additionally, if the compounds described herein are obtained in the form of acid addition salts, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is the free base, addition salts, particularly pharmaceutically acceptable addition salts, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art will recognize the various synthetic methods available for preparing non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic acids or organic acids. Inorganic acids from which salts are derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Organic acids from which salts are derived 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. By way of example only, salts derived from inorganic bases include 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 amines, secondary amines, and tertiary amines, such as alkylamines (i.e., NH2(alkyl)), dialkylamines (i.e., HN(alkyl)2), trialkylamines (i.e., N(alkyl)3), substituted alkylamines (i.e., NH2(substituted alkyl)), di(substituted alkyl)amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl)amines (i.e., N(substituted alkyl)3), alkenylamines (i.e., NH2(alkenyl)), dialkenylamines (i.e., HN(alkenyl)2), trialkenylamines (i.e., N(alkenyl)3), substituted alkenylamines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl)amines (i.e., HN(substituted alkenyl)2), tri(substituted alkenyl)amines (i.e., N(substituted alkenyl)3), monocyclic alkylamines, bicyclic alkylamines, or tricyclic alkylamines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), monoarylamines, diarylamines, or triarylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), or mixed amines, etc. By way of example only, specific examples of suitable amines include isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, etc.

[0065] Some compounds exist in the form of tautomers. Tautomers are in equilibrium with each other. For example, an amide-containing compound can exist in equilibrium with an imino acid tautomer. Regardless of which tautomer is shown and regardless of the nature of the equilibrium between the tautomers, one of ordinary skill in the art understands the compound to include both the amide and imino acid tautomers. Thus, an amide-containing compound should be understood to include its imino acid tautomer. Similarly, an imino acid-containing compound should be understood to include its amide tautomer.

[0066] The compounds described herein, or pharmaceutically acceptable salts thereof, include asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, which can be defined as (R)- or (S)-, or (D)- or (L)- for amino acids in terms of absolute stereochemistry. The present disclosure is intended to include all such possible isomers, as well as their racemic and optically pure forms. The optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as chromatography and / or fractional crystallization. Conventional techniques for the preparation / separation of individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high performance liquid chromatography (HPLC). When the compounds described herein contain an olefinic double bond or other geometrically asymmetric center, and unless otherwise specified, the compounds are expected to include E and Z geometric isomers.

[0067] "Stereoisomers" refer to compounds that are composed of the same atoms bonded by the same bonds but have different three-dimensional structures that are not interchangeable. The present disclosure encompasses various stereoisomers or mixtures thereof and includes "enantiomers", which are two stereoisomers whose molecules are non-superimposable mirror images of each other.

[0068] "Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other.

[0069] The relative configuration of the compounds depicted herein is indicated graphically using the "thick bond" style (bold or parallel lines), and the absolute stereochemistry is depicted using wedge bonds (bold or parallel lines).

[0070] "Prodrug" means any compound that, upon administration to a mammalian subject, releases the active parent drug in vivo according to the structures described herein. Prodrugs of the compounds described herein are prepared by modifying the functional groups present in the compounds described herein in such a way that the modification is cleavable in vivo to release the parent compound. Prodrugs can be prepared by modifying the functional groups present in the compound in such a way that the modification is cleaved in conventional handling or in vivo to afford the parent compound. Prodrugs include the compounds described herein in which a hydroxyl, amino, carboxyl or thiol group of the compounds described herein is bonded to any group that is cleavable in vivo to regenerate the free hydroxyl, amino or thiol group, respectively. Examples of prodrugs include (but are not limited to) esters (e.g., acetate, formate and benzoate derivatives), amides, guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl), etc. of the hydroxyl functional group in the compounds described herein. The preparation, selection and use of prodrugs are discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium 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 incorporated herein by reference in its entirety.

[0071] 2. Compound

[0072] The present disclosure provides compounds that are NLRP3 modulators. In certain embodiments, a compound of formula I is provided:

[0073]

[0074] or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers or prodrug thereof, wherein:

[0075] X is O or S;

[0076] Y is O or S;

[0077] A 1 、A 2 、A 3 and A 4 are each independently N, CH or CR 1 ; provided that A 1 、A2 , A 3 and A 4 at least one of which is CR 1 ;

[0078] Each R 1 is independently a halogen group, a cyano group, -NO2, -SF5, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, 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 ; where each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted by one to eight Z 1 ;

[0079] R 2 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -NO2, -SF5, -OR 11 , -C(O)R 12 , -C(O)OR 11 , -SR 11 , -NR 11 S(O) 0-2 -R 11 , -NR 11 S(O)0-2 N(R 11 )2, -NR 11 C(O)N(R 11 )2, -NR 11 C(O)OR 11 , -OC(O)R 11 , -OC(O)N(R 11 )2, a halogen group or a cyano group; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 haloalkyl is independently optionally substituted by one to eight Z 2 substituents;

[0080] R 4 and R 5 are independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted by one to eight Z 1 substituents; or

[0081] R 4 and R 5 together form a heterocyclic group or a heteroaryl ring optionally substituted by one to eight Z 1 substituents;

[0082] R 6 is hydrogen, a halogen group, a cyano group, a hydroxyl group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 heteroalkyl, C 3-10 cycloalkyl or heterocyclic group;

[0083] R 7 is hydrogen, a halogen group, a cyano group, a hydroxyl group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 heteroalkyl, C 3-10Cycloalkyl or heterocyclic group;

[0084] or R 6 is linked to R 7 to form a C 3-10 cycloalkyl or heterocyclic ring, wherein the C 3-10 cycloalkyl or heterocyclic ring may further independently optionally be substituted by one to five Z 1a substituents;

[0085] Each Z 1 is independently a halogen group, cyano group, -NO2, -SF5, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, 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 ; wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted by one to five Z 1a substituents;

[0086] Each Z 2 is independently a halogen group, cyano group, -NO2, -SF5, -OR 11 , -C(O)R 12 , -C(O)OR 11 , -NR 11 S(O) 0-2 -R 11 , -NR 11S(O) 0-2 N(R 11 )2, -NR 11 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 ;

[0087] Each R 11 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C 11 of R 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted by one to five Z 1a ;

[0088] R 12 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 haloalkyl;

[0089] Each Z 1a is independently hydroxy, halo, cyano, -NO2, -SF5, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, 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(R13 ) 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 ; wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted by one to five Z 1b substituted;

[0090] Each R 13 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C of R 13 alkyl, C 1-6 alkenyl, C 2-6 alkynyl, C 2-6 haloalkyl, C 1-6 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted by one to five Z 3-10 substituted; 1b substituted;

[0091] Each Z 1b is independently a halogen group, cyano group, hydroxyl group, -SH, -NH2, -NO2, -SF5, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, heterocyclic group, aryl, heteroaryl, -L-C 1-6 alkyl, -L-C 2-6 alkenyl, -L-C 2-6 alkynyl, -L-C 1-6 haloalkyl, -L-C 3-10 cycloalkyl, -L-heterocyclic group, -L-aryl or -L-heteroaryl; and

[0092] 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(C3-10 cycloalkyl)-, -N(heterocyclic group)-, -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(heterocyclic group)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-;

[0093] wherein 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, heterocyclic group, aryl and heteroaryl are further independently optionally substituted by one to five of the following groups: hydroxyl, halogen, 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 cycloalkyl, heterocyclic group, aryl or heteroaryl.

[0094] In certain embodiments, when one of R 4 and R 5 is hydrogen, the other of R 4 and R 5 is not C3 alkyl optionally substituted by a piperazinyl ring.

[0095] In certain embodiments, when R 2 is unsubstituted C 1-6 alkyl or unsubstituted C 2-6 alkenyl and one R 1 is unsubstituted C 1-6 alkyl, unsubstituted C 2-6 alkenyl, unsubstituted C 5-7 cycloalkyl, unsubstituted C 1-6 alkoxy, halogen, benzyl or hydroxyl; then:

[0096] R4 and R 5 is independently hydrogen, unsubstituted C 1-6 alkyl, unsubstituted C 2-6 alkenyl, unsubstituted C 5-7 cycloalkyl, unsubstituted aryl or aryl substituted with one Z 1 ; and

[0097] R 4 and R 5 together with the nitrogen to which they are attached are not unsubstituted piperidinyl, unsubstituted morpholinyl or piperazinyl substituted with C 1-6 alkyl or aryl.

[0098] In certain embodiments, when R 2 is -CH2-C(O)OR 11 ; then R 4 and R 5 together with the nitrogen to which they are attached are not unsubstituted morpholinyl.

[0099] In certain embodiments, there is provided a compound of formula I:

[0100] or a pharmaceutically acceptable salt, isotope - enriched analogue, stereoisomer, mixture of stereoisomers or prodrug thereof, wherein:

[0101] X is O or S;

[0102] Y is O or S;

[0103] A 1 、A 2 、A 3 and A 4 are each independently N, CH or CR 1 ; provided that at least one of A 1 、A 2 、A 3 and A 4 is CR 1 ;

[0104] Each R 1 is independently halo, cyano, -NO2, -SF5, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic, 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 ; wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted by one to eight Z 1 substituted;

[0105] R 2 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -NO2, -SF5, -OR 11 , -C(O)R 12 , -C(O)OR 11 , -SR 11 , -NR 11 S(O) 0-2 -R 11 , -NR 11 S(O) 0-2 N(R 11 )2, -NR 11 C(O)N(R 11 )2, -NR 11 C(O)OR 11 , -OC(O)R 11 , -OC(O)N(R 11 )2, halo or cyano; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 haloalkyl is independently optionally substituted by one to eight Z 2 substituted;

[0106] R 4 and R 5 are independently hydrogen, C1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted by one to eight Z 1 ; or

[0107] R 4 together with R 5 forms a heterocyclic group or heteroaryl ring optionally substituted by one to eight Z 1 ;

[0108] R 6 is hydrogen, halogen, cyano, hydroxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 heteroalkyl, C 3-10 cycloalkyl or heterocyclic group;

[0109] R 7 is hydrogen, halogen, cyano, hydroxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 heteroalkyl, C 3-10 cycloalkyl or heterocyclic group;

[0110] or R 6 is linked to R 7 to form a C 3-10 cycloalkyl or heterocyclic group ring, wherein said C 3-10 cycloalkyl or heterocyclic group ring may further independently optionally be substituted by one to five Z 1a ;

[0111] each Z 1 is independently halogen, cyano, -NO2, -SF5, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl, heteroaryl, -N(R 11 )2, -OR11 、-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;

[0112] Each Z 2 are independently halogen, cyano, -NO2, -SF5, -OR 11 、-C(O)OR 11 、-NR 11 S(O) 0-2 -R 11 、-NR 11 S(O) 0-2 N(R 11 )2.-NR 11 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 ;

[0113] 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 R 11 Each C1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted by one to five Z 1a ;

[0114] R 12 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 haloalkyl;

[0115] each Z 1a is independently hydroxy, halo, cyano, -NO2, -SF5, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, 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 ; where each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted by one to five Z 1b ;

[0116] each R 13 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C1-6 haloalkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each R 13 of the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted with one to five Z 1b substituents;

[0117] each Z 1b is independently a halogen group, cyano group, hydroxyl group, -SH, -NH2, -NO2, -SF5, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, heterocyclic group, aryl, heteroaryl, -L-C 1-6 alkyl, -L-C 2-6 alkenyl, -L-C 2-6 alkynyl, -L-C 1-6 haloalkyl, -L-C 3-10 cycloalkyl, -L-heterocyclic group, -L-aryl or -L-heteroaryl; and

[0118] 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(heterocyclic group)-, -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(heterocyclic group)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-;

[0119] wherein each C of Z 1b and L 1-6 alkyl, C2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, heterocyclic group, aryl, and heteroaryl are further independently optionally substituted with one to five of the following groups: hydroxy, halogen, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl, heterocyclic group, aryl, or heteroaryl.

[0120] In certain embodiments, there is provided a compound of formula I or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein:

[0121] X is O or S;

[0122] Y is O or S;

[0123] A 1 , A 2 , A 3 and A 4 are each independently N, CH, or CR 1 ; provided that at least one of A 1 , A 2 , A 3 and A 4 is CR 1 ;

[0124] Each R 1 is independently halogen, cyano, -NO2, -SF5, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, 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 ; wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted by one to eight Z 1 substituted;

[0125] R 2 is C 3-10 cycloalkyl; wherein the C 3-10 cycloalkyl is independently optionally substituted by one to eight Z 2 substituted;

[0126] R 4 and R 5 are independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted by one to eight Z 1 substituted; or

[0127] R 4 and R 5 together form a heterocyclic group or heteroaryl ring optionally substituted by one to eight Z 1 substituted;

[0128] R 6 is hydrogen, halogen, cyano, hydroxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 heteroalkyl, C 3-10 cycloalkyl or heterocyclic group;

[0129] R 7 is hydrogen, halogen, cyano, hydroxy, C 1-6 alkyl, C2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 heteroalkyl, C 3-10 cycloalkyl or heterocyclic group;

[0130] or R 6 is connected to R 7 to form a C 3-10 cycloalkyl or heterocyclic ring, wherein the C 3-10 cycloalkyl or heterocyclic ring may further independently optionally be substituted by one to five Z 1a substituents;

[0131] each Z 1 is independently a halogen group, cyano group, -NO2, -SF5, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, 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 ; wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted by one to five Z 1a substituents;

[0132] each Z 2 is independently a halogen group, cyano group, -NO2, -SF5, -OR11 、 -C(O)OR 11 、 -NR 11 S(O) 0-2 -R 11 、 -NR 11 S(O) 0-2 N(R 11 )2、 -NR 11 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 ;

[0133] Each R 11 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C 11 of R 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted with one to five Z 1a ;

[0134] Each Z 1a is independently hydroxy, halo, cyano, -NO2, -SF5, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, 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 ; wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted by one to five Z 1b substituted;

[0135] Each R 13 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C of R 13 alkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted by one to five Z 1b substituted;

[0136] Each Z 1b is independently a halogen group, cyano group, hydroxyl group, -SH, -NH2, -NO2, -SF5, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, heterocyclic group, aryl, heteroaryl, -L-C 1-6 alkyl, -L-C 2-6 alkenyl, -L-C 2-6 alkynyl, -L-C 1-6 haloalkyl, -L-C 3-10 cycloalkyl, -L-heterocyclic group, -L-aryl or -L-heteroaryl; and

[0137] 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(heterocyclic group)-, -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(heterocyclic group)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-;

[0138] wherein 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, heterocyclic group, aryl and heteroaryl are further independently optionally substituted by one to five of the following groups: hydroxy, halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl.

[0139] In certain embodiments of Formula I, X is O. In certain embodiments of Formula I, Y is O. In certain embodiments, X is S. In certain embodiments of Formula I, Y is S. In certain embodiments of Formula I, X is O and Y is S. In certain embodiments of Formula I, X is S and Y is O. In certain embodiments of Formula I, X and Y are O. In certain embodiments of Formula I, X and Y are S.

[0140] In certain embodiments, there is provided a compound of Formula II:

[0141]

[0142] or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers or prodrug thereof, wherein:

[0143] A 1 、A 2 、A 3and A 4 each independently is N, CH or CR 1 ; provided that A 1 , A 2 , A 3 and A 4 at least one of which is CR 1 ;

[0144] Each R 1 is independently a halogen group, cyano group, -NO2, -SF5, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, 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 ; wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted by one to eight Z 1 ;

[0145] R 2 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -NO2, -SF5, -OR 11 , -C(O)R 12 , -C(O)OR 11 , -SR 11 , -NR 11S(O) 0-2 -R 11 、-NR 11 S(O) 0-2 N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 C(O)OR 11 、-OC(O)R 11 、-OC(O)N(R 11 )2、halogen or cyano; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 haloalkyl is independently optionally substituted by one to eight Z 2 ;

[0146] R 4 and R 5 are independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted by one to eight Z 1 ; or

[0147] R 4 and R 5 together form a heterocyclic group or heteroaryl ring optionally substituted by one to eight Z 1 ;

[0148] R 6 is hydrogen, halogen, cyano, hydroxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 heteroalkyl, C 3-10 cycloalkyl or heterocyclic group;

[0149] R 7 is hydrogen, halogen, cyano, hydroxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6Alkoxy, C 1-6 haloalkoxy, C 2-6 heteroalkyl, C 3-10 cycloalkyl or heterocyclic group;

[0150] or R 6 is connected to R 7 to form a C 3-10 cycloalkyl or heterocyclic ring, wherein the C 3-10 cycloalkyl or heterocyclic ring may further independently optionally be substituted by one to five Z 1a substituents;

[0151] Each Z 1 is independently a halogen group, cyano group, -NO2, -SF5, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, 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 ; wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted by one to five Z 1a substituents;

[0152] Each Z 2 is independently a halogen group, cyano group, -NO2, -SF5, -OR 11 , -C(O)R 12 , -C(O)OR 11 , -NR11 S(O) 0-2 -R 11 、-NR 11 S(O) 0-2 N(R 11 )2.-NR 11 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 ;

[0153] 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 R 11 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;

[0154] R 12 C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-6 haloalkyl; wherein R 12 Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-6 The haloalkyl group is optionally substituted by one to five Z 2 replace;

[0155] 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 R13 , -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 ; wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted by one to five Z 1b substituted;

[0156] Each R 13 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C 13 of R 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted by one to five Z 1b substituted;

[0157] Each Z 1b is independently a halogen group, cyano group, hydroxyl group, -SH, -NH2, -NO2, -SF5, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, heterocyclic group, aryl, heteroaryl, -L-C 1-6 alkyl, -L-C 2-6 alkenyl, -L-C 2-6 alkynyl, -L-C 1-6 haloalkyl, -L-C 3-10cycloalkyl, -L-heterocyclic group, -L-aryl or -L-heteroaryl; and

[0158] 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(heterocyclic group)-, -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(heterocyclic group)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-;

[0159] wherein 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, heterocyclic group, aryl and heteroaryl are further independently optionally substituted with one to five of the following groups: hydroxy, halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl.

[0160] In certain embodiments, when one of R 4 and R 5 is hydrogen, the other of R 4 and R 5 is not a C3 alkyl optionally substituted with a piperazinyl ring.

[0161] In certain embodiments, when R 2 is unsubstituted C1-6 alkyl or unsubstituted C 2-6 alkenyl and one R 1 is unsubstituted C 1-6 alkyl, unsubstituted C 2-6 alkenyl, unsubstituted C 5-7 cycloalkyl, unsubstituted C 1-6 alkoxy, halo, benzyl or hydroxy; then:

[0162] R 4 and R 5 are non - independently hydrogen, unsubstituted C 1-6 alkyl, unsubstituted C 2-6 alkenyl, unsubstituted C 5-7 cycloalkyl, unsubstituted aryl or aryl substituted by one Z 1 ; and

[0163] R 4 and R 5 together with the nitrogen to which they are attached are not unsubstituted piperidyl, unsubstituted morpholinyl or piperazinyl substituted by C 1-6 alkyl or aryl.

[0164] In certain embodiments, when R 2 is - CH2 - C(O)OR 11 ; then R 4 and R 5 together with the nitrogen to which they are attached are not unsubstituted morpholinyl.

[0165] In certain embodiments, there is provided a compound of formula II, or a pharmaceutically acceptable salt, isotope - enriched analogue, stereoisomer, mixture of stereoisomers or prodrug thereof, wherein:

[0166] A 1 、A 2 、A 3 and A 4 are each independently N, CH or CR 1 ; provided that at least one of A 1 、A 2 、A 3 and A 4 is CR 1 ;

[0167] Each R 1 is independently halo, cyano, - NO2, - SF5, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, 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 ; wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted by one to eight Z 1 substituted;

[0168] R 2 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -NO2, -SF5, -OR 11 . -C(O)R 12 . -C(O)OR 11 . -SR 11 . -NR 11 S(O) 0-2 -R 11 . -NR 11 S(O) 0-2 N(R 11 )2. -NR 11 C(O)N(R 11 )2. -NR 11 C(O)OR 11 . -OC(O)R 11 . -OC(O)N(R 11 )2. halo or cyano; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6The haloalkyl is independently optionally substituted by one to eight Z 2 ;

[0169] R 4 and R 5 are independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted by one to eight Z 1 ; or

[0170] R 4 and R 5 together form a heterocyclic group or heteroaryl ring optionally substituted by one to eight Z 1 ;

[0171] R 6 is hydrogen, halo, cyano, hydroxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 heteroalkyl, C 3-10 cycloalkyl or heterocyclic group;

[0172] R 7 is hydrogen, halo, cyano, hydroxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 heteroalkyl, C 3-10 cycloalkyl or heterocyclic group;

[0173] or R 6 is connected to R 7 to form a C 3-10 cycloalkyl or heterocyclic group ring, wherein the C 3-10 cycloalkyl or heterocyclic group ring may further be independently optionally substituted by one to five Z 1a ;

[0174] Each Z 1 is independently halo, cyano, -NO2, -SF5, C 1-6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic, 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 ; wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic, aryl or heteroaryl is independently optionally substituted by one to five Z 1a ;

[0175] Each Z 2 is independently halo, cyano, -NO2, -SF5, -OR 11 , -C(O)OR 11 , -NR 11 S(O) 0-2 -R 11 , -NR 11 S(O) 0-2 N(R 11 )2, -NR 11 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 ;

[0176] Each R 11 is independently hydrogen, C 1-6 alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C of R 11 Alkyl, C 1-6 Alkenyl, C 2-6 Alkynyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted by one to five Z 1a Substituted;

[0177] Each Z 1a Independently is hydroxyl, halogen, cyano, -NO2, -SF5, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclic group, 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 ; wherein each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted by one to five Z 1b Substituted;

[0178] R 12 Is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-6 Haloalkyl;

[0179] Each R 13 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C of R 13 alkyl, C 1-6 alkenyl, C 2-6 alkynyl, C 2-6 haloalkyl, C 1-6 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted with one to five Z 3-10 ; 1b

[0180] Each Z 1b is independently a halogen group, cyano group, hydroxyl group, -SH, -NH2, -NO2, -SF5, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, heterocyclic group, aryl, heteroaryl, -L-C 1-6 alkyl, -L-C 2-6 alkenyl, -L-C 2-6 alkynyl, -L-C 1-6 haloalkyl, -L-C 3-10 cycloalkyl, -L-heterocyclic group, -L-aryl or -L-heteroaryl; and

[0181] 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(heterocyclic group)-, -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(heterocyclic group)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-;

[0182] wherein 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, heterocyclic group, aryl and heteroaryl are further independently optionally substituted by one to five of the following groups: hydroxy, halogen, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl.

[0183] In certain embodiments, each of A 1 , A 2 , A 3 and A 4 is independently CH or CR 1 ; provided that at least one of A 1 , A 2 , A 3 and A 4 is CR 1 .

[0184] In certain embodiments, one of A 1 , A 2 , A 3 and A 4 is N; one of A 1 , A 2 , A 3 and A 4 is CR 1 ; and the remaining A 1 , A 2 , A 3 and A 4 are independently CH or CR 1 .

[0185] In certain embodiments, A 1 , A 2 , A 3 and A 4Both of them in are N; A 1 , A 2 , A 3 and A 4 One of them in is CR 1 ; and the remaining A 1 , A 2 , A 3 and A 4 is CH or CR 1 .

[0186] In certain embodiments, A 2 is CR 1 and A 1 , A 3 and A 4 are each independently N, CH or CR 1 .

[0187] In certain embodiments, A 3 is CR 1 and A 1 , A 2 and A 4 are each independently N, CH or CR 1 .

[0188] In certain embodiments, each R 1 is independently a halogen group, a cyano group, C 1-6 alkyl, C 3-10 cycloalkyl, -N(R 11 )2, -OR 11 or -SR 11 ; wherein each C 1-6 alkyl or C 3-10 cycloalkyl is independently optionally substituted by one to eight Z 1 . In certain embodiments, each R 1 is independently a halogen group, a cyano group, C 1-6 alkyl, C 3-10 cycloalkyl, -OR 11 or -SR 11 ; wherein each C 1-6 alkyl or C 3-10 cycloalkyl is independently optionally substituted by one to eight Z 1 . In certain embodiments, each R 1 is independently a halogen group, a cyano group, C 1-6 alkyl, C 3-10 cycloalkyl, -OR 11 or -SR 11 ; wherein each C 1-6 alkyl is independently optionally substituted by one to eight Z 1 .

[0189] In certain embodiments, each R 1 is independently a halogen group, a cyano group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 haloalkyl group, a C 1-6 haloalkoxy group, -N(R 11 )2, -SR 11 or a C 3-10 cycloalkyl group. In certain embodiments, each R 1 is independently a halogen group, a cyano group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 haloalkyl group, a C 1-6 haloalkoxy group, -SR 11 or a C 3-10 cycloalkyl group. In certain embodiments, each R 1 is independently a halogen group, a cyano group, a C 1-6 alkyl group, a C 1-6 alkoxy group or a C 1-6 haloalkyl group. In certain embodiments, each R 1 is independently a halogen group or a C 1-6 alkyl group.

[0190] In certain embodiments, each R 1 is independently fluorine, chlorine, bromine, iodine, -CH3, -CHF2, -CF3, -OCH3, -OCHF2, -OCF3, -N(CH3)2, -S-CH3, 1,1,1-trifluoropropan-2-yl, cyclopropyl or cyclobutyl.

[0191] In certain embodiments, each R 1 is independently fluorine, chlorine, bromine, iodine, -CH3, -CHF2, -CF3, -OCHF2, -OCF3, 1,1,1-trifluoropropan-2-yl, -S-CH3 or cyclopropyl. In certain embodiments, each R 1 is independently fluorine, bromine or -CH3.

[0192] In certain embodiments, R 4 is hydrogen.

[0193] In certain embodiments, R 6 is hydrogen or a C 1-6 alkyl group. In certain embodiments, R 6 is hydrogen.

[0194] In certain embodiments, R 7 is hydrogen.

[0195] In certain embodiments, R 6is hydrogen, and R 7 is hydrogen.

[0196] In certain embodiments, R 4 is hydrogen, R 6 is hydrogen, and R 7 is hydrogen.

[0197] In certain embodiments, R 5 is C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein said C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted with one to five Z 1 ; or R 4 and R 5 together form a heterocyclic ring optionally substituted with one to eight Z 1 .

[0198] In certain embodiments, R 5 is C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein said C 3-10 cycloalkyl, heterocyclic group or heteroaryl is independently optionally substituted with one to five Z 1 .

[0199] In certain embodiments, R 4 and R 5 together form a heterocyclic ring optionally substituted with one to eight Z 1 .

[0200] In certain embodiments, R 5 is C 3-10 cycloalkyl, heterocyclic group or heteroaryl; wherein said C 3-10 cycloalkyl, heterocyclic group or heteroaryl is independently optionally substituted with one to five Z 1 .

[0201] In certain embodiments, R 5 is optionally substituted with one to five Z 1 substituted C 3-10 cycloalkyl. In certain embodiments, R 5 is optionally substituted with one to five Z 1 substituted heterocyclic group. In certain embodiments, R 5 is optionally substituted with one to five Z 1 substituted heteroaryl.

[0202] In certain embodiments, R 5 is C 1-6alkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein said C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted with one to five of the following groups: halo, -OR 11 , -C(O)OR 11 , cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl.

[0203] In certain embodiments, R 5 is C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein said C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted with one to five of the following groups: halo, -OR 11 , -C(O)OR 11 , cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl.

[0204] In certain embodiments, R 4 is hydrogen and R 5 is C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein said C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted with one to five of the following groups: halo, -OR 11 , -C(O)OR 11 , cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl.

[0205] In certain embodiments, R 4 is hydrogen, R 6 is hydrogen, R 7 is hydrogen and R 5 is C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein said C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted with one to five of the following groups: halo, -OR 11 , -C(O)OR 11 , cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl.

[0206] In certain embodiments, R 5 is cycloalkyl, heterocyclic, or heteroaryl; wherein said cycloalkyl, heterocyclic, or heteroaryl is independently optionally substituted with one to five of the following groups: halo, hydroxy, C 3-10 alkyl, C 3-10 haloalkyl, cycloalkyl, or -C(O)OR 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or -C(O)OR 11 .

[0207] In certain embodiments, R 5 is optionally substituted cycloalkyl having one to five of the following groups: halo, -OR 3-10 , -C(O)OR 11 , cyano, C 11 alkyl, C 1-6 haloalkyl, C 1-6 cycloalkyl, heterocyclic, aryl, or heteroaryl. In certain embodiments, R 3-10 is optionally substituted heterocyclic having one to five of the following groups: halo, -OR 5 , -C(O)OR 11 , cyano, C 11 alkyl, C 1-6 haloalkyl, C 1-6 cycloalkyl, heterocyclic, aryl, or heteroaryl. In certain embodiments, R 3-10 is optionally substituted heteroaryl having one to five of the following groups: halo, -OR 5 11 , -C(O)OR 11 , cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, heterocyclic, aryl, or heteroaryl.

[0208]

[0208] In certain embodiments, R 55-fluoropyrimidin-4-yl, 1-ethylpiperidin-3-yl, 1-cyclobutylpiperidin-3-yl, 3-hydroxy-3-methylcyclobutyl, 3-fluoropyridin-4-yl, tert-butyl 3,3-difluoropiperidine-1-carboxylate-5-yl, 5,5-difluoropiperidin-3-yl, 1-ethyl-5,5-difluoropiperidin-3-yl, 5-fluoropyrimidin-2-yl, pyrimidin-2-yl, 5-cyano-3-fluoropyridin-2-yl, 6-methoxypyridin-3-yl, 6-chloropyridin-3-yl, 5-fluoro-2-methylpyrimidin-4-yl, pyrimidin-4-yl, 2-(trifluoromethyl)pyrimidin-4-yl, 3-fluoropyridin-2-yl, 6-chloro-3-fluoropyridin-2-yl, 3,5-difluoropyridin-4-yl, 3,5-difluoropyridin-2-yl, 3,6-difluoropyridin-2-yl, 3-fluoro-5-(trifluoromethyl)pyridin-2-yl, 3,3-difluorocyclopentyl, 2-methyltetrahydro-2H-pyran-4-yl, 4-methyltetrahydro-2H-pyran-4-yl, 6-(trifluoromethyl)pyridin-3-yl, 2,2-difluorocyclopentyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl, 1-cyclobutyl-1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-5-yl, 4-fluoro-1-methyl-1H-pyrazol-5-yl, 2-cyclopropylpyrimidin-4-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl, 2-oxaspiro[3.3]heptan-6-yl, pyridin-3-yl, pyrimidin-5-yl, (tetrahydro-2H-pyran-3-yl)methyl, (4-methylmorpholin-3-yl)methyl, 4-cyano-2-fluorophenyl, 2,2-dimethyltetrahydro-2H-pyran-4-yl, 1-methyl-1H-indazol-6-yl, 4-fluoro-1-methyl-1H-pyrazol-3-yl, 1,4-dimethyl-1H-pyrazol-5-yl, 1,3-dimethyl-1H-pyrazol-5-yl, (4-methylmorpholin-2-yl)methyl, 1-methyl-6-oxopiperidin-3-yl, 1-(oxetan-3-yl)-1H-pyrazol-5-yl, 5-chloro-3-fluoropyridin-2-yl, 1-methyl-1H-pyrazol-3-yl, pyridazin-3-yl, pyrazin-2-yl, 1-phenylethyl, (tetrahydro-2H-pyran-4-yl)methyl, (tetrahydrofuran-3-yl)methyl, 1-cyclobutylethyl, 3-methoxycyclobutyl, 1-ethylpiperidin-3-yl, 1-(tert-butoxycarbonyl)pyrrolidin-2-yl, pyrrolidin-2-ylmethyl, (1-ethylpyrrolidin-2-yl)methyl, 4-(trifluoromethyl)pyrimidin-2-yl, 5-cyclopropylpyridin-2-yl, 6-chloro-5-fluoropyridin-3-yl, 3-cyano-5-fluoropyridin-2-yl, 3-chloro-5-fluoropyridin-2-yl, 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl, 3-(1H-pyrazol-1-yl)cyclobutyl, 3-fluorobicyclo[1.1.1] pent-1-yl, 5-cyanopyridin-2-yl, 5-chloropyrimidin-2-yl, pyridazin-4-yl, 5-fluoropyridin-3-yl, 1-cyclobutyl-1H-pyrazol-5-yl, 3-fluoro-5-methylpyridin-2-yl, tetrahydro-2H-pyran-3-yl, cyclobutyl, cyclobutylmethyl, (1-methyl-1H-pyrazol-5-yl)methyl, benzyl, (tetrahydrofuran-2-yl)methyl, (tetrahydro-2H-pyran-2-yl)methyl, 4-methyloxan-4-yl, 2-methyloxan-4-yl, 5-cyanopyrimidin-2-yl, 5-methylpyrimidin-2-yl, piperidin-3-yl, 1-(tert-butoxycarbonyl)piperidin-3-yl, 1-cyclopropylpiperidin-3-yl, 4-ethyl-1,4-oxazepan-6-yl; or R. 4 and R 5 form 3,4-dihydroquinolin-1(2H)-yl.

[0209] In certain embodiments, R 55-fluoropyrimidin-4-yl, 1-ethylpiperidin-3-yl, 1-cyclobutylpiperidin-3-yl, 3-hydroxy-3-methylcyclobutyl, 3-fluoropyridin-4-yl, tert-butyl 3,3-difluoropiperidine-1-carboxylate-5-yl, 5,5-difluoropiperidin-3-yl, 1-ethyl-5,5-difluoropiperidin-3-yl, 5-fluoropyrimidin-2-yl, pyrimidin-2-yl, 5-cyano-3-fluoropyridin-2-yl, 6-methoxypyridin-3-yl, 6-chloropyridin-3-yl, 5-fluoro-2-methylpyrimidin-4-yl, pyrimidin-4-yl, 2-(trifluoromethyl)pyrimidin-4-yl, 3-fluoropyridin-2-yl, 6-chloro-3-fluoropyridin-2-yl, 3,5-difluoropyridin-4-yl, 3,5-difluoropyridin-2-yl, 3,6-difluoropyridin-2-yl, 3-fluoro-5-(trifluoromethyl)pyridin-2-yl, 3,3-difluorocyclopentyl, 2-methyltetrahydro-2H-pyran-4-yl, 4-methyltetrahydro-2H-pyran-4-yl, 6-(trifluoromethyl)pyridin-3-yl, 2,2-difluorocyclopentyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl, 1-cyclobutyl-1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-5-yl, 4-fluoro-1-methyl-1H-pyrazol-5-yl, 2-cyclopropylpyrimidin-4-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl, 2-oxaspiro[3.3]heptan-6-yl, pyridin-3-yl, pyrimidin-5-yl, (tetrahydro-2H-pyran-3-yl)methyl, (4-methylmorpholin-3-yl)methyl, 4-cyano-2-fluorophenyl, 2,2-dimethyltetrahydro-2H-pyran-4-yl, 1-methyl-1H-indazol-6-yl, 4-fluoro-1-methyl-1H-pyrazol-3-yl, 1,4-dimethyl-1H-pyrazol-5-yl, 1,3-dimethyl-1H-pyrazol-5-yl, (4-methylmorpholin-2-yl)methyl, 1-methyl-6-oxopiperidin-3-yl, 1-(oxetan-3-yl)-1H-pyrazol-5-yl, 5-chloro-3-fluoropyridin-2-yl, 1-methyl-1H-pyrazol-3-yl, pyridazin-3-yl, pyrazin-2-yl, 1-phenylethyl, (tetrahydro-2H-pyran-4-yl)methyl, (tetrahydrofuran-3-yl)methyl, 1-cyclobutylethyl, 3-methoxycyclobutyl, 1-ethylpiperidin-3-yl, 1-(tert-butoxycarbonyl)pyrrolidin-2-yl, pyrrolidin-2-ylmethyl, (1-ethylpyrrolidin-2-yl)methyl, 4-(trifluoromethyl)pyrimidin-2-yl, 5-cyclopropylpyridin-2-yl, 6-chloro-5-fluoropyridin-3-yl, 3-cyano-5-fluoropyridin-2-yl, 3-chloro-5-fluoropyridin-2-yl, 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl, 3-(1H-pyrazol-1-yl)cyclobutyl, 3-fluorobicyclo[1.1.1] pent-1-yl, 5-cyanopyridin-2-yl, 5-chloropyrimidin-2-yl, pyridazin-4-yl, 5-fluoropyridin-3-yl, 1-cyclobutyl-1H-pyrazol-5-yl, 3-fluoro-5-methylpyridin-2-yl, tetrahydro-2H-pyran-3-yl, cyclobutyl, cyclobutylmethyl, (1-methyl-1H-pyrazol-5-yl)methyl, benzyl, (tetrahydrofuran-2-yl)methyl, (tetrahydro-2H-pyran-2-yl)methyl, 4-methyloxan-4-yl or 2-methyloxan-4-yl; or R. 4 and R 5 form 3,4-dihydroquinolin-1(2H)-yl.

[0210] In certain embodiments, R 5 is 5-fluoropyrimidin-4-yl, 1-ethylpiperidin-3-yl, 1-cyclobutylpiperidin-3-yl, 3-hydroxy-3-methylcyclobutyl, 3-fluoropyridin-4-yl, tert-butyl 3,3-difluoropiperidine-1-carboxylate-5-yl, 5,5-difluoropiperidin-3-yl or 1-ethyl-5,5-difluoropiperidin-3-yl.

[0211] In certain embodiments, R 2 is C 1-6 alkyl, C 1-6 haloalkyl, -OR 11 , -SR 11 or halo; wherein said C 1-6 alkyl is optionally substituted with one to eight Z 2 . In certain embodiments, R 2 is C 1-6 alkyl, C 1-6 haloalkyl, -OR 11 , -SR 11 or halo; wherein said C 1-6 alkyl is optionally substituted with -OH; and R 11 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or heterocyclic group; wherein the C 11 alkyl, C 1-6 cycloalkyl or heterocyclic group of R 3-10 is optionally substituted with one to five Z 1a .

[0212] In certain embodiments, R 2is fluorine, bromine, chlorine, -CH3, -OCH3, -CH2F, -OCH2F, -CHF2, -OCHF2, -CF3, -SCH3, 1,1-difluoroethyl, 2,2-difluoroethyl, 1-fluoroethyl, 2-fluoroethyl, 2-hydroxyethyl, 2,2,2-trifluoroethyl, 1-hydroxyethyl, 1,1,1-trifluoropropan-2-yl, 2,2,2-trifluoroethoxy, 5-fluoropyrimidin-2-yl, cyclopropyloxy, cyclobutyloxy, ethoxy, propan-2-yloxy, (3,3-dimethylcyclobutyl)oxy, (3-methylcyclobutyl)oxy, (3-methoxycyclobutyl)oxy, oxetan-3-yloxy, 2-fluoropropoxy, 2-methoxyethoxy, cyclopropyl(fluoro)methoxy, 1-cyclopropylethoxy, [1-(2,2,2-trifluoroethyl)azetidin-3-yl]oxy, (3-cyanocyclobutyl)oxy or (3-methoxycyclobutyl)oxy.

[0213] In certain embodiments, each Z 1a is independently a halogen group, a cyano group, -OR 13 , C 1-6 alkyl or C 3-10 cycloalkyl.

[0214] In certain embodiments, R 2 is C 1-6 alkyl, C 1-6 haloalkyl, -OR 11 or a halogen group; wherein the C 1-6 alkyl is optionally substituted with one to eight Z 2 . In certain embodiments, R 2 is C 1-6 alkyl, C 1-6 haloalkyl, -OR 11 or a halogen group; wherein the C 1-6 alkyl is optionally substituted with -OH. In certain embodiments, R 2 is C 1-6 alkyl, C 1-6 haloalkyl, -OR 11 or a halogen group; wherein the C 1-6 alkyl is optionally substituted with -OH. In certain embodiments, R 2 is C 1-6 alkyl, C 1-6 haloalkyl, -OR 11 or a halogen group; wherein the C 1-6 alkyl is optionally substituted with -OH; and each R 11 is independently hydrogen, C 1-6 alkyl or C 1-6 haloalkyl. In certain embodiments, R 2 is C 1-6alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, or C 1-6 haloalkoxy. In certain embodiments, R 2 is fluorine, bromine, -CH3, -OCH3, -CHF2, -OCHF2, 1,1-difluoroethyl, 2,2-difluoroethyl, 1-fluoroethyl, 2-fluoroethyl, 2-hydroxyethyl, 2,2,2-trifluoroethyl, 1-hydroxyethyl, or 1,1,1-trifluoropropan-2-yl.

[0215] In certain embodiments, R 2 is C 1-6 alkyl, C 1-6 haloalkyl, or -OR 11 wherein R 11 is C 1a alkyl optionally substituted with one to five Z 1-6 In certain embodiments, R 2 is C 1-6 alkyl or C 1-6 haloalkyl. In certain embodiments, R 2 is C 1-6 alkyl. In certain embodiments, R 2 is isopropyl.

[0216] In certain embodiments, R 2 is -OR 11 and R 11 is C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or heterocyclic group; wherein the C 11 of R 1-6 alkyl, C 3-10 cycloalkyl, or heterocyclic group is optionally substituted with one to five Z 1a In certain embodiments, R

[0217] is -OR 2 and R 11 is C 11 alkyl. In certain embodiments, R 1-6 is -OR 2 and R 11 is C 11 alkyl optionally substituted with one to five Z 1a In certain embodiments, R 3-10 is -OR 2 and R 11 is heterocyclic group optionally substituted with one to five Z 11 1a 1a substituted.

[0218] In certain embodiments, each Z 1a is independently a halogen group, a cyano group, -OR 13 , C 1-6 alkyl or C 3-10 cycloalkyl. In certain embodiments, each Z 1a is independently a cyano group, -OR 13 , C 1-6 alkyl or C 3-10 cycloalkyl.

[0219] In certain embodiments, R 2 is -C(R 14 )2R 15 ; each R 14 and R 15 is independently hydrogen, a halogen group, C 1-4 alkyl or C 1-4 haloalkyl. In certain embodiments, R 2 is -C(R 14 )2R 15 ; each R 14 is independently hydrogen, a halogen group, C 1-4 alkyl or C 1-4 haloalkyl, and R 15 is hydrogen.

[0220] In certain embodiments, R 2 is a C 2 cycloalkyl optionally substituted with one to eight Z 3-10 . In certain embodiments, R 2 is a cyclopropyl optionally substituted with one to eight Z 2 . In certain embodiments, R 2 is C 3-10 cycloalkyl. In certain embodiments, R 2 is cyclopropyl.

[0221] In certain embodiments, Z 1a is independently a halogen group.

[0222] In certain embodiments, each Z 1 is independently a halogen group, a hydroxyl group, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or -C(O)OR 11 .

[0223] In certain embodiments, each R 11 is independently hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10A cycloalkyl or heterocyclic group; wherein R 11 The C 1-6 alkyl, C 3-10 cycloalkyl or heterocyclic group is optionally substituted with one to five Z 1a . In certain embodiments, each Z 1a is independently a halogen group, a cyano group, -OR 13 , C 1-6 alkyl or C 3-10 cycloalkyl.

[0224] In certain embodiments, each R 11 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl.

[0225] In certain embodiments, each R 11 is independently hydrogen or C 1-6 alkyl. In certain embodiments, each R 11 is hydrogen.

[0226] In certain embodiments, R 12 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 haloalkyl.

[0227] In certain embodiments, each R 13 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl. In certain embodiments, each R 13 is independently hydrogen or C 1-6 alkyl.

[0228] In certain embodiments, R 2 is C 1-6 alkyl, R 4 is hydrogen, R 6 is hydrogen, and R 7 is hydrogen.

[0229] In certain embodiments, each of A 1 , A 2 , A 3 and A 4 is independently CH or CR 1; provided that A 1 、A 2 、A 3 and A 4 is at least one of CR 1 ; each R 1 is independently a halogen group, a cyano group, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, -N(R 11 )2, -SR 11 or C 3-10 cycloalkyl; R 2 is C 1-6 alkyl, C 1-6 haloalkyl, -SR 11 , -OR 11 or a halogen group; wherein the C 1-6 alkyl is optionally substituted by one to eight Z 2 ; R 4 is hydrogen; R 5 is C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein the C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted by one to five Z 1 ; or R 4 and R 5 together form a heterocyclic ring optionally substituted by one to eight Z 1 ; R 6 is hydrogen or C 1-6 alkyl; and R 7 is hydrogen.

[0230] In certain embodiments, one of A 1 , A 2 , A 3 and A 4 is N; one of A 1 , A 2 , A 3 and A 4 is CR 1 ; and the remaining A 1 , A 2 , A 3 and A 4 are independently CH or CR 1 ; each R 1 is independently a halogen group, a cyano group, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C1-6 haloalkoxy, -N(R 11 )2, -SR 11 or C 3-10 cycloalkyl; R 2 is C 1-6 alkyl, C 1-6 haloalkyl, -SR 11 , -OR 11 or halo; wherein said C 1-6 alkyl is optionally substituted with one to eight Z 2 ; R 4 is hydrogen; R 5 is C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein said C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted with one to five Z 1 ; or R 4 and R 5 together form a heterocyclic ring optionally substituted with one to eight Z 1 ; R 6 is hydrogen or C 1-6 alkyl; and R 7 is hydrogen.

[0231] In certain embodiments, two of A 1 , A 2 , A 3 and A 4 are N; one of A 1 , A 2 , A 3 and A 4 is CR 1 ; and the remaining A 1 , A 2 , A 3 and A 4 are CH or CR 1 ; each R 1 is independently halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, -N(R 11 )2, -SR 11 or C 3-10 cycloalkyl; R 2 is C 1-6 alkyl, C 1-6 haloalkyl, -SR 11 , -OR 11 or halo; wherein said C1-6 The alkyl group is optionally substituted by one to eight Z 2 ; R 4 is hydrogen; R 5 is C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein the C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted by one to five Z 1 ; or R 4 together with R 5 forms a heterocyclic ring optionally substituted by one to eight Z 1 ; R 6 is hydrogen or C 1-6 alkyl; and R 7 is hydrogen.

[0232] In certain embodiments, A 2 is CR 1 and A 1 , A 3 and A 4 are each independently N, CH or CR 1 ; each R 1 is independently halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, -SR 11 , -N(R 11 )2 or C 3-10 cycloalkyl; R 2 is C 1-6 alkyl, C 1-6 haloalkyl, -SR 11 , -OR 11 or halo; wherein the C 1-6 alkyl is optionally substituted by one to eight Z 2 ; R 4 is hydrogen; R 5 is C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein the C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted by one to five Z 1 ; or R 4 together with R 5 forms a heterocyclic ring optionally substituted by one to eight Z 1 ; R 6 is hydrogen or C 1-6 alkyl; and R7 is hydrogen.

[0233] In certain embodiments, A 3 is CR 1 and A 1 , A 2 and A 4 are each independently N, CH or CR 1 ; each R 1 is independently halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, -SR 11 , -N(R 11 )2 or C 3-10 cycloalkyl; R 2 is C 1-6 alkyl, C 1-6 haloalkyl, -SR 11 , -OR 11 or halo; wherein said C 1-6 alkyl is optionally substituted with one to eight Z 2 ; R 4 is hydrogen; R 5 is C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclic, aryl or heteroaryl; wherein said C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclic, aryl or heteroaryl are each independently optionally substituted with one to five Z 1 ; or R 4 and R 5 together form a heterocyclic ring optionally substituted with one to eight Z 1 ; R 6 is hydrogen or C 1-6 alkyl; and R 7 is hydrogen.

[0234] In certain embodiments, each of A 1 , A 2 , A 3 and A 4 is independently CH or CR 1 ; provided that at least one of A 1 , A 2 , A 3 and A 4 is CR 1 ; each R 1 is independently halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6Halogenoalkyl, C 1-6 halogenoalkoxy, -SR 11 or C 3-10 cycloalkyl; R 2 is C 1-6 alkyl, C 1-6 halogenoalkyl, -OR 11 or halogen; wherein said C 1-6 alkyl is optionally substituted by one to eight Z 2 ; R 4 is hydrogen; R 5 is C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein said C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted by one to five Z 1 ; or R 4 together with R 5 forms a heterocyclic ring optionally substituted by one to eight Z 1 ; R 6 is hydrogen or C 1-6 alkyl; and R 7 is hydrogen.

[0235] In certain embodiments, one of A 1 , A 2 , A 3 and A 4 is N; one of A 1 , A 2 , A 3 and A 4 is CR 1 ; and the remaining A 1 , A 2 , A 3 and A 4 are independently CH or CR 1 ; each R 1 is independently halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 halogenoalkyl, C 1-6 halogenoalkoxy, -SR 11 or C 3-10 cycloalkyl; R 2 is C 1-6 alkyl, C 1-6 halogenoalkyl, -OR 11 or halogen; wherein said C 1-6 alkyl is optionally substituted by one to eight Z 2 ; R 4 is hydrogen; R 5is C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein said C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted by one to five Z 1 ; or R 4 together with R 5 forms a heterocyclic ring optionally substituted by one to eight Z 1 ; R 6 is hydrogen or C 1-6 alkyl; and R 7 is hydrogen.

[0236] In certain embodiments, two of A 1 , A 2 , A 3 and A 4 are N; one of A 1 , A 2 , A 3 and A 4 is CR 1 ; and the remaining A 1 , A 2 , A 3 and A 4 are CH or CR 1 ; each R 1 is independently halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, -SR 11 or C 3-10 cycloalkyl; R 2 is C 1-6 alkyl, C 1-6 haloalkyl, -OR 11 or halo; wherein said C 1-6 alkyl is optionally substituted by one to eight Z 2 ; R 4 is hydrogen; R 5 is C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein said C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted by one to five Z 1 ; or R 4 together with R 5 forms a heterocyclic ring optionally substituted by one to eight Z 1 ; R 6 is hydrogen or C1-6 alkyl; and R 7 is hydrogen.

[0237] In certain embodiments, A 2 is CR 1 and A 1 、A 3 and A 4 are each independently N, CH, or CR 1 ; each R 1 is independently halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, -SR 11 or C 3-10 cycloalkyl; R 2 is C 1-6 alkyl, C 1-6 haloalkyl, -OR 11 or halo; wherein said C 1-6 alkyl is optionally substituted with one to eight Z 2 ; R 4 is hydrogen; R 5 is C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein said C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is independently optionally substituted with one to five Z 1 ; or R 4 and R 5 together form a heterocycloalkyl ring optionally substituted with one to eight Z 1 ; R 6 is hydrogen or C 1-6 alkyl; and R 7 is hydrogen.

[0238] In certain embodiments, A 3 is CR 1 and A 1 、A 2 and A 4 are each independently N, CH, or CR 1 ; each R 1 is independently halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, -SR 11 or C 3-10 cycloalkyl; R 2 is C 1-6Alkyl, C 1-6 haloalkyl, -OR 11 or halo; wherein said C 1-6 alkyl is optionally substituted by one to eight Z 2 ; R 4 is hydrogen; R 5 is C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein said C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted by one to five Z 1 ; or R 4 and R 5 together form a heterocyclic ring optionally substituted by one to eight Z 1 ; R 6 is hydrogen or C 1-6 alkyl; and R 7 is hydrogen.

[0239] In certain embodiments, each of A 1 , A 2 , A 3 and A 4 is independently CH or CR 1 ; provided that at least one of A 1 , A 2 , A 3 and A 4 is CR 1 ; each R 1 is independently halo, cyano, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 haloalkyl; R 2 is C 1-6 alkyl, C 1-6 haloalkyl or -OR 11 , wherein R 11 is C 1a alkyl optionally substituted by one to five Z 1-6 ; R 4 is hydrogen; R 5 is C 3-10 cycloalkyl, heterocyclic group or heteroaryl; wherein said C 3-10 cycloalkyl, heterocyclic group or heteroaryl is independently optionally substituted by one to five Z 1 ; R 6 is hydrogen; and R 7 is hydrogen.

[0240] In certain embodiments, A 1 , A 2 , A3 and A 4 one of which is N; A 1 , A 2 , A 3 and A 4 one of which is CR 1 ; and the remaining A 1 , A 2 , A 3 and A 4 are independently CH or CR 1 ; each R 1 is independently a halogen group, a cyano group, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 haloalkyl; R 2 is C 1-6 alkyl, C 1-6 haloalkyl or -OR 11 , where R 11 is optionally C 1a alkyl substituted by one to five Z 1-6 ; R 4 is hydrogen; R 5 is C 3-10 cycloalkyl, heterocyclic group or heteroaryl; where the C 3-10 cycloalkyl, heterocyclic group or heteroaryl is independently optionally substituted by one to five Z 1 ; R 6 is hydrogen; and R 7 is hydrogen.

[0241] In certain embodiments, A 1 , A 2 , A 3 and A 4 two of which are N; A 1 , A 2 , A 3 and A 4 one of which is CR 1 ; and the remaining A 1 , A 2 , A 3 and A 4 are CH or CR 1 ; each R 1 is independently a halogen group, a cyano group, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 haloalkyl; R 2 is C 1-6 alkyl, C 1-6 haloalkyl or -OR 11 , where R 11 is optionally substituted by one to five Z1a Substituted C 1-6 alkyl; R 4 is hydrogen; R 5 is C 3-10 cycloalkyl, heterocyclic group or heteroaryl; wherein said C 3-10 cycloalkyl, heterocyclic group or heteroaryl is independently optionally substituted by one to five Z 1 ; R 6 is hydrogen; and R 7 is hydrogen.

[0242] In certain embodiments, A 2 is CR 1 and A 1 , A 3 and A 4 are each independently N, CH or CR 1 ; each R 1 is independently halo, cyano, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 haloalkyl; R 2 is C 1-6 alkyl, C 1-6 haloalkyl or -OR 11 , wherein R 11 is optionally substituted by one to five Z 1a of C 1-6 alkyl; R 4 is hydrogen; R 5 is C 3-10 cycloalkyl, heterocyclic group or heteroaryl; wherein said C 3-10 cycloalkyl, heterocyclic group or heteroaryl is independently optionally substituted by one to five Z 1 ; R 6 is hydrogen; and R 7 is hydrogen.

[0243] In certain embodiments, A 3 is CR 1 and A 1 , A 2 and A 4 are each independently N, CH or CR 1 ; each R 1 is independently halo, cyano, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 haloalkyl; R 2 is C 1-6 alkyl, C 1-6 haloalkyl or -OR 11 , wherein R 11 is optionally substituted by one to five Z1a Substituted C 1-6 alkyl; R 4 is hydrogen; R 5 is C 3-10 cycloalkyl, heterocyclic group or heteroaryl; wherein said C 3-10 cycloalkyl, heterocyclic group or heteroaryl is independently optionally substituted by one to five Z 1 ; R 6 is hydrogen; and R 7 is hydrogen.

[0244] In certain embodiments, there is provided a compound selected from Table 1, or a pharmaceutically acceptable salt, isotope-enriched analogue, prodrug, stereoisomer or mixture of stereoisomers thereof:

[0245] Table 1

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259] In certain embodiments, there is provided a compound selected from Table 2, or a pharmaceutically acceptable salt, isotope-enriched analogue, prodrug, stereoisomer or mixture of stereoisomers thereof:

[0260] Table 2

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269] 3. Method

[0270] "Treatment" or "treating" is a means for obtaining a beneficial or desired result, including a clinical result. Beneficial or desired clinical results can include one or more of the following results: a) inhibiting the disease or disorder (e.g., reducing one or more symptoms caused by the disease or disorder and / or attenuating the degree of the disease or disorder); b) slowing or arresting 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 worsening or progression of the disease or disorder and / or preventing or delaying the spread of the disease or disorder); and / or c) alleviating the disease, i.e., causing the clinical symptoms to subside (e.g., alleviating the disease disorder, providing partial or total remission of the disease or disorder, enhancing the effect of another medicament, delaying the progression of the disease, improving quality of life and / or prolonging survival).

[0271] "Prevention" or "preventing" means any treatment that causes the clinical symptoms of a disease or disorder not to develop. In some embodiments, the compound can be administered to a subject (including a human) at risk of having the disease or disorder or having a family history of the disease or disorder.

[0272] "Subject" refers to an animal, such as a mammal (including a human), that has become or will become 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.

[0273] As used herein, the term "therapeutically effective amount" or "effective amount" of a compound or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers or prodrug thereof means an amount sufficient to effect treatment when administered to a subject to provide a therapeutic benefit (e.g., ameliorating symptoms or slowing disease progression). For example, a therapeutically effective amount can be an amount sufficient to alleviate the symptoms of a disease or disorder as described herein. The therapeutically effective amount can vary depending on the subject to be treated and the disease or disorder, the weight and age of the subject, the severity of the disease or disorder and the mode of administration, and can be readily determined by one of ordinary skill in the art.

[0274] In certain embodiments, the compound used in the methods described herein is a compound of Formula I:

[0275]

[0276] or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers or prodrug thereof, wherein:

[0277] X is O or S;

[0278] Y is O or S;

[0279] A 1 、A 2 、A 3 and A 4 are each independently N, CH or CR 1 ; provided that at least one of A 1 、A 2 、A 3 and A 4 is CR 1 ;

[0280] Each R 1 is independently halo, cyano, -NO2, -SF5, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocycloalkyl, 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 ; wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted by one to eight Z 1 substituents;

[0281] R 2 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, -NO2, -SF5, -OR 11 , -C(O)R 11 , -C(O)OR 11 , -SR 11 , -NR 11 S(O) 0-2 -R 11 , -NR 11 S(O) 0-2 N(R 11 )2, -NR 11 C(O)N(R 11 )2, -NR 11 C(O)OR 11 , -OC(O)R 11 , -OC(O)N(R 11 )2, halo group, cyano group, -NR 11 C(O)R 11 , -S(O)R 11 or -S(O)2R 11 ; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl or C 3-10 cycloalkyl is independently optionally substituted by one to eight Z 2 substituents;

[0282] R 4 and R 5 are independently hydrogen, C1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted by one to eight Z 1 ; or

[0283] R 4 together with R 5 forms an optionally substituted heterocyclic group or heteroaryl ring by one to eight Z 1 ;

[0284] R 6 is hydrogen, halogen, cyano, hydroxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 heteroalkyl, C 3-10 cycloalkyl or heterocyclic group;

[0285] R 7 is hydrogen, halogen, cyano, hydroxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 heteroalkyl, C 3-10 cycloalkyl or heterocyclic group;

[0286] or R 6 is connected to R 7 to form a C 3-10 cycloalkyl or heterocyclic group ring, wherein said C 3-10 cycloalkyl or heterocyclic group ring may further be independently optionally substituted by one to five Z 1a ;

[0287] each Z 1 is independently halogen, cyano, -NO2, -SF5, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl, heteroaryl, -N(R 11 )2, -OR11 , -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 ; wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted by one to five Z 1a substituents;

[0288] Each Z 2 is independently a halogen group, cyano group, -NO2, -SF5, -OR 11 , -C(O)R 11 , -C(O)OR 11 , -NR 11 S(O) 0-2 -R 11 , -NR 11 S(O) 0-2 N(R 11 )2, -NR 11 C(O)N(R 11 )2, -NR 11 C(O)R 11 , -OC(O)N(R 11 )2, -NR 11 C(O)OR 11 , -N(R 11 )2, -C(O)N(R 11 )2, -S(O) 0-2 R 11 or -S(O) 0-2 N(R 11 )2;

[0289] Each R11 independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C of R 11 alkyl, C 1-6 alkenyl, C 2-6 alkynyl, C 2-6 haloalkyl, C 1-6 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted by one to five Z 3-10 substituted; 1a

[0290] Each Z 1a is independently hydroxy, halo, cyano, -NO2, -SF5, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, 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 ; wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted by one to five Z 1b substituted;

[0291] Each R 13 is independently hydrogen, C 1-6 alkyl, C​2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C of R 13 alkyl, C 1-6 alkenyl, C 2-6 alkynyl, C 2-6 haloalkyl, C 1-6 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted with one to five Z 3-10 ; 1b substituted;

[0292] each Z 1b is independently a halogen group, cyano group, hydroxyl group, -SH, -NH2, -NO2, -SF5, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, heterocyclic group, aryl, heteroaryl, -L-C 1-6 alkyl, -L-C 2-6 alkenyl, -L-C 2-6 alkynyl, -L-C 1-6 haloalkyl, -L-C 3-10 cycloalkyl, -L-heterocyclic group, -L-aryl or -L-heteroaryl; and

[0293] 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(heterocyclic group)-, -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(heterocyclic group)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-;

[0294] wherein Z1b each C of L 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, heterocyclic group, aryl and heteroaryl are further independently optionally substituted by one to five of the following groups: hydroxy, halogen, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl.

[0295] The methods described herein can be applied to in vivo or ex vivo cell populations. "In vivo" means within a living individual, such as within an animal or a human. In this case, the methods described herein can be used therapeutically in an individual. "Ex vivo" means outside of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples, including body fluid or tissue samples obtained from an individual. Such samples can be obtained by methods well known in the art. Exemplary biological body 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 ex vivo to determine the optimal dosing schedule and / or dose of the disclosed compounds for a given indication, cell type, individual, and other parameters. Information gathered from such uses can be used for experimental purposes or in the clinic to set in vivo treatment regimens. Other ex vivo uses for which the compounds and compositions described herein may be suitable are described below or will be apparent to those skilled in the art. The compounds can be further characterized to examine safety or tolerable doses in human or non-human subjects. Such characterization can be examined using methods generally known to those skilled in the art.

[0296] In certain embodiments, compounds that modulate the activity of NOD-like receptor family pyrin domain-containing protein 3 (NLRP3), or pharmaceutically acceptable salts, isotope-enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, are provided. In certain embodiments, the compounds provided herein, or pharmaceutically acceptable salts, isotope-enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, inhibit the activation of NLRP3.

[0297] NLR proteins are involved in the immune system and help initiate and regulate the immune system's response to injury, toxins, or microbial invasion. NLRP3 (also known as cryopyrin-containing, 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 with other proteins into an inflammasome. Activation of NLRP3 by cellular stress causes inflammasome activation and downstream proteolytic events, including the formation of the bioactive pro-inflammatory 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, atherosclerosis, and the aging process, such as arterial wall inflammation.

[0298] In certain embodiments, a method of inhibiting the activity of an inflammasome (e.g., the NLRP3 inflammasome) is provided, the method comprising contacting a cell with an effective amount of a compound or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers, or prodrug thereof disclosed herein. The inhibition can be in vitro or in vivo.

[0299] In certain embodiments, a compound as disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers, or prodrug thereof, is provided for inhibiting the activity of an inflammasome (e.g., the NLRP3 inflammasome) (e.g., in vitro or in vivo).

[0300] In certain embodiments, the present disclosure provides the use of a compound or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers, or prodrug thereof as disclosed herein for manufacturing a medicament for inhibiting the activity of an inflammasome (e.g., the NLRP3 inflammasome) (e.g., in vitro or in vivo).

[0301] Chronic inflammatory responses have been associated with various types of cancer. During malignant transformation or cancer therapy, the inflammasome can become activated in response to certain signals; and IL-Iβ expression is elevated in a variety of cancers (e.g., breast cancer, prostate cancer, colon cancer, lung cancer, head and neck cancer, melanoma, etc.), and patients with tumors that produce IL-Iβ generally have a poor prognosis.

[0302] In certain embodiments, a method for treating a disease or disorder 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 or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers, or prodrug thereof disclosed herein.

[0303] In certain embodiments, provided is a method for treating a disease or disorder selected from the group consisting of autoinflammatory disorders, autoimmune disorders, neurodegenerative diseases, or cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers, or prodrug thereof as disclosed herein.

[0304] In certain embodiments, provided is a compound or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers, or prodrug thereof as disclosed herein for treating an autoinflammatory disorder, autoimmune disorder, neurodegenerative disease, or cancer in a subject in need thereof.

[0305] In certain embodiments, the present disclosure provides the use of a compound or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers, or prodrug thereof as disclosed herein for the manufacture of a medicament for treating or preventing an autoinflammatory disorder, autoimmune disorder, neurodegenerative disease, or cancer in a subject in need thereof.

[0306] In certain embodiments, provided is a method for treating inflammation, autoimmune diseases, cancer, infections, central nervous system diseases, metabolic diseases, cardiovascular diseases, respiratory diseases, liver diseases, kidney diseases, eye diseases, skin diseases, lymphatic disorders, psychological disorders, graft-versus-host disease, abnormal pain, and any disease in which an individual has been determined to carry a germline or somatic non-silent mutation in NLRP3, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers, or prodrug thereof as disclosed herein.

[0307] 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, hepatic system, metabolic system, respiratory system, central nervous system, can be cancer or other malignant diseases, and / or can be caused by or associated with a pathogen. It should be understood that these general embodiments defined according to broad categories of diseases, disorders, and afflictions are not mutually exclusive.

[0308] In certain embodiments, the disease or disorder includes inflammation, including inflammation that arises due to an inflammatory condition such as an autoinflammatory disease, inflammation that appears as a symptom of a non-inflammatory condition, inflammation that arises due to an 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), anti-synthetase syndrome, aplastic anemia, autoimmune adrenalitis, autoimmune hepatitis, autoimmune oophoritis, autoimmune polyendocrine failure, autoimmune thyroiditis, celiac disease, Crohn's disease, type 1 diabetes (T1D), Goodpasture 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, systemic sclerosis, systemic connective tissue disorders, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, alopecia totalis, Behçet's disease disease), Chagas' disease, autonomic neuropathy, 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 syndromes, leukemia including acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), adrenal cancer, anal cancer, basal 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 tumor family, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), gestational trophoblastic disease, glioma, Hodgkin lymphoma, Kaposi sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, liver cancer, lung carcinoid tumors, lymphoma including cutaneous T-cell lymphoma, malignant mesothelioma, melanoma skin cancer, Merkel cell skin cancer, multiple myeloma, nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral and oropharyngeal cancer, osteosarcoma, ovarian cancer, penile cancer, pituitary tumor, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, stomach cancer, testicular cancer, thymic cancer, thyroid cancer including papillary thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom macroglobulinemia and Wilms tumor; infections, including viral infections (such as from influenza virus, human immunodeficiency virus (HIV), alphaviruses (such as Chikungunya and Ross River virus), flaviviruses (such as dengue virus and Zika virus), herpesviruses (such as Epstein - Barr Virus, cytomegalovirus, varicella - zoster virus and KSHV), poxviruses (such as vaccinia virus (modified vaccinia virus Ankara) and myxoma virus), adenoviruses (such as adenovirus 5) or papillomavirus),Bacterial infections (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, 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, Salmonella typhimurium, Salmonella typhi, Borrelia burgdorferi, or Yersinia pestis),Fungal infections (e.g., from the genus Candida or Aspergillus), protozoal infections (e.g., from Plasmodium, Babesia, Giardia, Entamoeba, Leishmania or Trypanosomes), worm 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 diseases, Huntington's disease, cerebral malaria, brain damage 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 myocardial infarction (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, aneurysm including abdominal aortic aneurysm, and pericarditis including Dressler's syndrome; respiratory diseases including chronic obstructive pulmonary disease (COPD), asthma such as 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, nephrocalcinosis, glomerulonephritis, and diabetic nephropathy; eye diseases including diseases of the ocular epithelium, age-related macular degeneration (AMD) (dry and wet), uveitis, corneal infections, diabetic retinopathy, optic nerve injury, dry eye, and glaucoma; skin diseases including dermatitis such as contact dermatitis and atopic dermatitis, contact allergy, sunburn, skin lesions, hidradenitis suppurativa (HS), skin diseases caused by other cysts, and acne conglobata; lymphatic disorders such as lymphangitis and Castleman disease; psychological disorders such as depression and psychological stress; graft-versus-host disease; abnormal pain including mechanical allodynia; and any disease in which an individual has been determined to carry a germline or somatic non-silent mutation in NLRP3.,

[0309] In certain embodiments, the disease, disorder or condition is an autoinflammatory disease such as cryopyrin-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), hyperimmunoglobulin D 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 (AOSD), A20 haploinsufficiency (HA20), pediatric granulomatous arthritis (PGA), PLCG2-related antibody deficiency and immune dysregulation (PLAID), PLCG2-related autoinflammatory antibody deficiency and immune dysregulation (APLAID), or sideroblastic anemia with B cell immunodeficiency, periodic fever and developmental delay (SIFD).

[0310] In certain embodiments, a method for treating a disease or disorder selected from autoinflammatory and / or autoimmune disorders is provided, the autoinflammatory and / or autoimmune disorders being selected from cryopyrin-associated autoinflammatory syndrome (CAPS; such as familial cold autoinflammatory syndrome (FCAS)), Muckle-Wells syndrome (MWS), chronic infantile neurological cutaneous and articular (CINCA) syndrome, neonatal-onset multisystem inflammatory disease (NOMID), familial Mediterranean fever and 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 (such as prion diseases), the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers or prodrug thereof disclosed herein.

[0311] In certain embodiments, a method for treating a disease or disorder selected from cryopyrin-associated periodic syndrome (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), familial Mediterranean fever (FMF), pyogenic arthritis, pyoderma gangrenosum and acne syndrome (PAPA); hyperimmunoglobulin D 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, Schnitzler syndrome, Sweet syndrome, Behçet's disease, anti-synthetase syndrome, interleukin 1 receptor antagonist deficiency (DIRA), and A20 haploinsufficiency (HA20) is provided, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, an isotope-enriched analogue, a stereoisomer, a mixture of stereoisomers, or a prodrug thereof disclosed herein.

[0312] In certain embodiments, a method for treating a disease or disorder selected from Alzheimer's disease, atherosclerosis, asthma, allergic airway inflammation, cryopyrin-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 encephalomyelitis, 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, joint inflammation caused by chikungunya virus, or traumatic brain injury is provided, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, an isotope-enriched analogue, a stereoisomer, a mixture of stereoisomers, or a prodrug thereof disclosed herein.

[0313] In certain embodiments, a method is provided for treating a disease or disorder that is at least partially mediated by TNF-α. 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 or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs disclosed herein 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.

[0314] In certain embodiments, the disease or disorder is an autoinflammatory condition, an autoimmune condition, a neurodegenerative disease, or cancer.

[0315] In certain embodiments, the disease or disorder is an autoinflammatory condition and / or an autoimmune condition.

[0316] In certain embodiments, the disease or disorder is a neurodegenerative disease.

[0317] In certain embodiments, the disease or disorder is Parkinson's disease or Alzheimer's disease.

[0318] In certain embodiments, a method is provided for treating cancer, the method comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug disclosed herein.

[0319] In certain embodiments, the cancer is metastatic cancer, gastrointestinal cancer, skin cancer, non-small cell lung cancer, or colorectal adenocarcinoma.

[0320] In certain embodiments, a compound as disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, is provided for treating a neurodegenerative disease (such as Parkinson's disease or Alzheimer's disease) in a subject in need thereof.

[0321] In certain embodiments, a compound or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug disclosed herein is provided for treating cancer in a subject in need thereof.

[0322] In certain embodiments, a compound or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers or prodrug thereof, as disclosed herein, can be administered alone as the sole therapy or can additionally be administered in combination with one or more other substances and / or treatments. Such combination therapies can be achieved simultaneously, sequentially or by separate administration of the individual therapeutic components.

[0323] For example, therapeutic efficacy can be enhanced by the administration of an adjuvant (i.e., the adjuvant itself may have only minimal therapeutic benefit but, in combination with another therapeutic agent, enhances the overall therapeutic benefit to the individual). Or, by way of example only, the benefits experienced by an individual can be increased by the administration of a compound or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers or prodrug thereof, as disclosed herein, and another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit.

[0324] Other embodiments include the use of the compounds of the present disclosure in therapy.

[0325] 4. Kits

[0326] Kits are also provided herein, which include a compound or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers or prodrug thereof of the present disclosure and a suitable package. In certain embodiments, the kit further includes instructions for use. In one aspect, the kit includes a compound or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers or prodrug thereof of the present disclosure and labeling and / or instructions for use of the compound for treating an indication (including the diseases or disorders described herein).

[0327] Articles are also provided herein, which include a compound or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers or prodrug thereof described herein in a suitable container. The container can be a vial, bottle, ampule, pre-loaded syringe or intravenous bag.

[0328] 5. Pharmaceutical Compositions and Modes of Administration

[0329] The compounds provided herein are generally administered in the form of pharmaceutical compositions. Accordingly, the present disclosure also provides pharmaceutical compositions that contain one or more of the compounds described herein or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants, and excipients. Suitable pharmaceutically acceptable vehicles can include, for example, inert solid diluents and fillers, diluents (including sterile aqueous solutions and various organic solvents), penetration enhancers, solubilizers, and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, PA 17th ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd ed. (eds. G.S. Banker and C.T. Rhodes).

[0330] The pharmaceutical compositions can be administered in single-dose or multi-dose forms. The pharmaceutical compositions can be administered by a variety of methods, including, for example, rectal, buccal, intranasal, and transdermal routes. In certain embodiments, the pharmaceutical compositions can be administered by intraarterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or in the form of an inhalant.

[0331] One mode of administration is parenteral, such as by injection. Forms in which the pharmaceutical compositions described herein can be incorporated for administration by injection include, for example, aqueous or oily suspensions, or emulsions, containing sesame oil, corn oil, cottonseed oil, or peanut oil, and elixirs, mannitol, dextrose, or sterile aqueous solutions and similar pharmaceutical vehicles.

[0332] Oral administration can be another route for administering the compounds described herein. For example, it can be administered via capsules or enteric-coated tablets. In preparing pharmaceutical compositions that include at least one of the compounds described herein or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, the active ingredient is usually diluted and / or enclosed within such carriers as can be in the form of capsules, sachets, paper, or other containers. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Accordingly, the compositions can 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 the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0333] Some examples of suitable excipients include, for example, lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations may additionally include: lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl hydroxybenzoate and propyl hydroxybenzoate; sweetening agents; and flavoring agents.

[0334] Compositions comprising at least one compound described herein or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers or prodrug thereof can be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to a subject by procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Another formulation for use in the methods disclosed herein employs a transdermal delivery device ("patch"). Such transdermal patches can be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts. The construction and use of transdermal patches for delivering pharmaceutical agents are well known in the art. Such patches can be constructed for continuous, pulsatile or on-demand delivery of pharmaceutical agents.

[0335] With respect to the preparation of solid compositions such as tablets, the principal active ingredient can be mixed with a pharmaceutical excipient to form a solid preformulation composition that contains a homogeneous mixture of a compound described herein or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers or prodrug thereof. When referring to these preformulation compositions as homogeneous compositions, the active ingredient is uniformly dispersed throughout the composition such that the composition can be readily re-divided into equally effective unit dosage forms such as tablets, pills and capsules.

[0336] Tablets or pills of the compounds described herein can be coated or otherwise compounded to provide a dosage form that affords a long action time or the advantage of protection from the acidic conditions of the stomach. For example, a tablet or pill can include an inner dose and an outer dose component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to prevent disintegration in the stomach and to permit the complete entry of the inner component into the duodenum or to provide a delayed release. A variety of materials can 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.

[0337] Compositions for inhalation or insufflation may include solutions and suspensions and powders in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effects. In other embodiments, the compositions in pharmaceutically acceptable solvents may be nebulized using an inert gas. Nebulized solutions may be inhaled directly from the nebulizer device or the nebulizer device may be connected to a face mask or intermittent positive pressure ventilator. Solutions, suspensions or powder compositions may be administered in a suitable manner from the device delivering the formulation, preferably orally or nasally.

[0338] 6. Administration

[0339] The specific dose of the compounds of the present application for any particular subject will depend on a variety of factors including the activity of the particular compound employed, the age, weight, general health, sex, diet, time of administration, route of administration and rate of excretion of the subject being treated, drug combination and the severity of the particular disease. For example, the dose may be expressed as milligrams of the compound described herein per kilogram of subject body weight (mg / kg). A dose between about 0.1 and 150 mg / kg may be appropriate. In some embodiments, about 0.1 and 100 mg / kg may be appropriate. In other embodiments, a dose between 0.5 and 60 mg / kg may be appropriate. In some embodiments, a dose of about 0.0001 to about 100 milligrams per kilogram of body weight per day, about 0.001 to about 50 milligrams per kilogram of body weight or about 0.01 to about 10 milligrams per kilogram of body weight of the compound may be appropriate. Normalization according to the body weight of the subject is particularly applicable when adjusting the dose between subjects of widely different body sizes, such as when drugs are used in both children and adults or when converting an effective dose in a non-human subject such as a dog to a dose suitable for a human subject.

[0340] 7. Synthesis of Compounds

[0341] The compounds may be prepared using the methods disclosed herein and their conventional modifications (which will be apparent from the disclosure herein) and methods well known in the art. In addition to the teachings herein, conventional and well-known synthetic methods may also be used. The synthesis of the exemplary compounds described herein may be achieved as described in the following examples. If feasible, reagents and starting materials may be purchased from, for example, Sigma Aldrich or other chemical suppliers.

[0342] It should be understood that, unless otherwise stated, when typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are presented, other process conditions may also be used. The optimal reaction conditions may vary depending on the specific reactants or solvents used, but such conditions can be determined by those skilled in the art through routine optimization procedures.

[0343] In addition, conventional protecting groups ("PG") may be required to prevent certain functional groups from undergoing unwanted reactions. Protecting groups applicable to various functional groups and the conditions for protecting specific functional groups and removing the protection of specific functional groups are well known in the art. For example, numerous protecting groups are described in Wuts, P.G.M., Greene, T.W. and Greene, T.W. (2006). Greene's protective groups in organic synthesis. Hoboken, N.J., Wiley-Interscience and the references cited therein. For example, protecting groups for alcohols such as hydroxyl groups include silyl ethers (including trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), trimethoxymethylsilyloxymethyl (TOM) and triisopropylsilyl (TIPS) ethers), which can be removed by acid or fluoride ions such as NaF, TBAF (tetra-n-butylammonium fluoride), HF-Py or HF-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; dimethoxytriphenylmethyl, removed by acid; methoxymethyl ether, removed by acid; tetrahydropyranyl or tetrahydrofuranyl, removed by acid; and triphenylmethyl, removed by acid. Examples of amine protecting groups include benzyloxycarbonyl, removed by hydrogenolysis; p-methoxybenzylcarbonyl, removed by hydrogenolysis; tert-butoxycarbonyl, removed by strong concentrated acid (e.g., HCl or CF3COOH) or by heating to greater than about 80 °C; 9-fluorenylmethoxycarbonyl, removed by a base such as piperidine; acetyl, removed by treatment with a base; benzoyl, removed by treatment with a base; benzyl, removed by hydrogenolysis; carbamate, removed by acid and gentle heating; p-methoxybenzyl, removed by hydrogenolysis; 3,4-dimethoxybenzyl, removed by hydrogenolysis; p-methoxyphenyl, removed by ammonium cerium(IV) nitrate; tosyl, removed by strong concentrated acid (e.g., HBr or H2SO4) and a strong reducing agent (sodium in liquid ammonia or sodium naphthalide); troc (trichloroethyl chloroformate), removed by inserting Zn in the presence of acetic acid; and sulfonamides (Nosyl and Nps), removed by samarium iodide or tributyltin hydride.

[0344] In addition, the compounds of the present disclosure may contain one or more chiral centers. Therefore, if necessary, such compounds can be prepared or separated as pure stereoisomers, that is, prepared or separated as individual enantiomers or diastereomers, or prepared or separated as stereoisomer enriched mixtures. 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, the racemic mixture of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, etc.

[0345] 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 are available 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 standard reference texts, such as 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).

[0346] Universal synthesis

[0347] Scheme 1 illustrates a general method that can be used to synthesize compounds described herein, wherein X, Y, A 1 -A 4 , R 2 , R 4 , R 5 , R 6 and R 7Each of which is independently as defined herein, each R z is independently H or C 1-6 alkyl, and each LG is a leaving group (e.g., halogen). It is understood that any one or more of Compounds I-1 and I-5 or any product obtained by the methods outlined in Scheme I can be derivatized to give various Compounds of Formula I.

[0348] Scheme I

[0349]

[0350] In Scheme I, the Compound of Formula I can be prepared by starting with Compound I-1 and coupling it with Compound I-2. Alternatively, Compound I-1 is coupled with Compound I-3 to give Compound I-4. The appropriately substituted amine I-5 can be directly coupled with Compound I-4 under amide bond-forming reaction conditions to give the Compound of Formula I. Alternatively, when R z is C 1-6 alkyl, the ester can be cleaved to produce the corresponding carboxylic acid derivative, which, when reacted with the appropriately substituted amine I-5 under amide bond-forming reaction conditions, gives the Compound of Formula I.

[0351] Suitable starting materials and reagents can be purchased or prepared by methods known to those skilled in the art. After each reaction is complete, each of the intermediates or final compounds can be recovered and optionally purified by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration, etc.

[0352] In some embodiments, the various substituents of Compounds I-1, I-2, I-3, I-4, and I-5 as used in Scheme I are as defined for Formula I. However, the derivatization of Compounds I-1, I-2, I-3, I-4, and I-5 provides a variety of Compounds of Formula I.

[0353] In certain embodiments, there is provided a method for preparing a Compound of Formula I, the method comprising:

[0354] contacting a Compound of Formula I-1 with a Compound of Formula I-2 under conditions suitable for providing a Compound of Formula I.

[0355] In certain embodiments, there is provided a method for preparing a Compound of Formula I, the method comprising:

[0356] contacting a Compound of Formula I-4 with a Compound of Formula I-5 under conditions suitable for providing a Compound of Formula I.

[0357] In certain embodiments, there is provided a method for preparing a Compound of Formula I, the method comprising:

[0358] Contacting a compound of formula I-1 with a compound of formula I-3 under conditions suitable to afford a compound of formula I-4; and

[0359] Contacting a compound of formula I-4 with a compound of formula I-5 under conditions suitable to afford a compound of formula I.

[0360] Scheme II illustrates a general method that can be used to synthesize the compounds described herein, where A 1 -A 4 、R 2 、R 4 、R 5 、R 6 and R 7 each independently is as defined herein, each R z is independently H or C 1-6 alkyl, and each LG is a leaving group (e.g., halo). It should be understood that any one or more of the compounds II-1 and I-5 or any product obtained by the methods outlined in Scheme II can be derivatized to afford various compounds of formula II.

[0361] Scheme I

[0362]

[0363] In Scheme II, a compound of formula II can be prepared by starting with a compound II-1 and coupling it with a compound II-2. Alternatively, coupling of compound II-1 with compound II-3 provides compound II-4. A suitably substituted amine I-5 can be directly coupled with compound II-4 under amide bond-forming reaction conditions to afford a compound of formula II. Alternatively, when R z is C 1-6 alkyl, the ester can be cleaved to produce the corresponding carboxylic acid derivative, which when reacted with a suitably substituted amine I-5 under amide bond-forming reaction conditions yields a compound of formula II.

[0364] Suitable starting materials and reagents can be purchased or prepared by methods known to those skilled in the art. After each reaction is complete, each of the intermediates or final compounds can be recovered and optionally purified by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration, etc.

[0365] In some embodiments, the various substituents of compounds II-1, II-2, II-3, II-4, and I-5 as used in Scheme II are as defined with respect to formula II. However, derivatization of compounds II-1, II-2, II-3, II-4, and I-5 affords various compounds of formula II.

[0366] In certain embodiments, there is provided a method for preparing a compound of formula II, the method comprising:

[0367] Contacting a compound of Formula II-1 with a compound of Formula II-2 under conditions suitable for providing a compound of Formula II.

[0368] In certain embodiments, provided is a method for preparing a compound of Formula II, the method comprising:

[0369] Contacting a compound of Formula II-4 with a compound of Formula I-5 under conditions suitable for providing a compound of Formula II.

[0370] In certain embodiments, provided is a method for preparing a compound of Formula II, the method comprising:

[0371] Contacting a compound of Formula II-1 with a compound of Formula II-3 under conditions suitable for providing a compound of Formula II-4; and

[0372] Contacting a compound of Formula II-4 with a compound of Formula I-5 under conditions suitable for providing a compound of Formula II. Examples

[0373] The following examples are included to demonstrate specific embodiments of the disclosure. Those skilled in the art will appreciate that the techniques disclosed in the following examples represent techniques that function well in the practice of the disclosure and are thus considered to constitute specific modes of its practice. However, those skilled in the art will understand that, in light of the disclosure, many changes can be made to the specific embodiments disclosed without departing from the spirit and scope of the disclosure and still obtain the same or similar results.

[0374] General Experimental Methods

[0375] All solvents used were commercially available and used without further purification. Reactions were generally carried out using anhydrous solvents under an inert nitrogen atmosphere.

[0376] NMR Spectroscopy: 1 1H nuclear magnetic resonance (NMR) spectroscopy was performed using a Bruker Avance III equipped with a BBFO 300 MHz probe operating at 300 MHz or one of the following instruments: a Bruker Avance 400 instrument equipped with a DUAL 400 MHz S1 probe, a 6S1 400 MHz 5 mm 1 1H- 13Bruker Avance 400 instrument with C ID, Bruker Avance III 400 instrument equipped with a probe Broadband BBFO 5mm direct with nanobay, Bruker Mercury Plus 400 NMR spectrometer equipped with a Bruker 400BBO probe operating at 400 MHz. All deuterated solvents generally contain 0.03% to 0.05% v / v tetramethylsilane, which is used as a reference signal (set to δ0.00 for 1 H and 13 C). In some cases, unless otherwise stated, Bruker Advance 400 instrument operating at 400 MHz using the stated solvent at approximately room temperature was used for 1 H nuclear magnetic resonance (NMR) spectroscopy. In all cases, the NMR data was consistent with the proposed structure. Characteristic chemical shifts (δ) were given in parts per million using the conventional abbreviations for the designated major peaks: e.g., s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets; br, broad peak.

[0377] Thin layer chromatography: In cases where thin layer chromatography (TLC) was used, it refers to silica gel TLC using silica gel F254 (Merck) plates, and Rf is the distance traveled by the compound on the TLC plate divided by the distance traveled by the solvent. Column chromatography was carried out on silica gel cartridges using an automated flash chromatography system or on C18 cartridges in the case of reverse phase chromatography. Alternatively, thin layer chromatography (TLC) was carried out on (silica gel l 60F254) from Mancherey-Nagel and UV was generally used to observe the spots. In some cases, other observation methods were also employed. In these cases, the TLC plates were developed with iodine (produced by adding approximately 1 g I2 to 10 g silica gel and mixing well), ninhydrin (available from Aldrich), or Magic Stain (produced by mixing 25 g (NH4)6Mo7O 24 .4H2O, 5 g (NH4)2Ce(IV)(NO3)6 in 450 mL of water and 50 mL of concentrated H2SO4) to observe the compounds.

[0378] Liquid Chromatography-Mass Spectrometry and HPLC Analysis: HPLC analysis was performed on a Shimadzu 20AB HPLC system equipped with a photodiode array detector and a Luna-C18(2) 2.0×50 mm, 5 μm column: flow rate of 1.2 mL / min, 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). Detection by LCMS was performed at 220 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 100×30 mm, 5 μm; MPA: HCl / H2O = 0.04% or formic acid H2O = 0.2% (v / v); MPB: ACN. Neutral: Waters Xbridge 150×25, 5 μm; MPA: 10 mM NH4HCO3 in H2O; MPB: ACN. Gradient for both conditions: 10% MPB to 80% MPB in 12 minutes at a flow rate of 20 mL / min, then 100% MPB for 2 minutes, 10% MPB for 2 minutes, UV detector. SFC analysis was performed on a Thar analytical SFC system using 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, flow rate of 4 mL / min, gradient solvent mobile phase A (MPA, CO2): mobile phase B (MPB, MeOH + 0.05% (v / v) IPAm) (0.01 min, 10% MPB; 3 min, 40% MPB; 3.5 min, 40% MPB; 3.56 - 5 min, 10% MPB). SFC preparation was performed on a Thar 80 preparative SFC system using 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, flow rate of 65 mL / min, 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 was also used TMThe system collected LC-MS data. The system was equipped with a PDA detector and coupled to a Waters single quadrupole mass spectrometer operating in alternating positive and negative electrospray ionization modes. The column used was Cortecs UPLC C18, 1.6 μm, 2.1×50 mm. A linear gradient was applied, which started at 95% A (A: 0.1% formic acid in water) and terminated at 95% B (B: 0.1% formic acid in MeCN) over 2.0 min, and the total run time was 2.5 minutes. The column temperature was 40 °C and the flow rate was 0.8 mL / min.

[0379] Intermediate 1

[0380]

[0381] 2-Chloro-N-(cis-3-hydroxy-3-methylcyclobutyl)acetamide: To a solution of cis-3-amino-1-methylcyclobutanol hydrochloride (1.1 g, 7.99 mmol) in DCM (15 mL) were added DMF (2 mL) and N-methylmorpholine (2.43 g, 24.0 mmol). At -78 °C, a solution of 2-chloroacetyl chloride (903 mg, 7.99 mmol) in DCM (2 mL) was added dropwise to the reaction mixture. The reaction mixture was stirred at 20 °C for 2 h. Then the reaction mixture was concentrated under reduced pressure. The crude residue was purified by silica gel chromatography. 1 H NMR (400 MHz, CDCl3): δ 6.81 (br s, 1H), 4.10 - 3.96 (m, 3H), 2.59 - 2.48 (m, 2H), 2.14 - 2.04 (m, 2H), 1.39 (s, 3H).

[0382] Intermediate 2

[0383]

[0384] (R)-(1-Cyclobutylpiperidin-3-yl)tert-butyl carbamate: At 0 °C, to a solution of (R)-tert-butyl piperidin-3-ylcarbamate (10.0 g, 49.9 mmol) in methanol (100 mL) were added cyclobutanone (7.0 g, 100 mmol), acetic acid (6.0 g, 100 mmol) and sodium cyanoborohydride (5.33 g, 84.9 mmol). The reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude residue was diluted with water (100 mL) and extracted with EtOAc (3×40 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z = 229.2 [M+H] + .

[0385] (R)-1-Cyclobutylpiperidin-3-amine hydrochloride: (R)-(1-Ethylpiperidin-3-yl)carbamic acid tert-butyl ester (6.5 g, 25.5 mmol) was dissolved in HCl (50 mL, 4 N in dioxane). The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was used directly. LCMS: m / z = 191.1 [M+H] + 。

[0386] (R)-2-Chloro-N-(1-cyclobutylpiperidin-3-yl)acetamide: At 0 °C, N-methylmorpholine (12.1 g, 120 mmol) was added dropwise to a solution of (R)-1-ethylpiperidin-3-amine hydrochloride (5.7 g, 29.9 mmol) in DCM (50 mL), followed by the addition of 2-chloroacetyl chloride (3.38 g, 29.9 mmol). The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was diluted with ice-cold saturated aqueous NaHCO3 (10 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was used directly. LCMS: m / z = 231.1 [M+H] + 。

[0387] Intermediate 3

[0388]

[0389] 6-Bromo-4-hydroxyphtalazin-1(2H)-one: A solution of 5-bromoisobenzofuran-1,3-dione (30.0 g, 132 mmol) in AcOH (800 mL) was stirred at 125 °C for 1 h. The mixture was cooled to 25 °C, then hydrazine hydrate (7.10 g, 139 mmol) was added. The reaction mixture was stirred at 125 °C for 0.5 h. The reaction mixture was cooled to 25 °C, diluted with MeOH (400 mL) and concentrated under reduced pressure to give a solid, which was used directly. LCMS: m / z = 241.1, 243.1 [M+H] + 。

[0390] 6-Bromo-1,4-dichlorophthalazine: A solution of 6-bromo-4-hydroxyphtalazin-1(2H)-one (90.0 g, 373 mmol) in POCl3 (802 g, 5.23 mol) was stirred at 110 °C for 48 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was used directly. LCMS: m / z = 277.0, 278.9 [M+H]+ 6-Bromo-1,4-diiodophthalazine: To a solution of 6-bromo-1,4-dichlorophthalazine (50 g, 180 mmol) in acetone (600 mL) was added NaI (138 g, 918 mmol) and HI (2.0 g, 18.0 mmol). The reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was diluted with water (1000 mL) and extracted with EtOAc (2 × 800 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was wet milled with a 1:2 mixture of MTBE / PE at 20 °C for 30 min to give a residue, which was used directly. LCMS: m / z = 460.8, 462.8 [M+H] + 。

[0391] 6-Bromo-4-iodophthalazin-1-ol and 7-bromo-4-iodophthalazin-1-ol: To a solution of 6-bromo-1,4-diiodophthalazine (27.0 g, 58.6 mmol) in 1,4-dioxane (300 mL) was added NaOH (2 M, 293 mL). The reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was concentrated under reduced pressure to remove the organic solvent. The resulting solution was adjusted to pH = 4-5 with 12 M HCl. The reaction mixture was filtered and the filter cake was dried in vacuo to give a 1:1 mixture of 6-bromo-4-iodophthalazin-1-ol and 7-bromo-4-iodophthalazin-1-ol. LCMS: m / z = 350.9, 352.9 [M+H] + 。

[0392] Methyl 2-(6-bromo-4-iodo-1-oxophthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-4-iodo-1-oxophthalazin-2(1H)-yl)acetate: To a solution of 7-bromo-4-iodophthalazin-1-ol and 6-bromo-4-iodophthalazin-1-ol (1:1 mixture, 17.0 g, 48.4 mmol) in DMF (200 mL) was added methyl 2-bromoacetate (15.0 g, 96.9 mmol) and Cs2CO3 (32.0 g, 96.9 mmol). The reaction mixture was stirred at 20 °C for 12 h. The mixture was diluted with water (500 mL) and extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was wet milled with a 1:2 mixture of MTBE / PE at 20 °C for 30 min and then filtered to give a 1:1 mixture of methyl 2-(6-bromo-4-iodo-1-oxophthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-4-iodo-1-oxophthalazin-2(1H)-yl)acetate. LCMS: m / z = 422.8, 424.8 [M+H] + 。

[0393] Intermediate 4

[0394]

[0395] 1,4,6 - Tribromophthalazine: To a solution of 6 - bromo - 4 - hydroxyphtalazin - 1(2H) - one (10.0 g, 41.5 mmol) in DCE (100 mL) at 25 °C was added PBr5 (35.7 g, 82.9 mmol). The reaction mixture was stirred at 90 °C for 48 h. The reaction mixture was diluted with water (100 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was used directly. 1 H NMR (400 MHz, DMSO - d6): δ 8.41 - 8.34 (m, 2H), 8.16 (d, J = 8.8 Hz, 1H).

[0396] 4,6 - Dibromophthalazin - 1 - ol and 4,7 - dibromophthalazin - 1 - ol: A solution of 1,4,6 - tribromophthalazine (11.0 g, 30.0 mmol) in AcOH (110 mL) was stirred at 60 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (100 mL). The resulting mixture was filtered and the filter cake was dried under reduced pressure to give a residue, which was used directly as a 1:1 mixture of 4,6 - dibromophthalazin - 1 - ol and 4,7 - dibromophthalazin - 1 - ol. LCMS: m / z = 304.9, 306.9, 302.9 [M + H] + 。

[0397] Ethyl 2 - (4,6 - dibromo - 1 - oxophthalazin - 2(1H) - yl)acetate: At 0 °C, to a mixture of 4,6 - dibromophthalazin - 1 - ol and 4,7 - dibromophthalazin - 1 - ol in DMF (21 mL) (1:1 mixture, 2.10 g, 6.91 mmol) was added NaH (277 mg, 6.91 mmol, 60% purity), followed by ethyl 2 - bromoacetate (1.15 g, 6.91 mmol). The reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by preparative SFC. 1 HNMR (400 MHz, DMSO - d6): δ 8.20 - 8.16 (m, 2H), 8.08 (s, 1H), 5.03 - 4.75 (s, 2H), 4.19 - 4.15 (m, 2H), 1.28 - 1.07 (m, 3H).

[0398] Intermediate 5

[0399]

[0400] 6-Bromopyridine-2,3-dicarboxylic acid: To a solution of periodic acid (49.3 g, 216 mmol) and CCl4 (180 mL) in water (360 mL) was added RuCl3 (1.79 g, 8.65 mmol) and 2-bromoquinoline (9.00 g, 43.3 mmol). The reaction mixture was stirred at 20 °C for 16 h and then at 50 °C for 80 h. The reaction mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was used directly. LCMS: m / z = 245.9, 247.9 [M+H] + 。

[0401] 2-Bromofuro[3,4-b]pyridine-5,7-dione: A solution of 6-bromopyridine-2,3-dicarboxylic acid (6.00 g, 24.4 mmol) in acetic anhydride (10 mL) was stirred at 120 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was recrystallized from a 1:5 mixture of MTBE and PE (10 mL) to give a solid, which was used directly.

[0402] 6-Bromo-2-isobutyrylnicotinic acid: To a mixture of 2-bromofuro[3,4-b]pyridine-5,7-dione (2.00 g, 8.77 mmol) and CuBr (126 mg, 0.87 mmol) in THF (20 mL) at -78 °C was added isopropylmagnesium chloride (4.39 mL, 2 M in THF). The reaction mixture was stirred at -78 °C for 1 h. The reaction mixture was quenched by adding saturated aqueous NH4Cl solution (50 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 reverse-phase preparative HPLC. LCMS: m / z = 270.0, 272.0 [M-H] - 。

[0403] Methyl 6-bromo-2-isobutyrylnicotinate: At 0 °C, TMSCHN2 (1.46 mL, 2 M in n-hexane) was added to a solution of 6-bromo-2-isobutyrylnicotinic acid (530 mg, 1.95 mmol) in THF (5.0 mL). The reaction mixture was stirred at 20 °C for 12 h and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z = 286.1, 288.1 [M+H] + 。

[0404] 2-Bromo-8-isopropylpyrido[2,3-d]pyridazin-5(6H)-one: Hydrazine monohydrate (44 mg, 1.35 mmol) was added to a solution of methyl 6-bromo-2-isobutyrylnicotinate (350 mg, 1.22 mmol) in MeOH (5.0 mL). The reaction mixture was stirred at 25 °C for 3 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was used directly. 1 H NMR (400 MHz, CDCl3): δ = 10.28 (br s, 1H), 8.51 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 3.90 - 3.86 (m, 1H), 1.35 (d, J = 6.8 Hz, 6H).

[0405] Methyl 2-(2-bromo-8-isopropyl-5-oxopyrido[2,3-d]pyridazin-6(5H)-yl)acetate: Cs2CO3 (598 mg, 1.84 mmol) was added to a solution of 2-bromo-8-isopropylpyrido[2,3-d]pyridazin-5(6H)-one (246 mg, 0.91 mmol) and methyl 2-bromoacetate (155 mg, 1.01 mmol) in DMF (5 mL). The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was poured into ice water (30 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. LCMS: m / z = 340.1, 342.1 [M+H] + 。

[0406] Intermediate 6

[0407]

[0408] 2-(2,2-Difluoroacetyl)-4-(trifluoromethyl)benzoic acid: To a solution of 2-bromo-4-(trifluoromethyl)benzoic acid (1.0 g, 3.72 mmol) in THF (20 mL) at -78 °C was added n-BuLi (2.5 M in THF, 3.0 mL). The reaction mixture was stirred at -78 °C for 1 h, and then 2,2-difluoro-N-methoxy-N-methylacetamide (517 mg, 3.72 mmol) in the form of a THF (3.0 mL) solution was added dropwise at -78 °C. Then the reaction mixture was stirred at 20 °C for another 12 h. The resulting mixture was poured into ice-cold water (20 mL) and adjusted to pH = 10 by adding saturated aqueous Na2HCO3. The mixture was extracted with MTBE (3 × 10 mL) and the organic layer was discarded. Then the aqueous phase was adjusted to pH = 3 with aqueous HCl (3 N) 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 to give a residue, which was used directly. LCMS: m / z = 266.8 [M-H] - 。

[0409] 4-(Difluoromethyl)-6-(trifluoromethyl)phthalazin-1(2H)-one: To a solution of 2-(2,2-difluoroacetyl)-4-(trifluoromethyl)benzoic acid (600 mg, 2.24 mmol) in EtOH (10 mL) was added hydrazine monohydrate (220 mg, 4.78 mmol). The reaction mixture was stirred at 90 °C for 12 h. Then toluene (10 mL) was added and the reaction mixture was stirred at 110 °C for 2 h and then at 125 °C for another 12 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure to give a residue, which was used directly. LCMS: m / z = 265.0 [M+H] + 。

[0410] Methyl 2-(4-(difluoromethyl)-1-oxo-6-(trifluoromethyl)phthalazin-2(1H)-yl)acetate: To a solution of 4-(difluoromethyl)-6-(trifluoromethyl)phthalazin-1(2H)-one (360 mg, 1.36 mmol) in DMF (10 mL) was added Cs2CO3 (444 mg, 1.36 mmol). The reaction mixture was stirred at 20 °C for 30 min and cooled to 0 °C. Methyl 2-bromoacetate (208 mg, 1.36 mmol) was added dropwise to the reaction mixture at 0 °C. The reaction mixture was stirred at 20 °C for 2 h. The mixture was diluted with water (50 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 = 337.0 [M+H] +。 1 1H NMR (400 MHz, CDCl3): δ 8.62 (d, J = 8.4 Hz, 1H), 8.44 (s, 1H), 8.10 - 8.03 (m, 1H), 6.64 (t, J = 53.2 Hz, 1H), 4.99 (s, 2H), 3.82 (s, 3H).

[0411] Intermediate 7

[0412]

[0413] 4 - Bromo - 2 - (2,2 - difluoroacetyl) - 3 - fluorobenzoic acid: TMP (6.45 g, 45.7 mmol) was added to a solution of n - BuLi (2.5 M in hexane, 19.2 mL) in THF (50 mL) at - 78 °C. The reaction mixture was stirred at - 78 °C for 0.5 h. 4 - Bromo - 3 - fluorobenzoic acid (5.00 g, 22.8 mmol), in the form of a solution in THF (10 mL), was added to the reaction mixture. The reaction mixture was stirred at - 78 °C for 2 h and then warmed to - 60 °C. 2,2 - Difluoro - N - methoxy - N - methylacetamide (3.49 g, 25.1 mmol) was added to the reaction mixture. The mixture was stirred at - 25 °C for 4 h. The reaction mixture was warmed to 0 °C, quenched by the addition of saturated aqueous citric acid (30 mL), and filtered through a thin pad of diatomaceous earth. The filtrate 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, which was used directly. LCMS: m / z = 294.8, 296.8 [M - H] - 。

[0414] 6 - Bromo - 4 - (difluoromethyl) - 5 - fluorophthalazin - 1(2H) - one: Hydrazine monohydrate (207 mg, 4.04 mmol) was added to a solution of 4 - bromo - 2 - (2,2 - difluoroacetyl) - 3 - fluorobenzoic acid (1.0 g, 3.37 mmol) in EtOH (10 mL) and toluene (4 mL). The reaction mixture was stirred at 120 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was used directly. 1 1H NMR (400 MHz, DMSO - d6): δ 10.35 (br s, 1H), 8.26 - 8.22 (m, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.14 (t, J = 53.6, 1H).

[0415] Methyl 2-(6-bromo-4-(difluoromethyl)-5-fluoro-1-oxophthalazin-2(1H)-yl)acetate: To a solution of 6-bromo-4-(difluoromethyl)-5-fluorophthalazin-1(2H)-one (180 mg, 0.62 mmol) in DMF (2.0 mL) at 0 °C was added Cs2CO3 (200 mg, 0.62 mmol) and methyl 2-bromoacetate (104 mg, 0.66 mmol). The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was diluted with water (5 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 1H NMR (400 MHz, CDCl3): δ 8.20 (dd, J = 4.0, 7.6 Hz, 1H), 8.07 - 8.00 (m, 1H), 6.76 (t, J = 53.6 Hz, 1H), 4.99 (s, 2H), 3.81 (s, 3H).

[0416] Intermediate 8

[0417]

[0418] 4-Chloro-2-isobutyrylbenzoic acid: To a solution of 5-chloroisobenzofuran-1,3-dione (10.0 g, 54.8 mmol) in THF (100 mL) at 0 °C was added i-PrMgCl (30.1 mL, 2 M in THF). The reaction mixture was stirred at 0 °C for 4 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution (50 mL) and extracted with EtOAc (3 × 20 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. 1 1H NMR (400 MHz, CDCl3): δ 7.77 (d, J = 8.4 Hz, 1H), 7.39 (dd, J = 8.4, 2.4 Hz, 1H), 7.02 (d, J = 2.0 Hz, 1H), 3.02 - 2.94 (m, 1H), 1.01 (d, J = 6.8 Hz, 6H).

[0419] 6-Chloro-4-isopropylphthalazin-1(2H)-one: To a solution of 4-chloro-2-isobutyrylbenzoic acid (730 mg, 3.22 mmol) in EtOH (10 mL) was added hydrazine monohydrate (200 mg, 3.92 mmol). The reaction mixture was stirred at 90 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was triturated with 1:1 MTBE / PE (20 mL), filtered, and the solid collected from the filter cake was used directly. 11H NMR (400 MHz, DMSO-d6): δ 8.20 (d, J = 2.4 Hz, 1H), 8.10 (s, 1H), 7.96 (dd, J = 8.8, 2.4 Hz, 1H), 3.49 - 3.62 (m, 1H), 1.22 - 1.27 (m, 6H).

[0420] Intermediate 9

[0421]

[0422] 2-Bromo-6-(trifluoromethyl)nicotinic acid: To a solution of methyl 2-bromo-6-(trifluoromethyl)nicotinate (2.50 g, 8.80 mmol) in THF (20 mL) and H2O (5 mL) was added LiOH·H2O (1.10 g, 26.4 mmol). The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with aqueous HCl solution (1 N) to pH = 4 and extracted with EtOAc (15 × 2 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was used directly. 1 1H NMR (400 MHz, CDCl3): δ 10.99 - 10.51 (m, 1H), 8.38 (d, J = 7.8 Hz, 1H), 7.76 (d, J = 7.8 Hz, 1H).

[0423] 2-(2,2-Difluoroacetyl)-6-(trifluoromethyl)nicotinic acid: To a solution of 2-bromo-6-(trifluoromethyl)nicotinic acid (2.20 g, 8.15 mmol) in THF (20 mL) at -78 °C was added n-BuLi (2.5 M hexane solution, 7.2 mL) and 2,2-difluoro-N-methoxy-N-methylacetamide (1.50 g, 10.6 mmol). The reaction mixture was warmed to 20 °C and stirred for 16 h. The reaction mixture was diluted with water (10 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 reverse-phase preparative HPLC. 1 1H NMR (400 MHz, CDCl3): δ 8.63 - 8.35 (m, 1H), 8.04 (d, J = 8.0 Hz, 1H), 6.27 (t, J = 54.0 Hz, 1H).

[0424] 8-(Difluoromethyl)-2-(trifluoromethyl)pyrido[2,3-d]pyridazin-5(6H)-one: Hydrazine hydrate (27 mg, 0.51 mmol) was added to a solution of 2-(2,2-difluoroacetyl)-6-(trifluoromethyl)nicotinic acid (130 mg, 0.48 mmol) in EtOH (2 mL). The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was diluted with water (2 mL) and extracted with EtOAc (2 × 3 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, which was used directly. 1 1H NMR (400 MHz, CDCl3): δ 9.01 - 8.90 (m, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.27 (t, J = 52.8 Hz, 1H).

[0425] Methyl 2-(8-(difluoromethyl)-5-oxo-2-(trifluoromethyl)pyrido[2,3-d]pyridazin-6(5H)-yl)acetate: Cs2CO3 (295 mg, 0.90 mmol) and methyl 2-bromoacetate (55 mg, 0.36 mmol) were added to a solution of 8-(difluoromethyl)-2-(trifluoromethyl)pyrido[2,3-d]pyridazin-5(6H)-one (120 mg, 0.45 mmol) in DMF (2.0 mL). The reaction mixture was stirred at 20 °C for 12 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 × 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. 1 1H NMR (400 MHz, CDCl3): δ 8.94 (d, J = 8.4 Hz, 1H), 8.17 - 8.01 (m, 1H), 7.25 (t, J = 53.2 Hz, 1H), 5.06 (s, 2H), 3.89 - 3.74 (m, 3H).

[0426] Intermediate 9

[0427]

[0428] 4-Bromo-2-(2,2-difluoroacetyl)benzoic acid: To a solution of 4-bromo-2-iodobenzoic acid (20.0 g, 61.2 mmol) in THF (200 mL) at -78 °C was added n-BuLi (2.5 M in THF, 49 mL). The reaction mixture was stirred at -78 °C for 0.5 h, and then a solution of 2,2-difluoro-N-methoxy-N-methylacetamide (9.36 g, 67.3 mmol) in THF (20 mL) was added dropwise at -78 °C. The reaction mixture was then stirred at 20 °C for an additional 12 h. The reaction mixture was diluted with saturated aqueous NH4Cl (200 mL), extracted with MTBE (3 × 50 mL), and the organic layer was discarded. The aqueous phase was cooled to 0 °C, adjusted to pH = 3 using aqueous HCl (3 N), and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was used directly. LCMS: m / z = 276.9, 278.9 [M-H] - 。

[0429] 6-Bromo-4-(difluoromethyl)phthalazin-1(2H)-one: To a solution of 4-bromo-2-(2,2-difluoroacetyl)benzoic acid (2.0 g, 7.2 mmol) in toluene (30 mL) was added NH2NH2·H2O (703 mg, 13.8 mmol). The reaction mixture was stirred at 95 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was used directly. LCMS: m / z = 272.9, 274.9 [M-H] - 。

[0430] Methyl 2-(6-bromo-4-(difluoromethyl)-1-oxophthalazin-2(1H)-yl)acetate: To a solution of 6-bromo-4-(difluoromethyl)phthalazin-1(2H)-one (1.5 g, 5.45 mmol) in DMF (20 mL) at 0 °C was added Cs2CO3 (1.95 g, 6.00 mmol). The reaction mixture was stirred at 0 °C for 30 min, and then methyl 2-bromoacetate (834 mg, 5.45 mmol) was added. The reaction mixture was then stirred at 20 °C for an additional 2 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography. LCMS: m / z = 347.0, 349.0 [M+H] + 。

[0431] Intermediate 10

[0432]

[0433] Methyl 2-(4,6-dibromo-1-oxophthalazin-2(1H)-yl)acetate: To a mixture of 4,6-dibromo-2H-phthalazin-1-one (13.0 g, 43.0 mmol) and methyl 2-bromoacetate (13.0 g, 86.0 mmol) in DMF (130 mL) was added Cs2CO3 (28.0 g, 85.5 mmol). The reaction mixture was stirred at 20 °C for 12 h. The reaction mixture was diluted with water (100 mL) and filtered. The solid was collected and dried under reduced pressure to give a residue, which was used directly. LCMS: m / z = 374.8, 376.8, 378.8 [M+H] + 。

[0434] Intermediate 11

[0435]

[0436] Methyl 2-(6-bromo-4-methoxy-1-oxophthalazin-2(1H)-yl)acetate: A mixture of sodium metal (3.0 g, 133 mmol) in MeOH (70 mL) was stirred at 20 °C for 30 min and then concentrated under reduced pressure. Then the residue was added portionwise to a mixture of methyl 2-(4,6-dibromo-1-oxophthalazin-2(1H)-yl)acetate (5.0 g, 13.0 mmol) in MeOH (70 mL). The reaction mixture was stirred at 60 °C for 5 h. The reaction mixture was diluted with water (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 to give a residue, which was used directly. LCMS: m / z = 326.9, 329.0 [M+H] + 。

[0437] 2-(6-Bromo-4-hydroxy-1-oxophthalazin-2(1H)-yl)acetic acid: To a mixture of methyl 2-(6-bromo-4-methoxy-1-oxo-phthalazin-2-yl)acetate (1.8 g, 5.50 mmol) in 1,4-dioxane (5 mL) was added HBr (15 mL, 47% purity in water). The reaction mixture was stirred at 100 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was used directly. LCMS: m / z = 299.0, 300.9 [M+H] + 。

[0438] Methyl 2-(6-bromo-4-hydroxy-1-oxophthalazin-2(1H)-yl)acetate: At 0 °C, SOCl2 (11.9 g, 100 mmol) was added to a solution of 2-(6-bromo-4-hydroxy-1-oxophthalazin-2(1H)-yl)acetic acid (10.0 g, 33.4 mmol) in MeOH (5 mL). The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was used directly. LCMS: m / z = 312.9, 314.9 [M+H] + 。

[0439] Intermediate 12

[0440]

[0441] 5-Bromo-4-fluoro-3-hydroxyisobenzofuran-1(3H)-one: n-BuLi (2.5 M hexane solution, 219 mL) was added dropwise to a solution of TMP (80.6 g, 571 mmol) in THF (500 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h and then cooled to -45 °C. A solution of 4-bromo-3-fluorobenzoic acid (50.0 g, 228 mmol) in THF (200 mL) was added dropwise to the reaction mixture. The reaction mixture was stirred at -45 °C for an additional 5 h, and then DMF (25.0 g, 343 mmol) was added. The reaction mixture was then stirred at 20 °C for 14.5 h. The reaction mixture was diluted with aqueous HCl (3 M, 500 mL) and extracted with DCM (3 × 200 mL). The combined organic layers were washed with brine (400 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography. 1 H NMR (400 MHz, CD3CN): δ 7.89 (dd, J = 6.0, 8.0 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 6.72 (s, 1H), 5.99 (br s, 1H).

[0442] 6-Bromo-5-fluorophthalazin-1(2H)-one: NH2NH2·H2O (405 mg, 8.10 mmol) was added to a solution of 5-bromo-4-fluoro-3-hydroxyisobenzofuran-1(3H)-one (2.0 g, 8.10 mmol) in THF (40 mL). The reaction mixture was stirred at 20 °C for 3 h. The reaction mixture was diluted with water (50 mL), filtered, and the filter cake was dried under reduced pressure to give a residue, which was used directly. LCMS: m / z = 242.9, 244.9 [M+H] + 。

[0443] Intermediate 13

[0444]

[0445] 6-Bromo-4-chloro-5-fluorophthalazin-1(2H)-one: To a solution of 6-bromo-5-fluorophthalazin-1(2H)-one (5.0 g, 20.6 mmol) in DMF (50 mL) was added 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione (12.0 g, 51.4 mmol). The reaction mixture was stirred at 50 °C for 4 h. The reaction mixture was diluted with water (60 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography and further purified by reverse-phase preparative HPLC. LCMS: m / z = 276.8, 278.8, 280.8 [M+H] + 。

[0446] Methyl 2-(6-bromo-4-chloro-5-fluoro-1-oxophthalazin-2(1H)-yl)acetate: To a solution of 6-bromo-4-chloro-5-fluorophthalazin-1(2H)-one (200 mg, 0.72 mmol) in DMF (4.0 mL) was added Cs2CO3 (470 mg, 1.44 mmol) and methyl 2-bromoacetate (132 mg, 0.86 mmol). The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with water (8 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 crude residue was purified by silica gel column chromatography. LCMS: m / z = 348.8, 350.8, 352.8 [M+H] + 。

[0447] Intermediate 14

[0448]

[0449] 4,6-Dibromo-5-fluorophthalazin-1(2H)-one: To a solution of 6-bromo-5-fluorophthalazin-1(2H)-one (15.0 g, 61.7 mmol) in DMF (500 mL) at 0 °C was added K2CO3 (17.1 g, 123 mmol) and benzyltrimethylammonium tribromide (48.1 g, 123 mmol). The reaction mixture was stirred at 40 °C for 5 h. The reaction mixture was diluted with water and filtered. The filter cake was washed with water (3 × 500 mL) and dried under reduced pressure to give a residue, which was used directly. LCMS: m / z = 321.0, 323.0, 324.9 [M+H] + 。

[0450] Methyl 2-(4,6-dibromo-5-fluoro-1-oxophthalazin-2(1H)-yl)acetate: To a solution of 4,6-dibromo-5-fluorophthalazin-1(2H)-one (20.0 g, 62.1 mmol) in DMF (500 mL) at 0 °C was added Cs2CO3 (22.3 g, 68.3 mmol). The reaction mixture was stirred at 0 °C for 0.5 h, then methyl 2-bromoacetate (9.50 g, 62.1 mmol) was added dropwise. The reaction mixture was then stirred at 20 °C for an additional 2 h. The reaction mixture was cooled to 0 °C, diluted with water (1000 mL), and extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography. LCMS: m / z = 393.0, 395.0, 397.0 [M+H] + .

[0451] Intermediate 15

[0452]

[0453] Methyl 2-methyl-4-(trifluoromethyl)benzoate: To a solution of 2-methyl-4-(trifluoromethyl)benzoic acid (5.0 g, 24.5 mmol) in DMF (50 mL) at 0 °C were added K2CO3 (5.08 g, 36.7 mmol) and CH3I (3.82 g, 26.9 mmol). The reaction mixture was stirred at 20 °C for 3 h. The reaction mixture was diluted with water (150 mL) and extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography. 1 H NMR (400 MHz, CDCl3): δ 8.00 (d, J = 8.0 Hz, 1H), 7.55 - 7.47 (m, 2H), 3.93 (s, 3H), 2.66 (s, 3H).

[0454] Methyl 2-(dibromomethyl)-4-(trifluoromethyl)benzoate: To a solution of NBS (15.9 g, 89.4 mmol) in CCl4 (50 mL) were added benzoyl peroxide (866 mg, 3.58 mmol) and methyl 2-methyl-4-(trifluoromethyl)benzoate (3.9 g, 17.9 mmol). The reaction mixture was stirred at 85 °C for 12 h. The reaction mixture was cooled to 20 °C, filtered, and the filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography. 11H NMR (400 MHz, CDCl3): δ 8.42 (s, 1H), 8.05 - 7.98 (m, 2H), 7.63 (dd, J = 1.2, 8.4 Hz, 1H), 4.00 (s, 3H).

[0455] 6-(Trifluoromethyl)phthalazin-1-ol: To a solution of methyl 2-(dibromomethyl)-4-(trifluoromethyl)benzoate (6.4 g, 17.0 mmol) in MeOH (100 mL) was added NH2NH2·H2O (3.5 g, 68.1 mmol). The reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was triturated with MeOH (15 mL) and filtered. Then the filter cake was dried under reduced pressure, triturated with water (20 mL), and filtered. Then the filter cake was dried under reduced pressure to give a residue, which was used directly. LCMS: m / z = 215.2 [M + H] + 。

[0456] 4-Bromo-6-(trifluoromethyl)phthalazin-1-ol: To a solution of 6-(trifluoromethyl)phthalazin-1-ol (1.77 g, 8.27 mmol) in DMF (50 mL) at 0 °C was added K2CO3 (2.28 g, 16.5 mmol) and benzyltrimethylammonium tribromide (6.45 g, 16.5 mmol). The reaction mixture was stirred at 40 °C for 5 h. The reaction mixture was diluted with water (100 mL) and filtered. The collected solid was washed with water (3 × 20 mL) and dried under reduced pressure to give a residue, which was used directly. LCMS: m / z = 293.1, 295.1 [M + H] + 。

[0457] Methyl 2-(4-bromo-1-oxo-6-(trifluoromethyl)phthalazin-2(1H)-yl)acetate: To a solution of 4-bromo-6-(trifluoromethyl)phthalazin-1-ol (500 mg, 1.71 mmol) in DMF (10 mL) at 0 °C was added Cs2CO3 (556 mg, 1.71 mmol). The reaction mixture was stirred at 0 °C for 30 min, then methyl 2-bromoacetate (261 mg, 1.71 mmol) was added. The reaction mixture was stirred at 20 °C for an additional 1 h. The reaction mixture was diluted with water (40 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 crude residue was triturated with PE:MTBE (10:1, 11 mL) and dried under reduced pressure to give a residue, which was used directly. LCMS: m / z = 365.1, 367.1 [M + H] + 。

[0458] Intermediate 16

[0459]

[0460] 2-(4,6-Dibromo-1-oxo-phthalazin-2-yl)acetic acid: To a solution of methyl 2-(4,6-dibromo-1-oxo-phthalazin-2-yl)acetate (1.5 g, 4.0 mmol) in THF (18 mL) was added an aqueous solution of LiOH (8.0 mL, 1 M) at 25 °C. The mixture was stirred at 40 °C for 2 h. At 25 °C, an aqueous solution of HCl (10.0 mL, 1 M) was added and the mixture was diluted and extracted with EtOAc (2 × 50 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, which was used directly. LCMS: m / z = 361.0, 363.0, 365.0 [M+H] + 。

[0461] Examples 1 and 2

[0462] 2-(6-Bromo-4-isopropyl-1-oxophthalazin-2(1H)-yl)-N-(cis-3-hydroxy-3-methylcyclobutyl)acetamide and 2-(7-bromo-4-isopropyl-1-oxophthalazin-2(1H)-yl)-N-(cis-3-hydroxy

[0463] -3-methylcyclobutyl)acetamide

[0464]

[0465] 4-Bromo-2-isobutyrylbenzoic acid and 5-bromo-2-isobutyrylbenzoic acid: To a solution of 5-bromoisobenzofuran-1,3-dione (1.0 g, 4.41 mmol) in THF (10 mL) was added dropwise isopropylmagnesium chloride (2 M in THF, 2.43 mL, 4.86 mmol) at -10 °C. The reaction mixture was stirred at 0 °C for 3 h. The reaction mixture was poured into a saturated aqueous solution of NH4Cl (30 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue in the form of a mixture of isomers (1:1 molar ratio), which was used directly. LCMS: m / z = 268.9, 270.8 [M-H] - 。

[0466] 6-Bromo-4-isopropylphthalazin-1(2H)-one and 7-bromo-4-isopropylphthalazin-1(2H)-one: To a mixture of 4-bromo-2-isobutyrylbenzoic acid and 5-bromo-2-isobutyrylbenzoic acid (300 mg, 1.11 mmol, 1:1 molar ratio) in EtOH (5 mL) was added NH2NH2·H2O (169 mg, 3.32 mmol, 98% purity). The reaction mixture was stirred at 90 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue in the form of a mixture of isomers (1:1 molar ratio), which was used directly. LCMS: m / z = 267.0, 269.0 [M+H] + 。

[0467] 2-(6-Bromo-4-isopropyl-1-oxophthalazin-2(1H)-yl)-N-(cis-3-hydroxy-3-methylcyclobutyl)acetamide and 2-(7-bromo-4-isopropyl-1-oxophthalazin-2(1H)-yl)-N-(cis-3-hydroxy-3-methylcyclobutyl)acetamide: To a mixture of 6-bromo-4-isopropylphthalazin-1(2H)-one and 7-bromo-4-isopropylphthalazin-1(2H)-one) (100 mg, 0.37 mmol, 1:1 molar ratio) and 2-chloro-N-(cis-3-hydroxy-3-methylcyclobutyl)acetamide (66 mg, 0.37 mmol) in DMF (1.5 mL) was added Cs2CO3 (146 mg, 0.45 mmol). The reaction mixture was stirred at 90 °C for 1 h. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (4 × 5 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by reverse-phase HPLC to give:

[0468] 2-(6-Bromo-4-isopropyl-1-oxophthalazin-2(1H)-yl)-N-(cis-3-hydroxy-3-methylcyclobutyl)acetamide: LCMS: m / z = 408.0, 410.0 [M+H] + 。 1 1H NMR (400 MHz, CDCl3): δ 8.32 (br d, J = 8.8 Hz, 1H), 8.02 (s, 1H), 7.87 (d, J = 8.8 Hz, 1H), 6.54 (br s, 1H), 4.83 (s, 2H), 4.01 (m, 1H), 3.43 (m, 1H), 2.50 (br t, J = 10.0 Hz, 2H), 2.29 (br s, 1H), 2.01 (br t, J = 10.0 Hz, 2H), 1.39 - 1.33 (m, 9H).

[0469] 2-(7-bromo-4-isopropyl-1-oxophthalazin-2(1H)-yl)-N-(cis-3-hydroxy-3-methylcyclobutyl)acetamide: LCMS: m / z = 408.0, 410.0 [M+H] + 。 1 H NMR (400 MHz, CDCl3): δ 8.62 (d, J = 2.0 Hz, 1H), 7.94 (dd, J = 2.0, 8.8 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H), 6.50 (br d, J = 6.8 Hz, 1H), 4.84 (s, 2H), 4.06 - 3.96 (m, 1H), 3.45 (m, 1H), 2.55 - 2.46 (m, 2H), 2.06 - 1.97 (m, 2H), 1.37 - 1.34 (m, 9H).

[0470] Example 3

[0471] (R)-2-(6-bromo-4-isopropyl-1-oxophthalazin-2(1H)-yl)-N-(1-ethylpiperidin-3-yl)acetamide

[0472]

[0473] (R)-(tert-butyl (1-ethylpiperidin-3-yl)carbamate): To a solution of (R)-(tert-butyl piperidin-3-ylcarbamate) (10.0 g, 49.9 mmol) in MeCN (100 mL) at 0 °C was added dropwise K2CO3 (10.4 g, 74.9 mmol), followed by the addition of a solution of iodoethane (8.57 g, 54.9 mmol) in MeCN (10 mL). The reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude residue was diluted with water (100 mL) and extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was used directly. LCMS: m / z = 229.2 [M+H] + 。

[0474] (R)-1-ethylpiperidin-3-amine hydrochloride: (R)-(tert-butyl (1-ethylpiperidin-3-yl)carbamate) (5.0 g, 21.9 mmol) was dissolved in HCl (50 mL, 4 N in EtOAc). The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was used directly. LCMS: m / z = 129.2 [M+H] + 。

[0475] (R)-2-Chloro-N-(1-ethylpiperidin-3-yl)acetamide: To a solution of (R)-1-ethylpiperidin-3-amine hydrochloride (1.0 g, 4.97 mmol) in DCM (10 mL) at 0 °C was added dropwise Et3N (3.0 g, 29.8 mmol), followed by the addition of 2-chloroacetyl chloride (618 mg, 5.50 mmol). The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was diluted with ice-cold saturated aqueous NaHCO3 (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 to give a residue, which was used directly. LCMS: m / z = 205.1 [M+H] + .

[0476] (R)-2-(6-Bromo-4-isopropyl-1-oxophthalazin-2(1H)-yl)-N-(1-ethylpiperidin-3-yl)acetamide: To a solution of (R)-2-chloro-N-(1-ethylpiperidin-3-yl)acetamide (153 mg, 0.75 mmol) and 6-bromo-4-isopropylphthalazin-1(2H)-one (200 mg, 0.75 mmol) in DMF (3 mL) was added Cs2CO3 (488 mg, 1.50 mmol). The reaction mixture was stirred at 90 °C for 1 h. The reaction mixture was diluted with ice-cold water (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 crude residue was purified by reverse-phase HPLC. LCMS: m / z = 435.0, 437.0 [M+H] + . 1 1H NMR (400 MHz, CDCl3): δ 8.36 (d, J = 8.4 Hz, 1H), 8.02 (d, J = 1.6 Hz, 1H), 7.87 (dd, J = 1.6, 2.0 Hz, 1H), 6.55 (br s, 1H), 4.96 - 4.76 (m, 2H), 4.17 - 4.02 (m, 1H), 3.43 (m, 1H), 2.48 (br s, 1H), 2.42 - 2.31 (m, 2H), 2.31 - 2.20 (m, 2H), 2.13 (br s, 1H), 1.62 - 1.46 (m, 4H), 1.37 (d, J = m, 6H), 0.87 (t, J = 7.2 Hz, 3H).

[0477] Example 4

[0478] (R)-N-(1-Ethylpiperidin-3-yl)-2-(4-isopropyl-6-methyl-1-oxophthalazin-2(1H)-yl)acetamide

[0479]

[0480] To a solution of (R)-2-(6-bromo-4-isopropyl-1-oxophthalazin-2(1H)-yl)-N-(1-ethylpiperidin-3-yl)acetamide (30 mg, 0.07 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (26 mg, 0.21 mmol) in 1,4-dioxane (0.5 mL) and water (0.1 mL) were added Pd(dppf)Cl2 (5 mg, 0.007 mmol) and Cs2CO3 (45 mg, 0.14 mmol). The reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was diluted with ice-cold water (5 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 crude residue was purified by reverse-phase HPLC. LCMS: m / z = 371.1 [M+H] + 。 1 H NMR (400 MHz, CDCl3): δ 8.39 (d, J = 8.4 Hz, 1H), 7.65 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 6.59 (br s, 1H), 4.97 - 4.78 (m, 2H), 4.09 (br s, 1H), 3.45 - 3.55 (m, 1H), 2.58 (s, 3H), 2.43 (br s, 1H), 2.35 (br s, 2H), 2.28 - 2.22 (m, 2H), 2.14 (br s, 1H), 1.53 (m, 4H), 1.36 (d, J = 6.8 Hz, 6H), 0.83 (t, J = 7.2 Hz, 3H).

[0481] Example 5

[0482] (R)-2-(6-Bromo-4-isopropyl-1-oxophthalazin-2(1H)-yl)-N-(1-cyclopropylpiperidin-3-yl)acetamide

[0483]

[0484] To a mixture of methyl 2-(6-bromo-4-isopropyl-1-oxophthalazin-2(1H)-yl)acetate (80 mg, 0.24 mmol) and (R)-1-cyclopropylpiperidin-3-amine hydrochloride (125 mg, 0.71 mmol) in toluene (2 mL) and THF (2 mL) was added AlMe3 (0.35 mL, 2 M in toluene). The reaction mixture was stirred at 110 °C for 3 h. The reaction mixture was poured into ice-cold water (10 mL) and extracted with EtOAc (2 × 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 HPLC. LCMS: m / z = 447.1, 449.1 [M+H] + . 1 1H NMR (400 MHz, CDCl3): δ 8.36 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 1.8 Hz, 1H), 7.89 (dd, J = 8.4, 1.8 Hz, 1H), 6.42 (br s, 1H), 4.92 - 4.77 (m, 2H), 4.04 (br s, 1H), 3.50 - 3.37 (m, 1H), 2.63 (br s, 1H), 2.51 (br s, 1H), 2.27 (br s, 1H), 1.74 - 1.63 (m, 2H), 1.55 - 1.45 (m, 4H), 1.36 (m, 6H), 0.33 - 0.23 (m, 2H), -0.06 (m, 2H).

[0485] Example 6

[0486] 2-(6-Bromo-4-isopropyl-1-oxophthalazin-2(1H)-yl)-N-(5-fluoropyrimidin-4-yl)acetamide

[0487]

[0488] Methyl 2-(6-bromo-4-isopropyl-1-oxophthalazin-2(1H)-yl)acetate: To a solution of 6-bromo-4-isopropylphthalazin-1(2H)-one (0.50 g, 1.87 mmol) in DMF (5 mL) was added Cs2CO3 (1.22 g, 3.74 mmol) and methyl 2-bromoacetate (315 mg, 2.06 mmol). The reaction mixture was stirred at 90 °C for 1 h. The reaction mixture was diluted with EtOAc (10 mL), washed with brine (2 × 5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was used directly. LCMS: m / z = 339.1, 341.0 [M+H] + . 11H NMR (400 MHz, CDCl3): δ 8.34 (d, J = 8.8 Hz, 1H), 8.01 (d, J = 1.6 Hz, 1H), 7.85 (m, 1H), 4.94 (s, 2H), 3.79 (s, 3H), 3.41 (m, 1H), 1.35 (d, J = 6.8 Hz, 6H).

[0489] 2-(6-Bromo-4-isopropyl-1-oxophthalazin-2(1H)-yl)-N-(5-fluoropyrimidin-4-yl)acetamide: To a solution of 5-fluoropyrimidin-4-amine (100 mg, 0.88 mmol) and methyl 2-(6-bromo-4-isopropyl-1-oxophthalazin-2(1H)-yl)acetate (100 mg, 0.29 mmol) in toluene (1 mL) and THF (1 mL) was added AlMe3 (0.44 mL, 2 M in toluene). The reaction mixture was stirred at 110 °C for 3 h. Then the reaction mixture was quenched by adding water (0.5 mL) and filtered. The filtrate was extracted with EtOAc (1 × 5 mL) and the organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC. LCMS: m / z = 419.9, 421.9 [M+H] + 。 1 1H NMR (400 MHz, CDCl3): δ 8.77 (d, J = 2.0 Hz, 1H), 8.50 (d, J = 2.8 Hz, 1H), 8.37 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 1.6 Hz, 1H), 7.89 (m, 1H), 5.42 (s, 2H), 4.77 (s, 1H), 3.51 - 3.39 (m, 1H), 1.37 (d, J = 6.8 Hz, 6H).

[0490] Example 7

[0491] (R)-2-(6-Bromo-4-isopropyl-1-oxophthalazin-2(1H)-yl)-N-(1-(2,2,2-trifluoroethyl)piperidin-3-yl)acetamide

[0492]

[0493] (R)-tert-Butyl 3-(2-(6-bromo-4-isopropyl-1-oxophthalazin-2(1H)-yl)acetamido)piperidine-1-carboxylate: To a mixture of methyl 2-(6-bromo-4-isopropyl-1-oxophthalazin-2(1H)-yl)acetate (150 mg, 0.44 mmol) and (R)-tert-butyl 3-aminopiperidine-1-carboxylate (89 mg, 0.44 mmol) in THF (2 mL) was added AlMe3 (0.66 mL, 2 M in toluene). The reaction mixture was stirred at 110 °C for 3 h. The reaction mixture was poured into ice-cold water (10 mL) and extracted with EtOAc (2 × 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 column chromatography. LCMS: m / z = 407.1, 409.1 [M - 99] + 。

[0494] (R)-2-(6-Bromo-4-isopropyl-1-oxophthalazin-2(1H)-yl)-N-(piperidin-3-yl)acetamide hydrochloride: (R)-tert-Butyl 3-(2-(6-bromo-4-isopropyl-1-oxophthalazin-2(1H)-yl)acetamido)piperidine-1-carboxylate (70 mg, 0.14 mmol) was dissolved in HCl (10 mL, 4 N in EtOAc). The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was used directly. LCMS: m / z = 407.0, 409.0 [M + H] + 。

[0495] (R)-2-(6-Bromo-4-isopropyl-1-oxophthalazin-2(1H)-yl)-N-(1-(2,2,2-trifluoroethyl)piperidin-3-yl)acetamide: To a solution of (R)-2-(6-bromo-4-isopropyl-1-oxophthalazin-2(1H)-yl)-N-(piperidin-3-yl)acetamide hydrochloride (70 mg, 0.16 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (55 mg, 0.24 mmol) in DMF (2 mL) was added DIPEA (61 mg, 0.47 mmol). The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was poured into ice-cold water (10 mL) and extracted with EtOAc (2 × 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 HPLC. LCMS: m / z = 489.1, 491.1 [M + H] + 。 11H NMR (400 MHz, CDCl3): δ 8.35 (d, J = 8.6 Hz, 1H), 8.02 (d, J = 1.6 Hz, 1H), 7.88 (dd, J = 8.6, 1.8 Hz, 1H), 6.51 (br d, J = 7.6 Hz, 1H), 4.97 - 4.78 (m, 2H), 4.15 - 4.06 (m, 1H), 3.49 - 3.38 (m, 1H), 2.82 (quintet, J = 9.6, 5.6 Hz, 2H), 2.75 - 2.63 (m, 2H), 2.62 - 2.55 (m, 1H), 2.43 (br t, J = 10.4 Hz, 1H), 1.79 - 1.63 (m, 2H), 1.55 - 1.45 (m, 2H), 1.36 (dd, J = 6.8, 2.0 Hz, 6H).

[0496] Example 8

[0497] 2-(6-Bromo-4-isopropyl-1-oxophthalazin-2(1H)-yl)-N-(3-fluoropyridin-4-yl)acetamide

[0498]

[0499] 2-(6-Bromo-4-isopropyl-1-oxophthalazin-2(1H)-yl)acetic acid: To a solution of methyl 2-(6-bromo-4-isopropyl-1-oxophthalazin-2(1H)-yl)acetate (0.50 g, 1.47 mmol) in THF (10 mL) and water (10 mL) was added LiOH·H2O (124 mg, 2.95 mmol). The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was poured into water (50 mL) and extracted with MTBE (2 × 20 mL). Then the aqueous layer was adjusted to pH = 3 - 4 by adding aqueous HCl solution (3 M), and then extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was used directly. 1 1H NMR (400 MHz, DMSO-d6): δ 8.29 (d, J = 1.6 Hz, 1H), 8.21 (d, J = 8.4 Hz, 1H), 8.05 (dd, J = 2.0, 8.4 Hz, 1H), 4.78 (s, 2H), 3.69 - 3.55 (m, 1H), 1.25 (d, J = 6.8 Hz, 6H).

[0500] 2-(6-Bromo-4-isopropyl-1-oxophthalazin-2(1H)-yl)-N-(3-fluoropyridin-4-yl)acetamide: To a solution of 2-(6-bromo-4-isopropyl-1-oxophthalazin-2(1H)-yl)acetic acid (50 mg, 0.14 mmol) in DMF (1 mL) were added 3-fluoropyridin-4-amine (19 mg, 0.17 mmol), DIPEA (80 mg, 0.63 mmol) and HATU (117 mg, 0.31 mmol). The reaction mixture was stirred at 20 °C for 3 h. The reaction mixture was poured into ice-cold water (10 mL) and extracted with EtOAc (2 × 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 HPLC. LCMS: m / z = 418.9, 420.9 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 9.09 (br s, 1H), 8.39 (m, 2H), 8.35 - 8.28 (m, 2H), 8.06 (d, J = 1.2 Hz, 1H), 7.92 (dd, J = 1.6, 8.4 Hz, 1H), 5.05 (s, 2H), 3.46 (m, 1H), 1.39 (d, J = 6.8 Hz, 6H).

[0501] Example 9

[0502] 2-(6-Bromo-5-fluoro-4-isopropyl-1-oxophthalazin-2(1H)-yl)-N-(5-fluoropyrimidin-4-yl)acetamide

[0503]

[0504] 4-Bromo-3-fluoro-2-isobutyrylbenzoic acid: 2,2,6,6-Tetramethylpiperidine (6.77 g, 47.9 mmol) was added to a solution of n-BuLi (18.0 mL, 2.5 M in THF) in THF (50 mL) at -78 °C. The reaction mixture was stirred at -78 °C for 30 minutes, and then a solution of 4-bromo-3-fluorobenzoic acid (5.0 g, 22.8 mmol) in THF (10 mL) was added dropwise. The reaction mixture was stirred at -78 °C for another 2 hours. Thereafter, the reaction mixture was adjusted to -60 °C and N-methoxy-N-methylisobutyramide (3.29 g, 25.1 mmol) was added. The reaction mixture was stirred at -25 °C for 4 hours. The reaction mixture was warmed to 0 °C, quenched by addition of saturated aqueous citric acid (30 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 to give a residue, which was used directly. LCMS: m / z = 286.9, 288.9 [M-H] - 。 1 H NMR (400 MHz, DMSO-d6): δ 13.21 (br s, 1H), 7.95 (br s, 1H), 7.72 - 7.59 (m, 1H), 2.93 - 2.85 (m, 1H), 1.00 (d, J = 6.8 Hz, 6H).

[0505] 6-Bromo-5-fluoro-4-isopropylphthalazin-1(2H)-one: Hydrazine hydrate (530 mg, 10.4 mmol) was added to a solution of 4-bromo-3-fluoro-2-isobutyrylbenzoic acid (2.5 g, 8.65 mmol) in EtOH (20 mL). The reaction mixture was stirred at 90 °C for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was triturated with EtOH (10 mL) to give a residue, which was used directly. LCMS: m / z = 285.1, 287.0 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6): δ 12.43 (br s, 1H), 8.18 - 8.08 (m, 1H), 8.03 (m, 1H), 3.60 - 3.47 (m, 1H), 1.23 (br d, J = 6.0 Hz, 6H).

[0506] Methyl 2-(6-bromo-5-fluoro-4-isopropyl-1-oxophthalazin-2(1H)-yl)acetate: To a solution of 6-bromo-5-fluoro-4-isopropylphthalazin-1(2H)-one (450 mg, 1.58 mmol) in DMF (10 mL) at 0 °C was added Cs2CO3 (514 mg, 1.58 mmol). The reaction mixture was stirred at 0 °C for 30 min, and then a solution of methyl 2-bromoacetate (241 mg, 1.58 mmol) in DMF (2 mL) was added dropwise. The resulting mixture was stirred at 20 °C for 2.5 h. The reaction mixture was diluted with water (50 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 = 357.1, 359.1 [M+H] + 。 1 1H NMR (400 MHz, CDCl3): δ 8.18 (dd, J = 0.8, 8.4 Hz, 1H), 7.91 (dd, J = 6.4, 8.4 Hz, 1H), 4.93 (s, 2H), 3.79 (s, 3H), 3.65 - 3.61 (m, 1H), 1.31 (dd, J = 1.2, 6.8 Hz, 6H).

[0507] 2-(6-Bromo-5-fluoro-4-isopropyl-1-oxophthalazin-2(1H)-yl)-N-(5-fluoropyrimidin-4-yl)acetamide: To a mixture of 5-fluoropyrimidin-4-amine (142 mg, 1.26 mmol) and methyl 2-(6-bromo-5-fluoro-4-isopropyl-1-oxophthalazin-2(1H)-yl)acetate (150 mg, 0.42 mmol) in toluene (3 mL) and THF (3 mL) was added dropwise AlMe3 (0.6 mL, 2 M in toluene). The reaction mixture was stirred at 110 °C for 3 h. The reaction mixture was poured into ice-cold water (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 triturated with MTBE (10 mL) to give the desired product. LCMS: m / z = 438.0, 440.0 [M+H] + 。 11H NMR (400 MHz, CDCl3): δ 8.77 (d, J = 2.0 Hz, 1H), 8.63 (br s, 1H), 8.50 (d, J = 2.4 Hz, 1H), 8.22 (dd, J = 0.8, 8.4 Hz, 1H), 7.95 (dd, J = 6.4, 8.4 Hz, 1H), 5.46 (s, 2H), 3.73 - 3.59 (m, 1H), 1.33 (dd, J = 1.2, 6.8 Hz, 6H).

[0508] Example 10

[0509] 5 - [[2 - (6 - Bromo - 4 - isopropyl - 1 - oxo - phthalazin - 2 - yl) acetyl] amino] - 3,3 - difluoro - piperidine

[0510] -1 - tert - Butyl carboxylate

[0511]

[0512] 5 - [(2 - Chloroacetyl) amino] - 3,3 - difluoro - piperidine - 1 - tert - butyl carboxylate: To a mixture of 5 - amino - 3,3 - difluoro - piperidine - 1 - tert - butyl carboxylate (295 mg, 1.25 mmol) and N - methylmorpholine (379 mg, 3.74 mmol) in DMF (0.44 mL) and DCM (2.2 mL) at - 78 °C was added a solution of 2 - chloroacetyl chloride (141 mg, 1.25 mmol) in DCM (2 mL). The reaction mixture was stirred at 23 °C for 3 h. The reaction mixture was poured into water (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 to give a residue, which was used directly. 1 1H NMR (400 MHz, DMSO - d6): δ 8.30 - 8.26 (m, 1H), 4.16 - 4.05 (m, 2H), 4.04 - 3.80 (m, 4H), 2.97 - 2.72 (m, 1H), 2.35 - 2.29 (m, 1H), 2.05 - 1.99 (m, 1H), 1.45 - 1.29 (m, 9H).

[0513] tert-Butyl 5-[[2-(6-bromo-4-isopropyl-1-oxophthalazin-2-yl)acetyl]amino]-3,3-difluoropiperidine-1-carboxylate: To a mixture of 6-bromo-4-isopropyl-2H-phthalazin-1-one (150 mg, 0.56 mmol) and tert-butyl 5-[(2-chloroacetyl)amino]-3,3-difluoropiperidine-1-carboxylate (193 mg, 0.62 mmol) in MeCN (7.7 mL) was added Cs2CO3 (276 mg, 0.84 mmol). The reaction mixture was stirred at 60 °C for 18 h. The reaction mixture was poured into ice water (30 mL) and extracted with EtOAc (30 mL). The organic layer was washed with water (2 × 25 mL) and brine (25 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z = 543.1, 545.1 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6): δ 8.29 (d, J = 1.8 Hz, 1H), 8.24 - 8.20 (m, 2H), 8.05 (dd, J = 8.5, 1.8 Hz, 1H), 4.71 (s, 2H), 4.09 - 4.00 (m, 2H), 3.87 - 3.79 (m, 2H), 3.65 - 3.58 (m, 1H), 3.44 - 3.40 (m, 2H), 2.35 - 2.30 (m, 1H), 1.40 (s, 9H), 1.25 (d, J = 6.7 Hz, 6H).

[0514] Example 11

[0515] 2-(6-Bromo-4-isopropyl-1-oxophthalazin-2(1H)-yl)-N-(5,5-difluoropiperidin-3-yl)acetamide hydrochloride

[0516]

[0517] tert-Butyl 5-[[2-(6-bromo-4-isopropyl-1-oxophthalazin-2-yl)acetyl]amino]-3,3-difluoropiperidine-1-carboxylate (314 mg, 0.58 mmol) was dissolved in HCl (10 mL, 4N in 1,4-dioxane). The reaction mixture was stirred at 23 °C for 3 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was used directly. LCMS: m / z = 443.1, 445.1 [M+H] + 。 11H NMR (400 MHz, DMSO-d6): δ 8.61 (d, J = 7.5 Hz, 1H), 8.29 (d, J = 1.8 Hz, 1H), 8.20 (d, J = 8.5 Hz, 1H), 8.05 (m, 1H), 4.73 (s, 2H), 4.19 - 4.13 (m, 1H), 3.71 - 3.62 (m, 3H), 3.27 - 3.23 (m, 2H), 2.88 (m, 1H), 2.45 - 2.39 (m, 1H), 2.24 - 2.11 (m, 1H), 1.27 - 1.15 (m, 6H).

[0518] Example 12

[0519] 2-(6-Bromo-4-isopropyl-1-oxophthalazin-2(1H)-yl)-N-(1-ethyl-5,5-difluoropiperidin-3-yl)acetamide

[0520]

[0521] To a mixture of 2-(6-bromo-4-isopropyl-1-oxophthalazin-2(1H)-yl)-N-(5,5-difluoropiperidin-3-yl)acetamide hydrochloride (140 mg, 0.29 mmol) in MeCN (10 mL) was added iodoethane (55 mg, 0.35 mmol) and K2CO3 (121 mg, 0.88 mmol). The reaction mixture was stirred at 60 °C for 18 h. The reaction mixture was poured into ice water (50 mL) and extracted with EtOAc (50 mL). The organic layer was washed with water (2 × 30 mL) and 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 = 471.1, 473.1 [M+H] + 。 1 1H NMR (400 MHz, DMSO-d6): δ 8.29 (m, 1H), 8.21 (d, J = 8.5 Hz, 1H), 8.10 (t, J = 0.4 Hz, 1H), 8.05 (m, 1H), 4.70 (s, 2H), 4.02 - 3.85 (m, 2H), 3.65 - 3.58 (m, 2H), 2.98 - 2.90 (m, 1H), 2.84 - 2.79 (m, 1H), 2.35 - 2.17 (m, 3H), 2.01 - 1.95 (m, 1H), 1.26 - 1.21 (m, 6H), 0.98 (t, J = 7.2 Hz, 3H).

[0522] Example 13

[0523] 2-[6-Bromo-4-(1,1-difluoroethyl)-1-oxophthalazin-2-yl]-N-(5-fluoropyrimidin-4-yl)acetamide

[0524]

[0525] Ethyl 2-(6-bromo-4-(1-ethoxyvinyl)-1-oxophthalazin-2(1H)-yl)acetate: To a solution of ethyl 2-(4,6-dibromo-1-oxophthalazin-2-yl)acetate (0.50 g, 1.28 mmol) and tributyl(1-ethoxyvinyl)stannane (463 mg, 1.28 mmol) in DMF (8 mL) was added Pd(PPh3)4 (148 mg, 1.28 mmol). The reaction mixture was stirred at 80 °C for 3 h. The reaction mixture was quenched by addition of saturated aqueous KF solution (10 mL), then diluted with saturated aqueous NaHCO3 solution (10 mL). The reaction mixture was 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 crude residue was purified by silica gel column chromatography. LCMS: m / z = 381.0, 383.0 [M+H] + 。

[0526] Ethyl 2-(4-acetyl-6-bromo-1-oxophthalazin-2(1H)-yl)acetate: To a solution of ethyl 2-(6-bromo-4-(1-ethoxyvinyl)-1-oxophthalazin-2(1H)-yl)acetate (300 mg, 0.78 mmol) in 1,4-dioxane (8 mL) and water (1.5 mL) was added aqueous HCl solution (3 M, 0.78 mL). The reaction mixture was stirred at 50 °C for 0.5 h. The reaction mixture was poured into water (10 mL) and adjusted to pH = 7 with saturated aqueous NaHCO3 solution. 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. LCMS: m / z = 353.0, 355.1 [M+H] + 。

[0527] Ethyl 2-(6-bromo-4-(1,1-difluoroethyl)-1-oxophthalazin-2(1H)-yl)acetate: A solution of ethyl 2-(4-acetyl-6-bromo-1-oxophthalazin-2-yl)acetate (50 mg, 0.14 mmol) in BAST (2.51 g, 11.33 mmol) was stirred at 80 °C for 5 h. The reaction mixture was poured into saturated aqueous NaHCO3 (30 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. LCMS: m / z = 375.1, 377.2 [M+H] + 。

[0528] 2-[6-Bromo-4-(1,1-difluoroethyl)-1-oxophthalazin-2-yl]-N-(5-fluoropyrimidin-4-yl)acetamide: To a solution of ethyl 2-(6-bromo-4-(1,1-difluoroethyl)-1-oxophthalazin-2(1H)-yl)acetate (70 mg, 0.18 mmol) and 5-fluoropyrimidin-4-amine (25 mg, 0.22 mmol) in toluene (3.0 mL) was added AlMe3 (0.12 mL, 2 M in toluene). The reaction mixture was stirred at 80 °C for 4 h. The reaction mixture was poured into water (15 mL) and filtered. The filtrate was 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 reverse-phase preparative HPLC. LCMS: m / z = 442.0, 444.0 [M+H] + 。 1 1H NMR (400 MHz, CDCl3) δ 8.77 (d, J = 2.0 Hz, 1H), 8.52 (d, J = 2.4 Hz, 1H), 8.42 (s, 1H), 8.35 (d, J = 8.4 Hz, 2H), 8.00 - 7.90 (m, 1H), 5.56 (s, 2H), 2.10 (t, J = 19.2 Hz, 3H).

[0529] Example 14

[0530] 2-(6-Bromo-1-oxo-4-propan-2-ylphthalazin-2-yl)-N-(5-fluoropyrimidin-4-yl)propanamide

[0531]

[0532] Methyl 2-(6-bromo-4-isopropyl-1-oxophthalazin-2(1H)-yl)propionate: To a solution of 6-bromo-4-isopropylphthalazin-1(2H)-one (100 mg, 0.37 mmol) and methyl 2-bromopropionate (66 mg, 0.39 mmol) in DMF (3.0 mL) was added Cs2CO3 (244 mg, 0.75 mmol). The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was poured into water (15 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. LCMS: m / z = 353.0, 355.0 [M+H] + .

[0533] 2-(6-Bromo-1-oxo-4-propan-2-ylphthalazin-2-yl)-N-(5-fluoropyrimidin-4-yl)propanamide: To a solution of methyl 2-(6-bromo-4-isopropyl-1-oxophthalazin-2(1H)-yl)propionate (120 mg, 0.34 mmol) and 5-fluoropyrimidin-4-amine (50 mg, 0.44 mmol) in toluene (3.0 mL) was added AlMe3 (0.51 mL, 2 M in toluene). The reaction mixture was stirred at 80 °C for 4 h. The reaction mixture was quenched by addition of water (12 mL) and extracted with EtOAc (3 × 4 mL). The combined organic layers were washed with brine (4 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 434.0, 436.1 [M+H] + . 1 1H NMR (400 MHz, CDCl3) δ 9.23 (br s, 1H), 8.76 (d, J = 2.4 Hz, 1H), 8.47 (d, J = 2.4 Hz, 1H), 8.38 (d, J = 8.4 Hz, 1H), 8.04 (s, 1H), 7.90 (d, J = 8.4 Hz, 1H), 6.01 - 5.89 (m, 1H), 3.48 - 3.44 (m, 1H), 1.80 (d, J = 7.2 Hz, 3H), 1.40 (d, J = 6.8 Hz, 3H), 1.36 (d, J = 6.8 Hz, 3H).

[0534] Example 15

[0535] N-(5-Fluoropyrimidin-4-yl)-2-[1-oxo-4-propan-2-yl-6-(trifluoromethoxy)phthalazin-2-yl]acetamide

[0536]

[0537] Methyl 2-(4-isopropyl-1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phthalazin-2(1H)-yl)acetate: To a solution of methyl 2-(6-bromo-4-isopropyl-1-oxophthalazin-2(1H)-yl)acetate (500 mg, 1.47 mmol) in 1,4-dioxane (10 mL) were added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (562 mg, 2.21 mmol), KOAc (434 mg, 4.42 mmol), and Pd(dppf)Cl2 (11 mg, 0.01 mmol). The reaction mixture was stirred at 80 °C for 5 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. 1 H NMR (400 MHz, CDCl3): δ 8.44 (d, J = 8.0 Hz, 1H), 8.30 (s, 1H), 8.14 (d, J = 8.0 Hz, 1H), 4.96 (s, 2H), 3.78 (s, 3H), 3.61 (m, 1H), 1.35 (d, J = 6.0 Hz, 6H), 1.26 (s, 12H).

[0538] Methyl 2-(6-hydroxy-4-isopropyl-1-oxophthalazin-2(1H)-yl)acetate: To a solution of methyl 2-(4-isopropyl-1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phthalazin-2(1H)-yl)acetate (730 mg, 1.89 mmol) in 1,4-dioxane (3.0 mL) at 0 °C was added a solution of potassium peroxymonosulfate (1.28 g, 2.08 mmol) in water (3 mL). The reaction mixture was stirred at 20 °C for 4 h. The reaction mixture was poured into a saturated aqueous Na2S2O3 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 triturated with MTBE to give a residue, which was used directly. 1 H NMR (400 MHz, DMSO-d6): δ 8.14 (d, J = 8.8 Hz, 1H), 7.24 - 7.31 (m, 2H), 4.84 (s, 2H), 3.68 (s, 3H), 3.39 (m, 1H), 1.25 (d, J = 6.8 Hz, 6H).

[0539] Methyl 2-(4-isopropyl-1-oxo-6-(trifluoromethoxy)phthalazin-2(1H)-yl)acetate: A round-bottom flask containing CsF (330 mg, 2.17 mmol) was heated to 170 °C under vacuum for 0.5 h, then the vessel was backfilled with nitrogen and cooled to ambient temperature. Thereafter, AgOTf (465 mg, 1.81 mmol), Selectfluor (256 mg, 0.72 mmol), 2,4-di(tert-butyl)phenol (149 mg, 0.72 mmol), and N-(phenylsulfonyl)-N-fluoro-benzenesulfonamide (228 mg, 0.72 mmol) were added. Then a toluene (7 mL) solution of methyl 2-(6-hydroxy-4-isopropyl-1-oxophthalazin-2(1H)-yl)acetate (100 mg, 0.36 mmol) was added to the solid mixture, followed by 2-fluoropyridine (176 mg, 1.81 mmol) and trimethyl(trifluoromethyl)silane (257 mg, 1.81 mmol). The reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was diluted with EtOAc (10 mL), filtered through a thin pad of diatomaceous earth, which was washed with EtOAc (20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. 1 1H NMR (400 MHz, CDCl3): δ 8.54 (d, J = 8.8 Hz, 1H), 8.02 (br d, J = 7.2 Hz, 1H), 7.73 - 7.81 (m, 1H), 4.96 (s, 2H), 3.80 (s, 3H), 3.41 (m, 1H), 1.36 (d, J = 6.8 Hz, 6H).

[0540] N-(5-Fluoropyrimidin-4-yl)-2-[1-oxo-4-propan-2-yl-6-(trifluoromethoxy)phthalazin-2-yl]acetamide: To a solution of 5-fluoropyrimidin-4-amine (30 mg, 0.26 mmol), methyl 2-(4-isopropyl-1-oxo-6-(trifluoromethoxy)phthalazin-2(1H)-yl)acetate (30 mg, 0.09 mmol) in toluene (2.0 mL) and THF (1.0 mL) was added AlMe3 (0.13 mL, 2 M in toluene). The reaction mixture was stirred at 100 °C for 6 h. The reaction mixture was quenched by the addition of water (1 mL) and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 426.0 [M + H] + 。 11H NMR (400 MHz, CDCl3): δ 8.77 (s, 1H), 8.66 (br s, 1H), 8.58 (d, J = 8.4 Hz, 1H), 8.50 (s, 1H), 7.68 (s, 1H), 7.62 (d, J = 8.4 Hz, 1H), 5.46 (s, 2H), 3.44 (m, 1H), 1.38 (d, J = 6.8 Hz, 6H).

[0541] Example 16

[0542] 2-[6-(Difluoromethoxy)-1-oxo-4-propan-2-ylphthalazin-2-yl]-N-(5-fluoropyrimidin-4-yl)acetamide

[0543]

[0544] Methyl 2-(6-(difluoromethoxy)-4-isopropyl-1-oxophthalazin-2(1H)-yl)acetate: To a solution of methyl 2-(6-hydroxy-4-isopropyl-1-oxophthalazin-2(1H)-yl)acetate (100 mg, 0.36 mmol) and sodium 2-chloro-2,2-difluoroacetate (127 mg, 0.83 mmol) in DMF (3 mL) was added K2CO3 (125 mg, 0.90 mmol). The reaction mixture was stirred at 110 °C for 16 h. The reaction mixture was diluted with EtOAc (10 mL) and washed with H2O (3 × 5 mL). The organic layer was then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. 1 1H NMR (400 MHz, CDCl3): δ 8.51 (d, J = 8.8 Hz, 1H), 7.56 - 7.47 (m, 2H), 6.67 (t, J = 72 Hz, 1H), 4.96 (s, 2H), 3.79 (s, 3H), 3.44 - 3.38 (m, 1H), 1.35 (d, J = 6.8 Hz, 6H).

[0545] 2-[6-(Difluoromethoxy)-1-oxo-4-propan-2-ylphthalazin-2-yl]-N-(5-fluoropyrimidin-4-yl)acetamide: To a solution of methyl 2-(6-(difluoromethoxy)-4-isopropyl-1-oxophthalazin-2(1H)-yl)acetate (86 mg, 0.26 mmol), 5-fluoropyrimidin-4-amine (89 mg, 0.79 mmol) in toluene (1.0 mL) and THF (1.0 mL) was added AlMe3 (0.4 mL, 2 M in toluene). The reaction mixture was stirred at 110 °C for 3 h. The mixture was quenched with water (0.5 mL), filtered and extracted with EtOAc (5 mL). The organic layer was then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 408.0 [M+H] + 。 1 H NMR (400 MHz, CDCl3): δ 8.81 (br s, 1H), 8.77 (d, J = 2.0 Hz, 1H), 8.59 - 8.46 (m, 2H), 7.59 - 7.48 (m, 2H), 6.69 (t, J = 72.0 Hz, 1H), 5.42 (s, 2H), 3.47 - 3.41 (m, 1H), 1.37 (d, J = 6.8 Hz, 6H).

[0546] Example 17

[0547] 2-[6-Bromo-1-oxo-4-(1,1,1-trifluoropropan-2-yl)phthalazin-2-yl]-N-(5-fluoropyrimidin-4-yl)acetamide

[0548]

[0549] Ethyl 2-(6-bromo-1-oxo-4-(3,3,3-trifluoroprop-1-en-2-yl)phthalazin-2(1H)-yl)acetate and ethyl 2-(4-bromo-1-oxo-6-(3,3,3-trifluoroprop-1-en-2-yl)phthalazin-2(1H)-yl)acetate: To a solution of ethyl 2-(4,6-dibromo-1-oxophthalazin-2(1H)-yl)acetate (300 mg, 0.77 mmol) in 1,4-dioxane (3.0 mL) and water (1.5 mL) were added 4,4,6-trimethyl-2-(3,3,3-trifluoroprop-1-en-2-yl)-1,3,2-dioxaborinane (171 mg, 0.77 mmol), CsF (234 mg, 1.54 mmol) and Pd(dppf)Cl2 (56 mg, 0.08 mmol). The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was diluted with water (2 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (2 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC to give:

[0550] Ethyl 2-(6-bromo-1-oxo-4-(3,3,3-trifluoroprop-1-en-2-yl)phthalazin-2(1H)-yl)acetate: 1 1H NMR (400 MHz, CDCl3): δ 8.35 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.84 (s, 1H), 6.49 (s, 1H), 5.94 (s, 1H), 4.97 (s, 2H), 4.28 - 4.24 (m, 2H), 1.31 - 1.27 (m, 3H).

[0551] Ethyl 2-(4-bromo-1-oxo-6-(3,3,3-trifluoroprop-1-en-2-yl)phthalazin-2(1H)-yl)acetate:

[0552] 1 1H NMR (400 MHz, CDCl3): δ 8.46 (d, J = 8.8 Hz, 1H), 8.04 (s, 1H), 7.91 (d, J = 8.4 Hz, 1H), 6.23 (s, 1H), 6.01 (s, 1H), 4.95 (s, 2H), 4.30 - 4.22 (m, 2H), 1.31 - 1.27 (m, 3H).

[0553] Ethyl 2-(6-bromo-1-oxo-4-(1,1,1-trifluoropropan-2-yl)phthalazin-2(1H)-yl)acetate: TosN2H3 (221 mg, 1.18 mmol) and AcONa (97 mg, 1.18 mmol) were added to a solution of ethyl 2-(6-bromo-1-oxo-4-(3,3,3-trifluoroprop-1-en-2-yl)phthalazin-2(1H)-yl)acetate (80 mg, 0.20 mmol) in THF (1.0 mL) and water (0.5 mL). The reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was cooled to 20 °C, diluted with water (3 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 silica gel column chromatography. LCMS: m / z = 406.9, 408.9 [M+H] + 。

[0554] 2-[6-Bromo-1-oxo-4-(1,1,1-trifluoropropan-2-yl)phthalazin-2-yl]-N-(5-fluoropyrimidin-4-yl)acetamide: 5-Fluoropyrimidin-4-amine (25 mg, 0.22 mmol) and AlMe3 (0.11 mL, 2 M in toluene) were added to a solution of ethyl 2-(6-bromo-1-oxo-4-(1,1,1-trifluoropropan-2-yl)phthalazin-2(1H)-yl)acetate (30 mg, 0.07 mmol) in toluene (1.0 mL) and THF (1.0 mL). The reaction mixture was stirred at 90 °C for 3 h. The reaction mixture was diluted with water (3 mL) and extracted with EtOAc (3 × 2 mL). The combined organic layers were washed with brine (2 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 473.9, 475.9 [M+H] + 。 1 H NMR (400 MHz, CDCl3): δ 8.77 (d, J = 2.0 Hz, 1H), 8.51 (d, J = 2.4 Hz, 1H), 8.42 - 8.30 (m, 2H), 7.99 (s, 1H), 7.93 (dd, J = 1.6, 8.4 Hz, 1H), 5.67 (d, J = 16.8 Hz, 1H), 5.45 (d, J = 16.8 Hz, 1H), 4.12 - 4.04 (m, 1H), 1.63 (d, J = 7.2 Hz, 3H).

[0555] Example 18

[0556] 2-[4-Bromo-1-oxo-6-(1,1,1-trifluoropropan-2-yl)phthalazin-2-yl]-N-(5-fluoropyrimidin-4-yl)acetamide

[0557]

[0558] Ethyl 2-(4-bromo-1-oxo-6-(1,1,1-trifluoropropan-2-yl)phthalazin-2(1H)-yl)acetate: TosN2H3 (193 mg, 1.04 mmol) and AcONa (85 mg, 1.04 mmol) were added to a solution of ethyl 2-(4-bromo-1-oxo-6-(3,3,3-trifluoroprop-1-en-2-yl)phthalazin-2(1H)-yl)acetate (70 mg, 0.17 mmol) in THF (1.0 mL) and water (0.5 mL). The reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was diluted with water (3.0 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 silica gel column chromatography. LCMS: m / z = 406.9, 408.9 [M+H] + 。

[0559] 2-[4-Bromo-1-oxo-6-(1,1,1-trifluoropropan-2-yl)phthalazin-2-yl]-N-(5-fluoropyrimidin-4-yl)acetamide: 5-Fluoropyrimidin-4-amine (25 mg, 0.22 mmol) and AlMe3 (0.11 mL, 2 M in toluene) were added to a solution of ethyl 2-(4-bromo-1-oxo-6-(1,1,1-trifluoropropan-2-yl)phthalazin-2(1H)-yl)acetate (30 mg, 0.07 mmol) in toluene (1.0 mL) and THF (1.0 mL). The reaction mixture was stirred at 90 °C for 3 h. The reaction mixture was diluted with water (3 mL) and extracted with EtOAc (3 × 1.5 mL). The combined organic layers were washed with brine (2 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 474.0, 476.0 [M+H] + 。 1 H NMR (400 MHz, CDCl3): δ 8.75 (d, J = 2.0 Hz, 1H), 8.51 (d, J = 2.0 Hz, 1H), 8.46 (d, J = 8.4 Hz, 1H), 8.32 (br s, 1H), 7.93 (s, 1H), 7.83 (d, J = 7.6 Hz, 1H), 5.58 (s, 2H), 3.76 - 3.67 (m, 1H), 1.64 (d, J = 7.2 Hz, 3H).

[0560] Example 19

[0561] 2-(6-Cyclopropyl-1-oxo-4-propan-2-ylphthalazin-2-yl)-N-(5-fluoropyrimidin-4-yl)acetamide

[0562]

[0563] Methyl 2-(6-cyclopropyl-4-isopropyl-1-oxophthalazin-2(1H)-yl)acetate: To a solution of methyl 2-(6-bromo-4-isopropyl-1-oxophthalazin-2-yl)acetate (0.1 g, 0.29 mmol) in water (1.0 mL) and THF (2.0 mL) was added 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (248 mg, 1.47 mmol), CsF (134 mg, 0.88 mmol), and Pd(dppf)Cl2 (21.6 mg, 0.03 mmol). The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was quenched by addition of water (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. LCMS: m / z = 301.1 [M+H] + 。

[0564] 2-(6-Cyclopropyl-1-oxo-4-propan-2-ylphthalazin-2-yl)-N-(5-fluoropyrimidin-4-yl)acetamide: To a solution of methyl 2-(6-cyclopropyl-4-isopropyl-1-oxophthalazin-2(1H)-yl)acetate (69 mg, 0.23 mmol) and 5-fluoropyrimidin-4-amine (29 mg, 0.25 mmol) in toluene (3.0 mL) was added AlMe3 (0.15 mL, 2 M in toluene). The reaction mixture was stirred at 80 °C for 3 h. The reaction mixture was quenched by addition of water (10 mL) and filtered. The filtrate was 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 reverse-phase preparative HPLC. LCMS: m / z = 382.2 [M+H] + 。 11H NMR (400 MHz, CDCl3) δ 9.10 (br s, 1H), 8.78 (d, J = 2.0 Hz, 1H), 8.48 (d, J = 2.4 Hz, 1H), 8.39 (d, J = 8.4 Hz, 1H), 7.57 (s, 1H), 7.42 (d, 8.4 Hz, 1H), 5.33 (s, 2H), 3.54 - 3.50 (m, 1H), 2.17 - 2.06 (m, 1H), 1.37 (d, J = 6.8 Hz, 6H), 1.23 - 1.12 (m, 2H), 0.93 - 0.79 (m, 2H).

[0565] Example 20

[0566] N-(5-Fluoropyrimidin-4-yl)-2-(6-iodo-1-oxo-4-propan-2-ylphthalazin-2-yl)acetamide

[0567]

[0568] Methyl 2-(6-iodo-4-isopropyl-1-oxophthalazin-2(1H)-yl)acetate: To a solution of methyl 2-(6-bromo-4-isopropyl-1-oxophthalazin-2(1H)-yl)acetate (50 mg, 0.17 mmol) in 1,4-dioxane (5.0 mL) were added CuI (1.4 mg, 0.07 mmol), NaI (44 mg, 0.30 mmol) and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (2.1 mg, 0.14 mmol). The reaction mixture was degassed and purged with N2 three times, then stirred at 110 °C for 15 h. The reaction mixture was diluted with water (10 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 preparative TLC. LCMS: m / z = 386.8 [M+H] + .

[0569] N-(5-Fluoropyrimidin-4-yl)-2-(6-iodo-1-oxo-4-propan-2-ylphthalazin-2-yl)acetamide: To a solution of methyl 2-(6-iodo-4-isopropyl-1-oxophthalazin-2(1H)-yl)acetate (50 mg, 0.13 mmol) in toluene (1.0 mL) and THF (1.0 mL) was added 5-fluoropyrimidin-4-amine (29 mg, 0.26 mmol) and AlMe3 (0.06 mL, 2 M in toluene). The reaction mixture was stirred at 90 °C for 2 h. The reaction mixture was quenched by addition of water (2 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 reverse phase preparative HPLC. LCMS: m / z = 468.1 [M+H] + 。 1 1H NMR (400 MHz, CDCl3): δ 8.77 (d, J = 2.0 Hz, 1H), 8.71 (brs, 1H), 8.50 (d, J = 2.4 Hz, 1H), 8.26 (s, 1H), 8.21 (d, J = 8.4 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 5.41 (s, 2H), 3.48 - 3.41 (m, 1H), 1.36 (d, J = 6.8 Hz, 6H).

[0570] Example 21

[0571] 2-[6-(Difluoromethyl)-1-oxo-4-propan-2-ylphthalazin-2-yl]-N-(5-fluoropyrimidin-4-yl)acetamide

[0572]

[0573] Methyl 2-(4-isopropyl-1-oxo-6-vinylphthalazin-2(1H)-yl)acetate: To a solution of methyl 2-(6-bromo-4-isopropyl-1-oxophthalazin-2(1H)-yl)acetate (400 mg, 1.18 mmol) and potassium trifluoro(vinyl)borate (474 mg, 3.54 mmol) in DMSO (8.0 mL) was added K2CO3 (326 mg, 2.36 mmol) and Pd(dppf)Cl2 (86 mg, 0.12 mmol). The reaction mixture was stirred at 100 °C for 3 h. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (3 × 10 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 = 287.2 [M+H] + 。

[0574] Methyl 2-(6-formyl-4-isopropyl-1-oxophthalazin-2(1H)-yl)acetate: A solution of methyl 2-(4-isopropyl-1-oxo-6-vinyl-phthalazin-2-yl)acetate (440 mg, 1.54 mmol) in DCM (40 mL) was stirred at -78 °C under ozone at 15 psi for 0.5 h. The reaction was quenched by addition of Me2S (1.8 g, 29.0 mmol) and stirred at 20 °C for an additional 16 h. The reaction mixture was diluted with water (150 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue which was used directly. LCMS: m / z = 289.2 [M+H] + .

[0575] Methyl 2-(6-(difluoromethyl)-4-isopropyl-1-oxophthalazin-2(1H)-yl)acetate: A solution of methyl 2-(6-formyl-4-isopropyl-1-oxo-phthalazin-2-yl)acetate (220 mg, 0.76 mmol) in BAST (5.05 g, 22.8 mmol) was stirred at 20 °C for 16 h. The reaction mixture was diluted with saturated aqueous NaHCO3 (15 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. LCMS: m / z = 311.2 [M+H] + .

[0576] 2-[6-(Difluoromethyl)-1-oxo-4-propan-2-ylphthalazin-2-yl]-N-(5-fluoropyrimidin-4-yl)acetamide: To a solution of 5-fluoropyrimidin-4-amine (27 mg, 0.24 mmol) and methyl 2-(6-(difluoromethyl)-4-isopropyl-1-oxophthalazin-2(1H)-yl)acetate (50 mg, 0.16 mmol) in toluene (1.0 mL) and THF (1.0 mL) was added AlMe3 (0.24 mL, 2 M in toluene). The reaction mixture was stirred at 90 °C for 16 h. The reaction mixture was poured into 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 reverse phase preparative HPLC. LCMS: m / z = 392.1 [M+H] + . 11H NMR (400 MHz, CDCl3): δ 8.78 (d, J = 1.2 Hz, 1H), 8.68 (br s, 1H), 8.62 (d, J = 8.4 Hz, 1H), 8.50 (d, J = 2.4 Hz, 1H), 8.04 (s, 1H), 7.91 (d, J = 8.0 Hz, 1H), 6.83 (t, J = 56 Hz, 1H), 5.46 (s, 2H), 3.59 - 3.51 (m, 1H), 1.39 (d, J = 6.8 Hz, 6H).

[0577] Example 22

[0578] 2-(2-Bromo-5-oxo-8-propan-2-ylpyrido[2,3-d]pyridazin-6-yl)-N-(5-fluoropyrimidin-4-yl)acetamide

[0579]

[0580] 2-(2-Bromo-5-oxo-8-propan-2-ylpyrido[2,3-d]pyridazin-6-yl)-N-(5-fluoropyrimidin-4-yl)acetamide: To a solution of methyl 2-(2-bromo-8-isopropyl-5-oxopyrido[2,3-d]pyridazin-6(5H)-yl)acetate (30 mg, 0.09 mmol) and 5-fluoropyrimidin-4-amine (11 mg, 0.10 mmol) in toluene (2.0 mL) was added AlMe3 (0.06 mL, 2 M in toluene). The reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was cooled to ambient temperature, poured into saturated aqueous NH4Cl (10 mL), and extracted with EtOAc (3 × 5 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 reverse-phase preparative HPLC. LCMS: m / z = 421.0, 423.0 [M+H] + 。 1 1H NMR (400 MHz, CDCl3): δ 8.77 (d, J = 2.0 Hz, 1H), 8.57 - 8.49 (m, 2H), 8.40 (br s, 1H), 7.82 (d, J = 8.6 Hz, 1H), 5.52 (s, 2H), 3.95 - 3.85 (m, 1H), 1.35 (d, J = 6.8 Hz, 6H).

[0581] Example 23

[0582] N-(5-Fluoropyrimidin-4-yl)-2-(2-methylthio-5-oxo-8-propan-2-ylpyrido[2,3-d]pyridazin

[0583] -6-yl)acetamide

[0584]

[0585] Methyl 2-(8-isopropyl-2-(methylthio)-5-oxopyrido[2,3-d]pyridazin-6(5H)-yl)acetate: Sodium thiomethoxide (25 mg, 0.35 mmol) was added to a solution of methyl 2-(2-bromo-8-isopropyl-5-oxopyrido[2,3-d]pyridazin-6(5H)-yl)acetate (100 mg, 0.29 mmol) in DMF (2.0 mL). The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was poured into ice water (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 to give a residue, which was used directly. LCMS: m / z = 308.1 [M+H] + 。

[0586] N-(5-Fluoropyrimidin-4-yl)-2-(2-methylthio-5-oxo-8-propan-2-ylpyrido[2,3-d]pyridazin-6-yl)acetamide: AlMe3 (0.13 mL, 2 M in toluene) was added to a solution of methyl 2-(8-isopropyl-2-(methylthio)-5-oxopyrido[2,3-d]pyridazin-6(5H)-yl)acetate (62 mg, 0.20 mmol) and 5-fluoropyrimidin-4-amine (25 mg, 0.22 mmol) in toluene (3.0 mL). The reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was poured into saturated aqueous NH4Cl (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 reverse phase HPLC. LCMS: m / z = 389.1 [M+H] + 。 1 H NMR (400 MHz, CDCl3): δ 8.77 (s, 2H), 8.50 (d, J = 2.4 Hz, 1H), 8.41 (d, J = 8.6 Hz, 1H), 7.50 (d, J = 8.6 Hz, 1H), 5.42 (s, 2H), 3.92 (quin, J = 6.8 Hz, 1H), 2.69 (s, 3H), 1.44 - 1.28 (m, 6H).

[0587] Example 24

[0588] N-(5-Fluoropyrimidin-4-yl)-2-[5-oxo-8-propan-2-yl-2-(trifluoromethyl)pyrido[2,3-d]pyridazin-6-yl]acetamide

[0589]

[0590] Methyl 2-(8-isopropyl-5-oxo-2-(trifluoromethyl)pyrido[2,3-d]pyridazin-6(5H)-yl)acetate: To a solution of methyl 2-(2-bromo-8-isopropyl-5-oxopyrido[2,3-d]pyridazin-6(5H)-yl)acetate (100 mg, 0.29 mmol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (282 mg, 1.47 mmol) in DMF (1.0 mL) was added CuI (56 mg, 0.29 mmol). The reaction mixture was stirred at 100 °C for 12 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (2 × 3 mL). The combined organic layers were washed with brine (2 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LCMS: m / z = 330.1 [M+H] + 。

[0591] N-(5-Fluoropyrimidin-4-yl)-2-[5-oxo-8-propan-2-yl-2-(trifluoromethyl)pyrido[2,3-d]pyridazin-6-yl]acetamide: To a solution of methyl 2-(8-isopropyl-5-oxo-2-(trifluoromethyl)pyrido[2,3-d]pyridazin-6(5H)-yl)acetate (50 mg, 0.15 mmol) and 5-fluoropyrimidin-4-amine (26 mg, 0.23 mmol) in THF (0.5 mL) and toluene (1.0 mL) was added AlMe3 (0.23 mL, 2 M in toluene). The reaction mixture was stirred at 90 °C for 3 h. The reaction mixture was diluted with water (10 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 reverse-phase preparative HPLC. LCMS: m / z = 411.0 [M+H] + 。 1 H NMR (400 MHz, CDCl3): δ 8.95 (d, J = 8.4 Hz, 1H), 8.80 - 8.75 (m, 1H), 8.49 (s, 1H), 8.38 - 8.26 (m, 1H), 8.03 (d, J = 8.4 Hz, 1H), 5.56 (s, 2H), 4.04 - 4.03 (m, 1H), 1.38 (d, J = 6.8 Hz, 6H).

[0592] Example 25

[0593] 2-[4-(Difluoromethyl)-1-oxo-6-(trifluoromethyl)phthalazin-2-yl]-N-(5-fluoropyrimidin-2-yl)acetamide

[0594]

[0595] 2-[4-(Difluoromethyl)-1-oxo-6-(trifluoromethyl)phthalazin-2-yl]-N-(5-fluoropyrimidin-2-yl)acetamide: To a mixture of methyl 2-(4-(difluoromethyl)-1-oxo-6-(trifluoromethyl)phthalazin-2(1H)-yl)acetate (100 mg, 0.30 mmol), 5-fluoropyrimidin-2-amine (67 mg, 0.60 mmol) in toluene (2.0 mL) and THF (2.0 mL) was added AlMe3 (0.45 mL, 2 M in toluene). The reaction mixture was stirred at 90 °C for 3 hours. The reaction mixture was poured into ice-cold water (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 = 418.0 [M+H] + 。 1 1H NMR (400 MHz, DMSO-d6): δ 11.24 (br s, 1H), 8.79 (s, 2H), 8.57 (d, J = 8.4 Hz, 1H), 8.38 - 8.30 (m, 2H), 7.32 (t, J = 52.8 Hz, 1H), 5.23 (s, 2H).

[0596] Example 26

[0597] 2-[6-Bromo-4-(difluoromethyl)-5-fluoro-1-oxophthalazin-2-yl]-N-(5-fluoropyrimidin-2-yl)acetamide

[0598]

[0599] 2-[6-Bromo-4-(difluoromethyl)-5-fluoro-1-oxophthalazin-2-yl]-N-(5-fluoropyrimidin-2-yl)acetamide: To a solution of methyl 2-(6-bromo-4-(difluoromethyl)-5-fluoro-1-oxophthalazin-2(1H)-yl)acetate (75 mg, 0.21 mmol) in toluene (1.0 mL) and THF (1.0 mL) was added 5-fluoropyrimidin-2-amine (70 mg, 0.62 mmol) and AlMe3 (0.31 mL, 2 M in toluene). The reaction mixture was stirred at 90 °C for 3 hours. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 × 2 mL). The combined organic matter was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 446.0, 448.0 [M+H] + 。 11H NMR (400 MHz, CDCl3): δ 8.75 (brs, 1H), 8.50 (s, 2H), 8.23 - 8.19 (m, 1H), 8.06 - 8.00 (m, 1H), 6.80 - 6.76 (m, 1H), 5.57 (s, 2H).

[0600] Example 27

[0601] 2-[6-Bromo-4-(difluoromethyl)-5-fluoro-1-oxophthalazin-2-yl]-N-pyrimidin-2-ylacetamide

[0602]

[0603] 2-[6-Bromo-4-(difluoromethyl)-5-fluoro-1-oxophthalazin-2-yl]-N-pyrimidin-2-ylacetamide: To a solution of methyl 2-(6-bromo-4-(difluoromethyl)-5-fluoro-1-oxophthalazin-2(1H)-yl)acetate (300 mg, 0.82 mmol) in toluene (3.0 mL) and THF (1.0 mL) was added pyrimidin-2-amine (117 mg, 1.23 mmol) and AlMe3 (1.23 mL, 2 M in toluene). The reaction mixture was stirred at 90 °C for 4 h. The reaction mixture was diluted with water (2 mL) and extracted with EtOAc (3 × 2 mL). The combined organic layers were washed with brine (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 preparative TLC. LCMS: m / z = 427.9, 429.9 [M+H] + 。 1 1H NMR (400 MHz, CDCl3): δ 8.97 (s, 1H), 8.64 (d, J = 4.8 Hz, 2H), 8.22 (d, J = 8.4 Hz, 1H), 8.02 (dd, J = 6.0, 8.4 Hz, 1H), 7.06 (t, J = 4.8 Hz, 1H), 6.78 (t, J = 53.6 Hz, 1H), 5.67 (s, 2H).

[0604] Example 28

[0605] 2-[6-Bromo-4-(difluoromethyl)-5-fluoro-1-oxophthalazin-2-yl]-N-(5-cyano-3-fluoropyridin-2-yl)acetamide

[0606]

[0607] 2-[6-Bromo-4-(difluoromethyl)-5-fluoro-1-oxophthalazin-2-yl]-N-(5-cyano-3-fluoropyridin-2-yl)acetamide: To a solution of methyl 2-(6-bromo-4-(difluoromethyl)-5-fluoro-1-oxophthalazin-2(1H)-yl)acetate (100 mg, 0.27 mmol) and 6-amino-5-fluoronicotinonitrile (75 mg, 0.55 mmol) in toluene (2.0 mL) was added DABAL-Me3 (70 mg, 0.27 mmol). The reaction mixture was stirred at 60 °C for 1 h. The reaction mixture was quenched by addition of water (10 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 reverse-phase preparative HPLC. LCMS: m / z = 469.9, 471.9 [M+H] + 。 1 H NMR (400 MHz, CDCl3): δ 8.49 (d, J = 1.6 Hz, 1H), 8.24 (s, 1H), 8.21 (d, J = 8.4 Hz, 1H), 8.06 - 8.02 (m, 1H), 7.73 (dd, J = 9.2 Hz, 1.6 Hz, 1H), 6.79 (t, J = 52.8 Hz, 1H), 5.58 (s, 2H).

[0608] The following compounds are or can be prepared via procedures similar to those described above.

[0609]

[0610]

[0611] Example 32

[0612] 2-(6-Bromo-4-methoxy-1-oxophthalazin-2-yl)-N-(5-fluoropyrimidin-2-yl)acetamide (32)

[0613]

[0614] Methyl 2-(6-bromo-4-methoxy-1-oxophthalazin-2(1H)-yl)acetate: At 0 °C, MeONa (426 mg, 2.36 mmol, 5.4 M in MeOH) was added to a solution of methyl 2-(6-bromo-4-iodo-1-oxophthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-4-iodo-1-oxophthalazin-2(1H)-yl)acetate (1:1 mixture, 500 mg, 1.18 mmol) in MeOH (10 mL). The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was poured into saturated aqueous NH4Cl (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 chromatography. LCMS: m / z = 327.0, 329.0 [M+H] + 。

[0615] 2-(6-Bromo-4-methoxy-1-oxophthalazin-2-yl)-N-(5-fluoropyrimidin-2-yl)acetamide: To a solution of methyl 2-(6-bromo-4-methoxy-1-oxophthalazin-2(1H)-yl)acetate (100 mg, 0.31 mmol) in toluene (2.0 mL) and THF (1.0 mL) was added 5-fluoropyrimidin-2-amine (52 mg, 0.46 mmol) and AlMe3 (0.46 mL, 2 M in toluene). The reaction mixture was stirred at 90 °C for 6 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 × 2 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 = 408.0, 410.0 [M+H] + 。 1 1H NMR (400 MHz, CDCl3): δ 8.84 (br s, 1H), 8.48 (s, 2H), 8.30 (d, J = 8.4 Hz, 1H), 8.16 (s, 1H), 7.91 (d, J = 9.2 Hz, 1H), 5.24 (s, 2H), 4.00 (s, 3H).

[0616] The following compounds are or can be prepared via procedures similar to those described above.

[0617]

[0618]

[0619]

[0620]

[0621] Example 41

[0622]

[0623] 2-(6-Bromo-1-oxo-4-propan-2-ylphthalazin-2-yl)-N-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]acetamide: To a solution of 2-(6-bromo-4-isopropyl-1-oxo-phthalazin-2-yl)acetic acid (31 mg, 0.10 mmol) in DCM (2.5 mL) were added 3-fluoro-5-(trifluoromethyl)pyridin-2-amine (52 mg, 0.29 mmol) and DMAP (14 mg, 0.12 mmol). The reaction mixture was stirred at 23 °C for 15 minutes. EDC (46 mg, 0.24 mmol) was added to the reaction mixture. The reaction mixture was stirred at 23 °C for 24 hours. The reaction mixture was diluted with saturated NH4Cl solution (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 crude residue was purified by reverse phase HPLC. LCMS: m / z = 487.5, 489.5 [M+H] + 。 1 1H-NMR (400 MHz, CDCl3): δ 8.75 (s, 1H), 8.47 (d, J = 0.4 Hz, 1H), 8.36 (d, J = 8.5 Hz, 1H), 8.03 (d, J = 1.8 Hz, 1H), 7.88 (dd, J = 8.5, 1.8 Hz, 1H), 7.66 (dd, J = 9.5, 1.8 Hz, 1H), 5.30 (s, 2H), 3.47 - 3.38 (m, 1H), 1.36 (d, J = 6.8 Hz, 6H).

[0624] The following compounds are or can be prepared via procedures similar to those described above (coupling reagents used include T3P, DIC, EDC and HATU).

[0625]

[0626]

[0627]

[0628]

[0629]

[0630]

[0631]

[0632]

[0633]

[0634]

[0635]

[0636]

[0637]

[0638]

[0639]

[0640] Example 79

[0641]

[0642] 2-(6-Chloro-1-oxo-4-propan-2-ylphthalazin-2-yl)-N-[(3R)-1-ethylpiperidin-3-yl]acetamide: To a solution of 6-chloro-4-isopropylphthalazin-1(2H)-one (150 mg, 0.67 mmol) and (R)-2-chloro-N-(1-ethylpiperidin-3-yl)acetamide (207 mg, 1.01 mmol) in DMF (3.0 mL) was added Cs2CO3 (439 mg, 1.35 mmol). The reaction mixture was stirred at 90 °C for 1 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 391.2 [M+H] + . 1 1H NMR (400 MHz, CDCl3): δ 8.44 (d, J = 8.4 Hz, 1H), 7.84 (s, 1H), 7.71 (d, J = 8.4 Hz, 1H), 6.57 (s, 1H), 4.92 - 4.80 (m, 2H), 4.10 (s, 1H), 3.53 - 3.33 (m, 1H), 2.50 (s, 1H), 2.43 - 2.22 (m, 4H), 2.20 - 2.10 (m, 1H), 1.90 - 1.70 (m, 1H), 1.68 - 1.60 (m, 2H), 1.60 - 1.50 (m, 1H), 1.37 (d, J = 6.8 Hz, 6H), 0.94 - 0.73 (m, 3H).

[0643] Examples 80 and 81

[0644] 2-[6-bromo-4-(1-fluoroethyl)-1-oxo-phthalazin-2-yl]-N-pyrimidin-2-yl-acetamide (80) and 2-[7-bromo-4-(1-fluoroethyl)-1-oxo-phthalazin-2-yl]-N-pyrimidin-2-yl-acetamide (81)

[0645]

[0646] 2-(6-bromo-4-(1-ethoxyvinyl)-1-oxophthalazin-2(1H)-yl) acetate and methyl 2-(7-bromo-4-(1-ethoxyvinyl)-1-oxophthalazin-2(1H)-yl) acetate: To a solution of methyl 2-(6-bromo-4-iodo-1-oxo-phthalazin-2-yl) acetate and methyl 2-(7-bromo-4-iodo-1-oxophthalazin-2(1H)-yl) acetate (1:1 mixture, 1.0 g, 2.36 mmol) in 1,4-dioxane (30 mL) was added tributyl(1-ethoxyvinyl)stannane (854 mg, 2.36 mmol), Pd(PPh3)4 (137 mg, 0.12 mmol), LiCl (301 mg, 7.09 mmol) and CuI (1.35 g, 7.09 mmol). The reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was poured into brine (50 mL) and extracted with EtOAc (3 × 30 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 to give a 1:1 mixture of 2-(6-bromo-4-(1-ethoxyvinyl)-1-oxophthalazin-2(1H)-yl) acetate and methyl 2-(7-bromo-4-(1-ethoxyvinyl)-1-oxophthalazin-2(1H)-yl) acetate. LCMS: m / z = 336.9, 338.9 [M+H] + 。

[0647] Methyl 2-(4-acetyl-6-bromo-1-oxophthalazin-2(1H)-yl)acetate and methyl 2-(4-acetyl-7-bromo-1-oxophthalazin-2(1H)-yl)acetate: To a solution of methyl 2-(6-bromo-4-(1-ethoxyvinyl)-1-oxophthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-4-(1-ethoxyvinyl)-1-oxophthalazin-2(1H)-yl)acetate (1:1 mixture, 600 mg, 1.63 mmol) in 1,4-dioxane (5 mL) was added aqueous HCl solution (12 M, 2.72 mL). The reaction mixture was stirred at 23 °C for 5 h. The reaction mixture was poured into saturated aqueous NaHCO3 (30 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 to give a 1:1 mixture of methyl 2-(4-acetyl-6-bromo-1-oxophthalazin-2(1H)-yl)acetate and methyl 2-(4-acetyl-7-bromo-1-oxophthalazin-2(1H)-yl)acetate. LCMS: m / z = 339.1, 341.0 [M+H] + 。

[0648] Methyl 2-(6-bromo-4-(1-hydroxyethyl)-1-oxophthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-4-(1-hydroxyethyl)-1-oxophthalazin-2(1H)-yl)acetate: To a solution of methyl 2-(4-acetyl-6-bromo-1-oxophthalazin-2(1H)-yl)acetate and methyl 2-(4-acetyl-7-bromo-1-oxophthalazin-2(1H)-yl)acetate (1:1 mixture, 500 mg, 1.47 mmol) in THF (10 mL) at 0 °C was added NaBH4 (56 mg, 1.47 mmol). The reaction mixture was stirred at 0 °C for 5 h. The reaction mixture was poured into brine (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 to give a 1:1 mixture of methyl 2-(6-bromo-4-(1-hydroxyethyl)-1-oxophthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-4-(1-hydroxyethyl)-1-oxophthalazin-2(1H)-yl)acetate. LCMS: m / z = 341.0, 343.0 [M+H] + 。

[0649] Methyl 2-(6-bromo-4-(1-fluoroethyl)-1-oxophthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-4-(1-fluoroethyl)-1-oxophthalazin-2(1H)-yl)acetate: To a 1:1 mixture of methyl 2-(6-bromo-4-(1-hydroxyethyl)-1-oxophthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-4-(1-hydroxyethyl)-1-oxophthalazin-2(1H)-yl)acetate (250 mg, 0.73 mmol) was added BAST (1.20 g, 5.43 mmol). The reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was poured into saturated aqueous NaHCO3 (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 to give a 3:7 mixture of methyl 2-(6-bromo-4-(1-fluoroethyl)-1-oxophthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-4-(1-fluoroethyl)-1-oxophthalazin-2(1H)-yl)acetate. LCMS: m / z = 342.9, 344.9 [M+H] + 。

[0650] 2-[6-Bromo-4-(1-fluoroethyl)-1-oxo-phthalazin-2-yl]-N-pyrimidin-2-yl-acetamide and 2-[7-bromo-4-(1-fluoroethyl)-1-oxo-phthalazin-2-yl]-N-pyrimidin-2-yl-acetamide: To a solution of methyl 2-(6-bromo-4-(1-fluoroethyl)-1-oxophthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-4-(1-fluoroethyl)-1-oxophthalazin-2(1H)-yl)acetate (3:7 ratio, 150 mg, 0.44 mmol) in toluene (5.0 mL) and THF (1.0 mL) was added pyrimidin-2-amine (83 mg, 0.87 mmol) and AlMe3 (0.65 mL, 2 M in toluene). The reaction mixture was stirred at 95 °C for 5 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 × 2 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, followed by preparative SFC to give:

[0651] 2-[6-Bromo-4-(1-fluoroethyl)-1-oxo-phthalazin-2-yl]-N-pyrimidin-2-yl-acetamide (80): LCMS: m / z = 406.0, 408.0 [M+H] + 。 11H NMR (400 MHz, CDCl3): δ 9.10 (s, 1H), 8.64 (d, J = 4.0 Hz, 2H), 8.36 (d, J = 8.4 Hz, 1H), 8.26 (s, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.04 (s, 1H), 6.05 - 5.80 (m, 1H), 5.70 - 5.58 (m, 1H), 5.54 - 5.42 (m, 1H), 1.88 - 1.77 (m, 3H).

[0652] 2-[7-Bromo-4-(1-fluoroethyl)-1-oxo-phthalazin-2-yl]-N-pyrimidin-2-yl-acetamide (81): LCMS: m / z = 406.0, 408.0 [M+H] + . 1 1H NMR (400 MHz, CDCl3): δ 8.65 (d, J = 1.6 Hz, 1H), 8.61 (d, J = 4.0 Hz, 2H), 8.53 (s, 1H), 8.02 - 7.97 (m, 2H), 7.07 - 7.00 (m, 1H), 6.07 - 5.83 (m, 1H), 5.54 - 5.41 (m, 2H), 1.87 - 1.76 (m, 3H).

[0653] Examples 82 and 83

[0654] 2-[6-Bromo-1-oxo-4-(trifluoromethoxy)phthalazin-2-yl]-N-(5-fluoropyrimidin-4-yl)acetamide (82) and 2-[7-Bromo-1-oxo-4-(trifluoromethoxy)phthalazin-2-yl]-N-(5-fluoropyrimidin-4-yl)acetamide (83)

[0655]

[0656] 6-Bromo-4-hydroxy-2-(4-methoxybenzyl)phthalazin-1(2H)-one and 7-bromo-4-hydroxy-2-(4-methoxybenzyl)phthalazin-1(2H)-one: 5-Bromoisobenzofuran-1,3-dione (5.5 g, 24.3 mmol) was added to a solution of (4-methoxyphenyl)methylhydrazine (3.7 g, 24.3 mmol) in AcOH (10 mL). The reaction mixture was stirred at 140 °C for 16 h. The reaction mixture was cooled to ambient temperature, poured into saturated aqueous NH4Cl (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. The residue was wet milled in MTBE (50 mL) to afford a 1:1 mixture of 6-bromo-4-hydroxy-2-(4-methoxybenzyl)phthalazin-1(2H)-one and 7-bromo-4-hydroxy-2-(4-methoxybenzyl)phthalazin-1(2H)-one. LCMS: m / z = 361.0, 363.0 [M+H] + .

[0657] 6-Bromo-2-(4-methoxybenzyl)-4-(trifluoromethoxy)phthalazin-1(2H)-one and 7-bromo-2-(4-methoxybenzyl)-4-(trifluoromethoxy)phthalazin-1(2H)-one: A round-bottom flask containing CsF (1.26 g, 8.3 mmol) was heated under vacuum to 170 °C for 0.5 h. Then, the flask was backfilled with N2 and cooled to room temperature, after which AgOTf (1.77 g, 6.9 mmol), Selectfluor (980 mg, 2.76 mmol), 2,4-di(tert-butyl)phenol (570 mg, 2.76 mmol), and N-(phenylsulfonyl)-N-fluoro-benzenesulfonamide (870 mg, 2.76 mmol) were added. A solution of 6-bromo-4-hydroxy-2-(4-methoxybenzyl)phthalazin-1(2H)-one and 7-bromo-4-hydroxy-2-(4-methoxybenzyl)phthalazin-1(2H)-one (1:1 mixture, 500 mg, 1.38 mmol) in toluene (30 mL) was added to the solid mixture, followed by 2-fluoropyridine (670 mg, 6.90 mmol) and trimethyl(trifluoromethyl)silane (981 mg, 6.90 mmol). The reaction mixture was stirred at 20 °C for 32 h. The reaction mixture was filtered to remove solids and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford a 1:1 mixture of 6-bromo-2-(4-methoxybenzyl)-4-(trifluoromethoxy)phthalazin-1(2H)-one and 7-bromo-2-(4-methoxybenzyl)-4-(trifluoromethoxy)phthalazin-1(2H)-one. LCMS: m / z = 429.0, 430.9 [M+H] + .

[0658] 6-Bromo-4-(trifluoromethoxy)phthalazin-1(2H)-one and 7-bromo-4-(trifluoromethoxy)phthalazin-1(2H)-one: At 0 °C, CAN (11.2 g, 20.5 mmol) was added to a solution of 6-bromo-2-(4-methoxybenzyl)-4-(trifluoromethoxy)phthalazin-1(2H)-one and 7-bromo-2-(4-methoxybenzyl)-4-(trifluoromethoxy)phthalazin-1(2H)-one (1:1 mixture, 4.4 g, 10.3 mmol) in MeCN (50 mL) and water (10 mL). The reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was poured into saturated aqueous NaHCO3 (50 mL) and extracted with EtOAc (3 × 50 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 reverse-phase preparative HPLC to give a 1:1 mixture of 6-bromo-4-(trifluoromethoxy)phthalazin-1(2H)-one and 7-bromo-4-(trifluoromethoxy)phthalazin-1(2H)-one. LCMS: m / z = 308.0, 310.9 [M+H] + 。

[0659] Methyl 2-(6-bromo-1-oxo-4-(trifluoromethoxy)phthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-1-oxo-4-(trifluoromethoxy)phthalazin-2(1H)-yl)acetate: Methyl 2-bromoacetate (100 mg, 0.66 mmol) and Cs2CO3 (427 mg, 1.31 mmol) were added to a solution of 6-bromo-4-(trifluoromethoxy)phthalazin-1(2H)-one and 7-bromo-4-(trifluoromethoxy)phthalazin-1(2H)-one (1:1 mixture, 135 mg, 0.44 mmol) in DMF (5 mL). The reaction mixture was stirred at 50 °C for 5 h. The reaction mixture was poured into brine (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 to give a 1:1 mixture of methyl 2-(6-bromo-1-oxo-4-(trifluoromethoxy)phthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-1-oxo-4-(trifluoromethoxy)phthalazin-2(1H)-yl)acetate. LCMS: m / z = 380.9, 382.9 [M+H] + 。

[0660] 2-(6-Bromo-1-oxo-4-(trifluoromethoxy)phthalazin-2(1H)-yl)-N-(5-fluoropyrimidin-4-yl)acetamide and 2-(7-bromo-1-oxo-4-(trifluoromethoxy)phthalazin-2(1H)-yl)-N-(5-fluoropyrimidin-4-yl)acetamide: To a solution of methyl 2-(6-bromo-1-oxo-4-(trifluoromethoxy)phthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-1-oxo-4-(trifluoromethoxy)phthalazin-2(1H)-yl)acetate (1:1 mixture, 110 mg, 0.29 mmol) in toluene (5.0 mL) was added 5-fluoropyrimidin-4-amine (65 mg, 0.58 mmol) and AlMe3 (0.43 mL, 2 M in toluene). The reaction mixture was stirred at 110 °C for 3 h. The reaction mixture was poured into saturated aqueous NH4Cl (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 reverse-phase preparative HPLC to give:

[0661] 2-[6-Bromo-1-oxo-4-(trifluoromethoxy)phthalazin-2-yl]-N-(5-fluoropyrimidin-4-yl)acetamide: LCMS: m / z = 461.9, 463.9 [M+H] + 。 1 H NMR (400 MHz, CDCl3): δ 8.77 (s, 1H), 8.63 (d, J = 2.0 Hz, 1H), 8.52 (s, 1H), 8.19 (s, 1H), 8.03 (dd, J = 2.0, 8.4 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 5.52 (s, 2H).

[0662] 2-[7-Bromo-1-oxo-4-(trifluoromethoxy)phthalazin-2-yl]-N-(5-fluoropyrimidin-4-yl)acetamide: LCMS: m / z = 461.9, 463.9 [M+H] + 。 1 H NMR (400 MHz, CDCl3): δ 8.76 (s, 1H), 8.52 (s, 1H), 8.33 (d, J = 8.4 Hz, 1H), 8.19 (s, 1H), 8.08 (s, 1H), 8.00 (d, J = 8.4 Hz, 1H), 5.51 (s, 2H).

[0663] The following compounds are or can be prepared via procedures similar to those described above.

[0664]

[0665] Examples 85 and 86

[0666] 2-(6-Bromo-7-fluoro-1-oxo-4-propan-2-ylphthalazin-2-yl)-N-(5-fluoropyrimidin-4-yl)acetamide (85) and 2-(7-bromo-6-fluoro-1-oxo-4-propan-2-ylphthalazin-2-yl)-N-(5-fluoropyrimidin-4-yl)acetamide (86)

[0668]

[0669] 4-Bromo-5-fluorophthalic acid: NBS (4.29 g, 24.1 mmol) was added to a mixture of 5-fluoroisobenzofuran-1,3-dione (2.00 g, 12.0 mmol) in concentrated H2SO4 (20 mL). The reaction mixture was stirred at 50 °C for 12 h. The reaction mixture was poured into ice water (100 mL). The aqueous phase was 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 reverse-phase preparative HPLC. 1 H NMR (400 MHz, CDCl3): δ 8.03 (d, J = 6.6 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H).

[0670] 5-Bromo-6-fluoroisobenzofuran-1,3-dione: A mixture of 4-bromo-5-fluorophthalic acid (1.20 g, 4.56 mmol) in SOCl2 (8.20 g, 68.9 mmol) was stirred at 90 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue which was used directly. 1 H NMR (400 MHz, CDCl3): δ 8.27 (d, J = 5.6 Hz, 1H), 7.73 (d, J = 6.0 Hz, 1H).

[0671] 4-Bromo-5-fluoro-2-isobutyrylbenzoic acid and 5-bromo-4-fluoro-2-isobutyrylbenzoic acid: Isopropylmagnesium chloride (2.40 mL, 2 M in THF) was added to a solution of 5-bromo-6-fluoroisobenzofuran-1,3-dione (1.12 g, 4.57 mmol) in THF (20 mL) at -10 °C. The reaction mixture was stirred at -10 °C for 0.5 h. The reaction mixture was poured into saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (3 × 25 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a 1:1 mixture of 4-bromo-5-fluoro-2-(2-methylpropanoyl)benzoic acid and 5-bromo-4-fluoro-2-(2-methylpropanoyl)benzoic acid. LCMS: m / z = 289.0, 291.0 [M+H] + 。

[0672] Methyl 4-bromo-5-fluoro-2-isobutyrylbenzoate and methyl 5-bromo-4-fluoro-2-isobutyrylbenzoate: At 0 °C, TMSCHN2 (4.01 mL, 2 M in n-hexane) was added to a solution of 4-bromo-5-fluoro-2-isobutyrylbenzoic acid and 5-bromo-4-fluoro-2-isobutyrylbenzoic acid (1:1 mixture, 1.16 g, 4.01 mmol) in THF (10 mL). The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give a 1:1 mixture of methyl 4-bromo-5-fluoro-2-(2-methylpropanoyl)benzoate and methyl 5-bromo-4-fluoro-2-(2-methylpropanoyl)benzoate. LCMS: m / z = 303.0, 305.0 [M+H] + 。

[0673] 6-Bromo-7-fluoro-4-isopropylphthalazin-1(2H)-one and 7-bromo-6-fluoro-4-isopropylphthalazin-1(2H)-one: Hydrazine monohydrate (96.8 mg, 1.84 mmol) was added to a solution of methyl 4-bromo-5-fluoro-2-isobutyrylbenzoate and methyl 5-bromo-4-fluoro-2-isobutyrylbenzoate (1:1 mixture, 465 mg, 1.53 mmol) in MeOH (10 mL). The reaction mixture was stirred at 25 °C for 3 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was used directly in the form of a 1:1 mixture of 6-bromo-7-fluoro-4-isopropylphthalazin-1(2H)-one and 7-bromo-6-fluoro-4-isopropylphthalazin-1(2H)-one. LCMS: m / z = 285.0, 287.0 [M+H] + 。

[0674] Methyl 2-(6-bromo-7-fluoro-4-isopropyl-1-oxophthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-6-fluoro-4-isopropyl-1-oxophthalazin-2(1H)-yl)acetate: To a solution of 6-bromo-7-fluoro-4-isopropylphthalazin-1(2H)-one and 7-bromo-6-fluoro-4-isopropylphthalazin-1(2H)-one (1:1 mixture, 456 mg, 1.60 mmol) in DMF (5.0 mL) was added Cs2CO3 (1.04 g, 3.20 mmol) and methyl 2-bromoacetate (294 mg, 1.92 mmol). The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was poured into ice water (15 mL) and extracted with EtOAc (3 × 5 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 to give a 1:1 mixture of methyl 2-(6-bromo-7-fluoro-4-isopropyl-1-oxophthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-6-fluoro-4-isopropyl-1-oxophthalazin-2(1H)-yl)acetate. LCMS: m / z = 357.0, 359.0 [M+H] + 。

[0675] 2-(6-Bromo-7-fluoro-1-oxo-4-isopropylphthalazin-2-yl)-N-(5-fluoropyrimidin-4-yl)acetamide and 2-(7-bromo-6-fluoro-1-oxo-4-isopropylphthalazin-2-yl)-N-(5-fluoropyrimidin-4-yl)acetamide: To a solution of methyl 2-(6-bromo-7-fluoro-4-isopropyl-1-oxophthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-6-fluoro-4-isopropyl-1-oxophthalazin-2(1H)-yl)acetate (1:1 mixture, 175 mg, 0.49 mmol) in toluene (5.0 mL) was added 5-fluoropyrimidin-4-amine (83 mg, 0.73 mmol) and AlMe3 (0.37 mL, 2 M in toluene). The reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was poured into ice water (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 reverse-phase preparative HPLC to give:

[0676] 2-(6-Bromo-7-fluoro-1-oxo-4-isopropylphthalazin-2-yl)-N-(5-fluoropyrimidin-4-yl)acetamide: LCMS: m / z = 438.0, 440.0 [M+H] + 。 11H NMR (400 MHz, CDCl3): δ 8.77 (d, J = 1.6 Hz, 1H), 8.63 (br s, 1H), 8.50 (d, J = 2.2 Hz, 1H), 8.18 (d, J = 8.2 Hz, 1H), 8.14 (d, J = 6.0 Hz, 1H), 5.45 (s, 2H), 3.46 - 3.36 (m, 1H), 1.37 (d, J = 6.8 Hz, 6H).

[0677] 2-(7-Bromo-6-fluoro-1-oxo-4-propan-2-ylphthalazin-2-yl)-N-(5-fluoropyrimidin-4-yl)acetamide: LCMS: m / z = 438.0, 440.0 [M+H] + 。 1 1H NMR (400 MHz, CDCl3): δ 8.83 - 8.72 (m, 1H), 8.72 - 8.70 (m, 1H), 8.68 (br s, 1H), 8.50 (d, J = 2.0 Hz, 1H), 7.58 - 7.54 (m, 1H), 5.45 (s, 2H), 3.45 - 3.26 (m, 1H), 1.36 (d, J = 6.8 Hz, 6H).

[0678] Examples 87 and 88

[0679] N-(5-Fluoropyrimidin-4-yl)-2-[1-oxo-4-propan-2-yl-6-(trifluoromethyl)phthalazin-2-yl]acetamide (87) and N-(5-fluoropyrimidin-4-yl)-2-[1-oxo-4-propan-2-yl-7-(trifluoromethyl)phthalazin-2-

[0680] yl]acetamide (88)

[0681]

[0682] 5-(Trifluoromethyl) isobenzofuran-1,3-dione: A solution of 4-(trifluoromethyl)phthalic acid (1.00 g, 4.27 mmol) in SOCl2 (15.2 g, 128 mmol) was stirred at 50 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was used directly.

[0683] 2-Isobutyryl-4-(trifluoromethyl)benzoic acid and 2-isobutyryl-5-(trifluoromethyl)benzoic acid: At -10 °C, isopropylmagnesium chloride (0.23 mL, 2 M in THF) was added to a solution of 5-(trifluoromethyl)isobenzofuran-1,3-dione (100 mg, 0.46 mmol) in THF (2 mL). The reaction mixture was stirred at -10 °C for 2 h. The reaction mixture was diluted with water (2 mL) and extracted with EtOAc (2 × 3 mL). The combined organic layers were washed with brine (2 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue which was used directly in the form of a 1:1 mixture of 2-isobutyryl-4-(trifluoromethyl)benzoic acid and 2-isobutyryl-5-(trifluoromethyl)benzoic acid. LCMS: m / z = 258.9 [M-H] - .

[0684] 4-Isopropyl-6-(trifluoromethyl)phthalazin-1(2H)-one and 4-isopropyl-7-(trifluoromethyl)phthalazin-1(2H)-one: Hydrazine hydrate (302 mg, 5.92 mmol) was added to a solution of 2-isobutyryl-4-(trifluoromethyl)benzoic acid and 2-isobutyryl-5-(trifluoromethyl)benzoic acid (1:1 mixture, 1.40 g, 5.38 mmol) in EtOH (2 mL). The reaction mixture was stirred at 90 °C for 12 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue which was used directly in the form of a 1:1 mixture of 4-isopropyl-6-(trifluoromethyl)phthalazin-1(2H)-one and 4-isopropyl-7-(trifluoromethyl)phthalazin-1(2H)-one. LCMS: m / z = 257.1 [M+H] + .

[0685] Methyl 2-(4-isopropyl-1-oxo-6-(trifluoromethyl)phthalazin-2(1H)-yl)acetate and methyl 2-(4-isopropyl-1-oxo-7-(trifluoromethyl)phthalazin-2(1H)-yl)acetate: To a solution of 4-isopropyl-6-(trifluoromethyl)phthalazin-1(2H)-one and 4-isopropyl-7-(trifluoromethyl)phthalazin-1(2H)-one (1:1 mixture, 1.00 g, 3.90 mmol) in DMF (10 mL) was added methyl chloroacetate (847 mg, 7.81 mmol) and Cs2CO3 (3.81 g, 11.71 mmol). The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 50 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 to give a 1:1 mixture of methyl 2-(4-isopropyl-1-oxo-6-(trifluoromethyl)phthalazin-2(1H)-yl)acetate and methyl 2-(4-isopropyl-1-oxo-7-(trifluoromethyl)phthalazin-2(1H)-yl)acetate. LCMS: m / z = 329.1 [M+H] + .

[0686] N-(5-Fluoropyrimidin-4-yl)-2-(4-isopropyl-1-oxo-6-(trifluoromethyl)phthalazin-2(1H)-yl)acetamide and N-(5-fluoropyrimidin-4-yl)-2-(4-isopropyl-1-oxo-7-(trifluoromethyl)phthalazin-2(1H)-yl)acetamide: To a solution of methyl 2-(4-isopropyl-1-oxo-6-(trifluoromethyl)phthalazin-2(1H)-yl)acetate and methyl 2-(4-isopropyl-1-oxo-7-(trifluoromethyl)phthalazin-2(1H)-yl)acetate (1:1 mixture, 140 mg, 0.43 mmol) in THF (2.0 mL) and toluene (2.0 mL) was added 5-fluoropyrimidin-4-amine (96 mg, 0.85 mmol) and AlMe3 (0.64 mL, 2 M in toluene). The reaction mixture was stirred at 90 °C for 2 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 × 20 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 reverse-phase preparative HPLC to give:

[0687] N-(5-Fluoropyrimidin-4-yl)-2-[1-oxo-4-propan-2-yl-6-(trifluoromethyl)phthalazin-2-yl]acetamide: LCMS: m / z = 410.2 [M+H] + . 11H NMR (400 MHz, CDCl3): δ 8.77 (d, J = 2.0 Hz, 1H), 8.65 (d, J = 8.4 Hz, 2H), 8.50 (d, J = 2.4 Hz, 1H), 8.16 (s, 1H), 8.00 (d, J = 8.4 Hz, 1H), 5.50 (s, 2H), 3.63 - 3.44 (m, 1H), 1.39 (d, J = 6.8 Hz, 6H).

[0688] N-(5-Fluoropyrimidin-4-yl)-2-[1-oxo-4-propan-2-yl-7-(trifluoromethyl)phthalazin-2-yl]acetamide: LCMS: m / z = 410.2 [M+H] + 。 1 1H NMR (400 MHz, CDCl3): δ 8.79 (d, J = 12 Hz, 2H), 8.63 (br s, 1H), 8.51 (d, J = 2.4 Hz, 1H), 8.12 - 7.99 (m, 2H), 5.50 (s, 2H), 3.58 - 3.49 (m, 1H), 1.39 (d, J = 6.8 Hz, 6H).

[0689] Examples 89 and 90

[0690] 2-[6-Bromo-1-oxo-4-(trifluoromethyl)phthalazin-2-yl]-N-[(3R)-1-ethylpiperidin-3-yl]acetamide (89) and 2-[7-Bromo-1-oxo-4-(trifluoromethyl)phthalazin-2-yl]-N-[(3R)-1-ethylpiperidin-3-yl]acetamide (90)

[0691]

[0692] 4-Bromo-2-(2,2,2-trifluoroacetyl)benzoic acid and 5-bromo-2-(2,2,2-trifluoroacetyl)benzoic acid: To a solution of 5-bromo-isobenzofuran-1,3-dione (3.00 g, 13.2 mmol) in MeCN (30 mL) at 0 °C was added CsF (2.00 g, 13.2 mmol) and TMSCF3 (1.88 g, 13.2 mmol). The reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was then adjusted to pH = 11 with aqueous NaOH (2 N), extracted with EtOAc (3 × 10 mL), and the organic layer was discarded. The aqueous layer was adjusted to pH = 3 with aqueous HCl (3 N) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue which was used directly in the form of a 1:1 mixture of 4-bromo-2-(2,2,2-trifluoroacetyl)benzoic acid and 5-bromo-2-(2,2,2-trifluoroacetyl)benzoic acid. LCMS: m / z = 294.8, 296.8 [M-H] - 。

[0693] 6-Bromo-4-(trifluoromethyl)phthalazin-1(2H)-one and 7-bromo-4-(trifluoromethyl)phthalazin-1(2H)-one: To a solution of 4-bromo-2-(2,2,2-trifluoroacetyl)benzoic acid and 5-bromo-2-(2,2,2-trifluoroacetyl)benzoic acid (1:1 mixture, 2.30 g, 7.74 mmol) in EtOH (15 mL) was added hydrazine monohydrate (465 mg, 9.29 mmol). The reaction mixture was stirred at 90 °C for 16 h. Toluene (10 ml) was added to the reaction mixture. The reaction mixture was stirred at 110 °C for an additional 12 h. The reaction mixture was concentrated under reduced pressure. The residue was triturated with MTBE to give a residue which was used directly in the form of a 1:1 mixture of 6-bromo-4-(trifluoromethyl)phthalazin-1(2H)-one and 7-bromo-4-(trifluoromethyl)phthalazin-1(2H)-one. LCMS: m / z = 293.0, 295.0 [M+H] + 。

[0694] 2-[6-Bromo-1-oxo-4-(trifluoromethyl)phthalazin-2-yl]-N-[(3R)-1-ethylpiperidin-3-yl]acetamide and 2-[7-bromo-1-oxo-4-(trifluoromethyl)phthalazin-2-yl]-N-[(3R)-1-ethylpiperidin-3-yl]acetamide: To a solution of 6-bromo-4-(trifluoromethyl)phthalazin-1(2H)-one and 7-bromo-4-(trifluoromethyl)phthalazin-1(2H)-one (1:1 mixture, 200 mg, 0.69 mmol) in DMF (3 mL) was added (R)-2-chloro-N-(1-ethylpiperidin-3-yl)acetamide (154 mg, 0.75 mmol) and Cs2CO3 (222 mg, 0.68 mmol). The reaction mixture was stirred at 90 °C for 2 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC to give:

[0695] 2-[6-Bromo-1-oxo-4-(trifluoromethyl)phthalazin-2-yl]-N-[(3R)-1-ethylpiperidin-3-yl]acetamide: LCMS: m / z = 461.1, 463.1 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 8.34 (d, J = 8.4 Hz, 1H), 8.07 (s, 1H), 7.95 (dd, J = 8.6, 1.6 Hz, 1H), 6.76 (s, 1H), 4.90 (s, 2H), 4.14 (d, J = 3.6 Hz, 1H), 2.74 - 2.49 (m, 3H), 2.43 - 2.31 (m, 3H), 2.16 - 2.10 (m, 1H), 1.77 - 1.63 (m, 2H), 1.34 - 1.17 (m, 1H), 0.99 (t, J = 7.2 Hz, 3H).

[0696] 2-[7-Bromo-1-oxo-4-(trifluoromethyl)phthalazin-2-yl]-N-[(3R)-1-ethylpiperidin-3-yl]acetamide: LCMS: m / z = 461.1, 463.1 [M+H] + . 11H NMR (400 MHz, CDCl3): δ 8.65 (d, J = 2.0 Hz, 1H), 8.00 (dd, J = 8.8, 2.0 Hz, 1H), 7.83 (dd, J = 8.8, 1.5 Hz, 1H), 6.72 (br s, 1H), 4.93 (s, 2H), 4.18 (br s, 1H), 2.53 - 2.86 (m, 1H), 2.43 (br s, 3H), 2.18 (br s, 1H), 1.75 (br s, 1H), 1.42 - 1.59 (m, 3H), 1.34 - 1.17 (m, 1H), 0.99 (t, J = 7.2 Hz, 3H).

[0697] Example 91

[0698] 2-[6-Bromo-1-oxo-4-(2,2,2-trifluoroethyl)phthalazin-2-yl]-N-(5-fluoropyrimidin-4-yl)acetamide

[0699]

[0700] Methyl 4-bromo-2-((trimethylsilyl)ethynyl)benzoate: To a solution of methyl 4-amino-2-bromobenzoate (500 mg, 2.17 mmol) and ethynyltrimethylsilane (640 mg, 6.52 mmol) in DMF (10 mL) were added Pd(PPh3)2Cl2 (153 mg, 0.22 mmol), CuI (83 mg, 0.43 mmol) and Et3N (440 mg, 4.35 mmol). The reaction mixture was stirred at 110 °C for 2 h. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (2 × 30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. 1 1H NMR (400 MHz, CDCl3): δ 7.81 (d, J = 8.4 Hz, 1H), 6.83 (d, J = 2.4 Hz, 1H), 6.60 (dd, J = 2.4, 8.4 Hz, 1H), 4.01 (s, 2H), 3.87 (s, 3H), 0.27 (s, 9H).

[0701] Methyl 4-bromo-2-((trimethylsilyl)ethynyl)benzoate: At 0 °C, CuBr2 (1.53 g, 6.87 mmol) was added to a solution of methyl 4-bromo-2-((trimethylsilyl)ethynyl)benzoate (1.70 g, 6.87 mmol) and t-BuONO (2.13 g, 20.6 mmol) in MeCN (35 mL). The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was poured into water (30 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.

[0702] Methyl 4-bromo-2-ethynylbenzoate: K2CO3 (1.14 g, 8.23 mmol) was added to a solution of methyl 4-bromo-2-((trimethylsilyl)ethynyl)benzoate (1.28 g, 4.11 mmol) in MeOH (20 mL). The reaction mixture was stirred at 25 °C for 30 min. The reaction mixture was adjusted to pH = 7 with aqueous HCl (1 N) 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. 1 1H NMR (400 MHz, CDCl3): δ 7.85 - 7.75 (m, 2H), 7.56 - 7.53 (m, 1H), 3.93 (d, J = 3.6 Hz, 3H), 3.46 (s, 1H).

[0703] Methyl 4-bromo-2-(3,3,3-trifluoropropionyl)benzoate: AgNO3 (104 mg, 0.61 mmol) was added to a solution of methyl 4-bromo-2-ethynylbenzoate (735 mg, 3.07 mmol) and sodium trifluoromethanesulfinate (576 mg, 3.69 mmol) in NMP (14 mL). The reaction mixture was stirred at 70 °C for 16 h under O2 (15 psi). The reaction mixture was diluted with EtOAc (10 mL) and filtered through a thin pad of diatomaceous earth. The filtrate was diluted with water (20 mL) and extracted with EtOAc (3 × 5 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 = 322.9, 324.9 [M-H] - 。

[0704] 6-Bromo-4-(2,2,2-trifluoroethyl)phthalazin-1(2H)-one: Hydrazine hydrate (26 mg, 0.52 mmol) was added to a solution of methyl 4-bromo-2-(3,3,3-trifluoropropanoyl)benzoate (170 mg, 0.52 mmol) in EtOH (5 mL). The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was used directly. LCMS: m / z = 307.0, 309.0 [M+H] + .

[0705] Methyl 2-(6-bromo-1-oxo-4-(2,2,2-trifluoroethyl)phthalazin-2(1H)-yl)acetate: Cs2CO3 (318 mg, 0.98 mmol) and methyl 2-bromoacetate (75 mg, 0.49 mmol) were added to a solution of 6-bromo-4-(2,2,2-trifluoroethyl)phthalazin-1(2H)-one (100 mg, 0.33 mmol) in DMF (1.0 mL). The reaction mixture was stirred at 20 °C for 3 h. The reaction mixture was diluted with water (3 mL) and extracted with EtOAc (3 × 2 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography. LCMS: m / z = 379.1, 381.1 [M+H] + .

[0706] 2-[6-Bromo-1-oxo-4-(2,2,2-trifluoroethyl)phthalazin-2-yl]-N-(5-fluoropyrimidin-4-yl)acetamide: 5-Fluoropyrimidin-4-amine (89 mg, 0.80 mmol) and AlMe3 (0.40 mL, 2 M in toluene) were added to a solution of methyl 2-(6-bromo-1-oxo-4-(2,2,2-trifluoroethyl)phthalazin-2(1H)-yl)acetate (100 mg, 0.26 mmol) in toluene (1.0 mL) and THF (1.0 mL). The reaction mixture was stirred at 100 °C for 3 h. The reaction mixture was diluted with water (2 mL) and extracted with EtOAc (3 × 1 mL). The combined organic layers were washed with brine (2 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC. LCMS: m / z = 460.0, 462.0 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 8.76 (d, J = 2.0 Hz, 1H), 8.51 (d, J = 2.4 Hz, 1H), 8.37 (d, J = 9.2 Hz, 1H), 7.97 - 7.91 (m, 2H), 5.57 (s, 2H), 3.76 (q, J = 10.0 Hz, 2H).

[0707] Example 92

[0708] 2-(6-bromo-8-fluoro-1-oxo-4-propan-2-ylphthalazin-2-yl)-N-(5-fluoropyrimidin-4-yl)acetamide (92)

[0710]

[0711] 5-Bromo-3-fluorophthalic acid: To an aqueous solution (80 mL) of 4-bromo-2-fluoro-6-methylbenzoic acid (8.00 g, 34.3 mmol) was added KMnO4 (16.28 g, 103 mmol) and NaOH (5.49 g, 137 mmol). The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was filtered through a thin layer of diatomaceous earth. The filtrate was adjusted to pH = 3 with aqueous HCl (2 N) and extracted with DCM (3 × 150 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was used directly. 1 H NMR (400 MHz, DMSO-d6): δ 13.78 (br s, 2H), 7.95 (d, J = 1.6 Hz, 1H), 7.85 (s, 1H).

[0712] 6-Bromo-4-fluoroisobenzofuran-1,3-dione: A solution of 5-bromo-3-fluorophthalic acid (6.40 g, 24.3 mmol) in SOCl2 (164 g, 1.38 mol) was stirred at 90 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was used directly. 1 H NMR (400 MHz, CDCl3): δ 8.00 (s, 1H), 7.76 (dd, J = 0.8, 7.6 Hz, 1H).

[0713] 5-Bromo-3-fluoro-2-isobutyrylbenzoic acid and 4-bromo-2-fluoro-6-isobutyrylbenzoic acid: At -10 °C, isopropylmagnesium chloride (2.04 mL, 2 M in THF) was added to a solution of 6-bromo-4-fluoroisobenzofuran-1,3-dione (1.00 g, 4.08 mmol) in THF (20 mL). The reaction mixture was stirred at -10 °C for 3 h. The reaction mixture was quenched with NH4Cl (20 mL), adjusted to pH = 10 with aqueous Na2CO3 (2 N), and extracted with MTBE (20 mL). The organic layers were discarded. The aqueous layer was then adjusted to pH = 3 with aqueous HCl (2 N) and extracted with EtOAc (3 × 20 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, which was used directly in the form of a 1:1 mixture of 5-bromo-3-fluoro-2-isobutyrylbenzoic acid and 4-bromo-2-fluoro-6-isobutyrylbenzoic acid.

[0714] 6-Bromo-8-fluoro-4-isopropylphthalazin-1(2H)-one and 7-bromo-5-fluoro-4-isopropylphthalazin-1(2H)-one: Hydrazine hydrate (137 mg, 2.68 mmol) was added to a solution of 5-bromo-3-fluoro-2-isobutyrylbenzoic acid and 4-bromo-2-fluoro-6-isobutyrylbenzoic acid (1:1 mixture, 970 mg, 3.36 mmol) in EtOH (10 mL). The reaction mixture was stirred at 90 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was used directly in the form of a 1:1 mixture of 6-bromo-8-fluoro-4-isopropylphthalazin-1(2H)-one and 7-bromo-5-fluoro-4-isopropylphthalazin-1(2H)-one. LCMS: m / z = 285.1, 287.1 [M+H] + 。

[0715] Methyl 2-(6-bromo-8-fluoro-4-isopropyl-1-oxophthalazin-2(1H)-yl)acetate: Methyl 2-bromoacetate (955 mg, 6.24 mmol) and Cs2CO3 (2.03 g, 6.24 mmol) were added to a solution of 6-bromo-8-fluoro-4-isopropylphthalazin-1(2H)-one and 7-bromo-5-fluoro-4-isopropylphthalazin-1(2H)-one (1:1 mixture, 890 mg, 3.12 mmol) in DMF (10 mL). The reaction mixture was stirred at 50 °C for 3 h. The reaction mixture was diluted with water (50 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.

[0716] 2-(6-Bromo-8-fluoro-1-oxo-4-propan-2-ylphthalazin-2-yl)-N-(5-fluoropyrimidin-4-yl)acetamide: To a solution of methyl 2-(6-bromo-8-fluoro-4-isopropyl-1-oxophthalazin-2(1H)-yl)acetate (216 mg, 0.60 mmol) in toluene (2.0 mL) and THF (2.0 mL) was added 5-fluoropyrimidin-4-amine (82 mg, 0.72 mmol) and AlMe3 (0.9 mL, 2 M in toluene). The reaction mixture was stirred at 90 °C for 3 h. The reaction mixture was diluted with water (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 reverse phase preparative HPLC. LCMS: m / z = 438.0, 440.0 [M+H] + 。 1 H NMR (400 MHz, CDCl3): δ 8.76 (s, 1H), 8.59 (br s, 1H), 8.50 (d, J = 2.0 Hz, 1H), 7.83 (s, 1H), 7.60 - 7.55 (m, 1H), 5.43 (s, 2H), 3.46 - 3.32 (m, 1H), 1.36 (d, J = 6.8 Hz, 6H).

[0717] Examples 93 and 94

[0718] 2-[6-Bromo-4-(difluoromethyl)-1-oxo-phthalazin-2-yl]-N-pyrimidin-2-yl-acetamide (93) and 2-[7-bromo-4-(difluoromethyl)-1-oxo-phthalazin-2-yl]-N-pyrimidin-2-yl-acetamide (94)

[0719]

[0720] Mixture of methyl 2-(6-bromo-1-oxo-4-vinylphthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-1-oxo-4-vinylphthalazin-2(1H)-yl)acetate: To a solution of methyl 2-(6-bromo-4-iodo-1-oxophthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-4-iodo-1-oxophthalazin-2(1H)-yl)acetate (1:1 mixture, 2.00 g, 4.73 mmol) in 1,4-dioxane (30 mL) was added potassium trifluoro(vinyl)borate (697 mg, 5.20 mmol), CsF (2.15 g, 14.2 mmol) and Pd(dppf)Cl2 (346 mg, 0.47 mmol). The reaction mixture was stirred at 90 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give a 1:1 mixture of methyl 2-(6-bromo-1-oxo-4-vinylphthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-1-oxo-4-vinylphthalazin-2(1H)-yl)acetate. LCMS: m / z = 323.1, 325.1 [M+H] + 。

[0721] Mixture of methyl 2-(6-bromo-4-formyl-1-oxophthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-4-formyl-1-oxophthalazin-2(1H)-yl)acetate: At 15 psi and -78 °C, a solution of methyl 2-(6-bromo-1-oxo-4-vinylphthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-1-oxo-4-vinylphthalazin-2(1H)-yl)acetate (1:1 mixture, 1.50 g, 4.64 mmol) in DCM (10 mL) and EtOAc (15 mL) was stirred in an ozone atmosphere for 0.5 h. Then Me2S (2.88 g, 46.4 mmol) was added to the reaction mixture and the reactants were stirred at 20 °C for an additional 16 h. The reaction mixture was diluted with water (20 mL) and extracted with DCM (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 which was used directly in the form of a 1:1 mixture of methyl 2-(6-bromo-4-formyl-1-oxophthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-4-formyl-1-oxophthalazin-2(1H)-yl)acetate. LCMS: m / z = 325.0, 327.0 [M+H] + 。

[0722] Methyl 2-(6-bromo-4-(difluoromethyl)-1-oxophthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-4-(difluoromethyl)-1-oxophthalazin-2(1H)-yl)acetate: A solution of BAST (3.03 g, 13.7 mmol) in a mixture of methyl 2-(6-bromo-4-formyl-1-oxophthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-4-formyl-1-oxophthalazin-2(1H)-yl)acetate (1:1 mixture, 300 mg, 0.92 mmol) was stirred at 20 °C for 6 h. The reaction mixture was poured into an aqueous Na2CO3 solution (2 N, 5 mL) and extracted with EtOAc (3 × 2 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 to give a 1:1 mixture of methyl 2-(6-bromo-4-(difluoromethyl)-1-oxophthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-4-(difluoromethyl)-1-oxophthalazin-2(1H)-yl)acetate. LCMS: m / z = 347.0, 349.0 [M+H] + 。

[0723] 2-(6-Bromo-4-(difluoromethyl)-1-oxophthalazin-2(1H)-yl)-N-(pyrimidin-2-yl)acetamide and 2-(7-bromo-4-(difluoromethyl)-1-oxophthalazin-2(1H)-yl)-N-(pyrimidin-2-yl)acetamide: To a solution of a mixture of methyl 2-(6-bromo-4-(difluoromethyl)-1-oxophthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-4-(difluoromethyl)-1-oxophthalazin-2(1H)-yl)acetate (1:1 mixture, 180 mg, 0.52 mmol) in toluene (1.0 mL) and THF (1.0 mL) was added pyrimidin-2-amine (99 mg, 1.04 mmol) and AlMe3 (0.78 mL, 2 M in toluene). The reaction mixture was stirred at 100 °C for 3 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 × 2 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 to give:

[0724] 2-[6-Bromo-4-(difluoromethyl)-1-oxo-phthalazin-2-yl]-N-pyrimidin-2-yl-acetamide: LCMS: m / z = 410.1, 412.1 [M+H] + 。 11H NMR (400 MHz, CDCl3): δ 8.78 (br s, 1H), 8.63 (d, J = 4.8 Hz, 2H), 8.38 - 8.31 (m, 2H), 7.97 - 7.91 (m, 1H), 7.08 - 7.04 (m, 1H), 6.61 (t, J = 53.6 Hz, 1H), 5.61 (s, 2H).

[0725] 2-[7-Bromo-4-(difluoromethyl)-1-oxo-phthalazin-2-yl]-N-pyrimidin-2-yl-acetamide: LCMS: m / z = 410.1, 412.0 [M+H] + 。 1 1H NMR (400 MHz, CDCl3): δ 9.06 (s, 1H), 8.67 - 8.62 (m, 3H), 8.09 - 8.03 (m, 1H), 8.01 - 7.96 (m, 1H), 7.08 - 7.03 (m, 1H), 6.61 (t, J = 53.6 Hz, 1H), 5.62 (s, 2H).

[0726] Examples 95 and 96

[0727] 2-[6-Bromo-4-(difluoromethoxy)-1-oxophthalazin-2-yl]-N-(5-fluoropyrimidin-4-yl)acetamide (95) and 2-[7-Bromo-4-(difluoromethoxy)-1-oxophthalazin-2-yl]-N-(5-fluoropyrimidin-4-yl)acetamide (96)

[0728]

[0729] 6-Bromo-4-(difluoromethoxy)-2-(4-methoxybenzyl)phthalazin-1(2H)-one and 7-bromo-4-(difluoromethoxy)-2-(4-methoxybenzyl)phthalazin-1(2H)-one: At 0 °C, TBAB (22 mg, 0.07 mmol) and NaH (66 mg, 1.66 mmol, 60% purity) were added to a solution of 6-bromo-4-hydroxy-2-(4-methoxybenzyl)phthalazin-1(2H)-one and 7-bromo-4-hydroxy-2-(4-methoxybenzyl)phthalazin-1(2H)-one (1:1 mixture, 500 mg, 1.38 mmol) in DMF (10 mL). The reaction mixture was stirred at 0 °C for 1 h. Then dibromo(difluoro)methane (1.20 g, 5.52 mmol) was added to the reaction mixture. The reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was poured into saturated aqueous NH4Cl (30 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 to give a 1:1 mixture of 6-bromo-4-(difluoromethoxy)-2-(4-methoxybenzyl)phthalazin-1(2H)-one and 7-bromo-4-(difluoromethoxy)-2-(4-methoxybenzyl)phthalazin-1(2H)-one. LCMS: m / z = 361.0, 363.0 [M+H] + 。

[0730] 6-Bromo-4-(difluoromethoxy)phthalazin-1(2H)-one and 7-bromo-4-(difluoromethoxy)phthalazin-1(2H)-one: CAN (200 mg, 0.36 mmol) was added to a solution of 6-bromo-4-(difluoromethoxy)-2-(4-methoxybenzyl)phthalazin-1(2H)-one and 7-bromo-4-(difluoromethoxy)-2-(4-methoxybenzyl)phthalazin-1(2H)-one (1:1 mixture, 50 mg, 0.12 mmol) in MeCN (5.0 mL) and water (1.0 mL). The reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was poured into saturated aqueous NaHCO3 (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 to give a 1.4:1 mixture of 6-bromo-4-(difluoromethoxy)phthalazin-1(2H)-one and 7-bromo-4-(difluoromethoxy)phthalazin-1(2H)-one. LCMS: m / z = 291.0, 293.0 [M+H] + 。

[0731] Methyl 2-(6-bromo-4-(difluoromethoxy)-1-oxophthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-4-(difluoromethoxy)-1-oxophthalazin-2(1H)-yl)acetate: To a solution of 6-bromo-4-(difluoromethoxy)phthalazin-1(2H)-one and 7-bromo-4-(difluoromethoxy)phthalazin-1(2H)-one (1.4:1 mixture; 70 mg, 0.24 mmol) in DMF (2.0 mL) was added methyl 2-bromoacetate (55 mg, 0.36 mmol) and Cs2CO3 (235 mg, 0.72 mmol). The reaction mixture was stirred at 50 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give a mixture of methyl 2-(6-bromo-4-(difluoromethoxy)-1-oxophthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-4-(difluoromethoxy)-1-oxophthalazin-2(1H)-yl)acetate (1.3:1). LCMS: m / z = 362.9, 364.9 [M+H] + .

[0732] 2-[6-Bromo-4-(difluoromethoxy)-1-oxophthalazin-2-yl]-N-(5-fluoropyrimidin-4-yl)acetamide and 2-(7-bromo-4-(difluoromethoxy)-1-oxophthalazin-2(1H)-yl)-N-(5-fluoropyrimidin-4-yl)acetamide: To a solution of methyl 2-(6-bromo-4-(difluoromethoxy)-1-oxophthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-4-(difluoromethoxy)-1-oxophthalazin-2(1H)-yl)acetate (1.3:1 mixture, 15 mg, 0.04 mmol) in toluene (5.0 mL) was added AlMe3 (0.06 mL, 2 M in toluene) and 5-fluoropyrimidin-4-amine (9 mg, 0.08 mmol). The reaction mixture was stirred at 90 °C for 5 h. The reaction mixture was poured into saturated aqueous NH4Cl (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 reverse-phase preparative HPLC to give a 1.7:1 mixture of 2-[6-bromo-4-(difluoromethoxy)-1-oxophthalazin-2-yl]-N-(5-fluoropyrimidin-4-yl)acetamide and 2-[7-bromo-4-(difluoromethoxy)-1-oxophthalazin-2-yl]-N-(5-fluoropyrimidin-4-yl)acetamide. LCMS: m / z = 444.0, 446.0 [M+H] + .

[0733] Examples 97 and 98

[0734] 2-[6-bromo-4-(2-fluoroethyl)-1-oxo-phthalazin-2-yl]-N-pyrimidin-2-yl-acetamide (97) and 2-[7-bromo-4-(2-fluoroethyl)-1-oxo-phthalazin-2-yl]-N-pyrimidin-2-yl-acetamide (98)

[0735]

[0736] Methyl 2-(4-allyl-6-bromo-1-oxophthalazin-2(1H)-yl)acetate and methyl 2-(4-allyl-7-bromo-1-oxophthalazin-2(1H)-yl)acetate: To a solution of a mixture of methyl 2-(6-bromo-4-iodo-1-oxophthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-4-iodo-1-oxophthalazin-2(1H)-yl)acetate (1:1 mixture, 1.50 g, 3.55 mmol) in 1,4-dioxane (20 mL) was added 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (656 mg, 3.90 mmol), K2CO3 (1.47 g, 10.6 mmol) and Pd(PPh3)4 (410 mg, 0.36 mmol). The reaction mixture was stirred at 120 °C for 3 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 × 8 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 to give a 1:1 mixture of methyl 2-(4-allyl-6-bromo-1-oxophthalazin-2(1H)-yl)acetate and methyl 2-(4-allyl-7-bromo-1-oxophthalazin-2(1H)-yl)acetate. LCMS: m / z = 337.1, 339.1 [M+H] + 。

[0737] Methyl 2-(6-bromo-1-oxo-4-(2-oxoethyl)phthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-1-oxo-4-(2-oxoethyl)phthalazin-2(1H)-yl)acetate: A solution of methyl 2-(4-allyl-6-bromo-1-oxophthalazin-2(1H)-yl)acetate and methyl 2-(4-allyl-7-bromo-1-oxophthalazin-2(1H)-yl)acetate (1:1 mixture, 1.00 g, 2.97 mmol) in DCM (20 mL) was stirred for 12 minutes at -78 °C under an ozone atmosphere at 15 psi. Then Me2S (2.95 g, 47.5 mmol) was added to the reaction mixture. The reaction mixture was stirred at 20 °C for 16 hours. The reaction mixture was diluted with water (20 mL) and extracted with DCM (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 to give a 1:1 mixture of methyl 2-(6-bromo-1-oxo-4-(2-oxoethyl)phthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-1-oxo-4-(2-oxoethyl)phthalazin-2(1H)-yl)acetate. LCMS: m / z = 339.0, 341.0 [M+H] + 。

[0738] Methyl 2-(6-bromo-4-(2-hydroxyethyl)-1-oxophthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-4-(2-hydroxyethyl)-1-oxophthalazin-2(1H)-yl)acetate: NaBH4 (112 mg, 2.95 mmol) was added to a solution of methyl 2-(6-bromo-1-oxo-4-(2-oxoethyl)phthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-1-oxo-4-(2-oxoethyl)phthalazin-2(1H)-yl)acetate (1:1 mixture, 1.00 g, 2.95 mmol) in THF (10 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 4 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 a 1:1 mixture of methyl 2-(6-bromo-4-(2-hydroxyethyl)-1-oxophthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-4-(2-hydroxyethyl)-1-oxophthalazin-2(1H)-yl)acetate. LCMS: m / z = 341.0, 343.0 [M+H] + 。

[0739] Methyl 2-(6-bromo-4-(2-fluoroethyl)-1-oxophthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-4-(2-fluoroethyl)-1-oxophthalazin-2(1H)-yl)acetate: A solution of BAST (130 mg, 0.59 mmol) in methyl 2-(6-bromo-4-(2-hydroxyethyl)-1-oxophthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-4-(2-hydroxyethyl)-1-oxophthalazin-2(1H)-yl)acetate (1:1 mixture, 200 mg, 0.59 mmol) was stirred at 20 °C for 16 h. The reaction mixture was diluted with saturated aqueous NaHCO3 (2 mL) and extracted with EtOAc (3 × 1 mL). The organic layer was washed with brine (2 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give a 1:1 mixture of methyl 2-(6-bromo-4-(2-fluoroethyl)-1-oxophthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-4-(2-fluoroethyl)-1-oxophthalazin-2(1H)-yl)acetate. LCMS: m / z = 343.0, 345.0 [M+H] + 。

[0740] 2-[6-Bromo-4-(2-fluoroethyl)-1-oxo-phthalazin-2-yl]-N-pyrimidin-2-yl-acetamide and 2-[7-bromo-4-(2-fluoroethyl)-1-oxo-phthalazin-2-yl]-N-pyrimidin-2-yl-acetamide: To a solution of methyl 2-(6-bromo-4-(2-fluoroethyl)-1-oxophthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-4-(2-fluoroethyl)-1-oxophthalazin-2(1H)-yl)acetate (1:1 mixture, 70 mg, 0.21 mmol) in toluene (1.0 mL) and THF (1.0 mL) was added pyrimidin-2-amine (39 mg, 0.41 mmol) and DABAL-Me3 (18 mg, 0.25 mmol). The reaction mixture was stirred at 100 °C for 3 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 × 2 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 HPLC to give a 2:3 mixture of 2-[6-bromo-4-(2-fluoroethyl)-1-oxo-phthalazin-2-yl]-N-pyrimidin-2-yl-acetamide and 2-[7-bromo-4-(2-fluoroethyl)-1-oxo-phthalazin-2-yl]-N-pyrimidin-2-yl-acetamide. LCMS: m / z = 406.0, 408.0 [M+H] + 。

[0741] Examples 99 and 100

[0742] 2-[6-bromo-4-(2,2-difluoroethyl)-1-oxophthalazin-2-yl]-N-pyrimidin-2-ylacetamide (99) and 2-[7-bromo-4-(2,2-difluoroethyl)-1-oxophthalazin-2-yl]-N-pyrimidin-2-ylacetamide (100)

[0743]

[0744] (E)-Methyl 2-(6-bromo-4-(2-ethoxyvinyl)-1-oxophthalazin-2(1H)-yl)acetate and (E)-methyl 2-(7-bromo-4-(2-ethoxyvinyl)-1-oxophthalazin-2(1H)-yl)acetate mixture: To a solution of methyl 2-(6-bromo-4-iodo-1-oxophthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-4-iodo-1-oxophthalazin-2(1H)-yl)acetate (1:1 mixture, 500 mg, 1.18 mmol) in 1,4-dioxane (8 mL) was added (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (234 mg, 1.18 mmol), Cs2CO3 (1.16 g, 3.55 mmol), and Pd(dppf)Cl2 (87 mg, 0.12 mmol). The reaction mixture was stirred at 100 °C for 6 h. The reaction mixture was diluted with water (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 to give a 1:1 mixture of (E)-methyl 2-(6-bromo-4-(2-ethoxyvinyl)-1-oxophthalazin-2(1H)-yl)acetate and (E)-methyl 2-(7-bromo-4-(2-ethoxyvinyl)-1-oxophthalazin-2(1H)-yl)acetate. LCMS: m / z = 367.0, 369.0 [M+H] + 。

[0745] Methyl 2-(6-bromo-1-oxo-4-(2-oxoethyl)phthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-1-oxo-4-(2-oxoethyl)phthalazin-2(1H)-yl)acetate: To a solution of (E)-methyl 2-(6-bromo-4-(2-ethoxyvinyl)-1-oxophthalazin-2(1H)-yl)acetate and (E)-methyl 2-(7-bromo-4-(2-ethoxyvinyl)-1-oxophthalazin-2(1H)-yl)acetate (1:1 mixture, 300 mg, 0.82 mmol) in THF (3.0 mL) was added aqueous HCl solution (1 M, 10 mL). The reaction mixture was stirred at 80 °C for 1 hour. The reaction mixture was diluted with water (10 mL), adjusted to pH = 6 with aqueous NaHCO3 solution (1 M), and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (6 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was used directly in the form of a 1:1 mixture of methyl 2-(6-bromo-1-oxo-4-(2-oxoethyl)phthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-1-oxo-4-(2-oxoethyl)phthalazin-2(1H)-yl)acetate. LCMS: m / z = 338.8, 340.9 [M+H] + .

[0746] A mixture of methyl 2-(6-bromo-4-(2,2-difluoroethyl)-1-oxophthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-4-(2,2-difluoroethyl)-1-oxophthalazin-2(1H)-yl)acetate: A solution of methyl 2-(6-bromo-1-oxo-4-(2-oxoethyl)phthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-1-oxo-4-(2-oxoethyl)phthalazin-2(1H)-yl)acetate (1:1 mixture, 100 mg, 0.30 mmol) in BAST (2.02 g, 9.13 mmol) was stirred at 20 °C for 16 hours. The reaction mixture was poured into saturated aqueous NaHCO3 solution (4 mL) and extracted with EtOAc (3 × 3 mL). The combined organic layers were washed with brine (4 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC to give a 1:1 mixture of methyl 2-(6-bromo-4-(2,2-difluoroethyl)-1-oxophthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-4-(2,2-difluoroethyl)-1-oxophthalazin-2(1H)-yl)acetate. LCMS: m / z = 360.9, 362.9 [M+H] + .

[0747] 2-[6-Bromo-4-(2,2-difluoroethyl)-1-oxophthalazin-2-yl]-N-pyrimidin-2-ylacetamide and 2-[7-bromo-4-(2,2-difluoroethyl)-1-oxophthalazin-2-yl]-N-pyrimidin-2-ylacetamide: Under N2, pyrimidin-2-amine (55 mg, 0.58 mmol) and AlMe3 (2 M in toluene, 0.29 mL) were added to a solution of methyl 2-(6-bromo-4-(2,2-difluoroethyl)-1-oxophthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-4-(2,2-difluoroethyl)-1-oxophthalazin-2(1H)-yl)acetate (1:1 mixture, 70 mg, 0.19 mmol) in toluene (1 mL) and THF (1 mL). The reaction mixture was stirred at 100 °C for 3 h. The mixture was diluted with water (5 mL) and extracted with EtOAc (3 × 2 mL). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC to give a 5:4 mixture of 2-[6-bromo-4-(2,2-difluoroethyl)-1-oxophthalazin-2-yl]-N-pyrimidin-2-ylacetamide and 2-[7-bromo-4-(2,2-difluoroethyl)-1-oxophthalazin-2-yl]-N-pyrimidin-2-ylacetamide. LCMS: m / z = 424.0, 426.0 [M+H] + 。

[0748] Examples 101 and 102

[0749] 2-(6-Bromo-4-(1-hydroxyethyl)-1-oxophthalazin-2(1H)-yl)-N-(pyrimidin-2-yl)acetamide

[0750] (101 and 102)

[0751]

[0752] Methyl 2-(6-bromo-4-(1-ethoxyvinyl)-1-oxophthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-4-(1-ethoxyvinyl)-1-oxophthalazin-2(1H)-yl)acetate: To a solution of methyl 2-(6-bromo-4-iodo-1-oxophthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-4-iodo-1-oxophthalazin-2(1H)-yl)acetate (1:1 mixture, 1.0 g, 2.36 mmol) in 1,4-dioxane (30 mL) were added tributyl(1-ethoxyvinyl)stannane (854 mg, 2.36 mmol), Pd(PPh3)4 (137 mg, 0.12 mmol), LiCl (301 mg, 7.09 mmol) and CuI (1.35 g, 7.09 mmol). The reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was poured into brine (50 mL) and extracted with EtOAc (3 × 30 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 to give a 1:1 mixture of methyl 2-(6-bromo-4-(1-ethoxyvinyl)-1-oxophthalazin-2(1H)-yl)acetate and methyl 2-(7-bromo-4-(1-ethoxyvinyl)-1-oxophthalazin-2(1H)-yl)acetate. LCMS: m / z = 336.9, 338.9 [M+H] + .

[0753] Methyl 2-(4-acetyl-6-bromo-1-oxophthalazin-2(1H)-yl)acetate and methyl 2-(4-acetyl-7-bromo-1-oxophthalazin-2(1H)-yl)acetate: To a solution of methyl 2-(6-bromo-4-(1-ethoxyv...

Claims

1. A compound of formula I: or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof, wherein: X is O or S; Y is O 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 is independently a halogen group, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 1-6 haloalkoxy or -SR 11 ; R 2 is - OR 11 ; R 4 is hydrogen; R 5 is C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein said C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted by one to eight Z 1 substituents; or R 4 and R 5 together form an optionally one to eight Z 1 substituted heterocyclic ring; R 6 is hydrogen or C 1-6 alkyl; R 7 is hydrogen; Each Z 1 is independently a halogen group, a cyano group, a C 1-6 alkyl group, a C 3-10 cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -OR 11 or -C(O)OR 11 ; wherein each C 1-6 alkyl group, heterocyclic group, aryl group or heteroaryl group is independently optionally substituted by one to five Z 1a substituents; Each R 11 is independently C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or heterocyclic group; wherein each C 11 of R 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or heterocyclic group is independently optionally substituted by one to five Z 1a substituents; Each Z 1a is independently a hydroxyl group, a halogen group, a cyano group, C 1-6 alkyl, C 3-10 cycloalkyl, -OR 13 or -C(O)OR 13 ; wherein each C 1-6 alkyl is independently optionally substituted with one to five Z 1b substituents; Each R 13 is independently C 1-6 alkyl; and Each Z 1b is independently a halogen group; provided that: When one of R 4 and R 5 is H, the other of R 4 and R 5 is not a C3 alkyl group optionally substituted with a piperazinyl ring substituted group.

2. The compound or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof according to claim 1, wherein A 1 , A 2 , A 3 and A 4 each independently is CH or CR 1 ; provided that at least one of A 1 , A 2 , A 3 and A 4 is CR 1 .

3. The compound or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof according to claim 1, wherein one of A 1 , A 2 , A 3 and A 4 is N; one of A 1 , A 2 , A 3 and A 4 is CR 1 ; and the remaining A 1 , A 2 , A 3 and A 4 are independently CH or CR 1 .

4. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof, wherein A 1 , A 2 , A 3 and A 4 are two Ns; one of A 1 , A 2 , A 3 and A 4 is CR 1 ; and the remaining A 1 , A 2 , A 3 and A 4 are CH or CR 1 .

5. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof, wherein R 6 is hydrogen or methyl.

6. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof, wherein R 5 is C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein said C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently optionally substituted by one to five Z 1 substituents.

7. The compound according to any one of claims 1 - 4, or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof, wherein R 4 together with R 5 forms a heterocyclic ring optionally substituted with one to eight Z 1 substituents.

8. A compound or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof as claimed in any one of claims 1 to 4, wherein R 2 is -OR 11 , wherein each R 11 is independently C 1a alkyl optionally substituted with one to five Z 1-6 groups.

9. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof, wherein: A 2 is CR 1 and A 1 、A 3 and A 4 are each independently N, CH or CR 1 。 10. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof, wherein: A 3 is CR 1 and A 1 、A 2 and A 4 are each independently N, CH or CR 1 。 11. A compound or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof, which is selected from Table 1: Table 1 12. A compound or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof, which is selected from Table 2: Table 2 13. A pharmaceutical composition, which comprises the compound according to any one of the foregoing claims, or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof, and a pharmaceutically acceptable carrier.

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