Methods of preparing NEK7 activity modulators

Abstract

The invention disclosed herein provides improved medium-scale and large-scale processes for the preparation of chemical entities (eg., a compound or a pharmaceutically acceptable salt thereof) that degrade and / or otherwise inhibit NIMA Related Kinase 7 (NEK7), and intermediates of said processes.

Description

[0001] METHODS OF PREPARING NEK7 ACTIVITY MODULATORS

[0002] FIELD OF THE INVENTION

[0003] The invention disclosed herein provides improved medium-scale and large-scale processes for the preparation of chemical entities (e.g., a compound or a pharmaceutically acceptable salt thereof) that degrade and / or otherwise inhibit NIMA Related Kinase 7 (NEK7).

[0004] BACKGROUND

[0005] The processes of the present invention are useful for the preparation of compounds (or pharmaceutically acceptable salts thereof) that degrade and / or otherwise modulate (e.g., inhibit) NIMA Related Kinase 7 (NEK7). Said compounds are useful, e.g., for treating a subject (e.g., a human subject) having one or more disorders or diseases associated with NLRP3 inflammasome activation. Said disorders or diseases include but are not limited to, autoinflammatory and autoimmune disorders (e.g., gout, inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis), neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson’s disease), cardiovascular and metabolic disorders (e.g. pericarditis, atherosclerosis, type 2 diabetes, obesity and metabolic syndrome), fibrotic disorders (e.g. interstitial lung disease, chronic kidney disease), haematology (e.g. anaemia of inflammation) and eye disorders (e.g. macular degeneration). It is believed that the chemical entities described herein directly target (e.g., directly bind to) NEK7, thereby altering (e.g., attenuating) the inflammatory response modulated by the NLRP3 inflammasome.

[0006] PCT / US2024 / 039292 discloses compounds that degrade and / or otherwise modulate (e.g., inhibit) NEK7. The compounds disclosed therein are according to Formula (I):

[0007]

[0008] or pharmaceutically acceptable salts thereof, and include in particular N-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)benzyl)-2-methyl-2-(5-methylpyrimidin-2-yl)propanamide. The process for synthesis of this compound is disclosed in Example 1 of PCT / US2024 / 039292. An overview of the synthesis of N-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)benzyl)-2-methyl-2-(5-methylpyrimidin-2-yl)propenamide, which is representative of the syntheses of compounds of Formula (I), is reproduced below.

[0009]

[0010] In the process disclosed above, the key benzylic amine intermediate (4) is obtained in a 7-step reaction sequence starting from 5-bromo-1,3-dichloro-2-methylbenzene. Key carboxylic acid intermediate (5), made in three steps from ethyl 2-(5-bromopyrimidin-2-yl)acetate, can be coupled with the key benzylic amine intermediate (4) to form compound 14. Other compounds of Formula (I) disclosed in PCT / US2024 / 039292 are prepared in an similar manner to that set out above for compound 14.

[0011] The processes of preparation of compounds of Formula (I) disclosed in PCT / US2024 / 039292 have several disadvantages. Specifically, these processes include the use of the following reagents: tetrachlorocarbon (a toxic perchlorinated solvent); trimethylsilyl cyanide (a potent poison that behaves equivalently to hydrogen cyanide); Pd2(dba)3(a scarce palladium catalyst); ethyl 2-(5-bromopyrimidin-2-yl)acetate as the starting material for key carboxylic acid intermediate (5) (scarcely available); and MeB(OH)2 (a potentially genotoxic reagent). Further, key intermediate carboxylic acid (5) shown above (and other equivalent intermediates in accordance with Formula (I) of PCT / US2024 / 039292) are unstable and rapidly degrade in solution via decarboxylation, and their ester precursors are oils and cannot be purified at scale. Lastly, many intermediates require purification via column chromatography, which is not feasible at scale.

[0012] There is therefore a need for a simple and cost-effective method for the production of compounds of Formula (I) of PCT / US2024 / 039292, particularly for methods which do not require the use of scarce or toxic reagents, or generate unstable intermediates, and which proceeds at higher yields than the previous route.

[0013] SUMMARY OF THE INVENTION

[0014] The present invention provides high yielding, cost-effective and commercially scalable methods which do not require the use of scarce or toxic reagents, and / or generate unstable intermediates, for the synthesis of a compound of Formula (I):o

[0015]

[0016] (I), or a pharmaceutically acceptable salt thereof. The present invention achieves this by providing compounds of Formulas (2) and (3):

[0017] HX'

[0018] (3)

[0019] O

[0020]

[0021] Compounds of Formulas (2) and (3) can be reacted together to provide an intermediate compound (a compound of Formula (4) described herein) which is a precursor of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0022] Use of toxic reagents may also be avoided in the present invention by providing a compound of Formula (p):

[0023]

[0024] The compound of Formula (p) can be used to provide an intermediate compound (a compound of Formula (q) described herein) which is useful for providing a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0025] Specifically, in a first aspect, the invention provides a process comprising reacting a compound of Formula (2) with a compound of Formula (3) to yield a compound of Formula (4):HX'

[0026] O

[0027]

[0028] (4) wherein:

[0029] R1, R2a, and R2bare defined according to (A) and (B) described herein;

[0030] X is H; or halo;

[0031] Yi and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH;

[0032] R3is H; C1-2 alkyl, which is optionally substituted with 1-5 fluoro; fluoro; chloro; or cyano;

[0033] R4is chloro; bromo; or fluoro; optionally wherein it is provided that R4is fluoro when R3is chloro;

[0034] R5is C1-6 alkyl;

[0035] R6is Cl or OM;

[0036] X’ is an anion and M is a cation.

[0037] In a second aspect, the invention provides a compound of Formula (2):

[0038] HX’

[0039] O

[0040]

[0041] wherein:

[0042] X is H; or halo;Yi and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH;

[0043] R3is H; C1-2 alkyl, which is optionally substituted with 1-5 fluoro; fluoro; chloro; or cyano;

[0044] R4is chloro; bromo; or fluoro; optionally wherein it is provided that R4is fluoro when R3is chloro;

[0045] X’ is an anion.

[0046] In a third aspect, the invention provides a compound of Formula (3):

[0047]

[0048] (3)

[0049] wherein:

[0050] R1, R2a, and R2bare defined according to (A) and (B) described herein;

[0051] R6is Cl or OM; and

[0052] M is a cation.

[0053] In a fourth aspect, the invention provides a process comprising reacting a compound of Formula (n) with a compound of Formula (0) to yield a compound of Formula (p):

[0054]

[0055] (n) (o) wherein:

[0056] X is H; or halo;

[0057] Y1 and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH;

[0058] R3is C1-2 alkyl, which is substituted with 1-5 fluoro; fluoro; chloro; or cyano;R4is chloro; bromo; or fluoro; optionally wherein it is provided that R4is fluoro when R3is chloro; R5is C1-6 alkyl;

[0059] R7is fluoro; or chloro if neither R3nor R4are fluoro; and

[0060] Lg is a leaving group.

[0061] In a fifth aspect, the invention provides compound of Formula (p):

[0062]

[0063] (P)

[0064] wherein:

[0065] X is H; or halo;

[0066] Yi and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH;

[0067] R3is C1-2 alkyl, which is substituted with 1-5 fluoro; fluoro; chloro;

[0068] R4is chloro; bromo; or fluoro; optionally wherein it is provided that R4is fluoro when R3is chloro; and

[0069] Lg is a leaving group.

[0070] BRIEF DESCRIPTION OF DRAWINGS FIG. 1A depicts caspase-1 activity in the supernatant following treatment of human monocyte-derived macrophages with different doses of Compound 14 or selnoflast measured as a percentage relative to mean values in DMSO.

[0071] FIG. 1 B depicts IL-1 activity in the supernatant following treatment of human monocyte-derived macrophages with different doses of Compound 14 or selnoflast measured as a percentage relative to mean values in DMSO.

[0072] FIG. 2A depicts NEK7 degradation in spleens and peripheral blood mononuclear cells (PBMC) as analyzed by JESS and normalized to a-Tubulin.

[0073] FIG. 2B depicts the degree of joint swelling in rabbits following injections of PBS, MSU crystals (50 mg / mL), Compound 16 (10 mg / kg), prednisolone (3 mg / kg) and selnoflast (10 mg / kg).

[0074] FIG. 2C depicts improvement in CD31 staining in bone tissue from rabbits treated with PBS, MSU crystals (50 mg / mL), Compound 16 (10 mg / kg), prednisolone (3 mg / kg) and selnoflast (10 mg / kg).DETAILED DESCRIPTION

[0075] Reaction of compounds of Formula (2) and (3) to yield a compound of Formula (4) Compounds of Formulas (2) and (3) can be reacted together to provide an intermediate compound (a compound of Formula (4) described herein) which is a precursor of the compound of Formula (I) and salts thereof. This reaction step provides high yielding, cost-effective and commercially scalable methods which do not require the use of scarce or toxic reagents, and / or generate unstable intermediates.

[0076] In a first aspect, the invention provides a process comprising reacting a compound of Formula (2) with a compound of Formula (3) to yield a compound of Formula (4):

[0077]

[0078] wherein:

[0079] R1, R2a, and R2bare defined according to (A) and (B) below:

[0080] (A)

[0081] R1is:

[0082] • heteroaryl including 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc;

[0083] • heterocyclyl including 4-6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc;

[0084] • C3-7 cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc;

[0085] • heterocycloalkenyl including 3-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc; or• C6-10aryl optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc; and

[0086] each of R2aand R2bis independently selected from the group consisting of:

[0087] • C1-2 alkyl optionally substituted with from 1-5 Ra;

[0088] • C3-5 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rb;

[0089] • C1-4 alkoxy;

[0090] • C1-4 haloalkoxy; or

[0091] • cyano; or

[0092] R2aand R2btaken together with the carbon atom to which each is attached forms:

[0093] • C3-7 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rb;

[0094] • heterocyclyl including 4-7 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl is optionally substituted with 1 -4 substituents independently selected from the group consisting of oxo and Rb;

[0095]

[0096] R1taken together with (i) the carbon atom to which it is attached and (ii) and one of R2aand R2bforms:

[0097] • C8-10aryl optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc; or

[0098] • heteroaryl including 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc; and

[0099] the other of R2aand R2bis C1-2 alkyl optionally substituted with from 1-5 Ra;

[0100] X is H; or halo;

[0101] Y1 and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH;

[0102] R3is H; C1-2 alkyl, which is optionally substituted with 1-5 fluoro; fluoro; chloro; or cyano;

[0103] R4is chloro; bromo; or fluoro; optionally wherein it is provided that R4is fluoro when R3is chloro; R5is C1-6 alkyl;

[0104] R6is a leaving group, for example, Cl, Br, I, OH, OM, O(C=O)(Ci-e alkyl), O(C=O)(N3), O(Ci-e alkyl), or S(Ci-6alkyl);each occurrence of Rais independently selected from the group consisting of: -OH; -halo; -NReRf; C1-4 alkoxy; C1-4 haloalkoxy,; -C(=O)O(Ci-4alkyl); -C(=O)(Ci-4alkyl); -C(=O)OH; -CONR’R”; -S(O)I-2NR’R”; -S(O)1-2(C1-4alkyl); and cyano;

[0105] each occurrence of Rbis independently selected from the group consisting of: halo; cyano; C1-10 alkyl which is optionally substituted with from 1-6 independently selected Ra; C2-6 alkenyl; C2-6 alkynyl; C1-4 alkoxy; -O(Ci-3 alkylene)-(C3-e cycloalkyl); C1-4 haloalkoxy; -S(0)o-2(Ci-4alkyl); -NReRf; -OH; -S(O)I-2NR’R”; -NO2; -C(=0)(Ci-io alkyl); -C(=O)O(Ci-4alkyl); -C(=O)OH; and -C(=O)NR’R”;

[0106] each occurrence of Rcis independently selected from the group consisting of:

[0107] • C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rb;

[0108] • heterocyclyl or heterocycloalkenyl including 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rb;

[0109] • heteroaryl including 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with from 1-4 Rb; and

[0110] • Ce-io aryl optionally substituted with from 1-4 Rb;

[0111] each occurrence of Rdis independently selected from the group consisting of: C1-6 alkyl optionally substituted with from 1-3 independently selected Ra; -C(O)(Ci-4 alkyl); -C(O)O(Ci-4 alkyl); -CONR’R”; -S(O)I-2NR’R”; -S(O)I-2(CI-4 alkyl); -OH; and Ci-4alkoxy; and

[0112] each occurrence of Reand Rfis independently selected from the group consisting of: H; C1-6 alkyl; -C(O)(Ci-4 alkyl); -C(O)O(Ci-4alkyl); -CONR’R”; -S(O)I-2NR’R”; -S(O)i-2(Ci-4 alkyl); -OH; and Ci-4alkoxy; and

[0113] each occurrence of R’ and R” is independently selected from the group consisting of: H; and C1-4 alkyl; and

[0114] X’ is an anion and M is a cation.

[0115] In some embodiments, R1, R2a, and R2bare defined according to (A1) and (B1).

[0116] In some embodiments, M is an alkali metal cation such as Li+, Na+, or K+, an alkali earth metal cation such as Ca2+, or Mg2+, an organic cation such as NH4+, or a protonated amine such as C1-4 alkyl-NH3+), preferably an alkali metal cation, more preferably Na+or K+; X’ is any suitable anion which corresponds to the conjugate base of a strong acid, such as HSO4-, SO42-, NO3-, Cl-or Br, preferably Cl-or Br; and R6is Cl, Br, I, OH, OM, O(C=O)(C1-6 alkyl), O(C=O)(N3), O(C1-6 alkyl), or S(C1-6 alkyl); preferably Cl, or OM.

[0117] In some embodiments, R3is H; C1-2 alkyl, which is optionally substituted with 1-5 fluoro; fluoro; chloro; or cyano; R4is chloro; bromo; or fluoro; Y1 and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH; R6is Cl, Br, I, OH, OM, O(C=O)(Ci-e alkyl), O(C=O)(N3), O(Ci-e alkyl), or S(Ci-e alkyl); M is an alkali metal cation such as Li+, Na+ or K+, an alkali earth metal cation such as Ca2+, or Mg2+, an organic cation such as NH4+, or a protonated amine such as C1-4 alkyl- NH3+), preferably an alkali metal cation, more preferably Na+ orK+; and X’ is any suitable anion which corresponds to the conjugate base of a strong acid, such as HSO4-, SO42-, NO3-, Cl-or Br-.

[0118] In some embodiments, R3is fluoro or chloro; R4is fluoro or chloro; Y1 and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH; X is H; R6is Cl, Br, I, OH, OM; M is an alkali metal cation, preferably Na+or K+; and X’ is any suitable anion which corresponds to the conjugate base of a strong acid, such as Ch or Br. In some embodiments, R3and R4are each independently chloro; Y1 and Y2 are each independently CH; X is H; and X’ is any suitable anion which corresponds to the conjugate base of a strong acid, such as Ch or Br.

[0119] Reaction conditions

[0120] The compounds of Formulas (2) and (3) may be reacted under any suitable conditions, for instance under amide coupling conditions. Amide bond formation is a cornerstone reaction in organic synthesis, widely employed in the preparation of pharmaceuticals. The skilled person is familiar with wide variety of amide coupling conditions that would be suitable for coupling the compounds of Formulas (2) and (3). For instance, a typical approach might involve the activation of a carboxylic acid in the presence of an amine to form the desired amide.

[0121] The compounds of Formulas (2) and (3) may be reacted in the presence of a base and a solvent. In a further embodiment, the compounds of Formulas (2) and (3) may be reacted in the presence of a base, a solvent, and a coupling agent or an additive. In a further embodiment, the compounds of Formulas (2) and (3) may be reacted in the presence of a base, a solvent, a coupling agent and an additive.

[0122] Any suitable solvent may be used. The solvent may be water. The solvent may be a polar aprotic solvent. The solvent may be selected from ethyl acetate, DCM, DMF, THF, DMA, NMP, 2-MeTHF, and combinations thereof. Any suitable base may be used but typically the base is an amine. The amine may be selected from N, N-diisopropylethylamine, Et3N, pyridine and combinations thereof. The amine may be EteN.

[0123] The compounds of Formulas (2) and (3) may be reacted in the presence of a coupling reagent. Any suitable coupling reagent may be used.

[0124] The compounds of Formulas (2) and (3) may be reacted in the presence of a carbodiimide coupling reagent, a uranium-imonium reagent, T3P (1-propylphosphonic acid cyclic anhydride), T4P (1-butylphosphonic acid cyclic anhydride), thionyl chloride, oxalyl chloride, mukaiyama reagent, a preactivated ester such as NHS or PNP esters, or combinations thereof.

[0125] The carbodiimide coupling reagent may be selected from dicyclohexylcarbodiimide, (DCC), diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), a hydrochloride salt of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and combinations thereof.

[0126] The uranium-imonium reagent may be selected from HATU (O-(7-Azabenzotriazol-1-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate), HBTU (O-Benzotriazol-1-yl-N, N, N', N'-tetramethyluronium hexafluorophosphate), TBTU (O-(Benzotriazol-1-yl)-N, N, N', N'-tetramethyluronium tetrafluoroborate), TSTU (N, N, N', N'-Tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate), HCTU (O-(6-Chlorobenzotriazol-1-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate), PyClock (O-(6-Chlorobenzotriazol-1-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate), COMU (1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate), PyBOP (Benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate), PyAOP (7-Azabenzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate) and combinations thereof.The compounds of Formulas (2) and (3) may be reacted in the presence of an additive. Any suitable additive may be used. The additive may be selected from HOBt (1 -Hydroxybenzotriazole), HOOBt (HODhbt) (Hydroxy-3, 4-dihydro-4-oxo-1,2, 3-benzo-triazine), HOSu (N-Hydroxysuccinimide), HOAt (1-Hydroxy-7-aza-1 H-benzotriazole), Ethyl 2-cyano-2-(hydroximino)acetate, DMAP (4-(N, N-Dimethylamino)pyridine) and combinations thereof.

[0127] In some embodiments, the coupling agent is a carbodiimide coupling reagent, a uranium-imonium reagent, T3P (1-propylphosphonic acid cyclic anhydride), T4P (1-butylphosphonic acid cyclic anhydride), thionyl chloride, oxalyl chloride, mukaiyama reagent, or a preactivated ester such as NHS or PNP esters, and the additive is HATU, HBTU, TBTU, TSTU, HCTU, PyClock, COMU, PyBOP, or PyAOP. In some embodiments, the coupling agent is a carbodiimide coupling reagent such as EDC, DCC, or DIC, and the additive is HATU, HBTU, TBTU, TSTU, HCTU.

[0128] The compounds of Formulas (2) and (3) may be reacted at any suitable temperature. For instance the temperature may be 0-50°C. The compounds of Formulas (2) and (3) may be reacted at a temperature of 0-25°C. The compounds of Formulas (2) and (3) may be reacted at a temperature of 20-30°C. The compounds of Formulas (2) and (3) may be reacted at a temperature of 20-25°C.

[0129] In a preferred embodiment, the compounds of Formulas (2) and (3) may be reacted in the presence of T4P, Et3N and EtOAc, optionally at a temperature of 20-25°C.

[0130] The skilled person would understand that nature of the amide coupling may depend on the specific nature of the starting materials (2) and (3). For instance, where R6is selected such that Formula (3) defines an “activated” carboxylic acid (e.g. an acyl halide, an acid anhydride, an ester, etc., the reaction may proceed under mild conditions (e.g. at room temperature or below and optionally in the presence of an amine base). The presence of a coupling agent and / or additive may not be required.

[0131] Preparation of compounds of Formula (5)

[0132] The first aspect the invention may further comprise the step of reacting the compound of Formula (4) with acrylonitrile to provide a compound of Formula (5):

[0133]

[0134] wherein R1, R2a, and R2bmay be defined according to (A1) and (B1) described herein, and wherein Y1, Y2, R3, and R4 are defined as per compounds (2) and (3).Reaction conditions

[0135] The compound of Formula (5) may be prepared from the compound of Formula (4) by any suitable method, for instance conditions suitable for a Michael addition reaction. For instance, the compound of Formula (5) can be prepared by reacting the compound of Formula (4) with acrylonitrile in the presence of a base and a solvent.

[0136] Any suitable base may be used. For example, the base may be an amine or an inorganic base. The base may be selected from NaOMe, LiOMe, NaOEt, LiOEt, NaOtBu, LiOtBu, KOMe, KOEt, KOtBu, LiHMDS, NaHMDS, KHMDS, NaH, LiH, KH, DBU (1,8-diazabicyclo(5.4.0)undec-7-ene) or DBN (1,5-diazabicyclo(4.3.0)non-5-ene) and combinations thereof. The base may be KOtBu. Any suitable solvent may be used. The solvent may be an aprotic polar solvent. The solvent may comprise MeCN and / or THF. The solvent may comprise MeCN: THF in a ratio of from 1:0 to 0:1. The solvent may further comprise BHT (butylated hydroxytoluene) when no THF is present. The solvent may comprise MeCN: THF in a ratio of 2:3. The solvent may comprise BHT. The compound of Formula (4) and acrylonitrile may be reacted at a temperature of 0-5°C.

[0137] In a preferred embodiment, ethe compound of Formula (4) and acrylonitrile may be reacted in the presence of KOtBu and MeCN: THF 2:3, optionally at a temperature of 0-5°C.

[0138] Reactions of compounds of Formula (5)

[0139] In the first aspect the invention may further comprise the step of converting the compound of Formula (5) into a compound of Formula (6):

[0140]

[0141] wherein R1, R2a, and R2bmay be defined according to (A1) and (B1) described herein, and wherein Yi, Y2, R3, and R4 are defined as per compounds (2) and (3).

[0142] Reaction conditions

[0143] The compound of Formula (5) may be converted into the compound of Formula (6) by any suitable method, for instance under hydrolytic conditions. For instance, the compound of Formula (5) may be converted into the compound of Formula (6) in the presence of an acid and a solvent. Any suitable solvent may be used. The solvent may be a polar, high boiling point solvent. The high boiling point solvent may have a boiling point of 80°C or higher. The high boiling point solvent may have a boiling point of 100°C or higher. Thesolvent may be selected from toluene, formic acid, acetic acid, propionic acid, isobutyric acid or benzoic acid and combinations thereof. The solvent may be acetic acid. Any suitable acid may be used. The acid may be an organic acid or a mineral acid. In some embodiments, the acid may be selected from H2SO4, p-toluenesulfonic acid or methanesulfonic acid, and combinations thereof. The acid may be p-toluenesulfonic acid and / or methanesulfonic acid. The acid may be H2SO4.

[0144] The compound of Formula (5) may be converted into the compound of Formula (6) at a temperature of 80-140°C. The compound of Formula (5) may be converted into the compound of Formula (6) at a temperature of 115-120°C. The compound of Formula (5) may be converted into the compound of Formula (6) at a temperature of 80-100°C (preferably 80-90°C).

[0145] In a preferred embodiment, the compound of Formula (5) may be converted into the compound of Formula (6) in the presence of H2SO4, AcOH, optionally at a temperature of 80-90°C.

[0146] R5may be ‘Bu. In this situation, in the first aspect the invention may further comprise the step of converting the compound of Formula (5) into a compound of Formula (I). The compound of Formula (5) may be converted into the compound of Formula (I) by any suitable means, for instance a cyclisation reaction in the presence of acid and a solvent. Any suitable acid may be used. The acid may be an organic acid. In some embodiments the acid may be selected from p-toluenesulphonic acid, methanesulfonic acid and combinations thereof. Any suitable solvent may be used. The solvent may be selected from organic apolar solvents such as xylene, toluene and combinations thereof.

[0147] Preparing compounds of Formula (I) from compounds of Formula (6)

[0148] In the first aspect, the invention may further comprise the step of converting the compound of Formula (6) into a compound of Formula (I), under any suitable conditions, for instance by conditions suitable for a glutarimide formation. The compound of Formula (6) may be converted into the compound of Formula (I) in the presence of a base and a solvent. Any suitable base may be used. The base may be an inorganic base or a superbase. The base may be selected from LiHMDS, NaHMDS, KHMDS, NaH, KH and combinations thereof. The base may be LiHMDS. Any suitable solvent may be used. The solvent may be an aprotic, polar solvent. The aprotic, polar solvent may be water-free. The solvent may be selected from DMF, DMA, Me-THF, MeCN, NMP and combinations thereof.

[0149] The compound of Formula (6) may be converted into the compound of Formula (I) at a temperature of 40-50°C.

[0150] In a preferred embodiment, the compound of Formula (6) may be converted into the compound of Formula (I) in the presence of LiHMDS and THF, optionally at a temperature of 40-50°C.

[0151] Compounds of Formula (2)

[0152] In a second aspect, the invention provides compound of Formula (2):HX'

[0153] O

[0154]

[0155] (2)

[0156] wherein

[0157] X is H; or halo;

[0158] Yi and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH;

[0159] R3is H; C1-2 alkyl, which is optionally substituted with 1-5 fluoro; fluoro; chloro; or cyano;

[0160] R4is chloro; bromo; or fluoro; optionally wherein it is provided that R4is fluoro when R3is chloro; and

[0161] X’ is an anion.

[0162] In any aspect involving it, the compound of Formula (2) may be a compound wherein:

[0163] R3is H; C1-2 alkyl, which is optionally substituted with 1-5 fluoro; fluoro; chloro; or cyano;

[0164] R4is chloro; bromo; or fluoro;

[0165] Y1 and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH.

[0166] X’ is any suitable anion which corresponds to the conjugate base of a strong acid. For example, X’ may be HSO4-, SO42-, NO3-, Cl- or Br- in any aspect involving it, the compound of Formula (2) may be a compound wherein:

[0167] R3is fluoro or chloro;

[0168] R4is fluoro or chloro;

[0169] X is H;

[0170] Y1 and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH.

[0171] X’ is any suitable anion which corresponds to the conjugate base of a strong acid. For example, X’ may be Ch or Br.

[0172] In any aspect involving it, the compound of Formula (2) may be a compound wherein:

[0173] R3and R4are each independently chloro;X is H;

[0174] Yi and Y2 are each independently CH;

[0175] X’ is any suitable anion which corresponds to the conjugate base of a strong acid. For example, X’ may be Ch or Br.

[0176] Any of these compounds of Formula (2) may be reacted with any compound of Formula (3).

[0177] Preparing compounds of Formula (2)

[0178] The compound of Formula (2) may be prepared by a process comprising the steps:

[0179] (a) reacting a compound of Formula (a) with a compound of Formula (b) to yield a compound of Formula (c):

[0180] CN

[0181] O O

[0182]

[0183] (C) (b) converting the compound of Formula (c) into a compound of Formula (d):

[0184]

[0185] (c) (d)

[0186] (c) converting the compound of Formula (d) into a compound of Formula (e):

[0187] (d)(e)and / or

[0188]

[0189] (d) converting the compound of Formula (e) into the compound of Formula (2);

[0190] wherein:

[0191] R3is H; C1-2 alkyl, which is substituted with 1-5 fluoro; fluoro; chloro; or cyano;

[0192] R4is chloro; bromo; or fluoro; optionally wherein it is provided that R4is fluoro when R3is chloro; R7is fluoro; or chloro if neither R3nor R4are fluoro;

[0193] R5and R5’ are independently Ci-s alkyl;

[0194] Pg is a protecting group.

[0195] In some embodiments, R3is H; C1-2 alkyl, which is optionally substituted with 1-5 fluoro; fluoro; chloro; or cyano; R4is chloro; bromo; or fluoro; Y1 and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH. X’ is any suitable anion which corresponds to the conjugate base of a strong acid. For example, X’ may be HSO4-, SO42-, NO3-, Cl- or Br-.

[0196] In some embodiments, R3is fluoro or chloro; R4is fluoro or chloro; Y1 and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH, X’ is any suitable anion which corresponds to the conjugate base of a strong acid. For example, X’ may be Cl- or Br.

[0197] In some embodiments R3and R4are each independently chloro; Y1 and Y2 are each independently CH; X’ is any suitable anion which corresponds to the conjugate base of a strong acid. For example, X’ may be Cl- or Br.

[0198] In these embodiments, R7is preferably may be fluoro.

[0199] In these embodiments, Pg may be any suitable amine protecting group, preferably Boc.

[0200] Reaction conditions

[0201] a) Preparing a compound of Formula (c) from compounds of Formulas (a) and (b).

[0202] The compound of Formula (a) may be reacted with the compound of Formula (b) to yield a compound of formula (c) under any suitable conditions, for instance under conditions suitable for nucleophilic aromatic substitution. Suitable conditions include the presence of a base and a solvent. Any suitable base may be used, for instance an inorganic base or a superbase. For instance, the base may be selected from CsCO3, K2CO3 Na2CO3, K3PO4, DBU, DBN, LiHMDS, NaHMDS, KHMDS and combinations thereof. The base may be K2CO3. Any suitable solvent may be used. The solvent may be a high boiling point polar aprotic solvent. The high boiling point polar aprotic solvent may have a boiling point of 80°C or higher. The high boiling point polar aprotic solvent may have a boiling point of 100°C or higher. The solvent may be selected from DMA, DMF, NMP, 1,4-Dioxane and combinations thereof. The solvent may be DMF. The compound of Formula (a) may be reacted with the compound of Formula (b) at a temperature of 50 -120 °C. The compound of Formula (a) may be reacted with the compound of Formula (b) at a temperature of 50 - 100 °C. The compound of Formula (a) may be reacted with the compound of Formula (b) at a temperature of 55 - 80 °C. The compound of Formula (a) may be reacted with the compound of Formula (b) at a temperature of 60-70 °C.The compound of Formula (a) may be reacted with the compound of Formula (b) for a duration of 30 minutes – 48 hours. The compound of Formula (a) may be reacted with the compound of Formula (b) for a duration of 1 hour – 24 hours. The compound of Formula (a) may be reacted with the compound of Formula (b) for a duration of 4 hours.

[0203] Preferably, the compound of Formula (a) may be reacted with the compound of Formula (b) in step a) in the presence of K2CO3 and DMF, optionally at a temperature of 60 °C for a duration of 4 hours.

[0204] b) Conversion of the compound of Formula (c) into the compound of Formula (d)

[0205] The compound of Formula (d) may be prepared from a compound of Formula (c) by any suitable conditions, for instance under decarboxylation conditions. For instance, the compound of Formula (c) may be converted into the compound of Formula (d) in step b) in the presence of a catalyst and a solvent. Any suitable catalyst may be used. The catalyst may a catalyst for use in a Krapcho decarboxylation. The catalyst may be selected from NaCN, KCN, LiCI, NaCI, NaBr, Nal, LiI·H2O, Na2CO3·H2O, Na3PO4·12H2O Me4NOAc and combinations thereof. The catalyst may be LiCI. Any suitable solvent may be used. The solvent may be a polar, aprotic solvent. The solvent may be selected from DMSO, DMF, DMA and combinations thereof. The solvent may be DMSO. Preferably, the solvent comprises a polar, aprotic solvent and a polar, protic solvent. Preferably, the polar, aprotic solvent is selected from DMSO, DMF, DMA, THF and combinations thereof and the polar, protic solvent is selected from water, an alcohol, a carboxylic acid, an amine and combinations thereof. Preferably, the solvent comprises THF and water. The solvent may comprise water:THF in a ratio of from 1:10 to 1:250. The solvent may comprise water:THF in a ratio of from 1:20 to 1:100. The solvent may comprise water:THF in a ratio of from 1:25 to 1:75. Preferably, the solvent comprises water:THF in a ratio of 1:50.

[0206] The compound of Formula (c) may be converted into the compound of Formula (d) in step b) at a temperature of 90 -165 °C. The compound of Formula (c) may be converted into the compound of Formula (d) in step b) at a temperature of 95 -125 °C. The compound of Formula (c) may be converted into the compound of Formula (d) in step b) at a temperature of 95-105°C. Preferably, the compound of Formula (c) is converted into the compound of Formula (d) in step b) at a temperature of 100 -160 °C. More preferably, the compound of Formula (c) is converted into the compound of Formula (d) in step b) at a temperature of 130 -150 °C. Most preferably, the compound of Formula (c) is converted into the compound of Formula (d) in step b) at a temperature of 134 -140 °C.

[0207] Preferably, the compound of Formula (c) is converted into the compound of Formula (d) in step b) under a pressure of 1-10 MPa. More preferably, the compound of Formula (c) is converted into the compound of Formula (d) in step b) under a pressure of 2-5 MPa. Even more preferably, the compound of Formula (c) is converted into the compound of Formula (d) in step b) under a pressure of 3-4 MPa. Most preferably, the compound of Formula (c) is converted into the compound of Formula (d) in step b) under a pressure of 3.5 MPa.

[0208] Preferably, the compound of Formula (c) is converted into the compound of Formula (d) in step b) under flow conditions.

[0209] Preferably, the compound of Formula (c) is converted into the compound of Formula (d) in step b) under flow conditions using a residence time of from 1 minute to 2 hours. More preferably, the compound of Formula (c) is converted into the compound of Formula (d) in step b) under flow conditions using a residence time of from 10 minutes to 1 hour. Even more preferably, the compound of Formula (c) is converted into the compound of Formula (d) in step b) under flow conditions using a residence time of from 15 minutes to 40 minutes. Most preferably, the compound of Formula (c) is converted into the compound of Formula (d) in step b) under flow conditions using a residence time of 25 minutes.The compound of Formula (c) may be converted into the compound of Formula (d) in step b) for a duration of 30 minutes - 36 hours. The compound of Formula (c) may be converted into the compound of Formula (d) in step b) for a duration of 2 hours - 24 hours. The compound of Formula (c) may be converted into the compound of Formula (d) in step b) for a duration of 12 hours.

[0210] Preferably, the compound of Formula (c) may be converted into the compound of Formula (d) in step b) in the presence of LiCI, DMSO and water, optionally at a temperature of 95-105°C for a duration of 12 hours.

[0211] More preferably, the compound of Formula (c) is converted into the compound of Formula (d) in step b) in the presence of LiCI, THF and water, optionally at a temperature of 135-140°C, a pressure of 3.5MPa and under flow conditions using a residence time of 25 minutes.

[0212] c) Conversion of the compound of Formula (d) into the compound of Formula (e)

[0213] The compound of formula (e) may be prepared from a compound of formula (d) under any suitable conditions, for instance under nitrile-selective reducing conditions and amine protecting conditions. For instance, the compound of Formula (d) may be converted into the compound of Formula (e) in step c) in the presence of a reducing agent, a catalyst, a reagent for introducing a protecting group and one or more solvents.

[0214] Any suitable reducing agent and catalyst may be used. The catalyst may be a metal catalyst or an organocatalyst. Any suitable reducing agent may be used. The reducing agent may be a hydride reducing agent. The reducing agent and catalyst may be NaBFL and C0CI2, Raney-Ni and H2, or Pd / C and H2. The reagent for introducing a protecting group may be a reagent for introducing any suitable amine protecting group, for example Boc. The reagent for introducing Boc may be (Boc)2O or N-Boc-Benzotriazole. Any suitable solvent(s) may be used. The one or more solvents may be polar protic solvents or polar aprotic solvents. The one or more solvents selected from MeOH, EtOH, PrOH, BuOH, THF, DMF, MTBE 1,4-dioxane, and acetone. The compound of Formula (d) may be converted into the compound of Formula (e) in step c) in the presence two solvents. In this case, the first solvent may be a polar protic solvent, and the second solvent may be a polar aprotic solvent. The two solvents may be EtOH and THF.

[0215] The compound of Formula (d) may be converted into the compound of Formula (e) in step c) at a temperature of from -20 to 40°C. The compound of Formula (d) may be converted into the compound of Formula (e) in step c) at a temperature of from -10 to 25°C.

[0216] The compound of Formula (d) may be converted into the compound of Formula (e) in step c) for a duration of 30 minutes to 36 hours. The compound of Formula (d) may be converted into the compound of Formula (e) in step c) for a duration of 1-6 hours. The compound of Formula (d) may be converted into the compound of Formula (e) in step c) for a duration of 1 hour.

[0217] In a preferred embodiment, the compound of Formula (d) may be converted into the compound of Formula (e) in step c) in the presence of NaBH4, C0CI2, (Boc)2O, EtOH and THF, optionally at a temperature of from -10 to 25°C, for a duration of 1 hour.

[0218] d) Conversion of the compound of Formula (e) into the compound of Formula (2)

[0219] The compound of Formula (2) may be prepared from an intermediate compound of Formula (e). This conversion may take place via any suitable conditions, for instance under amine deprotection conditions. For instance, the compound of Formula (e) may be converted into the compound of Formula (2) in step d) above, in the presence of an acid and a solvent. Any suitable acid may be used. The acid may be an organic acid or a mineral acid. The acid may be selected from TFA, HCI, H2SO4, acetic acid, TsOH,Amberlyst 15 and combinations thereof. The acid may be HCI. The acid may be HCI which is generated in situ by using AcCI in EtOH or TMSCI in MeOH. Any suitable solvent may be used. The solvent may be a polar, aprotic solvent. The solvent may be selected from DCM, MeCN, DMF, THF, MeOH, EtOH, 1,4-dioxane, iPrOAc, 2-MeTHF, DMA, CPME, EtOAc, water and combinations thereof. The solvent may be EtOAc.

[0220] The compound of Formula (e) may be converted into the compound of Formula (2) in step d) at a temperature of 0 to 50 °C. The compound of Formula (e) may be converted into the compound of Formula (2) in step d) at a temperature of 15 to 25 °C. Preferably, the compound of Formula (e) is converted into the compound of Formula (2) in step d) at a temperature of 40 to 50 °C. The compound of Formula (e) may be converted into the compound of Formula (2) in step d) for a duration of 15 minutes to 18 hours. The compound of Formula (e) may be converted into the compound of Formula (2) in step d) for a duration of 1 hour. Preferably, compound of Formula (e) is converted into the compound of Formula (2) in step d) for a duration of 2 ~ 3 hours.

[0221] Preferably, the compound of Formula (e) may be converted into the compound of Formula (2) in step d) in the presence of HCI and EtOAc, optionally at a temperature of 15 to 25 °C for a duration of 1 hour.

[0222] More preferably, the compound of Formula (e) may be converted into the compound of Formula (2) in step d) in the presence of HCI and EtOAc, optionally at a temperature of 40 to 50 °C for a duration of 2 ~ 3 hours.

[0223] Compounds of Formula (3)

[0224] In a third aspect, the invention provides a compound of Formula (3):

[0225]

[0226] wherein:

[0227] R1, R2a, and R2bare defined according to (A) and (B) as described herein;

[0228] R6is a leaving group, for example, Cl, Br, I, OH, OM, O(C=O)(Ci-e alkyl), O(C=O)(N3), O(Ci-e alkyl), or S(Ci-6alkyl); and

[0229] M is a cation.

[0230] In any aspect involving it, the compound of Formula (3) may be a compound wherein M is an alkali metal cation such as Li+, Na+, or K+, an alkali earth metal cation such as Ca2+, or Mg2+, an organic cation such as NH4+, or a protonated amine such as C1-4 alkyl-NH3+), preferably an alkali metal cation, morepreferably Na+or K+; X’ is any suitable anion which corresponds to the conjugate base of a strong acid, such as HSO4-, SO42-, NO3-, Cl-or Br, preferably Cl-or Br; and R6is Cl, Br, I, OH, OM, O(C=O)(Ci-e alkyl), O(C=O)(N3), O(CI-6alkyl), or S(Ci-6alkyl); preferably Cl, or OM.

[0231] In any aspect involving it, the compound of Formula (3) may be a compound wherein:

[0232] R1, R2a, and R2bare defined according to (A1);

[0233] R1is any R1defined according to (A1);

[0234] R2aand R2bare each independently C1-2 alkyl optionally substituted with from 1-5 Ra;

[0235] M may be an alkali metal cation such as Li+, Na+or K+, alkali earth metal cations such as Ca2+, or Mg2+, organic cations such as NH4+, or protonated amines such as (C1-4 alkyl-NH3+). Preferably, M is an alkali metal cation, more preferably Na+or K+.

[0236] In any aspect involving it, the compound of Formula (3) may be a compound wherein:

[0237] R1, R2a, and R2bare defined according to (A)

[0238] R1is heteroaryl including 5-6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N and O, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc;

[0239] R2aand R2bare each independently C1-2 alkyl optionally substituted with from 1-5 Ra;

[0240] M may be an alkali metal cation such as Li+, Na+or K+, alkali earth metal cations such as Ca2+, or Mg2+, organic cations such as NH4+, or protonated amines such as (C1-4 alkyl-NH3+). Preferably, M is an alkali metal cation, more preferably Na+or K+.

[0241] In any aspect involving it, the compound of Formula (3) may be a compound wherein:

[0242] R1has the formula:

[0243] N

[0244] N

[0245]

[0246] -A), wherein Rn is methyl.

[0247] R2aand R2bare each independently methyl;

[0248] R3and R4are each independently chloro;

[0249] Y1 and Y2 are each independently CH.

[0250] M is an alkali metal cation, preferably Na+ or K+.

[0251] Any of these compounds of Formula (3) may be reacted with any compound of Formula (2).Preparing compounds of Formula (3)

[0252] The compound of Formula (3) may be prepared by a process comprising the steps:

[0253] a) reacting a compound of Formula (f) with a compound of Formula (g) to yield a compound of Formula (h):

[0254] R8O^^R1HaK CN

[0255]

[0256] (h)

[0257] b) converting the compound of Formula (h) into a compound of Formula (i):

[0258] J

[0259]

[0260] / CN - - C rNR1

[0261] (h) (') c) converting the compound of Formula (i) into a compound of Formula (j):

[0262] ^R1R^R1

[0263] CNNCR2b

[0264]

[0265] ; and / or d) converting the compound of Formula (j) into the compound of Formula (3).

[0266] wherein:

[0267] R1, R2aand R2bare defined according to (A) and (B)

[0268] R8is C1-6 alkyl or C3-5 cycloalkyl; and

[0269] Hal is a halogen, e.g. F, Cl, Br or I, preferably Cl.

[0270] In some embodiments, R1, R2aand R2bare defined according to (A1) and (B1).

[0271] In some embodiments, R1, R2a, and R2bare defined according to (A1), R1is any R1defined according to (A1); R2aand R2bare each independently C1-2 alkyl optionally substituted with from 1-5 Ra; M may be an alkali metal cation such as Li+, Na+or K+, alkali earth metal cations such as Ca2+, or Mg2+, organic cations such as NH4+, or protonated amines such as (C1-4 alkyl-NH3+). Preferably, M is an alkali metal cation, more preferably Na+or K+.

[0272] In some embodiments, R1, R2a, and R2bare defined according to (A1), R1is heteroaryl including 5-6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N and O, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc; R2aand R2bare each independently C1-2 alkyloptionally substituted with from 1-5 Ra; M may be an alkali metal cation such as Li+, Na+or K+, alkali earth metal cations such as Ca2+, or Mg2+, organic cations such as NH4+, or protonated amines such as (C1-4 alkyl-NH3+). Preferably, M is an alkali metal cation, more preferably Na+or K+.

[0273] X3^

[0274] X2

[0275] In some embodiments, R1has the formula:

[0276]

[0277] (Hl(III-A); wherein each of Xi, X2, X3, and X4 is, independently, CH or N; and R11is H, Rb, or Rc; R2aand R2bare each independently C1-2 alkyl; M is an alkali metal cation, preferably Na+or K+.

[0278] N

[0279] In some embodiments, R1has the formula: N

[0280]

[0281] -A), wherein Rn is methyl.

[0282] R2aand R2bare each independently methyl; R3and R4are each independently chloro; Y1 and Y2 are each independently CH; M is an alkali metal cation, preferably Na+or K+.

[0283] In these embodiments, R8may be Me, Et or ‘Bu. R8may be Me. R8may be Et. Preferably, R8is ‘Bu. Reaction conditions

[0284] a) reacting a compound of Formula (f) with a compound of Formula (g) to yield a compound of Formula (h)

[0285] The compound of Formula (f) may be reacted with the compound of Formula (g) in step a) under any suitable conditions, for instance under nucleophilic substitution conditions. For instance, the compound of Formula (f) may be reacted with the compound of Formula (g) in the presence of a base and a solvent to yield the compound of Formula (h). The base may be selected from CsCO3, Na2CO3, K2CO3, DBU, DBN, LiHMDS, NaHMDS, KHMDS, K3PO4 and combinations thereof. The base may be K3PO4. The solvent may be a high boiling point polar aprotic solvent. The high boiling point polar aprotic solvent may have a boiling point of 80°C or higher. The high boiling point polar aprotic solvent may have a boiling point of 100°C or higher. The solvent may be selected from DMA, DMF, NMP, 1,4-Dioxane combinations thereof. The solvent may be DMF.

[0286] The compound of Formula (f) may be reacted with the compound of Formula (g) in step a) at a temperature of 50-150°C. The compound of Formula (f) may be reacted with the compound of Formula (g) in step a) at a temperature of 100-150 °C. The compound of Formula (f) may be reacted with the compound of Formula (g) in step a) at a temperature of 120 °C.

[0287] The compound of Formula (f) may be reacted with the compound of Formula (g) in step a) for a duration of 30 minutes to 24 hours. The compound of Formula (f) may be reacted with the compound of Formula (g) in step a) for a duration of 1 hour to 7 hours. The compound of Formula (f) may be reacted with the compound of Formula (g) in step a) for a duration of 3.5 hours.

[0288] In preferred embodiments, the compound of Formula (f) may be reacted with the compound of Formula (g) in step a) in the presence of K3PO4 and DMF, optionally at a temperature of 120 °C and for a duration of 3.5 hours.

[0289] b) converting the compound of Formula (h) into a compound of Formula (i):The compound of Formula (h) may be converted into a compound of Formula (I) in step b) by any suitable conditions, for instance conditions suitable for decarboxylation. Conditions include the presence of an acid such as Amberlyst 15 and a solvent. The solvent may be selected from toluene, xylene, hexane, heptane, cyclohexane and combinations thereof. The solvent may be toluene.

[0290] The compound of Formula (h) may be converted into a compound of Formula (i) in step b) at a temperature of 50-140 °C. The compound of Formula (h) may be converted into a compound of Formula (i) in step b) at a temperature of 90-120 °C. The compound of Formula (h) may be converted into a compound of Formula (i) in step b) at a temperature of 110 °C.

[0291] The compound of Formula (h) may be converted into a compound of Formula (i) in step b) for a duration of 30 minutes – 48 hours. The compound of Formula (h) may be converted into a compound of Formula (i) in step b) for a duration of 1 hour – 24 hours. The compound of Formula (h) may be converted into a compound of Formula (i) in step b) at a temperature of 4 hours.

[0292] In a preferred embodiment, the compound of Formula (h) may be converted into a compound of Formula (i) in step b) in the presence of Amberlyst 15 and Toluene, optionally at a temperature of 110 °C, for a duration of 4 hours.

[0293] Alternatively, the compound of Formula (h) may be converted into a compound of Formula (i) in step b) in the presence of a catalyst and a solvent. The catalyst may be selected from NaCN, KCN, LiCI, NaCI, NaBr, Nal, LiI·H2O, Na2CO3·H2O, Na3PO4·12H2O, Me4NOAc and combinations thereof. The catalyst may be LiCI. The solvent may be selected from DMSO, DMF, DMA, NMP and combinations thereof. The solvent may be DMSO.

[0294] The compound of Formula (c) may be converted into the compound of Formula (d) in step b) at a temperature of 90 -165 °C. The compound of Formula (c) may be converted into the compound of Formula (d) in step b) at a temperature of 95 -125 °C. The compound of Formula (c) may be converted into the compound of Formula (d) in step b) at a temperature of 100°C.

[0295] The compound of Formula (c) may be converted into the compound of Formula (d) in step b) for a duration of 30 minutes - 36 hours. The compound of Formula (c) may be converted into the compound of Formula (d) in step b) for a duration of 2 hours - 24 hours. The compound of Formula (c) may be converted into the compound of Formula (d) in step b) for a duration of 12 hours.

[0296] In a preferred embodiment, the compound of Formula (c) may be converted into the compound of Formula (d) in step b) in the presence of LiCI, DMSO and water, optionally at a temperature of 100°C for a duration of 12 hours.

[0297] c) converting the compound of Formula (i) into a compound of Formula (j):

[0298] The compound of Formula (i) may be converted into the compound of Formula (j) in step c) under any suitable conditions, for instance under conditions suitable for alkylation. For instance, the compound of Formula (i) may be converted into the compound of Formula (j) in the presence of an alkylating agent, a base and a solvent. The alkylating agent may be selected from an akyl iodide, for instance having the structure l-R2a, l-R2t>, Br-R2a, Br-R2t>, Mel, Etl, 1,2-dibromoethane and combinations thereof. The alkylating agent may be Mel. The base may be selected from NaH, LiH, LiOMe, NaOMe, KOMe, LiOtBu, NaOtBu, KOtBu, LiHMDS, NaHMDS, KHMDS, DBU, DBN and combinations thereof. The base may be KOtBu. The solvent may be selected from toluene, xylene, heptane, hexane, cyclohexane and combinations thereof. The solvent may be toluene.The compound of Formula (i) may be converted into the compound of Formula (j) in step c) at a temperature of 0-100 °C. The compound of Formula (i) may be converted into the compound of Formula (j) in step c) at a temperature of 10-40 °C. The compound of Formula (i) may be converted into the compound of Formula (j) in step c) at a temperature of 25 °C.

[0299] The compound of Formula (i) may be converted into the compound of Formula (j) in step c) for a duration of 15 minutes to 3 hours. The compound of Formula (i) may be converted into the compound of Formula (j) in step c) for a duration of 1 hour.

[0300] In a preferred embodiment, the compound Formula (i) may be converted into the compound of Formula (j) in step c) in the presence of Mel, KO‘Bu and Toluene, optionally at a temperature of 25 °C for a duration of 1 hour.

[0301] d) converting the compound of Formula (j) into the compound of Formula (3).

[0302] The compound of Formula (j) may be converted into the compound of Formula (3) in step d) under any suitable conditions, for instance under conditions suitable for hydrolysis. Suitable conditions include the presence of a base and a solvent. The base may selected from LiOH, NaOH, KOH, CsOH, Ba(OH)2, Ca(OH)2and combinations thereof. The base may be KOH. The solvent may be a high boiling point aprotic solvent. The high boiling point polar aprotic solvent may have a boiling point of 80°C or higher. The high boiling point polar aprotic solvent may have a boiling point of 100°C or higher. The solvent may be selected from water, 1,4-dioxane, n-BuOH and combinations thereof. The solvent may be n-BuOH.

[0303] The compound of Formula (j) may be converted into the compound of Formula (3) in step d) at a temperature of 50-200 °C. The compound of Formula (j) may be converted into the compound of Formula (3) in step d) at a temperature of 100-150 °C. The compound of Formula (j) is converted into the compound of Formula (3) in step d) at a temperature of 120 °C.

[0304] The compound of Formula (j) is converted into the compound of Formula (3) in step d) for a duration of 1 hour to 36 hours. The compound of Formula (j) may be converted into the compound of Formula (3) in step d) for a duration of 6 hours to 24 hours. The compound of Formula (j) is converted into the compound of Formula (3) in step d) for a duration of 14 hours.

[0305] In preferred embodiments, the compound of Formula (j) may be converted into the compound of Formula (3) in step d) in the presence of KOH and n-BuOH, optionally at a temperature of 120°C for a duration of 14 hours.

[0306] Preparing compounds of Formula (p)

[0307] In a fourth aspect, the invention comprises reacting a compound of Formula (n) with a compound of Formula (o) to yield a compound of Formula (p):Lg

[0308]

[0309] (n) (o) (P) wherein:

[0310] X is H; or halo;

[0311] Yi and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH;

[0312] R3is C1-2 alkyl, which is substituted with 1-5 fluoro; fluoro; chloro; or cyano;

[0313] R4is chloro; bromo; or fluoro; optionally wherein it is provided that R4is fluoro when R3is chloro; R5is C1-6 alkyl;

[0314] R7is fluoro; or chloro if neither R3nor R4are fluoro; and

[0315] Lg is a leaving group.

[0316] In some embodiments, R3is fluoro or chloro; R4is fluoro or chloro; and Y1 and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH;

[0317] In some embodiments, X is H; R3is chloro; R4is chloro; and Y1 and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH, preferably wherein Y1 and Y2 are CH.

[0318] In these embodiments, R7is preferably fluoro.

[0319] In these embodiments, Lg is preferably Br.

[0320] In these embodiments, R5is preferably C1-4 alkyl, for instance Me, Et, i-Pr, and t-Bu, preferably Et.

[0321] Reaction conditions

[0322] The compound of Formula (n) may be reacted with the compound of Formula (0) under any suitable reaction conditions, for instance via conditions suitable for nucleophilic aromatic substitution. Typical conditions include reacting the compound of Formula (n) with the compound of Formula (o) in the presence of a base and a solvent.

[0323] The base may be any suitable base, for instance an inorganic base. The base may be selected from CsCO3, Na2CO3, K2CO3, DBU, DBN, LiHMDS, NaHMDS, KHMDS, K3PO4 and combinations thereof. The base may be K2CO3. The solvent may be a high boiling point polar aprotic solvent. The high boiling point polar aprotic solvent may have a boiling point of 80°C or higher. The high boiling point polar aprotic solvent may have a boiling point of 100°C or higher. The solvent may be selected from DMSO, DMF, DMA, NMP and combinations thereof. The solvent may be NMP.

[0324] The compound of Formula (n) may be reacted with the compound of Formula (0), at a temperature of 80-150°C. The compound of Formula (n) may be reacted with the compound of Formula (0), at a temperature of 115°C.The compound of Formula (n) may be reacted with the compound of Formula (o), for a duration of 1-48 hours. The compound of Formula (n) may be reacted with the compound of Formula (o), for a duration of 6-24 hours. The compound of Formula (n) may be reacted with the compound of Formula (o), for a duration of 15 hours.

[0325] In a preferred embodiment, the compound of Formula (n) may be reacted with the compound of Formula (o) in the presence of K2CO3 and NMP, optionally at a temperature of 115°C for a duration of 15 hours.

[0326] Preparing compounds of Formula (q)

[0327] The invention may further comprise the step of converting the compound of Formula (p) into a compound of Formula (q):

[0328] Lg

[0329]

[0330] (P) wherein:

[0331] X is H; or halo;

[0332] Yi and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH;

[0333] R3is C1-2 alkyl, which is substituted with 1-5 fluoro; fluoro; chloro; or cyano;

[0334] R4is chloro; bromo; or fluoro; optionally wherein it is provided that R4is fluoro when R3is chloro; R5is C1-6 alkyl;

[0335] and

[0336] Lg is a leaving group.

[0337] In some embodiments, R3is fluoro or chloro; R4is fluoro or chloro; and Y1 and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH;

[0338] In some embodiments, X is H; R3is chloro; R4is chloro; and Y1 and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH, preferably wherein Y1 and Y2 are CH.

[0339] In these embodiments, Lg is preferably Br.

[0340] In these embodiments, R5is preferably C1-4 alkyl, more preferably terf-butyl.

[0341] Reaction conditions

[0342] The compound of Formula (p) may be converted into the compound of Formula (q) under any suitable conditions, for instance conditions suitable for decarboxylation. For instance, the compound of Formula(p) may be converted into the compound of Formula (q). in the presence of a catalyst and a solvent. The catalyst may be selected from NaCN, KCN, LiCI, NaCI, NaBr, Nal, LiI·H2O, Na2CO3·H2O, Na3PO4·12H2O, Me4NOAc and combinations thereof. The catalyst may be LiCI. The solvent may be selected from DMSO, DMF, DMA, NMP, water and combinations thereof. The solvent may comprise water and NMP. The solvent may be water:NMP (1:2).

[0343] The compound of Formula (p) may be converted into the compound of Formula (q) at a temperature of

[0344] 90-165 °C. The compound of Formula (p) may be converted into the compound of Formula (q) at a temperature of 95-125 °C. The compound of Formula (p) may be converted into the compound of

[0345] Formula (q) at a temperature of 100 °C.

[0346] The compound of Formula (p) may be converted into the compound of Formula (q) for a duration of 1 hour to 36 hours. The compound of Formula (p) may be converted into the compound of Formula (q) for a duration of 5 hours to 24 hours. The compound of Formula (p) is converted into the compound of Formula (q) for a duration of 15 hours.

[0347] In a preferred embodiment, the compound of Formula (p) is converted into the compound of Formula (q) in the presence of LiCI and water:NMP (1:2), optionally at a temperature of 100°C for a duration of 15 hours.

[0348] Preparing compounds of Formula (r)

[0349] In the fourth aspect, the invention may further comprise the step of reacting the compound of Formula (q) with a compound of formula AA to yield a compound of Formula (r):

[0350] Y

[0351] or9

[0352] (AA)

[0353]

[0354] (r) wherein:

[0355] X is H; or halo;

[0356] Y1 and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH;

[0357] R3is C1-2 alkyl, which is substituted with 1-5 fluoro; fluoro; chloro; or cyano;

[0358] R4is chloro; bromo; or fluoro; optionally wherein it is provided that R4is fluoro when R3is chloro;

[0359] Lg is a leaving group; and

[0360] R9is C1-6 alkyl or C3-5 cycloalkyl.

[0361] In some embodiments, R3is fluoro or chloro; R4is fluoro or chloro; and Y1 and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH;In some embodiments, X is H; R3is chloro; R4is chloro; and Yi and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH, preferably wherein Y1 and Y2 are CH.

[0362] In these embodiments, Lg is preferably Br.

[0363] In these embodiments, R9is preferably C1-4 alkyl, preferably Me, Et or ‘Bu, more preferably ‘Bu.

[0364] Reaction conditions

[0365] The compound of Formula (q) may be reacted with the compound of formula AA under any suitable conditions, for instance conditions for a Michael addition reaction. For instance, the compound of Formula (q) may be reacted with the compound of formula AA in the presence of a base and a solvent. The base may be any suitable base, for instance a base selected from NaOMe, LiOMe, NaOEt, LiOEt, NaOtBu, LiOtBu, KOMe, KOEt, KOtBu, LiHMDS, NaHMDS, KHMDS, NaH, LiH, KH, DBU, DBN and combinations thereof. The base may be NaOMe. The solvent may be an aprotic polar solvent. The solvent may comprise MeCN and / or THF. The solvent may comprise MeCN and / or THF in a ratio of 1:0 to 0:1. The solvent may comprise MeCN. The solvent may further comprise BHT. The solvent may be THF.

[0366] The compound of Formula (q) may be reacted with the compound of formula AA at a temperature of from -20 to 40 °C. The compound of Formula (q) is reacted with the compound of formula AA at a temperature of from 0 to 20 °C. The compound of Formula (q) may be reacted with the compound of formula AA for a duration of 30 minutes to 24 hours. The compound of Formula (q) may be reacted with the compound of formula AA for a duration of 2 hours.

[0367] In a preferred embodiment, the compound of Formula (q) may be reacted with the compound AA in the presence of MeONa and THF, at a temperature of from 0 to 20°C for a duration of about 2 hours.

[0368] Preparing compounds of Formula (s)

[0369] In the fourth aspect the invention may further comprise the step of converting the compound of Formula (r) into a compound of Formula (s):

[0370] Lg

[0371] (r)

[0372]

[0373] wherein:

[0374] X is H; or halo;

[0375] Y1 and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH;R3is C1-2 alkyl, which is substituted with 1-5 fluoro; fluoro; chloro; or cyano;

[0376] R4is chloro; bromo; or fluoro; optionally wherein it is provided that R4is fluoro when R3is chloro; Lg is a leaving group; and

[0377] R9is C1-6 alkyl or C3-5 cycloalkyl.

[0378] In some embodiments, R3is fluoro or chloro; R4is fluoro or chloro; and Y1 and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH;

[0379] In some embodiments, X is H; R3is chloro; R4is chloro; and Y1 and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH, preferably wherein Y1 and Y2 are CH.

[0380] In these embodiments, Lg is preferably Br.

[0381] In these embodiments, R9is preferably C1-4 alkyl, preferably Me, Et or ‘Bu, more preferably ‘Bu.

[0382] Reaction conditions

[0383] The compound of Formula (r) may be converted into the compound of Formula (s) under any suitable conditions, for instance conditions suitable for glutarimide formation. For instance, the compound of Formula (r) may be converted into the compound of Formula (s) in the presence of an acid and a solvent. The acid may be selected from HI, HBr, H2SO4, HNO3, H3PO4, HF, formic acid, C6H5COOH, AcOH and combinations thereof. The acid may comprise H2SO4and HOAc. The acid may be selected from p-toluenesulphonic acid, methanesulfonic acid and combinations thereof. The solvent may be selected from xylene, toluene and combinations thereof.

[0384] The compound of Formula (r) may be converted into the compound of Formula (s) at a temperature of 50-150°C. The compound of Formula (r) may be converted into the compound of Formula (s) at a temperature of 70-120°C. The compound of Formula (r) may be converted into the compound of Formula (s) at a temperature of 90°C.

[0385] The compound of Formula (r) may be converted into the compound of Formula (s) for a duration of 30 minutes to 24 hours. The compound of Formula (r) may be converted into the compound of Formula (s) for a duration of 1 hour to 6 hours. The compound of Formula (r) may be converted into the compound of Formula (s) for a duration of 2 hours.

[0386] In a preferred embodiment, the compound of Formula (r) may be converted into the compound of Formula (s) in the presence of H2SO4and HOAc, optionally at a temperature of 90°C for a duration of 2 hours.

[0387] Preparing compounds of Formula (t)

[0388] In the fourth aspect, the invention may further comprise the step of converting the compound of Formula (s) into a compound of Formula (t):

[0389]

[0390] X is H; or halo;

[0391] Yi and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH;

[0392] R3is C1-2 alkyl, which is substituted with 1-5 fluoro; fluoro; chloro; or cyano;

[0393] R4is chloro; bromo; or fluoro; optionally wherein it is provided that R4is fluoro when R3is chloro; and

[0394] Lg is a leaving group.

[0395] In some embodiments, R3is fluoro or chloro; R4is fluoro or chloro; and Y1 and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH;

[0396] In some embodiments, X is H; R3is chloro; R4is chloro; and Y1 and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH, preferably wherein Y1 and Y2 are CH.

[0397] In these embodiments, Lg is preferably Br.

[0398] Reaction conditions

[0399] The compound of Formula (s) may be converted into the compound of Formula (t) by any suitable conditions, for instance under Negishi-type cyanation conditions. For instance, the compound of Formula (s) may be converted into the compound of Formula (t) in the presence of a catalyst, a solvent, a ligand and Zn(CN)2. The catalyst may be selected from Pd(0), Pd(ll), Ni(0), Ni(ll) and combinations thereof. The catalyst may be selected from Pd(PPh3)4, Pd(PtBu3)2, Pd(pda)2, Pd(dppf)Cl2, Pd(OAc)2, Ni(PPh3)4, Ni(acac)2, Ni(COD)2, NiCk, Pd2(dba)3and combinations thereof. The catalyst may be Pd2(dba)3The solvent may be a high boiling point polar aprotic solvent. The high boiling point polar aprotic solvent may have a boiling point of 80°C or higher. The high boiling point polar aprotic solvent may have a boiling point of 100°C or higher. The solvent may be selected from 1,3-dioxane, DMSO, DMA, DMF, NMP and combinations thereof. The solvent may be NMP. The ligand may be selected from DPPF, SPhos, DPPP, DPPB, Xantphos, DPPM, DPPE, DCPE, PPh3, P(c-hex)3, P(‘Bu)3, P(C6F5)3, P(2,4,6-Me3C6H2)3 and combinations thereof. The ligand may be DPPF.

[0400] The compound of Formula (s) may be converted into the compound of Formula (t) at a temperature of 20-200°C. The compound of Formula (s) may be converted into the compound of Formula (t) at atemperature of 70-130°C. The compound of Formula (s) may be converted into the compound of Formula (t) at a temperature of 100°C.

[0401] The compound of Formula (s) may be converted into the compound of Formula (t) for a duration of 2 to 48 hours. The compound of Formula (s) may be converted into the compound of Formula (t) for a duration of 6 to 24 hours.

[0402] The compound of Formula (s) may be converted into the compound of Formula (t) for a duration of 12 hours.

[0403] Preferably, the compound of Formula (s) may be converted into the compound of Formula (t) in the presence of Pd2(dba)3, DPPF, Zn(CN)2and NMP, optionally at a temperature of 100°C for a duration of 12 hours.

[0404] Preparing compounds of Formula (u)

[0405] In the fourth aspect, the invention may further comprise the step of converting the compound of Formula (t) into a compound of Formula (u):

[0406]

[0407] wherein:

[0408] X is H; or halo;

[0409] Yi and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH;

[0410] R3is C1-2 alkyl, which is substituted with 1-5 fluoro; fluoro; chloro; or cyano;

[0411] R4is chloro; bromo; or fluoro; optionally wherein it is provided that R4is fluoro when R3is chloro; and

[0412] Pg is a protecting group.

[0413] In some embodiments, R3is fluoro or chloro; R4is fluoro or chloro; and Y1 and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH;

[0414] In some embodiments, X is H; R3is chloro; R4is chloro; and Y1 and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH, preferably wherein Y1 and Y2 are CH.

[0415] In these embodiments, Pg is preferably an amine protecting group, for example Boc.Reaction conditions

[0416] The compound of Formula (t) may be converted into the compound of Formula (u) under any suitable conditions, for instance under nitrile-selective reducing conditions, and amine protecting conditions. For instance, the compound of Formula (t) may be converted into the compound of Formula (u) in the presence of hydrogen, a catalyst, a reagent for introducing an amine protecting group and one or more solvents. The catalyst may be selected from Raney Ni, palladium, platinum, cobalt boride, nickel boride and combinations thereof. The catalyst may be Raney Ni. The catalyst may be anhydrous Raney Ni. The one or more solvents may be polar aprotic solvents. The compound of Formula (t) may be converted into the compound of Formula (u) in the presence of two solvents. The solvents may be THF and DMF. The one or more solvents may be THF: DMF in a ratio of 1:0 to 0:1. The two solvents may be THF: DMF in a 1:1 ratio. The hydrogen pressure may be 1 atm to 20 atm. The reagent for introducing a protecting group may be a reagent for introducing Boc. The reagent for introducing Boc may be (Boc)2O or N-Boc-Benzotriazole. These reduction and protections steps may be performed sequentially or simultaneously in a one-pot reaction or sequentially in a multi-pot reaction.

[0417] The compound of Formula (t) may be converted into the compound of Formula (u) at a temperature of 20-80°C. The compound of Formula (t) may be converted into the compound of Formula (u) at a temperature of 40-70°C. The compound of Formula (t) may be converted into the compound of Formula (u) at a temperature of 60°C.

[0418] The compound of Formula (t) may be converted into the compound of Formula (u) for a duration of 2-24 hours. The compound of Formula (t) may be converted into the compound of Formula (u) for a duration of 6-18 hours. The compound of Formula (t) is converted into the compound of Formula (u) for a duration of 12 hours.

[0419] In a preferred embodiment, the compound of Formula (t) may be converted into the compound of Formula (u) in the presence of anhydrous Raney Ni, H2, (Boc)2O and THF: DMF (1:1), optionally at a temperature of 60°C for a duration of 12 hours.

[0420] Preparing compounds of Formula (v)

[0421] In the fourth aspect, the invention may further comprise the step of converting the compound of Formula (u) into the compound of Formula (v):

[0422] O

[0423]

[0424] (v)

[0425] wherein:X is H; or halo;

[0426] Yi and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH;

[0427] R3is C1-2 alkyl, which is substituted with 1-5 fluoro; fluoro; chloro; or cyano;

[0428] R4is chloro; bromo; or fluoro; optionally wherein it is provided that R4is fluoro when R3is chloro;

[0429] Pg is a protecting group.

[0430] X’ is an anion.

[0431] In some embodiments, R3is fluoro or chloro; R4is fluoro or chloro; and Y1 and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH;

[0432] In some embodiments, X is H; R3is chloro; R4is chloro; and Y1 and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH, preferably wherein Y1 and Y2 are CH.

[0433] In these embodiments, Pg is preferably an amine protecting group, for example Boc.

[0434] In these embodiments, X’ is preferably a suitable anion which corresponds to the conjugate base of a strong acid. For example, X’ may be HSO4-, SO42-, NO3-, Cl-or Br, Preferably Cl-or Br.

[0435] Reaction conditions

[0436] The compound of Formula (u) may be converted into the compound of Formula (v) under any suitable conditions, for instance under amine deprotection conditions. For instance, the compound of Formula (u) may be converted into the compound of Formula (v) in the presence of an acid and a solvent. The acid may be hydrochloric acid, p-toluenesulphonic acid, methanesulfonic acid, trifluoroacetic acid, phosphoric acid or amberlyst 15. The acid may be HCI. HCI may be generated in situ using a mixture of acetyl chloride and an alcohol, wherein the alcohol is selected from EtOH, MeOH, BuOH, PrOH and combinations thereof; optionally wherein the BuOH is selected fromnBuOH, 'BuOH, ‘BuOH and combinations thereof. The solvent may be selected from water, DCM, EtOAc, EtOH, MeOH, IPrOAc, 1,4-dioxane, 2-propanol, CPME and combinations thereof. The solvent may be EtOAc.

[0437] The compound of Formula (u) may be converted into the compound of Formula (v) at a temperature of 10-50°C. The compound of Formula (u) may be converted into the compound of Formula (v) at a temperature of 20-30°C. The compound of Formula (u) may be converted into the compound of Formula (v) at a temperature of 25°C.

[0438] The compound of Formula (u) may be converted into the compound of Formula (v) for a duration of 1 -24 hours. The compound of Formula (u) may be converted into the compound of Formula (v) for a duration of 2-12 hours. The compound of Formula (u) is converted into the compound of Formula (v) for a duration of 3 hours.

[0439] In a preferred embodiment, the compound of Formula (u) is converted into the compound of Formula (v) in the presence of HCI and EtOAc, optionally at a temperature of 25°C for a duration of 3 hours.

[0440] Preparing compounds of Formula (I) from compounds of Formula (v)

[0441] In the fourth aspect, the invention may further comprise the step of reacting the compound of Formula (v) with a compound of formula BB to yield a compound of Formula (I):BB o

[0442]

[0443] (v) (I),

[0444] wherein:

[0445] R1, R2a, and R2bare defined according to (A2) and (B2) defined herein;

[0446] X is H or halo;

[0447] Y1 and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH;

[0448] R3is H; C1-2 alkyl, which is optionally substituted with 1-5 fluoro; fluoro; chloro; or cyano;

[0449] R4is chloro; bromo; or fluoro; optionally wherein it is provided that R4is fluoro when R3is chloro;

[0450] X’ is an anion;

[0451] Z is Cl, OH or OM; and

[0452] M is a cation.

[0453] In some embodiments, R1is heteroaryl including 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc;

[0454] R2aand R2bare each independently C1-2 alkyl optionally substituted with from 1-5 Ra;

[0455] R3is H; C1-2 alkyl, which is optionally substituted with 1-5 fluoro; fluoro; chloro; or cyano;

[0456] R4is chloro; bromo; or fluoro; optionally wherein it is provided that R4is fluoro when R3is chloro;

[0457] Y1 and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH,

[0458] X’ is preferably a suitable anion which corresponds to the conjugate base of a strong acid. For example, X’ may be HSC, SO42-, NO3-, Cl-or Br, preferably Cl-or Br;

[0459] M is preferably an alkali metal cation such as Li+, Na+or K+, alkali earth metal cations such as Ca2+, or Mg2+, organic cations such as NH4+, or protonated amines such as (C1-4 alkyl-NH3+). Preferably, M is an alkali metal cation, more preferably Na+or K+.

[0460] In some embodiments, R1has the formula:

[0461]

[0462] (V-A), wherein Rn is methyl.

[0463] R2aand R2bare each independently methyl;

[0464] R3and R4are each independently chloro;

[0465] Yi and Y2 are each independently CH.X’ is preferably a suitable anion which corresponds to the conjugate base of a strong acid. For example, X’ may be HSC, SO42-, NO3-, Cl-or Br, preferably Cl-or Br;

[0466] M is preferably an alkali metal cation such as Li+, Na+or K+, alkali earth metal cations such as Ca2+, or Mg2+, organic cations such as NH4+, or protonated amines such as (C1-4 alkyl-NH3+). Preferably, M is an alkali metal cation, more preferably Na+or K+.

[0467] Reaction conditions

[0468] The compound of Formula (v) may be reacted with the compound of formula BB under amide coupling conditions, for example the amide coupling conditions recited herein.

[0469] Compounds of Formula (p)

[0470] In a fifth aspect, the invention provides a compound of Formula (p):

[0471]

[0472] (P)

[0473] wherein:

[0474] X is H; or halo;

[0475] Y1 and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH;

[0476] R3is C1-2 alkyl, which is substituted with 1-5 fluoro; fluoro; chloro;

[0477] R4is chloro; bromo; or fluoro; optionally wherein it is provided that R4is fluoro when R3is chloro; and

[0478] Lg is a leaving group.

[0479] In some embodiments, R3is fluoro or chloro; R4is fluoro or chloro; and Y1 and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH;

[0480] In some embodiments, X is H; R3is chloro; R4is chloro; and Y1 and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH, preferably wherein Y1 and Y2 are CH.

[0481] In these embodiments, Lg is preferably Br.

[0482] In these embodiments, R5is preferably C1-4 alkyl, for instance Me, Et, i-Pr, and t-Bu, preferably Et.

[0483] R5may be Me, Et or ‘Bu.Defining the compounds in the processes and products of the invention

[0484] The processes described herein can be used to synthesise a variety of compounds according to Formula (I). As such, the starting materials, intermediates, reaction processes, and final products described herein can be defined by the following. This applies to any appropriate embodiment (i.e. an embodiment concerning one of the following groups).

[0485] M may be an alkali metal cation such as Li+, Na+or K+, alkali earth metal cations such as Ca2+, or Mg2+, organic cations such as NH4+, or protonated amines such as (C1-4 alkyl-NH3+). Preferably, M is an alkali metal cation, more preferably Na+or K+.

[0486] X’ may be any suitable anion which corresponds to the conjugate base of a strong acid. For example, X’ may be HSO4; SO42-, NO3-, Cl-or Br. Preferably, X’ is Cl-or Br.

[0487] R6is a leaving group, for example, Cl, Br, I, OH, OM, O(C=O)(C1-6alkyl), O(C=O)(N3), O(C1-6alkyl), or S(C1-6alkyl). Preferably, R6is Cl, OM.

[0488] Lg may be Br or I. Lg is preferably Br.

[0489] Preferably, R1, R2a, and R2bmay be defined according to (A). More preferably, R1, R2a, and R2bmay be defined according to (A1).

[0490] R1may be heteroaryl including 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2. R1may be optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc. R1may be heteroaryl including 5-6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2. R1may be optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc.

[0491] R1may be heteroaryl including 6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2. R1may be optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc.

[0492] R1may be heteroaryl including 6 ring atoms, wherein 1-2 ring atoms are N, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc.

[0493] R1may be unsubstituted. R1may be substituted with one Rbor one Rc. R1may be substituted with one Rb. Rbmay be C1-10 alkyl, which is optionally substituted with 1-6 independently selected Ra. Rbmay be C1-6 alkyl, which is optionally substituted with 1-6 independently selected Ra. Rbmay be C1-3 alkyl, which is optionally substituted with 1-6 independently selected Ra. Rbmay be unsubstituted C1-3 alkyl. Rbmay be -CH3. Rbmay be C1-3 alkyl, which is substituted with 1-6 independently selected Ra. Ra, or each occurrence of Ra, may be an independently selected halo; optionally wherein Ra, or each occurrence of Ra, is fluoro. Rbmay be -CF3. Rbmay be -CHF2. Ra, or each occurrence of Ra, may be an independently selected C1-4 alkoxy. Ra, or each occurrence of Ra, may be -OCH3. Rbmay be CH2OCH3. Rbmay be C1-4 alkoxy. Rbmay be -OCH3. Rbmay be C1-4 haloalkoxy. Rbmay be -OCHF2. Rbmay be halo. Rbmay be fluoro. Rbmay be chloro. Rbmay be cyano. R1may be substituted with 1 Rc. Rcmay be C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc. Rcmay be C3-10 cycloalkyl which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rb. Rcmay be C3-6 cycloalkyl which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxoand Rb. Rcmay be cyclopropyl, which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rb.

[0494] R1may have the formula:

[0495]

[0496] wherein each of X1, X2, X3, and X4is, independently, CH or N; and R11is H, Rb, or Rc.

[0497] R1may have the formula:

[0498]

[0499] No more than two of X1, X1, and X3may be N. X2 may be N. Xi may be CH. X3 may be CH.

[0500] R1may have the formula:

[0501]

[0502] X1may be N. X2may be CH. X3may be CH.

[0503] R1may have the formula:

[0504]

[0505] (V-B).

[0506] X3may be N. X2may be CH. X1may be CH. R1may have the formula:

[0507]

[0508] R1may have the formula:

[0509]

[0510] R11may be H. R11may be Rb. R11may be unsubstituted C1-3 alkyl. R11may be CH3. R11may be C1-3 alkyl, which is substituted with from 1-6 independently selected Ra. Ra, or each occurrence of Ra, may be an independently selected halo. Ra, or each occurrence of Ra, may be fluoro. R11may be -CF3. R11may be - CHF2. Ra, or each occurrence of Ra, may be an independently selected C1-4 alkoxy. Ra, or each occurrence of Ra, may be -OCH3. R11may be CH2OCH3. R11may be C1-4 alkoxy. R11may be -OCH3. R11may be C1-4 haloalkoxy. R11may be -OCHF2. R11may be halo. R11may be fluoro. R11may be chloro. R11may be cyano. R11may be cyclopropyl, which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc.

[0511] R1may be heteroaryl including 8-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2. R1may be optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc. R1may be heteroaryl including 10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc.

[0512]

[0513] wherein whichever of X1to X4provides the position of attachment of the R1group to the rest of the molecule is carbon, the rest of X1to X4are each independently selected from CH, CR13or N, and each of X5to X8is independently selected from CH, CR13or N; wherein R13is Rbor Rc; and provided that no more than four of X1to X8are heteroatoms and no more than four of X1to X8are CR13; preferably wherein none of X1to X8are CR13.

[0514] R1may be:

[0515]

[0516] ; wherein whichever of X1to X4provides the position of attachment of the R1group to the rest of the molecule is carbon, the rest of X1to X4are each independently selected from CH, CR13or N, and each of X5to X8is independently selected from CH2, CHR13, NH, NR13, O or SO2; wherein R13is Rbor Rc; and provided that no more than four of X1to X8are heteroatoms and no more than four of X1to X8include an R13group; preferably wherein none of X1to X8include an R13group.v / VX / V'

[0517] R1may be:

[0518]

[0519] ; wherein Xi to X4 are each independently selected from CH, CR13or N, Xs is CH, CR13or N, and each of Xs to Xs is independently selected from CH2, CR13, NH, NR13, O or SO2; wherein R13is Rbor Rc; and provided that no more than four of Xi to Xs are heteroatoms and no more than four of Xi to Xs include an R13group; preferably wherein none of Xi to Xs include an R13group.

[0520] R1may be:

[0521]

[0522] ; wherein X1to X4are each independently selected from CH or N, X5is CH, CR13or N, and each of X5, X7and X8is independently selected from CH2, CHR13, NH, NR13, O or SO2; wherein R13is Rbor Rc; and provided that no more than four of X1to X8are heteroatoms and and no more than four of X1to X8include an R13group; preferably wherein none of X1to X8include an R13group.

[0523] R1may be:

[0524]

[0525] R1may be heteroaryl including 9 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc.

[0526] R1may be:

[0527]

[0528] ; wherein whichever of X1to X4provides the position of attachment of the R1group to the rest of the molecule is carbon, the rest of X1to X4are each independently selected from CH, CR13or N, X5and X6are independently selected from CH, CR13or N, and X7is selected from CH2, CHR13, NH, NR13, O or S; wherein R13is Rbor Rc; and provided that no more than four of X1to X7are heteroatoms and no more than four of X1to X7include an R13group; preferably wherein none of X1to X7include an R13group or wherein only one of X1to X7includes an R13group and the R13group is CH3.O

[0529] R1may be; wherein whichever of X1to X4provides the position of attachment of the R1group to the rest of the molecule is carbon, the rest of X1to X4are each independently selected from CH, CR13or N, X5and X7are independently selected from CH2, CHR13, NH, NR13or O; wherein R13is Rbor Rc; and provided that no more than four of X1to X7are heteroatoms and no more than four of X1to X7include an R13group; preferably wherein none of X1to X7include an R13group or wherein only one of X1to X7includes an R13group and the R13group is CH3.

[0530]

[0531] ; wherein X1to X4are each independently selected from CH, CR13or N; X5and X6are selected from CH, CR13or N, and X7is selected from NH, NR13or O; wherein R13is Rbor Rc; and provided that no more than four of X1to X7are heteroatoms and no more than four of X1to X7include an R13group; preferably wherein none of X1to X7include an R13group or wherein only one of X1to X7includes an R13group and the R13group is CH3.

[0532] R1may be:

[0533]

[0534] ; wherein whichever of X1to X4provides the position of attachment of the R1group to the rest of the molecule is carbon, the rest of X1to X4are each independently selected from CH, CR13or N, and X5to X7are each independently selected from CH2, CHR13, NH, NR13, O or SO2; wherein R13is Rbor Rc; and provided that no more than four of X1to X7are heteroatoms and no more than four of X1to X7include an R13group; preferably wherein none of X1to X7include an R13group or wherein only one of X1to X7includes an R13group and the R13group is CH3.

[0535] ; wherein X1to X4are each independently selected from CH, CR13or N, X5is CH or N and X6and X7are each independently selected from CH2, CHR13, NH, NR13, O or SO2; wherein R13is Rbor Rc; and provided that no more than four of X1to X7are heteroatoms and no more than four of X1to X7include an R13group; preferably wherein none of X1to X7include an R13group.R1may be:

[0536]

[0537] ; wherein Xi to X4 are each independently selected from CH, CR13or N, X6is CH or N and X5and X7are each independently selected from CH2, CHR13, NH, NR13, O or SO2; wherein R13is Rbor Rc; and provided that no more than four of Xi to X7 are heteroatoms and no more than four of Xi to X7include an R13group; preferably wherein none of Xi to X7 include an R13group.

[0538] R1may have the formula:

[0539]

[0540] (Vl-B), wherein:

[0541] X3is NH, O, or S;

[0542] X4 is N, O, or CH; and

[0543] X5is N or CH.

[0544] X3may be NH, O, or S; and X4 and X5 may be CH. X3 may be O or S; X4 may be CH; and X5 may be N. X3 may be NH, X4 may be N; and X5 may be CH. X3 may be N, X4 may be O; and X5 may be N.

[0545] R1may be heteroaryl including 5 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2. R1may be optionally substituted with 1-4 substituents independently selected from the group consisting of Rband Rc.

[0546] R1may have the formula:

[0547]

[0548] (Vl-C), wherein:

[0549] Xe is NH, NCH3, O, or S;

[0550] X7is N, C, CH, CCF3, CCHF2, C(cyclopropyl), or CCH3;

[0551] X8is N, C, CH, CCH3, CCF3, or COCH3;

[0552] X9is N, C, CH, CCH3, CCF3, or COCH3; and

[0553] X10 is N, C, CH, CCF3, CCHF2, C(cyclopropyl), or CCH3.

[0554] R1may have the formula:Xg Xg

[0555]

[0556] x6 (VI-C-1), wherein:

[0557] X6is NH, NCH3, O, or S;

[0558] X7is N, CH, CCF3, CCHF2, C(cyclopropyl), or CCH3;

[0559] X8is N, CH, or CCH3; and

[0560] X9is N, CH, or CCH3.

[0561] X8may be N. Xg may be N. X8may be O. X7may be CH, CCF3, CCHF2, C(cyclopropyl), or CCH3. X7may be CCH3.

[0562] R1may have the formula:

[0563] N - N

[0564]

[0565] H3C

[0566] X8may be O or S; and X7may be N. X8may be CH or CCH3; and Xg may be CH or CCH3.

[0567] R1may have the following characteristics:

[0568] X6is NH, NCH3, or O;

[0569] X7is CH or CCH3;

[0570] X8is N; and

[0571] X9is CH or CCH3.

[0572] R1may have the following characteristics:

[0573] X6is NCH3;

[0574] X7is CH or CCH3;

[0575] X8is N; and

[0576] Xg is N.

[0577] R1may be C6-10aryl optionally substituted with 1-4 substituents independently selected from the group consisting of Rb, and Rc.

[0578] R1may be phenyl optionally substituted with 1-4 substituents independently selected from the group consisting of Rb, and Rc.

[0579] R1may have the formula:

[0580]

[0581] (Vl-D); wherein each R11is independently selected from the group consisting of H, Rb, and Rc; each R12is independently selected from the group consisting of Rband Rc; and q is 0, 1, or 2.

[0582] R11may be H, fluoro, CN, CH3, CHF2, -SO2NH2, SO2CH3, -C(O)NH2, or cyclopropyl. R11may be H. R11may be CH3. R11may be CN. q may be 1. R12may be F.

[0583] Each of R2aand R2bmay be independently selected from the group consisting of H and C1-2 alkyl optionally substituted with from 1-5 Ra. Each of R2aand R2bmay be an independently selected C1-2 alkyl optionally substituted with from 1-5 Ra. Each of R2aand R2bmay be an independently selected unsubstituted C1-2 alkyl. Each of R2aand R2bmay be CH3.

[0584] R2aand R2btaken together with the carbon atom to which each is attached may form:

[0585] • C3-7 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rb; or

[0586] • heterocyclyl including 4-7 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl is optionally substituted with 1 -4 substituents independently selected from the group consisting of oxo and Rb.

[0587] R2aand R2btaken together with the carbon atom to which each is attached may form C3-7 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rb.

[0588] R2aand R2btaken together with the carbon atom to which each is attached may form:

[0589] O

[0590]

[0591] R2aand R2btaken together with the carbon atom to which each is attached may form heterocyclyl including 4-7 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rb.

[0592] R2aand R2btaken together with the carbon atom to which each is attached may form:

[0593]

[0594] R1, R2a, and R2bmay be defined according to (B).

[0595] R1taken together with (i) the carbon atom to which it is attached and (ii) and one of R2aand R2bmay form:

[0596] CH3

[0597]

[0598] wherein as indicated in the formula above, the other of R2aand R2bis CH3.

[0599] R1may be heterocycloalenyl including 3-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2. R1may be optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc. R1may be heterocycloalkenyl including 6 ring atoms.

[0600] R1may be heterocyclyl including 4-6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc.

[0601] R1may be heterocyclyl including 6 ring atoms.

[0602] R1may be C3-7 cycloalkyl optionally substituted with 1 -4 substituents independently selected from the group consisting of oxo, Rb, and Rc.

[0603] R1may be C5-6 cycloalkyl.

[0604]

[0605]

[0606] independently CH, CR15or N; wherein R14and R15are each independently Rbor Rc; optionally wherein only one of X1, X2and X3is CR15and R15is methyl or F and / or wherein R14is C1-2 alkyl or C1-2 fluoroalkyl. R1may be:

[0607]

[0608]

[0609] F..0.

[0610]

[0611]

[0612] R3may be Cl.

[0613] Particularly preferred compounds of Formula (I)

[0614] In a preferred embodiment applying to any appropriate aspect disclosed herein (i.e. any aspect including R1-R4, Yi, and Y2):R1, R2aand R2bare defined according to (A1);

[0615] R1is any R1defined according to (A1);

[0616] R2aand R2bare each independently C1-2 alkyl optionally substituted with from 1-5 Ra;

[0617] R3is H; C1-2 alkyl, which is optionally substituted with 1-5 fluoro; fluoro; chloro; or cyano;

[0618] R4is chloro; bromo; or fluoro; optionally wherein it is provided that R4is fluoro when R3is chloro;

[0619] Y1 and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH.

[0620] In a more preferred embodiment applying to any aspect disclosed herein, (i.e. any aspect including R1-R4, Y1, and Y2):

[0621] R1is heteroaryl including 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc; R2aand R2bare each independently C1-2 alkyl optionally substituted with from 1-5 Ra;

[0622] R3is H; C1-2 alkyl, which is optionally substituted with 1-5 fluoro; fluoro; chloro; or cyano;

[0623] R4is chloro; bromo; or fluoro; optionally wherein it is provided that R4is fluoro when R3is chloro;

[0624] Y1 and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH.

[0625] In a more preferred embodiment applying to any aspect disclosed herein, (i.e. any aspect including R1-R4, Y1, and Y2):

[0626] R1is heteroaryl including 5 or 6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N and O, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc;

[0627] R2aand R2bare each independently C1-2 alkyl optionally substituted with from 1-5 Ra;

[0628] R3is H; C1-2 alkyl, which is optionally substituted with 1-5 fluoro; fluoro; chloro; or cyano;

[0629] R4is chloro; bromo; or fluoro; optionally wherein it is provided that R4is fluoro when R3is chloro;

[0630] Y1 and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH.

[0631] In a more preferred embodiment applying to any aspect disclosed herein, (i.e. any aspect including R1-R4, Y1, and Y2):

[0632] R1has the formula:

[0633] Rn\ _ X3

[0634] x2

[0635] X<^3

[0636]

[0637] x4 (lll(III-A);

[0638] wherein each of Xi, X2, X3, and X4 is, independently, CH or N; and R11is H, Rb, or Rc;R2aand R2bare each independently C1-2 alkyl;

[0639] R3and R4are each independently fluoro or chloro;

[0640] Y1 and Y2 are each independently CH.

[0641] In a most preferred embodiment applying to any aspect disclosed herein, (i.e. any aspect including R1-R4, Y1, and Y2):

[0642] R1has the formula:

[0643]

[0644] (V-A), wherein Rn is methyl.

[0645] R2aand R2bare each independently methyl;

[0646] R3and R4are each independently chloro;

[0647] Y1 and Y2 are each independently CH.

[0648] Methods of Use

[0649] Compounds prepared as described herein can be used in the treatment of disorders in subjects in need thereof. Said disorders include, but are not limited to, those disorders caused by or associated with NLRP3 inflammasome activation.

[0650] Accordingly, in one embodiment, described herein is a method of treating a disorder caused by or associated with NLRP3 inflammasome activation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound prepared as described herein or a pharmaceutically acceptable salt thereof.

[0651] In some embodiments, the disorder is gout.

[0652] In some embodiments, the disorder is pericarditis.

[0653] In some embodiments, the disorder is a disorder of the immune system, hematopeoitic system, joints, renal system, gastro-intestinal tract, skin, eye, respiratory system, central nervous system, cardiovascular system, hepatic system, and / or endocrine system.

[0654] In some embodiments, the disorder is an autoinflammatory or autoimmune disorder.

[0655] In certain of these embodiments, the disorder is gout (e.g., acute and chronic gout, tophaceous gout, or pseudo-gout).

[0656] In certain of these embodiments, the disorder is inflammatory bowel disease.

[0657] In certain of these embodiments, the disorder is rheumatoid arthritis.

[0658] In certain of these embodiments, the disorder is multiple sclerosis.In some embodiments, the disorder is a neurodegenerative disorder (e.g., Alzheimer's disease). In some embodiments, the disorder is a cardiovascular or metabolic disorder (e.g., pericarditis, atherosclerosis, Type 2 diabetes, obesity, Wilson disease or metabolic syndrome).

[0659] In some embodiments, the disorder is obesity.

[0660] In some embodiments, the disorder is Wilson disease

[0661] In some embodiments, the disorder is a fibrotic disorder (e.g., interstitial lung disease or chronic kidney disease).

[0662] In some embodiments, the disorder is a disorder associated with hematology (e.g., anemia of inflammation).

[0663] In some embodiments, the disorder is an eye disorder (e.g., macular degeneration).

[0664] In some embodiments, the disorder is a disorder of the immune system, hematopeoitic system, joints, renal system, gastro-intestinal tract, skin, eye, respiratory system, central nervous system, cardiovascular system, hepatic system, and / or endocrine system.

[0665] In some embodiments, the disorder is a cancer, tumour or other malignancy.

[0666] In some embodiments, the disorder is selected from the group consisting of

[0667] (i) inflammatory reactions in the joints including acute and chronic gout, tophaceous gout, pseudogout, osteoarthritis, psoriatic arthritis, systemic juvenile idiopathic arthritis, adult-onset Still’s disease, relapsing polychondritis, tendonitis, frozen shoulder and pyogenic arthritis;

[0668] (ii) hyperactive inflammation with underlying genetic mutations, including auto-inflammatory diseases such as cryopyrin-associated periodic syndrome (CAPS): Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS) and neonatal-onset multisystem inflammatory disease (NOMID); familial Mediterranean fever (FMF), TNF receptor associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MVK), hyperimmunoglobuliemia D and periodic fever syndrome (HIDS), deficiency of interleukin 1 receptor (DIRA) antagonist), VEXAS syndrome, Majeed syndrome, pyoderma gangrenosum, acne and hidradenitis suppurative syndrome, haploinsufficency of A20, pediatric granulomatous arthritis (PGA), PLCG2-associated antibody deficiency and immune dysregulation (PLAID), sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD), Sweet’s syndrome, chronic non-bacterial osteomyelitis (CNO), chronic recurrent multifocal osteomyelitis (CRMO) and synovitis, acne, pustulosis, hyperostosis, osteitis syndrome (SAPHO) and any disease where an individual has been determined to carry a germline or somatic non-silent mutation in NLRP3 or NEK7 (iii) autoimmune diseases including multiple sclerosis (MS), rheumatoid arthritis, Behget’s disease, Sjogren’s syndrome, systemic sclerosis, mixed connective tissue disease, myositis, vasculitis, lupus, including systemic and cutaneous forms, lupus nephritis, type-1 diabetes, psoriasis and Schnitzler’s syndrome, Grave’s disease, thrombotic thrombocytopenic purpura, idiopathic thrombocytopenic purpura, microscopic polyangiitis, inflammatory bowel disease, colitis, Crohn’s disease;

[0669] (iv) respiratory diseases including chronic obstructive pulmonary disorder (COPD), acute respiratory distress syndrome (ARDS), steroid-resistant asthma, asbestosis, silicosis, sarcoidosis, cystic fibrosis and interstitial lung disease (ILD), including, but not limited to idiopathic pulmonary fibrosis (IPF), fibrotic hypersensitivity pneumonitis, rheumatoid arthritis-associated ILD, autoimmune myositis-associated ILD, systemic sclerosis-associated ILD, idiopathic interstitial pneumonia and progressive fibrosing ILD;(v) kidney disease including chronic kidney disease (CKD), including CKD associated with high uric acid, APOL1 mutations, complement-mediated kidney diseases such as C3 glomerulopathy, IgA nephropathy, atypical hemalytic uremic syndrome and membranous nepropathy, idiopathic nephrotic syndrome, oxalate nephropathy and diabetic nephropathy;

[0670] (vi) central nervous system diseases including Parkinson’s disease, Alzheimer’s disease, motor neuron disease, Huntington’s disease, cerebral malaria, post-traumatic brain injury, sub-arachnoid hemorrhage and brain injury from pneumococcal meningitis, cerebral amyloid angiopathy, migraine, depression, psychological stress;

[0671] (vii) ocular diseases including those of the ocular epithelium, age-related macular degeneration (AMD), corneal infection, uveitis and dry eye;

[0672] (viii) cardiovascular diseases including myocarditis, inflammatory cardiomyopathy, atherosclerosis, stroke, myocardial infarction, hypertension, abdominal aortic aneurism, pericarditis including Dressier’s syndrome, thromboembolism, ischemia reperfusion injury, transthyretin amyloidosis, vasculitis;

[0673] (ix) viral infections and subsequent immune hyperactivation including alphavirus including Chikungunya and Ross River virus, and flavivirus including Dengue and Zika viruses, COVID-19 / SARS-CoV-2, influenza, HIV;

[0674] (x) diseases of the hematopoietic system including anemia of inflammation (anemia of chronic disease), paroxysmal nocturnal hemaglobinuria (PNH), sickle cell disease;

[0675] (xi) liver disease including non-alcoholic steatohepatitis, alcoholic liver disease and drug-induced liver injury;

[0676] (xii) inflammatory reactions in the skin including contact hypersensitivity and sunburn, psoriasis, hidradenitis suppurativa (HS) and other cyst-causing skin diseases, dermatomyositis, pemphigus, pyoderma gangrenosum;

[0677] (xiii) metabolic diseases including obesity, metabolic syndrome, and Type 2 diabetes and related morbidities including diabetic foot ulcers, atherosclerosis, obesity, diabetic cardiomyopathy and diabetic retinopathy;

[0678] (xiv) cancers including lung cancer and lung cancer metastasis, pancreatic cancers, gastric cancers, myelodysplastic syndrome, leukemia and melanoma; polymyositis; graft-versus-host disease and transplant rejection;

[0679] (xv) infectious diseases including bacterial infections, including Clostridium species, viral infections, helminth infections; wound healing; sepsis; gangrene; and

[0680] (xvi) allergic diseases and Type 2 inflammation-associated diseases including asthma, atopic dermatitis, eosinophilic esophagitis, chronic obstructive pulmonary disease, chronic sinusitis, nasal polyps.

[0681] In another embodiment, described herein is a method of degrading NIMA Related Kinase 7 (NEK7) in a subject suffering from any one or more of the disorders described herein, comprising administering to the subject an effective amount of a compound of described herein or a pharmaceutically acceptable salt thereof.

[0682] In an aspect, the disclosure provides a compound or pharmaceutically acceptable salt as described herein for use in any of the above-recited methods of treatment. In a further aspect, the disclosure provides the use of a compound or pharmaceutically acceptable salt as described herein for the manufacture of amedicament for any of the above-recited methods of treatment. In an aspect, the disclosure provides a degrader conjugate as described herein for use in any of the above-recited methods of treatment.

[0683] DEFINITIONS

[0684] The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1-4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. Pharmaceutically acceptable salts of Compound A include those derived from suitable inorganic and organic acids and bases. In particular, “pharmaceutically acceptable salts” encompasses any multicomponent forms comprising Compound A and a suitable (in)organic acid or base, including salts in which the proton is completely transferred from the acid to the base, and cocrystals in which the proton remains in the acid molecule, and together the base and the acid form a unique crystal structure.

[0685] The present disclosure, in an alternative embodiment, also embraces isotopically labeled compounds which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. For example, a compound of the disclosure may have one or more H atom (or all H atoms) replaced with deuterium.

[0686] The term "halo" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

[0687] The term "alkyl" refers to a saturated acyclic hydrocarbon radical that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C1-10 indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. Alkyl groups can either be unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, iso-propyl, terf-butyl, n-hexyl. The term “saturated” as used in this context means only single bonds present between constituentcarbon atoms and other available valences occupied by hydrogen and / or other substituents as defined herein.

[0688] The term "haloalkyl" refers to an alkyl, in which one or more hydrogen atoms is / are replaced with an independently selected halo.

[0689] The term "alkoxy" refers to an -O-alkyl radical (e.g., -OCH3).

[0690] The term "alkylene" refers to a divalent alkyl (e.g., -CH2-).

[0691] The term "alkenyl" refers to an acyclic hydrocarbon chain that may be a straight chain or branched chain having one or more carbon-carbon double bonds. The alkenyl moiety contains the indicated number of carbon atoms. For example, C2-6 indicates that the group may have from 2 to 6 (inclusive) carbon atoms in it. Alkenyl groups can either be unsubstituted or substituted with one or more substituents.

[0692] The term "alkynyl" refers to an acyclic hydrocarbon chain that may be a straight chain or branched chain having one or more carbon-carbon triple bonds. The alkynyl moiety contains the indicated number of carbon atoms. For example, C2-6 indicates that the group may have from 2 to 6 (inclusive) carbon atoms in it. Alkynyl groups can either be unsubstituted or substituted with one or more substituents.

[0693] The term "aryl" refers to a 6-20 carbon mono-, bi-, tri- or polycyclic group wherein at least one ring in the system is aromatic (e.g., 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system, or more specifically 6-carbon monocyclic, or 10-carbon bicyclic); and wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, dihydro-1 H-indenyl and the like.

[0694] The term "cycloalkyl" as used herein refers to cyclic saturated hydrocarbon groups having, e.g., 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons, most preferably 3-6 ring carbons, wherein the cycloalkyl group may be optionally substituted. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl may include multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyl includes: bicyclo[1.1.0]butanyl, bicyclo[2.1.0]pentanyl, bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, bicyclo[2.1.1]hexanyl, bicyclo[3.2.0]heptanyl, bicyclo[4.1.0]heptanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[4.2.0]octanyl, bicyclo[3.2.1]octanyl, bicyclo[2.2.2]octanyl, and the like. Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentanyl, spiro[2.5]octanyl, spiro[3.5]nonanyl, spiro[3.5]nonanyl, spiro[3.5]nonanyl, spiro[4.4]nonanyl, spiro[2.6]nonanyl, spiro[4.5]decanyl, spiro[3.6]decanyl, spiro[5.5]undecanyl, and the like. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms.

[0695] The term "cycloalkenyl" as used herein means partially unsaturated cyclic hydrocarbon groups having 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkenyl group may be optionally substituted. Examples of cycloalkenyl groups include, without limitation, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. As partially unsaturated cyclic hydrocarbon groups, cycloalkenyl groups may have any degree of unsaturation provided that one or more double bonds is present in the ring, none of the rings in the ring system are aromatic, and the cycloalkenyl group is not fully saturated overall. Cycloalkenyl may include multiple fused and / or bridged and / or spirocyclic rings.The term “heteroaryl”, as used herein, means a mono-, bi-, tri- or polycyclic group having 5 to 20 ring atoms, alternatively 5, 6, 9, 10, or 14 ring atoms, preferably 5 to 10 ring atoms; and having 6, 10, or 14 pi electrons shared in a cyclic array; wherein at least one ring in the system is aromatic, and at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, and S (but does not have to be a ring which contains a heteroatom, e.g. tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl). Heteroaryl groups can either be unsubstituted or substituted with one or more substituents. Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromanyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, benzo[d][1,3]dioxolyl, 2,3-dihydrobenzofuranyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[b][1,4]oxathiinyl, isoindolinyl, and others. In some embodiments, the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl.

[0696] The term "heterocyclyl" refers to a mon-, bi-, tri-, or polycyclic saturated ring system with 3-16 ring atoms (e.g., 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system, preferably 5 or 6-membered monocyclic) having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like. Heterocyclyl may include multiple fused and bridged rings. Non-limiting examples of fused / bridged heteorocyclyl includes: 2-azabicyclo[1.1.0]butanyl, 2-azabicyclo[2.1.0]pentanyl, 2-azabicyclo[1.1.1]pentanyl, 3- azabicyclo[3.1.0]hexanyl, 5-azabicyclo[2.1.1]hexanyl, 3-azabicyclo[3.2.0]heptanyl octahydrocyclopenta[c]pyrrolyl, 3-azabicyclo[4.1.0]heptanyl, 7-azabicyclo[2.2.1]heptanyl, 6- azabicyclo[3.1.1]heptanyl, 7-azabicyclo[4.2.0]octanyl, 2-azabicyclo[2.2.2]octanyl, 3- azabicyclo[3.2.1]octanyl, 2-oxabicyclo[1.1.0]butanyl, 2-oxabicyclo[2.1.0]pentanyl, 2 oxabicyclo[1.1.1]pentanyl, 3-oxabicyclo[3.1.0]hexanyl, 5-oxabicyclo[2.1.1]hexanyl, 3- oxabicyclo[3.2.0]heptanyl, 3-oxabicyclo[4.1.0]heptanyl, 7-oxabicyclo[2.2.1]heptanyl, 6- oxabicyclo[3.1.1]heptanyl, 7-oxabicyclo[4.2.0]octanyl, 2-oxabicyclo[2.2.2]octanyl, 3- oxabicyclo[3.2.1]octanyl, and the like. Heterocyclyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentanyl, 4-azaspiro[2.5]octanyl, 1-azaspiro[3.5]nonanyl, 2-azaspiro[3.5]nonanyl, 7-azaspiro[3.5]nonanyl, 2-azaspiro[4.4]nonanyl, 6-azaspiro[2.6]nonanyl, 1,7-diazaspiro[4.5]decanyl, 7-azaspiro[4.5]decanyl 2,5-diazaspiro[3.6]decanyl, 3-azaspiro[5.5]undecanyl, 2-oxaspiro[2.2]pentanyl, 4-oxaspiro[2.5]octanyl, 1-oxaspiro[3.5]nonanyl, 2-oxaspiro[3.5]nonanyl, 7-oxaspiro[3.5]nonanyl, 2-oxaspiro[4.4]nonanyl, 6-oxaspiro[2.6]nonane, 1,7-dioxaspiro[4.5]decanyl, 2,5-dioxaspiro[3.6]decanyl, 1-oxaspiro[5.5]undecanyl, 3-oxaspiro[5.5]undecanyl, 3-oxa-9-azaspiro[5.5]undecanyl and the like. The term “saturated” as used in this context means only single bonds present between constituent ring atoms and other available valences occupied by hydrogen and / or other substituents as defined herein.

[0697] The term "heterocycloalkenyl" as used herein means partially unsaturated cyclic ring system with 3-16 ring atoms (e.g., 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system, preferably 6-membered monocyclic) having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic, said heteroatoms selected from O, N, or S (e.g., carbonatoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent. Examples of heterocycloalkenyl groups include, without limitation, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl. As partially unsaturated cyclic groups, heterocycloalkenyl groups may have any degree of unsaturation provided that one or more double bonds is present in the ring, none of the rings in the ring system are aromatic, and the heterocycloalkenyl group is not fully saturated overall. Heterocycloalkenyl may include multiple fused and / or bridged and / or spirocyclic rings.

[0698]

[0699] substituted with an oxo group; or (ii) a heteroaryl group.

[0700] As used herein, when a ring is described as being “aromatic”, it means said ring has a continuous, delocalized TT-electron system. Typically, the number of out of plane TT-electrons corresponds to the Huckel rule (4n+2). Examples of such rings include: benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thioazole, isoxazole, isothiazole, and the like.

[0701] As used herein, when a ring is described as being “partially unsaturated”, it means said ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributed to the ring itself; e.g., one or more double or triple bonds between constituent ring atoms), provided that the ring is not aromatic. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.

[0702] For the avoidance of doubt, and unless otherwise specified, for rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, cycloalkyl, and the like described herein) containing a sufficient number of ring atoms to form bicyclic or higher order ring systems (e.g., tricyclic, polycyclic ring systems), it is understood that such rings and cyclic groups encompass those having fused rings, including those in which the points of fusion are located (i) on adjacent ring atoms (e.g., [x.x. O] ring

[0703] systems, in which 0 represents a zero atom bridge (e.g.,

[0704]

[0705] )); (ii) a single ring atom (spiro-fusedring systems) (e.g., ), or (iii) a contiguous array of ring atoms

[0706] (

[0707]

[0708] bridged ring systems having all bridge lengths > 0) (e.g.,

[0709] In addition, atoms making up the compounds of the present embodiments are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include 13C and 14C.

[0710] In addition, the compounds generically or specifically disclosed herein are intended to include all

[0711] tautomeric forms. Thus, by way of example, a compound containing the moiety:

[0712]

[0713] encompasses the tautomeric form containing the moiety:

[0714]

[0715] . Similarly, a pyridinyl or pyrimidinyl moiety that is described to be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms.

[0716] Further, compounds described herein may exist in one or more stereoisomeric forms. In some cases, such forms may be described through an assignment of absolute configuration, whereas other cases, stereochemistry is unknown and may be assigned arbitrarily to isolated stereoisomers. Isolation of stereoisomers may be conducted using chiral separation.

[0717] Compounds described herein (for example compounds of Formula (I) or any subformula, or compounds of T able 1, or their synthetic precursors) having one enantiomeric form may epimerise into the other enantiomeric form if the chiral center is in a position susceptible to epimerization (for instance on the 3-position of the piperidine-2, 6-dione ring). Thus, unless it is specifically stated or the context indicates otherwise, disclosure of one stereoisomer with a chiral centre encompasses the isolated stereoisomer and a mixture, such as a racemic mixture, of the (R) and (S) stereoisomers if the stereoisomers epimerise. For

[0718] 0\ /

[0719] CK

[0720] Tn N H / X \

[0721] MeMe

[0722] Cl

[0723]

[0724] N ^0

[0725] H

[0726] example, a disclosure of a compound encompasses both isolated

[0727]

[0728] including a racemic mixture of the two stereoisomers. Similarly, compounds (for example compounds of Formula (I) or any subformula, or compounds of Table 1, or their synthetic precursors) comprising an epimerisable chiral center on the glutarimide ring disclosed herein without its stereoisomeric form indicated encompasses the isolated enantiomer and a mixture, such as a racemic mixture. For example, a disclosure of a compound

[0729]

[0730]

[0731] encompasses both isolated, isolated

[0732]

[0733]

[0734] , including a racemic mixture of the two stereoisomers.

[0735] As used herein, the phrase “optionally substituted” when used in conjunction with a structural moiety (e.g., alkyl) is intended to encompass both the unsubstituted structural moiety (i.e., none of the substitutable hydrogen atoms are replaced with one or more non-hydrogen substituents) and substituted structural moieties substituted with the indicated range of non-hydrogen substituents. For example, “CI-C4 alkyl optionally substituted with 1-4 Ra” is intended to encompass both unsubstituted C1-C4 alkyl and C1-C4 alkyl substituted with 1-4 Ra.

[0736] The reactions conducted herein may be conducted under any suitable conditions. These reaction conditions encompass the reagents, catalysts, solvents, temperatures, pressures, and other parameters under which a chemical reaction is performed. The skilled person is well versed in synthetic chemistry and would be aware of a range of techniques, reagents, and conditions for conducting each of the steps described herein. In addition, in each case, suitable reaction conditions are provided herein, which one of skilled in the art would be able to implement or adapt as needed.

[0737] The term "amide coupling conditions" as used herein refers to chemical conditions and reagents used to form an amide bond between a carboxylic acid (or a derivative thereof, such as an acyl chloride or ester) and an amine (such as ammonia or a primary / secondary amine).

[0738] The term “coupling reagent” as used herein refers to a chemical reagent used to facilitate the formation of a bond between two molecules, particularly those that would otherwise have difficulty reacting with each other. Non-limiting examples of coupling agents include T3P (1-propylphosphonic acid cyclic anhydride), T4P (1-butylphosphonic acid cyclic anhydride), EDC (1 -Ethyl-3-(3-dimethylaminopropyl)carbodiimide) DCC (dicyclohexylcarbodiimide), BOP (benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate), HATU (O-(7-Azabenzotriazol-1-yl)-N, N, N', N -tetramethyluronium hexafluorophosphate), HBTU (2-(1 H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate), CDI (carbonyldiimidazole) and DMTMM (4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride).

[0739] The term “base” as used herein refers to a molecule that can accept hydrogen ions (protons) or donate electron pairs. Bases include inorganic bases, organic bases and superbases. Inorganic bases include NaOMe, NaOEt, KOMe and KOEt. Organic bases include amine bases such as DBU (1,8-diazabicyclo(5.4.0)undec-7-ene) or DBN (1,5-diazabicyclo(4.3.0)non-5-ene), DIPEA (N, N-diisopropylethylamine), TEA (Et3N), pyridine, DEA (diethanolamine), n-Butylamine, Isopropylamine, NMM ( / V-methymorpholine), DABCO (1,4-diazabicyclo[2.2.2]octane) and piperidine. Superbases include lithium diisopropylamide (LDA), Sodium hydride (NaH), potassium hydride (KH), terf-butoxide (t-BuOK), NaOtBu, LiHMDS, NaHMDS, and KHMDS. Some chemical reactions described herein can be conducted under basic conditions, e.g. at a pH of greater than 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, or at least 14. Stronger bases can be made from the addition of alkali earth metals to hydrocarbons, amines and dihydrogen. Examples include butyl lithium, lithium diisopropylamide (LDA), Lithium diethylamide (LDEA), sodium amide, sodium hydride (NaH), and Lithium bis(trimethylsilyl)amide. Weaker bases include ammonia and amines, for example trialkylamines such as triethylamine and diisopropylethylamine, and anions of weak acids such as acetates (e.g. sodium acetate), potassium acetate, and carbonates (e.g. sodium carbonate, potassium carbonate).

[0740] The term “solvent” as used herein refers to is a molecule that has the ability to dissolve another molecule (the solute), forming a solution. Solvents are typically liquids. The solvent dissolves the solute without changing its chemical structure, allowing the solute to disperse evenly throughout the solvent. Many organic solvents are suitable for the chemical reactions described herein. For example, the reactions described herein may be conducted in an aprotic organic solvent. Suitable examples include: acetonitrile; dimethylsulfoxide (DMSO); dimethylformamide (DMF); dimethylacetamide; N-methylpyrrolidone; halogenated alkanes such as dichloromethane (DCM); aromatic compounds such as benzene, toluene, xylene, mesitylene, and naphthalene; alkanes such as hexane, heptane, and octane; ketones such as acetone; ether compounds such as diethyl ether, tetrahydrofuran (THF), derivatives of THF such as methyl-THF; ester compounds such as ethyl acetate and isopropylacetate; and amines such as pyridine. Proticsolvents may also be used in the reactions described herein. Protic solvents include: water; alcohols such as a C1-10 aliphatic branched or linear alcohols, in particular C1-C6 alcohols; and carboxylic acids such as methanoic acid, ethanoic acid, propanoic acid, etc. Preferred solvents include toluene, ethanol, ethyl acetate isopropyl acetate, methyl-THF, heptane and isopropanol. The reactions described herein may be carried out using solvents such as DCM, DME, DMF, dioxane and 1,2 dichloroethane. In certain embodiments, the amount of solvent in the reaction mixture is in the range of from 0.1 % to 99% (v / v), from 0.1 % to 80% (v / v), from 0.1 % to 75% (v / v), from 0.1 % to 50% (v / v), from 1 % to 40% (v / v), from 2% to 30% (v / v), from 4% to 25% (v / v) or from 5% to 20% (v / v).

[0741] The term “polar” as used herein refers to an uneven distribution of electrical charge within a molecule, resulting in a molecule having a partial positive charge on one side and a partial negative charge on the other. Non-limiting examples of polar solvents include water, ethanol (EtOH), methanol (MeOH), acetic acid, acetone, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), acetonitrile (CH3CN). The term “aprotic” as used herein refers to a lack of hydrogen atoms that can be easily donated in chemical reactions. In other words, an aprotic compound lacks acidic hydrogen atoms. Non-limiting examples of aprotic solvents include dimethylacetamide, dimethylformamide (DMF), N-methylpyrrolidone (NMP), 1,4-dioxane, acetone, dimethyl sulfoxide (DMSO), acetonitrile, tetrahydrofuran (THF), and ethyl acetate.

[0742] The term “acid” as used herein refers to a molecule that can donate a hydrogen ion (protons) or accepts an electron pair. Acids include mineral acids, organic acids and Lewis acids. Mineral acids include hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid and phosphoric acid. Organic acids include carboxylic acids and derivatives thereof such as acetic acid and benzoic acid; and halogenated acetic acids such as trifluoroacetic acid, and dichloroacetic acid. Organic acids also include formic acid, p-toluenesulfonic acid and methanesulfonic acid. Lewis acids include aluminium chloride, boron trifluoride, and titanium tetrachloride. Some chemical reactions described herein can be conducted under acidic conditions, e.g. at a pH of less than 7, no more than 6, no more than 5, no more than 4, no more than 3, no more than 2, or no more than 1.

[0743] The term “water-free” as used herein refers to the absence of water. This term may be used interchangeably with the term anhydrous. Where a reagent is described as water-free, it may comprise less than 5% water by weight, for example less than 4% water by weight, or less than 3% water by weight, or less than 1% water by weight, or less than 0.5% water by weight, or less than 0.1 % water by weight, or 0% water by weight.

[0744] The term “protecting group” as used herein refers to is a chemical group or functional group temporarily added to a molecule to shield or protect a reactive part of the molecule during a reaction. The protecting group can be easily removed at a later stage, restoring the original functional group present in the molecule. The protecting groups allows for controlling selectivity. Just as an example, a hydroxyl group (-OH) might be protected by converting it into a silyl ether (such as TBS) to prevent it from reacting during a certain step. After the reaction, the silyl group can be removed, regenerating the free hydroxyl group. Protecting groups include hydroxyl protecting groups (i.e. groups that protect alcohols or phenols, such as ethers, esters and silyl protecting groups), amine protecting groups (i.e. groups that protect amine functionalities, such as carbamates, sulfonamides, amides), carbonyl protecting groups (i.e. groups that protect aldehydes or ketones, such as acetals, ketals and hydrazones), carboxylic acid protecting groups (i.e. groups that protect carboxylic acids, such as esters and amides), and phosphate or thiol protecting groups (i.e. groups that protect phosphate or thiol groups such as alkyl, aryl esters and thioethers). Nonlimiting examples include tert-butyldimethylsilyl (TBD), tri methylsilyl (TMS), benzyl (Bn), methoxymethyl (MOM), trityl (Tr), acetals, ketals, dioxanes, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and Fmoc (fluorenylmethyloxycarbonyl).The term “catalyst” as used herein refers to a molecule that increases the rate of a chemical reaction without being consumed or permanently altered in the process. Catalysts include metal catalysts and organocatalysts. Metal catalysts include palladium, rhodium and nickel catalysts. For example, palladium catalysts include (Pd(PPh3)4, Pd(PtBu3)2, Pd(pda)2, Pd(dppf)Cl2, Pd(OAc)2, Pd2(dba)3). Nickel catalysts include (Ni(PPh3)4, Ni(acac)2, Ni(COD)2, NiCl2, Raney Ni). Other non-limiting catalysts include catalysts for use in Krapcho decarboxylations, for example NaCN, KCN, LiCI, NaCI, NaBr, Nal, LiI·H2O, Na2CO3·H2O, Na3PO4·12H2O, and Me4NOAc; and C0CI2.

[0745] The term “reducing agent” as used herein refers to a molecule that donates electrons to another molecule during a chemical reaction, causing that molecule to be reduced (i.e., it gains electrons). In the process, the reducing agent itself becomes oxidized (i.e. it loses electrons). Reducing agents include hydride reducing agent (for example, NaBH4 or LiAlH4), metallic reducing agents (for example Zinc, Iron or Magnesium) and metal ion reducing agents (for example, Iron (II) or Copper (I)).

[0746] The term “reagent” as used herein refers to a molecule used in a chemical reaction to cause or facilitate the reaction. Reagents as referred to herein include starting materials (reactants), catalysts and solvents.

[0747] The term “alkylating agent” as used herein refers to a compound that adds an alkyl group (a group derived from an alkane, such as a methyl group or an ethyl group) to another molecule. Non-limiting examples of alkylating agents include Mel, Etl, MeBr, EtBr, 1,2-dibromoethane, methyl tosylate, ethyl tosylate, methyl sulfonyl chloride, ethyl sulfonyl chloride, methyl triflate, diazomethane dimethyl sulfate (DMS) and diethyl sulfate (DES).

[0748] The term “leaving group” as used herein refers to a group or atom that detaches from a molecule during a chemical reaction, typically in a substitution or elimination process, to form a stable entity after the bond breaks. Leaving groups include halides (for example, fluoride, chloride, bromide and iodide), sulfonate esters (for example, tosylate, mesylate and triflate), sulphate groups, alcohols, water and amines. Specific leaving groups used herein include Cl, Br, I, OH, OM, O(C=O)(C1-6 alkyl), O(C=O)(N3), O(C1-6 alkyl), and S(C1-6 alkyl).

[0749] The term “ligand” as used herein refers to a molecule or ion that binds to a central metal atom or ion in a coordination complex, forming a coordination bond. Ligands can be simple ions (e.g. chloride) or more complex molecules (e.g. ethylenediamine) that donate one or more pairs of electrons to the metal centre to form the bond. Ligands described herein may be monodentate, bidentate or polydentate ligands.

[0750] Macrocyclic ligands are also included. Exemplary ligands include phosphine ligands, for example 1,1 ’-Bis(diphenylphosphino)ferrocene (dppf), 2-Dicyclohexylphosphino-2’,6’-dimethoxybiphenyl (SPhos), 1,3-Bis(diphenylphosphino)propane (dppp), 1,4-Bis(diphenylphosphino)butane (dppb), and Xantphos (4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene), Bis(diphenylphosphino)methane (DPPM), 1,2-Bis(diphenylphosphino)ethane (DPPE), 1,2-Bis(dicyclohexylphosphino)ethane (DCPE), PPhs, P(c-hex)3, P(‘BU)3, P(C6F5)3, and P(2,4,6-Me3C6H2)3.

[0751] The term “additive” as used herein refers to a substance that is added in small quantities to another substance to enhance or modify its properties, performance, or behaviour. For example, the additive may act as a stabiliser to prevent degradation of another molecule during a reaction. Exemplary additives include antioxidants, such as BHT, or additives for use with coupling reagents, for example those used in order to enhance reactivity and reduce the formation of epimers and N-acyl ureas during amide coupling reactions (for example, HOBt (1 -Hydroxybenzotriazole), HOOBt (HODhbt) (Hydroxy-3, 4-dihydro-4-oxo-1,2,3-benzo-triazine), HOSu (N-Hydroxysuccinimide), HOAt (1-Hydroxy-7-aza-1 H-benzotriazole), Ethyl 2-cyano-2-(hydroximino)acetate and DMAP (4-(N, N-Dimethylamino)pyridine)).The term “flow conditions” as used herein refers to reaction conditions in which reactions are conducted within a system (e.g. a flow reactor) that maintains a continuous and controlled flow of reagents through the system. Use of “flow conditions” allows for control over reaction conditions, for example the temperature, pressure, mixing rate and / or reaction time. It may include pumping fluid into a flow reactor or contacting two or more fluids via tubes of a flow reactor that join one another at a controlled rate. The flow reactor may be a Plug Flow Reactor (PFR), a Continuous Stirred-Tank Reactor (CSTR), a Tubular Flow Reactor, a Microflow Reactor, a Packed-Bed Flow Reactor, a Trickle-Bed Reactor, a Monolithic Flow Reactor, a Loop Flow Reactor, an Oscillatory Flow Reactor or a Spinning Disc Flow Reactor. “Flow conditions” do not include conditions for static or batch-based chemical reactions, for example static or batch-based chemical reactions carried out prior to or subsequent to the reaction carried out under flow conditions. The reaction carried out under flow conditions may nevertheless be used in conjunction with static or batch-based chemical reactions carried out prior to or subsequent to the reaction carried out under flow conditions (for example, static or batch-based reaction workups or purifications).

[0752] The term “residence time” as used herein refers to the average time that a molecule spends under certain reaction conditions (e.g., inside a reactor before leaving it). For example, when used in the context of flow conditions, the term “residence time” as used herein refers to the average time that a molecule spends under flow conditions (e.g., within a flow reactor before leaving it). Controlling the residence time may allow for certain factors of a synthesis (e.g., conversion of reagents, selectivity and yield) to be optimised.

[0753] The reactions described herein can be run for as long as needed to achieve completion of the reaction, or at least an acceptable yield of product. For example, the duration of the reaction may be less than 1 minute, less than 5 minutes, less than 10 minutes, less than 30 minutes, less than 1 hour, less than 2 hours, less than 3 hours, less than 5 hours, less than 10 hours, less than 20 hours, less than 30 hours less than 40 hours, less than 50 hours, less than 60 hours, less than 70 hours, less than 80 hours, less than 90 hours, or less than 100 hours. The reaction time may depend, inter alia, on the scale of the reaction. The skilled person can monitor the progress of the reaction in a number of different ways including by monitoring physical changes such as a change in colour, or by monitoring the reaction using analytical methods such as NMR, FT-IR, XRPD, or chromatography, for example thin layer chromatography (TLC) or liquid chromatography coupled to mass spectrometry (LC-MS).

[0754] Upon completion of the reactions described herein, the reaction mixture is optionally purified. Purification techniques are known to the skilled person and include: chromatography (e.g. HPLC, which may be reverse phase or normal phase); liquid-liquid separation, for example using multiple immiscible solvents; and / or liquid-solid separation, for example using filtration, decantation, (re)crystallisation (e.g. concentration induced crystallisation, antisolvent crystallisation and cooling induced crystallisation), trituration, evaporation, freeze drying.

[0755] The reactions described herein may be performed on any suitable scale. In one embodiment, the reaction mixture is of industrial scale. It may for example have a volume of at least 1 I, in particular at least 10 I, at least 100 I, or at least 1000 I. In another embodiment, the reaction mixture is of microscale. It may for example have a volume of 10 ml or less, in particular 1 ml or less, 100 pl or less, 10 pl or less or 1 pl or less.

[0756] The reactions described herein may be part of a series of reactions comprising a synthesis. Where multiple reactions are described, these can be conducted in a sequential fashion or in a one-pot fashion. Sequential reactions typically involve the completion of a first reaction, followed by work up and purification of that reaction, before a second reaction is conducted, continuing with further reactions until the desired product has been made. In contrast, in a one-pot fashion, a first reaction may be completed, and then asecond reaction may be conducted using one or more products of the first reaction without isolation. One pot reactions are advantageous because they avoid unnecessary purification steps, saving time and materials.

[0757] The expression "comprise", as used herein, besides its literal meaning also includes and specifically refers to the expressions "consist essentially of and "consist of. Thus, the expression "comprise" refers to embodiments wherein the subject-matter which "comprises" specifically listed elements may and / or indeed does encompass further elements as well as embodiments wherein the subject-matter which "comprises" specifically listed elements does not comprise further elements.

[0758] Numeric ranges described herein are inclusive of the numbers defining the range. The headings provided herein are not limitations of the various aspects or embodiments of this invention which can be read by reference to the specification as a whole. According to one embodiment, subject matter described herein as comprising certain steps in the case of methods or as comprising certain ingredients in the case of compositions refers to subject matter consisting of the respective steps or ingredients. It is preferred to select and combine specific aspects and embodiments described herein and the specific subject-matter arising from a respective combination of specific embodiments also belongs to the present disclosure.

[0759] The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features and advantages of the invention will be apparent from the description and drawings, and from the claims.

[0760] Non-Limiting Exemplary Compounds preparable by the invention

[0761] In some embodiments, the processes of the invention are used for producing a compound according to Formula (I) or any subformula as defined herein.

[0762] For instance, processes of the invention may be used to prepare compounds of Formula (I),

[0763]

[0764] H (I), or a pharmaceutically acceptable salt thereof.

[0765] In particular, the processes of the invention may be used to prepare a compound of one or more subformula selected from the group consisting of:

[0766]

[0767] (VIII-D)

[0768] (VIII-E)

[0769]

[0770] o

[0771] (VIII-F)

[0772] (VIII-G)

[0773] (VIII-I)

[0774]

[0775]

[0776]

[0777]

[0778]

[0779] , or a pharmaceutically acceptable salt thereof.

[0780] In the compounds of formula (I), (l-A), (l-B), (II), (Vlll-A), (Vlll-B), (Vlll-C), (Vlll-D), (Vlll-E), (Vlll-F), (VIII-G), (Vlll-H), (Vlll-I), (Vlll-P), or (Vlll-Q), or a salt thereof, R1may be selected from the group consisting of the following:

[0781]

[0782] Processes of the invention involving compounds of Formulas (2) and (3) can be used to prepare compounds of Formula (I) and its subformulae, or a pharmaceutically acceptable salt thereof, wherein R1, R2a, and R2bare defined according to (A) and (B) or more preferably (A1) and (B1) defined herein; X is H; or halo; Yi and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH; R3is H; C1-2 alkyl, which is optionally substituted with 1-5 fluoro; fluoro; chloro; or cyano; R4is chloro; bromo; or fluoro; optionally wherein it is provided that R4is fluoro when R3is chloro.

[0783] Processes of the invention involving compounds of Formulas (n) and (0) can be used to prepare compounds of Formula (I) and its subformulae, or a pharmaceutically acceptable salt thereof,, wherein R1, R2a, and R2bare defined according to (A2) and (B2) defined herein; X is H; or halo; Y1 and Y2 are CH or N, wherein at least one ofYi and Y2 is CH; R3is H; C1-2 alkyl, which is optionally substituted with 1-5 fluoro; fluoro; chloro; or cyano; R4is chloro; bromo; or fluoro; optionally wherein it is provided that R4is fluoro when R3is chloro. The processes of the invention may be used to prepare compounds of Formula (I) selected from the group consisting of the compounds delineated in Table 1 or a pharmaceutically acceptable salt thereof.

[0784] Table 1. Compounds Table

[0785]

[0786] A oNA N

[0787] 8 r£ > > ^1N

[0788] 8 \zz2 o — 8 = zz ZZ < o= V / \HIZ LJL

[0789] pr“ A o- oA PClCT^N' X)

[0790] Sf oAn p o H zz

[0791] oA p — — \ / / \ - - o / = Compound 16 ZZ 22 ZZ — \ / - Compound 17 Compound 18

[0792] ZZ /

[0793] '' o o

[0794] ' o pz

[0795] z / /

[0796] ^o Z

[0797] Comp u H p p o

[0798] o nd 19 Compound 20 Compound 21

[0799] \

[0800] N^N 0z

[0801] 22

[0802] i Z o p Z o — Z o \- \

[0803] A ^NV nzz ZTz

[0804] p —

[0805] 2°=

[0806] / NZZ- \ H^QT Qo- oJ°

[0807] A H U QAo- °.

[0808] pH

[0809] ClO^N^O ZI zzACH O

[0810] H OL^QCT o p y\ o \—^N H^O

[0811] (

[0812] p ( Q 7 —

[0813] Com ound 22 Compound 23 Q 7 —

[0814] \ zz Compound 24 ' o' o

[0815] s

[0816] s J

[0817] i zz- A xp cr 'N' x) H

[0818] Compound 25 o p Compound 26 r? Compound 27

[0819] \

[0820] A u 2 Z o \ —ZT zzFA? 8 2°= ^k AN^^ \Z o=c|£ ZZ zz

[0821] A H zz z

[0822] p LJ y\ °

[0823] H O=L ^ A pr z

[0824] ZI (K 'N^'O

[0825] HClo^isr ^o Xp o

[0826] H Q o oH pA p= < O P ^ o (A = Q — 7 ( / \ Q - Compound 28 Compound 29 Compound 307 — 2 z \ zzzz- / ZZ 2 ZZ 2 '' o o p> '' o o? " r il?

[0827] z

[0828] A H L ll ^

[0829] ciO^N^O

[0830] H

[0831] Compound 31 Compound 32 Compound 33

[0832] A N if A H

[0833] ci O A^N A^. O H

[0834] Compound 34 Compound 35 Compound 36

[0835] H2N / P J

[0836] o' T n?

[0837] A H I II

[0838] Cl

[0839] H

[0840]

[0841] Compound 37 Compound 38 Compound 39 / Zl oz

[0842] 0 < o o 0 \ y Z o \zz zz— y= Z o= y V o Z — £ o

[0843] IZ IZ [I J J r ii ^Z o=

[0844] ^^xoxp pHHClO^N^O H H

[0845] Sfn o H H ZI

[0846] \( °Z= ZI

[0847] o o=

[0848] Compound 40 — — / / \ \ — —

[0849] y y IZ IZ Compound 41 Compound 42 '' o o C)

[0850] xO $C La¥ 'x O / \

[0851] z'

[0852] n?

[0853] \O x X

[0854] O' zi

[0855] p o

[0856] Compound 43 Compound 44 Compound 45

[0857] \

[0858] y Z o —zz

[0859] $ IZ IZ _ 0o\- 5 o=

[0860] yr^ °

[0861] ZI Xp o

[0862] ZT ^ y< o=

[0863] °Z= y o=

[0864] ( z \ Q — 7 — iz /

[0865] zz /

[0866] Compound 46 p p Compound 47 ' o Compound 48

[0867] z Z— ' o

[0868] J o /

[0869] aHpp / ? O^ b W zx

[0870] '°' \ iz

[0871] p p O T1

[0872] Cly z=—

[0873] o CK 'N'^ X)

[0874] H CZ zw

[0875] \ \Tz -^7

[0876] ompound 49 Compound 50 Compound 51

[0877] y y y

[0878] O o Z— \

[0879] o Z— o Z—ZI8 yo=

[0880] \Z o= \Z= 0 £ IZ yo IZ=

[0881] p 06H- ° IZ IZ

[0882] ZI

[0883] oZ= ZT "■'A w O 00 o= y\ oZ= ( ( 2 o= y o0= Q — / / \ -ClZZQ O^zz7 — \ \ / / / - N 2 yzziz^O 0 o H '' o o x O /

[0884] S ■ Compound 52 Compound 53 Compound 54 '' o o px Z L

[0885] o' °

[0886] 0

[0887] XX Cl

[0888] A H |l 2.

[0889] CloX HXo

[0890] Compound 55 Compound 56 Compound 57

[0891] H2N / P

[0892] O^N' X)

[0893] H

[0894]

[0895] Compound 58 Compound 59 Compound 60\ \ I ro

[0896] Zo O?-.

[0897] C«Z (> Sxx"oo / / " O / _ _ p o o r?

[0898] IT^I0\ £ ' o 1! J nrzxiI )Oo°==IZ / = / IZ IZ IZ IZ H2N 'Q A H L }\ °=ip.

[0899] pr° AX

[0900] Sfn oCLCT^N HXD (XfpH o Q \ o=- p\ ZI

[0901] op=

[0902] \ o op p Op= — \ Q —

[0903] \ — 7 \

[0904] Compound 61 Q \ IZ — 7 \ — / \ \ / IZ — —

[0905] \ \ \ IZ IZ IZ Compound 62 Compound 63 d' o d'' o o 0

[0906] li^l 9

[0907] oxA A X a / O '

[0908] b A H L ip.

[0909] p “pQClO^N^O co xxx H H o

[0910] Compound 64 Compound 65 Compound 66

[0911] 2 o Z~ \ZT

[0912] H2Pl I Pro >\°

[0913] I='

[0914] Npp AN^^CI

[0915] ° A ZI H

[0916] O / =

[0917] ClO^N^O

[0918] H

[0919] Compound 67 z Z— Compound 68 Compound 69

[0920] oT

[0921] N^p o

[0922] <' Xx A ci W xc A H pip. p ci xL

[0923] O^N^O

[0924] HCLCXNX)

[0925] H CD Z \ - Compound o= VZ 70 Compound 71 Compound 72 yj \

[0926] ZI XX P zx c °z=HA H L I yyClO^N^OCLCXN HX)

[0927] H

[0928] Compound 73 Compound 74 Compound 75 F

[0929] 0

[0930] M'S 0 <ZXJUL ci

[0931] JXJL JL ZK ^XZCI0XPpN^^ciF^PPPP\^ A H [I 1 A H 1 |lClO^N^O

[0932] ClCLCXNX> O^N^O H H H

[0933] Compound 76 Compound 77 Compound 78

[0934] H

[0935] °< XX A Cl < XX A ci A H |l J

[0936] CLCAN^OClO^N^O H

[0937] H

[0938]

[0939] Compound 79 Compound 80 Compound 81A"

[0940] o

[0941] p H

[0942] Ck^hL

[0943] 8 =- Xzx£ £ IZ A > o“ A 2° H= IZ IZ IH - \ o=A IZ

[0944] fi AA ■ A? A^—>CQylO^N^O

[0945] Z QA— O AA A H

[0946] O AA ox ZT ZT

[0947] pounQdA 8 < Q 7 — \

[0948] Com 2 o A=\ \ ( o iz

[0949] V / X( — / — Compound 83 Com O / =

[0950] \ 2 pound 84 \- iz TZ iz —

[0951] 2 iz

[0952] ' o 0

[0953] '' o C> o' o o

[0954] / \ H^QT $

[0955] /

[0956] oClO^N^O

[0957] H

[0958] p p p p

[0959] Compound 85 Compound 86 Compound 87

[0960] \zx

[0961] , A 2A Z o~ \ — \ \zx zx zx

[0962] hL £ £ ^

[0963] IZ 5< ° \Z o= > A 2 o- o o- r i N IZ }\ )\°=°==

[0964] X

[0965] wA vA C

[0966] A H ML. A

[0967] ZT ZI Z Ar

[0968] I?°

[0969] ci Ux xU ZI Q

[0970] O^N^O o / = K o

[0971] M A ( Q — 7

[0972] H ^ o= ( Q 7 —

[0973] xz /

[0974] xz /

[0975] Compound 88 ( r? O _ Compound 89 ' o

[0976] ' o Compound 90 o X U_z\

[0977] o

[0978] " A u

[0979] A H I II / A\NH r n ii z z

[0980] CI(AN Cl xik xL H O^N^O H

[0981] Compound 91 Compound 92 £ £ Compound 93

[0982] £ IZ IZ

[0983] A> A Q? Q o AA o AA o AA Q 7 — \ ( Q / x — 72 — iz 2 izxz / '' o ' o o Compound 94 Compound 95 Compound 96

[0984] ClO^N^O

[0985] H

[0986] Compound 97 Compound 98 Compound 99 r £ y

[0987] HILA

[0988] Clcr^N^o H

[0989] Compound 100 Compound 101 Compound 102

[0990] 0

[0991] odA c (A^N H^O

[0992]

[0993] ox

[0994] o X C / ompound 103 Compound 104 Compound 105 20= \ZTIZ IZ 2 Z o — / V SXffH Q o- ( 2 o= 2 o=\ ZI

[0995] — / \ —

[0996] \ zz ZZ / ^ °= Compound 106zzo o Compound 107 Compound 108 w

[0997] o

[0998] Compound 109 Compound 110 Compound 111

[0999] 5, 0

[1000] N<;>sjj0i? IZ

[1001] kUk A / k.. i Al l zz C, / "' N--\

[1002] / \NH ir0A COHG V-\r o —clo 2 o=\

[1003] CT 'N' ADClckr O p / \ - ^^oHCQ-A H IZ 2 H

[1004] / \ -0N< 2 zz H 0 Compound 112 Compound 113zo

[1005] zo Compound 114

[1006] N-~! 0

[1007] s / C " iX / . ci O A^N A^OCLQINIQ p H H Compound 11 \5ZTCompound 116 5 Co 2°=m IZpound 117

[1008] ) IZ

[1009] HM-N o —

[1010] 0 \ / o=

[1011] -A A 1 Cl / \ H^Q w T -'I NA 1 Cl AANAA f)n o

[1012] H L Jl ^xHM kk O ZI ( Q — 7 \CIQ — 7ClQI 2 zz O^N^O 2 ZZ HciO^N^O N HX)

[1013] Hzzo o Compound 118 Compound 119 Compound 120 H dN-~. o 0 O o

[1014] 41 £ aNs 1 A ci ° Ac

[1015] NA A NHA I / LV 1.

[1016] Clcr^N^ociO'lhX HClCT 'N'^O o H H

[1017] Compound 121 Compound 122 Compound 123 P'N 0 N—. O CNZ0

[1018] < 1 1NAAN^¥CIAHII A H OL ~ClO^N^OClO^N^O

[1019] H HclO'lhXo H

[1020] Compound 124 Compound 125 Compound 126 p“N 0 -An 9

[1021] O rpYS / \ H

[1022] ClO^N^OClO^N^O

[1023] H H

[1024]

[1025] Compound 127 Compound 128 Compound 129°'~l

[1026] o \ZT^ c° o / ^ZCI2 d Z — / \ AN'PX

[1027] Oo- °0 / v-\ PAvH

[1028] N--' Cl ^ UXhHT0ZI

[1029] — / \ - IZ /

[1030] Compound 130 Compound 131 Compound 132zo

[1031] / -0 HN'NXX

[1032] O '

[1033] 0Z^ / ClH \~J

[1034] N' L I] ^z ’NHZCI

[1035] X>^ ° Af K / A

[1036] D ° y / \ / ^

[1037] \ p oo

[1038] i ^-N

[1039] Cl o Huo^N^O

[1040] H

[1041] / " Z \^. \ZT

[1042] Compound 133 Compound 13 ) o —

[1043] \ \< o= 5 o= 4 Compound 135 0

[1044] <°\ yJr

[1045] C p / Q-H5

[1046] Ci \ v? \ V ZI ZT

[1047] VQ\0z-- / \ / ~~\N' I |J ^--NHZCIN. I IT ^-NH / Cl >=0

[1048] / IZ / \ / 7 ~NHzo ^N\A [ 1Cl0 Cl 0 H0'XI X'I

[1049] Cl o H0

[1050] ?

[1051] Compound 136 Compound 137 Compound 138 F 0 o 0

[1052] Cl

[1053] F' \””JX”^''N — \ pi

[1054] ^A__H Y yG° 0 / \A N '^P / ClA / CV \ A V Z^, O PpCQ Q Tn klCl° H

[1055] F0N^ X o F CK 'N'^ X)

[1056] Ho

[1057] uH Compound 139 Compound 140 Compound 141

[1058] Cl 0 0

[1059] O^XA- N C I? H ° zv AY V-F-yycj\ ^y Y. / ^° UQ\ 7 — \ - F7^ y jl ci CT H IZ / °t5 Ya ^' T FClO^N^O F cr ^^o H H d Compound 142 Compound 143 Compound 144 0 0

[1060] ( / V^N-^x^xC!

[1061] p xc Xs^N p|

[1062] ' FClCF 'N^'O

[1063] H ° O^N^O H

[1064] Compound 145 Compound 146 Compound 147,°~N 0

[1065] / \ H^nr

[1066] ClO^N^O

[1067] H

[1068] Compound 148 Compound 149 Compound 150

[1069] N<sy0

[1070] A ^ClNA HHQH

[1071] Cl0<^N' X)ClO^N^O

[1072]

[1073] H Hp p p Compound 152 *first eluting Compound 153 ^second Compound 151 \ isomer eluting isome yr \ \ZT ZT ZTZ > Z o o — —o= / \Z o= IZ IZ Q

[1074] j Oo 05^- y^- ° - ° f> o- ZI ZI ZI

[1075] \^ o o=

[1076] Q 7 — \ / \ —

[1077] IZ iz / / Cl

[1078] H;5<

[1079] mpound 154 *first elutzzin o og Compound 155 ‘second ^Z- f Compound 156 isomer eluting isomer z y

[1080] X“V^CI

[1081] p

[1082] CI0'i^'N^50ClO^N^O H \ZIH y o Z—

[1083] Compound 157 Compound 158 Compound 159

[1084] Qo- °

[1085] NA s ZITr

[1086] Clcr^N^o

[1087] H

[1088] Compound 160 Compound 161 Compound 1620

[1089] A XINA Y r

[1090] ClO^N^O Cl J\ A

[1091] H O^N^OClO^N^O H H

[1092] Compound 163 Compound 164 Compound 165

[1093] N-0 0

[1094] A'Vapr

[1095] ClO^N^OClO^N^O

[1096] H H

[1097] Compound 166 Compound 167 Compound 168 \0

[1098] OcVV VNH / x=<", — \

[1099] Ul? CT

[1100] 0M. ZA AO

[1101] Cl J \ ^— \ )r

[1102] Cl 0NHClO^N^O H

[1103] 0A

[1104] Compound 169 Compound 170 Compound 171ci°\

[1105] ^NH J\-X NH / =( V— NH

[1106] ft. No'X- \ / - ( / °

[1107] \= / \-NH0

[1108] Cl 0 Cl X X

[1109] H

[1110]

[1111] Compound 172 Compound 173 Compound 174o F

[1112] \zxy o Z— A H IZ IZ Qs- ° AfCn olClcr ^ H^o Q ~ \^T o= c H

[1113] Compound 175 ( Q ( 7 — Q — /

[1114] \ \ xz IZ Compound 176 CoS:mpound 177

[1115] '' o o

[1116] K / ; O^NH

[1117] 0

[1118] o

[1119] oClcXrXo b H \

[1120] Compound 179 ‘sec o Zozx

[1121] nd Compound 180 *first eluting Compound 178 )o= \zx

[1122] O V Z- elutin IZg iso 0mZ o=6 V-e°r isomer pH

[1123] r^N 0

[1124] ZX ) / <>

[1125] zx o

[1126] \ / - \ IZ

[1127] Xcl

[1128] V z z H ' o

[1129] \\

[1130] Compound 181 Compound 182 Compound 183 F / \ o

[1131] F^^V^N 0 o

[1132] p p XHB'W' H- z

[1133] Z \ \

[1134] oZT zz

[1135] c o \ Z—ClO^N^O b:

[1136] i O^N x^kO H i b: IZ

[1137] Q Qoo-- °° H IZ

[1138] IZ

[1139] Compound 184 Compound 185 Compound 186

[1140] ZI ZI

[1141] P~N 0 £2 7 — \ C0O N " T A ci HAAH^V^V01\ IZ v *N^xrT^V’ — \ Q - 7 — \ A / \ N piTxz / xHIl xlxz' / o ' o Cl xLC' o O^N^Ol(T ^N' A)

[1142] f H H

[1143] Compound 187 Compound 188 Compound 189

[1144] Compound 190 Compound 191 Compound 192

[1145] A

[1146] %XA^YCIA H

[1147] H

[1148] Cl xk xk

[1149] O^N^O

[1150] HCLCXN HX) Compound 193 Compound 194 Compound 195

[1151]

[1152] o p \ 2°= o ZzzIZ IZ Qo- °ClO^AO

[1153] HH Q H

[1154] \^ o— o= zx Compound 1 > o=9\ Q 7 — \6 Compound 197 Compound 198

[1155] — \ iz / - iz /

[1156] ' o

[1157] zo

[1158] 7

[1159] o

[1160] \

[1161] ClO^N^O

[1162] \ o o H

[1163] Compound 199 A Compound 200 Compound 201

[1164] Z /

[1165] / =N 0 F. N'N O

[1166] °\A A|AX ZA XI iO=7 IZ IZ

[1167] A Vn

[1168] C' Q^N^O f)n QClO^N^O

[1169] H M \^ o= H

[1170] ( Q ( / — Q — 7

[1171] Compound 202 Compound 203 \ \ IZ IZ Compound 204FJ HOJ '' o o

[1172] Nu

[1173] " NJSZN^VCI" AY u

[1174] A H IKY A H lYL ^

[1175] o °

[1176] ciCT 'M^OCL(ANY

[1177] H H ) y

[1178] pz\

[1179] Compound 205 Compound 206 ComOo== / 7pound 207

[1180] IZ

[1181] 0 1 TZ

[1182] IZNX / N-^YCIHf> H Q

[1183] A UJL O^ o o - Q — 7 \CLCYN^O / \ - M y \ IZ H (~\ \ Q - 7 — TZ \ IZ'' o o Compound 208 Compound 209 Compound 210 ' o' o F. N-N 0 F\ / O.

[1184] F-^ — jL I _ Cl Y YY 9

[1185] 7 OKAN-~YYF N" N^A^^<CI / 'HL JL ^

[1186] ClCK 'N^O

[1187] HClcr A^o H

[1188] Compound 211 Compound 212 Compound 213

[1189] / ~~~1 0

[1190] y*o o

[1191] A H [I 1tAS'»AX7 " Vs-TV

[1192] ClO^N^OCl

[1193] HClO^N^O

[1194] H H

[1195] Compound 214 Compound 215 Compound 216

[1196] 0NXXXAN^^<

[1197] A H lYLCI

[1198] ^. »XVa-pA XVa-xVciCT 'M^OClO^N^OClO^N^O H H H

[1199] Compound 217 Compound 218 Compound 219

[1200]

[1201] p p,N'O 0 F. N-0 0

[1202] \ \ 0zx zx) z 0 z — p5~ °ClCr^N^OCl(A'N'^OClcr^N^o H H H ZI ZT

[1203] Compound 220 Compound 221 Comp °z=ound 222 P~N 0

[1204] p W n^Y

[1205] 0 0

[1206] /

[1207] CloA^O

[1208] HCL(AN H^O

[1209] Compound 224 *first eluting Compound 225 ^second Compound 223 C° / isomer eluting isomer FV Y^I FL N-NO= / 0 N-N 0

[1210] IZ — < X 11C|F%^ AA H^ Jv.cl

[1211] Hl\<^<CL(T^N 0cHA)Ck<:^N^Ol

[1212] Q — 7 \ H H Compound 226 Comxz /

[1213] pound 227 Compound 228zo

[1214] \.° n

[1215] v y-7

[1216] N-N P~N 0

[1217] cr A NH

[1218] k^\ / c

[1219] TJA. J

[1220] ci A A

[1221] p p O^N^O

[1222] ClO^N^O H

[1223] H

[1224] \ \zx ZTA

[1225] Compound 229 y VZ 00 Z-— Compound 230 Co'z / mpound 231

[1226] Q Qos-- °o= /

[1227] ° F O-N 0IZ

[1228] ZI ZIF" AJA \^ 0=;>CloA^O

[1229] H — \ - \ IZ w

[1230] V Compound 232 Compound 233 Compound 234 ' 0 \o=

[1231] 0

[1232] 0

[1233] 0

[1234] N AAA., / \^x.c i

[1235] AN11 -’XVj-fYN^S AA H AHLJL ^rclci A AlO^iAo

[1236] O^N^OC ciO^N^O H H H

[1237] Compound 235 Compound 236 Compound 237

[1238] Ho

[1239] CloAA

[1240] H

[1241]

[1242] Compound 238 Compound 239 Compound 240p p p a o \zz\ \ \zz zz zz2 Z d — ^ ^o= Y( o= HZ o- IZ

[1243] pytH° ' ZT ZT ZT ZT

[1244] Wf o °Z= °Z=

[1245] YZ“ — Compound 243 *first eluting Compound 241 IZ / Compound 242

[1246] isomer

[1247] ' o

[1248] 0 Q

[1249] o o

[1250] ) ) o

[1251] \

[1252] CW (V- N^N Y Y > \

[1253] o o

[1254] Y WoClO^N^O pClO^N^O z z H o H Compound 244 ‘second p

[1255] Compound 245 \zz

[1256] ) Z o \—zzCompound 246 eluting isomer

[1257] ZZ

[1258] 0 Y< \z

[1259] H Q IZs- o=z

[1260] p °

[1261] p o z—

[1262] A »pp ZT ZT cx°w NH z=\ > — \ oZ ZT Wf o

[1263] =

[1264] CN^O Qf -0

[1265] o

[1266] l(T ' / \ —

[1267] IZ / \ > YNH / / z / \ — Cl 0Hz IZ /

[1268] Compound 247 p Compound 248 ' o

[1269] ' o Compound 249 o 3=

[1270] \

[1271] CX°M ^1NH / n=<1 / — \ p0w

[1272] p p o o r~\z ZTF 0z\ \zz4

[1273] \ \zz z /

[1274] om ) / 4 \ ) o Z

[1275] C \2 H o= Z o — Z o V z-zxo — —

[1276] pound 250 o— Compound 251 Compound 252 pppH H H°02°=

[1277] y ty t TZ

[1278] ° / Z Z °°

[1279] T ■ ZZ ZIT ZT

[1280] = Pp o YY o ( Q 7 — z zzz / / / p.z' o Compound 253 Compound 254 Compound 255 i o o

[1281] O ' \ \

[1282] p-0 0

[1283] APpr

[1284] Fcr 'N' x)

[1285] H

[1286] Compound 256 Compound 257 Compound 258

[1287] Compound 259 Compound 260 Compound 261 0

[1288] A H

[1289] F(K 'N' X)

[1290] H

[1291]

[1292] p Compound 262 Compound 263 Compound 264 p \zz7 Z o — 70= \zziz i 7 X Z o —

[1293] ZTy t° C < Mo

[1294] ( \ Q — 7 TZ °Z=ZT ■ Compound 265 ' o Compound 266 Compound 267 / ~~o 0 o'

[1295] 0

[1296] A H 11 1 -FFA H

[1297] o

[1298] cl0*^N^0ClcYNY po

[1299] H H \zz

[1300] 7 Z o —

[1301] Compound 268 Compound 269 Compound 270

[1302] QGy-t°° ' p“N 0

[1303] ZT ■

[1304] FO^N^O H z z

[1305] o / /

[1306] Compound 273 *first eluting Compound 271 Compound 272

[1307] 4 isomer

[1308] FV YHl fl A"

[1309] oFo

[1310] p

[1311] p o AHil Jl z z

[1312] \ 2 Z o — \zz

[1313] \zz zzFoWClO^N^O 2 ) Z o Z o u_i> — — H H 01_

[1314] Compound 274

[1315] Qo4- ° ‘second

[1316] Compound 275 Compound 276 eluting isomer

[1317] ZT ZT ZT oZ=

[1318] OZ= V VI fl

[1319] R c c —o x A H A H |lzz / 0 it ' o o o'

[1320] FCT 'N^O

[1321] \FcA'i^Vo H H

[1322] Compound 277 Compound 278 Compound 279

[1323] P~N 0

[1324] M t,

[1325] F(X 'N' X)

[1326] H

[1327] Compound 280 Compound 281 Compound 282

[1328] N-> 0N-i 0

[1329] -< 1 2 ci -Cl A ciA HA HLA.

[1330] FCT 'N^O

[1331] HCIQYNY

[1332] Ho

[1333]

[1334] In preferred embodiments, the processes of the invention are used to prepare a compound of Formula (I) having the structure:

[1335]

[1336] , or a pharmaceutically acceptable salt thereof.

[1337] In preferred embodiments, the processes of the invention are used to prepare a compound of Formula (I) having the structure:

[1338]

[1339] or a pharmaceutically acceptable salt thereof.

[1340] In more preferred embodiments, the processes of the invention are used to prepare a compound of Formula (I) having the structure:

[1341]

[1342] or a pharmaceutically acceptable salt thereof.

[1343] For instance, the compound of Formula (I) may be a compound having the structure:

[1344]

[1345] or a mixture thereof, for example a racemic mixture thereof.Numbered embodiments

[1346] The present invention may be further defined by the following enumerated embodiments.

[1347] 1. A process comprising reacting a compound of Formula (2) with a compound of Formula (3) to yield a compound of Formula (4):

[1348]

[1349] (4) wherein:

[1350] R1, R2a, and R2bare defined according to (A) and (B) below:

[1351] (A)

[1352] R1is:

[1353] • heteroaryl including 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc;

[1354] • heterocyclyl including 4-6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc;

[1355] • C3-7 cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc;

[1356] • heterocycloalkenyl including 3-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc; or

[1357] • C6-10aryl optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc; andeach of R2aand R2bis independently selected from the group consisting of:

[1358] • C1-2 alkyl optionally substituted with from 1-5 Ra;

[1359] • C3-5 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rb;

[1360] • C1-4 alkoxy;

[1361] • C1-4 haloalkoxy; or

[1362] • cyano; or

[1363] R2aand R2btaken together with the carbon atom to which each is attached forms:

[1364] • C3-7 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rb;

[1365] • heterocyclyl including 4-7 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl is optionally substituted with 1 -4 substituents independently selected from the group consisting of oxo and Rb;

[1366]

[1367] R1taken together with (i) the carbon atom to which it is attached and (ii) and one of R2aand R2bforms:

[1368] • C8-10aryl optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc; or

[1369] • heteroaryl including 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc; and

[1370] the other of R2aand R2bis C1-2 alkyl optionally substituted with from 1-5 Ra;

[1371] X is H; or halo;

[1372] Y1 and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH;

[1373] R3is H; C1-2 alkyl, which is optionally substituted with 1-5 fluoro; fluoro; chloro; or cyano;

[1374] R4is chloro; bromo; or fluoro; optionally wherein it is provided that R4is fluoro when R3is chloro; R5is C1-6 alkyl;

[1375] R6a leaving group, for example, Cl, Br, I, OH, OM, O(C=O)(C1-6 alkyl), O(C=O)(N3), O(C1-6 alkyl), or S(C1-6 alkyl);

[1376] each occurrence of Rais independently selected from the group consisting of: -OH; -halo; -NReRf; C1-4 alkoxy; C1-4 haloalkoxy,; -C(=O)O(Ci-4alkyl); -C(=O)(Ci-4alkyl); -C(=O)OH; -CONR’R”; -S(O)I-2NR’R”; -S(O)1-2(C1-4alkyl); and cyano;each occurrence of Rbis independently selected from the group consisting of: halo; cyano; C1-10 alkyl which is optionally substituted with from 1-6 independently selected Ra; C2-6 alkenyl; C2-6 alkynyl; C1-4 alkoxy; -O(Ci-3 alkylene)-(C3-e cycloalkyl); C1-4 haloalkoxy; -S(0)o-2(Ci-4 alkyl); -NReRf; -OH; -S(O)I-2NR’R”; -NO2; -C(=0)(Ci-io alkyl); -C(=O)O(Ci-4alkyl); -C(=O)OH; and -C(=O)NR’R”;

[1377] each occurrence of Rcis independently selected from the group consisting of:

[1378] • C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rb;

[1379] • heterocyclyl or heterocycloalkenyl including 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rb;

[1380] • heteroaryl including 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with from 1-4 Rb; and

[1381] • Ce-io aryl optionally substituted with from 1-4 Rb;

[1382] each occurrence of Rdis independently selected from the group consisting of: C1-6 alkyl optionally substituted with from 1-3 independently selected Ra; -C(O)(Ci-4 alkyl); -C(O)O(Ci-4 alkyl); -CONR’R”; -S(O)I-2NR’R”; -S(O)I-2(CI-4 alkyl); -OH; and C1-4 alkoxy; and

[1383] each occurrence of Reand Rfis independently selected from the group consisting of: H; C1-6 alkyl; -C(O)(Ci-4 alkyl); -C(O)O(Ci-4alkyl); -CONR’R”; -S(O)I-2NR’R”; -S(O)i-2(Ci-4 alkyl); -OH; and C1-4 alkoxy; and

[1384] each occurrence of R’ and R” is independently selected from the group consisting of: H; and C1-4 alkyl; and

[1385] X’ is an anion and M is a cation.

[1386] 2. The process of embodiment 1, wherein the compounds of Formulas (2) and (3) are reacted under amide coupling conditions.

[1387] 3. The process of embodiments 1 or 2, wherein the compounds of Formulas (2) and (3) are reacted in the presence of a base and a solvent.

[1388] 4. The process of embodiment 3, wherein the solvent is water.

[1389] 5. The process of embodiment 3, wherein the solvent is an organic solvent, for example a polar aprotic solvent.6. The process of embodiment 5, wherein the solvent is selected from ethyl acetate, DCM, DMF, THF, DMA, NMP, 2-MeTHF and combinations thereof.

[1390] 7. The process of any of embodiments 3-6, wherein the base is an amine.

[1391] 8. The process of embodiment 7, wherein the base is selected from diisopropylethylamine (DIPEA), triethylamine (TEA), pyridine and combinations thereof.

[1392] 9. The process any of embodiments 2-8, wherein the compounds of Formulas (2) and (3) are reacted in the presence of a coupling agent.

[1393] 10. The process of embodiment 9, wherein the coupling reagent is a carbodiimide coupling reagent, a uranium-imonium reagent, T3P (1-propylphosphonic acid cyclic anhydride), T4P (1-butylphosphonic acid cyclic anhydride), thionyl chloride, oxalyl chloride, mukaiyama reagent or combinations thereof.

[1394] 11. The process of embodiment 10, wherein the carbodiimide coupling reagent is selected from diisopropylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, a hydrochloride salt of 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide and combinations thereof.

[1395] 12. The process of embodiment 10, wherein the uranium-imonium reagent is selected from HATU (O- (7-Azabenzotriazol-1-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate), HBTU (O-Benzotriazol-1-yl-N, N, N', N'-tetramethyluronium hexafluorophosphate), TBTU (O-(Benzotriazol-1-yl)-N, N, N', N'-tetramethyluronium tetrafluoroborate), TSTU (N, N, N', N'-Tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate), HCTU (O-(6-Chlorobenzotriazol-1-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate), PyClock (O-(6-Chlorobenzotriazol-1-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate), COMU (1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate), PyBOP (Benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate), PyAOP (7-Azabenzotriazol-1 -yloxy)tris(dimethylamino)phosphonium hexafluorophosphate) and combinations thereof.

[1396] 13. The process of any of embodiments 2-12, wherein the compounds of Formulas (2) and (3) are reacted in the presence of an additive.

[1397] 14. The process of embodiment 13, wherein the additive is selected from HOBt (1-Hydroxybenzotriazole), HOOBt (HODhbt) (Hydroxy-3, 4-dihydro-4-oxo-1,2, 3-benzo-triazine), HOSu (N-Hydroxysuccinimide), HOAt (1-Hydroxy-7-aza-1 H-benzotriazole), Ethyl 2-cyano-2-(hydroximino)acetate, DMAP (4-(N, N-Dimethylamino)pyridine) and combinations thereof.

[1398] 15. The process of any of embodiments 2-14, wherein the compounds of Formulas (2) and (3) are reacted at a temperature of 0-50°C.

[1399] 16. The process of embodiment 15, wherein the compounds of Formulas (2) and (3) are reacted at a temperature of 20-30°C.

[1400] 17. The process of embodiment 16, wherein the compounds of Formulas (2) and (3) are reacted at a temperature of 20-25°C.

[1401] 18. The process of any of embodiments 1-16, wherein the compounds of Formulas (2) and (3) are reacted in the presence of T4P, Et3N and EtOAc, at a temperature of 20-30°C.

[1402] 19. The process of any of embodiments 1-17, wherein the compounds of Formulas (2) and (3) are reacted in the presence of T4P, Et3N and EtOAc, at a temperature of 20-25°C.

[1403] 20. The process of any of embodiments 1-19, wherein:

[1404] R1, R2a, and R2bare defined according to (A1) and (B1) below:

[1405] (A1)

[1406] R1is:

[1407] • heteroaryl including 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc;

[1408] • heterocyclyl including 4-6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc;

[1409] • C3-7 cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc;

[1410] • heterocycloalkenyl including 3-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2,and wherein the heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc; or • C6-10aryl optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc; and

[1411] each of R2aand R2bis independently selected from the group consisting of:

[1412] • C1-2 alkyl optionally substituted with from 1-5 Ra;

[1413] • C3-5 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rb;

[1414] R2aand R2btaken together with the carbon atom to which each is attached forms:

[1415] • C3-7 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rb;

[1416] (B1)

[1417] R1taken together with (i) the carbon atom to which it is attached and (ii) and one of R2aand R2bforms:

[1418] • C8-10aryl optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc; or

[1419] • heteroaryl including 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc; and

[1420] the other of R2aand R2bis C1-2 alkyl optionally substituted with from 1-5 Ra.

[1421] 21. The process of any of embodiments 1-20, wherein:

[1422] R3is H; C1-2 alkyl, which is optionally substituted with 1-5 fluoro; fluoro; chloro; or cyano;

[1423] R4is chloro; bromo; or fluoro;

[1424] R6is Cl, Br, I, OH, OM, O(C=O)(C1-6 alkyl), O(C=O)(N3), O(C1-6 alkyl), or S(C1-6 alkyl);

[1425] M is an alkali metal cation such as Li+, Na+, or K+, an alkali earth metal cation such as Ca2+, or Mg2+, an organic cation such as NH4+, or a protonated amine such as C1-4 alkyl-NH3+

[1426] Y1 and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH; and

[1427] X’ is any suitable anion which corresponds to the conjugate base of a strong acid, such as HSO4-, SO42-, NO3-, Ch or Br.

[1428] 22. The process of any of embodiments 1-21, wherein:R3is fluoro or chloro;

[1429] R4is fluoro or chloro;

[1430] R6is Cl, Br, I, OH, OM, O(C=O)(Ci-6alkyl), O(C=O)(N3), O(Ci-6alkyl), or S(Ci-6alkyl)

[1431] M is an alkali metal cation such as Li+, Na+, or K+, an alkali earth metal cation such as Ca2+, or Mg2+, an organic cation such as NH4+, or a protonated amine such as C1-4 alkyl-NH3+;

[1432] Y1 and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH;

[1433] X is H; and

[1434] X’ is any suitable anion which corresponds to the conjugate base of a strong acid, such as Cl-or Br-.

[1435] 23. The process of any of embodiments 1-22, wherein:

[1436] R3and R4are each independently chloro;

[1437] R6is CI, or OM;

[1438] M is Na+or K+;

[1439] Y1 and Y2 are each independently CH;

[1440] X is H; and

[1441] X’ is Cl-or Br.

[1442] 24. The process of any preceding embodiment, further comprising the step of reacting the compound of Formula (4) with acrylonitrile to provide a compound of Formula (5):

[1443]

[1444] 25. The process of embodiment 25, wherein the compound of Formula (4) and acrylonitrile are reacted under Michael addition reaction conditions.26. The process of embodiments 24 or 25, wherein the compound of Formula (4) and acrylonitrile are reacted in the presence of a base and a solvent.

[1445] 27. The process of embodiment 26, wherein the base is selected from NaOMe, LiOMe, NaOEt, LiOEt, NaOtBu, LiOtBu, KOMe, KOEt, KOtBu, LiHMDS, NaHMDS, KHMDS, NaH, LiH, KH, DBU (1,8-diazabicyclo(5.4.0)undec-7-ene) or DBN (1,5-diazabicyclo(4.3.0)non-5-ene) and combinations thereof.

[1446] 28. The process of embodiment 27, wherein the base is KOtBu.

[1447] 29. The process of any of embodiments 26-28, wherein the solvent is an aprotic polar solvent.

[1448] 30. The process of embodiment 29, wherein the solvent comprises MeCN and / or THF.

[1449] 31. The process of embodiment 30, wherein the solvent comprises MeCN and / or THF, optionally wherein the solvent comprises MeCN: THF in a ratio of from 1:5 to 5:1, or from 2:3 to 3:2.

[1450] 32. The process of embodiment 31, wherein the solvent further comprises BHT (butylated hydroxytoluene) when no THF is present.

[1451] 33. The process of embodiment 31, wherein the solvent comprises MeCN: THF in a ratio of 2:3.

[1452] 34. The process of any of embodiments 29-33, wherein the solvent comprises BHT.

[1453] 35. The process of any of embodiments 25-34, wherein the compound of Formula (4) and acrylonitrile are reacted at a temperature of 0-5°C.

[1454] 36. The process of any of embodiments 25-31, 33 or 35, wherein the compound of Formula (4) and acrylonitrile are reacted in the presence of KOtBu and MeCN: THF 2:3, at a temperature of 0-5°C.

[1455] 37. The process of any preceding embodiment, wherein R5is ‘Bu.38. The process of embodiment 37, further comprising the step of converting the compound of Formula (5) into a compound of Formula (I):

[1456]

[1457] 39. The process of embodiment 38, wherein the compound of Formula (5) is converted into the compound of Formula (I) under glutarimide formation conditions.

[1458] 40. The process of embodiments 38 or 39, wherein the compound of Formula (5) is converted into the compound of Formula (I) in the presence of acid and a solvent.

[1459] 41. The process of embodiment 40, wherein the acid is selected from p-toluenesulphonic acid, methanesulfonic acid and combinations thereof.

[1460] 42. The process of any one of embodiments 40-41, wherein the solvent is selected from xylene, toluene and combinations thereof.

[1461] 43. The process of any of embodiments 24-37, further comprising the step of converting the compound of Formula (5) into a compound of Formula (6):

[1462]

[1463] 44. The process of embodiment 43, wherein the compound of Formula (5) is converted into the compound of Formula (6) under hydrolytic conditions.

[1464] 45. The process of embodiments 43 or 44, wherein the compound of Formula (5) is converted into the compound of Formula (6) in the presence of an acid and a solvent.

[1465] 46. The process of embodiment 45, wherein the solvent is a polar, high boiling point solvent; optionally wherein the high boiling point solvent has a boiling point of 80°C or higher; further optionally wherein the high boiling point solvent has a boiling point of 100°C or higher.

[1466] 47. The process of embodiment 46, wherein the solvent is selected from toluene, formic acid, acetic acid, propionic acid, isobutyric acid or benzoic acid and combinations thereof.

[1467] 48. The process of embodiment 47, wherein the solvent is acetic acid.

[1468] 49. The process of any of embodiments 45-48, wherein the acid is selected from H2SO4, p-toluenesulfonic acid or methanesulfonic acid, and combinations thereof.

[1469] 50. The process of any of embodiments 45-49, wherein the acid is p-toluenesulfonic acid and / or methanesulfonic acid.51. The process of embodiment 50, wherein the acid is H2SO4.

[1470] 52. The process of any of embodiments 43-51, wherein the compound of Formula (5) is converted into the compound of Formula (6) at a temperature of 80-140°C.

[1471] 53. The process of embodiment 52, wherein the compound of Formula (5) is converted into the compound of Formula (6) at a temperature of 115-120°C.

[1472] 54. The process of embodiment 53, wherein the compound of Formula (5) is converted into the compound of Formula (6) at a temperature of 80-100°C, preferably 80-90°C.

[1473] 55. The process of any of embodiments 43-54, wherein the compound of Formula (5) is converted into the compound of Formula (6) in the presence of H2SO4, AcOH, at a temperature of 80-90°C.

[1474] 56. The process of any of embodiments 43-55, further comprising the step of converting the compound of Formula (6) into a compound of Formula (I):

[1475]

[1476] 57. The process of embodiment 56, wherein the compound of Formula (6) is converted into the compound of Formula (I) under glutarimide formation conditions.

[1477] 58. The process of embodiments 56 or 57, wherein the compound of Formula (6) is converted into the compound of Formula (I) in the presence of a base and a solvent.

[1478] 59. The process of embodiment 58, wherein the base is selected from LiHMDS, NaHMDS, KHMDS, NaH, KH and combinations thereof.60. The process of embodiment 59, wherein the base is LiHMDS.

[1479] 61. The process of any of embodiments 58-60, wherein the solvent is an aprotic, polar solvent.

[1480] 62. The process of embodiment 61, wherein the aprotic, polar solvent is water-free.

[1481] 63. The process of embodiment 61 or 62, wherein the solvent is selected from DMF, DMA, Me-THF, MeCN, NMP and combinations thereof.

[1482] 64. The process of any of embodiments 56-63, wherein the compound of Formula (6) is converted into the compound of Formula (I) at a temperature of 40-50°C.

[1483] 65. The process of any of embodiments 56-64, wherein the compound of Formula (6) is converted into the compound of Formula (I) in the presence of LiHMDS and THF, at a temperature of 40-50°C.

[1484] 66. The process of any preceding embodiment, wherein the compound of Formula (2) is prepared by:

[1485] (a) reacting a compound of Formula (a) with a compound of Formula (b) to yield a compound of Formula (c):

[1486] o o

[1487]

[1488] R3is H; C1-2 alkyl, which is substituted with 1-5 fluoro; fluoro; chloro; or cyano;

[1489] R4is chloro; bromo; or fluoro; optionally wherein it is provided that R4is fluoro when R3is chloro;

[1490] R7is fluoro; or chloro if neither R3nor R4are fluoro; and

[1491] R5and R5’ are independently Ci-s alkyl.

[1492] (b) converting the compound of Formula (c) into a compound of Formula (d):CN

[1493] O O

[1494]

[1495] (c) converting the compound of Formula (d) into a compound of Formula (e):

[1496]

[1497] wherein:

[1498] Pg is a protecting group; and

[1499] (e) converting the compound of Formula (e) into the compound of Formula (2):

[1500]

[1501] The process of embodiment 66, wherein R7is fluoro.

[1502] The process of any of embodiments 66-67, wherein Pg is Boc.69. The process of any of embodiments 66-68, wherein the compound of Formula (a) is reacted with the compound of Formula (b) in step a) under conditions for nucleophilic aromatic substitution.

[1503] 70. The process of any of embodiments 66-69, wherein the compound of Formula (a) is reacted with the compound of Formula (b) in step a) in the presence of a base and a solvent.

[1504] 71. The process of embodiment 70, wherein the base is selected from CsCO3, K2CO3 Na2CO3, K3PO4, DBU, DBN, LiHMDS, NaHMDS, KHMDS and combinations thereof.

[1505] 72. The process of embodiment 71, wherein the base is K2CO3.

[1506] 73. The process of any of embodiments 70-72, wherein the solvent is a high boiling point polar aprotic solvent; optionally wherein the high boiling point polar aprotic solvent has a boiling point of 80°C or higher; further optionally wherein the high boiling point polar aprotic solvent has a boiling point of 100°C or higher.

[1507] 74. The process of embodiment 73, wherein the solvent is selected from DMA, DMF, NMP, 1,4-Dioxane and combinations thereof.

[1508] 75. The process of embodiment 74, wherein the solvent is DMF.

[1509] 76. The process of any one of embodiments 69-75, wherein the compound of Formula (a) is reacted with the compound of Formula (b) at a temperature of 50 -120 °C.

[1510] 77. The process of embodiment 76, wherein the compound of Formula (a) is reacted with the compound of Formula (b) at a temperature of 50 - 100 °C.

[1511] 78. The process of embodiment 77, wherein the compound of Formula (a) is reacted with the compound of Formula (b) at a temperature of 55 - 80 °C.

[1512] 79. The process of embodiment 78, wherein the compound of Formula (a) is reacted with the compound of Formula (b) at a temperature of 60-70 °C.80. The process of any one of embodiments 69-79, wherein the compound of Formula (a) is reacted with the compound of Formula (b) for a duration of 30 minutes – 48 hours.

[1513] 81. The process of embodiment 80, wherein the compound of Formula (a) is reacted with the compound of Formula (b) for a duration of 1 hour – 24 hours.

[1514] 82. The process of embodiment 81, wherein the compound of Formula (a) is reacted with the compound of Formula (b) for a duration of 4 hours.

[1515] 83. The process of any one of embodiments 69-82, wherein the compound of Formula (a) is reacted with the compound of Formula (b) in step a) in the presence of K2CO3 and DMF, at a temperature of 60 °C, for a duration of 4 hours.

[1516] 84. The process of any of embodiments 66-83, wherein the compound of Formula (c) is converted into the compound of Formula (d) under decarboxylation conditions.

[1517] 85. The process of any of embodiments 66-84, wherein the compound of Formula (c) is converted into the compound of Formula (d) in step b) in the presence of a catalyst and a solvent.

[1518] 86. The process of embodiment 85, wherein the catalyst is selected from NaCN, KCN, LiCI, NaCI, NaBr, Nal, LiI·H2O, Na2CO3·H2O, Na3PO4·12H2O Me4NOAc and combinations thereof.

[1519] 87. The process of embodiment 86, wherein the catalyst is LiCI.

[1520] 88. The process of any of embodiments 85-87, wherein the solvent is selected from DMSO, DMF, DMA and combinations thereof, optionally wherein the solvent is DMSO.

[1521] 89. The process of any of embodiments 85-87, wherein the solvent comprises a polar, aprotic solvent (e.g. DMSO, DMF, DMA, THF and combinations thereof) and a polar protic solvent (e.g., water, an alcohol, a carboxylic acid, an amine and combinations thereof), optionally wherein the solvent is THF and water.

[1522] 90. The process of any one of embodiments 84-89, wherein the compound of Formula (c) is converted into the compound of Formula (d) in step b) at a temperature of 90 -165 °C, optionally at a temperature of 95 -125 °C, further optionally at a temperature of 95-105°C.91. The process of embodiment 84-89, wherein the compound of Formula (c) is converted into the compound of Formula (d) in step b) at a temperature of 130 -150 °C, optionally at a temperature of 135 -140 °C.

[1523] 92. The process of any of embodiments 84-89 or 91, wherein the compound of Formula (c) is converted into the compound of Formula (d) in step b) under a pressure of 1-10 MPa, optionally 2-5 MPa, further optionally 3-4 MPa, further optionally 3.5 MPa.

[1524] 93. The process of any of embodiments 84-89, 91 or 92, wherein the compound of Formula (c) is converted into the compound of Formula (d) in step b) under flow conditions, optionally using a residence time of from 1 minute to 2 hours, further optionally using a residence time of from 10 minutes to 1 hour, further optionally using a residence time of from 15 minutes to 40 minutes, further optionally using a residence time of 25 minutes.

[1525] 94. The process of any of embodiments 84-93, wherein the compound of Formula (c) is converted into the compound of Formula (d) in step b) for a duration of 30 minutes – 36 hours, optionally for a duration of 2 hours – 24 hours, further optionally for a duration of 12 hours.

[1526] 95. The process of any one of embodiments 84-90 or 94, wherein the compound of Formula (c) is converted into the compound of Formula (d) in step b) in the presence of LiCI, DMSO and water, at a temperature of 95-105°C, for a duration of 12 hours.

[1527] 96. The process of any one of embodiments 84-87 or 91-94, wherein the compound of Formula (c) is converted into the compound of Formula (d) in step b) in the presence of LiCI, THF and water, at a temperature of 135-140°C, a pressure of 3.5MPa and under flow conditions using a residence time of 25 minutes.

[1528] 97. The process of any one of embodiments 66-96, wherein the compound of Formula (d) is converted into the compound of Formula (e) in step c) under nitrile-selective reducing conditions and amine protecting conditions.

[1529] 98. The process of any one of embodiments 66-97, wherein the compound of Formula (d) is converted into the compound of Formula (e) in step c) in the presence of a reducing agent, a catalyst, a reagent for introducing a protecting group and one or more solvents.99. The process of embodiment 98, wherein the reducing agent and catalyst are NaBH4and CoCl2, Raney-Ni and H2, or Pd / C and H2.

[1530] 100. The process of any of embodiments 98-99, wherein the reagent for introducing a protecting group is a reagent for introducing Boc.

[1531] 101. The process of embodiment 100, wherein the reagent for introducing Boc is (Boc)2O or N-Boc-Benzotriazole.

[1532] 102. The process of any of embodiments 98-101, wherein the one or more solvents are selected from MeOH, EtOH, PrOH, BuOH, THF, 1,4-dioxane, and acetone.

[1533] 103. The process of any of embodiments 98-102, wherein the compound of Formula (d) is converted into the compound of Formula (e) in step c) in the presence two solvents.

[1534] 104. The process of embodiment 103, wherein the two solvents are EtOH and THF.

[1535] 105. The process of any of embodiments 97-104, wherein the compound of Formula (d) is converted into the compound of Formula (e) in step c) at a temperature of from -20 to 40°C.

[1536] 106. The process of embodiment 105, wherein the compound of Formula (d) is converted into the compound of Formula (e) in step c) at a temperature of from -10 to 25°C.

[1537] 107. The process of any of embodiments 97-106, wherein the compound of Formula (d) is converted into the compound of Formula (e) in step c) for a duration of 30 minutes to 36 hours.

[1538] 108. The process of embodiment 107, wherein the compound of Formula (d) is converted into the compound of Formula (e) in step c) for a duration of 1 -6 hours.

[1539] 109. The process of embodiment 108, wherein the compound of Formula (d) is converted into the compound of Formula (e) in step c) for a duration of 1 hour.110. The process any of embodiments 97-109, wherein the compound of Formula (d) is converted into the compound of Formula (e) in step c) in the presence of NaBH4, CoCl2, (Boc)2O, EtOH and THF, at a temperature of from -10 to 25°C, for a duration of 1 hour.

[1540] 111. The process of any of embodiments 66-110, wherein the compound of Formula (e) is converted into the compound of Formula (2) in step d), under amine deprotection conditions.

[1541] 112. The process of any of embodiments 66-111, wherein the compound of Formula (e) is converted into the compound of Formula (2) in step d), in the presence of an acid and a solvent.

[1542] 113. The process of embodiment 112, wherein the acid is selected from TFA, HCI, H2SO4, acetic acid, TsOH, Amberlyst 15 and combinations thereof.

[1543] 114. The process of embodiment 113, wherein the acid is HCI, optionally wherein the HCI is generated in situ by using AcCI in EtOH or TMSCI in MeOH.

[1544] 115. The process of any one of embodiments 112-114, wherein the solvent is selected from DCM, MeCN, DMF, THF, MeOH, EtOH, 1,4-dioxane, iPrOAc, 2-MeTHF, DMA, CPME, EtOAc, water and combinations thereof.

[1545] 116. The process of embodiment 115, wherein the solvent is EtOAc.

[1546] 117. The process of any one of embodiments 111-116, wherein the compound of Formula (e) is converted into the compound of Formula (2) in step d) at a temperature of 0 to 50 °C.

[1547] 118. The process of embodiment 117, wherein the compound of Formula (e) is converted into the compound of Formula (2) in step d) at a temperature of 15 to 25 °C or wherein the compound of Formula (e) is converted into the compound of Formula (2) in step d) at a temperature of 40 to 50 °C.

[1548] 119. The process of any one of embodiments 111-118, wherein the compound of Formula (e) is converted into the compound of Formula (2) in step d) for a duration of 15 minutes to 18 hours.

[1549] 120. The process of any one of embodiments 119, wherein the compound of Formula (e) is converted into the compound of Formula (2) in step d) for a duration of 1 hour or wherein the compound of Formula (e) is converted into the compound of Formula (2) in step d) for a duration of 2 to 3 hours.121. The process of any one of embodiments 111-120, wherein the compound of Formula (e) is converted into the compound of Formula (2) in step d) in the presence of HCI and EtOAc at a temperature of 15 to 25 °C, for a duration of 1 hour or wherein the compound of Formula (e) is converted into the compound of Formula (2) in step d) in the presence of HCI and EtOAc at a temperature of 40 to 50 °C, for a duration of 2 to 3 hours.

[1550] 122. The process of any preceding embodiment, wherein the compound of Formula (3) is prepared by:

[1551] a) reacting a compound of Formula (f) with a compound of Formula (g) to yield a compound of Formula (h):

[1552] O

[1553] HarR’ CN

[1554]

[1555] wherein:

[1556] R8is C1-6 alkyl or C3-5 cycloalkyl; and

[1557] Hal is a halogen, e.g. F, Cl, Br or I, preferably Cl;

[1558] b) converting the compound of Formula (h) into a compound of Formula (i):

[1559] O

[1560]

[1561] CN CN

[1562] (h) (').

[1563] c) converting the compound of Formula (i) into a compound of Formula (j):

[1564] ^R1> R^R1

[1565] C

[1566]

[1567] NNCR2b

[1568] (j); and

[1569] d) converting the compound of Formula (j) into the compound of Formula (3):o2b

[1570] R2® R1R2< LR1

[1571] NCR- O^R6

[1572]

[1573] (3)

[1574] 123. The process of embodiment 122, wherein R8is Me, Et or ‘Bu.

[1575] 124. The process of embodiment 123, wherein R8is Me.

[1576] 125. The process of embodiment 123, wherein R8is Et.

[1577] 126. The process of embodiment 123, wherein R8is ‘Bu.

[1578] 127. The process of any of embodiments 122-126, wherein R1, R2a, and R2bare defined according to (A1), R1is any R1defined according to (A1); R2aand R2bare each independently C1-2 alkyl optionally substituted with from 1-5 Ra; R6is Cl, Br, I, OH, OM, O(C=O)(Ci-6alkyl), O(C=O)(N3), O(C1-6alkyl), or S(C1-6alkyl); and M is an alkali metal cation such as Li+, Na+or K+, alkali earth metal cations such as Ca2+, or Mg2+, organic cations such as NH4+, or protonated amines such as (C1-4alkyl-NH3+).

[1579] 128. The process of any of embodiments 122-127, wherein R1, R2a, and R2bare defined according to (A1), R1is heteroaryl including 5-6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N and O, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc; R2aand R2bare each independently C1-2 alkyl optionally substituted with from 1-5 Ra; and M is an alkali metal cation such as Li+, Na+ or K+, an alkali earth metal cation such as Ca2+, or Mg2+, an organic cation such as NH4+, or a protonated amine.

[1580] 129. The process of any of embodiments 122-128, wherein R1has the formula: (Ill(III-A); wherein each of Xi, X2, X3, and X4 is, independently, CH or N; and R11is H, Rb, or Rc; R2aand R2bare each independently C1-2 alkyl; and M is an alkali metal cation, preferably Na+ o

[1581]

[1582] r K+.130. The process of any of embodiments 122-129, wherein R1has the formula:

[1583]

[1584] (V-A), wherein Rn is methyl.

[1585] 131. The process of any of embodiments 122-130, wherein R2aand R2bare each independently methyl; and M is an alkali metal cation, preferably Na+ or K+.

[1586] 132. The process of any of embodiments 122-131, wherein the compound of Formula (f) is reacted with the compound of Formula (g) in step a) under nucleophilic substitution conditions.

[1587] 133. The process of any of embodiments 122-132, wherein the compound of Formula (f) is reacted with the compound of Formula (g) in step a) in the presence of a base and a solvent.

[1588] 134. The process of embodiment 133, wherein the base is selected from CsCO3, Na2CO3, K2CO3, DBU, DBN, LiHMDS, NaHMDS, KHMDS, K3PO4 and combinations thereof.

[1589] 135. The process of embodiment 134, wherein the base is K3PO4.

[1590] 136. The process of any of embodiments 133-135, wherein the solvent is a high boiling polar aprotic solvent; optionally wherein the high boiling polar aprotic solvent has a boiling point of 80°C or higher; further optionally wherein the high boiling point polar aprotic solvent has a boiling point of 100°C or higher.

[1591] 137. The process of embodiment 136, wherein the solvent is selected from DMA, DMF, NMP, 1,4-Dioxane combinations thereof.

[1592] 138. The process of embodiment 137, wherein the solvent is DMF.

[1593] 139. The process of any of embodiments 132-138, wherein the compound of Formula (f) is reacted with the compound of Formula (g) in step a) at a temperature of 50-150°C.

[1594] 140. The process of embodiment 139, wherein the compound of Formula (f) is reacted with the compound of Formula (g) in step a) at a temperature of 100-150 °C.141. The process of embodiment 140, wherein the compound of Formula (f) is reacted with the compound of Formula (g) in step a) at a temperature of 120 °C.

[1595] 142. The process of any one of embodiments 132-141, wherein the compound of Formula (f) is reacted with the compound of Formula (g) in step a) for a duration of 30 minutes to 24 hours.

[1596] 143. The process of embodiment 142, wherein the compound of Formula (f) is reacted with the compound of Formula (g) in step a) for a duration of 1 hour to 7 hours.

[1597] 144. The process of embodiment 143, wherein the compound of Formula (f) is reacted with the compound of Formula (g) in step a) for a duration of 3.5 hours.

[1598] 145. The process of any one of embodiments 132-144, wherein the compound of Formula (f) is reacted with the compound of Formula (g) in step a) in the presence of K3PO4 and DMF, at a temperature of 120 °C and a duration of 3.5 hours.

[1599] 146. The process of any of embodiments 122-145, wherein the compound of Formula (h) is converted into a compound of Formula (i) in step b) under conditions suitable for decarboxylation.

[1600] 147. The process of any of embodiments 122-146, wherein the compound of Formula (h) is converted into a compound of Formula (i) in step b) in the presence of Amberlyst 15 and a solvent.

[1601] 148. The process of embodiment 147, wherein the solvent is selected from toluene, xylene, hexane, heptane, cyclohexane and combinations thereof.

[1602] 149. The process of embodiment 148, wherein the solvent is toluene.

[1603] 150. The process of any of embodiments 146-149, wherein the compound of Formula (h) is converted into a compound of Formula (i) in step b) at a temperature of 50-140 °C.

[1604] 151. The process of embodiment 150, wherein the compound of Formula (h) is converted into a compound of Formula (i) in step b) at a temperature of 90-120 °C.152. The process of embodiment 151, wherein the compound of Formula (h) is converted into a compound of Formula (i) in step b) at a temperature of 110 °C.

[1605] 153. The process of any one of embodiments 146-152, wherein the compound of Formula (h) is converted into a compound of Formula (i) in step b) for a duration of 30 minutes – 48 hours.

[1606] 154. The process of embodiment 153, wherein the compound of Formula (h) is converted into a compound of Formula (i) in step b) for a duration of 1 hour – 24 hours.

[1607] 155. The process of embodiment 154, wherein the compound of Formula (h) is converted into a compound of Formula (i) in step b) at a temperature of 4 hours.

[1608] 156. The process of any one of embodiments 146-155, wherein the compound of Formula (h) is converted into a compound of Formula (i) in step b) in the presence of Amberlyst 15 and Toluene, at a temperature of 110 °C, for a duration of 4 hours.

[1609] 157. The process of any one of embodiments 123-124 or 127-132, wherein the compound of Formula (h) is converted into a compound of Formula (i) in step b) in the presence of a catalyst and a solvent.

[1610] 158. The process of embodiment 157, wherein the catalyst is selected from NaCN, KCN, LiCI, NaCI, NaBr, Nal, LiI·H2O, Na2CO3·H2O, Na3PO4·12H2O, Me4NOAc and combinations thereof.

[1611] 159. The process of embodiment 158, wherein the catalyst is LiCI.

[1612] 160. The process of any of embodiments 157-159, wherein the solvent is selected from DMSO, DMF, DMA, NMP and combinations thereof.

[1613] 161. The process of embodiment 160, wherein the solvent is DMSO.

[1614] 162. The process of any one of embodiments 157-161, wherein the compound of Formula (h) is converted into the compound of Formula (i) in step b) at a temperature of 90 -165 °C.

[1615] 163. The process of embodiment 162, wherein the compound of Formula (h) is converted into the compound of Formula (i) in step b) at a temperature of 95 -125 °C.164. The process of embodiment 163, wherein the compound of Formula (h) is converted into the compound of Formula (i) in step b) at a temperature of 100°C.

[1616] 165. The process of any one of embodiment 157-164, wherein the compound of Formula (h) is converted into the compound of Formula (i) in step b) for a duration of 30 minutes - 36 hours.

[1617] 166. The process of embodiment 165, wherein the compound of Formula (h) is converted into the compound of Formula (i) in step b) for a duration of 2 hours - 24 hours.

[1618] 167. The process of embodiment 166, wherein the compound of Formula (h) is converted into the compound of Formula (i) in step b) for a duration of 12 hours.

[1619] 168. The process of any one of embodiments 157-167, wherein the compound of Formula (h) is converted into the compound of Formula (i) in step b) in the presence of LiCI, DMSO and water, at a temperature of 100°C, for a duration of 12 hours.

[1620] 169. The process of any of embodiments 122-168, wherein the compound of Formula (i) is converted into the compound of Formula (j) in step c) under conditions suitable for alkylation.

[1621] 170. The process of any of embodiments 122-168, wherein the compound of Formula (i) is converted into the compound of Formula (j) in step c) in the presence of an alkylating agent, a base and a solvent.

[1622] 171. The process of embodiment 170, wherein the alkylating agent is selected from Mel, Etl, 1,2-dibromoethane and combinations thereof.

[1623] 172. The process of embodiment 171, wherein the alkylating agent is Mel.

[1624] 173. The process of any one of embodiments 170-172, wherein the base is selected from NaH, LiH, LiOMe, NaOMe, KOMe, LiOtBu, NaOtBu, KOtBu, LiHMDS, NaHMDS, KHMDS, DBU, DBN and combinations thereof.

[1625] 174. The process of embodiment 173, wherein the base is KOtBu.175. The process of any one of embodiments 170-174, wherein the solvent is selected from toluene, xylene, heptane, hexane, cyclohexane and combinations thereof.

[1626] 176. The process of embodiment 175, wherein the solvent is toluene.

[1627] 177. The process of any one of embodiment 169-176, wherein the compound of Formula (i) is converted into the compound of Formula (j) in step c) at a temperature of 0-100 °C.

[1628] 178. The process of embodiment 177, wherein the compound of Formula (i) is converted into the compound of Formula (j) in step c) at a temperature of 10-40 °C.

[1629] 179. The process of embodiment 178, wherein the compound of Formula (i) is converted into the compound of Formula (j) in step c) at a temperature of 25 °C.

[1630] 180. The process of any one of embodiments 169-179, wherein the compound of Formula (i) is converted into the compound of Formula (j) in step c) for a duration of 15 minutes to 3 hours.

[1631] 181. The process of embodiment 180, wherein the compound of Formula (i) is converted into the compound of Formula (j) in step c) for a duration of 1 hour.

[1632] 182. The process of any one of embodiments 169-181, wherein the compound Formula (i) is converted into the compound of Formula (j) in step c) in the presence of Mel, KO‘Bu and Toluene, at a temperature of 25 °C, for a duration of 1 hour.

[1633] 183. The process of any one of embodiments 122-182, wherein the compound of Formula (j) is converted into the compound of Formula (3) in step d) under conditions suitable for hydrolysis.

[1634] 184. The process of any one of embodiments 122-183, wherein the compound of Formula (j) is converted into the compound of Formula (3) in step d) in the presence of a base and a solvent.

[1635] 185. The process of embodiment 184, wherein the base is selected from LiOH, NaOH, KOH, CsOH, Ba(OH)2, Ca(OH)2and combinations thereof.

[1636] 186. The process of embodiment 185, wherein the base is KOH.187. The process of any one of embodiments 183-186, wherein the solvent is a high boiling point aprotic solvent; optionally wherein the high boiling point polar aprotic solvent has a boiling point of 80°C or higher; further optionally wherein the high boiling point polar aprotic solvent has a boiling point of 100°C or higher.

[1637] 188. The process of embodiment 187, wherein the solvent is selected from water, 1,4-dioxane, n-BuOH and combinations thereof.

[1638] 189. The process of embodiment 188, wherein the solvent is n-BuOH.

[1639] 190. The process of any one of embodiments 183-189, wherein the compound of Formula (j) is converted into the compound of Formula (3) in step d) at a temperature of 50-200 °C.

[1640] 191. The process of embodiment 190, wherein the compound of Formula (j) is converted into the compound of Formula (3) in step d) at a temperature of 100-150 °C.

[1641] 192. The process of embodiment 191, wherein the compound of Formula (j) is converted into the compound of Formula (3) in step d) at a temperature of 120 °C.

[1642] 193. The process of any one of embodiments 183-192, wherein the compound of Formula (j) is converted into the compound of Formula (3) in step d) for a duration of 1 hour to 36 hours.

[1643] 194. The process of embodiment 193, wherein the compound of Formula (j) is converted into the compound of Formula (3) in step d) for a duration of 6 hours to 24 hours.

[1644] 195. The process of embodiment 194, wherein the compound of Formula (j) is converted into the compound of Formula (3) in step d) for a duration of 14 hours.

[1645] 196. The process of any one of embodiments 183-195, wherein the compound of Formula (j) is converted into the compound of Formula (3) in step d) in the presence of KOH and n-BuOH, at a temperature of 120°C for a duration of 14 hours.

[1646] 197. A compound of Formula (2):HX'

[1647] O

[1648]

[1649] wherein

[1650] X is H; or halo;

[1651] Yi and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH;

[1652] R3is H; C1-2 alkyl, which is optionally substituted with 1-5 fluoro; fluoro; chloro; or cyano;

[1653] R4is chloro; bromo; or fluoro; optionally wherein it is provided that R4is fluoro when R3is chloro; and

[1654] X’ is an anion.

[1655] 198. The compound of embodiment 197, wherein:

[1656] R3is H; C1-2 alkyl, which is optionally substituted with 1-5 fluoro; fluoro; chloro; or cyano;

[1657] R4is chloro; bromo; or fluoro;

[1658] Y1 and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH; and

[1659] X’ is any suitable anion which corresponds to the conjugate base of a strong acid, such as HSO4-, SO42-, NO3-, Ch or Br.

[1660] 199. The compound of embodiment 198, wherein:

[1661] R3is fluoro or chloro;

[1662] R4is fluoro or chloro;

[1663] Y1 and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH;

[1664] X is H; and

[1665] X’ is any suitable anion which corresponds to the conjugate base of a strong acid, such as Cl-or Br-.200. The compound of embodiment 199, wherein:

[1666] R3and R4are each independently chloro;

[1667] Yi and Y2 are each independently CH;

[1668] X is H; and

[1669] X’ is any suitable anion which corresponds to the conjugate base of a strong acid, such as Cl-or Br-.

[1670] 201. A compound of Formula (3):

[1671] R2b

[1672] O'^^^R6

[1673]

[1674] (3)

[1675] wherein:

[1676] R1, R2a, and R2bare defined according to (A) and (B) as defined in embodiment 1;

[1677] R6is Cl, Br, I, OH, OM, O(C=O)(C1-6 alkyl), O(C=O)(N3), O(C1-6 alkyl), or S(C1-6 alkyl); and M is a cation.

[1678] 202. The compound of embodiment 201, wherein R1, R2a, and R2bare defined according to (A1), R1is any R1defined according to (A1); R2aand R2bare each independently C1-2 alkyl optionally substituted with from 1-5 Ra; and M is an alkali metal cation such as Li+, Na+ or K+, an alkali earth metal cation such as Ca2+, or Mg2+, an organic cation such as NH4+, or a protonated amine.

[1679] 203. The compound of embodiments 201 or 202, wherein R1, R2a, and R2bare defined according to (A1), R1is heteroaryl including 5-6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N and O, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc; R2aand R2bare each independently C1-2 alkyl optionally substituted with from 1-5 Ra; and M is an alkali metal cation such as Li+, Na+ or K+, an alkali earth metal cation such as Ca2+, or Mg2+, an organic cation such as NH4+, or a protonated amine.204. The compound of any of embodiments 201-203, wherein R1has the formula:

[1680] R11 - -X3^

[1681] x'\

[1682] X4(lll(III-A); wherein each of Xi, X2, X3, and X4 is, independently, CH or N; and R11is H, Rb, or Rc; R2aand R2bare each independently C1-2 alkyl; and M is an alkali metal cation, preferably Na+ or K

[1683]

[1684] +.

[1685] 205. The compound of any of embodiments 201-204, wherein R1has the formula:

[1686] R-11 \

[1687] N

[1688] N

[1689]

[1690] -A), wherein Rn is methyl.

[1691] 206. The compound of any of embodiments 201-205, wherein R2aand R2bare each independently methyl; and M is an alkali metal cation, preferably Na+ or K+.

[1692] 207. The process of any of embodiments 66-196, or the compound of any of embodiments 197-200, wherein R5is Me, Et or ‘Bu.

[1693] 208. The process of any of embodiments 66-196 or 207, or the compound of any of embodiments 197-200 or 207, wherein R5’ is Me, Et or ‘Bu.

[1694] 209. The process of any of embodiments 1-196 or 207-208, or the compound of any of embodiments 201-206, wherein R6is Cl.

[1695] 210. The process of any of embodiments 1-196 or 207-208, or the compound of any of embodiments 201-206 or 209, wherein R6is OM.

[1696] 211. A process comprising reacting a compound of Formula (n) with a compound of Formula (0) to yield a compound of Formula (p):X

[1697]

[1698] (n) (O) wherein:

[1699] X is H; or halo;

[1700] Y1 and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH;

[1701] R3is C1-2 alkyl, which is substituted with 1-5 fluoro; fluoro; chloro; or cyano;

[1702] R4is chloro; bromo; or fluoro; optionally wherein it is provided that R4is fluoro when R3is chloro; R5is C1-6 alkyl;

[1703] R7is fluoro; or chloro if neither R3nor R4are fluoro; and

[1704] Lg is a leaving group.

[1705] 212. The process of embodiment 211, wherein R3is fluoro or chloro; R4is fluoro or chloro; and Yi and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH.

[1706] 213. The process of embodiments 211 or 212, wherein X is H; R3is chloro; R4is chloro; and Y1 and Y2 are CH or N, wherein at least one ofYi and Y2is CH, preferably wherein Y1 and Y2 are CH.

[1707] 214. The process of any of embodiments 211-213, wherein R7is fluoro.

[1708] 215. The process of any of embodiments 211-214, wherein R5is C1-4 alkyl, for instance Me, Et, i-Pr, and t-Bu, wherein R5is preferably Et.

[1709] 216. The process of any of embodiments 211-215, wherein the compound of Formula (n) is reacted with the compound of Formula (0) under conditions suitable for nucleophilic aromatic substitution.

[1710] 217. The process of any of embodiments 211-216, wherein the compound of Formula (n) is reacted with the compound of Formula (o) in the presence of a base and a solvent.218. The process of embodiment 217, wherein the base is selected from CsCO3, Na2CO3, K2CO3, DBU, DBN, LiHMDS, NaHMDS, KHMDS, K3PO4 and combinations thereof.

[1711] 219. The process of embodiment 218, wherein the base is K2CO3.

[1712] 220. The process of any of embodiments 217-219, wherein the solvent is a high boiling point polar aprotic solvent; optionally wherein the high boiling point polar aprotic solvent has a boiling point of 80°C or higher; further optionally wherein the high boiling point polar aprotic solvent has a boiling point of 100°C or higher.

[1713] 221. The process of any of embodiments 217-220, wherein the solvent is selected from DMSO, DMF, DMA, NMP and combinations thereof.

[1714] 222. The process of embodiment 221, wherein the solvent is NMP.

[1715] 223. The process of any of embodiments 216-222, wherein the compound of Formula (n) is reacted with the compound of Formula (0), at a temperature of 80-150°C.

[1716] 224. The process of embodiment 223, wherein the compound of Formula (n) is reacted with the compound of Formula (0), at a temperature of 115°C.

[1717] 225. The process of any of embodiments 216-224, wherein the compound of Formula (n) is reacted with the compound of Formula (0), for a duration of 1-48 hours.

[1718] 226. The process of embodiment 225, wherein the compound of Formula (n) is reacted with the compound of Formula (0), for a duration of 6-24 hours.

[1719] 227. The process of embodiment 226, wherein the compound of Formula (n) is reacted with the compound of Formula (0), for a duration of 15 hours.

[1720] 228. The process of any of embodiments 216-227, wherein the compound of Formula (n) is reacted with the compound of Formula (o) in the presence of K2CO3 and NMP, at a temperature of 115°C, for a duration of 15 hours.229. The process of any of embodiments 211 -228, further comprising the step of converting the compound of Formula (p) into a compound of Formula (q):

[1721]

[1722] 230. The process of embodiment 229, wherein the compound of Formula (p) is converted into the compound of Formula (q) under conditions suitable for decarboxylation.

[1723] 231. The process of embodiments 229 or 230, wherein the compound of Formula (p) is converted into the compound of Formula (q) in the presence of a catalyst and a solvent.

[1724] 232. The process of embodiment 231, wherein the catalyst is selected from NaCN, KCN, LiCI, NaCI, NaBr, Nal, LiI·H2O, Na2CO3·H2O, Na3PO4·12H2O, Me4NOAc and combinations thereof.

[1725] 233. The process of embodiment 232, wherein the catalyst is LiCI.

[1726] 234. The process of any one of embodiments 231 -233, wherein the solvent is selected from DMSO, DMF, DMA, NMP, water and combinations thereof.

[1727] 235. The process of embodiment 234, wherein the solvent comprises water and NMP.

[1728] 236. The process of embodiment 235, wherein the solvent is water:NMP (1:2).

[1729] 237. The process of any one of embodiments 230-236, wherein the compound of Formula (p) is converted into the compound of Formula (q) at a temperature of 90-165 °C.

[1730] 238. The process of embodiment 237, wherein the compound of Formula (p) is converted into the compound of Formula (q) at a temperature of 95-125 °C.239. The process of embodiment 238, wherein the compound of Formula (p) is converted into the compound of Formula (q) at a temperature of 100 °C.

[1731] 240. The process of any one of embodiments 230-239, the compound of Formula (p) is converted into the compound of Formula (q) for a duration of 1 hour to 36 hours.

[1732] 241. The process of embodiment 240, wherein the compound of Formula (p) is converted into the compound of Formula (q) for a duration of 5 hours to 24 hours.

[1733] 242. The process of embodiment 241, wherein the compound of Formula (p) is converted into the compound of Formula (q) for a duration of 15 hours.

[1734] 243. The process of any one of embodiments 230-242, wherein the compound of Formula (p) is converted into the compound of Formula (q) in the presence of LiCI and water:NMP (1:2), at a temperature of 100°C, for a duration of 15 hours.

[1735] 244. The process of any of embodiments 229-243, further comprising the step of reacting the compound of Formula (q) with a compound of Formula AA to yield a compound of Formula (r):

[1736] O

[1737] (AA)

[1738]

[1739] wherein:

[1740] R9is C1-6 alkyl or C3-5 cycloalkyl.

[1741] 245. The process of embodiment 244, wherein the compound of Formula (q) is reacted with the compound of Formula AA under conditions suitable for a Michael addition reaction.246. The process of embodiments 244 or 245, wherein the compound of Formula (q) is reacted with the compound of formula AA in the presence of a base and a solvent.

[1742] 247. The process of embodiment 246, wherein the base is selected from NaOMe, LiOMe, NaOEt, LiOEt, NaOtBu, LiOtBu, KOMe, KOEt, KOtBu, LiHMDS, NaHMDS, KHMDS, NaH, LiH, KH, DBU, DBN and combinations thereof.

[1743] 248. The process of embodiment 247, wherein the base is NaOMe.

[1744] 249. The process of any one of embodiments 246-248, wherein the solvent is an aprotic polar solvent.

[1745] 250. The process of embodiment 249, wherein the solvent comprises MeCN and / or THF.

[1746] 251. The process of embodiment 250, wherein the solvent comprises MeCN and / or THF in a ratio of 1:0 to 0:1.

[1747] 252. The process of embodiment 251, wherein the solvent comprises MeCN.

[1748] 253. The process of embodiment 252, wherein the solvent further comprises BHT.

[1749] 254. The process of embodiment 250, wherein the solvent is THF.

[1750] 255. The process of any one of embodiments 245-254, wherein the compound of Formula (q) is reacted with the compound of formula AA at a temperature of from -20 to 40 °C.

[1751] 256. The process of embodiment 255, wherein the compound of Formula (q) is reacted with the compound of formula AA at a temperature of from 0 to 20 °C.

[1752] 257. The process of any one of embodiments 245-256, wherein the compound of Formula (q) is reacted with the compound of formula AA for a duration of 30 minutes to 24 hours.

[1753] 258. The process of embodiment 257, wherein the compound of Formula (q) is reacted with the compound of formula AA for a duration of 2 hours.259. The process of any one of embodiments 245-251 and 254-258, wherein the compound of Formula (q) is reacted with the compound AA in the presence of MeONa and THF, at a temperature of from 0 to 20°C for a duration of about 2 hours.

[1754] 260. The process of any of embodiments 244-259, further comprising the step of converting the compound of Formula (r) into a compound of Formula (s):

[1755]

[1756] 261. The process of embodiment 260, wherein R9is Me, Et or ‘Bu.

[1757] 262. The process of embodiment 261, wherein R9is Me.

[1758] 263. The process of embodiment 261, wherein R9is Et.

[1759] 264. The process of embodiment 261, wherein R9is ‘Bu.

[1760] 265. The process of any of embodiments 260-264, wherein the compound of Formula (r) is converted into the compound of Formula (s) under conditions suitable for glutarimide formation.

[1761] 266. The process of embodiment 262 or 263, wherein the compound of Formula (r) is converted into the compound of Formula (s) in the presence of an acid.

[1762] 267. The process of embodiment 266, wherein the acid is selected from HI, HBr, H2SO4, HNO3, H3PO4, HF, formic acid, C6H5COOH, AcOH and combinations thereof.

[1763] 268. The process of embodiment 266 or 267, wherein the acid comprises H2SO4and HOAc.269. The process of any one of embodiments 265-268, wherein the compound of Formula (r) is converted into the compound of Formula (s) at a temperature of 50-150°C.

[1764] 270. The process of embodiment 269, wherein the compound of Formula (r) is converted into the compound of Formula (s) at a temperature of 70-120°C.

[1765] 271. The process of embodiment 270, wherein the compound of Formula (r) is converted into the compound of Formula (s) at a temperature of 90°C.

[1766] 272. The process of any one of embodiments 265-271, wherein the compound of Formula (r) is converted into the compound of Formula (s) for a duration of 30 minutes to 24 hours.

[1767] 273. The process of embodiment 272, wherein the compound of Formula (r) is converted into the compound of Formula (s) for a duration of 1 hour to 6 hours.

[1768] 274. The process of embodiment 273 wherein the compound of Formula (r) is converted into the compound of Formula (s) for a duration of 2 hours.

[1769] 275. The process of any one of embodiments 265-274, wherein the compound of Formula (r) is converted into the compound of Formula (s) in the presence of H2SO4and HOAc, at a temperature of 90°C, for a duration of 2 hours.

[1770] 276. The process of embodiment 264, wherein the compound of Formula (r) is converted into the compound of Formula (s) in the presence of acid and a solvent.

[1771] 277. The process of embodiment 276, wherein the acid is selected from p-toluenesulphonic acid, methanesulfonic acid and combinations thereof.

[1772] 278. The process of any one of embodiments 276-277, wherein the solvent is selected from xylene, toluene and combinations thereof.

[1773] 279. The process of any of embodiments 260-278, further comprising the step of converting the compound of Formula (s) into a compound of Formula (t):

[1774]

[1775] 280. The process of embodiment 279, wherein the compound of Formula (s) is converted into the compound of Formula (t) under Negishi-type cyanation conditions.

[1776] 281. The process of embodiment 279 or 280, wherein the compound of Formula (s) is converted into the compound of Formula (t) in the presence of a catalyst, a solvent, a ligand and Zn(CN)2.

[1777] 282. The process of embodiment 281, wherein the catalyst is selected from Pd(0), Pd(ll), Ni(0), Ni(ll) and combinations thereof.

[1778] 283. The process of embodiment 282, wherein the catalyst is selected from Pd(PPh3)4, Pd(PtBu3)2, Pd(pda)2, Pd(dppf)Cl2, Pd(OAc)2, Ni(PPh3)4, Ni(acac)2, Ni(COD)2, NiCh, Pd2(dba)3and combinations thereof.

[1779] 284. The process of embodiment 283, wherein the catalyst is Pd2(dba)3.

[1780] 285. The process of any one of embodiments 281 -284, wherein the solvent is a high boiling point polar aprotic solvent; optionally wherein the high boiling point polar aprotic solvent has a boiling point of 80°C or higher; further optionally wherein the high boiling point polar aprotic solvent has a boiling point of 100°C or higher.

[1781] 286. The process of embodiment 285, wherein the solvent is selected from 1,3-dioxane, DMSO, DMA, DMF, NMP and combinations thereof.

[1782] 287. The process of embodiment 286, wherein the solvent is NMP.288. The process of any of embodiments 281-287, wherein the ligand is selected from DPPF, SPhos, DPPP, DPPB, Xantphos, DPPM, DPPE, DCPE, PPh3, P(c-hex)3, P(‘Bu)3, P(C6F5)3, P(2,4,6-Me3C6H2)3and combinations thereof.

[1783] 289. The process of embodiment 288, wherein the ligand is DPPF.

[1784] 290. The process of any one of embodiments 280-289, wherein the compound of Formula (s) is converted into the compound of Formula (t) at a temperature of 20-200°C.

[1785] 291. The process of embodiment 290, wherein the compound of Formula (s) is converted into the compound of Formula (t) at a temperature of 70-130°C.

[1786] 292. The process of embodiment 291, wherein the compound of Formula (s) is converted into the compound of Formula (t) at a temperature of 100°C.

[1787] 293. The process of embodiments 280-292, wherein the compound of Formula (s) is converted into the compound of Formula (t) for a duration of 2 to 48 hours.

[1788] 294. The process of embodiment 293, wherein the compound of Formula (s) is converted into the compound of Formula (t) for a duration of 6 to 24 hours.

[1789] 295. The process of embodiment 294, wherein the compound of Formula (s) is converted into the compound of Formula (t) for a duration of 12 hours.

[1790] 296. The process of any one of embodiments 280-295, wherein the compound of Formula (s) is converted into the compound of Formula (t) in the presence of Pd2(dba)3, DPPF, Zn(CN)2and NMP, at a temperature of 100°C for a duration of 12 hours.

[1791] 297. The process of any of embodiments 279-296, further comprising the step of converting the compound of Formula (t) into a compound of Formula (u):CN

[1792] O

[1793]

[1794] wherein:

[1795] Pg is a protecting group.

[1796] 298. The process of embodiment 297, wherein the compound of Formula (t) is converted into the compound of Formula (u) under nitrile-selective reducing conditions, and amine protecting conditions.

[1797] 299. The process of embodiments 297 or 298, wherein the compound of Formula (t) is converted into the compound of Formula (u) in the presence of hydrogen, a catalyst, a reagent for introducing a protecting group and one or more solvents.

[1798] 300. The process of embodiment 299, wherein the catalyst is selected from Raney Ni, palladium, platinum, cobalt boride, nickel boride and combinations thereof.

[1799] 301. The process of embodiment 300, wherein the catalyst is Raney Ni, optionally wherein the catalyst is anhydrous Raney Ni.

[1800] 302. The process of any one of embodiments 299-301, wherein the one or more solvents are polar aprotic solvents.

[1801] 303. The process of any of embodiments 299-302, wherein the compound of Formula (t) is converted into the compound of Formula (u) in the presence of two solvents.

[1802] 304. The process of embodiment 303, wherein the solvents are THF and DMF.

[1803] 305. The process of embodiment 304, wherein the one or more solvents are THF: DMF in a ratio of 1:0 to 0:1.306. The process of any of embodiments 303-304, wherein the two solvents are THF: DMF in a 1:1 ratio.

[1804] 307. The process of any one of embodiments 299-306, wherein the hydrogen pressure is 1 atm to 20 atm.

[1805] 308. The process of any of embodiments 299-307, wherein the reagent for introducing a protecting group is a reagent for introducing Boc.

[1806] 309. The process of embodiment 308, wherein the reagent for introducing Boc is (Boc)2O or N-Boc-Benzotriazole.

[1807] 310. The process of any one of embodiments 298-309, wherein the compound of Formula (t) is converted into the compound of Formula (u) at a temperature of 20-80°C.

[1808] 311. The process of embodiment 310, wherein the compound of Formula (t) is converted into the compound of Formula (u) at a temperature of 40-70°C.

[1809] 312. The process of embodiment 311, wherein the compound of Formula (t) is converted into the compound of Formula (u) at a temperature of 60°C.

[1810] 313. The process of any one of embodiments 298-312, wherein the compound of Formula (t) is converted into the compound of Formula (u) for a duration of 2-24 hours.

[1811] 314. The process of embodiment 313, wherein the compound of Formula (t) is converted into the compound of Formula (u) for a duration of 6-18 hours.

[1812] 315. The process of embodiment 314, wherein the compound of Formula (t) is converted into the compound of Formula (u) for a duration of 12 hours.

[1813] 316. The process of any one of embodiments 298-315, wherein the compound of Formula (t) is converted into the compound of Formula (u) in the presence of anhydrous Raney Ni, H2, (Boc)2O and THF: DMF (1:1), at a temperature of 60°C, for a duration of 12 hours.316. The process of any of embodiments 297-316, further comprising the step of converting the compound of Formula (u) into the compound of Formula (v):

[1814] O

[1815] (u)

[1816]

[1817] wherein X’ is an anion.

[1818] 317. The process of embodiment 316, wherein Pg is Boc.

[1819] 318. The process of embodiments 316 or 317, wherein the compound of Formula (u) is converted into the compound of Formula (v) under amine deprotection conditions.

[1820] 319. The process of any of embodiments 316-318, wherein the compound of Formula (u) is converted into the compound of Formula (v) in the presence of an acid and a solvent.

[1821] 320. The process of embodiment 319, wherein the acid is hydrochloric acid, p-toluenesulphonic acid, methanesulfonic acid, trifluoroacetic acid, phosphoric acid or amberlyst 15.

[1822] 321. The process of embodiment 320, wherein the acid is HCI.

[1823] 322. The process of embodiment 321, wherein the HCI is generated in situ using a mixture of acetyl chloride and an alcohol, wherein the alcohol is selected from EtOH, MeOH, BuOH, PrOH and combinations thereof; optionally wherein the BuOH is selected fromnBuOH, 'BuOH, ‘BuOH and combinations thereof.

[1824] 323. The process of any of embodiments 319-322, wherein the solvent is selected from water, DCM, EtOAc, EtOH, MeOH, IPrOAc, 1,4-dioxane, 2-propanol, CPME and combinations thereof.324. The process of embodiment 323, wherein the solvent is EtOAc.

[1825] 325. The process of any of embodiments 318-324, wherein the compound of Formula (u) is converted into the compound of Formula (v) at a temperature of 10-50°C.

[1826] 326. The process of embodiment 325, wherein the compound of Formula (u) is converted into the compound of Formula (v) at a temperature of 20-30°C.

[1827] 327. The process of embodiment 326, wherein the compound of Formula (u) is converted into the compound of Formula (v) at a temperature of 25°C.

[1828] 328. The process of any of embodiments 318-327, wherein the compound of Formula (u) is converted into the compound of Formula (v) for a duration of 1 -24 hours.

[1829] 329. The process of embodiment 328, wherein the compound of Formula (u) is converted into the compound of Formula (v) for a duration of 2-12 hours.

[1830] 330. The process of embodiment 329, wherein the compound of Formula (u) is converted into the compound of Formula (v) for a duration of 3 hours.

[1831] 331. The process of any of embodiments 318-330, wherein the compound of Formula (u) is converted into the compound of Formula (v) in the presence of HCI and EtOAc, at a temperature of 25°C, for a duration of 3 hours.

[1832] 332. The process of any of embodiments 316-331, further comprising the step of reacting the compound of Formula (v) with a compound of formula BB to yield a compound of Formula (I):

[1833] R3„

[1834] N R H R Z

[1835] p2b R2aO R-

[1836]

[1837] wherein:Z is Cl, OH or OM;

[1838] M is a cation; and

[1839] R1, R2a, and R2bare defined according to (A2) and (B2) below:

[1840] (A2)

[1841] R1is:

[1842] • heteroaryl including 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc;

[1843] • heterocyclyl including 4-6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc;

[1844] • C3-7 cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc;

[1845] • heterocycloalkenyl including 3-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc; or • C6-10aryl optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc; and

[1846] each of R2aand R2bis independently selected from the group consisting of:

[1847] • H;

[1848] • C1-2 alkyl optionally substituted with from 1-5 Ra;

[1849] • C3-5 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rb;

[1850] • C1-4 alkoxy;

[1851] • C1-4 haloalkoxy; or

[1852] • cyano; or

[1853] R2aand R2btaken together with the carbon atom to which each is attached forms:

[1854] • C3-7 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rb;

[1855] • heterocyclyl including 4-7 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl is optionally substituted with 1 -4 substituents independently selected from the group consisting of oxo and Rb;(B2)

[1856] R1taken together with (i) the carbon atom to which it is attached and (ii) and one of R2aand R2bforms:

[1857] • C8-10aryl optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc; or

[1858] • heteroaryl including 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc; and

[1859] the other of R2aand R2bis H or C1-2 alkyl optionally substituted with from 1-5 Ra;

[1860] each occurrence of Rais independently selected from the group consisting of: -OH; -halo; -NReRf; C1-4 alkoxy; C1-4 haloalkoxy,; -C(=O)O(Ci-4alkyl); -C(=O)(Ci-4alkyl); -C(=O)OH; -CONR’R”; -S(O)I-2NR’R”; -S(O)1-2(C1-4alkyl); and cyano;

[1861] each occurrence of Rbis independently selected from the group consisting of: halo; cyano; C1-10 alkyl which is optionally substituted with from 1-6 independently selected Ra; C2-6 alkenyl; C2-6 alkynyl; C1-4 alkoxy; -0(Ci-3 alkylene)-(C3-e cycloalkyl); C1-4 haloalkoxy; -S(0)o-2(Ci-4alkyl); -NReRf; -OH; -S(O)I-2NR’R”; -NO2; -C(=0)(Ci-io alkyl); -C(=O)O(Ci-4alkyl); -C(=O)OH; and -C(=O)NR’R”;

[1862] each occurrence of Rcis independently selected from the group consisting of:

[1863] • C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rb;

[1864] • heterocyclyl or heterocycloalkenyl including 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rb;

[1865] • heteroaryl including 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with from 1-4 Rb; and

[1866] • Cs-io aryl optionally substituted with from 1-4 Rb;

[1867] each occurrence of Rdis independently selected from the group consisting of: C1-6 alkyl optionally substituted with from 1-3 independently selected Ra; -C(O)(Ci-4 alkyl); -C(O)O(Ci-4 alkyl); -CONR’R”; -S(O)I-2NR’R”; -S(O)I-2(CI-4 alkyl); -OH; and Ci-4alkoxy; and

[1868] each occurrence of Reand Rfis independently selected from the group consisting of: H; C1-6 alkyl; -C(O)(Ci-4 alkyl); -C(O)O(Ci-4alkyl); -CONR’R”; -S(O)I-2NR’R”; -S(O)i-2(Ci-4 alkyl); -OH; and Ci-4alkoxy; andeach occurrence of R’ and R” is independently selected from the group consisting of: H; and C1-4 alkyl.

[1869] 333. The process of embodiment 332, wherein the compound of Formula (v) is reacted with the compound of formula BB under amide coupling conditions, for example the amide coupling conditions recited in embodiments 3-19.

[1870] 334. The process of embodiments 332 or 333, wherein:

[1871] R1is heteroaryl including 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc; R2aand R2bare each independently C1-2 alkyl optionally substituted with from 1-5 Ra;

[1872] R3is H; C1-2 alkyl, which is optionally substituted with 1-5 fluoro; fluoro; chloro; or cyano;

[1873] R4is chloro; bromo; or fluoro; optionally wherein it is provided that R4is fluoro when R3is chloro;

[1874] Y1 and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH,

[1875] X’ is a suitable anion which corresponds to the conjugate base of a strong acid (for example, HSOr, SO42-, NO3-, Cl-or Br, and preferably Cl-or Br);

[1876] M is an alkali metal cation such as Li+, Na+ or K+, an alkali earth metal cation such as Ca2+, or Mg2+, an organic cation such as NH4+, or a protonated amine.

[1877] 335. The process of any of embodiments 332-334, wherein R1has the formula:

[1878] N

[1879] N

[1880]

[1881] (V-A), wherein Rn is methyl.

[1882] 336. The process of any of embodiments 332-335, wherein R2aand R2bare each independently methyl; R3and R4are each independently chloro; Y1 and Y2 are each independently CH; X’ is a suitable anion which corresponds to the conjugate base of a strong acid (for example, HSO4-, SO42-, NO3-, Cl-or Br, and preferably Cl-or Br); and M is an alkali metal cation such as Li+, Na+ or K+, an alkali earth metal cation such as Ca2+, or Mg2+, an organic cation such as NH4+, or a protonated amines.

[1883] 337. A compound of Formula (p):

[1884]

[1885] (p)

[1886] wherein:

[1887] X is H; or halo;

[1888] Y1 and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH;

[1889] R3is C1-2 alkyl, which is substituted with 1-5 fluoro; fluoro; chloro;

[1890] R4is chloro; bromo; or fluoro; optionally wherein it is provided that R4is fluoro when R3is chloro; and

[1891] Lg is a leaving group.

[1892] 338. The compound of embodiment 337, wherein R3is fluoro or chloro; R4is fluoro or chloro; and Yi and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH.

[1893] 339. The compound of embodiments 337 or 338, wherein X is H; R3is chloro; R4is chloro; and Y1 and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH, preferably wherein Y1 and Y2 are CH.

[1894] 340. The process of any of embodiments 1-37, 38-196, or 208-336, or the compound of any of embodiments 197-200 or 337-339, wherein R5is Me, Et or ‘Bu.

[1895] 341. The process of any of embodiments 1-196, 332-336 or 340, or the compound of any of embodiments 201-206 or 340, wherein M is Na+or K+.

[1896] 342. The process of any of embodiments 1-196 or 340-341, or the compound of embodiment 197-200 or 340-341, wherein X’ is Cl or Br.343. The process of any of embodiments 211 -336 or 340-342, or the compound of embodiment 337-339 of 340-342, wherein Lg is Br or I.

[1897] 344. The process of embodiment 343, or the compound of embodiment 343, wherein Lg is Br.

[1898] 345. The process of any of embodiments 1-22, 24-196, 211 -335 or 340-344, or the compound of any of embodiments 197-199, 337-339 or 340-344, wherein Y1is CH.

[1899] 346. The process of any of embodiments 1-22, 24-196, 211 -335 or 340-345, or the compound of any of embodiments 197-199 or 337-345, wherein Y2is CH.

[1900] 347. The process of any of embodiments 1-21, 24-196, 211 -212, 214-336, or 340-346, or the compound of any of embodiments 197-198, 337-338 or 340-346, wherein X is H.

[1901] 348. The process of any of embodiments 1-196 or 332-347, or the compound of any of embodiments 201-210, wherein R1, R2a, and R2bare defined according to (A), (A1) or (A2).

[1902] 349. The process or compound embodiment 348, wherein R1is heteroaryl including 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc.

[1903] 350. The process or compound of embodiment 349, wherein R1is heteroaryl including 5-6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc.

[1904] 351. The process or compound of embodiment 350, wherein R1is heteroaryl including 6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc.

[1905] 352. The process or compound of embodiment 351, wherein R1is heteroaryl including 6 ring atoms, wherein 1-2 ring atoms are N, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc.353. The process of any of embodiments 348-352 or the compound of any one of embodiments 348-352, wherein R1is unsubstituted.

[1906] 354. The process of any of embodiments 348-352 or the compound of any one of embodiments 348-352, wherein R1is substituted with one Rbor one Rc.

[1907] 355. The process or compound of embodiment 354, wherein R1is substituted with one Rb.

[1908] 356. The process or compound of any one of embodiments 348-352 or 354-355, wherein Rbis C1-10 alkyl, which is optionally substituted with 1-6 independently selected Ra.

[1909] 357. The process or compound of embodiment 356, wherein Rbis C1-6alkyl, which is optionally substituted with 1-6 independently selected Ra.

[1910] 358. The process or compound of embodiment 357, wherein Rbis C1-3 alkyl, which is optionally substituted with 1-6 independently selected Ra.

[1911] 359. The process or compound of embodiment 358, wherein Rbis unsubstituted C1-3 alkyl.

[1912] 360. The process or compound of embodiment 359, wherein Rbis -CH3.

[1913] 361. The process or compound of embodiment 357, wherein Rbis C1-3 alkyl, which is substituted with 1-6 independently selected Ra.

[1914] 362. The process or compound of any one of embodiments 356-358 or 361, wherein Ra, or each occurrence of Ra, is an independently selected halo; optionally wherein Ra, or each occurrence of Ra, is fluoro.

[1915] 363. The process or compound of embodiment 362, wherein Rbis -CF3.

[1916] 364. The process or compound of embodiment 362, wherein Rbis -CHF2.365. The process or compound of any one of embodiments 356-358 or 361, wherein Ra, or each occurrence of Ra, is an independently selected C1-4 alkoxy.

[1917] 366. The process or compound of embodiment 365, wherein Ra, or each occurrence of Ra, is -OCH3.

[1918] 367. The process or compound of embodiment 366, wherein Rbis CH2OCH3.

[1919] 368. The process or compound of any of embodiments 348-354, wherein Rbis C1-4 alkoxy.

[1920] 369. The process or compound of embodiment 368, wherein Rbis -OCH3.

[1921] 370. The process or compound of any one of embodiments 348-354, wherein Rbis C1-4 haloalkoxy.

[1922] 371. The process or compound of embodiment 370, wherein Rbis -OCHF2.

[1923] 372. The process or compound of any of embodiments 348-354, wherein Rbis halo.

[1924] 373. The process or compound of embodiment 372, wherein Rbis fluoro.

[1925] 374. The process or compound of embodiment 372, wherein Rbis chloro.

[1926] 375. The process or compound of any of embodiments 348-354, wherein Rbis cyano.

[1927] 376. The process or compound of any one of embodiments 348-352 or 354, wherein R1is substituted with 1 Rc.

[1928] 377. The process or compound of embodiment 376, wherein Rcis C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc.

[1929] 378. The process or compound of embodiment 377, wherein Rcis C3-10 cycloalkyl which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rb.379. The process or compound of embodiment 378, wherein Rcis C3-6 cycloalkyl which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rb.

[1930] 380. The process or compound of embodiment 379, wherein Rcis cyclopropyl, which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rb.

[1931] 381. The process or compound of any one of embodiments 348-352, wherein R1has the formula:

[1932]

[1933] wherein each of Xi, X2, X3, and X4 is, independently, CH or N; and R11is H, Rb, or Rc, preferably wherein R1has the formula:

[1934]

[1935] 382. The process or compound of embodiment 381, wherein not more than two of X1, X2, and X3are N.

[1936] 383. The process or compound of embodiment 381 or 382, wherein X2 is N.

[1937] 384. The process or compound of any one of embodiments 381-383, wherein Xi is CH.

[1938] 385. The process or compound of any one of embodiments 381-384, wherein X3 is CH.

[1939] 386. The process or compound of any one of embodiments 348-352, wherein R1has the formula:

[1940]

[1941] 387. The process or compound of embodiment 381 or 382, wherein Xi is N.

[1942] 388. The process or compound of embodiment 381, 382 or 387, wherein X2 is CH.

[1943] 389. The process or compound of embodiment 381, 382 or 387-388, wherein X3 is CH.

[1944] 390. The process or compound of any one of embodiments 348-352, wherein R1has the formula:

[1945] Rn

[1946] T 1

[1947] N\

[1948] N(V-B).

[1949] 391. The process or compound of embodiment 381 or 382, wherein X3 is N.

[1950] 392. The process or compound of any one of embodiments 381, 382 or 391, wherein X2 is CH.

[1951] 393. The process or compound of any one of embodiments381, 382, 391 or 392, wherein Xi is CH.

[1952] 394. The process or compound of any one of embodiments 348-352, wherein R1has the formula:

[1953]

[1954] 395. The process or compound of any one of embodiments 348-352, wherein R1has the formula:

[1955] R11 —.

[1956]

[1957] 396. The process or compound of any one of embodiments 381-395, wherein R11is H.397. The process or compound of any one of embodiments 381-395, wherein R11is Rb.

[1958] 398. The process or compound of any one of embodiments 381-395, wherein R11is unsubstituted C1-3 alkyl.

[1959] 399. The process or compound of embodiment 398, wherein R11is CH3.

[1960] 400. The process or compound of any of embodiments 381-395, wherein R11is C1-3 alkyl, which is substituted with from 1-6 independently selected Ra.

[1961] 401. The process or compound of embodiment 400, wherein Ra, or each occurrence of Ra, is an independently selected halo.

[1962] 402. The process or compound of embodiment 401, wherein Ra, or each occurrence of Ra, is fluoro.

[1963] 403. The process or compound of embodiment 402, wherein R11is -CF3.

[1964] 404. The process or compound of embodiment 403, wherein R11is -CHF2.

[1965] 405. The process or compound of embodiment 400, wherein Ra, or each occurrence of Ra, is an independently selected C1-4 alkoxy.

[1966] 406. The process or compound of embodiment 405, wherein Ra, or each occurrence of Ra, is -OCH3.

[1967] 407. The process or compound embodiment 405, wherein R11is CH2OCH3.

[1968] 408. The process or compound of any one of embodiments 381-395, wherein R11is C1-4 alkoxy.

[1969] 409. The process or compound of embodiment 408, wherein R11is -OCH3.

[1970] 410. The process or compound of any one of embodiments 381-395, wherein R11is C1-4 haloalkoxy.411. The process or compound of embodiment 410, wherein R11is -OCHF2.

[1971] 412. The process or compound of any of embodiments 381-395, wherein R11is halo.

[1972] 413. The process or compound of embodiment 412, wherein R11is fluoro.

[1973] 414. The process or compound of embodiment 412, wherein R11is chloro.

[1974] 415. The process or compound of any one of embodiments 381 -395, wherein R11is cyano.

[1975] 416. The process or compound of any one of embodiments 381-395, wherein R11is cyclopropyl, which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc.

[1976] 417. The process or compound of embodiment 348, wherein R1is heteroaryl including 8-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc.

[1977] 418. The process or compound of embodiment 417, wherein R1is heteroaryl including 10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc.

[1978] 419. The process or compound of embodiment 418, wherein R1is:

[1979]

[1980] wherein whichever of Xi to X4 provides the position of attachment of the R1group to the rest of the molecule is carbon, the rest of Xi to X4 are each independently selected from CH, CR13or N, and each of X5 to Xs is independently selected from CH, CR13or N; wherein R13is Rbor Rc; and provided that no more than four of Xi to Xs are heteroatoms and no more than four of Xi to Xs are CR13; preferably wherein none of Xi to X8are CR13.420. The process or compound of embodiment 418, wherein R1is:

[1981]

[1982] wherein whichever of X1to X4provides the position of attachment of the R1group to the rest of the molecule is carbon, the rest of X1to X4are each independently selected from CH, CR13or N, and each of X5to X8is independently selected from CH2, CHR13, NH, NR13, O or SO2; wherein R13is Rbor Rc; and provided that no more than four of X1to X8are heteroatoms and no more than four of X1to X8include an R13group; preferably wherein none of X1to X8include an R13group.

[1983] jw\r

[1984] 421. The process or compound of embodiment 418, wherein R1is:

[1985]

[1986] wherein Xi to X4 are each independently selected from CH, CR13or N, X5 is CH, CR13or N, and each of Xs to Xs is independently selected from CH2, CR13, NH, NR13, O or SO2; wherein R13is Rbor Rc; and provided that no more than four of Xi to Xs are heteroatoms and no more than four of Xi to Xs include an R13group; preferably wherein none of Xi to Xs include an R13group.

[1987] 422. The process or compound of embodiment 418, wherein R1is: w

[1988]

[1989] herein Xi to X4 are each independently selected from CH or N, Xs is CH, CR13or N, and each of X5, X7 and Xs is independently selected from CH2, CHR13, NH, NR13, O or SO2; wherein R13is Rbor Rc; and provided that no more than four of Xi to Xs are heteroatoms and and no more than four of Xi to Xs include an R13group; preferably wherein none of Xi to Xs include an R13group.

[1990] 423. The process or compound of embodiment 348, wherein R1is:

[1991]

[1992] 424. The process or compound of embodiment 348, wherein R1is heteroaryl including 9 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc.

[1993] 425. The process or compound of embodiment 424, wherein R1is:

[1994]

[1995] wherein whichever of Xi to X4 provides the position of attachment of the R1group to the rest of the molecule is carbon, the rest of Xi to X4 are each independently selected from CH, CR13or N, X5 and Xe are independently selected from CH, CR13or N, and X?is selected from CH2, CHR13, NH, NR13, O or S; wherein R13is Rbor Rc; and provided that no more than four of Xi to X7 are heteroatoms and no more than four of Xi to X7 include an R13group; preferably wherein none of Xi to X7 include an R13group or wherein only one of Xi to X7 includes an R13group and the R13group is CH3.

[1996] 426. The process or compound of embodiment 424, wherein R

[1997]

[1998] 1is wherein whichever of Xi to X4 provides the position of attachment of the R1group to the rest of the molecule is carbon, the rest of Xi to X4 are each independently selected from CH, CR13or N, X5 and X7 are independently selected from CH2, CHR13, NH, NR13or O; wherein R13is Rbor Rc; and provided that no more than four of Xi to X7 are heteroatoms and no more than four of Xi to X7 include an R13group; preferably wherein none of Xi to X7 include an R13group or wherein only one of Xi to X7 includes an R13group and the R13group is CH3.427. The process or compound of embodiment 424, wherein R1is:

[1999]

[2000]

[2001] ; wherein Xi to X4 are each independently selected from CH, CR13or N; X5 and Xe are selected from CH, CR13or N, and X? is selected from NH, NR13or O; wherein R13is Rbor Rc; and provided that no more than four of Xi to X7 are heteroatoms and no more than four of Xi to X7 include an R13group; preferably wherein none of Xi to X7 include an R13group or wherein only one of Xi to X7 includes an R13group and the R13group is CH3.

[2002] 428. The process or compound of embodiment 424, wherein R1is:

[2003]

[2004] wherein whichever of Xi to X4 provides the position of attachment of the R1group to the rest of the molecule is carbon, the rest of Xi to X4 are each independently selected from CH, CR13or N, and X5 to X7 are each independently selected from CH2, CHR13, NH, NR13, O or SO2; wherein R13is Rbor Rc; and provided that no more than four of Xi to X7 are heteroatoms and no more than four of Xi to X7 include an R13group; preferably wherein none of Xi to X7 include an R13group or wherein only one of Xi to X7 includes an R13group and the R13group is CH3.

[2005] 429. The process or compound of embodiment 424, wherein R1is: wherein Xi to X4 are each independently selected from CH, CR13or N, X5 is CH or N a

[2006]

[2007] nd Xe and X?are each independently selected from CH2, CHR13, NH, NR13, O or SO2; wherein R13is Rbor Rc; and provided that no more than four of Xi to X7 are heteroatoms and no more than four of Xi to X7 include an R13group; preferably wherein none of Xi to X7 include an R13group.x5 x2II,x6 —: 3. TXK 4 0 he process or compound of embodiment 424, wherein R1is: wherein Xi to X4 are each independently selected from CH, CR13or N, Xe is CH or N and X5 and X? are each independently selected from CH2, CHR13, NH, NR13, O or SO2; wherein R13is Rbor Rc; and provided t

[2008]

[2009] hat no more than four of Xi to X7 are heteroatoms and no more than four of Xi to X7 include an R13group; preferably wherein none of Xi to X7 include an R13group.

[2010] 431. The process or compound of embodiment 424, wherein R1has the formula:

[2011]

[2012] ■5 (Vl-B), wherein:

[2013] X3is NH, O, or S;

[2014] X4 is N, O, or CH; and

[2015] X5is N or CH.

[2016] 432. The process or compound of embodiment 431, wherein X3is NH, O, or S; and X4 and X5 are CH.

[2017] 433. The process or compound of embodiment 431, wherein X3is O or S; X4 is CH; and X5 is N.

[2018] 434. The process or compound of embodiment 431, wherein X3is NH, X4 is N; and X5 is CH.

[2019] 435. The process or compound of embodiment 431, wherein X3is N, X4 is O; and X5 is N.

[2020] 436. The process or compound of embodiment 348, wherein R1is heteroaryl including 5 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of Rband Rc.

[2021] 437. The process or compound of embodiment 436, wherein R1has the formula:

[2022]

[2023] x6 (Vl-C), wherein:

[2024] Xe is NH, NCH3, O, or S;

[2025] X7is N, C, CH, CCF3, CCHF2, C(cyclopropyl), or CCH3;

[2026] X8is N, C, CH, CCH3, CCF3, or COCH3;

[2027] X9is N, C, CH, CCH3, CCF3, or COCH3; and

[2028] X10 is N, C, CH, CCF3, CCHF2, C(cyclopropyl), or CCH3.

[2029] 438. The process or compound of embodiment 436, wherein R1has the formula:

[2030] Xg X9

[2031] <0x6^ (VI-C-1), wherein:

[2032] X6is NH, NCH3, O, or S;

[2033] X7is N, CH, CCF3, CCHF2, C(cyclopropyl), or CCH3;

[2034] X8is N, CH, or CCH3; and

[2035] X9is N, CH, or CCH3.

[2036] 439. The process or compound of embodiment 437 or 438, wherein X8is N.

[2037] 440. The process or compound of any one of embodiments 437-439, wherein Xg is N.

[2038] 441. The process or compound of any one of embodiments 437-440, wherein X8is O.

[2039] 442. The process or compound of any one of embodiments 437-441, wherein X7is CH, CCF3, CCHF2, C(cyclopropyl), or CCH3.

[2040] 443. The process or compound of embodiment 442, wherein X7is CCH3.444. The process or compound of embodiment 436, wherein R1has the formula:

[2041] N - N

[2042]

[2043] 445. The process or compound of embodiment 437 or 438, wherein X6is O or S; and X7is N.

[2044] 446. The process or compound of embodiment 445, wherein X8is CH or CCH3; and X9is CH or CCH3.

[2045] 447. The process or compound of embodiment 437 or 438, wherein:

[2046] X6is NH, NCH3, or O;

[2047] X7is CH or CCH3;

[2048] X8is N; and

[2049] X9is CH or CCH3.

[2050] 448. The process or compound of embodiment 437 or 438, wherein:

[2051] X6is NCH3;

[2052] X7is CH or CCH3;

[2053] X8is N; and

[2054] Xg is N.

[2055] 449. The process or compound of embodiment 348, wherein R1is C6-10aryl optionally substituted with 1-4 substituents independently selected from the group consisting of Rb, and Rc.

[2056] 450. The process or compound of embodiment 449, wherein R1is phenyl optionally substituted with 1-4 substituents independently selected from the group consisting of Rb, and Rc.

[2057] 451. The process or compound of embodiment 450, wherein R1has the formula:Rn

[2058]

[2059] (Vl-D); wherein each R11is independently selected from the group consisting of H, Rb, and Rc; each R12is independently selected from the group consisting of Rband Rc; and q is 0, 1, or 2.

[2060] 452. The process or compound of embodiment 451, wherein R11is H, fluoro, CN, CH3, CHF2, -SO2NH2, SO2CH3, -C(O)NH2, or cyclopropyl.

[2061] 453. The process or compound of embodiment 452, wherein R11is H.

[2062] 454. The process or compound of embodiment 452, wherein R11is CH3.

[2063] 455. The process or compound of embodiment 452, wherein R11is CN.

[2064] 456. The process or compound of any one of embodiments 451 -455, wherein q is 1.

[2065] 457. The process or compound of embodiment 451, wherein R12is F.

[2066] 458. The process or compound of any one of embodiments 348-457, wherein each of R2aand R2bis independently selected from the group consisting of H and C1-2 alkyl optionally substituted with from 1-5 Ra.

[2067] 459. The process or compound of embodiment 458, wherein each of R2aand R2bis an independently selected C1-2 alkyl optionally substituted with from 1-5 Ra.

[2068] 460. The process or compound of embodiment 459, wherein each of R2aand R2bis an independently selected unsubstituted C1-2 alkyl.

[2069] 461. The process or compound of embodiment 460, wherein each of R2aand R2bis CH3.462. The process or compound of any one of embodiments 348-457, wherein R2aand R2btaken together with the carbon atom to which each is attached forms:

[2070] • C3-7 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rb;

[2071] • heterocyclyl including 4-7 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl is optionally substituted with 1 -4 substituents independently selected from the group consisting of oxo and Rb.

[2072] 463. The process or compound of embodiment 462, wherein R2aand R2btaken together with the carbon atom to which each is attached forms C3-7 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rb.

[2073] 464. The process or compound of embodiment 462 or 463, wherein R2aand R2btaken together with the carbon atom to which each is attached forms:

[2074]

[2075] 465. The process or compound of embodiment 462, wherein R2aand R2btaken together with the carbon atom to which each is attached forms heterocyclyl including 4-7 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rb.

[2076] 466. The process or compound of embodiment 465, wherein R2aand R2btaken together with the carbon atom to which each is attached forms:

[2077]

[2078] 467. The process of embodiment 1, or the compound of embodiment 201, wherein R1, R2a, and R2bare defined according to (B).468. The process or compound of embodiment 467, wherein R1taken together with (i) the carbon atom to which it is attached and (ii) and one of R2aand R2bforms:

[2079]

[2080] wherein as indicated in the formula above, the other of R2aand R2bis CH3.

[2081] 469. The process or compound of embodiment 348, wherein R1is heterocycloalkenyl including 3-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc.

[2082] 470. The process or compound of embodiment 469, wherein R1is heterocycloalkenyl including 6 ring atoms.

[2083] 471. The process or compound of embodiments 348, wherein R1is heterocyclyl including 4-6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc.

[2084] 472. The process or compound of embodiment 471, wherein R1is heterocyclyl including 6 ring atoms.

[2085] 473. The process or compound of embodiment 348, wherein R1is C3-7 cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc.

[2086] 474. The process or compound of embodiment 473, wherein R1is C5-6 cycloalkyl.

[2087] or

[2088] 475. The process or compound of embodiment 474, wherein

[2089]

[2090] R1is:X1^ / X3XK> / X3

[2091] X

[2092] 476. The process or compound of embodiment 348, wherein R1is:

[2093]

[2094] 2 A2 O

[2095]

[2096] , wherein Xi, X2 and X3 are each independently CH, CR15or N; wherein R14and R15are each independently Rbor Rc; optionally wherein only one of Xi, X2 and X3 is CR15and R15is methyl or F and / or wherein R14is C1-2 alkyl or C1-2 fluoroalkyl.

[2097] 477. The process or compound of embodiment 348, wherein R1is:

[2098] optional

[2099]

[2100] ly wherein R14is C1-2 alkyl or C1-2 fluoroalkyl.

[2101]

[2102]

[2103]

[2104]

[2105]

[2106] 479. The process of any of embodiments 56-196 or 332-336, wherein the compound of Formula (I) is a compound having the structure:

[2107] or

[2108]

[2109] 480. The process of any one of embodiments 56-196 or 332-336, wherein the compound of Formula (I) is a compound having the structure:or

[2110]

[2111] EXAMPLES

[2112] Procedures for making compounds described herein are provided below. Starting materials used in the following schemes can be purchased or prepared by methods described in the chemical literature, or by adaptations thereof, using methods known by those skilled in the art. In the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be chosen to be the conditions standard for that reaction, unless otherwise indicated.

[2113] Abbreviations: Ac: acetate; ACN: acetonitrile; Boc: terf-butyloxycarbonyl; BPO: benzoyl peroxide; brd: broad doublet; brdd: broad doublet of doublet; brs: broad singlet; brt: broad triplet; d: doublet; dba: dibenzylideneacetone; DCM: dichloromethane; dd: doublet of doublet; ddd: doublet of doublet of doublet; DMF: N, N-dimethylformamide; DMSO: dimethyl sulfoxide; DPPF: 1,1'-bis(diphenylphosphino)ferrocene; eq: equivalents; ESI: electrospray ionization; EtOAc: ethyl acetate; EtOH: ethanol; h: hours; HPLC: high-performance liquid chromatography; KF: Karl-Fischer; LiHMDS: lithium bis(trimethylsilyl)amide; m: multiplet; Me-THF: 2-methyltetrahydrofuran; MeOH: methanol; MS: mass spectrometry; n-BuOH: n-butanol; NBS: N-bromosuccinimide; NMR: nuclear magnetic resonance; NMP: N-methyl-2-pyrrolidone; q: quartet; s: singlet; PSI: pounds per square inch; quin: quintet; t: triplet; T4P: 1, 3, 5, 2,4,6-trioxatriphosphorinane 2,4,6-tributyl-2,4,6-trioxide; TBAF: tetra-n-butylammonium fluoride; TBME: terf-butyl methyl ether; td: triplet of doublet; TEA: triethylamine; THF: tetrahydrofuran; TMS: trimethylsilyl; tt: triplet of triplet.Example 1. Preparation of exemplary intermediate (1)

[2114]

[2115] Step 1. The reaction was performed as 2 batches in parallel. NMP (18.0 L, 5 V) was added into a 50.0 L reactor at 15 ~ 25 °C. 5-bromo-1,3-dichloro-2-fluorobenzene (4.50 kg, 18.4 mol, 1.00 eq.) was added into the reactor followed by K2CO3 (7.65 kg, 55.3 mol, 3.00 eq.) at 15 ~ 25 °C. Lastly, ethyl 2-cyanoacetate (2.71 kg, 24.0 mol, 2.56 L, 1.30 eq.) was added into the reactor at 15 ~ 25 °C. The mixture was heated to 115 °C and stirred at that temperature for 15 h under nitrogen atmosphere. The reaction was sampled and analysed for completion (HPLC). The mixture was cooled to 25 °C and divided into four batches. Each batch was poured into water (5 V, 22.5 L) and extracted with petroleum ether (4.50 L x 3). The aqueous phase was adjusted to pH = 3 ~ 4 with citric acid (solid) and stirred at 20 ~ 25 °C for 0.5 h. The mixture was filtered, and the four filter cakes of each batch were combined and washed with water (3.00 L). The products of the two batches of reaction were combined. Ethyl 2-(4-bromo-2,6-dichlorophenyl)-2-cyanoacetate (4.50 kg, 13.1 mol, 71.1% yield, 98.2% purity) was obtained as a white solid.

[2116] 1H-NMR (400 MHz, DMSO-d6) δ 7.99 (s, 2H), 6.35 (s, 1 H), 4.24 (q, 2H, J = 7.2 Hz), 1.20 (t, 3H, J = 7.2 Hz).

[2117] Step 2. The reaction was performed as 2 batches in parallel. NMP (14.0 L, 3.33 V) was added into a 50.0 L reactor at 15 ~ 25 °C. Ethyl 2-(4-bromo-2,6-dichlorophenyl)-2-cyanoacetate (4.30 kg, 12.8 mol, 1.00 eq.) followed by LiCI (1.35 kg, 31.9 mol, 654 mL, 2.50 eq.) in ice-water (7.00 L, 1.67 V) was added, and the reaction was heated to 100 °C and stirred at that temperature for 15 h under nitrogen atmosphere. The reaction was sampled and analysed for completion (HPLC). The reaction was cooled to 25 °C and divided into two batches. Water (28.0 L) was added to each batch, and the mixtures were stirred at 15 ~ 25 °C for 0.5 h. The mixtures were filtered, and the filter cakes were combined and washed with water (4.3 L). The products of the two reaction batches were combined and dried under vacuum at 45°C. 2-(4-bromo-2,6-dichlorophenyl)acetonitrile (6.46 kg, 24.2 mol, 94.8% yield, 99.2% purity) was obtained as a white solid.

[2118] 1H-NMR (400 MHz, DMSO-d6) δ 7.92 (s, 2H), 4.15 (s, 2H).Step 3. The reaction was performed as 2 batches in parallel. THF (16.2 L, 5.00 V) was added into a 50.0 L reactor at 20 °C. 2-(4-bromo-2,6-dichlorophenyl)acetonitrile (3.24 kg, 12.2 mol, 1.00 eq.) was added at 20 ~ 25 °C. Tert-butyl acrylate (1.57 kg, 12.2 mol, 1.78 L, 1.00 eq.) was added into the reactor at 0 ~ 5 °C under nitrogen atmosphere. NaOMe (66.1 g, 1.22 mol, 0.10 eq.) was added at 0 ~ 5°C under nitrogen atmosphere. The reaction was stirred at 20 ~ 25 °C for 2 h. The reaction was sampled and analysed for completion (HPLC). The mixture was divided into two batches for work-up, each of which was poured into ice water (16.5 L) at 0 ~ 5 °C. The mixtures were extracted with EtOAc (2 x 9.90 L, 3.00 V). The combined organic layers of each batch were washed with 10.0% NaCI solution (2 x 9.90 L, 3.00 V). The organic phases of both batches were combined, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. Te / T-butyl 4-(4-bromo-2,6-dichlorophenyl)-4-cyanobutanoate (9.20 kg, 22.9 mol, 93.7% yield, 97.9% purity) was obtained as an off-white solid.

[2119] 1H-NMR (400 MHz, CDCl3) δ 7.55 (s, 2H), 4.90 - 4.72 (m, 1 H), 2.38 - 2.47 (m, 2H), 2.27 - 2.11 (m, 1H), 1.46 (s, 9H).

[2120] Step 4. The reaction was performed as 2 batches in parallel. AcOH (23.1 L, 5.00 V, 24.2 kg) was charged into a 50.0 L reactor at 20 °C. Tert-butyl 4-(4-bromo-2,6-dichlorophenyl)-4-cyanobutanoate (4.62 kg, 11.8 mol, 1.00 eq.) was added at 20 ~ 25 °C. H2SO4(8.50 kg, 86.7 mol, 4.62 L, 7.37 eq.) was added at 20 °C. The reaction was stirred at 80 ~ 90 °C for 2 h under nitrogen atmosphere. The reaction was sampled and analysed for completion (HPLC). The mixture was divided into two batches for work-up, each of which was cooled to 0 ~ 10°C, poured into ice water (50.0 L) at 0 ~ 10 °C, and filtered. The filter cakes were combined and washed with water (200 L). The solid was combined and freeze-dried. 3-(4-bromo-2,6-dichlorophenyl)piperidine-2, 6-dione (7.52 kg, 22.2 mol, 94.3% yield, 99.3% purity) was obtained as a white solid.

[2121] 1H-NMR (400 MHz, DMSO-d6) δ 11.0 (s, 1 H), 7.87 - 7.76 (m, 2H), 4.85 - 4.63 (m, 2H), 2.90 - 2.81 (m, 1 H), 2.57 - 2.52 (m, 1 H), 2.41 - 2.30 (m, 1 H), 1.95 - 1.90 (m, 1 H).

[2122] Step 5. Six reactions were carried out in parallel. To a solution of 3-(4-bromo-2,6-dichlorophenyl)piperidine-2, 6-dione (600 g, 1.78 mol, 1.00 eq.) in NMP (3.00 L) were added Zn(CN)2 (223 g, 1.90 mol, 121 mL, 1.07 eq.), DPPF (19.2 g, 34.6 mmol, 0.02 eq.), and Pd2(dba)3(32.4 g, 35.4 mmol, 0.02 eq.) under nitrogen atmosphere. The reaction was stirred at 100 °C for 3 h. The reaction was sampled and analysed for completion (HPLC). The reaction mixture was poured into water (3.00 L) at 25 °C and filtered. The filter cakes of all six reactions were washed with H2O (2 x 5.00 L) at 25 °C and combined. The solid was dissolved in THF (45 L) and the solution was filtered through a Celite pad. The filtrate was concentrated under reduced pressure to afford crude 3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)benzonitrile (2.93 kg, 83.2% purity) as a yellow solid.

[2123] 1H-NMR (400 MHz, DMSO-d6) δ 11.0 (s, 1 H), 8.18 (s, 1 H), 8.11 (s, 1 H), 4.75 - 4.70 (m, 1 H), 2.86 -2.84 (m, 1 H), 2.58 - 2.53 (m, 1 H) 2.38 - 2.20 (m, 1 H), 2.17 (t, 1 H), 1.94 - 1.88 (m, 2H).

[2124] Step 6. Twenty reactions were carried out in parallel. Raney Nickel (33.5 g, 391 mmol, 1.65 eq.) was washed with THF: DMF = 1:1 (6 x 200 mL). DMF (350 mL), THF (350 mL), 3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)benzonitrile (67.0 g, 236 mmol, 1.00 eq.) and BOC2O (103 g, 473 mmol, 109 mL, 2.00 eq.) were added at 25 °C under nitrogen atmosphere. The reaction was stirred at 25 °C under H2 (15 psi) for 12 h. The reaction was sampled and analysed for completion (HPLC). 10 batches of the reactions were combined for workup. The reaction mixture was filtered through a Celite pad. The Celite pad was washed with THF (3 x 1.00 L) at 20 °C, and the filtrate was concentrated under reduced pressure. The reaction mixture was poured into H2O (1.00 L) and extracted with EtOAc (3 x 1.00 L). The organic layers of all batches were combined, washed with brine (2.00 L), dried over Na2SO4, filtered, and concentrated underreduced pressure to give a residue. The residue was purified by column chromatography (SiO2, 20 kg, Petroleum ether: Ethyl acetate = 5:1 to 1:1) to afford terf-butyl (3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)benzyl)carbamate (864 g, 47.1% yield, 95.0% purity) as yellow solid.

[2125] 1H-NMR (400 MHz, DMSO-d6) δ 10.9 (s, 1 H), 7.49 (s, 1 H), 7.36 (s, 1 H), 7.29 (s, 1 H), 4.57 (dd, J = 5.60, 12.8 Hz, 1 H), 4.12 (br d, J = 6.00 Hz, 2H), 2.88 - 2.82 (m, 1 H), 2.56 - 2.55 (m, 1H), 2.36 (br dd, J = 4.00, 13.6 Hz, 1H), 1.92 - 1.88 (m, 1 H), 1.40 (s, 9H).

[2126] Step 7. To a solution of HCI 2M in EtOAc (2.50 L, 2 M, 3.85 eq.) at 0 °C was added terf-butyl (3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)benzyl)carbamate (500 g, 1.29 mol, 1.00 eq.). The reaction was stirred at 25 °C for 12 h. The reaction was sampled and analysed for completion (HPLC). The reaction mixture was filtered at 25 °C, and the filter cake was washed with ethyl acetate (500 ml x 3) to afford 3-(4-(aminomethyl)-2,6-dichlorophenyl)piperidine-2, 6-dione hydrochloride (1) (430 g, 1.13 mol, 99.0% yield, 96.2% purity, HCI salt) as a white solid.

[2127] 1H-NMR (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 8.63 (br s, 3H), 7.75 - 7.68 (m, 2H), 4.62 (dd, J = 5.60, 12.8 Hz, 1 H), 4.05 - 4.00 (m, 2H), 2.89 - 2.87 (m, 1H), 2.57 (br dd, J = 2.00, 16.8 Hz, 1H), 2.37 (dq, J = 4.40, 13.2 Hz, 1H), 1.93 - 1.91 (m, 1 H). LCMS m / z 287.1 [M+H]+

[2128] Example 2. Preparation of exemplary intermediate (2)

[2129]

[2130] Step 1. DMF (5V) was charged into a reactor. K2CO3 (218.3 kg, 1579.5 mol, 4.0 eq.) was added, followed by diethyl malonate (82.5 kg, 516.0 mol, 1.3 eq.). The mixture was heated to 40 ~ 50 °C, then a solution of 3,5-dichloro-4-fluorobenzonitrile (75kg, 394.7 mol, 1.00 eq.) in DMF (2V) was added slowly. The reaction was heated to 55 ~ 65 °C and stirred at that temperature until completion was confirmed by an adequate in process control (IPC). The mixture was cooled to 20 ~ 35 °C and MTBE (11 V) was added to facilitate precipitation. The mixture was filtered, and the filter cake was reslurried in MTBE (11 V) before it was filtered again. The filter cake was then washed with MTBE (1 V). The combined MTBE filtrates were washed with 3N HCI (5 V) then with 10% NaCI aq. (2 x 5 V). The organic phase was concentrated to 1.4 ~ 1.6 V, before THF (15 V) was added to yield a solution of diethyl 2-(2,6-dichloro-4-cyanophenyl)malonate in THF (1140 kg THF solution, 111.2 kg intermediate based on assay of 9.75%, 336.8 mol, 99.03% purity, 85.3% yield based on assay), ready for direct use in the next step. It was found that Step 1 led to reduced levels of 3,5-dichloro-4-hydroxybenzonitrile being formed as an impurity.

[2131] 1H-NMR (400 MHz, DMSO-d6) δ 8.20 (s, 2H), 5.60 (s, 1 H), 4.16 - 4.21 (q, 4H), 1.17 - 1.20 (t, 6H).Step 2. The THF solution of diethyl 2-(2,6-dichloro-4-cyanophenyl)malonate (1140 kg, 9.75% assay, 336.8 mol, 1.00 eq.) was charged into a reactor, followed by LiCI (0.28 kg, 6.66 mol, 0.02 eq.) solution in 0.2V H2O. The reaction was performed in a flow reactor (flow rate: 0.4 L / min, residence time 25 min) at 135 ~ 140 °C under 3.3-3.7 MPa. The organic phase was concentrated to 1 ~ 2 V before a solvent exchange to n-heptane was performed. Therefore n-heptane (5 V) was added, and the mixture was concentrated to 2 ~ 3 V, this was repeated three times in total. The mixture was cooled to 35 ~ 45 °C and stirred at that temperature for 1 ~ 2 h. The mixture was cooled to 15-25 °C before the desired intermediate was filtered. The filter cake was washed with n-heptane. The cake was dried at 40 ~ 50 °C for to afford ethyl 2-(2,6-dichloro-4-cyanophenyl)acetate (106.70 kg, 336.8 mol, quantitative yield, 99.45% purity).

[2132] 1H-NMR (400 MHz, DMSO-d6) δ 8.16 (s, 2H), 4.11 - 4.16 (q, 2H), 4.06 (s, 2H) 1.17 - 1.20 (t, 3H).

[2133] Step 3. Step 3 was carried out twice in analogy to step 3 of Example 2a below, but it may be performed on a different scale to Step 3 of Example 2a. Two crude batches of ethyl 2-(4-(((terf-butoxycarbonyl)amino)methyl)-2,6-dichlorophenyl)acetate (Batch 1: 53.1 kg, 118.9 mol, 0 97.1% purity, 81.1% assay by qNMR, 68.6% assay yield; Batch 2: 58.2 kg, 139.0 mol, 95.9% purity, 86.5% assay by qNMR, 80.1% assay yield) have been isolated. The crude batches were charged to a reactor containing EtOH (1 V) and MTBE (1 V). The mixture was cooled to 0-10 °C and stirred at that temperature before the solids were filtered. The filter cake was washed with EtOH (0.25 V), then it was dried at 40 ~ 50 °C for 12 ~ 16 h to afford two ethyl 2-(4-(((ferf-butoxycarbonyl)amino)methyl)-2,6-dichlorophenyl)acetate batches that were combined (Total 82.90 kg, 228.8 mol, 68% yield, 99.6% purity, 99.4 assay by qNMR).

[2134] 1H-NMR (400 MHz, DMSO-d6) δ 7.51 - 7.56 (t, 1H), 7.34 (s, 2H), 6.53 (s, 1H), 4.09 - 4.14 (m, 4H), 3.94 (s, 2H), 1.40 (s, 8H) 1.17 - 1.20 (t, 3H).

[2135] Step 4. A reactor was charged with EtOAc (2 V) and ethyl 2-(4-(((terf-butoxycarbonyl)amino)methyl)-2,6-dichlorophenyl)acetate (82.90 kg, 228.8 mol, 1.00 eq.) was added. The mixture was heated to 40 ~ 50 °C before 4 M HCI in EtOAc (3 V) was added. The reaction was stirred at 40 ~ 50 °C for 2 ~ 3 hours and checked by I PC before the mixture was cooled to 0 ~ 10 °C. After stirring for an additional hour, the solids were filtered and the filter cake was washed with EtOAc (0.5 V). The solids were dried at 40 ~ 50 °C for 12 ~ 16 h to obtain ethyl 2-(4-(aminomethyl)-2,6-dichlorophenyl)acetate hydrochloride (2) (61.97 kg, 207.5 mol, 90.7% yield, 99.9% purity).

[2136] 1H-NMR (400 MHz, DMSO-d6) δ 8.58 (s, 3H), 7.71 (s, 2H), 4.10 - 4.15 (q, 2H), 4.05 (s, 2H) 3.98 (s, 2H), 1.18 - 1.21 (t, 3H).Example 2a. Further preparation of exemplary intermediate (2)

[2137]

[2138] Step 1. DMF (287.0 L, 7V) was charged into a reactor. 3,5-dichloro-4-fluorobenzonitrile (40.0 kg, 215.79 mol, 1.00 eq.) was added, followed by K2CO3 (119.3 kg, 863.16 mol, 4.0 eq.). The mixture was heated to 40 ~ 50 °C for 1 h, then diethyl malonate (45.1 kg, 280.53 mol, 1.3 eq.) was added over 1.5 h. The reaction was stirred at 55 ~ 65 °C until completion was confirmed via sampling of the mixture and HPLC analysis (2 ~ 5 h). The mixture was cooled to 20 ~ 35 °C and MTBE (5 V) was added. The mixture was stirred for 2.5 h. The mixture was filtered, and the remaining solids were resuspended in MTBE (5 V) and stirred for 7 h. The mixture was filtered and washed with MTBE (41 L, 1 V). The combined MTBE filtrates were washed with 3N HCI (5 V) then with 10% NaCI aq. (2 x 5 V). The organic phase was concentrated to 1.4 ~ 1.6 V, then dissolved with DMSO (310.6 L, 7.58 V) to give a solution of diethyl 2-(2,6-dichloro-4-cyanophenyl)malonate in DMSO (62.12 kg, 188.15 mol, 87.2% assay yield, 95.45% purity), ready for direct use in the next step.

[2139] 1H-NMR (400 MHz, DMSO-d6) δ 8.20 (s, 2H), 5.60 (s, 1 H), 4.16 - 4.21 (q, 4H), 1.17 - 1.20 (t, 6H).

[2140] Step 2. The DMSO solution of diethyl 2-(2,6-dichloro-4-cyanophenyl)malonate (62.12 kg, 188.15 mol, 1.00 eq.) was charged into a reactor, followed by LiCI (50.94 kg, 1204 mol, 6.40 eq.). Water (74.54 L, 1.2 V) was added slowly over 1 h to the mixture. The reaction was stirred at 90 ~ 100 °C until completion was confirmed via sampling of the mixture and HPLC analysis (12 ~ 16 h). The reaction was cooled to 25 °C. Water (5 V) and MTBE (10 V) were added, and the mixture was stirred for 4 h. The organic phase was concentrated to 2 ~ 3 V. n-heptane (5 V) was added, and the mixture was concentrated to 2 ~ 3 V. n-heptane (5 V) was added again, and the mixture was concentrated to 2 ~ 3 V, then the residue was slurried with n-heptane (2 V) at 25 °C for 1 ~ 2 h. The slurry was dried at 40 ~ 50 °C for 12 ~ 16 h to afford ethyl 2-(2,6-dichloro-4-cyanophenyl)acetate (43.41 kg, 168.2 mol, 89.39% yield, 100% pure).

[2141] 1H-NMR (400 MHz, DMSO-d6) δ 8.16 (s, 2H), 4.11 - 4.16 (q, 2H), 4.06 (s, 2H) 1.17 - 1.20 (t, 3H).

[2142] Step 3. The reactors were filled with nitrogen to normal pressure three times. THF (5 V), EtOH (5 V), C0CI2 (0.217 kg, 1.68 mol, 0.01 eq.), Boc2O (73.36 kg, 336.4 mol, 2.00 eq.) and ethyl 2-(2,6-dichloro-4-cyanophenyl)acetate (43.41 kg, 168.2 mol, 1.00 eq.) were charged into reactor 1 at 0 ~ 10 °C. Reactor 2 was charged with THF (5 V) and EtOH (5 V), and NaBH4 was added into reactor 2 at 5 ~ 15 °C. The mixture of reactor 1 was slowly added to reactor 2 at 5 ~ 15 °C over 8 h. The reaction was stirred at 5 ~ 15 °C until completion was confirmed via sampling of the mixture and HPLC analysis (2 ~ 3 h). The mixture was cooledto 0 ~ 15 °C, and 10% NH4CI aq. (3 V) was added. The mixture was filtered, and the organic phase was concentrated to 1 V. EtOAc (10 V) and 10% NaCI aq. (5 V) were added, and the organic phase was collected. 20% SH-silica gel was added to the organic phase at 45 ~ 55 °C, and the mixture was stirred for 12 ~ 15 h. The mixture was cooled to 15 ~ 25 °C and 20% MgSO4 was added. The mixture was stirred for 1 ~ 2 h, then it was filtered and the organic phase was concentrated to 2 ~ 3 V. n-heptane (5 V) was added, and the mixture was concentrated to 2 ~ 3 V. n-heptane (5 V) was added again, and the mixture was concentrated to 3 V, then the residue was slurried with n-heptane (1 V) at 0 ~ 10 °C for 2 ~ 3 h. The solid was filtered and washed with n-heptane (1 V), then it was dried at 40 ~ 50 °C for 12 ~ 16 h to afford ethyl 2-(4-(((terf-butoxycarbonyl)amino)methyl)-2,6-dichlorophenyl)acetate (41.61 kg, 115.2 mol, 68% yield, 90.62% purity).

[2143] 1H-NMR (400 MHz, DMSO-d6) δ 7.51 - 7.56 (t, 1H), 7.34 (s, 2H), 6.53 (s, 1H), 4.09 - 4.14 (m, 4H), 3.94 (s, 2H), 1.40 (s, 8H) 1.17 - 1.20 (t, 3H).

[2144] Step 4. A reactor was charged with EtOH (2 V) and ethyl 2-(4-(((terf-butoxycarbonyl)amino)methyl)-2,6-dichlorophenyl)acetate (41.61 kg, 114.87 mol, 1.00 eq.) was added. The mixture was cooled to 0 ~ 10 °C at the rate of 5 ~ 10 °C / h and stirred for 3 ~ 5 h. The resulting solid was filtered and washed with EtOH (0.25 V). It was dried at 40 ~ 50 °C for 10 ~ 16 h to give ethyl 2-(4-(((terf-butoxycarbonyl)amino)methyl)-2,6-dichlorophenyl)acetate (re-purified; 34.42 kg, 95.02 mol). A reactor was filled with nitrogen to normal pressure three times. EtOAc (1.5 V) was charged into the reactor, followed by the repurified ethyl 2-(4-(((terf-butoxycarbonyl)amino)methyl)-2,6-dichlorophenyl)acetate (2934.42 kg, 95.02 mol, 1.00 eq.). The mixture was warmed to 40 ~ 50 °C, then 4M HCI in EtOAc (3.0 V) was added slowly over 3 h. The reaction was stirred at 40 ~ 50 °C until completion was confirmed via sampling of the mixture and HPLC analysis (2 ~ 3 h). The mixture was cooled to 0 ~ 10 °C at the rate of 5 ~ 10 °C / h and stirred for an additional 1 ~ 2 h. The resulting solid was filtered, and the filter cake was washed with EtOAc (0.5 V). The mixture was dried at 40 ~ 50 °C for 12 ~ 16 h to obtain ethyl 2-(4-(aminomethyl)-2,6-dichlorophenyl)acetate hydrochloride (2) (25.58 kg, 86.0 mol, 90.7% yield, 99.7% purity).

[2145] 1H-NMR (400 MHz, DMSO-d6) δ 8.58 (s, 3H), 7.71 (s, 2H), 4.10 - 4.15 (q, 2H), 4.05 (s, 2H) 3.98 (s, 2H), 1.18 - 1.21 (t, 3H).

[2146] Example 3. Preparation of exemplary intermediate (3)

[2147] K3PO4Amberlyst 15 DMF, 120 °C, 3.5 h Toluene, 110 °C, 4 h

[2148] Mel, KO'Bu KOH Toluene, 25 °C, 1 h n-BuOH, 120 °C, 14 h

[2149] (3)

[2150]

[2151] Step 1. A 60 L reactor was charged with 2-chloro-5-methylpyrimidine (4.00 kg, 1 eq.) and potassium phosphate tribasic (16.50 kg, 2.5 eq.). DMF (12 V) was added, and the suspension was inertized. The mixture was heated to 120 °C over 1 h, then tert-butyl 2-cyanoacetate (5.27 kg, 1.2 eq.) was added over 30 min at 105 °C. The reaction was stirred at 120 °C until completion was confirmed by sampling and HPLC analysis (2.5 h). The mixture was cooled to 20 °C and filtered. The filter cake was washed with EtOAc (2 x 2 V) and dried for 1.5 h. The solid was split into two batches for further workup. Each portion was suspended in water (20 V), and HCI 32% (9 kg, 4 V) was added over 1 h until pH = 1 ~ 2 was reached. The two suspensions were stirred for 30 min, then filtered together on the same filter to combine the solids. The cake was washed with water (2 x 2 V) and dried (16 h). tert-butyl 2-cyano-2-(5-methylpyrimidin-2-yl)acetate was obtained as a yellow solid (7.783 kg, q-NMR: 77% w / w; corrected yield: 5.993 kg, 83%).

[2152] 1H-NMR (400 MHz, CDCl3) δ 8.58 - 8.59 (d, 2H, J = 2.7Hz), 7.64 (s, 3H), 2.22 (s, 3H), 1.54 (s, 9H).

[2153] Step 2. tert-butyl 2-cyano-2-(5-methylpyrimidin-2-yl)acetate (20.9 kg, containing water 55% w / w) was charged into a 60 L reactor. Toluene (50 kg, 5 V) was added, and the suspension was inertized. It was heated to 55 °C and azeotropic water / toluene distillation was performed (continuous mode) until KF = 0.8% was reached (corresponds to ca. 5% wt water; 7 L of water distilled off). In a 60 L reactor, Amberlyst 15 (2.3 kg, 20 wt%) was charged, followed by toluene (5 L). The suspension was inertized and transferred to the tert-butyl 2-cyano-2-(5-methylpyrimidin-2-yl)acetate suspension. The reaction was slowly heated to 110 °C over 1.5 h (gas evolution was observed starting at T = 65 ~ 70 °C and was well controlled). The reaction was stirred at 110 °C until completion was confirmed by sampling and HPLC analysis (4 h). The mixture was cooled to 20 °C and filtered. The filter pad was washed with a minimum amount of toluene. 61.5 kg of 2-(5-methylpyrimidin-2-yl)acetonitrile was isolated as a yellow solution in toluene, q-NMR: 9.75% w / w. Corrected yield: 5.996 kg, 91%. It was used as-is in the next step.

[2154] Step 3. 2-(5-methylpyrimidin-2-yl)acetonitrile (61 kg, 9.75% w / w) was charged in a 60 L reactor. The yellow solution was inertized and heated to 55 °C. Toluene was distilled off (16 L) to reach 8 V total toluene and KF = 0.016%. The solution was cooled to 25 °C and potassium tert-butoxide (10.28 kg, 2.05 eq.) was added in 3 equal portions, lodomethane (12.69 kg, 2.00 eq.) was added over 2 h, keeping the temperature below 32 °C. The reaction was stirred at 20 °C until completion was confirmed by sampling and HPLC analysis (1 h). The reaction was quenched with 30% NHs aqueous solution (0.7 L, 0.12 V) and stirred for 16 h. The mixture was transferred into a 100 L stirring vessel and washed with Na2COs aqueous solution (7% w / w, 30 L, 5 V). The organic layer was separated and washed with brine (30 L, 5 V), dried over Na2SO4 (7 kg), and filtered to afford 2-methyl-2-(5-methylpyrimidin-2-yl)propanenitrile as a solution in toluene (70.2 kg, 10% w / w, 95% ala). Purification was performed by crystallization in heptane together with a second batch: the mixture was transferred to a 100 L vessel, heated to 50 °C, and toluene was distilled out to reach 1.5 V residual solvent (2.5 V total). Heptane (65 kg, 8 V) was added, keeping the temperature below 40 °C, and crystallization began spontaneously. The suspension was cooled to 20 °C, stirred for 12 h, then cooled to 0 °C over 2 h and stirred for 1 h at this temperature. It was filtered, and the filter cake was washed twice with cold heptane (2 x 2 V) then dried on the nutsche with nitrogen overpressure and vacuum for 1 h. The wet material was transferred into 20 L flasks and dried under reduced pressure at 40 °C until constant weight was obtained. Pure 2-methyl-2-(5-methylpyrimidin-2-yl)propanenitrile was obtained as a brown solid (12.935 kg, >99% w / w, 99% ala, 88% yield corrected by q-NMR).

[2155] 1H-NMR (400 MHz, CDCl3) δ 8.58 (S, 2H), 2.33 (s, 3H), 1.79 (s, 6H).Step 4. A 100 L vessel was charged with 2-methyl-2-(5-methylpyrimidin-2-yl)propanenitrile (11.5 kg, 1.00 eq.) and n-butanol (80.5 L, 7 V). The mixture was inertized, and potassium hydroxide (8.41 kg, 2.10 eq.) was added. The reaction was heated to 120 °C and stirred until completion was confirmed by sampling and HPLC analysis (14 h). The product crystallized spontaneously in this time. The suspension was cooled to 50 °C and TBME (23 L, 2 V) was added. The mixture was further cooled to 25 °C and stirred for 1 h, then it was filtered. The filter cake was rinsed with n-butanol: TBME 1:1 (2 V) and then with TBME (2 x 2 V), then it was dried under reduced pressure at 40 °C. Potassium 2-methyl-2-(5-methylpyrimidin-2-yl)propanoate (13.35 kg, 61.22 mol, 87% yield) was obtained as an off-white solid.

[2156] 1H-NMR (400 MHz, D2O) δ 8.477 - 8.479 (d, 2H, J = 0.7 Hz), 2.25 (s, 3H), 1.46 (s, 6H).

[2157] Example 4. Preparation of Compound 14

[2158]

[2159] Step 1. Ethyl 2-(4-(aminomethyl)-2,6-dichlorophenyl)acetate hydrochloride (3.18 kg, 1.00 eq.) and EtOAc (7.5 V) were charged into a reactor. Triethylamine (3.71 kg, 3.5 eq.) was added, followed by potassium 2-methyl-2-(5-methylpyrimidin-2-yl)propanoate (2.45 kg, 1.05 eq.). The mixture was stirred for 5 minutes, cooled to 0 ~ 5 °C, then T4P 50% wt in EtOAc (11.29 kg, 1.5 eq.) was added dropwise over 1 h, keeping the temperature below 5 °C. The reaction was warmed to 25 °C and stirred until completion was confirmed by sampling and HPLC analysis (18 h). Me-THF (2 V) and water (2 V) were added, and the mixture was stirred for 5 ~ 10 min. A solution of 2 M K3PO4 in water (40% wt, 2 V) was added to reach pH = 7-8, and the mixture was heated to 40 °C to obtain a clear solution. The phases were separated at 40 °C, and the aqueous phase was extracted with EtOAc (2 V). The combined organic layers were washed with water (2 V) at 40 °C, then concentrated to 8 V. EtOAc (3 V) was added, and the mixture was concentrated to 8 V (this was done twice). MTBE (1 V) and n-heptane (4 V) were added slowly, and the mixture was cooled to -10 ~ -5 °C and stirred for 16 h. The mixture was filtered, and the filter cake was washed with heptane (2 x 1 V). The solid was dried at 40 °C to obtain ethyl 2-(2,6-dichloro-4-((2-methyl-2-(5-methylpyrimidin-2-yl)propanamido)methyl)phenyl)acetate (3987 g, 98.8% purity, 94.4% yield).

[2160] 1H-NMR (400 MHz, CDCl3) δ 8.60 (d, 2H, J = 0.6 Hz), 7.20 (s, 2H), 7.05 (s, 1 H), 4.43 - 4.44 (d, 2H, J = 6.0 Hz), 4.19 - 4.21 (q, 2H, J = 7.1 Hz), 3.97 (s, 2H) 2.33 (s, 3H), 1.73 (s, 7H), 1.28 (t, 3H, J = 7.1 Hz).

[2161] Step 2. Reactor 1 was charged with THF (6 V) and MeCN (4 V). Ethyl 2-(2,6-dichloro-4-((2-methyl-2-(5-methylpyrimidin-2-yl)propanamido)methyl)phenyl)acetate (3.963 kg, 1.00 eq.) was added, followed by molecular sieves (18% wt, 0.702 kg). The reactor was inertized and the mixture was cooled to 0 ~ 5 °C.Reactor 2 was charged with KOtBu (0.916 kg, 1.45 eq.) and THF (2 V). This solution was transferred from reactor 2 into reactor 1 slowly at 0 ~ 5 °C. Acrylonitrile (1.49 kg, 1.88 eq.) and THF (1 V) were charged into reactor 2. This solution was transferred from reactor 2 into reactor 1 slowly at 0 ~ 5 °C. The reaction was stirred until completion was confirmed by sampling and HPLC analysis (5 ~ 10 min after charging all of the acrylonitrile). Acetic acid (0.3 V) was added into the mixture at 0 ~ 5 °C to quench the reaction. The mixture was filtered over Celite, and the filter cake was washed with Me-THF (2 V). The filtrate was concentrated to 2 V, then Me-THF (3 V) was added, followed by a saturated solution of NaHCO3(5 V). The mixture was stirred for 30 - 60 min. IPA (1.5 V) was added, and the organic phase was separated. It was washed with a saturated solution of NaHCO3(5 V), then IPA (0.5 V) was added, and the phases were separated. Brine (5 V) was added, and the mixture was stirred for 30 - 40 min. IPA (0.5 V) was added, and the phases were separated. The organic phase was filtered over Celite, and the filter cake was washed with Me-THF (3 V). The organic phase was concentrated to 3 V and Me-THF (3 V) was added (this was done twice). The organic phase was concentrated to 3 V and AcOH (3 V) was added (this was done twice). The mixture was concentrated to 3 V to obtain ethyl 4-cyano-2-(2,6-dichloro-4-((2-methyl-2-(5-methylpyrimidin-2-yl)propanamido)methyl)phenyl)butanoate as a solution in AcOH (11.246 kg, assay: 31.8%, purity: 82.0%, weight corrected by assay: 3.576 kg, yield: 81.6%).

[2162] 1H-NMR (400 MHz, CDCl3) 58.59 - 8.60 (d, 2H, J = 0.5 Hz), 7.10 (s, 2H), 7.08 - 7.09 (m, 1H), 4.43 - 4.47 (m, 3H), 4.13 - 4.21 (m, 3H), 2.69 - 2.74 (m, 1H) 2.44 - 2.48 (t, 2H, J =7.2 Hz), 2.46 (s, 3H), 2.06 -2.18 (m, 3H), 1.73 (m, 9H), 1.26 - 1.30 (t, 2H, J =7.1 Hz), 1.23 - 1.34 (t, 3H, J = 7.2 Hz).

[2163] Step 3. Ethyl 4-cyano-2-(2,6-dichloro-4-((2-methyl-2-(5-methylpyrimidin-2-yl)propanamido)methyl)phenyl)butanoate solution in acetic acid (3.49 kg, 1.00 eq in 3 V) and acetic acid (11 kg, 3 V) were charged into a reactor. Sulfuric acid (12.1 kg, 15 eq.) was added slowly (caution: exotherm!). The mixture was heated to 80 °C and stirred until completion was confirmed by sampling and HPLC analysis (2 h). The mixture was cooled to 20 °C and water (2 V) was added (caution: exotherm!). The mixture was cooled below 10 °C, and NH328% aqueous solution (5 V) was added until pH ~ 4, keeping the temperature below 45 °C (caution: exotherm!). Me-THF (3 V) was added, the mixture was filtered, and the aqueous phase was separated. NH328% aqueous solution (5 V) was added to the organic phase until pH = 10. The mixture was filtered, and the aqueous phase was separated. The aqueous phases were combined, and NH3 28% aqueous solution (3 V) was added until pH = 10. Me-THF (3 V) was added to extract the aqueous phase. The combined organic phases were filtered over Celite, and the filtrate was concentrated to 1 V. Me-THF (2 V) was added, and the mixture was heated to 50 °C to obtain a clear solution, then cooled to 25 ~ 30 °C. Seed crystals (5% wt) were added, and the mixture was stirred for 16 h at 25 ~ 30 °C, then for 1 - 2 h at 0 ~ 5 °C. The mixture was filtered, and the filter cake was washed with cold Me-THF (1 V, 0 °C). The solid was dried under vacuum at 30 °C. Analysis showed that the filter cake contained salts and water, and the mother liquor still contained product. Therefore, the cake and mother liquor were reworked. The filter cake was dissolved in THF (5 L), dried over MgSO4, filtered, and the filter cake was washed with THF (1 L) to obtain Filtrate 1. The mother liquor was diluted with THF (10.5 L), dried over MgSO4, filtered, and the filter cake was washed with THF (2 L) to obtain Filtrate 2. Filtrate 1 and Filtrate 2 were combined and concentrated to 2 V. Me-THF (10.5 L) was added, and the mixture was concentrated to 2 V. Me-THF (7 L) was added, and the mixture was heated to 40 °C to dissolve all the solids. The mixture was then cooled to 20 °C and charged with seed crystals (5% wt). The mixture was stirred for 16 h at 20 °C, then cooled to 0 °C and stirred at 100 r / min, then it was filtered, and the filter cake was washed with Me-THF (3.5 L). The solid was dried under vacuum at 40 °C (24 h), then at 30 °C (24 h) to afford ethyl 5-amino-2-(2,6-dichloro-4-((2-methyl-2-(5-methylpyrimidin-2-yl)propanamido)methyl)phenyl)-5-oxopentanoate (2.38 kg, 92.1% purity, 82.1% q-NMR, 47.9% yield) as a light yellow solid.

[2164] 1H-NMR (400 MHz, CDCl3) 58.58 (d, 2H, J = 0.5 Hz), 7.14 - 7.17 (m, 3H), 5.77 (m, 1H), 5.57 (m, 1H), 4.33 - 4.48 (m, 3H), 4.14 - 4.18 (m, 2H) 3.88 - 3.95 (m, 1 H), 2.61 - 2.64 (m, 1 H), 2.06 - 2.32 (m, 5H), 1.89 - 2.05 (m, 4H),1.70 (s, 6H), 1.19 - 1.23 (m, 5H).

[2165] Step 4. THF (30.7 kg, 15 V) and ethyl 5-amino-2-(2,6-dichloro-4-((2-methyl-2-(5-methylpyrimidin-2-yl)propanamido)methyl)phenyl)-5-oxopentanoate (2.30 kg, 1.00 eq.) were charged into a reactor and heated to 40 °C. LiHMDS 1 M in THF solution (2.20 eq.) was added over 1 h. The reaction was stirred at 40 °C until completion was confirmed by sampling and HPLC analysis (1 h). The mixture was cooled to 20 °C, and acetic acid (4.5 eq.) was added to quench the reaction (pH 4 ~ 5). The mixture was concentrated to 1-2 V at 50 °C, then more acetic acid (1.5 eq.) was added, followed by MeOH (10 V), and the mixture was concentrated to 4-5 V at 50 °C. Water (10 V) was added, and the mixture was cooled to 0 °C and stirred for 16 h. It was filtered, and the filter cake was washed with MeOH / H2O 1 / 1 (2 V). After drying at 45 °C for 24 h, the cake still contained water and salts, so it was reworked. The filter cake was redissolved in THF (7 V), filtered over Celite, and the Celite was washed with THF (1 V). Water was separated, and the mixture was concentrated to 2 V. More THF (5 V) was added to dissolve the solids and separate more water. The organic phase was dried with Na2SO4, filtered, the cake was washed with THF (1 V), and the filtrate was concentrated to 2 V at 50 °C. Solids precipitated, so MeOH (10 L) was added, and the mixture was concentrated to 5 L at 50 °C. Solids once again precipitated, so water (10 V) was slowly added to the mixture, and it was cooled to 6 °C. It was filtered, and the filter cake was washed with EtOH / H2O 1 / 1 (2 V) at 0 °C. The wet cake (4.8 kg) was dried in an oven at 45 °C. To improve the assay purity, the solid was reworked a second time. The solid (1.29 kg, 2.871 mol. 1.00 eq.) was dissolved in DCM (9 V) and MeOH (1 V). The organic phase was washed with water twice (1 x 5 V, then 1 x 2 V), then it was concentrated to 4-5 V at 40 °C. Ethyl acetate (5 V) was added, and the mixture was stirred at 25 °C for 1 h. Solids gradually precipitated. The mixture was concentrated once again to 4-5 V at 40 °C. Ethyl acetate (5 V) was added, and the mixture was concentrated to 4-5 V at 40 °C. n-heptane (5 V) was added, and the mixture was concentrated to 4-5 V at 40 °C (this was done twice). The mixture was filtered, and the filter cake was washed with n-heptane (2 x 2 V). The solid was dried under vacuum at 45 °C to afford Compound 14 (1178.8 g, assay: 97.0%, purity: 98.5%, yield: 66.8%).

[2166] 1H-NMR (400 MHz, DMSO-d6) δ8.63 (d, 2H, J = 0.6 Hz), 7.37 - 7.45 (dd, 2H, J = 1.6, 26.6 Hz), 4.64 – 4.86 (q, 1H, J = 5.6 Hz), 4.38 (s, 2H), 2.80 - 2.86 (m, 1H), 2.53 - 2.58 (m, 1H), 2.33 (s, 3H), 2.02 - 2.06 (m, 1H), 1.64 (s, 6H).

[2167] Example 5 - Further synthetic routes

[2168] Further approaches for synthesising compounds according to Formula (I) are provided in the examples below. The synthetic information contained in these examples may be useful, inter alia, for preparing compounds and intermediates according to the presently claimed invention. For instance, one or more of the reaction steps detailed below may be incorporated into syntheses according to the present invention, e.g. as prior or subsequent processing steps. Moreover, any of the reaction schemes below may be modified by one skilled in the art to employ compounds of Formula (n), (o) and (p), thus avoiding the need for trimethylsilyl cyanide (a potent poison that behaves equivalently to hydrogen cyanide).General schemes and procedures

[2169] General Scheme 1.

[2170]

[2171] A general synthetic strategy that may be used to prepare compounds of Formula (I) is depicted in General Scheme 1. A benzylamine AA, where X is H or halo (for example F) and Yi and Y2 are C-H or N, wherein at least one of Y1 and Y2 is C-H, may be coupled with compound BB using any suitable amide coupling conditions to afford compounds of Formula (I). For example, Mukaiyama’s reagent may be used in a polar aprotic solvent such as DMF, in the presence of a base such as DIPEA. Other coupling reagent sets may be used, for example: EDCI and HOBt, or HATU and DIPEA. Q1is Cl or OH. The specific groups R1, R2a, R2b, R3, and R4are selected on the basis of the desired groups in the compound of Formula (I).

[2172] General Scheme 2.

[2173]

[2174] General Scheme 2 provides an exemplary synthetic procedure for the preparation of starting materials AA used in General Scheme 1. Compound AB, where W1is an electron-withdrawing group such as a nitrile or an ester, may be converted to a compound of formula AD via a Michael addition reaction with an acrylate of formula AC in the presence of a base (for example, sodium methoxide). Compound AE may be obtained from compound AD via cyclization in acidic medium. A mixture of sulfuric acid in acetic acid may be used at elevated temperature (for example, 90 degrees Celsius). A protected benzylamine of formula AF may be generated from AE via metal-catalysed coupling using a palladium catalyst (for example, Pd(OAc)2) together with the appropriate potassium trifluoroborate salt. Alternatively, the protected benzylamine maybe formed in a two-step process, first by cyanation of AE, then reduction of the cyanide. PG1is any suitable protecting group that is labile to treatment with acid. Removal of PG1in the presence of a strong acid such as HCI 2M in EtOAc affords compounds of formula AA. The specific groups R3and R4are selected on the basis of the desired groups in the compound of Formula (I).

[2175] General Scheme 3.

[2176] W2Methylation Hydrolysis

[2177]

[2178] CB General Scheme 3 provides an exemplary synthetic strategy for the preparation of (hetero)cyclic compounds of formula CO, which may be used as starting materials BB in General Scheme 1. Starting from a compound of formula CA, where W2is a nitrile, ester or carboxylic acid, compounds of formula CB can be obtained via an alkylation reaction with a methylating reagent in the presence of a base. For example, methyl iodide may be used in the presence of a base such as sodium hydride, tBuOK, CS2CO3 or LiHMDS, in a polar aprotic solvent such as THF or DMF. Carboxylic acids of formula CC may be obtained via hydrolysis of compound CB in basic or acidic medium. For example, 6 molar HCI or 60% H2SO4may be used for hydrolysis in acidic medium. NaOH or LiOH*H2O may be used for hydrolysis in basic medium. The hydrolysis can be carried out at elevated temperature (for example, 100 degrees Celsius). Z may be N, C-H, or C-R5. R5is selected on the basis of the desired groups in the compound of Formula (I).

[2179] General Scheme 4.

[2180] DB

[2181] Z. '<-Z (R16)n

[2182]

[2183] DC General Scheme 4 provides an exemplary synthetic strategy for the preparation of (hetero)cyclic compounds of formula DC, which may be used as starting materials BB in General Scheme 1. Starting from a compound of formula DA, where Hal1is any suitable halogen (e.g. Cl, Br or I), compounds of formula DC can be obtained via a metal-catalysed coupling reaction with a compound of formula DB, where Q2is a group such that DB is an a-dimethyl ester, isobutyronitrile, or a silyl ketyl acetal. A palladium catalyst can be used, for example Pd(PtBu3)2 in a polar aprotic solvent such as DMF, at elevated temperatures (100 degrees Celsius). Carboxylic acids of formula DD may be obtained via hydrolysis of compound DC in basic medium. A base such as LiOH*H2O may be used in a solvent mixture such as THF:H2O 1:1, and the hydrolysis can be carried out at elevated temperature (for example, 100 degrees Celsius). Z may be N, C-H, or C-R16. R16is selected on the basis of the desired groups in the compound of Formula (I).General Scheme 5.

[2184] Cyanation Methylation

[2185] COOH

[2186]

[2187] EA EB ED General Scheme 5 provides an exemplary synthetic strategy for the preparation of heterocyclic compounds of formula ED, which may be used as starting materials BB in General Scheme 1. Compounds of formula EB may be obtained from EA via a cyanation reaction. LG2is any suitable leaving group for nucleophilic substitution reactions (e.g. Cl, Br, I, OMs, OTf) and Y3may be C-H, C-R17, N, O, or S. Cyanating reagent systems such as TMSCN and TBAF in a polar aprotic solvent (for example, MeCN or THF) may be used. Next, compounds of formula EC may be obtained from EB via an alkylation reaction with a methylating reagent in the presence of a base. For example, methyl iodide may be used in the presence of sodium hydride, in a solvent such as DMF. Carboxylic acids of formula ED may be obtained via hydrolysis of compound EC in acidic medium. 6 molar HCI may be used as the solvent, and the hydrolysis can be carried out at elevated temperature (for example, 60 degrees Celsius). R17is selected on the basis of the desired groups in the compound of Formula (I).

[2188] General Scheme 6.

[2189] R8— LG1FB

[2190] Alkylation

[2191]

[2192] General Scheme 6 provides an exemplary synthetic strategy for the preparation of pyridones or pyridazinones of formula FF, which may be used as starting materials BB in General Scheme 1. A compound of formula FA may be alkylated with compound FB to afford compounds of formula FC. LG1is a leaving group suitable for nucleophilic substitution reactions (e.g. Cl, Br, I, OMs, OTf) and Y4may be C-H, C-R7or N. The reaction may be carried out in the presence of a base, for example sodium hydride, and in a solvent such as THF. Next, compounds of formula FC may be reacted with intermediate FD under metal-catalysed coupling conditions to afford compounds of formula FE. A palladium catalyst can be used, for example Pd(PtBu3)2 in a polar aprotic solvent such as DMF, at elevated temperature...

Claims

CLAIMS1. A process comprising reacting a compound of Formula (2) with a compound of Formula (3) to yield a compound of Formula (4):HX'x' y0^50wherein:R1, R2a, and R2bare defined according to (A) and (B) below:(A)R1is:• heteroaryl including 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc;• heterocyclyl including 4-6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc;• C3-7 cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc;• heterocycloalkenyl including 3-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc; or • C6-10 aryl optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc; andeach of R2aand R2bis independently selected from the group consisting of:• C1-2 alkyl optionally substituted with from 1-5 Ra;• C3-5 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rb;• C1-4 alkoxy;Ci-4haloalkoxy; orcyano; orR2aand R2btaken together with the carbon atom to which each is attached forms:• C3-7 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rb;• heterocyclyl including 4-7 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rb;R1taken together with (i) the carbon atom to which it is attached and (ii) and one of R2aand R2bforms:• Ca-io aryl optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc; or• heteroaryl including 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc; andthe other of R2aand R2bis C1-2 alkyl optionally substituted with from 1-5 Ra;X is H; or halo;Y1 and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH;R3is H; C1-2 alkyl, which is optionally substituted with 1-5 fluoro; fluoro; chloro; or cyano; R4is chloro; bromo; or fluoro; optionally wherein it is provided that R4is fluoro when R3is chloro; R5is C1-6 alkyl;R6is a leaving group, for example, Cl, Br, I, OH, OM, O(C=O)(Ci-6 alkyl), O(C=O)(N3), O(Ci-6 alkyl), or S(Ci-6 alkyl);each occurrence of Rais independently selected from the group consisting of: -OH; -halo; -NReRf; C1-4 alkoxy; C1-4 haloalkoxy; -C(=O)O(Ci-4alkyl); -C(=O)(Ci-4alkyl); -C(=O)OH; -CONR’R”; -S(O)I-2NR’R”; -S(O)I-2(CI-4alkyl); and cyano;each occurrence of Rbis independently selected from the group consisting of: halo; cyano; Ci-10 alkyl which is optionally substituted with from 1-6 independently selected Ra; C2-6 alkenyl; C2-6 alkynyl; Ci-4alkoxy; -O(Ci-3 alkylene)-(C3-6 cycloalkyl); Ci-4haloalkoxy; -S(0)o-2(Ci-4alkyl); -NReRf; -OH; -S(O)i-2NR’R”; -NO2; -C(=0)(Ci-io alkyl); -C(=O)O(Ci-4alkyl); -C(=O)OH; and -C(=O)NR’R”;each occurrence of Rcis independently selected from the group consisting of:• C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rb;• heterocyclyl or heterocycloalkenyl including 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(O)0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rb;• heteroaryl including 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with from 1-4 Rb; and• C6-10 aryl optionally substituted with from 1-4 Rb;each occurrence of Rdis independently selected from the group consisting of: C1-6 alkyl optionally substituted with from 1-3 independently selected Ra; -C(O)(Ci-4 alkyl); -C(O)O(Ci-4 alkyl); -CONR’R”; -S(O)I-2NR’R”; -S(O)I-2(CI-4 alkyl); -OH; and C1-4 alkoxy; andeach occurrence of Reand Rfis independently selected from the group consisting of: H; C1-6 alkyl; -C(O)(Ci-4alkyl); -C(O)O(Ci-4alkyl); -CONR’R”; -S(O)I-2NR’R”; -S(O)i-2(Ci-4 alkyl); -OH; and Ci- 4 alkoxy; andeach occurrence of R’ and R” is independently selected from the group consisting of: H; and C1-4 alkyl; andX’ is an anion and M is a cation.

2. The process of claim 1, wherein the compounds of Formulas (2) and (3) are reacted under amide coupling conditions.

3. The process of claims 1 or 2, wherein the compounds of Formulas (2) and (3) are reacted in the presence of a base and a solvent.

4. The process of claim 3, wherein the solvent is water.

5. The process of claim 3, wherein the solvent is an organic solvent, for example a polar aprotic solvent.

6. The process of claim 5, wherein the solvent is selected from ethyl acetate, DCM, DMF, THF, DMA, NMP, 2-MeTHF and combinations thereof.

7. The process of any of claims 3-6, wherein the base is an amine.

8. The process of claim 7, wherein the base is selected from diisopropylethylamine (DIPEA), triethylamine (TEA), pyridine and combinations thereof.

9. The process any of claims 2-8, wherein the compounds of Formulas (2) and (3) are reacted in the presence of a coupling agent.

10. The process of claim 9, wherein the coupling reagent is a carbodiimide coupling reagent, a uranium-imonium reagent, T3P (1-propylphosphonic acid cyclic anhydride), T4P (1-butylphosphonic acid cyclic anhydride), thionyl chloride, oxalyl chloride, mukaiyama reagent or combinations thereof.

11. The process of claim 10, wherein the carbodiimide coupling reagent is selected from diisopropylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, a hydrochloride salt of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and combinations thereof.

12. The process of claim 10, wherein the uranium-imonium reagent is selected from HATU (O-(7-Azabenzotriazol-1-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate), HBTU (O-Benzotriazol-1-yl-N, N, N', N'-tetramethyluronium hexafluorophosphate), TBTU (0-(Benzotriazol-1-yl)-N, N, N', N'-tetramethyluronium tetrafluoroborate), TSTU (N, N, N', N'-Tetramethyl-0-(N-succinimidyl)uronium tetrafluoroborate), HCTU (0-(6-Chlorobenzotriazol-1-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate), PyClock (0-(6-Chlorobenzotriazol-1-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate), COMU (1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate), PyBOP (Benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate), PyAOP (7-Azabenzotriazol-1 -yloxy)tris(dimethylamino)phosphonium hexafluorophosphate) and combinations thereof.

13. The process of any of claims 2-12, wherein the compounds of Formulas (2) and (3) are reacted in the presence of an additive.

14. The process of claim 13, wherein the additive is selected from HOBt (1-Hydroxybenzotriazole), HOOBt (HODhbt) (Hydroxy-3, 4-dihydro-4-oxo-1,2, 3-benzo-triazine), HOSu (N-Hydroxysuccinimide), HOAt (1-Hydroxy-7-aza-1H-benzotriazole), Ethyl 2-cyano-2-(hydroximino)acetate, DMAP (4-(N, N-Dimethylamino)pyridine) and combinations thereof.

15. The process of any of claims 2-14, wherein the compounds of Formulas (2) and (3) are reacted at a temperature of 0-50°C.

16. The process of any of claims 2-15, wherein the compounds of Formulas (2) and (3) are reacted at a temperature of 20-30°C.

17. The process of any of claims 1-16, wherein:R1, R2a, and R2bare defined according to (A1) and (B1) below:(A1)R1is:• heteroaryl including 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2,and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc;• heterocyclyl including 4-6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc;• C3-7 cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc;• heterocycloalkenyl including 3-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o- 2, and wherein the heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc; or • C6-10 aryl optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc; andeach of R2aand R2bis independently selected from the group consisting of:• C1-2 alkyl optionally substituted with from 1-5 Ra;• C3-5 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rb;R2aand R2btaken together with the carbon atom to which each is attached forms:• C3-7 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rb;(B1)R1taken together with (i) the carbon atom to which it is attached and (ii) and one of R2aand R2bforms:• Cs-io aryl optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc; or• heteroaryl including 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc; andthe other of R2aand R2bis C1-2 alkyl optionally substituted with from 1-5 Ra.

18. The process of claim 17, further comprising the steps of:reacting the compound of Formula (4) with acrylonitrile to provide a compound of Formula (5):converting the compound of Formula (5) into a compound of Formula (6):(6); andconverting the compound of Formula (6) into a compound of Formula (I):

19. The process of any of claims 1-18, wherein the compound of Formula (2) is prepared by a process comprising the steps:(a) reacting a compound of Formula (a) with a compound of Formula (b) to yield a compound of Formula (c):CNO O (a) (b) (c) wherein:R3is H; C1-2 alkyl, which is substituted with 1-5 fluoro; fluoro; chloro; or cyano;R4is chloro; bromo; or fluoro; optionally wherein it is provided that R4is fluoro when R3is chloro;R7is fluoro; or chloro if neither R3nor R4are fluoro; andR5and R5’ are independently C1-6 alkyl;(b) converting the compound of Formula (c) into a compound of Formula (d):CNO O(c) (d)(c) converting the compound of Formula (d) into a compound of Formula (e):, wherein:Pg is a protecting group; and / or(d) converting the compound of Formula (e) into the compound of Formula (2).

20. The process of any of claims 1-19, wherein the compound of Formula (3) is prepared by:a) reacting a compound of Formula (f) with a compound of Formula (g) to yield a compound of Formula (h):R(g) (h) wherein:R8is C1-6 alkyl or C3-5 cycloalkyl; andHal is a halogen, e g. F, Cl, Br or I, preferably Cl.

21. A process comprising reacting a compound of Formula (n) with a compound of Formula (0) to yield a compound of Formula (p):wherein:X is H; or halo;Yi and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH;R3is C1-2 alkyl, which is substituted with 1-5 fluoro; fluoro; chloro; or cyano;R4is chloro; bromo; or fluoro; optionally wherein it is provided that R4is fluoro when R3is chloro;R5is C1-6 alkyl;R7is fluoro; or chloro if neither R3nor R4are fluoro; andLg is a leaving group.

22. The process of claim 21, wherein the compound of Formula (n) is reacted with the compound of Formula (o) in the presence of a base and a solvent.

23. The process of claim 22, wherein the base is selected from CsCCh, Na2CC>3, K2CO3, DBU, DBN, LiHMDS, NaHMDS, KHMDS, K3PO4 and combinations thereof.

24. The process of any of claims 22-23, wherein the solvent is a high boiling point polar aprotic solvent; optionally wherein the high boiling point polar aprotic solvent has a boiling point of 80°C or higher; further optionally wherein the high boiling point polar aprotic solvent has a boiling point of 100°C or higher.

25. The process of claim 24, wherein the solvent is selected from DMSO, DMF, DMA, NMP and combinations thereof.

26. The process of any of claims 22-25, wherein the compound of Formula (n) is reacted with the compound of Formula (o), at a temperature of 80-150°C.

27. The process of any of claims 22-26, wherein the compound of Formula (n) is reacted with the compound of Formula (o), for a duration of 1-48 hours.

28. The process of any of claims 21-27, further comprising the step of converting the compound of Formula (p) into a compound of Formula (q):

29. The process of any preceding claim, wherein the process is a process for preparing a compound of Formula (I), or a subformula thereof described herein:or a pharmaceutically acceptable salt thereof.

30. A compound of Formula (2):wherein:X is H; or halo;Yi and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH;R3is H; C1-2 alkyl, which is optionally substituted with 1-5 fluoro; fluoro; chloro; or cyano; R4is chloro; bromo; or fluoro; optionally wherein it is provided that R4is fluoro when R3is chloro; andX’ is an anion.

31. A compound of Formula (3):R2b, wherein:R1, R2a, and R2bare defined according to (A) and (B) as defined in claim 1;R6is a leaving group, for example, Cl, Br, I, OH, OM, O(C=O)(Ci-6 alkyl), O(C=O)(N3), O(Ci-6 alkyl), or S(Ci-6 alkyl), preferably Cl or OM; andM is a cation, for example an alkali metal cation such as Li+, Na+, or K+, an alkali earth metal cation such as Ca2+, or Mg2+, an organic cation such as NH4+, or a protonated amine such as C1-4 alkyl-NH3+), preferably an alkali metal cation, more preferably Na+or K+.

32. A compound of Formula (p):LgY< YR3R4O.OR(P), wherein:X is H; or halo;Yi and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH;R3is C1-2 alkyl, which is substituted with 1-5 fluoro; fluoro; chloro;R4is chloro; bromo; or fluoro; optionally wherein it is provided that R4is fluoro when R3is chloro;R5is C1-6 alkyl;andLg is a leaving group.

33. The compound or process of any preceding claim, wherein:R1is any R1defined according to (A);R2aand R2bare each independently C1-2 alkyl optionally substituted with from 1-5 Ra;R3is H; C1-2 alkyl, which is optionally substituted with 1-5 fluoro; fluoro; chloro; or cyano; R4is chloro; bromo; or fluoro; optionally wherein it is provided that R4is fluoro when R3is chloro; Y1 and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH.

34. The compound or process of any preceding claim, wherein:R1is heteroaryl including 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(C)o-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc;R2aand R2bare each independently C1-2 alkyl optionally substituted with from 1-5 Ra;R3is H; C1-2 alkyl, which is optionally substituted with 1-5 fluoro; fluoro; chloro; or cyano; R4is chloro; bromo; or fluoro; optionally wherein it is provided that R4is fluoro when R3is chloro; Y1 and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH.

35. The compound or process of any preceding claim, wherein:R1is heteroaryl including 5 or 6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N and O, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc;R2aand R2bare each independently C1-2 alkyl optionally substituted with from 1-5 Ra;R3is H; C1-2 alkyl, which is optionally substituted with 1-5 fluoro; fluoro; chloro; or cyano; R4is chloro; bromo; or fluoro; optionally wherein it is provided that R4is fluoro when R3is chloro; Y1 and Y2 are CH or N, wherein at least one of Y1 and Y2 is CH.

36. The compound or process of any preceding claim, wherein:R1has the formula:■3.X2(III-A);wherein each of Xi, X2, X3, and X4 is, independently, CH or N; and R11is H, Rb, or Rc;R2aand R2bare each independently C1-2 alkyl;R3and R4are each independently fluoro or chloro;Y1 and Y2 are each independently CH.

37. The compound or process of any preceding claim, wherein:R1has the formula:NN(V-A), wherein Rn is methyl.R2aand R2bare each independently methyl;R3and R4are each independently chloro;Yi and Y2 are each independently CH.

38. The compound or process of any preceding claim, wherein: M is an alkali metal cation such as Li+, Na+, or K+, an alkali earth metal cation such as Ca2+, or Mg2+, an organic cation such as NH4+, or a protonated amine such as C1-4alkyl-NH3+), preferably an alkali metal cation, more preferably Na+orK+; X’ is any suitable anion which corresponds to the conjugate base of a strong acid, such as HSO4; SO42-, NO3, Cl-or Br, preferably Cl' or Br; and / or R6is Cl, Br, I, OH, OM, O(C=O)(Ci-6 alkyl), O(C=O)(N3), O(CI-6 alkyl), or S(Ci-6alkyl); preferably Cl, or OM.

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