Synthesis of a malt1 inhibitor

Abstract

Processes for preparing (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8- dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N- ((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide are described, which are useful for commercial manufacturing. The compound may be useful for the treatment of a disease, syndrome, condition, or disorder, particularly a MALT1- related disease, syndrome, condition, or disorder, including but not limited to, cancer and immunological diseases.

Description

SYNTHESIS OF A MALT1 INHIBITOR FIELD OF THE INVENTION

[0001] The present invention relates to synthesis a novel compound that is a MALT1 (mucosa- associated lymphoid tissue lymphoma translocation protein 1) inhibitor. The compound may be useful for the treatment of a disease, syndrome, condition, or disorder, particularly a MALT1- related disease, syndrome, condition, or disorder, including but not limited to, cancer and immunological diseases. BACKGROUND OF THE INVENTION

[0002] MALT1 (mucosa-associated lymphoid tissue lymphoma translocation 1) is a key mediator of the classical NFΚB signaling pathway. MALT1 is the only human paracaspase and transduces signals from the B cell receptor (BCR) and T cell receptor (TCR). MALT1 is the active subunit of the CBM complex which is formed upon receptor activation. The CBM complex consists of multiple subunits of three proteins: CARD11 (caspase recruitment domain family member 11), BCL10 (B-cell CLL / Lymphoma 10) and MALT1. MALT1 affects NFΚB signaling by two mechanisms: firstly, MALT1 functions as a scaffolding protein and recruits NF-ΚB signaling proteins such as TRAF6, TAB-TAK1 or NEMO-IKKα / β; and secondly, MALT1, as a cysteine protease, cleaves and thereby deactivates negative regulators of NF-ΚB signaling, such as RelB, A20 or CYLD. The ultimate endpoint of MALT1 activity is the nuclear translocation of the NF-ΚB transcription factor complex and activation of NF-ΚB signaling.

[0003] Constitutive activation of NF-ΚB signaling is the hallmark of ABC-DLBCL (Diffuse Large B cell Lymphoma of the Activated B Cell-like subtype), the more aggressive form of DLBCL. DLBCL is the most common form of non-Hodgkin’s lymphoma (NHL), accounting for approximately 25% of lymphoma cases while ABC-DLBCL comprises approximately 40% of DLBCL. NF-ΚB pathway activation is driven by mutations of signaling components, such as CD79A / B, CARD11, MYD88 or A20, in ABC-DLBCL patients.

[0004] The use of BTK inhibitors, for example Ibrutinib, provides clinical proof-of-concept that inhibiting NF-ΚB signaling in ABC-DLBCL is efficacious. MALT1 is downstream ofBTK in the NF-ΚB signaling pathway and a MALT1 inhibitor could target ABC-DLBCL patients not responding to Ibrutinib, mainly patients with CARD11 mutations, as well as treat patients that acquired resistance to Ibrutinib.

[0005] Small molecule tool compound inhibitors of MALT1 protease have demonstrated efficacy in preclinical models of ABC-DLBCL. Interestingly, covalent catalytic site and allosteric inhibitors of MALT1 protease function have been described, suggesting that inhibitors of this protease may be useful as pharmaceutical agents.

[0006] The chromosomal translocation creating the API2-MALT1 fusion oncoprotein is the most common mutation identified in MALT (mucosa-associated lymphoid tissue) lymphoma. API2-MALT1 is a potent activator of the NF-ΚB pathway. API2-MALT1 mimics ligand- bound TNF receptor, promotes TRAF2-dependent ubiquitination of RIP1 which acts as a scaffold for activating canonical NF-ΚB signaling. Furthermore, API2-MALT1 has been shown to cleave and generate a stable, constitutively active fragment of NF-ΚB-inducing kinase (NIK) thereby activating the non-canonical NF-ΚB pathway.

[0007] In addition to lymphomas, MALT1 has been shown to play a critical role in innate and adaptive immunity. MALT1 protease inhibitor can attenuate disease onset and progression of mouse experimental allergic encephalomyelitis, a mouse model of multiple sclerosis. Mice expressing catalytically inactive MALT1 mutant showed loss of marginal zone B cells and B1 B cells and general immune deficiency characterized as decreased T and B cell activation and proliferation. However, those mice also developed spontaneous multi-organ autoimmune inflammation at the age of 9 to 10 weeks. It is still poorly understood why MALT1 protease dead knock-in mice show a break of tolerance while conventional MALT1 KO mice do not. One hypothesis suggests the unbalanced immune homeostasis in MALT1 protease dead knock- in mice may be caused by incomplete deficiency in T and B cell but severe deficiency of immunoregulatory cells. Similarly, MALT deficiency in humans has been associated with combined immunodeficiency disorder. Given the difference between genetic mutation and pharmacological inhibition, a phenotype of MALT1 protease dead knock-in mice might not resemble that of patients treated with MALT1 protease inhibitors. A reduction of immunosuppressive T cells by MALT1 protease inhibition may be beneficial to cancer patients by potentially increasing antitumor immunity.

[0008] In order to provide sufficient active pharmaceutical ingredient to treat patients, there remains a need to develop efficient synthetic routes to compounds of interest.

[0009] WO2022 / 106857, EP2236496, WO2010 / 078294, US2004 / 133007 and WO2004 / 024707 describe preparation of compounds. SUMMARY OF THE INVENTION

[0010] The present invention is directed to the synthesis of the compound of Formula (I)

[0011] The compound of Formula (I) is also known as (1S,3R)-3-(4-((R)-2-chloro-8-methyl- 8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2- difluoro-1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide.

[0012] Unless otherwise indicated or clear from the context, all references to the structure of Formula (I) and (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide, in the context of this invention, might also refer to the pharmaceutically acceptable salts and solvates (including hydrates) thereof including any subgroup thereof or any combination of pharmaceutically acceptable salts and solvates thereof, even if not explicitly referred to, and are included in the scope of the present invention.

[0013] Where stereochemistry is specified by bonds which are shown as solid wedged or hashed wedged bonds, hashed or bold bonds, then that stereoisomer is so specified and defined.

[0014] It will be clear for a skilled person that a hashed bond and a bold bond on a 1,3- disubstituted cyclobutyl moiety as shown below:, whereby X1and X2represent substituents,indicate that the substituents on the cyclobutyl moiety have trans-configuration.

[0015] The stereodescriptor label “R” or “(R)” at a stereocenter designates that the stereocenter is purely of the R-configuration as defined in the art; likewise, the stereodescriptor label “S” or “(S)” means that the stereocenter is purely of the S-configuration. DETAILED DESCRIPTION OF THE INVENTION

[0016] The present invention is directed to the synthesis of the compound of Formula (I)DEFINITIONS

[0017] As used herein the term “1-(trifluoromethyl)-1l3-benzo[d][1,2]iodaoxol-3(1H)-one” refers to the following compound.

[0018] As used herein, the term “seeding” refers to the addition of crystalline material to a solution or mixture to initiate crystallisation or recrystallisation. A skilled person will understand that a small amount of initial seed material used in any reaction described herein, can be obtained via an analogous reaction protocol on small-scale without addition of seeds, by means of spontaneous nucleation.

[0019] Any formula given herein is intended to refer also to hydrates, solvates, and polymorphs of such compounds, and mixtures thereof, even if such forms are not listedexplicitly.

[0020] Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as2H,3H,11C,13C,14C,15N,18O,17O, respectively. Such isotopically labeled compounds are useful in metabolic studies (preferably with14C), reaction kinetic studies (with, for example2H or3H), detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients. Further, substitution with heavier isotopes such as deuterium (i.e.,2H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0021] Those skilled in the art will recognize that compounds and reagents used in the reactions of the invention may exist as salts. The invention contemplates the use of all salts of any compound used in a reaction exemplified herein.

[0022] Examples of salts include, without limitation, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates, methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.

[0023] When a compound or reagent used in a reaction of the invention contains a basicnitrogen, a salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as mandelic acid, citric acid, or tartaric acid, an amino acid, such as aspartic acid, glutaric acid or glutamic acid, an aromatic acid, such as benzoic acid, 2- acetoxybenzoic acid, naphthoic acid, or cinnamic acid, a sulfonic acid, such as laurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, any compatible mixture of acids such as those given as examples herein, and any other acid and mixture thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary level of skill in this technology.

[0024] Exemplary reactions useful in methods of the invention will now be described by reference to the illustrative synthetic schemes for their general preparation below and the specific examples that follow. Those skilled in the art will recognize that reactions may be performed in any suitable solvent. Those skilled in the art will also recognize that, except where specifically limited, reactions may be performed at a wide range of temperatures. Unless otherwise specified, reactions may be performed between the melting point and the reflux temperature of the solvent, and preferably between 0 °C and the reflux temperature of the solvent. Reactions may be heated employing conventional heating or microwave heating. Reactions may also be conducted in sealed pressure vessels above the normal reflux temperature of the solvent. ABBREVIATIONS

[0025] Herein and throughout the specification, the flowing abbreviations may be used.Abbreviation Term Boc2O di-tert-butyl dicarbonate Bredereck's reagent tert-butoxy bis(dimethylamino)methane BSA benzenesulfonic acidtBu, or t-Bu tert-butyl DCM dichloromethane de diastereomeric excess DMF dimethyl formamide DMSO dimethylsulfoxide ee enantiomeric excess Et ethyl EtOAc ethyl acetate Et3N triethylamine L-DTTA di-p-toluyl-L-tartaric acid Hexafluorophosphate Azabenzotriazole Tetramethyl HATU Uronium JohnPhos (2-biphenyl)di-tert-butylphosphine OAc acetate Me methyl MeCN acetonitrile MEK methylethylketone MeOH methanol MeTHF, or 2-MeTHF 2-methyl tetrahydrofuran MTBE methyl tert-butyl ether OAc acetate PE petroleum ether TEA triethylamine TFA trifluoroacetic acid Tf2O trifluoromethane sulfonic anhydride THF tetrahydrofuranGENERAL SCHEME 1 Main chain:Step 1:SM1 A

[0026] A solution of SM1 (34.4 kg, 0.178 mol), TEA (34.6 kg, 1.92 equiv.) and 2-MeTHF (295.8 kg) in a 3000L reactor was chilled to 0 °C and treated with a solution of propionylchloride (18.0 kg, 1.1 equiv.) in 2-MeTHF (60 kg) dropwise at -5 °C, over 3h, then allowed to come to room temperature. After stirring at 25 °C for 1h, reaction was complete; water (346 kg) was added. After phase separation, the aqueous phase was extracted with 2- MeTHF (90kg). The combined organic phases were concentrated to ~172 L. Fresh 2-MeTHF (300 kg) was added and concentrated to ~172 L. The dilution and concentration was repeated until the residual water was ≤0.03% by Karl Fischer.131.6 kg solution of A in 2-MeTHF was obtained, assay 31.9% wt%, assay yield 95.8%, HPLC purity 98.8%.1H NMR (DMSO-D6) δ: 7.4~7.2 (m, 5H), 4.6 (s, 1H), 4.5 (s, 1H), 4.1 (s, 1H), 4.1 (dq, 2H), 4.0 (s, 1H), 2.41 - 2.24 (m, 2H), 1.2 (dt, 3H), 0.98 (td, 3H) ppm. MS (ESI) m / z: 250 ([M + H]+).

[0027] Compound A may be obtained by the following alternative procedure. A solution of sodium bicarbonate (42.7 g, 5 equivalents, 508 mmol) in water (600 mL) was treated with a solution of ethyl benzylglycinate (20.0g, 98.2% wt, 1 equivalent, 102 mmol) in Me-THF (400 mL), followed by the dropwise addition of propionyl chloride (10.3 g, 9.75 mL, 1.1 equivalents, 112 mmol) at 10 °C over 0.5 hours, followed by stirring at 10 °C until the reaction was complete. The reaction was partitioned and the organic layer was concentrated below 45 °C under vacuum to give 24.9g product as an oil with 96.9% purity and 94.3% yield. Step 2:

[0028] A 3000L reactor was charged with t-BuOK (37.4 kg, 2.0 equiv.) and 2-MeTHF (894.0 kg). The solution of A obtained from step 1 (net: 41.6 kg, 166.86 mol) was added dropwise at 20 °C over 2h. After stirring at 20°C for 2h, the reaction was cooled to 5 °C, and the pH was adjusted to 6.91 with 10% citric acid (240kg) at 0-10 °C. After phase separation, the organic phase was washed with 5% NaCl aq. (220kg) and concentrated to ~7 Vol. below 45 °C under vacuum. The mixture was cooled to 40 °C and stirred for 2h.0.4% seeds of B was added. After stirring at 25 °C for 1h, n-heptane (206 kg) was added dropwise at 25 °C over 3h. The reaction mixture was cooled to 0 °C and stirred for 15h. The resulting suspension was filtered and the cake was rinsed with n-heptane (62.34 kg). After drying at 45 °C for 10 h, 30.6 kg B was obtained as a white solid, isolated yield 88.6%, HPLC purity 100%.1H NMR (DMSO-D6) δ: 7.36 - 7.13 (m, 5H), 4.46 (s, 2H), 3.63 (d, 2H), 3.34 (br s, 1H), 1.58 (s, 3H) MS (ESI) m / z: 204 ([M + H]+). Step 3:

[0029] A solution of B (28 kg, 137.76mol) and DMF (134.4kg) in a 2000L reactor was cooled to 0°C and treated with K2CO3 (56 kg). The reaction mixture was cooled to -5.5 °C and treated in parallel with a solution of Na2S2O4(4.8kg, 0.2 equiv.) in water (22.4 kg) and a solution of CF3I in 25% DMF solution (140 kg, 1.3 equiv.). After stirring for 2h, the mixture was filtered, and the cake was rinsed with MTBE (207 kg). H2O (89.6 kg) was added to the filtrate to perform the phase cut. The aqueous phase was extracted with MTBE (207.2 kg) twice. The combined organic layers were washed with 5% LiCl solution (140 kg) three times. The organic phase was concentrated to 2-3 Vol. below 30 °C under vacuum, followed by a solvent switch to THF, performed in triplicate, such that the final 5 Vol. was obtained with a Karl Fischer not more than 0.10%. 116.0 kg solution of C in THF was obtained, assay 27.5%, assay yield 85.3%, HPLC purity 92.2% purity.1H NMR (DMSO-D6) δ: 7.42 - 7.23 (m, 5H), 4.8 (d, 1H), 4.4 (d, 1H), 4.0 (s, 2H), 1.4 (s, 3H) MS (ESI) m / z: 270 ([M + H]+).

[0030] Compound C may be prepared by the following alternate procedure. A solution of 1-benzyl-3-methylpyrrolidine-2,4-dione (4.55 kg, 22387.21 mmol, 1.0 equiv) in DMF (45 L) in a 100L reactor was treated with NaH (0.98 kg, 24625.93 mmol, 1.1 equiv, 60%) by portions at 0 °C. The mixture was stirred for 0.5 h at 0 °C, chilled to -68 °C and treated with 1- (trifluoromethyl)-1λ3-benzo[d][1,2]iodaoxol-3(1H)-one (7.78 kg, 24625.93 mmol, 1.1 equiv.). The mixture was gradually warmed up to 25 °C, stirred for 1 h, and poured into a mixture of ice / water (90 L). The resulting mixture was extracted with EtOAc (2x50 L). The organic layers were combined, dried over anhydrous Na2SO4and concentrated under vacuum. The above procedure was repeated once for another batch of 4.55 kg. The residue was applied on a silica gel column and eluted with EtOAc / PE (1:4) to give 1-benzyl-3-methyl-3- (trifluoromethyl)pyrrolidine-2,4-dione (6.79 kg, 55.91%) as a light yellow oil. Step 4:

[0031] A 1000L reactor was charged with the solution of C obtained in step 3 (net: 31.9 kg, 118 mol) and THF (567.8 kg). LiAH4 solution in THF (2M) (130.8 kg, 3 equiv.) was added dropwise over 4h below 20 °C. The mixture was warmed to 60 °C and stirred for 2h followed by cooling to -5 °C and dropwise addition of H2O (14.4 kg), followed by addition of a solution of NaOH (14.4kg) in H2O (44.7kg). The resulting suspension was warmed to 25 °C and stirred for 1h. The reaction mixture was filtered with a diatomite pad (31.9kg) and the cake was rinsed with THF (283.9kg). The filtrate was concentrated to 2~3 Vol. below 45 °C under vacuum. DCM (341.3kg) and H2O (319kg) were added. Phase cut and concentrate the organic layer to 2-3 Vol. below 40 °C under vacuum. DCM (341.3kg) was added and concentrated to 5 Vol. repeatedly until the water content by Karl Fischer was not more than 0.02%.176.6 kg solution of D in DCM was obtained, assay 15.8%, assay yield 91.5%, HPLC purity 94.2%.

[0032] 1H NMR (DMSO-D6) δ: 7.3 (m, 5H), 5.3 (d, 2H), 3.9 (m, 1H), 3.5 (q, 2H), 3.0 (m, 1H), 2.6 (m, 1H), 2.2 (m, 1H), 1.2 (s, 3H).

[0033] MS (ESI) m / z: 260.1 ([M + H]+). Step 5:

[0034] A 3000L reactor was charged with DCM (600kg) and oxalyl chloride (21.9kg, 1.5 equiv.). The solution was cooled to -75 °C, and DMSO (27kg, 3 equiv.) was added. After stirring for 1h at -75 °C, 178.52 kg solution of D (net: 30 kg, 115.7mol) obtained in step 4 was added dropwise at -75 °C over 3h. After stirring for 1h at -75 °C, triethylamine (48kg, 4 equiv.) was added at -75 °C over 1h. After 1h stirring, the mixture was warmed to 20 °C, the organic phase was separated and washed with H2O (300kg) twice. The organic phase was concentrated to 2~4 Vol. below 30 °C under vacuum followed by a solvent swap to MeCN, resulting in 120.9 kg of DK solution, assay 23.1%, assay yield 93.8%, HPLC purity 96.4%.1H NMR (DMSO-D6) δ: 7.3 (m, 5H), 3.7 (s, 2H), 3.3 (m, 1H), 3.0 (m, 3H), 1.3 (s, 3H). MS (ESI) m / z: 258.1 ([M + H]+).

[0035] First, a solution of di-p-toluoyl-L-tartaric acid (46.92 kg, 1.1 eq.) dissolved in MeCN (306.6 kg) was prepared (L-DTTA solution). A stirred solution obtained from step 5 containing 27.6kg (107.3 mol) of DK in ~4 Vol. MeCNin a 3000L reactor was treated at 25oC with 24.6kg of the above L-DTTA solution over 1 hour followed by addition of 0.28kg of seeds of DP. After stirring for 6 hours at 25oC, the rest of L- DTTA solution (326.2 kg) was added slowly at 25oC for 8 hours. After stirring for additional 12 hours, the suspension was filtered and the cake was washed with MeCN (44 kg). Cake drying at 25 °C for 16 hr gave 27.8kg product DP as a white solid, assay yield 40.8%, diastereomeric excess (de) 90%, HPLC purity 99.1%. MS (ESI) m / z: 258.1 ([M + H]+). Step 7:

[0036] A 1000L reactor was charged with 2-MeTHF (172kg), DP (20kg, 31.1mol), and H2O (200kg). The mixture was chilled to 10 °C, treated with 5% NaHCO3aq. (70kg), followed by the addition of water (20kg). The mixture was stirred for 3 h at 10 °C, filtered, and the cake was washed with 2-MeTHF (334kg). The reaction was partitioned, and the organic phase was washed with H2O (100kg) twice and then concentrated to 2-3 Vol. below 40 °C under vacuum. The solvent was swapped with 2-MeTHF (90kg) twice and concentrated to 2-3 Vol. until the water content by Karl Fischer was not more than 0.4%. 29.1 kg solution of DS in 2-MeTHF was obtained, assay 27.2%, assay yield 98.7%. MS (ESI) m / z: 258.1 ([M + H]+).

[0037] A 500 L reactor was charged 2-MeTHF (67.6kg), DS solution in Me-THF (net: 7.86 kg, 30.55mol), Boc2O (6.68kg,1.05 equiv.) and 10wt% wet Pd / C (20wt%, 1.57 kg). The mixture was stirred at 25 °C under H2(10-20Psi) for 23 h. An additional 0.39kg 10wt% wet Pd / C was added to drive the reaction to completion. The suspension was filtered with a diatomite pad, and the cake was rinsed with 2-MeTHF (3ⅹ24.8kg). The filtrate was concentrated to 3~5 Vol. below 40 °C under vacuum, diluted with 2-MeTHF (67.6kg), and concentrated to 3~5 Vol. 25.85 kg solution of G in Me-THF was obtained, assay 27.5%, assay yield 87.1%, HPLC purity 88.4%.

[0038] This solution was concentrated to 3 Vol. (based on 7.04kg net G) and then solvent swapped with heptane (3ⅹ23.9kg) to final volume of 5 Vol. After stirring at 0 °C for 2h, the suspension was cooled to -15 °C and stirred for 2h. Filtration in three portions and drying for 15 h at 25 °C gave total 6.8kg product with 94.9% assay yield (against 7.04kg net G), 96.1~97.5% HPLC purity and 91.0~93.1% ee.1H NMR (DMSO-D6) δ: 4.0 (m, 3H), 3.5 (m, 1H), 1.4 (m, 3H), 1.3 (s, 9H). Step 9:

[0039] A 50 L reactor was charged 2-MeTHF (23kg), G (5.2kg,19.46mol) and tert-butoxy bis(dimethylamino)methane (5.37kg, 1.6 equiv.). The reaction mixture was heated to 50 °C, stirred for 5h, and concentrated to 3~5 Vol. below 45 °C under vacuum. The reaction was diluted with n-heptane (17.7kg) and concentrated to 8~10 Vol. below 45 °C under vacuum. The mixture was then heated to 70 °C, stirred for 2h, cooled to 50 °C, and stirred for 1h. The reaction was then cooled to 5 °C, stirred for 10 h, filtered, and the cake was washed with n-heptane (14.04kg). The cake was dried at 20 °C under vacuum for 16 h to give 5.83 kg H as a white solid, assay 97.7 %, assay yield 93.0%, ee 93.5%, HPLC purity 99.9%.

[0040] 1H NMR (DMSO-D6) δ: 7.3 (s, 1H), 3.6~4.2 (m, 1H), 1.4 (m, 9H), 1.2 (s, 3H).

[0041] MS m / z: 222.1 ([M - Boc]+).Step 10:

[0042] A 50L reactor was charged toluene (24.9kg), H (5.662kg, 17.6 mol), 3-chloro-1H- pyrazol-5-amine (2.15kg, 1.0 equiv.) and trifluoroacetic acid (2.21kg, 1.1 equiv.). The mixture was heated to 110 °C, stirred for 14 h, cooled to 15 °C and washed with 25% NaCl (28.3kg). 30.4kg organic phase after separation was obtained, assay19.3%, assay yield 88.6%, HPLC purity 89.0%,.1H NMR (DMSO-D6) δ: 9.0 (m, 1H), 7.1 (s, 1H), 4.4 (m, 1H), 4.1 (m, 1H), 1.9 (s, 3H), 1.5 (s, 9H). MS (ESI) m / z: 377.7 ([M + H]+). Step 11:

[0043] A 50L reactor was charged with the solution from step 10 (net: 6.64kg J,17.6mol) and 35% HCl (13.3kg). The mixture was stirred at 25 °C for 4h, followed by addition of 2M NaOH until the pH reached 8. The reaction was partitioned and the organic phase was washed with 5% NaCl (30kg). The organic phase was concentrated to 2.5 Vol. below 45 °C under vacuum, diluted with n-heptane (38.5kg), cooled to 0 °C and stirred for 3 h. The reaction was filtered; the cake was washed with n-heptane (4.5kg) and dried at 25 °C for 14 h to give 3.79 kg L as a white solid, assay 96.5%, assay yield 75.3%, HPLC purity 97.7%, ee 99.1%.1H NMR (DMSO-D6) δ: 8.4 (s, 1H), 7.3 (s, 3H), 6.8 (s, 1H), 6.1 (s, 1H), 3.9 (dd, 1H), 3.6 (dd, 1H), 1.8 (s, 3H)MS (ESI) m / z: 277.0 ([M + H]+). GENERAL SCHEME 2 Side chain:

[0044] A 250 L reactor was charged 4-bromobenzaldehyde SM (16 kg. 86.5 mol), THF (71.6kg) and ethyl 2-(diethoxyphosphoryl)propanoate (24kg, 1.2 equiv.). An aqueous solution of 40% NaOH (10.4kg, 1.2 equiv.) was added dropwise over 3.5h at 5-15 °C and stirred at 5-15 °C for 2h. The reaction was diluted with n-heptane (32 kg) and water (48 kg), stirred for 0.5h at 5-15 °C, and partitioned. The organic phase was washed with water (48 kg), concentrated followed by a solvent swap to ~3 Vol. diglyme solution (~48 L, 58.4 kg, Karl Fischer:0.1%). Assay: 36.7%, assay yield 93.9%, HPLC purity 96.2%. This solution was telescoped to next step.1H NMR (DMSO-D6) δ: 7.5 (s, 1H), 7.4 (m, 2H), 7.2 (m, 2H), 4.2 (q, 2H), 2.0 (s, 3H), 1.3 (t, 3H). MS (ESI) m / z: 270.9 ([M + H]+).

[0045] Alternatively, product M may be prepared by the following procedure: Into a 20 L 4-necked round-bottom flask was placed tetrahydrofuran (8 L). To the above mixture was added NaH (207.53 g, 5188.62 mmol, 1.2 equiv, 60%) in portions over 15 min at 0 °C. To the above mixture was added ethyl 2-(diethoxyphosphoryl)propanoate (1236.04 g, 5188.62 mmol, 1.2 equiv) dropwise over 40 min at 0 °C. The resulting mixture was stirred for additional 30 min at 0 °C. To the above mixture was 4-bromobenzaldehyde (800 g, 4323.85 mmol, 1.0 equiv) in THF (1600 mL) dropwise over 30 min at 0 °C~5 °C. The resulting mixture was stirred for additional 16 h at room temperature. The reaction was poured into ice water (12 L). The resulting mixture was extracted with EtOAc (2x10 L). The combined organic layers were washed with brine (3x7 L), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (10:1) to afford ethyl (2E)-3-(4- bromophenyl)-2-methylprop-2-enoate (1050 g, 90.23%) as a light yellow oil.Step 13:

[0046] A 1000 L reactor was charged with M (net:21.4kg, 79.5 mol) and benzenesulfonic acid (BSA) (1.25 kg, 0.01 equiv.). The mixture was heated to 130-140 °C over 4h, treated dropwise with a solution of sodium bromodifluoroacetate (109kg, 7.0 equiv.) in diethylene glycol monoethyl ether (257kg ,12 Vol.) over 12h at 130-140 °C. In process control analysis showed the reaction was not complete. An additional solution of 175kg sodium bromodifluoroacetate (2.9 equiv.) in diethylene glycol monoethyl ether was added over 7.5h. The reaction mixture was cooled to room temp, treated with n-heptane (146kg) and 10% NaCl aqueous solution (110kg), and partitioned. The organic layer was washed twice with H2O (2 x 110kg), concentrated to 2~3 Vol. below 40 °C, diluted with THF (95kg) and concentrated to 2~3 Vol. 89.4kg N was obtained (as a mixture of 1R, 3S and 1S, 3R) and used directly in the next step. assay 21.1%, assay yield 75.2%, HPLC purity 83.5%.1H NMR (DMSO-D6) δ: 7.4 (d, 2H), 7.0 (d, 2H), 4.2 (q, 2H), 3.5 (dd, 1H), 1.3 (t, 3H), 1.0 (s, 3H). MS (ESI) m / z: 319.0 ([M + H]+).

[0047] Alternatively, product N may be made by the following procedure: Into a 20 L 4- necked round-bottom flask was placed ethyl (2E)-3-(4-bromophenyl)-2-methylprop-2-enoate (1050 g, 3901.34 mmol, 1.0 equiv), toluene (7350 mL), tetrabutylammonium bromide (37.73 g, 117.04 mmol, 0.03 equiv). To the above mixture was added (bromodifluoromethyl)trimethylsilane (12677.93 g, 62421.50 mmol, 16 equiv) dropwise over 40 h at 110 °C (with a syringe pump). The resulting mixture was stirred for additional 5 hat 110 °C. The reaction was poured into ice water (10 L). The resulting mixture was extracted with petroleum ether (3x6 L). The combined organic layers were washed with brine (3x4 L), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (30 :1) to afford N (as a mixture of 1R, 3S and 1S, 3R) (1006 g, 80.80%) as a light yellow oil. Step 14:

[0048] A 1000L reactor was charged with N (Net:18.8 kg, 58.9 mol) and THF (34 kg). The mixture was stirred at 25~35 °C for 1h, followed by dropwise addition of 7% NaOH aqueous solution (102kg, 3 equiv.176.7mol) over 1.5h at 25-35 °C. After stirring at 25-35 °C for 4h, the reaction was diluted with MTBE (70 kg) and water (39 kg). The reaction was partitioned, and the aqueous phase was treated with 2N HCl (90kg) at 20-35 °C to adjust pH to 1.88, followed by the addition of MTBE (70 kg). The reaction was stirred for 1h at 20-30 °C and partitioned. The organic layer was washed with 5% NaCl (97 kg), concentrated and solvent swapped to ~2Vol.2-butanone solution (~38L). The reaction was diluted with additional 2-butanone (25.2 kg) and used in the next step without further purification. Total 64.8 kg of solution containing Q was obtained. assay 25.8%, assay yield 97.5%, HPLC purity 90.3%.1H NMR (DMSO-D6) δ: 13.3 (bs, 1H), 7.6 (d, 2H), 7.2 (d, 2H), 3.7 (q, 1H), 1.1 (s, 3H). MS (ESI) m / z: 288.8, 290.9

[0049] Product Q may also be made by the following alternative procedure: Into a 20 L 4-necked round-bottom flask was placed ethyl (trans)-3-(4-bromophenyl)-2,2-difluoro-1- methylcyclopropane-1-carboxylate (1006 g, 3152.16 mmol, 1.0 equiv), tetrahydrofuran (10 L), water (5 L), lithium hydroxide (226.48 g, 9456.48 mmol, 3.0 equiv). The resulting mixture was stirred for overnight at 25°C. The solvent of THF was concentrated under reduced pressure. The resulting mixture was diluted with water (20 L). The residue mixture was acidified to pH=3 with 2 M HCl. The precipitated solids were collected by filtration and washed with water (1x5 L). The white solid was naturally dried. This resulted in Q (795 g, 86.64%) as a white solid. Step 15:

[0050] A solution of (R)-(-)-1-cyclohexylethylamine (7.7kg, 1 equiv.), MeCN (84.6 kg), and 2-butanone (43 kg) in a 500 L reactor was treated dropwise with a solution of MeCN (86 kg) and Q (Net:16.6kg, 1 equiv., 57.0 mol) over 3hr at 15~25 °C. The reaction was stirred at 15- 25 °C for 2h after the addition, heated to 45-55 °C over 2h and stirred for 2h, followed by cooling to 15-25 °C over 2.5h and stirred for an additional 2h. The same heating and cooling cyle was repeated one more time, followed by stirring at 15-25 °C for 10h. The resulting suspension was filtered and the cake was washed with 25kg mixed solvent of MeCN / 2- butanone (2:1 v / v.). The cake was dried at 45 °C under vacuum under N2flow for 18h to give 8.96kg product R as a white solid, assay 99.9%, assay yield 37.5%, HPLC purity 99.5%, de 98.3%. MS (ESI) m / z: 288.8, 290.9Step 16&17:

[0051] A 250 L reactor was charged MTBE (46 kg) and R (Net:8.79 kg, 1 equiv., 2.1 mol). The mixture was treated with 2N HCl (15kg) at 15-25 °C, stirred for 1h and partitioned. The organic layer was washed with 5% NaCl (32 kg) and then solvent swapped to ~2 Vol. MeCN (~18 L, Karl Fischer:0.1%). The organic layer was diluted with MeCN (21.2 kg), and treated with HATU (8.75 kg,1.1 equiv.), SM6 (4.3Kg, 1.1 equiv.) and TEA (6.4 kg, 3.0 equiv.). The solution was stirred at 15-25 °C for 3h, cooled to 0~10 °C, and diluted with water (158kg) over 3 hr. The resulting suspension was stirred at -5-5 °C for 16h and filtered. The filter cake was washed with MeCN (30kg), and dried at 45 °C under vacuum with N2bleed for 15h.7.98kg product S was obtained as a white solid, assay 98.9%, assay yield 90%, HPLC purity 99.4%, ee 99.5%.1H NMR (DMSO-D6) δ: 8.6 (d, 1H), 7.6 (d, 2H), 7.3 (d, 2H), 4.4 (m, 1H), 3.9 (m, 1H), 3.6 (d,1H), 3.0 (s, 3H), 2.7 (m, 2H), 2.5 (m, 2H). MS (ESI) m / z: 423.2 [M+1]Endgame step Step 18:

[0052] A 250 L reactor was charged with L (3.63kg, 1.0 equiv. 13.1 mol), MeCN (28kg), S (5.8kg, 1.05 equiv.), K2CO3(3.6kg, 2 equiv.) and 2-(di-tert-butylphosphino)biphenyl (0.156kg, 0.08 equiv.). The reaction mixture was flushed with N2and evacuated three times below 0.08MPa at 20-30 °C. The reaction was treated with palladium(II) acetate (0.058kg, 0.04 equiv.) and flushed with nitrogen again, in the same manner. The mixture was heated to 55-65 °C and stirred for 16h, followed by cooling to 20-30 °C and treatment with 2-(di-tert- butylphosphino)biphenyl (JohnPhos, 0.156kg, 0.08 equiv.). The reaction mixture was flushed with N2and evacuated three times and treated with additional palladium(II) acetate (0.058kg, 0.04 equiv.) and flushed with N2and evacuated three times more at 20-30 °C. After stirring at 55-65 °C for 6h, the suspension was filtered at 35-45 °C and the cake was washed with MEK (3 x 18kg) three times. The filtrate was concentrated and solvent swapped with MEK to 2-3 Vol final volume until MeCN<2%. The solution was washed with NaHCO3 / N-acetyl cysteine (3 x 18kg) aqueous solution three times, concentrated to 6 Vol. and diluted with MeOH (14kg). The solution was heated to 55-65 °C over 1h, stirred for 5h, cooled to 45-55 °C over the following 2h and seeded with Formula (I) (0.075kg seed). The mixture was cooled to -5-5 °C over 5h, diluted with MeOH (29kg) over 1.5h, and stirred at -5-5 °C for 22h. The suspension was filtered and the cake was washed with MEK and dried for 19h at 35-45 °C to obtain 6.27kg final API as a white solid, assay 97.2%, assay yield 75.8%, HPLC purity 99.4%, Pd 511ppm.

[0053] The 6.27kg API was redissolved in MEK and washed by NaHCO3 / N-acetyl cysteine followed by recrystallization from MEK / MeOH to give 5.42kg Formula (I) after sieving as a white solid, assay 97.2%, assay yield 65.0%, HPLC purity 99.6%, Pd 4.2ppm.1H NMR (DMSO-D6) δ: 8.8 (s, 1H), 8.5 (d, 1H), 7.3 (m, 4H), 6.9 (s, 1H), 4.4 (m, 1H), 4.3 (m,1H), 4.2 (m, 1H), 3.8 (m, 1H), 3.5 (br, 1H), 2.9 (s, 3H), 2.6 (m, 2H), 2.4 (m, 2H), 1.9 (s, 3H), 1.2 (s, 3H). MS (ESI) m / z: 618.2, 620.1. Pharmacological Analysis Biological Examples

[0054] In vitro assays include assays that determine cell morphology, protein expression, and / or the cytotoxicity, enzyme inhibitory activity, and / or the subsequent functional consequences of treatment of cells with compounds of the invention. Alternate or additional in vitro assays may be used to quantitate the ability of the inhibitor to bind to protein or nucleic acid molecules within the cell.

[0055] Inhibitor binding may be measured by radiolabelling the inhibitor prior to binding, isolating the inhibitor / target molecule complex and determining the amount of radiolabel bound. Alternatively or additionally, inhibitor binding may be determined by running a competition experiment where new inhibitors are incubated with purified proteins or nucleic acids bound to known radioligands. Detailed conditions of exemplary systems for assaying a compound of Formula (I) of the present invention as MALT1 inhibitors are set forth in the Biological Examples below.

[0056] Such assays are exemplary and not intended to limit the scope of the invention. The skilled practitioner can appreciate that modifications can be made to conventional assays to develop equivalent or other assays that can be employed to comparably assess activity or otherwise characterize compounds as described herein. In Vitro Assays Biological Example 1 MALT1 Biochemical Protease Assay

[0057] MALT1 protease activity was assessed in an in vitro assay using a tetrapeptide as substrate and full-length MALT1 protein (Strep-MALT1(1-824)-His) purified from baculovirus-infected insect cells. The tetrapeptide LRSR is coupled to AMC (7-amino-4-methylcoumarin) and provides a quenched, fluorescent substrate for the MALT1 protease (SM Biochemicals). Cleavage of AMC from the Arginine residue results in an increase in coumarin fluorescence measured at 460 nm (excitation 355 nm). The final assay buffer consisted of 10 nM FL MALT1 protein, 200 µM Ac-LRSR-AMC, 50 mM Tris pH 7.5, 0.6 M Citrate, 1 mM dithiothreitol (DTT), 1 mM ethylenediaminetetraacetic acid (EDTA), 0.05% bovine serum albumin (BSA) and 1.5% dimethyl sulfoxide (DMSO). Test compounds were spotted at 50 nL in 100% DMSO per well of a black 384-Proxiplate (Perkin Elmer). Test compound concentrations ranged from 30 µM to 0.5 nM using 11 dilution steps (1:3). Background signal was measured from control wells containing assay buffer without enzyme which functions as low control (LC). High control (HC) values were generated using the reaction with enzyme but no compound treatment. Compounds were pre-incubated with MALT1 enzyme for 50 minutes at RT. Substrate was added subsequently, and fluorescence was measured in Labsystems fluoroskan at excitation 355 nm and emission 460 nm to determine time 0. The reaction was subsequently incubated for 4 h at RT and fluorescence was measured. For IC50calculations, timepoint 0 was subtracted from the 4 h timepoint to correct for any potential autofluorescence of the compounds. The enzyme reaction was linear during the 4 h incubation period. Characterization of the substrate Ac-LRSR-AMC determined the Michaelis constant KMat 200 µM. IC50values were calculated using the following formula (Z prime should be >0.5): LC = Median of the low control values = Low control: Reaction without enzyme HC = Median of the High control values = High Control: Reaction with enzyme %Effect = 100-[((sample-LC) / (HC-LC)) x 100] %Control = (sample / HC) x 100 %Controlmin = ((sample-LC) / (HC-LC)) x 100

[0058] A best-fit curve was fitted by a minimum sum of squares method to the plot of %Controlmin vs. compound concentration. From this an IC50value (inhibitory concentration causing 50 % inhibition) can be obtained. An estimate of the slope of the plot in terms of the Hill coefficient was also obtained. IC50Calculation:With y = estimated response UB = upper bound LB = lower bound h = Hill slope of curve CONC = concentration

[0059] Used in “Lexis Dose Response Curve Fitting” Version 1.0. Resultant MALT1_Biochemical activity (Ac-LRSR-AMC) IC50, 0.014 (µM) Biological Example 2 GloSensor reporter MALT1-mediated cleavage In Jurkat Cells

[0060] MALT1 GloSensorTMis a split luciferase reporter, which utilizes a genetically modified form of firefly luciferase (CP UltraGlo) split into 2 distinct domains by insertion of a RelB MALT1 cleavage site sequence PRLVSRGA. MALT1-induced cleavage allows for a conformational change that reestablishes a functional luciferase protein resulting in luminescence, and hence luciferase activity would be a surrogate of endogenous MALT1 protease activity. Jurkat MALT1 GloSensorTMwere generated by electroporation and, selected and maintained in the presence of 0.5 mg / mL Geneticin. MALT1 protease is basally inactive inJurkat cells and can be activated by treatment with PMA / Ionomycin. Small molecule MALT1 inhibitors added prior to PMA / Ionomycin addition prevent MALT1 protease activation and, therefore, the cleavage of the MALT1 GloSensor split luciferase reporter in a dose-dependent manner.

[0061] Jurkat MALT1 GloSensorTMcells were maintained in complete RPMI 1640 media containing 10% fetal bovine serum, 10mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), 100 units / mL of penicillin, 100 µg / mL of streptomycin and 0.5 mg / mL Geneticin. Prior to the assay, compounds were made 2.5-fold serial dilutions in DMSO. 100 nL of of test compounds were spotted per well of 384-well plates (Perkin Elmer, catalogue number 6007688). Jurkat cells were harvested by centrifuge at 1200 RPM for 5 min and suspended in fresh complete RPMI 1640 media with 2% GloSensor™ cAMP Reagent and preincubated for 45-60 minutes at 37 °C in a 5% CO2incubator. A volume of 50 uL of preincubated Jurkat MALT1 GloSensorTMcells (1 x 105cells) were seeded in each well of 384-well plate. Next, a volume 2 µL of diluted PMA / Ionomycin (2.5 mg / mL / 25 µM respectively, Sigma, catalogue number P1585 and 407953) in DMSO were added to each well. After incubation at 37 °C in 5% CO2incubator for 4 h, luminescence was measured on the Envision (Perkin Elmer) at 37 °C. IC50values were calculated using SmartFit in GeneData ScreenerÒ: . SmartFit uses the 4p curve fit equation seen below:Where: x = concentration y = activity S0= activity at bottom plateau of curve Sinf= activity at top plateau of curve S50= inflection point, halfway between S0and Sinfh = Hill slope of curve

[0062] Resultant Jurkat MALT1 GloSensor™ IC50 was 0.0034 mM. Biological Example 3 Human IL-6 / IL-10 Mesoscale Assay

[0063] OCI-Ly3 cells were propagated in RPMI-1640 (Sigma Aldrich) supplemented with 10% fetal bovine serum (HyClone), 2 mM L-glutamine (Sigma Aldrich) and 1% PenStrep (Sigma Aldrich). Cell passage number should not exceed 30. Cells should be kept between 0.5 – 1.5 million cells per mL during culturing.

[0064] For the Mesoscale assay, 100,000 OCI-Ly3 cells were seeded per well into black- colored 96-well plates with clear bottom (Corning®#3904) and test compounds were added in 9 dilution steps (1:2) ranging from 15 µM to 58.6 nM (final DMSO concentration 0.3%). DMSO control wells were used to determine the maximum signal (High Control (HC)). Treatment with reference compounds at an appropriate dose served as positive control for MALT1 inhibition and was used to determine the maximum inhibition (Low Control (LC)). Compounds and cells were incubated for 24 h at 37 °C and 5% CO2(assay volume is 150 µL). After 24 h of incubation 50 µL of the supernatant was transferred to an MSD plate (V-Plex Proinflammation Panel 1 (human) kit, Mesoscale (MSD)) and incubated for 2 h with vigorous shaking (600 rpm) at room temperature. Following incubation, plates were washed 3x with phosphate-buffered saline (PBS) + 0.05% Tween-20 and 25 µL detection antibody solution (IL- 6 & IL-10 antibodies in diluent 3 (MSD)) was added per well followed by 2 h of incubation with vigorous shaking (600 rpm) at room temperature. After 3x washes with PBS + 0.05% Tween-20, plates were incubated with 150 µL 2x Read Buffer T and read on SECTOR imager. Resultant data are shown in Table 1. Human IL6 Mesoscale assay (OCI-Ly3) Human IL10 Mesoscale assay (OCI-Ly3) IC50 (µM) IC50 (µM) 0.019 0.017 Biological Example 4 Proliferation Assays

[0065] OCI-Ly3 cells were propagated in RPMI-1640 with Glutamax (ThermoFisher) supplemented with 10% heat inactivated fetal bovine serum (ThermoFisher). Cells should be kept between 0.2 – 1.5 million cells per mL and passed every 3-4 days during culturing. OCI- Ly7 cells were propagated in IMDM (ThermoFisher) supplemented with 10% fetal bovine serum (HyClone), 2 mM L-glutamine (Sigma Aldrich) and 50 µg / mL Gentamycin. Cells should be kept between 0.15 – 3 million cells per mL and passed every 3-4 days during culturing. Cell passage numbers should not exceed 20.

[0066] To assess anti-proliferative effects, 450 nL of test compounds were spotted per well of U-bottom 96-well plates (Corning®, #3975).500 OCI-Ly3 or OCI-Ly7 cells were seeded in 150 µL media per well and incubated for 8 days at 37 °C and 5% CO2. Cell plating numbers were chosen based on growth curves to ensure linear cell growth. After 8 days of incubation, 100 µL of the plated cells were resuspended up and down by pipette and transferred to a flat bottom black plate (Corning®, #3904).50 µL CellTiterGLO reagent (Promega) were added to each well and luminescence was measured on Envision (Perkin Elmer) after 10 minutes shaking at 300 rpm followed by 10 minutes of incubation at room temperature in the dark.

[0067] IC50values were calculated using SmartFit in GeneData Screener: . SmartFit uses the 4p curve fit equation seen below:Where: x = concentration y = activity S0= activity at bottom plateau of curve Sinf = activity at top plateau of curve S50= inflection point, halfway between S0and Sinfh = Hill slope of curve

[0068] Resultant data are shown in Table 2:Anti-proliferation: OCI-Ly3 Anti-proliferation: OCI-Ly7 IC50 (µM) IC50 (µM) 0.043 5.0 ASPECTS 1. An aspect of the invention is a process for the synthesis of (1S,3R)-3-(4-((R)-2-chloro-8- methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6- yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1- carboxamide comprising the steps of process 1, process 2, or process 3, wherein: process 1 is isolation of a precipitate of (R)-1-benzyl-4-methyl-4-(trifluoromethyl)pyrrolidin- 3-one and a resolving agent comprising the steps of: a) contacting a mixture of (R) and (S) 1-benzyl-4-methyl-4-(trifluoromethyl)pyrrolidin-3- one with a resolving agent in the presence of a solvent to form a reaction mixture; b) allowing a precipitate to form in the reaction mixture; c) filtering the reaction mixture to isolate the precipitate formed in step b) of process 1; process 2 is preparation of 1-benzyl-3-methyl-3-(trifluoromethyl)pyrrolidine-2,4-dione by means of a process comprising contacting a solution of 1-benzyl-3-methylpyrrolidine-2,4-dione with CF3I, and Na2S2O4, in the presence of a baseprocess 3 is isolation of a precipitate of (1S,3R)-3-(4-bromophenyl)-2,2-difluoro-1- methylcyclopropane-1-carboxylic acid and a resolving agent comprising the steps of: a) contacting a mixture of (1S,3R)-3-(4-bromophenyl)-2,2-difluoro-1-methylcyclopropane- 1-carboxylic acid and (1R,3S)-3-(4-bromophenyl)-2,2-difluoro-1-methylcyclopropane-1- carboxylic acid with a resolving agent in the presence of a solvent to form a reaction mixture; b) allowing a precipitate to form in the reaction mixture; c) filtering the reaction mixture to isolate the precipitate formed in step b) of process 3.2. An aspect of the invention is the process of aspect 1, wherein the resolving agent in process 1 is di-p-toluoyl-L-tartaric acid. 3. An aspect of the invention is the process of aspect 1 or 2, wherein the solvent in process 1 is methanol, ethanol, 1-propanol, 1-butanol, 2-propanol, methyl ethyl ketone, acetonitrile, ethyl acetate, isopropyl acetate, in particular acetonitrile. 4. An aspect of the invention is the process of any one of the preceding aspects, wherein the base in process 2 is NaH or potassium carbonate, in particular potassium carbonate. 5. An aspect of the invention is the process of any one of the preceding aspects, wherein the solution in process 2 comprises dimethyl formamide. 6. An aspect of the invention is the process of any one of the preceding aspects, wherein the solution in process 2 further comprises water. 7. An aspect of the invention is the process of any one of the preceding aspects, wherein the solution in process 2 is contacted at a temperature of about -5.5 °C. 8. An aspect of the invention is the process of any one of the preceding aspects, wherein the resolving agent in process 3 is (R)-1-cyclohexylethan-1-amine. 9. An aspect of the invention is the process of any one of the preceding aspects, wherein the solvent in process 3 comprises acetonitrile. 10. An aspect of the invention is the process of any one of the preceding aspects, wherein the solvent in process 3 further comprises methyl ethyl ketone. 11. An aspect of the invention is a process for the isolation of a precipitate of (R)-1-benzyl-4- methyl-4-(trifluoromethyl)pyrrolidin-3-one and a resolving agent comprising the steps of: a) contacting a mixture of (R) and (S) 1-benzyl-4-methyl-4-(trifluoromethyl)pyrrolidin-3- one with a resolving agent in the presence of a solvent to form a reaction mixture; b) allowing a precipitate to form in the reaction mixture; c) filtering the reaction mixture to isolate the precipitate formed in step b). 12. An aspect of the invention is the process of aspect 11, wherein the resolving agent is di-p- toluoyl-L-tartaric acid. 13. An aspect of the invention is the process of aspect 11 or 12, wherein the solvent is methanol, ethanol, 1-propanol, 1-butanol, 2-propanol, methyl ethyl ketone, acetonitrile, ethyl acetate, isopropyl acetate, in particular acetonitrile.14. An aspect of the invention is the process of aspect 11, 12 or 13 wherein the precipitate is isolated in at least 85% diastereomeric excess. 15. An aspect of the invention is a complex of (R)-1-benzyl-4-methyl-4- (trifluoromethyl)pyrrolidin-3-one and di-p-toluoyl-L-tartaric acid. 16. An aspect of the invention is a process for the preparation of 1-benzyl-3-methyl-3- (trifluoromethyl)pyrrolidine-2,4-dione comprising contacting a solution of 1-benzyl-3- methylpyrrolidine-2,4-dione with CF3I, and Na2S2O4, in the presence of a base. 17. An aspect of the invention is the process of aspect 16, wherein the base is NaH or potassium carbonate, in particular potassium carbonate. 18. An aspect of the invention is the process of aspect 16 or 17, wherein the solution comprises dimethyl formamide. 19. An aspect of the invention is the process of aspect 16, 17 or 18, wherein the solution further comprises water. 20. An aspect of the invention is the process of any one of aspects 16-19, wherein the solution is contacted at a temperature of about -5.5 °C. 21. An aspect of the invention is the process of any one of aspects 16-20, wherein the 1-benzyl- 3-methyl-3-(trifluoromethyl)pyrrolidine-2,4-dione is prepared in at least 80% yield. 22. An aspect of the invention is a process for the isolation of a precipitate of (1S,3R)-3-(4- bromophenyl)-2,2-difluoro-1-methylcyclopropane-1-carboxylic acid and a resolving agent comprising the steps of: a) contacting a mixture of (1S,3R)-3-(4-bromophenyl)-2,2-difluoro-1-methylcyclopropane- 1-carboxylic acid and (1R,3S)-3-(4-bromophenyl)-2,2-difluoro-1-methylcyclopropane-1- carboxylic acid with a resolving agent in the presence of a solvent to form a reaction mixture; b) allowing a precipitate to form in the reaction mixture;c) filtering the reaction mixture to isolate the precipitate formed in step b). 23. An aspect of the invention is the process of aspect 22, wherein the resolving agent is (R)-1- cyclohexylethan-1-amine. 24. An aspect of the invention is the process of aspect 22 or 23, wherein the solvent comprises acetonitrile. 25. An aspect of the invention is the process of aspect 22, 23 or 24, wherein the solvent further comprises methyl ethyl ketone. 26. An aspect of the invention is the process of aspect 22, 23, 24 or 25, wherein the precipitate is isolated in at least 90% diastereomeric excess. 27. An aspect of the invention is a complex of (1S,3R)-3-(4-bromophenyl)-2,2-difluoro-1- methylcyclopropane-1-carboxylic acid and (R)-1-cyclohexylethan-1-amine.

[0069] While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and / or modifications as come within the scope of the following claims and their equivalents.

Claims

Claims 1. A process for the synthesis of (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8- dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N- ((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide comprising the steps of process 1, process 2, or process 3, wherein: process 1 is isolation of a precipitate of (R)-1-benzyl-4-methyl-4-(trifluoromethyl)pyrrolidin- 3-one and a resolving agent comprising the steps of: a) contacting a mixture of (R) and (S) 1-benzyl-4-methyl-4-(trifluoromethyl)pyrrolidin-3- one with a resolving agent in the presence of a solvent to form a reaction mixture; b) allowing a precipitate to form in the reaction mixture; c) filtering the reaction mixture to isolate the precipitate formed in step b) of process 1; process 2 is preparation of 1-benzyl-3-methyl-3-(trifluoromethyl)pyrrolidine-2,4-dione by means of a process comprising contacting a solution of 1-benzyl-3-methylpyrrolidine-2,4-dioneprocess 3 is isolation of a precipitate of (1S,3R)-3-(4-bromophenyl)-2,2-difluoro-1- methylcyclopropane-1-carboxylic acid and a resolving agent comprising the steps of: a) contacting a mixture of (1S,3R)-3-(4-bromophenyl)-2,2-difluoro-1-methylcyclopropane- 1-carboxylic acid and (1R,3S)-3-(4-bromophenyl)-2,2-difluoro-1-methylcyclopropane-1- carboxylic acid with a resolving agent in the presence of a solvent to form a reaction mixture; b) allowing a precipitate to form in the reaction mixture; c) filtering the reaction mixture to isolate the precipitate formed in step b) of process 3.

2. The process of claim 1, wherein the resolving agent in process 1 is di-p-toluoyl-L-tartaric acid.

3. The process of claim 1 or 2, wherein the solvent in process 1 is methanol, ethanol, 1-propanol,1-butanol, 2-propanol, methyl ethyl ketone, acetonitrile, ethyl acetate, isopropyl acetate, in particular acetonitrile.

4. The process of any one of the preceding claims, wherein the base in process 2 is NaH or potassium carbonate, in particular potassium carbonate.

5. The process of any one of the preceding claims, wherein the solution in process 2 comprises dimethyl formamide.

6. The process of any one of the preceding claims, wherein the solution in process 2 further comprises water.

7. The process of any one of the preceding claims, wherein the solution in process 2 is contacted at a temperature of about -5.5 °C.

8. The process of any one of the preceding claims, wherein the resolving agent in process 3 is (R)-1-cyclohexylethan-1-amine.

9. The process of any one of the preceding claims, wherein the solvent in process 3 comprises acetonitrile.

10. The process of any one of the preceding claims, wherein the solvent in process 3 further comprises methyl ethyl ketone.

11. A process for the isolation of a precipitate of (R)-1-benzyl-4-methyl-4- (trifluoromethyl)pyrrolidin-3-one and a resolving agent comprising the steps of: a) contacting a mixture of (R) and (S) 1-benzyl-4-methyl-4-(trifluoromethyl)pyrrolidin-3- one with a resolving agent in the presence of a solvent to form a reaction mixture; b) allowing a precipitate to form in the reaction mixture; c) filtering the reaction mixture to isolate the precipitate formed in step b).

12. The process of claim 11, wherein the resolving agent is di-p-toluoyl-L-tartaric acid.

13. The process of claim 11 or 12, wherein the solvent is methanol, ethanol, 1-propanol, 1- butanol, 2-propanol, methyl ethyl ketone, acetonitrile, ethyl acetate, isopropyl acetate, in particular acetonitrile.

14. The process of claim 11, 12 or 13 wherein the precipitate is isolated in at least 85% diastereomeric excess.

15. A complex of (R)-1-benzyl-4-methyl-4-(trifluoromethyl)pyrrolidin-3-one and di-p-toluoyl- L-tartaric acid.

16. A process for the preparation of 1-benzyl-3-methyl-3-(trifluoromethyl)pyrrolidine-2,4- dione comprising contacting a solution of 1-benzyl-3-methylpyrrolidine-2,4-dione with CF3I,.

17. The process of claim 16 wherein the base is NaH or potassium carbonate, in particular potassium carbonate.

18. The process of claim 16 or 17, wherein the solution comprises dimethyl formamide.

19. The process of claim 16, 17 or 18, wherein the solution further comprises water.

20. The process of claim 16, 17, 18 or 19, wherein the solution is contacted at a temperature of about -5.5 °C.

21. The process of any one of claims 16-20, wherein the 1-benzyl-3-methyl-3- (trifluoromethyl)pyrrolidine-2,4-dione is prepared in at least 80% yield.

22. An aspect of the invention is a process for the isolation of a precipitate of (1S,3R)-3-(4- bromophenyl)-2,2-difluoro-1-methylcyclopropane-1-carboxylic acid and a resolving agent comprising the steps of: a) contacting a mixture of (1S,3R)-3-(4-bromophenyl)-2,2-difluoro-1-methylcyclopropane- 1-carboxylic acid and (1R,3S)-3-(4-bromophenyl)-2,2-difluoro-1-methylcyclopropane-1- carboxylic acid with a resolving agent in the presence of a solvent to form a reaction mixture; b) allowing a precipitate to form in the reaction mixture; c) filtering the reaction mixture to isolate the precipitate formed in step b).

23. The process of claim 22, wherein the resolving agent is (R)-1-cyclohexylethan-1-amine.

24. The process of claim 22 or 23, wherein the solvent comprises acetonitrile.

25. The process of claim 22, 23 or 24, wherein the solvent further comprises methyl ethyl ketone.

26. The process of claim 22, 23, 24 or 25, wherein the precipitate is isolated in at least 90% diastereomeric excess.

27. A complex of (1S,3R)-3-(4-bromophenyl)-2,2-difluoro-1-methylcyclopropane-1-carboxylicacid and (R)-1-cyclohexylethan-1-amine.

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