Cinsebrutinib

CAS 2724962-58-5

2-fluoro-1-[(3S)-1-prop-2-enoylpiperidin-3-yl]-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxamide

• 2-fluoro-1-[(3S)-1-(prop-2-enoyl)piperidin-3-yl]-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxamide
• 2-fluoro-1-[(3S)-1-prop-2-enoylpiperidin-3-yl]-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxamide

CINSEBRUTINIB is a small molecule drug with a maximum clinical trial phase of II and has 1 investigational indication.

Cinsebrutinib is a Bruton’s tyrosine kinase inhibitor, extracted from patent WO2021207549 (compound 5-6). Cinsebrutinib has the potential for cancer study.

SCHEME

INTERMEDIATE

MAIN

SYN

example 5-6 [WO2021207549A1]

5-6 enantiomer A [WO2021207549A1]

GB005, Inc. WO2021207549
WO2021207549

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021207549&_cid=P22-MAAYAJ-91905-1

EXAMPLES 5-5, 5-6, 5-7

Preparation of rac-1-(1-acryloylpiperidin-3-yl)-2-fluoro-5,6,7,8,9,10-hexahydrocyclo- hepta[b]indole-4-carboxamide (Compound 5-5), (S)-1-(1-acryloylpiperidin-3-yl)-2-fluoro-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxamide (Compound 5-6) and (R)-1-(1-acryloylpiperidin-3-yl)-2-fluoro-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4- carboxamide (Compound 5-7)

STEP 1: 5-bromo-4-fluoro-2-iodoaniline

To a solution of 3-bromo-4-fluoroaniline (100.0 g, 526.3 mmol) in acetic acid (500 mL) was added N-iodosuccinimide (124.3 g, 552.5 mmol) in portions at 25 °C.

The reaction mixture was stirred for 2 hours at 25 °C. The mixture was concentrated under vacuum. The residue was diluted with saturated aqueous sodium carbonate (500 mL) and extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with water (500 mL) and brine (500 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was triturated with mixed solvents of ethyl acetate and petroleum ether (300 mL, 1:4, v/v) and filtered. The solid was washed with mixed solvents of ethyl acetate and petroleum ether (50 mL x 2, 1:4, v/v) and dried under reduced pressure to give 5-bromo-4-fluoro-2-iodoaniline (88.6 g, 53%) as a light blue solid.¹H NMR (300 MHz, DMSO-d6) δ 7.55 (d, J = 8.1 Hz, 1H), 6.98 (d, J = 6.3 Hz, 1H), 5.27 (brs, 2H).

STEP 2: (5-bromo-4-fluoro-2-iodophenyl)hydrazine hydrochloride

To a stirred suspension of 5-bromo-4-fluoro-2-iodoaniline (88.6 g, 280.5 mmol) in concentrated hydrochloric acid (443 mL) was added dropwise a solution of sodium nitrite (23.22 g, 337.0 mmol) in water (90 mL) at 0 °C. After stirring for 1 hour at 0 °C, the resulting mixture was added dropwise to a solution of stannous chloride dihydrate (126.61 g, 561.1 mmol) in concentrated hydrochloric acid (295 mL) at 0 °C and stirred for 1 hour at this temperature. The precipitate was collected by filtration, washed with concentrated hydrochloric acid (150 mL x 5) and ethyl acetate (300 mL), dried under reduced pressure to give (5-bromo-4-fluoro-2-iodophenyl)hydrazine hydrochloride (100.3 g, crude) as a light yellow solid.¹H NMR (400 MHz, DMSO-d6) δ 10.23 (brs, 3H), 7.89 (d, J = 8.0 Hz, 1H), 7.82 (brs, 1H), 7.31-7.22 (m, 1H).

STEP 3: 1-(5-bromo-4-fluoro-2-iodophenyl)-2-cycloheptylidenehydrazine To a solution of (5-bromo-4-fluoro-2-iodophenyl)hydrazine hydrochloride (80.0 g, 217.6 mmol) in methanol (400 mL) was added cycloheptanone (24.40 g, 217.6 mmol) at 20 °C. The reaction mixture was stirred for 1 hour at 20 °C. The precipitate was collected by filtration and dried under reduced pressure to give 1-(5-bromo-4-fluoro-2-iodophenyl)-2-cycloheptylidenehydrazine (72.0 g, 78%) as an off-white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 7.77 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 6.8 Hz, 1H), 7.39 (brs, 1H), 2.50-2.44 (m, 4H), 1.80-1.67 (m, 2H), 1.64-1.48 (m, 6H).

STEP 4: 1-bromo-2-fluoro-4-iodo-5,6,7,8,9,10-hexahydrocyclohepta[b]indole A mixture of 1-(5-bromo-4-fluoro-2-iodophenyl)-2-cycloheptylidenehydrazine (72.0 g, 169.4 mmol) and concentrated sulfuric acid (18 mL) in methanol (360 mL) was stirred for 16 hours at 80 °C. The methanol was removed under reduced pressure. The residue was basified with saturated aqueous sodium carbonate until pH = 10 and extracted with ethyl acetate (600 mL x 3). The combined organic layers were washed with water (500 mL x 2) and brine (500 mL), dried over anhydrous sodium sulfate and

filtered. The filtrate was concentrated under vacuum to give 1-bromo-2-fluoro-4-iodo-5,6,7,8,9,10-hexahydrocyclohepta[b]indole (43.0 g, 80% purity, 50%) as a brown solid.

¹H NMR (300 MHz, DMSO-d6) δ 10.95 (s, 1H), 7.37 (d, J = 8.7 Hz, 1H), 3.23-3.15 (m, 2H), 2.94-2.85 (m, 2H), 1.89-1.76 (m, 2H), 1.72-1.58 (m, 4H).

STEP 5: 1-bromo-2-fluoro-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4- carbonitrile

A mixture of 1-bromo-2-fluoro-4-iodo-5,6,7,8,9,10-hexahydrocyclohepta[b]indole (43.0 g, 80% purity, 84.3 mmol), zinc cyanide (4.95 g, 42.2 mmol) and tetrakis(triphenylphosphine)palladium (9.74 g, 8.4 mmol) in N,N-dimethylformamide (215 mL) was degassed and backfilled with nitrogen for three times. The reaction mixture was stirred under nitrogen at 90 °C for 2 hours. The cooled reaction mixture was diluted with water (1 L) and extracted with ethyl acetate (800 mL x 3). The combined organic layers were washed with water (500 mL x 3) and brine (800 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was triturated with acetonitrile (100 mL) and filtered. The solid was washed with acetonitrile (30 mL x 2) and dried under reduced pressure to give 1-bromo-2-fluoro-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carbonitrile (25.5 g, 94%) as a light yellow solid. ESI-MS [M-H]- calculated for (C14H12BrFN2) 305.02, 307.02, found: 304.95, 306.95.¹H NMR (300 MHz, DMSO-d₆) δ 11.99 (s, 1H), 7.58 (d, J = 9.0 Hz, 1H), 3.24-3.17 (m, 2H), 2.91-2.85 (m, 2H), 1.87-1.78 (m, 2H), 1.70-1.61 (m, 4H).

STEP 6: Tert-butyl 5-(4-cyano-2-fluoro-5,6,7,8,9,10- hexahydrocyclohepta[b]indol-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate A mixture of 1-bromo-2-fluoro-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carbonitrile (25.0 g, 81.4 mmol), tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (30.2 g, 97.7 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (5.96 g, 8.1 mmol) and potassium phosphate (51.8 g, 244.2 mmol) in tetrahydrofuran (125 mL) and water (31 mL) was degassed and backfilled with nitrogen for three times and stirred for 2 hours at 60 °C under nitrogen atmosphere. The cooled mixture was diluted with water (600 mL) and extracted with ethyl acetate (500 mL x 3). The combined organic layers was washed with water (500 mL x 2) and brine (500 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give tert-butyl 5-(4-cyano-2-fluoro-5,6,7,8,9,10-hexahydrocyclohepta[b]indol-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate (45 g, crude) as a brown solid, which was used directly in next step without purification. ESI-MS [M+H-tBu]⁺ calculated for (C₂₄H₂₈FN₃O₂) 354.22, found: 354.05.

STEP 7: Tert-butyl 5-(4-carbamoyl-2-fluoro-5,6,7,8,9,10- hexahydrocyclohepta[b]indol-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate To a mixture of 5-(4-cyano-2-fluoro-5,6,7,8,9,10-hexahydrocyclohepta[b]indol-1-yl)-3,6-dihydro-pyridine-1(2H)-carboxylate (45 g, crude) in ethanol (100 mL), tetrahydrofuran (100 mL) and water (100 mL) was added Parkin’s catalyst (2.0 g, 4.68 mmol). The reaction mixture was stirred for 16 hours at 90 °C. The cooled mixture was diluted with water (500 mL) and extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with water (500 mL x 2) and brine (500 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel eluting with ethyl acetate in petroleum ether (0 to 60%) to give tert-butyl 5-(4-carbamoyl-2-fluoro-5,6,7,8,9,10-hexahydrocyclohepta[b]indol-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate (20.0 g, 57% over two steps) as a light yellow solid. ESI-MS [M+H]⁺ calculated for (C24H30FN3O3) 428.23, found: 428.15.¹H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 8.02 (s, 1H), 7.46-7.38 (m, 2H), 5.79 (s, 1H), 4.10-3.97 (m, 1H), 3.95-3.83 (m, 1H), 3.80-3.57 (m, 1H), 3.51-3.23 (m, 1H), 2.99-2.85 (m, 2H), 2.82-2.69 (m, 2H), 2.30-2.21 (m, 2H), 1.86-1.72 (m, 2H), 1.70-1.50 (m, 4H), 1.41 (s, 9H).

STEP 8: Tert-butyl 3-(4-carbamoyl-2-fluoro-5,6,7,8,9,10- hexahydrocyclohepta[b]indol-1-yl)piperidine-1-carboxylate

To a solution of tert-butyl 5-(4-carbamoyl-2-fluoro-5,6,7,8,9,10-hexahydrocyclohepta[b]indol-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate (20 g, 46.8 mmol) in ethanol (300 mL) and tetrahydrofuran (300 mL) was added 10% Pd/C (15.0 g) under nitrogen atmosphere. The reaction mixture was degassed and backfilled with hydrogen for three times and stirred for 4 days at 50 °C under hydrogen (2 atm). The cooled mixture was filtered. The filtrate was concentrated under vacuum. The residue was recrystallized with tetrahydrofuran (100 mL) and petroleum ether (100 mL) to give tert-butyl 3-(4-carbamoyl-2-fluoro-5,6,7,8,9,10-hexahydrocyclohepta[b]indol-1-yl)piperidine-1-carboxylate (12.1 g, 60%) as an off-white solid. ESI-MS [M+H]⁺ calculated for (C₂₄H₃₂FN₃O₃) 430.24, found: 430.25.¹H NMR (400 MHz, DMSO-d₆) δ 10.75 (s, 1H), 8.00 (s, 1H), 7.46-7.35 (m, 2H), 4.17-3.86 (m, 2H), 3.55-3.43 (m, 1H), 3.31-3.10 (m, 1H), 3.08-2.63 (m, 5H), 2.14-1.96 (m, 1H), 1.93-1.60 (m, 9H), 1.39 (s, 9H).

STEP 9: 2-fluoro-1-(piperidin-3-yl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole- 4-carboxamide hydrochloride

Tert-butyl 3-(4-carbamoyl-2-fluoro-5,6,7,8,9,10-hexahydrocyclohepta[b]indol-1-yl)piperidine-1-carboxylate (12.1 g, 28.2 mmol) was dissolved in hydrogen chloride (150 mL, 4 M in 1,4-dioxane) and the solution was stirred for 2 hours at 25 °C. The mixture was concentrated under vacuum to give 2-fluoro-1-(piperidin-3-yl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxamide hydrochloride (13.4 g, crude) as a yellow solid. ESI-MS [M+H]⁺ calculated for (C₁₉H₂₄FN₃O) 330.19, found: 330.10.

STEP 10: 1-(1-acryloylpiperidin-3-yl)-2-fluoro-5,6,7,8,9,10- hexahydrocyclohepta[b]indole-4-carboxamide

To a mixture of 2-fluoro-1-(piperidin-3-yl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxamide hydrochloride (13.4 g, crude) and sodium bicarbonate (23.7 g, 282.0 mmol) in tetrahydrofuran (300 mL) and water (150 mL) was added acryloyl chloride (2.81 g, 31.0 mmol) at 0 °C. After stirring for 1 hour at 0 °C, the mixture was diluted with water (500 mL) and extracted with ethyl acetate (400 mL x 3). The combined organic layers were washed with water (500 mL x 2) and brine (500 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was recrystallized with tetrahydrofuran (290 mL), methanol (48 mL) and petroleum ether (330 mL) to give 1-(1-acryloylpiperidin-3-yl)-2-fluoro-

5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxamide (6.0 g, 56% over two steps) as a white solid. ESI-MS [M+H]⁺ calculated for (C₂₂H₂₆FN₃O₂) 384.20, found: 384.15.

STEP 11: (S)-1-(1-acryloylpiperidin-3-yl)-2-fluoro-5,6,7,8,9,10- hexahydrocyclohepta[b]indole-4-carboxamide and (R)-1-(1-acryloylpiperidin-3- yl)-2-fluoro-5,6,7,8,9,10-hexahydrocyclohepta[b]-indole-4-carboxamide

1-(1-acryloylpiperidin-3-yl)-2-fluoro-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxamide (6.0 g) was separated by Prep-SFC with the following conditions: Column: (R,R)-Whelk-01, 2.12 x 25 cm, 5 um; Mobile Phase A: CO₂, Mobile Phase B: IPA/DCM = 5:1; Flow rate: 200 mL/min; Gradient: 50% B; 220 nm; Injection Volume: 19 mL; Number Of Runs: 29; RT1: 4.97 min to afford assumed (S)-1-(1-acryloylpiperidin-3-yl)-2-fluoro-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxamide (2.55 g, 43%) as an off-white solid and RT2: 8.2 min to afford assumed (R)-1-(1-acryloylpiperidin-3-yl)-2-fluoro-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxamide (2.63 g, 44%) as an off-white solid.

Compound 5-6

ESI-MS [M+H]⁺ calculated for (C₂₂H₂₆FN₃O₂) 384.20, found: 384.20.¹H NMR (300 MHz, DMSO-d6) δ 10.75 (s, 1H), 8.00 (s, 1H), 7.49-7.31 (m, 2H), 6.93-6.72 (m, 1H), 6.18-6.02 (m, 1H), 5.73-5.56 (m, 1H), 4.67-4.42 (m, 1H), 4.27-4.05 (m, 1H), 3.63-3.41 (m, 1.5H), 3.19-3.02 (m, 1H), 3.00-2.79 (m, 4H), 2.70-2.62 (m, 0.5H), 2.21-2.02 (m, 1H), 2.01-1.87 (m, 1H), 1.86-1.61 (m, 7H), 1.57-1.37 (m, 1H).

Protein kinases are a large group of intracellular and transmembrane signaling proteins in eukaryotic cells. These enzymes are responsible for transfer of the terminal (gamma) phosphate from ATP to specific amino acid residues of target proteins.

Phosphorylation of specific amino acid residues in target proteins can modulate their activity leading to profound changes in cellular signaling and metabolism. Protein kinases can be found in the cell membrane, cytosol and organelles such as the nucleus and are responsible for mediating multiple cellular functions including metabolism, cellular growth and differentiation, cellular signaling, modulation of immune responses, and cell death. Serine kinases specifically phosphorylate serine or threonine residues in target proteins. Similarly, tyrosine kinases, including tyrosine receptor kinases, phosphorylate tyrosine residues in target proteins. Tyrosine kinase families include: TEC, SRC, ABL, JAK, CSK, FAK, SYK, FER, ACK and the receptor tyrosine kinase subfamilies including ERBB, FGFR, VEGFR, RET and EPH. Subclass I of the receptor tyrosine kinase superfamily includes the ERBB receptors and comprises four members: ErbB1 (also called epidermal growth factor receptor (EGFR)), ErbB2, ErbB3 and ErbB4.

Kinases exert control on key biological processes related to health and disease. Furthermore, aberrant activation or excessive expression of various protein kinases are implicated in the mechanism of multiple diseases and disorders characterized by benign and malignant proliferation, as well as diseases resulting from inappropriate activation of the immune system. Thus, inhibitors of select kinases or kinase families are considered useful in the treatment of cancer, vascular disease, autoimmune diseases, and inflammatory conditions including, but not limited to: solid tumors, hematological malignancies, thrombus, arthritis, graft versus host disease, lupus erythematosus, psoriasis, colitis, illeitis, multiple sclerosis, uveitis, coronary artery vasculopathy, systemic sclerosis, atherosclerosis, asthma, transplant rejection, allergy, ischemia, dermatomyositis, pemphigus, and the like.

Tec kinases are a family of non-receptor tyrosine kinases predominantly, but not exclusively, expressed in cells of hematopoietic origin. The Tec family includes TEC, Bruton’s tyrosine kinase (BTK), inducible T-cell kinase (ITK), resting lymphocyte kinase (RLK/TXK for Tyrosine Protein Kinase), and bone marrow-expressed kinase (BMX/ETK).

BTK is important in B-cell receptor signaling and regulation of B-cell development and activation. Mutation of the gene encoding BTK in humans leads to X-linked agammaglobulinemia which is characterized by reduced immune function, including impaired maturation of B-cells, decreased levels of immunoglobulin and peripheral B cells, and diminished T-cell independent immune response. BTK is activated by Src-family kinases and phosphorylates PLC gamma leading to effects on B-cell function and survival. Additionally, BTK is important for cellular function of mast cells, macrophage and neutrophils indicating that BTK inhibition is effective in treatment of diseases mediated by these and related cells including inflammation, bone disorders, and allergic disease. BTK inhibition is also important in survival of lymphoma cells indicating that inhibition of BTK is useful in the treatment of lymphomas and other cancers. As such, inhibitors of BTK and related kinases are of great interest as anti-inflammatory, as well as anti-cancer, agents. BTK is also important for platelet function and thrombus formation indicating that BTK-selective inhibitors are also useful as antithrombotic agents. Furthermore, BTK is required for inflammasome activation, and inhibition of BTK may be used in treatment of inflammasome-related disorders, including; stroke, gout, type 2 diabetes, obesity-induced insulin resistance, atherosclerosis and Muckle-Wells syndrome. In addition, BTK is expressed in HIV infected T-cells and treatment with BTK inhibitors sensitizes infected cells to apoptotic death and results in decreased virus production. Accordingly, BTK inhibitors are considered useful in the treatment of HIV-AIDS and other viral infections.

Further, BTK is important in neurological function. Specifically targeting BTK in the brain and CNS has the potential to significantly advance the treatment of neurological diseases such as progressive and relapsing forms of MS and primary CNS lymphoma (PCNSL).

PCNSL is a rare brain tumor with an annual incidence in the United States of approximately 1900 new cases each year and constitutes approximately 3% of all newly diagnosed brain tumors.

PCNSL is highly aggressive and unlike other lymphomas outside the CNS, prognosis remains poor despite improvements in treatments in the front-line setting. High dose methotrexate remains the backbone of treatment and is used in combination with other cytotoxic agents, and more recently the addition of rituximab. From initial diagnosis, 5-year survival has improved from 19% to 30% between 1990 and 2000 but has not improved in the elderly population (>70 years), due to 20% or more of these patients being considered unfit for chemotherapy. Tumor regression is observed in ~85% of patients regardless of the treatment modality in the front-line setting, however, approximately half of these patients will experience recurrent disease within 10 -18 months after initial treatment and most relapses occur within the first 2 years of diagnosis.

Thus, the prognosis for patients with relapsed/refractory PCNSL (R/R PCNSL) remains poor with a median survival of ~ 2 months without further treatment. As there is no uniform standard of care for the treatment of R/R PCNSL, participation in clinical trials is encouraged. New safe and effective treatments are urgently needed.

BTK is involved in the signal transduction in the B cell antigen receptor (BCR) signaling pathway and integrates BCR and Toll-like receptor (TLR) signaling. Genes in these pathways frequently harbor mutations in diffuse large B-cell lymphoma (DLBCL), including CD79B and myeloid differentiation primary response 88 (MyD88). Ibrutinib, a first-generation irreversible selective inhibitor of BTK, has been approved for chronic lymphocytic leukemia/small cell lymphocytic lymphoma (CLL/SLL), previously treated Mantle Cell lymphoma (MCL) and Marginal Zone

Lymphoma (MZL), Waldenström’s macroglobulin, and previously treated chronic Graft Versus Host Disease. In clinical studies the recommended dose of Ibrutinib (480 mg/d in CLL or 560 mg/d in MCL) was escalated to 840 mg to achieve adequate brain exposure in primary CNS lymphoma.

Aberrant activation of the NF-κB pathway in PCNSL is emerging as a potential mechanism for more targeted therapy. In particular, activating mutations of CARD11 as well as of MyD88 (Toll-like receptor pathway) have been implicated. The activating exchange of leucine to proline at position 265 of MyD88, noted to occur in between 38% (11/29) and50% (7/14) of patients, is the most frequent mutation identified thus far in PCNSL. In addition, the coding region of CD79B, a component of the B-cell receptor signaling pathway, appears to contain mutations in 20% of cases, suggesting that dysregulation of the B-cell receptor and NF-κB pathways contribute to the pathogenesis of PCNSL. These data suggest that BCR pathway mutations and BTK dependence are of particular relevance to PCNSL.

Recently, several clinical studies have reported substantial single-agent clinical activity in the treatment of PCNSL with response rates of 70-77%. The majority of patients, however, discontinued therapy by 9 months. Although Ibrutinib therapy has been reported to be generally well tolerated with manageable adverse events, there are reports of sometimes fatal fungal infections. Of note, escalating doses beyond 560 mg to 840mg/day have been used to achieve higher brain exposure and these higher doses may be associated with off-target effects mediated by Ibrutinib’s kinase selectivity profile. Finally, the combination of high dose Ibrutinib in conjunction with high-dose steroids may contribute to exacerbate the increased fungal infections. Therefore, there remains a need for BTK inhibitors with an improved efficacy and safety profile due to greater brain penetration and BTK inactivation rate with greater kinase selectivity.

There remains a need for compounds that modulate protein kinases generally, as well as compounds that modulate specific protein kinases, such as BTK, as well as compounds that modulate specific protein kinases and selectively cross the blood/brain barrier for related compositions and methods for treating diseases, disorders and conditions that would benefit from such modulation and selectivity.

[1]. Coburn, Craig Alan, et al. Preparation of pyridoindolecarboxamides and their analogs as BTK kinase inhibitors. WO2021207549.

/////////////Cinsebrutinib, 7BS8743F3E, PHASE 1