OA20759A - Benzimidazole derivatives. - Google Patents

Abstract

The invention relates to benzimidazoles of Formula (I) and pharmaceutically acceptable salts thereof, wherein R1 to R6 are as defined in the description; to their use in medicine; to compositions containing them; to processes for their preparation; and to intermediates used in such processes.

Description

BENZIMIDAZOLE DERIVATIVES

The invention relates to benzimidazole dérivatives, to their use in medicine, to compositions containing them, to processes for their préparation and to intermediates used în such processes. More especially the invention relates to inhibitors of interleukin-2-inducÎble T cell kinase (ITK) and their use in the treatment of diseases mediated by ITK, in particuiar skin diseases, such as dermatitis (e.g. atopie dermatitis).

Atopie dermatitis (AD) ts a common chronic inflammatory skin disease with a prevalence in both children and adults. AD patients suffer from dry and pruritic skin lésions which can greatly affect their quality of lîfe. Genetic and environmental factors can contribute to skin barrier disruption and immune hyper-activation which are key drivers of AD pathogenesis.

The pathogenic rôle for T cells and the Th2 cell-derived cytokines, IL-4 and IL-13, in AD has been shown through the clinical development of dupilumab, an antibody to the IL-4 receptor that blocks the activity of both IL-4 and IL-13. The important activity of these cytokines is also consistent with the early clinical efficacy that has been observed with Janus kinase (JAK) inhibitors, which block signaling of IL-4 and IL-13 as well as additional inflammatory cytokines produced in the skin. A therapeutic strategy that can effectively control the production of IL-4 and IL-13 is an alternative approach to modulate this pathway. Additionally, Th1 cells, Th22 cells, and Th17 cells and the cytokines which they produce, IFNy, IL-22, and IL-17, respectively, also contribute to AD pathogenesis.

An effective anti-inflammatory for AD would modulate the prédominant T cell driven inflammatory response. lnterleukin-2-inducible T cell kinase (ITK) is a member of the Tec family of tyrosine kinases. ITK expression is largely limited to immune cells such as T, natural kîller (NK), natural killer T (NKT), and mast cells. In T cells, ITK amplifies T cell receptor (TCR)-dependent signais to promote T cell activation, cytokine production, and T cell prolifération. ITK délétion or inhibition of ITK activity in T cells results in suppression of TCR-induced IL-4 and IL-13 production, which plays a central rôle in contributing to the pathophysiology of AD. An ITK inhibitor is expected to hâve additional efficacy compared to an antagonist of the IL-4 receptor, as ITK also

B 2 contributes to TCR-dependent production of numerous pro-inflammatory cytokines such as IL-2, IL-17, IL-22, IL-31, IFNy, and TNF-α. Additionally, ITK déficient CD8+ T cells demonstrate impaired cytotoxic T lymphocyte expansion, reduced degranulation and defective cytolytic capacity. ITK déficient mice and/or mice treated with an ITK inhibitor 5 demonstrate reduced disease in models of type I diabètes, lymphoproliférative disease, allergy/asthma, and airway hyperresponsiveness. Moreover, ITK-deficient mice or mice treated with an ITK inhibitor demonstrate reduced skin inflammation in models of dermatitis. Elevated levels of ITK were described in peripheral T cells from patients with moderate to severe AD, and ITK expression is elevated in skin lésions from AD 10 patients.

Additionally, tropomyosin receptor kinases (TRKs) are expressed by cells in the skin such as kératinocytes, neurons, mast cells, and basophils. Both TRKA and its ligand, nerve growth factor (NGF), are présent in the skin and their expression is enhanced in 15 AD skin lésions. Levels of NGF in skin lésions from AD patients hâve been demonstrated to correlate with itch severity. Cytokines IL-4 and IL-13 which contribute to AD pathogenesis hâve been demonstrated to enhance TRKA expression by kératinocytes. In addition to regulating development and maintenance of neurons, NGF can sensitize nociceptors and promote pruritis in the skin. Pruritis is a major factor 20 contributing to reduced quality of life for AD patients. A therapy which can suppress pruritis would not only provide relief for patients, but may also break the itch-scratch cycle which contributes to the barrier disruption and thus reduce the course and chronicity of the disease.

NGF is also expressed by and has effects on non-neuronal cells. NGF induces kératinocyte prolifération, promûtes basophil activation, stimulâtes mast cell degranulation, and contributes to neurogenic itch and inflammation. Furthermore, TRKA expression has been reported on TCR-stimulated peripheral blood T cells and T cells collected from synovial fluid from arthritis patients, and NGF induces prolifération of T cells. Thus, inhibiting TRKA in the skin may suppress dermal inflammation in addition to reducing pruritis.

These data suggest that an ITK inhibitor will suppress pathogenic T cell responses and reduce cytokine production, and therefore hâve therapeutic value in the treatment of a vanety of mflammatory and autoimmune diseases, including dermatological conditions, such as atopie dermatitis, contact dermatitis, psoriasis, alopecia areata, and vitiligo. Moreover an inhibitor of both ITK and TRKA activity should be of particular advantage in the treatment of dermatological conditions, such as those just mentioned (e.g. atopie dermatitis).

Référencés

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According to a first aspect of the invention there is provided a compound of Formula (I) or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait, wherein each R¹ is independently H or F;

R² is H, (Ci-C4)alkyl, hydroxy(Ci-C4)alkyl, (Ci-C₄)alkoxy(Ci-C4)alkyl or (Ci-C₄)alkyl substituted by one, two or three F;

each R³ is independently H, F, (C3-Cs)cycloalkyl, (Ci-C4)alkyl or (Ci-C4>alkyl substituted by one, two or three F; or both R³ taken together with the carbon atom to which they are attached form (Cs-Csjcycloalkyl;

o. o.

I J or I J

R⁴ is < * , wherein each heterocycie is optionally substituted by one or two substituents independently selected from oxo, (Ci-C4)alkyl, hydroxy(Ci-C₄)alkyl and (Ci-C4)alkyl substituted by one, two or three F; and

R⁵ and R⁶ are independently H; halogen; OH; CN; (Ci-C6)alkyl; hydroxy(Ci-Ce)alkyl; (Ci-C₄)alkoxy(Ci-C6)alkyl; (C-i-Csjalkyl substituted by one, two or three F; (Ci-Ce)alkoxy; □r (Ci-Cejalkoxy substituted by (Ci-C₄)alkoxy.

Described below are embodiments of this first aspect of the invention, where for convenience E1 is identical thereto.

E1 A compound of Formula (I) or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait, as defined above.

E2 A compound according to embodiment E1 or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait, wherein each R¹ is H or F.

E3 A compound according to embodiment E2 or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait, wherein each R¹ is H.

E4 A compound according to any one of embodiments E1 to E3 or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound orsaid sait, wherein R² is H or (Ci-C4)alkyl.

E5 A compound according to embodiment E4 or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait, wherein R² is H.

E6 A compound according to embodiment E4 or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait, wherein R² is methyl or ethyl.

E7 A compound according to embodiment E6 or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait, wherein R² is methyl.

E8 A compound according to embodiment E6 or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait, wherein R² is ethyl.

E9 A compound according to any one of embodiments El to E8 or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait, wherein each R³ is independently H, F or (Ci-C4)alkyl.

E10 A compound according to embodiment E9 or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait, wherein each R³ is independently H, F or methyl.

E11 A compound according to embodiment E10 or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait, wherein each R³ is F.

E12 A compound according to embodiment E10 or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait, wherein each R³ is H.

E13 A compound according to embodiment E10 or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait, wherein one R³ is H and the other R³ is methyl.

E14 A compound according to embodiment El 3 of Formula (la)

or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait.

E15 A compound according to any one of embodiments E1 to E14 or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait, wherein R⁴ is

optionally substituted by one or two substituents independently selected from oxo, (Ci-C4)alkyl and hydroxy(Ci-C4)alkyl.

El 6 A compound according to embodiment E15 or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait, wherein R⁴ is

optionally substituted by one or two substituents independently selected from oxo, methyl and hydroxymethyl.

E17 A compound according to embodiment El 6 or a pharmaceutically acceptable sait 5 thereof, or a pharmaceutically acceptable solvaté of said compound or said sait, wherein R⁴ is

E18 A compound according to embodiment E17 or a pharmaceutically acceptable sait 10 thereof, or a pharmaceutically acceptable solvaté of said compound or said sait, wherein R⁴ is

E19 A compound according to embodiment E16 or a pharmaceutically acceptable sait 15 thereof, or a pharmaceutically acceptable solvaté of said compound or said sait, wherein R⁴ is

N J optionally substituted by one or two substituents independently selected from oxo, methyl and hydroxymethyl.

E20 A compound according to embodiment E19 or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait, wherein R⁴ is

optionally substituted by oxo.

E21 A compound accordtng to embodiment E19 or a pharmaceutîcally acceptable sait thereof, or a pharmaceutîcally acceptable solvaté of said compound or said sait, wherein R⁴ is

optionally substituted by one or two methyl.

E22 A compound according to embodiment E19 or a pharmaceutîcally acceptable sait thereof, or a pharmaceutîcally acceptable solvaté of said compound or said sait, wherein R⁴ is

E23 A compound according to any one of embodiments E1 to E22 or a pharmaceutîcally acceptable sait thereof, or a pharmaceutîcally acceptable solvaté of said compound or said sait, wherein R⁵ and R⁵ are independently H; halogen; OH; CN; (Ci-C3)alkyl; hydroxy(Ci-C3)alkyl; (Ci-C3)alkoxy(Ci-C3)alkyl; (Ci-C3)alkyl substituted by one, two or three F; (Ci-C3)alkoxy; or (Ci-C3)alkoxy substituted by (Ci-C3)alkoxy.

E24 A compound according to embodiment E23 or a pharmaceutîcally acceptable sait thereof, or a pharmaceutîcally acceptable solvaté of said compound or said sait, wherein R⁵ is H, halogen, CN, (Ci-C6)alkyl, (Ci-C6)alkoxy or (Ci-C6)alkoxy substituted by (C-C^alkoxy.

E25 A compound according to embodiment E24 or a pharmaceutîcally acceptable sait thereof, or a pharmaceutîcally acceptable solvaté of said compound or said sait, wherein R⁵ is H, halogen, CN, (Ci-C3)alkyl, (Ci-C3)alkoxy or (Ci-C3)alkoxy substituted by (C-i-CsJalkoxy.

E26 A compound according to embodiment E25 or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait, wherein R⁵ is H, F, Br, CN, methyl, ethyl, methoxy or CH3O-CH2-CH2O-.

E27 A compound according to any one of embodiments E1 to E26 or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait, wherein R⁶ is H; halogen; OH; CN; (Ci-Ce)alkyl; hydroxy(Ci-Cs)alkyl; (Ci-C4)alkoxy(Ci-C6)alkyl; (Ci-Ce)alkyl substituted by one, two or three F; or (Ci-C6)alkoxy.

E28 A compound according to embodiment E27 or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait, wherein R^G is H; halogen; OH; CN; (Ci-Cs)alkyl; hydroxy(Ci-C3)alkyl; (Ci-C3)alkoxy(Ci-C3)alkyl; (Ci-C3)alkyl substituted by one, two or three F; or (Ci-C3)alkoxy.

E29 A compound according to embodiment E28, or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait, wherein R⁶ is H, F, Cl, Br, OH, CN, methyl, ethyl, hydroxymethyl, methoxymethyl, CHFz, CF3 or methoxy.

E30 A compound according to embodiment E1 or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait, selected from:

Example 1: (S)-/V’methyl-/\/-(6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopΓopa[f]indazol-3-yl)-1/7-benzo[d]imidazol·5-yl)-2morpholinopropanamide;

Example 2: /\/-methyl·/\/-(6-methyl-2-((4aS,5aR)-5a-methyl·1,4,4a,5,5a,6hexahydrocyclopropa[f|indazol-3-yl)-1H-benzo[d]imidazol-5-yl)-2morpholinopropanamide;

Example 3: (R)-/V-methyl-/V-(6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[f]indazol-3-yl)-1H-benzo[d]imidazol-5-yl)-2morpholinopropanamide;

Example 4: (R)-/v-methyl-/V-(6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[f]indazol-3-yl)-1H-benzo[d]imidazol-5-yl)-2-(tetrahydro-2Hpyran-4-yl)propanamide;

Example 5: Λ/-methyl-Λ/-(6-metl^yl·2-((4aS_I5aR)-5a-methyl·1,4,4a,5,5a,6hexahydrocyclopropa[f]indazol·3-yl)-1H-benzo[d]imidazol·5-yl)-2-(tetrahydro-2Hpyran-4-yl)propanamide;

Example 6: (S)-/V-ethyl-A/-(6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopiOpa[f]indazol-3-yl)-1H-benzo[d]imidazol-5-yl)-2morpholinopropanamide;

Example 7: (R)-W-methyk/V-(2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[f|indazol-3-yl)-1/-/-benzo[d]imidazol-5-yl)-2-(tetrahydro-2Hpyran-4-yl)propanamide;

Example 8: A/-methyl-/V-(2-((4aS₎5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[f]indazol-3-yl)-1H-benzo[d]imidazol-5-yl)-2-(tetrahydro-2Hpyran-4-yl)propanamide;

Exampîe 9: (S)-A/-methyl-A/-(2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[f]indazol-3-yl)-1/-/-benzo[d]imidazol-5-yl)-2-(tetrahydro-2/7pyran-4-yl)propanamide;

Example 10: /V-methyl-A/-(2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[f]indazol-3-yl)-1H-benzo[d]imidazol-5-yî)-2-(tetrahydro-2/-/pyran-4-yl)acetamide;

Example 11: 2,2-difluoro-/\/-methyl-/\/-(2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[fjindazol-3-yl)-1H-benzo[d]imidazol-5-yl)-2-(tetrahydro-2Hpyran-4-yl)acetamide;

Example 12: (R)-/V-(7-fluoro-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[f]indazol-3-yl)“1H-benzo[d]imidazol-5-yl)-/\/-methyl-2(tetra hyd ro-2H- py ra n-4-y I) p rop a na m id e ;

Example 13: (S)-/V-(2-((4aS,5aR)-5,5-difluoro-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[f]indazol-3-yl)-1H-benzo[d]rmidazol-5-yl)-A/-methyl-2morpholinopropanamide;

Example 14: (S)-Λ/-methyl·/V-¢2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[f]indazol-3-yl)-1H-benzo[d]Îmidazol-5-yl)-2morpholinopropanamide;

Example 15: (S)-/v-(7-fluoro-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[f]indazol-3-yl)-1/-/-benzo[d]imidazol-5-yl)-A/-methyl-2morpholinopropanamide;

Example 16: (S)-/V-ethyl-/V-(7-fluoro-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[f]indazol-3-yi)-1H-benzo[d]imidazol-5-yl)-2morpholinopropanamide;

Example 17: (S)-/V-(6-fluoro-2-((4aS,5aR)-5a-methyl-1,4,43,5,53,6hexahydrocyclopropa[f]indazol-3-yl)“1H-benzo[d]imidazol·5-yl)-Λ/-methyl-2morpholinopropanamide;

Example 18: (S)-/V-(6-ethyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[f]indazol-3-yl)-1H-benzo[d]imidazol-5-yl)-/\/-methyl-2morpholinopropanamide;

Example 19: (S)-/V-(6-methoxy-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[f]indazol-3-yl)-1/-/-benzo[d]imidazol-5-yl)-/\/-methyl-2morpholinopropanamide;

Example 20: (S)-A/-(6-bromo-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[f]indazol-3-yl)-1/-/-benzo[d]imidazol-5-yl)-/\/-methyl-2morpholinopropanamide;

Example 21 : (S)-/V-(6-cyano-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[f|indazol-3-yl)-1/-/-benzo[d]imidazol-5-yl)-A/-methyl-2morpholinopropanamide;

Example 22: (S)-N-(7-fluoro-2~((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[f]indazol-3-yl)-1H-benzo[d]imidazol-5-yl)-N-methyl-2-(3oxomorpholino)propanamide;

Example 23: (R)-N-(7-fluoro-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[f]indazol-3-yl)-1 H-benzo[d]imidazol-5-yl)-N-methyl-2-(3oxomorpholino)propanamide;

Example 24: (S)-/V-(6,7-difluoro-2-((4aS,5aR)-5a-methyl-1,4,43,5,53,6hex8hydrocyclopropa[f]indazol-3-yl)-1/-/-benzo[d]imidazol-5-yl)-/\/-methyl-2morpholinopropanamide;

Example 25: (S)-/V-(6.7-difluoro-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hex^hydrocyclopropa[f]indazol·3-yl)-1H-benzo[d]imidazol-5-yl)-Λ/-ethyl-2morpholinopropanamide;

Example 26: 2-((S)-2-(hydroxymethyl)morpholino)-A/-methyl-/v-(6“methyl-2((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f|indazol-3-yl)-1/-/benzo[d]imidazol-5-yl)acetamide;

Example 27: 2-(2-(Hydroxymethyi)morpholino)-/V-methyl-A/-(6’methyl-2((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydiOcyclopropa[f]indazol-3-yl)-1Hbenzo[d]imidazol'5-yl)acetamide;

Example 28: 2-((R)-2-(Hydroxymethyl)morpholino)-/\/-methyl-A/-(6-methyl-2((4aS,5aR)-5a-methyl-1 A4a,5₁5a,6-hexahydrocyclopropa[(|iridazol-3-yl)-1 Hbenzo[d]imidazol-5-yi)acetamide;

Example 29: 2-(2,2-Dîmethylmorpholino)-A/-methyl-/\/-(6-methyl-2-((4aS,5aR)-5amethyl-1,4,4a,5,5a,6- hexahydrocyclopropa[f|!ndazol-3-yl)-1 H-benzo[d]imidazol5-yl)acetamide;

Example 30: Methyl-A/-(6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[f|indazol-3-yl)-1/7-benzo[c/]imidazol-5-yl)-2'((R)-2methylmorpholino)acetamide;

Example 31 : Methyl-/\/-(6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[f|indazol-3-yl)-1H-benzo[d]imidazol-5-yl)-2-((S)-2methylmorpholino)acetamide;

Example 32: 2-((2R,6R)-2,6-Dimethylmorpholino)-/V-methyl-/V-(6-methyl-2((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydΓOcyclopropa[f]irΊdazol·3-yl)-1Hbenzo[d]imidazol-5'yl)acetamide;

Example 33: 2-((2S,6S)-2,6-Dimethylmorpholino)-/\/-methyl-/V’(6-methyl-2((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[nindazol-3-yl)-1Hbenzo[cf]imidazol-5-yl)acetamide;

Example 34: N-Methyl·/V-(6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[/]indazol-3-yl)-1/-/-benzo[cl]imidazol-5-yl)-2morpholinoacetamide;

Example 35: A/-Methyl-/V-(6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[f|indazol-3-yl)-1/7-benzo[i/]imidazol-5-yl)-2-(tetrahydrO“2Hpyran-4~yl)acetamide;

Example 36: /V-Methyl-/V-(6-methyl-2-((4aS,5aR)-5a-methy!-1,4,4a,5,5a,6hexahydrocyclopΓOpa[f|indazol·3-yl)-1H-benzo[d]imidazol·5-yl)“2-(3oxomorpholino)acetamide;

Example 37: (S)-/\/-(7-bromo-2-((4aS_T5a/^:?)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[f|indazol-3-yl)-1H-benzo[c/]imidazol-5-yl)-A/-methyl-2morpholinopropanamide;

Example 38: (S)-A/-(7-cyano-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopΓopa[f]indazol-3-yl)-1H-benzo[d]imidazol·5-yl)-Λ/-methyl-2morpholinopropanamide;

Example 39: (S)-A/-(7-hydroxy-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[f]Îndazol-3-yl)-1/7-benzo[d]imidazol-5-yl)-/\/-methyl-2morpholinopropanamide;

Example 40: (S)-N-(7-methoxy-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[f]indazol-3-yl)-1H-benzo[d]imidazol-5-yl)-/\/-methyl-2morpholinopropanamide;

Example 41 : (S)-/V-methyl-A/-(2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[f]indazol-3-yl)-7-(tΓifluoΓomethyl)-1H-benzo[d]imidazol·5-yl)2-morpholinopropanamide;

Example 42: (S)-/V-(7-(methoxymethyl)-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[f]indazol-3-yl)-1/-/-benzo[d]imidazol-5-yl)-/\/-methyl-2morpholinopropanamide;

Example 43: (S)-N-(7-chloro-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[/]indazol-3-yl)-1/-/-beπzo[c/]imidazol·5-yl)-Λ/-methyl-2morpholinopropanamide;

Example 44: (S)-/\/-{7’ethyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[/]indazol-3-yl)-1H-benzo[c/]Îmidazol-5-yl)-/V-methyl-2morpholinopropanamide;

Example 45: (S)-/V-(7-(hydroxymethyl)-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[^indazol-3-yl)-1H-benzo[c/]imidazol-5-yl)-A/-methyl-2morpholinopropanamide;

Example 46: (S)-/V-(7-fluoro-6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[/]mdazol-3-yl)-1 H-benzo[cf]imidazol-5-yl)-V-methyl-2morpholinopropanamide;

Example 47: (S)-A/-(6-fluoro-7-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[f]indazol-3-yl)ΊH-benzo[d]imidazol-5-yl)-Λ/'methyl·2morpholinopropanamide;

Example 48: (S)-/v-(7'(difluoromethyl)-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[f]Îndazol-3-yl)-1/-/-benzo[d]imidazol-5-yl)-/V-methyl-2morpholinopropanamide;

Example 49: (S)-/\/-(6'(2'methoxyethoxy)-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[f]indazol-3-yl)-1H’benzo[d]imidazol-5-yl)-N-methyl-2morpholinopropanamide;

Example 50: (S)-/\/-methyl-/\/-(7-methyl-2-((4aS,5aR)“5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[^indazol-3-yl)-1H-benzo[c/]Îmidazol-5-yl)-2morpholinopropanamide; and

Example 51 : (S)-N-(2-((4aS,5aR)-5,5-difluoro-5a-methyl-1,4,4a,5,5a,6hexahydrocycîopropa[/]indazol·3-yl)-7“methyl-1H-benzo[¢ί]imidazol-5-yl)-/\/methyl-2-morpholinopropanamide.

E31 A compound according to embodiment E1 or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait, selected from:

Example 52: (S)-N-(6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[f]indazol-3-yl)-1 H-benzo[d]imidazol-5-yl)-2morpholinopropanamide;

Example 53: (S)-N-(2-((4aS,5aR)-5,5-difluoro-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[f]indazol-3-yl)-5-methyl’1H-benzo[d]imidazol-6-yl)-Nmethyl-2-morpholinopropanamide;

Example 54: N-(6-cyano-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[f]indazol-3-yl)-1 H-benzo[d]imidazol-5-yl)-N-methyl-2(tetrahydro-2H-pyran-4-yl)acetamide;

Example 55: (R)-A/-(7-cyano-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[f]Îndazol-3-yl)-1 H-benzo[d]imidazol-5-yl)-N-methyl-2(tetrahydro-2H-pyran-4-yl)propenamide; and

Example 56: (S)-N-(methyl-¹³C-d3)-N-(6-methyl-2-((4aS,5aR)-5a-methyl- ^/a.S.Sa.G-hexahydrocyclopropa^indazol-S-yO-l H-benzo[d]imidazol-5-yl)-2morpholinopropanamide.

E32 A compound according to embodiment E1 or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait, selected from:

Example 1: (S)-A/-methyl-A/-(6-methyl-2-((4aS,5aR)--5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[f]indazol-3-yl)-1H-benzo[d]imidazol-5-yl)-2morpholinopropanamide;

Example 7: (R)-/V-methyl-N-(2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[f]indazol-3-yl)-1/-/-benzo[d]imidazol-5-yl)-2“(tetrahydro-2Hpyran-4-yl)propanamide;

Example 12: (R)-N-(7-fluoro-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[f]indazol-3-yl)-1H-benzo[d]imidazol·5-yl)'Λ/-methyl-2(tetrahydro-2H’pyran-4-yl)propanamide;

Example 15: (S)-N-(7-fluoro-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[f]indazol-3-yl)-1H-benzo[d]imidazol-5-yl)-A/-methyl-2morpholinopropanamide;

Example 16: (S)-A/-ethy[-A/-(7-fluoro-2-((4aS,5aR)-5a-methyl- 1,4,4a,5,5a,6hexahydrocyclopropa[f]indazol-3-yl)-1H-benzo[d]imidazol·5-yl)-2morpholinopropanamide;

Example 24: (S)Λ/-(6,7-diflυoro-2-((4aS,5aR)-5a-methyl·1,4,4a,5,5a,6hexahydrocyclopropa[f]indazol-3-yl)-1 H-benzo[d]imidazol-5-yl)-/\/-methyl·2morpholinopropanamide;

Example 25: (S)-/V-(6.7-difluoro-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydΓOcyclopropa[f]indazol·3-yl)-1H-benzo[d]imidazol-5-yl)-Λ/-ethyl-2morpholinopropanamide;

Example 46: (S)-/V-(7-fluoro-6-methyl-2-((4aS.5aR)-5a-methyl-1,4,4a,5,5a,6hexahydΓocyclopΓOpa[f|indazol-3-yl)-1/-/-benzo];cf]imidazol·5’yl)-Λ/-methyl-2morpholinopropanamide; and

Example 50: (S)-/V-methyl-A/-(7-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[f]indazol·3-yl)-1H-benzo[c/]imidazol-5-yl)“2morpholinopropanamide.

E33 The compound according to embodiment E32 which is (S)-/V-methyl-/V-(6-methyl2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)-1Hbenzo[d]imidazol-5-yl)-2-morpholinopropanamide, or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait.

E34 The compound according to embodiment E32 which is (R)-/V-methyl-/V-(2((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)-1 Hbenzo[d]imidazol-5-yl)-2-(tetrahydro-2H-pyran-4-yl)propanamide, or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait.

E35 The compound according to embodiment E32 which is (R)-A/-(7-fluoro-2((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3'yl)-1Hbenzo[d]imidazol-5-yl)-/V-methyl-2-(tetrahydro-2H-pyran-4-yl)propanamide, or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait.

E36 The compound according to embodiment E32 which is (S)-A/-(7-fluoro-2((4aS,5aR)-5a-methyl-1,4.4a_;5.5a,6-hexahydrocyclopropa[f]indazol-3-yl)1 H benzo[d]imidazol·5’yl)-Λ/-methyl-2-morpholinopropanamide, or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait.

E37 The compound according to embodiment E32 which is (S)-A/-ethyl-/V-(7-fluoro-2((4aS,5aR)-5a-methyl-1,4,4a_I5,5a_I6-hexahydrocyclopropa[f]indazol-3-yl)-1/7benzo[d]imidazol-5-yl)-2-morpholinopropanamide, or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait.

E38 The compound according to embodiment E32 which is (S)-/\/-(6,7-difluoro-2((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)-1Hbenzo[d]imidazol-5-yl)-/V-methyl-2-morpholinopropanamide, or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait.

E39 The compound according to embodiment E32 which is (S)-A/-(6.7-difluoro-2((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)-1Hbenzo[d]imidazol-5-yl)-Λ/-ethyl·2'morpholinopropanam^de, or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait.

E40 The compound according to embodiment E32 which is (S)-/V-(7-fluoro-6-methyl2-((4aS,5aR)-5a-methyl-1_I4,4a,5,5a,6-hexahydΓOcyclopropa[f|indazol·3-yl)-1Hbenzo[d]imidazol-5-yl)“Λ/-methyl·2-morpholinopropanamide_I or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait.

E41 The compound according to embodiment E32 which is (S)-A/-methyl-/\/-(7-methyl2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)-1/-/benzo[cf]rmÎdazol-5-yl)-2-morpholinopropanamide, or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait.

E42 The compound according to embodiment E33 which is (S)-N-methyl-/V-(6-methyl2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)-1Hbenzo[d]imidazol-5-yl)-2-morpholinopropanamide, or a pharmaceutically acceptable solvaté thereof.

E43 The compound according to embodiment E42 which is (S)-A/-methyl-/\/-(6-methyl2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol·3-yl)-1Hbenzo[d]imidazol-5-yl)-2-morpholinopropanamide, or a hydrate thereof.

E44 The compound according to embodiment E43 which is (S)-Λ/-methyl·/V-(6-methyl2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)-1Hbenzo[d]imidazol·5-yl)-2-morpholinopΓopanamide, dihydrate.

E45

The compound according to embodiment E33 which is

E46 A crystalline form of the compound according to embodiment E44.

E47 The crystalline form according to embodiment E46 with one, two, three, four or five PXRD peaks selected from 6.6°±0.2° 20, 7.4°±0.2° 2Θ. 11.0°±0.2° 2Θ. 11.6°±0.2° 2Θ, 15.7°±0.2° 20 and 17.7°±0.2° 2Θ,

E48 The crystalline form according to embodiment E47 with PXRD peaks at 6.6°±0.2°

2Θ, 11.0°±0.2° 20, 15.7°+0.2° 20 and 17.7°±0.2° 20.

E49 The crystalline form according to embodiment E47 with PXRD peaks at 6.6°±0.2° 20, 7.4°±0.2° 20, 11,0°+0.2° 2Θ and 11.6°±0.2° 2Θ.

E50 The crystalline form according to embodiment E47 with PXRD peaks at 7.4°±0.2° 2Θ, 11.6°±0.2° 20, 15.7°±0.2° 2Θ and 17.7°±0.2° 2Θ.

E51 The crystalline form according to embodiment E47 with PXRD peaks at 6.6°±0.2° 20 20, 7.4°±0.2° 20, 11.0^o+0.2° 2Θ, 11.6°±0.2° 2Θ, 15.7°+0.2° 2Θ and 17.7°±0.2° 20.

E52 The crystalline form according to embodiment E46 with PXRD peaks at 6.6^D±0.2° 2Θ, 7.4°±0.2° 20, 11.0°±0.2° 20, 11.6°+0.2° 2Θ, 13.3°±0.2° 2Θ, 15.7°±0.2° 20, 16.2°±0.2° 2Θ, 17.7°±0.2° 2Θ, 18.8°±0.2° 20 and 22.9°±0.2° 20.

Brief description ofthe Figures:

Figure 1 is the PXRD pattern for the compound of Example 1.1 (crystal Form 1).

Figure 2 is the PXRD pattern for the compound of Example 1,2a (crystal Form 2).

Figure 3 îs the PXRD pattern for the compound of Example 1.3 (crystal Form 3).

Figure 4 is an ORTEP diagram for the compound of Example 1.4 (crystal Form 2), drawn with displacement parameters at 50% probability and water molécules omitted for clarity.

Figure 5 is an ORTEP diagram for the compound of Example 1.4 (crystal Form 2), drawn with displacement parameters at 50% probability and water molécules shown.

Figure 6 is the TGA for the compound of Example 1.1 (crystal Form 1).

Figure 7 is the TGA for the compound of Example 1.3 (crystal Form 3).

In compounds of Formula (I):

• Alkyl means a straight or branched chain hydrocarbon group of formula -CnH(2n+i). Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl.

• Alkyloxy means an alkyl substituent attached through an oxygen atom. Examples of alkyloxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy and t-butoxy.

• Cycloalkyl means a cyclic hydrocarbon group of formula -CnH(2n-i) containing at least three carbon atoms. Examples of Cycloalkyl include cyclopropyl, cyclobutyl nd cyclopentyl.

• Examples of halogen include fluoro (F), chloro (Cl), bromo (Br) and iodo (I).

• Oxo refers to a double bonded oxygen (=O).

Hereinafter, ail référencés to compounds of the invention include compounds of Formula (1) or pharmaceutîcally acceptable salts, solvatés, or multi-component complexes thereof, or pharmaceutîcally acceptable solvatés or multi-component complexes of pharmaceutîcally acceptable salts of compounds of Formula (I), as discussed in more detail below.

Preferred compounds of the invention are compounds of Formula (I) or pharmaceutically acceptable salts thereof or pharmaceutically acceptable solvatés of said compounds or said salts.

Further preferred compounds of the invention are compounds of Formula (I) or pharmaceutically acceptable solvatés thereof.

Further preferred compounds of the invention are compounds of Formula (I) or pharmaceutically acceptable hydrates thereof.

Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, maiate, maleate, malonate, mesylate, methylsulphate, 1,5-naphathalenedisulfonate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stéarate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts.

Hemisalts of acids may also be formed, for example, hemisulphate and hemitartrate salts.

The skilled person will appreciate that the aforementioned salts include ones wherein the counterion is optically active, for example d-lactate, or racemic, for example dltartrate.

For a review on suitable salts, see “Handbook of Pharmaceutical Salts: Properties, Sélection, and Use by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

Pharmaceutically acceptable salts of compounds of Formula (I) may be prepared by one or more of three methods:

(i) by reacting the compound of Formula (I) with the desired acid;

(ir) by removmg an acid-labile protectmg group from a suitable precursor of the compound of Formula (I) using the desired acid; or (iii) by converting one sait of the compound of Formula (I) to another by reaction with an appropriate acid or by means of a suitable ion exchange column.

Ail three reactions are typically carried out in solution. The resulting sait may precipitate out and be collected by filtration or may be recovered by évaporation of the solvent. The degree of ionisation in the resulting sait may vary from completely ionised to almost non-ionised.

The compounds of Formula (I) or pharmaceutically acceptable salts thereof may exist in both unsolvated and solvated forms. The term ‘solvaté’ is used herein to describe a molecular complex comprising a compound of Formula (I) or a pharmaceutically acceptable sait thereof and one or more pharmaceutically acceptable solvent molécules, for example, éthanol. The term ‘hydrate’ is employed when said solvent is water. Pharmaceutically acceptable solvatés in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D2O, ds-acetone and de-DMSO.

A currently accepted classification System for organic hydrates is one that defines isolated site, channel, or metal-ion coordinated hydrates - see Polvmorphism in Pharmaceutical Solids by K. R. Morris (Ed. H. G. Brittain, Marcel Dekker, 1995), incorporated herein by reference. Isolated site hydrates are ones in which the water molécules are isolated from direct contact with each other by intervening organic molécules. In channel hydrates, the water molécules lie in lattice channels where they are next to other water molécules. In metal-ion coordinated hydrates, the water molécules are bonded to the métal ion.

When the solvent or water is tightly bound, the complex will hâve a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvatés and hygroscopic compounds, the water/solvent content will be dépendent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.

Also included within the scope of the invention are multi-component complexes (other than salts and solvatés) of compounds of Formula (I) or pharmaceutically acceptable salts thereof wherein the drug and at least one other component are présent in stoichiometric or non-stoichiometric amounts. Complexes of this type include clathrates (drug-host inclusion complexes) and co-crystals. The latter are typically defined as crystalline complexes of neutral molecular constituents which are bound together through non-covalent interactions, but could also be a complex of a neutral molécule with a sait. Co-crystals may be prepared by melt crystallisation, by recrystallisation from solvents, or by physically grinding the components together - see Chem Commun, 17, 1889-1896, by O. Almarsson and M. J. Zaworotko (2004), incorporated herein by reference. For a general review of multi-component complexes, see J Pharm Sel, 64 (8), 1269-1288, by Haleblian (August 1975), incorporated herein by reference.

The compounds of the invention may exist in a continuum of solid States ranging from fully amorphous to fully crystalline. The term ‘amorphous’ refers to a state in which the material lacks long range order at the molecular level and, depending upon température, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterised by a change of state, typically second order (‘glass transition’). The term ‘crystalline’ refers to a solid phase in which the material has a regular ordered internai structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will aiso exhibit the properties of a liquid, but the change from solid to liquid is characterised by a phase change, typically first order (‘melting point’).

The term ‘2 thêta’ or '29’ refers to the PXRD peak position in degrees along the x-axis. A typical error associated with PXRD peak position is up to +A 0.2° 2Θ (USP-941).

The compounds of the invention may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution). Mesomorphism arising as the resuit of a change in température is described as ‘thermotropic’ and that resulting from the addition of a second component, such as water or another solvent, is described as lyotropic. Compounds that hâve the potential to form lyotropic mesophases are described as ‘amphiphilic’ and consist of molécules which possess an ionic (such as -COO Na⁺, -COOK⁺, or -SÛ3'Na⁺) or non-ionic (such as -N-N⁺(CH₃)3) polar head group. For more information, see Crystals and the Polarizinq Microscope by N. H. Hartshome and A. Stuart, 4^th Edition (Edward Arnold, 1970), incorporated herein by reference.

The compounds of the invention may be administered as prodrugs. Thus certain dérivatives of compounds of Formula (I) which may hâve little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of Formula (I) having the desired activity, for example, by hydrolytic cleavage. Such dérivatives are referred to as ‘prodrugs’. Further information on the use of prodrugs may be found in ‘Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Sériés (T Higuchî and W Stella) and ‘Bioreversible Carriers in Drug Design’, Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association).

Prodrugs can, for example, be produced by replacing appropriate functionalities present in a compound of Formula (I) with certain moieties known to those skilled in the art as ‘pro-moieties’ as described, for example, in Design of Prodrugs by H Bundgaard (Elsevier, 1985).

Examples of prodrugs include phosphate prodrugs, such as dihydrogen or dialkyl (e.g. di-tert-butyl) phosphate prodrugs. Further examples of replacement groups in accordance with the foregoing examples and examples of other prodrug types may be found in the aforementioned references.

Also included within the scope of the invention are métabolites of compounds of Formula (I), that is, compounds formed in vivo upon administration of the drug. Examples of métabolites in accordance with the invention include, where the compound of Formula (I) contains a morpholinyl moiety according to embodiment E19, hydroxylethyl amines of Formula (Ib), and amines of Formulae (le), as shown below.

metabolism

The compounds M1 and M2 below, métabolites of the compound of Ex1, illustrate this aspect of the invention and are of particular interest.

Other examples of métabolites in accordance with the invention include:

(i) hydroxymethyl dérivatives (-CH3 —> -CH2OH);

(jj) where the compound of Formula (I) contains an alkoxy group, a hydroxy dérivative 10 thereof (-(Ci-Ce)alkoxy —> -OH); and (iii) where the compound of Formula (I) contains a phenyl moiety, a phénol dérivative thereof (-Ph -PhOH).

Formula (I) contains an asymmetric cyclopropaindazolyl moiety and is stéréospecifically defined (as the ‘4aS,5aR’ stereoisomer).

The skilled person will appreciate that one or more substituents in Formula (I) may introduce one or more additional asymmetric centres. An illustration of such an additional asymmetric centre is the asymmetric carbon atom of a compound of Formula (la) or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait, according to Embodiment E14, marked by an asterisk (*) in the représentation of Formula (la) below:

Compounds ofthe invention containing said one or more additional asymmetric centres can exist as two or more stereoisomers; included within the scope of the invention are ail such stereoisomers (including epimers) of the compounds of the invention and mixtures of two or more thereof.

Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optîcally pure precursor or resolution ofthe racemate (or the racemate of a sait or dérivative) using, for example, chiral high pressure liquid chromatography (HPLC).

Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of Formula (I) contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.

Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0,1% diethylamine. Concentration of the eluate affords the enriched mixture.

Chiral chromatography using sub-and supercritical fluids may be employed. Methods for chiral chromatography useful in some embodiments of the présent invention are known; see, for example, Smith, Roger M., Loughborough University, Loughborough, UK; Chromatographie Science Sériés (1998), 75 (Supercritical Fluid Chromatography 15 with Packed Columns), pp. 223-249 and references cited therein.

Mixtures of stereoisomers may be separated by conventional techniques known to those skilled in the art; see, for example, “Stereochemistry of Organic Compounds by E, L. Eliel and S. H. Wilen (Wiley, New York, 1994.

Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism (‘tautomerism’) and conformational isomerism can occur.

Tautomerism can take the form of proton tautomerism in compounds of Formula (I), as 25 illustrated below in Formula (!) generally, and Example 1 specifically, with respect to the benzimidazole group:

The skifled person will appreciate that proton tautomerism can also take place on the pyrazole ring in compounds of Formula (I).

While, for conciseness, the compounds of Formula (I) hâve been drawn herein in a single tautomeric form, ail possible tautomeric forms, and mixtures thereof, are included within the scope of the invention.

Conformational isomerism is a form of stereoisomerism in which the isomers of a 10 compound can be interconverted exclusively by rotations about single bonds. Such isomers are generally referred to as conformational isomers or conformers and, specifically, as rotamers. A “rotameric mixture, or “mixture of rotamers, describes a compound existing as a mixture of more than one of the possible conformational isomers. While, for conciseness, the compounds of Formula (I) hâve been drawn in a 15 single conformational form, ail possible conformers, and mixtures thereof, are included within the scope of the invention.

The scope of the invention includes ail crystal forms of the compounds of the invention, including racemates and racemic mixtures (conglomérâtes) thereof. Stereoisomeric 20 conglomérâtes may also be separated by the conventional techniques described herein just above.

The scope of the invention includes ail pharmaceutically acceptable isotopically-labelled compounds of the invention wherein one or more atoms are replaced by atoms having 25 the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which prédominâtes in nature.

Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of: hydrogen, such as ²H and ³H; carbon, such as ¹¹ C, ¹³C and ¹⁴C; fluorine, 30 such as ¹⁸F; chlorine, such as ^Cl; iodine, such as ¹²³l and ¹²⁵l; nitrogen, such as ¹³N and ¹⁵N; oxygen, such as ¹⁵O, ¹⁷O and ¹⁸O.

B 28

Certain isotopically-labelled compounds of the invention, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. ³H, and carbon-14, i.e. ¹⁴C, are 5 particularly useful for this purpose in view of their ease of incorporation and ready means of détection. Substitution with heavier isotopes such as deuterium (D), i.e. ²H, may afford certain therapeutic advantages resulting from greater metabolie stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as ¹¹C, ¹⁵O and ¹³N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

Isotopically-labeled compounds of Formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to 15 those described in the accompanying examples and préparations using an appropriate isotopically-labeled reagent in place of the non-iabeled reagent previously employed.

Also within the scope of the invention are intermediate compounds as hereinafter defined, ail salts, solvatés and complexes thereof, and ail solvatés and complexes of 20 salts thereof as defined hereinbefore for compounds of Formula (I). The invention includes ail polymorphe of the aforementioned species and crystal habits thereof.

When preparing a compound of Formula (I) in accordance with the invention, a person skilled in the art may routînely select the form of intermediate which provides the best 25 combination of features for this purpose. Such features include the melting point, solubility, processability and yield of the intermediate form and the resulting ease with which the product may be purified on isolation.

The compounds of the invention may be prepared by any method known in the art for 30 the préparation of compounds of analogous structure. In particular, the compounds of the invention can be prepared by the procedures described by reference to the schemes that follow, or by the spécifie methods described in the examples, or by similar processes to either.

k 29

The skilled person will appreciate that the experimental conditions set forth in the schemes that follow are illustrative of suitable conditions for effecting the transformations shown, and that it may be necessary or désirable to vary the précisé conditions employed for the préparation of compounds of Formula (I). It will be further 5 appreciated that it may be necessary or désirable to carry out the transformations in a different order from that described in the schemes, or to modify one or more of the transformations, to provide the desired compound of the invention.

Compounds of the présent invention contain two or more stereogenic centers, with the 10 stereochemical désignation (R) or (S). The skilled person will appreciate that ail the synthetic transformations can be conducted on either enantioenriched or racemic compounds, and that the resolution to the desired stereoisomer may take place at any point in the synthesis, using well known methods described herein and/or known in the art, 15

In addition, the skilled person will appreciate that it may be necessary or désirable at any stage in the synthesis of compounds of the invention to protect one or more sensitive groups, so as to prevent undesirable side reactions. In particular, it may be necessary or desirable to protect hydroxyl, carboxyl and/or amino groups. The 20 protecting groups used in the préparation of the compounds of the invention may be used in conventional manner; see, for example, those described in 'Greene’s Protective Groups in Organic Synthesis’ by Theodora W Greene and Peter G M Wuts, fifth édition, (John Wiley and Sons, 2014), incorporated herein by reference, and in particular chapters 2, 5 and 7 respectively, which also describes methods for the removal of such 25 groups.

In the following general processes and unless otherwise stated;

• R¹ to R⁶ are as previously defined for a compound of Formula (I);

• R is alkyl, such as ethyl, or in the case of Formulae 3 and 4, two R may be taken together with the oxygen atoms to which they are attached to form a cyclic acetal;

• PG is a suitable amino protecting group, such as a silyl ether (e.g. SEM), an alkoxy carbonyl (e.g. BOC), acetyl (Ac), benzyl (e.g. PMB) or dihydropyran (DHP) protecting group; and • X is F or Cl.

A substituted pyrazole of Formula 11 may be prepared as shown in Scheme 1.

Scheme 1

Compound 1 (3-methoxytoluene) can be reduced to the corresponding 1,4-diene Compound 2 by a Birch réduction (Mander, L. N. Comprehensive Organic Synthesis; Trost, B. M. and Fleming, I., Ed,; Pergamon: Oxford, 1991, Vol. 8, pp. 489-521), using an alkali métal such as Li or Na in liquid ammonia at températures below -30 °C.

Préparation of an olefinic acetal of Formula 3 from the 1,4-diene Compound 2 can proceed under catalytic acid conditions, e.g. using pTSA or CSA in the presence of alkyl primary alcohols such as MeOH or EtOH, or a diol such as ethylene glycol, with or without a solvent such as DCM or other aprotic solvent, at a température between 0-100 15 °C, such as 0-25 °C.

Conversion of an olefin of Formula 3 into a cyclopropane of Formula 4 may proceed via dihalocarbene addition or Sim mon s-Smith cyclopropanation (Charette, A. B.;

Beauchemm, A. Sim mon s-Smith Cyclopropanation Reaction. Org. React. 2001, 58, p 1415).

Deprotection of an acetal of Formula 4 to give a ketone of Formula 5 may be performed under acidic conditions, e.g. using HCl, H2SO4 or an organic acid such as pTSA, in a mixture of water and solvent such as THF.

Préparation of a diketone of Formula 6 can be achieved by reacting a ketone of Formula 5 with: i) a dialkyl oxalate and 1-3 équivalents of a strong base, such as LDA, LiHMDS or KOtBu, in a polar aprotic solvent such as THF, at -78 “C to 25 °C; or ii) with an alkoxide in a corresponding alcoholic solvent (e.g. EtONa in éthanol) at températures between 0 °C and reflux.

Condensation of a diketone of Formula 6 with hydrazine or hydrazine hydrate, in a protic solvent such as MeOH or EtOH, at 25 °C to reflux, can provide a pyrazole of Formula 7. A hydrazine sait, such as the HCl sait, may also be used together with a corresponding molar équivalent of inorganic (e.g. K2CO3) or organic (e.g. Et3N or iPr2NEt) base.

Protection of a pyrazole of Formula 7 can be performed with SEM-CI, DHP or another suitable protecting group to deliver a pyrazole of Formula 8, résolution of which to deliver the corresponding enantiomer of Formula 9 can be performed by supercritical fluid chromatography with the use of a chiral solid phase.

Réduction of an ester of Formula 9 to an alcohol of Formula 10 may be performed using LAH, in an aprotic solvent such as THF, at températures between 0 °C and reflux.

Oxidation of an alcohol of Formula 10 to an aldéhyde of Formula 11 can be effected by: i) using an agent, such as PCC, PDC, or MnOs, in an aprotic solvent; or ii) by catalysis, for example by using TEMPO/bleach and TPAP/NMO (Caron, S., Dugger, R. W., Gut Ruggeri, S., Ragan, J. A., Brown Ripin, D. H., Chem. Rev. 2006, 106, 2943-2989) or Swern oxidation conditions.

A compound of Formula (I) may be prepared as shown in Scheme 2, wherein R is H or PG.

Scheme 2

A 4-nitroaniline of Formula 12 may be acylated to provide an amide of Formula 13 with a carboxylic acid using standard amide coupling reagents such as EDCI, HATU, HBTU, or T3P; or by reaction with an alternate acylating agent, such an acid chloride or acyl imidazole, in a solvent such as DCM or DMF, in the presence of an organic base such 10 as EhN, at a température between 0 °C and reflux.

Alkylation of an amide of Formula 13 to provide an amide of Formula 14 may be effected with an alkylating agent such as an alkyl halide or tosylate, in the presence of a base such as KOtBu or LiHMDS, in a polar aprotic solvent such as DMF or THF.

A nitro aniline of Formula 15 may be prepared by substitution of X in a compound of Formula 14 with a nitrogen nucleophile, such as ammonia or benzyl or substituted benzyl amine, at 25 to 100 °C, either neat or in a solvent such as DMF or THF.

B 33

Réduction of a nitro aniline of Formula 15 (with concomitant deprotection, as required) can be performed under hydrogénation conditions with Pd catalyst, such as 10% Pd/C under 1-3 atm H2, in an alcoholic solvent such as MeOH or EtOH, at a température between 20 and 60 °C, to deliver orfho-diamines of Formula 16. Alternatively, when R -

H, réduction of the nitro group can be effected by use of a métal such as Zn or Fe in AcOH, at a température between 20 -100 °C.

A diamine of Formula 16 can be condensed with an aldéhyde of Formula 11 in a polar solvent, such as DMF with 2-5 eq DMSO, with an oxidant such as Na2S2O5, at a température between 90 and 150 °C, to deliver a benzimidazole of Formula 17. Alternatively, the condensation of compounds of Formulae 16 and 11 can proceed in the presence aqueous NaHSOa, and EtOH or other alcoholic solvent, at 60 °C to reflux.

Removal of the protecting group in a compound of Formula 17 to deliver the 15 corresponding compound of Formula (I) may be performed under conditions well known to the skilled person. For instance, when PG = SEM, the protecting group may be removed by use of TFA in DCM, optionally with added EtaSiH.

By processes directly corresponding to those described in Scheme 2, a compound of 20 Formula (I) may also be prepared from a 3-nitro aniline of Formula 18, according to Scheme 3.

Scheme 3

A compound of Formula (I) may also be synthesized according to Scheme 4, wherein R is H or PG.

A 4-nitro aniline of Formula 12 may be AFprotected with an appropriate protecting group such as BOC or Ac to deliver a compound of Formula 19, which in turn may be /Valkylated with an alkyl halide, as described in Scheme 2 above for the préparation of a compound of Formula 14, to deliver a compound of Formula 20,

A compound of Formula 20 may be substituted under conditions of aromatic 10 nucleophilic substitution to give a compound of Formula 21; which in turn may be reduced, e.g. under the conditions described above in Scheme 2 for the préparation of a compound of Formula 16, to give a diamine of Formula 22; and the diamine finally condensed with an aldéhyde of Formula 11 to deliver an orthogonally protected compound of Formula 23.

Sélective deprotection of the aniline protecting group of a compound of Formula 23 to deliver an aniline of Formula 24 can be achieved by reaction with ZnBr2 or TMSOTf (PG = BOC), in a non-polar solvent such as DCM; or by basic hydrolysis with aq. NaOH or KOH, in MeOH or EtOH, at reflux (PG = Ac).

An aniline of Formula 24 may be acylated under the conditions described above in Scheme 2 for the préparation of a benzimidazole of Formula 17, and the benzimidazole subsequently deprotected to provide a compound of Formula (I) under conditions well known to the skilled person, such as those described in Scheme 2 for the préparation of Formula (I).

Compounds of Formula (I) may also be synthesized according to Scheme 5.

io Scheme 5

A 1-bromo-3,4-diamino benzene of Formula 25 may be condensed with an aldéhyde of Formula 11, under the conditions described in Scheme 2 for the préparation of a compound of Formula 17, to provide a benzimidazole of Formula 26, which in turn may be protected by reaction with SEM-CI in an aprotic solvent such as THF or DMF, with a base such as NaH, KOtBu or LiHMDS, at a température between -78 °C and 60 °C, to provide a mixture of regioisomers of Formulae 27a and 27b. The compound of Formula 27b may be isolated therefrom by conventional techniques.

While the description of subséquent transformations is made with reference to Formula 27b, the skilled person will appreciate that:

i. the mixture of regioisomers of Formulae 27a and 27b may be employed in the ultimate préparation of a compound of Formula (I) (leading to the préparation of corresponding pairs of regioisomers of Formulae 29, 30 and 31 ); and ii. the regioisomers of compounds of Formula 29, 30 or 31 may also be isolated by conventional techniques and used in the ultimate préparation of a compound of Formula (I).

Transition métal catalyzed cross-coupling of a compound of Formula 27b with a protected amine dérivative such as t-butyl carbamate, otherwise known as a Buchwald/Hartwig coupling, provides a protected aniline of Formula 28. The crosscoupling reaction may be catalyzed by Pd or Cu métal and appropriate ligands and performed in a solvent such as toluene, t-amyl alcohol or 1,4-dioxane; with a range of bases including CS2CO3, LiHMDS, NaOtBu and KOtBu; and at températures between 20 and 120 °C.

A protected aniline of Formula 28 may be alkylated as described in Scheme 2 for the préparation of a compound of Formula 14 to deliver a compound of Formula 29. The subséquent steps of deprotection to deliver a compound of Formula 30, acylation to deliver a compound of Formula 31 and final deprotection to deliver a compound of Formula (I) may be carried out under conventional conditions, such as those described in Scheme 4 for the préparation of, respectively, compounds of Formulae 24, 17 and (l).

A compound of Formula (I) may also be synthesized according to Scheme 6.

A compound of Formula 28 may be deprotected, under the conditions described in Scheme 5 for the préparation of a compound of Formula 30, to deliver an aniline of

Formula 32, which may be acylated, under the conditions described in Scheme 2 for the préparation of a benzimidazole of Formula 17, to provide an amide of Formula 33.

An amide of Formula 33 may be N-alkylated to provide a compound of Formula 31, and subsequently deprotected to provide a compound of Formula (I), under conventional conditions, such as described in Scheme 2 respectively for the préparation of compounds of Formulae 14 and (I).

A compound of Formula (I) wherein R⁴ is a morpholinyl substituent may also be synthesized according to Scheme 7.

An aniline of Formula 30 may be acylated by use of acetyl chloride or acetic anhydride, neat or in an aprotic solvent such as DCM, with an organic base such as EtsN, at a 5 température between -20 and 60 °C, to deliver an N-acetyl compound of Formula 34.

A compound of Formula 34 may be treated with a strong base such as LDA in an aprotic solvent such as THF, followed by chlorination by a reagent such as benzene sulfonyl chloride, to deliver an α-chloro amide of Formula 35.

An amide of Formula 35 may be treated with the appropriate morpholine, in an aprotic solvent such as DMF or MeCN, in the presence of a base such as K2CO3 or NasCOa, and with addition of Nal, to provide a compound of Formula 31, which may then be deprotected to provide a compound of Formula (I) under conventional conditions, such 15 as those described in Scheme 2 for the préparation of a compound of Formula (I),

B 39

A compounds of Formula (I) may be transformed to alternative compound of Formula (I) by functionaî group in te rcon version s well known to those skilled in the art. For example, when R⁵ or R⁶ is haîogen, such as Br or Cl, additional transformation is possible using synthetic techniques such as transition métal mediated coupling reactions including 5 Suzuki and Buchwald/Hartwig cross couplings, cyanations and borylations, among other reactions, to manipulate substitution at those positions.

Compounds of Formulae 1, 12, 18 and 25 may be acquired from commercial sources, prepared by anaiogy with literature methods, or obtaîned by the methods described in 10 the Experimental section that follows or variations of the same, well known to the skilled person.

Ail new processes for preparing compounds of Formula (I) or a pharmaceutically acceptable salts thereof, and corresponding new intermediates employed therein, form 15 further aspects ofthe present invention.

Compounds of the invention intended for pharmaceutical use may be administered in amorphous or crystalline form or may exist in a continuum of solid States ranging from fully amorphous to fully crystalline. They may be obtaîned, for example, as solid piugs, 20 powders, or films by methods such as précipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.

Compounds ofthe invention may be administered by any suitable route in the form of a 25 pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term 'excipient’ is used herein to describe any ingrédient other than the compound(s) of the invention. The choice of excipient will to a large extent dépend on factors such as the mode of 30 administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

Modes of administration for compounds of the invention include oral, parentéral, topical, rectal, vaginal, ocular and aurai administration.

Oral administration may involve swallowing, so that a compound of the invention enters the gastrointestinal tract, or buccal or sublingual administration, such that the compound enters the bloodstream directly from the mouth.

Parentéral administration may involve injecting a compound of the invention into the bloodstream, muscle or an internai organ, where the injection may be intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrastemal, intracranial, intramuscular or subcutaneous. Parentéral administration may employ needle (including microneedle) injectors, needle-free injectors and infusion techniques.

Topical administration is preferred and includes:

• administration to the skin, nail, haïr, claw, hoof, mucosa;

• dermal or transdermal administration;

• intranasal administration or administration by inhalation;

• rectal or vaginal administration; and • administration directly to the eye or ear.

The term transdermal administration refers to the diffusion of a compound of the invention across the barrier of the skin, nail, hair, claw or hoof resulting from topical administration or other application of a composition. Transdermal delivery includes delivery through any portion of the skin, nail, hair, claw or hoof and absorption or perméation through the remaining portion.

Topical administration of a compound of the invention can resuit in distribution of the compound limited to the skin and surrounding tissues or, when the compound is removed from the treatment area by the bloodstream, can resuit in systemic exposure of the compound of the invention. Preferably, topical administration of a compound of the invention results in distribution of the compound limited to the skin and surrounding tissues. Where systemic exposure of the compound of the invention occurs, preferably the compound is rapidly metabolized so that systemic exposure of compound of the invention is minimized. Minimizing systemic exposure can reduce unwanted biological effects (i.e. side effects).

B 41

In another aspect the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient.

Pharmaceutical compositions suitable for the delivery of compounds of the invention and methods for their préparation will be readily apparent to those skilled in the art. Such compositions and préparative methods may be found in, for example, “Remington’s Pharmaceutical Sciences”, 19th Edition (Mack Publishing Company, 1995).

Pharmaceutical compositions are typically prepared by mixing a compound of the invention and one or more excipients. Excipients include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobie materials, gelatin, oils, solvents, water, buffers, stabilizing agents, 15 surfactants, wetting agents, lubricating agents, emulsifiers, suspendîng agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and the like. Solvents may include water, éthanol, propylene glycol, polyethylene glycols (e.g., PEG400, PEG300), and mixtures thereof. The excipient(s) are chosen to facilitate manufacture, or use, of the 20 pharmaceutical composition.

Pharmaceutical compositions may be prepared by conventional dissolution and mixing.

For example, the compound of the invention may be dissolved in a solvent in the présence of one or more of the excipients described above. The dissolution rate of 25 poorly water-soluble compounds may be enhanced by the use of a spray-dried dispersion, such as those described by Takeuchi, H., et al. in “Enhancement of the dissolution rate of a poorly water-soluble drug (tolbutamide) by a spray-drying solvent déposition method and disintegrants” J, Pharm. Pharmacol., 39, 769-773 (1987); and US2002/009494; incorporated herein by reference.

Solid dosage forms for oral administration of compounds of the invention include, for example, tablets, hard or soft capsules, lozenges, granules or powders, each containing at least one compound of the invention. In such solid dosage forms the compound of the invention is ordinarily combined with one or more pharmaceutically acceptable

B ⁴² excipients. Solid dosage forms for oral administration such as tablets and capsules may be prepared with enteric coatings.

Liquid dosage forms for oral administration of compounds of the invention include, for 5 example, pharmaceutically acceptable émulsions, solutions, suspensions, syrups, and élixirs containing inert diluents commonly used in the art (e.g. water). Such compositions also may comprise excipients, such as wetting, emulsifying, suspending, flavoring (e.g. sweetening), and/or perfuming agents.

Parentéral formulations of compounds of the invention are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffers (preferably buffering to a pH of from 3 to 9). Formulations for parentéral administration may also be stérile non-aqueous solutions, or dried (e.g. lyophilised) forms to be administered on reconstitution with a suitable vehicle such as stérile, pyrogen-free water.

Pharmaceutical compositions for topical or transdermal administration of a compound of the invention include ointments, pastes, creams, lotions, gels, suppositories, powders, solutions, sprays, drops, inhalants and patches. The compound of the invention is admixed under stérile conditions with a pharmaceutically acceptable topical carrier and 20 any preservatives or buffers as may be required. Compounds that are volatile may require admixture with formulating agents or with packaging materials to assure proper dosage delivery. Compounds of the invention that hâve poor skin permeability may require one or more perméation enhancers, whereas compounds rapidly absorbed through the skin may require formulation with absorption-retarding agents or barriers.

The term “pharmaceutically acceptable topical carrier refers to a carrier medium, suitable for topical application, that provides appropriate delivery of an effective amount of a compound of the invention, such as an inactive liquid or cream vehicle capable of suspending or dissolving the compound. The skilled person will appreciate that this 30 term encompasses carrier materials approved for use in topical cosmetics as well.

The terms “perméation enhancer” relates to an increase in the permeability of the skin, nail, hair, claw or hoof to the compound of the invention, so as to increase the rate and extent of perméation of the compound. The enhanced perméation can be observed, for example, by measuring the rate of diffusion of the drug through animai or human skin, nail, hair, claw or hoof using a diffusion cell apparatus. A diffusion cell is described by Merritt et al. Diffusion Apparatus for Skin Pénétration, J of Controlled Release, 1 (1984) pp. 161-162.

The ointments, pastes, creams, lotions, gels, suppositories, powders, solutions, sprays, drops, inhalants and patches for topical administration may contain, in addition to a compound of the invention, one or more pharmaceutically acceptable excipients, such animal or vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose dérivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, zinc oxide, preservatives, antioxidants, fragrances, emulsifiers, dyes, inert fillers, anti-irritants, tackifiers, fragrances, opacifiers, antioxidants, gelling agents, stabilizers, surfactants, émollients, coloring agents, preservatives, buffering agents, perméation enhancers. Such excipients should not interfère with the effectiveness of the bîological activity of the active agent and not be deleterious to the épithélial cells or their function.

Transdermal administration may be achieved by means of a transdermal patch. The transdermal patch may be of the ‘réservoir and porous membrane’ type or employ a ‘matrix System’.

The solubility of compounds of compounds of the invention used in the préparation of pharmaceutical compositions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.

Pharmaceutical compositions may be formulated to be immédiate and/or modified release. Conveniently compounds of the invention are formulated for immédiate release

Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted- and programmed-release. Thus compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include poly(dl-lactic-coglycolic)acid (PGLA) microspheres.

b 44

The compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable dérivatives thereof, or polyethylene glycolcontaining polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of 5 administration.

For administration to human patients, the total daily dose of the compounds of the invention is typically in the range 1mg to 10g, such as 60mg to 6g, for example lOOmg to 1.5g, depending on the mode of administration and efficacy. For example, 10 administration may require a total daily dose of from 200mg to 1g, such as from 250mg to 750mg. The total daily dose may be administered in single or divided doses and may, at the physician’s discrétion, fall outside of the typical range given herein. These dosages are based on an average human subject having a weight of about 60kg to 70kg. The physician will readily be able to determine doses for subjects whose weight 15 falls outside this range, such as infants and the elderly.

As noted above, the compounds of the invention are useful because they exhibit pharmacological activity in animais, i.e. inhibition of ITK. More particularly, the compounds of the invention are of use in the treatment of disorders for which an ITK 20 inhibitor is indicated.

Preferably the animal is a mammal, more preferably a human.

Preferably the compound of the invention also inhibits TRKA.

In a further aspect of the invention there is provided a compound of the invention for use as a médicament.

In a further aspect of the invention there is provided a compound of the invention for use 3û in the treatment of a disorder for which an ITK inhibitor is indicated.

In a further aspect of the invention there is provided use of a compound of the invention for the préparation of a médicament for the treatment of a disorder for which an ITK inhibitor is indicated.

In a further aspect of the invention there is provided a method of treating a disorder in an animal (preferably a mammal, more preferably a human) for which an ITK inhibitor is indicated, comprising administering to said animal a therapeutically effective amount of a compound of the invention.

Disorders or conditions for which an ITK inhibitor is indicated include inflammatory, autoimmune, dermatologie, eye, respiratory, joint, cardiovascular and neuroinflammatory diseases. The skilled person will appreciate that a given disease, disorder or condition may fall into more than one of the above categories,

More particularly, disorders or conditions for which an ITK inhibitor is indicated include:

• inflammatory disorders, such as allergie conjunctivitis, celiac diseases, proctitis, éosinophilie gastroenteritis, mastocytosis, inflammatory bowel disease (e.g. Crohn’s disease, ulcerative colitis, microscopie colitis (such as collagenous colitis or lymphocytic colitis), diversion colitis, Behcet’s disease, and indeterminate colitis), nephritis, retinitis, retinopathy, myositis, vasculitis, Sjogren’s syndrome, Wegener's granulomatosis, arteritis, sclerosing cholangitis, and éosinophilie esophagitis;

• autoimmune disorders, such as lupus nephritis, autoimmune hepatitis, myasthenia gravis, Guillain-Barre syndrome, and Graves' disease;

• eye disorders or conditions, including autoimmune diseases of the eye, keratoconjunctivitis, vernal conjunctivitis, non-infectious uveitis (e.g. uveitis associated with Behcet's disease and lens-induced uveitis), keratitis (e.g. herpetic keratitis and conical keratitis), corneal épithélial dystrophy, keratoleukoma, ocular premphigus, Mooren's ulcer, scleritis, retinitis, retinopathy, Grave’s ophthalmopathy, Vogt-Koyanagi-Harada syndrome, keratoconjunctivitis sicca (dry eye), phlyctenule, iridocyclitis, sarcoidosis, endocrine ophthalmopathy, sympathetic ophthalmitis, allergie conjunctivitis, and ocular neovascularization;

• dermatological conditions, such as eczema (e.g. chronic and dyshidrotic eczema), chronic itch, dermatitis (e.g. atopie, irritant contact, allergie contact, occupational, perioral, stasis, nummular, seborrheic, xerotic, eyelid, diaper, and hand dermatitis), vîtiligo, alopecia areata, pruritis (e.g. chronic idiopathic pruritus), psoriasis (e.g. plaque, guttate, inverse, pustular, nail, flexural palmoplantar, facial or érythrodermie psoriasis), scleroderma, pemphigus, dermatomyositis, neurodermatitis, skin flushing, urticaria, cutaneous lupus erythematosus (e.g. acute cutaneous lupus (acute skin lupus), subacute cutaneous lupus (subacute lupus), and chronic cutaneous lupus (discoid lupus)), keloid, sunburn, hypertrophie scar, idiopathic thrombocytopénie thrombotic purpura (also known as immune thrombocytopenia purpura (ITP)), ichthyosis (e.g. ichthyosis vulgaris), epidermal hyperplasia, acné, lichen planus, lichen sclerosis, rosacea, epidermolysis bullosa, intertrigo, keratosis pilaris, urticaria (e.g. chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria), molluscum contagiosum, Netherton syndrome, VogtKoyanagi-Harada syndrome, Sweet’s syndrome, pityriasis alba, vulvovaginitis, Sutton’s nevus/nevi, post inflammatory hypopigmentation, senile leukoderma, chemical/drug-induced leukoderma, palmoplantar pustulosis, pemphigoid, and hidradenitis suppurativa;

• respiratory conditions, such as rhinitis (e.g. allergie and perennial rhinitis), rhinorrhoea, nasal congestion, nasal inflammation, asthma (e.g. chronic asthma, inveterate asthma, late asthma, bronchial asthma, allergie asthma, intrinsic asthma, extrinsic asthma, and dust asthma), chronic obstructive pulmonary disease (COPD), chronic and acute bronchoconstriction, chronic bronchitis, emphysema, chronic éosinophilie pneumonia, acute lung injury (ACI), adult respiratory distress syndrome (ARDS), pulmonary vascular disease (PVD), pulmonary arterial hypertension (PAH), bronchiectasis, sinusitis, pulmonary sarcoidosis, and silicosis;

• joint disorders, such as arthritis (e.g. osteoarthritis, as well as psorîatic, rheumatoid, juvénile, and gouty arthritis), spondyloarthropathy (e.g. reactive arthritis (also known as Reiter's Syndrome) and axial spondyloarthritis (including ankylosing spondylitis)), cartilage inflammation, bone dégradation, and Still's disease;

• cardiovascular and metabolic disorders, such as diabètes (type 1 and type 2), diabetic neuropathy, cachexia, and Celiac Sprue; and • neuroinflammatory disorders, such as lupus (e.g. CNS, systemic and discoid lupus), diabetic neuropathy, and multiple sclerosis.

Allergie contact dermatitis (ACD) is a contact dermatitis characterised by an ailergic response to contact with a substance. An example of ACD is urushiol-induced contact dermatitis (also called toxicodendron dermatitis or rhus dermatitis), which is caused by the oil urushiol found in various plants, including poison ivy, poison oak, poison sumac

B 47 and the Chinese lacquer tree. Other allergens that can induce ACD include chromium, gold and nickel.

Irritant contact dermatitis (ICD) is a form of contact dermatitis that can be divided into 5 forms caused by Chemical irritants and those caused by physîcal irritants. Common

Chemical irritants include acids, alkalis, latex, oils, perfumes and preservatives in cosmetics, solvents, and surfactants,

Occupational dermatitis is an ACD or ICD arising from exposure to an allergen or irritant 10 in a work environment.

Additionally, an ITK inhibitor may be of use in treating certain viral and bacterial infections, transplant rejection, septic shock, acute or chronic graft-versus-host disease, polymyalgia rheumatica, sarcoidosis, Addison's disease and Raynaud's syndrome.

In one embodiment the disorder or condition for which an ITK inhibitor is indicated is a dermatological condition. In another embodiment the dermatological condition for which an ITK inhibitor is indicated is dermatitis. In another embodiment the dermatitis for which an ITK inhibitor is indicated is atopie dermatitis.

A compound of the invention may usefully be combined with one or more other pharmacologically active compounds. Such combinations offer the possibility of significant advantages, including patient compliance, ease of dosing and synergistic activity.

In a further aspect of the invention there is provided a compound of the invention in combination with another pharmacologically active compound, or with two or more other pharmacologically active compounds.

In such combinations the compound ofthe invention and other pharmacologically active compound(s) may be administered simultaneously, such as in a single dosage form (e.g. a composition for topical administration, such as a cream or an ointment), sequentially or separately.

The one or more additional therapeutic agents may be selected from any of the agents or types of agent that follow:

• an agent for treating autoimmune and/or inflammatory disorders, such as, sulfasalazine, mesalazine, azathioprine, an antibody (e.g. infliximab, adalimumab, belimumab, tanezumab, ranibizumab, bevacizumab, mepolizumab certolizumab, natalizumab, and vedolizumab), 6-mercaptopurine, hydroxychloroquine, mofetil, sodium mycophenolate, leflunomide, rituxan, solumedrol, depomedrol, a nonsteroidal anti-inflammatory drug (NSAID) (e.g. aspirin, ibuprofen, celecoxib, valdecoxib, WBI-1001 and MRX-6), and a corticosteroid (e.g. betamethasone, dexamethasone, and prednisone);

• an agent for treating dermatological conditions, such as an immunosuppressant (e.g. cyclosporin, tacrolimus, and pimecrolimus), an antibody (e.g. infliximab, adalimumab dupilumab, omalizumab, and efalizumab), a TNF inhibitor (e.g. etanercept), a PDE4 inhibitor (e.g. crisaborole), and a topical corticosteroid (e.g. fluocinonide, mapracorat, hydrocortisone, desonide, alclometasone, triamcinolone, and desoximetasone);

• an agent for treating respiratory conditions, such as oxymetazoline, rifampin, an anti-histamine (e.g. fexofenadine, loratidine, desloratidine, levocetirizine, methapyrilene, cetirizine), a leukotriene receptor antagonist (e.g. montelukast and zafirlukast), a 5-lipoxygenase actîvating protein (FLAP) antagonist, a muscarinic receptor antagonist (e.g. tiotropium and ipratropium), sodium cromoglycate, sodium nedocromil, a corticosteroid (e.g. budesonide, fluticasone, mometasone, dexamethasone, prednisolone, ciclesonide, and beclomethasone), a beta-2 agonist (e.g. salmeterol, albuterol, salbutamol, fenoterol, and formoterol), and an antibody (e.g. omalizumab);

• an agent for treating joint disorders, such as methotrexate, azathioprine, and an NSAID (e.g. aspirin, ibuprofen, celecoxib, valdecoxib, WBI-1001 and MRX-6);

• an agent for treating cardiovascular and metabolic disorders, such as ursodeoxycholic acid, chloroquine, quinacrine, methylnorephrine, phenylephrine, methoxamine, oxymetazoline, theophylline, a PDE5 inhibitor (e.g. sildenafil, vardenafil, and tadalafil), a PDE4 inhibitor (e.g. crisaborole, ibudilast, cilomilast, roflumilast, and ampremilast), and a kinin Bi or B2 receptor antagonist; and • an agent for treating neuroinflammatory disorder treatments, such as cyclophosphamide.

The one or more additional therapeutie agents may also be selected from any of the agents that follow:

• a JAK inhibitor, such as abrocitinib, baricitinib, brepocitinib cerdulatinlb, decernotinib, delgocitinib, fedratinib, filgotinib, gandotinib, ilginatînib, itacitinib, lestaurtinib, momelotinib, oclacitinib pacritinib, peficitinib, ritlecitinib, ruxolitinib, tofacitinib, upadacitinib, ATI-502, BMS-986165, JTE052, PF-06826647, SNA-152, and SHR-0302;

an aryl hydrocarbon receptor agonist such as, tapinarof;

an IRAK4 inhibitor such as PF-06650833;

a vitamin D analog, such as calcipotriene;

a retinoic acid dérivative such as, alitretinoin;

a liver X receptor (LXR) sélective agonist, such as VTP-38543;

an H4 receptor antagonist, such as, ZPL-389;

an NK1 receptor antagonist, such as, aprepitant and tradipitant;

a CRTH2 receptor antagonist, such as, fevipiprant and OC-459;

a chymase inhibitor, such as SUN 13834;

a GATA-3 inhibitor, such as SB-011 and GR-MD-02;

an ROR inverse agonist, such as VTP-43742, ARN6039, TAK-828 and JTE-451 ;

an immunomodulator, such as PF-06763809; and • an inhibitor of SYK and BTK, including but not limited to, R-348, fostamatinib, mastinib, mivavotinib, sperbrutinib, fenebrutinib, cerdulatinib, ibrutinib, entospletinib and tirabrutinib.

It is within the scope of the invention that two or more pharmaceutical compositions, at least one of which contains a compound of the invention, may conveniently be combined in the form of a kit suitable for coadministration of the compositions. Thus the kit of the invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is the familiar blister pack used for the packaging of tablets,

B 50 capsules and the like. The kit of the invention is particularly suitable for administering different dosage forms (e.g. top ica I, oral, parentéral, etc.), for administering the se pa rate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit typically comprises directions for 5 administration and may be provided with a so-called memory aid.

In another aspect the invention provides a pharmaceutical product (such as in the form of a kit) comprising a compound of the invention together with one or more additional therapeutically active agents as a combined préparation for simultaneous, separate or 10 sequential use in the treatment of a disorder for which an ITK inhibitor is indicated.

It is to be appreciated that ail references herein to treatment include curative, palliative and prophylactic treatment.

In the non-limiting Examples and Préparations set out below that illustrate the invention, and in the aforementioned Schemes, the following the abbreviations, définitions and analytical procedures may be referred to:

°2θ is degrees 2-Theta;

AcOH is acetic acid;

AC2O is acetic anhydride;

APC is allophycocyanin;

aq. is aqueous;

atm is atmosphère;

ATP is adenosine 5'-triphosphate disodium sait trihydrate;

BINAP is (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl);

Boc is terf-butoxycarbonyl;

BOC2O is BOC anhydride, di-tert-butyî dicarbonate;

br is broad;

BTFFH is fluorobis(tetramethylene)formamidinium hexafluorophosphate;

BTK is Bruton’s tyrosine kinase;

°C is degrees celcius;

CD3OD is deutero-methanol;

CDChis deutero-chloroform;

conc. is concentrated;

CSA is camphor sulphonic acid;

δ is Chemical shift;

d is doublet;

dd is doublet of doublets;

ddd is doublet of doublet of doublets;

dt is doublet of triplets;

DAST is diethylaminosulfur trifluoride;

DCM is dichloromethane;

DCE is 1,2-dichloroethane;

Dess-Martin periodinane is 3-oxo-1,3-dihydro-1Â⁵,2~benziodoxole-1,1,1-triyl triacetate;

DHP is dihydropyran;

DMAP is 4-dimethyiaminopyridine;

DMF is N,N-dimethylformamide;

DMSO is dimethyl sulfoxide;

EDCI is 1-ethyl-3-(3-dimethylaminopropyl)carbodÜmide hydrochloride;

ee is enantiomeric excess;

EDTA is ethylenediaminetetraacetic acid;

ESI-MS is electrospray ionization mass spectrometry;

EtOAc is ethyl acetate;

EtOH is éthanol;

EtONa is sodium ethoxide;

EtaN is triethylamine;

EtsSiH is triethylsilane;

g is gram;

h is hour(s);

HATU is 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide, hexafluorophosphate;

HBTU is N.N.N'.N’-tetramethyl-O-fl H-benzotriazol-1-yl)uronium hexafluorophosphate;

HEPES is (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid);

HPLC is high pressure liquid chromatography;

iPr2NEt is Ν,Ν-diisopropylethyl amine, also known as Hunig's base;

KOAc is potassium acetate;

KOtBu is potassium tert-butoxide;

b ⁵²

L is liter;

LAH is lithium aluminium hydride;

LCMS is liquid chromatography mass spectrometry;

LDA is lithium diisopropylamide;

LiHMDS is lithium hexamethyldisilazide, also known as lithium bis(trimethylsilyi)amide; m is multiplet;

M is molar;

MeCN is acetonitrile;

MeNHz is methyl amine;

MeOH is methanol;

MHz is mega Hertz;

min is minutes;

mL is millilîter;

mm is millimeter;

mmol is millimole;

mol is mole;

MS m/z is mass spectrum peak;

MTBE is methyl tert-butyl ether;

n-BuLi is n-butyl lithium;

NaHMDS is sodium bis(trimethylsilyl) amide;

NaOtBu is sodium fert-butoxide;

NMP is A/-Methyl-2-pyrrolidone;

NMR is nuclear magnetic résonance;

ORTEP is Oak Ridge Thermal Ellipsoid Plot;

PCC is pyridinium chlorochromate;

PDC is pyridinium dichromate;

Pd2(dba)3 is tris(dibenzylideneacetone)dipalladium(0);

Pd/C is palladium on carbon;

Pd(dppf)Cl2 is 1 ,T-bis(diphenylphosphino)ferrocene]dichloropalladium(ll);

Pd(OAc)2 is palladium(ll)acetate;

Pd(OH)2/C is palladium(ll)hydroxide on carbon;

Pd(Ph3P)4 is tetrakis(triphenylphosphine)palladium(0);

PE is petroleum ether;

PhCHa is toluene;

PMB is para-methoxybenzyl;

pTSA is p-toluenesulfonic acid monohydrate;

PXRD is powder X-ray diffraction;

q is quartet;

Qphos is 1,2,3,4,5-pentaphenyl-1 '-(di-fert-butylphosphino)ferrocene;

RT is room température;

s is singlet;

sat. is saturated;

SEM-CI is 2-(trimethylsilyl)ethoxymethyl chloride;

SFC is supercritical fluid chromatography;

SPhos is 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl;

SXRD is single crystal X-ray diffraction;

t is triplet;

ferf-BuDavePhos is 2-di-tert-butylphosphino-2'-(N,N-dimethylamino)biphenyl;

t-BuOH is fert-butanol;

TCEP is tris(2-carboxyethyl)phosphine;

TFA is trifluoroacetic acid;

TFAA is trifluoroacetic anhydride;

TGA is thermogravimetric analysis;

THF is tetrahydrofuran;

TMSCF3 is Trifluoromethyltrimethylsilane;

TMSOTf is Trimethylsilyl trifluoromethanesulfonate;

T3P is pro pylph os phonie anhydride;

Tris is tris(hydroxymethyl)aminomethane;

μηπ is micrometer;

v/v îs volume by volume;

w/v is volume by volume;

XantPhos is 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene; and

ZnEt2 is diethylzinc.

Unless otherwise stated ail reactions are run under a nitrogen atmosphère. When sodium hydride is used in the following procedures the weights are corrected to reflect its use as a 60% suspension in minerai oii. RT (room température) is generally taken to mean approximately 22 °C (± 5 °C). The term “concentrated” refers to the process of removal of volatile compounds, such as solvents, by use of a rotary evaporator under reduced pressure.

Ή and ¹⁹F Nuclear NMR spectra were in ail cases consistent with the proposed 5 structures. Characteristic δ for ¹H-NMR are reported relative to residual solvent signais (for CDCI3, ÔH = 7.27 ppm; for DMSO-de, δΗ = 2.50 ppm, for CD3OD, ÔH = 3.30 ppm, for DMF-d?, δΗ = 8.03 ppm) using conventional abbreviations for désignation of major peaks. The skilled person will appreciate that tautomers may be recorded within the NMR data and some exchangeable protons may not be visible. Likewise the skilled 10 person will appreciate that a mixture of rotamers may be recorded within the NMR data.

Mass spectra were recorded using either ESI-MS. Where relevant and unless otherwise stated the m/z data provided are for isotopes ¹⁹F, ³⁵CI, ⁷⁹Br and/or⁸¹ Br and 127|

Where préparative TLC or silica gel chromatography hâve been used, the skilled person will appreciate that any suitable solvent or solvent combination may be employed to purify the desired compound.

Nomenclature for the compounds of the Préparations and Examples that follow was generated using ChemDraw Professional 18.0, Perkin Elmer, in accordance with the IUPAC (International Union of Pure and Applied Chemistry).

Préparations

Préparation 1: 1 -methoxv-5-methylcyclohexa-l,4-diene

The reaction was carried out in 25 parallel batches. To a solution of 1-methoxy-3methylbenzene (500 g, 4.09 mol) in t-BuOH (1.5 L) and THF (1 L) was bubbled in anhydrous ammonia (1.4 kg, 82.2 mmol) while the reaction was kept between -60 and 30 50 °C. To the reaction mixture was then added lithium sand (62.5 g, 9.0 mol) by portions while maintaining the température between -60 and -50 °C and the reaction was stirred for 2 h. The reaction mixture was warmed slowly to -20 °C and the ammonia was allowed to evaporate. To the reaction was added NH4CI (500 g) and water (500 mL). The batches were combined, and the organic layer was separated. The aqueous layer was washed with EtOAc (5 L x2). The combined organic layers were then washed with brine (5 L) and the organic layer was dried (NazSCU) and concentrated to provide the title compound (10.1 kg, 80%). Ή NMR (400 MHz, CDCI3) δ 5.42 - 5.41 (m, 1 H), 4.65 - 4.63 (m, 1 H), 3.56 (s, 3H), 2.79 - 2.77 (m, 2H), 2.65 - 2.56 (m, 2H), 1.74-1.68 (m, 3H).

Préparation 2: 7-methyl-1.4-dioxaspiro|4.5]dec-7-ene

ΛΌ < j^^ch₃ ⁰

The reaction was carried out in 6 parallel batches. To a solution of Préparation 1 (500 g, 4.03 mol) in DCM (4.0 L) was added with p-toluenesulfonic acid monohydrate (46.8 g, 201 mmol) and ethylene glycol (399 g, 6.04 mol) between -10 and 0 °C. The mixture was stirred at approximately 0 °C for 0.5 h. The reaction batches were combined and washed with sat. aq. NaHCOs (5 L), water (5 L, 2x), dried (Na2SO4), filtered and concentrated to provide the title compound (14.2 kg). Ή NMR (400 MHz, CDCI3) Ô 5.40-5.34 (m, 1 H), 3.98-3.88 (m, 4H), 2.21-2.12 (m, 4H), 1.67 (d, 5H).

Préparation 3: 1-methvlsDirorbicvclo[4.1.01heptane-3,2'~ri ,31dioxolane1

The reaction was carried out in 10 parallel batches. A solution of ZnEtï (1.00 M, 5.14 L) in DCM (2.0 L) was cooled at 0 °C to which was added TFA (380 mL, 5.14 mol) dropwise at 0 °C. The mixture was stirred at 0 °C for 30 min after which CH2I2 (414 mL, 5.14 mol) was added dropwise at 0 °C. The mixture was stirred at 0 °C for 30 min. Préparation 2 (396 g, 2.57 moi) was added dropwise, maintaining the température at 0 °C and the resuiting mixture was stirred at 0 °C for 30 min. The reaction mixture was poured into water (1 L) and the batches were combined. The combined mixture was extracted with DCM (3x8 L). The combined organic phases were dried (Na2SO4), filtered and concentrated to provide the title compound (3.0 kg); ¹H NMR (400 MHz,

CDCI₃) δ 3.93 - 3.73 (m, 4H), 2.13 - 2.01 (m, 1 H), 1.84 - 1.79 (m, 1 H), 1.75 - 1.67 (m,

2H), 1.47 - 1.36 (m, 1 H), 1.27 (m, 1 H), 1.03 (s, 3H), 0.73 - 0.61 (m, 1 H), 0.35 - 0.25 (m,

2H).

Préparation 4: 1-methylbÎcvclo[4.1.0]heptan-3-one n CH₃

The reaction was carried out in 14 parallel batches. A solution of Préparation 3 (300 g, 1,78 mol) in THF (1.5 L) and water (300 mL) was treated with PTSAH2O (34.0 g, 178 mmol). The mixture was stirred at 60 °C for 3 h and then cooled to RT. The 14 batches were combined and treated with sat. aq. NaHCOa solution until the pH was between 6-7. The mixture was extracted with MTBE (3x8 L), dried (Na2SO4), filtered and concentrated. The residue was purified by chromatography (silica, EtOAc/PE = 0100%) to provide the title compound (1.2 kg, 39%). ¹H NMR (400 MHz, CDCh) δ 2.60 2.40 (m, 1H), 2.32 - 2.18 (m, 1H), 2.11 - 1.93 (m, 1 H), 1.34 - 1.17 (m, 1H), 1.17 - 1.05 (m, 4H), 0.95 - 0.86 (m, 1H), 0.85 - 0.74 (m, 2H), 0.43 - 0.33 (m, 1H).

Préparation 5: ethyl 2-(6-methyl-4-oxobicyclo[4.1.01heptan-3-yl)-2-oxoacetate ⁰ 'l EtO'-i'''· O

The reaction was carried out in four parallel batches. A solution of Préparation 4 (200 g, 1.61 mol) in EtOH (1.0 L) was treated with EtONa (126 g, 1.77 mol) at 0 °C. Diethyl oxalate (259 g, 1.77 mol, 242 mL) was added at 0 °C and the mixture was slowly warmed to 20 °C and stirred for 1 h. The four batches were combined and the mixture was poured into 1N HCl (5 L) and extracted with DCM (3x3 L). The combined organic extracts were dried (NasSOq), filtered and concentrated. The residue was purified by chromatography (silica, EtOAc/PE = 0-10%) to provide the title compound (1.4 kg, 97%). LC/MS m/z (M+H)⁺ - 225.0

Préparation 6: ethyl 5a-methyl-1,4,4a,5,5a,6-hexahvdrocvclopropaff|indazole-3carboxylate

The reaction was carried out in four parallel batches. To a solution of Préparation 5 (350 g, 1.56 mol) in EtOH (1.5 L) was added hydrazine hydrate (79.7 g, 1.56 mol) at 0 ’C. The resulting mixture was stirred at 20 °C for 2 h. The four reaction batches were 5 combined to which was added H2O (10 L) and extracted with DCM (3x8 L). The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE = 5-33%) to provide the title compound (800 g, 58%). ¹H NMR (400 MHz, DMSO-c/_s) δ 13.70 - 12.78 (m, 1H), 4.25 4.20 (m, 2H), 3.14 - 3.07 (m, 1H), 2.89 - 2.82 (m, 2H), 2.68 - 2.62 (m, 1H), 1.27 (br s, 10 3H), 1.20 (br s, 3H), 1.04 - 1.00 (m, 1H), 0.31 - 0.29 (m, 1H), 0.08 - 0.02 (m, 1H);

LC/MS m/z (M+H)⁺ = 221.0,

Préparation 6a: ethyl (4aR,5aS)-5a-methyl-1,4,4a,5,5a,6hexahvdrocyclopropa[flindazole-3-carboxvlate; and

Préparation 6b: ethyl (4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahvdrocvclopropafflindazole-3-carboxvlate

Préparation 6 was separated by chiral SPC (Chiral Tech OZ-H 250 mm x 4.6 mm x 5 μιτι column with a mobile phase of CO2(g)/ MeOH=80:20 with 0.2% NH4⁺(7N NH3 in

MeOH) and a flow rate of 3.0 mL/min).

6a: rétention time = 3.89 min, 100%ee, [α]²⁰ρ = +67.1 (c = 4.2, MeOH); LC/MS m/z (M+H)⁺ =221.1.

6b: rétention time = 4.76 min, 98.9%ee; [o]²⁰d = -80.2 (c = 4.7, MeOH); Ή NMR (400

MHz, DMSO-de) δ 13.44-12.80 (m, 1H), 4.20-4.12 (m, 2H), 3.25-3.10 (m, 1H), 3.09-2.99 (m, 1H), 2.96-2.86 (m, 1H), 2.82-2.71 (m, 1H), 2.63-2.52 (m, 1H), 1.25-1.18 (m, 3H),

1.14 (s, 3H), 1.02-0.92 (m, 1H), 0.34-0.20 (brs, 1H), 0Ό5-Ό.05 (br s, 1H).

Préparation 7a: ethyl (4aS,5aR)-5a-methvl-2-((2-(trimethylsilyl)ethoxv)methyl)2,4.4a,5,5a,6-hexahvdrocvclopropa[f]indazole-3-carboxylate; and

Préparation 7b: ethyl (4aS,5aR)-5a-methvi-1-((2-(trimethylsilvl)ethoxv)methvl)1 ^^a.S.Sa.e-hexahvdrocyclopropafflindazole-S-carboxylate

SEMI SEMI

A suspension of NaH (19.3 g, 483 mmol) in THF (500 mL) was treated with a solution of 5 Préparation 6b (103 g, 467.6 mmol) in THF (1.25 L) at 0 ’C. After 30 min, SEM-CI (81.9 g, 491 mmol) was added at 0 °C and the mixture was stirred at 0 °C for 3 h. The mixture was treated with sat. aq. NH4CI (500 mL) at 0 °C. The mixture was extracted with EtOAc (3 x 500 mL), washed with brine (500 mL), dried (MgSO4), filtered and concentrated. The crude product was purified by chromatography (silica,

EtOAc/heptanes = 7-18%) to provide the title compounds.

7a: (5.5 g, 3.3%);^ NMR (400 MHz, DMSO-cfe) δ 5.43 (br. s, 2H), 4.54 - 4.28 (m, 2H), 3.55 - 3.50 (m, 2H), 3.27 - 3.23 (m, 1H), 3.12 - 3.08 (m, 1H), 2.99 - 2.97 (m, 1H), 2.712.67 (m, 1 H), 1.60 -1.41 (m, 3H), 1.21 (s, 3H), 1.08 - 1.05 (m, 1 H), 0.89 - 0.85 (m, 2H), 0.41 - 0.39 (m, 1H), 0.21 - 0.19 (m, 1H), -0.03 (s, 9H).

7b: (138 g, 84%); ¹H NMR (400 MHz, DMSO-d₆) δ 5.64 (s, 2H), 4.32 - 4.25 (m, 2H), .49 - 3.44 (m, 2H), 3.20 - 3.16 (m, 1H), 2.95 - 2.88 (m, 2H). 2.67 - 2.62 (m, 1H), 1.32 1.28 (m, 3H), 1.21 (s, 3H), 1.05 - 0.95 (m, 1 H), 0.76 - 0.72 (m, 2H), 0.33 - 0.29 (m, 1 H), 0.04-0.01 (m, 1H), -0.1 (s, 9H); LC/MS m/z (M+H)⁺ = 351.3.

2û Préparation 8: ((4aS,5aR)-5a-methvl-1-((2-(trimethvlsilvl)ethoxv)methvl)-1,4,4a,5,5a.6hexahvdrocvclopropaff|indazol-3-vl)methanol

A suspension of L1AIH4 (14.94 g, 393.7 mmol) in THF (500 mL) at 0 °C was treated dropwise with a solution of Préparation 7b (138 g, 393.7 mmol) in THF (1 L). The 25 mixture was stirred at 15 °C for 2 h. The mixture was cooled to 0 °C and treated sequentially by dropwise addition of ΗξΟ (15 mL), 15 % aq. NaOH (15 mL) and H2O (30 mL), followed by addition of MgSO4., and EtOAc (500 mL). The resulting mixture was filtered and the filtrate was concentrated to provide the title compound (110 g, 91 %). ¹H

NMR (400 MHz, CDCh) δ 5.35 - 5.23 (m, 2H), 4.64 - 4.55 (m, 2H), 3.53 - 3.49 (m, 2H), 3.06 - 3.02 (m, 1 H), 2.86 - 2.81 (m, 2H), 2.67 -2.63 (m, 1H), 2.07-1.90 (m, 1H), 1.24 (s, 3H), 1.05 - 1.03 (m, 1H), 0.91 - 0.87 (m, 2H), 0.39 - 0.35 (m, 1H), 0.25 - 0.22 (m, 1H), 0.03 (d, 9H).

Préparation 9: (4aS,5aR)-5a~methvl-1-((2-(trimethvlsilvl)ethoxv)methvl)-1.4,4a.5,5a,6hexahydrocvclopropainindazole-3-carbaldehvde

.. .S EM

A solution of Préparation 8 (110.13 g, 0.36 mol) in DCM (1.5 L) was treated with activated ΜπΟξ (310 g, 3.57 mol) and the resulting mixture was stirred at 25 °C for 16 h. The mixture was filtered. The filtrate was concentrated, and the crude product was purified by chromatography (silica, EtOAc/PE = 3-10%) to provide the title compound (96 g, 88%). SPC method: Chiral Pak AD-3 150 mm x 4.6 mm x 3 pm, 5-40% (0.05% diethylamine in EtOH/CO2(g)) over 1.5 min, 2.5 mL/min, rétention time = 1.466 min 97.4%, 94.8%ee. Ή NMR (400 MHz. DMSO-cfe) δ 9.86 (s, 1H), 5.52 - 5.38 (m, 2H), 3.53- 3.49 (m, 2H), 3.16-3.11 (m, 2H), 2.93-2.82 (m, 1H), 2.69-2.65 (m, 1H), 1.22 (s, 3H), 1.08 - 1.02 (m, 1H), 0.84 - 0.80 (m, 2H), 0.40 - 0.39 (m, 1H), 0.10 - 0.08 (m, 1H), 0.07 (s, 9H); LC/MS m/z (M+H)⁺ = 307.3.

Préparation 10. 7,7-difluoro-1-methvlspirofbicvclo[4.1.0Îheptane-3,2'-(1,31dioxolane1 ch₃

F

The réaction was carried out in 26 batches in parallel. A solution of Préparation 2 (150 g, 972 mmol) in THF (1.20 L) was treated with TMSCF3 (276 g, 1.95 mol) and Nal (75.8 g, 506 mmol). The mixture was stirred at 70 °C for 16 h. The 26 reaction mixtures were cooled to room température and combined. The mixture was diluted with water (10 L) and extracted with MTBE (4x3 L). The organic phase was washed with brine (8 L), dried (NaaSC^), filtered and concentrated to obtain the title compound (4.30 kg, 83% yield).

Préparation 11: 7,7-difluoro-1-methylbicvclo[4.1.01heptan-3-one

CH₃

The reaction was carried out 5 batches in parallel. A mixture of Préparation 10 (860 g, 4.21 mol) in THF (10 L) was treated with 3M HCl (2.6 L) at 25 °C. The mixture was stirred at 25 °C for 16 hours. The 5 reactions were combined and extracted with MTBE (4 x 2.5 L), washed with sat. aq. NaHCOa (5 L) and brine (5 L). The organic phase was dried (NaaSCU), filtered and concentrated to deliver the title compound 11 (3.50 kg); ¹H NMR (400 MHz, CDCI₃) δ: 2.56 (br d, 1H), 2.38-2.13 (m, 4H), 2.01-1.89 (m, 1H), 1.491.38 (m, 1H), 1.27 (brs, 3H)

Préparation 12: ethyl 2-(7,7-difluoro-6-methvl-4-oxobicyclo[4.1.0]heptan-3-yl)-2oxoacetate ch₃

EtO O

The reaction was carried out 8 batches in parallel. A solution of Préparation 11 (250 g, 1.56 mol) in EtOH (1.25 L) was treated with EtONa (112 g, 1.65 mol) in portions at 0 °C. The résultant mixture was treated with diethyl oxalate (242 g, 1.65 mol) at 0 °C. The reaction mixture was stirred at 25 °C for 1 h. The 8 batches were combined. The mixture was poured into 3 M HCl solution (8.00 L) and extracted with DCM (3x2 L). The organic extracts were washed with brine (5 L), dried (Na2SÛ4), filtered and concentrated to deiiver the title compound 12 (3.20 kg, 98% yield)

Préparation 13: ethyl 5,5-difluoro-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropafflindazole-3-carboxvlate

F

The reaction was carried out 8 batches in parallel. A suspension of Préparation 12 (400 g, 1.54 mol) in EtOH (2 L) was treated with hydrazine hydrate (76.9 g, 1.54 mol) at 0 C.

The reaction was stirred at RT for 16 h. The eight reactions were combmed for workup. The reaction mixture was concentrated and the residue taken up in H2O (5.00 L) and extracted with EtOAc (5x2 L). The combined organic extracts were dried over (Na2SO₄), filtered and concentrated. The crude product was purified by recrystallization from 6:1 EtOAc/EtOH (3 L) at 20 °C to deliver the title compound 13 (1.0 Kg). ¹H NMR (400 MHz, CDCI3) δ: 12.03-10.65 (br m, 1H), 4.38 (q, 2H), 3.30-3.04 (m, 3H), 2.79 (dd, 1 H), 1.57 (br dd, 1 H), 1.34-1.43 (m, 6H); LC-MS (ES+) e/z [M+H] = 257.1

Préparation 14: chiral SFC séparation of enantiomers

Préparation 13 was separated by chiral SFC using a Chiral Tech AD-H 250 mm x

21.2mm 5 pm column with a mobile phase of CO2(g)/MeOH = 80:20 with 0.2% 7N NH3 in

MeOH and a flow rate of 200 mL/mîn.

SFC analytical method: Chiral Tech AD-H 250 mm x 4.6 mm x 5 pm A = CO2(g); B = 0.2% NHafas 7N NH3 in MeOH) in MeOH; gradient = 0-1 min 5% B, 1-9.5 min 5-60% B ramp; 9.5-10min 60-5% B ramp.

Prep. 14a, ethyl (4aR,5aS)-5,5-difluoro-5a-methyl-1 AAa.S.SaOhexahydrocyclopropaiflindazole-S-carboxvlate, 100% ee by SFC analytical method, rétention time = 4.605 min

Prep. 14b, ethyl (4aS,5aR)-5,5-difluoro-5a-methyl-1,4,43,5,53,6hexahvdrocvclopropafflindazole-3-carboxvlate, 99.85% ee by SFC analytical method, rétention time = 5.565 min

Préparation 15: ethyl (4aS,5aR)-5.5-difluoro-5a-methyl-1-((2(trimethylsilvl)ethoxv)methyl)-1,4,4a,5,5a,6-hexahvdrocvclopropaffîindazole-3carboxylate _zSEM N-N

F

A mixture of NaH (4.25 g, 106 mmol) in THF (20 mL) cooled to 0 °C was treated dropwise over 45 min with a solution of Préparation 14b (18.16 g, 70.87 mmol) in THF (100 mL). The mixture was stirred at 0 °C for 1 h and then treated dropwise with SEMCl (17.7 g, 106 mmol) in THF (80 mL). The résultant mixture was stirred at RT for 48 h. The reaction mixture was poured slowly over ice and extracted 3x with EtOAc. The organic extracts were combined, washed with brine, dried (MgSÛ4), filtered and concentrated. The crude product was purified by chromatography (silica, EtOAc/heptanes = 0-20%) to deliver 25.8 g (94%) of the title compound. ¹H NMR (400 MHz, CDCh) δ 5.50 - 5.40 (m, 2H), 4.40 (q, 2H), 3.55 - 3.47 (m, 2H), 3.26 - 3.05 (m, 3H), 2.76 (br dd, 1 H), 1.62 - 1.54 (m, 1 H), 1.44 - 1.35 (m, 6H), 0.94 - 0.81 (m, 2H), -0.03 (s, 9H); LC-MS m/z (M+H)⁺ = 387.4

Préparation 16: ((4aS,5aR)-5_I5-difluoro-5a-methvl·1-((2-(trimethvlsilvl)ethoxv)methvl)1₁4,4a,5₁5a,6-hexahvdrocvcloproDaffΊindazol·3-vl)methanol

SEW

To a solution of Préparation 15 (25.84 g, 66.86 mmol) in THF (100 mL) at approximately -5 °C was added a solution of LÎAIH4 (100 mL, 1M in THF) dropwise at such a rate as to control the température between 0 and 10 °C. The mixture was stirred at 0 °C for additional 1 h and gradually warmed to RT and stirred for an additional 4 h. The mixture was cooled to -10 °C and treated dropwise with 6 N NaOH (45 mL) over 30 min. Additional EtOAc was added to aid stirring of the thick mixture and the slurry was warmed to RT. Anhydrous MgSÜ4 was added and stirring continued for an additional 30 min. The mixture was filtered and the solids rinsed with EtOAc. The filtrate was concentrated and dried to deliver the title compound (21.89 g, 95%). Ή NMR (400 MHz,

CDCh) δ 5.38 - 5.21 (m, 2H), 4.60 (s, 2H), 3.55 - 3.41 (m, 2H), 3.08 (br d, 1 H), 2.98 20759

2.83 (m, 2H), 2.79 - 2.65 (m, 1H), 2.24 (br s, 1 H), 1.60 - 1.49 (m, 1 H), 1.40 (br s, 3H), 0.94 - 0.80 (m, 2H), -0.03 (s, 9H); LC-MS m/z (M+H)⁺ = 345.5.

Préparation 17: (4aS,5aR)-5,5-difluoro-5a-methvl-1-((2-(trimethylsilvl)ethoxv)methvl)1,4.4a. 5,5a, 6-hexahydrocycloproparf|indazole-3-carbaldehyde

A solution of Préparation 16 (21.89 g, 63.55 mmol) in DCM (25 mL) was cooled to 0 °C. A solution of Dess-Martin periodinane (33.7 g, 79.4 mmol) in DCM (250 mL) was added dropwise at 0 °C over approximately 20 min. The mixture was treated with 2.2% water/DCM (50 mL) added dropwise over 45 min at 0 °C. The mixture was warmed to RT and stirred for 4 h. The mixture was treated with 1 N NaOH (380 mL) and stirred for 30 min. The biphasic mixture was separated. The organic phase was washed with brine, dried (MgSOq), filtered and concentrated. The crude product was purified by chromatography (silica, EtOAc/heptanes = 0-50%) to deliver the title compound (17.8 g, 82%). ¹H NMR (400 MHz, CDCI₃) d 9.98 (s, 1H), 5.52-5.35 (m, 2H), 3.61-3.43 (m, 2H), 3.27-3.05 (m, 4H), 2.82-2.66 (m, 1H), 1.42 (m., 3H), 0.98-0.80 (m, 2H), 0.08 - -0.13 (m, 9H); LC-MS m/z (M+H)⁺ = 343.3.

Préparation 18: benzyl (S)-2-morpholinopropanoate

A solution of benzyl L-alaninate 4-methylbenzenesulfonate (500 g, 1.42 mol) in DMSO (3 L) was treated with Et₃N (624 g, 6.165 mol) and the mixture was cooled to 0 °C. A solution of 1-bromo-2-(2-bromoethoxy)ethane (429 g, 1.849 mol) in DMSO (1 L) was slowly added to the reaction. The resulting mixture was stirred at 25 °C for 36 h. Water (3 L) and EtOAc (2 L) were added to the mixture. The aqueous phase was extracted with EtOAc (2 x 1 L). The combined organic extracts were dried (Na2SÛ4), filtered and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE = 11%) to provide the title compound (290 g, 82%). ¹H NMR (400 MHz, DMSO-de) δ 7.42

- 7.31 (m, 5H), 5.19 (s, 2H), 3.79 - 3.66 (m, 4H), 3.35 - 3.30 (m, 1H), 2.69 - 2.56 (m, 4H), 1.32 - 1.29 (m, 3H).

Préparation 19: (S)-2-morpholinopropanoic acid çh₃

A solution of Préparation 18 (290 g, 1.56 mol) in MeOH (2.9 L) was treated with 10% Pd(OH)2/C (29 g) at 25 °C. The mixture was degassed and purged with N2 (3 times) and then stirred under an atmosphère of H2 for 36 h. The solid was removed by filtration and the filtrate concentrated. The resulting residue was washed with MTBE (200 mL x2) to provide the title compound (146 g, 79%). SFC analytical method: Chiral Tech IC 250 mm x 4.6 mm x 5 pm, 5 to 60% with 0.2% NH4⁺ (7 N in MeOH) in MeOH/COzfg), 3.0 mL/min, rétention time = 5.88 min, 100%ee; ¹H NMR (400 MHz, DMSO-de) δ 3.56 (s, 4H), 3.18-3.16 (m, 1H), 2.54-2.53 (m,4H), 1.17 - 1.15 (m, 3H); LC/MS m/z (M+H)⁺ = 160.1.

Préparation 20: 2-(tetrahydro-2/-/-pyran-4-yi)acetyi chloride

A solution of 2-(tetrahydro-2H-pyran-4-yl)acetic acid (17.3 g, 120 mmol) in DCM (400 mL) and DMF (1 mL) at 0 °C was treated with oxalyl chloride (30.5 g, 240 mmol). The mixture was then warmed to 20 °C and stirred for 16 h. The mixture was concentrated to give the title compound (19.5 g, quant.).

Préparation 21 : (R)-4-benzvl-3-(2-(tetrahvdro-2H-pyran-4-vl)acetvl)oxazolidin-2-one

A solution of 20 (14.2 g, 79.9 mmol) in THF (500 mL) at -78 °C was treated with n-BuLi (47.9 mL, 120 mmol). The mixture was then stirred at -78 °C for 2 h. A solution of 2(tetrahydro-2H-pyran-4-yl)acetyl chloride (19.5 g, 120 mmol) in THF (100 mL) was added at -78 ^QC and stirred for an additional 2 h. The mixture was then warmed to k 65 °C and then stirred for 16 h. The reaction was treated with sat. aq. NH4CI (400 mL) and the resulting biphasic mixture separated. The organic phase was dried (Na2SO₄) and concentrated. The residue was suspended in DCM/PE (50 mL/300 mL) and stirred at -50 °C for 30 min. The soiids were collected and dried to give the titie compound 5 (21.5 g, 89% yield). LC/MS m/z (M+H) = 303 .8.

Préparation 21a: (R)-4-benzvl-3-((R)-2-(tetrahvdro-2/-/-pyran-4-vl)propanovl)oxazolidin2-o ne

A solution of Préparation 21 (21.5 g, 70.8 mmoi) in THF (200 mL) at -78 °C was treated with NaHMDS (1M in THF, 106 mL). The mixture was stirred for 1 h and treated with methyl iodide (50.3 g, 354 mmol) at -78 °C. The reaction mixture was stirred at -78 °C for 2 h and then gradually warmed to 20 °C over 16 h. The reaction mixture was treated with sat. aq. NH4CI (300 mL) and the biphasic mixture separated. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE: 0-100%) to give the titie compound (15.5 g, 69%). Ή NMR (400 MHz, CDCI3) δ 7.32 - 7.11 (m, 5H), 4.62 (ddt, 1H), 4.20 4.07 (m, 2H), 4.02 (dd, 1H), 3.94 (dd, 1H), 3.65 - 3.54 (m, 1H), 3.33 (tt, 2H), 3.22 (dd, 1H), 2.72 (dd, 1H), 1.97- 1.87 (m, 1H), 1.64- 1.56 (m, 1H), 1.58-1.51 (m, 1H), 1.41 20 1.26 (m, 2H), 1.15 (d, 3H); LC/MS m/z (M+H)⁺ = 318.3.

Préparation 22: (R)-2-(tetrahydro-2/-/-pyran-4-vl)propanoic acid

A solution of Préparation 21a (15.5 g, 48.8 mmol) in THF/H2O (410 mL/255 mL) at 0 °C 25 was treated with LiOH HzO (10.2 g, 244 mmol) and 30% aq. H2O2 (27.7 g, 244 mmol).

The mixture was stirred at 0 °C for 1.5 h and then at 20 “C for 1.5 h. The mixture was treated with sat. aq. NaaSOa (300 mL) and the organic solvent was removed in vacuo. The mixture was washed with DCM (2 x 200 mL) and then treated with conc. HCL until pH = 1 was reached. The mixture was extracted with DCM (3 x 200 mL), and the extracts were combined and dried (NazSCU), filtered and concentrated to give the title compound 22 (6.12 g, 79% yield). (Reference: Evans, D. A, et al. J. Am. Chem. Soc. 1984, 106, 1154-1156) ¹H NMR (400 MHz, CDCh) δ 4.07 - 3.93 (m, 2H), 3.39 (dt, 2H), 2.30 (p, 1 H), 1.87 1.77 (m, 1H), 1.68 - 1.56 (m, 2H), 1.51 - 1.28 (m, 2H), 1.17 (d, 3H). [a]²⁰ _D = - 17.98 (c = 0.3 g/100 mL, EtOH); Chiral SFC (MeOH/CO₂, Chiral Tech IG, 5 to 60% over 10 min, 250 mm x 4.6 mm x 5 pm) rétention time = 3.42 min, 97% ee.

Préparation 23: (S)-2-(tetrahydro-2H-pvran-4-vl)propanoic acid

HO ch₃

The acid was prepared in an analogous manner to Préparation 22 (R)-2-(tetrahydro-2Hpyran-4-yl)propanoic acid using (S)-4-benzyloxazolidin-2-one in Step 2. ¹H NMR (400 MHz, CDCh) δ 4.07- 3.93 (m, 2H), 3.39 (tt, 2H), 2.30 (p, 1H), 1.81 (tdt, 1H), 1.61 (dddq, 2H), 1.51 - 1.28 (m, 2H), 1.17 (d, 3H). [a]²⁰ _D =+19.99 (c =0.3 g/100 mL, EtOH)

Préparation 24: benzyl 2-bromopropanoate

To a solution of 2-bromopropionic acid (5.0 g, 32.7 mmol) in DCM (100 mL) at 0 °C was added EtaN (3.64 g, 36.0 mmol), followed by benzyl chloroformate (5.58 g, 32.7 mmol) dropwise. After 10 min, DMAP (399 mg, 3.27 mmol) was added and the mixture stirred for 4 h at 30 °C. The mixture was poured into 1M HCl (15 mL) and brine (80 mL). The mixture was extracted with DCM (2 x 80 mL). The organic extracts were combined, dried (MgSCh), filtered and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE, 0-5%) to deliver the title compound (4.81 g, 86%). Ή NMR (400 MHz, CDCI3) δ 7.38 - 7.27 (m, 5H), 5.22 - 5.10 (m, 2H), 4.43 - 4.37 (m, 1 H), 1.80 (d, 3H); LC/MS m/z (M+Na)⁺ = 267.0.

Préparation 25: benzyl 2-(3-oxomorpholino)propanoate

A solution of morpholin-3-one (750 mg, 7.42 mmol) in THF (49 mL) at 5 °C was treated with NaH (475 mg, 11.9 mmol). After stirring for 30 min, Préparation 24 (16 g, 8.90 mmol) was added dropwise. After stirring at 25 °C for 3 h the mixture was diluted with sat. aq. NH4CI (30 mL) and water (20 mL). The mixture was extracted with EtOAc (2 x 60 mL) and the combined extracts were dried (MgSO₄), filtered and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE = 0- 70%) to give the title compound 25 (256 mg, 13%). Ή NMR (400 MHz, CDCh) δ 7.41 - 7.30 (m, 5H), 5.33 (q, 1H), 5.22 - 5.09 (m, 2H), 4.22 (s, 2H), 3.96 - 3.77 (m, 2H), 3.52 - 3.20 (m, 2H), 1.45 (d, 3H).

Préparation 26: 2-(3-oxomorpholino)propanoic acid o ch₃

O

To a mixture of Préparation 25 (256 mg, 0.98 mmol) in MeOH (10 mL) was added 10% Pd/C (50 % in water, 207 mg, 0.19 mmol). The mixture was stirred under H2 (1 atm) at 25 °C for 16 h. The reaction was filtered and the solids washed with MeOH (3 x 20 mL). The filtra te was concentrated to give the title compound 26 (167 mg, 99%). ¹H NMR (400 MHz, CDCh) δ 6.15 (bs, 1H), 5.16 (d, 1H), 4.24 (d, 2H), 4.06 - 3.82 (m, 2H), 3.55 -3.28 (m, 2H), 1.45 (dd, 3H).

Préparation 27: (S)-A/-(5-chloro-2-methvl-4-nitrophenvl)-2-morpholinopropanamide

To a solution of 5-chloro-2-methyl-4-nitroaniline (4.0 g, 21.4 mmol) and Préparation 19 (4.09 g 25.7 mmol) in pyridine (70 mL) was added EDCI (8.84 g, 46.1 mmol) at 20 °C. The mixture was stirred at 20 °C for 16 h. The mixture was treated with sat. aq. NH4CI (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organtc layers were dried (NasSCU), filtered and concentrated. The crude product was triturated with MTBE (100 mL) to provide the title compound (4.8 g, 68%). Ή NMR (400 MHz, CDCIs) ô 9.83 (S, 1H), 8.68 (s, 1 H), 7.87 (s, 1H), 3.87 - 378 (m, 4H), 3.35 - 3.29 (m, 1H), 2.72 - 2.62 (m, 2H), 2.37 (s, 3H), 1.39 - 1.38 (m, 3H).

Préparation 28: (S)-N-(5-chloro-2-methvl-4-nitrophenvl)-/V-methvl-2morpholinopropanamide

To a solution of Préparation 27 (5.50 g, 16.8 mmo!) in THF (75 mL) was added KOtBu (2.07 g, 18.5 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h and a solution of methyl iodide (2.62 g, 18.5 mmol) in THF (15 mL) was added dropwise at 0 °C. The mixture was stirred at 25 °C for 16 h. The reaction was treated with sat. aq. NH4CI (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated to provide the title compound (5.1 g, 89%). ¹H NMR (400 MHz, CDCI3) δ 7.92 - 7.81 (m, 1H), 7.72 (s, 0.5H), 7.32 (s, 0.5H), 3.79 - 3.47 (m, 4H), 3.21 - 3.19 (m, 3H), 3.39 - 2.83 (m, 1H), 2.62 - 2.51 (m, 2H), 2.43 - 2.29 (m, 3H), 2.22 - 2.16 (m, 2H), 1.18 -1.11 (m, 3H).

Préparation 29: (S)-/V-(5-((4-methoxvbenzvl)amino)-2-methyl-4-nitrophenvl)-A/-methvl-2morpholinopropanamide

To a mixture of Préparation 28 (320 g 936.3 mmol) in 4-methoxybenzyl amine (513.7 g, 3.74 mol) was added ammonium acetate (72.2 g, 936.3 mmol). The mixture was heated at 100 °C for 16 h. The mixture was diluted with in EtOAc (1.5 L) and washed with sat. aq. NH4CI (3 x 1.5 L) and concentrated. The crude product was purified by chromatography (silica, MeOH/DCM = 0-10%) to provide the title compound (261 g, 64%) as a solid. ¹H NMR (400 MHz, CDCh) δ 8.38 - 8.02 (m, 1H), 7.26 - 7.22 (m, 2H), 6.94 - 6.98 (m, 2H), 6.79 - 6.48 (m, 1 H), 4.57 - 4.47 (m, 2H), 3.87 - 3.81 (m, 3H), 3.61 3.51 (m, 5H), 3.14 - 3.11 (m, 3H), 3.03 - 2.83 (m, 1H), 2.56 - 2.40 (m, 2H), 2.30 - 2.04 (m, 4H), 1.14-1.01 (m, 3H).

Préparation 30: (S)-Λ/-(4,5-diamino-2-methvlphenvl)-Λ/-methvl·2morpholinopropanamide ch₃ ch₃ nh₂ nh₂

To a solution of Préparation 29 (256 g, 578.5 mmol) in DCM (1.25 L) was added TFA (1.28 L, 17.3 mol) and the mixture was stirred at 25 °C for 2 h. The mixture was concentrated and then diluted in DCM (1 L). The resulting mixture was adjusted to -pH 9 with sat. NazCOs and then was extracted with DCM (2 x 1 L). The combined organic layer was washed with brine (1 L), dried over Na2SO4, filtered and the filtrate was concentrated. The residue was dissolved in DCM (500 mL) to which 4 M HCI/dioxane (1 L) was added dropwise and stirred for 0.5 h. The mixture was concentrated and DCM (800 mL) was added. The resulting mixture was stirred for 16 h. The mixture was filtered, and the resulting filter cake was dried in vacuo to provide the HCl sait of (S)-N(4-amino-2-methyl-5-nitrophenyl)-/V-methyl-2-morpholinopropanamide (200 g) as a solid. In three separate batches, a hydrogénation vessel was charged with (S)-N-(4amino-2-methyl-5-nitrophenyl)-A/-methyl-2-morpholinopropanamide (66.6 g, 206.6 mmol) from above and MeOH (900 mL). To the reaction vessel was added 10% Pd/C (13 g, 41.32 mmol) and the mixture was purged with N2 followed by H2. The reaction was hydrogenated under 50 psi of H2 at 40 °C for 48 h. The reaction mixture was filtered (2x) and the filtrate were washed with MeOH (3 x 500 mL). The filtrate was concentrated to give a residue. The residue was dissolved in MeOH (1 L) to which Na2CO₃ (41.9 g, 395 mmol) was added and the mixture was stirred at 25 °C for 1 h. The mixture was filtered which was washed with MeOH (5 x 200 mL). The filtrate was concentrated. The residue was purified by chromatography (silica, DCM:MeOH 0-10% gradient) to provide the title compound (159.4 g, 89% yieîd). SFC method: Chiralpak IB N-5 250 mm x 4.6 mm x 5 pm, 5% (0.2% isopropyl amine in isopropanol/COz®) for 1 min then to 60% over 8 min, 2.5 mL/min, rétention time = 8.636 min, 98.42%, 96.85%ee. ¹H NMR (400 MHz, CDCh) δ 6.60 (s, 0.5H), 6.59 (s, 0.5H), 6.56 (s, 0.5H), 6.42 (s, 0.5H), 6.56 - 6.42 (m, 1H), 3.71 - 3.60 (m, 4H), 3.40 (br s, 4H), 3.17 - 3.07 (m, 4H), 2.66 - 2.57 (m, 2H), 2.40 - 2.31 (m, 2H), 2.16 (s, 1.5H), 2.06 (s, 1.5H), 1.19 - 1.12 (m, 3H); LC/MS m/z (M+H)⁺ = 293.2

Préparation 31 : /V-(4,5-diamino-2-methvlphenyl)-/\/-methvl-2-morpholinopropanamide

The title compound 31 was prepared in an analogous manner to Préparation 30, starting from (±)-2-morpholinopropanoic acid; LC/MS m/z (M+H)⁺ = 293.3.

Préparation 32: (S)-/\/-f3₁4-diaminophenvO-Λ/-methvl·2-morpholinopropanamide

The title compound was prepared analogously to Préparation 30 starting from 3-chloro4-nitroaniline and Préparation 19.

¹H NMR (400 MHz, CDCh) δ = 6.68 (d, 1H), 6.60 - 6.47 (m, 2H), 3.75 - 3.61 (m, 4H), 3.54 - 3.37 (m, 2H), 3.26 (q, 1H), 3.21 (s, 3H), 2.64 - 2.55 (m, 2H), 2.47 - 2.35 (m, 2H), 1.15 (d, 3H)

Préparation 33: /V-(5-chloro-2-ethylphenvl)acetamide

ch₃

5-chloro-2-ethylanilîne (405 mg, 2.6 mmol) was added to AC2O (10 mL, 110 mmol) with stirring at 25 °C. The reaction mixture was stirred for 3 h and filtered to collect the precipitate. The solids were rinsed with water (3 x 15 mL) and dried to give the title compound (496 mg, 96%). Ή NMR (400 MHz, CDCI3) δ 7.91 (s, 1H), 7.12 (t, 2H), 6.96 (s, 1H), 2.56 (q,2H), 2.21 (s, 3H), 1.22 (t, 3H); LC/MS m/z (M+H) =197.9;

Préparation 34: /V-(5-chloro-2-ethvl-4-nitrophenyl)acetamide

CH₃

ch₃

A solution of Préparation 33 (496mg 2.51 mmol) in conc. H2SO4 (2 mL) was cooled at 0 °C and treated with KNO3 (254 mg, 2.51 mmol) in portions and while keeping the internai température below 5 °C. The resulting mixture was stirred for 4 h between at a température between 0-5 °C. The mixture was poured into water (30 mL) and stirred for 10 min. The mixture was filtered and the collected solids washed with water (3 x 20 mL) and dried under vacuum to give the title compound (600 mg, 99%). ¹H NMR (400 MHz, CDCI3) δ 8.47 (s, 1H), 7.85 (d, 1H), 7.18 (s, 1H), 2.70 - 2.59 (m, 2H), 2.29 (s, 3H), 1.34 (t, 3H); LC/MS m/z (M+H) = 242.9

Préparation 35: 5-chloro-2-ethyl-4-nitroaniline

T T ch₃

A solution of Préparation 34 (450 mg, 1.85 mmol) in EtOH (10 mL) and water (5 mL) was treated with NaOH (371 mg, 9.27 mmol) at 25 °C. The resulting mixture was heated at 80 “C for 16 h. Additional NaOH (74.2 mg, 1.85 mmol) was added to the mixture and heating continued at 80 °C for an additional 16 h. The mixture was concentrated, diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were concentrated and purified by chromatography (silica, EtOAc/PE = 0 to 15%) to give the title compound (278 mg, 74%). Ή NMR (400 MHz, CDCh) δ 7.88 (s, 1 H), 6.70 (s, 1 H), 4.29 (s, 2H), 2.54 - 2.43 (m, 2H), 1.29 (t, 3H); LC/MS m/z (M+H) = 200.9.

Préparation 36. (S)-/\/-(3-fluoro-4-nitrophenvl)-2-morpholinopropanamide

A solution of 3-fluoro-4-nitroaniline (1.0 g, 6.41 mmol) in pyridine (20 mL) at 20 °C was treated with Préparation 19 (1.22 g, 7.69 mmol) and EDCI (1.46 g, 12.8 mmol). The mixture was stirred for 15 h, concentrated and diluted with EtOAc/H2O (150 mL/50 mL).

The organic layer was separated and the aqueous layer extracted with EtOAc (50 mL), The organic extracts were combined, washed with brine, dried (MgSCh), filtered and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE = 0-100%) to deliver the title compound (1.36 g, 72%). LC/MS m/z (M+H)⁺ = 298.0.

Préparation 37. (S)-A/-(3-fluoro-4-nitrophenyl)-/\/-methvl-2-morpholinopropanamide

A solution of Préparation 36 (1.36 g, 4.58 mmol) in THF (60 mL) at 0 °C was treated with NaH (274 mg, 6.86 mmol). After 30 min, methyl iodide (0.43 mL, 6.86 mmol) was 10 added and the mixture stirred for 16 h. The mixture was treated with sat. aq. NH4CI (1 mL) and then partitioned between EtOAc and H2O (150 mL/50 mL). The organic Iayer was separated and the aqueous Iayer extracted with EtOAc (100 mL). The organic extracts were collected, dried (MgSÛ4), filtered and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE = 0-100%) to deliver the title 15 compound (410 mg, 29%). LC/MS m/z (M+H)⁺= 312.1.

Préparation 38. (S)-/V-(3-amino-4-nitrophenyl)-/\/-methvl-2-morpholinopropanamide

A solution of Préparation 37 (370 mg, 1.19 mmol) in EtOH (30 mL) at 20 °C was treated 20 with conc. NH4OH (10 mL). The mixture was stirred for 15 h at 70 °C and the mixture was diluted with EtOAc/HzO (150/50 mL). The organic Iayer was separated and the aqueous layer extracted with EtOAc (50 mL). The organic extracts were combined, dried (Na2SO4), filtered, and concentrated to give the title compound (366 mg, 99%). LC/MS m/z (M+H)⁺= 309.1

Préparation 39: (S)-/\/-(5-amÎno-2-bromo-4-nitrophenvl)-/\/-methvl-2morpholinopropanamide

nh₂ no₂

A solution of Préparation 38 (270 mg,0.88 mmol) in AcOH (10 mL) at 20 °C was treated with Brs (140 mg, 0.88 mmol). The mixture was stirred for 1 h and the precipitate collected by filtration. The solids were purîfied by prep. HPLC (Phenomenex Gemini-NX 150 mm x 30 mm x 5 pm, H2O/CH3CN (0.05%NH40H), 18-58% over 10 min) to give the title compound (65 mg, 19%). ¹H NMR (400 MHz, DMSO-cfë) δ 8.25 (d, 1H), 7.69 (s, 1 H), 7.57 (s, 1 H), 7.23 (s, 0.6H), 7.07 (s, 0.4H), 3.54 - 3.46 (m, 3H), 3.37 - 3.33 (m, 2H), 3.04 (s, 3H), 2.41 (dt, 2H), 2.21-2.10 (m, 2H), 1.07 (d, 1.3H), 1.01 (d, 1.7H); LC/MS m/z (M+H)⁺ = 388.8/390.8 (⁷⁹Br, ^eiBr)

Préparation 40: (S)-A/-(4,5-diamino-2-bromophenvl)-A/-methvl-2morpholinopropanamide

A solution of 39 (40 mg, 0.10 mmol) in EtOH (3 mL) at 20 °C was treated with sat. aq. NH4CI (0.5 mL) and iron powder (17.3 mg, 0.31 mmol). The mixture was heated to 70 °C for 1 h and filtered. The filtrate was concentrated and the residue purîfied by prep-HPLC (Boston Prime C18, 150 x 30 mm x 5 pm; H20/MeCN(0.05% NH4OH) 16-39% over 10 min) to give the title compound (5 mg, 10%). ¹H NMR (400 MHz, DMSO-de) δ 6.75 (s, 0.3H), 6.72 (s, 0.7H), 6.58 (s, 0.7H), 6.47 (s, 0.3H), 4.91 (d, 2H), 4.82 (d, 2H), 3.55 - 3.46 (m, 4H), 3.09 (d, 2H), 2.96 (d, 3H), 1,06 (d, 1.3H), 1.01 (d, 1.7H). LC/MS m/z (M+H) = 357.0/359.1 (⁷⁹Br, ⁸¹Br)

Préparation 41: tert-butyl (5-fluoro-2-methvl-4-nitrophenyl)carbamate

A solution of 5-fluoro-2-methyl-4-nitroaniline (133 g, 781 mmol, 1 eq), DMAP (9.55 g, 78.1 mmol, 0.1 eq) and /Pr2NEt (202 g, 1.56 mol, 272 mL, 2 eq) in DCM (2 L) was treated with BOC2O (187 g, 859 mmol) at 20 °C. The mixture was stirred at 20 °C for 16 h and concentrated. The residue was dissolved in EtOAc (3 L) and washed sequentially with sat. aq. NH4CI (1 L), sat. aq. NaHCOs (1 L) and brine (1 L). The organic layer was dried (Na2SO4), filtered and concentrated. The residue was triturated with MeOH (3 L) and the solids collected by filtration to give the title compound (90 g, 374 mmol).

The filtrate was concentrated and the residue dissolved in MeOH (500 mL) and treated with K2CO3 (15.5 g). The mixture was stirred at 20 °C for 3 h. The mixture was filtered and the solids rinsed with MeOH. The filtrate was concentrated and the residue purified by chromatography (silica, EtOAc/PE = 0-10%) to give additional title compound (45 g, 166 mmol).

Both batches were combined to give overall title compound (135 g, 72%). ¹H NMR (400 MHz, CDCI3) δ 8.15 (d, 1H), 7.94 - 7.88 (m, 1H), 6.62 (s, 1H), 2.28 (s, 3H), 1.55 (s, 9H).

Préparation 42: fert-butyl (5-fluoro-2-methvl-4-nitrophenvl)carbamate ch₃ h₃c. ,0. .N. .F h c¥ ¥ ΥΎ ³ ch₃ ο

H₃C

A solution of Préparation 41 (131 g, 486 mmol) in THF (1.9 L) was treated with KOtBu (81.9 g, 730 mmol) at 0 °C and the mixture was stirred at 0 °C for 1 h. Methyl iodide (61 mL, 980 mmol) was added dropwise at 0 °C. The resulting mixture was stirred at 20 °C for 16 h. The reaction mixture was treated with sat. aq. NH4CI (500 mL) and extracted with EtOAc (1 L). The organic layer was washed with brine (500 mL), dried (NaaSO4), and concentrated to give the title compound (150 g, 95% yield). ¹H NMR (400 MHz, CDCi₃) δ 7.95 (d, 1H), 7.07 (d, 1H), 3.17 (s, 3H), 2.26 (s, 3H), 1.40 (d, 9H).

Préparation 43: tert-butyl (5-amÎno-2-methvl-4-nitrophenvl)(methyl)carbamate ch₃

H₃C_O_ N h₃c¥ Y T T ³ CH3 O ³ h3c -- no_?

A solution of Préparation 42 (450 g, 1.38 mol, 1 eq) in 7 M NH₃ in MeOH (7 M, 5.5 L) was heated at 58°C for 72 h. The mixture was concentrated. The residue was dissolved in EtOAc (2 L) and washed with brine (2 L). The orgamc layer was dned (Na2SO4), filtered and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE = 0-20%) to give the title compound (295 g, 76% yield). NMR (400 MHz, CDCh) δ 8.00 (s, 1H), 6.62 (s, 1H), 5.95 (s, 2H), 3.15 (s, 3H), 2.15 (d, 3H), 1.41 (s, 9H); LC/MS m/z (M+H-tert butyl) = 225.8.

Préparation 44: tert-butyl (4,5-diamino-2-methvlphenvl)(methyl)carbamate çh₃

A solution of Préparation 43 (98 g, 349 mmol) in MeOH (1 L) was treated with 10% Pd/C (10 g). The reaction was stirred at 40 °C under H2 (3 atm) for 24 h. The reaction was filtered and the solids rinsed with MeOH (3 x 500 mL). The filtrate was concentrated to give the title compound (68.3 g, 78%). ¹H NMR (400 MHz, DMSO-cfe) δ 6.32 (s, 1H), 6.27 (s, 1H), 4.37 (s, 2H), 4.29 (s, 2H), 2.96 (d, 3H), 1.89 (d, 3H), 1.44 (s, 3H), 1.28 (s, 6H;. LC/MS m/z (M+H-tert butyl) = 195.9.

Préparation 45: tert-butyl methvl-(6-methvl-2-((4aS,5aR)-5a-methvl·1-((2(trimethylsilvl)ethoxv)methvl)-1,4_Ί4a_τ5_l5a_l6-hexahvdrocvciopropa[f1iπdazol·3-vl)-1Hbenzo[d1imidazol-5-yl)carbamate

A solution of Préparation 44 (5.53 g, 23.5 mmol) and Na2S20s (2.24 g, 11.8 mmol) in DMF (124 mL) was treated with 9 (7.21 g, 23.5 mmol) and DMSO (4.6 g, 58.8 mmol) at RT. The mixture was heated at 110 °C for 16 h. The mixture was concentrated. The residue was diluted with EtOAc (500 mL) and washed with 3% aq. LiCI (100 mL). The organic layer was dried (MgSO₄), filtered and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE = 0-25%) to give the title compound (10.8g, 86%). ¹H NMR (400 MHz, CD3OD) δ 7.46 (t, 1H), 7.38 (s, 1H), 5.53 - 5.42 (m, 2H), 3.63 (t, 2H), 3.40 (d, 1H), 3.26 - 3.11 (m, 5H), 2.77 (d, 1H), 2.33 (s, 3H), 1.56 (s, 3H), 1.36 - 1.30 (m, 9H), 1.18 (dd, 1H), 0.96 - 0.84 (m, 2H), 0.45 (dd, 1H), 0.28 (t, 1H), -0.02 (s, 9H); LC/MS m/z (M+H)⁺ = 538.3.

Préparation 46: A/,6-dimethyl-2-((4aS,5aR)-5a-methvl-1-((2(trimethylsilyl)ethoxv)methvl)-1 ^/a.S.Sa.e-hexahydrocvcÎopropaiflindazol-S-vD-IHbenzordlimidazol-5-amine

A solution of Préparation 45 (10.86 g 20.2 mmol) in DCM (135 mL) was treated with ΖπΒγξ (22.7 g, 101 mmol) at 0 °C. The mixture was gradually warmed to RT and stirred for 16 h. The mixture was poured into sat. aq. NaHCOs (200 mL) and extracted with DCM (2 x 200 mL). The combined organic layers dned (MgSCu), filtered and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE = 0-20%) to give the titie compound (7.54 g, 85.3%). Chiral SPC (Chiral Pak AS-3, 150 mm x 4.6 mm x 3 pm; COz/EtOH with 0.05% /Pr2NEt, 5 to 40% over 5.5 min) rétention time = 2.93 min (97.2% ee); ¹H NMR (400 MHz, CD₃OD) δ 7.32 (s, 1H), 6.76 (s, 1H), 5.51 - 5.42 (m, 2H), 3.38 (t, 2H), 3.40 (d, 1H), 3.31 - 3.28 (m, 2H), 3.22 (s, 3H), 3.17 (m, 1H), 2.27 (s, 3H), 1.32 (s, 3H), 1.18 (m, 1H), 0.88 (m, 2H), 0.45 (dd, 1H), 0.28 (t, 1H), -0.02 (s, 9H); LC/MS m/z (M+H)⁺ = 438.3.

Préparation 47: /V-(3-fluoro-4-nitrophenyl)acetamide

H Y ΪΎ o VA no₂

3-Fluoro-4-nitroaniline (20 g, 128.1 mmol) was treated with AC2O (250 mL). The mixture was stirred for 16 h at RT and then diluted with water (100 mL). The precipitate was collected by filtration. The solids were taken up in EtOAc (100 mL), dried (Na2SO4), filtered and concentrated to give the titie compound 47 (23.0 g, 91% yield). ¹H NMR (400 MHz, CD3OD) δ 8.09 (t, 1H), 7.86 (dd, 1H), 7.38 (dt, 1H), 2.17 (s, 3H).

Préparation 48. A/-(3-fluoro-4-nitrophenvl)-/\/-methvlacetamide çh₃

A solution of Préparation 47 (23.0 g, 116.1 mmol) in DMF (300 mL) at 0 °C was treated with NaH (6.96 g, 174 mmol) and stirred for 20 min. Methyl iodide (33.0 g, 232 mmol) was added and the mixture was stirred for 2 h. The mixture was treated with water (100 mL) and the resulting mixture extracted with 10% MeOH/EtOAc (2 x 200 mL). The extracts were collected, dried (Na₂SO4), filtered and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE = 20- 50%) to give the title compound (16.0 g, 65% yield). Ή NMR (400 MHz, CDCh) δ 8.13 (t, 1H), 7.25-7.15 (m, 2H), 3.35 (s, 3H), 2.10 (s, 3H)

Préparation 49: A/-(3-amino-4-nitrophenvl)-A/-methvlacetamide

çh₃

A solution of Préparation 48 (16.0 g, 75.4 mmol) in EtOH (200 mL) at RT was treated with conc. NH4OH (13.2 g, 377 mmol). The mixture was heated at 50 °C for 3 days and the mixture concentrated. The residue was purified by chromatography (silica, EtOAc/PE = 40-80%) to give the title compound (7.5 g, 48% yield). ¹H NMR (400 MHz, CDCh) δ 8.17 (d, 1H), 6.66 (d, 1H), 6.54 (dd, 1H), 6.18 (s, 2H), 3.27 (s, 3H), 2.02 (s, 3H); LC/MS m/z (M+H)⁺ = 210.3.

Préparation 50: /V-(3,4-diaminophenvl)-A/-methylacetamide çh₃

A solution of Préparation 49 (6.5 g, 31.1 mmol) in MeOH (40 mL) was treated with 10% Pd/C (1.5 g). The mixture was stirred at 20 °C under H₂ (2 atm) for 3 hours. The mixture was filtered and the solids rinsed with MeOH (2 x 50 mL). The filtrate was concentrated to give the title compound (5.38 g, 96% yield). Ή NMR (400 MHz, CDCh) δ 6.71 -6.64 (m, 1H), 6.50 (d, 2H), 3.46 (d, 4H), 3.19 (s, 3H), 1.87 (s, 3H); LC/MS m/z (M+H)⁺ = 180.3.

Préparation 51 : A/-(3,5-difluoro-4-nitrophenvl)-/V-methvlacetamide çh₃

F

A solution of 5-bromo-1,3-difluoro-2-nitrobenzene (25.0 g, 105.0 mmol) in PhCHa (250 mL) at 25 °C under N2 was treated with N-methylacetamide (11.5 g, 158 mmol), CS2CO3 (68.5 g, 210 mmol), Pd2(dba)s (9.62 g, 10.5 mmol) XantPhos (6.08 g, 10.5 mmol) and aluminum(lll)triflate (9.96 g, 21 mmol). The mixture was heated at 100 °C for 15 h. The solids were removed by filtration and the filtrate concentrated. The residue was purified by chromatography (silica, EtOAc/PE = 0-100%) to give the title compound (8.75 g, 36%). ¹H NMR (400 MHz, CDCI3) δ 7.10 - 6.99 (m, 2H), 3.34 (s, 3H), 2.15 (s, 3H); LC/MS m/z (M+H)⁺ = 230.9.

Préparation 52: A/-(3-amino-5-fluoro-4-nitrophenvl)-/V-methylacetamide

A solution of Préparation 51 (8.75 g, 38.0 mmol) in EtOH (95 mL) was treated with conc. NH4OH (24 mL). The mixture was stirred at RT for 16 h and treated with water (120 mL). The mixture was extracted with EtOAc (2 x 80 mL). The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated to give the title compound (5.70 g, 66%). ¹H NMR (400 MHz, DMSO-de) δ 7.17 (s, 2H), 6.69 (t, 1H), 6.62 (dd, 1H), 3.15 (s, 3H), 1.99 (s, 3H). LC/MS m/z (M+H)⁺ = 227.9.

Préparation 53: /V-(3,4-diamino-5-fluorophenyl)-/\/-methylacetamide ch₃ h₃c_n_^nh₂ Y Y Y nh₂ F

A solution Préparation 52 (5.70 g, 25.1 mmol) in EtOH (150 mL) was treated with 10% Pd/C (700 mg). The mixture was stirred under H2 (1 atm) at 25 °C for 24 h. The mixture was filtered and the solids rinsed with EtOH. The filtrate was concentrated to give the title compound (4.6 g, 93%). ¹H NMR (400 MHz, DMSO-d₆) δ 6.32 (dd, 1H), 6.24 (dd, 1H), 5.01 (s, 2H), 4.52 (s, 2H), 3.02 (s, 3H), 1.74 (s, 3H); LC/MS m/z (M+H)⁺ = 198.1.

Préparation 54: /V-methyl-/V-(2-((4aS,5aR)-5a-methyl-1-((2(trimethvlsilvl)ethoxv)methvl)-1,4,4a,5,5a,6-hexahvdrocyclopropaiflindazol-3-yl)-1Hbenzord1imidazol-5-yl)acetamide

A solution of Préparation 50 (5.26 g, 29.4 mmol) in DMF (147 mL) was treated with NasSsOs (2.79 g, 14.7 mmol), 9 (9.0 g, 29.4 mmol) and DMSO (5.74 g, 73.4 mmol). The mixture was heated at 110 °C for 6 h and poured into 3% aq. LiCI (250 mL). The mixture was extracted with EtOAc (3 x 100 mL), dried (Na2SO4), filtered and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE = 0- 100%) to give the title compound (13 g, 95% yield). ¹H NMR (400 MHz, DMSO-de) rotomeric mixture δ 12.83 (s, 1H), 7.96 (s, 1 H), 7.67 (d, 0.5 x H), 7.59 (s, 0.5 x H), 7.48 (d, 0.5 x H), 7.33 (s, 0.5 x H), 7.16 - 7.06 (m, 1H), 5.55 - 5.28 (m, 2H), 3.23-3.12 (m, 3 H), 3.07 - 2.96 (m, 1 H), 2.89 (s, 3H), 2.76-2.64 (m, 4 H), 1.26 (s, 3H), 1.22 - 1.01 (m, 1H), 0.84 (dd, 2H), 0.41 (dd, 1H), 0.18 - 0.15 (m, 1H), -0.06 (s, 9H); LC/MS m/z (M+H)⁺ = 466.2.

Préparation 55: /V-methvl-2-((4aS.5aR)-5a-methvl-1-((2-(trimethvlsilvl)ethoxv)methvl)1,4,4a,5,5a,6-hexahvdrocvclopropa[flindazol-3-vl)-1H-benzord1imidazol-5-amine

A solution of Préparation 54 (2.70 g, 5.8 mmol) in EtOH (22 mL) at RT was treated with 5N NaOH (11.6 mL). The reaction was heated at 90 °C for 16 hours. Water (150 mL) was added to the mixture and the mixture was extracted with EtOAc (2 x 150 mL). The combined organic extracts were washed with brine (50 mL), dried (NasSO^, filtered and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE = 50-100%) to give the title compound 55 (93 mg, 38% yield). ¹H NMR (400 MHz, CD3OD) δ 7.39 (d, 1H), 6.78 -6.73 (m, 1H), 6.68 (dd, 1H), 5.47-5.39 (m, 2H), 3.66 3.50 (m, 2H), 3.37-3.31 (m, 1 H), 3.22-3.04 (m, 2H), 2.82 (s, 3H), 2.75 (d, 1H), 1.30 (s, 3H), 1.16 (dt, 1H), 0.88 (td, 2H), 0.43 (dd, 1H), 0.25 (t, 1H), -0.03 (s, 9H); LC/MS m/z (M+H)⁺ = 424.2.

Préparation 56: /V-(7-fluoro-2-((4aS,5aR)-5a-methvl-1-((2-(trimethvlsilvl)ethoxv)methyl)1 _l4,4a,5,5a,6-hexahvdrocvclopropaff1indazol-3-vl)-1/7-benzo[dlimidazol-5-vl)-/\/methylacetamide

A solution of Préparation 9 (6.53 g, 21.3 mmol) in DMF (106 mL) at 25 °C was treated with Préparation 53 (4.20 g, 21. 3 mmol), NasSaOs (2.02 g, 10.6 mmol) and DMSO (4.16 g, 53.2 mmol). The mixture was heated at 110 °C for 16 h and diluted with 3% aq. LiCI (50 mL). The mixture was extracted with EtOAc (2 x 50 mL). The organic extracts were combined dried (Na2SO4), filtered and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE = 0-75%) to give the title compound (7.55 g, 67%). ¹H NMR (400 MHz, CDCI3) δ 9.99 (d, 1H), 7.45 (d, 0.5H), 7.12 - 7.03 (m, 0.5H), 6.87 6.71 (m, 1H), 5.40 (qd, 2H), 3.62 - 3.45 (m, 3H), 3.30 (s, 3H), 3.23 - 3.05 (m, 2H), 2.75 (d, 1H), 1.90 (s, 3H), 1.29 (s, 3H), 1.16 (s, 1H), 0.91 (ddd, 2H), 0.43 (dt, 1H), 0.27 (d, 1H), -0.02 (d, 9H); LC/MS m/z (M+H)⁺ = 484.4.

Préparation 57: 7-fluoro-/V-methvl-2-((4aS,5aR)-5a-methyl-1-((2 (tnmethvlsilvl)ethoxv)methyl)-1,4,4a,5,5a,6-hexahvdrocvcloproparf|indazol-3-vl)-1H benzordlimidazol-5-amine

A solution of Préparation 56 (6.50 g, 13.44 mmol) in EtOH (51.7 mL) was treated with 5N NaOH (26.9 mL, 134 mmol). The reaction mixture was heated at 90 °C for 46 h. Water (200 mL) was added and the mixture extracted with EtOAc (2 x 200 mL). The organic extracts were combined, washed with brine (50 mL), drîed (Na2SO4), filtered and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE = 0-50%) to give the title compound (5.2 g, 75.9%). ¹H NMR (400 MHz, CD₃OD) δ 6.47 (s, 1H), 6.38 (dd, 1H), 5.48 - 5.38 (m, 2H), 3.60 (t, 2H), 3.37-3.30 (m, 1H), 3.21 - 3.08 (m, 2H), 2.83-2.72 (m, 1H), 2.80 (s, 3H), 1.29 (s, 3H), 1.15 (dt, 1H), 0.88 (td, 2H), 0.42 (dd, 1H), 0.25 (t, 1H), -0.03 (s, 9H); LC/MS m/z (M+H)⁺ = 442.2.

Préparation 58: A/-(5-fluoro-2-methyl-4-nitrophenyl)acetamide

5-fluoro-2-methyl-4-nitroaniline (9.5 g, 56 mmol) was added in portions to AczO (100 mL) at 15 °C. The reaction mixture was stirred at 15 “C for 36 h. The solids were collected by filtration and rinsed with water (3 x 50 mL). The solids were dried to give the title compound 58 (6.3 g, 53%).

The filtrate was extracted with EtOAc (100 mL). The organic layerwas washed with water (2 x 100 mL), sat. aq. Na2HCO3 (3 x 100 mL), dried (Na2SO4), filtered and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE = 0-100%) to give additional title compound 58 (4 g, 34%). M NMR (400 MHz, CDCI3) 6 8.34 (d, 1H), 7.94 (d, 1 H), 7.17 (s, 1H), 2.32 (s, 3H), 2.28 (s, 3H).

Préparation 59: /V-(5-fluoro-2-methvl-4-nitrophenvl)-/V-methvlacetamide çh₃

A solution of Préparation 58 (9.3 g, 43.8 mmol) in THF (220 mL) at 0 °C was treated with KOtBu (48.2 mL, 1M THF). The mixture was stirred 1 h at 0 °C and then treated with solution of methyl iodide (6.84 g, 48.2 mmol) in THF (20 mL). The mixture was warmed to 15 °C and stirred for 16 h. The mixture was treated with sat. aq. NH4CI (50 h 82 mL). The mixture was extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The crude productwas purified by chromatography (sîlica, EtOAc/PE = 20-50%) to give the title compound 59 (9.4 g, 95%). ¹H NMR (400 MHz, CDCh) δ 8.04 (d, 1H), 7.13 (d, 1H), 5 3.18 (s, 3H), 2.30 (s, 3H), 1.82 (s, 3H); LC/MS m/z (M+H)⁺ = 226.9.

Préparation 60: A/-(5-amino-2-methvl-4-nitrophenyl)-/V-methvlacetamide çh₃

A solution of Préparation 59 (10.3 g, 45.5 mmol) in EtOH (200 mL) at 15 °C was treated 10 with conc. NH4OH (200 mL). The mixture was heated at 50 °C and stirred for 40 h. The EtOH was removed under reduced pressure and the suspension was filtered to collect the solids. The solids were washed with water and dried to afford the title compound (9 g, 89%). ¹H NMR (400 MHz, CDCh) δ 8.07 (s, 1H), 6.65 (s, 1H), 6.05 (s, 2H), 3.15 (s, 3H), 2.15 (s, 3H), 1.82 (s, 3H); LC/MS m/z (M+H)⁺ = 224.1.

Préparation 61 : A/-(4₁5-diamino-2-methvlphenyl)-/V-methvlacetamide çh₃

A solution of Préparation 60 (8 g, 35.8 mmol) in EtOH (10 mL) was treated with of 10% Pd/C (1.3 g). The mixture was degassed with N2and backfilled with H2 three times.

The reaction mixture was stirred at 15 °C under H2 (1 atm) for 16 h. The mixture was filtered and the filtrate concentrated to give the title compound (7.7 g, 99%). ¹H NMR (400 MHz, CDCh) δ 6.57 (s, 1H), 6.46 (s, 1 H), 3.40 (s, 4H), 3.12 (s, 3H), 2.05 (s, 3H), 1.78 (s, 3H); LC/MS m/z (M+H)⁺ = 194.3.

Préparation 62: A/-methvl-/V-(6-methvl“2-((4aS.5aR)-5a-methvl-1-((2(trimethvlsilvl)ethoxy)methvl)-1,4,4a,5,5a,6-hexahvdrocvclopropa[f|indazol-3-yi)-1Hbenzo[dlÎmidazol-5-vl)acetamide

Préparation 61 (4 g, 20.7 mmol) and NazSaOs (1.97 g, 10.3 mmol) were mixed with solution of Préparation 9 (6.84 g, 22.3 mmol) in DMF (100 mL) and DMSO (3.7 mL). The mixture was heated at 110 °C for 16 h. The mixture was cooled to RT and 3% aq.

LiCI (150 mL) was added. The résultant solids were collected by filtration, washed with water, and dried to give the title compound (7.9 g, 80%). ¹H NM R (400 MHz, CDCh) δ 9.88 (s, 1 H), 7.58 (s, 1 H), 7.31 (s, 1 H), 5.50 - 5.26 (m, 2H), 3.55 (t, 3H), 3.23 (s, 3H), 3.20 - 3.05 (m, 2H), 2.74 (d, 1H), 2.32 (s, 3H), 1.79 (s, 3H), 1.29 (s, 3H), 1.16 (dt, 1 H), 0.90 (dd, 2H), 0.42 (dd, 1 H), 0.26 (t, 1 H), -0.03 (s, 9H); LC/MS m/z (M+H)⁺ = 480.4.

Préparation 63: A/-(4-fluoro-2-methvl-5-nitrophenyi)acetamide

H

4-Fluoro-2-methyl-5-nitroaniline (16.7 g, 98.2 mmol) was added to AC2O (200 mL) with stirring at 15 °C, and the mixture was stirred at 15 °C for 16 h. The mixture was treated with water (300 mL) and extracted with EtOAc (300 mL). The organic layer was washed with sat. aq. NazCOa (2 x 150 mL) and brine (100 mL). The organic layer was dried (Na₂SO₄), filtered and concentrated. The residue was triturated with EtOAc/PE (v/v=1:5, 100 mL). The resulting solid was collected by filtration and dried to give the title compound (15 g, 72%). Ή NMR (400 MHz, CDCI3) δ 8.52 (d, 1H), 7.13 (br d, 2H),

2.35 (s, 3H), 2.25 (s, 3H)

Préparation 64: A/-(4-amino-2-methvl-5-nitrophenvl)acetamide

H

A solution of Préparation 63 (15 g, 70.7 mmol) in EtOH (300 mL) was treated with conc.

NH4OH (198 g) at 30 °C and the mixture was stirred at 50 °C for 16 h. Additional conc. NH4OH (140 g) was added and the mixture was stirred at 50 °C for 16 h. Additional conc. NH4OH (46 g) was added and the mixture was stirred at 60 C for 16 h. The mixture was concentrated and the solids collected by filtration. The solids were washed with water (3x10 mL) and dried to deliver the title compound (14.0 g, 95%). ¹H NMR (400 MHz, CD3OD) δ 7.97 (s, 1H), 6.81 (s, 1H), 2.19 (s, 3H), 2.13 (s, 3H)

Préparation 63: /V-(4,5-diamino-2-methvlphenyl)acetamide

A suspension of Préparation 64 (2.50 g, 11.95 mmol) in EtOH (50 mL) was added to a suspension of 10% Pd/C (500 mg) in EtOH (10 mL). The mixture was degassed and refilled with H2 three times and the reaction mixture was stirred at 15 °C under H2 (1 atm) for 16 h. The mixture was filtered and the filtrate concentrated to deliver the title compound 65 (2.2 g. 103%). LC/MS m/z (M+H)⁺= 180.1.

Préparation 66: /V-(6-methvl-2-((4aS,5aR)-5a-methvl-1-((2-(trimethvisilyl)ethoxv)methyl)1 AAa.S.Sa.e-hexahydrocvcloproparflindazol-S-vD-IH-benzoFdlimidazol-S-vDacetamide

A solution of Préparation 65 (2.20 g, 12.28 mmol) in DMF (40 mL) was treated with Na₂S₂O₅ (1.17 g, 6.14 mmol), DMSO (2.18 mL, 30.7 mmol), and 9 (3.76 g, 12.3 mmol) in DMF (20 mL). The mixture was stirred at 100 °C for 16 h. The mixture was concentrated and the crude product purified by chromatography (silica, EtOAc/PE = ΟΙ 00% then MeOH/DCM 0-10%) to deliver the title compound 66 (5.3 g, 92%). LC/MS m/z (M+H)⁺= 466.2.

Préparation 67: /V-ethvl-6-methvl-2-((4aS,5aR)-5a-methvl-1-((2(trimethylsilvl)ethoxv)methvl)-1 ^^a.S.Sa.e-hexahvdrocvciopropaiflindazol-S-yD-IHbenzofdlimidazol-5-amine

A suspension of L1AIH4 (326 mg, 8.59 mmol) in THF (33 mL) at 0 °C was treated with a solution of Préparation 66 (2 g, 4.3 mmol) in THF (10 mL) and stirred at 20 °C for 72 h. The mixture was treated with NasSCU.HïO, followed by MgSO4 (4g). The mixture was stirred for 30 min. The mixture was diluted with EtOAc (20 mL) and filtered. The filtrate was concentrated and the residue was purified by chromatography (silica, EtOAc/PE = 0-50%) to give the title compound (1.03 g, 53%). ¹H NMR (400 MHz, CDCh) δ 9.55 (s, 1H), 7.51 (s, 1H), 7.10 (d, 1H), 6.57 (s, 1H), 5.43-5.27 (m, 2H), 3.60-3.50 (m, 3H), 3.28 - 3.13 (m, 3H), 3.09 (d, 1 H), 2.72 (d, 1 H), 2.25 (s, 3H), 1.35 (t, 3H), 1.28 (s, 3H), 1.14 (dt, 1H), 0.96-0.84 (m, 2H), 0.39 (dd, 1H), 0.28 (t, 1H), -0.03 (s, 9H); LC/MS m/z (M+H)⁺ = 452.3.

Préparation 68: (4aS,5aR)-5,5-difluoro-5a-methvl-1,4,4a,5₁5a,6hexahvdrocvclopropa[flindazole-3-carboxyÎic acid

A solution of Préparation 15 (1.0 g, 3.90 mmol) in MeOH (12 mL) and water (2.0 mL) at 20 °C was treated with NaOH (468 mg, 11.7 mmol). After 32 h, the mixture was concentrated and the residue diluted with H2O (10 mL) and the pH adjusted to 4-5 with 1M HCl. The resulting suspension was filtered to collect the solids. The solids were dried to give the title compound (900 mg, 100%). ¹H NMR (400 MHz, DMSO-de) δ 13.03 (bs, 2H), 3.16 (d, 1H), 3.03-2.97 (m, 3H), 2.76 (dd, 1H), 1.75 (d, 1H), 1.33 (d, 3H).; LC/MS m/z (M+H)⁺ = 228.8.

Préparation 69: (4aS_l5aR)-3-(5-bromo-7-fluoro-1H-benzo[d1imidazol-2-vl)-5a-methyl-1((2-(trimethvlsilvl)ethoxv)methvl)-1,4_l4a,5,5a,6-hexahvdrocvclopropaff1indazole

A solution of Préparation 9 (510 mg, 1.66 mmol) in DMF (20.8 mL) was treated with 5bromo-3-fluorobenzene-1,2-diamine (358 mg, 1.75 mmol) and NaïSaOs (380 mg, 2.00 mmol) at RT, The vial was sealed and heated in a microwave reactor at 150 °C for 2 h. The mixture was poured into 3% aq. LiCI (40 mL) and the mixture extracted with EtOAc (2 x 40 mL). The organic extracts were dried (N82SO4), filtered and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE = 0- 25%) to give the title compound (815 g, 98%). ¹H NMR (400 MHz, CD3OD) δ 7.50 (s, 1H), 7.23 - 7.07 (m, 1H), 5.52 - 5.41 (m, 2H), 3.61 (t, 2H), 3.42 - 3.32 (m, 1H), 3.25 - 3.07 (m, 2H), 2.812.72 (m, 1H), 1.30 (s, 3H), 1.26- 1.13 (m, 2H), 0.88 (td, 2H), 0.44 (dd, 1H), 0.25 (t, 1H), -0.04 (s, 9H).; LC/MS m/z (M+Na)⁺ = 514.7 (⁷⁹Br).

Préparation 70: (4aS,5aR)-3-(5-bromo-7-fluoro-1 H-benzo[d1imidazol-2-yl)-5a-methv1-

1,4,4a,S.Sa.G-hexahvdrocycloproparfiindazole

A solution of Préparation 69 (100 mg, 0.20 mmol) in TFA (2mL) at 10 °C was treated with EtsSiH (118 mg, 1.02 mmol). The mixture was stirred at 10 °C for 3 h. The mixture was concentrated and the residue treated with sat. aq. NazCCh. The mixture was extracted with EtOAc (3x15 mL). The organic extracts were dried (N32SO4), filtered and concentrated. The crude product was purified by chromatography [prep HPLC, H2O:MeCN (w/0.05% NH4OH)] to give the title compound (27.1 mg, 37%). ¹H NMR (400 MHz, CDsOD) ô 7.53 (s, 1H), 7.16 (d, 1H), 3.36-3.31 (m, 1H), 3.13 (dd, 1H), 3.06 (d, 1H), 2.77 (d, 1H), 1.29 (s, 3H), 1.20 - 1.09 (m, 1H), 0.41 (dd, 1H), 0.24 (t, 1H); LC/MS m/z (M+H)⁺ = 363.0 (⁷⁹Br).

Préparation 71a: (4aS,5aR)-3-(6-bromo-4-fluoro-1-((2-(trimethvlsilvl)ethoxv)methvl)-1Hbenzo[d1imidazol-2-vl)-5a-methvl-1-((2-(trimethvlsilvl)ethoxv)methvl)-1,4,43,5,53,6hexahvdrocyclopropamindazole

Préparation 71b: (4aS_l5aR)-3-(5-bromo-7-fluoro-1-((2-(trimethvlsilvl)ethoxv)methyl)-1/-/benzord1imidazol-2-vl)-5a-methvl-1-((2-(trimethvlsilyl)ethoxv)methvl)-1.4,4a,5,5a,6hexahydrocyclopropaffîindazole

A solution of Préparation 70 (1.53 g, 3.11 mmol) in THF (39 mL) at 0 °C was treated with NaH (149 mg, 3.73 mmol). After stirring for 30 min, SEM-CI (570 mg, 3.42 mmol) was added and the mixture stirred for 2 h at 10 °C. The mixture was treated with sat. aq. NH4CI (30 mL). The mixture was extracted with EtOAc (3 x 40 mL) and organic extracts were combined, dried (Na2SO4), filtered and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE = 0-15%) to give the title compounds as a mixture (1.60 g, 83%). ¹H NMR (400 MHz, CD3OD) δ 7.69 (dd, 1H), 7.26 (ddd, 1H), 6.24 - 5.97 (m, 2H), 5.53 - 5.46 (m, 2H), 4.10 (q, 1 H), 3.63 (dd, 2H), 3.53 - 3.36 (m, 2H), 3.28 - 3.17 (m, 2H), 3.16 - 3.03 (m, 1H), 2.78 (d, 1H), 1.31 (s, 3H), 1.24 (t, 1H), 1.15 (dt, 1H), 0.92 (td, 2H), 0.76 (dt, 2H), 0.48 -0.39 (m, 1H), 0.24 (td, 1H), -0.01 (s, 9H), -0.18 (s, 9H); LC/MS m/z (M+H)⁺ = 622.8 (⁷⁹Br).

Préparation 72a: tert-butyl (4-fluoro-2-((4aS,5aR)-5a-methyl-1-((2(trimethylsilyl)ethoxv)methvl)-1,4,4a,5,5a,6-hexahvdrocYClopropa[f1indazol-3-yl)-1-((2(trimethvlsilvl)ethoxv)methyl)-1H-benzo[dlimidazol-6-vl)carbamate

Préparation 72b: tert-butyl (7-fluoro-2-((4aS,5aR)-5a-methvl-1-((2(trimethvlsilvl)ethoxy)methvl)-1,4,4a,5,5a,6-hexahydrocvclopropa[f|indazol-3-vl)-1-((2(trimethvlsilvl)ethoxv)methvi)-1H-benzordlimidazol-5-vl)carbamate

A portion of the mixture of Préparations 71a and 71b (712 mg, 1.15 mmol), tert-Butyl carbamate (161 mg, 1.37 mmol), CS2CO3 (746 mg, 2.29 mmol) in tert-amyl aicohol (11.5 mL) was treated with Pd2(dba)3 (105 mg, 0.12 mmol) and tert-BuDavePhos (78 mg, 0.23 mmol). The reaction was heated at 100 °C for 23 h. The mixture was concentrated and the crude material purified by chromatography (silica, EtOAc/PE = 020%) to give the title compounds as a mixture (706 mg, 93%). ¹H NMR (400 MHz, CD₃OD) δ 7,72 (s, 1H), 7,40 - 7.21 (m, 1H), 7.07 (d, 1H), 6.08 - 5.89 (m, 2H), 5.48 (d, 2H), δ 3.69 - 3.57 (m, 2H), 3.46 (dd, 1H), 3.25 - 3.02 (m, 3H), 2.78 (d, 1H), 2.50 (d, 1H), 1.55 (s, 9H), 1.43 (d, 1H), 1.33- 1.23 (m, 5H), 1.20- 1.09 (m, 2H), 0.99-0.83 (m, 5H), 0.82-0.69 (m, 1H), 0.42 (dd, 1H), 0.25 (t, 1H), -0.00 (s, 9H), -0.13 (s, 9H).; LC/MS m/z (M+H)⁺ = 658.0

Préparation 73a: tert-butyl (4-fluorO’2-((4aS,5aR)-5a-methyl-1-((2(trimethylsÎlyl)ethoxv)methvl)-1,4.4a,5,5a,6-hexahvdrocyclopropa[f]indazol-3-yl)-1-((2(trimethvlsilvl)ethoxy)methvl)-1/7-benzordlimidazol-6-vl)(methvl)carbamate

Préparation 73b: tert-butyl (7-fluoro-2-((4aS,5aR)-5a-methyl-1-((2(trimethvlsilyl)ethoxy)methvl)-1,4,4a,5,5a.6-hexahvdrocycloproparf|indazol-3-vl)-1-((2(trimethvlsilvl)ethoxy)methvl)-1H-benzoidlimidazol-5-vl)(methvl)carbamate

A portion of the mixture of Préparations 72a and 72b (235 mg, 0.36 mmol) in THF (5 mL) at 0 °C was treated with NaH (21.4 mg, 0.54 mmol). The mixture was stirred at 15 °C for 30 min and treated with methyl iodide (61 mg, 0.43 mmol). The mixture was stirred for 16 h and treated with sat. aq. NH4CI (15 mL). The mixture was extracted with EtOAc (2 x 20 mL). The organic extracts were collected, dried (NaaSCH), filtered and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE = 0-30%) to give the title compounds as a mixture (120 mg, 50%) Ή NMR (400 MHz, CD3OD) ô 7.39 (d, 1 H), 7.01 (dd, 1 H), 6.16 - 5.95 (m, 2H), 5.50 (d, 2H), 3.68 - 3.56 (m, 2H), 3.46 (t, 2H), 3.27 - 3.05 (m, 4H), 2.79 (d, 1H), 1.46 (s, 9H), 1.31 (s, 3H), 1.18 1.13 (m, 1H), 0.97-0.85 (m, 2H), 0.82-0.71 (m, 2H), 0.43 (dd, 1H), 0.26 (t, 1H), -0.00 (s, 9H), -0.14 (s, 9H); LC/MS m/z (M+Na)⁺ = 694.0.

Préparation 74a: 4-fluoro-A/-methyl-2-((4aS,5aR)-5a-methvl-1-((2(trimethvlsilyl)ethoxv)methyl)-1,4,4a,5,5a,6-hexahvdrocvclopropafflindazol-3-vl)-1-((2(trimethvlsilvl)ethoxv)methvl)-1H-benzo[d1imidazol-6-amine

Préparation 74b: 7-fluoro-/V-methvl-2-((4aS,5aR)-5a-methyl-1-((2(trimethvlsilyl)ethoxy)methyl)-1 ,4,4a,5,5a,6-hexahvdrocvclopropaff|indazol-3-vÎ)-1-((2(trimethvisilvl)ethoxy)methvl)-1H-benzoÎd1imidazol-5-amine

The mixture of Préparations 73a and 73b (120 mg, 0.178 mmol) in DCM (2.0 mL) at 0 °C was treated with ZnBr2(201 mg, 0.89 mmol). The mixture was stirred for 12 h then treated with sat. aq. NaHCOs (10 mL) and the mixture extracted with DCM (2 x 20 mL). The organic extracts were combined, dried (N32SÛ4), filtered and concentrated to give the title compounds as a mixture (111 mg, 109%) ¹H NMR (400 MHz, CD3OD) δ 6.51 (d, 1H), 6.43 (dd, 1H), 5.97 (d, 1H), 5.86 (d, 1H), 5.47 (s, 2H), 3.62 (t, 2H), 3.41 (t, 2H), 3.25 - 3.03 (m, 3H), 2.84 (s, 3H), 2.82-2.75 (m, 1H), 1.30 (s, 3H), 1.17-1.10 (m, 1H), 0.92 (dd, 2H), 0.77 (t, 2H), 0.41 (dd, 1H), 0.25 (t, 1H), -0.00 (s, 9H), -0.13 (s, 9H); LC/MS m/z (M+Na)⁺ = 594.0.

Préparation 75a: tert-butyl ethvl(4-fluoro-2-((4aS,5aR)-5a-methyl-1-((2(trimethvlsilvl)ethoxv)methvl)-1.4.4a.5,5a,6-hexahYdrocvclopropaÎf|indazol-3-vl)-1-((2(trimethvlsilvl)ethoxv)methvl)-1H-benzo[d1imidazol-6-vl)carbamate

Préparation 75b: tert-butyl ethyl(7-fÎuoro-2-((4aS,5aR)-5a-methvl-1-((2(trimethvlsilvl)ethoxv)methvl)-1,4,4a,5,5a,6-hexahvdrocyclopropa[f]indazol-3-vl)-1-((2(tnmethvl$ilvl)ethoxv)methvl)-1H-benzofd1imidazol-5-vl)carbamate

A mixture of Préparations 72a and 72b (10.5 g, 16.0 mmol) in THF (160 mL) at 0 °C was treated with NaH (1.27 g, 31.9 mmol). The mixture was stirred for 30 min and treated with ethyl iodide (3.30 g, 21 mmol) and the mixture stirred for 16 h. The mixture was treated with sat. aq. NH4CI (150 mL). The mixture was extracted with EtOAc (2 x 200 mL) and the organic layers combined, dried (NazSCU), filtered and concentrated.

ao

The crude product was purified by chromatography (silica, EtOAc/PE = 0-10%) to give the title compounds as a mixture (8,26 g, 75%). LC/MS m/z (M+H)⁺ = 453.3.

Préparation 76a: N-ethyl-4-fluoro-2-((4aS,5aR)-5a-methvl-1-((25 (trimethvlsilvl)ethoxv)methyl)-1,4,4a,5,5a,6-hexahvdrocvclopropafflindazol-3-vÎ)-1-((2(trimethvlsilvl)ethoxv)methvl)-1H-benzofd1imidazol-6-amine

Préparation 76b: N-ethyl-7-fluoro-2-((4aS,5aR)-5a-methyl-1-((2(trimethylsilvl)ethoxv)methyl)-1,4,4a,5,5a,6-hexahvdrocvclopropaff|indazol-3-yl)-1-((2(trimethvlsilvl)ethoxv)methvl)-1H-benzordlimidazol-5-amine

A mixture of Préparations 75a and 75b (10.39 g, 15. 14 mmol) in DCM (151 mL) at 0 °C was treated with ZnBrs (17.1 g, 75.7 mmol). The reaction was warmed to 30 °C and stirred for 16 h. The mixture was poured into saturated NaHCOa (150 mL) and filtered. The filtrate was extracted with DCM (2 x 100 mL). The organic extracts were combined, 15 dried (Na₂SO4), filtered and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE = 0-10%) gave to give the title compounds as a mixture (6.14 g, 69.2%). LC/MS m/z (M+H) = 586.2.

Préparation 77: (4aS,5aR)-3-(5-bromo-6-fluoro-1/-/-benzofd1imidazol-2-vl)-5a-methvl-120 ((2-(trimethvlsilvl)ethoxv)methyl)-1,4,4a.5,5a,6-hexahvdrocyclopropa[f]indazole

A solution of Préparation 9 (467 mg, 1.52 mmol) in DMF (19 mL) was treated with 4bromo-5-fluorobenzene-1,2-diamine (328 mg, 1.60 mmol) and NaaSsOs (380 mg, 2.00 mmol) at RT. The via! was sealed and heated in a microwave reactor at 150 °C for 2 h. 25 The mixture was poured into 3% aq. LiCI (80 mL) and extracted with EtOAc (2 x 60 mL).

The organic layers were combined, dried (Na2SO4), filtered and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE = 0- 25%) to give the title compound (644 mg, 86%). Ή NMR (400 MHz, CDCh) Ô 9.96 (s, 1H), 7.98 (s, 1H), 7.57 (s, 1 H), 5.46 - 5.28 (m, 2H), 3.58 - 3.49 (m, 2H), 3.20 - 3.07 (m, 3H), 2.74 (d, 1 H), 1.29 (s, 3H), 1.21 - 1.10 (m, 1H), 0.95-0.83 (m, 2H), 0.43 (dd, 1H), 0.27 (t, 1H), -0.02 (s, 9H).

Préparation 78a: tert-butyl (6-fluoro-2-((4aS₁5aR)-5a-methyl-1-((2(tnmethylsilyl)ethoxv)methyl)-1,4,4a,5,5a,6-hexahvdrocvclopropa[f]indazol-3-yl)-1 -((2(trimethvlsilvl)ethoxv)methyl)-1H-benzordlimidazol-5-vl)carbamate

Préparation 78b: tert-butyl (5-fluoro-2-((4aS,5aR)-5a-methyl-1-((2(trimethvlsilvl)ethoxv)methyl)-1,4.4a,5,5a,6-hexahvdrocvclopropaff|indazol-3-vl)-1-((2(trimethvls^lvl)ethoxv)methvl)-1H-benzoΓd1imidazol·6-vl)carbamate

A mixture of Préparations 77 (800 mg, 1.29 mmol), t-butyl carbamate (181 mg, 1.54 mmol), and CS2CO3 (838 mg, 2.57 mmol) in fert-amyl alcohol (12.9 mL) was treated with Pd2(dba)3 (59 mg, 0.64 mmol) and (88 mg, 0.26 mmol). The mixture was heated to 100 °C for 16 h. Additional Pd?(dba)3 (59 mg, 0.64 mmol) and (88 mg, 0.26 mmol) was added and heating continued at 100 °C for 16 h. The mixture was concentrated and the residue purified by chromatography (silica, EtOAc/PE = 0- 20%) to give the title compounds compound as a mixture (480 mg, 57%). *H NMR (400 MHz, CDCh) δ 8.34 (d, 1H), 7.49 (t, 1H), 6.82 (s, 1H), 6.15 - 5.97 (m, 2H), 5.47 - 5.34 (m, 2H), 3.62 - 3.37 (m, 5H), 3.10 (t, 2H), 2.73 (d, 1H), 1.55 (s, 9H), 1.28 (s, 3H), 1.12 (s, 1H), 0.99 - 0.77 (m, 4H), 0.39 (dd, 1H), 0.26 (q, 1H), -0.02 (s, 9H), -0.13 (d, 9H); LC/MS m/z (M+H)⁺ = 658.3

Préparation 79a: tert-butyl (6-fluoro-2-((4aS,5aR)-5a-methyl-1-((2(trimethylsilyl)ethoxv)methvl)-1,4,4a,5,5a,6-hexahvdrocYCloproparf|indazol-3-yl)-1-((2(tnmethvlsilvl)ethoxv)methvl)-1H-benzofdlimidazol-5-vl)(methvl)carbamate

Préparation 79b tert-butyl (5-fluoro-2-((4aS,5aR)-5a-methvl-1-((2(trimethylsilyl)ethoxv)methvl)-1,4,4a,5,5a,6~hexahvdrocyclopropa[fÎindazol-3-vl)-1-((2(trimethvlsilvl)ethoxv)methyl)-1/-7-benzo[d1imidazol-6-vl)(methvl)carbamate

A portion of the mixture of Préparations 78a and 78b (230 mg, 0.35 mmol) in THF (4.6 mL) at 0 °C was treated with NaH (21.0 mg, 0.52 mmol). The mixture was stirred at 15 °C for 20 min and then treated wtih methyl iodide (124 mg, 0.87 mmol). After stirring for 5 16 h, the mixture was diluted with sat. aq. NH4CI (2 mL) and extracted with EtOAc (2 x mL). The organic extracts were collected, dried (NasSCU), filtered and concentrated. The crude material was purified by chromatography (sîlica, EtOAc/PE = 0-30%) to give the title compounds as a mixture (286 mg, 100%). ¹H NMR (400 MHz, CDCI3) δ 7.63 (s, 0.5H), 7.51 (d, 0.5H), 7.40 (s, 1H), 6.10 (d, 2H), 5.50 - 5.37 (m, 2H), 3.64 - 3.53 (m, 10 2H), 3.56 - 3.43 (m, 3H), 3.28 (d, 3H), 3.20 - 3.07 (m, 2H), 2.76 (d, 1 H), 1.38 (s, 7H),

1. 30 (d, 5H), 1.15 (dt, 1H), 0.98-0.81 (m, 4H), 0.42 (dd, 1H), 0.29 (t, 1H), 0.01 (s, 9H),

-0.09 (d, 9H); LC/MS m/z (M+H)⁺ = 672.5

Préparation 80a: 5-fluoro-/V-methvl-2-((4aS,5aR)-5a-methyl-1 -((215 (trimethylsilyl)ethoxv)methvl)-1,4,4a,5,5a,6-hexahvdrocvclopropamindazol3-vl)-1-((2(trimethvlsilyl)ethoxv)methvl)-1H-benzofdlimidazol-6-amine

Préparation 80b: 6-fluoro-/\/-methvl-2-((4aS,5aR)-5a-methvl-1 -((2(trimethvlsilvl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahvdrocvclopropaff|indazol-3-yl)-1-((2(trimethvlsilvl)ethoxv)methyl)-1H-benzo[dlimidazol-5-amine

A mixture of Préparations 79a and 79b (286 mg, 0.425 mmol) in DCM (4.26 mL) at 0 °C was treated with ZnBr₂ (479 mg, 2.13 mmol). After stirring at 15 °C for 12 h, the mixture was poured into sat. aq. NaHCOs (20 mL) and the resulting mixture was extracted with DCM (2 x 20 mL). The organic extracts were collected, dried (Na2SO4), filtered and 25 concentrated. The crude material was purified by chromatography (silica, EtOAc/PE = 0-40%) to give the title compounds as a mixture (160 mg, 66%). ¹H NMR (400 MHz, CDCI3) δ 7.41 (d, 0.57H), 7.21 (d, 0.43H), 7.07 (d, 0.43H), 6.73 (d, 0.57H), 6.06 (d, 1 H),

6.07 - 5.95 (m, 1H), 5.46 - 5.34 (m, 2H), 4.05 (s, 1 H), 3.61 - 3.37 (m, 5H), 3.09 (t, 2H), 2.94 (d, 3H), 2.73 (d, 1H), 1.30- 1.22 (m, 3H), 1.11 (d, 1H), 0.91 (t, 2H), 0.85-0.80 (m, 2H), 0.38 (dd, 1H), 0.26 (t, 1H), -0.02 (d, 9H), -0.12 (s, 9H); ¹⁹F NMR (376 MHz, CD3OD) δ -131.20.; LC/MS m/z (M+H)⁺ = 572

Préparation 81: 4-fluoro-2-methoxy-5-nitroaniiine

ch₃

A solution of 4-fluoro-2-methoxyaniline (1590 mg, 11.27 mmol) in conc.HsSCU (9.55 mL) was treated with solid KNO3 (1140 mg, 11.3 mmol) in portions while keeping the internai température below 5 °C. The resulting mixture was stirred for 2 h at 0 °C and mixture was poured into ice water (100 mL), neutralized slowly with solid Na^COs and extracted with EtOAc (2 x 60 mL). The organic layers were dried (Na2SO4), filtered and and concentrated to give the titie compound (2 g, 95%). Ή NMR (400 MHz, CDCI3) δ 7.42 (d, 1 H), 6.66 (d, 1 H), 3.96 (s, 3H), 1.60 (s, 2H); LC/MS m/z (M+H)⁺ =186.8.

Préparation 82: (S)-/V-(4-fluoro-2-methoxv-5-nitrophenyl)-2-morpholinopropanamide

A solution of Préparation 81 (590 mg, 3.17 mmol) and préparation 19 (605 mg, 3.80 mmol) in pyridine (45.3 mL) was treated with EDCI (1.22 g, 6.34 mmol). The mixture was stirred at RT for 16 h and then poured into water (30 mL). The resulting mixture was extracted with EtOAc (2 x 40 mL). The organic layers were combined, washed sequentially with sat. aq. NH4CI and brine, dried (MgSO4), filtered and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE = 0-50%) to give titie compound (586 mg, 77%). Ή NMR (400 MHz, CDCI3) ô 9.94 (s, 1H), 9.19 (d, 1H), 6.75 (d, 1H), 4.02 (s, 3H), 3.86 - 3.72 (m, 4H), 3.26 (q, 1H), 2.70 - 2.53 (m, 4H), 1.34 (d, 3H). ¹⁹F NMR (376 MHz, CDCI3) δ -118.16. LC/MS m/z (M+H) = 328.1; SFC method: Chiral Tech AD-3 150 mm x 4.6 mm x 3 pm, CO2/IPA (0.05% /Pr2NEt ) isocratic 40%, 2.5 mL/min, column température 40 “C, RT=4.027 min (99.31%)

Préparation 83: (S)-/V-(4-fluoro-2-methoxy-5-nitroDhenvl)-/V-methvl-2morpholinopropanamide

A mixture of Préparation 82 (586 mg, 1.79 mmol) in THF (25 mL) at 0 °C was treated 5 with NaH (107 mg, 2.69 mmol). The mixture was stirred at 20 °C for 30 min and treated with methyl iodide (305 mg, 2.15 mmol). After stirring for 16 h, the mixture was diluted with sat. aq. NH4CI (2 mL) and extracted with EtOAc (2 x 20 mL). The organic extracts were collected, dried (Na2SO4), filtered and concentrated. The crude material was purifîed by chromatography (silica, EtOAc/PE = 0-100%) to give the title compound 10 (423 mg, 69%). ¹H NMR (400 MHz, CDCI3) δ 8.30 (d, 0.5H), 7.98 (d, 0.5H), 6.86 (dd,

1H), 4.03 - 3.93 (m, 3H), 3.65 (t, 2H), 3.60 - 3.46 (m, 2H), 3.21 - 3.12 (m, 4H), 3.02 2.92 (m, 0.5H), 2.55 (dt, 1H), 2.48-2.37 (m, 0.5H), 2.24 (dp, 2H), 1.18 (d, 1H), 1.11 (d, 2H); LC/MS m/z (M+H) = 429.1.

Préparation 84: (S)-/V-(4,5-diamino-2-methoxvphenyl)-A/-methvl-2morpholinopropanamide

A mixture of Préparation 83 (400 mg, 0.934 mmol) in MeOH (10 mL) was treated with 10% Pd/C (100 mg) and MeOH (5 mL). The mixture was degassed and refilled with 20 Argon and H2 three times and then stirred under H2 (3 atm) at 25 °C for 24 h. Additional 10% Pd/C (100 mg) was added and the mixture was stirred under H2 (3 atm) at 25 °C for an additional 24 h. The reaction was filtered and the filtrate concentrated. The crude product was purified by chromatography (silica, MeOH/DCM = 0-10%) to give the title compound (239 mg, 83%). ¹H NMR (400 MHz, CDCI3) δ 7.41 - 7.29 (m, 3H), 6.60 25 (s, 1H), 6.35 (d, 1H), 4.46 (d, 1H), 3.74 (d, 3H), 3.72 - 3.60 (m, 4H), 3.18 - 3.12 (m,

4H), 2.63 - 2.52 (m, 1H), 2.51 - 2.39 (m, 3H), 1.19 (d, 1 H), 1.14 (d, 2H); LC/MS m/z (M+H) = 309.2.

Préparation 85: (S)-/V-(6-bromo-2-((4aS,5aR)-5a-methyÎ-1-((2(trimethvlsilvl)ethoxv)methyl)-1.4.4a.5.5a.6hexahvdrocyclopropa[flindazol-3-vl)-1 Hbenzordlimidazol-5-vi)-/V-methyl-2-morpholinopropanamide

A mixture of Préparation 40 (900 mg, 2.52 mmol) in DMF (30 mL) at 20 °C was treated with 9 (722 mg, 2.52 mmol) and NazSzOs (479 mg, 2.52 mmol). The mixture was heated at 110 °C for 15 h and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE = 0-100%) gave the title compound (703 mg, 43.4%). LC/MS m/z (M+H)⁺ = 643.2/645.2 (⁷⁹Br, ⁸¹Br).

Préparation 86a: (S)-A/-(6-bromo-2-((4aS,5aR)-5a-methvl-1-((2 (trimethylsilvl)ethoxv)methvl)-1.4.4a,5,5a,6-hexahvdrocvclopropa[f1indazol-3-vl)-1-((2 (trimethvlsilvl)ethoxv)methvl)-1H-benzord1imidazol-5-vl)-/\/-methvl-2 morpholinopropanamide

Préparation 86a: (S)-A/-(6-bromo-2-((4aS,5aR)-5a-methyl-1-((2 (trimethvlsilyl)ethoxv)methvl)-1,4,4a, 5,5a, 6-hexahvdrocvclopropaff|indazol-3-vl)-1-((2(trimethvlsilvl)ethoxv)methvl)-1H-benzo[d1imidazol-5-vl)-/V-methvl-2-

A solution of Préparation 85 (600 mg, 0.93 mmol) in THF (30 mL) at 0 °C was treated with NaH (48.5 mg, 1.21 mmol). After stirring for 30 min, SEM-CI (233 mg, 1,40 mmol) was added and the mixture stirred at 20 °C for 2 h. The mixture was treated with sat.

aq. NH4CI (1 mL) and diluted with 3:1 EtOAc/HaO (200 mL). The organic layer was collected and the aqueous layer was extracted with EtOAc (150 mL). The organic extracts were combined, dried (N32SO4), filtered and concentrated. The crude material was purified by chromatography (silica, EtOAc/PE = 0-100%) to give the title compounds as a mixture (705 mg, 98%). LC/MS m/z (M+H)⁺ = 773.0/775.0 (⁷⁹Br, ⁸¹ Br).

Préparation 87a: (S)-/V-(6-cvano-2-((4aS,5aR)-5a-methvl-1-((2(trimethyl$ilvl)ethoxv)methyl)-1,4,4a,5,5a,6-hexahvdrocvclopropa[flindazol-3-vl)-1-((2(trimethvlsilvl)ethoxv)methvl)-1/7-benzo[d1imidazol-5-vO-/V-methyl-2morpholinopropanannide

Préparation 87b: (S)-A/-(6-cyano-1-methvl-2-((4aS_l5aR)-5a-methyl-1-((2(trimethvlsilvl)ethoxv)methyl)-1,4,4a,5,5a,6-hexahvdrocvclopropaΓf]indazol·3-vO-1/7benzord]imidazol-5-yl)-/\/-methvl-2-morpholinopropanamide

A portion of the mixture of Préparations 86a and 86b (200 mg, 0.258 mmol) in NMP (10 mL) at 20 °C was treated with Pd(PPhs)4 (30.0 mg, 0.026 mmol) and Zn(CN)2 (152 mg, 1.29 mmol). The resulting mixture was heated in a microwave reactor at 160 “C for 1.5 h. The mixture was poured into EtOAc/HaO (50/10 mL) and the organic layer collected. The aqueous layer was extracted with EtOAc (50 mL). The organic extracts were combined, washed with brine, dried (Na2SO₄), filtered and concentrated. The crude material was purified by chromatography (silica, EtOAc/PE = 0-100%) to give the title compounds as a mixture (165 mg, 89%). LC/MS m/z (M+H)⁺ = 720.3.

Préparation 88. 4-bromo-2,3-difluoro-6-nitroaniline

Br^^.NO₂ II F'Y'NH₂ F

A solution of 2,3-difluoro-6-nîtroaniline (10.0 g, 57.4 mmol) in DMF (230 mL) at 15 °C was treated with /V-bromosuccinimide (12.3 g, 68.9 mmol). The mixture was heated at 90 °C for 6 h and then cooied to RT and poured into ice water. The mixture was extracted with EtOAc (2 x 100 mL) and the organic extracts combined, washed with brine and dried (Na2SO4), filtered and concentrated. The crude material was purified by chromatography (silica, EtOAc/PE - 0-20%) to give the title compound (13.5 g, 93%).

¹H NMR (400 MHz, CDCI₃) 6 8.22 (dd, 1H), 6.24 (s, 2H).

Préparation 89: 5-bromo-3,4-difluorobenzene-1,2-diamine nh₂

F y NH₂

F

A solution of Préparation 88 (13,5 g, 53.4 mmol) in EtOH (296 mL) at 20 °C was treated with SnCh (48.2 g, 213 mmol). The mixture was heated at 70 °C for 16 h and then 5 cooled to RT. The mixture was diluted with H2O (200 mL) and washed with sat. aq.

NaHCOe (200 mL). The mixture was filtered and the collected solids rinsed with EtOAc (100 mL). The filtrate was concentrated. The residue was purified b y chromatography (silica, EtOAc/PE = 0-60%) to give the title compound (8.50 g, 71.4%). '’H NMR (400 MHz, CDCh) δ 6.63 (dd, 1H), 3.49 (s, 2H), 3.35 (s, 2H); LC/MS m/z (M+H)⁺ = 10 223.1/225.0 (⁷⁹Br, ⁸¹Br),

Préparation 90: (4aS,5aR)-3-(5-bromo-6,7-difluoro-1H-benzo[dlimidazol-2-yl)-5amethvl-1-((2-(trimethv1silvl)ethoxv)methvl)-1,4,4a,5,5a,6-hexahvdrocycloproparflindazole

A solution of Préparation 89 (5.0 g, 22.42 mmol) in DMF (112 ml) at RT was treated with Préparation 9 (6.87 g, 22.4 mmol), Na2S20s (2.13 g, 11.2 mmol) and DMSO (4.38 g, 56.0 mmol). The reaction mixture was heated at 110 °C for 16 h. The mixture was poured into 3% aq. LiCI (100 mL) and extracted with EtOAc (2 x 80 mL). The organic extracts were combined, dried (Na2SO4), filtered and concentrated. The crude material was purified by chromatography (silica, EtOAc/PE = 0-20%) to give the title compound (10.17 g, 89%). LC/MS m/z (M+H) = 509.3/511.3 (⁷⁹Br, ⁸¹Br).

Préparation 91a: (4aS_I5aR)-3-(6-bromo-4,5-difluoro-1-((2-(trimethvlsilvl)ethoxv)methyl)1 H-benzo[d]imidazol-2-vl)-5a-methvl-1 -((2-(trimethvlsilvl)ethoxy)methvl)-1,4,4a,5,5a,625 hexahvdrocvcloDropa[f]indazole

Préparation 91 b: (4aS,5aR)-3-(5-bromo-6,7-difluoro-1 -((2-(trimethvlsilvl)ethoxy)methyl)1H-benzo[d1imidazol-2-vl)-5a-methyl-1-((2-(trimethvlsilvl)ethoxv)methvl)-1,4,43,5.53^ hexahvdrocycloproparflindazole

A solution of Préparation 90 (10.95 g, 2.49 mmol) in THF (269 mL) at 0 °C was added NaH (1.29 g, 32.2 mmol). After stirring for 30 min, SEM-CI (3.94 g, 23.6 mmol) was added and the mixture stirred for 3 h at RT. The mixture was poured into sat. aq. NH4CI 5 (150 mL) and extracted with EtOAc (2 x 100 mL). The organic extracts were collected, dried (NazSCL), filtered and concentrated. The crude material was purified by chromatography (silica, EtOAc/PE = 0-20%) to give the title compounds as a mixture (12.49 g, 90.8%). ¹H NMR (400 MHz, Methanol-oU) δ 7.74 (ddd, 1H), 6.26 - 5.99 (m, 2H), 5.49 (d, 2H), 3.63 (t, 2H), 3.45 (dt, 2H), 3.23 (dd, 2H), 3.08 (td, 1H), 2.78 (dd, 1H), 10 1.31 (s, 3H), 1.15 (dt, 1H), 0.91 (td, 2H), 0.77 (ddd, 2H), 0.43 (dd, 1H), 0.24 (q, 1H), 0.01 (d, 9H), -0.14 (s, 4H), -0.17 (s, 5H).

Préparation 92a: tert-butyl (4,5-difluoro-2-((4aS,5aR)-5a-methvl-1-((2(trimethvlsilvl)ethoxv)methyl)-1,4,4a,5,5a,6-hexahvdrocyclopropaif1indazol-3-vl)-1-((215 (trimethvlsilvl)ethoxy)methyl)-1H-benzordlimidazol-6-vl)carbamate

Préparation 92b: tert-butyl (6,7-difluoro-2-((4aS,5aR)-5a-methyl-1-((2(trimethvlsilvl)ethoxv)methyl)-1,4,4a.5.5a.6-hexahvdrocyclopropaff|indazol-3-vl)-1-((2(trimethvlsilvl)ethoxv)methvl)-1/7-benzo[d1imidazol-5-yl)carbamate

A portion of the mixture of Préparations 91a and 91b (9.45 g, 14.7 mmol) in terf-amyl alcohol (148 mL) at RT was treated with f-butyl carbamate (2.60 g, 22.2 mmol), CS2CO3 (9.63 g, 29.5 mmol), Pd2(dba)3 (1.35 g, 1.48 mmol) and (1.01 g, 2.95 mmol). The mixture heated at 100 °C for 16 h. The mixture was concentrated and the residue purified by chromatography (silica, EtOAc/PE = 0-16%) to give the title compounds as a mixture (4.24 g, 43%). LC/MS m/z (M+H) = 676.3.

Préparation 93a: 4,5-difluoro-2-((4aS,5aR)-5a-methyl-1-((2(trimethylsilvl)ethoxv)methvl)-1,4,4a,5,5a,6-hexahydrocvcloproparfiindazol-3-yl)-1-((2(trimethvlsilvÎ)ethoxyÎmethvl)-1H-benzordlimidazol-6-amine

Préparation 93b: 6,7-difluoro-2-((4aS,5aR)-5a-methyl-1-((2(trimethvlsilylÎethoxv)methvl)-1 ^a.S.Sa.e-hexahydrocyclopropaiflindazol-S-vD-l-itë(trimethvlsilvl)ethoxv)methyl)-1H-benzo[d1imidazol-5-amine

SEM

A mixture of 92a and 92b (5,27 g, 7.79 mmol) in DCM (78.0 mL) at 0 °C was treated with ZnBr₂ (8.78 g, 39.0 mmol). The mixture was stirred at 15 °C for 12 h and poured into sat. aq. NaHCO3(70mL). The mixture was extracted with DCM (2 x 80 mL) and the organic extracts combined, dried (Na2SO4), filtered and concentrated. The crude material was purified by chromatography (silica, EtOAc/PE = 0-25% then MeOH/EtOAc = 0-15%) to give the title compounds as a mixture (2.8 g, 62.4%). LC/MS m/z (M+H)⁺ =

576.3.

Préparation 94a: (S)-A/-(4,5-difluoro-2-((4aS,5aR)-5a-methvl-1-((2(trimethylsilvl)ethoxy)methvl)-1,4.4a,5,5a_l6-hexahvdrocvclopropaff]indazol-3-vl)-1-((2(trimethvlsilvl)ethoxv)methvl)-1H-benzo[d1imidazol-6-vl)-2-morpholinopropanamide Préparation 94b: (S)-A/-(6,7-difluoro-2-((4aS,5aR)-5a-methvl-1-((2(trimethylsilvl)ethoxv)methvl)-1,4,4a.5,5a,6-hexahvdrocvclopropa[flindazol-3-yl)-1-((2(trimethylsilvl)ethoxy)methvl)-1H-benzordlimidazoi-5-vl)-2-morpholinopropanamide

The mixture of Préparations 93a and 93b (2.80 g, 4.86 mmol) in pyridine (69.5 mL) at 0 °C was treated with Préparation 19 (1.12 g, 7.05 mmol) and EDCI (1.86 g, 9.72 mmol). The mixture was stirred at RT for 19h, diluted with H2O (100 mL) and extracted with EtOAc (2 x 100 mL). The organic extracts were combined, dried (Na2SO4), filtered and concentrated. The crude material was purified by chromatography (silica, EtOAc/PE =

100

0-25%) to give the title compounds as a mixture (3.07 g, 88.1%). LC/MS m/z (M+H) = 717.6.

Préparation 95a: (S)-/V-(4,5-difluoro-2-«4aS,5aR)-5a-methvl-1-((25 (trimethylsilvl)ethoxv)methvl)-1,4,4a,5,5a,6-hexahydrocvclopropa[flindazol-3-vl)-1-((2(trimethylsilyl)ethoxv)methvl)-1H-benzordlimidazol-6-vl)-/\/-methvl-2morpholinopropanamide

Préparation 95b: (S)-A/-(6_l7-difluoro-2-((4aS.5aR)-5a-methyl-1-((2(trimethvlsilyl)ethoxv)methyl)-1,4,4a,5.5a.6-hexahvdrocycloprooarflindazol-3-vl)-1-((210 (trïmethylsilvl)ethoxv)methvl)-1 H-benzofdlimidazol-5-yl)-/\/-methvl-2morpholinopropanamide

A solution of the mixture of Préparations 94a and 94b (3.07 g, 4.28 mmol) in THF (61 mL) at 0 °C was treated with NaH (257 mg, 6.42 mmol). After stirring 30 min at 15 °C, 15 methyl iodide (729 mg, 5.14 mmol) was added and the mixture stirred at RT 3 h. The mixture was diluted with sat. aq. NH4CI (80 mL) and extracted with EtOAc (2 x 80 mL). The organic extracts were combined, dried (Na2SO4), filtered and concentrated. The crude material was purîfied by chromatography (silica, EtOAc/PE = 0-50%) to give the title compounds as a mixture (3.26 g, 100%). LC/MS m/z (M+H) = 731.4,

Préparation 96a: (S)-A/-(4,5-difluoro-2-((4aS,5aR)-5a-methyl-1-((2(trimethylsilvl)ethoxv)methvl)-1,4,4a,5,5a,e-hexabydrocvclopropalïlindazol-B-y 1)-1-((2(trimethYlsilyl)ethoxy)methvl)-1H-benzo[d1imidazol-6-vl)-A/-ethyl-2morpholinopropanamide

Préparation 96b: (S)-/V-(6,7-difluoro-2-((4aS,5aR)-5a-methvl-1-((2(trimethylsilvl)ethoxv)methyl)-1,4,4a,5,5a,6-hexahvdrocvclopropa(f]indazol-3-vl)-1-((2(trimethylsilvl)ethoxy)methvl)-1H-benzo[dlimidazol-5-vl)-A/-ethvl-2morpholinopropanamide

101

A solution of a portion of the mixture of Préparations 94a and 94b (55 mg, 0.08 mmol) in THF (1.10 mL) at 0 °C was treated with NaH (4.60 mg, 0.12 mmol). After stirring 30 min at RT, ethyl iodide (14 mg, 0.09 mmol) was added and the mixture was stirred for 22 h.

The mixture was diluted with sat. aq. NH4CI (10 mL) and extracted with EtOAc (2 x 15 mL). The organic extracts were combined, dried (Na2SO₄), filtered and concentrated to give the title compound as a mixture. LC/MS m/z (M+H) = 745.1.

Préparation 97: /V-methyl-/V-(6-methvl-2-((4aS,5aF?)-5a-methvl-1-((210 (trimethvlsilvl)ethoxy)methvl)-1 _l4.4a,5.5a,6-hexahydrocyclopropafnindazol-3-vl)-1-((2(trimethvlsilvl)ethoxy)methyl)-1H-benzo[cflimidazol-5-vl)acetamide

A solution of Préparation 62 (4.74 g, 9.88 mmol) in THF (124 mL) at 0 °C was treated with NaH (474 mg, 11.9 mmol). The mixture was stirred at 0 °C for 30 min and SEM-CI 15 (1.81 g, 10.9 mmol) was added. The mixture was stirred at 0 °C for 1 h and warmed to °C and stirred for 1.5 h. The mixture was treated with sat. aq. NH4CI (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried (Na2SO₄), filtered and concentrated. The crude material was purified by chromatography (silica, EtOAc/PE = 0-40%) to give the title compound (2.42 g, 40%). LC/MS m/z (M+H)⁺ = 20 61 0.3.

Préparation 98: 2-chloro-A/-methyl-/\/-(6-methvl-2-((4aS_l5aR)-5a-methvl-1-((2(trimethvlsilvl)ethoxv)methvl)-1.4,4a,5,5a,6-hexahvdrocvclopropa[flindazol-3-vl)-1-((2(trimethylsilvl)ethoxy)methyl)-1H-benzofcf|imidazol-5-vl)acetamide

102

A solution of Préparation 97 (848 mg, 1.39 mmol) in THF (22 mL) at -10 °C was treated with a solution of LDA (0.76 mL, 2N in THF/heptane). The mixture was stirred at -10 °C for 30 min and benzenesulfonyl chloride (577 mg, 3.27 mmol) was added. The mixture was stirred for 2 h at -10 °C and then treated with sat. aq. NH4CI (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried (NazSCU), filtered and concentrated. The crude material was purified by chromatography (silica, EtOAc/PE = 0-30%) to give the title compound (404 mg, 45%). M NMR (400 MHz, CDCh) δ 7.71 (s, 1H), 7.39 (s, 1H), 6.20 - 5.93 (m, 2H), 5.53 - 5.33 (m, 2H), 3.92 - 3.66 (m, 2H), 3.57 (t, 2H), 3.54 - 3.47 (m, 2H), 3.47 - 3.38 (m, 1 H), 3.30 (s, 3H), 3.19 - 3.03 (m, 2H), 2.74 (d, 1H), 2.34 (d, 3H), 1.28 (d, 3H), 1.13 (dt, 1H), 0.91 (ddd, 2H), 0.86-0.72 (m, 2H), 0.460.33 (m, 1H), 0.26 (q, 1H), -0.02 (s, 9H), -0.12 (s, 9H); LC/MS m/z (M+H)⁺ = 644.3.

Préparation 99: (S)-A/-(4-amino-3-nitrophenvl)-A/-methvl-2-morpholinopropanamide

The title compound was prepared analogously to Préparation 38 starting from 4-chloro3-nitroaniline and Préparation 19. LC/MS m/z (M+H)⁺ = 309.0.

Préparation 100: (S)-A/-(4-amino-3-bromo-5-nitrophenvl)-A/-methyl-2morpholinopropanamide çh₃ çh₃ A^n < n T CK ) O

nh₂ no₂

Br

A solution of Préparation 99 (1.20 g, 3.89 mmol) in DMF (20 mL) at 20 °C was treated with bromine (1.24 g, 7.78 mmol). The mixture was stirred at 20 °C for 15 h. The mixture was cooled to 0 °C and treated with of Et₅N (10 mL). The mixture was concentrated under reduced pressure and the residue was purified by chromatography

103 (silica, EtOAc/PE = 0-100%) to give the titie compound (610 mg, 41%). LC/MS m/z (M+H)⁺ = 388.8 (⁸¹Br).

PreparationJj)lJSQTV_Ξ(3Jl·diém^lno_Σ^^ morpholinopropanamide

Br

A solution of Préparation 100 (900 mg, 2.32 mmol) in EtOH (80 mL) was treated with conc. HCl (1 mL) and iron powder (389 mg, 6.97 mmol). The mixture was stirred at 70 °C for 2 h. The mixture was cooled to 0 °C and adjusted to pH 7 by addition of conc.

NH4OH (2 mL). The mixture was filtered and the filtrate was concentrated. The residue was taken up in DCM (60 mL), stirred for 1 h, and filtered. The filtrate was concentrated to give the titie compound (802 mg, 87%). LC/MS m/z (M+H)⁺ = 356.9 (⁷⁹Br).

Préparation 102: (S)-/V-(7-bromo-2-((4aS,5aR)-5a-methyl-1-((215 (trimethvlsilvl)ethoxv)methvl)-1 ,4,4a,5,5a,6-hexahvdrocvcloproparflindazol-3-yl)-1HbenzoMimidazol-5-vl)-A/-methyl-2-morpholinopropanamide

A mixture of Préparation 9 (601 mg, 1.96 mmol) in DMF (25 mL) was added to 101 (700 mg, 1.96 mmol) and NasS^Os (373 mg, 1.96 mmol) and the mixture heated at 110 °C for 20 15 h. The mixture was concentrated and the residue was purified by chromatography (silica, EtOAc/PE = 0-100%) to give the titie compound (730 mg, 56%). ¹H NMR (400 MHz, CDCI3) δ 9.94 (s, 1 H), 7.59 (s, 1 H), 7.35 (s, 1 H), 5.53 - 5.24 (m, 2H), 3.66 (t, 4H), 3.61 - 3.48 (m, 3H), 3.31 (s, 3H), 3.25 - 3.06 (m, 3H), 2.75 (d, 1H), 2.56 (dt, 2H), 2.38 2.23 (m, 2H), 1.30 (s, 3H), 1.14 (t, 4H), 0.92 (ddd, 2H), 0.43 (dd, 1H), 0.26 (t, 1H), -0.01 25 (s, 9H); LC/MS m/z (M+H)⁺ = 645.0 (⁸¹ Br).

Préparation 103: (S)-/V-(4-bromo-2-((4aS,5aR)-5a-methyl-1-((2(trimethvlsilvl)ethoxv)methvl)-1,4,4a.5.5a.6-hexahvdrocvclopropafflindazol-3-vl)-1-((2

104 (trimethvlsilvl)ethoxv)meÎhvl)-1/7-benzo[cf]imidazol-6-vl)-/V-methvl-2morpholinopropanamide

A solution of Préparation 102 (700 mg, 1,09 mmol) in THF (50 mL) at 0 °C was treated with NaH (57 mg, 1.41 mmol) and SEM-CI (272 mg, 1.63 mmol). The mixture was warmed to RT and stirred for 2 h. The mixture was cooled to 0 °C and treated with sat. aq. NH4CI (1 mL). The mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with brine, dried (Na₂SO4), filtered and concentrated. The crude matériel was purified by chromatography (silica, EtOAc/PE = 0-100%) to give the title compound (770 mg, 92%). LC/MS m/z (M+H)⁺ = 775.2 (⁸¹ Br).

Préparation 104: (2-((4aS,5af?)-5a-methvl-1-((2-(trimethvlsiiyl)ethoxv)methvl)1,4,4a,5.5a_T6-hexahvdrocvclopropaf/1indazol-3-vl)-6-((S)-/\/-methvl-2morpholinopropanamido)-1-((2-(trimethγίsilvl)ethoxv)methyl)-1/7-benzofcflimidazol·4vDboronic acid

A solution of Préparation 103 (328 mg, 0.424 mmol) in 1,4-dioxane (20 mL) was treated with KOAc (125 mg, 1.27 mmol), bis(pinacolato)diboron (323 mg, 1.27 mmol), and Pd(dppf)CI₂ (31 mg, 0.0424 mmol). The mixture was heated to 100 °C and stirred for 15 h. The mixture was cooled to RT and concentrated. The residue was purified by chromatography (silica, EtOAc/PE = 0-100% then MeOH/EtOAc - 0-100%) to give the title compound (245 mg, 86%). LC/MS m/z (M+H)⁺ = 739.2 (⁷⁹Br).

Préparation 105: (S)-/V-(4-hydroxv-2-((4aS.5aR)-5a-methvl-1 -((2(trimethvlsilyl)ethoxv)methvl)-1.4,4a,5,5a,6-hexahvdrocvclopropaîf|indazol-3-vll·1-(C2

105 (trime thvlsilvl)ethoxv)methyl)-1H-benzo[cf|imidazol-6-vl)-A/-methvl-2morpholinopropanamide

A solution of Préparation 104 (350 mg, 0,224 mmol) in THF (30 mL) at 0 °C was treated 5 with a solution of NaBOaAHzO (104 mg, 0,673 mmol) in water (10 mL), The mixture was stirred at 20 °C for 5 h. The mixture was partitioned between water (10 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated to give the title compound (300 mg, 94%). LC/MS 10 m/z (M+H)⁺ = 711.3

Préparation 106: (S)-A/-(4-methoxy-2-((4aS.5aR)-5a-methvl-1,4,43,5,53,6hexahvdrocyclopropa[f|indazol-3-vl)-1H-benzo[cflimidazol-6-yl)-A/-methvl-2morpholinopropanamide

A solution of Préparation 105 (150 mg, 0.211 mmol) in DMF (3 mL) at 0 °C was treated with K2CO3 (88 mg, 0.63 mmol) and methyl iodide (45 mg, 0.32 mmol). The mixture was stirred at 20 °C for 2 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine, dried 20 (N32SO4), filtered and concentrated to give the title compound (153 mg, 100%). LC/MS m/z (M+H)⁺ = 725.3

Préparation 107: (4aS,5aR)-3-(5-bromo-7-(trifluoromethyl)-1 H-benzoMimidazol-2-yl)5a-methyl-1-((2-(trimethvlsilvl)ethoxv)methvl)-1,4,4a,5,5a,625 hexahydrocvcloproparflindazole

106

A solution of Préparation 9 (288 mg, 0.94 mmol) in DMF (10 mL) was treated with 5bromo-3-(trifluorDmethyl)benzene-1,2-diamine (240 mg, 0.94 mmol) and NasSaCh (179 mg, 0.94 mmol). The mixture was heated at 110 °C for 15 h and concentrated. The residue was purified by chromatography (silica, EtOAc/PE = 0-100%) to give the title compound (430 mg, 84%). LC/MS m/z (M+H)⁺ = 543.1 (⁸¹Br).

Préparation 108: (4aS.5aR)-3-(6-bromo-4-(trifluoromethyl)-1-((2(trimethvlsilvl)ethoxv)methvl)-1/-/-benzorcilimidazol-2-vl)-5a-methvl-1-((2(trimethvlsilvl)ethoxv)methvl)-1,4,4a,5_l5a,6-hexahvdrocvclopropaff|indazole

A solution of Préparation 107 (350 mg, 0.65 mmol) in THF (20 mL) at 0 °C was treated with NaH (34 mg, 0.84 mmol) and SEM-Cl (162 mg, 0.97 mmol). The mixture was warmed RT and stirred for 2 h. The mixture was cooled to 0 °C and treated with sat. aq. NH4CI (1 mL). The mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude material was purified by chromatography (silica, EtOAc/PE = 0-100%) to give the title compound (430 mg, 99%). LC/MS m/z (M+H)⁺ = 673.0 (⁸¹Br).

Préparation 109: fert-butyl (2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilvl)ethoxv)methyl)1.4,4a,5,5a.6-hexahvdrocvclopropa[flindazol-3-γl)-4-(trifluoΓomethvll·1-((2₌ (trimethvÎsilvl)ethoxv)methvl)-1H-benzord1imidazol-6-vl)carbamate

I 107

A solution of Préparation 108 (380 mg, 0.57 mmol) in 1,4-dioxane (10 mL) in fert-amyl aicohol (10 mL) was treated with BOC2O (199 mg, 1.7 mmol), CS2CO3 (369 mg, 1.13 mmol), (77 mg, 0.23 mmol), and Pd2(dba)3 (52 mg, 0.057 mmol). The mixture was heated at 100 °C for 15 h. The mixture was cooled to RT and concentrated. The 5 residue was purified by chromatography (silica, EtOAc/PE + 0-100%) to give the title compound (223 mg, 56%). LC/MS m/z (M+H)⁺ = 708.4

Préparation 110: 2-((4aS,5aR)-5a-methvl-1-((2-(trimethvlsilvl)ethoxv)methyl)1 _l4,4a,5,5a,6-hexahydrocvclopropa[flÎndazol-3-vl)-4-(trifluoromethvl)-1-((210 (trimethvlsilvl)ethoxy)methvl)-1H-benzo[cnimidazol-6-amine

SEM

A solution of Préparation 109 (220 mg, 0.31 mmol) in DCM (20 mL) was treated with ZnBr₂ (350 mg, 1.55 mmol). The mixture was stirred at RT for 15 h. The mixture was filtered and the filtrate was diluted with water (50 mL) and extracted with DCM (2 x 50 mL). The combined organîc layers were washed with brine, dried (Na2SÛ4), filtered and concentrated to give the title compound (170 mg, 90%). LC/MS m/z (M+H)⁺ - 608.2.

Préparation 111: (S)-A/-(2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilvl)ethoxv)methyl)1,4_l4a,5_τ5a,6-hexahvdrocvcloρropamindazol·3-yl)-4-(trifluoromethyl)-1-(G^ (trimethylsilvl)ethoxy)methvl)-1 H-benzoMimidazol-6-vl)-2-morpholinopropanamÎde

A solution of Préparation 110 (170 mg, 0.28 mmol) and 19 (89 mg, 0.56 mmol) in pyridine (5 mL) was treated with EDCI (107 mg, 0.56 mmol). The mixture was stirred at RT for 15 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude material was purified by chromatography (silica,

108

EtOAc/PE = 0-100%) to give the title compound (125 m, (60%). LC/MS m/z (M+H)⁺ = 749.4.

Préparation 112: (S)-/V-methyl-A/-(2-((4aS,5aR)-5a-methvl-1-((25 (trimethvlsilvl)ethoxv)methvl)-1,4,4a,5_l5a,6-hexahvdrocvclopropa(/|indazol-3-vl)-4(trifluoromethvl)-1-((2-(trimethvlsilvl)ethoxv)methvl)-1H-benzorcf|imidazol-6-vl)-2morpholinopropanamide

A solution of Préparation 111 (125 mg, 0.17 mmol) in THF (5 mL) at 0 °C was treated 10 with NaH (10 mg, 0.25 mmol) followed by methyl iodide (36 mg, 0.25 mmol). The mixture was warmed to RT and stirred for 2 h. The mixture was cooled to 0 °C and treated with sat. aq. NHÆI (0.3 mL). The mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine, dried (NazSOO, filtered and concentrated to give the title compound (127 mg, 15 99%).

Préparation 113: Methyl5-bromo-2-((4aS,5aR)-5a-methyl-1-((2(trimett^vlsilvl)ethoxv)methvl)-1,4,4a.5.5a,6-hexahvdrocvclopropaMindazol·3-vl)-1Hbenzofcf]imidazole-7-carboxvlate

A mixture of methyl 2,3-diamino-5-bromobenzoate (720 mg, 2.94 mmol), 9 (990 mg, 3.32 mmol) and NaHSOa (336 mg, 3.23 mmol) in EtOH (14.7 mL) and water (2.5 mL) was heated at 90 °C under air for 18 h. The mixture was cooled to RT and diluted with water. The mixture was extracted with DCM (x 3) and the combined organic layers 25 were dried (MgSOY filtered and concentrated. The residue was stirred in heptane:EtOAc (1:1, 10 mL) for 18 h and the résultant solids collected by filtration to give the title compound (842 mg, 54%) ofthe title compound as a beige solid. ¹H NMR (600 MHz, CDCI3) δ 10.85 (s, 1H), 8.18 (s, 1H), 8.01 (d, 1H), 5.50 - 5.33 (m, 2H), 4.02

109 (s, 3H), 3.61 -3.51 (m, 3H), 3.18 (dd, 1H), 3.13 (d, 1H), 2.74 (d, 1H), 1.29 (s, 3H), 1.17 (dt, 1H), 0.92 (td, 2H), 0.43 (dd, 1 H), 0.27 (t, 1H), -0.02 (s, 9H); LC/MS m/z (M+H)⁺ = 531.5.

Préparation 114: Methyl 6-bromo-2-((4aS.5a/^:?)-5a-methvl-1-((2(trimethy[silvl)ethoxv)methvl)-1,4.4a,5,5a,6-hexahvdrocvclopropafflindazol-3-vl)-1-((2(trimethvlsilvl)ethoxv)methyl)-1/-/-benzo[cf]imidazole-4-carboxvlate

A of suspension of NaH (4147 mg, 10.4 mmol) in THF (6 mL) at 0 °C was treated with a solution of Préparation 113 (2.77 g, 5.22 mmol) in THF (24 mL). The mixture was stirred at 0 °C for 30 min and then SEM-CI (1310 mg, 7.83 mmol) was added. The mixture was warmed to RT and stirred for 18 h. The mixture was cooled to 0 °C and treated with sat. aq. NH4CI (5 mL). The organic solvent was evaporated and the résultant mixture extracted with DCM (x 4). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated. The crude material was purified by chromatography (silica, EtOAc/PE = 0-60%) to give the title compound (2.88 g, 83%). Ή NMR (400 MHz, CDCI3) δ 8.10 (d, 1H), 7.92 (d, 1H), 6.18 (d, 2H), 5.49 - 5.33 (m, 2H), 4.06 (s, 3H), 3.63 (d, 1H), 3.52 (dt, 4H), 3.21 -3.08 (m, 2H), 2.74 (d, 1H), 1.29 (s, 3H), 1.15 (dt, 1H), 0.94 - 0.80 (m, 4H), 0.41 (dd, 1H), 0.29 (t, 1H), -0.02 (s, 9H), -0.12 (s, 9H).

Préparation 115: Methyl 2-((4aS,5aF?)-5a-methvl·1-((2-(trimethvlsilvl)ethoxv)methvl)1,4,4a,5,5a,6-hexahvdrocyclopropaif|indazol-3-vl)-6-(methvlamino)-1-((2(tnmethvlsilvl)ethoxv)methyl)-1H-benzorcf]imidazole-4-carboxvlate

A solution of Préparation 114 (420 mg, 0.635 mmol) in DMF (4.2 mL) was added to a vial containing MeNH2-HCI (64 mg, 0.95 mmol), Cul (10 mg, 0.051 mmol), Λ/-(2,6

110 dimethylphenyl)-6-hydroxypicolinamide (25 mg, 0.10 mmol) and K3PO4 (404 mg, 1.9 mmol). The mixture was heated at 110 °C for 20 h. The mixture was cooled to RT and diluted with EtOAc. The mixture was extracted with water (x 2). The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The crude material was purified by chromatography (silica, EtOAc/PE = 0-70%) to give the title compound (231 mg, 60%). ¹H NMR (400 MHz, CDCI3) δ 7.37 (d, 1H), 6.92 (d, 1H), 6.13 (d, 2H), 5.46 5.35 (m, 2H), 4.06 (s, 3H), 3.64 - 3.43 (m, 5H), 3.22 - 3.07 (m, 2H), 2.94 (s, 3H), 2.73 (d, 1H), 1.65 (s, 1H), 1.28 (s, 3H), 1.13 (dt, 1H), 0.94 - 0.87 (m, 2H), 0.86 - 0.76 (m, 2H), 0.39 (dd, 1H), 0.30 (t, 1H), -0.02 (s, 9H), -0.13 (s, 9H); LC/MS m/z (M+H)⁺ = 612.5.

Préparation 116: 2-((4aS.5aR)-5a-methvl-1-((2-(trimethvlsilvl)ethoxy)methvl)1,4.4a,5,5a,6-hexahydrocvclopropaHindazol-3-vl)-6-(methvlamino)-1-((2(trimethvlsilvl)ethoxv)methyl)-1/7-benzoMimidazol-4-vl)methanol

A solution of LiAIH₄ (15 mg, 0.39 mmol) in tetrahydrofuran (0.39 mL) at 0 °C was treated dropwise with a solution of Préparation 115 (158 mg, 0.26 mmol) in THF (1.3 mL). The mixture was warmed to RT and stirred for 1 h. The mixture was cooled to 0 °C and treated with sat. aq. Rochelle’s sait (potassium sodium tartrate). The mixture was extracted with EtOAc (x 2) and the combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated. The crude material was purified by chromatography (silica, EtOAc/heptanes = 20-100%) to give the title compound (103 mg, 68%). ¹H NMR (400 MHz, CDCI3) δ 6.59 (d, 1H), 6.46 (d, 1H), 6.17-5.94 (m, 2H), 5.47 - 5.34 (m, 2H), 5.06 (s, 2H), 4.75 (s, 1H), 3.65 - 3.45 (m, 4H), 3.39 (d, 1H), 3.10 (dd, 2H), 2.89 (s, 3H), 2.76 - 2.65 (m, 1H), 1.27 (s, 3H), 1.10 (dt, 1H), 0.91 (ddd, 2H), 0.88 - 0.79 (m, 2H), 0.39 (dd, 1 H), 0.25 (t, 1 H), -0.02 (s, 9H), -0.11 (s, 9H).

Préparation 117: (S)-/V-(4-(methoxvmethvi)-2-((4aS,5aR)-5a-methyl-1-((2(trimethvlsilvl)ethoxv)methyl)-1,4,4a,5,5a,6-hexahvdrocyclopropaîflindazol-3~vl)-1-((2(trimethvlsilvl)ethoxv)methvl)-1H-benzo[d]imidazol-6-vl)-/V-methyl-2morpholinopropanamide

111

A solution of Preparation116 (102 mg, 0.18 mmol) and 19 (42 mg, 0.262 mmol) in pyridine (1 mL) was treated with EDCI (84 mg, 0.44 mmol). The mixture was stirred at RT for 18 h. The mixture was concentrated and the residue was partitioned between

EtOAc and sat. aq. NaHCOs. The organic layer was separated and the aqueous layer was extracted with EtOAc (x 2). The combined organic layers were dried (Na2SÛ4), filtered and concentrated. The crude material was purified by chromatography (silica, [10:1 NH4OH/MeOH]/DCM = 0-16%) to provide a mixture of N- and O-acyl products. The mixture was taken up in THF (1 mL) and cooled to 0 “C. NaH (18 mg, 0.45 mmol) 10 was added and the mixture was stirred for 30 min and then treated with methyl iodide (42 mg, 0.30 mmol). The mixture was warmed to RT and stirred for 16 h. The mixture was cooled to 0 °C and treated with sat. aq. NH4CL The mixture was diluted with water and extracted with EtOAc (x 3). The combined organic layers were dried (MgSOq), filtered and concentrated. The crude material was purified by chromatography (silica, 15 EtOAc/heptanes = 20-100%) to give the title compound (61 mg, 47%). ¹H NMR (400 MHz, CDCI3) δ 7.33 (s, 1H), 7.21 (s, 1H), 6.08 (d, 2H), 5.49-5.36 (m, 2H), 4.98 (d, 2H), 3.65 (t, 4H), 3.59 - 3.55 (m, 2H), 3.54 (s, 3H), 3.53 - 3.43 (m, 3H), 3.33 (s, 3H), 3.25 (q, 1H), 3.17-3.02 (m, 2H), 2.73 (d, 1H), 2.64-2.51 (m, 2H), 2.39 (dd, 2H), 1.29 (s, 3H), 1.15 (d, 3H), 1.14 - 1.08 (m, 1H), 0.90 (ddd, 2H), 0.85 - 0.76 (m, 2H), 0.41 (dd, 1H), 20 0.27 (t, 1H), -0.02 (s, 9H), -0.12 (s, 9H).

Préparation 118: (4aS,5aR)-3-(5-bromo-7-chloro-1H-benzoitflimidazol-2-v0-5a-methyl1-((2-(trimethvlsilvl)ethoxv)methvl)-1_l4_l4a_l5,5a,6-hexahydrocvclopropa[f|indazole

A mixture of 1,2-diamino-5-bromo-3-chlorobenzene (200 mg, 0.90 mmol), NaHSOa (103 mg, 0.99 mmol) and Préparation 9 (304 mg, 0.99 mmol) in EtOH (3.7 mL) and water (0.8 mL) was heated at reflux for 16 h. The mixture was cooled to RT and diluted with

112 water. After removing the EtOH under reduced pressure, the mixture was extracted with EtOAc (x 3). The combined organic layers were dried (MgSO^, filtered and concentrated. The crude material was purified by chromatography (silica, EtOAc/heptanes = 0-30%) to give the title compound (410 mg, 89%). ¹H NMR (400 MHz, DMSO-d₆) δ 13.13 (s, 1H), 7.55 (d, 1H), 7.43 (d, 1H), 5.49 (d, 1H), 5.42 (d, 1H), 3.57-3.51 (m, 2H), 3.48 (d, 1H), 3.19 (d, 1H), 3.01 (dd, 1H), 2.73 (d, 1H), 1.27 (s, 3H), 1.16 (ddd, 1H), 0.84 (td, 2H), 0.41 (dd, 1H), 0.17 (dd, 1H), -0.06 (s, 9H); LC/MS m/z (M+H)⁺= 507.4 (⁷⁹Br).

Préparation 119a: (4aS,5aR)-3-(5-bromo-7-chloro-1-((2-(trimethvlsilvl)ethoxv)methvl)1H-benzo[d1imidazol-2-vl)-5a-methvl-1-((2-(trimethvlsilvl)ethoxv)methyl)-1,4,4a,5,5a,6hexahydrocyclopropafflindazole

Préparation 119b: (4aS,5aR)-3-(6-bromo-4-chloro-1-((2-(trimethvlsilvl)ethoxv)methyl)1H-benzoMimidazol-2-vi)-5a-rnethvl-1-((2-(trimethylsilvl)ethoxv)methy[)-1,4,4a, 5,5a, 6h exa hyd rocyclop ro paf fl i nd azo le

A solution of Préparation 118 (390 mg, 0.77 mmol) in THF (3.8 mL) was treated with NaH (59 mg, 1.54 mmol). The mixture was stirred at 0 °C for 30 min and SEM-CI (205 mg, 1.23 mmol) was added. The mixture was stirred at 0 °C for 1.5 h. The mixture was cooled to 0 °C and treated with sat. aq. NH₄CI. The THF was evaporated. The remaining mixture was extracted with EtOAc (x 4). The combined organic layers were dried (MgSO₄), filtered and concentrated. The crude material was purified by chromatography (silica, EtOAc/heptanes = 0-30%) to give the title compound as a mixture (425 mg, 87%). LC/MS m/z (M+H)⁺ = 637.6 (⁷⁹Br).

Préparation 120: 7-chloro-/V-methvl-2-((4aS,5aR)-5a-methyl-1 -((2(trimethvlsilvl)ethoxv)methyl)-1,4,4a,5,5a,6-hexahyd rocyclopropaHindazol-3-yl)-1-((2(trimethvlsilvl)ethoxv)methvl)-1H-benzofd|imidazol-5-amine

113

Préparation 121: 4-chloro-A/-methvl-2-((4aS,5aF?)-5a-methyl-1-((2(trimethvlsilvÎ)ethoxv)methyl)-1,4,4a,5,5a,6-hexahvdrocvclopropaMindazol-3-vl)-1-((2(trimethvlsilvl)ethoxv)methyl)-1 /7-benzo[d|imidazol-6-amine

A solution of a mixture of Préparations 119a and 119b (542 mg, 0.85 mmol) in DMF (5.7 mL) was added to MeNH^’HCI (86 mg, 1.27 mmol), Cul (13 mg, 0.068 mmol), N-(2,6dimethylphenyl)-6-hydroxypicolinamide (33 mg, 0.14 mmol) and K3PO4 (541 mg, 2.6 mmol). The mixture was heated at 110 “C for 18 h. The mixture was diluted with EtOAc and washed with water (x 3) and brine. The organic layer was dried (MgSO4), filtered and concentrated. The crude material was purified by chromatography (silica, EtOAc/heptanes = 0-30%) to give the title compounds. (Référencé: Bernhardson, D. J., Widlicka, D. W., Singer, R. A., Org. Process Res. Dev. 2019, 23, 1538-1551) Préparation: 120: (121 mg, 24%). ¹H NMR (400 MHz, CDCh) δ 6.66 (d, 1H), 6.58 (d, 1H), 6.03 (d, 2H), 5.44 - 5.34 (m, 2H), 3.59-3.44 (m, 5H), 3.11 (d, 2H), 3.07 (d, 1H), 2.89 (s, 3H), 2.71 (d, 1H), 1.28 (s, 3H), 1.11 (ddd, 1H), 0.95 - 0.87 (m, 2H), 0.86-0.77 (m, 2H), 0.38 (dd, 1H), 0.27 (dd, 1H), -0.02 (s, 9H), -0.12 (s, 9H). LC/MS m/z (M+H)⁺ = 588.6

Préparation 121: (162 mg, 33%). ¹H NMR (400 MHz, CDCh) δ 6.91 (d, 1H), 6.65 (d, 1H), 6.28 (d, 1H), 6.25 (d, 1H), 5.44 (d, 1H), 5.39 (d, 1H), 3.68 (brs, 1H), 3.57 (dd, 2H), 3.41-3.27 (m, 3H), 3.13 (d, 1H), 3.06 (dd, 1H), 2.88 (s, 3H), 2.73 (d, 1H), 1.28 (s, 3H), 1.10 (ddd, 1 H), 0.95 - 0.89 (m, 2H), 0.75 (td, 2H), 0.39 (dd, 1 H), 0.27 (dd, 1 H), -0.01 (s, 9H), -0.16 (s, 9H). LC/MS m/z (M+H)⁺ = 588.6

Préparation 122: (S)-/V-(7-chloro-2-((4aS,5aR)-5a-methyl-1-((2(trimethvlsilvl)ethoxv)methvl)-1,4,4a,5,5a,6-hexahydrocvclopropaHindazol-3-yl)-1-((2(trimethvlsilvl)ethoxy)methvl)-1H-benzo[d|imidazol-5-yl)-/V-methyl-2morpholinopropanamide

114

A mixture of Préparation 19 (24.4 mg, 0.15 mmol), 120 (82 mg, 0.14 mmol), pyridîne (0.56 mL, 0.70 mmol) and T3P (50 wt% in EtOAc, 0.17 mL, 0.28 mmol) in EtOAc (0.9 mL) was stirred at RT for 18 h. The mixture was treated with DMF (0.6 mL) and the 5 mixture was stirred at RT for an additional 24 h. The mixture was diluted with EtOAc and water. After séparation of layers, the organic layer was washed with water (x 2) and brine. The remaining organic fraction was dried (MgSO4), filtered and concentrated. The crude material was purified by chromatography (silica, EtOAc/heptanes, 10*80% gradient) to give the title compound (42.8 mg, 42%). ¹H NMR 10 (400 MHz, CDCI3) δ 7.55 (d, 1H), 7.21 (s, 1H), 6.38 (d, 2H), 5.45 (d, 1H), 5.41 (d, 1H),

3. 65 (dd, 4H), 3.60-3.54 (m, 2H), 3.40 (d, 2H), 3.31 (s, 3H), 3.23 (q, 1H), 3.14 (d, 1H), 3.06 (dd, 1H), 2.74 (d, 1H), 2.57 (ddd, 2H), 2.32 (ddd, 2H), 1.77 (brs, 1H), 1.28 (s, 3H), 1.18-1.06 (m, 4H), 0.91 (ddd, 2H), 0.78 (td, 2H), 0.41 (dd, 1H), 0.26 (dd, 1H), -0.02 (s, 9H), -0.16 (S, 9H); LC/MS m/z (M+H)⁺ = 729.7.

Préparation 123: /\/-(7-chloro-2-((4aS,5aR)-5a-methvl-1-((2(trimethvlsiivl)ethoxv)methyl)-1.4,4a₁5₁5a,6-hexahvdrocvclopropaΓf1indazol·3-vl)-1-((2:

(trimethvlsilvl)ethoxv)methvl)-1H-benzo[dlimidazol-5-vl)-A/-methvlacetamide

A solution of Préparation 120 (785 mg, 1.33 mmol) in DCM was cooled to 0 °C. The solution was treated with EtsN (0.56 mL, 4.00 mmol) and acetyl chloride (0.14 mL, 2.00 mmol). The mixture was stirred at 0 °C for 20 min and treated with sat. aq. NaHCOs. The aqueous layer was extracted with DCM (x 3), and the combined organic layers were dried (MgSO4), filtered and concentrated. The crude material was purified by chromatography (silica, EtOAc/heptanes = 0-50%) to give the title compound 123 (807 mg, 64%). LC/MS m/z (M+H)⁺ = 630.5.

115

Préparation 124: A/-methvl-/v-(2-((4aS.5aR)-5a-methyl-1-((2(trimethvlsilvl)ethoxv)methvl)-1,4.4a,5,5a,6-hexahvdrocvcloDropa[f|indazol-3-vl)-1-((2(trimethylsilvl)ethoxv)methvl)-7-vinvl-1H-benzo[d1imidazol-5-yl)acetamide.

ch₃

Y Y T W ?

° Y Y

J SEM ( ] ^H2^C NJ ”^CH3

A mixture of Préparation 123 (675 mg, 1.07 mmol), 2,4,6-Trivinylcyclotriboroxane pyridine complex (297 mg, 1.24 mmol), Pd(OAc)2 (9.3 mg, 0.04 mmol) and SPhos (34 mg, 0.08 mmol) in 1,4-dioxane (5.4 mL) was added 3 Μ K3PO4 (0.82 mL, 2.47 mmol). The mixture was heated at 100 °C for 20 h. The mixture was filtered and the solids rinsed with EtOAc. The filtrate was diluted with water and extracted with EtOAc (x 3). The combined organic extracts were dried (MgSOq), filtered and concentrated. The crude material was purified by chromatography (silica, EtOAc/heptanes = 0-50%) to give the title compound (391 mg, 59%). LC/MS m/z (M+H)⁺ = 622.5.

Préparation 124a: A/-(7-ethyl~2-((4aS,5aR)-5a-methyl-1-((2(trimethvlsilvl)ethoxv)methvl)-1,4,4a.5,5a.6-hexahvdrocvclopropa[flindazol-3-yl)-1~((2(trimethvlsilvl)ethoxv)methyl)-1 H-benzo[çflimidazol-5-vl)-A/-methvlacetamide

A solution of Préparation 124 (87 mg, 0.14 mmol) in MeOH (2 mL) was treated with 10% Pd/C (20 mg). The mixture was degassed with N2 and backfilled with H2three times. The mixture was stirred at RT under H2 (3 atm) for 18 h. The mixture was filtered and the filtrate concentrated to give the title compound (87 mg, quant.). ¹H NMR (600 MHz, CDCI3) δ 7.45 (d, 1H), 6.91 (d, 1H), 6.14 (q, 2H), 5.54-5.37 (m, 2H), 3.56 (t, 2H), 3.38 - 3.32 (m, 2H), 3.30 (s, 3H), 3.18 - 3.10 (m, 3H), 3.07 (dd, 1 H), 2.74 (d, 1 H), 1.97 (s, 1H), 1.88 (s, 3H), 1.34 (t, 3H), 1.27 (s, 3H), 1.11 (dt, 1 H), 0.91 (td, 2H), 0.79 0.64 (m, 2H), 0.39 (dd, 1H), 0.24 (t, 1H), -0.02 (s, 9H), -0.18 (s, 9H).

Préparation 125: 7-ethyl-A/-methyl-2-((4aS.5aR^l)-5a-methvl-1-((2(trimethvlsilvl)ethoxv)methyl)-1,4,4a,5,5a,6-hexahvdrocvclopropalflindazol-3-vl)-1-((2(trimethvlsilvlÎethoxv)methvl)-1H-benzo[d1imidazol-5-amine

A solution of Préparation 124 (86 mg, 0.14 mmol) in 1:1 EtOH:water was treated with KOH (155 mg, 2.76 mmol). The mixture was heated at 90 °C and stirred for 72 h. The mixture was cooled to RT and diluted with water extracted with DCM (x 3). The combined organic layers were dried (MgSCU), filtered and concentrated, The crude mate rial was purified by chromatography (silica, EtOAc/heptanes = 0- 80 % gradient) to give the title.compound (37 mg, 46%). NMR (400 MHz, CDCh) δ 6.88 (d, 1H), 6.51 (d, 1H), 6.13 - 5.90 (m, 2H), 5.50 - 5.29 (m, 2H), 3.57 (t, 2H), 3.33 (d, 1H), 3.25 (dd, 2H), 3.16 - 3.01 (m, 4H), 2.89 (s, 3H), 2.77 - 2.69 (m, 1H), 1.32 (t, 3H), 1.27 (s, 3H), 1.14-1.04 (m, 1H), 0.96 - 0.83 (m, 3H), 0.72 (td, 2H), 0.38 (dd, 1H), 0.26 (t, 1 H), -0.01 (s, 9H), -0.16 (s, 9H); LC/MS m/z (M+Hf = 582.5.

Préparation 126: (S)-/\Z-(7-ethyl-2-((4aS,5af?)-5a-methyl-1-((2(trimethvlsilvl)ethoxv)methyl)-1 _l4,4a,5,5a,6-hexahvdrocyclopropa[/1indazol-3-vl)-1-((2(trimethvlsilvl)ethoxv)methvl)-1/7-benzofcilimidazol-5-vl)-/V-methvl-2morpholinopropanamide

A solution of Préparation 125 (37 mg, 0.064 mmol) and Préparation 19 (15 mg, 0.095 mmol) in pyridine (1 mL) was treated with EDCI (31 mg, 0.159 mmol). The mixture was stirred at RT for 18 h. The mixture was concentrated and the residue was diluted with water. The organic layer was extracted with EtOAc (x 3). The combined organic layers 25 were dried (MgSO4), filtered and concentrated to give the title compound (45 mg, 98%).

¹H NMR (600 MHz, CDCh) δ 7.47 (s, 1 H), 6.92 (s, 1 H), 6.14 (s, 2H), 5.55 - 5.34 (m, 2H), 3.65 (dt, 4H), 3.57 (td, 2H), 3.40 - 3.33 (m, 2H), 3.33 (s, 3H), 3.26 (q, 1H), 3.15 (q,

117

3H), 3.06 (dd, 1 H), 2.75 (d, 1 H), 2.59 - 2.52 (m, 2H), 2.40 (dt, 2H), 1.34 (t, 3H), 1.29 (s, 3H), 1.25 (d, 1H), 1.17 (d, 3H), 1.15-1.06 (m, 1H), 0.92 (ddd, 2H), 0.75 (td, 2H), 0.40 (dd, 1H), 0.26 (t, 1H), -0.01 (s, 9H), -0.16 (s, 9H) ; LC/MS m/z (M+H)⁺ = 723.7.

Préparation 127: fert-butyl (4-chloro-2-((4aS,5aF?)-5a-methyl-1-((2(trimethvlsilvl)ethoxv)methyl)-1,4,4a.5,5a,6-hexahvdrocyclopropa|ï|indazol-3-v0-1-((2(trimethylsilvl)ethoxv)methyl)-1 H-benzol^-tf]imidazo1-6-yl)(methyl)carbamate

A solution of Préparation 121 (740 mg, 1.26 mmol) in THF (6.3 mL) was treated with Et3N (0.35 mL, 2.52 mmol), BocsO (412 mg, 1.89 mmol) and DMAP (154 mg, 1.26 mmol) at RT. The mixture was stirred at RT for 18 h and additional EtsN (0.35 mL, 2.52 mmol), BOC2O (412 mg, 1.89 mmol) and DMAP (154 mg, 1.26 mmol) were added. The reaction mixture was heated to 60 °C and stirred an additional 36 h. The mixture was concentrated and the residue purified by chromatography (silica, EtOAc/heptanes = 050%) to give the titie compound (637.3 mg, 74%). ¹H NMR (400 MHz, CDCI3) δ 7.33 (d, 1H), 7.20 (d, 1H), 6.08 (d, 2H), 5.43 (d, 1H), 5.39 (d, 1H), 3.59-3.46 (m, 5H), 3.30 (s, 3H), 3.20-3.07 (m, 2H), 2.73 (d, 1H), 1.44 (s, 9H), 1.28 (s, 3H), 1.17-1.08 (m, 1H), 0.95-0.88 (m, 2H), 0.86-0.78 (m, 2H), 0.40 (dd, 1H), 0.27 (dd, 1H), -0.02 (s, 9H), -0.12 (s, 9H).

Préparation 128: terEbutyl methvl(2-((4aS,5aR)-5a-methyl-1-((2(trimethvlsilvl)ethoxy)methvl)-1,4,4a, 5,5a,6-hexahyd rocyclopropaMindazol-3-vl)-1-((2(trimethvlsilv0ethoxv)methvl)-4-vinvl-1H-benzofd1imidazol-6-vl)carbamate

A mixture of Préparation 127 (450 mg, 0.71), vinylboronic anhydride pyridine complex (258 mg, 1.07 mmol), Pd(OAc)₂ (8.0 mg, 0.036 mmol) and SPhos (29.3 mg, 0.71 mmol) In 1,4-dioxane (3.6 mL) was treated with 3 Μ K3PO4 (0.71 mL, 2.14 mmol). The mixture

118 was heated at 100 °C for 20 h. The mixture was filtered and the sohds nnsed with EtOAc. The filtrate was diluted with water and extracted with EtOAc (x 3). The combined organic extracts were dried (MgSCU), filtered and concentrated. The crude material was purified by chromatography (silica, EtOAc/heptanes = 0-50%) to give the title compound (367 mg, 76%). Ή NMR (400 MHz, CDCb) δ 7.30 (d, 1H), 7.18 (dd, 1H), 7.15 (s, 1H), 6.62 (dd, 1H), 6.15 (d, 1H), 6.11 (d, 1H), 5.56 (dd, 1H), 5.43 (d, 1H), 5.39 (d, 1H), 3.61-3.49 (m, 5H), 3.31 (s, 3H), 3.18-3.09 (m, 2H), 2.73 (d, 1H), 1.43 (s, 9H), 1.29 (s, 3H), 1.13 (ddd, 1H), 0.91 (ddd, 2H), 0.87-0.79 (m, 2H), 0.41 (dd, 1H), 0.28 (dd, 1H), -0.02 (s, 9H), -0.12 (s, 9H).

Préparation 129: tert-butyl (4-formvl-2-((4aS.5aR)-5a-methyl-1-((2(trimethvlsilyl)ethoxv)methyl)-1,4,4a,5,5a,6-hexahvdrocvclopropa[f]indazol-3-vl)-1-((2(tnmethylsilvl)ethoxy)methvl)-1H-benzo[cflimidazol-6-vl)(methyl)carbamate

A solution of Préparation 128 (366 mg, 0.54 mmol) in pyridine (2.7 mL) and THF (2.7 mL) at 0 °C was treated with OsO4 (4 wt% in water, 5.1 mL, 0.81 mmol). The mixture was stirred at 0 °C for 2 h and then at RT for an additional 18 h. The mixture was treated with 10% aq. NaHSOa (15 mL) and stirred at RT for 3 h. The mixture was concentrated and extracted with DCM (x 4). The combined organic extracts were dried (Na2SO4), filtered and concentrated. This residue was dissolved in 2:1 THF/water (6 mL), cooled to 0 °C and treated with NalO4 (138 mg, 0.65 mmol). The mixture was stirred at 0 °C for 2.5 h. The mixture was filtered through Celite and MgSCU and the filtrate was concentrated. The residue was purified by chromatography (silica, EtOAc/heptanes = 10-50% gradient) to give the title compound (163 mg, 44%). ¹H NMR (400 MHz, CDCI₃) δ 10.92 (s, 1H), 7.77-7.56 (m, 2H), 6.19 (d, 1H), 6.15 (d, 1H), 5.45 (d, 1H), 5.40 (d, 1H), 3.64-3.48 (m, 5H), 3.34 (s, 3H), 3,13 (dd, 2H), 2.74 (d, 1H), 1.44 (s, 9H), 1.29 (s, 3H), 1.21-1.08 (m, 1H), 0.91 (ddd, 2H), 0.87-0.80 (m, 2H), 0.42 (dd, 1H), 0.28 (dd, 1H), -0.02 (s, 9H), -0.12 (s, 9H).

119

Préparation 130: tert-butyl (4-(hydroxvmethvl)-2-((4aS,5ab?)-5a-methYl-1-((2(trimethvlsilyl)ethoxy)methvl)-1,4,4a.5.5a.6-hexahvdrocyclopropaff]indazol-3-vl)-1-((2(trimethvlsilvl)ethoxv)methyl)-1H-benzoMimidazol-6-vl)(methyl)carbamate

A solution of Préparation 129 (30 mg, 0.044 mmol) in MeOH (1 mL) at 0 °C was treated with NaBH4 (8 mg, 0.22 mmol). The mixture was warmed to RT and stirred 2 h. The mixture was cooled to 0 °C and diluted with brine and water. The mixture was extracted with DCM (x 3) and the combined organic layers were dried (MgSCU), filtered and concentrated to give the title compound (19 mg, 63%). ¹H NMR (400 MHz, CDCh) δ 7.36-7.30 (m, 1H), 7.00 (s, 1H), 6.20-6.03 (m, 2H), 5.46-5.35 (m, 2H), 5.12 (d, 2H), 4.63 (s, 1H), 3.65 - 3.49 (m, 4H), 3.42 (d, 1H), 3.30 (s, 3H), 3.12 (d, 2H), 2.73 (d, 1H), 1.44 (s, 9H), 1.28 (s, 3H), 1.12 (dt, 1H), 0.91 (ddd, 2H), 0.88 - 0.78 (m, 2H), 0.41 (dd, 1H), 0.25 (t, 1H), -0.02 (s, 9H), -0.11 (s, 9H); LC/MS m/z (M+H)⁺ = 684.3.

Préparation 131 : (2-((4aS,5aR)-5a-methvl-1-((2-(trimethylsilvl)ethoxv)methyl)1,4_T4a,5,5a,6-hexahvdrocvclopropafflindazol-3-vl)-6-(methylamino)-1-((2(trïmethvlsilvl)ethoxv)methvl)-1H-benzoMimidazol-4-yl)methanol

A solution of Préparation 130 (19 mg, 0.028 mmol) in DCM (1 mL) at 0 °C was treated with 2,6-lutidine (9 mg, 0.083 mmol) and TMSOTf (19 mg, 0.083 mmol). The mixture was stirred at 0 °C for 2 h and treated with sat. aq. NaHCOs. The mixture was extracted with DCM (x 3). The combined organic layers were dried (MgSO4), filtered and concentrated to give the title compound (20 mg, quant.). Ή NMR (600 MHz, CDCh) δ 6.77 (d, 1H), 6.58 (d, 1H), 6.08 - 5.87 (m, 2H), 5.46 - 5.32 (m, 2H), 5.18 (s, 2H), 3.64 3.51 (m, 3H), 3.47 (ddd, 2H), 3.38 (d, 1H), 3.09 (t, 2H), 2.91 (s, 3H), 2.71 (d, 1H), 1.64 (s, 1 H), 1.28 (s, 3H), 1.11 (dq, 1H), 0.98 - 0.88 (m, 2H), 0.87 - 0.76 (m, 2H), 0.38 (dd, 1H), 0.33 - 0.24 (m, 1H), -0.02 (d, 9H), -0.13 (s, 9H); LC/MS m/z (M+H)⁺ = 584.5.

120

Préparation 132 (S)-A/-(4-(hydroxvmethvl)-2-((4aS,5aF?)-5a-methyl-1-((2(trimethvlsilvl)ethoxy)methvl)-1H-benzo[GÎ|imidazol-6-vl)-/V-methvl-2morpholinopropanamide

A solution of Préparation 131 (19 mg, 0.033 mmol) and Préparation 19 (10 mg, 0.065 mmol) in pyridine (1 mL) was treated with EDCI (25 mg, 0.13 mmol). The mixture was stirred at RT for 18 h. The mixture was concentrated and the residue was diluted with water and extracted with EtOAc (x 3). The combined organic layers were dried (MgSO4), filtered and concentrated to give the title compound (21 mg, 90%). ¹H NMR (600 MHz, CDCh) δ 7.41 -7.29 (m, 1 H), 6.99 (s, 1H), 6.14 (s, 2H), 5.50-5.33 (m, 2H), 5.25 - 5.03 (m, 2H), 4.55 (s, 1H), 3.64 (dd, 3H), 3.60 - 3.50 (m, 4H), 3.43 (d, 1H), 3.32 (s, 3H), 3.23 (d, 1H), 3.13 (dd, 2H), 2.74 (d, 1H), 2.63 - 2.47 (m, 3H), 2.37 (dt, 2H), 1.29 (s, 3H), 1.15 (d, 3H), 1.14 - 1.08 (m, 1H), 0.92 (td, 2H), 0.83 (dq, 2H), 0.43 (dd, 1H), 0.25 (t, 1H), -0.02 (d, 9H), -0.11 (d, 9H); LC/MS m/z (M+H)⁺ = 725.7.

Préparation 133: 3,4-difluoro-2-methylaniline h₃cY^f F

A solution of 1,2-difluoro-3-methyl-4-nitrobenzene (5 g, 28.9 mmol) in AcOH (150 mL) was treated with iron powder (9.68 g, 173 mmol) and the mixture stirred at RT for 16 h. The reaction was filtered and the filtrate was concentrated. The residue was taken up in EtOAc (300 mL) and washed with sat. aq. NaHCO₃ (500 mL). The organic layer was dried (NasSÜA), filtered and concentrated under reduced pressure to give the title compound (3.8 g, 92%). LC/MS m/z (M+H)⁺ = 143.8.

Préparation 134: (S)-/\/-(3,4-difluoro-2-methvlphenvl)-2-morpholinopropanamide

121

A solution of Préparation 133 (3.8 g, 26.6 mmol) and Préparation 19 (8.45 g, 53.1 mmol) in pyridine (200 mL) was treated with EDCI (10.2 g, 53.1 mmol). The mixture was stirred at RT for 16 h. The mixture was concentrated and the residue was diluted with water and extracted with EtOAc (x 3). The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude material was purified by chromatography (silica, EtOAc/PE = 0-30%) to give the title compound (6.9 g, 91%). LC/MS m/z (M+H)⁺ = 284.9.

Préparation 135 (S)-A/-(3,4-difluoro-2-methvlphenvl)-A/-methvl-2morpholinopropanamide ch₃ ch_: h₃c

A solution of Préparation 134 (6.9 g, 24.3 mmol) in THF (150 mL) at 0 °C was treated with NaH (1.94 g, 48.5 mmol). The mixture was stirred for 30 min and methyl iodide (5.17 g, 36.4 mmol) was added. The mixture was warmed to 20 °C and stirred for 16 h. The mixture was treated with water and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude material was purified by chromatography (silica, EtOAc/PE = 0-60%) to give the title compound (6.6 g, 91%). LC/MS m/z (M+H)⁺ = 298.9.

Préparation 136: (S)-/V-(3,4-difluoro-2-methvl-5-nitrophenvl)-/V-methvl-2morpholinopropanamide ch₃ çh_: JL

A solution of Préparation 135 (5 g, 16.8 mmol) in conc. H2SO4 (40 mL) at 5-10 ^DC was treated dropwise with conc. HNO3 (2.11 g, 33.5 mmol). The mixture was stirred at 5-10 °C fir 2 h and poured onto ice. The pH was adjusted to 7 with sat. aq. NazCOs and the mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were

122 dried (NasSCU), filtered and concentrated. The crude material was purified by chromatography (silica, EtOAc/PE = 0-40%) to give the title compound 136 (3.5 g, 61%). LC/MS m/z (M+H)⁺= 344.1.

Préparation 137: (S)-A/-(4-amino-3-fluoro-2-methyl-5-nitrophenyl)-A/-methvl-2morpholinopropanamide

A solution of Préparation 136 (3.5 g, 10.2 mmol) in THF (40 mL) at 20 °C was treated with conc. NH4OH (40 mL). The mixture was stirred for 16 h. The mixture was 10 extracted with EtOAc (2 x 200 mL). The combined organic layers were dried (NaaSO4), filtered and concentrated. The crude material was purified by chromatography (silica, EtOAc/PE = 0-100%) to give the title compound 137 (2.2 g, 63%). LC/MS m/z (M+H)⁺ = 341.0.

Préparation 138: (S)-/V-(4.5-diamino-3-fluoro-2-methvlphenvl)-A/-methvl-2morpholinopropanamide) ch₃ ch₃ nh₂ nh₂

A solution of Préparation 137 (2.2 g, 6.5 mmol) in AcOH (60 mL) was treated with iron powder (2.17 g, 38.8 mmol) and the mixture stirred at RT for 16 h. The mixture was 20 filtered and the filtrate was concentrated. The residue was taken up in EtOAc (100 mL) and washed with sat. aq. NaHCOa (30 mL). The organic layer was dried (Na2SO4), filtered and concentrated. The crude material was purified by chromatography (silica, EtOAc/PE = 0-100% then 0-10% MeOH/DCM gradient) to give the title compound (1.3 g, 65%). LC/MS m/z (M+H)⁺ = 311.1.

Préparation 139: 3-fluoro-2-methyl-6-nitroaniline

123

A solution of 1,3-difluoro-2-methyl-4-nitrobenzene (5 g, 28.9 mmol) in THF (100 mL) at 20 °C was treated with conc. NH4OH (100 mL). The mixture was stirred at RT for 16 h. The mixture was extracted with EtOAc (2 x 200 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude material was purified by chromatography (silica, EtOAc/PE = 0-15%) to give the title compound (3 g, 61%). NMR (400 MHz, CDCI3) δ 8.07 (dd, 1H), 6.46 (dd, 1H), 6.32 (s, 2H), 2.13 (d, 3H).

Préparation 140: 4-bromo-3-fluoro-2-methyl-6-nitroaniline

Br.

XI F'XX'NH₂ ch₃

A solution of Préparation 139 (3 g, 07.6 mmol) in MeCN (20 mL) at 20 °C was treated with /V-bromosuccinimide (3.77 g, 21.2 mmol). The mixture was stirred at 90 °C for 2 h. The mixture was cooled to RT and concentrated. The residue was purified by chromatography (silica, EtOAc/PE = 0-15%) to give the title compound (4.3 g, 98%). '’H NMR (400 MHz, CDCI3) δ 8.31 (d, 1H), 6.31 (s, 2H), 2.18 (dd, 3H).

Préparation 141: 5-bromo-4-fluoro-3-methvlbenzene-1,2-diamine

X ï

CH₃

A solution of Préparation 140 (4.3 g, 17.3 mmol) in AcOH (100 mL) was treated with iron powder (5.79 g, 104 mmol) and the mixture was stirred at RT for 1 h. The reaction was filtered and the filtrate concentrated. The residue was taken up in EtOAc (300 mL) and washed with sat. aq. NaHCOa (50 mL). The organic layer was dried (Na2SO4), filtered and concentrated. The crude material was purified by chromatography (silica, EtOAc/PE = 0-35%) to give the title compound 141 (3.44 g, 91%). ¹H NMR (400 MHz, CDCI3) δ 6.74 (d, 1H), 3.36 (s, 4H), 2.12 (d, 3H).

Préparation 142: tert-butyl (4-(difluoromethv1)-2-((4aS,5aR)-5a-methvl-1-((2(trimethvIsilvDethoxylmethvD-IAAa^.Sa.e-hexahvdrocvcloproparflindazol-S-vD-l-^(trimethvlsilvl)ethoxv)methy1)-1H-benzo[cflimidazol-6-vl)(methyl)carbamate

124

A solution of Préparation 129 (160 mg, 0.24 mmol) in anhydraus DCE (1.5 mL) was treated with DAST (0.047 mL, 0.35 mmol) at 0 °C. The mixture was warmed to RT and stirred for 18 h. The mixture was treated with sat. aq. NaHCCh. Additional water was added and the mixture was extracted with DCM (x 3). The combined organic layers were dried (MgSO^, filtered and concentrated. The crude material was purified by chromatography (silica, EtOAc/PE = 0-40%) to give the title compound (86.0 mg, 52%). ¹H NMR (400 MHz, CDCh) δ 7.51 (s, 1H), 7.43 (dd, 1H), 7.42 (s, 1 H), 6.14 (d, 1H), 6.10 (d, 1H), 5.44 (d, 1H), 5.39 (d, 1H), 3.61-3.50 (m, 4H), 3.48 (d, 1H), 3.34 (s, 3H), 3.17 3.05 (m, 2H), 2.73 (d, 1 H), 1.44 (s, 9H), 1.29 (s, 3H), 1.13 (ddd, 1H), 0.91 (ddd, 2H), 0.87-0.79 (m, 2H), 0.41 (dd, 1 H), 0.27 (dd, 1 H), -0.02 (s, 9H), -0.11 (s, 9H).

Préparation 143: 4-(difluoromethyl)-A/-methvl-2-((4aS,5aR)-5a-methvl-1-((2(trimethvlsilvl)ethoxv)methvl)-1,4_l4a,5_l5a,6-hexahvdrocvclopropa[flindazol-3-yl)-1-((2(trimethylsiivl)ethoxy)methvl)-1H-benzordlimidazol-6-amine

A solution of Préparation 142 (85 mg, 0.12 mmol) in DCM (1 mL) at 0 °C was treated with 2,6-lutidine (0.042 mL, 0.36 mmol) followed by TMSOTf (0.066 mL, 0.36 mmol). The mixture was stirred at 0 °C for 2 h. The mixture was treated with sat. aq. NaHCCh. The organic phase was separated and the aqueous layer was extracted with additional DCM (x 4). The combined organic extracts were dried (MgSO4), filtered and concentrated. The crude material was purified by chromatography (silica, EtOAc/PE = 0-50%) to give the title compound (61.9 mg, 85%). LC/MS m/z (M+H)⁺ = 604.5.

Préparation 144: (S)-/V-(4-(difluoromethvl)-2-((4aS,5aR)-5a-methvl-1-((2(trimethvlsilvl)ethoxv)methvl)-1,4,4a.5,5a,6-hexahvdrocvclopropa[flindazol-3-yl)-1-((220759

125 (trimethvlsίlvl)ethoxv)methvl)-1H-benzo[dlim^dazol·6-vl)-/v-methvl-2 morpholinopropanamide

A solution of Préparation 143 (61 mg, 0.10 mmol) and 19 (24 mg, 0.15 mmol) in pyridîne (1 mL) was treated with EDCI (48 mg, 0.25 mmol). The mixture was stirred at RT for 18 h. The mixture was concentrated and the residue was taken up in water and extracted with EtOAc (x 3). The combined organic layers were dried (MgSOz), filtered and concentrated to give the title compound (72 mg, 96%). LC/MS m/z (M+H)⁺ = 745.7,

Préparation 145: 4-fluoro-2-(2-methoxyethoxy)-1-nitrobenzene

A solution of 2-methoxyethanol (2.39 g, 31.4 mmol) in THF (40 mL) at 0 °C was treated with 1M KOtBu in THF (31.4 mL, 31.4 mmol), After 30 min, a solution of 2,4-difluoro-1nitrobenzene (5.0 g, 31.4 mmol) in THF (40 mL) was added, The mixture was stirred at 30 °C for 1 h and diluted with 1:1 HzOïEtOAc (100 mL), The layers were separated and the aqueous layer was extracted with EtOAc (50 mL). The organic extracts were dried, filtered and concentrated to give the title compound (6.76 g, 100%). ¹H NMR (400 MHz, CDCh) δ 7.93 (dd, 1H), 6.82 (dd, 1H), 6.72 (ddd, 1H), 4.29-4.15 (m, 2H), 3.87 - 3.73 (m, 2H), 3.45 (s, 3H).

Préparation 146: 4-fluoro-2-(2-methoxyethoxv)aniline

A solution of Préparation 145 (6.76 g, 31.4 mmol) in MeOH (200 mL) was treated with 10% Pd/C (600 mg,) and stirred under H2 (1 atm) for 16 h. The mixture was filtered and the filtrate concentrated to give the title compound (4.53 g, 78%). ¹H NMR (400 MHz, CDCh) δ 6.66 - 6.48 (m, 3H), 4.16 - 4.06 (m, 2H), 3.81 - 3.66 (m, 2H), 3.44 (s, 3H).

Préparation 147: 4-fluoro-2-(2-methoxvethoxv)-5-nitroaniline

126

A solution of Préparation 146 (615 mg, 3.32 mmol) in conc. H2SO4 at 5 °C was treated with KNOs (336 mg, 3.32 mmol). The mixture was stirred for 2 h and poured into ice water (50 mL). The aqueous mixture was extracted with EtOAc (2 x 40 mL). The organic extracts were combined, dried, filtered and concentrated to give the title compound (790 mg, 103%). ¹H NMR (400 MHz, CDCI3) δ 7.40 (d, 1H), 6.66 (d, 1H), 4.26 - 4.17 (m, 2H), 3.82 - 3.74 (m, 2H), 3.44 (s, 3H); LC/MS m/z (M+H)⁺ = 230.9.

Préparation 148: (S)-A/-(4-fluoro-2-(2-methoxvethoxv)-5-nitrophenvl)-2m 0 rph 0 lin op ropan amide

A solution of Préparation 147 (590 mg, 2.56 mmol) and Préparation 19 (490 mg, 3.08 mmol) in pyridine (37 mL) at 20 °C was treated with EDCI (983 mg, 5.13 mmol). The mixture was stirred at RT for 16 h and then poured into water (40 mL). The mixture was extracted with EtOAc (2 x 40 mL). The organic extracts were combined, dried (Na₂SO4), filtered and concentrated. The crude material was purified by chromatography (silica, EtOAc/PE = 0-50%) to give the title compound 148 (398 mg, 42%). ¹H NMR (400 MHz, CDCh) δ 10.01 (s, 1H), 9.29 (d, 1H), 6.76 (d, 1H), 4.33 4.21 (m, 2H), 3.91 - 3.78 (m, 6H), 3.46 (s, 3H), 3.27 (q, 1 H), 2.72 - 2.50 (m, 4H), 1.34 (d, 3H); LC/MS m/z (M+H)⁺ = 372.0.

Préparation 149: (S)-A/-(4-fluoro-2-(2-methoxvethoxv)-5-nitrophenvl)-/V-methvl-2 morpholinopropanamide

127

A solution of Préparation 148 (202 mg, 0.54 mmol) m THF (3 mL) at 0 C was treated with KOtBu (67 mg, 0.59 mmol). After stirring for 1 hr, a solution of methyl iodide (84.7 mg, 0.59 mmol) in THF (3 mL) was added and the mixture stirred at RT for 16 h. The mixture was treated with sat. aq. NH4CI (15 mL) and the mixture extracted with EtOAc (20 mL). The organic extract was combined, dried (Na2SO₄), filtered and concentrated. The crude material was purified by chromatography (silica, EtOAc/PE = 0- 100%) to give the title compound (262 mg, 92%). ¹H NMR (400 MHz, CDCh) δ 8.28 (d, 0.5H), 6.87 (dd, 1H), 4.31 - 4.17 (m, 2H), 3.78 - 3.67 (m, 2H), 3.63 (t, 2H), 3.57 - 3.43 (m, 1H), 3.38 (d, 3H), 3.17 (d, 3H), 2.61 - 2.14 (m, 4H), 1.18 (d, 1.5H), 1.10 (d, 1.5H).; ¹⁹F NMR (376 MHz, CDCh) δ -111.09. ; LC/MS m/z (M+H)⁺ = 386.1.

Préparation 150: (S)-/V-(4-amino-242-methoxvethoxy)-5-nitrûphenyl)-/V-methvl-2morpholinopropanamide

h₃c'°

A solution of Préparation 149 (262 mg, 0.68 mmol) in EtOH (5 mL) at 15 °C was treated with conc. NH₄OH (4.6 g, 130 mmol). The mixture was heated at 50 °C and stirred for 16 h. The mixture was concentrated, diluted with H₂O (10 mL) and extracted with EtOAc (2 x 10 mL). The aqueous layer was further extracted with MeOHOCM (10 mL:10 mL). The organic extracts were combined, dried, filtered and concentrated to give the title compound 150 (86 mg, 33%). LC/MS m/z (M+H) = 383.1.

Préparation 151 : (S)-Λ/-(4,5-diamino-2-(2-methoxvethoxv)phenvl)-Λ/-methvl·2morpholinopropanamide

128

A solution of Préparation 150 (86 mg, 0.22 mmol) in MeOH (2 mL) was treated with 10% Pd/C (23.6 mg). The mixture was degassed with argon (x 3) and then H2 (3 x). The mixture was then stirred under H2 (1 atm) for 20 h at RT. The mixture was filtered and the solids washed with MeOH (3 x). The filtrate was collected and concentrated. The residue was purified by chromatography (silica, EtOH/PE, 0-10%) to give the title compound 151 (71 mg, 73%). LC/MS m/z (M+H)⁺ = 353.1.

Préparation 152: (S)-/V-(6-(2-methoxvethoxv)-2-((4aS.5aR)-5a-methvl-1-((2(trimethylsilvl)ethoxv)methyÎ)-1,4,4a,5,5a,6-hexahvdrocvclopropafflindazol-3-yl)-1Hbenzofdlimidazol-5-vl)-/\/-methvl-2-morpholinopropanamide

A solution of Préparation 151 (71 mg, 0.20 mmol) and Na2S20s (19.1 mg, 0.10 mmol) in DMF (1.0 mL) was treated with 9 (62 mg, 0.20 mmol) and DMSO (39 mg, 0.50 mmol). The mixture was heated at 110 °C for 16 h and then poured into 3% aq. LiCI (5 mL). The mixture was extracted with EtOAc (10 mL). The organic extract was collected, dried (Na2SO4), filtered and concentrated. The crude material was purified by chromatography (silica, EtOAc/PE = 0-100%) to give the title compound (160 mg, 120%). LC/MS m/z (M+Hf = 639.3.

Préparation 153: (4aS.5aff)-3-(5-bromo-7-methvL1 H-benzo[d1imidazol-2-vl)-5a-methvl1-((2-(trimethvlsilyl)ethoxv)methvl)-1,4,4a,5,5a,6-hexahvdrocyclopropaiïlindazole

A solution of 5-bromo-3-methylbenzene-1,2-diamine (980 mg, 4.87 mmol) and Na2S2Û5 (463 mg, 2.44 mmol) in DMF (24 mL) were treated with 9 (1.49 g, 4.87 mmol) and DMSO (952 mg, 12.2 mmol). The mixture was heated at 110 °C for 16 h. The mixture was cooled to RT and poured into 3% aq. LiCI (100 mL). The solid was collected by filtration and the filtrate was extracted with EtOAc (2 x 100 mL). The organic layers

129 were combined with the collected solid and concentrated. The residue was purified by chromatography (silica, EtOAc/PE = 0-20%) to give the title compound (2.17 g, 91%). ¹H NMR (400 MHz, CD₃OD) δ 7.57 (s, 1H), 7.17 (dd, 1H), 5.58 - 5.40 (m, 2H), 3.61 (dd, 2H), 3.38 (d, 1H), 3.26 - 3.02 (m, 2H), 2.82 - 2.68 (m, 1H), 2.58 (s, 3H), 1.30 (s, 3H), 1.17 (dt, 1H), 0.96 -0.78 (m, 2H), 0.43 (dd, 1H), 0.26 (t, 1H), -0.04 (s, 9H); LC/MS m/z (M+H)⁺= 488.8.

Préparation 154: (4aS,5aR)-3-(6-bromo-4-methvl-1-((2-(trimethylsilvl)ethoxv)methyl)1/7-benzoMimidazol-2-vl)-5a-methvl-1-((2-(trimethvlsilvl)ethoxv)methvl)-1,4,4a, 5,5a, 6hexahydrocyclopropalïlindazole

A solution of Préparation 153 (1.87 g, 3.84 mmol) in THF (38 mL) at 0 °C was treated with NaH (184 mg, 4.6 mmol) and the mixture was stirred for 30 min. SEM-CI (703 mg, 4.22 mmol) was added and the mixture was warmed to RT and stirred for 2.5 h. The reaction was cooled to 5 °C and treated with sat. aq. NH4CI (20 mL). The mixture was extracted with EtOAc and the organic layer was concentrated. The residue was purified by chromatography (silica, EtOAc/PE = 0-10%) to give the title compound 154 (2.4 g, 92%). LC/MS m/z (M+H)⁺ = 618.9.

Préparation 155: tert-butyl (4-methvl-2-((4aS_l5aR)-5a-methyl-1-((2(trimethvlsilvl)ethoxv)methvl)-1,4,4a,5.5a,6-hexahvdrocvclopropaΓf|indazol·3-vl)-1-((2(trimethvlsilvl)ethoxv)methvl)-1/-/-benzofd1imidazol-6-vl)carbamate

A solution of Préparation 154 (800 mg, 1.29 mmol) in tert-amyl alcohol (13 mL) was treated with tert-butyl carbamate (182 mg, 1.55 mmol), CS2CO3 (844 mg, 2.59 mmol), QPhos (184 mg, 0.26 mmol), and Pd2(dba)₃ (59 mg, 0.065 mmol). The mixture was heated at 100 °C for 16 h. The mixture was cooled to RT and concentrated. The

130 residue was purified by chromatography (silica, EtOAc/PE = 0-20%) to give the title compound 500 mg (59%), LC/MS m/z (M+H)⁺ = 654.0.

Préparation 156: tert-butvl methvl(4-methvl-2-((4aS,5aR)-5a-methvl-1-((25 (trimethvlsiM)ethoxv)methyl)-1,4,4a_l5,5a,6-hexahvdrocvclopropar/1indazol-3-vl)-1-((2(trimethvlsilyl)ethoxv)methvl)-1/7-benzoΓcίlimidazol·6-vί)carbamate

A solution of Préparation 155 (500 mg, 0.77 mmol) in THF (11 mL) at 0 °C was treated with NaH (122 mg, 3.1 mmol). The mixture was stirred for 30 min and methyl iodide 10 (130 mg, 0.92 mmol) was added. The mixture was warmed to 15 °C and stirred for 16

h. The mixture was treated with of sat. aq. NH4CI and extracted with EtOAc (2 x 10 mL). The combined organic layers were concentrated. The residue was purified by chromatography (silica, EtOAc/PE = 0-20%) to give the title compound (308 mg, 74%). LC/MS m/z (M+H)⁺ = 668.0.

Préparation 157: V,4-dimethyl-2-((4aS.5aR')-5a-methvl-1-((2(trimethvlsilvl)ethoxv)methyl)-1 _l4,4a_l5,5a,6-hexahvdrocyclopropafflindazol-3-vl)-1-((2(trimethvlsÎlyl)ethoxv)methvl)-1/-/-benzoMimidazol-6-amine

A solution of Préparation 156 (380 mg, 0.57 mmol) in DCM (11 mL) at 0°C was treated with ZnBrz (641 mg, 2.84 mmol). The mixture was stirred at RT for 18 h. The mixture was poured into sat. aq. NaHCCh (20 mL) and extracted with DCM (2 x 20 mL). The combined organic layers were concentrated to give the title compound (170 mg, 90%). LC/MS m/z (M+H)⁺= 567.9.

131

Préparation 158: (S)-/v-methvl-A/-(4-methyl-2-((4aS,5aR)-5a-methvl-1-((2(trimethylsilyl)ethoxv)methvl)-1,4.4a,5,5a.6-hexahvdrocvclopropaffîindazol-3-yl)-1 -((2(trimethvlsilvl)ethoxv)methvl)-1H-benzorc(1imidazol-6-vl)-2-morpholinopropanamide

A solution of Préparation 157 (300 mg, 0.53 mmol) and Préparation 19 (124 mg, 0.63 mmol) in pyridine (7.6 mL) was treated with EDCI (203 mg, 1.1 mmol). The mixture was stirred at RT for 16 h. The mixture was partitioned between water (50 mL) and EtOAc (50 mL). The organic layer was separated and the organic layer concentrated to give the title compound (380 mg, quant.). LC/MS m/z (M+H)⁺ = 709.0.

Préparation 159: 2-bromo-4-fluoro-5-nitrobenzonitrile

To a solution of 2-bromo-4-fluorobenzonitrile (1.0 g, 5.0 mmol) in conc. H2SO4 (5.0 mL) was added KNO3 (556 mg, 5.50 mmol) in portions at 0 °C, and then stirred at 25 °C for 2 h. The reaction mixture was poured into ice water and the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (10 mL) dried (Na2SÛ4) and concentrated to give the title compound (1.2 g, 98%). ¹H NMR (400 MHz, CDCI3) δ 8.45 (d, J = 7.3 Hz, 1H), 7.75 (d, J = 9.5 Hz, 1H).

Préparation 160: 4-amino-2-bromo-5-nitrobenzonitrile

To a solution of Préparation 159 (1.10 g, 4.490 mmol) in THF (40 mL) was added conc. NH4OH (0.63 mL, 4.49 mmol) at 0 °C. The reaction was stirred at 25 °C for 1 h. The mixture was filtered, and the filtrate concentrated to give the title compound (1.02 g, 94 %). ¹H NMR (400 MHz, DMSO-cfe) Ô 8.51 (s, 1H), 8.17 (s, 2H), 7.40 (s, 1H).

Préparation 161: 4,5-diamino-2-bromobenzonitrile k 132

Br-^<^NH₂ 1 T ²

To a solution of Préparation 160 (1.11 g, 4,58 mmol) in EtOH (20 mL) and H2O (20 mL) was added NH4CI (1.23 g, 22,9 mmol) at 25 °C followed by iron powder (1.28 g, 22.9 mmol), The mixture was stirred at 25 °C for 16h, The reaction mixture was filtered through diatomaceous earth and filter cake was rinsed with EtOH (2 x 20 mL), and the filtrate concentrated. The residue was dissolved in EtOAc and washed with brine and the aqueous phase was extracted with EtOAc (2 x 20 mL), the combined organic extracts were dried (Na₂SO4), filtered and concentrated to give title compound (860 mg, 88%). Ή NMR (400 MHz, CDCh) δ 6.86 (s, 1H), 6.82 (s, 1H), 3.86 (s, 2H), 3.34 (s, 2H).

Préparation 162: 6-bromo-2-((4aS.5aR)-5a-methvl-1-((2-(trimethvlsilvl)ethoxy)methvl)1/^a^^a^-hexabydrocyclopropaiflindazol-S-vD-l H-benzo[d]imidazole-5-carbonitrile

To s solution of Préparation 161 (760 mg, 3.58 mmol) in DMF (15 mL) was added 15 Na2S20s (341 mg, 1.79 mmol), DMSO (700 mg, 8.96 mmol) and a solution of

Préparation 17 (1.21 g, 3.94 mmol) in DMF (3.0 mL). The reaction mixture was stirred at 110 °C for 16 h, then concentrated. The crude product was purified by silica gel chromatography (silica, EtOAc/PE = 0-30%) to give the title compound (1.38 g, 68%). LC/MS m/z (M+H)⁺= 499.1

Préparation 163: 6-bromo-2-((4aS,5aR)-5a-methyl-1-((2-(trimethvlsilvl)ethoxv)methvl)1,4,4a,5,5a,6-hexahvdrocvclopropaiflindazol-3-vl)-1-((2-(trimethvlsilvl)ethoxv)methyl)1 H-benzofd1imidazole-5-carbonitrile and 5-bromo-2-((4aS.5aR)-5a-methyl-1-((2(trimethvlsilvl)ethoxv)methvl)-1,4,4a,5,5a,6-hexahvdrocvclopropa[f)indazol-3-vl)-1-((225 (trimethylsilvl)ethoxy)methvl)-1 H-benzo[dlimidazole-6-carbonitrile

133

To a suspension of NaH (133 mg, 3.32 mmol) in THF (5.0 mL) was added a solution of Préparation 162 (1.380 g, 2.76 mmol) in THF (10 mL) at 0 °C. After stirring at 0 °C for 15 min, SEM-CI (0.69 g, 4.15mmol) was added dropwise and reaction mixture was 5 stirred at 20 °C for 2 h. The reaction mixture was poured onto ice and the mixture was extracted with EtOAc (3x10 mL). The combined organic layers were washed with brine (10 mL) dried (Na2SO4) and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE = 0-30%) to give the title compounds as a mixture (1.14 g, 66%). ¹H NMR (400 MHz, CDCh) δ 8.08 (d, 1H), 7.93 (d, 1H), 6.23-6.11 (m, 10 2H), 5.50 - 5.38 (m, 2H), 3.68 - 3.50 (m, 4H), 3.49 (m, 1H), 3.21 - 3.07 (m, 2H), 2.77 (d, J = 16.3 Hz, 1 H), 1.32 (s, 3H), 1.17 (dt, J = 10.0, 5.5 Hz, 1 H), 1.00 - 0.89 (m, 2H), 0.92 - 0.81 (m, 2H), 0.45 (dd, J = 8.8, 4.7 Hz, 1H), 0.28 (t, J = 5.1 Hz, 1H), 0.01 (s, 9H), -0.08 (d, J = 2.7 Hz, 9H); LC/MS m/z (M+H)⁺ = 629.1.

Préparation 164:2-((4aS,5aR)-5a-methvl-1-((2-(trimethylsilvl)ethoxv)methvl)1,4,4a,5,5a,6-hexahvdrocvcloproparflindazol-3-vl)-6-(methylamino)-1-((2(trimethvlsilvl)ethoxv)methyl)-1 H-benzo[d1imidazole-5-carbonitrile and 2-((4aS,5aR)-5amethvl·1-((2-(trimethvlsilvl)ethoxv)methvl)-1,4,4a,5,5a,6-hexahvdrocvciopropaίflindazoί3-vl)-5-(methvlamino)-1-((2-(trimethylsilvl)ethoxv)methvl)-1 H-benzofdlimidazole-620 carbonitrile

A solution of Préparation 163 (1.01 g, 1.61 mmol) in DMF (8 mL) was degassed with nitrogen. The solution was treated with N-(2,6-dimethylphenyl)-6-hydroxypicolinamide (156 mg, 0.64 mmol), K3PO4 (1.02 g, 4.82 mmol), Cul (153 mg, 0.80 mmol) and 2M

CH3NH2 in THF (99.8 mg, 3.21 mmol) at 20 °C. The reaction vial was sealed and heated at 110 °C for 16 h. The reaction mixture was concentrated. The crude product was purified by chromatography (silica, EtOAc/PE = 0-10%) to give the title compound as a mixture (670 mg, 68.7%). Ή NMR (400 MHz, CDCh) δ 7.87 (s, 0.5H), 7.65 (s, 0.5H), 7.01 (s, 0.5H), 6.67 (s, 0.5H), 6.15 - 6.01 (m, 2H), 5.49 - 5.36 (m, 2H), 4.64 (s,

0H), 3.63 - 3.49 (m, 5H), 3.53 - 3.40 (m, 1 H), 3.11 (t, J = 18.0 Hz, 2H), 2.99 (d, J = 5.6 h 134

Hz, 3H), 2.75 (d, J = 16.9 Hz, 1H), 1.30 (s, 3H), 1.14 (dt, J = 9.8, 5.3 Hz, 1H), 0.98 0.89 (m, 2H), 0.89 - 0.80 (m, 2H), 0.46 - 0.38 (m, 1 H), 0.27 (t, J = 5.0 Hz, 1H), -0.00 (d, J = 0.8 Hz, 9H), -0.09 (d, J = 4.3 Hz, 9H); LC/MS m/z (M+H)⁺ = 579.3.

Préparation 165: Step 1. methyl 6-bromo-2-((4aS,5aR)-5a-methvl-1-((2ίtrimethvlsilvl)ethoxv)methvD-1,4,4a.5.5a,6-hexahvdrocvclopΓopa[f1indazol·3-vl)-1 HbenzoTdlimidazole-4-carboxylate

To a solution of methyl 2,3-diamino-5-bromobenzoate (1.57 g, 6.41 mmol) in DMF (30 10 mL) at 20 °C was added Préparation 9 (1.96 g, 6.41 mmol) and NazSaOs (1.2 g, 6.40 mmol). The mixture was heated at 110 °C for 16 h then cooled to RT and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE = 0-75%) to give the title compound (1.23 g, 36%). LC/MS m/z (M+H)⁺ = 533.1 (⁸¹ Br).

Préparation 166:methyl 6-bromo-2-((4aS,5aR)-5a-methyl-1 -((2(trimethylsilvl)ethoxv)methyl)-1,4,4a.5.5a,6-hexahvdrocvclopropaÎflindazol-3-vl)-1-((2(trimethvlsilvl)ethoxv)methvi)-1H-benzofd1imidazole-4-carboxylate

To a solution of Préparation 165 (1.20 g, 2.26 mmol) in THF (50 mL) at 0 °C was added 20 NaH (117 mg, 2.93 mmol) and SEM-CI (565 mg, 3.39 mmol). The mixture was stirred for 20 h at RT. The reaction was treated with sat. aq. NH4CI (1.0 mL) and water (50 mL). The mixture was extracted with EtOAc (2 x 150 mL). The combined organic extracts were washed with brine, dried (NazSOi) and concentrated to give the title compound (1.49 g, 99%). LC/MS m/z (M+H)⁺ = 663.1 (⁸¹Br).

135

Préparation 167: 6-bromo-2-((4aS,5aR)-5a-methvl-1-((2-(trimethvlsilvl)ethoxv)methvl)1 ,4,4a,5,5a,6-hexahvdrocyclopropaÎf|indazol-3-vl)-1-((2-(trimethylsilvl)ethoxv)nnethvl)1 H-benzofdlimidazole-4-carboxylic acid

To a solution of Préparation 166 (900 mg, 1.36 mmol) in MeOH (50 mL) at RT was added 10% NaOH (5 mL). The mixture was stirred at RT for 15 h, cooled to 0 °C and acidified with 1N HCl to a pH ~1. The mixture was then diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The organic extracts were combined, dried (NasSO^ and concentrated to give the title compound (880 mg, 100%). LC/MS m/z (M+H)⁺ = 649.1 (⁸¹Br).

Préparation 168: 6-bromo-2-((4aS,5aR)-5a-methvl-1-((2-(trimethylsilvl)ethoxv)methvl)1,4,4a,5.5a_l6-hexahvdrocvclopropa[flindazol-3-vl)-1-((2-(trimethvlsilvl)ethoxv)methvl)1H-benzo[d1imidazole-4-carboxamide

To a solution of Préparation 167 (850 mg, 1.31 mmol) in DMF (10 mL) at RT was added HATU (649 mg, 1.71 mmol), EtsN (1 mL) and NH4CI (211 mg, 3.94 mmol). The mixture was stirred at RT for 15 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The organic extracts were combined, dried (Na2SO₄) and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE = 0-50%) to gîve the title compound (400 mg, 47%). LC/MS m/z (M+H)⁺ = 648.1 (⁸¹Br).

Préparation 169: 6-bromo-2-((4aS,5aR)-5a-methvl-1-((2-(trimethvlsilvl)ethoxv)methvl)1,4.4a,5,5a,6-hexahvdrocvclopropaffîindazol-3-vl)-1-((2-(trimethvlsilvl)ethoxv)methvl)1H-benzo[dlimÎdazole-4-carbonitrile

136

To a solution of Préparation 168 (400 mg, 0.62 mmol) in THF (20 mL) at 0 °C was added EtaN (375 mg, 3.71 mmol) and TFAA (390 mg, 1.86 mmol). The mixture was stirred at RT for 15 h. The mixture was diluted with 1:1 water/DCM (100 mL) and the layers separated. The aqueous layerwas extracted with DCM (50 mL). The combined organic extracts were washed with brine (50 mL), dried (Na₂SO<), filtered and concentrated to give the title compound (389 mg, 100%). LC/MS m/z (M+H)⁺ = 630.1 (⁸¹Br).

Préparation 170:tert-butyl (4-cyano-2-((4aS,5aR)-5a-methyl-1 -((2(trimethvlsilvl)ethoxv)methyl)-1 /^a.S.Sa.e-hexahvdrocycloproparflindazol-S-vD-l-itë(trimethylsilvl)ethoxv)methvl)1H-benzo[d1imidazol-6-vl)carbamate

To a solution of Préparation 169 (389 mg, 0.62 mmol) in tert-amyl alcohol (10 mL) and dioxane (10 mL) under N2 was added tert-butyl carbamate (217 mg, 1.86 mmol), CS2CO3 (403 mg, 1.24 mmol), tert-BuDavePhos (84.5 mg, 0.25 mmol) and Pd₂(dba)3 (57 mg, 0.06 mmol). The mixture was stirred at 100 °C for 15 h. The reaction was cooled to RT and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE = 0-75%) to give the title compound (320 mg, 78%). LC/MS m/z (M+H)⁺ = 665.3

Préparation 171: 6-amino-2-((4aS,5aR)-5a-methvl·1-((2-(trimethvlsilvl)ethoxv)methvl)1.4,4a,5,5a,6-hexahvdrocvclopropaif1indazol-3-vl)-1-((2-(trimethylsilvl)ethoxv)methvl)1H-benzo[d1imidazole-4-carbonitrile

137

A solution of Préparation 170 (540 mg, 0.81 mmol) in DCM (50 mL) was treated with ZnBr2 (914 mg, 4.06 mmol). The mixture was stirred at RT for 15 h. The reaction was filtered and the filtrate was taken up in DCM (150 mL) and washed with sat. aq. NaHCOs (50 mL). The layers were separated, and the aqueous layer extracted with DCM (50 mL). The combined organic extracts were washed with brine, dried (Na₂SO4) filtered and concentrated to give the titie compound (155 mg, 34%). LC/MS m/z (M+H)⁺ = 565.3

Préparation 172:(R)-N-(4-cyano-2-((4aS,5aR)-5a-methyl-1-((2(trimethylsilyl)ethoxv)methv1)-1,4,4a,5,5a,6-hexahvdrocyclopropa[flindazol-3-vl)-1-((2(tnmethylsilvl)ethoxy)methvl)-1 H-benzo[dlimidazol-6-vl)-2-(tetrahydro-2H-pvran-4vDpropenamide

To a solution of Préparation 171 (70 mg, 0.12 mmol) in THF (10 mL) at RT was added Préparation 22 (39 mg, 0.25 mmol), 2-chloro-1-methylpyridinium iodide (63 mg, 0.25 mmol) and iPr₂NEt (80 mg, 0.62 mmol). The mixture was stirred at 60 °C for 15 h. The reaction mixture was cooled to RT and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE = 0-100%) to give the titie compound (80 mg, 92%). LC/MS m/z (M+H)⁺ = 705.3

Préparation________173:_________________(R)-N-(4-cyano-2-((4aS.5aR)-5a-methyl-1-((2(trimethvlsilvl)ethoxv)methvl)-1,4,4a,5,5a,6-hexahydrocvcloproparf|indazol-3-vl)-1-((2(trimethylsilvl)ethoxv)methvl)-1H-benzo[dlimÎdazol-6-yl)-N-methvl-2-(tetrahvdro-2Hpyran-4-yl)propenamide

138

A solution of Préparation 172 (80 mg, 0.11 mmol) in THF (5 mL) at 0 °C was treated with NaH (6.81 mg, 0.17 mmol) and then Mel (24.2 mg, 0.17 mmol). The mixture was stirred at RT for 2 h. The mixture was treated with sat. aq. NH4CI (0.3 mL) and water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine, dried (NazSO4) and concentrated to give the title compound (82 mg, 100%). LC/MS m/z (M+H)⁺ = 719.4.

Examples

Example 1 : (S)-N-methyl-A/-(6-methyl-2-((4aS.5aR)-5a-methyl-1,4,4a,5.5a,6hexahvdrocyclopropa[flÎndazol-3-vl)-1H-benzordlimidazol-5-vl)-2morpholinopropanamide

Step 1: (S)-/V-methyl-/V-(6-methyl-2-((4aS,5aR)-5a-methvl-1-((2(trimethylsilyl)ethoxv)methyl)-1,4₁4a,5.5a,6-hexahydrocvclopropaΓf|indazol·3-γl)-1Hbenzo[d1imidazol-5-vl)-2-morpholinopropanamide

A mixture of Préparation 9 (20.2 g, 66.2 mmol) and NazSaOs (6.2 g, 32.6 mmol) was treated with a solution of Préparation 30 (20 g, 65.3 mmol), in DMF (114 mL). The mixture was treated with DMSO (11.6 mL, 163 mmol) and heated at 80 °C for 16 h. The mixture was cooled to RT and poured into ice-water. The pH of the mixture was adjusted to pH 7-8 using sat. aq. NaHCOa and the mixture was stirred for additional 2 h. The solids were collected by filtration. The solids were dissolved in DCM, washed with brine, water and dried (MgSÛ4), filtered and concentrated. The crude material was ) 139 purified by chromatography (silica, MeOH/EtOAc = 0-10%) to give the Step 1 title compound (32.0 g, 85%). ¹H NMR (400 MHz, CD₃OD) δ 7.69 - 7.32 (m, 2H), 5.53 - 5.40 (m, 2H), 3.77 - 3.55 (m, 4H), 3.52 - 3.36 (m, 1H), 3.27 - 3.20 (m, 3H), 3.19 - 3.03 (m, 3H), 2.81 - 2.72 (m, 1H), 2.63 - 2.49 (m, 2H), 2.44 - 2.31 (m, 3H), 2.30 - 2.20 (m, 2H),

1.22 - 1.14 (m, 3H), 1.13 - 1.08 (m, 1H), 0.94 - 0.84 (m, 7H), 0.49 - 0.41 (m, 1H), 0.30 0.22 (m, 1 H), 0.02--0.10 (m, 9H); LC/MS m/z (M+H)⁺ = 579.4.

Step 2: (S)-A/-methyl-/\/-(6-methvl-2-((4aS,5aR)-5a-methvl-1,4,4a_T5,5a,6hexahvdrocvclopΓOpa[flindazol-3-vl)-1H-benzoFd1imidazol·5-vl)-210 morpholinopropanamide

A solution of the sîlyl ether of Step 1 (30.4 g, 52.6 mmol) in DCM (50 mL) was cooled to 0 “C. A premixed solution of TFA (76.4 mL, 1 mol) in DCM (150 mL) was added dropwise over 30 min. The mixture was warmed to RT and then stirred for 16 h. The 15 mixture was treated with toluene (100 mL) and concentrated. The résultant residue was azeotroped with toluene (2 x 250 mL). The residue was dissolved in EtOH (210 mL), cooled to 0 °C and treated with conc. NH4OH (138 mL) dropwise over 30 min. The mixture was warmed to RT and stirred for 2 h. The solvent was concentrated and azeotroped with heptanes (2 x 200 mL). The residue was dissolved in DCM and 20 washed sequentially with aq. 1 N HaOH, brine, water, and then dried (MgSO4), filtered and concentrated. The résultant solid was azeotroped with diethyl ether (x 2). The resulting solid was recrystallized with 25% water/MeCN (300 mL), filtered and dried to give the title compound as a crystalline white solid (17.45 g, 74%). ¹H NMR (400 MHz, CD3OD) δ 7.68 - 7.32 (m, 2H), 3.79 - 3.56 (m, 4H), 3.51 - 3.33 (m, 1H), 3.27 - 3.20 (m, 25 3H), 3.16 - 3.01 (m, 3H), 2.81 - 2.72 (m, 1H), 2.61 - 2.49 (m, 2H), 2.45 - 2.31 (m, 3H),

2.32 - 2.22 (m, 2H), 1.34 - 1.25 (m, 3H), 1.23 - 1.01 (m, 4H), 0.45 - 0.35 (m, 1H), 0.30 0.21 (m, 1H); ¹H NMR (500 MHz, 140 °C, DMF-c/7) δ 12.52 (s, 1H), 12.09 (s, 1H), 7.58 (s, 1.5H), 7.46 (s, 0.5H), 3.68 - 3.60 (m, 4H), 3.61 -3.52 (m, 1H), 3.38 - 3.25 (br, s, 3H), 3.17 (d, 2H), 2.88 (t, 2H), 2.74 - 2.65 (m, 2H), 2.64 - 2.61 (br, s, 3H), 2.43 - 2.31 (m, 30 2H), 1.41(s, 3H), 1.29 - 1.11 (m, 4H), 0.56 - 0.50 (m, 1H), 0.37 - 0.32 (m, 1H); SFC method: Chiral Tech AD-H 250 mm x 4.6 mm x 5 pm, 10 to 60% with 0.2% isopropyl

I 140 amine in MeOH/CO2(g), 3.0 mL/min, column température 15 ’C, rétention time = 6.59 min (40.9%) and 9.54 min (59.1%), 100%ee. LC/MS m/z (M+H)⁺ - 449.1.

Example 1.1: (S)-/V-methvl-A/-(6-methvl-2-((4aS,5aR)-5a-methvl-1,4,4a,5,5a,65 hexahydrocvclopropa[fΊindazol·3-vl)-1H-benzoΓd1imίdazol-5-vl)-2morpholinopropanamide, dihydrate (crystal Form 1)

A solution ofthe silyl ether of Example 1 Step 1 (8.90 g, 15.4 mmol) in DCM (59 mL) and TFA (29 mL) was stirred for 16 h. The mixture was concentrated and the residue was azeotroped with toluene (2 x 100 mL). The residue was dissolved in a 3:2 (v/v) JO mixture of EtOH/conc. NFLOH (125 mL). The mixture was stirred at RT for 2 h. The solvent was concentrated and azeotroped with heptanes (2 x 50 mL). The residue was dissolved in DCM and washed sequentially with water and brine. The aqueous phase was extracted with DCM (3 x), dried (MgSCU), filtered and concentrated. The residue was purified by SFC (Princeton PPU 250 mm x 50 mm, 5 pm; Isocratic elution 75% 15 CO₂/25% (0.2% 7N MeOH/MeOH); 80 mL/min) to deliver solids (5.3 g). The solids (5.3 g) were dissolved in DCM (200 mL) and washed with (2 x 50 mL) deionized water. The aqueous layers were combined and extracted with DCM (2 x 50 mL). The combined DCM layers were dried (MgSO4), filtered through Celite®, concentrated and dried under vacuum to provide solids (4.5g). The solids (4.5 g) were suspended in 20 MeCN (90.4 mL) at RT, treated with water (22.3 mL) and the mixture was stirred at °C for 1 h until ail the solids were dissolved. The mixture was allowed to cool to RT over 18 h and then stirred at RT for 24 h. The solids were collected by filtration and dried under vacuum at 60 °C for 60 h to provide the title compound (3.55 g, 51%). NMR for the title compound was consistent with that for Example 1.

Powder X-Ray Diffraction (PXRD)

PXRD analysis was conducted using a Bruker AXS D8 Endeavor diffractometer equipped with a Cu radiation source. The divergence slit was set at 11 mm continuous illumination. Diffracted radiation was detected by a PSD-Lynx Eye detector, with the 30 detector PSD opening set at 2.949 degrees. The X-ray tube voltage and amperage were set to 40 kV and 40 mA respectively. Data was collected in the Theta-Theta goniometer at the Cu wavelength from 3.0 to 40.0 degrees 2-Theta using a step size of 0.016 degrees and a step time of 0.3 second. The antiscatter screen was set to a fixed distance of 1.5 mm. Sampies were rotated at 15/min during collection. Sampies were

I 141 prepared by placing them in a Silicon low background sample holder and rotated during collection. Data were collected using Bruker DIFFRAC Plus software and analysis was performed by EVA diffract plus software. The PXRD data file was not processed prier to peak searching. Using the peak search algorithm in the EVA software, peaks 5 selected with a threshold value of 1 were used to make preliminary peak assignments.

To ensure validity, adjustments were manually made; the output of automated assignments was visually checked and peak positions were adjusted to the peak maximum. Peaks with relative intensity of £ 3% were generally chosen. The peaks which were not resolved or were consistent with noise were not selected. A typical error 10 associated with the peak position from PXRD stated in USP is up to +/-0.2° 2-Theta (USP-941). The PXRD pattern for the title compound is provided in Figure 1 and the corresponding peak list is found in Table 1 below.

Thermogravimetric analysis (TGA)

TGA was conducted using a Discovery TGA (TA instruments) thermogravimetric analyzer. Samples of approximately 10 mg were weighed into aluminum pans and heated from ambient température to 250°C at 10°C/minute heating rate under nitrogen purge (10 mL/min for both sample chamber and balance). TGA for the title compound is provided in Figure 6. The observed weight loss of 7.4% is consistent with a 20 theoretical weight loss of 7.4% for Form 1 dihydrate.

Example 1.2a: (S)-/V-methyl-/\/-(6-methvl-2-((4aS,5aR)-5a-methvl-1,4,4a,5,5a,6hexahvdΓocvclopropaΓ^1indazol·3-vl)-1H-benzofd1ίmidazol-5-vl)-2morpholinopropanamide, dihydrate (crystal Form 2)

A solution of the silyl ether of Example 1 Step 1 (30.4 g, 52.6 mmol) in DCM (50 mL) was cooled to 0°C. A premixed solution of TFA (76.4 mL, 1 mol) in DCM (150 mL) was added dropwise over 30 min. The mixture was warmed to RT and then stirred for 16 h. The mixture was treated with toluene (100 mL) and concentrated. The résultant residue was azeotroped with toluene (2 x 250 mL). The residue was dissolved in EtOH (210 30 mL), cooled to 0 °C and treated with conc. NH4OH (138 mL) dropwise over 30 min. The mixture was warmed to RT and stirred for 2 h. The solvent was concentrated and azeotroped with heptanes (2 x 200 mL). The residue was dissolved in DCM and washed sequentially with aq. 1 N NaOH, brine, water, and then dried (MgSO4), filtered and concentrated. The résultant solid was azeotroped with diethyl ether (x 2) to afford h 142 solids (24 g). A suspension of these solids (24 g) in MeCN (240 mL) and water (60 mL) was heated at a température between 60 °C and 70 for 30 min. Undissolved solids were removed by filtration and the filtrate was cooled slowly to RT. Seed crystals (Example 1.1, Form 1) were added and the mixture was stirred at RT for about 24 h. 5 The solids were collected by filtration and dried under vacuum at 50 °C to provide the title compound (17.45 g, 74%).

¹H NMR (400 MHz, CD₃OD) δ 7.68 - 7.32 (m, 2H), 3.79 - 3.56 (m, 4H), 3.51 - 3.33 (m, 1H), 3.27 - 3.20 (m, 3H), 3.16 - 3.01 (m, 3H), 2.81 - 2.72 (m, 1H), 2.61 - 2.49 (m, 2H), 2.45 - 2.31 (m, 3H), 2.32 - 2.22 (m, 2H), 1.34- 1.25 (m, 3H), 1.23 - 1.01 (m, 4H), 0.45 10 0.35 (m, 1H), 0.30-0.21 (m, 1H); M NMR (500 MHz, 140 °C, DMF-d7) δ 12.52 (s, 1H),

12.09 (s, 1H), 7.58 (s, 1.5H), 7.46 (s, 0.5H), 3.68 - 3.60 (m, 4H), 3.61 - 3.52 (m, 1H), 3.38 - 3.25 (br, s, 3H), 3.17 (d, 2H), 2.88 (t, 2H), 2.74 - 2.65 (m, 2H), 2.64 - 2.61 (br, s, 3H), 2.43 - 2.31 (m, 2H), 1.41 (s, 3H), 1.29 - 1.11 (m, 4H), 0.56 - 0.50 (m, 1H), 0.37 0.32 (m, 1H); SFC method: Chiral Tech AD-H 250 mm x 4.6 mm x 5 pm, 10 to 60% with 15 0.2% isopropyl amine in MeOH/CO2(g), 3.0 mL/min, column température 15 “C, rétention time = 6.59 min (40.9%) and 9.54 min (59.1%), 100%ee. LC/MS m/z (M+H)⁺ = 449.1.

PXRD

PXRD was carried out according to the procedure set out for Example 1.1 (Form 1), but 20 with the divergence slit set at 10 mm, the detector PSD opening set at 2.99 degrees, and a step size of 0.02 degrees. The PXRD pattern for the title compound is provided in Figure 2 and has been aligned with the calculated powder pattern generated from the single crystal solution of Example 1.4 below. The corresponding peak list is found in Table 1 below.

Example 1.2b: (S)-Λ/-methvl-Λ/-(6-methvl·2-((4aS,5aR)-5a-methvl·1,4,43,5,53,6hexahvdrocvclopropaffÎÎndazol-3-vl)-1H-benzo[d1imid3zol-5-vl)-2morphoiinopropanamide, dihydrate (crystsl Form 2)

A solution of the silyl ether of Example 1 Step 1 (70.0 g, 120.9 mmol) in DCM (150 mL) 30 at about 0 °C was treated dropwise with a mixture of 1:1 (v/v) DCM/TFA (342 mL). The reaction mixture was warmed to RT and stirred for about 16 h. The mixture was concentrated and the residue was azeotroped with toluene (2 x). The residue was dissolved in éthanol (300 mL) and treated dropwise with conc. NH4OH (300 mL). The mixture was stirred at RT for about 24 h. The solvent was concentrated. The residue

143 was dissolved in DCM and washed sequentially with brine and water. The DCM extract was dried (MgSO4), filtered and concentrated. The residue was purified by chromatography (silica, EtOAc/PE “ 50-100% then MeOH/EtOAc 0-3%) to deliver the solids (batch 1, 31 g). A solution of the collected solids (2.0 g) in éthanol (12 mL) was heated to about 75 °C and water (18 mL) was added at a rate to keep the internai température above 70 °C. The mixture was cooled to about 60 °C and treated with additional solids (100 mg). The mixture was stirred at about 60 °C for about 2 h and then stirred at about 30 °C for about 18 h. The mixture was cooled to about 5 °C and stirred for about 1 h. The solids were collected by filtration, rinsed with 1:2 (v/v) ethanol/water and dried to provide solids (batch 2, 1.1 g). The remaining batch 1 solids (29 g) were suspended in MTBE (150 mL) and stirred at about 30 °C for about 48 h. The solids were collected by filtration, rinsed with MTBE and dried to provide solids (batch 3, 23 g). The combined batch 2 and batch 3 solids (24.1 g) were suspended in éthanol (150 mL) and heated to about 75 °C and water (220 mL) was added at a rate to keep the internai température above 70 °C. The solution was stirred at about 65 °C for about 1 h, at about 55 °C for about 1 h, at 45 °C for about 3 h and then at about 35 °C for about 48 h. The solids were collected by filtration, rinsed with 1:2 (v/v) ethanol/water and dried under vacuum to provide the title compound (20.5 g, 38 %). NMR and PXRD for the title compound were consistent with that for Example 1,2a

Example 1.3: (S)-/V-methvl-A/-(6-methvl-2-((4aS,5aR)-5a-methvl-1,4,4a,5,5a,6hexahvdrocvclopropa[f]indazol-3-vl)-1 H-ben zofd1imidazol-5-yl)-2morpholinopropanamide, hemihydrate (crystal Form 3) (S)-N-methyl-A/-(6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[f]indazol-3-yl)-1H-benzo[d]imidazol-5-yl)-2morpholinopropanamide, dihydrate (crystal Form 2) (400 mg) was suspended in MeCN (4 mL) and stirred at RT for about 18 h. The solids were collected by filtration and rinsed with MeCN (about 3 mL). The collected solids were dried under vacuum at 50 °C for 1.5 h to provide the title compound (300 mg, 89%).

TGA and PXRD

TGA and PXRD were respectively carried out according to the procedures set out in Examples 1.1 (Form 1) and 1.2a (Form 2). The PXRD pattern for the title compound is provided in Figure 3 and the corresponding peak list is found in Table 1 below. TGA for

144 the title compound is provided in Figure 7. The observed weight loss of 1.8% is consistent with a theoretical weight loss of 2% for Form 3 hemi-hydrate.

Table 1

PXRD peak lîst for crystal Forms 1,2 and 3 of, respectively, Examples 1.1,1,2a and 1.3

Form 1	Form 2 W	Form 3
Angle, °2θ (°2-Theta)	Relative Intensity, %	Angle, °2θ (°2-Theta)	Relative Intensity, %	Angle, °2θ (°2-Theta)	Relative Intensity, %
8.6	12	6.6	46	6.8	3
9.2	5	7.4	6	8.5	6
10.1	53	11.0	24	10.6	9
12.6	100	11.6	5	11.1	13
13.7	5	12.4	10	12.0	17
14.4	74	13.3	76	13.0	22
15.0	65	14.4	38	13.5	21
16.2	78	14.8	34	14.5	12
16.8	9	15.2	3	14.9	100
17.0	10	15.7	54	16.4	51
18.6	57	16.2	70	16.8	43
18.9	55	17.0	8	18.5	91
19.4	44	17.2	4	19.6	26
19.9	23	17.7	23	20.5	4
20.3	13	18.2	48	21.1	12
21.0	35	18.8	100	21.6	11
22.1	31	19.9	3	22.5	20
22.5	41	20.6	52	23.4	27
22.9	9	21.6	5	23.8	42
23.5	43	22.4	40	24.6	12
23.9	21	22.9	87	26,0	4
24.6	8	23.6	30	27.3	22
25.7	8	24.0	36	27.7	15
26.0	39	25.0	4	28.6	6

145

Form 1	Form 2 01	Form 3
Angle, °2θ (°2-Theta)	Relative Intensity, %	Angle, °2θ (°2-Theta)	Relative Intensity, %	Angle, °2Θ (°2-Theta)	Relative Intensity, %
26.4	31	25.5	11	29.0	8
27.2	12	26.0	22	29.9	13
27.6	3	26.7	39	33.9	3
29.2	12	28.0	6	34.5	4
29.4	16	28.4	32	35.4	5
29.8	9	29.1	10	37.4	3
30.7	22	29.9	13
31.2	7	30.7	3
31.8	6	31.1	8
32.7	6	31.5	6
33.6	7	32.0	6
35.0	7	32.6	4
35.4	15	32.9	8
36.4	8	33.3	5
37.7	5	34.4	7
38.3	4	35.7	3
		36.9	15
		38.1	9
		39.4	3
		39.5	4

Ol The PXRD pattern for Form 2 has been alignée! with the calculated powder pattern generated from the single crystal solution of Example 1.4 below.

146

Example 1.4: (S)-/\Z-methyl-A/-(6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocvcÎopropani!ndazol-3-vl)-1 H-benzoΓd1im^dazol·5-vl)-2morphoiinopropanamide, dihydrate (crystal Form 2) (S)-A/-methyl-A/-(6-methyî-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[f]indazol-3-yl)-1/-/-benzo[d]imidazol·5-yl)-2morpholinopropanamide, dihydrate (crystal Form 2) (30 mg) was dissolved in EtOAc (10 mL) in a 20 mL scintillation vial. The vial was covered with a cap but not tightened. The vial was left undisturbed at RT for about 26 days. During the elapsed time most of the solvent had evaporated leaving approxîmately 1 mL of EtOAc and the title compound.

Single Crystal X-Ray Diffraction (SXRD)

SX RD was performed on a Bruker D8 Venture diffractometer at room température. Data collection consisted of oméga and phi scans. The structure was solved by întrinsic phasing using SHELX software suite in the Orthorhombic space group P2i2i2i. The structure was subsequently refined by the full-matrix least squares method. Ail non-hydrogen atoms were found and refined using anisotropic displacement parameters. The final R-index was 3.92%. A final différence Fourier revealed no missing or misplaced électron density. Table 2 contains structural data from the SXRD analysis.

Table 2

Crystal structure data for the crystalline form of Example 1.4 (Form 2)

Empirical formula	C25 H36 N6 04
Formula weight	484.60
Température	296(2) K
Wavelength	1.54178 À
Crystal System	Orthorhombic
Space group	P212121
Unit cell dimensions	a = 6.6838(2) Â	a= 90°
b = 16.0450(4) À	β= 90°
c = 23.8703(6) Â	γ= 90°
Volume	2559.89(12) Â3
Z	4
Density (calcuiated)	1.257 Mg/m3

147

Goodness-of-fit on F2	1.043
Final R indices [l>2sigma(l)]	R1 = 0.0392, wR2 = 0.1026
R indices (ail data)	R1 = 0.0451, wR2 = 0.1048

The ORTEP diagram for one of the molécules in the asymmetric unit for the solution is presented in Figure 4, with displacement parameters at 50% probability and water molécules omitted from the figure for clarity. Figure 5 is an ORTEP diagram drawn with 5 displacement parameters at 50% probability and water molécules shown.

The PXRD peak list from the calculated powder pattern for Form 2 is given in Table 3.

Table 3

Calculated PXRD peak list from the SXRD data for (Form 2)

Angle (2-theta)	Relative Intensity (%)	Angle (2-theta)	Relative Intensity (%)
6.6	59	24.0	31
7.4	8	25.0	4
9.2	3	25.5	10
11.0	28	26.0	17
11.6	5	26.6	26
12.4	11	26.7	18
13.3	64	27.0	3
14.3	49	27.9	5
14.8	39	28.3	15
15.2	4	28.4	26
15.7	51	29.1	6
16.2	81	29.2	6
17.0	8	29.9	10
17.3	3	31.1	6
17.7	24	31.5	4
18.2	41	31.8	4
18.5	12	32.0	4
18.8	100	32.6	4
20.6	51	32.9	6

148

Angle (2-theta)	Relative Intensity (%)	Angle (2-theta)	Relative Intensity (%)
21.6	4	33.3	5
22.1	9	34.4	4
22.3	33	36.9	9
22.5	20	37.0	6
22.9	73	38.1	7
23.0	18	39.5	3

Comparison of the experimental PXRD data in Table 1 of crystal Form 2 (Example 1.2a) with the data in Table 3 for the calculated PXRD pattern of crystal Form 2 (Example 1.4) obtained from single crystal structure détermination shows good peak corrélation.

Example 2: A/-methyl-A/-(6-methvl-2-((4aS.5aR)-5a-methyl-1,4,4a,5,5a,6hexahvdrocvclopropaiflindazoi-3-vl)-1/-/-benzo[d]imidazol-5-vl)-2morpholinopropanamide çh₃ çh₃

Ο h₃c ^h / I ^j'CH₃

Example 2 was prepared following the procedure described for Example 1 from Préparation 31 (292 mg) and Préparation 9 (306 mg) to deliver 110 mg of the title compound. SFC method: Chiral Tech AD-H 250 mm x 4.6 mm x 5 pm, COs/MeOH (0.2% isopropyl amine) 5 to 60%, 3.0 mL/min, column température 15 ”C, rétention time = 6.33 min (13.42%), 6.74 min (24.37%), 8.35 min (35.92%), and 9.76 min (24.37%); LC/MS m/z (M+H)⁺ = 449.5.

Example 3: (R)-A/-methyl-/V-(6-methvl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahγdrocvclopΓopa[f|indazol-3-vl)-1H-benzoΓd1imidazol·5‘Vl>2morpholinopropanamide çh₃ çh₃

149

Step 1: (R)-/V-methvl-N-(6-methvl-2-((4aS,5aR)-5a-methvl-1-«2(trimethvlsilvl)ethoxy)methvn-1,4,4a.5,5a.6-hexahvdrocycloproparf|indazol-3-v0-1Hbenzoid1imidazol-5-vl)-2-morpholinopropanamide

A mixture of Préparation 46 (219 mg, 0.5 mmol), (R)-2-morpholinopropanoic acid (398 mg, 2.50 mmol), EDCI (959 mg, 5.00 mmol) in pyridine (10.0 mL) was heated at 80 °C for 16 h. The mixture was cooled to RT and diluted with EtOAc/water. The organic layer was separated and washed sequentially with sat. aqueous NH4CI, brine, dried (MgSO4), filtered and concentrated. The crude material was purified by chromatography (silica, 0-10% MeOH/EtOAc) to give the titie compound 160 (150 mg, 50%). ^ήΗ NMR (400 MHz, CD3OD) δ 7.68 (s, 1H), 7.53 (s, 1H), 5.62 - 5.38 (m, 2H), 3.71 - 3.57 (m, 6H), 3.43 (d, 1 H), 3.28 (d, 3H), 3.24 - 3.04 (m, 3H), 2.81 (d, 1 H), 2.67 2.49 (m, 2H), 2.47 (s, 2H), 2.36 (s, 1H), 2.31 (dd, 2H), 1.34 (d, 4H), 1.22 (d, 2H), 1.13 (dd, 1H), 0.98 - 0.88 (m, 2H), 0.48 (dd, 1H), 0.30 (t, 1H), 0.02 --0.02 (m, 9H); LC/MS m/z (M+H)⁺ = 579.6.

Step 2: (R)-Λ/-methvl-Λ/-(6-methvl·2-((4aS,5aR)-5a-methvl-1,4,4a,5,5a,6hexahvdrocvclopropaff]indazol-3-vl)-1H-benzofd1imidazol-5-yl)-2morpholinopropanamide

A solution of the silyl ether of Step 1 (150 mg, 0.259 mmol) in TFA (2 mL) was treated with EtsSIH (151 mg, 1.3 mmol). The mixture was stirred at room température for 1h. The mixture was concentrated and the residue triturated with toluene (2 x 10 mL). The residue was dissolved in EtOH (8 mL) and treated with conc. NH₄OH (2 mL). The mixture was stirred at RT for 2 h and concentrated. The residue was dissolved in DCM and washed sequentially with water and brine, dried (MgSCU), filtered and concentrated. The crude material was purified by chromatography (silica, MeOH-EtOAc = 0-10%) to give the titie compound (100 mg, 86%). SFC method: Chiral Tech AD-H 250 mm x 4.6

150 mm x 5 pm, CO2/MeOH (0.2% isopropyl amine) 5 to 60%, 3.0 mL/min, column température 15°C, RT=6.29 min (30.15%) and 8.38 min (69.20%), 99.37%ee; ¹H NMR (400 MHz, CD3OD) δ 7.65 (s, 1H), 7.51 (s, 1H), 3.70 - 3.56 (m, 4H), 3.42 - 3.34 (m, 1H), 3.26 (d, 3H), 3.19 - 3.02 (m, 3H), 2.79 (d, 1H), 2.64 - 2.49 (m, 2H), 2.45 (s, 2H), 2.35 (s, 1H), 2.34 - 2.22 (m, 2H), 1.31 (s, 3H), 1.25-1.15 (m, 2H), 1.12 (d, 2H), 0.44 (dd, 1H), 0.27 (t, 1H); LC/MS m/z (M+H)⁺ = 449.5.

Example 4: (R)-/V-methvl-/V-(6-methvl-2-((4aS,5aR)-5a-methvl-1,4,4a,5,5a,6hexahvdrocvcloproparflindazol-3-vl)-1H-benzo[d1imidazol-5-vl)-2-(tetrahvdro-2H-pyran

4-vl)propanamide

Step 1: (R)-A/-methyl-A/-(6-methvl-2-((4aS,5aR)-5a-methyl-1-((2(trimethylsilvl)ethoxv)methyl)-1,4,4a,5,5a,6-hexahvdrocvcloproparf|indazol-3-vl)-1/-/benzo[d1imidazol-5-yl)-2-(tetrahvdro-2H-pvran-4-yl)propanamide

A solution of Préparation 46 (120mg, 0.274 mmol) in THF (5 mL) was treated with /PraNEt (100 pL, 0.55 mmol), Préparation 22 (86.8 mg, 0.55 mmol) and 2-chloro-1methylpyridinium iodide (140 mg, 0.548 mmol). The mixture was heated at 60 °C for 16 h. Water (10 mL) was added and the mixture extracted with EtOAc (2 x 20 mL). The combined organic extracts were concentrated and the residue purified by silica gel chromatography (silica, EtOAc/PE = 0-85%) to give the title compound (165 mg, quant.). NMR (400 MHz, CD3OD) δ 7.52 (s, 2H), 5.55 - 5.43 (m, 2H), 3.91 (t, 2H), 3.64 (t, 2H), 3.48 - 3.34 (m, 3H), 3.25 (dd, 3H), 3.21 - 3.11 (m, 3H), 2.79 (d, 1 H), 2.42 2.35 (m, 3H), 2.20-2.10 (m, 1H), 2.01 - 1.91 (m, 1H), 1.82- 1.72 (m, 1H), 1.60 (t, 2H), 1.33 (s, 3H), 1.17 (dd, 1 H), 1.12 (d, 1H), 1.06 - 0.99 (m, 2H), 0.95-0.85 (m, 2H), 0.46 (dd, 1H), 0.28 (t, 1H), -0.02 (d, 9H); LC/MS m/z (M+H)⁺= 578.3.

151

Step 2: (R)-A/-methyl-A/-(6-methyl-2-((4aS,5aR)-5a-methyl-1,4,43,5,53,6hexahvdrocvclopropa[flindazol-3-vl)-1 H-benzo[d1imidazol-5-vl)-2-(tetrahvdro-2H-pvran4-yl)propanamide

A mixture of the silyl ether of Step 1 (3.7 g, 6.4 mmol) in TFA (45.7 mL) and EtaSiH (3.72 g, 32.0 mmol) was stirred at RT for 3 h and the mixture was concentrated. The residue was treated with sat. aq. NaHCOs until the pH=8 and extracted with EtOAc (2 x 30 mL). The extracts were combined, dried (MgSÛ4), filtered and concentrated. The crude product was purified by prep HPLC (YMC triart C18 250 x 50 mm x 7 μΜ, water (0.05% NI-UOHJ/MeCN from 26 to 66% over 10 min, 60 ml/min) to give the title compound (1.86 g, 64.9%). SFC method: Chiral Tech OD-3 100 mm x 4.6 mm x 3 pm, CO2/EtOH (0.05% ) 5 to 40%, 1.5 mL/min, column température 35 ’C, rétention time = 3.47 min (41.5%) and 3.55 min (58.5%), 100%ee; ¹H NMR (400 MHz, CD₃OD) δ 7.52 (s, 2H), 3.99 - 3.66 (m, 2H), 3.46-3.34 (m, 3H), 3.26 (d, 3H), 3.20 - 3.11 (m, 2H), 3.08 (d, 1H), 2,79 (d, 1H), 2.38 (d, 3H), 2.16 (t, 0.5H), 1.99 (dd, 0.5H), 1.78 (ddt, 1H), 1.60 (t, 2H), 1.31 (s, 3H), 1.18 (dt, 1H), 1.12 (d, 1H), 1.07-0.95 (m, 3H), 0.43 (dd, 1H), 0.27 (t, 1 H); LC/MS m/z (M+H)⁺ = 448.3.

Example 5: A/-methvl-A/-(6-methyl-2-((4aS,5aR)-5a-methvl-1,4,4a,5,5a,6hexahvdrocvcloproparf|indazol-3-vl)-1H-benzordlimidazol-5-vl)-2-(tetrahvdro-2H-pvran4-yi)propanamide

Example 5 was prepared analogously to Example 4 from Préparation 46 (100 mg) and 72 mg (±)-2-(tetrahydro-2H-pyran-4 yl)propanoic acid and purified by Prep-HPLC (Phenomenex Gemini-NX C18 150 mm x 30 mm x 5 μΜ, Water (0.04% NH4OH)/MeCN from 26 to 66% over 9 min, 25 ml/min) to give the title compound (63 mg, 51%). SFC method: Chiral Tech OD-3 100 mm x 4.6 mm x 3 μm, COs/EtOH (0.05% ) 5 to 40%, 2.8 mL/min, column température 35 ’C, rétention time = 3.39 min (15.8%), 3.46 min k 152 (26.0%), 3.54 min (35.6%) and 3.76 min (22.43%); ¹H NMR (400 MHz, CD3OD) δ 7.57 (d, 1H), 7.47 (d, 1H), 4.00-3.80 (m, 2H), 3.47-3.35 (m, 4H), 3.29-3.22 (m, 3H), 3.15 (dd, 1H), 3.08 (d, 1H), 2.79 (d, 1H), 2.38 (d, 3H), 2.16 (dd, 0.5H), 1.99 (t, 0.5H), 1.90 1.69 (m, 1H), 1.60 (t, 2H), 1.31 (m, 4H), 1.17 (dq, 1H), 1.11 (dd, 1 H), 1.03 (d, 2H), 0.43 (dd, 1 H), 0.27 (q, 1 H); LC/MS m/z (M+H) = 448.3.

Example 6: (S)-AFethyl~/V-(6-methvl-2-((4aS,5aR)-5a-methyi-1,4,4a,5,5a,6hexahvdrocvclopropa[f|indazol-3-vl)-1H-benzo[d1imidazol-5-vl)-2morpholinopropanamide

Step 1: (S)-N-ethvl-N-(6-methvl-2-((4aS,5aR)-5a-methyl-1-((2(trimethvIsilvDethoxvÎmethvD-IZ^a.S.Sa.S-hexahydrocvclopropalflindazol-S-vD-IHbenzold1imidazol-5-vl)-2-morpholinopropanamide

A solution of Préparation 67 (200 mg, 0.44 mmol) in pyridine (4.43 mL) at was treated wtih Préparation 19 (162 mg, 1.02 mmol) and EDCI (170 mg, 0.89 mmol). The mixtuire was stirred for 96 h, then was heated at 80 °C for an additional 24 h. The mixture was diluted with water and the mixture extracted with EtOAc (2 x 20 mL). The organic extracts were combined, dried (Na2SO4), filtered and concentrated. The crude material was purified by chromatography (silica, EtOAc/PE 0-100% then MeOH/DCM = 0-10%) to give the title compound (78 mg, 30%). LC/MS m/z (M+H)⁺ = 593.5.

Step 2: (S)-/\/-ethvl-A/-(6-methvl-2-((4aS,5aR)-5a-methvl-1,4,43,5,53,6hexahvdrocvcloproparf|ind3zol-3-vl)-1H-benzofdlimid8zol-5-vl)-225 morpholinopropanamide

153

A solution of the silyl ether of Step 1 (78 mg, 0.132 mmol) in TFA (1.5 mL) at 0-5 °C was treated with EtaSiH (80 mg, 0.69 mmol) . After stirring at 15 °C for 2 h, the solvent was removed and the reaction made basic with sat. aq. NasCOa. The mixture was extracted with premixed DCM/MeOH (10:1, 8 mL x 3) and the extracts combined. The concentrated and the residue purified by prep HPLC [YMC-Actus Triart Prep C18 150 mm x 30 mm x 5 μΜ, water (0.05% NH4OH)/MeCN from 43 to 63% over 10 min, 35 ml/min] to give the title compound (35 mg, 57%). SFC method: Chiral Tech AD-3 50 mm x 4.6 mm x 3 pm, COs/EtOH (0.05%) isocratic 40%, 4 mL/min, column température 35’C, rétention time = 0.45 min (51.01%) and 1.39 (48.99%), 100%ee; Ή NMR (400 MHz, DMSO-de) δ 12.88 (s, 1 H), 12.60 (d, 1H), 7.69-7.46 (m, 0.75H), 7.41 -7.33 (m, 1.25H), 4.11 (tq, 1 H), 3.51 - 3.42 (m, 2H), 3.11 - 2.94 (m, 5H), 2.74 (d, 1H), 2.46 (s, 2H), 2.35 (s, 3H), 2.22 (d, 2H), 2.12 - 2.04 (m, 1H), 2.02 (s, 1H), 1.25 (s, 3H), 1.13 0.91 (m, 7H), 0.37 (dd, 1H), 0.16 (d, 1H); LC/MS m/z (M+H)⁺ = 463.2.

Example 7: (R)-/\/-methyl-Λ/-(2-((4aS,5aR)-5a-methyl·1,4,4a,5,5a,6hexahvdrocvcloproparf|indazol-3-vl)-1H-benzoid'limidazol-5-vl)-2-(tetrahydro-2/-Fpvran4-vl)propanamide

Step 1 : (R)-/V-methvl-A/-(2-((4aS,5aR)-5a-methYl-1-((2-(trimethvlsilvl)ethoxv)methyl)1,4,4a_l5,5a_l6-hexahvdrocvclopropa[f|indazol-3-vl)-1/-/-benzo[d1imidazol-5-vl)-2(tetrahydro-2/-/-pvran-4-vl)propanamide

154

A solution of Préparation 55 (6.9 g, 16.3 mmol) and Préparation 22 (2.83 g, 17.9 mmol) in pyridine (163 mL) at RT was added EDCI (6.24 g, 32.6 mmol). The mixture was stirred at 25 °C for 16 h and diluted with water (150 mL) and brine (150 mL). The resulting aqueous mixture was extracted with EtOAc (2 x 300 mL) and the extracts dried (Na2SÛ4), filtered and concentrated. The crude material was purified by chromatography (silica, EtOAc/PE = 0-90%) to give the title compound (6.9 g, 75% yield). ¹H NMR (400 MHz, CDsOD) δ 7.77 (s, 0.5 H), 7.65 - 7.51 (m, 1 H), 7.40 (s, 0.5H), 7.14 (bs, 1H), 5.56 - 5.37 (m, 2H), 3.94 - 3.77 (m, 2H), 3.63 (t, 2H), 3.45 - 3.06 (m, 8H), 2.78 (d, 1H), 2.31 - 2.10 (m, 1H), 1.83 - 1.68 (m, 1H), 1.60 (d, 2H), 1.32 (s, 3H), 1.28-1.11 (m, 2H), 1.05 (d, 3H), 0.98-0.87 (m, 3H), 0.45 (dd, 1H), 0.27 (t, 1H), -0.03 (s, 9H); LC/MS m/z (M+H)⁺= 564.2.

Step 2: (R)-/V-methyl-A/-(2-((4aS,5aR)-5a-methvH,4,4a,5,5a,6hexahvdrocvclopropa[flindazol~3-vl)-1H-benzo[d1imidazol-5-vl)-2-(tetrahvdro-2H-pvran4-vl)propanamide

A solution of the silyl ether of Step 1 (6.9 g, 12.2 mmol) in TFA (122 mL) at 25 °C was treated with EtaSiH (7.12 g, 61.2 mmol). After stirring for 3 h, the mixture was concentrated and made basic with sat. sq. NaHCOa. The resulting mixture was extracted with EtOAc (2 x 100 mL). The organic extracts were dried (Na2SO4), filtered and concentrated. The crude material was purified by chromatography (silica, EtOAc/PE, 10-100%). The résultant material was purified further by chiral SFC (CO2/MeOH+ 1% NH4OH, Daicel OJ, 250 mm x 50 mm x 10 pm) to give the final product (3.43 g, 64.6%). ¹H NMR (400 MHz, CD3OD) δ 7.79-7.41 (m, 2H), 7.17 - 7.05 (m, 1H), 3.87 (td, 2H), 3.41-3.28 (m, 6H), 3.20 - 3.00 (m, 2H), 2.78 (d, 1H), 2.22 (dq, 1H), 1.75 (q, 1H), 1.60 (d, 2H), 1.29 (s, 3H), 1.24-1.12 (m, 2H), 1.05 (d, 3H), 1.00-0.88 (m, 1H), 0.42 (dd, 1H), 0.26 (t, 1H).; LC/MS m/z (M+H)⁺ - 434.3; analytical SFC (ChiralCel OJ-H 150 mm x 4.6 mm x 5 pm, COz/EtOH (0.05%DEA), 5 to 40%), rétention time = 4.91 min (100%).

155

Example 8: /v-methyl-A/-(2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahvdrocvclopΓOpaΓf|indazol·3-vl)-1H-benzoldlim^dazol-5-vl)-2-(tetΓahvdro-2H-pvran4-vl)propanamide

Example 8 was prepared analogously to Example 7 from Préparation 55 (350 mg) and (±)-2-(tetrahydro-2H-pvran-4-vl) propan oie acid (131 mg) and purified by prep HPLC (YMC-Actus Triart C18, 100 x 30 mm x 5 pm, H₂0/MeCN+0.05% NH₄OH, 38%-58% over 10 min) to deliver the title compound (150 mg, 39.4%). ¹H NMR (400 MHz, CD3OD) δ 7,79-7.38 (m, 2H), 7.13 (dd, 1 H), 3.87 (t, 2H), 3.41-3.33 (m, 3H), 3.31 (s, 3H), 3.19-3.10 (m, 1H), 3.07 (d, 1H), 2.78 (d, 1H), 2.21 (dq, 1H), 1.84 - 1.68 (m, 1H), 1.60 (d, 2H), 1.29 (s, 3H), 1.27 - 1.10 (m, 2H), 1.05 (d, 3H), 0.95 (qd, 1H), 0.42 (dd, 1 H), 0.26 (t, 1 H).; LC/MS m/z (M+H)⁺ = 434.3.;

Example 9: (S)-/V-methvl-A/-(2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahvdrocvclopropa[f|indazol-3-vl)-1/-/-benzo[dlimidazol-5-vl)-2-(tetrahvdro-2H-pyran4-yl)propanamide

Example 9 was prepared analogously to Example 7 from Préparation 55 (296 mg) and (S)-24tetrahydro-2H-Dvran-4-vl)propanoic acid (111 mg) and purified by Prep-HPLC (YMC-Actus triart C18, 100 x 30 mm x 5pm, H₂O/MeCN (0.05% NH4OH), 38 to 58% over 10 min) to give the title compound (102 mg). 'Ή NMR (400 MHz, CD3OD) δ 7.817.34 (m, 2H), 7.11 (dd, 1H), 3.86 (ddd, 2H), 3.41 - 3.31 (m, 3H), 3.31 (s, 3H), 3.13 (dd, 1H), 3.05 (d, 1H), 2.76 (d, 1H), 2.20 (dq, 1H), 1.73 (td, 1H), 1.58 (dd, 2H), 1.28 (s, 3H), 1.25-1.10 (m, 2H), 1.03 (d, 3H), 0.93 (qd, 1H), 0.40 (dd, 1H), 0.24 (t, 1H).; Chiral SFC (ChiralCel OJ-H 150 x 4.6 mm x 5 pm, CO₂/EtOH (0.05%DEA), 5 to 40%), rétention time =3.60 min.

156

Example 10: /V-methyl^/V-të-tMaS,5aR)-5a-methvi-1.4.43,5^ hexahvdrocyclopropa[f]indazol-3-vl)-1 H-benzo[dlim[dazol-5-yl)-2-(tetrahydro-2/-/ pyran4-vl)acetamide

Example 10 was prepared analogously to Example 7 from Préparation 55 (200 mg) and 2-(tetrahydro-2H-pyran-4-yl)acetic acid (82 mg) and purified by chiral SFC (Daicel Chiralcel OJ-H (250 mm x 30 mm x 5 pm), COa/EtOH w/ 0.1% NH4OH, 25% isocratic) to give the title compound (71 mg). ¹H NMR (400 MHz, CD3OD) δ 7.75-7.39 (m, 2H), 7.13 (d, 1H), 3.83 (dd, 2H), 3.41 - 3,32 (m, 4H), 3.14 (dd, 1H), 3.07 (d, 1H), 2.78 (d, 1H), 2.15 - 1.92 (m, 3H), 1.57 (d, 2H), 1.30 (s, 3H), 1.23 - 0.99 (m, 3H), 0.42 (dd, 1H), 0.26 (t, 1H); LC/MS m/z (M+H)⁺ = 420.3.

Example 11: 2,2-difluoro-/\/-methvl-/\/-(2-((4aS,5aR)-5a-methvl-1,4,43,5,53,6hex8hvdΓocyclopropaΓf|indazol·3-vl)-1H-benzo[d1imidazol-5-vl)-2-(tetr3hvdro-2/-/-pvran4-yl)acetamide

Example 11 was prepared analogously to Example 7 from Préparation 55 (200 mg) and 2,2-difluoro-2-(tetrahydro-2H-pyran-4-yl)acetic acid (170 mg) and purified by chiral SFC (Daicel Chiralcel OJ-H, 250 mm x 30 mm x 5 pm; CO2/EtOH (0.1% NH4OH), 25% isocratic) to give the title compound (60 mg). ¹H NMR (400 MHz, DMSO-de) δ 12.89 (s, 1H), 12.73 (d, 1H), 7.62 (d, 0.5H), 7.55 (d, 0.5H), 7.42 (d, 0.5H), 7.31 (s, 0.5H), 7.13 7.04 (m, 1H), 3.87 - 3.74 (m, 2H), 3.47-3.31 (m, 2H), 3.25 (s, 3H), 3.18 (t, 2H), 3.04 2.92 (m, 2H), 2.72 (d, 1H), 2.35-2.14 (m, 1H), 1.49 (d, 2H), 1.31-1.19 (m, 5H), 1.15 1.00 (m, 1H), 0.36 (dd, 1H), 0.14 (t, 1 H).; LC/MS m/z (M+H)⁺ = 582.3.

157

Example 12: (R)-/v-(7-fluoro-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahvdrocvclopropa[f]indazol-3-vl)-1 H-benzoΓd1imidazol-5-vl)-Λ/-methvl·2-(tetrahvdro2H-pyran-4-yl)propanamide

Step 1 : (R)-A/-(7-fluoro-2-((4aS.5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxv)methvl)1.4,4a,5,5a,6-hexahvdrocyclopΓOpaΓflindazol-3-vΠ-1H-benzoΓdlimidazol-5-vll·/V-methvl·

2-(tetrahvdro-2H-pvran-4-vl)propanamide

A solution of Préparation 57 (3,0 g, 6.79 mmol) in pyridine (67.9 mL) at 25 °C was added Préparation 22 (1.50 g, 9.51 mmol) and EDCI (2.87 g, 14.9 mmol). The mixture was stirred at 25 °C for 16 h and concentrated. The residue was diluted with water and extracted with EtOAc (5 x 100 mL). The organic extracts were combined, dried (Na₂SO4), filtered and concentrated. The crude matériel was purified by chromatography (silica, EtOAc/PE = 0-50%) to give the title compound (2.3 g, 58.2%). ¹H NMR (400 MHz, CD₃OD) δ 7.26 (bs, 1H), 6.97 (d, J = 10.9 Hz, 1H), 5.59 - 5.37 (m, 2H), 3.89 (td, J = 12.4, 11.9, 4.1 Hz, 2H), 3.63 (t, J = 7.9 Hz, 2H), 3.49 - 3.30 (m, 6H), 3.25 - 3.09 (m, 2H), 2.78 (d, J = 16.3 Hz, 1H), 2.24 (dq, J = 9.2, 6.7 Hz, 1H), 1.84 1.67 (m, 1H), 1.61 (d, J = 13.2 Hz, 2H), 1.36 - 1.13 (m, 6H), 1.07 (d, J = 6.8 Hz, 3H), 0.94 - 0.85 (m, 2H), 0.45 (dd, J = 8.9, 4.6 Hz, 1H), 0.27 (t, J = 5.1 Hz, 1H), -0.02 (s, 9H); LC/MS m/z (M+H)⁺ = 582.3.

Step 2: (R)-A/-(7-fluoro-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahvdrocvclopropa[f1indazol-3-yl)-1/-/-benzofdlimidazol-5-yl)-A/-methvl-2-(tetrahvdro2H-pyran-4-yl)propanamide

158

A solution of the silyl ether of step 1 (2.30 g, 3.95 mmol) in TFA (39.5 mL) at 5 °C was treated with EtaSiH (2.30 g, 19.8 mmol). After stirring 3 h at RT, the mixture was concentrated and the residue diluted with sat. aq Na2CO3. The mixture was extracted with EtOAc (2 x 30 mL) and the organic extracts combined, dried (Na2SO4), filtered and concentrated. The crude material was purified by chromatography (silica, EtOAc/PE = 20-100%). The compound was taken up in MeCN (10 mL), EtOH (10 mL) and H2O (150 mL) and lyophilized to give the title compound (1.78 g, 99%). ¹H NMR (400 MHz, CD3OD) δ 7.25 (s, 1H), 6.95 (d, 1H), 3.95 - 3.78 (m, 2H), 3.43 - 3.25 (m, 6H), 3.20 3.11 (m, 1H), 3.07 (d, 1H), 2.78 (d, 1H), 2.30 - 2.12 (m, 1H), 1.75 (q, 1H), 1.60 (t, 2H), 1.30 (s, 3H), 1.25-1.11 (m, 2H), 1.06 (d, 3H), 0.98 (dt, 1H), 0.42 (dd, 1H), 0.25 (t, 1 H).; LC/MS m/z (M+H) = 452.3.

Example 13: (S)-A/-(2-((4aS_l5aR)-5,5-dÎfluoro-5a-methyl-1,4,4a,5.5a,6hexahvdrocvclopropa[f|indazol-3-vl)-1/7-benzoid1imidazol-5-vl)-/V-methyl-2morpholinopropanamide

Step 1 : (4aS₁5aR)-A/-(2-amino-5-((S)-A/-methvl-2-morpholinopropanamido)phenyl)-5,5difluoro-5a-methyl-1.4,4a,5,5a,6-hexahydrocvcloproparf1indazole-3-carboxamide

159

To a solution of Préparation 68 (700 mg, 3.07 mmol) in DMF (40 mL) at RT was treated with HBTU (1.75 g, 4.60 mmol), DMAP (37.5 mg, 0.31 mmol), iPrzNEt (1.19 mg, 9.2 mmol) and 32 (854 mg, 3.07 mmol). The mixture was stirred at 80 °C for 16 h and diluted with sat. aq. NaHCOs (100 mL). The aqueous was extracted with EtOAc (4 x 100 mL) and the organic layers combined, dried (Na2SO4), filtered and concentrated. The crude product was purîfied by chromatography (silica, EtOAc/PE = 0-100%, then EtOAc/EtOH 3:1) to give the title compound (850 mg, 57%). LC/MS m/z (M+H)⁺ = 488.9.

Step 2: (S)-/X/-(2-((4aS,5aR)-5_l5-difluoro-5a-methyl-1,4,43,5,53,6hexahvdrocycloproparflindazol-3-yl)-1 H-benzo(d1imidazol-5-yl)-/V-methvl-2morpholinopropanamide

A mixture of the amide of step 1 (850 mg, 1,74 mmol) and AcOH (50 mL) was stirred at 90 °C for 16 h and concentrated. The residue was diluted with EtOAc (50 mL) and washed with saturated NazCOs. The aqueous layer was extracted with EtOAc (4 x 100 mL). The organic extracts were combined and concentrated. The residue was purîfied by prep-HPLC (Xtimiate C-18 150 x 25 mm x 5 pm, H2O/CH3CN (0.225% FA), 20 40% over 8 min) to give the title compound (289 mg, 35%). ¹H NMR (400 MHz, CD3OD) δ 7.75-7.49 (m, 2H), 7.18 (d, 1H), 3.70 - 3.56 (m, 4H), 3.33 (s, 3H), 3.23 (q, 1H), 3.14 (d, 1H), 2.86 (dd, 1H), 2.56 (dt, 2H), 2.40 (dd, 2H), 1.83 - 1.67 (m, 1H), 1.43 (d, 3H), 1.18 (d, 3H); LC/MS m/z (M+H)⁺ = 435.3.

Example 14: (S)-A/-methvl-/V-(2-((4aS,5aR)-5a-methyl-1,4,43,5,5a,6hexahvdrocvclopropa[flindazol-3-yl)-1/7-benzoid1imidazol-5-vl)-2morpholinopropanamide

160

Step 1 : (S)-A/-methvl-A/-(2-((4aS,5aR)-5a-methvÎ-1((2-(trimethyisilvl)ethoxv)methvl)1 _l4,4a,5,5a,6-hexahvdrocvclopropafflindazol-3-vl)-1/-/-benzordlimidazol-5-yl)-2morpholinopropanamide

A mixture of Préparation 32 (1.53 g, 5.5 mmol), Préparation 9 (1.69 g, 5.5 mmol) in

EtOH (27.5 mL) and water (2.75 mL) was treated with Na₂S₂O3 (1.14 g, 11.0 mml). The mixture was heated at 90 °C for 2 h. The mixture was concentrated and residue diluted with EtOAc and H₂O. The layers were separated and the aqueous layer extracted with 10 EtOAc (2 x). The organic extracts were combined, dried (Na₂SO4), filtered and concentrated. The crude product was purified by chromatography (silica, EtOAc/Heptanes = 10-100%, then EtOAc/MeOH = 0-15%) to give the title compound (2.41 g, 78%). LC/MS m/z (M+H)⁺ = 565.5.

Step 2: (S)-/V-methvl-/V-(2-((4aS,5aR)-5a-methyl-1.4,4a,5,5a,6hexahvdrocvclopropaiflÎndazol-3-vl)-1H-benzo[d1imidazol-5-vl)-2morpholinopropanamide

A solution of the silyl ether of step 1 (2.41 g, 4.26 mmol) in DCM (12.8 mL) at 0 °C was 20 treated wtih TFA (8.61 mL) and stirred at RT for 18 h. The mixture was concentrated and the residue dissolved in THF/MeOH and the pH adjusted to -10 with solid K2CO3. The mixture was diluted in 10%MeOH in DCM and washed with brine. The aqueous layer was extracted with 10%MeOH in DCM. The organic extracts were combined, dried, filtered and concentrated. The crude product was purified by chiral SFC

161 (Chiralcel OJ, 30 mm x 250 mm x 5 pm, CO2/MeOH (0.2% NH3), isocratic 25% over 10 min) to give the title compound (0.89 g, 48%). ¹H NMR (400 MHz, DMSO-cfe) δ 12.93 12.87 (m, 1H), 12.73 (d, J = 5.9 Hz, 1H), 7.63 (d, J = 8.4 Hz, 0.5H), 7.55 (s, 0.5H), 7.44 (d, J = 8.3 Hz, 0.5H), 7.35 (s, 0.5H), 7.07 (t, J = 9.9 Hz, 1H), 3.50 - 3.41 (m, 5H),3.233.13 (m, 4H), 2.98 (dd, J = 16.2, 8.6 Hz, 2H), 2.72 (d, J = 16.1 Hz, 1H), 2.46-2.35 (m, 2H), 2.31 - 2.11 (m, 2H), 1.23 (s, 3H), 1.15- 0.88 (m, 4H), 0.36 (dd, J = 8.8, 4.3 Hz, 1H), 0.14 (s, 1H).; LC/MS m/z (M+H)⁺ = 435.3.; Chiral SPC (Lux Cellulose-2, 150 x 4.6 mm x 3 pm, CO2/EtOH (0.1% ethanolamine, 1 to 40% EtOH) rétention time = 2.96 min

Example 15: (S)-A/-(7-fluoro-2-((4aS,5aR)-5a-methyl-1,4,4a_T5,5a,6hexahvdrocyclopropa[f]indazol-3-vl)-1H-benzo[dl!midazol-5-vl)-/\/-methvl-2morpholinopropanamide

Step 1 : (S)-/V-(4-fluoro-2-((4aS,5aRT5a-methvl-1-((2-(trimethvlsilvl)ethoxv)methyl)1,4,4a,5,5a.6-hexahydrocvclopropafflindazol-3-vl)-1-(ï2-(trimethvisilvl)ethoxy)methyl)1 H-benzofd1imidazol-6-vl)-Λ/-methvl·2··morpholinopropanamide and (S)-A/-(7-fluoro-2((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxv)methvl)-1,4,4a, 5,5a, 6hexahvdrocycloproparf|indazol-3-vl)-1-((2-(trimethvlsilvl)ethoxv)methyl)-1Hbenzord1imidazol-5-yl)-/V-methyl-2-morpholinopropanamide

A mixture of Préparations 74a and 74b (mg, 0.19 mmol) in pyridine (2.77 mL) at 15 °C was treated with 19 (45.6 mg, 0.23 mmol) and EDCI (74.4 mg, 0.39 mmol). The mixture was stirred for 16 h. The mixture was diluted with water and extracted with EtOAc (2 x 20 mL). The organic extracts were combined, dried (Na2SO4), filtered and concentrated to give the title compounds as a mixture (131 mg, 95 %). LC/MS m/z (M+Na)⁺= 735.1

162

Step 2: (S)-/V-(7-fluoro-2-((4aS,5aR)-5a-methyl-1,4.4a,5.5a.6hexahvdrocyclopropaff]indazol-3-vl)-1 H-benzo|'d^imιdazol-5-vl)-/V-methvl·2morphoÎinopropanamide

A mixture of the silyl ethers of step 1 (131 mg, 0.18 mmol) in TFA (1.84 mL) at 10 °C was treated wtih EtsSIH (107 mg, 0.92 mmol). After stirring 3 h, the mixture was concentrated and the residue made basic with sat. aq. Na2CÜ3. The mixture was extracted with EtOAc (3x15 mL) and the extracts combined. The solvent was removed and the residue was purified by prep HPLC (H2O: MeCN, 0.05% TFA) to give the title 10 compound (37 mg, 45%). ¹H NMR (400 MHz, CD3OD) δ 7.34 (s, 1H), 7.04 (d, 1H), 4.61 (s, 1H), 3.62 (ddd, 4H), 3.30 (s, 3H), 3.37 (d, 1H), 3.23 (q, 1H), 3.19 - 3.10 (m, 1H), 3.07 (d, 1H), 2.78 (d, 1H), 2.54 (dt, 2H), 2.36 (dt, 2H), 1.30 (s, 3H), 1.17 (d, 3H), 0.42 (dd, 1 H), 0.25 (t, 1 H); LC/MS m/z (M+H)⁺ = 453.3

Example 16: (S)-/V-ethyl-/\/-(7-fluoro-2-((4aS.5aR)-5a-methvl-1,4,4a,5.5a.6hexahydrocvclopropa[f|indazol-3-y[)-1 H-benzo[d]imidazol-5-yl)-2morpholinopropanamide

Step 1: (S)-A/-ethyl-A/-(4-fluoro-2-((4aS,5aR)-5a-methyl-1-((220 (trimethvlsilvl)ethoxy)methvl)-1,4_l4a,5,5a,6-hexahvdrocvclopropa[f1indazol-3-vl)-1-((2(trimethvlsilvl)ethoxv)methvl)-W-benzo[dlimidazol-6-vl)-2-morpholinopropanamide and (S)-A/-ethvl-/V-(7-fluoro-2-((4aS,5aR)-5a-methvl-1-((2-(trimethvlsilvl)ethoxv)methvl)1 _i4,4a,5,5a,6-hexahvdrocvclopropa[f|indazol-3-vl)-1-((2-(trimethvlsilvl)ethoxv)methyl)1/-/-benzord1imidazol-5-yl)-2-morpholinopropanamide

163

A mixture of Préparations 76a and 76b (6.14 g, 10.48 mmol) and 19 (1.46 g, 9.17 mmol) in pyridine (70 mL) at 30 °C was treated with EDCI (4.02 g, 21.0 mmol). After stirring for 16 h the solvent was removed and water was (80 mL) was added. The mixture was extracted with EtOAc (2 x 80 mL) and the organic extracts combined, dried (Na2SO4), filtered and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE = 0-50%) to give the title compounds as a mixture (5.13 g, 67%). LC/MS m/z (M+H) = 727.4

Step 2: (S)-/V-ethyl-/V-(7-fluoro-2-((4aS,5aR)-5a-methvl-1,4,4a,5,5a,6hexahvdrocvclopropaff]indazol-3-vl)-1H-benzo[d1imidazol-5-yl)-2morpholinopropanamide

A mixture of the silyl ethers of step 1 (5.13 g, 7.06 mmol) in TFA (35 mL) at 0 °C was treated with EtsSiH (4.1 g, 35.3 mmol). The mixture was stirred at 30 °C for 3 h. The mixture was concnetrated and the residue diluted with sat. aq. NaHCOs. The mixture was extracted with EtOAc (2 x 100 mL) and the organic extracts combined, dried (Na₂SO4), filtered and concentrated. The crude product was chromatographed (silica, EtOAc/PE = 0-50%. (2.66 g, 81%). The mixture was further purified by chiral SFC (Daicel Chiralpak AD, 250 mm x 50 mm x 10 pm; CO2/EtOH(0.1%NH4OH), 50% isocratic) to give the title compound (1.72 g, 52%). ¹H NMR (400 MHz, CD3OD) δ 7.31 (bs, 1H), 7.05 - 6.93 (m, 1H), 3.78 (s, 2H), 3.61 (ddd, 4H), 3.38 (d, 1H), 3.14 (dt, 2H), 3.06 (d, 1H), 2.76 (d, 1H), 2.53 (dt, 2H), 2.35 (dt, 2H), 1.28 (s, 3H), 1.20 - 1.11 (m, 7H), 0.40 (dd, 1H), 0.24 (t, 1H); LC/MS m/z (M+H)⁺ = 467.1.

164

Example 17: (S)-/v-(6-fluoro-2-((4aS,5aR)-5a-methyl-1,4.4a,5,5a.6hexahvdrocvcloproparf|indazol-3-vh-1H-benzordlimidazol-5-vl)-A/-methyl-2morpholinopropanamide

Step 1 : (S)-/V-(6-fÎuoro-2-((4aS_l5aR)-5a-methvl-1-((2-(trimethylsilvl)ethoxv)methyl)1.4,4a,5,5a.6-hexahvdrocvclopropa[flindazol·3-vO-1-((2-(trimethvlsilvl)ethoxv)methvO1 H-benzoΓdlimidazol·5-vlΐ-Λ/-methvl-2-moΓpholinoproDanamide and (S)-/\/-(5-fluoro-2((4aS,5aR)-5a-methvl-1-((2-(trimethvlsilyl)ethoxv)methvl)-1,4,4a,5,5a,6hexahvdrocycloproparflîndazol-3-vl)-1-((2-(trimethvlsilvl)ethoxv)methyl)-1/7benzofd1imidazol-6-vl)-/V-methvl-2-morpholinopropanamide

A mixture of Préparations 80a and 80b (170 mg, 0.29 mmol) in pyridine (4.95 mL) at 15 °C was treated with 19 (71 mg, 0.45 mmol) and EDCI (114 mg, 0.6 mmol). The mixtue was stirred for 2 days then diluted with water and extracted with EtOAc (2 x 20 mL). The organic extracts were collected, dried (Na2SO4), filtered and concentrated to give the title compounds as a mixture (180 mg, 85 %). LC/MS m/z (M+H)⁺ = 713.5

Step 2: (S)-A/-(6-fluoro-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocycloproparf^,|indazol-3-vl)-1/-/-benzo[d1imidazol-5-vl)-A/-methyl-2morpholinopropanamide

A mixture of the silyl ethers of step 1 (180 mg, 0.25 mmol) in TFA (2.52 mL) at 10 °C was treated withe EtsSiH (147 mg, 1.26 mmol). The mixture was stirred for 3 h and

165 concentrated. The mixture was made basic with sat. aq. NazCOa and extracted with EtOAc (3x8 mL). The combined extracts were concentrated and the residue was purified by prep HPLC (YMC-Triart Prep C18 150 mm x 40 mm x 7 μΜ, water (0.05% NH4OH)/MeCN from 42 to 62% over 10 min, 25 ml/min) to give the title compound (38 mg, 34%). Ή NMR (400 MHz, CD3OD) δ 7.72 - 7.39 (m, 2H), 3.69 - 3.50 (m, 4H), 3.39 (d, 1 H), 3.30 (d, 3H), 3.27 - 3.04 (m, 3H), 2.79 (d, 1 H), 2.54 (dt, 1 H), 2.41 (dd, 2H), 2.27 (ddd, 1H), 1.31 (s, 3H), 1.23 - 1.12 (m, 4H), 0.44 (dd, 1H), 0.27 (t, 1H); LC/MS m/z (M+H)⁺= 453.2.

Example 18: (S)-A/-(6-ethyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropaÎf|indazol-3-vl)-1/-/-benzordlimidazol-5-vl)-/V-methvl-2morpholinopropanamide

Example 18 was prepared analogously to Example 1 from 5-chloro-2-ethyl-4-nitroaniline to deliverthe title compound (50 mg, 57%). 1H NMR (400 MHz, CD3OD) δ 7.54 (s, 2H), 3.69 - 3.58 (m, 4H), 3.38 (d, 1 H), 3.27 (d, 3H), 3.20 - 3.01 (m, 3H), 2.87 - 2.72 (m, 1 H), 2.67 (q, 2H), 2.56 (d, 2H), 2.35 - 2.27 (m, 2H), 1.37 (dt, 3H), 1.31 (s, 3H), 1.19 (t, 2H), 1.11 (dd, J = 6.6, 1.7 Hz, 2H), 0.44 (dd, 1H), 0.28 (d, J = 5.6 Hz, 1H).; LC/MS m/z (M+H)⁺= 463.4.

Example 19: (S)-A/-(6-methoxv-2-((4aS.5aR)-5a-methvl-1,4,4a,5,5a,6hexahvdrocvclopropa[flindazol-3-vl)-1H-benzofdlimidazol-5-vl)-/\/-methvl·2morpholinopropanamide

Step 1 : (S)-/\/-(6-methoxv-2-((4aS,5aR)-5a-methvl·1-((2-(trimethvlsilvl)ethoxv)methvl)1.4.4a,5,5a,6-hexahvdrocyclopropamindazol-3-vl)-1H-benzofdlimidazol-5-yl)-/V-methyl· 2-morpholinopropanamide

166

A mixture of Préparation 84 (189 mg, 0.61 mmol), NazSaOs (126 mg, 0.66 mmol) in DMF (7.3 mL ) was treated with Préparation 9 (157 mg, 0.51 mmol). The mixture was heated in a microwave reactor at 150 °C for 2 h and poured into 3% aq. LiCI (20 mL) 5 and EtOAc (30 mL). The layers were separated and the aqueous layer extracted with

EtOAc (30 mL). The organic layers were collected, dried (NasSO^, filtered and concentrated. The crude product was chromatographed (silica, EtOAc/PE = 0-100%) to give the the title compound (201 mg, 44%). LC/MS m/z (M-»-H)⁺ = 595.3.

Step 2: (S)-/V-(6-methoxv-2-((4aS,5aR)-5a-methvl-1,4,4a,5,5a,6hexahvdrocvcloproparf]indazol-3-vl)-1H-benzo[dlimidazol-5-yl)-/\/-methvl-2morpholinopropanamide

A solution of the silyl ether of step 1 (201 mg, 0.338 mmol) in TFA (3.38 mL) at 0-5 °C 15 was treated with EtaSiH (196 mg, 1.69 mmol). The mixture was stirred at RT for 2 h and concentrated. The residue was made basic with sat. aq NaHCOs. The mixture was extracted with EtOAc (2 x 20 mL) and the extracts and concentrated. The residue was purified by prep HPLC (YMC Triart C18 150 mm x 30 mm x 7 μΜ, Water (0.05% NFUOHyMeCN from 25 to 75% over 10 min, 25 ml/min) to give the title compound (87 20 mg, 55%). Ή NMR (400 MHz, CD3OD) δ 7.56 (s, 1H), 7.28 (s, 1H), 3.94 (d, 3H), 3.63 (tq, 4H), 3.41 - 3.34 (m, 1H), 3.23 (d, 3H), 3.20 - 3.08 (m, 2H), 3.08 - 2.97 (m, 1H), 2.79 (d, 1H), 2.54 (dt, 1H), 2.44 (dt, 3H), 1.31 (s, 3H), 1.26 - 1.10 (m, 4H), 0.43 (dd, 1H), 0,27 (t, 1H); LC/MS m/z (M+H)⁺ = 465.2.

Example 20: (S)-A/-(6-bromo-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahvdrocvclopropaFflindazol-3-vl)-1/-/-benzofdlimidazol-5-vl)-A/-methvl-2morpholinopropanamide

A solution of Préparation 85 (100 mg, 0.155 mmol) in TFA (5.0 mL) at 0 °C was treated wtih EtaSiH (90.3 mg, 0.77 mmol). The mixture was stirred for 2 h and concentrated. The residue was dissolved in MeOH (10 mL) and treated with conc. NH4OH (1 mL).

The mixture was stirred at RT for 1 h and concentrated. The residue was purified by prep-HPLC (Boston Prime C18, 150 x 30 mm x 5 pm, H2O/MeCN (0.05% NH₄OH) 10 70% over 10 min) to give the title compound (61 mg, 76%). 'Ή NMR (400 MHz, DMSOde) δ 13.09 - 12.65 (m, 2H), 7.99-7.63 (m, 2H), 3.58 - 3.38 (m, 5H), 3.18 - 3.09 (m, 3H), 3.08 - 2.86 (m, 2H), 2.81 - 2.60 (m, 1 H), 2.46 - 2.28 (m, 2H), 2.24 - 1.91 (m, 2H),

IO 1.24 (s, 3H), 1.17 - 0.90 (m, 4H), 0.37 (dd, 1H), 0.15 (t, 1H).; LC/MS m/z (M+H)⁺ = 513.3/515.5 (⁷⁹Br, ⁸¹Br).

Example 21. (S)-/V-(6-cvano-2-((4aS,5aR)-5a-methvl-1,4,4a,5,5a,6hexahydrocvclopropa[flindazol-3-yl)-1/-/-benzoidlimidazol-5-vl)-A/-methyl-215 morpholinopropanamide

A mixture of Préparations 87a and 87b (150 mg, 0.21 mmol) in TFA (5 mL) was treated with EtsSiH (121 mg, 1.04 mmol) at 0 °C. The mixture was stirred for 2 h and concentrated. The residue was dissolved in MeOH (10 mL) and conc. NH₄OH (1 mL) was added. The mixture was stirred 1 h and the mixture was concentrated. The residue was purified by prep-HPLC (Boston Prime C18, 150 x 30 mm x 5 pm; H₂O/MeCN (0.2%FA), 23-45% over 10 min) to give the title compound (34 mg, 35%). ¹H NMR (400 MHz, DMSO-ds) δ 13.22-13.05 (m, 2H), 8.35 - 7.36 (m, 2H), 3.58 - 3.25 (m, 5H), 3.22 (d, 3H), 3.01 (dd, 2H), 2.80 - 2.56 (m, 2H), 2.44 - 2.27 (m, 2H), 2.12 - 1.90 (m, 2H), 1.25 (s, 3H), 1.18 - 0.95 (m, 34H), 0.38 (dd, 1H), 0.16 (t, 1H); LC/MS m/z (M+H)⁺ = 460.2.

) 168

Example 22: (S)-N-(7-fluoro-2-((4aS,5aR)-5a-methyl-1,4.4a,5,5a,6hexahvdrocvciopropaif|indazol-3-yl)-1 H-benzo[d1imidazol-5-v0-N-methyl-2-(3oxomorpholino)propanamide; and

Example 23: (R)-N-(7-fluoro-2-((4aS.5aR)-5a-methyl-1,4,4a,5.5a,65 hexahvdrocvclopropaffîindazol-S-vn-IH-benzofdlimidazol-S-vO-N-methvl^-Ooxomorpholinojpropanamide

Step 1 : A/-(4-fluoro-2-((4aS,5aR)-5a-methvl-1-((2-(trimethvlsilvl)ethoxv)methvt)1,4,4a,5.5a,6-hexahvdrocvcloDroparf|indazol-3-vl)-1-((2-(trimethvlsilvl)ethoxy)methvlÎ10 1 /-/-benzo[d1imidazol-6-yl)-/\/-methvl-2-(3-oxomorpholino)propanamide and A/-(7-fluoro2-((4aS,5aR)-5a-methyl-1 -((2-(trimethylsilyl)ethoxv)methyl)-1.4,4a,5,5a,6hexahvdrocvclopropaffîindazol-3-yl)-1-((2-(trimethvlsilvl)ethoxv)methyl)-1HbenzoÎd1imidazol-5-yl)-/\/-methvÎ-2-(3-oxomorpholino)propanamide

A mixture of Préparations 74a and 74b (150 mg, 0.26 mmol) and Préparation 26 (54.5 mg, 0.32 mmol) in pyridine (3.75 mL) at 25 °C was treated with EDCI (101 mg, 0.53 mmol). The mixture was stirred for 48h and diluted with water (20 mL). The mixture was extracted with EtOAc (3 x 20 mL). The organic extracts were combined, dried and concentrated to give the title compounds as a mixture (60 mg, 31%). LC/MS m/z (M+H)⁺ = 727.3.

Step 2: (S)-A/-(7-Îluoro-2-((4aS.5aR)-5a-methyl-1,4,4a,5,5a.6hexahvdrocvcloDroDarflindazol-3-yl)-1/-/-benzordlimidazol-5-vl)-/V-methyl-2-(3oxomorpholino)propanamide and (R)-A/-(7-fluoro-2-((4aS,5aR)-5a-methyl-1,4,43,5,53,625 hexahvdrocvcloproparf|indazol-3-vl)-1H-benzo[dlimidazol-5-vl)-A/-methvl-2-(3oxomorpholino)propanamide

169

A mixture of the silyl enol ethers of step 1 (85.0 mg, 0.12 mmol) in TFA (1.2 mL) at 5 °C was treated with EtsSiH (68.0 mg, 0.58 mmol). The mixture was stirred for 2 h and concentrated. The mixture was treated with sat. aq. NaHCOs and extracted with EtOAc 5 (3x8 mL). The organic extracts were combined, dried, filtered and concentrated and the residue was which was purified by prep-HPLC (Phenomenex Gemini NX-C18, 75 x 30 mm x 3 pm MeCN/H2O(0.225% FA), 29 - 49 % over 10 min). The mixture was separated by chiral SFC (Daicel ChiralPak AD, 250 mm x 30 mm x 10 pm, CO2/EtOH(0.1 % ΝΗλΟΗ), 55% isocratic) to give the title compounds with absolute 10 stereochemistry at C-2 methyl defined arbitrarily.

Example 22: ''H NMR (400 MHz, CD3OD) δ 7.44 - 7.40 (m 1H), 7.08 (d, 1H), 5.14 5.07 (m, 1H), 4.03 - 3.85 (m, 3H), 3.81 - 3.71 (m, 1H), 3.56 - 3.44 (m, 1H), 3.38 -3.25 (m, 4H), 3.14 (dd, 1H), 3.06 (d, 1H), 2.77 (d, 1H), 1.29 (s, 3H), 1.25 (d, 3H), 1.16 (dt, 15 1 H), 0.41 (dd, 1 H), 0.25 (t, 1H); LC/MS m/z (M+H)⁺= 467.1.

Example 23: ¹H NMR (400 MHz, CD3OD) δ 7.42 (s, 1H), 7.08 (d, 1H), 5.13 - 5.08 (m, 1 H), 4.00 - 3.86 (m, 3H), 3.82 - 3.70 (m, 1 H), 3.56 - 3.45 (m, 1 H), 3.39 - 3.24 (m, 4H), 3.14 (dd, 1H), 3.06 (d, 1H), 2.77 (d, 1H), 1.29 (s, 3H), 1.25 (d, 3H), 1.16 (dt, 1H), 0.41 20 (dd, 1H), 0.25 (t, 1H); LC/MS m/z (M+H)⁺ = 467.1.

Example 24: (S)-A/-(6,7-difluoro-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahvdrocycloproparf|indazol-3-vl)-1 H-benzo[dlimidazol-5-yl)-A/-methvl-2morpholinopropanamide

A mixture of Préparations 95a and 95b (3.26 g, 4.47 mmol) in TFA (45 mL) at 0 °C was treated with EtsSiH (2.60 g, 22.3 mmol). The mixture was stirred for 5 h and k 170 concentrated. The mixture was treated with sat. aq. NaHCOs and extracted with DCM (3 x 30 mL). The organic extracts were combined, dried, filtered and concentrated. The residue was chromatographed (silica, MeOH/EtOAc - 0-7%) and the isolated material dissolved in MeOH (30 mL)/H2O (50 mL). The solvent was removed by lyophilization to give the title compound (1.56 g, 69%). ¹H NMR (400 MHz, CDaOD) δ 7.56 - 7.30 (m, 1H), 3.67-3.46 (m, 4H), 3.44-3.22 (m, 5H), 3.22-3.09 (m, 1H), 3.06 (d, 1H), 2.77 (d, 1H), 2.58-2.29 (m, 3H), 2.19 (ddd, 1H), 1.29 (s, 3H), 1.15 (dd, 4H), 0.42 (dd, 1H), 0.24 (t, 1 H).; ¹⁹F NMR (377 MHz, CD3OD) δ -153.83.

Example 25: (S)-A/-(6.7-difluoro-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocvclopropafflindazol-3-yl)-1H-benzo[dlimidazol-5-vl)-/V-ethvl-2morpholinopropanamide

A mixture of Préparations 96a and 96b (120 mg, 0.16 mmol) in TFA (1.6 mL) at 5 °C 15 was treated with EtsSiH (93.6 mg, 0.81 mmol). The mixture was stirred 2 h and concentrated. The residue was diluted with sat. aq. NaHCOs (5 mL) and extracted with EtOAc (3 x 8 mL) The organic extracts were collected, dried, filtered and concentrated. The residue was purified by prep-HPLC (YMC Triart, 30 x 150 mm x 7 μπΊ, CH3CN/H2O (0.05% NH4OH), 46-66% over 10 min) to give the title compound (7.2 mg, 9%). ¹H 20 NMR (400 MHz, Methanol-ck) δ 7.41-7.26 (m„ 1H), 3.90 - 3.66 (m, 1H), 3.65 - 3.46 (m, 4H), 3.44-3.32 (m, 1H), 3.23-3.10 (m, 1H), 3.07 (d, 1H), 2.78 (d, 1H), 2.56-2.41 (m, 2H), 2.38 - 2.19 (m, 1H), 1.30 (s, 3H), 1.19 - 1.14 (m, 6H), 0.42 (dd, 1H), 0.25 (t, 1H); LC/MS m/z (M+H)⁺ = 485.1.

Example 26: 2-((S)-2-(hvdroxvmethvi)morpholino)-/V-methvl-/\/-(6-methvl-2-((4aS,5aRL

5a-methvl-1,4,4a,5,5a,6-hexahvdrocyclooropaîflindazol-3-vl)-1H-benzok/|imidazpl-5z vDacetamide

171

OH CH₃ 'tⁿvïywt ,- O A^An'vA.

h₃c h / y \Ί CH₃

Step 1: 2-((S)-2-(hvdroxvmethyl)morphoίino)-Λ/-methvl-Λ/-(6-methvl·2-((4aS,5a/^:?)-5arnethyl-1-((2-(trimethvlsilvl)ethoxv)methvl)-1 ,4,4a,5,5a,6-hexahvdrocyclopropa[f|indazol3-vl)-1-((2-(trimethvlsilyl)ethoxv)methvl)-1 H-benzo[d]imidazol-5-vhacetamide

A solution of Préparation 98 (130 mg, 0.20 mmol) and (S)-morpholin-2-ylmethanol (26 mg, 0.22 mmol) in MeCN (5 mL) was treated with Nal (40 mg, 0.27 mmol) and KgCOa (40 mg, 0.29 mmol). The mixture was heated at 80 °C for 16 h. The mixture was cooled to RT and concentrated. The residue was purîfied by chromatography (silica, EtOAc/PE = 0-100%, then MeOH/EtOAc = 0-20%) to give the title compound (108 mg, 74%). ¹H NMR (400 MHz, Chloroform-d) ô 7.71 (s, 1H), 7.36 (d, 1H), 6.22 - 6.07 (m, 1 H), 6.09 - 5.93 (m, 1 H), 5.42 (q, 2H), 3.94 - 3.73 (m, 4H), 3.71 - 3.37 (m, 8H), 3.26 (s, 3H), 3.19 - 3.01 (m, 2H), 2.96 - 2.68 (m, 4H), 2.34 (s, 4H), 1.38 - 1.27 (m, 3H), 1.17 1.01 (m, 2H), 0.91 (t, 2H), 0.87 - 0.73 (m, 2H), 0.40 (s, 1 H), 0.26 (d, 1 H), -0.02 (s, 9H), 0.11 (t, 9H); LC/MS m/z (M+H)⁺ = 725.4.

Step 2: 2-((S)-2-(hvdroxvmethvl)morDholino)-A/-methvl-A/-i6-methvl-2-((4aS,5aR)-5amethvl-1,4,4a,5,5a,6-hexahvdrocvclopropa[flindazol-3-vl)-1H-benzo[cf|imidazol-5yl)acetamide

A solution of the silyl ether of step 1 (108 mg, 0.149 mmol) in DCM (5 mL) at 15 °C was treated with TFA (1.5 mL). The mixture was stirred at 15 °C for 2 h and concentrated. The residue was taken up in MeOH (5 mL) and treated with conc. NH4OH (2 mL). The mixture was stirred at RT for 2 h. The mixture was concentrated and the residue purîfied by préparative HPLC (Welch Xtimate 75 mm x 40 mm x 3 pm, 16 to 56% MeCN k 172 in 0.05% NH4OH/water, 25 mL/min, 10 min) to give the title compound (16 mg, 23%). ¹H NMR (400 MHz, CDaOD) δ 7.68 - 7.39 (m, 2H), 3.77 (d, 1H), 3.72 - 3.52 (m, 2H), 3.52 - 3.40 (m, 2H), 3.40 - 3.33 (m, 2H), 3.24 (s, 3H), 3.19 - 2.93 (m, 3H), 2.86 - 2.59 (m, 4H), 2.35 (s, 3H), 2.19 - 2.04 (m, 1H), 1.85 (dt, 1H), 1.29 (s, 3H), 1.24 - 1.05 (m, 1H), 5 0.42 (dt, 1 H), 0.24 (t, 1 H); LC/MS m/z (M+H)⁺ = 465.3.

The title compounds in the table below were prepared by the procedure described in Example 18, or a procedure analogous thereto (by employing DIPEA+KaCOa/Nal), from the appropriate amine and 2-chloro-A/-methyl-/V'(6-methyl-2-((4aS,5aR)-5a-methyl-1 10 ((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[i]indazol-3-yl)-1((2-(trimethylsîlyl)ethoxy)methyl)-1 H-benzo[cf]imidazol-5-yl)acetamide (Préparation 98).

Ex	Structure and Name	Analytica Data
27	ch3 V S J H3C h / / HO' \Y-CH3 2-(2-(Hvdroxymethyl)morpholino)-/\/methvl-A/-(6-methvi-2-((4aS,5aR)-5amethyl-1,4,4a,5,5a,6- hexahydrocvclopropa[f|indazol-3-yl)-1Hbenzordlimidazol-5-yl)acetamide	Prep HPLC Method 1. 17 mg (18%). 1H NMR (400 MHz, CD3OD) δ 7.69 - 7.26 (m, 2H), 3.77 (d, 1 H), 3.72 - 3.53 (m, 2H), 3.50 - 3.36 (m, 2H), 3.37-3.30 (m, 2H), 3.24 (s, 3H), 3.19-2.95 (m, 3H), 2.852.68 (m, 3H), 2.64 (d, 1H), 2.35 (s, 3H), 2.16-2.02 (m, 1H), 1.84 (dt, 1H), 1.29 (s, 3H), 1.16 (dt, 1H), 0.42 (dd, 1H), 0.25 (t, 1H); LC/MS m/z (M+H)+ = 465.1.
28	çh3 O._ J n JJ £ H3C H / ) HO' \ς7ΟΗ3 2-((R)-2-(Hydroxvmethvl)morpholino)-/Vmethyl-A/-(6-methyl-2-((4aS,5af?)-5amethyl-1,4,43,5,53,6- hexahvdrocvcloproparf|indazol-3-vÎ)-1Hbenzofcf1imidazQl-5-vl)acetamide	Prep HPLC conditions: Method 2. 66 mg (25%). 1H NMR (400 MHz, CD3OD) δ 7.74 - 7.24 (m, 2H), 3.77 (d, 1H), 3.70 - 3.49 (m, 2H), 3.50 3.36 (m, 2H), 3.32 (d, 2H), 3.24 (s, 3H), 3.19-2.88 (m, 3H), 2.862.56 (m, 4H), 2.35 (s, 3H), 2.17 1.99 (m, 1H), 1.84 (dt, 1H), 1.29 (s, 3H), 1.22-1.10 (m, 1H), 0.42 (dd,

173

Ex	Structure and Name	Analytica Data
		1H), 0,25 (s, 1H); LC/MS m/z (M+H)+= 465.2.
29	çh3 h3cch3 H3C h Cj \l'CH3 2-(2.2-Dimethylmorpholino)-A/-methvl-V- (6-methyl-2-((4aS,5aR)-5a-methyl- 1,4,4a.5.5a.6- hexahvdrocvclopropa[f|indazol-3-vh-1H- benzoMÎmidazol-5-vl)acetamide	Prep HPLC conditions: Method 3; 53 mg (42%). 1H NMR (400 MHz, CD3OD) Ô 7.56 (s, 1H), 7.49 (s, 1H), 3.71 (d, 2H), 3.40 - 3.32 (m, 2H), 3.25 (s, 3H), 3.18-3.01 (m, 2H), 2.79 (t, 2H), 2.42 (s, 2H), 2.35 (s, 3H), 2.34 - 2.23 (m, 2H), 1.29 (s, 3H), 1.21 (s, 6H), 1.17-1.11 (m, 1 H), 0.48 - 0.34 (m, 1 H), 0.30 0.18 (m, 1H); LC/MS m/z (M+H)+ = 463.2.
30	çh3 CH* \^ch3 A/-Methyl-/\/-(6-methvl-2-((4aS15aF?)-5amethyl-1,4,4a,5,5a,6- hexahvdrocvclopropa[f|indazol-3-vO-1H-	Prep HPLC conditions: Method 4; 5 mg (8%). 1H NMR (400 MHz, CD3OD) δ 7.57 (s, 1 H), 7.53 - 7.40 (m, 1 H), 3.98 - 3.59 (m, 3H), 3.39 3.33 (m, 2H), 3.26 (s, 3H), 3.18 3.10 (m, 1H), 3.07 (d, 1H), 2.952.83 (m, 3H), 2.77 (d, 1 H), 2.35 (s, 3H), 2.32-2.13 (m, 1H), 2.051.86 (m, 1H), 1.29 (s, 3H), 1.16 (dt, 1H), 1.07 (dd, 3H), 0.42 (dd, 1H), 0.25 (q, 1 H); LC/MS m/z (M+H)+ = 449.3.
benzo[cf|imidazol-5-vi)-2-((F?)-2-
methvlmorpholino)acetamide
31	çh3 o Âh h3c H ( / CHa A/-Methyi-A/-(6-methyl-2-((4aS,5aR)-5amethyl-1,4,4a,5,5a,6- hexahvdrocvclopropa[f|indazol-3-yl)-1H-	Prep HPLC conditions: Method 5; 19 mg (28%). 1H NMR (400 MHz, CD3OD) δ 7.57 (s, 1H), 7.49 (s, 2H), 3.79 (dd, 1 H), 3.75 - 3.60 (m, 2H), 3.44 - 3.33 (m, 2H), 3.26 (s, 3H), 3.18-3.10 (m, 1 H), 3.07 (d, 1H), 2.99-2.81 (m, 2H), 2.77 (d,

174

Ex	Structure and Name	Analytica Data
	benzoMimidazol-5-yl)-2-((S)-2- methylmorpholino)acetamide	1H), 2.35 (s, 3H), 2.32-2.16 (m, 1H), 2.01 (d, 1H), 1.29 (s, 3H), 1.16 (dt, 1H), 1.07 (dd, 3H), 0.42 (dd, 1H), 0.25 (td, 1H); LC/MS m/z (M+H)+= 449.3.
32	çh3 O U ΓΗ H^C H ( 3 \gCH3 2-((2R16R)-2,6-DimethyÎmorpholino)-/Vmethyl-/V-(6-methvl-2-((4aS,5aR)-5amethyl-1,4,43,5,53,6- hexahydrocvclopropa[f]indazol-3-vl)-1HbenzoIdlimidazol-5-yl)acetamide	Prep HPLC conditions: Method 3; 24 mg (34%). 1H NMR (400 MHz, CD3OD) δ 7.56 (s, 1H), 7.49 (s, 1H), 3.99 (d, 2H), 3.50 - 3.33 (m, 2H), 3.26 (d, 3H), 3.18-3.10 (m, 1 H), 3.07 (d, 1 H), 2.93 - 2.68 (m, 2H), 2.53 (S, 2H), 2.35 (d, 3H), 2.34 - 2.17 (m, 2H), 1.29 (s, 3H), 1.27 1.11 (m, 7H), 0.42 (dd, 1 H), 0.30 0.19 (m, 1H); LC/MS m/z (M+H)+ = 463.2.
33	çh3 H3VNZvNïyNwN'NH J ο ; H3C H / ) CH3 <^CH3 2-((28,6S)-2,6-Dimethyimorpholino)-/Vmethyl-A/-(6-methyl-2-((4aS,5aR)-5amethyl-1,4,4a,5,5a,6- hexahydrocvclopropa[f|indazol-3-vl)-1Hbenzorc/]imidazol-5-vl)acetamide	Prep HPLC conditions: Method 6; 28 mg (39%). 1H NMR (400 MHz, CD3OD) δ 7.56 (S, 1H), 7.48 (d, 1H), 3.97 (tt, 2H), 3.42 - 3.33 (m, 1H), 3.25 (s, 3H), 3.18-3.10 (m, 1H), 3.07 (d, 1 H), 2.98 (dd, 1 H), 2.84 2.64 (m, 2H), 2.52 - 2.37 (m, 2H), 2.35 (d, 3H), 2.16 (dd, 2H), 1.29 (s, 3H), 1.18 (t, 7H), 0.42 (dd, 1 H), 0.24 (td, 1H); LC/MS m/z (M+H)+ = 463.2.

prep HPLC Conditions: Method 1 : Welch Xtimate C18 100 mm x 40 mm x 3 pm, 22 to 52% MeCN in 0.05% NH4OH/water, 25 mL/min, 10 min; Method 2 Welch Xtimate C18 100 mm x 40 mm x 3 pm, 32 to 52% MeCN in 0.05 NHUOH/water, 25 mL/min, 10 min;

Method 3: YMC-Actus Triart C18 100 mm x 30 mm x 5 pm, 42 to 62% MeCN in 0.05% NH4OH/water, 35 mL/min, 10 min; Method 4: YMC-Actus Triart C18 100 mm x 30 mm x

175 μιτι, 38 to 48% MeCN in 0.05% NHUOH/water, 35 mL/min, 10 min; Method 5: YMCActus Triart C18 100 mm x 30 mm x 5 μιτι, 40 to 60% MeCN in 0.05% NHUOH/water, 35 mL/min, 10 min; Method 6: Weich Xtimate C18 150 mm x 40 mm x 10 pm, 21 to 61% MeCN in 0.225% formic acid in water, 60 mL/min, 10 min.

The titie compounds in the table below were prepared by the procedure described for Example 3, from the appropriate acid and Préparation 46.

Ex	Structure and Name	Analytical data
34	çh3 oj O ΥΥΝ νΥ h3c h / / XA-CHa /V-Methyl-/V-(6-methvl-2-((4aS,5aR)-5amethyl-1,4,4a,5,5a,6- hexahvdrocvclopropafnindazol-3-yÎ)-1HbenzoΓGf]irΊπidazol·5-vl)-2- morpholinoacetamide	Prep HPLC conditions: Method 7; 44 mg (44%). 1H NMR (400 MHz, CD3OD) Ô 7.73 - 7.24 (m, 2H), 3.64 (t, 4H), 3.35 (d, 1H), 3.24 (d, 3H), 3.20 - 3.09 (m, 1 H), 3.06 (d, 1 H), 3.00 (dd, 1H), 2.75 (dd, 2H), 2.39 (s, 4H), 2.34 (s, 3H), 1.29 (s, 3H), 1.16 (dt, 1H), 0.42 (dd, 1H), 0.25 (t, 1H);
35	çh3 ΓΎΥίN YW-Z 'NH o AYnVY h3c h / / 'CH3 A/-Methyl-/V-(6-methyl-2-((4aS,5aR)-5a- methyl-1,4,4a,5,5a,6- hexahvdrocvciopropa[flindazol-3-v0-1H- benzoFcflimidazol-5-v0-2-(tetrahvdro-2H- pyran-4-vDacetamide	Prep HPLC conditions: Method 8; 36 mg (62%). 1H NMR (400 MHz, CD3OD) δ 7.48 (s, 2H), 3.94 - 3.75 (m, 2H), 3.43 - 3.33 (m, 3H), 3.24 (d, 3H), 3.13 (dd, 1H), 3.06 (d, 1H), 2.77 (d, 1H), 2.32 (s, 3H), 2.05 (d, 2H), 1.87 (q, 1H), 1.68-1.46 (m, 2H), 1.29 (s, 3H), 1.13 (ddd, 3H), 0.42 (dd, 1H), 0.25 (t, 1H); LC/MS m/z (M+H)+ = 434.3.
36	o ch3 oj O ΛΑ 'Λ h3c h / ? \Ych3 /V-Methvl-/V-(6-methyl-2-((4aS,5aR)-5a-	Prep HPLC conditions: Method 9, rétention time 2.30. LC/MS m/z (M+H)+ = 449.0

176

Ex	Structure and Name	Analytical data
	methyl-1,4,4a,5,5a,6- hexahvdrocvclopropaff|indazol-3-vl)-1Hbenzo[dlimidazol-5-yl)-2-(3oxomorpholino)acetamide

Prep HPLC conditions: Method 7: Phenomenex Gemini-NX 150 mm x 30 mm x 5 pm, 19 to 59% 0.05% NH4OH in MeCN/water, 30 mL/min, 10 min. Method 8: YMC-Actus Triart C18 100 mm x 30 mm x 5 pm, 40 to 60% MeCN in 0.05% NH₄OH/water, 35 5 mL/min, 10 min. Method 9: Agela Durashell C18 150 mm x 25 mm x 5 pm, i5-55% 0.225% formic acid in MeCN/water, 35 mL/min, 8 min gradient.

Example 37: (S)-A/-(7-bromo-2-((4aS,5aR)-5a-methyl-1.4,4a,5,5a,6hexahvdrocvclopropa[flindazol-3-vl)-1H-benzo[ci|imidazol-5-vD-/V-methvÎ-2 morpholinopropanamide

A solution of EtaSiH (117 mg, 1.01 mmol) in TFA (5 mL) at 0 °C was treated with Préparation 102 (130 mg, 0.202 mmol). The mixture was stirred at 0 °C for 2 h and concentrated. The residue was taken up in MeOH, cooled to 0 °C and treated with 15 conc. NH4OH (1 mL). The mixture was concentrated and the residue was purified by préparative HPLC (Boston Prime C18 150 mm x 30 mm x 5 pm, 35 to 55% MeCN in 0.05% NH₄OH/water, 25 mL/min, 10 min) to give the title compound (38 mg, 36%). ¹H NMR (400 MHz, DMSO-d₆) δ 13.05 (s, 1H), 12.96 (s, 1H), 7.42 (s, 1H), 7.40 (s, 1H), 3.48 (d, 5H), 3.31 - 3.23 (m, 1H), 3.19 (s, 3H), 3.16 (d, 1H), 3.00 (td, 2H), 2.74 (d, 1H), 20 2.47 - 2.36 (m, 1H), 2.23-2.01 (m, 2H), 1.25 (s, 3H), 1.13 (dt, 1H), 0.99 (d, 3H), 0.38 (dd, 1H), 0.17 (t, 1H); LC/MS m/z (M+H)⁺ = 514.9 (⁸¹Br).

177

Example 38: (S)-A/-(7-cvano-2-((4aS,5aR)-5a-methyl-1,4,43,5,53,6hexahvdrocvclopiOparflindazol-3-vl)-1/-/-benzo[dlimidazol-5-vh-A/-methyl-2morpholinopropanamide

Step 1 : (S)-A/-(4-cvano-2-((4aS,5aR)-5a-methvl-1-((2-(trimethvlsilvOethoxv)methvn1,4_l4a,5_I5a_l6-hexahvdrocvclopropai/1indazol-3-vl)“1-((2-(trimethylsilyl)ethoxv)methvl)1H-benzoFcf]imidazol·6-vl)-Λ/-methvl-2-morpholinopropaπamide

A solution of Préparation 103 (160 mg, 0.207 mmol) in NMP (10 mL) was treated with Pd(Ph3P)4 (24 m, 0.021 mmol) and Zn(CN)2 (121 mg, 1.03 mmol). The mixture was heated in a microwave reactor at 160 °C for 1 h. The mixture was cooled to RT and partitioned between water (10 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer was extracted with additional EtOAc (50 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude material was purified by chromatography (silica, EtOAc/PE = 0-100%) to give the title compound (120 mg, 81%). LC/MS m/z (M+H)⁺ = 720.4.

Step 2: (S)-/V-(7-cyano-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahvdrocycloproparf|indazol-3--vi)-1H-benzordlimidazol-5-vl)-/\/-methvl-2morpholinopropanamide

A solution of Et₃SiH (81 mg, 0.694 mmol) in TFA (5 mL) at 0 °C was treated with the silyl ether of step 1 (100 mg, 0.139 mmol). The mixture was stirred at 0 °C for 2 h and concentrated. The residue was taken up in MeOH and cooled to 0 °C. NH4OH (1 mL)

178 was added. The mixture was concentrated and the residue was purified by préparative HPLC (Boston Prime C18 150 mm x 30 mm x 5 pm, 22 to 47% MeCN in 0.2% formic acid in water, 25 mL/min, 10 min) to give the title compound (27 mg, 42%). ¹H NMR (400 MHz, DMSO-de) δ 13.35 (s, 1 H), 13.09 (s, 1 H), 7.73 (s, 2H), 3.53 - 3.40 (m, 5H), 3.20 (s, 3H), 3.14 (d, 1H), 3.02 (d, 2H), 2.75 (d, 1H), 2.37 (dd, 2H), 2.07 (s, 1H), 1.26 (s, 3H), 1.14 (s, 1H), 0.98 (d, 3H), 0.38 (dd, 1H), 0.17 (t, 1H); LC/MS m/z (M+H)⁺= 460.2.

Example 39: (S)-/V-(7-hvdroxv-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropaffl indazol-3-yl)-1 H-benzofdlimidazol-5-vl)-/\/-methvl-2morpholinopropanamide

A solution of EtaSiH (196 mg, 1.69 mmol) in TFA (5 mL) at 0 °C was treated with Préparation 105 (120 mg, 0.169 mmol). The mixture was stirred at 20 °C for 2 h and concentrated. The residue was taken up in MeOH, cooled to 0 °C and treated with conc. ΝΗλΟΗ (1 mL). The mixture was concentrated and the residue was purified by préparative HPLC (Boston Prime C18 150 mm x 30 mm x 5 pm, 25 to 45% MeCN in 0.05% NH4OH in water, 25 mL/min, 10 min) to give the title compound (28 mg, 37%). Analytical chiral SPC Column: Chiralpak AS-3 100 mm x 4.6 mm x 3 pm; Mobile phase; A/B: CO₂/EtOH (0.05% EtzNH); Gradient: 5% to 40% of B in 4 min and hold 40% for 2.5 min, then 5% of B for 1.5 min; Flow rate: 2.8mL/min Column temp.: 35 °C; rétention time = 2.760 min; LC/MS m/z (M+H)⁺ = 451.2.

Example 40: (S)-/V-(7-methoxv-2-((4aS,5aR)-5a-methvl-1,4,43,5,53,6hexahydrocvclopropaff|indazol-3-vl)1H-benzo[d1imidazol-5-yl)-/V-methyl-2morpholinopropanamide

I 179

A solution of EtsSÎH (120 mg, 1.03 mmol) in TFA (5 mL) at 0 °C was treated with Préparation 106 (150 mg, 0.207 mmol). The mixture was stirred at 0 °C for 2 h and concentrated. The residue was taken up in MeOH and cooled to 0 °C. The mixture was treated with conc. NH4OH (1 mL), concentrated and the residue was purified by 5 préparative HPLC (Boston Prime C18 150 mm x 30 mm x 5 pm, 32 to 55% MeCN in 0.05% NH4OH/water, 25 mL/min, 10 min) te give the title compound (11.4 mg, 12%). Ή NMR (400 MHz, DMSO-de) ô 12.84 (s, 1 H), 12.70 (s, 1H), 6.96 (s, 1H), 6.60 (s, 1 H), 3.96 (s, 3H), 3.49 (d, 5H), 3.39 (d, 0H), 3.29 (td, 1H), 3.27-3.19 (m, 1H), 3.19 (s, 3H), 3.10-2.89 (m, 2H), 2.73 (d, 1H), 2.47-2.38 (m, 1H), 2.24 (d, 2H), 1.25 (s, 3H), 1.16 10 1.04 (m, 1H), 1.03 (d, 3H), 0.37 (dd, 1 H), 0.16 (s, 1 H); LC/MS m/z (M+H)⁺ = 465.1.

Example 41 : (S)-/V-methyl-/V-(2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahvdrocvcloproparflindazol-3-vl)-7-(trifluoromethvl)-1H-benzordlimidazpl-5-yl)-2morpholinopropanamide

A solution of Et₃SiH (183 mg, 1.57 mmol) in TFA (5 mL) at 0 °C was treated with Préparation 112 (120 mg, 0.157 mmol). The mixture was stirred at RT for 2 h and concentrated. The residue was taken up in MeOH and cooled to 0 °C. The mixture was treated with conc. NH4OH (1 mL), concentrated and the residue was purified by préparative HPLC (Boston Prime C18 150 mm x 30 mm x 5 pm, 43 to 65% MeCN in 0.05% NH4OH/water, 25 mL/min, 10 min) to give the title compound (50 mg, 63%). ¹H NMR (400 MHz, DMSO-d₆) δ 13.23 (s, 1H), 13.02 (s, 1H), 7.68 (s, 1H), 7.50 (s, 1H), 3.55 - 3.37 (m, 4H), 3.30 (s, 2H), 3.22 (s, 3H), 3.13 (q, 1H), 3.08 - 2.90 (m, 2H), 2.75 (d, 1H), 2.45 -2.30 (m, 1H), 2.14 - 1.93 (m, 2H), 1.25 (s, 3H), 1.12 (dd, 1H), 0.97 (d, 3H), 0.37 (dd, 1H), 0.17 (t, 1 H); LC/MS m/z (M+H)⁺ = 503.1.

Example 42: (S)-A/-(7-(methoxvmethvl)-2-((4aS,5aR)-5a-methyl-1.4.4a,5.5a,6hexahvdrocvcloproparf)Îndazol-3-vl)-1H-benzofd1imidazol-5-vl)-/\/-methvl-27 morpholinopropanamide

180

A solution of Préparation 117 (61 mg, 0.083 mmol) in DCE (0.7 mL) at RT was treated with TFA (0.6 mL). The mixture was stirred for 16 h and concentrated. The residue was taken up in EtOH (0.7 mL) and cooled to 0 ’C. The mixture was treated with conc. NH4OH (0.2 mL) dropwise and the mixture was stirred at RT for 4 h. The mixture was diluted with water and extracted with 85:15% isopropanol/DCM (x 3). The combined organic layers were dried (Na2SÛ4), filtered and concentrated. The residue was purified by préparative HPLC (XBridge C18 19 mm x 100 mm x 5 pm, 5-95% MeCN (0.03% NH4OH)/water, 8.5 min, hold at 95% for 1.5 min, 25 mL/min) to give the title compound (23 mg, 59%). Rétention time = 1.74 min; LC/MS m/z (M+H)⁺ = 479.5.

Example 43: (5)-Λ/-(7-^10Γ0-2-((433,58/?)-53^6ΐΗνΙ-1,4,4a,5,5a,6hexahvdrocvclopropaiflindazol-3-yl)-1H-benzoMimidazol-5-yl)-/\/-methvl-2morpholinopropanamide

A solution of Préparation 122 (42 mg, 0.085 mmol) in TFA (0.6 mL) and DCE (0.5 mL) was stirred at RT for 2 h and treated with Et₃SiH (0.046 mL, 0.29 mmol). The mixture was stirred at RT for an additional 2 h. The mixture was concentrated and the residue was diluted with sat. aq. NaHCO₃. The mixture was extracted with EtOAc (x 3). The combined organic extracts were dried (MgSO4), filtered and concentrated. The crude material was purified by préparative HPLC (XBridge C18 19 mm x 100 mm x 5 pm, 595% MeCN (0.03% NH4OH)/water, 8.5 min, hold at 95% for 1.5 min, 25 mL/min) to give the title compound (17.3 mg, 63%). Rétention time = 2.04 min; LC/MS m/z (M+H)⁺ = 469.6.

181

Example 44: (S)-A/-(7-ethvl-2-((4aS.5a/?)-5a-methvl-1,4,4a,5,5a.6hexahvdrocvclopropa[f|indazol-3-vl)-1/7-benzofcf|imidazol-5-vl)-A/-methvl-2morpholinopropanamide

A solution of Préparation 126 (45 mg, 0.062 mmol) in DCE (0.5 mL) at RT was treated with TFA (0.2 mL) and EtaSiH (24 mg, 0.21 mmol). The mixture was stirred for 16 h and concentrated. The residue was taken up in DCM and sat. aq. NaHCOs. The layers were separated and the aqueous layer was extracted with EtOAc (x 2). The combined organic layers were dried (MgSO4), filtered and concentrated. The residue was purified préparative HPLC (XBridge C18 19 mm x 100 mm x 5 pm, 5-95% MeCN (0.03% NH4OH)/water, 8.5 min, hold at 95% for 1.5 min, 25 mL/min) to give the title compound (6.1 mg, 21%). LC/MS m/z (M+H)⁺ = 463.6; Rétention time 1.78 min.

Example 45: (S)-/V-(7-(hydroxvmethvl)-2-((4aS,5aR)-5a-methyl-1,4,4a,5.5a,615 hexahvdrocvclopropaïflindazol-3-vl)-1H-benzoMimidazol-5-vl)-/V-methvl-2morpholinopropanamide

A solution of Préparation 132 (20 mg, 0.028 mmol) in DCE (0.3 mL) at 0 °C was treated with TFA (157 mg, 1.38 mmol). The mixture was warmed to RT and stirred for 20 h.

The mixture was concentrated and taken up in EtOH, cooled to 0 °C, treated with conc. NH4OH (0.2 mL) and the mixture stirred for 3 h. The mixture was diluted with water and extracted with DCM (x 4) and 15% isopropanoî/DCM (x 3). The combined organic layers were dried (NaaSO4), filtered and concentrated. The residue was purified by preparative HPLC (XBridge C18 19 mm x 100 mm x 5 pm, 5-95% MeCN (0.03%

NH40H)/water, 8.5 min, hold at 95% for 1.5 min, 25 mL/min) to give the title compound (4.9 mg, 38%). Rétention time = 1.59; LC/MS m/z (M+H)⁺ = 465.6.

182

Example 46: (S)-/V-(7-fluoro-6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahvdrocvcloDropa[flindazol-3-Yl)-1H-benzorcf|imidazol-5-vl)-A/-methvl-2morpholinopropanamide

The title compound was prepared analogously to Example 1 from 138 (2.1 g, 3.52 mmol) and purified by prep HPLC (Chiralpak AD-3 50 mm x 6 mm x 3 pm, 40% isocratic (0.05% diethylamine in EtOH/COzsg)) 4 mL/min, column temp = 35 °C ) to give the title compound (1.3g, 79%). Rétention time = 0.38 min and 1.46 min; LC/MS m/z (M+H)⁺ = 467.1.

Example 47: (S)-/V-(6-fluoro-7-methvl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahvdrocvclopropa[flindazol-3-vl)-1H“benzordlimidazol-5-vl)-/V-methvl-2morpholinopropanamide

The title compound was prepared analogously to Example 41 from 5-bromo-4-fluoro-3methylbenzene-1,2-diamine. Purified by prep HPLC conditions: Welch Xtîmate 75 mm x 40 mm x 3 pm, 42 to 62% MeCN in 0.05% NH4OH in water, 25 mL/min, 10 min) to give the title compound (234 mg, 74%). Analytical SFC (Chiralpak AS-3 100 mm x 4.6 mm x 3 pm, A: CO2(g>; B: 0.05% diethylamine in EtOH; Gradient 5-40% B over 4 min, hold 40% B 2.5 min, 5% B for 1.5 min; 2.8 mL/min, column temp = 35 °C ), rétention time = 2.70 min; LC/MS m/z (M+H)⁺ = 467.2.

Example 48: (S)-/V-(7-(difluoΓomethvl)-2-((4aS,5aR)-5a-rπethvl·-1,4,4a,5,5a,6hexahvdrocvclopropa[flindazol-3-vl)-1H-benzo[dlimidazol-5-vl)-/V-methyl-2morpholinopropanamide

183

A solution of Préparation 144 (72 mg, 0,097 mmol) in DCE (0.6 mL) was treated with TFA (0.37 mL). The mixture was stirred at RT for 20 h. The mixture was concentrated and the resulting residue was dissolved in EtOH (1 mL), cooled to 0 °C and treated with conc. ΝΗλΟΗ (0.7 mL). The mixture was stirred at RT for 3 h. The mixture was diluted with water and extracted with DCM (x 4) followed by 15% Îsopropanol/DCM (x 3). The combined organic extracts were dried (N32SO4), filtered and concentrated. The residue was purified by prep HPLC (XBridge C18 19 mm x 100 mm x 5 pm, 5-95% MeCN (0.03% NH₄OH)/water, 8.5 min, hold at 95% for 1.5 min, 25 mL/min) to provide the title compound (27 mg, 57%). Rétention time = 2.16 min; LC/MS m/z (M+H)⁺ = 485.6.

Exemple 49: (S)-/X/-(6-(2-methoxvethoxv)-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahvdrocvclopropaΓf]indazol-3-v^)-1H-benzoΓd1imidazol·5-vl)-Λ/-methvl-2morpholinopropanamide

h₃C'°

A solution of Préparation 152 (160 mg, 0.25 mmol) in TFA (2.5 mL) at 5 ^DC was treated with EtaSiH (146 mg, 1.25 mmol). The mixture was stirred 2 h and the mixture was concentrated. The residue was diluted with sat. aq. NaHCOaand extracted with EtOAc (3x8 mL). The organic extracts were combined, dried, filtered and concentrated. The residue was purified by prep-HPLC (Phenomenex Gemini, NX-C18, 75 x 30 mm x 3 pm, water/CHaCN (0.05% NH₄OH), 10 -50% over 11 min) to give the title compound (2.5 mg, 2%). ¹H NMR (400 MHz, CD3OD) δ 7.67-7.16 (m, 2H), 4.26 - 4.18 (m, 2H), 3.81 - 3.72 (m, 2H), 3.65 - 357 (m, 4H), 3.40 (s, 3H), 3.24 (d, 3H), 3.19 - 3.01 (m, 2H), 2.77 (d, 1H), 2.57 - 2.36 (m, 4H), 1.30 (s, 3H), 1.27 - 1.08 (m, 3H), 0.42 (dd, 1H), 0.25 (t, 1 H).; LC/MS m/z (M+H)⁺ = 509.3.

184

Example 50: (S)-A/-methyl-/\/-(7-methvl-2-((4aS,5aR)-5a-methvl-1,4,4a,5,5a,6hexahvdrocyclopropa|ï|indazol-3-yl)-1H-benzo[d1imidazol-5-vl)-2morpholinopropanamide

Γ ^N CL J

A solution of Préparation 158 (380 mg, 0.54 mmol) in TFA (5.4 mL) at RT was treated with EtaSiH (321 mg, 2.7 mmol). The mixture was stirred at RT for 3 h and concentrated. The residue was made basîc with sat. aq. NaHCOs and extracted with EtOAc (3x15 mL). The combined organic layers were concentrated. The residue was purified by préparative HPLC (YMC Triart 150 mm x 30 mm x 5 pm, 27 to 67% MeCN in 0.05% NH4OH/water, 25 mL/min, 10 min) to give the title compound (108 mg, 45%). ¹H NMR (400 MHz, CD3OD) δ 7.36 (s, 1H), 6.99 (s, 1H), 3.62 (ddd, 4H), 3.36 (d, 1H), 3.31 (s, 3H), 3.26 - 3.10 (m, 2H), 3.07 (d, 1H), 2.78 (d, 1H), 2.63 (s, 3H), 2.54 (dt, 2H), 2.38 (dt, 2H), 1.30 (s, 3H), 1.20 - 1.14 (m, 3H), 1.16-1.13 (m, 1H), 0.41 (dd, 1 H), 0.26 (t, 1H); LC/MS m/z (M+H)⁺ = 448.9.

Example 51 : (S)-/\/-(2-((4aS,5aR)-5,5-difluoro-5a-methvl-1,4,4a,5,5a,6hexahvdrocvclopropa[f]indazol-3-vl)-7-methvl-1H-benzo[cflimidazol-5-vl)-A/-methyl-2morpholinopropanamide

The title compound was prepared analogously to Example 41 from 5-bromo-3methylbenzene-1,2-diamine and Préparation 17. Préparative HPLC conditions: Phenomenex Gemini-NX 150 mm x 30 mm x 5 pm, 24 to 64% MeCN in 0.05% NH4OH/water, 25 mL/min, 9 min) to give the title compound (56 mg, 39%). ¹H NMR (400 MHz, CD3OD) δ 7.48 - 7.25 (m, 1 H), 7.07 - 6.95 (m, 1 H), 3,72 - 3.57 (m, 4H), 3.26 - 3.19 (m, 1H), 3.14 (br d, 1H), 2.87 (dd, 1H), 2.69 - 2.52 (m, 5H), 2.46 - 2.35 (m, 2H), 1.80-1.71 (m, 1H), 1.44 (s, 3H), 1,18 (d, 3H); LC/MS m/z (M+H)⁺= 485.2.

185

Example 52: (S)-A/-(6-methyl-2-((4aS,5aR)-5a-methvl-1,4,4a,5,5a,6hexahvdrocvclopropa[flindazol-3-vl)-1H-benzofdlimidazol-5-vl)-2morpholinopropanamide

Step 1: 6-methvl-2-((4aS,5aR)-5a-methvl-1 -((2-(trimethvlsilvl)ethoxv)methyl)1,4,4a,5_l5a,6-hexahvdrocvclopropaÎf|indazol-3-vP-1 H-benzoidlimidazol-5-amine

A solution of Préparation 66 (1.50 g, 3.22 mmol) in éthanol (20 mL) was treated with aq. NaOH (10 M, 6.44 mL, 64.4 mmol) at 15 °C. The mixture was stirred at 90 °C for 18 h. The mixture was concentrated and the residue was extracted with EtOAc (3 x 100 mL). The combined organic layers were concentrated and crude product purîfied by chromatography (silica, EtOAc/PE = 30-50%) to deliver the title compound (984 g, 72%). LC/MS m/z (M+H)⁺ = 423.9.

Step 2: (S)-N-(6-methvl-2-((4aS,5aR)-5a-methvl-1-((2-(trimethvlsilvl)ethQxv)methyl)1,4,4a,5,5a,6-hexahvdrocyclopropa[flindazol-3-vl)-1 H-benzofdlimidazol-5-vl)-2morpholinopropanamide

Title compound was prepared analogously to Example 6 Step 1 from Préparation 16 (115 mg, 0.59 mmol) and silyl ether of step 1 (208 mg, 0.491 mmol) to deliver the title

186 compound (216 mg, 78%), 1H NMR (400 MHz, CDCb) δ 9,62 - 9.51 (m, 1H), 8.41 7.62 (m, 1H), 5.42 - 5.35 (m, 2H), 3.85 - 3.78 (m, 3 H), 3.59 - 3.55 (m, 2 H), 3.27 3.17 (m, 2H), 2.75-2.60 (m, 9H), 2.44-2.40 (m, 2H), 1.40-1.15 (m, 8 H), 0.92-0.85 (m, 2H), 0.42-0.38 (m , 1H), 0.01 - -0.08 (m, 9H); LC/MS m/z (M+H)⁺ = 565.1.

Step 3: (S)-/V-(6-methvl-2-((4aS,5aR)-5a-methvl-1,4,4a,5,5a,6hexahydrocvclopropa[f|indazol-3-vl)-1H-benzo[dlimidazol-5-yl)-2morpholinopropanamide

Title compound was prepared analogously to Example 6 Step 2 using silyl ether of step 2 (0.216 g, 0.382 mmol) and was purified by prep HPLC (Phenomenex Gemini NX-C18 30 mm x 74 mm x 3 pm, 17-57% MeCN (0.05% NH4OH)/water, 11 min, 25 mL/min) to provide the title compound (81 mg, 49%). ¹H NMR (400 MHz, CD3OD) δ 7.91 (s, 1H), 15 7.45 (br. s, 1H), 3.85 - 3.78 (m, 4H), 3.30 - 3.25 (m, 1H), 3.17 - 3.13 (m, 1H), 3.09 2.76 (m, 2H), 2.72-2.64 (m, 4H), 2.43 (s, 3H), 1.41 - 1.39 (m, 3H), 1.30 (m, 3H), 1.19 - 1.15 (m, 1 H), 0.44 - 0.39 (m, 1 H), 0.26 - 0.24 (m, 1 H); LC/MS m/z (M+H)⁺ = 435.1.

Example 53: (S)-N-(2-((4aS,5aR)-5,5-difluoro-5a-methyl-1,4,43,5,53,620 hex8hvdrocvcloproparflindazol-3-yl)-5-methvl-1H-benzo[dlimid8Zol-6-vl)-N-methyl-2morpholinopropanamide

Step 1 : (S)-N-(2-((4aS,5aR)-5,5-dJfluorQ-5a-methvl-1-((2-(trimethvÎsilvl)ethoxv)methyl)1,4_l4a_l5,5a,6-hexahvdrocvclopropa[Πindazol·3-vl)-5-methvl-1 H-benzordlimidazol-6-yl)25 N-methyl-2-morphoiinopropanamide

A mixture of préparation 17 (260 mg, 0.75 mmol) and NazSsOs (65 mg, 0.34 mmol) was treated with a solution of préparation 32 (200 mg, 0.68 mmol), in DMF (5 mL). The mixture was treated with DMSO (1 mL) and heated at 110 °C for 18 h. The mixture was cooled to RT and poured into ice-water and extracted using EtOAc. The layers were separated and the organic phase washed with brine, dried (MgSO4), filtered and concentrated to give Step 1 title compound (550 mg). LC/MS m/z (M+H)⁺ = 615.3,

Step 2: (S)-N-(2-((4aS,5aR)-5,5-difluoro-5a-methyl-1,4,4a,5,5a,610 hexahvdrocvciopropa[f]indazol-3-vl)-5-methyl-1 H-benzo[d1imidazol-6-yl)-N-methyl2morpholinopropanamide

To silyl ether from Step 1 (0,55 g, 0.72 mmol) cooled to 0 °C was added TFA (10 mL) followed by EtsSiH (0.83 mg, 7.16 mmol), The mixture was warmed to RT and stirred 15 for 1.5 h. The mixture was concentrated, neutralized using aq. sat. NaHCOa (20 mL), then extracted using EtOAc. The organic layers were combined, washed with brine, dried (MgSO4), filtered and concentrated. The crude product was purified by reverse phase HPLC (Phenomenex Gemini C18, 250 x 50 mm x 7 μΜ, water (0.05% NH4OH)/MeCN from 30 to 50% over 10 min, 35 ml/min) to give title compound (0.19 g, 20 55%). SFC method: Chiral Tech OD-3, 50 mm x 4.6 mm x 3 pm, 5 to 40% with 0.05% diethyl amine in EtOH/COzcg), 4.0 mL/min, column température 35 °C, rétention time = 1.58 min (43.1%) and 1.65 min (56.8%), 100%ee. LC/MS m/z (M+H)⁺ = 485.3.

188

Example 54: /v-(6-cvano-2-((4aS,5aF?)-5a-methyl-1,4,4a,5,5a.6hexahvdrocvclopropaff1indazol-3-vl)-1 H-benzo[d1imÎdazol-5-vl)-N-methvl-2-(tetrahvdro2H-pyran-4-vl)acetamide

Step 1 : A/-(5-cyano-2-((4aS,5aR)-5a-methyl-1 -((2-(trimethvlsilvl)ethoxv)methyl)1,4,4a,5,5a,6-hexahvdrocvclopropa[fÎindazol-3-vl)-1-((2-(trimethvlsilvl)ethoxy)methyl)1 H-benzoidlimidazol-6-vl)-/V-methvl-2-(tetrahvdro-2H-pvran-4-vl)acetamide and N-(6cvano-2-((4aS,5aR)-5a-methvl-1-((2-(trimethvlsilvl)ethoxv)methyl)-1,4,4a,5,5a,6hexahvdrocvcloDropa[fÎindazol-3-vl)-1-((2-(trimethvisilvl)ethoxv)methyl)-1 Hbenzo[d]imidazol-5-vl)-N-methyl-2-(tetrahvdro-2H-pyran-4-vl)acetamide

To a solution of Préparation 164 (100.0 mg, 0.1727 mmol) in DMF (5.0 mL) was added 2-(tetrahydro-2H-pyran-4-yl)acetic acid (25 mg 0.17 mmol), Ν,Ν,Ν',Ν'tetramethylchloroformamidinium hexafluorophosphate (72.7 mg, 0.259 mmol) and Nmethylimidazole; (28.4 mg, 0.345 mmol) at RT, then the reaction mixture was stirred at 60 C for 16h. The reaction mixture was treated with 3% aq. LiCI (10 mL) and extracted with EtOAc (3x5 mL). The combined organic layers were washed with brine (10 mL) and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE = 0-100%) to give the title compounds as a mixture (104 mg, 85%). LC/MS m/z (M+H)⁺ = 705.3

Step 2: A/-(6-cyano-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahvdrocvclopropa[f|indazol3-vl)-1H-benzo[d1imidazol-5-vl)-/\/-methvi-2-(tetrahvdro2H-pyran-4-yl)acetamide

189

A solution of the silyl ethers from step 1 (40 mg, 0.07 mmol) in TFA (2.0 mL) was cooled to 0 °C and EtaSiH (41 mg, 0.35 mmol) was added. The reaction was stirred at 0 °C for 2 h. The mixture was concentrated, neutralized with conc. NFUOH (20 mL) and extracted with EtOAc (x 2). The combined organic extracts were washed with brine, then dried (MgS0₄), filtered and concentrated. The crude product was purified by reverse phase HPLC (Phenomenex Gemini NX, 75 x 30 mm x 3 pM, water (0.05% NH40H)/MeCN from 13 to 53% over 9 min, 30 ml/min) to give the title compound (14.86 mg, 48%). SFC method; Chiral Tech OD-3, 50 mm x 4.6 mm x 3 pm, 5 to 40% with

0.05% diethyl amine in EtOH/CO2(gj, 2.8 mL/min, column température 35 °C, rétention time - 5.03 min (100%), 100%ee. ¹H NMR (400 MHz, DMSO-de) δ 13.09 (s, 1H), 13.04 (s, 1H), 8.27 (s, 0.5H), 8.13 (s, 0.5H), 7.95 (s, 0.5H), 7.55 (0.5H), 3.83 (d, 5H), 3.31 (m, 1H), 3.03 (d, 2H), 2.83 (d, 2H), 2.76 (d, 1H), 2.17 (s, 1H), 1.67 (d, 2H), 1.34 (qd, 2H), 1.26 (s, 4H), 1.23 (s, 1H), 1.13 (s, 1 H), 0,42 - 0.35 (m, 1H), 0.18 (s, 1H); LC/MS m/z (M+H)⁺= 445.2

Example 55: (R)-A/-(7-cyano-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahvdrocvclopropaΓf|indazol·3-vl)-1H-benzoΓd1ίmidazol-5-vl)-N-methvl-2-(tetrahvdΓO2H-pyran-4-vl)propanamide

To a Préparation 173 (82 mg, 0.18 mmol) cooled to 0 °C was added a mixture of TFA (5 mL) and EtaSiH (206 mg, 1.77 mmol). The mixture was stirred at RT for 15 h and the solvent was removed. The residue was dissolved in MeOH (10 mL) and treated with NH4OH (1 mL). The solvent was removed, and the crude material purified by prep25 HPLC (Boston Prime C-18 150 x 30 mm x 5 pm, H2O/CH3CN with 0.05% NH₄OH, 4065% over 10 min, 25 mL/min) to give the title compound (35 mg, 68%). ¹H NMR (400 MHz, DMSO-de) δ 7.66 (bs, 1H), 7.58 (s, 1H), 3.76 (t, 2H), 3.48 (d, 1H), 3.35-3.26 (m, k 190

2H), 3.20 (s, 4H), 3.02 (d, 2H), 2.76 (d, 1H), 2.11 - 1.95 (m, 1H), 1.66-1.58 (m, 1H), 1.48 (d, 2H), 1.26 (s, 3H), 1.19- 0.97 (m, 1 H), 0.93 (d, 3H), 0.88-0.80 (m, 1 H), 0.39 (dd, 1H), 0.17 (t, 1H). Chiral SFC (Chiralpak AD-3, 50 x 4.6 mm, 3 pm, CO₂/iPrOH with 0.05% Et₂NH, 5 to 40% 2 min, hold 1.2 min, 4 mL/min, T = 35 °C) Rt - 1.785 min (100% ee). LC/MS m/z (M+H)⁺ = 459.1.

Example 56: (S)-N-(methyl-¹³C-d3)-N-(6-methvl-2-((4aS,5aR)-5a-methvl-1,4,4a,5,5a,6hexahvdrocvclopropa[flindazol-3-yl)-1H-benzo[d1imidazol-5-vl)-2morpholinopropanamide

Example 56 was prepared following the procedure described for Example 1 with iodomethane-¹³CD3 in place of iodomethane to deliver 550 mg of the title compound. Analytical HPLC method: Eclipse XDB-C18 150 mm x 4.6 mm x 3.5 pm; H₂O/MeCN: 10-90% over 10 min, 1.0 mL/min, rétention time = 7.605 min (99.6%), LC/MS m/z (M+H)⁺ = 453.2.

Biological Assays

In Vitro Studies

IL-2-inducible T-cell Kinase (ITK) activity, ICso (nM)

ITK activity was determîned by measuring the effect of a test compound in an ITK enzyme assay.

.0 M HEPES Buffer pH 7.5 solution was prepared as follows: 238.3 g HEPES free acid (Sigma) and 800 mL of water were combined, and the mixture was stirred until complété 25 dissolution. The pH was adjusted to 7.5 via titration with 5N NaOH and the volume adjusted to WOOmL. The solution was filtered and sterilized.

ITK assay buffer was prepared as follows: 50 mL of HPLC-grade water was treated with 2 mL of 1.0 M HEPES Buffer, 500 pL of 2% Gelatin (Sigma), 1.0 mL of aqueous MgCI₂ 30 solution (1.0 M), and 1.0 mL of aqueous glutathione solution (0.5 M), and the solution

I 191 was mixed. The solution was brought to 99 mL in a graduated cylinder by addition of water and sterilized through a 0.2 pm filter. 0.1 mL of Brij-35™ Surfact-Amps™ Detergent Solution (10% w/v aqueous solution, ThermoFisher) and 1.0 mL of ATP (Teknova.100 mM) were added and the solution was mixed.

Préparation of 1.33X ITK enzyme solution was as follows: 49.99 mL of ITK assay buffer was treated with 4.1 pL of ITK enzyme (ITK FL (N-Flag and C-His tagged, ~72kDa) Lake Pharma, 0.25 mg/ml in a buffer containing 25 mM Tris pH 7.8, 150 mM NaCI, 10% glycerol and 2 mM TCEP) and the mixture was gently agitated. The resulting solution 10 was stored on ice. 30 Minutes prior to use, the enzyme solution was removed from ice and equilibrated to RT by incubation in a RT water bath.

Préparation of 4X ITK substrate solution was as follows: 50 mL of ITK assay buffer was treated with 100 pL of BTK peptide (China Peptide Company, 2 mM stock solution in 15 DMSO). The tube was capped, mixed by gently inverting the tube, and then stored on ice. 30 Minutes prior to use, the substrate solution was removed from ice and equilibrated to RT by incubation in a RT water bath.

At the time of assay, 7.5 pL of the 1.33X ITK enzyme solution was added to plate wells 20 containing 0.1 pL of varying concentrations of test compound in DMSO. The plate was incubated 30 min at RT. The plate wells were each treated with 2.5uL of the 4X ITK substrate solution and the plate was sealed (TopSeal™, Perkin Elmer). The plate was spun at 1000 rpm for 30 sec and then incubated for 60 min at RT. The seal was removed, and each well was treated with 10 pL of Stop/Detect Buffer (20mM HEPES 25 pH 7.5, 0.01% gelatin, 1 nM LANCE PT66 (Perkin Elmer), 16.5 pg/ml Surelight APC (Perkin Elmer), 10 mM EDTA, 250 mM NaCI). The plate was again covered and was spun at 1000 rpm for 30 seconds. The plate was allowed to incubate overnight at RT and in a closed carrier to reduce déhydration. The seal was removed, and the fluorescence was read with a plate reader with an excitation wavelength of 665 nm and 30 an émission wavelength of 615 nm. The concentrations and resulting effect values for the tested compound were plotted and the concentration of compound required for 50% effect (ICso) was determined with the four-parameter logistic dose response équation.

IC50 (uM) values for compounds of the invention are presented in the Table that follows.

192

IL-2-inhibition activitv, ICso (uM)

IL-2 inhibition activity in supernatants from activated CD4+ human T-cells was determined by measuring the effect of a test compound on the activity using the cisbio HTRF™ technology.

Human CD4+ T cells were activated with CD3/CD28 for 3 days and expanded for an additional 4-6 days (7 to 9 days total). On day 0, frozen CD4+ T cells were thawed, treated with CD3/CD28 Dynabeads, and incubated at 37°C/5%CO2. On day 3, the beads were removed, and the cells were diluted to 5x10⁶ cells/cm², placed in G-RexIO flask, and incubated at 37^OC/5%CO2. On day 7 to day 9 the cells were removed from the G-Rex flasks, counted and diluted back to 1x10^s cells/ml in standard tissue culture flask.

The expanded CD4+ T-cells were centrifuged at 300 x g for 10 minutes and resuspended to 0.5 million cells per ml (30,000 cells/well). 60 pl of CD4+ T cells were added per well to a 384 well plate containing 0.1 pL of varying concentrations of test compound in DMSO. The plates were incubated for 15 min at 37°C/5%CO2. 20 pl of diluted ImmunoCult™ (STEMCELL Technologies, 1:12.5 in T cell assay media) were added to ail wells of the plate (1:50 final assay concentration). The plates were incubated for an additional 20 to 24 hrs at 37°C/5%CO2. The plates were centrifuged at 300 x g for 10 minutes. 16 pL of supernatant was removed and combined with 4 pl of IL-2 HTRF Abs. (cisbio kit). Plates were incubated for 3 hours at RT and read with an EnVisîon plate reader at 665 nm and 615 nm wavelengths. The concentrations and resulting effect values for the tested compound were plotted and the concentration of compound required for 50% effect (ICso) was determined with the four-parameter logistic dose response équation.

ICso (uM) values for compounds ofthe invention are presented in the Table that follows.

Tropomyosin Receptor Kinase A (TRKA) activitv. % inhibition

Assays to détermine TRKA activity are known in the art; e.g. see those described in:

* Skerratt SE, étal. J. Med. Chem. (2016), 59(22):10084-10099

PMID: 27766865. DPI: 10.1021/acs.imedchem.6b00850

193

Bagal SK, et al,. J. Med. Chem. (2018), 61(15):6779-6800 PMID: 29944371. DPI: 10.1021/acs.jmedchem.8b00633

TRKA, also known as neurotrophic tyrosine kinase receptortype 1 (NTKR1) activity was 5 determined by measuring the effect of a test compound on the activity against the

NTRK1 enzyme using the ThermoFisher Z’-LYTE Assay fluorescence-based coupled enzyme format (www.thermofisher.com/seiectscreen). Test compounds were screened at a fixed concentration of 1 uM and the % inhibition was determined compared to Controls at a fixed AT P concentration of 1 mM. The resulting effect value for the tested io compound was compared to the assay Controls to détermine the % inhibition (%).

% Inhibition (%) values for compounds of the invention are presented in the Table that follows.

Table: 15 In Vitro Study Data

Ex#	ITK ICso (uM)1	ITK count (n)	IL-2 IC50 (uM)2	IL-2 count (n)	TRKA % inhibition (%)3	TRKA count (n)
1	0.006	13	0.039	14	108	2
2	NT		NT		NT
3	0.016	3	0.113	3	97	2
4	0.003	3	0.022	3	95	2
5	0.005	2	0.027	2	NT
6	0.011	3	0.101	3	102	2
7	0.002	9	0.013	7	106	2
8	0.005	2	0.026	2	NT
9	0.020	2	0.099	3	99	2
10	0.007	3	0.067	3	104	2
11	0.003	3	0.034	3	107	2
12	0.003	3	0.025	4	94	2
13	0.001	63	0.003	6	99	6

194

Ex#	ITK IC50 (uM)1	ITK count (n)	IL-2 IC50 (uM)2	IL-2 count (n)	TRKA % inhibition (%)3	TRKA count (n)
14	0.003	61	0.042	7	92	4
15	0.004	4	0.042	4	107	2
16	0.005	4	0.065	6	116	2
17	0.005	2	0.045	3	NT
18	0.009	3	0.091	3	100	2
19	0.009	3	0.057	3	98	4
20	0.005	3	0.053	3	98	2
21	0.009	3	0.098	3	91	2
22	0.044	3	0.340	3	93	2
23	0.124	3	0.304	3	101	2
24	0.008	3	0.106	4	105	2
25	0.013	3	0.101	3	101	2
26	0.012	4	0.212	2	99	2
27	0.017	3	0.289	2	NT
28	0.019	3	0.305	3	NT
29	0.012	3	0.058	4	NT
30	0.015	3	0.082	4	NT
31	0.013	3	0.075	4	99	2
32	0.016	3	0.083	4	99	2
33	0.011	3	0.068	4	NT
34	0.010	2	0.103	3	98	2
35	0.006	3	0.050	3	NT
36	0.005	3	0.096	3	97	2
37	0.009	2	0.130	3	96	2
38	0.007	3	0.085	3	96	2

195

Ex#	ITK IC50 (uM)1	ITK count (n)	IL-2 IC50 (uM)2	IL-2 count (n)	TRKA % inhibition (%)3	TRKA count (n)
39	0.008	3	0.082	3	97	2
40	0.019	3	0.103	3	96	2
41	0.034	4	0.176	4	96	2
42	0.038	3	0.200	4	98	2
43	0.016	3	0.171	3	96	2
44	0.028	4 1	0.219	3	94	4
45	0.017	4	0.365	3	97	2
46	0.006	3	0.047	4	95	4
47	0.029	3	0.161	3	98	2
48	0.017	4	0.207	3	95	2
49	0.012	2	0.100	2	98	2
50	0.016	5	0.126	3	97	2
51	0.002	4	0.019	4	97	2
52	0.121	3	0.274	3	109	2
53	0.001	3	0.010	4	96	2
54	0.272	3	4.570	2	NT
55	0.005	4	0.041	3	89	2
56	NT		NT		NT

Key:

¹ ITK IC50 values are presented as a géométrie mean of count n ² IL-2 ICso values are presented as a géométrie mean of count n ³ TRKA % inhibition values are presented as an arithmetic mean of count n

NT means not tested

Ail référénces mentioned hereinabove are incorporated by reference in their entirety.

Claims (29)

1. A compound of Formula (I)

2. A compound according to claim 1, or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait, wherein each R¹ is H.

3. A compound according to claim 1 or claim 2, or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait, wherein R² is H or (Ci-C4)alkyl.

4, A compound according to claim 3, or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait, wherein R² is methyl,

5. A compound according to any one of daims 1 to 4, or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait, wherein each R³ is independently H, F or (Ci-C4)alkyl.

5 or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait, wherein:

each R¹ is independently H or F;

6. A compound according to claim 5, or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait, wherein each R³ is independently H, F or methyl,

7, A compound according to claim 6, or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait, wherein one R³ is H and the other R³ is methyl.

8. A compound according to claim 7 of Formula (la)

or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait.

198

9. A compound according to any one of daims 1 to 8, or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait, wherein R⁴ is

optionally substituted by one or two substituents independently selected from oxo, (Ci-C4)alkyl and hydroxy(Ci-C4)alkyl.

10. A compound according to claim 9, or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait, wherein R⁴ is

10 R² is H, (Ci-C4)alkyl, hydroxy(Ci-C₄)alkyl, (Ci-C4)alkoxy(Ci-C4)alkyl or (Ci-C₄)alkyl substituted by one, two or three F;

each R³ is independently H, F, (Ca-Csjcycloalkyl, (Ci-C4)alkyl or (Ci-C4)alkyl substituted by one, two or three F; or both R³ taken together with the carbon atom

11, A compound according to claim 10, or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait, wherein R⁴ is

Λ

N J

12, A compound according to any one of daims 1 to 11, or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait, wherein R⁵ and R⁶ are independently H; halogen; OH; CN; (Ci-C3)alkyl; hydroxy(Ci-C3)alkyl; (Ci-C3)alkoxy(Ci-C₃)alkyl; (Ci-Cajalkyl substituted by one, two or three F; (Ci-Cajalkoxy; or (Ci-C3)alkoxy substituted by (Ci-C3)alkoxy.

13. A compound according to daim 12, or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait, wherein R⁵ is H, halogen, CN, (Ci-C₃)alkyl, (Ci-C₃)alkoxy or (Ci-C3)alkoxy substituted by (C-i-C3)alkoxy.

199

14. A compound according to claim 12 or claim 13, or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait, wherein R⁶ is H; halogen; OH; CN; (Ci-C3)alkyl; hydroxy(Ci-C3)alkyl; (Ci-C3)alkoxy(Ci-C3)alkyl; (Ci-C₃)alkyl substituted by one, two or three F; or (Ci-C3)alkoxy.

15. A compound according to claim 1, or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait, selected from:

(S)-N-methyl-N-(6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[f]indazol-3-yl)-1H-benzo[d]imidazol-5-yl)-2morpholinopropanamide;

(R)-N-methyl-N-(2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[f]indazol·3-yl)-1^/-benzo[d]imidazol-5-yl)-2-(tetrahydro-2/-fpyran-4-yl)propanamide;

(R)-N-(7-fluoro-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[f|indazol-3-yl)-1H-benzo[d]imidazol-5-yl)-A/-methyl-2(tetrahydro-2/-/-pyran-4-yl)propanamide;

(S)-Λ/-(7-fluoro-2-((4aS,5aR)-5a-methyl·1,4,4a,5_I5a,6hexahydrocyclopropa[f]indazol-3'yl)-1H-benzo[d]imidazol-5-yl)-/\/-methyl-2morpholinopropanamide;

(S)-/V-ethyl-/V-(7-fluoro-2-((4aS,5aR)-5a-methyM hexahydrocycîopropa[f]indazol-3-yl)-1/-/-benzo[d]imidazol-5-yl)-2morpholinopropanamide;

(S)-N-(6,7-dffluoro-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[f]indazol-3“yl)-1/-/-benzo[d]imidazol·5-yl)-Λ/-methyl-2morpholinopropanamide;

(S)-A/-(6.7-difluoro-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[f]indazol-3-yl)-1/-/-benzo[d]imidazol-5-yl)-/V-ethyl-2morpholinopropanamide;

(S)-/\/-(7-fluoro-6-methyl-2-((4aS,5a/^:?)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[f|indazQl-3-yl)-1/-/-benzo[d]imidazol-5-yl)-/\/-methyl-2morpholinopropanamide; and

200 (S)-N-methyl-/V-(7-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6hexahydrocyclopropa[(|indazol-3-yl)-1H-benzo[c/]imidazol-5-yl)-2morpholinopropanamide.

15 to which they are attached form (C3-C5)cycloalkyl;

R⁴ is selected from

wherein each heterocycle is optionally substituted by one or two substituents independently selected from oxo, (Ci-C4)alkyl, hydroxy(Ci-C4)alkyl and (Ci-C4)alkyl substituted by one, two or three

F; and

R⁵ and R⁶ are independently H; halogen; OH; CN; (Ci-Cs)alkyl; hydroxy(Ci-Ce)alkyl; (Ci-C4)alkoxy(Ci-Ce)alkyl; (Ci-Cs)alkyl substituted by one, two or three F; (Ci-Cs)alkoxy; or (Ci-Ce)alkoxy substituted by (Ci-C₄)alkoxy.

197

16. The compound according to claim 15 which is (S)-A/-methyl-A/-(6-methyl-2((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)-1Hbenzo[d]imidazol-5-yl)-2-morpholinopropanamide, or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait. ।

17. The compound according to claim 15 which is (R)-A/-methyl-/V-(2-((4aS,5aR)-5amethyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)-1H-benzo[d]imidazol-5yl)-2-(tetrahydro-2/-/-pyran-4-yl)propanamide, or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or said sait.

18. The compound according to claim 16 which is (S)-A/-methyl-/V-(6-methyl-2((4aS,5aR)-5a-methyi-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)-1Hbenzo[d]imidazol·5-yl)-2-morpholinopΓopanamide, or a hydrate thereof.

19. The compound according to claim 18 which is (S)-/V-methyl-/V-(6-methyl-2((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol·3-yl)-1Hbenzo[d]imidazol-5-yl)-2-morpholinopropanamide, dihydrate.

20. The compound according to claim 16 which is ch₃ çh₃ X N.

N H

21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20 and a pharmaceutically acceptable excipient.

201

22. A pharnnaceutical composition according to claim 21 adapted for topical administration.

23. A pharmaceutical composition according to claim 21 or claim 22 including one or more additional therapeutic agents.

24. A compound according to any one of daims 1 to 20 for use as a médicament.

25. A compound according to any one of daims 1 to 20 for use in the treatment of a disorder for which an ITK inhibitor is indicated.

26. A compound for use according to claim 25 wherein the disorder for which an ITK inhibitor is indicated is a dermatological disorder.

27. A compound for use according to daim 26 wherein the dermatological disorder is dermatitis.

28. A compound for use according to claim 27 wherein the dermatitis is atopie dermatitis.

29. Use of a compound according to any one of daims 1 to 20 for the préparation of a médicament for the treatment of a disorder for which an ITK inhibitor is indicated.