RU2803284C1 - Benzimidazole derivatives - Google Patents

Abstract

FIELD: pharmaceutical chemistry.

SUBSTANCE: group of inventions includes a compound of formula (I), its pharmaceutically acceptable salts, enantiomers, dihydrate (S)-N-methyl-N-(6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)-1H-benzo[d]imidazol-5-yl)-2-morpholinopropanamide, pharmaceutical composition and the use based on them. In formula (I), each R¹ is independently H or F; R² is either H or (C₁-C₄)alkyl; each R³ is independently H, F or (C₁-C₄)alkyl; R⁵ and R⁶ independently represent H; halogen; OH; CN; (C₁-C₆)alkyl; hydroxy(C₁-C₆)alkyl; (C₁-C₄)alkoxy(C₁-C₆)alkyl; (C₁-C₆)alkyl substituted with one, two or three F; (C₁-C₆)alkoxy; or (C₁-C₆)alkoxy substituted with (C₁-C₄)alkoxy; R⁴ is selected from or , each of which is optionally substituted with one or two substituents independently selected from oxo, (C₁-C₄)alkyl and hydroxy(C₁-C₄) alkyl.

EFFECT: benzimidazole derivatives exhibiting properties of ITK inhibitors.

26 cl, 7 dwg, 4 tbl, 56 ex

Description

The invention relates to benzimidazole derivatives, their use in medicine, compositions containing them, methods for their preparation and intermediate compounds used in such methods. More particularly, the invention relates to interleukin-2-inducible T-cell kinase (ITK) inhibitors and their use for the treatment of ITK-mediated diseases, in particular skin diseases such as dermatitis (eg, atopic dermatitis).

Atopic dermatitis (AD) is a common chronic inflammatory skin disease that occurs in both children and adults. Patients with AD suffer from dry and itchy skin lesions, which can greatly affect their quality of life. Genetic and environmental factors may contribute to skin barrier impairment and immune hyperactivation, which are key factors in the pathogenesis of AD.

The pathogenic role of T cells and Th2 cell-derived cytokines, IL-4 and IL-13 in AD was demonstrated in the clinical development of dupilumab, an anti-IL-4 receptor antibody 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 observed with Janus kinase (JAK) inhibitors, which block IL-4 and IL-13 signaling 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. In addition, Th1 cells, Th22 cells and Th17 cells and the cytokines they produce, IFNγ, IL-22 and IL-17, respectively, also contribute to the pathogenesis of AD.

An effective anti-inflammatory drug in AD could modulate the predominant inflammatory response driven by T cells. Interleukin 2-inducible T cell kinase (ITK) is a member of the Tec family of tyrosine kinases. ITK expression is largely restricted to immune cells such as T, natural killer (NK) cells, natural killer T (NKT) cells, and mast cells. In T cells, ITK amplifies T cell receptor (TCR)-dependent signals to promote T cell activation, cytokine production, and T cell proliferation. Deletion of ITK or inhibition of ITK activity in T cells results in suppression of TCR-induced IL-4 and IL-13 production, which plays a central role in the pathophysiology of AD. An ITK inhibitor is expected to have additional efficacy over an IL-4 receptor antagonist since ITK also promotes the TCR-dependent production of numerous proinflammatory cytokines such as IL-2, IL-17, IL-22, IL-31, IFNγ, and TNF-α. In addition, ITK-deficient CD8+ T cells exhibit impaired proliferation of cytotoxic T lymphocytes, reduced degranulation, and defective cytolytic capacity. ITK-deficient mice and/or mice treated with an ITK inhibitor show reduced morbidity in models of type I diabetes, lymphoproliferative disease, allergy/asthma, and airway hyperresponsiveness. Additionally, ITK-deficient mice or mice treated with an ITK inhibitor show reduced skin inflammation in dermatitis models. Increased levels of ITK have been described in peripheral T cells from patients with moderate to severe AD, and ITK expression is increased in skin lesions of patients with AD.

In addition, tropomyosin receptor kinases (TRKs) are expressed by skin cells such as keratinocytes, neurons, mast cells and basophils. Both TRKA and its ligand, nerve growth factor (NGF), are present in the skin and their expression is upregulated in AD skin lesions. NGF levels in skin lesions of AD patients have been shown to correlate with the severity of pruritus. The cytokines IL-4 and IL-13, which contribute to the pathogenesis of AD, have been shown to upregulate TRKA expression by keratinocytes. In addition to regulating neuronal development and maintenance, NGF can sensitize nociceptors and cause pruritus. Itching is a major factor contributing to decreased quality of life in patients with AD. A therapy that can suppress itch would not only provide relief to patients, but could also break the itch-scratch cycle that promotes barrier breakdown and thus reduce the progression and chronicity of the disease.

NGF is also expressed and has effects on non-neuronal cells. NGF induces keratinocyte proliferation, promotes basophil activation, stimulates mast cell degranulation, and promotes neurogenic itch and inflammation. In addition, TRKA expression on TCR-stimulated peripheral blood T cells and T cells collected from synovial fluid of arthritis patients has been reported, and NGF induces T cell proliferation. Thus, inhibition of TRKA in the skin may suppress skin inflammation in addition to reducing itching.

These data suggest that an ITK inhibitor will suppress pathogenic T cell responses and reduce cytokine production and therefore have therapeutic value in the treatment of various inflammatory and autoimmune diseases, including dermatological conditions such as atopic dermatitis, contact dermatitis, psoriasis, focal alopecia and vitiligo. Moreover, an inhibitor of both ITK and TRKA activity should be of particular benefit in the treatment of dermatological conditions such as those just mentioned (eg, atopic dermatitis).

Links

Benecke H, et al. Expert Opin. Invest. Drugs. 2013;22:1167-1179;

Bissonette R, Papp KA, et al. Brit. J. Derm. 2016;175:902-911;

Botchkarev VA, Yaar M, Peters EMJ et al. J. Invest. Dermatology. 2006;126:1719-1727;

Brunner PM, et al. J Allergy Clin Immunol. 2017;139(4S):S65-S76;

Kapnick SM, Stinchcombe JC, et al. Immunol. 2017;198:2699-2711;

Lin TA, McIntyre KW, et al. Biochemistry 2004;43:11056-11062;

Matsumura S, Terao M, et al. J. Derm. Science 2015;78:215-223;

Otsuka A, Nomura T, et al. Immunological Reviews. 2017;278:246-262;

Raychaudhuri SP, Raychaudhuri SK, et al. Arthritis & Rheumatism 2011;63:3243-3252;

Sabat R, Wolk K, et al. Seminars in Immunopathology 2019;41:359-377;

Sahu N, and August A. Curr. Top. Med. Chem. 2009;9:690-703;

Von Bonin A, Rausch A, et al. Exp. Derm. 2010;20:41-47;

Yamaguchi J, Aihara M, et al. J. Dermatol. Science. 2008;53:48-54

According to a first aspect of the invention there is provided a compound of formula (I)

or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt, wherein

each R ¹ is independently H or F;

R ² is H, (C ₁ -C ₄ )alkyl, hydroxy(C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )alkoxy(C ₁ -C ₄ )alkyl or (C ₁ -C ₄ )alkyl , substituted with one, two or three Fs;

each R ³ is independently H, F, (C ₃ -C ₅ )cycloalkyl, (C ₁ -C ₄ )alkyl or (C ₁ -C ₄ )alkyl substituted with one, two or three Fs; or both R ³ together with the carbon atom to which they are attached form (C ₃ -C ₅ )cycloalkyl;

R ⁴ represents or where each heterocycle is optionally substituted with one or two substituents independently selected from oxo, (C ₁ -C ₄ )alkyl, hydroxy(C ₁ -C ₄ )alkyl and (C ₁ -C ₄ )alkyl substituted with one, two or three F; And

R ⁵ and R ⁶ independently represent H; halogen; HE; CN; (C ₁ -C ₆ )alkyl; hydroxy(C ₁ -C ₆ )alkyl; (C ₁ -C ₄ )alkoxy(C ₁ -C ₆ )alkyl; (C ₁ -C ₆ )alkyl substituted with one, two or three F; (C ₁ -C ₆ )alkoxy; or (C ₁ -C ₆ )alkoxy, substituted (C ₁ -C ₄ )alkoxy.

Embodiments of this first aspect of the invention are described below, where for convenience E1 is identical to it.

E1 A compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt, as defined above.

E2 The compound of embodiment E1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt, wherein each R ¹ is H or F.

E3 The compound of embodiment E2, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt, wherein each R ¹ is H.

E4 The compound of any one of embodiments E1-E3, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt, wherein R ² is H or (C ₁ -C ₄ )alkyl.

E5 The compound of embodiment E4, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt, wherein ^R2 is H.

E6 The compound of embodiment E4, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt, wherein R ² is methyl or ethyl.

E7 The compound of embodiment E6, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt, wherein R ² is methyl.

E8 The compound of embodiment E6, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt, wherein R ² is ethyl.

E9 The compound of any one of embodiments E1-E8, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt, wherein each R ³ independently represents H, F or (C ₁ -C ₄ )alkyl.

E10 The compound of embodiment E9, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt, wherein each R ³ is independently H, F or methyl.

E11 The compound of embodiment E10, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt, wherein each ^R3 is F.

E12 The compound of embodiment E10, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt, wherein each ^R3 is H.

E13 The compound of embodiment E10, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt, wherein one R ³ is H and the other R ³ is methyl.

E14 Compound of embodiment E13 of formula (Ia)

or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt.

E15 The compound of any one of embodiments E1-E14, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt, wherein R ⁴ is

or ,

optionally substituted with one or two substituents independently selected from oxo, (C ₁ -C ₄ )alkyl and hydroxy(C ₁ -C ₄ )alkyl.

E16 The compound of embodiment E15, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt, wherein R ⁴ is

or ,

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

E17 The compound of embodiment E16, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt, wherein R ⁴ is

or .

E18 The compound of embodiment E17, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt, wherein R ⁴ is

.

E19 The compound of embodiment E16, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt, wherein R ⁴ is

,

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

E20 The compound of embodiment E19, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt, wherein R ⁴ is

,

optionally substituted with oxo.

E21 The compound of embodiment E19, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt, wherein R ⁴ is

,

optionally substituted with one or two methyls.

E22 The compound of embodiment E19, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt, wherein R ⁴ is

.

E23 The compound of any one of embodiments E1-E22, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt, wherein R ⁵ and R ⁶ independently represent H; halogen; OH; CN; (C ₁ -C ₃ )alkyl; hydroxy(C ₁ -C ₃ )alkyl; (C ₁ -C ₃ )alkoxy(C ₁ -C ₃ )alkyl; (C ₁ -C ₃ )alkyl substituted with one, two or three F; (C ₁ -C ₃ )alkoxy; or (C ₁ -C ₃ )alkoxy, substituted (C ₁ -C ₃ )alkoxy.

E24 The compound of embodiment E23, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt, wherein R ⁵ is H, halogen, CN, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy or (C ₁ -C ₆ )alkoxy, substituted (C ₁ -C ₄ )alkoxy.

E25 The compound of embodiment E24, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt, wherein R ⁵ is H, halogen, CN, (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )alkoxy or (C ₁ -C ₃ )alkoxy, substituted (C ₁ -C ₃ )alkoxy.

E26 The compound of embodiment E25, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt, wherein R ⁵ is H, F, Br, CN, methyl, ethyl, methoxy or CH ₃ O-CH ₂ -CH ₂ O-.

E27 The compound of any one of embodiments E1-E26, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt, wherein R ⁶ is H; halogen; OH; CN; (C ₁ -C ₆ )alkyl; hydroxy(C ₁ -C ₆ )alkyl; (C ₁ -C ₄ )alkoxy(C ₁ -C ₆ )alkyl; (C ₁ -C ₆ )alkyl substituted with one, two or three F; or (C ₁ -C ₆ )alkoxy.

E28 The compound of embodiment E27, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt, wherein R ⁶ is H; halogen; OH; CN; (C ₁ -C ₃ )alkyl; hydroxy(C ₁ -C ₃ )alkyl; (C ₁ -C ₃ )alkoxy(C ₁ -C ₃ )alkyl; (C ₁ -C ₃ )alkyl substituted with one, two or three F; or (C ₁ -C ₃ )alkoxy.

E29 The compound of embodiment E28, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt, wherein R ⁶ is H, F, Cl, Br, OH, CN, methyl, ethyl, hydroxymethyl, methoxymethyl, CHF ₂ . CF ₃ or methoxy.

E30 The compound of embodiment E1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt, selected from:

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

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

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

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

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

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

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

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

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

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

Example 11: 2,2-difluoro- N -methyl- N- (2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl )-1 H -benzo[d]imidazol-5-yl)-2-(tetrahydro-2 H -pyran-4-yl)acetamide;

Example 12: (R) -N- (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)- N -methyl-2-(tetrahydro-2 H -pyran-4-yl)propanamide;

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

Example 14: (S) -N -methyl- N- (2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)- 1 H -benzo[d]imidazol-5-yl)-2-morpholinopropanamide;

Example 15: (S) -N- (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) -N -methyl-2-morpholinopropanamide;

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

Example 17: (S) -N- (6-fluoro-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)- 1 H -benzo[d]imidazol-5-yl) -N -methyl-2-morpholinopropanamide;

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

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

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

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

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

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

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

Example 25: (S) -N- (6,7-difluoro-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl )-1 H -benzo[d]imidazol-5-yl) -N -ethyl-2-morpholinopropanamide;

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

Example 27: 2-(2-(Hydroxymethyl)morpholino) -N -methyl- N- (6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6- hexahydrocyclopropa[f]indazol-3-yl)-1 H -benzo[d]imidazol-5-yl)acetamide;

Example 28: 2-((R)-2-(Hydroxymethyl)morpholino) -N -methyl- N- (6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5, 5a,6-hexahydrocyclopropa[f]indazol-3-yl)-1 H -benzo[d]imidazol-5-yl)acetamide;

Example 29: 2-(2,2-Dimethylmorpholino) -N -methyl- N- (6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa [f]indazol-3-yl)-1 H -benzo[d]imidazol-5-yl)acetamide;

Example 30: Methyl- N- (6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl) -1H -benzo[d]imidazol-5-yl)-2-((R)-2-methylmorpholino)acetamide;

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

Example 32: 2-((2R,6R)-2,6-dimethylmorpholino) -N -methyl- N- (6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5 ,5a,6-hexahydrocyclopropa[f]indazol-3-yl)-1 H -benzo[d]imidazol-5-yl)acetamide;

Example 33: 2-((2S,6S)-2,6-dimethylmorpholino) -N -methyl- N- (6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5 ,5a,6-hexahydrocyclopropa[f]indazol-3-yl)-1 H -benzo[d]imidazol-5-yl)acetamide;

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

Example 35: N -Methyl- N- (6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)- 1 H -benzo[d]imidazol-5-yl)-2-(tetrahydro-2 H -pyran-4-yl)acetamide;

Example 36: N -Methyl- N- (6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)- 1 H -benzo[d]imidazol-5-yl)-2-(3-oxomorpholino)acetamide;

Example 37: (S) -N- (7-bromo-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)- 1 H -benzo[d]imidazol-5-yl) -N -methyl-2-morpholinopropanamide;

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

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

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

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

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

Example 43: (S) -N- (7-chloro-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)- 1 H -benzo[d]imidazol-5-yl) -N -methyl-2-morpholinopropanamide;

Example 44: (S) -N- (7-ethyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)- 1 H -benzo[d]imidazol-5-yl) -N -methyl-2-morpholinopropanamide;

Example 45: (S) -N- (7-(hydroxymethyl)-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl )-1 H -benzo[d]imidazol-5-yl) -N -methyl-2-morpholinopropanamide;

Example 46: (S) -N- (7-fluoro-6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3 -yl) -1H -benzo[ d ]imidazol-5-yl) -N -methyl-2-morpholinopropanamide;

Example 47: (S) -N- (6-fluoro-7-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3 -yl) -1H -benzo[d]imidazol-5-yl) -N -methyl-2-morpholinopropanamide;

Example 48: (S) -N- (7-(difluoromethyl)-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl )-1 H -benzo[d]imidazol-5-yl) -N -methyl-2-morpholinopropanamide;

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

Example 50: (S) -N -methyl- N- (7-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3 -yl) -1H -benzo[d]imidazol-5-yl)-2-morpholinopropanamide; And

Example 51: (S) -N- (2-(( 4aS , 5aR )-5,5-difluoro-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3 -yl)-7-methyl-1 H -benzo[d]imidazol-5-yl) -N -methyl-2-morpholinopropanamide.

E31 The compound of embodiment E1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt, selected from:

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

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

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

Example 55: (R) -N- (7-cyano-2-(( 4aS , 5aR )-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl )-1H-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-1,4,4a, _5,5a ,6 -hexahydrocyclopropa[f]indazol-3-yl)-1H-benzo[d]imidazol-5-yl)-2-morpholinopropanamide.

E32 The compound of embodiment E1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt, selected from:

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

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

Example 12: (R) -N- (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)- N -methyl-2-(tetrahydro-2 H -pyran-4-yl)propanamide;

Example 15: (S) -N- (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) -N -methyl-2-morpholinopropanamide;

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

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

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

Example 46: (S) -N- (7-fluoro-6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3 -yl) -1H -benzo[d]imidazol-5-yl) -N -methyl-2-morpholinopropanamide; And

Example 50: (S) -N -methyl- N- (7-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3 -yl) -1H -benzo[d]imidazol-5-yl)-2-morpholinopropanamide.

E33 The compound of embodiment E32 which is (S) -N -methyl- N- (6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6- hexahydrocyclopropa[f]indazol-3-yl) - 1 H -benzo[d]imidazol-5-yl)-2-morpholinopropanamide or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt.

E34 The compound of embodiment E32 which is (R) -N -methyl- N- (2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f] indazol-3-yl)-1 H -benzo[d]imidazol-5-yl)-2-(tetrahydro-2 H -pyran - 4-yl)propanamide or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the said compound or the said salt.

E35 The compound of embodiment E32 which is (R) -N- (7-fluoro-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f] indazol-3-yl) -1H -benzo[d]imidazol-5-yl) -N -methyl-2-(tetrahydro- 2H -pyran-4-yl)propanamide or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof the specified compound or the specified salt.

E36 The compound of embodiment E32 which is (S) -N- (7-fluoro-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f] indazol-3-yl) -1H - benzo[d]imidazol-5-yl) -N -methyl-2-morpholinopropanamide or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt.

E37 The compound of embodiment E32 which is (S) -N- ethyl- N- (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)-2-morpholinopropanamide or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt.

E38 The compound of embodiment E32 which is (S) -N- (6,7-difluoro-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[ f]indazol-3-yl) - 1 H -benzo[d]imidazol-5-yl) -N -methyl-2-morpholinopropanamide or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt.

E39 The compound of embodiment E32 which is (S) -N- (6,7-difluoro-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[ f]indazol-3-yl) - 1 H -benzo[d]imidazol-5-yl) -N -ethyl-2-morpholinopropanamide or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt.

E40 The compound of embodiment E32 which is (S) -N- (7-fluoro-6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6- hexahydrocyclopropa[f]indazol-3-yl) - 1 H- benzo[d]imidazol-5-yl) -N -methyl-2-morpholinopropanamide or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt.

E41 The compound of embodiment E32 which is (S) -N- methyl- N- (7-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6- hexahydrocyclopropa[f]indazol-3-yl) - 1 H- benzo[d]imidazol-5-yl)-2-morpholinopropanamide or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt.

E42 The compound of embodiment E33 which is (S) -N -methyl- N- (6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6- hexahydrocyclopropa[f]indazol-3-yl) - 1 H -benzo[d]imidazol-5-yl)-2-morpholinopropanamide or a pharmaceutically acceptable solvate thereof.

E43 The compound of embodiment E42 which is (S) -N -methyl- N- (6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6- hexahydrocyclopropa[f]indazol-3-yl) - 1 H -benzo[d]imidazol-5-yl)-2-morpholinopropanamide or its hydrate.

E44 The compound of embodiment E43 which is (S) -N -methyl- N- (6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6- hexahydrocyclopropa[f]indazol-3-yl) - 1 H -benzo[d]imidazol-5-yl)-2-morpholinopropanamide, dihydrate.

E45 The connection of embodiment E33, which is

.

E46 Crystalline form of the compound of embodiment E44.

E47 Crystalline form of embodiment E46 with one, two, three, four or five PXRD peaks selected from 6.6°±0.2° 2θ, 7.4°±0.2° 2θ, 11.0°±0 ,2° 2θ, 11.6°±0.2° 2θ, 15.7°±0.2° 2θ and 17.7°±0.2° 2θ.

E48 Crystalline form of embodiment E47 with PXRD peaks at 6.6°±0.2° 2θ, 11.0°±0.2° 2θ, 15.7°±0.2° 2θ, and 17.7°±0 ,2° 2θ.

E49 Crystalline form of embodiment E47 with PXRD peaks at 6.6°±0.2° 2θ, 7.4°±0.2° 2θ, 11.0°±0.2° 2θ, and 11.6°±0 ,2° 2θ.

E50 Crystalline form of embodiment E47 with PXRD peaks at 7.4°±0.2° 2θ, 11.6°±0.2° 2θ, 15.7°±0.2° 2θ and 17.7°±0 ,2° 2θ.

E51 Crystal form of embodiment E47 with PXRD peaks at 6.6°±0.2° 2θ, 7.4°±0.2° 2θ, 11.0°±0.2° 2θ, 11.6°±0 ,2° 2θ, 15.7°±0.2° 2θ and 17.7°±0.2° 2θ.

E52 Crystal form of embodiment E46 with PXRD peaks at 6.6°±0.2° 2θ, 7.4°±0.2° 2θ, 11.0°±0.2° 2θ, 11.6°±0 ,2° 2θ, 13.3°±0.2° 2θ, 15.7°±0.2° 2θ, 16.2°±0.2° 2θ, 17.7°±0.2° 2θ, 18 .8°±0.2° 2θ and 22.9°±0.2° 2θ.

Brief description of drawings

Figure 1 shows the PXRD pattern for the compound of Example 1.1 (crystalline form 1).

Figure 2 shows the PXRD pattern of the compound from Example 1.2a (crystalline form 2).

Figure 3 shows the PXRD pattern for the compound of Example 1.3 (crystalline form 3).

Figure 4 shows the ORTEP diagram for the compound of Example 1.4 (crystal form 2) plotted with 50% probability substitution parameters and water molecules omitted for clarity.

Figure 5 shows the ORTEP diagram for the compound of Example 1.4 (crystal form 2) plotted with bias parameters at 50% probability and water molecules shown.

Figure 6 shows the TGA of the compound from Example 1.1 (crystalline form 1).

Figure 7 shows the TGA of the compound from Example 1.3 (crystalline form 3).

In compounds of formula (I):

- Alkyl means a straight or branched chain hydrocarbon group of the formula -C _n H _(2n+1) . Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

- Alkyloxy means an alkyl substituent attached via an oxygen atom. Examples of alkyloxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and t-butoxy.

- Cycloalkyl means a cyclic hydrocarbon group of the formula -C _n H _(2n-1) containing at least three carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl and cyclopentyl.

- Examples of halogen include fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

- Oxo refers to oxygen with a double bond (=O).

Hereinafter, all references to compounds of the invention include compounds of formula (I) or pharmaceutically acceptable salts, solvates or multicomponent complexes thereof, or pharmaceutically acceptable solvates or multicomponent complexes of pharmaceutically acceptable salts of compounds of formula (I), as discussed in more detail below.

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

Other preferred compounds of the invention are the compounds of formula (I) or pharmaceutically acceptable solvates thereof.

Other preferred compounds of the invention are the compounds of formula (I) or pharmaceutically acceptable hydrates thereof.

Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate, cyclamate, edisilate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, gibensate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methyl sulfate, 1,5-naphthalene disulfonate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate /dihydrogen phosphate, pyroglutamate, sucrose, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate.

Hemisalts of acids, such as hemisulfate and hemitartrate, can also be formed.

One skilled in the art will understand that the above salts include salts in which the counterion is optically active, for example d-lactate, or racemic, for example dl-tartrate.

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

Pharmaceutically acceptable salts of the compounds of formula (I) can be prepared by one or more of three methods:

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

(ii) removing the acid-labile protecting group from a suitable precursor of the compound of formula (I) using the desired acid; or

(iii) converting one salt of a compound of formula (I) to another by reaction with an appropriate acid or using a suitable ion exchange column.

All three reactions are usually carried out in solution. The resulting salt may precipitate and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the resulting salt can vary from completely ionized to almost no ionization.

The compounds of formula (I) or pharmaceutically acceptable salts thereof may exist in either unsolvated or solvated forms. The term "solvate" is used herein to describe a molecular complex comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more molecules of a pharmaceutically acceptable solvent, such as ethanol. The term "hydrate" is used when said solvent is water. Pharmaceutically acceptable solvates according to the invention include solvates in which the crystallization solvent may be isotopically substituted, for example, D ₂ O, d ₆ -acetone and d ₆ -DMSO.

The currently accepted classification system for organic hydrates is one that defines hydrates with a dedicated site, channel or coordinated to metal ions - see Polymorphism in Pharmaceutical Solids by KR Morris (Ed. HG Brittain, Marcel Dekker, 1995), incorporated herein via link. Dedicated site hydrates are those in which the water molecules are isolated from direct contact with each other by intermediate organic molecules. In channel hydrates, water molecules lie in lattice channels, where they are close to other water molecules. In metal-ion-coordinated hydrates, water molecules are bound to the metal ions.

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

Also included within the scope of the invention are multicomponent complexes (different salts and solvates) of compounds of formula (I) or pharmaceutically acceptable salts thereof, in which the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts. Complexes of this type include clathrates (drug-host inclusion complexes) and cocrystals. The latter are usually defined as crystalline complexes of neutral molecular constituents that are associated with each other through non-covalent interactions, but can also represent a complex of a neutral molecule with a salt. Cocrystals can be prepared by melt crystallization, recrystallization from solvents, or physical grinding of the components together - see Chem Commun, 17, 1889-1896, O. Almarsson and M. J. Zaworotko (2004), incorporated herein by reference. For a general overview of multicomponent complexes, see J Pharm Sci, 64 (8), 1269-1288, Haleblian (August 1975), incorporated herein by reference.

The compounds of the invention may exist on a continuum of solid states ranging from completely amorphous to completely crystalline. The term "amorphous" refers to a state in which a material lacks long-range order at the molecular level and, depending on temperature, can exhibit the physical properties of a solid or a liquid. Typically such materials do not produce distinct X-ray diffraction patterns and, although exhibiting the properties of a solid, are more formally described as liquids. When heated, a transition occurs from solid to liquid properties, which is characterized by a change in state, usually of the second order (“glass transition”). The term "crystalline" refers to a solid phase in which the material has a regular, ordered internal structure at the molecular level and produces a distinct x-ray diffraction pattern with defined peaks. Such materials, when heated sufficiently, will also exhibit the properties of a liquid, but the transition from solid to liquid is characterized by a phase transition, usually first order ("melting point").

The term "2 theta" or "2θ" refers to the position of the PXRD peak in degrees along the x-axis. Typical error associated with PXRD peak position is up to +/- 0.2° 2θ (USP-941).

The compounds of the invention may also exist in a mesomorphic state (mesophase or liquid crystals) when exposed to suitable conditions. The mesomorphic state is intermediate between the true crystalline state and the true liquid state (melt or solution). Mesomorphism resulting from a change in temperature 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 capable of forming lyotropic mesophases are described as "amphiphilic" and consist of molecules that have ionic properties (e.g. -COO^-Na⁺, -COO^-K⁺ or -SO₃ ^-Na⁺) or nonionic (for example, -N^-N⁺(CH₃)₃) polar head group. For more information seeCrystals and the Polarizing Microscopeby N. H. Hartshorne and A. Stuart, 4^th edition (Edward Arnold, 1970), incorporated herein by reference.

The compounds of the invention can be administered as prodrugs. Thus, certain derivatives of compounds of formula (I), which may themselves have little or no pharmacological activity, may, when administered orally or applied to the body, be converted into compounds of formula (I) having the desired activity, for example, by hydrolytic cleavage . Such derivatives are called "prodrugs". Additional information on the use of prodrugs can be found in “Pro-drugs as Novel Delivery Systems,” Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and "Bioreversible Carriers in Drug Design", Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association).

Prodrugs can be prepared, for example, by replacing the appropriate functional groups present in the compound of formula (I) with certain moieties known to those skilled in the art as "prodrugs", as described, for example, in "Design of Prodrugs" by H Bundgaard ( Elsevier, 1985)

Examples of prodrugs include phosphate-based prodrugs, such as dihydrogen or dialkyl (eg, di-tert-butyl) phosphate prodrugs. Additional examples of substituent groups in accordance with the above examples and examples of other types of prodrugs can be found in the above references.

Also included within the scope of the invention are metabolites of compounds of formula (I), that is, compounds formed in vivo upon administration of a drug. Examples of metabolites in accordance with the invention include those in which the compound of formula (I) contains the morpholinyl group of embodiment E19, hydroxyethylamines of formula (Ib) and amines of formula (Ic), as shown below.

The following compounds M1 and M2, metabolites of the compound of Example 1, illustrate this aspect of the invention and are of particular interest.

Other examples of metabolites of the invention include:

(i) hydroxymethyl derivatives (-CH ₃ → -CH ₂ OH);

(ii) when the compound of formula (I) contains an alkoxy group, its derivative is hydroxy (-(C ₁ -C ₆ )alkoxy → -OH); And

(iii) when the compound of formula (I) contains a phenyl group, its phenolic derivative (-Ph → -PhOH).

Formula (I) contains an asymmetric cyclopropindazolyl group and is stereospecifically defined (as the stereoisomer "4aS,5aR").

One skilled in the art will appreciate that one or more substituents in formula (I) may introduce one or more additional asymmetric sites. An illustration of such an additional asymmetric center is the asymmetric carbon atom of a compound of formula (Ia) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or said salt according to Embodiment E14, indicated by an asterisk (*) in the representation of formula (Ia) below:

.

Compounds of the invention containing said one or more additional asymmetric centers may exist as two or more stereoisomers; Included within the scope of the invention are all such stereoisomers (including epimers) of the compounds of the invention and mixtures of two or more of them.

Conventional techniques for preparing/isolating individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or racemate salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).

Alternatively, the racemate (or 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 group, a base or acid such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture can be separated by chromatography and/or fractional crystallization, and one or both diastereoisomers converted to the corresponding pure enantiomer(s) by methods well known to one skilled in the art.

The chiral compounds of the invention (and their chiral precursors) can be obtained in enantiomerically enriched form using chromatography, usually HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, usually heptane or hexane, containing from 0 to 50% vol. isopropanol, usually from 2% to 20%, and from 0 to 5% vol. alkylamine, usually 0.1% diethylamine. The concentration of the eluate results in a rich mixture.

Chiral chromatography using sub- and supercritical fluids can be used. Chiral chromatography methods useful in some embodiments of the present invention are known; see, for example, Smith, Roger M., Loughborough University, Loughborough, UK; Chromatographic Science Series (1998), 75 (Supercritical Fluid Chromatography with Packed Columns), pp. 223-249 and references cited therein.

Mixtures of stereoisomers can be separated by conventional methods 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 across a low energy barrier, tautomeric isomerism ("tautomerism") and conformational isomerism can occur.

Tautomerism may take the form of proton tautomerism in compounds of formula (I), as shown below in formula (I) in general and in Example 1 in particular with respect to the benzimidazole group:

;

.

One skilled in the art will appreciate that proton tautomerism can also occur on the pyrazole ring in compounds of formula (I).

Although for brevity the compounds of formula (I) are presented herein in a single tautomeric form, all possible tautomeric forms and mixtures thereof are included within the scope of the invention.

Conformational isomerism is a form of stereoisomerism in which isomers of a compound can convert into each other solely by rotation around single bonds. Such isomers are usually called conformational isomers or conformers and, in particular, rotamers. "Rotamer mixture" or "mixture of rotamers" describes a compound that exists as a mixture of more than one of the possible conformational isomers. Although for brevity the compounds of formula (I) are depicted in a single conformational form, all possible conformers and mixtures thereof are included within the scope of the invention.

The scope of the invention includes all crystalline forms of the compounds of the invention, including their racemates and racemic mixtures (conglomerates). Stereoisomeric conglomerates can also be separated by conventional methods described herein just above.

The scope of the invention includes all pharmaceutically acceptable isotopically labeled compounds of the invention in which one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number prevailing in nature.

Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of: hydrogen, such as ² H and ³ H; carbon such as ¹¹ C, ¹³ C and ¹⁴ C; fluorine such as ¹⁸ F; chlorine such as ³⁶ Cl; iodine such as ¹²³ I and ¹²⁵ I; nitrogen such as ¹³ N and ¹⁵ N; oxygen such as ¹⁵ O, ¹⁷ O and ¹⁸ O.

Certain isotopically labeled compounds of the invention, for example those containing a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. Radioactive isotopes of tritium, i.e. ³ H and carbon-14, i.e. ¹⁴ C are particularly suitable for this purpose due to their ease of inclusion and convenient means of detection. Substitution with heavier isotopes such as deuterium (D), i.e. ^2H may provide certain therapeutic benefits due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and may therefore be preferred in some circumstances. Substitution with positron-emitting isotopes such as ¹¹ C, ¹⁵ O and ¹³ N can be useful in positron emission tomography (PET) studies to study substrate receptor occupancy.

Isotopically labeled compounds of formula (I) can generally be prepared by conventional methods known to those skilled in the art, or by methods similar to those described in the accompanying and preparation examples, using an appropriate isotope-labeled reagent in place of the previously used unlabeled reagent.

Also included within the scope of the invention are the intermediates as defined below, all of their salts, solvates and complexes, and all solvates and complexes of their salts as defined above for compounds of formula (I). The invention includes all polymorphs of the above-mentioned species and their crystalline habits.

When preparing a compound of formula (I) according to the invention, one skilled in the art can select in the usual manner the form of the intermediate that provides the best combination of properties for this purpose. Such characteristics include melting point, solubility, processability and yield of the intermediate form, and the resulting ease of purification of the product upon isolation.

The compounds of the invention can be prepared by any method known in the art for preparing compounds of similar structure. In particular, the compounds of the present invention can be prepared by the methods described with reference to the following schemes, or by the specific methods described in the examples, or by methods similar to both.

One skilled in the art will appreciate that the experimental conditions set forth in the following schemes illustrate suitable conditions for carrying out the transformations shown and that it may be necessary or desirable to vary the exact conditions used to prepare the compounds of formula (I). In addition, it will be understood that it may be necessary or desirable to carry out the transformations in an order different from the order described in the diagrams, or to modify one or more transformations to obtain the desired compound of the invention.

The compounds of the present invention contain two or more stereogenic centers with the stereochemical designation (R) or (S). One skilled in the art will appreciate that all synthetic transformations can be carried out with either enantioenriched or racemic compounds, and that resolution to the desired stereoisomer can occur at any point in the synthesis using well known methods described herein and/or known in the art. this field of technology.

In addition, one skilled in the art will appreciate that at any stage in the synthesis of the compounds of the invention, it may be necessary or desirable to protect one or more sensitive groups to prevent unwanted side reactions. In particular, it may be necessary or desirable to protect hydroxyl, carboxyl and/or amino groups. The protecting groups used in the preparation of the compounds of the invention can be used in the usual manner; see, for example, those described in "Greene's Protective Groups in Organic Synthesis" by Theodora W Greene and Peter G M Wuts, fifth edition, (John Wiley and Sons, 2014), incorporated herein by reference, and in particular , in Chapters 2, 5 and 7, respectively, which also describe how to remove such groups.

In the following general processes and unless otherwise noted:

- R ¹ - R ⁶ are as defined previously for the compound of formula (I);

- R is an alkyl such as ethyl, or in the case of formulas 3 and 4, two R can 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 (eg SEM), alkoxycarbonyl (eg BOC), acetyl (Ac), benzyl (eg PMB) or dihydropyran (DHP) protecting group; And

X represents F or Cl.

The substituted pyrazole of formula 11 can 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 Birch reduction (Mander, L.N. Comprehensive Organic Synthesis ; Trost, B.M. and Fleming, I., Ed.; Pergamon: Oxford, 1991 , Vol. 8, pp. 489-521), using an alkali metal such as Li or Na in liquid ammonia at temperatures below -30°C.

The preparation of the olefin acetal of formula 3 from the 1,4-diene compound 2 can be carried out under catalytic acidic conditions, for example using pTSA or CSA in the presence of primary alkyl alcohols such as MeOH or EtOH, or a diol such as ethylene glycol, with or without solvent it, such as DCM or other aprotic solvent, at a temperature of from 0 to 100°C, for example from 0 to 25°C.

Conversion of the olefin of formula 3 to the cyclopropane of formula 4 can occur via dihalocarbene addition or Simmons-Smith cyclopropanation (Charette, AB; Beauchemin, A. Simmons-Smith Cyclopropanation Reaction. Org. React. 2001 , 58 , p 1-415).

Deprotection of the acetal of formula 4 to produce the ketone of formula 5 can be carried out under acidic conditions, for example using HCl, H ₂ SO ₄ or an organic acid such as pTSA in a mixture of water and a solvent such as THF.

Preparation of the diketone of formula 6 can be achieved by reacting the ketone of formula 5 with: i) a dialkyl oxalate and 1-3 equivalents of a strong base such as LDA, LiHMDS or KOtBu, in a polar aprotic solvent such as THF, at a temperature of -78°C to 25°C; or ii) with the alkoxide in an appropriate alcohol solvent (eg EtONa in ethanol) at a temperature 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 yield a pyrazole of formula 7. A hydrazine salt such as an HCl salt can also be used in conjunction with the corresponding molar equivalent of an inorganic (eg K ₂ CO ₃ ) or organic (eg Et ₃ N or iPr ₂ NEt) base.

Protection of the pyrazole of formula 7 can be achieved using SEM-Cl, DHP or other suitable protecting group to deliver the pyrazole of formula 8, the separation of which to deliver the corresponding enantiomer of formula 9 can be achieved using supercritical liquid chromatography using a chiral solid phase.

Reduction of an ester of formula 9 to an alcohol of formula 10 can be carried out using LAH in an aprotic solvent such as THF at 0° C. to reflux.

Oxidation of the alcohol of formula 10 to the aldehyde of formula 11 can be accomplished: i) using an agent such as PCC, PDC or MnO ₂ in an aprotic solvent; or ii) catalysis, for example using TEMPO/bleach and TPAP/NMO (Caron, S., Dugger, RW, Gut Ruggeri, S., Ragan, JA, Brown Ripin, DH, Chem. Rev. 2006, 106, 2943 -2989) or Swern oxidation conditions.

The compound of formula (I) can be prepared as shown in Scheme 2, where R is H or PG.

Scheme 2

4-nitroaniline of formula 12 can be acylated to give the amide of formula 13 with a carboxylic acid using standard amide coupling reagents such as EDCI, HATU, HBTU or T3P; or reaction with an alternative acylating agent such as an acid chloride or an acylimidazole in a solvent such as DCM or DMF in the presence of an organic base such as Et ₃ N at 0°C to reflux.

Alkylation of the amide of formula 13 to give the amide of formula 14 can be accomplished 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.

Nitroaniline of formula 15 can be prepared by replacing X in the compound of formula 14 with a nitrogen-containing nucleophile, such as ammonia, benzyl or substituted benzylamine, at a temperature of from 25 to 100°C, either neat or in a solvent such as DMF. or THF.

Reduction of nitroaniline of formula 15 (with accompanying deprotection if necessary) can be carried out under hydrogenation conditions with a Pd catalyst such as 10% Pd/C, at 1-3 atm H ₂ , in an alcohol solvent such as MeOH or EtOH, at temperature from 20 to 60°C to obtain ortho -diamines of formula 16. Alternatively, when R=H, reduction of the nitro group can be carried out using a metal such as Zn or Fe in AcOH, at a temperature of 20-100°C.

The diamine of formula 16 can be condensed with the aldehyde of formula 11 in a polar solvent such as DMF with 2-5 eq. DMSO, with an oxidizing agent such as Na ₂ S ₂ O ₅ at a temperature of 90 to 150°C, to give benzimidazole of formula 17. Alternatively, the condensation of compounds of formulas 16 and 11 can occur in the presence of aqueous NaHSO ₃ and EtOH or other alcohol solvent at a temperature of 60°C to boiling temperature with reflux.

Removal of the protecting group in a compound of formula 17 to obtain the corresponding compound of formula (I) can be carried out under conditions well known to one skilled in the art. For example, when PG=SEM, the protecting group can be removed with TPA in DCM, optionally with the addition of Et ₃ SiH.

By methods directly corresponding to those described in Scheme 2, the compound of formula (I) can also be prepared from 3-nitroaniline of formula 18 in accordance with Scheme 3.

Scheme 3

The compound of formula (I) can also be synthesized according to Scheme 4, where R is H or PG.

Scheme 4

The 4-nitroaniline of formula 12 can be N -protected with an appropriate protecting group such as BOC or Ac to give the compound of formula 19, which in turn can be N -alkylated with an alkyl halide as described in Scheme 2 above to give the compound of formula 14, for delivery of the compound of formula 20.

The compound of formula 20 can be substituted under conditions of aromatic nucleophilic substitution to give the compound of formula 21; which in turn can be reduced, for example, under the conditions described above in Scheme 2 to obtain the compound of formula 16, to obtain the diamine of formula 22; and finally, the diamine is condensed with the aldehyde of formula 11 to obtain the orthogonally protected compound of formula 23.

Selective deprotection of the aniline protecting group of the compound of formula 23 to obtain aniline of formula 24 can be achieved by reaction with ZnBr ₂ or TMSOTf (PG=BOC) in a non-polar solvent such as DCM; or basic hydrolysis with aq. NaOH or KOH in MeOH or EtOH at reflux (PG=Ac).

Aniline of formula 24 can be acylated under the conditions described in Scheme 2 above to give benzimidazole of formula 17 and then deprotect the benzimidazole to give the compound of formula (I) under conditions well known to one skilled in the art, such as those described in Scheme 2 to obtain formula (I).

Compounds of formula (I) can also be synthesized according to Scheme 5.

Scheme 5

1-Bromo-3,4-diaminobenzene of formula 25 can be condensed with an aldehyde of formula 11 under the conditions described in Scheme 2 to prepare the compound of formula 17 to give benzimidazole of formula 26, which in turn can be protected by reaction with SEM-Cl in an aprotic solvent such as THF or DMF with a base such as NaH, KOtBu or LiHMDS at -78°C to 60°C to produce a mixture of regioisomers of formulas 27a and 27b. The compound of formula 27b can be isolated therefrom by conventional methods.

Although the description of the subsequent transformations is made with reference to formula 27b, one skilled in the art will understand that:

i. a mixture of regioisomers of formulas 27a and 27b can be used in the final preparation of the compound of formula (I) (resulting in the corresponding pairs of regioisomers of formulas 29, 30 and 31); And

ii. Regioisomers of compounds of formula 29, 30 or 31 can also be isolated by conventional methods and used in the final preparation of the compound of formula (I).

Transition metal-catalyzed cross-coupling of a compound of formula 27b with a protected amine derivative such as tert-butyl carbamate, also known as a Buchwald/Hartwig coupling, gives the protected aniline of formula 28. The cross-coupling reaction can be catalyzed by Pd or Cu metal and appropriate ligands and is carried out in a solvent, such as toluene, tert-amyl alcohol or 1,4-dioxane; with a number of bases including Cs ₂ CO ₃ , LiHMDS, NaOtBu and KOtBu; and at temperatures from 20 to 120°C.

The protected aniline of formula 28 can be alkylated as described in Scheme 2 to give the compound of formula 14 to give the compound of formula 29. Subsequent steps of deprotection to give the compound of formula 30, acylation to give the compound of formula 31 and final deprotection to give the compound of formula ( I) can be carried out under normal conditions, such as those described in Scheme 4 to obtain, respectively, the compounds of formulas 24, 17 and (I).

The compound of formula (I) can also be synthesized according to Scheme 6.

Scheme 6

The compound of Formula 28 can be deprotected under the conditions described in Scheme 5 to prepare the compound of Formula 30 to give the aniline of Formula 32, which can be acylated under the conditions described in Scheme 2 to give the benzimidazole of Formula 17 to give the amide of Formula 33.

The amide of formula 33 can be N-alkylated to give the compound of formula 31, and then deprotected to give the compound of formula (I) under conventional conditions such as those described in Scheme 2, respectively, to give the compounds of formula 14 and (I).

The compound of formula (I), where R ⁴ represents a morpholinyl substituent, can also be synthesized according to Scheme 7.

Scheme 7

Aniline of formula 30 can be acylated using acetyl chloride or acetic anhydride, alone or in an aprotic solvent such as DCM, with an organic base such as Et ₃ N, at -20 to 60°C to give the N -acetyl compound formulas 34.

The compound of formula 34 can be treated with a strong base such as LDA in an aprotic solvent such as THF, followed by chlorination with a reagent such as benzenesulfonyl chloride to give the α-chloramide of formula 35.

The amide of formula 35 can be treated with the appropriate morpholine in an aprotic solvent such as DMF or MeCN, in the presence of a base such as K ₂ CO ₃ or Na ₂ CO ₃ and with the addition of NaI to give the compound of formula 31, which can then be deprotected to obtain the compound of formula (I) under conventional conditions, such as those described in Scheme 2 for the preparation of the compound of formula (I).

Compounds of formula (I) can be converted into an alternative compound of formula (I) by interconversions of functional groups well known to those skilled in the art. For example, when R ⁵ or R ⁶ is a halogen such as Br or Cl, further conversion is possible using synthetic methods such as transition metal-mediated coupling reactions, including Suzuki and Buchwald/Hartwig cross-couplings, cyanidation and borylation, among others. other reactions, before manipulating the replacement in these positions.

Compounds of formulas 1, 12, 18 and 25 can be obtained from commercial sources, prepared in analogy with methods described in the literature, or prepared by the methods described in the "Experiments" section below, or variations thereof well known to one skilled in the art.

All new methods for preparing the compounds of formula (I) or their pharmaceutically acceptable salts and corresponding new intermediates used therein constitute additional aspects of the present invention.

The compounds of the invention for pharmaceutical use may be administered in amorphous or crystalline form or may exist on a continuum of solid states ranging from completely amorphous to completely crystalline. They can be obtained, for example, in the form of solid compacts, powders or films by methods such as precipitation, crystallization, freeze-drying, spray-drying or evaporation-drying. Microwave or radiofrequency drying can be used for this purpose.

The compounds of the invention can be administered by any suitable route in the form of a pharmaceutical composition adapted to such route and at a dose effective for the intended treatment. Typically, they are administered as a formulation in combination with one or more pharmaceutically acceptable excipients. The term "excipient" is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will depend largely on factors such as the route of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

Methods of administration of the compounds of the invention include oral, parenteral, topical, rectal, vaginal, ocular and oral administration.

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

Parenteral administration may involve injection of a compound of the invention into the bloodstream, muscle, or internal organ, where the injection may be intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, or subcutaneous. For parenteral administration, needle (including microneedle) injectors, needleless injectors, and infusion methods can be used.

Local administration is preferred and includes:

- introduction into the skin, nail, hair, claw, hoof, mucous membrane;

- demomal or transdermal administration;

- intranasal administration or administration by inhalation;

- rectal or vaginal administration; And

- injection directly into the eye or ear.

The term "transdermal administration" refers to the diffusion of a compound of the invention across the skin barrier, nail, hair, claws or hooves as a result of topical administration or other application of the composition. Transdermal delivery involves delivery through any part of the skin, nail, hair, claw or hoof and absorption or penetration through the remaining part.

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

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

Pharmaceutical compositions suitable for delivering the compounds of the invention and methods for their preparation will be apparent to those skilled in the art. Such compositions and preparation methods can be found, for example, in 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 swelling polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opaques, glidants, processing aids, dyes, sweeteners, fragrances, flavorings and the like. Solvents may include water, ethanol, propylene glycol, polyethylene glycols (eg, PEG400, PEG300), and mixtures thereof. The excipient(s) are selected to facilitate the manufacture or use of the pharmaceutical composition.

Pharmaceutical compositions can be prepared by conventional dissolution and mixing. For example, a compound of the invention may be dissolved in a solvent in the presence of one or more of the excipients described above. The dissolution rate of poorly water-soluble compounds can be increased by using spray-dried dispersions 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 deposition method and disintegrants” J. Pharm. Pharmacol ., 39, 769-773 (1987); and US2002/009494; incorporated herein by reference.

Solid dosage forms for oral administration of the 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, a compound of the invention is typically combined with one or more pharmaceutically acceptable excipients. Solid oral dosage forms, such as tablets and capsules, can be formulated with an enteric coating.

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

Parenteral formulations of the compounds of the invention are typically aqueous solutions, which may contain excipients such as salts, carbohydrates and buffers (preferably buffered to a pH of 3 to 9). Formulations for parenteral administration may also be sterile non-aqueous solutions or dried (eg, lyophilized) forms for administration upon reconstitution with a suitable vehicle, such as sterile 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 mixed under sterile conditions with a pharmaceutically acceptable topical carrier and any preservatives or buffers that may be required. Compounds that are volatile may require mixing with constituent agents or packaging materials to ensure proper dose delivery. Compounds of the invention that have poor skin permeability may require one or more penetration enhancers, while compounds that are 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 use that provides adequate 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. One skilled in the art will appreciate that this term also includes carrier materials approved for use in topical cosmetics.

The term "penetration enhancer" refers to increasing the permeability of the skin, nails, hair, claws or hooves of a compound of the present invention to increase the rate and extent of penetration of the compound. Increased penetration can be observed, for example, by measuring the rate of drug diffusion through the skin, nail, hair, claws or hooves of an animal or human using a diffusion cell apparatus. The diffusion cell is described by Merritt et al. Diffusion Apparatus for Skin Penetration, J of Controlled Release, 1 (1984) pp. 161-162.

Ointments, pastes, creams, lotions, gels, suppositories, powders, solutions, sprays, drops, inhalants and topical patches may contain, in addition to the compound of the invention, one or more pharmaceutically acceptable excipients, such as animal or vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, zinc oxide, preservatives, antioxidants, flavorings, emulsifiers, dyes, inert fillers, anti-irritants, tackifiers, fragrances, opacifiers, antioxidants , gelling agents, stabilizers, surfactants, emollients, dyes, preservatives, buffering agents, permeability enhancers. Such excipients should not interfere with the effectiveness of the biological activity of the active agent and should not have a deleterious effect on epithelial cells or their function.

Transdermal administration can be accomplished using a transdermal patch. The transdermal patch may be of the "reservoir and porous membrane" type or use a "matrix system".

The solubility of the compounds of the invention used in the preparation of pharmaceutical compositions can be increased through the use of appropriate formulation techniques, such as the inclusion of solubility enhancing agents.

Pharmaceutical compositions can be formulated for immediate and/or modified release. Conveniently, the compounds of the invention are formulated for immediate release.

Modified release formulations include delayed, extended, pulsed, controlled, targeted and programmed release. Thus, the 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.

The compounds of the invention can be combined with soluble macromolecular compounds, such as cyclodextrin and suitable derivatives thereof, or polyethylene glycol-containing polymers, to improve their solubility, dissolution rate, taste masking, bioavailability and/or stability for use in any of the above routes of administration.

For administration to human patients, the total daily dose of the compounds of the invention is generally from 1 mg to 10 g, for example from 60 mg to 6 g, for example from 100 mg to 1.5 g, depending on the route of administration and effectiveness. For example, a total daily dose of 200 mg to 1 g, such as 250 mg to 750 mg, may be required for administration. The total daily dose may be administered as a single dose or in divided doses and may, at the discretion of the physician, be outside the typical range specified herein. These dosages are based on an average human subject weighing approximately 60 to 70 kg. Your doctor will be able to easily determine doses for subjects whose weight is outside this range, such as infants and older adults.

As noted above, the compounds of the invention are useful in that they exhibit pharmacological activity in animals, i.e. inhibit ITK. More specifically, the compounds of the invention are useful for the treatment of diseases for which an ITK inhibitor is indicated.

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

Preferably, the compound of the invention also inhibits TRKA.

In yet another aspect of the invention, a compound of the invention is provided for use as a drug.

In another aspect of the invention, a compound of the invention is provided for use in the treatment of a disorder for which an ITK inhibitor is indicated.

In another aspect of the invention, the use of a compound of the invention is provided for the preparation of a medicament for the treatment of a disorder for which an ITK inhibitor is indicated.

In another aspect of the invention, there is provided a method of treating a disease 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.

Diseases or conditions for which an ITK inhibitor is indicated include inflammatory, autoimmune, dermatological, ocular, respiratory, joint, cardiovascular and neuroinflammatory diseases. One skilled in the art will appreciate that a given disease, disorder, or condition may fall under more than one of the above categories.

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

- inflammatory disorders such as allergic conjunctivitis, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis, microscopic colitis (eg, collagenous colitis or lymphocytic colitis), diversion colitis, Behçet's disease and unspecified colitis), nephritis, retinitis, retinopathy, myositis, vasculitis, Sjögren's syndrome, Wegener's granulomatosis, arteritis, sclerosing cholangitis and eosinophilic esophagitis;

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

- diseases or conditions of the eye, including autoimmune eye diseases, keratoconjunctivitis, vernal conjunctivitis, non-infectious uveitis (for example, uveitis associated with Behçet's disease and phacoantigenic uveitis), keratitis (for example, herpetic keratitis and conical keratitis), corneal epithelial dystrophy, keratoleukoma, ocular premphigus, Moray's ulcer, scleritis, retinitis, retinopathy, Graves' ophthalmopathy, Vogt-Koyanagi-Harada syndrome, keratoconjunctivitis sicca (dry eye), phlyctena, iridocyclitis, sarcoidosis, endocrine ophthalmopathy, sympathetic ophthalmitis, allergic conjunctivitis and ocular neovascularization;

- dermatological conditions such as eczema (eg chronic and dyshidrotic eczema), chronic pruritus, dermatitis (eg atopic, irritant contact, allergic contact, occupational, perioral, congestive, numular, seborrheic, xerotic, eyelid, diaper and hand dermatitis) , vitiligo, alopecia areata, pruritus (eg, chronic idiopathic pruritus), psoriasis (eg, plaque, guttate, inverse, pustular, nail, flexural palmoplantar, facial, or erythrodermic psoriasis), scleroderma, pemphigus, dermatomyositis, neurodermatitis, hyperemia skin, urticaria, cutaneous lupus erythematosus (eg, acute cutaneous lupus (acute cutaneous lupus), subacute cutaneous lupus (subacute lupus), and chronic cutaneous lupus (discoid lupus)), keloid, sunburn, hypertrophic scar, idiopathic thrombocytopenic thrombotic purpura (also known as immune thrombocytopenia purpura (ITP)), ichthyosis (eg, ichthyosis vulgaris), epidermal hyperplasia, acne, lichen planus, lichen sclerosus, rosacea, epidermolysis bullosa, intertrigo, keratosis pilaris, urticaria (eg, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria), molluscum contagiosum, Netherton syndrome, Vogt-Koyanagi-Harada syndrome, Sweet's syndrome, pityriasis alba, vulvovaginitis, Sutton's nevus/nevi, post-inflammatory hypopigmentation, senile leukoderma, chemical/drug leukoderma, palmoplantar pustulosis, pemphigoid and hidradenitis suppurativa;

- respiratory conditions such as rhinitis (for example, allergic and perennial rhinitis), rhinorrhea, nasal congestion, nasal inflammation, asthma (for example, chronic asthma, inveterate asthma, late-onset asthma, bronchial asthma, allergic asthma, internal asthma, exogenous asthma and dust asthma) chronic obstructive pulmonary disease (COPD), chronic and acute bronchoconstriction, chronic bronchitis, emphysema, chronic eosinophilic 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 diseases such as arthritis (for example, osteoarthritis, as well as psoriatic, rheumatoid, juvenile and gouty arthritis), spondyloarthropathy (for example, reactive arthritis (also known as Reiter's syndrome) and axial spondyloarthritis (including ankylosing spondylitis)), inflammation of the cartilage, bone degradation and Still's disease;

- cardiovascular and metabolic disorders such as diabetes (type 1 and type 2), diabetic neuropathy, cachexia and celiac sprue; And

- neuroinflammatory disorders such as lupus (eg CNS, systemic and discoid lupus), diabetic neuropathy and multiple sclerosis.

Allergic contact dermatitis (ACD) is a contact dermatitis characterized by an allergic reaction to contact with a substance. An example of ACD is urushiol-induced contact dermatitis (also called toxicodendron dermatitis or meadow dermatitis), which is caused by urushiol oil found in a variety of plants, including poison ivy, poison oak, poison sumac, and Chinese lacquer tree. Other allergens that can cause ACD include chromium, gold, and nickel.

Irritant contact dermatitis (ICD) is a form of contact dermatitis that can be divided into forms caused by chemical irritants and forms caused by physical irritants. Common chemical irritants include acids, alkalis, latex, oils, fragrances and preservatives in cosmetics, solvents and surfactants.

Occupational dermatitis is an ACD or ICD that occurs as a result of exposure to an allergen or irritant in the workplace.

In addition, an ITK inhibitor may be used in the treatment of 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 the ITK inhibitor is indicated is a dermatological disease. In another embodiment, the dermatological condition for which an ITK inhibitor is indicated is dermatitis. In another embodiment, the dermatitis for which the ITK inhibitor is indicated is atopic dermatitis.

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

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

In such combinations, a compound of the invention and other pharmacologically active compound(s) can be administered simultaneously, for example, in a unit dosage form (eg, a topical composition such as a cream or ointment), sequentially or separately.

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

- an agent for the treatment of autoimmune and/or inflammatory disorders, such as sulfasalazine, mesalazine, azathioprine, antibodies (for example, infliximab, adalimumab, Belimumab, Tanesumab, Ranibizumab, Bevacuumab, Metribolizumab, Nalizumab and Vedovolizumab), 6-Merkaptepurin , hydroxychlorokhin, mofetil, mycophenolate sodium, leflunomide, Rituxan, solumedrol, depomedrol, nonsteroidal anti-inflammatory drug (NSAID) (eg, aspirin, ibuprofen, celecoxib, valdecoxib, WBI-1001, and MRX-6) and corticosteroid (eg, betamethasone, dexamethasone, and prednisone);

- an agent for the treatment of dermatological conditions such as an immunosuppressant (eg, cyclosporine, tacrolimus and pimecrolimus), antibody (eg, infliximab, adalimumab, dupilumab, omalizumab and efalizumab), TNF inhibitor (eg, etanercept), PDE4 inhibitor (eg, crisaborole) and topical corticosteroid (eg, fluocinonide, mapracorate, hydrocortisone, desonide, alklometasone, triamcinolone, and deoxymethasone);

- an agent for the treatment of respiratory conditions such as oxymetazoline, rifampin, an antihistamine (eg, fexofenadine, loratidine, desloratidine, levocetirizine, metapyrylene, cetirizine), leukotriene receptor antagonist (eg, montelukast and zafirlukast), 5-lipoxygenase activating protein (FLAP) antagonist ), muscarinic receptor antagonist (eg, tiotropium and ipratropium), sodium cromoglycate, nedocromil sodium, corticosteroid (eg, budesonide, fluticasone, mometasone, dexamethasone, prednisolone, ciclesonide and beclomethasone), beta-2 agonist (eg, salmeterol, albuterol, salbutamol , fenoterol and formoterol) and antibody (eg, omalizumab);

- an agent for the treatment of joint disorders, such as methotrexate, azathioprine and NSAIDs (for example, aspirin, ibuprofen, celecoxib, valdecoxib, WBI-1001 and MRX-6);

- an agent for the treatment of cardiovascular and metabolic disorders, such as ursodeoxycholic acid, chloroquine, quinacrine, methylnorephrine, phenylephrine, methoxamine, oxymetazoline, theophylline, PDE5 inhibitor (eg, sildenafil, vardenafil and tadalafil), PDE4 inhibitor (eg, crisaborole, ibudilast , cilomilast, roflumilast and ampremilast) and a kinin B ₁ or B ₂ receptor antagonist; And

- an agent for the treatment of a neuroinflammatory disorder, such as cyclophosphamide.

One or more additional therapeutic agents may also be selected from any of the following:

- JAK inhibitors such as abrocitinib, baricitinib, brepocitinib, cerdulatinib, decernotinib, delgocitinib, fedratinib, filgotinib, gandotinib, ilginatinib, itacitinib, lestaurtinib, momelotinib, oclacitinib, pacritinib, peficitinib, ritlecitinib, ruxolitinib b, 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 derivative such as alitretinoin;

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

an H4 receptor antagonist such as ZPL-389;

- an NKI receptor antagonist such as aprepitant and tradipitant;

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

- a chymase inhibitor such as SUN 13834;

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

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

- an immunomodulator such as PF-06763809; And

- SYK and BTK inhibitor, 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, can be conveniently combined in a kit suitable for co-administration of the compositions. Thus, a kit of the invention includes two or more separate pharmaceutical compositions, at least one of which contains a compound of the invention, and means for storing said compositions separately, such as a container, a divided bottle or a divided foil pouch. An example of such a set is the known blister pack used for packaging tablets, capsules and the like. The kit of the invention is particularly suitable for administering different dosage forms (eg, topical, oral, parenteral, etc.), for administering individual compositions at different dosing intervals, or for titrating individual compositions against each other. To facilitate compliance, the kit usually contains instructions for use and may be equipped with a so-called memory device.

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

It should be understood that all references to treatment herein include curative, palliative and prophylactic treatment.

In the non-limiting examples and preparations set forth below, which illustrate the invention, and in the above diagrams, reference may be made to the following abbreviations, definitions and analytical procedures:

°2θ means degrees 2-theta;

AcOH means acetic acid;

Ac ₂ O means acetic anhydride;

APC stands for allophycocyanin;

aq. means watery;

atm. means atmosphere;

ATP means adenosine 5'-triphosphate disodium salt trihydrate;

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

Boc means tert -butoxycarbonyl;

BOC ₂ O means BOC anhydride, di- tert -butyl dicarbonate;

w means wide;

BTFFH means fluorobis(tetramethylene)formamidinium hexafluorophosphate;

BTK stands for Bruton's tyrosine kinase;

°C means degrees Celsius;

CD ₃ OD means deuteromethanol;

CDCl ₃ means deuterochloroform;

conc. means concentrated;

CSA stands for camphorsulfonic acid;

δ means chemical shift;

d means doublet;

dd means doublet of doublets;

ddd means doublet of doublets of doublets;

dt means doublet of triplets;

DAST stands for diethylaminosulfur trifluoride;

DCM means dichloromethane;

DCE means 1,2-dichloroethane;

Dess-Martin periodinan means 3-oxo-1,3-dihydro-1λ ⁵ ,2-benziodoxole-1,1,1-triyl triacetate;

DHP means dihydropyran;

DMAP means 4-dimethylaminopyridine;

DMF means N,N-dimethylformamide;

DMSO means dimethyl sulfoxide;

EDCI means 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride;

ei means enantiomeric excess;

EDTA means ethylenediaminetetraacetic acid;

ESI-MS means electrospray ionization mass spectrometry;

EtOAc means ethyl acetate;

EtOH means ethanol;

EtONa means sodium ethoxide;

Et ₃ N means triethylamine;

Et ₃ SiH means triethylsilane;

g means gram;

h means hour(s);

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

GBTU means N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate;

HEPES means (4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid);

HPLC means high pressure liquid chromatography;

iPr ₂ NEt means N,N-diisopropylethylamine, also known as Hunig's base;

KOAc means potassium acetate;

KOtBu means potassium tert -butoxide;

l means liter;

ALH means lithium aluminum hydride;

LCMS means liquid chromatography-mass spectrometry;

DAL means lithium diisopropylamide;

LiHMDS means lithium hexamethyldisilazide, also known as lithium bis(trimethylsilyl)amide;

m means multiplet;

M stands for molar;

MeCN means acetonitrile;

MeNH ₂ means methylamine;

MeOH means methanol;

MHz means it's megahertz;

min means minutes;

ml means milliliter;

mm means millimeter;

mmol means millimole;

mole means mole;

MS m/z means mass spectrum peak;

MTBE means methyl tert-butyl ether;

n -BuLi means n- butyllithium;

NaHMDS means sodium bis(trimethylsilyl)amide;

NaOtBu means sodium tert -butoxide;

NMP means N -methyl-2-pyrrolidone;

NMR stands for nuclear magnetic resonance;

ORTEP stands for Oak Ridge Thermal Ellipsoid Plot;

PCC stands for pyridinium chlorochromate;

PDC means pyridinium dichromate;

Pd ₂ (dba) ₃ means tris(dibenzylideneacetone)dipalladium(0);

Pd/C means palladium on carbon;

Pd(dppf)Cl ₂ means 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II);

Pd(OAc) ₂ means palladium(II) acetate;

Pd(OH) ₂ /C means palladium(II) hydroxide on carbon;

Pd(Ph ₃ P) ₄ means tetrakis(triphenylphosphine)palladium(0);

PE means petroleum ether;

PhCH ₃ means toluene;

PMB means para-methoxybenzyl;

p TSA means p -toluenesulfonic acid monohydrate;

PXRD stands for Powder X-Ray Diffraction;

ka means quartet;

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

RT means room temperature;

c means singlet;

nasysh. means saturated;

SEM-Cl means 2-(trimethylsilyl)ethoxymethyl chloride;

SLC means supercritical liquid chromatography;

SPhos means 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl;

SXRD stands for single crystal X-ray diffraction;

t means triplet;

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

t-BuOH means tert- butanol;

TCEP means tris(2-carboxyethyl)phosphine;

TFA means trifluoroacetic acid;

ATFA means trifluoroacetic anhydride;

TGA stands for thermogravimetric analysis;

THF means tetrahydrofuran;

TMSCF ₃ means trifluoromethyltrimethylsilane;

TMSOTf means trimethylsilyl trifluoromethanesulfonate;

T ₃ P means propylphosphonic anhydride;

Tris means tris(hydroxymethyl)aminomethane;

µm means micrometer;

v/v means volume per volume;

w/v means mass per volume;

XantPhos means 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; And

ZnEt ₂ means diethylzinc.

Unless otherwise stated, all reactions are carried out under nitrogen atmosphere. When sodium hydride is used in the following procedures, the weight is adjusted to reflect its use as a 60% suspension in mineral oil. RT (room temperature) is generally considered to mean approximately 22°C (±5°C). The term "concentrated" refers to the process of removing volatile compounds such as solvents using a rotary evaporator under reduced pressure.

The ¹ H and ¹⁹ F NMR spectra correspond in all cases to the expected structures. The δ characteristics for ¹ H NMR are given relative to the residual solvent signals (for CDCl ₃ , δH=7.27 ppm, for DMSO-d ₆ , δH=2.50 ppm, for CD ₃ OD, δH =3.30 ppm, for DMF-d ₇ , δH=8.03 ppm) using conventional abbreviations to designate the main peaks. One skilled in the art will appreciate that tautomers may be detected in the NMR data and some exchanged protons may not be visible. Likewise, one skilled in the art will appreciate that a mixture of rotamers can be detected in NMR data.

Mass spectra are recorded using ESI-MS. Where appropriate and unless otherwise noted, m/z data presented are for the isotopes ¹⁹ F, ³⁵ Cl, ⁷⁹ Br and/or ⁸¹ Br and ¹²⁷ I.

If preparative TLC or silica gel chromatography is used, one skilled in the art will appreciate that any suitable solvent or combination of solvents can be used to purify the desired compound.

The nomenclature of compounds in the following Preparation Examples and Examples was created using ChemDraw Professional 18.0, Perkin Elmer, in accordance with IUPAC (International Union of Pure and Applied Chemistry).

Examples of receiving

Preparation Example 1: 1-methoxy-5-methylcyclohexa-1,4-diene

The reaction is carried out in 25 parallel batches. Anhydrous ammonia (1.4 kg, 82.2 mmol) was bubbled into a solution of 1-methoxy-3-methylbenzene (500 g, 4.09 mol) in t-BuOH (1.5 L) and THF (1 L), at In this case, the reaction is maintained between -60 and -50°C. Lithium sand (62.5 g, 9.0 mol) was then added to the reaction mixture in portions while maintaining the temperature at -60 to -50°C, and the reaction mixture was stirred for 2 hours. The reaction mixture is slowly heated to ~20°C and the ammonia is allowed to evaporate. NH ₄ Cl (500 g) and water (500 ml) were added to the reaction mixture. The batches are combined and the organic layer is separated. The aqueous layer was washed with EtOAc (5 L x 2). The combined organic layers were then washed with brine (5 L), the organic layer was dried (Na ₂ SO ₄ ) and concentrated to give the title compound (10.1 kg, 80%). ^1H NMR (400 MHz, CDCl ₃ ) δ 5.42-5.41 (m, 1H), 4.65-4.63 (m, 1H), 3.56 (s, 3H), 2.79- 2.77 (m, 2H), 2.65-2.56 (m, 2H), 1.74-1.68 (m, 3H).

Preparation Example 2: 7-methyl-1,4-dioxaspiro[4.5]dec-7-ene

The reaction is carried out in 6 parallel batches. To a solution of Preparation Example 1 (500 g, 4.03 mol) in DCM (4.0 L) add p-toluenesulfonic acid monohydrate (46.8 g, 201 mmol) and ethylene glycol (399 g, 6.04 mol) at temperature from -10 to 0°C. The mixture is stirred at approximately 0°C for 0.5 hours. The reaction batches are combined and washed with sat. aqueous NaHCO ₃ (5 L), water (5 L, 2x), dry (Na ₂ SO ₄ ), filter and concentrate to give the title compound (14.2 kg). ^1H NMR (400 MHz, CDCl ₃ ) δ 5.40-5.34 (m, 1H), 3.98-3.88 (m, 4H), 2.21-2.12 (m, 4H), 1.67(d, 5H).

Preparation Example 3: 1-methylspiro[bicyclo[4.1.0]heptane-3,2'-[1,3]dioxolane]

The reaction is carried out in 10 parallel batches. A solution of ZnEt ₂ (1.00 M, 5.14 L) in DCM (2.0 L) was cooled to 0°C, and TPA (380 ml, 5.14 mol) was added dropwise at 0°C. The mixture was stirred at 0°C for 30 minutes, after which CH ₂ I ₂ (414 ml, 5.14 mol) was added dropwise at 0°C. The mixture is stirred at 0°C for 30 minutes. Preparation Example 2 (396 g, 2.57 mol) was added dropwise while maintaining the temperature at 0°C, and the resulting mixture was stirred at 0°C for 30 minutes. The reaction mixture is poured into water (1 L) and the batches are combined. The combined mixture was extracted with DCM (3 x 8 L). The combined organic phases are dried (Na ₂ SO ₄ ), filtered and concentrated to give the title compound (3.0 kg); ^1H NMR (400 MHz, CDCl ₃ ) δ 3.93-3.73 (m, 4H), 2.13-2.01 (m, 1H), 1.84-1.79 (m, 1H), 1.75-1.67 (m, 2H), 1.47-1.36 (m, 1H), 1.27 (m, 1H)), 1.03 (s, 3H), 0.73-0 .61 (m, 1H), 0.35-0.25 (m, 2H).

Preparation Example 4: 1-Methylbicyclo[4.1.0]heptan-3-one

The reaction is carried out in 14 parallel batches. A solution of Preparation Example 3 (300 g, 1.78 mol) in THF (1.5 L) and water (300 ml) was treated with pTSA-H ₂ O (34.0 g, 178 mmol). The mixture is stirred at 60°C for 3 hours and then cooled to RT. 14 batches are combined and processed sat. aqueous NaHCO ₃ until the pH is 6-7. The mixture is extracted with MTBE (3×8 L), dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by chromatography (silica, EtOAc/PE=0-100%) to give the title compound (1.2 kg, 39%). ^1H NMR (400 MHz, CDCl ₃ ) δ 2.60-2.40 (m, 1H), 2.32-2.18 (m, 1H), 2.11-1.93 (m, 1H), 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).

Preparation Example 5: Ethyl 2-(6-methyl-4-oxobicyclo[4.1.0]heptan-3-yl)-2-oxoacetate

The reaction is carried out in four parallel batches. A solution of Preparation Example 4 (200 g, 1.61 mol) in EtOH (1.0 L) was treated with EtONa (126 g, 1.77 mol) at 0°C. Add diethyl oxalate (259 g, 1.77 mol, 242 ml) at 0°C, the mixture is slowly warmed to 20°C and stirred for 1 hour. The four batches were combined and the mixture was poured into 1N HCl (5 L) and extracted with DCM (3 x 3 L). The combined organic extracts are dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by chromatography (silica, EtOAc/PE=0-10%) to give the title compound (1.4 kg, 97%). LC/MS m/z (M+H) ⁺⁼ 225.0

Preparation Example 6: Ethyl 5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3-carboxylate

The reaction is carried out in four parallel batches. To a solution of Preparation Example 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 hours. The four reaction batches are combined, H ₂ O (10 L) is added and extracted with DCM (3 x 8 L). The combined organic layers are dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE=5-33%) to give the title compound (800 g, 58%). ^1H NMR (400 MHz, DMSO- d6 ) 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 (USS, 3H), 1.20 (USS, 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.

Preparation example 6a: ethyl (4aR,5aS)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3-carboxylate; And

Preparation Example 6b: Ethyl (4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3-carboxylate

Preparation example 6 is separated using chiral SLC (Chiral Tech OZ-H column 250 mm × 4.6 mm × 5 μm with mobile phase CO _2(g) /MeOH=80:20 with 0.2% NH ₄ ⁺ (7N NH ₃ in MeOH) and flow rate 3.0 ml/min).

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

6b: retention time=4.76 min, 98.9% ee; [α]²⁰ _D=-80.2 (c=4.7, MeOH);¹H NMR (400 MHz, DMSO-d ₆ ) 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 (USH, 1H), 0.05-0.05 (USH, 1H).

Preparation example 7a: ethyl-(4aS,5aR)-5a-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3- carboxylate; And

Preparation example 7b: ethyl-(4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3- carboxylate

A suspension of NaH (19.3 g, 483 mmol) in THF (500 ml) was treated with a solution of Preparation Example 6b (103 g, 467.6 mmol) in THF (1.25 L) at 0°C. After 30 minutes, SEM-Cl (81.9 g, 491 mmol) was added at 0°C and the mixture was stirred at 0°C for 3 hours. The mixture is treated with sat. aqueous NH ₄ Cl (500 ml) at 0°C. The mixture is extracted with EtOAc (3×500 ml), washed with brine (500 ml), dried (MgSO ₄ ), filtered and concentrated. The crude product is purified by chromatography (silica, EtOAc/heptanes=7-18%) to give the title compounds.

7a: (5.5 g, 3.3%);¹H NMR (400 MHz, DMSO-d ₆ ) δ 5.43 (uss, 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), 2.71-2.67 (m, 1H), 1.60-1.41 (m, 3H) , 1.21 (s, 3H), 1.08-1.05 (m, 1H), 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-d ₆ ) δ 5.64 (s, 2H), 4.32-4.25 (m, 2H), 3.49-3.44 (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, 1H), 0.76-0.72 (m, 2H), 0.33-0.29 (m, 1H), 0.04-0.01 (m, 1H), - 0.1 (s, 9H); LC/MSm/z(M+N)⁺⁼351.3.

Preparation Example 8: ((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl )methanol

A suspension of LiAlH ₄ (14.94 g, 393.7 mmol) in THF (500 ml) at 0° C. was treated dropwise with a solution of Preparation Example 7b (138 g, 393.7 mmol) in THF (1 L). The mixture is stirred at 15°C for 2 hours. The mixture is cooled to 0°C and successively treated by adding dropwise H ₂ O (15 ml), 15% aq. NaOH (15 ml) and H ₂ O (30 ml) followed by the addition of MgSO ₄ and EtOAc (500 ml). The resulting mixture was filtered and the filtrate was concentrated to give the title compound (110 g, 91%). ^1H NMR (400 MHz, CDCl ₃ ) δ 5.35-5.23 (m, 2H), 4.64-4.55 (m, 2H), 3.53-3.49 (m, 2H), 3.06-3.02 (m, 1H), 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).

Preparation Example 9: (4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3-carbaldehyde

A solution of Preparation Example 8 (110.13 g, 0.36 mol) in DCM (1.5 L) was treated with activated MnO₂(310 g, 3.57 mol) and the resulting mixture was stirred at 25°C for 16 hours. The mixture is filtered. The filtrate is concentrated and the crude product is purified by chromatography (silica, EtOAc/PE=3-10%) to givespecified in header connection(96 g, 88%). SLC method: Chiral Pak AD-3 150 mm x 4.6 mm x 3 µm, 5-40% (0.05% diethylamine in EtOH/CO_2(g)) for 1.5 min, 2.5 ml/min, retention time = 1.466 min 97.4%, 94.8% e.i.¹H NMR (400 MHz, DMSO-d ₆ ) 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/MSm/z(M+N)⁺⁼307.3.

Preparation Example 10: 7,7-Difluoro-1-methylspiro[bicyclo[4.1.0]heptane-3,2'-[1,3]dioxolane]

The reaction is carried out in 2-6 batches in parallel. A solution of Preparation Example 2 (150 g, 972 mmol) in THF (1.20 L) was treated with 276 g (1.95 mol) TMSCF ₃ and 75.8 g (50.6 mmol) NaI. The mixture is stirred at 70°C for 16 hours. The 26 reaction mixtures are cooled to room temperature and combined. The mixture is diluted with water (10 L) and extracted with MTBE (4 x 3 L). The organic phase is washed with brine (8 L), dried (Na ₂ SO ₄ ), filtered and concentrated to give the title compound (4.30 kg, 83% yield).

Preparation Example 11: 7,7-difluoro-1-methylbicyclo[4.1.0]heptan-3-one

The reaction is carried out in 5 batches in parallel. The mixture from Preparation Example 10 (860 g, 4.21 mol) in THF (10 L) was treated with 3M HCl (2.6 L) at 25°C. The mixture is stirred at 25°C for 16 hours. 5 reactions are combined and extracted with MTBE (4x2.5 l), washed with sat. aqueous NaHCO ₃ (5 l) and salt solution (5 l). The organic phase is dried (Na ₂ SO ₄ ), filtered and concentrated to give the title compound 11 (3.50 kg); ¹ H NMR (400 MHz, CDCl ₃ ) δ: 2.56 (usd, 1H), 2.38-2.13 (m, 4H), 2.01-1.89 (m, 1H), 1.49 -1.38 (m, 1H), 1.27 (uss, 3H)

Preparation Example 12: Ethyl 2-(7,7-difluoro-6-methyl-4-oxobicyclo[4.1.0]heptan-3-yl)-2-oxoacetate

The reaction is carried out in 8 batches in parallel. A solution of Preparation Example 11 (250 g, 1.56 mol) in EtOH (1.25 L) was treated with EtONa (112 g, 1.65 mol) portionwise at 0°C. The resulting mixture was treated with diethyl oxalate (24.2 g, 1.65 mol) at 0°C. The reaction mixture is stirred at 25°C for 1 hour. 8 parties are united. The mixture was poured into 3 M HCl (8.00 L) and extracted with DCM (3 x 2 L). The organic extracts are washed with brine (5 L), dried (Na ₂ SO ₄ ), filtered and concentrated to give the title compound 12 (3.20 kg, 98% yield).

Preparation Example 13: Ethyl 5,5-difluoro-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3-carboxylate

The reaction is carried out in 8 batches in parallel. The suspension from Preparation Example 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 mixture was stirred at room temperature for 16 hours. Eight reactions are combined for processing. The reaction mixture was concentrated and the residue was taken up in H ₂ O (5.00 L) and extracted with EtOAc (5 x 2 L). The combined organic extracts are dried over (Na ₂ SO ₄ ), filtered and concentrated. The crude product was purified by recrystallization from 6:1 EtOAc/EtOH (3 L) at 20°C to give the title compound 13 (1.0 kg). ^1H NMR (400 MHz, CDCl ₃ ) δ: 12.03-10.65 (USM, 1H), 4.38 (q, 2H), 3.30-3.04 (m, 3H), 2.79 (dd, 1H), 1.57 (usdd, 1H), 1.34-1.43 (m, 6H); LC-MS (ER+) e/z [M+H]=257.1

Preparation Example 14: Chiral SLC separation of enantiomers

Preparation Example 13 was separated by chiral SLC using a Chiral Tech AD-H 250 mm x 21.2 mm x 5 µm column with a CO _2(g) /MeOH mobile phase of 80:20 with 0.2% 7N NH ₃ in MeOH and speed flow 200 ml/min.

Analytical SLC method: Chiral Tech AD-H 250 mm × 4.6 mm × 5 µm A=CO _2(g) ; B=0.2% NH ₃ (as 7N NH ₃ in MeOH) in MeOH; gradient=0-1 min 5% B, 1-9.5 min 5-60% B linear change; 9.5-10 min 60-5% B linear change.

Preparation example of 14a, ethyl-(4aR,5aS)-5,5-difluoro-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3-carboxylate, 100 % ee by analytical method SLC, retention time=4.605 min.

Preparation example 14b, ethyl (4aS,5aR)-5,5-difluoro-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3-carboxylate, 99.85 % ee analytical method SLC, retention time = 5.565 min.

Preparation Example 15: Ethyl-(4aS,5aR)-5,5-difluoro-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[ f]indazole-3-carboxylate

A mixture of 4.25 g (106 mmol) NaH in 20 ml THF, cooled to 0° C., is treated dropwise over 45 min with a solution of Preparation Example 14b (18.16 g, 70.87 mmol) in 100 ml THF. The mixture was stirred at 0°C for 1 hour and then treated dropwise with SEM-Cl (17.7 g, 106 mmol) in THF (80 ml). The resulting mixture was stirred at room temperature for 48 hours. The reaction mixture was slowly poured onto ice and extracted 3 times with EtOAc. The organic extracts are combined, washed with brine, dried (MgSO ₄ ) _, filtered and concentrated. The crude product was purified by chromatography (silica, EtOAc/heptanes=0-20%) to give 25.8 g (94%) of the title compound. ^1H NMR (400 MHz, CDCl ₃ ) 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 (ushdd, 1H), 1.62-1.54 (m, 1H), 1.44-1.35 (m, 6H), 0.94-0.81 (m, 2H), -0.03 (s, 9H); LC-MS m/z (M+H) ⁺⁼ 387.4

Preparation Example 16: ((4aS,5aR)-5,5-difluoro-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f ]indazol-3-yl)methanol

To a solution of Preparation Example 15 (25.84 g, 66.86 mmol) in THF (100 mL) at approximately -5° C., add a solution of LiAlH ₄ (100 mL, 1 M in THF) dropwise at a rate such that control the temperature. from 0 to 10°C. The mixture is stirred at 0°C for an additional 1 hour and gradually warmed to room temperature and stirred for an additional 4 hours. The mixture is cooled to -10°C and treated dropwise with 6N NaOH solution (45 ml) for 30 minutes. Additional EtOAc is added to aid mixing of the thick mixture and the slurry is warmed to room temperature. Add anhydrous MgSO ₄ and continue stirring for another 30 minutes. The mixture is filtered and the solids are washed with EtOAc. The filtrate was concentrated and dried to give the title compound (21.89 g, 95%). ^1H NMR (400 MHz, CDCl ₃ ) δ 5.38-5.21 (m, 2H), 4.60 (s, 2H), 3.55-3.41 (m, 2H), 3.08 ( usd, 1H), 2.98-2.83 (m, 2H), 2.79-2.65 (m, 1H), 2.24 (usd, 1H), 1.60-1.49 (m, 1H), 1.40 (brs, 3H), 0.94-0.80 (m, 2H), -0.03 (s, 9H); LC-MS m/z (M+H) ⁺⁼ 345.5.

Preparation Example 17: (4aS,5aR)-5,5-difluoro-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f] indazole-3-carbaldehyde

A solution of Preparation Example 16 (21.89 g, 63.55 mmol) in DCM (25 ml) was cooled to 0°C. Add a solution of Dess-Martin periodinane (33.7 g, 79.4 mmol) in DCM (250 ml) dropwise at 0° C. over about 20 minutes. The mixture is treated with 2.2% water/DCM (50 ml), adding dropwise over 45 minutes at 0°C. The mixture is warmed to room temperature and stirred for 4 hours. The mixture is treated with 1N NaOH solution (380 ml) and stirred for 30 minutes. The two-phase mixture is separated. The organic phase is washed with brine, dried (MgSO ₄ ) _, filtered and concentrated. The crude product was purified by chromatography (silica, EtOAc/heptanes=0-50%) to give the title compound (17.8 g, 82%). ^1H NMR (400 MHz, CDCl ₃ ) δ 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.

Preparation Example 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 mixture. The resulting mixture was stirred at 25°C for 36 hours. Water (3 L) and EtOAc (2 L) were added to the mixture. The aqueous phase is extracted with EtOAc (2×1 L). The combined organic extracts are dried (Na₂SO₄), filter and concentrate. The crude product is purified by chromatography (silica, EtOAc/PE=11%) to giveconnection specified in the header(290 g, 82%).¹H NMR (400 MHz, DMSO-d ₆ ) 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).

Preparation Example 19: (S)-2-morpholinopropanoic acid

A solution of Preparation Example 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 is degassed and purged with N₂(3 times), and then stirred under H atmosphere₂within 36 hours. The solid is removed by filtration and the filtrate is concentrated. The resulting residue is washed with MTBE (200 ml x2) to obtainspecified in the connection header(146 g, 79%). SLC Analytical Method: Chiral Tech IC 250 mm x 4.6 mm x 5 µm, 5 to 60% with 0.2% NH₄ ⁺(7N in MeOH) in MeOH/CO_2(g), 3.0 ml/min, retention time=5.88 min, 100% ee;¹H NMR (400 MHz, DMSO-d ₆ ) δ 3.56 (s, 4H), 3.18-3.16 (m, 1H), 2.54-2.53 (m, 4H), 1.17-1.15 (m, 3H); LC/MSm/z(M+N)⁺⁼160.1.

Preparation example 20: 2-(tetrahydro-2 H -pyran-4-yl)acetyl 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° is treated with oxalyl chloride (30.5 g, 240 mmol). The mixture is then heated to 20°C and stirred for 16 hours. The mixture was concentrated to give the title compound (19.5 g, quant.).

Preparation Example 21: (R)-4-benzyl-3-(2-(tetrahydro-2 H -pyran-4-yl)acetyl)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 is then stirred at -78°C for 2 hours. Add a solution of 2-(tetrahydro- 2H- pyran-4-yl)acetyl chloride (19.5 g, 120 mmol) in THF (100 ml) at -78°C and stir for an additional 2 hours. The mixture is then heated to 20°C and then stirred for 16 hours. The reaction is treated with sat. aqueous NH ₄ Cl (400 ml) and the resulting two-phase mixture is separated. The organic phase is dried (Na ₂ SO ₄ ) and concentrated. The residue is suspended in DCM/PE (50 ml/300 ml) and stirred at -50°C for 30 minutes. The solids were collected and dried to give the title compound (21.5 g, 89% yield). LC/MS m/z (M+H)= 303.8.

Preparation example 21a: (R)-4-benzyl-3-((R)-2-(tetrahydro-2 H -pyran-4-yl)propanoyl)oxazolidin-2-one

A solution of Preparation Example 21 (21.5 g, 70.8 mmol) in THF (200 mL) at -78° C. was treated with NaHMDS (1 M in THF, 106 mL). The mixture was stirred for 1 hour and treated with methyl iodide (50.3 g, 354 mmol) at -78°C. The reaction mixture was stirred at -78°C for 2 hours, and then gradually warmed to 20°C over 16 hours. The reaction mixture is treated with sat. aqueous NH ₄ Cl (300 ml) and the two-phase mixture is separated. The organic layer is washed with brine, dried (MgSO ₄ ) _, filtered and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE: 0-100%) to give the title compound (15.5 g, 69%). ^1H NMR (400 MHz, CDCl ₃ ) δ 7.32-7.11 (m, 5H), 4.62 (dd, 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), 1.41-1.26 (m, 2H), 1.15 (d, 3H); LC/MS m/z (M+H) ⁺⁼ 318.3.

Preparation Example 22: (R)-2-(tetrahydro-2 H -pyran-4-yl)propanoic acid

A solution of Preparation Example 21a (15.5 g, 48.8 mmol) in THF/H ₂ O (410 ml/255 ml) at 0° C. was treated with LiOH H ₂ O (10.2 g, 244 mmol) and 30 % aq. H ₂ O ₂ (27.7 g, 244 mmol). The mixture is stirred at 0°C for 1.5 hours, and then at 20°C for 1.5 hours. The mixture is treated with sat. aqueous Na ₂ SO ₃ (300 ml), and the organic solvent was removed in vacuo. The mixture is washed with DCM (2×200 ml) and then treated with conc. HCL until pH=1 is reached. The mixture was extracted with DCM (3×200 ml), the extracts were combined and dried (Na ₂ SO ₄ ), filtered and concentrated to give the title compound 22 (6.12 g, 79% yield). (Ref: Evans, DA, et al. J. Am. Chem. Soc. 1984, 106, 1154-1156)

¹H NMR (400 MHz, CDCl₃) δ 4.07-3.93 (m, 2H), 3.39 (dt, 2H), 2.30 (p, 1H), 1.87-1.77 (m, 1H), 1.68- 1.56 (m, 2H)), 1.51-1.28 (m, 2H), 1.17 (d, 3H). [α]²⁰ _D=-17.98 (c=0.3 g/100 ml, EtOH); Chiral SLC (MeOH/CO₂, Chiral Tech IG, 5 to 60% in 10 min, 250 mm × 4.6 mm × 5 µm), retention time = 3.42 min, 97% ee.

Preparation Example 23: (S)-2-(tetrahydro-2 H -pyran-4-yl)propanoic acid

The acid is prepared analogously to the example for the preparation of 22 (R)-2-(tetrahydro- 2H -pyran-4-yl)propanoic acid using (S)-4-benzyloxazolidin-2-one in step 2. ¹ H NMR (400 MHz, CDCl ₃ ) 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). [α] ²⁰ _D= +19.99 (c=0.3 g/100 ml, EtOH)

Preparation Example 24: Benzyl 2-bromopropanoate

To a solution of 2-bromopropionic acid (5.0 g, 32.7 mmol) in DCM (100 ml) at 0° C., add Et ₃ N (3.64 g, 36.0 mmol), and then add benzyl chloroformate ( 5.58 g, 32.7 mmol). After 10 minutes, DMAP (399 mg, 3.27 mmol) was added and the mixture was stirred for 4 hours at 30°C. The mixture is poured into 1M HCl (15 ml) and saline solution (80 ml). The mixture is extracted with DCM (2×80 ml). The organic extracts are combined, dried (MgSO ₄ ) _, filtered and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE, 0-5%) to give the title compound (4.81 g, 86%). ^1H NMR (400 MHz, CDCl ₃ ) δ 7.38-7.27 (m, 5H), 5.22-5.10 (m, 2H), 4.43-4.37 (m, 1H), 1.80(d, 3H); LC/MS m/z (M+Na) ⁺⁼ 267.0.

Preparation Example 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 minutes, Preparation Example 24 (16 g, 8.90 mmol) was added dropwise. After stirring at 25°C for 3 hours, the mixture is diluted with sat. aqueous NH ₄ Cl (30 ml) and water (20 ml). The mixture is extracted with EtOAc (2×60 ml), the combined extracts are dried (MgSO ₄ ), filtered and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE=0-70%) to give the title compound 25 (256 mg, 13%). ^1H NMR (400 MHz, CDCl ₃ ) 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).

Preparation Example 26: 2-(3-oxomorpholino)propanoic acid

To the mixture of Preparation Example 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 H ₂ (1 atm) at 25°C for 16 hours. The reaction mixture is filtered and the solids are washed with MeOH (3×20 ml). The filtrate was concentrated to give the title compound 26 (167 mg, 99%). ^1H NMR (400 MHz, CDCl ₃ ) δ 6.15 (brs, 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).

Receipt example 27: (S) -N- (5-chloro-2-methyl-4-nitrophenyl)-2-morpholinopropanamide

EDCI (8, 84 g, 46.1 mmol) at 20°C. The mixture is stirred at 20°C for 16 hours. The mixture is treated with sat. aqueous NH ₄ Cl (100 ml) and extracted with EtOAc (3×100 ml). The combined organic layers are dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was triturated with MTBE (100 ml) to give the title compound (4.8 g, 68%). ^1H NMR (400 MHz, CDCl ₃ ) δ 9.83 (s, 1H), 8.68 (s, 1H), 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).

Preparation Example 28: (S)-N-(5-chloro-2-methyl-4-nitrophenyl) -N -methyl-2-morpholinopropanamide

To a solution of Preparation Example 27 (5.50 g, 16.8 mmol) 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 hour and a solution of methyl iodide (2.62 g, 18.5 mmol) in THF (15 ml) was added dropwise at 0°C. The mixture is stirred at 25°C for 16 hours. The reaction is treated with sat. aqueous NH ₄ Cl (100 ml) and extracted with EtOAc (2×100 ml). The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated to give the title compound (5.1 g, 89%). ^1H NMR (400 MHz, CDCl ₃ ) 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).

Receipt example 29: (S) -N- (5-((4-methoxybenzyl)amino)-2-methyl-4-nitrophenyl) -N -methyl-2-morpholinopropanamide

Ammonium acetate (72.2 g, 936.3 mmol) was added to the mixture from Preparation Example 28 (320 g, 936.3 mmol) in 4-methoxybenzylamine (513.7 g, 3.74 mol). The mixture is heated at 100°C for 16 hours. The mixture is diluted with EtOAc (1.5 L) and washed with sat. aqueous NH ₄ Cl (3× 1.5 l) and concentrate. The crude product was purified by chromatography (silica, MeOH/DCM=0-10%) to obtain the title compound (261 g, 64%) as a solid. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.38-8.02 (m, 1H), 7.26-7.22 (m, 2H), 6.94-6.98 (m, 2H), 6.79-6.48 (m, 1H), 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).

Example of getting 30: (S) -N- (4,5-diamino-2-methylphenyl) -N -methyl-2-morpholinopropanamide

To a solution of Preparation Example 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 hours. The mixture is concentrated and then diluted in DCM (1 L). The resulting mixture is adjusted to ~pH 9 using sat. Na ₂ CO ₃ and then extracted with DCM (2×1 L). The combined organic layer was washed with brine (1 L), dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated. The residue was dissolved in DCM (500 ml), to which 4M HCl/dioxane solution (1 L) was added dropwise and stirred for 0.5 hour. The mixture is concentrated and DCM (800 ml) is added. The resulting mixture was stirred for 16 hours. The mixture is filtered and the resulting filter cake is dried in vacuo to give the HCl salt of (S) -N- (4-amino-2-methyl-5-nitrophenyl) -N- methyl-2-morpholinopropanamide (200 g) as a solid. . (S)-N-(4-Amino-2-methyl-5-nitrophenyl) -N -methyl-2-morpholinopropanamide (66.6 g, 206.6 mmol) above is charged into the hydrogenation vessel in three separate portions. and MeOH (900 ml). 10% Pd/C (13 g, 41.32 mmol) was added to the reaction vessel and the mixture was purged with N ₂ and then H ₂ . The reaction mixture is hydrogenated under H ₂ pressure at 50 psi. at 40°C for 48 hours. The reaction mixture is filtered (2 times) and the filtrate is washed with MeOH (3 times 500 ml). The filtrate is concentrated to obtain a residue. The residue was dissolved in MeOH (1 L), to which Na ₂ CO ₃ (41.9 g, 395 mmol) was added and the mixture was stirred at 25° C. for 1 hour. The mixture is filtered and washed with MeOH (5×200 ml). The filtrate is concentrated. The residue was purified by chromatography (silica, 0-10% DCM:MeOH gradient) to give the title compound (159.4 g, 89% yield). SLC Method: Chiralpak IB N-5 250 mm x 4.6 mm x 5 µm, 5% (0.2% isopropylamine in isopropanol/CO2 _(g) ) for 1 min, then up to 60% over 8 min, 2.5 ml/min, retention time=8.636 min, 98.42%, 96.85% ee. ^1H NMR (400 MHz, CDCl ₃ ) 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 (uss, 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.

Receiving example 31: N- (4,5-diamino-2-methylphenyl) -N -methyl-2-morpholinopropanamide

The title compound 31 was prepared in the same manner as the Preparation Example. 30, based on (±)-2-morpholinopropanoic acid; LC/MS m/z (M+H) ⁺⁼ 293.3.

Receipt example 32: (S) -N- (3,4-diaminophenyl)-N-methyl-2-morpholinopropanamide

The title compound was prepared analogously to Preparation Example 30, starting from 3-chloro-4-nitroaniline and Preparation Example 19.

^1H NMR (400 MHz, CDCl ₃ ) 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 (sq, 1H), 3.21 (s, 3H), 2.64-2.55 (m, 2H), 2.47-2.35 (m , 2H), 1.15 (d, 3H)

Receiving example 33: N- (5-chloro-2-ethylphenyl)acetamide

5-chloro-2-ethylaniline (405 mg, 2.6 mmol) was added to Ac ₂ O (10 ml, 110 mmol) with stirring at 25°C. The reaction mixture is stirred for 3 hours and filtered to collect the precipitate. The solids are washed with water (3 x 15 ml) and dried to give the title compound (496 mg, 96%). ^1H NMR (400 MHz, CDCl ₃ ) δ 7.91 (s, 1H), 7.12 (t, 2H), 6.96 (s, 1H), 2.56 (sq, 2H), 2.21 (s, 3H), 1.22 (t, 3H); LC/MS m/z (M+H)= 197.9.

Example of receiving 34: N- (5-chloro-2-ethyl-4-nitrophenyl)acetamide

A solution from Preparation Example 33 (496 mg 2.51 mmol) in conc. H ₂ SO ₄ (2 ml) is cooled to 0°C and treated with KNO ₃ (254 mg, 2.51 mmol) in portions, maintaining the internal temperature below 5°C. The resulting mixture is stirred for 4 hours at a temperature of 0-5°C. The mixture is poured into water (30 ml) and stirred for 10 minutes. The mixture is filtered and the collected solids are washed with water (3 x 20 ml) and dried in vacuo to give the title compound (600 mg, 99%). ^1H NMR (400 MHz, _CDCl3 ) 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.

Preparation Example 35: 5-chloro-2-ethyl-4-nitroaniline

A solution of Preparation Example 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 is heated at 80°C for 16 hours. Additional NaOH (74.2 mg, 1.85 mmol) was added to the mixture and heating was continued at 80°C for an additional 16 hours. The mixture is concentrated, diluted with water (20 ml) and extracted with EtOAc (2×20 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%). ^1H NMR (400 MHz, CDCl ₃ ) δ 7.88 (s, 1H), 6.70 (s, 1H), 4.29 (s, 2H), 2.54-2.43 (m, 2H) , 1.29 (t, 3H); LC/MS m/z (M+H)= 200.9.

Example of receiving 36. (S) -N- (3-fluoro-4-nitrophenyl)-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 Preparation Example 19 (1.22 g, 7.69 mmol) and EDCI (1.46 g, 12.8 mmol). The mixture is stirred for 15 hours, concentrated and diluted with EtOAc/H ₂ O (150 ml/50 ml). The organic layer was separated and the aqueous layer was extracted with EtOAc (50 ml). The organic extracts are combined, washed with brine, dried (MgSO ₄ ) _, filtered and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE=0-100%) to give the title compound (1.36 g, 72%). LC/MS m/z (M+H) ⁺⁼ 298.0.

Receipt example 37. (S) -N- (3-fluoro-4-nitrophenyl)-N-methyl-2-morpholinopropanamide

A solution of Preparation Example 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 minutes, methyl iodide (0.43 ml, 6.86 mmol) was added and the mixture was stirred for 16 hours. The mixture is treated with sat. aqueous NH ₄ Cl (1 ml) and then partitioned between EtOAc and H ₂ O (150 ml/50 ml). The organic layer was separated and the aqueous layer was extracted with EtOAc (100 ml). Organic extracts are collected, dried (MgSO ₄ ) _, filtered and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE=0-100%) to give the title compound (410 mg, 29%). LC/MS m/z (M+H) ⁺⁼ 312.1.

Example of receiving 38. (S) -N- (3-amino-4-nitrophenyl)-N-methyl-2-morpholinopropanamide

A solution of Preparation Example 37 (370 mg, 1.19 mmol) in EtOH (30 ml) at 20°C was treated with conc. NH ₄ OH (10 ml). The mixture is stirred for 15 hours at 70°C and diluted with EtOAc/H ₂ O (150/50 ml). The organic layer was separated and the aqueous layer was extracted with EtOAc (50 ml). The organic extracts are combined, dried (Na ₂ SO ₄ ), filtered and concentrated to give the title compound (366 mg, 99%). LC/MS m/z (M+H) ⁺⁼ 309.1.

Receipt example 39: (S) -N- (5-amino-2-bromo-4-nitrophenyl)-N-methyl-2-morpholinopropanamide

A solution of Preparation Example 38 (270 mg, 0.88 mmol) in AcOH (10 ml) at 20° C. was treated with Br ₂ (140 mg, 0.88 mmol). The mixture is stirred for 1 hour and the precipitate is collected by filtration. Solids are purified using prep. HPLC (Phenomenex Gemini-NX 150 mm x 30 mm x 5 µm, H ₂ O/CH ₃ CN (0.05% NH ₄ OH), 18-58% for 10 min) gave the title compound (65 mg , 19%). ^1H NMR (400 MHz, DMSO- d6 ) δ 8.25 (d, 1H), 7.69 (s, 1H), 7.57 (s _, 1H), 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 ( ⁷⁹ Br, ⁸¹ Br).

Example of getting 40: (S) -N- (4,5-diamino-2-bromophenyl)-N-methyl-2-morpholinopropanamide

A solution of 39 (40 mg, 0.10 mmol) in EtOH (3 ml) at 20°C is treated with sat. aqueous NH₄Cl (0.5 ml) and iron powder (17.3 mg, 0.31 mmol). The mixture is heated to 70°C for 1 hour and filtered. The filtrate is concentrated and the residue is purified by preparative HPLC (Boston Prime C18, 150 × 30 mm × 5 μm; H₂O/MeCN (0.05% NH₄OH) 16-39% for 10 min) to obtainspecified in the connection header.(5 mg, 10%).¹H NMR (400 MHz, DMSO-d ₆ ) 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/MSm/z(M+H)=357.0/359.1 (⁷⁹Br,⁸¹Br).

Receiving example 41: rubs -butyl(5-fluoro-2-methyl-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 i Pr ₂ NEt (202 g , 1.56 mol, 272 ml, 2 eq.) in DCM (2 L) was treated with BOC ₂ O (187 g, 859 mmol) at 20°C. The mixture is stirred at 20°C for 16 hours and concentrated. The residue is dissolved in EtOAc (3 L) and washed successively with sat. aqueous NH ₄ Cl (1 l), sat. aqueous NaHCO ₃ (1 l) and salt solution (1 l). The organic layer is dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was triturated with MeOH (3 L) and the solids were collected by filtration to give the title compound (90 g, 374 mmol).

The filtrate is concentrated and the residue is dissolved in MeOH (500 ml) and treated with K ₂ CO ₃ (15.5 g). The mixture is stirred at 20°C for 3 hours. The mixture is filtered and the solids are washed with MeOH. The filtrate was concentrated and the residue was purified by chromatography (silica, EtOAc/PE=0-10%) to give additional title compound (45 g, 166 mmol).

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

Example of receiving 42: rubs -butyl(5-fluoro-2-methyl-4-nitrophenyl)carbamate

A solution of Preparation Example 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 hour. Add methyl iodide (61 ml, 980 mmol) dropwise at 0°C. The resulting mixture was stirred at 20°C for 16 hours. The reaction mixture is treated with sat. aqueous NH ₄ Cl (500 ml) and extracted with EtOAc (1 L). The organic layer was washed with brine (500 ml), dried (Na ₂ SO ₄ ) and concentrated to give the title compound (150 g, 95% yield). ^1H NMR (400 MHz, CDCl ₃ ) δ 7.95 (d, 1H), 7.07 (d, 1H), 3.17 (s, 3H), 2.26 (s, 3H), 1.40 (d, 9H).

Example of getting 43: rubs -butyl(5-amino-2-methyl-4-nitrophenyl)(methyl)carbamate

A solution of Preparation Example 42 (450 g, 1.38 mol, 1 eq.) in 7 M NH ₃ in MeOH (7 M, 5.5 L) was heated at 58° C. for 72 hours. The mixture is concentrated. The residue is dissolved in EtOAc (2 L) and washed with brine (2 L). The organic layer is dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE=0-20%) to give the title compound (295 g, 76% yield). ^1H NMR (400 MHz, CDCl ₃ ) 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.

Example of getting 44: rubs -butyl(4,5-diamino-2-methylphenyl)(methyl)carbamate

A solution of Preparation Example 43 (98 g, 349 mmol) in MeOH (1 L) was treated with 10% Pd/C (10 g). The reaction mixture is stirred at 40°C in an atmosphere of H ₂ (3 atm) for 24 hours. The reaction mixture is filtered and the solids are washed with MeOH (3×500 ml). The filtrate was concentrated to give the title compound (68.3 g, 78%). ^1H NMR (400 MHz, DMSO- d6 ) 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.

Preparation 45: rubs -butylmethyl-(6-methyl-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f ]indazol-3-yl)-1H-benzo[d]imidazol-5-yl)carbamate

A solution of Preparation Example 44 (5.53 g, 23.5 mmol) and Na ₂ S ₂ O ₅ (2.24 g, 11.8 mmol) in DMF (124 ml) was treated with compound 9 (7.21 g, 23 .5 mmol) and DMSO (4.6 g, 58.8 mmol) at room temperature. The mixture is heated at 110°C for 16 hours. The mixture is concentrated. The residue is diluted with EtOAc (500 ml) and washed with 3% aq. LiCl (100 ml). The organic layer is dried (MgSO ₄ ), filtered and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE=0-25%) to give the title compound (10.8 g, 86%). ^1H NMR (400 MHz, CD ₃ OD) 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.

Preparation 46: N ,6-dimethyl-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole- 3-yl)-1H-benzo[d]imidazol-5-amine

A solution of Preparation Example 45 (10.86 g, 20.2 mmol) in DCM (135 ml) was treated with ZnBr ₂ (22.7 g, 101 mmol) at 0°C. The mixture is gradually warmed to room temperature and stirred for 16 hours. The mixture is poured into sat. aqueous NaHCO ₃ (200 ml) and extracted with DCM (2×200 ml). The combined organic layers are dried (MgSO ₄ ), filtered and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE=0-20%) to give the title compound (7.54 g, 85.3%). Chiral SLC (Chiral Pak AS-3, 150 mm × 4.6 mm × 3 µm; CO ₂ /EtOH with 0.05% i Pr ₂ NEt, from 5 to 40% in 5.5 min) retention time = 2 .93 min (97.2% e.i.); ^1H NMR (400 MHz, CD ₃ OD) 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.

Example of getting 47: N- (3-fluoro-4-nitrophenyl)acetamide

3-Fluoro-4-nitroaniline (20 g, 128.1 mmol) was treated with Ac ₂ O (250 ml). The mixture was stirred for 16 hours at room temperature and then diluted with water (100 ml). The precipitate is collected by filtration. The solids were dissolved in EtOAc (100 mL), dried (Na ₂ SO ₄ ), filtered and concentrated to give the title compound 47 (23.0 g, 91% yield). ^1H NMR (400 MHz, CD ₃ OD) δ 8.09 (t, 1H), 7.86 (dd, 1H), 7.38 (dt, 1H), 2.17 (s, 3H).

Receipt example 48. N- (3-fluoro-4-nitrophenyl) -N- methylacetamide

A solution of Preparation Example 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 minutes. Methyl iodide (33.0 g, 232 mmol) was added and the mixture was stirred for 2 hours. The mixture is treated with water (100 ml) and the resulting mixture is extracted with a mixture of 10% MeOH/EtOAc (2x200 ml). The extracts are collected, dried (Na ₂ SO ₄ ), 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). ^1H NMR (400 MHz, CDCl ₃ ) δ 8.13 (t, 1H), 7.25-7.15 (m, 2H), 3.35 (s, 3H), 2.10 (s, 3H)

Example of getting 49: N- (3-amino-4-nitrophenyl) -N- methylacetamide

A solution of Preparation Example 48 (16.0 g, 75.4 mmol) in EtOH (200 mL) at room temperature was treated with conc. NH ₄ OH (13.2 g, 377 mmol). The mixture is heated at 50°C for 3 days and the mixture is concentrated. The residue is purified by chromatography (silica, EtOAc/PE=40-80%) to give the title compound (7.5 g, 48% yield). ^1H NMR (400 MHz, CDCl ₃ ) 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.

Example of getting 50: N- (3,4-diaminophenyl) -N- methylacetamide

A solution of Preparation Example 49 (6.5 g, 31.1 mmol) in MeOH (40 ml) was treated with 10% Pd/C (1.5 g). The mixture is stirred at 20°C in an H ₂ atmosphere (2 atm) for 3 hours. The mixture is filtered and the solids are washed with MeOH (2×50 ml). The filtrate was concentrated to give the title compound (5.38 g, 96% yield). ^1H NMR (400 MHz, CDCl ₃ ) 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.

Example of getting 51: N- (3,5-difluoro-4-nitrophenyl) -N- methylacetamide

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

Example of getting 52: N- (3-amino-5-fluoro-4-nitrophenyl) -N- methylacetamide

A solution of Preparation Example 51 (8.75 g, 38.0 mmol) in EtOH (95 ml) was treated with conc. NH ₄ OH (24 ml). The mixture was stirred at room temperature for 16 hours and treated with water (120 ml). The mixture is extracted with EtOAc (2×80 ml). The combined organic extracts are washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated to give the title compound (5.70 g, 66%). ^1H NMR (400 MHz, DMSO- d6 ) 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.

Example of getting 53: N- (3,4-diamino-5-fluorophenyl) -N- methylacetamide

Prepare a solution of 52 (5.70 g, 25.1 mmol) in EtOH (150 ml) treated with 10% Pd/C (700 mg). The mixture is stirred under H atmosphere₂(1 atm) at 25°C for 24 hours. The mixture is filtered and the solids are washed with EtOH. The filtrate is concentrated to obtainspecified in the connection header(4.6 g, 93%).¹H NMR (400 MHz, DMSO-d ₆ ) 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/MSm/z(M+N)⁺=198.1.

Example of getting 54: N-methyl-N- (2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl) -1H -benzo[d]imidazol-5-yl)acetamide

A solution of Preparation Example 50 (5.26 g, 29.4 mmol) in DMF (147 ml) was treated with Na₂S₂O₅ (2.79 g, 14.7 mmol), 9 (9.0 g, 29.4 mmol) and DMSO (5.74 g, 73.4 mmol). The mixture is heated at 110°C for 6 hours and poured into a 3% aqueous solution of LiCl (250 ml). The mixture is extracted with EtOAc (3×100 ml), dried (Na₂SO₄), filter and concentrate. The crude product is purified by chromatography (silica, EtOAc/PE=0-100%) to give the title compound (13 g, yield 95%).¹H NMR (400 MHz, DMSO-d ₆ ) rotomeric mixture δ 12.83 (s, 1H), 7.96 (s, 1H), 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, 3H), 3.07-2.96 (m, 1H), 2.89 (s, 3H), 2.76-2.64 (m, 4H), 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/MSm/z(M+N)⁺⁼466.2.

Example of getting 55: N -methyl-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3- il) -1H -benzo[d]imidazol-5-amine

A solution of Preparation Example 54 (2.70 g, 5.8 mmol) in EtOH (22 mL) was treated with 5N NaOH (11.6 mL) at room temperature. The reaction mixture is heated at 90°C for 16 hours. Water (150 ml) was added to the mixture and the mixture was extracted with EtOAc (2×150 ml). The combined organic extracts are washed with brine (50 ml), dried (Na ₂ SO ₄ ), 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, CD ₃ OD) 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), 2H), 3.37-3.31 (m, 1H), 3.22-3.04 (m, 2H), 2. 82 (s, 3H), 2.75 (d, 1H), 1.30 (s, 3H), 1.16 (dt, 1H), 0.88 (d, 2H), 0.43 (dd, 1H ), 0.25 (t, 1H), -0.03 (s, 9H); LC/MS m/z (M+H) ⁺⁼ 424.2.

Example of getting 56: N -(7-fluoro-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole -3-yl)-1 N- benzo[d]imidazol-5-yl)- N- methylacetamide

A solution of Preparation Example 9 (6.53 g, 21.3 mmol) in DMF (106 ml) at 25° C. was treated with Preparation Example 53 (4.20 g, 21.3 mmol), Na ₂ S ₂ O ₅ (2 .02 g, 10.6 mmol) and DMSO (4.16 g, 53.2 mmol). The mixture is heated at 110°C for 16 hours and diluted with a 3% aqueous solution. LiCl (50 ml). The mixture is extracted with EtOAc (2×50 ml). The organic extracts are combined, dried (Na ₂ SO ₄ ), 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, CDCl ₃ ) 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 (kvd, 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.

Preparation example 57: 7-fluoro- N- methyl-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl )-1 N- benzo[d]imidazol-5-amine

A solution of Preparation Example 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 is heated at 90°C for 46 hours. Water (200 ml) was added and the mixture was extracted with EtOAc (2×200 ml). The organic extracts are combined, washed with brine (50 ml), dried (Na ₂ SO ₄ ), 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, CD ₃ OD) 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 (dt, 2H), 0.42 (dd, 1H), 0.25 (t, 1H), -0.03 ( s, 9H); LC/MS m/z (M+H) ⁺ =442.2.

Example of getting 58: N -(5-fluoro-2-methyl-4-nitrophenyl)acetamide

5-fluoro-2-methyl-4-nitroaniline (9.5 g, 56 mmol) was added portionwise to Ac ₂ O (100 ml) at 15°C. The reaction mixture is stirred at 15°C for 36 hours. The solids are collected by filtration and washed with water (3×50 ml). The solids are dried to give the title compound 58 (6.3 g, 53%).

The filtrate is extracted with EtOAc (100 ml). The organic layer is washed with water (2 x 100 ml), sat. aqueous Na ₂ HCO ₃ (3×100 ml), dry (Na ₂ SO ₄ ), filter and concentrate. The crude product was purified by chromatography (silica, EtOAc/PE=0-100%) to provide additional title compound 58 (4 g, 34%). ^1H NMR (400 MHz, CDCl ₃ ) δ 8.34 (d, 1H), 7.94 (d, 1H), 7.17 (s, 1H), 2.32 (s, 3H), 2.28 (c, 3H).

Example of getting 59: N -(5-fluoro-2-methyl-4-nitrophenyl)- N- methylacetamide

A solution of Preparation Example 58 (9.3 g, 43.8 mmol) in THF (220 mL) at 0° C. was treated with KOtBu (48.2 mL, 1 M THF). The mixture was stirred for 1 hour at 0°C and then treated with a solution of methyl iodide (6.84 g, 48.2 mmol) in THF (20 ml). The mixture is heated to 15°C and stirred for 16 hours. The mixture is treated with sat. aqueous NH₄Cl (50 ml). The mixture is extracted with EtOAc (2×50 ml). The combined organic extracts are washed with saline, dried (Na₂SO₄), filter and concentrate. The crude product is purified by chromatography (silica, EtOAc/PE=20-50%) to give the title compound 59 (9.4 g, 95%).¹H NMR (400 MHz, CDCl₃) δ 8.04 (d, 1H), 7.13 (d, 1H), 3.18 (s, 3H), 2.30 (s, 3H), 1.82 (s, 3H); LC/MSm/z(M+N)⁺=226.9.

Example of getting 60: N -(5-amino-2-methyl-4-nitrophenyl)- N- methylacetamide

A solution of Preparation Example 59 (10.3 g, 45.5 mmol) in EtOH (200 ml) at 15°C was treated with conc. NH ₄ OH (200 ml). The mixture is heated at 50°C and stirred for 40 hours. EtOH is removed under reduced pressure and the suspension is filtered to collect solids. The solids are washed with water and dried to give the title compound (9 g, 89%). ^1H NMR (400 MHz, CDCl ₃ ) 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.

Example of getting 61: N -(4,5-diamino-2-methylphenyl)- N- methylacetamide

Solution from Preparation Example 60 (8 g, 35.8 mmol) in EtOH (10 ml) was treated with 10% Pd/C (1.3 g). The mixture is degassed with N₂and fill in H three times₂. The reaction mixture is stirred at 15°C in an atmosphere of H₂ (1 atm) for 16 hours. The mixture is filtered and the filtrate is concentrated to obtainspecified in the connection header(7.7 g, 99%).¹H NMR (400 MHz, CDCl₃) δ 6.57 (s, 1H), 6.46 (s, 1H), 3.40 (s, 4H), 3.12 (s, 3H), 2.05 (s, 3H), 1.78 (s, 3H); LC/MSm/z(M+N)⁺=194.3.

Example of getting 62: N- methyl- N -(6-methyl-2-((4a S .5a R )-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[ f ]indazol-3-yl)-1 N- benzo[d]imidazol-5-yl)acetamide

Preparation Example 61 (4 g, 20.7 mmol) and Na ₂ S ₂ O ₅ (1.97 g, 10.3 mmol) were mixed with a solution of Preparation Example 9 (6.84 g, 22.3 mmol) in DMF (100 ml) and DMSO (3.7 ml). The mixture is heated at 110°C for 16 hours. The mixture is cooled to RT and 3% aq. is added. LiCl (150 ml). The resulting solid was collected by filtration, washed with water and dried to give the title compound (7.9 g, 80%). ^1H NMR (400 MHz, _CDCl3 ) δ 9.88 (s, 1H), 7.58 (s, 1H), 7.31 (s, 1H), 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, 1H), 0.90 (dd, 2H), 0.42 (dd, 1H), 0.26 (t , 1H), -0.03 (s, 9H); LC/MS m/z (M+H) ⁺⁼ 480.4.

Example of getting 63: N -(4-fluoro-2-methyl-5-nitrophenyl)acetamide

4-Fluoro-2-methyl-5-nitroaniline (16.7 g, 98.2 mmol) was added to Ac ₂ O (200 ml) with stirring at 15°C, and the mixture was stirred at 15°C for 16 hours. The mixture is treated with water (300 ml) and extracted with EtOAc (300 ml). The organic layer is washed with sat. aqueous Na ₂ CO ₃ (2 x 150 ml) and salt solution (100 ml). The organic layer is dried (Na ₂ SO ₄ ), filtered and concentrated. The residue is 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%). ^1H NMR (400 MHz, CDCl ₃ ) δ 8.52 (d, 1H), 7.13 (usd, 2H), 2.35 (s, 3H), 2.25 (s, 3H)

Example of getting 64: N -(4-amino-2-methyl-5-nitrophenyl)acetamide

A solution of Preparation Example 63 (15 g, 70.7 mmol) in EtOH (300 ml) was treated with conc. N.H.₄OH (198 g) at 30°C and the mixture was stirred at 50°C for 16 hours. Add more conc. N.H.₄OH (140 g) and the mixture was stirred at 50°C for 16 hours. Add more conc. N.H.₄OH (46 g) and the mixture was stirred at 60°C for 16 hours. The mixture is concentrated and the solids are collected by filtration. The solids are washed with water (3 x 10 ml) and dried to give 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)

Example of getting 63: N -(4,5-diamino-2-methylphenyl)acetamide

A suspension of Preparation Example 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 H ₂ three times, and the reaction mixture was stirred at 15° C. under an H ₂ atmosphere (1 atm) for 16 hours. The mixture was filtered and the filtrate was concentrated to give the title compound 65 (2.2 g, 103%). LC/MS m/z (M+H) ⁺⁼ 180.1.

Example of getting 66: N -(6-methyl-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole -3-yl)-1 N- benzo[d]imidazol-5-yl)acetamide

A solution of Preparation Example 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 is stirred at 100°C for 16 hours. The mixture is concentrated and the crude product is purified by chromatography (silica, EtOAc/PE=0-100%, then MeOH/DCM 0-10%) to give the title compound 66 (5.3 g, 92%). LC/MSm/z(M+N)⁺⁼466.2.

Example of getting 67: N- ethyl-6-methyl-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole -3-yl)-1 H -benzo[d]imidazol-5-amine

A suspension of LiAlH ₄ (326 mg, 8.59 mmol) in THF (33 ml) at 0°C was treated with a solution of Preparation Example 66 (2 g, 4.3 mmol) in THF (10 ml) and stirred at 20°C in within 72 hours. The mixture is treated with Na ₂ SO ₄ -H ₂ O, and then MgSO ₄ (4 g). The mixture is stirred for 30 minutes. The mixture is 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, CDCl ₃₎ 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, 1H), 2.72 (d , 1H), 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.

Preparation Example 68: (4aS,5aR)-5,5-difluoro-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3-carboxylic acid

A solution of Preparation Example 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 hours the mixture is concentrated and the residue is diluted with H ₂ O (10 ml) and the pH is adjusted to 4-5 with 1M HCl. The resulting suspension is filtered to collect solids. The solids are dried to give the title compound (900 mg, 100%). ^1H NMR (400 MHz, DMSO- d6 ) δ 13.03 (brs, 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.

Preparation example 69: (4aS,5aR)-3-(5-bromo-7-fluoro-1 H- benzo[d]imidazol-2-yl)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole

A solution of Preparation Example 9 (510 mg, 1.66 mmol) in DMF (20.8 ml) was treated with 5-bromo-3-fluorobenzene-1,2-diamine (358 mg, 1.75 mmol) and Na ₂ S ₂ O ₅ (380 mg, 2.00 mmol) at room temperature. The vial is hermetically sealed and heated in a microwave reactor at 150°C for 2 hours. The mixture is poured into 3% aq. LiCl (40 ml) and the mixture was extracted with EtOAc (2×40 ml). Organic extracts are dried (Na ₂ SO ₄ ), 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, CD ₃ OD) 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, 2H), 1H), 3.25-3.07 (m, 2H), 2.81-2.72 (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 ( ⁷⁹ Br).

Preparation example 70: (4aS,5aR)-3-(5-bromo-7-fluoro-1 H- benzo[d]imidazol-2-yl)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole

A solution of Preparation Example 69 (100 mg, 0.20 mmol) in TFA (2 ml) at 10° C. was treated with Et ₃ SiH (118 mg, 1.02 mmol). The mixture is stirred at 10°C for 3 hours. The mixture is concentrated and the residue is treated with sat. aqueous Na ₂ CO ₃ . The mixture is extracted with EtOAc (3×15 ml). Organic extracts are dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was purified by chromatography [preparative HPLC, H ₂ O:MeCN (w/0.05% NH ₄ OH)] to give the title compound (27.1 mg, 37%). ^1H NMR (400 MHz, CD ₃ OD) δ 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 ( ⁷⁹ Br).

Preparation example 71a: (4aS,5aR)-3-(6-bromo-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -benzo[d]imidazol-2-yl)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole

Preparation example 71b: (4aS,5aR)-3-(5-bromo-7-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -benzo[d]imidazol-2-yl)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole

A solution of Preparation Example 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 minutes, SEM-Cl (570 mg, 3.42 mmol) was added and the mixture was stirred for 2 hours at 10°C. The mixture is treated with sat. aqueous NH ₄ Cl (30 ml). The mixture is extracted with EtOAc (3×40 ml) and the organic extracts are combined, dried (Na ₂ SO ₄ ), 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, CD ₃ OD) δ 7.69 (dd, 1H), 7.26 (ddd, 1H), 6.24-5.97 (m, 2H), 5.53-5.46 (m, 2H), 4.10 (k, 1H), 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 ( ⁷⁹ Br).

Example of getting 72a: rubs -butyl(4-fluoro-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f] indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 N- benzo[d]imidazol-6-yl)carbamate

Example of getting 72b: rubs -butyl(7-fluoro-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f] indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 N- benzo[d]imidazol-5-yl)carbamate

Part of the mixture from Preparation Examples 71a and 71b (712 mg, 1.15 mmol), tert -butyl carbamate (161 mg, 1.37 mmol), Cs ₂ CO ₃ (746 mg, 2.29 mmol) in tert -amyl alcohol ( 11.5 ml) are treated with Pd ₂ (dba) ₃ (105 mg, 0.12 mmol) and tert -BuDavePhos (78 mg, 0.23 mmol). The reaction mixture is heated at 100°C for 23 hours. The mixture was concentrated and the crude product was purified by chromatography (silica, EtOAc/PE=0-20%) to give the title compounds as a mixture (706 mg, 93%). ^1H NMR (400 MHz, CD ₃ OD) 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

Example of receiving 73a: rubs -butyl(4-fluoro-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f] indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 N- benzo[d]imidazol-6-yl)(methyl)carbamate

Example of getting 73b: rubs -butyl(7-fluoro-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f] indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 N- benzo[d]imidazol-5-yl)(methyl)carbamate

A portion of the mixture from Preparation Examples 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 minutes and treated with methyl iodide (61 mg, 0.43 mmol). The mixture is stirred for 16 hours and treated with sat. aqueous NH₄Cl (15 ml). The mixture is extracted with EtOAc (2×20 ml). Organic extracts are collected, dried (Na₂SO₄), filter and concentrate. The crude product is purified by chromatography (silica, EtOAc/PE=0-30%) to giveconnections specified in the headeras a mixture (120 mg, 50%).¹H NMR (400 MHz, CD₃OD) δ 7.39 (d, 1H), 7.01 (dd, 1H), 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/MSm/z(M+Na)⁺⁼694.0.

Preparation example 74a: 4-fluoro- N- methyl-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl )-1-((2-(trimethylsilyl)ethoxy)methyl)-1 N- benzo[d]imidazol-6-amine

Preparation example of 74b: 7-fluoro- N- methyl-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl )-1-((2-(trimethylsilyl)ethoxy)methyl)-1 N- benzo[d]imidazol-5-amine

A mixture of Preparation Examples 73a and 73b (120 mg, 0.178 mmol) in DCM (2.0 mL) at 0° C. was treated with ZnBr ₂ (201 mg, 0.89 mmol). The mixture is stirred for 12 hours, then treated with sat. aqueous NaHCO ₃ (10 ml) and the mixture was extracted with DCM (2×20 ml). The organic extracts are combined, dried (Na ₂ SO ₄ ), filtered and concentrated to give the title compounds as a mixture (111 mg, 109%). ^1H NMR (400 MHz, CD ₃ OD) 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.

Example of receiving 75a: rubs -butylethyl(4-fluoro-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f] indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 N- benzo[d]imidazol-6-yl)carbamate

Example of getting 75b: rubs -butylethyl(7-fluoro-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f] indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 N- benzo[d]imidazol-5-yl)carbamate

A mixture of Preparation Examples 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 minutes and treated with ethyl iodide (3.30 g, 21 mmol) and the mixture was stirred for 16 hours. The mixture is treated with sat. aqueous NH ₄ Cl (150 ml). The mixture is extracted with EtOAc (2 x 200 ml) and the organic layers are combined, dried (Na ₂ SO ₄ ), filtered and concentrated. 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.

Preparation example 76a: N-ethyl-4-fluoro-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6 -hexahydrocyclopropa[f]indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 N- benzo[d]imidazol-6-amine

Preparation example 76b: N-ethyl-7-fluoro-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6 -hexahydrocyclopropa[f]indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 N- benzo[d]imidazol-5-amine

A mixture of Preparation Examples 75a and 75b (10.39 g, 15.14 mmol) in DCM (151 mL) at 0° C. was treated with ZnBr ₂ (17.1 g, 75.7 mmol). The reaction mixture is heated to 30°C and stirred for 16 hours. The mixture is poured into saturated NaHCO ₃ solution (150 ml) and filtered. The filtrate is extracted with DCM (2 x 100 ml). The organic extracts are combined, dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE=0-10%) to give the title compounds as a mixture (6.14 g, 69.2%). LC/MS m/z (M+H)= 586.2.

Preparation example 77: (4aS,5aR)-3-(5-bromo-6-fluoro-1 H- benzo[d]imidazol-2-yl)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole

A solution of Preparation Example 9 (467 mg, 1.52 mmol) in DMF (19 ml) was treated with 4-bromo-5-fluorobenzene-1,2-diamine (328 mg, 1.60 mmol) and Na ₂ S ₂ O ₅ (380 mg, 2.00 mmol) at CT. The vial is hermetically sealed and heated in a microwave reactor at 150°C for 2 hours. The mixture is poured into 3% aq. LiCl (80 ml) and extracted with EtOAc (2×60 ml). The organic layers are combined, dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE=0-25%) to give the title compound (644 mg, 86%). ^1H NMR (400 MHz, _CDCl3 ) δ 9.96 (s, 1H), 7.98 (s, 1H), 7.57 (s, 1H), 5.46-5.28 (m, 2H) , 3.58-3.49 (m, 2H), 3.20-3.07 (m, 3H), 2.74 (d, 1H), 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).

Example of getting 78a: rubs -butyl(6-fluoro-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f] indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -benzo[d]imidazol-5-yl)carbamate

Example of getting 78b: rubs -butyl(5-fluoro-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f] indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -benzo[d]imidazol-6-yl)carbamate

A mixture of preparation examples 77 (800 mg, 1.29 mmol), tert- butylcarbamate (181 mg, 1.54 mmol) and Cs ₂ CO ₃ (838 mg, 2.57 mmol) in tert -amyl alcohol (12.9 ml ) are treated with Pd ₂ (dba) ₃ (59 mg, 0.64 mmol) and (88 mg, 0.26 mmol). The mixture is heated to 100°C for 16 hours. Add additional Pd ₂ (dba) ₃ (59 mg, 0.64 mmol) and (88 mg, 0.26 mmol) and continue heating at 100°C for 16 hours. The mixture was concentrated and the residue was purified by chromatography (silica, EtOAc/PE=0-20%) to give the title compound as a mixture (480 mg, 57%). ^1H NMR (400 MHz, _CDCl3 ) 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 (sq, 1H), -0.02 (s, 9H), -0.13 (d, 9H); LC/MS m/z (M+H) ⁺ =658.3

Example of getting 79a: rubs -butyl(6-fluoro-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f] indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1 H-benzo[d]imidazol-5-yl)(methyl)carbamate

Example of receiving 79b rubs -butyl(5-fluoro-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f] indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1 H-benzo[d]imidazol-6-yl)(methyl)carbamate

A portion of the mixture from Preparation Examples 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 minutes and then treated with methyl iodide (124 mg, 0.87 mmol). After stirring for 16 hours, the mixture is diluted with sat. aqueous NH ₄ Cl (2 ml) and extracted with EtOAc (2×10 ml). Organic extracts are collected, dried (Na ₂ SO ₄ ), filtered and concentrated. The crude material was purified by chromatography (silica, EtOAc/PE=0-30%) to give the title compounds as a mixture (286 mg, 100%). ^1H NMR (400 MHz, _CDCl3 ) 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, 2H), 3.56-3.43 (m, 3H), 3.28 (d, 3H), 3 .20-3.07 (m, 2H), 2.76 (d, 1H), 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.

Preparation example 80a: 5-fluoro-N-methyl-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6 -hexahydrocyclopropa[f]indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1 H-benzo[d]imidazol-6-amine

Preparation example 80b: 6-fluoro-N-methyl-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6 -hexahydrocyclopropa[f]indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1 H-benzo[d]imidazol-5-amine

A mixture of Preparation Examples 79a and 79b (286 mg, 0.425 mmol) in DCM (4.26 ml) at 0° C. was treated with ZnBr ₂ (479 mg, 2.13 mmol). After stirring at 15°C for 12 hours, the mixture is poured into sat. aqueous NaHCO ₃ (20 ml) and the resulting mixture was extracted with DCM (2×20 ml). Organic extracts are collected, dried (Na ₂ SO ₄ ), filtered and concentrated. The crude material was purified by chromatography (silica, EtOAc/PE=0-40%) to give the title compound as a mixture (160 mg, 66%). ^1H NMR (400 MHz, CDCl ₃ ) δ 7.41 (d, 0.57H), 7.21 (d, 0.43H), 7.07 (d, 0.43H), 6.73 (d, 0.57H), 6.06 (d, 1H), 6.07-5.95 (m, 1H), 5.46-5.34 (m, 2H), 4.05 (s, 1H), 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); ¹⁹ F NMR (376 MHz, CD ₃ OD) δ -131.20; LC/MS m/z (M+H) ⁺ =572.

Preparation Example 81: 4-Fluoro-2-methoxy-5-nitroaniline

A solution of 4-fluoro-2-methoxyaniline (1590 mg, 11.27 mmol) in conc. H ₂ SO ₄ (9.55 ml) is treated with solid KNO ₃ (1140 mg, 11.3 mmol) in portions, maintaining the internal temperature below 5°C. The resulting mixture was stirred for 2 hours at 0°C and poured into ice water (100 ml), slowly neutralized with solid Na ₂ CO ₃ and extracted with EtOAc (2 x 60 ml). The organic layers are dried (Na ₂ SO ₄ ), filtered and concentrated to give the title compound (2 g, 95%). ^1H NMR (400 MHz, CDCl ₃ ) δ 7.42 (d, 1H), 6.66 (d, 1H), 3.96 (s, 3H), 1.60 (s, 2H); LC/MS m/z (M+H) ⁺ =186.8.

Example of receiving 82: (S)- N -(4-fluoro-2-methoxy-5-nitrophenyl)-2-morpholinopropanamide

A solution of Preparation Example 81 (590 mg, 3.17 mmol) and Preparation Example 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 room temperature for 16 hours and then poured into water (30 ml). The resulting mixture was extracted with EtOAc (2×40 ml). The organic layers are combined and washed sequentially with sat. aqueous NH ₄ Cl and brine, dry (MgSO ₄ ), filter and concentrate. The crude product was purified by chromatography (silica, EtOAc/PE=0-50%) to give the title compound (586 mg, 77%). ^1H NMR (400 MHz, _CDCl3 ) δ 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). ¹⁹ F NMR (376 MHz, CDCl3) δ -118.16. LC/MS m/z (M+H)= 328.1; SLC method: Chiral Tech AD-3 150 mm × 4.6 mm × 3 µm, CO ₂ /IPA (0.05% i Pr ₂ NEt), isocratic 40%, 2.5 ml/min, column temperature 40°C , RT=4.027 min (99.31%)

Example of receiving 83: (S)- N -(4-fluoro-2-methoxy-5-nitrophenyl)- N- methyl 2-morpholinopropanamide

A mixture from Preparation Example 82 (586 mg, 1.79 mmol) in THF (25 ml) at 0° C. was treated with NaH (107 mg, 2.69 mmol). The mixture is stirred at 20°C for 30 minutes and treated with methyl iodide (305 mg, 2.15 mmol). After stirring for 16 hours, the mixture is diluted with sat. aqueous NH ₄ Cl (2 ml) and extracted with EtOAc (2x20 ml). Organic extracts are collected, dried (Na ₂ SO ₄ ), filtered and concentrated. The crude material was purified by chromatography (silica, EtOAc/PE=0-100%) to give the title compound (423 mg, 69%). ^1H NMR (400 MHz, CDCl ₃ ) 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.

Example of receiving 84: (S)- N -(4,5-diamino-2-methoxyphenyl)-N-methyl-2-morpholinopropanamide

The mixture from Preparation Example 83 (400 mg, 0.934 mmol) in MeOH (10 ml) was treated with 10% Pd/C (100 mg) and MeOH (5 ml). The mixture is degassed and refilled with argon and H ₂ three times, and then stirred under H ₂ (3 atm) at 25° C. for 24 hours. An additional 10% Pd/C (100 mg) was added and the mixture was stirred under H ₂ (3 atm) at 25° C. for an additional 24 hours. The reaction mixture is filtered and the filtrate is 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, CDCl ₃ ) δ 7.41-7.29 (m, 3H), 6.60 (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, 1H), 1.14 (d, 2H); LC/MS m/z (M+H)= 309.2.

Example of getting 85: (S)- N -(6-bromo-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole -3-yl)-1 N- benzo[d]imidazol-5-yl)- N- methyl 2-morpholinopropanamide

The mixture from Preparation Example 40 (900 mg, 2.52 mmol) in DMF (30 ml) at 20°C was treated with compound 9 (722 mg, 2.52 mmol) and Na ₂ S ₂ O ₅ (479 mg, 2.52 mmol). The mixture is heated at 110°C for 15 hours and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE=0-100%) to give the title compound (703 mg, 43.4%). LC/MS m/z (M+H) ⁺⁼ 643.2/645.2 ( ⁷⁹ Br, ⁸¹ Br).

Example of receiving 86a: (S)- N -(6-bromo-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole -3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 N- benzo[d]imidazol-5-yl)- N- methyl 2-morpholinopropanamide

Example of receiving 86a: (S)- N -(6-bromo-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole -3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 N- benzo[d]imidazol-5-yl)- N- methyl 2-morpholinopropanamide

A solution of Preparation Example 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 minutes, SEM-Cl (233 mg, 1.40 mmol) was added and the mixture was stirred at 20°C for 2 hours. The mixture is treated with sat. aqueous NH ₄ Cl (1 ml) and diluted 3:1 EtOAc/H ₂ O (200 ml). The organic layer was collected and the aqueous layer was extracted with EtOAc (150 ml). The organic extracts are combined, dried (Na ₂ SO ₄ ), 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 ( ⁷⁹ Br, ⁸¹ Br).

Example of receiving 87a: (S)- N -(6-cyano-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole -3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H- benzo[d]imidazol-5-yl)- N- methyl 2-morpholinopropanamide

Example of receiving 87b: (S)- N -(6-cyano-1-methyl-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa [f]indazol-3-yl)- 1H- benzo[d]imidazol-5-yl)- N- methyl 2-morpholinopropanamide

A portion of the mixture of Preparation Examples 86a and 86b (200 mg, 0.258 mmol) in NMP (10 ml) at 20°C was treated with Pd(PPh ₃ ) _{4 (} 30.0 mg, 0.026 mmol) and Zn(CN) ₂ (152 mg, 1.29 mmol). The resulting mixture is heated in a microwave reactor at 160°C for 1.5 hours. The mixture was poured into EtOAc/H ₂ O (50/10 ml) and the organic layer was collected. The aqueous layer was extracted with EtOAc (50 ml). The organic extracts are combined, washed with brine, dried (Na ₂ SO ₄ ), 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.

Preparation example 88. 4-bromo-2,3-difluoro-6-nitroaniline.

A solution of 2,3-difluoro-6-nitroaniline (10.0 g, 57.4 mmol) in DMF (230 ml) at 15°C is treated with N- bromosuccinimide (12.3 g, 68.9 mmol). The mixture is heated at 90°C for 6 hours, then cooled to room temperature and poured into ice water. The mixture is extracted with EtOAc (2x100 ml) and the organic extracts are combined, washed with brine and dried (Na ₂ SO ₄ ), 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, CDCl ₃ ) δ 8.22 (dd, 1H), 6.24 (s, 2H).

Preparation Example 89: 5-bromo-3,4-difluorobenzene-1,2-diamine

A solution of Preparation Example 88 (13.5 g, 53.4 mmol) in EtOH (296 mL) at 20° C. was treated with SnCl ₂ (48.2 g, 213 mmol). The mixture is heated at 70°C for 16 hours and then cooled to RT. The mixture is diluted with H ₂ O (200 ml) and washed with sat. aqueous NaHCO ₃ (200 ml). The mixture is filtered and the collected solids are washed with EtOAc (100 ml). The filtrate is concentrated. The residue is purified by chromatography (silica, EtOAc/PE=0-60%) to give the title compound (8.50 g, 71.4%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.63 (dd, 1H), 3.49 (s, 2H), 3.35 (s, 2H); LC/MS m/z (M+H) ⁺ =223.1/225.0 ( ⁷⁹ Br, ⁸¹ Br).

Preparation example 90: (4aS,5aR)-3-(5-bromo-6,7-difluoro-1 H- benzo[d]imidazol-2-yl)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole

A solution of Preparation Example 89 (5.0 g, 22.42 mmol) in DMF (112 ml) at room temperature was treated with Preparation Example 9 (6.87 g, 22.4 mmol), Na ₂ S ₂ O ₅ (2. 13 g, 11.2 mmol) and DMSO (4.38 g, 56.0 mmol). The reaction mixture is heated at 110°C for 16 hours. The mixture is poured into 3% aq. LiCl (100 ml) and extracted with EtOAc (2×80 ml). The organic extracts are combined, dried (Na ₂ SO ₄ ), 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 ( ⁷⁹ Br, ⁸¹ Br).

Preparation example 91a: (4aS,5aR)-3-(6-bromo-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H- benzo[d]imidazol-2-yl)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole

Preparation example 91b: (4aS,5aR)-3-(5-bromo-6,7-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H- benzo[d]imidazol-2-yl)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole

NaH (1.29 g, 32.2 mmol) was added to a solution of Preparation Example 90 (10.95 g, 2.49 mmol) in THF (269 mL) at 0°C. After stirring for 30 minutes, SEM-Cl (3.94 g, 23.6 mmol) was added and the mixture was stirred for 3 hours at room temperature. The mixture is poured into sat. aqueous NH ₄ Cl (150 ml) and extracted with EtOAc (2×100 ml). Organic extracts are collected, dried (Na ₂ SO ₄ ), 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- d4 ) 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), 1.31 (s, 3H), 1. 15 (dt, 1H), 0.91 (dd, 2H), 0.77 (dd, 2H), 0.43 (dd, 1H), 0.24 (k, 1H), -0.01 (d, 9H), -0.14 (s, 4H), -0.17 (s, 5H).

Example of receiving 92a: rubs -butyl(4,5-difluoro-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[ f]indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 N- benzo[d]imidazol-6-yl)carbamate

Example of getting 92b: rubs -butyl(6,7-difluoro-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[ f]indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 N- benzo[d]imidazol-5-yl)carbamate

Part of a mixture of Preparation Examples 91a and 91b (9.45 g, 14.7 mmol) inrubs-amyl alcohol (148 ml) at RT is treatedrubs-butylcarbamate (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 is heated at 100°C for 16 hours. The mixture is concentrated and the residue is purified by chromatography (silica, EtOAc/PE=0-16%) to giveconnections specified in the headeras a mixture (4.24 g, 43%). LC/MSm/z(M+H) = 676.3.

Preparation example 93a: 4,5-difluoro-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocycloprop [f]indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 N- benzo[d]imidazol-6-amine

Preparation example 93b: 6,7-difluoro-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocycloprop [f]indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 N- benzo[d]imidazol-5-amine

A mixture of 92a and 92b (5.27 g, 7.79 mmol) in DCM (78.0 ml) at 0°C was treated with ZnBr ₂ (8.78 g, 39.0 mmol). The mixture is stirred at 15°C for 12 hours and poured into sat. aqueous NaHCO ₃ (70 ml). The mixture is extracted with DCM (2×80 ml) and the organic extracts are combined, dried (Na ₂ SO ₄ ), 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.

Example of receiving 94a: (S)- N -(4,5-difluoro-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f ]indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 N- benzo[d]imidazol-6-yl)-2-morpholinopropanamide

Example of receiving 94b: (S)- N -(6,7-difluoro-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f ]indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 N- benzo[d]imidazol-5-yl)-2-morpholinopropanamide

A mixture of Preparation Examples 93a and 93b (2.80 g, 4.86 mmol) in pyridine (69.5 ml) at 0° C. was treated with Preparation Example 19 (1.12 g, 7.05 mmol) and EDCI (1.86 g, 9.72 mmol). The mixture was stirred at room temperature for 19 hours, diluted with H ₂ O (100 ml) and extracted with EtOAc (2 x 100 ml). The organic extracts are combined, dried (Na ₂ SO ₄ ), filtered and concentrated. The crude material was purified by chromatography (silica, EtOAc/PE=0-25%) to give the title compounds as a mixture (3.07 g, 88.1%). LC/MS m/z (M+H)= 717.6.

Example of receiving 95a: (S)- N -(4,5-difluoro-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f ]indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 N- benzo[d]imidazol-6-yl)- N- methyl 2-morpholinopropanamide

Example of receiving 95b: (S)- N -(6,7-difluoro-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f ]indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 N- benzo[d]imidazol-5-yl)- N- methyl 2-morpholinopropanamide

A solution of a mixture of Preparation Examples 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 for 30 minutes at 15°C, methyl iodide (729 mg, 5.14 mmol) was added and the mixture was stirred at room temperature for 3 hours. The mixture is diluted with sat. aqueous NH ₄ Cl (80 ml) and extracted with EtOAc (2 x 80 ml). The organic extracts are combined, dried (Na ₂ SO ₄ ), filtered and concentrated. The crude material was purified 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.

Example of receiving 96a: (S)- N -(4,5-difluoro-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f ]indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 N- benzo[d]imidazol-6-yl)- N- ethyl-2-morpholinopropanamide

Example of receiving 96b: (S)- N -(6,7-difluoro-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f ]indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 N- benzo[d]imidazol-5-yl)- N- ethyl-2-morpholinopropanamide

A solution of part of the mixture of Preparation Examples 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 for 30 minutes at room temperature, ethyl iodide (14 mg, 0.09 mmol) was added and the mixture was stirred for 22 hours. The mixture is diluted with sat. aqueous NH ₄ Cl (10 ml) and extracted with EtOAc (2×15 ml). The organic extracts are combined, dried (Na ₂ SO ₄ ), filtered and concentrated to obtain the title compound as a mixture. LC/MS m/z (M+H)= 745.1.

Example of getting 97: N- methyl- N -(6-methyl-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole -3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H- benzo[d]imidazol-5-yl)acetamide

A solution of Preparation Example 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-Cl (1.81 g, 10.9 mmol) was added. The mixture is stirred at 0°C for 1 hour, heated to 10°C and stirred for 1.5 hours. The mixture is treated with sat. aqueous NH ₄ Cl (50 ml) and extracted with EtOAc (3×50 ml). The combined organic layers are dried (Na ₂ SO ₄ ), 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) ⁺ =610.3.

Preparation example 98: 2-chloro- N- methyl- N -(6-methyl-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole -3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H- benzo[d]imidazol-5-yl)acetamide

A solution of Preparation Example 97 (848 mg, 1.39 mmol) in THF (22 mL) at -10° C. was treated with a solution of DAL (0.76 mL, 2N in THF/heptane). The mixture was stirred at -10°C for 30 minutes and benzenesulfonyl chloride (577 mg, 3.27 mmol) was added. The mixture is stirred for 2 hours at -10°C and then treated with sat. aqueous NH ₄ Cl (20 ml) and extracted with EtOAc (3×30 ml). The combined organic layers are dried (Na ₂ SO ₄ ), filtered and concentrated. The crude material is purified by chromatography (silica, EtOAc/PE=0-30%) to give the title compound (404 mg, 45%). ^1H NMR (400 MHz, CDCl ₃ ) 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 , 1H), 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), 0.46-0.33 (m, 1H), 0.26 (kv, 1H), -0.02 (s, 9H), -0.12 (s, 9H); LC/MS m/z (M+H) ⁺ =644.3.

Example of getting 99: (S)- N -(4-amino-3-nitrophenyl)-N-methyl-2-morpholinopropanamide

The title compound was prepared analogously to Preparation Example 38, starting with 4-chloro-3-nitroaniline, and Preparation Example 19. LC/MS m/z (M+H) ⁺ =309.0.

Example of getting 100: (S)- N -(4-amino-3-bromo-5-nitrophenyl)- N- methyl 2-morpholinopropanamide

A solution of Preparation Example 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 is stirred at 20°C for 15 hours. The mixture is cooled to 0°C and treated with Et ₃ N (10 ml). The mixture was concentrated under reduced pressure and the residue was purified by chromatography (silica, EtOAc/PE=0-100%) to give the title compound (610 mg, 41%). LC/MS m/z (M+H) ⁺ =388.8 ( ⁸¹ Br).

Example of receiving 101(S)- N -(3,4-diamino-5-bromophenyl)- N- methyl 2-morpholinopropanamide

A solution of Preparation Example 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 is stirred at 70°C for 2 hours. The mixture is cooled to 0°C and adjusted to pH 7 by adding conc. NH ₄ OH (2 ml). The mixture is filtered and the filtrate is concentrated. The residue is dissolved in DCM (60 ml), stirred for 1 hour and filtered. The filtrate was concentrated to give the title compound (802 mg, 87%). LC/MS m/z (M+H) ⁺ =356.9 ( ⁷⁹ Br).

Example of receiving 102: (S)- N -(7-bromo-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole -3-yl)-1 H- benzo[d]imidazol-5-yl)- N- methyl-2-morpholinopropanamide

Mixture from Preparation Example 9 (601 mg, 1.96 mmol) in DMF (25 ml) add to 101 (700 mg, 1.96 mmol) and Na₂S₂O₅(373 mg, 1.96 mmol) and the mixture was heated at 110°C for 15 hours. The mixture is concentrated and the residue is purified by chromatography (silica, EtOAc/PE=0-100%), to givespecified in the connection header(730 mg, 56%).¹H NMR (400 MHz, CDCl₃) δ 9.94 (s, 1H), 7.59 (s, 1H), 7.35 (s, 1H), 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 (s, 9H); LC/MSm/z(M+H)⁺=645.0 (⁸¹Br).

Example of receiving 103: (S)- N -(4-bromo-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole -3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H- benzo[d]imidazol-6-yl)- N- methyl 2-morpholinopropanamide

A solution of Preparation Example 102 (700 mg, 1.09 mmol) in THF (50 mL) at 0° C. was treated with NaH (57 mg, 1.41 mmol) and SEM-Cl (272 mg, 1.63 mmol). The mixture is warmed to room temperature and stirred for 2 hours. The mixture is cooled to 0°C and treated with sat. aqueous NH ₄ Cl (1 ml). The mixture is diluted with water (50 ml) and extracted with EtOAc (2×150 ml). The combined organic layers are washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The crude material is 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).

Preparation example 104: (2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole- 3-yl)-6-((S)- N- methyl-2-morpholinopropanamido)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H- benzo[d]imidazol-4-yl)boronic acid

A solution of Preparation Example 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)Cl ₂ (31 mg, 0.0424 mmol). The mixture is heated to 100°C and stirred for 15 hours. The mixture is cooled to room temperature and concentrated. The residue is 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 ( ⁷⁹ Br).

Example of receiving 105: (S)- N -(4-hydroxy-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole -3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H- benzo[d]imidazol-6-yl)- N- methyl 2-morpholinopropanamide

A solution of Preparation Example 104 (350 mg, 0.224 mmol) in THF (30 ml) at 0° C. was treated with a solution of NaBO ₃ -4H ₂ O (104 mg, 0.673 mmol) in water (10 ml). The mixture is stirred at 20°C for 5 hours. The mixture is 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 (Na ₂ SO ₄ ), filtered and concentrated to give the title compound (300 mg, 94%). LC/MS m/z (M+H) ⁺ =711.3

Example of receiving 106: (S)- N -(4-methoxy-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)-1 H- benzo[d]imidazol-6-yl)- N- methyl-2-morpholinopropanamide

A solution of Preparation Example 105 (150 mg, 0.211 mmol) in DMF (3 mL) at 0° C. was treated with K ₂ CO ₃ (88 mg, 0.63 mmol) and methyl iodide (45 mg, 0.32 mmol). The mixture is stirred at 20°C for 2 hours. The mixture is diluted with water (10 ml) and extracted with EtOAc (2 x 50 ml). The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated to give the title compound (153 mg, 100%). LC/MS m/z (M+H) ⁺ =725.3

Preparation Example 107: (4aS,5aR)-3-(5-bromo-7-(trifluoromethyl)-1 H -benzo[d]imidazol-2-yl)-5a-methyl-1-((2-(trimethylsilyl) ) ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole

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

Preparation Example 108: (4aS,5aR)-3-(6-bromo-4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H- benzo[d]imidazol-2-yl)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole

A solution of Preparation Example 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 is warmed to room temperature and stirred for 2 hours. The mixture is cooled to 0°C and treated with sat. aqueous NH ₄ Cl (1 ml). The mixture is diluted with water (50 ml) and extracted with EtOAc (2×150 ml). The combined organic layers are washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The crude material is purified by chromatography (silica, EtOAc/PE=0-100%) to give the title compound (430 mg, 99%). LC/MS m/z (M+H) ⁺ =673.0 ( ⁸¹ Br).

Example of getting 109: tert- butyl-(2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3- yl)-4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H- benzo[d]imidazol-6-yl)carbamate

A solution of Preparation Example 108 (380 mg, 0.57 mmol) in 1,4-dioxane (10 ml) in tert -amyl alcohol (10 ml) was treated with BOC ₂ O (199 mg, 1.7 mmol), Cs ₂ CO ₃ (369 mg, 1.13 mmol) (77 mg, 0.23 mmol) and Pd ₂ (dba) ₃ (52 mg, 0.057 mmol). The mixture is heated at 100°C for 15 hours. The mixture is cooled to room temperature and concentrated. The residue is purified by chromatography (silica, EtOAc/PE+0-100%) to give the title compound (223 mg, 56%). LC/MS m/z (M+H) ⁺⁼ 708.4.

Preparation example 110: 2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3 -yl)-4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H- benzo[d]imidazol-6-amine

A solution of Preparation Example 109 (220 mg, 0.31 mmol) in DCM (20 ml) was treated with ZnBr ₂ (350 mg, 1.55 mmol). The mixture is stirred at room temperature for 15 hours. The mixture is filtered, the filtrate is diluted with water (50 ml) and extracted with DCM (2 x 50 ml). The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated to give the title compound (170 mg, 90%). LC/MS m/z (M+H) ⁺ =608.2.

Example of receiving 111: (S)- N -(2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl )-4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H- benzo[d]imidazol-6-yl)-2-morpholinopropanamide

A solution of Preparation Example 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 is stirred at room temperature for 15 hours. The mixture is diluted with water (50 ml) and extracted with EtOAc (2×50 ml). The combined organic layers are washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The crude material was purified by chromatography (silica, EtOAc/PE=0-100%) to give the title compound (125 m, (60%). LC/MS m/z (M+H) ⁺ =749.4.

Example of receiving 112: (S)- N- methyl -N -(2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl )-4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H- benzo[d]imidazol-6-yl)-2-morpholinopropanamide

A solution of Preparation Example 111 (125 mg, 0.17 mmol) in THF (5 mL) at 0° C. was treated with NaH (10 mg, 0.25 mmol) and then methyl iodide (36 mg, 0.25 mmol). The mixture is warmed to room temperature and stirred for 2 hours. The mixture is cooled to 0°C and treated with sat. aqueous NH ₄ Cl (0.3 ml). The mixture is diluted with water (50 ml) and extracted with EtOAc (2×50 ml). The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated to give the title compound (127 mg, 99%).

Preparation Example 113: Methyl 5-bromo-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa [f]indazol-3-yl)-1 H- benzo[d]imidazole-7-carboxylate

A mixture of methyl 2,3-diamino-5-bromobenzoate (720 mg, 2.94 mmol), 9 (990 mg, 3.32 mmol) and NaHSO ₃ (336 mg, 3.23 mmol) in EtOH (14.7 ml) and water (2.5 ml) are heated at 90°C in air for 18 hours. The mixture is cooled to RT and diluted with water. The mixture is extracted with DCM (x3) and the combined organic layers are dried (MgSO ₄ ), filtered and concentrated. The residue was stirred in heptane:EtOAc (1:1, 10 mL) for 18 hours and the resulting solids were collected by filtration to give the title compound (842 mg, 54%) as a beige solid. ^1H NMR (600 MHz, _CDCl3 ) δ 10.85 (s, 1H), 8.18 (s, 1H), 8.01 (d, 1H), 5.50-5.33 (m, 2H) , 4.02 (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, 1H), 0.27 (t, 1H), -0.02 ( s, 9H); LC/MS m/z (M+H) ⁺⁼ 531.5.

Preparation Example 114: Methyl 6-bromo-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa [f]indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H- benzo[d]imidazole-4-carboxylate

A suspension of NaH (4147 mg, 10.4 mmol) in THF (6 ml) at 0° C. was treated with a solution of Preparation Example 113 (2.77 g, 5.22 mmol) in THF (24 ml). The mixture was stirred at 0°C for 30 minutes, and then SEM-Cl (1310 mg, 7.83 mmol) was added. The mixture is warmed to room temperature and stirred for 18 hours. The mixture is cooled to 0°C and treated with sat. aqueous NH ₄ Cl (5 ml). The organic solvent is evaporated and the resulting mixture is extracted with DCM (x4). The combined organic layers are washed with brine, dried (MgSO ₄ ), filtered and concentrated. The crude material was purified by chromatography (silica, EtOAc/PE=0-60%) to give the title compound (2.88 g, 83%). ^1H NMR (400 MHz, CDCl ₃ ) 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).

Preparation Example 115: Methyl 2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole -3-yl)-6-(methylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H- benzo[d]imidazole-4-carboxylate

A solution of Preparation Example 114 (420 mg, 0.635 mmol) in DMF (4.2 ml) was added to a vial containing MeNH ₂ -HCl (64 mg, 0.95 mmol), CuI (10 mg, 0.051 mmol), N - (2,6-dimethylphenyl)-6-hydroxypicolinamide (25 mg, 0.10 mmol) and K ₃ PO ₄ (404 mg, 1.9 mmol). The mixture is heated at 110°C for 20 hours. The mixture is cooled to room temperature and diluted with EtOAc. The mixture is extracted with water (x2). The organic layer is washed with brine, dried (MgSO ₄ ), filtered and concentrated. The crude material is purified by chromatography (silica, EtOAc/PE=0-70%) to give the title compound (231 mg, 60%). ^1H NMR (400 MHz, _CDCl3 ) 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.

Preparation Example 116: 2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3 -yl)-6-(methylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H- benzo[d]imidazol-4-yl)methanol

A solution of LiAlH ₄ (15 mg, 0.39 mmol) in tetrahydrofuran (0.39 ml) at 0° C. is treated dropwise with a solution of Preparation Example 115 (158 mg, 0.26 mmol) in THF (1.3 ml). The mixture is warmed to room temperature and stirred for 1 hour. The mixture is cooled to 0°C and treated with sat. aqueous potassium-sodium tartrate (potassium-sodium tartrate). The mixture is extracted with EtOAc (x2) and the combined organic layers are washed with brine, dried (MgSO ₄ ), filtered and concentrated. The crude product was purified by chromatography (silica, EtOAc/heptanes=20-100%) to give the title compound (103 mg, 68%). ^1H NMR (400 MHz, CDCl ₃ ) 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, 1H), 0.25 (t, 1H), -0.02 (s, 9H), -0.11 (s , 9H).

Example of receiving 117: (S)- N -(4-(methoxymethyl)-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f ]indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H- benzo[d]imidazol-6-yl)- N- methyl-2-morpholinopropanamide

A solution of Preparation Example 116 (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 is stirred at room temperature for 18 hours. The mixture is concentrated and the residue is partitioned between EtOAc and sat. aqueous NaHCO ₃ . The organic layer was separated and the aqueous layer was extracted with EtOAc (x2). The combined organic layers are dried (Na ₂ SO ₄ ), filtered and concentrated. The crude material is purified by chromatography (silica, [10:1 NH ₄ OH/MeOH]/DCM=0-16%), yielding a mixture of N- and O -acyl products. The mixture is dissolved in THF (1 ml) and cooled to 0°C. NaH (18 mg, 0.45 mmol) was added and the mixture was stirred for 30 min and then treated with methyl iodide (42 mg, 0.30 mmol). The mixture is warmed to room temperature and stirred for 16 hours. The mixture is cooled to 0°C and treated with sat. aqueous NH ₄ Cl. The mixture is diluted with water and extracted with EtOAc (x3). The combined organic layers are dried (MgSO ₄ ), filtered and concentrated. The crude product was purified by chromatography (silica, EtOAc/heptanes=20-100%) to give the title compound (61 mg, 47%). ^1H NMR (400 MHz, _CDCl3 ) 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 (k, 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), 0.27 (t, 1H), -0.02 (s, 9H), -0. 12 (s, 9H).

Preparation example 118: (4aS,5aR)-3-(5-bromo-7-chloro- 1H- benzo[d]imidazol-2-yl)-5a-methyl-1-((2-(trimethylsilyl)ethoxy))methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole

1,2-Diamino-5-bromo-3-chlorobenzene mixture (200 mg, 0.90 mmol), NaHSO₃(103 mg, 0.99 mmol) and Preparation Example 9 (304 mg, 0.99 mmol) in EtOH (3.7 ml) and water (0.8 ml) were refluxed for 16 hours. The mixture is cooled to RT and diluted with water. After removing EtOH under reduced pressure, the mixture was extracted with EtOAc (x3). The combined organic layers are dried (MgSO₄), filter and concentrate. The crude material is purified by chromatography (silica, EtOAc/heptanes=0-30%) to givespecified in the connection header(410 mg, 89%).¹H NMR (400 MHz, DMSO-d ₆ ) 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 (dd, 1H), 0.84 (td, 2H), 0.41 (dd, 1H), 0.17 (dd, 1H), -0.06 (s, 9H); LC/MSm/z(M+H)⁺=507.4 (⁷⁹Br).

Example of obtaining 119a: (4aS,5aR)- 3 -(5-bromo-7-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-5a-methyl-1-((2-(trimethylsilyl) ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole

Preparation example 119b: (4aS,5aR)-3-(6-bromo-4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H- benzo[d]imidazol-2-yl)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole

A solution of Preparation Example 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-Cl (205 mg, 1.23 mmol) was added. The mixture is stirred at 0°C for 1.5 hours. The mixture is cooled to 0°C and treated with sat. aqueous NH ₄ Cl. The THF is evaporated. The remaining mixture is extracted with EtOAc (x4). The combined organic layers are dried (MgSO ₄₎ , filtered and concentrated. The crude material is 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 ( ⁷⁹ Br).

Preparation example 120: 7-chloro- N- methyl-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl )-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H- benzo[d]imidazol-5-amine

Preparation example 121: 4-chloro- N- methyl-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl )-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H- benzo[d]imidazol-6-amine

A solution of a mixture of Preparation Examples 119a and 119b (542 mg, 0.85 mmol) in DMF (5.7 ml) was added to MeNH ₂ -HCl (86 mg, 1.27 mmol), CuI (13 mg, 0.068 mmol), N -(2,6-dimethylphenyl)-6-hydroxypicolinamide (33 mg, 0.14 mmol) and K ₃ PO ₄ (541 mg, 2.6 mmol). The mixture is heated at 110°C for 18 hours. The mixture is diluted with EtOAc and washed with water (x3) and saline. The organic layer is dried (MgSO ₄ ), filtered and concentrated. The crude material is purified by chromatography (silica, EtOAc/heptanes=0-30%) to give the title compound (Ref: Bernhardson, DJ, Widlicka, DW, Singer, RA, Org. Process Res. Dev. 2019, 23, 1538-1551)

Preparation example: 120: (121 mg, 24%). ^1H NMR (400 MHz, CDCl ₃ ) 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

Preparation example 121: (162 mg, 33%). ^1H NMR (400 MHz, _CDCl3 ) 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 (dd, 1H), 0.95-0.89 (m, 2H), 0.75 (td, 2H), 0.39 (dd, 1H), 0.27 (dd, 1H), -0.01 (s, 9H), -0.16 (s, 9H). LC/MS m/z (M+H) ⁺ =588.6

Example of receiving 122: (S)- N -(7-chloro-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole -3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H- benzo[d]imidazol-5-yl)- N- methyl-2-morpholinopropanamide

A mixture of Preparation Example 19 (24.4 mg, 0.15 mmol), 120 (82 mg, 0.14 mmol), pyridine (0.56 mL, 0.70 mmol) and T ₃ P (50 wt.% in EtOAc, 0.17 ml, 0.28 mmol) in EtOAc (0.9 ml) was stirred at room temperature for 18 hours. The mixture is treated with DMF (0.6 ml) and the mixture is stirred at room temperature for an additional 24 hours. The mixture is diluted with EtOAc and water. After separation of the layers, the organic layer is washed with water (x2) and saline. The remaining organic fraction is dried (MgSO ₄ ), 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 (400 MHz, CDCl ₃ ) 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 ( k, 1H), 3.14 (d, 1H), 3.06 (dd, 1H), 2.74 (d, 1H), 2.57 (dd, 2H), 2.32 (dd, 2H), 1.77 (br, 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.

Example of getting 123: N -(7-chloro-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole -3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 N- benzo[d]imidazol-5-yl)- N- methylacetamide

A solution of Preparation Example 120 (785 mg, 1.33 mmol) in DCM was cooled to 0°C. The solution is treated with Et ₃ N (0.56 ml, 4.00 mmol) and acetyl chloride (0.14 ml, 2.00 mmol). The mixture is stirred at 0°C for 20 minutes and treated with sat. aqueous NaHCO ₃ . The aqueous layer was extracted with DCM (x3), the combined organic layers were dried (MgSO ₄ ), 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.

Example of getting 124: N- methyl- N -(2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl )-1-((2-(trimethylsilyl)ethoxy)methyl)-7-vinyl-1 H- benzo[d]imidazol-5-yl)acetamide.

A mixture of Preparation Example 123 (675 mg, 1.07 mmol), 2,4,6-trivinylcyclotriboroxanepyridine 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) add 3 MK ₃ PO ₄ (0.82 ml, 2.47 mmol). The mixture is heated at 100°C for 20 hours. The mixture is filtered and the solids are washed with EtOAc. The filtrate is diluted with water and extracted with EtOAc (x3). The combined organic extracts are dried (MgSO ₄ ), filtered and concentrated. The crude material is purified by chromatography (silica, EtOAc/heptanes=0-50%) to give the title compound (391 mg, 59%). LC/MS m/z (M+H) ⁺ =622.5.

Example of receiving 124a: N -(7-ethyl-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole -3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H- benzo[d]imidazol-5-yl)- N- methylacetamide

A solution of Preparation Example 124 (87 mg, 0.14 mmol) in MeOH (2 ml) was treated with 10% Pd/C (20 mg). The mixture is degassed with N ₂ and charged three times with H ₂ . The mixture was stirred at room temperature under H ₂ (3 atm) for 18 hours. The mixture is filtered and the filtrate is concentrated to give the title compound (87 mg, quantitative). ^1H NMR (600 MHz, CDCl ₃ ) δ 7.45 (d, 1H), 6.91 (d, 1H), 6.14 (k, 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 , 1H), 2.74 (d, 1H), 1.97 (s, 1H), 1.88 (s, 3H), 1.34 (t, 3H), 1.27 (s, 3H), 1 .11 (dt, 1H), 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).

Preparation example 125: 7-ethyl- N- methyl-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl )-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H- benzo[d]imidazol-5-amine

A solution of Preparation Example 124 (86 mg, 0.14 mmol) in 1:1 EtOH:water was treated with KOH (155 mg, 2.76 mmol). The mixture is heated to 90°C and stirred for 72 hours. The mixture is cooled to room temperature and diluted with water, extracted with DCM (x3). The combined organic layers are dried (MgSO ₄ ), filtered and concentrated. The crude material is purified by chromatography (silica, EtOAc/heptanes=0-80% gradient) to give the title compound (37 mg, 46%). ^1H NMR (400 MHz, CDCl ₃ ) 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, 1H), -0.01 (s, 9H), -0 ,16 (s, 9H); LC/MS m/z (M+H) ⁺ =582.5.

Example of receiving 126: (S)- N -(7-ethyl-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole -3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H- benzo[d]imidazol-5-yl)- N- methyl-2-morpholinopropanamide

A solution of Preparation Example 125 (37 mg, 0.064 mmol) and Preparation Example 19 (15 mg, 0.095 mmol) in pyridine (1 ml) was treated with EDCI (31 mg, 0.159 mmol). The mixture is stirred at room temperature for 18 hours. The mixture is concentrated and the residue is diluted with water. The organic layer is extracted with EtOAc (x3). The combined organic layers are dried (MgSO ₄ ), filtered and concentrated to give the title compound (45 mg, 98%). ^1H NMR (600 MHz, CDCl ₃ ) δ 7.47 (s, 1H), 6.92 (s, 1H), 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 (sq, 1H), 3.15 (kv, 3H), 3.06 (dd, 1H), 2.75 (d, 1H), 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 (dd, 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.

Example of getting 127: rubs -butyl(4-chloro-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f] indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H- benzo[d]imidazol-6-yl)(methyl)carbamate

A solution of Preparation Example 121 (740 mg, 1.26 mmol) in THF (6.3 mL) was treated with Et ₃ N (0.35 mL, 2.52 mmol), Boc ₂ O (412 mg, 1.89 mmol) and DMAP (154 mg, 1.26 mmol) at CT. The mixture was stirred at room temperature for 18 hours and additional Et ₃ N (0.35 ml, 2.52 mmol), Boc ₂ O (412 mg, 1.89 mmol) and DMAP (154 mg, 1.26 mmol) were added ). The reaction mixture is heated to 60°C and stirred for another 36 hours. The mixture was concentrated and the residue was purified by chromatography (silica, EtOAc/heptanes=0-50%) to give the title compound (637.3 mg, 74%). ^1H NMR (400 MHz, CDCl ₃ ) 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 (d, 1H), 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).

Example of getting 128: tert- butylmethyl(2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl )-1-((2-(trimethylsilyl)ethoxy)methyl)-4-vinyl-1 H- benzo[d]imidazol-6-yl)carbamate

Mixture of Preparation Example 127 (450 mg, 0.71), vinylboron 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 3M K ₃ PO ₄ (0.71 ml, 2.14 mmol). The mixture is heated at 100°C for 20 hours. The mixture is filtered and the solids are washed with EtOAc. The filtrate is diluted with water and extracted with EtOAc (x3). The combined organic extracts are dried (MgSO ₄ ), filtered and concentrated. The crude material was purified by chromatography (silica, EtOAc/heptanes=0-50%) to give the title compound (367 mg, 76%). ^1H NMR (400 MHz, CDCl ₃ ) 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 (dd, 1H), 0.91 (dd, 2H), 0.87-0.79 (m, 2H), 0.41 (dd, 1H), 0.28 (dd, 1H), -0.02 (s, 9H), -0.12 (s, 9H).

Example of getting 129: rubs -butyl(4-formyl-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f] indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H- benzo[d]imidazol-6-yl)(methyl)carbamate

A solution of Preparation Example 128 (366 mg, 0.54 mmol) in pyridine (2.7 ml) and THF (2.7 ml) at 0°C was treated with OsO ₄ (4 wt% in water, 5.1 ml, 0.81 mmol). The mixture is stirred at 0°C for 2 hours, and then at room temperature for another 18 hours. The mixture is treated with 10% aq. NaHSO ₃ (15 ml) and stir at room temperature for 3 hours. The mixture is concentrated and extracted with DCM (x4). The combined organic extracts are dried (Na ₂ SO ₄ ), filtered and concentrated. This residue is dissolved in THF/water 2:1 (6 ml), cooled to 0°C and treated with NaIO ₄ (138 mg, 0.65 mmol). The mixture is stirred at 0°C for 2.5 hours. The mixture is filtered through celite and MgSO ₄ and the filtrate is concentrated. The residue is purified by chromatography (silica, EtOAc/heptanes=10-50% gradient) to give the title compound (163 mg, 44%). ^1H NMR (400 MHz, _CDCl3 ) 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), 5.40 (d, 1H). 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).

Example of getting 130: tert- butyl(4-(hydroxymethyl)-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f ]indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H- benzo[d]imidazol-6-yl)(methyl)carbamate

A solution of Preparation Example 129 (30 mg, 0.044 mmol) in MeOH (1 ml) at 0° C. was treated with NaBH ₄ (8 mg, 0.22 mmol). The mixture is heated to RT and stirred for 2 hours. The mixture is cooled to 0°C and diluted with salt solution and water. The mixture was extracted with DCM (x3) and the combined organic layers were dried (MgSO ₄ ), filtered and concentrated to give the title compound (19 mg, 63%). ^1H NMR (400 MHz, CDCl ₃ ) 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 (dd, 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.

Preparation Example 131: (2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole- 3-yl)-6-(methylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H- benzo[d]imidazol-4-yl)methanol

A solution of Preparation Example 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 is stirred at 0°C for 2 hours and treated with sat. aqueous NaHCO ₃ . The mixture is extracted with DCM (x3). The combined organic layers are dried (MgSO ₄ ), filtered and concentrated to give the title compound (20 mg, quantitative). ^1H NMR (600 MHz, CDCl ₃ ) 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, 1H), 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.

Example of receiving 132 (S)- N -(4-(hydroxymethyl)-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f ]indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H- benzo[d]imidazol-6-yl)- N- methyl-2-morpholinopropanamide

A solution of Preparation Example 131 (19 mg, 0.033 mmol) and Preparation Example 19 (10 mg, 0.065 mmol) in pyridine (1 ml) was treated with EDCI (25 mg, 0.13 mmol). The mixture is stirred at room temperature for 18 hours. The mixture is concentrated, the residue is diluted with water and extracted with EtOAc (x3). The combined organic layers are dried (MgSO ₄ ), filtered and concentrated to give the title compound (21 mg, 90%). ^1H NMR (600 MHz, CDCl ₃ ) δ 7.41-7.29 (m, 1H), 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 , 9Н); LC/MS m/z (M+H) ⁺ =725.7.

Preparation example 133: 3,4-difluoro-2-methylaniline.

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 was stirred at room temperature for 16 hours. The reaction mixture is filtered and the filtrate is concentrated. The residue is dissolved in EtOAc (300 ml) and washed with sat. aqueous NaHCO ₃ (500 ml). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give the title compound (3.8 g, 92%). LC/MS m/z (M+H) ⁺ =143.8.

Example of receiving 134: (S)- N -(3,4-difluoro-2-methylphenyl)-2-morpholinopropanamide

A solution of Preparation Example 133 (3.8 g, 26.6 mmol) and Preparation Example 19 (8.45 g, 53.1 mmol) in pyridine (200 ml) was treated with EDCI (10.2 g, 53.1 mmol) . The mixture is stirred at room temperature for 16 hours. The mixture is concentrated, the residue is diluted with water and extracted with EtOAc (x3). The combined organic layers are dried (Na ₂ SO ₄ ), 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.

Example of receiving 135 (S)- N -(3,4-difluoro-2-methylphenyl)- N- methyl 2-morpholinopropanamide

A solution of Preparation Example 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 minutes and methyl iodide (5.17 g, 36.4 mmol) was added. The mixture is heated to 20°C and stirred for 16 hours. The mixture is treated with water and extracted with EtOAc (2×100 ml). The combined organic layers are dried (Na ₂ SO ₄ ), 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.

Example of receiving 136: (S)- N -(3,4-difluoro-2-methyl-5-nitrophenyl)- N- methyl 2-morpholinopropanamide

A solution from Preparation Example 135 (5 g, 16.8 mmol) in conc. H ₂ SO ₄ (40 ml) at 5-10°C is treated dropwise with conc. HNO ₃ (2.11 g, 33.5 mmol). The mixture is stirred at 5-10°C for 2 hours and poured onto ice. The pH is adjusted to 7 using sat. aqueous Na ₂ CO ₃ and the mixture was extracted with EtOAc (2 x 100 ml). The combined organic layers are dried (Na ₂ SO ₄ ), 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.

Receipt example 137: (S)- N -(4-amino-3-fluoro-2-methyl-5-nitrophenyl)- N- methyl-2-morpholinopropanamide

A solution of Preparation Example 136 (3.5 g, 10.2 mmol) in THF (40 ml) at 20°C was treated with conc. NH ₄ OH (40 ml). The mixture is stirred for 16 hours. The mixture is extracted with EtOAc (2×200 ml). The combined organic layers are dried (Na ₂ SO ₄ ), 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.

Example of receiving 138: (S)- N -(4,5-diamino-3-fluoro-2-methylphenyl)- N- methyl-2-morpholinopropanamide)

A solution of Preparation Example 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 was stirred at room temperature for 16 hours. The mixture is filtered and the filtrate is concentrated. The residue is dissolved in EtOAc (100 ml) and washed with sat. aqueous NaHCO ₃ (30 ml). The organic layer is dried (Na ₂ SO ₄ ), filtered and concentrated. The crude material is purified by chromatography (silica, EtOAc/PE=0-100%, then gradient 0-10% MeOH/DCM) to give the title compound (1.3 g, 65%). LC/MS m/z (M+H) ⁺ =311.1.

Preparation Example 139: 3-Fluoro-2-methyl-6-nitroaniline

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. NH ₄ OH (100 ml). The mixture is stirred at room temperature for 16 hours. The mixture is extracted with EtOAc (2 x 200 ml). The combined organic layers are dried (Na ₂ SO ₄ ), filtered and concentrated. The crude material was purified by chromatography (silica, EtOAc/PE=0-15%) to give the title compound (3 g, 61%). ^1H NMR (400 MHz, CDCl ₃ ) δ 8.07 (dd, 1H), 6.46 (dd, 1H), 6.32 (s, 2H), 2.13 (d, 3H).

Preparation Example 140: 4-bromo-3-fluoro-2-methyl-6-nitroaniline

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

Preparation Example 141: 5-bromo-4-fluoro-3-methylbenzene-1,2-diamine

A solution of Preparation Example 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 hour. The reaction mixture is filtered and the filtrate is concentrated. The residue is dissolved in EtOAc (300 ml) and washed with sat. aqueous NaHCO ₃ (50 ml). The organic layer is dried (Na ₂ SO ₄ ), 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, CDCl ₃₎ δ 6.74 (d, 1H), 3.36 (s, 4H), 2.12 (d, 3H).

Example of getting 142: tert- butyl-(4-(difluoromethyl)-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[ f]indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H- benzo[d]imidazol-6-yl)(methyl)carbamate

A solution of Preparation Example 129 (160 mg, 0.24 mmol) in anhydrous DCE (1.5 mL) was treated with DAST (0.047 mL, 0.35 mmol) at 0°C. The mixture is warmed to room temperature and stirred for 18 hours. The mixture is treated with sat. aqueous NaHCO ₃ . Additional water is added and the mixture is extracted with DCM (x3). The combined organic layers are dried (MgSO ₄ ), 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, _CDCl3 ) δ 7.51 (s, 1H), 7.43 (dd, 1H), 7.42 (s, 1H), 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, 1H), 1.44 (s, 9H), 1.29 (s, 3H), 1.13 (ddd , 1H), 0.91 (dd, 2H), 0.87-0.79 (m, 2H), 0.41 (dd, 1H), 0.27 (dd, 1H), -0.02 (s , 9H), -0.11 (s, 9H).

Preparation Example 143: 4-(difluoromethyl)- N- methyl-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl )-1-((2-(trimethylsilyl)ethoxy)methyl)-1 N- benzo[d]imidazol-6-amine

A solution of Preparation Example 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 is stirred at 0°C for 2 hours. The mixture is treated with sat. aqueous NaHCO ₃ . The organic phase is separated and the aqueous layer is extracted with additional DCM (x4). The combined organic extracts are dried (MgSO ₄ ), 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.

Example of receiving 144: (S)- N -(4-(difluoromethyl)-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f ]indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H- benzo[d]imidazol-6-yl)- N- methyl 2-morpholinopropanamide

A solution of Preparation Example 143 (61 mg, 0.10 mmol) and 19 (24 mg, 0.15 mmol) in pyridine (1 ml) was treated with EDCI (48 mg, 0.25 mmol). The mixture is stirred at room temperature for 18 hours. The mixture is concentrated, the residue is dissolved in water and extracted with EtOAc (x3). The combined organic layers are dried (MgSO ₄ ), filtered and concentrated to give the title compound (72 mg, 96%). LC/MS m/z (M+H) ⁺ =745.7.

Preparation Example 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 1 M KOtBu in THF (31.4 ml, 31.4 mmol). After 30 minutes, a solution of 2,4-difluoro-1-nitrobenzene (5.0 g, 31.4 mmol) in THF (40 ml) was added. The mixture is stirred at 30°C for 1 hour and diluted with a mixture of H ₂ O:EtOAc, 1:1 (100 ml). The layers are separated and the aqueous layer is extracted with EtOAc (50 ml). The organic extracts are dried, filtered and concentrated to give the title compound (6.76 g, 100%). ^1H NMR (400 MHz, CDCl ₃ ) 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).

Preparation Example 146: 4-Fluoro-2-(2-methoxyethoxy)aniline

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

Preparation Example 147: 4-Fluoro-2-(2-methoxyethoxy)-5-nitroaniline

A solution from Preparation Example 146 (615 mg, 3.32 mmol) in conc. H ₂ SO ₄ at 5°C is treated with KNO ₃ (336 mg, 3.32 mmol). The mixture was stirred for 2 hours and poured into ice water (50 ml). The aqueous mixture is extracted with EtOAc (2×40 ml). The organic extracts are combined, dried, filtered and concentrated to give the title compound (790 mg, 103%). ^1H NMR (400 MHz, CDCl ₃ ) 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.

Example of receiving 148: (S)- N -(4-fluoro-2-(2-methoxyethoxy)-5-nitrophenyl)-2-morpholinopropanamide

A solution of Preparation Example 147 (590 mg, 2.56 mmol) and Preparation Example 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 room temperature for 16 hours and then poured into water (40 ml). The mixture is extracted with EtOAc (2×40 ml). The organic extracts are combined, dried (Na ₂ SO ₄ ), 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, CDCl ₃ ) 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 (sq, 1H), 2.72-2.50 (m, 4H), 1.34 (d , 3H); LC/MS m/z (M+H) ⁺ =372.0.

Receipt example 149: (S)- N -(4-fluoro-2-(2-methoxyethoxy)-5-nitrophenyl)- N- methyl-2-morpholinopropanamide

A solution of Preparation Example 148 (202 mg, 0.54 mmol) in THF (3 mL) at 0° C. was treated with KOtBu (67 mg, 0.59 mmol). After stirring for 1 hour, a solution of methyl iodide (84.7 mg, 0.59 mmol) in THF (3 ml) was added and the mixture was stirred at room temperature for 16 hours. The mixture is treated with sat. aqueous NH₄Cl (15 ml) and the mixture was extracted with EtOAc (20 ml). The organic extract is combined, dried (Na₂SO₄), filter and concentrate. The crude material is purified by chromatography (silica, EtOAc/PE=0-100%) to givespecified in the connection header(262 mg, 92%).¹H NMR (400 MHz, CDCl₃) 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, CDCl₃) δ -111.09.; LC/MSm/z(M+N)⁺=386.1.

Example of getting 150: (S)- N -(4-amino-2-(2-methoxyethoxy)-5-nitrophenyl)- N- methyl-2-morpholinopropanamide

A solution of Preparation Example 149 (262 mg, 0.68 mmol) in EtOH (5 ml) at 15°C was treated with conc. NH ₄ OH (4.6 g, 130 mmol). The mixture is heated at 50°C and stirred for 16 hours. The mixture is concentrated, diluted with H ₂ O (10 ml) and extracted with EtOAc (2 x 10 ml). The aqueous layer was further extracted with MeOH:DCM (10 ml:10 ml). The organic extracts are combined, dried, filtered and concentrated to give the title compound 150 (86 mg, 33%). LC/MS m/z (M+H)= 383.1.

Example of receiving 151: (S)- N -(4,5-diamino-2-(2-methoxyethoxy)phenyl)- N- methyl-2-morpholinopropanamide

A solution of Preparation Example 150 (86 mg, 0.22 mmol) in MeOH (2 ml) was treated with 10% Pd/C (23.6 mg). The mixture is degassed with argon (3 times) and then with H ₂ (3 times). The mixture is then stirred under H ₂ (1 atm) for 20 hours at room temperature. The mixture is filtered and the solids are washed with MeOH (3 times). The filtrate is 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.

Example of receiving 152: (S)- N -(6-(2-methoxyethoxy)-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa [f]indazol-3-yl)-1 N- benzo[d]imidazol-5-yl)- N- methyl-2-morpholinopropanamide

A solution of Preparation Example 151 (71 mg, 0.20 mmol) and Na ₂ S ₂ O ₅ (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). mmol). The mixture is heated at 110°C for 16 hours and then poured into 3% aqueous LiCl solution (5 ml). The mixture is extracted with EtOAc (10 ml). The organic extract is collected, dried (Na ₂ SO ₄ ), filtered and concentrated. The crude material is purified by chromatography (silica, EtOAc/PE=0-100%) to give the title compound (160 mg, 120%). LC/MS m/z (M+H) ⁺ =639.3.

Preparation Example 153: (4aS,5aR)-3-(5-bromo-7-methyl-1 H- benzo[d]imidazol-2-yl)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole

A solution of 5-bromo-3-methylbenzene-1,2-diamine (980 mg, 4.87 mmol) and Na₂S₂O₅(463 mg, 2.44 mmol) in DMF (24 ml) treated with 9 (1.49 g, 4.87 mmol) and DMSO (952 mg, 12.2 mmol). The mixture is heated at 110°C for 16 hours. The mixture is cooled to RT and poured into 3% aq. LiCl (100 ml). The solid was collected by filtration and the filtrate was extracted with EtOAc (2×100 ml). The organic layers are combined with the collected solid and concentrated. The residue is purified by chromatography (silica, EtOAc/PE=0-20%) to givespecified in the connection header(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/MSm/z(M+N)⁺=488.8.

Preparation Example 154: (4aS,5aR)-3-(6-bromo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H- benzo[d]imidazol-2-yl)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole

A solution of Preparation Example 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 minutes. SEM-Cl (703 mg, 4.22 mmol) was added and the mixture was warmed to room temperature and stirred for 2.5 hours. The reaction mixture is cooled to 5°C and treated with sat. aqueous NH₄Cl (20 ml). The mixture is extracted with EtOAc and the organic layer is concentrated. The residue is purified by chromatography (silica, EtOAc/PE=0-10%), to givespecified in the connection header154 (2.4 g, 92%). LC/MSm/z(M+N)⁺=618.9.

Example of getting 155: rubs -butyl(4-methyl-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f] indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H- benzo[d]imidazol-6-yl)carbamate

A solution of Preparation Example 154 (800 mg, 1.29 mmol) inrubs-amyl alcohol (13 ml) is treatedrubs-butylcarbamate (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 is heated at 100°C for 16 hours. The mixture is cooled to room temperature and concentrated. The residue is purified by chromatography (silica, EtOAc/PE=0-20%) to give 500 mgspecified in the connection header(59%). LC/MSm/z(M+N)⁺=654.0.

Example of getting 156: rubs -butylmethyl(4-methyl-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f] indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H- benzo[d]imidazol-6-yl)carbamate

A solution of Preparation Example 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 minutes and methyl iodide (130 mg, 0.92 mmol) was added. The mixture is heated to 15°C and stirred for 16 hours. The mixture is treated with sat. aqueous NH ₄ Cl and extracted with EtOAc (2×10 ml). The combined organic layers are concentrated. The residue is purified by chromatography (silica, EtOAc/PE=0-20%) to give the title compound (308 mg, 74%). LC/MS m/z (M+H) ⁺ =668.0.

Example of getting 157: N, 4-dimethyl-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3 -yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H- benzo[d]imidazol-6-amine

A solution of Preparation Example 156 (380 mg, 0.57 mmol) in DCM (11 ml) at 0° C. was treated with ZnBr ₂ (641 mg, 2.84 mmol). The mixture is stirred at room temperature for 18 hours. The mixture is poured into sat. aqueous NaHCO ₃ (20 ml) and extracted with DCM (2×20 ml). The combined organic layers were concentrated to give the title compound (170 mg, 90%). LC/MS m/z (M+H) ⁺ =567.9.

Example of receiving 158: (S)- N -methyl- N -(4-methyl-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole -3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H- benzo[d]imidazol-6-yl)-2-morpholinopropanamide

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

Preparation Example 159: 2-bromo-4-fluoro-5-nitrobenzonitrile

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

Preparation Example 160: 4-amino-2-bromo-5-nitrobenzonitrile

To a solution of Preparation Example 159 (1.10 g, 4.490 mmol) in THF (40 ml) add conc. NH ₄ OH (0.63 ml, 4.49 mmol) at 0°C. The reaction mixture is stirred at 25°C for 1 hour. The mixture was filtered and the filtrate was concentrated to give the title compound (1.02 g, 94%). ^1H NMR (400 MHz, DMSO- d6 ) δ 8.51 (s, 1H), _8.17 (s, 2H), 7.40 (s, 1H).

Preparation Example 161: 4,5-diamino-2-bromobenzonitrile

To a solution of Preparation Example 160 (1.11 g, 4.58 mmol) in EtOH (20 ml) and H ₂ O (20 ml) add NH ₄ Cl (1.23 g, 22.9 mmol) at 25°C followed by the addition of iron powder (1.28 g, 22.9 mmol). The mixture is stirred at 25°C for 16 hours. The reaction mixture is filtered through diatomaceous earth, the filter cake is washed with EtOH (2×20 ml) and the filtrate is concentrated. The residue was dissolved in EtOAc and washed with brine, the aqueous phase was extracted with EtOAc (2×20 ml), the combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated to give the title compound (860 mg, 88%). ^1H NMR (400 MHz, CDCl ₃ ) δ 6.86 (s, 1H), 6.82 (s, 1H), 3.86 (s, 2H), 3.34 (s, 2H).

Preparation Example 162: 6-bromo-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f ]indazol-3-yl)-1H-benzo[d]imidazole-5-carbonitrile

To a solution of Preparation Example 161 (760 mg, 3.58 mmol) in DMF (15 ml) add Na ₂ S ₂ O ₅ (341 mg, 1.79 mmol), DMSO (700 mg, 8.96 mmol) and solution from Preparation Example 17 (1.21 g, 3.94 mmol) in DMF (3.0 mL). The reaction mixture is stirred at 110°C for 16 hours, then concentrated. The crude product was purified by chromatography on silica gel (silica, EtOAc/PE=0-30%) to give the title compound (1.38 g, 68%). LC/MS m/z (M+H) ⁺ =499.1

Preparation example 163: 6-bromo-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f ]indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-carbonitrile and 5-bromo-2-((4aS,5aR)-5a-methyl -1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl )-1H-benzo[d]imidazole-6-carbonitrile

To a suspension of NaH (133 mg, 3.32 mmol) in THF (5.0 mL) was added a solution of Preparation Example 162 (1.380 g, 2.76 mmol) in THF (10 mL) at 0°C. After stirring at 0°C for 15 minutes, SEM-Cl (0.69 g, 4.15 mmol) was added dropwise and the reaction mixture was stirred at 20°C for 2 hours. The reaction mixture was poured onto ice and the mixture was extracted with EtOAc (3×10 ml). The combined organic layers are washed with brine (10 ml), dried (Na ₂ SO ₄ ) 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, CDCl ₃ ) δ 8.08 (d, 1H), 7.93 (d, 1H), 6.23-6.11 (m, 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, 1H), 1.32 (s, 3H), 1.17 (dt, J=10.0, 5.5 Hz, 1H), 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.

Preparation Example 164: 2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3 -yl)-6-(methylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and 2-((4aS,5aR)-5a-methyl-1 -((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)-5-(methylamino)-1-((2-(trimethylsilyl )ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile

A solution of Preparation Example 163 (1.01 g, 1.61 mmol) in DMF (8 mL) was degassed with nitrogen. The solution is treated with N-(2,6-dimethylphenyl)-6-hydroxypicolinamide (156 mg, 0.64 mmol), K ₃ PO ₄ (1.02 g, 4.82 mmol), CuI (153 mg, 0.80 mmol ) and 2M CH ₃ NH ₂ in THF (99.8 mg, 3.21 mmol) at 20°C. The reaction vial is sealed and heated at 110°C for 16 hours. The reaction mixture is 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%). ^1H NMR (400 MHz, CDCl ₃ ) 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, 1H), 3.11 (t, J=18.0 Hz, 2H), 2.99 (d, J=5.6 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, 1H), 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.

Preparation Example 165: Step 1. Methyl-6-bromo-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a, 6-hexahydrocyclopropa[f]indazol-3-yl)-1H-benzo[d]imidazole-4-carboxylate

To a solution of methyl 2,3-diamino-5-bromobenzoate (1.57 g, 6.41 mmol) in DMF (30 ml) at 20° C., add Preparation Example 9 (1.96 g, 6.41 mmol) and Na ₂ S ₂ O ₅ (1.2 g, 6.40 mmol). The mixture is heated at 110°C for 16 hours, then cooled to room temperature 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).

Preparation Example 166: Methyl-6-bromo-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa [f]indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-4-carboxylate

To a solution of Preparation Example 165 (1.20 g, 2.26 mmol) in THF (50 mL) at 0°C add NaH (117 mg, 2.93 mmol) and SEM-Cl (565 mg, 3.39 mmol ). The mixture is stirred for 20 hours at room temperature. The reaction is treated with sat. aqueous NH ₄ Cl (1.0 ml) and water (50 ml). The mixture is extracted with EtOAc (2×150 ml). The combined organic extracts are washed with brine, dried (Na ₂ SO ₄ ) and concentrated to give the title compound (1.49 g, 99%). LC/MS m/z (M+H) ⁺ =663.1 ( ⁸¹ Br).

Preparation example 167: 6-bromo-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f ]indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-4-carboxylic acid

To a solution of Preparation Example 166 (900 mg, 1.36 mmol) in MeOH (50 mL) was added 10% NaOH (5 mL) at room temperature. The mixture is stirred at room temperature for 15 hours, cooled to 0°C and acidified with 1N HCl to pH ~1. The mixture is then diluted with water (50 ml) and extracted with EtOAc (3×50 ml). The organic extracts are combined, dried (Na ₂ SO ₄ ) and concentrated to give the title compound (880 mg, 100%). LC/MS m/z (M+H) ⁺ =649.1 ( ⁸¹ Br).

Preparation Example 168: 6-bromo-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f ]indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-4-carboxamide

To a solution from Preparation Example 167 (850 mg, 1.31 mmol) in DMF (10 ml) at room temperature add HATU (649 mg, 1.71 mmol), Et ₃ N (1 ml) and NH ₄ Cl (211 mg , 3.94 mmol). The mixture is stirred at room temperature for 15 hours. The mixture is diluted with water (50 ml) and extracted with EtOAc (3×50 ml). The organic extracts are combined, dried (Na ₂ SO ₄ ) and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE=0-50%) to give the title compound (400 mg, 47%). LC/MS m/z (M+H) ⁺ =648.1 ( ⁸¹ Br).

Preparation example 169: 6-bromo-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f ]indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-4-carbonitrile

To a solution of Preparation Example 168 (400 mg, 0.62 mmol) in THF (20 ml) at 0° C. add Et ₃ N (375 mg, 3.71 mmol) and ATPA (390 mg, 1.86 mmol). The mixture is stirred at room temperature for 15 hours. The mixture is diluted with 1:1 water/DCM (100 ml) and the layers are separated. The aqueous layer was extracted with DCM (50 ml). The combined organic extracts were washed with brine (50 ml), dried (Na ₂ SO ₄ ), filtered and concentrated to give the title compound (389 mg, 100%). LC/MS m/z (M+H) ⁺ =630.1 ( ⁸¹ Br).

Preparation Example 170: tert-butyl-(4-cyano-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a, 6-hexahydrocyclopropa[f]indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)carbamate

To a solution from Preparation Example 169 (389 mg, 0.62 mmol) inrubs-amyl alcohol (10 ml) and dioxane (10 ml) in an atmosphere of N₂addrubs-butylcarbamate (217 mg, 1.86 mmol), Cs₂CO₃(403 mg, 1.24 mmol),rubs-BuDavePhos (84.5 mg, 0.25 mmol) and Pd₂(dba)₃(57 mg, 0.06 mmol). The mixture is stirred at 100°C for 15 hours. The reaction is cooled to RT and concentrated. The crude product is purified by chromatography (silica, EtOAc/PE=0-75%) to givespecified in the connection header(320 mg, 78%). LC/MSm/z(M+H)⁺=665.3

Preparation Example 171: 6-Amino-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f ]indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-4-carbonitrile

A solution of Preparation Example 170 (540 mg, 0.81 mmol) in DCM (50 ml) was treated with ZnBr ₂ (914 mg, 4.06 mmol). The mixture is stirred at room temperature for 15 hours. The reaction mixture is filtered, the filtrate is taken up in DCM (150 ml) and washed with sat. aqueous NaHCO ₃ (50 ml). The layers are separated and the aqueous layer is extracted with DCM (50 ml). The combined organic extracts are washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated to give the title compound (155 mg, 34%). LC/MS m/z (M+H) ⁺ =565.3

Preparation Example 172: (R)-N-(4-cyano-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5, 5a,6-hexahydrocyclopropa[f]indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)-2-(tetrahydro-2H-pyran -4-yl)propenamide

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

Preparation Example 173: (R)-N-(4-cyano-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5, 5a,6-hexahydrocyclopropa[f]indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)-N-methyl-2-(tetrahydro -2H-pyran-4-yl)propenamide

A solution of Preparation Example 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 MeI (24.2 mg, 0.17 mmol). The mixture is stirred at room temperature for 2 hours. The mixture is treated with sat. aqueous NH ₄ Cl (0.3 ml) and water (50 ml) and extracted with EtOAc (2×50 ml). The combined organic extracts are washed with brine, dried (Na ₂ SO ₄ ) and concentrated to give the title compound (82 mg, 100%). LC/MS m/z (M+H) ⁺ =719.4.

Examples

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

Stage 1: (S)- N- methyl -N -(6-methyl-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole -3-yl)-1 N- benzo[d]imidazol-5-yl)-2-morpholinopropanamide

A mixture of Preparation Example 9 (20.2 g, 66.2 mmol) and Na ₂ S ₂ O ₅ (6.2 g, 32.6 mmol) was treated with a solution of Preparation Example 30 (20 g, 65.3 mmol) in DMF (114 ml). The mixture is treated with DMSO (11.6 ml, 163 mmol) and heated at 80°C for 16 hours. The mixture is cooled to room temperature and poured into ice water. The pH of the mixture is adjusted to pH 7-8 using sat. aqueous NaHCO ₃ and the mixture is stirred for another 2 hours. Solids are collected by filtration. The solids are dissolved in DCM, washed with brine, water and dried (MgSO ₄ ), filtered and concentrated. The crude material is purified by chromatography (silica, MeOH/EtOAc=0-10%) to give the title compound of Step 1 (32.0 g, 85%). ^1H NMR (400 MHz, CD ₃ OD) 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, 1H), 0.02-- 0.10 (m, 9H); LC/MS m/z (M+H) ⁺ =579.4.

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

A solution of the silyl ether from 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 minutes. The mixture is warmed to room temperature and then stirred for 16 hours. The mixture is treated with toluene (100 ml) and concentrated. The resulting residue is subjected to azeotropic distillation with toluene (2×250 ml). The residue is dissolved in EtOH (210 ml), cooled to 0°C and treated with conc. N.H.₄OH (138 ml) dropwise over 30 min. The mixture is warmed to room temperature and stirred for 2 hours. The solvent is concentrated and subjected to azeotropic distillation with heptanes (2×200 ml). The residue was dissolved in DCM and washed successively with aqueous 1N HaOH, brine, water, then dried (MgSO₄)_, filter and concentrate. The resulting solid is subjected to azeotropic distillation with diethyl ether (x2). The resulting solid was recrystallized from 25% water/MeCN (300 ml), filtered and dried to givespecified in the connection headeras 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, 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-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 (uss, 3H), 3.17 (d, 2H), 2.88 (t, 2H), 2.74-2, 65 (m, 2H), 2.64-2.61 (us, 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); SLC method: Chiral Tech AD-H 250 mm x 4.6 mm x 5 µm, 10 to 60% with 0.2% isopropylamine in MeOH/CO_2(g), 3.0 ml/min, column temperature 15°C, retention time = 6.59 min (40.9%) and 9.54 min (59.1%), 100% ee. LC/MSm/z(M+N)⁺=449.1.

Example 1.1: (S)- N -methyl- N -(6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)- 1H- benzo[d]imidazol-5-yl)-2-morpholinopropanamide, dihydrate (crystalline form 1)

A solution of the silyl ether from Example 1, Step 1 (8.90 g, 15.4 mmol) in DCM (59 ml) and TFA (29 ml) was stirred for 16 hours. The mixture is concentrated and the residue is azeotroped with toluene (2 x 100 ml). The residue is dissolved in a mixture of 3:2 (v/v) EtOH/conc. N.H.₄OH (125 ml). The mixture is stirred at room temperature for 2 hours. The solvent is concentrated and subjected to azeotropic distillation with heptanes (2×50 ml). The residue is dissolved in DCM and washed successively with water and brine. The aqueous phase is extracted with DCM (3 times), dried (MgSO₄), filter and concentrate. The residue is purified by SLC (Princeton PPU 250 mm x 50 mm, 5 µm; isocratic elution with 75% CO₂/25% (0.2% 7N MeOH/MeOH; 80 mL/min) to give solids (5.3 g). The solids (5.3 g) were dissolved in DCM (200 ml) and washed (2 x 50 ml) with deionized water. The aqueous layers were combined and extracted with DCM (2×50 ml). The combined DCM layers are dried (MgSO₄), filtered through Celite®, concentrate and dry in vacuo to give solids (4.5 g). The solids (4.5 g) were suspended in MeCN (90.4 ml) at room temperature, treated with water (22.3 ml) and the mixture was stirred at 58°C for 1 hour until all solids had dissolved. The mixture is allowed to cool to room temperature over 18 hours and then stirred at room temperature for 24 hours. The solids are collected by filtration and dried in vacuo at 60°C for 60 hours to obtainspecified in the connection header(3.55 g, 51%). NMR forspecified in the connection headercorresponds to that for example 1.

Powder X-ray Diffraction (PXRD)

PXRD analysis is performed using a Bruker AXS D8 Endeavor diffractometer equipped with a Cu radiation source. The divergence slit is set to constant illumination of 11 mm. The diffracted radiation is recorded by a PSD-Lynx Eye sensor with the PSD sensor aperture set at 2.949 degrees. The X-ray tube voltage and current are set to 40 kV and 40 mA, respectively. Data are collected in a Theta-Theta goniometer at Cu wavelengths from 3.0 to 40.0 degrees 2-Theta using a step size of 0.016 degrees and a step time of 0.3 seconds. The anti-scattering screen is installed at a fixed distance of 1.5 mm. Samples are rotated at 15 rpm during collection. Samples are prepared by placing them in a low-background silicone sample holder and rotating them during collection. Data are collected using Bruker DIFFRAC Plus software and analysis is performed using EVA diffract plus software. The PXRD data file is not processed before searching for peaks. Using the peak search algorithm in EVA software, peaks selected with a threshold value of 1 are used for preliminary peak assignment. To ensure reliability, adjustments are made manually; the results of the automatic assignments are checked visually and the peak positions are adjusted to peak maximum. Peaks with relative intensity ≥3% are typically selected. Peaks that were not resolved or were inconsistent with noise were not selected. Typical error associated with USP PXRD peak position is up to ±0.2° 2-theta (USP-941). The PXRD diagram for the title compound is shown in Figure 1 and the corresponding peak list is given in Table 1 below.

Thermogravimetric analysis (TGA)

TGA is performed using a Discovery TGA thermogravimetric analyzer (TA Instruments). Samples weighing approximately 10 mg are weighed into aluminum cups and heated from ambient temperature to 250°C at a heating rate of 10°C/min under nitrogen purge (10 ml/min for both sample chamber and balance). TGA of the title compound is presented in Figure 6. The observed mass loss of 7.4% is consistent with the theoretical mass loss of 7.4% for the dihydrate of Form 1.

Example 1.2a: (S)- N -methyl- N -(6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)- 1H- benzo[d]imidazol-5-yl)-2-morpholinopropanamide, dihydrate (crystalline form 2)

A solution of the silyl ether from 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 minutes. The mixture is warmed to room temperature and then stirred for 16 hours. The mixture is treated with toluene (100 ml) and concentrated. The resulting residue is subjected to azeotropic distillation with toluene (2×250 ml). The residue is dissolved in EtOH (210 ml), cooled to 0°C and treated with conc. NH ₄ OH (138 ml) dropwise over 30 minutes. The mixture is warmed to room temperature and stirred for 2 hours. The solvent is concentrated and subjected to azeotropic distillation with heptanes (2×200 ml). The residue is dissolved in DCM and washed successively with aqueous 1N NaOH, brine, water, then dried (MgSO ₄ ), filtered and concentrated. The resulting solid was azeotroped with diethyl ether (x2) to give solids (24 g). A suspension of these solids (24 g) in MeCN (240 ml) and water (60 ml) is heated at 60°C to 70°C for 30 minutes. Undissolved solids are removed by filtration and the filtrate is slowly cooled to room temperature. Seed crystals (Example 1.1, Form 1) are added and the mixture is stirred at room temperature for approximately 24 hours. The solids were collected by filtration and dried in vacuo at 50°C to give 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 -0.35 (m, 1H), 0.30-0.21 (m, 1H);¹H 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 (uss, 3H), 3.17 (d, 2H), 2.88 (t, 2H), 2.74 -2.65 (m, 2H), 2.64-2.61 (uss, 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); SLC method: Chiral Tech AD-H 250 mm x 4.6 mm x 5 µm, 10 to 60% with 0.2% isopropylamine in MeOH/CO_2(g), 3.0 ml/min, column temperature 15°C, retention time = 6.59 min (40.9%) and 9.54 min (59.1%), 100% ee. LC/MSm/z(M+N)⁺=449.1.

PXRD

PXRD is performed following the procedure outlined in Example 1.1 (Form 1), but with the divergence gap set to 10 mm, the sensor PSD aperture set to 2.99 degrees, and the step size set to 0.02 degrees. The PXRD pattern for the title compound is shown in Figure 2 and combined with the calculated powder pattern obtained from the single crystal solution of Example 1.4 below. The corresponding list of peaks is given in Table 1 below.

Example 1.2b: (S)-N-methyl- N -(6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)- 1H- benzo[d]imidazol-5-yl)-2-morpholinopropanamide, dihydrate (crystalline form 2)

A solution of the silyl ether of Example 1, Step 1 (70.0 g, 120.9 mmol) in DCM (150 ml) at about 0°C was treated dropwise with a 1:1 (v/v) mixture of DCM/TFA (342 ml). The reaction mixture is warmed to room temperature and stirred for approximately 16 hours. The mixture is concentrated and the residue is subjected to azeotropic distillation with toluene (2x). The residue is dissolved in ethanol (300 ml) and treated dropwise with conc. NH ₄ OH (300 ml). The mixture is stirred at room temperature for approximately 24 hours. The solvent is concentrated. The residue is dissolved in DCM and washed successively with brine and water. The DCM extract is dried (MgSO ₄ ), filtered and concentrated. The residue is purified by chromatography (silica, EtOAc/PE=50-100%, then MeOH/EtOAc 0-3%) to give a solid (batch 1, 31 g). A solution of the collected solids (2.0 g) in ethanol (12 ml) is heated to approximately 75°C and water (18 ml) is added at a rate to maintain the internal temperature above 70°C. The mixture is cooled to approximately 60°C and treated with additional solids (100 mg). The mixture is stirred at a temperature of about 60°C for about 2 hours, and then stirred at a temperature of about 30°C for about 18 hours. The mixture is cooled to approximately 5° and stirred for approximately 1 hour. The solids were collected by filtration, washed with 1:2 (v/v) ethanol/water and dried to give a solid (batch 2, 1.1 g). The remaining solids of batch 1 (29 g) are suspended in MTBE (150 ml) and stirred at about 30°C for about 48 hours. The solids were collected by filtration, washed with MTBE and dried to give solids (lot 3, 23 g). The combined solids of Lot 2 and Lot 3 (24.1 g) are suspended in ethanol (150 ml) and heated to approximately 75°, and then water (220 ml) is added at a rate to maintain the internal temperature above 70°. The solution is stirred at a temperature of about 65°C for about 1 hour, at a temperature of about 55°C for about 1 hour, at a temperature of 45°C for about 3 hours and then at a temperature of about 35°C for about 48 hours. The solids were collected by filtration, washed with ethanol/water 1:2 (v/v) and dried in vacuo to give the title compound (20.5 g, 38%). NMR and PXRD for the title compound are consistent with those for Example 1.2a.

Example 1.3: (S)- N -methyl- N -(6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)- 1H- benzo[d]imidazol-5-yl)-2-morpholinopropanamide, hemihydrate (crystalline form 3)

(S) -N -methyl- N- (6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl dihydrate ) -1H - benzo[d]imidazol-5-yl)-2-morpholinopropanamide (crystalline form 2) (400 mg) was suspended in MeCN (4 ml) and stirred at room temperature for about 18 hours. The solids are collected by filtration and washed with MeCN (about 3 ml). The collected solids were dried in vacuo at 50°C for 1.5 hours to give the title compound (300 mg, 89%).

TGA and PXRD

TGA and PXRD, respectively, are carried out in accordance with the procedures outlined in Examples 1.1 (Form 1) and 1.2a (Form 2). The PXRD diagram for the title compound is shown in Figure 3 and the corresponding peak list is given in Table 1 below. TGA for the title compound is presented in Figure 7. The observed mass loss of 1.8% is consistent with the theoretical mass loss of 2% for the Form 3 hemihydrate.

Table 1
List of PXRD peaks for crystal forms 1, 2 and 3, respectively, of Examples 1.1, 1.2a and 1.3 Form 1 Form 2 ^[1] 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 eleven 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 thirty 27.3 22 25.7 8 24.0 36 27.7 15 26.0 39 25.0 4 28.6 6 26.4 31 25.5 eleven 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

^[1] The PXRD pattern for Form 2 is combined with the calculated powder pattern obtained from the single crystal solution of Example 1.4 below.

Example 1.4: (S)- N -methyl- N -(6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)- 1H- benzo[d]imidazol-5-yl)-2-morpholinopropanamide, dihydrate (crystalline form 2)

(S) -N -methyl- N- (6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl dihydrate ) - 1 H- benzo[d]imidazol-5-yl)-2-morpholinopropanamide (crystalline form 2) (30 mg) was dissolved in EtOAc (10 ml) in a 20 ml scintillation tube. Close the bottle with a lid, but do not tighten it. The bottle is left alone at room temperature for approximately 26 days. In the intervening time, most of the solvent had evaporated, leaving approximately 1 mL of EtOAc and the title compound.

Single crystal X-ray diffraction (SXRD)

SXRD is performed on a Bruker D8 Venture diffractometer at room temperature. Data collection consists of omega and phi scans. The structure was resolved by the internal phasing method using the SHELX software package in the orthorhombic space group P2 ₁ 2 ₁ 2 ₁ . Subsequently, the structure is refined using the full-matrix least squares method. All atoms other than hydrogen are found and refined using anisotropic displacement parameters. The final R-index was 3.92%. The final Fourier difference does not reveal missing or misplaced electron density. Table 2 contains the structural data of the SXRD analysis.

table 2
Crystal structure data for crystal form of Example 1.4 (Form 2) Empirical formula C25 H36 N6 O4 Weight formula 484.60 Temperature 296(2) K Wavelength 1.54178 Å Crystal system Rhombic Space group P212121 Unit cell dimensions а=6.6838(2) Å α= 90° b=16.0450(4) Å β= 90° с=23.8703(6) Å γ= 90° Volume 2559.89(12) Å3 Z 4 Density (calculated) 1.257 mg/ ^m3 Adequacy on F2 1,043 Final indices R [I>2sigma(I)] R1=0.0392, wR2=0.1026 R indices (all data) R1=0.0451, wR2=0.1048

The ORTEP diagram for one of the molecules in the asymmetric solution block is presented in Figure 4, with the bias parameters for the 50% probability and water molecules omitted from the figure for clarity. Figure 5 shows an ORTEP diagram with 50% probability displacement parameters and water molecules shown.

The list of PXRD peaks from the calculated powder pattern for Form 2 is given in Table 3.

Table 3
Calculated list of PXRD peaks based on 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 eleven 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 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 for 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 the single crystal structure determination shows good peak correlation.

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

Example 2 was prepared following the same procedure as Example 1 from Preparation Example 31 (292 mg) and Preparation Example 9 (306 mg) to obtain 110 mg of the title compound. SLC method: Chiral Tech AD-H 250 mm × 4.6 mm × 5 µm, CO ₂ /MeOH (0.2% isopropylamine) from 5 to 60%, 3.0 ml/min, column temperature 15 ° ^C , time retention = 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)-N-methyl-N-(6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3 -yl)-1H-benzo[d]imidazol-5-yl)-2-morpholinopropanamide

Step 1: (R)-N-methyl-N-(6-methyl-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a ,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)-1 N- benzo[d]imidazol-5-yl)-2-morpholinopropanamide

Mixture from Preparation Example 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 ) heated at 80°C for 16 hours. The mixture was cooled to room temperature and diluted with EtOAc/water. The organic layer is separated and washed successively with sat. aqueous NH ₄ Cl solution, brine, dried (MgSO ₄ ), filtered and concentrated. The crude material was purified by chromatography (silica, 0-10% MeOH/EtOAc) to give the title compound 160 (150 mg, 50%). ^1H NMR (400 MHz, CD ₃ OD) δ 7.68 (s, 1H), 7.53 (s, 1H), 5.62-5.38 (m, 2H), 3.71-3.57 (m, 6H), 3.43 (d, 1H), 3.28 (d, 3H), 3.24-3.04 (m, 3H), 2.81 (d, 1H), 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)-N-methyl-N-(6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3 -yl)-1H-benzo[d]imidazol-5-yl)-2-morpholinopropanamide

A solution of the silyl ether from step 1 (150 mg, 0.259 mmol) in TFA (2 ml) was treated with Et ₃ SiH (151 mg, 1.3 mmol). The mixture is stirred at room temperature for 1 hour. The mixture is concentrated and the residue is triturated with toluene (2×10 ml). The residue is dissolved in EtOH (8 ml) and treated with conc. NH ₄ OH (2 ml). The mixture is stirred at room temperature for 2 hours and concentrated. The residue is dissolved in DCM and washed successively with water and brine, dried (MgSO ₄ ), filtered and concentrated. The crude material is purified by chromatography (silica, MeOH-EtOAc=0-10%) to give the title compound (100 mg, 86%). SLC method: Chiral Tech AD-H 250 mm × 4.6 mm × 5 µm, CO ₂ /MeOH (0.2% isopropylamine) from 5 to 60%, 3.0 ml/min, column temperature 15°, RT= 6.29 min (30.15%) and 8.38 min (69.20%), 99.37% ee; ^1H NMR (400 MHz, CD ₃ OD) 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)- N -methyl- N -(6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)-1H-benzo[d]imidazol- 5-yl)-2-(tetrahydro- 2H- piran - 4-yl)propanamide

Stage 1: (R)- N -methyl- N -(6-methyl-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole -3-yl)-1H-benzo[d]imidazol-5-yl)-2-(tetrahydro-2 H- piran - 4-yl)propanamide

To a solution of Preparation Example 46 (120 mg, 0.274 mmol) in THF (5 mL) add iPr ₂ NEt (100 μL, 0.55 mmol), Preparation Example 22 (86.8 mg, 0.55 mmol) and iodide 2 -chloro-1-methylpyridinium (140 mg, 0.548 mmol). The mixture is heated at 60°C for 16 hours. Water (10 ml) was added and the mixture was extracted with EtOAc (2×20 ml). The combined organic extracts were concentrated and the residue was purified by chromatography on silica gel (silica, EtOAc/PE=0-85%) to give the title compound (165 mg, quantitative). ^1H NMR (400 MHz, CD ₃ OD) 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, 1H), 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, 1H), 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.

Stage 2: (R)- N -methyl- N -(6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)-1H-benzo[d]imidazol- 5-yl)-2-(tetrahydro-2 H- pyran-4-yl)propanamide

A mixture of silyl ether from step 1 (3.7 g, 6.4 mmol) in TPA (45.7 ml) and Et ₃ SiH (3.72 g, 32.0 mmol) was stirred at room temperature for 3 hours and the mixture concentrate. The residue is treated with sat. aqueous NaHCO ₃ to pH=8 and extracted with EtOAc (2×30 ml). The extracts are combined, dried (MgSO ₄ ), filtered and concentrated. The crude product was purified by preparative HPLC (YMC triart C18 250 x 50 mm x 7 µM, water (0.05% NH ₄ OH)/MeCN 26 to 66% for 10 min, 60 ml/min) to give the title compound (1.86 g, 64.9%). SLC method: Chiral Tech OD-3 100 mm × 4.6 mm × 3 µm, CO ₂ /EtOH (0.05%) from 5 to 40%, 1.5 ml/min, column temperature 35°, retention time = 3.47 min (41.5%) and 3.55 min (58.5%), 100% ee; ^1H NMR (400 MHz, CD ₃ OD) 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, 3H), 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 (dd, 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, 1H); LC/MS m/z (M+H) ⁺ =448.3.

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

Example 5 was prepared analogously to Example 4 from Preparation Example 46 (100 mg) and 72 mg of (±)-2-(tetrahydro-2H-pyran-4-yl)propanoic acid and purified by preparative HPLC (Phenomenex Gemini-NX C18 150 mm × 30 mm x 5 µM, water (0.04% NH ₄ OH)/MeCN 26 to 66% for 9 min, 25 ml/min) to give the title compound (63 mg, 51%). SLC method: Chiral Tech OD-3 100 mm × 4.6 mm × 3 µm, CO ₂ /EtOH (0.05%) from 5 to 40%, 2.8 ml/min, column temperature 35°, retention time = 3.39 min (15.8%), 3.46 min (26.0%), 3.54 min (35.6%) and 3.76 min (22.43%); ^1H NMR (400 MHz, CD ₃ OD) 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, 4H), 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 (dk, 1H), 1.11 (dd, 1H), 1.03 (d, 2H), 0.43 (dd, 1H), 0.27 (kv, 1H); LC/MS m/z (M+H)= 448.3.

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

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

A solution of Preparation Example 67 (200 mg, 0.44 mmol) in pyridine (4.43 mL) was treated with Preparation Example 19 (162 mg, 1.02 mmol) and EDCI (170 mg, 0.89 mmol). The mixture is stirred for 96 hours, then heated at 80°C for another 24 hours. The mixture is diluted with water and the mixture is extracted with EtOAc (2×20 ml). The organic extracts are combined, dried (Na ₂ SO ₄ ), filtered and concentrated. The crude material is 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.

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

A solution of silyl ether from step 1 (78 mg, 0.132 mmol) in TFA (1.5 ml) at 0-5°C is treated with Et₃SiH (80 mg, 0.69 mmol). After stirring at 15°C for 2 hours, the solvent is removed and the reaction mixture is made alkaline with saturated aqueous Na₂CO₃. The mixture was extracted with premixed DCM/MeOH (10:1, 8 ml x 3) and the extracts were combined. The concentration and residue were purified by preparative HPLC [YMC-Actus Triart Prep C18 150 mm × 30 mm × 5 μM, water (0.05% NH₄OH)/MeCN from 43 to 63% for 10 min, 35 ml/min] to obtainspecified in the connection header(35 mg, 57%). SLC method: Chiral Tech AD-3 50 mm x 4.6 mm x 3 µm, CO₂/EtOH (0.05%), isocratic 40%, 4 ml/min, column temperature 35°, retention time = 0.45 min (51.01%) and 1.39 (48.99%), 100% e .And.;¹H NMR (400 MHz, DMSO-d ₆ ) δ 12.88 (s, 1H), 12.60 (d, 1H), 7.69-7.46 (m, 0.75H), 7.41-7.33 (m, 1.25H), 4 .11 (tkv, 1H), 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/MSm/z(M+N)⁺=463.2.

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

Step 1: (R)-N-methyl- N -(2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a, 5.5a, 6-hexahydrocyclopropa[f]indazol-3-yl)-1H-benzo[d]imidazol-5-yl)-2-(tetrahydro-2 H- piran - 4-yl)propanamide

To a solution of Preparation Example 55 (6.9 g, 16.3 mmol) and Preparation Example 22 (2.83 g, 17.9 mmol) in pyridine (163 mL) at room temperature, add EDCI (6.24 g, 32 .6 mmol). The mixture is stirred at 25°C for 16 hours and diluted with water (150 ml) and brine (150 ml). The resulting aqueous mixture was extracted with EtOAc (2×300 ml), the extracts were dried (Na ₂ SO ₄ ), 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, CD ₃ OD) δ 7.77 (s, 0.5H), 7.65-7.51 (m, 1H), 7.40 (s, 0.5H), 7. 14 (uss, 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)-N-methyl- N -(2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)- 1H- benzo[d]imidazol-5-yl)-2-(tetrahydro-2 H -pyran-4-yl)propanamide

A solution of the silyl ether from step 1 (6.9 g, 12.2 mmol) in TFA (122 ml) at 25° C. is treated with Et ₃ SiH (7.12 g, 61.2 mmol). After stirring for 3 hours, the mixture is concentrated and made alkaline with sat. aq. _NaHCO3 . The resulting mixture was extracted with EtOAc (2×100 ml). Organic extracts are dried (Na ₂ SO ₄ ), filtered and concentrated. The crude material is purified by chromatography (silica, EtOAc/PE, 10-100%). The resulting material was further purified by chiral SLC (CO ₂ /MeOH+1% NH ₄ OH, Daicel OJ, 250 mm × 50 mm × 10 μm) to obtain the final product (3.43 g, 64.6%). ^1H NMR (400 MHz, CD ₃ OD) 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 (dkv, 1H), 1.75 (kv, 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 SLC (ChiralCel OJ-H 150 mm x 4.6 mm x 5 µm, CO ₂ /EtOH (0.05% DEA), 5 to 40%), retention time = 4.91 min (100%).

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

Example 8 was prepared analogously to Example 7 from Preparation Example 55 (350 mg) and (±)-2-(tetrahydro -2H-pyran -4-yl)propanoic acid (131 mg) and purified by preparative HPLC (YMC-Actus Triart C18, 100 × 30 mm × 5 μm, H ₂ O/MeCN+0.05% NH ₄ OH, 38%-58% for 10 min) to give the title compound (150 mg, 39.4%). ^1H NMR (400 MHz, CD ₃ OD) δ 7.79-7.38 (m, 2H), 7.13 (dd, 1H), 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 (cd, 1H), 0.42 (dd, 1H), 0.26 (t, 1H); LC/MS m/z (M+H) ⁺⁼ 434.3;

Example 9: (S)-N-methyl- N -(2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)-1 N- benzo[d]imidazol-5-yl)-2-(tetrahydro-2H-pyran-4-yl)propanamide

Example 9 was prepared analogously to Example 7 from Preparation Example 55 (296 mg) and (S) -2-(tetrahydro -2H-pyran- 4-yl)propanoic acid (111 mg) and purified by preparative HPLC (YMC-Actus triart C18, 100 × 30 mm × 5 μm, H ₂ O/MeCN (0.05% NH ₄ OH), 38 to 58% over 10 min) to give the title compound (102 mg). ^1H NMR (400 MHz, CD ₃ OD) δ 7.81-7.34 (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 (kvd, 1H), 0.40 (dd, 1H), 0.24 (t, 1H); Chiral SLC (ChiralCel OJ-H 150 x 4.6 mm x 5 µm, CO ₂ /EtOH (0.05% DEA), 5 to 40%), retention time = 3.60 min.

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

Example 10 was prepared analogously to Example 7 from Preparation Example 55 (200 mg) and 2-(tetrahydro-2H-pyran-4-yl)acetic acid (82 mg) and purified by chiral SLC (Daicel Chiralcel OJ-H (250 mM × 30 mm × 5 µm, CO₂/EtOH w/0.1% NH₄OH, 25% isocratic mixture) to givespecified in the connection header(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/MSm/z(M+N)⁺=420.3.

Example 11: 2,2-difluoro- N -methyl- N -(2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)-1H-benzo[d]imidazol-5-yl) -2-(tetrahydro-2 H -pyran-4-yl)acetamide

Example 11 was prepared analogously to Example 7 from Preparation Example 55 (200 mg) and 2,2-difluoro-2-(tetrahydro-2H-pyran-4-yl)acetic acid (170 mg) and purified by chiral SLC (Daicel Chiralcel OJ-H , 250 mm × 30 mm × 5 µm, CO₂/EtOH (0.1% NH₄OH, 25% isocratic mixture) to givespecified in the connection header(60 mg).¹H NMR (400 MHz, DMSO-d ₆ ) 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, 1H); LC/MSm/z(M+N)⁺⁼582.3.

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

Stage 1: (R)- N -(7-fluoro-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole -3-yl)-1H-benzo[d]imidazol-5-yl)- N -methyl-2-(tetrahydro- 2H -pyran-4-yl)propanamide

To a solution of Preparation Example 57 (3.0 g, 6.79 mmol) in pyridine (67.9 ml) at 25° C., add Preparation Example 22 (1.50 g, 9.51 mmol) and EDCI (2.87 g, 14.9 mmol). The mixture is stirred at 25°C for 16 hours and concentrated. The residue is diluted with water and extracted with EtOAc (5×100 ml). The organic extracts are combined, dried (Na ₂ SO ₄ ), filtered and concentrated. The crude material was purified by chromatography (silica, EtOAc/PE=0-50%) to give the title compound (2.3 g, 58.2%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.26 (brs, 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 (dk, 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.

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

A solution of the silyl ether from step 1 (2.30 g, 3.95 mmol) in TFA (39.5 ml) at 5° C. is treated with Et ₃ SiH (2.30 g, 19.8 mmol). After stirring for 3 hours at RT, the mixture is concentrated and the residue is diluted with sat. aqueous solution of Na ₂ CO ₃ . The mixture is extracted with EtOAc (2×30 ml) and the organic extracts are combined, dried (Na ₂ SO ₄ ), filtered and concentrated. The crude material is purified by chromatography (silica, EtOAc/PE=20-100%). The compound was dissolved in MeCN (10 ml), EtOH (10 ml) and H ₂ O (150 ml) and lyophilized to give the title compound (1.78 g, 99%). ^1H NMR (400 MHz, CD ₃ OD) 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, 6H), 1H), 3.07 (d, 1H), 2.78 (d, 1H), 2.30-2.12 (m, 1H), 1.75 (sq, 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, 1H); LC/MS m/z (M+H)= 452.3.

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

Stage 1: (4aS,5aR)- N -(2-amino-5-((S)- N- methyl 2-morpholinopropanamido)phenyl)-5,5-difluoro-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3-carboxamide

To the solution from Preparation Example 68 (700 mg, 3.07 mmol) in DMF (40 ml) at RT add GBTU (1.75 g, 4.60 mmol), DMAP (37.5 mg, 0.31 mmol), iPr₂NEt (1.19 mg, 9.2 mmol) and 32 (854 mg, 3.07 mmol). The mixture is stirred at 80°C for 16 hours and diluted with sat. aqueous NaHCO₃(100 ml). The aqueous layer was extracted with EtOAc (4 x 100 ml) and the organic layers were combined, dried (Na₂SO₄), filter and concentrate. The crude product is purified by chromatography (silica, EtOAc/PE=0-100%, then EtOAc/EtOH 3:1) to givespecified in the connection header(850 mg, 57%). LC/MSm/z(M+N)⁺=488.9.

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

A mixture of the amide from step 1 (850 mg, 1.74 mmol) and AcOH (50 ml) was stirred at 90°C for 16 hours and concentrated. The residue is diluted with EtOAc (50 ml) and washed with saturated Na ₂ CO ₃ solution. The aqueous layer was extracted with EtOAc (4×100 ml). Organic extracts are combined and concentrated. The residue was purified by preparative HPLC (Xtimiate C-18 150 x 25 mm x 5 µm, H ₂ O/CH ₃ CN (0.225% FA), 20-40% over 8 min) to give the title compound (289 mg, 35 %). ^1H NMR (400 MHz, CD ₃ OD) δ 7.75-7.49 (m, 2H), 7.18 (d, 1H), 3.70-3.56 (m, 4H), 3.33 (s, 3H), 3.23 (sq, 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)-N-methyl- N -(2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)- 1H- benzo[d]imidazol-5-yl)-2-morpholinopropanamide

Step 1: (S)-N-methyl- N -(2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl )-1 N- benzo[d]imidazol-5-yl)-2-morpholinopropanamide

A mixture of Preparation Example 32 (1.53 g, 5.5 mmol), Preparation Example 9 (1.69 g, 5.5 mmol) in EtOH (27.5 ml) and water (2.75 ml) was treated with Na ₂ S ₂ O ₃ (1.14 g, 11.0 mmol). The mixture is heated at 90°C for 2 hours. The mixture is concentrated and the residue is diluted with EtOAc and H ₂ O. The layers are separated and the aqueous layer is extracted with EtOAc (2x). The organic extracts are combined, dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was purified by chromatography (silica, EtOAc/heptane=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)-N-methyl- N -(2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)-1 N- benzo[d]imidazol-5-yl)-2-morpholinopropanamide

A solution of the silyl ether from step 1 (2.41 g, 4.26 mmol) in DCM (12.8 ml) at 0° C. was treated with TFA (8.61 ml) and stirred at room temperature for 18 hours. The mixture is concentrated and the residue is dissolved in THF/MeOH and the pH is adjusted to ~10 with solid K ₂ CO ₃ . The mixture is diluted with 10% MeOH in DCM and washed with brine. The aqueous layer was extracted with 10% MeOH in DCM. The organic extracts are combined, dried, filtered and concentrated. The crude product was purified by chiral SLC (Chiralcel OJ, 30 mm x 250 mm x 5 µm, CO ₂ /MeOH (0.2% NH ₃ ), isocratic 25% for 10 min) to give the title compound (0.89 g , 48%). ^1H NMR (400 MHz, DMSO- d6 ) 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), 3.23-3.13 (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 SLC (Lux Cellulose-2, 150 x 4.6 mm x 3 µm, CO ₂ /EtOH (0.1% ethanolamine, 1 to 40% EtOH), retention time = 2.96 min.

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

Stage 1: (S)- N -(4-fluoro-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole -3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H- benzo[d]imidazol-6-yl)- N- methyl-2-morpholinopropanamide and (S)- N -(7-fluoro-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole -3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H- benzo[d]imidazol-5-yl)- N- methyl-2-morpholinopropanamide

A mixture of preparation examples 74a and 74b (mg, 0.19 mmol) in pyridine (2.77 ml) at 15°C was treated with compound 19 (45.6 mg, 0.23 mmol) and EDCI (74.4 mg, 0. 39 mmol). The mixture is stirred for 16 hours. The mixture is diluted with water and extracted with EtOAc (2 x 20 ml). The organic extracts are combined, dried (Na ₂ SO ₄ ), filtered and concentrated to give the title compounds as a mixture (131 mg, 95%). LC/MS m/z (M+Na) ⁺ =735.1

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

A mixture of silyl ethers from step 1 (131 mg, 0.18 mmol) in TFA (1.84 ml) at 10°C is treated with Et ₃ SIH (107 mg, 0.92 mmol). After stirring for 3 hours, the mixture is concentrated and the residue is made alkaline with sat. aqueous Na ₂ CO ₃ . The mixture is extracted with EtOAc (3×15 ml) and the extracts are combined. The solvent was removed and the residue was purified by preparative HPLC (H ₂ O:MeCN, 0.05% TFA) to give the title compound (37 mg, 45%). ^1H NMR (400 MHz, CD ₃ OD) 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 (k, 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, 1H) , 0.25 (t, 1H); LC/MS m/z (M+H) ⁺ =453.3

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

Stage 1: (S)- N- ethyl- N -(4-fluoro-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole -3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)-2-morpholinopropanamide and (S)- N- ethyl- N -(7-fluoro-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole -3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H- benzo[d]imidazol-5-yl)-2-morpholinopropanamide

A mixture of Preparation Examples 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 hours, the solvent was removed and water (80 ml) was added. The mixture is extracted with EtOAc (2×80 ml) and the organic extracts are combined, dried (Na ₂ SO ₄ ), 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.

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

A mixture of silyl ethers from step 1 (5.13 g, 7.06 mmol) in TFA (35 ml) at 0° C. is treated with Et ₃ SiH (4.1 g, 35.3 mmol). The mixture is stirred at 30°C for 3 hours. The mixture is concentrated and the residue is diluted with sat. aqueous NaHCO ₃ . The mixture is extracted with EtOAc (2×100 ml) and the organic extracts are combined, dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product is chromatographed (silica, EtOAc/PE=0-50% (2.66 g, 81%). The mixture is further purified by chiral SLC (Daicel Chiralpak AD, 250 mm x 50 mm x 10 µm; CO ₂ /EtOH (0.1% NH ₄ OH), 50% isocratic) to give the title compound (1.72 g, 52%) ¹ H NMR (400 MHz, CD ₃ OD) δ 7.31 (brs, 1H) , 7.05-6.93 (m, 1H), 3.78 (s, 2H), 3.61 (ddd, 4H), 3.38 (d, 1H), 3.14 (d, 2H), 3.06 (d, 1H), 2.76 (d, 1H), 2.53 (d, 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.

Example 17: (S)- N -(6-fluoro-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)- 1H -benzo[d]imidazol-5-yl)- N- methyl-2-morpholinopropanamide

Stage 1: (S)- N -(6-fluoro-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole -3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)-N-methyl-2-morpholinopropanamide and (S)- N -(5-fluoro-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole -3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)-N-methyl-2-morpholinopropanamide

A mixture of Preparation Examples 80a and 80b (170 mg, 0.29 mmol) in pyridine (4.95 ml) at 15°C was treated with compound 19 (71 mg, 0.45 mmol) and EDCI (114 mg, 0.6 mmol) . The mixture is stirred for 2 days, then diluted with water and extracted with EtOAc (2×20 ml). The organic extracts are collected, dried (Na ₂ SO ₄ ), filtered and concentrated to give the title compounds as a mixture (180 mg, 85%). LC/MS m/z (M+H) ⁺ =713.5

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

A mixture of silyl ethers from step 1 (180 mg, 0.25 mmol) in TFA (2.52 ml) at 10°C is treated with Et ₃ SiH (147 mg, 1.26 mmol). The mixture is stirred for 3 hours and concentrated. The mixture was made alkaline sat. aqueous Na ₂ CO ₃ and extracted with EtOAc (3×8 ml). The combined extracts were concentrated and the residue was purified by preparative HPLC (YMC-Triart Prep C18 150 mm x 40 mm x 7 µM, water (0.05% NH ₄ OH)/MeCN 42 to 62% for 10 min, 25 ml/min) to obtain the title compound (38 mg, 34%). ^1H NMR (400 MHz, CD ₃ OD) δ 7.72-7.39 (m, 2H), 3.69-3.50 (m, 4H), 3.39 (d, 1H), 3.30 (d, 3H), 3.27-3.04 (m, 3H), 3H), 2.79 (d, 1H), 2.54 (dt, 1H), 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)- N -(6-ethyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)- 1H -benzo[d]imidazol-5-yl)- N- methyl-2-morpholinopropanamide

Example 18 was prepared analogously to Example 1 from 5-chloro-2-ethyl-4-nitroaniline to give the title compound (50 mg, 57%). ^1H NMR (400 MHz, CD ₃ OD) δ 7.54 (s, 2H), 3.69-3.58 (m, 4H), 3.38 (d, 1H), 3.27 (d, 3H ), 3.20-3.01 (m, 3H), 2.87-2.72 (m, 1H), 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)- N -(6-methoxy-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)- 1H -benzo[d]imidazol-5-yl)- N- methyl-2-morpholinopropanamide

Stage 1: (S)- N -(6-methoxy-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole -3-yl)-1H-benzo[d]imidazol-5-yl)-N-methyl-2-morpholinopropanamide

A mixture from Preparation Example 84 (189 mg, 0.61 mmol), Na ₂ S ₂ O ₅ (126 mg, 0.66 mmol) in DMF (7.3 ml) was treated with Preparation Example 9 (157 mg, 0.51 mmol ). The mixture is heated in a microwave reactor at 150°C for 2 hours and poured into 3% aq. LiCl (20 ml) and EtOAc (30 ml). The layers are separated and the aqueous layer is extracted with EtOAc (30 ml). The organic layers are collected, dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product is subjected to chromatography (silica, EtOAc/PE=0-100%) to give the title compound. (201 mg, 44%). LC/MS m/z (M+H) ⁺ =595.3.

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

A solution of the silyl ether from step 1 (201 mg, 0.338 mmol) in TFA (3.38 ml) at 0-5°C is treated with Et ₃ SiH (196 mg, 1.69 mmol). The mixture is stirred at room temperature for 2 hours and concentrated. The residue was made alkaline with sat. aqueous NaHCO ₃ . The mixture is extracted with EtOAc (2×20 ml), extracts and concentrated. The residue was purified by preparative HPLC (YMC Triart C18 150 mm x 30 mm x 7 µM, water (0.05% NH ₄ OH)/MeCN 25 to 75% for 10 min, 25 ml/min) to give the title compound (87 mg, 55%). ^1H NMR (400 MHz, CD ₃ OD) 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 (d, 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)- N -(6-bromo-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)- 1H -benzo[d]imidazol-5-yl)- N- methyl-2-morpholinopropanamide

A solution of Preparation Example 85 (100 mg, 0.155 mmol) in TFA (5.0 ml) at 0°C was treated with Et₃SiH (90.3 mg, 0.77 mmol). The mixture is stirred for 2 hours and concentrated. The residue is dissolved in MeOH (10 ml) and treated with conc. N.H.₄OH (1 ml). The mixture is stirred at room temperature for 1 hour and concentrated. The residue was purified by preparative HPLC (Boston Prime C18, 150 × 30 mm × 5 μm, H₂O/MeCN (0.05% NH₄OH) 10-70% for 10 min) to obtainspecified in the connection header(61 mg, 76%).¹H NMR (400 MHz, DMSO-d ₆ ) 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, 1H), 2.46-2.28 (m, 2H), 2.24-1.91 ( m, 2H), 1.24 (s, 3H), 1.17-0.90 (m, 4H), 0.37 (dd, 1H), 0.15 (t, 1H); LC/MSm/z(M+H)⁺⁼513.3/515.5 (⁷⁹Br,⁸¹Br).

Example 21. (S)- N -(6-cyano-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)- 1H -benzo[d]imidazol-5-yl)- N- methyl-2-morpholinopropanamide

A mixture of Preparation Examples 87a and 87b (150 mg, 0.21 mmol) in TFA (5 ml) was treated with Et ₃ SiH (121 mg, 1.04 mmol) at 0°C. The mixture is stirred for 2 hours and concentrated. The residue is dissolved in MeOH (10 ml) and conc. NH ₄ OH (1 ml). The mixture is stirred for 1 hour and the mixture is concentrated. The residue was purified by preparative HPLC (Boston Prime C18, 150 x 30 mm x 5 µm; H ₂ O/MeCN (0.2% FA), 23-45% for 10 min) to give the title compound (34 mg, 35 %). ^1H NMR (400 MHz, DMSO- d6 ) 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.

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

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

Stage 1: N -(4-fluoro-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole -3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)- N -methyl-2-(3-oxomorpholino)propanamide and N -(7-fluoro-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole -3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)- N- methyl 2-(3-oxomorpholino)propanamide

A mixture of Preparation Examples 74a and 74b (150 mg, 0.26 mmol) and Preparation Example 26 (54.5 mg, 0.32 mmol) in pyridine (3.75 mL) at 25°C was treated with EDCI (101 mg, 0.32 mmol). 53 mmol). The mixture is stirred for 48 hours and diluted with water (20 ml). The mixture is extracted with EtOAc (3×20 ml). The organic extracts are combined, dried and concentrated to give the title compounds as a mixture (60 mg, 31%). LC/MS m/z (M+H) ⁺ =727.3.

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

A mixture of silylene ethers from step 1 (85.0 mg, 0.12 mmol) in TFA (1.2 ml) was treated with Et ₃ SiH (68.0 mg, 0.58 mmol) at 5°C. The mixture is stirred for 2 hours and concentrated. The mixture is treated with sat. aqueous NaHCO ₃ and extracted with EtOAc (3×8 ml). The organic extracts are combined, dried, filtered and concentrated, and the residue is purified by preparative HPLC (Phenomenex Gemini NX-C18, 75 mm × 30 mm × 3 μm MeCN/H ₂ O (0.225% FA), 29-49% for 10 min) . The mixture is separated by chiral SLC (Daicel ChiralPak AD, 250 mm x 30 mm x 10 µm, CO ₂ /EtOH (0.1% NH ₄ OH), 55% isocratic) to give the title compounds with absolute stereochemistry at C- 2 methyl is determined arbitrarily.

Example 22: ^1H NMR (400 MHz, CD ₃ OD) 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, 1H), 0.41 (dd, 1H), 0.25 (t, 1H); LC/MS m/z (M+H) ⁺ =467.1.

Example 23: ^1H NMR (400 MHz, CD ₃ OD) δ 7.42 (s, 1H), 7.08 (d, 1H), 5.13-5.08 (m, 1H), 4.00- 3.86 (m, 3H), 3.82-3.70 (m, 1H), 3.56-3.45 (m, 1H), 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 (dd, 1H), 0.25 (t, 1H); LC/MS m/z (M+H) ⁺ =467.1.

Example 24: (S)- N -(6,7-difluoro-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)- 1H- benzo[d]imidazol-5-yl)- N- methyl 2-morpholinopropanamide

A mixture of Preparation Examples 95a and 95b (3.26 g, 4.47 mmol) in TFA (45 ml) at 0° C. was treated with Et ₃ SiH (2.60 g, 22.3 mmol). The mixture is stirred for 5 hours and concentrated. The mixture is treated with sat. aqueous NaHCO ₃ and extracted with DCM (3×30 ml). The organic extracts are combined, dried, filtered and concentrated. The residue is chromatographed (silica, MeOH/EtOAc=0-7%) and the isolated product is dissolved in MeOH (30 ml)/H ₂ O (50 ml). The solvent was removed by lyophilization to give the title compound (1.56 g, 69%). ^1H NMR (400 MHz, CD ₃ OD) 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 (m 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, 1H); ¹⁹ F NMR (377 MHz, CD ₃ OD) δ -153.83.

Example 25: (S)- N -(6,7-difluoro-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)- 1H -benzo[d]imidazol-5-yl)- N- ethyl-2-morpholinopropanamide

A mixture of preparation examples 96a and 96b (120 mg, 0.16 mmol) in TFA (1.6 ml) at 5°C is treated with Et₃SiH (93.6 mg, 0.81 mmol). The mixture is stirred for 2 hours and concentrated. The residue is diluted with sat. aqueous NaHCO₃(5 ml) and extracted with EtOAc (3 x 8 ml). Organic extracts are collected, dried, filtered and concentrated. The residue was purified by preparative HPLC (YMC Triart, 30 × 150 mm × 7 μm, CH₃CN/H₂O (0.05%NH₄OH), 46-66% for 10 min) to obtainspecified in the connection header(7.2 mg, 9%).¹H NMR (400 MHz, methanol-d ₄) 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/MSm/z(M+N)⁺=485.1.

Example 26: 2-((S)-2-(hydroxymethyl)morpholino)- N -methyl- N -(6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)- 1H- benzo[d]imidazol-5-yl)acetamide

Step 1: 2-((S)-2-(hydroxymethyl)morpholino)- N -methyl- N -(6-methyl-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole -3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[ d ]imidazol-5-yl)acetamide

A solution of Preparation Example 98 (130 mg, 0.20 mmol) and (S) -morpholin-2-ylmethanol (26 mg, 0.22 mmol) in MeCN (5 ml) was treated with NaI (40 mg, 0.27 mmol) and K ₂ CO ₃ (40 mg, 0.29 mmol). The mixture is heated at 80°C for 16 hours. The mixture is cooled to room temperature and concentrated. The residue is purified 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) δ 7.71 (s, 1H), 7.36 (d, 1H), 6.22-6.07 (m, 1H), 6.09-5.93 (m, 1H), 5.42 (k, 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, 1H), 0.26 (d, 1H) , -0.02 (s, 9H), -0.11 (t, 9H); LC/MS m/z (M+H) ⁺ =725.4.

Step 2: 2-((S)-2-(hydroxymethyl)morpholino)- N -methyl- N -(6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)- 1H- benzo[d]imidazol-5-yl)acetamide

A solution of the silyl ether from step 1 (108 mg, 0.149 mmol) in DCM (5 ml) at 15°C is treated with TFA (1.5 ml). The mixture is stirred at 15°C for 2 hours and concentrated. The residue is dissolved in MeOH (5 ml) and treated with conc. NH ₄ OH (2 ml). The mixture is stirred at room temperature for 2 hours. The mixture is concentrated and the residue is purified by preparative HPLC (Welch Xtimate 75 mm x 40 mm x 3 µm, 16 to 56% MeCN in 0.05% NH ₄ OH/water, 25 ml/min, 10 min) to obtain the title connections. (16 mg, 23%). ^1H NMR (400 MHz, CD ₃ OD) 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), 0.42 (dt, 1H), 0.24 (t, 1H); LC/MS m/z (M+H) ⁺ =465.3.

The title compounds in the table below are prepared by the procedure described in Example 18 or a similar procedure (using DIPEA+K ₂ CO ₃ /NaI) from the appropriate amine and 2-chloro -N- methyl- N- (6- methyl-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl )-1-((2-(trimethylsilyl)ethoxy)methyl) -1H- benzo[d]imidazol-5-yl)acetamide (Preparation Example 98).

Example Structure and name Analytical data 27
2-(2-(Hydroxymethyl)morpholino)- N -methyl- N -(6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)- 1H- benzo[d]imidazol-5-yl)acetamide Preparative HPLC, method 1. 17 mg (18%). ^1H NMR (400 MHz, CD ₃ OD) δ 7.69-7.26 (m, 2H), 3.77 (d, 1H), 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), 2.85-2 .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
2-(( R) -2-(Hydroxymethyl)morpholino)- N -methyl- N -(6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)- 1H- benzo[d]imidazol-5-yl)acetamide Preparative HPLC conditions: Method 2. 66 mg (25%). ^1H NMR (400 MHz, CD ₃ OD) 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), 2.86-2.56 (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, 1H), 0.25 (s, 1H); LC/MS m/z (M+H) ⁺ =465.2. 29
2-(2,2-Dimethylmorpholino)- N -methyl- N -(6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocycloprop[f]indazol-3-yl)- 1H- benzo[d]imidazol-5-yl)acetamide Preparative HPLC conditions: Method 3; 53 mg (42%). ^1H NMR (400 MHz, CD ₃ OD) δ 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, 1H), 0.48-0 .34 (m, 1H), 0.30-0.18 (m, 1H); LC/MS m/z (M+H) ⁺ =463.2. thirty
N- Methyl- N -(6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)-1 N- benzo[d]imidazol-5-yl)-2-(( R) -2-methylmorpholino)acetamide Preparative HPLC conditions: Method 4; 5 mg (8%). ^1H NMR (400 MHz, CD ₃ OD) δ 7.57 (s, 1H), 7.53-7.40 (m, 1H), 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), 2.95-2.83 (m , 3H), 2.77 (d, 1H), 2.35 (s, 3H), 2.32-2.13 (m, 1H), 2.05-1.86 (m, 1H), 1. 29 (s, 3H), 1.16 (dt, 1H), 1.07 (dd, 3H), 0.42 (dd, 1H), 0.25 (k, 1H); LC/MS m/z (M+H) ⁺ =449.3. 31
N- Methyl- N -(6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)-1 N- benzo[d]imidazol-5-yl)-2-((S)-2-methylmorpholino)acetamide Preparative HPLC conditions: Method 5; 19 mg (28%). ^1H NMR (400 MHz, CD ₃ OD) δ 7.57 (s, 1H), 7.49 (s, 2H), 3.79 (dd, 1H), 3.75-3.60 (m, 2H ), 3.44-3.33 (m, 2H), 3.26 (s, 3H), 3.18-3.10 (m, 1H), 3.07 (d, 1H), 2.99- 2.81 (m, 2H), 2.77 (d, 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
2-((2R,6R)-2,6-Dimethylmorpholino)- N -methyl- N -(6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)- 1H- benzo[d]imidazol-5-yl)acetamide Preparative HPLC conditions: Stage 3; 24 mg (34%). ^1H NMR (400 MHz, CD ₃ OD) 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, 1H), 3.07 (d, 1H), 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, 1H), 0.30-0.19 (m, 1H); LC/MS m/z (M+H) ⁺ =463.2. 33
2-(( 2S, 6S)-2,6-Dimethylmorpholino)- N -methyl- N -(6-methyl-2-((4aS,5aR)- 5a -methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)- 1H- benzo[d]imidazol-5-yl)acetamide Preparative HPLC conditions: Method 6; 28 mg (39%). ^1H NMR (400 MHz, CD ₃ OD) 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, 1H), 2.98 (dd, 1H), 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, 1H), 0.24 (td, 1H); LC/MS m/z (M+H) ⁺ =463.2.

Preparative HPLC conditions: Method 1 : Welch Xtimate C18 100 mm x 40 mm x 3 µm, 22 to 52% MeCN in 0.05% NH ₄ OH/water, 25 ml/min, 10 min; Method 2: Welch Xtimate C18 100 mm x 40 mm x 3 µm, 32 to 52% MeCN in 0.05 NH ₄ OH/water, 25 ml/min, 10 min; Method 3 : YMC-Actus Triart C18 100 mm x 30 mm x 5 µm, 42 to 62% MeCN in 0.05% NH ₄ OH/water, 35 ml/min, 10 min; Method 4 : YMC-Actus Triart C18 100 mm x 30 mm x 5 µm, 38 to 48% MeCN in 0.05% NH ₄ OH/water, 35 ml/min, 10 min; Method 5 : YMC-Actus Triart C18 100 mm x 30 mm x 5 µm, 40 to 60% MeCN in 0.05% NH ₄ OH/water, 35 ml/min, 10 min; Method 6: Welch Xtimate C18 150 mm x 40 mm x 10 µm, 21 to 61% MeCN in 0.225% formic acid in water, 60 ml/min, 10 min.

The title compounds in the table below are prepared according to the procedure described for Example 3 from the corresponding acid and Preparation Example 46.

Example Structure and name Analytical data 34
N- Methyl- N -(6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)-1 N- benzo[d]imidazol-5-yl)-2-morpholinoacetamide Preparative HPLC conditions: Method 7; 44 mg (44%). ^1H NMR (400 MHz, CD ₃ OD) δ 7.73-7.24 (m, 2H), 3.64 (t, 4H), 3.35 (d, 1H), 3.24 (d, 3H ), 3.20-3.09 (m, 1H), 3.06 (d, 1H), 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
N- Methyl- N -(6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)-1 N- benzo[d]imidazol-5-yl)-2-(tetrahydro-2H-pyran-4-yl)acetamide Preparative HPLC conditions: Method 8; 36 mg (62%). ^1H NMR (400 MHz, CD ₃ OD) 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 (sq, 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
N- Methyl- N -(6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)-1H-benzo[d]imidazol- 5-yl)-2-(3-oxomorpholino)acetamide Preparative HPLC conditions: Method 9, retention time 2.30. LC/MS m/z (M+H) ⁺ =449.0

Preparative HPLC conditions:

Method 7 : Phenomenex Gemini-NX 150 mm × 30 mm × 5 µm, 19 to 59% 0.05% NH ₄ OH in MeCN/water, 30 ml/min, 10 min.

Method 8 : YMC-Actus Triart C18 100 mm × 30 mm × 5 µm, 40 to 60% MeCN in 0.05% NH ₄ OH/water, 35 ml/min, 10 min.

Method 9 : Agela Durashell C18 150 mm x 25 mm x 5 µm, i5-55% 0.225% formic acid in MeCN/water, 35 ml/min, 8 min gradient.

Example 37: (S)- N -(7-bromo-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)- 1H- benzo[d]imidazol-5-yl)- N- methyl-2-morpholinopropanamide

Et solution₃SiH (117 mg, 1.01 mmol) in TFA (5 ml) at 0° C. is treated with Preparation Example 102 (130 mg, 0.202 mmol). The mixture is stirred at 0°C for 2 hours and concentrated. The residue is placed in MeOH, cooled to 0°C and treated with conc. N.H.₄OH (1 ml). The mixture is concentrated and the residue is purified by preparative HPLC (Boston Prime C18 150 mm x 30 mm x 5 µm, 35 to 55% MeCN in 0.05% NH₄OH/water, 25 ml/min, 10 min) to obtainspecified in the connection header(38 mg, 36%).¹H NMR (400 MHz, DMSO-d ₆ ) 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), 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/MSm/z(M+H)⁺=514.9 (⁸¹Br).

Example 38: (S)- N -(7-cyano-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)- 1H -benzo[d]imidazol-5-yl)- N- methyl 2-morpholinopropanamide

Stage 1: (S)- N -(4-cyano-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole -3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H- benzo[d]imidazol-6-yl)- N- methyl-2-morpholinopropanamide

A solution of Preparation Example 103 (160 mg, 0.207 mmol) in NMP (10 ml) was treated with Pd(Ph ₃ P) ₄ (24 m, 0.021 mmol) and Zn(CN) ₂ (121 mg, 1.03 mmol). The mixture is heated in a microwave reactor at 160°C for 1 hour. The mixture is cooled to room temperature 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 are washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The crude material is purified by chromatography (silica, EtOAc/PE=0-100%) to give the title compound (120 mg, 81%). LC/MS m/z (M+H) ⁺ =720.4.

Stage 2: (S)- N -(7-cyano-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)- 1H -benzo[d]imidazol-5-yl)- N- methyl-2-morpholinopropanamide

Et solution₃SiH (81 mg, 0.694 mmol) in TFA (5 ml) at 0°C is treated with silyl ether from step 1 (100 mg, 0.139 mmol). The mixture is stirred at 0°C for 2 hours and concentrated. The residue is dissolved in MeOH and cooled to 0°C. Add NH₄OH (1 ml). The mixture is concentrated and the residue is purified by preparative HPLC (Boston Prime C18 150 mm x 30 mm x 5 µm, 22 to 47% MeCN in 0.2% formic acid in water, 25 ml/min, 10 min) to givespecified in the connection header(27 mg, 42%).¹H NMR (400 MHz, DMSO-d ₆ ) δ 13.35 (s, 1H), 13.09 (s, 1H), 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/MSm/z(M+N)⁺=460.2.

Example 39: (S)- N -(7-hydroxy-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)- 1H -benzo[d]imidazol-5-yl)- N- methyl-2-morpholinopropanamide

A solution of Et ₃ SiH (196 mg, 1.69 mmol) in TFA (5 ml) at 0° C. was treated with Preparation Example 105 (120 mg, 0.169 mmol). The mixture is stirred at 20°C for 2 hours and concentrated. The residue is placed in MeOH, cooled to 0°C and treated with conc. NH ₄ OH (1 ml). The mixture is concentrated and the residue is purified by preparative HPLC (Boston Prime C18 150 mm x 30 mm x 5 µm, 25 to 45% MeCN in 0.05% NH ₄ OH in water, 25 ml/min, 10 min) to obtain the title compounds (28 mg, 37%). Analytical chiral SLC column: Chiralpak AS-3 100 mm × 4.6 mm × 3 µm; Mobile phase: A/B: CO ₂ /EtOH (0.05% Et ₂ NH); Gradient: 5% to 40% B in 4 min and hold 40% for 2.5 min, then 5% B for 1.5 min; Flow rate: 2.8 ml/min. Column temperature: 35°C; holding time=2.760 min; LC/MS m/z (M+H) ⁺ =451.2.

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

Et solution₃SiH (120 mg, 1.03 mmol) in TFA (5 ml) at 0°C was treated with Preparation Example 106 (150 mg, 0.207 mmol). The mixture is stirred at 0°C for 2 hours and concentrated. The residue is dissolved in MeOH and cooled to 0°C. The mixture is treated with conc. N.H.₄OH (1 ml), concentrate and the residue is purified by preparative HPLC (Boston Prime C18 150 mm × 30 mm × 5 μm, 32 to 55% MeCN in 0.05% NH₄OH/water, 25 ml/min, 10 min) to obtainspecified in the connection header(11.4 mg, 12%).¹H NMR (400 MHz, DMSO-d ₆ ) δ 12.84 (s, 1H), 12.70 (s, 1H), 6.96 (s, 1H), 6.60 (s, 1H), 3.96 (s, 3H), 3.49 ( s 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 .16-1.04 (m, 1H), 1.03 (d, 3H), 0.37 (dd, 1H), 0.16 (s, 1H); LC/MSm/z(M+N)⁺=465.1.

Example 41: (S)-N-methyl- N -(2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)-7-(trifluoromethyl)- 1H- benzo[d]imidazol-5-yl)-2-morpholinopropanamide

Et solution₃SiH (183 mg, 1.57 mmol) in TFA (5 ml) at 0°C was treated with Preparation Example 112 (120 mg, 0.157 mmol). The mixture is stirred at room temperature for 2 hours and concentrated. The residue is dissolved in MeOH and cooled to 0°C. The mixture is treated with conc. N.H.₄OH (1 ml), concentrate and the residue is purified by preparative HPLC (Boston Prime C18 150 mm × 30 mm × 5 μm, 43 to 65% MeCN in 0.05% NH₄OH/water, 25 ml/min, 10 min) to obtainspecified in the connection header(50 mg, 63%).¹H NMR (400 MHz, DMSO-d ₆ ) 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 (sq, 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, 1H); LC/MSm/z(M+N)⁺=503.1.

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

A solution of Preparation Example 117 (61 mg, 0.083 mmol) in EDC (0.7 mL) was treated with TFA (0.6 mL) at room temperature. The mixture is stirred for 16 hours and concentrated. The residue is dissolved in EtOH (0.7 ml) and cooled to 0°C. The mixture is treated with conc. NH ₄ OH (0.2 ml) and the mixture was stirred at room temperature for 4 hours. The mixture is diluted with water and extracted with 85:15% isopropanol/DCM (x3). The combined organic layers are dried (Na ₂ SO ₄ ), filtered and concentrated. The residue is purified by preparative HPLC (XBridge C18 19 mm × 100 mm × 5 μm, 5-95% MeCN (0.03% NH ₄ OH)/water, 8.5 min, hold at 95% for 1.5 min, 25 ml/min) to obtain the title compound (23 mg, 59%). Hold time=1.74 min; LC/MS m/z (M+H) ⁺ =479.5.

Example 43: (S)- N -(7-chloro-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)- 1H- benzo[d]imidazol-5-yl)- N- methyl 2-morpholinopropanamide

A solution of Preparation Example 122 (42 mg, 0.085 mmol) in TFA (0.6 mL) and DCE (0.5 mL) was stirred at room temperature for 2 hours and treated with Et ₃ SiH (0.046 mL, 0.29 mmol) . The mixture is stirred at room temperature for another 2 hours. The mixture is concentrated and the residue is diluted with sat. aqueous NaHCO ₃ . The mixture is extracted with EtOAc (x3). The combined organic extracts are dried (MgSO ₄ ) _, filtered and concentrated. The crude product is purified by preparative HPLC (XBridge C18 19 mm x 100 mm x 5 µm, 5-95% MeCN (0.03% NH ₄ OH)/water, 8.5 min, hold at 95% for 1.5 min, 25 ml/min) to obtain the title compound (17.3 mg, 63%). Hold time=2.04 min; LC/MS m/z (M+H) ⁺ =469.6.

Example 44: (S)- N -(7-ethyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)- 1H- benzo[d]imidazol-5-yl)- N- methyl-2-morpholinopropanamide

A solution of Preparation Example 126 (45 mg, 0.062 mmol) in EDC (0.5 mL) at room temperature was treated with TFA (0.2 mL) and Et₃SiH (24 mg, 0.21 mmol). The mixture is stirred for 16 hours and concentrated. The residue is dissolved in DCM and sat. aqueous NaHCO₃. The layers are separated and the aqueous layer is extracted with EtOAc (x2). The combined organic layers are dried (MgSO₄), filter and concentrate. The residue was purified by preparative HPLC (XBridge C18 19 mm x 100 mm x 5 µm, 5-95% MeCN (0.03% NH₄OH)/water, 8.5 min, hold at 95% for 1.5 min, 25 ml/min) to obtainspecified in the connection header(6.1 mg, 21%). LC/MSm/z(M+N)⁺=463.6; Retention time 1.78 min.

Example 45: (S)- N -(7-(hydroxymethyl)-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)- 1H- benzo[d]imidazol-5-yl)- N- methyl-2-morpholinopropanamide

A solution of Preparation Example 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 is warmed to room temperature and stirred for 20 hours. The mixture is concentrated and dissolved in EtOH, cooled to 0°C, treated with conc. NH ₄ OH (0.2 ml) and the mixture was stirred for 3 hours. The mixture is diluted with water and extracted with DCM (x4) and 15% isopropanol/DCM (x3). The combined organic layers are dried (Na ₂ SO ₄ ), filtered and concentrated. The residue is purified by preparative HPLC (XBridge C18 19 mm × 100 mm × 5 μm, 5-95% MeCN (0.03% NH ₄ OH)/water, 8.5 min, hold at 95% for 1.5 min, 25 ml/min) to obtain the title compound (4.9 mg, 38%). Hold time=1.59; LC/MS m/z (M+H) ⁺ =465.6.

Example 46: (S)- N -(7-fluoro-6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)- 1H- benzo[d]imidazol-5-yl)- N- methyl 2-morpholinopropanamide

The title compound was prepared analogously to Example 1 of 138 (2.1 g, 3.52 mmol) and purified by preparative HPLC (Chiralpak AD-3 50 mm × 6 mm × 3 μm, 40% isocratic mixture (0.05% diethylamine in EtOH/CO _2(g) 4 ml/min, column temperature=35°C) to obtain the title compound (1.3 g, 79%) Retention time=0.38 min and 1.46 min; LC/ MS m/z (M+H) ⁺ =467.1.

Example 47: (S)- N -(6-fluoro-7-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)- 1H- benzo[d]imidazol-5-yl)- N- methyl-2-morpholinopropanamide

The title compound was prepared analogously to Example 41 from 5-bromo-4-fluoro-3-methylbenzene-1,2-diamine. Purify under preparative HPLC conditions: Welch Xtimate 75 mm x 40 mm x 3 µm, 42 to 62% MeCN in 0.05% NH ₄ OH in water, 25 ml/min, 10 min) to give the title compound (234 mg, 74%). Analytical SLC (Chiralpak AS-3 100 mm × 4.6 mm × 3 µm, A: CO _2(g) ; B: 0.05% diethylamine in EtOH; gradient 5-40% B over 4 min, hold 40% B for 2.5 min, 5% B for 1.5 min, 2.8 ml/min, column temperature=35°C), retention time=2.70 min; LC/MS m/z (M+H) ⁺ =467.2.

Example 48: (S)- N -(7-(difluoromethyl)-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)- 1H- benzo[d]imidazol-5-yl)- N- methyl-2-morpholinopropanamide

A solution of Preparation Example 144 (72 mg, 0.097 mmol) in EDC (0.6 mL) was treated with TFA (0.37 mL). The mixture is stirred at room temperature for 20 hours. The mixture is concentrated and the resulting residue is dissolved in EtOH (1 ml), cooled to 0°C and treated with conc. N.H.₄OH (0.7 ml). The mixture is stirred at room temperature for 3 hours. The mixture is diluted with water and extracted with DCM (x4) and then with 15% isopropanol/DCM (x3). The combined organic extracts are dried (Na₂SO₄), filter and concentrate. The residue was purified by preparative HPLC (XBridge C18 19 mm x 100 mm x 5 µm, 5-95% MeCN (0.03% NH₄OH)/water, 8.5 min, hold at 95% for 1.5 min, 25 ml/min) to obtainspecified in the connection header(27 mg, 57%). Hold time=2.16 min; LC/MSm/z(M+N)⁺=485.6.

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

A solution of Preparation Example 152 (160 mg, 0.25 mmol) in TFA (2.5 ml) at 5° C. was treated with Et ₃ SiH (146 mg, 1.25 mmol). The mixture is stirred for 2 hours and the mixture is concentrated. The residue is diluted with sat. aqueous NaHCO ₃ and extracted with EtOAc (3×8 ml). The organic extracts are combined, dried, filtered and concentrated. The residue was purified by preparative HPLC (Phenomenex Gemini, NX-C18, 75 x 30 mm x 3 µm, water/CH ₃ CN (0.05% NH ₄ OH), 10-50% for 11 min) to give the title compound (2.5 mg, 2%). ^1H NMR (400 MHz, CD ₃ OD) 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, 1H); LC/MS m/z (M+H) ⁺ =509.3.

Example 50: (S)- N -methyl- N -(7-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)- 1H- benzo[d]imidazol-5-yl)-2-morpholinopropanamide

A solution of Preparation Example 158 (380 mg, 0.54 mmol) in TFA (5.4 mL) was treated with Et ₃ SiH (321 mg, 2.7 mmol) at room temperature. The mixture is stirred at room temperature for 3 hours and concentrated. The residue was made alkaline with sat. aqueous NaHCO ₃ and extracted with EtOAc (3×15 ml). The combined organic layers are concentrated. The residue was purified by preparative HPLC (YMC Triart 150 mm x 30 mm x 5 µm, 27 to 67% MeCN in 0.05% NH ₄ OH/water, 25 mL/min, 10 min) to give the title compound (108 mg , 45%). ^1H NMR (400 MHz, CD ₃ OD) 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, 1H), 0.26 (t, 1H); LC/MS m/z (M+H) ⁺ =448.9.

Example 51: (S)- N -(2-((4aS,5aR)-5,5-difluoro-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)-7-methyl- 1H- benzo[d]imidazol-5-yl)- N- methyl 2-morpholinopropanamide

The title compound was prepared analogously to Example 41 from 5-bromo-3-methylbenzene-1,2-diamine and Preparation Example 17. Preparative HPLC Conditions: Phenomenex Gemini-NX 150 mm x 30 mm x 5 µm, 24 to 64% MeCN in 0.05% NH ₄ OH/water, 25 ml/min, 9 min) to give the title compound (56 mg, 39%). ^1H NMR (400 MHz, CD ₃ OD) δ 7.48-7.25 (m, 1H), 7.07-6.95 (m, 1H), 3.72-3.57 (m, 4H) , 3.26-3.19 (m, 1H), 3.14 (usd, 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.

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

Step 1: 6-methyl-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f] indazol-3-yl)-1H-benzo[d]imidazol-5-amine

A solution of Preparation Example 66 (1.50 g, 3.22 mmol) in ethanol (20 ml) was treated with aq. NaOH (10 M, 6.44 ml, 64.4 mmol) at 15°C. The mixture is stirred at 90°C for 18 hours. The mixture is concentrated and the residue is extracted with EtOAc (3×100 ml). The combined organic layers were concentrated and the crude product was purified by chromatography (silica, EtOAc/PE=30-50%) to give the title compound (984 g, 72%). LC/MS m/z (M+H) ⁺ =423.9.

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

The title compound was prepared analogously to Example 6, Step 1, from Preparation Example 16 (115 mg, 0.59 mmol) and the silyl ether from Step 1 (208 mg, 0.491 mmol), to givespecified in the connection header (216 mg, 78%).¹H NMR (400 MHz, CDCl₃) δ 9.62-9.51 (m, 1H), 8.41-7.62 (m, 1H), 5.42-5.35 (m, 2H), 3.85-3.78 (m, 3H), 3.59-3 .55 (m, 2H), 3.27-3.17 (m, 2H), 2.75-2.60 (m, 9H), 2.44-2.40 (m, 2H), 1.40 -1.15 (m, 8H), 0.92-0.85 (m, 8H), 2H), 0.42-0.38 (m, 1H), 0.01--0.08 (m, 9H); LC/MSm/z(M+N)⁺=565.1.

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

The title compound was prepared analogously to Example 6, Step 2, using the silyl ether obtained in Step 2 (0.216 g, 0.382 mmol) and purified by preparative HPLC (Phenomenex Gemini NX-C18 30 mm x 74 mm x 3 µm, 17- 57% MeCN (0.05% NH ₄ OH)/water, 11 min, 25 ml/min) to give the title compound (81 mg, 49%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.91 (s, 1H), 7.45 (brs, 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, 1H), 0.44-0.39 (m, 1H ), 0.26-0.24 (m, 1H); LC/MS m/z (M+H) ⁺ =435.1.

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

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

A mixture of Preparation Example 17 (260 mg, 0.75 mmol) and Na ₂ S ₂ O ₅ (65 mg, 0.34 mmol) was treated with a solution of Preparation Example 32 (200 mg, 0.68 mmol) in DMF (5 ml ). The mixture is treated with DMSO (1 ml) and heated at 110°C for 18 hours. The mixture is cooled to room temperature, poured into ice water and extracted with EtOAc. The layers are separated and the organic phase is washed with brine, dried (MgSO ₄ ), filtered and concentrated to give the title compound of Step 1 (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,6-hexahydrocyclopropa[f]indazol-3-yl )-5-methyl-1H-benzo[d]imidazol-6-yl)-N-methyl-2-morpholinopropanamide

To the silyl ether from step 1 (0.55 g, 0.72 mmol), cooled to 0° C., add TFA (10 ml), and then Et ₃ SiH (0.83 mg, 7.16 mmol). The mixture is warmed to room temperature and stirred for 1.5 hours. The mixture is concentrated, neutralized with aq. sat. NaHCO ₃ (20 ml), then extracted with EtOAc. The organic layers are combined, washed with brine, dried (MgSO ₄ ), filtered and concentrated. The crude product is purified by reverse phase HPLC (Phenomenex Gemini C18, 250 x 50 mm x 7 µM, water (0.05% NH ₄ OH)/MeCN 30 to 50% for 10 min, 35 ml/min) to obtain the above in the title compound (0.19 g, 55%). SLC method: Chiral Tech OD-3, 50 mm × 4.6 mm × 3 µm, 5 to 40% with 0.05% diethylamine in EtOH/CO _2(g) , 4.0 ml/min, column temperature 35 °C, retention time = 1.58 min (43.1%) and 1.65 min (56.8%), 100% ee. LC/MS m/z (M+H) ⁺ =485.3.

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

Stage 1: N -(5-cyano-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole -3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)- N- methyl 2-(tetrahydro-2H-pyran-4-yl)acetamide and N-(6-cyano-2-((4aS,5aR)-5a-methyl-1-((2-(trimethylsilyl)ethoxy)methyl) -1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl) -N-methyl-2-(tetrahydro-2 N -pyran-4-yl)acetamide

To a solution of Preparation Example 164 (100.0 mg, 0.1727 mmol) in DMF (5.0 ml) add 2-(tetrahydro-2H-pyran-4-yl)acetic acid (25 mg, 0.17 mmol) , N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (72.7 mg, 0.259 mmol) and N-methylimidazole; (28.4 mg, 0.345 mmol) at room temperature, then the reaction mixture was stirred at 60°C for 16 hours. The reaction mixture is treated with 3% aq. LiCl (10 ml) and extracted with EtOAc (3×5 ml). The combined organic layers are 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

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

A solution of the silyl ethers from step 1 (40 mg, 0.07 mmol) in TFA (2.0 ml) is cooled to 0°C and Et is added₃SiH (41 mg, 0.35 mmol). The reaction mixture is stirred at 0°C for 2 hours. The mixture is concentrated, neutralized with conc. N.H.₄OH (20 ml) and extracted with EtOAc (x2). The combined organic extracts are washed with brine then dried (MgSO₄), filter and concentrate. The crude product was purified by reverse phase HPLC (Phenomenex Gemini NX, 75 × 30 mm × 3 μM, water (0.05% NH₄OH)/MeCN from 13 to 53% for 9 min, 30 ml/min) to obtainspecified in the connection header(14.86 mg, 48%). SLC method: Chiral Tech OD-3, 50 mm x 4.6 mm x 3 µm, 5 to 40% with 0.05% diethylamine in EtOH/CO_2(g), 2.8 ml/min, column temperature 35°C, retention time = 5.03 min (100%), 100% ee.¹H NMR (400 MHz, DMSO-d₆) 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, 1H), 0.42-0.35 (m, 1H), 0.18 (s, 1H); LC/MSm/z(M+H)⁺=445.2

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

For preparation example 173 (82 mg, 0.18 mmol), cooled to 0°C, add a mixture of TFA (5 ml) and Et₃SiH (206 mg, 1.77 mmol). The mixture is stirred at room temperature for 15 hours and the solvent is removed. The residue is dissolved in MeOH (10 ml) and treated with NH₄OH (1 ml). The solvent is removed and the crude material is purified by preparative HPLC (Boston Prime C-18 150 x 30 mm x 5 µm, H₂O/CH₃CN with 0.05% NH₄OH, 40-65% in 10 min, 25 ml/min) to obtainspecified in the connection header(35 mg, 68%).¹H NMR (400 MHz, DMSO-d₆) δ 7.66 (uss, 1H), 7.58 (s, 1H), 3.76 (t, 2H), 3.48 (d, 1H), 3.35-3.26 (m, 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, 1H), 0.93 (d, 3H), 0.88-0.80 (m, 1H), 0.39 (dd, 1H), 0.17 (t, 1H). Chiral SLC (Chiralpak AD-3, 50×4.6 mm, 3 µm, CO₂/iPrOH with 0.05% Et₂NH, from 5 to 40% 2 min, holding time 1.2 min, 4 ml/min, T=35°C) RT=1.785 min (100% ee). LC/MSm/z(M+N)⁺=459.1.

Example 56: (S)-N-(methyl- ¹³ C-d ₃ )-N-(6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)-1H-benzo[d ]imidazol-5-yl)-2-morpholinopropanamide

Example 56 was prepared according to the procedure described for Example 1 with iodomethane- ¹³ CD ₃ instead of iodomethane to give 550 mg of the title compound. Analytical HPLC method: Eclipse XDB-C18 150 mm × 4.6 mm × 3.5 µm; H ₂ O/MeCN: 10-90% for 10 min, 1.0 ml/min, retention time = 7.605 min (99.6%), LC/MS m/z (M+H) ⁺ = 453.2 .

Biological tests

Research in vitro

IL-2-inducible T-cell kinase (ITK) activity, IC ₅₀ (nM)

ITK activity is determined by measuring the effect of a test compound in an ITK enzyme assay.

A 1.0 M solution of HEPES Buffer pH 7.5 is prepared as follows: 238.3 g of HEPES free acid (Sigma) and 800 ml of water are combined and the mixture is stirred until completely dissolved. The pH is adjusted to 7.5 by titration with 5N NaOH and the volume is adjusted to 1000 ml. The solution is filtered and sterilized.

ITK assay buffer is prepared as follows: 50 ml HPLC water is treated with 2 ml 1.0 M HEPES buffer, 500 µl 2% gelatin (Sigma), 1.0 ml aqueous MgCl ₂ (1.0 M) and 1.0 ml of an aqueous solution of glutathione (0.5 M), and the solution is stirred. The solution is adjusted to 99 ml in a graduated cylinder by adding water and sterilized through a 0.2 µm filter. Add 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) and mix the solution.

A 1.33X ITK enzyme solution is prepared as follows: 49.99 ml ITK assay buffer is treated with 4.1 µl ITK enzyme (ITK FL (N-Flag and C-His tagged, ~72 kDa) Lake Pharma, 0.25 mg /ml in a buffer containing 25 mM Tris, pH 7.8, 150 mM NaCl, 10% glycerol and 2 mM TCEP), and the mixture was gently shaken. The resulting solution is stored on ice. 30 minutes before use, the enzyme solution is removed from ice and equilibrated to room temperature by incubation in a water bath at RT.

The 4X ITK substrate solution is prepared as follows: 50 mL of ITK assay buffer is treated with 100 μL of BTK peptide (China Peptide Company, 2 mM stock solution in DMSO). The tube is capped, mixed by carefully inverting the tube, and then stored on ice. 30 minutes before use, the substrate solution is removed from ice and equilibrated to room temperature by incubation in a water bath at RT.

During the assay, 7.5 µl of 1.33X ITK enzyme solution is added to plate wells containing 0.1 µl of various concentrations of test compound in DMSO. The plate is incubated for 30 min at RT. Each well of the plate is treated with 2.5 μl of 4X ITK substrate solution and the plate is sealed (TopSeal™, Perkin Elmer). The plate is rotated at 1000 rpm for 30 s, and then incubated for 60 min at room temperature. The seal is removed and each well is treated with 10 μl of Stop/Detect Buffer (20 mM HEPES pH 7.5, 0.01% gelatin, 1 nM LANCE PT66 (Perkin Elmer), 16.5 μg/ml Surelight APC (Perkin Elmer) , 10 mM). EDTA, 250 mM NaCl). The plate is again covered and rotated at 1000 rpm for 30 seconds. The plate is incubated overnight at RT and in a closed carrier to reduce dehydration. The cap is removed and fluorescence is read using a plate reader with an excitation wavelength of 665 nm and an emission wavelength of 615 nm. The concentrations and resulting potency values for the test compound are plotted and the compound concentration required for 50% effect (IC ₅₀ ) is determined using a four-parameter logistic dose-response equation.

The IC ₅₀ (μM) for the compounds of the invention are presented in the following table.

IL-2 inhibitory activity, IC ₅₀ (µM)

IL-2 inhibitory activity in supernatants of activated human CD4+ T cells is determined by measuring the effect of a test compound on activity using cisbio HTRF™ technology.

Human CD4+ T cells activate CD3/CD28 for 3 days and proliferate for an additional 4 to 6 days (7 to 9 days total). On day 0, frozen CD4+ T cells are thawed, treated with CD3/CD28 Dynabeads and incubated at 37°C/5%CO ₂ . On day 3, microcarriers are removed and cells are diluted to 5 × 10 ⁵ cells/cm ² , placed in a G-Rex10 flask and incubated at 37°C/5%CO ₂ . From days 7 to 9, cells are removed from G-Rex flasks, counted, and diluted again to 1 × 10 ⁶ cells/ml in a standard tissue culture flask.

Expanded CD4+ T cells are centrifuged at 300 x g for 10 minutes and resuspended to a concentration of 0.5 million cells per ml (30,000 cells/well). 60 μl of CD4+ T cells are added per well to a 384-well plate containing 0.1 μl of various concentrations of test compound in DMSO. The plates are incubated for 15 minutes at 37°C/5%CO ₂ . 20 µl of diluted ImmunoCult™ (STEMCELL Technologies, 1:12.5 in T cell assay media) is added to all wells of the plate (final assay concentration 1:50). The plates are incubated for another 20 to 24 hours at 37°C/5%CO ₂ . The plates are centrifuged at 300×g for 10 minutes. 16 μl of supernatant was removed and combined with 4 μl of IL-2 HTRF Abs. (cisbio set). The plates are incubated for 3 hours at room temperature and read using an EnVision plate reader at wavelengths of 665 nm and 615 nm. Concentrations and resulting effect values for the test compound are plotted and the compound concentration required for 50% effect (IC ₅₀ ) is determined using a four-parameter logistic dose-response equation.

The IC ₅₀ (μM) for the compounds of the invention are presented in the following table.

Tropomyosin receptor kinase A (TRKA) activity, % inhibition

Assays for determining TRKA activity are known in the art; for example, see those described in:

- Skerratt SE, et al. J. Med. Chem. (2016), 59(22):10084-10099

PMID: 27766865. DOI: 10.1021/acs.jmedchem.6b00850

- Bagal SK, et al. J. Med. Chem. (2018), 61(15):6779-6800

PMID: 29944371. DOI: 10.1021/acs.jmedchem.8b00633

The activity of TRKA, also known as neurotrophic tyrosine kinase receptor type 1 (NTKR1), was determined by measuring the effect of a test compound on activity against the NTRK1 enzyme using the ThermoFisher Z'-LYTE Assay fluorescence-based coupled enzyme format (www.thermofisher.com/selectscreen) . Test compounds are screened at a fixed concentration of 1 μM and % inhibition is determined compared to controls at a fixed ATP concentration of 1 mM. The resulting effect value for the test compound is compared with control samples to determine the % inhibition (%).

The % inhibition (%) values for the compounds of the invention are presented in the following table.

Table:
Research data in vitro Example No. ITK IC ₅₀ (µM) ¹ Number of ITKs (n) IL-2 IC ₅₀ (µM) ² Number of IL-2 (n) % TRKA inhibition (%) ³ Number of dispensers (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 eleven 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 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 thirty 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 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 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 IC ₅₀ values are presented as geometric mean of quantity n,

² IL-2 IC ₅₀ values are presented as the geometric mean of the amount n,

³ % TRKA inhibition values are presented as the arithmetic mean of the amount n,

NT means not tested

All links mentioned above are incorporated by reference in their entirety.

Claims (49)

1. Compound of formula (I) or a pharmaceutically acceptable salt or enantiomer thereof, wherein: each R ¹ is independently H or F; R ² represents H or (C ₁ -C ₄ )alkyl; each R ³ independently represents H, F or (C ₁ -C ₄ )alkyl; R ⁴ selected from or , each of which is optionally substituted with one or two substituents independently selected from oxo, (C ₁ -C ₄ )alkyl and hydroxy(C ₁ -C ₄ ) alkyl; And R ⁵ and R ⁶ independently represent H; halogen; HE; CN; (C ₁ -C ₆ )alkyl; hydroxy(C ₁ -C ₆ )alkyl; (C ₁ -C ₄ )alkoxy(C ₁ -C ₆ )alkyl; (C ₁ -C ₆ )alkyl substituted with one, two or three F; (C ₁ -C ₆ )alkoxy; or (C ₁ -C ₆ )alkoxy, substituted (C ₁ -C ₄ )alkoxy. 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that each R ¹ represents H. 3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that R ² represents H. 4. The compound according to claim 3, or a pharmaceutically acceptable salt thereof, characterized in that R ² represents methyl. 5. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, characterized in that each R ³ independently represents H or (C ₁ -C ₄ ) alkyl. 6. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, characterized in that each R ³ independently represents H, F or methyl. 7. The compound according to claim 6, or a pharmaceutically acceptable salt thereof, characterized in that one R ³ represents H and the other R ³ represents methyl. 8. Compound according to claim 7 of formula (Ia) or a pharmaceutically acceptable salt thereof. 9. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, characterized in that R ⁴ represents or , each of which is optionally substituted with one or two substituents independently selected from oxo, (C ₁ -C ₄ )alkyl and hydroxy(C ₁ -C ₄ )alkyl. 10. The compound according to claim 9, or a pharmaceutically acceptable salt thereof, characterized in that R ⁴ represents or . 11. The compound according to claim 10, or a pharmaceutically acceptable salt thereof, characterized in that R ⁴ represents . 12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, characterized in that R ⁵ and R ⁶ independently represent H; halogen; HE; CN; (C ₁ -C ₃ )alkyl; hydroxy(C ₁ -C ₃ )alkyl; (C ₁ -C ₃ )alkoxy(C ₁ -C ₃ )alkyl; (C ₁ -C ₃ )alkyl substituted with one, two or three F; (C ₁ -C ₃ )alkoxy; or (C ₁ -C ₃ )alkoxy, substituted (C ₁ -C ₃ )alkoxy. 13. The compound according to claim 12, or a pharmaceutically acceptable salt thereof, characterized in that R ⁵ represents H, halogen, CN, (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )alkoxy or (C ₁ - C ₃ )alkoxy, substituted (C ₁ -C ₃ )alkoxy. 14. The compound according to claim 12 or 13, or a pharmaceutically acceptable salt thereof, characterized in that R ⁶ represents H; halogen; HE; CN; (C ₁ -C ₃ )alkyl; hydroxy(C ₁ -C ₃ )alkyl; (C ₁ -C ₃ )alkoxy(C ₁ -C ₃ )alkyl; (C ₁ -C ₃ )alkyl substituted with one, two or three F; or (C ₁ -C ₃ )alkoxy. 15. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from: (S) -N -methyl- N- (6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl) -1 H -benzo[d]imidazol-5-yl)-2-morpholinopropanamide; (R)- N -methyl- N -(2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)-1 H - benzo[d]imidazol-5-yl)-2-(tetrahydro- 2H -pyran-4-yl)propanamide; (R)- N -(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) -N -methyl-2-(tetrahydro- 2H -pyran-4-yl)propanamide; (S)- N -(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) -N -methyl-2-morpholinopropanamide; (S) -N -ethyl- N- (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)-2-morpholinopropanamide; (S)- N -(6,7-difluoro-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)-1 N -benzo[d]imidazol-5-yl)-N-methyl-2-morpholinopropanamide; (S)- N -(6,7-difluoro-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl)-1 H -benzo[d]imidazol-5-yl) -N -ethyl-2-morpholinopropanamide; (S)- N -(7-fluoro-6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl) -1 H -benzo[d]imidazol-5-yl) -N -methyl-2-morpholinopropanamide; And (S) -N -methyl- N- (7-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl) -1 H -benzo[d]imidazol-5-yl)-2-morpholinopropanamide. 16. The compound according to claim 15, which is (S) -N -methyl- N- (6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6 -hexahydrocyclopropa[f]indazol-3-yl)-1 H- benzo[d]imidazol-5-yl)-2-morpholinopropanamide or a pharmaceutically acceptable salt thereof. 17. The compound according to claim 15, which is (R)-N-methyl- N- (2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f ]indazol-3-yl)-1H-benzo[d]imidazol-5-yl)-2-(tetrahydro- 2H -pyran-4-yl)propanamide, or a pharmaceutically acceptable salt thereof. 18. The compound according to claim 16, which is (S) -N -methyl- N- (6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6 -hexahydrocyclopropa[f]indazol-3-yl)-1 H- benzo[d]imidazol-5-yl)-2-morpholinopropanamide. 19. A compound which is the dihydrate of (S) -N -methyl- N- (6-methyl-2-((4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[ f]indazol-3-yl)-1 H- benzo[d]imidazol-5-yl)-2-morpholinopropanamide. 20. The connection according to claim 16, which is . 21. A pharmaceutical composition having ITK inhibitor activity, containing a therapeutically effective amount of a compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. 22. Pharmaceutical composition according to claim 21, adapted for topical use. 23. Use of a compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof for the preparation of a medicament having ITK inhibitory activity for the treatment of a condition. 24. Use according to claim 23, wherein the condition is a dermatological disorder. 25. Use according to claim 24, where the dermatological disorder is dermatitis. 26. Use according to claim 24, wherein the dermatitis is atopic dermatitis.

Images