RU2790006C2 - 2-aminopyridine or 2-aminopyrimidine derivatives as cyclin-dependent kinase inhibitors - Google Patents

Abstract

FIELD: organic chemistry; pharmacology.

SUBSTANCE: group of inventions relates to the field of organic chemistry and pharmacology, namely to compounds having inhibitory activity of cyclin-dependent kinases (hereinafter – CDKs). A compound of the formula (IX) or its pharmaceutically acceptable salt is disclosed, where: R¹ is H, F, Cl, CN, C₁-C₂alkyl, or C₁-C₂fluoroalkyl, where each specified C₁-C₂alkyl and C₁-C₂fluoroalkyl is optionally substituted with R²⁰; R² is H, C₁-C₅alkyl, C₁-C₅fluoroalkyl, C₃-C₈cycloalkyl, oxetan-3-yl, azetidine-3-yl, or oxolan-3-yl, where each specified C₁-C₅alkyl and C₁-C₅fluoroalkyl is optionally substituted with R²⁰, and each specified C₃-C₈cycloalkyl and oxetan-3-yl, azetidine-3-yl, or oxolan-3-yl is optionally substituted with R²¹; R⁴ is H, C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₄alkoxy, or C₁-C₄fluoroalkoxy, where each specified C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₄alkoxy, and C₁-C₄fluoroalkoxy is optionally substituted with R²⁰; R⁶ is H, F, Cl, CN, CH₃, CH₂F, CHF₂, or CF₃; R⁷ and R⁸ are independently H, F, Cl, CN, C₁-C₂alkyl, C₁-C₂fluoroalkyl, C₁-C₂alkoxy, or C₁-C₂fluoroalkoxy, where each specified C₁-C₂alkyl, C₁-C₂fluoroalkyl, C₁-C₂alkoxy, and C₁-C₂fluoroalkoxy is optionally substituted with R²⁰; R⁹ is H, OH, or N(CH₃)₂; each R¹⁰ is independently F, CN, C₁-C₂alkyl, or C₁-C₂fluoroalkyl, where each specified C₁-C₂alkyl and C₁-C₂fluoroalkyl is optionally substituted with R²⁰; R¹¹ is H, C₁-C₄alkyl, C₁-C₄fluoroalkyl, SO₂R¹⁴, SO₂NR¹⁵R¹⁶, COR¹⁷, COOR¹⁷, or CONR¹⁸R¹⁹; R¹⁴ is C₁-C₄alkyl or C₁-C₄fluoroalkyl; each R¹⁵ and R¹⁶ is independently H or CH₃; R¹⁷ is C₁-C₄alkyl or C₁-C₄fluoroalkyl, where each specified C₁-C₄alkyl and C₁-C₄fluoroalkyl is optionally substituted with R²⁰; each R¹⁸ and R¹⁹ is independently H, C₁-C₄alkyl, or C₁-C₄fluoroalkyl, where each specified C₁-C₄alkyl and C₁-C₄fluoroalkyl is optionally substituted with R²⁰; each R²⁰ is independently OH, C₁-C₂alkoxy, C₁-C₂fluoroalkoxy, CN, or NR²²R²³; each R²¹ is independently F, OH, CN, NR²²R²³, C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₄alkoxy, or C₁-C₄fluoroalkoxy, where each specified C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₄alkoxy, and C₁-C₄fluoroalkoxy is optionally additionally substituted with OH, NH₂, NHCH₃, or N(CH₃)₂; each R²² and R²³ is independently H, C₁-C₂alkyl, or C₁-C₂fluoroalkyl, or R²² and R²³ can be taken together with a nitrogen atom, to which they are attached, to form an azetidinyl ring, which is optionally substituted with F or OH; and n is 0, 1, 2, 3, or 4. In addition, a pharmaceutical composition inhibiting activity of cyclin-dependent kinases (CDKs) is described, as well as a cancer treatment method including the administration of therapeutically effective amount of the specified compound to an object.

EFFECT: group of inventions provides effective cancer treatment.

15 cl, 6 tbl, 150 ex

Description

BACKGROUND OF THE INVENTION

The field of technology to which the invention belongs

The present invention relates to compounds of Formulas (I)-(XII) and their pharmaceutically acceptable salts, to pharmaceutical compositions containing such compounds and salts, and to their use. The compounds, salts and compositions of the present invention may be useful in the treatment of abnormal cell growth such as cancer in a subject.

Description of the prior art

Cyclin-dependent kinases (CDKs) and related serine/threonine protein kinases are important cellular enzymes that perform important functions in the regulation of cell division and proliferation. The catalytic units of CDKs are activated by regulatory subunits known as cyclins. At least sixteen mammalian cyclins have been identified (Johnson DG, Walker CL. Cyclins and Cell Cycle Checkpoints. Annu. Rev. Pharmacol. Toxicol. (1999) 39:295-312). Additional functions of cyclin/CDK heterodynes include transcriptional regulation, DNA repair, differentiation, and apoptosis (Morgan DO. Cyclin-dependent kinases: engines, clocks, and microprocessors. Annu. Rev. Cell. Dev. Biol. (1997) 13:261-291 ).

CDK inhibitors have been shown to be useful in the treatment of cancer. It has been shown that increased activity or temporary abnormal activation of CDK leads to the development of human tumors, and the development of human tumors is usually associated with changes in either the CDK proteins themselves or their regulators (Cordon-Cardo C. Mutations of cell cycle regulators: biological and clinical implications for human neoplasia Am J Pathol (1995) 147:545-560; Karp JE, Broder S. Molecular foundations of cancer: new targets for intervention Nat Med (1995) 1:309-320 Hall M, Peters G. Genetic alterations of cyclins, cyclin-dependent kinases, and Cdk inhibitors in human cancer Adv. Cancer Res. (1996) 68:67-108).

CDK4 and CDK6 are important regulators of cell cycle progression at the G1-S checkpoint, which are controlled by D-type cyclins and endogenous CDK INK4 inhibitors such as p16 ^INK4a (CDKN2A). Dysregulation of the cyclin D-CDK4/6-INK4-retinoblastoma (Rb) pathway has been reported to be associated with the development of resistance to endocrine therapy.

Mutations of CDK4 and CDK6 have been described in subsets of melanoma and other tumors (Zuo L, et al., Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma. Nature Genet. (1996) 12, 97-99; Ortega S, et al. Smalley KSM et al Identification of a novel subgroup of melanomas with KIT/cyclin-dependent kinase-4 overexpression Cancer Res (2008) 68: 5743-52). Amplifications of CDK regulatory subunits and cyclins and mutation, gene deletion or transcriptional silencing of endogenous INK4 CDK inhibitors have also been described as a mechanism by which this pathway can be activated (Smalley KSM (2008)).

The development of CDK inhibitors has been reviewed in the literature. For example, see Sánchez-Martínez et al. Cyclin dependent kinase (CDK) inhibitors as anticancer drugs, Bioorg. Med. Chem. Lett. (2015) 25:3420-3435 (and references cited therein). The use of CDK4/6 inhibitors in combination with endocrine therapy has shown significant efficacy in the treatment of hormone receptor (HR)-positive, advanced human epidermal growth factor 2 (HER2)-negative or metastatic breast cancer, and CDK4/6 inhibitors, including palbociclib, ribociclib, and abemaciclib have been approved in combination with first-line or second-line endocrine therapy.

However, treatment with CDK4/6 inhibitors may lead to side effects such as gastrointestinal and/or hematological toxicity, and acquired resistance may develop over time. New data suggest that cyclin D3-CDK6 may be associated with the observed hematological toxicity. (Malumbres et al., Mammalian Cells Cycle without the D-type Cyclin-Dependent Kinases Cdk4 and Cdk6, (2004) Cell 118(4):493-504; Sicinska et al. Essential Role for Cyclin D3 in Granulocyte Colony-Stimulating Factor -Driven Expansion of Neutrophil Granulocytes (2006), Mol Cell Biol 26(21): 8052-8060 Cooper et al A unique function for cyclin D3 in early B cell development, (2006), Nat Immunol 5(7 ):489-497). CDK4 has been identified as the only oncogenic factor in many breast cancers. Accordingly, a selective CDK4 inhibitor may provide an improved safety profile or increased overall efficacy due to the possibility of higher and/or continuous dosing compared to dual CDK4/6 inhibitors.

Accordingly, there remains a need for improved therapies for the treatment of cancer. It is believed that the compounds, compositions and methods of the present invention have one or more advantages, such as greater efficiency; the possibility of reducing side effects; the possibility of reducing drug interactions; the possibility of improving the dosing regimen or the possibility of overcoming resistance mechanisms, and the like.

SUMMARY OF THE INVENTION

The present invention partially provides compounds of Formulas (I)-(XII) and their pharmaceutically acceptable salts. Such compounds can inhibit the activity of CDKs, including CDK4 and/or CDK6, thus affecting biological functions. In some embodiments, the invention provides compounds that are selective for CDK4. Also provided are pharmaceutical compositions and medicaments containing compounds or salts of the invention, alone or in combination with additional anti-cancer therapeutic agents.

The present invention also partially provides methods for preparing the compounds, pharmaceutically acceptable salts and compositions of the invention and methods for using the above alone or in combination with additional anticancer therapeutic agents.

In one aspect, the invention provides a compound of Formula (I):

(I)

(I)

or a pharmaceutically acceptable salt thereof, in which:

And represents N or CH;

R ¹ represents H, F, Cl, CN, C ₁ -C ₂ alkyl, C ₁ -C ₂ fluoroalkyl or C ₁ -C ₂ alkoxy, in which each specified C ₁ -C ₂ alkyl and C ₁ -C ₂ fluoroalkyl optionally substituted with R ²⁰ ;

U is NR ² or CR ³ ;

V is N or CR ⁴ when U is NR ² ; And

V is NR ⁵ when U is CR ³ ;

X is CR ⁶ or N;

Y is CR ⁷ or N;

Z is CR ⁸ or N;

R ² and R ³ are H, C ₁ -C ₅ alkyl, C ₁ -C ₅ fluoroalkyl, C ₃ -C ₈ cycloalkyl, or 3-6 membered heterocyclyl, wherein said C ₁ -C ₅ alkyl and C ₁ are each -C ₅ fluoroalkyl is optionally substituted with R ²⁰ and each of said C ₃ -C ₈ cycloalkyl and 3-6 membered heterocyclyl is optionally substituted with R ²¹ ;

R ⁴ is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ fluoroalkoxy, C(O)R ^a , C(O)NR ^b ₂ , C ₃ -C ₈ cycloalkyl or 3-6 membered heterocyclyl, wherein each said C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy, and C ₁ -C ₄ fluoroalkoxy is optionally substituted with R ²⁰ , each said C ₃ -C ₈ cycloalkyl and 3-6 membered heterocyclyl is optionally substituted with R ²¹ , R ^a is C ₁ -C ₂ alkyl and each R ^b is independently H or C ₁ -C ₂ alkyl; And

R ⁵ is H, C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with R ²⁰ ; or

R ² may be taken together with R ⁴ or R ³ may be taken together with R ⁵ to form a 5-7 membered heterocyclic ring optionally containing an additional heteroatom selected from NR ²⁴ , O and S(O) _m as a member rings, the ring being optionally substituted with R ²¹ ;

R ⁶ is H, F, Cl, CN, CH ₃ , CH ₂ F, CHF ₂ or CF ₃ ;

R ⁷ and R ⁸ are independently H, F, Cl, CN, C ₁ -C ₂ alkyl, C ₁ -C ₂ fluoroalkyl, C ₁ -C ₂ alkoxy, or C ₁ -C ₂ fluoroalkoxy, wherein each C ₁ -C ₂ alkyl, C ₁ -C ₂ fluoroalkyl, C ₁ -C ₂ alkoxy and C ₁ -C ₂ fluoroalkoxy are optionally substituted with R ²⁰ ;

R ⁹ is H, OH, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ ;

each R ¹⁰ is independently F, CN, C ₁ -C ₂ alkyl, or C ₁ -C ₂ fluoroalkyl, wherein each said C ₁ -C ₂ alkyl and C ₁ -C ₂ fluoroalkyl is optionally substituted with R ²⁰ ;

Q is NR ¹¹ or O or

Q is CR ¹² R ¹³ in which R ¹² and R ¹³ are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing NR ¹¹ or O as a ring member, the ring optionally further substituted with R ¹⁰ ;

R ¹¹ is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, SO ₂ R ¹⁴ , SO ₂ NR ¹⁵ R ¹⁶ , COR ¹⁷ , COOR ¹⁷ or CONR ¹⁸ R ¹⁹ , wherein each C ₁ - C ₄ alkyl and C ₁ -C ₄ fluoroalkyl optionally substituted with R ²⁰ , SO ₂ R ¹⁴ , SO ₂ NR ¹⁵ R ¹⁶ , COR ¹⁷ , COOR ¹⁷ or CONR ¹⁸ R ¹⁹ ;

R ¹⁴ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl;

each R ¹⁵ and R ¹⁶ is independently H or CH ₃ ;

R ¹⁷ is C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₃ -C ₈ cycloalkyl, or 3-6 membered heterocyclyl, wherein each of C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optional substituted with R ²⁰ and each of said C ₃ -C ₈ cycloalkyl and 3-6 membered heterocyclyl is optionally substituted with R ²¹ ;

each R ¹⁸ and R ¹⁹ is independently H, C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each said C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with R ²⁰ ;

each R ²⁰ is independently OH, C ₁ -C ₂ alkoxy, C ₁ -C ₂ fluoroalkoxy, CN, NR ²² R ²³ , C ₃ -C ₈ cycloalkyl, or 3-6 membered heterocyclyl, wherein each C ₃ - C ₈ cycloalkyl and 3-6 membered heterocyclyl are optionally substituted with R ²¹ ;

each R ²¹ is independently F, OH, CN, NR ²² R ²³ , C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy or C ₁ -C ₄ fluoroalkoxy, in which each specified C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ fluoroalkoxy optionally further substituted with OH, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ ;

each R ²² and R ²³ is independently H, C ₁ -C ₃ alkyl, C ₁ -C ₃ fluoroalkyl, C ₃ -C ₈ cycloalkyl, or 3-6 membered heterocyclyl, wherein each is C ₁ -C ₃ alkyl and C ₁ -C ₃ fluoroalkyl is optionally further substituted with OH, C ₁ -C ₂ alkoxy or C ₁ -C ₂ fluoroalkoxy, and each said C ₃ -C ₈ cycloalkyl and 3-6 membered heterocyclyl is optionally further substituted with F, OH, C ₁ - C ₂ alkyl, C ₁ -C ₂ fluoroalkyl, C ₁ -C ₂ alkoxy or C ₁ -C ₂ fluoroalkoxy; or

R ²² and R ²³ can be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring in which said ring is optionally substituted with F, OH, C ₁ -C ₂ alkyl, C ₁ -C ₂ fluoroalkyl, C ₁ - C ₂ alkoxy or C ₁ -C ₂ fluoroalkoxy;

R ²⁴ is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, SO ₂ R ²⁵ , SO ₂ NR ²⁶ R ²⁷ , COR ²⁸ , COOR ²⁸ or CONR ²⁹ R ³⁰ ;

R ²⁵ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl;

each R ²⁶ and R ²⁷ is independently H or CH ₃ ;

R ²⁸ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with OH, C ₁ -C ₂ alkoxy, C ₁ -C ₂ fluoroalkoxy, CN, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ ;

each R ²⁹ and R ³⁰ is independently H, C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each said C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with OH, C ₁ -C ₂ alkoxy, C ₁ -C ₂ fluoroalkoxy, CN, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ ;

m is 0, 1 or 2;

n is 0, 1, 2, 3, or 4;

p is equal to 1, 2 or 3 and

q is 0, 1, 2 or 3;

in which the sum of p and q is an integer from 1 to 4.

In another aspect, the invention provides a compound of Formula (II):

(II)

(II)

or a pharmaceutically acceptable salt thereof, in which:

R ¹ is H, F, Cl, CN, C ₁ -C ₂ alkyl or C ₁ -C ₂ fluoroalkyl, wherein each C ₁ -C ₂ alkyl and C ₁ -C ₂ fluoroalkyl is optionally substituted with R ²⁰ ;

U is NR ² or CR ³ ;

V is N or CR ⁴ when U is NR ² ; And

V is NR ⁵ when U is CR ³ ;

X is CR ⁶ or N;

Y is CR ⁷ or N;

Z is CR ⁸ or N;

R ² and R ³ are H, C ₁ -C ₅ alkyl, C ₁ -C ₅ fluoroalkyl, C ₃ -C ₈ cycloalkyl, or 3-6 membered heterocyclyl, wherein said C ₁ -C ₅ alkyl and C ₁ are each -C ₅ fluoroalkyl is optionally substituted with R ²⁰ and each of said C ₃ -C ₈ cycloalkyl and 3-6 membered heterocyclyl is optionally substituted with R ²¹ ;

R ⁴ is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy or C ₁ -C ₄ fluoroalkoxy, wherein each is C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ fluoroalkoxy are optionally substituted with R ²⁰ ;

R ⁵ is H, C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with R ²⁰ ;

R ⁶ is H, F, Cl, CN, CH ₃ , CH ₂ F, CHF ₂ or CF ₃ ;

R ⁷ and R ⁸ are independently H, F, Cl, CN, C ₁ -C ₂ alkyl, C ₁ -C ₂ fluoroalkyl, C ₁ -C ₂ alkoxy, or C ₁ -C ₂ fluoroalkoxy, wherein each C ₁ -C ₂ alkyl, C ₁ -C ₂ fluoroalkyl, C ₁ -C ₂ alkoxy and C ₁ -C ₂ fluoroalkoxy are optionally substituted with R ²⁰ ;

R ⁹ is H, OH, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ ;

each R ¹⁰ is independently F, CN, C ₁ -C ₂ alkyl, or C ₁ -C ₂ fluoroalkyl, wherein each said C ₁ -C ₂ alkyl and C ₁ -C ₂ fluoroalkyl is optionally substituted with R ²⁰ ;

Q is NR ¹¹ or O or

Q is CR ¹² R ¹³ in which R ¹² and R ¹³ are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing NR ¹¹ or O as a ring member, the ring optionally further substituted with R ¹⁰ ;

R ¹¹ is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, SO ₂ R ¹⁴ , SO ₂ NR ¹⁵ R ¹⁶ , COR ¹⁷ , COOR ¹⁷ or CONR ¹⁸ R ¹⁹ ;

R ¹⁴ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl;

each R ¹⁵ and R ¹⁶ is independently H or CH ₃ ;

R ¹⁷ is C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, wherein each C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with R ²⁰ ;

each R ¹⁸ and R ¹⁹ is independently H, C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each said C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with R ²⁰ ;

each R ²⁰ is independently OH, C ₁ -C ₂ alkoxy, C ₁ -C ₂ fluoroalkoxy, CN or NR ²² R ²³ ;

each R ²¹ is independently F, OH, CN, NR ²² R ²³ , C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy or C ₁ -C ₄ fluoroalkoxy, in which each specified C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ fluoroalkoxy optionally further substituted with OH, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ ;

each R ²² and R ²³ is independently H, C ₁ -C ₂ alkyl or C ₁ -C ₂ fluoroalkyl or

R ²² and R ²³ may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring which is optionally substituted with F or OH;

n is 0, 1, 2, 3, or 4;

p is equal to 1, 2 or 3 and

q is 0, 1, 2 or 3;

in which the sum of p and q is an integer from 1 to 4.

In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention according to any of the formulas described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. In some embodiments, the implementation of the pharmaceutical composition contains two or more pharmaceutically acceptable carriers and/or excipients.

The invention also provides therapeutic methods and uses comprising administering a compound of the invention, or a pharmaceutically acceptable salt thereof.

In one aspect, the invention provides a method of treating abnormal cell growth, in particular cancer, in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof. The compounds of the invention may be administered as single agents, or may be administered in combination with other anti-cancer therapeutic agents, including standard care products suitable for the particular form of cancer.

In a further aspect, the invention provides a method of treating abnormal cell growth, in particular cancer, in a subject in need of such treatment, comprising administering to the subject an amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, in combination with an amount of an additional anti-cancer therapeutic agent, which together are amounts effective in the treatment of said abnormal cell growth.

In another aspect, the invention provides a compound of the invention, or a pharmaceutically acceptable salt thereof, for use in the treatment of abnormal cell growth, in particular cancer, in a subject.

In a further aspect, the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the treatment of abnormal cell growth, in particular cancer, in a subject.

In another aspect, the invention provides a pharmaceutical composition for use in the treatment of abnormal cell growth, in particular cancer, in a subject in need of such treatment, the pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

In another aspect, the invention provides a compound of the invention, or a pharmaceutically acceptable salt thereof, for use as a drug, in particular a drug for the treatment of abnormal cell growth such as cancer.

In yet another aspect, the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of abnormal cell growth, such as cancer, in a subject.

In another aspect, the invention provides a method for treating a CDK4-mediated disorder in a subject, comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable salt thereof, in an amount that is effective to treat said disorder, in particular cancer.

In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention according to any of the formulas described herein and a second pharmaceutically active agent.

In another aspect, the invention provides a compound of the invention according to any of the formulas described herein for use in the treatment of cancer, wherein said treatment comprises the administration of a second pharmaceutically active agent.

Each of the aspects and embodiments of the compounds of the present invention described below may be combined with one or more other embodiments of the compounds of the present invention described herein, without conflicting with the embodiment(s) with which they are combined.

In addition, each of the following embodiments describing the invention provides within its scope pharmaceutically acceptable salts of the compounds of the invention. Accordingly, the phrase "or its pharmaceutically acceptable salt" is meant in the description of all compounds described in this application, unless expressly indicated otherwise.

DETAILED DESCRIPTION OF THE INVENTION

The present invention may be more readily understood by reference to the following detailed description of the preferred embodiments of the invention and the Examples included herein. It should be understood that the terminology used in this specification is provided for the purpose of describing certain embodiments only and is not intended to be limiting. In addition, it should be understood that unless otherwise indicated in the present description, the terminology used in the present description should have its traditional meaning, as is known in the relevant field of technology.

Used in the present description, the singular form includes references to the plural, unless otherwise indicated. For example, a substituent includes one or more substituents. The term "approximately" means the presence of a value that falls within the accepted standard error of the mean, if considered by a person skilled in the art.

The invention described in this application can suitably be practiced in the absence of any element(s) not specifically disclosed in the present description. Thus, for example, in each case in the present description, any of the terms "comprising", "consisting essentially of" and "consisting of" can be replaced by any of the other two terms.

"Alkyl" refers to a saturated monovalent aliphatic hydrocarbon radical, including straight and branched chain groups having a certain number of carbon atoms. Alkyl substituents typically contain 1 to 12 carbon atoms ("C ₁ -C ₁₂ alkyl"), often 1 to 8 carbon atoms ("C ₁ -C ₈ alkyl"), or more commonly 1 to 6 carbon atoms ("C ₁ -C ₆ alkyl"), 1 to 5 carbon atoms ("C ₁ -C ₅ alkyl"), 1 to 4 carbon atoms ("C ₁ -C ₄ alkyl"), or 1 to 2 carbon atoms ("C ₁ -C ₂ alkyl"). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl, n-octyl and the like.

Alkyl groups described herein as optionally substituted may be substituted with one or more substituent groups as further defined in the claims, the substituent groups being independently selected unless otherwise indicated. The total number of substituent groups may be equal to the total number of hydrogen atoms in the alkyl fragment, if the degree of such substitution has a chemical meaning. Optionally substituted alkyl groups usually have 1 to 6 optional substituents, sometimes 1 to 5 optional substituents, 1 to 4 optional substituents, or preferably 1 to 3 optional substituents.

Optional substituents that are suitable for alkyl include, but are not limited to, C ₃ -C ₈ cycloalkyl, 3-12 membered heterocyclyl, C ₆ -C ₁₂ aryl and 5-12 membered heteroaryl, halogen, =O (oxo ), =S (thiono), =N-CN, =N-OR ^x , =NR ^x , -CN, -C(O)R ^x , -CO ₂ R ^x , -C(O)NR ^x R ^y , -SR ^x , -SOR ^x , -SO ₂ R ^x , -SO ₂ NR ^x R ^y , -NO ₂ , -NR ^x R ^y , -NR ^x C(O)R ^y , -NR ^x C(O)NR ^x R ^y , -NR ^x C(O)OR ^x , -NR ^x SO ₂ R ^y , -NR ^x SO ₂ NR ^x R ^y , -OR ^x , -OC(O)R ^x and -OC(O)NR ^x R ^y ; in which each R ^x and R ^y is independently H, C ₁ -C ₈ alkyl, C ₁ -C ₈ acyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, 3- 12-membered heterocyclyl, C ₆ -C ₁₂ aryl or 5-12-membered heteroaryl or R ^x and R ^y can be taken together with the N atom to which they are attached to form a 3-12-membered heterocyclyl or 5-12- membered heteroaryl, each optionally containing 1, 2 or 3 additional heteroatoms selected from O, N and S(O) _q , in which q is 0-2; each R ^x and R ^y is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, ═O, ═S, ═N-CN, ═N-OR', ═NR', -CN, -C(O )R', -CO ₂ R', -C(O)NR' ₂ , -SOR', -SO ₂ R', -SO ₂ NR' ₂ , -NO ₂ , -NR' ₂ , -NR'C( O)R', -NR'C(O)NR' ₂ , -NR'C(O)OR', -NR'SO ₂ R', -NR'SO ₂ NR' ₂ , -OR', -OC( O)R' and -OC(O)NR' ₂ in which each R' is independently H, C ₁ -C ₈ alkyl, C ₁ -C ₈ acyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, 3-12 membered heterocyclyl, C ₆ -C ₁₂ aryl or C ₅ -C ₁₂ heteroaryl; and wherein each said C ₃ -C ₈ cycloalkyl, 3-12 membered heterocyclyl, C ₆ -C ₁₂ aryl, and 5-12 membered heteroaryl is optionally substituted as further defined herein.

Typical substituent groups on alkyl include halogen, -OH, C ₁ -C ₄ alkoxy, -OC ₆ -C ₁₂ aryl, -CN, =O, -COOR ^x , -OC(O)R ^x , -C(O)NR ^x R ^y , -NR ^x C(O)R ^y , -NR ^x R ^y , C ₃ -C ₈ cycloalkyl, C ₆ -C ₁₂ aryl, 5-12 membered heteroaryl and 3-12 membered heterocyclyl; wherein each R ^x and R ^y is independently H or C ₁ -C ₄ alkyl or R ^x and R ^y taken together with the N to which they are attached form a 3-12 membered heterocyclyl or 5-12 membered heteroaryl a ring each optionally containing 1, 2 or 3 additional heteroatoms selected from O, N and S(O) _q , in which q is 0-2; in which each specified C ₃ -C ₈ cycloalkyl, C ₆ -C ₁₂ aryl, 5-12-membered heteroaryl and 3-12-membered heterocyclyl is optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, -OH, \u003d O, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₄ alkoxy-C ₁ -C ₆ alkyl, -CN, -NH ₂ , -NH(C ₁ -C ₄ alkyl) and -N(C ₁ -C ₄ alkyl) ₂ .

In some instances, substituted alkyl groups are specifically named with reference to the substituent group. For example, "haloalkyl" refers to an alkyl group having a certain number of carbon atoms, which is substituted with one or more halogen substituents, up to the available valency. Typically, haloalkyl groups contain 1-6 carbon atoms, 1-5 carbon atoms, 1-4 carbon atoms, or 1-2 carbon atoms and 1, 2, 3, 4, or 5 halogen atoms (i.e. "C ₁ -C ₅ haloalkyl", "C ₁ -C ₄ haloalkyl" or "C ₁ -C ₂ haloalkyl").

More specifically, fluorinated alkyl groups may be specifically referred to as "fluoroalkyl" groups (eg C ₁ -C ₅ , C ₁ -C ₄ or C ₁ -C ₂ fluoroalkyl groups) which are typically substituted with 1, 2, 3, 4 or 5 fluorine atoms. Thus, C ₁ -C ₄ fluoroalkyl includes trifluoromethyl (-CF ₃ ), difluoromethyl (-CF ₂ H), fluoromethyl (-CFH ₂ ), difluoroethyl (-CH ₂ CF ₂ H) and the like. Such groups may be further substituted with groups suitable for alkyl groups, as further described herein.

In some embodiments of the present invention, the alkyl and fluoroalkyl groups are optionally substituted with one or more optional substituents, and preferably 1 to 3 optional substituents that are independently OH, C ₁ -C ₂ alkoxy, C ₁ -C ₂ fluoroalkoxy, CN, or NR' ₂ in which each R' is independently H, C ₁ -C ₂ alkyl or C ₁ -C ₂ fluoroalkyl.

Similarly, "alkoxyalkyl" refers to an alkyl group having a certain number of carbon atoms that is substituted with one or more alkoxy substituents. Alkoxyalkyl groups usually contain 1-4 carbon atoms in the alkyl portion and are substituted with 1, 2 or 3 C ₁ -C ₄ alkoxy substituents. Such groups are sometimes described herein as C ₁ -C ₄ alkoxyC ₁ -C ₄ alkyl.

"Aminoalkyl" refers to an alkyl group having a certain number of carbon atoms that is substituted with one or more substituted or unsubstituted amino groups, as such the groups are further defined herein. Aminoalkyl groups typically contain 1-6 carbon atoms on the alkyl moiety and are substituted with 1, 2 or 3 amino substituents. Thus, C ₁ -C ₆ aminoalkyl includes, for example, aminomethyl (-CH ₂ NH ₂ ), N,N-dimethylaminoethyl (-CH ₂ CH ₂ N(CH ₃ ) ₂ ), 3-(N-cyclopropylamino)-propyl (-CH ₂ CH ₂ CH ₂ NH- ^c Pr) and N-pyrrolidinylethyl (-CH ₂ CH ₂ N-pyrrolidinyl).

"Hydroxyalkyl" refers to an alkyl group having a certain number of carbon atoms, which is substituted with one or more hydroxy substituents and usually contains 1-6 carbon atoms, preferably 1-4 carbon atoms and 1, 2 or 3 hydroxy (i.e. "C ₁ -C ₆ hydroxyalkyl"). Thus, C ₁ -C ₆ hydroxyalkyl includes hydroxymethyl (-CH ₂ OH) and 2-hydroxyethyl (-CH ₂ CH ₂ OH).

"Alkenyl" refers to an alkyl group, as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon double bond. Typically, alkenyl groups contain from 2 to 20 carbon atoms ("C ₂ -C ₂₀ alkenyl"), preferably from 2 to 12 carbon atoms ("C ₂ -C ₁₂ alkenyl"), more preferably from 2 to 8 carbon atoms ("C ₂ -C ₈ alkenyl") or 2 to 6 carbon atoms ("C ₂ -C ₆ alkenyl") or 2 to 4 carbon atoms ("C ₂ -C ₄ alkenyl"). Representative examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like. Alkenyl groups are unsubstituted or substituted with the same groups described herein as suitable for alkyl.

"Alkynyl" refers to an alkyl group, as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon triple bond. Alkynyl groups contain 2 to 20 carbon atoms ("C ₂ -C ₂₀ alkynyl"), preferably 2 to 12 carbon atoms ("C ₂ -C ₁₂ alkynyl"), more preferably 2 to 8 carbon atoms ("C ₂ -C ₈ alkynyl") or 2 to 6 carbon atoms ("C ₂ -C ₆ alkynyl") or 2 to 4 carbon atoms ("C ₂ -C ₄ alkynyl"). Representative examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like. The alkynyl groups are unsubstituted or substituted with the same groups described herein as suitable for alkyl.

As used herein, "alkylene" refers to a divalent hydrocarbyl group having a certain number of carbon atoms that can link two other groups together. Sometimes this refers to the group -(CH ₂ ) _t - in which t is 1-8 and preferably t is 1-6, t is 1-4 or t is 1-2. Such groups may be referred to as C ₁ -C ₈ alkylene, C ₁ -C ₆ alkylene, C ₁ -C ₄ alkylene, etc. If indicated, alkylene may also be substituted with other groups and may include one or more degrees of unsaturation (t .e. alkenylene or alkynylene moiety) or rings. The open valences of the alkylene need not be at opposite ends of the chain. Thus, branched alkylene groups such as -CH(Me)-, -CH ₂ CH(Me)- and -C(Me) ₂ - are also included within the scope of the term "alkylenes", as are cyclic groups such as cyclopropane- 1,1-diyl and unsaturated groups such as ethylene (-CH=CH-) or propylene (-CH ₂ -CH=CH-). Where an alkylene group is described as being optionally substituted, the substituents include substituents normally present on alkyl groups as described herein.

"Heteroalkylene" refers to an alkylene group as described above in which one or more non-contiguous carbon atoms of the alkylene chain are substituted with -N(R)-, -O- or -S(O) _x - wherein R is H or a group substituents suitable for the secondary amino moiety; and x is 0-2. For example, the group -O(CH ₂ ) _1-3 - is a "C ₂ -C ₄ "-heteroalkylene group in which one of the carbon atoms of the corresponding alkylene is substituted with O.

"Alkoxy" refers to a monovalent -O-alkyl group in which the alkyl moiety has a certain number of carbon atoms. Alkoxy groups typically contain from 1 to 8 carbon atoms ("C ₁ -C ₈ alkoxy"), or from 1 to 6 carbon atoms ("C ₁ -C ₆ alkoxy"), or from 1 to 4 carbon atoms ("C ₁ - C ₄ alkoxy"). For example, C ₁ -C ₄ alkoxy includes methoxy, ethoxy, isopropoxy, t-butyloxy (i.e. -OCH ₃ , -OCH ₂ CH ₃ , -OCH(CH ₃ ) ₂ , OC(CH ₃ ) ₃ ) and the like. . The alkoxy groups are unsubstituted or substituted on the alkyl moiety with the same groups described herein as suitable for alkyl. In particular, the alkoxy groups may be optionally substituted with one or more halogen atoms, and in particular with one or more fluorine atoms, up to the total number of hydrogen atoms present in the alkyl moiety. Such groups are referred to as "haloalkoxy" (or in the case of fluorination more specifically "fluoroalkoxy") groups having a certain number of carbon atoms and substituted with one or more halogen substituents. Usually such groups contain 1-6 carbon atoms, preferably 1-4 carbon atoms and sometimes 1-2 carbon atoms and 1, 2 or 3 halogen atoms (i.e. "C ₁ -C ₆ haloalkoxy", "C ₁ -C ₄ haloalkoxy" or "C ₁ -C ₂ haloalkoxy"). More specifically, fluorinated alkoxy groups may be specifically referred to as "fluoroalkoxy" groups, for example, C ₁ -C ₆ , C ₁ -C ₄ or C ₁ -C ₂ fluoroalkoxy groups, which are usually substituted with 1, 2 or 3 fluorine atoms. Thus, C ₁ -C ₄ fluoroalkoxy includes trifluoromethyloxy (-OCF ₃ ), difluoromethyloxy (-OCF ₂ H), fluoromethyloxy (-OCFH ₂ ), difluoroethyloxy (-OCH ₂ CF ₂ H) and the like.

Similarly, "thioalkoxy" refers to a monovalent -S-alkyl group in which the alkyl portion has the specified number of carbon atoms and is optionally substituted on the alkyl portion with the same groups as described herein as suitable for alkyl. For example, C ₁ -C ₄ thioalkoxy includes -SCH ₃ and -SCH ₂ CH ₃ .

"Cycloalkyl" refers to a non-aromatic saturated carbocyclic ring system containing a certain number of carbon atoms, which may be monocyclic, spirocyclic, bridged or fused bicyclic or polycyclic ring system, which is linked to the main molecule through the carbon atom of the cycloalkyl ring. Typically, the cycloalkyl groups of the invention contain 3 to 12 carbon atoms ("C ₃ -C ₁₂ cycloalkyl"), preferably 3 to 8 carbon atoms ("C ₃ -C ₈ cycloalkyl"). Partially unsaturated carbocyclic rings may be referred to as "cycloalkenyl" rings. Typical examples of cycloalkyl and cycloalkenyl rings include, for example, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptatriene, adamantane and the like. Cycloalkyl groups are unsubstituted or substituted with the same groups as described herein as suitable for alkyl except that cycloalkyl rings may also be substituted with alkyl groups having a certain number of carbon atoms, which may be further optionally substituted as described in this application .

Illustrative examples of cycloalkyl and cycloalkenyl rings include, but are not limited to, the following:

"Cycloalkylalkyl" is used to describe a cycloalkyl ring, typically C ₃ -C ₈ cycloalkyl, that is linked to the parent molecule via an alkylene linker, typically C ₁ -C ₄ alkylene. Cycloalkylalkyl groups are sometimes described by the total number of carbon atoms in the carbocyclic ring and the linker, and typically contain from 4 to 12 carbon atoms ("C ₄ -C ₁₂ cycloalkylalkyl"). Thus, the cyclopropylmethyl group is a C ₄ -cycloalkylalkyl group and cyclohexylethyl is a C ₈ -cycloalkylalkyl. The cycloalkylalkyl groups are unsubstituted or substituted on the cycloalkyl and/or alkylene moieties with the same groups described herein as suitable for alkyl groups.

The terms "heterocyclyl" or "heterocyclic" may be used interchangeably to refer to a non-aromatic saturated ring system containing the specified number of ring atoms, including at least one heteroatom selected from N, O, and S as a ring member, in which ring atoms S optionally substituted with one or two oxo groups (e.g., S(O) _x in which x is 0, 1 or 2) and in which the heterocyclic ring is linked to the parent molecule via a ring atom which may be C or N. Where specifically stated, such heterocyclic rings may be partially unsaturated. Heterocyclic rings include rings that are spirocyclic, bridged, or fused with one or more other heterocyclic or carbocyclic rings, wherein such spirocyclic, bridged, or fused rings may themselves be saturated, partially unsaturated, or aromatic to the extent that unsaturation or aromaticity is chemical meaning, provided that the point of attachment to the main molecule is an atom of the heterocyclic part of the ring system. Preferably, the heterocyclic rings contain 1 to 4 heteroatoms selected from N, O and S(O) _q as ring members, and more preferably 1 to 2 ring heteroatoms, provided that such heterocyclic rings do not contain two adjacent oxygen atoms.

Heterocyclyl groups are unsubstituted or substituted with suitable substituent groups, for example the same groups described herein as being suitable for alkyl except that heterocyclyl rings may also be substituted with alkyl groups having a certain number of carbon atoms, which may be further optionally substituted as described in this application. Such substituents may be present on a heterocyclic ring attached to the parent molecule or on a spirocyclic, bridged or fused ring attached to it. In addition, the N atoms in the ring are optionally substituted with groups suitable for an amine, for example, alkyl, acyl, carbamoyl, sulfonyl, and the like.

Heterocycles typically include 3-12 membered heterocyclyl groups, 3-10 membered heterocyclyl groups, 3-8 membered heterocyclyl groups, and more preferably 3-6 membered heterocyclyl groups as defined herein.

Illustrative examples of saturated heterocycles include, but are not limited to:

Illustrative examples of partially unsaturated heterocycles include, but are not limited to:

Illustrative examples of bridged, fused, and spiro heterocycles include, but are not limited to:

In some embodiments, heterocyclic groups contain 3-12 ring members, including both carbon and non-carbon heteroatoms, and often 3-8 or 3-6 ring members. In certain preferred embodiments, substituent groups containing 3-12 membered heterocycles are selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, and thiomorpholinyl rings, each of which is optionally substituted as described for a certain group of substituents, to the extent that such a substitution has a chemical meaning.

In some embodiments of the present invention, the cycloalkyl and heterocyclyl groups are optionally substituted with one or more optional substituents, and preferably 1 to 3 optional substituents that are independently F, OH, CN, NR' ₂ (in which each R' is independently H, C ₁ -C ₂ alkyl or C ₁ -C ₂ fluoroalkyl), C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy or C ₁ -C ₄ fluoroalkoxy, in which each specified C ₁ - C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ fluoroalkoxy are optionally further substituted with OH, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ .

It is understood that no more than two N, O or S atoms are generally bonded in series except when an oxo group is attached to N or S to form a nitro or sulfonyl group, or in the case of certain heteroaromatic rings such as triazine, triazole, tetrazole, oxadiazole , thiadiazole and the like.

The term "heterocyclylalkyl" can be used to describe a heterocyclic group of a certain size, which is connected to the main molecule through an alkylene linker of a given length. Typically, such groups contain an optionally substituted 3-12 membered heterocycle attached to the parent molecule via a C ₁ -C ₄ alkylene linker. Where indicated, such groups are optionally substituted on the alkylene portion with the same groups described herein as suitable for alkyl groups and on the heterocyclic portion with groups described as suitable for heterocyclic rings.

"Aryl" or "aromatic" refers to an optionally substituted monocyclic or fused bicyclic or polycyclic ring system having well known aromatic characteristics, in which at least one ring contains a fully conjugated pi electron system. Generally, aryl groups contain 6 to 20 carbon atoms ("C ₆ -C ₂₀ aryl") as ring members, preferably 6 to 14 carbon atoms ("C ₆ -C ₁₄ aryl") or more preferably 6 to 12 atoms carbon ("C ₆ -C ₁₂ aryl"). Fused aryl groups may include an aryl ring (e.g., a phenyl ring) fused to another aryl or heteroaryl ring, or fused to a saturated or partially unsaturated carbocyclic or heterocyclic ring, provided that the point of attachment to the parent molecule in such fused ring systems is an aromatic atom. part of the ring system. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and tetrahydronaphthyl. The aryl group is unsubstituted or substituted, as further described in this application.

Similarly, "heteroaryl" or "heteroaromatic" refers to monocyclic or fused bicyclic or polycyclic ring systems having well-known aromaticity characteristics, which contain the number of ring atoms indicated and include at least one heteroatom selected from N, O and S as a ring member in an aromatic ring. The inclusion of a heteroatom provides aromaticity in 5-membered rings as well as in 6-membered rings. Typically, heteroaryl groups contain 5 to 20 ring atoms ("5-20 membered heteroaryl"), preferably 5 to 14 ring atoms ("5-14 membered heteroaryl"), and more preferably 5 to 12 ring atoms ("5 -12-membered heteroaryl"). Heteroaryl rings are attached to the main molecule through a ring atom of the heteroaromatic ring so that aromaticity is retained. Thus, 6-membered heteroaryl rings can be attached to the main molecule through a C ring atom, while 5-membered heteroaryl rings can be attached to the main molecule through a C or N ring atom. Heteroaryl groups can also be fused to another aryl or a heteroaryl ring, or fused to a saturated or partially unsaturated carbocyclic or heterocyclic ring, provided that the point of attachment to the parent molecule in such fused ring systems is an atom of the heteroaromatic moiety of the ring system. Examples of unsubstituted heteroaryl groups often include, but are not limited to, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, benzofuran, benzothiophene, indole, benzimidazole, indazole, quinoline, isoquinoline, purine, triazine, naftriidine, and carbazole. In frequent preferred embodiments, the 5- or 6-membered heteroaryl groups are selected from the group consisting of pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, pyridinyl, and pyrimidinyl, pyrazinyl, or pyridazinyl rings. The heteroaryl group is unsubstituted or substituted as further described herein.

Aryl and heteroaryl moieties described herein as optionally substituted may be substituted with one or more substituent groups, which are independently selected unless otherwise indicated. The total number of substituent groups may be equal to the total number of hydrogen atoms in the aryl, heteroaryl, or heterocyclyl moiety, to the extent that such a substitution makes chemical sense and aromaticity is retained in the case of the aryl and heteroaryl rings. Optionally substituted aryl or heteroaryl groups usually have 1 to 5 optional substituents, sometimes 1 to 4 optional substituents, preferably 1 to 3 optional substituents, or more preferably 1 to 2 optional substituents.

Optional substituent groups suitable for use with aryl and heteroaryl rings include, but are not limited to: C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, 3- 12-membered heterocyclyl, C ₆ -C ₁₂ aryl and 5-12-membered heteroaryl; and halogen, =O, -CN, -C(O)R ^x , -CO ₂ R ^x , -C(O)NR ^x R ^y , -SR ^x , -SOR ^x , -SO ₂ R ^x , -SO ₂ NR ^x R ^y , -NO ₂ , -NR ^x R ^y , -NR ^x C(O)R ^y , -NR ^x C(O)NR ^x R ^y , -NR ^x C(O)OR ^x , -NR ^x SO ₂ R ^y , -NR ^x SO ₂ NR ^x R ^y , -OR ^x , -OC(O)R ^x and -OC(O)NR ^x R ^y ; in which each R ^x and R ^y is independently H, C ₁ -C ₈ alkyl, C ₁ -C ₈ acyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, 3- 12-membered heterocyclyl, C ₆ -C ₁₂ aryl or 5-12-membered heteroaryl, or R ^x and R ^y can be taken together with the N atom to which they are attached to form a 3-12-membered heterocyclyl or 5-12 -membered heteroaryl, each optionally containing 1, 2 or 3 additional heteroatoms selected from O, N and S(O) _z , in which z is 0-2; each R ^x and R ^y is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, ═O, ═S, ═N-CN, ═N-OR', ═NR', -CN, -C(O )R', -CO ₂ R', -C(O)NR' ₂ , -SR', -SOR', -SO ₂ R', -SO ₂ NR' ₂ , -NO ₂ , -NR' ₂ , - NR'C(O)R', -NR'C(O)NR' ₂ , -NR'C(O)OR', -NR'SO ₂ R', -NR'SO ₂ NR' ₂ , -OR' , -OC(O)R' and -OC(O)NR' ₂ , wherein each R' is independently H, C ₁ -C ₈ alkyl, C ₁ -C ₈ acyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, 3-12 membered heterocyclyl, C ₆ -C ₁₂ aryl or 5-12 membered heteroaryl; and each specified C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, 3-12 membered heterocyclyl, C ₆ -C ₁₂ aryl and 5-12 membered heteroaryl is optionally substituted as further defined herein.

In exemplary embodiments, the optional substitution on the aryl, heteroaryl, and heterocyclyl rings comprises one or more substituents, and preferably 1 to 3 substituents, independently selected from the group consisting of halo, C ₁ -C ₈ alkyl, -OH, C ₁ -C ₈ alkoxy, -CN, =O, -C(O)R ^x , -COOR ^x , -OC(O)R ^x , -C(O)NR ^x R ^y , -NR ^x C(O)R ^y , -SR ^x , -SOR ^x , -SO ₂ R ^x , -SO ₂ NR ^x R ^y , -NO ₂ , -NR ^x R ^y , -NR ^x C(O)R ^y , -NR ^x C(O)NR ^x R ^y , -NR ^x C(O)OR ^y -NR ^x SO ₂ R ^y , -NR ^x SO ₂ NR ^x R ^y , -OC(O)R ^x , -OC(O)NR ^x R ^y , C ₃ - C ₈ cycloalkyl, 3-12 membered heterocyclyl, C ₆ -C ₁₂ aryl, 5-12 membered heteroaryl, -O-(C ₃ -C ₈ cycloalkyl), O-(3-12 membered heterocyclyl), -O (C ₆ -C ₁₂ aryl) and -O-(5-12 membered heteroaryl); wherein each R ^x and R ^y is independently H or C ₁ -C ₄ alkyl or R ^x and R ^y taken together with the N to which they are attached form a 3-12 membered heterocyclyl or 5-12 membered heteroaryl a ring each optionally containing 1, 2 or 3 additional heteroatoms selected from O, N and S(O) _q , in which q is 0-2; and wherein each said C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₃ -C ₈ cycloalkyl, 3-12 membered heterocyclyl, C ₆ -C ₁₂ aryl, 5-12 membered heteroaryl, -O- (C ₃ -C ₈ cycloalkyl), -O-(3-12 membered heterocyclyl), -O-(C ₆ -C ₁₂ aryl) and -O-(5-12 membered heteroaryl), which is described as an optional substituent or is part of R ^x and R ^y , optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, -OH, =O, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₄ alkoxy-C ₁ -C ₆ alkyl, -CN, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl ) ₂ and N-pyrrolidinyl.

Examples of monocyclic heteroaryl groups include, but are not limited to:

Illustrative examples of fused heteroaryl groups include, but are not limited to:

"Arylalkyl" group refers to an aryl group, as described in this application, which is connected to the main molecule through alkylene or a similar linker. Arylalkyl groups are described by the total number of carbon atoms in the ring and linker. Thus, the benzyl group is a C ₇ -arylalkyl group and phenylethyl is a C ₈ -arylalkyl. Typically, arylalkyl groups contain 7-16 carbon atoms ("C ₇ -C ₁₆ arylalkyl"), in which the aryl portion contains 6-12 carbon atoms and the alkylene portion contains 1-4 carbon atoms. Such groups can also be represented as -C ₁ -C ₄ alkylene-C ₆ -C ₁₂ aryl.

"Heteroarylalkyl" refers to a heteroaryl group as described above that is attached to the parent molecule via an alkylene linker and differs from "arylalkyl" in that at least one ring atom of the aromatic moiety is a heteroatom selected from N, O, and S Heteroarylalkyl groups are sometimes described herein according to the total number of non-hydrogen atoms (ie, C, N, S, and O atoms) in the combined ring and linker, excluding substituent groups. Thus, for example, pyridinylmethyl may be referred to as "C ₇ "-heteroarylalkyl. Typically, unsubstituted heteroarylalkyl groups contain 6-20 non-hydrogen atoms (including C, N, S and O atoms) in which the heteroaryl portion typically contains 5-12 atoms and the alkylene portion typically contains 1-4 carbon atoms. Such groups can also be represented as -C ₁ -C ₄ alkylene-5-12-membered heteroaryl.

Similarly, "arylalkoxy" and "heteroarylalkoxy" refer to aryl and heteroaryl groups attached to the parent molecule via a heteroalkylene linker (i.e., -O-alkylene), in which the groups are described according to the total number of non-hydrogen atoms (i.e., C, N, S and O atoms) in the combined ring and linker. Thus, -O-CH ₂ -phenyl and -O-CH ₂ -pyridinyl groups will be referred to as C ₈ -arylalkoxy and C ₈ -heteroarylalkoxy groups, respectively.

When an arylalkyl, arylalkoxy, heteroarylalkyl, or heteroarylalkoxy group is described as being optionally substituted, substituents may be present either on the divalent linker portion or on the aryl or heteroaryl portion of the group. Substituents optionally present on the alkylene or heteroalkylene moiety are generally the same as described above for alkyl or alkoxy groups, while substituents optionally present on the aryl or heteroaryl moiety are the same as described above for aryl or heteroaryl groups in general.

"Hydroxy" refers to the OH group.

"Acyloxy" refers to a monovalent group -OC(O)alkyl, in which the alkyl moiety has a certain number of carbon atoms (usually C ₁ -C ₈ , preferably C ₁ -C ₆ or C ₁ -C ₄ ), which are optionally substituted with groups, suitable for alkyl. Thus, C ₁ -C ₄ acyloxy includes -OC(O)C ₁ -C ₄ alkyl substituent, for example, -OC(O)CH ₃ .

"Acyl" refers to a monovalent -C(O)alkyl group in which the alkyl moiety has the indicated number of carbon atoms (usually C ₁ -C ₈ , preferably C ₁ -C ₆ or C ₁ -C ₄ ) and may be optionally substituted with groups suitable for alkyl, for example by F, OH or alkoxy. Thus, optionally substituted -C(O)C ₁ -C ₄ alkyl includes unsubstituted acyl groups such as -C(O)CH ₃ (i.e. acetyl) and -C(O)CH ₂ CH ₃ (i.e. e. propionyl), as well as substituted acyl groups such as -C(O)CF ₃ (trifluoroacetyl), -C(O)CH ₂ OH (hydroxyacetyl), -C(O)CH ₂ OCH ₃ (methoxyacetyl), - C(O)CF ₂ H (difluoroacetyl) and the like.

"Acylamino" refers to a monovalent group, -NHC(O)alkyl or -NRC(O)alkyl, in which the alkyl moiety has the indicated number of carbon atoms (usually C ₁ -C ₈ , preferably C ₁ -C ₆ or C ₁ -C ₄ ) and is optionally substituted with groups suitable for alkyl. Thus, C ₁ -C ₄ acylamino includes -NHC(O)C ₁ -C ₄ alkyl substituent, for example -NHC(O)CH ₃ .

"Aryloxy" or "heteroaryloxy" refers to optionally substituted O-aryl or O-heteroaryl whenever aryl and heteroaryl are as further defined herein.

"Arylamino" or "heteroarylamino" refers to an optionally substituted -NH-aryl, -NR-aryl, -NH-heteroaryl, or -NR-heteroaryl whenever aryl and heteroaryl are as further defined herein, and R is a substituent suitable for an amine, for example an alkyl, acyl, carbamoyl or sulfonyl group or the like.

"Cyano" refers to the -C≡N group.

"Unsubstituted amino" refers to the group -NH ₂ . When amino is described as substituted or optionally substituted, the term includes groups of the form -NR ^x R ^y in which either R ^x and R ^y are independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, acyl, thioacyl, aryl, heteroaryl , cycloalkylalkyl, arylalkyl or heteroarylalkyl, in each case having the indicated number of atoms and optionally substituted, as described in this application. For example, "alkylamino" refers to the group -NR ^x R ^y in which one of R ^x and R ^y is an alkyl moiety and the other is H, and "dialkylamino" refers to -NR ^x R ^y in which both are from R ^x and R ^y are alkyl moieties in which alkyl moieties containing the specified number of carbon atoms (eg, -NH-C ₁ -C ₄ alkyl or -N(C ₁ -C ₄ alkyl) ₂ ). Generally, alkyl substituents on amines have 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, or more preferably 1 to 4 carbon atoms. The term also includes forms in which R ^x and R ^y are taken together with the N atom to which they are attached to form a 3-12 membered heterocyclyl or 5-12 membered heteroaryl ring, each of which may itself be optionally substituted as described in this application for heterocyclyl or heteroaryl rings, and which may contain from 1 to 3 additional heteroatoms selected from N, O and S(O) _x in which x is 0-2, as ring members, provided that such the rings do not contain two adjacent oxygen atoms.

"Halogen" or "halo" refers to fluorine, chlorine, bromine and iodine (F, Cl, Br, I). Preferably, halogen refers to fluorine or chlorine (F or Cl).

"Optional" or "optional" means that the event or circumstance described hereinafter may, but need not, occur, and the description includes cases where the event or circumstance occurs and cases where it does not.

The terms "optionally substituted" and "substituted or unsubstituted" may be used interchangeably to mean that a particular described group may have no non-hydrogen substituents (i.e., unsubstituted) or a group may have one or more non-hydrogen substituents (i.e., substituted) . Unless otherwise indicated, the total number of substituents that may be present is equal to the number of H atoms present in the unsubstituted form of the described group. When an optional substituent is attached via a double bond, such as an oxo (=O) substituent, the group occupies two available valences, so the total number of other substituents that are included is reduced by two.

Often, optionally substituted groups are substituted with 1 or more substituents independently selected from a list of optional substituents. In some embodiments, optionally substituted groups are substituted with 1, 2, 3, or more than 3 substituents independently selected from a list of optional substituents. For example, an alkyl group described as optionally substituted with R ^x means that the alkyl group is optionally substituted with 1 or more R ^x substituents independently selected from the list of R ^x substituents provided for the alkyl group. If necessary, the description of an optionally substituted group in this application may be changed to indicate that the group is optionally substituted with 1 or more of the indicated substituents. Where the optional substituents are selected from a list of alternatives, the selected groups are independently selected and may be the same or different.

Throughout the disclosure, it will be understood that the number and nature of the optional substituent groups will be limited to the extent that such substitutions make chemical sense.

In one aspect, the invention provides a compound of Formula (I):

(I)

(I)

or a pharmaceutically acceptable salt thereof, in which:

And represents N or CH;

R ¹ represents H, F, Cl, CN, C ₁ -C ₂ alkyl, C ₁ -C ₂ fluoroalkyl or C ₁ -C ₂ alkoxy, in which each specified C ₁ -C ₂ alkyl and C ₁ -C ₂ fluoroalkyl optionally substituted with R ²⁰ ;

U is NR ² or CR ³ ;

V is N or CR ⁴ when U is NR ² ; And

V is NR ⁵ when U is CR ³ ;

X is CR ⁶ or N;

Y is CR ⁷ or N;

Z is CR ⁸ or N;

R ² and R ³ are H, C ₁ -C ₅ alkyl, C ₁ -C ₅ fluoroalkyl, C ₃ -C ₈ cycloalkyl, or 3-6 membered heterocyclyl, wherein said C ₁ -C ₅ alkyl and C ₁ are each -C ₅ fluoroalkyl is optionally substituted with R ²⁰ and each of said C ₃ -C ₈ cycloalkyl and 3-6 membered heterocyclyl is optionally substituted with R ²¹ ;

R ⁴ is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ fluoroalkoxy, C(O)R ^a , C(O)NR ^b ₂ , C ₃ -C ₈ cycloalkyl or 3-6 membered heterocyclyl, wherein each said C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy, and C ₁ -C ₄ fluoroalkoxy is optionally substituted with R ²⁰ , each said C ₃ -C ₈ cycloalkyl and 3-6 membered heterocyclyl is optionally substituted with R ²¹ , R ^a is C ₁ -C ₂ alkyl and each R ^b is independently H or C ₁ -C ₂ alkyl; And

R ⁵ is H, C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with R ²⁰ ; or

R ² may be taken together with R ⁴ or R ³ may be taken together with R ⁵ to form a 5-7 membered heterocyclic ring optionally containing an additional heteroatom selected from NR ²⁴ , O and S(O) _m as a member rings, the ring being optionally substituted with R ²¹ ;

R ⁶ is H, F, Cl, CN, CH ₃ , CH ₂ F, CHF ₂ or CF ₃ ;

R ⁷ and R ⁸ are independently H, F, Cl, CN, C ₁ -C ₂ alkyl, C ₁ -C ₂ fluoroalkyl, C ₁ -C ₂ alkoxy, or C ₁ -C ₂ fluoroalkoxy, wherein each C ₁ -C ₂ alkyl, C ₁ -C ₂ fluoroalkyl, C ₁ -C ₂ alkoxy and C ₁ -C ₂ fluoroalkoxy are optionally substituted with R ²⁰ ;

R ⁹ is H, OH, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ ;

each R ¹⁰ is independently F, CN, C ₁ -C ₂ alkyl, or C ₁ -C ₂ fluoroalkyl, wherein each said C ₁ -C ₂ alkyl and C ₁ -C ₂ fluoroalkyl is optionally substituted with R ²⁰ ;

Q is NR ¹¹ or O or

Q is CR ¹² R ¹³ in which R ¹² and R ¹³ are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing NR ¹¹ or O as a ring member, the ring optionally further substituted with R ¹⁰ ;

R ¹¹ is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, SO ₂ R ¹⁴ , SO ₂ NR ¹⁵ R ¹⁶ , COR ¹⁷ , COOR ¹⁷ or CONR ¹⁸ R ¹⁹ , wherein each C ₁ - C ₄ alkyl and C ₁ -C ₄ fluoroalkyl optionally substituted with R ²⁰ , SO ₂ R ¹⁴ , SO ₂ NR ¹⁵ R ¹⁶ , COR ¹⁷ , COOR ¹⁷ or CONR ¹⁸ R ¹⁹ ;

R ¹⁴ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl;

each R ¹⁵ and R ¹⁶ is independently H or CH ₃ ;

R ¹⁷ is C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₃ -C ₈ cycloalkyl, or 3-6 membered heterocyclyl, wherein each of C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optional substituted with R ²⁰ and each of said C ₃ -C ₈ cycloalkyl and 3-6 membered heterocyclyl is optionally substituted with R ²¹ ;

each R ¹⁸ and R ¹⁹ is independently H, C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each said C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with R ²⁰ ;

each R ²⁰ is independently OH, C ₁ -C ₂ alkoxy, C ₁ -C ₂ fluoroalkoxy, CN, NR ²² R ²³ , C ₃ -C ₈ cycloalkyl, or 3-6 membered heterocyclyl, wherein each C ₃ - C ₈ cycloalkyl and 3-6 membered heterocyclyl are optionally substituted with R ²¹ ;

each R ²¹ is independently F, OH, CN, NR ²² R ²³ , C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy or C ₁ -C ₄ fluoroalkoxy, in which each specified C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ fluoroalkoxy optionally further substituted with OH, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ ;

each R ²² and R ²³ is independently H, C ₁ -C ₃ alkyl, C ₁ -C ₃ fluoroalkyl, C ₃ -C ₈ cycloalkyl, or 3-6 membered heterocyclyl, wherein each is C ₁ -C ₃ alkyl and C ₁ -C ₃ fluoroalkyl is optionally further substituted with OH, C ₁ -C ₂ alkoxy or C ₁ -C ₂ fluoroalkoxy, and each said C ₃ -C ₈ cycloalkyl and 3-6 membered heterocyclyl is optionally further substituted with F, OH, C ₁ - C ₂ alkyl, C ₁ -C ₂ fluoroalkyl, C ₁ -C ₂ alkoxy or C ₁ -C ₂ fluoroalkoxy; or

R ²² and R ²³ can be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring in which said ring is optionally substituted with F, OH, C ₁ -C ₂ alkyl, C ₁ -C ₂ fluoroalkyl, C ₁ - C ₂ alkoxy or C ₁ -C ₂ fluoroalkoxy;

R ²⁴ is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, SO ₂ R ²⁵ , SO ₂ NR ²⁶ R ²⁷ , COR ²⁸ , COOR ²⁸ or CONR ²⁹ R ³⁰ ;

R ²⁵ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl;

each R ²⁶ and R ²⁷ is independently H or CH ₃ ;

R ²⁸ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with OH, C ₁ -C ₂ alkoxy, C ₁ -C ₂ fluoroalkoxy, CN, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ ;

each R ²⁹ and R ³⁰ is independently H, C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each said C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with OH, C ₁ -C ₂ alkoxy, C ₁ -C ₂ fluoroalkoxy, CN, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ ;

m is 0, 1 or 2;

n is 0, 1, 2, 3, or 4;

p is equal to 1, 2 or 3 and

q is 0, 1, 2, or 3;

in which the sum of p and q is an integer from 1 to 4.

In another aspect, the invention provides a compound of Formula (II):

(II)

(II)

or a pharmaceutically acceptable salt thereof, in which:

R ¹ is H, F, Cl, CN, C ₁ -C ₂ alkyl or C ₁ -C ₂ fluoroalkyl, wherein each C ₁ -C ₂ alkyl and C ₁ -C ₂ fluoroalkyl is optionally substituted with R ²⁰ ;

U is NR ² or CR ³ ;

V is N or CR ⁴ when U is NR ² ; And

V is NR ⁵ when U is CR ³ ;

X is CR ⁶ or N;

Y is CR ⁷ or N;

Z is CR ⁸ or N;

R ² and R ³ are H, C ₁ -C ₅ alkyl, C ₁ -C ₅ fluoroalkyl, C ₃ -C ₈ cycloalkyl, or 3-6 membered heterocyclyl, wherein said C ₁ -C ₅ alkyl and C ₁ are each -C ₅ fluoroalkyl is optionally substituted with R ²⁰ and each of said C ₃ -C ₈ cycloalkyl and 3-6 membered heterocyclyl is optionally substituted with R ²¹ ;

R ⁴ is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy or C ₁ -C ₄ fluoroalkoxy, wherein each is C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ fluoroalkoxy are optionally substituted with R ²⁰ ;

R ⁵ is H, C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with R ²⁰ ;

R ⁶ is H, F, Cl, CN, CH ₃ , CH ₂ F, CHF ₂ or CF ₃ ;

R ⁷ and R ⁸ are independently H, F, Cl, CN, C ₁ -C ₂ alkyl, C ₁ -C ₂ fluoroalkyl, C ₁ -C ₂ alkoxy, or C ₁ -C ₂ fluoroalkoxy, wherein each C ₁ -C ₂ alkyl, C ₁ -C ₂ fluoroalkyl, C ₁ -C ₂ alkoxy and C ₁ -C ₂ fluoroalkoxy are optionally substituted with R ²⁰ ;

R ⁹ is H, OH, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ ;

each R ¹⁰ is independently F, CN, C ₁ -C ₂ alkyl, or C ₁ -C ₂ fluoroalkyl, wherein each said C ₁ -C ₂ alkyl and C ₁ -C ₂ fluoroalkyl is optionally substituted with R ²⁰ ;

Q is NR ¹¹ or O or

Q is CR ¹² R ¹³ in which R ¹² and R ¹³ are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing NR ¹¹ or O as a ring member, the ring optionally further substituted with R ¹⁰ ;

R ¹¹ is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, SO ₂ R ¹⁴ , SO ₂ NR ¹⁵ R ¹⁶ , COR ¹⁷ , COOR ¹⁷ or CONR ¹⁸ R ¹⁹ ;

R ¹⁴ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl;

each R ¹⁵ and R ¹⁶ is independently H or CH ₃ ;

R ¹⁷ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with R ²⁰ ;

each R ¹⁸ and R ¹⁹ is independently H, C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each said C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with R ²⁰ ;

each R ²⁰ is independently OH, C ₁ -C ₂ alkoxy, C ₁ -C ₂ fluoroalkoxy, CN or NR ²² R ²³ ;

each R ²¹ is independently F, OH, CN, NR ²² R ²³ , C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy or C ₁ -C ₄ fluoroalkoxy, in which each specified C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ fluoroalkoxy optionally further substituted with OH, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ ;

each R ²² and R ²³ is independently H, C ₁ -C ₂ alkyl or C ₁ -C ₂ fluoroalkyl or

R ²² and R ²³ may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring which is optionally substituted with F or OH;

n is 0, 1, 2, 3, or 4;

p is equal to 1, 2 or 3 and

q is 0, 1, 2 or 3;

in which the sum of p and q is an integer from 1 to 4.

In another aspect, the invention provides a compound of Formula (III):

(III)

(III)

or a pharmaceutically acceptable salt thereof, in which:

R ¹ is H, F, Cl, CN, C ₁ -C ₂ alkyl or C ₁ -C ₂ fluoroalkyl, wherein each C ₁ -C ₂ alkyl and C ₁ -C ₂ fluoroalkyl is optionally substituted with R ²⁰ ;

U is NR ² or CR ³ ;

V is N or CR ⁴ when U is NR ² ; And

V is NR ⁵ when U is CR ³ ;

X is CR ⁶ or N;

Y is CR ⁷ or N;

Z is CR ⁸ or N;

R ² and R ³ are H, C ₁ -C ₅ alkyl, C ₁ -C ₅ fluoroalkyl, C ₃ -C ₈ cycloalkyl, or 3-6 membered heterocyclyl, wherein said C ₁ -C ₅ alkyl and C ₁ are each -C ₅ fluoroalkyl is optionally substituted with R ²⁰ and each of said C ₃ -C ₈ cycloalkyl and 3-6 membered heterocyclyl is optionally substituted with R ²¹ ;

R ⁴ is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy or C ₁ -C ₄ fluoroalkoxy, wherein each is C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ fluoroalkoxy are optionally substituted with R ²⁰ ;

R ⁵ is H, C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with R ²⁰ ;

R ⁶ is H, F, Cl, CN, CH ₃ , CH ₂ F, CHF ₂ or CF ₃ ;

R ⁷ and R ⁸ are independently H, F, Cl, CN, C ₁ -C ₂ alkyl, C ₁ -C ₂ fluoroalkyl, C ₁ -C ₂ alkoxy, or C ₁ -C ₂ fluoroalkoxy, wherein each C ₁ -C ₂ alkyl, C ₁ -C ₂ fluoroalkyl, C ₁ -C ₂ alkoxy and C ₁ -C ₂ fluoroalkoxy are optionally substituted with R ²⁰ ;

R ⁹ is H, OH, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ ;

each R ¹⁰ is independently F, CN, C ₁ -C ₂ alkyl, or C ₁ -C ₂ fluoroalkyl, wherein each said C ₁ -C ₂ alkyl and C ₁ -C ₂ fluoroalkyl is optionally substituted with R ²⁰ ;

Q is NR ¹¹ or O or

Q is CR ¹² R ¹³ in which R ¹² and R ¹³ are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing NR ¹¹ or O as a ring member, the ring optionally further substituted with R ¹⁰ ;

R ¹¹ is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, SO ₂ R ¹⁴ , SO ₂ NR ¹⁵ R ¹⁶ , COR ¹⁷ , COOR ¹⁷ or CONR ¹⁸ R ¹⁹ ;

R ¹⁴ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl;

each R ¹⁵ and R ¹⁶ is independently H or CH ₃ ;

R ¹⁷ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with R ²⁰ ;

each R ¹⁸ and R ¹⁹ is independently H, C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each said C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with R ²⁰ ;

each R ²⁰ is independently OH, C ₁ -C ₂ alkoxy, C ₁ -C ₂ fluoroalkoxy, CN or NR ²² R ²³ ;

each R ²¹ is independently F, OH, CN, NR ²² R ²³ , C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy or C ₁ -C ₄ fluoroalkoxy, in which each specified C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ fluoroalkoxy optionally further substituted with OH, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ ;

each R ²² and R ²³ is independently H, C ₁ -C ₂ alkyl or C ₁ -C ₂ fluoroalkyl or

R ²² and R ²³ may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring which is optionally substituted with F or OH;

n is 0, 1, 2, 3, or 4;

p is equal to 1, 2 or 3 and

q is 0, 1, 2 or 3;

in which the sum of p and q is an integer from 1 to 4.

In another aspect, the invention provides a compound of Formula (IV):

(IV)

(iv)

or a pharmaceutically acceptable salt thereof, in which:

R ¹ is H, F, Cl, CN, C ₁ -C ₂ alkyl or C ₁ -C ₂ fluoroalkyl, wherein each C ₁ -C ₂ alkyl and C ₁ -C ₂ fluoroalkyl is optionally substituted with R ²⁰ ;

U is NR ² or CR ³ ;

V is N or CR ⁴ when U is NR ² ; And

V is NR ⁵ when U is CR ³ ;

X is CR ⁶ or N;

Y is CR ⁷ or N;

Z is CR ⁸ or N;

R ² and R ³ are H, C ₁ -C ₅ alkyl, C ₁ -C ₅ fluoroalkyl, C ₃ -C ₈ cycloalkyl, or 3-6 membered heterocyclyl, wherein said C ₁ -C ₅ alkyl and C ₁ are each -C ₅ fluoroalkyl is optionally substituted with R ²⁰ and each of said C ₃ -C ₈ cycloalkyl and 3-6 membered heterocyclyl is optionally substituted with R ²¹ ;

R ⁴ is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy or C ₁ -C ₄ fluoroalkoxy, wherein each is C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ fluoroalkoxy are optionally substituted with R ²⁰ ; And

R ⁵ is H, C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with R ²⁰ ; or

R ² may be taken together with R ⁴ or R ³ may be taken together with R ⁵ to form a 5-7 membered heterocyclic ring optionally containing an additional heteroatom selected from NR ²⁴ , O and S(O) _m as a member rings, the ring being optionally substituted with R ²¹ ;

R ⁶ is H, F, Cl, CN, CH ₃ , CH ₂ F, CHF ₂ or CF ₃ ;

R ⁷ and R ⁸ are independently H, F, Cl, CN, C ₁ -C ₂ alkyl, C ₁ -C ₂ fluoroalkyl, C ₁ -C ₂ alkoxy, or C ₁ -C ₂ fluoroalkoxy, wherein each C ₁ -C ₂ alkyl, C ₁ -C ₂ fluoroalkyl, C ₁ -C ₂ alkoxy and C ₁ -C ₂ fluoroalkoxy are optionally substituted with R ²⁰ ;

R ⁹ is H, OH, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ ;

each R ¹⁰ is independently F, CN, C ₁ -C ₂ alkyl, or C ₁ -C ₂ fluoroalkyl, wherein each said C ₁ -C ₂ alkyl and C ₁ -C ₂ fluoroalkyl is optionally substituted with R ²⁰ ;

Q is NR ¹¹ or O or

Q is CR ¹² R ¹³ in which R ¹² and R ¹³ are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing NR ¹¹ or O as a ring member, the ring optionally further substituted with R ¹⁰ ;

R ¹¹ is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, SO ₂ R ¹⁴ , SO ₂ NR ¹⁵ R ¹⁶ , COR ¹⁷ , COOR ¹⁷ or CONR ¹⁸ R ¹⁹ ;

R ¹⁴ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl;

each R ¹⁵ and R ¹⁶ is independently H or CH ₃ ;

R ¹⁷ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with R ²⁰ ;

each R ¹⁸ and R ¹⁹ is independently H, C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each said C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with R ²⁰ ;

each R ²⁰ is independently OH, C ₁ -C ₂ alkoxy, C ₁ -C ₂ fluoroalkoxy, CN or NR ²² R ²³ ;

each R ²¹ is independently F, OH, CN, NR ²² R ²³ , C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy or C ₁ -C ₄ fluoroalkoxy, in which each specified C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ fluoroalkoxy optionally further substituted with OH, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ ;

each R ²² and R ²³ is independently H, C ₁ -C ₂ alkyl or C ₁ -C ₂ fluoroalkyl or

R ²² and R ²³ may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring which is optionally substituted with F or OH;

R ²⁴ is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, SO ₂ R ²⁵ , SO ₂ NR ²⁶ R ²⁷ , COR ²⁸ , COOR ²⁸ or CONR ²⁹ R ³⁰ ;

R ²⁵ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl;

each R ²⁶ and R ²⁷ is independently H or CH ₃ ;

R ²⁸ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with OH, C ₁ -C ₂ alkoxy, C ₁ -C ₂ fluoroalkoxy, CN, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ ;

each R ²⁹ and R ³⁰ is independently H, C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each said C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with OH, C ₁ -C ₂ alkoxy, C ₁ -C ₂ fluoroalkoxy, CN, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ ;

m is 0, 1 or 2;

n is 0, 1, 2, 3, or 4;

p is equal to 1, 2 or 3 and

q is 0, 1, 2 or 3;

in which the sum of p and q is an integer from 1 to 4.

In another aspect, the invention provides a compound of Formula (V):

(V)

(V)

or a pharmaceutically acceptable salt thereof, in which:

R ¹ is H, F, Cl, CN, C ₁ -C ₂ alkyl or C ₁ -C ₂ fluoroalkyl, wherein each C ₁ -C ₂ alkyl and C ₁ -C ₂ fluoroalkyl is optionally substituted with R ²⁰ ;

U is NR ² or CR ³ ;

V is N or CR ⁴ when U is NR ² ; And

V is NR ⁵ when U is CR ³ ;

X is CR ⁶ or N;

Y is CR ⁷ or N;

Z is CR ⁸ or N;

R ² and R ³ are H, C ₁ -C ₅ alkyl, C ₁ -C ₅ fluoroalkyl, C ₃ -C ₈ cycloalkyl, or 3-6 membered heterocyclyl, wherein said C ₁ -C ₅ alkyl and C ₁ are each -C ₅ fluoroalkyl is optionally substituted with R ²⁰ and each of said C ₃ -C ₈ cycloalkyl and 3-6 membered heterocyclyl is optionally substituted with R ²¹ ;

R ⁴ is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy or C ₁ -C ₄ fluoroalkoxy, wherein each is C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ fluoroalkoxy are optionally substituted with R ²⁰ ; And

R ⁵ is H, C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with R ²⁰ ; or

R ² may be taken together with R ⁴ or R ³ may be taken together with R ⁵ to form a 5-7 membered heterocyclic ring optionally containing an additional heteroatom selected from NR ²⁴ , O and S(O) _m as a member rings, the ring being optionally substituted with R ²¹ ;

R ⁶ is H, F, Cl, CN, CH ₃ , CH ₂ F, CHF ₂ or CF ₃ ;

R ⁷ and R ⁸ are independently H, F, Cl, CN, C ₁ -C ₂ alkyl, C ₁ -C ₂ fluoroalkyl, C ₁ -C ₂ alkoxy, or C ₁ -C ₂ fluoroalkoxy, wherein each C ₁ -C ₂ alkyl, C ₁ -C ₂ fluoroalkyl, C ₁ -C ₂ alkoxy and C ₁ -C ₂ fluoroalkoxy are optionally substituted with R ²⁰ ;

R ⁹ is H, OH, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ ;

each R ¹⁰ is independently F, CN, C ₁ -C ₂ alkyl, or C ₁ -C ₂ fluoroalkyl, wherein each said C ₁ -C ₂ alkyl and C ₁ -C ₂ fluoroalkyl is optionally substituted with R ²⁰ ;

Q is NR ¹¹ or O or

Q is CR ¹² R ¹³ in which R ¹² and R ¹³ are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing NR ¹¹ or O as a ring member, the ring optionally further substituted with R ¹⁰ ;

R ¹¹ is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, SO ₂ R ¹⁴ , SO ₂ NR ¹⁵ R ¹⁶ , COR ¹⁷ , COOR ¹⁷ or CONR ¹⁸ R ¹⁹ ;

R ¹⁴ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl;

each R ¹⁵ and R ¹⁶ is independently H or CH ₃ ;

R ¹⁷ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with R ²⁰ ;

each R ¹⁸ and R ¹⁹ is independently H, C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each said C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with R ²⁰ ;

each R ²⁰ is independently OH, C ₁ -C ₂ alkoxy, C ₁ -C ₂ fluoroalkoxy, CN or NR ²² R ²³ ;

each R ²¹ is independently F, OH, CN, NR ²² R ²³ , C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy or C ₁ -C ₄ fluoroalkoxy, in which each specified C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ fluoroalkoxy optionally further substituted with OH, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ ;

each R ²² and R ²³ is independently H, C ₁ -C ₂ alkyl or C ₁ -C ₂ fluoroalkyl or

R ²² and R ²³ may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring which is optionally substituted with F or OH;

R ²⁴ is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, SO ₂ R ²⁵ , SO ₂ NR ²⁶ R ²⁷ , COR ²⁸ , COOR ²⁸ or CONR ²⁹ R ³⁰ ;

R ²⁵ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl;

each R ²⁶ and R ²⁷ is independently H or CH ₃ ;

R ²⁸ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with OH, C ₁ -C ₂ alkoxy, C ₁ -C ₂ fluoroalkoxy, CN, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ ;

each R ²⁹ and R ³⁰ is independently H, C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each said C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with OH, C ₁ -C ₂ alkoxy, C ₁ -C ₂ fluoroalkoxy, CN, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ ;

m is 0, 1 or 2;

n is 0, 1, 2, 3, or 4;

p is equal to 1, 2 or 3 and

q is 0, 1, 2 or 3;

in which the sum of p and q is an integer from 1 to 4.

In frequent embodiments of Formula (IV) and Formula (V), R ² is taken together with R ⁴ or R ³ is taken together with R ⁵ to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR ²⁴ , O and S(O) _m as a ring member, the ring being optionally substituted with R ²¹ .

In some embodiments, compounds of Formulas (I)-(V) have absolute stereochemistry as shown in one of Formulas (I-A), (I-B), (I-C) or (I-D); (II-A), (II-B), (II-C) or (II-D); (III-A), (III-B), (III-C) or (III-D); (IV-A), (IV-B), (IV-C) or (IV-D) and (V-A), (V-B), (V-C) or (V-D):

in which A in Formulas (I-A)-(I-D) represents N or CH; A in Formulas (II-A)-(II-D) is substituted with N; A in Formulas (III-A)-(III-D) is substituted with CH; A in Formulas (IV-A)-(IV-D) is substituted with N and A in Formulas (V-A)-(V-D) is substituted with CH; or a pharmaceutically acceptable salt of one of the above.

Each of the aspects and embodiments described herein with respect to Formula (I) is also applicable to compounds of Formulas (I-A), (I-B), (I-C) or (I-D).

Each of the aspects and embodiments described herein with respect to Formula (II) is also applicable to compounds of Formulas (II-A), (II-B), (II-C) or (II-D).

Each of the aspects and embodiments described herein with respect to Formula (III) is also applicable to compounds of Formulas (III-A), (III-B), (III-C) or (III-D).

Each of the aspects and embodiments described herein with respect to Formula (IV) is also applicable to compounds of Formulas (IV-A), (IV-B), (IV-C) or (IV-D).

Each of the aspects and embodiments described herein with respect to Formula (V) is also applicable to compounds of Formulas (V-A), (V-B), (V-C) or (V-D).

In compounds of Formula (I), A is N or CH. In some embodiments, A is N. In other embodiments, A is CH.

In the compounds of Formula (I), R ¹ is H, F, Cl, CN, C ₁ -C ₂ alkyl, C ₁ -C ₂ fluoroalkyl, or C ₁ -C ₂ alkoxy, wherein said C ₁ -C ₂ alkyl and C ₁ -C ₂ fluoroalkyl is optionally substituted with R ²⁰ . In some embodiments, R ¹ is F or Cl. In some such embodiments, R ¹ is F. In some such embodiments, R ¹ is Cl.

In the compounds of Formula (I) U represents NR ² or CR ³ ; V is N or CR ⁴ when U is NR ² ; and V is NR ⁵ when U is CR ³ . In some embodiments, U is NR ² and V is N or CR ⁴ . In some such embodiments, U is NR ² and V is CR ⁴ . In some such embodiments, U is NR ² and V is N. In some embodiments, U is CR ³ and V is NR ⁵ .

In compounds of Formula (I), X is CR ⁶ or N. In some embodiments, X is CR ⁶ . In some embodiments, X is N.

In compounds of Formula (I), Y is CR ⁷ or N. In some embodiments, Y is CR ⁷ . In some embodiments, Y is N.

In compounds of Formula (I), Z is CR ⁸ or N. In some embodiments, Z is CR ⁸ . In some embodiments, Z is N.

In frequent embodiments of Formula (I), X is CR ⁶ , Y is CR ⁷ and Z is CR ⁸ . In other embodiments of Formula (I), at least one of X, Y, and Z is N.

In some embodiments of Formula (I), R ² and R ³ are H, C ₁ -C ₅ alkyl, C ₁ -C ₅ fluoroalkyl, C ₃ -C ₈ cycloalkyl, or 3-6 membered heterocyclyl, wherein each said C ₁ -C ₅ alkyl and C ₁ -C ₅ fluoroalkyl are optionally substituted with R ²⁰ and each of said C ₃ -C ₈ cycloalkyl and 3-6 membered heterocyclyl is optionally substituted with R ²¹ .

In some such embodiments, R ² and R ³ are H, C ₁ -C ₅ alkyl, or C ₁ -C ₅ fluoroalkyl, wherein said C ₁ -C ₅ alkyl and C ₁ -C ₅ fluoroalkyl are each optionally substituted with R ²⁰ . In other such embodiments, R ² and R ³ are C ₃ -C ₈ cycloalkyl or 3-6 membered heterocyclyl, wherein said C ₃ -C ₈ cycloalkyl and 3-6 membered heterocyclyl are each optionally substituted with R ²¹ .

In some embodiments of Formula (I), R ² is C ₁ -C ₅ alkyl or C ₁ -C ₅ fluoroalkyl, wherein each of said C ₁ -C ₅ alkyl and C ₁ -C ₅ fluoroalkyl is optionally substituted with R ²⁰ . In some embodiments of Formula (I), R ³ is C ₁ -C ₅ alkyl or C ₁ -C ₅ fluoroalkyl, wherein each of said C ₁ -C ₅ alkyl and C ₁ -C ₅ fluoroalkyl is optionally substituted with R ²⁰ .

In some embodiments of Formula (I), R ⁴ is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ fluoroalkoxy, C(O)R ^a , C (O)NR ^b ₂ , C ₃ -C ₈ cycloalkyl or 3-6 membered heterocyclyl; in which each specified C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ fluoroalkoxy is optionally substituted with R ²⁰ , each specified C ₃ -C ₈ cycloalkyl and 3-6-membered heterocyclyl is optionally substituted with R ²¹ , R ^a is C ₁ -C ₂ alkyl, and each R ^b is independently H or C ₁ -C ₂ alkyl.

In some such embodiments, R ⁴ is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy, or C ₁ -C ₄ fluoroalkoxy, wherein each said C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ fluoroalkoxy are optionally substituted with R ²⁰ . In some such embodiments, R ⁴ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein said C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl are each optionally substituted with R ²⁰ . In some such embodiments, R ²⁰ is OH. In other such embodiments, R ²⁰ is C ₃ -C ₈ cycloalkyl or 3-6 membered heterocyclyl, wherein said C ₃ -C ₈ cycloalkyl and 3-6 membered heterocyclyl are each optionally substituted with R ²¹ .

In other such embodiments, R ⁴ is C(O)R ^a or C(O)NR ^b ₂ , wherein R ^a is C ₁ -C ₂ alkyl and each R ^b is independently H or C ₁ -C ₂ alkyl. In still other such embodiments, R ⁴ is C ₃ -C ₈ cycloalkyl or 3-6 membered heterocyclyl, wherein said C ₃ -C ₈ cycloalkyl and 3-6 membered heterocyclyl are each optionally substituted with R ²¹ .

In some embodiments of Formula (I), R ⁵ is H, C ₁ -C ₄ alkyl, or C ₁ -C ₄ fluoroalkyl, wherein each of said C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with R ²⁰ .

In other embodiments of Formula (I), R ² may be taken together with R ⁴ or R ³ may be taken together with R ⁵ to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR ²⁴ , O and S (O) _m as a ring member, the ring being optionally substituted with R ²¹ .

In some embodiments of Formula (I), R ² is taken together with R ⁴ to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR ²⁴ , O, and S(O) _m as a ring member, the ring optionally substituted by R ²¹ . In some such embodiments, the 5-7 membered heterocyclic ring contains O as an additional heteroatom. In some such embodiments, the 5-7 membered heterocyclic ring contains NR ²⁴ as an additional heteroatom.

In some embodiments of Formula (I), R ³ is taken together with R ⁵ to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR ²⁴ , O, and S(O) _m as a ring member, the ring optionally substituted by R ²¹ . In some such embodiments, the 5-7 membered heterocyclic ring contains O as an additional heteroatom. In some such embodiments, the 5-7 membered heterocyclic ring contains NR ²⁴ as an additional heteroatom.

In compounds of Formula (I), R ⁶ is H, F, Cl, CN, CH ₃ , CH ₂ F, CHF ₂ or CF ₃ . In some embodiments, R ⁶ is F or Cl. In some such embodiments, R ⁶ is F. In some such embodiments, R ⁶ is Cl. In some embodiments, R ⁶ is H. In other embodiments, R ⁶ is CN, CH ₃ , CH ₂ F, CHF _{2 ,} or CF ₃ .

In the compounds of Formula (I), R ⁷ and R ⁸ are independently H, F, Cl, CN, C ₁ -C ₂ alkyl, C ₁ -C ₂ fluoroalkyl, C ₁ -C ₂ alkoxy or C ₁ -C ₂ fluoroalkoxy, in which each specified C ₁ -C ₂ alkyl, C ₁ -C ₂ fluoroalkyl, C ₁ -C ₂ alkoxy and C ₁ -C ₂ fluoroalkoxy is optionally substituted with R ²⁰ . In some such embodiments, R ⁷ is H. In some such embodiments, R ⁸ is H. In some such embodiments, R ⁷ and R ⁸ are H.

In compounds of Formula (I), R ⁹ is H, OH, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ . In preferred embodiments of Formula (I), R ⁹ is OH.

In the compounds of Formula (I), each R ¹⁰ is independently F, CN, C ₁ -C ₂ alkyl or C ₁ -C ₂ fluoroalkyl, wherein each said C ₁ -C ₂ alkyl and C ₁ -C ₂ fluoroalkyl is optionally substituted with R ²⁰ . In some embodiments, n is 0 and R ¹⁰ is absent. In other embodiments, n is 1 or 2 and R ¹⁰ is independently F, CN, C ₁ -C ₂ alkyl, or C ₁ -C ₂ fluoroalkyl. In some embodiments, n is 1 or 2 and R ¹⁰ is independently F or CH ₃ .

In some embodiments of Formula (I), Q is NR ¹¹ or O. In some embodiments, Q is O. In some embodiments, Q is O, p is 2, and q is 1. In some such embodiments, n is 0 and R ¹⁰ is missing.

In other embodiments of Formula (I), Q is NR ¹¹ . In some embodiments, Q is NR ¹¹ , p is 2, and q is 1. In some such embodiments, R ¹¹ is SO ₂ R ¹⁴ . In other such embodiments, R ¹¹ is COR ¹⁷ . In some such embodiments, n is 0 and R ¹⁰ is absent.

In some embodiments of Formula (I), Q is CR ¹² R ¹³ in which R ¹² and R ¹³ are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing NR ¹¹ or O in as a ring member, the ring being optionally further substituted with R ¹⁰ . In some such embodiments, n is 0 and R ¹⁰ is absent.

In compounds of Formula (I) R ¹¹ is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, SO ₂ R ¹⁴ , SO ₂ NR ¹⁵ R ¹⁶ , COR ¹⁷ , COOR ¹⁷ or CONR ¹⁸ R ¹⁹ , in in which each specified C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with R ²⁰ , SO ₂ R ¹⁴ , SO ₂ NR ¹⁵ R ¹⁶ , COR ¹⁷ , COOR ¹⁷ or CONR ¹⁸ R ¹⁹ .

In some embodiments, R ¹¹ is SO ₂ R ¹⁴ . In other embodiments, R ¹¹ is COR ¹⁷ . In yet other embodiments, R ¹¹ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each of said C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with R ²⁰ , SO ₂ R ¹⁴ , SO ₂ NR ¹⁵ R ¹⁶ , COR ¹⁷ , COOR ¹⁷ or CONR ¹⁸ R ¹⁹ . In some such embodiments, R ¹¹ is C ₁ -C ₄ alkyl substituted with SO ₂ R ¹⁴ or COR ¹⁷ . In some such embodiments, R ¹¹ is C ₁ -C ₄ alkyl substituted with R ²⁰ .

In compounds of Formula (I) R ¹⁴ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl. In some embodiments, R ¹⁴ is C ₁ -C ₄ alkyl. In some such embodiments, R ¹⁴ is C ₁ -C ₂ alkyl. In some embodiments, R ¹⁴ is C ₁ -C ₄ fluoroalkyl. In some such embodiments, R ¹⁴ is C ₁ -C ₂ fluoroalkyl. In certain embodiments, R ¹⁴ is CH ₃ or C ₂ H ₅ .

In the compounds of Formula (I), each R ¹⁵ and R ¹⁶ is independently H or CH ₃ .

In the compounds of Formula (I) R ¹⁷ is C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₃ -C ₈ cycloalkyl or 3-6 membered heterocyclyl, in which each of the specified C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with R ²⁰ and each of said C ₃ -C ₈ cycloalkyl and 3-6 membered heterocyclyl is optionally substituted with R ²¹ . In some embodiments, R ¹⁷ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each of said C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with R ²⁰ . In some embodiments, R ¹⁷ is C ₃ -C ₈ cycloalkyl or 3-6 membered heterocyclyl, wherein each said C ₃ -C ₈ cycloalkyl and 3-6 membered heterocyclyl is optionally substituted with R ²¹ .

In the compounds of Formula (I), each R ¹⁸ and R ¹⁹ is independently H, C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein said C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl are each optionally substituted ^R20 .

In the compounds of Formula (I), each R ²⁰ is independently OH, C ₁ -C ₂ alkoxy, C ₁ -C ₂ fluoroalkoxy, CN, NR ²² R ²³ , C ₃ -C ₈ cycloalkyl or 3-6 membered heterocyclyl, in wherein each said C ₃ -C ₈ cycloalkyl and 3-6 membered heterocyclyl is optionally substituted with R ²¹ .

In some embodiments, each R ²⁰ is independently OH, C ₁ -C ₂ alkoxy, C ₁ -C ₂ fluoroalkoxy, CN, or NR ²² R ²³ . In some such embodiments, R ²⁰ is OH. In some such embodiments, R ²⁰ is OH, C ₁ -C ₂ alkoxy, or NR ²² R ²³ . In some such embodiments, R ²⁰ is OH. In some embodiments, R ²⁰ is C ₃ -C ₈ cycloalkyl or 3-6 membered heterocyclyl, wherein each of said C ₃ -C ₈ cycloalkyl and 3-6 membered heterocyclyl is optionally substituted with R ²¹ .

In the compounds of Formula (I), each R ²¹ is independently F, OH, CN, NR ²² R ²³ , C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy, or C ₁ -C ₄ fluoroalkoxy in which each specified C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ fluoroalkoxy is optionally further substituted with OH, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ . In some embodiments, each R ²¹ is independently F, OH, or C ₁ -C ₄ alkyl.

In some embodiments of Formula (I), each R ²² and R ²³ is independently H, C ₁ -C ₃ alkyl, C ₁ -C ₃ fluoroalkyl, C ₃ -C ₈ cycloalkyl, or 3-6 membered heterocyclyl, wherein each said C ₁ -C ₃ alkyl and C ₁ -C ₃ fluoroalkyl optionally further substituted with OH, C ₁ -C ₂ alkoxy or C ₁ -C ₂ fluoroalkoxy and each said C ₃ -C ₈ cycloalkyl and 3-6 membered heterocyclyl optionally further substituted with F, OH, C ₁ -C ₂ alkyl, C ₁ -C ₂ fluoroalkyl, C ₁ -C ₂ alkoxy, or C ₁ -C ₂ fluoroalkoxy.

In some such embodiments, each R ²² and R ²³ is independently H, C ₁ -C ₂ alkyl, or C ₁ -C ₂ fluoroalkyl. In some such embodiments, each R ²² and R ²³ is independently H, C ₁ -C ₂ alkyl, or C ₁ -C ₂ fluoroalkyl.

In some embodiments of Formula (I), R ²² and R ²³ may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring, wherein said ring is optionally substituted with F, OH, C ₁ -C ₂ alkyl, C ₁ -C ₂ fluoroalkyl, C ₁ -C ₂ alkoxy or C ₁ -C ₂ fluoroalkoxy. In some such embodiments, R ²² and R ²³ may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring which is optionally substituted with F, OH, or C ₁ -C ₂ alkyl.

In compounds of Formula (I) R ²⁴ is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, SO ₂ R ²⁵ , SO ₂ NR ²⁶ R ²⁷ , COR ²⁸ , COOR ²⁸ or CONR ²⁹ R ³⁰ . In some embodiments, R ²⁴ is H or C ₁ -C ₄ alkyl. In some embodiments, R ²⁴ is H or C ₁ -C ₂ alkyl.

In compounds of Formula (I) R ²⁵ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl. In some embodiments, R ²⁵ is C ₁ -C ₂ alkyl.

In the compounds of Formula (I), each R ²⁶ and R ²⁷ is independently H or CH ₃ .

In compounds of Formula (I), R ²⁸ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each of said C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with OH, C ₁ -C ₂ alkoxy, C ₁ -C ₂ fluoroalkoxy, CN, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ . In some embodiments, R ²⁸ is C ₁ -C ₄ alkyl optionally substituted with OH or C ₁ -C ₂ alkoxy. In some embodiments, R ²⁸ is C ₁ -C ₂ alkyl.

In the compounds of Formula (I), each R ²⁹ and R ³⁰ is independently H, C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein said C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl are each optionally substituted OH, C ₁ -C ₂ alkoxy, C ₁ -C ₂ fluoroalkoxy, CN, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ . In some embodiments, each R ²⁹ and R ³⁰ is independently H or C ₁ -C ₄ alkyl, wherein each said C ₁ -C ₄ alkyl is optionally substituted with OH or C ₁ -C ₂ alkoxy. In some embodiments, each R ²⁹ and R ³⁰ is independently H or C ₁ -C ₂ alkyl.

In compounds of Formula (I), m is 0, 1, or 2. In some embodiments, m is 2.

In compounds of Formula (I), n is 0, 1, 2, 3, or 4. In some embodiments, n is 0 and R ¹⁰ is absent. In some embodiments, n is 1 or 2.

In the compounds of Formula (I) p is 1, 2 or 3; in which the sum of p and q is an integer from 1 to 4. In some embodiments, p is 2. In other embodiments, p is 1. In some embodiments, the sum of p and q is an integer from 1 to 3.

In the compounds of Formula (I), q is 0, 1, 2 or 3; in which the sum of p and q is an integer from 1 to 4. In some embodiments, q is 1. In other embodiments, q is 0. In some embodiments, the sum of p and q is an integer from 1 to 3.

In some embodiments, p is 2 and q is 1. In other embodiments, p is 1 and q is 1. In other embodiments, p is 1 and q is 0. In further embodiments, the sum of p and q is an integer of 1 until 3.

In certain embodiments, the invention provides a compound of Formula (I), (IA), (IB), (IC), or (ID), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more of the following features: A is N; R ¹ is Cl; U is NR ² and V is CR ⁴ ; R ² is C ₁ -C ₅ alkyl or R ² is ISO-C ₃ H ₇ ; R ⁴ is C ₁ -C ₄ alkyl, wherein said C ₁ -C ₄ alkyl is optionally substituted with R ²⁰ , in which R ²⁰ is OH; or R ⁴ is CH(OH)CH ₃ or C(OH)(CH ₃ ) ₂ ; X is CR ⁶ ; R ⁶ is F; Y is CR ⁷ ; R ⁷ is H; Z is CR ⁸ ; R ⁸ is H; R ⁹ is OH; Q is O or Q is NR ¹¹ in which R ¹¹ is SO ₂ R ¹⁴ ; R ¹⁴ is C ₁ -C ₄ alkyl; n is 0 and R ¹⁰ is absent; p is 2 and q is 1.

In certain embodiments, the invention provides a compound of Formula (I), (IA), (IB), (IC), or (ID), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more of the following features: A is N; R ¹ is Cl; U is CR ³ and V is NR ⁵ ; R ³ is C ₁ -C ₅ alkyl or R ³ is ISO-C ₃ H ₇ ; R ⁵ is C ₁ -C ₄ alkyl, wherein said C ₁ -C ₄ alkyl is optionally substituted with R ²⁰ , wherein R ²⁰ is OH; X is CR ⁶ ; R ⁶ is F; Y is CR ⁷ ; R ⁷ is H; Z is CR ⁸ ; R ⁸ is H; R ⁹ is OH; Q is O or Q is NR ¹¹ in which R ¹¹ is SO ₂ R ¹⁴ ; R ¹⁴ is C ₁ -C ₄ alkyl; n is 0 and R ¹⁰ is absent; p is 2 and q is 1.

In a preferred embodiment, the invention provides a compound of Formula (I), (IA), (IB), (IC) or (ID) or a pharmaceutically acceptable salt thereof, wherein: A is N; R ¹ is Cl; U is NR ² ; R ² is C ₁ -C ₅ alkyl or R ² is ISO-C ₃ H ₇ ; V is CR ⁴ ; R ⁴ is C ₁ -C ₄ alkyl optionally substituted with R ²⁰ in which R ²⁰ is OH; or R ⁴ is CH(OH)CH ₃ or C(OH)(CH ₃ ) ₂ ; X is CR ⁶ ; R ⁶ is F; Y is CR ⁷ ; R ⁷ is H; Z is CR ⁸ ; R ⁸ is H; R ⁹ is OH; Q is O; n is 0 and R ¹⁰ is absent; p is 2 and q is 1.

In another preferred embodiment, the invention provides a compound of Formula (I), (IA), (IB), (IC) or (ID) or a pharmaceutically acceptable salt thereof, wherein: A is N; R ¹ is Cl; U is NR ² ; R ² is C ₁ -C ₅ alkyl or R ² is ISO-C ₃ H ₇ ; V is CR ⁴ ; R ⁴ is C ₁ -C ₄ alkyl optionally substituted with R ²⁰ in which R ²⁰ is OH; or R ⁴ is CH(OH)CH ₃ or C(OH)(CH ₃ ) ₂ ; X is CR ⁶ ; R ⁶ is F; Y is CR ⁷ ; R ⁷ is H; Z is CR ⁸ ; R ⁸ is H; R ⁹ is OH; Q is NR ¹¹ in which R ¹¹ is SO ₂ R ¹⁴ ; R ¹⁴ is C ₁ -C ₄ alkyl; n is 0 and R ¹⁰ is absent; p is 2 and q is 1.

In another embodiment, the invention provides a compound of Formula (I), (IA), (IB), (IC) or (ID), or a pharmaceutically acceptable salt thereof, wherein: A is N; R ¹ is Cl; U is NR ² ; R ² is C ₁ -C ₅ alkyl or R ² is ISO-C ₃ H ₇ ; V is CR ⁴ ; R ⁴ is C ₁ -C ₄ alkyl optionally substituted with R ²⁰ in which R ²⁰ is OH; or R ⁴ is CH(OH)CH ₃ or C(OH)(CH ₃ ) ₂ ; X is CR ⁶ ; R ⁶ is F; Y is CR ⁷ ; R ⁷ is H; Z is CR ⁸ ; R ⁸ is H; R ⁹ is OH; Q is O; n is 0 and R ¹⁰ is absent; p is 2 and q is 1.

In another preferred embodiment, the invention provides a compound of Formula (I), (IA), (IB), (IC) or (ID) or a pharmaceutically acceptable salt thereof, wherein: A is CH; R ¹ is Cl; U is NR ² ; R ² is C ₁ -C ₅ alkyl or R ² is ISO-C ₃ H ₇ ; V is CR ⁴ ; R ⁴ is C ₁ -C ₄ alkyl optionally substituted with R ²⁰ in which R ²⁰ is OH; or R ⁴ is CH(OH)CH ₃ or C(OH)(CH ₃ ) ₂ ; X is CR ⁶ ; R ⁶ is F; Y is CR ⁷ ; R ⁷ is H; Z is CR ⁸ ; R ⁸ is H; R ⁹ is OH; Q is NR ¹¹ in which R ¹¹ is SO ₂ R ¹⁴ ; R ¹⁴ is C ₁ -C ₄ alkyl; n is 0 and R ¹⁰ is absent; p is 2 and q is 1.

In certain embodiments, the invention provides a compound of Formula (I), (IA), (IB), (IC), or (ID), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more of the following features: A is CH; R ¹ is Cl; U is CR ³ and V is NR ⁵ ; R ³ is C ₁ -C ₅ alkyl or R ³ is ISO-C ₃ H ₇ ; R ⁵ is C ₁ -C ₄ alkyl, wherein said C ₁ -C ₄ alkyl is optionally substituted with R ²⁰ , wherein R ²⁰ is OH; X is CR ⁶ ; R ⁶ is F; Y is CR ⁷ ; R ⁷ is H; Z is CR ⁸ ; R ⁸ is H; R ⁹ is OH; Q is O or Q is NR ¹¹ in which R ¹¹ is SO ₂ R ¹⁴ ; R ¹⁴ is C ₁ -C ₄ alkyl; n is 0 and R ¹⁰ is absent; p is 2 and q is 1.

Each of the aspects and embodiments described herein with respect to Formula (I) is also applicable to compounds of Formulas (II)-(XII) that do not conflict with that aspect or embodiment.

In compounds of Formula (II), R ¹ is H, F, Cl, CN, C ₁ -C ₂ alkyl or C ₁ -C ₂ fluoroalkyl, wherein each of said C ₁ -C ₂ alkyl and C ₁ -C ₂ fluoroalkyl is optional substituted by R ²⁰ . In some embodiments, R ¹ is F or Cl. In some embodiments, R ¹ is F. In some embodiments, R ¹ is Cl.

In compounds of Formula (II), X is CR ⁶ or N. In some embodiments, X is CR ⁶ . In some embodiments, X is N.

In compounds of Formula (II), Y is CR ⁷ or N. In some embodiments, Y is CR ⁷ . In some embodiments, Y is N.

In compounds of Formula (II), Z is CR ⁸ or N. In some embodiments, Z is CR ⁸ . In some embodiments, Z is N.

In frequent embodiments of Formula (II), X is CR ⁶ , Y is CR ⁷ and Z is CR ⁸ . In other embodiments of Formula (II), at least one of X, Y, and Z is N.

In the compounds of Formula (II) U represents NR ² or CR ³ ; V is N or CR ⁴ when U is NR ² ; and V is NR ⁵ when U is CR ³ . In some embodiments, U is NR ² and V is N or CR ⁴ . In some such embodiments, U is NR ² and V is CR ⁴ . In some such embodiments, U is NR ² and V is N. In other embodiments, U is CR ³ and V is NR ⁵ .

In some embodiments of Formula (II), U is NR ² and R ² is H, C ₁ -C ₅ alkyl, C ₁ -C ₅ fluoroalkyl, C ₃ -C ₈ cycloalkyl, or 3-6 membered heterocyclyl, wherein each said C ₁ -C ₅ alkyl and C ₁ -C ₅ fluoroalkyl is optionally substituted with R ²⁰ and each said C ₃ -C ₈ cycloalkyl and 3-6 membered heterocyclyl is optionally substituted with R ²¹ .

In compounds of Formula (II), R ² and R ³ are H, C ₁ -C ₅ alkyl, C ₁ -C ₅ fluoroalkyl, C ₃ -C ₈ cycloalkyl, or 3-6 membered heterocyclyl, wherein each C ₁ - C ₅ alkyl and C ₁ -C ₅ fluoroalkyl are optionally substituted with R ²⁰ and each of said C ₃ -C ₈ cycloalkyl and 3-6 membered heterocyclyl is optionally substituted with R ²¹ .

In some such embodiments, R ² is C ₁ -C ₅ alkyl or C ₁ -C ₅ fluoroalkyl, wherein said C ₁ -C ₅ alkyl and C ₁ -C ₅ fluoroalkyl are each optionally substituted with R ²⁰ . In some such embodiments, R ² is C ₁ -C ₅ alkyl optionally substituted with R ²⁰ . In some such embodiments, R ²⁰ is OH. In certain embodiments, R ² is CH ₃ , C ₂ H ₅ , n-C ₃ H ₇ , iso-C ₃ H ₇ , n-C ₄ H ₉ , sec-C ₄ H ₉ , iso-C ₄ H _{9 each _ _ _ _} optionally substituted R ²⁰ . In certain embodiments, R ² is isopropyl or tert-butyl. In certain embodiments, R ² is isopropyl (iso-C ₃ H ₇ ). In some embodiments, R ² is C ₁ -C ₅ alkyl or C ₁ -C ₅ fluoroalkyl optionally substituted with R ²⁰ , wherein R ²⁰ is OH.

In other embodiments, R ² is C ₃ -C ₈ cycloalkyl or 3-6 membered heterocyclyl, wherein each said C ₃ -C ₈ cycloalkyl and 3-6 membered heterocyclyl is optionally substituted with R ²¹ . In some such embodiments, R ² is 3-6 membered heterocyclyl optionally substituted with R ²¹ . In certain embodiments, R ² is oxetan-3-yl or azetidin-3-yl, each optionally substituted with R ²¹ . In certain embodiments, R ² is oxetan-3-yl. In other embodiments, R ² is C ₃ -C ₈ cycloalkyl, wherein said C ₃ -C ₈ cycloalkyl is optionally substituted with R ²¹ . In some such embodiments, R ²¹ is F, OH, or C ₁ -C ₄ alkyl.

In some embodiments of the foregoing in which U is NR ² , V is N. In other embodiments of the foregoing in which U is NR ² , V is CR ⁴ .

In other embodiments of Formula (II), U is CR ³ and R ³ is H, C ₁ -C ₅ alkyl, C ₁ -C ₅ fluoroalkyl, C ₃ -C ₈ cycloalkyl, or 3-6 membered heterocyclyl, wherein each said C ₁ -C ₅ alkyl and C ₁ -C ₅ fluoroalkyl is optionally substituted with R ²⁰ and each said C ₃ -C ₈ cycloalkyl and 3-6 membered heterocyclyl is optionally substituted with R ²¹ .

In some such embodiments, R ³ is C ₁ -C ₅ alkyl or C ₁ -C ₅ fluoroalkyl, wherein said C ₁ -C ₅ alkyl and C ₁ -C ₅ fluoroalkyl are each optionally substituted with R ²⁰ . In some such embodiments, R ³ is C ₁ -C ₅ alkyl optionally substituted with R ²⁰ . In some such embodiments, R ²⁰ is OH or NR ²² R ²³ . In some such embodiments, R ²⁰ is OH. In some such embodiments, R ³ is CH ₃ , C ₂ H ₅ , n-C ₃ H ₇ , iso-C ₃ H ₇ , n-C ₄ H ₉ , sec-C ₄ H ₉ , iso-C ₄ H ₉ , t-C ₄ H ₉ , CHF ₂ , or CH ₂ CHF ₂ , each optionally substituted with R ²⁰ . In certain embodiments, R ³ is iso-C ₃ H ₇ or t-C ₄ H ₉ (ie, isopropyl or t-butyl). In certain embodiments, R ² is isopropyl.

In other embodiments, R ³ is C ₃ -C ₈ cycloalkyl or 3-6 membered heterocyclyl, wherein each said C ₃ -C ₈ cycloalkyl and 3-6 membered heterocyclyl is optionally substituted with R ²¹ . In some such embodiments, R ³ is 3-6 membered heterocyclyl optionally substituted with R ²¹ . In certain embodiments, R ³ is oxetan-3-yl or azetidin-3-yl optionally substituted with R ²¹ . In some such embodiments, R ²¹ is F, OH, or C ₁ -C ₄ alkyl. In certain embodiments, R ³ is oxetan-3-yl. In other embodiments, R ³ is C ₃ -C ₈ cycloalkyl, wherein said C ₃ -C ₈ cycloalkyl is optionally substituted with R ²¹ . In some such embodiments, R ²¹ is F, OH, or C ₁ -C ₄ alkyl.

In the above embodiments where U is CR ³ , V is NR ⁵ .

In some embodiments of Formula (II), V is CR ⁴ when U is NR ² .

In compounds of Formula (II), R ⁴ is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy or C ₁ -C ₄ fluoroalkoxy, wherein each C ₁ -C ₄ alkyl , C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ fluoroalkoxy are optionally substituted with R ²⁰ . In some embodiments, R ⁴ is H. In other embodiments, R ⁴ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each of said C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with R ²⁰ . In some such embodiments, R ⁴ is C ₁ -C ₄ alkyl optionally substituted with R ²⁰ . In some such embodiments, R ²⁰ is OH, OCH ₃ , NH ₂ , NHCH _{3 ,} or NH(CH ₃ ) ₂ . In some such embodiments, R ²⁰ is OH or NH ₂ . In some such embodiments, R ²⁰ is OH. In certain embodiments, R ⁴ is C ₁ -C ₂ alkyl optionally substituted with R ²⁰ , wherein R ²⁰ is OH or NH ₂ . In certain embodiments, R ⁴ optionally substituted with R ²⁰ (i.e., R ⁴ -R ²⁰ ) is H, CH ₃ , C ₂ H ₅ , CH ₂ OH, CH(OH)CH ₃ , CH ₂ CH ₂ OH or CH ₂ NH ₂ (i.e. methyl, ethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl or aminomethyl). In some embodiments, R ⁴ substituted with R ²⁰ is CH(OH)CH ₃ or C(OH)(CH ₃ ) ₂ . In other such embodiments, R ⁴ is C ₁ -C ₄ fluoroalkyl optionally substituted with R ²⁰ . In other embodiments, R ⁴ is C ₁ -C ₄ alkoxy or C ₁ -C ₄ fluoroalkoxy, wherein each of said C ₁ -C ₄ alkoxy and C ₁ -C ₄ fluoroalkoxy is optionally substituted with R ²⁰ .

In some embodiments of Formula (II), V is NR ⁵ when U is CR ³ .

In the compounds of Formula (II), R ⁵ is H, C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each said C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with R ²⁰ . In some embodiments, R ⁵ is H. In other embodiments, R ⁵ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each of said C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with R ²⁰ . In some such embodiments, R ⁵ is C ₁ -C ₄ alkyl optionally substituted with R ²⁰ . In other such embodiments, R ⁵ is C ₁ -C ₄ fluoroalkyl optionally substituted with R ²⁰ . In certain embodiments, R ⁵ is C ₁ -C ₂ alkyl or C ₁ -C ₂ fluoroalkyl. In certain embodiments, R ⁵ is CH ₃ , C ₂ H ₅ , CHF _{2 ,} or CH ₂ CHF ₂ (ie, methyl, ethyl, difluoromethyl, or difluoroethyl).

In compounds of Formula (II), R ⁶ is H, F, Cl, CN, CH ₃ , CH ₂ F, CHF ₂ or CF ₃ . In some embodiments, R ⁶ is H. In other embodiments, R ⁶ is F. In other embodiments, R ⁶ is Cl. In additional embodiments, R ⁶ is CN. In other embodiments, R ⁶ is CH ₃ , CH ₂ F, CHF ₂ or CF ₃ .

In the compounds of Formula (II), R ⁷ and R ⁸ are independently H, F, Cl, CN, C ₁ -C ₂ alkyl, C ₁ -C ₂ fluoroalkyl, C ₁ -C ₂ alkoxy or C ₁ -C ₂ fluoroalkoxy, in which each specified C ₁ -C ₂ alkyl, C ₁ -C ₂ fluoroalkyl, C ₁ -C ₂ alkoxy and C ₁ -C ₂ fluoroalkoxy is optionally substituted with R ²⁰ .

In some embodiments of Formula (II), R ⁷ is H. In other embodiments, R ⁷ is F or Cl. In additional embodiments, R ⁷ is C ₁ -C ₂ alkyl or C ₁ -C ₂ fluoroalkyl, wherein each of said C ₁ -C ₂ alkyl and C ₁ -C ₂ fluoroalkyl is optionally substituted with R ²⁰ . In some such embodiments, R ⁷ is CH ₃ optionally substituted with R ²⁰ . In some embodiments, R ⁷ is CH ₃ .

In some embodiments of Formula (II), R ⁸ is H. In other embodiments, R ⁸ is F or Cl. In additional embodiments, R ⁸ is C ₁ -C ₂ alkyl or C ₁ -C ₂ fluoroalkyl, wherein each of said C ₁ -C ₂ alkyl and C ₁ -C ₂ fluoroalkyl is optionally substituted with R ²⁰ . In some such embodiments, R ⁸ is CH ₃ optionally substituted with R ²⁰ . In some embodiments, R ⁸ is CH ₃ .

In some embodiments, R ⁷ and R ⁸ are H.

In compounds of Formula (II) R ⁹ is H, OH, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ . In some preferred embodiments, R ⁹ is OH. In other embodiments, R ⁹ is NH ₂ , NHCH _{3 ,} or N(CH ₃ ) ₂ . In additional embodiments, R ⁹ is H.

In the compounds of Formula (II), each R ¹⁰ is independently F, CN, C ₁ -C ₂ alkyl or C ₁ -C ₂ fluoroalkyl, wherein each said C ₁ -C ₂ alkyl and C ₁ -C ₂ fluoroalkyl is optionally substituted with R ²⁰ . In some embodiments, n is 0 and R ¹⁰ is absent. In other embodiments, n is 1, 2, 3, or 4 and each R ¹⁰ is independently F, CN, C ₁ -C ₂ alkyl, or C ₁ -C ₂ fluoroalkyl, wherein each is C ₁ -C ₂ alkyl and C ₁ -C ₂ fluoroalkyl is optionally substituted with R ²⁰ . In other embodiments, n is 1 or 2 and R ¹⁰ is independently F, CN, C ₁ -C ₂ alkyl, or C ₁ -C ₂ fluoroalkyl. In some embodiments, n is 1 or 2 and R ¹⁰ is independently F or CH ₃ .

In compounds of Formula (II), Q is NR ¹¹ or O or Q is CR ¹² R ¹³ in which R ¹² and R ¹³ are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring, containing NR ¹¹ or O as a ring member, the ring being optionally further substituted with R ¹⁰ .

In some embodiments of Formula (II), Q is NR ¹¹ . In some embodiments, Q is NR ¹¹ , p is 2, and q is 1. In some such embodiments, R ¹¹ is SO ₂ R ¹⁴ . In other such embodiments, R ¹¹ is COR ¹⁷ . In some such embodiments, n is 0 and R ¹⁰ is absent.

In compounds of Formula (II) R ¹¹ is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, SO ₂ R ¹⁴ , SO ₂ NR ¹⁵ R ¹⁶ , COR ¹⁷ , COOR ¹⁷ or CONR ¹⁸ R ¹⁹ . In some embodiments, R ¹¹ is H, C ₁ -C ₄ alkyl, or C ₁ -C ₄ fluoroalkyl. In some embodiments, R ¹¹ is H. In other embodiments, R ¹¹ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl. In some embodiments, R ¹¹ is C ₁ -C ₄ alkyl. In other embodiments, R ¹¹ is C ₁ -C ₄ fluoroalkyl. In some embodiments, R ¹¹ is SO ₂ R ¹⁴ , SO ₂ NR ¹⁵ R ¹⁶ , COR ¹⁷ , COOR ¹⁷ or CONR ¹⁸ R ¹⁹ . In some embodiments, R ¹¹ is SO ₂ R ¹⁴ or SO ₂ NR ¹⁵ R ¹⁶ . In some embodiments, R ¹¹ is SO ₂ R ¹⁴ . In other embodiments, R ¹¹ is SO ₂ NR ¹⁵ R ¹⁶ . In some embodiments, R ¹¹ is COR ¹⁷ , COOR ¹⁷ , or CONR ¹⁸ R ¹⁹ . In some embodiments, R ¹¹ is COR ¹⁷ . In some embodiments, R ¹¹ is COOR ¹⁷ . In other embodiments, R ¹¹ is CONR ¹⁸ R ¹⁹ .

In other embodiments of Formula (II), Q is O. In some embodiments, Q is O, p is 2, and q is 1. In some such embodiments, n is 0 and R ¹⁰ is absent.

In additional embodiments of Formula (II), Q is CR ¹² R ¹³ wherein R ¹² and R ¹³ are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing NR ¹¹ or O in as a ring member, the ring being optionally further substituted with R ¹⁰ . In some such embodiments, R ¹² and R ¹³ are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing NR ¹¹ as a ring member, the ring being optionally further substituted with R ¹⁰ . In other such embodiments, R ¹² and R ¹³ are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing O as a ring member, the ring being optionally further substituted with R ¹⁰ . In some such embodiments, R ¹² and R ¹³ are taken together to form a 4-membered optionally substituted heterocyclic ring. In other such embodiments, R ¹² and R ¹³ are taken together to form a 5-membered optionally substituted heterocyclic ring. In other such embodiments, R ¹² and R ¹³ are taken together to form a 6-membered optionally substituted heterocyclic ring. In each case, said 4-6 membered heterocyclic ring contains NR ¹¹ or O as a ring member and is optionally further substituted with R ¹⁰ , wherein R ¹⁰ and R ¹¹ are each as further defined herein. In some such embodiments, n is 0 and R ¹⁰ is absent.

In the above embodiments, each R ¹⁰ is independently selected from the group as defined herein.

In compounds of Formula (II) R ¹⁴ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl. In some embodiments, R ¹⁴ is C ₁ -C ₄ alkyl. In some embodiments, R ¹⁴ is C ₁ -C ₄ fluoroalkyl. In certain embodiments, R ¹⁴ is CH ₃ or C ₂ H ₅ (ie, methyl or ethyl).

In the compounds of Formula (II), each R ¹⁵ and R ¹⁶ is independently H or CH ₃ .

In the compounds of Formula (II), R ¹⁷ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each of said C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with R ²⁰ . In some embodiments, R ¹⁷ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl. In some embodiments, R ¹⁷ is C ₁ -C ₄ alkyl optionally substituted with R ²⁰ . In some embodiments, R ¹⁷ is C ₁ -C ₄ fluoroalkyl optionally substituted with R ²⁰ . In certain embodiments, R ¹⁷ is CH ₃ or C ₂ H ₅ .

In the compounds of Formula (II), each R ¹⁸ and R ¹⁹ is independently H, C ₁ -C ₄ alkyl, or C ₁ -C ₄ fluoroalkyl, wherein said C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl are each optionally substituted ^R20 . In some embodiments, each R ¹⁸ and R ¹⁹ is independently H, C ₁ -C ₄ alkyl, or C ₁ -C ₄ fluoroalkyl. In some embodiments, each R ¹⁸ and R ¹⁹ is independently H or C ₁ -C ₄ alkyl optionally substituted with R ²⁰ . In some embodiments, each R ¹⁸ and R ¹⁹ is independently H or C ₁ -C ₄ fluoroalkyl optionally substituted with R ²⁰ . In certain embodiments, each R ¹⁸ and R ¹⁹ is independently H, CH ₃ or C ₂ H ₅ .

In the compounds of Formula (II), each R ²⁰ is independently OH, C ₁ -C ₂ alkoxy, C ₁ -C ₂ fluoroalkoxy, CN or NR ²² R ²³ . In some embodiments, R ²⁰ is OH. In some such embodiments, R ²⁰ is OH, C ₁ -C ₂ alkoxy, or NR ²² R ²³ . In other embodiments, R ²⁰ is C ₁ -C ₂ alkoxy or C ₁ -C ₂ fluoroalkoxy. In additional embodiments, R ²⁰ is CN. In yet other embodiments, R ²⁰ is NR ²² R ²³ .

In the compounds of Formula (II), each R ²¹ is independently F, OH, CN, NR ²² R ²³ , C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy, or C ₁ -C ₄ fluoroalkoxy in which each specified C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ fluoroalkoxy is optionally further substituted with OH, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ . In some embodiments, R ²¹ is F. In some embodiments, R ²¹ is OH. In some embodiments, each R ²¹ is independently F, OH, or C ₁ -C ₄ alkyl. In other embodiments, R ²¹ is CN. In other embodiments, R ²¹ is C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy, or C ₁ -C ₄ fluoroalkoxy, wherein each C ₁ -C ₄ alkyl, C ₁ - C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ fluoroalkoxy are optionally further substituted with OH, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ .

In the compounds of Formula (II), each R ²² and R ²³ is independently H, C ₁ -C ₂ alkyl or C ₁ -C ₂ fluoroalkyl; or R ²² and R ²³ may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring which is optionally substituted with F or OH.

In some embodiments, each R ²² and R ²³ is independently H, C ₁ -C ₂ alkyl, or C ₁ -C ₂ fluoroalkyl. In certain embodiments, each R ²² and R ²³ is independently H or CH ₃ . In other embodiments, R ²² and R ²³ are taken together with the nitrogen atom to which they are attached to form an azetidinyl ring which is optionally substituted with F or OH.

In compounds of Formula (II), n is 0, 1, 2, 3, or 4. In some embodiments, n is 0 and R ¹⁰ is absent. In other embodiments, n is 1, 2, 3, or 4 and R ¹⁰ is as defined herein. In some embodiments, n is 1 or 2.

In compounds of Formula (II), p is 1, 2 or 3 and q is 0, 1, 2 or 3; in which the sum of p and q is an integer from 1 to 4. In some embodiments, the sum of p and q is an integer from 1 to 3.

In some embodiments, p is 2 and q is 1. In other embodiments, p is 2 and q is 2. In some embodiments, p is 1 and q is 0. In other embodiments, p is 1 and q is 1. In still in other embodiments, p is 1 and q is 2. In additional embodiments, p is 1 and q is 3. In some embodiments, p is 2. In other embodiments, p is 1. In some embodiments, q is 1. In other embodiments, implementation q is 0.

In certain embodiments, the invention provides a compound of Formula (II), (II-A), (II-B), (II-C), or (II-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more and more preferably four or more of the following features: R ¹ is Cl; U is NR ² and V is CR ⁴ ; R ² is C ₁ -C ₅ alkyl or R ² is ISO-C ₃ H ₇ ; R ⁴ is C ₁ -C ₄ alkyl, wherein said C ₁ -C ₄ alkyl is optionally substituted with R ²⁰ , in which R ²⁰ is OH; or R ⁴ is CH(OH)CH ₃ or C(OH)(CH ₃ ) ₂ ; X is CR ⁶ ; R ⁶ is F; Y is CR ⁷ ; Z is CR ⁸ ; R ⁷ and R ⁸ are H; R ⁹ is OH; Q is O or Q is NR ¹¹ in which R ¹¹ is SO ₂ R ¹⁴ ; R ¹⁴ is C ₁ -C ₄ alkyl; n is 0 and R ¹⁰ is absent; p is 2 and q is 1.

In certain embodiments, the invention provides a compound of Formula (II), (II-A), (II-B), (II-C), or (II-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more and more preferably four or more of the following features: R ¹ is Cl; U is CR ³ and V is NR ⁵ ; R ³ is C ₁ -C ₅ alkyl or R ³ is ISO-C ₃ H ₇ ; R ⁵ is C ₁ -C ₄ alkyl, wherein said C ₁ -C ₄ alkyl is optionally substituted with R ²⁰ ; R ²⁰ is OH; X is CR ⁶ ; R ⁶ is F; Y is CR ⁷ ; Z is CR ⁸ ; R ⁷ and R ⁸ are H; R ⁹ is OH; Q is O or Q is NR ¹¹ where R ¹¹ is SO ₂ R ¹⁴ ; R ¹⁴ is C ₁ -C ₄ alkyl; n is 0 and R ¹⁰ is absent; p is 2 and q is 1.

In a preferred embodiment, the invention provides a compound of Formula (II), (II-A), (II-B), (II-C) or (II-D) or a pharmaceutically acceptable salt thereof, wherein: R ¹ is Cl; U is NR ² ; R ² is C ₁ -C ₅ alkyl or R ² is ISO-C ₃ H ₇ ; V is CR ⁴ ; R ⁴ is C ₁ -C ₄ alkyl optionally substituted with R ²⁰ in which R ²⁰ is OH; or R ⁴ is CH(OH)CH ₃ or C(OH)(CH ₃ ) ₂ ; X is CR ⁶ ; R ⁶ is F; Y is CR ⁷ ; R ⁷ is H; Z is CR ⁸ ; R ⁸ is H; R ⁹ is OH; Q is O; n is 0 and R ¹⁰ is absent; p is 2 and q is 1.

In another preferred embodiment, the invention provides a compound of Formula (II), (II-A), (II-B), (II-C) or (II-D) or a pharmaceutically acceptable salt thereof, wherein: R ¹ is Cl ; U is NR ² ; R ² is C ₁ -C ₅ alkyl or R ² is ISO-C ₃ H ₇ ; V is CR ⁴ ; R ⁴ is C ₁ -C ₄ alkyl optionally substituted with R ²⁰ in which R ²⁰ is OH; or R ⁴ is CH(OH)CH ₃ or C(OH)(CH ₃ ) ₂ ; X is CR ⁶ ; R ⁶ is F; Y is CR ⁷ ; R ⁷ is H; Z is CR ⁸ ; R ⁸ is H; R ⁹ is OH; Q is NR ¹¹ in which R ¹¹ is SO ₂ R ¹⁴ ; R ¹⁴ is C ₁ -C ₄ alkyl; n is 0 and R ¹⁰ is absent; p is 2 and q is 1.

In compounds of Formula (III) R ¹ is H, F, Cl, CN, C ₁ -C ₂ alkyl or C ₁ -C ₂ fluoroalkyl, wherein each of said C ₁ -C ₂ alkyl and C ₁ -C ₂ fluoroalkyl is optional substituted by R ²⁰ . In some embodiments, R ¹ is F or Cl. In some embodiments, R ¹ is F. In some embodiments, R ¹ is Cl.

In compounds of Formula (III), X is CR ⁶ or N. In some embodiments, X is CR ⁶ . In some embodiments, X is N.

In compounds of Formula (III), Y is CR ⁷ or N. In some embodiments, Y is CR ⁷ . In some embodiments, Y is N.

In compounds of Formula (III), Z is CR ⁸ or N. In some embodiments, Z is CR ⁸ . In some embodiments, Z is N.

In frequent embodiments of Formula (III), X is CR ⁶ , Y is CR ⁷ and Z is CR ⁸ . In other embodiments of Formula (III), at least one of X, Y, and Z is N.

In the compounds of Formula (III) U represents NR ² or CR ³ ; V is N or CR ⁴ when U is NR ² ; and V is NR ⁵ when U is CR ³ . In some embodiments, U is NR ² and V is N or CR ⁴ . In some such embodiments, U is NR ² and V is CR ⁴ . In some such embodiments, U is NR ² and V is N. In other embodiments, U is CR ³ and V is NR ⁵ .

In some embodiments of Formula (III), U is NR ² and R ² is H, C ₁ -C ₅ alkyl, C ₁ -C ₅ fluoroalkyl, C ₃ -C ₈ cycloalkyl, or 3-6 membered heterocyclyl, wherein each said C ₁ -C ₅ alkyl and C ₁ -C ₅ fluoroalkyl is optionally substituted with R ²⁰ and each said C ₃ -C ₈ cycloalkyl and 3-6 membered heterocyclyl is optionally substituted with R ²¹ .

In the compounds of Formula (III) R ² and R ³ are H, C ₁ -C ₅ alkyl, C ₁ -C ₅ fluoroalkyl, C ₃ -C ₈ cycloalkyl or 3-6 membered heterocyclyl, in which each specified C ₁ - C ₅ alkyl and C ₁ -C ₅ fluoroalkyl are optionally substituted with R ²⁰ and each of said C ₃ -C ₈ cycloalkyl and 3-6 membered heterocyclyl is optionally substituted with R ²¹ .

In some such embodiments, R ² is C ₁ -C ₅ alkyl or C ₁ -C ₅ fluoroalkyl, wherein said C ₁ -C ₅ alkyl and C ₁ -C ₅ fluoroalkyl are each optionally substituted with R ²⁰ . In some such embodiments, R ² is C ₁ -C ₅ alkyl optionally substituted with R ²⁰ . In some such embodiments, R ²⁰ is OH. In certain embodiments, R ² is CH ₃ , C ₂ H ₅ , n-C ₃ H ₇ , iso-C ₃ H ₇ , n-C ₄ H ₉ , sec-C ₄ H ₉ , iso-C ₄ H _{9 each _ _ _ _} optionally substituted R ²⁰ . In certain embodiments, R ² is isopropyl or tert-butyl. In certain embodiments, R ² is isopropyl. In some embodiments, R ² is C ₁ -C ₅ alkyl or C ₁ -C ₅ fluoroalkyl optionally substituted with R ²⁰ , wherein R ²⁰ is OH.

In other embodiments, R ² is C ₃ -C ₈ cycloalkyl or 3-6 membered heterocyclyl, wherein said C ₃ -C ₈ cycloalkyl and 3-6 membered heterocyclyl are each optionally substituted with R ²¹ . In some such embodiments, R ² is 3-6 membered heterocyclyl optionally substituted with R ²¹ . In certain embodiments, R ² is oxetan-3-yl or azetidin-3-yl, each optionally substituted with R ²¹ . In certain embodiments, R ² is oxetan-3-yl. In other embodiments, R ² is C ₃ -C ₈ cycloalkyl, wherein said C ₃ -C ₈ cycloalkyl is optionally substituted with R ²¹ . In some such embodiments, R ²¹ is F, OH, or C ₁ -C ₄ alkyl.

In some such embodiments, R ³ is C ₁ -C ₅ alkyl or C ₁ -C ₅ fluoroalkyl, wherein said C ₁ -C ₅ alkyl and C ₁ -C ₅ fluoroalkyl are each optionally substituted with R ²⁰ . In some such embodiments, R ³ is C ₁ -C ₅ alkyl optionally substituted with R ²⁰ . In some such embodiments, R ²⁰ is OH or NR ²² R ²³ . In some such embodiments, R ²⁰ is OH. In some such embodiments, R ³ is CH ₃ , C ₂ H ₅ , n-C ₃ H ₇ , iso-C ₃ H ₇ , n-C ₄ H ₉ , sec-C ₄ H ₉ , iso-C ₄ H ₉ , t-C ₄ H ₉ , CHF ₂ , or CH ₂ CHF ₂ , each optionally substituted with R ²⁰ . In certain embodiments, R ³ is iso-C ₃ H ₇ or t-C ₄ H ₉ (ie, isopropyl or t-butyl). In certain embodiments, R ² is isopropyl.

In other embodiments, R ³ is C ₃ -C ₈ cycloalkyl or 3-6 membered heterocyclyl, wherein each said C ₃ -C ₈ cycloalkyl and 3-6 membered heterocyclyl is optionally substituted with R ²¹ . In some such embodiments, R ³ is 3-6 membered heterocyclyl optionally substituted with R ²¹ . In certain embodiments, R ³ is oxetan-3-yl or azetidin-3-yl optionally substituted with R ²¹ . In some such embodiments, R ²¹ is F, OH, or C ₁ -C ₄ alkyl. In certain embodiments, R ³ is oxetan-3-yl. In other embodiments, R ³ is C ₃ -C ₈ cycloalkyl, wherein said C ₃ -C ₈ cycloalkyl is optionally substituted with R ²¹ . In some such embodiments, R ²¹ is F, OH, or C ₁ -C ₄ alkyl.

In the above embodiments where U is CR ³ , V is NR ⁵ .

In some embodiments of Formula (III), V is CR ⁴ when U is NR ² .

In compounds of Formula (III) R ⁴ is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy or C ₁ -C ₄ fluoroalkoxy, wherein each C ₁ -C ₄ alkyl , C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ fluoroalkoxy are optionally substituted with R ²⁰ . In some embodiments, R ⁴ is H. In other embodiments, R ⁴ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each of said C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with R ²⁰ . In some such embodiments, R ⁴ is C ₁ -C ₄ alkyl optionally substituted with R ²⁰ . In some such embodiments, R ²⁰ is OH, OCH ₃ , NH ₂ , NHCH _{3 ,} or NH(CH ₃ ) ₂ . In some such embodiments, R ²⁰ is OH or NH ₂ . In some such embodiments, R ²⁰ is OH. In certain embodiments, R ⁴ is C ₁ -C ₂ alkyl optionally substituted with R ²⁰ , wherein R ²⁰ is OH or NH ₂ . In certain embodiments, R ⁴ -R ²⁰ is H, CH ₃ , C ₂ H ₅ , CH ₂ OH, CH(OH)CH ₃ , CH ₂ CH ₂ OH, or CH ₂ NH ₂ (i.e., methyl, ethyl , hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl or aminomethyl). In some embodiments, R ⁴ substituted with R ²⁰ is CH(OH)CH ₃ or C(OH)(CH ₃ ) ₂ . In other such embodiments, R ⁴ is C ₁ -C ₄ fluoroalkyl optionally substituted with R ²⁰ . In other embodiments, R ⁴ is C ₁ -C ₄ alkoxy or C ₁ -C ₄ fluoroalkoxy, wherein each of said C ₁ -C ₄ alkoxy and C ₁ -C ₄ fluoroalkoxy is optionally substituted with R ²⁰ .

In some embodiments of Formula (III), V is NR ⁵ when U is CR ³ .

In the compounds of Formula (III) R ⁵ is H, C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each said C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with R ²⁰ . In some embodiments, R ⁵ is H. In other embodiments, R ⁵ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each of said C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with R ²⁰ . In some such embodiments, R ⁵ is C ₁ -C ₄ alkyl optionally substituted with R ²⁰ . In other such embodiments, R ⁵ is C ₁ -C ₄ fluoroalkyl optionally substituted with R ²⁰ . In certain embodiments, R ⁵ is C ₁ -C ₂ alkyl or C ₁ -C ₂ fluoroalkyl. In certain embodiments, R ⁵ is CH ₃ , C ₂ H ₅ , CHF _{2 ,} or CH ₂ CHF ₂ (ie, methyl, ethyl, difluoromethyl, or difluoroethyl).

In compounds of Formula (III) R ⁶ is H, F, Cl, CN, CH ₃ , CH ₂ F, CHF ₂ or CF ₃ . In some embodiments, R ⁶ is H. In other embodiments, R ⁶ is F. In other embodiments, R ⁶ is Cl. In additional embodiments, R ⁶ is CN. In other embodiments, R ⁶ is CH ₃ , CH ₂ F, CHF ₂ or CF ₃ .

In compounds of Formula (III), R ⁷ and R ⁸ are independently H, F, Cl, CN, C ₁ -C ₂ alkyl, C ₁ -C ₂ fluoroalkyl, C ₁ -C ₂ alkoxy or C ₁ -C ₂ fluoroalkoxy, in which each specified C ₁ -C ₂ alkyl C ₁ -C ₂ fluoroalkyl, C ₁ -C ₂ alkoxy and C ₁ -C ₂ fluoroalkoxy is optionally substituted with R ²⁰ .

In some embodiments of Formula (III), R ⁷ is H. In other embodiments, R ⁷ is F or Cl. In additional embodiments, R ⁷ is C ₁ -C ₂ alkyl or C ₁ -C ₂ fluoroalkyl, wherein each of said C ₁ -C ₂ alkyl and C ₁ -C ₂ fluoroalkyl is optionally substituted with R ²⁰ . In some such embodiments, R ⁷ is CH ₃ optionally substituted with R ²⁰ . In some embodiments, R ⁷ is CH ₃ .

In some embodiments of Formula (III), R ⁸ is H. In other embodiments, R ⁸ is F or Cl. In additional embodiments, R ⁸ is C ₁ -C ₂ alkyl or C ₁ -C ₂ fluoroalkyl, wherein each of said C ₁ -C ₂ alkyl and C ₁ -C ₂ fluoroalkyl is optionally substituted with R ²⁰ . In some such embodiments, R ⁸ is CH ₃ optionally substituted with R ²⁰ . In some embodiments, R ⁸ is CH ₃ .

In some embodiments, R ⁷ and R ⁸ are H.

In compounds of Formula (III) R ⁹ is H, OH, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ . In some preferred embodiments, R ⁹ is OH. In other embodiments, R ⁹ is NH ₂ , NHCH _{3 ,} or N(CH ₃ ) ₂ . In additional embodiments, R ⁹ is H.

In the compounds of Formula (III), each R ¹⁰ is independently F, CN, C ₁ -C ₂ alkyl or C ₁ -C ₂ fluoroalkyl, wherein each said C ₁ -C ₂ alkyl and C ₁ -C ₂ fluoroalkyl is optionally substituted with R ²⁰ . In some embodiments, n is 0 and R ¹⁰ is absent. In other embodiments, n is 1, 2, 3, or 4 and each R ¹⁰ is independently F, CN, C ₁ -C ₂ alkyl, or C ₁ -C ₂ fluoroalkyl, wherein each is C ₁ -C ₂ alkyl and C ₁ -C ₂ fluoroalkyl is optionally substituted with R ²⁰ . In other embodiments, n is 1 or 2 and R ¹⁰ is independently F, CN, C ₁ -C ₂ alkyl, or C ₁ -C ₂ fluoroalkyl. In some embodiments, n is 1 or 2 and R ¹⁰ is independently F or CH ₃ .

In compounds of Formula (III) Q is NR ¹¹ or O or Q is CR ¹² R ¹³ in which R ¹² and R ¹³ are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring, containing NR ¹¹ or O as a ring member, the ring being optionally further substituted with R ¹⁰ .

In some embodiments of Formula (III), Q is NR ¹¹ . In some embodiments, Q is NR ¹¹ , p is 2, and q is 1. In some such embodiments, R ¹¹ is SO ₂ R ¹⁴ . In other such embodiments, R ¹¹ is COR ¹⁷ . In some such embodiments, n is 0 and R ¹⁰ is absent.

In compounds of Formula (III) R ¹¹ is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, SO ₂ R ¹⁴ , SO ₂ NR ¹⁵ R ¹⁶ , COR ¹⁷ , COOR ¹⁷ or CONR ¹⁸ R ¹⁹ . In some embodiments, R ¹¹ is H, C ₁ -C ₄ alkyl, or C ₁ -C ₄ fluoroalkyl. In some embodiments, R ¹¹ is H. In other embodiments, R ¹¹ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl. In some embodiments, R ¹¹ is C ₁ -C ₄ alkyl. In other embodiments, R ¹¹ is C ₁ -C ₄ fluoroalkyl. In some embodiments, R ¹¹ is SO ₂ R ¹⁴ , SO ₂ NR ¹⁵ R ¹⁶ , COR ¹⁷ , COOR ¹⁷ or CONR ¹⁸ R ¹⁹ . In some embodiments, R ¹¹ is SO ₂ R ¹⁴ or SO ₂ NR ¹⁵ R ¹⁶ . In some embodiments, R ¹¹ is SO ₂ R ¹⁴ . In other embodiments, R ¹¹ is SO ₂ NR ¹⁵ R ¹⁶ . In some embodiments, R ¹¹ is COR ¹⁷ , COOR ¹⁷ , or CONR ¹⁸ R ¹⁹ . In some embodiments, R ¹¹ is COR ¹⁷ . In some embodiments, R ¹¹ is COOR ¹⁷ . In other embodiments, R ¹¹ is CONR ¹⁸ R ¹⁹ .

In other embodiments of Formula (III), Q is O. In some embodiments, Q is O, p is 2, and q is 1. In some such embodiments, n is 0 and R ¹⁰ is absent.

In additional embodiments of Formula (III), Q is CR ¹² R ¹³ wherein R ¹² and R ¹³ are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing NR ¹¹ or O in as a ring member, the ring being optionally further substituted with R ¹⁰ . In some such embodiments, n is 0 and R ¹⁰ is absent. In some such embodiments, R ¹² and R ¹³ are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing NR ¹¹ as a ring member, the ring being optionally further substituted with R ¹⁰ . In other such embodiments, R ¹² and R ¹³ are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing O as a ring member, the ring being optionally further substituted with R ¹⁰ . In some such embodiments, R ¹² and R ¹³ are taken together to form a 4-membered optionally substituted heterocyclic ring. In other such embodiments, R ¹² and R ¹³ are taken together to form a 5-membered optionally substituted heterocyclic ring. In other such embodiments, R ¹² and R ¹³ are taken together to form a 6-membered optionally substituted heterocyclic ring. In each case, said 4-6 membered heterocyclic ring contains NR ¹¹ or O as a ring member and is optionally further substituted with R ¹⁰ , wherein R ¹⁰ and R ¹¹ are each as further defined herein. In some such embodiments, n is 0 and R ¹⁰ is absent.

In the above embodiments, each R ¹⁰ is independently selected from the group as defined herein.

In the compounds of Formula (III) R ¹⁴ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl. In some embodiments, R ¹⁴ is C ₁ -C ₄ alkyl. In some embodiments, R ¹⁴ is C ₁ -C ₄ fluoroalkyl. In certain embodiments, R ¹⁴ is CH ₃ or C ₂ H ₅ (ie, methyl or ethyl).

In the compounds of Formula (III), each R ¹⁵ and R ¹⁶ is independently H or CH ₃ .

In the compounds of Formula (III), R ¹⁷ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each of said C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with R ²⁰ . In some embodiments, R ¹⁷ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl. In some embodiments, R ¹⁷ is C ₁ -C ₄ alkyl optionally substituted with R ²⁰ . In some embodiments, R ¹⁷ is C ₁ -C ₄ fluoroalkyl optionally substituted with R ²⁰ . In certain embodiments, R ¹⁷ is CH ₃ or C ₂ H ₅ .

In the compounds of Formula (III), each R ¹⁸ and R ¹⁹ is independently H, C ₁ -C ₄ alkyl, or C ₁ -C ₄ fluoroalkyl, wherein said C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl are each optionally substituted ^R20 . In some embodiments, each R ¹⁸ and R ¹⁹ is independently H, C ₁ -C ₄ alkyl, or C ₁ -C ₄ fluoroalkyl. In some embodiments, each R ¹⁸ and R ¹⁹ is independently H or C ₁ -C ₄ alkyl optionally substituted with R ²⁰ . In some embodiments, each R ¹⁸ and R ¹⁹ is independently H or C ₁ -C ₄ fluoroalkyl optionally substituted with R ²⁰ . In certain embodiments, each R ¹⁸ and R ¹⁹ is independently H, CH ₃ or C ₂ H ₅ .

In compounds of Formula (III), each R ²⁰ is independently OH, C ₁ -C ₂ alkoxy, C ₁ -C ₂ fluoroalkoxy, CN or NR ²² R ²³ . In some embodiments, R ²⁰ is OH. In some such embodiments, R ²⁰ is OH, C ₁ -C ₂ alkoxy, or NR ²² R ²³ . In other embodiments, R ²⁰ is C ₁ -C ₂ alkoxy or C ₁ -C ₂ fluoroalkoxy. In additional embodiments, R ²⁰ is CN. In yet other embodiments, R ²⁰ is NR ²² R ²³ .

In the compounds of Formula (III), each R ²¹ is independently F, OH, CN, NR ²² R ²³ , C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy, or C ₁ -C ₄ fluoroalkoxy , in which each specified C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ fluoroalkoxy is optionally further substituted with OH, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ . In some embodiments, R ²¹ is F. In some embodiments, R ²¹ is OH. In some embodiments, each R ²¹ is independently F, OH, or C ₁ -C ₄ alkyl. In other embodiments, R ²¹ is CN. In other embodiments, R ²¹ is C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy, or C ₁ -C ₄ fluoroalkoxy, wherein each C ₁ -C ₄ alkyl, C ₁ - C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ fluoroalkoxy are optionally further substituted with OH, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ .

In the compounds of Formula (III), each R ²² and R ²³ is independently H, C ₁ -C ₂ alkyl or C ₁ -C ₂ fluoroalkyl or R ²² and R ²³ may be taken together with the nitrogen atom to which they are attached, with the formation of an azetidinyl ring, which is optionally substituted with F or OH.

In some embodiments, each R ²² and R ²³ is independently H, C ₁ -C ₂ alkyl, or C ₁ -C ₂ fluoroalkyl. In certain embodiments, each R ²² and R ²³ is independently H or CH ₃ . In other embodiments, R ²² and R ²³ are taken together with the nitrogen atom to which they are attached to form an azetidinyl ring which is optionally substituted with F or OH.

In compounds of Formula (III), n is 0, 1, 2, 3, or 4. In some embodiments, n is 0 and R ¹⁰ is absent. In other embodiments, n is 1, 2, 3, or 4 and R ¹⁰ is as defined herein. In some embodiments, n is 1 or 2.

In the compounds of Formula (III) p is 1, 2 or 3 and q is 0, 1, 2 or 3; in which the sum of p and q is an integer from 1 to 4. In some embodiments, the sum of p and q is an integer from 1 to 3.

In some embodiments, p is 2 and q is 1. In other embodiments, p is 2 and q is 2. In some embodiments, p is 1 and q is 0. In other embodiments, p is 1 and q is 1. In still in other embodiments, p is 1 and q is 2. In additional embodiments, p is 1 and q is 3. In some embodiments, p is 2. In other embodiments, p is 1. In some embodiments, q is 1. In other embodiments, implementation q is 0.

In certain embodiments, the invention provides a compound of Formula (III), (III-A), (III-B), (III-C), or (III-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more and more preferably four or more of the following features: R ¹ is Cl; U is NR ² and V is CR ⁴ ; R ² is C ₁ -C ₅ alkyl or R ² is ISO-C ₃ H ₇ ; R ⁴ is C ₁ -C ₄ alkyl, wherein said C ₁ -C ₄ alkyl is optionally substituted with R ²⁰ , in which R ²⁰ is OH; or R ⁴ is CH(OH)CH ₃ or C(OH)(CH ₃ ) ₂ ; X is CR ⁶ ; R ⁶ is F; Y is CR ⁷ ; Z is CR ⁸ ; R ⁷ and R ⁸ are H; R ⁹ is OH; Q is O or Q is NR ¹¹ in which R ¹¹ is SO ₂ R ¹⁴ ; R ¹⁴ is C ₁ -C ₄ alkyl; n is 0 and R ¹⁰ is absent; p is 2 and q is 1.

In certain embodiments, the invention provides a compound of Formula (III), (III-A), (III-B), (III-C), or (III-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more and more preferably four or more of the following features: R ¹ is Cl; U is CR ³ and V is NR ⁵ ; R ³ is C ₁ -C ₅ alkyl or R ³ is ISO-C ₃ H ₇ ; R ⁵ is C ₁ -C ₄ alkyl, wherein said C ₁ -C ₄ alkyl is optionally substituted with R ²⁰ ; R ²⁰ is OH; X is CR ⁶ ; R ⁶ is F; Y is CR ⁷ ; Z is CR ⁸ ; R ⁷ and R ⁸ are H; R ⁹ is OH; Q is O or Q is NR ¹¹ in which R ¹¹ is SO ₂ R ¹⁴ ; R ¹⁴ is C ₁ -C ₄ alkyl; n is 0 and R ¹⁰ is absent; p is 2 and q is 1.

In a preferred embodiment, the invention provides a compound of Formula (III), (III-A), (III-B), (III-C) or (III-D) or a pharmaceutically acceptable salt thereof, wherein: R ¹ is Cl; U is NR ² ; R ² is C ₁ -C ₅ alkyl or R ² is ISO-C ₃ H ₇ ; V is CR ⁴ ; R ⁴ is C ₁ -C ₄ alkyl optionally substituted with R ²⁰ in which R ²⁰ is OH; or R ⁴ is CH(OH)CH ₃ or C(OH)(CH ₃ ) ₂ ; X is CR ⁶ ; R ⁶ is F; Y is CR ⁷ ; R ⁷ is H; Z is CR ⁸ ; R ⁸ is H; R ⁹ is OH; Q is O; n is 0 and R ¹⁰ is absent; p is 2 and q is 1.

In another preferred embodiment, the invention provides a compound of Formula (III), (III-A), (III-B), (III-C) or (III-D) or a pharmaceutically acceptable salt thereof, wherein: R ¹ is Cl ; U is NR ² ; R ² is C ₁ -C ₅ alkyl or R ² is ISO-C ₃ H ₇ ; V is CR ⁴ ; R ⁴ is C ₁ -C ₄ alkyl optionally substituted with R ²⁰ in which R ²⁰ is OH; or R ⁴ is CH(OH)CH ₃ or C(OH)(CH ₃ ) ₂ ; X is CR ⁶ ; R ⁶ is F; Y is CR ⁷ ; R ⁷ is H; Z is CR ⁸ ; R ⁸ is H; R ⁹ is OH; Q is NR ¹¹ in which R ¹¹ is SO ₂ R ¹⁴ ; R ¹⁴ is C ₁ -C ₄ alkyl; n is 0 and R ¹⁰ is absent; p is 2 and q is 1.

In certain embodiments, the invention provides a compound of Formula (II), (II-A), (II-B), (II-C), or (II-D), or a pharmaceutically acceptable salt thereof, or a compound of Formula (III), (III- A), (III-B), (III-C) or (III-D) or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more of the following: R ¹ is F or Cl; U is NR ² and V is CR ⁴ ; R ² is C ₁ -C ₅ alkyl, C ₁ -C ₅ fluoroalkyl or 3-6 membered heterocyclyl or R ² is CH ₃ , ISO-C ₃ H ₇ , ISO-C ₄ H ₉ , sec-C ₄ H ₉ , tert-C ₄ H ₉ , CH ₂ F, CHF ₂ , CH ₂ CHF ₂ or oxetan-3-yl; R ⁴ is H or C ₁ -C ₄ alkyl, wherein said C ₁ -C ₄ alkyl is optionally substituted with OH, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ ; or R ⁴ is H, CH ₃ , C ₂ H ₅ , CH ₂ OH, CH(OH)CH ₃ , CH ₂ CH ₂ OH or CH ₂ NH ₂ ; X is CR ⁶ ; R ⁶ is H or F; Y is CR ⁷ ; Z is CR ⁸ ; R ⁷ and R ⁸ are H; R ⁹ is OH; n is 0 and R ¹⁰ is absent; Q is NR ¹¹ ; R ¹¹ is SO ₂ R ¹⁴ and R ¹⁴ is C ₁ -C ₄ alkyl; p is 2 and q is 1.

In certain embodiments, the invention provides a compound of Formula (II), (II-A), (II-B), (II-C), or (II-D), or a pharmaceutically acceptable salt thereof, or a compound of Formula (III), (III- A), (III-B), (III-C) or (III-D) or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more of the following: R ¹ is F or Cl; U is CR ³ and V is NR ⁵ ; R ³ is C ₁ -C ₅ alkyl, C ₁ -C ₅ fluoroalkyl or 3-6 membered heterocyclyl or R ³ is CH ₃ , ISO-C ₃ H ₇ , ISO-C ₄ H ₉ , sec-C ₄ H ₉ , tert-C ₄ H ₉ , CH ₂ F, CHF ₂ , CH ₂ CHF ₂ or oxetan-3-yl; R ⁵ is H or C ₁ -C ₄ alkyl or R ⁵ is H or CH ₃ ; X is CR ⁶ ; R ⁶ is H or F; Y is CR ⁷ ; Z is CR ⁸ ; R ⁷ and R ⁸ are H; R ⁹ is OH; n is 0 and R ¹⁰ is absent; Q is NR ¹¹ ; R ¹¹ is SO ₂ R ¹⁴ and R ¹⁴ is C ₁ -C ₄ alkyl; p is 2 and q is 1.

In certain embodiments, the invention provides a compound of Formula (II), (II-A), (II-B), (II-C), or (II-D), or a pharmaceutically acceptable salt thereof, or a compound of Formula (III), (III- A), (III-B), (III-C) or (III-D) or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more of the following: R ¹ is F or Cl; U is NR ² and V is N; R ² is C ₁ -C ₅ alkyl, C ₁ -C ₅ fluoroalkyl or 3-6 membered heterocyclyl or R ² is CH ₃ , ISO-C ₃ H ₇ , ISO-C ₄ H ₉ , sec-C ₄ H ₉ , tert-C ₄ H ₉ , CH ₂ F, CHF ₂ , CH ₂ CHF ₂ or oxetan-3-yl; X is CR ⁶ ; R ⁶ is H or F; Y is CR ⁷ ; Z is CR ⁸ ; R ⁷ and R ⁸ are H; R ⁹ is OH; n is 0 and R ¹⁰ is absent; Q is NR ¹¹ ; R ¹¹ is SO ₂ R ¹⁴ and R ¹⁴ is C ₁ -C ₄ alkyl; p is 2 and q is 1.

In compounds of Formula (IV) R ¹ is H, F, Cl, CN, C ₁ -C ₂ alkyl or C ₁ -C ₂ fluoroalkyl, wherein each of said C ₁ -C ₂ alkyl and C ₁ -C ₂ fluoroalkyl is optional substituted with R ²⁰ . In some embodiments, R ¹ is F or Cl. In some embodiments, R ¹ is F. In some embodiments, R ¹ is Cl.

In the compounds of Formula (IV) U represents NR ² or CR ³ ; V is N or CR ⁴ when U is NR ² ; And

V is NR ⁵ when U is CR ³ . In some embodiments, U is NR ² and V is N or CR ⁴ . In some such embodiments, U is NR ² and V is N. In some such embodiments, U is NR ² and V is CR ⁴ . In some embodiments, U is CR ³ and V is NR ⁵ .

In compounds of Formula (IV), X is CR ⁶ or N. In some embodiments, X is CR ⁶ . In some embodiments, X is N.

In compounds of Formula (IV), Y is CR ⁷ or N. In some embodiments, Y is CR ⁷ . In some embodiments, Y is N.

In compounds of Formula (IV), Z is CR ⁸ or N. In some embodiments, Z is CR ⁸ . In some embodiments, Z is N.

In frequent embodiments of Formula (IV), X is CR ⁶ , Y is CR ⁷ and Z is CR ⁸ . In other embodiments of Formula (IV), at least one of X, Y, and Z is N.

In some embodiments of Formula (IV), R ² and R ³ are H, C ₁ -C ₅ alkyl, C ₁ -C ₅ fluoroalkyl, C ₃ -C ₈ cycloalkyl, or 3-6 membered heterocyclyl, wherein each said C ₁ -C ₅ alkyl and C ₁ -C ₅ fluoroalkyl are optionally substituted with R ²⁰ and each of said C ₃ -C ₈ cycloalkyl and 3-6 membered heterocyclyl is optionally substituted with R ²¹ .

In some such embodiments, R ² and R ³ are H, C ₁ -C ₅ alkyl, or C ₁ -C ₅ fluoroalkyl, wherein said C ₁ -C ₅ alkyl and C ₁ -C ₅ fluoroalkyl are each optionally substituted with R ²⁰ . In other such embodiments, R ² and R ³ are C ₃ -C ₈ cycloalkyl or 3-6 membered heterocyclyl, wherein said C ₃ -C ₈ cycloalkyl and 3-6 membered heterocyclyl are each optionally substituted with R ²¹ . In some embodiments, R ² is C ₁ -C ₄ alkyl optionally substituted with R ²⁰ , wherein R ²⁰ is OH. In some embodiments, R ³ is C ₁ -C ₄ alkyl optionally substituted with R ²⁰ , wherein R ²⁰ is OH.

In some embodiments of Formula (IV), R ⁴ is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy, or C ₁ -C ₄ fluoroalkoxy, wherein each C ₁ -C 4 ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ fluoroalkoxy are optionally substituted with R ²⁰ . In some embodiments, R ⁴ is C ₁ -C ₄ alkyl optionally substituted with R ²⁰ , wherein R ²⁰ is OH.

In some embodiments of Formula (IV), R ⁵ is H, C ₁ -C ₄ alkyl, or C ₁ -C ₄ fluoroalkyl, wherein each of said C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with R ²⁰ . In some embodiments, R ⁵ is C ₁ -C ₄ alkyl optionally substituted with R ²⁰ . In some such embodiments, R ²⁰ is OH.

In some embodiments of Formula (IV), R ² may be taken together with R ⁴ or R ³ may be taken together with R ⁵ to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR ²⁴ , O and S (O) _m as a ring member, the ring being optionally substituted with R ²¹ . It should be understood that R ² is taken together with R ⁴ or R ³ is taken together with R ⁵ in combination with the atoms to which they are attached via a C ₃ -C ₅ alkylene or C ₃ -C ₅ heteroalkylene linker, the linker being optionally substituted as further defined in the present description.

In some embodiments of Formula (IV), R ² is taken together with R ⁴ to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR ²⁴ , O, and S(O) _m as a ring member, the ring optionally substituted by R ²¹ . In some such embodiments, the 5-7 membered heterocyclic ring contains O as an additional heteroatom. In some such embodiments, the 5-7 membered heterocyclic ring contains NR ²⁴ as an additional heteroatom.

In some embodiments, R ² is taken together with R ⁴ to form a 5-membered ring containing no additional heteroatoms (ie, pyrrolidine), which is optionally substituted with R ²¹ . In other embodiments, R ² is taken together with R ⁴ to form a 6-membered ring containing no additional heteroatoms (ie, piperidine), which is optionally substituted with R ²¹ . In other embodiments, R ² is taken together with R ⁴ to form a 6-membered ring containing NR ²⁴ (ie piperazine) which is optionally substituted with R ²¹ . In further embodiments, R ² is taken together with R ⁴ to form a 6-membered ring containing O or S (ie, morpholine or thiomorpholine) which is optionally substituted with R ²¹ . In additional embodiments, R ² is taken together with R ⁴ to form a 7-membered ring that may contain no additional heteroatoms (i.e., homopiperidine) or may contain NR ²⁴ (i.e., homopiperazine), in each case optionally substituted with R ²¹ .

In other embodiments of Formula (IV), R ³ is taken together with R ⁵ to form a 5-7 membered heterocyclic ring optionally containing an additional heteroatom selected from NR ²⁴ , O and S(O) _m as a ring member, the ring optionally substituted by R ²¹ . In some such embodiments, the 5-7 membered heterocyclic ring contains O as an additional heteroatom. In some such embodiments, the 5-7 membered heterocyclic ring contains NR ²⁴ as an additional heteroatom.

In some embodiments, R ³ is taken together with R ⁵ to form a 5-membered ring containing no additional heteroatoms (ie, pyrrolidine), which is optionally substituted with R ²¹ . In other embodiments, R ³ is taken together with R ⁵ to form a 6-membered ring containing no additional heteroatoms (ie piperidine) which is optionally substituted with R ²¹ . In other embodiments, R ³ is taken together with R ⁵ to form a 6-membered ring containing NR ²⁴ (ie piperazine) which is optionally substituted with R ²¹ . In additional embodiments, R ³ is taken together with R ⁵ to form a 6-membered ring containing O or S(O) _m (ie, morpholine or thiomorpholine) which is optionally substituted with R ²¹ . In additional embodiments, R ³ is taken together with R ⁵ to form a 7-membered ring that may contain no additional heteroatoms (i.e., homopiperidine) or may contain NR ²⁴ (i.e., homopiperazine), in each case optionally substituted with R ²¹ .

In compounds of Formula (IV) R ⁶ is H, F, Cl, CN, CH ₃ , CH ₂ F, CHF ₂ or CF ₃ . In some embodiments, R ⁶ is F or Cl. In some such embodiments, R ⁶ is F. In some such embodiments, R ⁶ is Cl. In some embodiments, R ⁶ is H. In other embodiments, R ⁶ is CN, CH ₃ , CH ₂ F, CHF _{2 ,} or CF ₃ .

In the compounds of Formula (IV), R ⁷ and R ⁸ are independently H, F, Cl, CN, C ₁ -C ₂ alkyl, C ₁ -C ₂ fluoroalkyl, C ₁ -C ₂ alkoxy or C ₁ -C ₂ fluoroalkoxy, in which each specified C ₁ -C ₂ alkyl, C ₁ -C ₂ fluoroalkyl, C ₁ -C ₂ alkoxy and C ₁ -C ₂ fluoroalkoxy is optionally substituted with R ²⁰ . In some such embodiments, R ⁷ is H. In some such embodiments, R ⁸ is H. In some such embodiments, R ⁷ and R ⁸ are H.

In compounds of Formula (IV) R ⁹ is H, OH, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ . In preferred embodiments of Formula (IV), R ⁹ is OH.

In the compounds of Formula (IV), each R ¹⁰ is independently F, CN, C ₁ -C ₂ alkyl or C ₁ -C ₂ fluoroalkyl, wherein each said C ₁ -C ₂ alkyl and C ₁ -C ₂ fluoroalkyl is optionally substituted with R ²⁰ . In some embodiments, n is 0 and R ¹⁰ is absent. In other embodiments, n is 1 or 2 and R ¹⁰ is independently F, CN, C ₁ -C ₂ alkyl, or C ₁ -C ₂ fluoroalkyl. In some embodiments, n is 1 or 2 and R ¹⁰ is independently F or CH ₃ .

In some embodiments of Formula (IV), Q is NR ¹¹ or O. In some embodiments, Q is O. In some embodiments, Q is O, p is 2, and q is 1. In some such embodiments, n is 0 and R ¹⁰ is missing.

In other embodiments of Formula (IV), Q is NR ¹¹ . In some embodiments, Q is NR ¹¹ , p is 2, and q is 1. In some such embodiments, R ¹¹ is SO ₂ R ¹⁴ . In other such embodiments, R ¹¹ is COR ¹⁷ . In some such embodiments, n is 0 and R ¹⁰ is absent.

In some embodiments of Formula (VI), Q is CR ¹² R ¹³ wherein R ¹² and R ¹³ are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing NR ¹¹ or O in as a ring member, the ring being optionally further substituted with R ¹⁰ . In some such embodiments, n is 0 and R ¹⁰ is absent.

In compounds of Formula (IV) R ¹¹ is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, SO ₂ R ¹⁴ , SO ₂ NR ¹⁵ R ¹⁶ , COR ¹⁷ , COOR ¹⁷ or CONR ¹⁸ R ¹⁹ . In some embodiments, R ¹¹ is SO ₂ R ¹⁴ . In other embodiments, R ¹¹ is COR ¹⁷ .

In compounds of Formula (IV) R ¹⁴ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl. In some embodiments, R ¹⁴ is C ₁ -C ₄ alkyl. In some such embodiments, R ¹⁴ is C ₁ -C ₂ alkyl. In some embodiments, R ¹⁴ is C ₁ -C ₄ fluoroalkyl. In some such embodiments, R ¹⁴ is C ₁ -C ₂ fluoroalkyl. In certain embodiments, R ¹⁴ is CH ₃ or C ₂ H ₅ .

In compounds of Formula (IV), each R ¹⁵ and R ¹⁶ is independently H or CH ₃ .

In the compounds of Formula (IV) R ¹⁷ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each of said C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with R ²⁰ . In some embodiments, R ¹⁷ is C ₁ -C ₄ alkyl, wherein each C ₁ -C ₄ alkyl is optionally substituted with R ²⁰ .

In the compounds of Formula (IV), each R ¹⁸ and R ¹⁹ is independently H, C ₁ -C ₄ alkyl, or C ₁ -C ₄ fluoroalkyl, wherein each of said C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted ^R20 .

In the compounds of Formula (IV), each R ²⁰ is independently OH, C ₁ -C ₂ alkoxy, C ₁ -C ₂ fluoroalkoxy, CN or NR ²² R ²³ .

In the compounds of Formula (IV), each R ²¹ is independently F, OH, CN, NR ²² R ²³ , C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy, or C ₁ -C ₄ fluoroalkoxy in which each specified C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ fluoroalkoxy is optionally further substituted with OH, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ . In some embodiments, each R ²¹ is independently F, OH, or C ₁ -C ₄ alkyl.

In some embodiments of Formula (IV), each R ²² and R ²³ is independently H, C ₁ -C ₂ alkyl, C ₁ -C ₂ fluoroalkyl. In other embodiments of Formula (IV), R ²² and R ²³ may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring in which said ring is optionally substituted with F or OH.

In compounds of Formula (IV) R ²⁴ is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, SO ₂ R ²⁵ , SO ₂ NR ²⁶ R ²⁷ , COR ²⁸ , COOR ²⁸ or CONR ²⁹ R ³⁰ . In some embodiments, R ²⁴ is H or C ₁ -C ₄ alkyl. In some embodiments, R ²⁴ is H or C ₁ -C ₂ alkyl.

In compounds of Formula (IV) R ²⁵ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl. In some embodiments, R ²⁵ is C ₁ -C ₂ alkyl.

In the compounds of Formula (IV), each R ²⁶ and R ²⁷ is independently H or CH ₃ .

In compounds of Formula (IV), R ²⁸ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each of said C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with OH, C ₁ -C ₂ alkoxy, C ₁ -C ₂ fluoroalkoxy, CN, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ . In some embodiments, R ²⁸ is C ₁ -C ₄ alkyl optionally substituted with OH or C ₁ -C ₂ alkoxy. In some embodiments, R ²⁸ is C ₁ -C ₂ alkyl.

In the compounds of Formula (IV), each R ²⁹ and R ³⁰ is independently H, C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein said C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl are each optionally substituted OH, C ₁ -C ₂ alkoxy, C ₁ -C ₂ fluoroalkoxy, CN, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ . In some embodiments, each R ²⁹ and R ³⁰ is independently H or C ₁ -C ₄ alkyl, wherein each said C ₁ -C ₄ alkyl is optionally substituted with OH or C ₁ -C ₂ alkoxy. In some embodiments, each R ²⁹ and R ³⁰ is independently H or C ₁ -C ₂ alkyl.

In compounds of Formula (IV), m is 0, 1, or 2. In some embodiments, m is 2.

In compounds of Formula (IV), n is 0, 1, 2, 3, or 4. In some embodiments, n is 0 and R ¹⁰ is absent. In some embodiments, n is 1 or 2.

In the compounds of Formula (IV) p is 1, 2 or 3; in which the sum of p and q is an integer from 1 to 4. In some embodiments, p is 2. In other embodiments, p is 1. In some embodiments, the sum of p and q is an integer from 1 to 3.

In the compounds of Formula (IV) q is 0, 1, 2 or 3; in which the sum of p and q is an integer from 1 to 4. In some embodiments, q is 1. In other embodiments, q is 0. In some embodiments, the sum of p and q is an integer from 1 to 3.

In some embodiments, p is 2 and q is 1. In other embodiments, p is 1 and q is 1. In other embodiments, p is 1 and q is 0. In further embodiments, the sum of p and q is an integer of 1 until 3.

In certain embodiments, the invention provides a compound of Formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more and more preferably four or more of the following features: R ¹ is Cl; U is NR ² and V is CR ⁴ ; R ² is C ₁ -C ₅ alkyl or R ² is ISO-C ₃ H ₇ ; R ⁴ is C ₁ -C ₄ alkyl, wherein said C ₁ -C ₄ alkyl is optionally substituted with R ²⁰ , in which R ²⁰ is OH; or R ⁴ is CH(OH)CH ₃ or C(OH)(CH ₃ ) ₂ ; X is CR ⁶ ; R ⁶ is F; Y is CR ⁷ ; R ⁷ is H; Z is CR ⁸ ; R ⁸ is H; R ⁹ is OH; Q is O or Q is NR ¹¹ in which R ¹¹ is SO ₂ R ¹⁴ ; R ¹⁴ is C ₁ -C ₄ alkyl; n is 0 and R ¹⁰ is absent; p is 2 and q is 1.

In certain embodiments, the invention provides a compound of Formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more and more preferably four or more of the following features: R ¹ is Cl; U is CR ³ and V is NR ⁵ ; R ³ is C ₁ -C ₅ alkyl or R ³ is ISO-C ₃ H ₇ ; R ⁵ is C ₁ -C ₄ alkyl, wherein said C ₁ -C ₄ alkyl is optionally substituted with R ²⁰ ; R ²⁰ is OH; X is CR ⁶ ; R ⁶ is F; Y is CR ⁷ ; R ⁷ is H; Z is CR ⁸ ; R ⁸ is H; R ⁹ is OH; Q is O or Q is NR ¹¹ where R ¹¹ is SO ₂ R ¹⁴ ; R ¹⁴ is C ₁ -C ₄ alkyl; n is 0 and R ¹⁰ is absent; p is 2 and q is 1.

In a preferred embodiment, the invention provides a compound of Formula (IV), (IV-A), (IV-B), (IV-C) or (IV-D) or a pharmaceutically acceptable salt thereof, wherein: R ¹ is Cl; U is NR ² ; R ² is C ₁ -C ₅ alkyl; V is CR ⁴ ; R ⁴ is C ₁ -C ₄ alkyl optionally substituted with R ²⁰ in which R ²⁰ is OH; X is CR ⁶ ; R ⁶ is F; Y is CR ⁷ ; R ⁷ is H; Z is CR ⁸ ; R ⁸ is H; R ⁹ is OH; Q is O; n is 0 and R ¹⁰ is absent; p is 2 and q is 1.

In another preferred embodiment, the invention provides a compound of Formula (IV), (IV-A), (IV-B), (IV-C) or (IV-D) or a pharmaceutically acceptable salt thereof, wherein: R ¹ is Cl ; U is NR ² ; R ² is C ₁ -C ₅ alkyl; V is CR ⁴ ; R ⁴ is C ₁ -C ₄ alkyl optionally substituted with R ²⁰ in which R ²⁰ is OH; X is CR ⁶ ; R ⁶ is F; Y is CR ⁷ ; R ⁷ is H; Z is CR ⁸ ; R ⁸ is H; R ⁹ is OH; Q is NR ¹¹ in which R ¹¹ is SO ₂ R ¹⁴ ; R ¹⁴ is C ₁ -C ₄ alkyl; n is 0 and R ¹⁰ is absent; p is 2 and q is 1.

In certain embodiments, the invention provides a compound of Formula (IV), (IV-A), (IV-B), (IV-C) or (IV-D), or a pharmaceutically acceptable salt thereof, wherein: R ¹ is Cl; U is NR ² ; V is CR ⁴ ; R ² is taken together with R ⁴ to form a 5-7 membered heterocyclic ring optionally containing an additional heteroatom selected from NR ²⁴ , O and S(O) _m as a ring member, the ring being optionally substituted with R ²¹ ; each R ²¹ is independently F, OH or C ₁ -C ₄ alkyl; X is CR ⁶ ; R ⁶ is F; Y is CR ⁷ ; R ⁷ is H; Z is CR ⁸ ; R ⁸ is H; R ⁹ is OH; Q is O or Q is NR ¹¹ in which R ¹¹ is SO ₂ R ¹⁴ ; R ¹⁴ is C ₁ -C ₄ alkyl; n is 0 and R ¹⁰ is absent; p is 2 and q is 1.

In certain embodiments, the invention provides a compound of Formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more and more preferably four or more of the following features: R ¹ is Cl; U is CR ³ ; V is NR ⁵ ; R ³ is taken together with R ⁵ to form a 5-7 membered heterocyclic ring optionally containing an additional heteroatom selected from NR ²⁴ , O and S(O) _m as a ring member, the ring being optionally substituted with R ²¹ ; each R ²¹ is independently F, OH or C ₁ -C ₄ alkyl; X is CR ⁶ ; R ⁶ is F; Y is CR ⁷ ; R ⁷ is H; Z is CR ⁸ ; R ⁸ is H; R ⁹ is OH; Q is O or Q is NR ¹¹ in which R ¹¹ is SO ₂ R ¹⁴ ; R ¹⁴ is C ₁ -C ₄ alkyl; n is 0 and R ¹⁰ is absent; p is 2 and q is 1.

In compounds of Formula (V), R ¹ is H, F, Cl, CN, C ₁ -C ₂ alkyl or C ₁ -C ₂ fluoroalkyl, wherein each of said C ₁ -C ₂ alkyl and C ₁ -C ₂ fluoroalkyl is optional substituted with R ²⁰ . In some embodiments, R ¹ is F or Cl. In some embodiments, R ¹ is F. In some embodiments, R ¹ is Cl.

In the compounds of Formula (V) U represents NR ² or CR ³ ; V is N or CR ⁴ when U is NR ² ; And

V is NR ⁵ when U is CR ³ . In some embodiments, U is NR ² and V is N or CR ⁴ . In some such embodiments, U is NR ² and V is N. In some such embodiments, U is NR ² and V is CR ⁴ . In some embodiments, U is CR ³ and V is NR ⁵ .

In compounds of Formula (V), X is CR ⁶ or N. In some embodiments, X is CR ⁶ . In some embodiments, X is N.

In compounds of Formula (V), Y is CR ⁷ or N. In some embodiments, Y is CR ⁷ . In some embodiments, Y is N.

In compounds of Formula (V), Z is CR ⁸ or N. In some embodiments, Z is CR ⁸ . In some embodiments, Z is N.

In frequent embodiments of Formula (V), X is CR ⁶ , Y is CR ⁷ and Z is CR ⁸ . In other embodiments of Formula (V), at least one of X, Y, and Z is N.

In some embodiments of Formula (V), R ² and R ³ are H, C ₁ -C ₅ alkyl, C ₁ -C ₅ fluoroalkyl, C ₃ -C ₈ cycloalkyl, or 3-6 membered heterocyclyl, wherein each said C ₁ -C ₅ alkyl and C ₁ -C ₅ fluoroalkyl are optionally substituted with R ²⁰ and each of said C ₃ -C ₈ cycloalkyl and 3-6 membered heterocyclyl is optionally substituted with R ²¹ .

In some such embodiments, R ² and R ³ are H, C ₁ -C ₅ alkyl, or C ₁ -C ₅ fluoroalkyl, wherein said C ₁ -C ₅ alkyl and C ₁ -C ₅ fluoroalkyl are each optionally substituted with R ²⁰ . In other such embodiments, R ² and R ³ are C ₃ -C ₈ cycloalkyl or 3-6 membered heterocyclyl, wherein said C ₃ -C ₈ cycloalkyl and 3-6 membered heterocyclyl are each optionally substituted with R ²¹ . In some embodiments, R ² is C ₁ -C ₄ alkyl optionally substituted with R ²⁰ , wherein R ²⁰ is OH. In some embodiments, R ³ is C ₁ -C ₄ alkyl optionally substituted with R ²⁰ , wherein R ²⁰ is OH.

In some embodiments of Formula (V), R ⁴ is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy, or C ₁ -C ₄ fluoroalkoxy, wherein each C ₁ -C 4 ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ fluoroalkoxy are optionally substituted with R ²⁰ . In some embodiments, R ⁴ is C ₁ -C ₄ alkyl optionally substituted with R ²⁰ , wherein R ²⁰ is OH.

In some embodiments of Formula (V), R ⁵ is H, C ₁ -C ₄ alkyl, or C ₁ -C ₄ fluoroalkyl, wherein each of said C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with R ²⁰ . In some embodiments, R ⁵ is C ₁ -C ₄ alkyl optionally substituted with R ²⁰ . In some such embodiments, R ²⁰ is OH.

In some embodiments of Formula (V), R ² may be taken together with R ⁴ or R ³ may be taken together with R ⁵ to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR ²⁴ , O and S (O) _m as a ring member, the ring being optionally substituted with R ²¹ . It should be understood that R ² is taken together with R ⁴ or R ³ is taken together with R ⁵ in combination with the atoms to which they are attached via a C ₃ -C ₅ alkylene or C ₃ -C ₅ heteroalkylene linker, the linker being optionally substituted as further defined in the present description.

In some embodiments of Formula (V), R ² is taken together with R ⁴ to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR ²⁴ , O, and S(O) _m as a ring member, the ring optionally substituted by R ²¹ . In some such embodiments, the 5-7 membered heterocyclic ring contains O as an additional heteroatom. In some such embodiments, the 5-7 membered heterocyclic ring contains NR ²⁴ as an additional heteroatom.

In some embodiments, R ² is taken together with R ⁴ to form a 5-membered ring containing no additional heteroatoms (ie, pyrrolidine), which is optionally substituted with R ²¹ . In other embodiments, R ² is taken together with R ⁴ to form a 6-membered ring containing no additional heteroatoms (ie, piperidine), which is optionally substituted with R ²¹ . In other embodiments, R ² is taken together with R ⁴ to form a 6-membered ring containing NR ²⁴ (ie piperazine) which is optionally substituted with R ²¹ . In further embodiments, R ² is taken together with R ⁴ to form a 6-membered ring containing O or S (ie, morpholine or thiomorpholine) which is optionally substituted with R ²¹ . In additional embodiments, R ² is taken together with R ⁴ to form a 7-membered ring that may contain no additional heteroatoms (i.e., homopiperidine) or may contain NR ²⁴ (i.e., homopiperazine), in each case optionally substituted with R ²¹ .

In other embodiments of Formula (V), R ³ is taken together with R ⁵ to form a 5-7 membered heterocyclic ring optionally containing an additional heteroatom selected from NR ²⁴ , O and S(O) _m as a ring member, the ring optionally substituted by R ²¹ . In some such embodiments, the 5-7 membered heterocyclic ring contains O as an additional heteroatom. In some such embodiments, the 5-7 membered heterocyclic ring contains NR ²⁴ as an additional heteroatom.

In some embodiments, R ³ is taken together with R ⁵ to form a 5-membered ring containing no additional heteroatoms (ie, pyrrolidine), which is optionally substituted with R ²¹ . In other embodiments, R ³ is taken together with R ⁵ to form a 6-membered ring containing no additional heteroatoms (ie piperidine) which is optionally substituted with R ²¹ . In other embodiments, R ³ is taken together with R ⁵ to form a 6-membered ring containing NR ²⁴ (ie piperazine) which is optionally substituted with R ²¹ . In further embodiments, R ³ is taken together with R ⁵ to form a 6-membered ring containing O or S(O) _m (ie, morpholine or thiomorpholine) which is optionally substituted with R ²¹ . In additional embodiments, R ³ is taken together with R ⁵ to form a 7-membered ring that may contain no additional heteroatoms (i.e., homopiperidine) or may contain NR ²⁴ (i.e., homopiperazine), in each case optionally substituted with R ²¹ .

In compounds of Formula (V), R ⁶ is H, F, Cl, CN, CH ₃ , CH ₂ F, CHF ₂ or CF ₃ . In some embodiments, R ⁶ is F or Cl. In some such embodiments, R ⁶ is F. In some such embodiments, R ⁶ is Cl. In some embodiments, R ⁶ is H. In other embodiments, R ⁶ is CN, CH ₃ , CH ₂ F, CHF _{2 ,} or CF ₃ .

In the compounds of Formula (V), R ⁷ and R ⁸ are independently H, F, Cl, CN, C ₁ -C ₂ alkyl, C ₁ -C ₂ fluoroalkyl, C ₁ -C ₂ alkoxy, or C ₁ -C ₂ fluoroalkoxy, in which each specified C ₁ -C ₂ alkyl, C ₁ -C ₂ fluoroalkyl, C ₁ -C ₂ alkoxy and C ₁ -C ₂ fluoroalkoxy is optionally substituted with R ²⁰ . In some such embodiments, R ⁷ is H. In some such embodiments, R ⁸ is H. In some such embodiments, R ⁷ and R ⁸ are H.

In compounds of Formula (V), R ⁹ is H, OH, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ . In preferred embodiments of Formula (V), R ⁹ is OH.

In the compounds of Formula (V), each R ¹⁰ is independently F, CN, C ₁ -C ₂ alkyl or C ₁ -C ₂ fluoroalkyl, wherein each said C ₁ -C ₂ alkyl and C ₁ -C ₂ fluoroalkyl is optionally substituted with R ²⁰ . In some embodiments, n is 0 and R ¹⁰ is absent. In other embodiments, n is 1 or 2 and R ¹⁰ is independently F, CN, C ₁ -C ₂ alkyl, or C ₁ -C ₂ fluoroalkyl. In some embodiments, n is 1 or 2 and R ¹⁰ is independently F or CH ₃ .

In some embodiments of Formula (V), Q is NR ¹¹ or O. In some embodiments, Q is O. In some embodiments, Q is O, p is 2, and q is 1. In some such embodiments, n is 0 and R ¹⁰ is missing.

In other embodiments of Formula (V), Q is NR ¹¹ . In some embodiments, Q is NR ¹¹ , p is 2, and q is 1. In some such embodiments, R ¹¹ is SO ₂ R ¹⁴ . In other such embodiments, R ¹¹ is COR ¹⁷ . In some such embodiments, n is 0 and R ¹⁰ is absent.

In some embodiments of Formula (V), Q is CR ¹² R ¹³ wherein R ¹² and R ¹³ are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing NR ¹¹ or O in as a ring member, the ring being optionally further substituted with R ¹⁰ . In some such embodiments, n is 0 and R ¹⁰ is absent.

In compounds of Formula (V), R ¹¹ is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, SO ₂ R ¹⁴ , SO ₂ NR ¹⁵ R ¹⁶ , COR ¹⁷ , COOR ¹⁷ or CONR ¹⁸ R ¹⁹ . In some embodiments, R ¹¹ is SO ₂ R ¹⁴ . In other embodiments, R ¹¹ is COR ¹⁷ .

In compounds of Formula (V), R ¹⁴ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl. In some embodiments, R ¹⁴ is C ₁ -C ₄ alkyl. In some such embodiments, R ¹⁴ is C ₁ -C ₂ alkyl. In some embodiments, R ¹⁴ is C ₁ -C ₄ fluoroalkyl. In some such embodiments, R ¹⁴ is C ₁ -C ₂ fluoroalkyl. In certain embodiments, R ¹⁴ is CH ₃ or C ₂ H ₅ .

In the compounds of Formula (V), each R ¹⁵ and R ¹⁶ is independently H or CH ₃ .

In compounds of Formula (V), R ¹⁷ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each of said C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with R ²⁰ . In some embodiments, R ¹⁷ is C ₁ -C ₄ alkyl, wherein each C ₁ -C ₄ alkyl is optionally substituted with R ²⁰ .

In the compounds of Formula (V), each R ¹⁸ and R ¹⁹ is independently H, C ₁ -C ₄ alkyl, or C ₁ -C ₄ fluoroalkyl, wherein said C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl are each optionally substituted ^R20 .

In the compounds of Formula (V), each R ²⁰ is independently OH, C ₁ -C ₂ alkoxy, C ₁ -C ₂ fluoroalkoxy, CN or NR ²² R ²³ .

In compounds of Formula (V), each R ²¹ is independently F, OH, CN, NR ²² R ²³ , C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy, or C ₁ -C ₄ fluoroalkoxy in which each specified C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ fluoroalkoxy is optionally further substituted with OH, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ . In some embodiments, each R ²¹ is independently F, OH, or C ₁ -C ₄ alkyl.

In some embodiments of Formula (V), each R ²² and R ²³ is independently H, C ₁ -C ₂ alkyl, C ₁ -C ₂ fluoroalkyl. In other embodiments of Formula (V), R ²² and R ²³ may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring in which said ring is optionally substituted with F or OH.

In compounds of Formula (V), R ²⁴ is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, SO ₂ R ²⁵ , SO ₂ NR ²⁶ R ²⁷ , COR ²⁸ , COOR ²⁸ or CONR ²⁹ R ³⁰ . In some embodiments, R ²⁴ is H or C ₁ -C ₄ alkyl. In some embodiments, R ²⁴ is H or C ₁ -C ₂ alkyl.

In compounds of Formula (V), R ²⁵ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl. In some embodiments, R ²⁵ is C ₁ -C ₂ alkyl.

In compounds of Formula (V), each R ²⁶ and R ²⁷ is independently H or CH ₃ .

In compounds of Formula (V), R ²⁸ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each of said C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with OH, C ₁ -C ₂ alkoxy, C ₁ -C ₂ fluoroalkoxy, CN, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ . In some embodiments, R ²⁸ is C ₁ -C ₄ alkyl optionally substituted with OH or C ₁ -C ₂ alkoxy. In some embodiments, R ²⁸ is C ₁ -C ₂ alkyl.

In the compounds of Formula (V), each R ²⁹ and R ³⁰ is independently H, C ₁ -C ₄ alkyl, or C ₁ -C ₄ fluoroalkyl, wherein said C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl are each optionally substituted OH, C ₁ -C ₂ alkoxy, C ₁ -C ₂ fluoroalkoxy, CN, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ . In some embodiments, each R ²⁹ and R ³⁰ is independently H or C ₁ -C ₄ alkyl, wherein each said C ₁ -C ₄ alkyl is optionally substituted with OH or C ₁ -C ₂ alkoxy. In some embodiments, each R ²⁹ and R ³⁰ is independently H or C ₁ -C ₂ alkyl.

In compounds of Formula (V), m is 0, 1, or 2. In some embodiments, m is 2.

In compounds of Formula (V), n is 0, 1, 2, 3, or 4. In some embodiments, n is 0 and R ¹⁰ is absent. In some embodiments, n is 1 or 2.

In compounds of Formula (V), p is 1, 2 or 3; in which the sum of p and q is an integer from 1 to 4. In some embodiments, p is 2. In other embodiments, p is 1. In some embodiments, the sum of p and q is an integer from 1 to 3.

In compounds of Formula (V), q is 0, 1, 2 or 3; in which the sum of p and q is an integer from 1 to 4. In some embodiments, q is 1. In other embodiments, q is 0. In some embodiments, the sum of p and q is an integer from 1 to 3.

In some embodiments, p is 2 and q is 1. In other embodiments, p is 1 and q is 1. In other embodiments, p is 1 and q is 0. In further embodiments, the sum of p and q is an integer of 1 until 3.

In certain embodiments, the invention provides a compound of Formula (V), (VA), (VB), (VC), or (VD), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more of the following: features: R ¹ is Cl; U is NR ² and V is CR ⁴ ; R ² is C ₁ -C ₅ alkyl or R ² is ISO-C ₃ H ₇ ; R ⁴ is C ₁ -C ₄ alkyl, wherein said C ₁ -C ₄ alkyl is optionally substituted with R ²⁰ , in which R ²⁰ is OH; or R ⁴ is CH(OH)CH ₃ or C(OH)(CH ₃ ) ₂ ; X is CR ⁶ ; R ⁶ is F; Y is CR ⁷ ; R ⁷ is H; Z is CR ⁸ ; R ⁸ is H; R ⁹ is OH; Q is O or Q is NR ¹¹ in which R ¹¹ is SO ₂ R ¹⁴ ; R ¹⁴ is C ₁ -C ₄ alkyl; n is 0 and R ¹⁰ is absent; p is 2 and q is 1.

In certain embodiments, the invention provides a compound of Formula (V), (VA), (VB), (VC), or (VD), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more of the following: features: R ¹ is Cl; U is CR ³ and V is NR ⁵ ; R ³ is C ₁ -C ₅ alkyl or R ³ is ISO-C ₃ H ₇ ; R ⁵ is C ₁ -C ₄ alkyl, wherein said C ₁ -C ₄ alkyl is optionally substituted with R ²⁰ ; R ²⁰ is OH; X is CR ⁶ ; R ⁶ is F; Y is CR ⁷ ; R ⁷ is H; Z is CR ⁸ ; R ⁸ is H; R ⁹ is OH; Q is O or Q is NR ¹¹ in which R ¹¹ is SO ₂ R ¹⁴ ; R ¹⁴ is C ₁ -C ₄ alkyl; n is 0 and R ¹⁰ is absent; p is 2 and q is 1.

In a preferred embodiment, the invention provides a compound of Formula (V), (VA), (VB), (VC) or (VD) or a pharmaceutically acceptable salt thereof, wherein: R ¹ is Cl; U is NR ² ; R ² is C ₁ -C ₅ alkyl; V is CR ⁴ ; R ⁴ is C ₁ -C ₄ alkyl optionally substituted with R ²⁰ in which R ²⁰ is OH; X is CR ⁶ ; R ⁶ is F; Y is CR ⁷ ; R ⁷ is H; Z is CR ⁸ ; R ⁸ is H; R ⁹ is OH; Q is O; n is 0 and R ¹⁰ is absent; p is 2 and q is 1.

In another preferred embodiment, the invention provides a compound of Formula (V), (VA), (VB), (VC) or (VD) or a pharmaceutically acceptable salt thereof, wherein: R ¹ is Cl; U is NR ² ; R ² is C ₁ -C ₅ alkyl; V is CR ⁴ ; R ⁴ is C ₁ -C ₄ alkyl optionally substituted with R ²⁰ in which R ²⁰ is OH; X is CR ⁶ ; R ⁶ is F; Y is CR ⁷ ; R ⁷ is H; Z is CR ⁸ ; R ⁸ is H; R ⁹ is OH; Q is NR ¹¹ in which R ¹¹ is SO ₂ R ¹⁴ ; R ¹⁴ is C ₁ -C ₄ alkyl; n is 0 and R ¹⁰ is absent; p is 2 and q is 1.

In certain embodiments, the invention provides a compound of Formula (V), (VA), (VB), (VC) or (VD), or a pharmaceutically acceptable salt thereof, wherein: R ¹ is Cl; U is NR ² ; V is CR ⁴ ; R ² is taken together with R ⁴ to form a 5-7 membered heterocyclic ring optionally containing an additional heteroatom selected from NR ²⁴ , O and S(O) _m as a ring member, the ring being optionally substituted with R ²¹ ; each R ²¹ is independently F, OH or C ₁ -C ₄ alkyl; X is CR ⁶ ; R ⁶ is F; Y is CR ⁷ ; R ⁷ is H; Z is CR ⁸ ; R ⁸ is H; R ⁹ is OH; Q is O or Q is NR ¹¹ in which R ¹¹ is SO ₂ R ¹⁴ ; R ¹⁴ is C ₁ -C ₄ alkyl; n is 0 and R ¹⁰ is absent; p is 2 and q is 1.

In certain embodiments, the invention provides a compound of Formula (V), (VA), (VB), (VC), or (VD), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more of the following: features: R ¹ is Cl; U is CR ³ ; V is NR ⁵ ; R ³ is taken together with R ⁵ to form a 5-7 membered heterocyclic ring optionally containing an additional heteroatom selected from NR ²⁴ , O and S(O) _m as a ring member, the ring being optionally substituted with R ²¹ ; each R ²¹ is independently F, OH or C ₁ -C ₄ alkyl; X is CR ⁶ ; R ⁶ is F; Y is CR ⁷ ; R ⁷ is H; Z is CR ⁸ ; R ⁸ is H; R ⁹ is OH; Q is O or Q is NR ¹¹ in which R ¹¹ is SO ₂ R ¹⁴ ; R ¹⁴ is C ₁ -C ₄ alkyl; n is 0 and R ¹⁰ is absent; p is 2 and q is 1.

In certain embodiments, the invention provides a compound of Formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D) or a pharmaceutically acceptable salt or compound of Formula (V), (VA) , (VB), (VC) or (VD) or a pharmaceutically acceptable salt thereof having a combination of two or more, preferably three or more, and more preferably four or more of the following: R ¹ is F or Cl; U is NR ² and V is CR ⁴ ; R ² is C ₁ -C ₅ alkyl, C ₁ -C ₅ fluoroalkyl or 3-6 membered heterocyclyl or R ² is CH ₃ , ISO-C ₃ H ₇ , ISO-C ₄ H ₉ , sec-C ₄ H ₉ , tert-C ₄ H ₉ , CH ₂ F, CHF ₂ , CH ₂ CHF ₂ or oxetan-3-yl; R ⁴ is H or C ₁ -C ₄ alkyl, wherein said C ₁ -C ₄ alkyl is optionally substituted with OH, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ ; or R ⁴ is H, CH ₃ , C ₂ H ₅ , CH ₂ OH, CH(OH)CH ₃ , CH ₂ CH ₂ OH or CH ₂ NH ₂ ; or R ² is taken together with R ⁴ to form a 5-7 membered heterocyclic ring optionally containing an additional heteroatom selected from NR ²⁴ , O and S(O) _m as a ring member, the ring being optionally substituted with R ²¹ ; or R ⁴ is CH(OH)CH ₃ or C(OH)(CH ₃ ) ₂ ; X is CR ⁶ ; R ⁶ is H or F; Y is CR ⁷ ; Z is CR ⁸ ; R ⁷ and R ⁸ are H; R ⁹ is OH; Q is NR ¹¹ ; R ¹¹ is SO ₂ R ¹⁴ ; R ¹⁴ is C ₁ -C ₄ alkyl; n is 0 and R ¹⁰ is absent; p is 2 and q is 1.

In certain embodiments, the invention provides a compound of Formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D) or a pharmaceutically acceptable salt or compound of Formula (V), (VA) , (VB), (VC) or (VD) or a pharmaceutically acceptable salt thereof having a combination of two or more, preferably three or more, and more preferably four or more of the following: R ¹ is F or Cl; U is CR ³ and V is NR ⁵ ; R ³ is C ₁ -C ₅ alkyl, C ₁ -C ₅ fluoroalkyl or 3-6 membered heterocyclyl or R ³ is CH ₃ , ISO-C ₃ H ₇ , ISO-C ₄ H ₉ , sec-C ₄ H ₉ , tert-C ₄ H ₉ , CH ₂ F, CHF ₂ , CH ₂ CHF ₂ or oxetan-3-yl; R ⁵ is H or C ₁ -C ₄ alkyl; or R ⁵ is H or CH ₃ ; or R ³ is taken together with R ⁵ to form a 5-7 membered heterocyclic ring optionally containing an additional heteroatom selected from NR ²⁴ , O and S(O) _m as a ring member, the ring being optionally substituted with R ²¹ ; X is CR ⁶ ; R ⁶ is H or F; Y is CR ⁷ ; Z is CR ⁸ ; R ⁷ and R ⁸ are H; R ⁹ is OH; n is 0 and R ¹⁰ is absent; Q is NR ¹¹ ; R ¹¹ is SO ₂ R ¹⁴ and R ¹⁴ is C ₁ -C ₄ alkyl; p is 2 and q is 1.

In the compounds of Formula (II) and (IV) R ¹ is H, F, Cl, CN, C ₁ -C ₂ alkyl or C ₁ -C ₂ fluoroalkyl, in which each specified C ₁ -C ₂ alkyl and C ₁ - C ₂ fluoroalkyl is optionally substituted with R ²⁰ .

In some embodiments of Formulas (II) and (IV), R ¹ is H. In other embodiments, R ¹ is F or Cl. In other embodiments, R ¹ is Cl. In additional embodiments, R ¹ is C ₁ -C ₂ alkyl or C ₁ -C ₂ fluoroalkyl, wherein each of said C ₁ -C ₂ alkyl and C ₁ -C ₂ fluoroalkyl is optionally substituted with R ²⁰ . In some such embodiments, R ¹ is CH ₃ optionally substituted with R ²⁰ . In certain embodiments, R ¹ is CH ₃ .

In the compounds of Formula (II) and (IV), the ring system containing U, V, X, Y and Z is a fused biaryl ring system.

In the compounds of Formula (II) and (IV) U represents NR ² or CR ³ . In some embodiments, U is NR ² . In other embodiments, U is CR ³ .

In compounds of Formula (II) and (IV) V is N or CR ⁴ when U is NR ² ; and V is NR ⁵ when U is CR ³ . In some such embodiments, V is CR ⁴ . In other such embodiments, V is N. In further such embodiments, V is NR ⁵ .

In compounds of Formula (II) and (IV), X is CR ⁶ or N. In some embodiments, X is CR ⁶ . In other embodiments, X is N.

In compounds of Formula (II) and (IV), Y is CR ⁷ or N. In some embodiments, Y is CR ⁷ . In other embodiments, Y is N.

In compounds of Formula (II) and (IV), Z is CR ⁸ or N. In some embodiments, Z is CR ⁸ . In other embodiments, Z is N.

In some embodiments of Formulas (II) and (IV), X is CR ⁶ , Y is CR ⁷ and Z is CR ⁸ . In some such embodiments, U is NR ² and V is CR ⁴ . In other such embodiments, U is NR ² and V is N. In yet other such embodiments, U is CR ³ and V is NR ⁵ .

In some embodiments of Formulas (II) and (IV), X is N, Y is CR ⁷ and Z is CR ⁸ .

In some embodiments of Formulas (II) and (IV), X is CR ⁶ , Y is N, and Z is CR ⁸ .

In some embodiments of Formulas (II) and (IV), X is CR ⁶ , Y is CR ⁷ and Z is N.

In some embodiments of Formulas (II) and (IV), X is N, Y is N, and Z is CR ⁸ .

In some embodiments of Formulas (II) and (IV), X is CR ⁶ , Y is N, and Z is N.

In some embodiments of Formulas (II) and (IV), X is N, Y is CR ⁷ and Z is N.

In other embodiments of Formulas (II) and (IV), at least one of X, Y and Z is N. In some such embodiments, U is NR ² and V is CR ⁴ . In other such embodiments, U is NR ² and V is N. In yet other such embodiments, U is CR ³ and V is NR ⁵ .

In additional embodiments of Formulas (II) and (IV), two of X, Y and Z are N. In some such embodiments, U is NR ² and V is CR ⁴ . In other such embodiments, U is NR ² and V is N. In yet other such embodiments, U is CR ³ and V is NR ⁵ .

In the compounds of Formula (III) and (V) R ¹ is H, F, Cl, CN, C ₁ -C ₂ alkyl or C ₁ -C ₂ fluoroalkyl, in which each specified C ₁ -C ₂ alkyl and C ₁ - C ₂ fluoroalkyl is optionally substituted with R ²⁰ .

In some embodiments of Formulas (III) and (V), R ¹ is H. In other embodiments, R ¹ is F or Cl. In other embodiments, R ¹ is Cl. In additional embodiments, R ¹ is C ₁ -C ₂ alkyl or C ₁ -C ₂ fluoroalkyl, wherein each of said C ₁ -C ₂ alkyl and C ₁ -C ₂ fluoroalkyl is optionally substituted with R ²⁰ . In some such embodiments, R ¹ is CH ₃ optionally substituted with R ²⁰ . In certain embodiments, R ¹ is CH ₃ .

In the compounds of Formula (III) and (V), the ring system containing U, V, X, Y and Z is a fused biaryl ring system.

In the compounds of Formula (III) and (V) U represents NR ² or CR ³ . In some embodiments, U is NR ² . In other embodiments, U is CR ³ .

In the compounds of Formula (III) and (V), V is N or CR ⁴ when U is NR ² ; and V is NR ⁵ when U is CR ³ . In some such embodiments, V is CR ⁴ . In other such embodiments, V is N. In further such embodiments, V is NR ⁵ .

In compounds of Formula (III) and (V), X is CR ⁶ or N. In some embodiments, X is CR ⁶ . In other embodiments, X is N.

In compounds of Formula (III) and (V), Y is CR ⁷ or N. In some embodiments, Y is CR ⁷ . In other embodiments, Y is N.

In compounds of Formula (III) and (V), Z is CR ⁸ or N. In some embodiments, Z is CR ⁸ . In other embodiments, Z is N.

In some embodiments of Formulas (III) and (V), X is CR ⁶ , Y is CR ⁷ and Z is CR ⁸ . In some such embodiments, U is NR ² and V is CR ⁴ . In other such embodiments, U is NR ² and V is N. In yet other such embodiments, U is CR ³ and V is NR ⁵ .

In some embodiments of Formulas (III) and (V), X is N, Y is CR ⁷ and Z is CR ⁸ .

In some embodiments of Formulas (III) and (V), X is CR ⁶ , Y is N, and Z is CR ⁸ .

In some embodiments of Formulas (III) and (V), X is CR ⁶ , Y is CR ⁷ and Z is N.

In some embodiments of Formulas (III) and (V), X is N, Y is N, and Z is CR ⁸ .

In some embodiments of Formulas (III) and (V), X is CR ⁶ , Y is N, and Z is N.

In some embodiments of Formulas (III) and (V), X is N, Y is CR ⁷ and Z is N.

In other embodiments of Formulas (III) and (V), at least one of X, Y, and Z is N. In some such embodiments, U is NR ² and V is CR ⁴ . In other such embodiments, U is NR ² and V is N. In still other such embodiments, U is CR ³ and V is NR ⁵ .

In additional embodiments of Formulas (III) and (V), two of X, Y, and Z are N. In some such embodiments, U is NR ² and V is CR ⁴ . In other such embodiments, U is NR ² and V is N. In still other such embodiments, U is CR ³ and V is NR ⁵ .

In certain embodiments of each of Formulas (I), (II), (III), (IV), and (V), the fused biaryl ring system containing U, V, X, Y, and Z is selected from the group consisting of:

in which ⃰ represents the point of attachment to the pyrimidine ring or pyridine ring and R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are as further defined in the present description.

In another aspect, the invention provides a compound of Formula (VI):

(VI)

(VI)

or a pharmaceutically acceptable salt thereof, in which:

R ¹ , R ² , R ⁴ , R ⁶ -R ²³ , Q, n, p and q are as defined for Formula (II); or

R ¹ , R ² , R ⁴ , R ⁶ -R ²³ , Q, m, n, p and q are as defined for Formula (IV).

In certain embodiments, the invention provides a compound of Formula (VI), (VI-A), (VI-B), (VI-C), or (VI-D), or a pharmaceutically acceptable salt thereof, wherein:

R ¹ , R ² , R ⁴ , R ⁶ -R ²³ and n are as defined for Formula (II).

In other embodiments, the invention provides a compound of Formula (VI), (VI-A), (VI-B), (VI-C) or (VI-D) or a pharmaceutically acceptable salt thereof, wherein:

R ¹ , R ² , R ⁴ , R ⁶ -R ³⁰ , m and n are as defined for Formula (IV).

In some embodiments, a compound of Formula (VI) has absolute stereochemistry as shown in one of Formulas (VI-A), (VI-B), (VI-C), or (VI-D):

or a pharmaceutically acceptable salt thereof.

Each of the aspects and embodiments described herein with respect to Formula (II) is also applicable to compounds of Formula (VI) that do not conflict with that aspect or embodiment.

Each of the aspects and embodiments described herein with respect to Formula (IV) is also applicable to compounds of Formula (VI) that do not conflict with that aspect or embodiment.

In certain embodiments, the invention provides a compound of Formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more and more preferably four or more of the following features: R ¹ is Cl; R ² is C ₁ -C ₅ alkyl or R ² is ISO-C ₃ H ₇ ; R ⁴ is C ₁ -C ₄ alkyl, wherein said C ₁ -C ₄ alkyl is optionally substituted with R ²⁰ , in which R ²⁰ is OH; or R ⁴ is CH(OH)CH ₃ or C(OH)(CH ₃ ) ₂ ; R ⁶ is F; R ⁷ is H; R ⁸ is H; R ⁹ is OH; Q is O or Q is NR ¹¹ where R ¹¹ is SO ₂ R ¹⁴ ; R ¹⁴ is C ₁ -C ₄ alkyl; n is 0 and R ¹⁰ is absent; p is 2 and q is 1.

In certain embodiments, the invention provides a compound of Formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more and more preferably four or more of the following features: R ¹ is Cl; R ³ is C ₁ -C ₅ alkyl or R ³ is ISO-C ₃ H ₇ ; R ⁵ is C ₁ -C ₄ alkyl, wherein said C ₁ -C ₄ alkyl is optionally substituted with R ²⁰ ; R ²⁰ is OH; R ⁶ is F; R ⁷ is H; R ⁸ is H; R ⁹ is OH; Q is O or Q is NR ¹¹ where R ¹¹ is SO ₂ R ¹⁴ ; R ¹⁴ is C ₁ -C ₄ alkyl; n is 0 and R ¹⁰ is absent; p is 2 and q is 1.

In a preferred embodiment, the invention provides a compound of Formula (IV), (IV-A), (IV-B), (IV-C) or (IV-D) or a pharmaceutically acceptable salt thereof, wherein: R ¹ is Cl; R ² is C ₁ -C ₅ alkyl; R ⁴ is C ₁ -C ₄ alkyl optionally substituted with R ²⁰ in which R ²⁰ is OH; R ⁶ is F; R ⁷ is H; R ⁸ is H; R ⁹ is OH; Q is O; n is 0 and R ¹⁰ is absent; p is 2 and q is 1.

In another preferred embodiment, the invention provides a compound of Formula (IV), (IV-A), (IV-B), (IV-C) or (IV-D) or a pharmaceutically acceptable salt thereof, wherein: R ¹ is Cl ; R ² is C ₁ -C ₅ alkyl; R ⁴ is C ₁ -C ₄ alkyl optionally substituted with R ²⁰ in which R ²⁰ is OH; R ⁶ is F; R ⁷ is H; R ⁸ is H; R ⁹ is OH; Q is NR ¹¹ in which R ¹¹ is SO ₂ R ¹⁴ ; R ¹⁴ is C ₁ -C ₄ alkyl; n is 0 and R ¹⁰ is absent; p is 2 and q is 1.

In certain embodiments, the invention provides a compound of Formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more and more preferably four or more of the following features: R ¹ is F or Cl; R ² is C ₁ -C ₅ alkyl, C ₁ -C ₅ fluoroalkyl or 3-6 membered heterocyclyl or R ² is CH ₃ , ISO-C ₃ H ₇ , ISO-C ₄ H ₉ , sec-C ₄ H ₉ , tert-C ₄ H ₉ , CH ₂ F, CHF ₂ , CH ₂ CHF ₂ or oxetan-3-yl; R ⁴ is H or C ₁ -C ₄ alkyl, wherein said C ₁ -C ₄ alkyl is optionally substituted with OH, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ ; or R ⁴ is H, CH ₃ , C ₂ H ₅ , CH ₂ OH, CH(OH)CH ₃ , CH ₂ CH ₂ OH or CH ₂ NH ₂ ; R ⁶ is H or F; R ⁷ and R ⁸ are H; R ⁹ is OH; Q is NR ¹¹ ; R ¹¹ is SO ₂ R ¹⁴ ; R ¹⁴ is C ₁ -C ₄ alkyl; n is 0 and R ¹⁰ is absent; p is 2 and q is 1.

In certain embodiments, the invention provides a compound of Formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more and more preferably four or more of the following features: R ¹ is F or Cl; R ² is C ₁ -C ₅ alkyl, C ₁ -C ₅ fluoroalkyl or 3-6 membered heterocyclyl or R ² is CH ₃ , ISO-C ₃ H ₇ , ISO-C ₄ H ₉ , sec-C ₄ H ₉ , tert-C ₄ H ₉ , CH ₂ F, CHF ₂ , CH ₂ CHF ₂ or oxetan-3-yl; R ⁴ is H or C ₁ -C ₄ alkyl, wherein said C ₁ -C ₄ alkyl is optionally substituted with OH, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ ; or R ⁴ is H, CH ₃ , C ₂ H ₅ , CH ₂ OH, CH(OH)CH ₃ , CH ₂ CH ₂ OH or CH ₂ NH ₂ ; or R ² is taken together with R ⁴ to form a 5-7 membered heterocyclic ring optionally containing an additional heteroatom selected from NR ²⁴ , O and S(O) _m as a ring member, the ring being optionally substituted with R ²¹ ; R ⁶ is H or F; R ⁷ and R ⁸ are H; R ⁹ is OH; Q is NR ¹¹ ; R ¹¹ is SO ₂ R ¹⁴ ; R ¹⁴ is C ₁ -C ₄ alkyl; n is 0 and R ¹⁰ is absent; p is 2 and q is 1.

In another aspect, the invention provides a compound of Formula (VII):

(VII)

(VII)

or a pharmaceutically acceptable salt thereof, in which:

R ¹ , R ³ , R ⁵ -R ²³ , Q, n, p and q are as defined for Formula (II); or

R ¹ , R ³ , R ⁵ -R ³⁰ , Q, m, n, p and q are as defined for Formula (IV).

In certain embodiments, the invention provides a compound of Formula (VII), (VII-A), (VII-B), (VII-C), or (VII-D), or a pharmaceutically acceptable salt thereof, wherein:

R ¹ , R ² , R ⁴ , R ⁶ -R ²³ and n are as defined for Formula (II).

In other embodiments, the invention provides a compound of Formula (VII), (VII-A), (VII-B), (VII-C), or (VII-D), or a pharmaceutically acceptable salt thereof, wherein:

R ¹ , R ² , R ⁴ , R ⁶ -R ³⁰ , m and n are as defined for Formula (IV).

In some embodiments, a compound of Formula (VII) has absolute stereochemistry as shown in one of Formulas (VII-A), (VII-B), (VII-C), or (VII-D):

or a pharmaceutically acceptable salt thereof.

Each of the aspects and embodiments described herein with respect to Formula (II) is also applicable to compounds of Formula (VII) that do not conflict with that aspect or embodiment.

Each of the aspects and embodiments described herein with respect to Formula (IV) is also applicable to compounds of Formula (VII) that do not conflict with that aspect or embodiment.

In certain embodiments, the invention provides a compound of Formula (VII), (VII-A), (VII-B), (VII-C), or (VII-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more and more preferably four or more of the following features: R ¹ is Cl; R ³ is C ₁ -C ₅ alkyl or R ³ is ISO-C ₃ H ₇ ; R ⁵ is C ₁ -C ₄ alkyl, wherein said C ₁ -C ₄ alkyl is optionally substituted with R ²⁰ ; R ²⁰ is OH; R ⁶ is F; R ⁷ is H; R ⁸ is H; R ⁹ is OH; Q is O or Q is NR ¹¹ where R ¹¹ is SO ₂ R ¹⁴ ; R ¹⁴ is C ₁ -C ₄ alkyl; n is 0 and R ¹⁰ is absent; p is 2 and q is 1.

In a preferred embodiment, the invention provides a compound of Formula (VII), (VII-A), (VII-B), (VII-C) or (VII-D) or a pharmaceutically acceptable salt thereof, wherein: R ¹ is Cl; R ³ is C ₁ -C ₅ alkyl; R ⁵ is C ₁ -C ₄ alkyl optionally substituted with R ²⁰ in which R ²⁰ is OH; R ⁶ is F; R ⁷ is H; R ⁸ is H; R ⁹ is OH; Q is O; n is 0 and R ¹⁰ is absent; p is 2 and q is 1.

In another preferred embodiment, the invention provides a compound of Formula (VII), (VII-A), (VII-B), (VII-C) or (VII-D) or a pharmaceutically acceptable salt thereof, wherein: R ¹ is Cl ; R ³ is C ₁ -C ₅ alkyl; R ⁵ is C ₁ -C ₄ alkyl optionally substituted with R ²⁰ in which R ²⁰ is OH; R ⁶ is F; R ⁷ is H; R ⁸ is H; R ⁹ is OH; Q is NR ¹¹ in which R ¹¹ is SO ₂ R ¹⁴ ; R ¹⁴ is C ₁ -C ₄ alkyl; n is 0 and R ¹⁰ is absent; p is 2 and q is 1.

In certain embodiments, the invention provides a compound of Formula (VII), (VII-A), (VII-B), (VII-C), or (VII-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more and more preferably four or more of the following features: R ¹ is F or Cl; R ³ is C ₁ -C ₅ alkyl, C ₁ -C ₅ fluoroalkyl or 3-6 membered heterocyclyl or R ³ is CH ₃ , ISO-C ₃ H ₇ , ISO-C ₄ H ₉ , sec-C ₄ H ₉ , tert-C ₄ H ₉ , CH ₂ F, CHF ₂ , CH ₂ CHF ₂ or oxetan-3-yl; R ⁵ is H or C ₁ -C ₄ alkyl or R ⁵ is H or CH ₃ ;, R ⁶ is H or F; R ⁷ and R ⁸ are H; R ⁹ is OH; Q is NR ¹¹ ; R ¹¹ is SO ₂ R ¹⁴ ; R ¹⁴ is C ₁ -C ₄ alkyl; n is 0 and R ¹⁰ is absent; p is 2 and q is 1.

In certain embodiments, the invention provides a compound of Formula (VII), (VII-A), (VII-B), (VII-C), or (VII-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more and more preferably four or more of the following features: R ¹ is F or Cl; R ³ is C ₁ -C ₅ alkyl, C ₁ -C ₅ fluoroalkyl or 3-6 membered heterocyclyl or R ³ is CH ₃ , ISO-C ₃ H ₇ , ISO-C ₄ H ₉ , sec-C ₄ H ₉ , tert-C ₄ H ₉ , CH ₂ F, CHF ₂ , CH ₂ CHF ₂ or oxetan-3-yl; R ⁵ is H or C ₁ -C ₄ alkyl or R ⁵ is H or CH ₃ ; or R ³ is taken together with R ⁵ to form a 5-7 membered heterocyclic ring optionally containing an additional heteroatom selected from NR ²⁴ , O and S(O) _m as a ring member, the ring being optionally substituted with R ²¹ ; R ⁶ is H or F; R ⁷ and R ⁸ are H; R ⁹ is OH; Q is NR ¹¹ ; R ¹¹ is SO ₂ R ¹⁴ ; R ¹⁴ is C ₁ -C ₄ alkyl; n is 0 and R ¹⁰ is absent; p is 2 and q is 1.

In another aspect, the invention provides a compound of Formula (VIII):

(VIII)

(VIII)

or a pharmaceutically acceptable salt thereof, in which:

R ¹ , R ² , R ⁶ -R ²³ , Q, n, p and q are as defined for Formula (II); or

R ¹ , R ² , R ⁶ -R ³⁰ , Q, m, n, p and q are as defined for Formula (IV).

In certain embodiments, the invention provides a compound of Formula (VIII), or a pharmaceutically acceptable salt thereof, wherein:

R ¹ , R ² , R ⁴ , R ⁶ -R ²³ and n are as defined for Formula (II).

In other embodiments, the invention provides a compound of Formula (VIII), or a pharmaceutically acceptable salt thereof, wherein:

R ¹ , R ² , R ⁴ , R ⁶ -R ³⁰ , m and n are as defined for Formula (IV).

In some embodiments, a compound of Formula (VIII) has absolute stereochemistry as shown in one of Formulas (VIII-A), (VIII-B), (VIII-C), or (VIII-D):

or a pharmaceutically acceptable salt thereof.

Each of the aspects and embodiments described herein with respect to Formula (II) is also applicable to compounds of Formula (VIII) that do not conflict with that aspect or embodiment.

Each of the aspects and embodiments described herein with respect to Formula (IV) is also applicable to compounds of Formula (VIII) that do not conflict with that aspect or embodiment.

In an embodiment, the invention provides a compound of Formula (VIII), (VIII-A), (VIII-B), (VIII-C) or (VIII-D), or a pharmaceutically acceptable salt thereof, wherein: R ¹ is Cl; R ² is C ₁ -C ₅ alkyl optionally substituted with R ²⁰ in which R ²⁰ is OH; R ⁶ is F; R ⁷ is H; R ⁸ is H; R ⁹ is OH; Q is O or Q is NR ¹¹ ; R ¹¹ is SO ₂ R ¹⁴ ; R ¹⁴ is C ₁ -C ₄ alkyl; n is 0 and R ¹⁰ is absent; p is 2 and q is 1.

In certain embodiments, the invention provides a compound of Formula (VIII), (VIII-A), (VIII-B), (VIII-C), or (VIII-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more and more preferably four or more of the following features: R ¹ is F or Cl; R ² is C ₁ -C ₅ alkyl, C ₁ -C ₅ fluoroalkyl or 3-6 membered heterocyclyl or R ² is CH ₃ , ISO-C ₃ H ₇ , ISO-C ₄ H ₉ , sec-C ₄ H ₉ , tert-C ₄ H ₉ , CH ₂ F, CHF ₂ , CH ₂ CHF ₂ or oxetan-3-yl; R ⁶ is H or F; R ⁷ and R ⁸ are H; R ⁹ is OH; Q is O or Q is NR ¹¹ ; R ¹¹ is SO ₂ R ¹⁴ ; R ¹⁴ is C ₁ -C ₄ alkyl; n is 0 and R ¹⁰ is absent; p is 2 and q is 1.

In certain embodiments of Formulas (I)-(VIII), the Q-containing ring is selected from the group consisting of:

in which ⃰ denotes the point of attachment to the 2-amino substituent.

In certain embodiments of Formulas (I)-(VIII), the Q-containing ring is selected from the group consisting of:

in which ⃰ denotes the point of attachment to the 2-amino substituent.

In certain embodiments of Formulas (I)-(VIII), the Q-containing ring is selected from the group consisting of:

in which ⃰ denotes the point of attachment to the 2-amino substituent.

In certain embodiments of Formulas (I)-(VIII), the Q-containing ring is selected from the group consisting of:

in which ⃰ denotes the point of attachment to the 2-amino substituent.

In another aspect, the invention provides a compound of Formula (IX):

(IX)

(IX)

or a pharmaceutically acceptable salt thereof, in which:

R ¹ , R ² , R ⁴ , R ⁶ -R ¹¹ , R ¹⁴ -R ²³ and n are as defined for Formula (II); or

R ¹ , R ² , R ⁴ , R ⁶ to R ¹¹ , R ¹⁴ to R ³⁰ , m and n are as defined for Formula (IV).

In some embodiments, the invention provides a compound of Formula (IX), or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ⁴ , R ⁶ -R ¹¹ , R ¹⁴ -R ²³ and n are as defined for Formula (II ).

In embodiments of Formula (IX) in which the substituent groups are as defined for Formula (II), the invention provides a compound of Formula (IX):

(IX)

(IX)

or a pharmaceutically acceptable salt thereof, in which:

R ¹ is H, F, Cl, CN, C ₁ -C ₂ alkyl or C ₁ -C ₂ fluoroalkyl, wherein each C ₁ -C ₂ alkyl and C ₁ -C ₂ fluoroalkyl is optionally substituted with R ²⁰ ;

R ² is H, C ₁ -C ₅ alkyl, C ₁ -C ₅ fluoroalkyl, C ₃ -C ₈ cycloalkyl, or 3-6 membered heterocyclyl, wherein said C ₁ -C ₅ alkyl and C ₁ -C ₅ are each fluoroalkyl is optionally substituted with R ²⁰ and each of said C ₃ -C ₈ cycloalkyl and 3-6 membered heterocyclyl is optionally substituted with R ²¹ ;

R ⁴ is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy or C ₁ -C ₄ fluoroalkoxy, wherein each is C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ fluoroalkoxy are optionally substituted with R ²⁰ ;

R ⁶ is H, F, Cl, CN, CH ₃ , CH ₂ F, CHF ₂ or CF ₃ ;

R ⁷ and R ⁸ are independently H, F, Cl, CN, C ₁ -C ₂ alkyl, C ₁ -C ₂ fluoroalkyl, C ₁ -C ₂ alkoxy, or C ₁ -C ₂ fluoroalkoxy, wherein each C ₁ -C ₂ alkyl, C ₁ -C ₂ fluoroalkyl, C ₁ -C ₂ alkoxy and C ₁ -C ₂ fluoroalkoxy are optionally substituted with R ²⁰ ;

R ⁹ is H, OH, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ ;

each R ¹⁰ is independently F, CN, C ₁ -C ₂ alkyl, or C ₁ -C ₂ fluoroalkyl, wherein each said C ₁ -C ₂ alkyl and C ₁ -C ₂ fluoroalkyl is optionally substituted with R ²⁰ ;

R ¹¹ is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, SO ₂ R ¹⁴ , SO ₂ NR ¹⁵ R ¹⁶ , COR ¹⁷ , COOR ¹⁷ or CONR ¹⁸ R ¹⁹ ;

R ¹⁴ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl;

each R ¹⁵ and R ¹⁶ is independently H or CH ₃ ;

R ¹⁷ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with R ²⁰ ;

each R ¹⁸ and R ¹⁹ is independently H, C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each said C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with R ²⁰ ;

each R ²⁰ is independently OH, C ₁ -C ₂ alkoxy, C ₁ -C ₂ fluoroalkoxy, CN or NR ²² R ²³ ;

each R ²¹ is independently F, OH, CN, NR ²² R ²³ , C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy or C ₁ -C ₄ fluoroalkoxy, in which each specified C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ fluoroalkoxy optionally further substituted with OH, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ ;

each R ²² and R ²³ is independently H, C ₁ -C ₂ alkyl or C ₁ -C ₂ fluoroalkyl or

R ²² and R ²³ may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring which is optionally substituted with F or OH; And

n is 0, 1, 2, 3, or 4.

In other embodiments, the invention provides a compound of Formula (IX'), or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ⁴ , R ⁶ -R ¹¹ , R ¹⁴ -R ²³ and n are as defined for Formula ( IV).

In embodiments of Formula (IX) in which the substituent groups are as defined for Formula (IV), the invention provides a compound of Formula (IX'):

(IX’)

(IX')

or a pharmaceutically acceptable salt thereof, in which:

R ¹ is H, F, Cl, CN, C ₁ -C ₂ alkyl or C ₁ -C ₂ fluoroalkyl, wherein each C ₁ -C ₂ alkyl and C ₁ -C ₂ fluoroalkyl is optionally substituted with R ²⁰ ;

R ² is H, C ₁ -C ₅ alkyl, C ₁ -C ₅ fluoroalkyl, C ₃ -C ₈ cycloalkyl, or 3-6 membered heterocyclyl, wherein said C ₁ -C ₅ alkyl and C ₁ -C ₅ are each fluoroalkyl is optionally substituted with R ²⁰ and each of said C ₃ -C ₈ cycloalkyl and 3-6 membered heterocyclyl is optionally substituted with R ²¹ ; And

R ⁴ is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy or C ₁ -C ₄ fluoroalkoxy, wherein each is C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ fluoroalkoxy are optionally substituted with R ²⁰ ; or

R ² can be taken together with R ⁴ to form a 5-7 membered heterocyclic ring optionally containing an additional heteroatom selected from NR ²⁴ , O and S(O) _m as a ring member, the ring being optionally substituted with R ²¹ ;

R ⁶ is H, F, Cl, CN, CH ₃ , CH ₂ F, CHF ₂ or CF ₃ ;

R ⁷ and R ⁸ are independently H, F, Cl, CN, C ₁ -C ₂ alkyl, C ₁ -C ₂ fluoroalkyl, C ₁ -C ₂ alkoxy, or C ₁ -C ₂ fluoroalkoxy, wherein each C ₁ -C ₂ alkyl, C ₁ -C ₂ fluoroalkyl, C ₁ -C ₂ alkoxy and C ₁ -C ₂ fluoroalkoxy are optionally substituted with R ²⁰ ;

R ⁹ is H, OH, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ ;

each R ¹⁰ is independently F, CN, C ₁ -C ₂ alkyl, or C ₁ -C ₂ fluoroalkyl, wherein each said C ₁ -C ₂ alkyl and C ₁ -C ₂ fluoroalkyl is optionally substituted with R ²⁰ ;

R ¹¹ is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, SO ₂ R ¹⁴ , SO ₂ NR ¹⁵ R ¹⁶ , COR ¹⁷ , COOR ¹⁷ or CONR ¹⁸ R ¹⁹ ;

R ¹⁴ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl;

each R ¹⁵ and R ¹⁶ is independently H or CH ₃ ;

R ¹⁷ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with R ²⁰ ;

each R ¹⁸ and R ¹⁹ is independently H, C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each said C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with R ²⁰ ;

each R ²⁰ is independently OH, C ₁ -C ₂ alkoxy, C ₁ -C ₂ fluoroalkoxy, CN or NR ²² R ²³ ;

each R ²¹ is independently F, OH, CN, NR ²² R ²³ , C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy or C ₁ -C ₄ fluoroalkoxy, in which each specified C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ fluoroalkoxy optionally further substituted with OH, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ ;

each R ²² and R ²³ is independently H, C ₁ -C ₂ alkyl or C ₁ -C ₂ fluoroalkyl or

R ²² and R ²³ may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring which is optionally substituted with F or OH;

R ²⁴ is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, SO ₂ R ²⁵ , SO ₂ NR ²⁶ R ²⁷ , COR ²⁸ , COOR ²⁸ or CONR ²⁹ R ³⁰ ;

R ²⁵ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl;

each R ²⁶ and R ²⁷ is independently H or CH ₃ ;

R ²⁸ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with OH, C ₁ -C ₂ alkoxy, C ₁ -C ₂ fluoroalkoxy, CN, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ ;

each R ²⁹ and R ³⁰ is independently H, C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each said C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with OH, C ₁ -C ₂ alkoxy, C ₁ -C ₂ fluoroalkoxy, CN, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ ;

m is 0, 1 or 2 and

n is 0, 1, 2, 3, or 4.

In some embodiments, a compound of Formula (IX) or (IX') has absolute stereochemistry as shown in one of Formulas (IX-A), (IX-B), (IX-C) or (IX-D) or Formulas ( IX'-A), (IX'-B), (IX'-C) or (IX'-D)

or a pharmaceutically acceptable salt thereof.

Each of the aspects and embodiments described herein with respect to Formula (II) is also applicable to compounds of Formulas (IX), (IX-A), (IX-B), (IX-C) or (IX-D), which do not conflict with such aspect or embodiment.

Each of the aspects and embodiments described herein with respect to Formula (IX) is also applicable to compounds of Formula (IX-A), (IX-B), (IX-C) or (IX-D).

In certain embodiments, the invention provides a compound of Formula (IX), (IX-A), (IX-B), (IX-C), or (IX-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more and more preferably four or more of the following features: R ¹ is Cl; R ² is C ₁ -C ₅ alkyl or R ² is ISO-C ₃ H ₇ ; R ⁴ is C ₁ -C ₄ alkyl, wherein said C ₁ -C ₄ alkyl is optionally substituted with R ²⁰ , in which R ²⁰ is OH; or R ⁴ is CH(OH)CH ₃ or C(OH)(CH ₃ ) ₂ ; R ⁶ is F; R ⁷ is H; R ⁸ is H; R ⁹ is OH; R ¹¹ is SO ₂ R ¹⁴ ; R ¹⁴ is C ₁ -C ₄ alkyl; n is 0 and R ¹⁰ is absent.

In a preferred embodiment, the invention provides a compound of Formula (IX), (IX-A), (IX-B), (IX-C) or (IX-D) or a pharmaceutically acceptable salt thereof, wherein: R ¹ is Cl; R ² is C ₁ -C ₅ alkyl or R ² is ISO-C ₃ H ₇ ; R ⁴ is C ₁ -C ₄ alkyl optionally substituted with R ²⁰ in which R ²⁰ is OH; or R ⁴ is CH(OH)CH ₃ or C(OH)(CH ₃ ) ₂ ; R ⁶ is F; R ⁷ is H; R ⁸ is H; R ⁹ is OH; R ¹¹ is SO ₂ R ¹⁴ ; R ¹⁴ is C ₁ -C ₄ alkyl; n is 0 and R ¹⁰ is absent.

In certain embodiments, the invention provides a compound of Formulas (IX), (IX-A), (IX-B), (IX-C), or (IX-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more and more preferably four or more of the following features: R ¹ is F or Cl; R ² is C ₁ -C ₅ alkyl, C ₁ -C ₅ fluoroalkyl or 3-6 membered heterocyclyl or R ² is CH ₃ , ISO-C ₃ H ₇ , ISO-C ₄ H ₉ , sec-C ₄ H ₉ , tert-C ₄ H ₉ , CH ₂ F, CHF ₂ , CH ₂ CHF ₂ or oxetan-3-yl; R ⁴ is H or C ₁ -C ₄ alkyl, wherein said C ₁ -C ₄ alkyl is optionally substituted with OH, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ ; or R ⁴ is H, CH ₃ , C ₂ H ₅ , CH ₂ OH, CH(OH)CH ₃ , CH ₂ CH ₂ OH or CH ₂ NH ₂ ; R ⁶ is H or F; R ⁷ and R ⁸ are H; R ⁹ is OH; n is 0 and R ¹⁰ is absent; R ¹¹ is SO ₂ R ¹⁴ and R ¹⁴ is C ₁ -C ₄ alkyl.

In certain embodiments, the invention provides a compound of Formulas (IX), (IX-A), (IX-B), (IX-C), or (IX-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more and more preferably four or more of the following features: R ¹ is Cl; R ² is C ₁ -C ₅ alkyl; R ⁴ is H or C ₁ -C ₄ alkyl, wherein said C ₁ -C ₄ alkyl is optionally substituted with R ²⁰ ; R ⁶ is F; R ⁷ and R ⁸ are H; R ⁹ is OH; R ¹¹ is SO ₂ R ¹⁴ ; R ¹⁴ is C ₁ -C ₄ alkyl; and R ²⁰ is OH.

Each of the aspects and embodiments described herein with respect to Formula (IV) is also applicable to compounds of Formulas (IX'), (IX'-A), (IX'-B), (IX'-C) or (IX '-D) that do not conflict with such aspect or embodiment.

Each of the aspects and embodiments described herein with respect to Formula (IX') is also applicable to compounds of Formula (IX'-A), (IX'-B), (IX'-C) or (IX'-D) .

In certain embodiments, the invention provides a compound of Formulas (IX'), (IX'-A), (IX'-B), (IX'-C), or (IX'-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more of the following: R ¹ is F or Cl; R ² is C ₁ -C ₅ alkyl, C ₁ -C ₅ fluoroalkyl or 3-6 membered heterocyclyl or R ² is CH ₃ , ISO-C ₃ H ₇ , ISO-C ₄ H ₉ , sec-C ₄ H ₉ , tert-C ₄ H ₉ , CH ₂ F, CHF ₂ , CH ₂ CHF ₂ or oxetan-3-yl; R ⁴ is H or C ₁ -C ₄ alkyl, wherein said C ₁ -C ₄ alkyl is optionally substituted with OH, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ ; or R ⁴ is H, CH ₃ , C ₂ H ₅ , CH ₂ OH, CH(OH)CH ₃ , CH ₂ CH ₂ OH or CH ₂ NH ₂ ; or R ² is taken together with R ⁴ to form a 5-7 membered heterocyclic ring optionally containing an additional heteroatom selected from NR ²⁴ , O and S(O) _m as a ring member, the ring being optionally substituted with R ²¹ ; R ⁶ is H or F; R ⁷ and R ⁸ are H; R ⁹ is OH; n is 0 and R ¹⁰ is absent; R ¹¹ is SO ₂ R ¹⁴ and R ¹⁴ is C ₁ -C ₄ alkyl.

In certain embodiments, the invention provides a compound of Formulas (IX'), (IX'-A), (IX'-B), (IX'-C), or (IX'-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more of the following: R ¹ is F or Cl; R ² is CH ₃ , ISO-C ₃ H ₇ , ISO-C ₄ H ₉ , sec-C ₄ H ₉ , tert-C ₄ H ₉ , CH ₂ F, CHF ₂ , CH ₂ CHF _{2 ,} or oxetane-3 -silt; R ⁴ is H, CH ₃ , C ₂ H ₅ , CH ₂ OH, CH(OH)CH ₃ , CH ₂ CH ₂ OH or CH ₂ NH ₂ ; or R ² is taken together with R ⁴ to form a 5-7 membered heterocyclic ring optionally substituted with R ²¹ ; each R ²¹ is independently F, OH, NH ₂ , C ₁ -C ₂ alkyl or C ₁ -C ₂ fluoroalkyl; R ⁶ is F; R ⁷ and R ⁸ are H; R ⁹ is OH; n is 0 and R ¹⁰ is absent; R ¹¹ is SO ₂ R ¹⁴ and R ¹⁴ is CH ₃ .

In certain embodiments, the invention provides a compound of Formulas (IX'), (IX'-A), (IX'-B), (IX'-C), or (IX'-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more of the following: R ¹ is Cl; R ² is C ₁ -C ₅ alkyl; R ⁴ is H or C ₁ -C ₄ alkyl, wherein said C ₁ -C ₄ alkyl is optionally substituted with R ²⁰ ; R ⁶ is F; R ⁷ and R ⁸ are H; R ⁹ is OH; R ¹¹ is SO ₂ R ¹⁴ ; R ¹⁴ is C ₁ -C ₄ alkyl; and R ²⁰ is OH.

In another aspect, the invention provides a compound of Formula (X):

(X)

(X)

or a pharmaceutically acceptable salt thereof, in which:

R ¹ is H, F, Cl, CN, C ₁ -C ₂ alkyl or C ₁ -C ₂ fluoroalkyl, wherein each C ₁ -C ₂ alkyl and C ₁ -C ₂ fluoroalkyl is optionally substituted with R ²⁰ ;

R ² is H, C ₁ -C ₅ alkyl, C ₁ -C ₅ fluoroalkyl, C ₃ -C ₈ cycloalkyl, or 3-6 membered heterocyclyl, wherein said C ₁ -C ₅ alkyl and C ₁ -C ₅ are each fluoroalkyl is optionally substituted with R ²⁰ and each of said C ₃ -C ₈ cycloalkyl and 3-6 membered heterocyclyl is optionally substituted with R ²¹ ;

R ⁴ is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy or C ₁ -C ₄ fluoroalkoxy, wherein each is C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ fluoroalkoxy are optionally substituted with R ²⁰ ;

R ⁶ is H, F, Cl, CN, CH ₃ , CH ₂ F, CHF ₂ or CF ₃ ;

R ⁷ and R ⁸ are independently H, F, Cl, CN, C ₁ -C ₂ alkyl, C ₁ -C ₂ fluoroalkyl, C ₁ -C ₂ alkoxy, or C ₁ -C ₂ fluoroalkoxy, wherein each C ₁ -C ₂ alkyl, C ₁ -C ₂ fluoroalkyl, C ₁ -C ₂ alkoxy and C ₁ -C ₂ fluoroalkoxy are optionally substituted with R ²⁰ ;

R ⁹ is H, OH, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ ;

each R ¹⁰ is independently F, CN, C ₁ -C ₂ alkyl, or C ₁ -C ₂ fluoroalkyl, wherein each said C ₁ -C ₂ alkyl and C ₁ -C ₂ fluoroalkyl is optionally substituted with R ²⁰ ;

each R ²⁰ is independently OH, C ₁ -C ₂ alkoxy, C ₁ -C ₂ fluoroalkoxy, CN or NR ²² R ²³ ;

each R ²¹ is independently F, OH, CN, NR ²² R ²³ , C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy or C ₁ -C ₄ fluoroalkoxy, in which each specified C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ fluoroalkoxy optionally further substituted with OH, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ ;

each R ²² and R ²³ is independently H, C ₁ -C ₂ alkyl or C ₁ -C ₂ fluoroalkyl or

R ²² and R ²³ may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring which is optionally substituted with F or OH; And

n is 0, 1, 2, 3, or 4.

In another aspect, the invention provides a compound of Formula (XI):

(XI)

(XI)

or a pharmaceutically acceptable salt thereof, in which:

R ¹ is H, F, Cl, CN, C ₁ -C ₂ alkyl or C ₁ -C ₂ fluoroalkyl, wherein each C ₁ -C ₂ alkyl and C ₁ -C ₂ fluoroalkyl is optionally substituted with R ²⁰ ;

R ² is H, C ₁ -C ₅ alkyl, C ₁ -C ₅ fluoroalkyl, C ₃ -C ₈ cycloalkyl, or 3-6 membered heterocyclyl, wherein said C ₁ -C ₅ alkyl and C ₁ -C ₅ are each fluoroalkyl is optionally substituted with R ²⁰ and each of said C ₃ -C ₈ cycloalkyl and 3-6 membered heterocyclyl is optionally substituted with R ²¹ ;

R ⁴ is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy or C ₁ -C ₄ fluoroalkoxy, wherein each is C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ fluoroalkoxy are optionally substituted with R ²⁰ ; or

R ² can be taken together with R ⁴ to form a 5-7 membered heterocyclic ring optionally containing an additional heteroatom selected from NR ²⁴ , O and S(O) _m as a ring member, the ring being optionally substituted with R ²¹ ;

R ⁶ is H, F, Cl, CN, CH ₃ , CH ₂ F, CHF ₂ or CF ₃ ;

R ⁷ and R ⁸ are independently H, F, Cl, CN, C ₁ -C ₂ alkyl, C ₁ -C ₂ fluoroalkyl, C ₁ -C ₂ alkoxy, or C ₁ -C ₂ fluoroalkoxy, wherein each C ₁ -C ₂ alkyl, C ₁ -C ₂ fluoroalkyl, C ₁ -C ₂ alkoxy and C ₁ -C ₂ fluoroalkoxy are optionally substituted with R ²⁰ ;

R ⁹ is H, OH, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ ;

each R ¹⁰ is independently F, CN, C ₁ -C ₂ alkyl, or C ₁ -C ₂ fluoroalkyl, wherein each said C ₁ -C ₂ alkyl and C ₁ -C ₂ fluoroalkyl is optionally substituted with R ²⁰ ;

each R ²⁰ is independently OH, C ₁ -C ₂ alkoxy, C ₁ -C ₂ fluoroalkoxy, CN or NR ²² R ²³ ;

each R ²¹ is independently F, OH, CN, NR ²² R ²³ , C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy or C ₁ -C ₄ fluoroalkoxy, in which each specified C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ fluoroalkoxy optionally further substituted with OH, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ ;

each R ²² and R ²³ is independently H, C ₁ -C ₂ alkyl or C ₁ -C ₂ fluoroalkyl or

R ²² and R ²³ may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring which is optionally substituted with F or OH;

R ²⁴ is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, SO ₂ R ²⁵ , SO ₂ NR ²⁶ R ²⁷ , COR ²⁸ , COOR ²⁸ or CONR ²⁹ R ³⁰ ;

R ²⁵ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl;

each R ²⁶ and R ²⁷ is independently H or CH ₃ ;

R ²⁸ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with OH, C ₁ -C ₂ alkoxy, C ₁ -C ₂ fluoroalkoxy, CN, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ ;

each R ²⁹ and R ³⁰ is independently H, C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each said C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with OH, C ₁ -C ₂ alkoxy, C ₁ -C ₂ fluoroalkoxy, CN, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ ;

m is 0, 1 or 2 and

n is 0, 1, 2, 3, or 4.

In some embodiments, a compound of Formula (X) or (XI) has absolute stereochemistry as shown in one of Formulas (X-A), (X-B), (X-C) or (X-D) or (XI-A), (XI-B) , (XI-C) or (XI-D):

or a pharmaceutically acceptable salt thereof.

Each of the aspects and embodiments described herein with respect to Formula (II) is also applicable to compounds of Formula (X), (X-A), (X-B), (X-C), or (X-D) that do not conflict with that aspect or embodiment. .

Each of the aspects and embodiments described herein with respect to Formula (X) also applies to compounds of Formula (X-A), (X-B), (X-C) or (X-D).

In certain embodiments, the invention provides a compound of Formula (X), (XA), (XB), (XC), or (XD), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more of the following: features: R ¹ is Cl; R ² is C ₁ -C ₅ alkyl or R ² is ISO-C ₃ H ₇ ; R ⁴ is C ₁ -C ₄ alkyl, wherein said C ₁ -C ₄ alkyl is optionally substituted with R ²⁰ , in which R ²⁰ is OH; or R ⁴ is CH(OH)CH ₃ or C(OH)(CH ₃ ) ₂ ; R ⁶ is F; R ⁷ is H; R ⁸ is H; R ⁹ is OH; n is 0 and R ¹⁰ is absent.

In a preferred embodiment, the invention provides a compound of Formula (X), (XA), (XB), (XC) or (XD) or a pharmaceutically acceptable salt thereof, wherein: R ¹ is Cl; R ² is C ₁ -C ₅ alkyl or R ² is ISO-C ₃ H ₇ ; R ⁴ is C ₁ -C ₄ alkyl optionally substituted with R ²⁰ in which R ²⁰ is OH; or R ⁴ is CH(OH)CH ₃ or C(OH)(CH ₃ ) ₂ ; R ⁶ is F; R ⁷ is H; R ⁸ is H; R ⁹ is OH; n is 0 and R ¹⁰ is absent.

In certain embodiments, the invention provides a compound of Formula (X), (XA), (XB), (XC), or (XD), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more of the following: features: R ¹ is F or Cl; R ² is C ₁ -C ₅ alkyl, C ₁ -C ₅ fluoroalkyl or 3-6 membered heterocyclyl or R ² is CH ₃ , ISO-C ₃ H ₇ , ISO-C ₄ H ₉ , sec-C ₄ H ₉ , tert-C ₄ H ₉ , CH ₂ F, CHF ₂ , CH ₂ CHF ₂ or oxetan-3-yl; R ⁴ is H or C ₁ -C ₄ alkyl, wherein said C ₁ -C ₄ alkyl is optionally substituted with OH, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ ; or R ⁴ is H, CH ₃ , C ₂ H ₅ , CH ₂ OH, CH(OH)CH ₃ , C(OH)(CH ₃ ) ₂ or CH ₂ CH ₂ OH; R ⁶ is H or F; R ⁷ is H; R ⁸ is H; R ⁹ is OH; n is 0 and R ¹⁰ is absent.

Each of the aspects and embodiments described herein with respect to Formula (IV) is also applicable to compounds of Formulas (XI), (XI-A), (XI-B), (XI-C) or (XI-D), which do not conflict with such aspect or embodiment.

Each of the aspects and embodiments described herein with respect to Formula (XI) is also applicable to compounds of Formulas (XI-A), (XI-B), (XI-C) or (XI-D).

In certain embodiments, the invention provides a compound of Formula (XI), (XI-A), (XI-B), (XI-C), or (XI-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more and more preferably four or more of the following features: R ¹ is Cl; R ² is C ₁ -C ₅ alkyl or R ² is ISO-C ₃ H ₇ ; R ⁴ is C ₁ -C ₄ alkyl, wherein said C ₁ -C ₄ alkyl is optionally substituted with R ²⁰ , in which R ²⁰ is OH; or R ⁴ is CH(OH)CH ₃ or C(OH)(CH ₃ ) ₂ ; R ⁶ is F; R ⁷ is H; R ⁸ is H; R ⁹ is OH; n is 0 and R ¹⁰ is absent.

In a preferred embodiment, the invention provides a compound of Formula (XI), (XI-A), (XI-B), (XI-C) or (XI-D) or a pharmaceutically acceptable salt thereof, wherein: R ¹ is Cl; R ² is C ₁ -C ₅ alkyl or R ² is ISO-C ₃ H ₇ ; R ⁴ is C ₁ -C ₄ alkyl optionally substituted with R ²⁰ in which R ²⁰ is OH; or R ⁴ is CH(OH)CH ₃ or C(OH)(CH ₃ ) ₂ ; R ⁶ is F; R ⁷ is H; R ⁸ is H; R ⁹ is OH; n is 0 and R ¹⁰ is absent.

In certain embodiments, the invention provides a compound of Formulas (XI), (XI-A), (XI-B), (XI-C), or (XI-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more and more preferably four or more of the following features: R ¹ is F or Cl; R ² is C ₁ -C ₅ alkyl, C ₁ -C ₅ fluoroalkyl or 3-6 membered heterocyclyl or R ² is CH ₃ , ISO-C ₃ H ₇ , ISO-C ₄ H ₉ , sec-C ₄ H ₉ , tert-C ₄ H ₉ , CH ₂ F, CHF ₂ , CH ₂ CHF ₂ or oxetan-3-yl; R ⁴ is H or C ₁ -C ₄ alkyl, wherein said C ₁ -C ₄ alkyl is optionally substituted with OH, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ ; or R ⁴ is H, CH ₃ , C ₂ H ₅ , CH ₂ OH, CH(OH)CH ₃ , C(OH)(CH ₃ ) ₂ or CH ₂ CH ₂ OH; R ⁶ is H or F; R ⁷ is H; R ⁸ is H; R ⁹ is OH; n is 0 and R ¹⁰ is absent.

In another aspect, the invention provides a compound of Formula (XII):

(XII)

(XII)

or a pharmaceutically acceptable salt thereof, in which:

And represents N or CH;

R ¹ is H, F or Cl;

R ² is H, C ₁ -C ₅ alkyl, C ₁ -C ₅ fluoroalkyl, C ₃ -C ₈ cycloalkyl, or 3-6 membered heterocyclyl, wherein said C ₁ -C ₅ alkyl and C ₁ -C ₅ are each fluoroalkyl is optionally substituted with R ²⁰ and each of said C ₃ -C ₈ cycloalkyl and 3-6 membered heterocyclyl is optionally substituted with R ²¹ ;

R ⁴ is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ fluoroalkoxy, C(O)R ^a , C(O)NR ^b ₂ , C ₃ -C ₈ cycloalkyl or 3-6 membered heterocyclyl, wherein each said C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy, and C ₁ -C ₄ fluoroalkoxy is optionally substituted with R ²⁰ , each said C ₃ -C ₈ cycloalkyl and 3-6 membered heterocyclyl is optionally substituted with R ²¹ , R ^a is C ₁ -C ₂ alkyl and each R ^b is independently H or C ₁ -C ₂ alkyl;

R ⁶ is H or F;

R ⁷ and R ⁸ are independently H, F, Cl, CN, C ₁ -C ₂ alkyl, C ₁ -C ₂ fluoroalkyl, C ₁ -C ₂ alkoxy, or C ₁ -C ₂ fluoroalkoxy;

Q is O or

Q is NR ¹¹ ;

R ¹¹ is SO ₂ R ¹⁴ or COR ¹⁷ ;

R ¹⁴ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl;

R ¹⁷ is C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₃ -C ₈ cycloalkyl, or 3-6 membered heterocyclyl, wherein each of C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optional substituted with R ²⁰ and each of said C ₃ -C ₈ cycloalkyl and 3-6 membered heterocyclyl is optionally substituted with R ²¹ ;

each R ²⁰ is independently OH, C ₁ -C ₂ alkoxy, C ₁ -C ₂ fluoroalkoxy, CN, NR ²² R ²³ , C ₃ -C ₈ cycloalkyl, or 3-6 membered heterocyclyl, wherein each C ₃ - C ₈ cycloalkyl and 3-6 membered heterocyclyl are optionally substituted with R ²¹ ;

each R ²¹ is independently F, OH, CN, NR ²² R ²³ , C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy or C ₁ -C ₄ fluoroalkoxy, in which each specified C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ fluoroalkoxy optionally further substituted with OH, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ ;

each R ²² and R ²³ is independently H, C ₁ -C ₃ alkyl, C ₁ -C ₃ fluoroalkyl, C ₃ -C ₈ cycloalkyl, or 3-6 membered heterocyclyl, wherein each is C ₁ -C ₃ alkyl and C ₁ -C ₃ fluoroalkyl is optionally further substituted with OH, C ₁ -C ₂ alkoxy or C ₁ -C ₂ fluoroalkoxy, and each said C ₃ -C ₈ cycloalkyl and 3-6 membered heterocyclyl is optionally further substituted with F, OH, C ₁ - C ₂ alkyl, C ₁ -C ₂ fluoroalkyl, C ₁ -C ₂ alkoxy or C ₁ -C ₂ fluoroalkoxy; or

R ²² and R ²³ can be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring in which said ring is optionally substituted with F, OH, C ₁ -C ₂ alkyl, C ₁ -C ₂ fluoroalkyl, C ₁ - C ₂ alkoxy or C ₁ -C ₂ fluoroalkoxy.

In some embodiments, a compound of Formula (XII) has absolute stereochemistry as shown in one of Formulas (XII-A), (XII-B), (XII-C), or (XII-D):

or a pharmaceutically acceptable salt thereof.

Each of the aspects and embodiments described herein with respect to Formulas (I)-(XI) is also applicable to compounds of Formulas (XII), (XII-A), (XII-B), (XII-C) or (XII -D) that do not conflict with such aspect or embodiment.

Each of the aspects and embodiments described herein with respect to Formula (XII) is also applicable to compounds of Formulas (XII-A), (XII-B), (XII-C) or (XII-D).

In some embodiments of Formulas (XII), (XII-A), (XII-B), (XII-C), or (XII-D), A is N. In some embodiments of Formulas (XII), (XII-A ), (XII-B), (XII-C) or (XII-D) A is CH.

In some embodiments of Formulas (XII), (XII-A), (XII-B), (XII-C), or (XII-D), R ¹ is Cl.

In some embodiments of Formulas (XII), (XII-A), (XII-B), (XII-C) or (XII-D) R ² is C ₁ -C ₅ alkyl or C ₁ -C ₅ fluoroalkyl, wherein each said C ₁ -C ₅ alkyl and C ₁ -C ₅ fluoroalkyl is optionally substituted with R ²⁰ . In some such embodiments, R ² is C ₁ -C ₅ alkyl. In certain embodiments, R ² is isopropyl.

In some embodiments of Formulas (XII), (XII-A), (XII-B), (XII-C), or (XII-D) R ² is C ₃ -C ₈ cycloalkyl or 3-6 membered heterocyclyl, wherein each said C ₃ -C ₈ cycloalkyl and 3-6 membered heterocyclyl is optionally substituted with R ²¹ .

In some embodiments of Formulas (XII), (XII-A), (XII-B), (XII-C), or (XII-D) R ⁴ is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy or C ₁ -C ₄ fluoroalkoxy, wherein each said C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ fluoroalkoxy is optionally substituted with R ²⁰ .

In some such embodiments, R ²⁰ is OH. In some embodiments, R ⁴ is C ₁ -C ₄ alkyl optionally substituted with R ²⁰ , wherein R ²⁰ is OH. In certain embodiments, R ⁴ is CH(OH)CH ₃ or C(OH)(CH ₃ ) ₂ .

In other such embodiments, R ²⁰ is C ₃ -C ₈ cycloalkyl or 3-6 membered heterocyclyl, wherein said C ₃ -C ₈ cycloalkyl and 3-6 membered heterocyclyl are each optionally substituted with R ²¹ . In some such embodiments, R ⁴ is C ₁ -C ₄ alkyl optionally substituted with R ²⁰ , wherein R ²⁰ is C ₃ -C ₈ cycloalkyl or 3-6 membered heterocyclyl, wherein each C ₃ -C ₈ cycloalkyl and 3-6 membered heterocyclyl are optionally substituted with R ²¹ .

In some embodiments of Formulas (XII), (XII-A), (XII-B), (XII-C), or (XII-D) R ⁴ is C(O)R ^a , C(O)NR ^b ₂ , R ^a is C ₁ -C ₂ alkyl and each R ^b is independently H or C ₁ -C ₂ alkyl.

In some embodiments of Formulas (XII), (XII-A), (XII-B), (XII-C) or (XII-D), R ⁴ is C ₃ -C ₈ cycloalkyl or 3-6 membered heterocyclyl, wherein each said C ₃ -C ₈ cycloalkyl and 3-6 membered heterocyclyl is optionally substituted with R ²¹ .

In some embodiments of Formulas (XII), (XII-A), (XII-B), (XII-C), or (XII-D), R ⁶ is F.

In some embodiments of Formulas (XII), (XII-A), (XII-B), (XII-C), or (XII-D), R ⁷ and R ⁸ are independently H or F. In some such embodiments, R ⁷ and R ⁸ are H.

In some embodiments of Formulas (XII), (XII-A), (XII-B), (XII-C), or (XII-D), Q is O.

In some embodiments of Formulas (XII), (XII-A), (XII-B), (XII-C), or (XII-D), Q is NR ¹¹ . In some such embodiments, R ¹¹ is SO ₂ R ¹⁴ . In some such embodiments, R ¹⁴ is C ₁ -C ₄ alkyl. In some such embodiments, R ¹¹ is COR ¹⁷ . In some such embodiments, R ¹⁷ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each of said C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with R ²⁰ . In some such embodiments, R ¹⁷ is C ₃ -C ₈ cycloalkyl or 3-6 membered heterocyclyl, wherein said C ₃ -C ₈ cycloalkyl and 3-6 membered heterocyclyl are each optionally substituted with R ²¹ .

In certain embodiments, the invention provides a compound of Formula (XII), (XII-A), (XII-B), (XII-C), or (XII-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more and more preferably four or more of the following features: A is N; R ¹ is Cl; R ² is C ₁ -C ₅ alkyl or R ² is ISO-C ₃ H ₇ ; R ⁴ is C ₁ -C ₄ alkyl, wherein said C ₁ -C ₄ alkyl is optionally substituted with R ²⁰ , in which R ²⁰ is OH; or R ⁴ is CH(OH)CH ₃ or C(OH)(CH ₃ ) ₂ ; R ⁶ is F; R ⁷ is H; R ⁸ is H and Q is O.

In certain embodiments, the invention provides a compound of Formula (XII), (XII-A), (XII-B), (XII-C), or (XII-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more and more preferably four or more of the following features: A is N; R ¹ is Cl; R ² is C ₁ -C ₅ alkyl or R ² is ISO-C ₃ H ₇ ; R ⁴ is C ₁ -C ₄ alkyl, wherein said C ₁ -C ₄ alkyl is optionally substituted with R ²⁰ , in which R ²⁰ is OH; or R ⁴ is CH(OH)CH ₃ or C(OH)(CH ₃ ) ₂ ; R ⁶ is F; R ⁷ is H; R ⁸ is H; Q is NR ¹¹ ; R ¹¹ is SO ₂ R ¹⁴ and R ¹⁴ is C ₁ -C ₄ alkyl.

In certain embodiments, the invention provides a compound of Formula (XII), (XII-A), (XII-B), (XII-C), or (XII-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more and more preferably four or more of the following features: A is CH; R ¹ is Cl; R ² is C ₁ -C ₅ alkyl or R ² is ISO-C ₃ H ₇ ; R ⁴ is C ₁ -C ₄ alkyl, wherein said C ₁ -C ₄ alkyl is optionally substituted with R ²⁰ , in which R ²⁰ is OH; or R ⁴ is CH(OH)CH ₃ or C(OH)(CH ₃ ) ₂ ; R ⁶ is F; R ⁷ is H; R ⁸ is H and Q is O.

In certain embodiments, the invention provides a compound of Formula (XII), (XII-A), (XII-B), (XII-C), or (XII-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more and more preferably four or more of the following features: A is CH; R ¹ is Cl; R ² is C ₁ -C ₅ alkyl or R ² is ISO-C ₃ H ₇ ; R ⁴ is C ₁ -C ₄ alkyl, wherein said C ₁ -C ₄ alkyl is optionally substituted with R ²⁰ , in which R ²⁰ is OH; or R ⁴ is CH(OH)CH ₃ or C(OH)(CH ₃ ) ₂ ; R ⁶ is F; R ⁷ is H; R ⁸ is H; Q is NR ¹¹ ; R ¹¹ is SO ₂ R ¹⁴ and R ¹⁴ is C ₁ -C ₄ alkyl.

In another aspect, the invention provides a compound selected from the group consisting of:

(3R,4R)-4-({5-chloro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino )-1-(methanesulfonyl)piperidin-3-ol;

(3R,4R)-4-({4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-1- (methanesulfonyl)piperidin-3-ol;

4-(1-tert-butyl-4-fluoro-1H-benzimidazol-6-yl)-5-fluoro-N-(1-methylpiperidin-4-yl)pyrimidin-2-amine;

(3R,4R)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino )-1-(methanesulfonyl)piperidin-3-ol;

(3R,4R)-4-({5-ethyl-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino )-1-(methanesulfonyl)piperidin-3-ol;

(3R,4R)-4-({5-chloro-4-[1-(propan-2-yl)-1H-benzotriazol-6-yl]pyrimidin-2-yl}amino)-1-(methanesulfonyl)piperidine -3-ola;

(3R,4R)-4-({4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]-5-methylpyrimidin-2-yl}amino) -1-(methanesulfonyl)piperidin-3-ol;

(3R,4R)-4-({4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]-5-methoxypyrimidin-2-yl}amino) -1-(methanesulfonyl)piperidin-3-ol;

(3R,4R)-4-({4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]-5-(propan-2-yl)pyrimidine -2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol;

(3R,4R)-4-({5-chloro-4-[4-fluoro-2-methyl-1-(oxetan-3-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino )-1-(methanesulfonyl)piperidin-3-ol;

(3R,4R)-4-({5-chloro-4-[4-fluoro-2-(hydroxymethyl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl )}amino)-1-(methanesulfonyl)piperidin-3-ol;

(3R,4R)-4-({4-[1-(azetidin-3-yl)-4-fluoro-2-methyl-1H-benzimidazol-6-yl]-5-fluoropyrimidin-2-yl}amino) -1-(methanesulfonyl)piperidin-3-ol;

(3R,4R)-4-{[4-(1-tert-Butyl-1H-benzimidazol-6-yl)-5-fluoropyrimidin-2-yl]amino}-1-(methanesulfonyl)piperidin-3-ol;

(3R,4R)-4-({5-fluoro-4-[2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-1- (methanesulfonyl)piperidin-3-ol;

(3R,4R)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino )piperidin-3-ol;

1-[(3R,4R)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2- yl}amino)-3-hydroxypiperidin-1-yl]ethanone;

(3R,4R)-4-{[4-(1-tert-butyl-4-fluoro-1H-benzimidazol-6-yl)-5-fluoropyrimidin-2-yl]amino}-1-(methanesulfonyl)piperidine- 3-ol;

(3S,4S)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino )-1-methylpiperidin-3-ol;

(3S,4S)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino )-1-(methanesulfonyl)piperidin-3-ol;

1,5-anhydro-3-[(5-chloro-4-{4-fluoro-2-[(1R)-1-hydroxyethyl]-1-(propan-2-yl)-1H-benzimidazol-6-yl }pyrimidin-2-yl)amino]-2,3-dideoxy-D-threo-pentitol;

1,5-anhydro-3-[(5-chloro-4-{4-fluoro-2-[(1S)-1-hydroxyethyl]-1-(propan-2-yl)-1H-benzimidazol-6-yl }pyrimidin-2-yl)amino]-2,3-dideoxy-D-threo-pentitol;

(2S)-1-[(3R,4R)-4-{[4-(1-tert-butyl-4-fluoro-1H-benzimidazol-6-yl)-5-chloropyrimidin-2-yl]amino}- 3-hydroxypiperidin-1-yl]-2-hydroxypropan-1-one;

(3R,4R)-4-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1H-benzimidazol-6-yl )]pyrimidin-2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol;

(3R,4R)-4-[(5-chloro-4-{4-fluoro-2-[(1R)-1-hydroxyethyl]-1-(propan-2-yl)-1H-benzimidazol-6-yl }pyrimidin-2-yl)amino]-1-(methanesulfonyl)piperidin-3-ol and

1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1H-benzimidazol-6-yl ]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol;

or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides a compound selected from the group consisting of compounds shown in the Examples provided herein, including A1-A94, B1-B2, C1-C2, D1-D6, E1, F1-F33, G1 and H1 -H11 inclusive, or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides (3R,4R)-4-[(5-chloro-4-{4-fluoro-2-[(1R)-1-hydroxyethyl]-1-(propan-2-yl)-1H- benzimidazol-6-yl}pyrimidin-2-yl)amino]-1-(methanesulfonyl)piperidin-3-ol or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides (3R,4R)-4-[(5-chloro-4-{4-fluoro-2-[(1R)-1-hydroxyethyl]-1-(propan-2-yl)-1H- benzimidazol-6-yl}pyrimidin-2-yl)amino]-1-(methanesulfonyl)piperidin-3-ol.

In another aspect, the invention provides a pharmaceutically acceptable salt of (3R,4R)-4-[(5-chloro-4-{4-fluoro-2-[(1R)-1-hydroxyethyl]-1-(propan-2-yl) -1H-benzimidazol-6-yl}pyrimidin-2-yl)amino]-1-(methanesulfonyl)piperidin-3-ol.

In another aspect, the invention provides 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1H- benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1H- benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol.

In another aspect, the invention provides a pharmaceutically acceptable salt of 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl) -1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol.

"Pharmaceutical composition" refers to a mixture of one or more compounds of the invention, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, as the active ingredient and at least one pharmaceutically acceptable carrier or excipient. In some embodiments, the implementation of the pharmaceutical composition contains two or more pharmaceutically acceptable carriers and/or excipients. In other embodiments, the pharmaceutical composition further comprises at least one additional anti-cancer therapeutic agent.

In one aspect, the invention provides a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. In some embodiments, the implementation of the pharmaceutical composition contains two or more pharmaceutically acceptable carriers and/or excipients.

In some embodiments, the pharmaceutical composition further comprises at least one additional anti-cancer therapeutic agent. In some such embodiments, the combination provides an additional, greater than additive or synergistic anticancer effect.

The term "adjuvant" is used to mean that the result of the combination of two compounds, components or target agents does not exceed the sum of each compound, component or target agent separately.

The term "synergism" or "synergistic" is used to mean that the result of the combination of two compounds, components or target agents is greater than the sum of each compound, component or target agent separately. This improvement in the disease, condition or disorder being treated is a "synergistic" effect. "Synergistic amount" is the amount of combination of two compounds, components or target agents, which leads to a synergistic effect, as "synergistic" is defined in the present description.

Determining the synergistic interaction between one or two components, the optimal range for effect, and the absolute dose ranges of each component for effect can be definitively measured by administering the components at various dose ranges and/or dose ratios to patients in need of such treatment. However, the observation of synergy in in vitro models or in vivo models can be a predictable effect in humans and other species, and there are in vitro models or in vivo models as described herein to measure the synergistic effect. The results of such studies can also be used to predict ranges of effective dose-plasma ratios and absolute doses and plasma concentrations required in humans and other species, for example, by applying pharmacokinetic and/or pharmacodynamic methods.

Unless otherwise indicated, all references herein to compounds of the invention include references to their salts, solvates, hydrates, and complexes, and to their solvates, hydrates, and salt complexes, including their polymorphs, stereoisomers, and isotopically labeled variants.

The compounds of the invention may exist in the form of pharmaceutically acceptable salts such as, for example, acid addition salts and base addition salts of compounds of one of the formulas provided herein. The term "pharmaceutically acceptable salt" as used herein refers to those salts that retain the biological efficacy and properties of the parent compound. Used in the present description, the phrase "pharmaceutically acceptable salt(s)", unless otherwise indicated, includes salts of acidic or basic groups that may be present in the compounds of the formulas disclosed in the present description.

For example, the compounds of the invention, which are basic in nature, are capable of forming a large number of salts with various inorganic and organic acids. Although such salts should be pharmaceutically acceptable for administration to animals, in practice it is often desirable to first isolate the compound of the present invention from the reaction mixture as a pharmaceutically unacceptable salt, and then simply convert the latter back to the free base of the compound by treatment with an alkaline reagent, and then convert the last free base to a pharmaceutically acceptable acid addition salt. Acid addition salts of the base compounds of this invention may be prepared by treating the base compound with a substantially equivalent amount of the selected mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. After evaporation of the solvent, the desired solid salt is obtained. The desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding an appropriate mineral or organic acid to the solution.

Acids that can be used to prepare pharmaceutically acceptable acid addition salts of those basic compounds that form non-toxic acid addition salts, i.e. salts containing pharmacologically acceptable anions such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate salts , phosphate, hydrogen phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate , benzenesulfonate, p-toluenesulfonate and pamoate.

Examples of salts include, but are not limited to, acetate, acrylate, benzenesulfonate, benzoate (such as chlorobenzoate, methyl benzoate, dinitrobenzoate, hydroxybenzoate, and methoxybenzoate), bicarbonate, bisulfate, bisulfite, bitartrate, borate, bromide, butyne-1,4-dioate salts. , calcium edetate, camsylate, carbonate, chloride, caproate, caprylate, clavulanate, citrate, decanoate, dihydrochloride, dihydrogen phosphate, edetate, edisilate, estolate, esylate, ethyl succinate, formate, fumarate, gluceptate, gluconate, glutamate, glycolate, glycolylarsanilate, heptanoate, hexine-1,6-dioate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, γ-hydroxybutyrate, iodide, isobutyrate, isothionate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, mesylate, metaphosphate, methanesulfonate, methyl sulfate, monohydrophosphate, mucate, napsilate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, nitrate, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phenylacetates, phenylbutyrate , phenylpropionate, phthalate, phosphate/diphosphate, polygalacturonate, propanesulfonate, propionate, propiolate, pyrophosphate, pyrosulfate, salicylate, stearate, subacetate, suberate, succinate, sulfate, sulfonate, sulfite, tannate, tartrate, theoclate, tosylate, and valerate.

Illustrative examples of suitable salts include organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary and tertiary amines and cyclic amines such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

Compounds of the invention which include a basic moiety such as an amino group may form pharmaceutically acceptable salts with various amino acids in addition to the acids mentioned above.

Alternatively, useful compounds that are acidic in nature may be able to form basic salts with various pharmacologically acceptable cations. Examples of such salts include alkali or alkaline earth metal salts, and in particular sodium and potassium salts. All these salts are obtained using standard methods. The chemical bases that are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those that form non-toxic base salts with the acidic compounds of this disclosure. These salts can be obtained by any suitable method, for example, by treating the free acid with an inorganic or organic base such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or an alkaline earth metal hydroxide, or the like. These salts can also be prepared by treating the corresponding acid compounds with an aqueous solution containing the desired pharmacologically acceptable cations and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they can also be prepared by mixing lower alcoholic solutions of acidic compounds and the desired alkali metal alkoxide together and then evaporating the resulting solution to dryness in the same manner as before. In any case, it is preferable to use stoichiometric amounts of reactants to ensure completeness of the reaction and maximum yields of the desired end product.

Chemical bases that can be used as reagents to prepare pharmaceutically acceptable base salts of the compounds of the invention that are acidic in nature are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to, salts derived from such pharmacologically acceptable cations such as alkali metal (e.g., potassium and sodium) and alkaline earth (e.g., calcium and magnesium) cations, ammonium, or water-soluble amine addition salts. such as N-methylglucamine (meglumine) and lower alkanolammonium and other basic salts of pharmaceutically acceptable organic amines.

Hemi-salts of acids and bases can also be formed, for example hemisulphate and hemicalcium salts.

For a review of suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the invention and forms of interconverting salts and free bases are known to the person skilled in the art.

Salts of the present invention can be obtained in accordance with methods known to the person skilled in the art. A pharmaceutically acceptable salt of the compounds of the invention can be readily prepared by mixing together solutions of the compound and the desired acid or base as needed. The salt may precipitate out of solution and be collected by filtration, or may be isolated by evaporating the solvent. The degree of ionization in a salt can vary from fully ionized to almost non-ionized.

The person skilled in the art will appreciate that the compounds of the invention in free base form having a basic functional group can be converted to acid addition salts by treatment with a stoichiometric excess of the appropriate acid. The acid addition salts of the compounds of the invention can be reconverted to the corresponding free base by treatment with a stoichiometric excess of a suitable base such as potassium carbonate or sodium hydroxide, usually in the presence of an aqueous solvent and at a temperature of from about 0°C to 100°C. The free base form can be isolated by standard methods such as extraction with an organic solvent. In addition, the acid addition salts of the compounds of the invention can be replaced by taking advantage of different salt solubility, volatility or acidity of acids, or by treatment with an appropriately loaded ion exchange resin. For example, the exchange can be affected by the reaction of a salt of the compounds of the invention with a slight stoichiometric excess of an acid with a lower pK than the acidic component of the original salt. This transformation is usually carried out at a temperature of from about 0°C to the boiling point of the solvent used as a medium for the technique. Similar exchanges are possible with base addition salts, usually via the free base form.

The compounds of the invention may exist in both unsolvated and solvated forms. When the solvent or water is strongly bound, the complex will have a well-defined stoichiometry regardless of humidity. However, when the solvent or water is loosely bound, as in channel solvates and hygroscopic compounds, the water/solvent content will depend on humidity and drying conditions. In such cases, non-stoichiometry will be the norm. The term "solvate" is used in this application to describe a molecular complex containing a compound of the invention and one or more molecules of a pharmaceutically acceptable solvent, such as ethanol. The term "hydrate" is used when the solvent is water. Pharmaceutically acceptable solvates according to the invention include hydrates and solvates in which the crystallization solvent may be isotopically substituted, for example D ₂ O, d ₆ -acetone, d ₆ -DMSO.

Also included within the scope of the invention are complexes such as clathrates, drug-host inclusion complexes, in which, unlike the aforementioned solvates, drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are drug complexes containing two or more organic and/or inorganic components, which may be in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionized, partially ionized, or non-ionized. For a review of such complexes, see J Pharm Sci, 64(8), 1269-1288 by Haleblian (August 1975), the disclosure of which is incorporated herein by reference in its entirety.

The invention also relates to prodrugs of the compounds of the formulas provided in the present description. Thus, certain derivatives of the compounds of the invention, which may themselves have little or no pharmacological activity, when administered to a patient, can be converted to the compounds of the invention, 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), the disclosures of which are incorporated herein in their entirety by reference.

Prodrugs according to the invention can, for example, be prepared by substituting the appropriate functional groups present in the compounds of the invention with certain moieties known to the person skilled in the art as "pro moieties", as described, for example, in "Design of Prodrugs" by H Bundgaard (Elsevier, 1985), the disclosure of which is incorporated herein in its entirety by reference.

Some non-limiting examples of prodrugs according to the invention include:

(i) if the compound contains a functional group of carboxylic acid (-COOH), its ester, for example, the replacement of hydrogen (C ₁ -C ₈ )alkyl;

(ii) if the compound contains an alcohol functional group (-OH), its ether, for example, the replacement of hydrogen with (C ₁ -C ₆ )alkanoyloxymethyl or a phosphate ether group; And

(iii) if the compound contains a primary or secondary amino functional group (-NH ₂ or -NHR, in which R ≠ H), its amide, for example, the replacement of one or both hydrogen atoms with a suitable metabolically labile group, such as an amide, carbamate, urea, phosphonate, sulfonate, etc.

Additional examples of substituent groups in accordance with the previous examples and examples of other types of prodrugs can be found in the above references.

Finally, certain compounds of the invention may themselves act as prodrugs of other compounds of the invention.

The scope of the invention also includes metabolites of the compounds of the formulas described in this application, ie, compounds formed in vivo upon administration of the drug.

), сплошного клина (

) или пунктирного клина (

). Применение сплошной линии для изображения связей асимметрических атомов углерода предназначено для обозначения, что включены все возможные стереоизомеры (например, определенные энантиомеры, рацемические смеси и т. д.) при этом атоме углерода. Применение или сплошного, или пунктирного клина для изображения связей асимметрических атомов углерода предназначено для обозначения, что только показанный стереоизомер предназначен для включения. Возможно, что соединения изобретения могут содержать более одного асимметрического атома углерода. В этих соединениях применение сплошной линии для изображения связей асимметрических атомов углерода предназначено для обозначения, что все возможные стереоизомеры предназначены для включения и присоединения стереоцентра. Например, если не указано иначе, предполагается, что соединения изобретения могут существовать в виде энантиомеров и диастереомеров или в виде рацематов и их смесей. Применение сплошной линии для изображения связей с одним или более асимметрическими атомами углерода в соединении изобретения и применение сплошного или пунктирного клина для изображения связей с другими асимметрическими атомами углерода в том же соединении предназначено для обозначения, что присутствует смесь диастереомеров.Compounds of the formulas provided herein may have asymmetric carbon atoms. The carbon-carbon bonds of the compounds of the invention may be depicted herein using a solid line (

), solid wedge (

) or dotted wedge (

). The use of a solid line to depict bonds of asymmetric carbon atoms is intended to indicate that all possible stereoisomers (eg, certain enantiomers, racemic mixtures, etc.) at that carbon atom are included. The use of either a solid wedge or a dotted wedge to represent asymmetric carbon bonds is intended to indicate that only the stereoisomer shown is intended to be included. It is possible that the compounds of the invention may contain more than one asymmetric carbon atom. In these compounds, the use of a solid line to depict the bonds of asymmetric carbon atoms is intended to indicate that all possible stereoisomers are intended to include and attach a stereocenter. For example, unless otherwise indicated, it is contemplated that the compounds of the invention may exist as enantiomers and diastereomers or as racemates and mixtures thereof. The use of a solid line to represent bonds to one or more asymmetric carbons in a compound of the invention, and the use of a solid or dotted wedge to represent bonds to other asymmetric carbons in the same compound is intended to indicate that a mixture of diastereomers is present.

Compounds of the invention which have chiral centers may exist as stereoisomers such as racemates, enantiomers or diastereomers.

Stereoisomers of the compounds of the formulas of the present disclosure may include cis and trans isomers, optical isomers such as (R)- and (S)-enantiomers, diastereomers, geometric isomers, rotational isomers, atropisomers, conformational isomers, and tautomers of the compounds of the invention, including compounds, exhibiting more than one type of isomerism; and mixtures thereof (such as racemates and diastereomeric pairs).

Also included are acid addition salts or base addition salts in which the counterion is optically active, eg d-lactate or l-lysine, or racemic, eg dl-tartrate or dl-arginine.

When any racemate crystallizes, two different types of crystalline substances are possible. The first type is the racemic compound (true racemate) mentioned above, in which one homogeneous form of crystalline substance is formed containing both enantiomers in equimolar amounts. The second type is a racemic mixture or conglomerate in which two forms of the crystalline substance are formed in equimolar amounts, each containing a single enantiomer.

The compounds of the invention may exhibit tautomerism and structural isomerism. For example, the compounds may exist in several tautomeric forms, including enol and imine forms, and keto and enamine forms, and geometric isomers, and mixtures thereof. All such tautomeric forms are included within the scope of the compounds of the invention. Tautomers exist as mixtures of a tautomer set in solution. In solid form, one tautomer usually predominates. Although a single tautomer may be described, the present invention includes all tautomers of the compounds of the formulas provided.

In addition, some of the compounds of the invention may form atropisomers (eg, substituted biaryls). Atropisomers are conformational stereoisomers that occur when rotation around a single bond in a molecule is prevented or severely retarded by steric interactions with other parts of the molecule, and the substituents at either end of the single bond are unsymmetrical. The interconversion of the atropisomers is slow enough to allow separation and isolation under predetermined conditions. The energy barrier to thermal racemization may be determined by the steric hindrance to the free rotation of one or more bonds forming a chiral axis.

If the compound of the invention contains an alkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers are possible. The cis/trans isomers can be separated by standard methods well known to those skilled in the art, such as chromatography and fractional crystallization.

Standard methods for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high performance liquid chromatography (HPLC) or supercritical fluid chromatography (SFC).

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

The chiral compounds of the invention (and their chiral precursors) can be obtained in an 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% isopropanol, usually from 2 up to 20%, and 0 to 5% alkylamine, typically 0.1% diethylamine. Concentration of the eluate provides an enriched mixture.

Stereoisomeric conglomerates can be separated by standard methods known to the person skilled in the art; see, for example, "Stereochemistry of Organic Compounds" by E L Eliel (Wiley, New York, 1994), the disclosure of which is hereby incorporated by reference in its entirety.

The enantiomeric purity of the compounds described in this application can be described in terms of enantiomeric excess (e.i.), which indicates the degree to which a sample contains one enantiomer in greater amounts than the other. A racemic mixture has an e.i. of 0%, while one completely pure enantiomer has an e.i. 100%. Similarly, diastereomeric purity can be described in terms of diastereomeric excess (d.i.).

The present invention also includes isotopically labeled compounds that are identical to the compounds shown in one of the provided formulas, except for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature.

The isotopically labeled compounds of the invention can generally be prepared by standard methods known to those skilled in the art, or by methods analogous to those described herein, using an appropriate isotopically labeled reagent in place of the unlabeled reagent used otherwise.

Examples of isotopes that may be included in the compounds of the invention include the isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as, but not limited to, ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³² P, ³⁵ S, ¹⁸ F and ³⁶ Cl. Certain isotopically labeled compounds of the invention, for example, compounds in which radioactive isotopes such as ³ H and ¹⁴ C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritium labeled ie ³ H and carbon-14 ie ¹⁴ C isotopes are most preferred due to their ease of preparation and detection. In addition, substitution with heavier isotopes such as deuterium, i.e. ² H, may provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some cases. Isotopically labeled compounds of the invention can generally be prepared using the procedures described in the Schemes and/or in the Examples and Preparations below by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products or mixtures thereof. They can be obtained, for example, in the form of a solid mass, powders or films using methods such as precipitation, crystallization, freeze drying, spray drying or evaporation drying. Microwave or RF drying may be used.

Therapeutic Methods and Applications

The invention further provides therapeutic methods and uses involving the administration of the compounds of the invention, or pharmaceutically acceptable salts thereof, alone or in combination with other therapeutic or palliative agents.

In one aspect, the invention provides a method of treating abnormal cell growth in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides a method of treating abnormal cell growth in a subject in need of such treatment, comprising administering to the subject an amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, in combination with an amount of an additional therapeutic agent (e.g., an anticancer therapeutic agent), amounts of which together are effective in treatment of said abnormal cell growth.

In another aspect, the invention provides a compound of the invention, or a pharmaceutically acceptable salt thereof, for use in the treatment of abnormal cell growth in a subject.

In a further aspect, the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the treatment of abnormal cell growth in a subject.

In another aspect, the invention provides a pharmaceutical composition for use in the treatment of abnormal cell growth in a subject in need of such treatment, the pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

In another aspect, the invention provides a compound of the invention, or a pharmaceutically acceptable salt thereof, for use as a drug, in particular a drug for the treatment of abnormal cell growth.

In yet another aspect, the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of abnormal cell growth in a subject.

In frequent embodiments of the methods provided herein, the abnormal cell growth is cancer. The compounds of the invention may be administered as single agents, or may be administered in combination with other anti-cancer therapeutic agents, in particular with standard care products suitable for the particular type of cancer.

In some embodiments, the provided methods result in one or more of the following effects: (1) inhibition of cancer cell proliferation; (2) inhibition of the invasiveness of cancer cells; (3) induction of apoptosis of cancer cells; (4) inhibition of cancer cell metastasis; or (5) inhibition of angiogenesis.

In another aspect, the invention provides a method of treating a CDK4-mediated disorder in a subject, comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable salt thereof, in an amount that is effective to treat said disorder, in particular cancer.

In preferred aspects and embodiments of the compounds, compositions, methods and uses described herein, the compounds of the invention are selective for CDK4 over CDK6. In frequent embodiments, the binding affinity for CDK6 is at least 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 40-fold, 50-fold, 60-fold, 75-fold, 100 times or more than 100 times greater than the binding affinity for CDK4.

Given the potential role of CDK6 in hematological toxicity such as neutropenia or leukopenia, a selective CDK4 inhibitor may provide an improved safety profile, improved dosing regimen (eg, by reducing the need for dose reductions or dosing intervals), and/or increased overall efficacy due to the possibility of higher doses, use of a continuous dosing regimen, and/or extended total treatment time compared to current dual CDK4/6 inhibitors. Animal models for assessing neutropenia are described in the art. For example, see Fine et al. A Specific Stimulator of Granulocyte Colony-Stimulating Factor Accelerates Recover from cyclophosphamide-Induced Neutropenia in the Mouse (1997) Blood, 90(2):795-802; Hu et al., Mechanistic Investigation of Bone Marrow Suppression Associated with Palbociclib and its Differentiation from Cytotoxic Chemotherapies (2016), Clin. Cancer Res. 22(8):2000-2008.

It may also be preferable to obtain selectivity for CDK4 over other CDKs such as CDK1, CDK2 or CDK9.

Compounds of the invention include compounds of any of the formulas described in this application, or their pharmaceutically acceptable salts.

In another aspect, the invention provides a method for inhibiting cancer cell proliferation in a subject, comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit cell proliferation.

In another aspect, the invention provides a method for inhibiting the invasiveness of cancer cells in a subject, comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit the invasiveness of the cells.

In another aspect, the invention provides a method for inducing apoptosis in cancer cells in a subject, comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable salt thereof, in an amount effective to induce apoptosis.

In another aspect, the invention provides a method for inhibiting cancer cell metastasis in a subject, comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit cell metastasis.

In another aspect, the invention provides a method for inhibiting angiogenesis in a subject, comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit angiogenesis.

In frequent embodiments of the methods provided herein, the abnormal cell growth is cancer. In some such embodiments, the cancer is selected from the group consisting of breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer (including NSCLC, SCLC, squamous cell carcinoma or adenocarcinoma), esophageal cancer, head and neck cancer , colorectal cancer, kidney cancer (including RCC), liver cancer (including HCC), pancreatic cancer, gastric cancer and thyroid cancer. In additional embodiments of the methods provided herein, the cancer is selected from the group consisting of breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, liver cancer, pancreatic cancer, and gastric cancer. .

In other embodiments, the cancer is breast cancer, including, for example, ER positive/HR positive, HER2 negative breast cancer; ER-positive/HR-positive, HER2-positive breast cancer; triple-negative breast cancer (TNBC) or inflammatory breast cancer. In some embodiments, the breast cancer is endocrine-resistant breast cancer, trastuzumab- or pertuzumab-resistant breast cancer, or breast cancer showing primary or acquired resistance to CDK4/CDK6 inhibition. In some embodiments, the breast cancer is advanced or metastatic breast cancer.

In some embodiments, a compound of the invention is administered as first line therapy. In other embodiments, a compound of the invention is administered as a second (or later) line therapy. In some embodiments, a compound of the invention is administered as a second (or later) line therapy following treatment with an endocrine therapeutic agent and/or a CDK4/CDK6 inhibitor. In some embodiments, a compound of the invention is administered as a second (or later) line therapy following treatment with an endocrine therapeutic agent, eg, an aromatase inhibitor, SERM, or SSRE. In some embodiments, a compound of the invention is administered as second (or later) line therapy following treatment with a CDK4/CDK6 inhibitor. In some embodiments, a compound of the invention is administered as a second (or later) line therapy following treatment with one or more chemotherapy regimens, for example, including taxanes or platinum agents. In some embodiments, a compound of the invention is administered as second-line (or later) therapy following treatment with HER2-targeting agents, such as trastuzumab.

As used herein, an "effective dosage" or "effective amount" of a drug, compound, or pharmaceutical composition is an amount sufficient to effect one or more beneficial or desirable effects, including the biochemical, histological, and/or behavioral symptoms of a disease, its complications, and intermediate pathological phenotypes present during the development of the disease. For therapeutic use, a "therapeutically effective amount" refers to that amount of a compound administered that will alleviate to some extent one or more of the symptoms of the disorder being treated. In relation to the treatment of cancer, a therapeutically effective amount refers to an amount that has the effect of (1) reducing the size of a tumor, (2) inhibiting (i.e. slowing to some extent, preferably stopping) tumor metastasis, (3) inhibiting to some extent (t e. slowing to some extent, preferably stopping) tumor growth or tumor invasiveness, (4) alleviating to some extent (or preferably eliminating) one or more signs or symptoms associated with cancer, (5) reducing the dose of other drugs needed to treat a disease, and/or (6) enhance the effect of another drug, and/or (7) delay the progression of a disease in a patient.

An effective dosage may be administered in one or more administrations. In the context of this invention, an effective dosage of a drug, compound, or pharmaceutical composition is an amount sufficient to effect prophylactic or therapeutic treatment, either directly or indirectly. As understood in a clinical context, an effective dosage of a drug, compound, or pharmaceutical composition may or may not be achieved in combination with another drug, compound, or pharmaceutical composition.

"Tumor" in relation to an object diagnosed or suspected of having cancer, refers to a malignant or potentially malignant neoplasm or tissue mass of any size and includes primary tumors and secondary neoplasms. A solid tumor is an abnormal growth or mass of tissue that usually does not contain cysts or fluid. Examples of solid tumors are sarcomas, carcinomas and lymphomas. Leukemias (cancers of the blood) usually do not form solid tumors (National Cancer Institute, Glossary of Cancer Terms).

"Tumor mass" or "tumor burden" refers to the total amount of tumor material distributed throughout the body. Tumor mass refers to the total number of cancer cells or the total size of the tumor(s) throughout the body, including the lymph nodes and bone marrow. The tumor mass can be determined using a variety of methods known in the art, such as, for example, using a caliper or while in the body using imaging techniques, such as ultrasound, bone scans, computed tomography (CT) or magnetic resonance imaging scans. tomography (MRI).

The term "tumor size" refers to the overall size of the tumor, which can be measured as the length and width of the tumor. The size of the tumor can be determined by various methods known in the art, such as, for example, by measuring the size of the tumor(s) after removal from the object, for example, using calipers, or while in the body using imaging techniques, for example, scanning bones, ultrasound, CT or MRI scans.

As used herein, "object" refers to a human or animal. In certain preferred embodiments, the subject is a human.

As used herein, the term "treating" or "treating" cancer means administering a compound of the present invention to a subject suffering from or diagnosed with cancer in order to achieve at least one beneficial therapeutic effect, such as, for example, a reduced number of cancer cells, reduced tumor size, reduced rate of cancer cell infiltration into peripheral organs, or reduced rate of tumor metastasis or tumor growth, reversal, amelioration, inhibition of progression, or prevention of the disorder or condition to which the term applies, or one or more symptoms of such disorder or condition. Used in the present description, the term "treatment", unless otherwise indicated, refers to the effect of treatment, as "treatment" is defined immediately above. The term "treatment" also includes adjuvant and neoadjuvant treatment of the subject.

With respect to this invention, useful or desirable clinical results include, but are not limited to, one or more of the following: reduced proliferation (or destruction) of neoplastic or cancerous cells; inhibition of metastases or neoplastic cells; shrinking or shrinking the size of the tumor; cancer remission; reduction of symptoms caused by cancer; improving the quality of life of cancer patients; reducing the dose of other medicines needed to treat cancer; delay in cancer progression; cancer treatment; overcoming one or more mechanisms of cancer resistance and/or increasing the survival of patients with cancer. Positive therapeutic effects in cancer can be measured in several ways (see, for example, W. A. Weber, Assessing tumor response to therapy, J. Nucl. Med. 50 Suppl. 1:1S-10S (2009). For example, in relation to inhibition of tumor growth ( T/C) according to National Cancer Institute (NCI) standards A T/C less than or equal to 42% is the minimum level of antitumor activity T/C < 10% is considered high level of antitumor activity, where T/C (%) = average volume treated tumor/mean control tumor volume ×100.

In some embodiments, the treatment achieved with a compound of the invention is defined by reference to any of the following: partial response (PR), complete response (CR), overall response (OR), progression-free survival (PFS), disease-free survival (DFS), and overall survival (OS). PFS, also referred to as Time to Tumor Progression, indicates the length of time during and after treatment that the cancer does not grow and includes the amount of time that patients experienced CR or PR, as well as the amount of time that patients experienced stable disease (SD). DFS refers to the period of time during and after treatment during which the patient does not experience disease. OS refers to the increase in lifespan compared to unexposed or untreated subjects or patients. In some embodiments, the response to the combination of the invention is any of PR, CR, PFS, DFS, OR, or OS, which is assessed using Solid Tumor Response Evaluation Criteria (RECIST) 1.1.

A treatment regimen with a compound of the invention that is effective in treating a patient with cancer may vary depending on factors such as disease state, age, and weight of the patient, and the ability of the therapy to elicit an anti-cancer response in the subject. While an embodiment of any of the aspects of the invention may not be effective in achieving a beneficial therapeutic effect in each subject, it must be effective against a statistically significant number of subjects as determined by any statistical test known in the art, such as Student's t-test , chi-square test, Mann-Whitney U-test, Kruskal-Wallis (H-test), Jonkhier-Terpstra test, and Wilcoxon test.

The terms "treatment regimen", "dosing protocol" and "dosing regimen" are used interchangeably to refer to the dose and timing of administration of each compound of the invention alone or in combination with another therapeutic agent.

"Reducing the intensity" means the reduction or improvement of one or more symptoms after treatment with a combination described in this application, compared with no administration of the combination. "Reducing the intensity" also includes reducing or reducing the duration of the symptom.

As used herein, "abnormal cell growth", unless otherwise indicated, refers to cell growth that is independent of normal regulatory mechanisms (eg, loss of contact inhibition). Abnormal cell growth can be benign (not cancerous) or malignant (cancerous).

Abnormal cell growth includes abnormal growth of: (1) tumor cells (tumors) that show increased expression of CDK4 and/or CDK6; (2) tumors that proliferate by aberrant activation of CDK4 and/or CDK6; and (3) tumors that are resistant to endocrine therapy, CDK4/6 inhibition, or HER2 antagonists.

Used in the present description, the term "additional anti-cancer therapeutic agent" means any one or more therapeutic agents other than the compound of the invention, which are used or can be used in the treatment of cancer. In some embodiments, such additional anticancer therapeutics include compounds derived from the following classes: mitosis inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, antiangiogenic agents, topoisomerase I and II inhibitors, plant alkaloids, hormonal agents and antagonists, growth factor inhibitors, radiation , signal transduction inhibitors such as protein tyrosine kinase and/or serine/threonine kinase inhibitors, cell cycle inhibitors, biological response modifiers, enzyme inhibitors, antisense oligonucleotides or oligonucleotide derivatives, cytotoxic agents, immuno-oncological agents, and the like.

In some embodiments, the additional anticancer agent is an endocrine agent, such as an aromatase inhibitor, SSRE, or SERM. In some such embodiments, a compound of the invention may be administered in combination with a standard care agent such as tamoxifen, exemestane, letrozole, fulvestrant, or anastrozole.

In other embodiments, a compound of the invention may be administered in combination with a chemotherapeutic agent such as docetaxel, paclitaxel, paclitaxel protein-coupled particles, cisplatin, carboplatin, oxaliplatin, capecitabine, gemcitabine, or vinorelbine.

In some embodiments, the additional anti-cancer agent is an anti-angiogenic agent, including, for example, VEGF inhibitors, VEGFR inhibitors, TIE-2 inhibitors, PDGFR inhibitors, angiopoietin inhibitors, PKCβ inhibitors, COX-2 (cyclooxygenase II) inhibitors, integrins (alpha-v /beta-3), inhibitors of MMP-2 (matrix metalloproteinase 2) and inhibitors of MMP-9 (matrix metalloproteinase 9). Preferred anti-angiogenic agents include sunitinib (Sutent™), bevacizumab (Avastin™), axitinib (AG 13736), SU 14813 (Pfizer) and AG 13958 (Pfizer). Additional anti-angiogenic agents include vatalanib (CGP 79787), sorafenib (Nexavar™), pegaptanib octasodium (Makugen™), vandetanib (Zactima™), PF-0337210 (Pfizer), SU 14843 (Pfizer), AZD 2171 (AstraZeneca), ranibizumab ( Lucentis™), Neovastat™ (AE 941), Tetrathiomolybdate (Coprexa™), AMG 706 (Amgen), VEGF Trap (AVE 0005), CEP 7055 (Sanofi-Aventis), XL 880 (Exelixis), Telatinib (BAY 57-9352 ) and CP-868596 (Pfizer). Other anti-angiogenic agents include enzastaurin (LY 317615), midostaurin (CGP 41251), perifosine (KRX 0401), teprenone (Selbex™) and UCN 01 (Kyowa Hakko). Other examples of anti-angiogenic agents include celecoxib (Celebrex™), parecoxib (Dynastat™), deracoxib (SC 59046), lumiracoxib (Prij™), valdecoxib (Bextra™), rofecoxib (Viox™), iguratimod (Kareram™), IP 751 ( Invedus), SC-58125 (Pharmacia), and etoricoxib (Arcoxia™). Additional anti-angiogenic agents include exisulind (Aptosin™), salsalate (Amigesic™), diflunisal (Dolobid™), ibuprofen (Motrin™), ketoprofen (Orudis™), nabumetone (Relafen™), piroxicam (Felden™), naproxicam (Aliv ™, Naprosyn™), diclofenac (Voltaren™), indomethacin (Indocin™), sulindac (Clinoril™), tolmetin (Tolectin™), etodolac (Lodin™), ketorolac (Toradol™), and oxaprozin (Deipro™). Additional anti-angiogenic agents include ABT 510 (Abbott), apratastat (TMI 005), AZD 8955 (AstraZeneca), incyclinide (Metastat™) and PCK 3145 (Procyon). Additional anti-angiogenic agents include acitretin (Neotigazon™), plitidepsin (Aplidin™), cilengtide (EMD 121974), combretastatin A4 (CA4P), fenretinide (4HPR), halofuginone (Tempostatin™), Panzem™ (2-methoxyestradiol), PF -03446962 (Pfizer), rebimastat (BMS 275291), catumaxomab (Removab™), lenalidomide (Revlimid™), squalamine (EVIZON™), thalidomide (Talomid™), Ukrain™ (NSC 631570), Vitaxin™ (MEDI 522), and zoledronic acid (Zometa™).

In other embodiments, the additional anti-cancer agent is a signal transduction inhibitor (eg, inhibitory agents by which regulatory molecules that regulate fundamental processes of cell growth, differentiation, and survival are passed within the cell). Signal transduction inhibitors include small molecules, antibodies, and antisense molecules. Signal transduction inhibitors include, for example, kinase inhibitors (eg tyrosine kinase inhibitors or serine/threonine kinase inhibitors) and cell cycle inhibitors. More specifically, signal transduction inhibitors include, for example, farnesyl protein transferase inhibitors, EGF inhibitor, ErbB-1 (EGFR), ErbB-2, pan erb, IGF1R inhibitors, MEK inhibitors, c-Kit, FLT-3 inhibitors, K-Ras inhibitors, PI3 kinases, JAK inhibitors, STAT inhibitors, Raf kinase inhibitors, Akt inhibitors, mTOR inhibitor, P70S6 kinase inhibitors, WNT pathway inhibitors, and multitarget kinase inhibitors.

Additional examples of anticancer agents that can be used in combination with the compound of the invention and the pharmaceutical compositions described herein include palbociclib (Ibrance®), ribociclib (Kiscali®), abemaciclib (Verzenio®), BMS 214662 (Bristol-Myers Squibb), lonafarnib (Sarasar™), pelitrexol (AG 2037), matuzumab (EMD 7200), nimotuzumab (TheraCIM h-R3™), panitumumab (Vectibix™), vandetanib (Zactima™), pazopanib (SB 786034), ALT 110 (Alteris Therapeutics ), BIBW 2992 (Boehringer Ingelheim) and Cerven™ (TP 38). Other examples include gefitinib (Iressa®), cetuximab (Erbitux®), erlotinib (Tarceva®), trastuzumab (Herceptin®), ado-trastuzumab emtansine (Kadcyla®), pertuzumab (Perjeta®), osimertinib (Tagrisso®), atezolizumab ( Tecentriq™), sunitinib (Sutent®), ibrutinib (Imbruvica®), imatinib (Glivec®), crizotinib (Xalkori®), lorlatinib (Lorbrena®), dacomitinib (Vizimpro®), bosutinib (Bosulif™), glasdegib (Daurismo™) ) Canertinib (CI 1033), Lapatinib (Tyverb™), Pelitinib (EKB 569), Miltefosine (Miltefosine™), BMS 599626 (Bristol-Myers Squibb), Lapuleucel-T (Neuvenge™), Neuvax™ (E75 Cancer Vaccine) , Osidem™ (IDM 1), mubritinib (TAK-165), CP-724714 (Pfizer), panitumumab (Vectibix™), ARRY 142886 (Array Biopharm), everolimus (Certican™), zotarolimus (Endevor™), temsirolimus (Torizel ™), AP 23573 (ARIAD) and VX 680 (Vertex), XL 647 (Exelixis), sorafenib (Nexavar™), LE-AON (Georgetown University) and GI-4000 (Globelmmune). Other signal transduction inhibitors include ABT 751 (Abbott), alvocidib (flavopiridol), BMS 387032 (Bristol Myers), EM 1421 (Erimos), indisulam (E 7070), seliciclib (CYC 200), BIO 112 (Onc Bio), BMS 387032 (Bristol-Myers Squibb) and AG 024322 (Pfizer) or PD-1 or PD-L1 antagonists, eg pembrolizumab (Keytruda®), nivolumab (Opdivo™) or avelumab (Bavencio®), abraxane.

In other embodiments, the additional anticancer agent is a so-called classical anticancer agent. Classical antitumor agents include, but are not limited to, hormonal modulators such as hormonal, antihormonal, androgen agonist, androgen antagonist and antiestrogen therapeutics, histone deacetylase (HDAC) inhibitors, DNA methyltransferase inhibitors, gene expression inhibitors or gene activators, ribonucleases, proteasome agents, topoisomerase I inhibitors, camptothecin derivatives, topoisomerase II inhibitors, alkylating agents, antimetabolites, poly(ADP-ribose)polymerase-1 (PARP-1) inhibitor (such as, for example, talazoparib (Talzenna®), olaparib, rucaparib, niraparib, iniparib, veliparib), microtubulin inhibitors, antibiotics, plant-derived spindle inhibitors, platinum coordination compounds, gene therapeutic agents, antisense oligonucleotides, vascular targeting agents (VTAs), and statins. Examples of classic anticancer agents used in combination therapy with a compound of the invention, optionally with one or more other agents, include, but are not limited to, glucocorticoids such as dexamethasone, prednisone, prednisolone, methylprednisolone, hydrocortisone, and progestins such as medroxyprogesterone, megestrol acetate ( Megeis), mifepristone (RU-486), selective estrogen receptor modulators (SERMs; such as tamoxifen, raloxifene, lasofoxifene, afimoxifene, arzoxifene, bazedoxifene, fispemifene, ormeloxifene, ospemifene, tesmilifene, toremifene, trilostane, and CHF 4227 (Cheisi)), selective estrogen receptor suppressors (SSREs; such as fulvestrant), exemestane (Aromasin), anastrozole (Arimidex), atamestane, fadrozole, letrozole (Femara), formestane; gonadotropin-releasing hormone (GnRH; also known as luteinizing hormone-releasing hormone [LHRH]) agonists such as buserelin (Suprefact), goserelin (Zoladex), leuprorelin (Lupron) and triptorelin (Trelstar), abarelix (Plenaxis), cyproterone, flutamide (Eulexin), megestrol, nilutamide (Nilandrone) and osateron, dutasteride, epristeride, finasteride, Serenoa repens (Sawfish), PHL 00801, abarelix, goserelin, leuprorelin, triptorelin, bicalutamide; antiandrogenic agents such as enzalutamide (Xtandi®), abiraterone acetate, bicalutamide (Casodex) and combinations thereof. Other examples of classic anticancer agents used in combination with a compound of the invention include, but are not limited to, PARP inhibitors such as talazoparib, olaparib, rucaparib, niraparib, iniparib, veliparib; suberolanilide hydroxamic acid (SAHA, Merck Inc./Aton Pharmaceuticals), depsipeptide (FR901228 or FK228), G2M-777, MC-275, pivaloyloxymethyl butyrate and PXD-101; Onconase (ranpirnase), PS-341 (MLN-341), Velcad (bortezomib), 9-aminocamptothecin, belothecan, BN-80915 (Roche), camptothecin, diflomothecan, edotecarin, exatecan (Daiichi), hymatecan, 10-hydroxycamptothecin, irinotecan HCl (Camptosar), Lurtotecan, Oratecin (Rubitecan, Supergen), SN-38, Topotecan, Camptothecin, 10-Hydroxy Camptothecin, 9-Aminocamptothecin, Irinotecan, SN-38, Edotecarin, Topotecan, Aclarubicin, Adriamycin, Amonafide, Amrubicin, Annamycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin, etoposide, idarubicin, galarubicin, hydroxyurea, nemorubicin, novanthrone (mitoxantrone), pyrarubicin, pixantrone, procarbazine, rebeccamycin, sobusoxane, tafluposide, valrubicin, Zinecard (dexrazoxane), nitrogen mustard N-oxide, cyclophosphamide AMD-473, Altretamine, AP-5280, Apaziquone, Brostallicin, Bendamustine, Busulfan, Carboquone, Carmustine, Chlorambucil, Dacarbazine, Estramustine, Fotemustine, Glufosfamide, Ifosfamide, KW-2170, Lomustine, Mafosfamide, Mechlorethamine, Melphalan, Mitobronitol, Mitobronitol olactol, mitomycin C, mitoxatron, nimustine, ranimustine, temozolomide, thiotepa, and platinum-coordinating alkylating compounds such as cisplatin, carboplatin, eptaplatin, lobaplatin, nedaplatin, oxaliplatin, streptozocin, satrplatin, and combinations thereof.

In yet other embodiments, the additional anti-cancer agent is so-called dihydrofolate reductase inhibitors (such as methotrexate and Neutrexin (trimetrexate glucuronate)), purine antagonists (such as 6-mercaptopurine ribozide, mercaptopurine, 6-thioguanine, cladribine, clofarabine (Clolar), fludarabine, nelarabine and raltitrexed), pyrimidine antagonists (such as 5-fluorouracil (5-FU), Alimta (premetrexed disodium, LY231514, MTA), capecitabine (Xeloda™), cytosine arabinoside, Gemzar™ (gemcitabine, Eli Lilly), Tegafur (UFT Orzel or Uforal and including TS-1 combination of tegafur, hymestat and otostat), doxyfluridine, carmofur, cytarabine (including oxphosphate, phosphate stearate, sustained release forms and liposomal forms), enocytabine, 5-azacytidine (Vidaza), decitabine and ethinylcitidine) and others antimetabolites such as eflornithine, hydroxyurea, leucovorin, nolatrexed (Timitac), triapine, trimetrexate, N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-meth ylamino]-2-thenoyl)-L-glutamic acid, AG-014699 (Pfizer Inc.), ABT-472 (Abbott Laboratories), INO-1001 (Inotek Pharmaceuticals), KU-0687 (KuDOS Pharmaceuticals), and GPI 18180 (Guilford Pharm Inc) and combinations thereof.

Other examples of classical antitumor cytotoxic agents include, but are not limited to, Abraxane (Abraxis BioScience, Inc.), Batabulin (Amgen), EPO 906 (Novartis), Vinflunin (Bristol-Myers Squibb Company), actinomycin D, bleomycin, mitomycin C, neocarzinostatin (Zinostatin), vinblastine, vincristine, vindesine, vinorelbine (Navelbine), docetaxel (Taxotere), Ortataxel, paclitaxel (including Taxoprexin DHA/paclitaxel conjugate), cisplatin, carboplatin, Nedaplatin, oxaliplatin (Eloxatin), Satraplatin, Camptosar, capecitabine ( Xeloda), Oxaliplatin (Eloxatin), Taxotere Alitretinoin, Kanfosfamide (Telcyta™), DMXAA (Antisoma), Ibandronic Acid, L-Asparaginase, Pegaspargase (Oncaspar™), Efaproxiral (Efaproxin™ - Radiotherapy), Bexarotene (Targretin™), Tesmilifen (DPPE - improves the effectiveness of cytotoxic agents), Teratop™ (Biomira), Tretinoin (Vesanoid™), tirapazamine (Trizaon™), gadolinium motexafine (Xcitrin™) Kotara™ (mAb), and NB1-3001 (Protox Therapeutics), poly glutamate-paclitaxel (Xiotax™), and combinations thereof. Additional examples of classical antitumor agents include, but are not limited to, Advexin (ING 201), TNFerade (GeneVec, a compound that expresses TNF-alpha in response to radiotherapy), RB94 (Baylor College of Medicine), Genasens (Oblimersen, Genta), Combretastatin A4P (CA4P), Oxi-4503, AVE-8062, ZD-6126, TZT-1027, Atorvastatin (Lipitor, Pfizer Inc.), Provastatin (Pravachol, Bristol-Myers Squibb), Lovastatin (Mevacor, Merck Inc.), Simvastatin (Zocor, Merck Inc.), Fluvastatin (Lescol, Novartis), Cerivastatin (Baycol, Bayer), Rosuvastatin (Crestor, AstraZeneca), Lovostatin, Niacin (Advicor, Kos Pharmaceuticals), Caduet, Lipitor, Torcetrapib, and combinations thereof.

In some embodiments, the additional anticancer agent is an epigenetic modulator, e.g., an inhibitor of EZH2, SMARCA4, PBRM1, ARID1A, ARID2, ARID1B, DNMT3A, TET2, MLL1/2/3, NSD1/2, SETD2, BRD4, DOT1L, HKMTsanti, PRMT1- 9, LSD1, UTX, IDH1/2 or BCL6.

In further embodiments, the additional anticancer agent is an immunomodulatory agent such as a CTLA-4, PD-1, or PD-L1 inhibitor (e.g., pembrolizumab, nivolumab, or avelumab), LAG-3, TIM-3, TIGIT, 4-1BB, OX40, GITR, CD40, or CAR-T cell therapy.

As used herein, "cancer" refers to any malignant and/or invasive growth or tumor caused by abnormal cell growth. Cancer includes solid tumors named for the type of cells that form them, cancers of the blood, bone marrow, or lymphatic system. Examples of solid tumors include sarcomas and carcinomas. Blood cancers include, but are not limited to, leukemia, lymphoma, and myeloma. Cancer also includes primary cancer that originates at a specific location in the body, metastatic cancer that has spread from where it started to other parts of the body, recurrence of the original primary cancer after remission, and second primary cancer, which is a new primary cancer in a person who already had a history of cancer of a different type than the last one.

In some embodiments of the methods provided herein, the cancer is selected from the group consisting of breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer (including NSCLC), esophageal cancer, head and neck cancer, cancer liver, pancreatic cancer and stomach cancer.

Dosage forms and treatment regimens

The administration of the compounds of the invention can be influenced by any method that allows the compounds to be delivered to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical and rectal administration.

Treatment regimens can be adjusted to provide the optimal desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased depending on the need of the therapeutic situation. It is particularly preferred to formulate parenteral compositions in unit dosage form for ease of administration and dosage uniformity. As used herein, unit dosage form refers to physically discrete units suitable as unit dosages for mammals to be treated; each unit contains a predetermined amount of active compound, calculated to obtain the desired therapeutic effect, in combination with the necessary pharmaceutical carrier. The definition of unit dosage forms of the invention is dictated by and directly dependent on (a) the unique characteristics of the chemotherapeutic agent and the specific therapeutic or prophylactic effect to be achieved, and (b) the limitations of the field of drug formulation of such an active compound for the treatment of sensitivity in of people.

Thus, one of ordinary skill in the art will appreciate, based on the disclosure provided herein, that the dose and dosing regimen are adjusted in accordance with methods well known in the therapeutic arts. Thus, the maximum tolerated dose can be easily established and the effective amount that provides a detectable therapeutic benefit to the patient can also be determined, as well as the time requirement for the administration of each agent to provide a detectable therapeutic benefit to the patient. Accordingly, while examples of certain dosages and administration regimens are provided herein, these examples do not in any way limit the dosage and administration regimen that may be provided to a patient in the practice of the present invention.

It should be noted that dosage values may vary depending on the type and severity of the condition to be alleviated and may include single or multiple doses. It should also be understood that for any particular subject, certain dosing regimens will need to be adjusted over time in accordance with individual needs and the professional judgment of the person administering or supervising the administration of the compositions, and that the dosage ranges set forth herein are only exemplary and are not intended to limiting the scope or practice of the claimed composition. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and/or laboratory values. Thus, the present invention encompasses dose escalation in the same patient, as determined by a person skilled in the art. Determination of suitable doses and regimens of administration of a chemotherapeutic agent is well known in the relevant art and will be clear to a person skilled in the art once he studies the ideas disclosed in the present description.

The amount of compound of the invention administered will depend on the subject being treated, the severity of the disorder or condition, the rate of administration, the distribution of the compound, and the discretion of the attending physician. However, an effective dosage ranges from about 0.001 to about 100 mg per kg of body weight per day, preferably from about 1 to about 35 mg/kg/day in single or divided doses. For a 70 kg human, this amount would be from about 0.05 to about 7 g/day, preferably from about 0.1 to about 2.5 g/day. In some cases, dosage levels below the lower end of the aforementioned range may be more than adequate, while in other cases even larger doses may be used without causing any harmful side effect, provided that such large doses are first divided into several smaller doses. for administration during the day.

Compositions and routes of administration

As used herein, a "pharmaceutically acceptable carrier" refers to a carrier or diluent that does not cause significant irritation to the body and does not interfere with the biological activity and properties of the administered compound.

A pharmaceutically acceptable carrier may include any conventional pharmaceutical carrier or excipient. The choice of carrier and/or excipient will largely depend on factors such as the particular route of administration, the effect of the carrier or excipient on solubility and stability, and the property of the dosage form.

Suitable pharmaceutical carriers include inert diluents or excipients, water, and various organic solvents (such as hydrates and solvates). If desired, pharmaceutical compositions may contain additional ingredients such as flavorings, binders, excipients, and the like. Thus, for oral administration, tablets containing various excipients such as citric acid can be used with various disintegrants such as starch, alginic acid and certain complex silicates and with binders such as sucrose, gelatin and acacia. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tabletting purposes. Solid compositions of a similar type can also be used in soft and hard gelatin capsules. Non-limiting examples of materials therefore include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the active compound therein may be combined with various sweetening or flavoring agents, coloring or coloring agents and, if desired, with emulsifiers or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerol, or their combinations.

The pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulation, solution suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment. or cream or for rectal administration as a suppository.

Exemplary forms for parenteral administration include solutions or suspensions of the active compounds in sterile aqueous solutions, for example, aqueous solutions of propylene glycol or dextrose. If desired, such dosage forms may be suitably buffered.

The pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages.

Pharmaceutical compositions suitable for the delivery of the compounds of the invention and methods for their preparation will be apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in "Remington's Pharmaceutical Sciences", 19th Edition (Mack Publishing Company, 1995), the disclosure of which is incorporated herein in its entirety by reference.

The compounds of the invention may be administered orally. Oral administration may include ingestion, such that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be used, in which the compound enters the blood stream directly from the mouth.

Formulations suitable for oral administration include solid formulations such as tablets containing particles, capsules, liquids or powders, lozenges (including liquid-filled), chewable tablets, multi- and nanoparticles, gels, solid solution, liposomes, films (including mucoadhesives) , capsules, sprays and liquid formulations.

Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be used as fillers in soft or hard capsules and typically include a carrier such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations can also be prepared by reconstitution of the solid, for example from sachets.

The compounds of the invention can also be used in rapidly dissolving, rapidly disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11(6), 981-986 by Liang and Chen (2001), the disclosure of which is incorporated herein in in its entirety by reference.

For tablet dosage forms, depending on the dose, the drug may comprise from 1 wt.% to 80 wt.% of the dosage form, more typically from 5 wt.% to 60 wt.% of the dosage form. In addition to the drug, tablets usually contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, sodium croscarmellose, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl substituted hydroxypropyl cellulose, starch, pregelatinized starch, and sodium alginate. Typically, the disintegrant will comprise from 1 wt.% to 25 wt.%, preferably from 5 wt.% to 20 wt.% of the dosage form.

Binders are commonly used to impart cohesive properties to the tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose and hydroxypropylmethylcellulose. Tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous, and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and dibasic calcium phosphate dihydrate.

Tablets may also optionally include surfactants such as sodium lauryl sulfate and polysorbate 80 and glidants such as silica and talc. When found, surfactants are typically present in amounts of 0.2 wt.% to 5 wt.% of the tablet, and glidants, typically 0.2 wt.% to 1 wt.% of the tablet.

Tablets also typically contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate. Glidants are usually present in amounts of from 0.25 wt.% to 10 wt.%, preferably from 0.5 wt.% to 3 wt.% tablets.

Other standard ingredients include antioxidants, colors, flavors, preservatives, and taste-masking agents.

Typical tablets contain up to about 80 wt.% drug, from about 10 wt.% to about 90 wt.% binder, from about 0 wt.% to about 85 wt.% diluent, from about 2 wt.% to about 10 wt.% disintegrant and from about 0.25 wt.% to about 10 wt.% sliding agent.

Mixtures of tablets can be compressed directly or with a roller to form tablets. Tablet blends or portions of blends may alternatively be wet, dry, or melt-granulated, melt-congealed, or extruded prior to tabletting. The final composition may include one or more layers and may be coated or uncoated or encapsulated.

The composition of tablets is discussed in detail in "Pharmaceutical Dosage Forms: Tablets, Vol. 1", by H. Lieberman and L. Lachman, Marcel Dekker, N.Y., N.Y., 1980 (ISBN 0-8247-6918-X), the disclosure of which is hereby incorporated by reference in its entirety.

Solid formulations for oral administration can be prepared with immediate and/or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release.

Suitable modified release formulations are described in US Pat. No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles can be found in Verma et al, Pharmaceutical Technology On-line, 25(2), 1- 14 (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298. The disclosure of these references is incorporated herein in its entirety by reference.

The compounds of the invention can also be administered directly into the bloodstream, into a muscle, or into an internal organ. Suitable routes of parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needleless injectors and infusion techniques.

Formulations for parenteral administration are usually aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably up to a pH of 3 to 9), but for some applications they may be more appropriately formulated as a sterile non-aqueous solution or in dried form for use in combination with a suitable vehicle such as sterile, pyrogen-free water.

The preparation of parenteral formulations under sterile conditions, for example by lyophilization, can be readily accomplished using standard pharmaceutical techniques well known to those skilled in the art.

The solubility of the compounds of the invention used in the preparation of parenteral solutions can be increased by the use of suitable preparation techniques such as the inclusion of solubility enhancing agents.

Compositions for parenteral administration can be obtained with immediate and/or modified release. Modified release formulations include delayed, sustained, 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 a modified release of the active compound. Examples of such formulations include drug-eluting stents and PGLA microspheres.

The compounds of the invention can also be administered topically to the skin or mucous membrane, ie dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, films, skin patches, implant capsules, implants, sponges, fibers, dressings, and microemulsions. You can also use liposomes. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration aids may be included; see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999). Other methods of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis, and injections with or without microneedles (eg, Powderject™, Bioject™, etc.). The disclosure of these references is incorporated herein in its entirety by reference.

Compositions for topical administration can be obtained with immediate and/or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release.

The compounds of the invention can also be administered intranasally or by inhalation, usually in the form of a dry powder (or alone, as a mixture, for example dry-mixed with lactose, or as mixed component particles, for example mixed with phospholipids such as phosphatidylcholine) from a powder inhaler or as an aerosol spray from a pressurized container, pump, spray, aerosol inhaler (preferably an aerosol inhaler using electrohydrodynamics to produce a fine mist) or nebulizer with or without the use of a suitable propellant such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may include a bioadhesive agent such as chitosan or cyclodextrin.

The pressurized container, pump, spray, aerosol inhaler or nebulizer contains a solution or suspension of the compound(s) of the invention containing, for example, ethanol, aqueous ethanol or a suitable alternative agent for dispersing, solubilizing or sustained release of the active substance, the propellant(s) as a solvent and an optional surfactant such as sorbitan trioleate, oleic acid or oligolactic acid.

Prior to use in a dry powder or suspension formulation, the drug product is micronized to a size suitable for inhalation delivery (typically less than 5 microns). This can be achieved by any suitable grinding method such as spiral jet milling, fluidized bed jet milling, supercritical fluid treatment to form nanoparticles, high pressure homogenization, or spray drying.

Capsules (made, for example, from gelatin or HPMC), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mixture of a compound of the invention, a suitable powder base such as lactose or starch, and a performance modifier such as l -leucine, mannitol or magnesium stearate. The lactose may be anhydrous or in the form of a monohydrate, the latter being preferred. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

A suitable solution formulation for use in an aerosol inhaler using electrohydrodynamics to produce a fine mist may contain from 1 μg to 20 mg of a compound of the invention per dosing, and the dosage volume may vary from 1 μl to 100 μl. A typical formulation includes a compound of the invention, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that can be used instead of propylene glycol include glycerin and polyethylene glycol.

Suitable flavoring agents such as menthol and levomenthol or sweeteners such as saccharin or sodium saccharin may be added to such inhalation/nasal formulations of the invention.

Compositions for inhalation/nasal administration can be obtained with immediate and/or modified release using, for example, poly(DL-lactic-coglycolic)acid (PGLA). Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release.

In the case of powder inhalers and aerosols, the dosage unit is determined by a valve that delivers a metered amount. Units in accordance with the invention are generally adapted to deliver a metered dose or "spray" containing the desired amount of a compound of the invention. The total daily dose may be administered as a single dose, or usually in divided doses throughout the day.

The compounds of the invention may be administered rectally or vaginally, for example in the form of a suppository, pessary or enema. Cocoa butter is the traditional base for suppositories, but various alternatives can be used if necessary.

Compositions for rectal/vaginal administration can be prepared with immediate and/or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release.

The compounds of the invention can also be administered directly to the eye or ear, usually in the form of drops of a micronized suspension or solution in isotonic pH-adjusted sterile saline. Other formulations suitable for ocular and otic administration include ointments, biodegradable (eg, absorbable gel sponges, collagen) and non-biodegradable (eg, silicone) implants, implant capsules, lenses, and particulate or vesicular particle systems such as niosomes or liposomes. A polymer such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulose polymer such as hydroxypropyl methylcellulose, hydroxyethylcellulose, or methylcellulose, or a heteropolysaccharide polymer such as gelan gum may be included along with a preservative such as benzalkonium chloride. Such formulations can also be delivered by iontophoresis.

Formulations for ophthalmic/ear administration can be prepared with immediate and/or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release.

Other technologies

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

For example, drug-cyclodextrin complexes have generally been found to be suitable for most dosage forms and routes of administration. Both inclusion complexes and non-inclusion complexes can be used. As an alternative to direct complexation with the drug, the cyclodextrin can be used as an auxiliary additive, i.e. as a carrier, diluent or solubilizer. The most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which can be found in PCT Publication Nos. .

The amount of active compound administered will depend on the subject being treated, the severity of the disorder or condition, the rate of administration, the distribution of the compound, and the discretion of the attending physician. However, an effective dosage is usually in the range of about 0.001 to about 100 mg per kg of body weight per day, and often from about 0.01 to about 35 mg/kg/day in single or divided doses. For a 70 kg human, this amount would be from about 0.07 mg/day to about 7000 mg/day, more typically from about 10 mg/day to about 1000 mg/day. Sometimes the dosage is approximately 10, 20, 30, 40, 50, 60, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 750, 800, 900 or 1000 mg/day. Sometimes the dosage is from about 10 mg/day to about 1000 mg/day, from about 10 mg/day to about 750 mg/day, from about 10 mg/day to about 600 mg/day, from about 10 mg/day to about 300 mg/day, from about 10 mg/day to about 150 mg/day, from about 20 mg/day to about 750 mg/day, from about 20 mg/day to about 600 mg/day, from about 20 mg/day up to about 300 mg/day, from about 20 mg/day to about 150 mg/day, from about 50 mg/day to about 750 mg/day, from about 50 mg/day to about 600 mg/day from about 50 mg/day day to about 300 mg/day, from about 50 mg/day to about 150 mg/day, from about 75 mg/day to about 750 mg/day, from about 75 mg/day to about 600 mg/day, from about 75 mg/day to about 300 mg/day or from approx. positively 75 mg/day to approximately 150 mg/day.

In some cases, dosage levels below the lower end of the above range may be more than adequate, while in other cases even higher doses may be used without causing any harmful side effect, provided that such large doses are usually divided into several small doses. for administration during the day.

Set of parts

Since it may be desirable to administer a combination of active compounds, for example for the purpose of treating a particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions, at least one of which contains a compound according to the invention, may conveniently be combined. in the form of 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 kit is the familiar blister pack used to pack tablets, capsules and the like.

The set of the invention is particularly suitable for administering different dosage forms, eg oral and parenteral, for administering separate compositions at different dosing intervals, or for titration of separate compositions against each other. To facilitate adherence to therapy, the kit usually includes instructions for use and may be provided with a reminder.

Combination Therapy

Used in the present description, the term "combination therapy" refers to the introduction of the compounds of the invention together with at least one additional pharmaceutical or drug (eg, anticancer agent) either sequentially or simultaneously.

As noted above, the compounds of the invention may be used in combination with one or more additional anticancer agents. The efficacy of the compounds of the invention in certain tumors may be enhanced by combination with other approved or experimental cancer treatments, e.g., radiation, surgery, chemotherapeutic agents, targeted therapy, agents that inhibit other signaling pathways that are not upregulated in tumors, and other agents. immune enhancing agents such as PD-1 or PD-L1 antagonists and the like.

When using combination therapy, one or more additional anticancer agents can be administered sequentially or simultaneously with the compound of the invention. In one embodiment, an additional anti-cancer agent is administered to a mammal (eg, a human) prior to administration of a compound of the invention. In another embodiment, the additional anti-cancer agent is administered to the mammal following administration of a compound of the invention. In another embodiment, an additional anti-cancer agent is administered to a mammal (eg, a human) concurrently with the administration of a compound of the invention.

The invention also relates to a pharmaceutical composition for the treatment of abnormal cell growth in a mammal, including a human, which contains an amount of a compound of the invention as defined above (including hydrates, solvates and polymorphs of said compound or a pharmaceutically acceptable salt thereof), in combination with one or more ( preferably one to three) additional anti-cancer therapeutic agents.

Synthesis methods

Compounds of the invention are prepared in accordance with the exemplary procedures and Schemes provided herein and modifications thereof known to those skilled in the art. Scheme 1 shows the general route for preparing pyrimidine compounds 6 containing various saturated heterocyclyl or cycloalkyl moieties (containing Q) and a heteroaromatic ring (containing U, V, X, Y and Z). It should be understood that the order of the steps may be reversed.

General scheme 1:

As shown in Scheme 1, the substituted dichloropyrimidines 1 are subjected to Suzuki coupling conditions with aryl- or heteroarylboronates 2 in the presence of a suitable catalyst (such as Pd(PPh ₃ ) ₄ or Pd(PPh ₃ ) ₂ Cl ₂ ) and a suitable base (such as Na ₂ CO ₃ or K ₂ CO ₃ ) in a suitable solvent system (such as dioxane:water or DME:water) to give aryl- or heteroaryl-substituted chloropyrimidines 4. Alternatively, aryl- or heteroaryl bromides 3 can be used in a Suzuki cross-coupling reaction after treating the bromine compound with bis(pinacolato)diborone, a suitable catalyst (such as Pd(OAc) ₂ or Pd(dppf)Cl ₂ ), a ligand (such as PCy ₃ ), and a base (such as KOAc or NaOAc) in a suitable solvent (such as DMSO or dioxane). The resulting heterobiaryl intermediates 4 are treated under conditions of nucleophilic chloride displacement with primary heterocyclylamine or cycloalkylamine 5 in the presence of a suitable base (such as DIPEA) in a suitable solvent (eg DMSO) to give amino-substituted pyrimidine compounds 6. When intermediate 4 is reacted with primary heterocyclylamine, Q in 5 and 6 is a suitably substituted amino group (eg NR ¹¹ ), a suitably protected amino group (eg carbamoyl, tetrahydropyranyl or trialkylsilyl protected amine) or oxygen. When intermediate 4 is reacted with a primary cycloalkylamine, Q at 5 and 6 is an optionally substituted carbon.

Alternatively, the heterobiaryl intermediates 4 can be subjected to Buchwald-Hartwig coupling conditions in the presence of a suitable amine 5, a suitable catalyst (e.g. Pd ₂ (dba) ₃ , chloro-2-(dimethylaminomethyl)ferrocen-1-yl-(dinorbornylphosphine)palladium, or Pd(OAc) ₂ ), BINAP and a suitable base (eg Cs ₂ CO ₃ ) in a suitable solvent (such as THF, dioxane or 2-methyl-2-butanol) to give compounds 6.

It will be apparent that reactive functional groups present at any position in intermediates 1-5 and penultimate compounds 6 can be masked using suitable protecting groups known to those skilled in the art. For example, such compounds may contain amine or hydroxyl moieties masked with protective groups (such as tert-butylcarbamate or tetrahydropyran) that can be removed using conditions known in the art (such as TFA or HCl) in a suitable solvent. In some embodiments, Q in compound 6 may be a protected amino group that is removed under standard conditions to give a free secondary amine, which is then reacted with a suitable reactive agent (e.g., sulfonyl halide, acyl halide, alkyl halide, or the like) to mount an R ¹¹ substituent.

Similar reactions can be used to obtain the corresponding pyridine derivatives, as illustrated in the examples provided in the present description.

General synthesis methods:

Abbreviations:

The following abbreviations are used throughout the Examples: "Ac" means acetyl, "AcO" or "OAc" means acetoxy, "ACN" means acetonitrile, "aq." means aqueous, "atm" means atmosphere(s), "BOC", "Boc" or "boc" means N-tert-butoxycarbonyl, "Bn" means benzyl, "Bu" means butyl, "nBu" means normal butyl, "tBu" means tert-butyl, "DBU" means 1,8-diazabicyclo[5.4.0]undec-7-ene, "Cbz" means benzyloxycarbonyl, "DCM" (CH ₂ Cl ₂ ) means methylene chloride, "d.i. » means diastereomeric excess, "DEA" means diethylamine, "DIPEA" means diisopropylethylamine, "DMA" means N,N-dimethylacetamide, "DME" means 1,2-dimethoxyethane, "DMF" means N,N-dimethylformamide, "DMSO" means dimethyl sulfoxide, "EDTA" stands for ethylenediaminetetraacetic acid, "e.i." means enantiomeric excess, "Et" means ethyl, "EtOAc" means ethyl acetate, "EtOH" means ethanol, "HOAc" or "AcOH" means acetic acid, "i-Pr" or " ^iPr " means isopropyl, "IPS" means isopropyl alcohol, “LAH” means lithium aluminum hydride, “LHMDS” means lithium hexamethyldisilazide (lithium bis(trimethylsilyl)amide), “mCPBA” means meta-chloroperoxybenzoic acid, “Me” means methyl, “MeOH” means methanol, “MC” means mass spectrometry, "MTBE" means methyl tert-butyl ether, "NCS" means N-chlorosuccinimide, "Ph" means phenyl, "TBHP" means tert-butyl hydroperoxide, "TFA" means trifluoroacetic acid, "THF" means tetrahydrofuran, "SFC" means supercritical fluid chromatography, "TLC" means thin layer chromatography, "Rf" means retention factor, "~" means approximately, "rt" means retention time, "h" means hours, "min" means minutes, "equiv. » means equivalents, "us." means saturated.

Scheme I:

As shown in Scheme I, a compound such as I (purchased or synthesized) can be borated with B ₂ Pin ₂ in the presence of a suitable catalyst system (such as PdCl ₂ (dppf) or Pd(OAc) ₂ +PCy ₃ ) with a suitable base (such as KOAc) in a suitable solvent (such as 1,4-dioxane or DMSO) to give a compound such as II. A compound such as II can be prepared and reacted in-situ. Alternatively, a compound such as II may be isolated prior to subsequent reactions to give the corresponding boronic acid or BPin ester. A compound such as II can be arylated with an aryl chloride such as III under standard Suzuki cross-coupling conditions in the presence of a suitable catalyst (such as Pd(PPh ₃ ) ₄ or PdCl ₂ (PPh ₃ ) ₂ ) with a suitable base (such as K ₂ CO ₃ or Na ₂ CO ₃ ) in a suitable solvent (such as DMSO or 1,4-dioxane) to give a compound such as IV. A compound such as IV may be coupled to an amine such as V to give a compound such as VI under standard nucleophilic aromatic substitution conditions (S _N Ar) in the presence of a suitable base (such as DIPEA) in a suitable solvent (such as DMSO). Alternatively, a compound such as IV may be coupled to an amine such as V to form a compound such as VI under standard Buchwald-Hartwig coupling conditions in the presence of a suitable catalyst system (such as Pd(OAc) ₂ +rac- BINAP or a complex of chloro-2-(dimethylaminomethyl)ferrocen-1-yl-(dinorbornylphosphine)palladium) with a suitable base (such as Cs ₂ CO ₃ ) in a suitable solvent (such as THF or 1,4-dioxane). In some cases, a compound such as VI may contain protecting groups that can be removed in an additional step in the synthetic sequence using conditions known in the art (Protective Groups in Organic Synthesis, A. Wiley-Interscience Publication, 1981 or Protecting groups , 10 Georg Thieme Verlag, 1994). Compounds in each step can be purified by standard methods such as column chromatography, crystallization, or reverse phase SFC or HPLC. If necessary, separation of the enantiomers of VI can be carried out by standard methods known in the art, such as chiral SFC or HPLC, to obtain individual enantiomers. The variables Q, U, V, X, Z, R ¹ and R ⁷ and R ⁹ are as defined in the embodiments, diagrams, examples and claims herein.

Scheme II:

As shown in Scheme II, a compound such as VII (prepared as in Scheme I) can be coupled to an aryl chloride such as VIII under standard Suzuki cross-coupling conditions with a suitable catalyst system (such as Pd(t-Bu ₃ P ) ₂ ) with a suitable base (such as K ₂ CO ₃ ) in a suitable solvent (such as 1,4-dioxane) to give a compound such as IX. A compound such as IX may be oxidized with a suitable oxidizing agent (such as oxone) to give a compound such as X. A compound such as X may be coupled to an amine such as XI under standard S _N Ar conditions in the presence of a suitable base (such as Na ₂ CO ₃ ) in a suitable solvent (such as THF) to give a compound such as XII. Compounds in each step can be purified by standard methods such as column chromatography, crystallization, or reverse phase SFC or HPLC. The variables R ¹ and R ⁴ are as defined in the embodiments, diagrams, examples and claims herein.

Scheme III:

As shown in Scheme III, an aryl bromide such as compound XIII can be converted to a boronate ester such as compound XIV with B ₂ Pin ₂ in the presence of a suitable catalyst (such as Pd ₂ Cl ₂ (dppf)) with a suitable base ( such as KOAc) in a suitable solvent (such as 1,4-dioxane). A compound such as XIV may be prepared and used in situ or isolated to give the corresponding boronate ester. A compound such as XIV may be coupled to an aryl chloride such as compound III under standard Suzuki cross-coupling conditions with a suitable catalyst (such as PdCl ₂ (PPh ₃ ) ₂ ) and a suitable base (such as Na ₂ CO ₃ ) in suitable solvent (such as 1,4-dioxane) to give a compound such as XV. A compound such as XV can be converted to a compound such as XVI in the presence of an excess of i-PrNH ₂ in a suitable solvent (such as DMSO). A compound such as XVI may be cyclized with an aldehyde such as XVII in the presence of a suitable reducing agent (such as Na ₂ S ₂ O ₄ ) in a suitable solvent (such as EtOH) to give a compound such as XVIII. A compound such as XVIII may be coupled to an amine such as XIX under standard Buchwald-Hartwig conditions in the presence of a suitable catalyst system (such as Pd(OAc) ₂ +rac-BINAP) and a suitable base (such as Cs ₂ CO ₃ ) in an appropriate solvent system (such as 1,4-dioxane or THF) to give a compound such as XX. Compounds in each step can be purified by standard methods such as column chromatography, crystallization, or reverse phase SFC or HPLC. The variables Q, R ¹ , R ⁴ , R ⁶ and R ⁷ are as defined in the embodiments, diagrams, examples and claims herein.

Scheme IV:

As shown in Scheme IV, a compound such as XXI (prepared as in Scheme I) can be coupled to an aryl chloride such as compound XXII under standard Suzuki cross-coupling conditions with a suitable catalyst (such as PdCl ₂ (PPh ₃ ) ₂ ) and a suitable base (such as Na ₂ CO ₃ ) in a suitable solvent (such as 1,4-dioxane) to give a compound such as XXIII. A compound such as XXIII may be coupled to an amine such as XIX under standard Buchwald-Hartwig coupling conditions with a suitable palladium catalyst system (such as Bretphos-Pd-G3 or Pd ₂ (dba) ₃ +rac-BINAP) with a suitable base (such as t-BuONa, Cs ₂ CO ₃ or phosphazene P ₂ -Et) in a suitable solvent (such as 1,4-dioxane or PhMe) to give a compound such as XXIV. In some cases, a compound such as XXIV may contain protecting groups that can be removed in an additional step in the synthetic sequence using conditions known in the art (Protective Groups in Organic Synthesis, A. Wiley-Interscience Publication, 1981 or Protecting groups , 10 Georg Thieme Verlag, 1994). Compounds in each step can be purified by standard methods such as column chromatography, crystallization, or reverse phase SFC or HPLC. The variables Q, Z, R ² , R ⁴ and R ⁶ are as defined in the embodiments, diagrams, examples and claims herein.

Scheme V:

As shown in Scheme V, an amine such as XI may be coupled to an aryl fluoride such as XXV to give a compound such as XXVI under standard S _N Ar conditions with a suitable base (such as DIPEA) in a suitable solvent (such as DMSO). A compound such as XXVI may be coupled to a compound such as XXVII (prepared as in Scheme I) under standard Suzuki cross-coupling conditions with a suitable catalyst (such as PdCl ₂ (PPh ₃ ) ₂ ) with a suitable base (such as Na ₂ CO ₃ ) in a suitable solvent (such as 1,4-dioxane) to give a compound such as XXVIII. Compounds in each step can be purified by standard methods such as column chromatography, crystallization, or reverse phase SFC or HPLC.

Scheme VI:

As shown in Scheme VI, a compound such as XXIX (prepared as in Scheme I or Scheme IV) can be converted to a compound such as XXX under a variety of conditions well known in the art, including:

i. Formation of a carbamate with chloroformate in the presence of a suitable base (such as NEt ₃ ) in a suitable solvent (such as DCM) to give a compound such as XXX in which R ¹¹ =CO ₂ R ¹⁷ .

ii. Formation of a tertiary amine in the presence of an aldehyde under standard reductive amination conditions with a suitable reducing agent (such as NaBH ₃ CN) in a suitable solvent (such as MeOH) or alkylation with an alkyl halide with a suitable base (such as NaHCO ₃ ) in a suitable solvent (such as EtOAc) with obtaining a compound such as XXX, in which R ¹¹ =C ₁ -C ₂ alkyl.

iii. Formation of a sulfonamide with sulfonyl chloride in the presence of a suitable base (such as NaHCO ₃ ) in a suitable solvent (such as EtOAc) to give a compound such as XXX wherein R ¹¹ =SO ₂ R ¹⁴

iv. Formation of an amide by acylation with an anhydride in the presence of a suitable base (such as TEA) in a suitable solvent (such as DCM) or a carboxylic acid in the presence of a suitable coupling agent (such as HATU or EDCI) and a suitable base (such as DIPEA) in a suitable solvent (such as DCM or DMF) to give a compound such as XXX wherein R ¹¹ =COR ¹⁷

In some cases, a compound such as XXX may contain protecting groups that can be removed in an additional step in the synthetic sequence using conditions known in the art (Protective Groups in Organic Synthesis, A. Wiley-Interscience Publication, 1981 or Protecting groups , 10 Georg Thieme Verlag, 1994). Compounds in each step can be purified by standard methods such as column chromatography, crystallization, or reverse phase SFC or HPLC. If necessary, separation of the XXX enantiomers can be carried out by standard methods known in the art, such as chiral SFC or HPLC, to obtain individual enantiomers.

The variables U, V, W, X, Z, R ¹ , R ⁷ , R ¹¹ , R ¹⁴ and R ¹⁷ are as defined in the embodiments, diagrams, examples and claims herein.

Scheme VII:

As shown in Scheme VII, a compound such as XXXI (prepared as in Scheme I) can be oxidized with a suitable oxidizing agent (such as MnO ₂ , SO ₃ ·pyr or TEMPO/NaClO) in a suitable solvent (such as CHCl ₃ or DCM ) to give a compound such as XXXII. A compound such as XXXII may be coupled to an amine such as XI under standard S _N Ar conditions in the presence of a suitable base (such as DIPEA) in a suitable solvent (such as DMSO) to give a compound such as XXXIII. Compounds in each step can be purified by standard methods such as column chromatography, crystallization, or reverse phase SFC or HPLC.

Scheme VIII

As shown in Scheme VIII, a compound such as XXXIV (prepared as in Scheme I) can be converted to a compound such as XXXV by oxidation with a suitable oxidizing agent (such as MnO ₂ ) in a suitable solvent (such as MeOH) followed by reductive amination in the presence of an amine with a suitable reducing agent (such as NaBH ₃ CN) in a suitable solvent (such as MeCN). Alternatively, a compound such as XXXIV can be activated by treatment with methanesulfonyl chloride in the presence of a suitable base (such as TEA) in a suitable solvent (such as DCM). Subsequent displacement of the mesylate with an amine in the presence of NaI and a suitable base (such as DIPEA) in a suitable solvent (such as MeCN) can provide a compound such as XXXV. Compounds in each step can be purified by standard methods such as column chromatography, crystallization, or reverse phase SFC or HPLC. Variables Q, R ²² and R ²³ are as defined in the embodiments, diagrams, examples and claims herein.

Scheme IX:

As shown in Scheme IX, a ketone such as XXXII (prepared as in Scheme VII) can be treated with a Grignard reagent (such as MeMgBr) in a suitable solvent (such as THF) to give a compound such as XXXVI. A compound such as XXXVI may be coupled to an amine such as XI under standard S _N Ar conditions in the presence of a suitable base (such as DIPEA) in a suitable solvent (such as DMSO) to give a compound such as XXXVII. Compounds in each step can be purified by standard methods such as column chromatography, crystallization, or reverse phase SFC or HPLC.

Obtaining intermediates

Preparation of (1S)-1-(6-bromo-1-tert-butyl-4-fluoro-1H-benzimidazol-2-yl)ethan-1-ol (Int-01) according to Scheme 1.

Scheme 1:

Stage 1: Synthesis of 5-bromo-N-tert-butyl-3-fluoro-2-nitroaniline (1b)

To a solution of 5-bromo-1,3-difluoro-2-nitrobenzene (1a) (5.0 g, 21.0 mmol) in DMSO (40.0 ml) was added 2-methyl-propan-2-amine , 21.0 mmol) and Cs ₂ CO ₃ (13.7 g, 42 mmol). The reaction mixture was stirred at 40° C. for 3 hours. TLC analysis (petroleum ether) indicated consumption of starting material. The reaction mixture was diluted with H ₂ O (20 ml) and was extracted with EtOAc (3×20 ml). The combined organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (ISCO, SiO ₂ , 0-10% EtOAc/petroleum ether) to give 5-bromo-N-tert-butyl-3-fluoro-2-nitroaniline (1b) (5.5 g, 90% yield as a red oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.13-7.01 (m, 2H), 6.94 (dd, J=1.9, 11.1 Hz, 1H), 1.40 ( s, 9H).

Stage 2: Synthesis of (1S)-1-(6-bromo-1-tert-butyl-4-fluoro-1H-benzimidazol-2-yl)ethan-1-ol (Int-01)

To a solution of 5-bromo-N-tert-butyl-3-fluoro-2-nitroaniline (1b) (1.5 g, 5.2 mmol) and (2S)-2-{[tert-butyl(dimethyl)silyl] hydroxy}propanal (1.94 g, 10.3 mmol) in EtOH (30.0 ml) and DMSO (7.5 ml) was added Na ₂ S ₂ O ₄ (4.5 g, 25.8 mmol). The reaction mixture was stirred at 80° C. for 16 hours. TLC analysis (EtOAc) indicated consumption of starting material. Added EtOAc (10 ml) and H ₂ O (5 ml) and the layers were separated. The aqueous layer was extracted with EtOAc (3×10 ml). The combined organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (ISCO, 12 g SiO ₂ , 0-20% EtOAc/petroleum ether) to give (1S)-1-(6-bromo-1-tert-butyl-4-fluoro-1H-benzimidazole -2-yl)ethan-1-ol (Int-01) (400 mg, 18% yield) as a yellow oil. m/z (ESI) for (C ₁₉ H ₃₀ BrFN ₂ OSi), 431.1 (M+H) ⁺ .

Preparation of 6-bromo-2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazole (Int-02 ) in accordance with Scheme 2.

Scheme 2:

Step 1: Synthesis of 5-bromo-3-fluoro-2-nitro-N-(propan-2-yl)aniline (2b)

A solution of 5-bromo-1,3-difluoro-2-nitrobenzene (1a) (25.0 g, 105 mmol) and isopropylamine (8.95 ml, 105 mmol) in DMSO (525 ml) was stirred at ambient temperature for 4 d, after which the mixture was concentrated. The crude residue was purified by flash chromatography (SiO ₂ , 0-30% EtOAc/heptane) to give 5-bromo-3-fluoro-2-nitro-N-(propan-2-yl)aniline (2b) (20, 3 g, 70% yield as a red/orange solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.07-6.98 (m, 2H), 6.89 (dd, J=2.0, 11.1 Hz, 1H), 3.88 ( dd, J=6.4, 13.9 Hz, 1H), 1.26-1.13 (m, 6H). m/z (ESI+) for (C ₉ H ₁₀ BrFN ₂ O ₂ ), 278.1 (M+H) ⁺ .

Step 2: Synthesis of 6-bromo-2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazole ( Int-02)

To a solution of 5-bromo-3-fluoro-2-nitro-N-(propan-2-yl)aniline (2b) (1.0 g, 3.2 mmol) and 2-{[tert-butyl(dimethyl)silyl ]hydroxy}-2-methylpropanal (655 mg, 3.2 mmol) in EtOH (8.0 ml) and DMSO (2.0 ml) was added Na ₂ S ₂ O ₄ (2.82 g, 16.2 mmol) . The slurry was stirred at 90° C. for 16 hours. LCMS analysis showed consumption of starting material to form a mass of the desired product. The reaction mixture was diluted with H ₂ O (200 ml) and was extracted with EtOAc (2×200 ml). The combined organic phases were washed with brine (150 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (Biotage, 40 g SiO ₂ , 1/10 EtOAc/petroleum ether) to give 6-bromo-2-(2-{[tert-butyl(dimethyl)silyl]oxy}propane-2- yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazole (Int-02) (1.2 g, 86% yield) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.51 (d, J=1.5 Hz, 1H), 7.09 (dd, J=1.5, 9.7 Hz, 1H), 5.62 (td, J=7.0, 14.0 Hz, 1H), 1.85 (s, 6H), 1.71-1.60 (m, 6H), 0.92 (s, 9H), 0, 21-0.17 (m, 6H).

Preparation of 6-bromo-4-fluoro-2-methyl-1-(oxetan-3-yl)-1H-benzimidazole (Int-03) according to Scheme 3.

Scheme 3:

Step 1: Synthesis of N-(5-bromo-3-fluoro-2-nitrophenyl)oxetan-3-amine (3a)

To a solution of 5-bromo-1,3-difluoro-2-nitrobenzene (1.5 g, 6.3 mmol) (1a) in DMSO (15.0 ml) mmol) and Cs ₂ CO ₃ (2.46 g, 7.56 mmol). The reaction mixture was stirred at 25° C. for 2 hours. TLC analysis (1/4 EtOAc/petroleum ether) showed consumption of starting material. The reaction mixture was diluted with brine (10 ml) and extracted with EtOAc (2×10 ml). The combined organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (ISCO, SiO ₂ , 0-30% EtOAc/petroleum ether) to give N-(5-bromo-3-fluoro-2-nitrophenyl)oxetan-3-amine (3a) (1, 0 g, 55% yield as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.59 (br.d, J=5.3 Hz, 1H), 7.04 (dd, J=1.8, 10.8 Hz, 1H) , 6.69 (s, 1H), 4.87-4.81 (m, 2H), 4.80-4.71 (m, 1H), 4.60-4.47 (m, 2H).

Step 2: Synthesis of 6-bromo-4-fluoro-2-methyl-1-(oxetan-3-yl)-1H-benzimidazole (Int-03)

To a solution of N-(5-bromo-3-fluoro-2-nitrophenyl)oxetan-3-amine (3a) (500 mg, 1.72 mmol) in EtOH (16.0 ml) and H ₂ O (4.0 ml) was added acetaldehyde (2.0 ml, 8.6 mmol) and Na ₂ S ₂ O ₄ (1.5 g, 8.6 mmol). The reaction mixture was sealed and stirred at 80° C. using microwave radiation for 10 h. LCMS analysis indicated consumption of starting material. The solution was cooled and partitioned between EtOAc (40 ml) and H ₂ O (20 ml). The combined layers were dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash chromatography (SiO ₂ , 0-100% EtOAc/petroleum ether) to give 6-bromo-4-fluoro-2-methyl-1-(oxetan-3-yl)-1H-benzimidazole (Int -03) (100 mg, 20% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.95 (s, 1H), 7.34 (br. d, J=10.0 Hz, 1H), 5.66 (br. t, J= 5.5 Hz, 1H), 5.11 (br. t, J=7.7 Hz, 2H), 5.03-4.88 (m, 2H), 2.55 (s, 3H). m/z (ESI+) for (C ₁₁ H ₁₀ BrFN ₂ O), 284.9 (M+H).

The intermediates in the table below were synthesized according to the methods used for the synthesis of (1S)-1-(6-bromo-1-tert-butyl-4-fluoro-1H-benzimidazol-2-yl)ethan-1-ol (Int -01), 6-bromo-2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazole ( Int-02) and 6-bromo-4-fluoro-2-methyl-1-(oxetan-3-yl)-1H-benzimidazole (Int-03). The following intermediates have been synthesized with non-critical modifications or substitutions of the illustrated procedures, which could be implemented by a person skilled in the art.

Connection number Structure/Name according to IUPAC nomenclature Analytical data Int-04

6-бром-4-фтор-1,2-диметил-1H-бензимидазол

6-bromo-4-fluoro-1,2-dimethyl-1H-benzimidazole m/z (ESI+) for (C ₉ H ₈ BrFN ₂ ), 242.6 (M+H) ⁺ Int-05

6-bromo-1-tert-butyl-2-[(1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl]-4-fluoro-1H-benzimidazole m/z (ESI+) for (C ₁₉ H ₃₀ BrFN ₂ OSi), 430.9 (M+H) ⁺ Int-06

tert-butyl-[(1R)-1-(6-bromo-1-tert-butyl-4-fluoro-1H-benzimidazol-2-yl)ethyl]carbamate m/z (ESI+) for (C ₁₈ H ₂₅ BrFN ₃ O ₂ ), 415.9 (M+H) ⁺ Int-07

6-bromo-4-fluoro-2-(oxetan-3-yl)-1-(propan-2-yl)-1H-benzimidazole ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.79 (d, J=1.5 Hz, 1H), 7.30 (dd, J=1.5, 10.1 Hz, 1H), 5 .01-4.91 (m, 4H), 4.80-4.66 (m, 1H), 4.55-4.42 (m, 1H), 1.49 (d, J=7.0 Hz , 6H); m/z (ESI+) for (C ₁₃ H ₁₄ BrFN ₂ O), 324.2 (M+H) ⁺ Int-08

tert-butyl-{1-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]cyclopropyl}carbamate ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.16 (br. s, 1H), 7.49 (d, J=1.0 Hz, 1H), 7.09 (dd, J=1.5, 9.5 Hz, 1H), 5.84 (br.s, 1H), 5.39 (br.s, 1H), 1.63 (s, 9H), 1.57 (s, 3H), 1, 46 (s, 6H), 1.39 (s, 9H); m/z (ESI+) for (C ₁₈ H ₂₃ BrFN ₃ O ₂ ), 357.9 (M-tBu+H) ⁺ Int-09

tert-butyl-{(1S)-1-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]ethyl}carbamate ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.58 (s, 1H), 7.49 (d, J=1.5 Hz, 1H), 7.12 (dd, J=9.7, 1, 5 Hz, 1H), 5.24-5.03 (m, 1H), 4.86 (n, J=6.9 Hz, 1H), 1.66-1.57 (m, 6H), 1, 47 (s, 9H), 1.35 (d, J=7.4 Hz, 3H) Int-10

6-bromo-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-fluoro-1-(2-fluoro-2-methylpropyl)-1H-benzimidazole m/z (ESI+) for (C ₁₈ H ₂₇ BrF ₂ N ₂ OSi), 433.1 (M+H) ⁺ Int-11

6-bromo-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-(1,1-difluoro-2-methylpropan-2-yl)-4-fluoro-1H-benzimidazole m/z (ESI+) for (C ₁₈ H ₂₆ BrF ₃ N ₂ OSi), 451.2 (M+H) ⁺ Int-12

6-bromo-2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)-1-(2,2-difluoroethyl)-4-fluoro-1H-benzimidazole m/z (ESI+) for (C ₁₈ H ₂₆ BrF ₃ N ₂ OSi), 450.8 (M+H) ⁺ Int-13

tert-butyl-[(2S)-2-(6-bromo-4-fluoro-2-methyl-1H-benzimidazol-1-yl)propyl]carbamate ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.32 (d, J=1.5 Hz, 1H), 7.04 (dd, J=9.6, 1.5 Hz, 1H), 5.13 (s, 1H), 4.73 (s, 1H), 3.70 (dt, J=11.5, 6.2 Hz, 1H), 3.47-3.38 (m, 1H), 2, 56 (s, 3H), 1.61 (d, J=7.0 Hz, 3H), 1.41 (s, 9H); m/z (ESI+) for (C ₁₆ H ₂₁ BrFN ₃ O ₂ ), 387.9 (M+H) ⁺ Int-14

6-bromo-4-fluoro-1-(1-methoxypropan-2-yl)-2-methyl-1H-benzimidazole ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.75 (d, J=1.6 Hz, 1H), 7.23 (dd, J=1.5, 10.1 Hz, 1H), 4 .78 (dd, J=4.6, 7.1, 8.9 Hz, 1H), 3.86 (dd, J=9.2, 10.4 Hz, 1H), 3.62 (dd, J =4.5, 10.5 Hz, 1H), 3.18 (s, 3H), 2.55 (s, 3H), 1.52 (d, J=7.1 Hz, 3H); m/z (APCI+) for (C ₁₂ H ₁₄ BrFN ₂ O), 301.0, 303.0 (M+H) ⁺ Int-15

6-bromo-2-ethyl-4-fluoro-1-(oxetan-3-yl)-1H-benzimidazole ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.97 (d, J=1.6 Hz, 1H), 7.34 (dd, J=10.2, 1.6 Hz, 1H), 5 .77-5.53 (m, 1H), 5.12 (t, J=7.7 Hz, 2H), 4.98 (dd, J=7.8, 5.3 Hz, 2H), 2, 88 (q, J=7.5 Hz, 2H), 1.29 (t, J=7.4 Hz, 3H); m/z (APCI+) for (C ₁₂ H ₁₂ BrFN ₂ O), 298.9 (M+H) ⁺ Int-16

tert-butyl-[(2R)-2-(6-bromo-4-fluoro-2-methyl-1H-benzimidazol-1-yl)propyl]carbamate ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.77-7.53 (m, 1H), 7.21 (br. d, J=10.0 Hz, 1H), 7.09-6, 92 (m, 1H), 6.65 (dd, J=2.0, 7.0 Hz, 1H), 4.71-4.60 (m, 1H), 4.45-4.33 (m, 1H), 3.83-3.60 (m, 2H), 1.61-1.46 (m, 5H), 1.32-1.20 (m, 8H); m/z (ESI+) for (C ₁₆ H ₂₁ BrFN ₃ O ₂ ), 387.9 (M+H) ⁺ Int-17

(6-bromo-1-cyclobutyl-4-fluoro-1H-benzimidazol-2-yl)methanol ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.63 (d, J=1.5 Hz, 1H), 7.13 (dd, J=1.5, 9.6 Hz, 1H), 5.31 -5.12(m, 1H), 4.94(s, 2H), 2.98-2.81(m, 2H), 2.65-2.49(m, 2H), 2.06-1 .87 (m, 2H), 0.92-0.90 (m, 9H), 0.10-0.07 (m, 6H); m/z (ESI+) for (C ₁₈ H ₂₆ BrFN ₂ OSi), 414.8 (M+H) ⁺ Int-18

6-bromo-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-(3,3-difluorocyclobutyl)-4-fluoro-1H-benzimidazole ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.51 (d, J=1.3 Hz, 1H), 7.19 (dd, J=1.5, 9.5 Hz, 1H), 5.27 (dquin, J=3.7, 8.7 Hz, 1H), 4.97 (s, 2H), 3.60-3.41 (m, 2H), 3.32-3.17 (m, 2H ), 0.92-0.90 (m, 9H), 0.12-0.10 (m, 6H); m/z (ESI+) for (C ₁₈ H ₂₄ BrF ₃ N ₂ OSi), (M+H) ⁺

Preparation of [6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]methanol (Int-19) according to Scheme 4.

Scheme 4:

A mixture of 5-bromo-3-fluoro-2-nitro-N-(propan-2-yl)aniline (2b) (994 mg, 3.59 mmol), Na ₂ S ₂ O ₄ (3.12 g, 17, 9 mmol) and glycolaldehyde dimer (517 mg, 4.30 mmol) in EtOH/H ₂ O (4:1, 50 ml) were stirred at 80°C for 21 h. The mixture was concentrated and partitioned between H ₂ O (100 ml) and EtOAc (100 ml). The layers were separated and the aqueous phase was extracted with EtOAc (3×100 ml). The combined organic phases were washed with water (50 ml) and brine (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by flash chromatography (SiO ₂ , 40-100% EtOAc/heptane) to give [6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]methanol (Int-19) (790 mg, 77% yield) as a white waxy solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.81 (d, J=1.5 Hz, 1H), 7.28 (dd, J=10.1, 1.6 Hz, 1H), 5 .71 (t, J=5.8 Hz, 1H), 4.95 (hept, J=6.8 Hz, 1H), 4.72 (d, J=5.7 Hz, 2H), 1.56 (d, J=6.9 Hz, 6H); m/z (APCI+) for (C ₁₁ H ₁₂ BrFN ₂ O), 286.8 (M+H) ⁺ .

Preparation of 6-bromo-4-fluoro-2-{[(oxan-2-yl)oxy]methyl}-1-(propan-2-yl)-1H-benzimidazole (Int-20) according to Scheme 5.

Scheme 5:

Solution of [6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]methanol (Int-19) (590 mg, 2.05 mmol), 3,4-dihydro- 2H-pyran (1.21 g, 1.3 ml, 14.4 mmol) and p-TSA acid monohydrate (35.4 mg, 0.205 mmol) in THF (21 ml) were stirred at reflux temperature for 4 h. The mixture was concentrated and purified using flash chromatography (SiO ₂ , 20-50% EtOAc/heptane) to obtain 6-bromo-4-fluoro-2-{[(oxan-2-yl)oxy]methyl}-1 -(propan-2-yl)-1H-benzimidazole (Int-20) (710 mg, 93% yield) as a viscous yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.85 (d, J=1.5 Hz, 1H), 7.31 (dd, J=10.1, 1.5 Hz, 1H), 4 .95-4.85 (m, 2H), 4.77-4.72 (m, 2H), 3.81-3.73 (m, 1H), 3.56-3.49 (m, 1H) , 1.74-1.61 (m, 2H), 1.58 (d, J=6.9 Hz, 6H), 1.55-1.45 (m, 4H); m/z (APCI+) for (C ₁₆ H ₂₀ BrFN ₂ O ₂ ), 370.9 (M+H) ⁺ .

Preparation of 6-bromo-4-fluoro-2-(methoxymethyl)-1-(propan-2-yl)-1H-benzimidazole (Int-21) according to Scheme 6.

Scheme 6:

To a solution of [6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]methanol (Int-19) (134 mg, 0.467 mmol) in 1,4-dioxane (4 .67 ml) KOtPn (25% in toluene, 0.265 ml, 0.560 mmol) was added. MeI (66.2 mg, 0.029 ml, 0.467 mmol) was added to the resulting dark reaction mixture at 0°C. After 15 minutes, LCMS analysis showed consumption of starting material to form a mass of the desired product. H ₂ O (5 ml) was added and the mixture was extracted with DCM (3×10 ml). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (12 g SiO ₂ , 0-100% EtOAc/heptane) to give (Int-21) (85 mg, 60% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.50 (d, J=1.47 Hz, 1H), 7.12 (dd, J=9.54, 1.47 Hz, 1H), 4.91 (dt, J=13.94, 6.97 Hz, 1H), 4.75 (s, 2H), 3.38 (s, 3H), 1.63 (d, J=6.97 Hz, 6H) .

Preparation of 6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazole (Int-22) according to Scheme 7.

Scheme 7:

Step 1: Synthesis of 5-bromo-3-fluoro-N ¹ -(propan-2-yl)benzene-1,2-diamine (7a)

Saturated aqueous NH ₄ Cl (150 ml) and Fe (25.2 g, 451 mmol). The reaction suspension was heated to 60° C. and stirred at this temperature for 3 hours. LCMS analysis indicated consumption of starting material. The reaction suspension was filtered and the filter cake was washed with EtOAc. The filtrate was concentrated. The residue was dissolved in EtOAc (200 ml) and filtered. The filtrate was washed with H ₂ O (200 ml). The combined aqueous washes were extracted with EtOAc (2×200 ml). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated to give 5-bromo-3-fluoro-N ¹ -(propan-2-yl)benzene-1,2-diamine (7a) (21.0 g, yield 94%). m/z (ESI+) for (C ₉ H ₁₂ BrFN ₂ ), 246.7 (M+H) ⁺ .

Step 2: Synthesis of 6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazole (Int-22)

Solution of 5-bromo-3-fluoro-N ¹ -(propan-2-yl)benzene-1,2-diamine (7a) (3.86 g, 15.6 mmol) in HC(OEt) ₃ (100 ml) stirred at 150° C. for 15 hours. LCMS analysis showed consumption of starting material to form a mass of the desired product. The solution was cooled to room temperature and concentrated to give 6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazole (Int-22) (4.02 g, >99% yield) as a black oil which was collected without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.04 (d, J=3.3 Hz, 1H), 6.66 (dd, J=2.0, 10.0 Hz, 1H), 6 .54 (s, 1H), 3.69-3.56 (m, 1H), 1.15 (d, J=6.2 Hz, 6H); m/z (ESI+) for (C ₁₀ H ₁₀ BrFN ₂ ), 258.7 (M+H) ⁺ .

Obtaining 6-bromo-1-tert-butyl-2-methyl-1H-benzimidazole (Int-23) in accordance with Scheme 8.

Scheme 8:

Synthesis of 6-bromo-1-tert-butyl-2-methyl-1H-benzimidazole (Int-23)

A mixture of 4-bromo-N ² -tert-butylbenzene-1,2-diamine (8a) (1.3 g, 5.35 mmol) and triethylorthoacetate (8.7 g, 53.5 mmol) was stirred at 148°C in within 1 hour. LCMS analysis showed the consumption of the starting material with the formation of the mass of the desired product. The solution was cooled to room temperature and concentrated. The residue was purified by flash chromatography (20 g SiO ₂ , 20% EtOAc/petroleum ether) to give 6-bromo-1-tert-butyl-2-methyl-1H-benzimidazole (Int-23) (1.23 g, 95% yield as a yellow oil. m/z (ESI+) for (C ₁₂ H ₁₅ BrN ₂ ), 268.7 (M+H) ⁺ .

Preparation of 6-bromo-5-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazole (Int-24) according to Scheme 9.

Scheme 9:

Step 1: Synthesis of 5-bromo-4-fluoro-2-nitro-N-(propan-2-yl)aniline (9b)

K 2 CO 3 (581 mg, 4.2 mmol ₎ was added to a suspension of 1-bromo-2,5-difluoro-4-nitrobenzene (9a) (1.0 g, 4.2 mmol) in _THF (10 ml) and i-PrNH ₂ (248 mg, 4.2 mmol). The mixture was stirred at ambient temperature for 16 hours. LCMS analysis showed consumption of starting material to form a mass of the desired product. The reaction solution was diluted with H ₂ O (30 ml) and was extracted with EtOAc (3×20 ml). The combined organic phases were washed with brine (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (ISCO, 20 g SiO ₂ , 10% EtOAc/petroleum ether) to give 5-bromo-4-fluoro-2-nitro-N-(propan-2-yl)aniline (9b) ( 900 mg, 77% yield as a yellow solid. m/z (ESI+) for (C ₉ H ₁₀ BrFN ₂ O ₂ ), 276.7 (M+H) ⁺ .

Stage 2: Synthesis of 5-bromo-4-fluoro-N ¹ -(propan-2-yl)benzene-1,2-diamine (9c)

Saturated aqueous _NH4Cl was added to a solution of 5-bromo-4-fluoro-2-nitro-N-(propan-2-yl)aniline (9b) (1.9 g, 6.9 mmol) in MeOH (30 ml) (15 ml) and Fe ⁰ (1.9 g, 34.3 mmol). The reaction suspension was stirred at 60° C. for 16 hours overnight. LCMS analysis showed consumption of starting material to form a mass of the desired product. The reaction suspension was filtered and the filter cake was washed with EtOH (50 ml). The combined filtrate was diluted with H ₂ O (100 ml) and was extracted with EtOAc (2×80 ml). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash chromatography (40 g SiO ₂ , 1:2 EtOAc/petroleum ether) to give 5-bromo-4-fluoro-N ¹ -(propan-2-yl)benzene-1,2-diamine ( 9c) (900 mg, 53% yield) as a brown gum. m/z (ESI+) for (C ₉ H ₁₂ BrFN ₂ ), 246.7 (M+H) ⁺ .

Step 3: Synthesis of 6-bromo-5-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazole (Int-24)

A mixture of 5-bromo-4-fluoro-N ¹ -(propan-2-yl)benzene-1,2-diamine (9c) (800 mg, 3.24 mmol) and triethylorthoacetate (5.3 g, 32.4 mmol ) was stirred at 148° C. for 1 hour. LCMS analysis showed consumption of starting material to form the desired product. The solution was cooled to room temperature and concentrated. The residue was combined with a 100 mg scale reaction and purified by flash chromatography (20 g SiO ₂ , 100% EtOAc) to give 6-bromo-5-fluoro-2-methyl-1-(propan-2-yl) -1H-benzimidazole (Int-24) (500 mg, 51% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.99 (d, J=6.2 Hz, 1H), 7.51 (d, J=9.5 Hz, 1H), 4.74 (sp , J=6.9 Hz, 1H), 2.55 (s, 3H), 1.53 (d, J=7.0 Hz, 6H); m/z (ESI ⁺ ) for (C ₁₁ H ₁₂ BrFN ₂ ), 270.9 (M+H) ⁺ .

The intermediates in the table below were synthesized according to the methods used for the synthesis of 6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazole (Int-22), 6-bromo-4-fluoro-1 -(propan-2-yl)-1H-benzimidazole (Int-23) and 6-bromo-5-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazole (Int-24). The following intermediates have been synthesized with non-critical modifications or substitutions of the illustrated procedures, which could be implemented by a person skilled in the art.

Connection number Structure/Name according to IUPAC nomenclature Analytical data Int-25

6-бром-4-фтор-1-(оксолан-3-ил)-1H-бензимидазол

6-bromo-4-fluoro-1-(oxolan-3-yl)-1H-benzimidazole ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.34 (s, 1H), 7.85 (d, J=1.6 Hz, 1H), 7.34 (dd, J=10.3, 1.6Hz, 1H), 5.30(ddt, J=8.4, 5.8, 3.1Hz, 1H), 4.13(td, J=8.4, 6.0Hz, 1H ), 4.01 (dd, J=10.0, 2.6 Hz, 1H), 3.93 (dd, J=10.0, 5.6 Hz, 1H), 3.87-3.78 ( m, 1H), 2.59-2.53 (m, 1H), 2.26-2.13 (m, 1H); m/z (ESI+) for (C ₁₁ H ₁₀ BrFN ₂ O), 258.7 (M+H) ⁺ Int-26

6-bromo-1-cyclopropyl-4-fluoro-1H-benzimidazole ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.90 (s, 1H), 7.53 (d, J=1.5 Hz, 1H), 7.15 (dd, J=1.5, 9, 8Hz, 1H), 3.36 (td, J=3.5, 7.0Hz, 1H),
1.24-1.17 (m, 2H), 1.10-1.03 (m, 2H); m/z (ESI+) for (C ₁₀ H ₈ BrFN ₂ ), 256.7 (M+H) ⁺ Int-27

tert-butyl-[2-(6-bromo-4-fluoro-1H-benzimidazol-1-yl)-2-methylpropyl]carbamate m/z (ESI+) for (C ₁₆ H ₂₁ BrFN ₃ O ₂ ), 387.6 (M+H) ⁺ Int-28

tert-butyl-[2-(6-bromo-4-fluoro-2-methyl-1H-benzimidazol-1-yl)-2-methylpropyl]carbamate m/z (ESI+) for (C ₁₇ H ₂₃ BrFN ₃ O ₂ ), 400.0 (M+H) ⁺

Preparation of tert-butyl {[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]methyl}methylcarbamate (Int-29) according to Scheme 10.

Scheme 10:

To a solution of 5-bromo-3-fluoro-N ¹ -(propan-2-yl)benzene-1,2-diamine (7a) (300 mg, 1.2 mmol) and tert-butylmethyl (2-oxoethyl) carbamate ( 421 mg, 2.43 mmol) in EtOH (4.0 ml) and DMSO (1.0 ml) was added Na ₂ S ₂ O ₄ (1.1 g, 6.1 mmol). The slurry was stirred at 80° C. for 16 hours. LCMS analysis showed consumption of starting material to form a mass of the desired product. The mixture was concentrated to dryness. The residue was purified by flash chromatography (Biotage, 20 g SiO ₂ , 25% EtOAc/petroleum ether) to give t-butyl{[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazole -2-yl]methyl}methylcarbamate (Int-29) (400 mg, 82% yield) as a yellow oil. m/z (ESI ⁺ ) for (C ₁₇ H ₂₃ BrFN ₃ O ₂ ), 401.6 (M+H) ⁺ .

The intermediates in the table below were synthesized according to the methods used for the synthesis of tert-butyl-{[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]methyl}methylcarbamate ( Int-29). The following intermediates have been synthesized with non-critical modifications or substitutions of the illustrated procedures, which could be implemented by a person skilled in the art.

Connection number Structure/Name according to IUPAC nomenclature Analytical data Int-30

трет-бутил-{2-[6-бром-4-фтор-1-(пропан-2-ил)-1H-бензимидазол-2-ил]пропан-2-ил}карбамат

tert-butyl-{2-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]propan-2-yl}carbamate m/z (ESI+) for (C ₁₈ H ₂₅ BrFN ₃ O ₂ ), 415.7 (M+H) ⁺ Int-31

6-bromo-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-fluoro-1-(1-methylcyclopropyl)-1H-benzimidazole ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.50 (d, J=1.6 Hz, 1H), 7.10 (dd, J=9.6, 1.6 Hz, 1H), 4.97 (s, 2H), 1.60 (s, 7H), 0.92 (s, 9H), 0.15 (s, 6H); m/z (ESI+) for (C ₁₈ H ₂₆ BrFN ₂ OSi), 414.9 (M+H) ⁺

Preparation of 6-bromo-4-fluoro-N-methyl-1-(propan-2-yl)-1H-benzimidazole-2-carboxamide (Int-32) according to Scheme 11.

Scheme 11:

Step 1: Synthesis of ethyl 6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazole-2-carboxylate (11a)

To a solution of 5-bromo-3-fluoro-N ¹ -(propan-2-yl)benzene-1,2-diamine (7a) (1.0 g, 4.05 mmol) and ethyl 2-oxoacetate (1, 65 g, 8.09 mmol) in EtOH (20.0 ml) and DMSO (5.0 ml) was added Na ₂ S ₂ O ₄ (3.5 g, 20.2 mmol). The slurry was stirred at 80° C. for 16 hours. LCMS analysis showed consumption of starting material to form a mass of the desired product. The mixture was diluted with H ₂ O (15 ml) and was extracted with EtOAc (15 ml). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (ISCO, 20 g SiO ₂ , 25% EtOAc/heptane) to give ethyl 6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazole-2-carboxylate (11a) (500 mg, 38% yield) as a solid. m/z (ESI+) for (C ₁₃ H ₁₄ BrFN ₂ O ₂ ), 328.7 (M+H) ⁺ .

Step 2: Synthesis of 6-bromo-4-fluoro-N-methyl-1-(propan-2-yl)-1H-benzimidazole-2-carboxamide (Int-32)

A mixture of ethyl 6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazole-2-carboxylate (11a) (200 mg, 0.608 mmol), DIPEA (236 mg, 1.82 mmol) and MeNH ₂ (22.6 mg, 0.729 mmol) in DMA (8.0 ml) was stirred at 80° C. for 16 hours. LCMS analysis showed consumption of starting material to form a mass of the desired product. The mixture was diluted with EtOAc (15 ml) and washed with H ₂ O (15 ml). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated. The resulting material was combined with the product of a parallel reaction with 48 mg of ethyl 6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazole-2-carboxylate to give 6-bromo-4-fluoro-N- methyl 1-(propan-2-yl)-1H-benzimidazole-2-carboxamide (Int-32) (200 mg, 83% yield). m/z (ESI+) for (C ₁₂ H ₁₃ BrFN ₃ O), 313.7 (M+H) ⁺ .

Preparation of 6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazole-2-carboxamide (Int-33) according to Scheme 12.

Scheme 12:

Ethyl 6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazole-2-carboxylate (11a) (200 mg, 0.608 mmol) was dissolved in a solution of ammonia in MeOH (7.0 N, 15 ml) and stirred at 85-90° C. for 16 hours. LCMS analysis showed consumption of starting material to form a mass of the desired product. The reaction mixture was cooled to room temperature and concentrated to give (Int-33) (190 mg, >99% yield) as a solid. m/z (ESI+) for (C ₁₁ H ₁₁ BrFN ₃ O), 299.7 (M+H) ⁺ .

Preparation of tert-butyl {1-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]-2-methylpropan-2-yl}carbamate (Int-34) in accordance with Diagram 13.

Scheme 13:

Step 1: Synthesis of tert-butyl-(4-{4-bromo-2-fluoro-6-[(propan-2-yl)amino]anilino}-2-methyl-4-oxobutan-2-yl)carbamate (13a )

To a stirred solution of 5-bromo-3-fluoro-N ¹ -(propan-2-yl)benzene-1,2-diamine (7a) (1.1 g, 4.5 mmol) in pyridine (10.0 ml) 3-[(tert-butoxycarbonyl)amino]-3-methylbutanoic acid (967 mg, 4.5 mmol) and EDCI (1.7 g, 8.9 mmol) were added at 0° C. under N ₂ atmosphere. The mixture was stirred at 25° C. for 4 hours. LCMS analysis showed consumption of starting material to form a mass of the desired product. The solution was diluted with H ₂ O (20 ml) and was extracted with EtOAc (3×20 ml). The combined organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (ISCO, 20 g SiO ₂ , 0-50% EtOAc/petroleum ether) to give 1-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazole -2-yl]-2-methylpropan-2-amine (13a) (1.6 g, 81% yield) as a white solid. m/z (ESI+) for (C ₁₉ H ₂₉ BrFN ₃ O ₃ ), 446.1 (M+H) ⁺ .

Step 2: Synthesis of 1-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]-2-methylpropan-2-amine (13b)

This reaction was carried out in three parallel batches. To solid 1-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]-2-methylpropan-2-amine (13a) (600 mg, 1.8 mmol) was added a solution of HCl (4.0 M in 1,4-dioxane, 10.0 ml). The mixture was stirred at 130°C for 15 min using microwave radiation. LCMS analysis showed consumption of starting material to form a mass of the desired product. The three reaction parties were combined and concentrated to dryness. The residue was dissolved in H ₂ O (10 ml) and the mixture was basified with NH ₄ OH to pH~9. The mixture was extracted with EtOAc (3×15 ml). The combined organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give 1-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]-2 -methylpropan-2-amine (13b) (1.2 g, >99% yield). m/z (ESI+) for (C ₁₄ H ₁₉ BrFN ₃ ), 329.9 (M+H) ⁺ .

Step 3: Synthesis of tert-butyl-{1-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]-2-methylpropan-2-yl}carbamate (Int -34)

To a solution of 1-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]-2-methylpropan-2-amine (13b) (1.2 g, 3, 7 mmol) in DCM (20 ml) was added DIPEA (473 mg, 3.7 mmol) and Boc ₂ O (958 mg, 4.4 mmol) at 0°C. The solution was stirred at 25° C. for 18 hours. LCMS analysis showed consumption of starting material to form a mass of the desired product. The reaction mixture was diluted with H ₂ O (15 ml) and the layers were separated. The aqueous layer was extracted with DCM (3×15 ml). The combined organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (ISCO, 20 g SiO ₂ , 0-51% EtOAc/petroleum ether) to give t-butyl-{1-[6-bromo-4-fluoro-1-(propan-2-yl )-1H-benzimidazol-2-yl]-2-methylpropan-2-yl}carbamate (Int-34) (1.6 g, >99% yield) as a brown solid. m/z (ESI+) for (C ₁₉ H ₂₇ BrFN ₃ O ₂ ), 430.0 (M+H) ⁺ .

The intermediate in the table below was synthesized according to the methods used for the synthesis of tert-butyl-{1-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]-2 -methylpropan-2-yl}carbamate (Int-34). The following intermediate has been synthesized with non-critical modifications or substitutions of the illustrated techniques, which could be implemented by a person skilled in the art.

Connection number Structure/Name according to IUPAC nomenclature Analytical data Int-35

трет-бутил-{3-[6-бром-4-фтор-1-(пропан-2-ил)-1H-бензимидазол-2-ил]-1,1-дифторпропан-2-ил}карбамат

tert-butyl-{3-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]-1,1-difluoropropan-2-yl}carbamate ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.47 (s, 1H), 7.11 (dd, J=1.1, 9.6 Hz, 1H), 6.30-5.97 (m, 1H), 5.72 (br. d, J=9.1 Hz, 1H), 4.72-4.57 (m, 1H), 4.52-4.30 (m, 1H), 3.34 -3.13 (m, 2H), 1.70-1.60 (m, 6H), 1.36 (s, 9H); m/z (ESI+) for (C ₁₈ H ₂₃ BrF ₃ N ₃ O ₂ ), 396.0 (M-tBu+H) ⁺

Preparation of 6-bromo-4-fluoro-2-(oxetan-2-yl)-1-(propan-2-yl)-1H-benzimidazole (Int-36) according to Scheme 14.

Scheme 14:

Step 1: Synthesis of N-{4-bromo-2-fluoro-6-[(propan-2-yl)amino]phenyl}oxetan-2-carboxamide (14a)

To a solution of 5-bromo-3-fluoro-N ¹ -(propan-2-yl)benzene-1,2-diamine (7a) (1.0 g, 4.05 mmol) in DMF (10.0 ml) was added oxetane-2-carboxylic acid (413 mg, 4.05 mmol). DIPEA (1.6 g, 12.1 mmol) and HATU (2.3 g, 6.1 mmol) were then added and the mixture was stirred for 16 hours. TLC analysis (25% EtOAc/petroleum ether) showed consumption of starting material. The solvent was removed under vacuum. The residue was diluted with saturated aqueous Na ₂ CO ₃ (100 ml). The solution was extracted with EtOAc (2×100 ml). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated to give N-{4-bromo-2-fluoro-6-[(propan-2-yl)amino]phenyl}oxetan-2-carboxamide (14a) (1 .5 g, 100% yield, which was used directly in the next step.

Step 2: Synthesis of 3-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]-3-hydroxypropyl acetate (14b)

Brown solution of N-{4-bromo-2-fluoro-6-[(propan-2-yl)amino]phenyl}oxetan-2-carboxamide (14a) (1.5 g, 4.5 mmol) in AcOH (20 ml) was stirred at 110° C. for 1.5 h. LCMS analysis indicated consumption of starting material to form a mass of product. The mixture was concentrated to dryness to give 3-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]-3-hydroxypropyl acetate (14b) (1.5 g, 62% yield ), which was directly used in the next step without further purification. m/z (ESI+) for (C ₁₅ H ₁₈ BrFN ₂ O ₃ ), 374.9 (M+H) ⁺ .

Step 3: Synthesis of 1-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]propan-1,3-diol (14c)

To a brown solution of 3-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]-3-hydroxypropyl acetate (14b) (1.5 g, 2.8 mmol) in MeOH (30 ml) was added K ₂ CO ₃ . The mixture was stirred at room temperature for 2 hours. LCMS analysis showed consumption of starting material to form a mass of product. The reaction mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by flash chromatography (Biotage, 40 g SiO ₂ , 0-30% MeOH/EtOAc) to give 1-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol- 2-yl]propan-1,3-diol (14c) (660 mg, 44% yield, 2 steps) as a pale brown solid. m/z (ESI+) for (C ₁₃ H ₁₆ BrFN ₂ O ₂ ), 332.9 (M+H) ⁺ .

Step 4: Synthesis of 6-bromo-4-fluoro-2-(oxetan-2-yl)-1-(propan-2-yl)-1H-benzimidazole (Int-36)

To a solution of 1-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]propan-1,3-diol (14c) (600 mg, 1.81 mmol) and TEA (275 mg, 2.72 mmol) in DCM (5.0 mL) and THF (5.0 mL) a solution of MsCl (208 mg, 7.25 mmol) in DCM was added dropwise at 0°C. After 2 hours, solid t-BuOK (813 mg, 7.25 mmol) was added in one portion. The resulting solution was stirred at room temperature for 2 hours. TLC analysis (EtOAc) showed consumption of starting material. The reaction mixture was concentrated to dryness. The residue was purified by flash chromatography (Biotage, EtOAc, Rf~0.5) to give 6-bromo-4-fluoro-2-(oxetan-2-yl)-1-(propan-2-yl)-1H- benzimidazole (Int-36) (300 mg, 53% yield) as a brown gum.

Preparation of 6-bromo-4-fluoro-2-(oxetan-2-yl)-1-(propan-2-yl)-1H-benzimidazole (Int-37) according to Scheme 15.

Scheme 15:

Step 1: Synthesis of tert-butyl-(2-{4-bromo-2-fluoro-6-[(propan-2-yl)amino]anilino}-2-oxoethyl)carbamate (15a)

To a solution of 5-bromo-3-fluoro-N ¹ -(propan-2-yl)benzene-1,2-diamine (7a) (504 mg, 2.4 mmol), N-(tert-butoxycarbonyl)glycine (393 mg, 2.2 mmol) and HATU (1.2 g, 3.1 mmol) in THF (10.0 ml) DIPEA (0.72 ml, 4.1 mmol) was added at 0°C. The mixture was stirred at 0° C. for 30 minutes and then at room temperature for 18 hours. LCMS analysis indicated complete consumption of starting material. The reaction mixture was quenched with water and then extracted with EtOAc (3×50 ml). The combined organic phases were washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (ISCO, 12 g SiO ₂ , 0-100% EtOAc/petroleum ether) to give t-butyl-(2-{4-bromo-2-fluoro-6-[(propane-2- yl)amino]anilino}-2-oxoethyl)carbamate (15a) (810 mg, 98% yield) as a foamy solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.06 (s, 1H), 7.22 (t, J=5.4 Hz, 1H), 6.64 (d, J=8.8 Hz , 1H), 6.60 (s, 1H), 4.98 (d, J=8.1 Hz, 1H), 3.68 (d, J=5.6 Hz, 2H), 3.62 (dd , J=6.6, 13.8 Hz, 1H), 1.40 (s, 9H), 1.13 (d, J=6.2 Hz, 6H); m/z (APCI+) for (C ₁₆ H ₂₃ BrFN ₃ O ₃ ), 404.0, 406.1 (M+H) ⁺ .

Stage 2: Synthesis of tert-butyl-{[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]methyl}carbamate (Int-37)

Solution of tert-butyl-(2-{4-bromo-2-fluoro-6-[(propan-2-yl)amino]anilino}-2-oxoethyl)carbamate (15a) (809 mg, 2.0 mmol) in AcOH (4.0 ml) was stirred at 90° C. for 3.5 hours. LCMS analysis showed some starting material remaining. The reaction mixture was stirred for another 2.5 h at 100°C. The reaction mixture was concentrated. The residue was purified by flash chromatography (ISCO, 12 g SiO ₂ , 0-100% EtOAc/heptane) to give t-butyl-{[6-bromo-4-fluoro-1-(propan-2-yl)-1H -benzimidazol-2-yl]methyl}carbamate (Int-37) (547 mg, 70% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.79 (d, J=1.3 Hz, 1H), 7.51 (br. s, 1H), 7.28 (dd, J=1, 3, 10.1 Hz, 1H), 4.97-4.78 (m, 1H), 4.45 (d, J=5.7 Hz, 2H), 1.53 (d, J=6.8 Hz, 6H), 1.39 (s, 9H); m/z (APCI+) for (C ₁₆ H ₂₁ BrFN ₃ O ₂ ), 388.0 (M+H) ⁺ .

Preparation of tert-butyl {1-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]ethyl}carbamate (Int-38) according to Scheme 16.

Scheme 16:

Step 1: Synthesis of tert-butyl-(1-{4-bromo-2-fluoro-6-[(propan-2-yl)amino]anilino}-1-oxopropan-2-yl)carbamate (16a)

^N- (tert-butoxycarbonyl)alanine, DIPEA (1.26 g, 9.7 mmol) and HATU (1.85 g, 4.9 mmol). The mixture was stirred at ambient temperature for 16 hours. LCMS analysis showed consumption of starting material to form a mass of the desired product. The reaction mixture was concentrated to dryness. The residue was purified by flash chromatography (ISCO, 20 g SiO ₂ , 30-50% EtOAc/petroleum ether) to give t-butyl-(1-{4-bromo-2-fluoro-6-[(propane-2- yl)amino]anilino}-1-oxopropan-2-yl)carbamate (16a) (1.14 g, 84% yield) as a white solid.

Stage 2: Synthesis of tert-butyl-{1-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]ethyl}carbamate (Int-38)

A mixture of tert-butyl-(1-{4-bromo-2-fluoro-6-[(propan-2-yl)amino]anilino}-1-oxopropan-2-yl)carbamate (16a) (4.4 g, 10.5 mmol) in AcOH (20 ml) was stirred at 120°C for 2 h. The solution was diluted with EtOAc (50 ml) and extracted with H ₂ O (50 ml). THF (100 ml) and Boc ₂ O (1.09 g, 5.0 mmol) were added to the aqueous solution. The mixture was stirred at room temperature for 16 hours. TLC analysis indicated consumption of the intermediate. The solution was diluted with H ₂ O (30 ml) and was extracted with EtOAc (30 ml). The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (ISCO, 20 g SiO ₂ , 25% EtOAc/petroleum ether) to give t-butyl-{1-[6-bromo-4-fluoro-1-(propan-2-yl)- 1H-benzimidazol-2-yl]ethyl}carbamate (Int-38) (1.1 g, 26% yield) as a resinous solid. m/z (ESI+) for (C ₁₇ H ₂₃ BrFN ₃ O ₂ ), 401.7 (M+H) ⁺ .

The intermediate in the table below was synthesized according to the methods used for the synthesis of tert-butyl-{1-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]ethyl} carbamate (Int-38). The following intermediate has been synthesized with non-critical modifications or substitutions of the illustrated techniques, which could be implemented by a person skilled in the art.

Connection number Structure/Name according to IUPAC nomenclature Analytical data Int-39

трет-бутил-(1-{[6-бром-4-фтор-1-(пропан-2-ил)-1H-бензимидазол-2-ил]метил}циклопентил)карбамат

tert-butyl-(1-{[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]methyl}cyclopentyl)carbamate ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.41 (s, 1H), 7.02 (d, J=9.7 Hz, 1H), 4.78 (n, J=7.0 Hz, 1H ), 4.66 (s, 1H), 3.35 (s, 2H), 1.89-1.59 (m, 8H), 1.54 (d, J=7.0 Hz, 6H), 1 .34 (br.d, J=6.7 Hz, 9H); m/z (ESI+) for (C ₁₈ H ₂₆ BrFN ₂ OSi), 454.1 (M+H) ⁺

Preparation of (1R)-1-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]ethan-1-ol (Int-40) according to Scheme 17.

Scheme 17:

A mixture of 5-bromo-3-fluoro-N ¹ -(propan-2-yl)benzene-1,2-diamine (7a) (5.74 g, 23.2 mmol) and (2R)-2-hydroxypropanoic acid ( 17.4 g, 193 mmol) was stirred at 82° C. for 44 h. The dark viscous mixture was carefully added to a stirred mixture of DCM (100 ml) and saturated NaHCO ₃ (250 ml) (gas evolution). The biphasic mixture was stirred at ambient temperature until gas evolution ceased. The layers were separated and the aqueous phase was extracted with DCM (2×100 ml). The combined organic phases were dried over MgSO ₄ , filtered and concentrated. The crude residue was purified by flash chromatography (SiO ₂ , 20-80% MTBE/heptane). Fractions containing the product were further purified by first concentrating to the minimum volume. The resulting residue was dissolved in a small volume of MTBE, then diluted with an equal volume of heptane. The solution was sonicated causing precipitation. The resulting suspension was concentrated until only a small amount of solvent remained. The supernatant was decanted. The solids were washed with 10% MTBE/heptane followed by a heptane wash and then dried under vacuum to give (1R)-1-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2- yl]ethan-1-ol (Int-40) (4.97 g, 71% yield) as a tan solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.79 (d, J=1.6 Hz, 1H), 7.26 (dd, J=1.5, 10.1 Hz, 1H), 5 .71 (d, J=6.5 Hz, 1H), 5.17-5.00 (m, 2H), 1.62-1.51 (m, 9H); m/z (APCI+) for (C ₁₂ H ₁₄ BrFN ₂ O), 300.8 (M+H) ⁺ .

The intermediates in the table below were synthesized according to the methods used for the synthesis of (1R)-1-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]ethan-1 -ola (Int-40). The following intermediates have been synthesized with non-critical modifications or substitutions of the illustrated procedures, which could be implemented by a person skilled in the art.

Connection number Structure/Name according to IUPAC nomenclature Analytical data Int-41

1-[6-бром-4-фтор-1-(пропан-2-ил)-1H-бензимидазол-2-ил]этан-1-ол

1-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]ethan-1-ol m/z (APCI+) for (C ₁₂ H ₁₄ BrFN ₂ O), 302.7 (M+H) ⁺ Int-42

(1S)-1-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]ethan-1-ol m/z (APCI+) for (C ₁₂ H ₁₄ BrFN ₂ O), 302.9 (M+H) ⁺

Preparation of 1-[6-bromo-1-(1,1-difluoropropan-2-yl)-4-fluoro-1H-benzimidazol-2-yl]ethan-1-ol (Int-43) according to Scheme 18.

Scheme 18:

Step 1: Synthesis of N-{4-bromo-2-[(1,1-difluoropropan-2-yl)amino]-6-fluorophenyl}-2-hydroxypropanamide (18b)

A mixture of 5-bromo-N ¹ -(1,1-difluoropropan-2-yl)-3-fluorobenzene-1,2-diamine (18a) (obtained as in Scheme 7, 1.0 g, 3.5 mmol) and 2-hydroxypropanoic acid (10.0 ml) was stirred at 85° C. for 16 hours. LCMS showed consumption of starting material to form a mass of the desired product. Added H ₂ O (15 ml) and EtOAc (15 ml) and the mixture was cooled to 0°C. The mixture was adjusted to pH~7 with 50% aqueous NaOH. The layers were separated. The aqueous layer was extracted with EtOAc (2×20 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (20 g SiO ₂ , 0-50% EtOAc/petroleum ether) to give N-{4-bromo-2-[(1,1-difluoropropan-2-yl)amino]-6- fluorophenyl}-2-hydroxypropanamide (18b) (1.0 g, 84% yield) as a dark oil. m/z (ESI) for (C ₁₂ H ₁₄ BrF ₃ N ₂ O ₂ ), 356.6 (M+H) ⁺ .

Step 2: Synthesis of 1-[6-bromo-1-(1,1-difluoropropan-2-yl)-4-fluoro-1H-benzimidazol-2-yl]ethan-1-ol (Int-43)

A solution of N-{4-bromo-2-[(1,1-difluoropropan-2-yl)amino]-6-fluorophenyl}-2-hydroxypropanamide (18b) (1.0 g, 3.0 mmol) in 1, 4-dioxane (10 ml) was stirred at 130°C for 15 min using microwave radiation. LCMS analysis showed consumption of starting material to form a mass of the desired product. The solution was concentrated to dryness. The residue was dissolved in H ₂ O (3 ml) and then basified with aqueous NH ₄ OH (1 ml) to pH~8. The solution was extracted with EtOAc (3×5 ml). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (ISCO, 20 g SiO ₂ , 1:1 EtOAc/petroleum ether) to give (Int-43) (400 mg, 42% yield) as a dark oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.47 (d, J=8.5 Hz, 1H), 7.16 (dd, J=1.5, 9.5 Hz, 1H), 6.31 -5.98 (m, 1H), 5.14 (br.dd, J=6.8, 10.3 Hz, 2H), 3.69-3.58 (m, 1H), 1.83-1 .70 (m, 6H); m/z (ESI) for (C ₁₂ H ₁₂ BrF ₃ N ₂ O), 338.7 (M+H) ⁺ .

Preparation of 6-bromo-2-(difluoromethyl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazole (Int-44) according to Scheme 19.

Scheme 19:

A mixture of 5-bromo-3-fluoro-N ¹ -(propan-2-yl)benzene-1,2-diamine (7a) and difluoroacetic anhydride (1.47 ml, 11.8 mmol) in AcOH (4.6 ml ) was stirred at 90°C for 3 h. The solvent was removed under vacuum. The residue was dissolved in DCM (30 ml). The mixture was adjusted to pH ~ 8-9 with 1.0 N. aqueous NaOH and the layers were separated. The organic layer was washed with brine (10 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (ISCO, 12 g SiO ₂ , 0-50% EtOAc/petroleum ether) to give 6-bromo-2-(difluoromethyl)-4-fluoro-1-(propan-2-yl)- 1H-benzimidazole (Int-44) (523 mg, 72% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.02 (d, J=1.5 Hz, 1H), 7.63-7.28 (m, 2H), 5.04-4.84 ( m, 1H), 1.60 (d, J=6.8 Hz, 6H); m/z (APCI+) for (C ₁₁ H ₁₀ BrF ₃ N ₂ ), 309.1 (M+H) ⁺ .

Obtaining 6-bromo-1-tert-butyl-4-fluoro-1H-benzimidazole (Int-45) in accordance with Scheme 20.

Scheme 20:

Step 1: Synthesis of N-(4-bromo-2,6-difluorophenyl)-N'-tert-butylmethanimidamide (20b)

A solution of 4-bromo-2,6-difluoroaniline (20a) (5.00 g, 24.0 mmol), triethylamine (4.86 g, 6.7 ml, 48.1 mmol) and N-tert-butylformamide (2 .92 g, 3.2 ml, 28.8 mmol) in PhMe (50 ml) was treated with POCl ₃ (5.53 g, 3.36 ml, 36.1 mmol) at 0°C (keeping the internal temperature below 20° C). The mixture was stirred at ambient temperature for 15 h and then quenched with aqueous Na ₂ CO ₃ (80 ml). The organic layer was collected. The aqueous layer was extracted with EtOAc (3×30 ml). The combined organic phases were washed with brine (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was suspended in EtOAc (5 ml) and petroleum ether (40 ml), suspended for 10 min and collected by filtration to give N-(4-bromo-2,6-difluorophenyl)-N'-tert-butylmethanimidamide (20b) (4.50 g, 64% yield) as a yellow solid. m/z (ESI+) for (C ₁₁ H ₁₃ BrF ₂ N ₂ ), 292.6 (M+H) ⁺ .

Stage 2: Synthesis of 6-bromo-1-tert-butyl-4-fluoro-1H-benzimidazole (Int-45)

KOtBu (2.60 g, 23.2 mmol) and the mixture was stirred at 80°C for 14 hours was Added H ₂ O (100 ml) and the mixture was extracted with EtOAc (3×50 ml). The combined organic phases were washed with brine (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified in two steps: first by flash chromatography (SiO ₂ , 20% EtOAc/petroleum ether), then by preparative HPLC on a Phenomenex Synergi Max-RP column (250×80 mm, particle size 10 μm, column temperature 25°C) which was eluted with 35-65% MeCN/H ₂ O (+0.225% formic acid) at a flow rate of 80 ml/min to give 6-bromo-1-tert-butyl-4-fluoro-1H-benzimidazole ( Int-45) (1.5 g, 36% yield) as a gray solid. m/z (ESI+) for (C ₁₁ H ₁₂ BrFN ₂ ), 270.9 (M+H) ⁺ .

The intermediate in the table below was synthesized according to the methods used for the synthesis of 6-bromo-1-tert-butyl-4-fluoro-1H-benzimidazole (Int-45). The following intermediate has been synthesized with non-critical modifications or substitutions of the illustrated techniques, which could be implemented by a person skilled in the art.

Connection number Structure/Name according to IUPAC nomenclature Analytical data Int-46

6-бром-4-фтор-2-метил-1-(пропан-2-ил)-1H-бензимидазол

6-bromo-4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazole m/z (ESI+) for (C ₁₁ H ₁₂ BrFN ₂ ), 270.6 (M+H) ⁺

Preparation of tert-butyl 3-(6-bromo-4-fluoro-2-methyl-1H-benzimidazol-1-yl)azetidine-1-carboxylate (Int-47) according to Scheme 21.

Scheme 21:

To a solution of 6-bromo-4-fluoro-2-methyl-1H-benzimidazole (21a) (271 mg, 1.18 mmol) and tert-butyl 3-iodazetidine-1-carboxylate (670 mg, 2.37 mmol) in DMF (5.9 ml) was added K ₂ CO ₃ (491 mg, 3.55 mmol). The reaction mixture was stirred at 100° C. for 16 hours. The reaction mixture was cooled to room temperature and applied to SiO ₂ . The crude material was purified by flash chromatography (SiO ₂ , 0-100% EtOAc/heptane) to give a mixture of regioisomers. These compounds were subsequently separated by preparative SFC on a Waters SFC 200 Glacier/Two ZymorSPHER HADP column (150×21.1 mm ID, particle size 5 µm) which was eluted with 10-35% MeOH/CO ₂ (100 bar , 35°C) with a flow rate of 80 ml/min to obtain tert-butyl-3-(6-bromo-4-fluoro-2-methyl-1H-benzimidazol-1-yl)azetidine-1-carboxylate (Int-47 ) (106 mg, 23% yield) as a solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.55 (d, J=1.5 Hz, 1H), 7.34 (dd, J=1.5, 10.1 Hz, 1H), 5 .41 (s, 1H), 4.48-4.37 (m, 2H), 4.28 (dd, J=5.1, 10.0 Hz, 2H), 2.56 (s, 3H), 1.46 (s, 9H); m/z (APCI+) for (C ₁₆ H ₁₉ BrFN ₃ O ₂ ), 384.0 (M+H) ⁺ .

Preparation of 6-bromo-2,4-dimethyl-1-(propan-2-yl)-1H-benzimidazole (Int-48) according to Scheme 22.

Scheme 22:

To a solution of 6-bromo-2,4-dimethyl-1H-benzimidazole (22a) (250 mg, 1.11 mmol) in anhydrous DMF (8.0 ml) was added 2-iodopropane (189 mg, 1.11 mmol) and NaH (60% dispersion in mineral oil, 222 mg, 5.55 mmol). The reaction mixture was stirred at ambient temperature for 16 hours. LCMS analysis showed consumption of starting material to form a mass of the desired product. The reaction was quenched with H ₂ O (3 ml) and then concentrated under vacuum. The crude residue was purified by flash chromatography (ISCO, 20 g SiO ₂ , 70% EtOAc/petroleum ether) to give 6-bromo-2,4-dimethyl-1-(propan-2-yl)-1H-benzimidazole (Int -48) (260 mg, 88% yield). m/z (ESI+) for (C ₁₂ H ₁₅ BrN ₂ ), 268.8 (M+H) ⁺ .

The intermediate in the table below was synthesized according to the methods used for the synthesis of 6-bromo-2,4-dimethyl-1-(propan-2-yl)-1H-benzimidazole (Int-48). The following intermediate has been synthesized with non-critical modifications or substitutions of the illustrated techniques, which could be implemented by a person skilled in the art.

Connection number Structure/Name according to IUPAC nomenclature Analytical data Int-49

6-бром-4-хлор-1-(пропан-2-ил)-1H-бензимидазол

6-bromo-4-chloro-1-(propan-2-yl)-1H-benzimidazole ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.05 (s, 1H), 7.84 (d, J=1.5 Hz, 1H), 7.39 (d, J=1.3 Hz, 1H ), 5.40 (q.d, J=6.6, 13.3 Hz, 1H), 1.62 (d, J=6.5 Hz, 6H); m/z (ESI+) for (C ₁₀ H ₁₀ BrClN ₂ ), 274.8 (M+H) ⁺

Obtaining tert-butyl-[1-(6-bromo-4-fluoro-2-methyl-1H-benzimidazol-1-yl)propan-2-yl]carbamate (Int-50) in accordance with Scheme 23.

Scheme 23:

Solid t-BuOK (294 mg, 2.62 mmol). The mixture was stirred at ambient temperature for 10 minutes followed by the addition of 1-[(tert-butoxycarbonyl)amino]propan-2-ylmethanesulfonate (888 mg, 3.51 mmol). The mixture was stirred at 60° C. under an Ar atmosphere for 17 hours. LCMS analysis showed ~50% starting material consumption. The reaction mixture was cooled to room temperature and additional t-BuOK (122 mg, 1.09 mmol) was added followed by additional 1-[(tert-butoxycarbonyl)amino]propan-2-ylmethanesulfonate (730 mg, 1.46 mmol). The mixture was stirred at 60° C. for 18 hours. LCMS analysis indicated ~65% conversion. The mixture was diluted with H ₂ O (30 ml) and was extracted with DCM (3×15 ml). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated. The crude mixture was purified by flash chromatography (20 g SiO ₂ , 10-65% EtOAc/petroleum ether). Fractions containing the desired product were collected and repurified by preparative HPLC on a YMC-Actus Triart C18 column (150×40 mm, particle size 5 µm) eluted with 33-73% MeCN/H ₂ O (0.05% NH ₄ OH) with a flow rate of 25 ml/min to obtain tert-butyl-[1-(6-bromo-4-fluoro-2-methyl-1H-benzimidazol-1-yl)propan-2-yl]carbamate (Int- 50) (112 mg, 16% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.58 (d, J=1.6 Hz, 1H), 7.08 (dd, J=11.1, 1.6 Hz, 1H), 4.48 (s, 1H), 4.21 (td, J=16.1, 14.5, 6.9 Hz, 2H), 4.06 (p, J=7.0 Hz, 1H), 2.63 ( s, 3H), 1.28-1.20 (m, 12H); m/z (ESI+) for (C ₁₆ H ₂₁ BrFN ₃ O ₂ ), 387.8 (M+H) ⁺ .

Obtaining tert-butyl-[1-(6-bromo-4-fluoro-2-methyl-1H-benzimidazol-1-yl)propan-2-yl]carbamate (Int-49) in accordance with Scheme 24.

Scheme 24:

A solution of 6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazole (Int-22) (500 mg, 1.94 mmol) in THF (20.0 ml) under N ₂ was cooled to -65°C dry ice/acetone bath. A solution of LDA (2.0 M in THF, 1.94 ml, 3.89 mmol) was added dropwise. The reaction mixture was stirred at the same temperature for 1 hour, followed by the addition of cyclopropyl methyl ketone (327 mg, 3.89 mmol). After 1 hour at -65° C., LCMS analysis showed consumption of starting material to mass the desired product. The reaction mixture was quenched with saturated aqueous NH ₄ Cl (10 ml). The phases were separated. The aqueous phase was extracted with EtOAc (3×15 ml). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash chromatography (ISCO, 1:3 EtOAc/petroleum ether) to give [1-(6-bromo-4-fluoro-2-methyl-1H-benzimidazol-1-yl)propan-2-yl ]carbamate (Int-51) (420 mg, 63% yield) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.52 (d, J=1.5 Hz, 1H), 7.12 (dd, J=1.5, 9.7 Hz, 1H), 5.46 -5.22 (m, 1H), 3.71 (s, 1H), 1.72 (s, 3H), 1.67 (dd, J=6.1, 6.8 Hz, 6H), 1, 41-1.30 (m, 1H), 0.77-0.67 (m, 1H), 0.64-0.53 (m, 2H), 0.52-0.44 (m, 1H); m/z (ESI+) for (C ₁₅ H ₁₈ BrFN ₂ O), 340.7 (M+H) ⁺ .

Preparation of (4R)-7-bromo-9-fluoro-4-methyl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole (Int-50) according to Scheme 25.

Scheme 25:

Step 1: Synthesis of (5R)-4-(5-bromo-3-fluoro-2-nitrophenyl)-5-methylmorpholin-3-one (25a)

To a solution of (5R)-5-methylmorpholin-3-one (500 mg, 4.34 mmol) in DMF (10.0 ml) was added NaH (60% dispersion in mineral oil, 208 mg, 5.21 mmol). The reaction suspension was stirred at ambient temperature for 30 min and then 5-bromo-1,3-difluoro-2-nitrobenzene (1a) (1.03 mg, 4.34 mmol) was added. The reaction slurry was stirred for 1 hour. LCMS analysis indicated consumption of starting material. H ₂ O (2 ml) was added and the reaction suspension was concentrated to dryness. The residue was dissolved in EtOAc (80 ml) and washed with H ₂ O (60 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was purified by flash chromatography (ISCO, 20 g SiO ₂ , 1:3 EtOAc/petroleum ether) to give (5R)-4-(5-bromo-3-fluoro-2-nitrophenyl)-5-methylmorpholine-3 -one (25a) (760 mg, 53% yield) as a light yellow solid. m/z (ESI+) for (C ₁₁ H ₁₀ BrFN ₂ O ₄ ), 334.3 (M+H) ⁺ .

Step 2: Synthesis of (5R)-4-(2-amino-5-bromo-3-fluorophenyl)-5-methylmorpholin-3-one (25b)

To a solution of (5R)-4-(5-bromo-3-fluoro-2-nitrophenyl)-5-methylmorpholin-3-one (25a) (760 mg, 2.28 mmol) in EtOH (16.0 ml) and H ₂ O (4.0 ml) was added Fe ⁰ (637 mg, 11.4 mmol) and NH ₄ Cl (610 mg, 11.4 mmol). The reaction suspension was stirred at 80° C. for 4 hours under N ₂ atmosphere. LCMS analysis showed complete consumption of the starting material to form a mass of the desired product. The reaction mixture was filtered and concentrated to dryness. The residue was purified by flash chromatography (SiO ₂ , 1:3 EtOAc/petroleum ether) to give (5R)-4-(2-amino-5-bromo-3-fluorophenyl)-5-methylmorpholin-3-one (25b) (420 mg, 61% yield) as light brown gum m/z (ESI+) for (C ₁₁ H ₁₂ BrFN ₂ O ₂ ), 303.1 (M+H) ⁺ .

Stage 3: Synthesis of (4R)-7-bromo-9-fluoro-4-methyl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole (Int-52)

A solution of (5R)-4-(2-amino-5-bromo-3-fluorophenyl)-5-methylmorpholin-3-one (25b) (420 mg, 1.39 mmol) in AcOH (6.0 mL) was stirred at 110° C. for 2 hours. LCMS analysis showed consumption of starting material to form a mass of the desired product. The reaction mixture was concentrated to dryness. The residue was dissolved in EtOAc (50 ml) and washed with saturated aqueous NaHCO ₃ (30 ml). The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated to give (4R)-7-bromo-9-fluoro-4-methyl-3,4-dihydro-1H-[1,4]oxazino[4,3-a ]benzimidazole (Int-52) (360 mg, 91% yield) as a light yellow solid. m/z (ESI+) for (C ₁₁ H ₁₀ BrFN ₂ O), 286.6 (M+H) ⁺ .

The intermediates in the table below were synthesized according to the methods used for the synthesis of (4R)-7-bromo-9-fluoro-4-methyl-3,4-dihydro-1H-[1,4]oxazino[4,3-a ]benzimidazole (Int-52). The following intermediates have been synthesized with non-critical modifications or substitutions of the illustrated procedures, which could be implemented by a person skilled in the art.

Connection number Structure/Name according to IUPAC nomenclature Analytical data Int-53

(4S)-7-бром-9-фтор-4-метил-3,4-дигидро-1H-[1,4]оксазино[4,3-a]бензимидазол

(4S)-7-bromo-9-fluoro-4-methyl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole m/z (ESI+) for (C ₁₁ H ₁₀ BrFN ₂ O), 286.6 (M+H) ⁺ Int-54

7-bromo-4-ethyl-9-fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole m/z (ESI+) for (C ₁₂ H ₁₂ BrFN ₂ O), 300.9 (M+H) ⁺ Int-55

tert-Butyl-7-bromo-9-fluoro-4-methyl-3,4-dihydropyrazino[1,2-a]benzimidazole-2(1H)-carboxylate ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.79 (d, J=1.5 Hz, 1H), 7.33 (dd, J=1.5, 10.3 Hz, 1H), 5 .21-4.96 (m, 1H), 4.75 (br. s, 1H), 4.26-4.09 (m, 1H), 3.67-3.57 (m, 2H), 1 .46 (s, 9H), 1.35 (br.d, J=6.3 Hz, 3H); m/z (ESI+) for (C ₁₆ H ₁₉ BrFN ₃ O ₂ ), 385.9 (M+H) ⁺ Int-56

7-bromo-5-fluoro-1,1-dimethyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole m/z (ESI+) for (C ₁₂ H ₁₂ BrFN ₂ ), 284.9 (M+H) ⁺

Preparation of 7-bromo-9-fluoro-4,4-dimethyl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole (Int-57) according to Scheme 26.

Scheme 26:

Step 1: Synthesis of 2-(5-bromo-3-fluoro-2-nitroanilino)-2-methylpropan-1-ol (26a)

K ₂ CO ₃ (9.3 g, 67.2 mmol) and 2-amino-2-methylpropan-1-ol (3.0 g, 33.6 mmol). The mixture was stirred at 80° C. for 1 hour. LCMS analysis showed consumption of starting material to form a mass of the desired product. The reaction mixture was cooled to room temperature, filtered and concentrated. The residue was purified by flash chromatography (ISCO, 80 g SiO ₂ , 15% EtOAc/petroleum ether) to give 2-(5-bromo-3-fluoro-2-nitroanilino)-2-methylpropan-1-ol (26a) (7.0 g, 68% yield) as a yellow solid. m/z (ESI+) for (C ₁₀ H ₁₂ BrFN ₂ O ₃ ), 307.0 (M+H) ⁺ .

Step 2: Synthesis of 2-(2-amino-5-bromo-3-fluoroanilino)-2-methylpropan-1-ol (26b)

Saturated aqueous NH ₄ Cl (10 ml) and Fe ⁰ (6.36 mg, 114 mmol) and the mixture was stirred at 80° C. for 1 hour. TLC analysis showed consumption of starting material. The mixture was filtered and concentrated to dryness. The residue was purified by flash chromatography (ISCO, 80 g SiO ₂ , 30% EtOAc/petroleum ether) to give 2-(2-amino-5-bromo-3-fluoroanilino)-2-methylpropan-1-ol (26b) (5.4 g, 86% yield) as a black oil. m/z (ESI+) for (C ₁₀ H ₁₄ BrFN ₂ O), 277.0, 279.0 (M+H) ⁺ .

Step 3: Synthesis of 2-[6-bromo-2-(chloromethyl)-4-fluoro-1H-benzimidazol-1-yl]-2-methylpropan-1-ol (26c)

Yellow solution of 2-(2-amino-5-bromo-3-fluoroanilino)-2-methylpropan-1-ol (26b) (1.8 g, 6.5 mmol) and 2-chloro-1,1,1- triethoxyethane (1.5 g, 9.7 mmol) in AcOH (10.0 ml) was stirred at 55°C for 8 min. LCMS analysis indicated consumption of starting material to form a mass of product. After cooling to room temperature, the reaction mixture was combined with parallel reactions, run in smaller quantities (5×100 mg). The combined reactions were basified with saturated aqueous NaHCO ₃ to pH~7-8 and extracted with EtOAc (3×20 ml). The combined organic phases were washed with brine (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (ISCO, 40 g SiO ₂ , 30% EtOAc/petroleum ether) to give 2-[6-bromo-2-(chloromethyl)-4-fluoro-1H-benzimidazol-1-yl]- 2-methylpropan-1-ol (26c) (2.0 g, 72% yield) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.90 (d, J=1.5 Hz, 1H), 7.36 (dd, J=1.3, 9.8 Hz, 1H), 5 .41 (t, J=5.6 Hz, 1H), 5.18 (s, 2H), 3.87 (d, J=5.3 Hz, 2H), 1.78 (s, 6H). m/z (ESI+) for (C ₁₂ H ₁₃ BrClFN ₂ O), 336.9 (M+H) ⁺ .

Stage 4: Synthesis of 7-bromo-9-fluoro-4,4-dimethyl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole (Int-57)

t-BuOK (251 mg, 2.23 mmol) at 0°C. The solution was stirred at 0°C for 30 min. LCMS analysis showed consumption of starting material to form a mass of the desired product. The reaction mixture was diluted with H ₂ O (10 ml) and was extracted with EtOAc (3×10 ml). The combined organic phases were washed with brine (15 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (ISCO, 20 g SiO ₂ , 30% EtOAc/petroleum ether) to give 7-bromo-9-fluoro-4,4-dimethyl-3,4-dihydro-1H-[1,4 ]oxazino[4,3-a]benzimidazole (Int-57) (420 mg, 94% yield) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.47 (d, J=1.5 Hz, 1H), 7.14 (dd, J=1.5, 9.5 Hz, 1H), 4.98 (s, 2H), 3.84 (s, 2H), 1.67 (s, 6H); m/z (ESI+) for (C ₁₂ H ₁₂ BrFN ₂ O), 298.7 (M+H) ⁺ .

Preparation of 7-bromo-9-fluoro-2,4,4-trimethyl-1,2,3,4-tetrahydropyrazino[1,2-a]benzimidazole (Int-58) according to Scheme 27.

Scheme 27:

To a solution of 2-[6-bromo-2-(chloromethyl)-4-fluoro-1H-benzimidazol-1-yl]-2-methylpropan-1-ol (26c) (500 mg, 1.49 mmol) and DIPEA ( 578 mg, 4.47 mmol) in MeCN (5.0 ml) was added dropwise MsCl (256 mg, 2.23 mmol). After the addition, the resulting solution was allowed to warm to room temperature and stirred for 1 hour. LCMS analysis showed consumption of starting material to form a mass of the desired product. DIPEA (963 mg, 7.45 mmol) and methylamine hydrochloride (201 mg, 2.98 mmol) were added to the solution. The resulting solution was stirred at 60° C. for 14 hours. LCMS analysis showed consumption of the mesylate intermediate to give a mass of the desired product. The reaction mixture was concentrated to dryness. The residue was purified by flash chromatography (ISCO, 20 g SiO ₂ , 30% EtOAc/petroleum ether) to give 7-bromo-9-fluoro-2,4,4-trimethyl-1,2,3,4-tetrahydropyrazino[ 1,2-a]benzimidazole (Int-58) (200 mg, 43% yield) as a yellow gum. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.46 (d, J=1.3 Hz, 1H), 7.11 (dd, J=1.4, 9.6 Hz, 1H), 3.77 (s, 2H), 2.68 (s, 2H), 2.50 (s, 3H), 1.67 (s, 6H); m/z (ESI+) for (C ₁₃ H ₁₅ BrFN ₃ ), 314.0 (M+H) ⁺ .

Preparation of 7-bromo-9-fluoro-1,4-dimethyl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole (Int-59) according to Scheme 28.

Scheme 28:

Step 1: Synthesis of 2-(5-bromo-3-fluoro-2-nitroanilino)propan-1-ol (28a)

To a solution of 5-bromo-1,3-difluoro-2-nitrobenzene (1a) (4.0 g, 16.8 mmol) in DMF (40.0 ml) was added _K2CO3 ( _4.65 g, 33 6 mmol) and 2-aminopropan-1-ol (1.26 g, 16.9 mmol). The mixture was stirred at 80° C. for 1 hour. TLC analysis (3:1 petroleum ether/EtOAc) showed consumption of starting material. After cooling to room temperature, the reaction mixture was diluted with H ₂ O (150 ml) and was extracted with EtOAc (2×150 ml). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated to give 2-(5-bromo-3-fluoro-2-nitroanilino)propan-1-ol (28a) (4.7 g, 93% yield) as yellow oil. m/z (ESI+) for (C ₉ H ₁₀ BrFN ₂ O ₃ ), 294.6 (M+H) ⁺ .

Step 2: Synthesis of 2-[6-bromo-2-(1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-fluoro-1H-benzimidazol-1-yl]propan-1-ol (28b )

To a yellow solution of 2-(5-bromo-3-fluoro-2-nitroanilino)propan-1-ol (28a) (1.3 g, 3.3 mmol) and 2-{[tert-butyl(dimethyl)silyl] hydroxy}propanal (1.0 g, 5.3 mmol) in EtOH (10.0 ml) and DMSO (3.0 ml) was added Na ₂ S ₂ O ₄ (2.9 g, 16.4 mmol). The slurry was stirred at 80° C. for 16 hours. LCMS analysis showed consumption of starting material to form a mass of the desired product. The mixture was concentrated to remove EtOH. The solution was diluted with EtOAc (100 ml) and washed with H ₂ O (50 ml). The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (ISCO, 20 g SiO ₂ , 25% EtOAc/petroleum ether) to give 2-[6-bromo-2-(1-{[tert-butyl(dimethyl)silyl]oxy}ethyl) -4-fluoro-1H-benzimidazol-1-yl]propan-1-ol (28b) (1.0 g, 71% yield) as a white solid. m/z (ESI+) for (C ₁₈ H ₂₈ BrFN ₂ O ₂ Si), 432.8 (M+H) ⁺ .

Step 3: Synthesis of 2-[6-bromo-4-fluoro-2-(1-hydroxyethyl)-1H-benzimidazol-1-yl]propan-1-ol (28c)

To a solution of 2-[6-bromo-2-(1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-fluoro-1H-benzimidazol-1-yl]propan-1-ol (28b) ( 1.0 g, 2.32 mmol) in THF (5.0 ml) was added TBAF (1.2 g, 4.64 mmol) at ambient temperature. After 1 hour, TLC analysis (100% EtOAc) indicated consumption of starting material. The reaction solution was diluted with EtOAc (100 ml) and washed with H ₂ O (2×50 ml). The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (ISCO, 20 g SiO ₂ , 80% EtOAc/petroleum ether) to give 2-[6-bromo-4-fluoro-2-(1-hydroxyethyl)-1H-benzimidazol-1-yl ]propan-1-ol (28c) (400 mg, 54% yield) as a white solid. m/z (ESI+) for (C ₁₂ H ₁₄ BrFN ₂ O ₂ ), 316.7 (M+H) ⁺ .

Step 4: Synthesis of 7-bromo-9-fluoro-1,4-dimethyl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole (Int-59)

A solution of 2-[6-bromo-4-fluoro-2-(1-hydroxyethyl)-1H-benzimidazol-1-yl]propan-1-ol (28c) (400 mg, 1.26 mmol) and TsOH (434 mg , 2.52 mmol) in PhMe (5.0 ml) was stirred at 120° C. for 16 h. Saturated aqueous NaHCO ₃ (20 ml) was added to the solution. The mixture was extracted with EtOAc (2×100 ml). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (ISCO, 20 g SiO ₂ , 80-90% EtOAc/petroleum ether) to give 7-bromo-9-fluoro-1,4-dimethyl-3,4-dihydro-1H-[1 ,4]oxazino[4,3-a]benzimidazole (Int-59) (300 mg, 80% yield, mixture of diastereoisomers) as a yellow oil. m/z (ESI+) for (C ₁₂ H ₁₂ BrFN ₂ O), 298.7 (M+H) ⁺ .

Preparation of 6-bromo-1-(propan-2-yl)-1H-benzotriazole (Int-60) according to Scheme 29.

Scheme 29:

To a solution of 4-bromo-N ² -(propan-2-yl)benzene-1,2-diamine (29a) (3.00 g, 13.1 mmol) in hydrobromic acid (2.0 M in H ₂ O, 30 ml) was added a solution of sodium nitrite (1.36 g, 19.6 mmol) in H ₂ O (15 ml) at 0°C. The reaction mixture was stirred at this temperature for 30 min, then left to warm to ambient temperature for 2 h. The reaction mixture was poured into saturated aqueous Na ₂ CO ₃ (150 ml) and was extracted with EtOAc (2×150 ml). The combined organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash chromatography (SiO ₂ , 0-30% EtOAc/petroleum ether) to give 6-bromo-1-(propan-2-yl)-1H-benzotriazole (Int-60) (2.50 g , 80% yield) as a brown oil. m/z (ESI+) for (C ₉ H ₁₀ BrN ₃ ), 239.6 (M+H) ⁺ .

Obtaining 2-(5-bromo-2-methyl-2H-indazol-3-yl)propan-2-ol (Int-61) in accordance with Scheme 30.

Scheme 30:

To a stirred solution of 5-bromo-2-methyl-2H-indazole (30a) (300 mg, 1.42 mmol) in THF (10.0 ml) was added LDA (2.0 M in THF, 2.13 ml, 4 .26 mmol) at -78°C. The reaction mixture was stirred at 0°C for 10 min and then cooled to -78°C. Acetone (124 mg, 2.14 mmol) was added to the reaction mixture at -78°C. The reaction mixture was then allowed to warm to ambient temperature and stirred for 18 hours. LCMS analysis showed consumption of starting material to form a mass of the desired product. The reaction was quenched with saturated aqueous NaHCO ₃ (10 ml) and the layers were separated. The aqueous layer was extracted with EtOAc (3×10 ml). The combined organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (ISCO, 20 g SiO ₂ , 0-100% EtOAc/petroleum ether) to give 2-(5-bromo-2-methyl-2H-indazol-3-yl)propan-2-ol (Int-61) (120 mg, 31% yield) as a colorless oil. m/z (ESI+) for (C ₁₁ H ₁₃ BrN ₂ O), 270.9 (M+H) ⁺ .

Preparation of 5-bromo-2-methyl-3-(propan-2-yl)-2H-indazole (Int-62) according to Scheme 31.

Scheme 31:

To a stirred solution of 2-(5-bromo-2-methyl-2H-indazol-3-yl)propan-2-ol (Int-61) in DCM (10 ml) was added TFA (847 mg, 7.43 mmol) and Et ₃ SiH (846 mg, 7.43 mmol) at 0°C. The mixture was stirred at 25° C. for 36 hours. LCMS analysis indicated consumption of starting material. The reaction was quenched with H ₂ O, adjusted to pH~8 with saturated aqueous NaHCO ₃ and extracted with DCM (3×10 ml). The combined organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (ISCO, 4 g SiO ₂ , 0-100% EtOAc/petroleum ether) to give 5-bromo-2-methyl-3-(propan-2-yl)-2H-indazole (Int- 62) (140 mg, 74% yield) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.91-7.88 (m, 1H), 7.50 (d, J=9.0 Hz, 1H), 7.29 (d, J=1, 8 Hz, 1H), 4.12 (s, 3H), 3.40 (td, J=7.2, 14.2 Hz, 1H), 1.49 (d, J=7.0 Hz, 6H) ; m/z (ESI+) for (C ₁₁ H ₁₃ BrN ₂ ), 252.8 (M+H) ⁺ .

Preparation of 9-bromo-7-fluoro-1,1-dimethyl-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazole (Int-61) according to Scheme 32.

Scheme 32:

Step 1: Synthesis of 2-(5-bromo-7-fluoro-2H-indazol-2-yl)ethan-1-ol (32b)

NaOMe (1.26 g, 23.3 mmol) and 2 -bromoethan-1-ol (2.0 g, 11.6 mmol) under N ₂ atmosphere. The resulting solution was stirred at 85° C. for 16 hours. The reaction mixture was cooled to room temperature. TLC analysis (1:1 EtOAc/petroleum ether) indicated partial consumption of starting material. The reaction mixture was concentrated to dryness and purified by flash chromatography (ISCO, 80 g SiO2, 0-100% EtOAc/petroleum ether) to give 2-(5-bromo-7-fluoro-2H-indazol-2-yl)ethan- 1-ol (32b) (950 mg, 32% yield) as a white solid. m/z (ESI+) for (C ₉ H ₈ BrFN ₂ O), 260.8 (M+H) ⁺ .

Step 2: Synthesis of 2-[5-bromo-7-fluoro-2-(2-hydroxyethyl)-2H-indazol-3-yl]propan-2-ol (32c)

A solution of 2-(5-bromo-7-fluoro-2H-indazol-2-yl)ethan-1-ol (32b) (550 mg, 2.12 mmol) in THF (10.0 ml) was purged with N ₂ and then a solution of LDA (2.0 M in THF, 2.34 ml, 4.67 mmol) was added at -78°C. The solution was stirred at -10°C for 30 min and then cooled again to -78°C. Acetone (247 mg, 4.25 mmol) was added to the solution. The resulting solution was stirred for 16 h at room temperature. LCMS analysis showed complete consumption of the starting material to form a mass of the desired product. The reaction was quenched with H ₂ O (30 ml) and extracted with EtOAc (50 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash chromatography (ISCO, 20 g SiO ₂ , 50-70% EtOAc/petroleum ether) to give 2-[5-bromo-7-fluoro-2-(2-hydroxyethyl)-2H-indazole- 3-yl]propan-2-ol (32c) (490 mg, 73% yield) as a colorless oil.

Stage 3: Synthesis of 9-bromo-7-fluoro-1,1-dimethyl-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazole (Int-63)

To a solution of 2-[5-bromo-7-fluoro-2-(2-hydroxyethyl)-2H-indazol-3-yl]propan-2-ol (32c) (490 mg, 0.61 mmol) in PhMe (10 0 ml) p-TSA (210 mg, 1.22 mmol) was added at 0°C. The mixture was stirred at 120° C. for 16 hours. LCMS analysis showed consumption of starting material to form a mass of the desired product. The reaction mixture was concentrated to dryness and the residue was purified by flash chromatography (ISCO, 20 g SiO ₂ , 50% EtOAc/petroleum ether) to give 9-bromo-7-fluoro-1,1-dimethyl-3,4-dihydro-1H -[1,4]oxazino[4,3-b]indazole (Int-63) (100 mg, 55% yield) as a yellow oil. m/z (ESI+) for (C ₁₂ H ₁₂ BrFN ₂ O), 298.6 (M+H) ⁺ .

Preparation of tert-butyl[2-(5-bromo-7-fluoro-2-methyl-2H-indazol-3-yl)propan-2-yl]carbamate (Int-64) according to Scheme 33.

Scheme 33:

Stage 1: Synthesis of 5-bromo-7-fluoro-2-methyl-2H-indazole (33a)

To a solution of 5-bromo-7-fluoro-1H-indazole (32a) (550 mg, 2.12 mmol) in EtOAc (30.0 ml) was added trimethyloxonium tertfluoroborate (1.97 g, 13.3 mmol). The resulting solution was stirred at ambient temperature for 5 hours. LCMS analysis showed consumption of starting material to form a mass of the desired product. The reaction solution was diluted with H ₂ O (20 ml) and was extracted with EtOAc (100 ml). The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash chromatography (ISCO, 40 g SiO ₂ , 20-25% EtOAc/petroleum ether) to give 5-bromo-7-fluoro-2-methyl-2H-indazole (33a) (1.6 g , 68% yield) as a pale yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.45 (d, J=2.7 Hz, 1H), 7.79 (d, J=1.3 Hz, 1H), 7.22 (dd , J=1.3, 11.0 Hz, 1H), 4.20 (s, 3H); m/z (ESI+) for (C ₈ H ₆ BrFN ₂ ), 230.9 (M+H) ⁺ .

Step 2: Synthesis of N-[2-(5-bromo-7-fluoro-2-methyl-2H-indazol-3-yl)propan-2-yl]-2-methylpropan-2-sulfinamide (33b)

To a solution of 5-bromo-7-fluoro-2-methyl-2H-indazole (33a) (1.0 g, 4.4 mmol) in PhMe (10 ml) was added a solution of LDA (2.0 M in THF, 2, 6 ml, 5.24 mmol) at -78°C. The reaction mixture was stirred at -78°C for 1 hour. Then 2-methyl-N-(propan-2-ylidene)propane-2-sulfinamide (704 mg, 4.4 mmol) was added to the reaction mixture at -78°C . The reaction mixture was allowed to warm to room temperature and stirred for 24 h. LCMS analysis showed complete consumption of the starting material to form the mass of the desired product. The reaction was quenched by adding saturated aqueous NH ₄ Cl (10 ml) and was extracted with EtOAc (2×30 ml). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash chromatography (ISCO, 20 g SiO ₂ , 30-40% MeOH/EtOAc) to give N-[2-(5-bromo-7-fluoro-2-methyl-2H-indazole-3- yl)propan-2-yl]-2-methylpropan-2-sulfinamide (33b) (420 mg, 25% yield) as a yellow gum. m/z (ESI+) for (C ₁₅ H ₂₁ BrFN ₃ OS), 392.0 (M+H) ⁺ .

Step 3: Synthesis of 2-(5-bromo-7-fluoro-2-methyl-2H-indazol-3-yl)propan-2-amine (33c)

To a yellow solution of N-[2-(5-bromo-7-fluoro-2-methyl-2H-indazol-3-yl)propan-2-yl]-2-methylpropan-2-sulfinamide (33b) (420 mg, 1.08 mmol) in MeOH (5.0 ml) was added concentrated HCl (1.0 ml) at room temperature. The reaction mixture was stirred for 2 hours. LCMS analysis showed consumption of starting material to form a mass of the desired product. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM (10 ml) and TEA (2 ml) was added. The mixture was stirred for 20 minutes. The reaction solution was extracted with DCM (2×20 ml). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated to give 2-(5-bromo-7-fluoro-2-methyl-2H-indazol-3-yl)propan-2-amine (33c) (300 mg, 97% yield as a yellow solid. m/z (ESI+) for (C ₁₁ H ₁₃ BrFN ₃ ), 268.9 (M+H) ⁺ .

Stage 4: Synthesis of tert-butyl-[2-(5-bromo-7-fluoro-2-methyl-2H-indazol-3-yl)propan-2-yl]carbamate (Int-64)

To a yellow solution of 2-(5-bromo-7-fluoro-2-methyl-2H-indazol-3-yl)propan-2-amine (33c) (300 mg, 0.75 mmol) in THF (3.0 ml ) was added saturated aqueous NaHCO ₃ (3.0 ml) and Boc ₂ O (659 mg, 3.0 mmol). The mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with H ₂ O (10 ml) and extracted with EtOAc (2×30 ml). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash chromatography (ISCO, 20 g SiO ₂ , EtOAc/petroleum ether) to give (Int-64) (240 mg, 82% yield) as a yellow oil. m/z (ESI+) for (C ₁₆ H ₂₁ BrFN ₃ O ₂ ), 387.6 (M+H) ⁺ .

Preparation of 5-bromo-7-fluoro-2-methyl-3-(propan-2-yl)-2H-indazole (Int-65) according to Scheme 34.

Scheme 34:

Stage 1: Synthesis of 5-bromo-7-fluoro-3-iodo-2-methyl-2H-indazole (34a)

To a solution of 5-bromo-7-fluoro-2-methyl-2H-indazole (33a) (500 mg, 2.18 mmol) in DCM (10.0 ml) was added bis(trifluoroacetoxy)iodobenzene (1.13 g, .62 mmol) and pyridine (259 mg, 3.27 mmol). The mixture was stirred at 30° C. for 30 min and then I ₂ (556 mg, 2.62 mmol) was added. The mixture was stirred at 30° C. for 16 hours. LCMS analysis showed consumption of starting material to form a mass of the desired product. The reaction mixture was diluted with EtOAc (50 ml) and then filtered. The filtrate was concentrated to dryness. The residue was purified by flash chromatography (ISCO, 40 g SiO ₂ , 30-40% EtOAc/petroleum ether) to give 5-bromo-7-fluoro-3-iodo-2-methyl-2H-indazole (34a) (700 mg, 90% yield) as a pale yellow solid. m/z (ESI+) for (C ₈ H ₅ BrFIN ₂ ), 354.8 (M+H) ⁺ .

Step 2: Synthesis of 5-bromo-7-fluoro-2-methyl-3-(prop-1-en-2-yl)-2H-indazole (34b)

A mixture of 5-bromo-7-fluoro-3-iodo-2-methyl-2H-indazole (34a) (400 mg, 1.13 mmol), isopropenylboronic acid pinacol ester (189 mg, 1.13 mmol), K ₂ CO ₃ (467 mg, 3.38 mmol) and Pd(dppf)Cl ₂ (82.5 mg, 0.113 mmol) in 1,4-dioxane (6.0 ml) and H ₂ O (1.0 ml) were stirred in N ₂ atmosphere at 100° C. for 3 hours. The reaction suspension turned black. LCMS analysis showed complete consumption of the starting material to form a mass of the desired product. The suspension was diluted with EtOAc (50 ml) and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO, 20 g SiO ₂ , 30% EtOAc/petroleum ether) to give 5-bromo-7-fluoro-2-methyl-3-(prop-1-en-2-yl)- 2H-indazole (34b) (270 mg, 89% yield) as a yellow oil. m/z (ESI+) for (C ₁₁ H ₁₀ BrFN ₂ ), 268.9 (M+H) ⁺ .

Step 3: Synthesis of 5-bromo-7-fluoro-2-methyl-3-(propan-2-yl)-2H-indazole (Int-65)

Solution of 5-bromo-7-fluoro-2-methyl-3-(prop-1-en-2-yl)-2H-indazole (34b) (270 mg, 1.0 mmol) and Rh(PPh ₃ ) ₃ Cl (92.8 mg, 0.1 mmol) in MeOH (10.0 ml) and THF (10.0 ml) was purged with H ₂ and then stirred at 50° C. for 16 h under H ₂ at a pressure of 50 lb/ sq. inch. LCMS analysis showed consumption of starting material to form a mass of the desired product. The reaction mixture was concentrated to dryness and the residue was purified by flash chromatography (ISCO, 1:1 EtOAc/petroleum ether) to give 5-bromo-7-fluoro-2-methyl-3-(propan-2-yl)-2H-indazole (Int-65) (300 mg, >99% yield) as a pale brown gum. m/z (ESI+) for (C ₁₁ H ₁₀ BrFN ₂ ), 270.8 (M+H) ⁺ .

Preparation of 6-bromo-1-(propan-2-yl)-1H-imidazo[4,5-b]pyridine (Int-66) according to Scheme 35.

Scheme 35:

Stage 1: Synthesis of 5-bromo-N ³ -(propan-2-yl)pyridine-2,3-diamine (35b)

TFA (2.25 ml, 29.3 mmol) and NaBH(OAc) ₃ (4.25 g, 20 mmol) at 0°C. The mixture was stirred at room temperature for 2 hours. EtOAc (50 ml) was added to quench the reaction. The mixture was washed with saturated aqueous NaHCO ₃ (40 ml) and brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (40 g SiO ₂ , 0-65% EtOAc/petroleum ether) to give 5-bromo-N ³ -(propan-2-yl)pyridin-2,3-diamine (35b) (2 .7 g, 89% yield as a brown gum. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.28 (d, J=2.1 Hz, 1H), 6.66 (d, J=1.8 Hz, 1H), 4.97 (br .s, 1H), 3.55 (td, J=6.1, 12.3 Hz, 1H), 1.15 (d, J=6.2 Hz, 6H); m/z (APCI) for (C ₈ H ₁₂ BrN ₃ ), 230.1, 232.2 (M+H) ⁺ .

Step 2: Synthesis of 6-bromo-1-(propan-2-yl)-1H-imidazo[4,5-b]pyridine (Int-66)

A mixture of 5-bromo-N ³ -(propan-2-yl)pyridine-2,3-diamine (35b) (1.5 g, 6.52 mmol) and Ac ₂ O (30.8 ml, 32.6 mmol ) in AcOH (12.5 ml) was stirred at 90°C overnight. The solvent was removed by evaporation. The residue was dissolved in DCM (50 ml) and adjusted to pH ~ 8-9 with aqueous NaOH (1.0 N). The organic layer was collected, washed with brine (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (24 g SiO ₂ , 10% MeOH/EtOAc) to give 6-bromo-1-(propan-2-yl)-1H-imidazo[4,5-b]pyridine (Int-66) (866 mg, 52% yield) as a light brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.42-8.32 (m, 2H), 4.76 (td, J=6.9, 13.8 Hz, 1H), 2.61 ( s, 3H), 1.54 (d, J=7.0 Hz, 6H); m/z (APCI) for (C ₉ H ₁₀ BrN ₃ ), 254.2, 256.1 (M+H) ⁺ .

Preparation of 5-chloro-2-methyl-3-(propan-2-yl)-3H-imidazo[4,5-b]pyridine (Int-67) according to Scheme 36.

Scheme 36:

To a suspension of K ₂ CO ₃ (4.1 g, 29.8 mmol) in DMSO (6.0 ml) was added 5-chloro-2-methyl-3H-imidazo[4,5-b]pyridine (36a) (1 .0 g, 5.7 mmol) and 2-bromopropane (2.8 ml, 29.8 mmol). The mixture was stirred for 20 h at room temperature and another 1 h at 60°C. LCMS analysis showed the consumption of the starting material with the formation of the mass of the desired product (a mixture of regioisomers ~4:1). The mixture was partitioned between H ₂ O (25 ml) and EtOAc (25 ml). The aqueous layer was extracted with EtOAc (3×25 ml). The combined organic layers were washed with H ₂ O (2×25 ml) and brine (25 ml), dried over Na ₂ SO ₄ , filtered and concentrated directly on SiO ₂ . The crude material was purified by flash chromatography (SiO ₂ , 80-100% EtOAc/heptane) to give 5-chloro-2-methyl-3-(propan-2-yl)-3H-imidazo[4,5-b] pyridine (Int-67) (950 mg, 76% yield) as the regioisomer eluting first. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.85 (d, J=8.3 Hz, 1H), 7.17 (d, J=8.3 Hz, 1H), 4.84 (p, J =7.0 Hz, 1H), 2.68 (s, 3H), 1.69 (d, J=7.0 Hz, 6H); m/z (APCI) for (C ₁₀ H ₁₂ ClN ₃ ), 209.9 (M+H) ⁺ .

Preparation of 6-bromo-1-(propan-2-yl)-1H-imidazo[4,5-b]pyridine (Int-68) according to Scheme 37.

Scheme 37:

Stage 1: Synthesis of N-tert-butyl-6-chloro-3-nitropyridine-2-amine (37b)

To a solution of 2,6-dichloro-3-nitropyridine (37a) in PhMe (30 ml) was added 2-methylpropan-2-amine (3.8 g, 51.8 mmol) at 0°C. The yellow solution was stirred at room temperature for 16 hours. LCMS analysis showed consumption of starting material to form a mass of the desired product. The reaction mixture was concentrated to dryness. The residue was purified by flash chromatography (ISCO, 20 g SiO ₂ , 100% petroleum ether) to give N-tert-butyl-6-chloro-3-nitropyridine-2-amine (37b) (4.7 g, 79% yield). %) as a yellow solid. m/z (ESI) for (C ₉ H ₁₂ ClN ₃ O ₂ ), 229.9 (M+H) ⁺ .

Stage 2: Synthesis of N ² -tert-butyl-6-chloropyridine-2,3-diamine (37c)

To a solution of N-tert-butyl-6-chloro-3-nitropyridine-2-amine (37b) (4.7 g, 20.5 mmol) in EtOH (200 ml) was added saturated aqueous NH ₄ Cl (60 ml) and Fe ⁰ (5.7 g, 102 mmol). The mixture was stirred at 60° C. for 3 hours. LCMS analysis showed consumption of starting material to form a mass of the desired product. The mixture was filtered and concentrated to remove EtOH. The mixture was diluted with H ₂ O (100 ml) and was extracted with EtOAc (200 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give N ² -tert-butyl-6-chloropyridine-2,3-diamine (37c) (3.9 g, 95% yield) as a black oil, which was used without further purification. m/z (ESI) for (C ₉ H ₁₄ ClN ₃ ), 199.9 (M+H) ⁺ .

Stage 3: Synthesis of 3-tert-butyl-5-chloro-3H-imidazo[4,5-b]pyridine (Int-68)

To a black mixture of N ² -tert-butyl-6-chloropyridine-2,3-diamine (37c) (3.0 g, 15.0 mmol) and CH(OEt) ₃ (4.5 g, 30.0 mmol) in PhMe (40.0 ml) p-TSA monohydrate (286 mg, 1.5 mmol) was added. The mixture was stirred for 16 h at 110°C. LCMS analysis showed consumption of starting material to form a mass of the desired product. The mixture was washed with saturated aqueous NaHCO ₃ (60 ml). The aqueous layers were extracted with EtOAc (2×100 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to give 3-tert-butyl-5-chloro-3H-imidazo[4,5-b]pyridine (Int-68) as a black solid which was collected without additional cleaning. m/z (ESI) for (C ₁₀ H ₁₂ ClN ₃ ), 209.8 (M+H) ⁺ .

Preparation of (3R,4R)-4-amino-1-(methanesulfonyl)piperidin-3-ol (Int-69) according to Scheme 38.

Scheme 38:

Step 1: Synthesis of tert-butyl-(3R,4R)-4-{[(benzyloxy)carbonyl]amino}-3-hydroxypiperidine-1-carboxylate (38b)

To a solution of tert-butyl-(3R,4R)-4-amino-3-hydroxypiperidine-1-carboxylate (38a) (13.0 g, 60.1 mmol) in DCM (100 ml) and saturated Na ₂ CO ₃ ( 100 ml) benzyl chloroformate (24.1 ml, 72.1 mmol, 50% in PhMe) was added dropwise at 0°C. The mixture was stirred for 4 h, then the organic phase was collected. The aqueous phase was extracted with DCM (2×100 ml). The combined organic phases were washed with H ₂ O (2×100 ml) and brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash chromatography (SiO ₂ , 0-60% EtOAc/hexane) to give t-butyl-(3R,4R)-4-{[(benzyloxy)carbonyl]amino}-3-hydroxypiperidine-1- carboxylate (38b) (18.0 g, 85% yield) as a light yellow oil. m/z (ESI+) for (C ₁₈ H ₂₆ N ₂ O ₅ ), 251.3 (M+H-Boc) ⁺ .

Step 2: Synthesis of benzyl-[(3R,4R)-3-hydroxy-1-(methanesulfonyl)piperidin-4-yl]carbamate (38c)

Solution of tert-butyl-(3R,4R)-4-{[(benzyloxy)carbonyl]amino}-3-hydroxypiperidine-1-carboxylate (38b) (18.0 g, 51.4 mmol) and HCl in EtOH (1 ,25 M in EtOH, 123 ml, 154 mmol) was stirred at ambient temperature for 6 h and then concentrated. The residue was diluted with EtOAc (100 ml). Added saturated aqueous NaHCO ₃ (100 ml) and the mixture was cooled to 0°C. Methansulfonyl chloride (6.5 ml, 83.9 mmol) was added dropwise and the mixture was stirred at this temperature for 4 hours. The layers were separated and the aqueous layer was extracted with EtOAc (2×100 ml). The combined organic phases were washed with H ₂ O (2×100 ml) and brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was triturated with pentane to give benzyl-[(3R,4R)-3-hydroxy-1-(methanesulfonyl)piperidin-4-yl]carbamate (38c) (12.0 g, 71% yield) as a white solid. m/z (ESI+) for (C ₁₄ H ₂₀ N ₂ O ₅ S), 329.4 (M+H) ⁺ .

Stage 3: Synthesis of (3R,4R)-4-amino-1-(methanesulfonyl)piperidin-3-ol (Int-69)

Solution of benzyl-[(3R,4R)-3-hydroxy-1-(methanesulfonyl)piperidin-4-yl]carbamate (38c) (12.0 g, 36.5 mmol) in DCM:MeOH (5:4, 180 ml) was stirred in the presence of 15% Pd/C (0.583 g, 5.48 mmol) in an atmosphere of hydrogen at ambient temperature for 16 h. The reaction mixture was filtered through celite and washed with methanol (100 ml). The filtrate was concentrated under reduced pressure to give (Int-69) (6.41 g, 90% yield) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 3.83 (ddd, J=11.6, 5.0, 2.2 Hz, 1H), 3.73 (ddt, J=12.3, 4, 8, 2.5 Hz, 1H), 3.46 (td, J=9.8, 5.0 Hz, 1H), 2.89-2.75 (m, 5H), 2.58 (dd, J =11.6, 10.1 Hz, 1H), (ddt, J=13.1, 5.0, 2.7 Hz, 1H), 1.66-1.54 (m, 1H); m/z (APCI+) for (C ₆ H ₁₄ N ₂ O ₃ S), 195.0 (M+H) ⁺ ; [α]D-19° (c 0.1, MeOH).

Preparation of (3R,4R)-4-amino-1-(methanesulfonyl)piperidin-3-ol (2S)-2-hydroxy-3-phenylpropanoic acid salt (Int-70) according to Scheme 39.

Scheme 39:

Stage 1: Synthesis of 1,2,3,6-tetrahydropyridine hydrochloride (39b)

To tert-butyl 3,6-dihydropyridine-1(2H)-carboxylate (39a) (150 g, 819 mmol) was added a solution of HCl (4.0 N in MeOH, 500 ml) and the mixture was stirred at room temperature for 16 hours LCMS analysis showed consumption of starting material. The reaction mixture was concentrated to dryness to give 1,2,3,6-tetrahydropyridine hydrochloride (39b) (97.9 g, >99% yield), which was used without further purification. ¹ H NMR (400 MHz, D ₂ O) δ 5.96 (tdd, J=1.7, 3.9, 10.5 Hz, 1H), 5.80-5.61 (m, 1H), 3 .65 (br. s, 2H), 3.31 (t, J=6.1 Hz, 2H), 2.49-2.28 (m, 2H).

Step 2: Synthesis of 1-(methanesulfonyl)-1,2,3,6-tetrahydropyridine (39c)

To a suspension of 1,2,3,6-tetrahydropyridine hydrochloride (39b) (97.9 g, 818 mmol) in DCM (1.0 L) was added TEA (248 g, 2.5 mol). The mixture was cooled to 0-5°C and then treated slowly dropwise with methanesulfonyl chloride (112 g, 982 mmol) while maintaining the reaction temperature <20°C. After the addition, the mixture was stirred for an additional 16 hours at room temperature. The reaction was quenched by slow addition of H ₂ O (1 L). The phases were separated. The aqueous layer was extracted with DCM (1.5 L). The combined organic layers were washed successively with saturated aq. NH ₄ Cl (500 ml), saturated aq. NaHCO ₃ (500 ml), saturated aq. NH ₄ Cl (500 ml) and brine (500 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The resulting yellow solid was triturated with DCM/petroleum ether (1:15, 500 ml). The solids were collected by filtration and dried under vacuum to give 1-(methanesulfonyl)-1,2,3,6-tetrahydropyridine (39c) (116 g, 88% yield) as a light yellow solid which was used without further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.86 (dtd, J=1.7, 4.0, 8.1 Hz, 1H), 5.71 (dtd, J=1.2, 3.4 , 8.5 Hz, 1H), 3.76 (quin, J=2.8 Hz, 2H), 3.37 (t, J=5.7 Hz, 2H), 2.81 (s, 3H), 2.26 (tt, J=2.9, 5.7 Hz, 2H).

Step 3: Synthesis of 3-(methanesulfonyl)-7-oxa-3-azabicyclo[4.1.0]heptane (39d)

To a solution of 1-(methanesulfonyl)-1,2,3,6-tetrahydropyridine (39c) (116 g, 720 mmol) in DCM (1.5 L) was added m-CPBA (175 g, 863 mmol) in portions. The mixture was stirred at ambient temperature for 48 hours. TLC analysis indicated consumption of starting material. The heterogeneous mixture was filtered to remove particulate matter. The filtrate was made basic with saturated aq. Na ₂ CO ₃ (1.0 L) and washed with saturated aq. Na ₂ SO ₃ (1.5 L). The aqueous layer was extracted with DCM (2×1.5 L). The combined organic layers were washed with brine (1.5 L), dried over Na ₂ SO ₄ , filtered and concentrated to give 3-(methanesulfonyl)-7-oxa-3-azabicyclo[4.1.0]heptane (39d) (120 g , 94% yield) as a light yellow solid which was used without further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.84 (ddd, J=1.0, 3.6, 14.3 Hz, 1H), 3.57 (d, J=14.3 Hz, 1H) , 3.36 (dd, J=2.0, 3.7 Hz, 1H), 3.34-3.26 (m, 2H), 3.09 (dd, J=4.7, 8.4, 12.9 Hz, 1H), 2.82 (s, 3H), 2.21-2.04 (m, 2H).

Step 4: Synthesis of (3R,4R)-4-amino-1-(methanesulfonyl)piperidin-3-ol (2S)-2-hydroxy-3-phenylpropanoic acid salt (Int-70)

To a solution of 3-(methanesulfonyl)-7-oxa-3-azabicyclo[4.1.0]heptane (39d) (10.0 g, 56 mmol) in MeCN (100 ml) mmol) and NH ₄ OH (14.1 g, 113 mmol). The mixture was stirred at ambient temperature for 48 hours. TLC analysis (1:1 petroleum ether/EtOAc) indicated remaining starting material. The reaction mixture was heated to 40° C. and stirred at this temperature for 36 hours. TLC analysis (1:1 petroleum ether/EtOAc) showed consumption of starting material. The reaction mixture was concentrated to dryness to give rac-(3R,4R)-4-amino-1-(methanesulfonyl)piperidin-3-ol (11 g, crude). The crude mixture containing rac-(3R,4R)-4-amino-1-(methanesulfonyl)piperidin-3-ol (11 g) was dissolved in MeOH (120 ml) and the mixture was refluxed until the solution did not become transparent. The mixture was cooled to room temperature and a solution of (2S)-2-hydroxy-3-phenylpropanoic acid (9.41 g, 56.6 mmol) in MeOH (30 ml) was added. The solution became cloudy followed by heavy precipitation. The mixture was stirred at reflux for 10 minutes and then allowed to cool slowly to room temperature. The solution was stirred at room temperature for 16 hours. The precipitate was collected by filtration. The solids were dissolved in MeOH (30 ml) and stirred at reflux for 10 minutes. The solution was slowly cooled to room temperature. The resulting precipitate was collected by filtration to obtain (3R,4R)-4-amino-1-(methanesulfonyl)piperidin-3-ol (2S)-2-hydroxy-3-phenylpropanoic acid salt (Int-70) (5.0 g, 25% yield as a white solid. Enantiomeric excess (97% ee) was determined for the corresponding N-CBz-protected derivative using chiral SFC on a Chiralpak AS-3 column (4.6×150 mm, particle size 3 μm, 35°C), which was eluted with 5 -40% EtOH/CO ₂ (+0.05% diethylamine) with a flow rate of 2.5 ml/min. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.35-7.13 (m, 5H), 4.14 (dd, J=3.5, 8.2 Hz, 1H), 3.89 (dd , J=2.1, 5.0, 11.7 Hz, 1H), 3.83-3.73 (m, 1H), 3.60 (dt, J=5.1, 10.0 Hz, 1H ), 3.13 (dd, J=3.4, 13.8 Hz, 1H), 2.98 (dd, J=4.5, 9.8, 12.1 Hz, 1H), 2.92- 2.77 (m, 5H), 2.69-2.56 (m, 1H), 2.18-2.02 (m, 1H), 1.78-1.60 (m, 1H).

Getting examples

Example 1 (Scheme A-1): Preparation of (3R,4R)-4-({5-chloro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6 -yl]pyrimidin-2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol

Scheme A-1:

Step 1: Synthesis of 4-fluoro-2-methyl-1-(propan-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- benzimidazole (A-1)

Suspension of 6-bromo-4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazole (Int-46) (90 g, 331.95 mmol), bis (pinacolato) diborone (126 g, 498 mmol), AcOK (80 g, 815.15 mmol), tricyclohexylphosphine (14 g, 49.8 mmol) and Pd(OAc) ₂ (7.45 g, 33.2 mmol) in DMSO (1.0 L) N ₂ was bubbled through and then stirred at 100° C. for 16 hours. TLC analysis (1:1 petroleum ether/EtOAc) indicated complete consumption of starting material. The black suspension was poured into H ₂ O (3.0 L) and extracted with EtOAc (2×3 L). The combined organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (Biotage, 1.0 kg, 0-40% EtOAc/petroleum ether) to give 4-fluoro-2-methyl-1-(propan-2-yl)-6-(4.4 ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazole (A-1) (77 g, 73% yield) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.69 (s, 1H), 7.33 (d, J=10.8 Hz, 1H), 4.77-4.61 (m, 1H), 2 .65 (s, 3H), 1.65 (d, J=7.0 Hz, 6H), 1.36 (s, 12H); m/z (ESI+) for (C ₁₇ H ₂₄ BFN ₂ O ₂ ), 319.2 (M+H) ⁺ .

Stage 2: Synthesis of 6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazole (A-2)

A mixture of 4-fluoro-2-methyl-1-(propan-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazole (A -1) (300 mg, 0.943 mmol), 2,4,5-trichloropyrimidine (259 mg, 0.16 ml, 1.41 mmol) and K ₂ CO ₃ (260 mg, 1.89 mmol) in 1.4 -dioxane (9 ml) and H ₂ O (3 ml) were purged with N ₂ for 5 min. Pd(PPh ₃ ) ₄ (54.5 mg, 0.047 mmol) was added and the mixture was purged with N ₂ for an additional 10 minutes. The mixture was stirred at 90°C for 16 h, then cooled to ambient temperature, diluted with H ₂ O (15 ml) and was extracted with EtOAc (3×10 ml). The combined organic phases were washed with brine (10 ml), dried over Na ₂ SO ₄ , filtered and concentrated. To this crude mixture was added the second crude mixture from the reaction in a similar manner in an amount of 100 mg. The residue was purified by flash chromatography (SiO ₂ , 100% EtOAc) to give 6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-2-methyl-1-(propan-2-yl)-1H -benzimidazole (A-2) (420 mg, 98% yield). m/z (ESI+) for (C ₁₅ H ₁₃ N ₄ FCl ₂ ), 338.9 (M+H) ⁺ .

Step 3: Synthesis of (3R,4R)-4-({5-chloro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2 -yl}amino)-1-(methanesulfonyl)piperidin-3-ol (Example A1)

To yellow suspension of 6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazole (A-2) (210 mg, 0.619 mmol) DIPEA (240 mg, 0.331 ml, 1.86 mmol) and (3R,4R)-4-amino-1-(methanesulfonyl)piperidin-3-ol (Int-69) (241 mg, 1.24 mmol). The mixture was stirred at 120°C for 16 h and then diluted with H ₂ O (20 ml) and was extracted with EtOAc (3×20 ml). The combined organic phases were washed with brine (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by preparative HPLC on an Agela Durashell C18 column (150×25 mm, particle size 5 μm; column temperature 25° C.) eluted with 34-54% MeCN/H ₂ O (+0.05% NH ₄ OH ) at a flow rate of 25 ml/min to give (3R,4R)-4-({5-chloro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6 -yl]pyrimidin-2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol (Example A1) (54.7 mg, 19% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.41 (s, 1H), 8.02-7.79 (m, 1H), 7.54-7.27 (m, 2H), 5, 24 (d, J=4.5 Hz, 1H), 4.86-4.71 (m, 1H), 3.86-3.74 (m, 1H), 3.60 (br.d, J= 9.5 Hz, 2H), 3.53-3.45 (m, 1H), 2.94-2.79 (m, 4H), 2.69-2.59 (m, 4H), 2.07 (s, 1H), 1.62-1.46 (m, 7H); m/z (ESI+) for (C ₂₁ H ₂₆ ClFN ₆ O ₃ S), 497.3 (M+H) ⁺ .

The examples in the table below were synthesized according to the methods used for the synthesis of (3R,4R)-4-({5-chloro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H -benzimidazol-6-yl]pyrimidin-2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol (Example A1). The following examples have been synthesized with non-breaking modifications or substitutions to the illustrated techniques that a person skilled in the art could implement. If necessary, separation of the enantiomers was carried out by standard methods known in the art, such as chiral SFC or HPLC, to obtain individual enantiomers.

Example number Structure/Name HCMS NMR A2

(3R,4R)-4-({5-фтор-4-[4-фтор-2-метил-1-(пропан-2-ил)-1H-бензимидазол-6-ил]пиримидин-2-ил}амино)-1-(метансульфонил)пиперидин-3-ол

(3R,4R)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino )-1-(methanesulfonyl)piperidin-3-ol 481.2 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.44 (d, J=4.03 Hz, 1H), 8.16-8.03 (m, 1H), 7.71-7.50 ( m, 1H), 7.32-7.17 (m, 1H), 5.28-5.19 (m, 1H), 4.90-4.74 (m, 1H), 3.87-3, 72 (m, 1H), 3.70-3.57 (m, 2H), 3.54-3.45 (m, 1H), 2.92 (s, 3H), 2.89-2.83 ( m, 1H), 2.73-2.66 (m, 1H), 2.64 (s, 3H), 2.36-2.30 (m, 1H), 1.60 (d, J=6, 85Hz, 6H), 1.57-1.50(m, 1H) A3

4-(1-tert-Butyl-4-fluoro-1H-benzimidazol-6-yl)-5-fluoro-N-(1-methylpiperidin-4-yl)pyrimidin-2-amine 401.1 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, CD ₃ OD) δ 8.51 (br. s, 1H), 8.43-8.34 (m, 3H), 7.82 (d, J=12.0 Hz, 1H ), 4.19-4.06 (m, 1H), 3.50-3.40 (m, 2H), 3.29-3.13 (m, 2H), 2.83 (s, 3H), 2.35-2.25 (m, 2H), 1.95-1.82 (m, 11H) A4

(3R,4R)-4-({4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-1- (methanesulfonyl)piperidin-3-ol 463.3 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.35 (d, J=5.3 Hz, 1H), 8.22 (s, 1H), 7.76 (d, J=12.3 Hz , 1H), 7.32 (d, J=5.5 Hz, 1H), 7.14 (d, J=7.8 Hz, 1H), 5.27 (br.d, J=4.0 Hz , 1H), 4.90-4.75 (m, 1H), 3.84 (br.s, 1H), 3.73-3.44 (m, 3H), 3.05-2.87 (m , 4H), 2.69-2.65 (m, 1H), 2.62 (s, 3H), 2.19-2.00 (m, 1H), 1.61 (d, J=6.3 Hz, 7H) A5

(3R,4R)-4-({4-[5-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-1- (methanesulfonyl)piperidin-3-ol 463.1 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.39-8.09 (m, 2H), 7.47-7.41 (m, 1H), 7.20 (d, J=7.8 Hz, 1H), 7.03 (br.s, 1H), 5.27 (br.s, 1H), 4.85-4.70 (m, 1H), 3.82 (br.s, 1H) , 3.75-3.60 (m, 2H), 3.56-3.45 (m, 1H), 2.91 (s, 3H), 2.88-2.79 (m, 1H), 2 .70-2.60 (m, 1H), 2.59 (s, 3H), 2.20-2.00 (m, 1H), 1.65-1.60 (m, 7H) A6

(3R,4R)-4-({5-chloro-4-[5-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino )-1-(methanesulfonyl)piperidin-3-ol 497.3 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.42 (s, 1H), 7.73 (d, J=6.0 Hz, 1H), 7.66-7.48 (m, 1H) , 7.44 (d, J=10.5 Hz, 1H), 5.22 (d, J=4.3 Hz, 1H), 4.85-4.70 (m, 1H), 3.79 ( br.s, 1H), 3.65-3.55 (m, 2H), 3.50-3.40 (m, 1H), 2.88 (br.s, 4H), 2.70-2, 60 (m, 1H), 2.58 (s, 3H), 2.08 (s, 1H), 1.60-1.45 (m, 7H) A7

(3R,4R)-4-({5-fluoro-4-[5-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino )-1-(methanesulfonyl)piperidin-3-ol 481.3 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.42 (d, J=2.0 Hz, 1H), 7.82 (d, J=6.0 Hz, 1H), 7.46 (d , J=10.8 Hz, 1H), 7.32 (br. s, 1H), 5.21 (d, J=4.5 Hz, 1H), 4.85-4.70 (m, 1H) , 3.73 (br. s, 1H), 3.67-3.56 (m, 2H), 3.50-3.40 (m, 1H), 2.88 (s, 3H), 2.86 -2.78(m, 1H), 2.70-2.60(m, 1H), 2.59(s, 3H), 2.07(s, 1H), 1.60-1.45(m , 7H) A8

(3R,4R)-4-{[5-chloro-4-(4-fluoro-1,2-dimethyl-1H-benzimidazol-6-yl)pyrimidin-2-yl]amino}-1-(methanesulfonyl)piperidine -3-ol 469.2 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.42 (s, 1H), 7.77 (br. s, 1H), 7.60-7.31 (m, 2H), 5.22 ( d, J=4.5 Hz, 1H), 3.81 (br. s, 1H), 3.79 (s, 3H), 3.67-3.55 (m, 2H), 3.50-3 .40 (m, 1H), 2.89 (s, 3H), 2.88-2.82 (m, 1H), 2.70-2.60 (m, 1H), 2.58 (s, 3H ), 2.04 (br. s, 1H), 1.59-1.42 (m, 1H) A9

(3R,4R)-4-{[5-chloro-4-(5-fluoro-1,1-dimethyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl)pyrimidine -2-yl]amino}-1-(methanesulfonyl)piperidin-3-ol 509.3 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.42 (s, 1H), 7.84 (br. s, 1H), 7.59-7.32 (m, 2H), 5.22 ( br.s, 1H), 3.78 (br.s, 1H), 3.59 (br.d, J=10.0 Hz, 2H), 3.48 (br.d, J=11.7 Hz , 1H), 3.08 (t, J=7.5 Hz, 2H), 2.89 (s, 3H), 2.86-2.79 (m, 1H), 2.69-2.61 ( m, 1H), 2.58-2.53 (m, 2H), 2.05 (br. s, 1H), 1.62 (s, 6H), 1.52 (br. d, J=11, 7Hz, 1H) A10

(3R,4R)-4-({5-chloro-4-[(4S)-9-fluoro-4-methyl-3,4-dihydro-1H-[1,4]oxazino[4,3-a] benzimidazol-7-yl]pyrimidin-2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol 511.2 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.44 (s, 1H), 7.89 (br. s, 1H), 7.58-7.39 (m, 2H), 5.22 ( d, J=4.5 Hz, 1H), 5.09-5.03 (m, 1H), 4.97-4.91 (m, 1H), 4.70 (br.d, J=5, 5 Hz, 1H), 4.17-4.10 (m, 1H), 4.06-3.98 (m, 1H), 3.82 (br.d, J=5.8 Hz, 1H), 3.67-3.57 (m, 2H), 3.50-3.40 (m, 1H), 2.93-2.82 (m, 4H), 2.70-2.60 (m, 1H ), 2.11-2.00 (m, 1H), 1.60-1.45 (m, 4H) A11

(3R,4R)-4-({5-chloro-4-[(4R)-9-fluoro-4-methyl-3,4-dihydro-1H-[1,4]oxazino[4,3-a] benzimidazol-7-yl]pyrimidin-2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol 511.2 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.44 (s, 1H), 7.82 (s, 1H), 7.59-7.44 (m, 2H), 5.23 (d, J=4.8 Hz, 1H), 5.13-5.07 (m, 1H), 5.02-4.96 (m, 1H), 4.42 (dd, J=3.0, 12, 0 Hz, 1H), 4.19 (ddd, J=3.5, 6.3, 10.0 Hz, 1H), 3.90-3.76 (m, 2H), 3.68-3.56 (m, 2H), 3.50-3.40 (m, 1H), 2.90 (s, 3H), 2.88-2.81 (m, 1H), 2.73-2.61 (m , 1H), 2.11-2.00 (m, 1H), 1.62-1.46 (m, 1H), 1.38 (d, J=6.3 Hz, 3H) A12

1,5-anhydro-3-[(5-chloro-4-{4-fluoro-2-[(1S)-1-hydroxyethyl]-1-(propan-2-yl)-1H-benzimidazol-6-yl }pyrimidin-2-yl)amino]-2,3-dideoxy-D-threo-pentitol 450.1 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, CD ₃ OD) δ 8.37-8.31 (m, 1H), 8.05 (s, 1H), 7.50 (br. d, J=11.5 Hz, 1H ), 5.39-5.29 (m, 1H), 5.23 (k, J=6.6 Hz, 1H), 4.03-3.88 (m, 3H), 3.63 (dt, J=4.8, 9.4 Hz, 1H), 3.48 (dt, J=2.0, 11.6 Hz, 1H), 3.21 (dd, J=9.8, 11.0 Hz , 1H), 2.19-2.09 (m, 1H), 1.75-1.53 (m, 10H) A13

1,5-anhydro-3-[(5-chloro-4-{4-fluoro-2-[(1R)-1-hydroxyethyl]-1-(propan-2-yl)-1H-benzimidazol-6-yl }pyrimidin-2-yl)amino]-2,3-dideoxy-D-threo-pentitol 450.3 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.43 (s, 1H), 8.09-7.83 (m, 1H), 7.59-7.32 (m, 2H), 5, 79 (br.d, J=6.4 Hz, 1H), 5.20-5.15 (m, 1H), 5.14-5.06 (m, 1H), 4.96 (br.d, J=5.2 Hz, 1H), 3.88-3.78 (m, 3H), 3.51 (br.s, 1H), 3.10-2.98 (m, 1H), 1.96 (br. s, 1H), 1.65-1.55 (m, 10H). one signal closed by residual water A14

(3R,4R)-4-({5-chloro-4-[4-fluoro-1-(oxolan-3-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-1- (methanesulfonyl)piperidin-3-ol 511.1 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.44 (s, 2H), 7.98 (br. s, 1H), 7.64-7.36 (m, 2H), 5.36 ( br.s, 1H), 5.22 (d, J=4.5 Hz, 1H), 4.20-4.12 (m, 1H), 4.07 (br.d, J=9.0 Hz , 1H), 4.01-3.94 (m, 1H), 3.88-3.78 (m, 2H), 3.67-3.56 (m, 2H), 3.49 (s, 1H ), 2.90 (s, 3H), 2.87-2.81 (m, 1H), 2.66 (b.t., J=10.8 Hz, 1H), 2.61-2.54 ( m, 1H), 2.32-2.20 (m, 1H), 2.10-1.99 (m, 1H), 1.60-1.47 (m, 1H) A15

(3R,4R)-4-{[5-chloro-4-(1-cyclopropyl-4-fluoro-1H-benzimidazol-6-yl)pyrimidin-2-yl]amino}-1-(methanesulfonyl)piperidine-3 -ol 481.2 [M+H] ⁺ (ESI) ¹ H NMR (4500 MHz, CD ₃ OD) δ 8.38 (s, 1H), 8.35 (s, 1H), 8.06 (s, 1H), 7.56 (dd, J=1.0 , 11.7 Hz, 1H), 3.98-3.92 (m, 1H), 3.85 (ddd, J=1.8, 4.7, 11.7 Hz, 1H), 3.76 ( dt, J=4.9, 9.0 Hz, 1H), 3.72-3.67 (m, 1H), 3.60 (m, 1H), 2.96 (dt, J=2.7, 11.9 Hz, 1H), 2.90 (s, 3H), 2.77 (dd, J=9.5, 11.6 Hz, 1H), 2.25 (br.dd, J=3.7 , 13.4 Hz, 1H), 1.80-1.61 (m, 1H), 1.31-1.22 (m, 2H), 1.20-1.09 (m, 2H) A16

(3R,4R)-4-({5-chloro-4-[4-chloro-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-1- (methanesulfonyl)piperidin-3-ol 521.1 [M+Na] ⁺ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.58 (s, 1H), 8.44 (s, 1H), 8.04 (s, 1H), 7.67 (d, J=1, 1 Hz, 1H), 7.55 (br. s, 1H), 5.23 (d, J=4.5 Hz, 1H), 4.83 (td, J=6.7, 13.4 Hz, 1H), 3.81 (br.d, J=5.6 Hz, 1H), 3.70-3.55 (m, 2H), 3.50-3.40 (m, 1H), 2.96 -2.77 (m, 4H), 2.72-2.61 (m, 1H), 2.06 (br.s, 1H), 1.64-1.46 (m, J=6.7 Hz , 7H) A17

(3R,4R)-4-{[4-(4-ethyl-9-fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazol-7-yl)-5 -fluoropyrimidin-2-yl]amino}-1-(methanesulfonyl)piperidin-3-ol 509.0 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.45 (d, J=4.0 Hz, 1H), 8.05 (s, 1H), 7.70 (d, J=12.0 Hz , 1H), 7.24 (d, J=7.8 Hz, 1H), 5.21 (d, J=4.5 Hz, 1H), 5.13-5.02 (m, 1H), 4 .99-4.89 (m, 1H), 4.54 (br. s, 1H), 4.22 (d, J=12.0 Hz, 1H), 4.04 (dd, J=3.5 , 12.3 Hz, 1H), 3.78 (br. s, 1H), 3.67-3.55 (m, 2H), 3.55-3.45 (m, 1H), 2.99- 2.83 (m, 4H), 2.75-2.61 (m, 1H), 2.21-2.05 (m, 1H), 2.00-1.84 (m, 2H), 1, 65-1.45 (m, 1H), 0.99 (t, J=7.5 Hz, 3H); [α] _D ²⁰ = -66 (c=0.1, MeOH) A18

(3R,4R)-4-{[5-fluoro-4-(9-fluoro-4,4-dimethyl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole- 7-yl)pyrimidin-2-yl]amino}-1-(methanesulfonyl)piperidin-3-ol 509.1 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.45 (d, J=3.8 Hz, 1H), 8.18 (s, 1H), 7.68 (br. d, J=11, 8 Hz, 1H), 7.26 (br.d, J=7.8 Hz, 1H), 5.23 (d, J=4.5 Hz, 1H), 4.99 (s, 2H), 3 .93 (s, 2H), 3.78 (br.s, 1H), 3.69-3.57 (m, 2H), 3.55-3.45 (m, 1H), 2.93-2 .83 (m, 4H), 2.71-2.65 (m, 1H), 2.11 (br. s, 1H), 1.65 (s, 6H), 1.56-1.46 (m , 1H) A19

1,5-anhydro-2,3-dideoxy-3-{[5-fluoro-4-(9-fluoro-4,4-dimethyl-3,4-dihydro-1H-[1,4]oxazino[4, 3-a]benzimidazol-7-yl)pyrimidin-2-yl]amino}-D-threo-pentitol 432.1 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.44 (d, J=4.0 Hz, 1H), 8.21 (br. s, 1H), 7.67 (d, J=12, 0 Hz, 1H), 7.23 (d, J=7.8 Hz, 1H), 5.02-4.93 (m, 3H), 3.93 (s, 2H), 3.87-3, 76 (m, 3H), 3.55-3.45 (m, 1H), 3.32 (br.s, 1H), 3.06 (t, J=10.4 Hz, 1H), 2.00 (br.s, 1H), 1.65 (d, J=1.8 Hz, 6H), 1.56-1.44 (m, 1H) A20

1,5-anhydro-3-{[5-chloro-4-(9-fluoro-1,4-dimethyl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole- 7-yl)pyrimidin-2-yl]amino}-2,3-dideoxy-D-threo-pentitol 447.8 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.33 (s, 1H), 7.64 (d, J=1.2 Hz, 1H), 7.47 (dd, J=1.2, 11, 2 Hz, 1H), 5.29 (br.d, J=5.9 Hz, 1H), 4.99 (c, J=6.6 Hz, 1H), 4.48 (c, J=6, 8 Hz, 1H), 4.12 (d, J=1.5 Hz, 2H), 4.06 (dd, J=5.0, 11.4 Hz, 1H), 3.99 (br.dd, J=4.3, 11.3 Hz, 1H), 3.89-3.80 (m, 1H), 3.63 (dt, J=5.0, 9.4 Hz, 1H), 3.46 (dt, J=2.1, 11.8 Hz, 1H), 3.18 (t, J=10.7 Hz, 1H), 2.10-2.01 (m, 1H), 1.80 ( d, J=6.6 Hz, 3H), 1.77-1.67 (m, 1H), 1.64 (d, J=6.6 Hz, 3H) A21

1,5-anhydro-3-{[5-chloro-4-(9-fluoro-1,4-dimethyl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole- 7-yl)pyrimidin-2-yl]amino}-2,3-dideoxy-D-threo-pentitol 447.8 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.33 (s, 1H), 7.62 (s, 1H), 7.47 (dd, J=1.1, 11.2 Hz, 1H), 5 .28 (br.d, J=5.7 Hz, 1H), 5.06-4.72 (m, 2H), 4.48 (c, J=6.6 Hz, 1H), 4.12 ( d, J=1.7 Hz, 2H), 4.06 (dd, J=5.0, 11.4 Hz, 1H), 3.99 (br.dd, J=4.3, 11.7 Hz , 1H), 3.90-3.80 (m, 1H), 3.63 (dt, J=4.8, 9.4 Hz, 1H), 3.51-3.42 (m, 1H), 3.18 (t, J=10.6 Hz, 1H), 2.09-2.01 (m, 1H), 1.81 (d, J=6.6 Hz, 3H), 1.77-1 .69 (m, 1H), 1.64 (d, J=6.6 Hz, 3H) A22

1,5-anhydro-3-{[5-chloro-4-(9-fluoro-2,4,4-trimethyl-1,2,3,4-tetrahydropyrazino[1,2-a]benzimidazol-7-yl )pyrimidin-2-yl]amino}-2,3-dideoxy-D-threo-pentitol 461.1 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.41 (s, 1H), 8.09-7.88 (m, 1H), 7.47 (br. s, 2H), 4.94 ( brd, J=5.4 Hz, 1H), 3.86-3.71 (m, 5H), 3.50 (br.s, 1H), 3.29-3.25 (m, 1H) , 3.03 (br. t, J=10.3 Hz, 1H), 2.75 (s, 2H), 2.44 (s, 3H), 1.95 (br. s, 1H), 1, 65 (s, 6H), 1.56-1.48 (m, 1H) A23

1,5-anhydro-3-({5-chloro-4-[2-(1-cyclopropyl-1-hydroxyethyl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-6-yl ]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol 490.0 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.42 (s, 1H), 8.12-7.87 (m, 1H), 7.63-7.26 (m, 2H), 5, 90-5.75 (m, 1H), 5.64 (s, 1H), 4.98 (br.d, J=5.0 Hz, 1H), 3.94-3.76 (m, 3H) , 3.58-3.48 (m, 1H), 3.32-3.27 (m, 1H), 3.03 (br. t, J=10.5 Hz, 1H), 2.05-1 .87 (m, 1H), 1.70-1.56 (m, 9H), 1.51 (br.d, J=13.1 Hz, 1H), 1.42-1.31 (m, 1H ), 0.74-0.61 (m, 1H), 0.55-0.34 (m, 3H); [α] _D ²² = -6 (c=0.1, MeOH) A24

1,5-anhydro-3-({5-chloro-4-[2-(1-cyclopropyl-1-hydroxyethyl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-6-yl ]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol 490.1 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.42 (s, 1H), 8.13-7.81 (m, 1H), 7.62-7.15 (m, 2H), 5, 90-5.75 (m, 1H), 5.64 (s, 1H), 4.97 (br.d, J=5.0 Hz, 1H), 3.94-3.70 (m, 3H) , 3.59-3.47 (m, 1H), 3.32-3.25 (m, 1H), 3.03 (br. t, J=10.3 Hz, 1H), 2.04-1 .84 (m, 1H), 1.70-1.57 (m, 9H), 1.55-1.45 (m, 1H), 1.42-1.31 (m, 1H), 0.74 -0.63 (m, 1H), 0.59-0.30 (m, 3H); [α] _D ²² = -22 (c=0.1, MeOH) A25

(3R,4R)-4-({5-chloro-4-[7-fluoro-2-methyl-3-(propan-2-yl)-2H-indazol-5-yl]pyrimidin-2-yl}amino )-1-(methanesulfonyl)piperidin-3-ol 496.9 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.40 (s, 1H), 8.18 (br. s, 1H), 7.57-7.34 (m, 2H), 5.22 ( br.s, 1H), 4.17 (s, 3H), 3.79 (br.s, 1H), 3.67-3.56 (m, 3H), 3.55-3.45 (m, 1H), 2.89 (s, 3H), 2.87-2.80 (m, 1H), 2.66 (br. t, J=10.5 Hz, 1H), 2.05 (br. s , 1H), 1.60-1.40 (m, 1H), 1.46 (br.d, J=6.7 Hz, 6H) A26

(3R,4R)-4-{[5-chloro-4-(7-fluoro-1,1-dimethyl-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazole- 9-yl)pyrimidin-2-yl]amino}-1-(methanesulfonyl)piperidin-3-ol 525.1 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.42 (s, 1H), 8.04 (br. s, 1H), 7.68-7.24 (m, 2H), 5.22 ( e, J=4.5 Hz, 1H), 4.46 (t, J=4.8 Hz, 2H), 4.22 (br. t, J=4.6 Hz, 2H), 3.93- 3.72 (m, 1H), 3.60 (br.d, J=8.8 Hz, 2H), 3.49 (br.d, J=11.3 Hz, 1H), 2.90 (s , 3H), 2.88-2.80 (m, 1H), 2.74-2.55 (m, 2H), 2.07 (br.d, J=10.8 Hz, 1H), 1, 70 (s, 6H), 1.53 (br.d, J=10.0 Hz, 1H) A27

1,5-anhydro-3-{[5-chloro-4-(7-fluoro-1,1-dimethyl-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazole- 9-yl)pyrimidin-2-yl]amino}-2,3-dideoxy-D-threo-pentitol 448.0 [M+H] ⁺ (ESI) ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.40 (s, 1H), 8.03 (br. s, 1H), 7.57-7.34 (m, 2H), 4.94 ( e, J=5.3 Hz, 1H), 4.45 (t, J=5.0 Hz, 2H), 4.21 (t, J=4.9 Hz, 2H), 3.86-3, 77 (m, 3H), 3.49 (br.d, J=4.1 Hz, 1H), 3.03 (t, J=10.5 Hz, 1H), 1.94 (br. s, 1H ), 1.68 (s, 6H), 1.57-1.40 (m, 1H); one proton is covered by the solvent peak A28

(3R,4R)-4-({5-chloro-4-[2-methyl-3-(propan-2-yl)-2H-indazol-5-yl]pyrimidin-2-yl}amino)-1- (methanesulfonyl)piperidin-3-ol 479.3 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.38 (s, 1H), 8.32-8.22 (m, 1H), 7.59 (br. s, 2H), 7.51- 7.35(m, 1H), 5.22(d, J=4.3Hz, 1H), 4.13(s, 3H), 3.84-3.74(m, 1H), 3.65 -3.53(m, 3H), 3.53-3.47(m, 1H), 2.89(s, 3H), 2.87-2.78(m, 1H), 2.69-2 .60 (m, 1H), 2.13-1.97 (m, 1H), 1.57-1.50 (m, 1H), 1.46 (d, J=6.8 Hz, 6H) A29

(3R,4R)-4-({5-chloro-4-[3-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-5-yl]pyrimidin-2-yl}amino)- 1-(methanesulfonyl)piperidin-3-ol 495.3 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.39 (s, 1H), 8.37-8.24 (m, 1H), 7.60 (br. d, J=7.0 Hz, 2H), 7.53-7.38 (m, 1H), 5.76 (s, 1H), 5.22 (d, J=4.5 Hz, 1H), 4.33 (s, 3H), 3.83-3.74 (m, 1H), 3.59 (m, 2H), 3.51-3.44 (m, 1H), 2.89 (s, 3H), 2.87-2, 79 (m, 1H), 2.68-2.60 (m, 1H), 2.10-1.99 (m, 1H), 1.75 (s, 6H), 1.58-1.46 ( m, 1H) A30

(3R,4R)-4-({5-chloro-4-[4-fluoro-2-(oxetan-3-yl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidine -2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol 539.2 [M+H] ⁺ (APCI) ¹ H NMR (400 MHz, DMSO-d ₆ , VT 80°C) δ 8.39 (s, 1H), 7.95 (d, J=1.0 Hz, 1H), 7.44 (dd, J =0.9, 11.9 Hz, 1H), 7.18 (d, J=7.7 Hz, 1H), 5.05-4.93 (m, 5H), 4.83-4.71 ( m, 1H), 4.64-4.50 (m, 1H), 3.88-3.75 (m, 1H), 3.72-3.60 (m, 1H), 3.59-3, 46 (m, 1H), 3.20 (d, J=4.6 Hz, 2H), 2.95-2.83 (m, 4H), 2.78-2.63 (m, 1H), 2 .12 (dd, J=3.4, 13.4Hz, 1H), 1.56 (d, J=6.8Hz, 6H) A31

(3R,4R)-4-({5-chloro-4-[4-fluoro-2-(oxetan-2-yl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidine -2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol 538.9 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, CD ₃ OD) δ 8.36 (s, 1H), 8.09-7.96 (m, 1H), 7.56-7.47 (m, 1H), 6.19 (dd, J=7.1, 7.9 Hz, 1H), 4.91-4.88 (m, 1H), 4.86-4.82 (m, 1H), 4.78-4.69 (m, 1H), 4.00-3.88 (m, 1H), 3.86-3.78 (m, 1H), 3.76-3.71 (m, 1H), 3.70-3 .64 (m, 1H), 3.51-3.40 (m, 1H), 3.21-3.08 (m, 1H), 2.98-2.89 (m, 1H), 2.88 (s, 3H), 2.79-2.68 (m, 1H), 2.27-2.17 (m, 1H), 1.74-1.62 (m, 7H) A32

(3R,4R)-4-({5-chloro-4-[4-fluoro-2-(oxetan-2-yl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidine -2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol 539.1 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, CD ₃ OD) δ 8.36 (s, 1H), 8.09-7.97 (m, 1H), 7.56-7.47 (m, 1H), 6.19 (dd, J=7.0, 7.9 Hz, 1H), 4.91-4.88 (m, 1H), 4.86-4.82 (m, 1H), 4.78-4.69 (m, 1H), 4.00-3.89 (m, 1H), 3.86-3.78 (m, 1H), 3.77-3.62 (m, 2H), 3.52-3 .38 (m, 1H), 3.20-3.08 (m, 1H), 2.98-2.90 (m, 1H), 2.88 (s, 3H), 2.79-2.67 (m, 1H), 2.31-2.16 (m, 1H), 1.71-1.63 (m, J=1.0, 6.9 Hz, 7H) A33

1,5-anhydro-3-({4-[2-carbamoyl-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-6-yl]-5-chloropyrimidin-2-yl}amino) -2,3-dideoxy-D-threo-pentitol 449.1 [M+H] ⁺ (ESI) ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.51-8.38 (m, 2H), 8.18-7.99 (m, 2H), 7.65-7.42 (m, 2H ), 6.04-5.80 (m, 1H), 4.98-4.91 (m, 1H), 3.90-3.73 (m, 3H), 3.57-3.44 (m , 1H), 3.10-2.96 (m, 1H), 2.05-1.85 (m, 1H), 1.62 (d, J=7.0 Hz, 6H), 1.53- 1.37 (m, 1H) A34

1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(methylcarbamoyl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl }amino)-2,3-dideoxy-D-threo-pentitol 463.2 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, CD ₃ OD) δ 8.36 (s, 1H), 8.15-8.04 (m, 1H), 7.54 (d, J=11.5 Hz, 1H), 6.04-5.83(m, 1H), 4.04-3.84(m, 3H), 3.70-3.55(m, 1H), 3.52-3.42(m, 1H ), 3.25-3.15 (m, 1H), 2.97 (s, 3H), 2.17-2.06 (m, 1H), 1.70 (d, J=6.8 Hz, 6H), 1.67-1.57 (m, 1H) A35

1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1H-benzimidazol-6-yl ]pyrimidin-2-yl}amino)-2,3-dideoxy-erythro-pentitol 464.1 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.44 (s, 1H), 8.05-7.87 (m, 1H), 7.53-7.27 (m, 1H), 7, 06-6.90 (m, 1H), 5.98-5.66 (m, 2H), 5.06-4.75 (m, 1H), 4.06-3.94 (m, 1H), 3.87-3.68 (m, 3H), 3.48-3.38 (m, 2H), 2.01-1.83 (m, 1H), 1.66 (s, 6H), 1, 63-1.55 (m, 7H); [α] _D ²⁰ = -41.9 (c=0.14, MeOH) A36

1,5-anhydro-3-({5-chloro-4-[1-(1,1-difluoropropan-2-yl)-4-fluoro-2-(1-hydroxyethyl)-1H-benzimidazol-6-yl ]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol 485.9 [M+H] ⁺ (ESI) ¹ H NMR (700 MHz, DMSO-d ₆ ) δ 8.42 (s, 1H), 8.13-7.73 (m, 1H), 7.60-7.27 (m, 2H), 6.63 -6.40(m, 1H), 6.00-5.82(m, 1H), 5.55-5.41(m, 1H), 5.22-5.13(m, 1H), 5 .01-4.85 (m, 1H), 3.91-3.74 (m, 3H), 3.53-3.45 (m, 1H), 3.07-2.97 (m, 1H) , 2.04-1.85 (m, 1H), 1.68 (d, J=7.1 Hz, 3H), 1.62 (d, J=6.7 Hz, 3H), 1.55- 1.42 (m, 1H); [α] _D ²² = -37.3 (c=0.1, MeOH)

Example A37 (Scheme A-2): Preparation of (3R,4R)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6 -yl]pyrimidin-2-yl}amino)piperidin-3-ol

Scheme A-2:

A solution of tert-butyl-(3R,4R)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin- 2-yl}amino)-3-hydroxypiperidine-1-carboxylate (A-3) (prepared as in Example A1, 1.25 g, 2.49 mmol) in DCM (10 ml) was treated with TFA (10 ml) and then stirred at ambient temperature for 1 h. The mixture was concentrated and the crude residue was dissolved in DCM (10 ml). The pH was adjusted to ~7-8 with NH ₄ OH. The product was extracted with water (20 ml). The aqueous phase was washed with DCM (3×15 ml). A white solid formed in the aqueous layer which was collected by filtration to give (3R,4R)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H- benzimidazol-6-yl]pyrimidin-2-yl}amino)piperidin-3-ol (Example A37) (880 mg, 88% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.47 (d, J=3.8 Hz, 1H), 8.10 (s, 1H), 7.73-7.57 (m, 1H) , 7.51-7.39(m, 1H), 5.69-5.62(m, 1H), 4.90-4.72(m, 1H), 4.43-4.30(m, 1H), 4.08-3.93(m, 1H), 3.90-3.77(m, 1H), 3.50-3.39(m, 2H), 3.07-2.96( m, 1H), 2.95-2.82 (m, 1H), 2.63 (s, 3H), 2.28-2.15 (m, 1H), 1.74-1.64 (m, 1H), 1.59 (d, J=6.8 Hz, 6H); m/z (ESI+) for (C ₂₀ H ₂₄ F ₂ N ₆ O), 403.1 (M+H) ⁺ .

Example A38 (Scheme A-3): Preparation of (3R,4R)-4-[(4-{1-[(2R)-1-aminopropan-2-yl]-4-fluoro-2-methyl-1H-benzimidazole -6-yl}-5-chloropyrimidin-2-yl)amino]-1-(methanesulfonyl)piperidin-3-ol

Scheme A-3:

To a solution of tert-butyl-{(2R)-2-[6-(5-chloro-2-{[(3R,4R)-3-hydroxy-1-(methanesulfonyl)piperidin-4-yl]amino}pyrimidine) -4-yl)-4-fluoro-2-methyl-1H-benzimidazol-1-yl]propyl}carbamate (A-4) (prepared as in Example A1, 130 mg, 0.212 mmol) in MeOH (2.5 ml) was added dropwise a solution of HCl (4.0 M in 1,4-dioxane, 2.5 ml) at 0°C. After the addition, the reaction solution was stirred at room temperature for 2 hours. LCMS analysis showed consumption of the starting material to form a mass of the desired product. The reaction mixture was concentrated to dryness. The residue was purified by preparative HPLC on a DuraShell column (150×25 mm, particle size 5 μm), which was eluted with 7-37% MeCN/H ₂ O (+0.05% HCl) at a flow rate of 30 ml/min to obtain ( 3R,4R)-4-[(4-{1-[(2R)-1-aminopropan-2-yl]-4-fluoro-2-methyl-1H-benzimidazol-6-yl}-5-chloropyrimidin-2 -yl)amino]-1-(methanesulfonyl)piperidin-3-ol (Example A38) (39.5 mg, 34% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.39 (s, 1H), 8.06-7.97 (m, 1H), 7.67-7.52 (m, 1H), 5, 06-4.79 (m, 1H), 3.81-3.70 (m, 1H), 3.66-3.54 (m, 3H), 3.51-3.43 (m, 1H), 3.42-3.33(m, 1H), 2.85(s, 3H), 2.82-2.77(m, 1H), 2.74(s, 3H), 2.68-2, 56 (m, 1H), 2.05-1.96 (m, 1H), 1.64 (d, J=6.8 Hz, 3H), 1.58-1.45 (m, 1H); m/z (ESI+) for (C ₂₁ H ₂₇ ClFN ₇ O ₃ S), 512.2 (M+H) ⁺ .

The examples in the table below were synthesized according to the methods used for the synthesis of (3R,4R)-4-({5-chloro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H -benzimidazol-6-yl]pyrimidin-2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol (Example A37) (Scheme A-2) and (3R,4R)-4-[(4-{ 1-[(2R)-1-aminopropan-2-yl]-4-fluoro-2-methyl-1H-benzimidazol-6-yl}-5-chloropyrimidin-2-yl)amino]-1-(methanesulfonyl)piperidine -3-ol (Example A38) (Scheme A-3). The following examples have been synthesized with non-critical modifications or substitutions to the illustrated techniques that a person skilled in the art could implement. If necessary, separation of the enantiomers was carried out by standard methods known in the art, such as chiral SFC or HPLC, to obtain individual enantiomers.

Example number Structure/Name HCMS NMR A39

(3R,4R)-4-[(4-{1-[(2S)-1-аминопропан-2-ил]-4-фтор-2-метил-1H-бензимидазол-6-ил}-5-хлорпиримидин-2-ил)амино]-1-(метансульфонил)пиперидин-3-ол

(3R,4R)-4-[(4-{1-[(2S)-1-aminopropan-2-yl]-4-fluoro-2-methyl-1H-benzimidazol-6-yl}-5-chloropyrimidin- 2-yl)amino]-1-(methanesulfonyl)piperidin-3-ol 534.2 [M+Na] ⁺ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.45-8.27 (m, 1H), 8.03-7.87 (m, 1H), 7.65-7.49 (m, 1H ), 5.08-4.85 (m, 1H), 3.83-3.68 (m, 1H), 3.67-3.56 (m, 2H), 3.54-3.35 (m , 2H), 2.91-2.79 (m, 4H), 2.75-2.61 (m, 4H), 2.12-1.95 (m, 1H), 1.71-1.50 (m, 4H) A40

(3R,4R)-4-({4-[1-(2-aminopropyl)-4-fluoro-2-methyl-1H-benzimidazol-6-yl]-5-chloropyrimidin-2-yl}amino)-1 -(methanesulfonyl)piperidin-3-ol 512.2 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.39 (s, 1H), 8.01-7.82 (m, 1H), 7.58-7.31 (m, 1H), 4, 48-4.34 (m, 2H), 3.82-3.72 (m, 1H), 3.71-3.63 (m, 1H), 3.63-3.54 (m, 2H), 3.51-3.42(m, 1H), 2.85(s, 3H), 2.82-2.73(m, 1H), 2.67-2.57(m, 4H), 2, 10-1.95 (m, 1H), 1.59-1.45 (m, 1H), 1.24 (d, J=6.5 Hz, 3H) A41

3-({4-[2-(2-aminopropan-2-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-6-yl]-5-chloropyrimidin-2-yl} amino)-1,5-anhydro-2,3-dideoxy-D-threo-pentitol 463.4 [M+H] ⁺ (ESI) ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.41 (s, 1H), 8.05-7.81 (m, 1H), 7.57-7.22 (m, 2H), 6, 24-6.06 (m, 1H), 4.99-4.89 (m, 1H), 3.90-3.73 (m, 3H), 3.54-3.46 (m, 1H), 3.32-3.30(m, 1H), 3.07-2.95(m, 1H), 2.33-2.22(m, 1H), 2.04-1.88(m, 1H ), 1.60-1.56 (m, 12H), 1.53-1.40 (m, 1H) A42

3-[(4-{2-[(1R)-1-aminoethyl]-1-tert-butyl-4-fluoro-1H-benzimidazol-6-yl}-5-chloropyrimidin-2-yl)amino]-1 ,5-anhydro-2,3-dideoxy-D-threo-pentitol 463.4 [M+H] ⁺ (ESI) ¹ H NMR (500 MHz, CD ₃ OD) δ 8.34 (s, 1H), 8.25-8.14 (m, 1H), 7.56-7.38 (m, 1H), 4.84 -4.77(m, 1H), 4.66-4.58(m, 1H), 4.01-3.94(m, 2H), 3.93-3.87(m, 1H), 3 .65-3.57 (m, 1H), 3.52-3.44 (m, 1H), 3.24-3.13 (m, 1H), 2.17-2.07 (m, 1H) , 1.94 (s, 9H), 1.68-1.61 (m, 1H), 1.59 (d, J=6.6 Hz, 3H) A43

3-({4-[2-(1-aminocyclopropyl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-6-yl]-5-chloropyrimidin-2-yl}amino)-1 ,5-anhydro-2,3-dideoxy-D-threo-pentitol 461.3 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.41 (s, 1H), 8.03-7.82 (m, 1H), 7.57-7.22 (m, 2H), 5, 50-5.24 (m, 1H), 4.99-4.91 (m, 1H), 3.91-3.75 (m, 3H), 3.57-3.44 (m, 1H), 3.09-2.96 (m, 1H), 2.63-2.54 (m, 1H), 2.06-1.86 (m, 1H), 1.62 (d, J=7.0 Hz, 6H), 1.56-1.41 (m, 1H), 1.21-1.13 (m, 2H), 1.03-0.94 (m, 2H) A44

1,5-anhydro-3-[(5-chloro-4-{4-fluoro-2-[(methylamino)methyl]-1-(propan-2-yl)-1H-benzimidazol-6-yl}pyrimidin- 2-yl)amino]-2,3-dideoxy-D-threo-pentitol 448.9 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.41 (s, 1H), 8.05-7.75 (m, 1H), 7.55-7.26 (m, 2H), 5, 11-5.01 (m, 1H), 4.99-4.89 (m, 1H), 3.99 (s, 2H), 3.88-3.74 (m, 3H), 3.54- 3.46 (m, 1H), 3.06-2.98 (m, 1H), 2.32 (s, 3H), 2.04-1.84 (m, 1H), 1.58 (d, J=7.0Hz, 6H), 1.53-1.40(m, 1H) A45

3-({4-[2-(2-Amino-2-methylpropyl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-6-yl]-5-chloropyrimidin-2-yl} amino)-1,5-anhydro-2,3-dideoxy-D-threo-pentitol 477.1 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, CD ₃ OD) δ 8.57 (s, 1H), 8.30 (s, 1H), 7.79-7.70 (m, 1H), 5.14-5.02 (m, 1H), 4.08-3.88 (m, 3H), 3.71-3.62 (m, 1H), 3.62-3.58 (m, 1H), 3.54 (s , 2H), 3.52-3.42 (m, 1H), 3.25-3.17 (m, 1H), 2.16-2.02 (m, 1H), 1.82-1.71 (m, 7H), 1.57 (s, 6H) A46

1,5-anhydro-3-{[5-chloro-4-(9-fluoro-4,4-dimethyl-1,2,3,4-tetrahydropyrazino[1,2-a]benzimidazol-7-yl)pyrimidine -2-yl]amino}-2,3-dideoxy-D-threo-pentitol 447.1 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ +D ₂ O) δ 8.38 (s, 1H), 7.96 (br. s, 1H), 7.39 (br. d, J=7.8 Hz, 2H), 4.95 (d, J=5.3 Hz, 1H), 4.03 (s, 2H), 3.81 (br.dd, J=5.3, 10.8 Hz, 3H ), 3.49 (br. s, 1H), 3.30 (br. t, J=11.2 Hz, 1H), 3.07-2.94 (m, 3H), 1.94 (br. s, 1H), 1.60 (s, 6H), 1.49 (br.d, J=9.5 Hz, 1H) A47

(3R,4R)-4-({4-[2-(1-aminoethyl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-6-yl]-5-chloropyrimidin-2- yl}amino)-1-(methanesulfonyl)piperidin-3-ol 526.3 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.43 (s, 1H), 7.92 (br. s, 1H), 7.57-7.31 (m, 2H), 5.23 ( e, J=4.5 Hz, 1H), 5.15 (td, J=6.9, 14.0 Hz, 1H), 4.35 (c, J=6.5 Hz, 1H), 3, 87-3.75 (m, 1H), 3.61 (br.d, J=8.5 Hz, 2H), 3.50 (br.d, J=12.3 Hz, 1H), 2.93 -2.82 (m, 4H), 2.66 (br. t, J=11.0 Hz, 1H), 2.20-2.04 (m, 3H), 1.67-1.42 (m , 10H); [α] _D ²⁰ = -13.3 (c=0.1, MeOH) A48

(3R,4R)-4-({4-[2-(1-aminoethyl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-6-yl]-5-chloropyrimidin-2- yl}amino)-1-(methanesulfonyl)piperidin-3-ol 526.3 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.43 (s, 1H), 8.05-7.87 (m, 1H), 7.59-7.30 (m, 2H), 5, 23 (d, J=4.5 Hz, 1H), 5.15 (quin, J=6.9 Hz, 1H), 4.35 (q, J=6.5 Hz, 1H), 3.81 ( br.d, J=5.8 Hz, 1H), 3.61 (br.d, J=9.3 Hz, 2H), 3.49 (br.d, J=12.3 Hz, 1H), 2.90 (s, 3H), 2.88-2.79 (m, 1H), 2.70-2.61 (m, 1H), 2.16 (br. s, 3H), 1.63- 1.47 (m, 10H); [α] _D ²⁰ = -18.1 (c=0.1, MeOH) A49

3-({4-[3-(2-aminopropan-2-yl)-7-fluoro-2-methyl-2H-indazol-5-yl]-5-chloropyrimidin-2-yl}amino)-1.5 -anhydro-2,3-dideoxy-D-threo-pentitol 435.0 [M+H] ⁺ (ESI) ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.53-8.26 (m, 2H), 7.61-7.28 (m, 2H), 4.99-4.88 (m, 1H ), 4.49 (s, 3H), 3.86-3.75 (m, 3H), 3.53-3.43 (m, 1H), 3.07-2.99 (m, 1H), 2.03-1.89(m, 1H), 1.72(s, 6H), 1.57-1.41(m, 1H) A50

(3R,4R)-4-[(5-chloro-4-{4-fluoro-2-[(1R)-1-hydroxyethyl]-1-(propan-2-yl)-1H-benzimidazol-6-yl }pyrimidin-2-yl)amino]piperidin-3-ol 448.9 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ , 80°C) δ 8.87 (br. s, 1H), 8.64 (br. s, 1H), 8.43 (s, 1H), 7, 99 (d, J=1.3 Hz, 1H), 7.51-7.38 (m, 2H), 5.24 (hept, J=7.6, 7.1 Hz, 1H), 5.13 (k, J=6.5 Hz, 1H), 3.38-3.23 (m, 2H), 3.06-2.95 (m, 1H), 3.05-2.80 (m, 1H ), 2.31-2.19 (m, 1H), 1.82-1.70 (m, 1H), 1.67-1.58 (m, 9H); two protons are covered by the solvent peak A51

3-({4-[1-(1-amino-2-methylpropan-2-yl)-4-fluoro-1H-benzimidazol-6-yl]-5-chloropyrimidin-2-yl}amino)-1.5 -anhydro-2,3-dideoxy-D-threo-pentitol 435.0 [M+H] ⁺ (ESI) ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.35 (s, 1H), 8.31 (s, 1H), 8.07-7.92 (m, 1H), 7.52-7, 30 (m, 1H), 3.88-3.69 (m, 3H), 3.56-3.43 (m, 1H), 3.38-3.21 (m, 1H), 3.11- 2.96 (m, 3H), 2.00-1.86 (m, 1H), 1.64 (s, 6H), 1.54-1.40 (m, 1H) A52

3-({4-[1-(1-amino-2-methylpropan-2-yl)-4-fluoro-2-methyl-1H-benzimidazol-6-yl]-5-chloropyrimidin-2-yl}amino) -1,5-anhydro-2,3-dideoxy-D-threo-pentitol 448.9 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, D ₂ O) δ 8.50-8.33 (m, 1H), 8.24-8.13 (m, 1H), 7.78-7.64 (m, 1H) , 4.03-3.89 (m, 3H), 3.87-3.80 (m, 2H), 3.74-3.62 (m, 1H), 3.59-3.44 (m, 1H), 3.30-3.20(m, 1H), 3.15-2.97(m, 3H), 2.12-1.97(m, 7H), 1.77-1.55( m, 1H) A53

3-[(4-{2-[(1S)-1-aminoethyl]-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-6-yl}-5-chloropyrimidin-2-yl) amino]-1,5-anhydro-2,3-dideoxy-D-threo-pentitol 448.9 [M+H] ⁺ (ESI) ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.41 (s, 1H), 8.07-7.87 (m, 1H), 7.54-7.25 (m, 2H), 5.15 -5.00(m, 1H), 4.97-4.85(m, 1H), 4.61-4.46(m, 1H), 3.87-3.75(m, 3H), 3 .59-3.48 (m, 1H), 3.07-2.98 (m, 1H), 2.03-1.89 (m, 1H), 1.60 (d, J=6.6 Hz , 6H), 1.55-1.45 (m, 4H) A54

3-({4-[2-(aminomethyl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-6-yl]-5-chloropyrimidin-2-yl}amino)-1.5 -anhydro-2,3-dideoxy-D-threo-pentitol 435.1 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) at 80°C δ = 8.40 (s, 1H), 8.10-7.98 (m, 1H), 7.48 (br. d, J= 11.0 Hz, 1H), 7.21-7.11(m, 1H), 4.89(m, 1H), 4.73(m, 1H), 4.36(m, 2H), 3, 84 (m, 4H), 3.66-3.50 (m, 1H), 3.35 (m, 2H), 3.11 (m, 1H), 2.14-1.99 (m, 1H) , 1.73-1.49 (m, 7H) A55

1,5-anhydro-3-{[5-chloro-4-(9-fluoro-4-methyl-1,2,3,4-tetrahydropyrazino[1,2-a]benzimidazol-7-yl)pyrimidin-2 -yl]amino}-2,3-dideoxy-D-threo-pentitol 433.1 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.42 (s, 1H), 7.83 (br. s, 1H), 7.58-7.31 (m, 2H), 4.95 ( d, J=5.3 Hz, 1H), 4.58 (br.s, 1H), 4.20-4.02 (m, 2H), 3.90-3.76 (m, 3H), 3 .51 (br.d, J=5.3 Hz, 2H), 3.30-3.24 (m, 1H), 3.12-2.99 (m, 2H), 1.95 (br.d , J=12.0 Hz, 1H), 1.50 (d, J=6.5 Hz, 4H); [α] _D ²⁰ =27.7 (c=0.13, MeOH) A56

1,5-anhydro-3-{[5-chloro-4-(9-fluoro-4-methyl-1,2,3,4-tetrahydropyrazino[1,2-a]benzimidazol-7-yl)pyrimidin-2 -yl]amino}-2,3-dideoxy-D-threo-pentitol 433.2 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.47-8.34 (m, 1H), 7.82 (br. s, 1H), 7.62-7.32 (m, 2H), 4.94 (d, J=5.3 Hz, 1H), 4.57 (br.s, 1H), 4.17-4.00 (m, 2H), 3.82 (br.dd, J= 4.9, 10.7 Hz, 3H), 3.50 (brs, 2H), 3.29-3.21 (m, 1H), 3.09-2.97 (m, 2H), 1 .97 (br. s, 1H), 1.58-1.41 (m, 4H); [α] _D ²⁰ =48.2 (c=0.13, MeOH) A57

3-({4-[2-(2-amino-3,3-difluoropropyl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-6-yl]-5-chloropyrimidin-2- yl}amino)-1,5-anhydro-2,3-dideoxy-D-threo-pentitol 499.4 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.41 (s, 1H), 8.08-7.80 (m, 1H), 7.57-7.28 (m, 2H), 6, 26-5.80 (m, 1H), 5.01-4.78 (m, 2H), 3.91-3.73 (m, 3H), 3.60-3.44 (m, 2H), 3.22-3.11 (m, 1H), 3.08-2.89 (m, 2H), 2.04-1.80 (m, 3H), 1.66-1.55 (m, 6H ), 1.53-1.44 (m, 1H) A58

3-({4-[2-(2-amino-3,3-difluoropropyl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-6-yl]-5-chloropyrimidin-2- yl}amino)-1,5-anhydro-2,3-dideoxy-D-threo-pentitol 499.0 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.42 (s, 1H), 7.98 (br. s, 1H), 7.56-7.17 (m, 2H), 6.21 ( td, J=55.6, 3.2 Hz, 1H), 4.91 (dc, J=20.7, 6.9, 6.1 Hz, 2H), 3.98-3.69 (m, 4H), 3.51 (s, 1H), 3.30-3.26 (m, 1H), 3.21-2.89 (m, 2H), 1.97 (br. s, 1H), 1 .60 (dd, J=6.9, 3.5 Hz, 6H), 1.57-1.45 (m, 1H) A59

3-[(4-{2-[(1-aminocyclopentyl)methyl]-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-6-yl}-5-chloropyrimidin-2-yl)amino ]-1,5-anhydro-2,3-dideoxy-D-threo-pentitol 503.1 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, CD ₃ OD) δ 8.34 (s, 1H), 8.05 (s, 1H), 7.49 (d, J=11.5 Hz, 1H), 5.07- 4.91(m, 1H), 4.03-3.85(m, 3H), 3.62(s, 1H), 3.53-3.43(m, 1H), 3.26-3, 14 (m, 3H), 2.19-2.10 (m, 1H), 1.92-1.78 (m, 4H), 1.77-1.56 (m, 11H)

Example A60 (Scheme A-4): Preparation of 1,5-anhydro-3-[(4-{1-tert-butyl-4-fluoro-2-[(1R)-1-hydroxyethyl]-1H-benzimidazole-6 -yl}-5-chloropyrimidin-2-yl)amino]-2,3-dideoxy-D-threo-pentitol

Scheme A-4:

To a solution of 1,5-anhydro-3-[(4-{1-tert-butyl-2-[(1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl]-4-fluoro-1H -benzimidazol-6-yl}-5-chloropyrimidin-2-yl)amino]-2,3-dideoxy-D-threo-pentitol (A-5) (prepared as in Example A1, 70.0 mg, 0.121 mmol ) in MeOH (1.0 ml) HCl (4.0 N in 1,4-dioxane, 3.0 ml) was added dropwise at 0°C. The solution was stirred at 30° C. for 4 hours. TLC analysis showed consumption of starting material. The solution was basified with NH ₄ OH to pH~9 and then concentrated to dryness. The residue was purified by preparative HPLC on a Boston Uni C-18 column (40×150 mm, particle size 5 μm), which was eluted with 13-53% MeCN/H ₂ O (+0.05% HCl) with a flow rate of 60 ml/ min. The material was repurified by preparative HPLC on a DuraShell column (150×25 mm, particle size 5 μm) eluted with 27-47% MeCN/H ₂ O (+0.05% NH ₄ OH) at a flow rate of 25 ml/min. to give 1,5-anhydro-3-[(4-{1-tert-butyl-4-fluoro-2-[(1R)-1-hydroxyethyl]-1H-benzimidazol-6-yl}-5-chloropyrimidin- 2-yl)amino]-2,3-dideoxy-D-threo-pentitol (Example A60) (4.2 mg, 8% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.41 (s, 1H), 8.04 (br. s, 1H), 7.54-7.32 (m, 1H), 5.53 ( d, J=7.9 Hz, 1H), 5.28-5.20 (m, 1H), 4.95 (d, J=5.3 Hz, 1H), 3.86-3.76 (m , 3H), 3.50 (br.s., J=1.2 Hz, 1H), 3.03 (br.s., J=10.3 Hz, 1H), 2.07 (s, 1H), 2.01-1.91 (m, 1H), 1.88 (s, 9H), 1.67 (d, J=6.2 Hz, 3H), 1.56-1.44 (m, 1H) ; one proton is covered by the solvent peak; m/z (ESI+) for (C ₂₂ H ₂₇ ClFN ₅ O ₃ ), 464.1 (M+H) ⁺ .

The examples in the table below were synthesized according to the methods used for the synthesis of 1,5-anhydro-3-[(4-{1-tert-butyl-4-fluoro-2-[(1R)-1-hydroxyethyl]-1H -benzimidazol-6-yl}-5-chloropyrimidin-2-yl)amino]-2,3-dideoxy-D-threo-pentitol (Example A60) (Scheme A-4). The following examples have been synthesized with non-critical modifications or substitutions to the illustrated techniques that a person skilled in the art could implement.

Example number Structure/Name HCMS NMR A61

1,5-ангидро-3-[(4-{1-трет-бутил-4-фтор-2-[(1S)-1-гидроксиэтил]-1H-бензимидазол-6-ил}-5-хлорпиримидин-2-ил)амино]-2,3-дидезокси-D-трео-пентитол

1,5-anhydro-3-[(4-{1-tert-butyl-4-fluoro-2-[(1S)-1-hydroxyethyl]-1H-benzimidazol-6-yl}-5-chloropyrimidin-2- yl)amino]-2,3-dideoxy-D-threo-pentitol 464.1 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, CD ₃ OD) δ 8.34 (s, 1H), 8.19 (s, 1H), 7.48 (d, J=11.3 Hz, 1H), 5.46 ( k, J=6.4 Hz, 1H), 4.02-3.87 (m, 3H), 3.66-3.57 (m, 1H), 3.48 (td, J=11.7, 2.3 Hz, 1H), 3.24-3.16 (m, 1H), 2.18-2.09 (m, 1H), 1.97 (s, 9H), 1.76 (d, J \u003d 6.4 Hz, 3H), 1.70-1.57 (m, 1H) A62

(3R,4R)-4-[(4-{1-tert-butyl-4-fluoro-2-[(1R)-1-hydroxyethyl]-1H-benzimidazol-6-yl}-5-chloropyrimidin-2- yl)amino]-1-(methanesulfonyl)piperidin-3-ol 541.0 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.42 (s, 1H), 8.26-7.97 (m, 1H), 7.44 (d, J=53.2 Hz, 2H) , 5.53 (d, J=7.8 Hz, 1H), 5.29-5.21 (m, 2H), 3.80 (s, 1H), 3.60 (d, 2H), 3, 48 (d, J=12.0 Hz, 1H), 2.93-2.78 (m, 4H), 2.71-2.60 (m, 1H), 2.07-1.96 (m, 1H), 1.88 (s, 9H), 1.67 (d, J=6.2 Hz, 3H), 1.53 (d, J=12.2 Hz, 1H) A63

1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(hydroxymethyl)-1-(1-methylcyclopropyl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino )-2,3-dideoxy-D-threo-pentitol 447.9 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, CD ₃ OD) δ 8.58 (s, 1H), 8.35 (d, J=1.1 Hz, 1H), 7.97 (d, J=11.0 Hz, 1H), 5.29 (s, 2H), 4.07-3.92 (m, 3H), 3.67 (td, J=9.6, 4.9 Hz, 1H), 3.54-3 .44 (m, 1H), 3.28-3.19 (m, 1H), 2.16-2.08 (m, 1H), 1.82-1.70 (m, 4H), 1.49 (s, 2H), 1.36 (s, 2H) A64

1,5-anhydro-3-({5-chloro-4-[4-fluoro-1-(2-fluoro-2-methylpropyl)-2-(hydroxymethyl)-1H-benzimidazol-6-yl]pyrimidin-2 -yl}amino)-2,3-dideoxy-D-threo-pentitol 468.2 [M+H] ⁺ (ESI) ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.42 (s, 1H), 7.91 (br. s, 1H), 7.42 (br. s, 2H), 5.72 (t, J=6.0 Hz, 1H), 4.91 (dd, J=5.4, 1.3 Hz, 1H), 4.79 (d, J=6.0 Hz, 2H), 4.63 ( d, J=22.6 Hz, 2H), 3.82 (kt, J=10.8, 6.4 Hz, 3H), 3.56-3.47 (m, 1H), 3.04 (t , J=10.4 Hz, 1H), 1.98 (br.s, 1H), 1.50 (cd, J=12.0, 4.5 Hz, 2H), 1.39 (s, 3H) , 1.35 (s, 3H) A65

(3R,4R)-4-({5-chloro-4-[1-cyclobutyl-4-fluoro-2-(hydroxymethyl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-1- (methanesulfonyl)piperidin-3-ol 524.9 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.47 (s, 1H), 8.18 (br. s, 1H), 7.61 (br. s, 2H), 5.25 (td, J=8.9, 17.6 Hz, 1H), 4.87 (s, 2H), 3.81 (br.s, 1H), 3.61 (br.d, J=10.3 Hz, 2H ), 3.49 (br.d, J=12.1 Hz, 1H), 2.90 (s, 3H), 2.85 (br. d, J=9.8 Hz, 3H), 2.71 -2.54 (m, 3H), 2.13-1.84 (m, 3H), 1.55 (br. s, 1H) A66

1,5-anhydro-3-({5-chloro-4-[1-(3,3-difluorocyclobutyl)-4-fluoro-2-(hydroxymethyl)-1H-benzimidazol-6-yl]pyrimidin-2-yl }amino)-2,3-dideoxy-D-threo-pentitol 483.9 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.46 (s, 1H), 7.99 (br. s, 1H), 7.77-7.37 (m, 2H), 5.30 ( br.d, J=3.7 Hz, 1H), 4.86 (s, 2H), 3.92-3.74 (m, 3H), 3.64-3.43 (m, 3H), 3 .43-3.25 (m, 3H), 3.04 (t, J=10.4 Hz, 1H), 2.16-1.86 (m, 1H), 1.61-1.39 (m , 1H)

Example A67 (Scheme A-5): Preparation of 1,5-anhydro-3-({5-chloro-4-[1-(2,2-difluoroethyl)-4-fluoro-2-(2-hydroxypropane-2) -yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol

Scheme A-5:

To a yellow solution of 1,5-anhydro-3-({5-chloro-4-[1-(2,2-difluoroethyl)-4-fluoro-2-(2-hydroxypropan-2-yl)-1H-benzimidazol- 6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol (A-6) (prepared as in Example A1, 200 mg, 0.33 mmol) in THF (10, 0 ml) was added TBAF (174 mg, 0.67 mmol) at room temperature. The mixture was stirred for 2 hours, after which LCMS analysis showed complete consumption of the starting material to form the mass of the desired product. The reaction was concentrated. The residue was dissolved in EtOAc (50 ml), washed with H ₂ O (2×50 ml) and brine (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative HPLC on a DuraShell column (150×25 mm, particle size 5 μm), which was eluted with 26-46% MeCN/H ₂ O (+0.05% NH ₄ OH) with a flow rate of 25 ml/min with obtaining 1,5-anhydro-3-({5-chloro-4-[1-(2,2-difluoroethyl)-4-fluoro-2-(2-hydroxypropan-2-yl)-1H-benzimidazol-6- yl)]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol (Example A67) (34.2 mg, 21% yield) as a white solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.42 (s, 1H), 7.88 (s, 1H), 7.56-7.34 (m, 2H), 6.41 (tt, J=55.9, 4.3 Hz, 1H), 5.98 (s, 1H), 5.04 (td, J=14.0, 4.2 Hz, 2H), 4.93 (d, J =5.4Hz, 1H), 3.88-3.74(m, 3H), 3.55-3.46(m, 1H), 3.03(t, J=10.4Hz, 1H) , 2.04-1.83 (m, 1H), 1.68 (d, J=1.8 Hz, 6H), 1.56-1.42 (m, 1H); one proton is covered by the solvent peak; m/z (ESI+) for (C ₂₁ H ₂₃ ClF ₃ N ₅ O ₃ ), 486.0 (M+H) ⁺ .

The example in the table below was synthesized according to the methods used for the synthesis of 1,5-anhydro-3-({5-chloro-4-[1-(2,2-difluoroethyl)-4-fluoro-2-(2- hydroxypropan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol (Example A67) (Scheme A-5). The following example has been synthesized with non-breaking changes or substitutions to the illustrated techniques that a person skilled in the art could implement.

Example number Structure/Name HCMS NMR A68

1,5-ангидро-2,3-дидезокси-3-({5-фтор-4-[4-фтор-2-(2-гидроксипропан-2-ил)-1-(пропан-2-ил)-1H-бензимидазол-6-ил]пиримидин-2-ил}амино)-D-трео-пентитол

1,5-anhydro-2,3-dideoxy-3-({5-fluoro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1H -benzimidazol-6-yl]pyrimidin-2-yl}amino)-D-threo-pentitol 448.2 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.43 (d, J=4.0 Hz, 1H), 8.21 (s, 1H), 7.62 (d, J=12.1 Hz , 1H), 7.19 (d, J=7.6 Hz, 1H), 5.92-5.70 (m, 2H), 4.96 (s, 1H), 3.91-3.73 ( m, 3H), 3.62-3.46 (m, 1H), 3.13-2.99 (m, 1H), 2.14-1.96 (m, 1H), 1.67 (s, 6H), 1.65-1.44 (m, 7H); one proton is covered by the solvent peak

Example A69 (Scheme A-6): Preparation of (3R,4R)-4-({5-chloro-4-[2-(difluoromethyl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazole -6-yl]pyrimidin-2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol

Scheme A-6:

To a solution of 6-(2,5-dichloropyrimidin-4-yl)-2-(difluoromethyl)-1-(propan-2-yl)-1H-benzimidazole (A-7) (prepared as in Example A1, 49, 6 mg, 0.132 mmol) in THF (1.32 ml) was added (3R,4R)-4-amino-1-(methanesulfonyl)piperidin-3-ol (Int-69) (38.5 mg, 0.198 mmol), Cs ₂ CO ₃ (129 mg 0.397 mmol), Pd(OAc) ₂ (6 mg, 0.0264 mmol) and rac-BINAP (17 mg, 0.0264 mmol). The mixture was purged with N ₂ for 10 min and then stirred for 105 min at 80° C. using microwave radiation. LCMS analysis showed complete consumption of the starting material to form a mass of the desired product. The reaction mixture was diluted with MeOH and then filtered through a filter disc (0.2 μm). The material was purified using preparative SFC on a Nacalai Cosmosil column with 3-hydroxyphenyl bonds (150×20 mm), which was eluted with 12-23% MeOH/CO ₂ at a flow rate of 85 ml/min to obtain (3R,4R)-4-( {5-chloro-4-[2-(difluoromethyl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-1-(methanesulfonyl) piperidin-3-ol (Example A69) (33.1 mg, 47% yield) as a solid. ¹ H NMR (400 MHz, DMSO-d ₆ , 80°C) δ = 8.43 (s, 1H), 8.10 (d, J=1.0 Hz, 1H), 7.57-7.23 (m, 3H), 5.14-5.02 (m, 1H), 4.97 (br.s, 1H), 3.90-3.75 (m, 2H), 3.73-3.63 (m, 2H), 3.55 (d, J=13.1 Hz, 1H), 2.89-2.86 (s, 3H), 2.78-2.66 (m, 1H), 2, 18-2.08 (m, 1H), 1.68 (d, J=6.8 Hz, 6H), 1.63-1.59 (m, 1H); m/z (APCI) for (C ₂₁ H ₂₄ ClF ₃ N ₆ O ₃ S), 533.0 (M+H) ⁺ .

Example A70 (Scheme A-7): Preparation of (3R,4R)-4-({5-ethyl-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6 -yl]pyrimidin-2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol

Scheme A-7:

Solution of 6-(2-chloro-5-ethylpyrimidin-4-yl)-4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazole (A-8) (prepared as in Example A1 , 80.0 mg, 0.240 mmol) in 2-methyl-2-butanol (6 ml) was treated with Cs ₂ CO ₃ (157 mg, 0.481 mmol) and (3R,4R)-4-amino-1-(methanesulfonyl)piperidine -3-ol (Int-69) (60.7 mg, 0.312 mmol) and purged with N ₂ . Chloro-2-(dimethylaminomethyl)ferrocen-1-yl-(dinorbornylphosphine)palladium (SK-CC02-A) (14.6 mg, 0.024 mmol) was added and the mixture was again purged with N ₂ . The reaction mixture was stirred at 120° C. for 16 hours. The crude mixture was combined with the second reaction in a similar manner in an amount of 30 mg and concentrated. The residue was partitioned between water (30 ml) and EtOAc (30 ml). The aqueous phase was extracted with EtOAc (30 ml). The combined organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified in two steps: first by preparative TLC (SiO ₂ , 10:1 DCM/MeOH, R _f =0.5) and then by preparative HPLC on an Xbridge column (150×30 mm, particle size 10 μm, column temperature 25°C), which was eluted with 15-55% MeCN/H ₂ O (+0.05% NH ₄ OH) at a flow rate of 25 ml/min, obtaining (3R,4R)-4-({5- ethyl-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol (Example A70) (25.4 mg, 22% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.27 (s, 1H), 7.60 (s, 1H), 7.12 (br. d, J=11.5 Hz, 1H), 6 .99 (br.d, J=7.5 Hz, 1H), 5.24 (d, J=4.3 Hz, 1H), 4.84-4.75 (m, 1H), 3.81- 3.74 (m, 1H), 3.65-3.55 (m, 2H), 3.49-3.44 (m, 1H), 2.89 (s, 3H), 2.87-2, 81 (m, 1H), 2.71-2.64 (m, 1H), 2.61 (s, 3H), 2.59-2.54 (m, 2H), 2.12-2.04 ( m, 1H), 1.57 (d, J=6.8 Hz, 6H), 1.54-1.45 (m, J=10.0 Hz, 1H), 1.04 (t, J=7 .5 Hz, 3H); m/z (ESI+) for (C ₂₃ H ₃₁ FN ₆ O ₃ S), 491.1 (M+H) ⁺ .

The examples in the table below were synthesized according to the methods used for the synthesis of (3R,4R)-4-({5-chloro-4-[2-(difluoromethyl)-4-fluoro-1-(propan-2-yl) -1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol (Example A70) (Scheme A-6) and (3R,4R)-4-({5 -ethyl-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-1-(methanesulfonyl)piperidine-3- ola (Example A65) (Diagram A-7). The following examples have been synthesized with non-critical modifications or substitutions to the illustrated techniques that a person skilled in the art could implement.

Example number Structure/Name HCMS NMR A71

(3R,4R)-4-({5-хлор-4-[2-этил-4-фтор-1-(оксетан-3-ил)-1H-бензимидазол-6-ил]пиримидин-2-ил}амино)-1-(метансульфонил)пиперидин-3-ол

(3R,4R)-4-({5-chloro-4-[2-ethyl-4-fluoro-1-(oxetan-3-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino )-1-(methanesulfonyl)piperidin-3-ol 525.1 [M+H] ⁺ (ESI) ¹ H NMR (700 MHz, DMSO-d ₆ ) δ 8.73-8.18 (m, 2H), 7.83-6.97 (m, 2H), 5.75 (ddd, J=13.2 , 7.7, 5.4 Hz, 1H), 5.19-5.08 (m, 2H), 5.07-4.89 (m, 2H), 3.79 (s, 1H), 3.67- 3.59 (m, 5H), 2.94-2.87 (m, 5H), 2.86-2.79 (m, 1H), 2.64 (t, J=10.3 Hz, 1H) , 1.57-1.44 (m, 1H), 1.30 (t, J=7.5 Hz, 3H) A72

(3R,4R)-4-{[5-chloro-4-(1-cyclopropyl-4-fluoro-2-methyl-1H-benzimidazol-6-yl)pyrimidin-2-yl]amino}-1-(methanesulfonyl )piperidin-3-ol 495.1 [M+H] ⁺ (ESI) ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.96 (s, 1H), 7.30-7.57 (m, 1H), 6.99-7.11 (m, 1H), 6, 89-6.98 (m, 1H), 4.74 (d, J=4.59 Hz, 1H), 3.30-3.38 (m, 1H), 3.15 (d, J=10, 64 Hz, 2H), 3.04 (d, J=12.10 Hz, 2H), 2.44 (s, 3H), 2.41 (d, J=2.38 Hz, 1H), 2.21 (s, 1H), 2.18 (s, 3H), 1.01-1.15 (m, 1H), 0.72-0.82 (m, 3H), 0.56-0.64 (m , 2H) A73

(3R,4R)-4-({5-chloro-4-[4-fluoro-1-(1-methoxypropan-2-yl)-2-methyl-1H-benzimidazol-6-yl]pyrimidin-2-yl }amino)-1-(methanesulfonyl)piperidin-3-ol 527.5 [M+H] ⁺ (APCI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.39 (s, 1H), 7.93 (d, J=1.3 Hz, 1H), 7.40 (dd, J=11.8, 1.3 Hz, 1H), 7.16 (d, J=7.6 Hz, 1H), 4.98 (d, J=4.6 Hz, 1H), 4.84 (ddd, J=8, 4, 7.0, 4.7 Hz, 1H), 3.90 (dd, J=10.5, 8.5 Hz, 1H), 3.82 (dd, J=12.3, 6.1, 4.3 Hz, 1H), 3.73 (dd, J=10.5, 4.8 Hz, 1H), 3.70-3.64 (m, 1H), 3.59-3.48 (m , 1H), 3.22 (s, 3H), 2.92 (dd, J=10.4, 2.0 Hz, 1H), 2.89 (s, 3H), 2.77-2.68 ( m, 1H), 2.62 (s, 3H), 2.18-2.08 (m, 1H), 1.68-1.50 (m, 5H); [α] _D ²² = +42.1 (c=0.1, MeOH) A74

(3R,4R)-4-({5-chloro-4-[4-fluoro-1-(1-methoxypropan-2-yl)-2-methyl-1H-benzimidazol-6-yl]pyrimidin-2-yl }amino)-1-(methanesulfonyl)piperidin-3-ol 527.5 [M+H] ⁺ (APCI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.39 (s, 1H), 7.93 (d, J=1.4 Hz, 1H), 7.39 (dd, J=11.8, 1.3 Hz, 1H), 7.16 (d, J=7.7 Hz, 1H), 4.97 (s, 1H), 4.91-4.73 (m, 1H), 3.89 ( dd, J=10.5, 8.5 Hz, 1H), 3.82 (dd, J=9.3, 7.9, 4.5 Hz, 1H), 3.72 (dd, J=10, 5, 4.8 Hz, 1H), 3.70-3.63(m, 1H), 3.58-3.52(m, 1H), 3.22(s, 3H), 2.94-2 .89 (m, 1H), 2.89 (s, 3H), 2.77-2.68 (m, 1H), 2.62 (s, 3H), 2.16-2.08 (m, 1H ), 1.60 (d, J=7.1 Hz, 5H) A75

(3R,4R)-4-({5-chloro-4-[4-fluoro-2-(methoxymethyl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl }amino)-1-(methanesulfonyl)piperidin-3-ol 527.1 [M+H] ⁺ (APCI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.40 (s, 1H), 8.00 (d, J=0.98 Hz, 1H), 7.38-7.51 (m, 1H) , 7.12-7.23(m, 1H), 4.96(s, 2H), 4.76(s, 2H), 3.75-3.89(m, 1H), 3.67(s , 2H), 3.47-3.58 (m, 1H), 3.37 (s, 3H), 2.89-2.94 (m, 1H), 2.88 (s, 3H), 2, 65-2.77 (m, 1H), 2.07-2.17 (m, 1H), 1.63 (d, J=6.97 Hz, 6H), 1.57-1.48 (m, 1H). A76

(3R,4R)-4-({5-fluoro-4-[2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-1- (methanesulfonyl)piperidin-3-ol 463.4 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, CD ₃ OD) δ 8.40 (s, 1H), 8.28 (d, J=4.2 Hz, 1H), 7.99 (dt, J=8.5, 1 .4 Hz, 1H), 7.65 (d, J=8.6 Hz, 1H), 3.95-3.66 (m, 4H), 2.98 (td, J=11.8, 2, 8 Hz, 1H), 2.91 (s, 3H), 2.78 (dd, J=11.5, 9.1 Hz, 1H), 2.67 (s, 3H), 2.36-2, 24 (m, 1H), 1.80-1.64 (m, 7H); one proton is covered by the solvent peak A77

(3R,4R)-4-{[4-(1-tert-Butyl-1H-benzimidazol-6-yl)-5-fluoropyrimidin-2-yl]amino}-1-(methanesulfonyl)piperidin-3-ol 463.3 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.47-8.34 (m, 3H), 7.91-7.83 (m, 1H), 7.82-7.75 (m, 1H ), 7.18 (br.d, J=7.7 Hz, 1H), 5.22 (d, J=4.4 Hz, 1H), 3.82-3.46 (m, 4H), 2 .95-2.80 (m, 4H), 2.69-2.65 (m, 1H), 2.18-2.02 (m, 1H), 1.75 (s, 9H), 1.63 -1.44 (m, 1H) A78

(3R,4R)-4-{[4-(1-tert-butyl-2-methyl-1H-benzimidazol-6-yl)-5-fluoropyrimidin-2-yl]amino}-1-(methanesulfonyl)piperidine- 3-ol 476.8 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.57-8.26 (m, 2H), 7.82 (d, J=8.4 Hz, 1H), 7.62 (d, J= 8.5 Hz, 1H), 7.16 (d, J=7.7 Hz, 1H), 5.24 (d, J=4.5 Hz, 1H), 3.84-3.72 (m, 1H), 3.72-3.59 (m, 2H), 3.52 (d, J=12.0 Hz, 1H), 2.92 (s, 3H), 2.90-2.81 (m , 1H), 2.78 (s, 3H), 2.71-2.60 (m, 1H), 2.19-2.05 (m, 1H), 1.84 (s, 9H), 1, 55 (k, J=11.5 Hz, 1H) A79

(3R,4R)-4-({4-[2,4-dimethyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]-5-fluoropyrimidin-2-yl}amino)-1 -(methanesulfonyl)piperidin-3-ol 476.9 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.38 (d, J=4.0 Hz, 1H), 8.08 (s, 1H), 7.64 (q, J=1.2 Hz , 1H), 7.16 (d, J=7.6 Hz, 1H), 5.23 (d, J=4.5 Hz, 1H), 4.78 (hept, J=6.8 Hz, 1H ), 3.83-3.71 (m, 1H), 3.70-3.56 (m, 2H), 3.55-3.46 (m, 1H), 2.96-2.82 (m , 4H), 2.71-2.64 (m, 1H), 2.60 (s, 3H), 2.54 (s, 3H), 2.09 (d, J=13.7 Hz, 1H) , 1.64-1.48 (m, 7H) A80

1,5-anhydro-2,3-dideoxy-3-{[5-fluoro-4-(7-fluoro-1,1-dimethyl-3,4-dihydro-1H-[1,4]oxazino[4, 3-b]indazol-9-yl)pyrimidin-2-yl]amino}-D-threo-pentitol 432.1 [M+H] ⁺ (ESI) ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.42 (d, J=4.0 Hz, 1H), 8.22 (s, 1H), 7.67 (d, J=13.1 Hz , 1H), 7.20 (br.d, J=7.8 Hz, 1H), 4.95 (d, J=5.3 Hz, 1H), 4.45 (t, J=5.0 Hz , 2H), 4.22 (t, J=5.0 Hz, 2H), 3.87-3.75 (m, 3H), 3.56-3.45 (m, 1H), 3.06 ( t, J=10.4 Hz, 1H), 2.00 (br.d, J=9.6 Hz, 1H), 1.70 (s, 6H), 1.55-1.42 (m, 1H ) A81

(3R,4R)-4-({4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]-5-(propan-2-yl)pyrimidine -2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol 504.9 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.41 (s, 1H), 7.50 (s, 1H), 7.10-6.95 (m, 2H), 5.23 (d, J=4.3 Hz, 1H), 4.86-4.73 (m, 1H), 3.77 (br.s, 1H), 3.67-3.54 (m, 2H), 3.50 -3.39 (m, 2H), 2.99-2.81 (m, 5H), 2.71-2.60 (m, 4H), 2.14-2.03 (m, 1H), 1 .56 (d, J=6.8 Hz, 6H), 1.45-1.25 (m, 6H) A82

(3R,4R)-4-({4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]-5-methoxypyrimidin-2-yl}amino) -1-(methanesulfonyl)piperidin-3-ol 493.1 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.30 (s, 1H), 8.25 (s, 1H), 7.70 (d, J=12.6 Hz, 1H), 6.80 (d, J=7.5 Hz, 1H), 5.24 (d, J=4.5 Hz, 1H), 4.88-4.73 (m, 1H), 3.83 (s, 3H) , 3.74 (m, 2H), 3.69-3.57 (m, 2H), 2.96-2.83 (m, 4H), 2.73-2.65 (m, 1H), 2 .61 (s, 3H), 2.12 (d, J=13.2 Hz, 1H), 1.66-1.46 (m, 7H) A83

(3R,4R)-4-({4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]-5-methylpyrimidin-2-yl}amino) -1-(methanesulfonyl)piperidin-3-ol 477.1 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, CD ₃ OD) δ 8.22 (s, 1H), 7.70 (d, J=1.3 Hz, 1H), 7.24 (dd, J=11.4, 1 .2 Hz, 1H), 3.93-3.78 (m, 2H), 3.75-3.62 (m, 2H), 2.87 (s, 4H), 2.77-2.64 ( m, 4H), 2.25 (m, 4H), 1.72-1.60 (m, 7H); one proton is covered by the solvent peak A84

(3R,4R)-4-({5-chloro-4-[1-(propan-2-yl)-1H-benzotriazol-6-yl]pyrimidin-2-yl}amino)-1-(methanesulfonyl)piperidine -3-ol 456.8 [M+H] ⁺ (ESI) ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.47 (s, 1H), 8.25 (br. s, 1H), 8.15 (d, J=8.6 Hz, 1H), 7 .72-7.68 (m, 1H), 7.53 (br. s, 1H), 5.29 (hept, J=6.7 Hz, 1H), 5.21 (m, 1H), 3, 80 (brs, 1H), 3.65-3.57 (m, 2H), 3.52-3.46 (m, 1H), 2.91-2.84 (m, 4H), 2, 66 (t, J=10.3 Hz, 1H), 2.10-2.01 (m, 1H), 1.66 (d, J=6.7 Hz, 6H), 1.58-1.49 (m, 1H) A85

(3R,4R)-4-({5-chloro-4-[2-methyl-1-(propan-2-yl)-1H-imidazo[4,5-b]pyridin-6-yl]pyrimidin-2 -yl}amino)-1-(methanesulfonyl)piperidin-3-ol 480.1 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.75 (d, J=2.0 Hz, 1H), 8.42-8.37 (m, 2H), 7.23 (d, J= 7.6 Hz, 1H), 4.84 (hept, J=6.8 Hz, 1H), 3.63 (m, 2H), 2.95-2.85 (m, 4H), 2.77- 2.64 (m, 4H), 2.19-2.08 (m, 1H), 1.80-1.74 (m, 3H), 1.61 (m, 7H) A86

(3R,4R)-4-({5-chloro-4-[2-methyl-3-(propan-2-yl)-3H-imidazo[4,5-b]pyridin-5-yl]pyrimidin-2 -yl}amino)-1-(methanesulfonyl)piperidin-3-ol 480.1 [M+H] ⁺ (ESI) ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.42 (s, 1H), 8.03 (d, J=8.2, 1.3 Hz, 1H), 7.77 (s, 1H) , 7.42 (s, 1H), 5.23 (s, 1H), 4.79 (g, J=6.8 Hz, 1H), 3.87-3.78 (m, 1H), 3. 68-3.56 (m, 3H), 2.92-2.82 (m, 4H), 2.71-2.63 (m, 4H), 2.10-2.01 (m, 1H), 1.67 (d, J=6.8 Hz, 6H), 1.53 (m, 1H)

Example A87 (Scheme A-8): Preparation of (3R,4R)-4-({5-chloro-4-[4-fluoro-2-(hydroxymethyl)-1-(propan-2-yl)-1H-benzimidazole -6-yl]pyrimidin-2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol

Scheme A-8:

A solution of (3R,4R)-4-({5-chloro-4-[4-fluoro-2-{[(oxan-2-yl)oxy]methyl}-1-(propan-2-yl)-1H- benzimidazol-6-yl]pyrimidin-2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol (A-9) (prepared as in Example A69, 88 mg, 0.15 mmol) in MeOH (3 0 ml) at 0°C was added a solution of HCl (4.0 N. in 1,4-dioxane, 0.55 ml, 2.2 mmol). After 2.5 hours, LCMS analysis showed consumption of starting material to form a mass of the desired product. The reaction mixture was concentrated to dryness. The residue was purified using preparative SFC on a Princeton Ha-Morpholine column (150×21.1 mm, particle size 5 μm, column temperature 35°C), which was eluted with 22-50% MeOH/CO ₂ at a flow rate of 60 ml/min s obtaining (3R,4R)-4-({5-chloro-4-[4-fluoro-2-(hydroxymethyl)-1-(propan-2-yl)-1H-benzimidazol-6-yl)]pyrimidin-2 -yl}amino)-1-(methanesulfonyl)piperidin-3-ol (Example A87) (15 mg, 20% yield) as a white solid. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.42 (s, 1H), 7.97 (s, 1H), 7.52-7.31 (m, 2H), 5.73 (t, J=5.5 Hz, 1H), 5.20 (d, J=5.0 Hz, 1H), 5.02 (hept, J=7.0 Hz, 1H), 4.77 (d, J= 5.7 Hz, 2H), 3.86-3.75 (m, 1H), 3.68-3.56 (m, 2H), 3.53-3.46 (m, 1H), 2.94 -2.80 (m, 4H), 2.71-2.60 (m, 1H), 2.06 (s, 1H), 1.66-1.47 (m, 7H); m/z (ESI+) for (C ₂₁ H ₂₆ ClFN ₆ O ₄ S), 512.8 (M+H) ⁺ .

Example A88 (Scheme A-9): Preparation of (3R,4R)-4-({4-[1-(azetidin-3-yl)-4-fluoro-2-methyl-1H-benzimidazol-6-yl]- 5-fluoropyrimidin-2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol

Scheme A-9:

Solution of tert-butyl 3-[6-(2-chloro-5-fluoropyrimidin-4-yl)-4-fluoro-2-methyl-1H-benzimidazol-1-yl]azetidine-1-carboxylate (A-10) (prepared as in Example A1, 75.0 mg, 0.170 mmol), (3R,4R)-4-amino-1-(methanesulfonyl)piperidin-3-ol (Int-69) (50.1 mg, 0.258 mmol ), Pd(OAc) ₂ (7.73 mg, 0.034 mmol), rac-BINAP (21.4 mg, 0.034 mmol) and Cs ₂ CO ₃ (168 mg, 0.516 mmol) in THF (1.7 ml) were stirred using microwave radiation at 80°C for 30 min. The mixture was purified by flash chromatography (SiO ₂ , 0-100% EtOAc/heptane). Fractions containing the product were concentrated, dissolved in DCM (5 ml) and treated with HCl (4.0 M in 1,4-dioxane, 1.0 ml). The mixture was stirred at ambient temperature for 4 hours. The solution was concentrated and the crude residue was purified by preparative HPLC on a Phenomenex Gemini NX C18 column (150 x 21.2 mm, particle size 5 μm) eluted with 20-100% MeCN/H ₂ O (+10 mM NH ₄ OAc) at a flow rate of 40 ml/min to give (3R,4R)-4-({4-[1-(azetidin-3-yl)-4-fluoro-2-methyl- 1H-benzimidazol-6-yl]-5-fluoropyrimidin-2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol (Example A88) (76 mg, 89% yield) as a solid. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.70 (s, 1H), 8.47-8.29 (m, 1H), 7.64 (d, J=12.0 Hz, 1H) , 7.15 (d, J=7.7 Hz, 1H), 5.43 (s, 1H), 4.27-3.87 (m, 4H), 3.79 (s, 1H), 3, 71-3.54 (m, 2H), 3.50 (s, 1H), 3.01-2.78 (m, 5H), 2.68 (t, J=10.3 Hz, 1H), 2 .56 (d, J=1.4 Hz, 3H), 2.12 (s, 1H), 1.62-1.43 (m, 1H); m/z (APCI+) for (C ₂₁ H ₂₅ F ₂ N ₇ O ₃ S), 494.2 (M+H) ⁺ .

Example A89 (Scheme A-10): Preparation of (3R,4R)-4-({5-chloro-4-[4-fluoro-2-methyl-1-(oxetan-3-yl)-1H-benzimidazol-6 -yl]pyrimidin-2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol

Scheme A-10:

Step 1: Synthesis of 6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-2-methyl-1-(oxetan-3-yl)-1H-benzimidazole (A-11)

A mixture of 6-bromo-4-fluoro-2-methyl-1-(oxetan-3-yl)-1H-benzimidazole (Int-03) (63.0 mg, 0.220 mmol), B ₂ Pin ₂ (84.2 mg , 0.331 mmol), KOAc (65.1 mg, 0.663 mmol) and PdCl ₂ (dppf) (18.0 mg, 0.022 mmol) in 1,4-dioxane (1.1 ml) were flushed with N ₂ for 10 min and then heated in a microwave oven at 90° C. for 1 h. The mixture was cooled to ambient temperature and PdCl ₂ (PPh ₃ ) ₂ (7.71 mg, 0.011 mmol), aqueous Na ₂ CO ₃ (2.0 M, 0.33 ml, 0.659 mmol) and 2,4,5-trichloropyrimidine (60.5 mg, 37.8 µl, 0.330 mmol). The mixture was purged with nitrogen for 10 minutes and then heated in a microwave oven at 110° C. for 70 minutes. The mixture was partitioned between water (2 ml) and EtOAc (2 ml). The aqueous phase was extracted with EtOAc (3×2 ml). The combined organic phases were concentrated to give 6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-2-methyl-1-(oxetan-3-yl)-1H-benzimidazole (A-11) which was collected without additional cleaning. m/z (APCI+) for (C ₁₅ H ₁₁ Cl ₂ FN ₄ O), 352.8 (M+H) ⁺ .

Step 2: Synthesis of (3R,4R)-4-({5-chloro-4-[4-fluoro-2-methyl-1-(oxetan-3-yl)-1H-benzimidazol-6-yl]pyrimidin-2 -yl}amino)-1-(methanesulfonyl)piperidin-3-ol (Example A89)

The crude 6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-2-methyl-1-(oxetan-3-yl)-1H-benzimidazole (A-11) was dissolved in THF (1.8 ml) . Added (3R,4R)-4-amino-1-(methanesulfonyl)piperidin-3-ol (Int-69) (64.4 mg, 0.331 mmol), Pd(OAc) ₂ (9.9 mg, 0.044 mmol) , rac-BINAP (27.5 mg, 0.044 mmol) and Cs ₂ CO ₃ (216 mg, 0.663 mmol) and the mixture was purged with N ₂ for 10 min. The mixture was stirred at 90°C for 1.5 h using microwave radiation. The mixture was cooled to ambient temperature, diluted with DMSO and filtered through a 0.2 micron filter disc. The crude material was purified by preparative SFC on a Princeton HA-morpholine column (150×21.1 mm, column particle size 5 μm, column temperature 35° C.), which was eluted with 15-50% MeOH/CO ₂ (+10 mM NH ₃ ) with a flow rate of 80 g/min. The material was repurified by preparative SFC using a Diacel DC pak SFC-B column (150×21.1 mm, particle size 5 μm, column temperature 35°C) eluted with 18-45% MeOH/CO ₂ at a flow rate of 80 g/min to obtain (3R,4R)-4-({5-chloro-4-[4-fluoro-2-methyl-1-(oxetan-3-yl)-1H-benzimidazol-6-yl]pyrimidin- 2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol (Example A89) (15.9 mg, 14% yield over two steps) as a white solid. ¹ H NMR (600 MHz, DMSO-d ₆ , 75°C) δ 8.40 (s, 1H), 8.35 (br. s, 1H), 7.49 (d, J=11.7 Hz, 1H), 7.20 (d, J=7.4 Hz, 1H), 5.76-5.71 (m, 1H), 5.16 (td, J=7.6, 2.7 Hz, 2H ), 5.09-5.04 (m, 2H), 5.01 (br.s, 1H), 3.85-3.78 (m, 1H), 3.70-3.62 (m, 2H ), 3.55-3.50 (m, 1H), 2.91-2.85 (m, 4H), 2.72-2.66 (m, 1H), 2.58 (s, 3H), 2.15-2.10 (m, 1H), 1.62-1.46 (m, 1H); m/z (APCI+) for (C ₂₁ H ₂₄ ClFN ₆ O ₄ S), 510.8 (M+H) ⁺ .

Example A90 (Scheme A-11): Preparation of (3R,4R)-4-({5-chloro-4-[4-fluoro-2-(hydroxymethyl)-1-(2,2,2-trifluoroethyl)-1H -benzimidazol-6-yl]pyrimidin-2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol

Scheme A-11:

6-(2,5-Dichloropyrimidin-4-yl)-4-fluoro-2-{[(oxan-2-yl)oxy]methyl}-1-(2,2,2-trifluoroethyl)-1H was added to the vial -benzimidazole (A-12) (prepared according to Example A89, 121 mg, 0.25 mmol), (3R,4R)-4-amino-1-(methanesulfonyl)piperidin-3-ol (Int-69) ( 73.6 mg, 0.38 mmol), Pd(OAc) ₂ (11.3 mg, 0.051 mmol), rac-BINAP (31.4 mg, 0.051 mmol), Cs ₂ CO ₃ (247 mg, 0.76 mmol) and THF (2.5 ml). The mixture was stirred at 80° C. using microwave radiation for 30 minutes. LCMS analysis showed consumption of starting material to form a mass of the desired product. The mixture was concentrated on SiO ₂ and purified by flash chromatography (ISCO, 12 g SiO ₂ , 0-100% EtOAc/heptane). Fractions containing the product were concentrated. The residue was dissolved in MeOH (5 ml) and treated with HCl (4.0N in 1,4-dioxane, 1.0 ml) and the mixture was stirred at ambient temperature for 16 hours overnight. LCMS analysis showed partial consumption of starting material. An additional aliquot of HCl (4.0 N in 1,4-dioxane, 1.0 ml) was added. The mixture was stirred for 6 hours, after which LCMS analysis indicated consumption of starting material. The mixture was concentrated and purified by preparative SFC on a Princeton HA-morpholine column (150×21.1 mm, particle size 5 μm, column temperature 35° C.), which was eluted with 14-50% MeOH/CO ₂ at 80 g/min s obtaining (3R,4R)-4-({5-chloro-4-[4-fluoro-2-(hydroxymethyl)-1-(2,2,2-trifluoroethyl)-1H-benzimidazol-6-yl])pyrimidine -2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol (Example A90) (17 mg, 12% yield) as a gum. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.46 (s, 1H), 7.99 (s, 1H), 7.58-7.41 (m, 2H), 5.93 (t, J=6.0Hz, 1H), 5.49(q, J=9.1Hz, 2H), 5.21(d, J=4.5Hz, 1H), 4.82(d, J= 5.8 Hz, 2H), 3.81 (s, 1H), 3.68-3.56 (m, 2H), 3.49 (d, J=12.1 Hz, 1H), 2.94- 2.77 (m, 4H), 2.72-2.61 (m, 1H), 2.02 (s, 1H), 1.60-1.44 (m, 1H); m/z (ESI+) for (C ₂₀ H ₂₁ ClF ₄ N ₆ O ₄ S), 522.9 (M+H) ⁺ .

Example A91 (Scheme A-12): Preparation of (3R,4R)-4-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2) -yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol

Scheme A-12:

A mixture of 2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)-6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-(propan-2- yl)-1H-benzimidazole (A-13) (prepared as in Example A89, 294 mg, 0.590 mmol), (3R,4R)-4-amino-1-(methanesulfonyl)piperidin-3-ol (Int-69 ) (149 mg, 0.767 mmol) and DIPEA (0.55 ml, 2.95 mmol) in DMSO (2.8 ml) were stirred at 90°C for 18 hours. The resulting solution was cooled to ambient temperature and partitioned between water (30 ml) and EtOAc (30 ml). The layers were separated and the aqueous phase was extracted with EtOAc (5×30 ml). The combined organic phases were washed with water (3×20 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The resulting yellow foam was dissolved in THF, cooled to 0°C and treated with TBAF (1.0 M in THF, 1.2 ml, 1.2 mmol). The resulting solution was allowed to warm to ambient temperature and stirred for 2.5 h before concentration. The residue was purified using preparative SFC on a ZymorSpher HADP column (150×21.2 mm, particle size 5 μm, column temperature 40°C), which was eluted with 18% MeOH/CO ₂ at a flow rate of 90 ml/min to obtain (3R, 4R)-4-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin- 2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol (Example A91) (137 mg, 43% yield) as a solid. ¹ H NMR (400 MHz, DMSO-d ₆ , 80°C) δ 8.39 (s, 1H), 7.98 (d, J=1.3 Hz, 1H), 7.40 (dd, J= 11.8, 1.3 Hz, 1H), 7.17 (d, J=7.7 Hz, 1H), 5.80 (r, J=6.8 Hz, 1H), 5.56 (s, 1H), 4.97 (d, J=4.5 Hz, 1H), 3.87-3.78 (m, 1H), 3.71-3.63 (m, 2H), 3.57-3 .51 (m, 1H), 2.93-2.85 (m, 4H), 2.75-2.67 (m, 1H), 2.16-2.09 (m, 1H), 1.70 (s, 6H), 1.63 (d, J=7.0 Hz, 7H); m/z (APCI+) for (C ₂₃ H ₃₀ ClFN ₆ O ₄ S), 540.8 (M+H) ⁺ .

Example A92 (Scheme A-13): Preparation of (3R,4R)-4-({5-chloro-4-[1-(1,1-difluoropropan-2-yl)-4-fluoro-2-(hydroxymethyl) -1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol

Scheme A-13:

2-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-6-(2,5-dichloropyrimidin-4-yl)-1-(1,1-difluoropropan-2-yl)-4 was added to the vial -fluoro-1H-benzimidazole (A-14) (prepared according to Example A89, 81 mg, 0.16 mmol), (3R,4R)-4-amino-1-(methanesulfonyl)piperidin-3-ol (Int -69) (46.7 mg, 0.24 mmol), Pd(OAc) ₂ (7.2 mg, 0.032 mmol), rac-BINAP (20.0 mg, 0.032 mmol), Cs ₂ CO ₃ (157 mg , 0.48 mmol) and THF (1.6 ml). The mixture was stirred at 80° C. in a microwave oven for 30 minutes. LCMS analysis showed consumption of starting material to form a mass of the desired product. The mixture was concentrated on SiO ₂ and purified by flash chromatography (ISCO, 12 g SiO ₂ , 0-100% EtOAc/heptane). Fractions containing product were concentrated and taken up in MeOH (5.0 ml). The mixture was treated with HCl (4.0N in 1,4-dioxane, 2.0 mL) and stirred at ambient temperature for 16 hours. LCMS analysis showed consumption of starting material to give a mass of the desired product. The mixture was concentrated to dryness and then purified by chiral SFC on a ChiralPak AS-H column (100×4.6 mm, particle size 3 μm) which was eluted with 5-60% MeOH/CO ₂ at a flow rate of 4.0 ml/min s obtaining (3R,4R)-4-({5-chloro-4-[1-(1,1-difluoropropan-2-yl)-4-fluoro-2-(hydroxymethyl)-1H-benzimidazol-6-yl] pyrimidin-2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol (Example A92) (7.4 mg, 8% yield) as the first eluting fraction. ¹ H NMR (400 MHz, DMSO-d ₆ , 80°C) δ 8.41 (s, 1H), 8.00 (s, 1H), 7.47 (d, J=11.6 Hz, 1H) , 7.19 (d, J=7.7 Hz, 1H), 6.52 (td, J=55.3, 3.7 Hz, 1H), 5.65 (t, J=5.7 Hz, 1H), 5.40-5.26 (m, 1H), 4.97 (d, J=4.6 Hz, 1H), 4.83 (d, J=5.6 Hz, 2H), 3, 87-3.76 (m, 1H), 3.72-3.62 (m, 2H), 3.59-3.51 (m, 1H), 2.95-2.84 (m, 4H), 2.75-2.66 (m, 1H), 2.17-2.09 (m, 1H), 1.75 (d, J=7.1 Hz, 3H), 1.65-1.54 ( m, 1H); m/z (ESI ⁺ ) for (C ₂₁ H ₂₄ ClF ₃ N ₆ O ₄ S), 522.9 (M+H) ⁺ ; [α] _D ²² = -26.5° (c=0.1 M, MeOH).

Example A93 (Scheme A-14): Preparation of (3R,4R)-4-[(5-chloro-4-{4-fluoro-2-[(1R)-1-hydroxyethyl]-1-(propane-2- yl)-1H-benzimidazol-6-yl}pyrimidin-2-yl)amino]-1-(methanesulfonyl)piperidin-3-ol

Scheme A-14:

Step 1: Synthesis of 5-bromo-3-fluoro-2-nitro-N-(propan-2-yl)aniline (A-16)

This conversion was carried out in four parallel batches. To a solution of 5-bromo-1,3-difluoro-2-nitrobenzene (A-15) (100 g, 420.2 mmol) in MeCN (2 L) was added i-PrNH ₂ (27.5 g, 441.2 mmol ) at 20-25°C (cooling in an ice bath) to obtain a yellow reaction solution. The resulting mixture was stirred at 35° C. for 60 hours. LCMS analysis showed consumption of starting material to form a mass of the desired product. The mixture was concentrated to dryness. The crude residue from four parallel reactions was combined and purified by flash chromatography (SiO ₂ , 0-2% EtOAc/petroleum ether) to give 5-bromo-3-fluoro-2-nitro-N-(propan-2-yl) aniline (A-16) (350 g, 75% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.09-7.00 (m, 2H), 6.90 (dd, J=11.1, 2.0 Hz, 1H), 3.94- 3.84 (m, 1H), 1.20 (d, J=6.3 Hz, 6H); m/z (ESI+) for (C ₉ H ₁₀ BrFN ₂ O ₂ ), 247.0 (M+H) ⁺ ; ¹⁹ F NMR (377 MHz, DMSO-d ₆ ) δ -116.9.

Step 2: Synthesis of 5-bromo-3-fluoro-N ¹ -(propan-2-yl)benzene-1,2-diamine (A-17)

To a stirred mixture of AcOH (2 L) and t-AmylOH (2 L) was added 5-bromo-3-fluoro-2-nitro-N-(propan-2-yl)aniline (A-16) (200 g, 721 mmol ) at 35°C. Fe ⁰ (282 g, 5.05 mol) was added in portions at 25-35° C. (cooling in an ice bath). The resulting mixture was stirred at 35° C. for 16 hours to give a white, yellowish or greyish suspension. TLC analysis (1:9 EtOAc/petroleum ether, R _f =0.8, UV254) showed consumption of starting material. The mixture was diluted with EtOAc (2 L) and H ₂ O (2 L). The mixture was neutralized by slow addition of solid Na ₂ CO ₃ . The suspension was filtered and the mixture was separated. The aqueous layer was extracted with EtOAc (3×1 L). The combined organic layers were washed with saturated aqueous NaHCO ₃ (2×1 L) and brine (2×1 L), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was combined with a parallel reaction in the same way with 150 g of 5-bromo-3-fluoro-2-nitro-N-(propan-2-yl)aniline (A-16). The mixture was purified by flash chromatography (SiO ₂ , 0-25% EtOAc/petroleum ether) to give 5-bromo-3-fluoro-N ¹ -(propan-2-yl)benzene-1,2-diamine (A- 17) (230 g, 74% yield) as a brown oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.55 (dd, J=10.0, 2.1 Hz, 1H), 6.38-6.34 (m, 1H), 4.93- 4.41 (m, 3H), 3.55 (hept, J=6.2 Hz, 1H), 1.14 (d, J=6.3 Hz, 6H); ¹⁹ F NMR (377 MHz, DMSO-d ₆ ) δ -132.8; m/z (ESI+) for (C ₉ H ₁₀ BrFN ₂ O ₂ ), 247.0 (M+H) ⁺ .

Step 3: Synthesis of (1R)-1-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]ethan-1-ol (Int-40)

A mixture of 5-bromo-3-fluoro-N ¹ -(propan-2-yl)benzene-1,2-diamine (A-17) (200.0 g, 809.4 mmol) and (2R)-2-hydroxypropanoic acid (605.1 g, 6.72 mol) was heated from 25°C to 85°C and then stirred at 85°C for 16 h. TLC analysis (1:1 EtOAc/petroleum ether), R _f =0, 5, UV254) showed consumption of starting material. The reaction mixture was cooled to 25°C and diluted with EtOAc (1 L) and H ₂ O (1 L). The mixture was basified with aqueous NaOH (50%, ~300 ml) to pH~8-9, keeping the internal temperature below 30° C. by cooling in an ice bath. The mixture was separated and the aqueous layer was extracted with EtOAc (2×1 L). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. MTBE (400 ml) and petroleum ether (200 ml) were added to the residue. A precipitate formed. The resulting suspension was stirred at 25° C. for 1 hour. The suspension was filtered off and the filter cake was washed with petroleum ether (2×80 ml). The filter cake was dried under vacuum to give (1R)-1-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]ethan-1-ol (Int-40 ) (150 g, 62% yield) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.80 (d, J=1.5 Hz, 1H), 7.27 (dd, J=10.1, 1.5 Hz, 1H), 5 .74 (d, J=6.6 Hz, 1H), 5.17-5.00 (m, 2H), 1.63-1.49 (m, 9H).

Step 4: Synthesis of (1R)-1-[4-fluoro-1-(propan-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-benzimidazol-2-yl]ethan-1-ol (A-18)

A stirred mixture of (1R)-1-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]ethan-1-ol (Int-40) (150.0 g , 498.1 mmol), B ₂ Pin ₂ (164.4 g, 647.5 mmol), PdCl ₂ (dppf) (18.2 g, 24.9 mmol) and KOAc (146.6 g, 1.49 mmol) in 1,4-dioxane (1.2 L) was heated from 25°C to 90°C. The reaction mixture was stirred at 90° C. for 3 h under N ₂ atmosphere. TLC analysis (1:1 EtOAc/petroleum ether, R _f =0.46, UV254) showed consumption of starting material. The reaction mixture was cooled to 25°C and quenched with H ₂ O (800 ml). The mixture was concentrated under vacuum to remove 1,4-dioxane. The residue was filtered off and the filter cake was washed with EtOAc (2×100 ml). The filtrate was extracted with EtOAc (2×800 ml, 400 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (SiO ₂ , 1:5 EtOAc/petroleum ether - 100% EtOAc) to give (1R)-1-[4-fluoro-1-(propan-2-yl)-6-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-2-yl]ethan-1-ol (A-18) (160 g, 92% yield) as light yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.73 (s, 1H), 7.35 (d, J=10.8 Hz, 1H), 5.17 (quin, J=6.4 Hz, 1H ), 4.95 (sept, J=7.0 Hz, 1H), 4.10 (d, J=7.0 Hz, 1H), 1.70-1.63 (m, 9H), 1.36 (s, 12H); m/z (ESI+) for (C ₁₈ H ₂₆ BFN ₂ O ₃ ), 348.9 (M+H) ⁺ .

Step 5: Synthesis of (1R)-1-[6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]ethan-1 -ola (A-19)

This conversion was carried out in two parallel batches. A stirred mixture of (1R)-1-[4-fluoro-1-(propan-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H -benzimidazol-2-yl]ethan-1-ol (A-18) (80 g, 230 mmol), 2,4,5-trichloropyrimidine (54.7 g, 299 mmol), Pd(PPh ₃ ) ₄ (26 .5 g, 22.9 mmol) and K ₂ CO ₃ (63.5 g, 459 mmol) in 1,4-dioxane (600 ml) and H ₂ O (250 ml) were purged with N ₂ . The mixture was stirred at 90° C. for 3 hours under N ₂ atmosphere. LCMS analysis showed consumption of starting material to form a mass of the desired product. The reaction mixture was cooled to room temperature and diluted with H ₂ O (500 ml). Two parallel reactions were combined and concentrated to remove 1,4-dioxane. The residue was filtered off and the filter cake was washed with EtOAc (2×150 ml). The mixture was separated. The organic layer was washed with brine (2 L), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (SiO ₂ , 1:5 EtOAc/petroleum ether → 100% EtOAc). Fractions containing the product were concentrated to ~400 ml, resulting in a precipitate. Solids were collected by filtration. The filter cake was washed with petroleum ether (200 ml) and dried under vacuum to give (1R)-1-[6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-(propan-2-yl) -1H-benzimidazol-2-yl]ethan-1-ol (A-19) (70 g, 39% yield) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.68 (s, 1H), 7.98 (d, J=1.5 Hz, 1H), 7.59 (dd, J=1.3, 11, 3 Hz, 1H), 5.19 (quin, J=7.0 Hz, 1H), 4.96 (sep, J=6.8 Hz, 1H), 3.11 (d, J=7.8 Hz , 1H), 1.75 (d, J=6.5 Hz, 3H), 1.71 (d, J=7.0 Hz, 6H); m/z (ESI+) for (C ₁₆ H ₁₅ Cl ₂ FN ₄ O), 368.8 (M+H) ⁺ .

Step 6: Synthesis of (3R,4R)-4-[(5-chloro-4-{4-fluoro-2-[(1R)-1-hydroxyethyl]-1-(propan-2-yl)-1H-benzimidazole -6-yl}pyrimidin-2-yl)amino]-1-(methanesulfonyl)piperidin-3-ol (Example A93)

This conversion was carried out in two parallel batches. To a stirred solution of (1R)-1-[6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]ethan-1- ol (A-19) (50 g, 135 mmol) and (3R,4R)-4-amino-1-(methanesulfonyl)piperidin-3-ol (Int-69) in DMSO (350 ml) DIPEA (85 7 g, 664 mmol). The reaction mixture was stirred at 60° C. for 56 hours. LCMS analysis showed consumption of starting material to form a mass of the desired product. The two parallel reactions were combined and filtered through a pad of celite. The filtrate was poured into a stirred saturated aqueous NaHCO ₃ solution (2 L). The mixture was extracted with DCM (3×2 L). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was dissolved in EtOAc (2 L). Sulfhydryl silica gel (Accela, 20 g, 0.7-1.4 mmol/g) was added and the mixture was stirred for 1 h at 30°C. The mixture was filtered and the filtrate was concentrated. The residue was purified by flash chromatography (SiO ₂ , 1:10 EtOAc/petroleum ether → 100% EtOAc). The product was taken up in EtOH (200 ml) and H ₂ O (800 ml) and then concentrated to remove EtOH. The aqueous solution was dried by lyophilization. The solids were dried at 50° C. for 48 hours under high vacuum to give (3R,4R)-4-[(5-chloro-4-{4-fluoro-2-[(1R)-1-hydroxyethyl]-1 -(propan-2-yl)-1H-benzimidazol-6-yl}pyrimidin-2-yl)amino]-1-(methanesulfonyl)piperidin-3-ol (Example A93) (95 g, 67% yield) as white solid. ¹ H NMR (400 MHz, 80°C, DMSO-d ₆ ) δ 8.40 (s, 1H), 7.99 (d, J=1.3 Hz, 1H), 7.42 (dd, J= 11.8, 1.3 Hz, 1H), 7.17 (d, J=7.7 Hz, 1H), 5.50 (d, J=6.2 Hz, 1H), 5.23 (hept, J=6.9Hz, 1H), 5.16-5.07(m, 1H), 4.97(d, J=4.6Hz, 1H), 3.88-3.77(m, 1H ), 3.73-3.62 (m, 2H), 3.58-3.52 (m, 1H), 2.94-2.86 (m, 4H), 2.76-2.68 (m , 1H), 2.17-2.08 (m, 1H), 1.69-1.54 (m, 10H); m/z (ESI+) for (C ₂₂ H ₂₈ ClFN ₆ O ₄ S), 526.8 (M+H) ⁺ ; [α] _D ²² = -11.4 (c=0.1, MeOH)

Example A94 (Scheme A-15): Preparation of 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2- yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol

Scheme A-15:

Step 1: Synthesis of 5-bromo-3-fluoro-2-nitro-N-(propan-2-yl)aniline (A-16)

This reaction was carried out in three parallel batches. To a stirred solution of 5-bromo-1,3-difluoro-2-nitrobenzene (A-15) (166 g, 697 mmol) in THF (1.7 L) was added i-PrNH ₂ (41.2 g, 697 mmol) and Cs ₂ CO ₃ . (455 g, 1.40 mol) at 15-30°C. After the addition, an exothermic effect was observed. The reaction mixture was stirred at 30° C. for 6 hours. TLC analysis (100% petroleum ether, UV254, R _f =0.35) showed consumption of starting material. United three reactionary parties. The combined mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (SiO ₂ , 0-2% EtOAc/petroleum ether) to give 5-bromo-3-fluoro-2-nitro-N-(propan-2-yl)aniline (A-16) ( 420 g, 72% yield as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.09-7.00 (m, 2H), 6.90 (dd, J=11.1, 2.0 Hz, 1H), 3.94- 3.84 (m, 1H), 1.20 (d, J=6.3 Hz, 6H); ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -116.9; m/z (ESI+) for (C ₉ H ₁₀ BrFN ₂ O ₂ ), 276.1 (M+H) ⁺ .

Step 2: Synthesis of 5-bromo-3-fluoro-N ¹ -(propan-2-yl)benzene-1,2-diamine (A-17)

This reaction was carried out in two parallel batches. NH ₄ Cl ( 81.1 g, 1.52 mol) in H ₂ O (0.9 L) and Fe ⁰ powder (212 g, 3.79 mol) at 15°C. The resulting mixture was heated to 68° C. (internal temperature) and stirred at the same temperature for 8 hours. TLC analysis (10% EtOAc/petroleum ether, UV254, R _f =0.8) showed consumption of starting material. The two reaction batches were cooled to room temperature and combined. The two reaction mixtures were combined and filtered. The filter cake was washed with MeOH (3×500 ml). The filtrate was concentrated in vacuo to remove most of the MeOH. The resulting aqueous mixture was extracted with EtOAc (3×1 L). The combined organic layers were washed with brine (2×800 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give 5-bromo-3-fluoro-N ¹ -(propan-2-yl)benzene-1,2-diamine (A-17) (350 g, 88% yield) as a violet solid which was used without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.55 (dd, J=10.0, 2.1 Hz, 1H), 6.38-6.34 (m, 1H), 4.93- 4.41 (m, 3H), 3.55 (hept, J=6.2 Hz, 1H), 1.14 (d, J=6.3 Hz, 6H); ¹⁹ F NMR (377 MHz, DMSO-d ₆ ) δ -132.8; m/z (ESI+) for (C ₉ H ₁₂ BrFN ₂ ), 246.6 (M+H) ⁺ .

Step 3: Synthesis of (1R)-1-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]ethan-1-ol (Int-20)

(2R)-2-hydroxypropanoic acid (951 g, 9.71 mol) was added to a 2 L 3-necked round bottom flask at 15° C. and the compound was heated to 85° C. (internal temperature). To the stirred solution at 85° C. was added portionwise 5-bromo-3-fluoro-N ¹ -(propan-2-yl)benzene-1,2-diamine (A-17) (300 g, 1.21 mol). The resulting mixture was stirred at 85°C (internal temperature) for 40 hours to obtain a purple reaction solution. TLC analysis (1:2 EtOAc/petroleum ether, UV254, R _f =0.8) showed consumption of starting material. The reaction mixture was cooled to room temperature and diluted with THF (1.5 L). The mixture was adjusted to pH~8 with saturated aqueous LiOH at 10-15° C. with cooling in an ice/water bath. The mixture was extracted with MTBE (3×1.5 L). The combined organic layers were washed with brine (2×800 ml), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated in vacuo to give (1R)-1-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]ethan-1-ol (A-18) ( 330 g, 90% yield as a brown solid, which was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.80 (d, J=1.5 Hz, 1H), 7.27 (dd, J=10.1, 1.5 Hz, 1H), 5 .74 (d, J=6.6 Hz, 1H), 5.17-5.00 (m, 2H), 1.63-1.49 (m, 9H); ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -126.3; m/z (ESI+) for (C ₁₂ H ₁₄ BrFN ₂ O), 302.6 (M+H) ⁺ .

Step 4: Synthesis of 1-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]ethan-1-one (A-20)

To a stirred solution of compound (1R)-1-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]ethan-1-ol (Int-20) (365 g , 1.21 mol) in CHCl ₃ (3 L) was added activated MnO ₂ (738 g, 8.48 mol) at room temperature. The reaction mixture was heated to 58° C. (internal temperature) and stirred at the same temperature for 16 h. TLC analysis (1:2 EtOAc/petroleum ether, UV254, R _f =0.3) showed consumption of starting material. The reaction mixture was cooled to room temperature and filtered through a pad of celite. The filter cake was washed with EtOAc (3×500 ml) and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (SiO ₂ , 0-30% EtOAc/petroleum ether) to give 1-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl ]ethan-1-one (A-20) (362 g, 99% yield) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.54 (d, J=1.6 Hz, 1H), 7.12 (dd, J=9.5, 1.5 Hz, 1H), 5.82 (hept, J=7.0 Hz, 1H), 2.79 (s, 3H), 1.56 (d, J=7.0 Hz, 6H); ¹⁹ F NMR (377 MHz, DMSO-d ₆ ) δ -124.1; m/z (ESI+) for (C ₁₂ H ₁₂ BrFN ₂ O), 300.6 (M+H) ⁺ .

Step 5: Synthesis of 2-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]propan-2-ol (A-21)

This reaction was carried out in two parallel batches. Solution of 1-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]ethan-1-one (A-20) (165 g, 552 mmol) in THF ( 1.7 l) was degassed and purged with N ₂ three times. The stirred solution was cooled to 0-5° C. (internal temperature) in an ice/brine bath and a solution of MeMgBr (3.0 M in Et ₂ O, 221 ml) was added dropwise. During the addition, the purple solution turned into a gray suspension. The resulting mixture was stirred at 0-5° C. with cooling in an ice bath and brine for 3 hours. TLC analysis (20% EtOAc/petroleum ether, UV254, R _f = 0.8) showed consumption of starting material. The reaction mixture was slowly quenched with saturated aqueous NH ₄ Cl (400 ml) at 0-5° C. with ice-brine bath cooling and then stirred at room temperature for 1 h. The two reaction batches were combined and diluted with EtOAc (1 L) . The organic layer was separated. The aqueous layer was extracted with EtOAc (2×1 L). The combined organic layers were dried over MgSO ₄ , filtered and concentrated. The crude residue was purified by flash chromatography (SiO ₂ , 0-50% EtOAc/petroleum ether) to give 2-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2- yl]propan-2-ol (A-21) (316 g, 91% yield) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.49 (d, J=1.6 Hz, 1H), 7.08 (dd, J=9.7, 1.5 Hz, 1H), 5.45 (hept, J=7.0 Hz, 1H), 2.87 (s, 1H), 1.77 (s, 6H), 1.63 (d, J=7.0 Hz, 6H); ¹⁹ F NMR (377 MHz, DMSO-d ₆ ) δ -126.3; m/z (ESI+) for (C ₁₃ H ₁₆ BrFN ₂ O), 314.7 (M+H) ⁺ .

Step 6: Synthesis of 2-[4-fluoro-1-(propan-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazole -2-yl]propan-2-ol (A-22)

2-[6-Bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]propan-2-ol (A-21) (300 g, 952 mmol), B ₂ Pin ₂ (290 g, 1.14 mol), Pd(dppf)Cl ₂ (34.8 g, 47.6 mmol), KOAc (280 g, 2.86 mol) and 1.4 -dioxane (2 l). The reaction mixture was degassed and purged with N ₂ three times. The reaction mixture was heated to 90°C (internal temperature) and stirred at this temperature for 3 h to obtain an orange suspension. TLC analysis (1:2 EtOAc/petroleum ether, UV254, R _f =0.4) showed consumption of starting material. The reaction mixture was cooled to room temperature and filtered. The filtrate was diluted with EtOAc (2 L) and washed with brine (2×1 L). The organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography (SiO ₂ , 10-50% EtOAc/petroleum ether) to give 2-[4-fluoro-1-(propan-2-yl)-6-(4,4,5,5- tetramethyl)-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-2-yl]propan-2-ol (A-22) (210 g, 61% yield) as a light yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.77 (s, 1H), 7.34 (d, J=10.8 Hz, 1H), 5.41 (hept, J=6.9 Hz, 1H ), 3.10 (s, 1H), 1.79 (s, 6H), 1.69 (d, J=7.0 Hz, 6H), 1.36 (s, 12H); ¹⁹ F NMR (377 MHz, DMSO-d ₆ ) δ -129.5; m/z (ESI+) for (C ₁₃ H ₁₆ FN ₂ O), 362.9 (M+H) ⁺ .

Step 7: Synthesis of 2-[6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]propan-2-ol (A -23)

This reaction was carried out in two parallel batches. To a mixture of the compound 2-[4-fluoro-1-(propan-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol- 2-yl]propan-2-ol (A-22) (100 g, 276 mmol) and Na ₂ CO ₃ (87.8 g, 828 mmol) in 1,4-dioxane (1 L) and H ₂ O ( 300 ml) was added 2,4,5-trichloropyrimidine (67.2 g, 359 mmol). The mixture was degassed and purged with N ₂ three times. Pd(PPh ₃ ) ₄ (31.9 g, 27.6 mmol) was added and the mixture was degassed and purged with N ₂ three times. The reaction mixture was placed in a preheated 100° C. oil bath and stirred at 90° C. (internal temperature) for 24 hours. LCMS showed consumption of starting material to yield a mass of desired product. The reaction mixture was cooled to room temperature. The two reaction mixtures were combined. The combined mixture was filtered and concentrated in vacuo to remove 1,4-dioxane. The residue was diluted with EtOAc (1 L) and the organic layer was collected. The aqueous layer was extracted with EtOAc (3×1 L). The combined organic layers were dried over MgSO ₄ , filtered, concentrated. The crude residue was purified by flash chromatography (SiO ₂ , 0-50% EtOAc in 1:5 petroleum ether/DCM). Fractions containing the product were concentrated under vacuum to ~200 ml with simultaneous precipitation of a white solid. The suspension was filtered and the filter cake was washed with petroleum ether (2×300 ml). The filter cake was collected and dried under vacuum to give 2-[6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]propane -2-ol (A-23) (112 g). The filtrate was concentrated and the residue was repurified by flash chromatography (SiO ₂ , 0-50% EtOAc in 1:5 petroleum ether/DCM). Fractions containing the product were concentrated under vacuum to ~50 ml with precipitation of additional product. The suspension was filtered and the filter cake was washed with petroleum ether (2×100 ml). The filter cake was collected and dried under vacuum to give an additional batch of 2-[6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl ]propan-2-ol (A-23) (41 g). Batches of product were combined to give 2-[6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]propan-2-ol ( A-23) (153 g, 71% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.01 (s, 1H), 8.06 (d, J=1.3 Hz, 1H), 7.41 (dd, J=11.5, 1.3 Hz, 1H), 5.85-5.72 (m, 2H), 1.67 (s, 6H), 1.61 (d, J=7.0 Hz, 6H); ¹⁹ F NMR (377 MHz, CDCl ₃ ) δ -128.2; m/z (ESI+) for (C ₁₇ H ₁₇ Cl ₂ FN ₄ O), 383.0 (M+H) ⁺ .

Step 8: Synthesis of 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1H-benzimidazole -6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol (Example A94)

2-[6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]propan-2- ol (A-23) (112 g, 292 mmol), 3-amino-1,5-anhydro-2,3-dideoxy-D-threo-pentitol hydrochloride (51.6 g, 336 mmol) and MeCN (1, 1 l). DIPEA (132 g, 1.02 mol, 178 ml) was added at room temperature. The reaction mixture was heated to 80°C (internal temperature) and stirred at the same temperature for 40 h to obtain a brown solution. LCMS analysis showed remaining starting material. Additional 3-amino-1,5-anhydro-2,3-dideoxy-D-threo-pentitol hydrochloride (6.73 g, 43.8 mmol) was added at 80°C (internal temperature) and the reaction mixture was stirred at 80 °C (internal temperature) for an additional 10 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in 1:1 EtOAc/H ₂ O (1.5 L). Some solid particles precipitated. EtOH (100 ml) was added. The organic layer was collected and the aqueous layer was extracted with EtOAc (2×500 ml). The combined organic layers were washed with H ₂ O (2×300 ml), dried over Na ₂ SO ₄ and filtered. Sulfhydryl silica gel (Accela, 8 g, 0.7-1.4 mmol/g) was added to the filtrate. The resulting mixture was stirred at room temperature for 1 hour and then filtered through a pad of celite. The treatment with sulfhydryl silica gel was repeated in an identical manner and the filtrate was concentrated to dryness. The crude residue was suspended in MeCN (500 ml) at room temperature for 16 hours. The suspension was filtered and the filter cake was washed with MeCN (2×100 ml). The filter cake was resuspended with MeCN (300 ml) at room temperature for 6 hours. The mixture was filtered and the filter cake was washed with MeCN (2×100 ml). The filter cake was collected and dried under vacuum and then dried in an oven (45°C for 20 h, 50°C for 64 h) to give 1,5-anhydro-3-({5-chloro-4 -[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy -D-threo-pentitol (Example A94) (90 g, 66% yield) as a white solid. ¹ H NMR (400 MHz, 80°C, DMSO-d ₆ ) δ 8.38 (s, 1H), 8.00 (s, 1H), 7.43 (d, J=11.8 Hz, 1H) , 7.13 (d, J=7.5 Hz, 1H), 5.80 (hept, J=7.0 Hz, 1H), 5.56 (s, 1H), 4.71 (d, J= 5.3 Hz, 1H), 3.91-3.79 (m, 3H), 3.61-3.52 (m, 1H), 3.41-3.31 (m, 1H), 3.12 -3.07 (m, 1H), 2.09-2.00 (m, 1H), 1.70 (s, 6H), 1.67-1.52 (m, 7H); ¹⁹ F NMR (377 MHz, CDCl ₃ ) δ -127.2; m/z (ESI+) for (C ₂₂ H ₂₇ ClFN ₅ O ₃ ), 464.2 (M+H) ⁺ ; [α] _D ²² = -12.6 (c=0.2, MeOH).

Alternative preparation of 2-[6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]propan-2-ol (A-23 ) in accordance with Diagram A-16

Step 1: Synthesis of 1-[6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]ethan-1-one (A -19)

To a solution of (1S)-1-[6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]ethan-1-ol (A-19) (3.86 g, 10.5 mmol) in DMSO (130 ml) was added Et ₃ N (10.6 g, 105 mmol). A complex of sulfur trioxide and pyridine (10 g, 62.7 mmol) was added and the mixture was stirred at ambient temperature. After 4 hours, LCMS analysis showed ~10% residual starting material. Added additional amount of complex of sulfur trioxide and pyridine (4.7 g). After 1 hour, LCMS analysis indicated consumption of starting material. The mixture was partitioned between H ₂ O and EtOAc. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with H ₂ O, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (ISCO, 80 g SiO ₂ , 10-40% EtAOc/heptane) to give 1-[6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-(propane -2-yl)-1H-benzimidazol-2-yl]ethan-1-one (A-24) (3.1 g, 80% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.06 (s, 1H), 8.20 (d, J=1.3 Hz, 1H), 7.55 (dd, J=11.4, 1.3 Hz, 1H), 5.77 (hept, J=7.1 Hz, 1H), 2.79 (s, 3H), 1.61 (d, J=7.0 Hz, 6H); m/z (APCI) for (C ₁₆ H ₁₃ Cl ₂ FN ₄ O), 366.8 (M+H) ⁺ .

Step 2: Synthesis of 2-[6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]propan-2-ol (A -23)

1-[6-(2,5-Dichloropyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]ethan-1-one solution (A-24) (3.1 g, 8.7 mmol) in THF (87 ml) was cooled to 0° C. under N ₂ atmosphere. A solution of methyl magnesium bromide (3.0 M in Et ₂ O, 4.0 ml, 12 mmol) was added dropwise. The mixture was stirred for 30 min at 0°C. LCMS analysis showed consumption of starting material to form a mass of the desired product. The reaction was quenched with saturated aqueous NH ₄ Cl and partitioned between EtOAc and H ₂ O. The aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (ISCO, 80 g SiO ₂ , 20-60% EtOAc/heptane) to give 2-[6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-(propane -2-yl)-1H-benzimidazol-2-yl]propan-2-ol (A-23) (3.11 g, 93% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.01 (s, 1H), 8.06 (d, J=1.3 Hz, 1H), 7.41 (dd, J=11.5, 1.3 Hz, 1H), 5.85-5.72 (m, 2H), 1.67 (s, 6H), 1.61 (d, J=7.0 Hz, 6H); m/z (APCI) for (C ₁₇ H ₁₇ Cl ₂ FN ₄ O), 382.8 (M+H) ⁺ .

Example B1 (Scheme B): Preparation of 4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]-2-{[(3R,4R)-3- hydroxy-1-(methanesulfonyl)piperidin-4-yl]amino}pyrimidine-5-carbonitrile

Scheme B:

Step 1: Synthesis of 4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]-2-(methylsulfanyl)pyrimidine-5-carbonitrile (B-1)

To a mixture of 4-chloro-2-(methylsulfanyl)pyrimidine-5-carbonitrile (150 mg, 0.808 mmol), 4-fluoro-2-methyl-1-(propan-2-yl)-6-(4.4.5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazole (A-1) (257 mg, 0.808 mmol) and K ₂ CO ₃ (335 mg, 2.42 mmol) in 1, 4-dioxane (15.0 ml) and H ₂ O (2.1 ml) was added Pd(t-Bu ₃ P) ₂ (41.3 mg, 0.0808 mmol). The reaction mixture was purged with N ₂ and then stirred at 80° C. for 1 hour. LCMS analysis showed consumption of starting material to form a mass of the desired product. The mixture was combined with the second reaction in the same way with 85.7 mg of 4-fluoro-2-methyl-1-(propan-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-benzimidazole (A-1). The mixture was diluted with EtOAc (20 ml) and washed with H ₂ O (5 ml). The aqueous layer was extracted with EtOAc (3×10 ml). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (Biotage, SiO ₂ , 1:1 petroleum ether/EtOAc) to give 4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6- yl]-2-(methylsulfanyl)pyrimidine-5-carbonitrile (B-1) (280 mg, 76% yield) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.78 (s, 1H), 8.31-8.22 (m, 1H), 7.82-7.72 (m, 1H), 2.71 ( s, 3H), 2.69 (s, 3H), 2.67-2.64 (m, 1H), 1.72 (d, J=6.8 Hz, 6H); m/z (ESI) for (C ₁₇ H ₁₆ FN ₅ S), 342.0 (M+H) ⁺ .

Step 2: Synthesis of 4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]-2-(methanesulfinyl)pyrimidine-5-carbonitrile (B-2)

To a solution of 4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]-2-(methylsulfanyl)pyrimidine-5-carbonitrile (B-1) (200 mg , 0.586 mmol) in THF (9.0 ml) and H ₂ O (4.5 ml) was added oxone (540 mg, 0.879 mmol) at 10°C. The resulting mixture was stirred at the same temperature for 1.5 hours. LCMS analysis showed consumption of the starting material to form a mass of the desired product. The reaction was combined with the parallel reaction in an identical manner with 80 mg of 4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]-2-(methylsulfanyl)pyrimidine-5-carbonitrile (B-1). The combined solution was diluted with EtOAc (20 ml) and washed with brine (10 ml). The aqueous layer was extracted with EtOAc (4×10 ml). The combined organic layers were washed with brine (10 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give 4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6- yl]-2-(methanesulfinyl)pyrimidine-5-carbonitrile (B-2) (250 mg, 85% yield) as a white to yellowish or greyish solid which was used without further purification. m/z (ESI) for (C ₁₇ H ₁₆ FN ₅ OS), 358.3 (M+H) ⁺ .

Step 3: Synthesis of 4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]-2-{[(3R,4R)-3-hydroxy-1- (methanesulfonyl)piperidin-4-yl]amino}pyrimidine-5-carbonitrile (Example B1)

To a mixture of 4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]-2-(methanesulfinyl)pyrimidine-5-carbonitrile (B-2) (120 mg , 0.336 mmol) and (3R,4R)-4-amino-1-(methanesulfonyl)piperidin-3-ol (Int-69) in THF (15.0 ml) were added Na ₂ CO ₃ (71.2 mg, 0.672 mmol). The resulting mixture was stirred at 65° C. for 12 hours. LCMS analysis showed consumption of starting material to form a mass of the desired product. The mixture was diluted with EtOAc (30 ml) and washed with H ₂ O (10 ml). The aqueous layer was extracted with EtOAc (2×20 ml). The combined organic layers were washed with brine (10 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative TLC (SiO ₂ , 10:1 DCM/MeOH, R _f =0.55). The material was further purified by preparative HPLC on a YMC-Actus Triart C18 column (150×30 mm, particle size 5 μm) which was eluted with 8-48% MeCN/H ₂ O (+0.225% formic acid) to give 4-[4 -fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]-2-{[(3R,4R)-3-hydroxy-1-(methanesulfonyl)piperidin-4-yl ]amino}pyrimidine-5-carbonitrile (Example B1) (50 mg, 31% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.82-8.74 (m, 1H), 8.43-8.32 (m, 1H), 8.21-8.11 (m, 1H ), 7.59-7.48 (m, 1H), 5.35-5.28 (m, 1H), 4.88-4.76 (m, 1H), 4.05-3.90 (m , 1H), 3.70-3.59 (m, 2H), 3.56-3.47 (m, 1H), 2.91-2.81 (m, 4H), 2.71-2.59 (m, 4H), 2.10-1.95 (m, 1H), 1.65-1.51 (m, 7H); m/z (ESI) for (C ₂₃ H ₂₇ FN ₆ O ₃ S), 488.1 (M+H) ⁺ .

The example in the table below was synthesized according to the methods used for the synthesis of 4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]-2-{[(3R ,4R)-3-hydroxy-1-(methanesulfonyl)piperidin-4-yl]amino}pyrimidine-5-carbonitrile (Example B1). The following example has been synthesized with non-critical modifications or substitutions to the illustrated techniques that a person skilled in the art could implement.

Example number Structure/Name HCMS NMR B2

(3R,4R)-4-({4-[4-фтор-1-(пропан-2-ил)-1H-бензимидазол-6-ил]-5-(трифторметил)пиримидин-2-ил}амино)-1-(метансульфонил)пиперидин-3-ол

(3R,4R)-4-({4-[4-fluoro-1-(propan-2-yl)-1H-benzimidazol-6-yl]-5-(trifluoromethyl)pyrimidin-2-yl}amino)- 1-(methanesulfonyl)piperidin-3-ol 516.9 [M+H]+ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.71-8.66 (m, 1H), 8.51 (s, 1H), 8.20-8.09 (m, 1H), 7, 64 (s, 1H), 7.23-7.14 (m, 1H), 5.27 (br. s, 1H), 4.79 (hept, J=6.6 Hz, 1H), 3.99 -3.80 (m, 1H), 3.67-3.56 (m, 2H), 3.54-3.42 (m, 1H), 2.94-2.77 (m, 4H), 2 .70-2.58 (m, 1H), 2.08-1.97 (m, 1H), 1.61-1.49 (m, 7H)

Example C1 (Scheme C-1): Preparation of (3R,4R)-4-({4-[5-chloro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]- 5-fluoropyrimidin-2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol

Scheme C-1:

Step 1: Synthesis of 2-chloro-4-(2-chloro-5-fluoro-4-nitrophenyl)-5-fluoropyrimidine (C-2)

KOAc (579 mg , 5.9 mmol) and B ₂ Pin ₂ (749 mg, 2.95 mmol). The mixture was purged with N ₂ and then PdCl ₂ (dppf) was added. The mixture was stirred at 70° C. using microwave radiation for 30 minutes. LCMS analysis showed consumption of starting material with conversion to boronate ester. To the mixture were added 2,4-dichloro-5-fluoropyrimidine, aqueous Na ₂ CO ₃ (2.0 M, 2.95 ml) and PdCl ₂ (dppf) (80 mg, 0.1 mmol). The mixture was stirred at 50° C. using microwave radiation for 2 hours. LCMS analysis showed consumption of the boronate ester to form the mass of the desired product. The mixture was combined with a parallel reaction in an identical manner with 100 mg of 1-bromo-2-chloro-5-fluoro-4-nitrobenzene (C-1). The combined mixture was partitioned between EtOAc and H ₂ O. The organic layer was washed with brine, dried over MgSO ₄ , filtered and concentrated on SiO ₂ . The crude material was purified by flash chromatography (ISCO, 40 g SiO ₂ , 0-30% EtOAc/heptane) to give 2-chloro-4-(2-chloro-5-fluoro-4-nitrophenyl)-5-fluoropyrimidine ( C-2) (120 mg, 20% yield) as a white to yellowish or grayish solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) 9.19 (d, J=1.3 Hz, 1H), 8.53 (d, J=6.7 Hz, 1H), 8.01 (d, J=11.0 Hz, 1H); m/z (ESI) for (C ₁₀ H ₃ Cl ₂ F ₂ N ₃ O ₂ ), 304.7 (M+H) ⁺ .

Step 2: Synthesis of 5-chloro-6-(2-chloro-5-fluoropyrimidin-4-yl)-2-methyl-1-(propan-2-yl)-1H-benzimidazole (C-3)

A mixture of 2-chloro-4-(2-chloro-5-fluoro-4-nitrophenyl)-5-fluoropyrimidine (C-2) (55 mg, 0.018 mmol) and i-PrNH ₂ (0.016 ml, 0.018 mmol) in DMSO (1 ml) was stirred at 50° C. using microwave radiation for 1.5 h. LCMS analysis indicated consumption of starting material. After cooling to room temperature, the mixture was diluted with EtOH (0.5 ml) and treated with acetaldehyde (39.6 mg, 0.05 ml, 0.899 mmol) and Na ₂ S ₂ O ₄ (156 mg, 0.899 mmol). The mixture was stirred at 80° C. for 16 hours overnight. LCMS analysis showed mass formation of the desired product. The mixture was concentrated to remove EtOH. The remaining DMSO solution was added dropwise to saturated aqueous NaHCO ₃ . The resulting yellow solids were collected by filtration and washed with H ₂ O. The solids were taken up in DCM/MeOH and concentrated to give 5-chloro-6-(2-chloro-5-fluoropyrimidin-4-yl)-2-methyl-1-( propan-2-yl)-1H-benzimidazole (C-3) (28 mg, 46% yield), which was used without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.05 (s, 1H), 7.97 (s, 1H), 7.79 (s, 1H), 4.79 (sep, J=6, 8 Hz, 1H), 2.62 (s, 3H), 1.55 (d, J=7.0 Hz, 6H). m/z (ESI) for (C ₁₀ H ₃ Cl ₂ F ₂ N ₃ O ₂ ), 304.7 (M+H) ⁺ .

Step 3: Synthesis of (3R,4R)-4-({4-[5-chloro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]-5-fluoropyrimidin-2- yl}amino)-1-(methanesulfonyl)piperidin-3-ol (Example C1)

To a solution of 5-chloro-6-(2-chloro-5-fluoropyrimidin-4-yl)-2-methyl-1-(propan-2-yl)-1H-benzimidazole (C-3) (28 mg, 0.083 mmol ) in THF (1.0 ml) was added (3R,4R)-4-amino-1-(methanesulfonyl)piperidin-3-ol (Int-69) (24.1 mg, 0.124 mmol) and Cs ₂ CO ₃ ( 81 mg, 0.25 mmol). The mixture was purged with N ₂ and then Pd(OAc) ₂ (3.71 mg, 0.0165 mmol) and rac-BINAP (10 mg, 0.0165 mmol) were added. The mixture was heated to 80° C. overnight. LCMS analysis showed consumption of starting material to form a mass of the desired product. The mixture was partitioned between EtOAc and H ₂ O. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO ₄ , filtered and concentrated. The residue was purified by preparative SFC on a HA-morpholine column (150 x 21.1 mm, particle size 5 μm, column temperature 35°C) eluted with 10-50% MeOH/CO ₂ at a flow rate of 80 g/min. The material was repurified by preparative SFC on a 3-hydroxyphenyl Nacalai Cosmosil column (150×20 mm, particle size 5 μm, column temperature 35°C) eluted with 12-50% MeOH/CO ₂ at a flow rate of 80 g/min s obtaining (3R,4R)-4-({4-[5-chloro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]-5-fluoropyrimidin-2-yl}amino )-1-(methanesulfonyl)piperidin-3-ol (Example C1) (16 mg, 38% yield) as a solid. ¹ H NMR (600 MHz, DMSO-d ₆ , 75°C) δ 8.35-8.33 (m, 1H), 7.71 (s, 1H), 7.68 (s, 1H), 6, 84 (d, J=7.3 Hz, 1H), 5.13 (d, J=4.0 Hz, 1H), 4.78-4.72 (m, 1H), 2.86-2.81 (m, 4H), 2.69-2.63 (m, 1H), 2.57 (s, 3H), 2.14-2.09 (m, 1H), 1.59-1.43 (m , 7H); four protons are hidden by the residual solvent peak; m/z (ESI) for (C ₂₁ H ₂₆ ClFN ₆ O ₃ S), 496.9 (M+H) ⁺ .

Example C2 (Scheme C-2): Preparation of 1,5-anhydro-3-({4-[2-(azetidin-3-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazole -6-yl]-5-chloropyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol

Scheme C-2:

Solution (C-4) (as prepared in Example C1, 155.0 mg, 0.22 mmol), 3-amino-1,5-anhydro-2,3-dideoxy-D-threo-pentitol (49.8 mg , 0.324 mmol) and DIPEA (126 mg, 0.173 mmol, 0.973 mmol) in DMSO (2 ml) were heated to 80° C. for 16 hours overnight. LCMS analysis showed consumption of starting material to form a mass of the desired product. The mixture was loaded directly onto SiO ₂ and purified by flash chromatography (ISCO, 12 g SiO ₂ , 0-100% EtOAc/heptane). Fractions containing product were concentrated, taken up in DCM (5 ml) and treated with HCl solution (4.0 N in 1,4-dioxane, 1.0 ml). After 15 minutes, LCMS analysis showed conversion to the desired product. The reaction mixture was concentrated to dryness. The residue was purified using preparative SFC on a ChiralPak IC column (column 21×250 mm, particle size 10 μm, column temperature 35°C), which was eluted with 60% MeOH/CO ₂ (+10 mm NH ₃ ) with a flow rate of 82 ml/ min to give 1,5-anhydro-3-({4-[2-(azetidin-3-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-6-yl)]- 5-chloropyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol (Example C2) (72 mg, 72% yield) as a solid. ¹ H NMR (400 MHz, DMSO-d6, 80°C) δ 8.39 (s, 1H), 7.96 (s, 1H), 7.45 (d, J=11.7 Hz, 1H), 7.13 (d, J=7.6 Hz, 1H), 4.78-4.58 (m, 2H), 4.39-4.29 (m, 1H), 4.15-3.99 ( m, 2H), 3.92-3.77 (m, 5H), 3.66-3.52 (m, 2H), 3.39-3.31 (m, 1H), 2.09-1, 97 (m, 1H), 1.64-1.53 (m, 7H); m/z (ESI) for (C ₂₂ H ₂₆ ClFN ₆ O ₂ ), 461.1 (M+H) ⁺ .

Example D1 (Scheme D-1): Preparation of (3R,4R)-4-[(5-chloro-4-{4-fluoro-2-[(1S)-1-hydroxyethyl]-1-(propane-2) -yl)-1H-benzimidazol-6-yl}pyridin-2-yl)amino]-1-(methanesulfonyl)piperidin-3-ol

Diagram D-1:

Step 1: Synthesis of (1S)-1-[6-(2,5-dichloropyridin-4-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]ethan-1 -ola (D-2):

To a solution of (1S)-1-[4-fluoro-1-(propan-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H -benzimidazol-2-yl]ethan-1-ol (D-1) (prepared as in Example A1, 650 mg, 1.87 mmol) in H ₂ O (2.0 ml) and 1,4-dioxane ( 7.0 ml) was added 2,5-dichloro-4-iodopyridine (562 mg, 2.05 mmol), Na ₂ CO ₃ (396 mg, 3.73 mmol) and Pd(PPh ₃ ) ₄ (216 mg, 0.187 mmol). The reaction mixture was stirred at 90° C. under N ₂ atmosphere. LCMS analysis showed consumption of starting material to form a mass of the desired product. The reaction mixture was concentrated to dryness. The residue was purified by flash chromatography (ISCO, 40 g SiO ₂ , 2:1 petroleum ether/EtOAc) to give (1S)-1-[6-(2,5-dichloropyridin-4-yl)-4-fluoro- 1-(propan-2-yl)-1H-benzimidazol-2-yl]ethan-1-ol (D-2) (490 mg, 71% yield) as a light yellow solid. m/z (ESI+) for (C ₁₇ H ₁₆ Cl ₂ FN ₃ O), 368.0 (M+H) ⁺ .

Step 2: Synthesis of (3R,4R)-4-[(5-chloro-4-{4-fluoro-2-[(1S)-1-hydroxyethyl]-1-(propan-2-yl)-1H-benzimidazole -6-yl}pyridin-2-yl)amino]-1-(methanesulfonyl)piperidin-3-ol (Example D1):

A heterogeneous mixture of (1S)-1-[6-(2,5-dichloropyridin-4-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]ethan-1-ol (D-2) (390 mg, 1.06 mmol), (3R,4R)-4-amino-1-(methanesulfonyl)piperidin-3-ol (Int-69) (411 mg, 2.12 mmol), Cs ₂ CO ₃ (1.04 g, 3.18 mmol) and Brettphos-Pd-G3 (96 mg, 0.106 mmol) in 1,4-dioxane (4.0 ml) and DMF (2.0 ml) were purged with N ₂ for 3 minutes and then stirred at 110° C. for 4 hours. LCMS analysis showed consumption of starting material to form a mass of the desired product. The reaction mixture was filtered and concentrated to dryness. The residue was purified by flash chromatography (ISCO, 40 g SiO ₂ , 0-15% MeOH/EtOAc) and then repurified by preparative HPLC on an Xtimate C18 column (250×80 mm, particle size 10 μm), which was eluted with 30 -50% MeCN/H ₂ O (+0.05% NH ₄ OH) with a flow rate of 25 ml/min. HPLC analysis showed some violation of enantiopure (e.i. 93%). The material was repurified with chiral preparative SFC on a Diacel Chiralpak AD-H column (250×30 mm, particle size 5 μm) eluted with 45% IPA/CO ₂ (+0.1% NH ₃ ) at a flow rate of 50 ml/ min, to give (3R,4R)-4-[(5-chloro-4-{4-fluoro-2-[(1S)-1-hydroxyethyl]-1-(propan-2-yl)-1H-benzimidazole -6-yl}pyridin-2-yl)amino]-1-(methanesulfonyl)piperidin-3-ol (Example D1) (40.1 mg, 7% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ +D ₂ O) δ 7.99 (br. s, 1H), 7.54 (s, 1H), 7.07 (d, J=10.8 Hz, 1H), 6.62 (s, 1H), 5.13-5.02 (m, 2H), 3.70-3.66 (m, 1H), 3.65-3.45 (m, 3H) , 2.85-2.80 (m, 4H), 2.70-2.62 (m, 1H), 2.05-2.00 (m, 1H), 1.59-1.4 (m, 10H); m/z (ESI+) for (C ₂₃ H ₂₉ ClFN ₅ O ₄ S), 525.8 (M+H) ⁺ .

Example D2 (Scheme D-2): Preparation of 1,5-anhydro-3-[(5-chloro-4-{4-fluoro-2-[(1S)-1-hydroxyethyl]-1-(propane-2- yl)-1H-benzimidazol-6-yl}pyridin-2-yl)amino]-2,3-dideoxy-D-threo-pentitol

Scheme D-2:

A suspension of (1S)-1-[6-(2,5-dichloropyridin-4-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]ethan-1-ol ( D-3) (as prepared in Example D1, 680 mg, 1.85 mmol), 3-amino-1,5-anhydro-2,3-dideoxy-D-threo-pentitol (324 mg, 2.77 mmol) , BINAP (92 mg, 0.148 mmol), t-BuONa (532 mg, 5.54 mmol) and Pd ₂ (dba) ₃ (84.6 mg, 0.092 mmol) in PhMe (15.0 ml) were purged with N ₂ in for 3 minutes and then stirred at 110° C. for 16 hours. LCMS analysis showed consumption of starting material to form a mass of the desired product. The reaction mixture was concentrated to dryness. The residue was purified by flash chromatography (ISCO, 40 g SiO ₂ , 0-20% MeOH/EtOAc). The material was repurified by preparative HPLC on an Xtimate C18 column (250×80 mm, particle size 10 μm) which was eluted with 30-50% MeCN/H ₂ O (+0.05% NH ₄ OH) at a flow rate of 25 ml/ min to obtain 1,5-anhydro-3-[(5-chloro-4-{4-fluoro-2-[(1S)-1-hydroxyethyl]-1-(propan-2-yl)-1H-benzimidazol- 6-yl}pyridin-2-yl)amino]-2,3-dideoxy-D-threo-pentitol (Example D2) (67 mg, 8% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.06 (s, 1H), 7.58 (d, J=1.3 Hz, 1H), 7.07 (dd, J=11.5, 1.3 Hz, 1H), 6.80 (d, J=7.3 Hz, 1H), 6.65 (s, 1H), 5.74 (d, J=6.5 Hz, 1H), 5 .24-5.01 (m, 3H), 3.84-3.71 (m, 3H), 3.08 (dd, J=9.5, 10.8 Hz, 1H), 2.06-1 .98 (m, 1H), 1.64-1.55 (m, 9H), 1.44-1.33 (m, 1H); two hydrogens are covered by the residual solvent peak; m/z (ESI+) for (C ₂₂ H ₂₆ ClFN ₄ O ₃ ), 449.1 (M+H) ⁺ .

The example in the table below was synthesized according to the methods used for the synthesis of 1,5-anhydro-3-[(5-chloro-4-{4-fluoro-2-[(1S)-1-hydroxyethyl]-1-( propan-2-yl)-1H-benzimidazol-6-yl}pyridin-2-yl)amino]-2,3-dideoxy-D-threo-pentitol (Example D2). The following example has been synthesized with non-breaking changes or substitutions to the illustrated techniques that a person skilled in the art could implement.

Example number Structure/Name HCMS NMR D3

(3R,4R)-4-[(5-хлор-4-{4-фтор-2-[(1R)-1-гидроксиэтил]-1-(пропан-2-ил)-1H-бензимидазол-6-ил}пиридин-2-ил)амино]-1-(метансульфонил)пиперидин-3-ол

(3R,4R)-4-[(5-chloro-4-{4-fluoro-2-[(1R)-1-hydroxyethyl]-1-(propan-2-yl)-1H-benzimidazol-6-yl }pyridin-2-yl)amino]-1-(methanesulfonyl)piperidin-3-ol 525.9 [M+H]+ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.07 (s, 1H), 7.59 (d, J=1.0 Hz, 1H), 7.07 (dd, J=11.4, 1.3 Hz, 1H), 6.83 (br.d, J=7.5 Hz, 1H), 6.64 (s, 1H), 5.74 (d, J=6.3 Hz, 1H) , 5.27 (d, J=4.5 Hz, 1H), 5.21-5.04 (m, 2H), 3.80-3.71 (m, 1H), 3.60-3.49 (m, 2H), 3.49-3.39 (m, 1H), 2.96-2.85 (m, 4H), 2.76-2.68 (m, 1H), 2.17-2 .07 (m, 1H), 1.65-1.51 (m, 9H), 1.49-1.33 (m, 1H)

Example D4 (Scheme D-3): Preparation of (3R,4R)-4-({5-chloro-4-[2-methyl-3-(propan-2-yl)-3H-imidazo[4,5-b ]pyridin-5-yl]pyridin-2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol

Diagram D-3:

To a solution of (D-4) (prepared as in Example D1, 78 mg, 0.24 mmol), (3R,4R)-4-amino-1-(methanesulfonyl)piperidin-3-ol (Int-69) ( 41 mg, 0.27 mmol), Pd(OAc) ₂ (3.4 mg, 0.015 mmol) and rac-BINAP (9.45 mg, 0.73 mmol) were added phosphazene base P ₂ -Et to give a bright orange reaction solution. The mixture was purged with N ₂ and then stirred at 110° C. for 16 hours overnight. LCMS analysis showed consumption of starting material to form a mass of the desired product. The reaction mixture was concentrated to dryness. The residue was purified by preparative SFC on a ZymorSPHER HADP column (150×21.1 mm, particle size 5 µm, column temperature 35°C) eluted with 12-50% MeOH/CO ₂ at a flow rate of 80 g/min. The material was repurified by preparative HPLC on a Phenomenex Gemini-NX C18 column (150×21 mm, particle size 5 μm) eluted with 15-70% MeCN/H ₂ O (+10 nM NH ₄ OAc) at a flow rate of 40 ml /min to form (3R,4R)-4-({5-chloro-4-[2-methyl-3-(propan-2-yl)-3H-imidazo[4,5-b]pyridin-5-yl ]pyridin-2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol (Example D4) (20 mg, 21% yield) as a solid. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.08 (s, 1H), 8.00 (d, J=8.2 Hz, 1H), 7.46 (d, J=8.2 Hz , 1H), 6.88 (d, J=7.4 Hz, 1H), 6.81 (s, 1H), 5.28-5.24 (m, 1H), 4.82 (hept, J= 6.7 Hz, 1H), 3.80-3.73 (m, 1H), 3.61-3.52 (m, 2H), 3.49-3.44 (m, 1H), 2.95 -2.87 (m, 4H), 2.72 (dd, J=11.4, 8.7 Hz, 1H), 2.63 (s, 3H), 2.15-2.10 (m, 1H ), 1.67 (dd, J=6.8, 1.6 Hz, 6H), 1.48-1.40 (m, 1H); m/z (APCI+) for (C ₂₁ H ₂₇ ClN ₆ O ₃ S), 478.9 (M+H) ⁺ .

The example in the table below was synthesized according to the methods used to synthesize (3R,4R)-4-({5-chloro-4-[2-methyl-3-(propan-2-yl)-3H-imidazo[4 ,5-b]pyridin-5-yl]pyridin-2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol (Example D4). The following example has been synthesized with non-breaking changes or substitutions to the illustrated techniques that a person skilled in the art could implement.

Example number Structure/Name HCMS NMR D5

1,5-ангидро-3-({5-хлор-4-[2-метил-3-(пропан-2-ил)-3H-имидазо[4,5-b]пиридин-5-ил]пиридин-2-ил}амино)-2,3-дидезокси-D-трео-пентитол

1,5-anhydro-3-({5-chloro-4-[2-methyl-3-(propan-2-yl)-3H-imidazo[4,5-b]pyridin-5-yl]pyridin-2 -yl}amino)-2,3-dideoxy-D-threo-pentitol 402.1 [M+H]+ (APCI) ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.06 (s, 1H), 7.99 (d, J=8.3 Hz, 1H), 7.45 (d, J=8.2 Hz , 1H), 6.89-6.86 (m, 1H), 6.80 (s, 1H), 5.06 (br. s, 1H), 4.81 (hept, J=6.4 Hz, 1H), 3.84-3.74 (m, 3H), 3.10-3.05 (m, 1H), 2.63 (s, 3H), 2.05-2.01 (m, 1H) , 1.67 (dd, J=6.8, 2.3 Hz, 6H), 1.44-1.36 (m, 1H); two protons are covered by the residual solvent peak

Example D6 (Scheme D-4): Preparation of (3R,4R)-4-{[4-(1-tert-butyl-4-fluoro-1H-benzimidazol-6-yl)-5-chloropyridin-2-yl] amino}piperidin-3-ol

Diagram D-4:

To a solution of tert-butyl-(3R,4R)-4-{[4-(1-tert-butyl-4-fluoro-1H-benzimidazol-6-yl)-5-chloropyridin-2-yl]amino}-3 -hydroxypiperidine-1-carboxylate (D-5) (prepared as in Example D1, 3.4 g, 5.9 mmol) in DCM (20.0 ml) was added a solution of HCl (1.0 M in EtOAc, 50 ml ). After 18 hours, LCMS analysis showed consumption of starting material to form a mass of the desired product. The reaction mixture was concentrated to dryness. The solid was taken up in H ₂ O (50 ml) and washed with EtOAc (50 ml). The aqueous layer was lyophilized to give (3R,4R)-4-{[4-(1-tert-butyl-4-fluoro-1H-benzimidazol-6-yl)-5-chloropyridin-2-yl]amino}piperidin-3 -ol hydrochloride (Example D6) (2.7 g, 99% yield) as a yellow solid. ¹ H NMR (400 MHz, D ₂ O) δ 9.35 (s, 1H), 8.12 (d, J=0.6 Hz, 1H), 8.11 (d, J=1.2 Hz, 1H), 7.56 (dd, J=10.3, 1.2 Hz, 1H), 7.22 (s, 1H), 4.02-3.92 (m, 2H), 3.63-3 .48 (m, 2H), 3.17 (td, J=12.9, 3.3 Hz, 1H), 3.05 (dd, J=12.7, 9.8 Hz, 1H), 2, 42-2.34 (m, 1H), 1.98-1.79 (m, 10H); m/z (ESI+) for (C ₂₁ H ₂₅ ClFN ₅ O), 418.2 (M+H) ⁺ .

Example E1 (Scheme E-1): Preparation of (3R,4R)-4-[(5-chloro-4-{4-fluoro-2-[(1S)-1-hydroxyethyl]-1-(propane-2) -yl)-1H-benzimidazol-6-yl}pyridin-2-yl)amino]-1-(methanesulfonyl)piperidin-3-ol

Diagram E-1:

Step 1: Synthesis of (1S)-1-[6-(2,5-dichloropyridin-4-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]ethan-1 -ola (E-1):

Solution of 5-chloro-2-fluoro-4-iodopyridine (200 mg, 0.78 mmol), (3S,4S)-4-amino-1-(methanesulfonyl)piperidin-3-ol (Int-69) (181 mg 0.93 mmol) and DIPEA (301 mg, 0.415 ml, 2.33 mmol) in DMSO (3.9 ml) were stirred at 100° C. for 16 hours. LCMS analysis showed consumption of starting material to form a mass of the desired product. The reaction mixture was loaded directly onto SiO ₂ and purified by flash chromatography (ISCO, 12 g SiO ₂ , 0-100% EtOAc/heptane) to give (3S,4S)-4-[(5-chloro-4-iodopyridine- 2-yl)amino]-1-(methanesulfonyl)piperidin-3-ol (E-1) (147 mg, 44% yield) as gum. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.93 (s, 1H), 7.08 (s, 1H), 4.85-4.73 (m, 1H), 4.01-3.90 ( m, 1H), 3.85-3.74 (m, 1H), 3.67-3.58 (m, 2H), 3.44 (p, J=6.7 Hz, 1H), 2.83 (s, 3H), 2.77 (dd, J=12.2, 2.8 Hz, 1H), 2.68-2.52 (m, 1H), 2.14-2.08 (m, 1H ), 1.75-1.56 (m, 1H); m/z (ESI+) for (C ₁₁ H ₁₅ ClIN ₃ O ₃ S), 431.8 (M+H) ⁺ .

Step 2: Synthesis of (3R,4R)-4-[(5-chloro-4-{4-fluoro-2-[(1S)-1-hydroxyethyl]-1-(propan-2-yl)-1H-benzimidazole -6-yl}pyridin-2-yl)amino]-1-(methanesulfonyl)piperidin-3-ol (Example E1):

To a solution of (3S,4S)-4-[(5-chloro-4-iodopyridin-2-yl)amino]-1-(methanesulfonyl)piperidin-3-ol (E-1) (147 mg, 0.341 mmol) in 1,4-dioxane (4.7 ml) was added 4-fluoro-2-methyl-1-(propan-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)-1H-benzimidazole (A-1) (108 mg, 0.341 mmol), aqueous Na ₂ CO ₃ (2.0 M, 0.51 ml), PdCl ₂ (PPh ₃ ) ₂ (12 mg, 0.017 mmol) and H ₂ O (0.4 ml). The mixture was stirred at 95° C. for 5 hours. LCMS analysis showed consumption of starting material to form a mass of the desired product. The reaction mixture was filtered through celite and concentrated. The material was purified using preparative SFC on a DCPak SFC-B column (150×21.2 mm, particle size 5 μm, column temperature 35°C), which was eluted with 25-35% MeOH/CO ₂ at a flow rate of 62 ml/min s obtaining (3R,4R)-4-[(5-chloro-4-{4-fluoro-2-[(1S)-1-hydroxyethyl]-1-(propan-2-yl)-1H-benzimidazol-6- yl}pyridin-2-yl)amino]-1-(methanesulfonyl)piperidin-3-ol (Example E1) (66 mg, 39% yield) as a white solid. ¹ H NMR (700 MHz, DMSO-d ₆ ) δ 8.06 (s, 1H), 7.54 (s, 1H), 7.03 (d, J=11.2 Hz, 1H), 6.81 (d, J=7.3 Hz, 1H), 6.64 (s, 1H), 5.29 (br. s, 1H), 4.83-4.76 (m, 1H), 3.78- 3.71 (m, 1H), 3.60-3.50 (m, 2H), 3.48-3.41 (m, 1H), 2.95-2.87 (m, 4H), 2. 74-2.68 (m, 1H), 2.60 (s, 3H), 2.14-2.09 (m, 1H), 1.56 (d, J=6.8 Hz, 6H), 1 .46-1.39 (m, 1H); m/z (APCI) for (C ₂₂ H ₂₇ ClFN ₅ O ₃ S), 495.9 (M+H) ⁺ .

Example F1 (Scheme F-1): Preparation of methyl-(3R,4R)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazole -6-yl]pyrimidin-2-yl}amino)-3-hydroxypiperidine-1-carboxylate

Diagram F-1:

To a solution of (3R,4R)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl }amino)piperidin-3-ol (Example A37) (prepared as in Chart A-1, 50 mg, 0.12 mmol) and TEA (18.9 mg, 0.186 mmol) in DCM (3.0 mL) at 0° C., methyl chloroformate (11.7 mg, 0.124 mmol) was added dropwise. The reaction mixture was stirred for 30 min at room temperature. LCMS analysis showed consumption of starting material to form a mass of the desired product. The solution was concentrated. The residue was partitioned between H ₂ O (20 ml) and EtOAc (20 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was combined with the second batch from the parallel reaction, identically with 50 mg of (3R,4R)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl )-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)piperidin-3-ol (Example A37). The mixture was purified by preparative HPLC on a DuraShell column (150×25 mm, particle size 5 μm) which was eluted with 22-72% MeCN/H ₂ O (+0.05% NH ₄ OH) at a flow rate of 25 ml/min, to methyl-(3R,4R)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2 -yl}amino)-3-hydroxypiperidine-1-carboxylate (Example F1) (48 mg, 42% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.43 (d, J=4.0 Hz, 1H), 8.13 (br. s, 1H), 7.61 (d, J=12, 2 Hz, 1H), 7.18 (d, J=7.7 Hz, 1H), 5.11 (d, J=4.8 Hz, 1H), 4.87-4.75 (m, 1H) , 4.08-3.75 (m, 3H), 3.60 (s, 3H), 3.51-3.45 (m, 1H), 3.01-2.67 (m, 2H), 2 .63 (s, 3H), 2.10-1.92 (m, 1H), 1.59 (d, J=6.8 Hz, 6H), 1.45-1.30 (m, 1H); m/z (ESI) for (C ₂₂ H ₂₆ F ₂ N ₆ O ₃ ), 461.4 (M+H) ⁺ .

The examples in the table below were synthesized according to the methods used for the synthesis of methyl-(3R,4R)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl) -1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-3-hydroxypiperidine-1-carboxylate (Example F1). The following examples have been synthesized with non-critical modifications or substitutions to the illustrated techniques that a person skilled in the art could implement. If necessary, separation of the enantiomers was carried out by standard methods known in the art, such as chiral SFC or HPLC, to obtain individual enantiomers.

Example number Structure/Name HCMS NMR F2

метил-(3R,4R)-4-({5-хлор-4-[4-фтор-1-(оксолан-3-ил)-1H-бензимидазол-6-ил]пиримидин-2-ил}амино)-3-гидроксипиперидин-1-карбоксилат

methyl-(3R,4R)-4-({5-chloro-4-[4-fluoro-1-(oxolan-3-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)- 3-hydroxypiperidine-1-carboxylate 491.1 [M+H]+ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.47-8.39 (m, 2H), 8.08-7.90 (m, 1H), 7.57-7.36 (m, 2H ), 5.41-5.30 (m, 1H), 5.09 (d, J=4.8 Hz, 1H), 4.19-3.77 (m, 7H), 3.59 (s, 3H), 3.51-3.39 (m, 1H), 3.02-2.64 (m, 2H), 2.62-2.52 (m, 1H), 2.29-2.18 ( m, 1H), 2.02-1.87 (m, 1H), 1.43-1.29 (m, 1H); [α] _D ²⁰ = -28.8 (c=1.0, MeOH) F3

methyl-(3R,4R)-4-({5-chloro-4-[4-fluoro-1-(oxolan-3-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)- 3-hydroxypiperidine-1-carboxylate 491.1 [M+H]+ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.45-8.40 (m, 2H), 8.05-7.91 (m, 1H), 7.56-7.37 (m, 2H ), 5.39-5.31 (m, 1H), 5.16-5.04 (m, 1H), 4.19-3.76 (m, 7H), 3.59 (s, 3H), 3.51-3.39 (m, 1H), 3.00-2.64 (m, 2H), 2.62-2.52 (m, 1H), 2.29-2.19 (m, 1H ), 2.05-1.87 (m, 1H), 1.42-1.29 (m, 1H); [α] _D ²⁰ = -4.9 (c=1.0, MeOH)

Example F4 (Scheme F-2): Preparation of (3R,4R)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6 -yl]pyrimidin-2-yl}amino)-1-methylpiperidin-3-ol

Scheme F-2:

To a solution of (3R,4R)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl }amino)piperidin-3-ol (Example A37) (prepared as in Scheme A-1, 50 mg, 0.12 mmol) in MeOH (3 ml) paraformaldehyde (100 mg, 1.11 mmol) and NaBH ₃ were added CN (100 mg, 1.59 mmol). The resulting solution was stirred at room temperature for 30 minutes. LCMS analysis showed consumption of starting material to form a mass of the desired product. The solution was filtered and the filtrate was combined in a parallel reaction identically with 50 mg of (3R,4R)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H- benzimidazol-6-yl]pyrimidin-2-yl}amino)-1-methylpiperidin-3-ol (Example A37) and concentrated. The residue was purified by preparative HPLC on an Agela Durashell C18 column (150×20 mm, particle size 5 μm) which was eluted with 0-38% MeCN/H ₂ O (0.225% formic acid) at a flow rate of 25 ml/min to obtain ( 3R,4R)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino) -1-methylpiperidin-3-ol formate (Example F4) (60.2 mg, 58% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.42 (d, J=4.1 Hz, 1H), 8.21-8.13 (m, 2H), 7.61 (d, J= 12.2 Hz, 1H), 7.10 (d, J=6.3 Hz, 1H), 5.22-4.57 (m, 2H), 3.65-3.52 (m, 2H), 2.99-2.88 (m, 1H), 2.81-2.72 (m, 1H), 2.63 (s, 3H), 2.24 (s, 3H), 2.08-1, 85 (m, 3H), 1.64-1.42 (m, 7H); m/z (ESI) for (C ₂₁ H ₂₆ F ₂ N ₆ O), 417.1 (M+H) ⁺ .

The examples in the table below were synthesized according to the methods used for the synthesis of (3R,4R)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H -benzimidazol-6-yl]pyrimidin-2-yl}amino)-1-methylpiperidin-3-ol (Example F4). The following examples have been synthesized with non-critical modifications or substitutions to the illustrated techniques that a person skilled in the art could implement.

Example number Structure/Name HCMS NMR F5

(3R,4R)-4-{[4-(1-трет-бутил-4-фтор-1H-бензимидазол-6-ил)-5-хлорпиримидин-2-ил]амино}-1-(2-гидроксиэтил)пиперидин-3-ола формиат

(3R,4R)-4-{[4-(1-tert-butyl-4-fluoro-1H-benzimidazol-6-yl)-5-chloropyrimidin-2-yl]amino}-1-(2-hydroxyethyl) piperidin-3-ol formate 463.3 [M+H]+ (ESI) ¹ H NMR (400 MHz, CD ₃ OD) δ 8.51-8.35 (m, 3H), 8.15 (s, 1H), 7.52 (d, J=11.5 Hz, 1H), 4.06-3.90 (m, 2H), 3.82 (t, J=5.6 Hz, 2H), 3.45-3.34 (m, 1H), 3.07-2.96 ( m, 2H), 2.92-2.70 (m, 2H), 2.48-2.30 (m, 1H), 1.87-1.75 (m, 10H); one proton is covered by the residual solvent peak F6

(3R,4R)-4-{[4-(1-tert-butyl-4-fluoro-1H-benzimidazol-6-yl)-5-chloropyrimidin-2-yl]amino}-1-[2-(dimethylamino )ethyl]piperidin-3-ol formate 490.3 [M+H]+ (ESI) ¹ H NMR (400 MHz, CD ₃ OD) δ 8.39 (s, 1H), 8.37-8.31 (m, 1H), 8.15 (s, 1H), 7.53 (d, J =11.5 Hz, 1H), 3.87-3.77 (m, 1H), 3.75-3.64 (m, 1H), 3.13-3.05 (m, 1H), 2, 94-2.79 (m, 3H), 2.65 (t, J=6.7 Hz, 2H), 2.55 (s, 6H), 2.27-2.07 (m, 3H), 1 .82 (s, 9H), 1.68-1.54 (m, 1H) F7

(3R,4R)-4-({5-chloro-4-[4-fluoro-2-(hydroxymethyl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl }amino)-1-(methanesulfonyl)piperidin-3-ol 417.2 [M+H]+ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.41-8.42 (m, 1H), 8.17 (s, 1H), 7.60-7.63 (m, 1H), 7, 06-7.07 (m, 1H), 4.85-4.79 (m, 2H), 3.60-3.50 (br.m, 2H), 2.91-2.88 (m, 1H ), 2.73-2.70 (m, 1H), 2.63 (s, 3H), 2.19 (s, 3H), 2.04-1.75 (m, 3H), 1.59- 1.62 (m, 6H), 1.51-1.40 (m, 1H); [α] _D ²⁰ =15.4 (c=0.41, CHCl ₃ )

Example F8 (Scheme F-3): Preparation of (3R,4R)-4-({5-chloro-4-[4-fluoro-2-methyl-1-(oxetan-3-yl)-1H-benzimidazol-6 -yl]pyrimidin-2-yl}amino)-1-(ethanesulfonyl)piperidin-3-ol

Diagram F-3:

(3R,4R)-4-({5-chloro-4-[4-fluoro-2-methyl-1-(oxetan-3-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl} mixture amino)piperidin-3-ol (F-1) (prepared as in Scheme A-1, 70 mg, 0.152 mmol) and NaHCO ₃ (204 mg, 2.43 mmol) in EtOAc (1.0 ml) and H ₂ O (1.0 ml) was cooled to 0°C. A solution of ethanesulfonyl chloride (20.8 mg, 0.162 mmol) in EtOAc (1.0 mL) was added dropwise over 10 minutes. The reaction mixture was stirred at 0° C. for 16 hours. LCMS analysis showed consumption of starting material to form a mass of the desired product. The reaction layers were separated. The aqueous layer was extracted with EtOAc (3×10 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative HPLC on a DuraShell column (150×25 mm, particle size 5 μm), which was eluted with 28-48% MeCN/H ₂ O (+0.05% NH ₄ OH) with a flow rate of 25 ml/min with obtaining (3R,4R)-4-({5-chloro-4-[4-fluoro-2-methyl-1-(oxetan-3-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl} amino)-1-(ethanesulfonyl)piperidin-3-ol (Example F8) (7 mg, 8% yield) as a white solid. ¹ H NMR (500 MHz, CD ₃ OD) δ 8.61 (br.s, 1H), 8.36 (s, 1H), 7.70-7.55 (br.m, 1H), 5.81 -5.72(m, 1H), 5.30-5.25(m, 2H), 5.22-5.17(m, 2H), 3.96-3.90(m, 1H), 3 .88-3.82 (m, 1H), 3.73-3.66 (m, 2H), 3.11-3.03 (m, 2H), 3.02-2.95 (m, 1H) , 2.83-2.77(m, 1H), 2.63(s, 3H), 2.26-2.17(m, 1H), 1.68-1.58(m, 1H), 1 .39-1.27 (m, 3H); m/z (ESI) for (C ₂₂ H ₂₆ ClFN ₆ O ₄ S), 525.3 (M+H) ⁺ .

The examples in the table below were synthesized according to the methods used for the synthesis of (3R,4R)-4-({5-chloro-4-[4-fluoro-2-methyl-1-(oxetan-3-yl)-1H -benzimidazol-6-yl]pyrimidin-2-yl}amino)-1-(ethanesulfonyl)piperidin-3-ol (Example F8). The following examples have been synthesized with non-critical modifications or substitutions to the illustrated techniques that a person skilled in the art could implement. If necessary, separation of the enantiomers was carried out by standard methods known in the art, such as chiral SFC or HPLC, to obtain individual enantiomers.

Example number Structure/Name HCMS NMR F9

(3R,4R)-4-({5-хлор-4-[4-фтор-2-(1-гидроксиэтил)-1-(пропан-2-ил)-1H-бензимидазол-6-ил]пиримидин-2-ил}амино)-1-(дифторметансульфонил)пиперидин-3-ол

(3R,4R)-4-({5-chloro-4-[4-fluoro-2-(1-hydroxyethyl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2 -yl}amino)-1-(difluoromethanesulfonyl)piperidin-3-ol 563.1 [M+H]+ (ESI) ¹ H NMR (400 MHz, CD ₃ OD) δ 8.38 (s, 1H), 8.06 (s, 1H), 7.51 (br. d, J=11.5 Hz, 1H), 6, 88-6.52 (m, 1H), 5.34 (td, J=6.9, 14.0 Hz, 1H), 5.23 (k, J=6.8 Hz, 1H), 4.09 -3.92 (m, 2H), 3.85 (br.d, J=13.7 Hz, 1H), 3.72 (dt, J=4.7, 9.0 Hz, 1H), 3, 29-3.21 (m, 1H), 3.08 (dd, J=9.5, 12.8 Hz, 1H), 2.30-2.22 (m, 1H), 1.77-1, 67 (m, 10H), 0.92 (br. t, J=6.5 Hz, 1H); [α] _D ²² = -8.3 (c=0.1, MeOH) F10

(3R,4R)-4-({5-chloro-4-[4-fluoro-2-(1-hydroxyethyl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2 -yl}amino)-1-(difluoromethanesulfonyl)piperidin-3-ol 584.9 [M+Na]+ (ESI) ¹ H NMR (400 MHz, CD ₃ OD) δ 8.38 (s, 1H), 8.06 (s, 1H), 7.62-7.41 (m, 1H), 6.90-6.48 (m, 1H), 5.40-5.31 (m, 1H), 5.24 (q, J=6.7 Hz, 1H), 4.06-3.92 (m, 2H), 3, 86 (br.d, J=13.2 Hz, 1H), 3.72 (td, J=4.6, 9.0 Hz, 1H), 3.31-3.21 (m, 1H), 3 .15-2.95 (m, 1H), 2.34-2.15 (m, 1H), 1.77-1.70 (m, 9H), 1.68-1.62 (m, 1H) ; [α] _D ²² = -25.6 (c=0.1, MeOH) F11

(3S,4R)-(rel)-4-[(5-chloro-4-{4-fluoro-2-[(1R)-1-hydroxyethyl]-1-(propan-2-yl)-1H-benzimidazole -6-yl}pyrimidin-2-yl)amino]-1-(methanesulfonyl)piperidin-3-ol 526.9 [M+H]+ (ESI) ¹ H NMR (400 MHz, CD ₃ OD) δ 8.39 (s, 1H), 8.04 (s, 1H), 7.48 (d, J=11.5 Hz, 1H), 5.40- 5.29(m, 1H), 5.23(k, J=6.8Hz, 1H), 4.15-4.07(m, 2H), 3.82-3.72(m, 2H) , 3.14 (br.d, J=11.8 Hz, 1H), 3.05 (dt, J=3.0, 12.2 Hz, 1H), 2.95 (s, 3H), 2, 12-2.00 (m, 1H), 1.90 (br.l, J=9.5 Hz, 1H), 1.75-1.70 (m, 9H) F12

(3S,4R)-(rel)-4-[(5-chloro-4-{4-fluoro-2-[(1R)-1-hydroxyethyl]-1-(propan-2-yl)-1H-benzimidazole -6-yl}pyrimidin-2-yl)amino]-1-(methanesulfonyl)piperidin-3-ol 526.9 [M+H]+ (ESI) ¹ H NMR (400 MHz, CD ₃ OD) δ 8.37 (s, 1H), 8.06 (s, 1H), 7.50 (d, J=11.5 Hz, 1H), 5.34 ( m, J=7.0, 13.9 Hz, 1H), 5.23 (m, J=6.7 Hz, 1H), 4.00-3.91 (m, 1H), 3.87-3 .81 (m, 1H), 3.78-3.66 (m, 2H), 2.95 (m, J=2.5, 12.0 Hz, 1H), 2.90 (s, 3H), 2.76 (m, J=9.5, 11.5 Hz, 1H), 2.29-2.20 (m, 1H), 1.75-1.65 (m, 10H) F13

(3S,4S)-4-[(5-chloro-4-{4-fluoro-2-[(1R)-1-hydroxyethyl]-1-(propan-2-yl)-1H-benzimidazol-6-yl }pyrimidin-2-yl)amino]-1-(methanesulfonyl)piperidin-3-ol 526.9 [M+H]+ (ESI) ¹ H NMR (400 MHz, CD ₃ OD) δ 8.37 (s, 1H), 8.06 (s, 1H), 7.50 (d, J=11.6 Hz, 1H), 5.34 ( m, J=6.9, 13.9 Hz, 1H), 5.23 (m, J=6.6 Hz, 1H), 4.00-3.92 (m, 1H), 3.84 (m , J=1.7, 4.6, 11.6 Hz, 1H), 3.79-3.65 (m, 2H), 2.99-2.91 (m, 1H), 2.90 (s , 3H), 2.80-2.67 (m, 1H), 2.28-2.21 (m, 1H), 1.76-1.63 (m, 10H) F14

(3S,4S)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino )-1-(methanesulfonyl)piperidin-3-ol 481.2 [M+H]+ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.43 (d, J=4.0 Hz, 1H), 8.12 (s, 1H), 7.62 (br. d, J=12, 3 Hz, 1H), 7.22 (br.d, J=7.0 Hz, 1H), 5.22 (br.d, J=4.3 Hz, 1H), 4.89-4.73 ( m, 1H), 3.77 (br.s, 1H), 3.61 (br.d, J=10.8 Hz, 2H), 3.49 (br.s, 1H), 2.91 (s , 3H), 2.89-2.82 (m, 1H), 2.71-2.64 (m, 1H), 2.63 (s, 3H), 2.09 (br. s, 1H), 1.60 (d, J=6.8 Hz, 6H), 1.52 (br.s, 1H) F15

(3R,4R)-4-{[4-(1-tert-Butyl-4-fluoro-1H-benzimidazol-6-yl)-5-fluoropyrimidin-2-yl]amino}-1-(methanesulfonyl)piperidine- 3-ol 481.1 [M+H]+ (ESI) ¹ H NMR (700 MHz, DMSO-d ₆ ) δ 8.42-8.34 (m, 2H), 8.21 (br.s., 1H), 7.65-7.54 (m, 1H) , 7.15 (d, J=7.7 Hz, 1H), 5.22-5.07 (m, 1H), 3.77-3.66 (m, 1H), 3.62-3.51 (m, 2H), 3.48-3.39 (m, 1H), 2.84 (s, 3H), 2.80 (dt, J=2.6, 11.7 Hz, 1H), 2, 61 (t, J=10.1 Hz, 1H), 2.04 (d, J=7.3 Hz, 1H), 1.69 (s, 9H), 1.53-1.42 (m, 1H )

Example F16 (Scheme F-4): Preparation of 1-[(3R,4R)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H- benzimidazol-6-yl]pyrimidin-2-yl}amino)-3-hydroxypiperidin-1-yl]ethan-1-one

Diagram F-4:

To a stirred solution of (3R,4R)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2- yl}amino)piperidin-3-ol trifluoroacetate (Example A37) (300 mg, 0.581 mmol) and triethylamine (226 mg, 0.31 ml, 2.24 mmol) in DCM (5 ml) was added Ac ₂ O (152 mg , 0.14 ml, 1.49 mmol). The mixture was stirred at ambient temperature for 2 h, then diluted with water (10 ml) and extracted with DCM (3×10 ml). The combined organic phases were washed with brine (10 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by preparative HPLC on an Agela Durashell C18 column (150×25 mm, particle size 5 μm, column temperature 25° C.), which was eluted with 15-55% MeCN/H ₂ O (+0.05% NH ₄ OH ) at a flow rate of 25 ml/min to give 1-[(3R,4R)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H- benzimidazol-6-yl]pyrimidin-2-yl}amino)-3-hydroxypiperidin-1-yl]ethan-1-one (Example F16) (22.0 mg, 9% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.43 (br. s, 1H), 8.13 (br. s, 1H), 7.61 (br. d, J=12.0 Hz, 1H), 7.28-7.13(m, 1H), 5.18-5.01(m, 1H), 4.89-4.75(m, 1H), 3.91-3.70( m, 2H), 3.18-2.75 (m, 2H), 2.69-2.60 (m, 3H), 2.33 (br. s, 1H), 2.01 (br. d, J=4.3 Hz, 4H), 1.59 (br.d, J=6.5 Hz, 7H), 1.36 (br.d, J=14.1 Hz, 1H); m/z (ESI+) for (C ₂₂ H ₂₆ F ₂ N ₆ O ₂ ), 445.4 (M+H) ⁺ .

Example F17 (Scheme F-5): Preparation of 1-[(3R,4R)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H- benzimidazol-6-yl]pyrimidin-2-yl}amino)-3-hydroxypiperidin-1-yl]-2-hydroxyethan-1-one

Diagram F-5:

K (3R,4R)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl} DIPEA (48.2 mg, 0.373 mmol) and HATU (70.9 mg, 0.186 mmol). The mixture was stirred at ambient temperature for 16 hours. LCMS analysis showed consumption of starting material to form a mass of the desired product. The reaction mixture was washed with H ₂ O (20 ml) and saturated aqueous NaHCO ₃ (20 ml). The combined aqueous layers were extracted with EtOAc (20 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative HPLC on a DuraShell column (150×25 mm, particle size 5 μm), which was eluted with 12-52% MeCN/H ₂ O (+0.05% NH ₄ OH) with a flow rate of 25 ml/min with obtaining 1-[(3R,4R)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2 -yl}amino)-3-hydroxypiperidin-1-yl]-2-hydroxyethan-1-one (Example F17) (8 mg, 14% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.44 (t, J=4.0 Hz, 1H), 8.14 (br. s, 1H), 7.62 (br. d, J= 12.0 Hz, 1H), 7.32-7.21 (m, 1H), 5.15 (dd, J=4.8, 9.3 Hz, 1H), 4.83 (hept, J=6 .9 Hz, 1H), 4.56 (t, J=5.0 Hz, 1H), 4.33 (br.d, J=9.3 Hz, 1H), 4.17-4.04 (m , 2H), 4.04-3.81 (m, 2H), 3.73-3.40 (m, 2H), 3.10-2.95 (m, 1H), 2.63 (s, 3H ), 2.09-1.97 (m, 1H), 1.60 (d, J=7.0 Hz, 6H), 1.48-1.33 (m, 1H); m/z (ESI+) for (C ₂₂ H ₂₆ F ₂ N ₆ O ₃ ), 461.3 (M+H) ⁺ .

The examples in the table below were synthesized according to the methods used for the synthesis of 1-[(3R,4R)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl )-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-3-hydroxypiperidin-1-yl]-2-hydroxyethan-1-one (Example F17). The following examples have been synthesized with non-breaking modifications or substitutions to the illustrated techniques that a person skilled in the art could implement.

Example number Structure/Name HCMS NMR F18

[(3R,4R)-4-({5-хлор-4-[4-фтор-1-(пропан-2-ил)-1H-бензимидазол-6-ил]пиримидин-2-ил}амино)-3-гидроксипиперидин-1-ил](оксетан-3-ил)метанон

[(3R,4R)-4-({5-chloro-4-[4-fluoro-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-3 -hydroxypiperidin-1-yl](oxetan-3-yl)methanone 488.9 [M+H]+ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.52 (s, 1H), 8.43 (d, J=4.8 Hz, 1H), 7.91 (br. s, 1H), 7 .42-7.40 (m, 2H), 5.24-5.11 (m, 1H), 4.88-4.77 (m, 1H), 4.76-4.58 (m, 4H) , 4.41-3.95 (m, 4H), 3.93-3.83 (m, 1H), 3.10-2.84 (m, 1H), 2.67-2.56 (m, 1H), 1.95-1.93 (m, 1H), 1.57 (d, J=6.8 Hz, 6H), 1.34-1.32 (m, 1H) F19

[(3R,4R)-4-({5-chloro-4-[4-fluoro-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-3 -hydroxypiperidin-1-yl](3-methyloxetan-3-yl)methanone 502.9 [M+H]+ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.54 (s, 1H), 8.44 (s, 1H), 7.91 (br. s, 1H), 7.64-7.35 ( m, 2H), 5.26-5.12 (m, 1H), 4.89-4.71 (m, 3H), 4.38-4.07 (m, 3H), 3.95-3, 83 (m, 1H), 3.58-3.38 (m, 1H), 3.12-2.94 (m, 1H), 2.92-2.79 (m, 1H), 2.66- 2.57(m, 1H), 2.08-1.89(m, 1H), 1.58(s, 3H), 1.57-1.49(m, 6H), 1.44-1, 30 (m, 1H) F20

(2R)-1-[(3R,4R)-4-({5-chloro-4-[4-chloro-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2- yl}amino)-3-hydroxypiperidin-1-yl]-2-hydroxypropan-1-one 515.1 [M+Na]+ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.58 (s, 1H), 8.48-8.36 (m, 1H), 8.04 (s, 1H), 7.67 (s, 1H), 7.55 (br. s, 1H), 5.15 (br. d, J=30.2 Hz, 1H), 4.98-4.77 (m, 2H), 4.51-3 .80 (m, 5H), 3.18-2.83 (m, 1H), 1.98 (s, 1H), 1.57 (d, J=6.7 Hz, 6H), 1.49- 1.26 (m, 2H), 1.18 (dd, J=9.2, 6.5 Hz, 3H) F21

(2S)-1-[(3R,4R)-4-{[4-(1-tert-butyl-4-fluoro-1H-benzimidazol-6-yl)-5-chloropyrimidin-2-yl]amino}- 3-hydroxypiperidin-1-yl]-2-hydroxypropan-1-one 490.9 [M+H]+ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.43 (s, 2H), 8.29-7.90 (m, 1H), 7.72-7.12 (m, 2H), 5, 13 (br. s, 1H), 4.96 (br. d, J=6.7 Hz, 1H), 4.49-4.13 (m, 2H), 4.09-3.84 (m, 2H), 3.50-3.46(m, 1H), 3.17-2.76(m, 2H), 2.08-1.92(m, 1H), 1.74(s, 9H) , 1.51-1.27 (m, 1H), 1.19 (br. t, J=7.5 Hz, 3H) F22

1-[(3R,4R)-4-{[4-(3-tert-butyl-3H-imidazo[4,5-b]pyridin-5-yl)-5-chloropyridin-2-yl]amino}- 3-hydroxypiperidin-1-yl]-2-hydroxyethan-1-one 459.0 [M+H]+ (ESI) ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.55 (s, 1H), 8.20-8.20 (m, 1H), 8.20-8.20 (m, 1H), 8, 19 (d, J=8.2 Hz, 1H), 8.11 (d, J=4.9 Hz, 1H), 7.54 (d, J=8.4 Hz, 1H), 6.98- 6.90 (m, 1H), 6.82 (d, J=9.3 Hz, 1H), 5.20 (dd, J=4.7, 11.2 Hz, 1H), 4.55 (t , J=5.2 Hz, 1H), 4.17-4.06 (m, 2H), 3.87 (br.d, J=13.7 Hz, 1H), 3.68-3.58 ( m, 1H), 3.19 (br. t, J=9.6 Hz, 1H), 3.12-3.00 (m, 1H), 2.09-2.00 (m, 1H), 1 .84-1.77 (m, 9H), 1.37-1.27 (m, 1H)

Example F23 (Scheme F-6): Preparation of 1-[(3R,4R)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H- benzimidazol-6-yl]pyrimidin-2-yl}amino)-3-hydroxypiperidin-1-yl]-2-(methylamino)ethan-1-one

Diagram F-6:

To a solution of (F-2) (prepared as in Example F17, 160 mg, 0.279) in DCM (10.0 ml) and TFA (10.0 ml). The mixture was stirred at ambient temperature for 1 hour. LCMS analysis showed consumption of starting material to form a mass of the desired product. The reaction solution was concentrated to dryness. The residue was dissolved in MeOH (5 ml) and treated with NH3•H ₂ O to bring to pH~7-8. The solution was concentrated. The residue was purified by preparative HPLC on a DuraShell column (150×25 mm, particle size 5 μm), which was eluted with 22-42% MeCN/H ₂ O (+0.05% NH ₄ OH) with a flow rate of 25 ml/min with obtaining 1-[(3R,4R)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2 -yl}amino)-3-hydroxypiperidin-1-yl]-2-(methylamino)ethan-1-one (Example F23) (35.2 mg, 27% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.43 (t, J=4.1 Hz, 1H), 8.13 (br. s, 1H), 7.61 (br. d, J= 12.1 Hz, 1H), 7.31-7.11 (m, 1H), 5.10 (br.l, J=4.5 Hz, 1H), 4.82 (td, J=6.8 , 13.8 Hz, 1H), 4.11-3.65 (m, 3H), 3.60-3.38 (m, 2H), 3.26-2.98 (m, 3H), 2, 70-2.53 (m, 4H), 2.27 (d, J=1.3 Hz, 3H), 2.02 (br. s, 1H), 1.59 (d, J=6.8 Hz , 6H), 1.45-1.29 (m, 1H); m/z (ESI+) for (C ₂₃ H ₂₉ F ₂ N ₇ O ₂ ), 474.5 (M+H) ⁺ .

The examples in the table below were synthesized according to the methods used for the synthesis of 1-[(3R,4R)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl )-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-3-hydroxypiperidin-1-yl]-2-(methylamino)ethan-1-one (Example F23). The following examples have been synthesized with non-breaking modifications or substitutions to the illustrated techniques that a person skilled in the art could implement. If necessary, separation of the enantiomers was carried out by standard methods known in the art, such as chiral SFC or HPLC, to obtain individual enantiomers.

Example number Structure/Name HCMS NMR F24

1-[(3R,4R)-4-({5-хлор-4-[4-фтор-1-(пропан-2-ил)-1H-бензимидазол-6-ил]пиримидин-2-ил}амино)-3-гидроксипиперидин-1-ил]-2-(метиламино)этан-1-он

1-[(3R,4R)-4-({5-chloro-4-[4-fluoro-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino) -3-hydroxypiperidin-1-yl]-2-(methylamino)ethan-1-one 476.2 [M+H]+ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.53 (s, 1H), 8.44 (d, J=5.3 Hz, 1H), 7.90 (br. s, 1H), 7 .97-7.84 (m, 1H), 7.61-7.36 (m, 2H), 5.10 (br. s, 1H), 4.82 (td, J=6.7, 13, 3 Hz, 1H), 4.35 (br.d, J=12.5 Hz, 1H), 4.04-3.80 (m, 2H), 3.75 (br.d, J=9.8 Hz, 1H), 3.51 (brs, 1H), 3.10-2.94 (m, 2H), 2.58 (brs, J=11.3 Hz, 1H), 2.28 (d, J=2.0 Hz, 3H), 1.90 (s, 1H), 1.56 (d, J=6.7 Hz, 6H), 1.38 (br.d, J=17, 2Hz, 1H) F25

1-[(3R,4R)-4-{[4-(1-tert-butyl-4-fluoro-1H-benzimidazol-6-yl)-5-chloropyrimidin-2-yl]amino}-3-hydroxypiperidine- 1-yl]-2-(methylamino)ethan-1-one 512.2 [M+Na]+ (ESI) ¹ H NMR (400 MHz, D ₂ O) δ 9.43-9.31 (m, 1H), 8.43 (s, 1H), 8.31 (br. s, 1H), 7.77 (br. .d, J=10.8 Hz, 1H), 4.46-3.98 (m, 4H), 3.85-3.56 (m, 2H), 3.32-2.82 (m, 2H ), 2.76 (d, J=3.0 Hz, 3H), 2.15-2.14 (m, 1H), 1.84 (s, 9H), 1.60-1.59 (m, 1H) F26

[(3R,4R)-4-{[4-(1-tert-butyl-4-fluoro-1H-benzimidazol-6-yl)-5-chloropyrimidin-2-yl]amino}-3-hydroxypiperidin-1- yl](3-fluoroazetidin-3-yl)methanone 520.0 [M+H]+ (ESI) ¹ H NMR (500 MHz, CD ₃ OD) δ 8.42-8.17 (m, 2H), 8.04 (s, 1H), 7.42 (d, J=11.4 Hz, 1H), 4.40-3.88 (m, 4H), 3.84-3.45 (m, 4H), 3.15-2.67 (m, 2H), 2.09 (d, J=13.4 Hz, 1H), 1.72 (s, 9H), 1.50-1.36 (m, 1H) F27

[(3R,4R)-4-({5-chloro-4-[4-fluoro-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-3 -hydroxypiperidin-1-yl](3-fluoroazetidin-3-yl)methanone 506.1 [M+H]+ (ESI) ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.45 (s, 1H), 8.35 (s, 1H), 7.82 (br. s, 1H), 7.55-7.04 ( m, 2H), 5.13 (dd, J=21.1, 4.8 Hz, 1H), 4.75 (p, J=6.7 Hz, 1H), 4.27-3.74 (m , 4H), 3.70-3.35 (m, 4H), 3.09-2.62 (m, 2H), 1.96 (br.s, J=33.6 Hz, 1H), 1, 49 (d, J=6.7 Hz, 6H), 1.43-1.23 (m, 1H) F28

(1-aminocyclopropyl)[(3R,4R)-4-({5-chloro-4-[4-fluoro-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl }amino)-3-hydroxypiperidin-1-yl]methanone 488.1 [M+H]+ (ESI) ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.52 (s, 1H), 8.43 (s, 1H), 7.90 (br. s, 1H), 7.59-7.21 ( m, 2H), 5.20 (br. s, 1H), 4.82 (td, J=6.7, 13.4 Hz, 1H), 4.25 (br. d, J=10.2 Hz , 1H), 4.17-3.94 (m, 1H), 3.88 (br.dd, J=3.2, 8.1 Hz, 1H), 3.49 (br.d, J=3 .4 Hz, 1H), 3.03 (br.s, 1H), 2.37-2.19 (m, 2H), 1.97 (br.s, 1H), 1.56 (d, J= 6.6 Hz, 6H), 1.46-1.24 (m, 1H), 0.79 (br.s, 2H), 0.71-0.53 (m, 2H) F29

(1-amino-3,3-difluorocyclobutyl)[(3R,4R)-4-({5-chloro-4-[4-fluoro-1-(propan-2-yl)-1H-benzimidazol-6-yl ]pyrimidin-2-yl}amino)-3-hydroxypiperidin-1-yl]methanone 538.0 [M+H]+ (ESI) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.54 (s, 1H), 8.44 (s, 1H), 7.91 (br. s, 1H), 7.56-7.32 ( m, 2H), 5.18 (d, J=70.6 Hz, 1H), 4.83 (n, J=6.8 Hz, 1H), 4.42-3.76 (m, 3H), 3.51 (d, J=65.9 Hz, 1H), 3.25-2.92 (m, 3H), 2.64-2.55 (m, 3H), 2.48-2.42 ( m, 1H), 1.99 (s, 1H), 1.57 (d, J=6.7 Hz, 6H), 1.52-1.30 (m, 1H) F30

(1-amino-3,3-difluorocyclobutyl)[(3R,4R)-4-{[4-(1-tert-butyl-4-fluoro-1H-benzimidazol-6-yl)-5-chloropyrimidin-2- yl]amino}-3-hydroxypiperidin-1-yl]methanone 552.2 [M+H]+ (ESI) ¹ H NMR (500 MHz, CD ₃ OD) δ 8.27 (d, J=5.1 Hz, 2H), 8.04 (s, 1H), 7.42 (d, J=11.4 Hz, 1H), 4.01-3.43 (m, 4H), 3.16-3.04 (m, 3H), 2.75-2.37 (m, 3H), 2.14-2.01 ( m, 1H), 1.72 (s, 9H), 1.48 (s, 1H) F31

(3S)-3-amino-1-[(3R,4R)-4-({5-chloro-4-[4-fluoro-1-(propan-2-yl)-1H-benzimidazol-6-yl] pyrimidin-2-yl}amino)-3-hydroxypiperidin-1-yl]-4,4,4-trifluorobutan-1-one 544.0 [M+H]+ (ESI) ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.45 (s, 1H), 8.41-8.28 (m, 1H), 7.83 (br. s, 1H), 7.65- 7.26 (m, 2H), 5.03 (dd, J=4.7, 12.5 Hz, 1H), 4.75 (td, J=6.7, 13.4 Hz, 1H), 4 .40-3.28 (m, 5H), 3.12-2.98 (m, 1H), 2.55-2.45 (m, 2H), 1.89 (br. s, 3H), 2 .02-1.79 (m, 1H), 1.50 (s, 6H), 1.36-1.21 (m, 1H) F32

3-amino-1-[(3R,4R)-4-{[4-(1-tert-butyl-4-fluoro-1H-benzimidazol-6-yl)-5-chloropyridin-2-yl]amino}- 3-hydroxypiperidin-1-yl]-2,2-difluoropropan-1-one 525.3 [M+H]+ (ESI) 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.38 (s, 1H), 8.08 (s, 1H), 7.69 (s, 1H), 7.12 (d, J=11.4 Hz, 1H), 6.90-6.83 (m, 1H), 6.65 (s, 1H), 5.30 (br.s, 1H), 4.19-4.01 (m, 2H) , 3.99-3.80 (m, 2H), 3.46 (br. s, 2H), 3.23-2.96 (m, 4H), 2.11 (br. t, J=12, 7 Hz, 1H), 1.72 (s, 9H), 1.39-1.23 (m, 1H)

Example F33 (Scheme F-7): Preparation of 2-[(3R,4R)-4-{[4-(3-tert-butyl-3H-imidazo[4,5-b]pyridin-5-yl)-5 -chloropyridin-2-yl]amino}-3-hydroxypiperidin-1-yl]-N-methylacetamide

Diagram F-7:

To a solution of (3R,4R)-4-{[4-(3-tert-butyl-3H-imidazo[4,5-b]pyridin-5-yl)-5-chloropyridin-2-yl]amino}piperidin- 3-ol (prepared as in Example D3, 100 mg, 0.249 mmol) in EtOH (6.0 ml) was added 2-bromo-N-methylacetamide (56.7 mg, 0.374 mmol) and a solution of saturated aqueous NaHCO ₃ (3 .0 ml). The mixture was stirred at 70° C. for 16 hours. TLC analysis (1:3 MeOH/EtOAc) showed consumption of starting material. The mixture was diluted with H ₂ O (10 ml) and was extracted with EtOAc (20 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative HPLC on a DuraShell column (150×25 mm, particle size 5 μm), which was eluted with 21-41% MeCN/H ₂ O (+0.05% NH ₄ OH) with a flow rate of 25 ml/min with obtaining 2-[(3R,4R)-4-{[4-(3-tert-butyl-3H-imidazo[4,5-b]pyridin-5-yl)-5-chloropyridin-2-yl]amino} -3-hydroxypiperidin-1-yl]-N-methylacetamide (Example F33) (45.5 mg, 39% yield) as a white solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.54 (s, 1H), 8.17 (d, J=8.4 Hz, 1H), 8.07 (s, 1H), 7.72 (br.d, J=4.6 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 6.85-6.80 (m, 2H), 4.91 (d, J=5.6Hz, 1H), 3.60-3.49(m, 2H), 2.91(d, J=2.0Hz, 2H), 2.89-2.85(m, 1H ), 2.68 (br.d, J=11.1 Hz, 1H), 2.62 (d, J=4.7 Hz, 3H), 2.18-2.09 (m, 1H), 2 .06-1.98 (m, 2H), 1.80 (s, 9H), 1.50-1.39 (m, 1H); m/z (ESI+) for (C ₂₃ H ₃₀ ClN ₇ O ₂ ), 472.2 (M+H) ⁺ .

Example G1 (Scheme G-1): 1-[6-(5-chloro-2-{[(3R,4R)-3-hydroxy-1-(methanesulfonyl)piperidin-4-yl]amino}pyrimidin-4- yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]ethan-1-one

Scheme G-1:

Step 1: Synthesis of 1-[6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]ethan-1-one (G -2)

To a solution of 1-[6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]ethan-1-ol (G-1 ) (obtained as in Example A1, 500 mg, 1.35 mmol) in CHCl ₃ (10 ml), MnO ₂ (824 mg, 9.48 mmol) was added. The mixture was stirred at 50° C. for 6 hours. LCMS analysis showed consumption of starting material to form a mass of the desired product. The mixture was filtered and concentrated. The residue was purified by flash chromatography (Biotage, SiO ₂ , 25% EtOAc/petroleum ether) to give 1-[6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-(propan-2- yl))-1H-benzimidazol-2-yl]ethan-1-one (G-2) (480 mg, 97% yield) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.73 (s, 1H), 8.10 (d, J=1.2 Hz, 1H), 7.64 (dd, J=1.3, 10, 9 Hz, 1H), 6.06-5.92 (m, 1H), 2.93 (s, 3H), 1.71 (d, J=7.1 Hz, 6H); m/z (ESI+) for (C ₁₆ H ₁₃ Cl ₂ FN ₄ O), 367.0 (M+H) ⁺ .

Step 2: Synthesis of 1-[6-(5-chloro-2-{[(3R,4R)-3-hydroxy-1-(methanesulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)-4- fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]ethan-1-one (Example G1)

To a solution of 1-[6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]ethan-1-one (G-2 ) (100 mg, 0.272 mmol) in DMSO (5.0 ml) was added DIPEA (106 mg, 0.817 mmol) and (3R,4R)-4-amino-1-(methanesulfonyl)piperidin-3-ol (Int-69 ). The mixture was stirred at 70° C. for 16 hours. LCMS analysis showed consumption of starting material to form a mass of the desired product. The mixture was diluted with H ₂ O (30 ml) and was extracted with EtOAc (2×30 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative TLC (SiO ₂ , 50% EtOAc/petroleum ether, R _f =0.4) to give 1-[6-(5-chloro-2-{[(3R,4R)-3-hydroxy- 1-(methanesulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]ethan-1-one (Example G1 ) (58.2 mg, 41% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.47 (s, 1H), 8.21-8.03 (m, 1H), 7.67-7.41 (m, 2H), 5, 86-5.72 (m, 1H), 5.23 (d, J=4.6 Hz, 1H), 3.88-3.75 (m, 1H), 3.68-3.56 (m, 2H), 3.53-3.44 (m, 1H), 2.90 (s, 3H), 2.87-2.81 (m, 1H), 2.79 (s, 3H), 2.66 -2.60 (m, 1H), 2.14-1.98 (m, 1H), 1.61 (d, J=7.0 Hz, 6H), 1.57-1.45 (m, 1H ); m/z (ESI+) for (C ₂₂ H ₂₆ ClFN ₆ O ₄ S), 525.2 (M+H) ⁺ .

Example H1 (Scheme H-1): Preparation of 1,5-anhydro-3-({5-chloro-4-[2-(chloromethyl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazole -6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol

Scheme H-1:

Step 1: Synthesis of 5-bromo-3-fluoro-2-nitro-N-(propan-2-yl)aniline (A-16)

To a solution of 5-bromo-1,3-difluoro-2-nitrobenzene (A-15) (35.0 g, 147 mmol) in THF (700 ml) was added i-PrNH ₂ (8.7 g, 147 mmol) and Cs ₂ CO ₃ (57.5 g, 176 mmol). The mixture was stirred at room temperature for 16 hours. LCMS analysis showed consumption of starting material to form a mass of the desired product. The reaction mixture was diluted with H ₂ O (300 ml) and was extracted with EtOAc (3×300 ml). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give 5-bromo-3-fluoro-2-nitro-N-(propan-2-yl)aniline (A-16) (40.0 g, 98% yield as a red solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.09-6.98 (m, 2H), 6.89 (dd, J=1.9, 11.1 Hz, 1H), 6.17 ( s, 1H), 3.88 (br. d, J=7.5 Hz, 1H), 1.19 (d, J=6.4 Hz, 6H); m/z (ESI+) for (C ₉ H ₁₀ BrFN ₂ O ₂ ), 276.7 (M+H) ⁺ .

Step 2: Synthesis of [6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]methanol (H-1)

To a solution of 5-bromo-3-fluoro-2-nitro-N-(propan-2-yl)aniline (A-16) (40.0 g, 144 mmol) in EtOH/H ₂ O (4:1, 700 ml) 1,4-dioxane-2,5-diol (20.8 g, 173 mmol) and Na ₂ S ₂ O ₄ (126 g, 722 mmol) were added. The mixture was stirred at reflux at 80° C. for 16 hours. LCMS analysis showed consumption of starting material to form a mass of the desired product. The mixture was diluted with H ₂ O (100 ml) and was extracted with EtOAc (3×300 ml). The combined organic layers were washed with saturated aqueous NaHCO ₃ , dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash chromatography (SiO ₂ , 0-100% EtOAc/petroleum ether) to give [6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl] methanol (H-1) (19.0 g, 46% yield) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.81 (d, J=1.5 Hz, 1H), 7.28 (dd, J=1.5, 10.0 Hz, 1H), 5, 72 (t, J=5.8 Hz, 1H), 5.01-4.87 (m, 1H), 4.72 (d, J=5.5 Hz, 2H), 1.56 (d, J =6.8 Hz, 6H); m/z (ESI+) for (C ₁₁ H ₁₂ BrFN ₂ O), 286.8 (M+H) ⁺ .

Step 3: Synthesis of 6-bromo-4-fluoro-2-{[(oxan-2-yl)oxy]methyl}-1-(propan-2-yl)-1H-benzimidazole (Int-20)

To a solution of [6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]methanol (H-1) (19.0 g, 66.2 mmol) in THF (250 ml) p-TSA (1.7 g, 6.62 mmol) and DHP (22.3 g, 265 mmol) were added. The mixture was stirred at 90° C. for 4 hours. LCMS analysis showed consumption of starting material to form a mass of the desired product. The reaction mixture was diluted with H ₂ O (100 ml) and was extracted with EtOAc (3×150 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (SiO ₂ , 0-100% EtOAc/petroleum ether) to give 6-bromo-4-fluoro-2-{[(oxan-2-yl)oxy]methyl}-1-(propane -2-yl)-1H-benzimidazole (Int-20) (18.0 g, 73% yield) as a pale yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.85 (d, J=1.5 Hz, 1H), 7.31 (dd, J=1.5, 10.1 Hz, 1H), 4 .97-4.84 (m, 2H), 4.78-4.68 (m, 2H), 3.83-3.71 (m, 1H), 3.57-3.46 (m, 1H) , 1.72-1.63 (m, 2H), 1.57 (d, J=6.8 Hz, 6H), 1.53-1.46 (m, 4H); m/z (ESI+) for (C ₁₆ H ₂₀ BrFN ₂ O ₂ ), 372.6 (M+H) ⁺ .

Step 4: Synthesis of 4-fluoro-2-{[(oxan-2-yl)oxy]methyl}-1-(propan-2-yl)-6-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)-1H-benzimidazole (H-2)

To suspension of 6-bromo-4-fluoro-2-{[(oxan-2-yl)oxy]methyl}-1-(propan-2-yl)-1H-benzimidazole (H-2) (8.0 g, 21.6 mmol), B ₂ Pin ₂ (6.6 g, 25.9 mmol) and KOAc (6.3 g, 64.6 mmol) in 1,4-dioxane (160 ml) were added PdCl ₂ (dppf) (0.788 g, 1.08 mmol) under N ₂ atmosphere. The mixture was stirred at 80° C. under N ₂ for 16 hours. LCMS analysis showed consumption of starting material to form a mass of the desired product. The mixture was cooled to room temperature, filtered through celite and concentrated to dryness. The residue was dissolved in H ₂ O (150 ml) and was extracted with EtOAc (3×150 ml). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (360 g SiO ₂ , 0-100% EtOAc/petroleum ether) to give 4-fluoro-2-{[(oxan-2-yl)oxy]methyl}-1-(propane-2 -yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazole (H-2) (9.4 g, 73% yield) as yellow solution. m/z (ESI+) for (C ₂₂ H ₃₂ BFN ₂ O ₄ ), 419.1 (M+H) ⁺ .

Step 5: Synthesis of 6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-2-{[(oxan-2-yl)oxy]methyl}-1-(propan-2-yl)-1H- benzimidazole (H-3)

A mixture of 4-fluoro-2-{[(oxan-2-yl)oxy]methyl}-1-(propan-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-benzimidazole (H-2) (6.0 g, 14.3 mmol), 2,4,5-trichloropyrimidine (3.95 g, 21.5 mmol) and K ₂ CO ₃ (3.96 g, 28.7 mmol) in 1,4-dioxane (90 ml) and H ₂ O (30 ml) were degassed with N ₂ for 5 min. Pd(PPh ₃ ) ₄ (829 mg, 0.717 mmol) was added and the mixture was degassed for an additional 10 minutes. The reaction mixture was stirred at 90° C. under N ₂ for 16 hours. LCMS analysis showed consumption of starting material to form a mass of the desired product. The reaction mixture was cooled to room temperature, diluted with H ₂ O (30 ml) and was extracted with EtOAc (3×100 ml). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (40 g SiO ₂ , 0-60% EtOAc/petroleum ether) to give 6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-2-{[(oxan-2 -yl)oxy]methyl}-1-(propan-2-yl)-1H-benzimidazole (H-3) (7.4 g, 99% yield) as a white solid. m/z (ESI+) for (C ₂₂ H ₃₂ BFN ₂ O ₄ ), 461.0 (M+H) ⁺ .

Step 6: Synthesis of 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-{[(oxan-2-yl)oxy]methyl}-1-(propan-2-yl) -1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol (H-4)

To a solution of 6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-2-{[(oxan-2-yl)oxy]methyl}-1-(propan-2-yl)-1H-benzimidazole ( H-3) (2.3 g, 19.8 mmol) in DMSO (150 ml) was added DIPEA (10.6 g, 82.4 mmol) and 3-amino-1,5-anhydro-2,3-dideoxy -D-threo-pentitol (7.2 g, 16.5 mmol). The mixture was stirred at 120° C. for 16 hours. LCMS analysis showed consumption of starting material to form a mass of the desired product. The reaction solution was diluted with H ₂ O (200 ml) and was extracted with EtOAc (3×200 ml). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (360 g SiO ₂ , 0-10% MeOH/DCM) to give 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-{[(oxane -2-yl)oxy]methyl}-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol (H -4) (4.8 g, 56% yield) as a yellow solid. m/z (ESI+) for (C ₂₅ H ₃₁ ClFN ₅ O ₄ ), 520.1 (M+H) ⁺ .

Step 7: Synthesis of 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(hydroxymethyl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]) pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol (H-5)

To a solution of 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-{[(oxan-2-yl)oxy]methyl}-1-(propan-2-yl)-1H -benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol (H-4) (4.7 g, 9.2 mmol) in MeOH (40.0 ml ) was added a solution of HCl (4 N. in 1,4-dioxane, 10.0 ml) dropwise at 0°C. The solution was stirred at 20° C. for 1 hour. LCMS analysis showed consumption of starting material to form a mass of the desired product. The reaction mixture was concentrated to dryness. The residue was purified by flash chromatography (80 g SiO ₂ , 1:10 MeOH/DCM) to give 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(hydroxymethyl)-1 -(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol (H-5) (3.2 g, 80 yield %) as a yellow oil. ¹ H NMR (400 MHz, CD ₃ OD) δ 1.77-1.78 (m, 1H), 1.80 (dd, J=6.90, 2.89 Hz, 5H), 2.06-2 .16 (m, 1H), 3.18-3.27 (m, 1H), 3.44-3.54 (m, 1H), 3.65 (s, 1H), 3.99 (br.dd , J=11.29, 5.02 Hz, 3H), 5.07 (s, 2H), 5.21 (s, 2H), 7.92 (d, J=11.04 Hz, 1H), 8 .36 (s, 1H), 8.49 (s, 1H); m/z (ESI+) for (C ₂₀ H ₂₃ ClFN ₅ O ₃ ), 436.2 (M+H) ⁺ .

Step 8: Synthesis of 1,5-anhydro-3-({5-chloro-4-[2-(chloromethyl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-6-yl]) pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol (H-6)

To a solution of 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(hydroxymethyl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2 -yl}amino)-2,3-dideoxy-D-threo-pentitol (H-5) (800 mg, 1.8 mmol) in DCM (10 ml) was added TEA (557 mg, 5.5 mmol). The mixture was cooled to 0° C. and treated dropwise with methanesulfonyl chloride (328 mg, 2.2 mmol). The mixture was stirred at ambient temperature for 3 hours. LCMS analysis indicated consumption of starting material. The reaction mixture was washed with H ₂ O. The aqueous layer was extracted with DCM (3×10 ml). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give 1,5-anhydro-3-({5-chloro-4-[2-(chloromethyl)-4-fluoro-1-(propane -2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol (H-6) (800 mg, 96% yield), which was collected without additional cleaning. m/z (ESI+) for (C ₂₀ H ₂₂ Cl ₂ FN ₅ O ₂ ), 454.1 (M+H) ⁺ .

Step 9: Synthesis of 1,5-anhydro-3-[(5-chloro-4-{4-fluoro-2-[(3-hydroxy-3-methylazetidin-1-yl)methyl]-1-(propan-2 -yl)-1H-benzimidazol-6-yl}pyrimidin-2-yl)amino]-2,3-dideoxy-D-threo-pentitol (Example H1)

To a solution of 1,5-anhydro-3-({5-chloro-4-[2-(chloromethyl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2 -yl}amino)-2,3-dideoxy-D-threo-pentitol (H-6) (100 mg, 0.22 mmol) in MeCN (2.0 ml) was added 3-methylazetidin-3-ol (19, 2 mg, 0.22 mmol), NaI (33.0 mg, 0.22 mmol) and DIPEA (142 mg, 1.1 mmol). The mixture was stirred under N ₂ at 25° C. for 3 hours. LCMS analysis showed consumption of starting material to form a mass of the desired product. The reaction solution was washed with H ₂ O (5 ml). The aqueous layer was extracted with DCM (3×5 ml). The combined organic layers were washed with brine (10 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by preparative HPLC on a YMC Triart column (30×150 mm, particle size 7 μm) which was eluted with 30-50% MeCN/H ₂ O (+0.05% NH ₄ OH) at a flow rate of 25 ml/ min to obtain 1,5-anhydro-3-[(5-chloro-4-{4-fluoro-2-[(3-hydroxy-3-methylazetidin-1-yl)methyl]-1-(propan-2- yl)-1H-benzimidazol-6-yl}pyrimidin-2-yl)amino]-2,3-dideoxy-D-threo-pentitol (Example H1) (23.5 mg, 21% yield) as white solid . ¹ H NMR (400 MHz, CD ₃ OD) δ 8.35 (s, 1H), 8.02 (s, 1H), 7.49 (d, J=11.4 Hz, 1H), 5.16 ( p.p., J=7.0 Hz, 1H), 4.03-3.87 (m, 5H), 3.61 (dt, J=4.8, 9.4 Hz, 1H), 3.48 (dt, J=2.2, 11.7 Hz, 1H), 3.30-3.27 (m, 2H), 3.24-3.19 (m, 1H), 3.18-3.14 (m, 2H), 2.19-2.08 (m, 1H), 1.68 (d, J=6.8 Hz, 6H), 1.67-1.59 (m, 1H), 1, 46 (s, 3H); m/z (ESI+) for (C ₂₄ H ₃₀ ClFN ₆ O ₃ ), 505.2 (M+H) ⁺ .

The examples in the table below were synthesized according to the methods used for the synthesis of 1,5-anhydro-3-({5-chloro-4-[2-(chloromethyl)-4-fluoro-1-(propan-2-yl) -1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol (Example H1). The following examples have been synthesized with non-breaking modifications or substitutions to the illustrated techniques that a person skilled in the art could implement.

Example number Structure/Name HCMS NMR H2

1,5-ангидро-3-[(5-хлор-4-{2-[(диметиламино)метил]-4-фтор-1-(пропан-2-ил)-1H-бензимидазол-6-ил}пиримидин-2-ил)амино]-2,3-дидезокси-D-трео-пентитол

1,5-anhydro-3-[(5-chloro-4-{2-[(dimethylamino)methyl]-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-6-yl}pyrimidin- 2-yl)amino]-2,3-dideoxy-D-threo-pentitol 463.1 [M+H]+ (ESI) ¹ H NMR (400 MHz, CD ₃ OD) δ 8.37 (s, 1H), 8.06 (s, 1H), 7.52 (d, J=11.5 Hz, 1H), 5.25- 5.18 (m, 1H), 3.88-4.06 (m, 3H), 3.80 (s, 2H), 3.63 (m, 1H), 3.36-3.54 (m, 1H), 3.16-3.29 (m, 1H), 2.31 (s, 6H), 2.03-2.20 (m, 1H), 1.69 (d, J=7.0 Hz , 6H), 1.58-1.67 (m, 1H) H3

1,5-anhydro-3-[(5-chloro-4-{4-fluoro-2-[(3-hydroxyazetidin-1-yl)methyl]-1-(propan-2-yl)-1H-benzimidazol- 6-yl}pyrimidin-2-yl)amino]-2,3-dideoxy-D-threo-pentitol 491.1 [M+H]+ (ESI) ¹ H NMR (400 MHz, CD ₃ OD) δ 8.35 (s, 1H), 8.02 (s, 1H), 7.49 (d, J=11.4 Hz, 1H), 5.16- 5.06(m, 1H), 4.35(t, J=6.2Hz, 1H), 4.01-3.89(m, 5H), 3.66-3.57(m, 3H) , 3.48 (dt, J=2.1, 11.7 Hz, 1H), 3.20 (dd, J=9.7, 11.1 Hz, 1H), 3.11-3.05 (m , 2H), 2.18-2.09 (m, 1H), 1.68 (d, J=7.0 Hz, 6H), 1.66-1.58 (m, 1H) H4

1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-{[(2S,3R)-3-hydroxy-2,3-dimethylazetidin-1-yl]methyl}-1- (propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol 519.3 [M+H]+ (ESI) ¹ H NMR (400 MHz, CD ₃ OD) δ 8.35 (s, 1H), 8.03 (s, 1H), 7.50 (d, J=11.6 Hz, 1H), 5.19- 5.10 (m, 1H), 4.04-3.89 (m, 5H), 3.61 (dt, J=4.7, 9.4 Hz, 1H), 3.48 (dt, J= 2.3, 11.7 Hz, 1H), 3.25-3.17 (m, 3H), 2.97 (d, J=6.7 Hz, 1H), 2.13 (td, J=2 .3, 13.2 Hz, 1H), 1.69 (dd, J=6.9, 12.9 Hz, 7H), 1.28 (s, 3H), 0.88 (d, J=6, 2Hz, 3H) H5

1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-{[(oxetan-3-yl)amino]methyl}-1-(propan-2-yl)-1H-benzimidazole -6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol 491.2 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, CD ₃ OD) δ 8.37 (s, 1H), 8.06 (s, 1H), 7.52 (d, J=11.8 Hz, 1H), 5.08- 5.16 (m, 1H), 4.80 (m, 2H), 4.46 (m, 2H), 4.11 (s, 2H), 3.90-4.08 (m, 4H), 3 .63 (m, 1H), 3.50 (m, 1H), 3.19-3.26 (m, 1H), 2.13 (m, 1H), 1.72 (d, J=6.7 Hz, 6H), 1.69-1.61 (m, 2H) H6

1,5-anhydro-3-[(5-chloro-4-{4-fluoro-2-[(3-fluoroazetidin-1-yl)methyl]-1-(propan-2-yl)-1H-benzimidazol- 6-yl}pyrimidin-2-yl)amino]-2,3-dideoxy-D-threo-pentitol 493.2 [M+H]+ (ESI) ¹ H NMR (400 MHz, CD ₃ OD) δ 8.35 (s, 1H), 8.03 (s, 1H), 7.49 (d, J=11.5 Hz, 1H), 5.25- 5.04 (m, 2H), 4.01 (s, 2H), 4.00-3.87 (m, 3H), 3.74-3.56 (m, 3H), 3.53-3, 44 (m, 1H), 3.43-3.37 (m, 1H), 3.37-3.32 (m, 1H), 3.20 (dd, J=9.7, 11.1 Hz, 1H), 2.18-2.09 (m, 1H), 1.68 (d, J=6.8 Hz, 6H), 1.66-1.58 (m, 1H) H7

1,5-anhydro-3-[(4-{2-[(azetidin-1-yl)methyl]-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-6-yl}-5 -chloropyrimidin-2-yl)amino]-2,3-dideoxy-D-threo-pentitol 475.2 [M+H]+ (ESI) ¹ H NMR (400 MHz, CD ₃ OD) δ 8.35 (s, 1H), 8.03 (s, 1H), 7.49 (d, J=11.4 Hz, 1H), 5.15- 5.07 (m, 1H), 4.01-3.89 (m, 5H), 3.61 (br.d, J=4.8 Hz, 1H), 3.52-3.44 (m, 1H), 3.35 (t, J=7.0 Hz, 4H), 3.20 (dd, J=9.7, 11.1 Hz, 1H), 2.16-2.08 (m, 3H ), 1.69 (d, J=7.0 Hz, 6H), 1.67-1.60 (m, 1H)

Example H8 (Chart H-2): 1,5-anhydro-3-({5-chloro-4-[4-fluoro-1-(propan-2-yl)-2-{[(propan-2-yl )amino]methyl}-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol

Scheme H-2:

Step 1: Synthesis of 1,5-anhydro-3-({5-chloro-4-[2-(dihydroxymethyl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-6-yl]) pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol (H-7)

A mixture of (3R,4R)-4-({5-chloro-4-[4-fluoro-2-(hydroxymethyl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2- yl}amino)-1-(methanesulfonyl)piperidin-3-ol (H-5) (900 mg, 2.1 mmol) and MnO ₂ (2.7 g, 31 mmol in MeOH (20.0 ml)) were stirred at 60° C. for 16 hours. LCMS analysis indicated consumption of starting material. The reaction mixture was filtered and the filter cake was washed with MeOH (20 ml). The filtrate was concentrated to dryness. The residue was purified by flash chromatography (ISCO, 20 g SiO ₂ , 1:10 MeOH/DCM) to give 1,5-anhydro-3-({5-chloro-4-[2-(dihydroxymethyl)-4-fluoro -1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol (H-7) (162 mg, yield 26 %) as a colorless oil. ¹ H NMR (400 MHz, CD ₃ OD) δ 1.69 (t, J=5.77 Hz, 7H), 2.00-2.23 (m, 1H), 3.18-3.26 (m , 1H), 3.50 (br.d, J=2.26 Hz, 1H), 3.63 (td, J=9.29, 5.02 Hz, 1H), 3.98 (br.dd, J=11.29, 4.52 Hz, 3H), 5.44-5.53 (m, 1H), 5.88 (s, 1H), 7.53 (br. d, J=11.54 Hz , 1H), 8.07 (s, 1H), 8.37 (s, 1H); m/z (ESI+) for (C ₂₀ H ₂₃ ClFN ₅ O ₄ ), 452.2 (M+H) ⁺ .

Step 2: Synthesis of 1,5-anhydro-3-({5-chloro-4-[4-fluoro-1-(propan-2-yl)-2-{[(propan-2-yl)amino]methyl} -1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol (Example H8)

To a solution of 1,5-anhydro-3-({5-chloro-4-[2-(dihydroxymethyl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2 -yl}amino)-2,3-dideoxy-D-threo-pentitol (H-7) (50 mg, 0.11 mmol) and i-PrNH ₂ (12.7 mg, 0.215 mmol) in MeOH (5, 0 ml) AcOH (6.4 mg, 0.107 mmol) was added. After stirring for 2 hours at ambient temperature, NaBH ₃ CN (13.5, 0.215 mmol) was added and the mixture was stirred for 16 hours overnight. LCMS analysis showed consumption of starting material to form a mass of the desired product. The reaction mixture was poured into an aqueous solution of Na ₂ CO ₃ (1.0 M, 5 ml) and was extracted with DCM (3×5 ml). The combined organic layers were washed with brine (15 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative HPLC on an Xtimate C18 column (250×80 mm, particle size 10 μm) which was eluted with 35-55% MeCN/H ₂ O (+0.05% NH ₄ OH) at a flow rate of 25 ml/min. to give 1,5-anhydro-3-({5-chloro-4-[4-fluoro-1-(propan-2-yl)-2-{[(propan-2-yl)amino]methyl}-1H -benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol (Example H8) (10.9 mg, 21% yield) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.37 (s, 1H), 8.05 (s, 1H), 7.51 (d, J=11.8 Hz, 1H), 5.05- 5.17 (m, 1H), 4.15 (s, 2H), 3.90-4.03 (m, 3H), 3.64 (m, 1H), 3.50 (m, 1H), 3 .13-3.26 (m, 1H), 2.85-2.95 (m, 1H), 2.15 (m, 1H), 1.71 (d, J=7.0 Hz, 6H), 1.66 (m, 1H), 1.16 (d, J=6.2 Hz, 6H); m/z (ESI+) for (C ₂₃ H ₃₀ ClFN ₆ O ₂ ), 477.1 (M+H) ⁺ .

The examples in the table below were synthesized according to the methods used for the synthesis of 1,5-anhydro-3-({5-chloro-4-[4-fluoro-1-(propan-2-yl)-2-{[( propan-2-yl)amino]methyl}-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol (Example H8). The following examples have been synthesized with non-breaking modifications or substitutions to the illustrated techniques that a person skilled in the art could implement.

Example number Structure/Name HCMS NMR H9

(3R,4R)-4-({5-хлор-4-[4-фтор-2-{[(оксетан-3-ил)амино]метил}-1-(пропан-2-ил)-1H-бензимидазол-6-ил]пиримидин-2-ил}амино)-1-(метансульфонил)пиперидин-3-ол

(3R,4R)-4-({5-chloro-4-[4-fluoro-2-{[(oxetan-3-yl)amino]methyl}-1-(propan-2-yl)-1H-benzimidazole -6-yl]pyrimidin-2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol 568.1 [M+H]+ (APCI) ¹ H NMR (700 MHz, DMSO-d ₆ ) δ 8.43 (s, 1H), 8.09-7.68 (m, 1H), 7.44 (d, J=35.3 Hz, 1H) , 5.01 (n, J=6.8 Hz, 1H), 4.59 (t, J=6.6 Hz, 2H), 4.35-4.26 (m, 2H), 4.00 ( s, 2H), 3.92 (d, J=11.1 Hz, 1H), 3.85-3.74 (m, 2H), 3.66-3.57 (m, 6H), 2.89 (s, 3H), 1.59 (d, J=6.8 Hz, 6H) H10

(3R,4R)-4-({5-chloro-4-[4-fluoro-1-(propan-2-yl)-2-{[(propan-2-yl)amino]methyl}-1H-benzimidazole -6-yl]pyrimidin-2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol 553.9 [M+H]+ (APCI) ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.96 (s, 1H), 7.62-7.39 (m, 1H), 7.09-6.82 (m, 2H), 4, 88-4.67 (m, 1H), 4.65-4.48 (m, 1H), 3.58 (s, 2H), 3.34 (d, J=6.1 Hz, 1H), 3 .15 (d, J=10.1 Hz, 1H), 2.46-2.37 (m, 4H), 2.31-2.25 (m, 1H), 2.19 (t, J=10 .4 Hz, 1H), 1.63-1.55 (m, 1H), 1.41 (br. s, 3H), 1.13 (d, J=7.0 Hz, 6H), 1.10 -1.01 (m, 1H), 0.56 (d, J=6.2Hz, 6H) H11

1,5-anhydro-3-[(5-chloro-4-{2-[(cyclopropylamino)methyl]-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-6-yl}pyrimidin- 2-yl)amino]-2,3-dideoxy-D-threo-pentitol 475.3 [M+H]+ (ESI) ¹ H NMR (400 MHz, CD ₃ OD) δ 8.37 (s, 1H), 8.05 (s, 1H), 7.51 (d, J=11.54 Hz, 1H), 5.07 ( dt, J=13.93, 6.84 Hz, 1H), 4.19 (s, 2H), 3.90-4.03 (m, 3H), 3.63 (td, J=9.41, 4.77 Hz, 1H), 3.50 (td, J=11.67, 2.01 Hz, 1H), 3.22 (dd, J=11.04, 9.79 Hz, 1H), 2, 26 (dt, J=6.71, 3.29 Hz, 1H), 2.12-2.18 (m, 1H), 1.69 (d, J=7.03 Hz, 6H), 1.60 -1.68 (m, 1H), 0.45-0.51 (m, 2H), 0.31-0.36 (m, 2H)

Biological analyzes and data

CDK4/cyclin D1 mobility shift assay

The aim of the CDK4/cyclin D1 assay is to evaluate inhibition (% inhibition, K _iapp and K _i values) in the presence of small molecule inhibitors using a fluorescent microfluidic mobility shift assay. CDK4/cyclin D1 catalyzes the production of ADP from ATP, which accompanies the transfer of phosphoryl to the substrate of the peptide 5-FAM-Dyrktide (5-FAM-RRRFRPASPLRGPPK) (SEQ ID NO:1). Mobility shift assay electrophoretically separates fluorescently labeled peptides (substrate and phosphorylated product) after kinase reaction. Both substrate and product are measured and the ratio of these values is used to determine the % conversion of substrate to product using the LabChip EZ Reader. Representative reaction solutions contained 2% DMSO (± inhibitor), 10 mM MgCl ₂ , 1 mM DTT, 3.5 mM ATP, 0.005% TW 20, 3 μM 5-FAM-Dyrktide, 3 nM (active sites) activated CDK4/cycline D1 in 40 mM HEPES buffer at pH 7.5.

Determination of K _i inhibitor for activated CDK4/cyclin D1 (2007 E1/2008+PO4) was initiated by the addition of ATP (final reaction volume 50 μl) after an eighteen minute pre-incubation of enzyme and inhibitor at 22° C. in reaction mixing. The reaction was stopped after 195 minutes by adding 50 μl of 30 mM EDTA. The determination of K _i was performed from a relative rate plot as a function of inhibitor concentration corresponding to the Morrison equation with enzyme concentration as a variable.

CDK6/cyclin D3 mobility shift assay

The aim of the CDK6/cyclin D3 assay is to evaluate inhibition (% inhibition, K _iapp and K _i values) in the presence of small molecule inhibitors using a fluorescent microfluidic mobility shift assay. CDK6/cyclin D3 catalyzes the production of ADP from ATP, which accompanies the transfer of phosphoryl to the substrate of the peptide 5-FAM-Dyrktide (5-FAM-RRRFRPASPLRGPPK) (SEQ ID NO:1). Mobility shift assay electrophoretically separates fluorescently labeled peptides (substrate and phosphorylated product) after kinase reaction. Both substrate and product are measured and the ratio of these values is used to determine the % conversion of substrate to product using the LabChip EZ Reader. Typical reaction solutions contained 2% DMSO (± inhibitor), 2% glycerol, 10 mM MgCl ₂ , 1 mM DTT, 3.5 mM ATP, 0.005% Tween 20 (TW-20), 3 μM 5-FAM-Dyrktide, 4 nM (active sites) activated CDK6/cyclin D3 in 40 mM HEPES buffer at pH 7.5.

The determination of the K _i inhibitor for activated CDK6/cyclin D3 (LJIC-2009G1/2010 +PO4) was initiated by the addition of ATP (final reaction volume 50 μl) after an eighteen minute pre-incubation of enzyme and inhibitor at 22° C. in reaction mixing. The reaction was stopped after 95 minutes by adding 50 μl of 30 mM EDTA. The determination of K _i was performed from a relative rate plot as a function of inhibitor concentration corresponding to the Morrison equation with enzyme concentration as a variable.

For CDK4 and CDK6 mobility shift assays, see also Morrison, J. F. (1969) Kinetics of the reversible inhibition of enzyme-catalysed reactions by tight-binding inhibitors, Biochimica et biophysica acta 185, 269-286 and Murphy, D. J. (2004) Determination of accurate KI values for tight-binding enzyme inhibitors: an in silico study of experimental error and assay design, Analytical biochemistry 327, 61-67.

Phosphoserine 795 Rb ELISA Assay

JEKO-1 or MV4-11 cells were seeded at 15,000 or 20,000 cells per well, respectively, in 100 μl of growth medium and left to incubate at 37° C. with 5% CO ₂ overnight. The next day, compounds were serially diluted starting at a maximum dose of 10 mM to obtain a 11-point 3-fold dilution curve in DMSO. Compounds were intermediately diluted 1:200 in growth media before diluting 1:5 on cells to a final concentration of 10 μM to 0.1 nM in 0.1% DMSO on cells. Cells JEKO-1 and MV4-11 were treated overnight at 37°C with 5% CO ₂ . Cells were lysed in 100 μl/well of CST lysis buffer on ice and transferred to pre-coated and sealed anti-phospho-Ser795 Rb ELISA plates for overnight incubation at 4°C. The plates were washed to remove residual unbound cellular proteins and antibody was added to determine total Rb for 90 minutes at 37°C. After washing to remove unbound total Rb antibody, the HRP labeled antibody was allowed to bind for 30 minutes at 37°C. After washing to remove unbound HRP antibody, Glo Substrate reagent was added and incubated in a place protected from light for 5-10 minutes. Plates were read in luminescence mode and IC ₅₀ values were calculated.

Biological activity

Bioactivity data for representative compounds of the invention are provided in Table 6. Ki (nM) data for CDK4 and CDK6 in vitro are provided using calorimetric assays. IC ₅₀ (nM) data based on CDK4 and CDK6 cells are provided for CDK4 and CDK6 using phospho-Rb S795 ELISA in JEKO-1 and MV4-11 cells.

Example No. CDK4D1
Ki (nM) CDK4 pRB S795 ELISA JEKO-1 cells
IC50 (nM) CDK6_D3
Ki (nM) CDK6 pRB S795 ELISA MV4-11 cells
IC50 (nM) A01 0.1 25.3 2.3 76.5 A02 0.1 88.6 2.5 163.3 A03 4.0 17.3 A04 0.6 329.6 11.4 289.2 A05 3.3 225.1 50.8 541.4 A06 1.4 87.4 17.5 192.2 A07 1.8 182.1 28.0 520.4 A08 1.1 4.8 A09 0.1 16.8 1.4 57.6 A10 0.6 72.7 10.4 195.3 A11 0.3 122.7 3.0 143.9 A12 0.6 29.8 7.9 108.5 A13 1.7 72.2 31.5 276.7 A14 0.5 4.6 A15 0.3 2.4 A16 0.2 25.7 2.7 98.1 A17 0.1 9.9 0.4 13.4 A18 0.2 25.0 2.3 77.2 A19 0.9 69.1 14.6 318.4 A20 2.7 20.4 A21 7.3 135.6 A22 3.2 49.7 A23 0.5 26.5 11.6 84.1 A24 1.3 40.1 16.4 166.9 A25 0.0 13.3 1.3 30.6 A26 0.2 12.2 4.2 24.3 A27 1.0 75.6 15.7 269.2 A28 0.5 99.2 6.2 131.1 A29 0.6 68.6 5.1 95.7 A30 0.2 51.6 4.9 63.5 A31 0.5 23.5 7.1 87.0 A32 0.9 7.1 A33 8.3 78.0 A34 11.1 102.1 A35 1.5 123.8 58.9 966.7 A36 0.2 19.6 3.7 43.9 A37 3.5 34.2 A38 0.5 455.7 10.2 598.1 A39 1.3 12.3 A40 0.3 85.5 3.5 346.5 A41 3.1 92.8 48.8 216.1 A42 6.0 54.7 A43 4.8 44.0 A44 4.9 76.5 113.9 408.0 A45 1.0 65.8 52.0 468.4 A46 2.3 40.5 A47 1.0 382.7 24.6 370.3 A48 0.1 36.5 2.3 58.9 A49 0.7 76.0 14.3 219.2 A50 17.0 109.5 A51 2.0 245.0 55.7 1528.4 A52 2.7 202.1 60.1 973.1 A53 0.6 67.3 16.7 208.3 A54 2.3 173.1 37.5 605.3 A55 3.2 197.8 64.9 283.5 A56 1.3 9.6 A57 0.4 49.0 19.1 269.1 A58 0.6 33.1 17.6 203.0 A59 0.6 47.7 56.7 521.4 A60 1.6 65.2 33.6 190.3 A61 0.2 11.4 2.6 33.5 A62 0.5 27.5 8.0 66.6 A63 0.9 9.7 A64 2.0 10.7 A65 0.6 3.5 A66 12.1 54.7 A67 1.4 15.5 A68 0.7 48.7 14.3 234.9 A69 0.7 101.4 4.9 237.7 A70 26.2 124.2 A71 0.8 94.9 11.4 286.9 A72 0.3 2.1 A73 0.9 72.0 16.1 188.1 A74 0.2 26.5 6.2 89.7 A75 0.3 33.2 5.0 102.8 A76 0.2 96.1 6.3 242.0 A77 0.3 61.1 4.9 126.4 A78 0.1 26.4 1.8 73.9 A79 1.8 598.0 17.6 1138.0 A80 0.5 72.9 14.7 216.7 A81 A82 3.8 24.6 A83 4.1 394.8 88.5 1223.0 A84 6.0 30.3 A85 9.9 62.8 A86 4.7 23.5 A87 0.2 40.1 2.8 97.7 A88 4.5 7318.0 80.4 10000.0 A89 0.5 118.4 12.0 570.3 A90 0.2 1.1 A91 0.1 14.9 1.7 25.7 A92 0.1 23.8 0.9 42.9 A93 0.2 34.7 4.4 61.4 A94 0.6 38.5 13.9 144.9 B01 0.1 65.6 1.5 129.0 B02 7.3 27.1 C01 5.2 176.4 98.1 1379.5 C02 4.1 583.7 89.3 1350.0 D01 0.4 1.7 D02 1.0 9.3 D03 0.6 4.7 D04 0.6 68.2 12.5 172.0 D05 2.2 85.7 39.4 258.0 D06 E01 0.1 17.0 1.4 37.9 F01 0.8 114.1 14.6 576.0 F02 4.3 39.9 F03 2.7 26.4 F04 F05 2.1 247.9 25.8 478.2 F06 1.5 160.6 27.8 134.4 F07 15.3 125.4 F08 0.5 108.4 11.5 311.3 F09 0.6 5.5 F10 0.5 41.3 6.1 152.7 F11 5.4 821.1 79.9 2402.1 F12 50.0 109.5 F13 11.6 81.1 F14 3.6 30.8 F15 0.0 34.4 1.0 39.8 F16 1.4 675.3 26.0 362.7 F17 0.5 83.2 8.3 126.6 F18 0.9 31.7 10.1 F19 1.5 11.8 F20 2.0 155.1 24.3 787.5 F21 0.4 59.5 7.7 246.2 F22 0.5 61.3 9.1 171.1 F23 1.0 691.9 11.0 1318.1 F24 2.1 19.9 F25 1.2 455.3 19.3 455.2 F26 0.1 142.8 4.6 182.3 F27 0.5 60.8 5.1 188.0 F28 2.2 190.5 22.3 745.2 F29 1.8 245.5 23.3 643.7 F30 0.5 66.1 12.5 377.1 F31 2.4 23.0 F32 0.9 171.6 12.8 628.3 F33 0.2 24.6 5.2 112.8 G01 0.4 5.9 H01 2.4 137.1 127.0 857.6 H02 0.8 52.1 20.0 117.9 H03 1.8 155.4 66.9 422.9 H04 0.8 63.4 38.2 220.9 H05 4.5 249.0 93.3 1470.2 H06 1.1 79.6 35.6 343.3 H07 1.4 48.3 43.0 409.1 H08 1.2 35.6 44.5 305.9 H09 0.9 205.1 18.6 230.3 H10 0.5 14.9 16.4 51.1 H11 0.7 43.4 22.1 295.1

All publications and patent applications cited in the specification are hereby incorporated by reference in their entirety. It will be apparent to a person skilled in the art that certain changes and modifications may be made without departing from the spirit or scope of the appended claims.

--->

SEQUENCE LIST

<110> PFIZER INC.

Chen, Ping

Cho-Schultz, Sujin

Deal, Judy

Gallego, Gary M

Jalaie, Mehran

Kania, Robert

Nair, Sajiv K

Ninkovic, Sacha

Orr, Suvi T

Palmer, Cynthia L

<120> Cyclin-dependent kinase inhibitors

<130> PC72436-03

<160> 1

<170> Patent Version 3.5

<210> 1

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construction

<220>

<221> other_characteristic

<222> (1)..(1)

<223> 5'FAM-labeled glutamine

<400> 1

Arg Arg Arg Phe Arg Pro Ala Ser Pro Leu Arg Gly Pro Pro Lys

1 5 10 15

<---

Claims (34)

1. Compound of Formula (IX):

(IX) or a pharmaceutically acceptable salt thereof, wherein: R ¹ is H, F, Cl, CN, C ₁ -C ₂ alkyl or C ₁ -C ₂ fluoroalkyl, wherein each C ₁ -C ₂ alkyl and C ₁ -C ₂ fluoroalkyl is optionally substituted with R ²⁰ ; R ² is H, C ₁ -C ₅ alkyl, C ₁ -C ₅ fluoroalkyl, C ₃ -C ₈ cycloalkyl, oxetan-3-yl, azetidin-3-yl or oxolan-3-yl, wherein each C ₁ -C ₅ alkyl and C ₁ -C ₅ fluoroalkyl is optionally substituted with R ²⁰ and each said C ₃ -C ₈ cycloalkyl and oxetan-3-yl, azetidin-3-yl or oxolan-3-yl is optionally substituted with R ²¹ ; R ⁴ is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy or C ₁ -C ₄ fluoroalkoxy, wherein each is C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ fluoroalkoxy are optionally substituted with R ²⁰ ; R ⁶ is H, F, Cl, CN, CH ₃ , CH ₂ F, CHF ₂ or CF ₃ ; R ⁷ and R ⁸ are independently H, F, Cl, CN, C ₁ -C ₂ alkyl, C ₁ -C ₂ fluoroalkyl, C ₁ -C ₂ alkoxy, or C ₁ -C ₂ fluoroalkoxy, wherein each C ₁ -C ₂ alkyl, C ₁ -C ₂ fluoroalkyl, C ₁ -C ₂ alkoxy and C ₁ -C ₂ fluoroalkoxy are optionally substituted with R ²⁰ ; R ⁹ is H, OH or N(CH ₃ ) ₂ ; each R ¹⁰ is independently F, CN, C ₁ -C ₂ alkyl, or C ₁ -C ₂ fluoroalkyl, wherein each said C ₁ -C ₂ alkyl and C ₁ -C ₂ fluoroalkyl is optionally substituted with R ²⁰ ; R ¹¹ is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, SO ₂ R ¹⁴ , SO ₂ NR ¹⁵ R ¹⁶ , COR ¹⁷ , COOR ¹⁷ or CONR ¹⁸ R ¹⁹ ; R ¹⁴ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl; each R ¹⁵ and R ¹⁶ is independently H or CH ₃ ; R ¹⁷ is C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with R ²⁰ ; each R ¹⁸ and R ¹⁹ is independently H, C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, wherein each said C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with R ²⁰ ; each R ²⁰ is independently OH, C ₁ -C ₂ alkoxy, C ₁ -C ₂ fluoroalkoxy, CN or NR ²² R ²³ ; each R ²¹ is independently F, OH, CN, NR ²² R ²³ , C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy or C ₁ -C ₄ fluoroalkoxy, in which each specified C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ fluoroalkoxy optionally further substituted with OH, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ ; each R ²² and R ²³ is independently H, C ₁ -C ₂ alkyl or C ₁ -C ₂ fluoroalkyl or R ²² and R ²³ may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring which is optionally substituted with F or OH; And n is 0, 1, 2, 3, or 4. 2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ¹ is F or Cl. 3. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ² is CH ₃ , iso-C ₃ H ₇ , iso-C ₄ H ₉ , sec-C ₄ H ₉ , tert-C ₄ H ₉ , CH ₂ F, CHF ₂ , CH ₂ CHF ₂ or oxetan-3-yl. 4. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is H or C ₁ -C ₄ alkyl, wherein said C ₁ -C ₄ alkyl is optionally substituted with OH, NH ₂ , NHCH _{3 ,} or N(CH ₃ ) ₂ . 5. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ⁶ is H or F. 6. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ⁹ is OH. 7. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ¹¹ is SO ₂ R ¹⁴ and R ¹⁴ is C ₁ -C ₄ alkyl. 8. Compound (3 R ,4 R )-4-[(5-chloro-4-{4-fluoro-2-[(1 R )-1-hydroxyethyl]-1-(propan-2-yl)-1 H -benzimidazol-6-yl}pyrimidin-2-yl)amino]-1-(methanesulfonyl)piperidin-3-ol or a pharmaceutically acceptable salt thereof. 9. A pharmaceutical composition that inhibits the activity of cyclin-dependent kinases (CDKs), containing a therapeutically effective amount of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. 10. A method of treating cancer in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof. 11. The method of claim 10 wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer, liver cancer, pancreatic cancer, stomach cancer and thyroid cancer. 12. The method according to claim 10, where the cancer is a breast cancer selected from the group consisting of ER-positive/HR-positive, HER2-negative breast cancer; ER-positive/HR-positive, HER2-positive breast cancer; triple negative breast cancer (TNBC), inflammatory breast cancer, and combinations thereof. 13. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, for use in the treatment of breast cancer in a subject in need of such treatment. 14. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, for use in the treatment of breast cancer, wherein said treatment comprises the administration of a second pharmaceutically active agent. 15. A method of treating cancer in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl )-1-(propan-2-yl)-1 H -benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D- threo -pentitol or a pharmaceutically acceptable salt thereof, wherein cancer is selected from the group consisting of lung cancer, colorectal cancer and prostate cancer.