EA042105B1 - 2-AMINO-PYRIMIDINE DERIVATIVES AS CYCLIN-DEPENDENT KINASE INHIBITORS - Google Patents

Description

This invention relates to compounds of formula (IX) or formula (X)

or to their pharmaceutically acceptable salts, in which the R groups from R ¹ to R ²³ and n are as defined in the description of the invention, to pharmaceutical compositions containing such compounds and salts, and to methods of using such compounds and salts for the treatment of cancer subject.

Field of invention

The present invention relates to compounds of formula (IX)-(X) and their pharmaceutically acceptable salts, to pharmaceutical compositions containing such compounds and salts, and to their uses. 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.

Prior Art

Cyclin-dependent kinases (CDKs) and related serine/threonine protein kinases are important cellular enzymes that perform critical 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: 295312). Additional functions of cyclin/CDK heterodynes include the regulation of transcription, DNA repair, differentiation, and apoptosis. (Morgan D.O. 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 transient abnormal activation of CDK leads to the development of human tumors, and human tumor development 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 through 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. Cyclin D-dependent kinases, INK4 inhibitors and cancer Biochim Biophys Acta (2002) 1602: 73-87 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 inhibitors of CDK INK4 have also been described as a mechanism by which this pathway can be activated (Smalley KSM (2008)).

The development of CDK inhibitors is reviewed in the literature. For example, see Sanchez-Martinez et al. Cyclin dependent kinase (CDK) inhibitors as anticancer drugs, Bioorg. Med. Chem. Lett. (2015) 25:3420-3435 (and references cited there). The use of CDK4/6 inhibitors in combination with endocrine therapy has shown significant efficacy in the treatment of hormone receptor (HR)-positive,

- 1 042105 human epidermal growth factor 2 (HER2)-negative advanced breast cancer or metastatic breast cancer, and CDK4/6 inhibitors, including palbociclib, ribociclib, and abemaciclib, have been approved for use in combination with endocrine therapy in first-line therapy. or second line.

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. Recent data suggest that cyclin D3-CDK6 may be associated with the observed haematological toxicity. (Malumbres et al., Mammalian Cells Cycle without the D-type CyclinDependent 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 driver for many breast cancers. Accordingly, a selective CDK4 inhibitor may provide an improved safety profile or increased overall efficacy due to the possibility of higher dose levels and/or continuous dosing compared to dual CDK4/6 inhibitors.

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

Brief summary of the invention

The present invention provides, inter alia, compounds of formula (IX)-(X) and their pharmaceutically acceptable salts. Such compounds can inhibit the activity of CDKs, including CDK4 and/or CDK6, thereby performing biological functions. In some embodiments of the invention, compounds are provided that are selective for CDK4. Pharmaceutical compositions containing compounds or salts of the invention are also provided.

In one aspect of the invention there is provided a compound of formula (X)

or a pharmaceutically acceptable salt thereof, wherein

R ¹ represents H, F, Cl, CN, C ₁ -C ₂ alkyl or C ₁ -C ₂ fluoroalkyl;

R ² is H, C1-C5 alkyl, C1-C5 fluoroalkyl, C3-C8 cycloalkyl, or a 3-6 membered heterocyclyl having one heteroatom selected from O and N, wherein said C1-C5 alkyl and C1-C5 fluoroalkyl are each optionally substituted with R ²⁰ . and each specified C3-C ₈ cycloalkyl and 3-6 membered heterocyclyl is optionally substituted with R ²¹ ;

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

R ⁶ is H, F, Cl, CN or CH ₃ ;

R ⁷ and R ⁸ are independently H, F or Cl;

R ⁹ is H, OH, NH2, NHCH3 or N(CH ₃ ) ₂ ;

each R ²⁰ is independently OH, C ₁ -C ₂ alkoxy or NR22R ²³ ;

each R ²¹ is independently F, OH, CN, NR22R ²³ or C ₁ -C ₄ alkyl;

each R ²² and R ²³ independently represents H or C ₁ -C ₂ alkyl; 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.

In one embodiment, the above compound is a compound having the formula (X-A),

- 2 042105

or a pharmaceutically acceptable salt thereof.

In another aspect of the invention there is provided a compound of formula (IX)

or a pharmaceutically acceptable salt thereof, wherein

R ¹ represents H, F, Cl, CN, C ₁ -C ₂ alkyl or C ₁ -C ₂ fluoroalkyl;

R ² is H, C1-C5 alkyl, C1-C5 fluoroalkyl, C3-C8 cycloalkyl, or a 3-6 membered heterocyclyl having one heteroatom selected from O and N, wherein said C1-C5 alkyl and C1-C5 fluoroalkyl are each optionally substituted with R ²⁰ . and each said C3-C8 cycloalkyl and 3-6 membered heterocyclyl is optionally substituted with R ²¹ ;

R ⁴ is H, C1-C ₄ alkyl or C1-C ₄ fluoroalkyl, where each C1-C ₄ alkyl and C1-C ₄ fluoroalkyl are optionally substituted with R ²⁰ ;

R ⁶ is H, F, Cl, CN or CH ₃ ;

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

R ⁹ is H, OH, NH2, NHCH3 or N(CH ₃ )2;

R ¹¹ is H, C1-C ₄ alkyl, SO2R ¹⁴ , COR ¹⁷ , COOR ¹⁷ or CONR18R ¹⁹ ;

R ¹⁴ is C1- _C4 alkyl or C1- _C4 fluoroalkyl;

R ¹⁷ is C1-C ₄ alkyl or C1-C ₄ fluoroalkyl, where each C1-C ₄ alkyl and C1-C ₄ fluoroalkyl are optionally substituted with R ²⁰ ;

each R ¹⁸ and R ¹⁹ independently represents H or C 1 -C ₄ alkyl;

each R ²⁰ is independently OH, C1-C ₂ alkoxy or NR22R ²³ ;

each R ²¹ is independently F, OH, CN, NR22R ²³ or C1- _C4 alkyl;

each R ²² and R ²³ independently represents H or C1-C ₅ alkyl; 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.

In one embodiment, the above compound is a compound having the formula (IX-A), .R ¹

NR ⁷

HL JL Χχ. -X .R ⁶ Ν Ν to ' IX ^r X l-g I Jj./ r' X

R ¹¹ (IX-A), or a pharmaceutically acceptable salt thereof.

In one embodiment, for a compound according to any of the formulas described herein, or a pharmaceutically acceptable salt thereof, R ¹ is Cl.

In one embodiment, for a compound of any formula described herein, or a pharmaceutically acceptable salt thereof, R ² is C 1 -C ₅ alkyl which is optionally substituted with R ²⁰ .

In one embodiment, for a compound according to any formula described herein, or a pharmaceutically acceptable salt thereof, R ⁴ is C 1 -C ₄ alkyl which is optionally substituted with R ²⁰ .

In one embodiment, for a compound according to any formula described herein, or a pharmaceutically acceptable salt thereof, R ²⁰ is OH.

- 3 042105

In one embodiment, for a compound according to any formula described herein, or a pharmaceutically acceptable salt thereof, R ⁶ is F, R ⁷ is H, and R ⁸ is

N.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

In another aspect of the invention, there is provided 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 yet another aspect of the invention, there is provided a method for treating cancer in a subject in need thereof, comprising administering to that subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.

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 it is combined.

In addition, each of the following embodiments describing this invention provides within its scope pharmaceutically acceptable salts of the compounds of the invention. Accordingly, the term, or a pharmaceutically acceptable salt thereof, is intended to be used in the description of all compounds described herein, unless expressly stated otherwise.

Detailed description of the invention

The present invention can be more easily understood in view of the following detailed description of the preferred embodiments of the invention and the examples included in the description. It should be understood that the terminology used here is provided for the purpose of describing particular embodiments only and is not intended to limit them. In addition, it should be understood that, unless otherwise noted here, the terminology used here should be given its traditional meaning, known in the art.

The singular form used here includes plural references unless otherwise noted. For example, a substituent includes one or more substituents. The term approximately means a value that falls within the generally accepted standard error of the mean, when considered by a person skilled in the art.

The invention described here can be suitably practiced in the absence of any(s) element(s) not specifically disclosed(s) here. Thus, for example, in each instance in this specification, any of the terms containing, consisting essentially of, and consisting of may 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 specific number of carbon atoms. Alkyl substituents usually contain from 1 to 12 carbon atoms (C ₁ -C ₁₂ alkyl), often from 1 to 8 carbon atoms (C 1 -C ₈ alkyl) or more often from 1 to 6 carbon atoms (C 1 -C ₆ alkyl), from 1 to 5 carbon atoms (C1-C ₅ alkyl), 1 to 4 carbon atoms (C1-C ₄ alkyl), or 1 to 2 carbon atoms (C1-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, wherein the substituents

- 4 042105 groups are independently selected unless otherwise indicated. The total number of substituent groups may be equal to the total number of hydrogen atoms on the alkyl group, in cases where such substitution is chemically justified. Optionally substituted alkyl groups usually have 1 to 6 possible substituents, sometimes 1 to 5 possible substituents, 1 to 4 possible substituents, or preferably 1 to 3 possible substituents.

Possible substituents suitable for alkyl include 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 , -CO2R ^x , -C(O)NR ^x R ^y , -SR ^x , -SOR ^x , -SO2R ^x , -SO2NR ^x R ^y , -NO2, -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 SO2R ^y , -NR ^x SO2NR ^x R ^y , -OR ^x , -OC(O)R ^x and -OC(O)NR ^x R ^y ; where each R ^x and R ^y is independently H, C1-C8 alkyl, C1-C8 acyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, 3-12 membered heterocyclyl, C6-C12 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 a 5-12 membered heteroaryl, each of which optionally contains 1, 2 or 3 additional heteroatoms selected from O, N and S(O)q, where 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', -CO2R', -C(O)NR'2, -SOR', -SO2R', -SO2NR'2, -NO2, -NR'2, -NR'C(O)R', -NR 'C(O)NR'2, -NR'C(O)OR', -NR'SO2R', -NR'SO ₂ NR' ₂ , -OR, -OC(O)R' and -OC(O) NR' ₂ where each R' is independently H, C1-C ₈ alkyl, C1-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-C ₁₂ heteroaryl; and where each specified C ₃ -C ₈ cycloalkyl, 3-12-membered heterocyclyl, C ₆ -C ₁₂ aryl and 5-12-membered heteroaryl is optionally substituted, as defined hereinafter, without limitation.

Common substituent groups on alkyl include halogen, -OH, C1-C ₄ alkoxy, -O-C 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 , C3-C8 cycloalkyl, Cv-C^aryl, 5-12 membered heteroaryl and 3-12 membered heterocyclyl; where each R ^x and R ^y is independently H or C 1 -C 4 alkyl, 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 rings, each of which optionally contains 1, 2 or 3 additional heteroatoms selected from O, N and S(O) _q where q is 0-2; where 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, = O, C1-C ₄ alkyl, C1-C ₄ alkoxy, C1-C ₆ haloalkyl, C1-C ₆ hydroxyalkyl, C ₁ -C ₄ alkoxy-C ₁ -C ₆ alkyl, -CN, -NH2, -NH groups ( C ₁ -C ₄ alkyl) and -N(C ₁ -C ₄ alkyl) ₂ .

In some cases, substituted alkyl groups are specifically named based on the substituent group. For example, haloalkyl refers to an alkyl group having the specified number of carbon atoms that is substituted with one or more halo substituents, up to the available valency numerical value. 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., C1- _C5 haloalkyl, C1- _C4 haloalkyl or C1- _C2 haloalkyl).

More specifically, fluorinated alkyl groups may specifically be referred to as fluoroalkyl groups (eg C1-C ₅ , C1-C4 or C1-C ₂ fluoroalkyl groups) which are typically substituted with 1, 2, 3, 4 or 5 fluorine atoms. Thus, C1-C ₄ fluoroalkyl includes trifluoromethyl (-CF ₃ ), difluoromethyl (-CF2H), fluoromethyl (-CFH2), difluoroethyl (-CH2CF2H) and the like. Such groups may be further substituted with groups suitable for alkyl groups, as further described here.

In some embodiments of the present invention, the alkyl and fluoroalkyl groups are optionally substituted with one or more possible substituents, and preferably 1-3 possible substituents, which are independently OH, C1-C ₂ alkoxy, C1-C ₂ fluoroalkoxy, CN, or NR' ₂ . where each R' independently represents H, C1-C ₂ alkyl or C1-C ₂ fluoroalkyl.

Similarly, alkoxyalkyl refers to an alkyl group having the indicated number of carbon atoms that is substituted with one or more alkoxy substituents. Alkoxyalkyl groups typically contain 1-4 carbon atoms in the alkyl moiety and are substituted with 1, 2 or 3 C1- _C4 alkyloxy substituents. Such groups are sometimes described herein as C1- _C4 alkyloxy-C1- _C4 alkyl.

Aminoalkyl refers to an alkyl group having the specified number of carbon atoms, which is substituted with one or more substituted or unsubstituted amino groups, such groups are further defined here. Aminoalkyl groups typically contain 1-6 carbon atoms on the alkyl moiety and are substituted with 1, 2 or 3 amino substituents. Thus, C1-C ₆ aminoalkyl includes, for example, aminomethyl (-CH2NH2), N,N-dimethylaminoethyl (-CH ₂ CH ₂ N(CH ₃ ) ₂ ), 3-(K-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 the indicated 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. C1-C ₆ hydroxyalkyl). Thus C1- _C6 hydroxyalkyl includes hydroxymethyl (-CH2OH) and 2-hydroxyethyl (-CH2CH2OH).

Alkenyl refers to an alkyl group, as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon double bond. Generally, alkenyl groups have 2 to 20 carbon atoms (C ₂ -C ₂₀ alkenyl), preferably 2 to 12 carbon atoms (C ₂ -C ₁₂ alkenyl), more preferably 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). Typical examples include ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like, without limitation. Alkenyl groups are unsubstituted or substituted with the same groups as 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 have 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 from 2 to 6 carbon atoms (C ₂ -C ₆ alkynyl), or from 2 to 4 carbon atoms (C ₂ -C ₄ alkynyl). Typical examples include ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like, without limitation. Alkynyl groups are unsubstituted or substituted with the same groups as described herein as suitable for alkyl.

When used here, the term alkylene refers to a divalent hydrocarbyl group having the specified number of carbon atoms, which can link two other groups together. Sometimes it refers to the group -(CH ₂ )t-, where 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 C1-C ₈ alkylene, C1-C ₆ alkylene, C1-C ₄ alkylene, and so on. If indicated, alkylene may also be substituted with other groups and may include one or more degrees of unsaturation (ie, an alkenylene or alkynylene moiety) or rings. The free 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-). When an alkylene group is described as possibly substituted, the substituents include substituents normally present on alkyl groups, as described herein.

Heteroalkylene refers to an alkylene group as described above, wherein one or more non-adjacent carbons of the alkylene chain are replaced by -N(R)-, -O- or -S(O) _x - where R is H or a substituent group suitable for secondary amino grouping, and x is 0-2. For example, the -O-(CH ₂ )1 group. _{3 -} represents a 'C ₂ -C ₄ '-heteroalkylene group, where one of the carbon atoms of the corresponding alkylene is replaced by O.

Alkoxy refers to a monovalent -O-alkyl group, where the alkyl moiety has the indicated number of carbon atoms. Alkoxy groups usually contain from 1 to 8 carbon atoms (C1-C ₈ alkoxy), or from 1 to 6 carbon atoms (C1-C ₆ alkoxy), or from 1 to 4 carbon atoms (C1-C ₄ alkoxy). For example, C1-C ₄ alkoxy includes methoxy, ethoxy, isopropoxy, t-butyloxy (ie, -OCH ₃ , -OCH2CH3, -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 optionally be 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, when fluorinated, more specifically, fluoroalkoxy) groups having the indicated number of carbon atoms and substituted with one or more halo 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 C1- _C2 haloalkoxy). More specifically, fluorinated alkoxy groups may be specifically referred to as fluoroalkoxy groups, eg C1-C6-, C1-C4- or C1- _C2 fluoroalkoxy groups, which are usually substituted with 1, 2 or 3 fluorine atoms. Thus, C1-C ₄ fluoroalkoxy includes trifluoromethyloxy (-OCF3), difluoromethyloxy (-OCF2H), fluoromethyloxy (-OCFH2), difluoroethyloxy (-OCH2CF2H), and the like.

Similarly, thioalkoxy refers to a monovalent -S-alkyl group, where the alkyl portion has the specified number of carbon atoms, and which is optionally substituted on the alkyl portion with the same groups as described herein as suitable for alkyl. For example, C1- _C4 thioalkoxy includes -SCH3 and -SCH2CH3.

Cycloalkyl refers to a non-aromatic saturated carbocyclic ring system containing the specified number of carbon atoms, which may be monocyclic, spirocyclic, bridged or fused bicyclic or polycyclic ring system, which is connected to the main molecule through the carbon atom of the cycloalkyl ring. Typically, the cycloalkyl groups according to the invention contain from 3 to 12 carbon atoms (C ₃ -C ₁₂ cycloalkyl), preferably from 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

- 6 042105 except that the cycloalkyl rings may also be substituted with alkyl groups having the indicated number of carbon atoms, which may be further optionally substituted as described here.

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

cyclopropane cyclobutane cyclopentane cyclopentene cyclohexane cyclohexene (cyclopropanyl (cyclobutanyl) (cyclopentanyl) (cyclopentenyl) (cyclohexanyl) (cyclohexenyl)

cycloheptane cycloheptene octahydroindan octahydropentalene decahydronaphthalene (cycloheptanyl) (cycloheptenyl) (octahydroindanyl) (octahydropentalenyl) (decahydronaphthalene)

adamantane bicyclo[1.1.1]pentane bicyclo[2.2.1]heptane bicyclo[2.2.2]octane (adamantyl) (bicyclo[1.1.1]pentanyl) (bicyclo[2.2.1]heptanyl) (bicyclo[2.2.2] octanyl)

Cycloalkylalkyl is used to describe a cycloalkyl ring, typically a C ₃ -C ₈ cycloalkyl, that is linked to the parent molecule via an alkylene linker, typically a C 1 -C ₄ alkylene. Cycloalkylalkyl groups are sometimes described by the total number of carbon atoms in the carbocyclic ring and linker, and they usually contain from 4 to 12 carbon atoms (C ₄ -C ₁₂ cycloalkylalkyl). Thus, a 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, where the S ring atoms are optionally substituted by one or two oxo groups (i.e. S(O)x, where x is 0, 1 or 2) and where the heterocyclic ring is connected to the main molecule through a ring atom, which may be C or N. If specifically indicated, 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, 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 as described herein as suitable for alkyl, except that heterocyclyl rings may also be substituted with alkyl groups having the indicated number of carbon atoms, which may optionally be further substituted, as described here. 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 ring atoms are optionally substituted with groups suitable for an amine, such as 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 in this specification.

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

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tetrahydrothiophene pyrrolidine tetrahydropyran tetrahydrothiopyran piperidine (tetrahydrothiophenyl) (pyrrolidinyl) (tetrahydropyranyl) (tetrahydrothiopyranyl) (piperidinyl)

oxepan (oxepanil) thiepane (thiepanil) azepan (azepanil)

1,4-dioxepan 1,4-oxathiepan (1,4-dioxepanil) (1,4-oxathiepanil)

1,4-oxaazepan (1,4-oxaazepanil)

1,4-thieazepane (1,4-thieazepanil)

1,4-diazepan (1,4-diazepanil)

1,4-dithiepan (1,4-dithiepanil)

Illustrative examples of partially unsaturated heterocycles include the following, without limitation:

Illustrative examples of bridged, condensed blowers, without limitation:

spiroheterocycles include the following

2-oxa-5-azabicyclo-3-oxa-8-azabicyclo-3-azabicyclo[2.2.1]heptane

[3.2.1]octane

[3.1.0]hexane

2-azabicyclo[3.1.0]hexane

8-azabicyclo[2.2.1]octane

2-azabicyclo[2.2.1]heptane

ABOUT

3-oxooctahydroindolizine

1,1-dioxydohexahydro- 1,1-dioxydohexahydro- 3-oxohexahydro[1,3]2,2-dioxido-2pyrido[1,2-(1][3.2.1]- pyrido[1,2]thiazolo[2 ,3-а]- oxazolo[3,4-а]pyridine thiaspiro[3.5]nonane oxathiazine pyridine

- 8 042105

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 some 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 for a particular substituent group, provided that such substitution has a chemical meaning.

In some embodiments of the present invention, the cycloalkyl and heterocyclyl groups are optionally substituted with one or more possible substituents, and preferably 1-3 possible substituents, which are independently F, OH, CN, NR' ₂ (wherein each R' is independently H, C1 -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, where each specified C 1 -C ₄ alkyl, C 1 -C ₄ fluoroalkyl , C1-C ₄ alkoxy and C1-C ₄ fluoroalkoxy optionally additionally substituted with OH, NH2, NHCH3 or N(CH ₃ ) ₂ .

It is understood that no more than two N, O, or S atoms are usually connected 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 the specified size, which is connected to the main molecule through an alkylene linker of the specified length. Typically, such groups contain a possibly substituted 3-12 membered heterocycle attached to the parent molecule via a C1- _C4 alkylene linker. Where so indicated, such groups are optionally substituted on the alkylene moiety with the same groups described herein as being suitable for alkyl groups, and on the heterocyclic moiety with groups described as being suitable for heterocyclic rings.

Aryl or aromatic refers to a possibly substituted monocyclic or fused bicyclic or polycyclic ring system having well-known aromaticity properties, where at least one ring contains a fully conjugated pi-electron system. Generally, aryl groups have 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 carbon atoms (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 atom aromatic part of the ring system. Examples of aryl groups include, without limitation, phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and tetrahydronaphthyl. The aryl group is unsubstituted or substituted as further described here.

Similarly, heteroaryl or heteroaromatic refers to monocyclic or fused bicyclic or polycyclic ring systems having well-known aromatic properties, 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 the C ring atom, while 5-membered heteroaryl rings can be attached to the main molecule through the 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 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, naftridine and carbazole, without limitation. 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 here.

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 on the aryl,

- 9 042105 heteroaryl or heterocyclyl part, to the extent that such a substitution has a chemical meaning and, in the case of aryl and heteroaryl rings, aromaticity is retained. Optionally substituted aryl or heteroaryl groups usually have 1 to 5 possible substituents, sometimes 1 to 4 possible substituents, preferably 1 to 3 possible substituents, or more preferably 1 to 2 possible substituents.

Possible 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 , -CO2R ^x , -C(O)NR ^x R ^y , -SR ^x , -SOR ^x , -SO2R ^x , -SO2NR ^x R ^y , - NO2, 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 SO2R ^y , -NR ^x SO2NR ^x R ^y , -OR ^x , -OC(O)R ^x and -OC(O)NR ^x R ^y ; where each R ^x and R ^y independently represents 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 of which optionally contains 1, 2 or 3 additional heteroatoms selected from O, N and S(O)z, where 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', -CO2R', -C(O)NR'2, SR', -SOR', -SO2R', -SO2NR'2, -NO2, -NR'2, -NR'C(O)R', -NR'C(O)NR'2, -NR'C(O)OR', -NR'SO2R', -NR'SO2NR'2, -OR', -OC(O)R' and -OC(O )NR' ₂ where each R' is independently H, C1-C ₈ alkyl, C1-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 said C1- _C8 alkyl, _C2 - _C8 alkenyl, _C2 - _C8 alkynyl, _C3 - _C8 cycloalkyl, 312-membered heterocyclyl, C6-C12aryl, and 5-12-membered heteroaryl are optionally substituted as defined here further.

In typical embodiments, the possible 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, C1- _C8 alkyl, -OH, C1- _C8 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 , -SO2R ^x , -SO2NR ^x R ^y , -NO2, -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 SO2R ^y , -NR ^x SO2NR ^x R ^y , -OC(O)R ^x , -OC(O)NR ^x R ^y , C3-C8 cycloalkyl, 312-membered heterocyclyl, C6-C12 aryl, 5- 12-membered heteroaryl, -O-(C3-C8 cycloalkyl), -O-(3-12 membered heterocyclyl), -O-(C6-C12 aryl) and -O-(5-12 membered heteroaryl); where each R ^x and R ^y is independently H or C 1 -C 4 alkyl, 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 rings, each of which optionally contains 1, 2 or 3 additional heteroatoms selected from O, N and S(O)q, where q is 0-2; and where each specified C1-C8 alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl, 3-12 membered heterocyclyl, C6-C12 aryl, 5-12 membered heteroaryl, -O-(C3-C8 cycloalkyl), -O-(3-12 membered heterocyclyl), -O-(C6-C12aryl) and -O-(5-12-membered heteroaryl), which is described as optionally substituent or is part of R ^x or R ^y , is optionally substituted with 1-3 substituents independently selected from the group, consisting of halogen, -OH, \u003d O, C1-C4 alkyl, C1-C ₄ alkoxy, C1-C ₆ haloalkyl, C1-C ₆ hydroxyalkyl, C ₁ -C ₄ alkoxy-C ₁ -C ₆ alkyl, -CN, - NH2, groups -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:

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pyrrole furan (pyrrolyl) (furanyl)

C thiophene (thiophenyl) pyrazole imidazole (pyrazolyl) (imidazolyl)

isoxazole oxazole (isoxazolyl) (oxazolyl) isothiazol (isothiazolyl) thiazole 1,2,3-triazole (thiazolyl) (1,2,3-triazolyl)

1,3,4-triazole (1,3,4-triazolyl)

1-oxa-2,3-diazol 1-oxa-2,4-diazol 1-oxa-2,5-diazol (1-oxa-2,3-diazolyl) (1-oxa-2,4-diazolyl) ( 1-oxa-2,5-diazolyl)

1-oxa-3,4-diazol 1-thia-2,3-diazol (1-oxa-3,4-diazolyl) (1-thia-2,3-diazolyl)

1-thia-2,4-diazol 1-thia-2,5-diazol (1-thia-2,4-diazolyl) (1-thia-2,5-diazolyl)

1-thia-3,4-diazole tetrazol (1-thia-3,4-diazolyl) (tetrazolyl) pyridine pyridazine pyrimidine (pyridinyl) (pyridazinyl) (pyrimidinyl)

pyrazine (pyrazinyl)

Illustrative examples of fused heteroaryl groups include the following, without limitation:

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(indazolyl pyrrolo 13,2-c I pyridine (pyrrolo [2,3-b] pyridinyl) (pyrrolo 12,3-c-pyridinyl) (pyrrolo [3,2-c] pyridinyl) (isoquinolinyl) (azakhinazoline ) ) (quinolinyl) (cinnolinyl) quinoxaline (quinoxalinyl) pyrazino [2,3-b] pyrazine pyrido 12,3-a d] pyrimidine (pyrido[3,4-d]pyrimidinyl) pyrido[3,4-b]pyrazine (pyrido[3,4-b]pyrazinyl) enzofuran (benzofuranyl)

1,5-naphthyridine (1,5-naphthyridinyl) I

1,6-naphthyridine (1,6-naphthyridinyl)

2,6-Naphthyridine (2,6-naphthyridinyl) pyrimido [4,5-d] pyrimidine pyrido [2,3 N-pyrimidine (pyrido [2,3-d] and p and midid and nyl) oenzotriazole (benzotriazolyl )

1,8-naphthyridine (1,8-naphthyridinyl) benzothiophene (benzothiophenyl)

1,7-naphthyridine (1,6-naphthyridinyl))

2,7-naphthyridine (2,7-naphthyridinyl) pyrido [3.2-d 1pyrimidine (pyrido [3,2-d] pyrimidinyl) pyrido [4,3 ^pyrimidine (pyrido [4,3-dj pyrimidinyl) 4-d]pyrimidine imidazo[1,2-a]pyridine imidazo[1,5-aI pyridine pyrazolo 4,3-c pyridine pyrazolo 13,4-c 1pyridine pyrazolo[3,4-b]pyridine pyrrolo 2,3- b pyridine pyrrolo [2,3-c] pyridine imidazo [4,5-b] pyridine pyrazolo [4,3-d] pyridine pyrrolo 3,2-b pyridine imidazo [4,5-c] pyridine (pyrrolo[3, 2-b]pyridinyl)(imidazo[4,5-b]pyridinyl)(imidazo[4,5-c]pyridinyl)(pyrazolo[4,3-P]pyridinyl)pyrazolo [1,5-a I pyridine pyrrolo[ I

- 12 042105

An arylalkyl group refers to an aryl group, as described herein, that is linked to the parent molecule via an alkylene or similar linker. Arylalkyl groups are described by the total number of carbon atoms in the ring and linker. Thus, the benzyl group is a C7 arylalkyl group and the phenylethyl is a C ₈ arylalkyl group. Typically, arylalkyl groups contain 7-16 carbon atoms (C ₇ -C ₁₆ arylalkyl), where the aryl portion contains 6-12 carbon atoms and the alkylene portion contains 1-4 carbon atoms. Such groups may also be 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 an arylalkyl group 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 here according to the total number of non-hydrogen atoms (ie, C, N, S and O atoms) in the ring and linker taken together, 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), where the heteroaryl portion typically contains 5-12 atoms and the alkylene portion typically contains 1-4 carbon atoms. Such groups may also be -C1-C4 alkylene-5-12 membered heteroaryl.

Similarly, arylalkoxy and heteroarylalkoxy refers to aryl and heteroaryl groups attached to the parent molecule via a heteroalkylene linker (i.e. -O-alkylene), where the groups are described according to the total number of non-hydrogen atoms (i.e. C, N, S and O) in ring and linker taken together. 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 possibly substituted, substituents may be on either the divalent linker moiety or on the aryl or heteroaryl moiety of the group. Substituents optionally present on the alkylene or heteroalkylene moiety are the same as described above for alkyl or alkoxy groups in general, while substituents optionally present on the aryl or heteroaryl moiety are the same as described above for aryl or heteroaryl groups in general. .

Hydroxy belongs to the OH group.

Acyloxy refers to a monovalent -OC(O)alkyl group wherein the alkyl moiety has the number of carbon atoms indicated (usually Ci-C ₈ , preferably C1-C6 or C1-C4) and which is optionally substituted with groups suitable for alkyl. Thus, C1-C ₄ acyloxy includes a substituent -OC(O)C1-C ₄ alkyl, for example -OC(O)CH ₃ .

Acyl refers to a monovalent -C(O)alkyl group wherein the alkyl moiety has the number of carbon atoms indicated (usually C1-C8, preferably C1-C6 or C1-C4) and which may optionally be substituted with groups suitable for alkyl, e.g. F , OH, or alkoxy. Thus, optionally substituted -C(O)C1-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. . 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)CF2H (difluoroacetyl) and the like.

Acylamino refers to a monovalent group, -NHC(O)alkyl or -NRC(O)alkyl, where the alkyl moiety has the number of carbon atoms indicated (usually C1-C8, preferably C1-C6 or C1-C4) and is optionally substituted with groups suitable for alkyl. Thus, C1-C ₄ acylamino includes a substituent -NHC(O)C ₁ -C ₄ alkyl, for example -NHC(O)CH ₃ .

Aryloxy or heteroaryloxy refers to an optionally substituted O-aryl or O-heteroaryl, where in each case aryl and heteroaryl are as defined hereinafter.

Arylamino or heteroarylamino refers to a possibly substituted group -NH-aryl, -NR-aryl, -NH-heteroaryl or -NR-heteroaryl, where in each case aryl and heteroaryl are as defined hereinafter and R is a substituent suitable for an amine, for example an alkyl, acyl, carbamoyl or sulfonyl group or the like.

Cyano belongs to the -C=N group.

The unsubstituted amino belongs to the -NH ₂ group. When amino is described as substituted or possibly substituted, this term includes groups of the form -NR ^x R ^y where each R ^x and R ^y is 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 herein. For example, alkylamino refers to the group -NR ^x R ^y where one of R ^x and R ^y is an alkyl moiety and the other is H, and dialkylamino refers to -NR ^x R ^y where both of R ^x and R ^y are alkyl groups, where the alkyl group has the specified number of carbon atoms (for example, -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 where 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

- 13 042105 be optionally substituted as described here for heterocyclyl or heteroaryl rings, and which may contain from 1 to 3 additional heteroatoms selected from N, O and S(O)x, where x is 02, as ring members, when provided that such 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).

Possible or possible means that the event or circumstance described below 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 the particular group being described may have no non-hydrogen substituents (i.e., unsubstituted), or the 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 a possible 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 included is reduced by two.

Often, possibly substituted groups are substituted with 1 or more substituents independently selected from a list of possible substituents. In some embodiments, optionally substituted groups are substituted with 1, 2, 3, or more than 3 substituents independently selected from a list of possible substituents. For example, an alkyl group described as optionally substituted with Rx means an alkyl group 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 a possibly substituted group may be changed herein to indicate that this group is optionally substituted with 1 or more of the indicated substituents. When possible substituents are selected from a list of alternatives, the selected groups are independently selected and may be the same or different.

Throughout the description it will be understood that the number and nature of possible substituent groups will be limited to the extent that such substitutions have a chemical meaning.

In one aspect of the invention, there is provided a compound of formula (IX), or a pharmaceutically acceptable salt thereof, wherein

R ¹ represents H, F, Cl, CN, C ₁ -C ₂ alkyl or C ₁ -C ₂ fluoroalkyl;

R ² is H, C1-C5 alkyl, C1-C5 fluoroalkyl, C3-C8 cycloalkyl, or a 3-6 membered heterocyclyl having one heteroatom selected from O and N, wherein said C1-C5 alkyl and C1-C5 fluoroalkyl are each optionally substituted with R ²⁰ . and each said C3- _C8 cycloalkyl and 3-6 membered heterocyclyl is optionally substituted with R ²¹ ;

R ⁴ is H, C1-C ₄ alkyl or C1-C ₄ fluoroalkyl, where each C1-C ₄ alkyl and C1-C ₄ fluoroalkyl are optionally substituted with R ²⁰ ;

R ⁶ is H, F, Cl, CN or CH ₃ ;

R ⁷ and R ⁸ are independently H, F, Cl, CN or C1-C ₂ alkyl;

R ⁹ is H, OH, NH2, NHCH3 or N(CH ₃ ) ₂ ;

R ¹¹ is H, C1-C ₄ alkyl, SO2R ¹⁴ , COR ¹⁷ , COOR ¹⁷ or CONR18R ¹⁹ ;

R ¹⁴ is C1- _C4 alkyl or C1- _C4 fluoroalkyl;

R ¹⁷ is C1-C ₄ alkyl or C1-C ₄ fluoroalkyl, where each C1-C ₄ alkyl and C1-C ₄ fluoroalkyl are optionally substituted with R ²⁰ ;

each R ¹⁸ and R ¹⁹ independently represents H or C 1 -C ₄ alkyl;

each R ²⁰ is independently OH, C1-C ₂ alkoxy or NR22R ²³ ;

each R ²¹ is independently F, OH, CN, NR22R ²³ or C1- _C4 alkyl;

each R ²² and R ²³ independently represents H or C1-C ₂ alkyl; 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.

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

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or a pharmaceutically acceptable salt thereof.

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

In some embodiments, the invention provides a compound of formula (IX), (IX-A), (IX-B), (IXC) 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 C1-C5 alkyl; or R ² is iso-C3H7; R ⁴ is C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted with R ²⁰ , where R ²⁰ is OH; or R ⁴ is CH(OH)CH3 or C(OH)(CH3)2; R ⁶ is F; R ⁷ is H; R ⁸ is H; R ⁹ is OH; R ¹¹ is SO2R ¹⁴ ; R ¹⁴ is C1-C4 alkyl; n is 0 and R ¹⁰ is absent.

In a preferred embodiment of the invention, there is provided a compound of formula (IX), (IX-A), (IXB), (IX-C) or (IX-D) or a pharmaceutically acceptable salt thereof, wherein: R ¹ is Cl; R ² is C1-C5 alkyl; or R ² is iso-C3H7; R ⁴ is C1-C4 alkyl, optionally substituted with R ²⁰ , where R ²⁰ is OH; or R ⁴ is CH(OH)CH3 or C(OH)(CH3)2; R ⁶ is F; R ⁷ is H; R ⁸ is H; R ⁹ is OH; R ¹¹ is SO2R ¹⁴ ; R ¹⁴ is C1-C4 alkyl; n is 0 and R ¹⁰ is absent.

In some 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 C1-C5 alkyl, C1-C5 fluoroalkyl or 3-6 membered heterocyclyl; or R ² is CH3, 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 , CH2CHF2 or oxetan-3-yl; R ⁴ is H or C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted with OH, NH2, NHCH3 or N(CH3)2; or R ⁴ is H, CH3, C ₂ H ₅ , CH ₂ OH, CH(OH)CH ₃ , CH ₂ CH ₂ OH or CH2NH2; 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 SO2R ¹⁴ ; and R ¹⁴ is C1- _C4 alkyl.

In particular embodiments, the invention provides a compound of formulas (IX), (IX-A), (IX-B), (IXC) 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 C1-C5 alkyl; R ⁴ is H or C1-C4 alkyl, where said C1-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 SO2R ¹⁴ ; R ¹⁴ is C1-C4 alkyl; and R ²⁰ is OH.

In another aspect of the invention, there is provided a compound of formula (X)

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or a pharmaceutically acceptable salt thereof, wherein

R ¹ represents H, F, Cl, CN, C1-C ₂ alkyl or C1-C ₂ fluoroalkyl;

R ² is H, C1-C5 alkyl, C1-C5 fluoroalkyl, C3-C8 cycloalkyl, or a 3-6 membered heterocyclyl having one heteroatom selected from O and N, wherein said C1-C5 alkyl and C1-C5 fluoroalkyl are each optionally substituted with R ²⁰ . and each said C3- _C8 cycloalkyl and 3-6 membered heterocyclyl is optionally substituted with R ²¹ ;

R ⁴ is H, C1-C ₄ alkyl or C1-C ₄ fluoroalkyl, where each C1-C ₄ alkyl and C1-C ₄ fluoroalkyl are optionally substituted with R ²⁰ ;

R ⁶ is H, F, Cl, CN or CH ₃ ;

R ⁷ and R ⁸ are independently H, F or Cl;

R ⁹ is H, OH, NH2, NHCH3 or N(CH ₃ )2;

each R ²⁰ is independently OH, C1-C ₂ alkoxy, or NR22R ²³ ;

each R ²¹ is independently F, OH, CN, NR ²² R ²³ or C ₁ -C ₄ alkyl;

each R ²² and R ²³ is independently H or C1-C2 alkyl; 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.

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

(X-C) (X-D) or a pharmaceutically acceptable salt thereof.

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

In some embodiments, the invention provides a compound of formula (X), (X-A), (X-B), (X-C), 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: R ¹ is Cl; R ² is C1-C5 alkyl; or R ² is ISO-C3H ₇ ; R ⁴ is C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted with R ²⁰ , where R ²⁰ is OH; or R ⁴ is CH(OH)CH3 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 of the invention, there is provided a compound of formula (X), (X-A), (X-B), (X-C) 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 C1-C4 alkyl, optionally substituted with R ²⁰ , where R ²⁰ is OH; or R ⁴ is CH(OH)CH3 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 some embodiments, the invention provides a compound of formulas (X), (X-A), (X-B), (X-C), 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: R ¹ is F or Cl; R ² is C1-C5 alkyl, C1-C5 fluoroalkyl or 3-6 membered heterocyclyl; or R ² is CH3, 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 , CH2CHF2 or oxetan-3-yl; R ⁴ is H or C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted with OH, NH2, -NHCH3 or N(CH3)2; or R ⁴ is H, CH3, 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 of the invention, there is provided a compound selected from the group consisting of:

(37?,47?)-4-({ 5-chloro-4-[4-fluoro-2-methyl-1 -(propan-2-yl)- 1H-benzimidazol-6yl]pyrimid in-2-yl } amino)-1-(methanesu lfonyl)piper idin-3-ol;

(37?,47?)-4-({ 4- [4-fluoro-2-methyl-1 -(propan-2-yl)-1 H-benzimidazol-6yl] pyrimidine in-2-yl } amino)- 1-(methanesu lfonyl)piper idin-3-ol;

4-(1-t/?et-butyl-4-fluoro-1H-benzimidazol-6-yl)-5-fluoro-M-(1-methylpiperidin4-yl)pyrimidin-2-amine;

(3R,4R)-4-({ 5-fluoro-4-[4-fluoro-2-methyl-1 -(propan-2-yl)- 1H-benzimidazol-6yl] pyrimide in-2-yl } amino) -1 -(methanesu lfonyl) piper idin-3 -ol;

(3R,4R)-4-({ 5 -ethyl-4-[4-fluoro-2-methyl-1 -(propan-2-yl)-1 H-benzimid azol-6yl] pyrimide in-2-yl } amino)-1-(methanesu lfonyl)piper idin-3-ol;

(37?,47?)-4-({5-chloro-4-[1-(propan-2-yl)- 1H-benzotriazol-6-yl]pyrimidin-2yl }amino)-1-(methanesulfonyl)piperide in-3-ol;

(37?,47?)-4-({ 4- [4-Fluoro-2-methyl-1 -(propan-2-yl)-1 H-benzimidazol-6-yl] -5 methylpyrimidin-2-yl } amino)-1-(methanesulfonyl)piper idin-3-ol;

(37?,47?)-4-({ 4- [4-fluoro-2-methyl-1 -(propan-2-yl)-1 H-benzimidazol-6-yl] -5 methoxypyrimid in-2-yl } amino)-1-(methanesulfonyl)piperide in-3-ol;

(37?,47?)-4-({ 4- [4-fluoro-2-methyl-1 -(propan-2-yl)-1 H-benzimidazol-6-yl] -5 - 17 042105 (propan- 2-yl)pyrimide in-2-yl}amino)-1-(methanesulfonyl)piper idin-3-ol;

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

(3D,4D)-4-({5-chloro-4-[4-fluoro-2-(hydroxymethyl)-1-(propan-2-yl)-1Hbenzimidazol-6-yl]pyrimidin-2-yl}amino )-1-(methanesulfonyl)piper idin-3-ol;

(3L,4A)-4-({4-[1-(azetidin-3-yl)-4-fluoro-2-methyl-1H-benzimidazol-6-yl]-5fluoropyrimide in-2-yl } amino)- 1-(methanesu lfonyl)piper idin-3-ol;

(3R,4R)-4-{[4-(1 -t/?eot-butyl-1H-benzimidazol-6-yl)-5-fluoropyrimidin-2yl]amino } -1 -(methanesulfonyl)piperide in-3 - ola;

(3R,4R)-4-({ 5 -fluoro-4- [2-methyl-1 -(propan-2-yl)-1 H-benzimidazol-6yl] pyrimid in-2-yl } amino)-1 - (methanesu lfonyl) piper idin-3-ol;

(3R,4R)-4-({ 5 -fluoro-4- [4-fluoro-2-methyl-1 -(propan-2-yl)-1 H-benzimid azol-6yl] pyrimide in-2-yl } amino)piper idin-3-ol;

1-[(37?,47?)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6yl] pyrimide in-2 -yl } amino)-3-hydroxypiperidin-1 -yl]ethanone;

(3R,4R)-4-{[4-(1 -ot/?eot-butyl-4-fluoro-1 H-benzimid azol-6-yl)-5-fluoropyrimidin2-yl]amino } -1 -( methanesulfonyl)piper idin-3-ol;

(3X,4X)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6yl] pyrimide in-2-yl } amino) -1-methylpiper idin-3-ol;

(35.45)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6yl] pyrimide in-2-yl } amino) -1-(methanesu lfonyl)piper idin-3-ol;

1,5-anhydro-3-[(5-chloro-4-{4-fluoro-2-[(1R)-1-hydroxyethyl]-1-(propan-2-yl)-1Hbenzimidazol-6-yl} pyrimidine -2-yl)amino]-2,3-d ideoxy-B-ot/?eo-pentitol;

1,5 -anhydro-3 - [(5 -chloro-4- {4-fluoro-2- [(1$)-1-hydroxyethyl] -1 - (propan-2-yl) -1Hbenzimidazol-6-yl } pyrimidin-2-yl)amino]-2,3-d ideoxy-O-l/rt-pentitol;

(2Х)-1-[(37?,47?)-4-{[4-(1-ot/?et-butyl-4-fluoro-1H-benzimidazol-6-yl)-5chloropyrimidin-2-yl] amino}-3-hydroxypiperidin-1-yl]-2-hydroxypropan-1-one;

(37?,47?)-4-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1Hbenzimidazol-6-yl ]pyrimidin-2-yl } amino)-1-(methanesulfonyl)piperidin-3-ol;

(37?,47?)-4-[(5-chloro-4-{4-fluoro-2-[(17?)-1-hydroxyethyl]-1-(propan-2-yl)-1-Abenzimidazol-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-O-t/?eo-pentitol, or a pharmaceutically acceptable salt thereof.

In another aspect of the invention, there is provided a compound selected from the group consisting of the compounds shown in the examples provided herein, including A1-A94, B1-B2, C1-C ₂ , D1-D6, E1, F1F33, G1 and H1-H11, inclusive, or a pharmaceutically acceptable salt thereof.

In another aspect of the invention, (3R,4R)-4-[(5-chloro-4-{4-fluoro-2-[(1R)-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.

In another aspect of the invention, there is provided (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.

In another aspect of the invention, a pharmaceutically acceptable salt of (3R,4R)-4-[(5-chloro4-{4-fluoro-2-[(1R)-1-hydroxyethyl]-1-(propan-2-yl)-1 H-benzimidazol-6-yl}pyrimidin-2-yl)amino]-1(methanesulfonyl)piperidin-3-ol.

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

- 18 042105

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

A 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 pharmaceutical composition contains two or more pharmaceutically acceptable carriers and/or excipients. In other embodiments, the pharmaceutical composition further comprises at least one additional anticancer therapeutic agent.

In one aspect of the invention, there is provided 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 pharmaceutical composition contains two or more pharmaceutically acceptable carriers and/or excipients.

The pharmaceutical composition may further comprise at least one additional anticancer therapeutic agent. Such a combination may provide an additive, more potent than additive or synergistic antitumor effect.

The term additive 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 taken separately.

The term synergy or synergy 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 taken separately. Such an improvement in the disease, condition or disorder being treated is a synergistic effect. A synergistic amount is the amount of a combination of two compounds, components, or target agents that results in a synergistic effect, where synergistic is defined in this specification.

Determination of a synergistic interaction between one or two components, the optimal range for such an effect, and the absolute dose ranges of each component for such an effect can be finally determined by administering the components in different dose ranges and/or dose ratios to patients in need of treatment. However, by observing synergism in in vitro models or in vivo models one can predict the effect in humans and other species, and there are in vitro models or in vivo models as described here to determine the synergistic effect. The results of such studies can also be used to predict ranges of effective dose-to-plasma ratios and absolute doses and plasma concentrations required in humans and other species, for example, through the use of 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 solvates, hydrates, and complexes of their salts, 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. As used herein, the term pharmaceutically acceptable salt refers to those salts that retain the biological efficacy and properties of the parent compound. Used here, the expression pharmaceutically acceptable(s) salt(s), unless otherwise indicated, includes salts of acidic or basic groups that may be present in the compounds with the formulas disclosed here.

For example, the compounds of the invention, which are basic in nature, are capable of forming a wide range 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 compound by treatment with an alkaline reagent and then convert the latter free base into a pharmaceutically acceptable acid addition salt. Acid addition salts of the base compounds of the present invention can 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 the appropriate mineral or organic acid to the solution.

Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e. salts containing pharmacologically acceptable anions such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, hydrogen phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, male - 19 042105 at, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate.

Examples of salts include acetate, acrylate, benzenesulfonate, benzoate (such as chlorobenzoate, methyl benzoate, dinitrobenzoate, hydroxybenzoate, and methoxybenzoate), bicarbonate, bisulfate, bisulfite, bitartrate, borate, bromide, butyne-1,4-dioate, calcium edetate, camsylate, carbonate , chloride, caproate, caprylate, clavulanate, citrate, decanoate, dihydrochloride, dihydrogen phosphate, edetate, edisylate, 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, mucat, napsilate, naphthalene-1 -sulfonate, naphthalene-2-sulfonate, nitrate, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phenylacetates, phenylbutyrate, phenylpropionate, phthalate, phosphate/diphosphate, polygalacturonate, propanesulfonate, propionate, propiolate, pi rophosphate, pyrosulfate, salicylate, stearate, subacetate, suberate, succinate, sulfate, sulfonate, sulfite, tannate, tartrate, theoclate, tosylate, and valerate, without limitation.

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 capable of forming 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 by conventional methods. The chemical bases that are used as reagents to prepare the pharmaceutically acceptable base salts of the present invention are those that form non-toxic base salts with the acidic compounds described herein. 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 obtained by treating the corresponding acidic compounds with an aqueous solution containing the required pharmacologically acceptable cations and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they can also be obtained by mixing together solutions of acidic compounds in lower aliphatic alcohols and the desired alkali metal alkoxide, and then evaporating the resulting solution to dryness in the same manner as before. In any case, stoichiometric amounts of reactants are preferably used 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 pharmacologically acceptable cations such as alkali metal (e.g. potassium and sodium) and alkaline earth metal (e.g. calcium and magnesium) cations, ammonium salts, or water-soluble amine addition salts, such as N-methylglucamine (meglumine), and lower alkanolammonium, and other basic salts of pharmaceutically acceptable organic amines.

Hemisalts of acids and bases, such as hemisulphate and hemicalcium salts, can also be formed.

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 for interconverting the salt form and the free base form are known to those skilled in the art.

The salts of the present invention may be prepared according to methods known to those 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 appropriate. The salt may precipitate out of solution and may be collected by filtration or may be isolated by evaporation of the solvent. The degree of ionization of a salt can vary from fully ionized to almost non-ionized.

Those skilled in the art will recognize that 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 converted back into the corresponding

- 20 042105 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 to 100°C. The free base form can be isolated by conventional methods such as extraction with an organic solvent. In addition, the acid addition salts of the compounds of the invention can be exchanged by taking advantage of the differential solubility of the salts, the volatility or acidity of the acids, or by treatment with an appropriately loaded ion exchange resin. For example, exchange can be affected by reacting a salt of the compounds of the invention with a slight stoichiometric excess of an acid with a lower pK than the acid 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 process. Similar exchanges are possible with base addition salts, usually with an intermediate formation of 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 weakly 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 here to describe a molecular complex containing a compound of the invention and one or more pharmaceutically acceptable solvent molecules, such as ethanol. The term hydrate is used when the solvent is water. Pharmaceutically acceptable solvates according to the invention include hydrates and solvates wherein the crystallization solvent may be isotopically substituted, eg D2O, d ₆ -acetone, d ₆ -DMSO (deuterated water, acetone, dimethyl sulfoxide).

Also disclosed herein are complexes such as clathrates, drug-host inclusion complexes, where, unlike the above 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 hereby incorporated by reference in its entirety.

It also discloses prodrugs of compounds with the formulas proposed here. Thus, certain derivatives of the compounds of the invention, which may themselves have little or no pharmacological activity, may be converted to the compounds of the invention when administered to a patient, 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 in Roche, American Pharmaceutical Association), the disclosures of which are incorporated herein by reference in their entirety.

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

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

(1) when the compound contains a functional group of carboxylic acid (-COOH), its ester, for example with the replacement of hydrogen by (C1-C ₈ )alkyl;

(2) when the compound contains an alcohol (OH) functional group, its ether, for example with hydrogen replaced by (C1-C ₆ )alkanoyloxymethyl or a phosphate ether group; and (3) when the compound contains a primary or secondary amine functional group (-NH2 or -NHR where R is not H), its amide, e.g. with one or both hydrogen atoms replaced by a suitable metabolically labile group, such as amide, carbamate, urea , phosphonate, sulfonate and so on.

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

Also disclosed herein are metabolites of the compounds of the formulas described herein, ie. compounds formed in vivo upon administration of a drug.

Compounds with the formulas given here may have asymmetric carbon atoms. The carbon-carbon bonds of the compounds of the present invention can be depicted here using

- 21 042105 using a solid line ( ), a solid wedge (-^) or a dotted wedge ( ). The use of a solid line to depict bonds to asymmetric carbons is an indication that all possible stereoisomers (eg, specific enantiomers, racemic mixtures, etc.) at that carbon are included. The use of either a solid wedge or a dotted wedge to depict bonds to asymmetric carbons is an indication that only the stereoisomer shown is considered to be included. Possibly, the compounds of the invention may contain more than one asymmetric carbon atom. In such compounds, the use of a solid line to depict bonds to asymmetric carbons is an indication that all possible stereoisomers are considered to be included on the attached 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 an indication 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 formulas herein 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 where 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 crystals are possible. The first type is the racemic compound (true racemate) above, where a single homogeneous crystal form is formed containing both enantiomers in equimolar amounts. The second type is a racemic mixture or conglomerate, where two forms of crystals 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, 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 tautomers in solution. In solid form, one tautomer usually predominates. Even though a single tautomer may be described, the present invention includes all tautomers of the compounds of the presented formulas.

In addition, some 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 blocked or greatly retarded by steric interactions with other parts of the molecule, and the substituents at either end of the single bond are not symmetrical. 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 free rotation of one or more bonds forming a chiral axis.

When a 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 conventional methods well known to those skilled in the art, such as chromatography and fractional crystallization.

Conventional methods for the preparation/isolation of the 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 pressure 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, with an acid or base, such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixture can be separated by chromatography and/or fractional crystallization, and one or both diastereoisomers can be converted to the corresponding pure enantiomer(s) by methods well known to the person 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

- 22 042105 up to 50% isopropanol, typically 2 to 20%, and 0 to 5% alkylamine, typically 0.1% diethylamine. Concentration of the eluate gives an enriched mixture.

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

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

The present invention also includes isotopically labeled compounds which are identical to those described by one of the formulas given, except that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature.

Isotopically labeled compounds of the invention can generally be prepared by conventional methods known to those skilled in the art, or by methods analogous to those described here, using an appropriate isotopically labeled reagent instead of the unlabeled reagent used otherwise.

Examples of isotopes that can be included in the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³² R, ³⁵ S, ¹⁸ F and ³⁶ Cl, without limitation. Certain isotopically labeled compounds of the invention, for example those incorporating radioactive isotopes such as ³ H and ¹⁴ C, are useful in drug and/or substrate tissue distribution assays. Tritium isotopes, i.e. ³ H, and carbon-14, i.e. ¹⁴ C are particularly preferred because of their ease of preparation and detection. In addition, substitution by heavier isotopes such as deuterium, i.e. ² H may provide certain therapeutic benefits due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances. The isotopically labeled compounds of the invention can generally be prepared by carrying out the processes disclosed in the Schemes and/or the Examples and Preparations below by replacing the isotopically labeled reagent with 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 solid compressed masses, powders or films by methods such as precipitation, crystallization, freeze drying, spray drying or evaporation drying. Microwave or RF drying can be used.

Therapeutic methods and applications.

The invention also provides therapeutic methods and uses comprising administering the compounds of the invention, or pharmaceutically acceptable salts thereof, alone or in combination with other therapeutic or palliative agents.

In one aspect of the invention, there is provided a method for treating cancer in a subject in need thereof, comprising administering to that 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 anticancer therapeutic agents, in particular standard care agents suitable for a particular cancer.

In some embodiments, the proposed methods lead to one or more than one 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 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 numerous 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-fold, or more than 100-fold greater than the affinity binding to CDK4.

Given the potential role of CDK6 in hematologic 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 interruptions), and/or increased overall efficacy. due to the possibility of higher dosages, use of a continuous dosing regimen and/or increased total treatment time compared to currently used dual CDK4/6 inhibitors.

- 23 042105

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 Cyclophophamide-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 herein, or their pharmaceutically acceptable salts.

In some embodiments, the cancer is selected from the group consisting of breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer (including NSCLC (non-small cell lung cancer), SCLC (small cell lung cancer), squamous cell carcinoma, or adenocarcinoma ), esophageal cancer, head and neck cancer, rectal cancer, kidney cancer (including RCC (renal cell carcinoma)), liver cancer (including HCC (hepatocellular carcinoma)), pancreatic cancer, gastric cancer (i.e. gastrointestinal intestinal tract) and thyroid cancer. In further 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 (estrogen receptor) positive/HR positive, HER2 negative breast cancer; HR-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-pertuzumab-resistant breast cancer, or breast cancer showing primary or acquired resistance to CDK4/CDK6 inhibition. In some embodiments, the breast cancer is an advanced stage 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 a hormone 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 a hormonal therapeutic agent such as an aromatase inhibitor, SERM (Selective Estrogen Receptor Modulator) or SERD (Selective Estrogen Receptor Suppressor). 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 programs, for example, including taxanes or platinum-based agents. In some embodiments, a compound of the invention is administered as a second (or later) line therapy following treatment with HER2-targeting agents, such as trastuzumab.

As used herein, the term effective dose or effective amount of a drug, compound, or pharmaceutical composition is an amount sufficient to produce a beneficial or desired effect on any one or more symptoms of a disease, including biochemical, histological and/or behavioral symptoms, its complications, and intermediate pathological phenotypes that occur during the development of the disease. For therapeutic use, a therapeutically effective amount refers to that amount of a compound administered that alleviates to some extent one or more symptoms of the disorder being treated. With regard to the treatment of cancer, a therapeutically effective amount refers to that amount which has the effect of (1) reducing the size of the tumor, (2) inhibiting (i.e. slowing to some extent, preferably stopping) tumor metastasis, (3) inhibiting to some extent (i.e. slow to some extent, preferably stop) tumor growth or tumor invasiveness, (4) relieve to some extent (or preferably eliminate) one or more of the signs or symptoms associated with cancer, (5) reduce doses of other drugs needed to treat the disease, and/or (6) enhance the effect of another drug, and/or (7) delay the development of the disease in the patient.

An effective dose may be administered in one or more administrations. For the purposes of this invention, an effective dose of a drug, compound, or pharmaceutical composition is an amount sufficient to effect prophylactic or therapeutic treatment, either directly or indirectly. In a clinical context, it is understood that an effective dose of a drug, compound, or pharmaceutical composition may or may not be achieved in combination with another drug, compound, or pharmaceutical composition.

- 24 042105

Tumor, in relation to a subject diagnosed with or suspected of having cancer, refers to a malignant or potentially malignant neoplasm or tissue formation of any size and includes primary tumors and secondary neoplasms. A solid tumor is an abnormal growth or formation of tissue that usually does not contain cysts or fluid areas. Examples of solid tumors are sarcomas, carcinomas and lymphomas. Leukemia (cancer of the blood) usually does not form solid tumors (National Cancer Institute, Cancer Glossary).

Tumor burden or tumor mass refers to the total amount of tumor substance distributed throughout the body. Tumor burden refers to the total number of cancer cells or the total size of tumor(s) throughout the body, including lymph nodes and bone marrow. Tumor burden can be determined by various methods known in the art, such as, for example, the use of calipers, or, if inside the body, the use of imaging techniques, such as ultrasound, bone scan, computed tomography (CT), or magnetic resonance imaging (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. Tumor size can be determined by various methods known in the art, such as, for example, measuring the size of the tumor(s) after removal from the subject, such as using calipers, or, if in the body, using imaging techniques, such as bone scan, ultrasound, CR (computed x-ray), or MRI.

As used herein, the term subject refers to a human or animal. In some preferred embodiments, the subject is a human.

As used herein, the term treat or treat 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, reduction in the number of cancer cells, reduction in tumor size, reduction in the rate of infiltration of cancer cells into peripheral organs, or the reduction in the rate of tumor metastasis or tumor growth, reversal, amelioration, inhibition of progression, or prevention of the disorder or condition to which the term is applied, or one or more of the symptoms of such disorder or condition. As used herein, the term treatment, unless otherwise indicated, refers to the act of treating where treatment is defined immediately above. The term treatment also includes adjuvant and neoadjuvant treatment of a subject.

For the purposes of this invention, useful or desirable clinical results include 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 cure; overcoming one or more cancer resistance mechanisms; and/or increasing the survival of cancer patients, without limitation. Positive therapeutic effects in cancer can be determined 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, with respect to tumor growth inhibition (T/C), according to the National Cancer Institute (NCI) standards, a T/C criterion of less than or equal to 42% is the minimum level of antitumor activity. A T/C of less than 10% is considered a high level of antitumor activity, where T/C (%) is the mean tumor volume in the treatment group/mean tumor volume in controls100.

In some embodiments, treatment with a compound of the invention is determined based on 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 during which the tumor does not grow, and includes the length of time that patients experienced CR or PR, as well as the length of time that patients experienced disease stabilization (SD). DFS refers to the length of time during and after treatment during which the patient is free from disease. OS refers to increased life expectancy compared to naive 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 cancer patient may vary depending on such factors as disease state, age and weight of the patient, and the ability of the therapy to elicit an antitumor response in the subject. Although an embodiment of any of the aspects of the invention may not be effective in achieving a beneficial therapeutic effect in every subject, it should work on a statistically significant number of subjects as determined by any statistical test known in the art, such as Student's t-test. , goodness-of-fit test, Mann-Whitney U-test, Kruskal-Wallis test (H-test), Jonkheer-Terpstra test, and Wilcoxon test.

The terms 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.

Improvement means the reduction or alleviation of one or more of the symptoms when treated with the combination described herein, as compared to no administration of the combination. Improvement also includes a reduction or reduction in the duration of the symptom.

As used herein, the term 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 (non-cancerous) or malignant.

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 resistant to endocrine therapy, CDK4/6 inhibition, or HER2 antagonists.

The term additional antitumor therapeutic agent as used herein means any one or more therapeutic agents other than a compound of the invention that is or may be used in the treatment of cancer. In some embodiments, such additional antitumor therapeutic agents 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, SERD, 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-bound particles, cisplatin, carboplatin, oxaliplatin, capecitabine, gemcitabine, or vinorelbine.

In some embodiments, the additional anticancer agent is an anti-angiogenic agent, including, for example, VEGF (vascular endothelial growth factor) inhibitors, VEGFR (vascular endothelial growth factor receptor), TIE-2 (tyrosine kinase with immunoglobulin-like loops and epidermal homologous domains) inhibitors. growth factor-2), PDGFR inhibitors (platelet growth factor receptor), angiopoietin inhibitors, PKCe inhibitors (β-isoform of protein kinase C), COX-2 inhibitors (cyclooxygenase-II), integrins (alpha-v / beta-3), MMP- 2 (matrix metalloproteinase 2) and MMP-9 inhibitors (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 (Macugen™), 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-868,596 (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 (Preige™), valdecoxib (Bextra™), rofecoxib (Vioxx™), iguratimod (Careram™), IP 751 ( Invedus), SC58125 (Pharmacia), and etoricoxib (Arcoxia™). Additional antiangiogenic agents include exisulind (Aptosyn™), salsalat (Amigesic™), diflunisal (Dolobid™), ibuprofen (Motrin™), ketoprofen (Orudis™), nabumetone (Relafen™), piroxicam (Feldene™), naproxen (Aleve™). , Naprosyn™), diclofenac (Voltaren™), indomethacin (Indocin™), sulindac (Clinoril™), tolmetin (Tolectin™), etodolac (Lodine™), ketorolac (Toradol™), and oxaprozin (Daypro™). Additional anti-angiogenic agents include ABT 510 (Abbott), apratastat (TMI 005), AZD 8955 (AstraZeneca), incyclinide (Metastat™) and PCK 3145 (Procyon). Additional antiangiogenic agents include acitretin (Neotigason™), plitidepsin (aplidine™), cilengitide (EMD 121974), combretastatin A4 (CA4P), fenretinide (4HPR), halofuginone

- 26 042105 (Tempostatin™), Panzem™ (2-methoxyestradiol), PF-03446962 (Pfizer), rebimastat (BMS 275291), catumaxomab (Removab™), lenalidomide (Revlimid™), squalamine (EVIZON™), thalidomide (Thalomid ™),

Ukrain™ (NSC 631570), Vitaxin™ (MEDI 522) and Zoledronic Acid (Zometa™).

In other embodiments, the additional anticancer agent is a signal transduction inhibitor (eg, an inhibitory agent by which regulatory molecules that control fundamental processes of cell growth, differentiation, and survival are signaled 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 (epidermal growth factor) inhibitor, ErbB-1 (EGFR), ErbB-2, pan-erb, IGF1R (insulin-like growth factor receptor 1) inhibitors, MEK ( mitogen-activated protein kinase), c-Kit inhibitors, FLT-3 inhibitors (FMS-like tyrosine kinase 3), K-Ras inhibitors, PI3 kinase inhibitors (phosphoinositide 3-kinase), JAK inhibitors (Janus kinase), STAT inhibitors (signal transducer and activator transcription), Raf kinase inhibitors, Akt inhibitors, mTOR inhibitor (mammalian target of rapamycin), P70S6 kinase inhibitors, WNT pathway inhibitors, and multidirectional kinase inhibitors.

Additional examples of anticancer agents that can be used in conjunction with a compound of the invention and the pharmaceutical compositions described herein include palbociclib (Ibrance®), ribociclib (Kisqali®), abemaciclib (Versenio®), 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 Cervene™ (TP 38). Other examples include gefitinib (Iressa®), cetuximab (Erbitux®), erlotinib (Tarceva®), trastuzumab (Herceptin®), ado-trastuzumab emtansine (Kadcyla®), pertuzumab (Perjeta®), osimertinib (Tagrisso®), atezolizumab ( Tecentrig™), sunitinib (Sutent®), ibrutinib (Imbruvica®), imatinib (Gleevec®), crizotinib (Xalkor®), lorlatinib (Lorbrena®), dacomitinib (Vizimpro®), bosutinib (Bosulif®), glasdegib (Daurismo™) ), canertinib (CI 1033), lapatinib (Tycerb™), pelitinib (EKB 569), miltefosine (Miltefosin™), BMS 599626 (Bristol-Myers Squibb), lapuleucel-T (Neuvenge™), NeuVax™ (cancer vaccine based on E75), Osidem™ (IDM 1), Mubritinib (TAK-165), CP-724,714 (Pfizer), Panitumumab (Vectibix™), ARRY 142886 (Array Biopharm), Everolimus (Certican™), Zotarolimus (Endeavour™), Temsirolimus (Torisel™), 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 (One Bio), BMS 387032 (Bristol-Myers Squibb) and AG 024322 (Pfizer), and AG 024322 (Pfizer), or antagonists of PD-1 (programmed cell death protein 1) or PD-L1 (programmed cell death receptor ligand 1), such as pembrolizumab (Keytruda® ), nivolumab (Opdivo™) or avelumab (Bavencio®), abraxane.

In other embodiments, the additional antitumor agent is a so-called classical antineoplastic agent. Classic antineoplastic agents include hormonal modulators such as hormonal, antihormonal, androgen agonists, androgen antagonists and antiestrogen therapeutic agents, histone deacetylase (HDAC) inhibitors, DNA methyltransferase inhibitors, silencers 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 therapy agents, antisense oligonucleotides, vascular targeting agents (VTAs), and statins, without limitation. Examples of classic antineoplastic agents used in combination therapy with a compound of the invention, possibly with one or more other agents, include 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 suppressants estrogen receptor activity (SERD; such as fulvestrant), exemestane (Aromasin), anastrozole (Arimidex), atamestane, fadrozole, letrozole (Femara), formestane; gonadotropin-releasing hormone (GnRH; also commonly called luteinizing hormone-releasing hormone [LHRH]) agonists such as buserelin (Suprefact), goserelin (Zoladex), leuprorelin (Lupron) and triptorelin (Trelstar), abarelix (Plenaxis), cyproterone, flutamide (Eulexin), megestrol, nilutamide (Nilandron) and osateron, dutasteride, epristeride, finasteride, Serenoa repens, PHL 00801, abarelix, goserelin, leuprorelin, triptorelin, bicalutamide; antiandrogenic agents such as enzalutamide (Xtandi®), abiraterone acetate, bicalutamide (Casodex); and combinations thereof, without limitation. Other examples of classical antineoplastic agents used in combination with a compound of the invention include PARP inhibitors such as talazoparib, olaparib, rucaparib, niraparib, iniparib, veliparib; suberoylanilide hydroxamic acid (SAHA, Merck Inc./Aton Pharmaceuticals), depsipeptide (FR901228 or FK228), G2M-777, MS-275, pivaloyloxymethyl butyrate, and PXD-101; onconase (ranpirnase), PS-341 (MLN-341), velcade (bortezomib), 9-aminocamptothecin, belothecan, BN-80915 (Roche), camptothecin, diflomothecan, edotecarin, exatecan (Daiichi), gimatecan, 10-hydroxycamptothecin, irinotecan HCl ( camptosar), lurtothecan, oratecin (Rubitecan, Supergen), SN-38, topotecan, camptothecin, 10-hydroxycamptothecin, 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, KW2170, lomustine, mafosfamide, mechlorethamine, melphalan, mitobronitol, mi tolactol, mitomycin C, mitoxatron, nimustine, ranimustine, temozolomide, thiotepa, and alkylating-type platinum coordination compounds such as cisplatin, carboplatin, eptaplatin, lobaplatin, nedaplatin, oxaliplatin, streptozocin, satrplatin, and combinations thereof, without limitation.

In other embodiments, the additional antitumor agent is so-called dihydrofolate reductase inhibitors (such as methotrexate and NeuTrexin (trimetrexate glucuronate)), purine antagonists (such as 6-mercaptopurine-riboside, mercaptopurine, 6-thioguanine, cladribine, clofarabine (clolar), fludarabine, nelarabine and raltitrexed), pyrimidine antagonists (such as 5-fluorouracil (5-FU), alimta (pemetrexed disodium, LY231514, MTA), capecitabine (Xeloda™), cytosine arabinoside, Gemzar™ (gemcitabine, Eli Lilly), tegafur ( UFT (tegafur/uracil) orzel or uforal and including TS-1 combination of tegafur, hymestat and otostat), doxyfluridine, carmofur, cytarabine (including oxphosphate, phosphate stearate, sustained release and liposomal formulations), enocytabine, 5-azacytidine (Vidaza ), decitabine, and ethinylcytidine) and other antimetabolites such as eflornithine, hydroxyurea, leucovorin, nolatrexed (Thymitag), triapine, trimetrexate, N-(5-[N(3,4-dihydro-2-methyl-4-oxoquinazoline-6 -ylmethyl )-N-methylamino]-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 classic antineoplastic cytotoxic agents include 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 (navelbin), docetaxel (taxotere), ortataxel, paclitaxel (including taxoprexin, DHA (docosahexaenoic acid)/paclitaxel conjugate), cisplatin, carboplatin, nedaplatin, oxaliplatin (eloxatin), satraplatin, camptosar, capecitabine (Xeloda ), oxaliplatin (Eloxatin), taxotere, alitretinoin, canfosfamide (Telcyta™), DMXAA (Antisoma), ibandronic acid, L-asparaginase, pegaspargase (Oncaspar™), efaproxiral (Efaproxyn™ - radiotherapy)), bexarotene (Targretin™), Tesmilifen (DPPE - improves the effectiveness of cytotoxic agents)), Theratope™ (Biomira), Tretinoin (Vesanoid™), Tirapazamine (Trizaone™), Gadolinium Motexafine (Xcytrin™) Cotara™ (mAb), and NBI-3001 (Protox Therapeutics) , polyglutamate-paclitaxel (Xyotax™) and combinations thereof, without limitation. Additional examples of classical antineoplastic agents include advexin (ING 201), TNFerade (GeneVec, a compound that expresses TNF-alpha (tumor necrosis factor alpha) in response to radiotherapy), RB94 (Baylor College of Medicine), genasens (Olimersen, Genta), combrestatin A4P (CA4P), Oxi-4503, AVE-8062, ZD-6126, TZT-1027, atorvastatin (Lipitor, Pfizer Inc.), pravastatin (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 their combinations, without restrictions on them.

In some embodiments, the additional antitumor agent is an epigenetic modulator, e.g., an inhibitor of either 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 additional embodiments, the additional anticancer agent is an immunomodulatory agent such as an inhibitor of CTLA-4 (cytotoxic T lymphocyte glycoprotein 4), PD-1 or PD-L1 (e.g. pembrolizumab, nivolumab or avelumab), LAG-3 (lymphocyte activation gene 3) , TIM-3 (tissue inhibitor of metalloproteinase-3), TIGIT (T-cell immuno- 28 042105 receptor with Ig domains and ITIM), 4-1BB, OX40, GITR (glucocorticoid-induced TNFR related protein), CD40, or CAR-T- cell therapy (T-cell therapy with a chimeric antigen receptor).

As used herein, the term 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 spreads 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 a different type of cancer 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, liver cancer. , pancreatic cancer and stomach cancer.

Dosage forms and dosing regimens.

The administration of the compounds of the invention can be influenced by any method that delivers the compounds to the site of action. These methods include oral routes of administration, intraduodenal routes of administration, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical and rectal administration.

Dosing regimens may 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 as required by the therapeutic situation. It is particularly useful to formulate parenteral compositions in unit dosage form for ease of administration and dosage uniformity. Unit dosage form, as used herein, refers to physically discrete units useful as unit doses for the treatment of mammalian subjects; wherein each unit contains a predetermined amount of the active compound, calculated to produce the desired therapeutic effect, in combination with the desired pharmaceutical carrier. The requirements for unit dosage forms of the invention are due to and directly dependent on (a) the unique characteristics of the chemotherapeutic agent and the particular therapeutic or prophylactic effect to be achieved, and (b) the limitations inherent in the field of compounding such an active compound for the treatment of sensitivity in humans.

Thus, those skilled in the art will appreciate from the disclosure provided herein that doses and dosing regimens are adjusted in accordance with methods well known in the therapeutic field. Those. the maximum tolerated dose can be easily set and the effective amount that provides a detectable therapeutic effect for the patient can also be determined, as well as the time requirements for administration of each agent to achieve a detectable therapeutic effect in the patient. Thus, although some dosing and administration regimens are given here as examples, these examples in no way limit the dosage and administration regimen that can be offered 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. In addition, it should be understood that for any particular subject, particular dosing regimens will need to be adjusted over time according to individual need and at the discretion of the person administering or supervising the administration of the compositions, and that the dosage ranges given herein are by way of example only. and are not intended to limit the scope or practice of the claimed composition. For example, doses may be adjusted based on pharmacokinetic and pharmacodynamic parameters, which may include clinical effects such as toxic effects and/or laboratory values. Thus, the present invention encompasses individual dose escalation for a patient as determined by the skilled artisan. Determination of suitable doses and regimens of administration of a chemotherapeutic agent is well known in the relevant field of technology and will be clear to a person skilled in the art after reading the guidance disclosed here.

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 dose is in the range of 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 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, dose 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 any harmful side effects, provided that such large doses are first divided. into several small doses for administration during the day.

Compositions and routes of administration.

As used herein, the term 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 type of 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 together with various disintegrants such as starch, alginic acid and certain complex silicates, and with binding agents such as sucrose, gelatin and gum arabic. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols, without limitation. In addition, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting. Solid compositions of a similar type may also be used in soft and hard gelatin capsules. Therefore, non-limiting examples of substances include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are required for oral administration, the active compound therein may be combined with various sweetening or flavoring agents, coloring or coloring agents and, if desired, emulsifiers or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin 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 ointment or cream or for rectal administration as a suppository.

Examples of forms for parenteral administration include solutions or suspensions of the active compounds in sterile aqueous solutions, for example in aqueous solutions of propylene glycol or dextrose. If desired, such dosage forms may be suitably buffered.

The pharmaceutical composition may be presented in unit dosage forms suitable for single administration of precise doses.

Pharmaceutical compositions suitable for delivering the compounds of the invention and methods for their preparation will be apparent to those skilled in the art. Such compositions and methods for preparing them can be found, for example, in Remington's Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995), the disclosure of which is incorporated herein by reference in its entirety.

The compounds of the invention may be administered orally. Oral administration may include swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be used, in which the compound enters the bloodstream directly from the mouth.

Formulations suitable for oral administration include solid preparations such as tablets, capsules containing particles, liquids or powders, lozenges (including liquid-filled), chewable tablets, multi- and nanoparticles, gels, solid solution, liposome, films (including mucoadhesive ), ovules, sprays and liquid preparations.

Liquid preparations 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 and/or suspending agents. Liquid preparations can also be by reconstitution of a solid, for example from sachets.

The compounds of the invention may also be used in rapidly dissolving, rapidly disintegrating dosage forms such as those described in Expert Opinion in Theotherapy Patents, 11(6), 981-986, Liang and Chen (2001), the disclosure of which is incorporated herein by reference in in its entirety.

For tablet dosage forms, depending on the dose, the drug may comprise from 1% to 80% by weight of the dosage form, more typically from 5% to 60% by weight 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 hydroxypropylcellulose, starch, pregelatinized starch, and sodium alginate. Typically, the disintegrant makes up from 1 to 25 wt.%, preferably from 5 to 20 wt.% of the dosage form.

Binders are typically used to impart cohesive properties to a tablet dosage form. 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 lubricants such as silica and talc. When present, surfactants are typically present in amounts of 0.2 to 5% by weight of the tablet, and glidants are typically in amounts of 0.2 to 1% by weight 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. Lubricants are usually present in amounts of 0.25 to 10% by weight, preferably 0.5 to 3% by weight of the tablet.

Other common 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.% lubricant.

Tablet blends can be compressed by direct compression or by rollers to form tablets. Tablet blends or portions of blends may alternatively be subjected to wet granulation, dry granulation or melt granulation, melt freezing or extrusion prior to tabletting. The final formulation may include one or more layers and may or may not be coated; or be encapsulated.

Tablet formulations are 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 incorporated herein by reference in its entirety.

Solid preparations for oral administration may be formulated for 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 techniques 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 into this specification by reference in their entirety.

The compounds of the invention may also be administered directly to the bloodstream, to a muscle, or to an internal organ. Suitable methods 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 uses they may be more conveniently formulated as a sterile non-aqueous solution or in dry form for use in combination with a suitable vehicle such as sterile, pyrogen-free water.

Preparation of parenteral preparations under sterile conditions, for example by lyophilization, can be easily carried out using standard pharmaceutical methods well known to those skilled in the art.

The solubility of the compounds of the invention used in the preparation of solutions for parenteral administration can be increased by the use of appropriate preparation techniques such as the inclusion of solubility enhancing agents.

Formulations for parenteral administration may be formulated as 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 implantable depot providing a modified release of the active compound. Examples of such formulations include drug-eluting stents and PLGA (lactic-glycolic acid) microspheres.

The compounds of the invention may also be administered topically to the skin or mucous membranes, i. dermal or transdermal. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, films, transdermal patches, cachets, implants, sponges, fibers, bandages, and microemulsions. Liposomes can also be used. 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 topical methods include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis, and microneedle or needleless (eg, Powderject™, Bioject™, etc.) injection. The disclosure of these sources is incorporated into this description of the invention by reference in their entirety.

Formulations for topical administration may be prepared for 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 (either alone, as a mixture, for example dry-mixed with lactose, or as a mixed particle, for example mixed with phospholipids such as phosphatidylcholine) from dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, nebulizer (preferably an electrohydrodynamic fine mist nebulizer) 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 contain a bioadhesive agent such as chitosan or cyclodextrin.

The pressurized container, pump, spray, nebulizer or nebulizer contains a solution or suspension of the compound(s) of the invention containing, for example, ethanol, an aqueous solution of ethanol or an alternative agent suitable for dispersion, solubilization or sustained release of the active substance, propellant(s) as a solvent and optionally a surfactant such as sorbitan trioleate, oleic acid or oligolactic acid.

Prior to use in a dry powder or suspension formulation, the drug 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 helical 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 modifier characteristics such as 1-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 a fine mist electrohydrodynamic nebulizer may contain 1 µg to 20 mg of a compound of the invention per push, and the push volume can range from 1 to 100 µl. A typical formulation contains 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 inhalation/nasal formulations of the invention.

Formulations for inhalation/nasal administration can be prepared with immediate and/or modified release using, for example, poly(DL-lactic-glycolic acid copolymer) (PGLA). Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release.

In the case of dry powder inhalers and aerosols, the dosage unit is determined by a valve that delivers a metered amount. Doses according to the invention are usually set to administer a metered amount or an injection containing the required amount of a compound of the invention. The total daily dose may be administered as a single dose or, more commonly, as 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 suppository base, but various alternative substances can be used if appropriate.

Formulations for rectal/vaginal administration may be formulated as immediate and/or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release.

The compounds of the invention may also be administered directly to the eye or ear, usually in the form of drops of a micronized suspension or solution in pH-adjusted isotonic sterile saline. Other formulations suitable for ophthalmic and otic administration include ointments, biodegradable (eg, absorbable gel sponges, collagen) and non-biodegradable (eg, silicone) implants, cachets, lenses, and particulate or vesicular systems such as niosomes or liposomes. A polymer such as a cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulose polymer such as hydroxypropyl methylcellulose, hydroxyethylcellulose or methylcellulose, or a heteropolysaccharide polymer such as gellan gum may be included along with a preservative such as benzalkonium chloride. Such drugs can also be delivered by iontophoresis.

Formulations for ophthalmic/ear administration may be formulated as immediate and/or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release.

Other techniques.

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

For example, drug-cyclodextrin complexes have been found to be generally useful 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 widely used for these purposes are alpha, beta and gamma cyclodextrins, examples of which can be found in the publication of international PCT applications WO 91/11172, WO 94/02518 and WO 98/55148, the disclosures of which are incorporated into this description of the invention by reference in in their entirety.

The amount of active compound administered will depend upon 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 dose 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 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 about 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 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 about 75 mg/day to about 150 mg/day.

In some cases, dose 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, such large doses being usually divided into several small doses for administration to during the day.

A set of components.

Since it may be desirable to administer a combination of active compounds, for example for the treatment of 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 of the invention, may conveniently be combined. in the form of a kit suitable for co-administration of the compositions. Thus, the 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 vial, or a divided foil pouch. An example of such a kit is the conventional blister pack used for the packaging of tablets, capsules and the like.

The kit according to the invention is particularly suitable for administering different dosage forms, for example oral and parenteral, for administering separate compositions at different dosing intervals, or for titration of separate compositions against each other. To help adherence to the treatment regimen, the kit usually includes instructions for use and may be provided with a reminder.

Combined therapy.

As used herein, the term combination therapy refers to the administration of a compound of the invention together with at least one additional pharmaceutical or drug agent (eg, antineoplastic 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 can be enhanced by combination with other approved or experimental cancer treatments, such as radiation, surgery, chemotherapeutic agents, targeted therapies, agents that inhibit other signaling pathways that are deregulated in tumors, and others. immune enhancing agents such as PD-1 or PD-L1 antagonists and the like.

When combination therapy is used, one or more additional anticancer agents may be administered sequentially or simultaneously with the compound of the invention. In one embodiment, an additional antitumor agent is administered to a mammal (eg, a human) prior to administration of a compound of the invention. In another embodiment, an additional anticancer agent is administered to a mammal after administration of a compound of the invention. In another embodiment, an additional antitumor agent is administered to a mammal (eg, a human) simultaneously 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 pharmaceutically acceptable salts thereof), in combination with one or more (preferably one to three) additional anticancer therapeutic agents.

Synthesis methods.

Compounds of the invention are prepared in accordance with the methods of the examples and with the schemes presented here, and their modifications known to specialists in this field of technology. Scheme 1 shows a general method for the preparation of pyrimidine compounds 6 having 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 changed.

General scheme 1.

As shown in Scheme 1, substituted dichloropyrimidines 1 are Suzuki coupled under appropriate 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(1,2-dimethoxyethane):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 a bromine-containing compound with bis(pinacolato)diboron, a suitable catalyst (such as Pd(OAc) ₂ or Pd(dppf)Cl ₂ ), a ligand (such as PCy ₃ ), and a base (such as like KOAc or NaOAc) in a suitable solvent (such as DMSO (dimethyl sulfoxide) or dioxane). The resulting heterobiaryl intermediates 4 are treated under conditions of nucleophilic chloride substitution with primary

- 34 042105 heterocyclylamine or cycloalkylamine 5 in the presence of a suitable base (such as DIPEA (diisopropylethylamine)) in a suitable solvent (eg DMSO) to give amino-substituted pyrimidine compounds 6. When intermediate 4 is reacted with primary heterocyclylamine, Q in compounds 5 and 6 is is an appropriately substituted amino group (eg NR ¹¹ ), an appropriately protected amino group (eg carbamoyl, tetrahydropyranyl or trialkylsilyl-protected amine) or oxygen. When intermediate 4 is reacted with a primary cycloalkylamine, Q in compounds 5 and 6 is a possibly substituted carbon.

Alternatively, 4 x heterobiaryl intermediates can be subjected to a Buchwald-Hartwig coupling of appropriate 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 (2,2'-bis(diphenylphosphano)-1,1'-binaphthyl)) and a suitable base (eg CS2CO3) in a suitable solvent (such as THF (tetrahydrofuran), dioxane or 2-methyl-2-butanol) to give compounds 6.

It should be understood that reactive functional groups present at any position in intermediates 1-5 and penultimate compounds 6 may be protected using suitable protecting groups known to those skilled in the art. For example, such compounds may contain amine or hydroxyl groups protected by protective groups (such as tert-butylcarbamate or tetrahydropyran) which can be removed under conditions known in the art (such as TFA (trifluoroacetic acid) 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 (eg, sulfonyl halide, acyl halide, alkyl halide, or the like) to introduce an R ¹¹ substituent.

Similar interactions can be used to obtain the corresponding pyridine derivatives, as shown here in the examples.

General methods of synthesis.

Abbreviations.

The following abbreviations are used in the examples: Ac means acetyl, AcO or OAc means acetoxy, ACN means acetonitrile, aq. means water, 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 1,8diazabicyclo[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 means 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 Pr means isopropyl, IPA means isopropyl alcohol, LAH means lithium aluminum hydride, LHMDS means lithium hexamethyldisilazide (bis(trimethylsilyl) lithium amide), mCPBA is meta-chloroperoxybenzoic acid, Me is methyl, MeOH is methanol, MS is mass spectrometry, MTBE is methyl t-butyl ether, NCS is N-chlorosuccinimide, Ph is phenyl, TBHP is t-butyl hydroperoxide, TFA means trifluoroacetic acid, THF means tetrahydrofuran, SFC means supercritical fluid chromatography, TLC means thin layer chromatography, Rf means retention fraction, ~ means approximately, rt means retention time, h means hours, min means minutes, equiv. means equivalents, sat. means saturated.

- 35 042105

Scheme I

As shown in Scheme I, a compound such as compound 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 plus PCy3) with a suitable base (such as KOAc) in an appropriate solvent (such as 1,4-dioxane or DMSO) to give a compound such as compound II. A compound, such as compound II, may be formed and reacted in-situ. Alternatively, a compound such as compound II may be isolated prior to subsequent reactions to give the corresponding boronic acid or BPin (bis(pinacolato)diboron) ester. A compound such as compound II can be arylated with an aryl chloride such as compound 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 K2CO3 or Na2CO3) in an appropriate solvent (such as DMSO or 1,4-dioxane) to give a compound such as compound IV. A compound such as compound IV may be coupled with an amine such as compound V to give a compound such as compound VI under standard nucleophilic aromatic substitution (SNAr) conditions In the presence of a suitable base (such as DIPEA) in an appropriate solvent ( such as DMSO). Alternatively, a compound such as compound IV may be coupled with an amine such as compound V to give a compound such as compound VI under standard Buchwald-Hartwig coupling conditions in the presence of a suitable catalyst system (such as Pd(OAc)2 plus rac-BINAP or chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium complex) with a suitable base (such as CS2CO3) in an appropriate solvent (such as THF or 1,4-dioxane). In some instances, a compound, such as compound VI, may contain protecting groups that can be removed by 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 at each stage can be purified by standard methods such as column chromatography, crystallization or reverse phase SFC or HPLC (high performance liquid chromatography). If necessary, the separation of the enantiomers of the compound VI can be carried out by standard methods known in the art, such as chiral SFC or HPLC, to obtain individual enantiomers. Variable radicals Q, U, V, X, Z, R ¹ , R ⁷ and R ⁹ are as defined here in the embodiments, schemes, examples and claims.

- 36 042105

Scheme II.

As shown in Scheme II, a compound such as Compound VII (prepared as shown in Scheme I) can be coupled with an aryl chloride such as Compound 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 K2CO3) in an appropriate solvent (such as 1,4-dioxane) to give a compound such as compound IX. A compound such as compound IX may be oxidized with a suitable oxidizing agent (such as oxone) to give a compound such as compound X. A compound such as compound X may be coupled with an amine such as compound XI under standard conditions S _N Ar in the presence of a suitable base (such as Na ₂ CO ₃ ) in an appropriate solvent (such as THF) to give a compound such as compound XII. Compounds at each stage can be purified by standard methods such as column chromatography, crystallization, or reverse phase SFC or HPLC. Variable radicals R ¹ and R ⁴ are as defined here in the embodiments, schemes, examples and claims.

- 37 042105

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 an appropriate solvent (such as 1,4-dioxane). A compound such as compound XIV may be generated and used in-situ or isolated to give the corresponding boronate ester. A compound such as compound XIV can be coupled with an aryl chloride such as compound III under standard Suzuki cross-coupling conditions with a suitable catalyst (such as PdCh(PPh ₃ ) ₂ ) and a suitable base (such as Na ₂ CO ₃ ) in an appropriate solvent (such as 1,4-dioxane) to give a compound such as Compound XV. A compound such as compound XV can be converted to a compound such as compound XVI in the presence of an excess of /-PrNfb in an appropriate solvent (such as DMSO). A compound such as compound XVI may be cyclized with an aldehyde such as compound XVII in the presence of a suitable reducing agent (such as Na ₂ S ₂ O ₄ ) in an appropriate solvent (such as EtOH) to give a compound such as compound XVIII. A compound such as compound XVIII can be coupled with an amine such as compound XIX under standard Buchwald-Hartwig coupling conditions in the presence of a suitable catalyst system (such as Pd(OAc) ₂ plus rac-BINAP) and a suitable base (such as CS2CO3) in an appropriate solvent system (such as 1,4-dioxane or THF) to give a compound such as Compound XX. Compounds at each stage can be purified by standard methods such as column chromatography, crystallization, or reverse phase SFC or HPLC. Variable radicals Q, R ¹ , R ⁴ , R ⁶ and R ⁷ are as defined here in the embodiments, schemes, examples and claims.

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Scheme IV.

χχιν

As shown in Scheme IV, a compound such as compound XXI (prepared as shown in Scheme I) can be coupled with an aryl chloride such as compound XXII under standard Suzuki cross-coupling conditions with a suitable catalyst (such as PdCh(PPh ₃ ) ₂ ) and a suitable base (such as Na ₂ CO ₃ ) in an appropriate solvent (such as 1,4-dioxane) to give a compound such as compound XXIII. A compound such as compound XXIII can be coupled with an amine such as compound XIX under standard Buchwald-Hartwig coupling conditions with a suitable palladium catalyst system (such as Brettphos-Pd-G3 or Pd ₂ (dba) ₃ plus rac-BINAP ) with a suitable base (such as tert-BuONa, CS2CO3 or phosphazene P ₂ -Et) in an appropriate solvent (such as 1,4-dioxane or PhMe (toluene)) to give a compound such as compound XXIV. In some cases, a compound, such as compound XXIV, may contain protecting groups that can be removed by 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 at each stage can be purified by standard methods such as column chromatography, crystallization, or reverse phase SFC or HPLC. Variable radicals Q, Z, R ² , R ⁴ and R ⁶ are as defined here in the embodiments, schemes, examples and claims.

Scheme V

Suzuki combination

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As shown in Scheme V, an amine such as compound XI may be coupled with an aryl fluoride such as compound XXV to give a compound such as compound XXVI under standard S _N Ar conditions with a suitable base (such as DIPEA) in the appropriate solvent (such as DMSO). A compound such as compound XXVI may be coupled with a compound such as compound XXVII (prepared as shown 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 Na2CO3) in an appropriate solvent (such as 1,4-dioxane) to give a compound such as compound XXVIII. Compounds at each stage 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 compound XXIX (prepared as shown in Scheme I or Scheme IV) can be converted to a compound such as compound 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 an appropriate solvent (such as DCM) to give a compound such as compound XXX, where R ¹¹ is CO2R 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 an appropriate solvent (such as EtOAc) with obtaining a compound such as compound XXX, where R ¹¹ represents 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 an appropriate solvent (such as EtOAc) to give a compound such as compound XXX where R ¹¹ is SO2R ¹⁴ .

IV. Amide formation via acylation with an anhydride in the presence of a suitable base (such as TEA) in an appropriate solvent (such as DCM) or a carboxylic acid in the presence of a suitable coupling agent (such as HATU (1-[bis(dimethylamino)methylene]-1H-1,2 ,3triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate) or EDCI (1-ethyl-3-(3dimethylaminopropyl)carbodiimide)) and a suitable base (such as DIPEA) in an appropriate solvent (such as DCM or DMF) with obtaining a compound, such as compound XXX, where R ¹¹ represents COR ¹⁷ .

In some instances, a compound, such as compound XXX, may contain protecting groups that can be removed by 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 at each stage can be purified by standard methods such as column chromatography, crystallization, or reverse phase SFC or HPLC. If necessary, separation of the enantiomers of compound XXX can be carried out by standard methods known in the art, such as chiral SFC or HPLC, to obtain individual enantiomers.

Variable radicals U, V, W, X, Z, R ¹ , R ⁷ , R11, R ¹⁴ and R ¹⁷ are as defined here in the embodiments, schemes, examples and claims.

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Scheme VII.

As shown in Scheme VII, a compound such as compound XXXI (prepared as shown in Scheme I) can be oxidized with a suitable oxidizing agent (such as MnO ₂ , SO3^pyr (pyridine) or TEMPO ((2,2,6,6 -tetramethylpiperidin-1-yl)oxyl)/NaC0) in an appropriate solvent (such as CHCl3 or DCM) to give a compound such as compound XXXII. A compound such as compound XXXII may be coupled with an amine such as compound XI under standard SNAr conditions in the presence of a suitable base (such as DIPEA) in an appropriate solvent (such as DMSO) to give a compound such as compound XXXIII. Compounds at each stage can be purified by standard methods such as column chromatography, crystallization, or reverse phase SFC or HPLC.

Scheme VIII.

2. S _n 2

As shown in Scheme VIII, a compound such as compound XXXIV (prepared as shown in Scheme I) can be converted to a compound such as compound XXXV by oxidation with a suitable oxidizing agent (such as MnO ₂ ) in an appropriate solvent (such as MeOH ) followed by reductive amination in the presence of an amine with a suitable reducing agent (such as NaBH3CN) in an appropriate solvent (such as MeCN). Alternatively, a compound such as compound XXXIV may be activated by treatment with methanesulfonyl chloride in the presence of a suitable base (such as TEA) in an appropriate 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 an appropriate solvent (such as MeCN) can give a compound such as compound XXXV. Compounds at each stage can be purified by standard methods such as column chromatography, crystallization, or reverse phase SFC or HPLC. Variable radicals Q, R ²² and R ²³ are as defined here in the embodiments, schemes, examples and claims.

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Scheme IX.

As shown in Scheme IX, a ketone such as compound XXXII (prepared as shown in Scheme VII) can be treated with a Grignard reagent (such as MeMgBr) in an appropriate solvent (such as THF) to give a compound such as compound XXXVI. A compound such as compound XXXVI can be coupled with an amine such as compound XI under standard SNAr conditions in the presence of a suitable base (such as DIPEA) in an appropriate solvent (such as DMSO) to give a compound such as compound XXXVII. Compounds at each stage can be purified by standard methods such as column chromatography, crystallization, or reverse phase SFC or HPLC.

Preparation of intermediate compounds.

Obtaining (1S)-1-(6-bromo-1-tert-butyl-4-fluoro-1H-benzimidazol-2-yl)ethan-1-ol (Int-01) according to scheme 1.

Scheme 1.

Step 1: Synthesis of 6-bromo-H-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-methylpropan-2-amine (1.54 g; 21 .0 mmol) and CS2CO3 (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 H2O (20 ml) and extracted with EtOAc (3x20 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; yield 90%) as red oil. 1H NMR (400 MHz, DMSO-d6) δ 7.13-7.01 (m, 2H), 6.94 (dd, J=1.9, 11.1 Hz, 1H), 1.40 (s, 9H).

Step 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]oxy} 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. EtOAc (10 ml) and H ₂ O (5 ml) were added and the layers were separated. The aqueous layer was extracted with EtOAc (3x10 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-benzimidazol-2-yl) ethanol-1-ol (Int-01) (400 mg; 18% yield) as yellow oil, m/z (ESI (electrospray ionization)) for (C ₁₉ H ₃₀ BrFN ₂ OSi) 431.1 (M+H )+.

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Preparation of 6-bromo-2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)-4-fluoro-1-(propan-2-yl)-Hbenzimidazole (Int-02) according to 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 days, after which the mixture was concentrated. The crude residue was purified by flash chromatography (SiO ₂ , 0-30% EtOAc/heptanes) to give 5-bromo-3-fluoro-2-nitro-Ni(propan-2-yl)aniline (2b) (20.3 g ; 70% yield) as a red/orange solid. 1H 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-2yl)-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]oxy }-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 suspension was stirred at 90°C for 16 hours. Analysis by LCMS (liquid chromatography-mass spectrometry) showed the consumption of the original substance with the formation of the desired mass of the product. The reaction mixture was diluted with H2O (200 ml) and extracted with EtOAc (2x200 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 , EtOAc/petroleum ether, 1/10) to give 6-bromo-2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl) -4-fluoro-1-(propan-2-yl)-III-benzimidazole (Int-02) (1.2 g; 86% yield) as a white solid. 1H 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).

Obtaining 6-bromo-4-fluoro-2-methyl-1-(oxetan-3-yl)-1H-benzimidazole (Int-03) according to scheme 3.

Scheme 3.

Stage 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 (EtOAc/petroleum ether, 1/4) indicated consumption of starting material. The reaction mixture was diluted with brine (10 ml) and extracted with EtOAc (2x10 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. 1H 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 (3а) (500 mg; 1.72 mmol) in EtOH (16.0 ml) and H2O (4.0 ml) acetaldehyde (2.0 ml; 8.6 mmol) and Na ₂ S ₂ O ₄ (1.5 g; 8.6 mmol) were added. The reaction mixture was sealed and stirred at 80°C under microwave radiation for 10 hours. LCMS analysis showed 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

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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 (CnH ₁₀ BrFN ₂ O) 284.9 (M+H).

The intermediates in the table below were synthesized by 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-bromo2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)-4-fluoro-1-(propan-2-yl)-1 H-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 minor modifications or substitutions in exemplary methods which can be carried out by a person skilled in the art.

Connection number Structure / Name according to SHRAS Analytical data Int-04 F /Hn II 1 H ^Me Me 6-bromo-4-fluoro-1,2-dimethyl-1Hbenzimidazole m!z (ESI+) for (C ₉ H ₈ BrFN ₂ ) 242.6 (M+H) ⁺ Int-05 F OTBS J Tn Me ml Me ^{Me Me} 1I-benzimidazole m/z (ESI+) for (Ci9H ₃ oBrFN ₂ OSi) 430.9 (M+H) ⁺ Int-06 F NHBoc ίϊ'Η B< N ^Me .. /T Me _{Me Me} )ethyl] carbamate m/z (ESI+) for (C18H ₂ 5BrEN0 ₂ ), 415.9 (M+H) ⁺

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Int-07 F £T hoo „ Z^Me Me 6-bromo-4-fluoro-2-(oxetan-3 -yl)-1 - (propan-2-yl)-1H-benzimidazole Ή NMR (400 MHz, DMSO-Tb) δ 7.79 (d, 7=1.5 Hz, 1H), 7.30 (dd, 7=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, 7=7.0 Hz, 6H); m/z (ESI+) for (Ci3Hi4BrFN ₂ O) 324.2 (M+H) ⁺ Int-08 F NHBoc _in days> /-Me Me mpem-butyl- {1 - [b-bromo-4-fluoro-1 (propan-2-yl) - 17 / -benzimidazol-2yl] cyclopropyl } carbamate ^X NMR (400 MHz, CDCh) δ 9.16 (br s, 1H), 7.49 (d, 7=1.0 Hz, 1H), 7.09 (dd, 7=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 (C1 ₈ H ₂ sBrFN0 ₂ ) 357.9 (M/Vi+H) ⁺ Int-09 F NHBoc £ΪΗ N Me ../-Me Me mpem-butyl- {(15)-1 - [b-bromo-4-fluoro1 -(propan-2-yl)-1 N-benzimidazol-2yl]ethyl } carbamate Ή NMR (400 MHz, CDCh) δ 9.58 (s, 1H), 7.49 (d, 7=1.5 Hz, 1H), 7.12 (dd, 7=9.7, 1.5 Hz, 1H), 5.24- 5.03 (m, 1H), 4.86 (p, 7=6.9 Hz, 1H), 1.66-1.57 (m, 6H), 1.47 (s, 9H), 1.35 (d, 7=7.4 Hz, ZN) int-10 F otbs £ ΪΗ Br^^N _p $CH ₃ CH ₃ m/z (ESI+) for (Ci8H ₂₇ BrF ₂ N ₂ OSi) 433.1 (M+H) ⁺

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Int-11 F _{OTBS £} rI Br^D _F H ₃ c-Af H 3 C F yl)-4fluoro-1H-benzimidazole m/z (ESI+) for (CisH26BrF ₃ N2OSi) 451.2 (M+H) ⁺ int-12 F A.N.OTBS [ Г f—(-Me β,-V/V^N Me F 6-bromo-2-(2-{[tert-butyl(dimethyl)silyl]oxy } propan-2yl)-1-(2,2-difluoroethyl)-4-fluoro-1-Abenzimidazole m/z (ESI+) for (C18H26BrEs#081) 450.8 (M+H) ⁺ Int-13 F Al p t f - ^Me L-Me NHBoc n-butyl-[(25)-2-(6-bromo-4-fluoro-2methyl- 1H-benzimidazol-1 yl)propyl] carbamate Ή NMR (400 MHz, CDC1 ₃ ) δ 7.32 (d, 7=1.5 Hz, 1H), 7.04 (dd, 7=9.6, 1.5 Hz, 1H), 5.13 (s, 1H), 4.73 (s, 1H), 3.70 (dt, 7=11.5, 6.2 Hz, 1H), 3.47-3.38 (m, 1H), 2.56 (s, 3H), 1.61 (d, 7=7.0 Hz , 3H), 1.41 (s, 9H); mlz (ESI+) for (Ci6H ₂ iBrFN ₃ O ₂ ) 387.9 (M+H) ⁺ Int-14 FxX-N [| F-Me ^Me OMe 6-bromo-4-fluoro-1-(1-methoxypropan-2yl)-2-methyl-1H-benzimidazole Ή NMR (400 MHz, DMSO-Tb) δ 7.75 (d, 7=1.6 Hz, 1H), 7.23 (dd, 7=1.5, 10.1 Hz, 1H), 4.78 (ddd, 7=4, 6, 7.1, 8.9 Hz, 1H), 3.86 (dd, 7=9.2, 10.4 Hz, 1H), 3.62 (dd, 7=4.5, 10.5 Hz, 1H), 3.18 (s, 3H), 2.55 (s, 3H), 1.52 (d, 7=7.1 Hz, ZN); m/z (APCI+ (chemical

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4.

yl)propyl]carbamate oenzimidazol-2-yl)methanol n-butyl-1(2n)-2-(6-bromo-4-fluoro2-methyl-1/7-benzimidazol-1 (m 9H), 0.12- 0.10 (t 6H), m/z (ESI+) for (CisH24BrF3N2OSi),

M+N

6-bromo-2-ethyl-4-fluoro-1 - (oxetan-3 yl) - n-benzimidazole

6-bromo-2-({ \mpemotil (dimethyl)silyl! oxy} methyl)-1 (3,3-difluorocyclobutyl)-4-fluoro-\H oenzimidazole ionization at atmospheric pressure)) for (SpHmBrBrXrO)

301.0, 303.0 (M+H

7.97 (d, 7=1.6 Hz, 1H), 7.34 (dd.

/=10.2, 1.6 Hz, 1H), 5.77-5.53 (m,

1H), 5.12 (t, 7=7.7 Hz, 2H), 4.98 dd, 7=7.8, 5.3 Hz, 2H), 2.88 (q, /=7.5 Hz, 2H), 1.29 ( t, 7=7.4 Hz.

ZN); m/z (APC1+) for (ClgNpBgEXrO) 298.9 (M+H)

7.77-7.53(m, 1H), 7.21(brd.

7=10.0Hz, 1H), 7.09-6.92(m, 1H),

6.65 (dd, 7=2.0, 7.0 Hz, 1H), 4.714.60 (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 (SzeHnshgExsOz) 387.9 (M+H) d, 7=1.5 Hz, 1H), 7.13 (dd, 7=1.5,

9.6 Hz, 1H), 5.31-5.12 (m, 1H), 4.94 s, 2H), 2.98-2.81 (m, 2H), 2.652.49 (m, 2H), 2.06-1.87 (m, 2H).

0.92-0.90 (m, 9H), 0.10-0.07 (m,

6H); m/z (ES1+) for

CisH26BrFN2OSi) 414.8 (M+H d, 7=1.3 Hz, 1H), 7.19 (dd, 7=1.5,

9.5 Hz, 1H), 5.27 (dquin, 7=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

Preparation of [6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]methanol (Int-19) according to the scheme (6-bromo-1-cyclobutyl-4-fluoro-\ HΉ NMR (400 MHz, DMSO-de) δ

Ή NMR (400 MHz, DMSO-de) δ

Ή NMR (400 MHz, CDCh) δ7.63 ¹ NMR (400 MHz, CDCh) δ 7.51

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) was stirred at 80°C for 21 hours. The mixture was concentrated and partitioned between H2O (100 ml) and EtOAc (100 ml). The layers were separated and the aqueous layer was extracted with EtOAc (3x100 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/heptanes) 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. 1H NMR (400 MHz, DMSO-d ₆ ) δ 7.81 (d, J=1.5 Hz, 1H),

7.28 (dd, J=10.1, 1.6Hz, 1H), 5.71 (t, J=5.8Hz, 1H), 4.95 (hept, J=6.8Hz, 1H), 4.72 (d, J=5.7 Hz, 2H), 1.56 (d,

J=6.9 Hz, 6H); m/z (APCI+) for (CnH^rF^O) 286.8 (M+H) ⁺ .

Preparation of 6-bromo-4-fluoro-2- {[(oxan-2-yl)oxy]methyl}-1 -(propan-2-yl)-1 H-benzimidazole (Int-20) according to Scheme 5.

Scheme 5.

A 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-toluenesulfonic acid (p-TSA) monohydrate (35.4 mg; 0.205 mmol) in THF (21 ml) were stirred at reflux for within 4 hours. The mixture was concentrated and purified by flash chromatography (SiO ₂ , 20-50% EtOAc/heptanes) to give 6-bromo-4-fluoro-2-{[(oxan-2-yl)oxy]methyl}-1-(propane -2-yl)-1Hbenzimidazole (Int-20) (710 mg; 93% yield) as a viscous yellow oil. 1H 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 (C16H ₂ 0BrFN ₂ O ₂ ) 370.9 (M+H) ⁺ .

Obtaining 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) was added KOtPn (25% in toluene; 0.265 ml; 0.560 mmol). 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 the desired weight of product. H ₂ O (5 ml) was added and the mixture was extracted with DCM (3x10 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/heptanes) to give compound (Int-21) (85 mg; 60% yield). 1H 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.

F Fe°, NH ₄ CI ^r H ₂ O/MeOH, 60 °C

2b me me exit 94%

HC(OEt) ₃

EtOH, H ₂ O yield 99%

stage 1 stage 2

Stage 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 showed consumption of starting material. The reaction suspension was filtered and the filter cake was washed with EtOAc. The filtrate was concentrated. The residue was taken up in EtOAc (200 ml) and filtered. The filtrate was washed with H ₂ O (200 ml). The combined aqueous washes were extracted with EtOAc (2x200 ml). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated to give 5-bromo-3fluoro-N ¹ -(propan-2-yl)benzene-1,2-diamine (7a) (21.0 g; 94% yield ). 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 the original

- 48 042105 substances with the formation of the required mass of the product. The solution was cooled to room temperature and concentrated to give 6-bromo-4-fluoro-1-(propαn-2-yl)-1H-benzimidazole (Int-22) (4.02 g; over 99% yield) as a black oil which was used without further purification. 1H NMR (400 MHz,

DMSO-d6) 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=6.2c H, 6H); m/z (ESI+) for (C10H ₁₀ BrFN ₂ ) 258.7 (M+H)+.

Obtaining 6-bromo-1-tert-butyl-2-methyl-1H-benzimidazoleα (Int-23) according to scheme 8.

Scheme 8.

CH ₃ C(OEt) ₃

148 °C output 86%

Br

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 desired mass of the 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-t-butyl-2-methyl-1H-benzimidazole (Int-23) (1.23 g; yield 95%) 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.

i-PrNH ₂ , K ₂ CO ₃

THF

9a yield 70%

Fe°, _NH4CI

H ₂ O/MeOH, 60 °C yield 53%

stage 1 stage 2 stage 3

CH ₃ C(OEt) ₃

148 °C output 51%

Step 1: Synthesis of 5-bromo-4-fluoro-2-nitro-N-(nponan-2-yl)aniline (9b).

K ₂ CO 3 ( ₅₈₁ , 4.2 mmol) and i -PrNH ₂ (248 mg; 4.2 mmol). The mixture was stirred at ambient temperature for 16 hours. LCMS analysis showed the consumption of the starting material with the formation of the desired mass of the product. The reaction solution was diluted with H ₂ O (30 ml) and was extracted with EtOAc (3x20 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)anilineα (9b) (900 mg, 77% yield, as a yellow solid, m/z (ESI+) for (C ₉ H ₁₀ BrPN ₂ O ₂ ) 276.7 (M+H)+.

Step 2: Synthesis of 5-bromo-4-fluoro-N ¹ -(propan-2-yl)benzene-1,2-diamine (9c).

Saturated aqueous NH ₄ Cl (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 the consumption of the starting material with the formation of the desired mass of the product. The reaction suspension was filtered and the filter cake was washed with EtOH (50 ml). The combined filtrate was diluted with H2O (100 ml) and extracted with EtOAc (2x80 ml). The combined organic phases were dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography (40 g SiO2, EtOAc/petroleum ether, 1:2) to give 5-bromo-4-fluoro-N ¹ -(propan-2-yl)benzene-1,2-diamine (9c ) (900 mg; 53% yield) as brown gum, m/z (ESI+) for (C9H ₁₂ BrFN ₂ ) 246.7 (M+H) ⁺ .

Step 3: Synthesis of 6-bromo-5-fluoro-2-methyl-1-(p-propan-2-yl)-1H-benzimidazole (Int-24).

Mixture of 5-bromo-4-fluoro-M-(propan-2-yl)benzene-1,2-diamine (9c) (800 mg; 3.24 mmol) and triethylorthoacetate (5.3 g; 32.4 mmol) stirred at 148°C for 1 hour. LCMS analysis indicated consumption of the starting material to form the desired product. The solution was cooled to room temperature and concentrated. The residue was combined with a batch from a parallel reaction run on a 100 mg scale and purified by flash chromatography (20 g SiO ₂ , 100% EtOAc) to give 6bromo-5-fluoro-2-methyl-1-(propan-2-yl )-1H-benzimidazole (Int-24) (500 mg; 51% yield). 1H NMR (400 MHz,

- 49 042105

DMSO-d6) δ 7.99 (d, J=6.2Hz, 1H), 7.51 (d, J=9.5Hz, 1H), 4.74 (spt, J=6.9Hz, 1H), 2.55 (s , 3Н), 1.53 (d, J=7.0

Hz, 6H); m/z (ESI+) for (C _n H ₁₂ BrFN ₂ ) 270.9 (M+H)+.

The intermediates in the table below were synthesized by 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-2yl)-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 minor modifications or substitutions in exemplary methods which can be carried out by one skilled in the art.

Connection number Structure/Name according to GORAS Analytical data Int-25 ΒγΆνά 6-bromo-4-fluoro-1 - (oxolan-3 -yl) - 1I-benzimidazole Ή NMR (400 MHz, DMSO-Je) δ 8.34 (s, 1H), 7.85 (d, 7=1.6 Hz, 1H), 7.34 (dd, 7=10.3, 1.6 Hz, 1H), 5.30 (ddt, 7=8.4, 5.8, 3.1Hz, 1H), 4.13 (td, 7=8.4, 6.0Hz, 1H), 4.01 (dd, 7=10.0, 2.6 Hz, 1H), 3.93 (dd, 7=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 (CnHioBrFN ₂ 0) 258.7 (M+H) ⁺ Int-26 F XX > b 6-bromo-1-cyclopropyl-4-fluoro- 1I-benzimidazole Ή NMR (400 MHz, CDC1 ₃ ) δ 7.90 (s, 1H), 7.53 (d, 7=1.5 Hz, 1H), 7.15 (dd, 7=1.5, 9.8 Hz, 1H), 3.36 (td, 7=3.5, 7.0 Hz, 1H), 1.24-1.17 (m, 2H), 1.10-1.03 (m, 2H); m/z (ESI+) for (CioH ₈ BrFN ₂ ) 256.7 (M+H) ⁺ Int-27 F jgo Br __^NHBoc ^Me Me m/z (ESI+) for (Ci6H ₂ iBrFN ₃ O ₂ ) 387.6 (M+H) ⁺ Int-28 F JI 1 y - ^Me Me _Me t /? eot-butyl-[2- (6-bromo-4-fluoro- m/z (ESI+) for (Ci ₇ H ₂₃ BrFN ₃ O ₂ ) 400.0 (M+H) ⁺ 2-methyl-177-benzimid azol-1-yl)2-methylpropyl] carbamate

Preparation of tert-butyl {[6-bromo-4-fluoro-1 -(propan-2-yl)-1 H-benzimidazol-2yl]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-butyl-methyl (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 suspension was stirred at 80°C for 16 hours. LCMS analysis showed

- 50 042105 consumption of the initial substance with the formation of the required mass of the 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 tert-butyl-{[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazole -2yl]methyl}methylcarbamate (Int-29) (400 mg; 82% yield) as 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 by 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 minor modifications or substitutions in exemplary methods which can be carried out by one skilled in the art.

Connection number Structure/Name according to IUPAC Analytical data Int-30 F NHBoc Г X )>—(“Me BfWW Me Ch /^ ^Me Me mpem-butyl- { 2- [6-bromo-4-fluoro-1 - (propan-2-yl) -177-benzimidazol-2yl] propane -2-yl } carbamate m/z (ESI+) for (CisH25BrFN ₃ O2) 415.7 (M+H) ⁺ Int-31 F Xw-N OTBS Me ^{z 47} Ή NMR (400 MHz, CDCE) δ 7.50 (d, 7=1.6 Hz, 1H), 7.10 (dd, 7=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 (Ci8H26BrFN 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 suspension was stirred at 80°C for 16 hours. LCMS analysis showed the consumption of the starting material with the formation of the desired mass of the product. The mixture was diluted with water H2O (15 ml) and 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/heptanes) 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 (Int32).

A mixture of ethyl 6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazole-2-carboxylate (11a) (200 mg; 0.608

- 51 042105 mmol), DIPEA (236 mg; 1.82 mmol) and MeNH ₂ (22.6 mg; 0.729 mmol) in DMA (8.0 ml) were stirred at 80°C for 16 hours. LCMS analysis showed the consumption of the starting material with the formation of the desired mass of the 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 from a parallel reaction carried out with 48 mg of ethyl 6-bromo-4-fluoro-1-(propan-2-yl)-1Pbenzimidazole-2-carboxylate to give 6-bromo-4-fluoro-N -methyl-1 -(propan-2-yl)-1 H-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 the consumption of the starting material with the formation of the desired mass of the product. The reaction mixture was cooled to room temperature and concentrated to give compound (Int-33) (190 mg; over 99% yield) as a solid, m/z (ESI+) for (CnHnBrFN ₃ O) 299.7 (M+H) ⁺ .

Obtaining tert-butyl- {1-[6-bromo-4-fluoro-1 - (propan-2-yl) -1 H-benzimidazol-2-yl] -2-methylpropan2-yl} carbamate (Int-34) according to scheme 13.

Scheme 13.

stage 3

Step 1: Synthesis of tert-butyl-(4-{4-bromo-2-fluoro-6-[(propan-2-yl)amino]anilino}-2-methyl-4oxobutan-2-yl)carbamate (13a) .

To a stirred solution of 5-bromo-3-fluoro-N-(propan-2-yl)benzene-1,2-diamine (7a) (1.1 g; 4.5 mmol) in pyridine (10.0 ml) was added 3-[(tert-butoxycarbonyl)amino]-3-methylbutanoic acid (967 mg; 4.5 mmol) and EDCI (1.7 g; 8.9 mmol) at 0° C. under N ₂ atmosphere. The mixture was stirred at 25°C for 4 hours. LCMS analysis showed the consumption of the starting material with the formation of the desired mass of the product. The solution was diluted with H2O (20 ml) and extracted with EtOAc (3x20 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-benzimidazol- 2-yl]-2-methylpropan-2-amine (13a) (1.6 g; 81% yield) as white solid, m/z (ESI+) for (C ₁₉ H ₂₉ BrPN 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 interaction 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) a solution of HCl (4.0 M in 1,4-dioxane; 10.0 ml) was added. The mixture was stirred at 130°C for 15 minutes at micro

- 52 042105 wave radiation. LCMS analysis showed the consumption of the starting material with the formation of the desired mass of the product. Three portions of the reaction mixture were combined and concentrated to dryness. The residue was taken up in H2O (10 ml) and the mixture was basified with NH4OH to pH about 9. The mixture was extracted with EtOAc (3x15 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]-2methylpropan- 2-amine (13b) (1.2 g; greater than 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]-2methylpropan-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 the consumption of the starting material with the formation of the desired mass of the product. The reaction mixture was diluted with H2O (15 ml) and the layers were separated. The aqueous layer was extracted with DCM (3x15 ml). The combined organic phases were washed with brine, dried over Na2SO4, 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-[6bromo-4-fluoro-1-(propan-2-yl)-1H -benzimidazol-2-yl]-2-methylpropan-2-yl}carbamate (Int-34) (1.6 g; over 99% yield) as brown solid, m/z (ESI+) for (C ₁₉ H ₂₇ BrFN ₃ O ₂ ) 430.0 (M+H)+.

The intermediate compound in the table below was synthesized by the methods used for the synthesis of tert-butyl-{1-[6-bromo-4-fluoro-1-(propan-2-yl)-1 H-benzimidazol-2-yl]-2- methylpropan2-yl}carbamate (Int-34). The following intermediate has been synthesized with minor modifications or substitutions in exemplary methods which can be carried out by a person skilled in the art.

Connection number Structure/Name according to IUPAC Analytical data Int-35 )—NHBoc /Me Me mpem-butyl-{3-[6-bromo-4-fluoro- 1-(propan-2-yl)-1Hbenzimidazol-2-yl]-1,1difluoropropan-2-yl} carbamate Ή NMR (400 MHz, CDCh) δ 7.47 (s, 1H), 7.11 (dd, 7=1.1, 9.6 Hz, 1H), 6.30-5.97 (m, 1H), 5.72 (br d, 7= 9.1 Hz, 1H), 4.72-4.57 (m, 1H), 4.524.30 (m, 1H), 3.34-3.13 (m, 2H), 1.70-1.60 (m, 6H), 1.36 (s, 9H) ; m/z (ESI+) for (С18Н2зВгГз№0 ₂ ) 396.0 (M-tBu+H) ⁺

- 53 042105

Preparation of 6-bromo-4-fluoro-2-(oxetan-2-yl)-1-(propan-2-yl)-1H-benzimidazole (Int-36) according to Scheme 14.

Scheme 14.

stage 1

ASON reflux

MsCI, TEA then t-BuOK DCM/THF yield 53%

K ₂ CO ₃

MeOH yield 44% (2 stages) stage 3

stage 4

Step 1: Synthesis of N{4-bromo-2-fluoro-6-[(propan-2-yl)amino]phenyl}oxetane-2-carboxamide (14a).

To a solution of 5-bromo-3-fluoro-N-(propan-2-yl)benzene-1,2-diamine (7 a) (1.0 g; 4.05 mmol) in DMF (10.0 ml) was added oxetane-2-carboxylic acid (413 mg; 4.05 mmol). Then DIPEA (1.6 g; 12.1 mmol) and HATU (2.3 g; 6.1 mmol) were 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 (2x100 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}oxetane-2-carboxamide (14a) (1 .5 g, 100% yield, which was taken directly to the next step.

Step 2: Synthesis of 3-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]-3hydroxypropyl 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 hours. LCMS analysis showed 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)-1 H-benzimidazol-2-yl]-3-hydroxypropyl acetate (14b) (1.5 g; 62 yield %), which was passed directly to the next stage without further purification, m/z (ESI+) for (C^H^B^Oz) 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]-3hydroxypropyl 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 -ul]propane-1,3-diol (14c) (660 mg; 44% yield, 2 steps) as 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) at 0° C. were added dropwise

- 54 042105 solution of MsCl (208 mg; 7.25 mmol) in DCM. 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) indicated consumption of starting material. The reaction mixture was concentrated to dryness. The residue was purified by flash chromatography (Biotage, EtOAc, Rf ca. 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.

1: Synthesis of tert-butyl-(2-{4-bromo-2-fluoro-6-[(propan-2-yl)amino]anilino}-2-oxoethyl)carbamate step (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 showed complete consumption of starting material. The reaction mixture was quenched with water and then extracted with EtOAc (3x50 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-[(propan-2-yl )amino]anilino}-2-oxoethyl)carbamate (15a) (810 mg; 98% yield) as a foamy solid. 1H 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=8.1Hz, 1H), 3.68 (d, J=5.6Hz, 2H), 3.62 (dd, J=6.6, 13.8Hz, 1H), 1.40 (s, 9H), 1.13 (d, J=6.2 Hz, 6H); m/z (APCI+) for (C16H18BrFN3O3) 404.0, 406.1 (M+H) ⁺ .

Step 2: Synthesis of tert-butyl {[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2yl]methyl}carbamate (Int-37).

A 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 hours at 100°C. The reaction mixture was concentrated. The residue was purified by flash chromatography (ISCO, 12 g SiO ₂ , 0-100% EtOAc/heptanes) 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. 1H 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 (16H21BrFN3O2) 388.0 (M+H) ⁺ .

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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-2yl)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 the consumption of the starting material with the formation of the desired mass of the 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-[(propan-2-yl )amino]anilino}1-oxopropan-2-yl)carbamate (16a) (1.14 g; 84% yield) as a white solid.

Step 2: Synthesis of tert-butyl {1-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2yl]ethyl}carbamate (Int-38).

A mixture of tert-butyl-(1-{4-bromo-2-fluoro-6-[(propan-2-yl)amino]anilino}-1-oxopropan-2yl)carbamate (16a) (4.4 g; 10. 5 mmol) in AcOH (20 ml) was stirred at 120°C for 2 hours. The solution was diluted with EtOAc (50 ml) and extracted with H2O (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 H2O (30 ml) and 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 tert-butyl-{1-[6-bromo-4-fluoro-1-(propan-2-yl)-1H -benzimidazol-2-yl]ethyl}carbamate (Int38) (1.1 g; 26% yield) as gummy solid, m/z (ESI+) for (C ₁₇ H ₂₃ BrPN ₃ O ₂ ) 401.7 ( M+H) ⁺ .

The intermediate in the table below was synthesized by 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 minor modifications or substitutions in exemplary methods which can be carried out by a person skilled in the art.

Connection number Structure/Name according to GORAS Analytical data Int-39 D-nhboc Dg L~Me Me from/?eo-butyl-( 1 - {[6-bromo-4-fluoro-1 (propan-2-yl)-17/-benzimidazol-2yl]methyl } cyclopentyl)carbamate C NMR (400 MHz, CDCh) δ 7.41 (s, 1H), 7.02 (d, 7=9.7 Hz, 1H), 4.78 (p, 7=7.0 Hz, 1H), 4.66 (s, 1H) , 3.35 (s, 2H), 1.89-1.59 (m, 8H), 1.54 (d, ./=7.0 Hz, 6H), 1.34 (br d, ./=6.7 Hz, 9H); m/z (ESI+) for (Ci8H26BrFN ₂ OSi) 454.1 (M+H) ⁺

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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)-2hydroxypropionic acid (17, 4 g; 193 mmol) was stirred at 82°C for 44 hours. 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 (2x100 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/heptanes). Product-containing fractions were first further purified by concentration to a minimum volume. The resulting residue was dissolved in a small volume of MTBE, then diluted with an equal volume of heptanes. 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/heptanes, then with heptanes 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. 1H NMR (400 MHz, DMSOd6) 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 by the methods used for the synthesis of (1R)-1-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]ethan-1-ol (Int-40). The following intermediates have been synthesized with minor modifications or substitutions in exemplary methods which can be carried out by one skilled in the art.

Connection number Structure/Name according to IUPAC Analytical data Int-41 F OH XX'W Βι-ΧΧΧ^Ν Me /~Me Me 1 - [6-bromo-4-fluoro-1 - (propan-2-yl) - 1H-benzimidazol-2-yl]ethan- Gol m/z (APCI+) for (Ci2Hi ₄ BrFN ₂ O) 302.7 (M+H) ⁺ Int-42 F Λχ-Ν OH L1H Me Λ-Me Me (15)-1-[6-bromo-4-fluoro-1-(propane-2 - yl)- 1//-benzimidazol-2-yl]ethan-1 -ol m/z (APCI+) for (Ci2Hi ₄ BrFN ₂ O) 302.9 (M+H) ⁺

Preparation of 1-[6-bromo-1-(1,1-difluoropropan-2-yl)-4-fluoro-1 H-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}-2hydroxypropanamide (18b).

A mixture of 5-bromo-N ¹ - (1,1-difluoropropan-2-yl) -3-fluorobenzene-1,2-diamine (18a) (obtained as yet

- 57 042105 is shown in diagram 7; 1.0 g; 3.5 mmol) and 2-hydroxypropionic acid (10.0 ml) were stirred at 85°C for 16 hours. LCMS analysis showed the consumption of the starting material with the formation of the desired mass of the product. H ₂ O (15 ml) and EtOAc (15 ml) were added and the mixture was cooled to 0°C. The pH of the mixture was adjusted to about 7 with 50% aqueous NaOH. The layers were separated. The aqueous layer was extracted with EtOAc (2x20 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-{4-6pom-2-[(1,1-difluoropropan-2-yl)amino]-6-fluorophenyl }-2-hydroxypropanamide (18b) (1.0 g; 84% yield) as 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-olα (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 minutes under microwave radiation. LCMS analysis showed the consumption of the starting material with the formation of the desired mass of the product. The solution was concentrated to dryness. The residue was taken up in H ₂ O (3 ml) and then basified with aqueous NH4OH (1 ml) to pH about 8. The solution was extracted with EtOAc (3x5 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 , EtOAc/petroleum ether, 1:1) to give compound (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) ⁺ .

Obtaining 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-diαmine (7a) and difluoroacetic acid anhydride (1.47 ml; 11.8 mmol) in AcOH (4, 6 ml) was stirred at 90°C for 3 hours. The solvent was removed under vacuum. The residue was taken up in DCM (30 ml). The pH of the mixture was adjusted to about 8-9 with 1.0N 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(propαn-2-yl)-1H- benzimidazole α (Int-44) (523 mg; 72% yield) as a white solid. 1H 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 (C11H ₁₀ BrF ₃ N ₂ ) 309.1 (M+H) ⁺ .

Obtaining 6-bromo-1-tert-butyl-4-fluoro-1H-benzimidazole (Int-45) according to 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° WITH). The mixture was stirred

- 58 042105 at ambient temperature for 15 hours and then quenched with aqueous Na2CO3 (80 ml). The organic layer was collected. The aqueous layer was extracted with EtOAc (3x30 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 minutes 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 (C11H13BrF2N2) 292.6 (M+H) ⁺ .

Stage 2: Synthesis of 6-bromo-1-tert-butyl-4-fluoro-1H-benzimidazole (Int-45).

To a solution of N-(4-bromo-2,6-difluorophenyl)-N'-tert-butylmethanimidamide (20b) (4.50 g; 15.5 mmol) in DMF (40 ml) was added KOtBu (2.60 g; 23.2 mmol) and the mixture was stirred at 80° C. for 14 hours. H2O (100 ml) was added and the mixture was extracted with EtOAc (3x50 ml). The combined organic phases were washed with brine (50 ml), dried over Na2SO4, 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 (250x80 mm, particle size 10 μm, column temperature 25°C) , which was eluted with 35-65% MeCN/H ₂ O (plus 0.225% formic acid) at a flow rate of 80 ml/min to give 6-bromo-1-tert-butyl-4fluoro-1H-benzimidazole (Int-45) ( 1.5 g, 36% yield as a gray solid, m/z (ESI+) for (C11H12BrFN2) 270.9 (M+H) ⁺ .

The intermediate in the table below was synthesized by 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 minor modifications or substitutions in exemplary methods which can be carried out by a person skilled in the art.

Connection number Structure/Name according to GORAS Analytical data Int-46 F II A / ^Me Br' ^X % ^ ^N . .. Ame Me 6-bromo-4-fluoro-2-methyl-1 -(propan2-yl)- 1/7-benzimidazole m/z (ESI+) for (CnHi2BrFN ₂ ) 270.6 (M+H) ⁺

Obtaining tert-butyl-3-(6-bromo-4-fluoro-2-methyl-III-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 K2CO3 (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 loaded onto 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 then separated by preparative SFC on a Waters SFC 200 Glacier/Two ZymorSPHER HADP column (150x21.1 mm ID, 5 µm particle size) which was eluted with 10-35% MeOH/CO ₂ (100 bar (10 MPa), 35°C) with a flow rate of 80 ml/min to obtain tert-butyl-3-(6-bromo4-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 (C16H19BrFN3O2) 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.

- 59 042105

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 the consumption of the starting material with the formation of the desired mass of the product. The reaction mixture was quenched with H2O (3 ml) and then concentrated in vacuo. 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 (CnHpBrN) 268.8 (M+H) ⁺ .

The intermediate in the table below was synthesized by 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 minor modifications or substitutions in exemplary methods which can be carried out by a person skilled in the art.

Connection number Structure/Name according to GORAS Analytical data Int-49 CI Vg/d L~Me Me 6-bromo-4-chloro-1 - (propan-2-yl) - 1I-benzimidazole Ή NMR (400 MHz, CDCh) δ 8.05 (s, 1H), 7.84 (d, 7=1.5 Hz, 1H), 7.39 (d, 7=1.3 Hz, 1H), 5.40 (quin.d, 7=6.6, 13.3 Hz, 1H), 1.62 (d, 7=6.5 Hz, 6H); m/z (E81+) for (CioHioBrClN 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) according to 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 approximately 50% consumption of starting material. The reaction mixture was cooled to room temperature and additional tBuOK (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 showed approximately 65% conversion. The mixture was diluted with water H2O (30 ml) and extracted with DCM (3x15 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 (150x40 mm, particle size 5 μm) which was eluted with 33-73% MeCN/H ₂ O (0.05% NH4OH) at a flow rate of 25 ml/min to give tert-butyl-[1-(6-bromo-4-fluoro-2-methyl-1H-benzimidazol-1-yl)propan-2-yl]carbamate (Int50) (112 mg; yield 16%). 1H 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 (1 ₆ H21BrFN3O2) 387.8 (M+H) ⁺ .

Obtaining tert-butyl-[1 -(6-bromo-4-fluoro-2-methyl-1 H-benzimidazol-1 -yl)propan-2-yl]carbamate (Int-49) according to 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 with dry ice/acetone bath. The solution was added dropwise

- 60 042105

LDA (lithium diisopropylamide) (2.0 M in THF; 1.94 ml; 3.89 mmol). 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 indicated consumption of the 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 (3x15 ml). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash chromatography (ISCO, EtOAc/petroleum ether, 1:3) to give [1-(6-bromo-4-fluoro-2-methyl-Hbenzimidazol-1-yl)propan-2-yl]carbamate (Int -51) (420 mg; 63% yield) as a white solid. ¹ H NMR (400 MHz, CDCl3) 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), 0.520.44 (m, 1H); m/z (ESI+) for (C15H18BrFN ₂ O) 340.7 (M+H) ⁺ .

Preparation of (4R)-7-bromo-9-fluoro-4-methyl-3,4-dihydro-1H-[1,4]oxazino[4,3-а]benzimidazoleα (Int-50) according to Scheme 24.

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 minutes and then 5-bromo-1,3-difluoro-2-nitrobenzene (1a) (1.03 mg; 4.34 mmol) was added. The reaction suspension was stirred for 1 hour. LCMS analysis showed consumption of starting material. H2O (2 ml) was added and the reaction suspension was concentrated to dryness. The residue was taken up 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 , EtOAc/petroleum ether, 1:3) to give (5R)-4-(5-bromo-3-fluoro-2nitrophenyl)-5-methylmorpholin-3-one (25 a) (760 mg; 53% yield) as light yellow solid, m/z (ESI+) for (C ₁₁ H ₁₀ BrFN ₂ CO 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° (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 with the formation of the desired mass of product. The reaction mixture was filtered and concentrated to dryness. The residue was purified by flash chromatography (SiO ₂ , EtOAc/petroleum ether, 1:3) to give (5R)-4-(2-αmino-5-bromo-3-fluorophenyl)-5-methylmorpholin-3one (25b) ( 420 mg, 61% yield as light brown gum, m/z (ESI+) for (C11H ₁₂ BrFN ₂ O ₂ ) 303.1 (M+H)+.

Step 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 the consumption of the starting material with the formation of the desired mass of the product. The reaction mixture was concentrated to dryness. The residue was taken up in EtOAc (50 ml) and washed with aqueous saturated NaHCO ₃ (30 ml). The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated to give (4R)-7-bromo-9-fluoro-4methyl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidαzolα (Int-52) (360 mg; 91% yield) as 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 by 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- 61 042105

52). The following intermediates have been synthesized with minor modifications or substitutions in exemplary methods which can be carried out by one skilled in the art.

Number Structure/Name according to Analytical data connections SHRAS Int-53 F Li Ή Me'(45)-7-bromo-9-fluoro-4-methyl-3,4-dihydro1 R-[1,4]oxazino[4,3-a]benzimidazole m/z (ESI+) for (CnHioBrFN ₂ 0) 286.6 (M+H) ⁺ Int-54 /хъ Вг^^_ue Me 7-bromo-4-ethyl-9-fluoro-3,4-dihydro- 1Н[1,4]oxazino[4,3-а]benzimidazole m/z (ESI+) for (Ci ₂ Hi ₂ BrFN ₂ O) 300.9 (M+H) ⁺ Int-55 F LX Ή __N—Boc Me ^Z Ή NMR (400 MHz, DMSO-J6) δ 7.79 (d, 7=1.5 Hz, 1H), 7.33 (dd, 7=1.5, 10.3 Hz, 1H), 5.21-4.96 (t, 1H ), 4.75 (br s, 1H), 4.264.09 (t, 1H), 3.67-3.57 (t, 2H), 1.46 (s, 9H), 1.35 (brd, 7=6.3 Hz, 3H); m/z (ESI+) for (С16Н19ВгГ№0 ₂ ) 385.9 (М+Н) ⁺ Int-56 .Al me x me 7-bromo-5-fluoro-1,1-dimethyl-2,3-dihydro- 1H-pyrrolo[ 1,2-a] benzimidazole m/z (ESI+) for (Ci ₂ Hi ₂ 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.

to ₂ from ₃

DMF, 80 °C yield 68%

Fe°, _NH4CI

EUN/H ₂ O, 80 °C yield 86%

CI^C(OEt) ₃

AcOH, 55 °C yield 7 2% stage 1 stage 2 steel 3

t-BuOK

THF, 0-5°C yield 94% stage 4

Stage 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 the consumption of the starting material with the formation of the desired mass of the 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° (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 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-methylpron-an-1-ol (26c).

A 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 minutes. LCMS analysis showed consumption of the starting material to form the product. After cooling to room temperature, the reaction mixture was combined with mixtures from parallel reactions carried out on a smaller scale (5x100 mg). The combined reactions were basified with saturated aqueous NaHCO ₃ to adjust the pH to about 7-8 and extracted with EtOAc (3x20 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 SiO2, 30% EtOAc/petroleum ether) to give 2-[6-bromo-2-(chloromethyl)-4-fluoro-1H-benzimidazol-1-yl]-2methylpropan- 1-ol (26c) (2.0 g; 72% yield) as a light yellow solid. 1H 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) ⁺ .

Step 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 minutes. LCMS analysis showed the consumption of the starting material with the formation of the desired mass of the product. The reaction mixture was diluted with H ₂ O (10 ml) and was extracted with EtOAc (3x10 ml). The combined organic phases were washed with brine (15 ml), dried over Na2SO4, 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. 1H 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) ⁺ .

Obtaining 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.

1. MsCI, DIPEA MeCN, 0°C

2. MeNH ₂ , 60 °C yield 43%

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 the consumption of the starting material with the formation of the desired mass of the 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 the desired weight of 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-2,4,4trimethyl-1,2,3,4-tetrahydropyrazino[1,2-a ]benzimidazole (Int-58) (200 mg; 43% yield) as a yellow gum. 1H 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) ⁺ .

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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.

stage 4

Stage 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 K ₂ CO ₃ (4.65 g; 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 (petroleum ether/EtOAc, 3:1) indicated consumption of starting material. After cooling to room temperature, the reaction mixture was diluted with H2O (150 ml) and extracted with EtOAc (2x150 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-benzimidazol1 -yl]propan-1-ol(2 8b) .

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]oxy }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 suspension was stirred at 80°C for 16 hours. LCMS analysis showed the consumption of the starting material with the formation of the desired mass of the product. The mixture was concentrated to remove EtOH. The solution was diluted with EtOAc (100 ml) and washed with H2O (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-ul]propan-1-ol (28b) (1.0 g; 71% yield) as white solid, m/z (ESI+) for (C ₁₅ 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-1yl]propan-1-ol (28b) ( 1.0 g; 2.32 mmol) in THF (5.0 ml) was added TBAF (tetrabutylammonium fluoride) (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 H2O (2x50 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-[6bromo-4-fluoro-2-(1-hydroxyethyl)-1H-benzimidazol-1-yl]propan- 1-ol (28c) (400 mg; 54% yield) as 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 hours. Saturated aqueous NaHCO ₃ (20 ml) was added to the solution. The mixture was extracted with EtOAc (2x100 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; diastereomeric mixture) as yellow oil, m/z (ESI+) for (C ₁₂ H ₁₂ BrFN ₂ O) 298, 7 (M+H) ⁺ .

- 64 042105

Preparation of 6-bromo-1-(propan-2-yl)-III-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 H2O; 30 ml ) was added a solution of sodium nitrite (1.36 g; 19.6 mmol) in H2O (15 ml) at 0°C. The reaction mixture was stirred at this temperature for 30 minutes then allowed to warm to ambient temperature over a 2 hour period. The reaction mixture was poured into saturated aqueous Na ₂ CO ₃ (150 ml) and was extracted with EtOAc (2x150 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) according to 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 minutes 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 the consumption of the starting material with the formation of the desired mass of the product. The reaction mixture was quenched with saturated aqueous NaHCO ₃ (10 ml) and the layers were separated. The aqueous layer was extracted with EtOAc (3x10 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-2methyl-2H-indazol-3-yl)propan-2-ol (Int- 61) (120 mg; 31% yield) as a colorless oil, m/z (ESI+) for (C _n H1 ₃ BrN2O) 270.9 (M+H) ⁺ .

Obtaining 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 showed consumption of starting material. The reaction mixture was quenched with H ₂ O, brought to a pH of about 8 with saturated aqueous NaHCO ₃ and was extracted with DCM (3x10 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 _n H1 ₃ BrN2) 252.8 (M+H) ⁺ .

- 65 042105

Preparation of 9-bromo-7-fluoro-1,1-dimethyl-3,4-dihydro-III-[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 (EtOAc/petroleum ether, 1:1) indicated partial consumption of starting material. The reaction mixture was concentrated to dryness and purified by flash chromatography (ISCO, 80 g SiO ₂ , 0100% EtOAc/petroleum ether) to give 2-(5-bromo-7-fluoro-2H-indazol-2-yl)ethan-1- ol (32b) (950 mg; 32% yield) as 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-a (32b) (550 mg; 2.12 mmol) in THF (10.0 mL) was purged with N2 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 minutes 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 hours at room temperature. LCMS analysis showed complete consumption of the starting material with the formation of the desired mass of product. The reaction mixture 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-(2hydroxyethyl)-2H-indazol-3-yl]propane -2-ol (32c) (490 mg; 73% yield) as a colorless oil.

Step 3: Synthesis of 9-bromo-7-fluoro-1,1-dimethyl-3,4-dihydro-III-[1,4]oxazino[4,3-6]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) was added p-TSA (210 mg; 1.22 mmol) at 0°C. The mixture was stirred at 120°C for 16 hours. LCMS analysis showed the consumption of the starting material with the formation of the desired mass of the 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-1,1dimethyl-3,4-dihydro-1H-[1 ,4]oxazino[4,3-b]indazole (Int-63) (100 mg; 55% yield) as yellow oil, m/z (ESI+) for (C ₁₂ H ₁₂ BrFN ₂ O) 298.6 ( M+H) ⁺ .

- 66 042105

Obtaining 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.

Step 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 tetrafluoroborate (1.97 g, 13.3 mmol). The resulting solution was stirred at ambient temperature for 5 hours. LCMS analysis showed the consumption of the starting material with the formation of the desired mass of the 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. 1H 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-2sulfinamide (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-yluden)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 hours. LCMS analysis showed complete consumption of the starting material with the formation of the desired mass of product. The reaction mixture was quenched by adding saturated aqueous NH ₄ Cl (10 ml) and was extracted with EtOAc (2x30 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-2Hindazol-3-yl)propan-2 -yl]-2-methylpropan-2-sulfinamide (33b) (420 mg; 25% yield) as yellow gum, m/z (ESI+) for (C ₁₅ H ₂₁ BrFN ₃ O ₃ ) 392.0 (M+ H) ⁺ .

Step 3: Synthesis of 2-(5-bromo-7-fluoro-2-methyl-2H-undazol-3-yl)pronan-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-2sulfinamide (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 the consumption of the starting material with the formation of the desired mass of the 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 (2x20 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-undazol-3-yl)propan-2-amine (33c) (300 mg; yield 97%) as a yellow solid, m/z (ESI+) for (C ₁₃ H ₁₅ BrFN ₃ ) 268.9 (M+H) ⁺ .

Step 4: Synthesis of tert-butyl-[2-(5-bromo-7-fluoro-2-methyl-2H-undazol-3-yl)n-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 H2O (10 ml) and extracted with EtOAc (2x30 ml). The combined organic phases were dried over Na ₂ SO ₄ ,

- 67 042105 was 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 ( 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.

Step 1: Synthesis of 5-bromo-7-fluoro-3-iodo-2-methyl-2H-indazole (34a).

Bis(trifluoroacetoxy)iodobenzene (1.13 g; 2 .62 mmol) and pyridine (259 mg; 3.27 mmol). The mixture was stirred at 30° C. for 30 minutes and then I ₂ (556 mg; 2.62 mmol) was added. The mixture was stirred at 30°C for 16 hours. LCMS analysis showed the consumption of the starting material with the formation of the desired mass of the 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 , 3040% EtOAc/petroleum ether) to give 5-bromo-7-fluoro-3-iodo-2-methyl-2H-indazole (34a) (700 mg; yield 90%) 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 atmosphere of N ₂ at 100°C for 3 hours. The reaction suspension turned black. LCMS analysis showed complete consumption of the starting material with the formation of the desired mass of 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 bubbled with H ₂ and then stirred at 50°C for 16 hours in an H 2 atmosphere at a pressure of 50 psi .inch (0.34 MPa). LCMS analysis showed the consumption of the starting material with the formation of the desired mass of the product. The reaction mixture was concentrated to dryness and the residue was purified by flash chromatography (ISCO, EtOAc/petroleum ether, 1:1) to give 5-bromo-7-fluoro-2-methyl-3-(propan-2-yl)-2H-indazole (Int65) (300 mg; over 99% yield) as a pale brown gum, m/z (ESI+) for (C11H10BrFN2) 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.

Ν ΝΗο c, c... acetone _{TFA NaB} (OAc) ₃ HJ[ 2 /-PrOAc JT AcOH, 90°C , _c 35b Me^Me

YIELD 89% Yield 52%

Stage 1: synthesis of 5-bromo-N ³ -(propan-2-yl)pyridine-2,3-diamine (35b).

To a solution of 5-bromopyridine-2,3-diamine (35a) (2.51 g; 13.4 mmol) and acetone (1.2 ml; 16 mmol) in iPrOAc (20 ml) was added 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 stop 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 SiO2, 0-65% EtOAc/petroleum ether) to give 5-bromo-N ³ -(propan-2-yl)pyridin-2,3-diamine (35b) (2.7 g;vyVg

- 68 042105 stroke 89%) in the form of brown resin. 1H NMR (400 MHz, DMSO-d6) 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)pyridin-2,3-diamine (35b) (1.5 g; 6.52 mmol) and Ac2O (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 taken up in DCM (50 ml) and the pH was adjusted to about 8-9 with aqueous NaOH (1.0 N). The organic layer was collected, washed with brine (50 ml), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (24 g SiO2, 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-d6) 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[4.5b]pyridine (36a) (1.0 g; 5.7 mmol) and 2-bromopropane (2.8 ml; 29.8 mmol). The mixture was stirred for 20 hours at room temperature and an additional 1 hour at 60°C. LCMS analysis showed consumption of the starting material to form the desired mass of product (mixture of regioisomers, about 4:1). The mixture was partitioned between H2O (25 ml) and EtOAc (25 ml). The aqueous layer was extracted with EtOAc (3x25 ml). The combined organic layers were washed with H2O (2x25 ml) and brine (25 ml), dried over Na ₂ SO ₄ , filtered and concentrated directly onto SiO ₂ . The crude material was purified by flash chromatography (SiO ₂ , 80-100% EtOAc/heptanes) to give 5-chloro-2-methyl-3(propan-2-yl)-3H-imidazo[4,5-b]pyridine ( Int-67) (950 mg; 76% yield) as the first eluting regioisomer. 1H 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.

37a t-BuNH ₂

PhMe yield 79%

stage 1

Fe°, _NH4CI

EtOH, H ₂ O, 60°C 95% yield

p-TSA, CH(OEt) ₃ PhMe, 110°C yield 95% stage 3

Step 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 the consumption of the starting material with the formation of the desired mass of the 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) ⁺ .

Step 2: Synthesis of N ² -tert-butyl-6-chloropyridine-2,3-diαmine (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 the consumption of the starting material with the formation of the desired mass of the product. The mixture was filtered and concentrated to remove EtOH. The mixture was diluted with water H2O (100 ml) and extracted with EtOAc (200 ml). The combined organic layers were dried over anhydrous Na2SO4, 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 additional purification, m/z (ESI) for (C9H ₁₄ ClN ₃ ) 199.9 (M+H) ⁺ .

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Step 3: Synthesis of 3-tert-butyl-5-chloro-3H-imidaαzo[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) p-TSA monohydrate (286 mg, 1.5 mmol) was added to PhMe (40.0 ml). The mixture was stirred for 16 hours at 110°C. LCMS analysis showed the consumption of the starting material with the formation of the desired mass of the product. The mixture was washed with saturated aqueous NaHCO ₃ (60 ml). The aqueous layers were extracted with EtOAc (2x100 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 used without additional purification, m/z (ESI) for (C ₁₀ H ₁₂ ClN ₃ ) 209.8 (M+H)+.

Obtaining (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-1carboxylate (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) was added dropwise benzyl chloroformate (24.1 ml; 72.1 mmol; 50% in PhMe) at 0°C. The mixture was stirred for 4 hours, then the organic phase was collected. The aqueous phase was extracted with DCM (2x100 ml). The combined organic phases were washed with H ₂ O (2x100 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/hexanes) to give t-butyl-(3R,4R)-4-{[(benzyloxy)carbonyl]amino}-3-hydroxypiperidine-1-carboxylate (3 8b) (18.0 g; 85% yield) as light yellow oil, m/z (ESI+) for (C ₁₅ 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 hours 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; 8.39 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 (2x100 ml). The combined organic phases were washed with H ₂ O (2x100 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 (C14H20N2O5S) 329.4 (M+H)+.

Step 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 a hydrogen atmosphere from a balloon at ambient temperature for 16 hours. The reaction mixture was filtered through celite and washed with methanol (100 ml). The filtrate was concentrated under reduced pressure to give compound (Int-69) (6.41 g, 90% yield) as a white solid. 1H NMR (400 MHz, CD3OD) 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 (C6H14N2O3S) 195.0 (M+H)+; [a]D -19° (c 0.1, MeOH).

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Preparation of (2S)-2-hydroxy-3-phenylpropionic acid salt (3R,4R)-4-amino-1-

(methanesulfonyl)piperidin-3-ol (Int-70) according to Scheme 39.

scheme 39.

Vos

HCI

MSCI, TEA

Meon

DCM

39a yield over 99%

39b exit 88%

0=5=0 I 39c ^Me m-CPBA DCM output 94% “0

Vp

ABOUT

Oh

_NH3

BUT

O=S=O

Me

1. LiBr, NH ₄ OH MeCN, 18-40 °C

2.

BUT

ABOUT

OHlnt-70

bn

MeOH, reflux

0=5=0

Me 39d yield 25% (2 stages)

Step 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; over 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).

TEA (248 g, 2.5 mol) was added to a suspension of 1,2,3,6-tetrahydropyridine hydrochloride (39b) (97.9 g, 818 mmol) in DCM (1.0 L). The mixture was cooled to 0-5°C and then treated with methanesulfonyl chloride (112 g; 982 mmol) slowly dropwise keeping the temperature of the reaction mixture below 20°C. After the addition, the mixture was stirred for an additional 16 hours at room temperature. The reaction was stopped by slow addition of H2O (1 L). The phases were separated. The aqueous layer was extracted with DCM (1.5 L). The combined organic phases 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 solid was collected by filtration and dried in vacuo to give 1-(methanesulfonyl)-1,2,3,6tetrahydropyridine (39c) (116 g; 88% yield) as a light yellow solid which was used without further purification. Ή 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 showed consumption of starting material. The heterogeneous mixture was filtered to remove solids. 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 (2x1.5 L). The combined organic phases 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. Ή 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 (ddd, J=4.7, 8.4, 12.9 Hz, 1H), 2.82 (s, 3H ), 2.21-2.04 (m, 2H).

Step 4: Synthesis of (2S)-2-hydroxy-3-phenylpropionic acid salt of (3R,4R)-4-amino-1(methanesulfonyl)piperidin-3-ol (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 NH4OH (14.1 g; 113 mmol). The mixture was stirred at ambient temperature for 48 hours. TLC analysis (petroleum ether/EtOAc, 1:1) indicated remaining starting material. The reaction mixture was heated to 40°C and stirred at this temperature for 36 hours. TLC analysis (petroleum ether/EtOAc, 1:1) 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-amio-1-(methanesulfonyl)piperidin-3-ol (11 g) was taken up in MeOH (120 ml) and the mixture heated to reflux until the solution became clear . The mixture was cooled to room temperature and a solution of (2S)-2-hydroxy-3-phenylpropionic acid (9.41 g; 56.6 mmol) in MeOH (30 ml) was added. The solution became cloudy, followed by intense 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 taken up in MeOH (30 ml) and stirred at reflux temperature for 10 minutes. The solution was slowly cooled to room temperature. The resulting precipitate was collected by filtration to give (2S)-2-hydroxy-3phenylpropionate salt (3R,4R)-4-amino-1-(methanesulfonyl)piperidin-3-ol (Int-70) (5.0 g; yield 25 %) as a white solid. Enantiomeric excess (e.i. 97%) was determined for the corresponding N-CBz-protected derivative by chiral SFC on a Chiralpak AS-3 column (4.6x150 mm, particle size 3 μm, 35°C), which was eluted with a mixture of 5-40 % EtOH/CO ₂ (plus 0.05% diethylamine) with a flow rate of 2.5 ml/min. 1H 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 (ddd, 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 (ddd, 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)-1Hbenzimidazol-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-(nponan-2-yl)-1H-benzimidazole (Int-46) (90 g; 331.95 mmol), bis(pinacolato)diboron (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 ) was sparged with N2 and then stirred at 100° C. for 16 hours. TLC analysis (petroleum ether/EtOAc, 1:1) showed complete consumption of starting material. The black suspension was poured into H2O (3.0 L) and extracted with EtOAc (2x3 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. 1Н 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 BBrFN ₂ O ₂ ) 319.2 (M+H)+.

Step 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)-1Hbenzimidazole (A-1 ) (300 mg; 0.943 mmol), 2,4,5-trichloropyrimidine (259 mg; 0.16 ml; 1.41 mmol) and

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K2CO3 (260 mg; 1.89 mmol) in 1,4-dioxane (9 ml) and H2O (3 ml) were bubbled with N2 for 5 minutes. Pd(PPh ₃ ) ₄ (54.5 mg; 0.047 mmol) was added and the mixture was sparged with N2 for another 10 minutes. The mixture was stirred at 90° C. for 16 hours, then cooled to ambient temperature, diluted with H2O (15 ml) and extracted with EtOAc (3x10 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 obtained from the reaction carried out in a similar manner on a scale 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-6yl]pyrimidin-2-yl }amino)-1-(methanesulfonyl)piperidin-3-ol (Example A1).

To a yellow suspension of 6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-2-methyl-1-(propan-2-yl)-1Hbenzimidazole (A-2) (210 mg; 0.619 mmol) in DMSO (5 ml) was added DIPEA (240 mg; 0.331 ml; 1.86 mmol) and (3R,4R)-4-amino-1-(methanesulfonyl)piperidin-3-ol (Int-69) (241 mg; 1.86 mmol) 24 mmol). The mixture was stirred at 120°C for 16 hours and then diluted with H ₂ O (20 ml) and was extracted with EtOAc (3x20 ml). The combined organic phases were washed with brine (20 ml), dried over Na2SO4, filtered and concentrated. The crude residue was purified by preparative HPLC on an Agela Durashell C18 column (150x25 mm, particle size 5 µm; column temperature 25°C) which was eluted with 34-54% MeCN/H ₂ O (plus 0.05% NH4OH) at a flow rate of 25 ml/min to obtain (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. 1H NMR (400 MHz, DMSO-d6) 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) , 2.692.59 (m, 4H), 2.07 (s, 1H), 1.62-1.46 (m, 7H); m/z (ESI+) for (C^ClF^OsS) 497.3 (M+H)+.

The examples in the table below were synthesized using the methods used to synthesize (3R,4R)-4-({5-chloro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1 H-benzimidazole -6-yl]pyrimidin-2-yl}amino)-1(methanesulfonyl)-piperidin-3-ol (Example A1). The following examples were synthesized with minor changes or substitutions in the exemplary methods that can be carried out by a person skilled in the art. 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 LCMS NMR A2 । \ Me O=S=O me Me (37?,47?)-4-({5-fluoro-4-[4-fluoro-2methyl-1 -(propan-2-yl)- 1Hbenzimidazol-6-yl]pyrimidin-2yl}amino)-1- 481.2 [M+H] ⁺ (ESI) Ή NMR (400 MHz, DMSO-Tb) δ 8.44 (d, ./=4.03 Hz, 1H), 8.168.03 (m, 1H), 7.71-7.50 (br, 1H), 7.32-7.17 (m, 1Н), 5.285.19 (m, 1Н), 4.90-4.74 (br, 1Н), 3.87-3.72 (m, 1Н), 3.703.57 (m, 2Н), 3.54-3.45 (br, 1Н), 2.92 ( s, 3H), 2.89–2.83 (w, 1H), 2.73–2.66 (w, 1H), 2.64 (s,

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(methanesulfonyl)piper idin-3-ol ZN), 2.36-2.30 (m, 1Н), 1.60 (d, 7=6.85 Hz, 6Н), 1.57-1.50 (br, 1Н) AZ Ny ^F ό Ν Me^ Me Me Me amine 401.1 [M+H] ⁺ (ESI) Ή NMR (400 MHz, CD3OD) δ 8.51 (br s, 1H), 8.43-8.34 (m, 3H), 7.82 (d, 7=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 ν'% D F HN N ]| BUT^D. DD II \ .N to J N—\ N Me-~/ 1\me O-S-O Me Me (37^47?)-4-({4-[4-Fluoro-2-methyl-1(propan-2-yl)- 1H-benzimidazol-6yl] pyrimide in-2-yl } amino)-1 (methanesulfonyl )piper idin-3-ol 463.3 [M+H] ⁺ (ESI) C NMR (400 MHz, DMSO-Tb) δ 8.35 (d, 7=5.3 Hz, 1H), 8.22 (s, 1H), 7.76 (d, 7=12.3 Hz, 1H), 7.32 (d, 7=5.5Hz, 1H), 7.14(d, 7=7.8Hz, 1H), 5.27(br d, 7=4.0Hz, 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, 7=6.3Hz, 7H) A5 dX Ϊ HN ^N °D ^Μ ΎΛβ O=S=O Me Me Me (37^47?)-4-({4-[5-fluoro-2-methyl-1(propan-2-yl)- 1H-benzimidazol- 6yl] pyrimide in-2-yl } amino)-1 (methanesulfonyl) piper idin-3 -ol 463.1 [M+H] ⁺ (ESI) Ή NMR (400 MHz, DMSO-Je) δ 8.39-8.09 (m, 2H), 7.47-7.41 (m, 1H), 7.20 (d, 7=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-

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2.00 (m, IH), 1.65-1.60 (m, 7H) Ab N^F HN^N^V^i ^HO vS to / N-? N Me—/ ι \ Me OSO _Me Me (ZD47?)-4-({5-chloro-4-[5-fluoro-2methyl-1 -(propan-2-yl)- 1Hbenzimidazol-6-yl]pyrimidin- 2yl } amino)-1-(methanesulfonyl)piperide in-3-ol 497.3 [M+H] ⁺ (ESI) Ή NMR (400 MHz, DMSO-Tb) δ 8.42 (s, IH), 7.73 (d, 7=6.0 Hz, IH), 7.66-7.48 (m, IH), 7.44 (d, 7=10.5 Hz, IH), 5.22 (d, 7=4.3 Hz, IH), 4.85-4.70 (m, IH), 3.79 (br s, IH), 3.653.55 (m, 2H), 3.50-3.40 (m , IH), 2.88 (br s, 4H), 2.70–2.60 (m, IH), 2.58 (s, 3H), 2.08 (s, IH), 1.60–1.45 (m, 7H) A7 hn ^ΗΟ γΑ ^ιι Α Λ “'-/Xe OSO Me Me (ZD47?)-4-({5-fluoro-4-[5-fluoro-2methyl-1 -(propan-2-yl)- 1Hbenzimidazol-6- yl]pyrimidin-2yl } amino)-1-(methanesulfonyl)piperidin-3-ol 481.3 [M+H] ⁺ (ESI) Ή NMR (400 MHz, DMSO-Tb) δ 8.42 (d, 7=2.0 Hz, IH), 7.82 (d, 7=6.0 Hz, IH), 7.46 (d, 7=10.8 Hz, IH), 7.32 (br s, IH), 5.21 (d, 7=4.5 Hz, IH), 4.854.70 (m, IH), 3.73 (br s, IH), 3.67-3.56 (m, 2H) , 3.50-3.40 (m, IH), 2.88 (s, 3H), 2.86-2.78 (m, IH), 2.70-2.60 (m, IH), 2.59 (s, 3H), 2.07 (s, IH), 1.601 .45(m, 7H) A8 N^Y ^CI HN Ν ΥΥ no. A. 11 \ ν SD / ^Ν —( U Me _Me O=S=O Me (3R,4R)-4-{ [5-chloro-4-(4-fluoro-1,2dimethyl-1H-benzimidazol-6yl) pyrimidin-2-yl]amino } -1 (methanesulfonyl)piperidin-3 -ol 469.2 [M+H] ⁺ (ESI) Ή NMR (400 MHz, DMSO-Je) δ 8.42 (s, IH), 7.77 (br s, IH), 7.60-7.31 (m, 2H), 5.22 (d, 7=4.5 Hz, IH), 3.81 (br s, IH), 3.79 (s, 3H), 3.67-3.55 (m, 2H), 3.50-3.40 (m, IH), 2.89 (s, 3H), 2.88-2.82 (m, IH), 2.702. 60 (m, IH), 2.58 (s, 3H), 2.04 (br s, IH), 1.59-1.42 (m, IH)

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A9 N^ ¹ HN N ]| 11 \ ^N N MeU^ O=S=O Me^^ ⁴ ^ Me (3 7.47)-4- {[5-chloro-4-(5-fluoro-1,1dimethyl-2,3-dihydro-1Hpyrrolo [ 1,2-а]benzimidazol-7yl)pyrimidin-2-yl]amino } -1 (methanesulfonyl)piper idin-3 -ol 509.3 [M+H] ⁺ (ESI) Ή NMR (400 MHz, DMSO-Te) 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 (brd, 7=10.0Hz, 2H), 3.48 (brd, 7=11.7Hz, 1H), 3.08 (t, 7=7.5Hz, 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, 7= 11.7Hz, 1H) A10 NV ^CI 11 D _F ΗΝ Νγ V 11 \ , ^Ν N Me-L ^ o \u003d o \_ _o / Me (37.47) -4- ({5-chloro-4-[(45) -9- fluoro-4methyl-3,4-dihydro-1Н-[1,4]oxazino[4,3-а]benzimidazol-7yl]pyrimide in-2-yl} amino)-1(methanesulfonyl)piperidin-3-ol 511.2 [M+H] ⁺ (ESI) Ή NMR (400 MHz, DMSO-Tb) δ 8.44 (s, 1H), 7.89 (br s, 1H), 7.58-7.39 (m, 2H), 5.22 (d, 7=4.5 Hz, 1H), 5.09 -5.03 (m, 1H), 4.97-4.91 (m, 1H), 4.70 (br d, 7=5.5 Hz, 1H), 4.17-4.10 (m, 1H), 4.06-3.98 (m, 1H), 3.82 (br d, 7=5.8 Hz, 1H), 3.673.57 (m, 2H), 3.50-3.40 (m, 1H), 2.93-2.82 (m, 4H), 2.702.60 (m, 1H) , 2.11-2.00 (m, 1H), 1.60-1.45 (m, 4H) All N^' A Dx/^xF HN NJ y no^ L 11 \ N _L ) N-4 N 4-[(47)-9-fluoro-4-methyl-3,4-dihydro-III[1,4]oxazino[4,3-a]benzimidazol-7yl]pyrimidin-2-yl } amino)- 1 - 511.2 [M+H] ⁺ (ESI) Ή NMR (400 MHz, DMSO-Je) δ 8.44 (s, 1H), 7.82 (s, 1H), 7.59-7.44 (m, 2H), 5.23 (d, 7=4.8 Hz, 1H), 5.13- 5.07 (m, 1H), 5.02-4.96 (m, 1H), 4.42 (dd, 7=3.0, 12.0 Hz, 1H), 4.19 (ddd, 7=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),

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(methanesulfonyl)piper idin-3-ol 2.90 (s, 3H), 2.88-2.81 (t, 1H), 2.73-2.61 (m, 1H), 2.11-2.00 (m, 1H), 1.62-1.46 (m, 1H), 1.38 (d, 7=6 .3 Hz, ZN) All N^ ^CI H CU 11 \ , ^Ν to A Ν-X ^{0 Me} -<>one hydroxyethyl] -1 - (propan-2yl) - 1//-benzimidazol-6yl } pyrimide in-2-yl) amino] -2,3 - dideoxy-O-p / rstlpentitol 450.1 [M+H] ⁺ (ESI) Ή NMR (400 MHz, CD3OD) δ 8.37-8.31 (m, IH), 8.05 (s, IH), 7.50 (brd, 7=11.5 Hz, IH), 5.39-5.29 (m, IH), 5.23 ( q, 7=6.6 Hz, IH), 4.03-3.88 (m, 3H), 3.63 (dt, 7=4.8, 9.4 Hz, IH), 3.48 (dt, 7=2.0, 11 .6 Hz, IH), 3.21 (dd, 7=9.8, 11.0 Hz, IH), 2.19-2.09 (m, IH), 1.751.53 (m, 10H) A13 Ν^' A hn ν γ V II \ ,Ν k J Ν—C. ° ^Me H >yun Meme 1,5 -anhydro-3 - [(5 -chloro-4- {4-φτορ-2[(17?) -1 -hydroxyethyl] -1 - (propan-2yl) - 1 / / -benzimidazol-6-yl}pyrimide in-2-yl)amino]-2,3 dideoxy-О-/u/?eo-pentitol 450.3 [M+H] ⁺ (ESI) ^{1 H} NMR (400 MHz, DMSO-de) δ 8.43 (s, IH), 8.09-7.83 (m, IH), 7.59-7.32 (m, 2H), 5.79 (br d, 7=6.4 Hz, IH ), 5.20-5.15 (m, IH), 5.14-5.06 (m, IH), 4.96 (br d, 7=5.2 Hz, IH), 3.883.78 (m, 3H), 3.51 (br s, IH ), 3.10-2.98 (m, IH), 1.96 (br s, IH), 1.65-1.55 (m, YuN); one signal blocked by residual water A14 Ν^' A HN N VV HO _CH A X-A II \ N k J Ν—Ί o=s=o 0 Me ° -[4-fluoro-1 - 511.1 [M+H] ⁺ (ESI) Ή NMR (400 MHz, DMSO-Te) δ 8.44 (s, 2H), 7.98 (br s, IH), 7.64-7.36 (m, 2H), 5.36 (br s, IH), 5.22 (d, 7=4 .5 Hz, IH), 4.20-4.12 (m, IH), 4.07 (br d, 7=9.0 Hz, IH), 4.01-3.94 (m, IH), 3.88-3.78 (m, 2H), 3.67 -

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(oxolan-3 -yl )-1 R-benz and mide azol-6yl] pyrimide in-2-yl } amino)-1 (methanesulfonyl) piper idin-3 -ol 3.56 (m, 2H), 3.49 (s, 1H), 2.90 (s, 3H), 2.87-2.81 (m, 1H), 2.66 (brt, 7=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 HN N ]| but^ SD T 1 \ , ^N L ) N-^ N> O=S=OV Me (37?,47?)-4-{[5-chloro-4-(1-cyclopropyl-4-fluoro-\Hbenzimidazole -6-yl)pyrimidin-2yl]amino } -1 -(methanesulfonyl)piperidin-3-ol 481.2 [M+H] ⁺ (ESI) Ή NMR (4500 MHz, CD ₃ OD) δ 8.38 (s, 1H), 8.35 (s, 1H), 8.06 (s, 1H), 7.56 (dd, 7=1.0, 11.7 Hz, 1H), 3.98-3.92 (m, 1H), 3.85 (ddd, 7=1.8, 4.7, 11.7 Hz, 1H), 3.76 (dt, 7=4.9, 9.0 Hz, 1H), 3.72 -3.67 (m, 1H), 3.60 (m, 1H), 2.96 (dt, 7=2.7, 11.9 Hz, 1H), 2.90 (s, 3H), 2.77 (dd, 7=9.5, 11.6 Hz, 1H), 2.25 (br dd, 7=3.7, 13.4 Hz, 1H), 1.801.61 (m, 1H), 1.31-1.22 (m, 2H), 1.20-1.09 (m , 2H) A16 N^ ¹ ΗΝ^Ν^^γ ⁰ ' ^Η0 Ό Ν Me—/ O=S=O Me Me (3R,4R)-4-({ 5-chloro-4-[4-chloro-1 (propane-2 -yl)- 1H-benzimidazol-6yl] pyrimide in-2-yl } amino)-1 (methanesulfonyl) piper idin-3 -ol 521.1 [M+Na] ⁺ (ESI) Ή NMR (400 MHz, DMSO-ds) δ 8.58 (s, 1H), 8.44 (s, 1H), 8.04 (s, 1H), 7.67 (d, 7=1.1Hz, 1H), 7.55 (brs, 1H ), 5.23 (d, 7=4.5Hz, 1H), 4.83 (td, 7=6.7, 13.4Hz, 1H), 3.81 (brd, 7=5.6Hz, 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, 7= 6.7Hz, 7H)

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A17 zA Λ/Χ/F HN N Vy HO..zk II\N V °=s=° V/ Me *first eluting stereoisomer (3 A,4A)-4-{[4-(4-ethyl-9-fluoro-3,4dihydro-1H-[1,4]oxazino[4,3 a]benzimidazol-7-yl)-5 fluoropyrimide in-2-yl]amino } -1 (methanesulfonyl)piper idin-3 -ol 509.0 [M+H] ⁺ (ESI) Ή NMR (400 MHz, DMSO-Je) δ 8.45 (d, 7=4.0 Hz, 1H), 8.05 (s, 1H), 7.70 (d, 7=12.0 Hz, 1H), 7.24 (d, 7=7.8 Hz, 1H), 5.21 (d, 7=4.5 Hz, 1H), 5.135.02 (m, 1H), 4.99-4.89 (m, 1H), 4.54 (br s, 1H), 4.22 (d, 7=12.0 Hz, 1H), 4.04 (dd, 7=3.5, 12.3 Hz, 1H), 3.78 (br s, 1H), 3.67-3.55 (m, 2H), 3.553 .45 (m, 1H), 2.99-2.83 (m, 4H), 2.75-2.61 (m, 1H), 2.212.05 (m, 1H), 2.00-1.84 (m, 2H), 1.65-1.45 (m, 1H), 0.99 (t, 7=7.5 Hz, ZN); [a] _D ²⁰ =-66 (c=0.l, MeOH) A18 n^< ^f ΗΝ^Ν ^<ί γγ ^: γ ^|Ξ ne zk A-^A II ' / ^{N Me} >/ ^S _o =s=o fluoro-4-(9-fluoro-4,4-d imethyl-3,4-dihydro- 1H-[1,4]oxazino[4,3-a]benzimidazol-7yl)pyrimidin-2-yl]amino} - 1 (methanesulfonyl)piper idin-3-ol 509.1 [M+H] ⁺ (ESI) ^X H NMR (400 MHz, DMSO-Tb) 5 8.45 (d, 7=3.8 Hz, 1H), 8.18 (s, 1H), 7.68 (brd, 7=11.8 Hz, 1H), 7.26 (br d, 7=7.8 Hz, 1H), 5.23 (d, 7=4.5 Hz, 1H), 4.99 (s, 2H), 3.93 (s, 2H), 3.78 (br s, 1H), 3.69- 3.57 (m, 2H), 3.553.45 (m, 1H), 2.93-2.83 (m, 4H), 2.71-2.65 (m, 1H), 2.11 (br s, 1H), 1.65 (s, 6H), 1.561 .46(m, 1H) A19 THOSE. zF ΗΝ Ν^γ neu zk А, Λ 11 ' z ^N V ^Me >/ ^N S Me< _o ) 1,5-anhydro-2,3-dide ezoxy-3 - {[5 - 432.1 [M+H] ⁺ (ESI) Ή NMR (400 MHz, DMSO-Tb) 5 8.44 (d, 7=4.0 Hz, 1H), 8.21 (br s, 1H), 7.67 (d, 7=12.0 Hz, 1H), 7.23 (d , 7=7.8 Hz, 1H), 5.02-4.93 (m, 3H), 3.93 (s, 2H),

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fluoro-4-(9-fluoro-4,4-dimethyl-3,4dihydro- 1H-[1,4]oxazino[4,3 a]benzimidazol-7-yl)pyrimidin-2yl]amino } -Ώ-mpeo- pentitol 3.87-3.76 (m, ZH), 3.55-3.45 (m, 1H), 3.32 (br s, 1H), 3.06 (t, 7=10.4 Hz, 1H), 2.00 (br s, 1H), 1.65 ( d, 7=1.8 Hz, 6H), 1.561.44 (m, 1H) A20 £m ^C| .A- Ά X HN ^Ν Υγ no^A SD Ό Χ ^{Ν 0} Me–4 X .. \ /–Me * „ „ '-o *second eluting stereoisomer 1,5-anhydro-3 - {[5-chloro- 4-(9-Fluoro-1,4-dimethyl-3,4-dihydro- 1H[1,4]oxazino[4,3-а]benzimidazol-7yl)pyrimidin-2-yl]amino } -2,3 dideoxy -O-otreo-pentitol 447.8 [M+H] ⁺ (ESI) ^X H NMR (400 MHz, CDCh) δ 8.33 (s, 1H), 7.64 (d, 7=1.2 Hz, 1H), 7.47 (dd, 7=1.2, 11.2 Hz, 1H), 5.29 (br d, 7=5.9Hz, 1H), 4.99 (q, 7=6.6Hz, 1H), 4.48 (q, 7=6.8Hz, 1H), 4.12 (d, 7=1, 5Hz, 2H), 4.06 (dd, 7=5.0, 11.4Hz, 1H), 3.99 (brdd,7=4.3, 11.3Hz, 1H), 3.89-3.80 (m, 1H) , 3.63 (dt, 7=5.0, 9.4Hz, 1H), 3.46 (dt, 7=2.1, 11.8Hz, 1H), 3.18 (t, 7=10.7Hz, 1H) , 2.10-2.01 (m, 1H), 1.80 (d, 7=6.6 Hz, ZN), 1.77-1.67 (m, 1H), 1.64 (d, 7=6.6 Hz, ZN) A21 A ^F HN N VV n^A LA Ό ⁰ Me—4 X „ V /—Me dimethyl-3,4-dihydro- 1H[1,4]oxazino[4,3-a]benzimidazol-7yl)pyrimidin-2-yl]amino } -2,3 dideoxy-O-otreo-pentitol 447.8 [M+H] ⁺ (ESI) Ή NMR (400 MHz, CDCh) δ 8.33 (s, 1H), 7.62 (s, 1H), 7.47 (dd, 7=1.1, 11.2 Hz, 1H), 5.28 (br d, 7=5, 7 Hz, 1H), 5.06-4.72 (m, 2H), 4.48 (q, 7=6.6 Hz, 1H), 4.12 (d, 7=1.7 Hz, 2H), 4.06 (dd, 7=5 .0, 11.4 Hz, 1H), 3.99 (brdd, 7=4.3, 11.7 Hz, 1H), 3.90-3.80 (m, 1H), 3.63 (dt, 7=4.8, 9, 4 Hz, 1H), 3.513.42 (m, 1H), 3.18 (t, 7=10.6 Hz, 1H), 2.09-2.01 (m, 1H),

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1.81 (d, 7=6.6 Hz, ZN), 1.77- 1.69 (m, 1Н), 1.64 (d, 7=6.6 Hz, ZN) A22 τΎ ¹ HN N VV NO.. Λ. AA II \ .N A Ά A _N > Me -7-yl)pyrimidin-2yl]amino} -2,3-dide ezoxy-O-ot/?eopentitol 461.1 [M+H] ⁺ (ESI) Ή NMR (400 MHz, DMSO-Tb) δ 8.41 (s, 1H), 8.09-7.88 (m, 1H), 7.47 (br s, 2H), 4.94 (br d, 7=5.4 Hz, 1H), 3.86-3.71 (m, 5H), 3.50 (br s, 1H), 3.29-3.25 (m, 1H), 3.03 (brt, 7=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 N ^{^ 1} A HN n γ ^Η °Ό h O Me-^ Av ^Me -hydroxyethyl)-4fluoro-1 -(propan-2-yl)- 1Hbenzimidazol-6-yl]pyrimidin-2yl} amino)-2,3-dideoxy-О-ot/?eopentitol 490.0 [M+H] ⁺ (ESI) Ή NMR (400 MHz, DMSO-Je) δ 8.42 (s, 1H), 8.12-7.87 (m, 1H), 7.63-7.26 (m, 2H), 5.905.75 (m, 1H), 5.64 (s, 1H ), 4.98 (br d, 7=5.0 Hz, 1H), 3.94-3.76 (m, 3H), 3.58-3.48 (m, 1H), 3.32-3.27 (m, 1H), 3.03 (brt, 7= 10.5 Hz, 1H), 2.05-1.87 (m, 1H), 1.70-1.56 (m, 9H), 1.51 (brd, 7=13.1 Hz, 1H), 1.421.31 (m, 1H), 0.74 -0.61 (m, 1H), 0.55-0.34 (m, 3H); [a] _D ²² =-6 (c=0.l, MeOH) A24 N^' ΗΝ^Ν^ηΑΑ but. A. AA 11 \ ,Ν ) N-7 About Me—/ AME MeT^H *second eluting A stereoisomer 490.1 [M+H] ⁺ (ESI) Ή NMR (400 MHz, DMSO-Te) δ 8.42 (s, 1H), 8.13-7.81 (m, 1H), 7.62-7.15 (m, 2H), 5.905.75 (m, 1H), 5.64 (s, 1H ), 4.97 (br d, 7=5.0 Hz, 1H), 3.94-3.70

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1,5-anhydro-3-({5-chloro-4-[2-(1cyclopropyl-1-hydroxyethyl)-4fluoro-1 -(propan-2-yl)- 1Hbenzimidazol-6-yl]pyrimidin-2yl} amino )-2,3-dide ezoxy-D-mpeo- pentitol (m, ZH), 3.59-3.47 (m, 1H), 3.32-3.25 (m, 1H), 3.03 (brt, 7=10.3 Hz, 1H), 2.04-1.84 (br, 1H), 1.70-1.57 (m, 9H), ESS-IES (m, 1H), 1.42–1.31 (br, 1H), 0.74–0.63 (m, 1H), 0.590.30 (br, 3H); [a] _D ²² \u003d -22 (c \u003d 0.1, MeOH) A25 N ^ ^CI but ^ A LA T] 1, ^N Me-γ ^N ' । \ Me OSO Me Me (3^,47?)-4-({5-chloro-4-[7-fluoro-2methyl-3-(propan-2-yl)-2R-indazol-5yl] pyrimide in-2 -yl } amino)-1 (methanesulfonyl)-piperide in-3 -ol 496.9 [M+H] ⁺ (ESI) Ή NMR (400 MHz, DMSO-Tb) 5 8.40 (s, 1Н), 8.18 (br s, 1Н), 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), 3.553.45 (m, 1H), 2.89 (s, 3H), 2.87-2.80 (m, 1H), 2.66 (br t, 7=10 .5 Hz, 1H), 2.05 (br s, 1H), 1.60-1.40 (m, 1H), 1.46 (brd, 7=6.7 Hz, 6H) A26 N^ ¹ ii A _F HN Ν ]| V but^ ILA IJ Ύ- ^N > Г Me^/~N O=S=O ^Me o-/ Me (37?,47?)-4- {[5-chloro-4-(7-fluoro-1,1d imethyl-3,4-dihydro- 1H- [1,4]oxazino[4,3-/>]indazol-9yl)pyrimidin-2-yl]amino } -1 (methanesulfonyl)piperidin-3-ol 525.1 [M+H] ⁺ (ESI) Ή NMR (400 MHz, DMSO-Tb) δ 8.42 (s, 1H), 8.04 (br s, 1H), 7.68-7.24 (m, 2H), 5.22 (d, 7=4.5 Hz, 1H), 4.46 (t, 7=4.8 Hz, 2H), 4.22 (br t, 7=4.6 Hz, 2H), 3.93-3.72 (m, 1H), 3.60 (br d, 7=8.8 Hz, 2H ), 3.49(br d, 7=11.3 Hz, 1H), 2.90 (s, 3H), 2.88-2.80 (m, 1H), 2.74-2.55 (m, 2H), 2.07 (br d, 7=10 .8 Hz, 1H), 1.7O (s, 6H), 1.53 (brd, 7=10.0 Hz, 1H)

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A27 N^' AX/xz ^F HN ^N VV no ^. -dihydro- 1H[1,4]oxazino[4,3-d]indazol-9yl)pyrimidin-2-yl]amino } -2,3 dideoxy-O-l/rso-pentitol 448.0 [M+H] ⁺ (ESI) Ή NMR (500 MHz, DMSO-Te) δ 8.40 (s, 1H), 8.03 (br s, 1H), 7.57-7.34 (m, 2H), 4.94 (d, 7=5.3 Hz, 1H), 4.45 (t, 7=5.0Hz, 2H), 4.21 (t, 7=4.9Hz, 2H), 3.86-3.77 (m, 3H), 3.49 (br d, 7=4.1Hz, 1H) , 3.03 (t, 7=10.5 Hz, 1H), 1.94 (br s, 1H), 1.68 (s, 6H), 1.57-1.40 (m, 1H); one proton covered by a solvent peak A28 N^ ¹ A hn ν γη GA T J t, ^Ν Me— _Λ । \ Me 0-S-0 _Me Me (3R,4R)-4-( { 5 -chloro-4- [2-methyl-3 - (propan-2-yl) -2R-indazol-5yl] pyrimide in-2 -yl } amino)-1 (methanesulfonyl)piper idin-3 -ol 479.3 [M+H] ⁺ (ESI) Ή NMR (400 MHz, DMSO-Te) 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, 7= 4.3 Hz, 1H), 4.13 (s, 3H), 3.84-3.74 (m, 1H), 3.65-3.53 (m, 3H), 3.533.47 m, 1H), 2.89 (s, 3H), 2.872. 78 (m, 1H), 2.69-2.60 (m, 1H), 2.13-1.97 (m, 1H), 1.571.50 (m, 1H), 1.46 (d, 7=6.8 Hz, 6H) A29 NY ^CI А hn ν γη no^ A. GA T J 1 Ά~ ^Ν “» o=s=o no Me (37?,47?)-4-({ 5-chloro-4-[3 -(2- hydroxypropan-2-yl)-2-methyl-2Naindazol-5-yl]pyrimidin-2yl } amino)-1-(methanesulfonyl)piperidin-3-ol 495.3 [M+H] ⁺ (ESI) Ή NMR (400 MHz, DMSO-Je) δ 8.39 (s, 1H), 8.37-8.24 (m, 1H), 7.60 (br d, 7=7.0 Hz, 2H), 7.53-7.38 (m, 1H) , 5.76 (s, 1H), 5.22 (d, 7=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

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(m, 1H) AZO GT” F HN^N'^AAR ^ΗΟ ϊΊ % ^ν 0=S=0 ' _Me £7 Me ⁰ (3D47?)-4-({5-chloro-4-[4-fluoro-2(oxetane-3 - yl)-1-(propan-2-yl)-\Hbenzimidazol-6-yl]pyrimidin-2yl}amino)-1(methanesulfonyl)piperidin-3-ol 539.2 [M+H] ⁺ (APCI) Ή NMR (400 MHz, DMSO-de, VT 80°C) δ 8.39 (s, 1H), 7.95 (d, 7=1.0 Hz, 1H), 7.44 (dd, 7=0.9, 11.9 Hz, 1H), 7.18 (d, 7=7.7 Hz, 1H), 5.05-4.93 (m, 5H), 4.83-4.71 (m, 1H), 4.644.50 (m, 1H), 3.88-3.75 ( m, 1H), 3.72-3.60 (m, 1H), 3.593.46 (m, 1H), 3.20 (d, 7=4.6 Hz, 2H), 2.95-2.83 (m, 4H), 2.782.63 ( m, 1H), 2.12 (dd, 7=3.4, 13.4 Hz, 1H), 1.56 (d, 7=6.8 Hz, 6H) A31 HN N NO. A. II \ ν Me^H O=S=° _Me Me -1 - (propan-2-yl) - 1Hbenzimidazol-6-yl] pyrimidin-2yl} amino) -1 (methanesulfonyl) piper idin-3 -ol 538.9 [M+H] ⁺ (ESI) SH NMR (400 MHz, CD3OD) δ 8.36 (s, 1H), 8.09-7.96 (m, 1H), 7.56-7.47 (m, 1H), 6.19 (dd, 7=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 As- A HN N Η no. A. CJk II ' to L Ν-7 Ν Me^/ λ. O=S=O Me _ο %7 Me 539.1 [M+H] ⁺ (ESI) Ή NMR (400 MHz, CD3OD) δ 8.36 (s, 1H), 8.09-7.97 (m, 1H), 7.56-7.47 (m, 1H), 6.19 (dd, 7=7.0, 7.9 Hz, 1H ), 4.91-4.88 (m, 1H), 4.86-4.82 (m, 1H),

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*second eluting stereoisomer (37?,47?)-4-({5-chloro-4-[4-fluoro-2(oxetan-2-yl)-1-(propan-2-yl)-\Hbenzimidazol-6 -yl]pyrimidin-2yl}amino)-1- (methanesulfonyl)piper idin-3-ol 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, 7=1.0, 6.9 Hz , 7H) AZZ NV ^CI HN N yy 11 ' // ^N to E N -< O ^Me A y _N H ₂ Me o' 1,5-anhydro-3 -( { 4- [2-carbamoyl-4fluoro-1 - (propane-2 -yl)- 1Hbenzimidazol-6-yl]-5chloropyrimidin-2-yl } amino)-2,3 dideoxy-O-l/rheo-pentitol 449.1 [M+H] ⁺ (ESI) Ή NMR (500 MHz, DMSO-Tb) 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, 7=7, 0 Hz, 6H), 1.531.37 (m, 1H) A34 HO ^ AA II \, Ν kJ NX ^{0 Μθ} Ά } ^NH Me o Me 1,5 - anhydro-3 - ({5 - chloro-4- [4-fluoro-2 (methylcarbamoyl) -1 - (propane-2 -yl)1H-benzimidazol-6-yl]pyrimidin-2yl } am i no)-2,3-d id ezoxy-O-l/rheopentitol 463.2 [M+H] ⁺ (ESI) Ή NMR (400 MHz, CD ₃ OD) δ 8.36 (s, 1H), 8.15-8.04 (m, 1H), 7.54 (d, 7=11.5 Hz, 1H), 6.045.83 (m, 1H), 4.04-3.84 (m, 3H), 3.70-3.55 (m, 1H), 3.523.42 (m, 1H), 3.25-3.15 (m, 1H), 2.97 (s, 3H), 2.17-2.06 (m, 1H ), 1.70 (d, 7=6.8 Hz, 6H), 1.67-1.57 (m, 1H) A35 ΗΝ Ν γΥ HO^A. AA A *first eluted ^Me Me Me stereoisomer 464.1 [M+H] ⁺ (ESI) Ή NMR (400 MHz, DMSO-Tb) δ 8.44 (s, 1H), 8.05-7.87 (m, 1H), 7.53-7.27 (m, 1H), 7.066.90 (m, 1H), 5.98-5.66 (m , 2H), 5.06-4.75 (m, 1H), 4.06-

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1,5-anhydro-3-({5-chloro-4-[4-fluoro-2(2-hydroxypropan-2-yl)-1-(propan2-yl)- 1H-benzimidazol-6yl]pyrimidin-2- yl } amino)-2,3 dideoxy-e/?shi/?o-pentitol 3.94 (m, 1H), 3.87-3.68 (br, 3H), 3.48-3.38 (m, 2H), 2.01-1.83 (m, 1H), 1.66 (s, 6H), 1.63-1.55 (m, 7H); [a] _D ²⁰ \u003d -41.9 (c \u003d 0.14, MeOH) A36 HN N Vy HO^ ΌCQ ° / (* y—on Me me * second eluted 1 stereoisomer 1,5-anhydro-3-({5-chloro-4-[1-(1,1d iftoropropan-2-yl)-4-fluoro-2-( 1 hydroxyethyl)-1H-benzimidazol-6yl]pyrimidin-2 -yl } amino)-2,3 dideoxy-O-l/rstApentitol 485.9 [M+H] ⁺ (ESI) Ή NMR (700 MHz, DMSO-Je) 5 8.42 (s, 1H), 8.13-7.73 (m, 1H), 7.60-7.27 (m, 2H), 6.636.40 (m, 1H), 6.00-5.82 (m , 1H), 5.55-5.41 (m, 1H), 5.225.13 (m, 1H), 5.01-4.85 (m, 1H), 3.91-3.74 (m, 3H), 3.533.45 (m, 1H), 3.07 -2.97 (m, 1H), 2.04-1.85 (m, 1H), 1.68 (d, 7=7.1 Hz, VN), 1.62 (d, 7=6.7 Hz, VN), 1.55-1.42 (m , 1H); [α]π ²² = -37.3 (c=0,l,MeOH)

Example A37 (Scheme A-2): Preparation of (3R,4R)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1Hbenzimidazol-6-yl ]pyrimidin-2-yl}amino)piperidin-3-ol.

Scheme A-2.

A-3 Example A3 7

A solution of tert-butyl-(3R,4R)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6yl]pyrimidin-2- yl}amino)-3-hydroxypiperidine-1-carboxylate (A-3) (prepared as shown 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 hour. The mixture was concentrated and the crude residue was taken up in DCM (10 ml). The pH was adjusted to about 7-8 with NH ₄ OH. The product was extracted with water (20 ml). The aqueous phase was washed with DCM (3x15 ml). A white solid formed in the aqueous layer which was collected by filtration to give (3R,4R)-4-({5-fluoro-4-[4fluoro-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. 1H 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, 3Н), 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-methyl1H-benzimidazol-6 -yl}-5-chloropyrimidin-2-yl)amino]-1-(methanesulfonyl)piperidin-3-ol.

Scheme A-3.

Me BocHN Me H ₂ N

A-4 Example A38

To a solution of tert-butyl-{(2R)-2-[6-(5-chloro-2-{[(3R,4R)-3-hydroxy-1-(methanesulfonyl)piperidin-4yl]amino}pyrimidin-4- yl)-4-fluoro-2-methyl-1H-benzimidazol-1-yl]propyl}carbamate (A-4) (prepared as shown in Example A1, 130 mg; 0.212 mmol) in MeOH (2.5 ml) HCl solution (4.0 M in 1,4-dioxane; 2.5 ml) was added dropwise at 0°C. After the addition, the reaction solution was stirred at com

- 86 042105 room temperature for 2 hours. LCMS analysis showed the consumption of the starting material with the formation of the desired mass of the product. The reaction mixture was concentrated to dryness. The residue was purified by preparative HPLC on a DuraShell column (150x25 mm, particle size 5 µm) which was eluted with 7-37% MeCN/H2O (plus 0.05% HCl) at a flow rate of 30 ml/min to give (3R,4R) -4-[(4-{1-[(2R)-1-α-minopropan-2-yl]-4-fluoro-2-methyl-III-benzimidazol-6-yl}-5-chloropyrimidin2-yl)amino]- 1-(methanesulfonyl)piperidin-3-ol (Example A38) (39.5 mg; 34% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-de) δ 8.39 (s, 1H), 8.06-7.97 (m, 1H), 7.67-7.52 (m, 1H), 5.064.79 (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), 2.822.77 (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 (C21H27ClFN ₇ O3S) 512.2 (M+H)+.

The examples in the table below were synthesized using the methods used to synthesize (3R,4R)-4-({5-chloro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol- 6-yl]pyrimidin-2-yl}αmino)-1(methanesulfonyl)-piperidin-3-ol (Example A37) (Scheme A-2) and (3R,4R)-4-[(4-{1-[ (2R)-1-aminopropan-2yl]-4-fluoro-2-methyl-1H-benzimidazol-6-yl}-5-chloropyrimidin-2-yl)amino]-1(methanesulfonyl)piperidin-3-ol (example A38) (diagram A-3). The following examples have been synthesized with minor changes or substitutions in the exemplary methods that can be carried out by a person skilled in the art. 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 LCMS NMR A39 Ny ^C ' but^ .A 11 \ N LJ nA N Me ">./ \ _l ~ ϊ _Λ \ Me O=S=O ) Me H ₂ N (ZD,4R)-4-[(4-{1- [(25)-1-aminopropan-2-yl]-4-fluoro-2methyl-1H-benzimidazol-6-yl}-5chloropyrimidin-2-yl)amino]-1(methanesulfonyl)piperide in-3-ol 534.2 [M+Na] ⁺ (ESI) ^1H NMR (400 MHz, DMSO-Tb) 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), 3.673.56 (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)

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A40 m^Ch^ ⁰¹ HO _V >\chL\ II \ ,Ν L) ν-4 Ν / ι \ Me o=s=o A. „„ ι ,, ,,ζ-Me Me Η ₂ Ν (3^3 ^)-4-({4-[1-(2-aminopropyl)-4-fluoro-2-methyl-\Ηbenzimidazol-6-yl]-5chloropyrimidin-2-yl}amino)-1(methanesulfonyl)piperidine-3 -ol 512.2 [M+H] ⁺ (ESI) Ή NMR (400 MHz, DMSO-J6) 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), 3.513.42 (m, 1H), 2.85 (s, 3H), 2.822.73 (m, 1H), 2.67-2.57 (m, 4H), 2.10-1.95 (m, 1H), 1.59-1.45 (m, 1H), 1.24 (d, ./=6.5 Hz, ZN) A41 ΗΝ^Ν ^< ηί ^ζ ^4' ^Ι= but. A. VsA 11 \ N LJ N-4 O Me—-/ u-Me Me _M ? ^NH 2 3-({4-[2-(2-Aminopropan-2-yl)-4-fluoro-1-(propan-2-yl)- 1Yabenzimidazol-6-yl]-5chloropyrimid in-2-yl} amino )-1,5anhydro-2,3-dideoxy-О-ot/?eopentitol 463.4 [M+H] ⁺ (ESI) ^1H NMR (500 MHz, DMSO-Je) 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), 3.323.30 (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), 1.531.40 (m, 1H) A42 N^ ¹ HN^N*yV ^F BUT. ^{0 Me} Meme 3-[(4-{2-[(17?)-1-aminoethyl]-1/lre/l-butyl-4-fluoro-\Nbenzimid azol-6-yl } -5chloropyrimidin-2-yl) amino]-1,5-anhydro-2,3-dideoxy-O-threopentitol 463.4 [M+H] ⁺ (ESI) Ή 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), 3.653.57 (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, ./=6.6 Hz, ZN)

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A43 N^ ¹ HO _K A Il \ , ^N LA n-4 ^{0 Me} H >NH ₂ Me Al 3-({4-[2-(1-aminocyclopropyl)-4fluoro-1 -(propan-2-yl)-1Hbenzimidazole -6-yl]-5chloropyrimide in-2-yl } amino)-1,5anhydro-2,3-dideoxy-D-mpeo- pentitol 461.3 [M+H] ⁺ (ESI) Ή NMR (400 MHz, DMSO-de) 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), 3.092.96 (m, 1H), 2.63-2.54 (m, 1H), 2.06-1.86 (m, 1H), 1.62 (d, ./=7.0 Hz, 6H), 1.56-1.41 (m, 1H), 1.211.13 (m, 2H), 1.03-0.94 (m, 2H) A44 NV ^CI HN N Vy II \,Ν k A N-D Ο Me-y ~V _NH Me me 1,5 -anhydro-3 - [(5 -chloro-4- {4-φτορ- 2- [(methylamino) methyl] -1 (propan-2-yl) - 1H-benzimidazol6-yl } pyrimidin-2-yl) amino] -2,3 dideoxyO-otreo-pentitol 448.9 [M+H] ⁺ (ESI) Ή NMR (400 MHz, DMSO-de) 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, ./=7.0 Hz, 6H), 1.53-1.40 (m, 1H) A45 N^Y ^CI xk HN N Yy ΗΟ^χΑ II \ // ^Ν / ^Ν -\ Me ο Μ _θ γ νγ _ΝΗ2 Me Me 3-({4-[2-(2-amino-2-methylpropyl)-4-fluoro- 1-(propan2-yl)-1H-benzimidazol-6-yl]-5chloropyrimide in-2-yl} amino)-1,5anhydro-2,3-d ideoxy-O-ot/(O-pentitol) 477.1 [M+H] ⁺ (ESI) Ή NMR (400 MHz, CD ₃ OD) δ 8.57 (s, 1H), 8.30 (s, 1H), 7.797.70 (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), 1.821.71 (m, 7H), 1.57 (s, 6H)

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A46 pd HN N kA ] | \ , ^{N Me} CL MeA / '~~NH -7-yl)pyrimidin2-yl]amino}-2,3-dide ezoxy-Dot/?eo-pentitol 447.1 [M+H] ⁺ (ESI) Ή NMR (400 MHz, DMSO7 ₆ +D ₂ O) δ 8.38 (s, 1H), 7.96 (br s, 1H), 7.39 (br d, 7=7.8 Hz, 2H), 4.95 (d, 7= 5.3 Hz, 1H), 4.03 (s, 2H), 3.81 (br dd, 7=5.3, 10.8 Hz, ZN), 3.49(br s, 1H), 3.30 (brt, 7=11, 2 Hz, 1H), 3.07-2.94 (m, 3H), 1.94 (br s, 1H), 1.60 (s, 6H), 1.49 (brd, 7=9.5 Hz, 1H) A47 N^W D ΗΝ Ν ]| ηΓ but _k L kW ] ] \ / Ν k J Ν-Κ N Me—/ \ _klLJ । \ *>—nh ₂ 0-S-0 -\Nbenzimidazol-6-yl]-5chloropyrimidin-2-yl } amino)-1 (methanesulfonyl)piperide in-3-ol 526.3 [M+H] ⁺ (ESI) ¹ H NMR (400 MHz, DMSO-Tb) δ 8.43 (s, 1H), 7.92 (br s, 1H), 7.577.31 (m, 2H), 5.23 (d, 7=4.5 Hz, 1H), 5.15 (td, 7=6.9, 14.0 Hz, 1H), 4.35 (q, 7=6.5 Hz, 1H), 3.873.75 (m, 1H), 3.61 (br d, 7=8, 5 Hz, 2H), 3.50 (br d, 7=12.3 Hz, 1H), 2.93-2.82 (m, 4H), 2.66 (br t, 7=11.0 Hz, 1H), 2.20-2.04 (m , 3H), 1.67-1.42 (m, 10H); [a] _D ²⁰ = -13.3 (c=0.l, MeOH) A48 Ν-γ ⁰¹ 11 '// ^Ν to J Ν—Ch Ν Me-Λ o=s=o mW ² Me )-4fluoro-1 -(propan-2-yl)- 1Hbenzimidazol-6-yl]-5chloropyrimidin-2-yl } amino)-1 (methanesulfonyl)piperide in-3-ol 526.3 [M+H] ⁺ (ESI) ^X H NMR (400 MHz, DMSO-Tb) δ 8.43 (s, 1H), 8.05-7.87 (m, 1H), 7.59-7.30 (m, 2H), 5.23 (d, 7=4.5 Hz, 1H) , 5.15 (quin, 7=6.9 Hz, 1H), 4.35 (q, 7=6.5 Hz, 1H), 3.81 (br d, 7=5.8 Hz, 1H), 3.61 (br d, 7 =9.3 Hz, 2H), 3.49 (br d, 7=12.3 Hz, 1H), 2.90 (s, 3H), 2.88-2.79 (m, 1H), 2.70-2.61 (m, 1H), 2.16 (brs, 3H), 1.63-1.47 (m, 10H); [a] _D ²⁰ \u003d -18,l (c \u003d 0,l, MeOH)

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A49 Ny ^{CI ΗΟ} "Α \ ILA, Τ1 X ” ΤΓ Mey ^N ' .. -A ^{Me Me} nh ₂ 3- ({4- [3- (2-aminopropan-2-yl) -7fluoro-2-methyl-2R- indazol-5-yl]5-chloropyrimidin-2-yl } amino)1,5-anhydro-2,3-dideoxy-Оot/?eo-pentitol 435.0 [M+H] ⁺ (ESI) Ή NMR (500 MHz, DMSO-Tb) δ 8.53-8.26 (m, 2H), 7.61-7.28 (m, 2H), 4.99-4.88 (m, 1H), 4.49 (s, 3.86-3.75 (m, 1H), 3.53-3.43 (m, 1H), 3.07-2.99 (m, 1H), 2.031.89 (m, 1H), 1.72 (s, 6H), 1.571.41 ( m, 1H) A50 La and Άήι ⁰ benzimidazol-6yl } pyrimide in-2yl)amino]piperidin-3-ol 448.9 [M+H] ⁺ (ESI) Ή NMR (400 MHz, DMSO-Tb, 80°C) δ 8.87 (br. s, 1H), 8.64 (br. s, 1H), 8.43 (s, 1H), 7.99 (d, 7=1.3 Hz , 1H), 7.51-7.38 (m, 2H), 5.24 (hept, 7=7.6, 7.1 Hz, 1H), 5.13 (q, 7=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 covered by a solvent peak A51 ΧΎ ⁰¹ .F HN N fY HO^ || \ N <7 Me N—7 Me-Ύ ^ΝΗ ₂ 3 -( { 4- [ 1 - (1-amino-2-methylpropan2-yl) -4-fluoro-1 /7-benzimidazol-bil] -5 - x lor p ir imid and n-2yl } amino)-1,5-anhydro-2,3 dideoxy-O-ot/dtApentitol 435.0 [M+H] ⁺ (ESI) Ή NMR (500 MHz, DMSO-Te) δ 8.35 (s, 1H), 8.31 (s, 1H), 8.077.92 (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)

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A52 7% Jk A HN N at no. ,ν AA II \ , ^Ν to > Me ND Me'X Me ^NHz 3 - ( { 4- [ 1 - (1-amino-2-methylpropan2-yl)-4-fluoro-2-methyl- 1Hbenzimidazol-6- yl]-5chloropyrimide in-2-yl } amino)-1,5anhydro-2,3-dideoxy-D-mpeopentitol 448.9 [M+H] ⁺ (ESI) Ή NMR (400 MHz, D ₂ O) δ 8.508.33 (m, 1H), 8.24-8.13 (m, 1H), 7.78-7.64 (m, 1H), 4.03-3.89 (br, 3H), 3.87-3.80 (m, 2H), 3.74-3.62 (br, 1H), 3.59-3.44 (m, 1H), 3.303.20 (m, 1H), 3.15-2.97 (br, 3H), 2.12-1.97 (m, 7H) , 1.77-1.55 (w, 1H) A53 PG xk Jk F HN Ν ΗΟ..Λ AA 11 ' // ^N to JN-4 O Me-~y _NH2 Me Me 3 - [(4- { 2-[( 15)-1 -aminoethyl] -4fluoro-1 -(propan-2-yl)- 1Hbenzimid azol-6-yl } -5chloropyrimidin-2-yl)amino] -1,5 anhydro-2,3 -d ideoxy-D-mpmpentitol 448.9 [M+H] ⁺ (ESI) ^1H NMR (600 MHz, DMSO-Tb) 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), 3.593.48 (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 NV ^CI HN N VV HO ^k AA II ' // ^Ν to J O Me ^ ^V _NHz Me 3 -( { 4-[2-(aminomethyl)-4-fluoro-1 (propan-2-yl)- 1H-benzimidazol6-yl]-5-chloropyrimidin-2yl } amino)-1,5-anhydro-2,3 dideoxy-O-otreo-pentitol 435.1 [M+H] ⁺ (ESI) ^X H NMR (400 MHz, DMSO-Te) at 80°C δ 8.40 (s, 1H), 8.107.98 (m, 1H), 7.48 (br d, 7=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)

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A55 xk 7k ^F HN Ν γ but^^A DD II\N to J n-4 about Me—Z . ^NH *first eluting stereoisomer 1,5-anhydro-3 - {[5-chloro-4-(9-fluoro- 4-methyl-1,2,3,4- tetrahydropyrazino[1,2- a] benzimide azol-7-yl) pyrimidine- 2-yl]amino}-2,3-dide ezoxy-D- from/?eo-pentitol 433.1 [M+H] ⁺ (ESI) Ή NMR (400 MHz, DMSO-Tb) δ 8.42 (s, 1H), 7.83 (br s, 1H), 7.587.31 (m, 2H), 4.95 (d, 7=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, 7=5.3 Hz, 2H), 3.30-3.24 (m, 1H), 3.12 -2.99 (m, 2H), 1.95 (brd, 7=12.0 Hz, 1H), 1.50 (d, 7=6.5 Hz, 4H); [a] _D ²⁰ =27.7 (c=0.13, MeOH) A56 /k 7k ^F HN N YY NSH /k DD II \ ,Ν Oh Me—Ζ D * „ „ '—NH *second eluting stereoisomer 1,5 -anhydro-3 - {[5 -chloro-4-(9-fluoro4-methyl-1,2,3,4tetrahydropyrazino[1,2а]benzimid azol-7-yl)pyrimidin2-yl]amino} -2 ,3-did ezoxy-Dot/?eo-pentitol 433.2 [M+H] ⁺ (ESI) Ή NMR (400 MHz, DMSO-Te) δ 8.47-8.34 (m, 1H), 7.82 (br s, 1H), 7.62-7.32 (m, 2H), 4.94 (d, 7=5.3 Hz, 1H) , 4.57 (br s, 1H), 4.17-4.00 (m, 2H), 3.82 (br dd, 7=4.9, 10.7 Hz, ZN), 3.50 (br s, 2H), 3.29-3.21 (m , 1H), 3.09–2.97 (m, 2H), 1.97 (br s, 1H), 1.581.41 (m, 4H); [a] _D ²⁰ =48.2 (c=0.13, MeOH) A57 N^ ¹ ΗΝ^Ν^ηΗ^ ¹³ n A. D D | | Tn F to J N-7 )—F O Me-γ *second eluted ^Me NH ₂ stereoisomer )-1H-benzimidazol-6-yl]-5- 499.4 [M+H] ⁺ (ESI) Ή NMR (400 MHz, DMSO-Te) 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), 3.223.11 (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)

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chlorine pyrimide in-2-yl } amino)-1,5anhydro-2,3-d ideoxy-O-p/rtpentitol A58 Τι ' // ^Ν \ k Y Ν - k ) - F O Me - / \ / * first Me * nh ₂ eluted stereoisomer 3- ({4- [2- (2-amino-3,3 difluoropropyl) -4-fluoro -1-(propan2-yl)-1H-benzimidazol-6-yl]-5chlor pyrimide in-2-yl} amino)-1,5anhydro-2,3-dideoxy-O-ot/?eopentitol 499.0 [M+H] ⁺ (ESI) Ή NMR (400 MHz, DMSO-de) δ 8.42 (s, 1H), 7.98 (br s, 1H), 7.567.17 (m, 2H), 6.21 (td, 7=55.6, 3.2 Hz, 1H), 4.91 (dq, 7=20.7, 6.9, 6.1 Hz, 2H), 3.98-3.69 (m, 4H), 3.51 (s, 1H), 3.30-3.26 (m, 1H), 3.212.89 (m, 2H), 1.97 (br s, 1H), 1.60 (dd, 7=6.9, 3.5 Hz, 6H), 1.57-1.45 (m, 1H) A59 N^ ^CI nTTT HO^ A. to 11 ' // ^N to 0 N-to GL O Me-\ 1 > ^Me h ₂ n 3-[(4-{2-[(1-aminocyclopentyl)methyl] -4 -fluoro-1-(propan-2-yl)1H-benzimidazol-6-yl}-5chloropyrimidin-2-yl)amino]-1,5anhydro-2,3-dideoxy-O-ot/?eopentitol 503.1 [M+H] ⁺ (ESI) ^1H NMR (400 MHz, CD ₃ OD) δ 8.34 (s, 1H), 8.05 (s, 1H), 7.49 (d, 7=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), 1.921.78 (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)-1hydroxyethyl]-1H-benzimidazol-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]-4fluoro-III-benzimidazole -6-yl}-5-chloropyrimidin-2-yl)amino]-2,3-dideoxy-P-threo-pentitol (A-5) (prepared as shown in Example A1; 70.0 mg; 0.121 mmol) in MeOH (1.0 ml) was added dropwise HCl (4.0 N. in 1,4-dioxane; 3.0 ml) 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 NH4OH to a pH of about 9 and then concentrated to dryness. The residue was purified by preparative HPLC on a Boston Uni C-18 column (40x150 mm, particle size 5 µm) which was eluted with 13-53% MeCN/H ₂ O (plus 0.05% HCl) at a flow rate of 60 ml/min. The material was repurified by preparative HPLC on a DuraShell column (150x25 mm, particle size 5 µm) which was eluted with 27-47% MeCN/H ₂ O (plus 0.05% NH4OH) at a flow rate of 25 ml/min to give 1. 5-anhydro-3-[(4-{1tert-butyl-4-fluoro-2-[(1R)-1-hydroxyethyl]-1H-benzimidazol-6-yl}-5-chloropyrimidin-2-yl)amino] -2,3dideoxy-P-threo-pentitol (Example A60) (4.2 mg; 8% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) 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 d, J=1.2 Hz, 1H), 3.03 (br t , 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 covered by a 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 using the methods used to synthesize 1,5-anhydro-3-[(4-{1-tert-butyl-4-fluoro-2-[(1R)-1-hydroxyethyl]-1H-benzimidazole- 6-yl} -5-94 042105 chloropyrimidin-2-yl)amino]-2,3-dideoxy-D-threo-pentitol (Example A60) (Scheme A-4). The following examples have been synthesized with minor changes or substitutions in the exemplary methods that can be carried out by a person skilled in the art.

Example number Structure/Name LCMS NMR A61 ΗΝ Ν ]| BUT^A. 11 \ , ^Ν to D Ν - to O me-^ -y _he ^Me Me me 1,5 -anhydro-3 - [(4- {1 -mpem-butyl4-fluoro-2- [(15) -1-hydroxyethyl ]1//-benzimidazol-6-yl}-5-chloropyrimidin-2-yl)amino]-2,3 dideoxy-O-otreo-pentitol 464.1 [M+H] ⁺ (ESI) Ή NMR (400 MHz, CD3OD) δ 8.34 (s, 1H), 8.19 (s, 1H), 7.48 (d, 7=11.3 Hz, 1H), 5.46 (q, 7=6.4 Hz, 1H) , 4.02-3.87 (m, 3H), 3.66-3.57 (m, 1H), 3.48 (td, 7=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, 7=6.4 Hz, ZN), 1.70-1.57 (m, 1H) A62 Ny ^CI HO _K A CA 11 \ ,N LJ n—C O=S=O Me _Μ ζ Me (37?,47?)-4-[(4-{ 1-tert-butyl-4fluoro-2-[( 17?)-1-hydroxyethyl]-\Hbenzimidazol-6-yl}-5chloropyrimidin-2-yl)amino]-1(methanesulfonyl)piperidin-3-ol 541.0 [M+H] ⁺ (ESI) Ή NMR (400 MHz, DMSO-Tb) δ 8.42 (s, 1H), 8.26-7.97 (m, 1H), 7.44 (d, 7=53.2 Hz, 2H), 5.53 (d, 7=7.8 Hz, 1H), 5.29-5.21 (m, 2H), 3.80 (s, 1H), 3.60 (d, 2H), 3.48 (d, 7=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, 7=6.2 Hz, ZN), 1.53 (d, 7=12.2 Hz , 1H) A63 but _h A II ' // ^N ° ^m~^ ^he 1,5 -anhydro-3 - ({5 -chloro-4- [4-fluoro- 2- (hydroxymethyl) -1 - (1 - methylcyclopropyl) -\ Nbenzimidazol-6-yl]pyrimidin-2yl } amino)-2,3-dideoxy-D- 447.9 [M+H] ⁺ (ESI) Ή NMR (400 MHz, CD3OD) δ 8.58 (s, 1H), 8.35 (d, 7=1.1 Hz, 1H), 7.97 (d, 7=11.0 Hz, 1H), 5.29 (s, 2H) , 4.07-3.92 (m, 3H), 3.67 (td, 7=9.6, 4.9 Hz, 1H), 3.54-3.44 (m, 1H), 3.28-3.19 (m, 1H), 2.162.08 ( m, 1H), 1.82-1.70 (m, 4H), 1.49 (s, 2H), 1.36 (s, 2H)

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threo-pentitol A64 -CI D. .F HN Ν VY but ^.A kYk ΤΙ \ ,Ν k J n-d ° ( 'Aoi Me ^p ⁶ 1,5 -anhydro-3 -({5 -chloro-4- [4- fluoro1-(2-fluoro-2-methylpropyl)-2(hydroxymethyl)-1Hbenzimidazol-6-yl]pyrimidin-2yl} amino)-2,3-dideoxy-Dothreo-pentitol 468.2 [M+H] ⁺ (ESI) ¹ H NMR (600 MHz, DMSO-Tb) δ 8.42 (s, IH), 7.91 (br s, IH), 7.42 (br s, 2H), 5.72 (t, 7=6.0 Hz, IH), 4.91 (dd, 7=5.4, 1.3 Hz, IH), 4.79 (d, 7=6.0 Hz, 2H), 4.63 (d, 7=22.6 Hz, 2H), 3.82 (qt, 7 =10.8, 6.4 Hz, ZN), 3.56-3.47 (m, IH), 3.04 (t, 7=10.4 Hz, IH), 1.98 (br s, IH), 1.50 (qd, 7= 12.0, 4.5Hz, 2H), 1.39(s, 3H), 1.35(s, 3H) A65 jOZ _F no^ A. ΊΟ Η ο4=ο εΤ ^ ^οη Me (37?,47?)-4-({5-chloro-4-[1-cyclobutyl-4-fluoro-2(hydroxymethyl)-Sbenzimidazol-6-yl ]pyrimidin-2yl } amino)-1-(methanesulfonyl)piperide in-3-ol 524.9 [M+H] ⁺ (ESI) Ή NMR (400 MHz, DMSO-Tb) δ 8.47 (s, IH), 8.18 (br s, IH), 7.61 (br s, 2H), 5.25 (td, 7=8.9, 17.6 Hz, IH ), 4.87 (s, 2H), 3.81 (br s, IH), 3.61 (br d, 7=10.3 Hz, 2H), 3.49 (br d, 7=12.1 Hz, IH), 2.90 (s , 3H), 2.85 (br t, 7=9.8 Hz, ZN), 2.71-2.54 (m, ZN), 2.13-1.84 (m, ZN), 1.55 (br s, IH) A66 HN N γ y no^A. 11 \ ν ⁰ _F And ^he F 2- 483.9 [M+H] ⁺ (ESI) Ή NMR (400 MHz, DMSO-Te) δ 8.46 (s, IH), 7.99 (br s, IH), 7.777.37 (m, 2H), 5.30 (br d, 7=3.7 Hz, IH), 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, 7=10.4 Hz, IH), 2.16- 1.86 (m, IH), 1.61-1.39 (m, IH) yl } amino)-2,3-dideoxy-Dotreo-pentitol

Example A67 (Scheme A-5): Preparation of 1,5-anhydro-3-({5-chloro-4-[1-(2,2-difluoroethyl)-4-fluoro-2-(2hydroxypropan-2-yl) -1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threopentitol.

Scheme A-5.

To a yellow solution of 1,5-anhydro-3-({5-chloro-4-[1-(2,2-difluoroethyl)-4-fluoro-2-(2-hydroxypropan-2yl)-1H-benzimidazole-6- yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol (A-6) (prepared as shown in Example A1; 200 mg; 0.33 mmol) in THF (10.0 ml) TBAF (174 mg; 0.67 mmol) was added at room temperature. The mixture was stirred for 2 hours, after which LCMS analysis showed complete consumption of the starting material with the formation of the desired mass of product. The reaction mixture was concentrated. The residue was taken up in EtOAc (50 ml), washed with H2O (2x50 ml) and brine (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative HPLC on

- 96 042105 DuraShell column (150x25 mm, particle size 5 µm) which was eluted with 26-46% MeCN/H2O (plus 0.05% NH ₄ OH) at a flow rate of 25 ml/min to give 1,5-anhydro- 3-({5-chloro-4-[1-(2,2difluoroethyl)-4-fluoro-2-(2-hydroxypropan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino )-2,3dideoxy-P-threo-pentitol (Example A67) (34.2 mg; 21% yield) as a white solid. 1H 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=5.4 Hz, 1H), 3.88-3.74 (m, 3H) , 3.55-3.46 (m, 1H), 3.03 (t, J=10.4 Hz, 1H), 2.04-1.83 (m, 1H), 1.68 (d, J=1.8 Hz, 6H), 1.56-1.42 (m, 1H); one proton covered by a 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 by the methods used to synthesize 1,5-anhydro-3-({5-chloro-4-[1-(2,2-difluoroethyl)-4-fluoro-2-(2-hydroxypropan-2-yl )-1H-benzimidazol-6yl]pyrimidin-2-yl}amino)-2,3-dideoxy-P-threo-pentitol (Example A67) (Scheme A-5). The following example was synthesized with minor changes or substitutions in the exemplary methods that can be carried out by a person skilled in the art.

Example number Structure/Name LCMS NMR A68 A ΗΝ Ν at γ neA. kA 11 \ N k P NK 0 Me-y \ _he Me MeMe 1,5-anhydro-2,3-d id ezoxy-3 ({5-fluoro-4-[4-fluoro-2-(2hydroxypropane-2- yl)-1 (propan-2-yl)-\Nbenzimidazol-6-yl] pyrimide in-2-yl } amino) O-p / rheo-pentitol 448.2 [M+H] ⁺ (ESI) Ή NMR (400 MHz, DMSO-Tb) 5 8.43 (d, 7=4.0 Hz, 1H), 8.21 (s, 1H), 7.62 (d, 7=12.1 Hz, 1H), 7.19 (d, 7=7.6 Hz, 1H), 5.92-5.70 (m, 2H), 4.96 (s, 1H), 3.91-3.73 (t, ZN), 3.62-3.46 (t, 1H), 3.13-2.99 (t, 1H), 2.14-1.96 (t, 1H), 1.67 (s, 6H), 1.65-1.44 (t, 7H); one proton covered by a solvent peak

Example A69 (Scheme A-6): Preparation of (3R,4R)-4-({5-chloro-4-[2-(difluoromethyl)-4-fluoro-1-(propan-2yl)-1H-benzimidazole-6 -yl]pyrimidin-2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol.

Scheme A-6.

Example A69

To a solution of 6-(2,5-dichloropyrimidin-4-yl)-2-(difluoromethyl)-1-(propan-2-yl)-1H-benzimidazole (A7) (prepared as shown in Example A1; 49.6 mg; 0.132 mmol) in THF (1.32 ml) was added (3R,4R)-4amino-1-(methanesulfonyl)piperidin-3-ol (Int-69) (38.5 mg; 0.198 mmol), CS2CO3 (129 mg; 0.397 mmol), Pd(OAc) ₂ (6 mg; 0.0264 mmol) and rac-BINAP (17 mg; 0.0264 mmol). The mixture was sparged with N2 for 10 minutes and then stirred for 105 minutes at 80° C. under microwave radiation. LCMS analysis showed complete consumption of the starting material with the formation of the desired mass of product. The reaction mixture was diluted with MeOH and then filtered through a filter disc (0.2 μm). The material was purified by preparative SFC on a 3-hydroxyphenyl-coupled Nacalai Cosmosil column (150x20 mm) which was eluted with 12-23% MeOH/CO ₂ at a flow rate of 85 ml/min to give (3R,4R)-4-({5 -chloro-4-[2-(difluoromethyl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2yl}amino)-1-(methanesulfonyl)piperidine-3- ol (Example A69) (33.1 mg; 47% yield) as a solid. 1H NMR (400 MHz, DMSO-d6, 80°C) δ=8.43 (s, 1H), 8.10 (d, J=1.0 Hz, 1H), 7.57-7.23 (m, 3H), 5.145.02 ( 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 (C21H24ClF ₃ N6O ₃ S) 533.0 (M+H)+.

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Example A70 (Scheme A-7): Preparation of (3R,4R)-4-({5-ethyl-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1Hbenzimidazol-6-yl ]pyrimidin-2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol.

Scheme A-7.

A solution of 6-(2-chloro-5-ethylpyrimidin-4-yl)-4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazole (A-8) (prepared as shown 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) piperidin-3-ol (Int-69) (60.7 mg; 0.312 mmol) and N2 was sparged. Chloro-2-(dimethylaminomethyl)-ferrocen-1-yl(dinorbornylphosphine)palladium (SK-CC02-A) (14.6 mg; 0.024 mmol) was added and the mixture was again sparged with N2. The reaction mixture was stirred at 120°C for 16 hours. The crude mixture was combined with the mixture obtained in the second interaction, carried out in a similar way on a scale 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 , DCM/MeOH, 10:1; Rf is 0.5) and then by preparative HPLC on an Xbridge column (150x30 mm, particle size 10 μm, column temperature 25°C ), which was eluted with 15-55% MeCN/H2O (plus 0.05% NH4OH) at a flow rate of 25 ml/min to give (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; yield 22%) as a white solid. 1H 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 ₂ 3H ₃₁ FN ₆ O ₃ S) 491.1 (M+H)+.

The examples in the table below were synthesized using the methods used to synthesize (3R,4R)-4-({5-chloro-4-[2-(difluoromethyl)-4-fluoro-1-(propan-2-yl)-1H- benzimidazol-6-yl]pyrimidin-2yl}amino)-1-(methanesulfonyl)-piperidin-3-ol (Example A70) (Scheme A-6) and (3R,4R)-4-({5-ethyl-4 -[4fluoro-2-methyl-1-(propan-2-yl)-1 H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol (Example A65) (Scheme A-7). The following examples have been synthesized with minor changes or substitutions in the exemplary methods that can be carried out by a person skilled in the art.

Example number Structure/Name LCMS NMR

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A71 Ν-γ ⁰¹ HN ^X N ^<? A< ^:! y ^F ΗΟ^7\ LA kJ l/ U ''—Me o=s=o Me (37.47)-4-( { 5 -chloro-4- [2-ethyl-4fluoro-1 - (oxetane-3 -yl)-\Nbenzimidazol-6-yl] pyrimide in-2yl } amino)-1 -(methanesulfonyl)piper idin-3 -ol 525.1 [M+H] ⁺ (ESI) Ή NMR (700 MHz, DMSO-Te) δ 8.73-8.18 (m, 2H), 7.83-6.97 (t, 2H), 5.75 (ddd, 7=13.2, 7.7, 5.4 Hz, 1H), 5.19-5.08 (t, 2H), 5.074.89 (t, 2H), 3.79 (s, 1H), 3.673.59 (t, 5H), 2.94-2.87 (t, 5H), 2.86- 2.79 (t, 1H), 2.64 (t, 7=10.3 Hz, 1H), 1.57-1.44 (t, 1H), 1.30 (t, 7=7.5 Hz, ZN) A72 At xk^s^F HN ^N || V HCk A LA 11 \ .N M th. ι <7 Me o=s=o X/ Me (37.47)-4- {[5-chloro-4-(1-cyclopropyl-4-fluoro-2-methyl-1Hbenzimidazol-6-yl)pyrimidin-2yl] amino}-1-(methanesulfonyl)piper idin-3-ol 495.1 [M+H] ⁺ (ESI) Ή NMR (600 MHz, DMSO-Te) δ 7.96 (s, 1H) 7.30-7.57 (t, 1H) 6.99-7.11 (t, 1H) 6.89-6.98 (t, 1H) 4.74 (d, 7=4.59 Hz, 1H) 3.303.38 (m, 1H) 3.15 (d, 7=10.64 Hz, 2H) 3.04 (d, 7=12.10 Hz, 2H) 2.44 (s, 3H) 2.41 (d, 7= 2.38 Hz, 1H) 2.21 (s, lH)2.18(s, 3H) 1.01-1.15 (m, 1H) 0.72-0.82 (m, 3H) 0.560.64 (m, 2H) A73 ΗΝ Ν |< nocD LA 11 \ ,Ν k J N-4f J _n ^Me X Me o=s=o ) Me O Me 4-fluoro-1 -(1 methoxypropan-2-yl)-2-methyl-1Yabenzimidazol-6-yl] pyrimide in-2yl } amino)-1 -(methanesulfonyl)piper idin-3 -ol 527.5 [M+H] ⁺ (APCI) Ή NMR (400 MHz, DMSO-Tb) δ 8.39 (s, 1H), 7.93 (d, 7=1.3 Hz, 1H), 7.40 (dd, 7=11.8, 1.3 Hz, 1H), 7.16 (d, 7=7.6Hz, 1H), 4.98 (d, 7=4.6Hz, 1H), 4.84 (ddd, 7=8.4, 7.0, 4.7Hz, 1H), 3.90 (dd, 7= 10.5, 8.5 Hz, 1H), 3.82 (ddd, 7=12.3, 6.1, 4.3 Hz, 1H), 3.73 (dd, 7=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, 7=10.4, 2.0 Hz, 1H), 2.89 (s, 3H), 2.77- 2.68(m,

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1H), 2.62 (s, 3H), 2.18–2.08 (br, 1H), 1.68–1.50 (m, 5H); [a] p ²² \u003d + 42, G (s \u003d 0.1, MeOH) A74 7¾ 4k % HN N yV GA II ' / ^N ΙΨ Me—/А ,ι A Me o=s=o 2 Me 0 Me [4-fluoro-1-(1methoxypropan-2-yl)-2-methyl-1Yabenzimidazol-6-yl]pyrimide in-2yl } amino)-1-(methanesulfonyl)piperidin-3-ol 527.5 [M+H] ⁺ (APCI) SH NMR (400 MHz, DMSO-Tb) δ 8.39 (s, 1H), 7.93 (d, 7=1.4 Hz, 1H), 7.39 (dd, 7=11.8, 1.3 Hz, 1H), 7.16 (d, 7=7.7 Hz, 1H), 4.97 (s, 1H), 4.91-4.73 (m, 1H), 3.89 (dd, 7=10.5, 8.5 Hz, 1H), 3.82 ( ddd, 7=9.3, 7.9, 4.5 Hz, 1H), 3.72 (dd, 7=10.5, 4.8 Hz, 1H), 3.703.63 (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, 7=7.1 Hz, 5H) A75 AV ⁰¹ ,4¾ 4k .f HN N yy GA II \ , ^N k J N-4 N Me-y V _o OSO me me Me (37?,47?)-4-({5-chloro-4-[4 -fluoro-2(methoxymethyl)-1 -(propan-2-yl)1H-benzimidazol-6yl]pyrimide in-2-yl} amino)-1(methanesulfonyl)piperide in-3-ol 527.1 [M+H] ⁺ (APCI) Ή NMR (400 MHz, DMSO-Te) δ 8.40 (s, 1H), 8.00 (d, 7=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, 7=6.97 Hz, 6H), 1.57-1.48 (m, 1H). A76 nV ^f a hn ^Ν (ϊ η no., GA II \ ,Ν k J Ν—Ch Ν Me—/ 1 \ Me OSO Me Me Me (3R,4R)-4-({ 5 -fluoro-4- [2- methyl-1 - 463.4 [M+H] ⁺ (ESI) ^{1 H} NMR (400 MHz, CD ₃ OD) δ 8.40 (s, 1H), 8.28 (d, 7=4.2 Hz, 1H), 7.99 (dt, 7=8.5, 1.4 Hz, 1H) , 7.65 (d, 7=8.6 Hz, 1H), 3.95-3.66 (m, 4H), 2.98 (td, 7=11.8, 2.8 Hz, 1H), 2.91 (s, 3H), 2.78 (dd,

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(propan-2-yl)-1 N-benzimidazol6-yl] pyrimide in-2-yl } amino)-1 (methanesulfonyl)piperide in-3-ol 7=11.5, 9.1 Hz, 1H), 2.67 (s, 3H), 2.36-2.24 (m, 1H), 1.80-1.64 (t, 7H); one proton covered by a solvent peak A77 n-= ^Yf A HN N ]| Y HC < A. LA II T N L A ν— N Me-/ O=S=O Me Me Me (37?,47?)-4- {[4-(1-mpem-butyl- 1H- benzimidazole-6 -yl)-5-fluoro pyrimide in-2-yl]amino}-1(methanesulfonyl)piperide in-3-ol 463.3 [M+H] ⁺ (ESI) Ή NMR (400 MHz, DMSO-Je) δ 8.47-8.34 (m, 3H), 7.91-7.83 (m, 1H), 7.82-7.75 (m, 1H), 7.18 (brd, 7=7.7 Hz, 1H ), 5.22 (d, 7=4.4 Hz, 1H), 3.82-3.46 (m, 4H), 2.95-2.80 (m, 4H), 2.69-2.65 (m, 1H), 2.182.02 (m, 1H ), 1.75 (s, 9H), 1.631.44 (m, 1H) A78 nV ^f A X ΗΝ Ν γη HO^ .A XA II \ ,Ν k J nA N Me~/ ¹ .. L Me O=S=O Me Me (37?,47?)-4- {[4-( 1-tert-Butyl-2methyl-1H-benzimidazol-6-yl)-5fluoro pyrimide in-2-yl]amino}-1(methanesulfonyl)piperide in-3-ol 476.8 [M+H] ⁺ (ESI) Ή NMR (400 MHz, DMSO-Te) δ 8.57-8.26 (m, 2H), 7.82 (d, 7=8.4 Hz, 1H), 7.62 (d, 7=8.5 Hz, 1H), 7.16 ( d, 7=7.7 Hz, 1H), 5.24 (d, 7=4.5 Hz, 1H), 3.84-3.72 (m, 1H), 3.72-3.59 (m, 2H), 3.52 (d, 7= 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 (q, 7=11.5Hz, 1H) A79 n^Y ^f ΗΝ ^Λ Αγ ^! but^^A LX 11 ' / ^N γ Me-/Ae O=S=O Me Me (37?,47?)-4-({4-[2,4-dimethyl-1- (propan-2-yl )- 1H-benzimidazol6-yl] -5-fluoropyrimidin-2yl } amino)-1 -(methanesulfonyl)- 476.9 [M+H] ⁺ (ESI) Ή NMR (400 MHz, DMSO-Te) δ 8.38 (d, 7=4.0 Hz, 1H), 8.08 (s, 1H), 7.64 (q, 7=1.2 Hz, 1H), 7.16 (d, 7=7.6Hz, 1H), 5.23(d, 7=4.5Hz, 1H), 4.78(hept, 7=6.8Hz, 1H), 3.83-3.71(m, 1H), 3.70-3.56 (m, 2H), 3.55-3.46 (m, 1H), 2.962.82 (m, 4H), 2.71-2.64 (m, 1H), 2.60 (s, 3H), 2.54 (s, 3H), 2.09 (d ,

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piperidin-3-ol 7=13.7 Hz, 1H), 1.64-1.48 (m, 7H) A80 n^Y ^f HH^M^DACHA but. kA 1 J to Me^N MeAJ ]oxazino[4,3 b]ind azol-9-yl)pyrimide in-2yl ]amino } M-threo-pg nititol 432.1 [M+H] ⁺ (ESI) Ή NMR (500 MHz, DMSO-Tb) δ 8.42 (d, 7=4.0 Hz, 1H), 8.22 (s, 1H), 7.67 (d, 7=13.1 Hz, 1H), 7.20 (br d , 7=7.8 Hz, 1H), 4.95 (d, 7=5.3 Hz, 1H), 4.45 (t, 7=5.0 Hz, 2H), 4.22 (t, 7=5.0 Hz, 2H), 3.873.75 (br, 3H), 3.56-3.45 (m, 1H), 3.06 (t, 7=10.4 Hz, 1H), 2.00 (br d, 7=9.6 Hz, 1H), 1.70 (s, 6H), 1.551.42 (m, 1H) A81 Me / k ΗΝ Ν ]| But. Ah qAch 11 \ , ^N to O N-h N Me-/ | \ Me 0-S-0 _Me Me (37?,47?)-4-({ 4- [4-fluoro-2-methyl-1 (propan-2-yl)- 1H-benzimidazol6-yl]-5- (propan-2-yl)pyrimidin2-yl } amino)-1-(methanesulfonyl)piperidin-3-ol 504.9 [M+H] ⁺ (ESI) Ή NMR (400 MHz, DMSO-Je) δ 8.41 (s, 1H), 7.50 (s, 1H), 7.106.95 (m, 2H), 5.23 (d, 7=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), 2.712.60 (m, 4H) , 2.14-2.03 (m, 1H), 1.56 (d, 7=6.8 Hz, 6H), 1.45-1.25 (m, 6H) A82 Me nV /k ^X^^ch^P HN N ]|Ί no. Αχ k ^ k 11 \ , Ν k ) Ν-4 Ν Me - / „ । „ \ Me O=S=O _Me Me (37?,47?)-4-({ 4- [4-fluoro-2-methyl-1 (propan-2-yl)- 1H-benzimidazol6-yl]-5 -methoxypyrimidin-2yl } amino)-1 -(methanesulfonyl)piper idin-3 -ol 493.1 [M+H] ⁺ (ESI) Ή NMR (400 MHz, DMSO-Te) δ 8.30 (s, 1H), 8.25 (s, 1H), 7.70 (d, 7=12.6 Hz, 1H), 6.80 (d, 7=7.5 Hz, 1H), 5.24 (d, 7=4.5 Hz, 1H), 4.884.73 (m, 1H), 3.83 (s, 3H), 3.74 (m, 2H), 3.69-3.57 (m, 2H), 2.962 .83 (m, 4H), 2.73-2.65 (m, 1H), 2.61 (s, 3H), 2.12 (d, 7=13.2 Hz, 1H), 1.66-1.46 (m, 7H)

- 102 042105

A83 A ΗΝ Ν ]| but^ >χ A A to J nU N Me—/ । \ _Me O=S=O 5-methylpyrimidin-2yl } amino)-1 -(methanesulfonyl)piperidin-3-ol 477.1 [M+H] ⁺ (ESI) Ή NMR (400 MHz, CD ₃ OD) δ 8.22 (s, 1H), 7.70 (d, 7=1.3 Hz, 1H), 7.24 (dd, 7=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 covered by a solvent peak A84 JkXLx ΗΝ Ν ]| η AA 1 1 ' ^Ν _Me— / ^{Ν Ν} O=S=O Me Me amino)-1(methanesulfonyl)piperide in-3-ol 456.8 [M+H] ⁺ (ESI) Ή NMR (600 MHz, DMSO-Tb) δ 8.47 (s, 1H), 8.25 (b s, 1H), 8.15 (d, 7=8.6 Hz, 1H), 7.72-7.68 (m, 1H), 7.53 ( br s, 1H), 5.29 (hept, 7=6.7 Hz, 1H), 5.21 (m, 1H), 3.80 (b s, 1H), 3.65-3.57 (m, 2H), 3.523.46 (m, 1H ), 2.91-2.84 (m, 4H), 2.66 (t, 7=10.3 Hz, 1H), 2.10-2.01 (m, 1H), 1.66 (d, 7=6.7 Hz, 6H), 1.58- 1.49(m, 1H) A85 XXL HN N AA N Ηθχ/ ^U AA 11 \ ,Ν to J nU V 1 (propan-2-yl)-1H-imidazo[4,5/>]pyridin-6-yl]pyrimidin-2yl} amino)-1-(methanesulfonyl)piperidin-3-ol 480.1 [M+H] ⁺ (ESI) Ή NMR (400 MHz, DMSO-Te) δ 8.75 (d, 7=2.0 Hz, 1H), 8.42-8.37 (m, 2H), 7.23 (d, 7=7.6 Hz, 1H), 4.84 ( hept, 7=6.8 Hz, 1H), 3.63 (m, 2H), 2.95-2.85 (m, 4H), 2.772.64 (m, 4H), 2.19-2.08 (m, 1H), 1.80-1.74 ( m, 3H), 1.61 (m, 7H) A86 480.1 [M+H] ⁺ Ή NMR (600 MHz, DMSO-Te) δ 8.42 (s, 1H), 8.03 (d, 7=8.2, 1.3 хх XI PL HN N |1 ΝχΑ 11 \ ^Ν to ) nA Υ ^Me A Me O=S=O Me Me (3R,4R)-4-( { 5 -chloro-4- [2-methyl-3 (propane- 2-yl)-3R-imidazo[4,5/>]pyridin-5-yl]pyrimidin-2yl } amino)-1-(methanesulfonyl)piperidin-3-ol (ESI) Hz, 1H), 7.77 (s, 1H), 7.42 (s, 1H), 5.23 (s, 1H), 4.79 (h, 7=6.8 Hz, 1H), 3.87-3.78 (m, 1H), 3.68 -3.56 (m, 3H), 2.92-2.82 (m, 4H), 2.712.63 (m, 4H), 2.10-2.01 (m, 1H), 1.67 (d, 7=6.8Hz, 6H), 1.53 (m, 1H)

- 103 042105

Example A87 (Scheme A-8): Preparation of (3R,4R)-4-({5-chloro-4-[4-fluoro-2-(hydroxymethyl)-1-(propan-2yl)-1H-benzimidazole-6 -yl]pyrimidin-2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol.

Scheme A-8.

(3R,4R)-4-({5-chloro-4-[4-fluoro-2- {[(oxan-2-yl)oxy]methyl}-1 -(propan-2-yl)-1Hbenzimidazole- solution 6-yl]pyrimidin-2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol (A-9) (prepared as shown 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 indicated consumption of starting material to form the desired weight of product. The reaction mixture was concentrated to dryness. The residue was purified by preparative SFC on a Princeton Ha-Morpholine column (150 x 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 to give (3R,4R)-4-({5-chloro-4-[4-fluoro-2-(hydroxymethyl)-1-(propan-2-yl)-1Hbenzimidazol-6-yl]pyrimidin-2-yl}amino )-1-(methanesulfonyl)piperidin-3-ol (Example A87) (15 mg; 20% yield) as a white solid. 1H 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=5.0Hz, 1H), 5.02 (hept, J=7.0Hz, 1H), 4.77 (d, J=5.7Hz, 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-1Hbenzimidazol-6-yl]-5- fluoropyrimidin-2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol.

Scheme A-9.

A solution of tert-butyl 3-[6-(2-chloro-5-fluoropyrimidin-4-yl)-4-fluoro-2-methyl-1H-benzimidazol-1yl]azetidine-1-carboxylate (A-10) (prepared as shown 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 CS2CO3 (168 mg; 0.516 mmol) in THF (1.7 mL) were stirred under microwave at 80°C for 30 minutes. The mixture was purified by flash chromatography (SiO ₂ , 0-100% EtOAc/heptanes). Product-containing fractions were concentrated, taken up 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 (150x21.2 mm, particle size 5 μm) which was eluted with 20-100% MeCN/H ₂ O (plus 10 mM NH ₄ OAc) at flow 40 ml/min to obtain (3R,4R)-4-({4-[1-(azetidin-3-yl)-4-fluoro-2-methyl-1H-benzimidazol-6-yl]-5fluoropyrimidin-2 -yl}amino)-1-(methanesulfonyl)piperidin-3-ol (Example A88) (76 mg; 89% yield) as a solid. 1H 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), 3.012.78 (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)+.

- 104 042105

Example A89 (Scheme A-10): Preparation of (3R,4R)-4-({5-chloro-4-[4-fluoro-2-methyl-1-(oxetan-3-yl)-1Hbenzimidazol-6-yl ]pyrimidin-2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol.

Scheme A-10.

Example A89

Step 1: Synthesis of 6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-2-methyl-1-(oxetan-3-yl)-1Hbenzimidazole (A-11).

6-Bromo-4-fluoro-2-methyl-1-(oxetan-3-yl)-1H-benzimidazole mixture (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 1,4dioxane (1.1 ml) were sparged with N 2 for 10 minutes and then heated in a microwave oven at 90° C. for 1 hour 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 sparged with nitrogen for 10 minutes and then heated in a microwave oven at 110°C for 70 minutes. partitioned between water (2 ml) and EtOAc (2 ml) The aqueous phase was extracted with EtOAc (3x2 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 used without further purification, m/z (APCI+) for (C ₁₅ H ₁₁ Cl ₂ FN ₄ O) 352.8 (M+ H) ⁺ .

Step 2: Synthesis of (3K,4K)-4-({5-chloro-4-[4-fluoro-2-methyl-1-(oxetan-3-yl)-1H-benzimidazol-6yl]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 (3K,4K)-4-amino-1-(methanesulfonyl)piperidin-3-ol (Int69) (64.4 mg; 0.331 mmol), Pd(OAc) ₂ (9.9 mg; 0.044 mmol), rac -BINAP (27.5 mg; 0.044 mmol) and CS2CO3 (216 mg; 0.663 mmol) and the mixture was sparged with N2 for 10 minutes. The mixture was stirred at 90°C for 1.5 hours under 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 (150x21.1 mm, particle size in the column 5 μm, column temperature 35°C), which was eluted with a mixture of 15-50% MeOH/CO ₂ (plus 10 mM NH3) with flow rate 80 g/min. The material was repurified by preparative SFC on a Diacel DC pak SFX-B column (150 x 21.1 mm, particle size 5 μm, column temperature 35° C.), which was eluted with 18-45% MeOH/CO ₂ at a flow rate of 80 g/min. to (3R,4R)-4-({5-chloro4-[4-fluoro-2-methyl-1-(oxetan-3-yl)-1 H-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. 1H NMR (600 MHz, DMSO-d ₆ , 75°C) δ 8.40 (s, 1H), 8.35 (bs, 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 (bs, 1H) , 3.853.78 (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), 2.152.10 (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) ⁺ .

- 105 042105

Example A90 (Scheme A-11): Preparation of (3R,4R)-4-({5-chloro-4-[4-fluoro-2-(hydroxymethyl)-1-(2,2,2trifluoroethyl)-1H-benzimidazole -6-yl]pyrimidin-2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol.

Scheme A-11.

hh ₂

NOCA

Ύ J Int-69 ⁴ NT o=s=o

Me

1. Pd(OAc) ₂ rac-BINAP, Cs ₂ CO ₃ THF, 80 °C, MW

2. HCI

MeOH/1,4-dioxane yield 12%

Example A90

6-(2,5-Dichloropyrimidin-4-yl)-4-fluoro-2-{[(oxan-2-yl)oxy]methyl}-1-(2,2,2trifluoroethyl)-1H-benzimidazole was added to the vial (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), CS2CO3 (247 mg; 0.76 mmol), and THF (2.5 ml). The mixture was stirred at 80°C under microwave radiation for 30 minutes. LCMS analysis showed the consumption of the starting material with the formation of the desired mass of the product. The mixture was concentrated on SiO ₂ and purified by flash chromatography (ISCO, 12 g SiO ₂ , 0-100% EtOAc/heptanes). Product-containing fractions were concentrated. The residue was taken up in MeOH (5 ml) and treated with HCl (4.0 N 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 showed consumption of starting material. The mixture was concentrated and purified by preparative SFC on a Princeton HA-Morpholine column (150x21.1 mm, particle size 5 μm, column temperature 35° C.), which was eluted with 14-50% MeOH/CO ₂ at a flow rate of 80 g/min s obtaining (3R,4R)-4-({5chloro-4-[4-fluoro-2-(hydroxymethyl)-1-(2,2,2-trifluoroethyl)-1H-benzimidazol-6-yl]pyrimidin-2yl} amino)-1-(methanesulfonyl)-piperidin-3-ol (Example A90) (17 mg; 12% yield) as a gum. 1H 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=6.0 Hz, 1H), 5.49 (q, J=9.1Hz, 2H), 5.21 (d, J=4.5Hz, 1H), 4.82 (d, J=5.8Hz, 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-fluoro1-(propan-2-yl) -1H-benzimidazole (A-13) (prepared as shown 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 (5x30 ml). The combined organic phases were washed with water (3x20 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 hours before concentration. The residue was purified by preparative SFC on a ZymorSpher HADP column (150x21.2 mm, particle size 5 μm, column temperature 40°C), which was eluted

- 106 042105 with a mixture of 18% MeOH/CO ₂ with a flow rate of 90 ml/min to obtain (3R,4R)-4-({5-chloro-4-[4-fluoro-2-(2hydroxypropan-2-yl)- 1-(propan-2-yl)-1 H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-1(methanesulfonyl)piperidin-3-ol (Example A91) (137 mg; 43% yield) in the form of a solid. 1H NMR (400 MHz, DMSO-d6, 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 (h, 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 (C23H3oC1FN60 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.

hh ₂

o=s=o

Me

1. Pd(OAc) ₂ rac-BINAP, Cs ₂ CO ₃ THF, 80 °C, MW

2. HCI MeOH/1,4-dioxane q

TBS yield 8%

Example A92

2-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-6-(2,5-dichloropyrimidin-4-yl)-1(1,1-difluoropropan-2-yl)-4- 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), CS2CO3 (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 the consumption of the starting material with the formation of the desired mass of the product. The mixture was concentrated on SiO ₂ and purified by flash chromatography (ISCO, 12 g SiO ₂ , 0-100% EtOAc/heptanes). Product-containing fractions 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 the consumption of the starting material with the formation of the desired mass of the product. The mixture was concentrated to dryness and then purified by chiral SFC on a ChiralPak AS-H column (100 x 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 to give ( 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 first eluting fraction. ¹ H NMR (400 MHz, DMSO-d6, 80°С) 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 (C21H24ClF3N6O4S) 522.9 (M+H) ⁺ ; [a]D ²² =-26.5° (c=0.1 M, MeOH).

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Example A93 (Scheme A-14): Preparation 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.

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 the consumption of the starting material with the formation of the desired mass of the product. The mixture was concentrated to dryness. The crude residue from four parallel reactions was combined and purified by flash chromatography (SiO ₂ , 02% 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. 1H 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-(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° (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 obtain a yellowish suspension. TLC analysis (EtOAc/petroleum ether 1:9; Rf=0.8; UV 254 (wavelength)) showed consumption of starting material. The mixture was diluted with EtOAc (2 L) and H2O (2 L). The mixture was neutralized by slowly adding solid Na ₂ CO ₃ . The suspension was filtered and the mixture was separated. The aqueous layer was extracted with EtOAc (3x1 L). The combined organic layers were washed with saturated aqueous NaHCO3 (2x1 L) and brine (2x1 L), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was combined with the residue from a parallel reaction carried out in a similar manner 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-fluoroN ¹ -(propan-2-yl)benzene-1,2-diamine (A-17) ( 230 g; 74% yield as a brown oil. 1H NMR (400 MHz, DMSO-d6) 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-d6) δ -132.8; m/z (ESI+) for (C9H _w BrFN2O2) 247.0 (M+H) ⁺ .

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Stage 3: Synthesis of (III)-1-[6-bromo-4-fluoro-1-(propan-2-yl)-III-benzimidazol-2-yl]ethan-1-ol (Int-40).

A mixture of 5-bromo-3-fluoro-N-(propan-2-yl)benzene-1,2-diamine (A-17) (200.0 g; 809.4 mmol) and (2R)-2hydroxypropionic acid (605 .1 g; 6.72 mol) was heated from 25°C to 85°C and then stirred at 85°C for 16 hours. TLC analysis (1:1 EtOAc/petroleum ether; Rf 0.5; UV 254) 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%; about 300 ml) to a pH of about 8-9, maintaining the internal temperature below 30° C. by cooling in an ice bath. The mixture was separated and the aqueous layer was extracted with EtOAc (2x1 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 and the filter cake was washed with petroleum ether (2x80 ml). The filter cake was dried under vacuum to give (H)-1-[6-bromo-4fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]ethan-1-ol (Int-40) ( 150 g, 62% yield as a light yellow solid. 1H 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) 1 H-benzimidazol-2-yl]ethan-1-ol (A-18).

(1R)-1-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]ethan-1-ol mixture (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 to 90°C. The reaction mixture was stirred at 90° C. for 3 hours under N2 atmosphere. TLC analysis (1:1 EtOAc/petroleum ether; Rf 0.46; UV 254) 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 and the filter cake was washed with EtOAc (2x100 ml). The filtrate was extracted with EtOAc (2x800 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 , EtOAc/petroleum ether, 1:5-100% EtOAc) to give (1R)-1-[4-fluoro-1-(propan-2-yl)-6-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1Hbenzimidazol-2-yl]ethan-1-ol (A-18) (160 g; 92% yield) as light yellow solid. 1H 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 (C18H ₂ 6BFN ₂ O3) 348.9 (M+H) ⁺ .

Step 5: Synthesis of (1R)-1-[6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol2-yl]ethan-1-ol (A-19).

This conversion was carried out in two parallel batches. A stirred mixture of (1R)-1-[4-fluoro1-(propan-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazole -2-yl]ethan-1-ol (A18) (80 g; 230 mmol), 2,4,5-trichloropyrimidine (54.7 g; 299 mmol), Pd(PPh ₃ ) ₄ (26.5 g; 22.9 mmol) and K2CO3 (63.5 g; 459 mmol) in 1,4-dioxane (600 ml) and H2O (250 ml) were sparged with N2. The mixture was stirred at 90° C. for 3 hours under N2. LCMS analysis showed the consumption of the starting material with the formation of the desired mass of the product. The reaction mixture was cooled to room temperature and diluted with H ₂ O (500 ml). The two parallel reactions were combined and concentrated to remove 1,4-dioxane. The residue was filtered and the filter cake was washed with EtOAc (2x150 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 from EtOAc/petroleum ether 1:5 to 100% EtOAc). Product-containing fractions were concentrated to about 400 ml resulting in precipitation. Solids were collected by filtration. The filter cake was washed with petroleum ether (200 ml) and dried under vacuum to give (1R)-1-[6-(2,5dichloropyrimidin-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. 1H 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=7.0Hz, 1H), 4.96 (sept, J=6.8Hz, 1H), 3.11 (d, J=7.8Hz, 1H), 1.75 (d, J=6.5 Hz, 3H), 1.71 (d, J=7.0 Hz, 6H); m/z (ESI+) for (Ci6Hi ₅ C1 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)-1Hbenzimidazol-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 DIPEA (85.7 g; 664 mmol). The reaction mixture was stirred at 60°C for 56 hours. LCMS analysis showed the consumption of the starting material with the formation of the desired mass of the product. The two parallel reactions were combined and filtered through a pad of celite. The filtrate was poured into stirred saturated aqueous NaHCO ₃ (2 L). The mixture was extracted with DCM (3x2 L). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was taken up 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 hour at 30°C. The mixture was filtered and the filtrate was concentrated. The residue was purified by flash chromatography (SiO ₂ ; EtOAc/petroleum ether 1:10 to 100% EtOAc). The product was taken up in EtOH (200 ml) and H2O (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)-1Hbenzimidazol-6-yl}pyrimidin-2-yl)amino]-1-(methanesulfonyl)-piperidin-3-ol (Example A93) (95 g; 67% yield) as white solid. 1H NMR (400 MHz, 80°C, DMSO-d6) 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=6.9 Hz, 1H), 5.16-5.07 ( m, 1H), 4.97 (d, J=4.6 Hz, 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 (C22H28ClFN6O4S) 526.8 (M+H)+; [a]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 interaction was carried out in three parallel batches. i-PrNH ₂ (41.2 g, 697 mmol) and CS2CO3 (455 g; 1.40 mol) at 15-30°C. Upon addition, an exothermic effect was observed. The reaction mixture was stirred at 30°C for 6 hours. TLC analysis (100% petroleum ether; UV 254; Rf 0.35) showed consumption of starting material. The three reactionary parties were united. 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-3fluoro-2-nitro-N-(propan-2-yl)aniline (A-16) (420 g; yield 72%) as a yellow solid. 1Н 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-d6) δ -116.9; m/z (ESI+) for (C9H _w BrFN2O2) 276.1 (M+H)+.

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Step 2: Synthesis of 5-bromo-3-fluoro-N-(propan-2-yl)benzene-1,2-diamine (A-17).

This interaction 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° 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; UV 254; Rf=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 (3x500 ml). The filtrate was concentrated in vacuo to remove most of the MeOH. The resulting aqueous mixture was extracted with EtOAc (3x1 L). The combined organic layers were washed with brine (2x800 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give 5-bromo-3-fluoro-N-(propan-2-yl)benzene-1,2-diamine (A-17 ) (350 g; 88% yield) as a purple solid which was used without further purification. ¹ H NMR (400 MHz, DMSO-d6) 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-d6) 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-Hydroxypropionic acid (951 g; 9.71 mol) was added to a 2 L three neck 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 5-bromo-3-fluoro-N ¹ -(propan-2-yl)benzene-1,2-diamine (A-17) (300 g; 1.21 mol) in portions. The resulting mixture was stirred at 85°C (internal temperature) for 40 hours to obtain a purple reaction solution. TLC analysis (EtOAc/petroleum ether, 1:2; UV 254; Rf=0.8) showed consumption of starting material. The reaction mixture was cooled to room temperature and diluted with THF (1.5 L). The pH of the mixture was adjusted to about 8 with saturated aqueous LiOH at 10-15° C. with cooling in an ice water bath. The mixture was extracted with MTBE (3x1.5 L). The combined organic layers were washed with brine (2x800 ml), dried over Na2SO4 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 passed on to the next step without further purification. 1H NMR (400 MHz, DMSO-d6) 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-d6) 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-benzimidazol2-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 hours. TLC analysis (EtOAc/petroleum ether, 1:2; UV 254; Rf=0.3) showed consumption of starting material. The reaction mixture was cooled to room temperature and filtered through a Celite pad. The filter cake was washed with EtOAc (3x500 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. 1H NMR (400 MHz, CDCU) 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-d6) δ -124.1; m/z (ESI+) for (C1 ₂ H1 ₂ 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 interaction was carried out in two parallel batches. Solution of 1-[6-bromo-4-fluoro-1-(propan2-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) by cooling 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. while cooling in an ice-brine bath for 3 hours. TLC analysis (20% EtOAc/petroleum ether; UV 254; Rf = 0.8) indicated consumption of starting material. The reaction mixture was slowly quenched with saturated aqueous NH ₄ Cl (400 ml) at 0-5° C. while cooling in an ice-brine bath and then stirred at room temperature for 1 hour. The two reaction batches were combined and diluted with EtOAc (1 L). The organic layer was separated. The aqueous layer was extracted with EtOAc (2x1 L). The combined organic layers were dried over MgSO ₄ , filtered and concentrated. The crude residue was purified by flash chromatography (SiO2, 0-50% EtOAc/petroleum ether) to give 2-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2yl]propan- 2-ol (A-21) (316 g; 91% yield) as a yellow solid. 1H 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-d6) δ -126.3; m/z (ESI+) for (C _n H16BrFN ₂ O) 314.7 (M+H) ⁺ .

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Step 6: Synthesis of 2-[4-fluoro-1-(propan-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1Hbenzimidazol-2 -yl]propan-2-ol (A-22).

2-[6-Bromo-4-fluoro-1-(propan-2-yl)-1Hbenzimidazol-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 N2 three times. The reaction mixture was heated to 90°C (internal temperature) and stirred at this temperature for 3 hours to obtain an orange suspension. TLC analysis (EtOAc/petroleum ether, 1:2; UV 254; Rf=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 (2x1 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)-1Hbenzimidazol-2-yl]propan-2-ol (A-22) (210 g; 61% yield) as a light yellow solid. 1Н 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 (C13H16FN 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-2yl]propan-2-ol (A-23 ).

This interaction was carried out in two parallel batches. To a mixture of 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) were added 2,4,5 trichloropyrimidine (67.2 g; 359 mmol). The mixture was degassed and purged with N2 three times. Pd(PPh ₃ ) ₄ (31.9 g; 27.6 mmol) was added and the mixture was degassed and purged with N2 three times. The reaction mixture was placed in a preheated oil bath at 100° C. and stirred at 90° C. (internal temperature) for 24 hours. LCMS showed the consumption of the original substance with the formation of the required mass of the 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 (3x1 L). The combined organic layers were dried over MgSO ₄ , filtered, concentrated. The crude residue was purified by flash chromatography (SiO2; 0-50% EtOAc in petroleum ether/DCM, 1:5). Product-containing fractions were concentrated under vacuum to a volume of about 200 ml with simultaneous precipitation of a white solid. The suspension was filtered and the filter cake was washed with petroleum ether (2x300 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-benzimidazol2-yl]propan-2 -ola (A-23) (112 g). The filtrate was concentrated and the residue was repurified by flash chromatography (SiO ₂ ; 0-50% EtOAc in petroleum ether/DCM, 1:5). Product-containing fractions were concentrated under vacuum to a volume of about 50 ml to precipitate further product. The suspension was filtered and the filter cake was washed with petroleum ether (2x100 ml). The filter cake was collected and dried under vacuum to give an additional portion of 2-[6-(2,5dichloropyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]propane -2-ol (A-23) (41 g). Portions of the product were combined to give 2-[6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1Hbenzimidazol-2-yl]propan-2-ol (A- 23) (153 g; 71% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) 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 (C17H17Cl 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)-1Hbenzimidazol-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-1,5anhydro-2,3-dideoxy-O-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 hours to obtain a brown solution. LCMS analysis showed remaining starting material. Additional 3-amino-1,5-anhydro-2,3-dideoxy-O-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 another 10 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was taken up in 1:1 EtOAc/H ₂ O (1.5 L). Some solids precipitated. EtOH (100 ml) was added. The organic layer was collected and the aqueous layer was extracted with EtOAc (2x500 ml). The combined organic layers were washed with H2O (2x300 ml), dried over Na2SO4 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.

- 112 042105

The treatment with sulfhydryl silica gel was repeated in the same 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 (2x100 ml). The filter cake was resuspended in MeCN (300 ml) at room temperature for 6 hours. The mixture was filtered and the filter cake was washed with MeCN (2x100 ml). The filter cake was collected and dried under vacuum and then dried in an oven (45°C for 20 hours, 50°C for 64 hours) to give 1,5-anhydro-3-({5-chloro-4-[ 4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1Hbenzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo -pentitol (Example A94) (90 g; 66% yield) as a white solid. 1H NMR (400 MHz, 80°С, 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, CDCl3) δ -127.2; m/z (ESI+) for (C^C^O3) 464.2 (M+H) ⁺ ; [a]D ²² = -12.6 (c=0.2, MeOH).

Alternative preparation of 2-[6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1Hbenzimidazol-2-yl]propan-2-ol (A-23) according to scheme A-16.

MeMgBr

THF, 0 °C yield 93%

Step 1: Synthesis of 1-[6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2yl]ethan-1-one (A-19 ).

To a solution of (1S)-1-[6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1 -(propan-2-yl)-1 H-benzimidazol-2yl]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 approximately 10% residual starting material. An additional complex of sulfur trioxide and pyridine (4.7 g) was added. After 1 hour, LCMS analysis showed consumption of starting material. The mixture was partitioned between H2O and EtOAc. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with H2O, 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-benzimidazol2-yl]ethan-1-one (A-24) (3.1 g; 80% yield) as a white solid. 1H 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^H^ChF^O) 366.8 (M+H) ⁺ .

Step 2: Synthesis of 2-[6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2yl]propan-2-ol (A-23 ).

Solution of 1-[6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]ethan-1one (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 minutes at 0°C. LCMS analysis showed the consumption of the starting material with the formation of the desired mass of the product. The reaction mixture was quenched with saturated aqueous NH4Cl and partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (2x). 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, 80 g SiO ₂ , 20-60% EtOAc/heptane) to give 2-[6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1(propan-2 -yl)-1H-benzimidazol-2-yl]propan-2-ol (A-23) (3.11 g; 93% yield) as a white solid

- 113 042105 substances. 1H NMR (400 MHz, DMSO-d6) 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.

1: Synthesis of 4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]-2 (methylsulfanyl)pyrimidine-5-carbonitrile step (B-1).

To a mixture of 4-chloro-2-(methylsulfanyl)pyrimidine-5-carbonitrile (150 mg; 0.808 mmol), 4-fluoro-2methyl-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 K2CO3 (335 mg; 2.42 mmol) in 1,4-dioxane (15 .0 ml) and H2O (2.1 ml) was added Pd(t-Bu ₃ P) ₂ (41.3 mg; 0.0808 mmol). The reaction mixture was sparged with N2 and then stirred at 80° C. for 1 hour. LCMS analysis showed the consumption of the starting material with the formation of the desired mass of the product. The mixture was combined with a second reaction mixture similarly prepared 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 (A1). The mixture was diluted with water EtOAc (20 ml) and washed with H2O (5 ml). The aqueous layer was extracted with EtOAc (3x10 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 ; petroleum ether/EtOAc, 1:1) 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. 1Н 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 H2O (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 the consumption of the starting material with the formation of the desired mass of the product. The reaction mixture was combined with a parallel reaction mixture similarly prepared with 80 mg of 4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]-2(methylsulfanyl)pyrimidin- 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 (4x10 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-5carbonitrile (B-2) (250 mg; 85% yield) as a yellowish 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)-3hydroxy-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)pyrimidine5-carbonitrile (B-2) (120 mg; 0.336 mmol) and (3R,4R)-4-amino-1-(methanesulfonyl)piperidin-3-ol (Int- 114 042105

69) Na2CO3 (71.2 mg; 0.672 mmol) was added to THF (15.0 ml). The resulting mixture was stirred at °C for 12 hours. LCMS analysis showed the consumption of the starting material with the formation of the desired mass of the product. The mixture was diluted with water EtOAc (30 ml) and washed with H2O (10 ml). The aqueous layer was extracted with EtOAc (2x20 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 ; DCM/MeOH, 10:1; Rf is 0.55). The material was further purified by preparative HPLC on a YMC-Actus Triart C18 column (150x30 mm, particle size 5 μm) which was eluted with 8-48% MeCN/H ₂ O (plus 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. 1Н 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), 3.703.59 (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 (C23H27FN6O3S) 488.1 (M+H)+.

The example in the table below was synthesized by the methods used to synthesize 4-[4fluoro-2-methyl-1-(propan-2-yl)-1 H-benzimidazol-6-yl]-2-{[(3R,4R)- 3-hydroxy-1(methanesulfonyl)piperidin-4-yl]amino}-pyrimidine-5-carbonitrile (Example B1). The following example was synthesized with minor changes or substitutions in the exemplary methods that can be carried out by a person skilled in the art.

Example number Structure/Name LCMS NMR AT 2 Ny ^CF3 L. HN Ν y no^ A. LA II \ N L Y N—7 N Me—/ O=S=O Me Me (37?,47?)-4-({4-[4-fluoro- 1-(propan2-yl)-1//-benzimidazol-6-yl]-5(trifluoromethyl)pyrimidin-2yl } amino)-1-(methanesulfonyl)piper idin-3-ol 516.9 [M+H]+ (ESI) Ή NMR (400 MHz, DMSO-Tb) 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 (br, 1H ), 5.27 (br s, 1H), 4.79 (hept, 7=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), 2.081.97 (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)-1Hbenzimidazol-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 B2Pin2 (749 mg; 2.95 mmol). The mixture was sparged with N2 and then PdCl ₂ (dppf) was added. The mixture was stirred at 70°C under microwave radiation for 30 minutes. LCMS analysis showed consumption of the starting material with conversion to the 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 under microwave radiation for 2 hours. LCMS analysis showed the consumption of boronate ester with the formation of the desired mass of product. The mixture was combined with a parallel reaction mixture similarly prepared with 100 mg of 1-bromo-2-chloro-5fluoro-4-nitrobenzene (C-1). The combined mixture was partitioned between EtOAc and H2O. 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/heptanes) to give 2-chloro-4-(2-chloro-5-fluoro-4-nitrophenyl)-5-fluoropyrimidine (C -2) (120 mg; 20% yield) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d6) 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)-1Hbenzimidazole (C-3).

A mixture of 2-chloro-4-(2-chloro-5-fluoro-4-nitrophenyl)-5-fluoropyrimidine (C-2) (55 mg; 0.018 mmol) and iPrNH ₂ (0.016 ml; 0.018 mmol) in DMSO (1 ml) was stirred at 50°C under microwave radiation for 1.5 hours. LCMS analysis showed consumption of starting material. After cooling to room temperature, the mixture was diluted with water 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 indicated the 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-4yl)-2-methyl-1-( propan-2-yl)-III-benzimidazole (C-3) (28 mg; 46% yield), which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 7.97 (s, 1H), 7.79 (s, 1H), 4.79 (spt, J=6.8 Hz, 1H), 2.62 (s, 3H), 1.55 (d, J=7.0 Hz, 6H). m/z (ESI) for (CwHsC^N^) 304.7 (M+H)+.

Step 3: Synthesis of (3R,4R)-4-({4-[5-chloro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]-5fluoropyrimidin-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)-1 H-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 CS2CO3 (81 mg ; 0.25 mmol). The mixture was sparged with N2 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 during the night. LCMS analysis showed the consumption of the starting material with the formation of the desired mass of the product. The mixture was partitioned between EtOAc and H2O. 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.), which was 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 (150x20 mm, particle size 5 μm, column temperature 35° C.), which was eluted with 12-50% MeOH/CO ₂ at a flow rate of 80 g/min to obtain ( 3R,4R)-4-({4-[5-chloro-2-methyl-1-(propan-2-yl)-1Hbenzimidazol-6-yl]-5-fluoropyrimidin-2-yl}amino)-1 - (methanesulfonyl)piperidin-3-ol (Example C1) (16 mg; 38% yield) as a solid. 1H NMR (600 MHz, DMSO-d ₆ , 75°C) δ 5 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 covered 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)-1Hbenzimidazol-6 -yl]-5-chloropyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol.

Scheme C-2.

A solution of compound (C-4) (prepared as in Example C1; 155.0 mg; 0.22 mmol), 3-amino-1,5-anhydro-2,3-dideoxy-O-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 at night. LCMS analysis showed the consumption of the starting material with the formation of the desired mass of the product. The mixture was loaded directly

- 116 042105 on SiO ₂ and purified by flash chromatography (ISCO, 12 g SiO ₂ , 0-100% EtOAc/heptanes). The product-containing fractions were concentrated, taken up in DCM (5 ml) and treated with a solution of HCl (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 by preparative SFC on a ChiralPak IC column (column size 21x250 mm, particle size 10 μm, column temperature 35° C.), which was eluted with 60% MeOH/CO ₂ (plus 10 mM NH ₃ ) at a flow rate of 82 ml/min to give 1,5-anhydro-3-({4-[2-(azetidin-3-yl)-4-fluoro-1-(propan-2-yl)-III-benzimidazol-6-yl]-5- chloropyrimidin2-yl}amino)-2,3-dideoxy-D-threo-pentitolα (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)+.

Reference Example D1 (Scheme D-1): Preparation of (3R,4R)-4-[(5-chloro-4-{4-fluoro-2-[(1S)-1hydroxyethyl]-1-(propan-2-yl )-1H-benzimidazol-6-yl}pyridin-2-yl)amino]-1(methanesulfonyl)piperidin-3-ol.

Scheme D-1.

Step 1: Synthesis of (1S)-1-[6-(2,5-duchloropyridin-4-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2yl]ethan-1-ol (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)-1Hbenzimidazole -2-yl]ethan-1-ol (D-1) (prepared as shown in Example A1; 650 mg; 1.87 mmol) in H2O (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 N2. LCMS analysis showed the consumption of the starting material with the formation of the desired mass of the product. The reaction mixture was concentrated to dryness. The residue was purified by flash chromatography (ISCO; 40 g SiO ₂ ; petroleum ether/EtOAc, 2:1) to give (1S)-1-[6-(2,5dichloropyridin-4-yl)-4-fluoro-1-(propane -2-yl)-1H-benzimudazol-2-yl]ethan-1-ol (D-2) (490 mg; 71% yield) as 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)-1Hbenzimidazol-6 -yl}pyridin-2-yl)amino]-1-(methanesulfonyl)-piperidin-3-ol (Reference Example D1).

A heterogeneous mixture of (1S)-1-[6-(2,5-dichloropyridin-4-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol2-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 sparged with N2 for 3 minutes and then stirred at 110°C for 4 hours. LCMS analysis showed the consumption of the starting material with the formation of the desired mass of the product. The reaction mixture was filtered and concentrated to dryness. The residue was purified by flash chromatography (ISCO, 40 g SiO2, 0-15% MeOH/EtOAc) and then re-purified by preparative HPLC on an Xtimate C18 column (250x80 mm, particle size 10 μm) eluted with 30-50% MeCN /H ₂ O (plus 0.05% NH4OH) with a flow rate of 25 ml/min. Through analysis

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HPLC showed some reduction in enantiopure (93% ee). The material was repurified by chiral preparative SFC on a Diacel Chiralpak AD-H column (250x30 mm, particle size 5 µm) which was eluted with 45% IPA/CO ₂ (plus 0.1% NH3) 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)-1 H-benzimidazol-6yl} pyridin-2-yl)amino]-1-(methanesulfonyl)piperidin-3-ol (Reference D1) (40.1 mg; 7% yield) as a white solid. 1H NMR (400 MHz, DMSO-d ₆ +D2O) 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 (C23H29ClFN5O4S) 525.8 (M+H)+.

Reference Example D2 (Scheme D-2): Preparation of 1,5-anhydro-3-[(5-chloro-4-{4-fluoro-2-[(1S)-1hydroxyethyl]-1-(propan-2-yl )-1 H-benzimidazol-6-yl}pyridin-2-yl)amino]-2,3-dideoxy-D-threopentitol.

Scheme D-2.

A suspension of (1S)-1-[6-(2,5-dichloropyridin-4-yl)-4-fluoro-1-(propan-2-yl)-1 H-benzimidazol-2yl]ethan-1-ol (D -3) (prepared as in example D1; 680 mg; 1.85 mmol), 3-amino-1,5-anhydro-2,3dideoxy-D-threo-pentitol (324 mg; 2.77 mmol), BINAP (92 mg; 0.148 mmol), t-BuONa (532 mg; 5.54 mmol) and Pd2(dba)3 (84.6 mg; 0.092 mmol) in PhMe (15.0 ml) were bubbled with N ₂ for 3 minutes and then stirred at 110°C for 16 hours. LCMS analysis showed the consumption of the starting material with the formation of the desired mass of the product. The reaction mixture was concentrated to dryness. The residue was purified by flash chromatography (ISCO, 40 g SiO2, 0-20% MeOH/EtOAc). The material was repurified by preparative HPLC on an Xtimate C18 column (250x80 mm, particle size 10 µm) which was eluted with 30-50% McCN/H ₂ O (plus 0.05% NH4OH) at a flow rate of 25 ml/min to give 1 ,5-anhydro-3-[(5-chloro-4-{4-fluoro-2-[(1S)-1-hydroxyethyl]-1-(propan-2-yl)-1Hbenzimidazol-6-yl}pyridin- 2-yl)amino]-2,3-dideoxy-D-threo-pentitol (Reference D2) (67 mg; 8% yield) as a white solid. 1H 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 covered by a 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 by the methods used to synthesize 1,5-anhydro-3-[(5-chloro-4-{4-fluoro-2-[(1S)-1-hydroxyethyl]-1-(propan-2-yl )-1H-benzimidazol-6-yl}pyridin2-yl)amino]-2,3-dideoxy-D-threo-pentitol (Reference Example D2). The following example was synthesized with minor changes or substitutions in the exemplary methods that can be carried out by a person skilled in the art.

Example number Structure/Name LCMS NMR D3 xc ^ΗΟ ν>χ kA II ' P k P N-D N Me-/ „ ι \ }— Me OSO me OH Me (37?,47?)-4-[(5-chloro-4-{4-fluoro -2[(1R)-1-hydroxyethyl]-1-(propan2-yl)-1H-benzimidazol-6yl}pyridine in-2-yl)amino]-1(methanesulfonyl)piperide in-3-ol 525.9 [M+H]+ (ESI) Ή NMR (400 MHz, DMSO-Tb) δ 8.07 (s, IH), 7.59 (d, 7=1.0 Hz, IH), 7.07 (dd, 7=11.4, 1.3 Hz, IH), 6.83 (br d, 7=7.5 Hz, IH), 6.64 (s, IH), 5.74 (d, 7=6.3 Hz, IH), 5.27 (d, 7=4.5 Hz, IH), 5.215.04 (m, 2H), 3.80-3.71 (m, IH), 3.60-3.49 (m, 2H), 3.49-3.39 (m, IH), 2.96-2.85 (m, 4H), 2.76-2.68 (m , IH), 2.17-2.07 (m, IH), 1.651.51 (m, 9H), 1.49-1.33 (m, IH)

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Reference Example D4 (Scheme D-3): Preparation of (3R,4R)-4-({5-chloro-4-[2-methyl-3-(propan-2-yl)-3Himidazo[4,5-b] pyridin-5-yl]pyridin-2-yl}amino)-1-(methanesulfonyl)-piperidin-3-ol.

Scheme D-3.

To a solution of compound (D-4) (prepared as shown 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 sparged with N2 and then stirred at 110° C. for 16 hours overnight. LCMS analysis showed the consumption of the starting material with the formation of the desired mass of the product. The reaction mixture was concentrated to dryness. The residue was purified by preparative SFC on a ZymorSPHER HADP column (150 x 21.1 mm, particle size 5 μm, column temperature 35° C.), which was 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 (150x21 mm, particle size 5 µm) which was eluted with 15-70% MeCN/H ₂ O (plus 10 nM NH4OAc) at a flow rate of 40 ml/min to give (3R,4R)-4-({5-chloro-4-[2-methyl-3-(propan-2-yl)-3H-imidazo[4,5b]pyridin-5-ul]pyridine-2-yl }amino)-1-(methanesulfonyl)piperidin-3-ol (Reference D4) (20 mg; 21% yield) as a solid. 1H 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 (C21H27CMO3S) 478.9 (M+H)+.

The example in the table below was synthesized using 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 (Reference D4). The following example was synthesized with minor changes or substitutions in the exemplary methods that can be carried out by a person skilled in the art.

Example number Structure/Name LCMS NMR D5 HO^ N.^4 11 \ N k x ¹ N -7 ^{0 Me} A Le Me 1,5 -anhydro-3 - ({5 -chloro-4- [2methyl-3 - (propan-2-yl) -3 /L imidazo[4,5-th]pyridine-5- 402.1 [M+H]+ (APCI) Ή NMR (600 MHz, DMSO-Tb) δ 8.06 (s, 1H), 7.99 (d, 7=8.3 Hz, 1H), 7.45 (d, 7=8.2 Hz, 1H), 6.89-6.86 ( m, 1H), 6.80 (s, 1H), 5.06 (br. s, 1H), 4.81 (hept, 7=6.4 Hz, 1H), 3.84-3.74 (m, 3H), 3.10-3.05 (m, 1H), 2.63 (s, 3H), 2.052.01 (m, 1H), 1.67 (dd, 7=6.8, 2.3 Hz, 6H), 1.44-1.36 (m, 1H), two protons, yl ] pyride in-2-yl } amino)-2,3 dideoxy-P-otreo-pentitol covered by residual solvent peak

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Reference Example D6 (Scheme D-4): Preparation of (3R,4R)-4-{[4-(1-tert-Butyl-4-fluoro-1Hbenzimidazol-6-yl)-5-chloropyridin-2-yl]amino } piperidine-3-ol.

Scheme D-4.

D-5

Example D6

To a solution of tert-butyl-(3R,4R)-4-{[4-(1-tert-butyl-4-fluoro-1 H-benzimidazol-6-yl)-5-chloropyridin-2yl]amino}-3-hydroxypiperidine- 1-carboxylate (D-5) (prepared as shown 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 the desired weight of 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-1Hbenzimidazol-6-yl)-5-chloropyridin-2-yl]amino}piperidin-3- hydrochloride ol (Example D6) (2.7 g; 99% yield) as a yellow solid. ¹ H NMR (400 MHz, D2O) 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^ClF^O) 418.2 (M+H)+.

Reference Example E1 (Scheme E-1): Preparation of (3R,4R)-4-[(5-chloro-4-{4-fluoro-2-[(1S)-1hydroxyethyl]-1-(propan-2-yl )-1H-benzimidazol-6-yl}pyridin-2-yl)amino]-1(methanesulfonyl)piperidin-3-ol.

Scheme E-1.

Step 1: Synthesis of (1S)-1-[6-(2,5-dichloro-pyridin-4-yl)-4-fluoro-1-(πpropan-2-yl)-1H-benzimidazol-2yl]ethan-1-ol (E-1).

5-Chloro-2-fluoro-4-iodopyridine solution (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 the consumption of the starting material with the formation of the desired mass of the product. The reaction mixture was loaded directly onto SiO ₂ and purified by flash chromatography (ISCO, 12 g SiO ₂ , 0-100% EtOAc/heptanes) to give (3S,4S)-4-[(5-chloro-4-iodopyridine-2 -yl)amino]-1-(methanesulfonyl)-piperidin-3-ol (E-1) (147 mg; 44% yield) as a gum. 1H 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,

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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 (C11H15CIIN3O3S) 431.8 (M+H) ⁺ .

Step 2: Synthesis of (3R,4R)-4-[(5-chloro-4-{4-fluoro-2-[(1S)-1-hydroxyethyl]-1-(propan-2-yl)-1Hbenzimidazol-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 (E1) (147 mg; 0.341 mmol) in 1, 4-dioxane (4.7 ml) was added 4-fluoro-2-methyl-1-(propan-2-yl)-6-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-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 H2O (0.4 ml). The mixture was stirred at 95°C for 5 hours. LCMS analysis showed the consumption of the starting material with the formation of the desired mass of the product. The reaction mixture was filtered through celite and concentrated. The material was purified by preparative SFC on a DCPak SFC-B column (150x21.2 mm, particle size 5 μm, column temperature 35°C), which was eluted with a mixture of 25-35% MeOH/CO ₂ with a flow rate of 62 ml/min to obtain ( 3R,4R)-4-[(5-chloro-4-{4-fluoro-2-[(1S)-1-hydroxyethyl]-1-(propan-2-yl)-1 H-benzimidazol-b-yl } pyridin2-yl)amino]-1-(methanesulfonyl)piperidin-3-ol (Reference E1) (66 mg; 39% yield) as a white solid. ¹ H NMR (700 MHz, DMSO-d6) 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 , 6Н), 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)-1Hbenzimidazol-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-6yl]pyrimidin-2-yl}amino )piperidin-3-ol (Example A37) (prepared as shown in scheme 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 minutes at room temperature. LCMS analysis showed the consumption of the starting material with the formation of the desired mass of the product. The solution was concentrated. The residue was partitioned between H2O (20 ml) and EtOAc (20 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The precipitate was combined with a second crop obtained in a parallel reaction carried out in a similar manner 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 (150x25 mm, particle size 5 μm) which was eluted with 22-72% MeCN/H ₂ O (plus 0.05% NH4OH) at a flow rate of 25 ml/min to give 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. 1H 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 ^ ₂ ^ Oz) 461.4 (M + H) ⁺ .

The examples in the table below were synthesized using the methods used to synthesize methyl-(3R,4R)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H- benzimidazol-6-yl]pyrimidin-2yl}amino)-3-hydroxypiperidine-1-carboxylate (Example F1). The following examples have been synthesized with minor changes or substitutions in the exemplary methods that can be carried out by a person skilled in the art. 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.

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Example number Structure/Name LCMS NMR F2 N^ ¹ ΗΝ^ΙΨ ^H °%1 Y> X gT ^M <A V *second eluted stereoisomer methyl-(37?,47?)-4-( 3-yl)-1Hbenzimidazol-6-yl]pyrimidin-2yl}amino)-3-hydroxypiperidine1-carboxylate 491.1 [M+H]+ (ESI) Ή NMR (400 MHz, DMSO-Tb) δ 8.47-8.39 (m, 2H), 8.08-7.90 (t, 1H), 7.57-7.36 (m, 2H), 5.415.30 (m, 1H), 5.09 (d , 7=4.8 Hz, 1H), 4.19-3.77 (t, 7H), 3.59 (s, ZN), 3.51-3.39 (t, 1H), 3.022.64 (t, 2H), 2.62-2.52 (t , 1Н), 2.29–2.18 (t, 1Н), 2.02–1.87 (t, 1Н), 1.43–1.29 (t, 1Н); [a] _D ²⁰ \u003d -28.8 (c \u003d 1.0, MeOH) F3 N^ ^C 'HO^ A. II \ n k ) N-7 ^Me Do D 3 -yl)-\Nbenzimidazol-6-yl]pyrimidin-2yl } amino)-3-hydroxypiperidine1-carboxylate 491.1 [M+H]+ (ESI) Ή NMR (400 MHz, DMSO-de) δ 8.45-8.40 (t, 2H), 8.05-7.91 (t, 1H), 7.56-7.37 (t, 2H), 5.395.31 (t, 1H), 5.16-5.04 (t, 1H), 4.19-3.76 (t, 7H), 3.59 (s, 3H), 3.51-3.39 (t, 1H), 3.00-2.64 (t, 2H), 2.62-2.52 (t, 1H), 2.292 .19 (t, 1H), 2.05-1.87 (t, 1H), 1.42-1.29 (t, 1H); [a] _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)-1Hbenzimidazol-6-yl ]pyrimidin-2-yl}amino)-1-methylpiperidin-3-ol.

Scheme F-2.

Example A37 _π _.

^{n g} Example F4

To a solution of (3R,4R)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6yl]pyrimidin-2-yl}amino )piperidin-3-ol (Example A37) (prepared as shown in Scheme A-1; 50 mg; 0.12 mmol) in MeOH (3 ml) was added paraformaldehyde (100 mg; 1.11 mmol) and NaBH ₃ CN (100 mg; 1.59 mmol). The resulting solution was stirred at room temperature for 30 minutes. LCMS analysis showed the consumption of the starting material with the formation of the desired mass of the product. The solution was filtered and the filtrate was combined with a parallel reaction mixture similarly prepared 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 (150x20 mm, particle size 5 µm) which was eluted with 0-38% MeCN/H2O (0.225% formic acid) at a flow rate of 25 ml/min to give the formic acid salt (3R, 4R)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1Hbenzimidazol-6-yl]-pyrimidin-2-yl}-amino)-1 -methylpiperidin-3-ol (Example F4) (60.2 mg; 58% yield) as a white solid. 1H 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), 2.812.72 (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 (C21H26F2N6O) 417.1 (M+H)+.

The examples in the table below were synthesized using the methods used to synthesize (3R,4R)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-III-benzimidazol- 6-yl]pyrimidin-2-yl}amino)1-methylpiperidin-3-ol (Example F4). The following examples have been synthesized with minor modifications or substitutions in the exemplary methods that can be performed by a person skilled in the art.

Example number Structure/Name LCMS NMR F5 no^A LA N Me-/ Y ^Me Me OH formic acid salt (37?,47?)-4{[4-(1-tert-butyl-D-fluoro-H/benzimidazol-6-yl)-5chloropyrimidin-2 -yl]-amino}-1 (2-hydroxyethyl)-piper idin-3 ol 463.3 [M+H]+ (ESI) Ή NMR (400 MHz, CD ₃ OD) δ 8.51-8.35 (m, 3H), 8.15 (s, 1H), 7.52 (d, 7=11.5 Hz, 1H), 4.06-3.90 (m, 2H), 3.82 (t, 7=5.6 Hz, 2H), 3.45-3.34 (m, 1H), 3.07-2.96 (t, 2H), 2.92-2.70 (t, 2H), 2.48-2.30 (t, 1H), 1.87-1.75 (t, YuN); one proton occluded by residual solvent peak F6 Ν^' A hn ^Ν ΥΎ ^{n (} aA \ LA 11 \ , ^N LJN - N Me- / ^Me Me Me Me fluoro-1Abenzimidazol-6-yl)-5chloropyrimidin-2-yl]-amino}-1 [2-(dimethylamino)ethyl]piper idin-3-ol 490.3 [M+H]+ (ESI) Ή NMR (400 MHz, CD3OD) δ 8.39 (s, 1H), 8.37-8.31 (m, 1H), 8.15 (s, 1H), 7.53 (d, 7=11.5 Hz, 1H), 3.87-3.77 ( m, 1H), 3.75-3.64 (m, 1H), 3.13-3.05 (m, 1H), 2.942.79 (m, 3H), 2.65 (t, 7=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 -A Ν Μθ^^θ Me _Me *second eluted stereoisomer )- 417.2 [M+H]+ (ESI) ^1H NMR (400 MHz, DMSO-Tb) 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 (brm, 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), 1H-benzimidazol-6-yl]pyrimide in-2-yl } amino)-1 (methanesulfonyl)piperide in-3-ol 1.59-1.62 (m, 6H), 1.51-1.40 (m, 1H); [a]c ²⁰ =15.4 (c=0.41, CHCI3)

Example F8 (Scheme F-3): Preparation of (3R,4R)-4-({5-chloro-4-[4-fluoro-2-methyl-1-(oxetan-3-yl)-1Hbenzimidazol-6-yl ]pyrimidin-2-yl}amino)-1-(ethanesulfonyl)-piperidin-3-ol.

Diagram F-3.

Mixture of (3R,4R)-4-({5-chloro-4-[4-fluoro-2-methyl-1-(oxetan-3-yl)-1H-benzimidazol-6-yl]pyrimidin-2yl}amino) piperidin-3-ol (F-1) (prepared as shown 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. Added drop by drop

- 123 042105 solution of ethanesulfonyl chloride (20.8 mg; 0.162 mmol) in EtOAc (1.0 ml) over a 10 minute period. The reaction mixture was stirred at 0°C for 16 hours. LCMS analysis showed the consumption of the starting material with the formation of the desired mass of the product. The reaction layers were separated. The aqueous layer was extracted with EtOAc (3x10 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 (150x25 mm, particle size 5 µm) which was eluted with 28-48% MeCN/H2O (plus 0.05% NH4OH) at a flow rate of 25 ml/min to give (3R,4R) -4-({5-chloro-4-[4-fluoro-2-methyl-1-(oxetan3-yl)-1 H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-1-(ethanesulfonyl )-piperidin-3-ol (Example F8) (7 mg; 8% yield) as a white solid. 1Н 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), 3.883.82 (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), 2.262.17 (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 using the methods used to synthesize (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 minor changes or substitutions in the exemplary methods that can be carried out by a person skilled in the art. 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 LCMS NMR F9 nLA ^HO <A AAT ] an k O N-4 J Me-y ~ _{y he} ° e "° ^Me Me (3R,4R)-4-( { 5 -chloro-4- [4-fluoro-2-( 1 hydroxyethyl)-1 -(propan-2-yl)17/-benzimidazol-6-yl]pyrimide in-2-yl } amino)-1 (difluoromethanesulfonyl)piper idin-3-ol 563.1 [M+H]+ (ESI) Ή NMR (400 MHz, CD3OD) δ 8.38 (s, 1H), 8.06 (s, 1H), 7.51 (br d, 7=11.5 Hz, 1H), 6.88-6.52 (m, 1H), 5.34 (td , 7=6.9, 14.0 Hz, 1H), 5.23 (q, 7=6.8 Hz, 1H), 4.09-3.92 (m, 2H), 3.85 (br d, 7=13.7 Hz, 1H), 3.72 (dt, 7=4.7, 9.0 Hz, 1H), 3.29-3.21 (m, 1H), 3.08 (dd, 7=9.5, 12.8 Hz, 1H), 2.30- 2.22 (m, 1H), 1.77-1.67 (m, 10H), 0.92 (br t, 7=6.5 Hz, 1H); [a] _D ²² = -8.3 (c=0.l, MeOH) F10 n^A ^but \А А А 11 \ ,Ν k О Ν—Ч η ϊ η АОН ⁰ А ⁰ Me me ρΆ (3R,4R)-4-( { 5 -chloro-4- [4-fluoro-2- ( 1 hydroxyethyl)-1 -(propan-2-yl)17/-benzimidazol-6-yl]- 584.9 [M+Na]+ (ESI) Ή NMR (400 MHz, CD3OD) δ 8.38 (s, 1H), 8.06 (s, 1H), 7.627.41 (m, 1H), 6.90-6.48 (m, 1H), 5.40-5.31 (m, 1H), 5.24 (q, 7=6.7 Hz, 1H), 4.06-3.92 (m, 2H), 3.86 (br d, 7=13.2 Hz, 1H), 3.72 (td, 7=4.6, 9, 0 Hz, 1H), 3.31-3.21 (m, 1H), 3.15-2.95 (m, 1H), 2.34-

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pyrimide in-2-yl } amino)-1 (difluoromethanesulfonyl)piperidin-3-ol 2.15 (m, IH), 1.77-1.70 (m, 9H), 1.68-1.62 (m, IH); [a] _D ²² = -25.6 (c=0.l, MeOH) Fil NV ^CI xk %χ<Α ΗΝ Ν γγ but,, A. CZx p* 1 \ N to Y N-4 V ^Μ θΎ >-jun OSO meme Me (35.47?)-(ge/)-4-[ (5-chloro-4-{4-fluoro2-[(1H)-1-hydroxyethyl]-1(propan-2-yl)- 1H-benzimidazol6-yl }pyrimidin-2-yl)amino]-1 (methanesulfonyl) piperide in-3-ol 526.9 [M+H]+ (ESI) Ή NMR (400 MHz, CD ₃ OD) δ 8.39 (s, IH), 8.04 (s, IH), 7.48 (d, 7=11.5 Hz, IH), 5.40-5.29 (m, IH), 5.23 ( q, 7=6.8 Hz, IH), 4.15-4.07 (m, 2H), 3.82-3.72 (m, 2H), 3.14 (brd, 7=11.8 Hz, IH), 3.05 (dt, 7= 3.0, 12.2 Hz, IH), 2.95 (s, 3H), 2.12-2.00 (m, IH), 1.90 (brd, 7=9.5 Hz, IH), 1.751.70 (m, 9H) F12 xk A/iA hn ν YY _he OSO Meme Me (35.47?)-(he/)-4-[(5-chloro-4-{4-fluoro2-[(17?)-1-hydroxyethyl]-1(propan-2-yl) - 1H-benzimidazol6-yl}pyrimidin-2-yl)amino]-1(methanesulfonyl)piperide in-3-ol 526.9 [M+H]+ (ESI) C NMR (400 MHz, CD ₃ OD) δ 8.37 (s, IH), 8.06 (s, IH), 7.50 (d, 7=11.5 Hz, IH), 5.34 (m, 7=7.0, 13 .9 Hz, IH), 5.23 (m, 7=6.7 Hz, IH), 4.00-3.91 (m, IH), 3.87-3.81 (m, IH), 3.783.66 (m, 2H), 2.95 ( m,/=2.5, 12.0 Hz, IH), 2.90 (s, 3H), 2.76 (m, 7=9.5, 11.5 Hz, IH), 2.292.20 (m, IH), 1.75-1.65(m, 10H) F13 Ν^' ^HO -A Vn Μ -ΑΥ.ΟΗ O \u003d S \u003d O mem / Me (35.45) -4- [(5 -chloro-4- { 4-fluoro-2 [(17?) -1 - hydroxyethyl] -1 -(propan-2-yl)-1H-benzimidazol-6yl } pyrimidin-2-yl)amino]-1 - 526.9 [M+H]+ (ESI) C NMR (400 MHz, CD ₃ OD) δ 8.37 (s, IH), 8.06 (s, IH), 7.50 (d, 7=11.6 Hz, IH), 5.34 (m, 7=6.9, 13 .9 Hz, IH), 5.23 (m, 7=6.6 Hz, IH), 4.00-3.92 (m, IH), 3.84 (m, 7=1.7, 4.6, 11.6 Hz, IH ), 3.79-3.65 (m, 2H), 2.992.91 (m, IH), 2.90 (s, 3H), 2.802.67 (m, IH), 2.28-2.21 (m, IH),

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(methanesulfonyl)piperide in-3-ol 1.76-1.63 (m, Yun) F14 HN N O=s=o L ^Me Me (35.45)-4-({5-fluoro-4-[4-fluoro-2methyl-1 -(propan-2-yl)-1Hbenzimidazol-6-yl]pyrimide in -2yl } amino)-1 -(methanesulfonyl)piper idin-3-ol 481.2 [M+H]+ (ESI) Ή NMR (400 MHz, DMSO-Je) δ 8.43 (d, 7=4.0 Hz, 1H), 8.12 (s, 1H), 7.62 (br d, 7=12.3 Hz, 1H), 7.22 (br d, 7=7.0 Hz, 1H), 5.22 (br d, 7=4.3 Hz, 1H), 4.89-4.73 (m, 1H), 3.77 (br s, 1H), 3.61 (br d, 7 =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, 7=6.8 Hz, 6H), 1.52 (br s, 1H). F15 N^ HN^N^Lpii^^/F HO^ A Jk II \ , ^N k JN-7 N Me--/ O=S=O Me _Me Me (37?,47?)-4- {[4- (1-ot/?eot-butyl-4fluoro-1H-benzimidazol-6-yl)-5fluoro pyrimide in-2-yl]amino} -1 (methanesulfonyl)piperide in-3 -ol 481.1 [M+H]+ (ESI) Ή NMR (700 MHz, DMSO-Tb) δ 8.42-8.34 (m, 2H), 8.21 (br. s., 1H), 7.65-7.54 (m, 1H), 7.15 (d, 7=7.7 Hz, 1H), 5.22-5.07 (m, 1H), 3.77-3.66 (m, 1H), 3.623.51 (m, 2H), 3.48-3.39 (m, 1H), 2.84 (s, 3H), 2.80 (dt, 7=2.6, 11.7Hz, 1H), 2.61 (1.7=10.1Hz, 1H), 2.04 (d, 7=7.3Hz, 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)-1Hbenzimidazol- 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-2yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl trifluoroacetate }amino)piperidin-3-ol (example A37) (300 mg; 0.581 mmol) and triethylamine (226 mg; 0.31 ml; 2.24 mmol) in DCM (5 ml) were added Ac ₂ O (152 mg; 0 .14 ml; 1.49 mmol). The mixture was stirred at ambient temperature for 2 hours, then diluted with water (10 ml) and extracted with DCM (3x10 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 (150x25 mm, particle size 5 µm, column temperature 25°C), which was eluted with 15-55% MeCN/H ₂ O (plus 0.05% NH4OH) 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)-1Hbenzimidazol-6-yl] pyrimidin-2-yl}amino)-3-hydroxypiperidin-1-yl]ethan-1-one (Example F16) (22.0 mg; 9% yield) as a white solid. 1H 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 (C22H26F2N6O2) 445.4 (M+H)+.

- 126 042105

Example F17 (Scheme F-5): Preparation of 1-[(3R,4R)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1Hbenzimidazol- 6-yl]pyrimidin-2-yl}amino)-3-hydroxypiperidin-1-yl]-2-hydroxyethan-1-one.

Diagram F-5.

To trifluoroacetate (3R,4R)-4-({5-fluoro-4-[4-fluoro-2-methyl-1 -(propan-2-yl)-1 H-benzimidazol-6yl]pyrimidin-2-yl} amino)-piperidin-3-ol (Example A37) (50 mg; 0.12 mmol) and glycolic acid (9.45 mg; 0.124 mmol) in DMF (4.0 ml) were added 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 the consumption of the starting material with the formation of the desired mass of the 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 (150x25 mm, particle size 5 μm) which was eluted with 12-52% MeCN/H ₂ O (plus 0.05% NH4OH) 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)-1Hbenzimidazol-6-yl]pyrimidin-2-yl}amino)- 3-hydroxypiperidin-1-yl]-2-hydroxyethan-1-one (Example F17) (8 mg; 14% yield) as a white solid. 1H 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, 9.3Hz, 1H), 4.83 (hept, J=6.9Hz, 1H), 4.56 (t, J=5.0Hz , 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 (C22H26F2N6O ₃ ) 461.3 (M+H) ⁺ .

The examples in the table below were synthesized using the methods used to synthesize 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 minor changes or substitutions in the exemplary methods that can be carried out by a person skilled in the art.

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Example number Structure/Name LCMS NMR F18 aX _f ^but x x k G N-U N Me—-/ fXo ^Me O-/ [(37?,47?)-4-({ 5-chloro-4-[4-fluoro-1 (propane-2- yl)- 1H-benzimidazol6-yl] pyrimidin-2-yl } amino)-3 hydroxypiperidin-1 yl] (oxetan-3 -yl) methanone 488.9 [M+H]+ (ESI) Ή NMR (400 MHz, DMSO-Te) δ 8.52 (s, 1H), 8.43 (d, 7=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), 4.413.95 (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, 7=6.8 Hz, 6H), 1.34-1.32 (m, 1H) F19 ΪΥ F ^Η0 Ό _Μ > ^Ν οΧ^ο ^{Me V} Me [(37?,47?)-4-({ 5-chloro-4-[4-fluoro-1 (propan-2-yl)-177-benzimidazole6- yl]pyrimidin-2-yl} amino)-3 hydroxypiperidin-1 -yl ](3 methyloxetan-3 -yl) methanone 502.9 [M+H]+ (ESI) ^X H NMR (400 MHz, DMSO-Tb) δ 8.54 (s, 1H), 8.44 (s, 1H), 7.91 (br s, 1H), 7.64-7.35 (m, 2H), 5.265.12 (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), 2.662.57 (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 N^' HO.A XX II \ Ν k / N—J Ν Me-γ Μθχ^Χθ _Me OH (27?)-1-[(37?,47?)-4-({5-chloro-4- [4chloro-1 -(propan-2-yl)-\Hbenzimidazol-6-yl]pyrimidin2-yl}amino)-3- 515.1 [M+Na] + (ESI) Ή NMR (400 MHz, DMSO-Tb) 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, 7=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, 7=6.7 Hz, 6H), 1.491.26 (m, 2H), 1.18 (dd, 7=9.2, 6.5 Hz, ZN)

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hydroxypiperidin-1-yl]-2hydroxypropan-1-one F21 NY ^CI HN N VV HCU HA 11 \ ,Ν LJN— N Me-y ^Me A ₀ ^Me Me OH (25)-1- [(3R,4R)-4- {[4-(1-mpembutyl-4-fluoro -1H-benzimidazol6-yl)-5-chloropyrimidin-2yl]amino}-3hydroxypiperidin-1-yl]-2hydroxypropan-1-one 490.9 [M+H]+ (ESI) Ή NMR (400 MHz, DMSO-Tb) 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, 7 =6.7 Hz, 1H), 4.494.13 (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 (brt, 7=7.5 Hz, ZN) F22 χχΓ HO^ Λ. N. A 11 \ Ν LJ N-Τ' Ν Me-y | A ₀ ^Me Me OH 1 - [(3R,4R)-4-{[4-(3-mpem-butyl3//-imidazo[4,5-/ >]pyridin-5yl)-5-chloropyridin-2yl]amino}-3hydroxypiperidin-1-yl]-2hydroxyethan-1-one 459.0 [M+H]+ (ESI) Ή NMR (500 MHz, DMSO-Τβ) δ 8.55 (s, 1H), 8.20-8.20 (m, 1H), 8.20-8.20 (m, 1H), 8.19 (d, 7=8.2 Hz, 1H), 8.11 (d, 7=4.9Hz, 1H), 7.54 (d, 7=8.4Hz, 1H), 6.98-6.90 (m, 1H), 6.82 (d, 7=9.3Hz, 1H) , 5.20 (dd, 7=4.7, 11.2 Hz, 1H), 4.55 (t, 7=5.2 Hz, 1H), 4.17-4.06 (m, 2H), 3.87 (br d, 7=13 .7 Hz, 1H), 3.68-3.58 (m, 1H), 3.19 (brt, 7=9.6 Hz, 1H), 3.12-3.00 (m, 1H), 2.092.00 (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)-1Hbenzimidazol- 6-yl]pyrimidin-2-yl}amino)-3-hydroxypiperidin-1-yl]-2-(methylamino)ethan-1-one.

Diagram F-6.

To a solution of compound (F-2) (prepared as shown 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 the consumption of the starting material with the formation of the desired mass of the product. The reaction solution was concentrated to dryness. The residue was taken up in MeOH (5 ml) and treated with ΝΗ ₃ ·Η ₂ Ο to adjust the pH to about 7-8. The solution was concentrated. The residue was purified by preparative HPLC on a DuraShell column (150x25 mm, particle size 5 μm) which was eluted with 22-42% MeCN/H ₂ O (plus 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)-3hydroxypiperidin-1-yl]-2-(methylamino)ethan-1-one (Example F23) (35.2 mg; 27% yield) as a white solid. 1H 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 d, J=4.5Hz, 1H), 4.82 (td, J=6.8, 13.8Hz, 1H), 4.11-3.65 (m, 3H), 3.603.38 (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 (C23H29F2N7O2) 474.5 (M+H) ⁺ .

The examples in the table below were synthesized using the methods used to synthesize 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 minor modifications or substitutions in the exemplary methods,

- 129 042105 which can be carried out by a person skilled in the art. 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 LCMS NMR F24 Ny ^{CI Η0} Ό Ν Me-γ Me .. -ΝΗ Me 1 -[(37?, 477)-4-( {5-chloro-4- [4-φτορ-1 (propan-2-yl)- 17/ -benzimidazol-6yl]iirimidin-2-yl } amino)-3 hydroxypiperidin-1 -yl]-2(methylamino)ethan-1-one 476.2 [M+H]+ (ESI) Ή NMR (400 MHz, DMSO-Tb) δ 8.53 (s, 1H), 8.44 (d, 7=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, 7=6.7, 13.3 Hz, 1H), 4.35 (br d, 7=12.5 Hz, 1H), 4.04 -3.80 (m, 2H), 3.75 (br d, 7=9.8 Hz, 1H), 3.51 (br s, 1H), 3.10-2.94 (m, 2H), 2.58 (br t, 7=11.3 Hz, 1H), 2.28 (d, 7=2.0 Hz, ZN), 1.90 (s, 1H), 1.56 (d, 7=6.7 Hz, 6H), 1.38 (br d, 7=17.2 Hz, 1H) F25 N ^ Y ^CI AX /% / F HN N JY AD 11 \, Ν LJ n-7 N Me- / A _o ^m 4e GL -NH Me 1 - [(37?,47?) -4- {[4- (1-tert-butyl-4fluoro-17/-benzimidazol-6-yl)-5chloropyrimidin-2-yl] amino } -3 hydroxypiperidin-1 -yl] -2(methylamino)ethan-1 -one 512.2 [M+Na] + (ESI) Ή NMR (400 MHz, D ₂ O) δ 9.439.31 (m, 1H), 8.43 (s, 1H), 8.31 (br s, 1H), 7.77 (br d, 7=10.8 Hz, 1H), 4.46-3.98 (m, 4H), 3.853.56 (m, 2H), 3.32-2.82 (m, 2H), 2.76 (d, 7=3.0 Hz, ZN), 2.15-2.14 (m, 1H), 1.84 (s, 9H), 1.60-1.59 (m, 1H) F26 N^A A HN N ]|V no. l. AD II \ ,ν L ) Ν— Ν Me-γ Me ΗΝ ³ [(3R,4R)-4-{[4-(1-tert-butyl-4- 520.0 [M+H]+ (ESI) Ή NMR (500 MHz, CD ₃ OD) δ 8.42-8.17 (m, 2H), 8.04 (s, 1H), 7.42 (d, 7=11.4 Hz, 1H), 4.403.88 (m, 4H), 3.84-3.45 (m, 4H), 3.15-2.67 (m, 2H), 2.09 (d, 7=13.4 Hz, 1H), 1.72 (s, 9H),

- 130 042105

fluoro-1H-benzimidazol-6-yl)-5chloropyrimidin-2-yl] amino } -3 hydroxypiperidin-1 -yl] (3 fluoroaz etidin-3 -yl) methanone 1.50-1.36(m, 1H) F27 N^ ¹ no^A SD 11 \ ,Ν L ) Ν- _F N Mey JAo ^Me nD [(37?,4R)-4-( { 5 -chloro-4- [4-fluoro-1 (propane-2- yl)-1H-benzimidazol-6yl]pyrimidin-2-yl}amino)-3 hydroxypiperidin-1-yl](3-fluoroaz etidin-3-yl)methanone 506.1 [M+H]+ (ESI) ^1H NMR (500 MHz, DMSO-Tb) δ 8.45 (s, 1H), 8.35 (s, 1H), 7.82 (br s, 1H), 7.55-7.04 (m, 2H), 5.13 (dd, 7=21 ,1, 4.8 Hz, 1H), 4.75 (p, 7=6.7 Hz, 1H), 4.27-3.74 (m, 4H), 3.70-3.35 (m, 4H), 3.092.62 (m, 2H ), 1.96 (br s, 7=33.6 Hz, 1H), 1.49 (d, 7=6.7 Hz, 6H), 1.43-1.23 (m, 1H) F28 N^ ¹ HN N VV DO X ^N Ν Mey Me νη ₂ (1-aminocyclopropyl) [(37?,47?)-4({5-chloro-4-[4-fluoro-1 -(propan-2yl)- 1H-benzimidazol-6yl]pyrimidin-2-yl}amino)-3 hydroxypiperidin-1 -yl] methanone 488.1 [M+H]+ (ESI) Ή NMR (500 MHz, DMSO-Tb) 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, 7=6.7, 13.4 Hz, 1H), 4.25 (br d, 7=10.2 Hz, 1H), 4.17-3.94 (m, 1H), 3.88 (br dd, 7=3 .2, 8.1 Hz, 1H), 3.49 (br d, 7=3.4 Hz, 1H), 3.03 (br s, 1H), 2.37-2.19 (m, 2H), 1.97 (br s, 1H) , 1.56 (d, 7=6.6 Hz, 6H), 1.46-1.24 (m, 1H), 0.79 (br s, 2H), 0.71-0.53 (m, 2H) F29 Ν^' but^ A. SD 11 \ ,Ν LJ Ν—7 Ν Mey ^F X>A ^{Me F v} nh ₂ 538.0 [M+H]+ (ESI) Ή NMR (400 MHz, DMSO-Tb) δ 8.54 (s, 1H), 8.44 (s, 1H), 7.91 (br s, 1H), 7.56-7.32 (m, 2H), 5.18 (d, 7=70, 6 Hz, 1H), 4.83 (p, 7=6.8 Hz, 1H), 4.42-3.76 (m,

- 131 042105

(1-amino-3,3difluorocyclobutyl) [(37?,47?)-4-({ 5 chloro-4-[4-fluoro-1 -(propan-2-yl)1H-benzimidazol-6-yl]pyrimidine -2-yl } amino)-3 hydroxypiperidin-1 -yl] methanone ZN), 3.51 (d, 7=65.9 Hz, 1Н), 3.25-2.92 (br, ZN), 2.64-2.55 (br, ZN), 2.48-2.42 (m, 1Н), 1.99 (s, 1Н) , 1.57 (d, 7=6.7 Hz, 6H), 1.52-1.30 (m, 1H) F30 NV ^CI A ΗΝ Ν γ y no _h A. XA 11 \ Ν k A Ν— Ν Me-X ^{Me Me F v} nh ₂ (1-amino-3,3-difluorocyclobutyl)[(3R,4R)-4-{ [4-(1-tert-Butyl-4fluoro-1H-benzimidazol-6-yl)-5chloropyrimidin-2-yl] amino } -3 hydroxypiperidin-1 -yl] methanone 552.2 [M+H]+ (ESI) Ή NMR (500 MHz, CD ₃ OD) δ 8.27 (d, 7=5.1 Hz, 2H), 8.04 (s, 1H), 7.42 (d, 7=11.4 Hz, 1H), 4.01-3.43 ( m, 4H), 3.16-3.04 (br, 3H), 2.75-2.37 (br, 3H), 2.142.01 (m, 1H), 1.72 (s, 9H), 1.48 (s, 1H) F31 N^y ^CI ns < .A LX 11 G N LJ ν-7 Ν Me-γ Ao ^Me F ₃ Ci 'NH ₂ (35)-3 -amino-1 -[(3R,4R)-4-({ 5chloro -4- [4-fluoro-1 - (propan-2-yl) 1H-benzimidazol-6-yl] pyrimidin-2-yl} amino)-3 hydroxypiperidin-1 -yl] -4,4,4 trifluorobutan-1 - He 544.0 [M+H]+ (ESI) Ή NMR (500 MHz, DMSO-Tb) 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, 7= 4.7, 12.5 Hz, 1H), 4.75 (td, 7=6.7, 13.4 Hz, 1H), 4.40-3.28 (m, 5H), 3.122.98 (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 AC/ HN ^yy no., a. XA T 1 \ ν Me-X ⁷ F^Ao ^Me Me Xn ₂ 3 -amino-1 - [(37?,47?) -4-{ [4-( 1 -tert-butyl-4-fluoro-1H-benzimidazole- 6yl)-5-chloropyride in-2-yl]amino }-3 hydroxypiperidin-1-yl]-2,2difluoropropan-1-one 525.3 [M+H]+ (ESI) 1H NMR (400 MHz, DMSO-Tb) δ 8.38 (s, 1H), 8.08 (s, 1H), 7.69 (s, 1H), 7.12 (d, 7=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 (brt, 7=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-5yl)-5-chloropyridine -2-yl]amino}-3-hydroxypiperidin-1-yl]-N-methylacetamide.

Scheme F-7.

To a solution of (3R,4R)-4-{[4-(3-tert-butyl-3H-imidazo[4,5-b]pyridin-5-yl)-5-chloropyridin-2yl]amino}piperidin-3- ol (prepared as shown in Example D3; 100 mg; 0.249 mmol) in EtOH (6.0

- 132 042105 ml) was added 2-bromo-N-methylαcetamide (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 (MeOH/EtOAc, 1:3) showed consumption of starting material. The mixture was diluted with water 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 (150x25 mm, particle size 5 µm) which was eluted with 21-41% MeCN/H ₂ O (plus 0.05% NH4OH) at a flow rate of 25 ml/min to give 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-methylα-cetamideα (Example F33) (45.5 mg; 39% yield) as a white solid. 1H 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=5.6 Hz, 1H), 3.60-3.49 (m, 2H) , 2.91 (d, J=2.0 Hz, 2H), 2.89-2.85 (m, 1H), 2.68 (br d, J=11.1 Hz, 1H), 2.62 (d, J=4.7 Hz, 3Н), 2.18-2.09 (m, 1H), 2.06-1.98 (m, 2H), 1.80 (s, 9H), 1.501.39 (m, 1Н); 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)n-iperidin-4yl]amino}pyrimidin-4-yl) -4-fluoro-1 -(propan-2-yl)-1 H-benzimidazol-2-yl]ethan-1 -one.

Scheme G-1.

Step 1: Synthesis of 1-[6-(2,5-dichloro-pyrimidin-4-yl)-4-fluoro-1-(propαn-2-yl)-1H-benzimidazol-2yl]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-1ol (G-1) ( obtained as shown in example A1; 500 mg; 1.35 mmol) in CHCl ₃ (10 ml) was added MnO ₂ (824 mg; 9.48 mmol). The mixture was stirred at 50°C for 6 hours. LCMS analysis showed the consumption of the starting material with the formation of the desired mass of the 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-2yl]ethan-1-one (G-2) (480 mg; 97% yield) as a white solid. 1H 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 (Cj^C^FN^) 367.0 (M+H) ⁺ .

Step 2: Synthesis of 1-[6-(5-chloro-2-{[(3R,4R)-3-hydroxy-1-(methanesulfonyl)-pineridin-4yl]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-1one (G-2) ( 100 mg; 0.272 mmol) in DMSO (5.0 ml) was added DIPEA (106 mg; 0.817 mmol) and (3R,4R)-4amino-1-(methanesulfonyl)piperidin-3-ol (Int-69). The mixture was stirred at 70°C for 16 hours. LCMS analysis showed the consumption of the starting material with the formation of the desired mass of the product. The mixture was diluted with water H ₂ O (30 ml) and was extracted with EtOAc (2x30 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, Rf = 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)-1Hbenzimidazol-2-yl]ethan-1-one (Example G1) (58, 2 mg, 41% yield as a white solid. 1Н 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

- 133 042105 (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 (C22H26CIFN6O4S) 525.2 (M+H) ⁺ .

Example H1 (Scheme H-1): Preparation of 1,5-anhydro-3-({5-chloro-4-[2-(chloromethyl)-4-fluoro-1-(propan-2yl)-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 the consumption of the starting material with the formation of the desired mass of the product. The reaction mixture was diluted with H2O (300 ml) and extracted with EtOAc (3x300 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 ; yield 98%) as a red solid. 1Н 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 _w BrFN2O2) 276.7 (M+H) ⁺ .

Step 2: Synthesis of [6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]methanol (H-1).

1 ,4-dioxane-2,5-diol (20.8 g; 173 mmol) and Na ₂ S ₂ O ₄ (126 g; 722 mmol). The mixture was stirred at reflux temperature 80°C for 16 hours. LCMS analysis showed the consumption of the starting material with the formation of the desired mass of the product. The mixture was diluted with H ₂ O water (100

- 134 042105 ml) and extracted with EtOAc (3x300 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-4fluoro-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, CD3OD) 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 the consumption of the starting material with the formation of the desired mass of the product. The reaction mixture was diluted with H2O (100 ml) and extracted with EtOAc (3x150 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), 1.721.63 (m, 2H), 1.57 (d, J=6.8 Hz , 6H), 1.53-1.46 (m, 4H); m/z (ESI+) for (C16H ₂ 0BrFN 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 ,2dioxaborolan-2-yl) -1 H-benzimidazole (H-2).

To a 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), B2Pin (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) in an N2 atmosphere. The mixture was stirred at 80° C. under N2 for 16 hours. LCMS analysis showed the consumption of the starting material with the formation of the desired mass of the product. The mixture was cooled to room temperature, filtered through celite and concentrated to dryness. The residue was taken up in H ₂ O (150 ml) and extracted with EtOAc (3x150 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 (360 g SiO ₂ , 0-100% EtOAc/petroleum ether) to give 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) (9.4 g; 73% yield) as a 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-2yl)-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-1,3,2dioxaborolan- 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) was degassed with N ₂ for 5 minutes. Pd(PPh ₃ ) ₄ (829 mg; 0.717 mmol) was added and the mixture was degassed for another 10 minutes. The reaction mixture was stirred at 90° C. under N2 for 16 hours.

LCMS analysis showed the consumption of the starting material with the formation of the desired mass of the product. The reaction mixture was cooled to room temperature, diluted with H2O (30 ml) and extracted with EtOAc (3x100 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-2yl) hydroxy]methyl}-1-(propan-2-yl)-1H-benzimidazole (H-3) (7.4 g; 99% yield) as 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)-1Hbenzimidazole (H- 3) (2.3 g; 19.8 mmol) in DMSO (150 ml) was added DIPEA (10.6 g; 82.4 mmol) and 3amino-1,5-anhydro-2,3-dideoxy-O-threo -pentitol (7.2 g; 16.5 mmol). The mixture was stirred at 120°C for 16 hours. LCMS analysis showed the consumption of the starting material with the formation of the desired mass of the product. The reaction solution was diluted with H ₂ O (200 ml) and extracted with EtOAc (3x200 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-6yl]-pyrimidin-2-yl}amino)-2,3-dideoxy-O-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)-1Hbenzimidazol-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

- 135 042105 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 dropwise a solution of HCl (4 N. in 1,4-dioxane; 10.0 ml) at 0°C. The solution was stirred at 20°C for 1 hour. LCMS analysis showed the consumption of the starting material with the formation of the desired mass of the product. The reaction mixture was concentrated to dryness. The residue was purified by flash chromatography (80 g SiO ₂ ; MeOH/DCM, 1:10) to give 1,5-anhydro-3-({5-chloro-4[4-fluoro-2-(hydroxymethyl)-1- (propan-2-yl)-1 H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3dideoxy-D-threo-pentitol (H-5) (3.2 g; 80% yield) as a yellow oil. 1H NMR (400 MHz, CD3OD) 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, 3 H) 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^OT^O3) 436.2 (M+H)+.

Step 8: Synthesis of 1,5-anhydro-3-({5-chloro-4-[2-(chloromethyl)-4-fluoro-1-(propan-2-ul)-1Hbenzimidazol-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-benzimidazol6-yl]pyrumidin-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 showed consumption of starting material. The reaction mixture was washed with NU. The aqueous layer was extracted with DCM (3x10 ml). The combined organic phases 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)-1 H-benzimidazol-6-yl]pyrimudin-2-ul}amino)-2,3-dideoxy-D-threo-pentitol (H-6) (800 mg; 96% yield), which was used without further purification , m/z (ESI+) for (C2oH22C12FN502) 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-dideoxu-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-6yl]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 atmosphere at 25° C. for 3 hours. LCMS analysis showed the consumption of the starting material with the formation of the desired mass of the product. The reaction solution was washed with H ₂ O (5 ml). The aqueous layer was extracted with DCM (3x5 ml). The combined organic layers were washed with brine (10 ml), dried over Na2SO4, filtered and concentrated. The crude residue was purified by preparative HPLC on a YMC Triart column (30x150 mm, particle size 7 µm) which was eluted with 30-50% MeCN/H2O (plus 0.05% NH4OH) at a flow rate of 25 ml/min to give 1.5 -anhydro-3-[(5-chloro-4-{4-fluoro-2-[(3-hydroxy-3-methylazetidin-1-yl)methyl]-1-(propan-2yl)-1H-benzimidazole-6 -yl}pyrimidin-2-yl)-amino]-2,3-dideoxy-D-threo-pentitol (Example H1) (23.5 mg; 21% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.35 (s, 1H), 8.02 (s, 1H), 7.49 (d, J=11.4 Hz, 1H), 5.16 (app 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 (C24H3oClFN6O3) 505.2 (M+H)+.

The examples in the table below were synthesized by 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-2yl}amino)-2,3-dodeoxy-D-threo-pentitol (example H1). The following examples have been synthesized with minor changes or substitutions in the exemplary methods that can be carried out by a person skilled in the art.

Example number Structure/Name LCMS NMR H2 AA 1] ' // ^Ν UN N- \ Me o me-γ Me Me 1,5 -anhydro-3 - [(5 -chloro-4- { 2[(dimethylamino)methyl] -4fluoro-1 - (propane- 2-yl)-\Nbenzimid azol-6-yl } pyrimidin-2-yl)amino]-2,3 dideoxy-O-p/p-p-pentitol 463.1 [M+H]+ (ESI) Ή NMR (400 MHz, CD ₃ OD) δ 8.37 (s, 1H) 8.06 (s, 1H) 7.52 (d, 7=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, 7= 7.0Hz, 6H) 1.58-1.67(m, 1H)

- 136 042105

nz GS F n^yTDkD “D A C JN—k 0 Me-γ ^^ _N /\ _he Me ^v 1,5-anhydro-3 - [(5-chloro-4- { 4fluoro-2- [(3-hydroxyaz etidin1-yl)methyl]-1-(propan-2-yl)1R-benzimidazol-6-yl}pyrimidin-2-yl)amino]-2,3 dideoxy-O-ot/?eo-pentitol 491.1 [M+H]+ (ESI) Ή NMR (400 MHz, CD3OD) δ 8.35 (s, 1H), 8.02 (s, 1H), 7.49 (d, 7=11.4 Hz, 1H), 5.16-5.06 (m, 1H), 4.35 (t, 7=6.2 Hz, 1H), 4.013.89 (m, 5H), 3.66-3.57 (m, 3H), 3.48 (dt, 7=2.1, 11.7 Hz, 1H), 3.20 (dd, 7=9.7, 11.1Hz, 1H), 3.11-3.05 (m, 2H), 2.18-2.09 (m, 1H), 1.68 (d, 7=7.0 Hz, 6H), 1.66-1.58 (m , 1H) H4 _N ^< ^CI n 1\A ^F but _to A DD T 1 \ ^N LJ ν—7 0 Me^/ \_κ/\.' ^{Me _} -1 - (propan-2-yl) - 1Hbenzimidazol-6-yl] pyrimide in-2-yl} amino) -2,3 dideoxy-O-p / rso-pentitol 519.3 [M+H]+ (ESI) Ή NMR (400 MHz, CD3OD) δ 8.35 (s, 1H), 8.03 (s, 1H), 7.50 (d, 7=11.6 Hz, 1H), 5.19-5.10 (m, 1H), 4.04-3.89 ( m, 5H), 3.61 (dt, 7=4.7, 9.4 Hz, 1H), 3.48 (dt, 7=2.3, 11.7 Hz, 1H), 3.25-3.17 (m, 3H), 2.97 (d, 7=6.7Hz, 1H), 2.13 (td, 7=2.3, 13.2Hz, 1H), 1.69 (dd, 7=6.9, 12.9Hz, 7H), 1.28 (s, 3H), 0.88 (d, 7=6.2 Hz, ZN) H5 N^' D X^-^F HN N Vy DD Ό c O me-γ V _NH Μθ γ -yl)amino]methyl } -1 -(propan-2-yl)1H-benzimidazol-6-yl]- 491.2 [M+H] ⁺ (ESI) Ή NMR (400 MHz, CD3OD) δ 8.37 (s, 1H) 8.06 (s, 1H) 7.52 (d, 7=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(br, 1H) 3.19-3.26 (m, 1H)2.13 (m, 1H) 1.72 (d, 7= 6.7Hz, 6H), 1.69-1.61(m, 2H)

- 137 042105

pyrimide in-2-yl } amino)-2,3 dideoxy-O-threo-pentitol H6 ns < LA II ' // ^N kp N-h 0 Me-γ Me ^v 1,5 -anhydro-3 - [(5 -chloro-4- { 4fluoro-2-[(3 -fluoroazetidin-1 yl)methyl] -1 -(propan-2-yl)- 1 / / benzimide azol-6-yl } pyrimidin-2-yl) amino] -2,3 dideoxy-O-thyreo-pentitol 493.2 [M+H]+ (ESI) Ή NMR (400 MHz, CD3OD) δ 8.35 (s, 1H), 8.03 (s, 1H), 7.49 (d, 7=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), 3.373.32 (m, 1H), 3.20 ( dd, 7=9.7, 11.1 Hz, 1H), 2.18-2.09 (m, 1H), 1.68 (d, 7=6.8 Hz, 6H), 1.66-1.58 (m, 1H) H7 Ny ^CI HOvA. LA % Ao Me 1,5 -anhydro-3 - [(4- { 2[(azetidin-1 -yl)methyl] -4-fluoro- 1 - (propan-2-yl) -1Hbenzimidazol-6-yl} - 5chloropyrimidin-2-yl)amino]2,3-dideoxy-О-ot/?eopentitol 475.2 [M+H]+ (ESI) Ή NMR (400 MHz, CD3OD) δ 8.35 (s, 1H), 8.03 (s, 1H), 7.49 (d, 7=11.4 Hz, 1H), 5.15-5.07 (m, 1H), 4.01-3.89 ( m, 5H), 3.61 (br d, 7-4.8 Hz, 1H), 3.52-3.44 (m, 1H), 3.35 (t, 7=7.0 Hz, 4H), 3.20 (dd, 7=9 .7, 11.1 Hz, 1H), 2.162.08 (m, 3H), 1.69 (d, 7=7.0 Hz, 6H), 1.67-1.60 (m, 1H)

Example H8 (Scheme H-2): 1,5-anhydro-3-({5-chloro-4-[4-fluoro-1-(propan-2-yl)-2-{[(propan-2yl)amino ]methyl}-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol.

Scheme H-2.

iPrNH ₂ , AsOH NaBH ₃ CN MeCN yield 21%

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).

Mixture of (3R,4R)-4-({5-chloro-4-[4-fluoro-2-(hydroxymethyl)-1-(propan-2-yl)-1H-benzimidazol-6yl]pyrimidin-2-yl} amino)-1-(methanesulfonyl)piperidin-3-ol (H-5) (900 mg; 2.1 mmol) and MnO ₂ (2.7 g;

mmol) in MeOH (20.0 ml) was stirred at 60°C for 16 hours. LCMS analysis showed 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 ; MeOH/DCM, 1:10) 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; 26% yield ) as a colorless oil. ¹ H NMR (400 MHz, CD3OD) δ 1.69 (t, J=5.77 Hz, 7H) 2.00- 138 042105

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 (C20H23CWN5O4) 452.2 (M+H) ⁺ .

Stage 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)-1Hbenzimidazol-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 mg, 0.215 mmol) was added and the mixture was stirred for 16 hours overnight. LCMS analysis showed the consumption of the starting material with the formation of the desired mass of the 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 (3x5 ml). The combined organic layers were washed with brine (15 ml), dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC on an Xtimate C18 column (250x80 mm, particle size 10 µm) which was eluted with 35-55% MeCN/H ₂ O (plus 0.05% NH4OH) at a flow rate of 25 ml/min to give 1. 5-anhydro3-({5-chloro-4-[4-fluoro-1-(propan-2-yl)-2-{[(propan-2-yl)amino]methyl}-1H-benzimidazol-6yl]pyrimidine -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, CD3OD) 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 ^^ClFNA) 477.1 (M+H) ⁺ .

The examples in the table below were synthesized using the methods used to synthesize 1,5-anhydro-3-({5-chloro-4-[4-fluoro-1-(propan-2-yl)-2-{[(propan-2 -yl)amino]methyl}-1H-benzimidazol-6yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol (Example H8). The following example was synthesized with minor changes or substitutions in the exemplary methods that can be carried out by a person skilled in the art.

Example number Structure/Name LCMS NMR H9 <t ^C| V -F ΗΝ Ν G Υ but ^ A XA to U N-4 _N_ Me—V _NH Me \__ Me / 7 568.1 [M+H]+ (APCI) Ή NMR (700 MHz, DMSO-Tb) δ 8.43 (s, 1H), 8.09-7.68 (m, 1H), 7.44 (d, 7=35.3 Hz, 1H), 5.01 (p, 7=6.8 Hz, 1H), 4.59 (t, 7=6.6 Hz, 2H), 4.35-4.26 (m, 2H), 4.00 (s,

- 139 042105

(3R,4R)-4-( { 5 -chloro-4- [4-fluoro-2{[(oxetan-3 -yl)amino]methyl } -1 (propan-2-yl)- 1//-benzimidazole -6yl]pyrimidin-2-yl } amino)-1 (methanesulfonyl)-piper idin-3 -ol 2H), 3.92 (d, 7=11.1 Hz, 1H), 3.85-3.74 (m, 2H), 3.66-3.57 (br, 6H), 2.89 (s, 3H), 1.59 (d, 7=6, 8Hz, 6H) H10 £m ^C| ΗΝ ^Ν |^ f no^A CA 11 \ ν OS-0 _Me < _Me Me Me (3R,4R)-4-( { 5 -chloro-4- [4-fluoro-1 (propan-2-yl) - 2-{[(propan-2yl)amino]methyl}-1/7benzimidazol-6-yl]pyrimidin-2yl}amino)-1-(methanesulfonyl)piperidin-3-ol 553.9 [M+H]+ (APCI) ¹ H NMR (600 MHz, DMSO-Tb) 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, 7=6.1 Hz, 1H), 3.15 (d, 7=10.1 Hz, 1H), 2.46-2.37 (m, 4H), 2.31 -2.25 (m, 1H), 2.19 (t, 7=10.4 Hz, 1H), 1.63-1.55 (m, 1H), 1.41 (br. s., 3H), 1.13 (d, 7=7.0 Hz, 6H), 1.10-1.01 (m, 1H), 0.56 (d, 7=6.2 Hz, 6H) neither Η N ^N [TV ^F NO. A 1 Ί \ , ^N kx ¹ N—4 O Me—( ^\_ _NH Me 1,5 -anhydro-3 -[(5 -chloro-4-{2[(cyclopropylamino)methyl] -4fluoro-1 -( propan-2-yl)-1Hbenzimidazol-6-yl } pyrimidin-2yl)amino]-2,3-dideoxyO-threopentitol 475.3 [M+H]+ (ESI) Ή NMR (400 MHz, CD ₃ OD) δ 8.37 (s, 1H), 8.05 (s, 1H), 7.51 (d, 7=11.54 Hz, 1H), 5.07 (dt, 7=13.93.6 .84 Hz, 1H), 4.19 (s, 2H), 3.90-4.03 (m, 3H), 3.63 (td, 7=9.41, 4.77 Hz, 1H), 3.50 (td, 7=11.67 , 2.01 Hz, 1H), 3.22 (dd, 7=11.04, 9.79 Hz, 1H), 2.26 (dt, 7=6.71, 3.29 Hz, 1H), 2.12-2.18 (m , 1H), 1.69 (d, 7=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.

Mobility shift analysis of the CDK4/cyclin D1 complex.

The purpose of the CDK4/cyclin D1 complex assay is to evaluate inhibition (% inhibition, K _iapp and K _i values) in the presence of small molecule inhibitors using a fluorescence mobility shift assay in a microfluidic system. The CDK4/cyclin D1 complex catalyses the formation of ADP (adenosine diphosphate) from ATP (adenosine triphosphate), which is accompanied by the transfer of phosphoryl to the substrate peptide 5-FAM-Dyrktide (5-FAM-RRRFRPASPLRGPPK) (SEQ ID NO:1). The mobility shift assay consists in the electrophoretic separation of fluorescently labeled peptides (substrate and phosphorylated product) after a kinase reaction. Both substrate and product are determined and the ratio of these values is used to determine the % conversion of substrate to product using a LabChip EZ reader. Typical reaction solutions contained 2% DMSO (±inhibitor), 10 mM MgCl ₂ , 1 mM DTT (dithiothreitol), 3.5 mM ATP, 0.005% TW-20 (polysorbate 20), 3 μM 5-FAM-Dyrktide, 3 nM (active sites) of activated CDK4/cyclin D1 complex in 40 mM HEPES buffer (N-(2hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid)) at pH 7.5.

The determination of inhibitory Ki for the activated CDK4/cyclin D1 complex (2007 E1/2008 + PO4) was started with the addition of ATP (final reaction volume 50 μl) after an eighteen minute pre-incubation of the enzyme and inhibitor at 22° C. in the reaction mixture. The reaction was stopped after 195 minutes by adding 50 μl of 30 mM EDTA. Ki determinations were made from a graph of fractional velocity as a function of inhibitor concentration corresponding to the Morrison equation with enzyme concentration as a variable.

Mobility shift analysis of the CDK6/cyclin D3 complex.

The purpose of the CDK6/cyclin D3 complex assay is to evaluate inhibition (% inhibition, Kiapp and Ki values) in the presence of small molecule inhibitors using a fluorescence mobility shift assay in a microfluidic system. The CDK6/cyclin D3 complex catalyzes the formation of ADP from ATP, which is accompanied by the transfer of phosphoryl to the substrate peptide 5FAM-Dyrktide (5-FAM-RRRFRPASPLRGPPK) (SEQ ID NO:1). Mobility shift analysis consists of

- 140 042105 electrophoretic separation of fluorescently labeled peptides (substrate and phosphorylated product) after kinase reaction. Both substrate and product are determined and the ratio of these values is used to determine the % conversion of substrate to product using a LabChip EZ reader.

Representative 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) of activated CDK6/cyclin D3 complex in 40 mM HEPES buffer at pH 7.5.

Determination of inhibitory Ki for the activated CDK6/cyclin D3 complex (LJIC2009G1/2010 +PO4) was started with the addition of ATP (final reaction volume 50 μl) after an eighteen minute pre-incubation of the enzyme and inhibitor at 22°C in the reaction mixture. The reaction was stopped after 95 minutes by adding 50 μl of 30 mM EDTA. Ki determinations were made from a graph of fractional velocity 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'.

ELISA assays (enzyme-linked immunosorbent assays) of phosphoserine 795 Rb.

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 following day, serial dilutions of the compounds were made from a maximum dose of 10 mM for an 11-point curve of 3-fold dilutions in DMSO. Compounds were intermediately diluted 1:200 in growth medium before dilution 1:5 in cells for a final concentration of 10 μM to 0.1 nM in 0.1% DMSO in cells. JEKO-1 and MV4-11 cells were treated overnight at 37°C with 5% CO ₂ . Cells were lysed on ice in 100 μl/well CST lysis buffer and transferred to pre-coated and blocked α anti-phospho-Ser807/811 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 (horseradish peroxidase) labeled antibody was left to bind for 30 minutes at 37°C. After washing to remove unbound HRP antibodies, the 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.

Data on biological activity for typical compounds according to the invention are presented in table.6. In vitro Ki (nM) data for CDK4 and CDK6 were obtained using calorimetric assays. IC ₅₀ (nM) data for CDK4 and CDK6 in cells were obtained for CDK4 and CDK6 using phospho-Rb S795 ELISA assays in JEKO-1 and MV4-11 cells.

Example No. CDK4/D1, Ki (nM) ELISA pRB S795 for CDK4 in JEKO-1 cells, IC50 (nM) CDK6/D3, Ki (nM) ELISA pRB S795 for CDK6 in 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 I,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 AYu 0.6 72.7 10.4 195.3 AN oh, s 122.7 h, o 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

- 141 042105

A20 2.7 20.4 A21 7.3 135.6 A22 3.2 49.7 A23 0.5 26.5 I,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 AZO 0.2 51.6 4.9 63.5 A31 0.5 23.5 7.1 87.0 A32 0.9 7.1 AZZ 8.3 78.0 A34 I,1 102.1 AZ 5 1.5 123.8 58.9 966.7 AZ 6 0.2 19.6 3.7 43.9 AZ 7 3.5 34.2 AZ 8 0.5 455.7 10.2 598.1 AZ 9 1.3 12.3 A40 oh, s 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

- 142 042105

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 oh, s 2.1 A73 0.9 72.0 16.1 188.1 A74 0.2 26.5 6.2 89.7 A75 oh, s 33.2 5.0 102.8 A76 0.2 96.1 6.3 242.0 A77 oh, s 61.1 4.9 126.4 A78 ο,ι 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

- 143 042105

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 BOI 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 DOI 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

- 144 042105

F08 0.5 108.4 I,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 I,6 81.1 F14 3.6 30.8 F15 oh oh 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 I,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 and about 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 NOZ 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 NUDE 0.5 14.9 16.4 51.1 NO 0.7 43.4 22.1 295.1

All publications and patent applications cited in the specification are herein incorporated by reference in their entirety. Those skilled in the art will appreciate that certain changes and modifications may be made without departing from the spirit or scope of the appended claims.

Claims (15)

CLAIM 1. Compound of formula (X) - 145 042105 or a pharmaceutically acceptable salt thereof, where R ¹ represents H, F, Cl, CN, C ₁ -C ₂ alkyl or C ₁ -C ₂ fluoroalkyl; R ² is H, C1-C5 alkyl, C1-C5 fluoroalkyl, C3-C8 cycloalkyl, or a 3-6 membered heterocyclyl having one heteroatom selected from O and N, wherein said C1-C5 alkyl and C1-C5 fluoroalkyl are each optionally substituted with R ²⁰ . and each specified C3-C ₈ cycloalkyl and 3-6 membered heterocyclyl is optionally substituted with R ²¹ ; R ⁴ is H, C1-C ₄ alkyl or C1-C ₄ fluoroalkyl, where each C1-C ₄ alkyl and C1-C ₄ fluoroalkyl are optionally substituted with R ²⁰ ; R ⁶ is H, F, Cl, CN or CH ₃ ; R ⁷ and R ⁸ are independently H, F or Cl; R ⁹ is H, OH, NH2, NHCH3 or N(CH ₃ )2; each R ²⁰ is independently OH, C ₁ -C ₂ alkoxy, or NR22R ²³ ; each R ²¹ is independently F, OH, CN, NR22R ²³ or C1- _C4 alkyl; each R ²² and R ²³ independently represents H or C1-C ₂ alkyl; 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. 2. The compound according to claim 1 having the formula (X-A) or a pharmaceutically acceptable salt thereof 3. A compound of formula (IX) or a pharmaceutically acceptable salt thereof, wherein R ¹ represents H, F, Cl, CN, C1-C ₂ alkyl or C1-C ₂ fluoroalkyl; R ² is H, C1-C5 alkyl, C1-C5 fluoroalkyl, C3-C8 cycloalkyl, or a 3-6 membered heterocyclyl having one heteroatom selected from O and N, wherein said C1-C5 alkyl and C1-C5 fluoroalkyl are each optionally substituted with R ²⁰ . and each specified C3-C ₈ cycloalkyl and 3-6 membered heterocyclyl is optionally substituted with R ²¹ ; R ⁴ is H, C1-C ₄ alkyl or C1-C ₄ fluoroalkyl, where each C1-C ₄ alkyl and C1-C ₄ fluoroalkyl are optionally substituted with R ²⁰ ; R ⁶ is H, F, Cl, CN or CH ₃ ; R ⁷ and R ⁸ are independently H, F, Cl, CN or C1- _C2 alkyl; R ⁹ is H, OH, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ ; R ¹¹ is H, C1-C ₄ alkyl, SO2R ¹⁴ , COR ¹⁷ , COOR ¹⁷ or CONR ¹⁸ R ¹⁹ ; R ¹⁴ is C1- _C4 alkyl or C1- _C4 fluoroalkyl; R ¹⁷ is C1-C ₄ alkyl or C1-C ₄ fluoroalkyl, wherein each C1-C ₄ alkyl and C1-C ₄ fluoroalkyl are optionally substituted with R ²⁰ ; each R ¹⁸ and R ¹⁹ independently represents H or C 1 -C ₄ alkyl; each R ²⁰ is independently OH, C1-C ₂ alkoxy or NR22R ²³ ; each R ²¹ is independently F, OH, CN, NR22R ²³ or C1- _C4 alkyl; each R ²² and R ²³ independently represents H or C1-C ₂ alkyl; 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. 4. The compound according to claim 3 having the formula (IX-A) - 146 042105 or a pharmaceutically acceptable salt thereof. 5. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C1. 6. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R ² is C 1 -C ₅ alkyl which is optionally substituted with R ²⁰ . 7. Connection according to any of the Mon. 1-6 or a pharmaceutically acceptable salt thereof, wherein R ⁴ is C1-C ₄ alkyl which is optionally substituted with R ²⁰ . 8. A compound according to claim 7, or a pharmaceutically acceptable salt thereof, wherein R ²⁰ is OH. 9. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R ⁶ is F, R ⁷ is H, and R ⁸ is H. 10. 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-O-threo-pentitol having the structure or a pharmaceutically acceptable salt thereof. 11. (3R,4R)-4-[(5-Chloro-4-{4-fluoro-2-[(1R-1-hydroxyethyl]-1-(propan-2-yl)-1 H-benzimidazol-6 - yl}pyrimidin-2-yl)amino]-1-(methanesulfonyl)piperidin-3-ol having the structure or a pharmaceutically acceptable salt thereof. 12. A pharmaceutical composition containing a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. 13. A pharmaceutical composition containing a compound according to claim 10 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. 14. A pharmaceutical composition containing a compound according to claim 11 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. 15. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of pi. 1-11 or a pharmaceutically acceptable salt thereof.