OA19876A - 2-Amino-Pyridine or 2-Amino-Pyrimidine derivatives as cyclin dependent kinase inhibitors. - Google Patents

Abstract

This invention relates to compounds of Formula (I)

Description

CYCLIN DEPENDENT KINASE INHIBITORS

BACKGROUND OF THE INVENTION

Field ofthe Invention

The présent invention relates to compounds of Formula (l)-(XII), and pharmaceutically acceptable salts thereof, to pharmaceutical compositions comprising such compounds and salts, and to the uses thereof. The compounds, salts and compositions ofthe présent invention may be useful for the treatment of abnormal cell growth, such as cancer, in a subject.

Description of the Related Art

Cyclin-dependent kinases (CDKs) and related serine/threonine protein kinases are important cellular enzymes that perform essential functions in regulating cell division and prolifération. The CDK catalytic units are activated by regulatory subunits known as cyclins. At 15 least sixteen mammalian cyclins hâve been identified (Johnson DG, Walker CL. Cyclins and Cell

Cycle Checkpoints. Annu. Rev. Pharmacol. Toxicol. (1999) 39:295-312). Additional functions of Cyclin/CDK hétérodynes include régulation of transcription, DNA repair, différentiation and apoptosis (Morgan DO. Cyclin-dependent kinases: engines, docks, and microprocessors. Annu. Rev. Cell. Dev. Biol. (1997) 13:261-291).

CDK inhibitors hâve been demonstrated to be useful in treating cancer. Increased activity or temporally abnormal activation of CDKs has been shown to resuit in the development of human tumors, and human tumor development is commonly associated with alterations 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 25 JE, Broder S. Molecular foundations of cancer: new targets for intervention. Nat. Med. (1995) 1:309-320; Hall M, Peters G. Genetic alterations of cyclins, cyclin-dependent kinases, and Cdk inhibitors in| human cancer. Adv. Cancer Res. (1996) 68:67-108). |

CDK4 and CDK6 are important regulators of cell cycle progression at the G1-S checkpoint, which are controlled by D-type cyclins and INK4 endogenous CDK inhibitors, such 30 as p16^,NK4a (CDKN2A). Dysrégulation ofthe cyclin D-CDK4/6-INK4---retinoblastoma (Rb) pathway has been reported to be associated with development of endocrine therapy résistance.

Mutations of CDK4 and CDK6 hâve been described in subgroups 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 35 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 the regulatory subunits of

CDKs and cyclins, and mutation, gene délétion, or transcriptional silencing of endogenous INK4

CDK inhibitors hâve also been reported as mechanism by which the pathway can be activated (Smalley KSM (2008)).

The development of CDK inhibitors has been reviewed in the literature. For example, see

Sanchez-Martinez et al. Cyclin dépendent kinase (CDK) inhibitors as anticancer drugs, Bioorg. Med. Chem. Lett. (2015) 25: 3420-3435 (and référencés cited therein). The use of CDK4/6 inhibitors in combination with endocrine therapy has demonstrated significant efficacy in the treatment of hormone receptor (HR)-positive, human epidermal growth factor 2 (HER2)-negative 10 advanced or metastatic breast cancers, and CDK4/6 inhibitors, including palbociclib, ribociclib and abemaciclib, hâve been approved in combination with endocrine therapy in a first-or secondline setting.

However, treatment with CDK4/6 inhibitors may resuit in adverse effects, such as gastrointestinal and/or hématologie toxicities, and acquired résistance may develop over time. 15 Emerging data suggest that cyclin D3-CDK6 may be linked to the observed hématologie toxicity.

(Malumbres et al., Mammalian Cells Cycle without the D-type Cyclin-Dependent Kinases Cdk4 and Cdk6, (2004) Cell 118(4):493-504; Sicinska et al. Essential Rôle 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, 20 (2006), Nat. Immunol. 5(7):489-497). CDK4 has been identified as the singular oncogenic driver in many breast cancers. Accordingly, a CDK4 sélective inhibitor may provide an improved safety profile or enhanced overall efficacy due to the potential of higher and/or continuous dosing compared to dual CDK4/6 inhibitors.

Accordingly, there remains a need for improved thérapies for the treatment of cancers. 25 The compounds, compositions and methods ofthe présent invention are believed to hâve one or more advantages, such as greater efficacy; potential to reduce side effects; potential to reduce drug-drug interactior|is; potential to enable an improved dosing schedule; or potential to overcome résistance mechanisms, and the like.

BRIEF SUMMARY OF THE INVENTION !

The présent invention provides, in part, compounds of Formula (l)-(XII) and pharmaceutically acceptable salts thereof. Such compounds can inhibit the activity of CDKs, including CDK4 and/or CDK6, thereby effecting biological functions. In some embodiments, the invention provides compounds that are sélective for CDK4. Also provided are pharmaceutical 35 compositions and médicaments comprising the compounds or salts of the invention, alone or in combination with additional anticancer therapeutic agents.

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

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

or a pharmaceutically acceptable sait thereof, wherein:

A is N or CH;

R¹ is H, F, Cl, CN, C1-C2 alkyl, C1-C2 fluoroalkyl or C1-C2 alkoxy, where each said C1-C2 alkyl and C1-C2 fluoroalkyl is optionally substituted by R²⁰;

UisNR²orCR³;

V is N or CR⁴ when U is NR²; and

V is NR⁵ when U is CR³;

X is CR⁶ or N;

Y is CR⁷ or N;

Z is CR⁸ or N;

R² and R³ are H, C1-C5 alkyl, C1-C5 fluoroalkyl, C3-C8 cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R²⁰ and each said C3-C8 cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R²¹;

R⁴ is H, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, C(O)R^a, C(O)NR^b ₂, 20 C3-C8 cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C4 alkyl, Ci-C^ fluoroalkyl,

C1-C4 alkoxy and C1-C4 fluoroalkoxy is optionally substituted by R²⁰, each said C3-C8 cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R²¹, R^a is C1-C2 alkyl, and each R^b is independently H or C1-C2 alkyl; and I

R⁵ is H, C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl 25 is optionally substituted by R²⁰; or

R² can be taken together with R⁴, or R³ can be taken together with R⁵, to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR²⁴, O and S(0)m as a ring member, which ring is optionally substituted by R²¹;

R⁶ is H, F, Cl, CN, CH₃, CH₂F, CHF₂ or CF₃;

R⁷ and R⁸ are independently H, F, Cl, CN, C1-C2 alkyl, C1-C2 fluoroalkyl, C1-C2 alkoxy or

C1-C2 fluoroalkoxy, where each said C1-C2 alkyl, C1-C2 fluoroalkyl, C1-C2 alkoxy and C1-C2 fluoroalkoxy is optionally substituted by R²⁰;

R⁹ is H, OH, NH₂, NHCH3 or N(CH₃)₂;

each R¹⁰ is independently F, CN, C1-C2 alkyl or C1-C2 fluoroalkyl, where each said C1-C2 alkyl and C1-C2 fluoroalkyl is optionally substituted by R²⁰;

Q is NR¹¹ or O; or

Q is CR¹²R¹³, where R¹² and R¹³ are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing NR¹¹ or O as a ring member, which 10 ring is optionally further substituted by R¹⁰;

R¹¹ is H, C1-C4 alkyl, C1-C4 fluoroalkyl, SO2R¹⁴, SO2NR¹⁵R¹⁶, COR¹⁷, COOR¹⁷ or CONR¹⁸R¹⁹, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R²⁰, SO2R¹⁴, SO2NR¹⁵R¹⁶, COR¹⁷, COOR¹⁷ or CONR¹⁸R¹⁹;

R¹⁴ is C1-C4 alkyl or C1-C4 fluoroalkyl;

each R¹⁵ and R¹⁶ is independently H or CH₃;

R¹⁷is C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C8 cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R²⁰ and each said C3-C8 cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R²¹;

each R¹⁸ and R¹⁹ is independently H, C1-C4 alkyl or C1-C4 fluoroalkyl, where each said 20 C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R²⁰;

each R²⁰ is independently OH, C1-C2 alkoxy, C1-C2 fluoroalkoxy, CN, NR²²R²³, C₃-Ce cycloalkyl or 3-6 membered heterocyclyl, where each said C₃-Ce cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R²¹;

each R²¹ is independently F, OH, CN, NR²²R²³, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy 25 or C1-C4 fluoroalkoxy, where each said C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy and C1-C4 fluoroalkoxy is optionally further substituted by OH, NH2, NHCH₃ or N(CH₃)2;

each R²² and R²³ is independently H, CrC₃ alkyl, CrC₃ fluoroalkyl, C₃-Ce cycloalkyl or ^-6 membered heterocyclyl, where each said C1-C3 alkyl and C1-C3 fluoroalkyl is optionally further substituted by OH, C1-C2 alkoxy or C1-C2 fluoroalkoxy and each said C3-C8 cycloalkyl and 3-6 30 membered heterocyclyl is optionally further substituted by F, OH, C1-C2 alkyl, C1-C2 fluoroalkyl, C1-C2 alkoxy or C1-C2 fluoroalkoxy; or I

R²² and R²³ may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring, where said ring is optionally substituted by F, OH, C1-C2 alkyl, C1-C2 fluoroalkyl, C1-C2 alkoxy or C1-C2 fluoroalkoxy;

R²⁴ is H, C1-C4 alkyl, C1-C4 fluoroalkyl, SO2R²⁵, SO2NR²⁶R²⁷, COR²⁸, COOR²⁸ or

CONR²⁹R³⁰;

R^{15 * * * * * * * * * 25} is C1-C4 alkyl or C1-C4 fluoroalkyl;

each R²⁶ and R²⁷ is independently H or CH3;

R²⁸ is C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by OH, C1-C2 alkoxy, C1-C2 fluoroalkoxy, CN, NH2, NHCH3 or N(CH3)₂;

each R²⁹ and R³⁰ is independently H, C1-C4 alkyl or C1-C4 fluoroalkyl, where each said

C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by OH, C1-C2 alkoxy, C1-C2 fluoroalkoxy, CN, NH₂, NHCH3 or N(CH₃)₂;

m is 0,1 or 2;

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

p is 1, 2 or 3; and q is 0,1, 2 or 3;

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

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

or a pharmaceutically acceptable sait thereof, wherein:

R¹ is H, F, Cl, CN, C1-C2 alkyl or C1-C2 fluoroalkyl, where each said C1-C2 alkyl and C1-C2 fluoroalkyl is optionally substituted by R²⁰;

U is NR² or CR³;

V is N or CR⁴ when U is NR²; and | 20 V is NR⁵ when U is CR³; |

X is CR⁶ or N;

Y is CR⁷ or N;

j Z is CR⁸ or N; j i R² and R³ are H, C1-C5 alkyl, C1-C5' fluoroalkyl, C3-C8 cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R²⁰ and each said C3-C8 cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R²¹;

R⁴ is H, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy or C1-C4 fluoroalkoxy, where each said

C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy and C1-C4 fluoroalkoxy is optionally substituted by R²⁰;

R⁵ is H, C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R²⁰;

R⁶ is H, F, Cl, CN, CH₃, CH₂F, CHF₂ or CF₃;

R⁷ and R⁸ are independently H, F, Cl, CN, Ci-C₂ alkyl, Ci-C₂ fluoroalkyl, Ci-C₂ alkoxy or Ci-C₂ fluoroalkoxy, where each said Ci-C₂ alkyl, Ci-C₂ fluoroalkyl, Ci-C₂ alkoxy and Ci-C₂ fluoroalkoxy is optionally substituted by R²⁰;

R⁹is H, OH, NH₂, NHCH₃ or N(CH₃)₂;

each R¹⁰ is independently F, CN, Ci-C₂ alkyl or Ci-C₂ fluoroalkyl, where each said Ci-C₂ alkyl and CrC₂ fluoroalkyl is optionally substituted by R²⁰;

Q is NR¹¹ or O; or

Q is CR¹²R¹³, where R¹² and R¹³ are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing NR¹¹ or O as a ring member, which ring is optionally further substituted by R¹⁰;

R¹¹ is H, C1-C4 alkyl, C1-C4 fluoroalkyl, SO2R¹⁴, SO2NR¹⁵R¹⁶, COR¹⁷, COOR¹⁷ or CONR¹⁸R¹⁹;

R¹⁴ is C1-C4 alkyl or C1-C4 fluoroalkyl;

each R¹⁵ and R¹⁶ is independently H or CH₃;

R¹⁷ is C1-C4 alkyl, C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R²⁰;

each R¹⁸ and R¹⁹ is independently H, C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R²⁰;

each R²⁰ is independently OH, CrC₂ alkoxy, Ci-C₂ fluoroalkoxy, CN or NR²²R²³;

each R²¹ is independently F, OH, CN, NR^R²³, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy or C1-C4 fluoroalkoxy, where each said C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy and C1-C4 fluoroalkoxy is optionally further substituted by OH, NH₂, NHCH₃ or N(CH₃)₂;

each R²² and R²³ is independently H, Ci-C₂ alkyl or Ci-C₂ fluoroalkyl; or | R²² and R²³ may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring, which is optionally substituted by F or OH;

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

i p is 1, 2 or3; and j ! qisO, 1,2or3; i wherein the sum of p and q is an integer from 1 to 4.

In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention, according to any of the formulae described herein, or a pharmaceutically acceptable sait thereof, and a pharmaceutically acceptable carrier or excipient.

In some embodiments, the pharmaceutical composition comprises two or more pharmaceutically acceptable carriers and/or excipients.

The invention also provides therapeutic methods and uses comprising administering a compound ofthe invention, or a pharmaceutically acceptable sait thereof.

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

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

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

In a further aspect, the invention provides the use of a compound of the invention, or a 20 pharmaceutically acceptable sait thereof, for the treatment of abnormal cell growth, in particular, cancer, in a subject.

In another aspect, the invention provides a pharmaceutical composition for use in the treatment of abnormal cell growth, in particular cancer, in a subject in need thereof, which pharmaceutical composition comprises a compound of the invention, or a pharmaceutically 25 acceptable sait thereof, and a pharmaceutically acceptable carrier or excipient.

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

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

In another aspect, the invention provides a method for the treatment of a disorder mediated by CDK4 in a subject, comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable sait thereof, in an amount that is effective for treating said disorder, 35 in particular, cancer.

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

In another aspect, the invention provides a compound of the invention, according to any 5 of the formulae described herein, for use in the treatment of cancer, wherein said treatment comprises the administration of a second pharmaceutically active agent.

Each of the aspects and embodiments of the compounds of the présent invention described below can be combined with one or more other embodiments of the compounds of the présent invention described herein not inconsistent with the embodiment(s) with which it is 10 combined.

In addition, each of the embodiments below describing the invention envisions within its scope the pharmaceutically acceptable salts of the compounds of the invention. Accordingly, the phrase “or a pharmaceutically acceptable sait thereof is implicit in the description of ail compounds described herein unless explicitly indicated to the contrary.

DETAILED DESCRIPTION OF THE INVENTION

The présent invention may be understood more readily by reference to the following detailed description of the preferred embodiments of the invention and the Examples included herein. It is to be understood that the terminology used herein is provided for the purpose of 20 describing spécifie embodiments only and is not intended to be limiting. It is further to be understood that unless specifically defined herein, the terminology used herein is to be given its traditional meaning as known in the relevant art.

As used herein, the singular form a, an, and the include plural référencés unless indicated otherwise. For example, a substituent includes one or more substituents. The term 25 about means having a value falling within an accepted standard of error of the mean, when considered by one of ordinary skill in the art.

The invention described herein suitably may be practiced in the absence of any element(s) not specifically disclosed herein. Thus, for example, in each instance herein any of the terms comprising, consisting essentially of, and consisting of' may be replaced with either of the 30 other two terms. ! !

Alkyl refers to a saturated, monovalent aliphatic hydrocarbon radical including straight chain and branched chain groups having the specified number of carbon atoms. Alkyl substituents typically contain 1 to 12 carbon atoms (“C1-C12 alkyl”), frequently 1 to 8 carbon atoms (“CrCe alkyl”), or more frequently 1 to 6 carbon atoms (“Ci-Ce alkyl”), 1 to 5 carbon atoms (“C1-C5 35 alkyl”), 1 to 4 carbon atoms (“C1-C4 alkyl”) or 1 to 2 carbon atoms (“C1-C2 alkyl”). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl, n-octyl and the like.

Alkyl groups described herein as optionally substituted may be substituted by one or more substituent groups, as further defined by the claims, which substituent groups are selected 5 independently unless otherwise indicated. The total number of substituent groups may equal the total number of hydrogen atoms on the alkyl moiety, to the extent such substitution makes Chemical sense. Optionally substituted alkyl groups typically contain from 1 to 6 optional substituents, sometimes 1 to 5 optional substituents, 1 to 4 optional substituents, or preferably 1 to 3 optional substituents.

Optional substituent that are suitable for alkyl include, but are not limited to, Ca-Ce cycloalkyl, 3-12 membered heterocyclyl, Ce-Ci₂ aryl and 5-12 membered heteroaryl, halo, =0 (oxo), =S (thiono), =N-CN, =N-OR^X, =NR^X, -CN, -C(0)R^x, -CO2R^X, -C(0)NR^xR^y, SR^X, -SOR^X, -SO2R^x, -S02NR^xR^y, -NO2, -NR^xR^y, -NR^xC(O)R^y, -NR^xC(0)NR^xR^y, NR^XC(O)OR^X, -NR^xS02R^y, -NR^xS02NR^xR^y, -OR^X, -0C(0)R^x and -0C(0)NR^xR^y; wherein each R^x 15 and R^y is independently H, CrCe alkyl, Ci-Ce acyl, C₂-Cs alkenyl, C^Ce alkynyl, Ca-Ce cycloalkyl,

3-12 membered heterocyclyl, C₆-Ci₂ aryl, or 5-12 membered heteroaryl, or R^x and R^y may be taken together with the N atom to which they are attached to form a 3-12 membered heterocyclyl or 5-12 membered heteroaryl, each optionally containing 1, 2 or 3 additional heteroatoms selected from O, N and S(0)q where q is 0-2; each R^x and R^y is optionally substituted with 1 to 3 20 substituents independently selected from the group consisting of halo, =0, =S, =N-CN, =N-OR', =NR', -CN, -C(0)R', -C02R', -C(O)NR'_2i -SOR', -SO₂R', -SO₂NR'_2i NO₂, -NR'_2i -NR'C(O)R', -NR'C(O)NR'₂, -NR'C(0)0R', -NR'SO₂R', -NR'SO₂NR'_2i -OR', -OC(O)R' and -OC(O)NR'_2i wherein each R' is independently H, Ci-Ce alkyl, Ci-Ce acyl, C^Ce alkenyl, C₂-Ce alkynyl, Ca-Ce cycloalkyl, 3-12 membered heterocyclyl, Ce-Ci₂ aryl, or Cs-Ci₂ heteroaryl; and wherein each said Ca-Ce cycloalkyl, 3-12 membered heterocyclyl, Ce-Ci₂ aryl and 5-12 membered heteroaryl is optionally substituted as further defined herein.

Typical substituent|groups on alkyl include halo, -OH, C1-C4 alkoxy, -O-Ce(-Ci₂ aryl, -CN, =0, -C00R^x, -OC(O)R^X, -C(O)NR^xR^y, -NR^xC(O)R^y, -NR^xR^y, C3-C8 cycloalkyl, C6-C12 aryl, 5-12 membered heteroaryl and 3-12 membered heterocyclyl; where each R^x and R^y is independently 30 H or C1-C4 alkyl, or R^x and R^y may be taken togetherwith the N to which they are'attached form a 3-12 membered heterocyclyl or 5-12 membered heteroaryl ring, each optionally containing 1, 2 or 3 additional heteroatoms selected from O, N and S(O)q where q is 0-2; wherein each said C3-C8 cycloalkyl, Ce-Ci₂ aryl, 5-12 membered heteroaryl and 3-12 membered heterocyclyl is optionally substituted by 1 to 3 substituents independently selected from the group consisting of halo, -OH, 35 =0, C1-C4 alkyl, C1-C4 alkoxy, Ci-Ce haloalkyl, CrCe hydroxyalkyl, C1-C4 alkoxy-Ci-Ce alkyl, -CN, -NH₂, -NH(Ci-C₄ alkyl) and -N(Ci-C₄ alkyl)₂.

• ¹⁰

In some instances, substituted alkyl groups are specifically named by reference to the substituent group. For example, “haloalkyl” refers to an alkyl group having the specified number of carbon atoms that is substituted by one or more halo substituents, up to the available valence number. Typically, haloalkyl groups contain 1-6 carbon atoms, 1-5 carbon atoms, 1-4 carbon 5 atoms or 1-2 carbon atoms and 1,2,3,4 or 5 halo atoms (i.e., “C1-C5 haloalkyl”, “C1-C4 haloalkyl” or “C1-C2 haloalkyl”).

More specifically, fiuorinated alkyl groups may be specifically referred to as “fluoroaikyl” groups, (e.g., C1-C5, Ci-C4or C1-C2 fluoroaikyl groups), which are typically substituted by 1, 2, 3, 4 or 5 fluoro atoms. Thus, a C1-C4 fluoroaikyl includes trifluoromethyl (-CF3), difluoromethyl 10 (-CF2H), fluoromethyl (-CFH₂), difluoroethyi (-CH2CF2H), and the like. Such groups may be further substituted by groups suitable for alkyl groups, as further described herein.

In some embodiments of the présent invention, alkyl and fluoroaikyl groups are optionally substituted by one or more optional substituents, and preferably by 1 to 3 optional substituents, which are independently OH, C1-C2 alkoxy, C1-C2 fluoroalkoxy, CN or NR’2, where each R’ is 15 independently H, C1-C2 alkyl or C1-C2 fluoroaikyl.

Similarly, “alkoxyalkyl” refers to an alkyl group having the specified number of carbon atoms that is substituted by one or more alkoxy substituents. Alkoxyalkyl groups typically contain 1-4 carbon atoms in the alkyl portion and are substituted by 1, 2 or 3 C1-C4 alkyoxy substituents. Such groups are sometimes described herein as C1-C4 alkyoxy-Ci-C4 alkyl.

“Aminoalkyl” refers to alkyl group having the specified number of carbon atoms that is substituted by one or more substituted or unsubstituted amino groups, as such groups are further defined herein. Aminoalkyl groups typically contain 1-6 carbon atoms in the alkyl portion and are substituted by 1, 2 or 3 amino substituents. Thus, a Ci-Ce aminoalkyl includes, for example, aminomethyl (-CH2NH2), /V,/V-dimethylaminoethyl (-CH₂CH2N(CH3)2), 3-(/V-cyclopropylamino)25 propyl (-CH2CH2CH2NH-^cPr) and Af-pyrrolidinylethyl (-CH2CH2-N-pyrrolidinyl).

“Hydroxyalkyl” refers to an alkyl group having the specified number of carbon atoms that is substituted by one or more hy(|roxy substituents, and typically contain 1-6 carbon a^oms, preferably 1-4 carbon atoms, and 1, 2 or 3 hydroxy (i.e., “CrCs hydroxyalkyl”). Thus, Ci-Ce 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. Typically, alkenyl groups hâve 2 to 20 carbon atoms (“C2-C20 alkenyl”), preferably 2 to 12 carbon atoms (“C2-C12 alkenyl”), more preferably 2 to 8 carbon atoms (“C2-C8 alkenyl”), or 2 to 6 carbon atoms (“C2-C6 alkenyl”), or 2 to 4 carbon atoms (“C2-C4 alkenyl”). Représentative examples include, but are not limited to, ethenyl, 1-propenyl, 35 2-properiÿl, 1-, 2-, or 3-butenyl, and the like. Alkenyl groups are unsubstituted or substituted by the same groups that are described herein as suitable for alkyl.

¹¹

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 hâve 2 to 20 carbon atoms (“C2-C20 alkynyl”), preferably 2 to 12 carbon atoms (“C2-C12 alkynyl”), more preferably 2 to 8 carbon atoms (“C2-C8 alkynyl”), or 2 to 6 carbon atoms (“C2-C6 alkynyl”), or 2 to 4 carbon atoms (“C2-C4 alkynyl”). Représentative examples include, but are not limited to, ethynyl, 1-propynyl,

2-propynyl, 1-, 2-, or 3-butynyI, and the like. Alkynyl groups are unsubstituted or substituted by the same groups that are described herein as suitable for alkyl.

Alkylene as used herein refers to a divalent hydrocarbyl group having the specified number of carbon atoms which can link two other groups together. Sometimes it refers to a group

-(CH₂)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 a Ci-C₈ alkylene, Ci-C₆ alkylene, C1-C4 alkylene, etc. Where specified, an alkylene can also be substituted by other groups and may include one or more degrees of unsaturation (i.e., an alkenylene or alkynlene moiety) or rings. The open valences of an alkylene need not be at opposite ends of the chain. Thus branched alkylene groups such as -CH(Me)-, -CH2CH(Me)15 and -C(Me)2- are also included within the scope of the term 'alkylenes', as are cyclic groups such as cyclopropan-1,1-diyl and unsaturated groups such as ethylene (-CH=CH-) or propylene (-CH2-CH=CH-). Where an alkylene group is described as optionally substituted, the substituents include those typically présent on alkyl groups as described herein.

Heteroalkylene refers to an alkylene group as described above, wherein one or more non-contiguous carbon atoms of the alkylene chain are replaced by -N(R)-, -O- or -S(O)x-, where R is H or a substituent group suitable for a secondary amino moiety and x is 0-2. For example, the group -Ο-(ΟΗ₂)ι-3- is a ‘C2-C4’-heteroalkylene group, where one of the carbon atoms of the corresponding alkylene is replaced by O.

“Alkoxy” refers to a monovalent -O-alkyl group, wherein the alkyl portion has the specified number of carbon atoms. Alkoxy groups typically contain 1 to 8 carbon atoms (“CrCe alkoxy”), or 1 to 6 carbon atoms (“Ci-Ce alkoxy”), or 1 to 4 carbon atoms (“C1-C4 alkoxy”). For example, C1-C4 alkoxy includes methoxy, |ethoxy, isopropoxy, tert-butyloxy (i.e., - |

OCH3, -OCH2CH3, -OCH(CH3)2, -OC(CH₃)₃), and the like. Alkoxy groups are unsubstituted or substituted on the alkyl portion by the same groups that are described herein as suitable for alkyl.

In particular, alkoxy groups may be optionally substituted by one or more halo atoms, and in I particular one or more fluoro atoms, up to ihe total number of hydrogen atoms présent on the I alkyl portion. Such groups are referred to as “haloalkoxy” (or, where fluorinated, more specifically as “fluoroalkoxy”) groups having the specified number of carbon atoms and substituted by one or more halo substituents, Typically such groups contain from 1-6 carbon atoms, preferably 1-4 carbon atoms, and sometimes 1-2 carbon atoms, and 1, 2 or 3 halo atoms (i.e., “CrCe haloalkoxy”, “C1-C4 haloalkoxy” or “C1-C2 haloalkoxy”). More specifically, fluorinated alkoxy _ 12 groups may be specifically referred to as “fluoroalkoxy” groups, e.g., Ci-C₆, C1-C4 or C1-C2 fluoroalkoxy groups, which are typically substituted by 1, 2 or 3 fluoro atoms. Thus, a C1-C4 fluoroalkoxy includes trifluoromethyloxy (-OCF3), difluoromethyloxy (-OCF2H), fluoromethyloxy (-OCFH2), difluoroethyloxy (-OCH2CF2H), and the like.

Similarly, “thioalkoxy” refers to a monovalent-S-alkyl group, wherein the alkyl portion has the specified number of carbon atoms and is optionally substituted on the alkyl portion by the same groups that are described herein as suitable for alkyl. For example, a C1-C4 thioalkoxy includes -SCH3 and -SCH2CH3.

Cycloalkyl refers to a non-aromatic, saturated carbocyclic ring system containing the 10 specified number of carbon atoms, which may be a monocyclic, spirocyclic, bridged or fused bicyclic or polycyclic ring system that is connected to the base molécule through a carbon atom of the cycloalkyl ring. Typically, the cycloalkyl groups of the invention contain 3 to 12 carbon atoms (“C3-C12 cycloalkyl”), preferably 3 to 8 carbon atoms (“C3-C8 cycloalkyl”). Partially unsaturated carbocyclic rings may be referred to as “cycloalkenyl” rings. Représentative examples of cycloalkyl and cycloalkenyl rings include, e.g., cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptatriene, adamantane, and the like. Cycloalkyl groups are unsubstituted or substituted by the same groups that are described herein as suitable for alkyl, except that cycloalkyl rings may also be substituted by alkyl groups having the specified number of carbon atoms, which may 20 be further optionally substituted as described herein.

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

cydopropane cyclobutane cyclopentane (cyclopropanyl) (cydobutanyf) (cydopentanyl)

cyclopentene cydohexane cydohexene (cydopentenyl) (cydohexanyl) (cydohexanyl)

cycloheptane (cydoheptanyt) octahydrolndane (octahydroîndanyl) octahydropentalene (octahydropentalenyl)

I decahydronaphthafene (decahydronapthalenyl) cydoheptene (cycloheptenyl)

adamantane bicydo[1.1.1]pentane bicydo[2J.1]heptane · —bicyclo[2.2.2]octane (adamantyt) (bicydo[1.1.1]pentanyl) (blcyclo[2.2.1]heptanyl) (bicydo[2.2.2]octanyl)

Cycloàlkylalkyl is used to describe a cycloalkyl ring, typically â C3-C8 cycloalkyl, which is connected to the base molécule through an alkylene linker, typically a C1-C4 alkylene.

Cycloalkylalkyl groups are sometimes described by the total number of carbon atoms in the _— 13 carbocyclic ring and linker, and typically contain from 4-12 carbon atoms (“C4-C12 cycloalkylalkyl”). Thus a cyclopropylmethyl group is a C4-cycloalkylalkyl group and a cyclohexylethyl is a Ce-cycloalkylalkyl. Cycloalkylalkyl groups are unsubstituted or substituted on the cycloalkyl and/or alkylene portions by the same groups that are 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 ring S 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 base molécule via a ring atom, which may be C or N. Where 10 specifically indicated, such heterocyclic rings may be partially unsaturated. Heterocyclic rings include rings which are spirocyclic, bridged, or fused to one or more other heterocyclic or carbocyclic rings, where such spirocyclic, bridged, or fused rings may themselves be saturated, partially unsaturated or aromatic to the extent unsaturation or aromaticity makes Chemical sense, provided the point of attachment to the base molécule is an atom of the heterocyclic portion of 15 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 contiguous oxygen atoms.

Heterocyclyl groups are unsubstituted or substituted by suitable substituent groups, for example the same groups that are described herein as suitable for alkyl, except that heterocycyl 20 rings may also be substituted by alkyl groups having the specified number of carbon atoms, which may be further optionally substituted as described herein. Such substituents may be présent on the heterocycylic ring attached to the base molécule, or on a spirocyclic, bridged or fused ring attached thereto. In addition, ring N atoms are optionally substituted by groups suitable for an amine, e.g., 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 heterc|cyclyl groups, in accordance with the définition herein. | i i

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

oxirane thiarane aziridine (oxiranyl) (thiaranyl) (aziridinyl) oxetane thiatane (oxetanyl) (thiatanyl) azetidine (azetidinyl) tetrahydrofuran (tetrahydrofuranyl)

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

piperazine thiomorpholine (piperazinyl) (thiomorpholinyl)

1,4-dioxane 1,4-oxathiarane (1,4-dioxanyl) (1,4-oxathiaranyl) morpholine 1,4-dithiane (morpholinyl) (1,4-dithianyl)

oxepane (oxepanyl) thiepane (thiepanyl) azepane (azepanyl)

1,4-dioxepane (1,4-dioxepanyl)

1,4-oxathiepane (1,4-oxathiepanyl)

1,4-oxaazepane (1,4-oxaazepanyl)

1,4-thieazepane (1,4-thieazapanyl)

1,4-diazepane (1,-diazepanyl)

1,4-dithiepane (1,4-dithiepanyl)

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

2H-pyran 3,4-dihydro-2H-pyran 5,6-dihydro-2H-pyran (2H-pyranyi) (3,4-dihydro-2H-pryanyl) (5,6-dihydro-2H-pyranyl)

1,2,3,4-tetrahydropyridine · 1,2,5,6-tetrahydropyridine (1,2,3,4-tetrahydropyridinyl) (1,2,5,6-tetrahyrodpyridinyl)

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

2-azabicyclo- 8-azabicycIo[3.1.0]hexane [2.2.1]octane

2-azabicyclo[2.2.1 ]heptane

2-oxa-5-azabicyclo[2.2.1]heptane

3-oxa-8-azabicyclo- 3-azabicyclo[3.2.1]octane [3.1.0]hexane

3-oxooctahydroindolizine

1,1 -dioxidohexahydropyrido[1,2]thiazolo[2,3-a]pyridine

3-oxohexahydro[1.3]oxazolo[3,4-a]pyridine

2,2-dioxido-2-thiaspiro[3.5]nonane

1,1 -dioxidohexahydropyrido[1,2-d][1,3,4]oxathiazine

In some embodiments, heterocyclic groups contain 3-12 ring members, including both carbon and non-carbon heteroatoms, and frequently 3-8 or 3-6 ring members. In certain preferred embodiments, substituent groups comprising 3-12 membered heterocycles are selected from 5 azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl and thiomorpholinyl rings, each of which are optionally substituted as described for the particular substituent group, to the extent such substitution makes Chemical sense.

In some embodiments of the présent invention, cycloalkyl and heterocyclyl groups are 10 optionally substituted by one or more optional substituents, and preferably by 1 to 3 optional substituents, which are independently F, OH, CN, NR’2 (where each R’ is independently H, C1-C2 alkyl or C1-C2 fluoroalkyl), C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy or C1-C4 fiuoroalkoxy, where each said C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy and C1-C4 fiuoroalkoxy is optionally further substituted by OH, NH₂, NHCH₃ or N(CH₃)2.

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

The term heterocyclylalkyl may be used to describe a heterocyclic group ofthe specified 20 size that is connected to the base molécule through an alkylene linker of the specified length.

Typically, such groups contain an optionally substituted 3-12 membered heterocycle attached to the base molécule through a C1-C4 alkylene linker. Where so indicated, such groups are optionally substituted on the alkylene portion by the same groups that are described herein as suitable for alkyl groups and on the heterocyclic portion by groups described as suitable for 25 heterocyclic rings.

¹⁶

Aryl or “aromatic” refer to an optionally substituted monocyclic or fused bicyclic or polycyclic ring system having the well-known characteristics of aromaticity, wherein at least one ring contains a completely conjugated pi-electron system. Typically, aryl groups contain 6 to 20 carbon atoms (C6-C20 aryl) as ring members, preferably 6 to 14 carbon atoms (Ce-Cu aryl) or 5 more preferably, 6 to 12 carbon atoms (C6-C12 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 the point of attachment to the base molécule on such fused ring Systems is an atom of the aromatic portion of the ring system. Examples, without limitation, of aryl groups include phenyl, biphenyl, naphthyl, anthracenyl, 10 phenanthrenyl, indanyl, indenyl, and tetrahydronaphthyl. The aryl group is unsubstituted or substituted as further described herein.

Similarly, heteroaryl or “heteroaromatic” refer to monocyclic or fused bicyclic or polycyclic ring Systems having the well-known characteristics of aromaticity that contain the specified number of ring atoms and include at least one heteroatom selected from N, O and S as 15 a ring member in an aromatic ring. The inclusion of a heteroatom permits aromaticity in 5-membered rings as well as 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 base molécule via a ring atom ofthe heteroaromatic ring, such that aromaticity is 20 maintained. Thus, 6-membered heteroaryl rings may be attached to the base molécule via a ring C atom, while 5-membered heteroaryl rings may be attached to the base molécule via a ring C or N atom. Heteroaryl groups may also be fused to another aryl or heteroaryl ring or fused to a saturated or partially unsaturated carbocyclic or heterocyclic ring, provided the point of attachment to the base molécule on such fused ring Systems is an atom of the heteroaromatic 25 portion of the ring system. Examples of unsubstituted heteroaryl groups often include, but are not limited to, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pfyrazine, benzofuran, benzothiophene, indole, benzimidazole, indazole, quinoline, isoquinoline, purine, triazine, naphthryidine and carbazole. In frequent preferred embodiments, 5- or 6-membered 30 heteroaryl groups are selected from the group consisting of pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazoiyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, pyridinyl and pyrimidinyl, pyrazinyl or pyridazinyl rings. The heteroaryl group is unsubstituted or substituted as further described herein.

Aryl and heteroaryl moieties described herein as optionally substituted may be substituted 35 by one or more substituent groups, which are selected independently unless otherwise indicated. The total number of substituent groups may equal the total number of hydrogen atoms on the aryl, heteroaryl or heterocyclyl moiety, to the extent such substitution makes Chemical sense and aromaticity is maintained m the case of aryl and heteroaryl rings. Optionally substituted aryl or heteroaryl groups typically contain from 1 to 5 optional substituents, sometimes 1 to 4 optional substituents, preferably 1 to 3 optional substituents, or more preferably from 1-2 optional substituents.

Optional substituent groups suitable for use with aryl and heteroaryl rings include, but are not limited to: Ci-Ce alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, 3-12 membered heterocyclyl, C6-C12 aryl and 5-12 membered heteroaryl; and halo, =0, -CN, -C(O)R^X, -C02R^x, -C(O)NR^xR^y, - SR^X, -SOR^X, -SO2R^X, -SO2NR^xR^y, -NO2, -NR^xR^y, -N R^xC(O)R^y, -NR^xC(O)NR^xR^y, -NR^XC(O)OR^X, -NR^xSO2R^y, -NR^xSO2NR^xR^y, -OR^X, -OC(O)R^X and -OC(O)NR^xR^y; where each R^x and R^y is independently H, Ci-Ce alkyl, CrCe acyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, 3-12 membered heterocyclyl, C6-Ci2 aryl, or 5-12 membered heteroaryl, or R^x and R^y may be taken together with the N atom to which they are attached to form a 3-12 membered heterocyclyl or 5-12 membered heteroaryl, each optionally containing 1,2 or 3 additional heteroatoms selected from O, N and S(O)Z where z is 0-2; each R^x and R^y is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, =0, =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'SO₂ R', -NR'SO2NR'₂, -OR', -OC(O)R' and -OC(O)NR'2, wherein each R' is independently H, Ci-C₈ alkyl, CrCe acyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, 3-12 membered heterocyclyl, C6-C12 aryl, or 5-12 membered heteroaryl; and each said Ci-Ce alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, 3-12 membered heterocyclyl, C6-C12 aryl and 5-12 membered heteroaryl is optionally substituted as further defined herein.

In typical embodiments, optional substitution on aryl, heteroaryl and heterocyclyl rings includes one or more substituents, and preferably 1 to 3 substituents, independently selected from the group consisting of halo, CrCe alkyl, -OH, Ci-Ce alkoxy, -CN, =0, -C(O)R^X, -COOR^X, -OC(O)k^x, -C(O)NR^xR^y, -NR^xC(O)R^y, -SR^X, -1

SOR^X, -SO2R^X, -SO2NR^xR^y, -NO2, -NR^xR^y, -NR^xC(O)R^y, -NR^xC(O)NR^xR^y, -NR^xC(O)OR^y NR^xSO2R^y, -NR^xSO2NR^xR^y, -0C(0)R^x, -OC(O)NR^xR^y, C3-C8 cycloalkyl, 3-12 membered heterocyclyl, C6-C12 aryl, 5-12 membered heteroaryl, -O-(C3-Cb cycloalkyl),-0-(3-12 membered । heterocyclyl), -O-(C6-Ci2 aryl) and -0-(5-12 membered heteroaryl); where each R^x and R^y is i independently H or C1-C4 alkyl, or R^x and R^y may be taken together with the N to which they are attached form a 3-12 membered heterocyclyl or 5-12 membered heteroaryl ring, each optionally containing 1, 2 or 3 additional heteroatoms selected from O, N and S(O)q where q is 0-2; and wherein each said CrCe alkyl, CrCe alkoxy, C3-C8 cycloalkyl, 3-12 membered heterocyclyl, C6-C12 aryl, 5-12 membered heteroaryl, -O-(C3-Ce cycloalkyl),-0-(3-12 membered _ 18 heterocyclyl), -O-(Ce-Ci2 aryl) and -0-(5-12 membered heteroaryl) that is described as an optional substituent or is part of R^x or R^y is optionally substituted by 1 to 3 substituents independently selected from the group consisting of halo, -OH, =0, C1-C4 alkyl, C1-C4 alkoxy, Οι-Ce haloalkyl, Ci-Cs hydroxyalkyl, C1-C4 aIkoxy-Ci-Ce alkyl, -CN, -NH2, -NH(Ci-C4 5 alkyl), -N(Ci-C4 alkyl)2 and N-pyrrolidinyl.

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

ô	ô	ô		ô N
pyrrole	furan	thiophene	pyrazole	imidazole
(pyrrolyl)	(furanyl)	(thiophenyl)	(pyrazolyl)	(imidazolyl)
/A GN	û N	GN	ô 'L- N	A N
isoxazole	oxazole	isothiazole	thiazolyl	1,2,3-triazole
(isoxazolyl)	(oxazolyl)	(isothiazolyl)	(thiazolyl)	(1,2,3-triazolyl)

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

1-oxa-2,3-diazole (1-oxa-2,3-diazolyl)

-oxa-2,4-diazole (1 -oxa-2,4-diazolyl)

N, ,N

1-oxa-2,5-diazole (1-oxa-2,5-diazolyl)

N-N

1-oxa-3,4-diazole (1-oxa-3,4-diazoIyi)

1-thia-2,3-diazole (1-thia-2,3-diazolyl)

1-thia-2,4-diazole (1-thia-2,4-diazolyl) _S.

N, ,N

1-thia-2,5-diazole (1-thia-2,5-diazolyl)

N-N

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

pyrazine (pyrazinyl)

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

benzofuran benzothiophene (benzofüranyl) (benzothiophenyl)

(indolyl)

benzimidazole (benzimidazolyl)

indazole (indazolyl)

benzotriazole (benzotriazolyl) pyrrolo[2,3-b]pyridine pyrrolo[2,3-c]pyridine pyrrolo[3,2-c]pyridine (pyrrolo[2,3-b]pyridinyl) (pyrrolo[2,3-c]pyridinyl) (pyrrolo[3,2-c]pyridinyl)

pyrrolo[3,2-b]pyridine (pyrrolo[3,2-b]pyridinyl) imidazo[4,5-b]pyridine imidazo[4,5-c]pyridine pyrazolo[4,3-d]pyridine (imidazo[4,5-b]pyridinyl) (imidazo[4,5-c]pyridinyl) (pyrazolo[4,3-d]pyidinyl)

pyrazolo[4,3-c]pyridine pyrazoio[3,4-c]pyridine pyrazolo[3,4-b]pyridine (pyrazolo[4,3-c]pyidinyl) (pyrazolo[3,4-c]pyidinyl) (pyrazolo[3,4-b]pyidinyl) isoindole (isoindolyi)

indazole purine (indazolyl) (purinyl) indolizine imidazo[1,2-a]pyridine imidazo[1,5-a]pyridine (indolininyl) (imidazo[1,2-a]pyridinyl) (imidazo[1,5-a]pyridinyl)

pyrazolo[1,5-a]pyridine (pyrazolo[1,5-a]pyridinyl) pyrrolo[1,2-b]pyridazine (pyrroio[1-2,b]pyridazinyl) imidazo[1,2-c]pyrimidine (imidazo[1,2-c]pyrimidinyl)

quinoline (quinolinyl)

isoquinoline (isoquinolinyl)

cinnoline (cinnolinyl)

quinazoline (azaquinazoline)

quinoxaline (quinoxalinyl)

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

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

1,8-naphthyridine (1,8-naphthyridinyl) phthalazine (phthalazinyl)

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

2,6-naphthyridine (2,6-naphthyridinyl)

2,7-naphthyridine (2,7-naphthyridinyl)

pyrido[3,2-d]pyrimidine (pyrido[3,2-d]pyrimidinyl) pyrido[4,3-d]pyrimidine (pyrido[4,3-d]pyrimidinyl) pyrido[3,4-d]pyrimidine (pyrido[3,4-d]pyrimidinyl)

pyrido[2,3-d]pyrimidine (pyrido[2,3-d]pyrimidinyl)

pyrido[2,3-b]pyrazine (pyrido[2,3-b]pyrazinyl)

pyrido[3,4-b]pyrazine (pyrido[3,4-b]pyrazinyl)

pyrimido[5,4-d]pyrimidine (pyrimido[5,4-d]pyrimidinyl) pyrazino[2,3-b]pyrazine (pyrazino[2,3-b]pyrazinyl) pyrimido[4,5-d]pyrimidine (pyrimido[4,5-d]pyrimidinyl)

An qrylalkyl group refers to an aryl group as described herein which is linked to the base molécule through an alkylene or similar linker. Arylalkyl groups are described by the total number of carbon atoms in the ring and linker. Thus, a benzyl group is a Cyarylalkyl group and a 5 phenylethyl is a Cs-arylalkyl. Typically, arylalkyl groups contain 7-16 carbon atoms (“C7-C16 arylalkyl”), wherein the aryl portion contains 6-12 carbon atoms and the alkylene portion contains 1-4 carbon atoms. Such groups may also be represented as -Ci-C4alkylene-C6-Ci2aryl.

Heteroarylalkyl refers to a heteroaryl group as described above that is attached to the base molécule through an alkylene linker, and differs from arylalkyl in that at least one ring atom 10 of the aromatic moiety is a heteroatom selected from N, O and S. Heteroarylalkyl groups are sometimes described herein according to the total number of non-hydrogen atoms (i.e., C, N, S and O atoms) in the ring and linker combined, excluding substituent groups. Thus, for example, pyridinylmethyl may be referred to as a “C7”-heteroarylalkyl. Typically, unsubstituted heteroarylalkyl groups contain 6-20 non-hydrogen atoms (including C, N, S and O atoms), wherein the heteroaryl portion typically contains 5-12 atoms and the alkylene portion typically contains 1-4 carbon atoms. Such groups may also be represented as -C1-C4 aikylene-5-12 membered heteroaryl.

Similarly, “arylalkoxy” and “heteroarylalkoxy” refer to aryl and heteroaryl groups, attached to the base molécule through a heteroaikylene linker (i.e., -O-alkylene-), wherein the groups are described according to the total number of non-hydrogen atoms (i.e., C, N, S and O atoms) in the ring and linker combined. Thus, -O-CHz-phenyl and -O-CHz-pyridinyl groups would be referred to as Ce-arylalkoxy and Ce-heteroarylaikoxy groups, respectively.

Where an arylalkyl, arylalkoxy, heteroarylalkyl or heteroarylalkoxy group is described as optionally substituted, the substituents may be on either the divalent linker portion or on the aryl or heteroaryl portion of the group. The substituents optionally présent on the alkylene or heteroaikylene portion are the same as those described above for alkyl or alkoxy groups generally, while the substituents optionally présent on the aryl or heteroaryl portion are the same as those described above for aryl or heteroaryl groups generally.

Hydroxy refers to an OH group.

“Acyloxy” refers to a monovalent group -OC(O)alkyl, wherein the alkyl portion has the specified number of carbon atoms (typically Οι-Ce, preferably Ci-Ce or C1-C4) that are optionally substituted by groups suitable for alkyl. Thus, C1-C4 acyloxy includes an -OC(O)Ci-C4 alkyl substituent, e.g., -OC(O)CH3.

“Acyl” refers to a monovalent group -C(O)alkyl, wherein the alkyl portion has the specified number of carbon atoms (typically CrCs, preferably Ci-Ce or C1-C4) and may be optionally substituted by groups suitable for alkyl, e.g., by F, OH or alkoxy. Thus, optionally substituted -C(O)Ci-C4 alkyl includes unsubstituted acyl groups, such as -C(O)CH3 (i.e., acetyl) and -C(O)CH₂CH₃ (i|e., propionyl), as well as substituted acyl groups èuch as -C(O)CF3 (trifluoroacetyl), -C(O)CH₂OH (hydroxyacetyl), -C(O)CH₂OCH3 (methoxyacetyl), -C(O)CF₂H (difluoroacetyl), and the like.

“Acylamino” refers to a monovalent group, -NHC(O)alkyl or -NRC(0)alkyl, wherein the alkyl portion has the specified number of carbon atoms (typically Ci-Ce, preferably Ci-Ce or C1-C4) and is optionally substituted by groups suitable for alkyl. Thus, C1-C4 acylamino includes an NHC(O)Ci-C4 alkyl substituent, e.g., -NHC(O)CH3.

“Aryloxy” or “heteroaryloxy” refer to optionally substituted O-aryl or O-heteroaryl, in each case where aryl and heteroaryl are as further defined herein.

‘Arylamino” or “heteroarylamino” refer to an optionally substituted -NH-aryl, -NR-aryl, NH-heteroaryl or -NR-heteroaryl, m each case where aryl and heteroaryl are as further defined herein and R represents a substituent suitable for an amine, e.g., an alkyl, acyl, carbamoyl or sulfonyl group, or the like.

Cyano refers to a -C=N group.

Unsubstituted amino refers to a group -NH2. Where the amino is described as substituted or optionally substituted, the term includes groups of the form -NR^xR^y, where each or 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 specified number of atoms and optionally substituted as described herein. For example, “alkylamino refers to a group -NR^xR^y, wherein one of R^x and R^y is an alkyl moiety and the other is H, and “dialkylamino” refers to -NR^xR^y wherein both of R^x and R^y are alkyl moieties, where the alkyl moieties having the specified number of carbon atoms (e.g., -NH-C1-C4 alkyl or-N(Ci-C4 aikyl)2). Typically, alkyl substituents on amines contain 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, or more preferably 1 to 4 carbon atoms. The term also includes forms wherein R^x and R^y are taken together with the N atom to which they are attached to form a 3-12 membered heterocyclyl or 5-12 membered heteroaryl ring, each of which may itself be optionally substituted as described herein for heterocyclyl or heteroaryl rings, and which may contain 1 to 3 additional heteroatoms selected from N, O and S(O)_X where x is 0-2 as ring members, provided that such rings do not contain two contiguous oxygen atoms.

“Halogen” or “halo” refers to fluoro, chloro, bromo and iodo (F, Cl, Br, I). Preferably, halo refers to fluoro or chloro (F or Cl).

Optional or optionally means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs and instances in which it does not.

The terms “optionally substituted” and “substituted or unsubstituted” may be used interchangeably to indicate th^t the particular group being described may hâve no nor^-hydrogen substituents (i.e., unsubstituted), or the group may hâve one or more non-hydrogen substituents (i.e., substituted). If not otherwise specified, the total number of substituents that may be présent is equal to the number of H atoms présent on the unsubstituted form of the group being described. Where an optional substituent is attached via a double bond, such as an oxo (=0) substituent, the group occupies two available valences, so the total number of other substituents that are included is reduced by two.

Frequently, optionally substituted groups are substituted by 1 or more substituents independently selected from the list of optional substituents. In some embodiments, optionally substituted groups are substituted by 1,2, 3, or more than 3 substituents independently selected

from the list of optional substituents. For example, an alkyl group described as optionally substituted by R^x means the alkyl group is optionally substituted by 1 or more R^x substituents independently selected from the list of R^x substituents provided for the alkyl group. Where deemed necessary, the description of an optionally substituted group herein may be revised to 5 state that the group is optionally substituted by 1 or more of the indicated substituents. In the case where optional substituents are selected from a list of alternatives, the selected groups are independently selected and may be the same or different.

Throughout the disclosure, it will be understood that the number and nature of optional substituent groups will be limited to the extent that such substitutions make Chemical sense. 10

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

or a pharmaceutically acceptable sait thereof, wherein: A is N or CH;

R¹ is H, F, Cl, CN, C1-C2 alkyl, C1-C2 fluoroalkyl or C1-C2 alkoxy, where each said C1-C2 alkyl and C1-C2 fluoroalkyl is optionally substituted by R²⁰;

U is NR² or CR³;

V is N or CR⁴ when U is N R²; and

V is NR⁵ when U is CR³;

X is CR⁶ or N; | |

Y is CR⁷ or N; .....

Z is CR⁸ or N; R² and R³ are H, C1-C5 alkyl, C1-C5 fluoroalkyl, C3-C8 cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R²⁰ and each said C3-C8 cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R²¹; R⁴ is H, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, C(O)R^a, C(O)NR^b2, C3-C8 cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy and C1-C4 fluoroalkoxy is optionally substituted by R²⁰, each said C3-C8 cycloalkyl _ 24 and 3-6 membered heterocyclyl is optionally substituted by R²¹, R^a is C1-C2 alkyl, and each R^b is independently H or C1-C2 alkyl; and .

R⁵ is H, C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R²⁰; or

R² can be taken together with R⁴, or R³ can be taken together with R⁵, to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR²⁴, O and S(O)m as a ring member, which ring is optionally substituted by R²¹;

R⁶ is H, F, Cl, CN, CH₃, CH₂F, CHF₂ or CF₃;

R⁷ and R⁸ are independently H, F, Cl, CN, C1-C2 alkyl, C1-C2 fluoroalkyl, C1-C2 alkoxy or

C1-C2 fluoroalkoxy, where each said C1-C2 alkyl, C1-C2 fluoroalkyl, C1-C2 alkoxy and C1-C2 fluoroalkoxy is optionally substituted by R²⁰;

R⁹ is H, OH, NH₂, NHCH₃ or N(CH₃)₂;

each R¹⁰ is independently F, CN, C1-C2 alkyl or C1-C2 fluoroalkyl, where each said C1-C2 alkyl and C1-C2 fluoroalkyl is optionally substituted by R²⁰;

Q is NR¹¹ or O; or

Q is CR¹²R¹³, where R¹² and R¹³ are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing NR¹¹ or O as a ring member, which ring is optionally further substituted by R¹⁰;

R¹¹ is H, C1-C4 alkyl, C1-C4 fluoroalkyl, SO2R¹⁴, SO₂NR¹⁵R¹⁶, COR¹⁷, COOR¹⁷ or

CONR¹⁸R¹⁹, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R²⁰, SO2R¹⁴, SO₂NR¹⁵R¹⁸, COR¹⁷, COOR¹⁷ or CONR¹⁸R¹⁹;

R¹⁴ is C1-C4 alkyl or C1-C4 fluoroalkyl;

each R¹⁵ and R¹⁶ is independently H or CH₃;

R¹⁷is C1-C4 alkyl, C1-C4 fluoroalkyl, C₃-C₃ cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R²⁰ and each said C₃-Ce cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R²¹;

| each R¹⁸ and R¹⁹ is independently H, c|i-C4 alkyl or C1-C4 fluoroalkyl, where each said

C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R²⁰;

each R²⁰ is independently OH, C1-C2 alkoxy, C1-C2 fluoroalkoxy, CN, NR²²R²³, C₃-Ce

I 30 cycloalkyl or 3-6 membered heterocyclyl, where each said C₃-C₈ cycloalkyl and 3-6 membered i heterocyclyl is optionally substituted by R²¹; I each R²¹ is independently F, OH, CN, N R²² R²³, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy or C1-C4 fluoroalkoxy, where each said C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy and C1-C4 fluoroalkoxy is optionally further substituted by OH, NH₂, NHCH₃ or N(CH₃)2;

each R²² and R²³ is independently H, Ci-C₃ alkyl, Ci-C₃ fluoroalkyl, C₃-Cs cycloalkyl or 3-6 membered heterocyclyl, where each said Ci-C₃ alkyl and Ci-C₃ fluoroalkyl is optionally further

substituted by OH, C1-C2 alkoxy or C1-C2 fluoroalkoxy and each said C3-C8 cycloalkyl and 3-6 membered heterocyclyl is optionally further substituted by F, OH, C1-C2 alkyl, C1-C2 fluoroalkyl, C1-C2 alkoxy or C1-C2 fluoroalkoxy; or

R²² and R²³ may be taken together with the nitrogen atom to which they are attached to 5 form an azetidinyl ring, where said ring is optionally substituted by F, OH, C1-C2 alkyl, C1-C2 fluoroalkyl, C1-C2 alkoxy or C1-C2 fluoroalkoxy;

R²⁴ is H, C1-C4 alkyl, C1-C4 fluoroalkyl, SO2R²⁵, SO₂NR²⁶R²⁷, COR²⁸, COOR²⁸ or CONR²⁹R³⁰;

R²⁵ is C1-C4 alkyl or C1-C4 fluoroalkyl; .

each R²⁶ and R²⁷ is independently H or CH3;

R²⁸ is C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by OH, C1-C2 alkoxy, C1-C2 fluoroalkoxy, CN, NH2, NHCH3 or N(CH3)2!

each R²⁹ and R³⁰ is independently H, C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by OH, C1-C2 alkoxy, C1-C2 fluoroalkoxy, 15 CN, NH₂, NHCH3 or N(CH₃)₂;

m is 0,1 or 2;

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

p is 1, 2 or 3; and q is 0,1,2 or 3;

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

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

I or a pharmaceutically acceptable sait thereof, whèrein:

I R¹ is H, F, Cl, CN, C1-C2 alkyl or C1-C2 fluoroalkyl,। where each said C1-C2 alkyl and C1-C2 fluoroalkyl is optionally substituted by R²⁰;

UisNR²ôrCR³;

V is N or CR⁴ when U is NR²; and '

V is NR⁵ when U is CR³;

X is CR⁶ or N;

Y is CR⁷ or N;

Z is CR⁸ or N; R² and R³ are H, C1-C5 alkyl, C1-C5 fluoroalkyl, C3-C8 cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R²⁰ and each said C3-C8 cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R²¹;

R⁴ is H, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy or C1-C4 fluoroalkoxy, where each said C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy and C1-C4 fluoroalkoxy is optionally substituted by R²⁰;

R⁵ is H, C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R²⁰;

R^B is H, F, Cl, CN, CH₃, CH₂F, CHF₂ or CF₃;

R⁷ and R⁸ are independently H, F, Cl, CN, CrC₂ alkyl, Ci-C₂ fluoroalkyl, Ci-C^ alkoxy or Ci-C₂ fluoroalkoxy, where each said CrC₂ alkyl, Ci-C₂ fluoroalkyl, CrC₂ alkoxy and Ci-C₂ fluoroalkoxy is optionally substituted by R²⁰;

R⁹is H, OH, NH₂, NHCH3 or N(CH₃)₂;

each R¹⁰ is independently F, CN, Ci-C₂ alkyl or Ci-C₂ fluoroalkyl, where each said CrC₂ alkyl and Ci-C₂ fluoroalkyl is optionally substituted by R²⁰;

Q is NR¹¹ or O; or

Q is CR¹²R¹³, where R¹² and R¹³ are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing NR¹¹ or O as a ring member, which ring is optionally further substituted by R¹⁰;

R¹¹ is H, C1-C4 alkyl, C1-C4 fluoroalkyl, SO2R¹⁴, SO2NR¹⁵R¹⁶, COR¹⁷, COOR¹⁷ or CONR¹⁸R¹⁹;

R¹⁴ is C1-C4 alkyl or C1-C4 fluoroalkyl;

each R¹⁵ and R¹⁶ is independently H or CH3;

R¹⁷ is C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R²⁰;

eaçh R¹⁸ and R¹⁹ is independently H, C1-C4 alkyl or Ci-C|4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R²⁰;

each R²⁰ is independently OH, Ci-C₂ alkoxy, Ci-C₂ fluoroalkoxy, CN or N R²²R²³;

each R²¹ is independently F, OH, CN, NR²²R²³, C1-C4 alkyl, |Ci-C4 fluoroalkyl, C1-C4 alkoxy or C1-C4 fluoroalkoxy, where each said C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy and C1-C4 fluoroalkoxy is optionally further substituted by OH, NH₂, NHCH3 or N(CH3)₂;

each R²² and R²³ is independently H, Ci-C₂ alkyl or Ci-C₂ fluoroalkyl; or

R²² and R²³ may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring, which is optionally substituted by F or OH;

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

p is 1, 2 or 3; and qisO, 1,2 or 3;

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

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

or a pharmaceutically acceptable sait thereof, wherein:

R¹ is H, F, Cl, CN, C1-C2 alkyl or C1-C2 fluoroalkyl, where each said C1-C2 alkyl and C1-C2 fluoroalkyl is optionally substituted by R²⁰;

U is NR² or CR³;

V is N or CR⁴ when U is NR²; and

V is NR⁵ when U is CR³;

X is CR⁶ or N;

Y is CR⁷ or N;

Z is CR⁸ or N;

R² and R³ are H, C1-C5 alkyl, C1-C5 fluoroalkyl, C3-C8 cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R²⁰ and each said C3-C8 cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R²¹;

R⁴ is H, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy or C1-C4 fiuoroalkoxy, where each said C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy and C1-C4 fiuoroalkoxy is optionally substituted by R²⁰;

R⁵ is H, Ci-^4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl| and C1-C4 fluoroalkyl is optionally substituted by R²⁰;

R⁶ is H, F, Cl, CN, CH₃, CH₂F, CHF₂ or CF₃;

R⁷ and R⁸ are independently H, F, Cl, CN, C1-C2 alkyl, C1-C2 fluoroalkyl, C1-C2 alkoxy or C1-C2 fluoroalkoxyl where each said C1-C2 alkyl, C1-C2 fluoroalkyl, C1-C2 alkoxy and C1-C2 25 fiuoroalkoxy is optionally substituted by R²⁰;

R⁹isH, OH, NH₂, NHCH3 or N(CH₃)₂;

each R¹⁰ is independently F, CN, C1-C2 alkyl or C1-C2 fluoroalkyl, where each said C1-C2 alkyl and C1-C2 fluoroalkyl is optionally substituted by R²⁰;

Q is NR¹¹ or O; or

Q is CR¹²R¹³, where R¹² and R¹³ are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing NR¹¹ or O as a ring member, which ring is optionally further substituted by R¹⁰;

R¹¹ is H, C1-C4 alkyl, C1-C4 fluoroalkyl, SO2R¹⁴, SO2NR¹⁵R¹⁶, COR¹⁷, COOR¹⁷ or CONR¹⁸R¹⁹;

R¹⁴ is C1-C4 alkyl or C1-C4 fluoroalkyl;

each R¹⁵ and R¹⁶ is independently H or CH3;

R¹⁷is C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R²⁰; each R¹⁸ and R¹⁹ is independently H, C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R²⁰;

each R²⁰ is independently OH, Ci-C₂ alkoxy, CrC₂ fluoroalkoxy, CN or N R²² R²³;

each R²¹ is independently F, OH, CN, NR^R²³, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy or C1-C4 fluoroalkoxy, where each said C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy and C1-C4 fluoroalkoxy is optionally further substituted by OH, NH₂, NHCH3 or N(CH3)2!

each R²² and R²³ is independently H, Ci-C₂ alkyl or Ci-C₂ fluoroalkyl; or

R²² and R²³ may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring, which is optionally substituted by F or OH;

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

p is 1, 2 or 3; and q is 0,1,2 or 3;

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

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

or a pharmaceutically acceptable sait thereof, wherein:

R¹ is H, F, Cl, CN, Ci-C₂ alkyl or C1-C2 fluoroalkyl, where each said C1-C2 alkyl and C1-C2 fluoroalkyl is optionally substituted by R²⁰;

U is NR² or CR³;

V is N or CR⁴ when U is N R²; and

V is NR⁵ when U is CR³; .

XisCR⁶orN;

Y is CR⁷ or N;

Z is CR⁸ or N;

R² and R³ are H, C1-C5 alkyl, C1-C5 fluoroalkyl, C3-C8 cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R²⁰ and each said C3-C8 cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R²¹;

R⁴ is H, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy or C1-C4 fluoroalkoxy, where each said C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy and C1-C4 fluoroalkoxy is optionally substituted by R²⁰; and

R⁵ is H, C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-G4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R²⁰; or

R² can be taken together with R⁴, or R³ can be taken together with R⁵, to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR²⁴, O and S(0)m as a ring member, which ring is optionally substituted by R²¹;

R⁶ is H, F, Cl, CN, CH₃, CH₂F, CHF₂ or CF₃;

R⁷ and R⁸ are independently H, F, Cl, CN, CrC₂ alkyl, Ci-C₂ fluoroalkyl, Ci-C₂ alkoxy or Ci-C₂ fluoroalkoxy, where each said CrC₂ alkyl, Ci-C₂ fluoroalkyl, Ci-C₂ alkoxy and Ci-C₂ fluoroalkoxy is optionally substituted by R²⁰;

R⁹is H, OH, NH₂, NHCH3 or N(CH₃)₂;

each R¹⁰ is independently F, CN, Ci-C₂ alkyl or Ci-C₂ fluoroalkyl, where each said Ci-C₂ alkyl and CrC₂ fluoroalkyl is optionally substituted by R²⁰;

Q is NR¹¹ or O; or

Q is CR¹²R¹³, where R¹² and R¹³ are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing NR¹¹ or O as a ring member, which ring is optionally further substituted bjy R¹⁰; |

R¹¹ is H, C1-C4 alkyl, C1-C4 fluoroalkyl, SO2R¹⁴, SO2NR¹⁵R¹⁶, COR¹⁷, COOR¹⁷ or CONR¹⁸R¹⁹; - ........

R¹⁴ is C1-C4 alkyl or C1-C4 fluôroalkyl;i each R¹⁵ and R¹⁶ is independently H or CH3;I

R¹⁷is C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R²⁰;l each R¹⁸ and R¹⁹ is independently H, C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkÿl and C1-C4 fluoroalkyl is optionally substituted by R²⁰;

each R²⁰ is independently OH, Ci-C₂ alkoxy, Ci-C^ fluoroalkoxy, CN or NR²²R²³;

each R²¹ is independently F, OH, CN, NR^R²³, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy or C1-C4 fluoroalkoxy, where each said C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy and C1-C4 fluoroalkoxy is optionally further substituted by OH, NH₂, NHCH3 or N(CH₃)₂;

each R²² and R²³ is independently H, C1-C2 alkyl or C1-C2 fluoroalkyl; or

R²² and R²³ may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring, which is optionally substituted by F or OH;

R²⁴ is H, C1-C4 alkyl, C1-C4 fluoroalkyl, SO2R²⁵, SO₂NR²⁶R²⁷, COR²⁸, COOR²⁸ or CONR²⁹R³⁰;

R²⁵ is C1-C4 alkyl or C1-C4 fluoroalkyl;

each R²⁶ and R²⁷ is independently H or CH3;

R²⁸ is C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by OH, C1-C2 alkoxy, C1-C2 fluoroalkoxy, CN, NH₂, NHCH3 or N(CH₃)₂;

each R²⁹ and R³⁰ is independently H, C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by OH, C1-C2 alkoxy, C1-C2 fluoroalkoxy, 15 CN, NH₂, NHCH₃ or N(CH₃)₂;

m is 0,1 or 2;

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

p is 1,2 or 3; and q is 0,1,2 or 3;

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

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

or a pharmaceutically acceptable sait thereof, wherein:

R¹ is H, F, Cl, CN, C1-C2 alkyl or C1-C2 fluoroalkyl, where each said C1-C2 alkyl and C1-C2 fluoroalkyl is optionally substituted by R²⁰;

UisNR²orCR³;

V is N or CR⁴ when U is NR²; and , : _:

V is NR⁵ when U is CR³; ‘ ^-

X is CR⁶ or N;

Y is CR⁷ or N;

ZisCR⁸orN; - : ·

R² and R³ are H, C1-C5 alkyl, C1-C5 fluoroalkyl, C3-C8 cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R²⁰ and each said C3-C8 cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R²¹;

R⁴ is H, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy or C1-C4 fluoroalkoxy, where each said C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy and C1-C4 fluoroalkoxy is optionally substituted by R²⁰; and

R⁵ is H, C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R²⁰; or

R² can be taken together with R⁴, or R³ can be taken together with R⁵, to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR²⁴, O and S(O)_m as a ring member, which ring is optionally substituted by R²¹;

R⁶ is H, F, Cl, CN, CH₃, CH₂F, CHF₂ or CF₃;

R⁷ and R⁸ are independently H, F, Cl, CN, Ci-C₂ alkyl, Ci-C₂ fluoroalkyl, Ci-C₂ alkoxy or Ci-C₂ fluoroalkoxy, where each said Ci-C₂ alkyl, Ci-C₂ fluoroalkyl, Ci-C₂ alkoxy and Ci-C₂ fluoroalkoxy is optionally substituted by R²⁰;

R⁹is H, OH, NH₂, NHCH3 or N(CH₃)₂;

each R¹⁰ is independently F, CN, Ci-C₂ alkyl or Ci-C₂ fluoroalkyl, where each said CrC₂ alkyl and Ci-C₂ fluoroalkyl is optionally substituted by R²⁰;

Q is NR¹¹ or O; or

Q is CR¹²R¹³, where R¹² and R¹³ are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing NR¹¹ or O as a ring member, which ring is optionally further substituted by R¹⁰;

R¹¹ is H, C1-C4 alkyl, C1-C4 fluoroalkyl, SO2R¹⁴, SO2NR¹⁵R¹⁶, COR¹⁷, COOR¹⁷ or CONR¹⁸R¹⁹;

| R¹⁴ is C1-C4 alkyl or C1-C4 fluoroalkyl; | each R¹⁵ and R¹⁸ is independently H or CH3;

R¹⁷ is C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is

I optionally substituted by R²⁰; |

I each R¹⁸ and R¹⁹ is independently H, C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R²⁰;

each R²⁰ is independently OH, Ci-C₂ alkoxy, Ci-C₂ fluoroalkoxy, CN or NR^R²³;

each R²¹ is independently F, OH, CN, N R²² R²³, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy or C1-C4 fluoroalkoxy, where each said C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy and C1-C4 fluoroalkoxy is optionally further substituted by OH, NH₂, NHCH3 or N(CH₃)₂;

_ ³² each R²² and R²³ is independently H, C1-C2 alkyl or C1-C2 fluoroaikyl; or

R²² and R²³ may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring, which is optionally substituted by F or OH;

R²⁴ is H, C1-C4 alkyl, C1-C4 fluoroaikyl, SO2R²⁵, SO2NR²⁶R²⁷, COR²⁸, COOR²⁸ or

CONR²⁹R³°;

R²⁵ is C1-C4 alkyl or C1-C4 fluoroaikyl;

each R²⁶ and R²⁷ is independently H or CH3;

R²⁸is C1-C4 alkyl or C1-C4 fluoroaikyl, where each said C1-C4 alkyl and C1-C4 fluoroaikyl is optionally substituted by OH, C1-C2 alkoxy, C1-C2 fluoroalkoxy, CN, NH₂, NHCH3 or N(CH3)2!

each R²⁹ and R³⁰ is independently H, C1-C4 alkyl or C1-C4 fluoroaikyl, where each said

C1-C4 alkyl and C1-C4 fluoroaikyl is optionally substituted by OH, C1-C2 alkoxy, C1-C2 fluoroalkoxy, CN, NH₂, NHCH3 or N(CH₃)₂;

m is 0,1 or 2;

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

p is 1,2 or 3; and q is 0,1, 2 or 3;

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

In frequent embodiments of Formula (IV) and Formula (V), R² is taken together with R⁴, or R³ is taken together with R⁵, to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR²⁴, O and S(O)_m as a ring member, which ring is optionally substituted by R²¹.

In some embodiments, the compounds of Formulae (I) to (V) hâve the absolute stereochemistry as shown in one of Formulae (l-A), (l-B), (l-C) or (l-D); (ll-A), (ll-B), (ll-C) or (IID); (IIl-A), (lll-B), (lll-C) or (lll-D); (IV-A), (IV-B), (IV-C) or (IV-D); and (V-A), (V-B), (V-C) or (V-D):

(l-C) to (V-C) (l-D) to (V-D) wherein A in Formula (l-A) to (l-D) is N or CH; A in Formula (ll-A) to (ll-D) is replaced by N; A in Formula (lll-A) to (lll-D) is replaced by CH; A in Formula (IV-A) to (IV-D) is replaced by N; and A in Formula (V-A) to (V-D) is replaced by CH; or a pharmaceutically acceptable sait of one ofthe foregoing.

Each ofthe aspects and embodiments described herein with respectto Formula (I) is also applicable to compounds of Formulae (l-A), (l-B), (l-C) or (l-D).

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

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

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

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

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

In compounds of Formula (I), R¹ is H, F, Cl, CN, C1-C2 alkyl, C1-C2 fluoroalkyl or C1-C2 alkoxy, where each said C1-C2 alkyl and C1-C2 fluoroalkyl is optionally substituted by R²⁰. In some embodiments, R^¹ is F or Cl. In some such embodiments, R¹ is F. In sJme such embodiments, R¹ is Cl.

In compounds of Formula (I), U is NR² or CR³; V is N or CR⁴ when U is NR²; and

V is NR⁵ when U is CR³. In some embodiments, U is NR² and V is N or CR⁴. In some such embodiments, U is NR² and V is CR⁴. In some such embodiments, U is NR² and V is N. In some embodiments, U is CR³ and V is NR⁵.

In compounds of Formula (I), X is CR⁶ or N. In some embodiments, X is CR⁶. In some embodiments, X is N,

In compounds of Formula (I), Y is CR⁷ or N. In some embodiments, Y is CR⁷. In some embodiments, Y is N.

λ ³⁴

In compounds of Formula (I), Z is CR⁸ or N. In some embodiments, Z is CR⁸. In some embodiments, Z is N.

In frequent embodiments of Formula (I), X is CR⁶, Y is CR⁷ and Z is CR⁸. In other embodiments of Formula (I), at least one ofX, Y and Z is N. . .. . - ________

In some embodiments of Formula (I), R² and R³ are H, C1-C5 alkyl, C1-C5 fluoroalkyl, C3-C8 cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R²⁰ and each said C3-C8 cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R²¹.

In some such embodiments, R² and R³ are H, C1-C5 alkyl or C1-C5 fluoroalkyl, where each 10 said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R²⁰. In other such embodiments, R² and R³ are C3-C8 cycloalkyl or 3-6 membered heterocyclyl, where each said C3-C8 cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R²¹.

In some embodiments of Formula (I), R² is C1-C5 alkyl or C1-C5 fluoroalkyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R²⁰. In some embodiments of 15 Formula (I), R³ is C1-C5 alky or C1-C5 fluoroalkyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R²⁰.

In some embodiments of Formula (I), R⁴ is H, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, C(O)R^a, C(O)NR^b2, C3-C8 cycloalkyl or 3-6 membered heterocyclyl; where each said C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy and C1-C4 fluoroalkoxy is optionally 20 substituted by R²⁰, each said C3-C8 cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R²¹, R^a is C1-C2 alkyl, and each R^b is independently H or C1-C2 alkyl.

In some such embodiments, R⁴ is H, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy or C1-C4 fluoroalkoxy, where each said C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy and C1-C4 fluoroalkoxy is optionally substituted by R²⁰. In some such embodiments, R⁴ is C1-C4 alkyl or C1-C4 fluoroalkyl, 25 , where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R²⁰. In some such embodiments, R²⁰ is OH. In other such embodiments, R²⁰ is C3-C8 cycloalkyl or 3-6 membered heterocyclyl, where eacf| said C3-C8 cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R²¹.

In other such embodiments, R⁴ is C(O)R^a or C(O)NR^b ₂, where R^a is C1-C2 alkyl, and each 30 R^b is independently H or C1-C2 alkyl. In still other such embodiments, R⁴ is C3-C8 cycloalkyl or 3-6 membered heterocyclyl, where each said C3-C8 cycloalkyl and 3-6 membered I heterocyclyl is optionally substituted by R²¹. .

In some embodiments of Formula (I), R⁵ is H, C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R²⁰.

Iri other embodiments of Formula (I), R² can be takeri together with R⁴, or R³ can be taken together with R⁵, to form a 5-7 membered heterocyclic ring, optionally containing an additional _ 35 heteroatom selected from NR²⁴, O and S(O)m as a ring member, which ring is optionally substituted by R²¹. - - In some embodiments of Formula (I), R² is taken together with R⁴ to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR²⁴,0 and S(O)m 5 as a ring member, which ring is optionally substituted by R²¹. In some such embodiments, the 57 membered heterocyclic ring contains O as an additional heteroatom. In some such embodiments, the 5-7 membered heterocyclic ring contains NR²⁴ as an additional heteroatom.

In some embodiments of Formula (I), R³ is taken together with R⁵to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR²⁴,0 and S(O)_m 10 as a ring member, which ring is optionally substituted by R²¹. In some such embodiments, the 57 membered heterocyclic ring contains O as an additional heteroatom. In some such embodiments, the 5-7 membered heterocyclic ring contains NR²⁴as an additional heteroatom.

In compounds of Formula (I), R⁶ is H, F, Cl, CN, CH3, CH2F, CHF2 or CF3. In some embodiments, R⁶ is F or Cl. In some such embodiments, R⁶ is F. In some such embodiments, 15 R⁶ is Cl. In some embodiments, R⁶ is H. In other embodiments, R⁶ is CN, CH3, CH2F, CHF2 or CF₃.

In compounds of Formula (I), R⁷ and R⁸ are independently H, F, Cl, CN, C1-C2 alkyl, C1-C2 fluoroalkyl, C1-C2 alkoxy or C1-C2 fluoroalkoxy, where each said C1-C2 alkyl, C1-C2 fluoroalkyl, C1-C2 alkoxy and C1-C2 fluoroalkoxy is optionally substituted by R²⁰. In some such embodiments, 20 R⁷ is H. In some such embodiments, R⁸ is H. In some such embodiments, R⁷ and R⁸ are H.

In compounds of Formula (I), R⁹ is H, OH, NH2, NHCH3 or N(CH3)2- In preferred embodiments of Formula (I), R⁹ is OH.

In compounds of Formula (I), each R¹⁰ is independently F, CN, C1-C2 alkyl or C1-C2 fluoroalkyl, where each said C1-C2 alkyl and C1-C2 fluoroalkyl is optionally substituted by R²⁰. In 25 some embodiments, n is 0 and R¹⁰ is absent. In other embodiments, n is 1 or 2 and R¹⁰ is independently F, CN, C1-C2 alkyl or C1-C2 fluoroalkyl. In some embodiments, n is 1 or 2 and R¹⁰ is independently F or CH3. | |

In some embodiments of Formula (I), Q is NR¹¹ or O. In some embodiments, Q is O. In some embodiments, Q is O, p is 2 and q is 1. In some such embodiments, n is 0 and R¹⁰ is 30 absent. ί i

In other embodiments of Formula (I), Q is NR¹¹. In some embodiments, Q is NR¹¹] p is 2 and q is 1. In some such embodiments, R¹¹ is SO2R¹⁴. In other such embodiments, R¹¹ is COR¹⁷. In some such embodiments, n is 0 and R¹⁰ is absent.

In some embodiments of Formula (I), Q is CR¹²R¹³, where R¹² and R¹³ are taken together 35 with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing _— 36

NR¹¹ or O as a ring member, which ring is optionally further substituted by R¹⁰. In some such embodiments, n is 0 and R¹⁰ is absent.

In compounds of Formula (I), R¹¹ is H, C1-C4 alkyl, C1-C4 fluoroalkyl, SO2R¹⁴, SO2NR¹⁵R¹⁶, COR¹⁷, COOR¹⁷ or CONR¹⁸R¹⁹, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally 5 substituted by R²⁰, SO2R¹⁴, SO2NR¹⁵R¹⁶, COR¹⁷, COOR¹⁷ or CONR¹⁸R¹⁹.

In some embodiments, R¹¹ is SO2R¹⁴. In other embodiments, R¹¹ is COR¹⁷. In still other embodiments, R¹¹ is C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R²⁰, SO2R¹⁴, SO₂NR¹⁵R¹⁶, COR¹⁷, COOR¹⁷ or CONR¹⁸R¹⁹. In some such embodiments, R¹¹ is C1-C4 alkyl substituted by SÜ2R¹⁴or COR¹⁷. In some such 10 embodiments, R¹¹ is C1-C4 alkyl substituted by R²⁰.

In compounds of Formula (I), R¹⁴is C1-C4 alkyl or C1-C4 fluoroalkyl. In some embodiments, R¹⁴is C1-C4 alkyl. In some such embodiments, R¹⁴is C1-C2 alkyl. In some embodiments, R¹⁴is C1-C4 fluoroalkyl. In some such embodiments, R¹⁴1SC1-C2fluoroalkyl. In particular embodiments, R¹⁴is CH₃ orC₂H₅.

In compounds of Formula (I), each R¹⁵ and R¹⁶ is independently H or CH₃.

In compounds of Formula (I), R¹⁷is C1-C4 alkyl, C1-C4 fluoroalkyl, C3-Ce cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R²⁰ and each said C3-C₃ cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R²¹. In some embodiments, R¹⁷ is C1-C4 alkyl or C1-C4 fluoroalkyl, where each said 20 C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R²⁰. In some embodiments, R¹⁷ is

C₃-Ce cycloalkyl or 3-6 membered heterocyclyl, where each said C₃-Ce cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R²¹.

In compounds of Formula (I), each R¹⁸ and R¹⁹ is independently H, C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R²⁰.

In compounds of Formula (I), each R²⁰ is independently OH, C1-C2 alkoxy, C1-C2 fiuoroalkoxy, CN, N R²² R²³, C₃-Ce cycloalkyl or 3-6 membered heterocyclyl, where each said C₃-Ce cycloalkyl and 3-6 membered heterocyclyl ijs optionally substituted by R²¹. |

In some embodiments, each R²⁰ is independently OH, C1-C2 alkoxy, C1-C2 fiuoroalkoxy, CN or N R²²R²³. In some such embodiments, R²⁰ is OH. In some such embodiments, R²⁰ is OH, 30 C1-C2 alkoxy or NR^Z2R²³. In some such embodiments, R²⁰ is OH, In some embodiments, R²⁰ is i

C₃-Ce cycloalkyl or 3-6 membered heterocyclyl, where each said C₃-Ce cycloalkyl and 3-6 I membered heterocyclyl is optionally substituted by R²¹.

In compounds of Formula (I), each R²¹ is independently F, OH, CN, N R²²R²³, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy or C1-C4 fiuoroalkoxy, where each said C1-C4 alkyl, C1-C4 35 fluoroalkyl, C1-C4 alkoxy and C1-C4 fiuoroalkoxy is optionally further substituted by OH, NH₂, NHCH₃ or N(CH₃)2. In some embodiments, each R²¹ is independently F, OH or C1-C4 alkyl.

_ ³⁷

In some embodiments of Formula (I), each R²² and R²³ is independently H, C1-C3 alkyl, C1-C3 fluoroalkyl, C3-C8 cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C3 alkyl and C1-C3 fluoroalkyl is optionally further substituted by OH, C1-C2 alkoxy or C1-C2 fluoroalkoxy and each said C3-C8 cycloalkyl and 3-6 membered heterocyclyl is optionally further substituted 5 by F, OH, Ci-C₂ alkyl, C1-C2 fluoroalkyl, C1-C2 alkoxy or C1-C2 fluoroalkoxy.

In some such embodiments, each R²² and R²³ is independently H, C1-C2 alkyl or C1-C2 fluoroalkyl. In some such embodiments, each R²² and R²³ is independently H, C1-C2 alkyl or C1-C2 fluoroalkyl.

In some embodiments of Formula (I), R²² and R²³ may be taken together with the nitrogen 10 atom to which they are attached to form an azetidinyl ring, where said ring is optionally substituted by F, OH, C1-C2 alkyl, C1-C2 fluoroalkyl, C1-C2 alkoxy or C1-C2 fluoroalkoxy. In some such embodiments, R²² and R²³ may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring, which is optionally substituted by F, OH or C1-C2 alkyl.

In compounds of Formula (I), R²⁴ is H, C1-C4 alkyl, C1-C4 fluoroalkyl, SO2R²⁵, SO2NR²⁶R²⁷, 15 COR²⁸, COOR²⁸ or CONR²⁹R³⁰. In some embodiments, R²⁴ is H or C1-C4 alkyl. In some embodiments, R²⁴ is H or C1-C2 alkyl.

In compounds of Formula (I), R²⁵ is C1-C4 alkyl or C1-C4 fluoroalkyl. In some embodiments, R²⁵ is C1-C2 alkyl.

In compounds of Formula (I), each R²⁶ and R²⁷ is independently H or CH3.

In compounds of Formula (I), R²⁸ is C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by OH, C1-C2 alkoxy, C1-C2 fluoroalkoxy, CN, NH2, NHCH3 or N(CH3)2. In some embodiments, R²⁸is C1-C4 alkyl optionally substituted by OH or C1-C2 alkoxy. In some embodiments, R²⁸is C1-C2 alkyl.

In compounds of Formula (I), each R²⁹ and R³⁰ is independently H, C1-C4 alkyl or C1-C4 25 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by OH, C1-C2 alkoxy, C1-C2 fluoroalkoxy, CN, NH2, NHCH3 or N(CH3)2. In some embodiments, each R²⁹ | and R³⁰ is independently H or C1-C4 alkyl where each said C1-C4 alkyl is optionally substituted by OH or C1-C2 alkoxy. In somë embodiments, each R²⁹ and R³⁰ is independently H or C1-C2 alkyl.

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

30; In compounds of Formula (I), n is 0,1, 2, 3 or 4. In some embodiments, n is 0 and R¹⁰ is

I absent. In some embodiments, n is 1 or2. I

In compounds of Formula (I), p is 1, 2 or 3; wherein the sum of p and q is an integer from 1 to 4. In some embodiments, p is 2. In other embodiments, p is 1. In some embodiments, the sum of p and q is an integer from 1 to 3. . ____ ς : s — ___ — 38

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

In some embodiments, p is 2 and q is 1. In other embodiments, p is 1 and q is 1. In other . 5 embodiments, p is 1 and q is 0. In further embodiments, the sum of p and q is an integer from 1 to 3.

In certain embodiments, the invention provides a compound of Formula (I), (l-A), (l-B), (ΙΟ) or (l-D), or a pharmaceutically acceptable sait thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: A is N; R¹ 10 is Cl; U is NR² and V is CR⁴; R² is C1-C5 alkyl; or R² is i-CsH?; R⁴ is C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by R²⁰, where R²⁰ is OH; or R⁴ is CH(OH)CH3 or C(OH)(CH3)2! X is CR⁶; R⁶ is F; Y is CR⁷; R⁷ is H; Z is CR⁸; R⁸ is H; R⁹ is OH; Q is O; or Q is NR¹¹, where R¹¹ is SO2R¹⁴ ; R¹⁴ is C1-C4 alkyl; n is 0 and R¹⁰ is absent; p is 2; and q is 1.

In certain embodiments, the invention provides a compound of Formula (I), (l-A), (l-B), (I15 C) or (l-D), or a pharmaceutically acceptable sait thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: A is N; R¹ is Cl; U is CR³ and V is NR⁵; R³ is C1-C5 alkyl; or R³ is 1-C3H7; R⁵ is C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by R²⁰, where R²⁰ is OH; X is CR⁶; R⁶ is F; Y is CR⁷; R⁷ is H; Z is CR⁸; R⁸ is H; R⁹ is OH; Q is O; or Q is NR¹¹, where R¹¹ is SO2R¹⁴; R¹⁴is C1-C4 alkyl; n is 0 and 20 R¹⁰ is absent; p is 2; and q is 1.

In a preferred embodiment, the invention provides a compound of Formula (I), (l-A), (l-B), (l-C) or (l-D), or a pharmaceutically acceptable sait thereof, wherein: A is N; R¹ is Cl; U is NR²; R² is C1-C5 alkyl; or R² is 1-C3H7; V is CR⁴; R⁴ is C1-C4 alkyl optionally substituted by R²⁰, where R²⁰ is OH; or R⁴ is CH(OH)CH₃ orC(OH)(CH₃)₂; X is CR⁶; R⁶ is F; Y is CR⁷; R⁷ is H; Z is CR⁸;

R⁸ is H; R⁹ is OH; Q is O; n is 0 and R¹⁰ is absent; p is 2; and q is 1.

In another preferred embodiment, the invention provides a compound of Formula (I), (IA), (I-|b), (l-C) or (l-D), or a pharmaceutically acceptable sait |thereof, wherein: A is N; R¹ is Cl; U is NR²; R² is C1-C5 alkyl; or R² is 1-C3H7; V is CR⁴; R⁴ is C1-C4 alkyl optionally substituted by R²⁰, where R²⁰ is OH; or R⁴ is CH(OH)CH₃ orC(OH)(CH₃)₂; X is CR⁶; R⁶ is F; Y is CR⁷; R⁷ is H; Z is 30 CR⁸; R⁸ is H; R⁹is OH; Q is NR¹¹, where R¹¹ is SO2R¹⁴; R¹⁴is C1-C4 alkyl; n is 0 and R¹⁰ is absent;

p is 2; and q is 1. I

In another embodiment, the invention provides a compound of Formula (I), (l-A), (l-B), (ΙΟ) or (l-D), or a pharmaceutically acceptable sait thereof, wherein: A is N; R¹ is Cl; U is NR²; R² is C1-C5 alkyl; or R² is 1-C3H7; V is CR⁴; R⁴ is C1-C4 alkyl optionally substituted by R²⁰, where R²⁰ 35 is OH; or R⁴ is CH(OH)CH₃ orC(OH)(CH₃)₂; X is CR⁶; R⁶ is F; Y is CR⁷; R⁷ is H; Z is CR⁸; R⁸ is H; R⁹ is OH; Q is O; n is 0 and R¹⁰ is absent; p is 2; and q is 1.

— 39

In another preferred embodiment, the invention provides a compound of Formula (I), (ΙΑ), (l-B), (l-C) or (l-D), or a pharmaceutically acceptable sait thereof, wherein: A is CH; R¹ is Cl; U is NR²; R² is C1-C5 alkyl; or R² is i-CsH?; V is CR⁴; R⁴ is C1-C4 alkyl optionally substituted by R²⁰, where R²⁰ is OH; or R⁴ is CH(OH)CH₃ orC(OH)(CH₃)₂; X is CR⁶; R⁶ is F; Y is CR⁷; R⁷ is H;

Z is CR⁸; R⁸ is H; R⁹is OH; Q is NR¹¹, where R¹¹ is SO₂R¹⁴; R¹⁴is C1-C4 alkyl; n is 0 and R¹⁰ is absent; p is 2; and q is 1.

In certain embodiments, the invention provides a compound of Formula (I), (l-A), (l-B), (ΙΟ) or (l-D), or a pharmaceutically acceptable sait thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: A is CH; R¹ 10 is Cl; U is CR³ and V is NR⁵; R³ is C1-C5 alkyl; or R³ is i-C3H?; R⁵ is C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by R²⁰, where R²⁰ is OH; X is CR⁶; R⁶ is F; Y is CR⁷; R⁷ is H; Z is CR⁸; R⁸ is H; R⁹ is OH; Q is O; or Q is NR¹¹, where R¹¹ is SO2R¹⁴; R¹⁴is C1-C4 alkyl; n is 0 and R¹⁰ is absent; p is 2; and q is 1.

Each ofthe aspects and embodiments described herein with respect to Formula (I) is also 15 applicable to compounds of Formulae (ll)-(XII) that are not inconsistent with such aspect or embodiment.

In compounds of Formula (II), R¹ is H, F, Cl, CN, C1-C2 alkyl or C1-C2 fluoroalkyl, where each said C1-C2 alkyl and C1-C2 fluoroalkyl is optionally substituted by R²⁰. In some embodiments, R¹ is F or Cl. In some embodiments, R¹ is F. In some embodiments, R¹ is Cl.

In compounds of Formula (II), X is CR⁶ or N. In some embodiments, X is CR⁶. In some embodiments, X is N,

In compounds of Formula (II), Y is CR⁷ or N. In some embodiments, Y is CR⁷. In some embodiments, Y is N.

In compounds of Formula (II), Z is CR⁸ or N. In some embodiments, Z is CR⁸. In some 25 embodiments, Z is N.

In frequent embodiments of Formula (II), X is CR⁶, Y is CR⁷ and Z is CR⁸. In other embodiments |of Formula (II), at least one of X, Y and Z is N. |

In compounds of Formula (II), U is NR² or CR³; V is N or CR⁴ when U is NR²; and V is NR⁵ when U is CR³. In some embodiments, U is NR² and V is N or CR⁴. In some such 30 embodiments,! U is NR² and V is CR⁴. In some such embodiments, U is NR² and V is N. In other embodiments,! U is CR³ and V is NR⁵. I

In some embodiments of Formula (II), U is NR²and R² is H, C1-C5 alkyl, C1-C5 fluoroalkyl, C3-Ce cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R²⁰ and each said C3-Ce cycloalkyl and 3-6 membered heterocyclyl is ’ 35 optionally substituted by R²¹.

⁴⁰

In compounds of Formula (II), R² and R³ are H, C1-C5 alkyl, C1-C5 fluoroalkyl, C3-C8 cycloalkyl or 3-6 membered heterocyclyl/where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R²⁰ and each said C₃-C₈ cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R²¹. — .

In some such embodiments, R² is C1-C5 alkyl or C1-C5 fluoroalkyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R²⁰. In some such embodiments, R² is C1-C5 alkyl optionally substituted by R²⁰. In some such embodiments, R²⁰ is OH. In particular embodiments, R² is CH3, C2H5, n-CsH?, 1-C3H7, n-C4H9, S-C4H9, Î-C4H9, t-C4Hg, CHF2 or CH2CHF2 (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, difluoromethyl or 10 difluoroethyl), each optionally substituted by R²⁰. In spécifie embodiments, R² is isopropyl or tertbutyl. In spécifie embodiments, R² is isopropyl (i-CsH?) In some embodiments, R² is C1-C5 alkyl or C1-C5 fluoroalkyl optionally substituted by R²⁰ where R²⁰is OH.

In other embodiments, R² is C₃-C₈ cycloalkyl or 3-6 membered heterocyclyl, where each said C3-C8 cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R²¹. In some such embodiments, R² is 3-6 membered heterocyclyl optionally substituted by R²¹. In particular embodiments, R² is oxetan-3-yl or azetidin-3-yI, each optionally substituted by R²¹. In spécifie embodiments, R² is oxetan-3-yl. In other embodiments, R² is C3-C8 cycloalkyl, where said C3-C8 cycloalkyl is optionally substituted by R²¹. In some such embodiments, R²¹ is F, OH or C1-C4 alkyl.

In some embodiments ofthe foregoing where U is NR², V is N. In other embodiments of the foregoing where U is N R², V is CR⁴.

In other embodiments of Formula (II), U is CR³ and R³ is H, C1-C5 alkyl, C1-C5 fluoroalkyl, C3-C8 cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R²⁰ and each said C3-C8 cycloalkyl and 3-6 membered heterocyclyl is 25 optionally substituted by R²¹.

In some such embodiments, R³ is C1-C5 alkyl or C1-C5 fluoroalkyl, where each said C1-C5 alkyl and C1-C5 fluoroal|<yl is optionally substituted by R²⁰. In some such embodiments, R³ is C1-C5 alkyl optionally substituted by R²⁰. In some such embodiments, R²⁰is OH or N R²² R²³. In some such embodiments, R²⁰ is OH. In some such embodiments, R³ is CH3, C2H5, n-CsH?, 1-C3H7, n-.

C4H9, S-C4H9, i-C4H₉. t-C4H₉, CHF₂ or CH2CHF2, each optionally substituted bÿ R²⁰. In spécifie embodiments, R³ is i-CsH/or t-C4H₉(i.e., isopropyl or tert-butyl). In spécifie embodiments, R² is isopropyl.

In other embodiments, R³ is C3-C8 cycloalkyl or 3-6 membered heterocyclyl, where each said C3-C8 cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R²¹. In some 35 such embodiments, R³ is 3-6 membered heterocyclyl optionally substituted by R²¹. In particular embodiments, R³ is oxetan-3-yl or azetidin3-yl optionally substituted by R²¹. In some such embodiments, R²¹ is F, OH or C1-C4 alkyl. In spécifie embodiments, R³ is oxetan-3-yl. In other embodiments, R³ is C3-C8 cycloalkyl, where said C3-C8 cycloalkyl is optionally substituted by R²¹. In some such embodiments, R²¹ is F, OH or C1-C4 alkyl.

In the foregoing embodiments where U is CR³, V is NR⁸. —

In some embodiments of Formula (II), V is CR⁴ when U is NR².

In compounds of Formula (II), R⁴ is H, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy or C1-C4 fluoroalkoxy, where each said C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy and C1-C4 fluoroalkoxy is optionally substituted by R²⁰. In some embodiments, R⁴ is H. In other embodiments, R⁴ is C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally 10 substituted by R²⁰. In some such embodiments, R⁴ is C1-C4 alkyl optionally substituted by R²⁰. In some such embodiments, R²⁰ is OH, OCH3, NH2, NHCH3 or NH(CH3)2. In some such embodiments, R²⁰ is OH or NH2. In some such embodiments, R²⁰ is OH. In certain embodiments, R⁴ is Ci-C2 alkyl optionally substituted by R²⁰, where R²⁰ is OH or NH2. In spécifie embodiments, R⁴ optionally substituted by R²⁰ (i.e., R⁴-R²⁰) is H, CH3, C2Hs, CH2OH, CH(OH)CH3, CH2CH2OH 15 or CH2NH2(i.e., methyl, ethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl or aminomethyl). In some embodiments, R⁴ substituted by R²⁰ is CH(OH)CH3 or C(OH)(CH3)2. In other such embodiments, R⁴ is C1-C4 fluoroalkyl optionally substituted by R²⁰. In other embodiments, R⁴ is C1-C4 alkoxy or C1-C4 fluoroalkoxy, where each said C1-C4 alkoxy and C1-C4 fluoroalkoxy is optionally substituted by R²⁰.

In some embodiments of Formula (II), V is NR⁵ when U is CR³.

In compounds of Formula (II), R⁵ is H, C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R²⁰. In some embodiments, R⁵ is H. In other embodiments, R⁵ is C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R²⁰. In some such embodiments, R⁵ is C1-C4 alkyl 25 optionally substituted by R²⁰. In other such embodiments, R⁵ is C1-C4 fluoroalkyl optionally substituted by R²⁰. In spécifie embodiments, R⁵ is CrC2 alkyl or Ci-C2 fluoroalkyl. In spécifie embodiments, R⁵ is CH3, C₂(t₅. CHF₂ or CH₂CHF₂ (i.e., methyl, ethyl, difluoronjethyl or difluoroethyl). _ — _

In compounds of Formula (II), R⁶ is H, F, Cl, CN, CH3, CH2F, CHF2 or CF3. In some 30 embodiments, R⁶ is H. In other embodiments, R⁶ is F. In other embodiments, R⁶ is Cl. In further embodiments, R⁶ is CN. In other embodiments, R⁶ is CH3, CH2F, CHF₂ or CF3. I

In compounds of Formula (II), R⁷ and R⁸ are independently H, F, Cl, CN, Ci-C₂ alkyl, CrC₂ fluoroalkyl, CrC₂ alkoxy or Ci-C₂ fluoroalkoxy, where each said CrC₂ alkyl, Ci-C₂ fluoroalkyl, Ci-C₂ alkoxy and Ci-C₂ fluoroalkoxy is optionally substituted by.R²⁰. :. : ~

In some embodiments of Formula (II), R⁷ is H. In other embodiments, R⁷ is F or Cl. In further embodiments, R⁷ is Ci-C₂ alkyl or Ci-C₂ fluoroalkyl, where each said Ci-C₂ alkyl and CrC₂ fluoroalkyl is optionally substituted by R²⁰. In some such embodiments, R⁷ is CH3, optionally substituted by R²⁰. In some embodiments, R⁷ is CH₃. ~

In some embodiments of Formula (II), R⁸ is H. In other embodiments, R⁸ is F or Cl. In further embodiments, R⁸ is C1-C2 alkyl or C1-C2 fluoroalkyl, where each said C1-C2 alkyl and C1-C2 5 fluoroalkyl is optionally substituted by R²⁰. In some such embodiments, R⁸ is CH3, optionally substituted by R²⁰. In some embodiments, R⁸ is CH3.

In some embodiments, R⁷ and R⁸ are H.

In compounds of Formula (11), R⁹is H, OH, NH2, NHCH3 or N(CH3)2. In some preferred embodiments, R⁹ is OH. In other embodiments, R⁹ is NH2, NHCH3 or N(CH₃)2. In further 10 embodiments, R⁹ is H.

In compounds of Formula (11), each R¹⁰ is independently F, CN, C1-C2 alkyl or C1-C2 fluoroalkyl, where each said C1-C2 alkyl and C1-C2 fluoroalkyl is optionally substituted by R²⁰. In some embodiments, n is 0 and R¹⁰ is absent. In other embodiments, n is 1, 2, 3 or 4 and each R¹⁰ is independently F, CN, C1-C2 alkyl or C1-C2 fluoroalkyl, where each said C1-C2 alkyl and 15 C1-C2 fluoroalkyl is optionally substituted by R²⁰. In other embodiments, n is 1 or 2 and R¹⁰ is independently F, CN, C1-C2 alkyl or C1-C2 fluoroalkyl. In some embodiments, n is 1 or 2 and R¹⁰ is independently F or CH₃.

In compounds of Formula (II), Q is NR¹¹ or O; or Q is CR¹²R¹³, where R¹² and R¹³ are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic 20 ring containing NR¹¹ or O as a ring member, which ring is optionally further substituted by R¹⁰.

In some embodiments of Formula (II), Q is NR¹¹. In some embodiments, Q is NR¹¹, p is 2 and q is 1. In some such embodiments, R¹¹ is SO2R¹⁴. In other such embodiments, R¹¹ is COR¹⁷. In some such embodiments, n is 0 and R¹⁰ is absent.

In compounds of Formula (II), R¹¹ is H, C1-C4 alkyl, C1-C4 fluoroalkyl, SO2R¹⁴, SO2NR¹⁵R¹⁶, 25 COR¹⁷, COOR¹⁷ or CONR¹⁸R¹⁹. In some embodiments, R¹¹ is H, C1-C4 alkyl or C1-C4 fluoroalkyl. In some embodiments, R¹¹ is Hr In other embodiments, R¹¹ is C1-C4 alkyl or C1-C4 fluoroalkyl. In some embodiments, R¹¹ is C1-C4 alkyl. l|n other embodiments, R¹¹ is C1-C4 fluoroalkyl. In some| embodiments, R¹¹ is SO2R¹⁴, SO2NR¹⁵R¹⁶, COR¹⁷, COOR¹⁷ or CONR¹⁸R¹⁹. In some embodiments, R¹¹ is SO2R¹⁴ or SO2NR¹⁵R¹⁶. In some embodiments, R¹¹ is SO2R¹⁴. In other 30 embodiments, R¹¹ is SO2NR¹⁵R¹⁶. In some embodiments, R¹¹ is COR¹⁷, COOR¹⁷ or CONR¹⁸R¹⁹J In some embodiments, R¹¹ is COR¹⁷i. In some embodiments, R¹¹ is COOR¹⁷. In other embodiments, R¹¹ is CONR¹⁸R¹⁹.

In other embodiments of Formula (II), Q is O. In some embodiments, Q is O, p is 2 and q is1. In some suclrembodiments, n is 0 and R¹⁰ is absent. ........ . :......

Ih further embodiments of Formula (II), Q is CR¹²R¹³, where R¹² and R¹³ are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing

NR¹¹ or O as a ring member, which ring is optionally further substituted by R¹⁰. In some such embodiments, R¹² and R¹³ are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing NR¹¹ as a ring member, which ring is optionally furthersubstituted by R¹⁰..In othersuch embodiments, R¹²and R¹³ are taken togetherwith the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing O as a ring member, which ring is optionally further substituted by R¹⁰. In some such embodiments, R¹² and R¹³ are taken together to form a 4-membered optionally substituted heterocyclic ring. In other such embodiments, R¹² and R¹³ are taken together to form a 5-membered optionally substituted heterocyclic ring. In other such embodiments, R¹² and R¹³ are taken together to form a 6membered optionally substituted heterocyclic ring. In each case, said 4-6 membered heterocyclic ring contains NR¹¹ or O as a ring member and is optionally further substituted by R¹⁰, where each of R¹⁰ and R¹¹ is as further defined herein. In some such embodiments, n is 0 and R¹⁰ is absent.

In the foregoing embodiments, each R¹⁰ is independently selected from the group as defined herein.

In compounds of Formula (II), R¹⁴ is C1-C4 alkyl or C1-C4 fluoroaikyl. In some embodiments, R¹⁴ is C1-C4 alkyl. In some embodiments, R¹⁴ is C1-C4 fluoroaikyl. In spécifie embodiments, R¹⁴ is CH3 or C2H5 (i.e., methyl or ethyl).

In compounds of Formula (II), each R¹⁵ and R¹⁶ is independently H or CH3.

In compounds of Formula (II), R¹⁷is C1-C4 alkyl or C1-C4fluoroaikyl, where each said C1-C4 alkyl and C1-C4 fluoroaikyl is optionally substituted by R²⁰. In some embodiments, R¹⁷ is C1-C4 alkyl or C1-C4 fluoroaikyl. In some embodiments, R¹⁷ is C1-C4 alkyl optionally substituted by R²⁰. In some embodiments, R¹⁷ is C1-C4 fluoroaikyl optionally substituted by R²⁰. In spécifie embodiments, R¹⁷ is CH3 or C2H5.

In compounds of Formula (II), each R¹⁸ and R¹⁹ is independently H, C1-C4 alkyl or C1-C4 fluoroaikyl, where each said C1-C4 alkyl and C1-C4 fluoroaikyl is optionally substituted by R²⁰. In some embodiments, each R¹⁸ and R¹⁹ is independently H, C1-C4 alkyl or C1-C4 fluoroaikyl. In some embodiments, each R¹⁸ and R¹⁹ is indepentjlently H or C1-C4 alkyl optionally substituted by R²⁰. In some embodiments, each R¹⁸ and R¹⁹ is independently H or C1-C4 fluoroaikyl optionally substituted by R²⁰. In spécifie embodiments, each R¹⁸and R¹⁹ is independently H, CH3 or C2H5.

In compounds of Formula (II), each R²⁰ is independently OH, C1-C2 alkoxy, C1-C2 fluoroalkoxy, CN or NR²²R²³. In some embodiments, R²⁰ is OH. In some such embodiments, R²⁰ is OH, C1-C2 alkoxy or N R²² R²³. In other embodiments, R²⁰ is C1-C2 alkoxy or C1-C2 fluoroalkoxy. In further embodiments, R²⁰ is CN. In still other embodiments, R²⁰ is N R²² R²³.

In compounds of Formula (II), each R²¹ is independently F, OH, CN, N R²² R²³, C1-C4 . alkyl, C1-C4 fluoroaikyl, C1-C4 alkoxÿ or C1-C4 fluoroalkoxy, where each said C1-C4 alkyl, C1-C4 fluoroaikyl, C1-C4 alkoxy and C1-C4 fluoroalkoxy is optionally further substituted by OH, NH2, _ 44

NHCHa or N(CH₈)2. In some embodiments, R²¹ is F. In some embodiments, R²¹ is OH. In some embodiments, each R²¹ is independently F, OH or C1-C4 alkyl. In other embodiments, R²¹ is CN. In other embodiments, R²¹ is C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy or C1-C4 fluoroalkoxy, where each said C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy and C1-C4 fluoroalkoxy is optionally further substituted by OH, NH2, NHCH3 or N(CH3)2.

In compounds of Formula (II), each R²² and R²³ is independently H, C1-C2 alkyl or C1-C2 fluoroalkyl; or R²² and R²³ may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring, which is optionally substituted by F or OH.

In some embodiments, each R²² and R²³ is independently H, C1-C2 alkyl or C1-C2 10 fluoroalkyl. In spécifie embodiments, each R²² and R²³ is independently H or CH3. In other embodiments, R²² and R²³ are taken together with the nitrogen atom to which they are attached to form an azetidinyl ring, which is optionally substituted by F or OH.

In compounds of Formula (II), n is 0,1, 2, 3 or 4. In some embodiments, n is 0 and R¹⁰ is absent. In other embodiments, n is 1, 2, 3 or 4 and R¹⁰ is as defined herein. In some 15 embodiments, n is 1 or 2.

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

In some embodiments, p is 2 and q is 1. In other embodiments, p is 2 and q is 2. In some embodiments, p is 1 and q is 0. In other embodiments, p is 1 and q is 1. In still other embodiments, 20 p is 1 and q is 2. In further embodiments, p is 1 and q is 3. In some embodiments, p is 2. In other embodiments, p is 1. In some embodiments, q is 1. In other embodiments, q is 0.

In certain embodiments, the invention provides a compound of Formula (II), (ll-A), (ll-B), (ll-C) or (II-D), or a pharmaceutically acceptable sait thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R¹ is Cl; U 25 is NR² and V is CR⁴; R² is C1-C5 alkyl; or R² is 1-C3H7; R⁴ is C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by R²⁰, where R²⁰ is OH; or R⁴ is CH(OH)CH3 or C(OH)(CH3)2î X is CR⁶; R⁶ is Y is CR⁷; Z is CR⁸; R⁷ and R⁸ are H; R⁹ is OH; Q is 0; or Q is NR¹¹, where R¹¹ is SO2R¹⁴; R¹⁴ is C1-C4 alkyl; n is 0 and R¹⁰ is absent; p is 2; and q is 1.

In certain embodiments, the invention provides a compound of Formula (II), (ll-A), (ll-B), 30 (H-C) or (ll-D), or a pharmaceutically acceptable sait thereof, having a combination of two or more, preferably three or more, and more preferably four or morè, of the following features: R¹ is Cl; U is CR³ and V is NR⁵; R³ is C1-C5 alkyl; or R³ is 1-C3H7; R⁵ is C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by R²⁰; R²⁰ is OH; X is CR⁶; R⁶ is F; Y is CR⁷; Z is CR⁸; R⁷ and R⁸ are H; R⁹ is OH; Q is O; or Q is NR¹¹, where R¹¹ is SO2R¹⁴; R¹⁴ is C1-C4 alkyl; n is 0 and R¹⁰ is absent; p is 35 2;andqis1. .

_ ⁴⁵

In a preferred embodiment, the invention provides a compound of Formula (II), (ll-A), (IIB), (ll-C) or (ll-D), or a pharmaceutically acceptable sait thereof, wherein: R¹ is Cl; U is NR²; R² is C1-C5 alkyl; or R² is i-C3H7; V is CR⁴; R⁴ is C1-C4 alkyl optionally substituted by R²⁰, where R²⁰ is OH; or R⁴ is CH(OH)CH3 orC(OH)(CH₃)₂; X is CR⁶; R⁶ is F; Y is CR⁷; R⁷ is H; Z is CR⁸; R⁸ is 5 H; R⁹is OH; Q is O; n is 0 and R¹⁰ is absent; p is 2; and q is 1.

In another preferred embodiment, the invention provides a compound of Formula (II), (IIA), (ll-B), (ll-C) or (ll-D), or a pharmaceutically acceptable sait thereof, wherein: R¹ is Cl; U is NR²; R² is C1-C5 alkyl; or R² is i-C3H7; V is CR⁴; R⁴ is C1-C4 alkyl optionally substituted by R²⁰, where R²⁰ is OH; or R⁴ is CH(OH)CH3 or C(OH)(CH₃)₂; X is CR⁶; R⁶ is F; Y is CR⁷; R⁷ is H; Z is 10 CR⁸; R⁸ is H; R⁹ is OH; Q is NR¹¹, where R¹¹ is SO₂R¹⁴; R¹⁴ is C1-C4 alkyl; n is 0 and R¹⁰ is absent;

p is 2; and q is 1.

In compounds of Formula (III), R¹ is H, F, Cl, CN, Ci-C₂ alkyl or Ci-C₂ fluoroalkyl, where each said Ci-C₂ alkyl and Ci-C₂fluoroalkyl is optionally substituted by R²⁰. In some embodiments, R¹ is F or Cl. In some embodiments, R¹ is F. In some embodiments, R¹ is Cl.

In compounds of Formula (III), X is CR⁶ or N. In some embodiments, X is CR⁶. In some embodiments, X is N,

In compounds of Formula (III), Y is CR⁷ or N. In some embodiments, Y is CR⁷. In some embodiments, Y is N.

In compounds of Formula (III), Z is CR⁸ or N. In some embodiments, Z is CR⁸. In some 20 embodiments, Z is N.

In frequent embodiments of Formula (III), X is CR⁶, Y is CR⁷ and Z is CR⁸. In other embodiments of Formula (III), at least one of X, Y and Z is N.

In compounds of Formula (III), U is NR² or CR³; V is N or CR⁴ when U is NR²; and V is NR⁵ when U is CR³. In some embodiments, U is NR² and V is N or CR⁴. In some such 25 embodiments, U is NR² and V is CR⁴. In some such embodiments, U is NR² and V is N. In other embodiments, U is CR³ and V is NR⁵.

In sc|me embodiments of Formula (III), U is NR²and R² is H, IC1-C5 alkyl, C1-C5 fluoroalkyl, C3-Ce cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R²⁰ and each said C3-Ce cycloalkyl and 3-6 membered heterocyclyl is 30 optionally substituted by R²¹. I

In compounds of Formula (III), R² and R³ are H, C1-C5 alkyl, C1-C5 fluoroalkyl, C3-Ce cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R²⁰ and each said C3-Ce cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R²¹, r: 7 / ' .

In some such embodiments, R² is C1-C5 alkyl or C1-C5 fluoroalkÿl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R²⁰. In some such embodiments, R² is

C1-C5 alkyl optionally substituted by R²⁰. In some such embodiments, R²⁰ is OH. In particular embodiments, R² is CHs, C2H5, n-CsHy/i-CsH?, n-C4Hg, S-C4H9, i-C4Hg, t-C4Hg, CHF2 or CH2CHF2 (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, difiuoromethyl or difluoroethyl), each optionally substituted by R²⁰. Jn spécifie embodiments, R² is isopropyl or tertbutyl. In spécifie embodiments, R² is isopropyl. In some embodiments, R² is C1-C5 alkyl or C1-C5 fluoroalkyl optionally substituted by R²⁰ where R²⁰is OH.

In other embodiments, R² is C3-C8 cycloalkyl or 3-6 membered heterocyclyl, where each said C3-C8 cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R²¹. In some such embodiments, R² is 3-6 membered heterocyclyl optionally substituted by R²¹. In particular embodiments, R² is oxetan-3-yl or azetidin-3-yl, each optionally substituted by R²¹. In spécifie embodiments, R² is oxetan-3-yl. In other embodiments, R² is C3-C8 cycloalkyl, where said C3-C8 cycloalkyl is optionally substituted by R²¹. In some such embodiments, R²¹ is F, OH or C1-C4 alkyl.

In some such embodiments, R³ is C1-C5 alkyl or C1-C5 fluoroalkyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R²⁰. In some such embodiments, R³ is C1-C5 alkyl optionally substituted by R²⁰. In some such embodiments, R²⁰is OH or N R²²R²³. In some such embodiments, R²⁰ is OH. In some such embodiments, R³ is CH3, C2H5, n-CsH?, 1-C3H7, nC4H₉, s-C4H₉, i-C4H₉, t-C4Hg, CHF₂ or CH2CHF2, each optionally substituted by R²⁰. In spécifie embodiments, R³ is 1-C3H7 or t-C4Hg (i.e., isopropyl or tert-butyl). In spécifie embodiments, R² is isopropyl.

In other embodiments, R³ is Ο₃-Ο₈ cycloalkyl or 3-6 membered heterocyclyl, where each said C3-C8 cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R²¹. In some such embodiments, R³ is 3-6 membered heterocyclyl optionally substituted by R²¹. In particular embodiments, R³ is oxetan-3-yl or azetidin3-yl optionally substituted by R²¹. In some such embodiments, R²¹ is F, OH or C1-C4 alkyl. In spécifie embodiments, R³ is oxetan-3-yl. In other embodiments, R³ is C3-C8 cycloalkyl, where said C3-C8 cycloalkyl is optionally substituted by R²¹. In some such embodiments, R²¹ is F, OH or C1-C4 alkyl. |

In the foregoing embodiments where U is CR³, V is NR⁵.

In some embodiments of Formula (III), V is CR⁴ when U is NR².

In compounds of Formula (III), R⁴ is H, C1-C4 alkyl, C1-C4fluoroalkyl, C1-C4 alkoxy or C1-C4 fluoroalkoxy, where ëaeh said C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy and C1-C4 fluoroalkoxy is optionally substituted by R²⁰. In some embodiments, R⁴ is H. In other embodiments, R⁴ is C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-G4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R²⁰. In some such embodiments, R⁴ is Cî-C4 alkyl optionally substituted by R²⁰. In some such embodiments, R²⁰ is OH, OCH3, NH2, NHCH3 or NH(CH3)2. In some such embodiments, R²⁰ is OH or NH2. In some such embodiments, R²⁰ is OH. In certain embodiments,

R⁴ is C1-C2 alkyl optionally substituted by R²⁰, where R²⁰ is OH or NH2. In spécifie embodiments,

R⁴-R²⁰ is H, CH3, C2H5, CH2OH, CH(OH)CH3, CH2CH2OH or CH2NH2 (i.e., methyl, ethyl, - hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl or aminomethyl). In some embodiments, R⁴ substituted by R²⁰ is CH(OH)CH3 or C(OH)(CH₃)₂. In other sUch embodiments, R⁴ is C1-C4 fluoroalkyl optionally substituted by R²⁰. In other embodiments, R⁴ is C1-C4 alkoxy or C1-C4 fiuoroalkoxy, where each said C1-C4 alkoxy and C1-C4 fiuoroalkoxy is optionally substituted by R²⁰. ~ - - ..... In some embodiments of Formula (III), V is NR⁵ when U is CR³.

In compounds of Formula (III), R⁵ is H, C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R²⁰. In some embodiments, R⁵ is H. In other embodiments, R⁵ is C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R²⁰. In some such embodiments, R⁵ is C1-C4 alkyl optionally substituted by R²⁰. In other such embodiments, R⁵ is C1-C4 fluoroalkyl optionally substituted by R²⁰. In spécifie embodiments, R⁵ is C1-C2 alkyl or C1-C2 fluoroalkyl. In spécifie embodiments, R⁵ is CH₃, C2H5. CHF₂ or CH2CHF2 (i.e., methyl, ethyl, difluoromethyl or difluoroethyl).

In compounds of Formula (III), R⁶ is H, F, Cl, CN, CH3, CH2F, CHF2 or CF3. In some embodiments, R⁶ is H. In other embodiments, R⁶ is F. In other embodiments, R⁶ is Cl. In further embodiments, R⁶ is CN. In other embodiments, R⁶ is CH3, CH2F, CHF2 or CF₃.

In compounds of Formula (III), R⁷ and R⁸ are independently H, F, Cl, CN, C1-C2 alkyl, C1-C2 fluoroalkyl, C1-C2 alkoxy or C1-C2 fiuoroalkoxy, where each said C1-C2 alkyl, C1-C2 fluoroalkyl, C1-C2 alkoxy and C1-C2 fiuoroalkoxy is optionally substituted by R²⁰.

In some embodiments of Formula (III), R⁷ is H. In other embodiments, R⁷ is F or Cl. In further embodiments, R⁷ is C1-C2 alkyl or C1-C2 fluoroalkyl, where each said C1-C2 alkyl and C1-C2 fluoroalkyl is optionally substituted by R²⁰. In some such embodiments, R⁷ is CH3, optionally substituted by R²⁰. In some embodiments, R⁷ is CH3. ------- _

In some embodiment^ of Formula (III), R⁸ is H. In other embodiments, R⁸ is|F or Cl. In further embodiments, R⁸ is C1-C2 alkyl or C1-C2 fluoroalkyl, where each said C1-C2 alkyl and C1-C2 fluoroalkyl is optionally substituted by R²⁰. In some such embodiments, R⁸ is CH3, optionally substituted by R²⁰. In some embodiments, R⁸ is CH3. I

In some embodiments, R⁷ and R⁸ are H. I

In compounds of Formula (III), R⁹is H, OH, NH2, NHCH3 or N(CH3)2. In some preferred embodiments, R⁹ is OH. In other embodiments, R⁹ is NH2, NHCH3 or N(CH₃)2. In further 2 embodiments, R⁹ is H. . . . . . „ . . . .......

In compounds of Formula (III), each R¹⁰ is independently F, CN, C1-C2 alkyl or C1-C2 fluoroalkyl, where each said C1-C2 alkyl and C1-C2 fluoroalkyl is optionally substituted by R²⁰. In _ ⁴⁸ some embodiments, n is 0 and R¹⁰ is absent. In other embodiments, n is 1, 2, 3 or 4 and each R¹⁰ is independently F, CN, C1-C2 alkyl or Ci-C2 fluoroalkyl, where each said Ci-C2 alkyl and Ci-C2 fluoroalkyl is optionally substituted by R²⁰. In other embodiments, n is 1 or 2 and R¹⁰ is independently F, CN, Ci-C2 alkyl or Ci-C₂ fluoroalkyl. In some embodiments, n is 1 or 2 and R¹⁰.

is independently F or CH3.

In compounds of Formula (III), Q is NR¹¹ or O; or Q is CR¹²R¹³, where R¹² and R¹³ are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing NR¹¹ or O as a ring member, which ring is optionally further substituted by R¹⁰.

In some embodiments of Formula (III), Q is NR¹¹. In some embodiments, Q is NR¹¹, p is 10 2 and q is 1. In some such embodiments, R¹¹ is SO₂R¹⁴. In other such embodiments, R¹¹ is

COR¹⁷. In some such embodiments, n is 0 and R¹⁰ is absent.

In compounds of Formula (III), R¹¹ is H, C1-C4 alkyl, C1-C4 fluoroalkyl, SO2R¹⁴, SO2NR¹⁵R¹⁶, COR¹⁷, COOR¹⁷ or CONR¹⁸R¹⁹. In some embodiments, R¹¹ is H, C1-C4 alkyl or C1-C4 fluoroalkyl. In some embodiments, R¹¹ is H. In other embodiments, R¹¹ is C1-C4 alkyl or 15 C1-C4 fluoroalkyl. In some embodiments, R¹¹ is C1-C4 alkyl. In other embodiments, R¹¹ is C1-C4 fluoroalkyl. In some embodiments, R¹¹ is SO2R¹⁴, SO2NR¹⁵R¹⁶, COR¹⁷, COOR¹⁷ or CONR¹⁸R¹⁹. In some embodiments, R¹¹ is SO2R¹⁴ or SO2NR¹⁵R¹⁶. In some embodiments, R¹¹ is SO2R¹⁴. In other embodiments, R¹¹ is SO2NR¹⁵R¹⁶. In some embodiments, R¹¹ is COR¹⁷, COOR¹⁷ or CONR¹⁸R¹⁹. In some embodiments, R¹¹ is COR¹⁷. In some embodiments, R¹¹ is COOR¹⁷. In other 20 embodiments, R¹¹ is CONR¹⁸R¹⁹.

In other embodiments of Formula (III), Q is O. In some embodiments, Q is O, p is 2 and qis1. In some such embodiments, n is 0 and R¹⁰ is absent.

In further embodiments of Formula (III), Q is CR¹²R¹³, where R¹² and R¹³ are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring 25 containing NR¹¹ or O as a ring member, which ring is optionally further substituted by R¹⁰. In some such embodiments, n is 0 and R¹⁰ is absent. In some such embodiments, R¹² and R¹³ are taken together with the C atom to which thefy are attached to form a 4-6 membered heterocyclic ripg containing NR¹¹ as a ring member, which ring is optionally further substituted by R¹⁰. In other such embodiments, R¹² and R¹³ are taken together with the C atom to which they are attached to . 30 form a 4-6 membered heterocyclic ring containing O as a ring member, which ring is optionally further substituted by R¹⁰. In some such embodiments, R¹² and R¹³ are taken together to form a 4-membered optionally substituted heterocyclic ring. In other such embodiments, R¹² and R¹³ are taken together to form a 5-membered optionally substituted heterocyclic ring. In other such embodiments, R¹² and R¹³ are taken together to form a 6-membered optionally substituted 35 heterocyclic ring. In each case, said 4-6 membered heterocyclic ring contains NR¹¹ or O as a ⁴⁹ ring member and is optionally further substituted by R¹⁰, where each of R¹⁰ and R¹¹ is as further defined herein. In some such embodiments, n is 0 and R¹⁰ is absent.

In the foregoing embodiments, each R¹⁰ is independently selected from the group as defined herein. — . ... ----------- . _ ---------- ------ .. ---5 In compounds of Formula (III), R¹⁴ is C1-C4 alkyl or C1-C4 fluoroalkyl. In some embodiments, R¹⁴ is C1-C4 alkyl. In some embodiments, R¹⁴ is C1-C4 fluoroalkyl. In spécifie embodiments, R¹⁴ is CH3 or C2H5 (i.e., methyl or ethyl). In compounds of Formula (III), each R¹⁵ and R¹⁶ is independently H or CH3.

In compounds of Formula (III), R¹⁷ is C1-C4 alkyl or C1-C4 fluoroalkyl, where each said

C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R²⁰. In some embodiments, R¹⁷is

C1-C4 alkyl or C1-C4 fluoroalkyl. In some embodiments, R¹⁷ is C1-C4 alkyl optionally substituted by R²⁰. In some embodiments, R¹⁷ is C1-C4 fluoroalkyl optionally substituted by R²⁰. In spécifie embodiments, R¹⁷ is CH₃ or C2H5.

In compounds of Formula (III), each R¹⁸ and R¹⁹ is independently H, C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R²⁰. In some embodiments, each R¹⁸ and R¹⁹ is independently H, C1-C4 alkyl or C1-C4 fluoroalkyl. In some embodiments, each R¹⁸ and R¹⁹ is independently H or C1-C4 alkyl optionally substituted by R²⁰. In some embodiments, each R¹⁸ and R¹⁹ is independently H or C1-C4 fluoroalkyl optionally substituted by R²⁰. In spécifie embodiments, each R¹⁸ and R¹⁹ is independently H, CH₃ or C2H5.

In compounds of Formula (III), each R²⁰ is independently OH, C1-C2 alkoxy, C1-C2 fluoroalkoxy, CN or N R²²R²³. In some embodiments, R²⁰ is OH. In some such embodiments, R²⁰ is OH, C1-C2 alkoxy or NR^R²³. In other embodiments, R²⁰ is C1-C2 alkoxy or C1-C2 fluoroalkoxy. In further embodiments, R²⁰ is CN. In still other embodiments, R²⁰ is NR²²R²³.

In compounds of Formula (III), each R²¹ is independently F, OH, CN, N R²² R²³, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy or C1-C4 fluoroalkoxy, where each said C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy and C1-C4 fluoroalkoxy is optionally further substituted by OH, NH2, | NHCH₃ or N(CH₃)2. In some embodiments, R²] is F. In some embodiments, R²¹ is OH. In some | embodiments, each R²¹ is independently F, OH or C1-C4 alkyl. In other embodiments, R²¹ is CN. In other embodiments, R²¹ is C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy or C1-C4 | 30 fluoroalkoxy, where each said C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy and C1-C4 i

I fluoroalkoxy is optionally further substituted by ÔH, NH2, NHCH₃ or N(CH₃)2. i

In compounds of Formula (III), each R²² and R²³ is independently H, C1-C2 alkyl or C1-C2 fluoroalkyl; or R²² and R²³ may be taken together with the nitrogen atom to which they are attached ..... to form an azetidinyl ring, which is optionally substituted by E or OH. . . _ - .

Ih some embodiments, each R²² and R²³ is independently H, C1-C2 alkyl or C1-C2 fluoroalkyl. In spécifie embodiments, each R²² and R²³ is independently H or CH₃. In other embodiments, R²² and R²³ are taken together with the nitrogen atom to which they are attached to form an azetidinyl ring, which is optionally substituted by F or OH.

In compounds of Formula (III), n is 0,1,2,3 or 4. In some embodiments, n is 0 and R¹⁰ is absent. In other embodiments, n is 1, 2, 3 or 4 and R¹⁰ is as defined herein. In some 5 embodiments, n is 1 or 2.

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

In some embodiments, p is2 and q is 1. In other embodiments, p is 2 and q is 2. In some 10 embodiments, p is 1 and q is 0. In other embodiments, p is 1 and q is 1. In still other embodiments, p is 1 and q is 2. In further embodiments, p is 1 and q is 3. In some embodiments, p is 2. In other embodiments, p is 1. In some embodiments, q is 1. In other embodiments, q is 0.

In certain embodiments, the invention provides a compound of Formula (III), (lll-A), (IIIB), (lll-C) or (lll-D), or a pharmaceutically acceptable sait thereof, having a combination of two or 15 more, preferably three or more, and more preferably four or more, of the following features: R¹ is Cl; U is NR² and V is CR⁴; R² is C1-C5 alkyl; or R² is i-C₃H₇; R⁴ is C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by R²⁰, where R²⁰ is OH; or R⁴ is CH(OH)CH3 or C(OH)(CH3)2, X is CR⁶; R⁶ is F; Y is CR⁷; Z is CR⁸; R⁷ and R⁸ are H; R⁹ is OH; Q is O; or Q is NR¹¹, where R¹¹ is SO2R¹⁴; R¹⁴ is C1-C4 alkyl; n is 0 and R¹⁰ is absent; p is 2; and q is 1.

In certain embodiments, the invention provides a compound of Formula (III), (lll-A), (IIIB), (lll-C) or (lll-D), or a pharmaceutically acceptable sait thereof, having a combination of two or more, preferably three or more, and more preferably four or more.of the following features: R¹ is Cl; U is CR³ and V is NR⁵; R³ is C1-C5 alkyl; or R³ is i-C₃H₇; R⁵ is C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by R²⁰; R²⁰ is OH; X is CR⁶; R⁶ is F; Y is CR⁷; Z is CR⁸; R⁷ and R⁸ 25 are H; R⁹ is OH; Q is O; or Q is NR¹¹, where R¹¹ is SO2R¹⁴; R¹⁴ is C1-C4 alkyl; n is 0 and R¹⁰ is absent; p is 2; and q is 1.

| In a preferred embodiment, the invention provides a compound of Formula (III), (lll-A), (IIl-B), (lll-C) or (lll-D), or a pharmaceutically acceptable sait thereof, wherein: R¹ is Cl; U is NR²; R² is C1-C5 alkyl; or R² is i-C3H7; V is CR⁴; R⁴ is C1-C4 alkyl optionally substituted by R²⁰, where 30 R²⁰ is OH; or R⁴ is CH(OH)CH3 or C(OH)(CH₃)₂; X is CR⁶; R⁶ is F; Y is CR⁷; R⁷ is H; Z is CR⁸;

R⁸ is H; R⁹ is OH; Q is O; n is 0 and R¹⁰ is absent; p is 2; and q is 1.

In another preferred embodiment, the invention provides a compound of Formula (III), (IIIA), (lll-B), (lll-C) or (lll-D), or a pharmaceutically acceptable sait thereof, wherein: R¹ is Cl; U is NR²; R² is C1-C5 alkyl; or R² is i-C3H7; V is CR⁴; R⁴ is C1-C4 alkyl optionally substituted by R²⁰, 35 where R²⁰ is OH; or R⁴ is CH(OH)CH3 orC(OH)(CH₃)₂; X is CR⁶; R⁶ is F; Y is CR⁷; R⁷ is H; Z is _— 51

CR⁸; R⁸ is H; R⁹is OH; Q is NR¹¹, where R¹¹ is SO2R¹⁴; R¹⁴is C1-C4 alkyl; n is 0 and R¹⁰ is absent;

p is 2; and q is 1. In certain embodiments, the invention provides a compound of Formula (II), (ll-A), (ll-B), (ll-C) or (ll-D), br a pharmaceutically acceptable sait theréof, or a compound of Formula (lll), (III5 A), (lll-B), (lll-C) or (Ill-D), or a pharmaceutically acceptable sait thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R¹ is F or Cl; U is NR² and V is CR⁴; R² is C1-C5 alkyl, C1-C5 fluoroalkyl or 3-6 membered heterocyclyl; or R² is CH3,1-C3H7, i-C4Hg,s-C4Hg, t-C4Hg, CH2F.CHF2, CH2CHF2 or oxetan-3-yl; R⁴ is H or C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by OH, NH2, NHCH3 or N(CH3)2î or R⁴ is H, CH₃, C2H5, CH₂OH, CH(OH)CH₃, CH2CH2OH or CH2NH2; X is CR⁶; R⁶ is H or F; Y is CR⁷; Z is CR⁸; R⁷ and R⁸ are H; R⁹ is OH; n is 0 and R¹⁰ is absent; Q is NR¹¹; R¹¹ is SO2R¹⁴; and R¹⁴is C1-C4 alkyl; p is 2; and q is 1.

In certain embodiments, the invention provides a compound of Formula (II), (ll-A), (ll-B), (ll-C) or (ll-D), or a pharmaceutically acceptable sait thereof, or a compound of Formula (lll), (III15 A), (lll-B), (lll-C) or (III-D), or a pharmaceutically acceptable sait thereof, having a combination of two or more, preferably three or more, and more preferably four or more, ofthe following features: R¹ is F or Cl; U is CR³ and V is NR⁵; R³ is C1-C5 alkyl, C1-C5 fluoroalkyl or 3-6 membered heterocyclyl; or R³ is CH3,1-C3H7, i-C4Hg.s-C4Hg, t-C4Hg, CH2F.CHF2, CH2CHF2 or oxetan-3-yl; R⁵ is H or C1-C4 alkyl; or R⁵ is H or CH₃; X is CR⁶; R⁶ is H or F; Y is CR⁷; Z is CR⁸; R⁷ and R⁸ are H;

R⁹ is OH; n is 0 and R¹⁰ is absent; Q is NR¹¹; R¹¹ is SO2R¹⁴; and R¹⁴is C1-C4 alkyl; p is 2; and q is 1.

In certain embodiments, the invention provides a compound of Formula (II), (ll-A), (ll-B), (ll-C) or (ll-D), or a pharmaceutically acceptable sait thereof, or a compound of Formula (lll), (IIIA), (lll-B), (lll-C) or (lll-D), or a pharmaceutically acceptable sait thereof, having a combination of 25 two or more, preferably three or more, and more preferably four or more, of the following features:

R¹ is F or Cl; U is NR² and V is N; R² is Ci-C₅ alkyl, C1-C5 fluoroalkyl or 3-6 membered heterocyclyl; or R² is CH3,1-C3H7, i-C4Hg, s-C4Hg, t-C4Hg, CH2F, c(tF2, CH2CHF2 or oxetan-3-yl; X is CR⁶; R⁶ is H or F; Y is CR⁷; Z is CR⁸; R⁷ and R⁸ are H; R⁹ is OH; n is 0 and R¹⁰ is absent; Q is NR¹¹; R¹¹ is SO2R¹⁴; and R¹⁴is C1-C4 alkyl; p is 2; and q is 1.

In compounds of Formula (IV), R¹ is H, F, Cl, CN, C1-C2 alkyl or C1-C2 fluoroalkyl, where each said C1-C2 alkyl and C1-C2fluoroalkyl is optionally substitutecl by R²⁰. In some embodiments, R¹ is F or Cl. In some embodiments, R¹ is F. In some embodiments, R¹ is Cl.

In compounds of Formula (IV), U is NR² or CR³; V is N or CR⁴ when U is NR²; and

V is NR⁵ when U is CR³. In some embodiments, U is NR² and V is N or CR⁴. In some such. 35 embodiments, U is NR² and V is N. In some such embodiments, U is NR² and V is CR⁴. In some embodiments, U is CR³ and V is NR⁵.

— 52

In compounds of Formula (IV), X is CR⁶ or N. In some embodiments, X is CR⁶. In some embodiments, X is N, ...

In compounds of Formula (IV), Y is CR⁷ or N. In some embodiments, Y is CR⁷. In some embodiments, Y is N.

In compounds of Formula (IV), Z is CR⁸ or N. In some embodiments, Z is CR⁸. In some embodiments, Z is N.

In frequent embodiments of Formula (IV), X is CR⁶, Y is CR⁷ and Z is CR⁸. In other embodiments of Formula (IV), at least one of X, Y and Z is N.

In some embodiments of Formula (IV), R² and R³ are H, C1-C5 alkyl, C1-C5 fluoroalkyl, 10 C3-C8 cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R²⁰ and each said C₃-C₈ cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R²¹.

In some such embodiments, R² and R³ are H, C1-C5 alkyl or C1-C5 fluoroalkyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R²⁰. In other such embodiments, 15 R² and R³ are C3-C8 cycloalkyl or 3-6 membered heterocyclyl, where each said C3-C8 cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R²¹. In some embodiments, R² is C1-C4 alkyl optionally substituted by R²⁰ where R²⁰is OH. In some embodiments, R³ is C1-C4 alkyl optionally substituted by R²⁰ where R²⁰is OH.

In some embodiments of Formula (IV), R⁴ is H, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy 20 or C1-C4 fluoroalkoxy, where each said C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy and C1-C4 fluoroalkoxy is optionally substituted by R²⁰. In some embodiments, R⁴ is C1-C4 alkyl optionally substituted by R²⁰ where R²⁰is OH.

In some embodiments of Formula (IV), R⁵ is H, C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R²⁰. In some embodiments, 25 R⁵ is C1-C4 alkyl optionally substituted by R²⁰. In some such embodiments, R²⁰ is OH.

In some embodiments of Formula (IV), R² can be taken together with R⁴, or R³ can be taken together wjth R⁵, to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR²⁴,0 and S(O)_m as a ring member, which ring is optionally substituted by R²¹. It will be understood that R² is taken together with R⁴, or R³ is taken together 30 with R⁵ in combination with the atoms to which they are attached through {a C3-C5 alkylene or C3C5 heteroalkylene linker, which linker is optionally substituted as further dèflned herein.

In some embodiments of Formula (IV), R² is taken together with R⁴ to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR²⁴, O and S(O)_m as a ring member, which ring is. optionally substituted by R²¹. In some such 35 embodiments, the 5-7 membered heterocyclic ring contains O as an additional heteroatom. In _ 53 some such embodiments, the 5-7 membered heterocyclic ring contains NR²⁴ as an additional heteroatom. - .

In some embodiments, R² is taken together with R⁴ to form a 5-membered ring containing no additional heteroatoms (i.e., pyrrolidine),.which is optionally substituted by R²¹. In other 5 embodiments, R² is taken together with R⁴ to form a 6-membered ring containing no additional heteroatoms (i.e., piperidine), which is optionally substituted by R²¹. In other embodiments, R² is taken together with R⁴ to form a 6-membered ring containing NR²⁴(i.e., piperazine), which is optionally substituted by R²¹. In further embodiments, R² is taken together with R⁴ to form a 6membered ring containing O or S (i.e., morpholine or thiomorphoiine), which is optionally 10 substituted by R²¹. In further embodiments, R² is taken together with R⁴ to form a 7-membered ring which may contain no additional heteroatoms (i.e., homopiperidine) or may contain NR²⁴ (i.e., homopiperazine), in each case optionally substituted by R²¹.

In other embodiments of Formula (IV), R³ is taken together with R⁵ to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR²⁴, 15 O and S(O)_m as a ring member, which ring is optionally substituted by R²¹. In some such embodiments, the 5-7 membered heterocyclic ring contains O as an additional heteroatom. In some such embodiments, the 5-7 membered heterocyclic ring contains NR²⁴ as an additional heteroatom.

In some embodiments, R³ is taken together with R⁵ to form a 5-membered ring containing 20 no additional heteroatoms (i.e., pyrrolidine), which is optionally substituted by R²¹. In other embodiments, R³ is taken together with R⁵ to form a 6-membered ring containing no additional heteroatoms (i.e., piperidine), which is optionally substituted by R²¹. In other embodiments, R³ is taken together with R⁵ to form a 6-membered ring containing NR²⁴ (i.e., piperazine), which is optionally substituted by R²¹. In further embodiments, R³ is taken together with R⁵ to form a 625 membered ring containing O or S(O)_m (i.e., morpholine or thiomorphoiine), which is optionally substituted by R²¹. In further embodiments, R³ is taken together with R⁵ to form a 7-membered ring which may contain no ^dditional heteroatoms (i.e., homopiperidine) or may con|tain NR²⁴ (i.e., homopiperazine), in each case optionally substituted by R²¹.

In compounds of Formula (IV), R⁶ is H, F, Cl, CN, CH3, CH2F, CHF2 or CF3. In some 30 embodiments, R⁶ is F or Cl. In some such embodiments, R⁶ is F. In some such embodiments, R⁶ is Cl. In some embodiments, R⁶ is H. In other embodiments, R⁶ is CN, CH₃, CH2F, CHF2 or CF₃.

In compounds of Formula (IV), R⁷ and R⁸ are independently H, F, Cl, CN, C1-C2 alkyl, C1-C2 fluoroaikyl, C1-C2 alkoxy or C1-C2 fluoroalkoxy, where each said C1-C2 alkyl, Cî-C2 35 fluoroalkÿl, C1-C2 alkoxy and C1-C2 fluoroalkoxy is optionally sübstituted bÿ R²⁰. In some such _ ⁵⁴ embodiments, R⁷ is H. In some such embodiments, R⁸ is H. In some such embodiments, R⁷ and R⁸ are H.

In compounds of Formula (IV), R⁹ is H, OH, NH2, NHCH3 or N(CH3)2. In preferred embodiments of Formula (IV), R⁹ is OH.

In compounds of Formula (IV), each R¹⁰ is independently F, CN, C1-C2 alkyl or C1-C2 fluoroalkyl, where each said C1-C2 alkyl and C1-C2 fluoroalkyl is optionally substituted by R²⁰. In some embodiments, n is 0 and R¹⁰ is absent. In other embodiments, n is 1 or 2 and R¹⁰ is independently F, CN, C1-C2 alkyl or C1-C2 fluoroalkyl. In some embodiments, n is 1 or 2 and R¹⁰ is independently F or CH3. — ~

In some embodiments of Formula (IV), Q is NR¹¹ or O. In some embodiments, Q is O. In some embodiments, Q is O, p is 2 and q is 1. In some such embodiments, n is 0 and R¹⁰ is absent.

In other embodiments of Formula (IV), Q is NR¹¹. In some embodiments, Q is NR¹¹, p is 2 and q is 1. In some such embodiments, R¹¹ is SO2R¹⁴. In other such embodiments, R¹¹ is 15 COR¹⁷. In some such embodiments, n is 0 and R¹⁰ is absent.

In some embodiments of Formula (VI), Q is CR¹²R¹³, where R¹² and R¹³ are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing NR¹¹ or O as a ring member, which ring is optionally further substituted by R¹⁰. In some such embodiments, n is 0 and R¹⁰ is absent.

In compounds of Formula (IV), R¹¹ is H, C1-C4 alkyl, C1-C4 fluoroalkyl, SO2R¹⁴,

SO2NR¹⁵R¹⁶, COR¹⁷, COOR¹⁷ or CONR¹⁸R¹⁹. In some embodiments, R¹¹ is SO2R¹⁴. In other embodiments, R¹¹ is COR¹⁷.

In compounds of Formula (IV), R¹⁴ is C1-C4 alkyl or C1-C4 fluoroalkyl. In some embodiments, R¹⁴ is C1-C4 alkyl. In some such embodiments, R¹⁴ is C1-C2 alkyl. In some embodiments, R¹⁴ is C1-C4 fluoroalkyl. In some such embodiments, R¹⁴ is C1-C2 fluoroalkyl. In particular embodiments, R¹⁴ is CH3 or C2H5TIn compounds of Formula (lÿ), each R¹⁵ and R¹⁶ is independently H or CH3. |

In compounds of Formula (IV), R¹⁷is C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R²⁰. In some embodiments, R¹⁷ is

C1-C4 alkyl, where each said C1-C4 alkyl is optionally substituted by R²⁰.I

In compounds of Formula (IV), each R¹⁸ and R¹⁹ is independently H, C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R²⁰.

In compounds of Formula (IV), each R²⁰ is independently OH, C1-C2 alkoxy, C1-C2 fluoroalkoxy, CN, or N R²² R²³. ... . ... . . . .... .. .

In compounds of Formula (IV), each R²¹ is independently F, OH, CN, NR²²R²³, C1-C4 alkyl,

C1-C4 fluoroalkyl, C1-C4 alkoxy or C1-C4 fluoroalkoxy, where each said C1-C4 alkyl, C1-C4 _ ⁵⁵ fluoroalkyl, C1-C4 alkoxy and C1-C4 fluoroalkoxy is optionally further substituted by OH, NH2, NHCH3 or N(CH3)2. In some embodiments, each R²¹ is independently F, OH or C1-C4 alkyl.

In some embodiments of Formula (IV), each R²² and R²³ is independently H, C1-C2 alkyl, C1-C2 fluoroalkyl. In other embodiments of Formula (IV), R²² and R²³ may be taken together with 5 the nitrogen atom to which they are attached to form an azetidinyl ring, where said ring is optionally substituted by F or OH.

In compounds of Formula (IV), R²⁴ is H, C1-C4 alkyl, C1-C4 fluoroalkyl, SO2R²⁵, SO2NR²⁶R²⁷, COR²⁸, COOR²⁸ or CONR²⁹R³⁰. In some embodiments, R²⁴ is H or C1-C4 alkyl. In some embodiments, R²⁴ is H or C1-C2 alkyl. .. 10 In compounds of Formula (IV), R²⁵ is C1-C4 alkyl or C1-C4 fluoroalkyl. . In some embodiments, R²⁵ is C1-C2 alkyl.

In compounds of Formula (IV), each R²⁶ and R²⁷ is independently H or CH3.

In compounds of Formula (IV), R²⁸is C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by OH, C1-C2 alkoxy, C1-C2 fluoroalkoxy, CN, NH₂, NHCH3 or N(CH3)2. In some embodiments, R²⁸is C1-C4 alkyl optionally substituted by OH or C1-C2 alkoxy. In some embodiments, R²⁸is C1-C2 alkyl.

In compounds of Formula (IV), each R²⁹ and R³⁰ is independently H, C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by OH, C1-C2 alkoxy, C1-C2 fluoroalkoxy, CN, NH₂, NHCH3 or N(CH3)2. In some embodiments, each R²⁹ 20 and R³⁰ is independently H or C1-C4 alkyl where each said C1-C4 alkyl is optionally substituted by OH or C1-C2 alkoxy. In some embodiments, each R²⁹ and R³⁰ is independently H or C1-C2 alkyl.

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

In compounds of Formula (IV), n is 0,1, 2, 3 or 4. In some embodiments, n is 0 and R¹⁰ 25 is absent. In some embodiments, n is 1 or 2.

In compounds of Formula (IV), p is1,2 or 3; wherein the sum of p and q is an integer from 1 to 4. In some embodiments, p is 2. In oth^r embodiments, p is 1. In some embodiments, the sum of p and q is an integer from 1 to 3. In compounds of Formula (IV), q is 0,1, 2 or 3; wherein the sum of p and q is an integer 30 from 1 to 4. In some embodiments, q is 1. In other embodiments, q is 0. In some embodiments, the sum of p and q is an integer from 1 to 3. i

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

Ih certain embodiments, the invention provides a compound of Formula (IV), (IV-A), (IVB), (IV-C) or (IV-D), or a pharmaceutically acceptable sait thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R¹ is Cl; U is NR² and V is CR⁴; R² is C1-C5 alkyl; or R² is 1-C3H7; R⁴ is C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by R²⁰, where R²⁰ is OH; or R⁴ is CH(OH)CH3 or C(OH)(CH3)2; X is CR⁶; R⁶ is F; Y is CR⁷; R⁷ is H; Z is CR⁸; R⁸ is H; R⁹ is OH; Q is O; or Q is NR¹¹, where R¹¹ is SO2R¹⁴ ; R¹⁴ is C1-C4 alkyl; n is 0 and R¹⁰ is absent; p is 2; and q is 1.

In certain embodiments, the invention provides a compound of Formula (IV), (IV-A), (IVB), (IV-C) or (IV-D), or a pharmaceutically acceptable sait thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R¹ is Cl; U is CR³ and V is NR⁵; R³ is C1-C5 alkyl; or R³ is 1-C3H7; R⁵ is C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by R²⁰; R²⁰ is OH; X is CR⁶; R⁶ is F; Y is CR⁷; R⁷ is H; Z is CR⁸; R⁸ is H; R⁹ is OH; Q is O; or Q is NR¹¹, where R¹¹ is SO2R¹⁴; R¹⁴is C1-C4 alkyl; n is 0 and R¹⁰ is absent; p is 2; and q is 1.

In a preferred embodiment, the invention provides a compound of Formula (IV), (IV-A), (IV-B), (IV-C) or (IV-D), or a pharmaceutically acceptable sait thereof, wherein: R¹ is Cl; U is NR²; R² is C1-C5 alkyl; V is CR⁴; R⁴ is C1-C4 alkyl optionally substituted by R²⁰, where R²⁰ is OH; X is CR⁶; R⁶ is F; Y is CR⁷; R⁷ is H; Z is CR⁸; R⁸ is H; R⁹ is OH; Q is O; n is 0 and R¹⁰ is absent; p is 2; and q is 1.

In another preferred embodiment, the invention provides a compound of Formula (IV), (IVA), (IV-B), (IV-C) or (IV-D), or a pharmaceutically acceptable sait thereof, wherein: R¹ is Cl; U is NR²; R² is C1-C5 alkyl; V is CR⁴; R⁴ is C1-C4 alkyl optionally substituted by R²⁰, where R²⁰ is OH; X is CR⁶; R⁶ is F; Y is CR⁷; R⁷ is H; Z is CR⁸; R⁸ is H; R⁹is OH; Q is NR¹¹, where R¹¹ is SO2R¹⁴; R¹⁴ is C1-C4 alkyl; n is 0 and R¹⁰ is absent; p is 2; and q is 1.

In certain embodiments, the invention provides a compound of Formula (IV), (IV-A), (IVB), (IV-C) or (IV-D), or a pharmaceutically acceptable sait thereof, wherein: R¹ is Cl; U is NR²; V is CR⁴; R² is taken together with R⁴ to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR²⁴, O and S(O)iïras a ring member, which | ring is optionally substituted by R²¹; each R²¹ is indep|endently F, OH or C1-C4 alkyl; X is CR⁶; R⁶ is F; Y is CR⁷; R⁷ is H; Z is CR⁸; R⁸ is H; R⁹is OH; Q is O; or Q is NR¹¹, where R¹¹ is SO2R¹⁴; R¹⁴ is C1-C4 alkyl; n is 0 and R¹⁰ is absent; p is 2; and q is 1.

! In certain embodiments, the invention provides a compound of Formula (IV), (IV-A), (IVI B), (IV-C) or (IV-D), or a pharmaceutically acceptable sait thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R¹ is Cl; U is CR³; V is NR⁵; R³ is taken together with R⁵ to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR²⁴, O and S(O)_m as.a ring _ member, which ring is optionally substituted bÿ R²¹; each R²¹ is independently F, OH or C1-C4 _ ⁵⁷ alkyl; X is CR⁶; R⁶ is F; Y is CR⁷; R⁷ is H; Z is CR⁸; R⁸ is H; R⁹ is OH; Q is O; or Q is NR¹¹, where R¹¹ is SO2R¹⁴; R¹⁴ is C1-C4 alkyl; n is 0 and R¹⁰ is absent; p is 2; and q is 1.

In compounds of Formula (V), R¹ is H, F, CI, CN, C1-C2 alkyl or C1-C2 fluoroalkyl, where each said C1-C2 alkyl and C1-C2 fluoroalkyl is optionally substituted by R²⁰. In some embodiments, 5 R¹ is F or Cl. In some embodiments, R¹ is F. In some embodiments, R¹ is Cl.

In compounds of Formula (V), U is NR² or CR³; V is N or CR⁴ when U is NR²; and

V is NR⁵ when U is CR³. In some embodiments, U is NR² and V is N or CR⁴. In some such embodiments, U is NR² and V is N. In some such embodiments, U is NR² and V is CR⁴. In some embodiments, U is CR³ and V is NR⁵.

In compounds of Formula (V), X is CR⁶ or N. In some embodiments, X is CR⁶. In some embodiments, X is N,

In compounds of Formula (V), Y is CR⁷ or N. In some embodiments, Y is CR⁷. In some embodiments, Y is N. '

In compounds of Formula (V), Z is CR⁸ or N. In some embodiments, Z is CR⁸. In some 15 embodiments, Z is N.

In frequent embodiments of Formula (V), X is CR⁶, Y is CR⁷ and Z is CR⁸. In other embodiments of Formula (V), at least one of X, Y and Z is N.

In some embodiments of Formula (V), R² and R³ are H, C1-C5 alkyl, C1-C5 fluoroalkyl, C3-C8 cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl 20 is optionally substituted by R²⁰ and each said C3-C8 cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R²¹.

In some such embodiments, R² and R³ are H, C1-C5 alkyl or C1-C5 fluoroalkyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R²⁰. In other such embodiments, R² and R³ are C₃-C₈ cycloalkyl or 3-6 membered heterocyclyl, where each said C₃-C₈ cycloalkyl 25 and 3-6 membered heterocyclyl is optionally substituted by R²¹. In some embodiments, R² is C1-C4 alkyl optionally substituted by R²⁰ where R²⁰is OH. In some embodiments, R³ is C1-C4 alkyl optionally substituted by R²⁰ where R²⁰ is OH. |

In some embodiments of Formula (V), R⁴ is H, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy or C1-C4 fluoroalkoxy, where each said C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy and C1-C4 30 fluoroalkoxy is optionally substituted by R²⁰. In some embodiments, R⁴ is C1-C4 alkyl optionally substituted by R²⁰ where R²⁰is OH. I

In some embodiments of Formula (V), R⁵ is H, C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-G4 fluoroalkyl is optionally substituted by R²⁰. In some embodiments, R⁵ is C1-C4 alkyl optionally substituted by R²⁰. In some such embodiments, R²⁰ is OH.

In some embodiments of Formula (V), R² can be taken together with R⁴, or R³ cari bë taken together with R⁵, to form a 5-7 membered heterocyclic ring, optionally containing an — 58 additional heteroatom selected from NR²⁴,0 and S(O)_m as a ring member, which ring is optionally substituted by R²¹. It will be understood that R² is taken together with R⁴, or R³ is taken together with R⁵ in combination with the atoms to which they are attached through a C3-C5 alkylene or C3C5 heteroalkyiene linker, which linker is optionally substituted as further defined herein. -------- 5 In some embodiments of Formula (V), R² is taken together with R⁴ to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR²⁴,0 and S(O)_m as a ring member, which ring is optionally substituted by R²¹. In some such embodiments, the 57 membered heterocyclic ring contains O as an additional heteroatom. In some such embodiments, the 5-7 membered heterocyclic ring contains NR²⁴as an additional heteroatom.

In some embodiments, R² is taken together with R⁴ to form a 5-membered ring containing no additional heteroatoms (i.e., pyrrolidine), which is optionally substituted by R²¹. In other embodiments, R² is taken together with R⁴ to form a 6-membered ring containing no additional heteroatoms (i.e., piperidine), which is optionally substituted by R²¹. In other embodiments, R² is taken together with R⁴ to form a 6-membered ring containing NR²⁴ (i.e., piperazine), which is optionally substituted by R²¹. In further embodiments, R² is taken together with R⁴ to form a 6membered ring containing O or S (i.e., morpholine or thiomorpholine), which is optionally substituted by R²¹. In further embodiments, R² is taken together with R⁴ to form a 7-membered ring which may contain no additional heteroatoms (i.e., homopiperidine) or may contain NR²⁴(i.e., homopiperazine), in each case optionally substituted by R²¹.

In other embodiments of Formula (V), R³ is taken together with R⁵ to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR²⁴,0 and S(O)_m as a ring member, which ring is optionally substituted by R²¹. In some such embodiments, the 57 membered heterocyclic ring contains O as an additional heteroatom. In some such embodiments, the 5-7 membered heterocyclic ring contains NR²⁴as an additional heteroatom.

In some embodiments, R³ is taken together with R⁵ to form a 5-membered ring containing no additional heteroatoms (i.e., pyrrolidine), which is optionally substituted by R²¹. In other embodiments, f^³ is taken together with R⁵ to form a 6-membered rinc| containing no additional heteroatoms (i.e., piperidine), which is optionally substituted by R²¹. In other embodiments, R³ is taken together with R⁵ to form a 6-membered ring containing NR²⁴ (i.e., piperazine), which is optionally substituted by R²¹. In further embodiments, R³ is taken together with R⁵ to form a 6membered ring' containing O or S(O)_m (i.e., morpholine or thiomorpholine), which is optionally substituted by R²¹. In further embodiments, R³ is taken together with R⁵ to form a 7-membered ring which may contain no additional heteroatoms (i.e., homopiperidine) or may contain NR²⁴(i.e., homopiperazine), in each case optionally substituted by R²¹.

In compounds of Formula (V), R⁶ is H, F, CI, CN, CH3, CH2F, CHF2 or CF3. In some embodiments, R⁶ is F or Cl. In some such embodiments, R⁶ is F. In some such embodiments,

R⁶ is Cl. In some embodiments, R⁶ is H. In other embodiments, R⁶ is CN, CH3, CH2F, CHF2 or

CF₃. In compounds of Formula (V), R⁷ and R⁸ are independently H, F, Cl, CN, C1-C2 alkyl, C1-C2 fluoroalkyl, C1-C2 alkoxy or C1-C2 fluoroalkoxy,‘where each said C1-C2 alkyl, C1-C2 fluoroalkyl, C1-C2 alkoxy and C1-C2 fluoroalkoxy is optionally substituted by R²⁰. In some such embodiments, R⁷ is H. In some such embodiments, R⁸ is H. In some such embodiments, R⁷ and R⁸ are H.

In compounds of Formula (V), R⁹ is H, OH, NH2, NHCH3 or N(CH3)2. In preferred embodiments of Formula (V), R⁹ is OH. _ - In compounds of Formula (V), each R¹⁰ is independently F, CN, C1-C2 alkyl or C1-C2 fluoroalkyl, where each said C1-C2 alkyl and C1-C2 fluoroalkyl is optionally substituted by R²⁰. In some embodiments, n is 0 and R¹⁰ is absent. In other embodiments, n is 1 or 2 and R¹⁰ is independently F, CN, C1-C2 alkyl or C1-C2 fluoroalkyl. In some embodiments, n is 1 or 2 and R¹⁰ is independently F or CH3.

In some embodiments of Formula (V), Q is NR¹¹ or O. In some embodiments, Q is O. In some embodiments, Q is O, p is 2 and q is 1. In some such embodiments, n is 0 and R¹⁰ is absent.

In other embodiments of Formula (V), Q is NR¹¹. In some embodiments, Q is NR¹¹, p is 2 and q is 1. In some such embodiments, R¹¹ is SO2R¹⁴. In other such embodiments, R¹¹ is COR¹⁷. In some such embodiments, n is 0 and R¹⁰ is absent.

In some embodiments of Formula (V), Q is CR¹²R¹³, where R¹² and R¹³ are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing NR¹¹ or O as a ring member, which ring is optionally further substituted by R¹⁰. In some such embodiments, n is 0 and R¹⁰ is absent.

In compounds of Formula (V), R¹¹ is H, C1-C4 alkyl, C1-C4 fluoroalkyl, SO2R¹⁴, SO2NR¹⁵R¹⁶, COR¹⁷, COOR¹⁷ or CONR¹⁸R¹⁹. In some embodiments, R¹¹ is SO2R¹⁴. In other - embodiments, R¹¹ is CO|r¹⁷. |

In compounds of Formula (V), R¹⁴ is C1-C4 alkyl or C1-C4 fluoroalkyl. In some embodiments, R¹⁴ is C1-C4 alkyl. In some such embodiments, R¹⁴ is C1-C2 alkyl. In some embodiments, R¹⁴is Ci-'C4 fluoroalkyl. In some such embodiments, R¹⁴is C1-C2 fluoroalkyl. In particular embodiments,! R¹⁴ is CH₃ or C2H5. I

In compounds of Formula (V), each R¹⁵ and R¹⁶ is independently H or CH3.

In compounds of Formula (V), R¹⁷ is C1-C4 alkyl or C1-C4 fluoroalkyl, where each said : C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R²⁰. In some embodiments, R¹⁷is _ C1-C4 alkyl, where each said C1-C4 alkyl is optionally substituted by R²⁰.

— 60

In compounds of Formula (V), each R¹⁸ and R¹⁹ is independently H, C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R²⁰.

In compounds of Formula (V), each R²⁰ is independently OH, C1-C2 alkoxy, C1-C2 fiuoroalkoxy, CN, or N R²² R²³. ... __________ Y________ ~Y— . ... ..

In compounds of Formula (V), each R²¹ is independently F, OH, CN, N R²² R²³, C1-C4 alkyl,

C1-C4 fluoroalkyl, C1-C4 alkoxy or C1-C4 fiuoroalkoxy, where each said C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy and C1-C4 fiuoroalkoxy is optionally further substituted by OH, NH2, NHCH3 or N(CH3)2. In some embodiments, each R²¹ is independently F, OH or C1-C4 alkyl.

In some embodiments of Formula (V), each R²² and R²³ is independently H, C1-C2 alkyl,

C1-C2 fluoroalkyl. In other embodiments of Formula (V), R²² and R²³ may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring, where said ring is optionally substituted by F or OH.

In compounds of Formula (V), R²⁴ is H, C1-C4 alkyl, C1-C4 fluoroalkyl, SO2R²⁵, SO₂NR²⁶R²⁷, COR²⁸, COOR²⁸ or CONR²⁹R³°. In some embodiments, R²⁴ is H or C1-C4 alkyl. In 15 some embodiments, R²⁴ is H or C1-C2 alkyl.

In compounds of Formula (V), R²⁵ is C1-C4 alkyl or C1-C4 fluoroalkyl. . In some embodiments, R²⁵ is C1-C2 alkyl.

In compounds of Formula (V), each R²⁶ and R²⁷ is independently H or CH3.

In compounds of Formula (V), R²⁸is C1-C4 alkyl or C1-C4 fluoroalkyl, where each said

C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by OH, C1-C2 alkoxy, C1-C2 fiuoroalkoxy, CN, NH2, NHCH3 or N(CH3)2. In some embodiments, R²⁸is C1-C4 alkyl optionally substituted by OH or C1-C2 alkoxy. In some embodiments, R²⁸ is C1-C2 alkyl.

In compounds of Formula (V), each R²⁹ and R³⁰ is independently H, C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by OH, 25 C1-C2 alkoxy, C1-C2 fiuoroalkoxy, CN, NH2, NHCH3 or N(CH3)2. In some embodiments, each R²⁹ and R³⁰ is independently H or C1-C4 alkyl where each said C1-C4 alkyl is optionally substituted by OH or C1-C2 alkoxy. In some ^mbodiments, each R²⁹ and R³⁰ is independently H or φ-ΰ₂ alkyl.

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

In compounds of Formula (V), n is 0, 1, 2, 3 or 4. In some embodiments, n is 0 and R¹⁰ is absent. In some embodiments, n is 1 or 2. I

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

_ ⁶¹

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

In some embodiments, p is 2 and q is 1. In other embodiments, p is 1 and q is 1. In other. .

embodiments, p is 1 and q is 0. In further embodiments, the sum of p and q is an integer from 1 to 3.

In certain embodiments, the invention provides a compound of Formula (V), (V-A), (V-B), (V-C) or (V-D), or a pharmaceutically acceptable sait thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R¹ is

Cl; U is NR² and V is CR⁴; R² is C1-C5 alkyl; or R² is 1-C3H7; R⁴ is C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by R²⁰, where R²⁰is OH; or R⁴ is CH(OH)CH3 orC(OH)(CH3)2; X is CR⁶; R⁶ is F; Y is CR⁷; R⁷ is H; Z is CR⁸; R⁸ is H; R⁹ is OH; Q is O; or Q is NR¹¹, where R¹¹ is SO2R¹⁴ ; R¹⁴is C1-C4 alkyl; n is 0 and R¹⁰ is absent; p is 2; and q is 1.

In certain embodiments, the invention provides a compound of Formula (V), (V-A), (V-B), (V-C) or (V-D), or a pharmaceutically acceptable sait thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R¹ is Cl; U is CR³ and V is NR⁵; R³ is C1-C5 alkyl; or R³ is 1-C3H7; R⁵ is C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by R²⁰; R²⁰ is OH; X is CR⁶; R⁶ is F; Y is CR⁷; R⁷ is H; Z is CR⁸; R⁸ is H; R⁹ is OH; Q is O; or Q is NR¹¹, where R¹¹ is SO2R¹⁴; R¹⁴is C1-C4 alkyl; n is 0 and R¹⁰ is absent; p is 2; and q is 1.

In a preferred embodiment, the invention provides a compound of Formula (V), (V-A), (VB), (V-C) or (V-D), or a pharmaceutically acceptable sait thereof, wherein: R¹ is Cl; U is NR²; R² is C1-C5 alkyl; V is CR⁴; R⁴ is C1-C4 alkyl optionally substituted by R²⁰, where R²⁰ is OH; X is CR⁶; R⁶ is F; Y is CR⁷; R⁷ is H; Z is CR⁸; R⁸ is H; R⁹is OH; Q is O; n is 0 and R¹⁰ is absent; p is 2; and 25 q is 1.

In another preferred embodiment, the invention provides a compound of Formula (V), (VA), (V-B), (V-C) or (V-D), or a pharmacei|tically acceptable sait thereof, wherein: R¹ is Cl; U is | NR²; R² is C1-C5 alkyl; V is CR⁴; R⁴ is C1-C4 alkyl optionally substituted by R²⁰, where R²⁰ is OH; X is CR⁶; R⁶ is F; Y is CR⁷; R⁷ is H; Z is CR⁸; R⁸ is H; R⁹ is OH; Q is NR¹¹, where R¹¹ is SO2R¹⁴;

R¹⁴ is C1-C4 alkyl; n is 0 and R¹⁰ is absent; p is 2; and q is 1. j

In certain embodiments, the invention provides a compound of Formula (V), (V-A), (V-B), i (V-C) or (V-D), or a pharmaceutically acceptable sait thereof, wherein: R¹ is Cl; U is NR²; V is CR⁴; R² is taken together with R⁴ to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from.NR²⁴, O and S(O)_m as a ring member, which ring is optionally substituted by R²¹; each R²¹ is independently F, OH of C1-C4 alkyl; X is CR⁶; R⁶ is F; Y is CR⁷; R⁷ is H; Z is CR⁸; R⁸ is H; R⁹is OH; Q is O; or Q is NR¹¹, where R¹¹ is SO2R¹⁴; R¹⁴is CrC4 alkyl; n is 0 and R¹⁰ is absent; p is 2; and q is 1.

In certain embodiments, the invention provides a compound of Formula (V), (V-A), (V-B), (V-C) or (V-D), or a pharmaceutically acceptable sait thereof, having a.combination of two or more, preferably three or more, and more preferably four or more, of the following features: R¹ is Cl; U is CR³; V is NR⁵; R³ is taken together with R⁵ to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR²⁴, O and S(O)m as a ring member, which ring is optionally substituted by R²¹; each R²¹ is independently F, OH or C1-C4 alkyl; X is CR⁶; R⁶ is F; Y is CR⁷; R⁷ is H; Z is CR⁸; R⁸ is H; R⁹ is OH; Q is O; or Q is NR¹¹, where R¹¹ is SO2R¹⁴; R¹⁴ is C1-C4 alkyl; n is 0 and R¹⁰ is absent; p is 2; and q is 1.

In certain embodiments, the invention provides a compound of Formula (IV), (IV-A), (IVB), (IV-C) or (IV-D), or a pharmaceutically acceptable sait thereof, or a compound of Formula (V), (V-A), (V-B), (V-C) or (V-D), or a pharmaceutically acceptable sait thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R¹ is F or Cl; U is NR² and V is CR⁴; R² is C1-C5 alkyl, C1-C5 fluoroaikyl or 3-6 membered heterocyclyl; or R² is CH3,1-C3H7,1-C4H9, S-C4H9, t-C4Hg, CH2F.CHF2, CH2CHF2 or oxetan-3-yl; R⁴ is H or C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by OH, NH2, NHCH3 or N(CH3)2! or R⁴ is H, CH3, C2H5, CH2OH, CH(OH)CH3, CH2CH2OH or CH2NH2; or R² is taken together with R⁴ to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR²⁴, O and S(O)m as a ring member, which ring is optionally substituted by R²¹; or R⁴ is CH(OH)CH₃ orC(OH)(CH₃)₂; X is CR⁶; R⁶ is H or F; Y is CR⁷; Z is CR⁸; R⁷ and R⁸ are H; R⁹ is OH; Q is NR¹¹; R¹¹ is SO2R¹⁴; R¹⁴is C1-C4 alkyl; n is 0 and R¹⁰ is absent; p is 2; and q is 1.

In certain embodiments, the invention provides a compound of Formula (IV), (IV-A), (IVB), (IV-C) or (IV-D), or a pharmaceutically acceptable sait thereof, or a compound of Formula (V), (V-A), (V-B), (V-C) or (V-D), or a pharmaceutically acceptable sait thereof, having a combination of two or more, preferably three or more, and more preferably four ormore, of the following features: R¹ is F or Cl; U is CR³ and V is NR⁵; R³ is φι-Cs alkyl, C1-C5 fluoroaikyl or 3-6 membered heterocyclyl; or R³ is CH3, 1-C3H7, i-C4Hg.s-C4H9, t-C4Hg, CH2F.CHF2, CH2CHF2 or oxetan-3-yl; R⁵ is H or C1-C4 alkyl; or R⁵ is H or CH3; or R³ is taken together with R⁵ to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR²⁴,0 and S(O)_m as a ring member, which ring is optionally substituted by R²¹; X is CR⁶; R⁶ is H or F; Y is CR⁷; Z is CR⁸; R⁷ and R⁸ are H; R⁹ is OH; n is 0 and R¹⁰ is absent; Q is NR¹¹; R¹¹ is SO2R¹⁴; and R¹⁴is C1-C4 alkyl; p is 2; and q is 1. . — _________

In compounds of Formula (II) and (IV), R¹ is H, F, Cl, CN, C1-C2 alkyl or C1-C2 fluoroaikyl, where each said C1-C2 alkyl and C1-C2 fluoroaikyl is optionally substituted by R²⁰.

In some embodiments of Formula (II) and (IV), R¹ is H. In other embodiments, R¹ is F or

Cl. In other embodiments, R¹ is Cl. In further embodiments, R¹ is C1-C2 alkyl or C1-C2 fluoroalkyl, where each said C1-C2 alkyl and C1-C2 fluoroalkyl is optionally substituted by R²⁰. In some such embodiments, R¹ is CH3, optionally substituted by R²⁰. In particular embodiments, R¹ is CH3.

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

In compounds of Formula (II) and (IV), U is NR² or CR³. In some embodiments, U is NR². In other embodiments, U is CR³.

In compounds of Formula (II) and (IV), V is N or CR⁴ when U is NR²; and V is NR⁵ when U is CR³. In some such embodiments, V is CR⁴. In other such embodiments, V is N. In further such embodiments, V is NR⁵.

In compounds of Formula (ll) and (IV), X is CR⁶ or N. In some embodiments, X is CR⁶.

In other embodiments, X is N.

In compounds of Formula (II) and (IV), Y is CR⁷ or N. In some embodiments, Y is CR⁷.

In other embodiments, Y is N.

In compounds of Formula (II) and (IV), Z is CR⁸ or N. In some embodiments, Z is CR⁸.

In other embodiments, Z is N.

In some embodiments of Formula (II) and (IV), X is CR⁶, Y is CR⁷ and Z is CR⁸. In some such embodiments, U is NR²and V is CR⁴. In other such embodiments, U is NR²and V is N. In still other such embodiments, U is CR³ and V is NR⁵.

In some embodiments of Formula (II) and (IV), X is N, Y is CR⁷, and Z is CR⁸.

In some embodiments of Formula (II) and (IV), X is CR⁶, Y is N, and Z is CR⁸.

In some embodiments of Formula (ll) and (IV), X is CR⁶, Y is CR⁷, and Z is N.

In some embodiments of Formula (II) and (IV), X is N, Y is N, and Z is CR⁸.

In some embodiments of Formula (II) and (IV), X is CR⁶, Y is N, and Z is N.

In some embodiments of Formula (ll) and (IV), X is N, Y is CR⁷; and Z is N. --------------— | In other embodiments of Formula (II) and (IV), at lea^t one of X, Y and Z is N. In some such embodiments, U is NR²and V is CR⁴. In other such embodiments, U is NR²and V is N. In still other such embodiments, U is CR³ and V is NR⁵. .....

i In further embodiments of Formula (II) and (IV), two of X, Y and Z are N. In some such embodiments, U is NR²and V is CR⁴. In other such embodiments, U is NR²and V is N. In still other such embodiments, U is CR³ and V is NR⁵.

In compounds of Formula (III) and (V), R¹ is H, F, Cl, CN, C1-C2 alkyl or C1-C2 fluoroalkyl, where each said C1-C2 alkyl and C1-C2 fluoroalkyl is.optionally substituted by R²⁰.

In some embodiments of Formula (III) and (V), R¹ is H. In other embodiments, R¹ is F or Cl. In other embodiments, R¹ is Cl. In further embodiments, R¹ is C1-C2 alkyl or C1-C2 fluoroalkyl, — ⁶⁴ where each said C1-C2 alkyl and C1-C2 fluoroalkyl is optionally substituted by R²⁰. In some such embodiments, R¹ is CH3, optionally substituted by R²⁰. In particular embodiments, R¹ is CH₃.

In compounds of Formula (III) and (V), the ring system comprising U, V, X, Y and Z is a fused biaryl ring system. ------ ...... _ ~ . *. · _ . — ,

In compounds of Formula (III) and (V), U is NR² or CR³. In some embodiments, U is

NR². In other embodiments, U is CR³.

In compounds of Formula (lll) and (V), V is N or CR⁴ when U is NR²; and V is NR⁵ when U is CR³. In some such embodiments, V is CR⁴. In other such embodiments, V is N. In further such embodiments, V is NR⁵. .

In compounds of Formula (II!) and (V), Xis CR⁶ or N. In some embodiments, Xis CR⁶.

In other embodiments, X is N.

In compounds of Formula (lll) and (V), Y is CR⁷ or N. In some embodiments, Y is CR⁷.

In other embodiments, Y is N.

In compounds of Formula (lll) and (V), Z is CR⁸ or N. In some embodiments, Z is CR⁸.

In other embodiments, Z is N.

In some embodiments of Formula (lll) and (V), X is CR⁶, Y is CR⁷ and Z is CR⁸. In some such embodiments, U is NR²and V is CR⁴. In other such embodiments, U is NR²and V is N. In still other such embodiments, U is CR³ and V is NR⁵.

In some embodiments of Formula (lll) and (V), X is N, Y is CR⁷, and Z is CR⁸.

In some embodiments of Formula (lll) and (V), X is CR⁶, Y is N, and Z is CR⁸.

In some embodiments of Formula (lll) and (V), X is CR⁶, Y is CR⁷, and Z is N.

In some embodiments of Formula (lll) and (V), X is N, Y is N, and Z is CR⁸.

In some embodiments of Formula (lll) and (V), X is CR⁶, Y is N, and Z is N.

In some embodiments of Formula (lll) and (V), X is N, Y is CR⁷, and Z is N.

In other embodiments of Formula (11!) and (V), at least one of X, Y and Z is N. In some such embodiments, U is NR²and V is CR⁴. In other such embodiments, U is NR²and V is N. In still other suc|h embodiments, U is CR³ and V is NR⁵. |

In further embodiments of Formula (lll) and (V), two of X, Y and Z are N. In some such embodiments, U is NR²and V is CR⁴. In other such embodiments, U is NR²and V is N. In still 30 other such embodiments, U is CR³ and V is NR⁵. I

In particular embodiments of each of Formulae (I), (II), (lll), (IV) and (V), the fused biaryl ring system comprising U, V, X, Y and Z is selected from the group consisting of:

where the * represents the point of attachment to the pyrimidine ring or pyridine ring, and

R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are as further defined herein. j

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

or a pharmaceutically acceptable sait thereof, wherein:_____

R¹, R², R⁴, R⁶ to R²³, Q, n, p and q are as defined for Formula (II); or

R¹, R², R⁴, R⁶ to R³⁰, Q, m, n, p and q are as defined for Formula (IV).

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

R¹, R², R⁴, R⁶ to R²³ and n are as defined for Formula (II).

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

R¹, R², R⁴, R⁶ to R³⁰, m and n are as defined for Formula (IV).

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

or a pharmaceutically acceptable sait thereof.

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

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

In certain embodiments, the invention provides a compound of Formula (VI), (Vl-A), (VIB), (Vl-C) or (Vl-D), or a pharmaceutically acceptable sait thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R¹ is Cl; R² is C1-C5 alkyl; or R² is i-C3H7; R⁴ is Ci-C4 alkyl, where said Ci-C₄ alkyl is optionally substituted by R²⁰, where R²⁰ is OH; or R⁴ is CH(OH)CH3 or C(OH)(CH3)2; R⁶ is F; R⁷ is H; R⁸ is H; R⁹ is OH; Q is O; or Q is NR¹¹, where R¹¹ is SO2R¹⁴ ; R¹⁴is CrC₄ alkyl; n is 0 and R¹⁰ is absent; p is 2; and q is 1.

In certain embodiments, the invention provides a compound of Formula (VI), (Vl-A), (VIB), (Vl-C) or (Vl-D), or a pharmaceutically acceptable sait thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R¹ is Cl; R³ is C1-C5 alkyl; or R³ is i-C3H7; R⁵ is C1-C4 alkyl, where said CrC4 alkyl is optionally substituted by R²⁰; R²⁰is OH; R⁶ is F; R⁷ is H; R⁸ is H; R⁹ is OH; Q is O; or Q is NR¹¹, where R¹¹ is SO2R¹⁴; R¹⁴is CrC₄ alkyl; n is 0 and R¹⁰ is absent; p is 2; and q is 1.

In a preferred embodiment, the invention provides a compound of Formula (VI), (Vl-A), (Vl-B), (Vl-C) or (Vl-D), or a pharmaceutically acceptable sait thereof, wherein: R¹ is Cl; R² is C1-C5 alkyl; R⁴ is Ci-C₄ alkyl optionally substituted by R²⁰, where R²⁰ is OH; R⁶ is F; R⁷ is H; R⁸ is H; R⁹ is OH; Q is O; n is 0 and R¹⁰ is absent; p is 2; and q is 1.

In another preferred embodiment, the invention provides a compound of Formula (VI), (VIA), (Vl-B), (Vl-C) or (Vi-D), or a pharmaceutically acceptable sait thereof, wherein: R¹ is Cl; R² is C1-C5 alkyl; R⁴ is C1-C4 alkyl optionally Substituted by R²⁰, where R²⁰ is OH; R⁶ is F; R⁷ is H; F^⁸ is H; R⁹is OH; Q is NR¹¹, where R¹¹ is SO2R¹⁴; R¹⁴is C1-C4 alkyl; n is 0 and R¹⁰ is absent; p is 2; and q is 1.

In certain embodiments, the invention provides a compound of Formula (VI), (Vl-A), (VIB), (Vl-C) or (Vl-D), or a pharmaceutically acceptable sait thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R¹ is F or Cl; R² is C1-C5 alkyl, C1-C5 fluoroalkyl or 3-6 membered heterocyclyl; or R² is CH3, i-C3H7, i-C4H9, s-C4H9, t-C4H9, CH2F, CHF2, CH2CHF2 or oxetan-3-yl; R⁴ is H or Ci-C4 alkyl, where said C1-C4 alkyl is optionally substituted by OH, NH2, NHCH₃ or N(CH₃)₂; or R⁴ is H, CH₃, C2H5, ⁶⁸

CH2OH, CH(OH)CH_3i CH₂CH₂OH or CH₂NH₂; R⁶ is H or F; R⁷ and R⁸ are H; R⁹ is OH; Q is NR¹¹;

R¹¹ is SO₂R¹⁴; R¹⁴ is C1-C4 alkyl; n is 0 and R¹⁰ is absent; p is 2; and q is 1.

In certain embodiments, the invention provides a compound of Formula (VI), (Vl-A), (VIB), (Vl-C) or (Vl-D), or a pharmaceutically acceptable sait thereof, having a combination of two 5 or more, preferably three or more, and more preferably four or more, of the following features: R¹ is F or Cl; R² is C1-C5 alkyl, C1-C5 fluoroalkyl or 3-6 membered heterocyclyl; or R² is CH3, i-C3H7, i-C4H9, S-C4H9, t-C4H9, CH2F, CHF2i CH2CHF2 or oxetan-3-yi; R⁴ is H or C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by OH, NH2, NHCH₃ or N(CH₃)₂; or R⁴ is H, CH3, C2Hs, CH2OH, CH(OH)CH3i CH2CH2OH or CH2NH2; or R² is taken together with R⁴ to form a 5-7 10 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR²⁴, O and S(O)m as a ring member, which ring is optionally substituted by R²¹; R⁶ is H or F; R⁷ and R⁸ are H; R⁹ is OH; Q is NR¹¹; R¹¹ is SO₂R¹⁴; R¹⁴ is C1-C4 alkyl; n is 0 and R¹⁰ is absent; p is 2; and q is 1.

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

or a pharmaceutically acceptable sait thereof, wherein:

R¹, R³, R⁵ to R²³, Q, n, p and q are as defined for Formula (II); or

R¹, R³, R⁵ to R³⁰, Q, m, n, p and q are as defined for Formula (IV).

In particular embodiments, the invention provides a compound of Formula (VII), (VII-A), 20 (Vll-B), (Vll-C) or (Vll-D), or a pharmaceutically acceptable sait thereof, wherein:

R¹, R², R⁴, R⁶ to R²³ and n are as defined for Formula (II).

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

R¹, R², R⁴, R⁶ to R³⁰, m and n are as defined for Formula (IV).

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

(Vll-A) (Vll-B)

(Vll-C) (Vll-D) or a pharmaceutically acceptable sait thereof.

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

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

In certain embodiments, the invention provides a compound of Formula (VII), (Vll-A), (VIIB), (Vll-C) or (Vll-D), or a pharmaceutically acceptable s^ilt thereof, having a combination of two or more, preferably three or more, and more preferably four or more, ofthe following features: R¹ is Cl; R³ is C1-C5 alkyl; or R³ is 1-C3H7; R⁵ is C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by R²⁰; R²⁰ is OH; R⁶ is F; R⁷ is H; R⁸ is H; R⁹ is OH; Q is O; or Q is NR¹¹, where R¹¹ isSO₂R¹⁴; R¹⁴is C1-C4 alkyl; n is 0 and R¹⁰ is absent; p is 2; and q is 1.

In a preferred embodiment, the invention provides a compound of Formula (VII), (Vll-A), (Vll-B), (Vll-C) or (Vll-D), or a pharmaceutically acceptable sait thereof, wherein: R¹ is Cl; R³ is C1-C5 alkyl; R⁵ is C1-C4 alkyl optionally substituted by R²⁰, where R²⁰ is OH; R⁶ is F; R⁷ is H; R⁸ is H; R⁹is OH; Q is O; n is 0 and R¹⁰ is absent; p is 2; and q is 1.

In another preferred embodiment, the invention provides a compound of Formula (VII), (Vll-A), (Vll-B), (Vll-C) or (Vll-D), or a pharmaceutically acceptable sait thereof, wherein: R¹ is Cl;

R³ is C1-C5 alkyl; R⁵ is C1-C4 alkyl optionally substituted by R²⁰, where R²⁰ is OH; R⁶ is F; R⁷ is

H; R⁸ is H; R⁹is OH; Q is NR¹¹, where R¹¹ is SO2R¹⁴; R¹⁴is C1-C4 alkyl; n is 0 and R¹⁰ is absent; p is 2; and q is 1.

In certain embodiments, the invention provides a compound of Formula (VII), (Vll-A), (VIIB), (Vll-C) or (Vll-D), or a pharmaceutically acceptable sait thereof, having a combination of two or more, preferably three or more, and more preferably four or more, ofthe following features: R¹ is F or Cl; R³ is C1-C5 alkyl, C1-C5 fluoroalkyl or 3-6 membered heterocyclyl; or R³ is CH3, 1-C3H7, i-C4Hg, S-C4H9, t-C4Hg, CH2F.CHF2, CH2CHF2 or oxetan-3-yl; R⁵ is H or C1-C4 alkyl; or R⁵ is H or CH3;R⁶ is H or F; R⁷ and R⁸ are H; R⁹ is OH; Q is NR¹¹; R¹¹ is SO2R¹⁴; R¹⁴ is C1-C4 alkyl; n is 0 and R¹⁰ is absent; p is 2; and q is 1. ------ -----In certain embodiments, the invention provides a compound of Formula (VII), (Vll-A), (VIIB), (Vll-C) or (Vll-D), or a pharmaceutically acceptable sait thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R¹ is F or CI; R³ is C1-C5 alkyl, C1-C5 fluoroalkyl or 3-6 membered heterocyclyl; or R³ is CH3,1-C3H7, i-C4Hg, s-C4Hg, t-C4Hg, CH2F.CHF2, CH2CHF2 or oxetan-3-yl; R⁵ is H or C1-C4 alkyl; or R⁵ is H or CH3; or R³ is taken together with R⁵ to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR²⁴, O and S(O)m as a ring member, which ring is optionally substituted by R²¹; R⁶ is H or F; R⁷ and R⁸ are H; R⁹ is OH; Q is NR¹¹;R¹¹ is SO2R¹⁴; R¹⁴is C1-C4 alkyl; n is 0 and R¹⁰ is absent; p is 2; and q is 1.

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

or a pharmaceutically acceptable sait thereof, wherein:

R¹,' R², R⁶ to R²³, Q, n, p and q are as defined for Formula (II); or

R¹ J R², R⁶ to R³⁰, Q, m, n, p and q are as defined for Formôla (IV).

In particular embodiments, the invention provides a compound of Formula (VIII), or a pharmaceutically acceptable sait thereof, wherein: ⁷ R¹, R², R⁴, R⁶ to R²³ and n are as defined for Formula (liy— __ _

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

R¹, R², R⁴, R⁶ to R³⁰, m and n are as defined for Formula (IV).

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

(Vlll-C) (Vlll-D) or a pharmaceutically acceptable sait thereof. Each of the aspects and embodiments described herein with respect to Formula (II) is also applicable to compounds of Formula (VIII) that are not inconsistent with such aspect or embodiment.

Each of the aspects and embodiments described herein with respect to Formula (IV) is also applicable to compounds of Formula (VIII) that are not inconsistent with such aspect or embodiment. | I

In an embodiment, the invention provides a compound of Formula (VIII), (Vlll-A), (Vlll-B), (Vlll-C) or (Vlll-D), or a pharmaceutically acceptable sait thereof, wherein: R¹ is Cl; R² is C1-C5 alkyl optionally substituted by R²⁰, where R²⁰ is OH; R⁶ is F; R⁷ is H; R⁸ is H; R⁹is OH; Q is O; or Q is NR¹¹; R¹¹ is SO2R¹⁴; R¹⁴is C1-C4 alkyl; n is 0 and R¹⁰ is absent; p is 2; and q is 1.

In certain embodiments, the invention provides a compound of Formula (VIII), (Vlll-A), 20 (Vlll-B), (Vlll-C) or (Vlll-D), or a pharmaceutically acceptable sait thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R¹ is F or Cl; R² is C1-C5 alkyl, C1-C5 fluoroalkyl or 3-6 membered heterocyclyl; or R² is CH₃, i-C₃H₇,1-C4H9. S-C4H9, t-C₄H₉, CH₂F, CHF₂, CH2CHF2 or oxetan-3-yl; R⁶ is H or F; R⁷ and R⁸ are H; R⁹ is OH; Q is O; or Q is NR¹¹; R¹¹ is SO2R¹⁴; R¹⁴is C1-C4 alkyl; n is 0 and R¹⁰ is absent; p is 2; and q is 1.

In particular embodiments of Formulae (I) to (VIII), the ring comprising Q is selected from the group consisting of:

where the * represents the point of attachment to the 2-amino substituent.

In particular embodiments of Formulae (I) to (VIII), the ring comprising Q is selected from the group consisting of:

where the * represents the point of attachment to the 2-amino substituent.

In particular embodiments of Formulae (I) to (VIII), the ring comprising Q is selected from 5 the group consisting of:

where the * represents the point of attachment to the 2-amino substituent. !

In spécifie embodiments of Formulae (I) to (VIII), the ring comprising Q is selected from the group consisting of:

where the * represents the point of attachment to the 2-amino substituent.

or a pharmaceutically acceptable sait thereof, wherein:

R¹, R², R⁴, R⁶ to R¹¹, R¹⁴ to R²³ and n are as defined for Formula (II); or

R¹, R², R⁴, R⁶ to R¹¹, R¹⁴ to R³⁰, m and n are as defined for Formula (IV).

In somé embodiments, the invention provides a compound of Formula (IX), or a pharmaceutically acceptable sait thereof, wherein R¹, R², R⁴, R⁶ to R¹¹, R¹⁴ to R²³ and n are as defined for Formula (II).

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

R¹

R⁷

H

R⁶

R⁸

N

R?

(R'°)n

R²

R⁴

R¹¹ (IX) or a pharmaceutically acceptable sait thereof, wherein:

R¹ is H, F, Cl, CN, C1-C2 alkyl or C1-C2 fluoroalkyl, where each said C1-C2 alkyl and C1-C2 fluoroalkyl is optionally substituted by R²⁰;

R² is H, C1-C5 alkyl, C1-C5 fluoroalkyl, C3-C8 cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R²⁰ and each said C3-C8 cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R²¹;

R⁴ is H, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy or C1-C4 fluoroalkoxy, where each said C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy and C1-C4 fluoroalkoxy is optionally substituted .byR²⁰; .

I R⁶ is H, F, Cl, CN, CH₃, CH₂F, CHF₂ or CF₃; '

R⁷ and R⁸ are independently H, F, Cl, CN, C1-C2 alkyl, C1-C2 fluoroalkyl, C1-C2 alkoxy or । C1-C2 fluoroalkoxy, where each said C1-C2 alkyl, C1-C2 fluoroalkyl, C1-C2 alkoxy and C1-C2 । fluoroalkoxy is optionally substituted by R²⁰; !

R⁹ is H, OH, NH₂, NHCH3 or N(CH₃)₂;

each R¹⁰ is independently F, CN, C1-C2 alkyl or C1-C2 fluoroalkyl, where each said C1-C2 alkyl and C1-C2 fluoroalkyl is optionally substituted by R²⁰;

R¹¹ is H, C1-C4 alkyl, Ç1-C4 fluoroalkyl, SO2R¹⁴, SQ₂NR¹⁵R¹⁶, COR¹⁷, COOR¹⁷ or CONR¹⁸R¹⁹;

R¹⁴ is C1-C4 alkyl or C1-C4 fluoroalkyl;

each R¹⁵ and R¹⁶ is independently H or CH₃;

R¹⁷is C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R²⁰;

each R¹⁸ and R¹⁹ is independently H, C1-C4 alkyl or C1-C4 fluoroalkyl, where each said

C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R²⁰;

each R²⁰ is independently OH, C1-C2 alkoxy, C1-C2 fluoroalkoxy, CN or NR²²R^{23 * 25};

each R²¹ is independently F, OH, CN, NR^R²³, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy or C1-C4 fluoroalkoxy, where each said C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy and C1-C4 fluoroalkoxy is optionally further substituted by OH, NH2, NHCH₃ or N(CH₃)2;

each R²² and R²³ is independently H, C1-C2 alkyl or C1-C2 fluoroalkyl; or

R²² and R²³ may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring, which is optionally substituted by F or OH; and n is 0,1, 2, 3 or 4.

In other embodiments, the invention provides a compound of Formula (IX’), or a pharmaceutically acceptable sait thereof, wherein R¹, R², R⁴, R⁶ to R¹¹, R¹⁴ to R²³ and n are as defined for Formula (IV).

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

or a pharmaceutically acceptable sait thereof, wherein:

R¹ is H, F, Cl, CN, C1-C2 alkyl or C1-C2 fluoroalkyl, where each said C1-C2 alkyl and

C1-C2 fluoroalkyl is optionally substituted by R²⁰; i

R² is H, C1-C5 alkyl, C1-C5 fluoroalkyl, C₃-Ce cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R²⁰ and each said

C₃-Ce cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R²¹; and

R⁴ is H, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy or C1-C4 fluoroalkoxy, where each said C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy and C1-C4 fluoroalkoxy is optionally substituted by R²⁰; or

R² can be taken together with R⁴ to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR²⁴, O and S(O)_m as a ring member, which ring is optionally substituted by R ,

R⁶ is H, F, Cl, CN, CH3, CH2F, CHF2 or CF3; —- R⁷ and R⁸ are independently H, F, Cl, CN, Ci-C2 alkyl, Ci-C₂ fluoroalkyl, Ci-C₂ alkoxy or C1-C2 fiuoroalkoxy, where each said C1-C2 alkyl, C1-C2 fluoroalkyl, C1-C2 alkoxy and C1-C2 fiuoroalkoxy is optionally substituted by R²⁰;

R⁹ is H, OH, NH₂, NHCH₃ or N(CH₃)₂;

each R¹⁰ is independently F, CN, C1-C2 alkyl or C1-C2 fluoroalkyl, where each said C1-C2 alkyl and C1-C2 fluoroalkyl is optionally substituted by R²⁰;

R¹¹ is H, C1-C4 alkyl, C1-C4 fluoroalkyl, SO2R¹⁴, SO₂NR¹⁵R¹⁶, COR¹⁷, COOR¹⁷ or CONR¹⁸R¹⁹;

R¹⁴ is C1-C4 alkyl or C1-C4 fluoroalkyl;

each R¹⁵ and R¹⁶ is independently H or CH₃;

R¹⁷ is C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R²⁰;

each R¹⁸ and R¹⁹ is independently H, C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R²⁰;

each R²⁰ is independently OH, C1-C2 alkoxy, C1-C2 fiuoroalkoxy, CN or N R²²R²³;

each R²¹ is independently F, OH, CN, NR²²R²³, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy or C1-C4 fiuoroalkoxy, where each said C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy and C1-C4 fiuoroalkoxy is optionally further substituted by OH, NH2, NHCH₃ or N(CH₃)2;

each R²² and R²³ is independently H, C1-C2 alkyl or C1-C2 fluoroalkyl; or

R²² and R²³ may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring, which is optionally substituted by F or OH;

R²⁴ is H, C1-C4 alkyl, C1-C4 fluoroalkyl, SO2R²⁵, SO₂NR²⁸R²⁷, COR²⁸, COOR²⁸ or

CONR²⁹R³⁰; | I

R²⁵ is C1-C4 alkyl or C1-C4 fluoroalkyl;

each R²⁶ and R²⁷ is independently H or CH₃;

R²⁸ is C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by OH, C1-C2 alkoxy, C1-C2 fiuoroalkoxy, CN, NH2, NHCH₃ or N(CH₃)2;

each R²⁹ and R³⁰ is independently H, C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by OH, C1-C2 alkoxy, C1-C2 fiuoroalkoxy, CN, NH2, NHCH₃ or N(CH₃)2;

m is 0,1 or 2; and n is 0,1,2, 3 or 4.

In some embodiments, the compound of Formula (IX) or (IX’) has the absolute stereochemistry as shown in one of Formulae (IX-A), (IX-B), (IX-C) or (IX-D), or Formulae (IXA), (IX’-B), (IX’-C) or (IX’-D)

or a pharmaceutically acceptable sait thereof.

— Each of the aspects and embodiments described herein with respect to Formula (II) is also applicable to compounds of Form|jlae (IX), (1X-A), (IX-B), (IX-C) or (IX-D) that are not| inconsistent with such aspect or embodiment.

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

In certain embodiments, the invention provides a compound of Formula (IX), (IX-A), (IXB), (IX-C) or (IX-D), or a pharmaceutically acceptable sait thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R¹ is CI,\R² is C1-C5 alkyl; or R² is 1-C3H7; R⁴ is C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by R²⁰, where R²⁰ is OH; or R⁴ is CH(OH)CH3 or C(OH)(CH3)2; R⁶ is F; R⁷ is H; R⁸ is H; R⁹ is OH; R¹¹ is SO2R¹⁴; R¹⁴ is C1-C4 alkyl; n is 0 and R¹⁰ is absent.

⁷⁹

In a preferred embodiment, the invention provides a compound of Formula (IX), (IX-A), (IX-B), (IX-C) or (IX-D),or a pharmaceutically acceptable sait thereof, wherein: R¹ is Cl; R² is C1-C5 alkyl; or R² is i-C₃H₇; R⁴ is C1-C4 alkyl optionally substituted by R²⁰; where R²⁰ is OH; or R⁴ is

CH(OH)CH₃ orC(OH)(CH₃)₂; R⁶ is F; R⁷ is H; R⁸ is H; R⁹is OH; R¹¹ is SO2R¹⁴; R¹⁴is C1-C4 alkyl;

n is 0 and R¹⁰ is absent.

In certain embodiments, the invention provides a compound of Formulae (IX), (IX-A), (IXB), (IX-C) or (IX-D), or a pharmaceutically acceptable sait thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features:R¹ is F or Cl; R² is C1-C5 alkyl, C1-C5 fluoroalkyl or 3-6 membered heterocyclyl; or R² is CH₃, i-C₃H₇, 10 i-C4H₉. s-C₄H₉, t-C₄H₉, CH₂F, CHF_2i CH2CHF2 or oxetan-3-yl; R⁴ is H or C1-C4 alkyl, where said

C1-C4 alkyl is optionally substituted by OH, NH2, NHCH₃ or N(CH₃)2î or R⁴ is H, CH₃, C2H5, CH2OH, CH(OH)CH₃, CH2CH2OH or CH2NH2; R⁶ is H or F; R⁷ and R⁸ are H; R⁹ is OH; n is 0 and R¹⁰ is absent; R¹¹ is SO2R¹⁴; and R¹⁴is C1-C4 alkyl. —

In spécifie embodiments, the invention provides a compound of Formulae (IX), (IX-A), (IX15 B), (IX-C) or (IX-D), or a pharmaceutically acceptable sait thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R¹ is Cl; R² is C1-C5 alkyl; R⁴ is H or C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by R²⁰; R⁶ is F; R⁷ and R⁸ are H; R⁹is OH; R¹¹ is SO2R¹⁴; R¹⁴is C1-C4 alkyl; and R²⁰ is OH.

Each of the aspects and embodiments described herein with respect to Formula (IV) is 20 also applicable to compounds of Formulae (IX’), (IX’-A), (IX’-B), (IX’-C) or (IX’-D) that are not inconsistent with such aspect or embodiment.

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

In certain embodiments, the invention provides a compound of Formulae (IX’), (IX’-A), 25 (IX’-B), (IX’-C) or (IX’-D), or a pharmaceutically acceptable sait thereof, having a combination of two or more, preferably three or more, and more preferably four or more,ofthe following features: | R¹ is F or Cl; R² is C1-C5 alkyl, Ci-C£fluorôalkyl |)r 3-6 membered heterocyclyl; or R² is CH3, iC3H7, i-C4H9, s-C4H9, t-C4H9, CH2F, CHF2, CH2CHF2 or oxetan-3-yl; R⁴ is H or C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by OH, NH2, NHCH3 orN(CH₃)2; or R⁴ is H, CH₃, C2H5, 30 CH2OH, CH(OH)CH₃, CH2CH2OH or CH₂NH₂; or R² is taken together with R⁴ to form a 5-7

I membered heterocyclic ring, optionally containing an additional heteroatom selected from NR²⁴,

O and S(O)_m as a ring member, which ring is optionally substituted by R²¹; R⁶ is H or F; R⁷ and R⁸ are H; R⁹ is OH; n is 0 and R¹⁰ is absent; R¹¹ is SO2R¹⁴; and R¹⁴ is C1-C4 alkyl.

In spécifie embodiments, the invention provides a compound of Formulae (IX’), (IX’-A), 35 (IX’-B), (IX’-C) or (IX’-D), or a pharmaceutically acceptable sait thefêof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features:R¹ is F or Cl; R² is CH3,1-C3H7, i-C4H9,s-C4H9, t-C4H9, CH2F, CHF2, CH2CHF2 or oxetan3-yl; R⁴ is H, CH3, C₂H₅, CH₂OH, CH(OH)CH₃, CH₂CH₂OH or CH₂NH₂; or R² is taken together with R⁴ to form a 5-membered heterocyclic ring optionally substituted by R²¹; each R²¹ is independently F, OH, NH₂, Ci-C₂ alkyl or Ci-C₂ fluoroalkyl; R⁶ is F; R⁷ and R⁸ are H; R⁹ is OH; n is 0 and R¹⁰ is absent; R¹¹ is SO₂R¹⁴; and R¹⁴is CH3.

In spécifie embodiments, the invention provides a compound of Formulae (IX’), (IX’-A), (IX’-B), (IX’-C) or (IX’-D), or a pharmaceutically acceptable sait thereof, having a combination of two or more, preferably three or more, and more preferably four or more, ofthe following features: R¹ is Cl; R² is C1-C5 alkyl; R⁴ is H or C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted 10 by R²⁰; R⁶ is F; R⁷ and R⁸ are H; R⁹ is OH; R¹¹ is SO₂R¹⁴; R¹⁴ is C1-C4 alkyl; and R²⁰ is OH.

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

or a pharmaceutically acceptable sait thereof, wherein:

R¹ is H, F, Cl, CN, Ci-C₂ alkyl or Ci-C₂ fluoroalkyl, where each said C1-C2 alkyl and C1-C2 fluoroalkyl is optionally substituted by R²⁰;

R² is H, C1-C5 alkyl, C1-C5 fluoroalkyl, C3-C8 cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R²⁰ and each said C3-C8 cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R²¹;

। R⁴ is H, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy (j)r C1-C4 fluoroalkoxy, where each said C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy and C1-C4 fluoroalkoxy is optionally substituted by R²⁰;

R⁶ is H, F, Cl, CN, CH₃, CH₂F, CHF₂ or CF₃;

। R⁷ and R⁸ are independently H, F, Cl, CN, C1-C2 alkyl, C1-C2 fluoroalkyl, C1-C2 alkoxy or C1-C2 fluoroalkoxy, where each said C1-C2 alkyl, C1-C2; fluoroalkyl, C1-C2 alkoxy and C1-C2 fluoroalkoxy is optionally substituted by R²⁰;

R⁹ is H, OH, NH₂, NHCH3 or N(CH₃)₂; ________ each R¹⁰ is independently F, CN, C1-C2 alkyl or C1-C2 fluoroalkyl, where each said C1-C2 alkyl and C1-C2 fluoroalkyl is optionally substituted by R²⁰;

each R²⁰ is independently OH, C1-C2 alkoxy, C1-C2 fluoroalkoxy, CN or N R²²R²³;

each R²¹ is independently F, OH, CN, N R²²R²³, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy or C1-C4 fluoroalkoxy, where each said C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy and C1-C4 fluoroalkoxy is optionally further substituted by OH, NH2, NHCH3 or N(CH3)2!

each R²² and R²³ is independently H, C1-C2 alkyl or C1-C2 fluoroalkyl; or

R²² and R²³ may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring, which is optionally substituted by F or OH; and n is 0,1, 2, 3 or 4.

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

or a pharmaceutically acceptable sait thereof, wherein:

R¹ is H, F, Cl, CN, C1-C2 alkyl or C1-C2 fluoroalkyl, where each said C1-C2 alkyl and C1-C2 fluoroalkyl is optionally substituted by R²⁰;

R² is H, C1-C5 alkyl, C1-C5 fluoroalkyl, C3-C8 cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R²⁰ and each said C3-C₈ cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R²¹;

R⁴ is H, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy or C1-C4 fluoroalkoxy, where each said C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy and C1-C4 fluoroalkoxy is optionally substituted by R²⁰;

or

R² can be taken together with R⁴ to form a 5-7 membered heterocyclic ring, optionally containing dn additional heteroatom selected from NR²⁴, O and S(0)_m as a ring member, which ring is optionally substituted by R²¹;

R⁶ is H, F, Cl, CN, CH₃, CH₂F, CHF₂ or CF₃; I i

R⁷ and R⁸ are independently H, F, Cl, CN, C1-C2 alkyl, C1-C2 fluoroalkyl, C1-C2 alkoxy or C1-C2 fluoroalkoxy, where each said C1-C2 alkyl, C1-C2 fluoroalkyl, C1-C2 alkoxy and C1-C2 fluoroalkoxy is optionally substituted by R²⁰;

R⁹is H, OH, NH₂, NHCH₃ or N(CH₃)₂;

each R¹⁰ is independently F, CN, C1-C2 alkyl or C1-C2 fluoroalkyl, where each said C1-C2 alkyl and C1-C2 fluoroalkyl is optionally substituted by R²⁰;

each R²⁰ is independently OH, C1-C2 alkoxy, C1-C2 fluoroalkoxy, CN or N R²² R²³;

each R²¹ is independently F, OH, CN, NR²²R²³, C1-C4 alkyl, C1-C4 fluoroaikyl, C1-C4 alkoxy or C1-C4 fluoroalkoxy, where each said C1-C4 alkyl, C1-C4 fluoroaikyl, C1-C4 alkoxy and C1-C4 fluoroalkoxy is optionally further substituted by OH, NH2, NHCH3 or N(CH3)2î each R²² and R²³ is independently H, C1-C2 alkyl or C1-C2 fluoroalkÿl; or 5 R²² and R²³ may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring, which is optionally substituted by F or OH;

R²⁴ is H, C1-C4 alkyl, C1-C4 fluoroaikyl, SO2R²⁵, SO₂NR²⁶R²⁷, COR²⁸, COOR²⁸ or CONR²⁹R³⁰;

R²⁵ is C1-C4 alkyl or C1-C4 fluoroaikyl; 10 each R²⁶ and R²⁷ is independently H or CH3;

R²⁸ is C1-C4 alkyl or C1-C4 fluoroaikyl, where each said C1-C4 alkyl and C1-C4 fluoroaikyl is optionally substituted by OH, C1-C2 alkoxy, C1-C2 fluoroalkoxy, CN, NH2, NHCH3 or N(CH3)2!

each R²⁹ and R³⁰ is independently H, C1-C4 alkyl or C1-C4 fluoroaikyl, where each said C1-C4 alkyl and C1-C4 fluoroaikyl is optionally substituted by OH, C1-C2 alkoxy, C1-C2 fluoroalkoxy, 15 CN, NH₂, NHCH₃ or N(CH₃)₂;

m is 0,1 or 2; and n is 0,1, 2, 3 or 4.

In some embodiments, the compound of Formula (X) or (XI) has the absoiute stereochemistry as shown in one of Formulae (X-A), (X-B), (X-C) or (X-D) or (Xl-A), (Xl-B), (Xl-C) or (Xl-D):

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

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

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

In certain embodiments, the invention provides a compound of Formula (X), (X-A), (X-B), (X-C) or (X-D), or a pharmaceutically acceptable sait thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R¹ is Cl; R² is C1-C5 alkyl; or R² is i-C3H7; R⁴ is C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by R²⁰, where R²⁰ is OH; or R⁴ is CH(OH)CH3 orC(OH)(CH₃)₂; R⁶ is F; R⁷ is H; R⁸ is H; R⁹ is OH; n is 0 and R¹⁰ is absent.

In a preferred embodiment, the invention provides a compound of Formula (X), (X-A), (XB), (X-C) or (X-D),or a pharmaceutically acceptable sait thereof, wherein: R¹ is Cl; R² is C1-C5 alkyl; or R² is i-C3H7; R⁴ is C1-C4 alkyl optionally substituted by R²⁰, where R²⁰ is OH; or R⁴ is CH(OH)CH3 orC(OH)(CH₃)₂; R⁶ is F; R⁷ is H; R⁸ is H; R⁹ is OH; n is 0 and R¹⁰ is absent.

In certain embodiments, the invention provides a compound of Formulae (X), (X-A), (XB), (X-C) or (X-D), or a pharmaceutically acceptable sait thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R¹ is F or Cl; R² is C1-C5 alkyl, C1-C5 fluoroalkyl or 3-6 membered heterocyclyl; or R² is CH3, i-C3H7, iC4H9i s-C4H9, t-C4H9, CH2F, CHF2i CH2CHF2 or oxetan-3-yl; R⁴ is H or C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by OH, NH2, NHCH₃ or N(CH₃)₂; or R⁴ is H, CH₃, C₂Hs, CH₂OH, CH(OH)CH_3i C(OH)(CH₃)₂ orCH₂CH₂OH; R⁶ is H or F; R⁷ is H; R⁸ is H; R⁹ is OH; n is 0 and R¹⁰ is absent.

Each of the aspects and embodiments described herein with respect to Forr|nula (IV) is also applicable to compounds of Formulae (XI), (Xl-A), (Xl-B), (Xl-C) or (Xl-D) that are not inconsistent with such aspect or embodiment.

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

In certain embodiments, the invention provides a compound of Formula (XI), (Xl-A), (XIB), (Xl-C) or (Xl-D), or a pharmaceutically acceptable sait thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R¹ is Cl; R² is C1-C5 alkyl; or R² is i-C₃H₇; R⁴ is C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by R²⁰, where R²⁰ is OH; or R⁴ is CH(OH)CH₃ orC(OH)(CH₃)2; R⁶ is F; R⁷ is H; R⁸ is

H; R⁹ is OH; n is 0 and R¹⁰ is absent.

In a preferred embodiment, the invention provides a compound of Formula (XI), (Xl-A), (Xl-B), (Xl-C) or (Xl-D),or a pharmaceutically acceptable sait thereof, wherein: R¹ is Cl; R² is C1-C5 alkyl; or R² is i-C3H7; R⁴ is C1-C4 alkyl optionally substituted by R²⁰, where R²⁰ is OH; or R⁴ is CH(OH)CH3 orC(OH)(CH₃)₂; R⁶ is F; R⁷ is H; R⁸ is H; R⁹ is OH; n is 0 and R¹⁰ is absent.

In certain embodiments, the invention provides a compound of Formulae (XI), (Xl-A), (XIB), (Xl-C) or (Xl-D), or a pharmaceutically acceptable sait thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R¹ is F or Cl; R² is C1-C5 alkyl, C1-C5 fluoroalkyl or 3-6 membered heterocyclyl; or R² is CH3, i-C3H7, i-C4H9, S-C4H9, t-C4H9, CH2F, CHF2i CH2CHF2 or oxetan-3-yl; R⁴ is H or C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by OH, NH2, NHCH3 or N(CH₃)2î or R⁴ is H, CH₃, C2H5, CH2OH, CH(OH)CH₃, C(OH)(CH₃)₂ orCH₂CH₂OH; R⁶ is H or F; R⁷ is H; R⁸ is H; R⁹ is OH; n is 0 and R¹⁰ is absent.

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

or a pharmaceutically acceptable sait thereof, wherein:

A is N or CH;

R¹ is H, F or Cl;

R² is H, C1-C5 alkyl, C1-C5 fluoroalkyl, C3-Ce cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R²⁰ and each said C3-Ce cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R²¹;

R⁴ is H, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, C(O)R^a, C(O)NR^b2, C3-Cs cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy and C1-C4 fluoroalkoxy is optionally substituted by R²⁰, each said C3-Ce cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R²¹, R^a is C1-C2 alkyl, and each R^b is independently H or C1-C2 alkyl; ..... . ·

R⁶ is H or F;

R⁷ and R⁸ are independently H, F, Cl, CN, C1-C2 alkyl, C1-C2 fluoroalkyl, C1-C2 alkoxy or C1-C2 fluoroalkoxy; .

Q is O; or

QisNR¹¹;

R¹¹ is SO2R¹⁴ or COR¹⁷;

R¹⁴ is C1-C4 alkyl or C1-C4 fluoroalkyl;

R¹⁷ is C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C8 cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R²⁰ and each said C3-C8 cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R²¹;

each R²⁰ is independently OH, C1-C2 alkoxy, C1-C2 fluoroalkoxy, CN, NR²²R²³, C3-C8 cycloalkyl or 3-6 membered heterocyclyl, where each said C3-C8 cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R²¹;

each R²¹ is independently F, OH, CN, N R²²R²³, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy or C1-C4 fluoroalkoxy, where each said C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy and C1-C4 15 fluoroalkoxy is optionally further substituted by OH, NH2, NHCH3 or N(CH3)2;

each R²² and R²³ is independently H, C1-C3 alkyl, C1-C3 fluoroalkyl, C3-C8 cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C3 alkyl and C1-C3 fluoroalkyl is optionally further substituted by OH, C1-C2 alkoxy or C1-C2 fluoroalkoxy and each said C3-C8 cycloalkyl and 3-6 membered heterocyclyl is optionally further substituted by F, OH, C1-C2 alkyl, C1-C2 fluoroalkyl, 20 C1-C2 alkoxy or C1-C2 fluoroalkoxy; or

R²² and R²³ may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring, where said ring is optionally substituted by F, OH, C1-C2 alkyl, C1-C2 fluoroalkyl, C1-C2 alkoxy or C1-C2 fluoroalkoxy.

In some embodiments, the compound of Formula (XII) has the absolute stereochemistry 25 as shown in one of Formulae (Xll-A), (Xll-B), (Xll-C) or (Xll-D):

(Xll-A) (Xll-B)

(Xll-C) (Xll-D) or a pharmaceutically acceptable sait thereof.

Each of the aspects and embodiments described herein with respect to Formula (l)-(XI) 5 is also applicable to compounds of Formulae (XII), (Xll-A), (Xll-B), (Xll-C) or (Xll-D) that are not inconsistent with such aspect or embodiment.

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

In some embodiments of Formulae (XII), (Xll-A), (Xll-B), (Xll-C) or (Xll-D), A is N. In some 10 embodiments of Formulae (XII), (Xll-A), (Xll-B), (Xll-C) or (Xll-D), A is CH.

In some embodiments of Formulae (XII), (Xll-A), (Xll-B), (Xll-C) or (Xll-D), R¹ is Cl.

In some embodiments of Formulae (XII), (Xll-A), (Xll-B), (Xll-C) or (Xll-D), R² is C1-C5 alkyl or C1-C5 fluoroalkyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R²⁰. In some such embodiments, R² is C1-C5 alkyl. In spécifie embodiments, R² 15 is isopropyl.

In some embodiments of Formulae (XII), (Xll-A), (Xll-B), (Xll-C) or (Xll-D), R² is C3-C8 cycloalkyl or 3-6 membered heterocyclyl, where each said C3-C8 cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R²¹.

In some embodiments of Formulae (XII), (Xll-A), (Xll-B), (Xll-C) or (Xll-D), R⁴ is H, C1-C4 20 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy or C1-C4 fluoroalkoxy, where each said C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy and C1-C4 fluoroalkoxy is optioifially substituted by R²⁰.

In some such embodiments, R²⁰ is OH. In some embodiments, R⁴ is C1-C4 alkyl optionally substituted by R²⁰where R²⁰ is OH. In spécifie embodiments, R⁴ is CH(OH)CH3 orC(OH)(CH3)2. I l ^! In other such embodiments, R²⁰ is C3-C8 cycloalkyl or 3-6 membered heterocyclyl, where 25 each said GrCe cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R²¹. In some such embodiments, R⁴ is C1-C4 alkyl optionally substituted by R²⁰ where R²⁰ is C3-C8 cycloalkyl or 3-6 membered heterocyclyl, where each said C3-C8 cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R²¹. - ------In some embodiments of Formulae (XII), (Xll-A), (Xll-B), (Xll-C) or (Xll-D), R⁴ is C(O)R^a, 30 C(O)NR^b2, R^a is C1-C2 alkyl, and each R^b is independently H or C1-C2 alkyl.

In some embodiments of Formulae (XII), (Xll-A), (Xll-B), (Xll-C) or (Xll-D), R⁴ is C3-C8 cycloalkyl or 3-6 membered heterocyclyl, where each said C3-C8 cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R²¹.

In some embodiments of Formulae (XII), (Xll-A), (Xll-B), (Xll-C) or (Xll-D), R⁶ is F.

In some embodiments of Formulae (XII), (Xll-A), (Xll-B), (Xll-C) or (Xll-D), R⁷ and R⁸ are independently H or F. In some such embodiments, R⁷ and R⁸ are H.

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

In some embodiments of Formulae (XII), (Xll-A), (Xll-B), (Xll-C) or (Xll-D), Q is NR¹¹. In some such embodiments, R¹¹ is SO2R¹⁴. In some such embodiments, R¹⁴is C1-C4 alkyl. In some such embodiments, R¹¹ is COR¹⁷. In some such embodiments, R¹⁷ is C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R²⁰. In some such embodiments, R¹⁷is C3-C8 cycloalkyl or 3-6 membered heterocyclyl, where each said C3-C8 cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R²¹.

In certain embodiments, the invention provides a compound of Formula (XII), (Xll-A), (XIIB), (Xll-C) or (Xll-D), or a pharmaceutically acceptable sait thereof, having a combination of two or more, preferably three or more, and more preferably four or more, ofthe following features: A is N; R¹ is Cl; R² is C1-C5 alkyl; or R² is 1-C3H7; R⁴ is C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by R²⁰, where R²⁰ is OH; or R⁴ is CH(OH)CH3 orC(OH)(CH3)2; R⁶ is F; R⁷ is H; R⁸ is H; and Q is O.

In certain embodiments, the invention provides a compound of Formula (XII), (Xll-A), (XIIB), (Xll-C) or (Xll-D), or a pharmaceutically acceptable sait thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: A is N; R¹ is Cl; R² is C1-C5 alkyl; or R² is 1-C3H7; R⁴ is C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by R²⁰, where R²⁰ is OH; or R⁴ is CH(OH)CH3 or C(OH)(CH3)2; R⁶ is F; R⁷ is H; R⁸ is H; Q is NR¹¹; R¹¹ is SO2R¹⁴; and R¹⁴is C1-C4 alkyl.

In certain embodiments, the invention provides a compound of Formula (XII), (Xll-A), (XIIB), (XIl-c|) or (Xll-D), or a pharmaceutically acceptable sait there|of, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: A is CH; R¹ is Cl; R² is C1-C5 alkyl; or R² is 1-C3H7; R⁴ is C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by R²⁰, where R²⁰ is OH; or R⁴ is CH(OH)CH3 orC(OH)(CH3)2; R⁶ is F; R⁷ is H; R⁸ is H; and Q is O. i

In certain embodiments, the invention provides a compound of Formula (XII), (Xll-A), (XIIB), (Xll-C) or (Xll-D), or a pharmaceutically acceptable sait thereof, having a combination of two or more, preferably three or more, and more preferably four or more, ofthe following features: A is CH; R¹ is Cl; R² is C1-C5 alkyl; or R² is 1-C3H7; R⁴ is C1-C4 alkyl, where said C1-C4 alkyl is _A 88 optionally substituted by R²⁰, where R²⁰ is OH; or R⁴ is CH(OH)CH3 orC(OH)(CH3)2; R⁶ is F; R⁷ is H; R⁸ is H; Q is NR¹¹; R¹¹ is SO2R¹⁴; and R¹⁴is C1-C4 alkyl.

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

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

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

4-(1-tert-butyl-4-fIuoro-1H-benzimidazol-6-yl)-5-fluoro-N-(1-methylpiperidin-410 yI)pyrimidin-2-amine;

(3R,4R)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol;

(3R,4R)-4-({5-ethyl-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol;

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

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

(3R,4R)-4-({4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]-520 methoxypyrimidin-2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol;

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

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

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

(3R,4R)-4-{[4-(1-tert-butyl-1H-benzimidazol-6-yl)-5-fluoropyrimidin-2-yl]amino}-130 (methanesulfonyl)piperidin-3-ol; j (3R,4R)-4-({5-fluoro-4-[2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2yl}amino)-1-(methanesulfonyl)piperidin-3-ol;

(3R,4R)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin2-yl}amino)piperidin-3-ol;

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

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

(3S,4S)-4-({5-fIuoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin2-yl}amino)-1-methylpiperidin-3-ol;

(3S,4S)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin2-yl}amino)-1-(methanesuIfonyl)piperidin-3-ol;

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

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

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

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

(3R,4R)-4-[(5-chloro-4-{4-fluoro-2-[(1 R)-1 -hydroxyethyl]-1 -(propan-2-yl)-1 Hbenzimidazol-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)-1 Hbenzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-t/jreo-pentitol;

or a pharmaceutically acceptable sait thereof.

In another aspect, the invention provides a compound selected from the group consisting of the compounds exemplified in the Examples provided herein, including A1-A94, B1-B2, 01C2, D1-D6, E1, F1-F33, G1 and H1-H11, inclusive, or a pharmaceutically acceptable sait thereof.

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

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

In another aspect, the invention provides a pharmaceutically acceptable sait of (3R,4R)4-[(5-chloro-4-{4-fluoro-2-[(1 R)-1 -hydroxyethyl]-1 -(propan-2-yl)-1 H-benzimidazol-6-yl}pyrimidin2-yl)amino]-1-(methanesulfonyl)piperidin-3-ol. I

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

— 90

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

In another aspect, the invention provides a pharmaceutically acceptable sait of 1,55 anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yI)-1 -(propan-2-yl)-1 H-benzimidazoI-6yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-t/7reo-pentitol.

A pharmaceutical composition refers to a mixture of one or more of the compounds of the invention, or a pharmaceutically acceptable sait, solvaté, hydrate or prodrug thereof as an active ingrédient, and at least one pharmaceutically acceptable carrier or excipient. In some 10 embodiments, the pharmaceutical composition comprises 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, the invention provides a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable sait thereof, and a pharmaceutically 15 acceptable carrier or excipient. In some embodiments, the pharmaceutical composition comprises two or more pharmaceutically acceptable carriers and/or excipients.

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

The term “additive” is used to mean that the resuit of the combination of two compounds, components or targeted agents is no greater than the sum of each compound, component or targeted agent individually.

The term “synergy” or “synergistic” are used to mean that the resuit of the combination of two compounds, components or targeted agents is greater than the sum of each compound, 25 component or targeted agent individually. This improvement in the disease, condition or disorder being treated is a “synergistic” effect. A “synergistic amount” is an amount of the combination of the two compounds, components (or targeted agents that results in a synergistic effecjt, as “synergistic” is defined herein.

Determining a synergistic interaction between one or two components, the optimum range 30 for the effect and absolute dose ranges of each component for the effect may be definitively measured by administration of the components over different dose ranges, and/or dose ratios to patients in need of treatment. However, the observation of synergy in in vitro models or in vivo models can be prédictive of the effect in humans and other species and /n vitro models or in vivo models exist, as described herein, to measure a synergistic effect. The results of such studies . 35 can also be used to predict effective dose and plasma concentration ratio ranges and the absolute _ 91 doses and plasma concentrations required in humans and other species such as by the application of pharmacokinetic and/or pharmacodynamies methods.

Unless indicated otherwise, ail référencés herein to the inventive compounds include référencés to salts, solvatés, hydrates and complexes thereof, and to solvatés, hydrates and 5 complexes of salts thereof, including polymorphs, stereoisomers, and isotopically labelled versions thereof.

Compounds of the invention may exist in the form of pharmaceutically acceptable salts such as, e.g., acid addition salts and base addition salts of the compounds of one of the formulae provided herein. As used herein, the term “pharmaceutically acceptable sait” refers to those salts 10 which retain the biological effectiveness and properties of the parent compound. The phrase “pharmaceutically acceptable salt(s), as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be présent in the compounds of the formulae disclosed herein.

For example, the compounds of the invention that are basic in nature are capable of 15 forming a wide variety of salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animais, it is often désirable in practice to initially isolate the compound of the présent invention from the reaction mixture as a pharmaceutically unacceptable sait and then simply couvert the latter back to the free base compound by treatment with an alkaline reagent and subsequently couvert the latter free base to 20 a pharmaceutically acceptable acid addition sait. The acid addition salts of the base compounds of this invention can be prepared by treating the base compound with a substantially équivalent amount of the selected minerai or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or éthanol. Upon évaporation of the solvent, the desired solid sait is obtained. The desired acid sait can also be precipitated from a solution of the free base in 25 an organic solvent by adding an appropriate minerai or organic acid to the solution.

The acids that may be used to prépare pharmaceutically acceptable acid addition salts of such basic compounds of those that form |non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, 30 citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, giuconate, glucuronate, saccharatë, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate salts.

Examples of salts include, but are not limited to, acetate, acrylate, benzenesulfonate, benzoate (such as chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, and 35 methoxybenzoate), bicarbonaté, bisulfate, bisulfite, bitartrate, borate, bromide, butyne-1,4-dioate, calcium edetate, camsylate, carbonate, chloride, caproate, caprylate, _ 92 clavulanate, citrate, decanoate, dihydrochloride, dihydrogenphosphate, edetate, edislyate, estolate, esylate, ethylsuccinate, formate, fumarate, gluceptate, gluconate, glutamate, glycollate, glycollylarsanilate, heptanoate, hexyne-1,6-dioate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, γ-hydroxybutyrate, iodide, isobutyrate, isothionate, lactate, 5 lactobionate, laurate, malate, maleate, malonate, mandelate, mesylate, metaphosphate, methane-sulfonate, methylsulfate, monohydrogenphosphate, mucate, napsylate, naphthalene-1-sulfonate, naphthalene-2-suIfonate, nitrate, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phenylacetates, phenylbutyrate, phenylpropionate, phthalate, phospate/diphosphate, polygalacturonate, propanesulfonate, propionate, propiolate, 10 pyrophosphate, pyrosulfate, salicylate, stéarate, subacetate, suberate, succinate, sulfate, sulfonate, sulfite, tannate, tartrate, teoclate, tosylate and valerate salts.

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, 15 potassium, magnésium, manganèse, iron, copper, zinc, aluminum and lithium.

The compounds of the invention that 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, the compounds useful that are acidic in nature may be capable of forming 20 base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali métal or alkaline-earth métal salts and particularly, the sodium and potassium salts. These salts are ail prepared by conventional techniques. The Chemical bases which are used as reagents to préparé the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds herein. These salts may be prepared by 25 any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali métal hydroxide or alkaline earth | métal hydroxide, or the like. These salts can also tj»e prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced 30 j pressure. Alternatively, they may also be prepared I by mixing lower alkanolic solutions of the I acidic compounds and the desired alkali métal alkbxide together, and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric quantifies of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final product. ------ — — ·

The Chemical bases that may be used as reagents to préparé 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, those derived from such pharmacologically acceptable cations such as alkali métal cations (e.g., potassium and sodium) and alkaline earth métal cations (e.g., calcium and magnésium), ammonium or water-soluble amine addition salts such as. . : N-methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.

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

For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Sélection, and Use by Stahl and Wermuth (Wiley-VCH, 2002). Methods for making pharmaceutically acceptable salts of compounds of the invention, and of interconverting sait and free base forms, are known to one of skill in the art.

Salts of the présent invention can be prepared according to methods known to those of skill in the art. A pharmaceutically acceptable sait of the inventive compounds can be readily prepared by mixing together solutions of the compound and the desired acid or base, as appropriate. The sait may precipitate from solution and be collected by filtration or may be recovered by évaporation of the solvent. The degree of ionization in the sait may vary from completely ionized to almost non-ionized.

Itwill be understood bythose of skill in the artthatthe compounds ofthe invention in free base form having a basic functionality may be converted to the acid addition salts by treating with a stoichiometric excess of the appropriate acid. The acid addition salts of the compounds of the invention may be reconverted to the corresponding free base by treating with a stoichiometric excess of a suitable base, such as potassium carbonate or sodium hydroxide, typically in the presence of aqueous solvent, and at a température of between about 0° C and 100° C. The free base form may be isolated by conventional means, such as extraction with an organic solvent. In addition, acid addition salts ofthe compounds ofthe invention may be interchanged bytaking — advantjage of differential solubilities of the salts, volatilities or ^cidities of the acids, or by treating with the appropriately loaded ion exchange resin. For example, the interchange may be affected by the reaction of a sait of the compounds of the invention with a slight stoichiometric excess of an acid of a lower pK than the acid component of the starting sait. This conversion is typically carried out at a température between about 0°C and the boiling point of the solvent being used as the medium for the procedure. Similar exchanges are possible with base addition salts, typically via the intermediacy of the free base form. .

The compounds ofthe invention may exist in both unsolvated and solvated forms. When.... ...... the solvent or water is tightly bound, thé complex will hâve a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvatés and hygroscopic compounds, the water/solvent content will be dépendent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm. The term 'solvaté’ is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molécules, for example, éthanol. The term ‘hydrate’ is employed when the solvent is water. Pharmaceutically acceptable solvatés in accordance with the invention include hydrates and solvatés wherein the solvent of crystallization may be isotopically substituted, e.g. D2O, de-acetone, de-DMSO.

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

The invention also relates to prodrugs of the compounds of the formulae provided herein. Thus, certain dérivatives of compounds of the invention which may hâve little or no pharmacological activity themselves can, when administered to a patient, be converted into the inventive compounds, for example, by hydrolytic cleavage. Such dérivatives are referred to as ‘prodrugs’. Further information on the use of prodrugs may be found in ‘Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Sériés (T Higuchi and W Stella) and ‘Bioreversible Carriers in Drug Design’, Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association), the disclosures of which are incorporated herein by reference in their entireties.

Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities présent in the inventive compounds with certain moieties known to those skilled in the art as ‘pro-moieties’ as described, for example, in Design of Prodrugs by H Bundgaard (Elsevier, 1985), the disclosure of which is incorporated herein by reference in its entirety. | |

Some non-limiting examples of prodrugs in accordance with the invention include:

(i) where the compound contains a carboxylic acid functionality (-COOH), an ester thereof, for example, replacement of the hydrogen with (Ci-Ceialkyl; j (ii) where the compound contains an alcohol functionality (-ÔH), an ether thereof, for example, replacement of the hydrogen with (Ci-Cejalkanoyloxymethyl, or with a phosphate ether group; and - · (iii) where the compound contains a:primary or secondary amino functionality (-NH2 or -NHR where R # H), an amide thereof, for example, replacement of one or both hydrogens _ 95 with a suitably metabolically labile group, such as an amide, carbamate, urea, phosphonate, sulfonate, etc. Further examples of replacement groups in accordance with the foregoing examples and examples of other prodrug types may be found in the aforementioned references. -

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

Also included within the scope of the invention are métabolites of compounds of the formulae described herein, i.e., compounds formed in vivo upon administration ofthe drug.

The compounds of the formulae provided herein may hâve asymmetric carbon atoms.

The carbon-carbon bonds of the compounds of the invention may be depicted herein using a solid line (------), a solid wedge ( ^— ), or a dotted wedge (.....^ml111 ). The use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that ail possible stereoisomers (e.g. spécifie enantiomers, racemic mixtures, etc.) at that carbon atom are included. The use of either a solid or dotted wedge to depict bonds to asymmetric carbon atoms is meant to indicate that only the stereoisomer shown is meant to be included. It is possible that compounds of the invention may contain more than one asymmetric carbon atom. In those compounds, the use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that ail possible stereoisomers are meant to be included and the attached stereocenter. For example, unless stated otherwise, it is intended thatthe compounds ofthe invention can exist as enantiomers and diastereomers or as racemates and mixtures thereof. The use of a solid line to depict bonds to one or more asymmetric carbon atoms in a compound of the invention and the use of a solid or dotted wedge to depict bonds to other asymmetric carbon atoms in the same compound is meant to indicate that a mixture of diastereomers is present.

Compounds ofthe invention that hâve chiral centers may exist as stereoisomers, such as 25 racemates, enantiomers, or diastereomers.

Stereoisomers ofthe compounds ofthe formulae herein can include cis and trans isomers, optical isomers such as|(R) and (S) enantiomers, diastereomers, géométrie istjmers, 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). i

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

When any racemate crystallizes, crystals of two different types are possible. The first type 35 is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts. The second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer. .

The compounds of the invention may exhibit the phenomena of tautomerism and structural isomerism. For example, the compounds may exist in several tautomeric forms, including the enol and imine form, and the keto and enamine form and géométrie isomers and mixtures thereof. Ail such tautomeric forms are included within the scope of compounds of the invention. Tautomers exist as mixtures of a tautomeric set in solution. In solid form, usually one tautomer prédominâtes. Even though one tautomer may be described, the présent invention includes ail tautomers of the compounds of the formulae provided.

In addition, some of the compounds of the invention may form atropisomers (e.g., substituted biaryls). Atropisomers are conformational stereoisomers which occur when rotation about a single bond in the molécule is prevented, or greatly slowed, as a resuit of steric interactions with other parts of the molécule and the substituents at both ends of the single bond are unsymmetrical. The interconversion of atropisomers is slow enough to allow séparation 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.

Where a compound of the invention contains an alkenyl or alkenylene group, géométrie cisltrans (or Z/E) isomers are possible. Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.

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

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

Chiral compounds of the¹ invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1% _ diethylamihe. Concentration of the eluaté affords the enriched mixture.

Stereoisomeric conglomérâtes may be separated by conventional techniques 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 may be described in terms of .. enantiomeric excess (ee), which indicates the degree to which a sample contains one enantiomer in greater amounts than the other. A racemic mixture has an ee of 0%, while a single completely pure enantiomer has an ee of 100%. Similarly, diastereomeric purity may be described in terms of diasteriomeric excess (de).

The présent invention also includes isotopically-Iabeled compounds, which are identical to those recited in one of the formulae provided, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.

Isotopically-Iabeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-Iabeled reagent in place of the non-labeled reagent otherwise employed.

Examples of isotopes that may be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as, but not limited to, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³²P, ³⁵S, ¹⁸F and ³⁶CI. Certain isotopically-Iabeled compounds of the invention, for example those into which radioactive isotopes such as ³H and ¹⁴C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes are particularly preferred for their ease of préparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., ²H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically-Iabeled compounds of the invention may generally be prepared by carrying out th^ procedures disclosed in the Schemes and/or in the | Examples and Préparations below, by substituting an isotopically-Iabeled reagent for a non-isotopically-labeled reagent.

Compounds of the invention intended for pharmaceutical use may be administered as i crystalline or amorphous products, or mixtures thereof. They may be obtained, for example, as i solid plugs, powders, or films by methods such as précipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used. Therapeutic Methods and Uses . __________ . .. _ .

_— 98

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

In one aspect, the invention provides a method for the treatment of abnormal cell growth 5 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable sait thereof.

In another aspect, the invention provides a method for the treatment of abnormal cell growth in a subject in need thereof, comprising administering to the subject an amount of a compound of the invention, or a pharmaceutically acceptable sait thereof, in combination with an 10 amount of an additional therapeutic agent (e.g., an anticancer therapeutic agent), which amounts are together effective in treating said abnormal cell growth.

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

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

In another aspect, the invention provides a pharmaceutical composition for use in the treatment of abnormal cell growth in a subject in need thereof, which pharmaceutical composition comprises a compound of the invention, or a pharmaceutically acceptable sait thereof, and a 20 pharmaceutically acceptable carrier or excipient.

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

In yet another aspect, the invention provides the use of a compound of the invention, or a 25 pharmaceutically acceptable sait thereof, for the manufacture of a médicament for the treatment of abnormal cell growth in a subject. . . | In frequent embodiments of the methods provided herein, the abnormal cell growth is cancer. Compounds of the invention may be administered as single agents or may be administered in combination with other anti-cancer therapeutic agents, in particular with standard of care agents 30 appropriate for the particular cancer. ί

I In some embodiments, the methods provided resuit in one or more of the following effects:

(1) inhibiting cancer cell prolifération; (2) inhibiting cancer cell invasiveness; (3) inducing apoptosis of cancer cells; (4) inhibiting cancer cell metastasis; or (5) inhibiting angiogenesis.

In another aspect, the invention provides a method for the treatment of a disorder mediated 35 by CDK4 in a subject, comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable sait thereof, in an amount that is effective for treating said disorder, in particular cancer.

In preferred aspects and embodiments of the compounds, compositions, methods and uses described herein, the compounds of the invention are sélective for CDK4 over CDK6. In frequent embodiments, the binding affinity for CDK6 is at least 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 40-fold, 50-fold, 60-fold, 75-fold, 100-fold, or greater than 100-fold largerthan the binding affinity for CDK4.

In view of the potentiel rôle of CDK6 in hématologie toxicities, such as neutropenia or leukopenia, a CDK4 sélective inhibitor may provide an improved safety profile, improved dosing schedule (e.g., by decreasing the need for dose réduction or dosing holidays), and/or enhanced overall efficàcy, due to the potential of higher dosing, use of a continuous dosing regimen, and/or extended time of overall treatment as compared to current dual CDK4/6 inhibitors. Animal models to assess neutropenia are described in the art. For example, see Fine et al. A Spécifie Stimulator of Granulocyte Colony-Stimulating Factor Accélérâtes Recover from Cyclophophamide-lnduced Neutropenia in the Mouse (1997) Blood, 90(2):795-802; Hu et al., Mechanistic Investigation of Bone Marrow Suppression Associated with Palbociclib and its Différentiation from Cytotoxic Chemotherapies (2016), Clin. Cancer Res. 22(8):2000-2008.

It may also be préférable to obtain selectivity for CDK4 over other CDKs, such as CDK1, CDK2 or CDK9.

Compounds ofthe invention include compounds of any ofthe formulae described herein, or pharmaceutically acceptable salts thereof.

In another aspect, the invention provides a method of inhibiting cancer cell prolifération in a subject, comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable sait thereof, in an amount effective to inhibit cell prolifération.

In another aspect, the invention provides a method of inhibiting cancer cell invasiveness in a subject, comprising administering to ihe subject a compound of the invention, or a phaifmaceutically acceptable sait thereof, in an amount effective to inhibit cell invasiveness.

In another aspect, the invention provides a method of inducing apoptosis in cancer cells in a subject, comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable sait thereof, in an amount effective to induce apoptosis.

I In another aspect, the invention provides a method of inhibiting cancer cell metastasis in a subject, comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable sait thereof, in an amount effective to inhibit cell metastasis......

In another aspect, the invention provides a method of inhibiting angiogenesis in a subject,. comprising administéring to the subject a compoünd of the invention, or a pharmaceutically acceptable sait thereof, in an amount effective to inhibit angiogenesis.

— 100

In frequent embodiments of the methods provided herein, the abnormal cell growth is cancer. In some such embodiments, the cancer is selected from the group consisting of breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer (including NSCLC, SCLC, squamous cell carcinoma or adenocarcinoma), esophageal cancer, head and 5 neck cancer, colorectal cancer, kidney cancer (including RCC), liver cancer (including HCC), pancreatic cancer, stomach (i.e., gastric) cancer 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 stomach cancer.

In other embodiments, the cancer is breast cancer, including, e.g., ER-positive/HR-positive,

HER2-negative breast cancer; ER-positive/HR-positive, HER2-positive breast cancer; triple négative breast cancer (TNBC); or inflammatory breast cancer. In some embodiments, the breast cancer is endocrine résistant breast cancer, trastuzumab or pertuzumab résistant breast cancer, or breast cancer demonstrating primary or acquired résistance to CDK4/CDK6 inhibition. In some 15 embodiments, the breast cancer is advanced or metastatic breast cancer.

In some embodiments, the compound of the invention is administered as first line therapy. In other embodiments, the compound of the invention is administered as second (or later) line therapy. In some embodiments, the compound ofthe invention is administered as second (or later) line therapy following treatment with an endocrine therapeutic agent and/or a CDK4/CDK6 inhibitor.

In some embodiments, the compound of the invention is administered as second (or later) line therapy following treatment with an endocrine therapeutic agent, e.g., an aromatase inhibitor, a SERM or a SERD. In some embodiments, the compound ofthe invention is administered as second (or later) line therapy following treatment with a CDK4/CDK6 inhibitor. In some embodiments, the compound of the invention is administered as second (or later) line therapy following treatment with one or more chemotherapy regimens, e.g., including taxanes or platinum agents. In some embodiments, the compound of the invention is administered as second (or later) line therapy following treatment with HER2 targeted agents, e.g., trastuzumab. |

As used herein, an “effective dosage or “effective amount” of drug, compound or pharmaceutical composition is an amount sufficient to affect any one or more bénéficiai or 30 desired, including biochemical, histological and / or behavioral symptoms, of the disease, its complications and intermediate pathological phenotypes presenting¹ during development of the disease. For therapeutic use, a “therapeutically effective amount” refers to that amount of a compound being administered which will relieve to some extent one or more ofthe symptoms of the disorder being treated. In reference.to the treatment of cancer, a therapeutically effective 35 amount refers to that amount which has the effect of (1) reducing the size of the tumor, (2) inhibiting (that is, slowing to some extent, preferably stopping) tumor metastasis, (3) inhibiting to

101 some extent (that is, slowing to some extent, preferably stopping) tumor growth or tumor invasiveness, (4) relieving to some extent (or, preferably, eliminating) one or more signs or symptoms associated with the cancer, (5) decreasing the dose of other médications required to treat the disease, and/or (6) enhancing the effect of another médication, and/or (7) delaying the progression of the disease in a patient.

An effective dosage can be administered in one or more administrations. For the purposes of this invention, an effective dosage of drug, compound, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly. As is understood in the clinical context, an effective dosage of drug, 10 compound or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound or pharmaceutical composition.

“Tumor” as it applies to a subject diagnosed with, or suspected of having, a cancer refers to a malignant or potentially malignant neoplasm or tissue mass of any size and includes primary tumors and secondary neoplasms. A solid tumor is an abnormal growth or mass of tissue that 15 usually does not contain cysts or liquid areas. Examples of solid tumors are sarcomas, carcinomas, and lymphomas. Leukaemia’s (cancers of the blood) generally do not form solid tumors (National Cancer Institute, Dictionary of Cancer Terms).

“Tumor burden” or “tumor load’, refers to the total amount of tumorous material distributed throughout the body. Tumor burden refers to the total number of cancer cells or the total size of 20 tumor(s), throughout the body, including lymph nodes and bone marrow. Tumor burden can be determined by a variety of methods known in the art, such as, e.g., using callipers, or while in the body using imaging techniques, e.g., ultrasound, bone scan, computed tomography (CT), or magnetic résonance imaging (MRI) scans.

The term “tumor size” refers to the total size of the tumor which can be measured as the 25 length and width of a tumor. Tumor size may be determined by a variety of methods known in the art, such as, e.g., by measuring the dimensions of tumor(s) upon removal from the subject, e.g., using callipers, c|r while in the body using imaging techniques, e.g., bon^ scan, ultrasound, CR or MRI scans. ---- ~ ~

As used herein, subject refers to a human or animal subject. In certain preferred 30 embodiments, the subject is a human.

The term “treat” or “treating” a cancer as used herein means to administer a compound of the présent invention to a subject having cancer, or diagnosed with cancer, to achieve at least one positive therapeutic effect, such as, for example, reduced number of cancer cells, reduced tumor size, reduced rate of cancer cell infiltration into peripheral organs, or reduced rate of tumor . 35 métastasés or tumôr growth, réversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or

102 condition. The term treatment, as used herein, unless otherwise indicated, refers to the act of treating as treating is defined immediately above. The term “treating also includes adjuvant and neo-adjuvant treatment of a subject.

For the purposes of this invention, bénéficiai or desired clinical results include, but are hot limited to, one or more ofthe following: reducing the prolifération of (or destroying) neoplastic or cancerous cell; inhibiting metastasis or neoplastic cells; shrinking or decreasing the size of a tumor; remission of the cancer; decreasing symptoms resulting from the cancer; increasing the quality of life of those suffering from the cancer; decreasing the dose of other médications required to treat the cancer; delaying the progression of the cancer; curing the cancer; overcôming one or more résistance mechanisms of the cancer; and/or prolonging survival of patients the cancer. Positive therapeutic effects in cancer can be measured in several ways (see, for example, W. A. Weber, Assessing tumor response to therapy, J. Nucl. Med. 50 Suppl. 1:1S10S (2009). For example, with respect to tumor growth inhibition (T/C), according to the National Cancer Institute (NCI) standards, a T/C less than or equal to 42% is the minimum level of antitumor activity. A T/C <10% is considered a high anti-tumor activity level, with T/C (%) = médian tumor volume of the treated / médian tumor volume of the control x 100.

In some embodiments, the treatment achieved by a compound of the invention is defined by reference to any of the following: partial response (PR), complété response (CR), overall response (OR), progression free survival (PFS), disease free survival (DFS) and overall survival (OS). PFS, also referred to as “Time to Tumor Progression” indicates the length of time during and after treatment that the cancer does not grow and includes the amount of time patients hâve experienced a CR or PR, as well as the amount of time patients hâve experienced stable disease (SD). DFS refers to the length of time during and after treatment that the patient remains free of disease. OS refers to a prolongation in life expectancy as compared to naïve or untreated subjects or patients. In some embodiments, response to a combination ofthe invention is any of PR, CR, PFS, DFS, OR or OS that is assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 respons^ criteria. |

The treatment regimen for a compound ofthe invention that is effective to treat a cancer patient may vary according to factors such as the disease state, âge, and weight of the patient, and the ability of the therapy to elicit an anti-cancer response in the subject. iWhile an embodiment of any of the aspects of the invention may not be effective in achieving la positive therapeutic effect in every subject, it should do so in a statistically significant number of subjects as determined by any statistical test known in the art such as the Student’s t-test, the chi2-test the U-test according to Mann and Whitney, the Kruskal-Wallis test (H-test), Jonckheere-Terpstrattesty and the Wilcon bn-test. .

103

The terms “treatment regimen”, “dosing protocol” and “dosing regimen” are used interchangeably to refer to the dose and timing of administration of each compound of the invention, alone or in combination with another therapeutic agent.

“Ameliorating” means a lessening or improvement of one or more symptoms upon. treatment with a combination described herein, as compared to not administering the combination. “Ameliorating” also includes shortening or réduction in duration of a symptom.

“Abnormal cell growth”, as used herein, unless otherwise indicated, refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). Abnormal cell growth may be benign (not cancerous), or malignant (cancerous).

Abnormal cell growth includes the abnormal growth of: (1)tumor cells (tumors) that show increased expression of CDK4 and/or CDK6; (2) tumors that proliferate by aberrant CDK4 and/or CDK6 activation; and (3) tumors that are résistant to endocrine therapy, CDK4/6 inhibition, or HER2 antagonists.

The term “additional anticancer therapeutic agent” as used herein means any one or more therapeutic agent, other than a compound of the invention, that is or can be used in the treatment of cancer. In some embodiments, such additional anticancer therapeutic agents include compounds derived from the following classes: mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, anti-angiogenesis agents, topoisomerase I and II inhibitors, plant alkaloids, hormonal agents and antagonists, growth factor inhibitors, radiation, signal transduction inhibitors, such as inhibitors of protein tyrosine kinases and/or serine/threonine kinases, cell cycle inhibitors, biological response modifiers, enzyme inhibitors, antisense oligonucleotides or oligonucleotide dérivatives, cytotoxics, immuno-oncology agents, and the like.

In some embodiments, the additional anticancer agent is an endocrine agent, such as an aromatase inhibitor, a SERD or a SERM. In some such embodiments, a compound of the invention may be administered in combination with a standard of care agent, such as tamoxifen, exemestane, letrozole, fulvestrant, or anastrozole.

In other embodiments, a compound of the invention may be administered in combinatio|i 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-angiogenesis agent, including for example VEGF inhibitors¹, VEGFR inhibitors, TIE-2 inhibitors, PDGFR inhibitors, angiopoetin inhibitors, ΡΚΟβ inhibitors, COX-2 (cyclooxygenase II) inhibitors, integrins (alphav/beta-3), MMP-2 (matrix-metalloproteinase 2) inhibitors, and MMP-9 (matrix-metalloproteinase 9) inhibitors. Preferred anti-angiogenesis agents include sunitinib (Sutent™), bevacizumab (Avastin™), axitinib (AG 13736), SU 14813 (Pfizer), and AG 13958 (Pfizer). Additional antiangiogenesis agents include vatalanib (CGP 79787), Sorafenib (Nexavar™), pegaptanib _ 104 octasodium (Macugen™), vandetanib (Zactima™), PF-0337210 (Pfizer), SU 14843 (Pfizer), AZD 2171 (AstraZeneca), ranibizumab (Lucentis™), Neovastat™ (AE 941), tetrathiomolybdata (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-angiogenesis agents 5 include enzastaurin (LY 317615), midostaurin (CGP 41251), perifosine (KRX 0401), teprenone (Selbex™) and UCN 01 (Kyowa Hakko). Other examples of anti-angiogenesis agents include celecoxib (Celebrex™), parecoxib (Dynastat™), deracoxib (SC 59046), lumiracoxib (Preige™), valdecoxib (Bextra™), rofecoxib (Vioxx™), iguratimod (Careram™), IP 751 (Invedus), SC-58125 (Pharmacia) and etoricoxib (Arcoxia™). Yet further anti-angiogenesis agents include exisulind . 10 (Aptosyn™), salsalate (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™). Yet further antiangiogenesis agents include ABT 510 (Abbott), apratastat (TMI 005), AZD 8955 (AstraZeneca), 15 incyclinide (Metastat™), and PCK 3145 (Procyon). Yet further anti-angiogenesis agents include acitretin (Neotigason™), plitidepsin (aplidine™), cilengtide (EMD 121974), combretastatin A4 (CA4P), fenretinide (4HPR), halofuginone (Tempostatin™), Panzem™ (2-methoxyestradiol), PF-03446962 (Pfizer), rebimastat (BMS 275291), catumaxomab (Removab™), lenalidomide (Revlimid™), squalamine (EVIZON™), thalidomide (Thalomid™), Ukrain™ (NSC 631570), 20 Vitaxin™ (MEDI 522), and zoledronic acid (Zometa™).

In other embodiments, the additional anti-cancer agent is a signal transduction inhibitor (e.g., inhibiting the means by which regulatory molécules that govern the fondamental processes of cell growth, différentiation, and survival communicated within the cell). Signal transduction inhibitors include small molécules, antibodies, and antisense molécules. Signal transduction 25 inhibitors include for example kinase inhibitors (e.g., tyrosine kinase inhibitors or serine/threonine kinase inhibitors) and cell cycle inhibitors. More specifically signal transduction inhibitors include, | for example, farnesyl protein transferase inhibiteurs, EGF inhibitor, ErbB-1 (EGFR), ErbB-2, pan erb, IGF1R inhibitors, MEK, c-Kit inhibitors, FLT-3 inhibitors, K-Ras inhibitors, PI3 kinase inhibitors, JAK inhibitors, STAT inhibitors, Raf kinase inhibitors, Akt inhibitors, mTOR inhibitor, 130 P70S6 kinase inhibitors, inhibitors of the WNT pathway and multi-targeted kinase inhibitors.

i Additional examples of anti-cancer agents which may be used in conjunction with a compound of the invention and pharmaceutical compositions described herein include palbociclib (Ibrance®), ribociclib (Kisqali®), abemaciclib (Verzenio®), BMS 214662 (Bristol-Myers Squibb), lonafamib (Sarasar™), pelitrexol (AG 2037), matuzumab (EMD 7200), nimotuzumab (TheraCIM 35 h-R3™), panitumumab (Vectibix™), Vandetanib (Zactima™), pazopanib (SB 786034), ALT 110 (Alteris Therapeutics), BIBW 2992 (Boehringer lngelheim),and Cervene™ (TP 38). Other

105 examples include gefitinib (Iressa®), cetuximab (Erbitux®), erlotinib (Tarceva®), trastuzumab (Herceptin®), ado-trastuzumab emtansine (Kadcyla®), pertuzumab (Perjeta®), osimertinib (Tagrisso®), atezolizumab (Tecentriq™), sunitinib (Sutent®), ibrutinib (Imbruvica®), imatinib (Gleevec®), crizotinib (Xalkor®), lorlatinib (Lorbrena®), dacomitinib (Vizimpro®), bosutinib i (Bosulif®), glasdegib (Daurismo™), canertinib (Cl 1033), lapatinib (Tycerb™), pelitinib (EKB 569), miltefosine (Miltefosin™), BMS 599626 (Bristol-Myers Squibb), Lapuleucel-T (Neuvenge™), NeuVax™ (E75 cancer vaccine), Osidem™ (IDM 1), mubritinib (TAK-165), CP-724,714 (Pfizer), panitumumab (Vectibix™), ARRY 142886 (Array Biopharm), everolimus (Certican™), zotarolimus (Endeavor™), 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), or PD-1 or PD-L1 antagonists, e.g., pembrolizumab (Keytruda®), nivolumab (Opdivo™), or avelumab (Bavencio®). abraxane,

In other embodiments, the additional anti-cancer agent is a so-called classical antineoplastic agent. Classical antineoplastic agents include but are not limited to hormonal modulators such as hormonal, anti-hormonal, androgen agonist, androgen antagonist and antiestrogen therapeutic agents, histone deacetylase (HDAC) inhibitors, DNA methyltransferase inhibitors, silencing agents or gene activating agents, ribonucleases, proteosomics, Topoisomerase I inhibitors, Camptothecin dérivatives, Topoisomerase II inhibitors, alkylating agents, antimetabolites, poly(ADP-ribose) polymerase-1 (PARP-1) inhibitor (such as, e.g., talazoparib (Talzenna®), olaparib, rucaparib, niraparib, iniparib, veliparib), microtubulin inhibitors, antibiotics, plant derived spindle inhibitors, platinum-coordinated compounds, gene therapeutic agents, antisense oligonucleotides, vascular targeting agents (VTAs), and statins. Examples of classical antineoplastic agents used in combination therapy with a compound of the invention,optionally with one or more other agents include, but are|not limited to, glucocorticoids, such as dexamethasone, prednisone, prednisolone, méthylprednisolone, hydrocortisone, and progestins such as medroxyprogesterone, megestrol acetate (Megace), mifepristone (RU-486), Sélective Estrogen Receptor Modulators (SERMs; such as! tamoxifen, raloxifene, lasofoxifene, afimoxifene, arzoxifene, bazedoxifene, fispemifene, ormeloxifene, ospemifene, tesmilifene, toremifene, trilostane and CHF 4227 (Cheisi), Sélective Estrogen-Receptor Downregulators (SERD’s; such as fulvestrant), exemestane (Aromasin), anastrozole (Arimidex), atamestane, fadrozole, letrozole (Femara),. formestane; gonadotropin-releasing hormone (GnRH; also commonly referred to as luteinizing hormone-releasing hormone [LHRH]) agonists such as buserelin (Suprefact), goserelin (Zoladex), leuprorelin (Lupron), and triptorelin (Trelstar), abarelix

106 (Plenaxis), cyproterone, flutamide (Eulexin), megestrol, nilutamide (Nilandron), and osaterone, dutasteride, epristeride, finasteride, Serenoa repens, PHL 00801, abarelix, goserelin, leuprorelin, triptorelin, bicalutamide; antiandrogen agents, such as enzalutamide (Xtandi®), abiraterone acetate, bicalutamide (Casodex); and combinations thereof. Other examples of classical antineoplastic agents used in combination with a compound of the invention include but are not limited to PARP inhibitors, such as talazoparib, olapariv, rucaparib, niraparib, iniparib, veiiparib; suberolanilide hydroxamic acid (SAHA, Merck Inc./Aton Pharmaceuticals), depsipeptide (FR901228 or FK228), G2M-777, MS-275, pivaloyioxymethyl butyrate and PXD-101; Onconase (ranpirnase),PS-341 (MLN-341), Velcade (bortezomib), 9-aminocamptothecin, belotecan, BN10 80915 (Roche), camptothecin, difiomotecan, edotecarin, exatecan (Daiichi), gimatecan, 10hydroxycamptothecin, irinotecan HCl (Camptosar), lurtotecan, Orathecin (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, hydroxycarbamide, nemorubicin, novantrone (mitoxantrone), pirarubicin, pixantrone, procarbazine, rebeccamycin, sobuzoxane, tafluposide, valrubicin, Zinecard (dexrazoxane), nitrogen mustard N-oxide, cyclophosphamide, AMD-473, altretamine, AP-5280, apaziquone, brostallicin, bendamustine, busuifan, carboquone, carmustine, chlorambucil, dacarbazine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine, mafosfamide, mechlorethamine, melphalan, mitobronitol, mitolactol, mitomycin C, mitoxatrone, nimustine, ranimüstine, temozolomide, thiotepa, and platinum-coordinated alkylating compounds such as cisplatin, carboplatin, eptaplatin, lobaplatin, nedaplatin, oxaliplatin, streptozocin, satrplatin, and combinations thereof.

In still other embodiments, the additional anti-cancer agent is a so called dihydrofolate reductase inhibitors (such as methotrexate and NeuTrexin (trimetresate glucuronate)), purine antagonists (such as 6-mercaptopurine riboside, mercaptopurine, 6-thioguanine, cladribine, clofarabin^ (Clolar), fludarabine, nelarabine, and raltitrexed), pyrirfiidine antagonists (such as 5fluorouracil (5-FU), Alimta (premetrexed disodium, LY231514, MTA), capecitabine (Xeloda™), cytosine arabinoside, Gemzar™ (gemcitabine, Eli Lilly), Tegafur (UFT Orzel or Uforal and including TS-1 combination of tegafur, gimestat and otostat), doxifluridine, carmofur, cytarabine (including bcfosfate, phosphate stéarate, sustained release and liposomal forms), enocitabine, 5azacitidine (Vidaza), decitabine, and ethynylcytidine) and other antimetabolites such as eflornithine, hydroxyurea, leucovorin, nolatrexed (Thymitaq), triapine, trimetrexate, N-(5-[N-(3,4dihydro-2-methyl-4-oxoquinazoiin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamic acid, AG35 014699 (Pfizer Inc.), ABT-472 (Abbott Laboratories), INO-1001 (Inotek Pharmacèuticals), KU0687 (KuDOS Pharmaceuticals) and GP118180 (Guiiford Pharm Inc) and combinations thereof.

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Other exemples of classical antineoplastic cytotoxic agents include, but are not limited to,

Abraxane (Abraxis BioScience, Inc.), Batabulin (Amgen),EPO 906 (Novartis), Vinflunine (BristolMyers Squibb Company), actinomycih D, bleomycin, mitomycin C, nèocarzinostatin (Zinostatin), Vinblastine, vincristine, vindesine, vinorelbine (Navelbine), docetaxel (Taxotere), Ortataxel, paclitaxel (including Taxoprexin a DHA/paciltaxel conjugate), cisplatin, carboplatin, Nedaplatin, oxaliplatin (Eloxatin), Satraplatin, Camptosar, capecitabine (Xeloda), oxaliplatin (Eloxatin), Taxotere alitretinoin, Canfosfamide (Telcyta™), DMXAA (Antisoma), ibandronic acid, Lasparaginase, pegaspargase (Oncaspar™), Efaproxiral (Efaproxyn™ - radiation therapy), bexarotene (Targretin™), Tesmilifene (DPPE - enhances efficacy of cytotoxics), Theratope™ (Biomira), Tretinoin (Vesanoid™), tirapazamine (Trizaone™), motexafin gadolinium (Xcytrin™) Cotara™ (mAb), and NBI-3001 (Protox Therapeutics), polyglutamate-paclitaxel (Xyotax™) and combinations thereof. Further examples of classical antineoplastic agents include, but are not limited to, as Advexin (ING 201), TNFerade (GeneVec, a compound which express TNFalpha in response to radiotherapy), RB94 (Baylor College of Medicine), Genasense (Oblimersen, Genta), Combretastatin A4P (CA4P), Oxi-4503, AVE-8062, ZD-6126, TZT-1027, Atorvastatin (Lipitor, Pfizer Inc.), Provastatin (Pravachol, Bristol-Myers Squibb), Lovastatin (Mévacor, Merck Inc.), Simvastatin (Zocor, Merck Inc.), Fluvastatin (Lescol, Novartis), Cerivastatin (Baycol, Bayer), Rosuvastatin (Crestor, AstraZeneca), Lovostatin, Niacin (Advicor, Kos Pharmaceuticals), Caduet, Lipitor, torcetrapib, and combinations thereof.

In some embodiments, the additional anti-cancer agent is an epigenetic modulator, for example an inhibitor or EZH2, SMARCA4, PBRM1, ARID1A, ARID2, ARID1B, DNMT3A, TET2, MLL1/2/3, NSD1/2, SETD2, BRD4, DOT1L, HKMTsanti, PRMT1-9, LSD1, UTX, IDH1/2 or BCL6.

In further embodiments, the additional anti-cancer agent is an immunomodulatory agent, such as an inhibitor of CTLA-4, PD-1 or PD-L1 (e.g., pembrolizumab, nivolumab or avelumab), LAG-3, TIM-3, TIGIT, 4-1BB, OX40, GITR, CD40, or a CAR-T-cell therapy.

As used herein “cancer refers to any malignant and/or invasive growth or tumor caused by abnormal cell growth. Cancer includes solid tumors named for the type o[f cells that form them, cancer of blood, bone marrow, or the lymphatic system. Examples of solid tumors include sarcomas and carcinomas. Cancers of the blood include, but are not limited to, leukemia, lymphoma and myeloma. Cancer also includes primary cancer that originates at a spécifie site in the body, a meta'static cancer that has spread from the place in which it Istarted to other parts ofthe body, a récurrence from the original primary cancer after remission, and a second primary cancer that is a new primary cancer in a person with a history of previous cancer of a different type from the latter one. . . ...... _____________

Iri some èmbodiments ofthe methods provided herein, the cancer is selected from the group consisting of breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate _ 108 cancer, lung cancer (including NSCLC), esophageal cancer, head and neck cancer, liver cancer, pancreatic cancer and stomach cancer.

Dosage Forms and Regimens

Administration of the compounds of the invention may be affected by any method that 5 enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parentéral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical, and rectal administration.

Dosage regimens may be adjusted to provide the optimum desired response. For example, a single bolus may be administered, several divided doses may be administered over 10 time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parentéral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form, as used herein, refers to physically discrète units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The spécification for the dosage unit forms of the invention are dictated by and directly dépendent on (a) the unique characteristics of the chemotherapeutic agent and the particular therapeutic or prophylactic effect to be achieved, and (b) the limitations inhérent in the art of compounding such an active compound for the treatment of sensitivity in individuals.

Thus, the skilled artisan would appreciate, based upon the disclosure provided herein, that the dose and dosing regimen is adjusted in accordance with methods well-known in the therapeutic arts. That is, the maximum tolerable dose can be readily established, and the effective amount providing a détectable therapeutic benefit to a patient may also be determined, as can the temporal requirements for administering each agent to provide a détectable therapeutic benefit to the patient. Accordingly, while certain dose and administration regimens are exemplified herein, these examples in no way limit the dose and administration regimen that may be provided to a patienj in practicing the présent invention. |

It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated and may include single or multiple doses. It is to be further understood that for 30 any particular subject, spécifie dosage regimens should be adjusted over time according to the individual need and the prdfessional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice ofthe claimed composition. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamie parameters, which may include ....

clinical effects such as toxic effects and/or laboratory values. Thus, the présent invention encompasses intra-patient dose-escalation as determined by the skilled artisan. Determining

109 appropriate dosages and regimens for administration of the chemotherapeutic agent are well-known in the relevant art and would be understood to be encompassed by the skilled artisan once provided the teachings disclosed herein.

The amount of the compound ofthe invention administered will be dépendent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discrétion of the prescribing physician. However, an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to about 7 g/day, preferably about 0.1 to about 2.5 g/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adéquate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.

Formulations and Routes of Administration

As used herein, a pharmaceutically acceptable carrier refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties ofthe administered compound.

The pharmaceutical acceptable carrier may comprise any conventional pharmaceutical carrier or excipient. The choice of carrier and/or excipient will to a large extent dépend on factors such as the particular mode of administration, the effect of the carrier or excipient on solubility and stability, and the nature of the dosage form.

Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents (such as hydrates and solvatés). The pharmaceutical compositions may, if desired, contain additional ingrédients such as flavorings, binders, excipients and the like. Thus for oral administration, tablets containing various excipients, such as citric acid may be employed together with various disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia. Examples, without limitation^ of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch,cellulose dérivatives, gelatin, vegetable oils and polyethylene glycols. Additionally, lubricating agents such as magnésium stéarate, sodium lauryl sulfate and talc are often useful for tableting purposes. Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules. Non-limiting examples of materials, therefore, include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or élixirs are desired for oral administration the active compound therein may be combined with.various sweetening or flavoring agents, coloririg matters or dyes and, if desired, emulsifying agents or suspending — 110 agents, together with diluents such as water, éthanol, propylene glycol, glycerin, or combinations thereof. The pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution 5 suspension, for parentéral injection as a stérile solution, suspension or émulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.

Exemplary parentéral administration forms include solutions or suspensions of active compounds in stérile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms may be suitably buffered, if desired. .

The pharmaceutical composition may be in unit dosage forms suitable for single administration of précisé dosages.

Pharmaceutical compositions suitable for the delivery of compounds of the invention and methods for their préparation will be readily apparent to those skilled in the art. Such compositions and methods for their préparation can be found, for example, in ‘Remington’s Pharmaceutical 15 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 involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from 20 the mouth.

Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films (including muco-adhesive), ovules, sprays and liquid formulations.

Liquid formulations include suspensions, solutions, syrups and élixirs. Such formulations may be used as fillers in soft or hard capsules and typically include a carrier, for example, water, | éthanol, polyethylene glycol, propylene glycolj methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.

! 30 The compounds ofthe invention mayialso be used in fast-dissolving, fast-disintegrating

I dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986 by Liang and Chen (2001), the disclosure of which is incorporated herein by reference in its entirety. '

For tablet dosage forms, depending on dose, the drug may make up from 1 wt% to 80 wt% of the dosage form, more typically from 5 wt% to 60 wt% of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples ôf disintegrants include sodium

111 starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium alginate. Generally, the disintegrant.will comprise from 1 wt% to 25 wt%, preferably from . 5 wt% to 20 wt% of the dosage form.

Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. 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 surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as Silicon dioxide and talc. When present, surface active agents are typically in amounts of from 0.2 wt% to 5 wt% of the tablet, and glidants typically from 0.2 wt% to 1 wt% of the tablet.

Tablets also generally contain lubricants such as magnésium stéarate, calcium stéarate, zinc stéarate, sodium stearyl fumarate, and mixtures of magnésium stéarate with sodium lauryl sulphate. Lubricants generally are present in amounts from 0.25 wt% to 10 wt%, preferably from 0.5 wt% to 3 wt% of the tablet.

Other conventional ingrédients include anti-oxidants, colorants, flavoring agents, preservatives and taste-masking agents.

Exemplary 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 may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded | before tableting. The final formulation may include orje or more layers and may be coated or uncoated; or encapsulated.

The formulation of tablets is discussed in detail in “Pharmaceutical Dosage Forms:

i Tablets, Vol. Γ, by H. Lieberman and L. Lachman, [Marcel Dekker, N.Y., N.Y., 1980 (ISBN I 0-8247-6918-X), the disclosure of which is incorporatecl herein by reference in its entirety.

Solid formulations for oral administration may be formuiated to be immédiate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. ... . . . . .

Suitable modified release formulations are described in U.S. Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and _ ¹¹² 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 disclosures of these référencés are incorporated herein by reference in their entireties.

The compounds of the invention may also be administered directly into the blood stream, 5 into muscle, or into an internai organ. Suitable means for parentéral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parentéral administration include needle (including micro needle) injectors, needle-free injectors and infusion techniques.

Parentéral formulations are typically aqueous solutions which may contain excipients 10 such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a stérile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as stérile, pyrogen-free water.

The préparation of parentéral formulations under stérile conditions, for example, by lyophilization, may readily be accomplished using standard pharmaceutical techniques well 15 known to those skilled in the art.

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

Formulations for parentéral administration may be formulated to be immédiate and/or 20 modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Thus, compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and PGLA microspheres.

The compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, [solutions, creams, ointments, dusting powders, dressi|igs, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, minerai oil, liquid petrolatum, white petrolatum, glycerin, 30 polyethylene glycol and propylene glycol. Pénétration enhancers may be incorporated; see, for examplè, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999). Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and micro needle or needle-free (e.g. Powderject™, Bioject™, etc.) injection. The disclosures of these référencés are incorporated herein by reference in their entireties. 19876

113

Formulations for topical administration may be formulated to be immédiate 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, 5 typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed eomponent particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aérosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as

1,1,1,2-tetrafluoroethane or 1,1,1.,2,3,3,3-heptafluoropropane. For intranasal use, the powder may include a bioadhesive agent, for example, chitosan or cyclodextrin.

The pressurized container, pump, spray, atomizer, or nebulizer contains a solution or suspension of the compound(s) of the invention comprising, for example, éthanol, aqueous éthanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the 15 active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.

Prior to use in a dry powder or suspension formulation, the drug product is micronized to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical 20 fluid processing 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 mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as l-leucine, mannitol, or magnésium stearate. The lactose may be anhydrous or in the form of the 25 monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

A suitabl^ solution formulation for use in an atomizer using electrohydrodynamics to produce a fine mist may contain from 1 pg to 20mg of the compound of the invention per actuation and the actuation volume may vary from 1 pL to 100pL. Atypical formulation includes a compound 30 of the invention, propylene glycol, stérile water, éthanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyéthylène glycol.

Suitable flavors, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration. ...... . ..

Formulations for inhaled/intranasal administration may be formulated to be immédiate and/or modified release using, for example, poly(DL-lactic-coglycolic acid (PGLA). Modified ¹¹⁴ release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. . ... ..........

In the casé of dry powder inhalers and aérosols, the dosage unit is determined by means of a valve which delivers a metered amount. Units in accordance with the invention are typically 5 arranged to administer a metered dose or “puff” containing a desired mount of the compound of the invention. The overall daily dose may be administered in a single dose or, more usually, as divided doses throughout the day.

Compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but 10 various alternatives may be used as appropriate. ------Formulations for rectal/vaginal administration may be formulated to be immédiate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

Compounds ofthe invention may also be administered directlyto the eye or ear, typically 15 in the form of drops of a micronized suspension or solution in isotonie, pH-adjusted, stérile saline.

Other formulations suitable for ocular and aurai administration include ointments, biodégradable (e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular Systems, such as niosomes or liposomes. A polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for 20 example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.

Formulations for ocular/aural administration may be formulated to be immédiate and/or 25 modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, or programmed release. . .

Other Technologies | |

Compounds ofthe invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable dérivatives thereof or polyethylene glycol-containing polymers, in 30 order to improve their solubility, dissolution rate, taste-masking, bioavaiiability and/or stability for use in any of the aforemehtioned modes of administration. I

Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, the cyclodextrin may be used as an 35 auxiliaryâdditive, i.e. as â carrier, diluent, or solubilizer. Most commonly used for these pürposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in PCT Publication

115

Nos. WO 91/11172, WO 94/02518 and WO 98/55148, the disclosures of which are incorporated herein by reference in their entireties.

The amount of the active compound administered will be dépendent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the 5 compound and the discrétion ofthe prescribing physician. However, an effective dosage is typically in the range of about 0.001 to about 100 mg per kg body weight per day, and frequently about 0.01 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.07 mg/day to about 7000 mg/day, more commonly, 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, 10 300, 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 to 600 mg/day, from about 20 mg/day to about 15 to 300 mg/day, from about 20 mg/day to about to 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 instances, dosage levels below the lower limit of the aforesaid range may be more than adéquate, while in other cases still larger doses may be used without causing any harmful side effect, with such larger doses typically divided into several smaller doses for administration throughout the day.

Kit-of-Parts

Inasmuch as it may désirable to administer a combination of active compounds, for example, for the purpose of treating a particular disease or condition, it is within the scope of the présent invention that two or more| pharmaceutical compositions, at least one of which contains a compound in accordance with the invention, may conveniently be combined in the form of a kit suitable for coadministration of the compositions. Thus, the kit of the invention includes two or 30 more separate pharmaceutical compositions, at least one of which contains a compound of the invention, and means for separatèly retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like. ......

The kit ofthe invention is particularly suitable for administering different dosage forms, for. 35 example, oral and parentéral, for administering the separate compositions at different dosage ¹¹⁶ intervals, or for titrating the separate compositions against one another. To assist compliance, the kit typically includes directions for administration and may be provided with a memory aid.

Combination Therapy

As used herein, the term “combination therapy” refers to the administration of a compound of the invention together with an at least one additional pharmaceutical or médicinal agent (e.g., an anti-cancer agent), either sequentially or simultaneously.

As noted above, the compounds ofthe invention may be used in combination with one or 10 more additional anti-cancer agents. The efficacy of the compounds of the invention in certain tumors may be enhanced by combination with other approved or experimental cancer thérapies, e.g., radiation, surgery, chemotherapeutic agents, targeted thérapies, agents that inhibit other signaling pathways that are dysregulated in tumors, and other immune enhancing agents, such as PD-1 or PD-L1 antagonists and the like.

When a combination therapy is used, the one or more additional anti-cancer agents may be administered sequentially or simultaneously with the compound of the invention. In one embodiment, the additional anti-cancer agent is administered to a mammal (e.g., a human) prior to administration of the compound of the invention. In another embodiment, the additional anti-cancer agent is administered to the mammal after administration of the compound of the invention. In another embodiment, the additional anti-cancer agent is administered to the mammal (e.g., a human) simultaneously with the administration ofthe compound ofthe invention.

The invention also relates to a pharmaceutical composition for the treatment of abnormal cell growth in a mammal, including a human, which comprises an amount of a compound of the invention, as defined above (including hydrates, solvatés and polymorphs of said compound or 25 pharmaceutically acceptable salts thereof), in combination with one or more (preferably one to three) additional anti-cancer therapeutic agents.

Synthetic Methods | · |

Compounds of the invention are prepared according to the exemplary procedures and Schemes provided herein, and modifications thereof known to those of skill in the art. Scheme 1 30 shows a general route for making pyrimidine compounds 6 having varying saturated heterocyclyl i or cycloalkyl moieties (comprising Q) and aiheteroaromatic ring (comprising U, V, X, Y and Z). It i will be understood that the order ofthe steps could be reversed. .....

General Scheme 1: - ~

As exemplified in Scheme 1, substituted dichloropyrimidines 1 are subjected to Suzuki coupling conditions with aryl or heteroaryl boronates 2 in the presence of a suitable catalyst (such as Pd(PPh₃)4 or Pd(PPh₃)₂CI₂) and a suitable base (such as Na₂CO₃ or K₂CO₃) in a suitable 5 solvent system (such as dioxane:water or DME:water) to afford an aryl- or heteroaryl-substituted chloropyrimidines 4. Alternatively, aryl or heteroaryl bromides 3 can be utilized in the Suzuki cross-coupling following treatment of the bromo compound with bis(pinacolato)diboron, a suitable catalyst (such as Pd(OAc)₂ or Pd(dppf)CI₂), ligand (such as PCy₃) and base (such as KOAc or NaOAc) in a suitable solvent (such as DMSO or dioxane). The resulting heterobiaryl 10 intermediates 4 are treated under nucleophilic chloride displacement conditions with a primary heterocyclylamine or cycloalkylamine 5 in the presence of a suitable base (such as DIPEA) in a suitable solvent (e.g., DMSO), to afford amino-substituted pyrimidine compounds 6. When intermediate 4 is reacted with a primary heterocyclylamine, Q in 5 and 6 represents an appropriately substituted amino group (e.g., NR¹¹), an appropriately protected amino group (e.g., 15 a carbamoyl, tetrahyrdopyranyl or trialkylsilyl protected amine) or oxygen. When intermediate 4 is reacted with a primary cycloalkylamine, Q in 5 and 6 represents an optionally substituted carbon.

Alternatively, the heterobiaryl intermediates 4 can be subjected to Buchwald-Hartwig | coupling conditions in the presence of a suitable apnine 5, a suitable catalyst (e.g., Pd₂(dba)₃, 20 chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)-palladium or Pd(OAc)₂, BINAP and a suitable base (e.g., Cs₂CO₃) in a suitable solvent (such as THF, dioxane or 2| methyl-2-butanol) to afford the compounds 6. j j It will be understood that reactive functional groups présent at any position in intermediates 1 to 5 and penultimate compounds 6 may be masked using suitable protecting 25 groups known to those of skill in the art. For examples, such compounds may contain amine or hydroxyl moieties masked with protecting groups (such as tert-butylcarbamate or tetrahydropyran) that can be removed via conditions known in art (such as TFA or HCl) in a suitable solvent. In some embodiments, Q in compound 6 may represent a protected amino group, which is removed under standard conditions to provide a free secondary amine that is

118 further we reacted with a suitabiy reactive reagent (e.g., a sulfonyi halide, acyl halide, alkyl halide or the like) to install the R¹¹ substituent.

Analogous reactions could be used to préparé the corresponding pyridine dérivatives, as exemplified in the examples herein. : . —

General Synthetic Methods:

Abbreviations:

The following abbreviations are used throughout the Examples: “Ac” means acetyl, “AcO” or “OAc” means acetoxy, “ACN” means acetonitrile, “aq” means aqueous, “atm” means atmosphere(s), “BOC”, “Boc” or “boc” means N-terf-butoxycarbonyl, “Bn” means benzyl, “Bu” means butyl, “nBu” means normal-butyl, “tBu” means terf-butyl, “DBU” means 1,8diazabicyclo[5.4.0]undec-7-ene, “Cbz” means benzyloxycarbonyl, “DCM” (CH2CI2) means methylene chloride, “de” means diastereomeric excess, “DEA” means diethylamine, “DIPEA” means diisopropyl ethyl amine, “DMA” means Λ/,/V-dimethylacetamide, “DME” means 1,2dimethoxyethane, DMF means Λ/,/V-dimethyl formamide, “DMSO means dimethyisulfoxide, “EDTA” means ethylenediaminetetraacetic acid, “ee” means enantiomeric excess, “Et” means ethyl, “EtOAc means ethyl acetate, “EtOH” means éthanol, “HOAc” or “AcOH” means acetic acid, “i-Pr” or ^oiPr” means isopropyl, “IPA” means isopropyl alcohol, “l_AH” means lithium aluminum hydride, “LHMDS means lithium hexamethyldisilazide (lithium bis(trimethylsilyl)amide), “mCPBA” means meta-chloroperoxy-benzoic acid, “Me” means methyl, “MeOH” means methanol, “MS” means mass spectrometry, MTBE means methyl terf-butyl ether, “NCS” means N-chlorosuccinimide, “Ph” means phenyl, “TBHP” means terf-butyl hydroperoxide, “TFA” means trifluoroacetic acid, “THF” means tetrahydrofuran, “SFC” means supercritical fluid chromatography, “TLC” means thin layer chromatography, “Rf” means rétention fraction, “~” means approximately, “rt” means rétention time, “h” means hours, “min” means minutes, “equiv” means équivalents, “sat.” means saturated.

Sche^ne I: | i !

119

A = Cl or Br

Pd-catalyst B₂Pin₂

M = BPin or B(OH)₂

Suzuki coupling

base-mediated S_NAr or Buchwald-Hartwig coupling

As exemplified in Scheme I, a compound such as I (purchased or synthesized) can be borylated with B₂Pin₂ in the presence of a suitable catalyst system (such as PdCI₂(dppf) or Pd(OAc)₂ + PCy₃) with a suitable base (such as KOAc) in an appropriate solvent (such as 1,4dioxane or DMSO) to provide a compound such as II. A compound such as II can be generated and reacted in-situ. Alternatively, a compound such as II can be isolated prior to subséquent reactions to provide the corresponding boronic acid or BPin ester. A compound such as II can undergo arylation with an aryl chloride such as III under standard Suzuki cross-coupling conditions in the presence of a suitable catalyst (such as Pd(PPh₃)4 or PdCI₂(PPh₃)₂) with a suitable base (such as K₂CO₃ or Na₂CO₃) in an appropriate solvent (such as DMSO or 1,4dioxane) to provide a compound such as IV. A compound such as IV can be coupled with an amine such as V to provide a compound such as VI under standard nucleophilic aromatic substitution conditions (3νΑγ) in the presence of a suitable base (such as DIPEA) in an appropriate sollvent (such as DMSO). Alternatively, a compound such las IV can be coupled with an amine such as V to provide a compoünd such as VI under standard Buchwaid-Hartwig coupling conditions in the presence of a suitable catalyst system (such as Pd(OÀc)₂ + rac-BINAP or chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphin'e)palladium complex) with a suitable base (such as Cs₂CO₃) in an appropriate solvent (such as THF or 1,4-dioxane). In some cases a compound such as VI may contain protecting groups, which can be removed by an additional step in the synthetic sequence using conditions known in the art (Protective Groups in Organic Synthesis, A. Wiley-lnterscience Publication, 1981 or Protecting groups, 10 Georg Thieme Verlag, 1994). Compounds at every step may be purified by standard techniques, such as column chromatography, crystallization, or reverse phase SFC or HPLC. If necessary,

120 séparation ofthe enantiomers ofVI may be carried out understandard methods known in the art such as chiral SFC or HPLC to afford single enantiomers. Variables Q, U, V, X, Z, R¹, and R⁷, and R⁹ are as defined as in the embodiments, schemes, examples, and claims herein.

Scheme II:

Me

Suzuki coupling

Me oxidation

i

SO₂Me base-mediated S_NAr

Me

As shown in Scheme II, a compound such a VII (prepared as in Scheme I) can be coupled to an aryl chloride such as VIII under standard Suzuki cross-coupling conditions with a suitable 10 catalyst system (such as Pd(t-Bu3P)2) with a suitable base (such as K2CO3) in an appropriate solvent (such as 1,4-dic^xane) to provide a compound such as IX. A compound éuch as IX can be oxidized with a suitable oxidant (such as oxone) to provide a compound such as X. A compound such as X can be coupled to an amine such as XI under standard 8νΑγ conditions in the presence of a suitable base (such as NazCOs) in an appropriate solvent (such as THF) to provide a 15 compound such as XIIJ Compounds at every step may be purified by standard,techniques, such as column chromatography, crystallization, or reverse phase SFC or HPLC. Variables R¹, and R⁴ are as defined as in the embodiments, schemes, examples, and claims herein.

Scheme lll:

121

Pd-catalyst B₂Pin₂

Suzuki coupling

Buchwald-Hartwig coupling

As shown in Scheme lll^ an aryl bromide such as compound XIII can be converted to a boronate ester such as compound XIV with B₂Pin₂ in the presence of a suitable catalyst (such as

Pd2Cl2(dppf)) with a suitable base (such as KOAc) in an appropriate solvent (such as 1,4dioxane). A compound such as XIV can be generated and used in-situ or isolated to provide the corresponding boronate ester. A compound such as XIV can be coupled with an aryl chloride such as compound III under standard Suzuki cross-coupling conditions with a suitable catalyst (such as PdCl2(PPh₃)₂) and suitable base (such as Na2CO₃) in an appropriate solvent (such as

1,4-dioxane) to provide a compound such as XV. A compound such as XV can be converted to a compound such as XVI in the presence of excess /-PrNH2 in an appropriate solvent (such as DMSO). A compound such as XVI can be cyclized with an aldéhyde such as XVII in the presence of a suitable reductant (such as Na2S2O4) in an appropriate solvent (such as EtOH) to provide a _ 122 compound such as XVIII. A compound such as XVIII can be coupled with an amine such as XIX under standard Buchwald-Hartwig conditions in the presence of a suitable catalyst system (such as Pd(OAc)2 + rac-BINAP) and a suitable base (such as Cs₂CO₃) in an appropriate solvent system (such as 1,4-dioxane or THF) to provide a compound such as XX. Compounds ât every step may be purified by standard techniques, such as column chromatography, crystallization, or reverse phase SFC or HPLC. Variables Q, R¹, R⁴, R⁶, and R⁷ are as defined as in the embodiments, schemes, examples, and claims herein.

Scheme IV:

XXI

XXIV

As shown in Scheme IV, a compound such as XXI (prepared as 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 £s PdCI₂(PPh3)2) and a suitable base (such as Na₂CO3)| in an appropriate solvent (such as 1,4-dioxane) to provide a compound such as XXIII. A compound such as XXIII can be coupled with an amine such as XIX under standard BuchwaldHartwig coupling conditions with a suitable palladium catalyst system (such as Bretphos-Pd-G3 or Pd₂(dba)3 + rac-BINAP) with a suitable base (such as f-BuONa, CS2CO3, or phosphazene P2-¹ Et) in an appropriate solvent (such as 1,4-dioxane or PhMe) to provide a compound such as

XXIV. In some cases a compound such as XXIV may contain protecting groups, which can be removed by an additional step . in the synthetic sequence using. conditions known in the art____ . .

(Protective Groups in Organic Synthesis, A. Wiley-lnterscience Publication, 1981 or Protecting groups, 10 Georg Thieme Verlag, 1994). Compounds at every step may be purified by standard

123 techniques, such as column chromatography, crystallization, or reverse phase SFC or HPLC.

Variables Q, Z, R², R⁴, and R⁶, are as defined as in the embodiments, schemes, examples, and claims herein.

Scheme V:

XXV

XXVI o=s=o

Me base-mediated SNAr

O=S=O

Me

Suzuki coupling

As shown in Scheme V, an amine such as XI can be coupled with an aryl fluoride such । as XXV to provide a compound such as XXVI under standard 3νΑγ conditions with a suitable base (such as DIPEA) in an appropriate solvent (such as DMSO). A compound such as XXVI 10 can coupled with a compound such as XXVII (prepared as in Scheme I) under standard Suzuki , cross-coupling conditions with a suitable catalyst (such as PdCl2(PPh3)z) with a suitable base i i । (such as Na2COs) in an appropriate solvent (such as 1,4-dioxane) to provide a compound such as XXVIII. Compounds at every step may be purified by standard techniques, such as column chromatography, crystallization, or reverse phase SFC or HPLC.

124

As shown in Scheme VI, a compound such as XXIX (Prepared as in Scheme I or Scheme 5 IV) can be converted to a compound such as XXX under various conditions well known in the art including:

i. Carbamate formation with a chloroformate in the presence of a suitable base (such as NEU) in an appropriate solvent (such as DCM) to provide a compound such as XXX wherein R¹¹ = CO2R¹⁷.

ii. Tertiary amine formation in the presence of a aldéhyde under standard reductive amination conditions with a suitable reducing agent (such as NaBH₃CN) in a suitable solvent (such as MeOH) or alkylation with an alkyl halide with a suitable base (such as NaHCO₃) in an appropriate solvent (such as EtOAc) to provide a compound such as XXX where in R¹¹ = C1-C2 alkyl.

iii. Sulfonamide formation with a sulfonyl chloride in the presence of a suitable base (such as NaHCO₃) in an appropriate solvent (such as EtOAc) to provide a compound such as XXX where in R¹¹ = SO₂R¹⁴ iv. Amide formation via acylation with an anhydride in the presence of a suitable base I (such as TEA) in an appropriate solvent (suchl as DCM) or a carboxylic acid in the presence of a suitable coupling agent (such as HATU or EDCI) and a suitable base (such as DIPEA) in an appropriate solvent (such as DCM or DMF) to provide a 25 compound such as XXX where in R¹¹ = COR¹⁷ !

In some cases, a compound such as XXX may contain protecting groups, which can be removed by an additional step in the synthetic sequence using conditions known in the art (Protective Groups in Organic Synthesis, A. Wiley-lnterscience Publication, 1981 or Protecting 30 groups, 10 Georg Thieme Verlag, 1994). Compounds at every step may be purified by standard techniques, such as column chromatography, crystallization, or reverse phase SFC or HPLC. If

125 necessary, séparation of the enantiomers of XXX may be carried out under standard methods known in the art such as chiral SFC or HPLC to afford single enantiomers.

Variables U, V, W, X, Z, R¹, R⁷, R¹¹, R¹⁴, and R¹⁷ are as defined as in the embodiments, schemes, examples, and claims herein? _ _ ------ . :

Scheme VII:

SNAr

NH₂

XI

As shown in Scheme VII, a compound such as XXXI (prepared as in Scheme I) can be oxidized with a suitable oxidant (such as MnO2, SO3*pyr, or TEMPO/NaCIO) in an appropriate 10 solvent (such as CHCh or DCM) to provide a compound such as XXXII. A compound such as XXXII can be coupled with an amine such as XI under standard S_NAr conditions in the presence of a suitabl^ base (such as DIPEA) in an appropriate solvent (sûch as DMSO) to provide a compound such as XXXIII. Compounds at every step may be purified by standard techniques, such as column chromatography, crystallization, or reverse phase SFC or HPLC.

j . I

Scheme VIÎI I

1. oxidation

2. reductive amination

- - or . .

1. mesylation

2. S_n2

126

A shown in Scheme VIII, a compound such as XXXIV (prepared as in Scheme I) can be converted to a compound such as XXXV by oxidation with a suitable oxidant (such as Mn02) in an appropriate solvent (such as MeOH) followed by reductive amination in the presence of an amine with a suitable reductant (such as NaBHaCN) in an appropriate solvent (such as MeCN).

Alternatively, a compound such as XXXIV can be activated by treatment with methanesulfonyl chloride in the presence of a suitable base (such as TEA) in an appropriate solvent (such as DCM). Subséquent displacement of the mesylate with an amine in the presence of Nal and a suitable base (such as DIPEA) in an appropriate solvent (such as MeCN) can provide a compound such as XXXV. Compounds at every step may be purified by standard techniques, 10 such as column chromatography, crystallization, or reverse phase SFC or HPLC. Variables Q, R²², and R²³ are as defined as in the embodiments, schemes, examples, and claims herein.

Scheme IX:

MeMgBr

XXXVII

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

127

Préparation of (1S)-1-(6-bromo-1-tert-butyl-4-fluoro-1H-benzimidazol-2-yl)ethan-1-oI (Int01) according to Scheme 1.

Préparation of intermediates

Scheme 1:

t-BuNH₂ Cs₂CO₃

DMSO

90% yield step 1

OHC^OTBS fsj| Me

Na₂S₂O4

EtOH, H₂O

18% yield

lnt-01 step 2

Step 1: Synthesis of 5-bromo-/V-terf-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 was stirred at 40 °C for 3 h. TLC analysis (petroleum ether) showed consumption of the starting material. The reaction was diluted with H2O (20 mL) and extracted with EtOAc (3x20 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (ISCO, SiO₂, 0-10% EtOAc/petroleum ether) to provide 5-bromo-/V-fert-butyl-3-fluoro-2-nitroaniline (1b) (5.5 g, 90% yield) as a red oil. ¹H NMR (400 MHz, DMSO-d₆) δ 7.13 - 7.01 (m, 2H), 6.94 (dd, J = 1.9,11.1 Hz, 1 H), 1.40 (s, 9H).

Step 2: Synthesis of (1S)-1-(6-bromo-1-tert-butyI-4-fluoro-1H-benzimidazol-2-yl)ethan-1-ol (lnt-01)

To a solution of 5-bromo-/V-fert-butyl-3-fluoro-2-nitroaniline (1b) (1.5 g, 5.2 mmol) and (2S)-2-{[tert-butyl(dimethyl)sil|rl]oxy}propanal (1.94 g, 10.3 mmol) in EtOH (30.0 mL) ^nd DMSO (7.5 mL) was added Na2S2O4 (4.5 g, 25.8 mmol). The reaction was stirred at 80 °C for 16 h. TLC analysis (EtOAc) showed consumption ofthe starting material. EtOAc (10 mL) and H2O (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 Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (ISCO, 12 g SiO2, 0-20% EtOAc/petroleum ether) to provide (1S)-1-(6-bromo-1-ferf-butyl-4-fluoro-1H-benzimidazol-2yl)ethan-1-ol (lnt-01) (400 mg, 18% yield) as a yellow oil. m/z (ESI) for (CigH3oBrFN20Si), 431.1 (M+H)⁺.

128

Préparation of 6-bromo-2-(2-([tert-butyl(dimethyl)silyl]oxy}propan-2-yl)-4-fluoro-1 (propan-2-yl)-1H-benzimidazole (lnt-02) according to Scheme 2.

Scheme 2:

i-PrNH₂ CS2CO3

DMSO

70% yield step 1

OHC OTBS

.. Μθ Me

N3₂S£O₄

EtOH, DMSO H₂O

86% yield step 2

F

Br

OTBS -(-Me Me

Me lnt-02

Step 1 : Synthesis of 5-bromo-3-fluoro-2-nitro-N-(propan-2-yI)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 température for 4 d, after which the mixture was concentrated. The crude residue was purified by flash 10 chromatography (SiO₂, 0-30% EtOAc/heptanes) to provide 5-bromo-3-fluoro-2-nitro-N-(propan2-yl)aniline (2b) (20.3 g, 70% yield) as a red/orange solid. ¹H NMR (400 MHz, DMSO-de) 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 (C₉H₁₀BrFN₂O2), 278.1 (M+H)⁺.

Step 2: Synthesis of 6-bromo-2-(2-{[tert-butyI(dimethyl)silyl]oxy}propan-2-yl)-4-fluoro-1(propan-2-yl)-1 H-benzimidazole (lnt-02)

To a solution of 5-bromo-3-fluoro-2-nitro-A/-(propan-2-yl)aniline (2b) (1.0 g, 3.2 mmol) and 2-{[fert-butyl(dimethyl)silyl]oxy}-2-methylpropanal (655 mg, 3.2 mmol) in EtOH (8.0 mL) and DMSO (2.0 mL) was added Na₂S2O4 (2.82 g, 16.2 mmol). The suspension was stirred at 90 °C 20 for 16 h. LCMS analysis showed consumption ofthe starting material with formation ofthe desired product mass. 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 Na₂S(j)4, filtered, and concentrated. The residue was purified by flash chromatography (Biotage, 40 g SiO₂, 1/10 EtOAc/petroleum ether) to provide 6-bromo-2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)25 4-fluoro-1-(propan-2-yl)-1H-benzimida2ole (lnt-02) (1.2 g, 86% yield) as a white solid. ¹H NMR (400 MHz, CDCI3) 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, l4.0 Hz, 1H), 1.85 (s, 6H), 1.71 - 1.60 (m, 6H), 0.92 (s, 9H), 0.21 - 0.17 (m, 6H).

Préparation of 6-bromo-4-fluoro-2-methyl-1-(oxetan-3-yl)-1H-benzimidazoIe (lnt-03) according to Scheme 3.

129

Scheme 3:

DMSO

55% yield step 1

ch₃cho

NS₂S₂O₄

EtOH, H₂O

20% yield step 2 lnt-03

Step 1: Synthesis of N-(5-bromo-3-fluoro-2-nitrophenyl)oxetan-3-amine (3a)

To a solution of 5-bromo-1,3-difluoro-2-nitrobenzene (1.5 g, 6.3 mmol) (1 a) in DMSO (15.0 mL) was added oxetan-3-amine (507 mg, 6.93 mmol) and CS2CO3 (2.46 g, 7.56 mmol). The reaction was stirred at 25 °C for 2 h. TLC analysis (1/4 EtOAc/petroleum ether) showed consumption of the starting material. The reaction was diluted with brine (10 mL) and extracted with EtOAc (2x10 mL). The combined organic phases were washed with brine, dried over Na₂SO4, filtered, and concentrated. The residue was purified by flash chromatography (ISCO,

S1O2, 0-30% EtOAc/petroleum ether) to provide /V-(5-bromo-3-fiuoro-2-nitrophenyl)oxetan-3amine (3a) (1.0 g, 55% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-de) δ 7.59 (br d, J = 5.3 Hz, 1 H), 7.04 (dd, J = 1.8,10.8 Hz, 1 H), 6.69 (s, 1 H), 4.87 - 4.81 (m, 2H), 4.80 - 4.71 (m, 1 H), 4.60 - 4.47 (m, 2H).

Step 2: Synthesis of 6-bromo-4-fluoro-2-methyl-1-(oxetan-3-yl)-1H-benzimidazoIe (lnt-03)

To a solution of /V-(5-bromo-3-fluoro-2-nitrophenyI)oxetan-3-amine (3a) (500 mg, 1.72 mmol) in EtOH (16.0 mL) and H₂O (4.0 mL) was added acetaldehyde (2.0 mL, 8.6 mmol) and Na₂S₂O4 (1.5 g, 8.6 mmol). The reaction was sealed and stirred at 80 °C with microwave irradiation for 10 h. LCMS analysis showed consumption of the starting material. The solution 20 was cooled and partitioned between EtOAc (40 mL) and H₂O (20 mL). The combined layers were dried over Na2SO4, filtered, and concentrated. The crude residue was purified by flash | chromatography (S1O2, 0-100% EtOAc/petroleum ether) to provide 6-bromo-4-fluoro-2-methyI-1(oxetan-3-yl)-1H-benzimidazole (lnt-03) (100 mg, 20% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.95 (s, 1H), 7.34 (br d, J = 10.0 Hz, 1H), 5.66 (br t, J = 5.5 Hz, 1H), 5.11 (br | 25 t, J = 7.7 Hz, 2H), 5.03 - 4.88 (m, 2H), 2.55 (s, 3H). mlz (ESI+) for (CnHi₀BrFN2O), 284.9 (M+H).

The intermediates in the below table were synthesized according to the methods used for the synthesis of (1S)-1-(6-bromo-1-fert-butyI-4-fluoro-1H-benzimidazol-2-yl)ethan-1-ol (lnt-01), 6-bromo-2-(2-{[ferf-butyl(dimethyl)silyl]oxy}propan-2-yl)-4-fIuoro-1-(propan-2-yl)-1H30 benzimidazole (lnt-02) and 6-bromo-4-fluoro-2-methyl-1-(oxetan-3-yi)-1H-benzimidazole (lnt03). The following intermediates were synthesized with non-critical changes or substitutions to the exemplified procedures that someone who is skilled in the art would be able to realize.

130

Compound number	Structure/IUPAC Name	Analytical data
lnt-04	F <^r-N Il [ Me Me 6-bromo-4-fluoro-1,2-dimethyI-1 Hbenzimidazole	m/z (ESI+) for (CgH8BrFN2), 242.6 (M+H)+
lnt-05	F /A- N OTBS / Th Me A~Me Me Me 6-bromo-1 -tert-bu ty l-2-[( 1 R)-1 - {[tert- butyl(dimethyl)silyl]oxy}ethyl]-4- fluoro-1 H-benzimidazole	m/z (ESI+) for (Ci9H3oBrFN20Si), 430.9 (M+H)+
lnt-06	F NHBoc Πη Br N Me Μ ^Μθ Me Me tert-butyl [(1R)-1-(6-bromo-1-tert- butyl-4-fluoro-1 H-benzimidazol-2yl)ethyl]carbamate	m/z (ESI+) for (C18H25BrFN3O2), 415.9 (M+H)+
lnt-07	F /AN 1 P Br^^^N I .. /Me 1 Me 6-bromo-4-fluoro-2-(oxetan-3-yl)- 1-(propan-2-yl)-1 H-benzimidazole । i	1H NMR (400 MHz, DMSO-cfe) δ 7.79 (d, J= 1.5 Hz, 1H), 7.30 (dd, J = 1.5,10.1 Hz, 1H), 5.01 -4.91 (m, 4H), 4.80 - 4.66 (m, 1 H), 4.55 - 4.42 (m, 1 H), 1.49 (d, J = 7.0 Hz, 6H); m/z (ESI+) for (Ci3Hi4BrFN2O), 324.2 (M+H)+
lnt-08	F -N NHBoc /Me Me	1H NMR (400 MHz, CDCI3) δ 9.16 (brs, 1H), 7.49 (d, J= 1.0 Hz, 1H), 7.09 (dd, J = 1.5, 9.5 Hz, 1H), 5.84 (br s, 1 H), 5.39 (br s, 1 H), 1.63 (s, 9H), 1.57 (s, 3H), 1.46 (s, 6H), 1.39 (s, 9H); m/z (ESI+) for

131

	tert-butyl {1-[6-bromo-4-fluoro-1(propan-2-yl)-1 H-benzimidazol-2yl]cyclopropyl}carbamate	(Ci8H23BrFN3O2), 357.9 (MtBu+H)+
lnt-09	.. F NHBoc Γ |ΊΓ Me „ À-Me Me tert-butyl {(1S)-1-[6-bromo-4- fluoro-1-(propan-2-yl)-1 H- benzimidazol-2-yl]ethyl}carbamate	1H NMR (400 MHz, CDCI3) δ 9.58 (s,1H), 7.49 (d, J =1.5 Hz, 1H), 7.12 (dd, J = 9.7,1.5 Hz, 1H), 5.24 -5.03 (m, 1H), 4.86 (p, J =6.9 Hz, 1H), 1.66-1.57 (m, 6H), 1.47 (s, 9H), 1.35 (d, J = 7.4 Hz, 3H)
lnt-10	F OTBS F v~ch3 ch3 6-bromo-2-({[tertbutyl(dimethyl)silyl]oxy}methyl)-4fluoro-1-(2-fluoro-2-methylpropyl)1/7-benzimidazole	m/z (ESI+) for (Ci8H27BrF2N2OSi), 433.1 (M+H)+
lnt-11	F OTBS Η3Ο-γ/ h3c μ 6-bromo-2-({[tertbutyl(dimethyl)silyl]oxy}methyl)-1- (1,1-difluoro-2-methylpropan-2-yl)4-fluoro-1 H-benzimidazole	m/z (ESI+) for (Ci8H26BrF3N2OSi), 451.2(M+H)+
lnt-12 I	F OTBS JL JL Me F-Y F 6-bromo-2-(2-{[tertbutyl(dimethyl)silyl]oxy}propan-2yl)-1-(2,2-difluoroethyI)-4-fluoro1H-benzimidazole	m/z (ESI+) for (Ci8H26BrF3N2OSi), 1 450.8 (M+H)+

132

lnt-13	F fi T y-Me Rr^^N ^Me NHBoc tert-butyl [(2S)-2-(6-bromo-4fluoro-2-methyl-1 H-benzimidazoI1-yl)propyl]carbamate	1H NMR (400 MHz, CDCI3) δ 7.32 (d, J = 1.5 Hz, 1 H), 7.04 (dd, J = 9.6, 1.5 Hz, 1H), 5.13 (s, 1H), 4.73 (s, 1H), 3.70 (dt, J = 11.5, 6.2 Hz, 1 H), 3.47 - 3.38 (m, 1 H), 2.56 (s, 3H), 1.61 (d, J = 7.0 Hz, 3H), 1.41 (s, 9H); mlz (ESI+) for (C16H2iBrFN3O2), 387.9 (M+H)+
Int-14	F /Y-n ]| I —Me Me OMe 6-bromo-4-fluoro-1 -(1 methoxypropan-2-yl)-2-methyl-1 Hbenzimidazole	1H NMR (400 MHz, DMSO-d6) δ 7.75 (d, J= 1.6 Hz, 1 H), 7.23 (dd, J =1.5, 10.1 Hz, 1H), 4.78 (ddd, J = 4.6, 7.1, 8.9 Hz, 1H), 3.86 (dd, J = 9.2,10.4 Hz, 1H), 3.62 (dd, J = 4.5, 10.5 Hz, 1H), 3.18 (s, 3H), 2.55 (s, 3H), 1.52 (d, J= 7.1 Hz, 3H); mlz (APCI+) for (Ci2Hi4BrFN2O), 301.0, 303.0 (M+H)+
Int-15	F Me Ό 6-bromo-2-ethyl-4-fluoro-1 (oxetan-3-yl)-1 H-benzimidazole	1H NMR (400 MHz, DMSO-d6) δ 7.97 (d, J = 1.6 Hz, 1H), 7.34 (dd, J = 10.2, 1.6 Hz, 1 H), 5.77 - 5.53 (m, 1H), 5.12 (t, J = 7.7 Hz, 2H), 4.98 (dd, J = 7.8, 5.3 Hz, 2H), 2.88 (q, J = 7.5 Hz, 2H), 1.29 (t, J = 7.4 Hz, 3H); mlz (APCI+) for (Ci2H12BrFN2O), 298.9 (M+H)+ I
lnt-16	F - /Y--N il I Me Br^^^N ?'Me NHBoc tert-butyl [(2R)-2-(6-bromo-4- fluoro-2-methyl-1 H-benzimidazol1 -yl)propyl]carbamate	1H NMR (400 MHz, DMSO-d6) δ 7.77 - 7.53 (m, 1H), 7.21 (br d, J = 10.0 Hz, 1 H), 7.09 - 6.92 (m, 1 H), 6.65 (dd, J = 2.0, 7.0 Hz, 1H), 4.71 -4.60 (m, 1H), 4.45-4.33 (m, 1H), 3.83-3.60 (m, 2H), 1.61 1.46 (m, 5H), i.32 - 1.20 (m, 8H); mlz (ESI+) for (Ci6H2iBrFN3O2), 387.9 (M+H)*

133 lnt-17

(6-bromo-1 -cyclobutyl-4-fluoro-1 Hbenzimidazol-2-yl)methanol ¹H NMR (400 MHz, CDCI₃) 57.63 (d, J = 1.5 Hz, 1H), 7.13 (dd, J = 1.5, 9.6 Hz, 1H), 5.31 -5.12 (m, 1H), 4.94 (s, 2H), 2.98 - 2.81 (m, 2H), 2.65 - 2.49 (m, 2H), 2.06 1.87 (m, 2H), 0.92 - 0.90 (m, 9H), 0.10 - 0.07 (m, 6H); m/z (ESI+) for (Ci₈H₂₆BrFN₂OSi), 414.8 (M+H)⁺ lnt-18

6-bromo-2-({[tertbutyl(dimethyl)silyl]oxy}methyl)-1(3,3-difIuorocyclobutyl)-4-fluoro1H-benzimidazole ¹H NMR (400 MHz, CDCI3) 5 7.51 (d, J = 1.3 Hz, 1H), 7.19 (dd, J = 1.5, 9.5 Hz, 1H), 5.27 (dquin, J = 3.7, 8.7 Hz, 1H), 4.97 (s, 2H), 3.60 -3.41 (m, 2H), 3.32-3.17 (m, 2H), 0.92-0.90 (m, 9H), 0.120.10 (m, 6H); m/z (ESI+) for (Ci₈H₂4BrF₃N₂OSi), (M+H)⁺

Préparation of [6-bromo-4-fIuoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]methanol (lnt-19) according to Scheme 4.

Scheme 4:

Na₂S₂O₄

EtOH/H₂O

77% yield

A mixture of 5-bromo-3-fluoro-2-nitro-A/-(propan-2-yl)aniline (2b) (994 mg g, 3.59 mmol), Na₂S₂Ü4 (3.12 g, 17.9 mmol), and glycolaldéhyde dimer (517 mg, 4.30 mmol) in EtOH/H₂O (4:1, i I mL) was stirred at 80 ’C for 21 h. The mixture was concentrated and partitioned between H₂O 10 (100 mL) and EtOAc (100 mL). The layers were separated and the aqueous phase iextracted with

EtOAc (3x100 mL). The combined organic phases were washed with water (50 mL) and brine (50 mL), dried over Na₂SO4, filtered, and concentrated. The crude product was purified by flash chromatography (SiO₂, 40-100% EtOAc/heptanes) to provide [6-bromo-4-fIuoro-1-(propan-2-yl)1H-benzimidazol-2-yl]methanol (lnt-19) (790 mg, 77% yield) as a white waxy solid. ¹H NMR (400

MHz, DMSO-d₈) δ 7.81 (d, J = 1.5 Hz, 1H), 7.28 (dd, J = 10.1, 1.6 Hz, 1H), 5.71 (t, J = 5.8 Hz,

134

1H), 4.95 (hept, J = 6.8 Hz, 1H), 4.72 (d, J = 5.7 Hz, 2H), 1.56 (d, J = 6.9 Hz, 6H); m/z (APCI+) for (CnHi2BrFN₂O), 286.8 (M+H)⁺. ------- _ _

Préparation of 6-bromo-4-fluoro-2-{[(oxan-2-yl)oxy]methyl}-1 -(propan-2-yl)-1 H5 benzimidazole (lnt-20) according to Scheme 5.

Scheme 5:

DHP, TsOHH₂O

THF

86% yield

A solution of [6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]methanol (lnt-19) 10 (590 mg, 2.05 mmol), 3,4-dihydro-2H-pyran (1.21 g, 1.3 mL, 14.4 mmol) and p-TSA acid monohydrate (35.4 mg, 0.205 mmol) in THF (21 mL) was stirred at reflux température for 4 h. The mixture was concentrated and purified by flash chromatography (SiO₂, 20-50% EtOAc/heptanes) to provide 6-bromo-4-fIuoro-2-{[(oxan-2-yl)oxy]methyl}-1-(propan-2-yl)-1/7benzimidazole (lnt-20) (710 mg, 93% yield) as a viscous yellow oil. ¹H NMR (400 MHz, DMSO15 d₆) 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 (C₁₆H₂₀BrFN₂O₂), 370.9 (M+H)⁺.

Préparation of 6-bromo-4-fluoro-2-(methoxymethyl)-1 -(propan-2-yl)-1 H-benzimidazole 20 (lnt-21) according to Scheme 6.

Scheme 6:

KOtBu, Mel

1,4-dioxane

60% yield

To a solution of [6-bromo~4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]methanoll(lnt25 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). To the résultant dark reaction mixture at 0 °C was added Mel (66.2 mg, 0.029 mL, 0.467 mmol). After 15 min LCMS analysis showed consumption ofthe starting material with formation of the desired product mass. H₂O (5 mL) was added and the mixture was extracted with DCM (3x10 mL). The combined organic phases were dried over Na₂SO4, filtered, and concentrated. The residue was purified by flash chromatography (12 g SiO₂, 0-100%

135

EtOAc/heptanes) to provide (lnt-21) (85 mg, 60% yield). ¹H NMR (400 MHz, CDCI3) δ 7.50 (d, J = 1.47 Hz, 1 H) 7.12 (dd, J = 9.54,1.47 Hz, 1 H) 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).

Préparation of 6-bromo-4-fIuoro-1-(propan-2-yI)-1H-benzimidazole (lnt-22) according to

Scheme 7.

Scheme 7:

Fe°, NH4CI

H₂O/MeOH, 60 C

94% yield

HC(OEt)₃

EtOH, H₂O 99% yield

step 1 step 2

Step 1: Synthesis of 5-bromo-3-fluoro-N¹-(propan-2-yl)benzene-1,2-diamine (7a)

To a solution of 5-bromo-3-fluoro-2-nitro-N-(propan-2-yl)aniline (2b) (25.0 g, 90.2 mmol) in MeOH (300 mL) was added saturated aqueous NH4CI (150 mL) and Fe (25.2 g, 451 mmol). The reaction suspension was heated to 60 °C and stirred at this température for 3 h. LCMS analysis showed consumption of the 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 H2O (200 mL). The combined aqueous washes were extracted with EtOAc (2x200 mL). The combined organic phases were dried over Na₂SO4, filtered, and concentrated to provide 5-bromo-3-fluoro-/V¹-(propan-2yl)benzene-1,2-diamine (7a) (21.0 g, 94% yield). m/z (ESI+) for (CgHi2BrFN2), 246.7 (M+H)⁺.

Step 2: Synthesis of 6-bromo-4-fluoro-1-(|j)ropan-2-yl)-1H-benzimidazole (lnt-22)

A solution of 5-bromo-3-fluoro-/V¹-(propan-2-yl)benzene-1,2-diamine (7a) (3.86 g, 15.6 mmol) in HC(OEt)3 (100 mL) was stirred at 150 °C for 15 h. LCMS analysis showed consumption of the starting material with formation of the. desired product mass. The solution was cooled to room température and concentrated to provide 6-bromo-4-fluoro-1-(propan-2-yl)-1H25 benzimidazole (lnt-22) (4.02 g, >99% yield) as a black oil, which was taken on without further purification. ¹H NMR (400 MHz, DMSO-cfe) δ 8.04 (d, J = 3.3 Hz, 1H), 6.66 (dd, J = 2.0, 10.0 Hz, 1H), 6.54 (s, 1H), 3.69 - 3.56 (m, 1H), 1.15 (d, J = 6.2 Hz, 6H); m/z (ESI+) for (CioHi_OBrFN2), 258.7 (M+H)⁺.

136

Préparation of 6-bromo-1-terf-butyl-2-methyl-1H-benzimidazole (lnt-23) according to

Scheme 8.

Scheme 8: „

JL CH₃C(0Et)₃ L T Me

Br ^^NH ----------- Br ^^^N.

148’C Æ-Me

8a ^Me .L^Me lnt-23 Me _Me ^Me 86% yield

Synthesis of 6-bromo-1-fert-butyl-2-methyl-1H-benzimidazole (lnt-23)

A mixture of 4-bromo-/\/²-fert-butylbenzene-1,2-diamine (8a) (1.3 g, 5.35 mmol) and triethyl orthoacetate (8.7 g, 53.5 mmol) was stirred at 148 °C for 1 h. LCMS analysis showed consumption of the starting material with formation of the desired product mass. The solution was cooled to room température and concentrated. The residue was purified by flash chromatography (20 g S1O2, 20% EtOAc/petroleum ether) to provide 6-bromo-1 -fert-butyl-2-methyl- 1Hbenzimidazole (lnt-23) (1.23 g, 95% yield) as a yellow oil. mlz (ESI+) for (Ci2Hi₅BrN₂), 268.7 (M+H)⁺.

Préparation of 6-bromo-5-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazoIe (lnt-24) according to Scheme 9.

Scheme 9:

i-PrNH₂, K₂CO₃

THF

9a 70% yield

H₂O/MeOH, 60 ’C

Fe°, NH4CI

CH₃C(OEt)₃ 148 ’C

51% yield step 1

53% yield step 2 step 3

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

To a suspension of 1-bromo-2,5-difluoro-4-nitrobenzene (9a) (1.0 g, 4.2 mmol) in THF (10 mL) was added K2CO3 (581,4.2 mmol) and /-PrNH2 (248 mg, 4.2 mmol). The mixture was stirred at ambient température for 16 h. LCMS analysis showed consumption of the starting material with formation of the desired product mass. The reaction solution was diluted with H2O (30 mL) and extracted with EtOAc (3x20 mL). The combined organic phases were washed with brine (20 mL), _ ¹³⁷ dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (ISCO, 20 g SiO2,10% EtOAc/petroleum ether) to provide 5-bromo-4-fluoro-2-nitro-/V-(propan-2yl)aniline (9b) (900 mg, 77% yield) as a yellow solid. mlz (ESI+) for (CgHioBrFN202), 276.7 (M+H)⁺. '

Step 2: Synthesis of 5-bromo-4-fIuoro-N¹-(propan-2-yl)benzene-1,2-diamine (9c)

To a solution of 5-bromo-4-fluoro-2-nitro-/V-(propan-2-yl)aniline (9b) (1.9 g, 6.9 mmol) in MeOH (30 mL) was added saturated aqueous NH4CI (15 mL) and Fe° (1.9 g, 34.3 mmol). The reaction suspension was stirred at 60 °C for 16 h overnight. LCMS analysis showed consumption 10 of the starting material with formation of the desired product mass. 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 S1O2, 1:2 EtOAc/petroleum ether) to provide 5-bromo-4-fluoro-A/¹-(propan-2-yl)benzene15 1,2-diamine (9c) (900 mg, 53% yield) as a brown gum. mlz (ESI+) for (C9Hi₂BrFN₂), 246.7 (M+H)⁺.

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

A mixture of 5-bromo-4-fiuoro-/V¹-(propan-2-yl)benzene-1,2-diamine (9c) (800 mg, 3.24 20 mmol) and triethyl orthoacetate (5.3 g, 32.4 mmol) was stirred at 148 °C for 1 h. LCMS analysis showed consumption of the starting material with formation of the desired product. The solution was cooled to room température and concentrated. The residue was combined with a parallel reaction run on 100 mg scale and purified by flash chromatography (20 g S1O2,100% EtOAc) to provide 6-bromo-5-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazole (lnt-24) (500 mg, 51% 25 yield). ¹H NMR (400 MHz, DMSO-d₆) δ 7.99 (d, J = 6.2 Hz, 1H), 7.51 (d, J = 9.5 Hz, 1H), 4.74 (spt, J = 6.9 Hz, 1H), 2.55 (s, 3H), 1.53 (d, J = 7.0 Hz, 6H); mlz (ESI+) for (CiiHi₂BrFN₂), 270.9 (M+H)j. | „

The intermediates in the below table were synthesized according to the methods used for 30 the synthesis of 6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimiàazole (lnt-22), 6-bromo-4-fluoro1-(propan-2-yl)-1H-benzimidazole (lnt-23), and 6-bromo-5-fluoro-2-methyl-1-(propan-2-yl)-1Hbenzimidazole (lnt-24). The following intermediates were synthesized with non-critical changes or substitutions to the exemplified procedures that someone who is skilled in the art would be abletorealize. -------- . .. . ... ..... . .. . . . . ..

' —

138

Compound number	Structure/IUPAC Name	Analytical data
lnt-25	F XX x> Jo 6-bromo-4-fluoro-1-(oxolan-3-yl)1H-benzimidazole	1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 7.85 (d, J = 1.6 Hz, 1H), 7.34 (dd, J =10.3, 1.6 Hz, 1H), 5.30 (ddt, J= 8.4, 5.8, 3.1 Hz, 1H), 4.13 (td, J= 8.4, 6.0 Hz, 1H), 4.01 (dd, J =10.0, 2.6 Hz, 1H), 3.93 (dd, J = 10.0, 5.6 Hz, 1H), 3.87 - 3.78 (m, 1H), 2.59 - 2.53 (m, 1H), 2.26-2.13 (m, 1 H).; m/z (ESI+) for (CnHioBrFN20), 258.7 (M+H)*
lnt-26	' F XX > 6-bromo-1 -cyclopropyl-4-fluoro- 1H-benzimidazole	1H NMR (400 MHz, CDCI3) δ 7.90 (s, 1H), 7.53 (d, J = 1.5 Hz, 1H), 7.15 (dd, J = 1.5, 9.8 Hz, 1H), 3.36 (td, J = 3.5, 7.0 Hz, 1H), 1.24-1.17 (m, 2H), 1.10-1.03 (m, 2H); mlz (ESI+) for (Ci0H8BrFN2), 256.7 (M+H)*
lnt-27	F XX x> __,NHBoc Me Me fert-butyl [2-(6-bromo-4-fIuoro-1H- benzimidazol-1-yl)-2methylpropyl]carbamate	mlz (ESI+) for (Ci6H2iBrFN3O2), 387.6 (M+H)*
lnt-28 |	F JL IJ —Μθ __^NHBoc Me Me fert-buty! [2-(6-bromo-4-fluoro-2- methyl-1/7-benzimidazol-1-yl)-2methylpropyl]carbamate	I mlz (ESI+) for (Ci7H23BrFN3O2), 400.0 (M+H)*

Préparation of tert-butyl {[6-bromo-4-fiuoro-1-(propan-2-yl)-1H-benzimidazol-2yl]methyl}methylcarbamate (lnt-29) according to Scheme 10.

139

Scheme 10: -

Me

N32S2O4

EtOH, DMSO, 80 °C

82% yield

To a solution of S-bromo-S-fluoro-A^-Cpropan^-ylJbenzene-l ,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 Na2S₂O4 (1.1 g, 6.1 mmol). The suspension was stirred at 80 °C for 16 h. LCMS analysis showed consumption of the starting material with formation of the desired product mass. The mixture was concentrated to dryness. The residue was purified by flash chromatography (Biotage, 20 g SiO₂,25% EtOAc/petroleum ether) to provide fert-butyl {[6-bromo4-fluoro-1-(propan-2-yl)-1/7-benzimidazol-2-yl]methyl}methylcarbamate (lnt-29) (400 mg, 82% yield) as a yellow oil. m/z (ESI+) for (Ci7H₂3BrFN3O₂), 401.6 (M+H)⁺.

The intermediates in the below table were synthesized according to the methods used for the synthesis of tert-butyl {[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2yl]methyl)methylcarbamate (lnt-29). The following intermediates were synthesized with noncritical changes or substitutions to the exemplified procedures that someone who is skilled in the art would be able to realize.

Compound number	Structure/IUPAC Name	Analytical data I
lnt-30	j F I NHBoc f T —(Me Me /Me Me tert-butyl {2-[6-bromo-4-fluoro-1- (propan-2-yl)-1H-benzimidazol-2yl]propan-2-yl)carbamate	t m/z (ESI+) for (C18H25BrFN3O2), 415.7 (M+H)+

140

lnt-31

F 0TBS Me 6-bromo-2-({[tertbutyl(dimethyl)silyl]oxy}methyl)-4fluoro-1 -(1 -methylcyclopropyl)-1 Hbenzimidazole

1H NMR (400 MHz, CDCI3) δ 7.50 (d, J = 1.6 Hz, 1H), 7.10 (dd, J = 9.6, 1.6 Hz, 1H), 4.97 (s, 2H), 1.60 (s, 7H), 0.92 (s, 9H), 0.15 (s, 6H); m/z (ESI+) for (CieH26BrFN2OSi), 414.9 (M+H)+

Préparation of 6-bromo-4-fluoro-/V-methyl-1-(propan-2-yl)-1H-benzimidazole-2carboxamide (lnt-32) according to Scheme 11.

Scheme 11:

F ethyl 2-oxoacetate

N a₂S₂O4

DMSO, EtOH, 80’C Br . „ /Me

38% yield _11a Me step 1

NH₂Me, DIPEA «fan 5 DMA, ⁸⁰ ’^c step Z

Step 1: Synthesis of ethyl 6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazole-2carboxylate (11a) . . . .. .. .

To a solution of 5-bromo-p-fluoro-/V¹-(propan-2-yl)benzene-1,2-diamine (7a) (1.0 |g, 4.05 10 mmol) and ethyl 2-oxoacetate (1.65 g, 8.09 mmol) in EtOH (20.0 mL) and DMSO (5.0 mL) was added Na₂S2O4 (3.5 g, 20.2 mmol). The suspension was stirred at 80 °C for 16 h. LCMS analysis showed consumption of the starting material with formation of the desired product mass. The mixture was diluted with H2O (15|mL) and extracted with EtOAc (15 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash 15 chromatography (ISCO, 20 g S1O2, 25% EtOAc/heptanes) to provide 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 (Ci3H₁₄BrFN2O₂), 328.7 (M+H)⁺.

141

Step 2: Synthesis of 6-bromo-4-fluoro-N-methyl-1-(propan-2-yl)-1H-benzimidazoIe-2carboxamide (lnt-32)

A mixture of ethyl 6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazole-2-carboxylate (11a) (200 mg, 0.608 mmol), DIPEA (236 mg, 1.82 mmol), and MeNH₂ (22.6 mg, 0.729 mmol) in 5 DMA (8.0 mL) was stirred at 80 °C for 16 h. LCMS analysis showed consumption ofthe starting material with formation ofthe desired product mass. The mixture was diluted with EtOAc (15 mL) and washed with H₂O (15 mL). The combined organic phases were dried over Na₂SÜ4, filtered, and concentrated. The material obtained was combined the product of a parallel reaction run with 48 mg of ethyl 6-bromo-4-fIuoro-1-(propan-2-yl)-1H-benzimidazole-2-carboxylate to provide 610 bromo-4-fluoro-N-methyl-1-(propan-2-yl)-1H-benzimidazole-2-carboxamide (lnt-32) (200 mg, 83% yield). m/z (ESI+) for (Ci₂Hi₃BrFN₃O), 313.7 (M+H)⁺.

Préparation of 6-bromo-4-fiuoro-1-(propan-2-yl)-1H-benzimidazole-2-carboxamide (lnt-33) according to Scheme 12.

Scheme 12:

nh₃

MeOH, 85-90 ’C

83% yield

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 8520 90 °C for 16 h. LCMS analysis showed consumption ofthe starting material with formation ofthe desired product mass. The reaction mixture was cooled to room température and concentrated to provide (lnt-33) (190 mg, >99% yield) as a solid. m/z (ESI+) for (CnHnBrFN₃O), 299.7 (M+H)⁺.

Préparation of ferf-butyl {1-[6-brom|o-4-fIuoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]-225 methylpropan-2-yl}carbamate (lnt-34) according to Scheme 13.

Scheme 13:

142

F

EDCI pyridine

81% yield

HCl 1,4-dioxane MW, 130 °C >99% yield step 1 step 2

BOC2O, DIPEA

DCM >99% yield

step 3

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

To a stirring solution of S-bromo-S-fluoro-A^-Îpropan^-ylJbenzene-l^-diamine (7a) (1.1 g, 4.5 mmol) in pyridine (10.0 mL) was added 3-[(terf-butoxycarbonyl)amino]-3-methylbutanoic acid (967 mg, 4.5 mmol) and EDCI (1.7 g, 8.9 mmol) at 0 °C under an atmosphère of N2. The mixture was stirred at 25 °C for 4 h. LCMS analysis showed consumption of starting material with formation ofthe desired product mass. The solution was diluted with H2O (20 mL) and extracted with EtOAc (3x20 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 S1O2, 0-50% EtOAc/petroleum ether) to provide 1-[6-bromo-4-fluoro-1-(propan-2-yl)-1Hbenzimidazol-2-yl]-2-methylpropan-2-amine (13a) (1.6 g, 81% yield) as a white solid. mlz (ESI+) for (Ci₉H29BrFN3O₃), 446.1 (M+H)⁺. I

Step 2: Synthesis of 1-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]-2• methylpropan-2-amine (13b) । j This reaction was run in three parallel batches. To the solid 1-[6-bromo-4-fIuoro-1(propan-2-yl)-1H-benzimidazol-2-yI]-2-methylpropan-2-amine (13a) (600 mg, 1.8 mmol) was added a solution of HCl (4.0 M in 1,4-dioxane, 10.0 mL). The mixture was stirred at 130 °C for 15 20 min under microwave irradiation. LCMS analysis showed consumption ofthe starting material with formation of the desired product mass. The three reaction batches were combined and concentrated to dryness. The residue was taken up in H2O (10 mL) and the mixture was basified with NH4OH to pH ~9. The mixture was extracted with EtOAc (3x15 mL). The combined organic ¹⁴³ phases were washed with brine, dried over Na2SO4, filtered, and concentrated to provide 1-[6bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]-2-methylpropan-2-amine (13b) (T.2 g, >99% yield). m/z (ESI+) for (Ci₄Hi₉BrFN₃), 329.9 (M+H)⁺.

Step 3: Synthesis of tert-butyl {1-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazoI-2-yl]2-methylpropan-2-yl}carbamate (lnt-34)

To a solution of 1-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]-2methylpropan-2-amine (13b) (1.2 g, 3.7 mmol) in DCM (20 mL) was added DIPEA (473 mg, 3.7 mmol) and BOC2O (958 mg, 4.4 mmol) at 0 °C. The solution was stirred at 25 °C for 18 h. LCMS 10 analysis showed consumption ofthe starting material with formation of the desired product mass.

The reaction 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 SiO2, 0-51% EtOAc/petroleum ether) to provide tert-butyl {1-[6-bromo-4-fluoro-115 (propan-2-yl)-1H-benzimidazol-2-yl]-2-methylpropan-2-yl}carbamate (lnt-34) (1.6 g, >99% yield) as a brown solid. m/z (ESI+) for (Ci₉H27BrFN₃O2), 430.0 (M+H)⁺.

The intermediate in the below table was synthesized according to the methods used for the synthesis of tert-butyl {1-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]-220 methylpropan-2-yl}carbamate (lnt-34). The following intermediate was synthesized with noncritical changes or substitutions to the exemplified procedures that someone who is skilled in the art would be able to realize.

Compound number	Structure/IUPAC Name	Analytical data
I lnt-35 i	F î )—NHBoc /Me Me tert-butyl {3-[6-bromo-4-fluoro-1- (propan-2-yl)-1H-benzimidazol-2_ yl]-1,1-difluoropropan-2yljcarbamate	1H NMR (400 MHz, CDCI3) δ 7.47 (|s, 1 H), 7.11 (dd, J = 1.1,9.6 Hz, 1H), 6.30 - 5.97 (m, 1H), 5.72 (br d, J = 9.1 Hz, 1 H), 4.72 - 4.57 (m, !1 H), 4.52 - 4.30 (m, 1 H), 3.34 0.13 (m, 2H), 1.70 - 1.60 (m, 6H), 1.36 (s, 9H); m/z (ESI+) for ~ (Ci8H23BrF3N3O2),‘396.0 (M- ‘ ..... tBu+H)+

144

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

Scheme 14:

HATU, DIPEA

DMF

100% yield step 1

AcOH reflux step 2

MsCI, TEA then t-BuOK DCM/THF

53% yield

K₂CO₃

MeOH 44% yield (2 steps) step 3

Br step 4

/Me lnt-36 Me

Step 1: Synthesis of N-{4-bromo-2-fluoro-6-[(propan-2-yl)amino]phenyl}oxetane-210 carboxamide (14a)

To a solution of 5-bromo-3-fluoro-/V¹-(propan-2-yl)benzene-1,2-diamine (7a) (1.0 g, 4.05 I I 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 h. TLC analysis (25% EtOAc/petroleum ether) showed consumption of the starting material. The solvent was removed in vacuum. The residue was diluted with saturated aqueous NazCOa (100 mL). The solution was extracted with EtOAc (2x100 mL). The combined organic phases were dried over Na2SO₄, filtered, and concentrated to provide A/-{4-bromo-2-fluoro-6-[(propan-219876 _ ¹⁴⁵ yl)amino]phenyl)oxetane-2-carboxamide (14a) (1.5 g, 100% yield), which was taken on directly to the next step.

Step 2: Synthesis of 3-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]-35 hydroxypropyl acetate (14b)

A brown solution of /V-{4-bromo-2-fIuoro-6-[(propan-2-yl)amino]phenyl}oxetane-2carboxamide (14a) (1.5 g, 4.5 mmol) in AcOH (20 mL) was stirred at 110 °C for 1.5 h. LCMS analysis showed consumption of the starting material with formation of the product mass. The mixture was concentrated to dryness to provide 3-[6-bromo-4-fluoro-1-(propan-2-y 1)-1/710 benzimidazol-2-yl]-3-hydroxypropyl acetate (14b) (1.5 g, 62% yield), which was taken directly into the next step without further purification, mlz (ESI+) for (CisHi8BrFN2O3), 374.9 (M+H)⁺.

Step 3: Synthesis of 1-[6-bromo-4-fIuoro-1-(propan-2-yl)-1H-benzimidazoI-2-yl]propane1,3-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 K2CO3. The mixture was stirred at room température for 2 h. LCMS analysis showed consumption of the starting material with formation of the product mass. The reaction mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by flash chromatography (Biotage, 40 g S1O2, 20 0-30% MeOH/EtOAc) to provide 1-[6-bromo-4-fluoro-1-(propan-2-yl)-1/7-benzimidazol-2yl]propane-1,3-diol (14c) (660 mg, 44% yield, 2 steps) as a pale brown solid. mlz (ESI+) for (Ci3Hi₆BrFN₂O2), 332.9 (M+H)⁺.

Step 4: Synthesis of 6-bromo-4-fIuoro-2-(oxetan-2-yl)-1-(propan-2-yl)-1H-benzimidazole 25 (lnt-36)

To a solution of 1-[6-bromo-4-fIuoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]propane-1,3diol (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 was added a solution of MsCI (208 mg, 7.25 mmol) in DCM drop-wise. After 2 h, solid t-BuOK (813 mg, 7.25 mmol) was added in one portion. The resulting solution was stirred at room 30 température for 2 h. TLC analysis (EtOAc) showed consumption of the starting material. The reaction was concentrated to dryness. The residue was purified by flash chromatography (Biotage, EtOAc, Rf~0.5) to provide 6-bromo-4-fluoro-2-(oxetan-2-yl)-1-(propan-2-y 1)-1/7benzimidazole (lnt-36) (300 mg, 53% yield) as a brown gum.

Préparation ôf 6-bromo-4-fIuoro-2-(oxetan-2-ÿl)-1 -(propan-2-yl)-1 H-benzimidâzole (lnt-37) according to Scheme 15.

146

Scheme 15:

step 1

AcOH . _ reflux step 2

Step 1: Synthesis of tert-butyl (2-{4-bromo-2-fIuoro-6-[(propan-2-yl)amino]anilino}-25 oxoethyl)carbamate (15a)

To a solution of 5-bromo-3-fluoro-/V¹-(propan-2-yl)benzene-1,2-cliamine (7a) (504 mg, 2.4 mmol), /V-(fert-butoxycarbonyl)gIycine (393 mg, 2.2 mmol), and HATU (1.2 g, 3.1 mmol) in THF (10.0 mL) at 0 °C was added DIPEA (0.72 mL, 4.1 mmol). The mixture was stirred at 0 °C for 30 min and then room température for 18 h. LCMS analysis showed complété consumption of the 10 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 Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (ISCO, 12 g SiO2, 0-100% EtOAc/petroleum ether) to provide tert-butyl (2-{4-bromo-2-fluoro-6-[(propan-2yl)amino]anilino}-2-oxoethyI)carbamate (15a) (810 mg, 98% yield) as a foamy solid. ¹H NMR (400 15 MHz, DMSO-de) δ 9.06 (s, 1H), 7.22 (t, J = 5.4 Hz, 1H), 6.64 (d, J = 8.8 Hz, 1H), 6.60 (s, 1H), 4.98 (d, J= 8.1 Hz, 1H), 3.68 (d, J = 5.6 Hz, 2H), 3.62 (dd, J = 6.6, 13.8 Hz, 1H), 1.40 (s; 9H), 1.13 (d, J = 6.2 Hz, 6H); mlz (4pCI+) for (Ci6H23BrFN₃O3), 404.0, 406.1 (M+H)⁺. |

Step 2: Synthesis of tert-butyl {[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazoI-220 yl]methyl}carbamate (lnt-37) i i

A solution of tert-butyl (2-{4-bromo-2-fIuoro-6-[(propan-2-yl)amino]anilino}-2oxoethyl)carbamate (15a) (809 mg, 2.0 mmol) in AcOH (4.0 mL) was stirred at 90 °C for 3.5 h. LCMS analysis showed some remaining starting material. The reaction was stirred for an additional 2.5 h at 100 °C; The reaction mixture was concentrated.-The residue was purified by25 flash chromatography (ISCO, 12g SiO₂,0-100% EtOAc/heptanes) to provide tert-butyl {[6-bromo4-fIuoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]methyl}carbamate (lnt-37) (547 mg, 70% yield) as

147 a white solid. ¹H NMR (400 MHz, DMSO-cfe) δ 7.79 (d, J= 1.3 Hz, 1H), 7.51 (br. s., 1H), 7.28 (dd,

J= 1.3, 10.1 Hz,TH), 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); mlz (APCI+) for (Ci6H2iBrFN₃O₂), 388.0 (M+H)⁺.

Préparation of tert-butyl {1-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2yl]ethyl}carbamate (lnt-38) according to Scheme 16:

Scheme 16:

Me HATU, DIPEA

DMF

85% yield step 1

step 2

I.AcOH 120 ’C

2. BOC2O THF/H₂O

26% yield

Step 1: Synthesis of tert-butyl (1-{4-bromo-2-fluoro-6-[(propan-2-yl)amino]anilino}1-oxopropan-2-yl)carbamate (16a)

To a solution of S-bromo-S-fluoro-A/Xpropan^-yljbenzene-l^-diamine (7a) (900 mg, 3.2 mmol) in DMF (8.0 mL) were added A/-(tert-butoxycarbonyl)alanine, DIPEA (1.26 g, 9.7 mmol), and HATU (1.85 g, 4.9 mmol). The mixture was stirred at ambient température for 16 h. LCMS analysis showed consumption ofthe starting material with formation ofthe desired product mass. The reaction mixture was concentrated to dryness. The residue was purified by flasn chromatography (ISCO, 20 g SiO₂, 30-50% EtOAc/petroleum ether) to provide tert-butyl (1-{4bromo-2-fluoro-6-[(propan-2-yl)amino]anilino}-1-oxopropan-2-yl)carbamate (16a) (1.14 g, 84% yield) as a white solid. i ;

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

A mixture of tert-butyl (1-{4-bromo-2-fIuoro-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 °Cfor 2 h. The solution was diluted with EtOAc (50 mL) and extracted with H₂O (50 mL). To the aqueous solution was _ 148 added THF (100 mL) and BOC2O (1.09 g, 5.0 mmol). The mixture was stirred at room température for 16 h. TLC analysis showed consumption of the intermediate. The solution was diluted with H₂O (30 mL) and extracted with EtOAc (30 mL). The organic phase was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (ISCO, 20 g SiO2, 5 25% EtOAc/petroleum ether) to provide fert-butyl {1-[6-bromo-4-fluoro-1-(propan-2-yl)-1/-/benzimidazol-2-yl]ethyl}carbamate (lnt-38) (1.1 g, 26% yield) as a gummy solid. mlz (ESI+) for (Ci₇H2₃BrFN₃O2), 401.7 (M+H)⁺.

The intermediate in the below table was synthesized according to the methods used for the synthesis of—tert-butyl {1-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2yl]ethyl}carbamate (lnt-38). The following intermediate was synthesized with non-critical changes or substitutions to the exemplified procedures that someone who is skilled in the art would be able to realize.

Compound number	Structure/IUPAC Name	Analytical data
lnt-39	Αχ '-/-NHBoc b Ar /^Me Me fert-butyl (1-{[6-bromo-4-fluoro-1- (propan-2-yl)-1H-benzimidazol-2yl]methyl}cyclopentyl)carbamate	1H NMR (400 MHz, CDCI3) δ 7.41 (s, 1H), 7.02 (d, J = 9.7 Hz, 1H), 4.78 (p, J = 7.0 Hz, 1H), 4.66 (s, 1H), 3.35 (s, 2H), 1.89-1.59 (m, 8H), 1.54 (d, J = 7.0 Hz, 6H), 1.34 (br d, J = 6.7 Hz, 9H); mlz (ESI+) for (Ci8H26BrFN2OSi), 454.1 (M+H)+

Préparation of (1R)-1-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]ethan-1-ol (lnt-40) according to Scheme 17. |

Scheme 17:

neat, 80 'C

149

A mixture ofthe 5-bromo-3-fIuoro-N¹-(propan-2-yI)benzene-1,2-diamine (7a) (5.74 g, 23.2 mmol) and (2R)-2-hydroxypropanoic acid (17.4 g, 193 mmol) was stirred at 82 ^eC for 44 h. The dark, viscous mixture was carefully added into a stirring mixture of DCM (100 mL) and saturated NaHCOs (250 mL) (gas évolution). The biphasic mixture was stirred at ambient température until 5 gas évolution ceased. The layers were separated and the aqueous phase extracted was with DCM (2x100 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated. The crude residue was purified by flash chromatography (S1O2, 20-80% MTBE/heptanes). The fractions containing product were further purified by first concentrating to a minimum volume. The resulting residue was dissolved in a small volume of MTBE then diluted 10 with an equal volume of heptanes. The solution was sonicated, causing précipitation. The resulting suspension was concentrated until only a small amount of solvent remained. The supernatant was decanted off. The solids were rinsed with 10% MTBE/heptanes followed by heptanes and then dried under vacuum to provide (1R)-1-[6-bromo-4-fluoro-1-(propan-2-yl)-1Hbenzimidazol-2-yl]ethan-1-ol (lnt-40) (4.97 g, 71% yield) as a tan solid. ¹H NMR (400 MHz, 15 DMSO-d₆) 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 (Ci₂Hi4BrFN₂O) 300.8 (M+H)⁺.

The intermediates in the below table were synthesized according to the methods used for the synthesis of (1R)-1-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]ethan-1-ol (Int20 40). The following intermediates were synthesized with non-critical changes or substitutions to the exemplified procedures that someone who is skilled in the art would be able to realize.

Compound number	Structure/IUPAC Name	Analytical data
lnt-41	F Me .. JMe Me 1 -[6-bromo-4-fluoro-1 -(propan-2yl )-1 /-/-benzimidazol-2-yl]ethan-1 ol	m/z (APCI+) for (C12H14BrFN2O), ' 302.7 (M+H)+
lnt-42	- - F OH ----------- J-Me _ _ Me ......	m/z (APCI+) for (Ci2Hi4BrFN2O), 302.9 (M+H)+

150

-

(1 S)-1 -[6-bromo-4-fiuoro-1 (propan-2-yl)-1H-benzimidazol-2yl]ethan-1-ol

• - * -

Préparation of 1-[6-bromo-1-(1,1-difluoropropan-2-yl)-4-fluoro-1H-benzimidazol-2yl]ethan-1-ol (lnt-43) according to Scheme 18

Scheme 18

neat

84% yield

HCl 1,4-dioxane 42% yield

step 1 step 2

Step 1: Synthesis of /V-{4-bromo-2-[(1,1-difluoropropan-2-yl)amino]-6-fIuorophenyl}-2hydroxypropanamide (18b)

A mixture of 5-bromo-/\r-(1,1-difluoropropan-2-yl)-3-fiuorobenzene-1,2-diamine (18a) (Prepared as in Scheme 7,1.0 g, 3.5 mmol) and 2-hydroxypropanoic acid (10.0 mL) was stirred at 85 °C for 16 h. LCMS indicated consumption of the starting material with formation of the desired product mass. H₂O (15 mL) and EtOAc (15 mL) were added and the mixture was cooled to 0 °C. The mixture was adjusted to pH ~7 with 50% aqueous NaOH. The layers were separated.

The aqueoLs layer was extracted with EtOAc (2x20 mL). The comtJined organic layers were dried over Na₂SO4, filtered, and concentrated. The residue was purified by flash chromatography (20 g SiO₂,0-50% EtOAc/petroleum ether) to provide A/-{4-bromo-2-[(1,1-difluoropropan-2-yl)amino]6-fluorophènyl)-2-hydroxypropanamide (18b) (1.0 g, 84% yield)¹ as a dark oil. m/z (ESI) for (Ci₂Hi4BrF₃N₂O₂), 356.6 (M+H)⁺. ¹

Step 2: Synthesis of 1-[6-bromo-1-(1,1-difluoropropan-2-yl)-4-fluoro-1H-benzimidazol-2yl]ethan-1- (lnt-43)

A solution of /V-{4-bromo-2-[(1,1-difluoropropan-2-yl)amino]-6-fluorophenyi}-2hydroxypropanamide (18b) (1.0 g, 3.0 mmol) in 1,4-dioxane (10 mL) was stirred at 130 °C for 15 ¹⁵¹ min with microwave irradiation. LCMS analysis showed consumption of the starting material with formation of the desired product mass. The solution was concentrated to dryness. The residue was taken up in H2O (3 mL) and then basified with aqueous NH4OH (1 mL) to pH -8 m. The solution was extracted with EtOAc (3x5 mL). The combined organic layèrs were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (ISCO, 20 g S1O2,1:1 EtOAc/petroleum ether) to provide (lnt-43) (400 mg, 42% yield) as a dark oil. ¹H NMR (400 MHz, CDCI₃) 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 (Ci2Hi2BrF₃N₂O), 338.7 (M+H)⁺. _ .

----- -------Préparation of 6-bromo-2-(difIuoromethyl)-4-fIuoro-1-(propan-2-yl)-1H-benzimidazo!e (Int44) according to Scheme 19.

Scheme 19:

A mixture of 5-bromo-3-fluoro-/V¹-(propan-2-yl)benzene-1,2-diamine (7a) and difluoroacetic anhydride (1.47 mL, 11.8 mmol) in AcOH (4.6 mL) was stirred at 90 °C for 3 h. The solvent was removed by vacuum. The residue was taken up into DCM (30 mL). The mixture was adjusted to pH ~8-9 with 1.0 N aqueous NaOH and the layers were separated. The organic layer 20 was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (ISCO, 12 g S1O2, 0-50% EtOAc/petroleum ether) to provide 6bromo-2-(difluoromethyl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazole (lnt-44) (523 mg, 72% yield) as a white solid. ¹H| NMR (400 MHz, DMSO-d₆) δ 8.02 (d, J = 1.5 Hz, 1 H)| 7.63 - 7.28 (m, 2H), 5.04 - 4.84 (m, 1H), 1.60 (d, J = 6.8 Hz, 6H); m/z (APCI+) for (CiiHioBrF₃N₂), 309.1 (M+H)*.

Préparation of 6-bromo-1-tert-butyl-4-fIuoro-1H-benzimidazole (lnt-45) according to

I j

Scheme 20. i i

Scheme 20:

152

POCI₃, TEA

PhMe, 10-20 ’C

64% yield

step 1 step 2

t-BuOK DMF, 70-75 ’C

36% yield

Step 1: Synthesis of N-(4-bromo-2,6-difluorophenyl)-N^,-ferf-butyImethanimîdamide (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 /V-tert-butylformamide (2.92 g, 3.2 mL, 28.8 mmol) in PhMe (50 mL) was treated with POCI3 (5.53 g, 3.36 mL, 36.1 mmol) at 0 C (maintaining an internai température below 20 ’C). The mixture was stirred at ambient température for 15 h 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 Na2SO4, filtered, and concentrated. The crude residue was suspended in EtOAc (5 mL) and petroleum ether (40 mL), slurried for 10 min, and collected by filtration to provide A/-(4-bromo-2,6difluorophenyO-Af-fert-butylmethanimidamide (20b) (4.50 g, 64% yield) as a yellow solid. m/z (ESI+) for (CnHi3BrF2N₂), 292.6 (M+H)⁺.

Step 2: Synthesis of 6-bromo-1-terf-butyl-4-fIuoro-1H-benzimidazole (lnt-45)

To a solution of A/-(4-bromo-2,6-difluorophenyl)-AT-tert-butylmethanimidamide (20b) (4.50 g, 15.5 mmol) in DMF (40 m^) was added KOtBu (2.60 g, 23.2 mmol) and the mixtur^ was stirred at 80 ’C for 14 h. 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 stages, first by flash chromatography (S1O2, 20 20% EtÔAc/petroleum ether) then by préparative HPLC on a Phenomenex Synergi Max-RP column (250 x 80 mm, 10 pm particle size, column température of 25 ’C), which was eluted with 35-65% MeCN/H₂O (+0.225% formic acid) with flow rate of 80 mL/min to provide 6-bromo-1-tert-. .

butyl-4-fluoro-1H-benzimidazole (lnt-45) (1.5 g, 36% yield) as a grey solid. m/z (ESI+) for (Ci 1 Hi₂BrFN₂), 270.9 (M+H)⁺.

153

The intermediate in the below table was synthesized according to the methods used for the synthesis of 6-bromo-1-tert-butyl-4-fluoro-1H-benzimidazole (lnt-45). The following intermediate was synthesized with non-critical changés or substitutions to the exemplified procedures that someone who is skilled in the art would be able to realize.

Compound number	Structure/ IUPAC name	Analytical data
lnt-46	F i[ £ —Me M / ~Me Me 6-bromo-4-fluoro-2-methyl-1 - (propan-2-yl)-1 H-benzimidazole	m/z (ESI+) for (CnHi2BrFN2), 270.6 (M+H)+

Préparation of fert-butyl 3-(6-bromo-4-fluoro-2-methyl-1H-benzimidazol-1-yl)azetidine-1carboxylate (lnt-47) according to Scheme 21.

Scheme 21:

I—<N-Boc

K₂CO₃

DMF

23% yield

To a solution of 6-bromo-4-fluoro-2-methyl-1/7-benzimidazole (21a) (271 mg, 1.18 mmol) and tert-butyl 3-iodoazetidine-1-carboxyIate (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 h. The reaction mixture was cooled to room température and loaded onto SiO₂. The crude material was purified via flash chromatography (SiO₂, 0-1 (|0% EtOAc/heptane) to provide a mixture of regioisom^rs. These compounds were subsequently separated by préparative SFC on a Waters SFC 200 Glacier/Two ZymorSPHER HADP column (150 x 21.1 mm I.D.,5 pm particle size), which was eluted with 10-35% MeOH/CO2 (100 bar, 35 ’C) with a flow rate of 80 mL/min to provide tert-butyl 3-(6-bromo-4-fluoro-2-methyI-1H-benzimidazol-1-yl)azetidine-1-carboxyIate (lnt-47) (106 mg, 23% yield) as a solid. Ή NMR (400 MHz, DMSO-d₆) 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 (APÇI+) for (Ci₆H₁₉BrFN₃O2), 384.0 (M+H)⁺.

Préparation of 6-bromo-2,4-dimethyl-1-(propan-2-yl)-1H-benzimidazole (lnt-48) according to Scheme 22.

154

Scheme 22:

Me

22a

2-iodopropane - NaH /

DMF

88% yield

Me

To a solution of 6-bromo-2,4-dimethyI-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 minerai oil, 222 mg, 5.55 mmol). The réaction mixture was stirred at ambient température 16 h. LCMS analysis showed consumption ofthe starting material with formation of the desired product mass. The reaction was quenched with Η₂Ο (3 mL) and then concentrated under vacuum. The crude residue was purified by flash chromatography (ISCO, 20 g S1O2, 70%

EtOAc/petroleum ether) to provide 6-bromo-2,4-dimethyl-1-(propan-2-yl)-1H-benzimidazole (Int48) (260 mg, 88% yield). m/z (ESI+) for (C₁₂Hi₅BrN2), 268.8 (M+H)⁺.

The intermediate in the below table was synthesized according to the methods used for the synthesis of 6-bromo-2,4-dimethyl-1-(propan-2-yl)-1H-benzimidazole (lnt-48). The following 15 intermediate was synthesized with non-critical changes or substitutions to the exemplified procedures that someone who is skilled in the art would be able to realize.

Compound number	Structure/ IUPAC name	Analytical data
lnt-49	ci XX > । /'Me Me 6-bromo-4-chloro-1 -(propan-2-yl)- I 1 H-benzimidazole i	1H NMR (400 MHz, CDCI3) δ 8.05 (s, 1H), 7.84 (d, J= 1.5 Hz, 1H), 7.39 (d, J =1.3 Hz, 1H), 5.40 (quin.d, J= 6.6,13.3 Hz, 1H), 1.62 (d, J = 6.5 Hz, 6H); m/z (ESI+) for (CioHioBrCIN2), 274.8 (M+H)+

Préparation of fert-butyl [1-(6-bromo-4-fiuoro-2-methyl-1H-benzimidazol-1-yl)propan-2yl]carbamate (lnt-50) according to Scheme 23.

Scheme 23:

To a solution of 6-bromo-4-fluoro-2-methyl-1H-benzimidazole (23a) (500 mg, 2.18 mmol) in anhydrous THF (15.0 mL) was added solid f-BuOK (294 mg, 2.62 mmol). The mixture was stirred at ambient température for 10 min followed by addition of 1-[(tert5 butoxycarbonyl)amino]propan-2-yl methanesulfonate (888 mg, 3.51 mmol). The mixture was stirred at 60 °C under an atmosphère of Ar for 17 h. LCMS analysis showed -50% consumption ofthe starting material. The reaction was cooled to room température and additional f-BuOK (122 mg, 1.09 mmol) was added followed by additional 1-[(tert-butoxycarbonyl)amino]propan-2-yl methanesulfonate (730 mg, 1.46 mmol). The mixture was stirred at 60 °C for 18 h. LCMS analysis 10 showed -65% conversion. The mixture was diluted with H2O (30 mL) and extracted with DCM (3x15 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated. The crude mixture was purified by flash chromatography (20 g SiO2, 10-65% EtOAc/petroleum ether). The fractions containing the desired product were collected and re-purified by préparative HPLC on a YMC-Actus Triart C18 column (150x40 mm, 5 pm particle size), which was eluted with 33-73% MeCN/H2O (0.05% NH4OH) with a flow rate of 25 mL/min to provide fert-butyl [1-(6bromo-4-fluoro-2-methyl-1H-benzimidazol-1-yI)propan-2-yl]carbamate (lnt-50) (112 mg, 16% yield). ¹H NMR (400 MHz, CDCI3) 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 (Ci6H2iBrFN₃O₂), 387.8 (M+H)⁺.

Préparation of tert-butyl [1-(6-bromo-4-fluoro-2-methyl-1H-benzimidazol-1-yl)propan-2yl]carbamate (lnt-49) according to Scheme 24.

Scheme 24:

F ^F

JL cyclopropyl methyl ketone JL n 1/ i A :: l· * Am.

₂₅ lnt-22 M/^Me ₆₃._Ayielcl ----------- lnt-51 Me^^Me A solution of 6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazole (lnt-22) (500 mg, 1.94 mmol) in THF (20.0 mL) under a N2 atmosphère was cooled to -65 °C with a dry ice/acetone bath. A solution of LDA (2.0 M in THF, 1.94 mL, 3.89 mmol) was added drop-wise. The reaction mixture was stirred at the same température for 1 h followed by the addition of cyclopropyl methyl ketone

156 (327 mg, 3.89 mmol). After 1 h at -65 °C LCMS analysis showed consumption of the starting material with conversion to the desired product mass. The reaction mixture was quenched with saturated aqueous NH4CI (10 mL). The phases were separated. The aqueous phase was extracted with EtOAc (3x15 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated. The crude residue was purified by flash chromatography (ISCO, 1:3 EtOAc/petroleum ether) to provide [1-(6-bromo-4-fIuoro-2-methyl-1H-benzimidazol-1-yl)propan2-yl]carbamate (lnt-51) (420 mg, 63% yield) as a white solid. ¹H NMR (400 MHz, CDCI3) δ 7.52 (d, J = 1.5 Hz, 1H), 7.12 (dd, J = 1.5, 9.7 Hz, 1H), 5.46 - 5.22 (m, 1H), 3.71 (s, 1H), 1.72 (s, 3H), 1.67 (dd, J = 6.1, 6.8 Hz, 6H), 1.41 - 1.30 (m, 1H), 0.77 - 0.67 (m, 1H), 0.64 - 0.53 (m, 2H), 0.52 - 0.44 (m, 1H); m/z (ESI+) for (Ci5Hi₈BrFN₂O), 340.7 (M+H)⁺.

Préparation of (4R)-7-bromo-9-fluoro-4-methyl-3,4-dihydro-1 ,4]oxazino[4,3a]benzimidazole (lnt-50) according to Scheme 24.

Scheme 25:

o

step 2 step 1

AcOH step 3

91% yield

Step 1: Synthesis of (5R)-4-(5-bromo-3-fIuoro-2-nitrophenyl)-5-methylmorpholin-3-one (25a) - ......

I I

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 minerai oil, 208 mg, 5.21 mmol). The reaction suspension was stirred at ambient température for 30 min and then 5-bromo-1,3-difluoro-2-nitrobenzene (1a) (1.03 mg, 4.34 mmol) was added. The réaction süspehsion was stirred for 1 h. LCMS analysis showed consumption ofthe starting material. H2O (2 mL) was added and the reaction suspension was concentrated to dryness. The residue was taken up into EtOAc (80 mL) and was washed with H2O (60 mL). The organic layer was dried over Na2SÜ4, filtered, and concentrated to dryness.

157

The residue was purified by flash chromatography (ISCO, 20 g S1O2,1:3 EtOAc/petroleum ether) to provide (5R)-4-(5-bromo-3-fluoro-2-nitrophenyl)-5-methylmorpholin-3-one (25a) (760 mg, 53% yield) as a light yellow solid. m/z (ESI+) for (CnHioBrFN20₄), 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 H₂O (4.0 mL) were added Fe° (637 mg, 11.4 mmol) and NH4CI (610 mg, 11.4 mmol). The reaction suspension was stirred at 80 ^eC for 4 h under an 10 atmosphère of N2. LCMS analysis indicated complété consumption ofthe starting material with formation of the desired product mass. The reaction mixture was filtered and concentrated to dryness. The residue was purified by flash chromatography (S1O2,1:3 EtOAc/petroleum ether to provide (5R)-4-(2-amino-5-bromo-3-fluorophenyl)-5-methyImorpholin-3-one (25b) (420 mg, 61% yield) as a light brown gum. m/z (ESI+) for (CnHi2BrFN2O2), 303.1 (M+H)⁺.

Step 3: Synthesis of (4R)-7-bromo-9-fluoro-4-methyl-3,4-dihydro-1H-[1,4]oxazino[4,3a]benzimidazole (lnt-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 h. LCMS analysis showed 20 consumption of the starting material with formation of the desired product mass. The reaction mixture was concentrated to dryness. The residue was taken up in EtOAc (50 mL) and washed with aqueous saturated NaHCOa (30 mL). The organic phase was dried over Na2SO4, filtered, and concentrated to provide (4R)-7-bromo-9-fluoro-4-methyl-3,4-dihydro-1H-[1,4]oxazino[4,3a]benzimidazole (lnt-52) (360 mg, 91% yield) as a light-yellow solid. m/z (ESI+) for 25 (CnHioBrFN₂0), 286.6 (M+H)⁺.

The intenjiediates in the below table were synthesized according |to the methods used for the synthesis of (4R)-7-bromo-9-fluoro-4-methyl-3,4-dihydro-1/-/-[1,4]oxazino[4,3a]benzimidazole (lnt-52). The following intermediates were synthesized with non-critical changes 30 or substitutions to the exemplified procedures that someone who is skilled in the art would be able to realize. I I

Compound number

Structure/ IUPAC name

Analytical data

158

lnt-53	F Αχ i m/ (4S)-7-bromo-9-fluoro-4-methyl3,4-dihydro-1 H-[1,4]oxazino[4,3a]benzimidazole	m/z (ESI+) for (CnHioBrFN20), 286.6 (M+H)+
Int-54	F zAn Lia Br'^^N_p Me 7-bromo-4-ethyl-9-fluoro-3,4dihydro-1 H-[î ,4]oxazino[4,3a]benzimidazole	m/z (ESI+) for (Ci2Hi2BrFN2O), 300.9 (M+H)+
lnt-55	F __N—Boc Me' fert-butyl 7-bromo-9-fluoro-4methyl-3,4-dihydropyrazino[1,2a]benzimidazole-2(1 H)carboxylate	1H NMR (400 MHz, DMSO-d6) δ 7.79 (d, J = 1.5 Hz, 1H), 7.33 (dd, J = 1.5, 10.3 Hz, 1 H), 5.21 - 4.96 (m, 1H), 4.75 (brs, 1H), 4.264.09 (m, 1H), 3.67 - 3.57 (m, 2H), 1.46 (s, 9H), 1.35 (brd, J =6.3 Hz, 3H); m/z (ESI+) for (Ci6Hi9BrFN3O2), 385.9 (M+H)+
lnt-56	F .Ah ΜεΆ Me 7-brdmo-5-fluoro-1,1 -dimethyl-2,3dihydro-1 H-pyrrolo[1,2a]benzimidazole	m/z (ESI+) for (Ci2Hi2BrFN2), 284.9 (M+H)|+

i

Préparation of 7-bromo-9-fluoro-4,4-dimethyl-3,4-dihydro-1H-[1,<4]oxazino[4₎3a]benzimidazole (lnt-57) according to Scheme 26.

Scheme 26:

159

Br

1a

Br

N0₂

NH₂ o

Me l/*'-.·

Me

K₂CO₃

F____DMF 80’C

68% yield step 1

Br

F NO₂

26a

NH Më-Y Me

Fe°, NH₄CI nh₂

EtOH/H₂O, 80 ’C

OH ‘

86% yield step 2

Br NH

Me^Y^OH

26b ^Me

CI^C(OEt)₃ step 3

AcOH, 55 ’C

Me .. lnt-57 Me t-BuOK

N

N

94% yield

THF. 0-5 ’C

72% yield step 4

Step 1: Synthesis of 2-(5-bromo-3-fluoro-2-nitroanilino)-2-methylpropan-1-ol (26a)

To a yellow solution of 5-bromo-1,3-difluoro-2-nitrobenzene (1a) (8.0 g, 33.6 mmol) in DMF (30 mL) were added K2CO3 (9.3 g, 67.2 mmol) and 2-amino-2-methylpropan-1-ol (3.0 g, 5 33.6 mmol). The mixture was stirred at 80 °C for 1 h. LCMS analysis showed consumption of the starting material with formation of the desired product mass. The reaction was cooled to room température, filtered, and concentrated. The residue was purified by flash chromatography (ISCO, 80 g S1O2, 15% EtOAc/petroleum ether) to provide 2-(5-bromo-3-fluoro-2-nitroanilino)-2methylpropan-1-ol (26a) (7.0 g, 68% yield) as a yellow solid. m/z (ESI+) for (CioHi2BrFN203), 10 307.0 (M+H)⁺.

Step 2: Synthesis of 2-(2-amino-5-bromo-3-fluoroanilino)-2-methylpropan-1-ol (26b)

To a solution of 2-(5-bromo-3-fluoro-2-nitroanilino)-2-methylpropan-1-ol (26a) (7.0 g, 22.8 mmol) in EtOH (50 mL) was added saturated aqueous NH4CI (10 mL) and Fe° (6.36 mg, 114 15 mmol) and the mixture was stirrec| at 80 °C for 1 h. TLC analysis showed consumption |of the starting material. The mixture was filtered and concentrated to dryness. The residue was purified by flash chromatography (ISCO, 80 g SiO2, 30% EtOAc/petroleum ether) to provide 2-(2-amino5-bromo-3-fluoroanilino)-2-methylpropan-1-ol (26b) (5.4 g, 86% yield) as a black oil. m/z (ESI+) for (C₁₀H₁₄BrFN₂O), 277.0, 279.0 (M+H)⁺. i

Step 3: Synthesis of 2-[6-bromo-2-(chloromethyl)-4-fIuoro-1H-benzimidazol-1-yl]-2methylpropan-1-ol (26c) _ . .

A yellow solution 2-(2-amino-5-bromo-3-fluoroanilino)-2-methyIpropan-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

160 °C for 8 min. LCMS analysis showed consumption of the starting material with formation of the product mass. After cooling to room température the reaction mixture was combined with parallel reactions run on smaller sale (5x100 mg). The combined reaction mixtures were basified with saturated aqueous NaHCO₃ to adjust to pH ~7-8 and extracted with EtOAc (3x20 mL). The 5 combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (ISCO, 40 g SiO2, 30% EtOAc/petroleum ether) to provide 2-[6-bromo-2-(chloromethyl)-4-fluoro-1/7-benzimidazol-1-yl]2-methylpropan-1-ol (26c) (2.0 g, 72% yield) as a light yellow solid. ¹H NMR (400 MHz, DMSOd₆) 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), 10 3.87 (d, J = 5.3 Hz, 2H), 1.78 (s, 6H). m/z (ESI+) for (Ci₂Hi₃BrCIFN₂O), 336.9 (M+H)*.

Step 4: Synthesis of 7-bromo-9-fluoro-4,4-dimethyl-3,4-dihydro-1H-[1,4]oxazino[4,3a]benzimidazole (lnt-57)

To a solution of 2-[6-bromo-2-(chloromethyl)-4-fluoro-1H-benzimidazol-1-yl]-215 methylpropan-1-ol (26c) in THF (5.0 mL) was added t-BuOK (251 mg, 2.23 mmol) at 0 °C. The solution was stirred at 0 °C for 30 min. LCMS analysis showed consumption of the starting material with formation of the desired product mass. The reaction mixture was diluted with H₂O (10 mL) and 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 20 chromatography (ISCO, 20 g S1O2,30% EtOAc/petroleum ether) to provide 7-bromo-9-fIuoro-4,4dimethyl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole (lnt-57) (420 mg, 94% yield) as a yellow solid. ¹H NMR (400 MHz, CDCI₃) δ 7.47 (d, J = 1.5 Hz, 1 H), 7.14 (dd, J = 1.5, 9.5 Hz, 1 H), 4.98 (s, 2H), 3.84 (s, 2H), 1.67 (s, 6H); m/z (ESI+) for (Ci₂Hi2BrFN₂O), 298.7 (M+H)*.

Préparation of 7-bromo-9-fluoro-2,4,4-trimethyl-1,2,3,4-tetrahydropyrazino[1,2a]benzimidazole (lnt-58) according to Scheme 27.

Scheme 27:

I.MsCI, DIPEA MeCN, 0 ’C

2. MeNH₂, 60 ’C

43% yield

To a solution of 2-[6-bromo-2-(chloromethyl)-4-fluoro-1H-benzimidazol-1-yl]-2methylpropan-1-ol (26c) (500 mg, 1.49 mmol) and DIPEA (578 mg, 4.47 mmol) in MeCN (5.0 mL) was added MsCI (256 mg, 2.23 mmol) drop-wise. After addition, the resulting solution was allowed to warm to room température and stirred for 1 h. LCMS analysis showed consumption of

161 the starting material with formation ofthe desired product mass. To the solution was added DIPEA (963 mg, 7.45 mmol) and methylamine hydrochloride (201 mg, 2.98 mmol). The resulting solution was stirred at 60 °C for 14 h. LCMS analysis showed consumption ofthe mesylate intermediate with formation of the desired product mass. The reaction mixture was concentrated to dryness.

The residue was purified by flash chromatography (ISCO, 20 g S1O2, 30% EtOAc/petroleum ether) to provide 7-bromo-9-fIuoro-2,4,4-trimethyl-1,2,3,4-tetrahydropyrazino[1,2a]benzimidazole (lnt-58) (200 mg, 43% yield) as a yellow gum. ¹H NMR (400 MHz, CDCI3) 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 (Ci₃H₁₅BrFN₃), 314.0 (M+H)⁺.

Préparation of 7-bromo-9-fluoro-1,4-dimethyl-3,4-dihydro-1H-[1_>4]oxazino[4,3a]benzimidazole (lnt-59) according to Scheme 28.

Scheme 28:

DMF, 80 C

93% yield

K₂CO₃

O

OTBS

Me

Na₂S₂O₄

EtOH/DMSO, 80 C

71% yield

step 2 step 3

TBAF THF

54% yield

TsOH

PhMe, 120 °C

80% yield step 4

Step 1: Synthesis of 2-(5-bromo-3-fluoro-2-nitroanilino)propan-1-ol (28a) । To a solution of 5-bromo-1,3-difluoro-2-nitrobenzene (1a) (4.0 g, 16.8 mmol) in DMF (40.0 । mL) was added K2CO3 (4.65 g, 33.6 mmol) and 2-aminopropan-1-ol (1.26 g, 16.9 mmol). The mixture was stirred at 80 °C for 1 h. TLC analysis (3:1 petroieum ether/EtOAc) showed consumption of the starting material. After cooling to room température, the reaction mixture was diluted with H2O (150 mL) and extracted with EtOAc (2x150 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated to provide 2-(5-bromo-3-fluoro-2nitroanilino)propan-1-ol (28a) (4.7 g, 93% yield) as a yellow oil. m/z (ESI+) for (C9HioBrFN₂0₃),

294.6 (M+H)⁺.

162

Step 2: Synthesis of 2-[6-bromo-2-(1-{[fert-butyl(dimethyl)silyl]oxy}ethyl)-4-fluoro-1Hbenzimidazol-1-yl]propan-1-ol (28b)

To a yellow solution of 2-(5-bromô-3-fluoro-2-nitroanilino)prdpàn-1-ol (28a) (1.3 g, 3.3 . mmol) and 2-{[fert-butyl(dimethyl)silyl]oxy}propanal (1.0 g, 5.3 mmol) in EtOH (10.0 mL) and DMSO (3.0 mL) was added Na2S2O4 (2.9 g, 16.4 mmol). The suspension was stirred at 80 °C for 16 h. LCMS analysis showed consumption of the starting material with formation of the desired product mass. The mixture was concentrated to remove the EtOH. The solution was diluted with EtOAc (100 mL) and washed with H₂O (50 mL). The organic phase was dried over Na₂SO4, filtered, and concentrated. The residue was purified by flash chromatography (ISCO, 20 g S1O2, 25% EtOAc/petroleum ether) to provide 2-[6-bromo-2-(1-{[tert-butyl(dimethyl)silyl]oxy]ethyl)-4fiuoro-1H-benzimidazol-1-yl]propan-1-ol (28b) (1.0 g, 71% yield) as a white solid. m/z (ESI+) for (Ci₈H₂₈BrFN₂O₂Si), 432.8 (M+H)⁺.

Step 3: Synthesis of 2-[6-bromo-4-fluoro-2-(1-hydroxyethyl)-1H-benzimidazol-1-yl]propan1-01 (28c)

To a solution of 2-[6-bromo-2-(1-{[tert-butyl(dimethyl)silyl]oxy)ethyl)-4-fIuoro-1Hbenzimidazol-1-yl]propan-1-ol (28b) (1.0 g, 2.32 mmol) in THF (5.0 mL) was added TBAF (1.2 g, 4.64 mmol) at ambient température. After 1 h, TLC analysis (100% EtOAc) showed consumption of the starting material. The reaction solution was diluted with EtOAc (100 mL) and washed with H₂O (2x50 mL). The organic phase was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (ISCO, 20 g S1O2, 80% EtOAc/petroleum ether) to provide 2-[6-bromo-4-fluoro-2-(1-hydroxyethyl)-1H-benzimidazol-1-yl]propan-1-ol (28c) (400 mg, 54% yield) as a white solid. m/z (ESI+) for (C₁₂Hi₄BrFN2O2), 316.7 (M+H)⁺.

Step 4: Synthesis of 7-bromo-9-fIuoro-1,4-dimethyI-3,4-dihydro-1H-[1,4]oxazino[4,3ajber^zimidazole (lnt-59) |

A solution of 2-[6-bromo-4-fluoro-2-(1-hydroxyethyl)-1H-benzimidazol-1-yl]propan-1-ol (28c) (400 mg, 1.26 mmol) and TsOH (434 mg, 2.52 mmol) in PhMe (5.0 mL) was stirred at 120 °C for 16 h. To the solution was added saturated aqueous NaHCOs (20 mL). The mixture was extracted with EtOAc (2x100 mL). The combined organic I phases were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (ISCO, 20 g S1O2, 80-90% EtOAc/petroleum ether) to provide 7-bromo-9-fluoro-1,4-dimethyl-3,4-dihydro-1/-/[1,4]oxazino[4,3-a]benzimidazole (lnt-59) (300 mg, 80% yield, diastereoisomeric mixture) as a yellow oil. m/z (ESI+) for (Ci2Hi₂BrFN2O), 298.7 (M+H)⁺. ' .

163

Préparation of 6-bromo-1-(propan-2-yl)-1H-benzotriazole (lnt-60) according to Scheme 29.

Scheme 29:

HBr, NaNO₂

H₂O

80% yield

To a solution of 4-bromo-A/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 température for 30 min then allowed to warm to ambient température over a period of 2 h. The reaction mixture was poured into saturated aqueous Na₂CO3 (150 mL) and extracted with EtOAc (2x150 mL). The combined organic phases were washed with brine, dried over Na₂SO4, filtered, and concentrated. The crude residue was purified by flash chromatography (SiO₂, 0-30% EtOAc/petroleum ether) to provide 6-bromo-1-(propan-2-yl)-1/-/-benzotriazole (lnt-60) (2.50 g, 80% yield) as a brown oil. m/z (ESI+) for (C₉Hi₀BrN₃), 239.6 (M+H)⁺.

Préparation of 2-(5-bromo-2-methyl-2H-indazol-3-yl)propan-2-ol (lnt-61) according to Scheme 30.

Scheme 30:

30a

LDA; acetone

THF

31% yield

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 (| °C for 10 min and then cooled to -78 °C. Acetone (124 rpg, 2.14 mmol) was added to the reaction mixture at -78 °C. The reaction was then allowed to warm to ambient température and stirred for 18 h. LCMS analysis showed consumption ofthe starting material with formation of the desired | product mass. The reaction was quenched with saturated aqueous NaHCOs (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 Na₂SO4, filtered, and concentrated. The residue was purified by flash chromatography (ISCO, 20 g SiO₂, 0-100% EtOAc/petroleum ether) to provide 2-(5-bromo-2-methyl-2H-indazol-3-yl)propan-2-ol (lnt-61) (120 mg, 31% yield) as a colorless oil. m/z (ESI+) for (CnHi₃BrN₂O(, 270.9 (M+H)⁺.

164

Préparation of 5-bromo-2-methyl-3-(propan-2-yl)-2H-indazole (lnt-62) according to

Scheme 31.

Scheme 31:

74% yield

To a stirring solution of 2-(5-bromo-2-methyl-2H-indazol-3-yl)propan-2-ol (lnt-61) in DCM (10 mL) were added TFA (847 mg, 7.43 mmol) and Et₃SiH (846 mg, 7.43 mmol) at 0 °C. The mixture was stirred at 25 °C for 36 h. LCMS analysis showed consumption of the starting material. The reaction was quenched with H2O, adjusted to pH ~8 with saturated aqueous NaHCOs, and extracted with DCM (3x10 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (ISCO, 4 g SiO2, 0-100% EtOAc/petroleum ether) to provide 5-bromo-2-methyl-3-(propan-2-yl)-2Hindazole (lnt-62) (140 mg, 74% yield) as a yellow oil. ¹H NMR (400 MHz, CDCI₃) 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, 1 H), 1.49 (d, J = 7.0 Hz, 6H); m/z (ESI+) for (CnHi₃BrN₂), 252.8 (M+H)⁺.

Préparation of 9-bromo-7-fIuoro-1,1-dimethyl-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazole (lnt-61) according to Scheme 32.

Scheme 32:

Br^°^H NaOMe

MeOH, 85 *C | 32% yield step 1

32b

LDA; acetone

73% yield

THF, -78 C - rt

p-TSA PhMe, 120 ’C i ! 55% yield step 3

F

Step 1: Synthesis of 2-(5-bromo-7-fluoro-2H-indazol-2-yl)ethan-1-ol (32b) ..... '

To a solution of 5-bromo-7-fluoro-1H-indazole (32a) (2.5 g, 11.6 mmol) in MeOH (10.0 mL) was added NaOMe (1.26 g, 23.3 mmol) and 2-bromoethan=1-ol (2.0 g, 11.6 mmol) under an

165 atmosphère of N2. The résultant solution stirred at 85 °C for 16 h. The reaction mixture was cooled to room température. TLC analysis (1:1 EtOAc/petroleum ether) showed partial consumption of the starting material. The réaction mixture was concentrated to dryness and purified by flash chromatography (ISCO, 80 g S1O2, 0-100% EtOAc/petroleum ethër) to provide 2-(5-bromo-75 fluoro-2H-indazol-2-yl)ethan-1-ol (32b) (950 mg, 32% yield) as a white solid. m/z (ESI+) for (C₉H₈BrFN₂O), 260.8 (M+H)⁺.

Step 2: Synthesis of 2-[5-bromo-7-fiuoro-2-(2-hydroxyethyl)-2H-indazol-3-yl]propan-2-ol (32c)

A solution of 2-(5-bromo-7-fluoro-2H-indazol-2-yl)ethan-1-ol (32b) (550 mg, 2.12 mmol) in THF (10.0 mL) was purged with 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 min and then cooled back to -78 ^eC. To the solution was added acetone (247 mg, 4.25 mmol). The resulting solution was stirred for 16 h at room température. LCMS analysis showed complété consumption ofthe starting material with formation of the desired product mass. The reaction was quenched with H2O (30 mL) and extracted with EtOAc (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The crude residue was purified by flash chromatography (ISCO, 20 g SiO2, 5070% EtOAc/petroleum ether) to provide 2-[5-bromo-7-fluoro-2-(2-hydroxyethyl)-2H-indazol-3yI]propan-2-ol (32c) (490 mg, 73% yield) as a colorless oil.

Step 3: Synthesis of 9-bromo-7-fIuoro-1,1-dimethyl-3,4-dihydro-1H-[1,4]oxazino[4,3b]indazole (lnt-63)

To a solution of 2-[5-bromo-7-fIuoro-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 25 mixture was stirred at 120 °C for 16 h. LCMS analysis indicated consumption of the starting material with formation of the desired product mass. The reaction mixture was concentrated to dryness and the residue was| purified by flash chromatography (ISCO, 20 g Si(^2, 50% EtOAc/petroleum ether) to provide 9-bromo-7-fluoro-1,1-dimethyl-3,4-dihydro-1H[1,4]oxazino[4,3-b]indazole (lnt-63) (100 mg, 55% yield) as a yellow oil. m/z (ESI+) for (C₁₂Hi₂BrFN₂O), 298.6 (M+H)⁺. j i

Préparation of tert-butyl [2-(5-bromo-7-fiuoro-2-methyl-2H-indazol-3-yl)propan-2yl]carbamate (lnt-64) according to Scheme 33.

Schemè 33:

166

step 1 step 2

HCl cfnn 3 MeOH step 3

97% yield

Boc₂O, NaHCO₃

EtOAc, H₂O 82% yield

step 4

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 tertrafluoroborate (1.97 g, 13.3 mmol). The resulting solution was stirred at ambient température for 5 h. LCMS analysis showed consumption of starting material with formation of the desired product mass. The reaction solution was diluted with H2O (20 mL) and extracted with EtOAc (100 mL). The organic phase was dried over Na2SO4, filtered, and concentrated. The crude residue was purified by flash chromatography (ISCO, 40 g S1O2, 20-25% EtOAc/petroleum ether) to provide 5-bromo-7-fIuoro-2-methyl-2H-indazole (33a) (1.6 g, 10 68% yield) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.45 (d, J = 2.7 Hz, 1 H), 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 (C₈H₆BrFN2), 230.9 (M+H)⁺. ... - . _ --------I I

Step 2: Synthesis of N-[2-(5-bromo-7-fluoro-2-methyI-2H-indazol-3-yI)propan-2-yl]-215 methylpropane-2-sulfinamide (33b)

To a solution of 5-bromo-7-fluoro-2-methyl-2/7-indazole (33a) (1.0 g, 4.4 mmol) in PhMej (10 mL) was added a solution of LDA (2.0 M in THF, 2.6 mL, 5.24 mmol) at -78 ^eC. The réaction! mixture was stirred at -78 °C for 1 h. 2-Methyl-/V-(propan-2-ylidene)propane-2-sulfinamide (704 mg, 4.4 mmol) was then added to the reaction mixture at -78 ^eC. The reaction mixture was allowed to warm to room température and stirred for 24 h. LCMS analysis showed complété consumption of the starting material with formation of the desired product mass; The reaction was quenched by addition of saturated aqueous NH₄CI (10 mL) and extracted with EtOAc (2x30 mL). The ¹⁶⁷ combined organic phases were dried over Na2SO4, filtered, and concentrated. The crude residue was purified by flash chromatography (ISCO, 20 g S1O2, 30-40% MeOH/EtOAc) to provide N-[2(5-bromo-7-fluoro-2-methyl-2H-indazol-3-yl)propan-2-yl]-2-methylpropane-2-sulfinamide (33b) (420 mg, 25% yield) as a yellow gum. m/z (ESI+) for (CisH2iBrFN3OS), 392.0 (M+H)⁺.

Step 3: Synthesis of 2-(5-bromo-7-fIuoro-2-methyl-2H-indazol-3-yl)propan-2-amine (33c)

To a yellow solution of /V-[2-(5-bromo-7-fiuoro-2-methyl-2H-indazol-3-yl)propan-2-yl]-2methylpropane-2-sulfinamide (33b) (420 mg, 1.08 mmol) in MeOH (5.0 mL) was added concentrated HCl (1.0 mL) at room température. The reaction mixture was stirred for 2 h. LCMS 10 analysis showed consumption ofthe starting material with formation ofthe desired product mass. 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 min. The reaction solution was extracted with DCM (2x20 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated to provide 2-(5-bromo-7-fluoro-2-methyl-2/7-indazol-315 yl)propan-2-amine (33c) (300 mg, 97% yield) as a yellow solid. m/z (ESI+) for (CnHi3BrFN₃), 268.9 (M+H)⁺.

Step 4: Synthesis of tert-butyl [2-(5-bromo-7-fiuoro-2-methyl-2H-indazol-3-yl)propan-2yl]carbamate (lnt-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 NaHCOs (3.0 mL) and BOC2O (659 mg, 3.0 mmol). The mixture was stirred at room température for 16 h. The reaction solution was diluted with H2O (10 mL) and extracted with EtOAc (2x30 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated. The crude residue was purified by flash chromatography (ISCO, 20 g SiO2, EtOAc/petroleum ether) to provide (lnt-64) (240 mg, 82% yield) as a yellow oil. m/z (ESI+) for (Ci6H2iBrFN₃O₂), 387.6 (M+H)⁺.

II

Préparation of 5-bromo-7-fluoro-2-methyl-3-(propan-2-yl)-2H-indazole (lnt-65) according to Scheme 34.

30j

I Scheme 34:I

168

BPin

step 1

PdCI₂(dppf), K₂C0₃

1,4-dioxane/H₂0,100 °C Br

89% yield step 2 step 3

Rh(PPH₃)₃CI, H₂ THF/MeOH 50 psi, 50 °C

100% yield

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

To a solution of 5-bromo-7-fluoro-2-methyl-2H-indazoIe (33a) (500 mg, 2.18 mmol) in DCM (10.0 mL) was added 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 h (556 mg, 2.62 mmol) was added. The mixture was stirred at 30 °C for 16 h. LCMS analysis showed consumption of the starting material with formation of the desired product mass. 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 S1O2,30-40% EtOAc/petroleum ether) to provide 5-bromo-7-fIuoro-3-iodo-2-methyl-2H-indazole (34a) (700 mg, 90% yield) as a pale yellow solid. m/z (ESI+) for (C8H₅BrFIN2), 354.8 (M+H)⁺.

Step 2: Synthesis of 5-bromo-7-fIuoro-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), K2CO3 ( 467 mg, 3.38 mmol), and Pd(dppf)Cl2 (82.5 mg, 0.113 mmol) in 1,4-dioxane (6.0 mL) and H2O (1.0 mL) was stirred under — an [atmosphère of N2 at 100 °C for 3 h. The reaction suspension became black. LCMS analysis showed complété consumption ofthe starting material with formation ofthe desired product mass.

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 S1O2, 30% EtOAc/petroleum ether) to provide 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 (CnHioBrFN₂), 268.9 (M+H)⁺.

Step 3: Synthesis of 5-bromo-7-fiuoro-2-methyl-3-(propan-2-yl)<-2H-indazole (lnt-65)

A solution of 5-bromo-7-fluoro-2-methyl-3-(prop-1-en-2-yl)-2/7-indazole (34b) (270 mg,

1.0 mmol) and Rh(PPh₃)₃CI (92.8 mg, 0.1 mmol) in MeOH (10.0 mL) and THF (10.0 mL) was

169 sparged with H2 and then stirred at 50 °C for 16 h under H2 at a pressure of 50 psi. LCMS analysis showed consumption of the starting material with formation of the desired product mass. The reaction mixture was concentrated to dryness and the residue was purified by flash chromatography (ISCO, 1:1 EtOAc/petroleum ether) to provide 5-bromo-7-fluoro-2-methyl-3(propan-2-yl)-2H-indazole (lnt-65) (300 mg, >99% yield) as a pale brown gum. m/z (ESI+) for (CiiHi₀BrFN2), 270.8 (M+H)⁺.

Préparation of 6-bromo-1-(propan-2-yl)-1H-imidazo[4,5-b]pyridine (lnt-66) according to Scheme 35.

Scheme 35:

acetone TFA, NaB(OAc)₃H /-PrOAc

^35a 89% yield

NH₂

NH

At^O

AcOH, 90°C

52% yield

JMe lnt-66 Me

Step 1: Synthesis of S-bromo-AP-fpropan^-ylJpyridine^.S-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 /-PrOAc (20 mL) were 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 température for 2 h. EtOAc (50 mL) was added to quench the reaction. The mixture was washed with saturated aqueous NaHCOs (40 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (40 g S1O2,0-65% EtOAc/petroleum ether) to provide S-bromo-AP-Îpropan2-yl)pyridine-2,3-diamine (35b) (2.7 g, 89% yield) as a brown gum. ¹H NMR (400 MHz, DMSOd₆) 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, 1 H), 1.15 (d, J = 6.2 Hz, 6H); m/z (APCI) for (C₈Hi₂BrN₃), 230.1,232.2 (M+H)⁺.

Step 2: Syrjthesis of 6-bromo-1-(propan-2-yl)-1H-imidazo[4,5-bJpyridine (lnt-66)

A mixture of 5-bromo-N³-(propan-2-yl)pyridine-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 adjusted to pH ~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 S1O2, 10% MeOH/EtOAc) to provide 6-bromo-1-(propan-2-yl)-1H-imidazo[4,5-b]pyridine (lnt-66) (866 mg, 52% yield) as a light brown solid. ¹H NMR (400 MHz, DMSO-cfe) δ 8.42 - 8.32 (m, 2H), 4.76 (td, J = 6.9,13.8 Hz, 1 H), 2.61 (s, 3H), 1.54 (d, J = 7.0 Hz, 6H); m/z (APCI) for (C9H₁₀BrN₃), 254.2,256.1 (M+H)⁺. ..... 19876

170

Préparation of 5-chloro-2-methyl-3-(propan-2-yl)-3H-imîdazo[4,5-b]pyridine (lnt-67) according to Scheme 36.

Scheme 36:

36a /-PrBr K₂CO₃

DMS0

76% yield

To a slurry of K₂CO3 (4.1 g, 29.8 mmol) in DMSO (6.0 mL) were added 5-chloro-2-methyî3H-imidazo[4,5-b]pyridine (36a) (1.0 g, 5.7 mmol) and 2-bromopropane (2.8 mL, 29.8 mmol). The mixture was stirred for 20 h at room température and an additional 1 h at 60 °C. LCMS analysis 10 showed consumption of the starting material with formation of the desired product mass (~4:1 mixture of regioisomers). 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 Na2SO4, filtered, and concentrated directly onto S1O2. The crude material was purified by flash chromatography (SiO2, 80-100% 15 EtOAc/heptanes) to provide 5-chloro-2-methyl-3-(propan-2-yl)-3H-imidazo[4,5-b]pyridine (lnt-67) (950 mg, 76% yield) as the first eluting regioisomer. ¹H NMR (400 MHz, CDCI3) 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 (C₁₀Hi2CIN₃), 209.9 (M+H)⁺.

Préparation of 6-bromo-1-(propan-2-yl)-1H-imidazo[4,5-b]pyridine (lnt-68) according to

Scheme 37.

Scheme 37:

37a 79% yield । step 1 ^^-NOz ί T Fe°, NH4CI

CI^N^NH -------..Y.. EtOH, H₂O, 6O’(

37b Me I Me ^z

Me

95% yield step 2

37c Me J. Me Me । p-TSA, CH(0Et)₃ PhMe, 110 ’C

95% yield step 3 cr N' N „ A~Me lnt-68 ^Me Me

Step 1 : Synthesis of AMert-butyl-6-chloro-3-nitropyridin-2-amine (37b)

171

To a solution of 2,6-dichloro-3-nitropyridine (37a) in PhMe (30 mL) was added 2methylpropan-2-amme (3.8 g, 51.8 mmol) at 0 C. The yellow solution was stirred at room température for 16 h. LCMS analysis showed consumption of the starting material with formation ofthe desired product mass. The reaction was concentrated to dryness. The residue was purified by flash chromatography (ISCO, 20 g S1O2, 100% petroleum ether) to provide /V-tert-butyl-6chloro-3-nitropyridin-2-amine (37b) (4.7 g, 79% yield) as a yellow solid. m/z (ESI) for (C9H12CIN3O2), 229.9 (M+H)⁺.

Step 2: Synthesis of M-terf-butyl-6-chloropyridine-2,3-diamine (37c) - —

To a solution of A/-tert-butyl-6-chloro-3-nitropyridin-2-amine (37b) (4.7 g, 20.5 mmol) in EtOH (200 mL) was added saturated aqueous NH4CI (60 mL) and Fe° (5.7 g, 102 mmol). The mixturewas stirred at60 °Cfor3 h. LCMS analysis indicated consumption ofthe starting material with formation ofthe desired product mass. The mixture was filtered and concentrated to remove EtOH. The mixture was diluted with H2O (100 mL) and extracted with EtOAc (200 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to provide Af-tert-butyl-e-chloropyridine^.S-diamine (37c) (3.9 g, 95% yield) as a black oil, which was taken on without further purification, m/z (ESI) for (C9H14CIN3), 199.9 (M+H)⁺.

Step 3: Synthesis of 3-tert-butyl-5-chloro-3H-imidazo[4,5-b]pyridine (lnt-68)

To a black mixture of AF-fert-butyl-e-chloropyridine^.S-diamine (37c) (3.0 g, 15.0 mmol) and CH(OEt)3 (4.5 g, 30.0 mmol) in PhMe (40.0 mL) was added p-TSA monohydrate (286 mg, 1.5 mmol). The mixture was stirred for 16 h at 110 °C. LCMS analysis showed consumption of the starting material with formation of the desired product mass. The mixture was washed with saturated aqueous NaHCOs (60 mL). The aqueous layers were extracted with EtOAc (2x100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to provide 3fert-butyl-5-chloro-3H-imidazo[4,5-b]pyridine (lnt-68) as a black solid, which was taken on without further purification, m/z (ESI) for (C10H12CIN3), 209.8 (M+H)⁺. |

Préparation of (3R,4R)-4-Amino-1-(methanesulfonyl)piperidin-3-ol (lnt-69) according to Scheme 38. | '

Scheme 38:

172

CbzCI, Na₂CO₃

H₂O/DCM

85% yield step 1

NHCbz

HO.

N i Boc

38b

HO

1. HCl, EtOH

NHCbz

H0_KÂ

2. NaHCO₃, MsCI EtOAc/H₂O

71% yield step 2

N

38c H step 3

H₂, Pd/C DCM/MeOH

90% yield

NH₂

Int-69 SO₂Me

Step 1: Synthesis of tert-butyl (3R,4R)-4-{[(benzyloxy)carbonyl]amino}-3hydroxypiperidine-1-carboxylate (38b)

To a solution of tert-butyl (3R,4R)-4-amino-3-hydroxypiperidine-1-carboxylate (38a) (13.0 5 g, 60.1 mmol) in DCM (100 mL) and saturated Na₂CO₃ (100 mL) was added benzyl chloroformate (24.1 mL, 72.1 mmol, 50 % in PhMe) drop-wise at 0 °C. The mixture was stirred for 4 h then the organic phase was collected. The aqueous phase was extracted with DCM (2x100 mL). The combined organic phases were washed with H₂O (2x100 mL) and brine (100 mL), dried over Na₂SO4, filtered, and concentrated. The crude residue was purified by flash chromatography 10 (SiO₂, 0-60% EtOAc/hexanes) to provide tert-butyl (3R,4R)-4-{[(benzyloxy)carbonyl]amino}-3hydroxypiperidine-1-carboxylate (38b) (18.0 g, 85% yield) as a light yellow oil. m/z (ESI+) for (Ci8H₂₆N₂O₅), 251.3 (M+H-Boc)⁺.

Step 2: Synthesis of benzyl [(3R,4R)-3-hydroxy-1-(methanesulfonyl)piperidin-415 yl]carbamate (38c)

A solution of fert-butyl (3R,4R)-4-{[(benzyloxy)carbonyl]amino}-3-hydroxypiperidine-1carbox-ylate (38b) (18.0 g, 51.4 mmol) and HCl in EtOH (1.25 M in EtOH, 123 mL, 154 mmol) was stirred at ambient température for| 6 h and then concentrated. The residue was diluted w|th EtOAc (100 mL). Saturated aqueous NaHCOs (100 mL) was added and the mixture was cooled 20 to 0 °C. Methanesulfonyl chloride (6.5 mL, 83.9 mmol) was added drop-wise and the mixture was stirred at this température for 4 h. The layers were separated and the aqueous layer extracted with EtOAc (2x100 mL). The combined organic phases were washed with H₂O (2x100 mL) and brine (100 mL), dried over Na₂SO4, filtered, and concentrated. The residue was triturated with pentaneto provide 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 (Ci4H₂₀N₂O₅S), 329.4 (M+H)⁺. _

Step 3: Synthesis of (3R,4R)-4-amino-1-(methanesulfonyl)piperidin-3-ol (lnt-69) ¹⁷³

A 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) under a balloon of hydrogen at ambient température for 16 h. The reaction mixture was filtered through celite and washed with methanol (100 mL). The filtrate was 5 concentrated under reduced pressure to provide (lnt-69) (6.41 g, 90% yield) as 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).

Préparation of (3/?,4R)-4-amino-1-(methanesulfonyl)piperidin-3-ol (2S)-2-hydroxy-3phenylpropanoic acid sait (lnt-70) according to Scheme 39.

Scheme 39:

Boc

39a

HCl

MeOH >99% yield

MsCI, TEA

DCM

88% yield

O=S=O i 39c ^Me m-CPBA DCM

94% yield

lnt-70

1. LIBr, NH4OH MeCN, 18-40 C

MeOH, reflux

O=S=O Me

39d

-, 5 । 25% yield (2 steps)

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 HCI (4.0 N in MeOH, 500 mL) and tije mixture was stirred at room température for 16 h. LCMS analysis showed consumption of the starting material. The reaction was concentrated 20 to dryness to provide 1,2,3,6-tetrahydropyridine hydrochloride (39b) (97.9 g, >99% yield), which was taken on without further purification. ¹H NMR (400 MHz, D2O) δ 5.96 (tdd, J = 1.7, 3.9,10.5 Hz, 1H), 5.80-5.61 (m, 1H), 3.65 (brs, 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)

174

To a slurry of 1,2,3,6-tetrahydropyridine hydrochloride (39b) (97.9 g, 818 mmol) in DCM (1.0 L) was added TEA (248 g, 2.5 mol). The mixture was cooled to 0-5 °C and then treated slowly dropwise with methane sulforiylchloride (112 g, 982 mmol), maintaining the reaction température <20 °C._ After addition the mixture was stirred a further 16 h at room température. ______ 5 The reaction was quenched by slow addition of H2O (1. L). The phases were separated. The aqueous layer was extracted with DCM (1.5 L). The combined organics were washed successively with saturated aqueous NH4CI (500 mL), saturated aqueous NaHCOa (500 mL), saturated aqueous NH4CI (500 mL), and brine (500 mL), dried over Na2SO4, filtered, and concentrated. The résultant yellow solid was triturated with DCM/petroleum ether (1:15,500 mL).

The solids were collected by filtration and dried under vacuum to provide l-(methanesulfonyl)1,2,3,6-tetrahydropyridine (39c) (116 g, 88% yield) as a light yellow solid, which was taken on without further purification. ¹H NMR (400 MHz, CDCI3) 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) portion-wise. The mixture was stirred at ambient température for 48 h. TLC analysis indicated consumption of the starting material. The 20 heterogeneous mixture was filtered to remove the solids. The filtrate was basified with saturated aqueous Na2COs (1.0 L) and washed with saturated aqueous Na2SO3 (1.5 L). The aqueous layer was extracted with DCM (2x1.5 L). The combined organics were washed with brine (1.5 L), dried over Na2SO4, filtered, and concentrated to provide 3-(methanesulfonyl)-7-oxa-3azabicyclo[4.1.0]heptane (39d) (120 g, 94% yield) as a light yellow solid, which was taken on without further purification. ¹H NMR (400 MHz, CDCI3) δ 3.84 (ddd, J = 1.0, 3.6, 14.3 Hz, 1H), 3.57 (d, J = 14.3 Hz, 1 H), 3.36 (dd, J = 2 0, 3.7 Hz, 1H), 3.34 - 3.26 (m, 2H), 3.09 (ddd, J=4.7, έ.4, 12.9 Hz, 1 H), 2.82 (s, 3H), 2.21 - 2.04 (m, 2H). |

Step 4: Synthesis of (3R,4R)-4-amino-1-(methanesulfonyl)piperidin-3-ol (2S)-2-hydroxy-3I I .

phenylpropanoic acid sait (lnt-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) was added LiBr (1.96 g, 22.6 mmol) and NH4OH (14.1 g, 113 mmol). The mixture was stirred at ambient température for 48 h. TLC analysis (1:1 petroleum ether/EtOAc) indicated remaining starting material. The reaction mixture was warmed to 40 °C 35 and stirred at this température for 36 h. TLC analysis (1:1 petroleum ether/EtOAc) indicated consumption of the starting material. The reaction was concentrated to dryness to provide rac19876

175 (3R,4R)-4-amino-1-(methanesulfonyl)piperidin-3-ol (11 g, crude). The crude mixture containing rac-(3R,4R)-4-amino-1-(methanesulfonyI)piperidin-3-ol (11 g) was taken up in MeOH (120 mL) and the mixture was warmed to reflux until the solution became clear. The mixture was cooled to room température and a solution of (2S)-2-hydroxy-3-phenylpropanoic acid (9.41 g, 56.6 mmol) in MeOH (30 mL) was added. The solution tumed cloudy followed by extensive précipitation. The mixture was stirred at reflux for 10 min and then allowed to slowly cool to room température. The solution was stirred at room température for 16 h. The precipitate was collected by filtration. The solids were taken up in MeOH (30 mL) and stirred at reflux for 10 min. The solution was slowly cooled to room température. The résultant precipitate was collected by filtration to provide (3R,4R)-4-amino-1-(methanesulfonyl)piperidin-3-ol (2S)-2-hydroxy-3-phenylpropanoic acid sait (lnt-70) (5.0 g, 25% yield) as a white solid. Enantiomeric excess (97% ee) was determined for the corresponding N-CBz protected dérivative by chiral SFC with a Chiralpak AS-3 column (4.6x150 mm, 3 pm particle size, 35 °C), which was eluted with 5-40% EtOH/COz (+0.05% diethylamine) with a flow rate of 2.5 mL/min. ¹H NMR (400 MHz, CD3OD) 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, 1 H), 3.13 (dd, J = 3.4, 13.8 Hz, 1 H), 2.98 (ddd, J = 4.5, 9.8,12.1 Hz, 1 H), 2.92 - 2.77 (m, 5H), 2.69 - 2.56 (m, 1 H), 2.18 - 2.02 (m, 1H), 1.78 - 1.60 (m, 1H).

Préparation of Examples

Example 1 (Scheme A-1): Préparation of (3/?,4R)-4-({5-chloro-4-[4-fluoro-2-methyl-1(propan-2-y])-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-1-(methanesu!fonyl)piperidin-3ol

Scheme A-1:

i

176

lnt-46

Pd(OAc)₂, PCy₃ AcOK, B₂Pin₂

DMSO, 100 “C . 73% yield

Pd(PPh₃)₄, K₂CO₃ 1,4-dioxane, 90 'C

98% yield

Me

DIPEA

DMSO, 120 °C

19% yield

Step 1: Synthesis of 4-fIuoro-2-methy 1-1-(propan-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1H-benzimidazole (A-1)

A suspension of 6-bromo-4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazole (lnt-46) 5 (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 h. TLC analysis (1:1 petroleum ether/EtOAc) showed complété consumption of the 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 10 brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (Biotage, 1.0 kg, 0-40% EtOAc/petroleum ether) to provide 4-fIuoro-2-methyl-1(propan-2-yl)-6-(4,|4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimid^zole (A-1) (77 g, 73% yield) as a yellow solid. ¹H NMR (400 MHz, CDCI₃) 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 (C17H24BFN2O2), 15 319.2 (M+H)⁺. |

Step 2: Synthesis of 6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-2-methyl-1-(propan-2-yl)-1Hbenzimidazole (A-2)

A mixture of 4-fluoro-2-methyl-1-(propan-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan20 2-yl)-1H-benzimidazole (A-1) (300 mg, 0.943 mmol), 2,4,5-trichloropyrimidine (259 mg, 0.16 mL,

1.41 mmol) and K2CO3 (260 mg, 1.89 mmol) in 1,4-dioxane (9 mL) and H2O (3 mL) was sparged _ ¹⁷⁷ with N₂for 5 min. Pd(PPh3)4 (54.5 mg, 0.047 mmol) was added and the mixture was sparged with N₂for an additional 10 min. The mixture was stirred at 90 °C for 16 h before being cooled to . ambient température, diluted with H₂O (15 mL), and extracted with EtOAc (3x10 mL). The combined organic.phases were washed with brine (10 mL), dried over.Na₂SO4, filtered, and . .

concentrated. To this crude mixture was added a second crude mixture from a reaction run in analogous fashion on a 100 mg scale. The résidé was purified by flash chromatography (SiO₂, 100% EtOAc) to provide 6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-2-methyl-1-(propan-2-yl)-1Hbenzimidazole (A-2) (420 mg, 98% yield). m/z (ESI+) for (Ci₅Hi₃N₄FCI₂), 338.9 (M+H)⁺.

Step 3: Synthesis of (3R,4R)-4-({5-chloro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1HbenzimidazoI-6-yl]pyrimidin-2-yl}amino)-1-(methanesulfonyl)piperidin-3-oI (Example A1)

To a yellow suspension of 6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-2-methyl-1-(propan-2yl)-1H-benzimidazole (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 (lnt-69) (241 mg, 15 1.24 mmol). The mixture was stirred at 120 °C for 16 h and then diluted with H₂O (20 mL) and 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 préparative HPLC with an Agela Durashell C18 column (150x25 mm, 5 pm particle size; column température 25 ’C), which was eluted with 34-54% MeCN/H₂O (+0.05% NH4OH) with a flow rate of 25 mL/min to provide (3R,4R)-4-({5-chloro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6yl]pyrimidin-2-yI}amino)-1-(methanesulfonyI)piperidin-3-ol (Example A1) (54.7 mg, 19% yield) as a yellow solid. Ή NMR (400 MHz, DMSO-£/₆) δ 8.41 (s, 1H), 8.02 - 7.79 (m, 1H), 7.54 - 7.27 (m, 2H), 5.24 (d, J = 4.5 Hz, 1 H), 4.86 - 4.71 (m, 1 H), 3.86 - 3.74 (m, 1 H), 3.60 (br d, J = 9.5 Hz, 2H), 3.53 - 3.45 (m, 1H), 2.94 - 2.79 (m, 4H), 2.69 - 2.59 (m, 4H), 2.07 (s, 1H), 1.62 - 1.46 (m, 7H);

m/z (ESI+) for (C₂iH₂6CIFN₆O₃S), 497.3 (M+H)⁺.

The examples in th^ below table were synthesized according to the method^ used for the synthesis of (3R,4R)-4-({5-chloro-4-[4-fluoro-2-methyI-1 -(propan-2-yl)-1 /-/-benzimidazol-6yl]pyrimidin-2-yl}amino)-1-(methanesulfonyl)piperidin-3-oI (Example A1). The following 30 examples were synthesized with non-critical changes or substitutions to thé exemplified procedures that someonel who is skilled in the art would be able to realize. 'If necessary, séparation ofthe enantiomers ofwas carried out understandard methods known in the art, such as chiral SFC or HPLC, to afford single enantiomers. ; --------- . — .

Example	Structure/Name	LCMS	NMR
number

178

A2	Ν^γρ JJ ---------'y > —y n k J N J N Me—/ \. i \ Me 0—S—O Me Me (3R,4R)-4-({5-fluoro-4-[4-fluoro2-methyl-1 -(propan-2-yl)-1 Hbenzimidazol-6-yl]pyrimidin-2yl}amino)-1- (methanesulfonyl)piperidin-3-ol	481.2 [M+H]* (ESI)	1H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J = 4.03 Hz, 1H), 8.16 - 8.03 (m, 1H), 7.71 - 7.50 (m, 1H), 7.32 - 7.17 (m,-1H), 5.28-5.19 (m, 1H), 4.90-4.74 (m, 1H), 3.87-3.72 (m, 1H), 3.70 - 3.57 (m, 2H), 3.54 - 3.45 (m, 1 H), 2.92 (s, 3H), 2.89 2.83 (m, 1 H), 2.73 - 2.66 (m, 1 H), 2.64 (s, 3H), 2.36-2.30 (m, 1H), 1.60 (d, J =6.85 Hz, 6H), 1.57-1.50 (m, 1H)
A3	n-Vf J HN N T Jn T 'J--7 Me Me Me 4-(1-fert-butyl-4-fluoro-1H- benzimidazol-6-yl)-5-fluoro-/V(1-methylpiperidin-4yl)pyrimidin-2-amine	401.1 [M+H]* (ESI)	1H NMR (400 MHz, CD3OD) δ 8.51 (brs, 1H), 8.43-8.34 (m, 3H), 7.82 (d, J =12.0 Hz, 1H), 4.19-4.06 (m, 1H), 3.503.40 (m, 2H), 3.29-3.13 (m, 2H), 2.83 (s, 3H), 2.35 - 2.25 (m, 2H), 1.95-1.82 (m, 11 H)
A4	hn nY y HO^Â. JJ Tl \ ,N < J n-4 N Me—/ i \ Me O-S-O Me Me (3R,4R)-4-({4-[4-fluoro-2- methyl-1 -(propan-2-yl)-1 Hbenzimidazol-6-yl]pyrimidin-2yljamino) J (methanesulfonyl)piperidin-3-ol	463.3 [M+H]* (ESI)	1H NMR (400 MHz, DMSO-cfe) δ 8.35 (d, J= 5.3 Hz, 1H), 8.22 (s, 1H), 7.76 (d, J =12.3 Hz, 1H), 7.32 (d, J =5.5 Hz, 1H), 7.14 (d, J = 7.8 Hz, 1H), 5.27 (brd, J = 4.0 Hz, 1H), 4.90-| 4.75 (m, 1H), 3.84 (br s, 1H), 3.73 - 3.44 (m, 3H), 3.05 - 2.87 (m, 4H), 2.69-2.65 (m, 1H),| 2.62 (s, 3H), 2.19-2.00 (m,j 1H), 1.61 (d, J = 6.3 Hz, 7H)

179

A5	N'Y F λ AA ΗΝ Ν Υη HCX χ ΠΑ II \ ,Ν k J ν-4 N Me—/ ι \ Me O-S-O Me Me (3R,4R)-4-({4-[5-fluoro-2methyl-1 -(propan-2-yl)-1 Hbenzimidazol-6-yl]pyrimidin-2yl}amino)-1(methanesulfonyl)piperidin-3-ol	463.1 [M+H]+ (ESI)	1H NMR (400 MHz, DMSO-cfe) δ 8.39 - 8.09 (m, 2H), 7.47 7.41 (m, 1H), 7.20 (d, J = 7.8 Hz, 1 H), 7.03 (brs, 1 H), 5.27 (brs, 1H), 4.85-4.70 (m, 1H), 3.82 (br s, 1 H), 3.75 - 3.60 (m, 2H), 3.56-3.45 (m, 1H), 2.91 (s, 3H), 2.88-2.79 (m, 1H), 2.70 — 2.60 (m, 1H), 2.59 (s, 3H), 2.20- 2.00 (m, 1H), 1.65 1.60 (m, 7H)
A6	nV F A A A HN N ]ίη HO. AA Il \ ,N L J n-4 N Me—/ i \ Me O-S-0 Me Me (3R,4R)-4-({5-chloro-4-[5fluoro-2-methyl-1-(propan-2-yl)1 H-benzimidazol-6-yl]pyrimidin2-yl}amino)-1(methanesulfonyI)piperidin-3-ol	497.3 [M+H]* (ESI)	1H NMR (400 MHz, DMSO-d6) 6 8.42 (s, 1H), 7.73 (d, J =6.0 Hz, 1H), 7.66-7.48 (m, 1H), 7.44 (d, J= 10.5 Hz, 1H), 5.22 (d, J = 4.3 Hz, 1 H), 4.85 - 4.70 (m, 1H), 3.79 (br s, 1H), 3.653.55 (m, 2H), 3.50 - 3.40 (m, 1H), 2.88 (br s, 4H), 2.702.60 (m, 1H), 2.58 (s, 3H), 2.08 (s, 1H), 1.60-1.45 (m, 7H)
A7	n'A F A A A hn n ji η ho. y. VA il \ ,N - LJ. n-4 . . N Me—/ i \ Me . O-S-O Me Me ' (3R,4R)-4-({5-fluoro-4-[5-fluoro2-m ethyl-1 -( pro pan-2-y 1)-1/7benzimidazol-6-yl]pyrimidin-2yl}amino)-1- (methanesuIfonyI)piperidin-3-ol	481.3 [M+H]* (ESI)	1H NMR (400 MHz, DMSO-d6) δ 8.42 (d, J= 2.0 Hz, 1H), 7.82 (d, J =6.0 Hz, 1H), 7.46 (d, J = 10.8 Hz, 1H), 7.32 (brs, 1H), . 5.21 (d, J = 4.5 Hz, 1H), 4.854.70 (m, 1H), 3.73 (brs, 1H), 3.67 - 3.56 (m, 2H), 3.50 - 3.40 (m, 1H), 2.88 (s, 3H), 2.86 - 2.78 (m, 1H), 2.70 - 2.60 (m, 1H), 2.59 (s,3H), 2.07 (s, 1H), 1.60-1.45 (m,7H)

180

A8	N-ycl ΗΝ^Ν^Αγ^^ hov.λ L II \ ,Ν . k J N-4f _ _ Ν ΜθΖ Me O=S=O Me (3R,4R)-4-{[5-chloro-4-(4fluoro-1,2-dimethyl-1 Hbenzimidazol-6-yl)pyrimidin-2yl]amino}-1(methanesulfonyl)piperidin-3-ol	469.2 [M+H]* (ESI)	1H NMR (400 MHz, DMSO-de) δ 8.42 (s, 1H), 7.77 (brs, 1H), 7 60 - 7.31 (m, 2H), 5.22 (d, J = 4.5 Hz, 1H); 3.81 (brs, 1H); 3.79 (s, 3H), 3.67 - 3.55 (m, 2H),3.50 - 3.40 (m, 1 H), 2.89 (s, 3H), 2.88-2.82 (m, 1H), 2.70-2.60 (m, 1 H), 2.58 (s, 3H), 2.04 (brs, 1H), 1.59-1.42 (m, 1H)
A9	nV HN N 7i ho^a Là Il \ N LJ N-Ÿ N Me-^/ \ O=S=O Më/X^ Me (3R,4R)-4-{[5-chloro-4-(5fluoro-1,1-dimethyl-2,3-dihydro1 H-pyrrolo[1,2-a]benzimidazol7-yl)pyrimidin-2-yl]amino}-1(methanesulfonyl)piperidin-3-ol	509.3 [M+H]+ (ESI)	1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 7.84 (brs, 1H), 7.59 - 7.32 (m, 2H), 5.22 (br s, 1 H), 3.78 (br s, 1 H), 3.59 (br d, J = 10.0 Hz, 2H), 3.48 (br d, J = 11.7 Hz, 1H), 3.08 (t, J = 7.5 Hz, 2H), 2.89 (s, 3H), 2.86 2.79 (m, 1H), 2.69-2.61 (m, 1H), 2.58-2.53 (m, 2H), 2.05 (brs, 1H), 1.62 (s, 6H), 1.52 (br d, J =11.7 Hz, 1H)
A10	Ν^γ'01 JL -sîLx^^F HN N || L^k Il \ N k J N— N Me··/ \ o=s=o V/ Me (3R,4R)-4-({5-chloro-4-[(4S)-9fluoro-4-methyI-3,4-dihydro-1 H[1,4]oxazino[4,3a]benzimidazol-7-yI]pyrimidin2-yl}amino)-1(methanesulfonyl)piperidin-3-or	5l|l.2 [M+H]+ (ESI) i	1H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H), 7.89 (brs, 1H), 7.58 - 7.39 (m, 2H), 5.22 (d, J = 4.5 Hz, 1H), 5.09-5.03 (m, 1H), 4.97-4.91 (m, 1H), 4.70 (brd, J = 5.5 Hz, 1H), 4.174.10 (m, 1H), 4.06-3.98 (m, 1 H), 3.82 (br d, J = 5.8 Hz, 1 H), 3.67 - 3.57 (m, 2H), 3.50 - 3.40 (m, 1H), 2.93 - 2.82 (m, 4H), 2.70 - 2.60 (m, 1 H), 2.11 - 2.00 (m, 1H), 1.60-1.45 (m, 4H)

181

A11	N^VCI . xk J^x^^-F HN N HO^xk ΙχχΑ Tl \ ,N ψ (,e^M o=s=o V/ Me (3R,4R)-4-({5-chloro-4-[(4R)-9fluoro-4-methyl-3,4-dihydro-1 H[1,4]oxazino[4,3a]benzimidazol-7-yl]pyrimidin2-yl}amino)-1- (methanesuIfonyl)piperidin-3-ol	511.2 [M+H]+ (ESI)	1H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H), 7.82 (s, 1H), 7.59 - 7.44 (m, 2H), 5.23 (d, J = 4.8 Hz, 1H), 5.13-5.07 (m, 1H), 5.02-4.96 (m, 1H), 4.42 (dd, J =3.0,12.0 Hz, 1H), 4.19 (dd*d, J = 3.5, 6.3,10.0 Hz, 1H), 3.90 - 3.76 (m, 2H), 3.68 - 3.56 (m, 2H), 3.50 — 3.40 (m, 1H), 2.90 (s, 3H), 2.88 - 2.81 (m,1H), 2.73-2.61 (m, 1H), 2.11-2.00 (m, 1H), 1.62-1.46 (m, 1H), 1.38 (d, J =6.3 Hz, 3H)
A12	ν·^<01 xk HN N HO^^< ICY Il ' //N k U N-X O Me-( ^0Η Me^e 1,5-anhydro-3-[(5-chloro-4-{4fluoro-2-[(1S)-1-hydroxyethyl]- 1 -(propan-2-yl)-1 H- benzimidazol-6-yl)pyrimidin-2yl)amino]-2,3-dideoxy-D-#jreopentitol	450.1 [M+H]+ (ESI)	1H NMR (400 MHz, CD3OD) δ 8.37-8.31 (m, 1H), 8.05 (s, 1H), 7.50 (brd, J= 11.5 Hz, 1H), 5.39-5.29 (m, 1H), 5.23 (q, J =6.6 Hz, 1H), 4.03-3.88 (m, 3H), 3.63 (dt, J = 4.8, 9.4 Hz, 1H), 3.48 (dt, J =2.0,11.6 Hz, 1H), 3.21 (dd, J =9.8,11.0 Hz, 1H), 2.19-2.09 (m, 1H), 1.75-1.53 (m, 10H)
A13 I	N'^V'01 HN^N^Xr^V1 HC^xk Il V ,N k χΙ n-4 0 ΜθΥ >·..ΟΗ . Mewe 1,5-anhydro-3-[(5-chloro-4-{4fluoro-2-[(1 R)-1-hydro xyethyl]- 1 -(propan-2-yl)-1 Hbenzimidazol-6-yl}pyrimidin-2yl)amino]-2,3-dideoxy-D-t/7reopentitol	450.3 [M+H]+ (ESI)	Ή NMR (400 MHz, DMSO-d6) 8.43 (s, 1H), 8.09-7.83 (m, 1H), 7.59-7.32 (m, 2H), 5.79 (brd, J =6.4 Hz, 1H), 5.20|5.15(m, 1H), 5.14-5.06 (m, ÏH), 4.96 (br d, J = 5.2 Hz, 1 H), 3.88 - 3.78 (m, 3H), 3.51 (br s, 1H), 3.10-2.98 (m, 1H), 1.96 (brs, 1H), 1.65-1.55 (m, 10H). one signal obscured by residual water

182

A14	N^CI JL HN N J| I I \ ,N LJ N— rA o=s=o 4 \ Me ° *first eluting stereoisomer (3R,4R)-4-({5-chloro-4-[4fluoro-1-(oxolan-3-yl)-1Hbenzimidazol-6-yl]pyrimidin-2yl}amino)-1(methanesulfonyl)piperidin-3-ol	511.1 [M+H]+ (ESI)	Ή NMR (400 MHz, DMSO-d6) δ 8.44 (s, 2H), 7.98 (brs, 1H), 7.64 - 7.36 (m, 2H), 5.36 (br s, 1H), 5.22 (d, J = 4.5 Hz, 1 H), 4.20 - 4.12 (m, 1H), 4.07 (br d, J = 9.0 Hz, 1H), 4.01-3.94 (m, 1H), 3.88 - 3.78 (m, 2H), 3.67 3.56 (m, 2H), 3.49 (s, 1 H), 2.90 (s, 3H), 2.87-2.81 (m, 1H), 2.66 (brt, J =10.8 Hz, 1H), 2.61 -2.54 (m, 1H), 2.32 -2.20 (m, 1H), 2.10-1.99 (m, 1H), 1.60-1.47 (m, 1H)
A15	N^1 JL HN N ]| HO. L^L Il \ ,N Ψ X o=s=o n/ Me (3R,4R)-4-{[5-chloro-4-(1 cyclopropyI-4-fluoro-1 Hbenzimidazol-6-yl)pyrimidin-2yl]amino}-1- (methanesulfonyl)piperidin-3-ol	481.2 [M+H]+ (ESI)	1H NMR (4500 MHz, CD3OD) δ 8.38 (s, 1H), 8.35 (s, 1H), 8.06 (s,1H), 7.56 (dd, J = 1.0, 11.7 Hz, 1H), 3.98-3.92 (m, 1 H), 3.85 (ddd, J = 1.8, 4.7,11.7 Hz, 1H), 3.76 (dt, J = 4.9, 9.0 Hz, 1H), 3.72-3.67 (m, 1H), 3.60 (m, 1H), 2.96 (dt, J =2.7,11.9 Hz, 1H), 2.90 (s, 3H), 2.77 (dd, J =9.5, 11.6 Hz, 1H), 2.25 (br dd, J =3.7, 13.4 Hz, 1H), 1.801.61 (m, 1H), 1.31-1.22 (m, 2H), 1.20-1:09 (m, 2H)
A16	N^1 HnAnA^/^CI HO. Λ. > . LM\ III \ ,N L J I n-^ N Me--/ O=S=O Me (3R,4R)-4-({5-chioro-4-[4chIoro-1-(propan-2-yl)-1Hbenzimidazol-6-yl]pyrimidin-2-	521.1 [M+Na]+ (ESI)	1H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 8.44 (s, 1H), 8.04 (s, 1H), 7.67 (d, J =1.1 Hz, 1H), 7.55 (brs, 1 H)! 5.23 (d, J = 4.5 Hz, 1H), 4.83 (td, J = 6.7,13.4 Hz, 1H), 3.81 (brd, J = 5.6 Hz, 1H), 3.70-3.55 (m, 2H), 3.50 - 3.40 (m, 1 H), 2.96 2.77 (m, 4H), 2.72 - 2.61 (m,

183

—	yl}amino)-1(methanesulfonyl)piperidin-3-ol		1H), 2.06 (brs, 1H), 1.64-1.46 (m, J =6.7 Hz, 7H)
A17	ΗΝΛ ΝΑργΡ AA L 1 \ ,n o=s=o Vo/ Me *first eluting 2 stereoisomer (3R,4R)-4-{[4-(4-ethyl-9-fIuoro3,4-dihydro-1H[1,4]oxazino[4,3a]benzimidazol-7-yl)-5fluoropyrimidin-2-yl]amino}-1(methanesulfonyl)piperidin-3-ol	509.0 [M+H]+ (ESI)	1H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J = 4.0 Hz, 1H), 8.05 (s, 1H), 7.70 (d, J =12.0 Hz, 1H), 7.24 (d, J =7.8 Hz, 1H), 5.21 (d, J = 4.5 Hz, 1H), 5.13- 5.02 (m, 1H), 4.99-4.89 (m, 1H), 4.54 (brs, 1H), 4.22 (d, J = 12.0 Hz, 1H), 4.04 (dd, J = 3.5,12.3 Hz, 1H), 3.78 (brs, 1H), 3.67 - 3.55 (m, 2H), 3.55 3.45 (m, 1H), 2.99-2.83 (m, 4H), 2.75-2.61 (m, 1H), 2.21 2.05 (m, 1H), 2.00-1.84 (m, 2H), 1.65-1.45 (m, 1H), 0.99 (t, J = 7.5 Hz, 3H); [a]D 20 = -66 (c=0.1,MeQH)
A18	n^Yf A HN N YV HO^ A. AA Il \ /N Me N-/ o=s=o MeAQ/ Me (3R,4R)-4-{[5-fIuoro-4-(9-fluoro- 4,4-dimethyl-3,4-dihydro-1 H[1,4]oxazino[4,3-, a]benzimidazol-7-yl)pyrlmidin2-yi]amino}-1(methanesuIfonyl)piperidin-3-ol	509.1 [M+H]+ (ESI)	1H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J = 3.8 Hz, 1H), 8.18 (s, 1H), 7.68 (brd, J=11.8 Hz, 1 H), 7.26 (br d, J = 7.8 Hz, 1 H), 5.23 (d, J = 4.5 Hz, 1H), 4.99 (s, 2H), 3.93 (s, 2H), 3.78 (br s, 1H), 3.69 - 3.57 (m, 2H), 3.55 3.45 (m, 1H), 2.93-2.83 (m, 4H), 2.71-2.65 (m, 1H), 2.11 (brs, 1H), 1.65 (s, 6H), 1.561.46 (m,1H)
A19	aIAp HN N |A HO^^k AA i Ί \ ,N : A 1,5-anhydro-2,3-dideoxy-3-{[5fluoro-4-(9-fluoro-4,4-dimethyl-	432.1 [M+H]+ (ESI)	1H NMR (400 MHz, DMSO-de) δ 8.44 (d, J = 4.0 Hz, 1 H), 8.21 (brs, 1H), 7.67 (d, J = 12.0 Hz, 1H), 7.23 (d, J =7.8 Hz, 1H), 5.02 - 4.93 (m, 3H), 3.93 (s, 2H), 3.87 - 3.76 (m, 3H), 3.55 -

184

	3,4-dihydro-1H- [1,4]oxàzino[4,3a]benzimidazol-7-yl)pyrimidin2-yl]amino}-D-t/7reo-pentitol	- -- ’ -	3.45 (m, 1H), 3.32 (brs, 1H), 3.06 (t, J= 10.4 Hz,1H), 2.00 (br s, 1H), 1.65 (d, J = 1.8 Hz, 6H), 1.56 - 1.44 (m,1H)
A20	HN N y . HCUxk Il ' Z/N ° Me—4 \ „ V 7—Me *second eluting 0 stereoisomer 1,5-anhydro-3-{[5-chloro-4-(9fluoro-1,4-dimethyl-3,4-dihydro- 1 H-[1,4]oxazino[4,3a]benzimidazol-7-yl)pyrimidin2-yl]amino}-2,3-dideoxy-Dthreo-pentitol	447.8 [M+H]+ (ESI)	1H NMR (400 MHz, CDCI3) δ 8.33 (s, 1H), 7.64 (d, J =1.2 Hz, 1 H), 7.47 (dd, J = 1.2,11.2 Hz, 1H), 5.29 (br d, J = 5.9 Hz, 1H),4.99 (q, J = 6.6 Hz,1H), 4.48 (q, J = 6.8 Hz, 1 H), 4.12 (d, J = 1.5 Hz, 2H), 4.06 (dd, J = 5.0,11.4 Hz, 1H), 3.99 (br dd, J =4.3, 11.3 Hz, 1H), 3.893.80 (m, 1H), 3.63 (dt, J = 5.0, 9.4Hz, 1H), 3.46 (dt, J = 2.1, 11.8 Hz, 1H), 3.18 (t, J = 10.7 Hz, 1H), 2.10-2.01 (m, 1H), 1.80 (d, J =6.6 Hz, 3H), 1.771.67 (m, 1H), 1.64 (d, J = 6.6 Hz, 3H)
A21	ΗΝ^Ν^ψ^ HO^ Il ' J ν-λ ° Me—4 \ _____γ _y— Me *first eluting 0 stereoisomer 1,5-anhydro-3-{[5-chIoro-4-(9fluoro-1,4-dimethÿl-3,4-dihydro- 1 H-[1,4]oxazino[4,3a]benzimidazol-7-yl)pyrimidin2-yl]amino}-2,3-dideoxy-Dtbreo-pentitol	447.8 [M+H]+ (ESI)	1H NMR (400 MHz, CDCI3) δ 8.33 (s, 1H), 7.62 (s, 1H), 7.47 (dd, J = 1.1, 11.2 Hz, 1H), 5.28 (brd, J=5.7 Hz, 1H), 5.064.72 (m, 2H), 4.48 (q, J- 6.6 Hz, 1 H), 4.12 (d, J =1.7 Hz, 2H), 4.06 (dd, J = 5.0,11.4 Hz, -1H),-3.99 (br dd, J = 4.3,11.7 Hz, 1 H), 3.90 - 3.80 (m, 1 H), 3.63 (dt, J = 4.8, 9.4 Hz, 1H), 3.51-3.42 (m, 1H), 3.18 (t, J = 10.6 Hz, 1 H), 2.09 - 2.01 (m, -1 H),1.81 (d, J = 6.6 Hz, 3H). 1.77-1.69 (m, 1H), 1.64 (d, J = - ’ 6.6 Hz, 3H)

185

A22	N^CI Ηθ/χ UA Il \ ,N Y/ Me Me-Λ / Me 1,5-anhydro-3-{[5-chloro-4-(9- fluoro-2,4,4-trimethyl-1,2,3,4tetrahydropyrazino[1,2- a]benzimidazol-7-yl)pyrimidin2-yl]amino}-2,3-dideoxy-Dfhreo-pentitol	461.1 [M+H]* (ESI)	1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1 H), 8.09 - 7.88 (m, 1 H), 7.47 (br s, 2H), 4.94 (br d, J = 5.4 Hz, 1H), 3.86-3.71 (m, 5H), 3.50 (br s, 1 H), 3.29 - 3.25 (m, 1H), 3.03 (brt, J =10.3 Hz, 1 H), 2.75 (s, 2H), 2.44 (s, 3H), 1.95 (brs, 1H), 1.65 (s, 6H), 1.56 - 1.48 (m, ï H)
A23	n^<ci JL HO^A. YY. Il \ N L J n-4 .. O Me—/ \^Me *first eluting Me 0H stereoisomer 1,5-anhydro-3-({5-chloro-4-[2(1 -cyclopropyl-1 -hydroxyethyl)4-fluoro-1 -(propan-2-yl)-1 Hbenzimidazol-6-yl]pyrimidin-2yl}amino)-2,3-dideoxy-D-tbreopentitol	490.0 [M+H]* (ESI)	1H NMR (400 MHz, DMSO-de) δ 8.42 (s, 1H), 8.12-7.87 (m, 1H), 7.63 - 7.26 (m, 2H), 5.90 5.75 (m, 1H), 5.64 (s, 1H), 4.98 (brd, J =5.0 Hz, 1H), 3.943.76 (m, 3H), 3.58 - 3.48 (m, 1H), 3.32-3.27 (m, 1H), 3.03 (brt, J =10.5 Hz, 1H), 2.051.87 (m, 1H), 1.70-1.56 (m, 9H), 1.51 (brd, J =13.1 Hz, 1H), 1.42-1.31 (m, 1H), 0.740.61 (m, 1H), 0.55-0.34 (m, 3H); Md22 = -6 (c=0.1, MeOH)
A24	N-ycl LÀ Il ' //N L J N—< 0 Me—/ V^Me MeÂ^On ‘second eluting stereoisomer 1,5-anhydro-3-({5-chloro-4-[2(1 -cyclopropyl-1 -hydroxyethyl)4-fluoro-1-(propan-2-yl)-1/7benzimidazol-6-yl]pyrimidin-2-	I 490.11 [M+H]* (ESI)	1H NMR (400 MHz, DMSO-d6) 6 8.42 (s, 1H), 8.13-7.81 (m, 1H), 7.62 - 7.15 (m, 2H), 5.90 5.75 (m, 1H), 5.64 (s, 1H), 4.97 (brd, J =5.0 Hz, 1 H), 3.943.70 (m, 3H), 3.59 - 3.47 (m, 1 H), 3.32-3.25 (m, 1H), 3.03 (brt, J =10.3 Hz, 1H), 2.04 1.84 (m, 1 H), 1.70 -1.57 (m, 9H), 1.55 - 1.45 (m, 1 H), 1.42 1.31 (m, 1 H), 0.74-0.63 (m,

186

	yl}amino)-2,3-dideoxy-D-f/7reopentitol	- -- .	1H), 0.59-0.30 (m, 3H); [ah22 = -22(c=0.1,MeOH)
A25	N'^YCI JL HN n L A LJ K 'N Y ΜθΎ Me O=S=O Me Me (3R,4R)-4-({5-chloro-4-[7fluoro-2-methyl-3-(propan-2-yl)2H-indazol-5-yl]pyrimidin-2yl}amino)-1(methanesulfonyl)piperidin-3-ol	496.9 [M+H]* (ESI)	1H NMR (400 MHz, DMSO-d6) 5 8.40 (s, 1H), 8.18 (brs, 1H), 7.57 - 7.34 (m, 2H), 5.22 (br s, 1H), 4.17 (s, 3H), 3.79 (brs, 1H), 3.67 - 3.56 (m, 3H), 3.55 3.45 (m, 1H), 2.89 (s, 3H), 2.87 -2.80 (m, 1H), 2.66 (brt, J = 10.5 Hz, 1H), 2.05 (brs, 1H), 1.60-1.40 (m, 1H), 1.46 (brd, J =6.7 Hz, 6H)
A26	N-YCI JL HN n YY HO. II___À LJ L-N Μθ>/Λ O=S=O Me o-/ Me (3R,4R)-4-{[5-chloro-4-(7fluoro-1,1-dimethyl-3,4-dihydro1 H-[1,4]oxazino[4,3-b]indazol9-yl)pyrimidin-2-yl]amino}-1(methanesulfonyl)piperidin-3-ol	525.1 [M+H]* (ESI)	1H NMR (400 MHz, DMSO-d6) 5 8.42 (s, 1H), 8.04 (brs, 1H), 7.68 - 7.24 (m, 2H), 5.22 (d, J = 4.5 Hz, 1H), 4.46 (t, J = 4.8 Hz, 2H), 4.22 (brt, J = 4.6 Hz, 2H),3.93 - 3.72 (m, 1H), 3.60 (brd, J =8.8 Hz, 2H), 3.49 (br d, J=11.3 Hz, 1H), 2.90 (s, 3H), 2.88 - 2.80 (m, 1H), 2.74 2.55 (m, 2H), 2.07 (br d, J = 10.8 Hz, 1 H), 1.70 (s, 6H), 1.53 (brd, J =10.0 Hz, 1 H)
ί Α27|	n^Yci JL HN N T| HCYxk *1___X U L-N Me^YN Me k / O—* 1,5-anhydro-3-{[5-chloro-4-(7fluoro-1,1-dimethyl-3,4-dihydro- 1 H-[1,4]oxazino[4,3-b]indazol- 9-yI)pyrimidin-2-yl]amino}-2I3dideoxy-D-fhreo-pentitol	448.0 [M+H]* (ESI)	1H h^MR (500 MHz, DMSO-cfe) 5 8.40 (s, 1H), 8.03 (brs, 1H), 7.57 - 7.34 (m, 2H), 4.94 (d, J = 5.3 Hz, 1 H), 4.45 (t, J = 5.0 Hz, 2H), 4.21 (t, J = 4.9 Hz, 2H),3.86 - 3.77 (m, 3H), 3.49 (brd, J = 4.1 Hz, 1H), 3.03(t, J = 10.5 Hz, 1H), 1.94 (brs, 1H), 1.68 (s, 6H), 1.57-1.40 (m,

187

			1 H); one proton obscured by solvent peak
A28	N-VC' Λ A hok/\ LA l J L ^N^ Me—(/ N> o-s-o Me Me (3R,4R)-4-({5-chloro-4-[2methyl-3-(propan-2-yl)-2Hindazol-5-yl]pyrimidin-2yl}amino)-1(methanesulfonyl)piperidin-3-ol	479.3 [M+H]+ (ESI)	1H NMR (400 MHz, DMSO-</6) 5 8.38 (s, 1H), 8.32-8.22 (m, 1 H), 7.59 (br s, 2H), 7.51 - 7.35 (m, 1H), 5.22 (d, J = 4.3 Hz, 1H), 4.13 (s, 3H), 3.84-3.74 (m, 1H), 3.65-3.53 (m, 3H), 3.53-3.47 m, 1H), 2.89 (s, 3H), 2.87 - 2.78 (m, 1H), 2.69 2.60 (m, 1H), 2.13-1.97 (m, 1 H), 1.57-1.50 (m, 1H), 1.46 (d, J =6.8 Hz, 6H)
A29	Λ A HN N^iP] HO^Â. U___1 T J λ 'St Me O=S=O HO Me (3R,4R)-4-({5-chloro-4-[3-(2hydroxypropan-2-yl)-2-methyl2H-indazol-5-yl]pyrimidin-2yl}amino)-1(methanesulfonyl)piperidin-3-ol	495.3 [M+H]+ (ESI)	1H NMR (400 MHz, DMSO-d6) 5 8.39 (s, 1H), 8.37-8.24 (m, 1 H), 7.60 (br d, J = 7.0 Hz, 2H), 7.53-7.38 (m, 1H), 5.76 (s, 1H), 5.22 (d, J =4.5 Hz, 1H), 4.33 (s, 3H), 3.83 - 3.74 (m, 1H), 3.59 (m, 2H), 3.51-3.44 (m, 1H), 2.89 (s, 3H), 2.872.79 (m, 1H), 2.68-2.60 (m, 1H), 2.10-1.99 (m, 1H), 1.75 (s, 6H), 1.58-1.46 (m, 1H)
A30	I HN N Y HO^ /k AA Il ' //N k J N-K N Me—/ O=S=O Me [Tl I Me 0 (3R,4R)-4-({5-chloro-4-[4fluoro-2-(oxetan-3-yl)-1 (propan-2-yl)-1 H-benzimidazoI6-yl]pyrimidin-2-yl}amino)-1(methanesulfonyl)piperidin-3-ol	539.2 [M+H]+ (APCI)	1H NMR (400 MHz, DMSO-d6, VT 80°C) 5 8.39 (s, 1H), 7.95 (d, J= 1.0 Ης|, 1H), 7.44 (dd, J = 0.9, 11.9 Hz, 1H), 7.18 (d, J = 7.7 Hz, 1H), 5.05-4.93 (m, 5H), 4.83 - 4.71 (m, 1H), 4.64 4.50 (m, 1Hj, 3.88-3.75 (m, 1H), 3.72 - 3.60 (m, 1H), 3.59 3.46 (m, 1H), 3.20 (d, J = 4.6 Hz, 2H), 2.95 - 2.83 (m;4H), 2.78 - 2.63 (m, 1H), 2.12 (dd, J

188

			= 3.4,13.4 Hz, 1H), 1.56 (d, J = 6.8 Hz, 6H)
A31	aX^f HN N T AA Il ' //N k fi N—X n Me-γ 0=8=0 Μβ o^7 Me *first eluting stereoisomer (3R,4R)-4-({5-chloro-4-[4fluoro-2-(oxetan-2-yl)-1 (propan-2-yl)-1 H-benzimidazol6-yl]pyrimidin-2-yl}amino)-1(methanesulfonyl)piperidin-3-ol	538.9 [M+H]+ (ESI)	1H NMR (400 MHz, CD3OD) δ 8.36 (s, 1H), 8.09-7.96 (m, 1H), 7.56-7.47 (m, 1H), 6.19 (dd, J = 7.1,7.9 Hz, 1H), 4.91 4.88 (m, 1H), 4.86-4.82 (m, 1 H), 4.78 - 4.69 (m, 1 H), 4.00 3.88 (m, 1H), 3.86-3.78 (m, 1H), 3.76-3.71 (m, 1H), 3.703.64 (m, 1H), 3.51 -3.40 (m, 1H), 3.21-3.08 (m, 1H), 2.982.89 (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	ajC^f HN N HO. AA Il ' //N k fi N—X n Me-γ 0=S=0 Me 0^7 Me *second eluting stereoisomer (3R,4R)-4-({5-chloro-4-[4fluoro-2-(oxetan-2-yl)-1 (propan-2-yl)-1 H-benzimidazol6-yl]pyrimidin-2-yl}amino)-1 (methanesulfonyl)piperidin-3-ol	539.1 [M+HJ* (ESI)	1H NMR (400 MHz, CD3OD) δ 8.36 (s, 1H), 8.09-7.97 (m, 1H), 7.56-7.47 (m, 1H), 6.19 (dd, J =7.0, 7.9 Hz, 1H), 4.91 4.88 (m, 1H), 4.86-4.82 (m, 1H), 4.78-4.69 (m, 1H), 4.003.89 (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), 1^1-1-63 (m, J =1.0, 6.9 Hz, 7H)
A33	N^0' HN Ν^ιγ^ ΗΟ^Λ i AA Il ' //N k fi N—X O Me-^ Λ NH2 Me o 1,5-anhydro-3-({4-[2carbamoyl-4-fluoro-1 -(propan2-yl)-1 /-/-benzimidazol-6-yl]-5-	449.1 [M+H]+ (ESI)	1H NMR (500 MHz, DMSO-de) δ 8.51 -8.38 (m,2H), 8.187.99 (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,

189

	chloropyrimidin-2-yl}amino)- 2,3-dideoxy-D-threo-pentitol		1H), 1.62 (d, J =7.0 Hz, 6H), 1.53 - 1.37 (m, 1 H)
A34	N^J A HN N J y JJ Il ' //N k > N—\ ° MeJ JJnh Me o Me 1,5-anhydro-3-({5-chloro-4-[4fluoro-2-(methylcarbamoyl)-1(propan-2-yl)-1 H-benzimidazol6-yl]pyrimidin-2-yl)amino)-2,3dideoxy-D-fhreo-pentitol	463.2 [M+H]+ (ESI)	1H NMR (400 MHz, CD3OD) δ 8.36 (s, 1H), 8.15-8.04 (m, 1H), 7.54 (d, J =11.5 Hz, 1H), 6.04-5.83 (m, 1H), 4.04-3.84 (m, 3H), 3.70-3.55 (m, 1H), 3.52 - 3.42 (m, 1H), 3.25 - 3.15 (m, 1H), 2.97 (s, 3H), 2.172.06 (m, 1H), 1.70 (d, J =6.8 Hz, 6H), 1.67-1.57 (m, 1H)
A35	HN N y^ HO^^k JJ il ' //N k J N—\ O Me^ -y0H *first eluting Me MeMe stereoisomer 1,5-anhydro-3-({5-chloro-4-[4- fluoro-2-(2-hydroxypropan-2y I )-1 -(propan-2-yl)-1 Hbenzimidazol-6-yl]pyrimidin-2yl)amino)-2,3-dideoxy-e/ythropentitol	464.1 [M+H]+ (ESI)	1H NMR (400 MHz, DMSO-d6) 6 8.44 (s, 1H), 8.05-7.87 (m, 1H), 7.53 - 7.27 (m, 1H), 7.06 6.90 (m, 1H), 5.98-5.66 (m, 2H), 5.06 - 4.75 (m, 1H), 4.06 3.94 (m, 1H), 3.87-3.68 (m, 3H), 3.48 - 3.38 (m, 2H), 2.01 1.83 (m, 1H), 1.66 (s, 6H), 1.63 -1.55 (m, 7H); [a]o20 =-41.9 (c=0.14, MeOH)
A36	JOC^f hn N yy< HO^xk ° p' ÿ—OH Me Me *second eluting stereoisomer j 1,5-anhydro-3-({5-chloro-4-[1(1,1-difluoropropan-2-yl)-4fluoro-2-(1 -hydroxyethyl)-1 Hbenzimidazol-6-yl]pyrimidin-2yl}amino)-2,3-dideoxy-D-fhreopentitol	485.9 [M+H]+ (ESI)	1H NMR (700MHz, DMSO-cf6) δ 8.42 (s, 1H), 8.13-7.73 (m, 1H), 7.60-7.27 (m, 2H), 6.63 J 6.40 (m, 1H), 6.00-5.82 (m, 1H), 5.55-5.41 (m, 1H), 5.22- 5.13 (m, 1 H), 5.01 -4.85(m, ' 1H), 3.91 - 3.74 (m, 3H), 3.53 3.45 (m, 1H), 3.07-2.97 (m, 1H), 2.04-1.85 (m, 1H),1.68 (d, J=7.1 Hz, 3H), 1.62 (d, J = 6.7 Hz, 3H), 1.55-1.42 (m,

190

1H); [a]D 22 = -37.3 (c=0.1, MeOH)

Example A37 (Scheme A-2): Préparation of (3R,4R)-4-({5-fluoro-4-[4-fiuoro-2-methyl-1(propan-2-yI)-1H-benzimidazol-6-yi]pyrimidin-2-yl}amino)piperidin-3-oI

Scheme A-2:

A-3 Example A37

A solution of tert-butyl (3R,4R)-4-({5-fIuoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1Hbenzimidazol-6-yl]pyrimidin-2-yl}amino)-3-hydroxypiperidine-1-carboxylate (A-3) (prepared as in Example A1,1.25 g, 2.49 mmol) in DCM (10 mL) was treated with TFA (10 mL) and then stirred at ambient température for 1 h. The mixture was concentrated and the crude residue was taken up into DCM (10 mL). The pH was adjusted to ~7-8 with NH4OH. 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 provide (3R,4R)-4-({5-fluoro-4-[4-fluoro-2methyl-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-d₆) δ 8.47 (d, J = 3.8 Hz, 1H), 8.10 (s, 1H), 7.73 - 7.57 (m, 1H), 7.51 - 7.39 (m, 1H), 5.69 - 5.62 (m, 1H), 4.90 - 4.72 (m, 1H), 4.43 - 4.30 (m, 1H), 4.08 - 3.93 (m, 1H), 3.90 - 3.77 (m, 1H), 3.50 - 3.39 (m, 2H), 3.07 - 2.96 (m, 1H), 2.95 - 2.82 (m, 1H), 2.63 (s, 3H), 2.28 - 2.15 (m, 1H), 1.74 - 1.64 (m, 1H), 1.59 (d, J = 6.8 Hz, 6H); m/z (ESI+) for (C20H24F2N6O), 403.1 (M+H)⁺.

Example A38 (Scheme A-3): Préparation of (3R,4R)-4-[(4-{1-[(2R)-1-aminopropan-2-yl]-4fluoro-2-methyl-1H-benzimidazol-6-yl}-5-chloropyrimidin-2-yl)amino]-1(methanesulfonyl)piperidin-3-ol .

Scheme A-3:

191

Example A3S

HCl

MeOH, 1,4-dioxane 34% yield tert-butyl {(2R)-2-[6-(5-chloro-2-{[(3R,4R)-3-hydroxy-1 (methanesulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)-4-fIuoro-2-methyl-1H-benzimidazol-1yl]propyl)carbamate (A-4) (Prepared as in Example A1,130 mg, 0.212 mmol) in MeOH (2.5 mL) was added a solution of HCl (4.0 M in 1,4-dioxane, 2.5 mL) dropwise at 0 °C. After the addition the reaction solution was stirred at room température for 2 h. LCMS analysis showed consumption ofthe starting material with formation ofthe desired product mass. The reaction was concentrated to dryness. The residue was purified by préparative HPLC on a DuraShell column (150x25 mm, 5 pm particle size) which was eluted with 7-37% MeCN/HsO (+0.05% HCl) with a flow rate of 30 mL/min to provide (3R,4R)-4-[(4-{1-[(2R)-1-aminopropan-2-yl]-4-fluoro-2-methyl1H-benzimidazol-6-yl}-5-chloropyrimidin-2-yl)amino]-1-(methanesuIfonyl)piperidin-3-ol (Example A38) (39.5 mg, 34% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-de) δ 8.39 (s, 1 H), 8.06 - 7.97 (m, 1 H), 7.67 - 7.52 (m, 1 H), 5.06 - 4.79 (m, 1 H), 3.81 - 3.70 (m, 1 H), 3.66 - 3.54 (m, 3H), 3.51 - 3.43 (m, 1H), 3.42 - 3.33 (m, 1H), 2.85 (s, 3H), 2.82 - 2.77 (m, 1H), 2.74 (s, 3H),

2.68 - 2.56 (m, 1 H), 2.05 - 1.96 (m, 1 H), 1.64 (d, J = 6.8 Hz, 3H), 1.58 - 1.45 (m, 1 H); m/z (ESI+) for (C₂iH27CIFN₇O3S), 512.2 (M+H)⁺.

The examples in the below table were synthesized according to the methods used for the synthesis of (3R,4R)-4-({5-hloro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1/7-benzimidazol-620 yl]pyrimidin-2-yl)amino)-1-(methanesulfonyl)piperidin-3-ol (Example A37) (Scheme A-2) and । (3R,4R)-4-[(4-{1-[(2R)-1-aminopropan-2-yl]-4-fluoro-2-rnethyl-1/-/-benzimidazol-6-yl}-5chloropyrimidin-2-yl)amino]-1-(methanesulfonyl)piperidin-3-ol (Example A38) (Scheme A-3). The following examples were synthesized with non-critical changes or substitutions to the , exemplified procedures that someone who is skilled in the art would be able to realize. If

I !

i necessary, séparation of the enantiomers was carried out under standard methods known in the art, such as chiral SFC or HPLC, to afford single enantiomers.

Example	Structure/Name	LCMS	NMR
number			--

192

A39	N-ycl ΗΝ^Ν<Υ''<^ HO^^k Il \ ,N k J N— N Mei·./ o=s=o ) Me H2N (3R,4R)-4-[(4-{1-[(2S)-1aminopropan-2-yl]-4-fluoro-2methyl-1 H-benzimidazol-6-yÎ}5-chloropyrimidin-2-yl)amino]1-(methanesulfonyl)piperidin-3ol	534.2 [M+Na]+ (ESI)	1H NMR (400 MHz, DMSO-cfe) δ 8.45-8.27 (m, 1H), 8.037.87 (m, 1H), 7.65-7.49 (m, 1H), 5.08-4.85 (m, 1H), 3.833.68 (m, 1H), 3.67-3.56 (m, 2H), 3.54 - 3.35 (m, 2H), 2.91 2.79 (m, 4H), 2.75 - 2.61 (m, 4H), 2.12-1.95 (m, 1H), 1.71 1.50 (m, 4H)
A40	N-YCI HO^xk kxA Il ' //N i \ Me o=s=o L·.. 1 >1 Μθ Me H2N (3R,4R)-4-({4-[1-(2aminopropyl)-4-fluoro-2-methyl1 H-benzimidazol-6-yl]-5chloropyrimidin-2-yl}amino)-1(methanesulfonyl)piperidin-3-ol	512.2 [M+H]+ (ESI)	1H NMR (400 MHz, DMSO-d6) 6 8.39 (s, 1H), 8.01-7.82 (m, 1H), 7.58-7.31 (m, 1H), 4.484.34 (m, 2H), 3.82- 3.72 (m, 1H), 3.71-3.63 (m, 1H), 3.633.54 (m, 2H), 3.51 - 3.42 (m, 1H), 2.85 (s, 3H), 2.82-2.73 (m, 1H), 2.67-2.57 (m,4H), 2.10-1.95 (m, 1 H), 1.59-1.45 (m, 1H), 1.24 (d, J =6.5 Hz, 3H)
A41 ί	N^YCI HC^xk Il ' //N k y N-χ „ O Me-γ y,Me Μθ Me' 3-({4-[2-(2-aminopropan-2-yl)4-fluoro-1 -(propan-2-yl)-1 Hbenzimidazol-6-yl]-5chloropyrimidin-2-yl)amino)1,5-anhydro-2,3-dideoxy-Dtbreo-pentitol	463.4 [M+H]+ (ESI)	1H NMR (500 MHz, DMSO-de) 6 8.41 (s, 1H), 8.05-7.81 (m, 1H), 7.57-7.22 (m, 2H), 6.24^.06 (m, 1 H), 4.99 - 4.89 (m, 1H), 3.90-3.73 (m, 3H), 3.543.46 (m, 1H), 3.32-3.30 (m, 1l}l), 3.07-2.95 (m, 1H), 2.33^.22 (m, 1H), 2.04-1.88 (m, 1H), 1.60-1.56 (m, 12H), 1.53 -1.40(m, 1H)

193

A42	N^' xk hn nY y il ' //N k > N-X ° mX J^nh2 Me MeMè 3-[(4-{2-[(1R)-1-aminoethyl]-1fert-butyl-4-fluoro-1 Hbenzimidazol-6-yl}-5chloropyrimidin-2-yl)amino]-1,5anhydro-2,3-dideoxy-D-threopentitol	463.4 [M+H]* (ES!)	1H NMR (500 MHz, CD3OD) δ 8.34 (s, 1H), 8.25-8.14 (m, 1H), 7.56-7.38 (m, 1H), 4.844.77 (m, 1H), 4.66-4.58 (m, 1H), 4.01 - 3.94 (m, 2H), 3.933.87 (m, 1H), 3.65-3.57 (m, 1H), 3.52 - 3.44 (m, 1H), 3.24 3.13 (m, 1H), 2.17-2.07 (m, 1H), 1.94 (s, 9H), 1.68 -1.61 (m, 1H), 1.59 (d, J = 6.6 Hz, 3H)
A43	Ν^γει HO.. A 'LÿÀ Il ' z/N k x1 N-X ° MeY j\-NH2 Me 3-({4-[2-(1-aminocyclopropyl)4-fluoro-1 -(propan-2-yl)-1 Hbenzimidazol-6-yl]-5chloropyrimidin-2-yl}amino)1,5-anhydro-2,3-dideoxy-Dthreo-pentitol	461.3 [M+H]* (ESI)	1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 8.03-7.82 (m, 1H), 7.57-7.22 (m, 2H), 5.505.24 (m, 1H), 4.99-4.91 (m, 1H), 3.91 - 3.75 (m, 3H), 3.57 - 3.44 (m, 1H), 3.09-2.96 (m, 1H), 2.63 - 2.54 (m, 1H), 2.06 - 1.86 (m, 1H), 1.62 (d, J =7.0 Hz, 6H), 1.56-1.41 (m, 1H), 1.21 - 1.13 (m, 2H), 1.03-0.94 (m, 2H)
A44	N^yCI HhA/VV^ HO^xk LiA Il ' //N k S N-X Me—γ VNH I Me Me 1,5-anhydro-3-[(5-chloro-4-{4fluoro-2-[(methylamino)methyl]- 1 -(propan-2-yl)-1 Hbenzimidazol-6-yl}pyrimidin-2yl)amino]-2,3-dideoxy-D-f/7reopentitol	448.9 [M+H]* (ESI)	1H 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), 2.0411.84 (m, 1H), 1.58 (d, J = 7.0 Hz, 6H), 1.53-1.40 (m, 1H)

194

A45	ΗΝ^Ν^^^^^ίΑ HO^ AA Il ' //N A> .. .N-\ Me O Me—γ \—(-NH2 Me Me 3-({4-[2-(2-amino-2methylpropyl)-4-fluoro-1(propan-2-yl)-1 H-benzimidazol6-yi]-5-chloropyrimidin-2yl}amino)-1,5-anhydro-2,3dideoxy-D-threo-pentitol	477.1 [M+H]* (ESI)	1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.30 (s, 1H), 7.79 - 7.70 (m, 1H), 5.14-5.02 (m, 1H), 4.08 - 3.88 (m, 3H), 3.71 3.62 (m, 1H), 3.62-3.58 (m, 1H), 3.54 (s, 2H), 3.52-3.42 (m, 1H), 3.25-3.17 (m, 1H), 2.16-2.02 (m, 1H), 1.82-1.71 (m, 7H), 1.57 (s, 6H)
A46	hn n AA il \ /N Me N-/ MeA ) '—NH 1,5-anhydro-3-{[5-chloro-4-(9fluoro-4,4-dimethyI-1,2,3,4tetrahydropyrazino[1,2a]benzimidazol-7-yl)pyrimidin2-yi]amino}-2,3-dideoxy-Dfhreo-pentitol	447.1 [M+H]* (ESI)	1H NMR (400 MHz, DMSO-d6 + D2O)5 8.38(s, 1H), 7.96 (brs, 1H), 7.39 (br d, J = 7.8 Hz, 2H), 4.95 (d, J =5.3 Hz, 1H), 4.03 (s, 2H), 3.81 (brdd, J=5.3, 10.8 Hz, 3H), 3.49 (br s, 1H), 3.30 (brt, J = 11.2 Hz, 1H), 3.07 - 2.94 (m, 3H), 1.94 (br s, 1H), 1.60 (s, 6H), 1.49 (brd, J = 9.5 Hz, 1H)
A47	ΗΝ^Ν^η/^Α ho. AA Il ' //N k S N—\ N Me^ A O=S=b MeM/ Me *single stereoisomer (3R,fR)-4-({4-[2-(1aminoethy^)-4-fIuoro-1-(propan2-yl)-1 /-/-benzimidazol-6-yl]-5chloropyrimidin-2-yl}amino)-1(methanesulfonyl)piperidin-3-ol	526.3 [M+H]* (ESI)	1H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 7.92 (brs, 1H), 7.57 - 7.31 (m, 2H), 5.23 (d, J = 4.5 Hz, 1H), 5.15 (td, J = 6.9, 14.0 Hz, 1H), 4.35 (q, J =6.5 Hz, 1H), 3.87-3.75 (m, 1H), 3.61 (br d, J = 8.5 Hz, 2H), 3.50 (brd, J =12.3 Hz, fl H), 2.932.82 (m, 4H), 2.66 (brt, J = 11.0 Hz, 1H), 2.20-2.04 (m, 3H), 1.67 - 1.42 (m, 10H); [a]D 20 = -13.3 (c=0.1 , MeOH)

195

A48	Ν^’ JL. HN N Y Y ho^A YY Il ' //N k A N—K N Me^ Λ N o=s=o MeM/ 2 Me ‘single stereoisomer (3R,4R)-4-({4-[2-(1aminoethyl)-4-fluoro-1-(propan2-yl)-1 H-benzimidazol-6-yl]-5chloropyrimidin-2-yl}amino)-1 (methanesulfonyl)piperidin-3-ol	526.3 [M+H]+ (ESI)	1H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 8.05-7.87 (m, 1H), 7.59-7.30 (m, 2H), 5.23 (d, J =4.5 Hz, 1H), 5.15 (quin, J = 6.9 Hz, 1 H), 4.35 (q, J = 6.5 Hz, 1H), 3.81 (brd, J =5.8 Hz, 1 H), 3.61 (br d, J = 9.3 Hz, 2H), 3.49 (brd, J =12.3 Hz, 1H), 2.90 (s, 3H), 2.88 - 2.79 (m, 1H), 2.70-2.61 (m, 1H), 2.16 (br s, 3H), 1.63 - 1.47 (m, 10H); [α]ο20 = -18.1 (c=0.1 , MeOH)
A49	N^’ JL ^^Y^^x-F hn nYY HOK A L. Y LJ L? (J Me-Y~N« Z\ Me Me nh2 3-({4-[3-(2-aminopropan-2-yl)7-fluoro-2-methyl-2H-indazol-5yl]-5-chloropyrimidin-2yl]amino)-1,5-anhydro-2,3dideoxy-D-fhreo-pentitol	435.0 [M+H]+ (ESI)	1H NMR (500 MHz, DMSO-d6) δ 8.53 - 8.26 (m, 2H), 7.61 7.28 (m, 2H), 4.99 - 4.88 (m, 1H), 4.49 (s, 3H), 3.86-3.75 (m, 3H), 3.53-3.43 (m, 1H), 3.07 - 2.99 (m, 1H), 2.03 - 1.89 (m, 1H), 1.72 (s, 6H), 1.571.41 (m, 1H)
A50	ΗΝ Ν Υγ HO. A. YY Il ' /N N MeYN~Y,i0H . MeMe (3R,4R)-4-[(5-chloro-4-{4fluoro-2-[(1 R)-1 -hydroxyethyl]1 -(propan-2-ÿl)-1 Hbenzimidazol-6-yI}pyrimidin-2yl)amino]piperidin-3-ol	448.9 [M+H]+ (ESI)	1H NMR (400 MHz, DMSO-d6, 80 °Ο)δ8.87 (br. s, 1H), 8.64 (br.s, 1H), 8.43 (s, 1H), 7.99 (d, J = 1.3 Hz, 1 H), 7.51 - 7.38 (m, 2H), 5.24 (hept, J= 7.6, |.1 Hz, 1 H), 5.13 (q, J = 6.5 Hz, 1H), 3.38-3.23 (m, 2H), 3.06 -2.95 (m, 1H), 3.05-2.80 (m, 1H), 2.31 -2.19 (m, 1H), 1.82 -1.70 (m, 1H), 1.67 — 1.58 (m, 9H); two protons obscured by solvent peak

196

A51	ÎjÇyF HN N y LA Il A ,N LJ Me. N-y 0 MeA ^NH2 3-({4-[1-(1-amino-2- methylpropan-2-yl)-4-fluoro-1 Hbenzimidazol-6-yl]-5chloropyrimidin-2-yl}amino)1,5-anhydro-2,3-dideoxy-Dfhreo-pentitol	435.0 [M+H]* (ESI)	1H NMR (500 MHz, DMSO-de) δ 8.35 (s, 1 H), 8.31 (s, 1 H), 8.07 - 7.92 (m, 1 H), 7.52 - 7.30 (m, 1H), 3.88-3.69 (m, 3H), 3.56-3.43 (m, 1H), 3.38-3.21 (m, 1 H), 3.11 -2.96(m,3H), 2.00-1.86 (m, 1H), 1.64 (s, 6H), 1.54- 140 (m, 1H)
A52	JOX^f HN Ν γ^ y HCK/A L-Jk Il ' //N < J Me N-ξ Me^Y Me v~nh2 3-({4-[1-(1-amino-2methylpropan-2-yl)-4-fluoro-2methyl-1 H-benzimidazol-6-yl]- 5-chloropyrimidin-2-yl}amino)1,5-anhydro-2,3-dideoxy-Dfbreo-pentitol	448.9 [M+H]* (ESI)	1H NMR (400 MHz, D2O) δ 8.50 -8.33 (m, 1H), 8.24-8.13 (m, 1H), 7.78 - 7.64 (m, 1H), 4.03 3.89 (m, 3H), 3.87 - 3.80 (m, 2H), 3.74 - 3.62 (m, 1H), 3.59 3.44 (m, 1H), 3.30-3.20 (m, 1H), 3.15-2.97 (m, 3H), 2.121.97 (m, 7H), 1.77-1.55 (m, 1H)
A53	ï T ΗΟκΑ LA Il ' //N k S N-X O Me-γ ^Νύ Me Me ' 3-[(4-{2-[(1 S)-1-aminoethyl]-4- fluoro-1-(propan-2-yl)-1 Hbenzimidazol-6-yl}-5- : chloropyrimidin-2-yl)amino]-1,5anhydro-2,3-dideoxy-D-fbreopentitol	448.9 [M+H]* (ESI)	1H NMR (600MHz, DMSO-d6) 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, 1 H), 3.873.75 (m, 3H), 3.59 - 3.48 (m, 1H), 3.07 - 2.98 (m, 1H), 2.03 1.89 (m, 1H), 1.60 (d, J = 6.6 Hz, 6H), 1.55-1.45 (m, 4H)

197

A54	N^C' ΗΝ^Ν^Α^ψF HC^A^ AA Il ' //N k S N—x O Me^ ~VNH2 Me 3-({4-[2-(aminomethyl)-4-fluoro1-(propan-2-yl)-1Hbenzimidazol-6-yl]-5chloropyrimidin-2-yl}amino)1,5-anhydro-2,3-dideoxy-Dtereo-pentitol	435.1 [M+H]+ (ESI)	1H NMR (400 MHz, DMSO-d6) at 80oC δ = 8.40 (s, 1 H), 8.10 7.98 (m, 1H), 7.48 (brd, J = 11.0 Hz, 1 H), 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), 2.141.99(m, 1H), 1.73- 1.49 (m, 7H)
A55	HN N |< HO—Â AA Il \ ,N LA N-4 o Me—4 \ NH first eluting stereoisomer 1,5-anhydro-3-{[5-chloro-4-(9fluoro-4-methyl-1,2,3,4tetrahydropyrazino[1,2a]benzimidazoI-7-yl)pyrimidin2-yl]amino}-2,3-dideoxy-Dfhreo-pentitol	433.1 [M+H]+ (ESI)	1H NMR (400 MHz, DMSO-d6) 5 8.42 (s, 1H), 7.83 (brs, 1H), 7.58 - 7.31 (m, 2H), 4.95 (d, J = 5.3 Hz, 1H), 4.58 (brs, 1H), 4.20 - 4.02 (m, 2H), 3.90 - 3.76 (m, 3H), 3.51 (brd, J =5.3 Hz, 2H), 3.30 - 3.24 (m, 1H), 3.12 2.99 (m, 2H), 1.95 (brd, J = 12.0 Hz, 1H), 1.50 (d, J =6.5 Hz, 4H); [a]D 20 = 27.7 (c=0.13 , MeOH)
A56	riA HN N HO^zk AA Il \ ,N LA N-4 0 Me—4 ‘second eluting NH stereoisomer 1,5-anhydro-3-{[5-chloro-4-(9fluoro-4-methyl-1,2,3,4— tetrahydropyrazino[1,2- a]benzimidazoi-7-yl)pyrimidin2-yi]amino}-2,3-dideoxy-Dfhreo-pentitol	433.2 [M+H]+ (ESI)	1H NMR (400 MHz, DMSO-d6) 5 8.47 - 8.34 (m, 1H), 7.82 (br s, 1H), 7.62-7.32 (m, 2H), 4.94 (d, J = 5.3 Hz, 1 H),.4.57 (brs, 1H), 4.17-4.00 (m, 2H), 3.82 (brdd, J = 4.9,10.7 Hz, 3H), 3.50 (br s, 2H), 3.29 - 3.21 (m, 1H), 3.09- 2.97 (m, 2H), 1.97 (brs, 1 H), 1.58-1.41 (m, 4H); [a]D 20 = 48.2 (c=0.13 , MeOH)

198

A57	Ν^’ A HN N^rfY AA Il ' //N F\ k fi N-X >—F 0 Me— ‘second eluting Me nh2 stereoisomer 3-({4-[2-(2-amino-3,3difluoropropyl)-4-fluoro-1(propan-2-yl)-1 H-benzimidazol6-yl]-5-chloropyrimidin-2yl}amino)-1,5-anhydro-2,3dideoxy-D-fhreo-pentitol	499.4 [M+H]* (ESI)	1H NMR (400 MHz, DMSO-d6) 5 8.41 (s, 1H), 8.08-7.80 (m, 1H), 7.57 - 7.28 (m, 2H), 6.26 5.80 (m, 1H), 5.01 -4.78 (m, 2H), 3.91 - 3.73 (m, 3H), 3.60 3.44 (m, 2H), 3.22 - 3.11 (m, 1 H), 3.08 - 2.89 (m, 2H), 2.04 1.80 (m, 3H), 1.66- 1.55 (m, 6H), 1.53-1.44 (m, 1H)
A58	N^YCI A hn Ν γ y AA Il ' //N F\ k fi N-X )— F O Me-γ \ ‘first eluting Me nh2 stereoisomer 3-({4-[2-(2-amino-3,3difluoropropyl)-4-fluoro-1(propan-2-yl)-1 H-benzimidazol6-yl]-5-chloropyrimidin-2yl}amino)-1,5-anhydro-2,3dideoxy-D-frireo-pentitol	499.0 [M+H]* (ESI)	1H NMR (400 MHz, DMSO-cfe) 5 8.42 (s, 1H), 7.98 (brs, 1H), 7.56 - 7.17 (m, 2H), 6.21 (td, J = 55.6, 3.2 Hz, 1H), 4.91 (dq, J = 20.7, 6.9, 6.1 Hz, 2H), 3.98 3.69 (m, 4H), 3.51 (s, 1H), 3.30 -3.26 (m, 1H), 3.21-2.89 (m, 2H), 1.97 (brs, 1H), 1.60 (dd, J = 6.9, 3.5 Hz, 6H), 1.57-1.45 (m, 1H)
A59 I I	A HN N AA Il ' //N k fi N-X γΎ o Me-γ \ 1 > Me h2n 3-[(4-{2-[(1aminocyclopentyl)methyl]-4fluoro-1-(propan-2-yl)-1Hbenzimidazol-6-yl}-5chloropyrimidin-2-yI)amino]-1,5anhydro-2,3-dideoxy-D-fhreopentitol	503.1 [M+H]* (ESI)	1H NMR (400 MHz, CD3OD) 5 Έ.34 (s, 1H), 8.05 (s, 1H), 7.49 (d, J = 11.5 Hz, 1H), 5.07 -4.91 , (m,· 1 H), 4.03 - 3.85 (m, 3H), ! 3.62 (s, 1 H), 3.53-3.43 (m, 1H), 3.26 - 3.14 (m, 3H), 2.19 - 2.10 (m, 1 H), 1.92-1 78 (m, 4H), 1.77 -1.56 (m, 11 H)

199

Example A60 (Scheme A-4): Préparation of 1,5-anhyd ro-3-[(4-{1-tert-butyl-4-fluoro-2-[(1R)1-hydroxyethyl]-1H-benzimidazol-6-yI}-5-chloropyrimidin-2-yI)amino]-2,3-dideoxy-Dthreo-pentito!

Scheme A-4 . .

Example A60

To a solution of 1,5-anhydro-3-[(4-{1-fert-butyl-2-[(1R)-1-{[tertbutyl(dimethyl)silyI]oxy}ethyl]-4-fluoro-1H-benzimidazol-6-yl}-5-chloropyrimidin-2-yl)amino]-2,3dideoxy-D-threo-pentitol (A-5) (Prepared as in Example A1,70.0 mg, 0.121 mmol) in MeOH (1.0 mL) was added HCl (4.0 N in 1,4-dioxane, 3.0 mL) dropwise at 0 °C. The solution was stirred at 30 °C for 4 h. TLC analysis showed consumption of the starting material. The solution was basified with NH4OH to pH ~9 and then concentrated to dryness. The residue was purified by préparative HPLC on a Boston Uni C-18 column (40x150 mm, 5 pm particle size), which was eluted with 13-53% MeCN/H2O (+0.05% HCl) with a flow rate of 60 mL/min. The material was repurified by préparative HPLC on a DuraShell column (150x25 mm, 5 pm particle size), which was eluted with 27-47% MeCN/H2O (+0.05% NH4OH) with a flow rate of 25 mL/min to provide 1,5anhydro-3-[(4-{1 -tert-butyI-4-fluoro-2-[(1 R)-1 -hydroxyethyl]-1 H-benzimidazol-6-yl}-5chloropyrimidin-2-yl)amino]-2,3-dideoxy-D-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 (brd, J = 1.2 Hz, 1H), 3.03 (brt, J =10.3 Hz, 1H), 2.07 (s, 1H), 2.01 -1.91 (m, 1H), 1.88 (s, 9H), 1.67 (d, J = 6.^ Hz, 3H), 1.56 -1.44 (m, 1H); one proton obscured bj| solvent peak; m/z (ESI+) for (C22H27CIFN5O3), 464.1 (M+H)⁺.

The examples in the below table were synthesized according to the methods used for the synthesis of 1,5-anhydro-3-[(4-{1-tert-butyl-4-fIuoro-2-[(1 R)-1-hydroxyethyl]-1 /7-benzimidazol-6yl}-5-chloropyrimidin-2-yl)amino]-2,3-dideoxy-D-f/7reo-pentitol (Example A60) (Scheme A-4). The following examples were synthesized with non-critical changes or substitutions to the exemplified procedures that someone who is skilled in the art would be able to realize.

Example number

Structure/Name

LCMS

NMR

200

A61	N-yCI HN^AyJ HO^ LA k A N-X θ Μθχ A^oh Me Me Me 1,5-anhydro-3-[(4-{1-tert-butyl4-fluoro-2-[(1S)-1hydroxyethyl]-1 /7-benzimidazol6-yl}-5-chloropyrimidin-2yl)amino]-2,3-dideoxy-D-threopentitol	464.1 [M+H]+ (ESI)	1H NMR (400 MHz, CD3OD) δ 8.34 (s, 1H), 8.19 (s, 1H), 7.48 (d, J=11.3 Hz, 1H), 5.46 (q, J = 6.4 Hz, 1H), 4.02-3.87 (m, 3H), 3.66 - 3.57 (m, 1 H), 3.48 (td, J=11.7, 2.3 Hz, 1H), 3.24 -3.16(m, 1H), 2.18-2.09 (m, 1H), 1.97 (s, 9H), 1.76 (d, J = 6.4 Hz, 3H), 1.70-1.57 (m, 1H)
A62	nY<ci HN^N^AfHL F Il \ ,N LJ ή-4 N )OH O=S=O Me Μβ Me (3R,4R)-4-[(4-{1 -tert-butyl-4fluoro-2-[(1 R)-1 -hydroxy ethyl] - 1 H-benzimidazol-6-yl}-5chloropyrimidin-2-yl)amino]-1(methanesuIfonyi)piperidin-3-ol	541.0 [M+H]+ (ESI)	1H NMR (400 MHz, DMSO-cfe) δ 8.42 (s, 1H), 8.26-7.97 (m, 1H), 7.44 (d, J =53.2 Hz, 2H), 5.53 (d, J = 7.8 Hz, 1H), 5.29 5.21 (m, 2H), 3.80 (s, 1H), 3.60 (d,2H), 3.48 (d, J =12.0 Hz, 1H), 2.93-2.78 (m, 4H), 2.71 -2.60 (m, 1H), 2.07-1.96 (m, 1 H), 1.88 (s, 9H), 1.67 (d, J = 6.2 Hz, 3H), 1.53 (d, J =12.2 Hz, 1H)
A63	N^H' JL F HN N ]|^Y LA Il ' „N A AL - . A ^OH 1,5-annydro-3-({5-chloro-4-[4fluoro-2-(hydroxymethyl)-1 -(1 methylcyclopropyl)-1 HbenzimWazol-6-yl]pyrimidin-2yl}amino)-2,3-dideoxy-D-tereopentitol	447.9 [M+H]+ (ESI)	1H NMR (400 MHz, CD3OD) δ 8.58 (s, 1H), 8.35 (d, J =1.1 Hz, 1H), 7.97 (d, J = 11.0 Hz, 1H), 5.29 (s, 2η, 4.07-3.92 (m, 3H), 3.67 (td, J =9.6, 4.9 Hz, 1H), 3.54 - 3.44 (m, 1H), 3.28-3.19 (m,i1 H), 2.162.08 (m, 1H), 1.82-1.70 (m, 4H), 1.49 (s, 2H), 1.36 (s, 2H)

201

A64	ΗΝ Ν ψ^>< HO^A. Il ' //N ° ( k_OH ΜΛΜβ 1,5-anhydro-3-({5-chIoro-4-[4fluoro-1 -(2-fluoro-2methylpropyl)-2(hydroxymethyl)-l Hbenzimidazol-6-yl]pyrimidin-2yl}amino)-2,3-dideoxy-D-f/7reopentitol	468.2 [M+H]+ (ESI)	1H NMR (600 MHz, DMSO-de) 5 8.42 (s, 1H), 7.91 (brs, 1H), 7.42 (br s, 2H), 5.72 (t, J = 6.0 Hz, 1H), 4.91 (dd, J=5.4,1.3 Hz, 1 H), 4.79 (d, J =6.0 Hz, 2H), 4.63 (d, J = 22.6 Hz, 2H), 3.82 (qt, J = 10.8, 6.4 Hz, 3H), 3.56 - 3.47 (m, 1H), 3.04 (t, J = 10.4 Hz, 1H), 1.98 (brs, 1H), 1.50 (qd, J= 12.0, 4.5 Hz, 2H), 1.39 (s, 3H), 1.35 (s, 3H)
A65	ΝΎγ oXo EÎ Ah Me (3R,4R)-4-({5-chloro-4-[1cyclobutyl-4-fluoro-2(hydroxymethyl)-l Hbenzimidazol-6-yl]pyrimidin-2yl}amino)-1(methanesulfonyl)piperidin-3-ol	524.9 [M+H]+ (ESI)	1H NMR (400 MHz, DMSO-d6) 5 8.47 (s, 1H), 8.18 (brs, 1H), 7.61 (br s, 2H), 5.25 (td, J = 8.9,17.6 Hz, 1H), 4.87 (s, 2H), 3.81 (brs, 1H), 3.61 (brd, J = 10.3 Hz, 2H), 3.49 (brd, J = 12.1 Hz, 1H), 2.90 (s, 3H), 2.85 (brt, J =9.8 Hz, 3H), 2.71 2.54 (m, 3H), 2.13-1.84 (m, 3H), 1.55 (brs, 1H)
A66	N-VCI JL HN N Tl ' //N F? F 1,5-anhydro-3-({5-chloro-4-[1(3,3-difIuorocyclobutyl)-4fluoro-2-(hydroxymethyl)-1 Hbenzimidazol-6-yl]pyrimidin-2yl}amino)-2,3-dideoxy-D-threopentitol	483.9 [M+H]+ (ESI)	1H NMR (400 MHz, DMSO-cfe) 5 8.46 (s, 1H), 7.99 (brs,|lH), 7.77 - 7.37 (m, 2H), 5.30 (br d, J =3.7 Hz, 1H), 4.86 (s, 2H), 3.92 - 3.74 (m, 3H), 3.64 J 3.43 (m, 3H), 3.43 - 3.25 (m, 3H), 3.04 (t, J = 10.4 Hz, 1H), 2.161.86 (m, 1H), 1.61-1.39 (m, 1H)

202

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

Scheme A-5

TBAF

THF

21% yield

Example A67

To a yellow solution 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-fhreo-pentitol (A-6) (Prepared as in Example A1,200 mg, 0.33 mmol) in THF (10.0 mL) was added TBAF (174 mg, 0.67 mmol) at room température. The mixture was stirred for 2 h, at which time LCMS analysis indicated complété consumption of starting material with formation ofthe desired product mass. The reaction was concentrated. The residue was taken up in EtOAc (50 mL), washed with H2O (2x50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by préparative HPLC on a DuraShell column (150x25 mm, 5 pm particle size), which was eluted with 26-46% MeCN/H2O (+0.05% NH4OH) with a flow rate of 25 mL/min to provide 1,5-anhydro-3-({5-chloro-4-[1 -(2,2-difluoroethyl)-4-fluoro-2-(2-hydroxypropan-2-yl)-1 Hbenzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-f/7reo-pentitol (Example A67) (34.2 mg, 21% yield) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.42 (s, 1H), 7.88 (s, 1H), 7.56 7.34 (m, 2H), 6.41 (tt, J = 55.9, 4.3 Hz, 1H), 5.98 (s, 1H), 5.04 (td, J = 14.0, 4.2 Hz, 2H), 4.93 (d, J=5.4Hz, 1 H)r 3.88 - 3.74 (m,3H), 3.55 - 3.46 (m,1 H), 3.03 (t,J =10.4 Hz,' 1 H), 2.04-1.83 (m, 1H), 1.68 (d, J= 1.8 Hz, 6H), 1.56 - j.42 (m, 1 H); one proton obscured by solvent peak; m/z\ (ESI+) for (C21H23CIF3N5O3), 486.0 (M+H)⁺.

The example in the below table Was synthesized according to the methods used for the' synthesis of 1,5-anhydro-3-({5-chloro-4-[1 -(2,2-difluoroethyl)-4-fluoro-2-(2-hydroxypropan-2-yl)1 H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-fhreo-pentitol (Example A67) (Scheme A-5). The following example was synthesized with non-critical changes or substitutions to the exemplified procédures that someone who is skilled in the art would be able to realize.

Example number

Structure/Name

LCMS

NMR

203

A68

JOC^f HN N HO.X JA Il ' z/N k S N-K O Me—y -y0H Me MeMe . 1,5-anhydro-2,3-dideoxy-3-({5fluoro-4-[4-fluoro-2-(2- hydroxypropan-2-yl)-1 -(propan2-yl)-1H-benzimidazol-6yl]pyrimidin-2-yl}amino)-Dfhreo-pentitol

448.2 [M+H]* (ESI)

1H NMR (400 MHz, DMSO-de) 5 8.43 (d, J = 4.0 Hz, 1H), 8.21 (s, 1H), 7.62 (d, J= 12.1 Hz, 1H), 7.19 (d, J =7.6 Hz, 1H), 5.92 - 5.70 (m, 2H), 4.96 (s, 1H), 3.91-3.73 (m, 3H), 3.62 -3.46 (m, 1H), 3.13-2.99 (m, 1H), 2.14-1.96 (m, 1 H), 1.67 (s, 6H), 1.65-1.44 (m, 7H); one proton obscured by solvent peak

Example A69 (Scheme A-6): Préparation of (3R,4R)-4-({5-chloro-4-[2-(difIuoromethyl)-4fluoro-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl)amino)-15 (methanesulfonyl)piperidin-3-ol

Scheme A-6:

lnt-69

Pd(OAc)₂, rac-BINAP Cs₂CO₃

THF, 80 C, _MW

47% yield

To a solution of 6-(2,5-dichloropyrimidin-4-yl)-2-(difluoromethyl)-1-(propan-2-yI)-1H10 benzimidazole (A-7) (prepared as in Example A1,49.6 mg, 0.132 mmol) in THF (1.32 mL) were | added (3R,4R)-4-amino-1-(methanesulfonyl)piperidin-3-ol (lnt-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 min and then stirred for 105 min at 80 °C with microwave irradiation. LCMS analysis indicated complété consumption of the starting material 15 with formation of the desired product mass. The reaction was diluted with MeOH and then filtered through a filter dise (0.2 pm). The material was purified by préparative SFC on a Nacalai Cosmosil 3-hydroxyphenyl-bonded column (150x20 mm), which was eluted with 12-23% MeOH/CO₂ with

204 a flow rate of 85 mL/min to provide (3R,4R)-4-({5-chloro-4-[2-(difluoromethyl)-4-fluoro-1-(propan2-y I )-1 H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-1 -(methanesulfonyl)piperidin-3-ol (Example A69) (33.1 mg, 47% yield) as a solid. ¹H NMR (400 MHz, DMSO-cfe, 80 °C) δ = 8.43 (s, 1H), 8.10 (d, J = 1.0 Hz, 1H), 7.57- 7.23 (m, 3H), 5.14-5.02 (m, 1H), 4.97 (br. s., 1H), 3.90 -3.75 (m, 2H), 3.73 - 3.63 (m, 2H), 3.55 (d, J = 13.1 Hz, 1H), 2.89 - 2.86 (s, 3H), 2.78 - 2.66 (m, 1H), 2.18 - 2.08 (m, 1H), 1.68 (d, J = 6.8 Hz, 6H), 1.63-1.59 (m, 1H); m/z (APCI) for (C21H24CIF3N6O3S), 533.0 (M+H)⁺.

Example A70 (Scheme A-7): Préparation of (3R,4R)-4-({5-ethyl-4-[4-fluoro-2-methyl-1(propan-2-yl)-1H-benzimidazol-6-yI]pyrimidin-2-yI}amino)-1-(methanesuIfonyl)piperidin-3ol

Scheme A-7:

A solution of 6-(2-chloro-5-ethylpyrimidin-4-yl)-4-fluoro-2-methyl-1-(propan-2-yl)-1Hbenzimidazole (A-8) (prepared as in Example A1, 80.0 mg, 0.240 mmol) in 2-methyI-2-butanoI (6 mL) was treated with CS2CO3 (157 mg, 0.481 mmol) and (3R,4R)-4-amino-1(methanesulfonyl)piperidin-3-ol (lnt-69) (60.7 mg, 0.312 mmol) and sparged with N₂. Chloro-2(dimethylaminomethyl)-ferrocen-1-yl-(dinorbomylphosphine)palladium (SK-CC02-A) (14.6 mg, 0.024 mmol) was added and the mixture again sparged with N2. The reaction mixture was stirred at 120 °C for 16 h. The crude mixture was combined with a second reaction run in analogous fashion on a 30 mg scale 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 Na2SO4, filtered, and concentrated. The crude residue was purified in two stages, first by préparative TLC (SiO₂,10:1 DCM/MeOH, RpO.5) and then by préparative HPLC with ah Xbridge column (150x30mm, 10 pm particle size, column température 25 °C), which was eluted with 15-55% MeCN/H₂O (+0.05% NH₄OH) with a flow rate of 25 mL/min to provide (3R,4R)-4-({5-ethyl-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H19876 — 205 benzimidazol-6-yl]pyrimidin-2-yl)amino)-1-(methanesulfonyl)piperidin-3-ol (Example A70) (25.4 mg, 22% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) 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, 1 H), 4.84 - 4.75 (m, 1H), 3.81-3.74 (m, 1 H), 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 (C23H31FN6O3S), 491.1 (M+H)⁺.

The examples in the below table were synthesized according to the methods used for the synthesis of (3R,4R)-4-({5-chloro-4-[2-(difluoromethyl)-4-fluoro-1-(propan-2-yl)-1Hbenzimidazol-6-yl]pyrimidin-2-yl}amino)-1-(methanesuIfonyl)piperidin-3-ol (Example A70) (Scheme A-6) and (3R,4R)-4-({5-ethyl-4-[4-fluoro-2-methyI-1-(propan-2-yl)-1H-benzimidazol-6yI]pyrimidin-2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol (Example A65) (Scheme A-7). The following examples were synthesized with non-critical changes or substitutions to the exemplified procedures that someone who is skilled in the art would be able to realize.

Example number	Structure/Name	LCMS	NMR
A71	N^1 A -^L^s-F AA k J N-/ ΕΥ \_Me O-S-O Q_J Me (3R,4R)-4-({5-chloro-4-[2-ethyl4-fluoro-1 -(oxetan-3-yl)-1 Hbenzimidazol-6-yl]pyrimidin-2yl}amino)-1(methanesulfonyl)piperidin-3-ol	525.1 [M+H]+ (ESI)	1H NMR (700 MHz, DMSO-d6) δ 8.73-8.18 (m, 2H), 7.836.97 (m, 2H), 5.75 (ddd, J = 13.2, 7.7, 5.4 Hz, 1H), 5.195.08 (m, 2H), 5.07-4.89 (m, 2H), 3.79 (s, 1H), 3.67-3.59 (m, 5H), 2.94-2.87 (m,5H), 2.86 —12.79 (m, 1 H), 2.64 (t, J = 10.3 Hz, 1H), 1.57-1.44 (m, 1H), 1.30 (t, J =7.5 Hz, 3H)
A72	jLTC' xk x^ ^F H N HO-xk AA Il ' //N o=s=o Me Me (3R,4R)-4-{[5-chloro-4-(1- cyclopropyl-4-fluoro-2-methyl-	495.1 [M+H]+ (ESI)	1H NMR (600 MHz, DMSO-d6) δ 7.96 (s, 1H) 7.30-7.57 (m, 1H) 6.99-7.11 (m, 1H) 6.896.98 (m, 1H) 4.74 (d, J = 4.59 Hz, 1 H) 3.30 - 3.38 (m, 1 H) 3.15 (d, J = 10.64 Hz, 2H) 3.04 (d, J = 12.10 Hz, 2H) 2.44 (s,

206

	1 H-benzimidazol-6-yl)pyrimidin2-yl]amino}-1(methanesuIfonyl)piperidin-3-ol	-	3H)2.41 (d, J =2.38 Hz, 1H) 2.21 (s, 1H)2.18(s, 3H)1.01 1.15 (m, 1H) 0.72-0.82 (m, 3H) 0.56 - 0.64 (m, 2H)
A73	HN N HO. AA Il \ ,N L J n-4 N Me—/ i *\ Me o=s=o p Me O Me ‘first eluting stereoisomer (3R,4R)-4-({5-chloro-4-[4fluoro-1-(1-methoxypropan-2yl)-2-methyl-1 H-benzimidazol6-yl]pyrimidin-2-yl)amino)-1(methanesulfonyl)piperidin-3-ol	527.5 [M+H]+ (APCI)	1H NMR (400 MHz, DMSO-d6) 5 8.39 (s, 1H), 7.93 (d, J =1.3 Hz, 1H), 7.40 (dd, J =11.8,1.3 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1 H), 4.98 (d, J = 4.6 Hz, 1 H), 4.84 (ddd, J = 8.4, 7.0, 4.7 Hz, 1H), 3.90 (dd, J =10.5, 8.5 Hz, 1H), 3.82 (ddd, J =12.3, 6.1, 4.3 Hz, 1H), 3.73 (dd, J =10.5, 4.8 Hz, 1H), 3.70-3.64 (m, 1H), 3.59-3.48 (m, 1H), 3.22 (s, 3H), 2.92 (dd, J =10.4, 2.0 Hz, 1H), 2.89 (s, 3H), 2.772.68 (m, 1H), 2.62 (s, 3H), 2.18 -2.08 (m, 1H), 1.68-1.50 (m, 5H); [ah22 = +42.1° (c=0.1, MeOH)
A74	da HN ho. AA Il ' /N Sr Me— i Λ Me | O=S=O y Me O Me ‘second eluting j stereoisomer (3R,4/?)-4-({5-chloro-4-[4fluoro-1-(1-methoxypropan-2yl)-2-methyl-1 H-benzimidazol6-yl]pyrimidin-2-yl)amino)-1(methanesulfonyl)piperidin-3-ol	527.5 [M+H]+ (APCI)	1H NMR (400 MHz, DMSO-d6) 5 8.39 (s, 1H), 7.93 (d, J= 1.4 Hz, 1H), 7.39 (dd, J = 11.8,1.3 Hz, 1H), 7.16 (d, J = 7.7 Hz, 1H), 4.97 (s, 1H), 4.91-4.73 (m, 1H), 3.89 (^d, J =10.5, 8.5 Hz, 1H), 3.82 (ddd, J= 9.3, 7.9, 4.5 Hz, 1H), 3.72 (dd, J= 10.5, 4.8 Hz, 1H), 3.70 — 3.63 (m, 1 H), 3.58 - 3.52 (m, 1 H), 3.22 (s, 3H), 2.94-2.89 (m, 1H), 2.89 (s, 3H), 2.77 - 2.68 (m, 1H), 2.62 (s, 3H), 2.16-2.08 (m, 1H), 1.60 (d, J =7.1 Hz, 5H)

207

A75	HO^xk T 1 · Lu N . .. . kx1 N-K N Me-γ O-S-O Me Me Me (3R,4R)-4-({5-chloro-4-[4fluoro-2-(methoxymethyl)-1 (propan-2-yl)-1 H-benzimidazol6-yl]pyrimidin-2-yl}amino)-1(methanesulfonyl)piperidin-3-ol	527.1 [M+H]* (APCI)	1H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1 H), 8.00 (d, J = 0.98 Hz, 1H), 7.38- 7.51 (m, 1H), 7.12 - 7.23 (m, 1 H), 4.96 (s, 2H), 4.76 (s, 2H), 3.75 - 3.89 (m, 1H), 3.67 (s, 2H), 3.473.58 (m, 1H), 3.37 (s, 3H), 2.89 -2.94 (m, 1H), 2.88 (s, 3H), 2.65 - 2.77 (m, 1H), 2.07 - 2.17 (m, 1H), 1.63 (d, J =6.97 Hz, 6H), 1.57-1.48 (m, 1H).
A76	n^ JL Y HN HO»_xk YY Il ' //N k A N-K N Me—/ i \ Me O-S-O Me Me (3R,4R)-4-({5-fluoro-4-[2methyl-1-(propan-2-yl)-1Hbenzimidazol-6-yl]pyrimidin-2yl)amino)-1(methanesulfonyl)piperidin-3-ol	463.4 [M+H]* (ESI)	1H NMR (400 MHz, CD3OD) δ 8.40 (s, 1H), 8.28 (d, J =4.2 Hz, 1H), 7.99 (dt, J =8.5, 1.4 Hz, 1H), 7.65 (d, J =8.6 Hz, 1H), 3.95-3.66 (m, 4H), 2.98 (td, J= 11.8, 2.8 Hz, 1H), 2.91 (s,3H), 2.78 (dd, J=11.5, 9.1 Hz, 1H), 2.67 (s, 3H), 2.362.24 (m, 1H), 1.80-1.64 (m, 7H); one proton obscured by solvent peak
A77	n-Vf JL Y HN Ν'ηΥΥ HO. A L Y Il \ ,N k J N— N Me—/ O=S=Ol Μβ^θ Me 1 (3R,4R)-4-{[4-(1 -tert-butyl-1Hbenzimidazol-6-yl)-5fluoropyrimidin-2-yl]amino}-1(methanesulfonyl)piperidin-3-ol	463.3 [M+H]* (ESI)	1H NMR (400 MHz, DMSO-d6) δ 8.47 - 8.34 (m, 3H), 7.91 7.83 (m, 1H), 7.82-7.75 (m, 1H), 7.18 (brd, J = 7.7 Hz, 1H), 5.22 (d, J =4.4 Hz, 1H)I,3.823.46 (m, 4H), 2.95 - 2.80 (m, 4H), 2.69-2.65 (m, 1H), 2.182.02 (m, 1H), 1.75 (s, 9H), 1.63 -1.44(m, 1H) 1

208

A78	JL JL . . HN nJAi . HO^A^ LA Il ' //N k J N-X N Me-/ i .. Z\ Me O=S=O Me Me Me (3R,4R)-4-{[4-(1 -tert-butyl-2methyl-1 H-benzimidazol-6-yl)5-fluoropyrimidin-2-yI]amino}-1(methanesulfonyl)piperidin-3-ol	476.8 [M+H]* (ESI)	1H NMR (400 MHz, DMSO-d6) δ 8.57 - 8.26 (m, 2H), 7.82 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1 H), 7.16 (d, J = 7.7 Hz, T 1H), 5.24 (d, J = 4.5 Hz, 1H), 3.84-3.72 (m, 1H), 3.723.59 (m, 2H), 3.52 (d, J= 12.0 Hz, 1H), 2.92 (s, 3H), 2.902.81 (m, 1 H), 2.78 (s, 3H), 2.71 -2.60 (m, 1H), 2.19-2.05 (m, 1H), 1.84 (s, 9H), 1.55 (q, J = 11.5 Hz, 1H)
A79	N^yF HO., LA L ,J n-4 N Me—/ _ i \ Me O-S-O Me Me (3R,4R)-4-({4-[2,4-dimethyl-1 - (propan-2-yl)-1 H-benzimidazol6-yl]-5-fIuoropyrimidin-2yl}amino)-1- (methanesuIfonyl)piperidin-3-ol	476.9 [M+H]* (ESI)	1H NMR (400 MHz, DMSO-cfe) 6 8.38 (d, J = 4.0 Hz, 1 H), 8.08 (s, 1H), 7.64 (q, J =1.2 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 5.23 (d, J = 4.5 Hz, 1H), 4.78 (hept, J =6.8 Hz, 1H), 3.833.71 (m, 1H), 3.70-3.56 (m, 2H), 3.55-3.46 (m, 1H), 2.96 - 2.82 (m, 4H), 2.71 - 2.64 (m, 1H), 2.60 (s, 3H), 2.54 (s, 3H), 2.09 (d, J =13.7 Hz, 1 H), 1.64 -1.48 (m,7H)
A80	hoa â. LA l J L'N Y Me N ΜθΆ / O—/ 1,5-anhydro-2,3-dideoxy-3-{[5fluoro-4-(7-fluoro-1,1-dimethyI3,4-dihydro-1H[1,4]oxazino[4,3-b]indazol-9yl)pyrimidin-2-yl]amino}-Dfhreo-pentitol	432.1 [M+H]* (ESI)	1H NMR (500 MHz, DMSO-d6) δ 8.42 (d, J = 4.0 Hz, 1 H), 8.22 (s, 1H), 7.67 (d, J =13.1 Hz, 1 H), 7.20 (br d, J = 7.8 Hz, 1 H), 4.95 (d, J = 5.3 Hz, 1H), 4.45 (t, J = 5.0 Hz, 2H), 4.22 (t, J = 5.0 Hz, 2H), 3.87 - 3.75 (m, 3H), 3.56 - 3.45 (m, 1H), 3.06 (t, J = 10.4 Hz,1H), 2.00 (br d, J = 9.6 Hz, 1 H), 1.70 (s, 6H), 1.551.42 (m,1H)

209

A81	Me N^Y^Me - HO^Â. AA Il \ ,N k J N-^ N Me—/ i \ Me O-S-O Me Me (3R,4R)-4-({4-[4-fluoro-2methyl-1 -(propan-2-yl)-1 Hbenzimidazol-6-yl]-5-(propan-2yl)pyrimidin-2-yl}amino)-1(methanesulfonyl)piperidin-3-ol	504.9 [M+H]* (ESI)	1H NMR (400 MHz, DMSO-d6) 5 8.41 (s, 1H), 7.50 (s, 1H), 7.10 - 6.95 (m, 2H), 5.23J[d, J = 4.3 Hz, 1 H), 4.86-4.73 (m, 1H), 3.77 (brs, 1H), 3.67-3.54 (m, 2H), 3.50 - 3.39 (m, 2H), 2.99 - 2.81 (m, 5H), 2.71 - 2.60 (m, 4H), 2.14 -2.03 (m, 1H), 1.56 (d, J = 6.8 Hz, 6H), 1.45 1.25 (m, 6H)
A82	Me nV A -îA/^^F hn n || ηΑ HO^A AA Il ' //N k fi N—X N Me—/ i \ Me O-S-0 Me Me (3R,4R)-4-({4-[4-fluoro-2methyl-1-(propan-2-yl)-1Hbenzimidazol-6-yl]-5methoxypyrimidin-2-yl)amino)1 -(methanesulfonyl)piperidin-3ol	493.1 [M+H]* (ESI)	1H NMR (400 MHz, DMSO-d6) 5 8.30 (s, 1H), 8.25 (s, 1H), 7.70 (d, J =12.6 Hz, 1H), 6.80 (d, J =7.5 Hz, 1H), 5.24 (d, J = 4.5 Hz, 1H), 4.88-4.73 (m, 1H), 3.83 (s, 3H), 3.74 (m, 2H), 3.69 - 3.57 (m, 2H), 2.96 2.83 (m, 4H), 2.73 - 2.65 (m, 1H), 2.61 (s, 3H), 2.12 (d, J = 13.2 Hz, 1H), 1.66-1.46 (m, 7H)
A83	N^VMe A HN N T| HO«_^\ AA Il \ ,n k fi N-# I V Me^ Ae । O=S=O Me Me (3R,4R)-4-({4-[4-fluoro-2methyl-1-(propan-2-yI)-1H- ! benzimidazol-6-yl]-5methylpyrimidin-2-yl}amino)-1 (methanesulfonyl)piperidin-3-ol	477.1 [M+H]* (ESI)	1H NMR (400 MHz, CD3OD) 5 8.22 (s, 1 H), 7.70 (d, J =1.3 Hz, 1H), 7.24 (dd,J= 11.4,1.2 Hz, 1H), 3.93-3.78 (m, 2H), 3.75 - 3.62 (m, 2H), 2.87 (s, 4H), 2.77 - 2.64 (m, 4H), 2.25 (m, 4H), 1.72-1.60 (m, 7H); one proton obscured by solvent peak ......

210

A84	• jOrcl HN HCL· Il \ „N N Me—/N~N' O=S=O Me Me (3R,4R)-4-({5-chloro-4-[1(propan-2-yl)-1 H-benzotriazol6-yl]pyrimidin-2-yI}amino)-1(methanesulfonyl)piperidin-3-ol	456.8 [M+H]* (ESI)	1H NMR (600 MHz, DMSO-d6) δ 8.47 (s, 1H), 8.25 (b s, 1H), 8.15 (d, J = 8.6 Hz, 1H), 7.72 7.68 (m, 1H), 7.53 (bfs/IH), 5.29 (hept, J =6.7 Hz, 1H), 5.21 (m, 1H), 3.80 (b s, 1H), 3.65 - 3.57 (m, 2H), 3.52 3.46 (m, 1 H), 2.91-2.84 (m, 4H), 2.66 (t, J = 10.3 Hz, 1H), 2.10-2.01 (m, 1H), 1.66 (d, J = 6.7 Hz, 6H), 1.58-1.49 (m, 1H)
A85	ίΎ HN^N^Yr^N LA Il \ ,N k J n-4 > Me< Λο O=s=o Me Me (3R,4R)-4-({5-chloro-4-[2methyl-1-(propan-2-yl)-1 Himidazo[4,5-b]pyridin-6yl]pyrimidin-2-yl}amino)-1(methanesulfonyl)piperidin-3-ol	480.1 [M+H]* (ESI)	1H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J = 2.0 Hz, 1H), 8.42 - 8.37 (m, 2H), 7.23 (d, J = 7.6 Hz, 1H), 4.84 (hept, J = 6.8 Hz, 1 H), 3.63 (m, 2H), 2.95 - 2.85 (m, 4H), 2.77 - 2.64 (m, 4H), 2.19-2.08 (m, 1H), 1.801.74 (m, 3H), 1.61 (m, 7H)
A86	jOC ΗΝ Νγ^ HO^xk Nx Il ' //N < fi N—Y _N_ Me-γ O—S—O Me Me (3R,4R)-4-({5-chloro-4-[2- methyl-3-(propan-2-yl)-3Himidazo[4,5-b]pyridin-5yl]pyrimidin-2-yl}amino)-1(methanesulfonyl)piperidin-3-oI	480. Ί [M+H]* (ESI^	1H NMR (600 MHz, DMSO-d6) δ 8.42 (s, 1H), 8.03 (d, J =8.2, 1.3 Hz, 1H), 7.77 (s, 1H), 7.42 (s, 1H), 5.23 (s, 1H), 4.79 (h, J = 6.8 Hz, 1H), 3.87 - 3.78 (m, 1 H), 3.68 - 3.56 (m, 3H), 2.92 - 2.82 (m, 4H), 2.71 - 2.63 (m, 4H), 2.10-2.01 (m, 1H), 1.67 (d, J = 6.8 Hz, 6H), 1.53 (m, 1H)

211

Example A87 (Scheme A-8): Préparation of (3/?,4R)-4-({5-chloro-4-[4-fluoro-2(hydroxymethyI)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-1(methanesulfonyl)piperidin-3-ol

Scheme A-8

HCl

MeOH, 1,4-dioxane 20% yield

Me

Example A87

A solution of (3R,4R)-4-({5-chloro-4-[4-fluoro-24[(oxan-2-yI)oxy]methyl}-1-(propan-2-yI)1 H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-1 -(methanesulfonyl)piperidin-3-ol (A-9) (Prepared as in Example A69, 88 mg, 0.15 mmol) in MeOH (3.0 mL) at 0 °C was added a solution of HCl (4.0 10 N in 1,4-dioxane, 0.55 mL, 2.2 mmol). After 2.5 h, LCMS analysis showed consumption of the starting material with formation of the desired product mass. The reaction mixture was concentrated to dryness. The residue was purified by préparative SFC on a Princeton HaMorpholine column (150x21.1 mm, 5 pm particle size, column température at 35 °C), which was eluted with 22-50% MeOH/CO2 with a flow rate of 60 mL/min to provide (3R,4R)-4-({5-chloro~415 [4-fluoro-2-(hydroxymethyl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-1(methanesulfonyl)piperidin-3-ol (Example A87) (15 mg, 20% yield) as a white solid. ¹H NMR (600 MHz, DMSO-de) δ 8.42 (s, 1H), 7.97 (s, 1H), 7.52 - 7.31 (m, 2H), 5.73 (t, J = 5.5 Hz, 1H), 5.20 (d, J = 5.0 Hz, 1 H), 5.02 (hept, J = 7.0 Hz, 1 H), 4.77 (d, J = 5.7 Hz, 2H), 3.86 - 3.75 (m, 1 H), 3.68 - 3.56 (m, 2H), 3.53 - 3.46 (m, 1 H), 2.94 - 2.80 (m, 4H), 2.71 - 2.60 (m, 1 H), 2.06 (s, 1 H), 1.66 20 — 1.47 (m, 7H); m/z (ESI+) for (C21H26CIFN6O4S), 512.8 (M+H)⁺.

Example A88 (Scheme A-9): Préparation of (3R,4R)-4-({4-[1-(azetidin-3-yl)-4-fIuoro-2methyl-1 H-benzimidazol-6-yl]-5-fluoropyrimidin-2-yl}amino)-1 (methanesuIfonyl)piperidin-3-ol

Scheme A-9:

212

HO nh₂

lnt-69

O=S=O Me

1.Pd(OAc)₂ rac-BINAP, Cs₂CO₃ THF, 80 ’C, μW

2- HCl DCM, 1,4-dioxane

89% yield (2 steps)

A solution of fert-butyl 3-[6-(2-chloro-5-fIuoropyrimidin-4-yl)-4-fIuoro-2-methyl-1/-/benzimidazol-1-yl]azetidine-1 -carboxylate (A-10) (Prepared as in Example A1, 75.0 mg, 0.170 mmol), (3R,4R)-4-amino-1-(methanesulfonyl)piperidin-3-ol (lnt-69) (50.1 mg, 0.258 mmol), 5 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) was stirred under microwave irradiation at 80 °C for 30 min. The mixture was purified via flash chromatography (S1O2, 0-100% EtOAc/heptanes). The product-containing fractions were concentrated, taken up into DCM (5 mL), and treated with HCl (4.0 M in 1,4dioxane, 1.0 mL). The mixture was stirred at ambient température for 4 h. The solution was 10 concentrated and the crude residue was purified by préparative HPLC on a Phenomenex Gemini NX C18 column (150x21.2 mm, 5 pm particle size), which was eluted with 20-100% MeCN/H2O (+10 mM NH4OAC) with a flow rate of 40 mL/min to provide (3R,4R)-4-({4-[1-(azetidin-3-yI)-4fluoro-2-methyl-1H-benzimidazol-6-yl]-5-fluoropyrimidin-2-yl}amino)-1(methanesulfonyI)piperidin-3-ol (Example A88) (76 mg, 89% yield) as a solid. ¹H NMR (600 MHz, 15 DMSO-de) δ 8.70 (s, 1H), 8.47-8.29 (m, 1H), 7.64 (d, J = 12.0 Hz, 1H), 7.15 (d, J= 7.7 Hz, 1H), 5.43 (s, 1H), 4.27-3.87 (m, 4H), 3.79 (s, 1H), 3.71-3.54 (m, 2H), 3.50 (s, 1H), 3.01-2.78 (m, 5H), 2.68 (t, J = 10.3 Hz, 1H), 2.56 (d, J = 1.4 Hz, 3H), 2.12 (s, 1H), 1.62 - 1.43 (m, 1H); m/z (APCI+) for (C2iH25F₂N₇O₃S), 494.2 (M+H)⁺.

Example A89 (Scheme A-10): Préparation of (3/?,4R)-4-({5-chloro-4-[4-fluoro-2-methyl-1(oxetan-3-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-1-(methanesu!fonyI)piperidin-3ol

Scheme A-10:

213

PdCI₂(dppf), B₂Pin₂, KOAc

1,4-dioxane, 90 ’C, pW then PdCI₂(PPh₃)₂, Na₂CO₃ H₂0,110 °C, pW

Exemple A89

Pd(OAc)₂, rac-BINAP Cs₂CO₃ THF, 90 ’C, pW

14% yield, (2 steps)

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

A mixture of 6-bromo-4-fluoro-2-methyl-1-(oxetan-3-yl)-1H-benzimidazole (Int-03) (63.0 5 mg, 0.220 mmol), B2Pin2 (84.2 mg, 0.331 mmol), KOAc (65.1 mg, 0.663 mmol), and PdCb(dppf) (18.0 mg, 0.022 mmol) in 1,4-dioxane (1.1 mL) was sparged with N2 for 10 min and then heated in a microwave at 90 °C for 1 h. The mixture was cooled to ambient température and charged with PdCl2(PPh3)2 (7.71 mg, 0.011 mmol), aqueous Na₂CO₃ (2.0 M, 0.33 mL, 0.659 mmol) and 2,4,5-trichloropyrimidine (60.5 mg, 37.8 uL, 0.330 mmol). The mixture was sparged with nitrogen 10 for 10 min and then heated in the microwave at 110 °C for 70 min. The mixture was 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 provide 6-(2,5-dichloropyrimidin-4-yl)4-fluoro-2-methyl-1-(oxetan-3-yl)-1H-benzimidazole (A-11), which was taken on without further purification, m/z (APCI+) for (C15H11CI2FN4O), 352.8 (M+H)⁺.

¹⁵ I !

Step 2: Synthesis of (3R,4R)-4-({5-chloro-4-[4-fluoro-2-methyl-1-(oxetan-3-yl)-1Hbenzimidazol-6-yl]pyrimidin-2-yl}amino)-1-(methanesulfonyI)piperidin-3-ol (Example A89)

Crude 6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-2-methyI-1-(oxetan-3-yl)-1H-benzimidazole (A-11) was dissolved in THF (1.8 mL). (3R,4R)-4-Amino-1-(methanesulfonyl)piperidin-3-oî (Int20 69) (64.4 mg, 0.331 mmol), Pd(OAc)₂ (9.9 mg, 0.044 mmol), rac-BINAP (27.5 mg, 0.044 mmol), and CS2CO3 (216 mg, 0.663 mmol) were added and the mixture was sparged with N2 for 10 min.

The mixture was stirred at 90 °C for 1.5 h with microwave irradiation. The mixture was cooled to

214 ambient température, diluted with DMSO and filtered through a 0.2 micron filter dise. The crude material was purified by préparative SFC with a Princeton HA-morpholine column (150x21.1 mm, pm column particle size, column température of 35 °C), which was eluted with 15-50%

MeOH/CO2 (+10 mM NH3) with a flow rate of 80 g/min. The material was re-purified by préparative

SFC with a Diacel DC pak SFC-B (150x21.1 mm, 5 pm particle size, column température of 35 °C), which was eluted with 18-45% MeOH/CO2 with a flow rate of 80 g/min to provide (3R,4R)-4({5-chloro-4-[4-fIuoro-2-methyl-1-(oxetan-3-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-1(methanesulfonyl)piperidin-3-ol (Example A89) (15.9 mg, 14% yield over two steps) as a white solid. ¹H NMR (600 MHz, DMSO-d₆,75 °C) δ 8.40 (s, 1H), 8.35 (b s, 1H), 7.49 (d, J =11.7 Hz,

1H), 7.20 (d, J = 7.4 Hz, 1H), 5.76 - 5.71 (m, 1 H), 5.16 (td, J = 7.6, 2.7 Hz, 2H), 5.09 - 5.04 (m,

2H), 5.01 (b s, 1H), 3.85 - 3.78 (m, 1H), 3.70 - 3.62 (m, 2H), 3.55 - 3.50 (m, 1H), 2.91 - 2.85 (m, 4H), 2.72-2.66 (m, 1H), 2.58 (s, 3H), 2.15-2.10 (m, 1H), 1.62-1.46 (m, 1H); m/z (APCI+) for (C21H24CIFN6O4S), 510.8 (M+H)⁺.

Example A90 (Scheme A-11): Préparation of (3R,4R)-4-({5-chIoro-4-[4-fluoro-2(hydroxymethyI)-1-(2,2,2-trifluoroethyl)-1H-benzimidazol-6-yl]pyrimidin-2-yl)amino)-1(methanesulfonyl)piperidin-3-ol

Scheme A-11 nh₂

o=s=o Me

1.Pd(OAc)₂ rac-BINAP, Cs₂CO₃ THF, 80 ’C, pW

2. HCl MeOH/1,4-dioxane

12% yield

Example A90

To a vial was added 6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-2-{[(oxan-2-yl)oxy]methyl}-1(2,2,2-trifIuoroethyl)-1H-benzimidazôle (A-12) (Prepared according to Example A89, 121^ mg, 0.25 mmol), (3R,4R)-4-amino-1-(methanesulfonyl)piperidin-3-ol (lnt-69) (73.6 mg, 0.38 mlnol), Pd(OAc)2 (11.3 mg, 0.051 mmol), rac-BINAP (31.4 mg, 0.051 mmol), CS2CO3 (247 mg, 0.76 25 mmol), and THF (2.5 mL). The mixture was stirred at 80 °C with microwave irradiation for 30 min. LCMS analysis showed consumption ofthe starting material with formation ofthe desired product mass. The mixture was concentrated on S1O2 and purified by flash chromatography (ISCO, 12 g S1O2, 0-100% EtOAc/heptanes). The product containing-fractions were concentrated. The _ ²¹⁵ 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 température for 16 h overnight. LCMS analysis showed partial consumption ofthe 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 h, at which time LCMS analysis indicated consumption 5 of the starting material. The mixture was concentrated and purified by préparative SFC with a

Princeton HA-morpholine column (150x21.1 mm, 5 pm particle size, column température 35 °C), which was eluted with 14-50% MeOH/CO2 at 80 g/min to provide (3R,4R)-4-({5-chloro-4-[4-fluoro2-(hydroxymethyl)-1-(2,2,2-trifluoroethyl)-1/7-benzimidazol-6-yl]pyrimidin-2-yl}amino)-1(methanesulfonyl)piperidin-3-ol (Example A90) (17 mg, 12% yield) as a gum. ¹H NMR (400 MHz, 10 DMSO-de) δ 8.46 (s, 1 H), 7.99 (s, 1 H), 7.58 - 7.41 (m, 2H), 5.93 (t, J = 6.0 Hz, 1 H), 5.49 (q, J =

9.1 Hz, 2H), 5.21 (d, J = 4.5 Hz, 1H), 4.82 (d, J = 5.8 Hz, 2H), 3.81 (s, 1H), 3.68-3.56 (m, 2H), 3.49 (d, J = 12.1 Hz, 1H), 2.94-2.77 (m, 4H), 2.72-2.61 (m, 1H), 2.02 (s, 1H), 1.60-1.44 (m, 1H); m/z (ESI+) for (C20H21CIF4N6O4S), 522.9 (M+H)*.

Example A91 (Scheme A-12): Préparation of (3R,4R)-4-({5-chloro-4-[4-fluoro-2-(2hydroxypropan-2-yI)-1-(propan-2-yI)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-1(methanesulfonyl)piperidin-3-ol

Scheme A-12

A mixture of 2-(2-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl)-6-(2,5-dichloropyrimidin-4-yl)4-fluoro-1-(propan-2-yl)-1H-benzimidazole (A-13) (Prepared as in Example A89, 294 mg, 0.590 mmol), (3R,4R)-4-amino-1-(methanesulfonyl)piperidin-3-ol (lnt-69) (149 mg, 0.767 mmol), and DIPEA (0.55 mL, 2.95 mmol) in DMSO (2.8 mL) was stirred at 90 °C for 18 h. The resulting 25 solution was cooled to ambient température and partitioned between water (30 mL) and EtOAc (30 mL). The layers were separated and the aqueous phase was extracted with EtOAc (5x 30 mL). The combined organic phases were washed with water (3x20 mL), dried over Na2SO4, filtered, and concentrated. The résultant 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 _ 216 to ambient température and stirred for 2.5 h before being concentrated. The residue was purified by préparative SFC with a ZymorSpher HADP column (150 x 21.2mm, 5 pm particle size, 40 °C column température), which was eluted with 18% MeOH/CO2 with a flow rate of 90 mL/min to provide (3R,4R)-4-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1 -(propan-2-yl)-1 H5 benzimidazol-6-yl]pyrimidin-2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol (Example A91) (137 mg, 43% yield) as 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, 1 H), 4.97 (d, J = 4.5 Hz, 1 H), 3.87 - 3.78 (m, 1 H), 3.71 - 3.63 (m, 2H), 3.57 - 3.51 (m, 1 H), 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, 10 7H); m/z (APCI+) for (C23H₃oCIFN₆0₄S), 540.8 (M+H)⁺.

Example A92 (Scheme A-13): (3R,4R)-4-({5-chloro-4-[1-(1,1-difluoropropan-2-yl)-4-fIuoro2-(hydroxymethyl)-1H-benzimidazoI-6-yI]pyrimidin-2-yl)amino)-1(methanesulfonyl)piperidin-3-ol

Scheme A-13 nh₂

o=s=o Me

1. Pd(OAc)₂ rac-BINAP, Cs₂CO₃ THF, 80 •C, pW

2. HCl MeOH/1,4-dioxane O _f/-f tbs ₈o_{/o yie}|_d

Example A92

To a vial was added 2-({[fert-butyl(dimethyl)silyl]oxy}methyl)-6-(2,5-dichloropyrimidin-4yl)-1-(1,1-difluoropropan-2-yl)-4-fiuoro-1H-benzimidazole (A-14) (Prepared according to 20 । Example A89, 81 mg, 0.16 mmol), (3R,4R)-4-Amino-1-(methanesulfonyl)piperidin-3-oI (lnt-69) ’ ' i j (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 for 30 min. LCMS analysis showed consumption of the starting material with formation of the desired product mass. The mixture was concentrated onto S1O2 and purified by flash chromatography (ISCO, 12 g S1O2, 0-100% EtOAc/heptanes). The product-containing fractions were concentrated and taken up in MeOH (5.0 mL). The mixture was treated with HCl (4.0 N in

1,4-dioxane, 2.0 mL) and stirred at ambient température for 16 h. LCMS analysis showed ²¹⁷ consumption of the starting material with formation of the desired product mass. The mixture was concentrated to dryness and then purified by chiral SFC with a ChiralPak AS-H column (100x4.6 mm, 3 pm particle size), which was eluted with 5-60% MeOH/CO2 with a flow rate of 4.0 mL/min to provide (3R,4R)-4-({5-chlorô-4-[1-(1,1-diflüoropropan-2-yI)-4-fIûoro-2-(hydroxymethyl)-1H5 benzimidazol-6-yl]pyrimidin-2-yl)amino)-1-(methanesulfonyl)piperidin-3-ol (Example A92) (7.4 mg, 8% yield) as the first eluting fraction. ¹H NMR (400 MHz, DMSO-d₆, 80 °C) δ 8.41 (s, 1H), 8.00 (s, 1H), 7.47 (d, J = 11.6 Hz, 1H), 7.19 (d, J = 7.7 Hz, 1H), 6.52 (td, J = 55.3, 3.7 Hz, 1H), 5.65 (t, J = 5.7 Hz, 1H), 5.40 - 5.26 (m, 1H), 4.97 (d, J = 4.6 Hz, 1H), 4.83 (d, J = 5.6 Hz, 2H), 3.87 - 3.76 (m, 1 H), 3.72 - 3.62 (m, 2H), 3.59 - 3.51 (m, 1 H), 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 (C21H24CIF3N6O4S), 522.9 (M+H)⁺; [ajo²² = -26.5° (c=0.1 M, MeOH).

Example A93 (Scheme A-14): Préparation of (3R,4/?)-4-[(5-chloro-4-{4-fluoro-2-[(1/?)-1hydroxyethyl]-1-(propan-2-yl)-1H-benzimidazol-6-yl)pyrimidin-2-y l)amino]-115 (methanesulfonyl)piperidin-3-ol

Scheme A-14:

Br

Α-15

FPrNH₂

MeCN, 35 C

218

NO₂

Me ^A-¹⁶

Fe°, AcOH t-AmylOH, 35 C

Br

Me

nh₂

A-17

Me

75% yield

74% yield

HO

O ,OH °C

62% yield

Cl

Pd(PPh₃)₄, K₂CO₃

H₂O 1,4-dioxane, 90 ’C

DIPEA DMSO, 60 °C

67% yield

Cl

Cl ^PinB

A-18

OH Me Me

B₂Pin₂, KOAc PdCI₂(dppf)

Me

NH₂

lnt-69

39% yield

1,4-dioxane, 90’C Ç ^Μβ Λ >OH Me Me lnt-40

92% yield

Step 1: Synthesis of 5-bromo-3-fluoro-2-nitro-/V-(propan-2-yl)aniline (A-16)

This transformation was run in four parallel batches. To a solution 5-bromo-1,3-difluoro5 2-nitrobenzene |(A-15) (100 g, 420.2 mmol) in MeCN (2 L) was addejl /-PrNH2 (27.5 g, 441.2 mmol) at 20-25 °C (ice-bath cooling) to provide a yellow reaction solution. The resulting mixture was stirred at 35 “C for 60 h. LCMS analysis showed consumption of the starting material with formation of the desired product mass. The mixture was concentrated to dryness. The crude residue from the four parallel reactions were combined and purified by flash chromatography (S1O2, 0-2% EtOAc/petroleum ether) to provide 5-bromo-3-fIuoro-2-nitro-A/-(propan-2-yl)aniline (A-16) (350 g, 75% yield) as a yellow solid. ¹H NMR (400 MHz, DMSp-de) 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 (C9HioBrFN202), .247.0 (M+H)⁺; ¹⁹F NMR (377 MHz, DMSO-d6) δ-116.9. _ . .

Step 2: Synthesis of S-bromo-S-fluoro-AF-fpropan-Z-yObenzene-l ,2-diamine (A-17)

219

To a stirred mixture of AcOH (2 L) and f-AmylOH (2 L) was added 5-bromo-3-fluoro-2nitro-/V-(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 (ice-bath cooling). The resulting mixture was stirred at 35 °C for 16 h to provide an off-white slurry. TLC analysis (1:9 EtOAc/petroleum ether, Rf = 0.8, UV254) showed consumption of the starting material. The mixture was diluted with EtOAc (2 L) and H2O (2 L).

The mixture was neutralized by slow addition of solid Na2CO3. The slurry 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 NaHCOs (2x1 L) and brine (2x1 L), dried over Na2SO4, filtered, and concentrated. The residue was combined with a parallel reaction in an 10 identical fashion with 150 g of 5-bromo-3-fluoro-2-nitro-N-(propan-2-yl)aniline (A-16). The mixture was purified by flash chromatography (S1O2, 0-25% EtOAc/petroleum ether) to provide 5-bromo3-fluoro-/V¹-(propan-2-yl)benzene-1,2-diamine (A-17) (230 g, 74% yield) as a brown oil. ¹H NMR (400 MHz, DMSO-cfe) 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); ¹⁹F NMR (377 MHz, DMSO-d₆) δ-132.8; m/z 15 (ESI+) for (C₉HioBrFN20₂), 247.0 (M+H)⁺.

Step 3: Synthesis of (1R)-1-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]ethan1-ol (lnt-40)

To a mixture of 5-bromo-3-fluoro-/V¹-(propan-2-yl)benzene-1,2-diamine (A-17) (200.0 g , 20 809.4 mmol) and (2R)-2-hydroxypropanoic acid (605.1 g, 6.72 mol) was heated from 25 °C to 85 °C and then stirred at 85 °C for 16 h. TLC analysis (1:1 EtOAc/petroleum ether), Rf = 0.5, UV254) showed consumption of the starting material. The reaction mixture was cooled to 25 °C and diluted with EtOAc (1 L) and H2O (1 L). The mixture was basified with aqueous NaOH (50%, -300 mL) to pH -8-9, maintaining the internai température below 30 °C by cooling with an ice-bath. 25 The mixture was separated and the aqueous layer was extracted with EtOAc (2x1 L). The combined organics layers were dried over Na2SO4, filtered, and concentrated. To the residue was added MTBE (400 mL) Ànd petroleum ether (200 mL). A precipitate was formek The résultant slurry was stirred at 25 °C for 1 h. The slurry was filtered and the filter cake was washed with petroleum ether (2 x 80 mL). The filter cake was dried in vacuum to provide (1R)-1-[6-bromo-430 fluoro-1-(propan-2-yl)-lH-benzimidazol-2-yl]ethan-1-ol (lnt-40) (150 g, 62% yield) as a lightyellow solid. ¹H NMR (40θ 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).

Step 4: Synthesis of (1 R)-1-[4-fluoro-1-(propan-2-y 1)-6-(4,4,5,5-tetramethyl-1,3,235 dioxaborolan-2-yl)-1H-benzimidazol-2-yl]ethan-1-ol (A-18) _ 220

A stirred mixture of (1 R)-1-[6-bromo-4-fluoro-1-(propan-2-yi)-1 H-benzimidazol-2-yl]ethan1 -ol (lnt-40) (150.0 g, 498.1 mmol), B₂Pin₂ (164.4 g, 647.5 mmol), PdCI₂(dppf) (18.2 g, 24.9 mmol) and KOAc (146.6 g, 1.49 mmol) in 1,4-dioxane (1.2 L) was heated from 25 °C to 90 °C. The reaction mixture was stirred at 90 °C for 3 h under N₂. TLC analysis (1:1 EtOAc/petroleum ether, 5 Rf = 0.46, UV254) indicated consumption ofthe starting material. The reaction mixture was cooled to 25 °C and quenched with H₂O (800 mL). The mixture was concentrated in vacuum to remove the 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 Na₂SO4, filtered, and concentrated. The residue was purified by flash chromatography 10 (SiO₂, 1:5 EtOAc/petroleum ether - 100% EtOAc) to provide (1R)-1-[4-fluoro-1-(propan-2-yl)-6(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-2-yl]ethan-1-ol (A-18) (160 g, 92% yield) as a light-yellow solid. ¹H NMR (400 MHz, CDCI₃) 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 (Ci₈H₂6BFN₂O₃), 348.9 (M+H)⁺.

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

This transformation was carried out in two parallel batches. A stirred mixture of (1R)-1-[4fluoro-1-(propan-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-220 yl]ethan-1-ol (A-18) (80 g, 230 mmol), 2,4,5-trichloropyrimidine (54.7 g, 299 mmol), Pd(PPh3)4 (26.5 g, 22.9 mmol), and K2CO3 (63.5 g, 459 mmol) in 1,4-dioxane (600 mL) and H₂O (250 mL) was sparged with N₂. The mixture was stirred at 90 °C for 3 h under N₂. LCMS analysis showed consumption of the starting material with formation of the desired product mass. The reaction mixture was cooled to room température and diluted with H₂O (500 mL). The two parallel 25 reactions were combined and concentrated to remove the 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 ¢), dried over Na₂SO4, filtered, and concentrated. The Residue was purified by flash chromatography (SiO₂, 1:5 EtOAc/petroleum ether ·» 100% EtOAc). The product-containing fractions were concentrated to ~400 mL, resulting in précipitation. The solids 30 were collected by filtration. The filter cake was washed with petroleum ether (200 mL) and the dried in vacuum to provide (1R)-1-[6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1/7benzimidazol-2-yl]ethan-1-ol (A-19) (70 g, 39% yield) as a white solid. ¹H NMR (400 MHz, CDCI3) δ 8.68 (s, 1H), 7.98 (d, J = 1.5 Hz, 1H), 7.59 (dd, J = 1.3, 11.3 Hz, 1H), 5.19 (quin, J = 7.0 Hz, 1H), 4.96 (sept, J = 6.8 Hz, 1H), 3.11 (d, J= 7.8 Hz, 1H), 1.75 (d, J= 6.5 Hz, 3H), 1.71 (d, J = 7.0

Hz, 6H); m/z (ESI+) for (C₁₆H₁₅CI₂FN₄O), 368.8 (M+H)⁺.

221

Step 6: Synthesis of (3R,4R)-4-[(5-chloro-4-{4-fluoro-2-[(1R)-1-hydroxyethyl]-1-(propan-2yi)-1H-benzimidazoI-6-yl)pyrimidin-2-yl)amino]-1-(methanesulfonyl)piperidin-3-ol (Example A93) .· .

This transformation was carried out in two parallel batches. To a stirred solution of (1R)5 1 -[6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1 -(propan-2-yl)-1 /-/-benzimidazol-2-yl]ethan-1 -ol (A-19) (50 g, 135 mmol) and (3R,4R)-4-amino-1-(methanesulfonyl)piperidin-3-ol (lnt-69) in DMSO (350 mL) was added DIPEA (85.7 g, 664 mmol). The reaction mixture was stirred at 60 °C for 56 h. LCMS analysis showed consumption ofthe starting material with formation ofthe desired product mass. The two parallel reactions were combined and filtered through a pad of celite. The filtrate 10 was poured into stirring saturate aqueous NaHCOs (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 h at 30 °C. The mixture was filtered and the filtrate was concentrated. The residue was purified by flash chromatography (S1O2, 1:10 EtOAc/petroleum 15 ether 100% EtOAc). The product was taken up in EtOH (200 mL) and H2O (800 mL) and then concentrated to remove the EtOH. The aqueous solution was dried by lyopilization. The solids were dried at 50 °C for 48 h under high vacuum to provide (3R,4R)-4-[(5-chloro-4-{4-fluoro-2[(1R)-1-hydroxyethyl]-1-(propan-2-yl)-1H-benzimidazol-6-yl}pyrimidin-2-yl)amino]-1(methanesulfonyl)piperidin-3-ol (Example A93) (95 g, 67% yield) as a white solid. ¹H NMR (400 20 MHz, 80 °C, DMSO-de) δ 8.40 (s, 1 H), 7.99 (d, J = 1.3 Hz, 1 H), 7.42 (dd, J = 11.8, 1.3 Hz, 1 H), 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 (C22H₂₈CIFN₆O₄S), 526.8 (M+H)⁺; Md²² = -11.4 (c=0.1, MeOH)

222

Example A94 (Scheme A-15): Préparation of 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2hydroxypropan-2-yl)-1-(propan-2-yl)-1H-benzimidazol-6-yI]pyrimidin-2-yl)amino)-2,3dideoxy-D-fhreo-pentitoI

Scheme A-15:

;-PrNH₂, Cs₂CO₃

THF, 30 ’C 72% yield

Fe°, NH₄CI

H₂O, MeOH, 68 ’C

88% yield

’C

90% yield

MeMgBr

THF, 0 ’C 91% yield

MnO₂

CHCI3, 58 ’C 99% yield

lnt-20

B₂Pin₂, KOAc PdCI₂(dppf) 1,4-dioxane, 90 ’C

61% yield

A-22

DIPEA MeCN, 80 ’C

66% yield

Step 1: Synthesis of 5-bromo-3-fluoro-2-nitro-A/-(propan-2-yl)aniline (A-16)

This reaction was carried out in three parallel batches. To a stirred solution of 5-bromo10 1,3-difluoro-2-nitrobenzene (A-15) (166 g, 697 mmol) in THF (1.7 L) was added /-PrNH₂ (41.2 g,

223

697 mmol) and CS2CO3 (455 g, 1.40 mol) at 15-30 °C. Upon addition an exotherm was detected.

The reaction mixture was stirred at 30 °C for 6 h. TLC analysis (100% petroleum ether, UV254, Rf = 0.35) showed consumption of the starting material. The three reaction batches were combined. The combined mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by flash chromatography (S1O2,0-2% EtOAc/petroleum ether) to provide 5-bromo-3-fluoro-2-nitro-/V-(propan-2-yl)aniline (A-16) (420 g, 72% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d6) 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); ¹⁹F NMR (376 MHz, DMSO-d6) δ -116.9; m/z (ESI+) for (C₉HioBrFN20₂), 276.1 (M+H)⁺.

Step 2: Synthesis of 5-bromo-3-fluoro-/V¹-(propan-2-yl)benzene-1,2-diamine (A-17)

This reaction was carried out in two parallel batches. To a stirred solution of 5-bromo-3fluoro-2-nitro-A/-(propan-2-yl)aniline (A-16) (210 g, 758 mmol) in MeOH (1.8 L) was added NH4CI (81.1 g, 1.52 mol) in H2O (0.9 L) and Fe° powder (212 g, 3.79 mol) at 15 “C. The resulting mixture was heated to 68 °C (internai température) and stirred at the same température for 8 h. TLC analysis (10% EtOAc/petroleum ether, UV254, Rf = 0.8) showed consumption of the starting material. The two reaction batches were cooled to room température and combined. The two reaction mixtures were combined and filtered. The filter cake was washed with MeOH (3x500 mL). The filtrate was concentrated under vacuum to remove most of the MeOH. The résultant aqueous mixture was extracted with EtOAc (3x1 L). The combined organic layers were washed with brine (2x800 mL), dried over Na₂SO₄, filtered, and concentrated to provide 5-bromo-3-fluoro/\T-(propan-2-yl)benzene-1,2-diamine (A-17) (350 g, 88% yield) as a purple solid, which was taken on without further purification. ¹H NMR (400 MHz, DMSO-cfe) 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); ¹⁹F NMR (377 MHz, DMSO-c/₆) δ -132.8; m/z (ESI+) for (C₉Hi₂BrFN2), 246.6 (M+H)⁺.

SteJ 3: Synthesis of (1R)-1-[6-bromo-4-fluoro-1-(propan^2-yl)-1H-benzimidazol-2-yl]ethan1-ol(lnt-20) ...... ......

। To a 2 L three-neck round bottom flask was added (2R)-2-hydroxypropanoic acid (951 g, 9.71^ mol) at 15 °C and compound was heated to 85 °C (internai température). To the stirred solution at 85 ^eC was added S-bromo-S-fluoro-A/Ypropan^-yljbenzene-lYdiamine (A-17) (300 g, 1.21 mol) portion-wise. The resulting mixture was stirred at 85 °C (internai température) for 40 h to provide a purple reaction solution. TLC analysis (1:2 EtOAc/petroleum ether, UV254, Rf = 0.8) showed consumption of the starting material. The réaction mixture was cooled to room température and diluted with THF (1.5 L). The mixture was adjusted to pH -8 with saturated aqueous LiOH at 10-15 °C with ice-water bath cooling. The mixture was extracted with MTBE

224 (3x1.5 L). The combined organic layers were washed with brine (2x800 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under vacuum to provide (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 taken on to the next step without further purification. ¹H NMR (400 MHz, DMSO-cfe) 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); ¹⁹F NMR (376 MHz, DMSO-d₆) δ -126.3; m/z (ESI+) for (Ci₂Hi4BrFN₂O), 302.6 (M+H)⁺.

Step 4: Synthesis of 1-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]ethan-1one (A-20)

To a stirred solution of compound (1R)-1-[6-bromo-4-fIuoro-1-(propan-2-yl)-1Hbenzimidazol-2-yl]ethan-1-ol (lnt-20) (365 g, 1.21 mol) in CHCi₃ (3 L) was added activated MnO₂ (738 g, 8.48 mol) at room température. The reaction mixture was heated to 58 °C (internai température) and stirred at the same température for 16 h. TLC analysis (1:2 EtOAc/petroleum ether, UV254, Rf = 0.3) showed consumption ofthe starting material. The reaction mixture was cooled to room température and filtered through a pad of Celite. The filter cake was washed with EtOAc (3x500 mL) and the filtrate was concentrated under vacuum. The residue was purified by flash chromatography (SiO₂, 0-30% EtOAc/petroleum ether) to provide 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, CDCI3) 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); ¹⁹F NMR (377 MHz, DMSO-de) δ -124.1; m/z (ESI+) for (Ci2Hi₂BrFN₂O), 300.6 (M+H)⁺.

Step 5: Synthesis of 2-[6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]propan-2ol(A-21)

This réaction was carried out in two parallel batches. A solutitjin of 1-[6-bromo-4-fIuoro-1(propan-2-yl)-1/7-benzimidazol-2-yl]ethan-1-one (A-20) (165 g, 552 mmol) in THF (1.7 L) was degassed and purged with N₂ three times. The stirred solution was cooled to 0-5 °C (internai temperature).with ice-brine bath cooling and a solution of MeMgBr (3.0 M in Et₂0,221 mL) was added drop-wise. During the addition the purple solution turned to a gray slurry. The resulting mixture was stirred at 0-5 °C with ice-brine bath cooling for 3 h. TLC analysis (20% EtOAc/petroleum ether, UV254, Rf = 0.8) showed consumption of the starting material. The reaction mixture was slowly quenched with saturated aqueous NH₄CI (400 mL) at 0-5 °C with icebrine bath cooling and then stirred at room température for 1 h. The two reaction batches were combined and diluted with EtOAc (1 L). The organic layer was separated. The aqueous layer was extracted with EtOAc (2x1 L). The combined organic layers were dried over MgSO4, filtered, and

225 concentrated. The crude residue was purified by flash chromatography (SIO₂, 0-50%

EtOAc/petroleum ether) to provide 2-[6-bromo-4-fluoro-1-(propan-2-yl)-1/7-benzimidazol-2yl]propan-2-ol (A-21) (316 g, 91% yield) as a yellow solid.. ¹H NMR (400 MHz, CDCI3) 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); ¹⁹F NMR (377 MHz, DMSO-de) δ -126.3; m/z (ESI+) for (C₁₃Hi₆BrFN₂O), 314.7 (M+H)⁺.

Step 6: Synthesis of 2-[4-fIuoro-1-(propan-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)-1H-benzimidazoI-2-yl]propan-2-ol (A-22)

A 3 L three-neck round bottom flask was charged with 2-[6-bromo-4-fluoro-1-(propan-2yl)-1H-benzimidazol-2-yl]propan-2-ol (A-21) (300 g, 952 mmol), Β2ΡΪΠ2 (290 g, 1.14 mol), Pd(dppf)Cl2 (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 (internai température) and stirred at this température for 3 h to provide an orange slurry. TLC analysis (1:2 EtOAc/petroleum ether, UV254, Rf = 0.4) showed consumption of the starting material. The reaction mixture was cooled to room température and filtered. The filtrate was diluted with EtOAc (2 L) and washed with brine (2x1 L). The organic layer was dried over MgSO₄, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (SiO2, 10-50% EtOAc/petroleum ether) to provide 2-[4-fluoro-1-(propan-2-yl)-6-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)-1/7-benzimidazol-2-yl]propan-2-oI (A-22) (210 g, 61% yield) as a light yellow solid. ¹H NMR (400 MHz, CDCI3) 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); ¹⁹F NMR (377 MHz, DMSO-de) δ -129.5; m/z (ESI+) for (Ci₃Hi₆FN₂O), 362.9 (M+H)⁺.

Step 7: Synthesis of 2-(6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1Hbenzimidazol-2-yl]propan-2-ol (A-23) ।

This reaction was carried out in two parallel batches. To a mixture of compound 2-[4fluoro-1-(propan-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaboroIan-2-yl)-1H-benzimidazol-2yl]propan-2-ol (A-22) (100 g, 276 mmol), and Na₂CÛ3 (87. 8 g, 828 mmol) in 1,4-dioxane (1 L) ί !

and H₂O (300 mL) was added 2,4,5-trichloropyrimidine (67.2 g, 359 mmol)_f The mixture was degassed and purged with N₂ three times. Pd(PPhs)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 into a pre-heated oil bath at 100 °C and stirred at 90 °C (internai température) for 24 h. LCMS showed consumption ofthe starting material with formation ofthe desired productmass. The reaction was cooled to room température. The two reaction mixtures were combined. The combined mixture was filtered and concentrated under vacuum to remove the 1,4-dioxane. The residue was diluted

226 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 MgSO4, filtered, concentrated. The crude residue was purified by flash chromatography (S1O2, 0-50% EtOAc in 1:5 petroleum ether/DCM). The pfoduct-containing fractions were concentrated under vacuum to -200 mL with concomitant précipitation 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 provide 2-(6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1 H-benzimidazol-2yl]propan-2-ol (A-23) (112 g). The filtrate was concentrated and residue was re-purified by flash chromatography (S1O2, 0-50% EtOAc in 1:5 petroleum ether/DCM). The product-containing fractions were concentrated under vacuum to -50 mL with précipitation of additional 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 provide an additional batch of 2-(6-(2,5dichloropyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]propan-2-ol (A-23) (41 g). The product batches were combined to provide 2-(6-(2,5-dichIoropyrimidin-4-yl)-4-fiuoro-1 (propan-2-yI)-1H-benzimidazol-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); ¹⁹F NMR (377 MHz, CDCI3) δ 128.2; m/z (ESI+) for (C17H17CI2FN4O), 383.0 (M+H)⁺.

Step 8: Synthesis of 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol (Example A94)

A 2 L three-neck round bottom flask was charged with 2-(6-(2,5-dichloropyrimidin-4-yl)-4fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]propan-2-oI (A-23) (112 g, 292 mmol), 3-amino-1,5anhydro-2,3-dideoxy-D-f/7reo-pentitol hydrochloride (51.6 g, 336 mmol), and MeCN (1.1 L). DIPEA (132 g, 1.02 mol, 178 mL) was added at room température. The reaction mixture was heated to 80 °C (internai température) and stirred at the same température for 40 h to'provide a brown solution. LCMS analysis showed remaining starting material. Additional 3-amino-1,5anhydro-2,3-dideoxy-D-f/7reo-pentitol hydrochloride (6.73 g, 43.8 mmol) was added at 80 °C (internai température) and the reaction was stirred at 80 ^eC (internai température) for an additional 10 h. The reaction mixture was cooled to room température and concentrated under vacuum. The residue was taken up in 1:1 EtOAc/H2O (1.5 L). Some solids were 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. To the filtrate was added sulfhydryl silica gel (Accela, 8 g, 0.7-1.4 mmol/g). The resulting mixture was stirred at room température for 1 h and then filtered through a pad of Celite.

_ 227

Treatment with sulfhydryl silica gel was repeated in identical fashion and the filtrate was concentrated to dryness. The crude residue was slurried in MeCN (500 mL) at room température for 16 h. The suspension was filtered and the filter cake was washed with MeCN (2x100 mL). The filter cake was slurried again with MeCN (300 mL) at room température for 6 h. The mixture was 5 filtered and the filter cake was washed with MeCN (2x100 mL). The filter cake was collected and dried under vacuum and then dried in a drying oven (45 °C for 20 h, 50 °C for 64 h) to provide 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1H-benzimidazol6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-f/7reo-pentitol (Example A94) (90 g, 66% yield) as a white solid. ¹H NMR (400 MHz, 80 °C, DMSO-d6) δ 8.38 (s, 1H), 8.00 (s, 1H), 7.43 (d, J = 11.8 10 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), 2.092.00 (m, 1H), 1.70 (s, 6H), 1.67-1.52 (m, 7H); ¹⁹F NMR (377 MHz, CDCI3) δ -127.2; m/z (ESI+) for (C22H27CIFN5O3), 464.2 (M+H)⁺; [ajo²² = -12.6 (c=0.2, MeOH).

Alternative préparation of 2-(6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1Hbenzimidazol-2-yl]propan-2-ol (A-23) to Scheme A-16

SO₃«pyr, TEA

DMSO 80% yield

MeMgBr THF, 0 ’C

93% yield

Step 1: Synthesis of 1-(6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1H20 benzimidazol-2-yl]ethan-1-one (A-19)

To a solution of (1S)-1-(6-(2,5-dichIoropyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1Hbenzimidazol-2-yl]ethan-1-ol (A-19) (3.86 g, 10.5 mmol) in DMSO (130 mL) was added Et₃N (10.6 g, 105 mmol). Sulfur trioxide pyridine complex (10 g, 62.7 mmol) was added and mixture stirred — 228 at ambient température. After 4 h LCMS analysis showed -10% residual starting material. Additional sulfur trioxide pyridine complex (4.7 g) was added. After 1 h LCMS analysis showed consumption of the starting material Th mixture was partitioned between H2O and EtOAc. The aqueous layer was extracted with EtOAc (3x). Thé combinedidrganic layers were washed with 5 H2O, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (ISCO, 80 g S1O2, 10-40% EtAOc/heptane) to provide 1-(6-(2,5dichloropyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]ethan-1-one (A-24) (3.1 g, 80% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) 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); 10 m/z (APCI) for (C16H13CI2FN4O), 366.8 (M+H)⁺.

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

A solution of 1-(6-(2,5-dichloropyrimidin-4-yI)-4-fiuoro-1 -(propan-2-yl)-1 H-benzimidazoi-215 yl]ethan-1-one (A-24) (3.1 g, 8.7 mmol) in THF (87 mL) was cooled to 0 °C under an atmosphère of N2. A solution of méthylmagnésium bromide (3.0 M in Et20, 4.0 mL, 12 mmol) was added dropwise. The mixture was stirred for 30 min at 0 “C. LCMS analysis indicated consumption of starting material with formation of the desired product mass. The reaction was quenched with saturated aqueous NH4CI and partitioned between EtOAc and H2O. The aqueous layer was 20 extracted with EtOAc (2x). The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (ISCO, 80 g S1O2, 20-60% EtOAc/heptane) to provide 2-(6-(2,5-dichioropyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1Hbenzimidazol-2-yl]propan-2-ol (A-23) (3.11 g, 93% yield) as a white solid. ¹H NMR (400 MHz, DMSO-de) 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 25 (m, 2H), 1.67 (s, 6H), 1.61 (d, J = 7.0 Hz, 6H); m/z (APCI) for (C17H17CI2FN4O), 382.8 (M+H)⁺.

| Example B1 (Scheme B): Préparation |of 4-[4-fluoro-2-methyl-1-(propan-2-yl)-1Hbenzimidazol-6-yl]-2-{[(3R,4R)-3-hydroxy-1-(methanesulfonyl)piperidin-4yl]amino}pyrimidine-5-carbonitriie

I³⁰ ί

I Scheme B: I

229

Pd(t-Bu₃P)₂ K₂CO₃

1,4-dioxane, H₂O, 80 °C

76% yield

oxone

THF, H₂O

85% yield

Na₂CO₃

THF, 65 ’C

31% yield

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

To a mixture of 4-chloro-2-(methylsulfanyl)pyrimidine-5-carbonitrile (150 mg, 0.808 mmol), 4-fluoro-2-methyl-1-(propan-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1Hbenzimidazole (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-Bu₃P)₂ (41.3 mg, 0.0808 mmol). The reaction was sparged with N₂ and then stirred at 80 °C for 1 h. LCMS analysis indicated consumption of the starting material with formation of the desired product mass. The mixture was combined with a second reaction run in the identical fashion with 85.7 mg 4-fluoro-2-methyl-1-(propan-2-yl)-6-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazole (A-1). The mixture was diluted with EtjOAc (20 mL) and washed with H₂O (5 mL). The aqueouè layer was extracted with EtOAc (3x10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (Biotage, SiO₂, 1:1 petroleum ether/EtOAc) to provide 4-[4-fluoro-2-methyl-1-(propan-2-yl)-1/7-benzimidazol-6-yl]-2(methylsulfanyl)pyrimidine-5-carbonitriIe (B-1) (280 mg, 76% yield) as a yellow solid. ¹H NMR (400 MHz, CDCI₃) 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 (C₁₇Hi₆FN₅S), 342.0 (M+H)*.

Step 2: Synthesis of 4-[4-fluoro-2-methyl-1-(propan-2-yI)-1H-benzimidazol-6-yl]-2(methanesulfinyl)pyrimidine-5-carbonitrile (B-2) — 230

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 résultant mixture was stirred at the same température for 1.5 h: LCMS analysis showed consumption of the starting material with 5 formation ofthe desired product mass. The reaction was combined with a parallel reaction run in identical fashion with 80 mg 4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazoI-6-yl]-2(methylsuIfanyi)pyrimidine-5-carbonitrile (B-1). The combined solution was diluted with EtOAc (20 mL) and washed with brine (10 mL). The aqueous layer was extracted with EtOAc (4x10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and 10 concentrated to provide 4-[4-fluoro-2-methyl-1-(propan-2-yl)-1/-/-benzimidazol-6-yl]-2(methanesulfinyl)pyrimidine-5-carbonitrile (B-2) (250 mg, 85% yield) as an off-white solid, which was taken on without further purification, m/z (ESI) for (C17H16FN5OS), 358.3 (M+H)⁺.

Step 3: Synthesis of 4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]-215 {[(3R,4R)-3-hydroxy-1 -(methanesulfonyI)piperidin-4-yl]amino}pyrimidine-5-carbonitrile (Example B1)

To a mixture of 4-[4-fiuoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yI]-2(methanesulfinyl)pyrimidine-5-carbonitrile (B-2) (120 mg, 0.336 mmol) and (3R,4R)-4-amino-1(methanesuifonyI)piperidin-3-ol (lnt-69) in THF (15.0 mL) was added Na₂CO₃ (71.2 mg, 0.672 20 mmol). The résultant mixture was stirred at 65 °C for 12 h. LCMS analysis indicated consumption of the starting material with formation of the desired product mass. The mixture was diluted with 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 Na2SO4, filtered, and concentrated. The residue was purified by préparative TLC (SiO₂,10:1 DCM/MeOH, 25 Rf = 0.55). The material was further purified by préparative HPLC with a YMC-Actus Triait C18 column (150x30 mm, 5 pm particle size), which was eluted with 8-48% MeCN/H2O (+0.225% formic acid) to provide 4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-beijzimidazol-6-yi]-2-{[(3R,4R)-3hydroxy-1-(methanesulfonyl)piperidin-4-yl]amino}pyrimidine-5-carbonitrile (Example B1) (50 mg, 31% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.82 - 8.74 (m, 1H), 8.43 - 8.32 (m, 30 1 H), 8.21 -^f 8.11 (m, 1 H), 7.59 - 7.48 (m, 1 H), 5.35 - 5.28 (m, 1 H), À.88 - 4.76 (m, 1 H),4.05 - 3.90 (m, 1H), 3.^70 - 3.59 (m, 2H), 3.56 - 3.47 (m, 1H), 2.91 - 2.81 (m, 4^), 2.71 - 2.59 (m, 4H), 2.10 1.95 (m, 1 H), 1.65 - 1.51 (m, 7H); m/z (ESI) for (C₂₃H₂7FN₆O₃S), 488.1 (M+H)⁺.

The example the below table was synthesized according to the methods used for the synthesis of 4-[4-fluoro-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

231 example was synthesized with non-critical changes or substitutions to the exemplified procedures that someone who is skilled in the art would be able to realize.

Example number	Structure/Name	-LCMS	NMR
B2	n^YCF3 ho^a LA Tl \ ,N L J N— N Me—/ O-S—O Me Me (3R,4R)-4-({4-[4-fIuoro-1- (propan-2-yl)-1 H-benzimidazol6-yl]-5(trifluoromethyl)pyrimidin-2yl}amino)-1- (methanesulfonyl)piperidin-3-ol	516.9 [M+H]+ (ESI)	1H NMR (400 MHz, DMSO-d6) 5 8.71-8.66 (m, 1H), 8.51 (s, 1H), 8.20-8.09 (m, 1H), 7.64 (s, 1H), 7.23-7.14 (m, 1H), 5.27 (brs, 1H), 4.79 (hept, J = 6.6 Hz, 1H), 3.99-3.80 (m, 1H), 3.67 - 3.56 (m, 2H), 3.54 3.42 (m, 1H), 2.94-2.77 (m, 4H), 2.70 - 2.58 (m, 1H), 2.08 1.97 (m, 1H), 1.61-1.49 (m, 7H)

Example C1 (Scheme C-1): Préparation of (3R,4R)-4-({4-[5-chloro-2-methyl-1-(propan-25 yi)-1H-benzimidazol-6-yl]-5-fIuoropyrimidin-2-yl}amino)-1-(methanesuIfonyl)piperidin-3-oI

Scheme C-1:

C-1 then PdCI₂(PPh₃)₂, Na₂CO₃ H₂0,50 °C

PdCI₂(dppf), B₂Pin₂, KOAc

1,4-dioxane, 70 ’C

20% yield

NH₂

/_rPrNH₂

DN|SO, 50“C then acetaldehyde Na₂S₂O₄ EtOH, 80 *C

46% yield

O=S=O Me

Pd(OAc)₂ rac-BINAP, Cs₂CO₃

THF, 80 ’C

38% yield

232

Step 1: Synthesis of 2-chloro-4-(2-chloro-5-fluoro-4-nitrophenyl)-5-fluoropyrimidine (C-2)

To a solution of 1-bromo-2-chloro-5-fluoro-4-nitrobenzene (C-1) (0.5 g, 1.97 mmol) in 1,4dioxane (10.0 mL) were added KOAc (579 mg, 5.9 mmol) and B₂Pin2 (749 mg, 2.95 mmol). The mixture was sparged with N2 and then PdCl2(dppf) was added. The mixture was stirred at 70 °C 5 with microwave irradiation for 30 min. LCMS analysis indicated consumption of the starting material with conversion to the boronate ester. To the mixture were added 2,4-dichloro-5fluoropyrimidine, aqueous Na2CÜ3 (2.0 M, 2.95 mL), and PdCl2(dppf) (80 mg, 0.1 mmol). The mixture was stirred at 50 °C with microwave irradiation for 2 h. LCMS analysis indicated consumption of the boronate ester with formation of the desired product mass. The mixture was 10 combined with a parallel reaction run in an identical fashion with 100 mg 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 MgSO₄, filtered, and concentrated onto S1O2. The crude material was purified by flash chromatography (ISCO, 40 g S1O2, 0-30% EtOAc/heptanes) to provide 2-chloro-4-(2-chloro-5-fIuoro-4-nitrophenyl)-5-fluoropyrimidine (C-2) 15 (120 mg, 20% yield) as an off-white solid. ¹H NMR (400 MHz, DMSO-c/e) 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 (C10H3CI2F2N3O2), 304.7 (M+H)⁺.

Step 2: Synthesis of 5-chloro-6-(2-chloro-5-fIuoropyrimidin-4-yl)-2-methyl-1-(propan-2-yl)1H-benzimidazole (C-3)

A mixture of 2-chloro-4-(2-chloro-5-fluoro-4-nitrophenyl)-5-fluoropyrimidine (C-2) (55 mg,

0.018 mmol) and /-PrNH₂ (0.016 mL, 0.018 mmol) in DMSO (1 mL) was stirred at 50 °C with microwave irradiation for 1.5 h. LCMS analysis indicated consumption of the starting material. After cooling to room température the mixture was diluted with EtOH (0.5 mL) and treated with acetaldehyde (39.6 mg, 0.05 mL, 0.899 mmol) and Na₂S₂O₄ (156 mg, 0.899 mmol). The mixture 25 was stirred at 80 °C for 16 h overnight. LCMS analysis indicated formation of the desired product mass. The mixture was concentrated to remove the EtOH. The remaining solution in DMSO was added dropwise to saturateà aqueous NaHCOs. The résultant yellow solids were [collected by filtration and washed with H2O. The solids were taken up into DCM/MeOH and concentrated to provide 5-chloro-6-(2-chloro-5-fluoropyrimidin-4-yl)-2-methyl-1-(propan-2-yl)-1H-benzimidazole 30 (C-3) (28 mg, 46% yield), which was taken on without further purification. ¹H NMR (400 MHz,

DMSO-de) δ 9.05 (s, 1H), 7.97 (s, 1H), 7.79 (s, 1 H), 4.79 (spt, J = 6.8 Hz, 1H), 2.62 Js, 3H), 1.55 (d, J =7.0 Hz, 6H). m/z (ESI) for (C10H3CI2F2N3O2), 304.7 (M+H)⁺.

Step 3: Synthesis of (3/?,4R)-4-({4-[5-chIoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-635 yl]-5-fluoropyrimidin-2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol (Example C1)

233

To a solution of 5-chloro-6-(2-chloro-5-fluoropyrimidin-4-yl)-2-methyl-1-(propan-2-yl)-1/7benzimidazole (C-3) (28 mg, 0.083 mmol) in THF (1.0 mL) were added (3R,4R)-4-amino-1(methanesulfonyl)piperidin-3-ol (lnt-69) (24.1 mg, 0.124 mmol) and CS2CO3 (81 mg, 0.25 mmol).

The mixture wàs 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 overnight. LCMS analysis indicated consumption of the starting material with formation of the desired product mass. The mixture was partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by préparative SFC with an HA-morpholine column (150x21.1 mm, 5 pm particle size, 35 °C column température), which was eluted with 10-50% MeOH/CO2 with a flow rate of 80 g/min. The material was re-purified by préparative SFC with a Nacalai Cosmosil 3hydroxyphenyl column (150x20 mm, 5 pm particle size. 35 °C column température), which was eluted with 12-50% MeOH/CO2 with a flow rate of 80 g/min to provide (3R,4R)-4-({4-[5-chloro-2methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]-5-fluoropyrimidin-2-yl}amino)-115 (methanesulfonyl)piperidin-3-ol (Example C1) (16 mg, 38% yield) as a solid. ¹H NMR (600 MHz, DMSO-d₆, 75 °C) δ 8.35 - 8.33 (m, 1H), 7.71 (s, 1H), 7.68 (s, 1H), 6.84 (d, J = 7.3 Hz, 1H), 5.13 (d, J = 4.0 Hz, 1H), 4.78 - 4.72 (m, 1H), 2.86 - 2.81 (m, 4H), 2.69 - 2.63 (m, 1H), 2.57 (s, 3H), 2.14 - 2.09 (m, 1H), 1.59 - 1.43 (m, 7H); four protons obscured by residual solvent peak; m/z (ESI) for (C21H26CIFN6O3S), 496.9 (M+H)⁺.

Example C2 (Scheme C-2): Préparation of 1,5-anhydro-3-({4-[2-(azetidin-3-yl)-4-fluoro-1(propan-2-yl)-1H-benzimidazol-6-yl]-5-chloropyrimidin-2-yl}amino)-2,3-dideoxy-D-fhreopentitol

Scheme C-2:

A solution of (C-4) (as prepared in Example C1, 155.0 mg, 0.22 mmol), 3-amino-1,5anhydro-2,3-dideoxy-D-t/7reo-pentitol (49.8 mg, 0.324 mmol), and DIPEA (126 mg, 0.173 mmol,

0.973 mmol) in DMSO (2 mL) was heated to 80 °C for 16 h overnight. LCMS analysis showed consumption ofthe starting material with formation ofthe desired product mass. The mixture was loaded directly onto S1O2 and purified by flash chromatography (ISCO, 12 g SiO2, 0-100%

234

EtOAc/heptanes). The product-containing fractions were concentrated, taken up into DCM (5 mL), and treated with a solution of HCl (4.0 N in 1,4-dioxane, 1.0 mL). After 15 min, LCMS analysis showed conversion to the desired product. The reaction was concentrated to dryness.

The residue was purified by préparative SFC with a ChiralPak IC column (21x250 mm column,

10 pm particle size, 35 °C column température), which was eluted with 60% MeOH/CO2 (+10 mM

NH3) with a flow rate of 82 mL/min to provide 1,5-anhydro-3-({4-[2-(azetidin-3-yl)-4-fluoro-1(propan-2-yl)-1H-benzimidazol-6-yI]-5-chloropyrimidin-2-yl}amino)-2,3-dideoxy-D-fhreo-pentitol (Example C2) (72 mg, 72% yield) as a solid. ¹H 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 10 (m, 1 H), 4.15 - 3.99 (m, 2H), 3.92 - 3.77 (m, 5H), 3.66 - 3.52 (m, 2H), 3.39 - 3.31 (m, 1 H), 2.09 1.97 (m, 1H), 1.64 - 1.53 (m, 7H); m/z (ESI) for (C22H26CIFN6O2), 461.1 (M+H)⁺.

Example D1 (Scheme D-1): Préparation of(3/?,4R)-4-[(5-chloro-4-{4-fluoro-2-[(1S)-1hydroxyethyl]-1-(propan-2-yl)-1H-benzimidazol-6-yl}pyridin-2-yl)amino]-115 (methanesulfonyl)piperidin-3-ol

Scheme D-1:

Me OH

D-1

Pd(PPh₃)₄, Na₂CO₃

71% yield

H₂0,1,4-dioxane, 90 ’C

nh₂

o=s=o

Me

Brettphos-Pd-G₃ Cs₂CO₃ DMF, 1,4-dioxane, 110 °C

7% yield

Step 1: Synthesis of (1S)-1-[6-(2,5-dichloropyridin-4-yl)-4-fiuoro-1-(propan-2-yl)-1H benzimidazol-2-yl]ethan-1-ol (D-2):

235

To a solution of (1S)-1-[4-fluoro-1-(propan-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yI)-1H-benzimidazol-2-yI]ethan-1-ol (D-1) (Prepared as in Example A1, 650 mg, 1.87 mmol) in H₂O (2.0 mL) and 1,4-dioxane (7.0 mL) were added 2,5-dichloro-4-iodopyridine (562 mg, 2.05 mmol), Na₂CO3 (396 mg, 3.73 mmol), and Pd(PPh₃)4 (216 mg, 0.187 mmol). The reaction mixture was stirred at 90 °C under an atmosphère of N₂. LCMS analysis showed consumption of the starting material with formation of the desired product mass. The reaction was concentrated to dryness. The residue was purified by flash chromatography (ISCO, 40 g SiO₂, 2:1 petroleum ether/EtOAc) to providé (1S)-1-[6-(2,5-dichloropyridin-4-yl)-4-fluoro-1 -(propan-2yl)-1H-benzimidazol-2-yl]ethan-1-ol (D-2) (490 mg, 71% yield) as a light yellow solid. m/z (ESI+) for (Ci7Hi₆CI₂FN₃O), 368.0 (M+H)⁺.

Step 2: Synthesis of (3/?,4R)-4-[(5-chloro-4-{4-fluoro-2-[(1S)-1-hydroxyethyl]-1-(propan-2yl)-1 H-benzimidazol-6-yl}pyridin-2-yl)amino]-1 -(methanesulfonyl)piperidin-3-ol (Example D1):

A heterogeneous mixture of (1S)-1-[6-(2,5-dichloropyridin-4-yl)-4-fluoro-1-(propan-2-yl)1H-benzimidazol-2-yl]ethan-1-ol (D-2) (390 mg, 1.06 mmol), (3R,4R)-4-amino-1(methanesuIfonyl)piperidin-3-ol (lnt-69) (411 mg, 2.12 mmol), Cs₂CO3 (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) was sparged with N₂ for 3 min and then stirred at 110 °C for 4 h. LCMS analysis showed consumption of the starting material with formation of the desired product mass. The reaction was filtered and concentrated to dryness. The residue was purified by flash chromatography (ISCO, 40 g SiO₂, ΟΙ 5% MeOH/EtOAc) and then re-purified by préparative HPLC with a Xtimate C18 column (250x80 mm, 10 pm particle size), which was eluted with 30-50% MeCN/H₂O (+0.05% NH4OH) with a flow rate of 25 mL/min. HPLC analysis found some érosion of enatiopurity (93% ee). The material was re-purified by chiral préparative SFC with a Diacel Chiralpak AD-H column (250x30 mm, 5 pm particle size), which was eluted with 45% IPA/CO₂ (+0.1% NH3) with a flow ratë of 50 mL/min to | provide (3R,4R)-4-[(5-chloro-4-{4-fluoro-2-t(1 S)-1 -hydroxyethyl]-1 -(propan-2-yl)-1 Hbenzimidàzol-6-yl)pyridin-2-yl)amino]-1-(methanesulfonyl)piperidin-3-ol (Example D1) (40.1 mg, 7% yield) as a white solid. ¹H NMR (400 MHz, DMSO-de+ D₂O) δ 7.99 (br s, 1 H), 7.54 (s, 1H), 17.07 (d, J = 10.8 Hz, 1H), 6.62 (s, 1H), 5.13 - 5.02 (mj 2H), 3.70 - 3.66 (m, 1H), 3.65 -3.45 m, ί 3H), 2.85 - 2.80 (m, 4H), 2.70 - 2.62 (m, 1H), 2.05 2.θθ' (m, 1H), 1.59 - 1.4 (m, 10H); m/z (ESI+) for (C₂3H₂₉CIFN₅O4S), 525.8 (M+H)⁺.

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

236

Scheme D-2:

A suspension of (1 S)-1-[6-(2,5-dichloropyridin-4-yl)-4-fluoro-1-(propan-2-yl)-1Hbenzimidazol-2-yl]ethan-1-ol (D-3) (as prepared in Example D1, 680 mg, 1.85 mmol), 3-amino1,5-anhydro-2,3-dideoxy-D-fhreo-pentitol (324 mg, 2.77 mmol), BINAP (92 mg, 0.148 mmol), tBuONa (532 mg, 5.54 mmol), and Pd2(dba)3 (84.6 mg, 0.092 mmol) in PhMe (15.0 mL) was sparged with N2 for 3 min and then stirred at 110 °C for 16 h. LCMS analysis showed consumption of the starting material with formation of the desired product mass. The reaction was concentrated to dryness. The residue was purified by flash chromatography (ISCO, 40 g S1O2, 0-20% MeOH/EtOAc). The material was re-purified by préparative HPLC with a Xtimate C18 column (250x80 mm, 10 pm particle size), which was eluted with 30-50% MeCN/H2O (+0.05% NH4OH) with a flow rate of 25 mL/min to provide 1,5-anhydro-3-[(5-chloro-4-{4-fIuoro-2-[(1S)-1hydroxyethyl]-1-(propan-2-yI)-1H-benzimidazol-6-yl}pyridin-2-yI)amino]-2,3-dideoxy-D-f/jreopentitol (Example D2) (67 mg, 8% yield) as a white solid¹H NMR (400 MHz, DMSO-ds) 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 obscured by residual solvent peak; m/z (ESI+) for (C22H26CIFN4O3), 449.1 (M+H)⁺.

the example the below table was synthesized according to the methods used for the synthesis of 1,5-anhydro-3-[(5-chloro-4-{4-fluoro-2-[(1 S)-1-hydroxyethyl]-1 -(propan-2-yl)-1 Hbenzimidazol-6-yl}pyridin-2-yl)amino]-2,3-dideoxy-D-t/7reo-pentitol (Example D2). The following example was synthesized with non-critical changes or substitutions to the exemplified procedures that someone who is skilled in the art would be able to realize.

Example number

Structure/Name

LCMS

NMR

237

D3

- - HO. Â L ri ' //N k J N-X N Μβ-γ ~yMe O-S-O Me OH Me (3R,4R)-4-[(5-chloro-4-{4- fluoro-2-[(1 R)-1 -hydroxyethyl]- 1-(pro pan-2-yl )-1/7- bénzimidazol-6-yl}pyridin-2- yl)amino]-1- (methanesulfonyl)piperidin-3-ol

525.9 [M+H]+ (ESI)

1H NMR (400 MHz, DMSO-d6) 5 8.07 (s, 1H), 7.59 (d, J =1.0 Hz, 1H), 7.07 (dd, J=11.4,1.3 Hz, 1H), 6.83 (brd, J = 7.5 Hz, 1H), 6.64 (s, 1H), 5.74 (d, J = 6.3 Hz, 1H), 5.27 (d, J = 4.5 Hz, 1H), 5.21-5.04 (m, 2H), 3.80-3.71 (m, 1H), 3.60- 3.49 (m, 2H), 3.49 - 3.39 (m, 1 H), 2.96 - 2.85 (m, 4H), 2.76 - 2.68 (m, 1H), 2.17-2.07 (m, 1H), 1.65-1.51 (m, 9H), 1.49- 1.33 (m, 1H)

Example D4 (Scheme D-3): Préparation of (3/?,4/?)-4-({5-chloro-4-[2-methyl-3-(propan-2-yl)3H-imidazo[4,5-b]pyridin-5-yl]pyridin-2-yI}amino)-1-(methanesuIfonyI)piperidin-3-ol

Scheme D-3:

nh₂

ΗΟ^χΑ | Ί lnt-69 o=s=o Me

Pd(OAc)2, BINAP P₂-Et

Example D4

PhMe, 110 ’C

21% yield

To a solution of (D-4) (Prepared as in Example D1,78 mg, 0.24 mmol), (3R,4R)-4-amino1-(methanesulfonyl)piperidin-3-ol (lnt-69) (41 mg, 0.27 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol), 10 and rac-BINAP (9.45 mg, 0.73 mmol) was added phosphazene base P2-Et to provide a bright orange reaction solution. The mixture was sparged with N2 and then stirred at 110 °C for 16 h overnight. LCMS analysis indicated consumption of the starting material with formation of the desired product mass. The reaction was concentrated to dryness. The residue was purified by préparative SFC with a ZymorSPHER HADP column (150x21.1 mm, 5 pm particle size, 35 °C 15 column température), which was eluted with 12-50% MeOH/CO2 with a flow rate of 80 g/min. The material was repurified by préparative HPLC with a Phenomenex Gemini-NX C18 column

238 (150x21 mm, 5 pm particle size), which was eluted with 15-70% MeCN/FW (+10 nM NH4OAC) with a flow rate of 40 mL/min to provide (3R,4R)-4-({5-chloro-4-[2-methyl-3-(propan-2-yl)-3Himidazo[4,5-b]pyridin-5-yl]pyridin-2-yl}amino)-1-(methanesulfohyl)piperidin-3-ol (Example D4) (20 mg, 21% yield) as a sôlid. ¹H NMR (600 MHz, DMSO-cfe) δ 8.08 (s_r1H),'8?00 (d, J = 8.2 Hz,------5 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, 1 H), 3.80 - 3.73 (m, 1 H), 3.61 - 3.52 (m, 2H), 3.49 - 3.44 (m, 1 H), 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 (C21H27CIN6O3S), 478.9 (M+H)⁺.

The exârriple the below table was synthesized according to the methods used for the synthesis of (3R,4/?)-4-({5-chloro-4-[2-methyl-3-(propan-2-yl)-3H-imidazo[4,5-b]pyridin-5yl]pyridin-2-yi}amino)-1-(methanesulfonyl)piperidin-3-ol (Example D4). The following example was synthesized with non-critical changes or substitutions to the exemplified procedures that someone who is skilled in the art would be able to realize.

239

Example number	Structure/Name	LCMS	NMR
D5	χχ01 HO^< N. A - Il ' /N“ Me 1,5-anhydro-3-({5-chloro-4-[2methyl-3-(propan-2-yl)-3Himidazo[4,5-b]pyridin-5yl]pyridin-2-yl}amino)-2,3dideoxy-D-fhreo-pentitol	402.1 [M+H]+ (APCI)	1H NMR (600 MHz, DMSO-de) δ 8.06 (s, 1H), 7.99 (d, J =8.3 Hz, 1H), 7.45 (d, J =8.2 Hz, 1H), 6.89-6.86 (m, 1H), 6.80 (s, 1H), 5.06 (br. s, 1H), 4.81 (hept, J = 6.4 Hz, 1H), 3.843.74 (m, 3H), 3.10-3.05 (m, 1H), 2.63 (s, 3H), 2.05-2.01 (m, 1H), 1.67 (dd, J =6.8, 2.3 Hz, 6H), 1.44-1.36 (m, 1H) two protons obscured by residual solvent peak

Example D6 (Scheme D-4): Préparation of (3R,4R)-44[4-(1-tert-butyl-4-fIuoro-1Hbenzimidazol-6-yl)-5-chloropyridin-2-yl]amino}piperidin-3-ol

Scheme D-4:

D-5

Example D6

To a solution of ferf-buty (3R,4R)-4-{[4-(1-fe/i-butyl-4-fIuoro-1H-benzimidazol-6-yl)-5chloropyridin-2-yl]amino}-3-hydroxypiperidine-1-carboxylate (D-5) (Prepared as in Example D1, 10 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 h LCMS analysis showed consumption ofthe starting material with formation ofthe desired product mass. The reaction was concentrated to dryness. The solid was taken up in H2O (50 mL) and washed with EtOAc (50 mL). The aqueous layer was lyophilized to provide (3R,4R)-4-{[4-(1fert-butyl-4-fIuoro-1H-benzimidazol-6-yl)-5-chloropyridin-2-yl]amino}piperidin-3-ol hydrochloric acid sait (Example D6) (2.7 g, 99% yield) as a yellow solid. ¹H 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,

240

9.8 Hz, 1H), 2.42 - 2.34 (m, 1H), 1.98 - 1.79 (m, 10H); m/z (ESI+) for (C₂iH₂5CIFN₅O), 418.2 (M+H)⁺.

Example E1 (Scheme E-1): Préparation of (3R,4R)-4-[(5-chloro-4-{4-fIuoro-2-[(1S)-15 hydroxyethyI]-1-(propan-2-yl)-1H-benzimidazol-6-yl}pyridin-2-yi)amino]-1(methanesulfonyl)piperidin-3-ol

Scheme E-1:

DIPEA

DMSO, 100 ’C

44% yield

PdCI₂(PPh₃)₂ Na₂CO₃ H₂0,1,4-dioxane

39% yield, 95 ’C

Step 1: Synthesis of (1S)-1-[6-(2,5?dichloropyridin-4-yl)-4-fluoro-1-(propan-2-yl)-1Hbenzimidazol-2-yl]ethan-1-ol (E-1): '

A solution of 5-chloro-2-fluoro-4-iodopyridine (200 mg, 0.78 mmol), (3S,4S)-4-amino-1(methanesulfonyl)piperidin-3-ol (lnt-69) (181 mg, 0.93 mmol), and DIPEA (301 mg, 0.415 mL, 2.33 mmol) in DMSO (3.9 mL) was stirred at 100 °C for 16 h. LCMS analysis showed consumption 15 of the starting material with formation of the desired product mass. The reaction was loaded directly onto SiO₂ and purified by flash chromatography (ISCO, 12 g SiO₂, 0-100% EtOAc/heptanes) to provide (3S,4S)-4-[(5-chioro-4-iodopyridin-2-yl)amino]-1(methanesulfonyl)piperidin-3-ol (E-1) (147 mg, 44% yield) as a gum. ¹H NMR (400 MHz, CDCI3) 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 19876

241

3.58 (m, 2H), 3.44 (p, J = 6.7 Hz, 1H), 2.83 (s, 3H), 2.77 (dd, J = 12.2, 2.8 Hz, 1H), 2.68 - 2.52 (m, 1H), 2.14-2.08 (m,1H), 1.75-1.56 (m, 1 H); m/z (ESI+) for (C11H15CIIN3O3S), 431.8 (M+H)⁺.

Step 2: Synthesis of (3R,4R)-4-[(5-chIoro-4-{4-fIuoro-2-[(1S)-1-hydroxyethyl]-1-(propan-25 yl)-1H-benzimidazol-6-yl}pyridin-2-yl)amino]-1-(methanesulfonyl)piperidin-3-ol (Example E1):

To a solution of (3S,4S)-4-[(5-chloro-4-iodopyridin-2-yl)amino]-1(methanesulfonyl)piperidin-3-ol (E-1) (147 mg, 0.341 mmol) in 1,4-dioxane (4.7 mL) was added 4-fluoro-2-methyl-1 -(propan-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yI)-1 H10 benzimidazole (A-1) (108 mg, 0.341 mmol), aqueous Na₂COs (2.0 M, 0.51 mL), PdCI₂(PPh3)2 (12 mg, 0.017 mmol), and H₂O (0.4 mL). The mixture was stirred at 95 °C for 5 h. LCMS analysis showed consumption of the starting material with formation of the desired product mass. The reaction was filtered through celite and concentrated. The material was purified by préparative SFC with a DCPak SFC-B column (150x21.2 mm, 5 pm particle size, column température 35 °C), which was eiuted with 25-35% MeOH/CO₂ with a flow rate of 62 mL/min to provide (3R,4R)-4-[(5chloro-4-{4-fluoro-2-[(1S)-1-hydroxyethyl]-1-(propan-2-yl)-1H-benzimidazol-6-yl}pyridin-2yl)amino]-1-(methanesulfonyl)piperidin-3-ol (Example E1) (66 mg, 39% yield) as a white solid. ¹H 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, 1 H), 2.95 - 2.87 (m, 4H), 2.74 - 2.68 (m, 1 H), 2.60 (s, 3H), 2.14 - 2.09 (m, 1H), 1.56 (d, J = 6.8 Hz, 6H), 1.46 - 1.39 (m, 1H); m/z (APCI) for (C^H^CIFNsOsS), 495.9 (M+H)⁺.

Example F1 (Scheme F-1): Préparation of methyl (3R,4R)-4-({5-fIuoro-4-[4-fIuoro-2-methyl25 1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-3-hydroxypiperidine-1carboxylate | Scheme F-1: |

To a solution of (3R,4R)-4-({5-fiuoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H30 benzimidazol-6-yl]pyrimidin-2-yl}amino)piperidin-3-ol (Example A37) (Prepared as in Scheme A1,50 mg, 0.12 mmol) and TEA (18.9 mg, 0.186 mmol) in DCM (3.0 mL) at 0 °C was added methyl _ 242 chloroformate (11.7 mg, 0.124 mmol) dropwise. The reaction was stirred for 30 min at room température. LCMS analysis showed consumption of the starting material with formation of the desired product mass. The solution was concentrated. The residue was partitioned between H₂O (20 mL) and EtOAc (20 mL). The organic layer was dried over Na₂SO4, filtered, and concentrated.

The residue was combined with a second batch obtained from a parallel reaction run in identical fashion with 50 mg of (SR^RH-QS-fluorcM-^-fluoro^-methyl-l-Îpropan^-yO-IH-benzimidazole-yllpyrimidin^-ylJaminoJpiperidin-S-ol (Example A37). The mixture was purified by préparative HPLC with DuraShell column (150x25 mm, 5 pm particle size), which was eluted with 22-72% MeCN/H₂O (+0.05% NH4OH) with a flow rate of 25 mL/min to provide methyl (3R,4R)-4-({5-fluoro10 4-[4-fIuoro-2-methyl-1-(propan-2-yl)-1/7-benzimidazol-6-yl]pyrimidin-2-yl}amino)-3hydroxypiperidine-1-carboxylate (Example F1) (48 mg, 42% yield) as a white solid. ¹H NMR (400 MHz, DMSO-de) δ 8.43 (d, J = 4.0 Hz, 1H), 8.13 (brs, 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), 15 1.45 -1.30 (m, 1 H); m/z (ESI) for (C₂₂H₂₆F₂N₆O3), 461.4 (M+H)⁺.

The examples in the below table were synthesized according to the methods used for the synthesis of methyl (3R,4R)-4-({5-fIuoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6yl]pyrimidin-2-yl}amino)-3-hydroxypiperidine-1-carboxylate (Example F1). The following 20 examples were synthesized with non-critical changes or substitutions to the exemplified procedures that someone who is skilled in the art would be able to realize. If necessary, séparation ofthe enantiomers was carried out understandard methods known in the art, such as chiral SFC or HPLC, to afford single enantiomers.

Example number	Structure/Name	LCMS	NMR
F2	N^C' hnAAhYF HO^ LA Il \ ,N L J N— ï A Μ'ΌΛο V ‘second eluting stereoisomer methyl (3R,4R)-4-({5-chloro-4[4-fluoro-1-(oxolan-3-yl)-1 Hbenzimidazol-6-yI]pyrimidin-2-	491.1 [M+H]+ (ESI)	|1H NMR (400 MHz, DMSO-cfe) 5 8.47 — 8.39 (m, 2H), 8.087.90 (m, 1H), 7.57-7.36 (m, I2H), 5.41 -5.30 (m, 1H), 5.09 i(d, J =4.8 Hz, 1H), 4.19-3.77 (m, 7H), 3.59 (s, 3H), 3.51 3.39 (m, 1H), 3.02-2.64 (m, 2H), 2.62-2.52 (m, 1H), 2.29 - 2.18 (m, 1H), 2.02-1.87 (m,

243

	yl}amino)-3-hydroxypiperidine- 1-carboxylate		1H), 1.43-1.29 (m, 1H);[a]D 20 =-28.8 (c=1.0, MeOH)
	Il J e -		1H NMR (400 MHz, DMSO-d6)
	HN N^Yy		δ 8.45 - 8.40 (m, 2H), 8.05 -
	Tl \ ,N		7.91 (m, 1H), 7.56 - 7.37 (m,
	ï M		2H), 5.39-5.31 (m, 1H), 5.16
	θΥ	491.1	-5.04 (m, 1H), 4.19-3.76 (m,
F3	‘first eluting stereoisomer	[M+H]+	7H), 3.59 (s, 3H), 3.51 - 3.39
	methyl (3R,4R)-4-({5-chloro-4[4-fluoro-1-(oxolan-3-yl)-1 Hbenzimidazol-6-yl]pyrimidin-2yl}amino)-3-hydroxypiperidine1-carboxylate	(ESI)	(m, 1H), 3.00-2.64 (m, 2H), 2.62 - 2.52 (m, 1H), 2.29 - 2.19 (m, 1H), 2.05-1.87 (m, 1 H), 1.42 -1.29 (m, 1 H); [a]D 20 = -4.9 (c=1.0, MeOH)

Example F4 (Scheme F-2): Préparation of (3R,4R)-4-({5-fIuoro-4-[4-fluoro-2-methyl-1(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amïno)-1-methylpiperidin-3-ol

Scheme F-2:

To a solution of paraformaldéhyde NaBH₃CN

MeOH

58% yield

Example F4 (3R,4R)-4-({5-fluoro-4-[4-f]uoro-2-methyl-1 -(propan-2-yI)-1 H10 benzimidazol-6-yl]pyrimidin-2-yl}amino)piperidin-3-ol (Example A37) (Prepared as in Scheme A1, 50 mg, 0.12 mmol) in MeOH (3 mL) was added paraformaldéhyde (100 mg, 1.11 mmol) and NaBHsCN (100 mg, 1.59 mmol). The résultant solution was stirred at room température for 30 min. LCMS analysis showed consumption of starting material with formation of the desired product mass. -The solution was filtered and the filtrate was combined with a parallel reaction run in an identical fashion with 50 mg (3R,4R)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H15 (150x20 mm, 5 pm particle size), which was eluted with 0-38% MeCN/H2O (0.225% formic acid) with a flow rate of 25 mL/min to provide (3R,4R)-4-({5-fluoro-4-[4-fluoro-2-methyI-1-(propan-2-yl)1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-1-methylpiperidin-3-ol formic acid sait (Example F4) benzimidazol-6-yl]pyrimidin-2-yI}amino)-1-methylpiperidin-3-ol (Example A37) and concentrated. The residue was purified by préparative HPLC with an Agela Durashell C18 column

244 (60.2 mg, 58% yield) as a white solid. ¹H NMR (400 MHz, DMSO-de) 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, 1 H), 5.22-4.57 (m, 2H), 3.65

- 3.52 (m, 2H), 2.99 - 2.88 (m, 1H), 2.81 - 2.72 (m, 1H), 2.63 (s, 3H), 2.24 (s, 3H), 2.08 - 1.85 (m, 3H), 1.64 - 1.42 (m, 7H); m/z (ESI) for (C2iH₂6F₂N₆O), 417.1 (M+H)⁺. 5 The examples in the below table were synthesized according to the methods used for the synthesis of (3R,4R)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1 H-benzimidazol-6yi]pyrimidin-2-yl)amino)-1-methylpiperidin-3-ol (Example F4). The following examples were synthesized with non-critical changes or substitutions to the exemplified procedures that someone who is skilled in the art would be able to realize. _

Example number	Structure/Name	LCMS	NMR
F5	N-YC' A HN N [|Ί HO^^k AA ri \ ,N L J n— n Mey( Me Me OH (3R,4R)-4-{[4-(1 -tert-butyl-4fluoro-1 H-benzimidazol-6-yl)-5chloropyrimidin-2-yl]amino}-1(2-hydroxyethyl)piperidin-3-ol formic acid sait	463.3 [M+H]+ (ESI)	1H NMR (400 MHz, CD3OD) δ 8.51-8.35 (m, 3H), 8.15 (s, 1H), 7.52 (d, J=11.5 Hz, 1H), 4.06 - 3.90 (m, 2H), 3.82 (t, J = 5.6 Hz, 2H), 3.45 - 3.34 (m, 1H), 3.07-2.96 (m, 2H), 2.92 - 2.70 (m, 2H), 2.48 - 2.30 (m, 1 H), 1.87 -1.75 (m, 10H); one proton obscured by residual solvent peak
F6	Ν'^Α hnx^n'At<^<f HO^zk AA Il \ ,N L J N— N Me—/ Me Me A Me Me (3R,4R)-4-{[4-(1 -tert-butyl-4fiuoro-1 H-benzimidazol-6-yl)-5chIoropyrimidin-2-yl]amino}-1[2’ (dimethylamino)ethyl]piperidin3-ol formic acid sait	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, J = 11.5 Hz, 1H), 3.^7-3.77 (m, 1H), 3.75-3.64 (m, 1H), 3.13 - 3.05 (m, 1H), 2.94-2.79 (m, 3H), 2.65 (t, J ='6.7 Hz, 2H), 2.55 (s, 6H), 2.27 - 2.07 (m, 3H), 1.82 (s, 9H), 1.68-1.54 (m, 1H)

245

F7

A HN N TT A N Me-/ Me Me ‘second eluting stereoisomer (3R,4R)-4-({5-chloro-4-[4fluoro-2-(hydroxymethyl)-1(propan-2-yi)-1 H-benzimidazol6-yl]pyrimidin-2-yl}amino)-1 (methanesulfonyl)piperidin-3-ol

417.2 [M+H]+ (ESI)

1H NMR (400 MHz, DMSO-d6) δβ.41-8.42 (m, 1H), 8.17 (s, 1 H), 7.60-7.63 (m, 1H), 7.067,07 (m, 1H), 4.85-4.79 (m, 2H), 3.60 - 3.50 (br m, 2H), 2.91-2.88 (m, 1H), 2.73-2.70 (m, 1H), 2.63 (s, 3H), 2.19 (s, 3H), 2.04 -1.75 (m, 3H), 1.591.62 (m, 6H), 1.51-1.40 (m,. 1H); [a]o20 = 15.4 (c=041, CHCI3)

Example F8 (Scheme F-3): Préparation of (3/?,4R)-4-({5-chloro-4-[4-fluoro-2-methyI-1(oxetan-3-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-1-(ethanesulfonyl)piperidin-3-ol

Scheme F-3:

EtSO₂CI NaHCO₃

EtOAc, H₂O, 0 °C

8% yield

A mixture of (3R,4R)-4-({5-chloro-4-[4-fluoro-2-methyl-1-(oxetan-3-yl)-1H-benzimidazol6-yl]pyrimidin-2-yl}amino)piperidin-3-ol (F-1) (Prepared as in Scheme A-1, 70 mg, 0.152 mmol) and NaHCO₃ (204 mg, 2.43 mmol) in EtOAc (1.0 mL) and H2O (1.0 mL) was cooled to 0 °C. A 10 solution of ethanesulfonyl chloride (20.8 mg, 0.162 mmol) in EtOAc (1.0 mL) was added dropwise over a period of 10 min. The réaction was stirred at 0 °C for 16 h. LMCS analysis |showed consumption of the starting material with formation of the desired product mass. The reaction layers were separated. The aqueous layer was extracted with EtOAc (3x10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by 15 préparative HPLC with a DuraShell column (150x25 mm, 5 pm particle size), which was eluted with 28-48% MeCN/H₂O (+0.05% NH₄OH) with a flow rate of 25 mL/min to provide (3R,4R)-4-({5chloro-4-[4-fluoro-2-methyl-1 -(oxetan-3-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. ¹H NMR (500 MHz, CD₃OD) 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 20 (m, 2H), 5.22-517 (m, 2H), 3.96 - 3.90 (m, 1 H), 3.88-3.82 (m, 1 H), 3.73 - 3.66 (m, 2H), 3.11

246

-3.03 (m,2H), 3.02-2.95 (m, 1H), 2.83-2.77 (m, 1H), 2.63 (s, 3H), 2.26-2.17 (m, 1H), 1.68

- 1.58 (m, 1 H), 1.39 - 1.27 (m, 3H); m/z (ESI) for (C22H26CIFN6O4S), 525.3 (M+H)⁺.

The examples in the below table were synthesized according to the methods used for the synthesis of (3R,4R)-4-({5-chloro-4-[4-fIuoro-2-methyI-1-(oxetan-3-yI)-1H-benzimidazol-6yl]pyrimidin-2-yl}amino)-1-(ethanesulfonyl)piperidin-3-ol (Example F8). The following examples were synthesized with non-critical changes or substitutions to the exemplified procedures that someone who is skilled in the art would be able to realize. If necessary, séparation of the enantiomers of was carried out under standard methods known in the art, such as chiral SFC or

HPLC, to afford single enantiomers.

Example number	Structure/Name	LCMS	NMR
F9	Ν^1 JL hn nY y LJ, Il ' //N ΜβΆ aoh °-S-° Me Me F^F (3R,4R)-4-({5-chloro-4-[4fluoro-2-(1 -hydroxyethyl)-1 (propan-2-yl)-1 H-benzimidazol6-yl]pyrimidin-2-yl}amino)-1(difluoromethanesulfonyl)piperi din-3-ol	563.1 [M+HJ+ (ESI)	1H NMR (400 MHz, CD3OD) δ 8.38 (s, 1H), 8.06 (s, 1H), 7.51 (brd, J =11.5 Hz, 1H), 6.886.52 (m, 1H), 5.34 (td, J= 6.9, 14.0 Hz, 1H), 5.23 (q, J =6.8 Hz, 1H), 4.09-3.92 (m, 2H), 3.85 (brd, J= 13.7 Hz, 1H), 3.72 (dt, J = 4.7, 9.0 Hz, 1H), 3.29 - 3.21 (m, 1H), 3.08 (dd, J = 9.5, 12.8 Hz, 1H), 2.30 - 2.22 (m, 1H), 1.77-1.67 (m, 10H), 0.92 (brt, J =6.5 Hz, 1H); [afo^-e.S (c=0.1,MeOH)
F10	ïV 1 HN N ]|< ΗΟ^χ< LyL, Il ' //N Y Μβ^ O-S-O Me Me j F^F (3R,4R)-4-({5-chloro-4-[4fluoro-2-(1-hydroxyethyl)-1(propan-2-yl)-1 H-benzimidazol6-yl]pyrimidin-2-yl}amino)-1-	584.9 [M+Na]+ (ESI)	1H NMR (400 MHz, CD3OD) δ 8.38 (s, 1H), 8.06 (s, 1 H), 7.62 -7.41 (m, 1H), 6.90-6.48 (m, 1H), 5.40-5.31 (m, 1H), 5.24 (q, J =6.7 Hz, 1 H),4.06 - 3.92 (m, 2H), 3.86 (brd, J =13.2 Hz, 1 H), 3.72 (td, J = 4.6, 9.0 Hz, 1H), 3.31-3.21 (m, 1H), 3.15 - 2.95 (m, 1H), 2.34 - 2.15 (m, 1H), 1.77-1.70 (m,9H),

247

	(difluoromethanesulfonyl)piperi din-3-ol		1.68-1.62(01,1^:(010^ = - 25.6(c=0.1, MeOH)
F11	N^YCI HO,, x^. keiJs r* i \ ,N k J n-4 V MeY >-..OH O-S-O Meue Me (3S,4R)-(re/)-4-[(5-chloro-4-{4- fluoro-2-[(1 R)-1 -hydroxyethyl]- 1 -(propan-2-yl)-1 H- benzimidazol-6-yl}pyrimidin-2yl)amino]-1(methanesulfonyl)piperidin-3-ol	526.9 [M+H]+ (ESI)	1H NMR (400 MHz, CD3OD) δ 8.39 (s, 1H), 8.04 (s, 1H), 7.48 (d, J= 11.5 Hz, 1H), 5.40-5.29 (m, 1H), 5.23 (q, J =6.8 Hz, 1 H), 4.15 - 4.07 (m, 2H), 3.82 3.72 (m, 2H), 3.14 (br d, J = 11.8 Hz, 1H), 3.05 (dt, J =3.0, 12.2 Hz, 1H), 2.95 (s, 3H), 2.12 -2.00 (m, 1 H), 1.90 (brd, J = 9.5 Hz, 1H), 1.75-1.70 (m, 9H)
F12	xk J\X^XF HO,, χ-\ k^k r 1 \ ,N k J n-4 Y MeY >..·ΟΗ 0-S-O Mewe7 Me (3S,4R)-(re/)-4-[(5-chloro-4-{4- fluoro-2-[(1 R)-1-hydroxyethyl]- 1 -(propan-2-yl)-1 H- benzimidazol-6-yl}pyrimidin-2yl)amino]-1- (methanesulfonyl)piperidin-3-ol	526.9 [M+H]+ (ESI)	1H NMR (400 MHz, CD3OD) δ 8.37 (s, 1H), 8.06 (s, 1H), 7.50 (d, J=11.5 Hz, 1H), 5.34 (m, J = 7.0, 13.9 Hz, 1H), 5.23 (m, J = 6.7 Hz, 1H), 4.00-3.91 (m, 1H), 3.87-3.81 (m, 1H), 3.783.66 (m, 2H), 2.95 (m, J = 2.5, 12.0 Hz, 1H), 2.90 (s, 3H), 2.76 (m, J= 9.5,11.5 Hz, 1H), 2.29 2.20 (m, 1H), 1.75-1.65 (m, 10H)
F13	xk HN N fl “'A Ύν k χ* N-4 V MeY Λ...ΟΗ - 0-S-O Me^e Me (3S,4S)-4-[(5-chloro-4-{4fIuoro-2-[(1 R)-1 -hydroxyethyl]1-(propan-2-yl)-1Hbenzimidazol-6-yl}pyrimidin-2yl)amino]-1(methanesulfonyl)piperidin-3-ol	526.9 [M+H]+ (ESI)	1H NMR (400 MHz, CD3OD) δ 8.37 (s, 1 H), 8.06 (s, 1 H), 7.50 (d, J = 11.6 Hz, 1H), 5.34 (m, J = 6.9,13.9 Hz, 1H), 5.23 (m, J = 6.6 Hz, 1H), 4.00-3.92 (m, 1H), 3.84 (m, J = 1.7, 4.6,11.6 Hz, 1H), 3.79-3.65 (m, 2H), 2.99-2.91 (m, 1H),2.90(s, 3H), 2.80 - 2.67 (m, 1H), 2.28 2.21 (m, 1H), 1.76-1.63 (m, 10H)

248

F14	A F HN N Ti A I1 MeA Xfe O=S=O Me Me (3S,4S)-4-({5-fluoro-4-[4-fluoro2-methy!-1 -(propan-2-yl)-1 Hbenzimidazol-6-yl]pyrimidin-2yl}amino)-1- (methanesulfonyl)piperidin-3-oI	481.2 [M+HJ+ (ESI)	1H NMR (400 MHz, DMSO-d6) 5 8.43 (d, J = 4.0 Hz, 1H), 8.12 (s, 1H), 7.62 (brd, J = 12.3 Hz, 1H), 7.22 (br d, J = 7.0 Hz, 1H), 5.22 (br d, J = 4.3 Hz, 1 H), 4.89 -4.73 (m, 1H), 3.77 (brs, 1H), 3.61 (brd, J = 10.8 Hz, 2H), 3.49 (brs, 1H), 2.91 (s, 3H), 2.89 - 2.82 (m, 1H), 2.71 - 2.64 (m, 1H), 2.63 (s, 3H), 2.09 (br s, 1H), 1.60 (d, J = 6.8 Hz, 6H), 1.52 (brs, 1H).
			1H NMR (700 MHz, DMSO-d6)
	n^A		5 8.42 - 8.34 (m, 2H), 8.21 (br.
	JL HN		s., 1H), 7.65-7.54 (m, 1H),
	HO^/X LA Il \ ,N		7.15 (d, J =7.7 Hz, 1H), 5.22-
F15	k > N— N Me-/ O=S=O MeZL Me	481.1 [M+HJ+	5.07 (m, 1H), 3.77-3.66 (m, 1H), 3.62-3.51 (m, 2H), 3.48-
	(3R,4R)-4-{[4-(1 -fert-butyl-4fluoro-1 H-benzimidazol-6-yl)-5-	(ESI)	3.39 (m, 1H), 2.84 (s, 3H), 2.80 (dt, J = 2.6, 11.7 Hz, 1H), 2.61
	fIuoropyrimidin-2-yl]amino}-1(methanesulfonyl)piperidin-3-ol		(t, J =10.1 Hz, 1H), 2.04 (d, J = 7.3 Hz, 1H), 1.69 (s, 9H), 1.531.42 (m, 1H)

Example F16 (Scheme F-4): Préparation of 1-[(3R,4R)-4-({5-fluoro-4-[4-fIuoro-2-methyl-1(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-3-hydroxypiperidin-1-yl]ethan1-o|ne I

Scheme F-4:

Example A37

Example F16

To a stimng solution of (3R,4R)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1Hbenzimidazol-6-yl]pyrimidin-2-yi}amino)piperidin-3-ol trifluoroacetate (Example A37) (300 mg,

249

0.581 mmol) and triethylamine (226 mg, 0.31 mL, 2.24 mmol) in DCM (5 mL) was added AC2O (152 mg, 0.14 mL, 1.49 mmol). The mixture was stirred at ambient température for 2 h before being diluted with water (10 mL) and extracted with DCM (3x10 mL). The combined organic phases were washed with brine (10 mL), dried over Na₂SO4, filtered, and concentrated. The crude residue was purified by préparative HPLC with an Agela Durashell C18 column (150x25 mm, 5 pm particle size, 25 °C column température), which was eluted with 15-55% MeCN/H2O (+0.05% NH4OH) with a flow rate of 25 mL/min to provide 1-[(3R,4R)-4-({5-fluoro-4-[4-fIuoro-2-methyI-1(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yI}amino)-3-hydroxypiperidin-1-yl]ethan-1-one (Example F16) (22.0 mg, 9% yield) as a white solid. ¹H NMR (400 MHz, DMSO-de) δ 8.43 (br s, 10 1H), 8.13 (brs, 1H), 7.61 (brd, J = 12.0 Hz, 1H), 7.28 - 7.13 (m, 1H), 5.18 - 5.01 (m, 1H), 4.894.75 (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)⁺.

Example F17 (Scheme F-5): Préparation of 1-[(3R,4R)-4-({5-fIuoro-4-[4-fluoro-2-methyl-1(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-3-hydroxypipéridin-1-yl]-2hydroxyethan-1-one

Scheme F-5:

To . (3R,4R)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazoI-6yl]pyrimidin-2-yl}amino)piperidin-3-ol trifluoroacetate (Example A37) (50 mg, 0.12 mmol) and glycolic acid| (9.45 mg, 0.124 mmol) in DMF (4.0 mL) were added dJpEA (48.2 mg, 0.373 mmol) and HATU (70.9 mg, 0.186 mmol). The mixture was stirred at ambient température for 16 h. LCMS analysis showed consumption ofthe starting material with formation ofthe desired product mass. The reaction mixture was washed with H2O (20 mL) and satôrated aqueous NaHCO₃ (20 mL). The combined aqueous layers were extracted with EtOAc (20 mL). The combined organic layers were dried over Na₂SO4, filtered, and concentrated. The residue was purified by préparative HPLC with a DuraShell column (150x25 mm, 5 pm particle size), which was eluted with 12-52% MeCN/H₂O (+0.05% NH₄OH) with a flow rate of 25 mL/min to provide 1-[(3R,4R)-430 ({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazoÎ-6-yl]pyrimidin-2-yl}amino)-3hydroxypiperidin-1-yl]-2-hydroxyethan-1-one (Example F17) (8 mg, 14% yield) as a white solid.

250 ¹H NMR (400 MHz, DMSO-d₆) δ 8.44 (t, J = 4.0 Hz, 1H), 8.14 (brs, 1H), 7.62 (brd, J = 12.0 Hz, 1H), 7.32 - 7.21 (m, 1H), 5.15 (dd, J = 4.8, 9.3 Hz, 1H), 4.83 (hept, J = 6.9 Hz, 1H), 4.56 (t, J = 5.0 Hz, 1H), 4.33 (br d, J = 9.3 Hz, 1H), 4.17 - 4.04 (m, 2H), 4.04 - 3.81 (m, 2H), 3.73 - 3.40 (m, 2H), 3.10 - 2.95 (m, 1H), 2.63 (s, 3H), 2.09 - 1.97 (m, 1H), 1.60 (d, J = 7.0 Hz, 6H),1.48 - 1.33 5 (m, 1 H); m/z (ESI+) for (C22H26F2N6O3), 461.3 (M+H)⁺.

The examples in the below table were synthesized according to the methods used for the synthesis of 1-[(3R,4R)-4-({5-fiuoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6yl]pyrimidin-2-yl}amino)-3-hydroxypiperidin-1-yl]-2-hydroxyethan-1-one (Example F17). The 10 following examples were synthesized with non-critical changes or substitutions to the exemplified procedures that someone who is skilled in the art would be able to realize.

251

Example number	Structure/Name	LCMS	NMR
F18	N-YCI A hn nYV HCLxk AA Il \ ,N L J N—/ N Me-γ /-A0 _Me O-J [(3R,4R)-4-({5-chloro-4-[4- fluoro-1-(propan-2-yl)-1 Hbenzimidazol-6-yl]pyrimidin-2yl}amino)-3-hydroxypiperidin-1yl](oxetan-3-yl)methanone	488.9 [M+H]+ (ESI)	1H NMR (400 MHz, DMSO-de) δ 8.52 (s, 1H), 8.43 (d, J = 4.8 Hz, 1H), 7.91 (brs, 1H), 7.427.40 (m, 2H), 5.24-5.11 (m, 1H), 4.88 - 4.77 (m, 1H), 4.76 4.58 (m, 4H), 4.41 - 3.95 (m, 4H), 3.93 - 3.83 (m, 1H), 3.10 2.84 (m, 1H), 2.67-2.56 (m, 1H), 1.95-1.93 (m, 1H), 1.57 (d, J =6.8 Hz, 6H), 1.34-1.32 (m, 1H)
F19	n O HN^ HO^xk SA oA^o V Me [(3R,4R)-4-( fluoro-1-(prc benzimidazolyl}amino)-3-hy yl](3-mett yl)me	^Cl N tX \An N— Me—γ Me [5-chloro-4-[4- >pan-2-yl)-1H6-yl]pyrimidin-2droxypiperidin-1iyloxetan-3thanone	502.9 [M+H]+ (ESI)	1H NMR (400 MHz, DMSO-de) δ 8.54 (s, 1H), 8.44 (s, 1H), 7.91 (brs, 1H), 7.64-7.35 (m, 2H), 5.26 - 5.12 (m, 1H), 4.89 4.71 (m, 3H), 4.38-4.07 (m, 3H), 3.95 - 3.83 (m, 1H), 3.58 3.38 (m, 1H), 3.12-2.94 (m, 1H), 2.92 - 2.79 (m, 1H), 2.66 2.57 (m, 1H), 2.08-1.89 (m, 1H), 1.58 (s, 3H), 1.57-1.49 (m, 6H), 1.44-1.30 (m, 1H) I
F20	Nx HN HO^A. Me-Ao ÔH . (2R)-1-[(3R,4F [4-chloro-1-(p benzimidazol-	Αχ” N— Me—γ Me ?)-4-({5-chloro-4- ropan-2-yl)-1H- 6-yl]pyrimidin-2-	515.1 [M+Na]+ (ESI)	1H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 8.48 - 8.36 (m, 1H), 8.04 (s, 1H), 7.67 (s, 1H), 7.55 (brs, 1H), 5.15 (brd, J = 30.2 Hz, 1H), 4.98-4½ (m, 2H), 4.51-3.80 (m, 5H), 3.18 -2.83 (m, 1H), 1.98 (s, 1H), 1.57 (d, J=6.7 Hz, 6H), 1.491.26 (m, 2H), 1.18 (dd, J = 9.2, 6.5 Hz, 3H)

252

	yl}amino)-3-hydroxypiperidin-1 yl]-2-hydroxypropan-1-one
F21	N-VCI A HN N q, ««.A IA Il \ N k J N— N Me—/ Me^AQ Me Me OH (2S)-1-[(3R,4R)-4-{[4-(1-tertbutyl-4-fluoro-1 H-benzimidazol6-yl)-5-chloropyrimidin-2yl]amino}-3-hydroxypiperidin-1yl]-2-hydroxypropan-1 -one	490.9 [M+H]+ (ESI)	1H NMR (400 MHz, DMSO-cfe) δ 8.43 (s, 2H), 8.29- 7.90 (m, 1H), 7.72-7.12 (m, 2H), 5.13 (brs, 1H), 4.96 (brd, J = 6.7 Hz, 1H), 4.49-4.13 (m,2H), 4.09 - 3.84 (m, 2H), 3.50 - 3.46 (m, 1H), 3.17-2.76 (m, 2H), 2.08-1.92 (m, 1H), 1.74 (s, 9H), 1.51-1.27 (m, 1H), 1.19 (brt, J =7.5 Hz, 3H)
F22	JOA ΗΝ'^Άίι^ HO.^k nLA il \ /N TT Me—7^ [ΆΟ Me Me OH 1 -[(3R,4R)-4-{[4-(3-tert-butyl3H-imidazo[4,5-b]pyridin-5-yl)5-chloropyridin-2-yl]amino}-3hydroxypiperidin-1 -yl]-2hydroxyethan-1-one I	459.0 [M+H]+ (ESI)	1H NMR (500 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.20-8.20 (m, 1H), 8.20-8.20 (m, 1H), 8.19 (d, J =8.2 Hz, 1H), 8.11 (d, J = 4.9 Hz, 1H), 7.54 (d, J =8:4 Hz, 1H), 6.98-6.90 (m, 1H), 6.82 (d, J =9.3 Hz, 1H), 5.20 (dd, J = 4.7,11.2 Hz, 1H), 4.55 (t, J = 5.2 Hz, 1H), 4.17-4.06 (m, 2H), 3.87 (brd, J =13.7 Hz, 1H), 3.68-3.58 (m, 1H), 3.19 (brt, J = 9.6 Hz, 1H), 3.12 -3.00 (m, 1H), 2.09-2.00 (m, 1H), 1.84-1.77 (m, 9H), 1.371.27 (m, 1 H)

Example F23 (Scheme F-6): Préparation of 1-[(3/?,4/?)-4-({5-fIuoro-4-[4-fluoro-2-methyl-1(propan-2-yl)-1 W-benzimidazol-6-yl]pyrimidin-2-yl}amino)-3-hydroxypiperidin-1 -y l]-25 (methylamino)ethan-l-one .....

Scheme F-6:

To a solution of (F-2) (prepared as in Example F17, 160 mg, 0.279) in DCM (10.0 mL) and TFA (10.0 mL). The mixture was stirred at ambient température for 1 h. LCMS analysis showed consumption of the starting material with formation of the desired product mass. The 5 reaction solution was concentrated to dryness. The residue was taken up in MeOH (5 mL) and treated with ΝΗ3Ή2Ο to adjust to pH -7-8. The solution was concentrated. The residue was purified by préparative HPLC with a DuraShell column (150x25 mm, 5 pm particle size), which was eluted with 22-42% MeCN/H₂O (+0.05% NH₄OH) with a flow rate of 25 mL/min to provide 1[(3R,4R)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-210 y|}amino)-3-hydroxypiperidin-1-yl]-2-(methylamino)ethan-1-one (Example F23) (35.2 mg, 27% yield) as a white solid. ¹H NMR (400 MHz, DMSO-cfe) δ 8.43 (t, J = 4.1 Hz, 1H), 8.13 (br s, 1H), 7.61 (brd, J=12.1 Hz, 1H), 7.31-7.11 (m, 1H), 5.10 (brd, J = 4.5 Hz, 1H), 4.82 (td, J= 6.8,13.8 Hz, 1H), 4.11 - 3.65 (m, 3H), 3.60 - 3.38 (m, 2H), 3.26 - 2.98 (m, 3H), 2.70 - 2.53 (m, 4H), 2.27 (d, J = 1.3 Hz, 3H), 2.02 (br s, 1H), 1.59 (d, J = 6.8Hz, 6H), 1.45 - 1.29 (m, 1H); m/z (ESI+) for 15 (C₂₃H₂₉F₂N₇O₂), 474.5 (M+H)⁺.

The examples in the below table were synthesized according to the methods used for the synthesis of 1-[(3R,4R)-4-({5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6yl]pyrimidin-2-yl}amino)-3-hydroxypiperidin-1-yl]-2-(methylamino)ethan-1-one (Example F23).

The following examples were synthesized with non-critical changes or substitutions to the exemplified procedures that someone who is skilled in the art would be able to realize. If necessary, séparation of the enantiomers was iarried out under standard methods known in the art, such as chiral SFC or HPLC, to afford single enantiomers.

Example number

Structure/Name j __________________________________________________________________________________i

LCMS

NMR

254

F24	N-yc' H0^< Tl \ ,N LJ N— N Me—/ Me ,, -NH Me 1 -[(3R,4R)-4-({5-chloro-4-[4fluoro-1-(propan-2-yl)-1 H- benzimidazol-6-yl]pyrimidin-2yl}amino)-3-hydroxypiperidin-1yl]-2-(methylamino)ethan-1-one	476.2 [M+H]+ (ESI)	1H NMR (400 MHz, DMSO-d6) 5 8.53 (s, 1H), 8.44 (d, J =5.3 Hz, 1 H), 7.90 (brs, 1H), 7.977.84 (m, 1H), 7.61-7.36 (m, 2H), 5.10 (brs, 1H), 4.82 (td, J = 6.7, 13.3 Hz, 1H), 4.35 (brd, J = 12.5 Hz, 1H), 4.04-3.80 (m, 2H), 3.75 (br d, J = 9.8 Hz, 1H), 3.51 (brs, 1H), 3.10-2.94 (m, 2H), 2.58 (brt, J = 11.3 Hz,1H), 2.28 (d, J =2.0 Hz, 3H), 1.90 (s, 1H), 1.56 (d, J = 6.7 Hz, 6H), 1.38 (brd, J = 17.2 Hz, 1H)
F25	N^<CI hcx^\ L^\ L J N— N Me-/ Ao Μθ Me „ zNH Me 1 -[(3R,4R)-4-{[4-(1 -tert-butyl-4fluoro-1 H-benzimidazol-6-yl)-5chloropyrimidin-2-yl]amino}-3hydroxypiperidin-1 -yl]-2(methylamino)ethan-l-one	512.2 [M+Na]+ (ESI)	1H NMR (400 MHz, D2O) 5 9.43 -9.31 (m, 1H), 8.43 (s, 1H), 8.31 (brs, 1H), 7.77 (brd, J = 10.8 Hz, 1H), 4.46-3.98 (m, 4H), 3.85 - 3.56 (m, 2H), 3.32 2.82 (m, 2H), 2.76 (d, J =3.0 Hz, 3H), 2.15-2.14 (m, 1H), 1.84 (s, 9H), 1.60-1.59 (m, 1H)
F26	nV' JL HN N ]|Y ho.â UA L J N— N Me-γ Me Me HN^ [(3R,4R)-4-{[4-(1-tert-butyl-4fluoro-1 H-benzimidazol-6-yl)-5chloropyrimidin-2-yl]amino}-3hydroxypiperidin-1-yl](3fIuoroazetidin-3-yl)methanone	520.Ô [M+H]+ (ESI)	1H NMR (500 MHz, CD3OD) 5 8.42-8.17 (m, 2H), 8.04 (s, 1H), 7.42 (d, J = 11.4 Hz, 1H), 4.40 - 3.88 (m, 4H), 3.84 3.45 (m, 4H), 3.15-2.67 (m, 2H), 2.09 (d, J =13.4 Hz, 1H), 1.72 (s, 9H), 1.50-1.36 (m, 1H)

255

F27	N^YC' JL „F hn nV y AA L J N— N Me—/ jA0 Me HN3 [(3R,4R)-4-({5-chloro-4-[4fluoro-1-(propan-2-yl)-1Hbenzimidazol-6-yl]pyrimidin-2yl}amino)-3-hydroxypiperidin-1 yl](3-fluoroazetidin-3yl)methanone	506.1 [M+H]+ (ESI)	1H NMR (500 MHz, DMSO-de) 5 8.45 (s, 1H), 8.35 (s, 1H), 7.82 (br s, 1H), 7.55 - 7.04 (m, 2H), 5.13 (dd, J = 21.1, 4.8 Hz, 1H), 4.75 (p, J =6.7 Hz, 1H), 4.27 - 3.74 (m, 4H), 3.70 3.35 (m,4H), 3.09-2.62 (m, 2H), 1.96 (brs, J =33.6 Hz, 1H), 1.49 (d, J = 6.7 Hz, 6H), 1.43-1.23 (m, 1H)
F28	N^C' HnA^A'^A HO^^k AA Il T .N L J N-^ N Me—/ Z^Aq Me nh2 (1 -aminocyclopropyl)[(3R,4R)4-({5-chloro-4-[4-fluoro-1 (propan-2-yl)-1 H-benzimidazol6-yl]pyrimidin-2-yl}amino)-3hydroxypiperidin-1yl]methanone	488.1 [M+H]+ (ESI)	1H NMR (500 MHz, DMSO-d6) 5 8.52 (s, 1H), 8.43 (s, 1H), 7.90 (brs, 1H), 7.59-7.21 (m, 2H), 5.20 (br s, 1H), 4.82 (td, J = 6.7, 13.4 Hz, 1H), 4.25 (brd, J =10.2 Hz, 1H), 4.17-3.94 (m, 1H), 3.88 (brdd, J =3.2, 8.1 Hz, 1H), 3.49 (brd, J =3.4 Hz, 1H), 3.03 (brs, 1H), 2.372.19 (m, 2H), 1.97 (brs, 1H), 1.56 (d, J =6.6 Hz, 6H), 1.461.24 (m, 1H), 0.79 (brs, 2H), 0.71 - 0.53 (m, 2H)
1 1 1 F29 I	N^CI A A^^^f HN^N'^V HO. A LA Il \ ,N L J N— N Me—/ f v nh2 (1-amino-3,3- difluorocyclobutyl)[(3R,4R)-4({5-chloro-4-[4-fluoro-1(propan-2-yl)-1 /7-benzimidazol6-yl]pyrimidin-2-yl}amino)-3-	538.0 [M+H]+ (ESI)	1H NMR (400 MHz, DMSO-d6) δ |δ.54 (s, IH), 8.44 (s, 1H), 7.91 (br s, 1 H), 7.56 - 7.32 (m, 2H), 5.18 (d, J =70.6 Hz, 1H), 4.83 (p, J= 6.8 Hz, 1H), 4.42 3.76 (m, 3H), 3.51 (d, J = 65.9 Hz, 1H), 3.25-2.92 (m, 3H), 2.64-2.55 (m, 3H), 2.48- 2.42 (m, 1H), 1.99 (s, 1H), 1.57 (d, J = 6.7 Hz, 6H), 1.52-1.30 (m, 1H)

256

	hydroxypiperidin-1yl]methanone
F30	N-YC' A-^Lx^xF HN N [|Y ΗΟ^χΑ L-Y Tl \ ,N k ,J N— N Me—/ F>/\Yo Me Me F v nh2 (1-amino-3,3difluorocyclobutyI)[(3R,4R)-4{[4-(1 -tert-butyl-4-fluoro-1 Hbenzimidazol-6-yl)-5- chloropyrimidin-2-yl]amino}-3hydroxypiperidin-1yl]methanone	552.2 [M+H]+ (ESI)	1H NMR (500 MHz, CD3OD) δ 8.27 (d, J =5.1 Hz, 2H), 8.04 (s, 1H), 7.42 (d, J = 11.4 Hz, 1 H), 4.01 -3.43 (m, 4H), 3.16 - 3.04 (m, 3H), 2.75 - 2.37 (m, 3H), 2.14-2.01 (m, 1H), 1.72 (s, 9H), 1.48 (s, 1H)
F31	A Y/^xF Hy N ΗΟ»^χ< *k/k Il \ ,N Me— Ao Me f3ct ''nh2 (3S)-3-amino-1 -[(3R,4R)-4-({5chloro-4-[4-fluoro-1-(propan-2yl)-1 H-benzimidazol-6yl]pyrimidin-2-yl}amino)-3hydroxypiperidin-1 -yl]-4,4,4trifluorobutan-1 -one	544.0 [M+H]+ (ESI)	1H NMR (500 MHz, DMSO-d6) 5 8.45 (s, 1H), 8.41-8.28 (m, 1H), 7.83 (brs, 1H), 7.65-7.26 (m, 2H), 5.03 (dd, J =4.7,12.5 Hz, 1H), 4.75 (td, J =6.7, 13.4 Hz, 1H), 4.40-3.28 (m, 5H), 3.12 - 2.98 (m, 1H), 2.55 - 2.45 (m, 2H), 1.89 (br s, 3H), 2.02 1.79 (m, 1H), 1.50 (s, 6H), 1.36 -1.^1 (m, 1H)
F32	i ΗΝ^/ΥΥ i ho*/\ YY I Il \ ,N k J N— N Me—/ AÂO Me Me A 3-amino-1-[(3R,4R)-44[4-(1- tert-butyl-4-fluoro-1 H-	525.3 [M+HJ+ (ESI)	1H NMR (400 MHz, DMSO-cfe) δ 8.38 (s, 1H), 8.08 (s, 1H), 7.69 (s, 1H), 7.12 (d, J= 11.4 Hz, 1H), 6.90-6.83 (m, 1H), 6.65 (s, 1H), 5.30 (brs, 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, J =

257

benzimidazol-6-yl)-5chloropyridin-2-yl]amino}-3hydroxypiperidin-1-yl]-2,2difluoropropan-1-one

12.7 Hz, 1H), 1.72 (s, 9H), 1.39 -1.23 (m, 1H)

Example F33 (Scheme F-7): Préparation of 2-[(3R,4R)-4-{[4-(3-tert-butyI-3H-imidazo[4,5b]pyridin-5-yl)-5-chIoropyridin-2-yl]amino}-3-hydroxypiperidin-1-yl]-N-methyIacetamide

Scheme F-7:

To a solution of (3R,4R)-4-{[4-(3-tert-butyl-3H-imidazo[4,5-b]pyridin-5-yl)-5-chloropyridin2-yl]amino}piperidin-3-ol (Prepared as in Example D3, 100 mg, 0.249 mmol) in EtOH (6.0 mL) was added 2-bromo-N-methylacetamide (56.7 mg, 0.374 mmol) and a solution of saturated aqueous NaHCO₃ (3.0 mL). The mixture was stirred at 70 “C for 16 h. TLC analysis (1:3 MeOH/EtOAc) indicated consumption of the starting material. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (20 mL). The organic layer was dried over Na₂SO4, filtered, and concentrated. The residue was purified by préparative HPLC with a DuraShell column (150x25 mm, 5 pm particle size), which was eluted with 21-41% MeCN/H₂O (+0.05% NH4OH) with a flow rate of 25 mL/min to provide 2-[(3R,4R)-4-{[4-(3-terf-butyl-3H-imidazo[4,5-b]pyridin-5yl)-5-chloropyridin-2-yl]amino}-3-hydroxypiperidin-1-yl]-A/-methylacetamide (Example F33) (45.5 mg, 39% yield) as a white solid. ¹H NMR (500 MHz, DMSO-ds) δ 8.54 (s, 1H), 8.17 (d, J= 8.4 Hz, 1H), 8.07 (s, 1H), 7.72 (br i, J = 4.6 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 6.85 - 6.80 l(m, 2H), 4.91 (d, J = 5.6 Hz, 1 H), 3.60 - 3.49 (m, 2H), 2.91 (d, J = 2.0 Hz, 2H), 2.89 - 2.85 (m, 1 H), 2.68 (br d,

J =11.1 Hz, 1H), 2.62 (d, J = 4.7 Hz, 3H), 2.18 -2.09 (m, 1H), 2.06 - 1.98 (m, 2H), 1.80(s, 9H),

1.50 - 1.39 (m, 1 H); m/z (ESI+) for (C₂3H₃oClN₇02), 472.2 (M+H)⁺. '

Example G1 (Scheme G-1): 1-[6-(5-chloro-2-{[(3R,4R)-3-hydroxy-1(methanesulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1H25 benzimïdazol-2-yl]ethan-1-one

Scheme G-1:

258

nh₂

Example G1

Step 1: Synthesis of 1-[6-(2,5-dichloropyrimidin-4-yl)-4-fIuoro-1-(propan-2-yl)-1Hbenzimidazol-2-yl]ethan-1-one (G-2)

To a solution of 1-[6-(2,5-dichloropyrimidin-4-yI)-4-fluoro-1-(propan-2-yl)-1H5 benzimidazol-2-yl]ethan-1-ol (G-1) (Prepared as in Example A1, 500 mg, 1.35 mmol) in CHCI3 (10 mL) was added MnÛ2 (824 mg, 9.48 mmol). The mixture was stirred at 50 °C for 6 h. LCMS analysis showed consumption ofthe starting material with formation ofthe desired product mass. The mixture was filtered and concentrated. The residue was purified by flash chromatography (Biotage, SiO₂,25% EtOAc/petroleum ether) to provide 1-[6-(2,5-dichloropyrimidin-4-yl)-4-fluoro10 1-(propan-2-yl)-1/7-benzimidazol-2-yI]ethan-1-one (G-2) (480 mg, 97% yield) as a white solid. ¹H NMR (400 MHz, CDCI3) 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 (C16H13CI2FN4O), 3|67.0 (M+H)⁺.

Step 2: Synthesis of 1-[6-(5-chloi-o-2-{[(3R,4R)-3-hydroxy-1-(methanesulfonyl)piperidin-4yl]amino}pyrimidin-4-yl)-4-fluoro-jl-(propan-2-yl)-1H-benzimidazoI-2-yl]ethan-1-one । (Example G1) . _ __________ _

To a solution of 1-[6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1Hbenzimidazol-2-yl]ethan-1-one (G-2) (100 mg, 0.272 mmol) in DMSO (5.0 mL) was added DIPEA (106 mg, 0.817 mmol) and (3R,4R)-4-amino-1-(methanesulfonyl)piperidin-3-ol (lnt-69). The mixture was stirred at 70 °C for 16 h. LCMS analysis showed consumption of the starting material with formation of the desired product mass. The mixture was diluted with H2O (30 mL) and

259 extracted with EtOAc (2x30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by préparative TLC (S1O2, 50% EtOAc/petroleum ether, R_f = 0.4) to provide 1-[6-(5-chloro-2-{[(3R,4R)-3-hydroxy-1-(methanesulfonyl)piperidin-4yl]amino}pyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]ethan-1-one (Example 5 G1) (58.2 mg, 41% yield) as a white solid. ¹H NMR (400 MHz, DMSO-cfe) δ 8.47 (s, 1H), 8.21 8.03 (m, 1H), 7.67 - 7.41 (m, 2H), 5.86 - 5.72 (m, 1H), 5.23 (d, J = 4.6 Hz, 1H), 3.88 - 3.75 (m, 1H), 3.68 - 3.56 (m, 2H), 3.53 - 3.44 (m, 1H), 2.90 (s, 3H), 2.87 - 2.81 (m, 1H), 2.79 (s, 3H), 2.66 - 2.60 (m, 1H), 2.14 -1.98 (m, 1H), 1.61 (d, J = 7.0 Hz, 6H), 1.57 -1.45 (m, 1H); m/z (ESI+) for (C22H26CIFN6O4S), 525.2 (M+H)⁺.

260

Example H1 (Scheme H-1): Préparation of 1,5-anhydro-3-({5-chIoro-4-[2-(chloromethyl)-4fIuoro-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amlno)-2,3-dideoxy-D-tbreopentitol ’

Scheme H-1:

APrNH₂ Cs₂CO3

THF

98% yield

no₂ ^Na2S2°⁴

Me^NH EtOH, H₂O, 80 °C Me A-16 46% yield

Me p-TSA, DHP THF, 90 ’C

PdCI₂(dppf) KOAc, B₂Pin₂

1,4-dioxane, 80 °C

73% yield

73% yield

DIPEA DMSO, 120 C

56% yield

MsCI, TEA DCM

96% yield

261

Step 1: Synthesis of 5-bromo-3-fIuoro-2-nitro-A/-(propan-2-yI)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 /-PrNH2 (8.7 g, 147 mmol) and CS2CO3 (57.5 g, 176 mmol). The mixture was stirred at room température for 16 h. LCMS analysis showed consumption ofthe starting material 5 with formation of the desired product mass. The reaction was diluted with H2O (300 mL) and extracted with EtOAc (3x300 mL). The combined organic layers were washed with brine, dried over Na2SÛ4, filtered, and concentrated to provide 5-bromo-3-fluoro-2-nitro-/V-(propan-2yl)aniline (A-16) (40.0 g, 98% yield) as a red solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.09 - 6.98 (m, 2H), 6.89 (dd, J = 1.9,11.1 Hz, 1H), 6.17 (s, 1H), 3.88 (brd, J =7.5 Hz, 1H), 1.19 (d, J = 6.4 10 Hz, 6H); m/z (ESI+) for (CgHioBrFN₂02), 276.7 (M+H)⁺.

Step 2: Synthesis of [6-bromo-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]methanol (H1)

To a solution of 5-bromo-3-fIuoro-2-nitro-/V-(propan-2-yl)aniline (A-16) (40.0 g, 144 mmol) 15 in EtOH/H2O (4:1,700 mL) was added 1,4-dioxane-2,5-diol (20.8 g, 173 mmol) and Na2S2O4 (126 g, 722 mmol). The mixture was stirred at reflux for 80 °C for 16 h. LCMS analysis showed consumption ofthe starting material with formation ofthe desired product mass. The mixture was diluted with H₂O (100 mL) and extracted with EtOAc (3x300 mL). The combined organic layers were washed with saturated aqueous NaHCOs, dried over Na2SO4, filtered, and concentrated. 20 The crude residue was purified by flash chromatography (S1O2, 0-100% EtOAc/petroleum ether) to provide [6-bromo-4-fIuoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]methanol (H-1) (19.0 g, 46% yield) as a white solid. ¹H 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 (CiiHi2BrFN₂O), 286.8 (M+H)⁺.

Step 3: Synthesis of 6-bromo-4-fluoro-2-{[(oxan-2-yl)oxy]methyl}-1-(propan-2-yl)-1Wbenzintadazole (lnt-20)I

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)was added p-TSA (1.7 g, 6.62 mmol) and DHP (22.3 g, 265 II mmol)J The mixture was stirred at 90 °C for 4 h. LCMS analysis showed consumption of the i ‘.

starting material with formation of the desired product mass. The reaction was diluted with H2O (100 mL) and extracted with EtOAc (3x150 mL). The combined organic layers were dried over

Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (S1O2, ΟΙ 00% EtOAc/petroleum ether) to provide 6-bromo-4-fluoro-2-{[(oxan-2-yl)oxy]methyl}-1-(propan35 2-yl)-1H-benzimidazole (lnt-20) (18.0 g, 73% yield) as a pale yellow solid. ¹H NMR (400 MHz,

DMSO-d₆) 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 19876

262

4.68 (m, 2H), 3.83 - 3.71 (m, 1H), 3.57 - 3.46 (m, 1H), 1.72 - 1.63 (m, 2H), 1.57 (d, J = 6.8 Hz,

6H), 1.53-1.46 (m,4H); m/z (ESI+) for (C₁₆H₂₀BrFN₂O₂), 372.6 (M+H)⁺.

Step 4: Synthesis of 4-fIuoro-2-{[(oxan-2-yl)oxy]methyl}-1-(propan-2-yl)-6-(4,4,5,55 tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazole (H-2)

To a suspension of 6-bromo-4-fluoro-2-{[(oxan-2-yl)oxy]methyl}-1-(propan-2-yl)-1Hbenzimidazole (H-2) (8.0 g, 21.6 mmol), B₂Pin₂ (6.6 g, 25.9 mmol), and KOAc (6.3 g, 64.6 mmol) in 1,4-dioxane (160 mL) was added PdCI₂(dppf) (0.788 g, 1.08 mmol) under N₂. The mixture was stirred at 80 ^eC under N₂ for 16 h. LCMS analysis indicated consumption of the starting material 10 with formation of the desired product mass. The mixture was cooled to room température, filtered through celite, and concentrated to dryness. The residue was taken up in H₂O (150 mL) and extracted with EtOAc (3x150 mL). The combined organics were washed with brine, dried over Na₂SO4, filtered, and concentrated. The residue was purified by flash chromatography (360 g SiO₂, 0-100% EtOAc/petroleum ether) to provide 4-fluoro-2-{[(oxan-2-yl)oxy]methyl}-1-(propan15 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 (C₂₂H₃₂BFN₂O4), 419.1 (M+H)⁺.

Step 5: Synthesis of 6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-2-{[(oxan-2-yl)oxy]methyl}-1(propan-2-yl)-1H-benzimidazole (H-3)

A mixture of 4-fluoro-2-{[(oxan-2-yl)oxy]methyl)-1-(propan-2-yl)-6-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)-1H-benzimidazole (H-2) (6.0 g, 14.3 mmol), 2,4,5-trichIoropyrimidine (3.95 g, 21.5 mmol), and K₂CO₃ (3.96 g, 28.7 mmol) in 1,4-dioxane (90 mL) and H₂O (30 mL) was degassed with N₂ for 5 min. Pd(PPh₃)4 (829 mg, 0.717 mmol) was added and the mixture was degassed for an additional 10 min. The reaction was stirred at 90 °C under N₂ for 16 h. LCMS 25 analysis showed consumption of the starting material with formation of the desired product mass.

The reaction was cooled to room température, diluted with H₂O (30 mL), and extracted with EtOAc (3x100 mL). Th^ combined organic layers were washed with brine, dri^d over Na₂SO4, filtered, and concentrated. The residue was purified by flash chromatography (40 g SiO₂, 0-60% EtOAc/petroleum ether) to provide 6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-2-{[(oxan-230 yI)oxy]methyl}-1-(propan-2-yl)-1H-benzimidazole (H-3) (7.4 g, 99% yield) as a white solid. m/z (ESI+) for (C₂₂H₃₂BFN₂O₄), 461.0 (M+H)⁺. i

Step 6: Synthesis of 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-{[(oxan-2-yl)oxy]methyl}-1(propan-2-yl)-1H-benzïmidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol (H35 4)

263

To a solution of 6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-2-{[(oxan-2-yl)oxy]methyl}-1(propan-2-yl)-1H-benzimidazole (H-3) (2.3 g, 19.8 mmol) in DMSO (150 mL) was added DIPEA (10.6 g, 82.4 mmol) and 3-amino-1,5-anhydro-2,3-dideoxy-D-f/7reo-pentitol (7.2 g, 16.5 mmol). The mixture was stirred at 120 °C for 16 h. LCMS analysis showed consumption of the starting 5 material with formation of the desired product mass. The reaction solution was diluted with H₂O (200 mL) and extracted with EtOAc (3x200 mL). The combined organic layers were washed with brine, dried over Na₂SO4, filtered, and concentrated. The residue was purified by flash chromatography (360 g SiO_2l 0-10% MeOH/DCM) to provide 1,5-anhydro-3-({5-chloro-4-[4fluoro-2-{[(oxan-2-yl)oxy]methyl}-1-(propan-2-yl)-1/-/-benzimidazol-6-yl]pyrimidin-2-yl}amino)10 2,3-dideoxy-D-f/7reo-pentitol (H-4) (4.8 g, 56% yield) as a yellow solid. m/z (ESI+) for (C₂₅H3iCIFN₅O4), 520.1 (M+H)⁺.

Step 7: Synthesis of 1,5-anhydro-3-({5-chloro-4-[4-fiuoro-2-(hydroxymethyl)-1-(propan-2yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-t/ireo-pentitoi (H-5)

To a solution of 1,5-anhydro-3-({5-chloro-4-[4-fIuoro-2-{[(oxan-2-yl)oxy]methyl}-1(propan-2-yl)-1 H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-f/7neo-pentitol (H-4) (4.7 g, 9.2 mmol) in MeOH (40.0 mL) was added a solution of HCl (4 N in 1,4-dioxane, 10.0 mL) dropwise at 0 °C. The solution was stirred at 20 °C for 1 h. LCMS analysis showed consumption ofthe starting material with formation ofthe desired product mass. The reaction mixture was concentrated to dryness. The residue was purified by flash chromatography (80 g SiO₂, 1:10 MeOH/DCM) to provide 1,5-anhydro-3-({5-chloro-4-[4-fIuoro-2-(hydroxymethyl)-1-(propan-2-yl)1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-f/7reo-pentitol (H-5) (3.2 g, 80% yield) as a yellow oil. ¹H NMR (400 MHz, CD₃OD) δ 1.77 - 1.78 (m, 1 H) 1.80 (dd, J = 6.90, 2.89 Hz, 5H) 2.06 - 2.16 (m, 1 H) 3.18 - 3.27 (m, 1 H) 3.44 - 3.54 (m, 1 H) 3.65 (s, 1 H) 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, 1 H) 8.36 (s, 1 H) 8.49 (s, 1 H); m/z (ESI+) for (C₂₀H₂₃CIFN₅O₃), 436.2 (M+H)⁺.

Step 8: Synthesis of 1,5-anhydro-3-({5-chloro-4-[2-(chloromethyl)-4-fluoro-1-(propan-2-yl)1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-f/jreo-pentitol (H-6)

To a solution of1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(hydroxymethyl)-1-(propan-2-yl)1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-f/)reo-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 with methanesulfonyl chloride (328 mg, 2.2 mmol)Tlropwise. The mixture was stirred at ambient température for 3 h. LCMS analysis showed consumption of the starting material.

Reaction was washed with H₂O. The aqueous layer was extracted with DCM (3x10 mL). The combined organics were washed with brine, dried over Na₂SO4, filtered, and concentrated to

264 provide 1,5-anhydro-3-({5-chIoro-4-[2-(chloromethyl)-4-fIuoro-1-(propan-2-yl)-1H-benzimidazol6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol (H-6) (800 mg, 96% yield), which was taken on without further purification, m/z (ESI+) for (C20H22CI2FN5O2), 454.1 (M+H)⁺.

265

Step 9: Synthesis of 1,5-anhydro-3-[(5-chloro-4-{4-fluoro-2-[(3-hydroxy-3-methylazetîdin1-yI)methyl]-1-(propan-2-yI)-1H-benzimidazol-6-yl}pyrimidin-2-yl)amino]-2,3-dideoxy-Dfhreo-pentitol (Example H1)

To a solution of 1,5-anhydro-3-({5-chloro-4-[2-(chloromethÿl)-4-fluoro-1-(prôpan-2-yl)-1H5 benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-fhreo-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), Nal (33.0 mg, 0.22 mmol) and DIPEA (142 mg, 1.1 mmol). The mixture was stirred under an atmosphère of N₂ at 25 °C for 3 h. LCMS analysis showed consumption of the starting material with formation of the desired product mass. The reaction solution was washed with H₂O (5 mL). The aqueous layer 10 was extracted with DCM (3x5 mL). The combined organic layers were washed with brine (10 mk), dried over Na₂SO4, filtered, and concentrated. The crude residue was purified by préparative HPLC with a YMC Triart column (30x150 mm, 7 pm particle size), which was eluted with 30-50% MeCN/H₂O (+0.05% NH4OH) with a flow rate of 25 mL/min to provide 1,5-anhydro-3-[(5-chloro4-{4-fluoro-2-[(3-hydroxy-3-methylazetidin-1 -yl)methyl]-1 -(propan-2-yl)-1 H-benzimidazol-615 yl}pyrimidin-2-yl)amino]-2,3-dideoxy-D-t/?reo-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, 1 H), 1.46 (s, 3H); m/z (ESI+) for (C₂4H₃₀CIFN₆O₃), 505.2 (M+H)⁺.

The examples in the below table were synthesized according to the methods used for the synthesis of 1,5-anhydro-3-({5-chloro-4-[2-(chloromethyl)-4-fluoro-1-(propan-2-yl)-1/7benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-f/7reo-pentitol (Example H1). The 25 following examples were synthesized with non-critical changes or substitutions to the exemplified procedures that someone who is skilled in the art would be able to realize.

Example number	Structure/Name	LCMS	NMR......
H2	A HN N ]| | HO^>< JA Il ' //N N—\ Me O Me—/ \ - - . .....: \ - —N%	463.1 [M+H]+	1H NMR (400 MHz, CD3OD) δ 8.37 (s, 1H) 8.06 (s, 1H) 7.52 (d, J = 11.5Hz, 1H) 5.25-5.18 (m, 1 H) 3.88 -4.06 (m, 3H)
--	Me Me 1,5-anhydro-3-[(5-chloro-4-{2[(dimethylamino)methyl]-4fluoro-1 -(propan-2-yl)-1 H-	(ESI)	3.80 (s, 2H) 3.63 (m, 1 H) 3.36 - 3.54(m, 1H) 3.16 - 3.29 (m, 1H) 2.31 (s, 6H) 2.03 - 2.20 (m, 1H)

266

	benzimidazol-6-yl)pyrimidin-2yl)amino]-2,3-dideoxy-D-f/jreopentitol		1.69 (d, J =7.0 Hz, 6H)1.58- 1.67 (m,1H)
H3	A x\^F ΗΟ^χ\ AA Il ' //N k^x1 N—Y Λ ο Μθ^ Λ,/^οη Me v 1,5-anhydro-3-[(5-chloro-4-{4fluoro-2-[(3-hydroxyazetidin-1 yl)methyl]-1-(propan-2-yl)-1Hbenzimidazol-6-yI}pyrimidin-2yl)amino]-2,3-dideoxy-D-t/7reopentitol	491.1 [M+HJ+ (ESI)	1H NMR (400 MHz, CD3OD) δ 8.35 (s, 1H), 8.02 (s, 1H), 7.49 (d, J=11.4 Hz, 1H), 5.16-5.06 (m, 1H), 4.35 (t, J =6.2 Hz, 1H), 4.01 - 3.89 (m, 5H), 3.66 3.57 (m, 3H), 3.48 (dt, J =2.1, 11.7 Ηζ, ΊΗ), 3.20 (dd, J = 9.7, 11.1 Hz, 1H), 3.11-3.05 (m, 2H), 2.18-2.09 (m, 1H), 1.68 (d, J = 7.0 Hz, 6H), 1.66-1.58 (m, 1H)
H4	Jk -JAxïî^F HN HC^xk AA Il ' Z/N k x* N-X . „ . O Me-γ V^Me Me V OH Me 1,5-anhydro-3-({5-chloro-4-[4fluoro-2-{[(2S,3R)-3-hydroxy2,3-dimethylazetidin-1- yl]methyl}-1 -(propan-2-yl)-1 Hbenzimidazol-6-yl]pyrimidin-2yl}amino)-2,3-dideoxy-D-fbreopentitol	519.3 [M+H]+ (ESI)	1H NMR (400 MHz, CD3OD) δ 8.35 (s, 1H), 8.03 (s, 1H), 7.50 (d, J = 11.6 Hz, 1H), 5.19-5.10 (m, 1 H), 4.04-3.89 (m, 5H), 3.61 (dt, J = 4.7, 9.4 Hz, 1H), 3.48 (dt, J = 2.3, 11.7 Hz, 1H), 3.25 - 3.17 (m, 3H), 2.97 (d, J = 6.7 Hz, 1H), 2.13 (td, J = 2.3, 13.2 Hz, 1H), 1.69 (dd, J = 6.9, 12.9 Hz, 7H), 1.28 (s, 3H), 0.88 (d, J =6.2 Hz, 3H)
H5	N-ycl HO^xk AA Il ' //N k J N-X O Me—γ \_NH Me Ά ^0 1,5-anhydro-3-({5-chloro-4-[4fluoro-2-{[(oxetan-3yl)amino]methyl}-1 -(propan-2-	^491.2 „ [M+H]* (ESI)	1H NMR (400 MHz, CD3OD) δ 8.37 (s, 1H) 8.06 (s, 1H) 7.52 (d, J = 11.8 Hz, 1H) 5.08-5.16 (m, 1H) 4.80 (m, 2H) 4.46 (m, 2H) 4.11 (s, 2H) 3.90 - 4.08 (m, 4H) 3.63 (m, 1H) 3.50 (m, 1H) 3.19-3.26 (m, 1H) 2.13 (m, 1 H) 1.72 (d, J =6.7 Hz, 6H), 1.69-1.61 (m, 2H)

267

	y l)-1 H-benzimidazol-6yl]pyrimidin-2-yl}amino)-2,3dideoxy-D-fhreo-pentitol		- ... : - . - ....
H6	nV JL HN n HCk A. L-A Il 'A k A N-X Λ 0 Me^ VN/\_F Me v 1,5-anhydro-3-[(5-chloro-4-{4fluoro-2-[(3-fluoroazetidin-1 yl)methyl]-1 -(propan-2-yl)-1 Hbenzimidazol-6-yl}pyrimidin-2yl)amino]-2,3-dideoxy-D-threopentitol	493.2 [M+H]+ (ESI)	1H NMR (400 MHz, CD3OD) δ 8.35 (s, 1H), 8.03 (s, 1H), 7.49 (d, J = 11.5 Hz, 1H), 5.25-5.04 (m, 2H), 4.01 (s, 2H), 4.00 3.87 (m, 3H), 3.74 - 3.56 (m, 3H), 3.53 - 3.44 (m, 1H), 3.43 3.37 (m, 1H), 3.37-3.32 (m, 1H), 3.20 (dd, J = 9.7, 11.1 Hz, 1H), 2.18-2.09 (m, 1H), 1.68 (d, J =6.8 Hz, 6H), 1.66-1.58 (m, 1H)
H7	n^Y<ci hnAA^H ΠΑ Il ' A k A N-X Λ O Me—γ VN/\ 1,5-anhydro-3-[(4-{2-[(azetidin1 -yl)methyl]-4-fluoro-1 -(propan2-yl)-1 /7-benzimidazol-6-yl}-5chloropyrimidin-2-yl)amino]-2,3dideoxy-D-fhreo-pentitol	475.2 [M+H]+ (ESI)	1H NMR (400 MHz, CD3OD) δ 8.35 (s, 1H), 8.03 (s, 1H), 7.49 (d, J = 11.4 Hz, 1H), 5.15-5.07 (m, 1H), 4.01-3.89 (m, 5H), 3.61 (brd, J =4.8 Hz, 1H), 3.52 -3.44 (m, 1H), 3.35 (t, J =7.0 Hz, 4H), 3.20 (dd, J =9.7,11.1 Hz, 1H), 2.16-2.08 (m, 3H), 1.69 (d, J =7.0 Hz, 6H), 1.671.60 (m, 1 H)

Example H8 (Scheme H-2): 1,5-anhydro-3-({5-chloro-4-[4-fluoro-1-(propan-2-yl)-2{[(pr|opan-2-yl)amino]methyl}-1H-benzimidazol-6-yl]pyriijfiidin-2-yl}amino)-2,3-dideoxy-Dthreo-pentitol

Scheme H-2:

268

MnO₂

MeOH, 60 “C ..

26% yield

IPrNH₂, AcOH NaBH₃CN MeCN

21% yield

Step 1: Synthesis of 1,5-anhydro-3-({5-chloro-4-[2-(dihydroxymethyi)-4-fluoro-1-(propan2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol (H-7)

A mixture (3R,4R)-4-({5-chloro-4-[4-fluoro-2-(hydroxymethyl)-1-(propan-2-yl)-1H5 benzimidazol-6-yl]pyrimidin-2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol (H-5) (900mg, 2.1 mmol) and MnO₂ (2.7 g, 31 mmol in MeOH (20.0 mL) was stirred at 60 ^eC for 16 h. LCMS analysis showed consumption of the starting material. The reaction 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 SiO2, 1:10 MeOH/DCM) to provide 1,5-anhydro-3-({510 chloro-4-[2-(dihydroxymethyl)-4-fluoro-1 -(propan-2-yl)-1 H-benzimidazol-6-yl]pyrimidin-2yl}amino)-2,3-dideoxy-D-fhreo-pentitol (H-7) (162 mg, 26% yield) as a colorless oil. ¹H NMR (400 MHz, CD3OD) δ 1.69 (t, J = 5.77 Hz, 7H) 2.00 - 2.23 (m, 1H) 3.18 - 3.26 (m, 1H) 3.50 (br d, J = 2.26 Hz, 1H) 3.63 (td, J = 9.29, 5.02 Hz, 1H) 3.98 (br. dd, J = 11.29, 4.52 Hz, 3H) 5.44 - 5.53 (m, 1H) 5.88 (s, 1 H) 7.53 (br d, J = 11.54 Hz, 1H) 8.07 (s, 1H) 8.37 (s, 1H); m/z (ESI+) for (C₂oH₂₃CIFN₅f)4), 452.2 (M+H)⁺. |

Step 2: Synthesis of 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-f/ireo- . pentitol (Example H8) I

To a solution 1,5-anhydro-3-({5-chloro-4-[2-(dihydroxymethyl)-4-fluoro-1-(propan-2-yl)1/7-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol (H-7) (50mg, 0.11 mmol) and /-PrNH₂ (12.7 mg, 0.215 mmol) in MeOH (5.0 mL) was added AcOH (6.4 mg, 0.107 mmol). After stirring for 2 h at ambient température NaBHsCN (13.5, 0.215 mmol) was added and the mixture was stirred for 16 h overnight. LCMS analysis showed consumption of the starting

269 material with formation of the desired product mass. The reaction was poured into a solution aqueous NazCOs (1.0 M, 5 mL) and 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 préparative HPLC with an Xtimate C18 column (250x80 mm, 10 pm particle size), which was eluted with 35-55% MeCN/H2O (+0.05% NH4OH) with a flow rate of 25 mL/min to provide 1,5-anhydro-3-({5-chloro-4-[4-fluoro-1 -(propan-2-yl)-2-{[(propan-2-yl)amino]methyl}-1 Hbenzimidazol-6-yl]pyrimidin-2-yi}amino)-2,3-dideoxy-D-f/jneo-pentitol (Example H8) (10.9 mg, 21% yield) as a white solid. ¹H 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, 1 H) 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 (C23H30CIFN6O2), 477.1 (M+H)⁺.

The examples in the below table was synthesized according to the methods used for the synthesis of 1,5-anhydro-3-({5-chloro-4-[4-fluoro-1 -(propan-2-yl)-2-{[(propan-2-yl)amino]methyl}15 1H-benzimidazol-6-yl]pyrimidin-2-yl)amino)-2,3-dideoxy-D-f/7reo-pentitol (Example H8). The following example was synthesized with non-critical changes or substitutions to the exemplified procedures that someone who is skilled in the art would be able to realize.

Example number	Structure/Name	LCMS	NMR
H9	HN N LY |L HCxX AA k J N-K N Me—γ ~VNH O=s=o U < Me /7 O (3R,4R)-4-({5-chloro-4-[4flLoro-2-{[(oxetan-3- yl)amino]methyl}-1 -(propan-2yl)-1H-benzimidazol-6yl]p^rimidin-2-yl}amino)-1(methanesulfonyl)piperidin-3-ol	568.1 [M+H]+ (APCI)	1H NMR (700 MHz, DMSO-d6) δ 8.43 (s, 1H), 8.09-7.68 (m, 1H), 7.44 (d, J =35 3 Hz, 1H), 5.01 (p, J = 6.8 Hz, 1H), 4.59 (t, J = 6.6 Hz, 2H), 4.35 - 4.26 (m, 2H), 4.00 (s, 2H), 3.92 (d, J = 11.1 Hz, 1H), 3(85 — 3.74 (m, 2H), 3.66 - 3.57 (m, 6H), 2.89 (s, 3H), 1.59 (d, J = 6.8 Hz, 6H)

270

H10	HO^A. AA Il ' //N k J N-X _ γ MeA NH O-S-O Me X- Me Me Me (3R,4R)-4-({5-chloro-4-[4fluoro-1 -(propan-2-yl)-2{[(propan-2-yl)amino]methyl}1 H-benzimidazol-6-yl]pyrimidin2-yl)amino)-1(methanesulfonyl)piperidin-3-ol	553.9 [M+H]+ (APCI)	1H NMR (600 MHz, DMSO-de) δ 7.96 (s, 1H), 7.62-7.39 (m, 1H), 7.09 - 6.82 (m, 2H), 4.88 - 4.67 (m, 1 H), 4.65-4.48 (m, 1H), 3.58 (s, 2H), 3.34 (d, J = 6.1 Hz, 1H), 3.15 (d, J =10.1 Hz, 1H), 2.46-2.37 (m, 4H), 2.31- 2.25 (m, 1H), 2.19 (t, J = 10.4 Hz, 1H), 1.63-1.55 (m, 1H), 1.41(br.s., 3H), 1.13 (d, J = 7.0 Hz, 6H), 1.10-1.01 (m, 1H), 0.56 (d, J =6.2 Hz, 6H)
H11	N-VCI A <A^î^/F HN N T| HO^/k AA Il ' //N k fi N-X O Me-y \_NH Me 1,5-anhydro-3-[(5-chloro-4-{2[(cyclopropylamino)methyl]-4fluoro-1 -(propan-2-yl)-1 Hbenzimidazol-6-yl)pyrimidin-2yl)amino]-2,3-dideoxy-D-f/7reopentitol	475.3 [M+HJ+ (ESI)	1H NMR (400 MHz, CD3OD) δ 8.37 (s, 1H), 8.05 (s, 1H), 7.51 (d, J = 11.54 Hz, 1H), 5.07 (dt, J = 13.93, 6.84 Hz, 1H), 4.19 (s, 2H), 3.90 - 4.03 (m, 3H), 3.63 (td, J = 9.41, 4.77 Hz, 1H), 3.50 (td, J =11.67, 2.01 Hz, 1H), 3.22 (dd, J =11.04, 9.79 Hz, 1H), 2.26 (dt, J = 6.71, 3.29 Hz, 1H), 2.12-2.18 (m, 1H), 1.69 (d, J = 7.03 Hz, 6H), 1.601.68 (m, 1H), 0.45-0.51 (m, 2H), 0.31 - 0.36 (m, 2H)

Biological Assavs and Data | I

CDK4/Cyclin D1 mobilitv shift assay

The purpose CDK4/Cyclin D1 assay is to evaluate the inhibition (% inhibition, Ki_app and Ki 5 values) in the presence of small molécule inhibitors by using a fluorescence based microfluidic mobility shift assay. CDK4/Cyclîn D1 catalyzes the production of ADP from ATP that accompanies the phosphoryl transfer to the substrate peptide 5-FAM-Dyrktide (5-FAM-RRRFRPASPLRGPPK) (SEQ ID NO:1). The mobility shift assay electrophoretically séparâtes the fluorescently labeled peptides (substrate and phosphorylated product) following the kinase reaction. Both substrate 10 and product are measured and the ratio of these values is used to generate %Conversion of substrate to product by the LabChip EZ Reader. Typical reaction solutions contained 2% DMSO

271 (± inhibitor), 10 mM MgCI₂, 1 mM DTT, 3.5 mM ATP, 0.005% TW-20, 3 μΜ 5-FAM-Dyrktide, 3 nM (active sites) activated CDK4/Cyclin D1 in 40 mM HEPES buffer at pH 7.5.

Inhibitor Ki déterminations for activated CDK4/Cyclin D1 (2007 E1/2008 +PO4) were initiated with the addition of ATP (50 pL final reaction volume), following a eighteen minute pre-incubation of enzyme and inhibitor at 22 °C in the reaction mix. The reaction was stopped after 195 minutes by the addition of 50 pL of 30 mM EDTA. Ki déterminations were made from a plot of the fractional velocity as a function of inhibitor concentration fit to the Morrison équation with the enzyme concentration as a variable.

CDK6/Cyclin D3 mobilitv shift assay

The purpose of the CDK6/Cyclin D3 assay is to evaluate the inhibition (% inhibition, Ki_app and Ki values) in the presence of small molécule inhibitors by using a fluorescence based microfluidic mobility shift assay. CDK6/Cyclin D3 catalyzes the production of ADP from ATP that accompanies the phosphoryl transfer to the substrate peptide 5-FAM-Dyrktide (5-FAM-RRRFRPASPLRGPPK) (SEQ ID NO:1). The mobility shift assay electrophoretically séparâtes the fluorescently labeled peptides (substrate and phosphorylated product) following the kinase reaction. Both substrate and product are measured and the ratio of these values is used to generate %conversion of substrate to product by the LabChip EZ Reader. Typical reaction solutions contained 2% DMSO (± inhibitor), 2% glycerol, 10 mM MgCI₂,1 mM DTT, 3.5 mM ATP, 0.005% Tween 20 (TW-20), 3 pM 5-FAM-Dyrktide, 4 nM (active sites) activated CDK6/Cyclin D3 in 40 mM HEPES buffer at pH 7.5.

Inhibitor K déterminations for activated CDK6/Cyclin D3 (LJIC-2009G1/2010 +PO4) were initiated with the addition of ATP (50 pL final reaction volume), following a eighteen minute pre-incubation of enzyme and inhibitor at 22 °C in the reaction mix. The reaction was stopped after 95 minutes by the addition of 50 pL of 30 mM EDTA. Ki déterminations were made from a plot of the fractional velocity as a function of inhibitor concentration fit to the Morrison équation with the enzyme concentration as a variable. ,

For CDK4 and CDK6 mobility shift assays, see also Morrison, J. F. (1969) Kinetics of the réversible inhibition of enzyme-catalysed reactions by tight-binding inhibitors, Biochimlca et blophysica acta 185, 269-286; and Murphy, D. J. (2004) Détermination of accurâte Kl values for tight-binding enzyme inhibitors: an in Jsilico study of experimental error and assay design, Analytical biochemistry 327, 61-67.

Phospho-Serine 795 Rb ELISA Assays

JEKO-1 or MV4-11 cells were seeded at 15,000 or 20,000 cells per well, respectively, in

100 pL growth media and allowed to incubate at 37°C with 5% CÔ₂ overnight. The following day, compounds were serially diluted from a 10 mM top dose for an 11-point 3-fold dilution curve in

DMSO. Compounds were intermediately diluted 1:200 into growth media prior to diluting 1:5 on

272 cells for final concentration 10 μΜ to 0.1 nM in 0.1% DMSO on cells. JEKO-1 and MV4-11 cells were treated were treated overnight, at 37°C with 5% CO2. Cells were lysed in 100 pL/well CST lysis buffer on ice and transferred to pre-coated and blocked anti-phospho-Ser795 Rb ELISA plates for overnight incubation at 4°C. Plates were washed to remove residual, unbound cellular proteins and total Rb détection antibody added for 90 minutes at 37°C. Following wash to remove unbound total Rb antibody, the HRP tagged antibody was allowed to bind for 30 minutes at 37°C. Following wash to remove unbound HRP antibody, Glo Substrate Reagent was added and incubated protected from light for 5 to 10 minutes. Plates were read in luminescence mode and IC50 values calculated.

Biological Activity ...... .....

Biological activity data for représentative compounds of the invention are provided inTable 6. CDK4 and CDK6 in vitro Ki (nM) data are provided using calorimetric assays. CDK4 and CDK6 cell-based IC50 (nM) data are provided for CDK4 and CDK6 using phospho-Rb S795 ELISA assays in JEKO-1 and MV4-11 cells.

Example No.	CDK4D1 Ki (nM)	CDK4 pRB S795 ELISA JEKO-1 cells IC50 (nM)	CDK6_D3 Ki (nM)	CDK6 pRB S795 ELISA MV4-11 cells IC50 (nM)
A01	0.1	25.3	2.3	76.5
A02	0.1	88.6	2.5	163.3
A03	4.0		17.3
A04	0.6	329.6	11.4	289.2
A05	3.3	225.1	50.8	541.4
A06	1.4	87.4	17.5	192.2
A07	1.8	182.1	28.0	520.4
A08	1.1		4.8
A09	0.1	16.8	1.4	57.6
A10	0.6	72.7	10.4	195.3
A11	0.3	122.7	3.0	143.9
A12	0.6	29.8	7.9	108.5
A13	1.7	72.2 |	31.5	276.7
A14	0.5		- 4.6
A15	0.3		2.4
A16	0.2	25.7	2.7	98.1
A17	0.1	9.9 i	0.4	13.4
A18	0.2	25.0 !	2.3	77.2
A19	0.9	69.1 I	14.6	318.4
A20	2.7		20.4
A21	7.3		135.6
A22	3.2		49.7
A23	0.5	26.5	11.6	84.1
A24	1.3	40.1	16.4	166.9
A25	0.0	13.3	1.3	30.6
A26	0.2	12.2	4.2	24.3
A27	1.0	75.6	15.7	269.2

273

A28	0.5	99.2	6.2	131.1
A29	0.6	68.6	5.1	95.7
A30	0.2	51.6	4.9	63.5
A31	0.5	23.5	7.1	87.0
A32	0.9		7.1
A33	8.3		78.0
A34	11.1		102.1
A35	1.5	123.8	58.9	966.7
A36	0.2	19.6	3.7	43.9
A37	3.5		34.2
A38	0.5	455.7	10.2	598.1
A39	1.3		12.3
A40	0.3	85.5	3.5	346.5
A41	3.1	92.8	48.8	216.1
A42	6.0		54.7
A43	4.8		44.0
A44	4.9	76.5	113.9	408.0
A45	1.0	65.8	52.0	468.4
A46	2.3		40.5
A47	1.0	382.7	24.6	370.3
A48	0.1	36.5	2.3	58.9
A49	0.7	76.0	14.3	219.2
A50	17.0		109.5
A51	2.0	245.0	55.7	1528.4
A52	2.7	202.1	60.1	973.1
A53	0.6	67.3	16.7	208.3
A54	2.3	173.1	37.5	605.3
A55	3.2	197.8	64.9	283.5
A56	1.3		9.6
A57	0.4	49.0	19.1	269.1
A58	0.6	33.1	17.6	203.0
A59	0.6	47.7	56.7	521.4
A60	1.6	65.2	33.6	190.3
A61	0.2	11.4	2.6	33.5
A62	0.5	27.5	8.0	66.6
A63	0.9		9.7
A64	2.0		10.7
	A65	0.6			3.5
	A66	12.1			54.7
A67	1.4		15.5
A68	0.7	..... 48.7	14.3	234.9
A69	0.7	101.4	4.9	237.7
	A70	26.2			124.2
	A71	0.8	94.9		11.4	286.9
A72	0.3		2.1
A73	0.9	72.0	16.1	188.1
A74	0.2	26.5 .	. 6.2	. 89.7
A75	0.3	33.2	5.0	102.8
A76	0.2	96.1	6.3	242.0
A77	0.3	61.1	4.9	126.4
A78	0.1	26.4	1.8	73.9
A79	1.8	598.0	17.6	1138.0

274

A80	0.5	72.9	14.7	216.7
A81
A82	3.8		24.6
A83	4.1	394.8	88.5	1223.0
A84	6.0	. · -- - -	- - 30.3
A85	9.9		62.8
A86	4.7		23.5
A87	0.2	40.1	2.8	97.7
A88	4.5	7318.0	80.4	10000.0
A89	0.5	118.4	12.0	570.3
A90	0.2		1.1
A91	0.1	14.9	1.7	25.7
A92	0.1	23.8	0.9	42.9
A93	0.2	34.7	4.4	61.4
A94	0.6	38.5	13.9	144.9
B01	0.1	65.6	1.5	129.0
B02	7.3		27.1
C01	5.2	176.4	98.1	1379.5
C02	4.1	583.7	89.3	1350.0
D01	0.4		1.7
D02	1.0		9.3
D03	0.6		4.7
D04	0.6	68.2	12.5	172.0
D05	2.2	85.7	39.4	258.0
D06
E01	0.1	17.0	1.4	37.9
F01	0.8	114.1	14.6	576.0
F02	4.3		39.9
F03	2.7		26.4
F04
F05	2.1	247.9	25.8	478.2
F06	1.5	160.6	27.8	134.4
F07	15.3		125.4
F08	0.5	108.4	11.5	311.3
F09	0.6		5.5
F10	0.5	41.3	6.1	152.7
F11	5.4	821.1	79.9	2402.1
F12	50.0		109.5
F13	11.6	.. .	81.1	. . _
F14	3.6		30.8
F15	0.0	34.4	1.0	39.8
F16	1.4	675.3	26.0	362.7
F17I	0.5	83.2	8.3 ।	126.6
F18I	0.9	31.7	10.1 I
F19	1.5		11.8
F20	2.0	155.1	24.3	787.5
F21	0.4	59.5	7.7	246.2
F22	0.5	61.3	9.1	171.1
F23	1.0	691.9	11.0	1318.1
F24	2.1		19.9
F25	1.2	455.3	19.3	455.2
F26	0.1	142.8	4.6	182.3

	275
	F27	0.5	60.8	5.1	188.0	- . . - —
F28	2.2	190.5	22.3	745.2
F29	1.8	245.5	23.3	643.7
F30	0.5	66.1	12.5	377.1
F31	2.4		- 23.0
F32	0.9	171.6	12.8	628.3
F33	0.2	24.6	5.2	112.8
G01	0.4		5.9
H01	2.4	137.1	127.0	857.6
H02	0.8	52.1	20.0	117.9
H03	1.8	155.4	66.9	422.9
H04	0.8	63.4	38.2	220.9
H05	4.5	249.0	93.3	1470.2
H06 -	1.1	79.6	35.6	343.3
H07	1.4	48.3	43.0	409.1
H08	1.2	35.6	44.5	305.9
H09	0.9	205.1	18.6	230.3
H10	0.5	14.9	16.4	51.1
H11	0.7	43.4	22.1	295.1

Ail publications and patent applications cited in the spécification are herein incorporated by reference in their entirety. It will be apparent to those of ordinary skill in the art that certain changes and modifications may be made thereto without departing from the spirit or scope of 5 the appended claims.

Claims (10)

Claims

1. A compound of Formula (X):

or a pharmaceutically acceptable sait thereof, wherein: .... .......

R¹ is H, F, Cl, CN, C1-C2 alkyl or C1-C2 fluoroalkyl, where each said C1-C2 alkyl and C1-C2 fluoroalkyl is optionally substituted by R²⁰;

R² is H, C1-C5 alkyl, C1-C5 fluoroalkyl, C3-C8 cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R²⁰ and each said C3-C8 cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R²¹;

R⁴ is H, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy or C1-C4 fluoroalkoxy, where each said C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy and C1-C4 fluoroalkoxy is optionally substituted by R²⁰;

R⁶ is H, F, Cl, CN, CH₃, CH₂F, CHF₂ or CF₃;

R⁷ and R⁸ are independently H, F, Cl, CN, C1-C2 alkyl, C1-C2 fluoroalkyl, C1-C2 alkoxy or C1-C2 fluoroalkoxy, where each said C1-C2 alkyl, C1-C2 fluoroalkyl, C1-C2 alkoxy and C1-C2 fluoroalkoxy is optionally substituted by R²⁰;

R⁹ is H, OH, NH₂, NHCH₃ or N(CH₃)₂;

each R¹⁰ is independently F, CN, C1-C2 alkyl or C1-C2 fluoroalkyl, where each said C1-C2 alkyl and C1-C2 fluoroalkyl is optionally substituted by R²⁰;

each R²⁰ is independently OH, C1-C2 alkoxy, C1-C2 fluoroalkoxy, CN or N R²²R²³;

each R²¹ is independently F, OH, CN, NR²²R²³, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy or C1-C4 fluoroalkoxy, where each said C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy and C1-C4 fluoroalkoxy is optionally further substituted by OH, NH2, NHCH3 or N(CH3)2; I each R²² and R²³ is independently H, C1-C2 alkyl or C1-C2 fluoroalkyl; or

R²² and R²³ may be taken together with the nitrogen atom to whîch they are attached to form an azetidinyl ring, which is optionally substituted by F or OH; and | nisO, 1,2, 3 or 4. ' '

2. The compound of claim 1, having the Formula (X-A):

277

or a pharmaceutically acceptable sait thereof.

3. A compound of Formula (IX):

R¹¹ (IX)

4. The compound of claim 3, having the Formula (IX-A):

x^ .R¹ n r⁷

R¹¹ (IX-A)

20 or a pharmaceutically acceptable sait thereof.

5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable sait thereof, wherein R¹ is Cl.

5 R¹⁷ is C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R²⁰;

each R¹⁸ and R¹⁹ is independently H, C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R²⁰;

each R²⁰ is independently OH, Ci-C₂ alkoxy, CrC₂ fluoroalkoxy, CN or N R²²R²³;___

10 each R²¹ is independently F, OH, CN, NR²²R²³, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy or C1-C4 fluoroalkoxy, where each said C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy and C1-C4 fluoroalkoxy is optionally further substituted by OH, NH₂, NHCH₃ or N(CH₃)₂;

each R²² and R²³ is independently H, Ci-C₂ alkyl or Ci-C₂ fluoroalkyl; or

R²² and R²³ may be taken together with the nitrogen atom to which they are attached to

15 form an azetidinyl ring, which is optionally substituted by F or OH; and n is 0,1, 2, 3 or 4.

5 or a pharmaceutically acceptable sait thereof, wherein:

R¹ is H, F, Cl, CN, C1-C2 alkyl or C1-C2 fluoroalkyl, where each said C1-C2 alkyl and C1-C2 fluoroalkyl is optionally substituted by R²⁰;

R² is H, C1-C5 alkyl, C1-C5 fluoroalkyl, C3-Ce cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R²⁰ and each said 10 C3-Ce cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R²¹;

R⁴ is H, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy or C1-C4 fluoroalkoxy, where each said C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy and C1-C4 fluoroalkoxy is optionally substituted by R²⁰;

R⁶ is H, F, Cl, CN, CH₃, CH₂F, CHF₂ or CF₃;

15 R⁷ and R⁸ are independently (1, F, CI, CN, C1-C2 alkyl, C1-C2 fluoroalkyl, C1-C2 alkox^ or

C1-C2 fluoroalkoxy, where each said C1-C2 alkyl, C1-C2 fluoroalkyl, C1-C2 alkoxy and C1-C2 fluoroalkoxy is optionally substituted by R²⁰; ---------------- . --------------- ----R⁹ is H, OH, NH₂, NHCH₃ or N(CH₃)₂; !

each R¹⁰ is independently F, CN, C1-C2 alkyl or C1-C2 fluoroalkyl, where each said C1-C2 20 alkyl and C1-C2 fluoroalkyl is optionally substituted bÿ R²⁰;

278

R¹¹ is H, C1-C4 alkyl, G-C4 fluoroalkyl, SO2R¹⁴, SO₂NR¹⁵R¹⁶, COR¹⁷, COOR¹⁷ or

CONR¹⁸R¹⁹;

R¹⁴ is C1-C4 alkyl or C1-C4 fluoroalkyl;

each R¹⁵ and R¹⁶ is independently H or CH₃;

6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable sait 25 thereof, wherein R² is C1-C5 alkyl, where said C1-C5 alkyl is optionally substituted by R²⁰.

279 ^^^

7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable sait thereof, wherein R⁴ is C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by R²⁰.

8. The compound of claim 7, or a pharmaceutically acceptable sait thereof, wherein R²⁰ is OH.

5

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable sait thereof, wherein R⁶ is F, R⁷ is H, and R⁸ is H.

10. 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1 -(propan-2-yl)-1 HbenzimidazoI-6-yi]pyrimidin-2-yl}amino)-2,3-dideoxy-D-f/7reo-pentitol, having the structure:

or a pharmaceutically acceptable sait thereof.

11. (3R,4R)-4-[(5-chloro-4-{4-fluoro-2-[(1 R)-1 -hydroxyethyl]-1 -(propan-2-yl)-1 H- benzimidazol-6-yl}pyrimidin-2-yl)amino]-1-(methanesulfonyl)piperidin-3-ol, having the structure:

15 or a pharmaceutically acceptable sait thereof.

112. A pharmaceutical composition comprising the compound of any one of claims 1 to 9, or a pharmaceutically acceptable sait thereof, and a j pharmaceutically acceptable carrier or excipient.

280

A pharmaceutical composition comprising the compound of claim 10, or a pharmaceutically acceptable sait thereof, and a pharmaceutically acceptable carrier or excipient.

14. A pharmaceutical composition comprising the compound of claim 11, or a 5 pharmaceutically acceptable sait thereof, and a pharmaceutically acceptable carrier or excipient.

15. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable sait thereof, for use in a method for the treatment of cancer in a subject in need thereof.

16. Use of the compound of any one of claims 1 to 11, or a pharmaceutically acceptable sait

10 thereof, in the manufacture of a médicament for the treatment of cancer in a subject in need thereof.