C Y CLOALKYLIDENE CARBOXYLIC ACIDS AND DERIVATIVES AS BTK

INHIBITORS

RELATED APPLICATIONS

This application claims priority to Indian Provisional Patent Application Nos. IN 201921035147 filed on August 31, 2019, and IN 201921035148 filed on August 31, 2019, the contents of which are hereby incorporated by reference in their entirety.

FILED OF THE INVENTION

The present invention relates to novel cycloalkylidene carboxylic acids and derivatives thereof as Bruton tyrosine kinase (BTK) inhibitors, process of preparation thereof, and to the use of the compounds in the preparation of pharmaceutical compositions for the therapeutic treatment of disorders involving mediation of BTK in humans.

BACKGROUND OF THE INVENTION

Involvement of BTK in signal transduction pathways regulating B-cell proliferation, differentiation and survival has been a ground breaking discovery and has led to developments of drugs for the treatment of B-cell malignancies. Improper /auto activated BTK signaling is considered to be the major cause in several haematological malignancies such as chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL)(Li et al. Journal of Med. CHem., 2014, 57(12), 5112-5128; Seng-Lai Tan et al., Pharmacology and Therapeutics, 2013, 138, 294-309).

First in class BTK inhibitor, Ibrutinib, which is disclosed in U.S. Patent No. 7514444 is presently marketed in United States for the treatment of mantle cell lymphoma, chronic lymphocytic leukemia/ small lymphocytic lymphoma, Waldenstrom’s macroglobulinemia and marginal zone lymphoma (MZL) under the trade name Imbruvica ^® . Ibrutinib irreversibly inhibits BTK kinase activity by covalently reacting with the C481 amino acid residue in the adenosine triphosphate binding site.

WIPO Publication Nos. W02015002894A1, WO2015084857A1, WO

2013010868A1, WO2011152351A1, WO2014188173A1, W02014100748A1,

WO2013155347, WO2014130856, WO2015165279A1, WO2015018333A1, WO

2017127371 A1, WO 2017066014, W02017046604A1, and WO 2016109219 A1; U.S. Publication Nos. US20150005277, and US20140079690 all disclose various compounds as BTK inhibitors.

WIPO Publication No. W02018002958A1 discloses novel diacylhydrazide compounds as BTK inhibitors. United States Publication No. US20030153752A1 and WIPO Publication Nos. W02001072751A1, W02001019829A2, W002080926A1, W02002076986A1,

W02005074603A2, W02005097800A1, W02005037836A2, and W02010065898A2 disclose various compounds as protein tyrosine kinase inhibitors. Recently acalabrutinib, a selective irreversible BTK inhibitor has been approved by

USFDA for the treatment of mantle cell lymphoma and marketed under the trade name Calquence®. Acalabrutinib also reacts to cysteine residue in the BTK active site thereby causing BTK inhibition.

Despite ibrutinib’s activity in CLL, acquired resistance to ibrutinib does develop in a subset of heavily pretreated patients and is most commonly mediated by mutation of BTK cysteine-481, the amino acid of BTK with which ibrutinib irreversibly reacts, to serine (C481S). C481S BTK mutation has been reported to diminish ibrutinib’s potency up to 500- fold and prevents its covalent binding, rendering it unable to effect irreversible inhibition of BTK (Reiff et al. Blood, 2018, 132 (10), 1039-1049). C481S mutation is thought to be the predominant mechanism for the emerging resistance to irreversible inhibitors of BTK and the C481S-mutant patients currently have limited treatment options.

Several novel BTK inhibitors have recently been developed which inhibit the wild type and mutant (C481S) forms of BTK and are currently in different phases of clinical trials, for example ARQ-531 (Phase I clinical Trial), Vecabrutinib (Phase II clinical Trial) and LOXO-305 (Phase II clinical Trial).

WIPO Publication No. WO2019161152A1 discloses BTK inhibitors inhibiting both wild type and C481S mutant BTK.

The present inventors have found novel cycloalkylidene compounds which have shown inhibitory activity both in wild type and C481S mutant forms of BTK.

SUMMARY OF THE INVENTION

The present invention provides a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein R _A is selected from , hydroxyl and -N(R ₁₅ )R ₁₆ ; ring Hy is selected from the moieties below: wherein represents the position of attachment to ring A and “)” represents the position of attachment to W; ring A is selected from wherein R ₅ is one or more groups independently selected from hydrogen, halogen, hydroxyl,

-C _1-6 alkyl, -N(C _1-6 alkyl) ₂ , -NH(C _1-6 alkyl), -C _1-6 haloalkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, -OC _1-6 alkyl, -OC _3-6 alkenyl, -OC _3-6 alkynyl, -SC _{1 -6} alkyl, -CN, -C(O)C _1-4 alkyl, -C(O)C _3-6 cycloalkyl, -C(O)OH, -C(O)NH ₂ , -C(O)N(C _1-6 alkyl) ₂ , -C(O)NH(C _1-6 alkyl), -NHC(O)C _1-4 alkyl, and -N(C _1-4 alky 1)C(O)C _1-4 alkyl and when R ₅ is -OC _3-6 alkenyl or -OC _3-6 alkynyl, the double or triple bond, respectively, is not on the carbon directly attached to the oxygen atom; Y ₁ is selected from CH and nitrogen; Y ₂ is selected from CH and nitrogen;

Y3 is selected from CH and nitrogen;

Y4 is selected from nitrogen, oxygen and sulfur;

“[” represents the position of attachment to group Y and “{” represents the position of attachment to ring Hy;

W is either absent or selected from -CH ₂ -, -(CH ₂ ) ₂ -, -NH- and — NH-CH ₂ -; wherein — represents point of attachment to ring Hy;

Y is selected from-O-, -S-, -NH-, -N(C _1-4 alkyl)-, -N(CHO)-, -N(COOH)-, -N(COOC _1-6 alkyl)-, -C(C _1-2 alkyl) ₂ -, -C(O)-, -S(O)-, -S(O) ₂ -, -CH=CH-, -CH ₂ -, -N(CH ₂ CN)-, -C(O)NH- -, -NHC(O)-, -CH ₂ O-, -OCH ₂ -, -S(O) ₂ NH-, -NHS(O) ₂ --, -CH ₂ -NHC(O)-, -C(O)NH- CH ₂ — , -N(C _1-6 alkyl)C(O)— and -C(O)-N(C _1-6 alkyl)—, wherein —represents point of attachment of group Y to ring A; ring B is selected from a 6 to 10 membered aryl, C _3-7 cycloalkyl and 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms each independently selected from nitrogen, oxygen and sulfur; wherein the aryl or heteroaryl group of ring B is unsubstituted or substituted with one or more groups independently selected from halogen, hydroxyl, C _1-6 alkyl, -N(C _1-6 alkyl) ₂ , - NH(C _1-6 alkyl), -C _1-6 haloalkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, -OC _1-6 alkyl, -OC _3-6 alkenyl, - OC _3-6 alkynyl, -SC _1-6 alkyl, -CN, -C(O)C _3-6 Cycloalkyl, -C(O)OH, -C(O)NH ₂ , -C(O)N(C _1-6 alkyl) ₂ , -C(O)NH(C _1-6 alkyl), -NHC(O)C _1-4 alkyl and -N(C _1-4 alkyl)C(O)C _1-4 alkyl;

R ₁ is selected from hydrogen, halogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 haloalkyl, C _3- halocycloalkyl, C _1-6 hydroxyalkyl, C _3-6 hydroxycycloalkyl, -C _1-6 alkyl-O-C _1-6 alkyl, -

CONR ₆ R ₇ , -(CH ₂ ) _P NH ₂ , and -CN; R ₆ and R ₇ are independently selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1- 6 hydroxyalkyl, and C _1-6 haloalkyl; or R ₆ and R ₇ together with the nitrogen atom to which they are attached form a 3 -7 membered heterocycloalkyl ring optionally containing one or two additional heteroatoms independently selected from oxygen, sulfur, and -N(R ₈ )-, wherein R ₈ is hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, hydroxyl or -OCH3; p is an integer ranging from 1 to 3;

R ₂ and R ₃ are each independently selected from hydrogen, C _2-6 hydroxyalkyl, C _2-6 haloalkyl and C _1-4 alkyl optionally substituted with C _3-6 cycloalkyl; or R ₂ and R ₃ together with the nitrogen atoms to which they are attached form a 4-7 membered heterocycloalkyl ring;R ₄ is selected from -C(O)C _1-6 alkyl, -C(O)C _3-6 cycloalkyl, -C(S)C _1-6 alkyl, -C(S)C _3-6 cycloalkyl, -C(S)C _3-6 cycloalkenyl , -SO ₂ C _1-6 alkyl, -CHO and - CN; or wherein R ₉ , R ₁₀ , and R ₁₁ are independently selected from hydrogen, C _1-6 alkyl, halogen, C _{3- 6} cycloalkyl, C _1-6 haloalkyl, C _3-6 halocycloalkyl, C _1-6 hydroxyalkyl, C _3-6 hydroxycycloalkyl, -C _1-6 alkyl-O-C _3-6 cycloalkyl, -CN, -C(O)NR ₁₂ R ₁₃ , -(CH ₂ )qC(O)NR ₁₂ R ₁₃ , C _1-6 cyanoalkyl, - C(O)OH, -C(O)OC _1-6 alkyl, -(CH ₂ ) _q C(O)OH, -(CH ₂ ) _q C(O)OC _1-6 alkyl, -(CH ₂ ) _q NR ₁₂ R ₁₃ , and a 4 to 7 membered heterocycloalkyl containing 1 or 2 heteroatoms wherein each heteroatom is independently selected from oxygen, sulfur and N( R ₁₄ ); or R ₉ and R ₁₀ taken together form a 3 to 6 membered carbocyclic ring; wherein q is an integer selected from 1 to 4; R ₁₂ and R ₁₃ are independently selected from hydrogen and C _1-6 alkyl; or R ₁₂ and R ₁₃ together with the nitrogen atom to which they are attached forms a 4 to 7 membered heterocycloalkyl ring;

R ₁₄ is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkyl-O-C _1-6 alkyl, and C _1-6 aminoalkyl;

R ₁₅ is hydrogen or -C _1-3 alkyl;

R ₁₆ is selected from hydrogen, hydroxyl, -OC _1-6 alkyl, -C _1-6 alkyl-O-C _1-6 alkyl, C _{1- 6} hydroxyalkyl and -C _1-3 alkyl-C(O)N(R ₁₇ )R ₁₈ ;

R ₁₇ is hydrogen or -C _1-3 alkyl; and R ₁₈ is selected from hydrogen, hydroxyl, -C _{1- 3} alkyl and -OC _1-3 alkyl; m is an integer selected from 1, 2 and 3; n is an integer selected from 1, 2 and 3; provided that when R _A is then ring Hy is selected from: wherein represents the position of attachment to ring A and “)” represents the position of attachment to W.

The compounds of the present invention were found to be potent and selective BTK inhibitors and can be useful in treatment of the diseases mediated by BTK enzyme.

DEFINITION

“ Pharmaceutically acceptable salt ” according to the invention include those formed with either organic and inorganic acids or bases. Pharmaceutically acceptable acid addition salts include those formed from hydrochloric, hydrobromic, sulfuric, citric, tartaric, phosphoric, acetic, trifluoroacetic, triphenylacetic, phenylacetic, succinic, oxalic, fumaric, maleic, glutamic, aspartic, oxalacetic, methanesulphonic, ethanesulphonic, p- toluenesulphonic, benzenesulphonic, naphthalenesulphonic or naphthalenedisulphonic, salicylic, glutaric, gluconic, mandelic, cinnamic, ascorbic, oleic, naphthoic, hydroxynaphthoic (for example 1- or 3-hydroxy-2 -naphthoic), benzoic, 4-methoxybenzoic, 2- or 4-hydroxybenzoic, 4-chlorobenzoic, 4-phenylbenzoic acids and butane- 1,4-disulfonic acid. Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium and salts with organic bases such as dicyclohexylamine and N-methyl-D- glucamine.

The term "alkyl" refers to a saturated hydrocarbon chain radical that includes solely carbon and hydrogen atoms in the backbone, either linear or branched and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, «-propyl, 1-methylethyl (isopropyl), «-butyl, «-pentyl, and 1,1-dimethylethyl (t-butyl). The alkyl chain may have 1 to 13 carbon atoms unless specified otherwise. Unless set forth or recited to the contrary, all alkyl groups described or claimed herein may be unsubstituted or substituted with groups selected from halogen, -OC _1-6 alkyl, -OC _3-6 cycloalkyl, CN, -COOH, -COO-C _1-3 alkyl, - CON(-C _1-3 alkyl), -NO ₂ , -SO ₂ C _1-3 alkyl, -SO ₂ N-C _1-3 alkyl, and -CO-C _1-3 alkyl.

The numerical in phrases like “C _1-6 alkyl” indicates that there are 1 to 6 carbon atoms in the alkyl chain.

The term alkenyl refers to a hydrocarbon chain containing at least one carbon- carbon double bond, and may have (E) or ( Z) configuration. An alkenyl group may contain

2 to 8 carbon atoms unless specified otherwise. Unless set forth or recited to the contrary all alkenyl groups described or claimed herein may form part of a straight or branched chains. The non-limiting examples of alkenyl groups include ethylene, 2-propenyl (allyl), 2-methyl- 2-propenyl and 2-butenyl. Unless set forth or recited to the contrary, all alkenyl groups described or claimed herein may be straight chain or branched, unsubstituted or substituted with groups selected from halogen, -OC _1-6 alkyl, -OC _3-6 cycloalkyl, CN, -COOH, -COO-C _1-

₃ alkyl, -CON(-C _1-3 alkyl), -NO ₂ , -SO ₂ C _1-3 alkyl, -SO ₂ N-C _1-3 alkyl, and -CO-C _1-3 alkyl.

The term “ alkynyF refers to a hydrocarbon chain having at least one carbon-carbon triple bond. An alkynyl group may contain 2 to 8 carbon atoms unless specified otherwise. Unless set forth or recited to the contrary all alkynyl groups described or claimed herein may form part of a straight or branched chains. The non-limiting examples of alkynyl groups include 2-propynyl and 3-butynyl. Unless set forth or recited to the contrary, all alkynyl groups described or claimed herein may be unsubstituted or substituted with one or more groups selected from halogen, -OC _1-6 alkyl, -OC _3-6 cycloalkyl, CN, -COOH, -COO-C _1-3 alkyl, -CON(-C _1-3 alkyl), -NO ₂ , -SO ₂ C _1-3 alkyl, -SO ₂ N-C _1-3 alkyl, and -CO-C _1-3 alkyl.

The term cycloalkyf refers to a non-aromatic mono, multicyclic, bridged multicyclic or spiromulticyclic ring system of about 3 to about 12 carbon atoms unless specified otherwise. Monocyclic rings include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Examples of simple multicyclic cycloalkyl groups include, but not limited to perhydronapththyl and perhydroindenyl; bridged multicyclic groups include adamantyl and norbomyl etc., and spiromulticyclic groups includes spiro(4,4)non-2-yl, etc. Unless set forth or recited to the contrary, all cycloalkyl groups described or claimed herein may be unsubstituted or substituted with groups selected from halogen, -OC _1-6 alkyl, -OC _3-6 cycloalkyl, CN, -COOH, -COO-C _1-3 alkyl, -CON(-C _1-3 alkyl), -NO ₂ , -SO ₂ C _1-3 alkyl, -SO ₂ N-C _1-3 alkyl, -CO-C _1-3 alkyl.

The term “cycloalkenyl” refers to a non-aromatic monocyclic or bicyclic, 3 to 12 membered cycloalkyl ring system, with at least one carbon-carbon double bond. Representative examples of cycloalkenyl include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl and cyclohexenyl. Unless set forth or recited to the contrary, all cycloalkenyl groups described or claimed herein may be unsubstituted or substituted.

The term “ heterocycloalkyl" refers to a cycloalkyl ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples of heterocycloalkyl groups include azetidine, pyrrolidineyl, piperidine, piperazine, morpholine, thiomorpholine and 1,3-oxazine. Unless set forth or recited to the contrary, all heterocycloalkyl groups described or claimed herein may be unsubstituted or substituted.

The term “aryl” or “ aromatic ring ” refers to an aromatic radical having 6 to 10 carbon atoms, including a monocyclic or bicyclic aromatic system. The bicyclic aryl group includes an aromatic ring fused to a saturated, partially unsaturated ring, or aromatic ring. The bicyclic aryl group may be attached to the rest of the molecule at any suitable position including a position on the aromatic ring or the saturated or partially unsaturated ring. Typical aryl groups include, but are not limited to phenyl, naphthyl, tetrahydronaphthyl, indanyl (e.g., 1-indanyl and 5-indanyl) and indenyl. Unless set forth or recited to the contrary, all aryl groups described or claimed herein may be unsubstituted or substituted.

The term “ heteroaryl ” refers to 5 to 10 membered aromatic heterocyclic ring radicals with one or more heteroatoms independently selected from nitrogen, oxygen and sulfur. The heteroaryl ring may be a mono- or bi-cyclic ring system and includes fused ring systems (at least one of which is aromatic). The heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. Examples of such heteroaryl rings include, but are not limited to, oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazoyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, quinolinyl, isoquinolinyl, quinazolinyl, purinyl, quinoxalinyl, quinolinyl, isoquinobnyl, thiadiazolyl, indolizinyl, imidazo[1,2-a]pyridyl and phthalazinyl. Unless set forth or recited to the contrary, all heteroaryl groups described or claimed herein may be unsubstituted or substituted.

The term “ halogen ”, as used herein refers to a halogen radical which includes chloro, fluoro, bromo and iodo. Similarly the terms "haloalkyl", "halocycloalkyl" refers to halogen substituted alkyl and cycloalkyl, respectively.

The term carbocyclic" refers to a saturated or unsaturated monocyclic or bicyclic ring in which all atoms of all rings are carbons. Unless otherwise specified, throughout this disclosure, carbocyclic is used as a synonym of “non-aromatic carbocyclic” and includes 3 to 13 carbon atoms. The examples of carbocyclic ring are cycloalkyl and cycloalkenyl rings as defined earlier in the specification.

The term "hydroxyalkyl" refers to an alkyl chain substituted with one or more hydroxyl (-OH) groups. The hydroxyl group may be present at any of the chain carbon atoms including the terminal carbon atom.

The term "hydroxycycloalkyl" refers to a cycloalkyl group substituted with one or more hydroxyl (-OH) groups.

The term "aminoalkyl" refers an alkyl chain substituted with one or more amino (- NH ₂ ) groups. The amino group may be present at any of the chain carbon atoms including the terminal carbon atom.

The term "cyanoalkyl" refers an alkyl chain substituted with one or more cyano (- CN) groups. The cyano group may be present at any of the chain carbon atoms including the terminal carbon atom.

The term “effective amount ” as used herein refers to an amount of the compound which is sufficient, upon single or multiple dose administration(s) to a subject, in curing, alleviating, relieving or partially addressing the clinical manifestation of a given disease or state and its complications beyond that expected in the absence of such treatment. Thus, the result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. It is understood that “a therapeutically effective amount” can vary from subject to subject depending on age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician.

The term “ treating ” or “ treatment ” as used herein refer to completely or partially curing, alleviating, ameliorating, improving, relieving, delaying onset of, inhibiting progression of, reducing severity of, and/or reducing incidence of one or more symptoms or features of a particular disease, disorder, and/or condition.

The term “ subject ” as used herein refer to either a human or a non-human animal. The term includes mammals such as humans, primates, livestock animals (e.g., bovines and porcines), companion animals (e.g., canines and felines) and rodents (e.g., mice and rats).

The term “ deuterated analog ” as used herein refers to compounds of the present disclosure wherein at least one hydrogen atom has been replaced by a deuterium atom. The deuterated analog of the disclosure may be a fully or partially deuterium substituted derivative. DETAILED DESCRIPTION OF THE INVENTION

Accordingly, in one aspect, the present invention provides a compound of Formula or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein

R _A is selected from hydroxyl and -N( R ₁₅ ) R ₁₆ ; ring Hy is selected from the moieties below: wherein represents the position of attachment to ring A and “)” represents the position of attachment to W; ring A is selected from: wherein R ₅ is one or more groups independently selected from hydrogen, halogen, hydroxyl,

-C _1-6 alkyl, -N(C _1-6 alkyl) ₂ , -NH(C _1-6 alkyl), -C _1-6 haloalkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, - OC _1-6 alkyl, -OC _3-6 alkenyl, -OC _3-6 alkynyl, -SC _1-6 alkyl, -CN, -C(O)C _1-4 alkyl, -C(O)C _3-6 cycloalkyl, -C(O)OH, -C(O)NH ₂ , -C(O)N(C _1-6 alkyl) ₂ , -C(O)NH(C _1-6 alkyl), -NHC(O)C _1-4 alkyl, and -N(C _1-4 alkyl)C(O)C _1-4 alkyl, and when R ₅ is -OC _3-6 alkenyl or -OC _3-6 alkynyl, the double or triple bond, respectively, is not on the carbon directly attached to the oxygen atom; Y ₁ is selected from CH and nitrogen;

Y ₂ is selected from CH and nitrogen;

Y ₃ is selected from CH and nitrogen;

Y ₄ is selected from nitrogen, oxygen and sulfur;

“[” represents the position of attachment to group Y and “{” represents the position of attachment to ring Hy;

W is either absent or selected from -CH ₂ -, -(CH ₂ ) ₂ -, -NH- and — NH-CH ₂ -; wherein — represents point of attachment to ring Hy;

Y is selected from -O-, -S-, -NH-, -N(CH alkyl)-, -N(CHO)-, -N(COOH)-, -N(COOC _1-6 alkyl)-, -C(C _1-2 alkyl) ₂ -, -C(O)-, -S(O)-, -S(O) ₂ -, -CH=CH-, -CH ₂ -, -N(CH ₂ CN)-, -C(O)NH-

-, -NHC(O)— , -CH ₂ O-, -OCH ₂ --, -S(O) ₂ NH-, -NHS(O) ₂ -, -CH ₂ -NHC(O)-, -C(O)NH- CH ₂ — , -N(C _1-6 alkyl)C(O)— and -C(O)-N(C _1-6 alkyl)—, wherein —represents point of attachment of group Y to ring A; ring B is selected from 6 to 10 membered aryl, C _3-7 cycloalkyl and 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms each independently selected from nitrogen, oxygen and sulfur; wherein aryl or heteroaryl group of ring B is unsubstituted or substituted with one or more groups independently selected from halogen, hydroxyl, C _1-6 alkyl, -N(C _1-6 alkyl) ₂ , -NH(C _1- 6 alkyl), -C _1-6 haloalkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, -OC _1-6 alkyl, -OC _3-6 alkenyl, -OC _3-6 alkynyl, -SC _1-6 alkyl. -CN, -C(O)C _3-6 Cycloalkyl, -C(O)OH, -C(O)NH ₂ , -C(O)N(C _1-6 alkyl) ₂ , -C(O)NH(C _1-6 alkyl), -NHC(O)C _1-4 alkyl and -N(C _1-4 alkyl)C(O)C _1-4 alkyl;

R ₁ is selected from hydrogen, halogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 haloalkyl, C _{3- 6} halocycloalkyl, C _1-6 hydroxyalkyl, C _3-6 hydroxycycloalkyl, -C _1-6 alkyl-O-C _1-6 alkyl, - CONR ₆ R ₇ , -(CH ₂ ) _P NH ₂ , and -CN; R ₆ and R ₇ are independently selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _{1- 6} hydroxyalkyl, and C _1-6 haloalkyl; or R ₆ and R ₇ together with the nitrogen atom to which they are attached form a 3 -7 membered heterocycloalkyl ring optionally containing one or two additional heteroatoms independently selected from oxygen, sulfur, and -N( R ₈ )-, wherein R ₈ is hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, hydroxyl or -OCH3; p is an integer ranging from 1 to 3;

R ₂ and R ₃ are each independently selected from hydrogen, C _2-6 hydroxyalkyl, C _2-6 haloalkyl and C _1-4 alkyl optionally substituted with C _3-6 cycloalkyl; or R ₂ and R ₃ together with the nitrogen atoms to which they are attached form a 4-7 membered heterocycloalkyl ring; R ₄ is selected from -C(O)C _1-6 alkyl, -C(O)C _3-6 cycloalkyl, -C(S)C _1-6 alkyl, -C(S)C ₃ - 6 cycloalkyl, -C(S)C _3-6 cycloalkenyl , -SO ₂ C _1-6 alkyl, -CHO and -CN; or R ₄ is a moiety selected from: wherein R ₉ , R ₁₀ , and R ₁₁ are independently selected from hydrogen, C _1-6 alkyl, halogen, C ₃ - 6 cycloalkyl, C _1-6 haloalkyl, C _3-6 halocycloalkyl, C _1-6 hydroxyalkyl, C ₃ - ₆ hydroxy cycloalkyl, -C _1-6 alkyl-O-C _3-6 cycloalkyl, -CN, -C(O)NR ₁₂ R ₁₃ , -(CH ₂ )qC(O)NR ₁₂ R ₁₃ , C _1-6 cyanoalkyl, - C(O)OH, -C(O)OC _1-6 alkyl, -(CH ₂ ) _q C(O)OH, -(CH ₂ ) _q C(O)OC _1-6 alkyl, -(CH ₂ ) _q N R ₁₂ R ₁₃ , and a 4 to 7 membered heterocycloalkyl containing 1 or 2 heteroatoms wherein each heteroatom is selected from oxygen, sulfur and N(R ₁₄ ); or R ₉ and R ₁₀ taken together forms a 3 to 6 membered carbocyclic ring; wherein q is an integer selected from 1 to 4; R ₁₂ and R ₁₃ are independently selected from hydrogen and C _1-6 alkyl; or R ₁₂ and R ₁₃ together with the nitrogen atom to which they are attached form a 4 to 7 membered heterocycloalkyl ring;

R ₁₄ is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkyl-O-C _1-6 alkyl, and C _1-6 aminoalkyl;

R ₁₅ is hydrogen or -C _1-3 alkyl;

R ₁₆ is selected from hydrogen, hydroxyl, -OC _1-6 alkyl, -C _1-6 alkyl-O-C _1-6 alkyl, C _1- 6hydroxyalkyl and -C _1-3 alkyl-C(O)N(R ₁₇ )R ₁₈ ; R ₁ 7 is hydrogen or -C _1-3 alkyl; and R ₁₈ is selected from hydrogen, hydroxyl, - C _{1- 3} alkyl and -OC _1-3 alkyl; m is an integer selected from 1, 2 and 3; n is an integer selected from 1, 2 and 3; provided that when R _A is , then ring Hy is selected from: wherein represents the position of attachment to ring A and “)” represents the position of attachment to W.

The compounds of Formula I may involve one or more embodiments. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, any other embodiment defined herein. Thus the invention contemplates all possible combinations and permutations of the various independently described embodiments.

In one embodiment, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein R _A is selected from hydroxyl and -N(R ₁₅ )R ₁₆ ; ring Hy is selected from the moieties below: wherein represents the position of attachment to ring A and “)” represents the position of attachment to W; ring A is wherein R ₈ is one or more groups independently selected from hydrogen, halogen, hydroxyl, -C _1-6 alkyl, -N(C _1-6 alkyl) ₂ , -NH(C _1-6 alkyl), -C _1-6 haloalkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, -

OC _1-6 alkyl, -OC _3-6 alkenyl, -OC _3-6 alkynyl, -SC _1-6 alkyl, -CN, -C(O)C _1-4 alkyl, -C(O)C _3-6 cycloalkyl, -C(O)OH, -C(O)NH ₂ , -C(O)N(C _1-6 alkyl) ₂ , -C(O)NH(C _1-6 alkyl), -NHC(O)C _1-4 alkyl, and -N(C _1-4 alkyl)C(O)C _1-4 alkyl and when R ₅ is -OC _3-6 alkenyl, or -OC _3-6 alkynyl, the double or triple bond, respectively, is not on the carbon directly attached to the oxygen atom; Y ₁ is selected from CH and nitrogen;

Y ₂ is selected from CH and nitrogen;

Y ₃ is selected from CH and nitrogen;

Y ₄ is selected from nitrogen, oxygen and sulfur;

“[” represents the position of attachment to group Y and “{” represents the position of attachment to ring Hy;

W is either absent or selected from-CH ₂ -, or — NH-CH ₂ -; wherein — represents point of attachment to ring Hy;

Y is selected from-O-, -S-, -NH-, -N(C _1-4 alkyl)-, -N(CHO)-, -N(COOH)-, -N(COOC _1-6 alkyl)-, -C(C _1-2 alkyl) ₂ -, -C(O)-, -S(O)-, -S(O) ₂ -, -CH=CH-, -CH ₂ -, -N(CH ₂ CN)-, -C(O)NH-

-, -NHC(O)--, -CH ₂ O--, -OCH ₂ -, -S(O) ₂ NH-, -NHS(O) ₂ --, -CH ₂ -NHC(O)-, -C(O)NH- CH ₂ — , -N(C _1-6 alkyl)C(O)-- and -C(O)-N(C _1-6 alkyl)—, wherein —represents point of attachment of group Y to ring A; ring B is phenyl or a 5 or 6 membered heteroaryl containing 1 to 3 heteroatoms each independently selected from nitrogen, oxygen and sulfur; wherein phenyl or heteroaryl group of ring B is unsubstituted or substituted with one or more groups independently selected from halogen, hydroxyl, C _1-6 alkyl, -C _1-6 haloalkyl, - OC _1-6 alkyl, -SC _1-6 alkyl. -CN, -C(O)C _3-6 cycloalkyl, -C(O)OH, and -C(O)NH ₂ ;

R ₁ is selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl,

- CONR ₆ R ₇ , -(CH ₂ ) _P NH ₂ , and -CN; R ₆ and R are independently selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1- 6 hydroxyalkyl, and C _1-6 haloalkyl; or R ₆ and R ₇ together with the nitrogen atom to which they are attached form a 3 -7 membered heterocycloalkyl ring optionally containing one or two additional heteroatoms independently selected from oxygen, sulfur, and -N(R ₈ )-, wherein R ₈ is hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, hydroxyl or -OCH3; p is an integer ranging from 1 to 3;

R ₂ and R ₃ are each independently selected from hydrogen, C _2-6 hydroxyalkyl, C _2-6 haloalkyl and C _1-4 alkyl optionally substituted with C _3-6 cycloalkyl; R ₄ is a moiety selected from: wherein R ₉ , R ₁₀ , and R ₁₁ are independently selected from hydrogen, C _1-6 alkyl, halogen, C ₃ - ₆ cycloalkyl, C _1-6 haloalkyl, C _3-6 halocycloalkyl, C _1-6 hydroxyalkyl, C _3-6 hydroxy cycloalkyl, -C _1-6 alkyl-0-C _3-6 cycloalkyl, -CN, -C(O)NR ₁₂ R ₁₃ , -(CH ₂ )qC(O)NR ₁₂ R ₁₃ , C _1-6 cyanoalkyl, - C(O)OH, -C(O)OC _1-6 alkyl, -(CH ₂ ) _q C(O)OH, -(CH ₂ ) _q C(O)OC _1-6 alkyl, -(CH ₂ ) _q NR ₁₂ R ₁₃ , and a 4 to 7 membered heterocycloalkyl containing 1 or 2 heteroatoms wherein each heteroatom is independently selected from oxygen, sulfur and N(R ₁₄ ); or R ₉ and R ₁₀ taken together forms a 3 to 6 membered carbocyclic ring;wherein q is an integer selected from 1 to 4; R ₁₂ and R ₁₃ are independently selected from hydrogen, C _1-6 alkyl; or R ₁₂ and R ₁₃ together with the nitrogen atom to which they are attached forms a 4 to 7 membered heterocycloalkyl ring;

R ₁₄ is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkyl-O-C _1-6 alkyl, and C _1-6 aminoalkyl;

R ₁₅ is hydrogen or -C _1-3 alkyl;

R ₁₆ is selected from hydrogen, hydroxyl, -OC _1-6 alkyl, -C _1-6 alkyl-O-C _1-6 alkyl, C _{1- 6} hydroxyalkyl and -C _1-3 alkyl-C(O)N(R ₁₇ R ₁₈ ; R ₁₇ is hydrogen and -C _1-3 alkyl; and R ₁₈ is selected from hydrogen, hydroxyl, -C _{1- 3} alkyl and -OC _1-3 alkyl; m is an integer selected from 1, and 2; and n is an integer selected from 1, and 2; provided that when R _A is . then ring Hy is selected from: wherein represents the position of attachment to ring A and “)” represents the position of attachment to W.

In another embodiment, the present invention provides the compounds of Formula

I, wherein ring A is wherein Y ₁ and Y ₂ both are CH, thus forming a phenyl ring. In another embodiment, Y ₁ is CH and Y ₂ is nitrogen, thus forming a pyridine ring. In another embodiment, both Y ₁ and Y ₂ are nitrogen, thus forming a pyrimidine ring.

In another embodiment, R ₅ is one to three groups independently selected from hydrogen, halogen, hydroxyl, -C _1-6 alkyl, -N(C _1-6 alkyl) ₂ , -NH(C _1-6 alkyl), -C _1-6 haloalkyl, - OC _1-6 alkyl, -SC _1-6 alkyl, -CN, -C(O)C _1-4 alkyl, -C(O)OH, -C(O)NH ₂ , -C(O)N(C _1-6 alkyl) ₂ , -C(O)NH(C _1-6 alkyl), -NHC(O)C _1-4 alkyl and -N(C _1-4 alkyl)C(O)C _1-4 alkyl. In another embodiment, R ₅ is one to three groups independently selected from hydrogen, halogen, hydroxyl, C _1-6 alkyl, -C _1-4 haloalkyl, -OC _1-4 alkyl and -CN. In another embodiment, R ₅ is one or two groups independently selected from hydrogen, halogen, -OC _1-4 alkyl and C _1-4 alkyl. In another embodiment, R ₅ is one or two groups independently selected from hydrogen, fluoro, methyl and methoxy.

In another embodiment, the present invention provides the compounds of Formula I, wherein ring A is phenyl and is optionally substituted with one or more groups independently selected from halogen, -OC _1-4 alkyl, hydroxyl and -C _1-4 haloalkyl, preferably with halogen.

In another embodiment, the present invention provides the compound of Formula I, wherein W is absent. In another embodiment, W is -CH ₂ -.

In another embodiment, Y is selected from-O-, -S-, -NH-, -N(C _1-4 alkyl)-, -N(CHO)- , -N(COOH)-, -N(COOC _1-6 alkyl)-, -C(C _1-2 alkyl) ₂ -, -C(O)-, -S(O)-, -S(O) ₂ -, -CH=CH-, - CH ₂ -, -N(CH ₂ CN)-, -C(O)NH--, -NHC(O)-, -CH ₂ O-, -OCH ₂ -, -S(O) ₂ NH-, -NHS(O) ₂ -, -CH ₂ -NHC(O)-, -C(O)NH-CH ₂ - , -N(C _1-6 alkyl)C(O)— and -C(O)-N(C _1-6 alkyl)-, wherein —represents point of attachment of group Y to ring A. In another embodiment, Y is -O-, -S-, -NH-, -C(O)NH-- or -NHC(O)-- . In another embodiment, Y is -O-. In yet another embodiment, Y is -C(O)NH— or -NHC(O)— .

In another embodiment, the present invention provides the compounds of Formula I, wherein ring B is phenyl or 5 or 6 membered heteroaryl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. In another embodiment, ring B is phenyl. In yet another embodiment, ring B is pyridine.

In another embodiment, the phenyl or heteroaryl group of ring B is unsubstituted. In another embodiment, the phenyl or heteroaryl group of ring B is substituted with one or more groups independently selected from halogen, hydroxyl, C _1-6 alkyl, -C _1-6 haloalkyl, - OC _1-6 alkyl, -SC _1-6 alkyl, -CN, -C(O)C _3-6 cycloalkyl, -C(O)OH and -C(O)NH ₂ , preferably halogen.

In another embodiment, ring B is phenyl unsubstituted or substituted with one or more groups independently selected from halogen, hydroxyl, C _1-6 alkyl, -C _1-6 haloalkyl, - OC _1-6 alkyl, -SC _1-6 alkyl, -CN, -C(O)C _3-6 Cyeloalkyl, -C(O)OH and -C(O)NH ₂ , preferably halogen.

In another embodiment, ring B is substituted with one or more groups independently selected from fluoro, methoxy and ethoxy. In another embodiment, ring B is phenyl unsubstituted or substituted with one or more groups independently selected from fluoro, methoxy and ethoxy.

In another embodiment, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein R _A is wherein R ₂ , R ₃ and R ₄ are as defined earlier in the specification.

In another embodiment, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, or deuterated analog thereof, wherein R _A is ring Hy is selected from the moieties below: ring A is wherein R ₅ is one or more groups independently selected from hydrogen, halogen, hydroxyl

-C _1-6 alkyl, -C _1-6 haloalkyl, -OC _1-6 alkyl, and -SC _1-6 alkyl; Y ₁ is CH;

Y ₂ is CH;

W is either absent or -CH ₂ -;

Y is -O- or -C(O)NH-CH ₂ — , wherein — represents point of attachment to ring Hy; ring B is phenyl or pyridinyl wherein phenyl or pyridinyl is unsubstituted or substituted with one or more groups independently selected from halogen, C _1-6 alkyl, -C _1-6 haloalkyl, -OC _1-6 alkyl, and -SC _1-6 alkyl;

R ₁ is selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, and -CN;

R ₂ and R ₃ are each independently selected from hydrogen, and C _1-4 alkyl; R ₄ is a moiety selected from: wherein R ₉ is hydrogen, R ₁₀ is hydrogen and R ₁₁ is selected from hydrogen, C _1-6 alkyl, and -(CH ₂ )qNR ₁₂ R ₁₃ , wherein q is an integer selected from 1 to 2; R ₁₂ and R ₁₃ are independently selected from hydrogen, and C _1-6 alkyl; or R ₁₂ and R ₁₃ together with the nitrogen atom to which they are attached form a 4 to 6 membered heterocycloalkyl ring; m is an integer selected from 1, and 2; and n is an integer selected from 1, and 2.

In another embodiment, the present invention provides the compound of Formula I or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein R _A is wherein R ₂ and R ₃ are each independently selected from hydrogen and C _1-4 alkyl optionally substituted with C _3-6 cycloalkyl, and R ₄ is a moiety selected from wherein R ₉ is selected from hydrogen, C1- ₃ alkyl and halogen; R ₁₀ is selected from hydrogen, C _1-3 alkyl and halogen; and

R ₁₁ is selected from hydrogen, C _1-4 alkyl, halogen, C _3-6 cycloalkyl, C _1-6 haloalkyl, C ₃ - 6 halocycloalkyl, C _1-6 hydroxyalkyl, C _3-6 hydroxycycloalkyl, -C _1-6 alkyl-0-C _3-6 cycloalkyl, -

CN, -C(O)NR ₁₂ R ₁₃ , -(CH ₂ ) _q C(O)NR ₁₂ R ₁₃ , C _1-6 cyanoalkyl, -C(O)OH, -C(O)OC _1-6 alkyl, -

(CH ₂ ) _q C(O)OH, -(CH ₂ )qC(O)OC _1-6 alkyl and -(CH ₂ )qNR ₁₂ R ₁₃ ; wherein R ₁₂ and R ₁₃ are independently selected from hydrogen, and C _1-6 alkyl; or R ₁₂ and R ₁₃ together with the nitrogen atom to which they are attached forms a 4 to 7 membered heterocycloalkyl ring. In another embodiment, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein wherein R _A is

R ₂ and R ₃ are each independently selected from hydrogen and C _1-4 alkyl optionally substituted with C _3-6 cycloalkyl, R ₄ is a moiety selected from wherein R ₉ is hydrogen, R ₁₀ is hydrogen,

R ₁₁ is selected from hydrogen, C _1-4 alkyl, halogen, C _3-6 cycloalkyl, C _1-6 haloalkyl, C ₃ - 6 halocycloalkyl, C _1-6 hydroxyalkyl, C _3-6 hydroxycycloalkyl, -C _1-6 alkyl -O-C _3-6 cycloalkyl, -

CN, -C(O)NR ₁₂ R ₁₃ , -(CH ₂ ) _q C(O)NR ₁₂ R ₁₃ , C _1-6 cyanoalkyl, -C(O)OH, -C(O)OC _1-6 alkyl, - (CH ₂ ) _q C(O)OH, -(CH ₂ ) _q C(O)OC _1-6 alkyl and -(CH ₂ )qNR ₁₂ R ₁₃ ; wherein R ₁₂ and R ₁₃ are independently selected from hydrogen, and C _1-6 alkyl; or R ₁₂ and R ₁₃ together with the nitrogen atom to which they are attached form a 4 to 7 membered heterocycloalkyl ring. In another embodiment, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, or deuterated analog thereof, wherein R _A is selected from , hydroxyl and -N(R ₁₅ )R ₁₆ ; ring Hy is selected from the moieties below: wherein represents the position of attachment to ring A and “)” represents the position of attachment to W; ring A is wherein R ₅ is one or more groups independently selected from hydrogen, halogen, hydroxyl

-C _1-6 alkyl, -C _1-6 haloalkyl, -OC _1-6 alkyl, -SC _1-6 alkyl; Y ₁ is CH; Y ₂ is CH;

W is either absent or -CH ₂ -;

Y is -O- or -C(O)NH-CH ₂ -- , wherein --represents point of attachment of group Y to ring A; ring B is phenyl or pyridinyl wherein phenyl or pyridinyl is unsubstituted or substituted with one or more groups independently selected from halogen, C _1-6 alkyl, -C _1-6 haloalkyl, -OC _1-6 alkyl, and -SC _1-6 alkyl;

R ₁ is selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, and -CN;

R ₂ and R ₁ are each independently selected from hydrogen, and C _1-4 alkyl; R ₄ is a moiety selected from: wherein R ₉ is hydrogen, R ₁₀ is hydrogen and R ₁₁ is selected from hydrogen, C _1-6 alkyl, and -(CH ₂ )qNR ₁₂ R ₁₃ , wherein q is an integer selected from 1 to 2; R ₁₂ and R ₁₃ are independently selected from hydrogen, and C _1-6 alkyl; or R ₁₂ and R ₁₃ together with the nitrogen atom to which they are attached forms a 4 to 6 membered heterocycloalkyl ring;

R ₁₅ is hydrogen or -C _1-3 alkyl; R ₁₆ is selected from hydrogen, hydroxyl, -OC _1-6 alkyl, -C _1-6 alkyl-O-C _1-6 alkyl, C _{1- 6} hydroxyalkyl and -C _1-3 alkyl-C(O)N(R ₁₇ )R ₁₈ ;

R ₁ 7 is hydrogen or -C _1-3 alkyl; and R ₁₈ is selected from hydrogen, hydroxyl, -C _{1- 3} alkyl and -OC _1-3 alkyl; m is an integer selected from 1, and 2; and n is an integer selected from 1, and 2; provided that when R _A is then ring Hy is selected from: wherein represents the position of attachment to ring A and “)” represents the position of attachment to W.

In another embodiment, R ₂ and R ₃ are each independently selected from hydrogen and methyl.

In another embodiment, R ₁₁ is selected from hydrogen, C _1-4 alkyl and - (CH ₂ )qNR ₁₂ R ₁₃ ; wherein R ₁₂ and R ₁₃ are independently selected from hydrogen and C _1-6 alkyl, and q is 1.

In another embodiment, R ₁₁ is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl and -CH ₂ N(CH ₃ ) ₂ .

In another embodiment, R ₁ is selected from hydrogen, halogen, C _1-6 alkyl, and -CN. In another embodiment, R ₁ is selected from hydrogen, fluoro, methyl and -CN.

In another embodiment, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein R _A is hydroxyl.

In another embodiment, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein R _A is -N(R ₁₅ )R ₁₆ , wherein

R ₁₅ is hydrogen or -C _1-3 alkyl;

R ₁₆ is selected from hydrogen, hydroxyl, -OC _1-6 alkyl, -C _1-6 alkyl-O-C _1-6 alkyl, C _1-6 hydroxyalkyl and -C _1-3 alkyl-C(O)N(R ₁₇ )R ₁₈ ; R ₁₇ is hydrogen or -C _1-3 alkyl; and R ₁₈ is selected from hydrogen, hydroxyl, -C _{1- 3} alkyl and -OC _1-3 alkyl.

In another embodiment, R _A is selected from hydroxyl, -NH ₂ , -NH-OH, -NH-OCH ₃ , -NH-propoxymethyl, and -NH-CH ₂ C(O)-NH-0CH ₃ .

In another embodiment, the present invention provides the compound of Formula I or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein m and n both are integer 1. In another embodiment, m and n both are integer 2. In another embodiment, m is integer 2 and n is integer 1.

In another embodiment, the present invention provides the compounds of Formula I or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein ring Hy is and W is — NH-CH ₂ -; wherein — represents point of attachment to ring Hy.

In another embodiment, ring Hy is andW is -NH-.

In another embodiment, the present invention provides compounds of Formula I, wherein R _A is . and wherein R ₂ and R ₃ together with the nitrogen atoms to which they are attached form a 4-7 membered heterocycloalkyl ring, thus forming the compounds as represented below:

In another embodiment, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein ring A is wherein R ₈ is one or more groups independently selected from hydrogen, halogen, hydroxyl, -C _1-6 alkyl, -N(C _1-6 alkyl) ₂ , -NH(C _1-6 alkyl), -C _1-6 haloalkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, and -OC _1-6 alkyl, Y ₁ is CH; Y ₂ is CH;

“[” represents the position of attachment to group Y and “{” represents the position of attachment to ring Hy;

W is either absent or -CH ₂ -;

Y is -O-; ring B is phenyl unsubstituted or substituted with one or more groups independently selected from halogen, hydroxyl, C _1-6 alkyl, -C _1-6 haloalkyl, -OC _1-6 alkyl, -SC _1-6 alkyl, - CN, -C(O)C _3-6 cycloalkyl, -C(O)OH, and -C(O)NH ₂ .

In another embodiment, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein ring A is wherein R ₈ is one or more groups independently selected from hydrogen, halogen, hydroxyl, -C _1-6 alkyl, -N(C _1-6 alkyl) ₂ , -NH(C _1-6 alkyl), -C _1-6 haloalkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, and -OC _1-6 alkyl, Y ₁ is CH; Y ₂ is CH;

“[” represents the position of attachment to group Y and “{” represents the position of attachment to ring Hy;

W is either absent or -CH ₂ -;

Y is -O-; ring B is phenyl unsubstituted or substituted with one or more groups independently selected from halogen, hydroxyl, C _1-6 alkyl, -C _1-6 haloalkyl, -OC _1-6 alkyl, -SC _1-6 alkyl, - CN, -C(O)C _3-6 cycloalkyl, -C(O)OH, and -C(O)NH ₂ ; and

R _A IS

In another embodiment, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein ring Hy is wherein represents the position of attachment to ring A and “)” represents the position of attachment to W; ring A is wherein R ₅ is one or more groups independently selected from hydrogen, halogen, hydroxyl, -C _1-6 alkyl, -N(C _1-6 alkyl) ₂ , -NH(C _1-6 alkyl), -C _1-6 haloalkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, and -OC _1-6 alkyl; Y ₁ is CH; Y ₂ is CH; “[” represents the position of attachment to group Y and “{” represents the position of attachment to ring Hy;

W is either absent or -CH ₂ -;

Y is -O-; ring B is phenyl unsubstituted or substituted with one or more groups independently selected from halogen, hydroxyl, C _1-6 alkyl, -C _1-6 haloalkyl, -OC _1-6 alkyl, -SC _1-6 alkyl, - CN, -C(O)C _3-6 cycloalkyl, -C(O)OH, and -C(O)NH ₂ .

In another embodiment, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein ring Hy is wherein represents the position of attachment to ring A and “)” represents the position of attachment to W; ring A is wherein R ₅ is one or more groups independently selected from hydrogen, halogen, hydroxyl, -C _1-6 alkyl, -N(C _1-6 alkyl) ₂ , -NH(C _1-6 alkyl), -C _1-6 haloalkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, and -OC _1-6 alkyl; Y ₁ is CH; Y ₂ is CH;

“[” represents the position of attachment to group Y and “{” represents the position of attachment to ring Hy ;

W is either absent or -CH ₂ -;

Y is -O-; ring B is phenyl unsubstituted or substituted with one or more groups independently selected from halogen, hydroxyl, C _1-6 alkyl, -C _1-6 haloalkyl, -OC _1-6 alkyl, -SC _1-6 alkyl, - CN, -C(O)C _3-6 cycloalkyl, -C(O)OH, and -C(O)NH ₂ ; and R _A is

In another embodiment, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein R _A is selected from , hydroxyl and -N(R ₁₅ )R ₁₆ ; wherein represents the position of attachment to ring A and “)” represents the position of attachment to W; ring A is wherein R ₅ is one or more groups independently selected from hydrogen, halogen, -C _1-6 alkyl, and -OC _1-6 alkyl; Y ₁ is CH; Y ₂ is CH;

“[” represents the position of attachment to group Y and “{” represents the position of attachment to ring Hy; W is absent;

Y is -O- or -C(O)NH-CH ₂ — , wherein —represents point of attachment of group Y to ring A; ring B is phenyl unsubstituted or substituted with one or more groups independently selected from halogen, and -OC _1-6 alkyl;

R ₁ is hydrogen;

R ₂ and R ₃ each independently is hydrogen; R ₄ is a moiety selected from: wherein R ₉ is hydrogen, R ₁₀ is hydrogen,

R ₁₁ is selected from hydrogen, and C _1-6 alkyl; R ₁₅ is hydrogen;

R ₁₆ is selected from hydrogen, and -C _1-3 alkyl-C(O)N(R ₁₇ )R ₁₈ ; R ₁₇ is hydrogen; and R ₁₈ is -OC _1-3 alkyl; m is 2 and n is 2.

In another embodiment, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein R _A is selected from hydroxyl and -N(R ₁₅ )R ₁₆ ; ring Hy is selected from: wherein represents the position of attachment to ring A and “)” represents the position of attachment to W; ring A is wherein R ₅ is one or more groups independently selected from hydrogen or halogen, Y ₁ is CH; Y ₂ is CH;

“[” represents the position of attachment to group Y and “{” represents the position of attachment to ring Hy;

W is either absent or -CH ₂ -;

Y is -O-; ring B is phenyl unsubstituted or substituted with one or more groups independently selected from halogen;

R ₁ is hydrogen or halogen;

R ₂ and R ₃ each independently is hydrogen; R ₄ is a moiety selected from: wherein R ₉ is hydrogen, R ₁₀ is hydrogen,

R ₁₁ is selected from hydrogen, and C _1-6 alkyl; R ₁₅ is hydrogen;

R ₁₆ is selected from hydroxyl, and -OC _1-6 alkyl; m is an integer selected from 1, and 2; and n is an integer selected from 1, and 2; provided that when R _A is , then ring Hy is selected from: wherein represents the position of attachment to ring A and “)” represents the position of attachment to W.

In another embodiment, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein R _A is selected from and hydroxyl; ring Hy is selected from the moieties below: wherein represents the position of attachment to ring A and “)” represents the position of attachment to W; ring A is wherein R ₅ is one or more groups independently selected from hydrogen, halogen, and - C _1-6 alkyl; Y ₁ is CH; Y ₂ is CH; wherein “[” represents the position of attachment to group Y and “{” represents the position of attachment to ring Hy;

W is absent;

Y is -O-; ring B is phenyl unsubstituted or substituted with one or more groups independently selected from halogen;

R ₁ is hydrogen, or -CN;

R ₂ is hydrogen, R ₃ is selected from hydrogen, and C _1-4 alkyl; R ₄ is a moiety selected from: wherein R ₉ is hydrogen, R ₁₀ is hydrogen, and

R ₁₁ is selected from hydrogen, C _1-6 alkyl, -(CH ₂ )qNR ₁₂ R ₁₃ , wherein q is 1; R ₁₂ and R ₁₃ are each independently selected from hydrogen and C _1-6 alkyl; m is an integer selected from 1, and 2; and n is an integer selected from 1, and 2; provided that when R _A is , then ring Hy is selected from: wherein represents the position of attachment to ring A and “)” represents the position of attachment to W.

In another embodiment, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein R _A is selected from , and hydroxyl; wherein represents the position of attachment to ring A and “)” represents the position of attachment to W; ring A is wherein R ₅ is one or more groups independently selected from halogen and -C _1-6 alkyl; Y ₁ is CH; Y ₂ is CH;

“[” represents the position of attachment to group Y and “{” represents the position of attachment to ring Hy;

W is either absent or -CH ₂ -,

Y is -O-; ring B is phenyl;

R ₁ is hydrogen;

R ₂ and R ₃ each independently is hydrogen; R ₄ is a moiety selected from: wherein R ₉ is hydrogen, R ₁₀ is hydrogen,

R ₁₁ is selected from hydrogen, and C _1-6 alkyl; m is an integer selected from 1, and 2; and n is an integer selected from 1, and 2; provided that when R _A is , then ring Hy is selected from wherein represents the position of attachment to ring A and “)” represents the position of attachment to W.

In another embodiment, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein ring W is absent, R ₁ is hydrogen, m is 2 and n is 2.

The present invention also covers the endo-isomers of compounds of Formula I wherein the exocyclic double bond in the compound of Formula I shifts into the ring via hydrogen shift such as [1,3] -hydrogen shift, to form endocyclic double bond. For example, when m is 1, the endocyclic isomer of the compound of Formula I can be represented as: wherein ring B, Y, ring A, ring Hy, W, n, R ₁ , and R _A are as defined previously in the specification.

Similarly, when m is 2, the endocyclic isomer of the compound of Formula I can be represented as: wherein ring B, Y, ring A, ring Hy, W, n, R ₁ , and R _A are as defined previously in the specification.

In another aspect, the present invention provides a compound of Formula la or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein R _A is selected from , hydroxyl and -N(R ₁₅ )R ₁₆ ; ring Hy is selected from the moieties below: wherein represents the position of attachment to ring containing Y ₁ and Y ₂ and “)” represents the position of attachment to W; R ₅ is one or more groups independently selected from hydrogen, halogen, hydroxyl,

-C _1-6 alkyl, -N(C _1-6 alkyl) ₂ , -NH(C _1-6 alkyl), -C _1-6 haloalkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, -

OC _1-6 alkyl, -OC _3-6 alkenyl, -OC _3-6 alkynyl, -SC _1-6 alkyl, -CN, -C(O)C _1-4 alkyl, -C(O)C _3-6 cycloalkyl, -C(O)OH, -C(O)NH ₂ , -C(O)N(C _1-6 alkyl) ₂ , -C(O)NH(C _1-6 alkyl), -NHC(O)C _1-4 alkyl, and -N(C _1-4 alkyl)C(O)C _1-4 alkyl, and when R ₅ is -OC _3-6 alkenyl or -OC _3-6 alkynyl, the double or triple bond, respectively, is not on the carbon directly attached to the oxygen atom; Y ₁ is CH;

Y 2 is CH;

W is either absent or selected from -CH ₂ -, -(CH ₂ ) ₂ -, -NH- and — NH-CH ₂ -; wherein — represents point of attachment to ring Hy; R _B is one or more groups independently selected from hydrogen, halogen, hydroxyl, C _1-6 alkyl, -N(C _1-6 alkyl) ₂ , -NH(C _1-6 alkyl), -C _1-6 haloalkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, -OC _1- 6 alkyl, -OC _3-6 alkenyl, -OC _3-6 alkynyl, -SC _1-6 alkyl, -CN, -C(O)C _3-6 cyeloalkyl, -C(O)OH, - C(O)NH ₂ , -C(0)N(C _1-6 alkyl) ₂ , -C(O)NH(C _1-6 alkyl), -NHC(0)C _1-4 alkyl and -N( C _1-4 alkyl)C(O)C _1-4 alkyl;

R ₁ is selected from hydrogen, halogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 haloalkyl, C _3-6 halocycloalkyl, C _1-6 hydroxyalkyl, C _3-6 hydroxycycloalkyl, -C _1-6 alkyl-O-C _1-6 alkyl, -CONR ₆ R ₇ , -(CH ₂ ) _P NH ₂ , and -CN; R ₆ and R are independently selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1- 6 hydroxyalkyl, and C _1-6 haloalkyl; or R ₆ and R ₇ together with the nitrogen atom to which they are attached form a 3 -7 membered heterocycloalkyl ring optionally containing one or two additional heteroatoms independently selected from oxygen, sulfur, and -N(R ₈ )-, wherein R ₈ is hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, hydroxyl or -OCH ₃ ; p is an integer ranging from 1 to 3;

R ₂ and R ₃ are each independently selected from hydrogen, C _2-6 hydroxyalkyl, C _2-6 haloalkyl and C _1-4 alkyl optionally substituted with C _3-6 cycloalkyl; or R ₂ and R ₃ together with the nitrogen atoms to which they are attached form a 4-7 membered heterocycloalkyl ring; R ₄ is selected from -C(O)C _1-6 alkyl, -C(O)C _3-6 cycloalkyl, -C(S)C _1-6 alkyl, -C(S)C ₃ - 6 cycloalkyl, -C(S)C _3-6 cycloalkenyl , -SO ₂ C _1-6 alkyl, -CHO and -CN; or R ₄ is a moiety selected from: wherein R ₉ , R ₁₀ , and R ₁₁ are independently selected from hydrogen, C _1-6 alkyl, halogen, C ₃ - 6 cycloalkyl, C _1-6 haloalkyl, C _3-6 halocycloalkyl, C _1-6 hydroxyalkyl, C _3-6 hydroxycycloalkyl, -C _1-6 alkyl -O-C _3-6 cycloalkyl, -CN, -C(O)NR ₁₂ R ₁₃ , -(CH ₂ )qC(O)NR ₁₂ R ₁₃ , C _1-6 cyanoalkyl, - C(O)OH, -C(O)OC _1-6 alkyl, -(CH ₂ ) _q C(O)OH, -(CH ₂ ) _q C(O)OC _1-6 alkyl, -(CH ₂ ) _q NR ₁₂ R ₁₃ , and a 4 to 7 membered heterocycloalkyl containing 1 or 2 heteroatoms, wherein each heteroatom is independently selected from oxygen, sulfur and N(R ₁₄ ); or R ₉ and R ₁₀ taken together form a 3 to 6 membered carbocyclic ring; wherein q is an integer selected from 1 to 4; R ₁₂ and R ₁₃ are independently selected from hydrogen, and C _1-6 alkyl, or R ₁₂ and R ₁₃ together with the nitrogen atom to which they are attached forms a 4 to 7 membered heterocycloalkyl ring; R ₁₄ is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkyl-O-C _1-6 alkyl, and C _1-6 aminoalkyl; R ₁₅ is hydrogen or -C _1-3 alkyl;

R ₁₆ is selected from hydrogen, hydroxyl, -OC _1-6 alkyl, -C _1-6 alkyl-O-C _1-6 alkyl, C _1-6 hydroxyalkyl and -C _1-3 alkyl-C(O)N(R ₁₇ )R ₁₈ ; R ₁₇ is hydrogen, or -C _1-3 alkyl; and R ₁₈ is selected from hydrogen, hydroxyl, -C _1-3 alkyl and -OC _1-3 alkyl; m is an integer selected from 1, 2 and 3; n is an integer selected from 1, 2 and 3; provided that when R _A is , then ring Hy is selected from: wherein represents the position of attachment to ring containing Y ₁ and Y ₂ and “)” represents the position of attachment to W.

In another embodiment of above aspect, the present invention provides a compound of Formula la or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein R _A is selected from , hydroxyl and -N(R ₁₅ )R ₁₆ ; ring Hy is selected from the moieties below: wherein represents the position of attachment to ring containing Y ₁ and Y ₂ and “)” represents the position of attachment to W; R ₅ is one or more groups independently selected from hydrogen, halogen, hydroxyl,

-C _1-6 alkyl, -C _1-6 haloalkyl, -OC _1-6 alkyl, and -SC _1-6 alkyl; Y ₁ is CH;

Y ₂ is CH;

W is either absent or selected from -CH ₂ -, and — NH-CH ₂ -; wherein — represents point of attachment to ring Hy;

R _B is one or more groups independently selected from hydrogen, halogen, hydroxyl, C _1-6 alkyl, -C _1-6 haloalkyl, -OC _1-6 alkyl, and -SC _1-6 alkyl;

R ₁ is selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, and -CN;

R ₂ and R ₃ are each independently selected from hydrogen, and C _1-4 alkyl optionally substituted with C _3-6 cycloalkyl; R ₄ is a moiety selected from: wherein R ₉ is hydrogen; R ₁₀ is hydrogen; and R ₁₁ is selected from hydrogen, C _1-6 alkyl, halogen, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, -CN, -C _1-6 cyanoalkyl, and -(CH ₂ )qNR ₁₂ R ₁₃ , wherein q is an integer selected from 1 to 2; R ₁₂ and R ₁₃ are independently selected from hydrogen, and C _1-6 alkyl, or R ₁₂ and R ₁₃ together with the nitrogen atom to which they are attached forms a 4 to 6 membered heterocycloalkyl ring;

R ₁₅ is hydrogen or -C _1-3 alkyl;

R ₁₆ is selected from hydrogen, hydroxyl, -OC _1-6 alkyl, -C _1-6 alkyl-O-C _1-6 alkyl, C _{1- 6} hydroxyalkyl and -C _1-3 alkyl-C(O)N(R ₁₇ )R ₁₈ ; R ₁₇ is hydrogen, or -C _1-3 alkyl; and R ₁₈ is selected from hydrogen, hydroxyl, -C _{1- 3} alkyl and -OC _1-3 alkyl; m is an integer selected from 1, and 2; n is an integer selected from 1, and 2; provided that when R _A is , then ring Hy is selected from: wherein represents the position of attachment to ring containing Y ₁ and Y ₂ and “)” represents the position of attachment to W.

In another embodiment of above aspect, the present invention provides a compound of Formula la or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein ring Hy is selected from the moieties below: wherein represents the position of attachment to ring containing Y ₁ and Y ₂ and “)” represents the position of attachment to W; R ₅ is one or more groups independently selected from hydrogen, halogen, hydroxyl, -C _1-6 alkyl, -C _1-6 haloalkyl, -OC _1-6 alkyl, and -SC _1-6 alkyl; Y ₁ is CH; Y ₂ is CH;

W is either absent or -CH ₂ -;

R _B is one or more groups independently selected from hydrogen, halogen, C _1-6 alkyl, -C _1-6 haloalkyl, -OC _1-6 alkyl, and -SC _1-6 alkyl; R ₁ is selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, and -CN;

R ₂ and R ₃ are each independently selected from hydrogen, and C _1-4 alkyl; R ₄ is a moiety selected from: wherein R ₉ is hydrogen, R ₁₀ is hydrogen and R ₁₁ is selected from hydrogen, C _1-6 alkyl, and -(CH ₂ )qNR ₁₂ R ₁₃ , wherein q is an integer selected from 1 to 2; R ₁₂ and R ₁₃ are independently selected from hydrogen, and C _1-6 alkyl, or R ₁₂ and R ₁₃ together with the nitrogen atom to which they are attached forms a 4 to 6 membered heterocycloalkyl ring; m is an integer selected from 1, and 2; n is an integer selected from 1, and 2.

In another embodiment of above aspect, the present invention provides a compound of Formula la or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein R _B is one to five groups independently selected from hydrogen, halogen, hydroxyl, C _1-6 alkyl, and -OC _1-6 alkyl. In another embodiment, R _B is one to five groups independently selected from hydrogen, fluoro, methyl, ethyl, methoxy and ethoxy. In another embodiment, R _B is one to three groups independently selected from hydrogen, fluoro, and methoxy.

In another embodiment of above aspect, the present invention provides a compound of Formula la or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein R ₅ is one to three groups independently selected from hydrogen, halogen, -C _1-6 alkyl, and -OC _1-6 alkyl. In another embodiment, R ₅ is one to three groups independently selected from hydrogen, fluoro, methyl and methoxy.

In another embodiment of above aspect, R ₁ is selected from hydrogen, fluoro, alkyl and -CN. In another embodiment, R ₁ is selected from hydrogen, fluoro, methyl and -CN. In another embodiment, R ₁ is hydrogen.

In another embodiment of the above aspect, the present invention provides a compound of Formula la or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, R _A is selected from R ₂ and R ₃ are each independently selected from hydrogen, and C _1-4 alkyl; R ₄ is a moiety selected from: wherein R ₉ is hydrogen, R ₁₀ is hydrogen, and R ₁₁ is selected from hydrogen, C _1-6 alkyl, halogen, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, -CN, -C _1-6 cyanoalkyl, and -(CH ₂ )qN R ₁₂ R ₁₃ , wherein q is an integer selected from 1 to 2; R ₁₂ and R ₁₃ are independently selected from hydrogen, and C _1-6 alkyl.

In another embodiment, R ₂ and R ₃ are each independently selected from hydrogen and methyl.

In another embodiment, R ₁₁ is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl and -CH ₂ N(CH ₃ ) ₂ .

In another embodiment of the above aspect, the present invention provides a compound of Formula la or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein R _A is hydroxyl.

In another embodiment of the above aspect, the present invention provides a compound of Formula la or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein W is absent. In another embodiment, W is -CH ₂ -.

In another embodiment of the above aspect, the present invention provides a compound of Formula la or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein m and n both are integer 2. In another embodiment, m and n both are integer 1. In another embodiment, m is 2 and n is 1.

In another embodiment of the above aspect, the present invention provides a compound of Formula la or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein ring Hy is W is absent, R ₁ is hydrogen, m is 2 and n is 2. In another embodiment of above aspect, the present invention provides a compound of Formula la or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein R _A is selected from . hydroxyl and -N(R ₁₅ )R ₁₆ ; wherein represents position of attachment to ring containing Y ₁ and Y ₂ and “)” represents position of attachment to W; R ₅ is one or more groups independently selected from hydrogen, halogen, -C _1-6 alkyl, and -OC _1-6 alkyl, Y ₁ is CH; Y ₂ is CH;

W is absent;

R _B is one or more groups independently selected from hydrogen, halogen, and -OC _1-6 alkyl;

R ₁ is hydrogen;

R ₂ and R ₃ each independently is hydrogen; R ₄ is a moiety selected from: wherein R ₉ is hydrogen, R ₁₀ is hydrogen, and R ₁₁ is selected from hydrogen, and C _1-6 alkyl; R ₁₅ is hydrogen;

R ₁₆ is selected from hydrogen, and -C _1-3 alkyl-C(O)N(R ₁₇ )R ₁₈ ; R ₁₇ is hydrogen; and R ₁₈ is -OC _1-3 alkyl; m is 2 and n is 2. In another embodiment of above aspect, the present invention provides a compound of Formula la or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein R _A is selected from hydroxyl and -N(R ₁₅ )R ₁₆ ; ring Hy is selected from the moieties below: wherein represents position of attachment to ring containing Y ₁ and Y ₂ and “)” represents position of attachment to W; R ₅ is one or more groups independently selected from hydrogen or halogen, Y ₁ is CH; Y ₂ is CH;

W is either absent or -CH ₂ -;

R _B is one or more groups independently selected from hydrogen and halogen,

R ₁ is hydrogen or halogen;

R ₂ and R ₃ each independently is hydrogen; R ₄ is a moiety selected from: wherein R ₉ is hydrogen, R ₁₀ is hydrogen, and R ₁₁ is selected from hydrogen, and C _1-6 alkyl; R ₁₅ is hydrogen;

R ₁₆ is selected from hydroxyl, and -OC _1-6 alkyl; m is an integer selected from 1, and 2; n is an integer selected from 1, and 2; provided that when R _A is then ring Hy is selected from: wherein represents position of attachment to ring containing Y ₁ and Y ₂ and “)” represents position of attachment to W.

In another embodiment of above aspect, the present invention provides a compound of Formula la or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein R _A is selected from and hydroxyl; ring Hy is selected from the moieties below: wherein represents position of attachment to ring containing Y ₁ and Y ₂ and “)” represents position of attachment to W; wherein R ₅ is one or more groups independently selected from hydrogen, halogen, and

-C _1-6 alkyl; Y ₁ is CH; Y ₂ is CH;

W is absent;

R _B is one or more groups independently selected from hydrogen and halogen;

R ₁ is hydrogen, or -CN;

R ₂ is hydrogen; R ₃ is selected from hydrogen, and C _1-4 alkyl; R ₄ is a moiety selected from: wherein R ₉ is hydrogen, R ₁₀ is hydrogen, and R ₁₁ is selected from hydrogen, C _1-6 alkyl, and -(CH ₂ )qNR ₁₂ R ₁₃ , wherein q is 1; R ₁₂ and R ₁₃ are each independently selected from hydrogen and C _1-6 alkyl; m is an integer selected from 1, and 2; n is an integer selected from 1, and 2; provided that when R _A is , then ring Hy is selected from: wherein represents position of attachment to ring containing Y ₁ and Y ₂ and “)” represents position of attachment to W.

In another embodiment of above aspect, the present invention provides a compound of Formula la or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein R _A is selected from and hydroxyl; ring Fly is wherein represents position of attachment to ring containing Y ₁ and Y ₂ and “)” represents position of attachment to W; R ₅ is one or more groups independently selected from hydrogen, halogen, and -C _1-6 alkyl, Y ₁ is CH; Y ₂ is CH;

W is either absent or -CH ₂ -,

R _B is hydrogen;

R ₁ is hydrogen;

R ₂ and R ₃ each independently is hydrogen; R ₄ is a moiety selected from: wherein R ₉ is hydrogen, R ₁₀ is hydrogen, and R ₁₁ is selected from hydrogen, and C _1-6 alkyl; m is an integer selected from 1, and 2; n is an integer selected from 1, and 2; provided that when R _A is then ring Hy is selected from wherein represents position of attachment to ring containing Y ₁ and Y ₂ and “) represents position of attachment to W.

In another aspect, the present invention provides a compound of Formula lb or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein ring Hy is selected from the moieties below: wherein represents the position of attachment to ring A and “)” represents the position of attachment to W; ring A is selected from wherein R ₅ is one or more groups independently selected from hydrogen, halogen, hydroxyl, -C _1-6 alkyl, -N(C _1-6 alkyl) ₂ , -NH(C _1-6 alkyl), -C _1-6 haloalkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, -OC _1-6 alkyl, -OC _3-6 alkenyl, -OC _3-6 alkynyl, -SC _1-6 alkyl, -CN, -C(O)C _1-4 alkyl, - C(O)C _3-6 cycloalkyl, -C(O)OH, -C(O)NH ₂ , -C(O)N(C _1-6 alkyl) ₂ , -C(O)NH(C _1-6 alkyl), - NHC(O)C _1-4 alkyl, and -N(C _1-4 alkyl)C(O)C _1-4 alkyl, and when R ₅ is -OC _3-6 alkenyl or -OC ₃ - 6 alkynyl, the double or triple bond, respectively, is not on the carbon directly attached to the oxygen atom; Y ₁ is selected from CH and nitrogen; Y ₂ is selected from CH and nitrogen;

Y3 is selected from CH and nitrogen;

Y4 is selected from nitrogen, oxygen and sulfur;

“[” represents the position of attachment to group Y and “{” represents the position of attachment to ring Hy;

W is either absent or selected from -CH ₂ -, -(CH ₂ ) ₂ -, -NH- and — NH-CH ₂ -; wherein — represents point of attachment to ring Hy;

Y is selected from -O-, -S-, -NH-, -N(C _1-4 alkyl)-, -N(CHO)-, -N(COOH)-, - N(C00C _1-6 alkyl)-, -C(C _1-2 alkyl) ₂ -, -C(O)-, -S(O)-, -S(O) ₂ -, -CH=CH-, -CH ₂ -, -

N(CH ₂ CN)-, -C(O)NH~, -NHC(O)--, -CH ₂ O-, -OCH ₂ -, -S(O) ₂ NH-, -NHS(O) ₂ -, -CH ₂ - NHC(O)— , -C(O)NH-CH ₂ - , -N(C _1-6 alkyl)C(O)- and -C(O)-N(C _1-6 alkyl)-, wherein - represents point of attachment of group Y to ring A; ring B is selected from 6 to 10 membered aryl, C _3-7 cycloalkyl and 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms each independently selected from nitrogen, oxygen and sulfur; wherein the aryl or heteroaryl group of ring B is unsubstituted or substituted with one or more groups independently selected from halogen, hydroxyl, C _1-6 alkyl, -N(C _1-6 alkyl) ₂ , - NH(C _1-6 alkyl), -C _1-6 haloalkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, -OC _1-6 alkyl, -OC _3-6 alkenyl, - OC _3-6 alkynyl, -SC _1-6 alkyl, -CN, -C(O)C _3-6 Cycloalkyl, -C(O)OH, -C(O)NH ₂ , -C(O)N(C _1-6 alkyl) ₂ , -C(O)NH(C _1-6 alkyl), -NHC(O)C _1-4 alkyl and -N(C _1-4 alkyl)C(O)C _1-4 alkyl; R ₁ is selected from hydrogen, halogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 haloalkyl, C ₃ - 6 halocycloalkyl, C _1-6 hydroxyalkyl, C _3-6 hydroxycycloalkyl, -C _1-6 alkyl-O-C _1-6 alkyl, - CONR ₆ R ₇ , -(CH ₂ ) _P NH ₂ , and -CN; R ₆ and R are independently selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1- 6 hydroxyalkyl, and C _1-6 haloalkyl; or R ₆ and R ₇ together with the nitrogen atom to which they are attached form a 3 -7 membered heterocycloalkyl ring optionally containing one or two additional heteroatoms independently selected from oxygen, sulfur, and -N(R ₈ )-, wherein R ₈ is hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, hydroxyl or -OCH3; p is an integer ranging from 1 to 3;

R ₂ and R ₃ are each independently selected from hydrogen, C _2-6 hydroxyalkyl, C _2-6 haloalkyl and C _1-4 alkyl optionally substituted with C _3-6 cycloalkyl; or R ₂ and R ₃ together with the nitrogen atoms to which they are attached form a 4-7 membered heterocycloalkyl ring; R ₄ is selected from -C(O)C _1-6 alkyl, -C(O)C _3-6 cycloalkyl, -C(S)C _1-6 alkyl, -C(S)C ₃ -

6 cycloalkyl, -C(S)C _3-6 cycloalkenyl , -SO ₂ C _1-6 alkyl, -CHO and -CN; or R ₄ is a moiety selected from: wherein R ₉ , R ₁₀ , and R ₁₁ are independently selected from hydrogen, C _1-6 alkyl, halogen, C ₃ - 6 cycloalkyl, C _1-6 haloalkyl, C _3-6 halocycloalkyl, C _1-6 hydroxyalkyl, C _3-6 hydroxycycloalkyl,

-C _1-6 alkyl-0-C _3-6 cycloalkyl, -CN, -C(O)NR ₁₂ R ₁₃ , -(CH ₂ ) _q C(O)NR ₁₂ R ₁₃ , C _1-6 cyanoalkyl, - C(O)OH, -C(O)OC _1-6 alkyl, -(CH ₂ ) _q C(O)OH, -(CH ₂ ) _q C(O)OC _1-6 alkyl, -(CH ₂ ) _q NR ₁₂ R ₁ , and a 4 to 7 membered heterocycloalkyl containing 1 or 2 heteroatoms wherein each heteroatom is independently selected from oxygen, sulfur and N(R ₁₄ ): or R ₉ and R ₁₀ taken together forms a 3 to 6 membered carbocyclic ring; wherein q is an integer selected from 1 to 4; R ₁₂ and R ₁₃ are independently selected from hydrogen, and C _1-6 alkyl, or R ₁₂ and R ₁₃ together with the nitrogen atom to which they are attached forms a 4 to 7 membered heterocycloalkyl ring; R ₁₄ is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkyl-O-C _1-6 alkyl, and C _1-6 aminoalkyl; m is an integer selected from 1, 2 and 3; and n is an integer selected from 1, 2 and 3.

In another embodiment of above aspect, the present invention provides a compound of Formula lb or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein ring Hy is selected from the moieties below: wherein represents the position of attachment to ring A and “)” represents the position of attachment to W; ring A is wherein R ₈ is one or more groups independently selected from hydrogen, halogen, hydroxyl, -C _1-6 alkyl, -C _1-6 haloalkyl, -OC _1-6 alkyl, and -SC _1-6 alkyl, Y ₁ is CH; Y ₁ is CH; “[” represents the position of attachment to group Y and “{” represents the position of attachment to ring Hy;

W is either absent or selected from -CH ₂ -, and — NH-CH ₂ -; wherein — represents point of attachment to ring Hy;

Y is selected from -O-, and -C(O)NH-CH ₂ — , wherein —represents point of attachment of group Y to ring A; ring B is selected from phenyl, and 5 to 6 membered heteroaryl containing 1 to 3 heteroatoms each independently selected from nitrogen, oxygen and sulfur; wherein the phenyl or heteroaryl group of ring B is unsubstituted or substituted with one or more groups independently selected from halogen, hydroxyl, C _1-6 alkyl, -C _1-6 haloalkyl, - SC _1-6 alkyl, and -OC _1-6 alkyl;

R ₁ is selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, and -CN; R ₂ and R ₃ are each independently selected from hydrogen, and C _1-4 alkyl optionally substituted with C _3-6 cycloalkyl; R ₄ is a moiety selected from: wherein R ₉ is hydrogen, R ₁₀ is hydrogen and R ₁₁ is selected from hydrogen, C _1-6 alkyl, halogen, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, -CN, -C _1-6 cyanoalkyl, and -(CH ₂ )qNR ₁₂ R ₁₃ , wherein q is an integer selected from 1 to 2; R ₁₂ and R ₁₃ are independently selected from hydrogen, and C _1-6 alkyl, or R ₁₂ and R ₁₃ together with the nitrogen atom to which they are attached forms a 4 to 6 membered heterocycloalkyl ring; m is an integer selected from 1, and 2, and n is an integer selected from 1, and 2.

In another embodiment of above aspect, the present invention provides a compound of Formula lb or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein ring Hy is selected from the moieties below: wherein represents the position of attachment to ring A and “)” represents the position of attachment to W; ring A is wherein R ₅ is one or more groups independently selected from hydrogen, halogen, hydroxyl, -C _1-6 alkyl, -C _1-6 haloalkyl, -OC _1-6 alkyl, and -SC _1-6 alkyl; Y ₁ is CH; Y ₂ is CH; “[” represents the position of attachment to group Y and “{” represents the position of attachment to ring Hy; W is either absent or -CH ₂ -;

Y is -O-, or -C(O)NH-CH ₂ — , wherein — represents point of attachment of group Y to ring

A; ring B is selected from phenyl, or pyridinyl wherein phenyl or pyridinyl is unsubstituted or substituted with one or more groups independently selected from halogen, C _1-6 alkyl, -C _1-6 haloalkyl, -OC _1-6 alkyl, and -SC _1-6 alkyl;

R ₁ is selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, and -CN;

R ₂ and R ₃ are each independently selected from hydrogen, and C _1-4 alkyl; R ₄ is a moiety selected from: wherein R ₉ is hydrogen, R ₁₀ is hydrogen and R ₁₁ is selected from hydrogen, C _1-6 alkyl, and -(CH ₂ )qNR ₁₂ R ₁₃ , wherein q is an integer selected from 1 to 2, R ₁₂ and R ₁₃ are independently selected from hydrogen, and C _1-6 alkyl; or R ₁₂ and R ₁₃ together with the nitrogen atom to which they are attached forms a 4 to 6 membered heterocycloalkyl ring; m is an integer selected from 1, and 2; n is an integer selected from 1, and 2.

In another embodiment of above aspect, the present invention provides a compound of Formula lb or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein R ₅ is one to three groups independently selected from hydrogen, halogen, -C _1-6 alkyl, and -OC _1-6 alkyl. In another embodiment, R ₅ is one to three groups independently selected from hydrogen, fluoro, methyl and methoxy.

In another embodiment, the present invention provides a compound of Formula lb or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein ring B is phenyl or pyridinyl, wherein the phenyl or pyridinyl, is unsubstituted or substituted with one to five groups independently selected from halogen, hydroxyl, C _1-6 alkyl, and -OC _1-6 alkyl. In another embodiment, ring B is phenyl. In another embodiment, phenyl group of ring B is unsubstituted. In another embodiment, phenyl group of ring B is substituted with one to five groups independently selected from fluoro, methyl, ethyl, methoxy and ethoxy. In another embodiment, phenyl group of ring B is substituted with one to three groups independently selected from fluoro, and methoxy. In another embodiment of above aspect, R ₁ is selected from hydrogen, fluoro, alkyl and -CN. In another embodiment, R ₁ is selected from hydrogen, fluoro, methyl and -CN. In another embodiment, R ₁ is hydrogen.

In another embodiment, R ₂ and R ₃ are each independently selected from hydrogen and methyl.

In another embodiment, R ₁₁ is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl and -CH ₂ N(CH ₃ ) ₂ .

In another embodiment of the above aspect, the present invention provides a compound of Formula lb or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein W is absent. In another embodiment, W is -CH ₂ -.

In another embodiment of the above aspect, the present invention provides a compound of Formula lb or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein m and n both are integer 2. In another embodiment, m and n both are integer 1. In another embodiment, m is 2 and n is 1. In another embodiment of the above aspect, the present invention provides a compound of Formula lb or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein ring Hy is , W is absent, R ₁ is hydrogen, m is 2 and n is 2.

In another embodiment of the above aspect, the present invention provides a compound of Formula lb or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein wherein represents the position of attachment to ring A and “)” represents the position of attachment to W; ring A is wherein R ₅ is one or more groups independently selected from hydrogen, halogen, -C _1-6 alkyl, and -OC _1-6 alkyl; Y ₁ is CH; Y ₂ is CH; “[” represents the position of attachment to group Y and “{” represents the position of attachment to ring Hy;

W is absent;

Y is -O-, or -C(O)NH-CH ₂ — , wherein — represents point of attachment of group Y to ring

A; ring B is phenyl unsubstituted or substituted with one or more groups independently selected from halogen, or -OC _1-6 alkyl,

R ₁ is hydrogen;

R ₂ and R ₃ each independently is hydrogen; R ₄ is a moiety selected from: wherein R ₉ is hydrogen, R ₁₀ is hydrogen, and R ₁₁ is selected from hydrogen, and C _1-6 alkyl; m is 2 and n is 2.

In another embodiment of the above aspect, the present invention provides a compound of Formula lb or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein ring Hy is selected from the moieties below: wherein represents the position of attachment to ring A and “)” represents the position of attachment to W; ring A is wherein R ₈ is one or more groups independently selected from hydrogen and halogen, Y ₁ is CH; Y ₂ is CH;

“[” represents the position of attachment to group Y and “{” represents the position of attachment to ring Hy;

W is either absent or -CH ₂ -;

Y is-O-; ring B is phenyl unsubstituted or substituted with one or more groups independently selected from halogen,

R ₁ is hydrogen or halogen;

R ₂ and R ₃ each independently is hydrogen; R ₄ is a moiety selected from: wherein R ₉ is hydrogen, R ₁₀ is hydrogen, and R ₁₁ is selected from hydrogen, and C _1-6 alkyl, m is an integer selected from 1, and 2; and n is an integer selected from 1, and 2.

In another embodiment of the above aspect, the present invention provides a compound of Formula lb or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein ring Hy is selected from the moieties below: wherein represents the position of attachment to ring A and “)” represents the position of attachment to W; ring A is wherein R ₅ is one or more groups independently selected from hydrogen, halogen, and

-C _1-6 alkyl; Y ₁ is CH; Y ₂ is CH; wherein “[” represents the position of attachment to group Y and “{” represents the position of attachment to ring Hy;

W is absent;

Y is -O-; ring B is phenyl unsubstituted or substituted with one or more groups independently selected from halogen;

R ₁ is hydrogen, or -CN;

R ₂ is hydrogen; R ₃ is selected from hydrogen, and C _1-4 alkyl; R ₄ is a moiety selected from: wherein R ₉ is hydrogen, R ₁₀ is hydrogen, and

R ₁₁ is selected from hydrogen, C _1-6 alkyl, and -(CH ₂ )qNR ₁₂ R ₁₃ , wherein q is 1; R ₁₂ and R ₁₃ are each independently selected from hydrogen and C _1-6 alkyl; m is an integer selected from 1, and 2; and n is an integer selected from 1, and 2;

In another embodiment of the above aspect, the present invention provides a compound of Formula lb or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein ring Hy is selected from: wherein represents the position of attachment to ring A and “)” represents the position of attachment to W; ring wherein R ₈ is one or more groups independently selected from halogen, and -C _1-6 alkyl, Y ₁ is CH; Y ₂ is CH;

“[” represents the position of attachment to group Y and “{” represents the position of attachment to ring Hy;

W is either absent or -CH ₂ -,

Y is -O-; ring B is phenyl;

R ₁ is hydrogen;

R ₂ and R ₃ each independently is hydrogen; R ₄ is a moiety selected from: wherein R ₉ is hydrogen, R ₁₀ is hydrogen, and R ₁₁ is selected from hydrogen, and C _1-6 alkyl; m is an integer selected from 1, and 2; and n is an integer selected from 1, and 2.

In another aspect, the present invention provides a compound of Formula Ic or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein ring Hy is selected from the moieties below: wherein represents position of attachment to ring containing Y ₁ and Y ₂ and “)” represents position of attachment to W; R ₅ is one or more groups independently selected from hydrogen, halogen, hydroxyl, -C _1-6 alkyl, -N(C _1-6 alkyl) ₂ , -NH(C _1-6 alkyl), -C _1-6 haloalkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, - OC _1-6 alkyl, -OC _3-6 alkenyl, -OC _3-6 alkynyl, -SC _1-6 alkyl, -CN, -C(O)C _1-4 alkyl, -C(O)C _3-6 cycloalkyl, -C(O)OH, -C(O)NH ₂ , -C(O)N(C _1-6 alkyl) ₂ , -C(O)NH(C _1-6 alkyl), -NHC(O)C _1-4 alkyl, and -N(C _1-4 alkyl)C(O)C _1-4 alkyl, and when R ₅ is -OC _3-6 alkenyl or -OC _3-6 alkynyl, the double or triple bond, respectively, is not on the carbon directly attached to the oxygen atom; Y ₁ is CH; Y ₂ is CH;

W is either absent or selected from -CH ₂ -, -(CH ₂ ) ₂ -, -NH- and — NH-CH ₂ -; wherein — represents point of attachment to ring Hy;

R _B is one or more groups independently selected from hydrogen, halogen, hydroxyl, C _1-6 alkyl, -N(C _1-6 alkyl) ₂ , -NH(C _1-6 alkyl), -C _1-6 haloalkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, -OC _1- 6 alkyl, -OC _3-6 alkenyl, -OC _3-6 alkynyl, -SC _1-6 alkyl, -CN, -C(O)C _3-6 Cycloalkyl, -C(O)OH, - C(O)NH ₂ , -C(O)N(C _1-6 alkyl) ₂ , -C(O)NH(C _1-6 alkyl), -NHC(O)C _1-4 alkyl and -N(C _1-4 alkyl)C(O)C _1-4 alkyl;

R ₁ is selected from hydrogen, halogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 haloalkyl, C ₃ - 6 halocycloalkyl, C _1-6 hydroxyalkyl, C _3-6 hydroxycycloalkyl, -C _1-6 alkyl-O-C _1-6 alkyl, - CONR ₆ R ₇ , -(CH ₂ ) _P NH ₂ , and -CN; R ₆ and R are independently selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1- 6 hydroxyalkyl, and C _1-6 haloalkyl; or R ₆ and R ₇ together with the nitrogen atom to which they are attached form a 3 -7 membered heterocycloalkyl ring optionally containing one or two additional heteroatoms independently selected from oxygen, sulfur, and -N(R ₈ )-, wherein R ₈ is hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, hydroxyl or -OCH3; p is an integer ranging from 1 to 3;

R ₂ and R ₃ are each independently selected from hydrogen, C _2-6 hydroxyalkyl, C _2-6 haloalkyl and C _1-4 alkyl optionally substituted with C _3-6 cycloalkyl; or R ₂ and R ₃ together with the nitrogen atoms to which they are attached form a 4-7 membered heterocycloalkyl ring; R ₄ is selected from -C(O)C _1-6 alkyl, -C(O)C _3-6 cycloalkyl, -C(S)C _1-6 alkyl, -C(S)C ₃ -

6 cycloalkyl, -C(S)C _3-6 cycloalkenyl , -SO ₂ C _1-6 alkyl, -CHO and -CN; or R ₄ is a moiety selected from: wherein R ₉ , R ₁₀ , and R ₁₁ are independently selected from hydrogen, C _1-6 alkyl, halogen, C ₃ - 6 cycloalkyl, C _1-6 haloalkyl, C _3-6 halocycloalkyl, C _1-6 hydroxyalkyl, C _3-6 hydroxy cycloalkyl,

-C _1-6 alkyl-0-C _3-6 cycloalkyl, -CN, -C(O)NR ₁₂ R ₁₃ , -(CH ₂ )qC(O)NR ₁₂ R ₁₃ , C _1-6 cyanoalkyl, - C(O)OH, -C(O)OC _1-6 alkyl, -(CH ₂ ) _q C(O)OH, -(CH ₂ ) _q C(O)OC _1-6 alkyl, -(CH ₂ ) _q NR ₁₂ R ₁₃ , and a 4 to 7 membered heterocycloalkyl containing 1 or 2 heteroatoms wherein each heteroatom is independently selected from oxygen, sulfur and N(R ₁₄ ); or R ₉ and R ₁₀ taken together forms a 3 to 6 membered carbocyclic ring; wherein q is an integer selected from 1 to 4; R ₁₂ and R ₁₃ are independently selected from hydrogen, and C _1-6 alkyl, or R ₁₂ and R ₁₃ together with the nitrogen atom to which they are attached forms a 4 to 7 membered heterocycloalkyl ring; R ₁₄ is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkyl-O-C _1-6 alkyl, and C _1-6 aminoalkyl; m is an integer selected from 1, 2 and 3; and n is an integer selected from 1, 2 and 3.

In another embodiment of above aspect, the present invention provides a compound of Formula Ic or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein ring Hy is selected from the moieties below: wherein represents the position of attachment to ring containing Y ₁ and Y ₂ and “)” represents the position of attachment to W; R ₅ is one or more groups independently selected from hydrogen, halogen, hydroxyl, -C _1-6 alkyl, -C _1-6 haloalkyl, -SC _1-6 alkyl and -OC _1-6 alkyl; Y ₁ is CH; Y ₂ is CH;

W is either absent or selected from -CH ₂ -, and — NH-CH ₂ -; wherein — represents point of attachment to ring Hy;

R _B is one or more groups independently selected from hydrogen, halogen, hydroxyl, C _1-6 alkyl, -C _1-6 haloalkyl, -SC _1-6 alkyl and -OC _1-6 alkyl;

R ₁ is selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, and - CN;

R ₂ and R ₃ are each independently selected from hydrogen, and C _1-4 alkyl optionally substituted with C _3-6 cycloalkyl; R ₄ is a moiety selected from: wherein R ₉ is hydrogen, R ₁₀ is hydrogen and R ₁₁ is selected from hydrogen, C _1-6 alkyl, halogen, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, -CN, -C _1-6 cyanoalkyl, and -(CH ₂ )qNR ₁₂ R ₁₃ , wherein q is an integer selected from 1 to 2; R ₁₂ and R ₁₃ are independently selected from hydrogen, and C _1-6 alkyl, or R ₁₂ and R ₁₃ together with the nitrogen atom to which they are attached forms a 4 to 6 membered heterocycloalkyl ring; m is an integer selected from 1, and 2; n is an integer selected from 1, and 2. In another embodiment of above aspect, the present invention provides a compound of Formula Ic or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein ring Hy is selected from the moieties below: R ₅ is one or more groups independently selected from hydrogen, halogen, hydroxyl, -C _1-6 alkyl, -C _1-6 haloalkyl, -SC _1-6 alkyl and -OC _1-6 alkyl; Y ₁ is CH; Y ₂ is CH;

W is either absent or selected from -CH ₂ -, and — NH-CH ₂ -; wherein — represents point of attachment to ring Hy;

R _B is one or more groups independently selected from hydrogen, halogen, hydroxyl, C _1-6 alkyl, -C _1-6 haloalkyl, -SC _1-6 alkyl and -OC _1-6 alkyl;

R ₁ is selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, and -CN;

R ₂ and R ₃ are each independently selected from hydrogen, and C _1-4 alkyl optionally substituted with C _3-6 cycloalkyl; R ₄ is a moiety selected from: wherein R ₉ is hydrogen, R ₁₀ is hydrogen and and R ₁₁ is selected from hydrogen, C _1-6 alkyl, and -(CH ₂ )qNR ₁₂ R ₁₃ , wherein q is an integer selected from 1 to 2; R ₁₂ and R ₁₃ are independently selected from hydrogen, and C _1-6 alkyl, or R ₁₂ and R ₁₃ together with the nitrogen atom to which they are attached forms a 4 to 6 membered heterocycloalkyl ring.

In another embodiment of above aspect, the present invention provides a compound of Formula Ic or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein R _B is one to five groups independently selected from hydrogen, halogen, hydroxyl, C _1-6 alkyl, and -OC _1-6 alkyl. In another embodiment, R _B is one to five groups independently selected from hydrogen, fluoro, methyl, ethyl, methoxy and ethoxy. In another embodiment, R _B is one to three groups independently selected from hydrogen, fluoro, and methoxy.

In another embodiment of above aspect, the present invention provides a compound of Formula Ic or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein R ₅ is one to three groups independently selected from hydrogen, halogen, -C _1-6 alkyl, and -OC _1-6 alkyl. In another embodiment, R ₅ is one to three groups independently selected from hydrogen, fluoro, methyl and methoxy.

In another embodiment of above aspect, R ₁ is selected from hydrogen, fluoro, alkyl and -CN. In another embodiment, R ₁ is selected from hydrogen, fluoro, methyl and -CN. In another embodiment, R ₁ is hydrogen.

In another embodiment of above aspect, R ₄ is a moiety selected from: wherein R ₉ is hydrogen, R ₁₀ is hydrogen, and R ₁₁ is selected from hydrogen, C _1-6 alkyl, halogen, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, -CN, -C _1-6 cyanoalkyl, and -(CH ₂ )qNR ₁₂ R ₁₃ , wherein q is an integer selected from 1 to 2; and R ₁₂ and R ₁₃ are independently selected from hydrogen, and C _1-6 alkyl.

In another embodiment, R ₂ and R ₃ are each independently selected from hydrogen and methyl.

In another embodiment, R ₁₁ is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl and H ₂ N(CH ₃ ) ₂ .

In another embodiment of the above aspect, the present invention provides a compound of Formula Ic or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein W is absent. In another embodiment, W is -CH ₂ -.

In another embodiment of the above aspect, the present invention provides a compound of Formula Ic or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein m and n both are integer 2. In another embodiment, m and n both are integer 1. In another embodiment, m is 2 and n is 1. In another embodiment of the above aspect, the present invention provides a compound of Formula Ic or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, ring Hy is W is absent, R ₁ is hydrogen, m is 2 and n is 2.

In another embodiment of above aspect, the present invention provides a compound of Formula Ic or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein ring Hy is wherein represents position of attachment to ring containing Y ₁ and Y ₂ and “)” represents position of attachment to W; R ₅ is one or more groups independently selected from hydrogen, halogen, -C _1-6 alkyl, and -OC _1-6 alkyl, Y ₁ is CH; Y ₂ is CH;

W is absent;

R _B is one or more groups independently selected from hydrogen, halogen, and -OC _1-

₆ alkyl;

R ₁ is hydrogen;

R ₂ and R _B each independently is hydrogen; R ₄ is a moiety selected from: wherein R ₉ is hydrogen, R ₁₀ is hydrogen, and R ₁₁ is selected from hydrogen, and C _1-6 alkyl; m is 2 and n is 2. In another embodiment of above aspect, the present invention provides a compound of Formula Ic or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein ring Hy is selected from the moieties below: wherein represents position of attachment to ring containing Y ₁ and Y ₂ and “) represents position of attachment to W; R ₅ is one or more groups independently selected from hydrogen and halogen, Y ₁ is CH; Y ₂ is CH;

W is either absent or -CH ₂ -;

R _B is one or more groups independently selected from hydrogen and halogen,

R ₁ is hydrogen or halogen;

R ₂ and R ₃ each independently is hydrogen; R ₄ is a moiety selected from the groups provided below: wherein R ₉ is hydrogen, R ₁₀ is hydrogen, and R ₁₁ is selected from hydrogen, and C _1-6 alkyl; m is an integer selected from 1, and 2; and n is an integer selected from 1, and 2;

In another embodiment of above aspect, the present invention provides a compound of Formula Ic or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein ring Hy is selected from the moieties below: wherein “ ” represents position of attachment to ring containing Y ₁ and Y ₂ and “)” represents position of attachment to W; wherein R ₅ is one or more groups independently selected from hydrogen, halogen, and -C _1-6 alkyl; Y ₁ is CH; Y ₂ is CH;

W is absent;

R _B is one or more groups independently selected from hydrogen and halogen;

R ₁ is hydrogen, or -CN;

R ₂ is hydrogen; R ₃ is selected from hydrogen, and C _1-4 alkyl; R ₄ is a moiety selected from: wherein R ₉ is hydrogen, R ₁₀ is hydrogen, and

R ₁₁ is selected from hydrogen, C _1-6 alkyl, and -(CH ₂ )qNR ₁₂ R ₁₃ , wherein q is 1; R ₁₂ and R ₁₃ are each independently selected from hydrogen and C _1-6 alkyl; m is an integer selected from 1, and 2; and n is an integer selected from 1, and 2.

In another embodiment of above aspect, the present invention provides a compound of Formula Ic or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein ring Hy is wherein represents position of attachment to ring containing Y ₁ and Y ₂ and “)” represents position of attachment to W; R ₅ is one or more groups independently selected from hydrogen, halogen, and -C _1-6 alkyl, Y ₁ is CH; Y ₂ is CH;

W is either absent or -CH ₂ -,

R _B is hydrogen;

R ₁ is hydrogen;

R ₂ and R ₃ each independently is hydrogen;

Rr is a moiety selected from: wherein R ₉ is hydrogen, R ₁₀ is hydrogen, and R ₁₁ is selected from hydrogen, and C _1-6 alkyl; m is an integer selected from 1, and 2; and n is an integer selected from 1, and 2.

In another aspect, the present invention provides a compound of Formula Id or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein R _A is selected from , hydroxyl and -N(R ₁₅ )R ₁₆ ; R ₅ is one or more groups independently selected from hydrogen, halogen, hydroxyl, -C _1-6 alkyl, -N(C _1-6 alkyl) ₂ , -NH(C _1-6 alkyl), -C _1-6 haloalkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, - OC _1-6 alkyl, -OC _3-6 alkenyl, -OC _3-6 alkynyl, -SC _1-6 alkyl, -CN, -C(O)C _1-4 alkyl, -C(O)C _3-6 cycloalkyl, -C(O)OH, -C(O)NH ₂ , -C(O)N(C _1-6 alkyl) ₂ , -C(O)NH(C _1-6 alkyl), -NHC(O)C _1-4 alkyl, and -N(C _1-4 alkyl)C(O)C _1-4 alkyl, and when R ₅ is -OC _3-6 alkenyl or -OC _3-6 alkynyl, the double or triple bond, respectively, is not on the carbon directly attached to the oxygen atom; Y ₁ is CH;

Y ₂ is CH;

W is either absent or selected from -CH ₂ -, and -(CH ₂ ) ₂ -;

R _B is one or more groups independently selected from hydrogen, halogen, hydroxyl, C _1-6 alkyl, -N(C _1-6 alkyl) ₂ , -NH(C _1-6 alkyl), -C _1-6 haloalkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, -OC _{1- 6} alkyl, -OC _3-6 alkenyl, -OC _3-6 alkynyl, -SC _1-6 alkyl, -CN, -C(O)C _3-6 Cyeloalkyl, -C(O)OH, - C(O)NH ₂ , -C(O)N(C _1-6 alkyl) ₂ , -C(O)NH(C _1-6 alkyl), -NHC(O)C _1-4 alkyl and -N(C _1-4 alkyl)C(O)C _1-4 alkyl;

R ₁ is selected from hydrogen, halogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 haloalkyl, C ₃ - 6 halocycloalkyl, C _1-6 hydroxyalkyl, C _3-6 hydroxycycloalkyl, -C _1-6 alkyl-O-C _1-6 alkyl, - CONR ₆ R ₇ , -(CH ₂ ) _P NH ₂ , and -CN; R ₆ and R are independently selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1- 6 hydroxyalkyl, and C _1-6 haloalkyl; or R ₆ and R ₇ together with the nitrogen atom to which they are attached form a 3 -7 membered heterocycloalkyl ring optionally containing one or two additional heteroatoms independently selected from oxygen, sulfur, and -N(R ₈ )-, wherein R ₈ is hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, hydroxyl or -OCH3; p is an integer ranging from 1 to 3;

R ₂ and R ₃ are each independently selected from hydrogen, C _2-6 hydroxyalkyl, C _2-6 haloalkyl and C _1-4 alkyl optionally substituted with C _3-6 cycloalkyl; or R ₂ and R ₃ together with the nitrogen atoms to which they are attached form a 4-7 membered heterocycloalkyl ring; R ₄ is selected from -C(O)C _1-6 alkyl, -C(O)C _3-6 cycloalkyl, -C(S)C _1-6 alkyl, -C(S)C ₃ - 6 cycloalkyl, -C(S)C _3-6 cycloalkenyl , -SO ₂ C _1-6 alkyl, -CHO and -CN; or R ₄ is a moiety selected from: wherein R ₉ , R ₁₀ , and R ₁₁ are independently selected from hydrogen, C _1-6 alkyl, halogen, C ₃ - 6 cycloalkyl, C _1-6 haloalkyl, C _3-6 halocycloalkyl, C _1-6 hydroxyalkyl, C _3-6 hydroxy cycloalkyl, -C _1-6 alkyl-0-C _3-6 cycloalkyl, -CN, -C(O)NR ₁₂ R ₁₃ , -(CH ₂ )qC(O)NR ₁₂ R ₁₃ , C _1-6 cyanoalkyl, - C(O)OH, -C(O)OC _1-6 alkyl, -(CH ₂ ) _q C(O)OH, -(CH ₂ ) _q C(O)OC _1-6 alkyl, -(CH ₂ ) _q NR ₁₂ R ₁₃ , and a 4 to 7 membered heterocycloalkyl containing 1 or 2 heteroatoms wherein each heteroatom is independently selected from oxygen, sulfur and N(R ₁₄ ); or R ₉ and R ₁₀ taken together forms a 3 to 6 membered carbocyclic ring; wherein q is an integer selected from 1 to 4; R ₁₂ and R ₁₃ are independently selected from hydrogen, and C _1-6 alkyl, or R ₁₂ and R ₁₃ together with the nitrogen atom to which they are attached forms a 4 to 7 membered heterocycloalkyl ring; R ₁₄ is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkyl-O-C _1-6 alkyl, and C _1-6 aminoalkyl; R ₁₅ is hydrogen or -C _1-3 alkyl;

R ₁₆ is selected from hydrogen, hydroxyl, -OC _1-6 alkyl, -C _1-6 alkyl-O-C _1-6 alkyl, C _{1- 6} hydroxyalkyl and -C _1-3 alkyl-C(O)N(R ₁₇ )R ₁₈ ; R ₁₇ is hydrogen, or -C _1-3 alkyl; and R ₁₈ is selected from hydrogen, hydroxyl, -C _1- 3alkyl and -OC _1-3 alkyl; m is an integer selected from 1, 2 and 3; and n is an integer selected from 1, 2 and 3.

In another embodiment of above aspect, the present invention provides a compound of Formula Id or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein R _A is selected from hydroxyl and -N(R ₁₅ )R ₁₆ ; wherein R ₅ is one or more groups independently selected from hydrogen, halogen, hydroxyl, -C _1-6 alkyl, -C _1-6 haloalkyl, -OC _1-6 alkyl, and -SC _1-6 alkyl;

W is either absent or selected from -CH ₂ -, and -(CH ₂ ) ₂ -;

R _B is one or more groups independently selected from hydrogen, halogen, C _1-6 alkyl, -C _1-6 haloalkyl, -OC _1-6 alkyl, and -SC _1-6 alkyl;

R ₁ is selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, and -CN;

R ₂ and R ₃ are each independently selected from hydrogen, and C _1-4 alkyl; R ₁ is selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, and -CN;

R ₂ and R ₃ are each independently selected from hydrogen, and C _1-4 alkyl optionally substituted with C _3-6 cycloalkyl; R ₄ is a moiety selected from: wherein R ₉ is hydrogen, R ₁₀ is hydrogen and R ₁₁ is selected from hydrogen, C _1-6 alkyl, and -(CH ₂ )qNR ₁₂ R ₁₃ , wherein q is an integer selected from 1 to 2; R ₁₂ and R ₁₃ are independently selected from hydrogen, and C _1-6 alkyl, or R ₁₂ and R ₁₃ together with the nitrogen atom to which they are attached forms a 4 to 6 membered heterocycloalkyl ring;

R ₁₅ is hydrogen or -C _1-3 alkyl;

R ₁₆ is selected from hydrogen, hydroxyl, -OC _1-6 alkyl, -C _1-6 alkyl-O-C _1-6 alkyl, C _1- 6hydroxyalkyl and -C _1-3 alkyl-C(O)N(R ₁₇ )R ₁₈ ; R ₁₇ is hydrogen, or -C _1-3 alkyl; and R ₁₈ is selected from hydrogen, hydroxyl, -C _1- 3alkyl and -OC _1-3 alkyl; m is an integer selected from 1, and 2; and n is an integer selected from 1, and 2.

In another embodiment of above aspect, the present invention provides a compound of Formula Id or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein R _A is R ₅ is one or more groups independently selected from hydrogen, halogen, hydroxyl, -C _1-6 alkyl, -C _1-6 haloalkyl, -OC _1-6 alkyl, and -SC _1-6 alkyl; Y ₁ is CH; Y ₂ is CH;

W is either absent or -CH ₂ -;

R _B is one or more groups independently selected from hydrogen, halogen, C _1-6 alkyl, -C _1-6 haloalkyl, -OC _1-6 alkyl, and -SC _1-6 alkyl;

R ₁ is selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, and -CN; R ₂ and R ₃ are each independently selected from hydrogen, and C _1-4 alkyl; R ₄ is a moiety selected from: wherein R ₉ is hydrogen, R ₁₀ is hydrogen and R ₁₁ is selected from hydrogen, C _1-6 alkyl, and -(CH ₂ )qNR ₁₂ R ₁₃ , wherein q is an integer selected from 1 to 2; R ₁₂ and R ₁₃ are independently selected from hydrogen, and C _1-6 alkyl, or R ₁₂ and R ₁₃ together with the nitrogen atom to which they are attached forms a 4 to 6 membered heterocycloalkyl ring; m is an integer selected from 1, and 2; and n is an integer selected from 1, and 2.

In another embodiment of above aspect, the present invention provides a compound of Formula Id or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein R _A is hydroxyl.

In another embodiment of above aspect, the present invention provides a compound of Formula Id or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein R _A is

R ₂ and R ₃ are each independently selected from hydrogen, and C _1-4 alkyl; R ₄ is a moiety selected from: wherein R ₉ is hydrogen, R ₁₀ is hydrogen, and R ₁₁ is selected from hydrogen, C _1-6 alkyl, halogen, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, -CN, -C _1-6 cyanoalkyl, and -(CH ₂ ) _q NR ₁₂ R ₁₃ , wherein q is an integer selected from 1 to 2; and R ₁₂ and R ₁₃ are independently selected from hydrogen, and C _1-6 alkyl.

In another embodiment, R ₂ and R ₃ are each independently selected from hydrogen and methyl. In another embodiment, R ₁₁ is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl and -CH ₂ N(CH ₃ ) ₂ .

In another embodiment of above aspect, the present invention provides a compound of Formula Id or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein R _B is one to five groups independently selected from hydrogen, halogen, hydroxyl, C _1-6 alkyl, and -OC _1-6 alkyl. In another embodiment, R _B is one to five groups independently selected from hydrogen, fluoro, methyl, ethyl, methoxy and ethoxy. In another embodiment, R _B is one to three groups independently selected from hydrogen, fluoro, and methoxy. In another embodiment of above aspect, the present invention provides a compound of Formula Id or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein R ₈ is one to three groups independently selected from hydrogen, halogen, -C _1-6 alkyl, and -OC _1-6 alkyl. In another embodiment, R ₅ is one to three groups independently selected from hydrogen, fluoro, methyl and methoxy. In another embodiment of above aspect, R ₁ is selected from hydrogen, fluoro, alkyl and -CN. In another embodiment, R ₁ is selected from hydrogen, fluoro, methyl and -CN. In another embodiment, R ₁ is hydrogen.

In another embodiment of the above aspect, the present invention provides a compound of Formula Id or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein W is absent. In another embodiment, W is -CH ₂ -.

In another embodiment of the above aspect, the present invention provides a compound of Formula Id or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein m and n both are integer 2. In another embodiment, m and n both are integer 1. In another embodiment, m is 2 and n is 1. In another embodiment of the above aspect, the present invention provides a compound of Formula Id or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein W is absent, R ₁ is hydrogen, m is 2 and n is 2.

In another embodiment of above aspect, the present invention provides a compound of Formula Id or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein R _A is selected from hydroxyl and -N(R ₁₅ )R ₁₆ ; R ₅ is one or more groups independently selected from hydrogen, halogen, -C _1-6 alkyl, and -O C _1-6 alkyl; Y ₁ is CH; Y ₂ is CH;

W is absent;

R _B is one or more groups independently selected from hydrogen, halogen, and

-OC _1-6 alkyl;

R ₁ is hydrogen;

R ₂ and R ₃ each independently is hydrogen; R ₄ is a moiety selected from: wherein R ₉ is hydrogen, R ₁₀ is hydrogen, and R ₁₁ is selected from hydrogen, and C _1-6 alkyl;

R ₁₅ is hydrogen;

R ₁₆ is selected from hydrogen, and -C _1-3 alkyl-C(O)N(R ₁₇ )R ₁₈ ; R ₁₇ is hydrogen; and R ₁₈ is -OC _1-3 alkyl; m is 2 and n is 2. In another embodiment of above aspect, the present invention provides a compound of Formula Id or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein R _A is selected from hydroxyl and -N(R ₁₅ )R ₁₆ ; R ₅ is one or more groups independently selected from hydrogen or halogen, Y ₁ is CH; Y ₂ is CH;

W is either absent or -CH ₂ -;

R _B is one or more groups independently selected from hydrogen and halogen;

R ₁ is hydrogen or halogen;

R ₂ and R ₃ each independently is hydrogen; R ₄ is a moiety selected from: wherein R ₉ is hydrogen, R ₁₀ is hydrogen, and R ₁₁ is selected from hydrogen, and C _1-6 alkyl; R ₁₅ is hydrogen;

R ₁₆ is selected from hydroxyl, and -OC _1-6 alkyl; m is an integer selected from 1, and 2; and n is an integer selected from 1, and 2.

In another embodiment of above aspect, the present invention provides a compound of Formula Id or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein R _A is selected from and hydroxyl; wherein R ₅ is one or more groups independently selected from hydrogen, halogen, and -Ci -6 alkyl; Y ₁ is CH; Y ₂ is CH;

W is absent;

R _B is one or more groups independently selected from hydrogen and halogen;

R ₁ is hydrogen, or -CN;

R ₂ is hydrogen; R ₃ is selected from hydrogen, and C _1-4 alkyl; R ₄ is a moiety selected from: wherein R ₉ is hydrogen, R ₁₀ is hydrogen, and

R ₁₁ is selected from hydrogen, C _1-6 alkyl, and -(CH ₂ )qNR ₁₂ R ₁₃ , wherein q is 1; R ₁₂ and R ₁₃ are each independently selected from hydrogen and C _1-6 alkyl; m is an integer selected from 1, and 2; n is an integer selected from 1, and 2.

In another embodiment of above aspect, the present invention provides a compound of Formula Id or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein R _A is selected from and hydroxyl; R ₅ is one or more groups independently selected from hydrogen, halogen, and -C _1-6 alkyl; Y ₁ is CH; Y ₂ is CH;

W is either absent or -CH ₂ -,

R _B is hydrogen;

R ₁ is hydrogen;

R ₂ and R ₃ each independently is hydrogen; R ₄ is a moiety selected from: wherein R ₉ is hydrogen, R ₁₀ is hydrogen,

R ₁₁ is selected from hydrogen, and C _1-6 alkyl; m is an integer selected from 1, and 2; n is an integer selected from 1, and 2;

In another aspect, the present invention provides a compound of Formula Ie or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein R ₅ is one or more groups independently selected from hydrogen, halogen, hydroxyl, -C _1-6 alkyl, -N(C _1-6 alkyl) ₂ , -NH(C _1-6 alkyl), -C _1-6 haloalkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, - OC _1-6 alkyl, -OC _3-6 alkenyl, -OC _3-6 alkynyl, -SC _1-6 alkyl, -CN, -C(O)C _1-4 alkyl, -C(O)C _3-6 cycloalkyl, -C(O)OH, -C(O)NH ₂ , -C(O)N(C _1-6 alkyl) ₂ , -C(O)NH(C _1-6 alkyl), -NHC(O)C _1-4 alkyl, and -N(C _1-4 alkyl)C(O)C _1-4 alkyl and when R ₅ is -OC _3-6 alkenyl or -OC _3-6 alkynyl, the double or triple bond, respectively, is not on the carbon directly attached to the oxygen atom; Y ₁ is CH; Y ₂ is CH;

W is either absent or selected from -CH ₂ -, and -(CH ₂ ) ₂ -;

R _B is one or more groups independently selected from hydrogen, halogen, hydroxyl, C _1-6 alkyl, -N(C _1-6 alkyl) ₂ , -NH(C _1-6 alkyl), -C _1-6 haloalkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, -OC _1- 6 alkyl, -OC _3-6 alkenyl, -OC _3-6 alkynyl, -SC _1-6 alkyl, -CN, -C(O)C _3-6 Cycloalkyl, -C(O)OH, - C(O)NH ₂ , -C(O)N(C _1-6 alkyl) ₂ , -C(O)NH(C _1-6 alkyl), -NHC(O)C _1-4 alkyl and -N(C _1-4 alkyl)C(O)C _1-4 alkyl;

R ₁ is selected from hydrogen, halogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 haloalkyl, C ₃ - 6 halocycloalkyl, C _1-6 hydroxyalkyl, C _3-6 hydroxycycloalkyl, -C _1-6 alkyl-O-C _1-6 alkyl, - CONR ₆ R ₇ , -(CH ₂ ) _P NH ₂ , and -CN; R ₆ and R are independently selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1- 6 hydroxyalkyl, and C _1-6 haloalkyl; or R ₆ and R ₇ together with the nitrogen atom to which they are attached form a 3 -7 membered heterocycloalkyl ring optionally containing one or two additional heteroatoms independently selected from oxygen, sulfur, and -N(R ₈ )-, wherein R ₈ is hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, hydroxyl or -OCH3; p is an integer ranging from 1 to 3;

R ₂ and R ₃ are each independently selected from hydrogen, C _2-6 hydroxyalkyl, C _2-6 haloalkyl and C _1-4 alkyl optionally substituted with C _3-6 cycloalkyl; or R ₂ and R ₃ together with the nitrogen atoms to which they are attached form a 4-7 membered heterocycloalkyl ring; R ₄ is selected from -C(O)C _1-6 alkyl, -C(O)C _3-6 cycloalkyl, -C(S)C _1-6 alkyl, -C(S)C ₃ - 6 cycloalkyl, -C(S)C _3-6 cycloalkenyl , -SO ₂ C _1-6 alkyl, -CHO and -CN; orR ₄ is a moiety selected from: wherein R ₉ , R ₁₀ , and R ₁₁ are independently selected from hydrogen, C _1-6 alkyl, halogen, C ₃ - ₆ cycloalkyl, C _1-6 haloalkyl, C _3-6 halocycloalkyl, C _1-6 hydroxyalkyl, C _3-6 hydroxy cycloalkyl, -C _1-6 alkyl-O-C _3-6 cycloalkyl, -CN, -C(O)NR ₁₂ R ₁₃ , -(CH ₂ )qC(O)NR ₁₂ R ₁₃ , C _1-6 cyanoalkyl, - C(O)OH, -C(O)OC _1-6 alkyl, -(CH ₂ ) _q C(O)OH, -(CH ₂ ) _q C(O)OC _1-6 alkyl, -(CH ₂ ) _q NR ₁₂ R ₁₃ , and a 4 to 7 membered heterocycloalkyl containing 1 or 2 heteroatoms wherein each heteroatom is independently selected from oxygen, sulfur and N(R ₁₄ ); or R ₉ and R ₁₀ taken together forms a 3 to 6 membered carbocyclic ring; wherein q is an integer selected from 1 to 4; R ₁₂ and R ₁₃ are independently selected from hydrogen, and C _1-6 alkyl, or R ₁₂ and R ₁₃ together with the nitrogen atom to which they are attached forms a 4 to 7 membered heterocycloalkyl ring; R ₁₄ is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkyl-O-C _1-6 alkyl, and C _1-6 aminoalkyl; m is an integer selected from 1, 2 and 3; and n is an integer selected from 1, 2 and 3.

In another embodiment of the above aspect, the present invention provides a compound of Formula Ie or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein R ₅ is one or more groups independently selected from hydrogen, halogen, hydroxyl, -C _1-6 alkyl, -C _1-6 haloalkyl, -OC _1-6 alkyl, and -SC _1-6 alkyl; Y ₁ is CH; Y ₂ is CH;

W is either absent or -CH ₂ -,

R _B is one or more groups independently selected from hydrogen, halogen, C _1-6 alkyl, -C _1-6 haloalkyl, -OC _1-6 alkyl, and -SC _1-6 alkyl;

R ₁ is selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, and -CN;

R ₂ and R ₃ are each independently selected from hydrogen, and C _1-4 alkyl optionally substituted with C _3-6 cycloalkyl; R ₄ is a moiety selected from: wherein R ₉ is hydrogen, R ₁₀ is hydrogen and R ₁₁ is selected from hydrogen, C _1-6 alkyl, and -(CH ₂ )qNR ₁₂ R ₁₃ , wherein q is an integer selected from 1 to 2; R ₁₂ and R ₁₃ are independently selected from hydrogen, and C _1-6 alkyl, or Rn and R ₁₃ together with the nitrogen atom to which they are attached forms a 4 to 6 membered heterocycloalkyl ring; m is an integer selected from 1, and 2; and n is an integer selected from 1, and 2.

In another embodiment of the above aspect, the present invention provides a compound of Formula Ie or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein R _B is one to five groups independently selected from hydrogen, halogen, hydroxyl, C _1-6 alkyl, and -OC _1-6 alkyl. In another embodiment, R _B is one to five groups independently selected from hydrogen, fluoro, methyl, ethyl, methoxy and ethoxy. In another embodiment, R _B is one to three groups independently selected from hydrogen, fluoro, and methoxy.

In another embodiment of above aspect, the present invention provides a compound of Formula Ie or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein R ₅ is one to three groups independently selected from hydrogen, halogen, -C _1-6 alkyl, and -OC _1-6 alkyl. In another embodiment, R ₅ is one to three groups independently selected from hydrogen, fluoro, methyl and methoxy.

In another embodiment of above aspect, R ₁ is selected from hydrogen, fluoro, alkyl and -CN. In another embodiment, R ₁ is selected from hydrogen, fluoro, methyl and -CN. In another embodiment, R ₁ is hydrogen.

In another embodiment of the above aspect, the present invention provides a compound of Formula Ie or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein:

R ₂ and R ₃ are each independently selected from hydrogen, and C _1-4 alkyl; R ₄ is a moiety selected from: wherein R ₉ is hydrogen, R ₁₀ is hydrogen, and R ₁₁ is selected from hydrogen, C _1-6 alkyl, halogen, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, -CN, -C _1-6 cyanoalkyl, and -(CH ₂ )qNR ₁₂ R ₁₃ , wherein q is an integer selected from 1 to 2; R ₁₂ and R ₁₃ are independently selected from hydrogen, and C _1-6 alkyl.

In another embodiment, R ₂ and R ₃ are each independently selected from hydrogen and methyl.

In another embodiment, R ₁₁ is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl and -CH ₂ N(CH ₃ ) ₂ .

In another embodiment of the above aspect, the present invention provides a compound of Formula Ie or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein W is absent. In another embodiment, W is -CH ₂ -.

In another embodiment of the above aspect, the present invention provides a compound of Formula Ie or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein m and n both are integer 2. In another embodiment, m and n both are integer 1. In another embodiment, m is 2 and n is 1.

In another embodiment of the above aspect, the present invention provides a compound of Formula Ie or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein W is absent, R ₁ is hydrogen, m is 2 and n is 2.

In another embodiment of above aspect, the present invention provides a compound of Formula Ie or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein R ₅ is one or more groups independently selected from hydrogen, halogen, -C _1-6 alkyl, and -OC _1-6 alkyl; Y ₁ is CH; Y ₂ is CH;

W is absent;

R _B is one or more groups independently selected from hydrogen, halogen, and - OC _1-6 alkyl;

R ₁ is hydrogen;

R ₂ and R ₃ each independently is hydrogen; R ₄ is a moiety selected from: wherein R ₉ is hydrogen, R ₁₀ is hydrogen, and R ₁₁ is selected from hydrogen, and C _1-6 alkyl; m is 2 and n is 2.

In another embodiment of above aspect, the present invention provides a compound of Formula Ie or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein R ₅ is one or more groups independently selected from hydrogen and halogen, Y ₁ is CH; Y ₂ is CH;

W is either absent or -CH ₂ -;

R _B is one or more groups independently selected from hydrogen and halogen,

R ₁ is hydrogen or halogen;

R ₂ and R ₃ each independently is hydrogen; R ₄ is a moiety selected from: wherein R ₉ is hydrogen, R ₁₀ is hydrogen, and R ₁₁ is selected from hydrogen, and C _1-6 alkyl; m is an integer selected from 1, and 2; and n is an integer selected from 1, and 2.

In another embodiment of above aspect, the present invention provides a compound of Formula Ie or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein R ₅ is one or more groups independently selected from hydrogen, halogen, and -C _1-6 alkyl; Y ₁ is CH; Y ₂ is CH;

W is absent;

R _B is one or more groups independently selected from hydrogen and halogen;

R ₁ is hydrogen, or -CN;

R ₂ is hydrogen; R ₃ is selected from hydrogen, and C _1-4 alkyl; R ₄ is a moiety selected from: wherein R ₉ is hydrogen, R ₁₀ is hydrogen;

R ₁₁ is selected from hydrogen, C _1-6 alkyl, and -(CH ₂ )qNR ₁₂ R ₁₃ , wherein q is 1; R ₁₂ and R ₁₃ are each independently selected from hydrogen and C _1-6 alkyl; m is an integer selected from 1, and 2; and n is an integer selected from 1, and 2.

In another embodiment of above aspect, the present invention provides a compound of Formula Ie or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein R ₅ is one or more groups independently selected from hydrogen, halogen, and -C _1-6 alkyl; Y ₁ is CH; Y ₂ is CH;

W is either absent or -CH ₂ -,

R _B is hydrogen;

R ₁ is hydrogen;

R ₂ and R ₃ each independently is hydrogen; R ₄ is a moiety selected from: wherein R ₉ is hydrogen, R ₁₀ is hydrogen, and R ₁₁ is selected from hydrogen, and C _1-6 alkyl; m is an integer selected from 1, and 2; and n is an integer selected from 1, and 2.

In another embodiment, the compounds of Formula I is selected from:

N'-[2-[ 3-[ [ 4-Amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[2.3-d]pyrimidi n-1- yl]methyl]cyclobutylidene]acetyl]but-2-ynehydrazide;

(E)-N'-[2-[ 3-[ [ 4-Amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[2.3-d]pyrimidi n-1- yl]methyl] cyclobutylidene] acetyl] but-2-enehy drazide ; N'-[2-[ 3-[ [ 4-Amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[2.3-d]pyrimidi n-1- yl]methyl]cyclobutylidene]acetyl]prop-2-enehydrazide;

(E)-N'-[2-[4-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazo lo[2.3-d]pyrimidin-1- yl]cyclohexylidene]acetyl]but-2-enehydrazide; N'-[2-[ 4- [ 4-Amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[2.3-d]pyrimidi n-1- yl]cyclohexylidene]acetyl]but-2-ynehydrazide; N'-[2-[ 4- [ 4-Amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[2.3-d]pyrimidi n-1- yl]cyclohexylidene]acetyl]prop-2-enehydrazide; N'-[2-[4-[4-amino-3-(4- phenoxyphenyl)pyrazolo[2.3-d]pyrimidin-1- yl]cyclohexylidene]acetyl]but-2-ynehydrazide; N'-[2-[4-[4-amino-3-(4- phenoxyphenyl)pyrazolo[2.3-d]pyrimidin-1- yl]cyclohexylidene]acetyl]prop-2-enehydrazide;

N'-[2-[4-[4-Amino-5-(2-fluoro-4-phenoxy-phenyl)pyrrolo[2. 3-d]pyrimidn-7- yl]cyclohexylidene]acetyl]prop-2-enehydrazide;

(E)-N'-[2-[4-[4-Amino-5-(2-fluoro-4-phenoxy-phenyl)pyrrol o[2.3-d]pyrimidn-7- yl]cyclohexylidene]acetyl]but-2-enehydrazide;

N'-[2-[4-[4-Amino-5-(2-fluoro-4-phenoxy-phenyl)pyrrolo[2. 3-d]pyrimidn-7- yl]cyclohexylidene]acetyl]but-2-ynehydrazide;

(E)-N'-[ 2-[4- [4-Amino-5 -(4-phenoxyphenyl)pyrrolo [2,3 -d]pyrimidin-7- yl]cyclohexylidene]acetyl]but-2-enehydrazide; N'-[ 2-[ 3-[ 4-Amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[2.3-d]pyrimidi n-1- yl]cyclobutylidene]acetyl]prop-2-enehydrazide; N'-[ 2-[ 3-[ 4-Amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[2.3-d]pyrimidi n-1- yl]cyclobutylidene]acetyl]but-2-ynehydrazide; N'-[2-[4-[4-Amino-3-(2-fluoro-4-phenoxy-phenyl)pyrrolo[3.4-d ]pyrimidn-1- yl] cyclohexy lidene] acetyl] -N-methyl-but-2-ynchydrazide;

N'-[2-[4-[4-Amino-3-(2-fluoro-4-phenoxy-phenyl)pyrrolo[3. 4-d]pyrimidn-1- yl] cyclohexy lidene] acetyl] -N-methyl-prop-2-enehydrazide;

N'-[2-[4-[4-Amino-3 -[3 -fluoro-4-(2-fluorophenoxy)phenyl]pyrazolo]3.4-d]pyrimidn-1- yl]cyclohexylidene]acetyl]but-2-ynehydrazide;

N'-[2-[4-[4-Amino-3 -[3 -fluoro-4-(2-fluorophenoxy)phenyl]pyrazolo]3.4-d]pyrimidn-1- yl]cyclohexylidene]acetyl]prop-2-enehydrazide;

N'-[2-[4-[4 -Amino-5-(4-phenoxyphenyl)pyrrolo[2.3-d]pyrimidin-7- yl]cyclohexylidene]acetyl]but-2-ynehydrazide;

N'-[2-[4-[4 -Amino-5-(4-phenoxyphenyl)pyrrolo[2.3-d]pyrimidin-7- yl]cyclohexylidene]acetyl]prop-2-enehydrazide;

N'-[2-[4-[6-Amino-8-oxo-7-(4-phenoxyphenyl)purin-9-yl]cyc lohexylidene ]acetyl ]but-2- ynehydrazide;

(E)-N'-[2-[4-[6-Amino-8 -oxo-7-(4-phenoxy phenyl )purin-9-yl]cyclohexylidene ]acety] ]bu 2-enehydrazide; N'-[2-[4-[6-Amino-8 -oxo-7-(4-phenoxy phenyl )purin-9-yl]cyclohexylidene ]acetyl ]prop- enehydrazide;

(E)-N'-[2-[4-[4-Amino-5-[4-(2.6-difluorophenoxy)phenyl ]pyrrol[3- pyrimidin-7- il]cyclohexylidene]acetyl]but-2-enehydrazide;

N'-[2-[4-[4-Amino-5-[4-(2.6-difluorophenoxy)phenyl ]pyrrol[3- pyrimidin-7- yl]cyclohexylidene]acetyl]but-2-ynehydrazide;

N'-[2-[4-[4-Amino-5-[4-(2.6-difluorophenoxy)phenyl ]pyrrol[3- pyrimidin-7- yl]cyclohexylidene]acetyl]prop-2-enehydrazide;

N'-[2-[4-[4-Amino-3-[4-(2-fluorophenoxy)phenyl ]pyrrol[4- pyrimidin-1- yl]cyclohexylidene]acetyl]prop-2-enehydrazide;

(E)-N'-[2-[4-[4-Amino-5-[4-(2-pyridyloxy)phenyl ]pyrrol[3- pyrimidin-7- yl]cyclohexylidene]acetyl]but-2-enehydrazide;

N'-[2-[4-[4 -Amino-5-[4-(2-pyridyloxy)phenyl ]pyrrol[3- pyrimidin-7- yl]cyclohexylidene]acetyl]prop-2-enehydrazide;

N'-[2-[4-[4-Amino-3-[4-(2.6-difluorophenoxy)phenyl ]pyrrol[3- pyrimidin-1- yl]cyclohexylidene]acetyl]prop-2-enehydrazide; N'-[2-[4-[4-Amino-3-[4-(2,6-difluorophenoxy)phenyl ]pyrazolo[3,4-d]p rimidin- 1 - yl]cyclohexylidene]acetyl]but-2-ynehydrazide; (E)-N'-[2-[4-[4-Amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[ 3,4-d]pyrimidin-1- yl]cyclohexylidene]acetyl]-4-(dimethylamino)but-2-enehydrazi de; (E)-N'-[2-[4-[4-Amino-3-[4-(2.6-difluorophenoxy)phenyl ]pyrazolo]3,4-d]p rimidin- 1 - yl]cyclohexylidene]acetyl]but-2-enehydrazide;

2- [3 -[[4-Amino-3 -(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidm- 1 - yl]methyl]cyclobutybdene]acetic acid;

2- [3 -[[4-Amino-3 -(2-fluoro-4-phenoxy-phenyl)pyrazolo [3,4-d]pyrimidm- 1 - yl Imethyl |cyclobiitylidene]-N-methoxy-acetamide:

2- [3 -[[4-Amino-3 -(2-fluoro-4-phenoxy-phenyl)pyrazolo [3,4-d]pyrimidm- 1 - yl ]methyl ]cyclobutylidene ]-N-[ (1S)-2-methoxy- 1 -methyl -ethyl |acetamide:

2- [[2-[3 - [[4-Amino-3 -(2-fluoro-4-phenoxy-phenyl)pyrazolo [3,4-d]pyrimidin-1- yl]methyl] cyclobutylidene] acetyl] amino] -A-methoxy-acetamide ;

2-[[2-[4-[4-Amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3 ,4-d]pyrimidin- ly 1] cyclohexy lidene] acetyl] amino] -A-methoxy-acetamide ;

2- [3 -[[4-Amino-3 -(2-fluoro-4-phenoxy-phenyl)pyrazolo [3,4-d]pyrimidin-1- yl]methyl] cy clobutylidene] acetamide ;

2- [4-[4-Amino-3 -(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1- yl]cyclohexylidene]-N-methoxy -acetamide;

2- [4-[4-Amino-3 -(2-fluoro-4-phenoxy-phenyl)pyrazolo [3,4-d]pyrimidin-1- yl] cyclohexylidene] ethanehy droxamic acid;

2- [4-[4-Amino-3-(4-phenoxyphenyl)pyrazolo[2.3-d]pyrimidin-1- yl] cyclohexylidene] ethanehy droxamic acid;

2- [4-[4-Amino-3 -(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1- yl] cyclohexylidene] acetamide ;

2- [4-[4-Amino-3 -(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1- yl] cyclohexylidene] acetic acid;

2- [4-[4-Amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1- yl] cyclohexylidene] acetic acid;

2- [4-[4-Amino-3 3-fluoro-4-(2-fluorophenoxy)phenyl ]pyrazolo[3,4-d]pyrimidin-1- yl] cyclohexylidene] acetic acid; 2-[4-[4-Amino-3-[4-(2-fluorophenoxy)phenyl]pyrazolo[3,4-d]py rimidin-1- yl]cyclohexylidene]acetic acid;

2-[4-[4-Amino-3-[4-(2.6-difluorophenoxy)phenyl]pyrazolo[3 ,4-d]pyrimidin-1- yl]cyclohexylidene] acetic acid;

2-[4-[4-Amino-3-[4-(3-methoxyphenoxy)phenyl]pyrazolo[3,4- d]pyrimidin-1- yl]cyclohexylidene] acetic acid;

N'-[2-[ 3-[[[6-Amino-5-(4-phenoxyphenyl)pyrimidin-4- yl]amino]methyl]cyclobutylidene]acetyl]prop-2-enehydrazide; 2-[3-[[[6-Amino-5-(4-phenoxyphenyl)pyrimidin-4- yl]amino]methyl]cyclobutylidene]acetic acid;

2-[4-[4-Amino-3-[4-[[(5 -fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazolo [3,4-d] pyrimidin-1-yl] cyclohexylidene] acetic acid ;

N-[[ 4-[4-Amino-1-[ 4-[ 2-oxo-2-(2-prop-2- enoylhydrazino)ethylidene] cyclohexyl]pyrazolo[3,4-d]pyrimidin-3-yl ]phenyl ]methyl ] -5 - fluoro-2-methoxy-benzamide;

2-[3-[8-Amino-1-(2-fluoro-4-phenoxy-phenyl)imidazo[1,5-a] pyrazin-3- yl]cyclobutylidene]acetic acid;

N- [2-[3-[8-Amino-1-(2-fluoro-4-phenoxy-phenyl)imidazo[1,5-a]py razin-3- yl]cyclobutylidene]acetyl]prop-2-enehydrazide;

2-[3-[8-Amino-1 -(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl]cyclobutylidene ]acetic acid;

2- [4-[4-Amino-3 -(2-methoxy-4-phenoxy-phenyl)pyrazolo [3,4-d]pyrimidin-1- yl]cy clohexy bdene] acetic acid;

N'-[2-[4-[4-Amino-3-(2-methoxy-4-phenoxy-phenyl)pyrazolo[ 3,4-d]pyrimidin-1- yl]cyclohexylidene]acetyl]prop-2-enehydrazide;

2- [4-[4-Amino-3 -(2 -methyl -4-phenoxy-phenyl)pyrazolo [3,4-d]pyrimidm- 1 - yl] cyclohexylidene] acetic acid;

2- [4-[4-Amino-3 -(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1- yl]cyclohexylidene]-2-fluoro-acetic acid;

2- [4-[4-Amino-3 -(2-fluoro-4-phenoxy-phenyl)pyrazolo [3,4-d]pyrimidin-1- yl] cyclohexylidene]-2-cyano-acetic acid; N'-[2-[4-[4-Amino-3-(2-methyl-4-phenoxy-phenyl)pyrazolo[3,4- d]pyrimidin-1 yl]cyclohexylidene]acetyl]prop-2-enehydrazide;

2- [4-[4-Amino-3- [4-(2-pyridyloxy)phenyl]pyrazolo[3,4-d]pyrimidin-1- yl]cyclohexylidene] acetic acid;

N'-[2-[4-[4-Amino-3-(2-methy -4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1- yl]cyclohexylidene]acetyl]but-2-ynehydrazide;

N'-[2-[4-[4-Amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3 ,4-d]pyrimidin-1- yl]cyclohexylidene]-2-fluoro-acetyl]prop-2-enehydrazide;

2- [4-[4-Amino-3 -(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]cyclohexylid ene] -2- fluoro-acetic acid;

N'-[2-[4-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrim idin-1-yl]cyclohexylidene]- 2-fluoro-acetyl]prop-2-enehydrazide;

N'-[2-[3 -[8-Amino- 1 -(4-phenoxyphenyl)imidazo [1,5-a]pyrazin-3 - yl]cyclobutylidene]acetyl]prop-2-enehydrazide;

N'-[2- [4-[4-Amino-3 -[4-(2-pyridyloxy)phenyl]pyrazolo[3,4-d]pyrimidin-1- yl]cyclohexylidene]acetyl]prop-2-enehydrazide;

N'-[2- [4-[4-Amino-3 -[4-(2-pyridyloxy)phenyl]pyrazolo [3,4-d]pyrimidin-1- yl]cyclohexylidene]acetyl]but-2-ynehydrazide;

2- [4-[4-Amino-3 -(2-fluoro-4-phenoxy-phenyl)pyrazolo [3,4-d]pyrimidin-1- yl]cyclohexylidene]propanoic acid;

2- [4-[4-Amino-3 -(2-fluoro-4-phenoxy-phenyl)pyrazolo [3,4-d]pyrimidin-1- yl] cyclobutylidene] -A -prop -2-enoyl-propanehydrazide ; and pharmaceutically acceptable salts thereof or deuterated analogs thereof.

In another embodiment, the compounds of Formula I is selected from:

N'-[2-[3-[[4-Amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[ 2.3-d]pyrimidin-1 yl]methyl]cyclobutylidene]acetyl]but-2-ynehydrazide;

(E)-N'-[2-[3-[[4-Amino-3-(2-fluoro-4-phenoxy-phenyl)pyraz olo[3,4-d]pyrimidin-1 yl]methyl] cyclobutylidene] acetyl] but-2-enehy drazide ;

N'-[2-[3-[[4-Amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[ 2.3-d]pyrimidin-1- yl]methyl]cyclobutylidene]acetyl]prop-2-enehydrazide; (E)-N'-[2-[4-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[ 2.3-d]pyrimidin-1- yl]cyclohexylidene]acetyl]but-2-enehydrazide;

N'-[2-[4-[4-amino -3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[2.3-d]pyrimidin-1- yl]cyclohexylidene]acetyl]but-2-ynehydrazide;

N'-[2-[4-[4-amino -3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[2.3-d]pyrimidin-1 yl]cyclohexylidene]acetyl]prop-2-enehydrazide;

N'-[2-[4-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrim idin-1- yl]cyclohexylidene]acetyl]but-2-ynehydrazide;

N'-[2-[4-[4-amino -3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1 yl]cyclohexylidene]acetyl]prop-2-enehydrazide;

N'-[2-[4-[4-Amino-5-(2-fluoro-4-phenoxy-phenyl)pyrrolo[2. 3-d]pyrimidin-7- yl]cyclohexylidene]acetyl]prop-2-enehydrazide;

(E)-N'-[2-[4-[4-Amino-5-(2-fluoro-4-phenoxy-phenyl)pyrrol o[2.3-d]pyrimidin-7- yl]cyclohexylidene]acetyl]but-2-enehydrazide;

N'-[2-[4-[4-Amino-5-(2-fluoro-4-phenoxy-phenyl)pyrrolo[2. 3-d]pyrimidin-7- yl]cyclohexylidene]acetyl]but-2-ynehydrazide;

N'-[2-[4-[4-Amino-5-(2-fluoro-4-phenoxy-phenyl)pyrrolo[2. 3-d]pyrimidin-7- yl]cyclohexylidene]acetyl]but-2-ynehydrazide;

N'-[ 2-| 3-| 4-Amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidi n-1- yl]cyclobutylidene]acetyl]prop-2-enehydrazide;

N'-[ 2-| 3-| 4-Amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidi n-1- yl]cyclobutylidene]acetyl]but-2-ynehydrazide;

N'-[2-[4-[4-amino -3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1- yl] cyclobutylidene] acetyl] -N-methy -but-2-ynchydrazidc ;

N'-[2-[4-[4-Amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo|3 .4-d|pyrimidin-1- yl lcyclohexylidene]acetyl] -N-methy prop-2-cnchydrazidc:

N'-[2-[4-[4-Amino-3 -[3 -fluoro-4-(2-fluorophenoxy)phenyl]pyrazolo [3,4-d]pyrimidin-1- yl]cyclohexylidene]acetyl]but-2-ynehydrazide;

N'-[2-[4- [4-Amino-3 -[3 -fluoro-4-(2-fluorophenoxy)phenyl]pyrazolo [3,4-d]pyrimidin-1- yl]cyclohexylidene]acetyl]prop-2-enehydrazide;

N'-[2-[4-[4-Amino-5-(4-phenoxyphenyl)pyrrolo[2.3-d]pyrimi din-7- yl]cyclohexylidene]acetyl]but-2-ynehydrazide; N'-[2-[4-[4-Amino-5-(4-phenoxyphenyl)pyrrolo[2.3-d]pyrimidin -7- yl]cyclohexylidene]acetyl]prop-2-enehydrazide;

N'-[2-[4-[6-Amino-8-oxo-7-(4-phenoxyphenyl)purin-9-yl]cyc lohexylidene]acetyl]but-2- ynehydrazide;

(E)-N'-[2-[4-[6-Amino-8 -oxo-7-(4-phenoxy phenyl )purin-9-yl ]cyclohexylidene]acetyl]but- 2-enehydrazide;

N'-[2-[4-[6-Amino-8-oxo-7-(4-phenoxyphenyl)purin-9-yl ]cyclohexylidene]acetyl]prop-2- enehydrazide;

(E)-N'-[2-[4-[4-Amino-5-[4-(2.6-difluorophenoxy)phenyl ]pyrrolo[2.3-d]pyrimidin-7- yl]cyclohexylidene]acetyl]but-2-enehydrazide;

N'-[2-[4-[4-Amino-5-[4-(2.6-difluorophenoxy)phenyl ]pyrrolo[2.3-d]pyrimidin-7- yl]cyclohexylidene]acetyl]but-2-ynehydrazide;

N'-[2-[4-[4-Amino-5-[4-(2.6-difluorophenoxy)phenyl ]pyrrolo[2.3-d]pyrimidin-7- yl]cyclohexylidene]acetyl]but-2-ynehydrazide;

N'-[2-[4-[4-Amino-3-[4-(2-fluorophenoxy)phenyl ]pyrazolo]3,4-d] rimidin- 1 - yl]cyclohexylidene]acetyl]prop-2-enehydrazide; (E)-N'-[2-[4-[4-Amino-5-[4-(2-pyridyloxy)phenyl ]pyrrolo[2.3-d]pyrimidin-7- yl]cyclohexylidene]acetyl]but-2-enehydrazide;

N'-[2-[4-[4-Amino-5-[4-(2-pyridyloxy)phenyl]pyrrolo[2.3-d ]pyrimidm-7- yl]cyclohexylidene]acetyl]prop-2-enehydrazide;

N'-[2-[4-[4-Amino-3-[4-(2.6-difluorophenoxy)phenyl ]pyrazolo]3,4-d] rimidin- 1 - yl]cyclohexylidene]acetyl]prop-2-enehydrazide;

N'-[2-[4-[4-Amino-3-[4-(2.6-difluorophenoxy)phenyl ]pyrazolo]3,4-d] rimidin- 1 - yl]cyclohexylidene]acetyl]but-2-ynehydrazide;

(E)-N'-[2-[4-[4-Amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazo lo[3,4-d]pyrimidin-1- yl]cyclohexylidene]acetyl]-4-(dimethylamino)but-2-enehydrazi de;

(E)-N'-[2-[4-[4-Amino-3-[4-(2.6-difluorophenoxy)phenyl ]pyrazolo]3,4-d] rimidin- 1 - yl]cyclohexylidene]acetyl]but-2-enehydrazide;

N'-[2-[3-[[[6-Amino-5-(4-phenoxyphenyl)pyrimidin-4- yl]amino]methyl]cyclobutylidene]acetyl]prop-2-enehydrazide; N-[[ 4-[4-Amino-1-[ 4-[2-oxo-2-(2-prop-2- enoylhydrazino)ethylidene] cyclohexyl]pyrazolo [3,4-d]pyrimidin-3-yl ]phenyl]methyl] -5 - fluoro-2-methoxy-benzamide;

N'-[2-[3-[8-Amino-1 -(2-fluoro-4-phenoxy-phenyl)imidazo[1,5-a]pyrazin-3- yl]cyclobutylidene]acetyl]prop-2-enehydrazide;

N'-[2-[4-[4-Amino-3-(2-methoxy-4-phenoxy-phenyl)pyrazolo[ 3,4-d]pyrimidin-1- yl]cyclohexylidene]acetyl]prop-2-enehydrazide;

N'-[2-[4-[4-Amino-3-(2-methy -4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1- yl]cyclohexylidene]acetyl]prop-2-enehydrazide;

N'-[2-[4-[4-Amino-3-(2-methy -4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1- yl]cyclohexylidene]acetyl]but-2-ynehydrazide;

N'-[2-[4-[4-Amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3 ,4-d]pyrimidin-1- yl]cyclohexylidene]-2-fluoro-acetyl]prop-2-enehydrazide;

N'-[2-[4-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrim idin-1-yl |cyclohexylidene|- 2-fluoro-acetyl]prop-2-enehydrazide;

N'-[2-[3 -[8-Amino- 1 -(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3 - yl]cyclobutylidene]acetyl]prop-2-enehydrazide;

N'-[2-[4-[4-Amino-3-[4-(2-pyridyloxy)phenyl]pyrazolo [3,4-d]pyrimidin-1- yl]cyclohexylidene]acetyl]prop-2-enehydrazide;

N'-[2-[4-[4-Amino-3 -[4-(2-pyridyloxy)phenyl]pyrazolo [3,4-d]pyrimidin-1- yl]cyclohexylidene]acetyl]but-2-ynehydrazide;

2-[4-[4-Amino-3 -(2-fluoro-4-phenoxy-phenyl)pyrazolo [3,4-d]pyrimidin-1- yl] cyclobutylidene] -A -prop -2-enoyl-propanehydrazide ; and pharmaceutically acceptable salts thereof or deuterated analogues thereof.

In another embodiment, the compounds of Formula I is selected from:

2-[3-[[4-Amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo [3,4-d]pyrimidin-1- yl]methyl]cyclobutylidene]acetic acid;

2-[3-[[4-Amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo [3,4-d]pyrimidin-1- yl]methyl]cyclobutylidene]-A-methoxy-acetamide;

2-[3-[[4-Amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo [3,4-d]pyrimidin-1- yl Imethyl |cyclobutylidene ]-N-[(1 )-2-methoxy- 1 -methyl -ethyl |acetamide: 2- [[2-[3 - [[4-Amino-3 -(2-fluoro-4-phenoxy-phenyl)pyrazolo [3,4-d]pyrimidin-1- yl]methyl] cy clobutylidene] acetyl] amino] -A-methoxy-acetamide ;

2-[[2-[4-[4-Amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3 ,4-d]pyrimidin- ly 1] cyclohexy lidene] acetyl] amino] -A-methoxy-acetamide ;

2- [3 -[[4-Amino-3 -(2-fluoro-4-phenoxy-phenyl)pyrazolo [3,4-d]pyrimidin-1- yl]methyl] cy clobutylidene] acetamide ;

2- [4-[4-Amino-3 -(2-fluoro-4-phenoxy-phenyl)pyrazolo [3,4-d]pyrimidin-1- yl]cyclohexylidene]-N-methoxy -acetamide;

2- [4-[4-Amino-3 -(2-fluoro-4-phenoxy-phenyl)pyrazolo [3,4-d]pyrimidin-1- yl] cyclohexylidene] ethanehy droxamic acid;

2- [4-[4-Amino-3 -(4-phenoxyphenyl)pyrazolo [3,4-d]pyrimidin-1- yl] cyclohexylidene] ethanehy droxamic acid;

2- [4-[4-Amino-3 -(4-phenoxyphenyl)pyrazolo [3,4-d]pyrimidin-1- yl] cyclohexylidene] acetamide ;

2- [4-[4-Amino-3 -(2-fluoro-4-phenoxy-phenyl)pyrazolo [3,4-d]pyrimidin-1- yl] cyclohexylidene] acetic acid;

2- [4-[4-Amino-3 -(4-phenoxyphenyl)pyrazolo [3,4-d]pyrimidin-1- yl] cyclohexylidene] acetic acid;

2- [4-[4-Amino-3-|3-fluoro-4-(2-fluorophenoxy)phenyl]pyrazolo[2 .3-d]pyrimidin-1- yl] cyclohexylidene] acetic acid;

2- [4-[4-Amino-3-[4-(2-fluorophenoxy)phenyl ]pyrazolo[2.3-d]pyrimidin-1- yl] cyclohexylidene] acetic acid;

2- [4-[4-Amino-3-[4-(2.6-difluorophenoxy)phenyl ]pyrazolo[2.3-d]pyrimidin-1- yl] cyclohexylidene] acetic acid;

2- [4-[4-Amino-3- [4-(3 -methoxyphenoxy)phenyl]pyrazolo [3,4-d]pyrimidin-1- yl] cyclohexylidene] acetic acid;

2-[3-[[[6-Amino-5-(4-phenoxyphenyl)pyrimidin-4- yl]amino]methyl]cyclobutylidene]acetic acid;

2- [4-[4-Amino-3 -[4-[ [(5 -fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazolo [3 ,4- d] pyrimidin-1-yl] cyclohexylidene] acetic acid;

2-[3-[8-Amino-1 -(2-fluoro-4-phenoxy-phenyl)imidazo[1,5-a]pyrazin-3- yl]cyclobutylidene]acetic acid; 2-[3-[8-Amino-1 -(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl]cyclobutylidene ]acetic acid;

2- [4-[4-Amino-3 -(2-methoxy-4-phenoxy-phenyl)pyrazolo [3,4-d]pyrimidin-1- yl]cyclohexylidene] acetic acid;

2- [4-[4-Amino-3 -(2 -methyl -4-phenoxy-phenyl)pyrazolo [3,4-d]pyrimidin-1- yl]cyclohexylidene] acetic acid;

2- [4-[4-Amino-3 -(2-fluoro-4-phenoxy-phenyl)pyrazolo [3,4-d]pyrimidin-1- yl]cyclohexylidene]-2-fluoro-acetic acid;

2- [4-[4-Amino-3 -(2-fluoro-4-phenoxy-phenyl)pyrazolo [3,4-d]pyrimidin-1- yl]cyclohexylidene]-2-cyano-acetic acid;

2- [4-[4-Amino-3- [4-(2-pyridyloxy)phenyl]pyrazolo [3,4-d]pyrimidin-1- yl]cyclohexylidene] acetic acid;

2- [4-[4-Amino-3 -(4-phenoxyphenyl)pyrazolo [3,4-d]pyrimidin-1-yl]cyclohexylidene] -2- fluoro-acetic acid;

2- [4-[4-Amino-3 -(2-fluoro-4-phenoxy-phenyl)pyrazolo [3,4-d]pyrimidin-1- yl]cyclohexylidene]propanoic acid; and pharmaceutically acceptable salts thereof or deuterated analogs thereof.

In another embodiment, the compounds of Formula I is selected from: (E)-N'-[2-[4-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[ 2.3-d]pyrimidin-1 yl]cyclohexylidene]acetyl]but-2-enehydrazide;

N'- [2-[4-[4-Amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[2.3-d]p yrimidin-1- yl]cyclohexylidene]acetyl]but-2-ynehydrazide;

2-[[2-[4-[4-Amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3 ,4-d]pyrimidin- ly 1] cyclohexy lidene] acetyl] amino] -A-methoxy-acetamide ;

N'- [2-[4-[4-Amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[2.3-d]p yrimidin-1- yl]cyclohexylidene]acetyl]prop-2-enehydrazide;

N'-[2-[4-[4-Amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrim idin-1- yl]cyclohexylidene]acetyl]but-2-ynehydrazide;

N'-[2-[4-[4-Amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrim idin-1- yl]cyclohexylidene]acetyl]prop-2-enehydrazide; 2- [4-[4-Amino-3 -(4-phenoxyphenyl)pyrazolo [3,4-d]pyrimidin-1- yl] cyclohexy lidene] acetamide ;

N'-[2-[4-[4-Amino-3-[4-(2-fluorophenoxy)phenyl ]pyrazolo[3,4-d]pyrimidin-1- yl]cyclohexylidene]acetyl]prop-2-enehydrazide;

N'-[2-[4-[4-Amino-3-[4-(2.6-difluorophenoxy)phenyl ]pyrazolo[3,4-d]pyrimidin-1- yl]cyclohexylidene]acetyl]prop-2-enehydrazide;

2- [4-[4-Amino-3- [4-(3 -methoxyphenoxy)phenyl]pyrazolo [3,4-d]pyrimidin-1- yl] cyclohexy lidene] acetic acid;

2- [4-[4-Amino-3 -[4-[ [(5 -fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazolo [3 ,4- d] pyrimidin-1-yl] cyclohexy lidene] acetic acid ;

A- 114-|4-Amino- 1 -[ 4-[ 2-oxo-2-(2-prop-2- enoylhydrazino)ethylidene] cyclohexyl]pyrazolo [3,4-d]pyrimidin-3-yl |phenyl |methyl | -5 - fluoro-2-methoxy-benzamide;

2- [4-[4-Amino-3 -(2-fluoro-4-phenoxy-phenyl)pyrazolo [3,4-d]pyrimidin-1- yl] cyclohexy lidene] acetic acid; and pharmaceutically acceptable salts thereof or deuterated analogs thereof.

In another embodiment, the compounds of Formula I is selected from: (E)- N'-[2-[ 4-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo [3,4-d]pyrimidin-1- yl]cyclohexylidene]acetyl]but-2-enehydrazide;

N'-[2-[ 4-[4-Amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo [3,4-d]pyrimidin-1- yl]cyclohexylidene]acetyl]but-2-ynehydrazide;

N'-[2-[4-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3 ,4-d]pyrimidin-1- yl]cyclohexylidene]acetyl]prop-2-enehydrazide;

N'-[2-[4-[4-Amino-3-(4-phenoxyphenyl)pyrazolo [3,4-d]pyrimidin-1- yl]cyclohexylidene]acetyl]but-2-ynehydrazide;

N'-[2-[4-[4-Amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrim idin-1- yl]cyclohexylidene]acetyl]prop-2-enehydrazide;

N'-[2-[4-[4-Amino-3-[4-(2-fluorophenoxy)phenyl ]pyrazolo[3,4-d]pyrimidin-1- yl]cyclohexylidene]acetyl]prop-2-enehydrazide;

N'-[2-[4-[4-Amino-3-[4-(2.6-difluorophenoxy)phenyl ]pyrazolo[3,4-d]pyrimidin-1- yl]cyclohexylidene]acetyl]prop-2-enehydrazide; and pharmaceutically acceptable salts thereof or deuterated analogs thereof.

Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

In another embodiment, the present invention provides deuterated analogs of compound of Formula I, compound of Formula la, compound of Formula lb, compound of Formula Ic, compounds of Formula Id, or compounds of Formula Ie wherein one to more hydrogen atom is replaced with deuterium. Such compounds can be synthesized by means well known in the art, for example by employing starting material in which one or more hydrogen have been replaced with deuterium. Deuterated analogs may have improved drug metabolism and pharmacokinetics properties, See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. 5(12):524-527 (1984).

The compounds described herein were found to be potent BTK inhibitors and therefore are believed to be useful as medicaments, particularly for the treatment of diseases or disorders that benefit from the inhibition of BTK enzyme. The compounds of the present invention were showing BTK inhibitory activity in both wild and C481S mutant context. The compounds of the present invention can be used as selective agents as inhibitors of BTK either alone or in combination with other related kinases inhibitors, or any other appropriate drugs. Thus the compound of present invention are believed to be useful in treating cancer, particularly in haematological malignancies such as chronic lymphocytic leukaemia (CLL), mantle cell lymphoma (MCL), follicular lymphoma (FL) or even disorder such as diffused large B-cell lymphoma (DLBCL), in which the activated B-cell need to be controlled or the proliferation needs to be down regulated.

Thus in another aspect, the present invention provides a method for treating a subject suffering with a BTK mediated disorder or disease comprising administering to the subject an effective amount of compound of Formula I, compound of Formula la, compound of Formula lb, compound of Formula Ic, compound of Formula Id, compound of Formula Ie or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof.

In another embodiment, the BTK mediated disorders or disease can be selected from, but not limited to, B-cell proliferative disorders such as diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, small lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocyte leukemia, lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, Burkitt lymphoma/leukemia, and lymphomatoid granulomatosis.

Thus in one embodiment, the BTK mediated disorders or disease is a B-cell proliferative disorder. In another embodiment, the B-cell proliferative disorder is selected from diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, small lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocyte leukemia, lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, Burkitt lymphoma/leukemia, and lymphomatoid granulomatosis.

In another embodiment, the present invention provides a method for treating a subject suffering with a BTK mediated disorder or disease comprising administering to the subject an effective amount of compound of Formula I, compound of Formula la, compound of Formula lb, compound of Formula Ic, compound of Formula Id, compound of Formula Ie or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein the BTK mediated disorder or disease is chronic graft versus host disease.

In another embodiment, the present invention provides a method for treating a B- cell proliferative disorder comprising administering to a subject in need thereof an effective amount of compound of Formula I, compound of Formula la, compound of Formula lb, compound of Formula Ic, compound of Formula Id, compound of Formula Ie or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof.

In another embodiment, the present invention provides a method for treating a B- cell proliferative disorder comprising administering to a subject in need thereof an effective amount of compound of Formula I, compound of Formula la, compound of Formula lb, compound of Formula Ic, compound of Formula Id, compound of Formula Ie or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein the B- cell proliferative disorder is selected from diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, small lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocyte leukemia, lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, Burkitt lymphoma/leukemia, and lymphomatoid granulomatosis.

In one embodiment of any of the methods of treatment described herein, the subject has failed to respond to treatment with one or more BTK inhibitors such as ibrutinib or acalabrutinib prior to treatment with a compound of the present invention.

In another embodiment, the subject suffers from a disease (e.g., a cancer) that is resistant to ibrutinib and/or acalabrutinib.

In one embodiment of any of the methods of treatment described herein, the subject has a mutant BTK with a mutation at amino acid 481. In another embodiment, the subject has the BTK mutation C481S.

Yet another embodiment is a method of treating a subject suffering from a BTK mediated disorder or disease comprising (i) detecting a mutant BTK in a sample from the subject, and (ii) administering to the subject an effective amount of compound of Formula I, compound of Formula la, compound of Formula lb, compound of Formula Ic, compound of Formula Id, compound of Formula Ie or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof. In one embodiment, the mutant BTK is a drug-resistant mutation, such as a mutation at amino acid 481, such as C481S.

Pharmaceutical Composition

The compounds disclosed herein may be formulated into a composition that additionally comprises suitable pharmaceutically acceptable carriers, including excipients and other compounds that facilitate administration of the compound to a subject. The pharmaceutical compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable excipients. Such pharmaceutical compositions and the processes for preparing the same are described, for example, in Remington: The Science and Practice of Pharmacy (D. B. Troy, Editor, 21st Edition, Lippincott, Williams & Wilkins, 2006), the contents of which are incorporated herein by reference in their entirety.

Thus, in one embodiment, the present invention provides a pharmaceutical composition comprising a compound of Formula I, compound of Formula la, compound of Formula lb, compound of Formula Ic, compound of Formula Id, compound of Formula Ie or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, with a pharmaceutically acceptable carrier, diluent, or excipient. Suitable doses of the compounds for use in treating the diseases or disorder as described herein can be determined by those skilled in the relevant art. Therapeutic doses are generally identified through a dose ranging study in humans based on preliminary evidence derived from animal studies. Doses must be sufficient to result in a desired therapeutic benefit without causing unwanted side effects. The mode of administration, dosage forms, and suitable pharmaceutical excipients can also be understood and adjusted by those skilled in the art.

General synthetic methods for the preparation of compound of Formula I:

List of Abbreviations:

HATU : 1 -[ Bis(dimethylamino)methylene] - 1H- 1,2,3 -triazolo [ 4.5-b ]pyridinium 3 -oxide hexafluorophosphate

EDC: 1 -Ethyl-3 -(3 -dimethylaminopropyl)carbodiimide

EDC.HCI: 1 -Ethyl-3 -(3 -dimethylaminopropyl)carbodiimide hydrochloride

DCC : N, N'-Dicyclohexy lcarbodiimide

BOP: Benzotriazol-l-yloxytris(dirnethylamino)phosphonium hexafluorophosphate

PTSA: p-Toluenesulfonic acid

DMAP or 4-DMAP: 4-Dimethylaminopyridine

TMS: Trimethylsilyl

TBDMS: tert-Butyldimethylsilyl

THP: Tetrahydropyranyl

MOM: Methoxymethyl ether

NBS: N- B ro m o s iicci n i m i de .

NIS: N-Iodosuccinimide Hal: Halogen

DMF: N, N- Dimethylformamide TEA: Triethylamine NMP : N-Methyl-2-Pyrrolidone THE : Tetrahydrofuran cone. HCI: Concentrated Hydrochloric Acid

The starting materials used for the synthesis of the compounds described herein may be synthesized or can be obtained from commercial sources. The compounds described herein and other related compounds having different substituents can be synthesized using techniques and materials known to those of skill in the art, such as described for example in March, ADVANCED ORGANIC CHEMISTRY 4 ^th Ed., (Wiley 1992): Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3 ^rd Ed., (Wiley, 1999). Other methods for the synthesis of compounds are described herein may be found in International Patent Publication No. WO 01/01982901, and U.S. Patent Publication No. US 2003/0153752 A1. General methods for the preparation of compound as disclosed herein may be derived from known reactions in the field, and the reactions may be modified by the use of appropriate reagents and conditions, as would be recognized by the skilled person, for the introduction of the various moieties found in the formulae as provided herein. As a guide, the following synthetic methods may be utilized.

The products of the reactions may be isolated and purified if desired, using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.

Compounds described herein may be prepared using synthetic methods described herein as a single isomer or a mixture of isomers. A non-limiting example of a synthetic approach towards the preparation of compounds of Formula (I) is shown in General schemes below.

General Synthetic Routes

Ring A, ring B, ring Hy, Y, W, m, n, R ₁ , R ₂ , R ₃ R ₄ , R ₁₅ , and R ₁₆ in the compounds of General Scheme A set forth above, are as defined earlier in the specification for compound of Formula I. LG is a leaving group such as mesylate or tosylate; PG is protected ketone group (e.g. cyclic or acyclic ketals) or it can be an protected alcohol such as -OBz.

As per the General Scheme A above, synthesis of the compound of Formula I can take place via different routes as described. Route A: The heterocyclic compound 13 (e.g., 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4- d]|pyrimidin-4-aminc reacts with

(i) compound 10.2 bearing either a leaving group such as mesylate or tosylate optionally in the presence of a base or

(ii) an alcohol compound, such as compound 10.1, under neutral conditions via a Mitsunobu reaction to furnish alkylated compound 10.3.

Compound 10.3 contains protecting group -PG, which is a protected ketone group (e.g. cyclic or acyclic ketals) or it can be a protected alcohol such as -OBz. Compound 10.3 is deprotected using suitable de-protection method (e.g. acidic de-protection of ketals) or palladium catalyzed de -protection followed by conversion by known chemicals methods to generate ketone 10.4. The formed ketone can be reacted with a suitably substituted phosphonate ester (wherein R ₁ is as defined previously and R ₁₉ is C _1-6 alkyl under Homer Witting reaction or Witting reaction conditions to produce cycloalkylidine esters 10.5 (wherein R ₁₉ is C _1-6 alkyl). The cycloalkylidine ester 10.5 upon hydrolysis gives acid compound of Formula I wherein R _A = -OH.

The compound of Formula I wherein R _A = -OH can be activated with a suitable activating agent, such as HATU or EDC or mixed anhydrides and reacted with suitably substituted hydrazine to produce alkenylacylhydrazides, which on coupling with a suitable acid generate a compound of Formula I wherein R _A = -N(R ₂ )N(R ₃ )R ₄ . A1ternatively, the compound of Formula I wherein R _A is -OH can be directly coupled with a suitably substituted hydrazide compound 5, wherein R ₂ , R ₃ and R ₄ are as defined previously under the known peptide coupling reaction conditions to provide the compound of Formula I wherein R _A = -N(R ₂ )N(R ₃ )R ₄ . In similar manner, activated compound of Formula I wherein R _A = -OH can be reacted with ammonia or suitable substituted hydroxylamine to generate a compound of Formula I wherein R _A = -NR ₁₅ R ₁₆ .

Route B: The heterocyclic compound of formula 10.6, wherein R ₂₃ = halogen such as Br or I and PG is protected C=0 group, can react with a suitably substituted boronate ester (for example, compound 26 or boronic acid (for example, compound 27 wherein ring B, ring A, group Y are as defined previously for the compound of Formula I and R is hydrogen or C _1-6 alkyl under Suzuki coupling conditions to give compound 10.3 A1ternatively, the compound of formula 10.6 with R ₂₃ as hydrogen (for example 6-amino-9-( 1 4-dioxaspiro[4.5]decan-8-yl)-7H-purin-8-one) can be reacted via CHan-Lam coupling with a suitable boronic acid to give compound 10.3. Compound 10.3 can be further transformed into a desired compound of Formula I by process analogous to route A.

Route C: A1ternatively, the compound 10.6 with PG as a protected C=O group can be de- protected using a suitable reagent such as aq. acetic acid, or trifluoroacetic acid, to give corresponding ketone 10.7. The ketone 10.7 after multiple steps as described in route A (for conversion of compound 10.4 through 10.5 and the acid form of compound I to the compound of formula I where R _A is NR ₂ NR ₃ R ₄ ) can generate cycloalkylidinehydrazide 10.9. Specifically the ketone 10.7 is converted (e.g., via known methods of condensation such as a Homer Witting reaction or Witting reaction) to produce a cycloalkylidine ester, which can undergo hydrolysis to give the acid compound 10.8 which can be coupled with suitably substituted hydrazide, for example, with hydrazide compound 5,

(wherein R ₂ , R ₃ and R ₄ are as defined previously) to generate cycloalkylidinehydrazide 10.9. Compound 10.9 can be reacted with a suitably substituted boronate ester or boronic acid, for example, with under Suzuki reaction or CHan

Lam coupling conditions to gives a cycloalkylidinehydrazide compound of Formula I (where R _A = NR ₂ NR ₃ R ₄ ). In one embodiment, the compound of Formula I, wherein W is absent, R _A is -N(R ₂ )- N(R ₃ )R ₄ , can be synthesized as shown in Scheme I below: The groups ring A, ring B, R ₁ , R ₂ , R ₃ , R ₄ , m and n defined in the compounds of

Scheme I are as defined earlier in the specification. Ring Hy defined in the compounds of Scheme I are selected from pyrazolo[3,4-d]pyrimidin-4-aminc. pyrrolo[2.3-d]pyrimidin-4- amine, 6-amino-7,9-dihydropurin-8-one and 5-amino-pyrazole-4-carboxamide moieties

Synthetic precursors useful in Scheme I include ketal-protected ketones, i.e. compound 1 (wherein R ₁₇ a and R ₁₈ a are C _1-6 alkyl or R ₁₇ a and R ₁₈ a together with the oxygen atoms to which they are attached form a cyclic ketal), which are commercially available or can be synthesized by known methods of selective protection and de-protection of ketones. The protected ketone compound 1 can be reacted with a suitably substituted phosphonate ester 2 (wherein R ₁₉ is C _1-6 alkyl) under Homer-Wittig reaction conditions in the presence of a suitable base and solvent to provide ester compound 3. The ester compound 3 can be hydrolyzed using an acid or base in a suitable solvent to yield compound 4. Compound 4 can be coupled with a suitably substituted hydrazine 5 by using a standard peptide coupling method to furnish compound 6. The compound 5 can be obtained by coupling a suitable mono protected hydrazine with different acids using conventional amide coupling methods and can be deprotected at the end to give the desired free hydrazine, for example a tertiary butyl carbazate can be coupled with acrylic acid using HATU or EDC and the product formed can be deprotected with stronger acidic salts, trifluoroacetic acid, or stronger acids such as hydrochloric acid or PTSA to yield a salt of compound 5. Compound 6 can be deprotected using suitable acids such as hydrochloric acid or sulphuric acid, to provide compound 7. Compound 7 can be reduced to compound 8 with the help of a reducing agent such as sodium borohydride in a suitable solvent. Compound 8 can be reacted with compound 13 under Mitsunobu reaction conditions to generate some of the compounds of Formula I.

The compound 13 can be synthesized by schemes (i-iii) set forth below.

In one embodiment, the compound 13 (wherein ring A and ring B are as defined earlier in the specification for the compound of Formula I; Y is selected from -O-, -S-, - NH-, -N(C _1-4 alkyl)- and -N(CH ₂ CN)-; and ring Hy is pyrazolo [3,4-d]pyrimidin-4-aminc moiety) can be prepared as shown in Scheme (i) below:

The groups ring A and ring B in the compounds of Scheme (i) are as defined earlier in the specification for certain compound of Formula I and group Y in the compounds of Scheme (i) is selected from -O-, -S-, -NH- , -N(C _1-4 alkyl)- and -N(CH ₂ CN)-.

Compound 9a can be reacted with the compound 10a (wherein Xi is halogen and M is an electron withdrawing group such as -N02,-CN, -COOH, or -COOCH3) by a facile nucleophilic displacement of the Xi group, or by a copper mediated Ullman coupling to provide a compound 11a. Compound 11a can be converted into its respective acid 12 by methods in the art, e.g. conversion of nitrile to acids, conversion of nitro to acids via reduction, Sandmayer reaction and then displacement of halides with cyanides followed by hydrolysis, or conversion of esters to acids via hydrolysis. The acid 12 can be analogously converted into compound 13 via synthetic procedures in the literature, for example, as reported in CHinese patent application CN103965201 A. In another embodiment, compound 13 (wherein ring A and ring B are as defined earlier in the specification for compound of Formula I; Y is selected from -O-, -NH-, -N(C _1- 4 alkyl)-and -N(CH ₂ CN)-; and ring Hy is pyrazolo [3,4-d]pyrimidin-4-aminc moiety) can be prepared by following the synthetic scheme as shown in Scheme (ii) below:

The groups ring A and ring B in the compounds of Scheme (ii) are as defined earlier in the specification for compound of Formula I and group Y in the compounds of Scheme (ii) is selected from -O-, -NH- , -S-, -NHC(O)— , -NHS(O) ₂ — , -N(C _1-4 alkyl)- and - N(CH ₂ CN).

Compound 9b (wherein D is boronic acid) can be reacted with the compound 10b (wherein J is a suitably substituted functional group which can later be converted into acid e.g. -COOH,-CN, -Br, -I, or -COOCH3) under CHan Lam coupling reaction conditions (J. Org. CHem, 2012, 77, 6, 2878-2884; Org. Lett., 2001, 3, 13, 2077-2079; Org. Lett., 2013, 15, 2314-2317; Synlett, 2014, 25, 505-508) to form compound lib. Examples of the compound 10b include, but are not limited to, 4-bromophenol, 4-bromo-3-flurophenol, 4- bromo-2-fluorophenol, 4-bromo-2-chlorophenol, and 4-bromo-3,5-difluorophenol. The coupling can be suitably carried out in a solvent such as dichloromethane or 1,4-dioxane by using a catalyst, preferably a copper catalyst such as Cu(OAc) ₂ , CuCH, or Cu(OCF ₃ ) ₂ , in the presence of a suitable base such as trimethylamine, pyridine, DMAP or 2,6-lutidine. Compound lib can be converted into acid 12 via a metal halogen exchange reaction with alkyl lithium (e.g., at a low temperature such as at a temperature of -20 °C to -70°C) followed by quenching with solid carbon dioxide, orlib can be converted into its respective acid indirectly by first converting it into a respective nitrile using a reagent such as CuCN, and then conversion into the desired acid 12 by hydrolysis. The acid 12 can be converted to compound 13 by following the analogous process described in CHinese patent publication CN103965201 A.

In another embodiment, the compound 13 (wherein ring A and ring B are as defined earlier in the specification for compound of Formula I; Y is selected from -O-, -S-, -NH-, - N(C _1-4 alkyl)- and -N(CH ₂ CN)-; and ring Hy is pyrrolo[2.3-d]pyrimidin-4-amine moiety) can be prepared as shown in Scheme (iii) below:

Acid 12 can be converted into ketone compound 12a by methods known in the art such as by preparation of a Weinreb amide and then adding Grignard reagents. The compound 12a then can be converted into compound 13 having ring Hy as pyrrolo[2,3- d]pyrimidin-4-aminc moiety. This synthesis involves multiple steps which are analogous to some of the methods described in literature [Organic Process Research & Development 2007, 11, 825-835; WO00/17203, US6001839A]

In another embodiment, the compound of Formula I, wherein W is selected fram- CH ₂ , -(CH ₂ ) ₂ -, -NH- and — NH-CH ₂ -, and R _A is -N(R ₂ )-N(R ₃ )R ₄ , can be synthesized as shown in Scheme II below:

The groups ring A, ring B, R ₁ , R ₂ , R ₃ , R ₄ , m, n and W in the compounds of Scheme II are as defined earlier in the specification for the compound of Formula I. Ring Hy in the compounds of Scheme II are selected from pyrazolo [3,4-d]pyrimidin-4-amine, pyrrolo[2,3- d] p y ri m i d in -4 -am i n e . 6-amino-7,9-dihydropurin-8-one and 5-amino- 1H-pyrazolc-4- carboxamide moieties. PG is a protecting group described as below. The compound 14 (wherein PG is an alcohol protecting group such as TMS, TBDMS, acetate, benzoyl, THP, and MOM) can react in an analogous manner as discussed in general scheme I to furnish the compound of Formula I. Compound 14 is either commercially available or can be synthesized from a suitably protected alcohol by the methods known in the art. Examples of such alcohols include, but are not limited to, 1,4- dioxaspiro[4.5]decan-8-ylmethanol and 5,8-dioxaspiro[3.4]octan-2-ylmethanol.

In another embodiment, the compound of Formula I, wherein ring Hy is pyrazolo[3,4- d]pyrimidin-4-aminc moiety, R _A is -N(R ₂ )-N(R ₃ )R ₄ and ring A, ring B, Y, W, R ₁ , R ₂ , R ₃ , R ₄ , m and n are as defined earlier in the specification can be synthesized as shown in Scheme III below:

The groups ring A, ring B, R ₁ , R ₂ , R ₃ , R ₄ , m, n and W in the compounds of Scheme III are as defined earlier in the specification for the compound of Formula I.

Compound 19 can be reacted with compound 20 (wherein LG is a leaving group such as mesylate, tosylate or nosylate), under nucleophilic SN2 reaction condition in a suitable solvent such as N. N-dimethylformamide. N-methyl-2-pyrolidone. or dimethylsulphoxide, in the presence of a suitable base such as potassium carbonate or cesium carbonate, to give compound 21. Compound 21 can be deprotected to obtain compound 22 and further transformed in multiple steps to compound 25 by following the analogous processes described in Scheme I. Treatment of compound25 with a compound 26 or27 under Suzuki-Miyara coupling reaction conditions provides a certain compounds of Formula I. The coupling can be conveniently carried out in a suitable solvent such as toluene, dioxane, dimethoxyethane or tetrahydrofuran, using a suitable catalyst, for example di-(tri-o-tolylphosphine)-palladium-(II)-chloride,tris-(dibe nzylideneacetone)- dipalladium(O) with o-tolylphosphine, 1,1'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride-dichloromethanecomplex, or tetrakis(triphenylphosphine)- palladium(O), palladium(II)acetate, in the presence of a suitable base such as potassium carbonate, cesium carbonate, triethylamine, sodium phosphate, or potassium phosphate. The compound 26 can be synthesized from compound lib (wherein J is halogen), by reaction with a boron reagent, such as bis(pinacolato)diboron, under Miyaura borylation reaction conditions. The compound 27 (wherein R is C _1-6 alkyl) can be synthesized by carrying out metalation of halides of compound lib with bases such as butyl lithium or phenyl lithium, at low temperature followed by quenching with trialkyl borate to yield compound27 which in certain circumstances can be used as such or converted into corresponding acid (compound 27, wherein R is hydrogen).

In another embodiment, the compound of Formula I, wherein ring Hy is pyrrolo[2,3- d]pyrimidin-4-aminc moiety, R _A is -N(R ₂ )-N(R ₃ )R ₄ and ring A, ring B, Y, W, R ₁ , R ₂ , R ₃ , R ₄ , m and n are as defined earlier in the specification; can be synthesized as shown in Scheme IV below: The groups ring A, ring B, R ₁ , R ₂ , R ₃ , R ₄ , , m, n and W in the compounds of Scheme IV are as defined earlier in the specification for the compound of Formula I. R ₁₇ a and R ₁₈ a are as defined earlier in the specification.

Compound 28 can be reacted with a halogenating agent such as NBS, NIS, or bromine to generate compound 29. Compound 29 can be reacted with alcohol compound 20b under Mitsunobu reaction conditions to give compound 30, which on treatment with ammonia or by conducting a two-step protocol involving aryl amine such as benzyl amine or dibenzylamine or 4-methoxybenzylamine followed by de-arylation can provide compound 31. The compound of Formula I can be generated via multiple steps from compound 31 by following similar analogous steps as described in Scheme III.

In another embodiment, the compound of Formula I, wherein ring Hy is 6-amino- 7,9-dihydropurin-8-one moiety, R _A is -N(R ₂ )-N(R ₃ )R ₄ and ring A, ring B, Y, W, R ₁ , R ₂ , R ₃ , R ₄ , m and n are as defined earlier in the specification can be prepared as shown in Scheme V below. The groups ring A, ring B, R ₁ , R ₂ , R ₃ , R ₄ , , m, n and W in the compounds of Scheme V are as defined earlier in the specification for the compound of Formula I. R ₁₇ a and R ₁₈ a are as defined earlier in the specification.

A dihalo-heteroaryl compound 32 can be reacted with an amine compound 33 (wherein PG is a suitable amino group protecting group such as benzyl) in a suitable solvent, such as dioxane, dichloromethane, and the like, to provide compound 34. Displacement of the second halo group by an amino compound 35 yields compound 36. This reaction can be carried out in a suitable solvent such as dichloromethane, dioxane, tetrahydrofuran, and the like, and in the presence of a suitable base such as triethylamine or di- isopropylethylamine. The nitro group in the compound 36 can be reduced with reagents, such as Zn and ammonium chloride or SnCI ₂ , in a suitable solvent, such as acetic acid or ethanol to afford compound 37.

Compound 37 can be cyclized to form benzimidazolone compound 38 by treating compound 37 in an organic solvent such as dichloromethane and the like, with carbonyldiimidazole, phosgene or a phosgene equivalent, in the presence of a base such as triethylamine or diisopropylethylamine and the like. Removal of the protecting group PG of compound 38 followed by ketone deprotection provides compound 39. Compound 39 can be reacted with phosphonate ester 2 in the presence of a base such as LiHMDS or NaH to give compound 40, which on subsequent hydrolysis by using a base or an acid in a suitable solvent gives compound 41. The compound 41 can be coupled with hydrazine compound 5 using standard peptide coupling methods to give compound 42. Reaction of 42 with aryl boronic acid 27 via a copper mediated coupling (CHan-Lam coupling) can give compound of Formula I.

In another embodiment, the compound of Formula I, wherein ring Hy is imidazo[1,5-a]pyrazin-8-amine moiety, R _A is -N(R ₂ )-N(R ₃ )R ₄ and ring A, ring B, Y, W,

R ₁ , R ₂ , R ₃ , R ₄ , m and n are as defined earlier in the specification can be prepared as shown in Scheme VI below:

The groups ring A, ring B, R ₁ , R ₂ , R ₃ , R ₄ , m, n and W in the compounds of Scheme VI are as defined earlier in the specification for the compound of Formula I. R ₁₇ a and R ₁₈ a are as defined earlier in the specification.

As per scheme VI, the compound of Formula I can be prepared by following the analogous process given in WO 2013/010868. A commercially available (3-chloropyrazin- 2-yl)methanamine hydrochloride 43, can be reacted with a suitably protected ketal acid 44 under standard amide coupling conditions to furnish compound 45. Examples of ketal acid 44 include, but are not limited to, 1,4-dioxaspiro[4.5]decane-8-carboxylic acid, and 5,8- dioxaspiro[3.4]octane-2-carboxylic acid, which are commercially available or can be synthesized by methods known in the art. Compound 45 can be reacted with phosphorous oxychloride in a suitable solvent such as 1,4-dioxane or THF to give cyclized product 46. Compound 46 on treatment with N-b ro m o s ucci n i m i dc (NBS) or N-iodosuccinimidc (NIS) gives the corresponding bromo or iodo substituted compound of general formula 47, which on further reaction with aq. ammonia gives amine compound 48. Compound 48 can be converted to a certain compounds of Formula I by following the analogous process of Scheme-Ill described above.

In another embodiment, the compound of Formula I, wherein ring Hy is 4-amino pyrimidine moiety, R _A is -N(R ₂ )-N(R ₃ )R ₄ and ring A, ring B, Y, R ₁ , R ₂ , R ₃ , R ₄ , m and n are as defined earlier in the specification; and W is — NH-CH ₂ - can be prepared as shown in Scheme VII below:

The groups ring A, ring B, R ₁ , R ₂ , R ₃ , R ₄ , m, and n and in the compounds of Scheme VII are as defined earlier in the specification for the compound of Formula I. R ₁₇ a and R ₁₈ a are as defined earlier in the specification. W is — NH-CH ₂ -

As per scheme VII, a suitably substituted dihalopyrimidines of general formula 49 can react with amine of general formula 50 via nucleophilic aromatic substitution reaction, to give compound 51. Compound 51 can be reacted with acids such as aq. acetic acid or aq. hydrochloric acid to give compound 52. Compound 52 can be converted into compound of Formula I in a manner analogous to Scheme-Ill. In another embodiment, the compound of Formula I, wherein ring Hy is 5-amino- pyrazole-4-carboxamide moiety, R _A is -N(R ₂ )-N(R ₃ )R ₄ and ring A, ring B, Y, W, R ₁ , R ₂ , R ₃ , R ₄ , m and n are as defined earlier in the specification can be prepared as shown in Scheme VIII below:

The groups ring A, ring B, R ₁ , R ₂ , R ₃ , R ₄ , m, n and W in the compounds of Scheme VIII are as defined earlier in the specification for the compound of Formula I. R ₁₇ a and R ₁₈ a are as defined earlier in the specification.

As per Scheme VIII, a commercially available 3-amino-4-cyanopyrazole 53 can react with NBS or NIS to give corresponding halo derivative of general formula 54 Compound 54 can react with compound 20 in presence of a suitable base in a suitable solvent to give compound 55 The nitrile hydrolysis of compound 55 can give amide 56 The amide 56 can be converted into compound of Formula I, in an analogous manner to Scheme III. In another embodiment, the compound of Formula I, wherein ring Hy is pyrazolo[3,4-d]pyrimidin-4-aminc moiety, R _A is hydroxyl or -N(R ₁₅ )R ₁₆ and ring B, Y, ring A, m, n, R ₁ , R ₂ , R ₁₅ and R ₁₆ are as defined earlier in the specification; W is either absent or selected from -CH ₂ - and -(CH ₂ ) ₂ - can be synthesized as shown in Scheme-IX below:

The group R ₂₀ in the compounds of Scheme-IX is , group PG is a protected carbonyl group such as acetals and ketals, W is absent, -CH ₂ - or -(CH ₂ ) ₂ - and m, n, ring B, Y, ring A & R ₁ are as defined earlier in the specification. As per scheme-IX, halogenation of 4-aminopyrazolo[2.3-d]pyrimidine (1.1) can be performed using N-bromosuccinimide or N-iodosuccinimide in suitable solvent such as DMF, THF or acetonitrile, at a suitable temperature to provide compound 1.2 (wherein Hal is halogen). Treatment of compound 1.2 with compound 1.3 (L is a leaving group such as halogen, mesylate, tosylate or triflate; W is absent, -CH ₂ - or -(CH ₂ ) ₂ and PG is a protected carbonyl group such as acetals and ketals) can provide compound 1.4. Coupling of compound 1.4 with boronic acid compound of formula R ₂₀ B(OH) ₂ (wherein R ₂₀ is or boronate ester of Formula R ₂₀ B(OR ₂₁ ) ₂ (wherein R ₂₀ is and R ₂₁ is lower alkyl such as methyl or ethyl) under Suzuki coupling conditions can provide compound 1.5. The coupling reaction can be carried out in a suitable solvent such as THF, dioxane or acetonitrile with water as co-solvent, in presence of a suitable base such as Na ₂ CO ₃ , K ₂ CO ₃ or K ₃ PO ₄ and a suitable catalyst such as Pd(PPh ₃ ) ₄ , or Pd(ddpf)CI ₂ complex with DCM and at a suitable temperature. The compound 1.5 then can be de-protected using acetic acid/water or hydrochloric acid to provide keto compound 1.6 which then can be coupled with a suitably substituted Wittig reagent such as trimethylphosphonoacetate, or triethylphosphonoacetate, in a suitable solvent such as THF, and dioxane, and using a suitable base such as sodium hydride, butyl lithium, or LiHMDS, and at a suitable temperature to provide the ester compound 1.7 (wherein R ₂₂ is lower alkyl such as methyl or ethyl). The compound 1.7 on hydrolysis under acidic (Cone. H ₂ SO ₄ , Cone. HCI) or basic (NaOH, Ba(OH) ₂ , or KOH) conditions in suitable solvent (like ethanol, methanol, water or their mixtures with THF or dioxane) can provide the compound of Formula I (wherein ring Hy is pyrazolo[3,4-d]pyrimidin-4-aminc moiety and R _A is -OH), which can be further coupled with a substituted or un-substituted amine (for example, NH(R ₁₅ )R ₁₆ ) using a suitable peptide coupling agent such as EDC.HCI, DCC, HATU or BOP , in a suitable solvent such as DMF, THF or DCM to provide corresponding amides (compound of Formula I, wherein ring Hy is pyrazolo[3,4-d]pyrimidin-4-aminc moiety and R _A is -N(R ₁₅ )R ₁₆ ) disclosed in this invention.

In another embodiment, the compound of Formula I, wherein ring Hy is imidazo[1,5-a]pyrazin-8-amine moiety, R _A is hydroxyl or -N(R ₁₅ )R ₁₆ and ring B, Y, ring A, m, n, R ₁ , R ₂ , R ₁₅ and R ₁₆ are as defined earlier in the specification; W is either absent or selected from -CH ₂ - and -(CH ₂ ) ₂ can be synthesized as shown in Scheme-X below: The group R ₂₀ in the compounds of Scheme-X is group PG is a protected carbonyl group such as acetals and ketals; W is absent, -CH ₂ - or -(CH ₂ ) ₂ - and m, n, ring B, Y, ring A & R ₁ are as defined earlier in the specification.

As per Scheme-X, reduction of 3-chloropyrazine-2-carbonitrile (2.1) can be accomplished by hydrogenation in the presence of suitable catalyst system and solvent, for example raney nickel and acetic acid to provide amine compound 1.2 which on treatment with compound 2.3 (wherein PG is a carbonyl protecting group) in a suitable solvent such as DCM, DMF or THF, in presence of a base such as DIPEA, TEA or 4-DMAP, and in presence of a coupling agent such as EDC.HCI, HATU, BOP or DCC, can provide compound 2.4. Cyclisation of compound 2.4 using a condensation reagent such as phosphorus oxychloride, in a suitable solvent such as DCM, ethyl acetate or acetonitrile, at a suitable temperature can provide compound 2.5. Subsequent halogenation of compound 2.5 can be accomplished using A-bromosuccinimide or N-iodosiiccinimide in a suitable solvent such as THF, DMF or DCM, to obtain compound 2.6. Compound 2.7 can be obtained from compound 2.6 by reacting with ammonia (gas) in isopropanol or methanol at elevated temperature in a pressure vessel. Compound 2.7 can be further coupled with boronic acid of formula R ₂₀ B(OH) ₂ or boronate ester of formula R ₂₀ B(OR ₂₁ ) ₂ in presence of suitable Pd catalyst like Pd(PPh ₃ ) ₄ or Pd(ddpf)CI ₂ complex with DCM, and a suitable base like sodium or potassium carbonate in dioxane/water to provide compound 2.8. Compound 2.8 then can be de-protected using acetic acid/water or hydrochloric acid at a suitable temperature to provide keto compound 2.9 which then can be coupled with a suitably substituted Wittig reagent such as trimethylphosphonoacetate or triethylphosphonoacetate, in a suitable solvent such as THF, or dioxane, and in presence of a suitable base such as sodium hydride, butyl lithium, or LiHMDS, at a suitable temperature to provide compound 2.10. Compound 2.10 on hydrolysis under acidic (Cone. H ₂ SO ₄ , Cone. HCI) or basic

(NaOH, Ba(OH) ₂ , or KOH) conditions in suitable solvent (like ethanol, methanol, water or their mixtures with THF or dioxane) can provide compound of Formula I (wherein ring Hy imidazo[1,5-a]pyrazin-8-amine moiety and R _A is -OH), which can further coupled with a substituted or un-substituted amines (for example, NH(R ₁₅ )R ₁₆ ) using a suitable peptide coupling agent such as EDC.HCI, DCC, HATU or BOP, in a suitable solvent such as DMF, THF, or DCM to provide corresponding amides (compound of Formula I, wherein ring Hy imidazo[1,5-a]pyrazin-8-amine moiety and R _A is -N(R ₁₅ )R ₁₆ ) disclosed in this invention. In another embodiment, the compound of Formula I, wherein ring Hy is 6-amino- 7,9-dihydropurin-8-one moiety, R _A is hydroxyl or -N(R ₁₅ )R ₁₆ and ring B, Y, ring A, m, n,

R ₁ , R ₂ , R ₁₅ and R ₁₆ are as defined earlier in the specification; W is either absent or selected from -CH ₂ -, -(CH ₂ ) ₂ -, -NH- and — NH-CH ₂ - can be synthesized as shown in Scheme-XI below:

The group R ₂₀ in the compounds of Scheme-XI is group PG is a protected carbonyl group such as acetals and ketals; group PGi is an amine protecting group such as benzyl; W is absent or selected from -CH ₂ -, -(CH ₂ ) ₂ -, -NH- and — NH-CH ₂ - ; and m, n, ring B, Y, ring A & R ₁ are as defined earlier in the specification.

As per scheme-XI, 4,6-dichloro-5-nitropyrimidine (3.1) can be reacted with protected amine compound 3.2 (such as dibenzyl amine or bis-(4-methoxybenzylamine) in suitable solvent such as DCM, DMF, THF or dioxane, in presence of a suitable base such as DIPEA, TEA or pyridine, and at a suitable temperature to give compound 3.3. Compound 3.3 on amination with compound 3.4 in a suitable solvent such as THF, dioxane or DMF, in presence of a suitable base such as DIPEA, TEA or pyridine, and at a suitable temperature can provide compound 3.5. Reduction of compound 3.5 using a metal reagent such as zinc, iron or tin, in a water miscible solvent such as ethanol, methanol or THF, and in the presence or absence of an acid such as acetic acid, or hydrochloric acid, can provide compound 3.6. Cyclization of compound 3.6 using CDI or triphosgene in a suitable solvent such as THF, dioxane or DCM and using a suitable base such as DIPEA, TEA or pyridine, can provide compound 3.7. Compound 3.7 on coupling with boronic acid of formula R ₂₀ B(OH) ₂ in the presence of a copper salt (Copper(II)acetate) and a base such as triethylamine or pyridine, and drying agent in a suitable solvent such as dichloromethane, acetonitrile or toluene, can provide compound 3.8. Compound 3.8 on further de-protection under acidic condition or palladium catalysed deprotection conditions can provide compound 3.9. Compound 3.9 can be further coupled with a suitably substituted Wittig reagent such as trimethylphosphonoacetate, or triethylphosphonoacetate, in suitable solvents like THF, and dioxane and using a suitable base like sodium hydride, butyl lithium, or LiHMDS and, at a suitable temperature can provide compound 3.10. Compound 3.10 can be further hydrolyzed under acidic (cone. H ₂ SO ₄ , cone. HCI) or basic (NaOH, Ba(OH) ₂ , or KOH) conditions in suitable solvent (like ethanol, methanol, water or their mixtures with THF or dioxane) to provide the compound of Formula I (wherein ring Hy is 6-amino-7,9- dihydropurin-8-one moiety and R _A is -OH), which can further be coupled with a substituted or un-substituted amines (for example, NH(R ₁₅ )R ₁₆ ) using a suitable peptide coupling agent such as EDC.HCI, DCC, HATU or BOP, in a suitable solvent such as DMF, THF, or DCM to provide corresponding amides (compound of Formula I, wherein ring Hy is 6-amino-7,9- dihydropurin-8-one moiety and R _A is -N(R ₁₅ )R ₁₆ ) disclosed in this invention.

In another embodiment, the compound of Formula I, wherein ring Hy is 4- aminopyrimidine moiety, R _A is hydroxyl or -N( R ₁₅ )R ₁₆ and ring B, Y, ring A, m, n, R ₁ , R ₂ , R ₁₅ and R ₁₆ are as defined earlier in the specification; W is — NH-CH ₂ -; can be synthesized as shown in Scheme -XII below: The group R ₂₀ in the compounds of Scheme-XII is group PG is a protected carbonyl group such as acetals and ketals; W is — NH-CH ₂ -; and m, n, ring B, Y, ring A & R ₁ are as defined earlier in the specification.

As per Scheme-XII, 5,6-dichloropyrimidin-4-amine (4.1) can be reacted with compound 4.2 (PG is a protected carbonyl group such as acetals and ketals) in a suitable solvent such as DMF, NMP, dioxane or THF, and in the presence of suitable base such as DIPEA, TEA or pyridine, and at a suitable temperature to provide compound 4.3, which on coupling with boronic acid of formula R ₂₀ B(OH) ₂ or boronate ester R ₂₀ B(OR ₂₁ ) ₂ in presence of a suitable Pd catalyst like Pd(PPh ₃ ) ₄ or Pd(ddpf)CI ₂ complex with DCM and a suitable base such as sodium carbonate or potassium carbonate in dioxane/water can provide compound 4.4. Compound 4.4 on deprotection using acetic acid/water or Cone. HCI can provide a keto compound 4.5 which on coupling with a suitably substituted Wittig reagent such as trimethylphosphonoacetate, or triethylphosphonoacetate, in presence of a suitable base such as sodium hydride, butyl Lithium, or LiHMDS, using an appropriate solvent like THF, dioxane or acetonitrile and at a suitable temperature can provide ester compound 4.6. Compound 4.6 can be hydrolysed under acidic (cone. H ₂ SO ₄ , cone. HCI) or basic (NaOH, Ba(OH) ₂ , or KOH) conditions in suitable solvent (like ethanol, methanol, water or their mixtures with THF or dioxane) to provide the compound of Formula I (wherein ring Hy 4- aminopyrimidine moiety and R _A is -OH), which can further be coupled with a substituted or un-substituted amines (for example, NH(R ₁₅ )R ₁₆ ) using a suitable peptide coupling agent such as EDC.HCI, DCC, HATU or BOP, in a suitable solvent such as DMF, THF, or DCM to provide corresponding amides (compound of Formula I, wherein ring Hy 4- aminopyrimidine moiety and R _A is -N(R ₁₅ )R ₁₆ ) disclosed in this invention.

The compound of Formula I can be converted into its pharmaceutically acceptable salt by treating the compound of Formula I with appropriate acid or base in a suitable solvent.

The compound of Formula la, compound of Formula lb, compound of Formula Ic, compound of Formula Id, or compound of Formula Ie can be prepared by following the processes as described above. Similarly, the compound of Formula la, compound of Formula lb, compound of

Formula Ic, compound of Formula Id or compound of Formula Ie can be converted into their pharmaceutically acceptable salt by treating them with appropriate acid or base in a suitable solvent. The representative compounds of Formula I are presented in Table 1 below:

Table 1: Compounds of Formula I

*Ph=Phenyl

The present invention is further illustrated in detail with reference to the following examples. It is desired that the example be considered in all respect as illustrative and are not intended to limit the scope of the claimed invention. Examples:

The compounds of Formula I were prepared as described below. All solvents and reagents were used as obtained from commercial sources unless otherwise indicated. H- NMR spectra were recorded with a Bruker® spectrometer operating at 400 or 500 MHz. Step 1: To a stirred solution of 3-bromo- 1H-pyrazolo[3,4-d]pyrimidin-4-amine (II, 10 g , 47.16 mmol) in DMF (100 ml) were added potassium carbonate 19.54 g (141 mmol) and compound VIII (26.88 g, 117 mmol). The flask contents were stirred at around 95 °C for 16 hr. and progress of the reaction was monitored by Thin Layer CHromatography (TLC). Reaction mixture was poured into (1.0 lit) water and extracted into ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude was purified by column chromatography (silica gel, 10- 80 % ethyl acetate in hexane) to give compound (III) (8.0 g).

Step 2: A mixture of 3-bromo-l-[(3,3-dimethoxycyclobutyl)methyl]pyrazolo[3,4- d]pyrimidin-4-amine (III, 5g ), glacial acetic acid (50 ml) and water (50 ml) was stirred at 80 °C for 16 hr. The reaction mixture was concentrated in vacuum and the resulting residue was dissolved into DCM, washed with aq. saturated sodium bicarbonate solution till effervescence ceased. The layer was dried over anhydrous Na ₂ SO ₄ and concentrated to yield compound (IV) (4.0 g).

Step 3: To a stirred solution of dimethylphosphonoacetate (3.19 g, 17.5 mmol) in THF (10 ml ) at -10°C was charged 1M LiHMDS solution (16.2 ml, 16.2 mmol) during 5 minutes. The reaction mixture was further cooled to -78 °C and charged a solution of3-[(4-amino-3- bromo-pyrazolo[3,4-d]pyrimidin-1-yl)methyl ] cyclobutanone (IV, 4.0 g, 13.5 mmol) in THF (45 ml) during 10 min. The reaction mixture was allowed to warm to room temperature and quenched with glacial acetic acid (2.0 ml). The reaction mixture was concentrated and the resulting residue was portioned between (1:1) mixture of ethyl acetate and water. The organic layer was concentrated under vacuum. The residue was taken into amixture of THF: MeOH: water (1:1: 1) (60 ml) and charged Ba(OH) ₂ .8H ₂ O (6.4 g, 20 mmol). The reaction was heated at around 80 °C for 2 hr and acidified with glacial acetic acid to pH = 6.0. The reaction mixture was concentrated and residue were treated with water. The solid formed was filtered and dried at 60 °C, to afford compound (V) (4.0 g).

Step 4: To a stirred solution of 2-[3-[(4-amino-3-bromo-pyrazolo[3,4-d]pyrimidin-1 yl)methyl]cyclobutylidene] acetic acid (V, 4.0 g, 11.8 mmol) in DMF (16 ml) at 0°C were charged TEA (3.27 ml, 23.6 mmol) and HATU ( 4.9 g, 12.9 mmol). The reaction mixture was stirred for 5 minutes and charged hydrazine hydrate (12 ml). The flask contents were stirred for 5 minutes and poured into water. The precipitates were filtered and washed with water. Wet cake was dried at 60°C for 2 hr under vacuum, to afford compound (VI) (4.0 g). Step 5: To a stirred solution 2-[ 3-[ (4-amino-3-bromo-pyrazolo[3,4-d]pyrimidin-1- yl)methyl]cyclobutylidene]acetohydrazide (VI, 1.0 g, 2.83 mmol) in DMF (4 ml) was charged 2-butynoic acid (0.31 g, 3.69 mmol) and N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (EDC.HCI) (0.88 g, 5.67 mmol). The reaction mixture was stirred at room temperature for 1 hr, and poured into water. The solid was filtered, washed with water and suction dried. The solid was further dried at 60 °C for 3-4 hr to get compound (VII) (1.0 g).

Step 6: A mixture of N'-[ 2-[ 3-[ (4-amino-3-bromo-pyrazolo[3,4-d]pyrimidin-1- yl)methyl]cyclobutylidene]acetyl]but-2-ynehydrazide (VII, 1 g, 2.39 mmol), 1,4-dioxane (10 ml), potassium carbonate (0.98 g, 7.17 mmol), water (3 ml), 2-(2-fluoro-4-phenoxy- phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (IX, 1.12 g, 3.58 mmol), and PdCH(dppf).DCM complex (0.19 g, 0.23 mmol) was refluxed for 4-5 hr under inert atmosphere. The reaction mixture was concentrated in vacuum and crude was partitioned between (1: 1) mixture of ethyl acetate: water (200 ml) at hot condition. The organic layer was concentrated and the crude was purified by silica gel column chromatography to afford compound (1.1).

Example 2: (E-N'-[2-[3-[[4-Amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[ 3.4- d] pyrimidin-1-yl]methyl]cyclobutylidene]acetyl]but-2-enehydraz ide (I.2)

This compound was synthesized in analogous manner from compound (VI) as described in example 1, except crotonic acid was taken in step 5 instead of 2-butynoic acid.

Example _ 3: _N'-[2-[3-[[4-Amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo [3,4- d]pyrimidin-l-yl]methyl]cvclobutylidenelacetyl]prop-2-enehvd razide (I.3)

This compound was synthesized in analogous manner from compound (VI) as described in example 1, except acrylic acid was used in step 5 instead of 2-butynoic acid. Example 4: (E)-N'- [2-[4- [4-Amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo [3,4- d] pyrimidin- 1-yl] cyclohexylidenel acetyl] but-2-enehydrazide (I.4)

A. Synthesis of 1,4-dioxaspiro[4.5]decan-8-yl methanesulfonate (Compound X) Step 1.1: To a 0°C cooled and stirred solution of 1,4-dioxaspiro[4.5]decan-8-one (25g, 160 mmol) in (1:4) mixture of methanol: DCM (250 ml) was added sodium borohydride (2.1 g, 56 mmol) in three portions during 30 minutes. The reaction mixture was stirred for 1 hr and quenched by careful addition of acetone (7.5 ml) and 18 % aqueous ammonium chloride solution (50 ml). The organic layer was separated and the aqueous layer was again extracted with DCM. The combined organic layer was washed with water, brine and dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum to afford compound (Xa) (22 g).

Step 2.1: To the 0 °C cooled and stirred solution of 1,4-dioxaspiro[4.5]decan-8-ol (Xa, 20 g, 126 mmol) in DCM (200 ml) was added triethylamine (32 ml). A solution of methane sulphonyl chloride (10.8 ml) in DCM (10 ml) was added and stirred for 1 hr. The reaction mixture was allowed to warm to room temperature and quenched with water. Organic layer was separated, washed with water and dried. The organic layer was concentrated under vacuum. The yellow crude syrup was triturated with di-isopropyl ether. The free flowing solid was fdtered and dried under nitrogen blanket to give compound (X) (20 g). B. Synthesis of (E)-N'- [2-[4-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4- d] pyrimidin- 1-yl] cyclohexylidene] acetyl] but-2-enehydrazide (1.4)

Step 1: A mixture of 3-bromo- 1H-pyrazolo[3.4-d]pyrimidin-4-aminc (II, 100 g, 0.467 mol), DMF (800 ml), potassium carbonate (198 g, 1.4 mol) and 1,4-dioxaspiro[4.5]decan- 8-yl methane sulfonate compound (X, 220 g, and 0.934 mol) was stirred for 16 hr at 90 °C. The progress of the reaction was monitored by TLC for completion. Once complete, the reaction was diluted with THF (1 Lit), refluxed for 30 minutes and fdtered at hot condition. The fdtered solid was washed with hot THF. The combined mother liquors were concentrated under vacuum and residue were treated with water. The solid formed was fdtered and washed with water. The fdtered solid was pressed and was suspended in toluene (400 ml) at hot, stirred for 30 minutes and fdtered. The wet cake was dried at 60 °C under vacuum to afford compound (XI) (100 g).

Step 2: A mixture of 3-bromo-l-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazolo[3,4-d]pyri midin- 4-amine (XI, 12 g, 33.9 mmol), glacial acetic acid (84 ml) and water (36 ml) was stirred at 80 °C for 16 hr. The reaction mixture was concentrated under vacuum, residue was taken in DCM and washed with aqueous sodium bicarbonate solution till effervescence subsided. The DCM layer was concentrated to give compound (XII) (10 g).

Step 3: To a stirred solution of trimethylphosphonoacetate (4.93 g, 33.84 mmol) in THF (30 ml) at 0°C was added 1M LiHMDS solution (33 ml) during 2 minutes. The reaction mixture was further cooled to -78 °C and a solution of 3-bromo-l-(l,4- dioxaspiro[4.5]decan-8-yl)pyrazolo[3,4-d]pyrimidin-4-amine (XII, lOg, 28.2 mmol) in THF (100 ml) was added during a course of 30 minutes. The flask contents were allowed to warm to room temperature and stirred for 16 hr. The reaction mixture was quenched with (1:1) mixture of acetic acid: water (15ml) and concentrated. The crude residue was extracted into (1: 1) mixture of ethyl acetate: water. The organic layer was separated, dried and concentrated under vacuum to afford compound (XIII) (8.0 g).

Step 4: A mixture of methyl 2-|4-(4-amino-3-bromo-pyrazolo[3,4-d]pyrimidin- l- yl)cyclohexylidene] acetate (XIII, 5 g, 13.66 mmol), (1:1: 1) mixture of THF:water:methanol (75 ml) and barium hydroxide octahydrate( 6.47 g, 20.49 mmol) was refluxed for 2 hr. The reaction mixture was cooled to room temperature and acidified with glacial acetic acid (pH = 6.0). The reaction mixture was concentrated under vacuum and treated with water. The precipitate was filtered, washed with water and suction dried. The wet cake was dried in an air oven at 65°C for 12 hr., to give compound (XIV) (5 g).

Step 5: To a stirred solution of 2-[4-(4-amino-3-bromo-pyrazolo[3,4-d]pyrimidin-1 yl)cyclohexylidene]acetic acid ( XIV, 5 g,14.2 mmol) in DMF( 20 ml) at 0°C were added TEA (4.9 ml, 35.5 mmol) and HATU ( 6.47g,17 mmol). The reaction mixture was stirred for 5 minutes and added hydrazine hydrate (20 ml, 25 mmol). The reaction mixture was stirred for 2 minute and poured into (1:1) mixture of ethyl acetate: water (300 ml). The organic layer was separated, washed with water, brine and concentrated under reduced pressure to give compound (XV) (5.0 g). Step 6: To a stirred solution of 2-[4-(4-amino-3-bromo-pyrazolo[3,4-d]pyrimidin- 1- yl)cyclohexylidene]acetohydrazide (XV, 2 g, 5 mmol) in DMF (10 ml) at 25 °C were added crotonic acid (0.5g, 6 mmol ), and EDC.HCI (1.98 g, 5 mmol). The reaction mixture was stirred for 1 hr and poured into water. The precipitates were fdtered, washed with water and suction dried in air, followed by drying at 60 °C to give compound (XVI) (1.5 g).

Step 7: A mixture of (E)-N'-[ 2-[ 4-(4-amino-3-bromo-pyrazolo[3.4-d]pyrimidin- 1- yl)cyclohexylidene]acetyl]but-2-enehydrazide (XVI, lg, 2.39 mmol), 1,4-dioxane (7 ml), potassium carbonate (0.98 g, 7.17 mmol), water (3 ml), compound (IX, 1.5 g, 4.78 mmol) and PdCH(dppf)DCM complex (0.19 g, 0.23 mmol) was refluxed at 90 °C for 4 hr. The reaction mixture was concentrated and residue was purified by silica gel column chromatography to afford compound (1.4).

Example _ 5: _N'-[2-[4- [4-Amin-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo [3,4- d] pyrimidin-1-yl]cyclohexylidene]acetyl]but-2-ynehydrazide (I.5) This compound was synthesized in analogous manner from compound (XV) as described in example 4, except 2-butynoic acid was used in step 6 instead of crotonic acid.

Example _ 6 : _ N'- [2-[4-[4-Amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo [3.4- d] pyrimidin-1-yl]cyclohexylidene]acetyl]prop-2-enehydrazide (I.6)

This compound was synthesized in analogous manner from compound (XV) as described in example 4, except acrylic acid was used in step 6 instead of crotonic acid.

Example 7: N'- [2-[4-[4-Amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-l - yl]cyclohexylidene]acetyl]prop-2-enehydrazide (I.8)

A. Synthesis of N'-[2-(4-Hydroxycyclohexylidene)acetyl]prop-2-enehydrazide (XXII) Step 1.1: To a cooled and stirred solution of trimethylphosphonoacetate (18 ml, 124.8 mmol) in THF (30 ml) at 0°C was added 1M solution of LiHMDS (115 ml, 115.25 mmol) during 5 minutes. The reaction mixture was stirred for 5 minutes and further cooled to -78 °C. A solution of 1,4-dioxaspiro[4.5]decan-8-one (15g, 96 mmol) in THF (150 ml) was added to above solution during 20 minutes. The reaction mixture was allowed to warm to room temperature and stirred for 16 hr. The reaction mixture was concentrated under vacuum and crude was portioned between (1:1) mixtures of ethyl acetate: water. The organic layer was separated, concentrated under vacuum to afford compound (XVIII, 13g).

Step 2.1: A mixture of methyl 2-(1,4-dioxaspiro[4.5]decan-8-ylidene)acetate (XVIII, 13 g, 61.2 mmol) in (1: 1:1), THF: methanol: water (180 ml), barium hydroxide octahydrate (29 g, 100 mmol) was refluxed at 80 °C for 2 hr. The reaction mixture was concentrated under reduced pressure and residue was treated with water and acidified with glacial acetic acid (pH = 6). The mixture was extracted with ethyl acetate and the organic layer was separated, and concentrated to afford compound (XIX, 10 g).

Step 3.1: To a stirred solution of 2-(1,4-dioxaspiro[4.5]decan-8-ylidene)acetic acid (XIX, 10 g,50 mmol) in DMF( 40 ml) at 0°C was added DIPEA (di-isopropylethylamine) ( 25.8 ml, 65.5 mmol) and HATU (22.98 g, 60.4 mmol) under nitrogen atmosphere. The reaction mixture was stirred for 5 minutes and added acryloylhydrazide hydrochloride (XX, 8 g, and 65.5 mmol). The reaction mixture was allowed to warm to room temperature and stirred for lhr. The reaction mixture was quenched into water and extracted into ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford compound (XXI) (8.0 g).

Step 4.1: A mixture of N'-[2-( 1,4 -dioxaspiro[4.5]decan-8-ylidene)acetyl]prop-2- enehydrazide (XXI, 10 g,45 mmol) and aqueous 85 % acetic acid (100 ml) was stirred at 60 °C for 24 hr. The reaction mixture was concentrated under vacuum and residue was taken into (1:4) mixture of THF: methanol (100 ml), transferred into round bottom flask and stirring was started. The reaction was cooled to 0 °C and added sodium borohydride (1.66 g, 45 mmol) and stirred for 1 hr. The reaction was quenched using acetone (2 ml) and concentrated under vacuum. The residue was purified by silica gel column chromatography (silica gel, 10 % methanol in DCM) to afford Compound (XXII, 5g).

B. Synthesis of N'-[2-[4-[4-Amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidi n-l- yl] cyclohexylidene] acetyl] prop-2-enehydr azide (1.8)

To amixture of 3-(4-phenoxyphenyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-amine (XVII, 0.5 g, 1.64 mmol), triphenylphosphine (1.0 g, 4.1 mmol), N'-[ 2-(4- hydroxycyclohexylidene)acetyl]prop-2-enehydrazide (XV, 0.92 g, 4.1 mmol), and THF (10 ml) was added diisopropylazodicarboxylate (0.82 ml, 4.1 mmol) at room temperature. The reaction mixture was stirred for 16 hr and concentrated. The crude was purified by silica gel column chromatography to afford compound (1.8).

Step 1: To a stirred solution of 4-chloro-7H-pyrrolo[2.3-d]pyrimidine (XXIII, 40 g, 260 mmol) in DMF (160 ml) was added NIS (61.5 g, 279 mmol) in one portion. The reaction mixture was stirred for 24 hr and poured into water (2.5 lit). The precipitates were filtered, washed with water (200 ml) and suction dried. The wet cake was re-dissolved in ethyl acetate, dried over anhydrous sodium sulfate and concentrated. The solid was fdtered from hexanes (100 ml) and dried at 60 °C, resulting in compound (XXIV, 65 g).

Step 2: To an oven dried three neck round bottom flask equipped with addition funnel, nitrogen purge, rubber septum and thermometer pocket was cannulated THF (650 ml). To the above flask, 4-chloro-5-iodo-7H-pyrrolo[2.3-d]pyrimidine (XXIV, 65 g, 232 mmol), 1,4-dioxaspiro[4.5]decan-8-ol (Xa, 55 g,348 mmol) and triphenylphsophine (152 g,581 mmol) were added respectively. The reaction mixture was stirred at room temperature and DIAD (117.56 g, 581 mmol) was added dropwise during course of 30 minutes. The reaction mixture was stirred for 16 hr and concentrated. The crude was purified by column chromatography (silica gel, 10 % ethyl acetate in hexane) to afford compound (XXV, 80g). Step 3: A mixture of 4-chloro-5-iodo-7-( 1 4-dioxaspiro[4.5]dccan-8-yl)-7H-pyrrolo[2.3- d] pyrimidine (XXV, 80 g, 190 mmol), 1,4-dioxane (800 ml) and 25% aqueous ammonia (400 ml) were stirred in autoclave at 90°C for 16 hr. The reaction mixture from autoclave was transferred into round bottom flask and concentrated. The residue were treated with water and filtered. Solid was dried at 50 °C under vacuum for 3 hr resulting in compound (XXVI, 70 g).

Step 4: A mixture of 7-( 1,4-dioxaspiro[4.5]decan-8-yl)-5-iodo-pyrrolo[2.3-d]pyrimidi n-4- amine (XXVI, 50 g, 125 mmol) and 85 % glacial acetic acid (400 ml) was heated at 90 °C for 16 hr. The reaction mixture was concentrated and residue was taken into DCM (400 ml). The DCM layer was washed with aqueous saturated sodium bicarbonate solution, washed with brine and dried. The organic layer was concentrated under reduced pressure to afford compound (XXVII, 40 g).

Step 5: To a stirred solution of trimethylphosphonoacetate (5.28 ml, 36.5 mmol) in THF (30 ml) at 0 °C was added a solution of 1M LiHMDS (36.5 ml, 36.5 mmol) .The reaction mixture was stirred for 5 minutes and cooled to -78 °C. A solution of 4-(4-amino-5-iodo- pyrrolo[2.3-d]pyrimidin-7-yl)cyclohexanone(XXVII, 10 g, 28.8 mmol) in THF (100 ml) was added to previously cooled solution during a course of 15 minutes .The reaction mixture was allowed to warm to room temperature and stirred for 16 hr. The reaction was quenched with aqueous 50 % acetic acid (17 ml, 144 mmol) and concentrated under vacuum. The crude residue was dissolved in ethyl acetate and washed with water. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum to afford compound (XXVIII) (10 g). Step 6: A mixture of methyl 2-[4-(4-amino-5-iodo-pyrrolo[2.3-d]pyrimidin-7- yl)cyclohexylidene]acetate(XXVIII, 10 g, 24.25 mmol), barium hydroxide octahydrate (11.5 g, 36.38 mmol), THF (50 ml), methanol (50 ml)and water (50 ml) was refluxed at 80 °C for 2 hr. The reaction mixture was acidified using glacial acetic acid (7.28 ml, 121 mmol) and concentrated under vacuum. The residue were triturated with water and filtered. The filtered solid was pressed and dried, which gave compound (XXIX) (8 g).

Step 7: To a stirred solution of 2-[4-(4-amino-5-iodo-pyrrolo[2.3-d]pyrimidin-7- yl)cyclohexylidene] acetic acid (XXXI, 8 g, 20.09 mmol) in DMF (32 ml) at 0°C was added TEA (6.9 ml, 50 mmol) and HATU (8.39 g, 22.09 mmol). A solution of hydrazine hydrate (32 ml) was added, stirred for 2 minutes and dumped into water (320 ml). The precipitated solid was filtered, washed with water and suction dried. The solid was further dried at 60 °C for 2 hr. The dried solid was dissolved in DMF (32 ml), added acrylic acid (1.44 g, 20.09 mmol) and EDC hydrochloride (7.67 g, 40.18 mmol) at 0°C. The reaction mixture was stirred for 1 hr and poured into water. The solid was filtered, washed with water and dried under vacuum to afford compound (XXX, 7.0 g).

Step 8: A mixture of N'-[ 2-[4-(4-amino-5-iodo-pyrrolo[2.3-d]pyrimidin-7- yl)cyclohexylidene]acetyl]prop-2-enehydrazide(XXX, 1 g,2.14 mmol), potassium carbonate (0.88 g, 6.4 mmol), compound (IX, 0.87g, 2.78 mmol), water (3.0 ml), PdCH (dppf) DCM complex ( 0.17g, 0.2 mmol) in 1,4-dioxane (10 ml) was refluxed at 90 °C for 3-4 hr. The reaction mixture was concentrated and crude was purified by column chromatography to afford the title compound (1.9).

Example 9: (E)- N'- [2-[4-[4-Amino-5-(2-fluoro-4-phenoxy-phenyl)pyrrolo [2,3- d] pyrimidin-7-yl] cvclohexylidenel acetyl] but-2-enehydrazide (I.10)

This compound was synthesized in analogous manner from compound (XXIX) as described in example 8, except using crotonic acid in step 7 instead of acrylic acid.

Example _ 10: _ N'- [2-[4-[4-Amino-5-(2-fluoro-4-phenoxy-phenyl)pyrrolo [2,3- d] pyrimidin-7-yl] cvclohexylidenel acetyl]but-2-vnehvdrazide (I.11 )

This compound was synthesized in analogous manner from compound (XXIX) as described in example 8, except using 2-butynoic acid in step 7 instead of acrylic acid.

Example 11: N'- [2-[4-[6-Amino-8-oxo-7-f4-phenoxyphenyl)purin-9- yl] cyclohexylidenel acetyl] but-2-ynehydrazide (I.21)

A. Synthesis of l,4-Dioxaspiro[4.5]decan-8-amine (XXXIII):

A solution of 1,4-dioxaspiro[4.5]decan-8-one (9.36 g, 60 mmol) in methanol (60 ml) was saturated with ammonia purge during 30 minutes. The reaction was transferred into autoclave, added 10 % palladium on carbon (1 g) and hydrogenated at 4 bar hydrogen pressure for 16 hr. The reaction mixture was fdtered over hyflow bed and mother liquor was concentrated under vacuum, to obtain compound (XXXIII).

B. Synthesis of N'-[2-[4-[6-Amino-8-oxo-7-(4-phenoxyphenyl)pur n-9- yl] cyclohexylidene] acetyl] but-2-ynehydrazide (1.21)

Step 1: A mixture of 5-nitropyrimidine-4,6-diol (10 g, 63.6 mmol), NN-dimethy anilinc (12 ml, 95 mmol) and phosphoryl chloride (64.42 g, 44.5 mmol) was stirred at 125-130 °C for 2 hr. The reaction mixture was cooled to 60 °C, concentrated and residue was quenched into ice. The quenched mass was stirred at 0 °C for an hour and solid was filtered. The filtered solid was washed with water and dried at 60 °C for 15 hr. to afford compound (XXXI) as an off white solid (8.2 g). Step 2: A mixture of 4,6-dichloro-5-nitro-pyrimidine (XXXI, 8.4 g, 43.3 mmol), TEA (12.1 ml, 86.6 mmol), dibenzylamine (10.3 g, 52.2 mmol) and 1,4-dioxane (100 ml) was stirred at 25 °C for lhr. The reaction mixture was quenched into water, stirred for 10 minutes and layers were separated. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum, whereby compound (XXXII) was obtained (12.8 g) as a pale yellow solid Step 3: A mixture of A,A-dibenzyl-6-chloro-5-nitro-pyrimidin-4-amine (XXXII, 10 g, 28.1 mmol), TEA (8.0 ml, 57.2 mmol), l,4-dioxa-spiro[4.5]dec-8-ylamine (XXXIII, 4.47 g, 28.4 mmol), and 1,4-dioxane (100 ml) was stirred at 75 °C for 4 hr. The reaction mixture was cooled to room temperature, quenched into water and extracted into ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was column purified using a mixture of 10 % methanol: DCM, to give compound (XXXIV) as pale yellow solid (11 g).

Step 4: To a stirred solution of N ⁴ ,N ⁴ -dibenzyl-N ⁶ -(1,4-dioxaspiro[4.5]decan-8-yl)-5-nitro- pyrimidine-4,6-diamine(XXXIV,5 g,10.5 mmol) in ethyl acetate (100 ml) at 0°C were added zinc metal (6.25 g, 94.5 mmol) and aqueous 3.0M ammonium chloride solution ( 3.25 ml) . The reaction mixture was brought to room temperature and stirred for 4 hr. The reaction mixture was filtered over hyflow bed and filtrate was concentrated under vacuum. The residues were treated with water, filtered, washed with minimum water and dried at 50 °C under vacuum for 4 hr, to give compound (XXXV) as an off white solid (4.3 g)

Step 5: A mixture of N ⁴ ,N ⁴ -dibenzyl-N ⁶ -(1,4-dioxaspiro[4.5]decan-8-yl)pyrimidine-4, 5,6- triamine (XXXV, 500 mg, 1.12 mmol), TEA (0.3 ml, 2.2mmol), and triphosgene (133 mg, 0.44 mmol) in DCM (10 ml) was stirred at 0°C for 2 hr. The reaction mixture was quenched by water and layers were separated. The aqueous layer was again extracted with DCM, combined with previous organics and dried. The DCM layer was concentrated and residue was triturated with diethyl ether, which on filtration afforded (450 mg) compound (XXXVI). as an off white solid.

Step 6: A mixture of 6-(dibenzylamino)-9-( 1 4-dioxaspiro[4.5]decan-8-yl)-7H-purin-8- one(XXXVI, 450 mg, 0.95 mmol ), 20 % Pd(OH) ₂ (450 mg, 0.66 mmol) , ethyl acetate( 10 ml), and methanol (10 ml) were stirred under hydrogen atmosphere at 75 °C for 15 hr. The reaction mixture was brought to room temperature, filtered over hyflow bed and concentrated under reduced pressure. The residues were purified by column chromatography using 10% methanol in DCM, to give compound (XXXVII) as an off white solid (150 mg). Step 7: A solution of 6-amino-9-( 1.4-dioxaspiro[4.5]dccan-8-yl)-7H-purin-8-onc (XXXVII, 500 mg, 1.71 mmol ) in glacial acetic acid (5 ml) was stirred at 90 °C for 16 hr. The reaction mixture was cooled to 50 °C and concentrated. The residue were dissolved in DCM (100 ml) and washed with aqueous saturated sodium bicarbonate solution. The organic layer was separated, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude solid was triturated with ether, filtered and dried under vacuum to obtain compound (XXXVIII) as an off white solid (400 mg).

Step 8: To a stirred solution of trimethylphosphonoacetate (0.38 ml, 2.6 mmol) in THF (2.0 ml ) at 0°C was added 1M LiHMDS solution (2.0 ml, 2 mmol) during a course of 10 minutes. The reaction mixture was stirred for 5 minutes and cooled to -78 °C. A solution of 6-amino- 9-(4-oxocyclohexyl)-7H-purin-8-onc (XXXVIII, 500 mg, 2 mmol) in THF (5.0 ml) was added to previously cooled solution during a course of 30 minutes. The reaction mixture was allowed to warm to room temperature and stirred for 16 hr. The reaction mixture was quenched with 50 % aqueous acetic acid (0.6 ml, 10 mmol) and concentrated under vacuum. The residue was treated with water and formed solid was filtered. The wet solid was dried at 60 °C for 2 hr. to afford compound (XXXIX) as an off white solid. (500 mg).

Step 9: A mixture of methyl 2-[4-(6-amino-8-oxo-7H-piirin-9-yl)cyclohexylidene|acctatc (XXXIX, 500 mg, 1.65 mmol), (1:1: 1) THF: methanol: water (15 ml), and barium hydroxide octahydrate (0.78 g, 2.47 mmol) was refluxed at 80 °C for 2 hr. The reaction mixture was concentrated, acidified with glacial acetic acid (0.5 ml, 8.25 mmol), diluted with water (20 ml) and filtered. The solid was washed with water and dried at 60 °C for 2 hr., to afford compound (XL, 500 mg) as an off white solid.

Step 10: To a stirred solution of 2-[4-(6-amino-8-oxo-7H-purin-9- yl)cyclohexylidene] acetic acid (XL, 500 mg, 1.73 mmol) in DMF (2.5 ml) at 0 °C were added TEA (0.48 ml, 3.46 mmol) and HATU (0.72 g, 1.9 mmol). The reaction mixture was stirred for 5 minutes and added hydrazine hydrate (2 ml). The reaction was stirred for 2 minutes and poured into (1: 1) mixture of ethyl acetate: water. The layers were separated and the organic layer was washed with water and dried over anhydrous sodium sulphate. The organic layer was concentrated, to give compound (XLI, 500 mg) pale yellow solid.

Step 11: A mixture of 2-[4-(6-amino-8-oxo-7H-piirin-9-yl)cyclohexylidene |acctohydrazidc (XLI, 500 mg, 1.72 mmol), 2-butynoicacid (145 mg, 1.72 mmol), in DMF (2.0 ml) was stirred at room temperature and added EDC.HCI (659 mg, 3.44 mmol). The reaction was stirred for 1 hr and poured into water (40 ml). The precipitate formed was filtered, washed with water and dried at 60 °C to give compound (XLII) as an off white solid (400 mg). Step 12: A mixture of N'- 2-[4-(6 -amino-8-oxo-7H-purin-9-yl)cyclohexylidene|acetyl |but- 2-ynehydrazide (XLII, 400 mg, 1.0 mmol), cupric acetate (300 mg, 2 mmol), phenylboronicacid (365 mg, 3 mmol) in DCM (10 ml) was stirred at 0°C. To the reaction mixture were added TEA (0.5 ml, 4 mmol) and 4 A° molecular sieves (400 mg). The reaction mixture was stirred for 24 hr under oxygen atmosphere. The reaction mass was filtered and the mother liquor was concentrated. The crude was purified by column chromatography to afford Compound (I. 21)

Example 12: - - [2-[4-[6-Amino -8-oxo-7-(4-phenoxyphenyl)purin-9- yl] cyclohexylidene]acetyl]but-2-enehydrazide (I.22) This compound was synthesized in analogous manner from compound (XLI) as described in example 11, except crotonic acid was used instead of 2-butynoic acid.

Example 13: - [2-[4-[6-Amino -8-oxo-7-(4-phenoxyphenyl)purin-9- yl] cyclohexylidene]acetyl]prop-2-enehydrazide (I.23)

This compound was synthesized in analogous manner from compound (XLI) as described in example 11, except acrylic acid was used instead of 2-butynoic acid.

Step 1: Sodium borohydride (85 g, 2.24 mol) was added in small portions to a stirred solution of 1,4-cyclohexanedione monoethylene ketal (1000 g, 6.4 mol) in DCM (8 vol) and methanol (2 vol). This solution was stirred at 0°C for two hours. Acetone (74 ml, 1.28 mol) was added slowly, followed by a solution of ammonium chloride (363 g, 6.72 mol) in 200 ml water. Organic layer was separated and aqueous layer was again extracted with DCM. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulphate and concentrated in vacuum to give colourless oil. Yield 980 g. Step 2: Triethylamine (1187 ml) was added to a stirred and cooled (below 0°C) solution of compound from step-1 (750 g, 4.74 mol) in DCM (5000 ml). A solution of methane sulfonyl chloride (464 ml, 5.68 mol) in DCM (2500 ml) was added and the reaction mixture was stirred for two hours. Reaction was quenched with water. Organic layer was separated, washed with water, brine and finally dried over anhydrous sodium sulphate and concentrated under vacuum to yield the title compound. Yield 950g. N-Bromosuccinimide (692 g, 3.8 mol) was added to a stirred suspension of 1H- pyrazolo-[3,4-d]pyrimidin-4-amine (500 g, 3.7 mol) in DMF (2.5 litre). The reaction mixture was stirred at 70-80°C for 3h. The reaction mixture was poured slowly into water at 55-60°C and then stirred for 1h. The reaction mixture was filtered, washed with water and dried in an air oven. Yield 560 g.

Potassium carbonate (967 g, 7.0 mol) was added to a stirred suspension of3-bromo- 1H-pyrazolo[3,4-d]pyrimidin-4-amine (500 g, 2.33 mol) in DMF (4000 ml). The resulting mixture was stirred at 90 °C for 30 min. To this mixture was added 1,4- dioxaspiro[4.5]decan-8-ylmethanesulfonate (992 g, 4.2 mol). The resulting suspension was stirred at 90-95 °C for 16 hr. The reaction mixture was filtered at 65-70 °C over cloth and washed with hot THF (4000 ml). Filtrate was concentrated under vacuum, water was added and the solid was filtered and then dried in an air oven at 55-60 °C for 12-16h. Yield 600g. Example 17: Preparation of l-bromo-2-fluoro-4-phenoxybenzene To a stirred solution of 4-bromo-3-fluorophenol (500 g, 2.6 mol) in DCM (500 ml) was added phenylboronic acid (638 g, 5.23 mol), copper (II) acetate (575 g, 2.8 mol) and molecular sieves 4Ǻ (500 g). The resulting mixture was cooled to 0°C, and triethyl amine (1095 ml, 7.85 mol) was added drop wise. The reaction mixture was then stirred overnight under oxygen atmosphere. DCM was then removed under vacuum and n-hexane (5000 ml) was added and stirred at 50-55°C for one hour and then filtered hot. The filtered cake was washed with hot n-hexane. The combined filtrate was washed with 4M HCI, 4M NaOH, water and brine. The organic layer was then concentrated under vacuum to give title compound. Yield 550g. Example 18: Preparation of 2-(2-fluoro-4- phenoxyphenyl)-4.5-dimethyl-1.3.2- dioxaborolane

To a stirred solution of l-bromo-2-fluoro-4-phenoxybenzene (200 g, 0.75 mol) in 1,4-dioxane (1600 ml) was added /v.v(pinacoloto)diboron (228 g, 0.89 mol), potassium acetate (221 g, 2.25 mol) and /e/ra&A(triphenylphosphine)palladium(0) (43.3 g, 0.0375 mol). The resulting mixture was then refluxed for 8-10h. The reaction mixture was allowed to cool to room temp and then filtered. The filtrate was concentrated in vacuum and co distilled first with ethyl acetate and then toluene. Added n-Hexane to concentrated mass and stirred at 0-5°C for 4-6h resulting in precipitation of title compound as white solid. Filtered the solid and suction dried under vacuum. Yield lOOg.

Example 19: Preparation of 1-(1,4-dioxoaspiro[4.51decan-8-yl)-3-(4- phenoxyphenyl)pyrazolo [3,4-d] pyrimidin-4-amine

To a stirred suspension of 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4- amine (34.5 g, 0.11 mol) in DMF (200 ml) was added potassium carbonate (39.3 g, 0.28 mol) and stirred at 90-95°C for 30 min, followed by addition of 1,4-dioxaspiro[4.5]decan- 8-ylmethanesulfonate (45 g, 0.19 mol) and continued to stir at 90-95°C overnight. Cooled the reaction mixture to 60-65 °C and then fdtered, and washed the fdtered cake with hot THF (350 ml). Filtrate was then concentrated under vacuum resulting in red syrupy mass, methanol (105 ml) was added and stirred for 30min at room temp followed by filtration of precipitated product, suction dried under vacuum to get title compound as brown solid. Yield 25g.

To a stirred suspension of 3-bromo-l-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazolo-(3,4- d)pyrimidin-4-amine (95 g, 0.26 mol) in 1,4-dioxane (750 ml) and water (180 ml) was added 2-(2 -fluoro-4-phenoxyphenyl)-4, 5-dimethyl- 1, 3, 2-dioxaborolane (100 g, 0.32 mol), potassium carbonate (91 g, 0.66 mol) and [1, 1'-bis(diphenylphosphino)ferrocene dichloropalladium (II) complex with DCM (22 g, 0.026 mol). The resulting suspension was heated to 95-100°C for 3-4h. A1lowed the reaction mixture to cool to room temperature, separated organic layer, concentrated under vacuum. The product was purified by silica-gel column chromatography to get title compound as off white solid. Yield 50g.

Example 21: Preparation of Methyl 2-[4-[4-amino-3-(2-fluoro-4-phenoxy- phenyl)pyrazolo[3.,4-dlpyrimidin-l-yl] cyclohexylidenel acetate

Step 1: A stirred solution of l-(1,4-dioxaspiro[4.5]decan-8-yl)-3-(2-fluoro-4-phenoxy- phenyl)pyrazolo[3,4-d]pyrimidin-4-aminc (70 g, 0.15 mol) in acetic acid (5 vol) and water (2 vol) was heated at 85°C to 90°C overnight. The reaction mixture was allowed to cool room temp and concentrated under vacuum, ethyl acetate (5 vol) was added to concentrated syrupy mass and stirred, followed by washing with sat aq. sodium bicarbonate solution, water and brine. The organic layer was separated and concentrated under vacuum resulting in light brown solid. Yield 60g.

Step 2: To a stirred and cooled(-65°C to -70°C) solution of trimethyl phosphonoacetate (26 ml, 0.139 mol) in THF (120 ml) was added drop wise 1M LiHMDS solution in THF, the resulting solution is stirred for 30 min, followed by addition of compound obtained in step- 1 as a suspension in THF(360 ml). The reaction mixture is then allowed to warm to room temp and stirred overnight. Acetic acid (10% Aq sol, 40ml) was added slowly to quench the reaction mixture and stirred for another 15-20 min. The reaction mixture was then concentrated under vacuum, co-distilled with toluene, followed by purification on silica-gel chromatography to get title compound as an off white solid. Yield 60g.

Example _ 22: _ Preparation _ of _ 2- [4- [4-amino-3-t2-fluoro-4-phenoxy- phenyl)pyrazolo[3.,4-dlpyrimidin-l-yl]cvclohexylidene]acetic acid (1.44)

To a stirred solution of methyl 2-[4-[4-amino-3-(2-fluoro-4-phenoxy- phenyl)pyrazolo[3,4-d]pyrimidin-1-yl |cyclohexylidene ]aectate (60 g, 0.12 mol) in THF (300 ml) and methanol (300 ml) mixture was added barium hydroxide (60 g, 0.19 mol), followed by addition of water (240 ml). The resulting mixture was then heated at 65-70 °C for 3-4 hr. The reaction mixture was then cooled to room temp and acidified with aq. acetic acid (50%) and then concentrated under vacuum resulting in light brown solid which was then purified by silica-gel chromatography to get title compound.

Examnle 23: Preparation of 4-14-amino-4-(4-phenoxyphenyl)pyrazolol3.4- d] pyrimidin-l-yl] cyclohexanone

A solution of l-(l,4-dioxoaspiro[4.5]decan-8-yl)-3-(4- phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-amine (25g, 0.05mol) in acetic acid (125ml) and water (50ml) was heated at 80-85°C overnight. The reaction mixture was cooled to room temp and concentrated under vacuum. Ethyl acetate (100ml) was added to concentrated syrupy mass and then washed with saturated aq. sodium bicarbonate, water, brine and followed by drying over sodium sulphate and concentrated under vacuum to get title compound as pale yellow solid. Yield 21 g.

Example 24: Preparation of 2-[4-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3.,4- d]pyrimidin-l-yl]cvclohexylidenel acetic acid (1.45)

Step 1: To a stirred and cooled (-65 °C to -75 °C) solution of trimethyl phosphonoacetate (2.54 ml, 0.015 mol) in THF (35 ml) was added 1M LiHMDS solution in THF drop wise and stirred for 30 min, followed by addition of 4-[4-amino-4-(4- phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl |cyclohexanone (5 g, 0.012 mol) suspension in THF (15 ml). The resulting solution was allowed to warm to room temp and stirred overnight. Aq acetic acid(10%) was added to quench the reaction mixture to pH 5-6. The reaction mixture was concentrated under vacuum, ethyl acetate (100 ml) was added to concentrated mass, washed with water and dried over sodium sulphate and then concentrated under vacuum resulting in off white solid. Yield 4.6 g. Step 2: Added barium hydroxide (4.3 g, 0.013 mol) to a solution of product (4.3 g, 0.009 mol) obtained in step-1 in 63 ml (1: 1: 1 mixture of THF, methanol and water). The reaction mixture was then heated to 80 °C for 2-3 hr. The reaction mixture was cooled to room temp and concentrated under vacuum, water was added to concentrated mass, acidified with 1M HCI to pH 4-5 and then extracted with DCM. Organic layer was separated, dried over sodium sulphate and concentrated under vacuum to get title compound as off white solid. Yield 4 g.

Example 25: Preparation of (3,3-dimethoxycvclobutyl)methanol

To a stirred and cooled (0-5 °C) solution of methyl 3,3- dimethoxycyclobutanecarboxylate (50 g, 0.28 mol) (prepared as described in J.Org.Chem 1996, 61, 6,2174) in THF(500 ml) was added lithium aluminium hydride (11 g, 0.28 mol) in small portions. The reaction mixture was quenched by adding water slowly, the resulting biphasic mixture was fdtered, organic layer was separated and dried over sodium sulphate, followed by concentration under vacuum to get title compound as colorless oil. Yield 40 g.

Example 26: Preparation of 1-[(3,3-dimethoxycvclobutyl)methyl]-3-(2-fluoro-4- phenoxy-phenyl)pyrazolo[3.,4-d]pyrimidin-4-amine

To a stirred suspension of 3-(2-fluoro-4-phenoxy-phenyl)-1H-pyrazolo|3.4- t/| py ri m i d i n -4-amine (26 g, 0.08 mol) in DMF (260 ml) was added (3,3- dimethoxycyclobutyl)methyl methanesulfonate (29 g, 0.13 mol). The resulting mixture was then heated at 80-90 °C overnight. The reaction mixture was allowed to cool to room temp and then concentrated under vacuum. Ethyl acetate (500 ml) was added to concentrated mass and then extracted with water. The organic layer was then separated, washed with brine, concentrated under vacuum and purified by silica-gel chromatography to get title compound as pale yellow solid. Yield 20 g.

Example 27: Preparation of methyl-2- 13-114-Amino-3-(2-fluoro-4-phenoxy- phenyl)pyr azolo[3,4-d] pyrimidin- 1-yl]methyl] butylidenel acetate

Step 1: A stirred solution of l-[(3,3-dimethoxycyclobutyl)methyl]-3-(2-fluoro-4-phenoxy- phenyl)pyrazolo[3,4-d]pyrimidin-4-aminc (5 g, 0.01 mol) in acetic acid (50 ml) and water (50 ml) was stirred overnight. The reaction mixture was concentrated under vacuum and residue was taken up into DCM (200 ml) and washed with aq. saturated sodium bicarbonate solution, water and brine. The organic layer was separated, dried over sodium sulphate and concentrated under vacuum resulting in off white solid. Yield 4.3 g.

Step 2: To a stirred and cooled (-65 °C to -70 °C) solution of trimethylphosphonoacetate (2.19 ml, 0.013 mol) in THF (20 ml) was added drop wise LiHMDS solution in 1M THF (13 ml, 0.012 mol) over a period 5 min and the resulting mixture was stirred for 30 min, followed by addition of solution of intermediate (4.2 g, 0.01 mol) in THF (20 ml) obtained in step 1. The resulting mixture was allowed to warm to 0 °C and then quenched with water, concentrated under vacuum. Ethyl acetate (50 ml) was added to residue and washed with water (10 ml). The organic layer was separated dried over sodium sulphate and concentrated under vacuum. The product was purified by silica-gel chromatography to give title compound as off white solid. Yield 3.5 g.

Example _ 28: _ Preparation _ of _ 2- [3- [4-amino-3-(2-fluoro-4-phenoxy- phenyl)pyrazolo[3.,4-d]pyrimidin-l-yl]methyllcvclobutylidene l acetic acid (1.34) To a solution of methyl-2-[3-[[4-amino-3-(2-fluoro-4-phenoxy- phenyl)pyrazolo[3,4-d]pyrimidin-1-yl ]methyl]cyclobutylidene] acetate (3.14 g, 0.007 mol) in 45 ml (1:1:1) mixture of THF, methanol and water was added barium hydroxide(3.38g, O.Olmol) and the resulting reaction mixture was refluxed at 80 °C for 2 hr. The reaction mixture was cooled to room temp, diluted with water and acidified to pH 4 to 5 using cone. HCI and then concentrated under vacuum, the resulting residue was extracted into DCM and then washed with water and dried over sodium sulphate. The product was then purified by silica-gel chromatography to give title compound.

To a stirred solution of 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4- £/|pyrimidin-1-yl ]methyl]cyclobutylidene]acetic acid (0.2 g) in DMF, cooled to 0-5 °C was added triethylamine (0.15 ml, 0.001 mol) and HATU (0.17 g, 0.0004 mol) and the resulting mixture was stirred for 5-10 min, followed by addition of methoxylamine hydrochloride (0.04 g, 0.0005 mol) and then stirred for 30 min. The reaction mixture was quenched using water (50ml) and then extracted with «-butanol (50 ml). The organic layer was separated, dried over sodium sulphate and then concentrated under vacuum. The product was purified by silica-gel chromatography to get title compound.

Example 30: Preparation of 2-[[2-[3-[[4-Amino-3-(2-fluoro-4-phenoxy-phenyl) pyrazolo[3,4-d] pyrimidin- 1-vH methyll cvclobutylidenel acetyl] aminol -N- methoxyacetamide (1.37)

To a stirred solution of 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4- d]pyrimidin-1-yl |methyl |cyclobutylidcnc |acctic acid (0.2 g) in DMF, cooled to 0-5 °C, was added triethylamine (0.1 ml, 0.67 mmol) and HATU (0.17 g,0.45 mmol) and stirred for 5- 10 min, followed by addition of O-methylglycine hydroxamate (0.056 g, 0.54 mmol, prepared as described by Severin E S et al, Izvestiya Akademii Nauk SSSR, seriya khimicheskaya, 1967, pg 1386-1388) and then stirred for 1 hr. The reaction mixture was then poured into water (50 ml), and precipitates were fdtered off. The product was purified by silica-gel chromatography to get title compound.

To a stirred and cooled (0-5 °C) solution of 2-[4-[4-amino-3-(4- phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl |cyclohexylidene |acctic acid (0.2 g, 0.43 mmol) in DMF (3 ml) was added triethylamine (0.18 ml, 1.3 mmol), HATU (0.16 g, 0.43 mmol) and stirred for 5-10 min, followed by addition of methoxylamine hydrochloride (0.04 g, 0.56 mmol), stirring was continued for another 1 hr. The reaction mixture was then poured into water with stirring, resulting in precipitation of title compound.

To a stirred and cooled (0-5 °C) solution of 2-[4-[4-amino-3-(4- phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl |cyclohexylidene|acctic acid (0.22 g, 0.48 mmol) in DMF (3 ml) was added triethylamine (0.33 ml, 2.3 mmol), HATU (0.18 g, 0.48 mmol) and stirred for 5-10 min, followed by addition of hydroxylamine hydrochloride (0.09 g, 1.4 mmol), stirring was continued for another 30 min and then reaction mixture was poured into water and the precipitated product was filtered and purified by silica-gel chromatography to give title compound.

A: Synthesis of 4,4,5,5-tetramethyl-2-(4-phenoxyphenyl)-l,3,2-dioxaborolane (XLIII)

A mixture of 4-bromodiphenyl ether (20 g, 0.08 mol), bispinacolato diboron (24.4 g, 0.096 mol) and potassium acetate (23.64 g, 0.24 mol) in 1,4-dioxane (200 ml) was stirred at room temperature and flushed with nitrogen. Palladium /e/rate-triphenyl phosphine (9.24 g, 0.008mol) was added and the reaction was refluxed for 3-4 hr at 100 °C. The reaction mixture was concentrated and purified by flash column chromatography using hexane: ethyl acetate (90: 10) to give borate ester 15 g (XLIII). B:

Step 1: Synthesis of N'-[(2-chlorophenyl) methyl] -3 -oxo-cyclobutanecarboxamide (XL VI)

A stirred suspension of (3-chloropyrazin-2-yl)methanamine HCI (100 g, 0.55 mol) in DCM (500 ml) was cooled at 0-5 °C and maintained under nitrogen atmosphere. To this cooled reaction mixture 3-oxocyclobutanecarboxylic acid (69.3 g, 0.6 mol) and triethylamine (306 ml, 2.2 mol) were added. After stirring for 15 min at 0-5 °C HATU (231 g, 0.6 mol) was added and the mixture was allowed to stir at 25-30 °C overnight. The mixture was portioned between ethyl acetate and water, layers were cut and organic layer was brine washed, dried over anhydrous sodium sulphate. The residue was chromatographed in a solvent mixture (ethyl acetate/hexane) to provide title compound (XL VI) as colorless oil. Yield = 104 g.

Step 2: Synthesis of 3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutanone (XL VII)

A solution of N-[(2-chlorophenyl (methyl |-3-oxo-cyclobutanecarboxamide XL VI (100 g, 0.4 mol) was prepared in a mixture of ethyl acetate (800 ml) and DMF (100 ml) and cooled to 0-5 °C. To above was added phosphorous oxychloride (49 ml, 0.52 mol) slowly dropwise while maintaining temperature below 5 °C. The reaction mixture was stirred at 0- 5 °C for 4-5 hr. The reaction mixture was poured into aqueous sodium carbonate, maintaining (pH 8-9), the quenched mass was stirred for 15-20 minutes and portioned between mixture of ethyl acetate and water. The organic layer was separated, water washed, dried and concentrated under vacuum to give crude which was purified by column chromatography (hexanes/ethyl acetate), to give title compound as colorless oil. Yield = 50 g·

Step 3: Synthesis of 3-(l-bromo-8-chloro-imidazo[1,5-a]pyrazin-3-yl)cyclobutanone

(XL VIII)

To a 0-5 °C cooled and stirred solution of 3-(8-chloroimidazo[1,5-a]pyrazin-3- yl)cyclobutanone (50 g,0.22 mol) in DMF (100 ml) was added 44.2g A-bromosuccinimide in small portions. The reaction mixture was stirred for 3-4 hr at room temperature. The reaction mixture was poured into water (1 L) and stirred for 30 minutes. The crude product was filtered, dried under vacuum for 1 hr, and the obtained solid was purified via column chromatography (ethyl acetate: hexanes) to give compound XL VIII, as an off white solid. Yield = 53 g.

Step 4: Synthesis of 3-(l-bromo-8-chloro-imidazo[1,5-a]pyrazin-3-yl)cyclobutanol (XLIX) A stirred solution of 3-(l-bromo-8-chloro-imidazo[1,5-a]pyrazin-3- yl)cyclobutanone (51 g, 0.17 mol) in THF (400 ml) and methanol (100 ml) was cooled to 0- 5 °C, followed by addition of sodium borohydride (3.2 g, 0.08 mol) in small portions. The reaction mixture was stirred at room temp for 1-2 h and then concentrated under vacuum. DCM (250 ml) was added to concentrated mass and then washed with water and dried over anhydrous sodium sulphate. The crude product was purified by silica-gel column chromatography (hexane/ethyl acetate) to give title product (XLIX) as an off white solid. Yield = 45 g.

Step 5: Synthesis of 3-(8-amino-l-bromo-imidazo[1,5-a]pyrazin-3-yl)cyclobutanol (L)

A suspension of 3-(l-bromo-8-chloro-imidazo[1,5-a]pyrazin-3-yl)cyclobutanol (XLIX, 45 g, 0.15 mol) in a mixture of iso- propyl alcohol (500 ml) , and 25 % aqueous ammonia (300 ml) was autoclaved in stainless steel autoclave at 90-95 °C . The reaction resulted in pressure of 3-4 kg/cm ² . The reaction mixture continued to stir 90-95 °C for 5-6 hr and was then cooled to room temperature. The reaction mixture was concentrated under vacuum, and portioned between water and DCM. The organic layer was separated, dried, and concentrated to give title compound as brown solid. Yield = 25 g.

Step 6: Synthesis of 3-[8-amino-l-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3- yl] cyclobutanol (LI)

To a stirred solution of 3-(8-amino-l-bromo-imidazo[1,5-a]pyrazin-3- yl)cyclobutanol (L, 5 g, 0.01 mol) in a mixture of 1,4-dioxane (35 ml) and water (15 ml) was added 4,4,5,5-tetramethyl-2-(4-phenoxyphenyl)-l,3,2-dioxaborolane (6.8 g, 0.02 mol) and potassium carbonate (6.1 g, 0.04 mol). The catalyst bis (diphenylphosphino)fcrroccnc |dichloro palladium (II) complex with DCM was added and the mixture refluxed under nitrogen atmosphere for 4-5 hr. The reaction mixture was cooled to room temperature and organic layer was separated. The aqueous layer was back extracted with DCM (200 ml) and joined with earlier organic layer. The combined organics were concentrated, then purified by silica-gel column chromatography gave title compound as light brown solid. Yield = 2.9 g.

Step 7: Synthesis of 3-[8-amino-l-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3- yl]cyclobutanone (LII)

To a 0-5 °C cooled suspension of 3-[8-amino-l-(4-phenoxyphenyl)imidazo[1,5- ]pyrazin-3-yl] cyclobutanol (LI) (2.7 g, 0.007 mol) in DCM (100 ml) was added Dess- martin periodinane (6.1 g, 0.01 mol) in small portions. The reaction mixture was stirred for 4-5 hr and then quenched with sat. aqueous sodium bicarbonate solution (50 ml), and layers were cut. The organic layer was water washed, dried, and concentrated. The crude was purified by silica gel column chromatography to afford compound (LII) as an off white solid. Yield = 1.5 g.

Step 8 : Synthesis of methyl 2-[3-[8-amino-l-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3- yl]cyclobutylidene] acetate (LIII)

To a -15 to -20 °C cooled, stirred solution of trimethylphosphonoacetate (0.7 ml, 0.004 mol) in THF (10 ml) was added 1M in THF solution of LiHMDS (1.0 ml, 0.006 mol) keeping nitrogen atmosphere. The reaction was stirred for 5-10 minutes and a solution of 3- [8-amino-l-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl]cyclo butanone LII (1.5 g, 0.004 mol) in THF (15 ml) was added slowly dropwise. The reaction mixture was then stirred overnight at room temp, followed by quenching with 50% aqueous acetic acid solution till pH = 4-5. The reaction mixture was then concentrated under vacuum, the residue was portioned between DCM and water and layers were cut. The organic layer was concentrated and crude was column purified to give compound (LIII) as an off white solid. Yield = 900 mg.

Step 9: Synthesis of 2-[3-[8-amino-l-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3- yl]cyclobutylidene]acetic acid (1.56)

A mixture of methyl 2-[3-[8-amino-l-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3- yl]cyclobutylidene] acetate (LIII, 500 mg, 0.001 mol), 1,4-dioxane (5 ml), water (2 ml) and lithium hydroxide monohydrate (60 mg) was heated at 60 °C for 4 hr. The reaction mixture was concentrated under vacuum, and the residue was suspended in water and acidified with IN aqueous hydrochloric acid. The precipitated solid was filtered and dried, to give title compound as light brown solid. Yield = 0.35 g.

A solution of 2-[3-[8-Amino-1 -(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3- yl]cyclobutylidene] acetic acid (300 mg, 0.0007 mol) in DMF (5 ml) was cooled to 0-5 °C, followed by addition of HATU (330 mg, 0.0008 mol) and DIPEA (0.37 ml, 0.002 mol). The mixture was stirred for 10 min and then acryloyl hydrazidehydrochloride (280 mg, 0.001 mol) was added. The reaction mixture was stirred for 1 hr at 0-5 °C, and then poured into another flask having water (100 ml) kept under stirring. The resulting solid was filtered, suction dried under vacuum and then purified by silica gel column chromatography (DCM/MeOH) to get title compound as white solid. Yield = 100 mg. Example 35: 2-[3-[[[6-Amino-5-(4-phenoxyphenyl)pyrimidin-4- yl]aminolmethyl]cvclobutylidenel acetic acid (I.51)

Step 1: Synthesis of 4,6-dimethoxy-5-(4-phenoxyphenyl)pyrimidine. (LIV)

To a mixture of 5-bromo-4,6-dimethoxy-pyrimidine (14 g, 64 mmol), 4- phenoxyphenylboronic acid (20.5 g, 128 mmol, potassium carbonate (17.6 g, 128 mmol), palldium tetrakistriphenylphosphine (3.5 g, 3 mmol), ethanol (50 ml), and 1,4-dioxane (50 ml) was refluxed at 95 °C for 20 hr. The reaction mixture was brought to room temperature and fdtered. The fdtrate was concentrated under vacuum and crude was purified by column chromatography (ethyl acetate: hexanes, 1:3) to give compound (LIV) as light green solid, 15.1 g. Step 2: (Phenoxyphenyl)pyrimidine-4,6-diol (LV)

A mixture of 4,6-dimethoxy-5-(4-phenoxyphenyl)pyrimidine (15 g) and (1:1) mixture of glacial acetic acid and concentrated hydrochloric acid (150 ml) was refluxed for 4-5 hr. The reaction mixture was cooled to room temperature and filtered. The wet filter cake was water washed (50 ml), and then dried at 60 °C for 1 hr to give compound (LV) as off white solid. Yield = 12.2 g.

Step 3: Synthesis of 4,6-dichloro-5-(4-phenoxyphenyl)pyrimidine (LVI)

A miture of 5-(4-phenoxyphenyl)pyrimidine-4,6-diol (12 g) and phosphorus trichloride (48 ml) was heated at reflux for 4-5 hr. After completion of reaction, excess phosphorous trichloride was distilled off under vacuum, and residue was column purified (hexane: ethyl acetate, 4: 1) to give compound (LVI) as pale yellow solid. Yield = 6.5 g. Step 4: 6-CHloro-N-(5,8-dioxaspiro[3.4]octan-2-ylmethyl)-5-(4-phenox yphenyl)pyrimidin- 4-amine (LVIII)

To a stirred solution of 4,6-dichloro-5-(4-phenoxyphenyl) pyrimidine compound LVI (5 g) were added DMF (25 ml), triethylamine (7 ml, 0.05 mol, 1.5 eq), 5,8- dioxaspiro[3.4]octan-2-ylmethanamine (compound LVII) (5.8 g, 0.034 mol, 1.0 eq) and heated the flask to 120 °C for 18-20 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated, dried and concentrated. The crude was purified by chromatography (mobile phase- hexane: ethyl acetate, 70:30) to obtain compound LVIII as syrupy mass - 4.2 g.

Step 5: Synthesis of N ⁶ -(5,8-dioxaspiro[3.4]octan-2-ylmethyl)-N ⁴ -[(4- methoxyphenyl)methyl]-5-(4-phenoxyphenyl)pyrimidine-4, 6-diamine (LIX)

To a solution of 6-chloro-N-(5,8-dioxaspiro[3.4]octan-2-ylmethyl)-5-(4- phenoxyphenyl)pyrimidin-4-amine (compound LVIII) (4.0 g) in DMF (5 ml) was added 4- methoxybenzylamine (5 ml) and heated at 140 °C for 18-19 hr. The reaction mixture was poured into water (50 ml) and extracted with DCM. The organic layer was concentrated and crude was purified by silica gel column chromatography using a mixture of ethyl acetate and hexane. Compound (LIX) obtained as off white solid. Yield = 4.0 g.

Step 6: Synthesis of 3-[[[6-chloro-5-(4-phenoxyphenyl)pyrimidin-4- yl]amino]methyl]cyclobutanone (LX) N ⁶ -(5,8-dioxaspiro[3.4]octan-2-ylmethyl)-N ⁴ -[(4-methoxyphenyl)methyl]-5-(4- phenoxyphenyl)pyrimidine-4, 6-diamine (LIX) was dissolved in (1:1:1) mixture of 1,4- dioxane, water, and trifluoroacetic acid. The resulting mixture was heated at 110 °C for 16- 18 hr. After completion of reaction, the reaction mixture was poured into 50 g ice and the acid was neutralized using aqueous sodium bicarbonate. The mixture was then extracted into DCM. The organic layer was concentrated under vacuum and residue after trituration with diethyl ether afforded compound (LX) as light brown solid, 2.1 g. Synthesis _ of _ methyl _ 2-[3-[ [ [6-amino-5-(4-phenoxyphenyl)pyrimidin-4- yllaminolmethyllcvclobutylidenelacetate (LXI)

To a -60 °C cooled solution of trimethylphosphonoacetate (1 g, 5.5 mmol) in THF (20 ml) was added LiHMDS solution (1M in THF, 5.5 ml). The reaction mixture was stirred for 10-15 minutes, then solution of compound LX (1.55 g, 4.37 mmol) in THF (20 ml) was added in a dropwise manner. The reaction mixture was allowed to warm to room temperature and stirred for 16 hr. The reaction mixture was quenched into mixture of acetic acid (1.0 ml) and water (5 ml) till neutralization. The reaction mixture was concentrated and residue portioned in a mixture of ethyl acetate (50 ml) and water (50 ml). The organic layer was separated, dried and concentrated to give off white solid. Yield = 1.55 g.

Synthesis of 2-[3-[ [ [6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl]amino]methyl- cyclobutylidenel acetic acid (I.51 )

To a solution of methyl 2-[3-[[[6-amino-5-(4-phenoxyphenyl)pyrimidin-4- yl]amino]methyl]cyclobutylidene]acetate (LXI, 0.8g, 1.37 mmol), 1,4-dioxane (8 ml) was added 0.9 g (13.7 mmol) sulfuric acid at room temperature. The reaction mixture was heated to 105 °C for 12-13 hours. The reaction mixture was then poured over crushed ice (25 g) and stirred for 15 mins. The solid was separated out by fdtration and washed with DM water (2 x 10 ml), dried, and triturated with diethyl ether to afford an off white solid, 0.37g.

Example 36: N'- 2-[3-[ [ [6 -Amino-5-(4-phenoxyphenyl)pyrimidin-4- yll aminol methyll cyclobutylidenel acetyll prop-2-enehydrazide (1.50)

2-[3-[[[6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl]amino]m ethyl- cyclobutylidene] acetic acid (0.25 g, 0.6 mmol) was dissolved in DMF (2 ml), and di- isopropyl ethylamine (0.54 ml, 3 mmol) was added. The reaction mixture was cooled to 0- 5 °C and then HATU (0.28 g, 0.78 mmol) was added along with acryloylhydrazide hydrochloride (142 mg, 0.74 mmol). The mixture was stirred at 0-5 °C for 15 mins and then stirred at room temperature for 1 hr. The reaction mixture was poured into water (50 ml) and filtered. The wet cake was re-dissolved into DCM (50 ml) and concentrated to give crude, which was purified on column chromatography to give an off white solid. Yield =

0.12 g.

Step 1: Synthesis of N-[(4-chlorophenyl)methyl ]-5-fluoro-2-methoxy-benzamide (LXII) To a stirred solution of 5-fluoro-2-methoxybenzoic acid (4.5 g, 0.026 mol) in DCM (25 ml) was added oxalyl chloride (2.7 ml, 0.031 mol), and a few drops DMF. The mixture was then stirred at room temperature for 2-3 hours. After completion of reaction, the solvents were removed under vacuum at 50 °C. The residue was dissolved into DCM (25 ml) and di-isopropyl ethylamine (9.2 ml, 0.052 mol) was added followed by, 4- chlorobenzylamine (4.24 g, 0.031 mol) at 0-5 °C. The reaction mixture was stirred at room temperature for lhr. After completion of reaction, the mixture was washed with water (2 x 10 ml). The organic layer was concentrated and crude was column purified using hexanes: ethyl acetate 90: 10 to get 6.0 g of an off white solid. Step 2: Synthesis of 5-fluoro-2-methoxy-N-[[4-(4,4,5,5-tetramethyl-l,3,2-dioxabor olan-2- yl)phenyl]methyl]benzamide (LXIII)

To a solution of N'-[(4-chlorophenyl)methyl]-5-fluoro-2-methoxy-benzamide (6.0 g) in 1,4-dioxane (120 ml) was added bispinacolato diboron (7.6 g, 0.03 mol, 1.5 eq), potassium acetate, (5.88 g,0.06 mol), tris(dibenzylacetone)di-palladium (190 mg , 0.0002 mol), and Xphos (380 mg, 0.0008 mol). The reaction mixture was refluxed for 20-21 hr. The reaction mixture was fdtered over hyflow bed and mother liquor was concentrated. The residue was column purified using mobile phase hexane: ethyl acetate (85: 15) to get an off white solid, 7 g.

B2)

Step 1: Synthesis of N-[ [4-[ 4-amino- 1 -( 1 4-dioxaspiro[4.5]decan-8-yl)pyrazolo| 3.4- d]pyrimidin-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide (LXV)

Took 2 g (5.6 mol, 1.0 eq) of 3-bromo-l-(1,4-dioxaspiro[4.5]decan-8- yl)pyrazolo[3,4-d]pyrimidin-4-amine (LXIV) into 100 ml RB flask with 2.4 g (6.4 mol, 1.2 eq) of 5-fluoro-2-methoxy-N-[[4-(4,4,5,5-tetramethyl-l,3,2-dioxabor olan-2- yl)phenyl]methyl]benzamide, 250 mg palladium-ferrocene DCM complex, 2.4 g (16.8 mol, 3 eq) potassium carbonate, 16 ml dioxane, up in 8 ml water and then heated the reaction mixture to reflux for 3-4 hr. After completion of reaction, organic layer was separated and concentrated. Purified the crude by column chromatography using mobile phase DCM: MeOH, 95:05 to get white solid - 3.0 g.

Step 2: Synthesis of N-[ [4-[ 4-amino- 1 -(4-oxocyclohexyl)pyrazolo|3.4-d|pyrimidin-3- yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide (LXVI)

A- 114-| 4-amino- 1 -( 1 4-dioxaspiro| 4.5 |decan-8-yl)pyrazolo| 3.4-d |pyrimidin-3- yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide (LXV) was taken into 100 ml R _B flask with 21 ml acetic acid, and 9 ml water and refluxed the reaction mixture for 4 hr. After completion of reaction, distilled off the reaction mixture and poured saturated sodium bicarbonate into the reaction mixture and extracted the product using ethyl acetate. Distilled off the ethyl acetate to get 2.3 g of white solid.

Step 3: Synthesis of methyl 2-[4-[4-amino-3-[4-[[(5-fluoro-2-methoxy- benzoyl)amino]methyl]phenyl]pyrazolo[2.3-d]pyrimidin-1 yl]cyclohexylidene]acetate

(LXVII)

Took 0.06 ml (0.5 mmol, 1.0 eq) trimethylphoshpinoacetate into 50 ml R _B flask with 5 ml tetrahydrofuran and cooled the reaction mixture to 0-5 °C. CHarged in lots 22 mg sodium hydride into the reaction mixture and stirred the reaction mixture for 1 hr at RT. Then charged 0.25 g (0.5 mmol, 1.0 eq) of N'-[[4-[4-amino-l-(4- oxocyclohexyl)pyrazolo[2.3-d]pyrimidin-3-yl]phenyl]methyl]-5 -fluoro-2-methoxy- benzamide into above reaction mixture at 0-5 °C and stirred the reaction mixture at RT for overnight. After completion of reaction, quenched the reaction into dilute acetic acid and extracted the product using ethyl acetate. Concentrated the ethyl acetate layer and triturated the concentrate with diethyl ether to get 0.3 g of light brown solid.

Step 4: Synthesis of 2-[4-[4-amino-3-[4-[[(5-fluoro-2-methoxy- benzoyl)amino]methyl]phenyl]pyrazolo[2.3-d]pyrimidin-1-yl]cy clohexylidene]acetic acid (1.52)

Ester compound LXVII (0.7 g, 0.7 mmol, 1.0 eq) was taken into 25 ml RB flask with 550 mg barium hydroxide, 3.5 ml water, 3.5 ml tetrahydrofuran, 3.5 ml methanol and the reaction mixture was stirred at room temperature overnight. After completion of reaction, reaction was quenched with dil. acetic acid till pH was 5-6 and then extracted the product using ethyl acetate. The organic layer was concentrated and the crude product was purified by column chromatography using mobile phase DCM: MeOH (95:05) to get white solid of title compound, 0.35 g.

Example 38: Synthesis of N-[ [4-[ 4-amino-l-[4-[2-oxo-2-(2-prop-2- enoylhvdrazino)ethylidenel cvclohexyl] pyr azolo[3,4-d] pyrimidin-3-yl] phenyl] methyl] - 5-fluoro-2-methoxy-benzamide (I.53)

Compound 1.52 (0.25 g,0.4 mmol) was taken into 25 ml R _B flask with 5 ml DMF, 0.42 ml (2.35 mmol) DIPEA at 0-5 °C, and then 0.215 g (0.56 mmol) HATU was added. The reaction mixture was stirred for 5 mins and then 0.157 g (0.6 mmol) pro-2- enehydrazide-PTSA salt was added. The mixture was stirred at room temperature for 1 hr. After completion of reaction, reaction was poured into water and extracted with ethyl acetate and then purified by column chromatography using mobile phase DCM:MeOH, 95:05 to get white solid which was leached in diethyl ether to get 120 mg white solid. Table 2 set forth below provides characterization data (proton NMR) of compounds of Formula I. The compounds for which data is provided below but for which a description of the synthesis is not explicitly provided above were made in analogous manner to the synthetic procedures provided above.

Table 2: CHemical name and proton NMR data for compound of Formula I Biological Data:

BTK Enzyme Assay

The inhibitory activity of test compounds was evaluated in an enzyme assay employing the ADP-Glo™ Platform (Promega Corp.). Briefly lOng of hBTK is pre- incubated with vehicle (DMSO)/test compound (varying concentrations) for 15 minutes in the reaction buffer (40mM Tris buffer pH 7.5 containing 20mM MgC12.6H ₂ 0, 2mM MnCH. 0.05mM DTT and 0.1% BSA). The enzymatic reaction is initiated by addition of 0.5mg of substrate Poly (Glu4, Tyrl) with 15mM ultrapure ATP and incubated for 30 minutes at room temperature. The reaction is terminated by addition of ADP-Glo™ Reagent (1 : 1 to reaction mixture) and incubated for an additional 40 minutes at room temperature to deplete the remaining ATP. Kinase detection reagent (1: 1 to terminated reaction mixture) is added and the reaction is further continued for 30 minutes at room temperature. The kinase detection reagent converts the ADP to ATP and the ATP generated is measured in luminescence mode in a micro plate reader. The luminescence in the vehicle (DMSO) control is compared to that of the test compound treated sample to determine the inhibitory activity of the compound.

BTK (C481S) Enzyme Assay

The inhibitory activity of test compounds was evaluated in an enzyme assay employing the ADP-Glo™ Platform (Promega Corp.). Briefly, 5ng of hBTK (C481S) is pre-incubated with vehicle (DMSO)/test compound (varying concentrations) for 15 minutes in the reaction buffer (40mM Tris buffer pH 7.5 containing 20mM MgC12.6H ₂ 0, 2mM MnCh additional 40 minutes at room temperature to deplete the remaining ATP. Kinase detection reagent (1: 1 to terminated reaction mixture) is added and the reaction is further continued for 30 minutes at room temperature. The kinase detection reagent converts the ADP to ATP and the ATP generated is measured in luminescence mode in a micro plate reader. The luminescence in the vehicle (DMSO) control is compared to that of the test compound treated sample to determine the inhibitory activity of the compound.

Table 3 provides percent inhibition of BTK (wild type) and BTK (C481S mutant) at 10 nM for some representative compounds. Table 3. Inhibition of BTK (wild type) and BTK (C481S) at 10 nM

*A= Greater than 70% inhibition at the tested concentration

B= 60-69% inhibition at the tested concentration C= 50-59% inhibition at the tested concentration D=40-49% inhibition at the tested concentration

E= less than 40% inhibition at the tested concentration.