WO2022087371A1 - Novel bicyclic compounds - Google Patents

Abstract

A novel class of compounds as KRas G12C inhibitors. Also disclosed are pharmaceutical compositions of the KRas G12C inhibitors and methods of treating KRas G12C associated diseases.

Description

NOVEL BICYCLIC COMPOUNDS TECHNICAL FIELD [0001] Disclosed herein is a novel class of heterocyclic compounds as KRas G12C inhibitors. BACKGROUND [0002] The well-known role of KRAs in malignancy and the discovery of these frequent mutations in KRas in various tumor types made KRas a highly attractable target of the pharmaceutical industry for cancer therapy. Notwithstanding thirty years of large scale discovery efforts to develop inhibitors of KRas for treating cancer, progress has been very limited in developing safe and efficacious KRas inhibitors. [0003] Despite many failed efforts to target KRas, compounds that inhibit KRas activity are still highly desirable and under investigation, including those that disrupt effectors such as guanine nucleotide exchange factors. Clearly there remains a continued interest and effort to develop inhibitors of KRas, particularly inhibitors of activating KRas mutants, including KRas G12C. [0004] Thus, there is a need to develop new KRas G12C inhibitors that demonstrate sufficient efficacy, stability and/or safety for treating KRas G12C-mediated cancer. SUMMARY [0005] An aspect of the patent document provides a compound of Formula I or a pharmaceutically acceptable salt thereof,

wherein: A is a bond, C_1-3alkylene-O, C(=O)O, O, S or NR^a; B is a 4-12 membered saturated or partially saturated monocyclic, bridged or spirocyclic ring, wherein the saturated or partially saturated monocyclic ring is optionally substituted with one or more R⁵; R¹ is selected from the group consisting of hydrogen, cyano, C(O)OR^m, C(O)N(R^m)₂, C(O) C_1- 6alkyl, haloalkyl, C_1-6alkyl, hydroxyC_1-6alkyl, dihydroxyC1-10alkyl, cycloalkyl, heterocycloalkyl, C_1-6alkylene-cycloalkyl, C_1-6alkylene-heterocycloalkyl, C_1-6alkylene-aryl, C_1-6alkylene- heteroaryl, C_1-6alkylene-N(R^m)2, C_1-6alkylene-N(R^m)(COR^m), C_1-6alkylene-N(R^m)(C_1-6alkylene- aryl), C_1-6alkylene-N(R^m)(C_1-6alkylene-heteroaryl), C_1-6alkylene-N(R^m)(C(O)C_1-6alkylene-aryl), C_1-6alkylene-N(R^m)(C(O)C_1-6alkylene-heteroaryl), spirocyclic ring, and bridged ring, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl moiety of these substituents is optionally substituted with one or more of halogen, acyl, CN, haloalkyl, hydroxyl, oxo, C_1-6alkyl, OC1- ₆alkyl, hydroxyC_1-6alkyl, C_1-6alkylene-N(R^m)₂, C_1-6alkylene-N(R^m)(COR^m), N(R^m)₂, cycloalkyl, heterocycloalkyl, C_1-6alkylene-heterocycloalkyl, C_1-6alkylene-aryl, and C_1-6alkylene-heteroaryl; provided that when A is O, S or NR^a, R¹ is not cyano; R² is C(O)CR^b=CR^cR^d, SO₂(O)CR^b=CR^cR^d, C(O)CΞCR^c, or SO₂(O)CΞCR^c; R³ in each instance is independently C_1-6alkyl, C_1-6alkylene-CN, oxo, haloalkyl, hydroxyl or halogen; L is a bond, --C(O)--, or C_1-3alkylene; R⁴ hydrogen, cycloalkyl, heterocyclyl, aryl, C_1-6alkylene-aryl, C_1-6alkylene-heteroaryl, or heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, or heteroaryl moiety of these substituents is optionally substituted with one or more substituents selected from the group consisting of halogen, C_1-6alkyl, OC_1-6alkyl, hydroxyC_1-6alkyl, C_1-6alkylene-N(R^m)₂, C_1- 6alkylene-N(R^m)(COR^m), CN, CF3, OH, N(R^m )2, haloC_1-6alkyl, and cycloalkyl; R⁵ is selected from the group consisitng of oxo, C_1-6alkyl, OC_1-6alkyl, hydroxylC_1-6alkyl, C_1- 6alkylene-CN, C_1-6alkylene OC_1-6alkyl, C2-C4 alkynyl, haloalkyl, cyano, C(O)OR^m, C(O)N(R^m)2, N(R^m)2, , C_1-6alkylene-N(R^m)2, C_1-6alkylene-aryl, C_1-6alkylene- heteroaryl; C(O)OC_1-6alkyl, C(O)N(R^m)2, and C(O)C_1-6alkyl; R^a is selected from the group consisitng of hydrogen, C_1-6alkyl, heteroalkyl, C(O)C_1-6alkyl, C(O)R^m and C(O)N(R^m)₂; R^b is selected from the group consisting of hydrogen, deuterium, halogen, C_1-6alkyl, OC_1-6alkyl, hydroxyl-C_1-6alkyl, halo-C_1-6alkyl, N(R^m)(C(O) C_1-6alkyl), C_1-6alkylene-OC_1-6alkyl, C_1-6alkylene- heteroaryl, and C_1-6alkylene-aryl; R^c and R^d are independently selected from the group consisting of hydrogen, deuterium, CN, halogen, C_1-6alkyl, halo-C_1-6alkyl, hydroxyl-C_1-6alkyl, C_1-6alkylene-OC_1-6alkyl, C_1-6alkylene- N(C_1-6alkyl)(halo-C_1-6alkyl), , C_1-6alkylene-N(R^m )₂, C_1-6alkylene-N(R^m)(COR^m), CON(R^m)₂, cycloalkyl, heterocycloalkyl, heteroC_1-6alkyl, heteroaryl, aryl, C_1-6alkylene-heteroaryl, C1- ₆alkylene-aryl, C_1-6alkylene-cycloalkyl, and C_1-6alkylene-heterocycloalkyl, wherein the cycloalkyl, heterocycloalkyl, heteroaryl, or aryl moiety of these is optionally substituted with one or more of halogen, C_1-6alkyl, OC_1-6alkyl, CN, and halo-C_1-6alkyl; R^a and R^d optionally link up to form a 5 to 8 membered, partially unsaturated ring, wherein the ring is optionally substituted with oxo or C_1-6alkyl; R^m in each instance is independently hydrogen, C_1-6alkyl, acyl, heteroalkyl, hydroxyl-C_1-6alkyl, wherein optionally two R^m together with the nitrogen they are attached to link up to form a heterocyclic ring; m is 0, 1 or 2; n is 0, 1 or 2; and p is 0, 1 or 2. [0006] Also provided are pharmaceutical compositions comprising a therapeutically effective amount of a compound of Formula I disclosed herein or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. [0007] Another aspect provides a method for inhibiting KRas G12C activity in a cell, comprising contacting the cell in which inhibition of KRas G12C activity is desired with an effective amount of a compound of Formula I disclosed herein or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof. [0008] Another aspect provides a method for treating cancer comprising administering to a subject having cancer a therapeutically effective amount of a compound of Formula (I) disclosed herein or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof. DESCRIPTION OF THE DRAWINGS [0009] Figure 1 shows the synethesis of a sample compound of Formula I. [0010] Figure 2 shows the synethesis of a sample compound of Formula I. [0011] Figure 3 shows the synethesis of a sample compound of Formula I. [0012] Figure 4 shows two example compounds and their activities. DETAILED DESCRIPTION [0013] This patent document discloses a novel class of KRas G12C inhibitors. These compounds are capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of KRas G12C. [0014] While the following text may reference or exemplify specific embodiments of a compound, substituent, use thereof, it is not intended to limit the scope of the compound, substituent or its use to such particular reference or examples. Various modifications may be made by those skilled in the art, in view of scientific and practical considerations, such as replacement of the substituent and treatment of different diseases. [0015] The articles "a" and "an" as used herein refer to "one or more" or "at least one," unless otherwise indicated. That is, reference to any element or component of an embodiment by the indefinite article "a" or "an" does not exclude the possibility that more than one element or component is present. [0016] The term "acyl” refers to –C(O)CH₃, –C(O)CH₂CH₃, –C(O)CH₂CH₂CH₃, or – C(O)CH₂CH₂CH₂CH₃. [0017] The term "alkyl" refers to a hydrocarbon or a hydrocarbon chain which may be either straight-chained or branched. The term "C_1-6 alkyl" refers to alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms. Non-limiting examples include groups such as CH₃, (CH₂)2CH₃, CH₂CH(CH₃)CH₃, and the like. Similarly, the term "C_2-5 alkyl" refers to alkyl groups having 2, 3, 4 or 5 carbon atoms. [0018] The term "alkylene" refers to methylene or a hydrocarbon chain which may be either straight-chained or branched. Different from alkyl which has only one point of bonding with other groups or atoms, alkylene has two points of bonding. Non-limiting examples include groups such as CH₂, (CH₂)₂, CH₂CH(CH₃), and the like. A C_1-6alkylene has 1, 2, 3, 4, 5 or 6 carbons. A C_1-3alkylene has 1, 2, or 3 carbons. [0019] The term "C2-10 alkenyl" refers to a hydrocarbon chain, straight-chained or branched with one or more double bonds in the chain. As is generally known in the art, a double bond requires two adjacent sp2 hybridized carbons. A C_2-10 alkeny, for example, may have any number of carbons from 2 to 10. Nonlimiting examples include CH₂CH=CHCH₃ and CH₂CH=CHCH₂CH₃. [0020] The term "alkelene” refers to a hydrocarbon chain, straight-chained or branched, with one or two double bonds in the chain. Different from alkenyl which has only one point of bonding with other groups or atoms, alkelene has two points of bonding. A C2-10 alkenlene, for example, has from 2 to 10 carbon atoms. Nonlimiting examples include CH=CH and CH₂CH=CHCH₂CH₂. [0021] The term "alkylene-CN” refers to an alkyl chain having a CN group. Examples include CH₂CH₂CN and CH₂CN. [0022] The term "cycloalkyl" refers to saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 ring carbons, for example 3 to 8 carbons, and as a further example 3 to 6 carbons, wherein the cycloalkyl group additionally is optionally substituted. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. [0023] The term "aryl" group refers to a C_6-14 aromatic moiety comprising one to three aromatic rings, which is optionally substituted. Examples of aryl groups include, without limitation, phenyl, naphthyl, anthracenyl, fluorenyl, and dihydrobenzofuranyl. [0024] The term "arylene" group refers to a C_6-14 aromatic moiety comprising one to three aromatic rings, which is optionally substituted. Different from aryl, arylene has two points of bonding with other groups or atoms. Examples of aryl groups include, without limitation, phenylene, naphthylene, anthracenylene, fluorenylene, and dihydrobenzofuranylene. [0025] The term “haloalkyl” refers to a C₆-₁₀alkyl chain, straight or branched, in which one or more hydrogen has been replaced by a halogen. Non-limiting examples of haloalkyls include CHF₂, CFH₂, CF₃, CH₂CF₂, CH₂CF₃, and CH₂CH₂F. In some embodiments, the alkyl in haloalkyl has 1, 2, 3 or 4 carbons. [0026] The term “heteroalkyl” refers to a C6-10alkyl group, straight or branched, wherein one or more carbon atoms in the chain are replaced by a heteroatom selected from the group consisting of O, S, N and NR^m. In some embodiments, the alkyl in heteroalkyl has 1 to 10 carbons. In some embodiments, the alkyl in heteroalkyl has 2, 3, 4 or more than 2 carbons. [0027] The term “hydroxyalkyl” refers to to a C₁-₁₀alkyl chain, straight or branched, wherein a carbon is substituted with a hydroxyl group. The carbon the hydroxyl is attached to is a primary carbon or secondary carbon. In some embodiments, the alkyl in hydroxylalkyl has 2, 3, 4 or more than 2 carbons. [0028] The term “dihydroxyalkyl” refers to to a C2-10alkyl chain, straight or branched, wherein two carbons are each substituted with a hydroxyl group. In some embodiments, the alkyl in dihydroxylalkyl has 2, 3, 4 or more than 2 carbons. [0029] The term “heterocyclyl” or “heterocyclic” group is a ring structure having from about 3 to about 12 atoms (3-12 membered ring), for example 4 to 8 atoms (4, 5, 6, 7 or 8 membered ring), wherein one or more atoms are selected from the group consisting of N, O, and S, the remainder of the ring atoms being carbon. The heterocyclyl may be a monocyclic, a bicyclic, a spirocyclic or a bridged ring system. Examples of heterocyclic groups include, without limitation, epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidinonyl, thiomorpholinyl, thiomorpholinyl 1,1 dioxide, morpholinyl, oxazepanyl, azabicyclohexanes, azabicycloheptanes and oxa azabiocycloheptanes. Specifically excluded from the scope of this term are compounds having adjacent annular O and/or S atoms. [0030] The term “heteroaryl” refers to groups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to three heteroatoms per ring selected from the group consisting of N, O, and S. Examples of heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, furanyl, furazanyl, imidazolinyl, imidazolyl, 1H- indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5- thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. [0031] The term “biologically active agent” refers to any agent capable of eliciting a response in a biological system such as, for example, living cell(s), tissue(s), organ(s), and being(s). Biologically active agents can include natural and/or synthetic agents. Thus, a biologically active agent is intended to be inclusive of any substance intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease or in the enhancement of desirable physical or mental development and conditions in a subject. [0032] The term “subject” refers to humans or animals including for example sheep, horses, cattle, pigs, dogs, cats, rats, mice, birds, and reptiles. Preferably, the subject is a human or other mammal. [0033] The term “KRas G12C-associated disease or disorder” as used herein refers to diseases or disorders associated with or mediated by or having a KRas G12C mutation. A non- limiting example of a KRas G12C-associated disease or disorder is a KRas G12C-associated cancer. [0034] The term “effective amount” or “therapeutically effective amount” of a compound is an amount that is sufficient to ameliorate, or in some manner reduce a symptom or stop or reverse progression of a condition, or negatively modulate or inhibit the activity of KRas G12C. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective. [0035] The term “pharmaceutically acceptable” refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues, organs, and/or bodily fluids of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio. [0036] The term “pharmaceutically acceptable carrier” refers to a chemical compound that facilitates the delivery or incorporation of a compound or therapeutic agent into cells or tissues. [0037] The term “pharmaceutically acceptable salts” means salts of compounds of the present invention which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Non-limiting examples of such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; or with organic acids such as 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, 2-naphthalenesulfonic acid, 3-phenylpropionic acid, 4,4 ′ -methylenebis(3-hydroxy- 2-ene-1-carboxylic acid), 4-methylbicyclo[2.2.2]oct-2-ene- 1-carboxylic acid, acetic acid, aliphatic mono- and dicarboxylic acids, aliphatic sulfuric acids, aromatic sulfuric acids, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclopentanepropionic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, heptanoic acid, hexanoic acid, hydroxynaphthoic acid, lactic acid, laurylsulfuric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, o-(4-hydroxybenzoyl)benzoic acid, oxalic acid, p-chlorobenzenesulfonic acid, phenyl-substituted alkanoic acids, propionic acid, p-toluenesulfonic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tartaric acid, tertiarybutylacetic acid, and trimethylacetic acid. Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Non-limiting examples of acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, and N-methylglucamine. It should be recognized that the particular anion or cation forming a part of any salt of this invention is not critical, so long as the salt, as a whole, is pharmacologically acceptable. Additional examples of pharmaceutically acceptable salts and their methods of preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (P. H. Stahl & C. G. Wermuth eds., Verlag Helvetica Chimica Acta, 2002). [0038] The term “pharmaceutical composition” refers to a mixture of a compound disclosed herein with other chemical components, such as diluents or additional carriers. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a pharmaceutical composition exist in the art including, but not limited to, oral, injection, aerosol, parenteral, and topical administration. In some embodiments, pharmaceutically acceptable salts of the compounds disclosed herein are provided. [0039] The term "treating" or "treatment" of any disease or condition refers, in some embodiments, to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In some embodiments "treating" or "treatment" refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In some embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In some embodiments, "treating" or "treatment" refers to delaying the onset of the disease or disorder, or even preventing the same. “Prophylactic treatment” is to be construed as any mode of treatment that is used to prevent progression of the disease or is used for precautionary purpose for persons at risk of developing the condition. [0040] An aspect of the disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof,

wherein: A is a bond, C_1-3alkylene-O (O attached to R¹), C(=O)O (non-carbonyl O is attached to R¹), O, S or NR^a; B is a 4-12 membered saturated or partially saturated monocyclic, bridged or spirocyclic ring, wherein the saturated or partially saturated monocyclic ring is optionally substituted with one or more R⁵; R¹ is selected from hydrogen, cyano, C(O)OR^m, C(O)N(R^m)2, C(O) C_1-6alkyl, halo C_1-6alkyl, C1- 6alkyl, hydroxyC_1-6alkyl, dihydroxyC_1-10alkyl, C_1-6alkylene-O-C_1-6alkyl, cycloalkyl, heterocycloalkyl, C_1-6alkylene-cycloalkyl, C_1-6alkylene-heterocycloalkyl, C_1-6alkylene-aryl, C1- 6alkylene-heteroaryl, C_1-6alkylene-N(R^m)₂, C_1-6alkylene-N(R^m)(COR^m), C_1-6alkylene-N(R^m)(C_1- 6alkylene-aryl), C_1-6alkylene-N(R^m)(C_1-6alkylene-heteroaryl), C_1-6alkylene-N(R^m)(C(O)C1- 6alkylene-aryl), C_1-6alkylene-N(R^m)(C(O)C_1-6alkylene-heteroaryl), spirocyclic ring, and bridged ring, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl moiety of these substituents is optionally substituted with one or more of halogen, acyl, CN, haloalkyl, hydroxyl, oxo, C1- 6alkyl, OC_1-6alkyl, hydroxyC_1-6alkyl, C_1-6alkylene-N(R^m)₂, C_1-6alkylene-N(R^m)(COR^m), N(R^m)₂, cycloalkyl, heterocycloalkyl, C_1-6alkylene-heterocycloalkyl, C_1-6alkylene-aryl, and C_1-6alkylene- heteroaryl; provided that the combination or bonding between A and R¹ complies with valency rule and when A is O, S, C_1-3alkylene-O, C(=O)O or NR^a, R¹ is not cyano; R² is C(O)CR^b=CR^cR^d, SO2CR^b=CR^cR^d, C(O)CΞCR^c, or SO2CΞCR^c; R³ in each instance is independently C_1-6alkyl, C_1-6alkylene-CN, oxo, haloalkyl, hydroxyl or halogen; L is a bond, --C(O)--, or C_1-3alkylene; R⁴ hydrogen, cycloalkyl, heterocyclyl, aryl, C_1-6alkylene-aryl, C_1-6alkylene-heteroaryl, or heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, or heteroaryl moiety of these substituents is optionally substituted with one or more substituents selected from the group consisting of halogen, C_1-6alkyl, OC_1-6alkyl, hydroxyC_1-6alkyl, C_1-6alkylene-N(R^m)₂, C_1- 6alkylene-N(R^m)(COR^m), CN, CF3, OH, N(R^m )2, haloC_1-6alkyl, and cycloalkyl; R⁵ is selected from the group consisitng of oxo, C_1-6alkyl, OC_1-6alkyl, hydroxylC_1-6alkyl, C_1- 6alkylene-CN, C_1-6alkylene OC_1-6alkyl, C2-4alkynyl, haloalkyl, cyano, C(O)OR^m, C(O)N(R^m)2, N(R^m)2, , C_1-6alkylene-N(R^m)2, C_1-6alkylene-aryl, C_1-6alkylene-heteroaryl; C(O)OC_1-6alkyl, C(O)N(R^m)2, and C(O)C_1-6alkyl; R^a is selected from the group consisitng of hydrogen, C_1-6alkyl, heteroalkyl, C(O)C_1-6alkyl, C(O)R^m and C(O)N(R^m)₂; R^b is selected from the group consisting of hydrogen, deuterium, halogen, C_1-6alkyl, OC_1-6alkyl, hydroxyl-C_1-6alkyl, halo-C_1-6alkyl, N(R^m)(C(O) C_1-6alkyl), C_1-6alkylene-OC_1-6alkyl, C_1-6alkylene- heteroaryl, and C_1-6alkylene-aryl; R^c and R^d are independently selected from the group consisting of hydrogen, deuterium, CN, halogen, C_1-6alkyl, halo-C_1-6alkyl, hydroxyl-C_1-6alkyl, C_1-6alkylene-OC_1-6alkyl, C_1-6alkylene- N(C_1-6alkyl)(halo-C_1-6alkyl), , C_1-6alkylene-N(R^m )₂, C_1-6alkylene-N(R^m)(COR^m), CON(R^m)₂, cycloalkyl, heterocycloalkyl, heteroC_1-6alkyl, heteroaryl, aryl, C_1-6alkylene-heteroaryl, C1- ₆alkylene-aryl, C_1-6alkylene-cycloalkyl, and C_1-6alkylene-heterocycloalkyl, wherein the cycloalkyl, heterocycloalkyl, heteroaryl, or aryl moiety of these is optionally substituted with one or more of halogen, C_1-6alkyl, OC_1-6alkyl, CN, and halo-C_1-6alkyl; R^a and R^d optionally link up to form a 5 to 8 membered, partially unsaturated ring, wherein the ring is optionally substituted with oxo or C_1-6alkyl; R^m in each instance is independently hydrogen, C_1-6alkyl, acyl, heteroalkyl, hydroxyl-C_1-6alkyl, wherein optionally two R^m together with the nitrogen they are attached to link up to form a heterocyclic ring; m is 0, 1 or 2; n is 0, 1 or 2; and p is 0, 1 or 2. [0041] In various embodiments, a subsitutent designator may be present in multiple moieties of a compound. Unless noted otherwise, the subsitutent designator can be same or different. For instance, the R^m of C_1-6alkylene-N(R^m)₂ for R¹ is independent from the R^m of C_1- 6alkylene-N(R^m)2 for R⁴ and they can be same or different. Likewise, the two R^ms in N(R^m)2 for R⁵ can be same or different. [0042] In some embodiments, R^a is hydrogen, or C_1-6alkyl. [0043] In some embodiments, A is S or NH. In some embodiments, A is a bond. In some embodiments, A is a C_1-2alkylene-O, where O is attached to R¹. In some embodiments, A is C(O)O wherein the non-carbonyl O is attached to R¹. [0044] In some embodiments, R¹ is selected from the group consisting of heteroaryl, C1- ₃alkylene-heterocycloalkyl, C_1-3alkylene-cycloalkyl, and C_1-3alkylene-heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl moiety of these substituents is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, haloalkyl, hydroxyl, oxo, C_1-6alkyl, OC_1-6alkyl, hydroxyC_1-6alkyl, cycloalkyl, or heterocycloalkyl. In some embodiments, R¹ is C_1-3alkylene-heterocycloalkyl, wherein the heterocycloalkyl is 5 or 6 membered and is optionally substituted with one or more of halogen, C_1-6alkyl, OC_1-6alkyl or cycloalkyl. In some embodiments, R¹ is C_1-6alkylene-N(R^m)2. In some embodiments, A is O or S. In some embodiments, R¹ is heterocycloalkyl, and A is a bond. [0045] In some embodiments, A is O or C1-2alkylene-O (O is attached to R¹), and R¹ is optionally substituted C_1-6alkylene-heterocycloalkyl. In some embodiments, A is a bond, and R¹ is selected from the group consisting of cyano, C(O)OR^m, C(O)N(R^m)₂, C(O) C_1-6alkyl, haloalkyl, heterocycloalkyl, spirocyclic ring, and bridged ring, wherein the heterocycloalkyl, spirocyclic ring, and bridged ring are optionally substituted. In some embodiments, A is O, and R¹ is selected from the group consisting of C(O)OR^m, C(O)N(R^m)2, C(O) C_1-6alkyl, haloalkyl, heterocycloalkyl, spirocyclic ring, and bridged ring, wherein the heterocycloalkyl, spirocyclic ring, and bridged ring are optionally substituted. In some embodiments, A is a bond, and R¹ is cyano. In some embodiments, A is C_1-2alkylene-O (methylene-O or ethylene-O where O is attached to R¹), and R¹ is selected from the group consisting of C(O)OR^m, C(O)N(R^m)2, C(O) C_1-6alkyl, C1-2alkylene- heterocycloalkyl, haloalkyl, heterocycloalkyl, spirocyclic ring, and bridged ring, wherein the heterocycloalkyl, spirocyclic ring, and bridged ring moieties of these substituents are unsubstituted or substituted with one or more of the above mentioned substituents in R¹. In some embodiments, A is C(O)O, R¹ is unsubstituted or substituted C_1-6alkyl, C_1-2alkylene-heterocycloalkyl, haloalkyl, heterocycloalkyl, spirocyclic ring, or bridged ring. [0046] In some embodiments, A is O or C1-2alkylene-O (methylene-O or ethylene-O where O is attached to R¹), and R¹ is optionally substituted heterocycloalkyl or optionally substituted C_1- 6alkylene-heterocycloalkyl, wherein the heterocycloalkyl is a fused bicylic ring. Nonlimiting examples of fused bicylic rings include the following, where any ring atom of the bicyclic system can be attached to A directly or via a C_1-6alkylene chain. [0047] In some emodiments, A is O or C1-2alkylene-O (methylene-O or ethylene-O where O is attached to R¹), R¹ is the following optionally substituted ring: [0048] Nonlimiting examples of optionally substituted R¹ heterocyclyls or heterocyclyl moieties of R¹ include azetidinyl, C_1-3alkylene -substituted azetidinyl (e.g., methylazetidinyl), halo-substituted azetidinyl (e.g., difluoroazetidinyl), tetrahydropyran, pyrrolidinyl, C_1-3alkylene- substituted pyrrolidinyl (e.g., methylpyrrolidinyl, dimethylpyrrolidinyl, and isopropylpyrrolidinyl), cycloalkylene-C_1-3alkylene-pyrrolidinyl, hydroxypyrrolindinyl, halo- substituted pyrrolidinyl (e.g., fluoropyrrolidinyl and difluoropyrrolidinyl), methoxyethylpyrrolidinyl, (N-methyl)methoxypyrrolidinyl, piperazinyl, dimethylaminylpyrrolidinyl, morpholinyl, methylmorpholinyl, 1,4-oxazepanyl, piperdinyl, C1-C3 alkyl-substituted piperidinyl (e.g., methylpiperidinyl), acylpiperdinyl, cyanopiperdinyl, cycloalkylpiperdinyl, halopiperdinyl (e.g., fluoropiperdinyl), dihalopiperdinyl (e.g., difluoropiperdinyl), alkoxypiperdinyl, pyrrolidonyl, piperidonyl, thiomorpholinyl-1,1-dioxide, 3- azabicyclo[3.1.0]hexanyl, oxa-5-azabicyclo[2.2.1]heptan-5-yl, and azabicyclo[2.2.1]heptan-2-yl. [0049] In some embodiments, A is O or or C_1-2alkylene-O, R¹ is one of the following, wherein the nitrogen of the heterocyclic rings is optionally substituted with a C_1-6alkyl and each of the chiral centers can be R, or S. The compound can be an individual enantiomer, a racemi mixture and or a mixture of diasteromers. R^m is as defined above. In some embodiments, R^m is H or C_1- 6alkyl (e.g. methyl, ethyl or propyl). In some embodiments, the heterocyclic ring is a 4-8 or 4-6 membered ring. [0050] The spirocyclic ring system or a bridged ring system can be optionally substituted with R^e. The spirocyclic ring or bridged ring is attached to the core aryl group through its ring nitrogen. The optional sustituent may be on any ring atoms. In some embodiments, the optional sustituent is attached to the second nitrogen of the spirocyclic ring or bridged ring. Nonlimiting examples of bridged ring systems include diazabicycloheptanes and diazabicyclooctanes. In some embodiments, the bridged ring system is diazabicyclo [3.2.1]octan-8-yl or diazabicyclo [3.2.1]octan-3-yl. [0051] Nonlimiting examples of spirocyclic ring system include the following: [0052] R^e is selected from C_1-6alkyl, C_1-6alkylene-CN, haloalkyl, C_1-6alkylene-OC_1-6alkyl, C(O)OR^m, C(O)N(R^m)2, C_1-6alkylene-N(R^m)2 heteroaryl, C(O)C_1-6alkyl, C(O)R^m and C(O)N(R^m)₂. [0053] In some embodiments, R^b is selected from hydrogen, deuterium, halogen, C_1-6alkyl, halo-C_1-6alkyl, hydroxyl-C_1-6alkyl, and N(R^m)(C(O)C_1-6alkyl). In some embodiments, R¹ is C(O)CR^b=CR^cR^d. In some embodiments, R^b is H, deuterium or F. In some embodiments, one or both of R^c and R^d are selected from the group consisting of hydrogen, deuterium, halogen, CN, C_1-6alkyl, halo-C_1-6alkyl, hydroxyl-C_1-6alkyl, CON(R^m)2, C_1-6alkylene-OC_1-6alkyl, C_1-6alkylene- N(R^m)2, C_1-6alkylene-N(R^m)(COR^m), heterocycloalkyl, heteroaryl, aryl, C_1-6alkylene- heterocycloalkyl, C_1-6alkylene-heteroaryl, C_1-6alkylene-aryl, wherein the heterocycloalkyl, heteroaryl, or aryl moiety of these substituents (heteroaryl, aryl, C_1-6alkylene-heterocycloalkyl, C1- ₆alkylene-heteroaryl, C_1-6alkylene-aryl) is optionally substituted with one or more of halogen, C_1- 6alkyl, or OC_1-6alkyl. [0054] In some embodiments, only one of R^c and R^d is hydrogen or deuterium and the other is not hydrogen or deuterium. In some embodiments, R^c and R^d are both H. In some embodiments, R^b is fluorine. [0055] In some embodiments, one of R^c and R^d is C_1-3alkylene-heterocycloalkyl, C1- ₃alkylene-cycloalkyl, heteroaryl or C_1-3alkylene-heteroaryl, each of which is optionally substituted with one or more of halogen, CN, haloalkyl, hydroxyl, oxo, C_1-6alkyl, OC_1-6alkyl, hydroxyC1- ₆alkyl, cycloalkyl, or heterocycloalkyl. In some embodiments, one of R^c and R^d is C1-3alkylene- heterocycloalkyl, wherein the heterocycloalkyl is 5 or 6 membered and is optionally substituted with one or more of halogen, C1-6alkyl, OC1-6alkyl or cycloalkyl. [0056] In some embodiments, R² is C(O)CR^b=CR^cR^d or SO2(O)CRb=C R^cR^d. The alkene moiety in C(O)CR^b=C R^cR^d or SO2(O)CR^b=C R^cR^d may be in E or Z configuration. [0057] In some emodiments, B is an optionally substituted 5 or 6 membered cyclic ring. In some embodiments, B is a spirocyclic ring system. Non-limiting examples of spirocyclic ring systems with attached R² include: [0058] In some embodiments, B is optionally substituted with C_1-3alkylene- CN (e.g. CH₂CN), C_1-6alkylene OC_1-6alkyl, C2-C4 alkynyl, or haloalkyl. [0059] In some embodiments, B is a NH or NR^a, R² can be any of the above desribed heterocycloalkyls. [0060] In some embodiments, p is 1. In some embodiments, m is 0. [0061] In some embodiments, R⁴ is aryl or heteroaryl, wherein each of aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, C_1-6alkyl, OC_1-6alkyl, hydroxyC_1-6alkyl, dihydroxyalkyl, CN, CF₃, N(R^m )₂, haloC_1-6alkyl, and cycloalkyl. In some embodiments, R⁴ is optionally substituted naphthalyl, indoyl, indazolyl, quinolinyl, isoquinolinyl, pyridinyl or benzothiazolyl optionally substituted with one or more of halogen, C_1-6alkyl, hydroxyC_1-6alkyl, CN, CF₃, N(R^m)₂, haloC_1-6alkyl, and cycloalkyl. In some embodiments, L is a bond. [0062] Nonlimiting examples of R⁴ include the following. Any carbon of the rings can be substituted with one or more of halogen, C_1-6alkyl, hydroxyC_1-6alkyl, CN, CF₃, N(R^m)₂, haloC_1- 6alkyl, and cycloalkyl. In some embodiments, L is a bond and the ring is substituted with one or more halogens.

[0063] In some embodiments, R⁵ is oxo (=O), C_1-6alkyl, C_1-6alkylene-CN, C_1-6alkylene OC_1-6alkyl, C2-C4 alkynyl, haloalkyl, cyano, C(O)OR^m, C(O)N(R^m)₂, C_1-6alkylene-N(R^m)₂, C_1- 6alkylene-aryl, C_1-6alkylene-heteroaryl; C(O)OC_1-6alkyl, C(O)N(R^m)2, C(O)C_1-6alkyl. In some embodiments, R⁵ is selected from the group consisting of oxo, C_1-6alkyl, C_1-6alkylene-CN, C2-C4 alkynyl, haloalkyl, cyano, and C(O)OR^m; and wherein n is 1. In some embodiments, R⁵ is C1- ₃alkylene-CN (e.g. Cand n is 1. In cases where B is substituted with R⁵, each of the one or more chiral centers may independently be an R or S configuration. In some embodiments, n is 1 and the chiral center in B has an R configuration. [0064] In some embodiments, Formula I is one of the following compounds. The chiral center may have a R or S configuration. For compounds that have two chiral centers, their stereochemistry may be RR, RS, SR, or SS.

[0065] In further examples, compounds of Formula I are defined as follows: Table 1

m=0, n=0 or 1, p=1, L= bond, A is CH₂O or C(=O)O

[0066] In further examples, compounds of Formula I are defined as follows: Table 2 m=0, n=0 or 1, p=1, L= bond, A=bond

[0067] The synthesis of the compounds of Formula I can be accomplished by various approaches using known synthetic techniques. For example, Intermediate IV can be readily prepared from commercially available material as illustrated below. Couplding reaction between X (halogen) and B ring leads to Intermediate III. P¹ (e.g. Boc) and P² (E.g. CBZ or benzyl) are protecting groups which can be selectively removed. After selective removal of P¹, substituent R’ can be introduced via a coupling reaction to provide intermediate II. Subsequent removal of P² followed by acylation or sulfonylation and other steps if necessary affords compound I. Various modifications of this approach are certainly feasiable. For instance, the B ring may be first acylated or sulfonylated before being coupled to Intermediate IV. The R group in the intermediates can be different from the R in Formula I and may undergo additional chemistry conversions if necessary. [0068] Pharmaceutical Composition and Kit [0069] Another aspect of the patent document provides a pharmaceutical composition comprising a KRas G12C inhibitor of the compound of Formula I disclosed herein and a pharmaceutically acceptable carrier, excipient, or diluent. Compounds of this patent document may be formulated by any method well known in the art and may be prepared for administration by any route, including, without limitation, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or intrarectal. [0070] Nonlimiting examples of pharmaceutically acceptable carriers include physiologically acceptable surface active agents, glidants, plasticizers, diluents, excipients, smoothing agents, suspension agents, film forming substances, and coating assistants. Preservatives, stabilizers, dyes, sweeteners, fragrances, flavoring agents, and the like may be provided in the pharmaceutical composition. For example, sodium benzoate, ascorbic acid and esters of p-hydroxybenzoic acid may be added as preservatives. In addition, antioxidants and suspending agents may be used. In various embodiments, alcohols, esters, sulfated aliphatic alcohols, and the like may be used as surface active agents. Suitable exemplary binders include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, and the like. Suitable exemplary disintegrants include starch, carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, sodium carboxymethylstarch, and the like. Suitable exemplary solvents or dispersion media include water, alcohol (for example, ethanol), polyol (for example, glycerol, propylene glycol, and polyethylene glycol, sesame oil, corn oil, and the like), and suitable mixtures thereof that are physiologically compatible. Suitable exemplary solubilizing agents include polyethylene glycol, propylene glycol, D-mannitol, benzylbenzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, and the like. Suitable exemplary suspending agents include surfactants such as stearyltriethanolamine, sodium laurylsulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate, coconut oil, olive oil, sesame oil, peanut oil, soya and the like; and hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and the like. Suitable exemplary isotonic agent includes sodium chloride, glycerin, D-mannose, and the like. Suitable exemplary buffer agents include buffer solutions of salts, such as phosphate, acetates, carbonates, and citrates. Suitable exemplary soothing agents include benzyl alcohol, and the like. Suitable exemplary antiseptic substances include para-oxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, and the like. Suitable exemplary antioxidants include sulfite salts, ascorbic acid, and the like. Suitable exemplary sealers include, but are not limited to HPMC (or hypromellose), HPC, PEG and combinations thereof. Suitable exemplary lubricants include magnesium stearate, calcium stearate, talc, colloidal silica, hardened oil and the like. [0071] In further exemplary embodiments for solid preparations, carriers or excipients include diluents, lubricants, binders, and disintegrants. In exemplary embodiments for liquid preparations, carriers include solvents, solubilizing agents, suspending agents, isotonic agents, buffer agents, soothing agents, and the like. Acceptable additional carriers or diluents for therapeutic use and the general procedures for the preparation of pharmaceutical compositions are well known in the pharmaceutical art, and are described, for example, in Remington’s Pharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, PA (1990), which is incorporated herein by reference in its entirety. [0072] The compound of Formula I may also be in its pharmaceutically acceptable salt form. Examples of such salts include, but are not limited to acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid. The compounds can also be administered as pharmaceutically acceptable quaternary salts known by those skilled in the art, which specifically include the quaternary ammonium salt, wherein the counterion include, for example, chloride, bromide, iodide, —O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate). [0073] A related aspect provides a kit, which includes a compound of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof and an instruction for treating or preventing diseases associated with KRas G12C. In some embodiments, the kit further includes an additional agent such as anti-cancer agent. [0074] Non-limiting examples of the additional anti-cancer agent include alkylating agents: Busulfan, dacarbazine, ifosfamide, hexamethylmelamine, thiotepa, dacarbazine, lomustine, chlorambucil, procarbazine, altretamine, estramustine phosphate, mechlorethamine, streptozocin, temozolomide, Semustine cyclophosphamide; platinum agents: spiroplatin, tetraplatin, ormaplatin, iproplatin, ZD-0473 (AnorMED), oxaliplatin carboplatin, lobaplatin (Aeterna), satraplatin (Johnson Matthey), BBR-3464 (Hoffmann-La Roche), SM-11355 (Sumitomo), AP-5280 (Access), cisplatin, arboplatin, cisplatin, satraplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, temozolomide, procarbazin; antimetabolites: azacytidine, Floxuridine, 2-chlorodeoxyadenosine, 6-mercaptopurine, 6- thioguanine, cytarabine, 2-fluorodeoxy cytidine, methotrexate, tomudex, fludarabine, raltitrexed, trimetrexate, deoxycoformycin, pentostatin, hydroxyurea, decitabine (SuperGen), clofarabine (Bioenvision), irofulven (MGI Pharma), DMDC (Hoffmann-La Roche), ethynylcytidine (Taiho) gemcitabine, capecitabine; topoisomerase inhibitors: amsacrine, epirubicin, etoposide, teniposide or mitoxantrone, 7-ethyl- 10-hydroxy-camptothecin, dexrazoxanet (TopoTarget), pixantrone (Novuspharma), rebeccamycin analogue (Exelixis), BBR-3576 (Novuspharma), rubitecan (SuperGen), irinotecan (CPT-11), topotecan; antitumor antibiotics: valrubicin, therarubicin, idarubicin, rubidazone, plicamycin, porfiromycin mitoxantrone (novantrone), amonafide, azonafide, anthrapyrazole, oxantrazole, losoxantrone, MEN-10755 (Menarini), GPX-100 (Gem Pharmaceuticals), Epirubicin, mitoxantrone, doxorubicin; antimitotic agents: colchicine, vinblastine, vindesine, dolastatin 10 (NCI), rhizoxin (Fujisawa), mivobulin (Warner-Lambert), cemadotin (BASF), RPR 109881A (Aventis), TXD 258 (Aventis), epothilone B (Novartis), T 900607 (Tularik), T 138067 (Tularik), cryptophycin 52 (Eli Lilly), vinflunine (Fabre), auristatin PE (Teikoku Hormone), BMS 247550 (BMS), BMS 184476 (BMS), BMS 188797 (BMS), taxoprexin (Protarga), SB 408075 (GlaxoSmithKline), Vinorelbine, Trichostatin A, E7010 (Abbott), PG-TXL (Cell Therapeutics), IDN 5109 (Bayer), A 105972 (Abbott), A 204197 (Abbott), LU 223651 (BASF), D 24851 (ASTAMedica), ER-86526 (Eisai), combretastatin A4 (BMS), isohomohalichondrin-B (PharmaMar), ZD 6126 (AstraZeneca), AZ10992 (Asahi), IDN-5109 (Indena), AVLB (Prescient NeuroPharma), azaepothilone B (BMS), BNP-7787 (BioNumerik), CA-4 prodrug (OXiGENE), dolastatin-10 (NIH), CA-4 (OXiGENE), docetaxel, vincristine, paclitaxel; aromatase inhibitors: aminoglutethimide, atamestane (BioMedicines), letrozole, anastrazole, YM- 511 (Yamanouchi), formestane, exemestane; thymidylate synthase inhibitors: pemetrexed (Eli Lilly), ZD-9331 (BTG), nolatrexed (Eximias), CoFactor^TM (BioKeys); dna antagonists: trabectedin (PharmaMar) ; glufosfamide (Baxter International), albumin + 32P (Isotope Solutions), thymectacin (NewBiotics), edotreotide (Novartis), mafosfamide (Baxter International), apaziquone (Spectrum Pharmaceuticals), O6 benzyl guanine (Paligent); farnesyltransferase inhibitors: arglabin (NuOncology Labs), lonafarnib (Schering-Plough), BAY- 43-9006 (Bayer), tipifarnib (Johnson & Johnson), perillyl alcohol (DOR BioPharma); pump inhibitors: CBT-1 (CBA Pharma), tariquidar (Xenova), MS-209 (Schering AG), zosuquidar trihydrochloride (Eli Lilly), biricodar dicitrate (Vertex); histone acetyltransferase inhibitors: tacedinaline (Pfizer), SAHA (Aton Pharma), MS-275 (Schering AG), pivaloyloxymethyl butyrate (Titan), depsipeptide (Fujisawa); metalloproteinase inhibitors: Neovastat (Aeterna Laboratories), marimastat (British Biotech), CMT-3 (CollaGenex), BMS-275291 (Celltech); ribonucleoside reductase inhibitors: gallium maltolate (Titan), triapine (Vion), tezacitabine (Aventis), didox (Molecules for Health); tnf alpha agonists/antagonists: virulizin (Lorus Therapeutics), CDC-394 (Celgene), revimid (Celgene); endothelin a receptor antagonist: atrasentan (Abbott), ZD-4054 (AstraZeneca), YM-598 (Yamanouchi); retinoic acid receptor agonists: fenretinide (Johnson & Johnson), LGD-1550 (Ligand), alitretinoin (Ligand); immuno-modulators: Pembrolizumab (formerly lambrolizumab, brand name Keytruda); interferon, oncophage (Antigenics), GMK (Progenics), adenocarcinoma, vaccine (Biomira), CTP-37 (AVI BioPharma), IRX-2 (Immuno-Rx), PEP-005 (Peplin Biotech), synchrovax vaccines (CTL Immuno), melanoma vaccine (CTL Immuno), p21 RAS vaccine (GemVax) , MAGE-A3 (GSK), nivolumab (BMS), abatacept (BMS), dexosome therapy (Anosys), pentrix (Australian Cancer Technology), ISF-154 (Tragen), cancer vaccine (Intercell), norelin (Biostar), BLP-25 (Biomira), MGV (Progenics), ß-alethine (Dovetail), CLL therapy (Vasogen), Ipilimumab (BMS), CM-10 (cCam Biotherapeutics), MPDL3280A (Genentech); hormonal and antihormonal agents: estrogens, conjugated estrogens, ethinyl estradiol, chlortrianisen, idenestrol, hydroxyprogesterone caproate, medroxyprogesterone, testosterone, testosterone propionate, fluoxymesterone, methyltestosterone, diethylstilbestrol, megestrol, bicalutamide, flutamide, nilutamide, dexamethasone, prednisone, methylprednisolone, prednisolone, aminoglutethimide, leuprolide, octreotide, mitotane, P-04 (Novogen), 2- methoxyestradiol (EntreMed), arzoxifene (Eli Lilly), tamoxifen, toremofine, goserelin, Leuporelin, bicalutamide; photodynamic agents: talaporfin (Light Sciences), Theralux (Theratechnologies), motexafin gadolinium (Pharmacyclics), Pd-bacteriopheophorbide (Yeda), lutetium texaphyrin (Pharmacyclics), hypericin; and kinase inhibitors: afatinib, osimertinib, poziotinib (Spectrum), imatinib (Novartis), leflunomide (Sugen/Pharmacia), ZD1839 (AstraZeneca), erlotinib (Oncogene Science), canertinib (Pfizer), squalamine (Genaera), SU5416 (Pharmacia), SU6668 (Pharmacia), ZD4190 (AstraZeneca), ZD6474 (AstraZeneca), vatalanib (Novartis), PKI166 (Novartis), GW2016 (GlaxoSmithKline), EKB-509 (Wyeth), trastuzumab (Genentech), OSI-774 (Tarceva^TM), CI-1033 (Pfizer), SU11248 (Pharmacia), RH3 (York Medical), Genistein, Radicinol, Met-MAb (Roche), EKB-569 (Wyeth), kahalide F (PharmaMar), CEP-701 (Cephalon), CEP-751 (Cephalon), MLN518 (Millenium), PKC412 (Novartis), Phenoxodiol (Novogen), C225 (ImClone), rhu-Mab (Genentech), MDX- H210 (Medarex), 2C4 (Genentech), MDX-447 (Medarex), ABX-EGF (Abgenix), IMC-1C11 (ImClone), Tyrphostins, Gefitinib (Iressa), PTK787 (Novartis), EMD 72000 (Merck), Emodin, Radicinol, Vemurafenib (B-Raf enzyme inhibitor, Daiichi Sankyo), SR-27897 (CCK A inhibitor, Sanofi-Synthelabo), tocladesine (cyclic AMP agonist, Ribapharm), alvocidib (CDK inhibitor, Aventis), CV-247 (COX-2 inhibitor, Ivy Medical), P54 (COX-2 inhibitor, Phytopharm), CapCell^TM (CYP450 stimulant, Bavarian Nordic), GCS-100 (gal3 antagonist, GlycoGenesys), G17DT immunogen (gastrin inhibitor, Aphton), efaproxiral (oxygenator, Allos Therapeutics), PI- 88 (heparanase inhibitor, Progen), tesmilifene (histamine antagonist, YM BioSciences), histamine (histamine H2 receptor agonist, Maxim), tiazofurin (IMPDH inhibitor, Ribapharm), cilengitide (integrin antagonist, Merck KGaA), SR-31747 (IL-1 antagonist, Sanofi-Synthelabo), CCI-779 (mTOR kinase inhibitor, Wyeth), exisulind (PDE V inhibitor, Cell Pathways), CP-461 (PDE V inhibitor, Cell Pathways), AG-2037 (GART inhibitor, Pfizer), WX-UK1 (plasminogen activator inhibitor, Wilex), PBI-1402 (PMN stimulant, ProMetic LifeSciences), bortezomib (proteasome inhibitor, Millennium), SRL-172 (T cell stimulant, SR Pharma), TLK-286 (glutathione S transferase inhibitor, Telik), PT-100 (growth factor agonist, Point Therapeutics), midostaurin (PKC inhibitor, Novartis), bryostatin-1 (PKC stimulant, GPC Biotech), CDA-II (apoptosis promotor, Everlife), SDX-101 (apoptosis promotor, Salmedix), rituximab (CD20 antibody, Genentech, carmustine, Mitoxantrone, Bleomycin, Absinthin, Chrysophanic acid, Cesium oxides, BRAF inhibitors, PDL1 inhibitors, MEK inhibitors, bevacizumab, angiogenesis inhibitors, dabrafenib, ceflatonin (apoptosis promotor, ChemGenex); BCX-1777 (PNP inhibitor, BioCryst), ranpirnase (ribonuclease stimulant, Alfacell), galarubicin (RNA synthesis inhibitor, Dong-A), tirapazamine (reducing agent, SRI International), N, acetylcysteine (reducing agent, Zambon), R- flurbiprofen (NF-kappaB inhibitor, Encore), 3CPA (NF-kappaB inhibitor, Active Biotech), seocalcitol (vitamin D receptor agonist, Leo), 131-I-TM-601 (DNA antagonist, TransMolecular), eflornithine (ODC inhibitor , ILEX Oncology), minodronic acid (osteoclast inhibitor, Yamanouchi), indisulam (p53 stimulant, Eisai), aplidine (PPT inhibitor, PharmaMar), gemtuzumab (CD33 antibody, Wyeth Ayerst), PG2 (hematopoiesis enhancer, Pharmagenesis), Immunol^TM (triclosan oral rinse, Endo), triacetyluridine (uridine prodrug , Wellstat), SN-4071 (sarcoma agent, Signature BioScience), TransMID-107^TM (immunotoxin, KS Biomedix), PCK- 3145 (apoptosis promotor, Procyon), doranidazole (apoptosis promotor, Pola), CHS-828 (cytotoxic agent, Leo), trans-retinoic acid (differentiator, NIH), MX6 (apoptosis promotor, MAXIA), apomine (apoptosis promotor, ILEX Oncology), urocidin (apoptosis promotor, Bioniche), Ro-31-7453 (apoptosis promotor, La Roche), brostallicin (apoptosis promotor, Pharmacia), β-lapachone, gelonin, cafestol, kahweol, caffeic acid, Tyrphostin AG , PD-1 inhibitors, CTLA-4 inhibitors, sorafenib, BRAF inhibitors, mTOR inhibitors (e.g. Vistusertib, everolimus/Afinitor, rapamycin, dactolisib, BGT226, SF1126, PKI-587, NVPBE235) and Pan- HER inhibitor (e.g. afatinib, neratinb, AC480). [0075] In some embodiments, the additional anti-cancer agent is selected from bevacizurnab, bortezomib, capecitabine, cetuximab, fluorouracil, imatinib, irinotecan, leucovorin, oxaliplatin, panitumumab, pemetrexed, temozolomide, cisplatin, paclitaxel, erlotinib, sunitinib, lapatinib, sorafenib, carboplatin, doxorubicin, docetaxel, gemcitabine, etoposide, gefitinib, PD153035, cetuximab, bevacizumab, panitumumab, trastuzumab, anti-c-Met antibodies, gefitinib, ZD6474, EMD-72000, pariitumab, ICR-62, CI-1033, lapatinib, AEE788, EKB-569, EXEL 7647/EXEL 0999, erlotinib, imatinib, sorafinib, sunitinib, dasatinib, vandetinib, temsirolimus, PTK787, pazopanib, AZD2171, everolimus, seliciclib, AMG 706, axitinib, PD0325901, PKC-412, CEP701, XL880, bosutinib, BIBF1120, BIBF1120, nilotinib, AZD6244, HKI-272, MS-275, BI2536, GX15-070, AZD0530, enzastaurin, MLN-518, ARQ197, CM101, IFN-.alpha., IL-12, platelet factor-4, suramin, SU5416, thrombospondin, VEGFR antagonists, angiostatic steroids plus heparin, Cartilage-Derived Angiogenesis Inhibitory Factor, matrix metalloproteinase inhibitors, batimastat, marimastat, angiostatin, endostatin, 2-methoxyestradiol, tecogalan, thrombospondin, .alpha.V.beta.3 inhibitors, linomide, and ADH-1, chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine, melphalan, uracil mustard, thiotepa, busulfan, carmustine, lomustine, streptozocin, carboplatin, cisplatin, satraplatin, oxaliplatin, altretamine, ET-743, XL119, dacarbazine, chlormethine, bendamustine, trofosfamide, uramustine, fotemustine, nimustine, prednimustine, ranimustine, semustine, nedaplatin, triplatin tetranitrate, mannosulfan, treosulfan, temozolomide, carboquone, triaziquone, triethylenemelamine, procarbazin, doxorubicin, daunorubicin, epirubicin, idarubicin, anthracenedione, mitoxantrone, mitomycin C, bleomycin, dactinomycin, plicatomycin, irinotecan, camptothecin, rubitecan, belotecan, etoposide, teniposide, topotecan, paclitaxel, taxol, docetaxel, BMS-275183, xyotax, tocosal, vinorlebine, vincristine, vinblastine, vindesine, vinzolidine, etoposide, teniposide, ixabepilone, larotaxel, ortataxel, tesetaxel, ispinesib, fluorouracil, floxuridine, methotrexate, xeloda, arranon, leucovorin, hydroxyurea, thioguanine, mercaptopurine, cytarabine, pentostatin, fludarabine phosphate, cladribine, asparaginase, gemcitabine, pemetrexed, bortezomib, aminopterin, raltitrexed, clofarabine, enocitabine, sapacitabine, azacitidine. [0076] Further examples of the secondary anticancer agent include SHP2 inhibitors (e.g. RMC-4550 and RMC-4630), phosphatase inhibitors (e.g. Tautomycin) CDK 4/6 inhibitors (abemaciclib (Lilly), palbociclib (Pfizer)) and protein-protein interaction disruptors (BI 1701963). [0077] Method of Inhibiting KRas G12C Activity or Treating Cancer [0078] Another aspect of the patent document provides for methods for inhibiting KRas G12C activity in a cell. The method inludes contacting the cell in which inhibition of KRas G12C activity is desired with an effective amount of a compound of Formula I, pharmaceutically acceptable salt thereof or pharmaceutical composition containing the compound or pharmaceutically acceptable salt thereof. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. [0079] As used herein, the term “contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, “contacting” a KRas G12C with a compound provided herein includes the administration of a compound provided herein to an subject, such as a human, having KRas G12C, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the KRas G12C. [0080] By negatively modulating the activity of KRas G12C, the methods described herein are designed to inhibit undesired cellular proliferation resulting from enhanced KRas G12C activity within the cell. The cells may be contacted in a single dose or multiple doses in accordance with a particular treatment regimen to effect the desired negative modulation of KRas G12C. The degree of covalent modification of KRas G12C may be monitored in vitro using well known methods, including those described in Example A below. In addition, the inhibitory activity of exemplary compounds in cells may be monitored, for example, by measuring the inhibition of KRas G12C activity of the amount of phosphylated ERK, including those described in Example B below, to assess the effectiveness of treatment and dosages may be adjusted accordingly by the attending medical practitioner. [0081] Another aspect of the patent document provides a method of treating cancer in a subject in need thereof. The method includes administering to the subject a therapeutically effective amount of a compound of Formula I, pharmaceutically acceptable salt thereof or pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof. [0082] The composition, kit and method provided herein may be used for the treatment of a wide variety of cancers including tumors such as lung, prostate, breast, brain, skin, cervical carcinomas, testicular carcinomas, etc. More particularly, cancers that may be treated by the compositions and methods of the invention include, but are not limited to tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas. More specifically, these compounds can be used to treat: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma. In certain embodiments, the cancer is non-small cell lung cancer. [0083] In some embodiments, the suject is a human. In some embodiments, the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented. In some embodiments, the subject has been identified or diagnosed as having a cancer having a KRas G12C mutation (e.g., as determined using a regulatory agency-approved, e.g., FDA- approved, assay or kit). In some embodiments, the subject has a tumor that is positive for a KRas G12C mutation (e.g., as determined using a regulatory agency-approved assay or kit). The subject can be a subject with a tumor(s) that is positive for a KRas G12C mutation (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject can be a subject whose tumors have a KRas G12C mutation (e.g., where the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having a KRas G12C gene-associated cancer. In some embodiments, the subject has a clinical record indicating that the subject has a tumor that has a KRas G12C mutation (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein). [0084] In some embodiments of any of the methods or uses described herein, an assay is used to determine whether the suject has KRas G12C mutation using a sample (e.g., a biological sample or a biopsy sample (e.g., a paraffin-embedded biopsy sample) from a suject (e.g., a suject suspected of having a KRas G12C-associated cancer, a patient having one or more symptoms of a KRas G12C-associated cancer, and/or a suject that has an increased risk of developing a KRas G12C-associated cancer) can include, for example, next generation sequencing, immunohistochemistry, fluorescence microscopy, break apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR). As is well-known in the art, the assays are typically performed, e.g., with at least one labelled nucleic acid probe or at least one labelled antibody or antigen-binding fragment thereof. [0085] In some embodiments, the method further includes administering to the subject an additional anti-cancer agent. Examples of the additional anti-cancer agents are as described above. [0086] Administration Regimen [0087] The compound of Formula I, or a pharmaceutically acceptable salt thereof or a pharmaceutically composition thereof for the methods or kit described herein described herein may be administered to the subject by any suitable means. Non-limiting examples of methods of administration include, among others, (a) administration though oral pathways, which administration includes administration in capsule, tablet, granule, spray, syrup, or other such forms; (b) administration through non-oral pathways such as rectal, vaginal, intraurethral, intraocular, intranasal, or intraauricular, which administration includes administration as an aqueous suspension, an oily preparation or the like or as a drip, spray, suppository, salve, ointment or the like; (c) administration via injection, subcutaneously, intraperitoneally, intravenously, intramuscularly, intradermally, intraorbitally, intracapsularly, intraspinally, intrasternally, or the like, including infusion pump delivery; as well as (d) administration topically; as deemed appropriate by those of skill in the art for bringing the active compound into contact with living tissue. [0088] Advantageously, the compound of Formula I, or a pharmaceutically acceptable salt thereof or a pharmaceutically composition thereof for administrations described above are prepared into dosage forms in a unit dose suited to fit a dose of the active ingredients. Such dosage forms in a unit dose include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc. [0089] In exemplary embodiments of the pharmaceutical composition of the compound of Formula I, or a pharmaceutically acceptable salt thereof for oral administration, the composition can be a tablet, coated tablet, capsule, caplet, cachet, lozenges, gel capsule, hard gelatin capsule, soft gelatin capsule, troche, dragee, dispersion, powder, granule, pill, liquid, an aqueous or non- aqueous liquid suspension, an oil-in-liquid or oil-in-water emulsion, including sustained release formulations that are known in the art. For pediatric and geriatric applications, suspensions, syrups and chewable tablets are especially suitable. [0090] The therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof required as a dose will depend on the route of administration, the type of subject, including human, being treated, and the physical characteristics of the specific subject under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize. More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein. [0091] In non-human animal studies, applications of potential products are commenced at higher dosage levels, with dosage being decreased until the desired effect is no longer achieved adverse side effects disappear. The dosage may range broadly, depending upon the desired effects and the therapeutic indication. Typically, dosages may be about 10 microgram/kg to about 100 mg/kg body weight, preferably about 100 microgram/kg to about 10 mg/kg body weight. Alternatively dosages may be based and calculated upon the surface area of the patient, as understood by those of skill in the art. [0092] The exact formulation, route of administration and dosage for the pharmaceutical compositions can be chosen by the individual physician in view of the patient’s condition. (see e.g., Fingl et al. 1975, in “The Pharmacological Basis of Therapeutics”, which is hereby incorporated herein by reference in its entirety, with particular reference to Ch. 1, p. 1). In some embodiments, the dose range of the compound of Formula I, or a pharmaceutically acceptable salt thereof administered to the subject or patient can be from about 0.5 to about 1000 mg/kg of the patient’s body weight. The dosage may be a single one or a series of two or more given in the course of one or more days, as is needed by the patient. In instances where human dosages for compounds have been established for at least some conditions, those same dosages, or dosages that are about 0.1% to about 500%, more preferably about 25% to about 250% of the established human dosage may be used. [0093] It should be noted that the attending physician would know how to and when to terminate, interrupt, or adjust administration due to toxicity or organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adequate (precluding toxicity). The magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the condition to be treated and to the route of administration. The severity of the condition may, for example, be evaluated, in part, by standard prognostic evaluation methods. Further, the dose and perhaps dose frequency will also vary according to the age, body weight, and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine. [0094] Although the exact dosage will be determined on a drug-by-drug basis, in most cases, some generalizations regarding the dosage can be made. The daily dosage regimen for an adult human patient may be, for example, an oral dose of about 0.1 mg to 2000 mg of the active ingredient, preferably about 1 mg to about 500 mg, e.g. 5 to 200 mg. In other embodiments, an intravenous, subcutaneous, or intramuscular dose of the active ingredient of about 0.01 mg to about 100 mg, preferably about 0.1 mg to about 60 mg, e.g. about 1 to about 40 mg is used. In cases of administration of a pharmaceutically acceptable salt, dosages may be calculated as the free acid. In some embodiments, the composition is administered 1 to 4 times per day. Alternatively the compound of Formula I, or a pharmaceutically acceptable salt thereof may be administered by continuous intravenous infusion, preferably at a dose of up to about 1000 mg per day. As will be understood by those of skill in the art, in certain situations it may be necessary to administer the compound of Formula I, or a pharmaceutically acceptable salt thereof disclosed herein in amounts that exceed, or even far exceed, the above-stated, preferred dosage range in order to effectively and aggressively treat particularly aggressive diseases or infections. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof will be administered for a period of continuous therapy, for example for a week or more, or for months or years. [0095] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is formulated into a dosage form for release for a period of 1 to 12, typically 3 to 12 hours, more typically 6-12 hours after administration. In some embodiments, the oral pharmaceutical compositions described herein may be administered in single or divided doses, from one to four times a day. The oral dosage forms may be conveniently presented in unit dosage forms and prepared by any methods well known in the art of pharmacy. [0096] The compound of Formula I or a pharmaceutically acceptable salt thereof can be evaluated for efficacy and toxicity using known methods. For example, the toxicology of the compound may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans. Alternatively, the toxicity in an animal model, such as mice, rats, rabbits, or monkeys, may be determined using known methods. The efficacy of a particular compound may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. Recognized in vitro models exist for nearly every class of condition. Similarly, acceptable animal models may be used to establish efficacy of chemicals to treat such conditions. When selecting a model to determine efficacy, the skilled artisan can be guided by the state of the art to choose an appropriate model, dose, and route of administration, and regime. Of course, human clinical trials can also be used to determine the efficacy of the compound of Formula I, or a pharmaceutically acceptable salt thereof in humans. [0097] The compound of Formula I or a pharmaceutically acceptable salt thereof may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions comprising the compound of Formula I, or a pharmaceutically acceptable salt thereof formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. [0098] The concentration and route of administration to the patient will vary depending on the cancer to be treated. The compounds, pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising such compounds and salts also may be co-administered with other anti-cancer agents, e.g., chemotherapy, or used in combination with other treatments, such as radiation or surgical intervention, either as an adjuvant prior to surgery or post-operatively. [0099] Examples [0100] The following examples do not limit the scope of available synthesis routes and the structural variation of the compounds. Likewise, each of the synthetic intermediates can also be prepared by various approaches. [0101] Example 1 [0102] The mixture of aminopyrazine (5.0 g, 52.570 mmol) and 2-bromoethylpyruvate (11.7 g, 60.456 mmol) in anhydrous ethanol (80 mL) was heated under continuous nitrogen flow at reflux for 16 hours. The reaction mixture was treated with charcoal (1.0 g), filtered through a Celite pad and concentrated under reduced pressure. The crude was purified by combi flash using 40 g silica gel column as standard phase and 80% Ethyl acetate/Hexane as mobile phase to get ethyl imidazo[1,2-a]pyrazine-2-carboxylate (3.0 g, 29.95 %, yellowish solid). ¹H NMR (400 MHz, Chloroform-d) δ 7.96 (d, J = 4.7 Hz, 3H), 7.27 – 7.25 (m, 1H), 9.19 (d, J = 1.5 Hz, 2H), 8.26 (s, 2H), 8.09 (dd, J = 4.7, 1.6 Hz, 2H). [0103] The mixture of aminopyrazine (20.0 g, 210.52 mmol) and 2-bromoethylpyruvate ( 50.4 g, 258.94 mmol) in anhydrous Dimethoxyethane (200 mL) over 1 h at rt. After 3 h, the mixture is cooled to 0° C. and filtered. The solid is washed with ether (200 mL) and dried under vacuum. The solid is heated in refluxing EtOH (800 mL) for 3 h. The mixture is concentrated, the residue is dissolved in CHCl3 (300 mL), and basified to pH 9 with sat. NaHCO3 (200 mL). The suspension is filtered through a pad of diatomaceous earth, which is washed with water (200 mL) and CHCl3 (3×300 mL). The phases are separated, and the aqueous layer extracted with CHCl3 (300 mL). The combined organic extracts are dried over Na2SO4, filtered and concentrated. The residue is crystallized from EtOH (500 mL) to get ethyl imidazo[1,2-a]pyrazine-2-carboxylate (9.0 g, 25.25 %, brown solid). [0104] To a solution of ethyl imidazo[l,2-a]pyrazine-2-carboxylate (200 g, 1.046 mmol) in 5.0 mL ethyl alcohol was added 20 mg 10% Pd-C, then the mixture was stirred at room temperature for 12 hours under 40 psi hydrogen atmosphere. The reaction mixture was filtered through celite bed, the celite bed was washed with excess 10 % methanol in DCM. The filtrate was concentrated under reduced pressure to get the crude ethyl 5,6,7,8-tetrahydroimidazo[1,2- a]pyrazine-2-carboxylate (250 mg, Light brown sticky mass).¹H NMR (600 MHz, Chloroform-d) δ 7.50 (s, 1H), 4.33 (q, J = 7.2, 7.1 Hz, 2H), 4.10 (s, 2H), 4.00 (t, J = 5.5 Hz, 2H), 3.69 (q, J = 7.0,Hz, 2H), 3.24 (t, J = 5.5Hz, 2H), 1.21 (t, J = 7.0 Hz, 3H). [0105] The mixture of ethyl 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate (1.0 g, 5.235 mmol) and Triethylamine (2.1 mL, 15.70 mmol) in Dichloromethane (20 mL) and in cooling condition added Di-tert-butyl dicarbonate (1.6 mL, 10.47 mmol) the mixture was stirred for 12 hours. And the rcm was dissolved with H20 extracted with CHCl3 and. The combined organic extracts are dried over Na2SO4, filtered and concentrated. purified by combi flash using 12 g silica gel column as standard phase and 35% Ethyl acetate/Hexane as mobile phase to get 7- (tert-butyl) 2-ethyl 5,6-dihydroimidazo[1,2-a]pyrazine-2,7(8H)-dicarboxylate (800 mg, 78.27 %, off-white solid). ¹H NMR (400 MHz, Chloroform-d) δ 7.55 (s, 1H), 4.72 (s, 2H), 4.36 (q, J = 7.1, Hz, 2H), 4.04 (t, J = 5.4, Hz, 2H), 3.86 (t, J = 5.4, Hz, 2H), 1.37 (t, J = 7.1, Hz, 3H). [0106] To a solution of ethyl imidazo[l,2-a]pyrazine-2-carboxylate (3.0 g, 15.701 mmol) in 180 mL ethyl alcohol was added (10.8 mL, 47.103 mmol) of Di-tert-butyl dicarbonate and 10% Pd-C (300 mg) was added to the mixture, then the mixture was stirred at room temperature for 16 hours under 60 psi hydrogen atmosphere. The reaction mixture was filtered through celite bed, the celite bed was washed with excess 10 % methanol in DCM. The filtrate was concentrated under reduced pressure to get the crude 7-(tert-butyl) 2-ethyl 5,6-dihydroimidazo[1,2-a]pyrazine- 2,7(8H)-dicarboxylate (3.5 g, 56.38%, off-white solid). ¹H NMR (400 MHz, Chloroform-d) δ 7.54 (s, 1H), 4.72 (s, 2H), 4.35 (q, J = 7.1, 7.0 Hz, 2H), 4.04 (t, J = 5.4, Hz, 2H), 3.86 (t, J = 5.4, Hz, 2H), 1.47 (s, 9H), 1.37 (t, J = 7.1, Hz, 3H). [0107] To a solution of 7-(tert-butyl) 2-ethyl 5,6-dihydroimidazo[1,2-a]pyrazine-2,7(8H)- dicarboxylate (100 mg, 0.338 mmol) in 4.0 mL acetonitrile and the mixture was cooled to 0°C added N-Bromosuccinimide (63 mg, 0.355 mmol), then the mixture was heated at reflux for 1 hour and rcm was extracted with water (5 mL) and EtOAC (2×10 mL) The organic extracts are dried over Na2SO4, filtered and concentrated. The crude was purified by combi flash using 4.0 g silica gel column as standard phase and 35% Ethyl acetate/Hexane as mobile phase to get 7-(tert-butyl) 2-ethyl 3-bromo-5,6-dihydroimidazo[1,2-a]pyrazine-2,7(8H)-dicarboxylate (108 mg, 85.71 %, off-white solid). ¹H NMR (300 MHz, Chloroform-d) δ 4.71 (s, 2H), 4.39 (q, J = 7.1, Hz, 2H), 3.99 – 3.86 (m, 2H), 1.47 (s, 9H), 1.40 (t, J = 7.1, 7.1 Hz, 3H). [0108] To a solution of 7-(tert-butyl) 2-ethyl 5,6-dihydroimidazo[1,2-a]pyrazine-2,7(8H)- dicarboxylate (100 mg, 0.338 mmol) in 4.0 mL Carbon tetrachloride and mixture was cooled to 0°C added N-Bromosuccinimide (72 mg, 0.406 mmol) and Benzoyl peroxide (0.79 mg, 0.003 mmol) then the mixture was heated 60^oC for 3 hours and rcm was extracted with water (5 mL) and EtOAC (2×10 mL) The organic extracts are dried over Na2SO4, filtered and concentrated under reduced pressure to get the crude 7-(tert-butyl) 2-ethyl 3-bromo-5,6-dihydroimidazo[1,2- a]pyrazine-2,7(8H)-dicarboxylate (130 mg, off-white solid). [0109] To a Seal tube 7-(tert-butyl) 2-ethyl 3-bromo-5,6-dihydroimidazo[1,2-a]pyrazine- 2,7(8H)-dicarboxylate (20 g, 5.31 mmol) in Toluene (20 mL), benzyl (S)-2- (cyanomethyl)piperazine-1-carboxylate (1.5 g, 5.87 mmol) and Cs2CO3 (5.19 g, 15.93 mmol) were added and purged with argon for 30 minutes, then BINAP (0.49 g, 0.796 mmol) and Pd₂(dba)₃ (0.24 g, 0.265 mmol) was added under argon atmosphere, purged with argon for 15 min and then vessel was sealed and reaction carried out at 100 °C for 16 hours. The progress of reaction was monitor by TLC. After completion of reaction mixture was quenched with ammonium chloride (50 ml) solution and EtOAc(3*50 ml).The organic layer was dried over anhydrous sodium sulphate, filtered. The filtrate was concentrated under reduced pressure to afford crude compound. The crude product was purified by combi flash column chromatography (column size, 80 g, 60 – 120 mesh solica gel) eluent 75-80 % EtOAc/Hexane and the fraction was dried under reduced pressure. (300 mg, Yellowish fluppy solid). [0110] To a Seal tube ethyl (S)-3-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1- yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate (300 mg, 0.663 mmol) in toluene (10 mL), 1-bromo-8-chloro naphthalene (208 mg, 0.862 mmol) and Cesium carbonate (540 mg, 1.658 mmol) were added and bubbled with argon for 15 minutes, then BINAP (61.8 mg, 0.099 mmol) and Tris (dibenzylidene acetone) dipalladium(0) (30.3 mg 0.033 mmol) were added under argon atmosphere, bubbled with argon for 10 min and then vessel was sealed and reaction carried out at 100 °C for 16 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure. . The brown solid was purified by combi flash using 12 g silica gel column as standard phase and 75-80% Ethyl acetate : hexane as mobile phase to afford the title compound (170 mg, ,Light yellow solid). [0111] To a RB flask ethyl (S)-3-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1- yl)-7-(8-chloronaphthalen-1-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate (20 mg, 0.0326 mmol) in THF (2.0 mL), Pd/C (30 mg) were under argon atmosphere. Reaction carried out under hydrogen atmosphere for 16 hours. The progress of reaction was monitor by TLC.After completion of reaction mixture was filter by celite and wash with ethanol. The organic layer was dried over anhydrous sodium sulphate, filtered. The filtrate was concentrated under reduced pressure to afford crude compound. (14 mg, browinish solid). [0112] Example 2 [0113] To a solution of 7-(tert-butyl) 2-ethyl 3-bromo-5,6-dihydroimidazo[1,2-a]pyrazine- 2,7(8H)-dicarboxylate (500 mg, 1.336 mmol) in 10.0 mL Ethanol in water (4:1) and the mixture was cooled to 0°C added Lithium hydroxide (126 mg, 5.344 mmol), then the mixture was stirred rt for 12 hour and rcm was concentrated and extracted with water (20 mL) and EtOAC (3×20mL) The organic extracts are dried over Na2SO4, The crude to get 3-bromo-7-(tert-butoxycarbonyl)- 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid (540 mg, Crude). [0114] The mixture of 3-bromo-7-(tert-butoxycarbonyl)-5,6,7,8-tetrahydroimidazo[1,2- a]pyrazine-2-carboxylic acid (200 mg, 0.577 mmol) and Ammonium chloride (77 mg, 1.44mmol) in Dimethylformamide (5.0 mL) and in cooling condition added Hexafluorophosphate Azabenzotriazole Tetramethyl (439 mg, 1.15 mmol) N,N-Diisopropylethylamine (77 mg, 1.44mmol) the mixture was stirred for rt 12 hours. And the rcm was dissolved with H20 extracted with CHCl3 and. The combined organic extracts are dried over Na2SO4, filtered and concentrated get tert-butyl 3-bromo-2-carbamoyl-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (198 mg, crude). [0115] Acryloylchlorid (2.3 mL, 27 mmol) was added dropwise to a stirred ice-cold solution of tert-butyl piperazine-1-carboxylate (5.0 g, 26.83 mmol) and triethylamine ( 3.7 mL, 26.83 mmol) in dichloromethane (60 mL) at 0°C.The mixture was then stirred and allowed to come to room temperature over 3 hours. 1M Hydrochloric acid solution(50 mL) was added to the mixture, and the two layers were separated. The organic phase was washed with saturated sodium hydrogen carbonate solution (2*50 ml) and saturated sodium chloride solution (50 ml) and dried over Na2SO4. The residue is to get tert-butyl 4-acryloylpiperazine-1-carboxylate (6.0 g,(Crude) brown solid).

[0116] The mixture of tert-butyl 4-acryloylpiperazine-1-carboxylate (2.0 g, 26.83 mmol) was dissolved in DCM (40mL) and TFA (10 mL) was added. The mixture was stirred at room temperature for 20 minutes,then diluted with toluene and evaporated to dryness. The residue was dissolved in DCM, and washed with NaOH (1M, 2 mL) and with brine. The solvent was removed under reduced pressure and the residue is to get 1-(piperazin-1-yl)prop-2-en-1-one the crude was used for the next step without further purification (700 mg, (pale yellow solid)).

[0117] The mixture of tert-butyl 3-bromo-2-carbamoyl-5,6-dihydroimidazo[1,2- a]pyrazine-7(8H)-carboxylate (1.0 g, 2.896 mmol) in DMF (10 mL) and Cyanuric chloride (534 mg, 2.896 mmol) pinch wise at 0°C. The mixture was stirred and allowed to come to room temperature over 2 hours, The reaction mixture was diluted with saturated sodium bicorbonate and extracted with ethyl acetate. The organic layer was separated, washed with brine solution and dried over sodium sulphate, concentrated under reduced pressure. The crude was purified by combi flash using 12 g silica gel column as standard phase and 30% Ethyl acetate/Hexane as mobile to get tert- butyl 3-bromo-2-cyano-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (850 mg, % white solid)).

[0118] To a Seal tube tert-butyl 3-bromo-2-cyano-5,6-dihydroimidazo[1,2-a]pyrazine- 7(8H)-carboxylate (50 mg, 0.153 mmol in toluene (2 mL), 1-(piperazin-1-yl)prop-2-en-1-one ( 34 mg, 0.184 mmol) and Cesium carbonate (99.6 mg, 0.23 mmol) were added and bubbled with argon for 15 minutes, then 2,2'-bis(diphenylphosphaneyl)-1,1'-binaphthalene (14.3 mg, 0.023 mmol) and tris(dibenzylideneacetone) dipalladium(0) (7.0 mg, 0.007 mmol) were added under argon atmosphere, bubbled with argon for 10 min and then vessel was sealed and reaction carried out at 100°C for 3 hours. The reaction mixture was diluted with saturated ammonium chloride in water and extracted to dichloromethane. The organic layer was separated, washed with brine solution and dried over sodium sulphate, filtered and concentrated under reduced pressure.to get tert-butyl 3-(4-acryloylpiperazin-1-yl)-2-cyano-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate. (55 mg, Crude). [0119] To a Seal tube tert-butyl 3-bromo-2-cyano-5,6-dihydroimidazo[1,2-a]pyrazine- 7(8H)-carboxylate (50 mg, 0.153 mmol in toluene (2 mL), 1-(piperazin-1-yl)prop-2-en-1-one ( 34 mg, 0.184 mmol) and Cesium carbonate (99.6 mg, 0.306 mmol) were added and bubbled with argon for 15 minutes, then 2,2'-bis(diphenylphosphaneyl)-1,1'-binaphthalene (14.3 mg, 0.023 mmol) and tris(dibenzylideneacetone) dipalladium(0) (7.0 mg, 0.007 mmol) were added under argon atmosphere, bubbled with argon for 10 min and then vessel was sealed and reaction carried out at 150°C for 1 hour in microwave. The reaction mixture was diluted with saturated ammonium chloride in water and extracted to dichloromethane. The organic layer was separated, washed with brine solution and dried over sodium sulphate, filtered and concentrated under reduced pressure.to get tert-butyl 3-(4-acryloylpiperazin-1-yl)-2-cyano-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)- carboxylate. (49 mg, Crude). [0120] To a Seal tube tert-butyl 3-bromo-2-cyano-5,6-dihydroimidazo[1,2-a]pyrazine- 7(8H)-carboxylate (50 mg, 0.153 mmol in 1,4 Dioxane (2 mL), 1-(piperazin-1-yl)prop-2-en-1-one ( 34 mg, 0.184 mmol) and Cesium carbonate (99.6 mg, 0.306 mmol) were added and bubbled with argon for 15 minutes, then 2,2'-bis(diphenylphosphaneyl)-1,1'-binaphthalene (14.3 mg, 0.023 mmol) and tris(dibenzylideneacetone) dipalladium(0) (7.0 mg, 0.007 mmol) were added under argon atmosphere, bubbled with argon for 10 min and then vessel was sealed and reaction carried out at 150°C for 1.5 hours in microwave. The reaction mixture was diluted with saturated ammonium chloride in water and extracted to dichloromethane. The organic layer was separated, washed with brine solution and dried over sodium sulphate, filtered and concentrated under reduced pressure.to get tert-butyl 3-(4-acryloylpiperazin-1-yl)-2-cyano-5,6-dihydroimidazo[1,2- a]pyrazine-7(8H)-carboxylate. (49 mg, Crude). [0121] To a Seal tube tert-butyl 3-bromo-2-cyano-5,6-dihydroimidazo[1,2-a]pyrazine- 7(8H)-carboxylate (10 mg, 0.030 mmol in DMF (1 mL), piperazine ( 5.2 mg, 0.06 mmol) and Potassium carbonate (12 mg, 0.09 mmol) were added and bubbled with argon for 15 minutes, and Copper(I) iodide (1.7 mg, 0.009 mmol) were added under argon atmosphere, bubbled with argon for 10 min and then vessel was sealed and reaction carried out at 150°C for 1 hour in Microwave. The reaction mixture was diluted with saturated ammonium chloride in water and extracted to dichloromethane. The organic layer was separated, washed with brine solution and dried over sodium sulphate, filtered and concentrated under reduced pressure to get tert-butyl 2-cyano-3- (piperazin-1-yl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (14 mg, Crude). [0122] To a Seal tube tert-butyl 3-bromo-2-cyano-5,6-dihydroimidazo[1,2-a]pyrazine- 7(8H)- (20 mg, 0.061 mmol and N,N-Diisopropylethylamine ( 15.8 mg, 0.122 mmol) in DMSO (1 mL), piperazine ( 26 mg, 0.30 mmol) were added sealed and reaction carried out at 150°C for 1 hour in microwave. The reaction mixture was diluted with saturated ammonium chloride in water and extracted to Ethyl acetate. The organic layer was separated, washed with brine solution and dried over sodium sulphate, filtered and concentrated under reduced pressure to get tert-butyl 2- cyano-3-(piperazin-1-yl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (29 mg, Crude). [0123] To a Seal tube tert-butyl 3-bromo-2-cyano-5,6-dihydroimidazo[1,2-a]pyrazine- 7(8H)-carboxylate (50 mg, 0.153 mmol in DMF (2 mL), piperazine ( 26.4 mg, 0.306 mmol) and Potassium carbonate (63.5 mg, 0.460 mmol) were added and bubbled with argon for 15 minutes, then Copper(I) iodide (8.7 mg, 0.046 mmol) were added under argon atmosphere, bubbled with argon for 10 min and then vessel was sealed and reaction carried out at 150°C for 1 hour in Microwave. The reaction mixture was diluted in water and extracted to Ethyl acetate. The organic layer was separated, washed with brine solution and dried over sodium sulphate, filtered and concentrated under reduced pressure to get tert-butyl 2-cyano-3-(piperazin-1-yl)-5,6- dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (30 mg,(67%) gummy solid). [0124] To a Seal tube tert-butyl 3-bromo-2-cyano-5,6-dihydroimidazo[1,2-a]pyrazine- 7(8H)-carboxylate (10 mg, 0.030 mmol piperazine ( 100 mg) and Potassium carbonate (12.4mg, 0.090 mmol) were added and Copper(I) iodide (0.87 mg, 0.004mmol) were vessel was sealed and reaction carried out at 150^o C 1 hour in Microwave. The reaction mixture was diluted in water and extracted to Ethyl acetate. The organic layer was separated, washed with brine solution and dried over sodium sulphate, filtered and concentrated under reduced pressure. to get tert-butyl 2- cyano-3-(piperazin-1-yl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (80 mg,31.71% gummy liquid). [0125] To a Seal tube tert-butyl 3-bromo-2-cyano-5,6-dihydroimidazo[1,2-a]pyrazine- 7(8H)-carboxylate (10 mg, 0.03 mmol in DMF (0.2 mL) and piperazine ( 400 mg,) and then vessel was sealed and reaction carried out at 150°C for 1h and 150^oC 1 hour in Microwave. The reaction mixture was diluted in water and extracted to Ethyl acetate. The organic layer was separated, washed with brine solution and dried over sodium sulphate, filtered and concentrated under reduced pressure to get tert-butyl 2-cyano-3-(piperazin-1-yl)-5,6-dihydroimidazo[1,2-a]pyrazine- 7(8H)-carboxylate (30 mg, Crude). [0126] To a solution of tert-butyl 2-cyano-3-(piperazin-1-yl)-5,6-dihydroimidazo[1,2- a]pyrazine-7(8H)-carboxylate (30 mg, 0.090mmol) was added dropwise to a stirred ice-cold solution of Acryloyl chloride (5.7 mg, 0.063 mmol) and triethylamine ( 9.1 mg, 0.090 mmol) in dichloromethane (2 mL) at 0°C.The mixture was then stirred and allowed to come to roomtemperature over 3 hours.1M Hydrochloric acid solution(50 mL) was added to the mixture, and the two layers were separated. The organic phase was washed with saturated sodium hydrogen carbonate solution (2*5 ml) and saturated sodium chloride solution (2 ml) and dried over Na2SO4. The residue is to get tert-butyl 3-(4-acryloylpiperazin-1-yl)-2-cyano-5,6-dihydroimidazo[1,2- a]pyrazine-7(8H)-carboxylate (20 mg,white gummy solid). [0127] To a Seal tube tert-butyl 3-bromo-2-cyano-5,6-dihydroimidazo[1,2-a]pyrazine- 7(8H)-carboxylate (50 mg, 0.153 mmol in DMF (2 mL), piperazine ( 26.4 mg, 0.306 mmol) and Potassium carbonate (63.5 mg, 0.460 mmol) were added and bubbled with argon for 15 minutes, then Copper(I) iodide (4.3 mg, 0.022 mmol) were added under argon atmosphere, bubbled with argon for 10 min and then vessel was sealed and reaction carried out at 100°C for 1h and 130^oC 1 hour in Microwave. The reaction mixture was diluted in water and extracted to Ethyl acetate. The organic layer was separated, washed with brine solution and dried over sodium sulphate, filtered and concentrated under reduced pressure to get tert-butyl 2-cyano-3-(piperazin-1-yl)-5,6- dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (40 mg, Crude). [0128] To a Seal tube tert-butyl 3-bromo-2-cyano-5,6-dihydroimidazo[1,2-a]pyrazine- 7(8H)-carboxylate (50 mg, 0.153 mmol in DMF (2 mL), piperazine ( 26.4 mg, 0.306 mmol) and Potassium carbonate (63.5 mg, 0.460 mmol) were added and bubbled with argon for 15 minutes, then Copper(I) iodide (4.3 mg, 0.022 mmol) were added under argon atmosphere, bubbled with argon for 10 min and then vessel was sealed and reaction carried out at 150^oC 1 hour in Microwave. The reaction mixture was diluted in water and extracted to Ethyl acetate. The organic layer was separated, washed with brine solution and dried over sodium sulphate, filtered and concentrated under reduced pressure. Crude was furified frep-TLC with 90% ethyl acetate in exane to get tert-butyl 2-cyano-3-(piperazin-1-yl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)- carboxylate (40 mg,87% gummy liquid). [0129] To a solution of tert-butyl 2-cyano-3-(piperazin-1-yl)-5,6-dihydroimidazo[1,2- a]pyrazine-7(8H)-carboxylate (120 mg, 0.36mmol) was added dropwise to a stirred ice-cold solution of Acryloyl chloride (90.5 mg, 0.25 mmol) and triethylamine (36.5 mg, 0.36 mmol) in dichloromethane (4 mL) at 0°C.The mixture was then stirred and allowed to come to roomtemperature over 3 hours.1M Hydrochloric acid solution(50 mL) was added to the mixture, and the two layers were separated. The organic phase was washed with saturated sodium hydrogen carbonate solution (2*5 ml) and saturated sodium chloride solution (2 ml) and dried over Na2SO4. The residue is to get tert-butyl 3-(4-acryloylpiperazin-1-yl)-2-cyano-5,6-dihydroimidazo[1,2- a]pyrazine-7(8H)-carboxylate (50mg, 35.97% mg, yellowish gummy solid). ¹H NMR (300 MHz, Chloroform-d) δ 7.47 (s, 2H), 6.64 – 6.18 (m, 3H), 5.70 (dd, J = 10.4, 1.9 Hz, 2H), 2.92 (d, J = 22.4 Hz, 2H), 1.48 (s, 9H), 7.32 – 7.20 (m, 1H). [0130] To a Seal tube tert-butyl 3-bromo-2-cyano-5,6-dihydroimidazo[1,2-a]pyrazine- 7(8H)-carboxylate (10 mg, 0.03 mmol in Benzyl piperazine (0.1 mL,) and then vessel was sealed and reaction carried out at 150°C for 1h and 150^oC 1 hour in Microwave. The reaction mixture was diluted in water and extracted to Ethyl acetate. The organic layer was separated, washed with brine solution and dried over sodium sulphate, filtered and concentrated under reduced pressure to get tert-butyl 3-(4-benzylpiperazin-1-yl)-2-cyano-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)- carboxylate (14 mg, Crude). [0131] The mixture of tert-butyl 3-(4-acryloylpiperazin-1-yl)-2-cyano-5,6- dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (38 mg, 0.098mmol) was dissolved in DCM (0.5 mL) and TFA (0.04 mL) was added. The mixture was stirred at room temperature for 20 minutes,then diluted with toluene and evaporated to dryness. The residue was dissolved in DCM, and washed with NaOH (1M, 2 mL) and with brine. The solvent was removed under reduced pressure and the residue is to get 3-(4-acryloylpiperazin-1-yl)-5,6,7,8-tetrahydroimidazo[1,2- a]pyrazine-2-carbonitrile the crude was used for the next step without further purification (44 mg, (pale yellow solid)). [0132] The mixture of tert-butyl 3-(4-benzylpiperazin-1-yl)-2-cyano-5,6- dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (50 mg, 0.118mmol) was dissolved in DCM (0.5 mL) and TFA (0.1 mL) was added. The mixture was stirred at room temperature for 20 minutes,then diluted with toluene and evaporated to dryness. The residue was dissolved in DCM, and washed with NaOH (1M, 2 mL) and with brine. The solvent was removed under reduced pressure and the residue is to get 3-(4-benzylpiperazin-1-yl)-5,6,7,8-tetrahydroimidazo[1,2- a]pyrazine-2-carbonitrile the crude was used for the next step without further purification (35 mg, (pale yellow solid)). [0133] The mixture of tert-butyl 3-(4-benzylpiperazin-1-yl)-2-cyano-5,6- dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (150 mg, 0.45mmol) was dissolved in DCM (0.5 mL) and TFA (3.0 mL) was added. The mixture was stirred at room temperature for 20 minutes,then diluted with toluene and evaporated to dryness. The residue was dissolved in DCM, and washed with NaOH (1M, 2 mL) and with brine. The solvent was removed under reduced pressure and the residue is to get 3-(4-benzylpiperazin-1-yl)-5,6,7,8-tetrahydroimidazo[1,2- a]pyrazine-2-carbonitrile the crude was used for the next step without further purification (110 mg, (pale yellow solid)). [0134] To BINAP (3.0 mg, 0.004 mmol) and Pd2(dba)3 (2.1 mg, 0.002 mmol) under argon was added toluene (1.0 ml) and the reaction bubbled with Argon for 10 minutes followed by heating to 100°C for 10 minutes. The reaction was cooled to room temperature and 3-(4- benzylpiperazin-1-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carbonitrile (35 mg, 0.124mmol) and Sodium Tert-Butoxide (11.9 mg, 0.124 mmol) were added to the dark solution as solids. Finally, 1-bromo-2-(methoxymethoxy)benzen (26.9 mg, 0.124 mmol) was added (as the oil) and the reaction heated to 100°C for 1 hour. The reaction was cooled to room temperature and concentrated in vacuo. The residue was dissolved in MeoH in DCM 5% and the organics washed with water and brine. The combined organics were dried over Na2SO4 and concentrated in vacuo. The residue was then loaded on the CombiFlash and chromatographed using 0%-->650% EtOAc/Hexanes as eluent. Fractions containing clean product were combined and concentrated in vacuo to afford 3-(4-benzylpiperazin-1-yl)-7-(2-(methoxymethoxy)phenyl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazine-2-carbonitrile (48 mg crude). ¹H NMR (400 MHz, Chloroform- d) δ 8.03 (d, J = 0.9 Hz, 1H), 7.53 (d, J = 8.3 Hz, 1H), 7.43 – 7.15 (m, 3H), 4.78 (d, J = 2.8 Hz, 1H), 3.71 – 3.40 (m, 3H), 1.00 – 0.76 (m, 3H), -0.07 (s, 9H). [0135] To a solution of 3-(4-benzylpiperazin-1-yl)-7-(2-(methoxymethoxy)phenyl)- 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carbonitrile (20 mg 0.043 mmol) in 1.0 mL ethanol was added 10 mg 10% Pd-C, then the mixture was stirred at room temperature for 12 hours under hydrogen atmosphere. The reaction mixture was filtered through celite bed, the celite bed was washed with excess 10 % methanol in DCM. The filtrate was concentrated under reduced pressure to get the crude 7-(2-(methoxymethoxy)phenyl)-3-(piperazin-1-yl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazine-2-carbonitrile (12 mg, Light brown sticky mass). [0136] To a solution of 3-(4-benzylpiperazin-1-yl)-7-(2-(methoxymethoxy)phenyl)- 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carbonitrile (20 mg 0.043 mmol) in 1.0 mL of DCM was added and Triethyl amine ( catalytic amount), 1-Chloroethylchloroformate (13 mg 0.09 mmol) was added drop wise at 0⁰C, warmed to rt and stirred for 2 hours at rt. Then DCM was removed using vaccum, the resulting residue was dissolved in Methanol 1 ml and stirred for 2 hours at 60⁰C. concentrated under reduced pressure to get the crude 7-(2- (methoxymethoxy)phenyl)-3-(piperazin-1-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2- carbonitrile (6 mg, Light brown sticky mass).

[0137] To a Seal tube tert-butyl 3-bromo-2-cyano-5,6-dihydroimidazo[1,2-a]pyrazine- 7(8H)-carboxylate (50 mg, 0.153 mmol in Toluene (2 mL), 1-Cbz-Piperazine ( 50 mg, 0.229 mmol) and Cesium carbonate (99.6 mg, 0.306 mmol) were added and bubbled with argon for 15 minutes, then 2,2'-bis(diphenylphosphaneyl)-1,1'-binaphthalene (14.3 mg, 0.023 mmol) and tris(dibenzylideneacetone) dipalladium(0) (7.0 mg, 0.007 mmol) were added under argon atmosphere, bubbled with argon for 10 min and then vessel was sealed and reaction carried out at 100°C for 16 hour. The reaction mixture was diluted with saturated ammonium chloride in water and extracted to dichloromethane. The organic layer was separated, washed with brine solution and dried over sodium sulphate, filtered and concentrated under reduced pressure. To get tert- butyl 3-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-cyano-5,6-dihydroimidazo[1,2-a]pyrazine- 7(8H)-carboxylate (30 mg, 79.82 yellow solid).

[0138] To a Seal tube tert-butyl 3-bromo-2-cyano-5,6-dihydroimidazo[1,2-a]pyrazine- 7(8H)-carboxylate (1.0 g, 3.06 mmol in Toluene (15 mL), 1-Benzylpiperazine (810 mg, 4.59 mmol) and Sodium tert-butoxide (1.5g, 15.9 mmol) were added and bubbled with argon for 15 minutes, then 2,2'-bis(diphenylphosphaneyl)-1,1'-binaphthalene (763 mg, 1.22 mmol) and tris(dibenzylideneacetone) dipalladium(0) (589 mg, 0.64 mmol) were added under argon atmosphere, bubbled with argon for 10 min and then vessel was sealed and reaction carried out at 100°C for 16 hr. The reaction mixture was diluted with saturated ammonium chloride in water and extracted to dichloromethane. The organic layer was separated, washed with brine solution and dried over sodium sulphate, filtered and concentrated under reduced pressure. To get tert-butyl 3- (4-benzylpiperazin-1-yl)-2-cyano-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (550 mg, 42.61% yellow solid). [0139] The mixture of tert-butyl 3-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-cyano-5,6- dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (50 mg, 0.107mmol) was dissolved in DCM (0.5 mL) and TFA (0.1 mL) was added. The mixture was stirred at room temperature for 1h ,then diluted with toluene and evaporated to dryness. The residue was dissolved in DCM, and washed with NaOH (1M, 2 mL) and with brine. The solvent was removed under reduced pressure and the residue is to get 3-(4-benzylpiperazin-1-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2- carbonitrile the crude was used for the next step without further purification (40 mg, (pale yellow solid)). [0140] To a solution of get tert-butyl 3-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-cyano- 5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (20 mg 0.043 mmol) in 1.0 mL ethanol was added 10 mg 10% Pd-C, then the mixture was stirred at room temperature for 12 hours under hydrogen atmosphere. The reaction mixture was filtered through celite bed, the celite bed was washed with excess 10 % methanol in DCM. The filtrate was concentrated under reduced pressure to get the crude tert-butyl 2-cyano-3-(piperazin-1-yl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)- carboxylate (18 mg, Light brown sticky mass). [0141] To BINAP (2.9 mg, 0.004 mmol) and Pd2(dba)3 (2.1 mg, 0.002 mmol) under argon was added toluene (1.0 ml) and the reaction bubbled with Argon for 10 minutes followed by heating to 100°C for 10 minutes. The reaction was cooled to room temperature benzyl 4-(2-cyano- 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)piperazine-1-carboxylate (40 mg, 0.119mmol) and Sodium Tert-Butoxide (11.4 mg, 0.119 mmol) were added to the dark solution as solids. Finally, 2-bromo-1-fluoro-3-(methoxymethoxy)benzene (41.9 mg, 0.178 mmol) was added (as the oil) and the reaction heated to 100°C for 20 hour. The reaction was cooled to room temperature and concentrated in vacuo. The residue was dissolved in MeoH in DCM 5% and the organics washed with water and brine. The combined organics were dried over Na2SO4 and concentrated in vacuo. The residue was then loaded on the CombiFlash and chromatographed using 0%-->650% EtOAc/Hexanes as eluent. Fractions containing clean product were combined and concentrated in vacuo to afford benzyl 4-(2-cyano-7-(2-fluoro-6-(methoxymethoxy)phenyl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazin-3-yl)piperazine-1-carboxylate (09 mg 17% yellowish solid). [0142] To a solution of 7-(2-(methoxymethoxy)phenyl)-3-(piperazin-1-yl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazine-2-carbonitrile (100 mg, 0.27 mmol) was added dropwise to a stirred ice-cold solution of Acryloyl chloride (24 mg, 0.27 mmol) and triethylamine (27.4 mg, 0.27 mmol) in dichloromethane (2 mL) at 0°C.The mixture was then stirred and allowed to come to roomtemperature over 3 hours. 1M Hydrochloric acid solution(5.0 mL) was added to the mixture, and the two layers were separated. The organic phase was washed with saturated sodium hydrogen carbonate solution (2*5 ml) and saturated sodium chloride solution (2 ml) and dried over Na2SO4. The residue is to get 3-(4-acryloylpiperazin-1-yl)-7-(2-(methoxymethoxy)phenyl)- 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carbonitrile (50 mg, 41.28% yello solid crude). [0143] To BINAP (0.67 mg, 0.001 mmol) and Pd2(dba)3 (0.49 mg, 0.0005 mmol) under argon was added toluene (1.0 ml) and the reaction bubbled with Argon for 10 minutes followed by heating to 100°C for 10 minutes. The reaction was cooled to room temperature benzyl 4-(2-cyano- 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)piperazine-1-carboxylate (10 mg, 0.027 mmol) and Sodium Tert-Butoxide (2.6 mg, 0.027 mmol) were added to the dark solution as solids. Finally, 1- bromo-2-(methoxymethoxy)benzene (8.8 mg, 0.040 mmol) was added (as the oil) and the reaction heated to 100°C for 20 hour. The reaction was cooled to room temperature and concentrated in vacuo. The residue was dissolved in MeoH in DCM 5% and the organics washed with water and brine. The combined organics were dried over Na2SO4 and concentrated in vacuo. The residue was then loaded on the CombiFlash and chromatographed using 0%-->650% EtOAc/Hexanes as eluent. Fractions containing clean product were combined and concentrated in vacuo to afford benzyl 4-(2-cyano-7-(2-fluoro-6-(methoxymethoxy)phenyl)-5,6,7,8-tetrahydroimidazo[1,2- a]pyrazin-3-yl)piperazine-1-carboxylate (07 mg 82.15% yellowish solid). [0144] To a solution of benzyl 4-(2-cyano-7-(2-(methoxymethoxy)phenyl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazin-3-yl)piperazine-1-carboxylate (25 mg 0.049 mmol) in 1.5 mL ethanol was added 12.5 mg 50% Pd-C, then the mixture was stirred at room temperature for 12 hours under hydrogen atmosphere. The reaction mixture was filtered through celite bed, the celite bed was washed with excess 10 % methanol in DCM. The filtrate was concentrated under reduced pressure to get the crude 7-(2-(methoxymethoxy)phenyl)-3-(piperazin-1-yl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazine-2-carbonitrile (22 mg, Light brown sticky mass). [0145] To a solution of 3-(4-acryloylpiperazin-1-yl)-7-(2-(methoxymethoxy)phenyl)- 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carbonitrile (5 mg 0.0118 mmol) in 0.5 mL DCM was added and cooling condition added (0.02 mL) Trifluoroacetic acid, then the mixture was stirred at room temperature for 24 hours under Nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to get the crude 3-(4-acryloylpiperazin-1-yl)-7-(2-hydroxyphenyl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazine-2-carbonitrile (3 mg, yellowish gummy liquid). [0146] Example 3 [0147] To BINAP (0.67 mg, 0.001 mmol) and Pd2(dba)3 (0.49 mg, 0.0005 mmol) under argon was added toluene (1.0 ml) and the reaction bubbled with Argon for 10 minutes followed by heating to 100°C for 10 minutes. The reaction was cooled to room temperature benzyl 4-(2-cyano- 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)piperazine-1-carboxylate (10 mg, 0.027 mmol) and Sodium Tert-Butoxide (2.6 mg, 0.027 mmol) were added to the dark solution as solids. Finally, 4- bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (8.8 mg, 0.040 mmol) was added (as the oil) and the reaction heated to 100°C for 20 hour. The reaction was cooled to room temperature and concentrated in vacuo. The residue was dissolved in MeoH in DCM 5% and the organics washed with water and brine. The combined organics were dried over Na2SO4 and concentrated in vacuo. The residue was then loaded on the CombiFlash and chromatographed using 0%-->650% EtOAc/Hexanes as eluent. Fractions containing clean product were combined and concentrated in vacuo to afford benzyl 4-(2-cyano-7-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)- 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)piperazine-1-carboxylate (07 mg 82.15% yellowish solid). [0148] To a solution of benzyl 4-(2-cyano-7-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H- indazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)piperazine-1-carboxylate (100 mg 0.16 mmol) in 1.0 mL ethanol was added 20 mg 20% Pd-C, then the mixture was stirred at room temperature for 3 hours under hydrogen atmosphere. The reaction mixture was filtered through celite bed, the celite bed was washed with excess 10 % methanol in DCM. The filtrate was concentrated under reduced pressure to get the crude 3-(piperazin-1-yl)-7-(1-((2- (trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2- carbonitrile (80 mg, Light brown sticky mass). [0149] To a solution of 3-(piperazin-1-yl)-7-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H- indazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carbonitrile (80 mg, 0.16 mmol) was added dropwise to a stirred ice-cold solution of Acryloyl chloride (14.9 mg, 0.16 mmol) and triethylamine (16.9 mg, 0.16 mmol) in dichloromethane (2 mL) at 0°C.The mixture was then stirred and allowed to come to roomtemperature over 3 hours.1M Hydrochloric acid solution(5.0 mL) was added to the mixture, and the two layers were separated. The organic phase was washed with saturated sodium hydrogen carbonate solution (2*5 ml) and saturated sodium chloride solution (2 ml) and dried over Na2SO4. The residue is to get 3-(4-acryloylpiperazin-1-yl)-7-(1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2- carbonitrile (70 mg, 87.5% white solid). [0150] To a Seal tube tert-butyl 3-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-carbamoyl- 5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (10. mg, 0.016 mmol in tert-Butanol (0.5 mL), Potassium tert-butoxide (5.4 mg, 0.048 mmol) and then vessel was sealed and reaction carried out at 60°C for 16 hour. The reaction mixture was Acidified with KHSO4 in and extracted to dichloromethane MeOH 10%. The organic layer was separated, washed with brine solution and dried over sodium sulphate, filtered and concentrated under reduced pressure. To get 3-(piperazin- 1-yl)-7-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,2- a]pyrazine-2-carboxamide (8 mg, Crude). [0151] To a solution of 3-(4-acryloylpiperazin-1-yl)-7-(1-((2- (trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2- carbonitrile (6.0 mg 0.011 mmol) in 0.2 mL DCM was added and cooling condition added (0.02 mL) Trifluoroacetic acid, then the mixture was stirred at room temperature for 24 hours under Nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to get the crude 3-(4-acryloylpiperazin-1-yl)-7-(1H-indazol-4-yl)-5,6,7,8-tetrahydroimidazo[1,2- a]pyrazine-2-carbonitrile.(3 mg, Crude) [0152] Example 4 [0153] To a solution of 2-bromophenol (1.0 g, 5.78 mmol) in DCM (10 mL) was added chloro(methoxy)methane (697 mg, 8.67 mmol) and N,N-Diisopropylethylamine (1.4 g, 11.56 mmol) and the reaction stirred ON at rt. The reatcion was next diluted with EtOAc and the organics washed with water (2x), brine, dried over Na2SO4 and concentrated in vacuo. The material was chromatographed using 5% EtOAc/Hex as eluent to give 1-bromo-2-(methoxymethoxy)benzene (1.1 g, 87.71% yield colourless liquid). [0154] To a solution of 4-bromo-1H-indazole (2.0 g, 10.15 mmol) in DCM (20 mL) was added 2-(Trimethylsilyl)ethoxymethyl chloride (2.5 g, 15.22 mmol) and Sodium hydride (564 mg, 14.11 mmol) and the reaction stirred 6h at rt. The reatcion was next diluted with EtOAc and the organics washed with water (2x), brine, dried over Na2SO4 and concentrated in vacuo. The material was chromatographed using 5% EtOAc/Hex as eluent to give 4-bromo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-indazole (1.7 g, 87.71 % yield colourless liquid ). [0155] To a solution of 2-bromo-3-fluorophenol (2.0 g, 10.47 mmol) in THF (20 mL) was added chloro(methoxy)methane (1.2g, 15.70 mmol) and Sodium hydride (544 mg, 13.61 mmol) and the reaction stirred 6h at rt. The reatcion was next diluted with EtOAc and the organics washed with water (2x), brine, dried over Na2SO4 and concentrated in vacuo. The material was chromatographed using 5% EtOAc/Hex as eluent to give 2-bromo-1-fluoro-3- (methoxymethoxy)benzene (1.9 g, 89.78 % yield colourless liquid ). [0156] Example 5 [0157] To a stirred solution of tert-butyl 5,6 dihydroimidazo[1,2-a]pyrazine-7(8H)- carboxylate (3.0 g, 0.0134 mmol) in Toluene (25 ml) and THF (5 ml) added NBS (2.51 g, 0.0141 mmol) in portion at rt under nitrogen atmoshpere. Reflux the reaction mixture at 1100C for 2 h. After completion of reaction mixture was quenched with ammonium chloride (100 ml) solution and EtOAc (3*50.0 ml). The organic layer was dried over anhydrous sodium sulphate, filtered. The filtrate was concentrated under reduced pressure to afford crude compound. [0158] To a solution of tert-butyl (3R)-3-(hydroxymethyl)piperazine-l-carboxylate (10 g, 46.24 mmol) in ethyl acetate (100 mL) and water (100 mL) was added sodium bicarbonate (11.6 g, 138.71 mmol) in one portion, then benzyl carbonochloridate (39.33 g, 69.35 mmol, 30% in toluene) was added to the solution slowly with stirring at 0 °C for 20 minutes. The resulted solution was stirred at ambient temperature for 16 hours. The reaction mixture was diluted with DCM (100 mL ).The organic layer was separated from the reaction solution, and washed with water (100 mL). The aqueous phase was extracted with DCM (100 mL). The organic layer was collected and combined, washed with water (100 mL x 3), brine (100 mL), dried over sodium sulfate, concentrated under reduced pressure to give a yellow liquid. The yellow liquid was purified by combi flash using 80 g silica gel column as standard phase and 40-50% ethyl acetate : hexane as mobile phase to get 1-benzyl 4-(tert-butyl) (R)-2-(hydroxymethyl)piperazine-1,4-dicarboxylate (15.0 g, 92.59%, Light yellow sticky liquid).

[0159] To a solution of 1 -benzyl 4-(tert-butyl) (R)-2- (((methylsulfonyl)oxy)methyl)piperazine-l,4- dicarboxylate (6.0 g, 0.014 mmol) in N,N-dimethyl acetamide (60 mL) was added sodium cyanide (1.3 g, 0.028 mmol) and heated at 55°C for 24h. The reaction mass was quenched with brine solution.The mixture was partitioned between EtOAc/brine, and the organic layer was washed with brine (3x 50 mL), ), dried over sodium sulfate, concentrated under reduced pressure to give a yellow liquid.

[0160] To a stirred solution of 1-benzyl 4-(tert-butyl) (S)-2-(cyanomethyl)piperazine-1,4- dicarboxylate (3.0 g, 0.0083 mmol) in DCM (5.0 mL) and 4 M HCl in dioxane (15.0 mL) was added drop wise at 0 ⁰C. The mixture was stirred at room temperature for one hour, then the reaction mass was concentrated to dryness. The resulting residue was triturated in pentane to get the tittle compound (3.0 g, 91.85% - Yellowish sticky solid).

[0161] To a Seal tube tert-butyl 3-bromo-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)- carboxylate (5 mg, 0.0165 mmol) in Toluene (0.5 mL), benzyl (S)-2-(cyanomethyl)piperazine-1- carboxylate (4 mg, 0.0165 mmol) and Cesium carbonate (10 mg, 0.0330 mmol) were added and purged with argon for 30 minutes, then CataCXiumA (1 mg, 0.0033 mmol) was added under argon atmosphere, purged with argon for 10 min and then vessel was sealed and reaction carried out at 100 °C for 16 hours. The desired product was formed and it was confirmed by LCMS. [0162] To a Seal tube tert-butyl 5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (200 mg, 0.896 mmol) in Tolune (4 mL) and DMF(1 ml), NIS (211 mg, 0.941 mmol) were added portionwise and reaction carried out at 110 °C for 2 hours. The progress of reaction was monitor by TLC. After completion of reaction mixture was quenched with ammonium chloride (100 ml) solution and EtOAc (3*15 ml). The organic layer was dried over anhydrous sodium sulphate, filtered. The filtrate was concentrated under reduced pressure to afford crude compound. The desired product was formed and it was confirmed by LCMS and ¹H-NMR. [0163] To a RB tert-butyl 3-bromo-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (100 mg, 0.331 mmol) in THF (2 mL), Trimethylborat (56.36 mg, 0.542 mmol) were added. ((CH₃)2CH(MgCl2)Li (0.4 ml, 0.508 mmol) was added dropwise at 00C under argon atmosphere. Reaction carried out at 60 °C for 16 hours. The desired product was formed and it was confirmed by LCMS. [0164] To a Seal tube tert-butyl 3-bromo-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)- carboxylate (200 mg, 0.771 mmol) in DCM (2 mL), Trifloeoacetic acid (2 ml, 0.132 mmol) was added at rt and stirred for 15 min. Then TEA (497 mg, 3.855 mmol) and (Trifloro acettic anhydride (242 mg, 1.155 mmol) were added dropwised at 0⁰C Reaction carried out at rt for 2 hours. [0165] To a Seal tube ethyl 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate (10 mg, 0.051 mmol) in toluene (0.5 mL), 1-bromo-8-chloro naphthalene (12 mg, 0.051mmol) and Cesium carbonate (49 mg, 0.153 mmol) were added and purged with argon for 15 minutes, then BINAP (1.2 mg, 0.002 mmol) and Tris (dibenzylidene acetone) dipalladium(0) (1 mg, 0.001mmol) were added under argon atmosphere, purged with argon for 10 min and then vessel was sealed and reaction carried out at 90 °C for 16 hours. [0166] To a stirred solution of Nitronium tetrafluoroborate (22 mg, 0.167 mmol) in 1 ml of anhydrous acetonitrile, under nitrogen, was added a solution of 1-(3-bromo-5,6- dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2,2,2-trifluoroethan-1-one (20 mg, 0.067 mmol) in 1 ml of dry acetonitrile at -45⁰C. The mixture was warmed at room temperature for 3 hr. The reaction mixture was then quenched with saturated sodiumbicarbonate in water and extracted with ethylacetate. [0167] To a solution of the benzyl (S)-4-(7-(8-chloronaphthalen-1-yl)-2-(hydroxymethyl)- 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)-2-(cyanomethyl)piperazine-1-carboxylate (10 mg, 0.0175 mmol) in methylene chloride (3 mL) was added triphenylphosphine (6 mg, 0.0288 mmol) followed by careful addition of carbon tetrabromide (8 mg, 0.0288 mmol) at 0⁰C. The reaction mixture was allowed to stir for 16 hours at room temperature. Water was added and the organic layer was washed with brine, dried over sodium sulfate and the solvent was removed in vacuo (30 mg, brown sticky mass). [0168] Example 6 [0169] To a Paar shaker flask ethyl imidazo[1,2-a]pyrazine-2-carboxylate (6.9 g, 0.036 mmol) in EtOH (20 mL), Di-tert-butyldicarbonate (15.9 g, 0.072 mmol) and Pd/C (0697 g) were under argon atmosphere. Reaction carried out under hydrogen atmosphere for 48 hours. The desired product was formed and it was confirmed by LCMS and purity by HPLC. [0170] To a stirred solution of 7-(tert-butyl) 2-ethyl 5,6-dihydroimidazo[1,2-a]pyrazine- 2,7(8H)-dicarboxylate (2.7 g, 0.009 mmol) in ACN (10 mL), N-bromosuccinamide(1.7 g, 0.009 mmol) was added under argon atmosphere at 0⁰C. Heated the Reaction at 75⁰C for 1 h. [0171] To a Seal 7-(tert-butyl) 2-ethyl 3-bromo-5,6-dihydroimidazo[1,2-a]pyrazine- 2,7(8H)-dicarboxylate (100 mg, 0.267mmol) in Toluene (2 mL), benzyl (S)-2- (cyanomethyl)piperazine-1-carboxylate (83.14 mg, 0.320 mmol) and Cs2CO3 (260 mg,0.801mmol) were added and purged with argon for 30 minutes, then BINAP (24 mg,0.040mmol) and Pd2(dba)3 (12 mg, 0.013 mmol) was added under argon atmosphere, purged with argon for 10 min and then vessel was sealed and reaction carried out at 100 °C for 16 hours. The desired product was formed and it was confirmed by LCMS. [0172] To a stirred solution of 7-(tert-butyl) 2-methyl (S)-3-(4-((benzyloxy)carbonyl)-3- (cyanomethyl)piperazin-1-yl)-5,6-dihydroimidazo[1,2-a]pyrazine-2,7(8H)-dicarboxylate (700 mg, 1.299 mmol) in DCM (4.0 mL) and 4 M HCl in dioxane (10.0 mL) was added drop wise at 0 ⁰C. The mixture was stirred at room temperature for one hour, then the reaction mass was concentrated to dryness. The residue was quenched with sat. sodium bicarbonate at 0 ⁰C and extracted in 10% methanol in DCM. The organic layer was dried over anhydrous sodium sulphate. The solvent was removed under reduced pressure to get the tittle compound (550 mg, Crude, Light yellow thick liquid). [0173] To a stirred solution of 7-(tert-butyl) 2-ethyl (S)-3-(4-((benzyloxy)carbonyl)-3- (cyanomethyl)piperazin-1-yl)-5,6-dihydroimidazo[1,2-a]pyrazine-2,7(8H)-dicarboxylate (240 mg, 0.434 mmol) in DCM (2.0 mL) and 4 M HCl in dioxane (5.0 mL) was added drop wise at 0 ⁰C. The mixture was stirred at room temperature for one hour, then the reaction mass was concentrated to dryness. The residue was quenched with sat. sodium bicarbonate at 0 ⁰C and extracted in 10% methanol in DCM. The organic layer was dried over anhydrous sodium sulphate. The solvent was removed under reduced pressure to get the tittle compound (200 mg, Crude, Light yellow thick liquid). [0174] To a Seal tube ethyl (S)-3-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1- yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate (10 mg, 0.022 mmol) in toluene (1 mL), 1-bromo-8-chloro naphthalene (7 mg, 0.029 mmol) and Cesium carbonate (18 mg, 0.055 mmol) were added and bubbled with argon for 15 minutes, then Ruphos (2 mg, 0.003 mmol) and Tris (dibenzylidene acetone) dipalladium(0) (1.6 mg, 0.002 mmol) were added under argon atmosphere, bubbled with argon for 10 min and then vessel was sealed and reaction carried out at 100 °C for 16 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure to give a crude title compound (20 mg, crude, brown thick mass). [0175] To a stirred solution of ethyl (S)-7-(8-chloronaphthalen-1-yl)-3-(3- (cyanomethyl)piperazin-1-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate (35 mg, 0.073 mmol ) in DCM (4 mL) was added triethylamine (11 mg, 0.109 mmol) and then acryloyl chloride (8 mg, 0.088 mmol) diluted in DCM (0.5 mL) was added drop wise at -40 °C. The resulting mixture was stirred at -40 °C for 30 minutes. The reaction mixture was diluted with saturated ammonium chloride in water and extracted to dichloromethane. The organic layer was separated, washed with brine solution and dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude was purified by preparative TLC plate using 3% methanol in DCM as amobile phase.Further purified by preparative HPLC purification method to get ethyl (S)- 3-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(8-chloronaphthalen-1-yl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate (5.5 mg, 14.47%, White solid). [0176] Example 7 [0177] To a solution of ethyl (S)-3-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1- yl)-7-(8-chloronaphthalen-1-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate (10 mg, 0.016 mmol) in ethanol (1 mL) was added Sodium borohydride (1 mg, 0.024 mmol) at 0 °C. After stirring at RT for 24h, the mixture was heated to 55 °C & stirred for 24 h at same temperature, then reaction mass was cooled to RT, concentrated to give a white solid which was quenched with sat. ammonium chloride at 0 ⁰C and extracted in ethyl acetate. The organic layer was dried over anhydrous sodium sulphate. The solvent was removed under reduced pressure to get the tittle compound (10 mg, Crude, Light brown sticky mass). [0178] To a solution of ethyl (S)-3-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1- yl)-7-(8-chloronaphthalen-1-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate (50 mg, 0.082 mmol) in THF:EtOH:3:2 (2.5 mL) was added Lithium hydroxide monohydrate (7 mg, 0.163 mmol) dissolved in water (0.5 mL) drop wise at 0 °C. After stirring at RT for 48h, the mixture was, concentrated to give a white residue, which was diluted with water and acidified with KHSO4 at 00C and extracted in ethyl acetate. The organic layer was dried over anhydrous sodium sulphate. The solvent was removed under reduced pressure to get the tittle compound (40 mg, Crude, Light brown sticky solid).

[0179] To a solution of (S)-3-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)- 7-(8-chloronaphthalen-1-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid (50 mg, 0.085 mmol) and Triethylamine (17 mg, 0.170 mmol) in THF (2.0 mL) at -10 °C under nitrogen atmosphere was added Isobutyl chloroformate (20 mg, 0.145 mmol) dropwise. The reaction mixture was stirred for 1 h at 0 °C, then filtered the triethylamine hydrochloride, washed with minimum THF. Then filtrate was treated dropwise with a solution of sodium borohydride (6 mg, 0.170 mmol) in water (0.2 mL) at 0 °C. The mixture was stirred overnight at room temperature and quenched slowly with a saturated solution of ammonium chloride (5mL). The aqueous layer was extracted thrice with CH₂Cl2 (20mL). The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was mixed with APSL-0043- 056-C1 and purified by prep TLC plate using 90% ethylacetate in hexane as amobile phase to afford the tittle compound (20 mg, 29.41%, Off white sticky solid).

[0180] To a solution, stirred under nitrogen gas, of benzyl (S)-4-(7-(8-chloronaphthalen- 1-yl)-2-(hydroxymethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)-2- (cyanomethyl)piperazine-1-carboxylate (5 mg, 0.088 mmol) in dimethylformamide (1 mL ) were added Potassium carbonate (4 mg, 0.263 mmol) and (R)-(1-methylpyrrolidin-3-yl)methyl 4- methylbenzenesulfonate (3 mg, 0.105 mmol). The reaction mixture was stirred at roomtemperature for 6 h. Further stirred for 16 hours at 70 °C. The reaction mixture was then quenched with saturated ammonium chloride in water and acidified with KHSO4 at 0⁰C and extracted in ethyl acetate. The organic layer was dried over anhydrous sodium sulphate. The solvent was removed under reduced pressure (5 mg, Crude, Brown sticky mass).

[0181] To a solution, stirred under nitrogen gas, of benzyl (S)-4-(7-(8-chloronaphthalen- 1-yl)-2-(hydroxymethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)-2- (cyanomethyl)piperazine-1-carboxylate (10 mg, 0.018 mmol) in dimethylformamide (1 mL ) were added Sodium hydride (1 mg, 0.026 mmol) and (R)-(1-methylpyrrolidin-3-yl)methyl 4- methylbenzenesulfonate (5 mg, 0.026 mmol) at 0 °C . The reaction mixture was stirred at same temperature for 6 h. Further stirred for 30 minutes at room temperature. The reaction mixture was then quenched with saturated ammonium chloride in water and acidified with KHSO4 at 0⁰C and extracted in ethyl acetate. The organic layer was dried over anhydrous sodium sulphate. The solvent was removed under reduced pressure (10 mg, Crude, Brown sticky mass).

[0182] Example 8 [0183] A 100 mL round bottom flask was charged with (S)-3-(4-((benzyloxy)carbonyl)-3- (cyanomethyl)piperazin-1-yl)-7-(8-chloronaphthalen-1-yl)-5,6,7,8-tetrahydroimidazo[1,2- a]pyrazine-2-carboxylic acid (20 mg, 0.0342 mmol), diphenyl phosphoryl azide (18 mg, 0.066 mmol), triethylamine (6.6 mg, 0.066 mmol) and tert-butanol (1.0 mL). The mixture was stirred at 80 °C for 16 h. Reaction progress was monitored by LC-MS. Work-up: the solvent was evaporated. The reaction mixture was diluted with saturated ammonium chloride in water and extracted to dichloromethane. The organic layer was separated, washed with brine solution and dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude was purified by preparative TLC plate using 80% ethyl acetate in hexane as amobile phase to get the tittle compound (4 mg, 18.18%, Off white solid)

[0184] Example 9 [0185] To a solution of benzyl (S)-4-(7-(8-chloronaphthalen-1-yl)-2-(hydroxymethyl)- 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)-2-(cyanomethyl)piperazine-1-carboxylate (20 mg, 0.029 mmol) in 2 mL THF was added 10% Pd-C (50 mg). Then the mixture was stirred at room temperature for 48 hours under hydrogen bladder pressure. The reaction mixture was filtered through celite bed, the celite bed was washed with excess 10 % methanol in DCM. The filtrate was concentrated under reduced pressure to give a title compound (15 mg, Crude, Light yellow brown mass).

[0186] To a stirred solution of (S)-2-(4-(7-(8-chloronaphthalen-1-yl)-2-(hydroxymethyl)- 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)piperazin-2-yl)acetonitrile (15 mg, 0.034 mmol ) in DCM (4 mL) was added triethylamine (6 mg, 0.051 mmol) and then acryloyl chloride (4 mg, 0.042 mmol) diluted in DCM (0.5 mL) was added drop wise at -40 °C. The resulting mixture was stirred at -40 °C for 30 minutes. The reaction mixture was diluted with saturated ammonium chloride in water and extracted to dichloromethane. The organic layer was separated, washed with brine solution and dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude was purified by preparative TLC plate using 3% methanol in DCM as amobile phase (1.5 mg, Light yellow sticky solid).

[0187] Example 10 [0188] To a solution of the (S)-(1-methylpyrrolidin-2-yl) methanol (500 mg, 4.341 mmol) in methylene chloride (10 mL) was added triphenylphosphine (1.48 g, 5.644 mmol) followed by careful addition of carbon tetrabromide (1.87 g, 5.644 mmol) at 0⁰C. The reaction mixture was allowed to stir for 1 hour at room temperature. Water was added and the organic layer was washed with brine, dried over sodium sulfate and the solvent was removed in vacuo. The resulting oil was purified by silica gel chromatography (1:3 hexanes/ethyl acetate). Bromide as a clear oil (170 mg, 21.99%, clear oil).

[0189] To a solution, stirred under nitrogen gas, of benzyl (S)-4-(7-(8-chloronaphthalen- 1-yl)-2-(hydroxymethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)-2- (cyanomethyl)piperazine-1-carboxylate (10 mg, 0.018 mmol) in THF (1 mL ) were added Sodium hydride (1 mg, 0.026 mmol) and (S)-2-(bromomethyl)-1-methylpyrrolidine (5 mg, 0.026 mmol) at 0 °C . The reaction mixture was stirred at same temperature for 6 h. The reaction mixture was allowed to room temperature and stirred for 24 h. Further stirred for 8 hours at 55 °C.The reaction mixture was then quenched with saturated ammonium chloride in water and acidified with KHSO4 at 0⁰C and extracted in ethyl acetate. The organic layer was dried over anhydrous sodium sulphate. The solvent was removed under reduced pressure (20 mg, Crude, Brown sticky mass).

[0190] To a solution, stirred under nitrogen gas, of benzyl (S)-4-(7-(8-chloronaphthalen- 1-yl)-2-(hydroxymethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)-2- (cyanomethyl)piperazine-1-carboxylate (10 mg, 0.018 mmol) in THF (1 mL ) were added LiHMDS (0.03 mL, 0.026 mmol) and (S)-2-(bromomethyl)-1-methylpyrrolidine (5 mg, 0.026 mmol) at -40 °C . The reaction mixture was stirred at same temperature for 1 h.The reaction mixture was then quenched with saturated ammonium chloride in water and acidified with KHSO4 at 0⁰C and extracted in ethyl acetate. The organic layer was dried over anhydrous sodium sulphate. The solvent was removed under reduced pressure (20 mg, Crude, Brown sticky mass).

[0191] Example 11 [0192] To a Seal tube methyl (S)-3-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin- 1-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate (550 mg, 1.254 mmol) in toluene (8 mL), 1-bromo-8-chloro naphthalene (394 mg, 1.631 mmol) and Cesium carbonate (1.02 g, 3.135 mmol) were added and bubbled with argon for 15 minutes, then (2,2′-bis(diphenyl phosphino)-1,1 ′-binaphthyl) (117 mg, 0.188 mmol) and Tris (dibenzylidene acetone) dipalladium(0) (57 mg, 0.062 mmol) were added under argon atmosphere, bubbled with argon for 10 min and then vessel was sealed and reaction carried out at 100 °C for 16 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure. The crude was purified by combi flash using (12 g) silica gel column as standard phase and 4-6% methanol in dichloromethane as mobile phase to give a title compound (600 mg, 79.89%, light yellow solid).

[0193] To a solution of ethyl (S)-3-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1- yl)-7-(8-chloronaphthalen-1-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate (600 mg, 1.001 mmol) in THF:EtOH:3:2 (5 mL) was added Lithium hydroxide monohydrate (84 mg, 2.003 mmol) dissolved in water (1.0 mL) drop wise at 0 °C. After stirring at RT for 48h, the mixture was, concentrated to give a white residue, which was diluted with water and acidified with KHSO4 at 0⁰C and extracted in ethyl acetate. The organic layer was dried over anhydrous sodium sulphate. The solvent was removed under reduced pressure to get the tittle compound (550 mg, Crude, Light brown sticky solid).

[0194] To a solution of (S)-3-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)- 7-(8-chloronaphthalen-1-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid (20 mg, 0.034 mmol) in dry THF (1 mL) at 0 °C (ice bath) was added a 2 M solution of BH3 -DMS (0.05 mL, 0.103 mmol). The ice bath was removed, and the reaction was stirred for 16 h at RT, then reaction mass was cooled with an ice bath, and MeOH (1 mL) was added slowly. The reaction was concentrated to dryness. MeOH (1 mL) was added to the solid residue, stirred for 15 min, and then concentrated to dryness (30 mg, Crude, Light brown sticky mass).

[0195] To a solution of benzyl (S)-4-(7-(8-chloronaphthalen-1-yl)-2-(hydroxymethyl)- 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)-2-(cyanomethyl)piperazine-1-carboxylate (20 mg, 0.029 mmol) in 2 mL THF was added 10% Pd-C (50 mg). Then the mixture was stirred at room temperature for 48 hours under hydrogen bladder pressure. The reaction mixture was filtered through celite bed, the celite bed was washed with excess 10 % methanol in DCM. The filtrate was concentrated under reduced pressure to give a title compound (15 mg, Crude, Light yellow brown mass).

[0196] To a stirred solution of (S)-2-(4-(7-(8-chloronaphthalen-1-yl)-2-(hydroxymethyl)- 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)piperazin-2-yl)acetonitrile (15 mg, 0.034 mmol ) in DCM (4 mL) was added triethylamine (6 mg, 0.051 mmol) and then acryloyl chloride (4 mg, 0.042 mmol) diluted in DCM (0.5 mL) was added drop wise at -40 °C. The resulting mixture was stirred at -40 °C for 30 minutes. The reaction mixture was diluted with saturated ammonium chloride in water and extracted to dichloromethane. The organic layer was separated, washed with brine solution and dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude was purified by preparative TLC plate using 3% methanol in DCM as amobile phase (1.5 mg, Light yellow sticky solid).

[0197] Example 12 [0198] Inhibition of KRas G12C-dependent Cell Growth [0199] This example illustrates that exemplary compounds inhibit the growth of tumor cell lines that express KRas G12C. The cellular inhibition of KRAs G12C by exemplary compounds was determined by measuring the amount of a downstream marker of KRas activity, phosphorylated ERK (“Phospho-ERK”). [0200] Cell Lines and Culture conditions: H23 and H1373 cell lines were obtained from AddexBio. They were grown in a T-75 flask in RPMI Medium containing 10% fetal bovine serum and penicillin-streptomycin at 37oC in a humidified, 5% CO2 incubator. [0201] Proliferation assay: H23 or H1373 cells (100 µl, 2,500 cells/well) were plated in a 96-well plate and incubated overnight at 37oC in a humidified, 5% CO2 incubator. Next day, medium was replaced with 100 µl of fresh growth medium containing serially diluted test compounds in duplicate wells. After 72 hour incubation with the compound, cell viability was measured in a luminometer after the addition of 100 µL/well CellTiterGlo reagent (Promega) as recommended by the manufacturer. [0202] Serial dilutions of test compounds: Test compounds were serially diluted 5-fold in DMSO starting from 10 mM to 0.64 µM. These serially diluted compounds were diluted 100 fold in growth medium (2 µl to 200 µl) followed by another 10 fold dilution in growth medium (25 µl to 250 µl). Final concentration of compounds in the growth medium ranged between 10 µM to 0.64 nM. [0203] Quantitative analysis of phospho-ERK protein levels in H23 and H1373 cell lines: Similar to proliferation assay, a 8-point dose response curve will be generated in duplicate. In cell western will be done using phosphor-ERK and total-ERK antibodies. Detection will be done using anti-rabbit and anti-mouse secondary antibodies. Imaging and quantification will be on LICOR. [0204] Example 13 [0205] This example illustrates additional procedures in testing the compounds disclosed herein. Coupled Nucleotide Exchange Assay: Purified GDP-bound KRAS protein (aa 1- 169), containing both G12C and C118A amino acid substitutions and an N-terminal His-tag, was pre- incubated with a compound dose-response titration for 2 hours in assay buffer (25 mM HEPES pH 7.4, 10 mM MgCh, and 0.01% Triton X-100). Following compound preincubation, purified SOS protein (aa 564-1049) and GTP (Roche 10106399001) were added to the assay wells and incubated for an additional hour. To determine the extent of inhibition of SOS-mediated nucleotide exchange, purified GST-tagged cRAF (aa 1-149), nickel chelate AlphaLISA acceptor beads (PerkinElmer AL108R), and AlphaScreen glutathione donor beads (PerkinElmer 6765302) were added to the assay wells and incubated for 10 minutes. The assay plates were then read on a PerkinElmer EnVision Multilabel Reader, using AlphaScreen® technology, and data were analyzed using a 4- parameter logistic model to calculate IC50 values. [0206] Phospho-ERKl/2 MSD Assay: MIA PaCa-2 (ATCC® CRL-1420™) and A549 (ATCC® CCL-185™) cells were cultured in RPMI 1640 Medium (ThermoFisher Scientific 11875093) containing 10% fetal bovine serum (ThermoFisher Scientific 16000044) and lx penicillin-streptomycin-glutamine (ThermoFisher Scientific 10378016). Sixteen hours prior to compound treatment, MIA PaCa-2 or A549 cells were seeded in 96-well cell culture plates at a density of 25,000 cells/well and incubated at 37°C, 5% CO2. A compound dose-response titration was diluted in growth media, added to appropriate wells of a cell culture plate, and then incubated at 37°C, 5% CO2 for 4 hours. Following compound treatment, cells were stimulated with 10 ng/mL EGF (Roche 11376454001) for 10 min, washed with ice-cold Dulbecco's phosphate-buffered saline, no Ca²⁺ or Mg²⁺ (ThermoFisher Scientific 14190144), and then lysed in RIPA buffer (50 mM Tris-HCl pH 7.5, 1% Igepal, 0.5% sodium deoxycholate, 150 mM NaCl, and 0.5% sodium dodecyl sulfate) containing protease inhibitors (Roche 4693132001) and phosphatase inhibitors (Roche 4906837001). Cell lysates were stored frozen at -80°C overnight. Phosphorylation of ERK1/2 in compound-treated lysates was assayed using Phospho-ERKl/2 Whole Cell Lysate kits (Meso Scale Discovery K151DWD) according to the manufacturer's protocol. Assay plates were read on a Meso Scale Discovery Sector Imager 6000, and data were analyzed using a 4-parameter logistic model to calculate IC50 values. [0207] It will be appreciated by persons skilled in the art that the invention described herein is not limited to what has been particularly shown and described. Rather, the scope of the invention is defined by the claims which follow. It should further be understood that the above description is only representative of illustrative examples of embodiments. The description has not attempted to exhaustively enumerate all possible variations. The alternate embodiments may not have been presented for a specific substituent of the compound, or a step of the method, and may result from a different combination of described substituent or step, or that other undescribed alternate embodiments may be available for a compound or method, is not to be considered a disclaimer of those alternate embodiments. It will be appreciated that many of those un-described embodiments are within the literal scope of the following claims, and others are equivalent.

Claims

CLAIMS 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof,

A is a bond, O, S, NR^a, C_1-3alkylene-O wherein O is attached to R¹, B is a 4-12 membered saturated or partially saturated monocyclic, bridged or spirocyclic ring, wherein the saturated or partially saturated monocyclic ring is optionally substituted with one or more R⁵; R¹ is selected from the group consisting of hydrogen, cyano, C(O)OR^m, C(O)N(R^m)₂, C(O) C_1- 6alkyl, haloalkyl, C_1-6alkyl, hydroxyC_1-6alkyl, dihydroxyC1-10alkyl, cycloalkyl, heterocycloalkyl, C_1-6alkylene-cycloalkyl, C_1-6alkylene-heterocycloalkyl, C_1-6alkylene-aryl, C_1-6alkylene- heteroaryl, C_1-6alkylene-N(R^m)₂, C_1-6alkylene-N(R^m)(COR^m), C_1-6alkylene-N(R^m)(C_1-6alkylene- aryl), C_1-6alkylene-N(R^m)(C_1-6alkylene-heteroaryl), C_1-6alkylene-N(R^m)(C(O)C_1-6alkylene-aryl), C_1-6alkylene-N(R^m)(C(O)C_1-6alkylene-heteroaryl), spirocyclic ring, and bridged ring, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl moiety of these substituents is optionally substituted with one or more of halogen, acyl, CN, haloalkyl, hydroxyl, oxo, C_1-6alkyl, OC_1- 6alkyl, hydroxyC_1-6alkyl, C_1-6alkylene-N(R^m)2, C_1-6alkylene-N(R^m)(COR^m), N(R^m)2, cycloalkyl, heterocycloalkyl, C_1-6alkylene-heterocycloalkyl, C_1-6alkylene-aryl, and C_1-6alkylene-heteroaryl; provided that when R¹ is cyano, A is a bond; R² is C(O)CR^b=CR^cR^d, SO2CR^b=CR^cR^d, C(O)CΞCR^c, or SO2CΞCR^c; R³ in each instance is independently C_1-6alkyl, C_1-6alkylene-CN, oxo, haloalkyl, hydroxyl or halogen; L is a bond, --C(O)--, or C_1-3alkylene; R⁴ hydrogen, cycloalkyl, heterocyclyl, aryl, C_1-6alkylene-aryl, C_1-6alkylene-heteroaryl, or heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, or heteroaryl moiety of these substituents is optionally substituted with one or more substituents selected from the group consisting of halogen, C_1-6alkyl, OC_1-6alkyl, hydroxyC_1-6alkyl, C_1-6alkylene-N(R^m)₂, C_1- 6alkylene-N(R^m)(COR^m), CN, CF3, OH, N(R^m )2, haloC_1-6alkyl, and cycloalkyl; R⁵ is selected from the group consisitng of oxo, C_1-6alkyl, OC_1-6alkyl, hydroxylC_1-6alkyl, C1- ₆alkylene-CN, C_1-6alkylene OC_1-6alkyl, C2-C4 alkynyl, haloalkyl, cyano, C(O)OR^m, C(O)N(R^m)2, N(R^m)2, , C_1-6alkylene-N(R^m)2, C_1-6alkylene-aryl, C_1-6alkylene- heteroaryl; C(O)OC_1-6alkyl, C(O)N(R^m)₂, and C(O)C_1-6alkyl; R^a is selected from the group consisting of hydrogen, C_1-6alkyl, heteroalkyl, C(O)C_1-6alkyl, C(O)R^m and C(O)N(R^m)2; R^b is selected from the group consisting of hydrogen, deuterium, halogen, C_1-6alkyl, OC_1-6alkyl, hydroxyl-C_1-6alkyl, halo-C_1-6alkyl, N(R^m)(C(O) C_1-6alkyl), C_1-6alkylene-OC_1-6alkyl, C_1-6alkylene- heteroaryl, and C_1-6alkylene-aryl, R^c and R^d are independently selected from the group consisting of hydrogen, deuterium, CN, halogen, C_1-6alkyl, halo-C_1-6alkyl, hydroxyl-C_1-6alkyl, C_1-6alkylene-OC_1-6alkyl, C_1-6alkylene- N(C_1-6alkyl)(halo-C_1-6alkyl), , C_1-6alkylene-N(R^m )₂, C_1-6alkylene-N(R^m)(COR^m), CON(R^m)₂, cycloalkyl, heterocycloalkyl, heteroC_1-6alkyl, heteroaryl, aryl, C_1-6alkylene-heteroaryl, C1- ₆alkylene-aryl, C_1-6alkylene-cycloalkyl, and C_1-6alkylene-heterocycloalkyl, wherein the cycloalkyl, heterocycloalkyl, heteroaryl, or aryl moiety of these is optionally substituted with one or more of halogen, C_1-6alkyl, OC_1-6alkyl, CN, and halo-C_1-6alkyl; R^a and R^d optionally link up to form a 5 to 8 membered, partially unsaturated ring, wherein the ring is optionally substituted with oxo or C_1-6alkyl; R^m in each instance is independently hydrogen, C_1-6alkyl, acyl, heteroalkyl, hydroxyl-C_1-6alkyl or halo-C_1-6alkyl, wherein optionally two R^m together with the nitrogen they are attached to link up to form a heterocyclic ring; m is 0, 1 or 2; n is 0, 1 or 2; and p is 0, 1 or 2.

2. The compound or the pharmaceutically acceptable salt thereof of claim 1, wherein A is C1-2alkylene-O, S or NH.

3. The compound or the pharmaceutically acceptable salt thereof any one of claims 1-2, wherein R¹ is selected from the group consisting of heterocycloalkyl, C_1-6alkylene- heterocycloalkyl, C_1-6alkylene-heteroaryl, and C_1-6alkylene-N(R^m)2.

4. The compound or the pharmaceutically acceptable salt thereof any one of claims 1-3, wherein A is C1-2alkylene-O, R¹ is optionally substituted C_1-6alkylene-heterocycloalkyl.

5. The compound or the pharmaceutically acceptable salt thereof of claim 1, wherein A is a bond, R¹ is selected from the group consisting of cyano, C(O)OR^m, C(O)N(R^m)₂, C(O) C_1-6alkyl, haloalkyl, heterocycloalkyl, spirocyclic ring, and bridged ring, wherein the heterocycloalkyl, spirocyclic ring, and bridged ring are optionally substituted.

6. The compound or the pharmaceutically acceptable salt thereof of any one of claims 1 and 5, wherein A is a bond, R¹ is cyano.

7. The compound or the pharmaceutically acceptable salt thereof of any one of claims 1-6, wherein R² is C(O)CR^b=CR^cR^d, R^b is selected from the group consisting of hydrogen, deuterium, halogen, C_1-6alkyl, halo-C_1-6alkyl, hydroxyl-C_1-6alkyl, and N(R^m)(C(O)C_1-6alkyl).

8. The compound or the pharmaceutically acceptable salt thereof any one of claims 1-7, wherein one of R^c and R^d is selected from the group consisting of hydrogen, deuterium, halogen, CN, C_1-6alkyl, halo-C_1-6alkyl, hydroxyl-C_1-6alkyl, CON(R^m)₂, C_1-6alkylene-OC_1-6alkyl, C_1- 6alkylene-N(R^m )2, C_1-6alkylene-N(R^m)(COR^m), heterocycloalkyl, heteroaryl, aryl, C_1-6alkylene- heterocycloalkyl, C_1-6alkylene-heteroaryl, and C_1-6alkylene-aryl, wherein the heterocycloalkyl, heteroaryl, or aryl moiety of these is optionally substituted with one or more of halogen, C1- 6alkyl, and OC_1-6alkyl; wherein the other of R^c and R^d is hydrogen or deuterium.

9. The compound or the pharmaceutically acceptable salt thereof any one of claims 1-8, wherein the alkene in C(O)CR^b=CR^cR^d for R² is a trans configuration

10. The compound or the pharmaceutically acceptable salt thereof any one of claims 1-9, wherein one of R^c and R^d is C_1-3alkylene-heterocycloalkyl, C_1-3alkylene-cycloalkyl, or C1- ₃alkylene-heteroaryl, wherein the heterocycloalkyl, cloalkyl or heteroaryl moiety of these substituents is optionally substituted with one or more of halogen, CN, haloalkyl, hydroxyl, oxo, C_1-6alkyl, OC_1-6alkyl, hydroxyC_1-6alkyl, cycloalkyl, or heterocycloalkyl.

11. The compound or the pharmaceutically acceptable salt thereof any one of claims 1-10, wherein one of R^c and R^d is C_1-3alkylene-heterocycloalkyl, wherein the heterocycloalkyl is 5 or 6 membered and is optionally substituted with one or more of halogen, C_1-6alkyl, OC_1-6alkyl and cycloalkyl.

12. The compound or the pharmaceutically acceptable salt thereof any one of claims 1-11, wherein p is 1.

13. The compound or the pharmaceutically acceptable salt thereof any one of claims 1-12, wherein m is 0.

14. The compound or the pharmaceutically acceptable salt thereof any one of claims 1-13, wherein B is a 6-membered ring.

15. The compound or the pharmaceutically acceptable salt thereof any one of claims 1-14, wherein R⁴ is aryl or heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of halogen, C_1-6alkyl, hydroxyC_1-6alkyl, CN, CF₃, N(R^m )2, haloC_1-6alkyl, and cycloalkyl.

16. The compound or the pharmaceutically acceptable salt thereof any one of claims 1-15, wherein L is a bond.

17. The compound or the pharmaceutically acceptable salt thereof any one of claims 1-16, wherein R⁵ is is selected from the group consisting of oxo, C_1-6alkyl, C_1-6alkylene-CN, C1- ₆alkylene OC_1-6alkyl, C2-C4 alkynyl, haloalkyl, cyano, C(O)OR^m, C(O)N(R^m)₂, C_1-6alkylene- N(R^m)2, C_1-6alkylene-aryl, C_1-6alkylene-heteroaryl; C(O)OC_1-6alkyl, C(O)N(R^m)2, and C(O)C1- ₆alkyl.

18. The compound or the pharmaceutically acceptable salt thereof any one of claims 1-17, wherein R⁵ is selected from the group consisting of oxo, C_1-6alkyl, C_1-6alkylene-CN, C2-C4 alkynyl, haloalkyl, cyano, and C(O)OR^m; and wherein n is 1.

19. A pharmaceutical composition, comprising a therapeutically effective amount of a compound of Formula (I) according to any one of claims 1-18 or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

20. A method for inhibiting KRas G12C activity in a cell, comprising contacting the cell in which inhibition of KRas G12C activity is desired with an effective amount of a compound of Formula (I) according to any one of claims 1-18 or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof.

21. A method for treating cancer comprising administering to a subject having cancer a therapeutically effective amount of a compound of Formula (I) according to any one of claims 1- 18 or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof.

22. The method of claim 21, wherein the cancer is selected from the group consisting of Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial ‘carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma.

23. The method of any one of claims 21-22, wherein the cancer is a KRas G12C-associated cancer.

24. The method of any one of claims 21-23, wherein the cancer is non-small cell lung cancer.

25. The method of any one of claims 21-23, wherein the cancer is colon cancer.

26. The method of any one of claims 21-23, wherein the cancer is pancratic cancer.

27. The method of any one of claims 21-26, further comprising administering to the subject an additional anti-cancer agent.

28. The method of claim 27, wherein the additional anti-cancer agent is selecte from the group cosnsiting of alkylating agent, platinum agent, antimetabolite, topoisomerase inhibitor, antitumor antibiotics, antimitotic agent, aromatase inhibitor, thymidylate synthase inhibitor, dna antagonist, farnesyltransferase inhibitor, pump inhibitor, histone acetyltransferase inhibitor, metalloproteinase inhibitor, ribonucleoside reductase inhibitor, tnf alpha agonist/antagonist, endothelin receptor antagonist, retinoic acid receptor agonist, immuno-modulator, hormonal and antihormonal agent, photodynamic agent, SHP2 inhibitors, CDK 4/6 inhibitors, protein-protein interaction disruptors, phosphatase inhibitors and kinase inhibitor.

29. The method of claim 27, wherein the additional anti-cancer agent is selecte from the group cosnsiting of poziotinib, bevacizurnab, bortezomib, capecitabine, cetuximab, fluorouracil, imatinib, irinotecan, leucovorin, oxaliplatin, panitumumab, pemetrexed, temozolomide, cisplatin, paclitaxel, erlotinib, sunitinib, lapatinib, sorafenib, carboplatin, doxorubicin, docetaxel, gemcitabine, etoposide, gefitinib, PD153035, cetuximab, bevacizumab, panitumumab, trastuzumab, anti-c-Met antibodies, gefitinib, ZD6474, EMD-72000, pariitumab, ICR-62, CI- 1033, lapatinib, AEE788, EKB-569, EXEL 7647/EXEL 0999, erlotinib, imatinib, sorafinib, sunitinib, dasatinib, vandetinib, temsirolimus, PTK787, pazopanib, AZD2171, everolimus, seliciclib, AMG 706, axitinib, PD0325901, PKC-412, CEP701, XL880, bosutinib, BIBF1120, BIBF1120, nilotinib, AZD6244, HKI-272, MS-275, BI2536, GX15-070, AZD0530, enzastaurin, MLN-518, ARQ197, CM101, IFN-.alpha., IL-12, platelet factor-4, suramin, SU5416, thrombospondin, VEGFR antagonists, angiostatic steroids plus heparin, Cartilage-Derived Angiogenesis Inhibitory Factor, matrix metalloproteinase inhibitors, batimastat, marimastat, angiostatin, endostatin, 2-methoxyestradiol, tecogalan, thrombospondin, .alpha.V.beta.3 inhibitors, linomide, and ADH-1, chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine, melphalan, uracil mustard, thiotepa, busulfan, carmustine, lomustine, streptozocin, carboplatin, cisplatin, satraplatin, oxaliplatin, altretamine, ET-743, XL119, dacarbazine, chlormethine, bendamustine, trofosfamide, uramustine, fotemustine, nimustine, prednimustine, ranimustine, semustine, nedaplatin, triplatin tetranitrate, mannosulfan, treosulfan, temozolomide, carboquone, triaziquone, triethylenemelamine, procarbazin, doxorubicin, daunorubicin, epirubicin, idarubicin, anthracenedione, mitoxantrone, mitomycin C, bleomycin, dactinomycin, plicatomycin, irinotecan, camptothecin, rubitecan, belotecan, etoposide, teniposide, topotecan, paclitaxel, taxol, docetaxel, BMS-275183, xyotax, tocosal, vinorlebine, vincristine, vinblastine, vindesine, vinzolidine, etoposide, teniposide, ixabepilone, larotaxel, ortataxel, tesetaxel, ispinesib, fluorouracil, floxuridine, methotrexate, xeloda, arranon, leucovorin, hydroxyurea, thioguanine, mercaptopurine, cytarabine, pentostatin, fludarabine phosphate, cladribine, asparaginase, gemcitabine, pemetrexed, bortezomib, aminopterin, raltitrexed, clofarabine, enocitabine, sapacitabine, and azacitidine.