BTK INHIBITORS

FIELD OF THE INVENTION

The present invention relates to Btk inhibitor compounds, to pharmaceutical compositions comprising these compounds and to their use in therapy. In particular, the present invention relates to the use of Btk inhibitor compounds in the treatment of Bruton's Tyrosine Kinase (Btk) mediated disorders.

BACKGROUND OF THE INVENTION

B lymphocyte activation is key in the generation of adaptive immune responses. Derailed B lymphocyte activation is a hallmark of many autoimmune diseases and modulation of this immune response is therefore of therapeutic interest. Recently the success of B cell therapies in autoimmune diseases has been established. Treatment of rheumatoid arthritis (RA) patients with Rituximab (anti-CD20 therapy) is an accepted clinical therapy . More recent clinical trial studies show that treatment with Rituximab also ameliorates disease symptoms in relapsing remitting multiple sclerosis (RRMS) and systemic lupus erythematosus (SLE) patients. This success supports the potential for future therapies in autoimmune diseases targeting B cell immunity.

Bruton's tyrosine kinase (Btk) is a Tec family non- receptor protein kinase, expressed in B cells and myeloid cells. The function of Btk in signaling pathways activated by the engagement of the B cell receptor (BCR) and FcsRl on mast cells is well established. In addition, a function for Btk as a downstream target in Toll like receptor signaling was suggested. Functional mutations in Btk in human results in the primary immunodeficiency disease called XLA which is characterized by a defect in B cell development with a block between pro- and pre-B cell stage. This results in an almost complete absence of B lymphocytes in human causing a pronounced reduction of serum immunoglobulin of all classes. These finding support the key role for Btk in the regulation of the production of auto-antibodies in autoimmune diseases. In addition, regulation of Btk may affect BCR-induced production of pro-inflammatory cytokines and chemokines by B cells, indicating a broad potential for Btk in the treatment of autoimmune diseases. With the regulatory role reported for Btk in FcsR-mediated mast cell activation, Btk inhibitors may also show potential in the treatment of allergic responses [Gilfillan et al, Immunological Reviews 288 (2009) pp 149- 169].

Furthermore, Btk is also reported to be implicated in RANKL-induced osteoclast differentiation [Shinohara et al, Cell 132 (2008) pp794-806] and therefore may also be of interest for the treatment of bone resorption disorders.

Other diseases with an important role for dysfunctional B cells are B cell malignancies. Indeed anti-CD20 therapy is used effectively in the clinic for the treatment of follicular lymphoma, diffuse large B-cell lymphoma and chronic lymphocytic leukemia [Lim et al, Haematologica, 95 (2010) pp 135- 143]. The reported role for Btk in the regulation of proliferation and apoptosis of B cells indicates there is potential for Btk inhibitors in the treatment of B cell lymphomas as well. Inhibition of Btk seems to be relevant in particular for B cell lymphomas due to chronic active BCR signaling [Davis et al, Nature, 463 (2010) pp88-94].

Some classes of Btk inhibitor compounds have been described as kinase inhibitors e.g. Imidazo[l,5-f][l,2,4]triazine compounds have been described in

WO2005097800 and WO2007064993; Imidazo[l,5-a]pyrazine compounds have been described in WO2005037836 and WO2001019828 as IGF-1R enzyme inhibitors.

Some of the Btk inhibitors reported are not selective over Src-family kinases. With dramatic adverse effects reported for knockouts of Src-family kinases, especially for double and triple knockouts, this is seen as prohibitive for the development of Btk inhibitors that are not selective over the Src-family kinases.

Both Lyn-deficient and Fyn-deficient mice exhibit autoimmunity mimicking the phenotype of human lupus nephritis. In addition, Fyn-deficient mice also show pronounced neurological defects. Lyn knockout mice also show an allergic-like phenotype, indicating Lyn as a broad negative regulator of the IgE-mediated allergic response by controlling mast cell responsiveness and allergy-associated traits [Odom et al, J. Exp. Med., 199 (2004) ppl491-1502]. Furthermore, aged Lyn knock-out mice develop severe splenomegaly (myeloid expansion) and disseminated

monocyte/macrophage tumors [Harder et al, Immunity, 15 (2001) pp603-615]. These observations are in line with hyperresponsive B cells, mast cells and myeloid cells, and increased Ig levels observed in Lyn-deficient mice. Female Src knockout mice are infertile due to reduced follicle development and ovulation [Roby et al, Endocrine, 26 (2005) pp 169- 176]. The double knockouts Src ^' Tyn ^{" "} and Src ^{" "} Yes ^{" "} show a severe phenotype with effects on movement and breathing. The triple knockouts Src ^{" "} Fyn ^{" "} Yes ^{' _} die at day 9.5 [Klinghoffer et al, EMBO J., 18 (1999) pp2459-2471]. For the double knockout Src ^" Tick ^{" "} , two thirds of the mice die at birth, with surviving mice developing osteopetrosis, extramedullary hematopoiseis, anemia, leukopenia [Lowell et al, Blood, 87 (1996) ppl780-1792].

Hence, an inhibitor that inhibits multiple or all kinases of the Src-family kinases simultaneously may cause serious adverse effects.

SUMMARY OF THE INVENTION

The present invention provides comounds which inhibit Btk activity, their use for treatment of Btk mediated diseases and disorders, in particular autoimmune diseases and inflammatory diseases, as well as pharmaceutical compositions comprising such compounds and pharmaceutical carriers.

DETAILED DESCRIPTION

The object of the present invention is to provide Bruton's Tyrosine Kinase (Btk) inhibitor compounds, to pharmaceutical compositions comprising these compounds and to their use in therapy. In particular, the present invention relates to the use of Btk inhibitor compounds in the treatment of Btk mediated disorders.

More specifically, the present invention provides Btk inhibitor compounds according to Formula I or pharmaceutically acceptable salts thereof

Formula I, wherein:

Ai, A ₂ , A ₃ , and A4 are independently C, CH, CR ¹¹ or N and bicyclic ring system E- G is selected from the group consisting of:

R is independently selected from the group consisting of: a) deuterium, b) H, c) halogen, d) cyano, e) C¾,

f) COOH, g) C0 ₂ (l-6C)alkyl, h) CO(l-6C)alkyl, i) CO H(l-6C)alkoxy,

J) CO H(l-6C)alkyl, k) CONdi(l-6C)alkyl,

1) (l-6C)alkyl, m) (3-7C)cycloalkyl, n) (l-6C)alkoxy, o) (6-10C)aryl,

P) (l-5C)heteroaryl, q) (2-6C)alkenyl,

(2-6C)alkynyl, and s) (4-7C)heterocycloalkyl,

R ¹¹ is optionally substituted with one or more groups selected from: halogen, (1- 6C)alkyl, (l-5C)alkoxy, hydroxyl, or oxo;

R ¹² is independently selected from the group consisting of H, (l-3C)alkyl, (1- 3C)alkyl HC(0), and (l-3C)alkylOC(0); wherein in aromatic ring K

Bi is N or C(R ⁷ );

B ₂ is N or C(R ⁸ );

B ₃ is N or C(R ⁹ );

B ₄ is N or C(R ¹⁰ );

R ⁷ is H, halogen, OH, (l-3C)alkyl, (l-3C)alkoxy or halo(l-3C)alkyl, CN; any alkoxy may optionally be substituted with one, two or three halogen;

R ⁸ is H, halogen, OH, (l-3C)alkyl, (l-3C)alkoxy or halo(l-3C)alkyl, CN; any alkoxy may optionally be substituted with one, two or three halogen; R ⁹ is H, halogen, OH, (l-3C)alkyl, (l-3C)alkoxy or halo(l-3C)alkyl, CN; any alkoxy may optionally be substituted with one, two or three halogen;

R ¹⁰ is H, halogen, OH, (l-3C)alkyl, (l-3C)alkoxy or halo(l-3C)alkyl, CN; any

alkoxy may optionally be substituted with one, two or three halogen; wherein in heteroaromatic ring L

W is CH or N;

X is CH, N, O or S;

Y is C(R ⁶ ), N, O or S; Z is CH, N or a bond;

R ⁵ is H, halogen, cyano, (l-4C)alkyl, (l-5C)alkoxy, (3-6C)cycloalkyl or (3- 6C)cycloalkoxy; any alkyl, alkoxy, cycloalkyl or cycloalkocy of R ⁵ may optionally be substituted with one, two or three halogen; or R ⁵ is (6-10C)aryl, (1- 5C)heteroaryl or (2-6C)heterocycloalkyl, the aryl or heterocycloalkyl of which may optionally be substituted with halogen, (l-6C)alkyl, (l-3C)alkoxy;

R ⁶ is H, halogen, cyano, (l-6C)alkyl, or (l-6C)alkoxy„ any alkyl or alkoxy of R ⁶ may optionally be substituted with one, two or three halogen or cyano; or

R ⁵ and R ⁶ together can form a carbocyclic or heterocyclic 5 to 6 -membered ring, and optionally be unsaturated or aromatic; or R ⁵ and R ⁶ together can form (3- 7C)cycloalkenyl or (2-6C)heterocycloalkenyl; each optionally substituted with (l-3C)alkyl or with one or more halogen;

Q is C=0 or C(R ^f ) ₂ ;

T is C(R ^e ) ₂ , O, NR ^e , or a bond;

U is C(R ^d ) ₂ , O, or NR ^d ;

V is C(R ^g ) ₂ , O, or a bond;

R ^c , R ^d , R ^e , and R ^f are each independently selected from H, halogen, (l-6C)alkyl, and hydroxyl; any alkyl group of R ^c , R ^d , R ^e , or R ^f may optionally be substituted with hydroxyl; R ^g is independently selected from H, halogen, (l-6C)alkyl, (l-6C)alkoxy, halo(l- 6C)alkyl, and hydroxyl; with the proviso that:

1) up to 2 atoms of X, Y, and Z can simultaneously be a heteroatom;

2) when one atom selected from X, Y is O or S, then Z is a bond and the other atom selected from X, Y cannot be O or S;

3) when Z is CH or N, then Y is C(R ⁶ ) or N and X is C, or N;

4) in ring K, up to 2 of Bi, B ₂ , B ₃ and B ₄ can be N; and

5) when Q is C(R ^f ) ₂ , then T is C(R ^e ) ₂ .

The terms as used herein refer to the following:

Halogen means fluorine, chlorine, bromine or iodine. Fluorine, chlorine or bromine being preferred halogens, fluorine or chlorine being more preferred.

Alkyl means a branched or unbranched alkyl group having the recited number of carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, n-pentyl and n-hexyl. For example, a (l-3C)alkyl means a branched or unbranched alkyl group having 1, 2 or 3 carbon atoms.

Haloalkyl means a branched or unbranched alkyl group having the recited number of carbon atoms, in which one and up to all hydrogen atoms are replaced by a halogen; halogen is as defined herein. Examples of such branched or straight chained haloalkyl groups useful in the present invention include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl and n-butyl substituted independently with one or more halos, e.g., fluoro, chloro, bromo and iodo. For example, a halo(l-3C)alkyl means a branched or unbranched alkyl group having 1, 2, or 3 carbon atoms, in which at least one hydrogen atom is replaced by a halogen. Examples of "haloalkyl" include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, and perfluoro-n-propyl.

Alkoxy means an alkoxy group having the recited number of carbon atoms, the alkyl moiety having the same meaning as previously defined. Alkenyl means a branched or unbranched alkenyl group having the recited number of carbon atoms, such as ethenyl, 2-propenyl, isobutenyl, 2-butenyl, and n-pentenyl. Alkynyl means a branched or unbranched alkynyl group having the recited number of carbon atoms, such as ethynyl, propynyl, 2-propynyl, n-butynyl, 2-butynyl, n- pentynyl, isopentynyl, isohexynyl or n-hexynyl.

Cycloalkyl means a cycloalkyl group having the recited number of carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. cyclopropyl, cyclobutyl, or cyclopentyl;

Heterocycloalkyl means a heterocycloalkyl group having the recited number of carbon atoms, preferably 2-5 carbon atoms, more preferably 3-5 carbon atoms; and one or two heteroatoms selected from N, O and/or S, which may be attached via a heteroatom if feasible, or a carbon atom. Preferred heteroatoms are N or O.

Preferred are piperidine, morpholine, pyrrolidine and piperazine. Most preferred (l-5C)heterocycloalkyl is pyrrolidine. Heterocycloalkyl may be a 4-8 membered monocyclic or 8-10 membered bicyclic ring having 1-5 heteroatoms, the ring being saturated, unsaturated or aromatic. Heterocycloalkyl includes heteroaryl. Heteroaryl is a 5-6 membered monocyclic aromatic ring or a fused bicyclic aromatic ring having 6-10 members, and 1-6 heteroatoms selected from N, O or S. Heterocycloalkyl includes, but is not limited to, (l-5C)Heterocycloalkyl, (1- 6C)Heterocycloalkyl, (2-5C)Heterocycloalkyl, (2-6C)Heterocycloalkyl, and (3- 7C)Heterocycloalkyl. Preferred heteroaryl groups are tetrazolyl, imidazolyl, thiadiazolyl, pyridyl, pyrimidyl, triazinyl, thienyl, furyl, quinoline, isoquinoline and indole .

Aryl means an aromatic hydrocarbon ring having the recited number of carbon atoms, such as phenyl, naphthyl, tetrahydronaphthyl or indenyl. The preferred aryl group is phenyl.

Cycloalkoxy means a cycloalkyl group having the recited number of carbon atoms, with the same meaning as previously defined, attached via a ring carbon atom to an exocyclic oxygen atom, such as cycloproxyl, cyclobutoxyl, or cyclopentoxyl.

Di[alkyl]amino means an amino group, disubstituted with alkyl group(s), each

independently containing the recited number of carbon atoms and having the same meaning as previously defined. Preferred di[alkyl]amino group is dimethylamino.

Hydroxyalkyl means an alkyl group as previously defined, substituted with a hydroxyl group.

Cycloalkenyl means a cycloalkenyl group having the recited number of carbon atoms, preferably 5-7 carbon atoms. Preferred cycloalkenyl groups are cyclopentenyl or cyclohexenyl.

Cycloalkyl(l-4C)alkyl means an alkyl group having 1-4 carbon atoms with the same meaning as previously defined, substituted with a cycloalkyl group having the recited number of carbon atoms as previously defined.

Cycloalkoxy(l-4C)alkyl means an alkyl group having 1-4 carbon atoms with the same meaning as previously defined, substituted with a cycloalkoxy group having the recited number of carbon atoms as previously defined. The cycloalkoxy group is linked via the exocyclic oxygen to the alkyl group.

Aryl(l-6C)alkyl means an alkyl group having 1-6 carbon atoms with the same meaning as previously defined, substituted with a aryl group having the recited number of carbon atoms as previously defined.

Heteroaryl(l-6C)alkyl means an alkyl group having 1-6 carbon atoms with the same meaning as previously defined, substituted with a heteroaryl group having the recited number of carbon atoms as previously defined.

Heterocycloalkyl(l-6C)alkyl means an alkyl group having 1-6 carbon atoms with the same meaning as previously defined, substituted with a heterocycloalkyl group having the recited number of carbon atoms as previously defined.

Alkoxy(l-6C)alkyl means an alkyl group having 1-6 carbon atoms with the same

meaning as previously defined, substituted with an alkoxy group the alkyl moiety of which having the recited number of carbon atoms as previously defined. Examples of "alkoxy alkyl" include, but are not limited to,

methoxymethyl, 1-methoxy ethyl, 2-ethoxy ethyl, and 1, 1-dimethoxy ethyl.

In the above definitions with multifunctional groups, the attachment point is at the last group.

When, in the definition of a substituent, is indicated that "all of the alkyl groups" of said substituent are optionally substituted, this also includes the alkyl moiety of an alkoxy group.

A circle in a ring of Formula I indicates that the ring is aromatic or that it has the requisite number of double bonds to complete the valence.

Depending on the ring formed, the nitrogen, if present in T, U, W, X, Y or Z, may carry a hydrogen.

The term "substituted" means that one or more hydrogens on the designated atom/atoms is/are replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. "Stable compound" or "stable structure" is defined as a compound or structure that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

The term "optionally substituted" means optional substitution with the specified groups, radicals or moieties.

The term pharmaceutically acceptable salt is well known in the art. They may be obtained during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable mineral acid such as hydrochloric acid, phosphoric acid, or sulfuric acid, or with an organic acid such as for example ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid, methanesulfonic acid, and the like. The acid function can be reacted with an organic or a mineral base, like sodium hydroxide, potassium hydroxide or lithium hydroxide.

Aspects of the invention

In one aspect the invention relates to a compound according to Formula I wherein ring K is defined as:

Bi is C(R ⁷ ), B ₂ is C(R ⁸ ), B ₃ is C(R ⁹ ), and B ₄ is C(R ¹⁰ ); or

Bi is N, B ₂ is N, B ₃ is C(R ⁹ ), and B ₄ is C(R ¹⁰ ); or

Bt is N, B ₂ is C(R ⁸ ), B ₃ is N, and B ₄ is C(R ¹⁰ ); or

Bt is N, B ₂ is C(R ⁸ ), B ₃ is C(R ⁹ ), and B ₄ is N; or Bi is C(R ⁷ ), B ₂ is C(R ⁸ ), B ₃ is N, and B ₄ is N; or

Bi is C(R ⁷ ), B ₂ is N, B ₃ is C(R ⁹ ), and B ₄ is N.

In another aspect the invention relates to a compound of Formula I wherein ring K is defined as: Bi is C(R ⁷ ), B ₂ is C(R ⁸ ), B ₃ is C(R ⁹ ), and B ₄ is C(R ¹⁰ ), and wherein R ⁷ , R ⁸ , R ⁹ and R ¹⁰ each are H, halogen, (l-3C)alkyl, (l-3C)alkoxy or halo(l-3C)alkyl; any alkoxy may optionally be substituted one, two or three halogen;

In yet another aspect the invention relates to a compound according to Formula I wherein ring L is selected from the group consisting of pyridyl, pyrimidyl, pyridazyl, triazinyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, thiadiazolyl, and isothiazolyl.

In yet another aspect the invention relates to a compound according to Formula I wherein ring L is selected from the group consisting of pyridyl, pyrimidyl, and thiazolyl. In a preferred aspect, ring L is pyridyl.

In another aspect the invention relates to a compound according to Formula I wherein R ⁵ is selected from the group consisting of hydrogen, fluorine, chlorine, CN, cyclopropyl, cyclobutyl, oxetanyl, (l-3C)alkyl, (1-5C) alkoxy, and (l-5C)cycloalkoxy; the alkyl, alkoxy, cycloalkyl and cycloalkoxy of which are optionally substituted with one or more halogen.

In another aspect the invention relates to a compound according to Formula I wherein R ⁵ is selected from the group consisting of hydrogen, fluorine, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopropoxyl, and trifluoromethyl.

In yet another aspect the invention relates to a compound according to Formula I wherein R ¹¹ is selected from the group consisting of H, ² H, F, CI, Br, Me, C ² H ₃ , ethyl, cyclopropyl and vinyl. Preferably, R ¹¹ is H.

In yet another aspect the invention relates to a compound according to Formula I wherein are C or N and bicyclic ring system E-G is selected from the group consisting

Preferably, is H. In yet another aspect the invention relates to a compound according to Formula I wherein A ₁ -A4 are C or N and bicyclic ring system E-G is

Preferably, is H.

In one aspect the invention relates to a compound having Formula la

Formula la or a pharmaceutically acceptable salt or solvate thereof.

In another aspect the invention relates to a compound having Formula lb

Formula lb

or a pharmaceutically acceptable salt or solvate thereof.

In another aspect the invention relates to a compound having Formula Ic

Formula Ic harmaceutically acceptable salt or solvate thereof. In yet another aspect the invention relates to a compound having Formula Id

Formula Id

or a pharmaceutically acceptable salt or solvate thereof.

The invention also relates to those compounds wherein all specific definitions for Ai-Ae, B!-B ₄ , Q, T, U, V, W, X, Y, Z, R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ^c , R ^d , R ^e , R ^f , and R ^g and all substituent groups in the various aspects of the inventions defined here above occur in any combination within the definition of the Btk inhibitor compounds of Formula I or pharmaceutically acceptable salts thereof.

In still another aspect the invention relates to a compound according to Formula I or a pharmaceutically acceptable salt or solvate thereof selected from the group consisting of :

4-{8-amino-3-[(6S,8aS)-3-oxohexahydro[l,3]oxazolo[3,4-a]pyri din-6-yl]imidazo[l,5- a]pyrazin- 1 -yl } -N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aR)-3-oxohexahydro[l,3]oxazolo[3,4-a]pyri din-6-yl]imidazo[l,5- a]pyrazin- 1 -yl } -N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4- { 8-amino-3 - [(6R, 8aS)-2-methyl-3 -oxooctahydroimidazo [ 1 , 5 -a]pyridin-6- yl]imidazo[l,5-a]pyrazin-l-yl}-N-[4-(trifluoromethyl)pyridin -2-yl]benzamide; 4- { 8-amino-3 - [(6R, 8aS)-3 -oxooctahydroindolizin-6-yl] imidazo [ 1 , 5 -ajpyrazin- 1 -yl } -N- [4-(trifluoromethyl)pyridin-2-yl]benzamide;

4- { 8-amino-3 - [(6R, 8aS)-3 -oxooctahydroindolizin-6-yl] imidazo [ 1 , 5 -ajpyrazin- 1 -yl } -N- [4-(cyclopropyloxy)pyridin-2-yl]benzamide;

4- { 8-amino-3 - [(6R, 8aS)-3 -oxooctahydroindolizin-6-yl] imidazo [ 1 , 5 -ajpyrazin- 1 -yl } -N- pyridin-2-ylbenzamide;

4-{8-amino-3-[(6S,8aR)-3-oxooctahydroindolizin-6-yl]imidazo[ l,5-a]pyrazin-l-yl}-N- (4-cyclobutylpyridin-2-yl)benzamide;

4- { 8-amino-3 - [(6R, 8aS)-3 -oxooctahydroindolizin-6-yl] imidazo [ 1 , 5 -a]pyrazin- 1 -yl } -N- (5 -methyl- 1 , 3 -thiazol-2-yl)benzamide;

4-{8-amino-3-[(6S,8aR)-3-oxooctahydroindolizin-6-yl]imidazo[ l,5-a]pyrazin-l-yl}-N- pyridin-2-ylbenzamide;

4-{8-amino-3-[(6S,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[ l,5-a]pyrazin-l-yl}-N- [4-(trifluoromethyl)pyridin-2-yl]benzamide;

4- { 8-amino-3 - [(6R, 8aR)-3 -oxooctahydroindolizin-6-yl] imidazo [ 1 , 5 -a]pyrazin- 1 -yl } -N- [4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxohexahydro[l,3]oxazolo[3,4-a]pyri din-6-yl]imidazo[l,5- a]pyrazin- 1 -yl } -N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6S,8aR)-3-oxohexahydro[l,3]oxazolo[3,4-a]pyri din-6-yl]imidazo[l,5- a]pyrazin- 1 -yl } -N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4- { 8-amino-3 - [(6R, 8aS)-3 -oxooctahydroindolizin-6-yl] imidazo [ 1 , 5 -a]pyrazin- 1 -yl } -N- [4-(difluoromethyl)pyridin-2-yl]-3-fluorobenzamide;

4- { 8-amino-3 - [(6R, 8aS)-3 -oxooctahydroindolizin-6-yl] imidazo [ 1 , 5 -a]pyrazin- 1 -yl } -N- (4-cyanopyridin-2-yl)-3-fluorobenzamide;

4- { 8-amino-3 - [(6R, 8aS)-3 -oxooctahydroindolizin-6-yl] imidazo [ 1 , 5 -a]pyrazin- 1 -yl } -N- (4-cyclopropylpyridin-2-yl)-3-fluorobenzamide;

4- { 8-amino-3 - [(6R, 8aS)-3 -oxooctahydroindolizin-6-yl] imidazo [ 1 , 5 -a]pyrazin- 1 -yl } -N- [4-(difluoromethyl)pyridin-2-yl]benzamide;

4- { 8-amino-3 - [(6R, 8aS)-3 -oxooctahydroindolizin-6-yl] imidazo [ 1 , 5 -a]pyrazin- 1 -yl } -N- (4-ethylpyridin-2-yl)benzamide;

4- { 8-amino-3 - [(6R, 8aS)-3 -oxooctahydroindolizin-6-yl] imidazo [ 1 , 5 -a]pyrazin- 1 -yl } -N- (4-cyclopropylpyridin-2-yl)benzamide; 4- { 8-amino-3 - [(6R, 8aS)-3 -oxooctahydroindolizin-6-yl] imidazo [ 1 , 5 -a]pyrazin- 1 -yl } -3 - methoxy-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4- { 8-amino-3 - [(6R, 8aS)-3 -oxooctahydroindolizin-6-yl] imidazo [ 1 , 5 -a]pyrazin- 1 -yl } -N- [4-( 1 , 1 -difluoroethyl)pyridin-2-yl] -3 -fluorobenzamide;

4- { 8-amino-3 - [(6R, 8aS)-3 -oxooctahydroindolizin-6-yl] imidazo [ 1 , 5 -a]pyrazin- 1 -yl } -2- methyl-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4- { 8-amino-3 - [(6R, 8aS)-3 -oxooctahydroindolizin-6-yl] imidazo [ 1 , 5 -a]pyrazin- 1 -yl } -3 - fluoro-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4- { 8-amino-3 - [(6R, 8aS)-3 -oxooctahydroindolizin-6-yl] imidazo [ 1 , 5 -a]pyrazin- 1 -yl } -2- fluoro-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4- { 8-amino-3 - [(6R, 8aS)-3 -oxooctahydroindolizin-6-yl] imidazo [ 1 , 5 -a]pyrazin- 1 -yl } -N- [4-(l, l-difluoroethyl)pyridin-2-yl]-2-fluorobenzamide;

4- { 8-amino-3 - [(6R, 8aS)-3 -oxooctahydroindolizin-6-yl] imidazo [ 1 , 5 -a]pyrazin- 1 -yl } -N- [4-(difluoromethyl)pyridin-2-yl]-2-fluorobenzamide;

4- { 8-amino-3 - [(6R, 8aS)-3 -oxooctahydroindolizin-6-yl] imidazo [ 1 , 5 -a]pyrazin- 1 -yl } -N- (4-cyclopropylpyridin-2-yl)-2-fluorobenzamide;

4- { 8-amino-3 - [(6R, 8aS)-3 -oxooctahydroindolizin-6-yl] imidazo [ 1 , 5 -a]pyrazin- 1 -yl } -N- (4-cyclopropylpyridin-2-yl)-2-methylbenzamide;

4- { 8-amino-3 - [(6R, 8aS)-3 -oxooctahydroindolizin-6-yl] imidazo [ 1 , 5 -a]pyrazin- 1 -yl } -N- [4-(3-fluorooxetan-3-yl)pyridin-2-yl]benzamide;

4- { 8-amino-3 - [(6R, 8aS)-3 -oxooctahydroindolizin-6-yl] imidazo [ 1 , 5 -a]pyrazin- 1 -yl } -N- [4-( 1 -fluoro- 1 -methylethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(lR,6R,8aS)-l-methyl-3-oxohexahydro[l,3]oxazol o[3,4-a]pyridin-6- yl]imidazo[ 1 , 5-a]pyrazin- 1 -yl } -3 -fluoro-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(lR,6R,8aS)-l-methyl-3-oxohexahydro[l,3]oxa zolo[3,4-a]pyridin-6- yl]imidazo[ 1 , 5-a]pyrazin- 1 -yl } -N-(4-cyclopropylpyridin-2-yl)-3 -fluorobenzamide;

4-{8-amino-3-[(l S,6R,8aS)-l-methyl-3-oxohexahydro[l,3]oxazolo[3,4-a]pyridin- 6- yl]imidazo[ 1 , 5-a]pyrazin- 1 -yl } -3 -fluoro-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4- { 8-amino-3 - [(6R, 8aS)-3 -oxooctahydroindolizin-6-yl] imidazo [ 1 , 5 -a]pyrazin- 1 -yl } -N- (4-cyanopyridin-2-yl)-2-fluorobenzamide;

4- { 8-amino-3 - [(6R, 8aS)-3 -oxooctahydroindolizin-6-yl] imidazo [ 1 , 5 -a]pyrazin- 1 -yl } -N- (4-cyanopyridin-2-yl)-3-methoxybenzamide; 4- { 8-amino-3 - [(6R, 8aS)-3 -oxooctahydroindolizin-6-yl] imidazo [ 1 , 5 -ajpyrazin- 1 -yl } -N (4-cyanopyridin-2-yl)-2-methylbenzamide;

4-{8-amino-3-[(l S,6R,8aS)-l-methyl-3-oxohexahydro[l,3]oxazolo[3,4-a]pyridin- 6- yl]imidazo[ 1 , 5-a]pyrazin- 1 -yl } -N-(4-cyclopropylpyridin-2-yl)-3 -fluorobenzamide;

4- { 8-amino-3 - [(6R, 8aS)-3 -oxooctahydroindolizin-6-yl] imidazo [ 1 , 5 -ajpyrazin- 1 -yl } -N (4-cyclopropylpyridin-2-yl)-3-methoxybenzamide;

4- { 8-amino-3 - [(7R, 9aS)-4-oxooctahydropyrido [2, 1 -c] [ 1 ,4]oxazin-7-yl] imidazo [1,5- a]pyrazin-l-yl}-3-fluoro-N-[4-(trifluoromethyl)pyridin-2-yl] benzamide;

4- { 8-amino-3 - [(7R, 9aS)-4-oxooctahydro-2H-pyrido [ 1 ,2-a]pyrazin-7-yl] imidazo [1,5- a]pyrazin- 1 -yl } -N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4- { 8-amino-3 - [(7 S, 9aR)-4-oxooctahydro-2H-pyrido [ 1 ,2-a]pyrazin-7-yl] imidazo [1,5- a]pyrazin- 1 -yl } -N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4- { 8-amino-3 - [(6R, 8aS)-3 -oxooctahydroindolizin-6-yl] imidazo [ 1 , 5 -ajpyrazin- 1 -yl } -2- chloro-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4- { 8-amino-3 - [(6R, 8aS)-3 -oxooctahydroindolizin-6-yl] imidazo [ 1 , 5 -a]pyrazin- 1 -yl } -N [4-(cyclopropyloxy)pyridin-2-yl]-3-fluorobenzamide;

4-{8-amino-3-[(3S,9aS)-6-oxooctahydro-2H-quinolizin-3-yl]imi dazo[l,5-a]pyrazin-l- yl}-3-fluoro-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(3R,9aR)-6-oxooctahydro-2H-quinolizin-3-yl]imi dazo[l,5-a]pyrazin-l- yl}-3-fluoro-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(l S,6R,8aS)-l-methyl-3-oxohexahydro[l,3]oxazolo[3,4-a]pyridin- 6- yl]imidazo[ 1 , 5-a]pyrazin- 1 -yl } -N-(4-cyclopropylpyridin-2-yl)benzamide;

4-{8-amino-3-[(lR,6R,8aS)-l-methyl-3-oxohexahydro[l,3]oxazol o[3,4-a]pyridin-6- yl]imidazo[ 1 , 5-a]pyrazin- 1 -yl } -N-(4-cyclopropylpyridin-2-yl)benzamide;

4-{8-amino-3-[(l S,6R,8aS)-l-methyl-3-oxohexahydro[l,3]oxazolo[3,4-a]pyridin- 6- yl]imidazo[l,5-a]pyrazin-l-yl}-N-[4-(trifluoromethyl)pyridin -2-yl]benzamide;

4-{8-amino-3-[(lR,6R,8aS)-l-methyl-3-oxohexahydro[l,3]oxazol o[3,4-a]pyridin-6- yl]imidazo[l,5-a]pyrazin-l-yl}-N-[4-(trifluoromethyl)pyridin -2-yl]benzamide;

4-{8-amino-3-[(7R,9aS)-2-methyl-4-oxooctahydro-2H-pyrido[l,2 -a]pyrazin-7- yl]imidazo[l,5-a]pyrazin-l-yl}-N-[4-(trifluoromethyl)pyridin -2-yl]benzamide;

4-{8-amino-3-[(7S,9aR)-2-methyl-4-oxooctahydro-2H-pyrido[l,2 -a]pyrazin-7- yl]imidazo[l,5-a]pyrazin-l-yl}-N-[4-(trifluoromethyl)pyridin -2-yl]benzamide; 4-{8-amino-3-[(6R,8aS)-l, l-dimethyl-3-oxohexahydro[l,3]oxazolo[3,4-a]pyridin-6- yl]imidazo[l,5-a]pyrazin-l-yl}-N-[4-(trifluoromethyl)pyridin -2-yl]benzamide;

4-{8-amino-3-[(lR,6R,8aS)-l-methyl-3-oxohexahydro[l,3]oxazol o[3,4-a]pyridin-6- yl]imidazo[ 1 , 5-a]pyrazin- 1 -yl } -N-(4-cyclopropylpyridin-2-yl)-3 -methoxybenzamide;

4- { 8-amino-3 - [(7R, 9aR)-4-oxooctahydro-2H-pyrido [ 1 ,2-a]pyrazin-7-yl] imidazo [1,5- ajpyrazin- 1 -yl } -N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(7R,9aS)-octahydropyrido[2, l-c][l,4]oxazin-7-yl]imidazo[l,5-a]pyrazin l-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(7S,9aR)-octahydropyrido[2, l-c][l,4]oxazin-7-yl]imidazo[l,5-a]pyrazin l-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4- { 8-amino-3 - [(7 S, 9aS)-4-oxooctahydro-2H-pyrido [ 1 ,2-a]pyrazin-7-yl] imidazo [1,5- a]pyrazin- 1 -yl } -N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4- { 8-amino-3 - [(2 S, 6 S, 8aR)-2-hydroxy-3 -oxooctahydroindolizin-6-yl] imidazo [1,5- a]pyrazin- 1 -yl } -N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4- { 8-amino-3 - [(2R, 6R, 8aS)-2-hydroxy-3 -oxooctahydroindolizin-6-yl] imidazo [1,5- ajpyrazin- 1 -yl } -N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4- { 8-(methylamino)-3 -[(6R, 8aS)-3 -oxooctahydroindolizin-6-yl] imidazo [ 1 , 5-a]pyrazin- l-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4- { 8- [(ethylcarbamoyl)amino] -3 - [(6R, 8aS)-3 -oxooctahydroindolizin-6-yl] imidazo [1,5- ajpyrazin- 1 -yl } -N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4- { 8-amino-3 - [( 1 R, 6R, 8aS)- 1 -methyl-3 -oxooctahydroindolizin-6-yl] imidazo [1,5- a]pyrazin- 1 -yl } -N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4- { 8-amino-3 - [( 1 S, 6R, 8aR)- 1 -methyl-3 -oxooctahydroindolizin-6-yl] imidazo [1,5- ajpyrazin- 1 -yl } -N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4- { 8-amino-3 - [( 1 S, 6R, 8aR)- 1 -methyl-3 -oxooctahydroindolizin-6-yl] imidazo [1,5- a]pyrazin- 1 -yl } -N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4- { 8-amino-3 - [( 1 R, 6R, 8aS)- 1 -methyl-3 -oxooctahydroindolizin-6-yl] imidazo [1,5- ajpyrazin- 1 -yl } -N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(7R,9aS)-2-(2-hydroxyethyl)-4-oxooctahydro-2H- pyrido[l,2-a]pyrazin- 7-yl] imidazo [ 1 , 5 -ajpyrazin- 1 -yl } -N- [4-(trifluoromethyl)pyridin-2-yl]benzamide;

4- { 8-amino-3 - [(2R, 6 S, 8aR)-2-hydroxy-3 -oxooctahydroindolizin-6-yl] imidazo [1,5- a]pyrazin- 1 -yl } -N-[4-(trifluoromethyl)pyridin-2-yl]benzamide; 4- { 8-amino-3 - [(2 S, 6R, 8aS)-2-hydroxy-3 -oxooctahydroindolizin-6-yl] imidazo [1,5- a]pyrazin- 1 -yl } -N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4- { 8-amino-3 - [(6R, 8aS)-3 -oxooctahydroindolizin-6-yl] imidazo [ 1 , 5 -a]pyrazin- 1 -yl } -3 - ethoxy-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(3R,7R,9aS)-3-methyl-4-oxooctahydropyrido[2, l-c][l,4]oxazin-7- yl]imidazo[l,5-a]pyrazin-l-yl}-N-[4-(trifluoromethyl)pyridin -2-yl]benzamide;

4- { 8-amino-3 - [(6R, 8aS)-3 -oxooctahydroindolizin-6-yl] imidazo [ 1 , 5 -a]pyrazin- 1 -yl } -3 - (benzyloxy)-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4- { 8-amino-3 - [(6R, 8aS)-3 -oxooctahydroindolizin-6-yl] imidazo [ 1 , 5 -a]pyrazin- 1 -yl } -3 - (difluoromethoxy)-N-[4-(trifluoromethyl)pyridin-2-yl]benzami de;

4- { 8-amino-3 - [(2 S, 6R, 8aR)-2-hydroxy-3 -oxooctahydroindolizin-6-yl] imidazo [1,5- a]pyrazin- 1 -yl } -N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4- { 8-amino-3 - [(2R, 6 S, 8aS)-2-hydroxy-3 -oxooctahydroindolizin-6-yl] imidazo [1,5- a]pyrazin- 1 -yl } -N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

methyl { 3 - [(6R, 8aS)-3 -oxooctahydroindolizin-6-yl] - 1 -(4- { [4-(trifluoromethyl)pyridin- 2-yl] carbamoyl } phenyl)imidazo [ 1 , 5 -a]pyrazin-8-yl } carbamate;

4- { 8-amino-3 - [(2R, 6 S, 8aS)-2-hydroxy-3 -oxooctahydroindolizin-6-yl] imidazo [1,5- a]pyrazin- 1 -yl } -N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4- { 8-amino-3 - [(2 S, 6R, 8aR)-2-hydroxy-3 -oxooctahydroindolizin-6-yl] imidazo [1,5- a]pyrazin- 1 -yl } -N-[4-(trifluoromethyl)pyridin-2-yl]benzamide; and

4-{8-amino-3-[(6R,8aR)-3-oxotetrahydro-lH-[l,3]oxazolo[4,3-c ][l,4]oxazin-6- yl]imidazo[l,5-a]pyrazin-l-yl}-N-[4-(trifluoromethyl)pyridin -2-yl]benzamide.

In still another aspect the invention relates to:

4- { 8-amino-3 - [(6R, 8aS)-3 -oxooctahydroindolizin-6-yl] imidazo [ 1 , 5 -a]pyrazin- 1 -yl } -N- [4-(trifluoromethyl)pyridin-2-yl]benzamide;

4- { 8-amino-3 - [(6R, 8aS)-3 -oxooctahydroindolizin-6-yl] imidazo [ 1 , 5 -a]pyrazin- 1 -yl } -N- (4-cyclopropylpyridin-2-yl)-3-fluorobenzamide;

4- { 8-amino-3 - [(6R, 8aS)-3 -oxooctahydroindolizin-6-yl] imidazo [ 1 , 5 -a]pyrazin- 1 -yl } -N- (4-cyclopropylpyridin-2-yl)benzamide;

4- { 8-amino-3 - [(6R, 8aS)-3 -oxooctahydroindolizin-6-yl] imidazo [ 1 , 5 -a]pyrazin- 1 -yl } -3 - methoxy-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide; 4- { 8-amino-3 - [(6R, 8aS)-3 -oxooctahydroindolizin-6-yl] imidazo [ 1 , 5 -a]pyrazin- 1 -yl } -3 - fluoro-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(lR,6R,8aS)-l-methyl-3-oxohexahydro[l,3]oxazol o[3,4-a]pyridin-6- yl]imidazo[ 1 , 5-a]pyrazin- 1 -yl } -3 -fluoro-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4- { 8-amino-3 - [(7R, 9aS)-4-oxooctahydropyrido [2, 1 -c] [ 1 ,4]oxazin-7-yl] imidazo [1,5- a]pyrazin-l-yl}-3-fluoro-N-[4-(trifluoromethyl)pyridin-2-yl] benzamide;

4-{8-amino-3-[(3S,9aS)-6-oxooctahydro-2H-quinolizin-3-yl]imi dazo[l,5-a]pyrazin-l- yl}-3-fluoro-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(7R,9aS)-2-methyl-4-oxooctahydro-2H-pyrido[l,2 -a]pyrazin-7- yl]imidazo[l,5-a]pyrazin-l-yl}-N-[4-(trifluoromethyl)pyridin -2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-l, l-dimethyl-3-oxohexahydro[l,3]oxazolo[3,4-a]pyridin-6- yl]imidazo[l,5-a]pyrazin-l-yl}-N-[4-(trifluoromethyl)pyridin -2-yl]benzamide;

4-{8-amino-3-[(7R,9aS)-octahydropyrido[2, l-c][l,4]oxazin-7-yl]imidazo[l,5-a]pyrazin- l-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4- { 8-amino-3 - [(6R, 8aS)-3 -oxooctahydroindolizin-6-yl] imidazo [ 1 , 5 -a]pyrazin- 1 -yl } -3 - ethoxy-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(3R,7R,9aS)-3-methyl-4-oxooctahydropyrido[2, l-c][l,4]oxazin-7- yl]imidazo[l,5-a]pyrazin-l-yl}-N-[4-(trifluoromethyl)pyridin -2-yl]benzamide; and

4- { 8-amino-3 - [(6R, 8aS)-3 -oxooctahydroindolizin-6-yl] imidazo [ 1 , 5 -a]pyrazin- 1 -yl } -3 - (difluoromethoxy)-N-[4-(trifluoromethyl)pyridin-2-yl]benzami de.

In another aspect the invention relates to:

4- { 8-amino-3 - [(6R, 8aS)-3 -oxooctahydroindolizin-6-yl] imidazo [ 1 , 5 -a]pyrazin- 1 -yl } -N- [4-(trifluoromethyl)pyridin-2-yl]benzamide;

4- { 8-amino-3 - [(6R, 8aS)-3 -oxooctahydroindolizin-6-yl] imidazo [ 1 , 5 -a]pyrazin- 1 -yl } -N- (4-cyclopropylpyridin-2-yl)-3-fluorobenzamide;

4- { 8-amino-3 - [(6R, 8aS)-3 -oxooctahydroindolizin-6-yl] imidazo [ 1 , 5 -a]pyrazin- 1 -yl } -N- (4-cyclopropylpyridin-2-yl)benzamide;

4- { 8-amino-3 - [(6R, 8aS)-3 -oxooctahydroindolizin-6-yl] imidazo [ 1 , 5 -a]pyrazin- 1 -yl } -3 - methoxy-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(7R,9aS)-2-methyl-4-oxooctahydro-2H-pyrido[l,2 -a]pyrazin-7- yl]imidazo[l,5-a]pyrazin-l-yl}-N-[4-(trifluoromethyl)pyridin -2-yl]benzamide; and 4-{8-amino-3-[(3R,7R,9aS)-3-methyl-4-oxooctahydropyrido[2, l-c][l,4]oxazin-7- yl]imidazo[l,5-a]pyrazin-l-yl}-N-[4-(trifluoromethyl)pyridin -2-yl]benzamide.

The Btk inhibitor compounds of the invention having Formula I inhibit the Btk kinase activity. All compounds of the invention have an EC50 of 10 μΜ or lower. In another aspect the invention relates to compounds of Formula I which have an EC50 of less than 100 nM. In yet another aspect the invention relates to compounds of Formula I which have an EC50 of less than 10 nM.

The term EC50 means the concentration of the test compound that is required for 50% inhibition of its maximum effect in vitro.

In another aspect the invention relates to compounds of Formula I or

pharmaceutically acceptable salts thereof, which have an IC50 of less than 100 nM. In yet another aspect the invention relates to the compounds of Formula I or

pharmaceutically acceptable salts thereof, which have an IC50 of less than 10 nM.

The term IC50 means the concentration of the test compound that is required for 50% inhibition of its maximum effect in vitro.

BTK enzymatic activity was determined with the LANCE (Lanthanide Chelate Excite) TR-FRET (Time-resolved fluorescence resonance energy transfer) assay. In this assay, the potency (IC ₅₀ ) of each compound was determined from an eleven point (1 :3 serial dilution; final compound concentration range in assay from 1 μΜ to 0.017 nM) titration curve using the following outlined procedure. To each well of a black non- binding surface Corning 384-well microplate (Corning Catalog #3820), 5 nL of compound (2000 fold dilution in final assay volume of 10 ιΏ) was dispensed, followed by the addition of 7.5 μΐ, of lx kinase buffer (50 mM Hepes 7.5, 10 mM MgCl ₂ , 0.01% Brij-35, 1 mM EGTA, 0.05% BSA & 1 mM DTT) containing 10.18 pg/μΐ, (133.3 pM) of BTK enzyme (recombinant protein from baculovirus-transfected S/9 cells: full-length BTK, 6HIS-tag cleaved). Following a 60 minute compound & enzyme incubation, each reaction was initiated by the addition of 2.5 μΙ_, lx kinase buffer containing 8 μΜ biotinylated "A5" peptide (Biotin-EQEDEPEGDYFEWLE-NH2), and 100 μΜ ATP. The final reaction in each well of 10 μ consists of 100 pM ΛΒΤΚ, 2 μΜ biotin-A5- peptide, and 25 μΜ ATP. Phosphorylation reactions were allowed to proceed for 120 minutes. Reactions were immediately quenched by the addition of 20 uL of lx quench buffer (15 mM EDTA, 25 mM Hepes 7.3, and 0.1% Triton X-100) containing detection reagents (0.626 nM of LANCE-Eu-W1024-anti-phospho Tyrosine antibody, PerkinElmer and 86.8 nM of Streptavidin-conjugated Dylight 650, Dyomics/ThermoFisher Scientific). After 60 minutes incubation with detection reagents, reaction plates were read on a PerkinElmer En Vision plate reader using standard TR- FRET protocol. Briefly, excitation of donor molecules (Eu-chelate:anti-phospho- antibody) with a laser light source at 337 nm produces energy that can be transferred to Dylight-650 acceptor molecules if this donor: acceptor pair is within close proximity. Fluorescence intensity at both 665 nm (acceptor) and 615 nm (donor) are measured and a TR-FRET ratio calculated for each well (acceptor intensity/donor intensity). IC ₅₀ values were determined by 4 parameter robust fit of TR-FRET ratio values vs. (Log ₁₀ ) compound concentrations.

The Btk activity can also be determined in B cell lines such as Ramos cells or in primary cell assays, e.g. PBMC or whole blood from human, monkey, rat or mouse or isolated splenocytes from monkey, rat or mouse. Inhibition of Btk activity can be investigated measuring anti-IgM-induced ΜΙΡΙβ production (Ramos, PBMC, splenocytes), H ₂ 0 ₂ -induced Btk and PLCy2 phosphorylation (Ramos cells), or anti- IgM-induced B cell proliferation or CD86 expression on primary B cells (PBMC and splenocytes).

Regulation of Btk activity can also be determined on human, monkey, rat or mouse mast cells following activation FcsR induced degranulation, cytokine production and CD63 induced cell surface expression.

Furthermore, regulation of Btk activity can be determined on CD 14+ monocytes differentiated following treatment with M-CSF to osteoclasts and activated with

RANKL.

Activity of Btk inhibitors can be investigated in mouse splenocytes following administration in vivo. In a typical experiment mice can be euthanized 3h following compound administration. Spleens can be extracted from the treated mice for splenocyte isolation. Splenocytes can be plated in 96 well culture plates and stimulated with anti- IgM, without further addition of compounds. Anti-IgM-induced B cell stimulation and inhibition thereof by Btk inhibitors can be measured by B cell proliferation, ΜΙΡΙβ production or CD86 expression on CD 19+ splenocyte B cells. Efficacy of Btk inhibitors can also be investigated in the mouse collagen induced arthritis model using a therapeutic protocol with start of treatment following onset of disease, measuring disease score, X-ray analysis of bone destruction, cartilage breakdown and histology of joints

Efficacy of Btk inhibitors on the regulation of activated mast cells can be investigated in vivo using the passive cutaneous anaphylaxis model.

The effect of Btk inhibitors on bone resorption in vivo can be investigated using the rat OVX model. In this model ovariectomized animals develop symptoms of osteoporosis that may be regulated using a Btk inhibitor.

The compounds of Formula I can form salts which are also within the scope of this invention. Reference to a compound of Formula (I) herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of Formula (I) contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. Such acidic and basic salts used within the scope of the invention are pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts. Salts of the compounds of Formula (I) may be formed, for example, by reacting a compound of Formula (I) with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates,

benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates,

camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like. Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley- VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The

Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The

Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference.

Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others.

The compounds of Formula I may have the ability to crystallize in more than one form, a characteristic known as polymorphism, and it is understood that such

polymorphic forms ("polymorphs") are within the scope of Formula I. Polymorphism generally can occur as a response to changes in temperature or pressure or both and can also result from variations in the crystallization process. Polymorphs can be

distinguished by various physical characteristics known in the art such as x-ray diffraction patterns, solubility and melting point.

The compounds of Formula I may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of Formula I as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention embraces all geometric and positional isomers. For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.

Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g. chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g. hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of Formula I may be atropisomers (e.g. substituted biaryls) and are considered as part of this invention.

Enantiomers can also be separated by use of chiral HPLC column.

It is also possible that the compounds of Formula I may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.

All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers. Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms "salt", "solvate", "ester",

"prodrug" and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.

A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in

Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American

Pharmaceutical Association and Pergamon Press. The term "prodrug" means a compound (e.g, a drug precursor) that is transformed in vivo to yield a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (e.g. by metabolic or chemical processes), such as, for example, through hydrolysis in blood. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

The compounds having Formula I or the pharmaceutically acceptable salts or solvates thereof may form hydrates or solvates. It is known to those of skill in the art that charged compounds form hydrated species when lyophilized with water, or form solvated species when concentrated in a solution with an appropriate organic solvent. The compounds of this invention include the hydrates or solvates of the compounds listed.

One or more compounds of the invention having Formula I or the

pharmaceutically acceptable salts or solvates thereof may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. "Solvate" means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. "Hydrate" is a solvate wherein the solvent molecule is H ₂ 0.

In the compounds of Formula I, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of generic Formula I. For example, different isotopic forms of hydrogen (H) include protium (1H) and deuterium ( ² H). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. Isotopically- enriched compounds within generic Formula I can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.

Certain isotopically-labelled compounds of Formula I (e.g. those labeled with ³ H and ¹⁴ C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., ³ H) and carbon- 14 (i.e., ¹⁴ C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ² H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labelled compounds of Formula I can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herinbelow, by substituting an appropriate isotopically labeled reagent for a non-isotopically labeled reagent.

The compounds having Formula I and pharmaceutical compositions thereof can be used to treat or prevent a variety of conditions, diseases or disorders mediated by Bruton's Tyrosine kinase (Btk). Such conditions, diseases or disorders include, but are not limited to: (1) arthritis, including rheumatoid arthritis, juvenile arthritis, psoriatic arthritis and osteoarthritis; (2) asthma and other obstructive airways diseases, including chronic asthma, late asthma, airway hyper-responsiveness, bronchitis, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, adult respiratory distress syndrome, recurrent airway obstruction, and chronic obstruction pulmonary disease including emphysema; (3) autoimmune diseases or disorders, including those designated as single organ or single cell-type autoimmune disorders, for example Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis of pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis,

Goodpasture's disease, autoimmune thrombocytopenia including idiopathic

thrombopenic purpura, sympathetic ophthalmia, myasthenia gravis, Graves' disease, primary biliary cirrhosis, chronic aggressive hepatitis, ulcerative colitis and

membranous glomerulopathy, those designated as involving systemic autoimmune disorder, for example systemic lupus erythematosis, immune thrombocytopenic purpura, rheumatoid arthritis, Sjogren's syndrome, Reiter's syndrome, polymyositis- dermatomyositis, systemic sclerosis, polyarteritis nodosa, multiple sclerosis and bullous pemphigoid, and additional autoimmune diseases, which can be B-cell (humoral) based or T-cell based, including Cogan's syndrome, ankylosing spondylitis, Wegener's granulomatosis, autoimmune alopecia, Type I or juvenile onset diabetes, and thyroiditis; (4) cancers or tumors, including alimentary/gastrointestinal tract cancer, colon cancer, liver cancer, skin cancer including mast cell tumor and squamous cell carcinoma, breast and mammary cancer, ovarian cancer, prostate cancer, lymphoma and leukemia

(including but not limited to acute myelogenous leukemia, chronic myelogenous leukemia, mantle cell lymphoma, NHL B cell lymphomas (e.g. precursor B-ALL, marginal zone B cell lymphoma, chronic lymphocytic leukemia, diffuse large B cell lymphoma, Burkitt lymphoma, mediastinal large B-cell lymphoma), Hodgkin lymphoma, NK and T cell lymphomas; TEL-Syk and ITK-Syk fusion driven tumors, myelomas including multiple myeloma, myeloproliferative disorders kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer, brain cancer, melanoma including oral and metastatic melanoma, Kaposi's sarcoma, proliferative diabetic retinopathy, and angiogenic-associated disorders including solid tumors, and pancreatic cancer; (5) diabetes, including Type I diabetes and complications from diabetes; (6) eye diseases, disorders or conditions including autoimmune diseases of the eye,

keratoconjunctivitis, vernal conjunctivitis, uveitis including uveitis associated with Behcet's disease and lens-induced uveitis, keratitis, herpetic keratitis, conical keratitis, corneal epithelial dystrophy, keratoleukoma, ocular premphigus, Mooren's ulcer, scleritis, Grave's ophthalmopathy, Vogt-Koyanagi-Harada syndrome,

keratoconjunctivitis sicca (dry eye), phlyctenule, iridocyclitis, sarcoidosis, endocrine ophthalmopathy, sympathetic ophthalmitis, allergic conjunctivitis, and ocular neovascularization; (7) intestinal inflammations, allergies or conditions including Crohn's disease and/or ulcerative colitis, inflammatory bowel disease, coeliac diseases, proctitis, eosinophilic gastroenteritis, and mastocytosis; (8) neurodegenerative diseases including motor neuron disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, or neurodegenerative disease caused by traumatic injury, strike, glutamate neurotoxicity or hypoxia; ischemic/ reperfusion injury in stroke, myocardial ischemica, renal ischemia, heart attacks, cardiac hypertrophy, atherosclerosis and arteriosclerosis, organ hypoxia; (9) platelet aggregation and diseases associated with or caused by platelet activation, such as arteriosclerosis, thrombosis, intimal hyperplasia and restenosis following vascular injury; (10) conditions associated with cardiovascular diseases, including restenosis, acute coronary syndrome, myocardial infarction, unstable angina, refractory angina, occlusive coronary thrombus occurring post-thrombolytic therapy or post-coronary angioplasty, a thrombotically mediated cerebrovascular syndrome, embolic stroke, thrombotic stroke, transient ischemic attacks, venous thrombosis, deep venous thrombosis, pulmonary embolus, coagulopathy, disseminated intravascular coagulation, thrombotic

thrombocytopenic purpura, thromboangiitis obliterans, thrombotic disease associated with heparin-induced thrombocytopenia, thrombotic complications associated with extracorporeal circulation, thrombotic complications associated with instrumentation such as cardiac or other intravascular catheterization, intra-aortic balloon pump, coronary stent or cardiac valve, conditions requiring the fitting of prosthetic devices, and the like; (11) skin diseases, conditions or disorders including atopic dermatitis, eczema, psoriasis, scleroderma, pruritus and other pruritic conditions; (12) allergic reactions including anaphylaxis, allergic rhinitis, allergic dermatitis, allergic urticaria, angioedema, allergic asthma, or allergic reaction to insect bites, food, drugs, or pollen; (13) transplant rejection, including pancreas islet transplant rejection, bone marrow transplant rejection, graft- versus-host disease, organ and cell transplant rejection such as bone marrow, cartilage, cornea, heart, intervertebral disc, islet, kidney, limb, liver, lung, muscle, myoblast, nerve, pancreas, skin, small intestine, or trachea, and xeno transplantation; (14) low grade scarring including scleroderma, increased fibrosis, keloids, post-surgical scars, pulmonary fibrosis, vascular spasms, migraine, reperfusion injury, and post-myocardial infarction.

The invention thus provides compounds of Formula (I) and salts, solvates and physiologically functional derivatives thereof for use in therapy, and particularly in the treatment of diseases and conditions mediated by inappropriate Btk activity.

The inappropriate Btk activity referred to herein is any Btk activity that deviates from the normal Btk activity expected in a particular mammalian subject. Inappropriate Btk activity may take the form of, for instance, an abnormal increase in activity, or an aberration in the timing and or control of Btk activity. Such inappropriate activity may result then, for example, from overexpression or mutation of the protein kinase leading to inappropriate or uncontrolled activation.

In a further embodiment, the present invention is directed to methods of regulating, modulating, or inhibiting Btk for the prevention and/or treatment of disorders related to unregulated or inappropriate Btk activity.

In a further embodiment, the present invention provides a method of treatment of a mammal suffering from a disorder mediated by Btk activity, which comprises administering to said mammal an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, or a physiologically functional derivative thereof.

In a further embodiment, the present invention provides for the use of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a

physiologically functional derivative thereof, in the preparation of a medicament for the treatment of a disorder mediated by Btk activity.

In a further embodiment said disorder mediated by Btk activity is asthma. In a further embodiment said disorder is rheumatoid arthritis. In yet another embodiment, said disorder is cancer. In a further embodiment said disorder is ocular conjunctivitis.

Yet another aspect of the present invention provides a method for treating diseases caused by or associated with Fc receptor signaling cascades, including FceRI and/or FcgRI-mediated degranulation as a therapeutic approach towards the treatment or prevention of diseases characterized by, caused by and/or associated with the release or synthesis of chemical mediators of such Fc receptor signaling cascades or degranulation. In addition, Btk is known to play a critical role in immunotyrosine-based activation motif (IT AM) singaling, B cell receptor signaling, T cell receptor signaling and is an essential component of integrin beta (1), beta (2), and beta (3) signaling in neutrophils. Thus, compounds of the present invention can be used to regulate Fc receptor, IT AM, B cell receptor and integrin signaling cascades, as well as the cellular responses elicited through these signaling cascades. Non-limiting examples of cellular responses that may be regulated or inhibited include respiratory burst, cellular adhesion, cellular

degranulation, cell spreading, cell migration, phagocytosis, calcium ion flux, platelet aggregation and cell maturation. A further aspect of the invention resides in the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament to be used for the treatment of Btk-mediated diseases or Btk-mediated conditions.

A further aspect of the invention resides in the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament to be used for the treatment of chronic B cell disorders in which T cells play a prominent role.

In yet another aspect the invention resides in the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament to be used for the treatment of Btk-mediated diseases or conditions. These include, but are not limited to, the treatment of B cell lymphomas resulting from chronic active B cell receptor signaling.

Thus, the compounds according to the invention may be used in therapies to treat or prevent diseases Bruton's Tyrosine Kinase (Btk) mediated disorders. Btk mediated disorders or Btk mediated condition as used herein, mean any disease state or other deleterious condition in which B cells, mast cells, myeloid cells or osteoclasts play a central role. These diseases include but are not limited to, immune, autoimmune and inflammatory diseases, allergies, infectious diseases, bone resorption disorders and proliferative diseases.

Immune, autoimmune and inflammatory diseases that may be treated or prevented with the compounds of the present invention include rheumatic diseases (e.g.

rheumatoid arthritis, psoriatic arthritis, infectious arthritis, progressive chronic arthritis, deforming arthritis, osteoarthritis, traumatic arthritis, gouty arthritis, Reiter's syndrome, polychondritis, acute synovitis and spondylitis), glomerulonephritis (with or without nephrotic syndrome), Goodpasture's syndrome, (and associated glomerulonephritis and pulmonary hemorrhage), atherosclerosis, autoimmune hematologic disorders (e.g.

hemolytic anemia, aplasic anemia, idiopathic thrombocytopenia, chronic idiopathic thrombocytopenic purpura (ITP), and neutropenia), autoimmune gastritis, and autoimmune inflammatory bowel diseases (e.g. ulcerative colitis and Crohn's disease), irritable bowel syndrome, host versus graft disease, allograft rejection, chronic thyroiditis, Graves' disease, Sjorgren's disease, scleroderma, diabetes (type I and type II), active hepatitis (acute and chronic), pancreatitis, primary billiary cirrhosis, myasthenia gravis, multiple sclerosis, systemic lupus erythematosis, psoriasis, atopic dermatitis, dermatomyositis, contact dermatitis, eczema, skin sunburns, vasculitis (e.g. Behcet's disease), ANCA-associated and other vasculitudes, chronic renal insufficiency, Stevens- Johnson syndrome, inflammatory pain, idiopathic sprue, cachexia, sarcoidosis, Guillain-Barre syndrome, uveitis, conjunctivitis, kerato conjunctivitis, otitis media, periodontal disease, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock, myasthenia gravis, pulmonary interstitial fibrosis, asthma, bronchitis, rhinitis, sinusitis, pneumoconiosis, pulmonary insufficiency syndrome, pulmonary emphysema, pulmonary fibrosis, silicosis, chronic inflammatory pulmonary disease (e.g. chronic obstructive pulmonary disease) and other inflammatory or obstructive disease on airways.

Allergies that may be treated or prevented include, among others, allergies to foods, food additives, insect poisons, dust mites, pollen, animal materials and contact allergans, type I hypersensitivity allergic asthma, allergic rhinitis, allergic conjunctivitis.

Infectious diseases that may be treated or prevented include, among others, sepsis, septic shock, endotoxic shock, sepsis by Gram-negative bacteria, shigellosis, meningitis, cerebral malaria, pneumonia, tuberculosis, viral myocarditis, viral hepatitis (hepatitis A, hepatitis B and hepatitis C), HIV infection, retinitis caused by cytomegalovirus, influenza, herpes, treatment of infections associated with severe burns, myalgias caused by infections, cachexia secondary to infections, and veterinary viral infections such as lentivirus, caprine arthritic virus, visna-maedi virus, feline immunodeficiency virus, bovine immunodeficiency virus or canine immunodeficiency virus.

Bone resorption disorders that may be treated or prevented include, among others, osteoporosis, osteoarthritis, traumatic arthritis, gouty arthritis and bone disorders related with multiple myeloma.

Proliferative diseases that may be treated or prevented include, among others, non-Hodgkin lymphoma (in particular the subtypes diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL)), B cell chronic lymphocytic leukemia and acute lymphoblastic leukemia (ALL) with mature B cell, ALL in particular.

In particular the compounds of Formula I or pharmaceutically acceptable salts may be used for the treatment of B cell lymphomas resulting from chronic active B cell receptor signaling. Included herein are methods of treatment and/ or pharmaceutical compositions in which at least one compound of Formula I or a pharmaceutically acceptable salt thereof is administered in combination with at least one other active agent. The other active agent is an anti-inflammatory agent, an immunosuppressant agent, or a

chemotherapeutic agent. Anti-inflammatory agents include but are not limited to NSAIDs, non-specific and COX-2 specific cyclooxgenase enzyme inhibitors, gold compounds, corticosteroids, methotrexate, tumor necrosis factor receptor (TNF) receptors antagonists, immunosuppressants and methotrexate.

Examples of NSAIDs include, but are not limited to, ibuprofen, flurbiprofen, naproxen and naproxen sodium, diclofenac, combinations of diclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal, piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen, sodium nabumetone, sulfasalazine, tolmetin sodium, and hydroxychloroquine. Examples of NSAIDs also include COX-2 specific inhibitors such as celecoxib, valdecoxib, lumiracoxib and/or etoricoxib.

In some embodiments, the anti-inflammatory agent is a salicylate. Salicylates include by are not limited to acetylsalicylic acid or aspirin, sodium salicylate, and choline and magnesium salicylates.

The anti-inflammatory agent may also be a corticosteroid. For example, the corticosteroid may be cortisone, dexamethasone, methylprednisolone, prednisolone, prednisolone sodium phosphate, or prednisone.

In additional embodiments the anti-inflammatory agent is a gold compound such as gold sodium thiomalate or auranofin.

The invention also includes embodiments in which the anti-inflammatory agent is a metabolic inhibitor such as a dihydrofolate reductase inhibitor, such as methotrexate or a dihydroorotate dehydrogenase inhibitor, such as leflunomide.

Other embodiments of the invention pertain to combinations in which at least one anti-inflammatory agent is an anti-C5 monoclonal antibody (such as eculizumab or pexelizumab), a TNF antagonist, such as entanercept, or infliximab, which is an anti- TNF alpha monoclonal antibody.

Still other embodiments of the invention pertain to combinations in which at least one active agent is an immunosuppressant agent, such as an immunosuppressant compound chosen from methotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine, and mycophenolate mofetil.

B-cells and B-cell precursors expressing BTK have been implicated in the pathology of B-cell malignancies, including, but not limited to, B-cell lymphoma, lymphoma (including Hodgkin's and non-Hodgkin's lymphoma), hairy cell lymphoma, multiple myeloma, chronic and acute myelogenous leukemia and chronic and acute lymphocytic leukemia.

BTK has been shown to be an inhibitor of the Fas/APO-1 (CD-95) death inducing signaling complex (DISC) in B-lineage lymphoid cells. The fate of leukemia/lymphoma cells may reside in the balance between the opposing proapoptotic effects of caspases activated by DISC and an upstream anti-apoptotic regulatory mechanism involving BTK and/or its substrates (Vassilev et al, J. Biol. Chem. 1998, 274, 1646-1656).

It has also been discovered that BTK inhibitors are useful as chemosensitizing agents, and, thus, are useful in combination with other chemotherapeutic agents, in particular, drugs that induce apoptosis. Examples of other chemotherapeutic agents that can be used in combination with chemosensitizing BTK inhibitors include

topoisomerase I inhibitors (camptothecin or topotecan), topoisomerase II inhibitors (e.g. daunomycin and etoposide), alkylating agents (e.g. cyclophosphamide, melphalan and BCNU), tubulin directed agents (e.g. taxol and vinblastine), and biological agents (e.g. antibodies such as anti CD20 antibody, IDEC 8, immunotoxins, and cytokines).

Btk activity has also been associated with some leukemias expressing the bcr-abl fusion gene resulting from translocation of parts of chromosome 9 and 22. This abnormality is commonly observed in chronic myelogenous leukemia. Btk is constitutively phosphorylated by the bcr-abl kinase which initiates downstream survival signals which circumvents apoptosis in bcr-abl cells. (N. Feldhahn et al. J. Exp. Med. 2005 201(11): 1837-1852).

While it is possible that, for use in therapy, a compound of Formula (I), as well as salts, solvates and physiological functional derivatives thereof, may be administered as the raw chemical, it is possible to present the active ingredient as a pharmaceutical composition. Accordingly, the invention further provides a pharmaceutical composition, which comprises a compound of Formula (I) and salts, solvates and physiological functional derivatives thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. The compounds of the Formula (I) and salts, solvates and physiological functional derivatives thereof, are as described above. The carrier(s), diluent(s) or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. In accordance with another aspect of the invention there is also provided a process for the preparation of a pharmaceutical composition including admixing a compound of the Formula (I), or salts, solvates and physiological functional derivatives thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients.

Pharmaceutical compositions of the present invention may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Such a unit may contain, for example, 5μg to 1 g, preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg of a compound of the Formula (I), depending on the condition being treated, the route of administration and the age, weight and condition of the patient. Such unit doses may therefore be administered more than once a day. Preferred unit dosage compositions are those containing a daily dose or sub-dose (for administration more than once a day), as herein above recited, or an appropriate fraction thereof, of an active ingredient. Furthermore, such pharmaceutical compositions may be prepared by any of the methods well known in the pharmacy art.

Pharmaceutical compositions of the present invention may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, topical, inhaled, nasal, ocular, sublingual, subcutaneous, local or parenteral (including intravenous and intramuscular) route, and the like, all in unit dosage forms for administration. Such compositions may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s). Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.

In a further embodiment, the present invention provides a pharmaceutical composition adapted for administration by the oral route, for treating, for example, rheumatoid arthritis.

In a further embodiment, the present invention provides a pharmaceutical composition adapted for administration by the nasal route, for treating, for example, allergic rhinitis. In a further embodiment, the present invention provides a pharmaceutical composition adapted for administration by the inhaled route, for treating, for example, asthma, Chronic Obstructive Pulmonary disease (COPD) or Acute Respiratory Distress Syndrome (ARDS).

In a further embodiment, the present invention provides a pharmaceutical composition adapted for administration by the ocular route, for treating, diseases of the eye, for example, conjunctivitis.

In a further embodiment, the present invention provides a pharmaceutical composition adapted for administration by the parenteral (including intravenous) route, for treating, for example, cancer.

For parenteral administration, the pharmaceutical composition of the invention may be presented in unit-dose or multi-dose containers, e.g. injection liquids in predetermined amounts, for example in sealed vials and ampoules, and may also be stored in a freeze dried (lyophilized) condition requiring only the addition of sterile liquid carrier, e.g. water, prior to use.

Mixed with such pharmaceutically acceptable auxiliaries, e.g. as described in the standard reference, Gennaro, A.R. et al, Remington: The Science and Practice of Pharmacy (20th Edition., Lippincott Williams & Wilkins, 2000, see especially Part 5: Pharmaceutical Manufacturing), the active agent may be compressed into solid dosage units, such as pills, tablets, or be processed into capsules or suppositories. By means of pharmaceutically acceptable liquids the active agent can be applied as a fluid composition, e.g. as an injection preparation, in the form of a solution, suspension, emulsion, or as a spray, e.g. a nasal spray.

For making solid dosage units, the use of conventional additives such as fillers, colorants, polymeric binders and the like is contemplated. In general any pharmaceutically acceptable additive which does not interfere with the function of the active compounds can be used. Suitable carriers with which the active agent of the invention can be administered as solid compositions include lactose, starch, cellulose derivatives and the like, or mixtures thereof, used in suitable amounts. For parenteral administration, aqueous suspensions, isotonic saline solutions and sterile injectable solutions may be used, containing pharmaceutically acceptable dispersing agents and/or wetting agents, such as propylene glycol or butylene glycol. Pharmaceutical compositions of the present invention which are adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.

For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agent can also be present.

Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin sheaths. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation. A disintegrating or solubilizing agent such as agar- agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate,

carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets. A powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen. As an alternative to granulating, the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil. The lubricated mixture is then compressed into tablets. The compounds of the present invention can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps. A clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.

Oral fluids such as solution, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like can also be added.

Where appropriate, dosage unit compositions for oral administration can be microencapsulated. The formulation can also be prepared to prolong or sustain the release, for example, by coating or embedding particulate material in polymers, wax or the like.

The compounds of Formula (I), and salts, solvates and physiological functional derivatives thereof, can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

The compounds of Formula (I) and salts, solvates and physiological functional derivatives thereof may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide- phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.

Dosage forms for inhaled administration may conveniently be formulated as aerosols or dry powders.

For compositions suitable and/or adapted for inhaled administration, it is preferred that the compound or salt of Formula (I) is in a particle-size-reduced form, and more preferably the size-reduced form is obtained or obtainable by micronisation. The preferable particle size of the size-reduced (e.g. micronised) compound or salt or solvate is defined by a D50 value of about 0.5 to about 10 microns (for example as measured using laser diffraction).

Aerosol formulations, e.g. for inhaled administration, can comprise a solution or fine suspension of the active substance in a pharmaceutically acceptable aqueous or non-aqueous solvent. Aerosol formulations can be presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device or inhaler. Alternatively the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve (metered dose inhaler) which is intended for disposal once the contents of the container have been exhausted.

Where the dosage form comprises an aerosol dispenser, it preferably contains a suitable propellant under pressure such as compressed air, carbon dioxide or an organic propellant such as a hydrofluorocarbon (F£FC). Suitable HFC propellants include 1, 1, 1,2,3,3,3-heptafluoropropane and 1, 1, 1,2-tetrafluoroethane. The aerosol dosage forms can also take the form of a pump-atomiser. The pressurised aerosol may contain a solution or a suspension of the active compound. This may require the incorporation of additional excipients e.g. co-solvents and/or surfactants to improve the dispersion characteristics and homogeneity of suspension formulations. Solution formulations may also require the addition of co-solvents such as ethanol. Other excipient modifiers may also be incorporated to improve, for example, the stability and/or taste and/or fine particle mass characteristics (amount and/or profile) of the formulation.

For pharmaceutical compositions suitable and/or adapted for inhaled

administration, it is preferred that the pharmaceutical composition is a dry powder inhalable composition. Such a composition can comprise a powder base such as lactose, glucose, trehalose, mannitol or starch, the compound of Formula (I) or salt or solvate thereof (preferably in particle-size-reduced form, e.g. in micronised form), and optionally a performance modifier such as L-leucine or another amino acid, and/or metals salts of stearic acid such as magnesium or calcium stearate. Preferably, the dry powder inhalable composition comprises a dry powder blend of lactose and the compound of Formula (I) or salt thereof. The lactose is preferably lactose hydrate e.g. lactose monohydrate and/or is preferably inhalation-grade and/or fine-grade lactose. Preferably, the particle size of the lactose is defined by 90% or more (by weight or by volume) of the lactose particles being less than 1000 microns (micrometres) (e.g. 10- 1000 microns e.g. 30-1000 microns) in diameter, and/or 50% or more of the lactose particles being less than 500 microns (e.g. 10-500 microns) in diameter. More preferably, the particle size of the lactose is defined by 90% or more of the lactose particles being less than 300 microns (e.g. 10-300 microns e.g. 50-300 microns) in diameter, and/or 50% or more of the lactose particles being less than 100 microns in diameter. Optionally, the particle size of the lactose is defined by 90% or more of the lactose particles being less than 100-200 microns in diameter, and/or 50% or more of the lactose particles being less than 40-70 microns in diameter. It is preferable that about 3 to about 30%) (e.g. about 10%) (by weight or by volume) of the particles are less than 50 microns or less than 20 microns in diameter. For example, without limitation, a suitable inhalation-grade lactose is E9334 lactose (10% fines) (Borculo Domo

Ingredients, Hanzeplein 25, 8017 J D Zwolle, Netherlands).

Optionally, in particular for dry powder inhalable compositions, a pharmaceutical composition for inhaled administration can be incorporated into a plurality of sealed dose containers (e.g. containing the dry powder composition) mounted longitudinally in a strip or ribbon inside a suitable inhalation device. The container is rupturable or peel- openable on demand and the dose of e.g. the dry powder composition can be

administered by inhalation via the device such as the DISKUS® device(GlaxoSmithKline). Other dry powder inhalers are well known to those of ordinary skill in the art, and many such devices are commercially available, with representative devices including Aerolizer® (Novartis), Airmax™ (IV AX),

ClickHaler® (Innovata Biomed), Diskhaler® (GlaxoSmithKline), Accuhaler

(GlaxoSmithKline), Easyhaler® (Orion Pharma), Eclipse™ (Aventis), FlowCaps® (Hovione), Handihaler® (Boehringer Ingelheim), Pulvinal® (Chiesi), Rotahaler® (GlaxoSmithKline), SkyeHaler™ or Certihaler™ (SkyePharma), Twisthaler (Schering- Plough), Turbuhaler® (AstraZeneca), Ultrahaler® (Aventis), and the like.

Dosage forms for ocular administration may be formulated as solutions or suspensions with excipients suitable for ophthalmic use.

Dosage forms for nasal administration may conveniently be formulated as aerosols, solutions, drops, gels or dry powders.

Pharmaceutical compositions adapted for administration by inhalation include fine particle dusts or mists, which may be generated by means of various types of metered, dose pressurized aerosols, nebulizers or insufflators.

For pharmaceutical compositions suitable and/or adapted for intranasal

administration, the compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof may be formulated as a fluid formulation for delivery from a fluid dispenser. Such fluid dispensers may have, for example, a dispensing nozzle or dispensing orifice through which a metered dose of the fluid formulation is dispensed upon the application of a user-applied force to a pump mechanism of the fluid dispenser. Such fluid dispensers are generally provided with a reservoir of multiple metered doses of the fluid formulation, the doses being dispensable upon sequential pump actuations. The dispensing nozzle or orifice may be configured for insertion into the nostrils of the user for spray dispensing of the fluid formulation into the nasal cavity. A fluid dispenser of the aforementioned type is described and illustrated in WO-A-2005/044354, the entire content of which is hereby incorporated herein by reference. The dispenser has a housing which houses a fluid discharge device having a compression pump mounted on a container for containing a fluid formulation. The housing has at least one finger- operable side lever which is movable inwardly with respect to the housing to cam the container upwardly in the housing to cause the pump to compress and pump a metered dose of the formulation out of a pump stem through a nasal nozzle of the housing. A particularly preferred fluid dispenser is of the general type illustrated in FIGS. 30-40 of WO-A-2005/044354.

The invention further includes a pharmaceutical composition of a compound of Formula I or pharmaceutically acceptable salts thereof, as hereinbefore described, in combination with packaging material suitable for said composition, said packaging material including instructions for the use of the composition for the use as hereinbefore described.

The following are examples of representative pharmaceutical dosage forms for the compounds of this invention:

Injectable Suspension (I.M.) mg/ml

Compound of Formula I 10

Methylcellulose 5.0

Tween 80 0.5

Benzyl alcohol 9.0

Benzalkonium chloride 1.0

Water for injection to a total volume of 1 ml

Tablet mg/tablet

Compound of Formula I 25

Microcrystalline Cellulose 415

Providone 14.0

Pregelatinized Starch 43.5

Magnesium Stearate 2.5

500

Capsule mg/capsule

Compound of Formula I 25

Lactose Powder 573.5

Magnesium Stearate 1.5

600 Aerosol Per canister

Compound of Formula I 24 mg

Lecithin, F Liquid Concentrate 1.2 mg

Trichlorofluoromethane, NF 4.025 gm

Dichlorodifluoromethane, NF 12.15 gm

It will be appreciated that when the compound of the present invention is administered in combination with other therapeutic agents normally administered by the inhaled, intravenous, oral or intranasal route, that the resultant pharmaceutical composition may be administered by the same routes.

It should be understood that in addition to the ingredients particularly mentioned above, the compositions may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

A therapeutically effective amount of a compound of the present invention will depend upon a number of factors including, for example, the age and weight of the animal, the precise condition requiring treatment and its severity, the particular compound having Formula I, the nature of the formulation, and the route of

administration, and will ultimately be at the discretion of the attendant physician or veterinarian. However, an effective amount of a compound of Formula (I) for the treatment of diseases or conditions associated with inappropriate Btk activity, will generally be in the range of 5 μg to 100 mg/kg body weight of recipient (mammal) per day and more usually in the range of 5 μg to 10 mg/kg body weight per day. This amount may be given in a single dose per day or more usually in a number (such as two, three, four, five or six) of sub-doses per day such that the total daily dose is the same. An effective amount of a salt or solvate, thereof, may be determined as a proportion of the effective amount of the compound of Formula (I) per se.

In general parenteral administration requires lower dosages than other methods of administration which are more dependent upon absorption. However, a dosage for humans preferably contains 0.0001-25 mg of a compound of Formula I or

pharmaceutically acceptable salts thereof per kg body weight. The desired dose may be presented as one dose or as multiple subdoses administered at appropriate intervals throughout the day, or, in case of female recipients, as doses to be administered at appropriate daily intervals throughout the menstrual cycle. The dosage as well as the regimen of administration may differ between a female and a male recipient.

The present invention also relates to a pharmaceutical composition comprising a compound of Formula I or pharmaceutically acceptable salt thereof in admixture with pharmaceutically acceptable auxiliaries and optionally other therapeutic agents. The auxiliaries must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof.

The invention further includes a pharmaceutical composition comprising at least one compound of Formula I or pharmaceutically acceptable salts thereof in combination with at least one other therapeutically active agent.

Compounds of the present invention, and their salts and solvates, and

physiologically functional derivatives thereof, may be employed alone or in

combination with other therapeutic agents for the treatment of Btk mediated diseases and conditions associated with inappropriate Btk activity. Combination therapies according to the present invention thus comprise the administration of at least one compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a physiologically functional derivative thereof, and the use of at least one other pharmaceutically active agent. The compound(s) of Formula (I) and the other pharmaceutically active agent(s) may be administered together or separately and, when administered separately this may occur simultaneously or sequentially in any order. The amounts of the compound(s) of Formula (I) and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.

For the treatment of the inflammatory diseases, rheumatoid arthritis, psoriasis, inflammatory bowel disease, COPD, asthma and allergic rhinitis a compound of Formula I may be combined with one or more other active agents such as: (1) T F-a inhibitors such as infliximab (Remicade®), etanercept (Enbrel®), adalimumab

(Humira®), certolizumab pegol (Cimzia®), and golimumab (Simponi®); (2) nonselective COX-I/COX-2 inhibitors (such as piroxicam, diclofenac, propionic acids such as naproxen, flubiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, etodolac, azapropazone, pyrazolones such as phenylbutazone, salicylates such as aspirin); (3) COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib and etoricoxib); (4) other agents for treatment of rheumatoid arthritis including methotrexate, leflunomide, sulfasalazine, azathioprine, cyclosporin, tacrolimus, penicillamine, bucillamine, actarit, mizoribine, lobenzarit, ciclesonide, hydroxychloroquine, d-penicillamine, aurothiomalate, auranofin or parenteral or oral gold, cyclophosphamide, Lymphostat-B, BAFF/ APRIL inhibitors and CTLA-4-Ig or mimetics thereof; (5) leukotriene biosynthesis inhibitor, 5 -lipoxygenase (5-LO) inhibitor or 5 -lipoxygenase activating protein (FLAP) antagonist such as zileuton; (6) LTD4 receptor antagonist such as zafirlukast, montelukast and pranlukast; (7) PDE4 inhibitor such as roflumilast, cilomilast, AWD- 12-281 (Elbion), and PD- 168787 (Pfizer); (8) antihistaminic HI receptor antagonists such as cetirizine, levocetirizine, loratadine, desloratadine, fexofenadine, astemizole, azelastine, levocabastine, olopatidine, methapyrilene and chlorpheniramine; (9) al- and a2- adrenoceptor agonist vasoconstrictor sympathomimetic agent, such as propylhexedrine, phenylephrine, phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, and ethylnorepinephrine hydrochloride; (10) anticholinergic agents such as ipratropium bromide, tiotropium bromide, oxitropium bromide, aclindinium bromide, glycopyrrolate, (R,R)-glycopyrrolate, pirenzepine, and telenzepine; (11) β-adrenoceptor agonists such as metaproterenol, isoproterenol, isoprenaline, albuterol, formoterol (particularly the fumarate salt), salmeterol (particularly the xinafoate salt), terbutaline, orciprenaline, bitolterol mesylate, fenoterol, and pirbuterol, or methylxanthanines including theophylline and aminophylline, sodium cromoglycate; (12) insulin-like growth factor type I (IGF-1) mimetic; (13) glucocorticosteroids, especially inhaled glucocorticoid with reduced systemic side effects, such as prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide and mometasone furoate; (14) kinase inhibitors such as inhibitors of the Janus Kinases (JAK 1 and/or JAK2 and/or JAK 3 and/or TYK2), p38 MAPK and IKK2; (15) B-cell targeting biologies such as rituximab (Rituxan®); (16) selective costimulation modulators such as abatacept (Orencia); (17) interleukin inhibitors, such as IL-1 inhibitor anakinra (Kineret) and IL-6 inhibitor tocilizumab (Actemra). The present invention also provides for "triple combination" therapy, comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof together with beta2-adrenoreceptor agonist and an anti-inflammatory corticosteroid. Preferably this combination is for treatment and/or prophylaxis of asthma, COPD or allergic rhinitis. The beta2-adrenoreceptor agonist and/or the anti-inflammatory corticosteroid can be as described above and/or as described in WO 03/030939 Al . Representative examples of such a "triple" combination are a compound of Formula (I) or a pharmaceutically acceptable salt thereof in combination with the components of Advair® (salmeterol xinafoate and fluticasone propionate), Symbicort® (budesonide and formoterol fumarate), or Dulera® (mometasone furoate and formoterol).

For the treatment of cancer a compound of Formula I may be combined with one or more of an anticancer agents. Examples of such agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (editors), 6 ^th edition (February 15, 2001), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer involved. Such anti-cancer agents include, but are not limited to, the following: (1) estrogen receptor modulator such as diethylstibestral, tamoxifen, raloxifene, idoxifene, LY353381, LY117081, toremifene, fluoxymestero, and SH646; (2) other hormonal agents including aromatase inhibitors (e.g., aminoglutethimide, tetrazole anastrozole, letrozole and exemestane), luteinizing hormone release hormone (LURH) analogues, ketoconazole, goserelin acetate, leuprolide, megestrol acetate and mifepristone; (3) androgen receptor modulator such as finasteride and other 5a-reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole, and abiraterone acetate; (4) retinoid receptor modulator such as bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid, a-difluoromethylornithine, ILX23-7553, trans-N-(4'-hydroxyphenyl) retinamide, and N-4-carboxyphenyl retinamide; (5) antiproliferative agent such asantisense RNA and DNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and INX3001, and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin, doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine, cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed, paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine, 2 ' -deoxy-2 ' -methylidenecytidine, 2 ' -fluoromethylene-2 ' -deoxycytidine, N6-[4-deoxy-4-[N2-[2(E),4(E)-tetradecadienoyl]glycylamino]-L -glycero-B-L-manno- heptopyranosyl]adenine, aplidine, ecteinascidin, troxacitabine, aminopterin, 5- flurouracil, floxuridine, methotrexate, leucovarin, hydroxyurea, thioguanine (6-TG), mercaptopurine (6-MP), cytarabine, pentostatin, fludarabine phosphate, cladribine (2- CDA), asparaginase, gemcitabine, alanosine, swainsonine, lometrexol, dexrazoxane, methioninase, and 3-aminopyridine-2-carboxaldehyde thiosemicarbazone; (6) prenyl - protein transferase inhibitor including farnesyl-protein transferase (FPTase), geranylgeranyl-protein transferase type I (GGPTase-I), and geranylgeranyl-protein transferase type-II (GGPTase-II, also called Rab GGPTase); (7) HMG-CoA reductase inhibitor such as lovastatin, simvastatin, pravastatin, atorvastatin, fluvastatin and rosuvastatin; (8) angiogenesis inhibitor such as inhibitors of the tyrosine kinase receptors Flt-1 (VEGFRl) and Flk-l/KDR (VEGFR2), inhibitors of epidermal-derived, fibroblast-derived, or platelet derived growth factors, MMP (matrix metalloprotease) inhibitors, integrin blockers, interferon-a, interleukin-12, erythropoietin (epoietin-a), granulocyte-CSF (filgrastin), granulocyte, macrophage-CSF (sargramostim), pentosan polysulfate, cyclooxygenase inhibitors, steroidal anti-inflammatories,

carboxyamidotriazole, combretastatin A-4, squalamine, 6-O-chloroacetyl-carbonyl)- fumagillol, thalidomide, angiostatin, troponin- 1, angiotensin II antagonists, heparin, carboxypeptidase U inhibitors, and antibodies to VEGF, endostatin, ukrain, ranpirnase, IM862, acetyldinanaline, 5 -amino- 1 - [ [3 , 5 -dichloro-4-(4-chlorobenzoyl)phenyl] methyl] - lH-l,2,3-triazole-4-carboxamide,CM101, squalamine, combretastatin, RPI4610, NX31838, sulfated mannopentaose phosphate, and 3-[(2,4-dimethylpyrrol-5- yl)methylene]-2-indolinone (SU5416); (9) PPAR-γ agonists, PPAR-δ agonists, thiazolidinediones (such as DRF2725, CS-011, troglitazone, rosiglitazone, and pioglitazone), fenofibrate, gemfibrozil, clofibrate, GW2570, SB219994, AR-H039242, JTT-501, MCC-555, GW2331, GW409544, NN2344, KRP297, P0110, DRF4158, NN622, GI262570, PNU182716, DRF552926, 2-[(5,7-dipropyl-3-trifluoromethyl-l,2- benzisoxazol-6-yl)oxy]-2-methylpropionic acid (disclosed in USSN 09/782,856), and (2R)-7-(3-(2-chloro-4-(4-fluorophenoxy)phenoxy)propoxy)-2-et hylchromane-2- carboxylic acid (disclosed in USSN 60/235,708 and 60/244,697); (9) inhibitor of inherent multidrug resistance including inhibitors of p-glycoprotein (P-gp), such as LY335979, XR9576, OC144-093, R101922, VX853 and PSC833 (valspodar); (10) inhibitor of cell proliferation and survival signaling such as inhibitors of EGFR (for example gefitinib and erlotinib), inhibitors of ERB-2 (for example trastuzumab), inhibitors of IGF1R such as MK-0646 (dalotuzumab), inhibitors of CD20 (rituximab), inhibitors of cytokine receptors, inhibitors of MET, inhibitors of PI3K family kinase (for example LY294002), serine/threonine kinases (including but not limited to inhibitors of Akt such as described in (WO 03/086404, WO 03/086403, WO 03/086394, WO

03/086279, WO 02/083675, WO 02/083139, WO 02/083140 and WO 02/083138), inhibitors of Raf kinase (for example BAY-43-9006 ), inhibitors of MEK (for example CI- 1040 and PD-098059) and inhibitors of mTOR (for example Wyeth CCI-779 and Ariad AP23573); (11) a bisphosphonate such as etidronate, pamidronate, alendronate, risedronate, zoledronate, ibandronate, incadronate or cimadronate, clodronate, EB-1053, minodronate, neridronate, piridronate and tiludronate; (12) γ-secretase inhibitors, (13) agents that interfere with receptor tyrosine kinases (RTKs) including inhibitors of c-Kit, Eph, PDGF, Flt3 and c-Met; (14) agent that interferes with a cell cycle checkpoint including inhibitors of ATR, ATM, the Chkl and Chk2 kinases and cdk and cdc kinase inhibitors and are specifically exemplified by 7-hydroxystaurosporin, flavopiridol, CYC202 (Cyclacel) and BMS-387032; (15) BTK inhibitors such as PCI32765, AVL- 292 and AVL-101; (16) PARP inhibitors including iniparib, olaparib, AGO 14699, ABT888 and MK4827; (16) ERK inhibitors; (17) mTOR inhibitors such as sirolimus, ridaforolimus, temsirolimus, everolimus; (18) cytotoxic/cyto static agents.

"Cytotoxic/cyto static agents" refer to compounds which cause cell death or inhibit cell proliferation primarily by interfering directly with the cell's functioning or inhibit or interfere with cell mytosis, including alkylating agents, tumor necrosis factors, intercalators, hypoxia activatable compounds, microtubule inhibitors/microtubule- stabilizing agents, inhibitors of mitotic kinesins, inhibitors of histone deacetylase, inhibitors of kinases involved in mitotic progression, antimetabolites; biological response modifiers; hormonal/anti-hormonal therapeutic agents, haematopoietic growth factors, monoclonal antibody targeted therapeutic agents, topoisomerase inhibitors, proteasome inhibitors and ubiquitin ligase inhibitors.

Examples of cytotoxic agents include, but are not limited to, sertenef, cachectin, chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine, melphalan, uracil mustard, thiotepa, busulfan, carmustine, lomustine, streptozocin, tasonermin, lonidamine, carboplatin, altretamine, dacarbazine, procarbazine, prednimustine, dibromodulcitol, ranimustine, fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine, improsulfan tosilate, trofosfamide, nimustine, dibrospidium chloride, pumitepa, lobaplatin, satraplatin, profiromycin, cisplatin, irofulven,

dexifosfamide, cis-aminedichloro(2-methyl-pyridine)platinum, benzylguanine, glufosfamide, GPXIOO, (trans, trans, trans)-bis-mu-(hexane-l,6-diamine)-mu-[diamine- platinum(II)]bis[diamine(chloro)platinum (II)]tetrachloride, diarizidinylspermine, arsenic trioxide, 1 -( 11 -dodecylamino- 10-hydroxyundecyl)-3 , 7-dimethylxanthine, zorubicin, doxorubicin, daunorubicin, idarubicin, anthracenedione, bleomycin, mitomycin C, dactinomycin, plicatomycin, bisantrene, mitoxantrone, pirarubicin, pinafide, valrubicin, amrubicin, antineoplaston, 3'-deamino-3'-morpholino-13-deoxo- 10-hydroxycarminomycin, annamycin, galarubicin, elinafide, MEN10755, and 4- demethoxy-3-deamino-3-aziridinyl-4-methylsulphonyl-daunorubi cin.

An example of a hypoxia activatable compound is tirapazamine.

Examples of proteasome inhibitors include but are not limited to lactacystin and bortezomib.

Examples of microtubule inhibitors/microtubule-stabilising agents include vincristine, vinblastine, vindesine, vinzolidine, vinorelbine, vindesine sulfate, 3',4'- didehydro-4'-deoxy-8'-norvincaleukoblastine, podophyllotoxins (e.g., etoposide (VP- 16) and teniposide (VM-26)), paclitaxel, docetaxol, rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin, RPR109881, BMS 184476, vinflunine, cryptophycin, anhydrovinblastine, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L- proline-t-butylamide, TDX258, the epothilones (see for example U.S. Pat. Nos.

6,284,781 and 6,288,237) and BMS 188797.

Some examples of topoisomerase inhibitors are topotecan, hycaptamine, irinotecan, rubitecan, 6-ethoxypropionyl-3 ',4'-0-exo-benzylidene-chartreusin, lurtotecan, 7-[2-(N-isopropylamino)ethyl]-(20S)camptothecin, B P1350, BNPIl lOO, BN80915, BN80942, etoposide phosphate, teniposide, sobuzoxane, 2'-dimethylamino- 2'-deoxy-etoposide, GL331, N-[2-(dimethylamino)ethyl]-9-hydroxy-5,6-dimethyl-6H- pyrido [4,3 -b] carbazole- 1 -carboxamide, asulacrine, 2,3 -(methylenedioxy)-5 -methyl-7- hydroxy-8-methoxybenzo[c]-phenanthridinium, 5-(3-aminopropylamino)-7, 10- dihydroxy-2-(2-hydroxy ethylaminomethyl)-6H-pyrazolo [4, 5 , 1 -de] acridin-6-one, N- [ 1 - [2-(diethylamino)ethylamino]-7-methoxy-9-oxo-9H hioxanthen-4-ylmethyl]formami N-(2-(dimethylamino)ethyl)acridine-4-carboxamide, 6-[[2-(dimethylamino)- ethyl]amino]-3-hydroxy-7H-indeno[2, l-c]quinolin-7-one, and dimesna.

Examples of inhibitors of mitotic kinesins include, but are not limited to inhibitors of KSP, inhibitors of MKLP1, inhibitors of CE P-E, inhibitors of MCAK, inhibitors of Kifl4, inhibitors of Mphosphl and inhibitors of Rab6-KIFL.

Examples of "histone deacetylase inhibitors" include, but are not limited to, vorinostat, trichostatin A, oxamflatin, PXD101, MG98, valproic acid and scriptaid.

"Inhibitors of kinases involved in mitotic progression" include, but are not limited to, inhibitors of aurora kinase, inhibitors of Polo-like kinases (PLK; in particular inhibitors of PLK- 1), inhibitors of bub- 1 and inhibitors of bub-Rl . An example of an "aurora kinase inhibitor" is VX-680.

"Antiproliferative agents" includes antisense RNA and DNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and INX3001, and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin, doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine, cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed, paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine, 2 ' -deoxy-2 ' -methylidenecytidine, 2 ' -fluoromethylene-2 ' -deoxycytidine, N6-[4-deoxy-4-[N2-[2,4-tetradecadienoyl]glycylamino]-L-glyce ro-B-L-manno- heptopyranosyl]adenine, aplidine, ecteinascidin, troxacitabine, aminopterin, 5- flurouracil, floxuridine, methotrexate, leucovarin, hydroxyurea, thioguanine (6-TG), mercaptopurine (6-MP), cytarabine, pentostatin, fludarabine phosphate, cladribine (2- CDA), asparaginase, gemcitabine, alanosine, swainsonine, lometrexol, dexrazoxane, methioninase, and 3-aminopyridine-2-carboxaldehyde thiosemicarbazone.

Non-limiting examples of suitable agents used in cancer therapy that may be combined with compounds of Formula I include, but are not limited to, abarelix;

aldesleukin; alemtuzumab; alitretinoin; allopurinol; altretamine; amifostine; anastrozole; arsenic trioxide; asparaginase; azacitidine; bendamustine; bevacuzimab; bexarotene; bleomycin; bortezomib; busulfan; calusterone; capecitabine; carboplatin; carmustine; cetuximab; chlorambucil; cisplatin; cladribine; clofarabine; cyclophosphamide;

cytarabine; dacarbazine; dactinomycin, actinomycin D; dalteparin; darbepoetin alfa; dasatinib; daunorubicin; degarelix; denileukin diftitox; dexrazoxane; docetaxel; doxorubicin; dromostanolone propionate; eculizumab; Elliott's B Solution; eltrombopag; epirubicin; epoetin alfa; erlotinib; estramustine; etoposide phosphate; etoposide;

everolimus; exemestane; filgrastim; floxuridine; fludarabine; fluorouracil; fulvestrant; gefitinib; gemcitabine; gemtuzumab ozogamicin; goserelin acetate; histrelin acetate; hydroxyurea; ibritumomab tiuxetan; idarubicin; ifosfamide; imatinib mesylate;

interferon alfa 2a; interferon alfa-2b; irinotecan; ixabepilone; lapatinib; lenalidomide; letrozole; leucovorin; leuprolide acetate; levamisole; lomustine; meclorethamine, nitrogen mustard; megestrol acetate; melphalan, L-PAM; mercaptopurine; mesna;

methotrexate; methoxsalen; mitomycin C; mitotane; mitoxantrone; nandrolone phenpropionate; nelarabine; nilotinib; Nofetumomab; ofatumumab; oprelvekin;

oxaliplatin; paclitaxel; palifermin; pamidronat; panitumumab; pazopanib; pegademase; pegaspargase; Pegfilgrastim; pemetrexed disodium; pentostatin; pipobroman; plerixafor; plicamycin, mithramycin); porfimer sodium; pralatrexate; procarbazine; quinacrine; Rasburicase; raloxifene hydrochloride; Rituximab; romidepsin; romiplostim;

sargramostim; sargramostim; satraplatin; sorafenib; streptozocin; sunitinib maleate; tamoxifen; temozolomide; temsirolimus; teniposide; testolactone; thioguanine; thiotepa; topotecan; toremifene; tositumomab; trastuzumab; tretinoin; uracil mustard; valrubicin; vinblastine; vincristine; vinorelbine; vorinostat; and zoledronate.

It will be clear to a person skilled in the art that, where appropriate, the other therapeutic ingredient(s) may be used in the form of salts, for example as alkali metal or amine salts or as acid addition salts, or prodrugs, or as esters, for example lower alkyl esters, or as solvates, for example hydrates, to optimise the activity and/or stability and/or physical characteristics, such as solubility, of the therapeutic ingredient. It will be clear also that, where appropriate, the therapeutic ingredients may be used in optically pure form.

The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical composition and thus pharmaceutical compositions comprising a combination as defined above together with a pharmaceutically acceptable diluent or carrier represent a further aspect of the invention. These combinations are of particular interest in respiratory diseases and are conveniently adapted for inhaled or intranasal delivery. The individual compounds of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical compositions. Preferably, the individual compounds will be administered simultaneously in a combined pharmaceutical composition. Appropriate doses of known therapeutic agents will be readily appreciated by those skilled in the art.

General Synthesis

The 8-amino-imidazo[l,5-a]pyrazine, 4-amino-imidazo[l,5- J[l,2,4]triazine, 4- amino-pyrazolo[3,4-d]pyrimidine and 4-amino-pyrrolo[l,2- J[l,2,4]triazine derivatives of the present invention can be prepared by methods well known in the art of organic chemistry. See, for example, J. March, 'Advanced Organic Chemistry' 4 ^th Edition, John Wiley and Sons. During synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This is achieved by means of conventional protecting groups, such as those described in T.W. Greene and P.G.M. Wutts 'Protective Groups in Organic Synthesis' 3 ^rd Edition, John Wiley and Sons, 1999. The protective groups are optionally removed at a convenient subsequent stage using methods well known in the art.

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

8-amino-imidazo[l,5-a]pyrazine compounds of formula I, wherein Ri-R _x have the previously defined meanings, can be prepared by the general synthetic route shown in scheme I.

Scheme I

Reduction of 3-chloropyrazine-2-carbonitrile (II) can be accomplished by hydrogenation in the presence of a suitable catalyst system and solvent, for example Raney-Nickel ethanol to provide (3-chloropyrazin-2-yl)methanamine (III). This can then be reacted with the bicyclic carboxylic acid (IV). The reaction of IV can be carried out in a solvent such as DMF, THF or DCM in the presence of a base such as DIPEA, N-methylmorpholine, 4-DMAP or triethylamine and in the presence of a coupling reagent such as PyBOP, TBTU, EDCI or HATU to form N-((3-chloropyrazin-2- yl)methyl)amide (V). Cyclisation chloropyrazine (V) can be performed using condensation reagents like phosphorousoxychloride under heating conditions to provide the 8-chloroimidazo[l,5-a]pyrazine derivatives VI. Subsequent bromination can be accomplished using bromine or N-bromosuccinimide in a suitable solvent like DCM or DMF at appropriate temperature to obtain compounds of formula VII. 8- Aminoimidazo[l,5-a]pyrazine derivatives (VIII) can be prepared from compounds VII using ammonia(gas) in isopropanol at elevated temperature in a pressure vessel (>4 atm). Compounds of formula I can be prepared from compounds of formula VIII using an appropriate boronic acid or pinacol ester (IX), in the presence of a suitable palladium catalyst system, for example bis(diphenylphosphino)ferrocene palladium(II)chloride complex or tetrakis(triphenylphosphine)palladium(0) in the presence of an inorganic base like potassium carbonate, cesium carbonate or potassium phosphate in a suitable solvent system like combinations of dioxane and water. Palladium catalysts and conditions to form either the pinacol esters or to couple the boronic acids or pinacol esters with the l-bromoimidazo[l,5-a]pyrazin-8-amine are well known to the skilled organic chemist - see, for example, Ei-ichi Negishi (Editor), Armin de Meijere (Associate Editor), Handbook of Organopalladium Chemistry for Organic Synthesis, John Wiley and Sons, 2002. The bicyclic carboxylic compounds like IV can be readily prepared using methods well known to the skilled organic chemist, illustrated in schemes.

Scheme II

Most of this bicyclic carboxylic compounds can be prepared from the common starting material methyl 2-methyl-5-pyridinecarboxylate 1. Scheme II shows the preparation of compound 4 and 5. Compound 1 was converted to 2 by oxidation using mCPBA to N- oxide, followed by treatment with acetic anhydride to rearrange to acetate. The pyrdine ring in 2 was then saturated with sodiumcyanoborohydride, followed by protection of the amine with Cbz with treatment of CbzCl under basic condition such as TEA, and finally hydrolysis of the acetate to using sodium hydroxide in methanol with water to provide compound 3. Compound 3 was then treated with lithium hydroxide in tetrahydronfuran with water, the carbamate was formed along with the hydrolysis of the ester to acid provided bicyclic acid compound 4. The hydroxy in intermediate 3 is oxidized to aldehyde 6 using oxidation condition suchs as TPAP/NMO. Methyl magnesium bromide addition to the aldehyde provides the secondary alcohol 7 which is converted to the carbamate 8 using the same basic condition lithium hydroxide in tetrahydrofuran with water.

Scheme III

The intermediate 2 was converted to hydroxymethylpyridine-5-carboxylate 5; and then the hydroxyl can be alkylated by ethyl 2-bromoacetate to compound under sodium hydride as base in THF to provide compound 9. The reductive condition described before using sodium cyanoborohydride to saturate the pyridine ring, followed by treatment with base for the lactam formationi generated compound 10. Finally the methyl ester was hydro lysized to acid 11.

Scheme IV

Scheme IV shows the preparation of bicyclic acid 15. The common starting material 1 was bromoated using BS to benzylic bromide 12. The benzylic bromide was used to alkylate methyl N-Cbz-glycineester to 13. The the pyridine was reduced using the same condition, followed by lactam formation to 14 and hydrolysis of ester to acid 15.

19

Scheme V

The bicyclic acid 19 was prepared using the synthetic scheme V. The common starting material 1 reacted with ethyl oxazylate in acetic anhydride with heating to provide the 1,2-unsaturated ester 16. Hydrogenation using palladium hydroxide on carbon as catalyst in acetic acid reduces the pyridine to piperidine 17. When 17 was treated with base such as triethyl amine in methanol, the lactam 18 was formed. The methyl ester is hydro lyzed by treatment with sodium methoxide in methanol to trans bicyclic acid 19.

24

Scheme VI

Scheme VI illustrates the preparation of bicyclic acid 24. Niggishi coupling of methyl 6- bromonicotinate 20 with (4-ethoxy-4-oxobutyl)zinc(II) bromide catalyzed with palladium provide compound 21. The pyridine ring is then reduced using sodium cyanoborohydride in acetic acid to 22, followed by ring closure by heating in toluene to lactam 23. Hydrolysis of the ester provided 24. Substited bicyclic acid 19 and 24 are prepared in the similar ways decribed in scheme V and VI.

The present invention also includes within its scope all stereoisomeric forms of the Btk inhibitor compounds according to the present invention resulting, for example, because of configurational or geometrical isomerism. Such stereoisomeric forms are enantiomers, diastereoisomers, cis and trans isomers etc. For example where azepane-2- carboxylic acid is used as amino acid, there exists a mixture of two enantiomers. In the case of the individual stereoisomers of compounds of Formula I or salts or solvates thereof, the present invention includes the aforementioned stereoisomers substantially free, i.e., associated with less than 5%, preferably less than 2% and in particular less than 1% of the other stereoisomer. Mixtures of stereoisomers in any proportion, for example a racemic mixture comprising substantially equal amounts of two enantiomers are also included within the scope of the present invention.

For chiral compounds, methods for asymmetric synthesis whereby the pure stereoisomers are obtained are well known in the art, e.g. synthesis with chiral induction, synthesis starting from chiral intermediates, enantioselective enzymatic conversions, separation of stereoisomers using chromatography on chiral media. Such methods are described in Chirality in Industry (edited by A.N. Collins, G.N. Sheldrake and J. Crosby, 1992; John Wiley). Likewise methods for synthesis of geometrical isomers are also well known in the art.

The Btk inhibitor compounds of the present invention, which can be in the form of a free base, may be isolated from the reaction mixture in the form of a

pharmaceutically acceptable salt. The pharmaceutically acceptable salts may also be obtained by treating the free base of Formula I with an organic or inorganic acid such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, maleic acid, malonic acid, methanesulphonic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, and ascorbic acid.

The Btk inhibitor compounds of the present invention may also exist as amorphous solids. Multiple crystalline forms are also possible. All the physical forms are included within the scope of the present invention. Preparation of solvates is generally known. Thus, for example, M. Caira et al, J. Pharmaceutical Sci., 93(3). 601-611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water. Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et al, AAPS PharmSciTech., 5(1). article 12 (2004); and A. L. Bingham et al, Chem. Commun. 603-604 (2001). A typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods. Analytical techniques such as, for example IR spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).

The invention is illustrated by the following examples.

Examples

The following examples are illustrative embodiments of the invention, not limiting the scope of the invention in any way. Reagents are commercially available or are prepared according to procedures in the literature.

Mass Spectrometry: Electron Spray spectra were recorded on the Applied Biosystems API- 165 single quad mass spectrometer in alternating positive and negative ion mode using Flow Injection. The mass range was 120-2000 Da. and scanned with a step rate of 0.2 Da. and the capillary voltage was set to 5000 V. N ₂ gas was used for nebulisation.

LC-MS spectrometer (Waters) Detector: PDA (200-320 nm), Mass detector: ZQ and Eluent : A: acetonitrile with 0.05% trifluoroacetic acid , B: acetronitrile/water = 1/9 (v/v) with 0.05% trifluoroacetic acid.

Method A: LC-MS

Column Agilent TC-C18, 50x2. lmm, 5 μιη

A : H ₂ 0 ( 0.1% TFA)

Mobile Phase B: MeCN ( 0.05% TFA)

Gradient Stop Time :4.5 min Time (min) B%

0 1

0.4 1

3.4 90

3.9 100

3.91 1

Sample injection

volume 2 μΐ

Flow Rate 0.8 ml/min

Wavelength 220 nm

Oven Tern. 50 ^° C

MS polarity ESI POS

Method B: LC-MS

Column Agilent TC-C18, 50x2. lmm,

A : H ₂ 0 ( 0.1% TFA)

Mobile Phase B: MeCN ( 0.05% TFA)

Stop Time :4.5 min

Time (min) B%

0 1

0.4 1

3.4 90

3.9 100

Gradient 3.91 1

Sample injection

volume 2 μΐ

Flow Rate 0.8 ml/min

Wavelength 220 nm

Oven Temp. 50 ^° C

MS polarity ESI POS

Method C:

Sample Info : Easy- Access Method: 'l-Short_TFA_Pos'

Method Info : B222 Column Agilent SBC (3.0x50 mm, 1.8 μπι); Flow 1.0 mL/min; solvent A: H ₂ O-0.1% TFA;

solvent B: MeCN-0.1% TFA;

GRADIENT TABLE: 0 min: 10% B, 0.3 min: 10%B, 1.5min: 95% B, 2.70min: 95% B, 2.76 min: 10% B

stop time 3.60 min, PostTime 0.70 min. Method D:

Sample Info : Easy- Access Method: 'l Fast'

Method Info : A330 Column Agilent Zorbax SB-C18 (2.1x30 mm, 3.5 μιη);

Flow 2.0 mL/min;

solvent A: H ₂ O-0.1% TFA;

solvent B: MeCN-0.1% TFA;

GRADIENT TABLE: 0.01 min: 10% B, 1.01 min:95% B, 1.37 min:95% B, 1.38 min: 10% B,

stop time 1.7min, PostTime=OFF Method E:

Mobile Phase: 0.1% TFA in MeCN and 0.1% TFA in Water

Column: Xterra 2.1x20mm 3.5 μιη IS or SunFire

Flow rate = 1.5 mL/min

Injection Volume = 5

Column Heater = 50 °C

Run time= 4 min

Flow rate = 1.5 mL/min

Injection Volume = 5

Gradient:

Time %A %B

0.00 95 5

3.00 5 95

3.25 2 98

3.26 95 5

Method F:

Mobile Phase: A: 0.1% TFA in MeCN and B: 0.1% TFA

Column: Xterra 2.1x20mm 3.5 μιη IS or SunFire

Flow rate = 1.5 mL/min

Injection Volume = 5 μί

Column Heater = 50 °C Run time= 2 min

Flow rate = 1.5 mL/min

Injection Volume = 5 μL·

Gradient:

Time %A %B

0.00 95 5

0.75 5 95

1.25 2 98

1.26 95 5

Method G:

Acquity UPLC BEH-C 18 (2.1 X 50mm, 1.7 μιη); Flow 1 mL/min.

5% - 100% MeCN in 1.4 min

0.1% H ₃

Preparative HPLC was conducted on a column (50 x 10 mm ID, 5μ ^η ι, Xterra Prep MS C I 8) at a flow rate of 5 ml/min, injection volume 500 μΐ, at room temperature and UV Detection at 210 nm.

The following abbreviations are used throughout the application with respect to chemical terminology:

HATU 0-(7-Azabenzotriazol- l-yl)- l, l,3,3-tetramethyluroniumhexafluoro phosphate

Cbz Benzyloxycarbonyl

DMF N,N-Dimethylformamide

DCM Dichloromethane

EtOAc Ethyl acetate

DIPEA N,N-Diisopropylethylamine

THF Tetrahydrofuran

EtOH Ethanol

EDCI.HC1 1 -(3 -Dimethylaminopropyl)-3 -ethylcarbodiimide hydrochloride

4-DMAP 4-Dimethylaminopyridine

PyBOP O-Benzotriazole- 1 -yl-oxy-trispyrrolidinophosphonium hexafluoropho sphate

TBTU O-Benzotriazol- 1 -yl-N,N,N' ,Ν' -tetramethyluronium tetrafluoroborate

HBr Hydrogen bromide

HC1 Hydrogen chloride

HOAc Acetic acid

POCI3 Phosphorous oxychloride

HPLC High Pressure Liquid Chromatography

UPLC Ultra Performance Liquid Chromatography

LiHMDS Lithium hexamethyldisilazide

MeOH Methanol

DCM Dichloromethane

n-BuLi n-Butyllithium

C0 ₂ Carbondioxide

NaHC0 ₃ Sodium bicarbonate

K ₃ P0 ₄ Potassium phosphate

P(Cy) ₃ Tricyclohexylphosphine

Pd(OAc) ₂ Palladium(II) acetate

Na ₂ S0 ₄ Sodium sulfate

Na ₂ C0 ₃ Sodium carbonate

DAST Diethylaminosulfur trifluoride

Cs ₂ C0 ₃ Cesium carbonate

Et ₂ 0 Diethylether

Na ₂ S ₂ 0 ₃ Sodium thiosulfate

Na ₂ S ₂ 0 ₄ Sodium hydrosulfite

NaC BH ₃ Sodium cyanoborohydride

H ₄ C1 Ammonium chloride

MgS0 ₄ Magnesium sulfate

LiOH Lithium hydroxide

IPA Isopropylamine

TFA Trifluoroacetic acid

Cbz-Cl Benzylchloroformate

PE Petroleum ether EA Ethyl acetate

NaHMDS Sodium hexamethyldisilazide

10% Pd/C 10% Palladium on carbon

TEA Triethylamine

CDI Ι, Γ-Carbonyl diimidazole

DMI 1 , 3 -Dimethyl-2-imidazolidinone

BS N-Bromosuccinimide

z-PrOH 2-Propanol

K ₂ C0 ₃ Potassium carbonate

Pd(dppf)Cl ₂ l, l'-Bis(diphenylphosphino)ferrocene palladium (II) chloride, complex withdichloromethane

Et ₃ N Triethylamine

2-BuOH 2-Butanol

LCMS Liquid Chromatography / Mass Spectrometry

MeCN Acetonitrile

H ₃ Ammonia

CD ₃ I Trideuteromethyl iodide

CD ₃ OD Tetradeuteromethanol

CH ₃ I Iodomethane

CBr ₄ Carbon tetrabromide

Tris-HCl Tris(hydroxymethyl)aminomethane hydrochloride

MgCl ₂ Magnesium chloride

NaN ₃ Sodium azide

DTT Dithiothreitol

DMSO Dimethyl sulfoxide

IMAP Immobilized Metal Ion Affinity-Based Fluorescence Polarization

ATP Adenosine triphosphate

MnCl ₂ Manganese(II) chloride

DMA Dimethylacetamide

IPA Isopropyl alcohol

TPP triphenylphosphine

DIAD Diisopropyl azodicarboxylate DMB 2,4-dimethoxybenzyl

DCE Dichloroethane

DEAD Diethyl azodicarboxylate

ACN Acetonitrile

RT (rt) Room Temperature

Aq Aqueous

EtOH Ethanol

MPLC Medium Pressure Liquid Chromoatography

Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

X-phos 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

Examples

The following examples are illustrative embodiments of the invention, not limiting the scope of the invention in any way. Reagents are commercially available or are prepared according to procedures in the literature.

Mass Spectrometry: Electron Spray spectra were recorded on the Applied Biosystems API- 165 single quad mass spectrometer in alternating positive and negative ion mode using Flow Injection. The mass range was 120-2000 Da. and scanned with a step rate of 0.2 Da. and the capillary voltage was set to 5000 V. N ₂ gas was used for nebulisation.

LC-MS spectrometer (Waters) Detector: PDA (200-320 nm), Mass detector: ZQ

Eluens : A: acetonitrile with 0.05% trifluoroacetic acid , B: acetronitrile/water = 1/9 (v/v) with 0.05%) trifluoroacetic acid.

Intermediate 1

(6R.8aS)-6-(8-amino-l-bromoimidazo[1.5-a]pyrazin-3-yntetrahy dro-lH-oxazolo[3.4- a]pyridin-3(5H)-one (a) trans- 1 -benzyl 3 -methyl 6-(acetoxymethyl)piperidine- 1.3 -dicarboxylate

To a solution of methyl 6-(acetoxymethyl)nicotinate (75 g, 358.5 mmol) in AcOH (1000 mL) was added NaBH ₃ CN (45.2 g, 717 mmol) portionwise at rt. The solution was stirred overnight. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in H ₂ 0 (770 mL) and the pH was adjusted to 8 with aqueous NaHC0 ₃ . The resulting mixture was cooled to 0°C, to which Cbz-Cl (122 g,716 mmol) was added dropwise. The mixture was stirred at rt overnight and extracted with DCM (2 x 500 mL). The organic layer was dried over Na ₂ S0 ₄ and concentrated in vacuo and the residue was purified by column chromatography with silica gel eluted by 5-30% ethyl acetate in petroleum ether (60-90 fraction) preparative HPLC to give to trans- 1 -benzyl 3-methyl 6-(acetoxymethyl)piperidine-l,3-dicarboxylate (42 g,33.6% yield) MS: M/Z(M+1):349.9. Retention Time: 1.053.

(b) trans- 1 -benzyl 3 -methyl 6-(hydroxymethyl)piperidine- 1.3 -dicarboxylate

To a solution of trans- 1 -benzyl 3-methyl 6-(acetoxymethyl)piperidine-l,3-dicarboxylate (8.8 g, 25.2 mmol) in MeOH (88 mL) was added HC1 (2.2ml, 12M). The resulting solution was stirred at refluxe overnight and cooled to rt. After removal of solvent in vacuo, the residue was purified by chromatography to give 4.3 g of trans- 1 -benzyl 3- methyl 6-(hydroxymethyl)piperidine-l,3-dicarboxylate. ¹ HNMR (400 MHz, CD ₃ OD) δ= 7.39 (s, 5H), 5.15 (s, 2H), 4.38 - 4.26 (m, 2H), 3.73 - 3.67 (m, 4H), 3.66 - 3.58 (m, 1H), 2.97 (br. s., 1H), 2.48 (tt, J=4.1, 11.8 Hz, 1H), 1.98 - 1.84 (m, 1H), 1.78 - 1.57 (m, 1H).

(c) (3 S.6RV1 -benzyl 3-methyl 6-(hydroxymethyl)piperidine- 1.3 -dicarboxylate & (3R.6 S 1 -benzyl 3 -methyl 6-(hydroxymethyl)piperidine- 1.3 -dicarboxylate 4.3 g of trans- 1 -Benzyl 3-methyl 6-(hydroxymethyl)piperidine-l,3-dicarboxylate was resolved with chiral HPLC to give two enantiomers. (Instrument: Thar 200; Column: AD 250mm x50mm, 5 um; Mobile phase: A: Supercritical C0 ₂ , B: MeOH, A:B = 85: 15 at 160 ml/min; Column Temp: 38°C; Nozzle Pressure: 100 Bar; Nozzle Temp: 60°C; Evaporator Temp: 20°C; Trimmer Temp: 25°C; Wavelength: 220 nm) 1.3 g of (3 S,6R)-1 -benzyl 3-methyl 6-(hydroxymethyl)piperidine-l,3-dicarboxylate(El) was obtained followed by 1.1 g of (3R,6S)-1 -benzyl 3-methyl 6- (hydroxymethyl)piperidine-l,3-dicarboxylate (E2).

(d) (3S.6R)-l-((benzyloxy)carbonyn-6-(hydroxymethynpiperidine-3- carboxylic acid To a mixture of (3 S,6R)-1 -benzyl 3-methyl 6-(hydroxymethyl)piperidine-l,3- dicarboxylate (1.0 g, 3.25 mmol) in MeOH/H ₂ 0 (6 mL/3 mL) was added Lithium hydroxide monohydrate (273 mg, 6.5 mmol). The reaction mixture was stirred at 25 °C overnight. The mixture was concentrated in vacuo, acidified by IN HCl to pH 5-6, and then extracted with EA. The organic layer was washed with brine, dried over Na ₂ S0 ₄ , and concentrated in vacuo to give (3S,6R)-l-((benzyloxy)carbonyl)-6- (hydroxymethyl)piperidine-3-carboxylic acid (780 mg, 81.8% yield). ¹ HNMR (400 MHz, CD ₃ OD): δ= 7.32-7.40 (m, 5H), 5.16 (s, 2H), 4.30-4.36 (m, 2H), 3.60-3.73 (m, 2H), 2.93-3.02 (m, 1H), 2.39-2.46 (m, 1H), 1.89-1.97 (m, 2H), 1.59-1.77 (m, 2H).

(e) (6S.8aR)-3-oxohexahydro-lH-oxazolo[3.4-a]pyridine-6-carboxyl ic acid

A mixture of (3 S,6R)-1 -benzyl 3-methyl 6-(hydroxymethyl)piperidine-l,3- dicarboxylate (2.7 g, 8.785 mmol) in tetrahydrofuran/H ₂ 0 (30 mL) was added LiOH (737 mg, 17.57 mmol). The mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with ethyl acetate (100 mL)l time and the aqueous layer was lyophilized to give (6S,8aR)-3-oxohexahydro-lH-oxazolo[3,4-a]pyridine-6- carboxylic acid (1.6 g, 100% yield). MS (ESI): M/Z (M+l): 186.07.

(f) (6S.8aR)-N-((3-chloropyrazin-2-ynmethyn-3-oxohexahydro-lH-ox azolo[3.4- a]pyridine-6-carboxamide

A mixture of (6S,8aR)-3-oxohexahydro-lH-oxazolo[3,4-a]pyridine-6-carboxyl ic acid (1 g, 5.4 mmol) in dichloromethane (10 mL) was added triethylamine(l g, 5.4 mmol) and isobutyl chloroformate (590 mg, 4.32 mmol) at 0 °C . The mixture was stirred at room temperature for 2 hours. (3-Chloro-pyrazin-2-yl)-methylamine (966 mg, 5.39 mmol) was added portionwise, followed by another 3 eq triethylamine. The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo and purified on silica gel chromatography (PE: THF = 50%~100%) to afford (6S,8aR)-N-((3-chloropyrazin-2-yl)methyl)-3-oxohexahydro-lH- oxazolo[3,4- a]pyridine-6-carboxamide (230 mg, 14% yield).

¹ HNMR(400MHz, DMSO-d6): δ= 8.64 (d, J = 6.4 Hz, 1 H), 8.61 (t, J = 5.6 Hz, 1 H), 8.44 (d, J = 6.0 Hz, 1 H), 4.53-4.49 (m, 2 H), 4.37 (t, J = 8.0 Hz, 1 H), 3.92-3.88 (m, 1 H), 2.91 (J = 12.0 Hz, 1 H), 2.42-2.33 (m, 1 H), 1.93 (d, J = 13.2 Hz, 1 H), 1.86-1.81 (m, 1 H), 1.63-1.52 (m, 1 H), 1.30-1.23 (m, 1 H). MS (ESI): M/Z (M+l): 311.08.

(c) (6R.8aS)-6-(8-chloroimidazo [ 1.5 -a]pyrazin-3 -yOtetrahydro- 1 H-oxazolo [3.4- a]pyridin-3(5H) -one

A mixture of (6S,8aR)-N-((3-chloropyrazin-2-yl)methyl)-3-oxohexahydro-lH- oxazolo[3,4-a]pyridine-6-carboxamide (290 mg, 0.932 mmol) in CH3CN (5 mL) was added POCl ₃ (715 mg, 4.66 mmol) at 0 °C. The mixture was stirred at 30 °C for 15 hours. The reaction mixture was poured into ice water, basified by NaHC0 ₃ and extracted with dichloromethane/propan-2-ol (3 : 1, 30 mL><3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo to afford (6R,8aS)-6-(8-chloroimidazo[l,5-a]pyrazin-3-yl)tetrahydro-lH - oxazolo[3,4-a]pyridin-3(5H)-one (270 mg, 98% yield).

¹ HNMR(400 MHz, CDC1 ₃ ): δ= 7.81 (s, 1H), 7.71 (d, J = 5.6 Hz, 1 H), 7.38 (d, J = 4.8 Hz, 1 H), 4.49 (t, J = 8.0 Hz, 1 H), 4.14-4.11 (m, 1 H), 4.10-4.02 (m, 1 H), 3.89-3.82 (m, 1 H), 3.29-3.23 (m, 1 H), 3.20-3.12 (m, 1 H), 2.27-2.20 (m, 2 H), 2.17-2.03 (m, 2 H). MS (ESI): M/Z (M+l):293.07.

(d) (6R.8aS)-6-(l-bromo-8-chloroimidazo[1.5-a]pyrazin-3-yntetrah ydro-lH- oxazolo[3.4-a] pyridin-3(5H)-one

A mixture of (6R,8aS)-6-(8-chloroimidazo[l,5-a]pyrazin-3-yl)tetrahydro-lH - oxazolo[3,4-a] pyridin-3(5H)-one (270 mg, 0.922 mmol) in DMF (3 mL) was added 1- bromo-pyrrolidine-2,5-dione (181 mg, 1.015 mmol). The mixture was stirred at room temperature for 1 hour and quenched with saturated sodium bicarbonate. The resulting mixture was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give (6R,8aS)-6-(l-bromo-8-chloroimidazo[l,5-a]pyrazin-3-yl)tetra hydro-lH-oxazolo[3,4- a]pyridin-3(5H)-one (310 mg, 90% yield). ¹ HNMR (400 MHz, DMSO-d6): δ = 8.47 ~ 8.46 (d, J = 4 Hz, 1 H), 7.44- 7.45 (d, J = 4 Hz, 1 H), 4.46 -4.40 (m, 2 H), 3.98 - 3.95 (m, 1 H), 3.88 - 3.83 (m, 2H), 3.27- 3.21 (t, J = 12 Hz, 1 H), 2.07 - 2.04 (d, J = 12 Hz, 1 H), 1.93 -1.89 (m, 1 H), 1.76 - 1.67 (m, 1 H), 1.59 - 1.47 (m, 4 H). MS (ESI): M/Z (M+l):371.

(e) (6R.8aS)-6-(8-amino- 1 -bromoimidazo[ 1.5-a]pyrazin-3 -yOtetrahydro- 1H- oxazolo[3.4-a] pyridin-3(5H)-one

A mixture of (6R,8aS)-6-(l-bromo-8-chloroimidazo[l,5-a]pyrazin-3-yl)tetra hydro-lH- oxazolo [3,4-a]pyridin-3(5H)-one (30 mg, 0.08 mmol) in H ₄ OH/ z-PrOH (3 mL/3 mL) was stirred at 100 °C in a sealed tube for 7 h. The reaction mixture was cooled to room temperature and concentrated in vacuo to afford (6R,8aS)-6-(8-amino-l- bromoimidazo[ 1 , 5-a]pyrazin-3 -yl)tetrahydro- lH-oxazolo[3 ,4-a]pyridin-3 (5H)-one (10 mg, 35% yield). MS (ESI): M/Z (M+l)=352.03.

Intermediate 2

(6S.8aR)-6-(8-amino-l-bromoimidazo[1.5-a]pyrazin-3-yntetrahy dro-lH-oxazolo[3.4- a]pyridin-3(5H)-one

(a) (6R.8aS)-3-oxohexahydro-lH-oxazolo[3.4-a]pyridine-6-carboxyl ic acid

To a mixture of (3R,6S)-1 -benzyl 3-methyl 6-(hydroxymethyl)piperidine-l,3- dicarboxylate (2.7 g, 8.785 mmol) in tetrahydrofuran/H ₂ 0 (1 : 1, 30 mL ) was added LiOH (737 mg g, 17.57 mmol). The resulting mixture was stirred at room temperature for 1 hour and extracted with ethyl acetate (100 mL). The aqueous layer was lyophilized to give (6R,8aS)-3-oxohexahydro-lH-oxazolo[3,4-a]pyridine-6-carboxyl ic acid (1.6 g, 100% yield). ¹ HNMR (400 MHz, DMSO-d6): δ= 12.62 (s, 1 H), 4.36 (t, J = 8.4 Hz, 1 H), 3.89-3.74 (m, 1 H), 3.70-3.63 (m, 1 H), 2.90-2.84 (m, 1 H), 2.37-2.29 (m, 1 H), 2.07-2.03 (m, 1 H), 1.85-1.82 (m, 1 H), 1.55-1.40 (m, 1 H), 1.37-1.22 (m, 1 H). MS (ESI): M/Z (M+l): 185.8.

(b) (6R.8aS)-N-(Y3 -chloropyrazin-2-yQmethyO-3 -oxohexahydro- 1 H-oxazolo [3 A- a]pyridine-6-carboxamide To a mixture of (6R,8aS)-3-oxohexahydro-lH-oxazolo[3,4-a]pyridine-6-carboxyl ic acid (150 mg, 0.810 mmol) in dichloro methane (5 mL ) was added triethylamine(344 mg, 3.24 mmol) and isobutyl chloroformate(l 16 mg, 0.851 mmol) at 0 °C. The mixture was stirred at room temperature for 2 hours, to which (3-Chloro-pyrazin-2-yl)- methylamine (145 mg, 0.810 mmol) was added portionwise, followed by another 3 eq triethylamine. The mixture was stirred at room temperature for additional 3 hours. The reaction mixture was concentrated in vacuo and purified by silica gel chromatography (PE:THF= 50%~100%) to afford (6R,8aS)-N-((3-chloropyrazin-2-yl)methyl)-3- oxohexahydro-lH-oxazolo[3,4-a]pyridine-6-carboxamide (40 mg, 16% yield). MS (EI): M/Z (M+l): 311.1. (c) (6 S.8aR)-6-(8-chloroimidazo [ 1.5 -a]pyrazin-3 -yOtetrahydro- 1 H-oxazolo [3.4- a]pyridin-3(5H)-one

To a mixture of (6R,8aS)-N-((3-chloropyrazin-2-yl)methyl)-3-oxohexahydro-lH- oxazolo[3,4-a]pyridine-6-carboxamide (60 mg, 0.205 mmol) in CH ₃ CN (3 mL ) was added POCl ₃ (157 mg, 1 mmol) at 0 °C. The mixture was stirred at 30 °C for 15 hours. The reaction mixture was poured into ice water, basified by solid NaHC0 ₃ and extracted with dichloromethane/Propan-2-ol(3 : l, 20mL><3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated to afford (6S,8aR)-6-(8-chloroimidazo [l,5-a]pyrazin-3-yl)tetrahydro-lH-oxazolo[3,4-a]pyridin- 3(5H)-one (50 mg, 88% yield). MS (EI): M/Z (M+l):293.00. (d) (6S.8aR)-6-(l-bromo-8-chloroimidazo[1.5-a]pyrazin-3-yntetrah ydro-lH- oxazolo[3.4-a] pyridin-3(5H)-one To a mixture of (6S,8aR)-6-(8-chloroimidazo[l,5-a]pyrazin-3-yl)tetrahydro-lH - oxazolo[3,4-a]pyridin-3(5H)-one (50 mg, 0.17 mmol) in DMF (3 mL ) was added 1- bromo-pyrrolidine-2,5-dione (34.2 mg, 0.192 mmol). The mixture was stirred at room temperature for 1 hour and quenched with saturated sodium bicarbonate. The resulting mixture was extracted with ethyl acetate, the combined organic layer was washed with brine (10mL><3), dried over anhydrous sodium sulfate and concentrated to give (6S,8aR)-6-(l-bromo-8-chloroimidazo[l,5-a]pyrazin-3-yl)tetra hydro-lH-oxazolo[3,4- a]pyridin-3(5H)-one (80 mg, 100% yield). ¹ HNMR (400 MHz, DMSO-d6): δ= 8.47 ~ 8.46 (d, J = 4 Hz, 1 H), 7.45 -7.44 (d, J = 4 Hz, 1 H), 4.46 ~ 4.40 (m, 2 H), 3.98 ~ 3.95 (m, 1 H), 3.88 ~ 3.83 (m, 2 H), 3.27 ~ 3.21 (t, J= 12 Hz, 1 H), 2.07 ~ 2.04 (d, J= 12 Hz, 1 H), 1.93 ~ 1.89 (m, 1 H), 1.76 ~ 1.67 (m, 1 H), 1.60 ~ 1.47 (m, 1 H). (ESI): M/Z (M+l): M/Z (M+3) 372.9 : (M+l) 371 = 10 : 7.5

(e) (6S.8aR)-6-(8-amino- 1 -bromoimidazo[ 1.5-a]pyrazin-3 -yOtetrahydro- 1H- oxazolo[3.4-a] pyridin-3(5H)-one

A mixture of (6S,8aR)-6-(l-bromo-8-chloroimidazo[l,5-a]pyrazin-3-yl)tetra hydro-lH- oxazolo [3,4-a]pyridin-3(5H)-one (80 mg, 0.215 mmol) in H ₄ OH/i-PrOH (4 mL/4mL) was stirred at 100 °C in sealed tube for 7 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to afford crude product which was purified by prep-TLC to give (6S,8aR)-6-(8-amino-l-bromoimidazo[l,5-a]pyrazin-3- yl)tetrahydro-lH-oxazolo[3,4-a]pyridin-3(5H)-one (20 mg, 27% yield).

MS (ESI): M/Z (M+l)=352.03.

Intermediate 3

(2S.5S)-benzyl 2-(acetoxymethyn-5-(l-bromo-8-((2.4-dimethoxybenzynamino)- imidazo [ 1.5 -a] pyrazin-3 -yOpiperidine- 1 -carboxylate

(a) trans- 1 -benzyl 3 -methyl 6-(acetoxymethyl)piperidine- 1.3 -dicarboxylate To a solution of methyl 6-(acetoxymethyl)nicotinate (75 g, 358.5 mmol) in AcOH (1000ml) was added NaBH ₃ CN (45.2 g, 717 mmol) portionwise at rt. The solution was stirred overnight. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in H ₂ 0 (770 ml) and the pH was adjusted to 8 with aqueous NaHC0 ₃ . The resulting mixture was cooled to 0 °C , to which Cbz-Cl (122 g,716 mmol) was added dropwise. The mixture was stirred at rt overnight and extracted with DCM (2 x 500 mL). The organic layer was dried over Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by column chromatography with silica gel eluted by 5-30% ethyl acetate in petroleum ether (60-90 fraction) preparative HPLC to give to trans- 1 -benzyl 3-methyl 6-(acetoxymethyl)piperidine-l,3-dicarboxylate (42 g,33.6% yield). MS:M/Z (M+l):349.9. Retention Time: 1.053 min.

(b) trans- 1 -benzyl 3 -methyl 6-(hydroxymethyl)piperidine- 1.3 -dicarboxylate

To a solution of trans- 1 -benzyl 3-methyl 6-(acetoxymethyl)piperidine-l,3- dicarboxylate (8.8 g, 25.2 mmol) in MeOH (88 ml) was added HC1 (2.2ml, 12M). The resulting solution was stirred at reflux overnight. After this cooled to r.t and removal of the solvent in vacuo, .the residue was purified by chromatography on silica gel to give 4.3 g of trans- 1 -benzyl 3-methyl 6-(hydroxymethyl)piperidine-l,3-dicarboxylate. ¹ HNMR (400 MHz, CD30D) δ= 7.39 (s, 5H), 5.15 (s, 2H), 4.38 - 4.26 (m, 2H), 3.73 - 3.67 (m, 4H), 3.66 - 3.58 (m, 1H), 2.97 (br. s., 1H), 2.48 (tt, J=4.1, 11.8 Hz, 1H), 1.98 - 1.84 (m, 1H), 1.78 - 1.57 (m, 1H).

(c) (3S.6S)-l-benzyl 3-methyl 6-(hydroxymethyl)piperidine- 1.3 -dicarboxylate & (3R.6RV 1 -benzyl 3 -methyl 6-(hydroxymethyl)piperidine- 1.3 -dicarboxylate

4.3 g of trans- 1 -benzyl 3-methyl 6-(hydroxymethyl)piperidine-l,3-dicarboxylate was resolved with chiral HPLC to give two enantiomers. (Instrument: Thar 200;

Column: AD 250mm*50mm,5um; Mobile phase: A: Supercritical C0 ₂ , B: MeOH, A:B =85: 15 at 160 ml/min; Column Temp: 38 °C; Nozzle Pressure: lOOBar; Nozzle Temp: 60°C; Evaporator Temp: 20°C; Trimmer Temp: 25 °C; Wavelength: 220 nm) 1.3 g of (3S,6S)-l-benzyl 3-methyl 6-(hydroxymethyl)-piperidine- 1,3 -dicarboxylate was obtained followed by 1.1 g of (3R,6R)-1 -benzyl 3-methyl 6-(hydroxymethyl)piperidine- 1,3-dicarboxylate.

(d) (3S.6S)-l-((benzyloxy)carbonyl)-6-(hydroxymethynpiperidine-3 -carboxylic acid To a mixture of (3 S,6S)-1 -benzyl 3-methyl 6-(hydroxymethyl)piperidine-l,3- dicarboxylate (1.0 g, 3.25 mmol) in MeOH/H ₂ 0 (6 mL/3 mL) was added Lithium hydroxide monohydrate (273 mg, 6.5 mmol). The reaction mixture was stirred at 25 °C overnight. The mixture was concentrated in vacuo, acidified with IN HCl to(pH 5-6, and extracted with EA. The organic layer was washed with brine, dried over Na ₂ S0 ₄ , concentrated in vacuo to give (3S,6S)-l-((benzyloxy)carbonyl)-6- (hydroxymethyl)piperidine-3-carboxylic acid (780 mg, 81.8% yield). ¹ HNMR (400 MHz, CD ₃ OD): δ= 7.32 - 7.40 (m, 5 H), 5.16 (s, 2 H), 4.30 - 4.36 (m, 2 H), 3.60 - 3.73 (m, 2 H), 2.93 - 3.02 (m, 1 H), 2.39 - 2.46 (m, 1 H), 1.89 - 1.97 (m, 2 H), 1.59 - 1.77 (m, 2 H).

(e)(2 S.5R)-benzyl5 -(Y(3 -chloropyrazin-2-yDmethyDcarbamoyl)-2- (hydroxymethyOpiperidine- 1 -carboxylate

To a solution of (3S,6S)-l-((benzyloxy)carbonyl)-6-(hydroxymethyl)piperidine- 3-carboxylic acid (0.78 g, 2.66 mmol) in 20 mL of DMF was added HATU (1.21 g, 3.2 mmol). After stiring for 30 min under N ₂ , (3-Chloro-pyrazin-2-yl) methanamine hydrochloride (0.48 g, 2.66 mol) and Et ₃ N (0.8 g, 7.98 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours under N ₂ . The mixture was partitioned between EA and water. The organic layer was washed with 1 N HCl and water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford (2S,5R)-benzyl 5-(((3- chloropyrazin-2-yl)methyl)carbamoyl)-2-(hydroxymethyl) piperidine-l-carboxylate (0.7 g, 63.0% yield). ¹ HNMR (400 MHz, CD ₃ OD): δ= 8.50 - 8.54 (m, 1 H), 8.35 (d, J= 2.4 Hz, 1 H), 7.31 - 7.41 (m, 5 H), 5.16 (s, 2 H), 4.63 (s, 2 H), 4.34 - 4.38 (m, 1 H), 4.21 - 4.25 (m, 1 H), 3.72 - 3.77 (m, 1 H), 3.63 - 3.67 (m, 1 H), 3.01 - 3.07 (m, 1 H), 2.46 - 2.54 (m, 1 H), 1.80 - 1.93 (m, 3 H), 1.61 - 1.71 (m, 1 H). MS (ESI): M/Z (M+l): 419.1. ffl (2S.5RVbenzyl 2-(acetoxymethvn-5-(((3-chloropyrazin-2-vnmethylV carbamoyDpiperidine - 1 -carboxylate

To a mixture of (2S,5R)-benzyl 5-(((3-chloropyrazin-2-yl)methyl)carbamoyl)-2- (hydroxymethyl) piperidine-l-carboxylate (500 mg, 1.2 mmol) in 4 mL of DCM was added acetyl chloride (141 mg, 1.8 mmol) and pyridine (190 mg, 2.4 mmol). The reaction mixture was stirred at 25 °C overnight. The mixture was poured into aq.

NH C1, and extracted with DCM. The organic layer was dried over Na ₂ S0 ₄ , concentrated in vacuo and purified by flash chromatography to give (2S,5R)-benzyl 2- (acetoxymethyl)-5-(((3-chloropyrazin-2-yl)methyl)carbamoyl) piperidine- 1 -carboxylate (240 mg43.6% yield). ¹ HNMR (400 MHz, CD ₃ OD): δ= 8.31 ~ 8.50 (m, 2 H), 7.29 ~ 7.36 (m, 5 H), 5.10 - 5.15 (m, 2 H), 4.55 ~ 4.61 (m, 3 H), 4.12 ~ 4.38 (m, 3 H), 3.04 ~ 3.14 (m, 1 H), 2.46 ~ 2.54 (m, 1 H), 1.66 ~ 1.86 (m, 7 H). MS (ESI): M/Z (M+l): 461.0.

(g) (2R.5R)-benzyl 2-(acetoxymethyl)-5-(l-bromo-8-((2.4- dimethoxybenzyl)amino)imidazo [ 1.5-a]pyrazin-3 -yOpiperidine- 1 -carboxylate

(2S,5R)-benzyl 2-(acetoxymethyl)-5-(((3-chloropyrazin-2-yl)methyl)- carbamoyl)piperidine -1 -carboxylate (100 mg, 0.22 mmol) was converted to the title compound (90 mg) using procedures analogous to those described for synthesis of Intermediate 19, steps h. ¹ HNMR (400MHz, CDC1 ₃ ): δ= 7.34 ~ 7.38 (m, 5 H), 7.10 ~ 7.14 (m, 1 H), 6.90 ~ 6.99 (m, 1 H), 6.74 ~ 6.76 (m, 1 H), 6.43 ~ 6.50 (m, 2 H), 5.11 - 5.23 (m, 2 H), 4.65 ~ 4.71 (m, 3 H), 4.18 ~ 4.39 (m, 3 H), 3.88 (s, 3 H), 3.80 (s, 3 H), 2.98 ~ 3.24 (m, 2 H), 1.81 ~ 1.98 (m, 7 H). MS (ESI): M/Z (M/M+2 = 1/1) 652.1/654.1.

Intermediate 4

(2R.5R)-benzyl 2-(acetoxymethyn-5-(l-bromo-8-((2.4-dimethoxybenzynamino)- imidazo [ 1.5 -a] pyrazin-3 -yDpiperidine- 1 -carboxylate

The title compound (90 mg) was prepared using from SM using analogous procedures as Intermediate 19. ¹ HNMR (400 MHz, CDC1 ₃ ): δ= 7.34 ~ 7.38 (m, 5 H),

7.10 ~ 7.14 (m, 1 H), 6.90 ~ 6.99 (m, 1 H), 6.74 ~ 6.76 (m, 1 H), 6.43 ~ 6.50 (m, 2 H),

5.11 ~ 5.23 (m, 2 H), 4.65 ~ 4.71 (m, 3 H), 4.18 - 4.39 (m, 3 H), 3.88 (s, 3 H), 3.80 (s, 3 H), 2.98 - 3.24 (m, 2 H), 1.81 - 1.98 (m, 7 H). MS (ESI): M/Z (M/M+2 = 1/1)

652.1/654.1.

Intermediate 5

(6R, 8aS)-6-(8-amino- 1 -bromoimidazo[ 1 , 5-a]pyrazin-3 -yl)hexahydroindolizin-3 (2H)- one

(a) (EV methyl 6-(3 -ethoxy-3 -oxoprop- 1 -en- 1 -yPnicotinate

containing mixture of ethyl 2-oxoacetate (155 g, 0.76 mol) and methyl 6- methylnicotinate (50 g, 0.33mol) in 300 mL of acetic anhtdride was refluxed at 130 °C for two days and concentrated in vacuo. The resultant crudewas purified by silica gel chromatography (eluent: 20%EA/hex) to afford (E)-methyl 6-(3 -ethoxy-3 -oxoprop- 1- en-l-yl)nicotinate (57 g, .242 mol, 73% yield). LCMS data: Rt. =1.42 min, m/z 236 (M+H) ⁺ ; ; ¹ HNMR (CDC1 ₃ , 500 Hz): 9.24 (1H, d, J = 2 Hz); 8.333 (1H, dd J = 6 Hz); 7.20 (1H, d, J =16 Hz); 7.511 (1H, d, J = 8Hz); 7.042 (1H, d, J = 15.5 Hz); 4.310 (q, J = 7 Hz); 3.988 (3H, s), 1.366 (3H, t, J = 7 Hz).

(b) methyl 3 -oxooctahydroindolizine-6-carboxylate

To a 500 ml vessel charged with (E)-methyl 6-(3 -ethoxy-3 -oxoprop- 1 -en- l-yl)nicotinate (10 g) in acetic acid (100 mL) was addedpalladium hydroxide on carbon (20%, 2.5 g). The vessel was loaded on ParShaker and the mixture was exposed to hydrogen at 40 psi for 18 hours. The catalyst was filtered under nitrogen stream and washed with ethyl acetate. The filtrate was then concentrated in vacuo to afford methyl 3- oxooctahydroindolizine-6-carboxylate. LCMS data: R _t 0.22 min; m/z 244.3 (M+H) ⁺ .

(c) Methyl 3 -oxooctahydroindolizine-6-carboxylate

Methyl 6-(3 -ethoxy-3 -oxopropyl)piperidine-3-carboxylate (103.5 g, 0.425 mol) was refluxed in a mixture of TEA (100 ml, 0717 mol) and MeOH (500 ml) for 18 h and concentrated in vacuo. The residue was purified by silicagel chromatography (eluent: 3% 2N H ₃ in MeOH/DCM) to afford a mixture of cis/trans isomers methyl 3- oxooctahydroindolizine-6-carboxylate (94 g, 4/1 ratio). LCMS data: R _t 1.07 min; m/z 198 (M+H) ⁺ .

(d) Trans 3-oxooctahydroindolizine-6-carboxylic acid

A solution of methyl 3-oxooctahydroindolizine-6-carboxylate (94 g, 477 mmol) in methanol (1000 mL) was heated from rt to 50 °C. While the solution was being heated, 25% NaOMe in methanol (215 mL, 940 mmol). The reaction mixture was stirred at 50 °C for 4.5 h and concentrated in vacuo to afford a solid. This solid was dissolved in water (300 mL), resulting in the formation of a gray solid. This solid was filtered off, and the filtrate was then reconcentrated (water bath at 60 °C) to provide a white solid. This 60 °C solid was dissolved in water (100 mL) and cooled in an ice bath. Once the solution had reached 5 °C, aq. 6 M HCl (165 mL, 990 mmol) was added dropwise while maintaining the temperature below 23 °C. Solids formed as the addition continued. This mixture was stirred for -30 min while the solution cooled to 5 °C, and then it was filtered. The isolated solid was washed with cold water and then dried under a nitrogen flush overnight to afford the mixture of enantiomers trans 3-oxooctahydroindolizine-6- carboxylic acid (66.44 g, 363 mmol, 76 % yield) as a white solid. LCMS data: R _t 0.92 min; m/z 184.12 (M+H) ⁺ . ¹ HNMR (CDC1 ₃ , 500 MHz, ppm): 9.42 (1H, br), 4.38 (1H, ddd, J = 13.2, 4.1, 1.6 Hz), 3.44 (1H, m), 2.76 (1H, t, J = 12.7 Hz), 2.42 (3H, m), 2.24 (2H, m), 1.97 (1H, ddd, J = 13.2, 6.8, 3.3 Hz), 1.61 (2H, m), 1.23 (1H, M).

(e) (6R,8aS) 3-oxooctahydroindolizine-6-carboxylic acid and (6S,8aR) 3- oxooctahydroindolizine-6-carboxylic acid

The two enantiomers of trans 3-oxooctahydroindolizine-6-carboxylic acid were separated on Chiral HPLC (IC column, 4.6x150mm, 50%IPA+TFA/CO ₂ , 2.5ml/min. lOObar, 35°C) to give (6S,8aR)-3-oxooctahydroindolizine-6-carboxylic acid (El, Rt = 3.1 min, > 99%ee) followed by (6R,8aS)-3-oxooctahydroindolizine-6-carboxylic acid (E2, Rt = 4.2 min, >99%ee).

(f) (6R.8aS)-N-((3-chloropyrazin-2-ynmethyl)-3-oxooctahydroindol izine-6- carboxamide

HATU (15.91 g, 41.8 mmol) was added to a stirred, cooled 0 °C mixture of (6R,8aS)-3- oxooctahydroindolizine-6-carboxylic acid (7.3 g, 39.8 mmol), (3-chloropyrazin-2- yl)methanamine hydrochloride (7.89 g, 43.8 mmol) and DIPEA (10.44 ml, 59.8 mmol) in CH ₂ C1 ₂ (25 ml) and the mixture was stirred at room temperature for 1 h. and then concentrated. The residue was purified by column chromatography on silica gel (Isco 240 g silica gel), eluting with CH ₂ Cl ₂ /MeOH (50/1) to give (6R,8aS)-N-((3- chloropyrazin-2-yl)methyl)-3-oxooctahydroindolizine -6-carboxamide (11.15g, 36.1 mmol, 91 % yield) as a white solid. LC-MS: R _t 1.09 min; m/z 309.11 (M+H) ⁺ ; ¹ HNMR (CDC1 ₃ , 500 Hz): 8.38 (1H, d, J = 2 Hz), 8.25 (1H, d, J = 2 Hz), 7.37 (1H, dd, J = 4 and 4.5 Hz), 4.56-4.72 (2H, m, l), 4.29 (1H, dd, J = 13 and 4.5 Hz),3.42-3.47 (m, l), 2.81 (1H, t, J = 13 Hz), 2.35 (2H, t, J = 8 Hz), 2.17-2.23 (1H, m), 2.04 (1H, d, J = 13.5 Hz), 1.94-1.96 (1H, m), 1.74-1.82 (1H, m), 1.55-1.62 (1H, m), 1.16-1.24 (1H, m).

(g) (6R.8aS)-6-(8-chloroimidazo[ 1.5-a]pyrazin-3 -yOhexahydroindolizin-3 (2H)-one POCI ₃ (5.85 ml, 62.7 mmol) was added to a stirred, cooled 0 °C mixture of (6R,8aS)-N- ((3 -chloropyrazin-2-yl)methyl)-3 -oxooctahydroindolizine-6-carboxamide (3228.2 mg, 10.46 mmol) in Acetonitrile (20 ml), to which DMF (0.810 ml, 10.46 mmol) was added. The mixture was stirred at room temperature for overnight, and poured into iced water, to which powdered NaHC0 ₃ was added until pH ~8. The mixture was extracted with DCM, dried over MgS0 ₄ , filtered and concentrated. The residue was purified by column chromatography on silica gel (ISCO, 40g), eluting with CH ₂ Cl ₂ /MeOH (25/1) to give (6R, 8aS)-6-(8-chloroimidazo [ 1 , 5-a]pyrazin-3 -yl)hexahydroindolizin-3 (2H)-one

(1.9981 g, 6.87 mmol, 65.7 % yield) as a colorless oil. R _t 1.15 min; m/z 291.12 (M+H) ⁺ ; ¹ HNMR (CDC1 ₃ , 500 Hz): 7.72 (1H, d, J = 4.5 Hz), 7.39 (1H, d, J = 5 Hz), 4.40-4.42 (1H, m), 3.62-3.67 (1H, m), 3.03-3.08 (2H, m), 2.11-2.51 (8H, m), 1.70-1.77 (1H, m), 1.39-1.46 (1H, m).

(h) (6R.8aS)-6-( 1 -bromo-8-chloroimidazo[ 1.5-a]pyrazin-3 -yQhexahydroindolizin- 3(2H)-one BS (1.468 g, 8.25 mmol) was added to a stirred mixture of (6R,8aS)-6-(8- chloroimidazo[l,5-a]pyrazin-3-yl)hexahydroindolizin-3(2H)-on e (1.9981 g, 6.87 mmol) in acetonitrile (25 ml) and the mixture was stirred at room temperature for 1 h. The reaction was quenched with sat. NaHC0 ₃ , exctracted with DCM, dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel (ISCO gold 40g), eluting with CH ₂ Cl ₂ /MeOH (40/1) to give (6R,8aS)-6-(l-bromo-8- chloroimidazo[l,5-a]pyrazin-3-yl)hexahydroindolizin-3(2H)-on e (2.2g, 5.95 mmol, 87 % yield) as a white solid. R _t 1.24 min; m/z 368.97 and 370.98 (M+H) ⁺ .

(i) (6R.8aS)-6-(8-amino- 1 -bromoimidazo[ 1.5-a]pyrazin-3 -yQhexahydroindolizin- 3(2H)-one

A stirred mixture of (6R,8aS)~6-(l-bromo-8-chloroimidazo[l,5-a] pyrazin-3- yl)hexahydroindolizin-3(2H)-one (2.2109g, 5.98 mmol) in 100 mL of 2N H ₃ in 2- propanol was heated in a sealed tube at 120 °C for 24 h. and concentrated in vacuo. The residue was purified by column chromatography on silica gel (ISCO, 80g), eluting with CH ₂ Cl ₂ /MeOH(15/l) to afford (6R,8aS)-6-(8-amino-l-bromoimidazo[l,5-a]pyrazin-3- yl)hexahydroindolizin-3(2H)-one (2.04 g, 5.84 mmol, 98 % yield) as a white solid. R _t 1.16 min; m/z 350.0 and 352.0 (M+H) ⁺ .

Intermediate 6

(6S.8aR)-6-(8-amino- 1 -bromoimidazo[ 1.5-a]pyrazin-3 -yOhexahydroindolizin-3 (2H)- one

The title compound (6S,8aR)-6-(8-amino-l-bromoimidazo[l,5-a]pyrazin-3-yl) hexahydroindolizin-3(2H)-one was prepared using the same steps of Intermediate 5 (f-I) using (6S,8aR)-3-oxooctahydroindolizine-6-carboxylic acid (Intermediate 5, step e) as the starting material.

Intermediate 7

4-(8-amino-3-((6R.8aS)-2-methyl-3-oxooctahydroimidazo[1.5-a] pyridin-6- yl)imidazo[ 1.5-a]pyrazin- 1 -yn-N-(4-(trifluoromethynpyridin-2-ynbenzamide

(a) (3S.6R)-l-benzyl 3-methyl 6-(methoxymethyOpiperidine-1.3-dicarboxylate

Nl,Nl,N8,N8-tetramethylnaphthalene-l,8-diamine (3.66 g, 17.08 mmol) and Me ₃ OBF ₄ (2.52 g, 17.08 mmol) was added to a solution of (3 S,6R)-1 -benzyl 3-methyl 6- (hydroxymethyl)piperidine-l,3-dicarboxylate (1.75 g, 5.69 mmol) in dichloro methane (18mL) at room temperature. After stirring for 1 hour, saturated NaHC0 ₃ solution was added and filtered, the filtrate was extracted with dichloro methane (200 mL><3), the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to afford the crude product, which was purified by silica gel column chromatography (PE:THF= 50%~100%) to give (3 S,6R)-1 -benzyl 3-methyl 6- (methoxymethyl)piperidine-l,3-dicarboxylate (1.5 g, 82% yield). ¹ HNMR (400 MHz, CD ₃ OD): δ= 7.41 - 7.27 (m, 5H), 5.21 - 5.13 (m, 1H), 5.10 - 5.03 (m, 1H), 4.46 (d, J=14.1 Hz, 1H), 4.39 (q, J=6.5 Hz, 1H), 3.65 - 3.55 (m, 4H), 3.49 - 3.42 (m, 1H), 3.35 - 3.28 (m, 6H), 3.18 (dd, J=4.0, 14.1 Hz, 1H), 2.67 (br. s., 1H), 2.03 - 1.96 (m, 1H), 1.90 - 1.74 (m, 2H), 1.64 - 1.57 (m, 1H). MS (EI): M/Z (M+l): 322.16

(b) (3S.6R)-l-((benzyloxy)carbonyn-6-(methoxymethyl)piperidine-3 -carboxylic acid

A mixture of (3 S,6R)-1 -benzyl 3-methyl 6-(methoxymethyl)piperidine-l,3- dicarboxylate (1.54 g, 4.79 mmol) and LiOH (0.605 g, 14.4 mmol) in tetrahydrofuran/ H ₂ 0 (150 mL, 1 : 1) was stirred at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate and the aqueous layer was acidified with 1 N HCl, extracted with ethyl acetate (100 mLx3). the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to afford (3S,6R)-1- ((benzyloxy)carbonyl)-6-(methoxymethyl)piperidine-3-carboxyl ic acid (1.5 g, 100% yield).

¹ HNMR (400 MHz, CDC1 ₃ ): δ = 7.41 - 7.24 (m, 5H), 5.24 - 5.18 (m, 1H), 5.13 - 5.06 (m, 1H), 4.56 (d, J=14.1 Hz, 1H), 4.43 (d, J=5.3 Hz, 1H), 3.55 - 3.43 (m, 2H), 3.15 (dd, J=4.0, 14.1 Hz, 1H), 2.67 (br. s., 1H), 2.10 (s, 1H), 1.89 - 1.80 (m, 2H), 1.72 - 1.63 (m, 1H). MS (EI): M/Z (M+l): 308.14

(c) (2R.5S)-benzyl5-(((3-chloropyrazin-2-yl)methyncarbamoyl)-2- (methoxymethyOpiperidine- 1 -carboxylate

A mixture of (3S,6R)-l-((benzyloxy)carbonyl)-6-(methoxymethyl)piperidine- 3- carboxylic acid (1.5 g, 4.88 mmol), (3-chloropyrazin-2-yl)methanamine (0.875 g, 4.88 mmol), HATU (2 g, 5.4 mmol) and triethylamine (1.97 g, 19.52 mmol) in dichloromethane (20 mL) was stirred at room temperature for 12 hours. The mixture was concentrated to afford the crude product, which was purified by silica gel column chromatography (PE:EA= 100%~60%) to give (2R,5S)-benzyl 5-(((3-chloropyrazin-2- yl)methyl)carbamoyl)-2-(methoxymethyl)piperidine-l-carboxyla te (2.0 g, 95% yield).

¹ HNMR (400 MHz, CDC1 ₃ ): δ= 8.26 (d, J=2.5 Hz, 1H), 8.22 (s, 1H), 7.26 (s, 6H), 5.19 - 5.11 (m, 1H), 5.07 - 5.01 (m, 1H), 4.67 (d, J=16.8 Hz, 1H), 4.52 - 4.40 (m, 3H), 3.63 - 3.57 (m, 1H), 3.54 - 3.47 (m, 1H), 3.36 (s, 3H), 3.28 (dd, J=3.4, 14.9 Hz, 1H), 2.63 (br. s., 1H), 2.18 (d, J=12.8 Hz, 1H), 1.93 - 1.75 (m, 2H), 1.66 (d, J=2.3 Hz, 1H). MS (EI): M/Z (M+l): 433.16 (d)(2S.5R)-benzyl5-(8-chloroimidazo[1.5-a]pyrazin-3-yn-2- (methoxymethyPpiperidine- 1 -carboxylate

To a mixture of (2R,5S)-benzyl 5-(((3-chloropyrazin-2-yl)methyl)carbamoyl)-2- (methoxymethyl)piperidine-l -carboxylate (60 mg, 0.138 mmol) in CH ₃ CN (3 mL ) was added POCl ₃ (106 mg, 0.69 mmol) at 0 °C. The mixture was stirred at 30 °C for 15 hours. The reaction mixture was poured into ice water, basified with NaHC0 ₃ and extracted with dichloromethane/Propan-2-ol(3 : l, 10mL><3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated to afford (2S,5R)-benzyl5-(8-chloroimidazo[l,5-a]pyrazin-3-yl)-2- (methoxymethyl)piperidine-l -carboxylate (57 mg, 98% yield).

¹ HNMR (400 MHz, CDC1 ₃ ): δ = 7.72 (s, 1H), 7.46 (d, J=5.0 Hz, 1H), 7.32 - 7.28 (m, 3H), 7.20 (d, J=4.8 Hz, 1H), 7.14 (br. s., 2H), 4.96 (s, 2H), 4.36 (t, J=5.4 Hz, 1H), 4.12 (d, J=14.1 Hz, 1H), 3.75 - 3.67 (m, 1H), 3.64 - 3.56 (m, 2H), 3.32 - 3.24 (m, 2H), 2.47 - 2.36 (m, 1H), 2.29 - 2.11 (m, 2H), 1.76 - 1.67 (m, 1H). MS (EI): M/Z (M+l): 415.15. (e)(2S.5R)-benzyl5-(l-bromo-8-chloroimidazo[1.5-a]pyrazin-3- yl)-2- (methoxymethyPpiperidine- 1 -carboxylate

A mixture of (2S,5R)-benzyl5-(8-chloroimidazo[l,5-a]pyrazin-3-yl) -2- (methoxymethyl)piperidine-l -carboxylate (1 g, 2.4 mmol) in CH ₃ CN (10 mL ) was added l-bromopyrrolidine-2,5-dione (0.5 g, 2.65 mmol). The mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water and extracted with dichloromethane. The combined organic layer was washed with brine 3, dried over anhydrous sodium sulfate and concentrated in vacuo to give (2S,5R)- benzyl5-(l-bromo-8-chloroimidazo[l,5-a]pyrazin-3-yl)-2-(meth oxymethyl)piperidine- 1 -carboxylate (1.2 g, yield 100%). ¹ HNMR (400 MHz, CDC1 ₃ ): δ= 7.43 (d, J=4.8 Hz, 1H), 7.34 - 7.29 (m, 3H), 7.18 (d, J=4.8 Hz, 3H), 4.99 (s, 2H), 4.33 (quin, J=5.8 Hz, 1H), 4.06 (dd, J=3.4, 13.9 Hz, 1H), 3.70 (dd, J=6.3, 9.8 Hz, 1H), 3.64 - 3.60 (m, 1H), 3.37 (s, 3H), 2.77 (s, 2H), 2.43 - 2.33 (m, 1H), 2.28 - 2.19 (m, 1H), 2.19 - 2.09 (m, 1H), 1.74 - 1.65 (m, 1H). MS (EI): M/Z (M+l): 493.06. ffl(2S.5R)-benzyl5-(8-amino-l-bromoimidazo[1.5-a]pyrazin-3-y P-2- (methoxymethyPpiperidine- 1 -carboxylate A mixture of (2S,5R)-benzyl5-(l-bromo-8-chloroimidazo[l,5-a]pyrazin-3-yl) -2- (methoxymethyl)piperidine-l-carboxylate (60 mg, 0.096 mmol) in H ₄ OH/ i-PrOH (3 mL:3mL )was stirred at 100 °C in a sealed tube for 7 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to afford (2S,5R)-benzyl 5-(8- amino- 1 -bromoimidazo[ 1 , 5-a]pyrazin-3 -yl)-2-(methoxymethyl)piperidine- 1 -carboxylate (40 mg, 89% yield).

MS (EI): M/Z (M+l): 474.1 1.

Intermediate 8

( 1 S.6R.8aS)-6-(8-amino- 1 -bromoimidazo[ 1.5-a]pyrazin-3 -yD- 1 -methyltetrahydro- 1H- oxazolo[3.4-a]pyridine-3(5H)-one

(a) (3R.6 S 1 -benzyl 3 -methyl 6-( 1 -hydroxy ethyDpiperidine- 1.3 -dicarboxylate

To a solution of (3R,6S)-l-benzyl 3-methyl 6-formylpiperidine- 1,3 -dicarboxylate (12.4 g, 40.7 mmol) in dry THF (190 mL) at -78 °C was added methylmagnesium bromide (19 ml, 3Min THF) dropwise. The reaction mixture was stirred at -78°C for 2 hrs and quenched with aq. H ₄ C1. The resulting mixture was dulited with DCM (100 mL) and H ₂ 0 (100 mL), the organic layer was washed with brine (100 mL), dried over Na ₂ S0 ₄ , and concetrated in vacuo The crude product was purified by column chromatography on silica gel eluted with PE/EA (100%-40%) to give (3R,6S)-l-benzyl-3-methyl 6-(l- hydroxyethyPpiperidine- 1,3 -dicarboxylate (6.5 g, yield 50.0%). ¹ HNMR (400 MHz,

CD ₃ OD): δ= 7.41 - 7.26 (m, 5H), 5.19 - 5.04 (m, 2H), 4.51 - 4.42 (m, 1H), 4.05 - 3.88 (m, 1H), 3.55 (br. s., 3H), 3.10 (d, J=9.8 Hz, 1H), 2.66 (br. s., 1H), 1.99 - 1.82 (m, 3H), 1.77 - 1.56 (m, 1H), 1.19 (d, J=6.0 Hz, 1H), 1.08 (d, J=6.0 Hz, 2H).

MS (ESI): M/Z (M+l): 322.4.

(b) (6R.8aS)-l-methyl-3-oxohexahydro-lH-oxazolo[3.4-a]pyridine-6 -carboxylic acid To a solution of (3R,6S)-1 -benzyl 3-methyl 6-( 1 -hydroxy ethyPpiperidine- 1,3- dicarboxylate (6.5 g, 20.2 mmol) in THF/H ₂ 0 (1/1, 150 ml) was added lithium hydorxide monohydrate (1.7 g, 40.4 mmol) portionwise. The resulting solution was stirred at 25 °C for 12 hrs under N2. The reaction was acidified to pH 5-6 with HC1, then dried by lyophilization to give a solid. The solid was extracted by DCM, then the organic layer was concentrated in vacuo to afford (6R,8aS)-l -methyl-3 -oxohexahydro- lH-oxazolo[3,4-a]pyridine-6-carboxylic acid (3 g, yield 75 %). ¹ HNMR (400 MHz, CD ₃ OD) : δ= 4.76 (quin, J=6.9 Hz, IH), 4.29 (quin, J=6.3 Hz, IH), 4.00 (dtd, J=1.5, 4.9, 13.2 Hz, IH), 3.77 - 3.64 (m, IH), 3.31 - 3.27 (m, IH), 3.06 - 2.87 (m, IH), 2.53 - 2.36 (m, IH), 2.32 - 2.17 (m, IH), 2.04 - 1.93 (m, IH), 1.73 (qd, J=3.3, 12.5 Hz, IH), 1.68 - 1.45 (m, 2H), 1.44 - 1.32 (m, 3H). MS (ESI): M/Z (M+l): 200.1.

(c) (6R.8aS)-N-(Y3 -chloropyrazin-2-yDmethyl)- 1 -methyl-3 -oxohexahydro- 1 H- oxazolo[3.4-a]pyridine-6-carboxamide

To a solution of (6R,8aS)-l-methyl-3-oxohexahydro-lH-oxazolo[3,4-a]pyridine-6 - carboxylic acid (600 mg, 3.02 mmol) in dry DCM (12 mL) at 5 °C wa added oxalyl dichloride (1.15 g, 9.04 mmol) dropwise followed by DMF (3 drops). The reaction mixture was stirred at 30 °C for 2 h and concentrated in. The crude product was dissolved in DCM (3 ml), to which a solution of (3-chloropyrazin-2-yl)methanamine (594 mg, 3.32 mmol) TEA (640 mg, 6.04 mmol) in DCM (10 ml) was added and the resulting mixture was stirred at 30 °C for 12 hrs. The reaction was dulited with DCM (20 mL) and H ₂ 0 (20 mL), the organic layer was washed with brine (20 mL), dried over Na ₂ S0 ₄ and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluted with PE/THF (100%-40 %) to give (6R,8aS)-N- ((3-chloropyrazin-2-yl)methyl)-l-methyl-3-oxohexahydro-lH-ox azolo[3,4-a]pyridine- 6-carboxamide (800 mg, 55.3 % yield). ¹ HNMR (400 MHz, CD ₃ OD): δ= 8.55 (d, J=2.5 Hz, IH), 8.36 (d, J=2.5 Hz, IH), 4.77 (quin, J=6.8 Hz, IH), 4.65 (s, 2H), 4.30 (quin, J=6.2 Hz, IH), 3.98 - 3.90 (m, IH), 3.78 - 3.70 (m, IH), 3.12 - 3.00 (m, IH), 2.51 (ttd, J=4.1, 12.1, 16.0 Hz, IH), 2.19 - 2.07 (m, IH), 2.00 (dd, J=3.5, 13.1 Hz, IH), 1.81 - 1.66 (m, 2H), 1.55 - 1.39 (m, 3H), 1.35 (d, J=6.5 Hz, 2H). MS (ESI): M/Z (M+l): 325.1.

(d) (6R.8aS)-6-(8-chloroimidazo[ 1.5-a]pyrazin-3 -yO- 1 -methyltetrahydro- 1H- oxazolo[3.4-a]pyridin-3(5H)-one

To a solution of (6R,8aS)-N-((3-chloropyrazin-2-yl)methyl)-l -methyl-3 -oxohexahydro- lH-oxazolo[3,4-a]pyridine-6-carboxamide (700 mg, 2.16 mmol) in anhydrous acetonitrile (10 mL) was added POCl ₃ (1.6 g, 10.77 mmol) at an ice water bath followed by DMF (160 mg, 2.16 mmol). The resulting mixture was stirred at 25 °C for 12 h. The reaction was poured to an ice-water mixture, neutralized with powdered sodium bicarbonate and extracted with DCM (20 mL x 3). The organic layer was washed with brine (30 mL), dried over Na ₂ S0 ₄ , and concentrated in vacuo to give (6R,8aS)-6-(8- chloroimidazo[l,5-a]pyrazin-3-yl)-l-methyltetrahydro-lH-oxaz olo[3,4-a]pyridin-3(5H)- one (630 mg, 95% yield). ¹ HNMR (400 MHz, CD ₃ OD): δ = 8.26 - 8.20 (m, 1H), 7.85 (s, 1H), 7.39 (d, J=5.0 Hz, 1H), 4.84 - 4.76 (m, 1H), 4.36 (quin, J=6.2 Hz, 1H), 4.07 - 3.97 (m, 1H), 3.87 (ddd, J=3.6, 7.7, 11.7 Hz, 1H), 3.54 - 3.33 (m, 2H), 2.30 - 2.14 (m, 1H), 2.10 - 1.78 (m, 3H), 1.77 - 1.54 (m, 1H), 1.47 - 1.38 (m, 3H). MS (ESI): M/Z (M+l): 306.1.

(e) (6R.8aS)-6-( 1 -bromo-8-chloroimidazo[ 1.5-a]pyrazin-3 -yD- 1 -methyltetrahydro- 1H- oxazolo[3.4-a]pyridin-3(5H)-one

To a solution of (6R,8aS)-6-(8-chloroimidazo[l,5-a]pyrazin-3-yl) -1-methyltetrahydro- lH-oxazolo[3,4-a]pyridin-3(5H)-one (50 mg, 0.163 mmol) in anhydrous DMF (1 mL) was added BS (30.5 mg, 0.17 mmol), and the resulting mixture was stirred for 2 hrs, and poured into an ice-water (10 mL). Sat. NaHC0 ₃ was added to the stirred mixture, which was then filtered and the cake was dissolved with ethyl acetate (50 mL), washed with H ₂ 0 (30 mL x 10). The organic layer was washed with brine (30 mL), dried over Na ₂ S0 ₄ , and concetrated in vacuo to afford (6R,8aS)-6-(l-bromo-8-chloroimidazo[l,5- a]pyrazin-3-yl)-l-methyltetrahydro-lH-oxazolo[3,4-a]pyridin- 3(5H)-one (56 mg, 89.2% yield). ¹ HNMR (400 MHz, CD ₃ OD) : δ = 8.21 (d, J=5.0 Hz, 1H), 7.36 (d, J=5.3 Hz, 1H), 4.82 - 4.79 (m, 1H), 4.60 (s, 1H), 4.01 (d, J=10.5 Hz, 1H), 3.86 (ddd, J=3.6, 7.9, 11.8 Hz, 1H), 3.33 (br. s., 1H), 2.22 (d, J=14.1 Hz, 1H), 1.96 - 1.85 (m, 1H), 1.83 - 1.77 (m, 1H), 1.70 (dt, J=3.4, 12.5 Hz, 1H), 1.39 (d, J=6.5 Hz, 3H). MS (ESI): M/Z (M+2): 386.8.

(f) (6R.8aS)-6-(8-amino- 1 -bromoimidazo[ 1.5-a]pyrazin-3 -yD- 1 -methyltetrahydro- 1H- oxazolo[3.4-a]pyridin-3(5H)-one

To a solution of c(6R,8aS)-6-(l-bromo-8-chloroimidazo[l,5-a]pyrazin-3-yl)-l- methyltetrahydro-lH-oxazolo[3,4-a]pyridin-3(5H)-one (400 mg, 1.04 mmol) in z ^' -PrOH (4 mL) was added ammonia hydrate (4 mL), and the resulting mixture was heated at 100 °C for 12 hrs and concentrated to afford (6R,8aS)-6-(8-amino-l-bromoimidazo [l,5-a]pyrazin-3-yl)-l-methyltetrahydro-lH-oxazolo [3,4-a]pyridin-3(5H)-one (400 mg). MS (ESI): M/Z (M+2): 367.9; Retention time : 0.548 min.

(g) ( 1 S.6R.8aS)-6-(8-amino- 1 -bromoimidazo[ 1.5-a]pyrazin-3 -yl)- 1 -methyltetrahydro- lH-oxazolo[3.4-a]pyridin-3(5H)-one

(6R, 8aS)-6-(8-amino- 1 -bromoimidazo[ 1 , 5-a]pyrazin-3 -yl)- 1 -methyltetrahydro- 1H- oxazolo[3,4-a]pyridin-3(5H)-one (400 mg , 1.1 mmol) was separated by chiral separation to afford ((l S,6R,8aS)-6-(8-amino-l-bromoimidazo[l,5-a]pyrazin-3-yl)-l- methyl tetrahydro-lH-oxazolo[3,4-a]pyridin-3(5H)-one, (Retention time: 7.46 min), (100 mg, 52.6% yield) followed by ((lR,6R,8aS)-6-(8-amino-l-bromoimidazo[l,5- a]pyrazin-3-yl)-l -methyltetrahydro -lH-oxazolo[3,4-a]pyridin-3(5H)-one (Intermediate 9). Separation conditionTnstrument: Berger MultiGramTM SFC , Mettler Toledo Co, Ltd; Column: AS 250 mm x30 mm, 5 um;Mobile phase: A: Supercritical C0 ₂ , B: MeOH (0.05% H ₄ OH) , A:B = 73 :27 at 60ml/min; Column Temp: 38 °C; Nozzle Pressure: lOOBar;

Nozzle Temp: 60 °C;

Evaporator Temp: 20 °C;

Trimmer Temp: 25°C;

Wavelength: 220 nm

(6R, 8aS)-6-(8-amino- 1 -bromoimidazo[ 1 , 5-a]pyrazin-3 -yl)- 1 -methyltetrahydro- 1H- oxazolo[3,4-a]pyridin-3(5H)-one:

¹ HNMR (400 MHz, CD ₃ OD) : δ = 7.59 (d, J=5.0 Hz, 1H), 6.98 (d, J=5.0 Hz, 1H), 4.60 (br. s., 1H), 4.35 (t, J=6.1 Hz, 1H), 3.97 (dd, J=2.9, 12.7 Hz, 1H), 3.49 - 3.41 (m, 1H), 3.27 - 3.16 (m, 1H), 2.15 (d, J=12.5 Hz, 1H), 2.09 - 2.01 (m, 1H), 1.91 - 1.79 (m, 1H), 1.65 - 1.53 (m, 1H), 1.45 (d, J=6.3 Hz, 3H). MS (ESI): M/Z (M+2): 367.9.

Intermediate 9

(lR.6R.8aS)-6-(8-amino- 1 -bromoimidazo[ 1.5-a]pyrazin-3-yO- 1 -methyltetrahydro- 1H- oxazolo[3.4-a]pyridin-3(5H)-one

(( 1R,6R, 8aS)-6-(8-amino- 1 -bromoimidazo[ 1 , 5-a]pyrazin-3 -yl)- 1 -methyltetrahydro lH-oxazolo[3,4-a]pyridin-3(5H)-one was isolated as pek 2 as described in Intermediate 8, step g. ( ¹ HNMR (400 MHz, CD ₃ OD) : δ = 7.58 (d, J=5.0 Hz, 1H), 6.98 (d, J=5.3 Hz, 1H), 4.60 (br. s., 1H), 3.97 (d, J=8.5 Hz, 1H), 3.89 - 3.78 (m, 1H), 3.28 - 3.17 (m, 2H), 2.20 (d, J=13.6 Hz, 1H), 1.88 (d, J=13.8 Hz, 1H), 1.82 - 1.75 (m, 1H), 1.69 (dt, J=3.4, 12.5 Hz, 1H), 1.38 (d, J=6.5 Hz, 3H). MS (ESI): M/Z (M+2): 367.9.

Intermediate 10E1 and 10E2

^' ~~o and o

(7R.9aS)-7-(8-amino- 1 -bromoimidazo[ 1.5-a]pyrazin-3 -yl)hexahydropyrido[2.1 - c] [ 1.4]oxazin-4(3H)-one & (7S.9aR)-7-(8-amino- 1 -bromoimidazo[ 1.5-a]pyrazin-3 - y0hexahydropyrido[2.1 -c] [ 1.4]oxazin-4(3H)-one a) methyl 6-((2-ethoxy-2-oxoethoxy)methyl)nicotinate

To a solution of methyl 6-(hydroxymethyl)nicotinate (15.0 g, 89.7 mmol) in tetrahydrofuran (300 mL) was added NaH (4.7 g, 10.4 mmol, 60%) in one portion at 0 °C . After 30 min, ethyl 2-bromoacetate (14.9 mL, 134.6 mmol) was added to the reaction mixture. The reaction mixture was heated to 70 °C overnight and quenched with saturated NaHC0 ₃ and extracted with ethyl acetate (150 mL><3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude product, which was purified by silica gel column chromatography (EA: PE = 10%~70%) to give methyl 6-((2-ethoxy-2- oxoethoxy)methyl)nicotinate (12.0 g, 53.1% yield). ¹ HNMR (400 MHz, CDC1 ₃ ): δ= 9.12 (d, J=1.5 Hz, IH), 8.29 (dd, J=8.2, 2.1 Hz, IH), 7.60 (d, J=8.0 Hz, IH), 4.79 (s, 2H), 4.20-4.25 (m, 4H), 3.93 (s, 3H), 1.25-1.30 ppm (m, 3H). MS (ESI): M/Z (M+l): 253.9. b) trans-methyl 4-oxooctahydropyrido[2.1 -c] [ 1.4]oxazine-7-carboxylate

To a solution of methyl 6-((2-ethoxy-2-oxoethoxy)methyl)nicotinate (8.0 g, 31.6 mmol) in AcOH (100 ml) was added NaBH ₃ CN (6.0 g, 94.8 mmol) portionwise at 0 °C and the reaction mixture was stirred at rt overnight. The reaction mixture was concentrated in vacuo and the residue was dissolved in H ₂ 0 (100 ml) and basified withaqueous

NaHC0 ₃ to pH 8. The reaction mixture was extracted with EA (100 mLx3). The organic layer was dried over Na ₂ S0 ₄ and concentrated in vacuo. The residue was dissolved into MeOH (300 ml) and the resulting mixture was refluxed for 4 h and concentrated in vacuo to afford the crude product, which was purified by silica gel column chromatography (THF:PE = 10%~80%) to give trans-methyl 4- oxooctahydropyrido[2, l-c][l,4]oxazine-7-carboxylate (2.55 g, 41.1% yield). ¹ HNMR (400 MHz, CDC1 ₃ ): δ= 4.85-4.97 (m, IH), 4.05-4.19 (m, 2H), 3.96 (dd, J=11.9, 4.4 Hz, IH), 3.67 (s, 3H), 3.50 (dd, J=11.9, 6.9 Hz, IH), 3.36 (qd, J=7.3, 4.1 Hz, IH), 2.52-2.62 (m, IH), 2.43 (tt, J=12.0, 3.8 Hz, IH), 2.18 (dt, J=13.5, 2.4 Hz, IH), 1.69-1.82 (m, IH), 1.55-1.67 (m, IH), 1.33-1.46 ppm (m, IH). MS (ESI): M/Z (M+l): 213.9.

c) trans-4-oxooctahydropyrido[2.1 -c] [ 1.4]oxazine-7-carboxylic acid

To a solution of methyl 4-oxooctahydropyrido[2, l-c][l,4]oxazine-7-carboxylate (2.55 g, 12.0 mmol) in tetrahydrofuran (100 mL) was added a solution of lithium hydroxide monohydrate (1.0 g) in H ₂ 0 (24 mL) and the reaction mixture was stirred at room temperture overnight under N ₂ atmosphere. The organic layer was evoprated under vacuum. The aqueous layer was acidified to pH 2 with 2M HC1 and lyophilized to afford the crude trans-4-oxooctahydropyrido[2, l-c][l,4]oxazine-7-carboxylic acid (2.2 g, 92.4% yield), which was used in next step without purification. ¹ HNMR (400 MHz, D ₂ 0): δ= 3.86-4.01 (m, 2H), 3.67 (dd, J=11.2, 3.4 Hz, IH), 3.51 (dd, J=l 1.3, 7.8 Hz, 2H), 3.23-3.33 (m, IH), 2.90-2.99 (m, IH), 2.52-2.63 (m, IH), 2.11 (d, J=10.0 Hz, IH), 1.82-1.92 (m, IH), 1.44-1.62 ppm (m, 2H) . MS (ESI): M/Z (M+l): 199.9. d) trans-N-((3-chloropyrazin-2-ynmethyl)-4-oxooctahydropyrido[2 .1-c][1.4]oxazine-7- carboxamide A mixture of trans-4-oxooctahydropyrido[2, l-c][l,4]oxazine-7-carboxylic acid (2.2 g, 11.0 mmol), (3-chloropyrazin-2-yl)methanamine hydrochloride (2.2 g, 3.70 mmol), HATU (6.3 g, 16.6 mmol ) and triethylamine (4.7 mL, 33.1 mmol ) in dichloromethane (100 mL) was stirred at room temperature for 4 hours. The reaction mixture was washed with water (150 mL) and extracted with dichloromethane (50 mLx 3) and the combined organic layers were concentrated in vacuo to afford the crude product, which was purified by silica gel column chromatography (THF: PE = 10%~100%) to give trans-N-((3-chloropyrazin-2-yl)methyl)-4-oxooctahydropyrido[ 2, l-c][l,4]oxazine-7- carboxamide (2.1 g, 58.3% yield). ¹ HNMR (400 MHz, CD ₃ OD): δ = 8.54 (d, J=2.4 Hz, IH), 8.34 (d, J=2.3 Hz, IH), 4.74 (dt, J=12.9, 1.9 Hz, IH), 4.60-4.67 (m, 2H), 4.11 (s, 2H), 4.02 (dd, J=11.9, 4.3 Hz, IH), 3.56-3.65 (m, 2H), 3.43-3.53 (m, IH), 2.67-2.76 (m, IH), 2.49 (tt, J=11.8, 3.7 Hz, IH), 2.05-2.15 (m, IH), 1.77-1.88 (m, 2H), 1.50 ppm (dd, J=l 1.8, 3.9 Hz, IH). MS (ESI): M/Z (M+l): 325.1. e) trans-7-(8-chloroimidazo[ 1.5-a]pyrazin-3 -yl)hexahydropyrido[2.1 -c] [ 1.4]oxazin- 4(3H)-one

To a solution of trans-N-((3-chloropyrazin-2-yl)methyl)-4-oxooctahydropyrido [2, 1- c][l,4]oxazine-7-carboxamide (1.3 g, 4.0 mmol) in anhydrous dichloromethane (100 mL) at 0 °C was added dimethylformamide (52 uL, 0.68 mmol), pyridine (3.25 mL, 40.0 mmol) and followed by POCl ₃ (1.82 mL, 20.0 mmol).. The resulting mixture was stirred at 25 ^° C for 5 h under a stream of nitrogen. The reaction mixture was poured into an ice-water mixture, neutralized with powerded sodium bicarbonate and extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na ₂ S0 ₄ and concentrated under vacuum to give a crude product. The crude product was purified by column chromatography on silica gel eluting with (THF: PE = 10% ~ 100%) to give trans-7-(8-chloroimidazo[ 1 , 5-a]pyrazin-3 -yl)hexahydropyrido[2, 1 -c] [ 1 ,4]oxazin-4(3H)- one (0.40 g, yield 33.3 %). 1H MR (400MHz, CDC1 ₃ ) δ = 7.81 (s, IH), 7.72 (dd, J=5.0, 0.8 Hz, IH), 7.37 (d, J=5.0 Hz, IH), 4.93 (dt, J=13.3, 2.1 Hz, IH), 4.20 (d, J=4.0 Hz, 2H), 4.07 (dd, J=12.0, 4.3 Hz, IH), 3.66 (dd, J=12.0, 6.0 Hz, IH), 3.52-3.60 (m, IH), 3.07-3.17 (m, IH), 2.78-2.89 (m, IH), 2.17-2.28 (m, 2H), 1.92 (dq, J=13.4, 3.2 Hz, IH), 1.62-1.70 ppm (m, IH) . MS (ESI): M/Z (M+l): 307.1. f) trans-7-(l-bromo-8-chloroimidazo[1.5-a]pyrazin-3-yl)hexahydr opyrido[2.1- c] [ 1.4 ^" |oxazin-4(3H)-one

N-bromosuccinimide (0.26 g, 1.43 mmol) was added to a solution of trans-7-(8- chloroimidazo [ 1 , 5 -a]pyrazin-3 -yl)hexahydropyrido [2, 1 -c] [ 1 ,4]oxazin-4(3H)-one (0.40 g, 1.30 mmol) in dimethylformamide (4 mL) and stirred at 25°C for 2h under a stream of nitrogen. The reaction was quenched with aqueous NaHC0 ₃ (40 mL),and extracted with EA (20 mL x3). The combined organic phase was washed with water (10 mL*5),followed by brine(10 mL). The organic phase was dried over anhydrous Na ₂ S0 ₄ and concentrated under vacuum to afford trans-7-(l-bromo-8-chloroimidazo[l,5- a]pyrazin-3-yl) hexahydropyrido[2, l-c][l,4]oxazin-4(3H)-one (0.50 g, yield 100%). 1H NMR (400MHz, CD ₃ OD) δ = 8.20 (d, J=5.0 Hz, 1H), 7.36 (d, J=5.3 Hz, 1H), 4.77-4.82 (m, 1H), 4.15 (s, 2H), 4.08 (dd, J=l 1.5, 4.0 Hz, 1H), 3.58-3.75 (m, 3H), 2.95 (t, J=12.4 Hz, 1H), 2.15-2.24 (m, 1H), 1.94-2.03 (m, 1H), 1.91 (d, J=3.3 Hz, 1H), 1.64-1.78 ppm (m, 1H) . MS (ESI): M/Z (M/M+2 = 1/1) 385.0/387.0.

g) trans-7-(8-amino- 1 -bromoimidazo[ 1.5-a]pyrazin-3 -yl)hexahydropyrido[2.1 - c] [ 1.4 ^" |oxazin-4(3H)-one

Trans-7-(l-bromo-8-chloroimidazo[l,5-a]pyrazin-3-yl) hexahydropyrido[2, l- c][l,4]oxazin-4(3H)-one (0.50 g, 1.30 mmol) was dissolved in H ₄ OH (6 mL) and i- PrOH (6 mL) and stirred at 110 °C for 12 h in a sealed tube. Then the reaction was cooled and concentrated at reduced pressure to afford 0.47 g of trans-7-(8-amino-l- bromoimidazo[ 1 , 5-a] pyrazin-3 -yl)hexahydropyrido[2, 1 -c] [ 1 ,4]oxazin-4(3H)-one, which was used directly in the next step without further purification. MS (ESI): M/Z (M/M+2 = 10/8) 366.0/368.0. (Condition : 5-95AB_220&254.M; R.T. :0.29) h) (7R.9aS)-7-(8-amino- 1 -bromoimidazo[ 1.5-a]pyrazin-3 -yl)hexahydropyrido[2.1 - c] [ 1.4 ^" |oxazin-4(3H)-one

Trans-7-(8-amino-l-bromoimidazo[l,5-a]pyrazin-3-yl)hexahy dropyrido[2, l- c][l,4]oxazin-4(3H)-one (0.47g, 1.3mmol) were separated by chiral separation (Instrument: Berger MultiGramTM SFC , Mettler Toledo Co, Ltd; Column : OD 250mm*30mm,5um; Mobile phase: A: Supercritical C0 ₂ , B: MeOH , A:B =65:35 at 50ml/min; Column Temp: 38°C; Nozzle Pressure: lOOBar; Nozzle Temp: 60°C; Evaporator Temp: 20°C ; Trimmer Temp: 25°C; Wavelength: 220nm) to obtain the compounds El : ((7R,9aS)-7-(8-amino-l-bromoimidazo[l,5-a]pyrazin-3- yl)hexahydropyrido[2, l-c][l,4]oxazin-4(3H)-one, (Rt = 6.29 min), 0.21 g, 44.7%). 1H MR (400MHz, CD ₃ OD) δ = 7.60 (d, J=5.5 Hz, IH), 7.00 (d, J=5.0 Hz, IH), 4.80 (dt, J=12.8, 1.9 Hz, IH), 4.16 (s, 2H), 4.09 (dd, J=11.5, 4.0 Hz, IH), 3.64-3.68 (m, IH), 3.57 (br. s., IH), 3.22-3.30 (m, IH), 2.91 (t, J=12.5 Hz, IH), 2.20 (d, J=13.1 Hz, IH), 1.87- 2.00 (m, 2H), 1.67-1.77 ppm (m, IH). MS (ESI): M/Z (M+l): 367.2.

(7S.9aR)-7-(8-amino- 1 -bromoimidazo[ 1.5-a]pyrazin-3-yOhexahydropyrido[2.1 - c] [ 1.4 ^" |oxazin-4(3HV one

E2: ((7S,9aR)-7-(8-amino-l-bromoimidazo[l,5-a]pyrazin-3-yl)hexah ydropyrido[2, l- c][l,4] oxazin-4(3H)-one (Rt = 6.83 min), 0.17g, 36.1%) was prepared by following the procedure of intermediate 11. 1H NMR (400MHz, CD ₃ OD) ) δ = 7.60 (d, J=5.5 Hz, IH), 7.00 (d, J=5.0 Hz, IH), 4.80 (dt, J=12.8, 1.9 Hz, IH), 4.16 (s, 2H), 4.09 (dd, J=l 1.5, 4.0 Hz, IH), 3.64-3.68 (m, IH), 3.57 (br. s., IH), 3.22-3.30 (m, IH), 2.91 (t, J=12.5 Hz, IH), 2.20 (d, J=13.1 Hz, IH), 1.87-2.00 (m, 2H), 1.67-1.77 ppm (m, IH). MS (ESI): M/Z (M+l): 367.2.

Intermediate 11

1 -bromo-3 -((7R.9aS)-octahydropyrido[2.1 -c] [ 1.4]oxazin-7-yl)imidazo[ 1.5-a]pyrazin-8-

(a) 1 -bromo-3 -(Y7R.9aSV octahydropyrido [2.1 -c] [ 1.4]oxazin-7-yl)imidazo [1.5- a] pyrazin- 8 -amine

To a solution of (7R,9aS)-7-(8-amino-l-bromoimidazo[l,5-a]pyrazin-3- yl)hexahydropyrido[2, l-c][l,4]oxazin-4(3H)-one (80 mg, 0.22 mmol) in lOmL of THE was added 10 M of BH ₃ .SMe ₂ (O. l lmL, 1.09 mmol) at 0 °C and stirred at room temperture overnight. Then the reaction mixture was quenched with MeOHand concentrated under vacuum to afford the crude product (60 mg, 78.0%), which was used in the next step without purification.

1H NMR (400MHz, DMSO-d6) : δ= 7.83 (d, J=5.8 Hz, IH), 7.67 (d, J=5.0 Hz, IH), 6.97 (d, J=5.0 Hz, IH), 6.91 (d, J=5.8 Hz, IH), 4.12 (d, J=5.0 Hz, IH), 3.75 (d, J=10.0 Hz, IH), 3.69 - 3.60 (m, IH), 3.51 (t, J=10.5 Hz, IH), 3.10 (t, J=10.5 Hz, IH), 2.89 (d, J=9.5 Hz, IH), 2.61 (d, J=10.8 Hz, IH), 2.38 - 2.16 (m, 2H), 2.05 - 1.91 (m, 2H), 1.61 - 1.47 (m, 2H), 1.31 - 1.17 (m, IH). MS (ESI): M/Z (M+l): 353.1.

Intermediate 12

l-bromo-3-((7S,9aR)-octahydropyrido[2, l-c][l,4]oxazin-7-yl)imidazo[l,5-a]pyrazin-8- amine

The procedure is as shown in Intermediate 56. (7S,9aR)-7-(8-amino-l- bromoimidazo[ 1 , 5-a]pyrazin-3 -yl)hexahydropyrido[2, 1 -c] [ 1 ,4]oxazin-4(3H)-one was reduced by BH ₃ .SMe ₂ to give l-bromo-3-((7S,9aR)-octahydropyrido[2, l-c][l,4]oxazin- 7-yl)imidazo[l,5-a]pyrazin-8-amine (30 mg, 52.0%) as a colorless oil. 1H NMR (400MHz, DMSO-d6) δ = 7.83 (d, J=5.8 Hz, IH), 7.67 (d, J=5.0 Hz, IH), 6.97 (d, J=5.0 Hz, IH), 6.91 (d, J=5.8 Hz, IH), 4.12 (d, J=5.0 Hz, IH), 3.75 (d, J=10.0 Hz, IH), 3.69 -

3.60 (m, IH), 3.51 (t, J=10.5 Hz, IH), 3.10 (t, J=10.5 Hz, IH), 2.89 (d, J=9.5 Hz, IH),

2.61 (d, J=10.8 Hz, IH), 2.38 - 2.16 (m, 2H), 2.05 - 1.91 (m, 2H), 1.61 - 1.47 (m, 2H), 1.31 - 1.17 (m, IH). MS (ESI): M/Z (M+l): 353.1.

Intermediate 13

(7R.9aS)-7-(8-amino- 1 -bromoimidazo[ 1.5-a]pyrazin-3 -yOhexahydro- lH-pyrido[ 1.2- a]pyrazin-4(6H)-one

(a) methyl 6-(bromomethyl)nicotinate

To a solution of methyl 6-methylnicotinate (30 g, 197 mmol) and BS (52.7 g, 296 mmol) in CC1 ₄ (300 mL) was added AIBN (3 g). Then the reaction mixture was heated to 80 °C and stirred for overnight. Then the reaction mixture was cooled and filtered, and the filtrate was concentrated under vacuum to give a crude residue. The crude residue was purified by silica gel column chromatography (PE/EA = 5/1) to give methyl 6-(bromomethyl)nicotinate (10 g, yield 22.2 %). 1H NMR (400MHz, CDC1 ₃ ) δ = 9.17 (d, J=1.5 Hz, IH), 8.30 (dd, J=2.0, 8.0 Hz, IH), 7.54 (d, J=8.0 Hz, IH), 4.58 (s, 2H), 3.96 (s, 3H).

(b) methyl 6-((((benzyloxy)carbonyn(2-methoxy-2-oxoethyl)amino)methyl)n icotinate

To a solution of methyl 6-(bromomethyl)nicotinate (10 g, 43 mmol) and methyl 2- (((benzyloxy)carbonyl)amino)acetate (14.5 g, 65 mmol) in DMF (200 mL) was added K ₂ C0 ₃ (29.6 g, 215 mmol). Then the mixture was stirred at room temperature for overnight. Then the reaction mixture was poured into water and extracted with EA (200 ml*3). The combined organic phase was washed with brine (500 mL) and dried over anhydrous Na ₂ S0 ₄ and filtered. The filtrate was concentrated under vacuum , ad purified by silica gel column chromatography (PE/EA = 2/1) to give methyl 6- ((((benzyloxy)carbonyl)(2-methoxy-2-oxoethyl)amino)methyl)ni cotinate (2.7 g, yield 16.8 %). 1H NMR (400MHz, CDC1 ₃ ) δ = 9.11 (dd, J=1.5, 6.0 Hz, IH), 8.30 - 8.13 (m, IH), 7.47 (d, J=8.0 Hz, IH), 7.35 - 7.25 (m, 5H), 5.17 (d, J=5.3 Hz, 2H), 4.73 (d, J=14.3 Hz, 2H), 4.19 - 4.10 (m, 2H), 3.95 (d, J=1.8 Hz, 3H), 3.74 - 3.61 (m, 3H).

(c) (trans)-2-benzyl 7-methyl 4-oxohexahydro-lH-pyrido[1.2-a]pyrazine-2.7(6H)- dicarboxylate To a solution of methyl 6-((((benzyloxy)carbonyl)(2-methoxy-2-oxoethyl) amino)methyl)nicotinate (2.5 g, 6.7 mmol) in AcOH (25 mL) was added NaBH ₃ CN (1.3 g, 20 mmol) in portions at 10 °C. The solution was stirred for overnight at room temperature. The reaction mixture was concentrated under reduced pressure to give a crude residue. The residue was dissolved in H ₂ 0 (50 ml) and aqueous NaHC0 ₃ was added to achieve pH = 8. The mixture was the extracted with EA (50 ml*3). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na ₂ S0 ₄ and concentrated under vacuum to give a crude of methyl 6- ((((benzyloxy)carbonyl)(2-methoxy-2-oxoethyl)amino)methyl)pi peridine-3-carboxylate (2.8 g). The crude of methyl 6-((((benzyloxy)carbonyl)(2-methoxy-2-oxoethyl) amino)methyl)piperidine-3-carboxylate (2.8 g, 7.9 mmol) in MeOH (30 mL) was stirred at 70 °C for 12 h under a stream of nitrogen. Then the mixture was concentrated under vacuum and the residue purified by silica gel column chromatography (PE/THF = 1/1) to give (trans)-2-benzyl 7-methyl 4-oxohexahydro-lH-pyrido[l,2-a]pyrazine-2,7(6H)- dicarboxylate (2 g, yield 74 %). 1H NMR (400MHz, CD ₃ OD) δ = 7.49 - 7.24 (m, 5H), 5.16 (d, J=3.3 Hz, 2H), 4.86 - 4.78 (m, IH), 4.22 - 4.03 (m, 2H), 3.98 - 3.87 (m, IH), 3.70 (s, 3H), 3.43 (d, J=8.8 Hz, 2H), 2.69 - 2.56 (m, IH), 2.45 (tt, J=3.9, 12.1 Hz, IH), 2.15 (d, J=13.1 Hz, IH), 1.81 (dd, J=2.5, 4.5 Hz, IH), 1.74 - 1.58 (m, IH).

(d) (trans)-2-((benzyloxy)carbonyn-4-oxooctahydro-lH-pyrido[1.2- a]pyrazine-7- carboxylic acid

To a solution of (trans)-2-benzyl 7-methyl 4-oxohexahydro-lH-pyrido[l,2-a] pyrazine- 2,7(6H)-dicarboxylate (1.2 g, 3.5 mmol) in THF/H ₂ 0 (1 : 1, 20 ml) was added LiOH.H ₂ 0 (290 mg, 7.0 mmol) portionwise. The resulting solution was stirred at 25 °C for 12 h under N ₂ . The reaction was acidified to pH = 5 with HC1 (1M), and then extracted with DCM/i-PrOH (4/1, 30 mL* 10). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give (trans)-2- ((benzyloxy)carbonyl)-4-oxooctahydro-lH-pyrido[l,2-a]pyrazin e-7-carboxylic acid (700 mg, yield 92.1 %). 1H NMR (400MHz, CD ₃ OD) δ = 7.46 - 7.27 (m, 5H), 5.23 - 5.06 (m, 2H), 4.25 - 4.16 (m, IH), 4.08 - 3.99 (m, IH), 3.87 (dd, J=10.0, 15.3 Hz, IH), 3.63 (dd, J=2.9, 12.4 Hz, IH), 3.02 (t, J=12.7 Hz, IH), 2.80 (tt, J=4.0, 12.2 Hz, IH), 2.29 (d, J=10.5 Hz, IH), 2.10 - 1.93 (m, 2H), 1.77 - 1.52 (m, 2H). (e) (trans)-benzyl 7-(((3-chloropyrazin-2-yl)methyl)carbamoyn-4-oxohexahydro-lH - pyrido [1.2-a]pyrazine-2(6H)-carboxylate

A mixture of (trans)-2-((benzyloxy)carbonyl)-4-oxooctahydro-lH-pyrido[l,2 -a] pyrazine-7-carboxylic acid (1.3 g, 3.9 mmol), (3-chloropyrazin-2-yl)methanamine hydrochloride (840 mg, 4.7 mmol), HATU (2.2 g, 5.8 mmol) and TEA (1.6 g, 15.6 mmol) in DMF (20 mL) was stirred at 25 °C for overnight. Then the reaction mixture was poured into water and extracted with EA (50 ml*3). The combined organic phase was washed with brine (100 mL), dried over Na ₂ S0 ₄ , concentrated under vacuum i to give the crude residue, which was purified by silica gel column chromatography (PE/THF = 1/3) to give (trans)-benzyl 7-(((3-chloropyrazin-2-yl)methyl)carbamoyl)-4- oxohexahydro-lH-pyrido[l,2-a]pyrazine-2(6H)-carboxylate (600 mg, yield 35.3 %). 1H NMR (400MHz, CD ₃ OD) δ = 8.52 (d, J=2.5 Hz, 1H), 8.33 (d, J=2.3 Hz, 1H), 7.40 - 7.29 (m, 5H), 5.15 (br. s., 2H), 4.77 - 4.67 (m, 1H), 4.12 (br. s., 1H), 3.96 - 3.85 (m, 1H), 3.48 (br. s., 2H), 2.71 (t, J=12.5 Hz, 1H), 2.52 - 2.36 (m, 1H), 2.11 - 1.97 (m, 2H), 1.90 - 1.71 (m, 2H).

(f) (trans)-benzyl 7-(8-chloroimidazo[L5-a]pyrazin-3-yn-4-oxohexahydro-lH-pyrid o [ 1.2-a]pyrazine-2(6H)-carboxylate

To a solution of (trans)-benzyl 7-(((3-chloropyrazin-2-yl)methyl)carbamoyl)-4- oxohexahydro -lH-pyrido[l,2-a]pyrazine-2(6H)-carboxylate (0.5 g, 1.1 mmol) in DCM (15 mL) was added DMF (13 mg, 0.18 mmol) and pyridine (0.88 mL, 11 mmol). Then to this solution was added POCl ₃ (0.52 mL, 5.5 mmol) at 0 °C and stirred for 6 h. The reaction mixture was poured into an ice-water mixture, neutralized with powdered sodium bicarbonate, and extracted with DCM(30 mL* 10). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give (trans)-benzyl-7-(8-chloroimidazo[l,5-a]pyrazin-3-yl)-4-oxoh exahydro-lH- pyrido[l,2-a]pyrazine-2(6H)-carboxylate (300 mg, yield 62.5 %). 1H NMR (400MHz, CD ₃ OD) δ = 8.18 (d, J=4.5 Hz, 1H), 7.85 (s, 1H), 7.38 (dd, J=3.6, 5.6 Hz, 5H), 7.33 (dd, J=3.0, 5.8 Hz, 1H), 5.17 (br. s., 2H), 4.84 - 4.75 (m, 1H), 4.19 (br. s., 2H), 3.99 - 3.84 (m, 1H), 3.72 (t, J=6.7 Hz, 1H), 3.63 (br. s., 2H), 3.03 - 2.93 (m, 1H), 2.23 - 2.16 (m, 1H), 1.64 (d, J=12.0 Hz, 1H), 1.40 (s, 1H). (g) (trans)-benzyl 7-( 1 -bromo-8-chloroimidazo[ 1.5-a]pyrazin-3 -yl)-4-oxohexahydro- lH-pyrido[1.2-a]pyrazine-2(6H)-carboxylate

N-bromosuccinimide (146 mg, 0.82 mmol) was added to a solution of benzyl 7-(8- chloroimidazo[ 1 ,5-a]pyrazin-3-yl)-4-oxohexahydro- lH-pyrido[ 1 ,2-a]pyrazine-2(6H)- carboxylate (300 mg, 0.68 mmol) in DMF (6 mL) and stirred at 25 °C for 2h under N ₂ . The reaction was quenched with NaHC0 ₃ and H ₂ 0, and extracted with EA (20 mL*3). The organic layer was washed with water (40 mL*3), and with brine, dried over anhydrous Na ₂ S0 ₄ , and concentrated to afford (trans)-benzyl 7-(l-bromo-8- chloroimidazo[l,5-a]pyrazin-3-yl)-4-oxohexahydro-lH-pyrido [l,2-a]pyrazine-2(6H)- carboxylate (300 mg, yield 88.2%). 1H NMR (400MHz, CD ₃ OD) δ = 8.19 (dd, J=0.8, 5.0 Hz, 1H), 7.86 (d, J=0.8 Hz, 1H), 7.42 - 7.35 (m, 5H), 5.19 (br. s., 2H), 4.83 (ddd, J=2.0, 4.0, 13.1 Hz, 1H), 4.21 (br. s., 2H), 4.01 - 3.89 (m, 1H), 3.64 (br. s., 2H), 2.98 (t, J=12.4 Hz, 1H), 2.22 (d, J=14.8 Hz, 1H), 2.11 - 1.89 (m, 2H), 1.66 (d, J=8.0 Hz, 1H).

(h) (7R.9aS)-benzyl 7-(8-amino- 1 -bromoimidazo [ 1.5 -a]pyrazin-3 -yl)-4-oxohexahydro- lH-pyrido[1.2-a]pyrazine-2(6H)-carboxylate

(Trans)-benzyl 7-(l-bromo-8-chloroimidazo[l,5-a]pyrazin-3-yl) -4-oxohexahydro-lH- pyrido[l,2-a]pyrazine-2(6H)-carboxylate (300 mg, 0.6 mmol) was dissolved in NH OH (7 mL) and i-PrOH (7 mL) and stirred at 100 ⁰ C for 12 h in a sealed tube. Then the reaction was cooled and concentrated under reduced pressure to afford 300 mg of (trans)-benzyl 7-(8-amino- 1 -bromoimidazo [ 1 , 5-a]pyrazin-3 -yl)-4-oxohexahydro- 1H- pyrido[l,2-a]pyrazine-2(6H)-carboxylate (crude), which was purified by chiral HPLC to give (7R, 9aS)-benzyl 7-(8-amino- 1 -bromoimidazo [ 1 , 5 -a]pyrazin-3 -yl)-4-oxohexahydro- lH-pyrido[l,2-a]pyrazine-2(6H)-carboxylate(0.1 g, 33.3%). (ESI): M/Z (M+l): M/Z (M+3) 501 : (M+l) 499 = 10 : 8 (Condition : 5-95AB_1.5min; R.T. :0.756). The chiral HPLC condition was [Instrument : Thar 80; Column : AS 250mm*20mm,20um; Mobile phase: A: Supercritical C0 ₂ , B: MeOH , A:B =55:45 at 80ml/min; Column Temp: 38 ° C; Nozzle Pressure: lOOBar; Nozzle Temp: 60 ° C; Evaporator Temp: 20 ° C; Trimmer Temp: 25 ⁰ C; Wavelength: 220nm].

(i) (7R.9aSV 7-(8-amino- 1 -bromoimidazo [ 1.5 -a]pyrazin-3 -yOhexahydro- 1 H-pyrido [1.2- a] pyrazin-4(6H)-one (7R, 9aS)-benzyl 7-(8-amino- 1 -bromoimidazo [1,5 -a]pyrazin-3 -yl)-4-oxohexa hydro- 1 H- pyrido[l,2-a]pyrazine-2(6H)-carboxylate (100 mg, 0.2 mmol) in HBr/HOAc (2 mL) was stirred at room temperature for 0.5 h. Isopropyl alcohol (5 mL) was then added to the reaction mixture and filtered. The filter cake was added to water (20 mL), and adjusted to pH = 9 with solid NaHC0 ₃ . The mixture was then extracted with DCM/i-PrOH (3/1, 10 mL*3). The organic layer was washed with brine, dried over anhydrous Na ₂ S0 ₄ , and concentrated under vacuum to afford of (7R,9aS)-7-(8-amino-l -bromoimidazo [1,5- a]pyrazin-3-yl)hexahydro-lH-pyrido[l,2-a]pyrazin-4(6H)-one (60 mg, yield 82.2%). 1H MR (400MHz, CD ₃ OD ) δ = 7.57 (d, J=5.3 Hz, 1H), 7.00 (d, J=5.0 Hz, 1H), 4.86 - 4.71 (m, 1H), 3.58 - 3.47 (m, 1H), 3.43 (d, J=4.3 Hz, 1H), 3.29 - 3.14 (m, 2H), 2.89 - 2.74 (m, 2H), 2.16 (d, J=13.6 Hz, 1H), 2.00 - 1.85 (m, 2H), 1.72 - 1.58 (m, 1H).

Intermediate 14

(7S.9aR)-7-(8-amino- 1 -bromoimidazo [ 1.5-a]pyrazin-3-yl)hexahydro- lH-pyrido[ 1.2- a]pyrazin-4(6H)-one

(a) (7 S.9aR)-benzyl 7-(8-amino- 1 -bromoimidazo [ 1.5 -a]pyrazin-3 -yO-4-oxohexahydro - lH-pyrido[1.2-a]pyrazine-2(6H)-carboxylate

(Trans)-benzyl 7-( 1 -bromo-8-chloroimidazo[ 1 , 5-a]pyrazin-3 -yl) -4-oxohexahydro- 1H- pyrido[l,2-a]pyrazine-2(6H)-carboxylate (300 mg, 0.6 mmol) was dissolved in H ₄ OH (7 mL) and i-PrOH (7 mL) and stirred at 100 ⁰ C for 12 h in a sealed tube. Then the reaction mixture was cooled and concentrated under reduced pressure to afford 300 mg of (trans)-benzyl 7-(8-amino- 1 -bromoimidazo [ 1 , 5-a]pyrazin-3 -yl)-4-oxohexahydro- 1H- pyrido[l,2-a]pyrazine-2(6H)-carboxylate (crude), which was purified by chiral HPLC to give (7 S, 9aR)-benzyl 7-(8-amino- 1 -bromoimidazo [ 1 , 5 -a]pyrazin-3 -yl)-4-oxohexahydro- lH-pyrido[l,2-a]pyrazine-2(6H)-carboxylate (60 mg, 20%). (ESI): M/Z (M+l): M/Z (M+3) 501 : (M+l) 499 = 10 : 8 (Condition : 5-95AB_1.5min; R.T. :0.760). The chiral HPLC condition was [Instrument : Thar 80; Column : AS 250mm*20mm,20um; Mobile phase: A: Supercritical C0 ₂ , B: MeOH , A:B =55:45 at 80ml/min; Column Temp: 38 ° C; Nozzle Pressure: lOOBar; Nozzle Temp: 60 ° C; Evaporator Temp: 20 ° C; Trimmer Temp: 25 ⁰ C; Wavelength: 220nm].

(b) (7 S.9aR)-7-(8-amino- 1 -bromoimidazo [ 1.5 -a]pyrazin-3 -yOhexahydro- 1 H-pyrido [1.2- a] pyrazin-4(6H)-one

(7 S, 9aR)-benzyl 7-(8-amino- 1 -bromoimidazo [ 1 , 5 -a]pyrazin-3 -yl) -4-oxohexahydro- lH-pyrido[l,2-a]pyrazine-2(6H)-carboxylate (60 mg, 0.12 mmol) was dissolved in HBr/HOAc (2 mL) and stirred at room temperature for 0.5 h. Isopropyl alcohol (5 mL) was added to the mixture andfiltered. The filter cake was added to water (20 mL), and adjusted to pH = 9 with solid NaHC0 ₃ . The mixture was then extracted with DCM/i- PrOH (3/1, 10 mL*3). The organic layer was washed with brine, dried over Na ₂ S0 ₄ ,and concentrated under vacuum to afford of (7S,9aR)-7-(8-amino-l- bromoimidazo[ 1 , 5-a]pyrazin-3 -yl)hexahydro- 1 H-pyrido [ 1 ,2-a]pyrazin-4(6H)-one (40 mg, yield 90.9%). (ESI): M/Z (M+l): M/Z (M+3) 367 : (M+l) 365 = 10 : 8 (Condition : 5-95AB_1.5min; R.T. :0.142)

Intermediate 15

(7R.9aS)-7-(8-amino- 1 -bromoimidazo [ 1.5-a]pyrazin-3 -yO-2-methylhexahydro- 1H- pyrido[ 1.2-a]pyrazin-4(6H)-one

(a) (7R.9aS)-7-(8-amino- 1 -bromoimidazo [ 1.5 -a]pyrazin-3 -yO-2-methylhexahydro- 1 H- pyrido [1.2-a]pyrazin-4(6H)-one

To a solution of (7R,9aS)-7-(8-amino-l-bromoimidazo[l,5-a]pyrazin-3-yl) hexahydro- lH-pyrido[l,2-a]pyrazin-4(6H)-one (200 mg, 0.55 mmol) in methanol (16 mL) was added formaldehyde (37%, 2.8 mL), NaBH ₃ CN (340 mg, 5.48 mmol) and HOAc (5.2 mL) . Then the mixture was stirred at 25 °C for 2 h. Then the reaction mixture was added to water (30 mL) and adjusted to pH = 9 with solid NaHC0 ₃ .=, The mixture was then extracted with DCM (20 mL*3). The organic layer was washed with brine, dried over Na ₂ S0 ₄ , concentrated under vacuum to afford of (7R,9aS)-7-(8-amino-l- bromoimidazo[ 1 , 5-a]pyrazin-3 -yl)-2-methylhexahydro - lH-pyrido[ 1 ,2-a]pyrazin-4(6H)- one (0.1 g, yield 48.15%). 1H NMR (400MHz, CD ₃ OD) δ = 7.57 (d, J=5.3 Hz, IH), 6.99 (d, J=5.0 Hz, IH), 4.83 - 4.75 (m, IH), 3.19 (d, J=16.6 Hz, 2H), 3.07 - 2.95 (m, 2H), 2.86 (t, J=12.4 Hz, IH), 2.43 (dd, J=7.3, 12.0 Hz, IH), 2.35 (s, 3H), 2.16 (d, J=13.1 Hz, IH), 2.03 - 1.87 (m, 2H), 1.76 - 1.58 (m, IH).

Intermediate 16

(7S.9aR)-7-(8-amino-l-bromoimidazo[1.5-a]pyrazin-3-yn-2-meth ylhexahydro-lH- pyrido[ 1.2-a]pyrazin-4(6H)-one

(a) (7 S.9aR)-7-(8-amino- 1 -bromoimidazo [ 1.5 -a]pyrazin-3 -yO-2-methylhexahydro- 1 H- pyrido [1.2-a]pyrazin-4(6H)-one

To a solution of (7S,9aR)-7-(8-amino-l-bromoimidazo[l,5-a]pyrazin-3-yl) hexahydro- lH-pyrido[l,2-a]pyrazin-4(6H)-one (200 mg, 0.55 mmol) in methanol (16 mL) was added formaldehyde (37%, 2.8 mL), NaBH ₃ CN (340 mg, 5.48 mmol) and HOAc (5.2 mL) . The mixture was stirred at 25 °C for 2 h. Then the reaction mixture was added to water (30 mL), and adjusted to pH = 9 with solid NaHC0 ₃ . The mixture was extracted with DCM (20 mL*3). The organic layer was washed with brine, dried over anhydrous Na ₂ S0 ₄ and concentrated under vacuum to afford of (7S,9aR)-7-(8-amino-l- bromoimidazo[ 1 , 5-a]pyrazin-3 -yl)-2-methylhexahydro - lH-pyrido[ 1 ,2-a]pyrazin-4(6H)- one (0.08 g, yield 38.5%). 1H NMR (400MHz, CD ₃ OD) δ = 7.57 (d, J=5.3 Hz, IH), 6.99 (d, J=5.0 Hz, IH), 4.84 - 4.72 (m, IH), 3.65 - 3.51 (m, IH), 3.27 - 3.13 (m, 2H), 3.07 - 2.94 (m, 2H), 2.86 (t, J=12.5 Hz, IH), 2.44 (dd, J=7.5, 12.3 Hz, IH), 2.35 (s, 3H), 2.03 - 1.88 (m, 2H), 1.76 - 1.60 (m, IH).

Intermediate 17E1 and 17E2

(7 S, 9aS)-7-(8-amino- 1 -bromoimidazo [ 1 , 5 -a]pyrazin-3 -yl)hexahydro- 1 H-quinolizin-

4(6H)-one

(7R, 9aR)-7-(8-amino- 1 -bromoimidazo [ 1 , 5 -a]pyrazin-3 -yl)hexahydro- 1 H-quinolizin-

4(6H)-one

(a) methyl 6-(4-ethoxy-4-oxobuty0nicotinate

To the solution of methyl 6-bromonicotinate (7.2g, 35.32 mmol) in anhydrous THF (200 mL) was added Pd(PPh ₃ ) ₄ (1.92 g, 1.66 mmol), followed by (4-ethoxy-4- oxobutyl)zinc(II) bromide (100 mL, 49.99 mmol). The resulting mixture was stirred at room tempereture overnight. The mixture was quenched with sat. aq. H ₄ C1 and H ₂ 0 (200 mL) and extracted with EA (35 mL*3). The combined organic phase was dried over sodium sulfate, filtered, concentrated to give a crude product. The crude was purified by column chromatography on silica gel eluting with PE / EA (0-60%) to give methyl 6-(4-ethoxy-4-oxobutyl)nicotinate (5.4g, 43%) as a light yellow oil. 1H NMR (400MHz, CDC1 ₃ ) δ = 9.13 (d, J=1.5 Hz, 1H), 8.20 (dd, J=2.3, 8.0 Hz, 1H), 7.39 - 6.98 (m, 1H), 4.12 (q, J=7.0 Hz, 2H), 3.94 (s, 3H), 2.96 - 2.72 (m, 2H), 2.36 (t, J=7.3 Hz, 2H), 2.15 - 1.98 (m, 2H), 1.25 (t, J=7.2 Hz, 3H).

(b) methyl 6-(4-ethoxy-4-oxobuty0piperidine-3 -carboxylate

To the solution of methyl 6-(4-ethoxy-4-oxobutyl)nicotinate (5.4 g, 21.51 mmol) in AcOH (60 mL) was added NaBCH ₃ (4.06 g, 64.54 mmol) at 10°C. The mixture was stirred at room temperature overnight. The mixture was concentrated under vacuum.. The residue was basified to PH 7-8 with NaHC0 ₃ , and H ₂ 0 (150 mL) and extracted with DCM/i-PrOH (3 : 1) (25 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give methyl 6-(4-ethoxy-4- oxobutyl)piperidine-3-carboxylate (5.3g, 95.49%) as a yellow oil. 1H NMR (400MHz, CDC1 ₃ ) δ = 6.58 (br. s., 1H), 4.18 - 4.07 (m, 2H), 3.74 - 3.61 (m, 3H), 3.28 - 3.10 (m, 1H), 2.99 - 2.83 (m, 2H), 2.43 - 2.30 (m, 2H), 2.04 (s, 3H), 1.81 - 1.47 (m, 6H), 1.32 - 1.21 (m, 3H).

(c) (racemic)-methyl 6-oxooctahydro-lH-quinolizine-3-carboxylate

The solution of methyl 6-(4-ethoxy-4-oxobutyl)piperidine-3-carboxylate (5.3 g, 20.62 mmol) in toluene (80 mL) was refluxed for 6h. The mxiture was concentrated under vacuum .and the residue was purified by Prep HPLC to give (trans)-methyl 6- oxooctahydro-lH-quinolizine-3-carboxylate (1.87g) as a yellow oil. 1H NMR (400MHz, CDC1 ₃ ) δ = 5.04 - 4.95 (m, 1H), 3.72 - 3.65 (m, 3H), 3.34 - 3.21 (m, 1H), 2.59 - 2.33 (m, 4H), 2.21 - 2.1 1 (m, 1H), 2.09 - 1.99 (m, 1H), 1.89 - 1.77 (m, 2H), 1.73 - 1.60 (m, 2H), 1.60 - 1.48 (m, 1H), 1.45 - 1.33 (m, 1H).

(d) (trans)-6-oxooctahydro-lH-quinolizine-3-carboxylic acid

LiOH (0.89 g, 21.30 mmol) was added to the solution of (trans)-methyl 6-oxooctahydro- lH-quinolizine-3-carboxylate (1.8 g, 8.52 mmol) in THF (20 mL) and H ₂ 0 (20 mL). The mixture was stirred at room temperature for 2 h. The mixture was then acidified to pH 5-6 and partitoned with H ₂ 0 (50 mL) and DCM/i-PrOH (3 : 1) (15 mL*3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give (trans)-6-oxooctahydro-lH-quinolizine-3-carboxylic acid (0.92 g, 84.49%) as a white solid.

1H NMR (400MHz, CHLOROFORM-d) δ = 5.08 - 4.98 (m, 1H), 3.32 - 3.20 (m, 1H), 2.58 - 2.40 (m, 3H), 2.39 - 2.30 (m, 1H), 2.18 (d, J=13.1 Hz, 1H), 2.08 - 1.98 (m, 1H), 1.88 - 1.77 (m, 2H), 1.73 - 1.62 (m, 2H), 1.57 - 1.46 (m, 1H), 1.44 - 1.35 (m, 1H).

(e) (trans)- -((3-chloropyrazin-2-yl)methyl)-6-oxooctahydro-lH-quinolizin e-3- carboxamide

A mixture of (trans)-6-oxooctahydro-lH-quinolizine-3-carboxylic acid (520 mg, 2.64 mmol), (3-chloropyrazin-2-yl)methanamine hydrochloride (570 mg, 3.17 mmol), HATU (1.50 g, 3.95 mmol) and TEA (0.79 g, 7.91 mmol) in DCM (13 mL) was stirred at 25 °C overnight. The mixture was quenched with H ₂ 0 (40 mL) and extracted with DCM (15 mL*3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by column chromatography on silica gel eluting with PE / THF (0-60%) to give (trans)-N- ((3 -chloropyrazin-2-yl)methyl)-6-oxooctahydro- 1 H-quinolizine-3 -carboxamide (0.7 g, 82.35%) as a light yellow solid. 1H NMR (400MHz, CDC13) δ = 8.53 - 8.41 (m, 1H), 8.33 (d, J=2.5 Hz, 1H), 6.96 (br. s., 1H), 5.08 - 4.88 (m, 1H), 4.73 - 4.61 (m, 2H), 3.40 - 3.26 (m, 1H), 2.72 - 2.57 (m, 1H), 2.47 - 2.28 (m, 3H), 2.12 - 2.00 (m, 2H), 1.89 - 1.77 (m, 4H), 1.73 - 1.62 (m, 1H), 1.58 - 1.47 (m, 1H).

(f) (trans)-7-(8-chloroimidazo[1.5-a]pyrazin-3-ynhexahydro-lH-qu inolizin-4(6H)-one

To a solution of (trans)-N-((3-chloropyrazin-2-yl)methyl)-6-oxooctahydro -1H- quinolizine-3-carboxamide (1.16 g, 3.6 mmol) in anhydrous DCM (18 mL) at 0 °C was added dimethylformamide (44.7 mg, 0.61 mmol), Pyridine (2.84 g, 36 mmoL), and followed by POCl ₃ (2.71g, 18.0 mmol) . The resulting mixture was stirred at 0 °C for 3 h. The reaction was poured to an ice-water mixture , neutralized with powdered sodium bicarbonate and extracted with DCM (10 mL*3). The organic layer was washed with brine, dried over Na ₂ S0 ₄ and concentrated to dryness under vacuum. The crude product was purified by column chromatography on silica gel eluting with PE / THF (0- 80%) to give (trans)-7-(8-chloroimidazo[l,5-a]pyrazin-3-yl)hexahydro-lH-q uinolizin- 4(6H)-one (0.34 g, 31.1%) as a white solid. 1H NMR (400MHz, CDC1 ₃ ) δ = 7.85 - 7.74 (m, 2H), 7.36 (d, J=5.0 Hz, 1H), 5.01 (td, J=2.3, 13.1 Hz, 1H), 3.54 - 3.40 (m, 1H), 3.15 - 2.99 (m, 1H), 2.75 - 2.64 (m, 1H), 2.53 - 2.32 (m, 2H), 2.26 - 2.19 (m, 2H), 2.17 - 2.07 (m, 1H), 2.00 - 1.85 (m, 2H), 1.82 - 1.70 (m, 1H), 1.66 - 1.62 (m, 1H), 1.59 - 1.52 (m, 1H).

(g) (trans)-7-( 1 -bromo-8-chloroimidazo[ 1.5-a]pyrazin-3 -yOhexahydro- lH-quinolizin- 4(6H)-one

N-bromosuccinimide (265.5 mg, 1.5 mmol) was added to a solution of (trans)-7-(8- chloroimidazo[l,5-a]pyrazin-3-yl)hexahydro-lH-quinolizin-4(6 H)-one (380 mg, 1.25 mmol) in DMF (8 mL) and stirred at 25 °C for 2 h under a stream of N ₂ . The reaction was partitioned with H ₂ 0 (35 mL) and EA (10 mL*3). The organic layer was washed with brine, dried over anhydrous Na ₂ S0 ₄ and concentrated to dryness under vacuum to afford (trans)-7-( 1 -bromo-8-chloroimidazo [ 1 , 5 -a]pyrazin-3 -yl) hexahydro- 1 H- quinolizin-4(6H)-one ) (445 mg, 92.7%) as a light yellow solid. 1H NMR (400MHz, CDCI ₃ ) δ = 7.76 (d, J=5.3 Hz, 1H), 7.34 (d, J=5.0 Hz, 1H), 5.03 - 4.91 (m, 1H), 3.45 (dtd, J=2.6, 6.2, 11.8 Hz, 1H), 3.08 - 2.95 (m, 1H), 2.74 - 2.61 (m, 1H), 2.50 - 2.32 (m, 2H), 2.30 - 2.07 (m, 3H), 1.98 - 1.83 (m, 2H), 1.81 - 1.69 (m, 1H), 1.66 - 1.62 (m, 1H), 1.58 - 1.49 (m, 1H).

(h) (trans)-7-(8-amino- 1 -bromoimidazo[ 1.5-a]pyrazin-3 -yDhexahydro- lH-quinolizin- 4(6H)-one

(Trans)-7-(l-bromo-8-chloroimidazo[l,5-a]pyrazin-3-yl) hexahydro-lH-quinolizin- 4(6H)-one ) (355 mg, 0.92mol) was dissolved in NH ₄ OH (5 mL) and i-PrOH (5 mL) and stirred at 100 ° C for 12 h in a sealed tube. Then the reaction was cooled to room temperature and concentrated under reduced pressure to give (trans)-7-(8-amino-l- bromoimidazo[l,5-a]pyrazin-3-yl) hexahydro-lH-quinolizin-4(6H)-one (310mg, 91.9%) as a yellow solid. MS (ESI): M/Z (M+l): 365.7.

(i) (7 S, 9aS)-7-(8-amino- 1 -bromoimidazo [ 1 , 5 -a]pyrazin-3 -yl)hexahydro- 1 H-quinolizin- 4(6H)-one

(Trans)-7-(8-amino- 1 -bromoimidazo [ 1 , 5 -a]pyrazin-3 -yl)hexahydro- 1 H-quinolizin- 4(6H)-one was purified by SFC to give (7S,9aS)-7-(8-amino-l-bromoimidazo[l,5-a] pyrazin-3-yl)hexahydro-lH-quinolizin-4(6H)-one (55 mg, 17.7%) (Rt = 7.07 min) as a yellow solid material. . The chiral HPLC condition was [Instrument : Thar 200; Column : OJ 250mm*20mm,20um; Mobile phase: A: Supercritical C0 ₂ , B: EtOH

(0.05% NH ₃ H ₂ 0 ) , A:B =80:20 at 70ml/min; Column Temp: 38°C; Nozzle Pressure: lOOBar; Nozzle Temp: 60°C; Evaporator Temp: 20°C; Trimmer Temp: 25°C; Wavelength: 220nm. 1H NMR (400MHz, CDC1 ₃ ) δ = 7.30 (d, J=5.0 Hz, 1H), 7.04 (d, J=5.0 Hz, 1H), 5.72 (br. s., 2H), 5.04 - 4.93 (m, 1H), 3.41 (d, J=10.3 Hz, 1H), 3.04 - 2.89 (m, 1H), 2.66 (t, J=12.3 Hz, 1H), 2.47 - 2.31 (m, 2H), 2.19 - 2.05 (m, 2H), 2.03 - 1.91 (m, 2H), 1.80 - 1.47 (m, 4H).

(7S,9aS)-7-((3S)-8-amino-l-bromo-3,8a-dihydroimidazo[l,5- a]pyrazin-3-yl)hexahydro- lH-quinolizin-4(6H)-one (E2) (Trans)-7-(8-amino-l-bromoimidazo[l,5-a]pyrazin-3- yl)hexahydro-lH-quinolizin-4(6H)-one was purified by SFC to give (7S,9aS)-7-((3S)-8- amino- 1 -bromo-3 , 8a-dihydroimidazo [ 1 , 5 -a]pyrazin-3 -yl)hexahydro- 1 H-quinolizin- 4(6H)-one (70 mg, 22.6%) (Rt = 6.15 min) as a yellow solid. 1H NMR (400MHz, CDCI ₃ ) δ = 7.30 (d, J=5.0 Hz, 1H), 7.04 (d, J=5.0 Hz, 1H), 5.72 (br. s., 2H), 5.04 - 4.93 (m, 1H), 3.41 (d, J=10.3 Hz, 1H), 3.04 - 2.89 (m, 1H), 2.66 (t, J=12.3 Hz, 1H), 2.47 - 2.31 (m, 2H), 2.19 - 2.05 (m, 2H), 2.03 - 1.91 (m, 2H), 1.80 - 1.47 (m, 4H).

Intermediate 18

(a) (S)-methyl 2-(benzylamino)-3-((tert-butyldiphenylsilynoxy)propanoate

(S)-methyl 2-(benzylamino)-3-hydroxypropanoate (5g, 23.9 mmol) was dissolved in 100 mL of CH ₂ C1 ₂ . Et3 (2.9g, 28.7 mmol) was added followed by a catalytic amount of DMAP (0.15g, (1.2 mmol). The reaction mixture was cooled to 0 °C and TBS-C1 (6.9g, 25.09 mmol) was added. The mixture was then warmed to rt and stirred for overnight. The mixture was quenched with water (100 mL) and extracted with CH ₂ C1 ₂ (100 mL). The organic layer was washed with sat H ₄ C1, dried over Na ₂ S0 ₄ and concentrated to give (S)-methyl 2-(benzylamino)-3-((tert-butyldiphenylsilyl)oxy) propanoate (10.2 g, 95%). LCMS: [M+H] ⁺ : 448.13; Rt= 2.01 min, 4 min, RY).Used as such for the next step without any further purification.

(b) (R)-2-(benzylamino)-3-((tert-butyldiphenylsilynoxy)propan-l- ol

To (S)-methyl 2-(benzylamino)-3-((tert-butyldiphenylsilyl)oxy)propanoate (5g, 11.17 mmol) in 100 mL of THF was added MeOH (0.5 ml) followed by 2.0 M LiBH4 in THF (6.7 mL). The reaction mixture was stirred at rt for 16hrs and then quenched with slow addition of sat. aq H ₄ C1 (100 mL). The mixture was extracted with EtOAc(3X100 mL) , dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated to give (R)-2-(benzylamino)-3-((tert-butyldiphenylsilyl)oxy)propan-l -ol (4.4 g, 94%). LCMS: [M+H] ⁺ : 422.20; Rt= 1.22 min, 2 min, RY). Used as such for the next step without any further purification.

(c) ((2R.5R)-4-benzyl-5-(((tert-butyldiphenylsilynoxy)methynmorp holin-2-yl)

methanol

(R)-2-(benzylamino)-3-((tert-butyldiphenylsilyl)oxy)propan-l -ol (6g, 14.3 mmol) was dissolved in 100 mL toluene, (S)-(+)-epichlorohydrin(1.58g, 17.2 mmol) was added and followed then by the slow addition of lithium perchlorate (1.82g, 17.2 mmol) over 30 min. The reaction was stirred at rt for 48h. A solution of sodium methoxide (25 wt % inCH30H) 25 mL was then added and the mixture was stirred for 3 days. Saturated aq H ₄ C1 (100 mL) was added, and the product was extracted with EtOAc (3X100 mL). The combined organics were washed with brine, dried over anhydrous MgS0 ₄ , filtered, and evaporated to dryness to give the crude product, which was purified by chromatography eluting with 20-50% EtOAc in hexanes to afford product ((2R,5R)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)mo rpholin-2-yl)methanol (2.6g, 38%). LCMS: [M+H] ⁺ :476.17, Rt= 1.15 min, 2 min, RY).

(d) (2R.5RVtert-butyl 5-(((tert-butyldiphenylsilvnoxy)methvn-2-(hvdroxymethvn morpholine-4-carboxylate

((2R,5R)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)mo rpholin-2-yl)methanol (4g, 8.41 mmol) was dissolved in 100 mL Ethanol at 20 °C, BOC ₂ 0 (2.2 g, 10.09 mmol) added followed by Et ₃ N (0.86g, 8.41 mmol) . The reaction mixture was degassed with N2 for -10 min. Pd(OH)2 (1.2g, 1.68 mmol) was added slowly and degassed with N2 for another 10 min. The reaction was hydrogenated with the Parr apparatus at 45-50 psi of ¾ O/N (20 hrs ). The mixture was then purged with N2, filtered on a pad of celite, and rinsed with EtOH (200 mL). The filtrate was concentrated to dryness to give a residue. The residue was dissolved in EtOAc (200 ml) and washed with water (150 mLx2). The organic phase was dried over MgS0 ₄ , filtered and concentrated under vacuum to afford a crude product, which wascolumn purified on silica gel using 5- 20%MeOH in DCM to give (2R,5R)-tert-butyl 5-(((tert-butyldiphenylsilyl)oxy)methyl)- 2-(hydroxymethyl) morpholine-4-carboxylate (2.6g, 64%). LCMS: [M+H] ⁺ :486.11, Rt= 1.43 min, 2 min, RY).

(e) (2R.5RVtert-butyl 5-(((tert-butyldiphenylsilvnoxy)methylV2-(((3-chloro pyrazin-2-ynmethyl)carbamoynmorpholine-4-carboxylate

(2R,5R)-tert-butyl 5-(((tert-butyldiphenylsilyl)oxy)methyl)-2-(hydroxymethyl) morpholine-4-carboxylate (2g, 4.12 mmol) was dissolved in 100 mL CH ₂ C1 ₂ and cooled to 0 °C. TEMPO(0.13 g, 0.82 mmol) was added, followed by (diacetoxyiodo)benzene (2.65 g, 8.24 mmol). The ice bath was removed, and the reaction was allowed to warm to room temperature and stirred overnight. The mixture was diluted with 200 mL ethyl acetate and washed with 10% Na ₂ S ₂ 0 ₃ , aq. satd. NaHC0 ₃ , and brine. The organic phase was dried with Na ₂ S0 ₄ , filtered and concentrated to give (2R,5R)-4-(tert-butoxycarbonyl)-5-(((tert-butyl diphenylsilyl)oxy)methyl)morpholine-2-carboxylic acid (1.36g, 66%). LCMS: [M- H] ⁺ :498.23 Rt= 1.33 min, 2 min, RY). Used as such for the next step without any further purification. (2R,5R)-4-(tert-butoxycarbonyl)-5-(((tert-butyldiphenylsilyl )oxy)methyl)morpholine-2- carboxylic acid (1.5g, 3.0 mmol) and (3-chloropyrazin-2-yl)methanamine. HC1 salt (0.54g, 3.0 mmol) were dissolved in DMF 100 mL. To the reaction mixture was added Et ₃ N (0.76g, 6.0 mmol) followed by slow addition of HATU (1.37g, 3.6 mmol) at 0 °C. The reaction was stirred at rt for 1 day under a stream of nitrogen and then quenched with sat. NaHC0 ₃ (100 mL) and extracted with EtOAc(2xl 50 mL). The combined organic layer was washed with water (200 mL) , brine (200mL), dried over anhydrous Na ₂ S0 ₄ , filtered, and evaporated. The crude residue was subjected to column purification using 20-50% EtOAc/Hex. to give (2R,5R)-tert-butyl 5-(((tert- butyldiphenylsilyl)oxy) methyl)-2-(((3-chloropyrazin-2- yl)methyl)carbamoyl)morpholine-4-carboxylate (0.86g, 46%). LCMS: [M-Boc +H] ⁺ :525.25 Rt= 2.74 min, 2 min, RY).

(f) (2R.5R)-tert-butyl 5-(((tert-butyldiphenylsilyl)oxy)methyl)-2-(8-chloro imidazo[1.5-a]pyrazin-3-yl)morpholine-4-carboxylate

(2R,5R)-tert-butyl 5-(((tert-butyldiphenylsilyl)oxy)methyl)-2-(((3-chloropyrazi n -2- yl)methyl)carbamoyl)morpholine-4-carboxylate (1.2g, 1.92 mmol) was dissolved in 1 : 1 (25 mL) mixture of acetonitrile:DMF. POCl ₃ (0.613 mL, 6.72 mmol) was added slowly at 0 °C. The reaction mixture was stirred at 40 °C for 45 mins under a stream of nitrogen. The reaction was cooled in an ice bath and poured into AMMONIUM HYDROXIDE (40 mL) solution cooled in an ice bath. The resultant mixture was extracted with EtOAc(3x50 mL), dried over anhydrous Na ₂ S0 ₄ , filtered, and evaporated to give crude product, which was column purified (using 20-30%) EtOAc in hex )to give (2R,5R)-tert-butyl 5-(((tert-butyldiphenylsilyl)oxy)methyl) -2-(8-chloroimidazo[l,5- a]pyrazin-3-yl)morpholine-4-carboxylate product 1 (0.57 g, 49%>) . LCMS: [M-Boc +H] ⁺ : 507.1 1 ; Rt= 1.40 min, 2 min, RY).

(g) (2R.5R)-tert-butyl 2-( 1 -bromo-8-chloroimidazo[ 1.5-a]pyrazin-3 -yl)-5-(((tert- butyldiphenylsilyl)oxy)methynmorpholine-4-carboxylate

To (2R,5R)-tert-butyl 5-(((tert-butyldiphenylsilyl)oxy)methyl)-2-(8-chloroimidazo [l,5-a]pyrazin-3-yl)morpholine-4-carboxylate (0.5g, 0.82 mmol) in 10 mL DMF at 0 °C, was added N-BROMOSUCCINIMIDE (0.15 g, 0.82 mmol) and stirred for lh at r. . . The reaction was quenched with 1M. Na ₂ S ₂ 0 ₃ (aq) solution (20 mL) and extracted with EtOAc (3X25 mL). The organic ohase was dried with Na ₂ S0 ₄ and concentrated to dryness to give the product (2R,5R)-tert-butyl 2-(l-bromo-8-chloroimidazo[l,5- a]pyrazin-3-yl)-5-(((tert-butyldiphenylsilyl)oxy)methyl)morp holine-4-carboxylate (0.496 g, 88%).Taken to next step without purification. LCMS: [M-Boc +H] ⁺ : 587.04; Rt= 1.42 min, 2 min, RY). (h) (hy2R.5RVtert-butyl 2-(l-bromo-8-((2.4-dimethoxybenzynamino midazo [1.5- a]pyrazin-3-yn-5-(((tert-butyldiphenylsilynoxy)methynmorphol ine-4- carboxylate

(2R,5R)-tert-butyl 2-(l-bromo-8-chloroimidazo[l,5-a]pyrazin-3-yl)-5-(((tert-but yl diphenylsilyl)oxy)methyl)morpholine-4-carboxylate (0.5g, 0.729 mmol), (2,4- dimethoxyphenyl)methanamine (0.25g, 1.46 mmol) and N-ethyl- _N -isopropylpropan-2- amine (0.283g, 2.186 mmol) were disolved in 20 mL 1,4-dioxane stirred at r.t for overnight. . Another 1 equiv. of (2,4-dimethoxyphenyl)methanamine was added and heated to 50°C and stirred for one more overnight. The reaction mixture was then concentrated under vacuum to give the crude (2R,5R)-tert-butyl 2-(l-bromo-8-((2,4- dimethoxybenzyl)amino)imidazo[l,5-a]pyrazin-3-yl)-5-(((tert- butyldiphenylsilyl)oxy)methyl)morpholine-4-carboxylate(0.516 g, 87%). LCMS: [M+H] ⁺ : 818.31, Rt= 1.28 min, 2 min, RY).

Intermediate I

N-(4-(3 -fiuorooxetan-3 -yl)pyridin-2-y0-4-(4.4.5.5-tetramethyl- 1.3.2-dioxaborolan-2- yObenzamide

(a) 3 -(2-chloropyridin-4-y0oxetan-3 -ol

To a solution of of 2-chloro-4-iodopyridine (1.0 g, 4.18 mmol) in anhydrous THF (10 mL) was added n-BuLi (3.34 mL, 8.35 mmol) at -78 °C. The mixture was stirred at -78 °C for 20 mins. Then oxetan-3-one (361 mg, 5.01 mmol) was added at -78 °C and the mixture was stirred at -78 °C for 50 mins. The mixture was quenched with saturated H ₄ CI (10 mL) and extracted with ethyl acetate (100 mLx3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to afford the crude product, which was purified on silica gel chromatography (EA: PE = 5% ~ 40%) to afford 3-(2-chloropyridin-4-yl)oxetan-3-ol (620 mg, yield 86%) as a yellow solid. (ESI): M/Z (M+l): 352 (Condition: 0-60AB_3MIN; R.T. : 1.303).

(b) 2-chloro-4-(3 -fiuorooxetan-3 -yOpyridine To a solution of 3-(2-chloropyridin-4-yl)oxetan-3-ol (650 mg , 3.50 mmol ) in dichloromethane (10 mL) was added DAST (847 mg , 5.25 mmol ) at -78 °C .The resulting mixture was stirred at -78 °C for 3 hrs and then warmed to room temperature and stirred for another 12 hours. The mixture was quenched by the addition of Sat. NaHC0 ₃ and extracted with dichloromethane (50 mL><3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to afford the crude product, which was purified on silica gel chromatography (EA: PE = 10% ~ 50%) to give 2-chloro-4-(3-fluorooxetan-3-yl)pyridine (120 mg, yield 18%) as a yellow solid. (ESI): M/Z (M+l): 188.0 (Condition: 5-95AB_1.5MIN; R.T. :0.597).

(c) -(4-(3 -fluorooxetan-3 -yl)pyridin-2-yl)-4-(4.4.5.5 -tetramethyl- 1.3.2-dioxaborolan-2- yObenzamide

To a clear solution of 2-chloro-4-(3 -fluorooxetan-3 -yl)pyridine (120 mg, 0.64 mmol) and 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide (174 mg ,0.70 mmol) in dioxane (6 mL ) was added xant-Phos (catalytic amount) followed by Pd(pddf)Cl ₂ (catalytic amount) under a stream of nitrogen.. Then the mixture was heated to 100 °C and stirred for 12 hours. The reaction mixture was then cooled to room temperature and filtered. The filtrate was concentrated in vacuum and purified on silica gel chromatography (EA: PE = 5% ~ 40%) to give N-(4-(3 -fluorooxetan-3 -yl)pyridin-2-yl)- 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide (70 mg, yield 27%) as a yellow solid. (ESI): M/Z (M+l): 399.1 (Condition: 5-95AB_1.5MIN; R.T. :0.897).

Intermediate II

-(4-cyanopyridin-2-yl)-3 -fluoro-4-(4.4.5.5 -tetramethyl- 1.3.2-dioxaborolan-2- yObenzamide

( a ) tert-butyl (4-cyanopyridin-2-yl)carbamate

A degassed mixture of 2-chloroisonicotinonitrile (10 g, 72.2 mmol), Carbamic acid tert- butyl ester (10.15 g, 86.6 mmol), Cs ₂ C0 ₃ (47 g, 144.4 mmol), X-phos (4.3 g, 9.02 mmol) and Pd(OAc) ₂ (810 mg, 3.6 mmol) in 150 mL of 1,4-dioxane was stirred at 80 ^° C for 2.5 hrs under a stream of N ₂ . The mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum to give a crude product, which was purified by silica gel column chromatography (PE : EA = 20 - 50 %) to give tert-butyl (4- cyanopyridin-2-yl)carbamate (12.0 g, yield: 76%). ¹ HNMR (400MHz, CDC1 ₃ ) : δ= 9.14 (br. s., 1H), 8.46 (dd, J=0.8, 5.3 Hz, 1H), 8.34 (s, 1H), 7.16 (dd, J=1.4, 5.1 Hz, 1H), 1.56 (s, 9H). MS (ESI): M/Z (M+l): 220.1.

( b ) 2-aminoisonicotinonitrile

To a solution of tert-butyl (4-cyanopyridin-2-yl)carbamate (6.5 g, 29.6 mmol) in 60 mL of DCM was added 20 mL of trifluoroacetic acid. The reaction was stirred at r.t. for 2 hrs, and then concentrated to dryness under vacuum. Aq. NaHC0 ₃ (10 mL) was added and extracted with EA (20 mL * 3). The organic layer was washed with brine (20 mL), dried over Na ₂ S0 ₄ and concentrated under vacuum to give 3.5 g crude of compound 2- aminoisonicotinonitrile. ¹ HNMR (400MHz, CDC1 ₃ ) : δ= 8.20 (d, J=5.3 Hz, 1H), 6.82 (dd, J=1.0, 5.3 Hz, 1H), 6.69 (s, 1H), 4.77 (br. s., 2H). MS (ESI): M/Z (M+l): 120.1.

( C ) 4-bromo-N 4-cyanopyridin-2-yD-3-fluorobenzamid

To a solution of 4-bromo-3-fluorobenzoic acid (8.2 g, 37.7 mmol) in 80 mL of DCM was added Oxalyl dichloride (14.4 g, 113.1 mmol) and 8 drops of DMF at 0°C . After stirring for 1 h, the mixture was concentrated under vacuum and dissolved in 70 mL of THF, and added to a solution of compound 2-aminoisonicotinonitrile (5.4 g, 45.3 mmol) in 90 mL of THF at 0°C . The reaction was stirred at 30°C for 12 hrs. The mixture was filtered and the filtrate was concentrated under vacuum to give a crude product. The crude product was purified by silica gel column chromatography (PE : EA = 20 - 60 %) to give 4-bromo-N-(4-cyanopyridin-2-yl)-3-fluorobenzamide (4.7 g, yield: 39.2%). ¹ HNMR (300MHz, DMSO-d6) : δ= 11.46 (s, 1H), 8.67 (d, J=5.1 Hz, 1H), 8.48 (s, 1H), 8.02 (dd, J=2.0, 9.7 Hz, 1H), 7.94 - 7.86 (m, 1H), 7.85 - 7.80 (m, 1H), 7.66 (dd, J=1.3, 4.9 Hz, 1H). MS (ESI): M/Z (M+2): 320.9.

( d ) N-(4-cyanopyridin-2-yl)-3 -fluoro-4-(4 A 5.5-tetramethyl- 1.3.2-dioxaborolan-2- yObenzamide

A degassed mixture of 4-bromo-N-(4-cyanopyridin-2-yl)-3-fluorobenzamide (900 mg, 2.8 mmol), Bispinacolatodiboron (929 mg, 3.65 mmol), KOAc (824 mg, 8.4 mmol), and Pd(dppf)Cl ₂ (143 mg, 0.2 mmol) in 15 mL of 1,4-dioxane was stirred at 90°C for 12 hrs under a stream of N ₂ . The mixture was cooled to room temperature and H ₂ 0 (10 mL) was added. It was then extracted with ethyl acetate (15 mL * 3). The organic layers were washed with brine (20 mL), dried over Na ₂ S0 ₄ , and concentrated under vacuum to give a crude product, which was purified by silica gel column chromatography (PE : EA = 20 ~ 80 %) to give N-(4-cyanopyridin-2-yl)-3-fluoro-4-(4,4,5,5-tetramethyl-l,3, 2- dioxaborolan-2-yl)benzamide (700 mg, yield: 68%). ¹ HNMR (400MHz, CDC1 ₃ ) : δ= 8.72 (s, IH), 8.70 (s, IH), 8.48 (dd, J=0.8, 5.0 Hz, IH), 7.89 (dd, J=5.8, 7.8 Hz, IH), 7.66 (dd, J=1.5, 7.5 Hz, IH), 7.61 (dd, J=1.4, 9.4 Hz, IH), 7.32 (dd, J=1.3, 5.0 Hz, IH), 1.39 (s, 12H). MS (ESI): M/Z (M+l): 368.2.

Intermediate III

N-(4-cyanopyridin-2-yn-2-fluoro-4-(4.4.5.5-tetramethyl-L3.2- dioxaborolan-2- yObenzamide

(a) 4-bromo-N-(4-cyanopyridin-2-yl)-2-fluorobenzamide

To a solution of 4-bromo-2-fluorobenzoic acid (3.03 g, 13.8 mmol) in anhydrous DMF (30 mL) was added HATU (5.25 g, 13.8 mmol), and stirred at 30°C for 30 min. Tri- ethylamine (3.8 g, 37.8 mmol) was added, followed by 2-aminoisonicotinonitrile (1.5 g, 12.6 mmol. The mixture was stirred at 30 °C for 12 hrs. H ₂ 0 (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL * 3). The organic layers were washed with brine(20 mL), dried over Na ₂ S0 ₄ evaporated, and purified by flash chromatography (PE : EA = 20 ~ 60%) to get the compound 4-bromo-N-(4- cyanopyridin-2-yl)-2-fluorobenzamide (1.56 g, yield: 39%). ¹ HNMR (400MHz,

CDC1 ₃ ) : δ= 8.71 (s, IH), 8.50 (d, J=4.5 Hz, IH), 8.03 (t, J=8.4 Hz, IH), 7.89 (t, J=8.2 Hz, IH), 7.51 (dd, J=1.6, 8.4 Hz, IH), 7.46 - 7.42 (m, IH), 7.33 (dd, J=1.4, 5.1 Hz, IH). MS (ESI): M/Z (M+2): 320.9.

(b) N-(4-cvanopyridin-2-vn-2-fluoro-4-(4.4.5.5-tetramethyl-1.3.2 -dioxaborolan-2- yObenzamide

A degassed mixture of 4-bromo-N-(4-cyanopyridin-2-yl)-2-fluorobenzamide (1.2 g, 3.7 mmol), Bispinacolatodiboron (1.2 g, 4.8 mmol), KOAc (1.1 g, 11.2 mmol), Cy ₃ P (84 mg, 0.3 mmol), and Pd(OAc) ₂ (67 mg, 0.3 mmol) in 30 mL of 1,4-dioxane was stirred at 90 °C for 12 hrs. The mixture was cooled to room temperature and H ₂ 0 (50 mL) added. The mixture was extracted with ethyl acetate (50 mL * 3). The organic layer was washed with brine(50 mL), dried over Na ₂ S0 ₄ , concentrated under vacuum to give a crude product, which was then purified by flash chromatography (PE : EA = 20 - 60 %) to give the compound N-(4-cyanopyridin-2-yl)-3-fluoro-4-(4,4,5,5-tetramethyl-l,3, 2- dioxaborolan-2-yl)benzamide (500 mg, yield: 38%). ¹ HNMR (400MHz, CDC1 ₃ ) : δ= 8.72 (s, 1H), 8.49 (d, J=5.0 Hz, 1H), 8.12 (t, J=7.7 Hz, 1H), 7.73 (d, J=7.8 Hz, 1H), 7.62 (d, J=12.0 Hz, 1H), 7.37 (s, 1H), 7.31 (d, J=4.0 Hz, 1H), 1.36 (s, 12H). MS (ESI): M/Z (M+l): 368.2.

Intermediate IV

(a) 4-bromo-N-(4-cyanopyridin-2-yl)-3-methoxybenzamide

To the solution of 2-aminoisonicotinonitrile (1.4g, 11.75mmol) in toluene (60mL) was added Al(Me) ₃ (5.87ml, 11.75mmol) at room tempereture. After stiring for 30min, methyl 4-bromo-3-methoxybenzoate (2.88g, 11.75mmol) was added. The reaction was refluxed for 3h. The mixture was quenched with IN HCl and partitioned with H ₂ 0 (45 mL) and EA (10 mL*3). The EA layer was dried, filterted, concentrated, and purified by column chromatography on silica gel (PE: EA = 0-60%) to give 4-bromo-N-(4- cyanopyridin-2-yl)-3-methoxybenzamide (2.55g, 65.38%) as a white solid. 1H NMR (400MHz, CDC1 ₃ ) δ = 8.69 (s, 1H), 8.65 (br. s., 1H), 8.49 (dd, J=0.8, 5.0 Hz, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.51 (d, J=2.0 Hz, 1H), 7.33 - 7.29 (m, 2H), 4.01 (s, 3H).

(b) N-(4-cyanopyridin-2-yl)-3-methoxy-4-(4,4,5,5-tetramethyl-l,3 ,2-dioxaborolan-2- yl)benzamide To the solution of 4-bromo-N-(4-cyanopyridin-2-yl)-3-methoxybenzamide (2.55g, 7.68 mmol) in dioxane (50ml) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2- dioxaborolane) (2.92g, 11.52mmol), KOAc (2.25g, 23.04mmol), and Pd(dppf)Cl ₂ (0.275g, 0.38mmol). The mixture was purged with N ₂ and stirred at 90°C for 2h. The mixture was partitioned with H ₂ 0 (85 mL) and EA (20 mL*3). The EA layer was purified by column chromatography on silica gel (PE: EA = 0-55%) to give N-(4- cyanopyridin-2-yl)-3 -methoxy-4-(4,4, 5 , 5 -tetramethyl- 1,3,2- dioxaborolan-2- yl)benzamide ( 0.99g, 34%) as a white solid. 1H NMR (400MHz, CDC1 ₃ ) δ = 8.83 - 8.63 (m, 2H), 8.47 (dd, J=0.8, 5.0 Hz, 1H), 7.78 (d, J=7.5 Hz, 1H), 7.45 (d, J=1.3 Hz, 1H), 7.39 (dd, J=1.4, 7.7 Hz, 1H), 7.30 (dd, J=1.3, 5.0 Hz, 1H), 3.93 (s, 3H), 1.38 (s, 12H)

Intermediate V

N-(4-cyanopyridin-2-yn-2-methyl-4-(4.4.5.5-tetramethyl-1.3.2 -dioxaborolan-2- yObenzamide

2-methyl-4-(4,4,5,5-tetramethyl -l,3,2-dioxaborolan-2-yl)benzamide (2.4 g, 9.19 mmol) was prepared following the same procedure as in Intermediate IV. To a clear solution of 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benz amide (2.4 g, 9.19 mmol) and 2-chloroisonicotinonitrile (1.4 g, 10.11 mmol) in dioxane (50 mL ) was added xant-Phos (catalytic amount) followed by Pd(pddf)Cl ₂ (336 mg, 0.46 mmol) under a stream of nitrogen. Then the mixture was heated to 100 °C and stirred for 12 hours. The mixture was then cooled to room temperature and filtered. The filtrate was concentrated under vacuum and purified on silica gel chromatography (EA: PE = 5% ~ 40%) to give N-(4-cyanopyridin-2-yl)-2-methyl-4-(4,4,5,5-tetramethyl-l,3, 2- dioxaborolan-2-yl)benzamide (1.4 g, yield 42%) as a yellow solid. 1H NMR (400MHz, CD ₃ OD ) δ = 8.58 (s, 1H), 8.53 (d, J=5.0 Hz, 1H), 7.70 - 7.63 (m, 2H), 7.50 (d, J=7.3 Hz, 1H), 7.43 (dd, J=1.3, 5.0 Hz, 1H), 2.47 (s, 3H), 1.36 (s, 12H).

Intermediate VI

2-methyl-4-(4.4.5.5 e ramethyl-1.3.2-dioxaborolan-2-yl)-N-(4- (trifluoromethy0pyridin-2-y0benzamide

(a) 4-bromo-2-methyl-N-(4-(trifluoromethynpyridin-2-ynbenzamide

To a solution of 4-bromo-2-methylbenzoic acid ( 5 g, 0.023 mmol) in dichloromethane (50 mL) was added (COCl) ₂ ( 8.85 g, 0.069 mmol) at 0 °C. The mixture was stirred at room temperature, for 2 hours and then evaporated and dissolved in tetrahydrofuran (100 mL) . 4-(trifluoromethyl)pyridin-2-amine ( 7.5 g, 0.046 mmol) was added portionwise at 0 °C. The reaction mixture was stirred at 80 °C overnight. The mixture was cooled to room temperature and filteredthe filtrate was concentrated to dryness to give 4-bromo-2-methyl-N-(4-(trifluoromethyl)pyridin-2-yl)benzamid e. (6 g, yield 70%).

(ESI): M/Z (M+l): M/Z (M+3) 361 : (M+l) 359 (Condition: 5-95AB_1.5MIN; R.T. :0.904)

(b )2-methyl-4-(4.4.5.5-tetramethyl-1.3.2-dioxaborolan-2-vn-N-( 4- (trifluoromethy0pyridin-2-y0benzamide

To a degassed mixture of 4-bromo-2-methyl-iV-(4-(trifluoromethyl)pyridin-2- yl)benzamide ( 3 g, 8.356 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2- dioxaborolane) ( 2.5 g, 9.8 mmol) in dioxane (50 mL) was added Pd(dppf)C12(catalytic amount) and KOAc (2.45 g, 25 mmol) under N ₂ . The mixture was heated to 100 °C and stirred for 3 hour. The reaction mixture was cooled to room temperature and concentrated under vacuum to give a crude product, which was and purified on silica gel chromatography (PE: EA = 100% ~ 80%) to afford 2-methyl-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-N-(4-(trifluoromethyl)pyridin-2-yl) benzamide ( 3 g, yield 88%). 1H MR (400MHz, DMSO-d6) : δ= 11.31 (s, 1H), 8.63 (d, J=5.3 Hz, 1H), 8.52 (s, 1H), 7.92 (s, 1H), 7.59 - 7.47 (m, 4H), 2.38 (s, 3H), 1.31 - 1.27 (m, 13H). MS (ESI): M/Z (M+l):407.1.

Intermediate VII

(4-((4-cyclopropylpyridin-2-yl)carbamoyn-3-fluorophenynboron ic acid

To a solution of 4-cyclopropylpyridin-2-amine (0.5 g, 3.7 mmol) and 4-borono-2- fluorobenzoic acid (0.7 g, 4.1 mmol) in 5 mL of DMF was added DIEA (0.95 g, 7.5 mmol). After stirring for 5 min at 0 °C, HATU (1.56 g, 4.1 mmol) was added, and the resulting mixture was stirred at room temperature overnight, and then stirred at 80 °C for 5 hours. The reaction mixture was cooled to room temperature and treated with water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na ₂ S0 ₄ and concentrated under vacuum to give a crude residue. The residue was purified by column chromatography on silica gel (EA/MeOH = 20/1) to afford (4-((4-cyclopropylpyridin-2-yl)carbamoyl)-3-fluorophenyl)bor onic acid (0.7 g, yield 63.6%).

MS-ESI (m/z): 301 (M+l) + (Acq Method: 0-60AB_2min;Rt: 0.98 min) Intermediate VIII

N-(4-cyclopropylpyridin-2-yl)-2-methyl-4-(4.4.5.5-tetramethy l-1.3.2-dioxaborolan-2- yObenzamide

(a) 4-bromo-2-methylbenzamide To a solution of 4-bromo-2-methylbenzoic acid ( 8 g, 0.037 mmol) in dichloromethane (80 mL) was added (COCl) ₂ (9.4 mL) at 0 °C. The mixture was stirred at room temperature for 2 hoursand then evaporated to dryness under vacuum and dissolved in dichloromethane (80 mL) and added to a solution of H ₄ OH ( 4.2 g, 0.09 mmol) in dichloromethane (20 mL) at 0 ⁰ C. The reaction mixture was stirred at 25 °C for 1 h and filtered. The filtrate was dried to give 4-bromo-2-methylbenzamide ( 8 g, yield 100%).

(ESI): M/Z (M+l): M/Z (M+3) 216 : (M+l) 214 (Condition: 5-95AB_1.5MIN; R.T. :0.647)

(b) 2-methyl-4-(4.4.5.5-tetramethyl-1.3.2-dioxaborolan-2-ynbenza mide

To a degassed mixture of 4-bromo-2-methylbenzamide (5 g, 0.023 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) ( 6.5 g, 0.025 mmol) in dioxane (100 mL) was added Pd(dppf)Cl ₂ (950 mg, 0.002 mmol) and KOAc (6.8 g, 0.069 mmol) under N ₂ . The mixture was heated to 100 °C and stirred for 3 hours. The reaction mixture was cooled to room temperature and concentrated to dryness under vacuum to give a crude product, which waspurified on silica gel chromatography ( PE: EA = 100% ~ 60%) to afford 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)benzamide (3.6 g, yield 60%). 1H NMR (400MHz, CD ₃ OD ) :δ= 7.66 - 7.59 (m, 1H), 7.41 (d, J=7.5 Hz, 1H), 2.45 (s, 3H), 1.40 - 1.33 (m, 12H). MS (ESI): M/Z (M+l):262.1.

(c) N-(4-cyclopropylpyridin-2-yn-2-methyl-4-(4.4.5.5-tetramethyl -1.3.2-dioxaborolan-2- yObenzamide

To a degassed mixture of 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzamide (3.5 g, 0.013 mol) and 2-chloro-4-cyclopropylpyridine ( 2.3 g, 0.015 mol) in dioxane (60 mL) was added Pd ₂ (dba) ₃ (614 mg, 0.65 mmol) Xant-phos (700 mg, 0.0013 mol) and Cs ₂ C0 ₃ (8.7 g, 0.026 mmol) under N ₂ . The mixture was stirred at 100 °C for 13 hours. The reaction was cooled to room temperature and concentrated to dryness - under vacuum to give a crude product, whic was purified on silica gel chromatography ( PE: EA = 100% ~ 70%) to afford N-(4-cyclopropylpyridin-2-yl)-2- methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzam ide (1.5 g, yield 30%). 1H NMR (400MHz, CD ₃ OD ) δ = 8.10 (d, J=5.3 Hz, 1H), 7.93 (s, 1H), 7.70 - 7.63 (m, 2H), 7.48 (d, J=7.5 Hz, 1H), 6.87 (dd, J=1.4, 5.4 Hz, 1H), 2.46 (s, 4H), 2.02 - 1.93 (m, 1H), 1.36 (s, 15H), 1.17 - 1.11 (m, 2H), 0.90 - 0.83 (m, 2H). MS (ESI): M/Z (M+l):379.2.

Intermediate IX

(a) 4-(trifluoromethyl)-2-vinylpyridine

A mixture of 2-chloro-4-(trifluoromethyl)pyridine (10 g, 55.2 mmol), potassium vinyl trifluoroborate (11 g ,82.8 mmol), Pd(dppf)Cl ₂ (500 mg) and K ₂ C0 ₃ (15.2 g, 110.4 mmol) in the mixed solvent of dioxane (150 mL) and H ₂ 0 (15 mL) was stirred at 110 °C for 1.5 hrs under a stream of N ₂ . The reaction mixture was cooled to room temperature, filtered and evaporated to give a crude residue.. The residue was purified by column chromatography on silica gel eluted with PE: EA= 10: 1 to afford 4- (trifluoromethyl)-2-vinylpyridine (4.5g , 47.4%).

MS-ESI (m/z): 174.0(M+1) ⁺ (Acq Method: 10-80AB_2min; Rt: 0.94 min)

(b) 4-(trifluoromethyl)picolinaldehyde

To a solution of 4-(trifluoromethyl)-2-vinylpyridine (4.5 g, 25.8 mmol) and Os0 ₄ (60 mg, 2.58 mmol) in THF (50mL) was added NaI0 ₄ (l l g, 51.4 mmol). The resulting mixture was stirred at room temperature for 3 hours. The mixture was treated with H ₂ 0 and extracted with EA. The EA layer was washed with brine, dried over Na ₂ S0 ₄ , and filtered. The filtrate was distilled under normal pressure to give the crude 4- (trifluoromethyl)picolinaldehyde, which was used in the next step directly.

MS-ESI (m/z): 176.2 (M+l) ⁺ (Acq Method: 10-80AB_2min; Rt: 0.24 min)

(c) 6-bromo-2-(4-(trifluoromethyl)pyridin-2-yn-lH-benzo[d]imidaz ole

To a solution of the crude of 4-(trifluoromethyl)picolinaldehyde and 4-bromobenzene- 1,2-diamine (4.1 g, 22.7 mmol) in THF (200 mL) was added IBD (15 g, 45.3 mmol) under ice-bath. The mixture was stirred at this temperature for 0.5 hour. . The solvent was removed under reduced pressure and the residue was dissolved in EA. The resulting solution was washed with water (30 mL><3), brine and dried over anhydrous Na ₂ S0 ₄ . The organic phase was concentrated under reduced pressure to give a brick red residue, which was purified by column chromatography on silica gel (PE:EtOAc = 5: 1) to afford 6-bromo-2-(4-(trifluoro methyl)pyridin-2-yl)-lH-benzo[d]imidazole (4 g, two steps: 45.1%).

MS-ESI (m/z): 342.2 (M+l) ⁺ (Acq Method: 10-80AB_2min; Rt: 1.12min)

(d) 6-bromo-2-(4-(trifluoromethynpyridin-2-yl)-l-((2-(trimethyls ilynethoxy)methyn- lH-benzo[d] imidazole

To a solution of 6-bromo-2-(4-(trifluoromethyl)pyridin-2-yl)-lH-benzo[d]imida zole (4 g, 9.3 mmol) in anhydrous THF (50 mL) was added NaH 60% in mineral oil (372 mg, 9.3 mmol) in portions. After the addition was completed, the mixture was stirred at 22 °C for 10 min. To the mixture was added (2-(chloromethoxy)ethyl)trimethylsilane (1.54 g, 9.3 mmol) dropwise, and the resulting mixture was stirred at 22 °C for a further 2 hours. The mixture was treated with water (50 mL) and extracted with EA (50 mL><3). The combined EA layer was washed with brine , dried over anhydrous Na ₂ S0 ₄ and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (PE:EtOAc = 10: 1) to afford 6-bromo-2-(4- (trifluoromethyl)pyridin-2-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazole (4.38 g, 100%).

MS-ESI (m/z): 473.9 (M+l) ⁺ (Acq Method: 10-80AB_2min; Rt: 1.38 min)

(e) 6-Γ4.4.5.5-tetramethyl- 1.3.2-dioxaborolan-2-vn-2-(4-(trifluoromethvnpyridin-2-ylV 1 - (Y2- (trimethylsilynethoxy)methyl)-lH-benzo[d]imidazole

A mixture of 6-bromo-2-(4-(trifluoromethyl)pyridin-2-yl)-l-((2-

(trimethylsilyl)ethoxy)methyl)-lH- benzo[d]imidazole (4.38 g, 9.3mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (2.6 g, 10.2 mmol), KOAc (2.23 g, 23.3 mmol), Pd2(dba)3 (446 mg, 0.76 mmol) and TCP (213 mg, 0.76 mmol) in dioxane (100 mL) was stirred at 110 °C for 2 hours under a stream of nitrogen . After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under vacuum to give a crude residue, which was purified by column chromatography on silica gel (PE:EtOAc = 10: 1) to afford the title product (4.5g, 93.2%).

MS-ESI (m/z): 520.2 (M+l) ⁺ (Acq Method: 10-80AB_2min; Rt: 1.178 min) Intermediate X

N-(4-(difluoromethynpyridin-2-yn-4-(4.4.5.5-tetramethyl-1.3. 2-dioxaborolan-2- yObenzamide

(a) 2-bromo-4-(difluoromethynpyridine

To a solution of 2-bromoisonicotinaldehyde (2g, 10.752 mmol) in dichloromethane was added DAST( 6.613g, 32.257 mmol) at -78 °C. The mixture was warmed to room temperature slowly in 2 hours. The reaction mixture was quenched with saturated sodium bicarbonate and extracted with dichloromethane. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated to give 2- bromo-4-(difluoromethyl)pyridine (2 g, yield 90%). ¹ HNMR (400MHz, CDC1 ₃ ): 5=8.52-8.51 (d, J = 8.0 Hz, 1 H), 7.63 (s, 1 H), 7.40-7.38 (d, J = 8.0 Hz, 1 H), MS (ESI): M/Z (M+l)=207.95.

(bW-(4-(difluoromethvnpyridin-2-vn-4-(4.4.5.5-tetramethyl-1. 3.2-dioxaborolan-2- yObenzamide

To a degassed mixture of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide ( 1.5g, 6.07 mmol) and 2-bromo-4-(difluoromethyl)pyridine (1.515g, 7.284 mmol) in dioxane was added Pd ₂ (dba) ₃ (catalytic amount) , X-phos (catalytic amount) and Cs ₂ C0 ₃ (3.956g, 12.141 mmol) under N ₂ atmosphere. The mixture was stirred at 100 °C overnight. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated, and the residue was purified on silic-gel to give N-(4- (difluoromethyl)pyridin-2-yl) -4-(4,4, 5 , 5 -tetramethyl- 1 , 3 ,2-dioxaborolan-2- yl)benzamide (1.8 g, yield 79%).

¹ HNMR (400MHz, DMSO-d6): δ= 8.55-8.54 (d, J = 4 Hz, 1 H), 8.39 (s, 1 H), 8.02-8.00 (d, J = 8.0 Hz, 2 H), 7.79-7.77 (d, J= 8.0 Hz, 2 H), 7.34-7.33 (d, J = 4 Hz, 1 H), 7.29-7.01 (t, J= 52 Hz, 1 H), 1.30 (s, 12 H), MS (ESI): M/Z (M+l)=375.16. Intermediate XI

N-(4-ethoxypyridin-2-yl)-4-(4.4.5.5 etramethyl-l J.2-dioxaborolan-2-yl)benzamide To a degassed mixture of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide ( 9.4g, 38 mmol) and 2-chloro-4-ethoxypyridine ( 5g, 31.7 mmol) in dioxane was added Brettphos-prePd (catalytic amount) and CS ₂ CO ₃ (12.3 g, 37.8 mmol) under N ₂ atmosphere. The mixture was heated to 100 °C and stirred for 3.5 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated, and the residue was purified on silic-gel (PE: EA = 100% ~ 30%) to give N-(4- ethoxypyridin-2-yl)-4-(4,4, 5, 5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)benzamide (8.8 g, yield 75%). ¹ HNMR (400MHz, CDC1 ₃ ): 5=8.74 (s, 1 H), 8.05-8.02(m, 1 H), 8.01 (s, 1 H), 7.94-7.89 (m, 4 H), 6.60-6.59 (m, 1 H), 4.20-4.14 (m, 2 H), 1.47-1.43 (m, 3 H), 1.36 (s, 12 H), MS (ESI): M/Z (M+l)=369.19.

Intermediate XII

iV-(4-(l. l -difluoroethy0pyridin-2-y0-4-(4.4.5.5 -tetramethyl- 1.3.2-dioxaborolan-2- yObenzamide

(a) 2-bromo-N-methoxy-N-methylisonicotinamide

To a solution of 2-bromoisonicotinic acid (40.4 g, 0.2 mol) in 200 mL of dry DMF was added CDI (32.4 g, 0.2 mol) in portions. After stirring for 30 min under N ₂ atmosphere Ν,Ο-methylhydroxylamine hydrochloride (19.5 g, 0.2 mol) was added and the mixture was stirred at room temperature overnight under N ₂ atmosphere. The mixture was diluted with water and extracted with EtOAc. The combined organic phase was washed with water and brine, dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo to afford a crude residue, which was purified by flash chromatography on silica gel to give compound 2-bromo-N-methoxy-N-methylisonicotinamide (28 g, yield 57%). ¹ HNMR (400MHz, DMSO-d6): δ= 8.50 (d, J = 4.8 Hz, 1 H), 7.79 (s, 1 H), 7.59 (d, J = 4.8 Hz, 1 H), 3.56 (s, 3 H), 3.27 (s, 3 H). MS (ESI): M/Z (M/M+2 = 1/1) 244.7/246.7

(b) 1 -(2-bromopyridin-4-yl)ethanone

To a solution of 2-bromo-N-methoxy-N-methylisonicotinamide (27 g, 0.11 mol) in 200 mL of dry THF was added 3 M MeMgBr (44 mL, 0.132 mol) at -78 °C under N ₂ atmosphere. The mixture was stirred at -78 °C for 2 hrs under N ₂ , and then quenched with aq. H ₄ Cl, and extracted with EtOAc. The organic phase was washed with water and brine, dried over Na ₂ S0 ₄ , filtered and concentrated under vacuum to afford a crude residue, which was purified by flash chromatography on silica gel to give l-(2- bromopyridin-4-yl)ethanone (20 g, yield: 90.9%). ¹ HNMR (400MHz, DMSO-d6): δ= 8.59 (d, J= 4.8 Hz, 1 H), 8.01 (s, 1 H), 7.82 (d, J= 4.8 Hz, 1 H), 2.61 (s, 3 H).

(c) 2-bromo-4-( 1.1 -difluoroethyOpyridine

To a solution of l-(2-bromopyridin-4-yl)ethanone (20 g, 0.1 mol) in 200 mL of DCM was added DAST (40.3 g, 0.25 mol) at 0 °C. The reaction mixture was stirred overnight, and slowly poured into aq. NaHC0 ₃ and extracted with DCM. The organic phases were washed with water and brine, dried over Na ₂ S0 ₄ , filtered and concentrated under vacuum to give a crude residue, which was purified by flash chromatography on silica gel to give 2-bromo-4-(l, l-difluoroethyl)pyridine (18.5 g, yield: 84.1%). ¹ HNMR (400MHz, DMSO-d6): δ= 8.56 (d, J = 5.2 Hz, 1 H), 7.86 (s, 1 H), 7.65 (d, J = 4.8 Hz, 1 H), 2.00 (t, J= 19.2 Hz, 3 H). MS (ESI): M/Z (M M+2 = 1/1) 222.0/224.0

(d) Ν-Γ4-Γ 1.1 - difluoroethyl)pyridin-2-y l)-4-(4.4.5.5 -tetramethyl- 1.3.2-dioxaborolan-2-y 1) benzamide

2-bromo-4-(l, l-difluoroethyl)pyridine was used to prepare N-(4-(l, l- difluoroethyl)pyridin-2-yl)-4-(4,4,5,5-tetramethyl-l,3,2-dio xaborolan-2-yl)benzamide. The procedure of intermediate AG was followed. 1H MR (400MHz, CDC1 ₃ ) δ = 8.73 (s, 1H), 8.56 (s, 1H), 8.38 (d, J=5.3 Hz, 1H), 7.97 - 7.89 (m, 4H), 7.22 (d, J=5.3 Hz, 1H), 1.96 (t, J=18.3 Hz, 3H), 1.37 (s, 12H)

Intermediate XIII N-(4-cvclopropoxypyridin-2-vn-4-(4.4.5.5-tetramethyl-1.3.2- dioxaborolan-2-yObenzamide

(a) 2-chloro-4-cyclopropoxypyridine

To a solution of 2-chloropyridin-4-ol (1 g, 7.75 mmol) in DMA (10 ml) was added bromocyclopropane (2.8 g, 23.2 mmol), Nal (1.16 g, 7.75 mmol) and CS ₂ CO ₃ (5 g, 15.5 mmol). The mixture was stirred at MW 170 °C for 20 minutes, and then MW 180 °C for 30 minutes. The reaction mixture was extracted with EA. The organic layer was dried and concentrated. The residue was purified by flash column chromatography to give 300 mg of 2-chloro-4-cyclopropoxypyridine.

1H NMR (400MHz, CDC1 ₃ ) δ = 8.19 (d, J=5.8 Hz, IH), 7.02 (d, J=2.0 Hz, IH), 6.87 (dd, J=2.0, 5.8 Hz, IH), 3.80 (tt, J=3.0, 6.0 Hz, IH), 0.91 - 0.75 (m, 4H)

(b) N-(4-cyclopropoxypyridin-2-yD-4-(4 A 5.5 -tetramethyl- 1.3.2-dioxaborolan-2- yObenzamide

N-(4-cyclopropoxypyridin-2-yl)-4-(4,4,5,5-tetramethyl-l,3 ,2-dioxaborolan-2- yl)benzamide was preapred following the procedure of intermediate AG. 1H NMR (400 MHz, CDCI ₃ ) δ= 9.12 (br. s., IH), 8.27 (d, J=2.01 Hz, IH), 8.20 (d, J=5.52 Hz, IH), 8.07 (d, J=6.02 Hz, IH), 7.66 (d, J=7.78 Hz, IH), 7.37 (d, J=7.78 Hz, IH), 6.62-6.73 (m, IH), 6.42-6.49 (m, IH), 3.84-3.94 (m, IH), 1.37 (s, 12H), 0.78-0.94 (m, 4H)

Intermediate XIV 3-fluoro-4-(4A5.5-tetramethyl-l .3.2-dioxaborolan-2-yl)-N-(4-(trifluoromethyl)pyridin- 2-yl)benzamide

(a) 4-bromo-3-fluoro-N-(4-(trifluoromethynpyridin-2-ynbenzamide

To a stirring solution of 4-bromo-3-fluorobenzoic acid (19.6 g, 90 mmol), 4- (trifluoromethyl)pyridin-2-amine (16.2 g, 0.1 mol) and TEA (50 mL) in dry THF (300 mL) was added HATU (41.8 g, 0.11 mol) portionwise. The reaction mixture was stirred at room temperature for 20 hrs and at 60 °C for another 40 hrs. The resulting mixture was concentrated in vacuo and the residue was purified by flash chromatograph on silica gel (EA/PE: 5% to 15%) to give compound 4-bromo-3-fluoro-N-(4- (trifluoromethyl)pyridin-2-yl)benzamide. (26.8 g, yield: 82%)

(b) 3 -fluoro-4-(4.4.5.5-tetramethyl- 1.3.2-dioxaborolan-2-yl)-N-(4-

(trifluoromethyOpyridin-2 -yPbenzamide

A degassed mixture of 4-bromo-3-fluoro-N-(4-(trifluoromethyl)pyridine -2- yl)benzamide (26.8 g, 74 mmol), Bis(pinacolato)diboron (22.6 g, 90 mmol), TCP (1.24 g, 4.44 mmol), Pd(dba)2 (2.6 g, 4.44 mmol) and KOAc (21.8 g, 220 mmol) in dry dioxane (400 mL) was stirred at 110 °C overnight under N ₂ atmosphere. After cooling to room temperature, the resulting mixture was filtered and concentrated under vacuum to afford a crude residue. The residue was purified by flash column chromatograph on silica gel (EA/PE: 5% to 20%) to give 3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzam ide. (20 g, yield: 66%) Intermediate XV

4-(4.4.5.5-Tetramethyl-1.3.2-dioxaborolan-2-vn-N-(4-(trifluo romethvnpyridin-2- yObenzamide

This compound was prepared, in an analogues manner as described in Intermediate XIV, starting from 4-(trifluoromethyl)pyridin-2-amine and 4-bromobenzoic acid, to afford the title compound 4-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)-N-(4-

(trifluoromethyl)pyridin-2-yl) benzamide. Intermediate XVI

N-(4-(difluoromethyl)pyridin-2-yl)-3 -fluoro-4-(4 A 5.5 -tetramethyl- 1.3.2-dioxaborolan- 2-yl)benzamide

(a) tert-butyl (4-(difluoromethyDpyridin-2-yl)carbamate

A degassed mixture of 2-chloro-4-(difluoromethyl)pyridine (6.3 g, 38.5 mmol), Carbamic acid tert-butyl ester (5.4 g, 46.2 mmol), CS ₂ CO ₃ (25 g, 77 mmol), X-phos (1.83 g, 3.85 mmol) and Pd(OAc) ₂ (430 mg, 1.925 mmol) in 40 mL of 1,4-dioxane was stirred at 90 °C for 2h under a stream of N ₂ . The mixture was concentrated under vacuum to give a crude product, which was purified by silica gel column chromatography to give tert-butyl (4-(difluoromethyl)pyridin-2-yl)carbamate (7.57 g, yield: 80.5%). ¹ HNMR (400MHz, DMSO-d6): δ= 10.11 (s, 1 H), 8.38 (d, J = 5.2 Hz, 1 H), 7.99 (s, 1 H), 7.16 (d, J= 4.8 Hz, 1 H), 7.07 (t, J= 55.2 Hz, 1 H), 1.46 (s, 9 H). T

(b) 4-(difluoromethyDpyridin-2-amine

To a solution of tert-butyl (4-(difluoromethyl)pyridin-2-yl)carbamate (6.8 g, 27.8 mmol) in 40 mL of DCM was added 20 mL of trifluoroacetic acid. The reaction was stirred at r.t. for 1 h and then concentrated under vacuum. Aq. NaHC0 ₃ was added and extracted with EA. The organic layer was washed with brine, dried over Na ₂ S0 ₄ , concentrated i to give 4 g crude of compound 4-(difluoromethyl)pyridin-2-amine. ¹ HNMR (400MHz, DMSO-d6): δ= 8.00 (d, J = 5.2 Hz, 1 H), 6.88 (t, J = 55.6 Hz, 1 H), 6.56 (d, J = 5.6 Hz, 1 H), 6.54 (s, 1 H), 6.27 (s, 2 H).

(c) 4-bromo-N-(4-(difluoromethynpyridin-2-yl)-3-fluorobenzamide

To a solution of 4-bromo-3-fluorobenzoic acid (5 g, 22.8 mmol) in 100 mL of DCM was added Oxalyl dichloride (8.7 g, 68.5 mmol) and 5 drops of DMF at 0 °C. After stirring for 1 h, the mixture was concentrated under vacuum and dissolved in 20 mL of THF, and added to a solution of 4-(difluoromethyl)pyridin-2-amine (3.9 g, 27.36 mmol) in 30 mL of THF at 0 C. The reaction was stirred at r.t for 30 min and at 80 C overnight. After cooling to r.t, the mixture was filtered and the filtrate was concentrated under vacuum to give a crude residue, which was purified by silica gel column chromatography to give 4-bromo-iV-(4-(difluoromethyl)pyridin-2-yl)-3- fluorobenzamide (4.9 g, yield: 62.3%). ¹ HNMR (400MHz, DMSO-d6): δ= 11.26 (s, 1 H), 8.56 (d, J= 4.8 Hz, 1 H), 8.37 (s, 1 H), 8.01 (d, J= 10.0 Hz, 1 H), 7.78 ~ 7.90 (m, 2 H), 7.35 (d, J= 5.2 Hz, 1 H), 7.15 (t, J= 55.2 Hz, 1 H). MS (ESI): M/Z (M/M+2 = 1/1): 344.5/346.5

(d) N-(4-(difluoromethvnpyridin-2-vn-3 -fluoro-4-(4.4.5.5 -tetramethyl- 1.3.2- dioxaborolan-2 -yPbenzamide

A degassed mixture of 4-bromo-N-(4-(difluoromethyl)pyridin-2-yl)-3-fluorobenzamide (4.9 g, 14.2 mmol), Bispinacolatodiboron (5.4 g, 21.3 mmol), KOAc (4.2 g, 42.6 mmol) and Pd(dppf)Cl ₂ (1.04 g, 1.42 mmol) in 60 mL of 1,4-dioxane was stirred at 90 °C for 2h under a stream of N ₂ . The mixture was concentrated under vacuum to give a crude product, which was purified by silica gel column chromatography to give N-(4- (difluoromethyl)pyridin-2-yl)-3 -fluoro -4-(4,4, 5 , 5 -tetramethyl- 1 , 3 ,2-dioxaborolan-2- yl)benzamide (5.4 g, yield: 96.9%). ¹ HNMR (400MHz, DMSO-d6): δ= 11.25 (s, 1 H), 8.56 (d, J = 4.8 Hz, 1 H), 8.37 (s, 1 H), 7.85 (d, J= 7.6 Hz, 1 H), 7.74 ~ 7.79 (m, 2 H), 7.35 (d, J = 5.2 Hz, 1 H), 7.15 (t, J = 55.2 Hz, 1 H), 1.31 (s, 12 H). MS (ESI): M/Z (M+l): 392.9.

Intermediate XVII

3-fluoro-N-(4-methoxypyridin-2-yn-4-(4.4.5.5-tetramethyl-1.3 .2-dioxaborolan-2- yObenzamide

1 g of 3-fluoro-N-(4-methoxypyridin-2-yl)-4-(4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2 -yl)benzamide was obtained following the same procedure described for Intermediate XV. 1H MR (400 MHz, CDC1 ₃ ): δ= 8.72 (brs, 1 H), 8.07 (d, J = 5.6 Hz, 1 H), 8.00 (d, J= 2.0 Hz, 1 H), 7.86 (dd, Ji = 5.6 Hz, J ₂ = 7.6 Hz, 1 H), 7.59 ~ 7.66 (m, 2 H), 6.64 (dd, Ji = 2.0 Hz, J2 = 6.0 Hz, 1 H), 3.91 (s, 3 H), 1.37 (s, 12 H).

Intermediate XVIII

N-(4-( 1.1 -difluoroethyl)pyridin-2-yl)-3 -fluoro-4-(4.4.5.5-tetramethyl- 1.3.2- dioxaborolan-2-yObenzamide (d) tert-butyl (4-(l. l-difluoroethyl)pyridin-2-yl)carbamate 4 g of of N-(4-(l, l-difluoroethyl)pyridin-2-yl)-3-fluoro-4-(4,4,5,5-tetramethy l-l,3,2 - dioxaborolan-2-yl)benzamide was obtained following the procedure described for Intermediate XV. 1H NMR (400MHz, CDC1 ₃ ): δ= 9.56 (brs, 1 H), 8.60 (s, 1 H), 8.36 (d, J = 5.2 Hz, 1 H), 7.88 (dd, J = 6.0 Hz, J ₂ = 7.6 Hz, 1 H), 7.67 ~ 7.76 (m, 2 H), 7.24 ~ 7.25 (m, 1 H), 1.96 (t, J= 18.4 Hz, 3 H), 1.38 (s, 12 H).

Intermediate XIX

3 -fluoro-N-(4-methylpyridin-2-vO-4-(4.4.5.5-tetramethyl- 1.3.2-dioxaborolan-2- yObenzamide

3 -fluoro-N-(4-methylpyridin-2-yl)-4-(4,4, 5, 5-tetramethyl- 1 ,3 ,2-dioxaborolan-2- yl)benzamide was prepared following procedure described for Intermediate XV. 1H NMR (400MHz, CDC1 ₃ -) delta = 8.61 (br, s., 1H), 8.21 (s, 1H), 8.14 (d, J=5.0 Hz, 1H), 7.91 - 7.82 (m, 1H), 7.62 (dd, J=8.8, 15.8 Hz, 2H), 6.92 (d, J=4.5 Hz, 1H), 2.41 (s, 3H), 1.38 (s, 12H); MS (APCI): m/z (M+l): 357.2.

Intermediate XX

N-(4-ethylpyridin-2-ylV3 -fluoro-4-(4.4.5.5-tetramethyl- 1.3.2-dioxaborolan-2- yObenzamide

N-(4-ethylpyridin-2-yl)-3 -fluoro-4-(4,4, 5, 5-tetramethyl- 1 ,3 ,2-dioxaborolan-2- yl)benzamide was prepared followed same procedure of intermediate XV. 1H MR (400MHz, CDC1 ₃ ): 5=8.81 (s, 1 H), 8.24 (s, 1 H), 8.12-8.11 (d, J = 4 Hz, 1 H), 7.86-7.83 (m, 1 H), 7.66-7.59 (m, 2 H), 6.93-6.92 (d, J = 4 Hz, 1 H), 2.73-2.67 (m, 2 H), 1.38 (s, 12 H), 1.30-1.26 (t, J = 8 Hz, 3 H),MS MS (EI): M/Z (M+l): 371.19. Intermediate XXI

3 -fluoro-N-(pyridin-2-yO-4-(4 A 5.5-tetramethyl- 1.3.2-dioxaborolan-2-y0benzamide 3 -fluoro-N-(pyridin-2-yl)-4-(4,4, 5, 5-tetramethyl- 1 , 3 ,2-dioxaborolan-2-yl)benzamide was prepared followed the procedure of intermediate XV. ¹ HNMR (400MHz, CDC1 ₃ ): δ= 8.64 (brs, 1 H), 8.36 (d, J= 8.0 Hz, 1 H), 8.28 - 8.30 (m, 1 H), 7.86 (dd, J = 6.0 Hz, J2 = 7.6 Hz, 1 H), 7.75 - 7.79 (m, 1 H), 7.10 (dd, J = 0.8 Hz, J ₂ = 5.2 Hz, 1 H), 7.08 (dd, Ji = 0.8 Hz, J2 = 5.2 Hz, 1 H), 7.07 - 7.11 (m, 1 H), 1.38 (s, 12 H).

Intermediate XXII

3-methoxy-4-(4.4.5.5-tetramethyl-1.3.2-dioxaborolan-2-vn-N-( 4- (trifluoromethyDpyridin-2-yDbenzamide

(a) 3-methoxy-4-(4.4.5.5-tetramethyl-1.3.2-dioxaborolan-2-ynbenz oic acid

A solution of 4-borono-3-methoxybenzoic acid (500 mg, 2.55 mmol) and pinacol (330 mg, 2.79 mmol) in THF (5 ml) and toluene (5 ml) was stirred at 40 °C overnight. After cooling the mixture was partitioned with water and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The crude 3-methoxy-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzoic acid was used in the next step without further purification.

(b) 3-methoxy-4-(4.4.5.5-tetramethyl-1.3.2-dioxaborolan-2-ynbenz oyl chloride

To a solution of 3-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)ben zoic acid (700 mg, 2.52 mmol) in DCM (20 ml) was added 2 drops of DMF, the mixture was cooled to 0 °C under ice-water bath, and followed by the addition of oxalyl dichloride (629 mg, 5.03 mmol). The reaction mixture was stirred at 0°C for 2 hours. The solvent was concentrated in vacuo, and the crude 3-methoxy-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzoyl chloride was used in the next step directly.

(c) 3-methoxy-4-(4.4.5.5-tetramethyl-1.3.2-dioxaborolan-2-yn-N-( 4-(trifluoromethyl) pyridin-2-yl) benzamide

To a solution of 3-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)ben zoyl chloride (700 mg, 2.36 mmol) in THF (50 ml) was added 4-(trifluoromethyl)pyridin-2- amine (574 mg, 3.55 mmol). The resulting mixture was stirred at 80 °C overnight. The mixture was cooled to room temperature, the volatiles were concentrated in vacuo and the residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 3/1 v/v%) to afford the title compound Intermediate XXI 1 (546 mg, three steps: 54.8%).

MS-ESI (m/z): 423 (M+l) ⁺ (Acq Method: 10-80AB_2min; Rt: 1.26 min).

Intermediate XXIII 2-fluoro-4-(4A5.5-tetramethyl-l .3.2-dioxaborolan-2-yl)-N-(4-(trifluoromethyl)pyridin-

2-yl)benzamide

This compound was prepared, in an analogues manner as described for Intermediate XV, starting from 4-bromo-2-fluorobenzoic acid, to afford the title compound (74.3%).

MS-ESI (m/z): 411 (M+l) ⁺ (Acq Method: 10-80AB_2min; Rt: 1.55 min).

1H MR (400MHz, DMSO-d ₆ ) δ = 11.41 (s, 1H), 8.66 (d, J=5.1 Hz, 1H), 8.51 (s, 1H), 7.84 - 7.66 (m, 1H), 7.64 - 7.51 (m, 2H), 7.45 (d, J=10.2 Hz, 2H), 1.29 (s, 12H).

Intermediate XXIX

2-chloro-4-(4A5.5-tetramethyl-l .3.2-dioxaborolan-2-yl)-N-(4-(trifluoromethyl)pyridin-

2-yl)benzamide

(a) 4-bromo-2-chloro-N-(4-(trifluoromethynpyridin-2-ynbenzamide

To a solution of methyl 4-bromo-2-chlorobenzoate (1.15 g, 7.1 mmol) in toluene (20 ml) was added dropwise Me ₃ Al (5 ml, 2 M in toluene, 10 mmol) under nitrogen protection at room temperature. After the addition was completed the mixture was stirred for further 10 min, and 4-(trifluoromethyl)pyridin-2-amine (1.76 g,7.1 mmol) was added. The resulting mixture was then heated at reflux for 8 h. After cooling the mixture was quenched with water, extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over anhydrous Na ₂ S0 ₄ , and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 6/1 v/v%) to give 4-bromo-2-chloro-N- (4-(trifluoromethyl)pyridin-2-yl)benzamide (1.88 g, 67.6 %).

(b) 2-chloro-4-(4.4.5.5-tetramethyl-1.3.2-dioxaborolan-2-vn-N-(4 - (trifluoromethyDpyridin-2-yl) benzamide

This compound was prepared, in an analogues manner as described in Intermediate AL step (b), starting from 6.8 g of 4-bromo-2-chloro-N-(4-(trifluoromethyl)pyridin-2- yl)benzamide, to afford the title compound, Intermediate XXIX (3.2 g, 47%). MS-ESI (m/z): 427 (M+l) ⁺ (Acq Method: 10-80AB_2min; Rt: 1.44 min).

1H NMR (400MHz, CD ₃ OD ) δ = 8.63 - 8.46 (m, 2H), 7.84 - 7.69 (m, 2H), 7.58 (s, 1H), 7.40 (br. s., 1H), 1.35 (s, 12H).

Intermediate XXX

N-(5-Ethylthiazol-2-yl)-4-(4.4.5.5-tetramethyl-1.3.2-dioxabo rolan-2-yl)benzamide

This compound was prepared, in an analogues manner as described for Intermediate XV, starting from 5-methylthiazol-2-amine, to afford the title compound Intermediate XXX. Intermediate XXXI:

N-(4-isopropoxypyridin-2-yl)-4-(4.4.5.5-tetramethyl-1.3.2-di oxaborolan-2-yn

benzamide

(a) 4-bromo-N-(4-isopropoxypyridin-2-yDbenzamide.

A soluiton of 4-isopropoxypyridin-2-amine (1.019 g, 6.70 mmol) and DMAP (0.709 g, 5.81 mmol) in MeCN (5.0 ml) under N2 was treated with 4-bromobenzoyl chloride (1.0 g, 4.47 mmol) dissolved in MeCN ( 5.0 ml) and the mixture stirred at rt overnight.. The mixture was diluted with DCM and washed with water (x2). The aqueous layer was washed with DCM and the combined organics washed with brine, dried (MgSC^) and concentrated to afford a cream solid. Purification on a 40 g column on the CombiFlash RF, eluting with 0 to 20 % EtOAc / Hexane (24 CV) afforded 1.33 g of the title compound as a white solid. ^m/z (M+2): 237.01.

(b) N-(4-isopropoxypyridin-2-ylV4-(4.4.5.5-tetramethyl-1.3.2- dioxaborolan-2-yDbenzamide

A 4 ml vial containing 4-bromo-N-(4-isopropoxypyridin-2-yl)benzamide from Step a 1(0.1 g, 0.298 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (0.083 g, 0.328 mmol), and Potassium acetate (0.088 g, 0.895 mmol) was treated with Dioxane (1.0 ml), and the mixture degassed with house vacuum and backfilled with N2 (x2). 2nd generation X-phos precatalyst (0.047 g, 0.060 mmol) as a slurry in dioxane (0.5 ml) under N2 was then added via a syringe and the resulting cream suspension was then stirred at 70 °C for 2 h. The mixture was dilute with EtOAc, filtered and concentrate. Purification on a 12 g column on the CombiFlash Rf, eluting with 0 to 40 % EtOAc / Hexane afforded 70 mg of theTitle compound Intermediate XXXI . m/z (M+l): 383.22.

Intermediate XXXII

N-(4-Cyanopyridin-2-yl)-4-(4 A 5.5-tetramethyl- 1.3.2-dioxaborolan-2-y0benzamide This compound was prepared, in an analogous manner as described in

Intermediate A, starting from 2-aminoisonicotinonitrile, to afford the title compound (1.3 g, 99%).

Example 1:

4-(8-amino-3-((6S.8aS)-3-oxohexahydro-lH-oxazolo[3.4-a]pyrid in-6-yl)imidazo[1.5- ajpyrazin- 1 -yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide

(a) 4-(8-((2.4-dimethoxybenzyl)amino)-3-((3S.6S)-6-(hydroxymethy npiperidin-3- yOimidazo [ 1.5 -ajpyrazin- 1 -yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide To a solution of ((2S,5S)-5-(8-((2,4-dimethoxybenzyl)amino)-l-(4-((4-(trifluo romethyl) pyridin-2-yl)carbamoyl)phenyl)imidazo[l,5-a]pyrazin-3-yl)pip eridin-2-yl)methyl acetate (120 mg, 0.17 mmol) in 3 mL of MeOH was added NaOMe (46 mg, 0.85 mmol). The reaction mixture was stirred at room temperature for 3 h under N ₂ . The mixture was poured into aq. H ₄ C1, extracted with DCM. The organic layer was dried over Na ₂ S0 ₄ , and concentrated in vacuo to give 110 mg of crude 4-(8-((2,4- dimethoxybenzyl)amino)-3- ((3S,6S)-6-(hydroxymethyl)piperidin-3-yl)imidazo[l,5- a]pyrazin-l-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide , which was used in the next step directly. MS-ESI (m/z): 662.0 (M+l) + (Acq Method: 10-80AB_2min; Rt: 0.888 min).

(b) 4-(8-((2.4-dimethoxybenzyl)amino)-3-((6S.8aS)-3-oxohexahydro -lH-oxazolo[3.4- ajpyridin -6-yl)imidazo[ 1.5-a]pyrazin- 1 -yl)-N-(4-(trifluoromethyDpyridin-2- yObenzamide

Carbonyldiimidazole (28 mg, 0.17 mmol) and DMAP (5 mg) were added to a solution of compound 4-(8-((2,4-dimethoxybenzyl)amino)-3-((3S,6S)-6-

(hydroxymethyl)piperidin-3 -yl) imidazo[ 1 , 5-a]pyrazin- 1 -yl)-N-(4-

(trifluoromethyl)pyridin-2-yl)benzamide (110 mg crude, 0.17 mmol) in 2 mL of DCM and the resulting mixture was stirred at room temperature for 3 hours. The mixture was diluted with DCM, washed with water and brine, dried over Na ₂ S0 ₄ , filtered, and concentrated in vacuo to give HOmgcrudeof the title compound, 4-(8-((2,4- dimethoxybenzyl)amino)-3-((6S,8aS)-3-oxohexahydro-lH-oxazolo [3,4-a]pyridin-6- yl)imidazo[ 1 , 5-a]pyrazin- 1 -yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide, which was used in the next step directly. MS-ESI (m/z): 688.2 (M+l) + (Acq Method: 10- 80AB_2min; Rt: 1.003 min).

(c) 4-(8-amino-3-((6S.8aS)-3-oxohexahydro-lH-oxazolo[3.4-a]pyrid in-6- yl)imidazo[ 1.5-a] pyrazin- 1 -yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide

A mixture of 4-(8-((2,4-dimethoxybenzyl)amino)-3-((6S,8aS)-3-oxohexahydro -lH- oxazolo[3,4-a]pyridin-6-yl)imidazo[l,5-a]pyrazin-l-yl)-N-(4- (trifluoromethyl)pyridin- 2-yl)benzamide (110 mg crude, 0.16 mmol) in 1 mL of trifluoroacetic acid was stirred at 90 ^° C for 2 h, and concentrated in vacuo. After purification byprep-HPLC, 4-(8-amino- 3 -((6 S, 8aS)-3 -oxohexahydro- 1 H-oxazolo [3 ,4-a]pyridin-6-yl)imidazo [ 1 , 5 -a]pyrazin- 1 - yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (30 mg, yield 34.9%) was obtained. 1H MR (400 MHz, CD ₃ OD): δ= 8.63 ~ 8.66 (m, 2 H), 8.19 (d, J = 6.8 Hz, 2 H), 7.92 (d, J= 6.8 Hz, 2 H), 7.86 (d, J = 6.0 Hz, 1 H), 7.47 (d, J= 4.0 Hz, 1 H), 7.05 (d, J= 6.0 Hz, 1 H), 4.53 (t, J= 8.0 Hz, 1 H), 3.98 ~ 4.08 (m, 3 H), 3.69 (s, 1 H), 3.52 ~ 3.56 (m, 1 H), 2.34 - 2.46 (m, 2 H), 2.18 ~ 2.23 (m, 1 H), 1.78 - 1.82 (m, 1 H).

LCMS Method: WUXIAB01.M

Retention time: 2.452 min

(M+H)+ m/z : 538.2.

Example 2:

4-(8-amino-3-((6R.8aR)-3-oxohexahydro-lH-oxazolo[3.4-a]pyrid in-6-ynimidazo[1.5- ajpyrazin- 1 -yl)-N-(4-(trifluoromethynpyridin-2-ynbenzamide

(a) 4-(8-((2.4-dimethoxybenzyl)amino)-3 -(Y6R.8aR)-3 -oxohexahydro- lH-oxazolo[3.4- ajpyridin -6-yl)imidazo[ 1.5-a]pyrazin- 1 -yl)-N-(4-(trifluoromethyDpyridin-2- yObenzamide

To a mixture of (2R,5R)-benzyl 5-(8-((2,4-dimethoxybenzyl) amino)- 1-(4-((4- (trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)imidazo [ 1 , 5 -a]pyrazin-3 -yl)-2- (hydroxymethyl)piperidine-l-carboxylate (40 mg) in 3 mL of MeOH was added NaOMe (54 mg, 1 mmol). The reaction mixture was stirred at room temperature for 24 h, and then at 40 °C for 6 hours under N ₂ . The mixture was poured into aq. H ₄ C1, extracted with DCM (20 mL). The organic layer was dried over Na ₂ S0 ₄ , and concentrated in vacuo to give 40 mg crude of 4-(8-((2,4-dimethoxybenzyl)amino)-3- ((6R,8aR)-3-oxohexahydro-lH-oxazolo[3,4-a]pyridin-6-yl)imida zo[l,5-a]pyrazin-l-yl)- N-(4-(trifluoromethyl)pyridin-2-yl)benzamide, which was used in the next step directly. MS-ESI (m/z): 688.1 (M+l) ⁺ (Acq Method: 10-80AB_2min; Rt: 1.068 min). (b) 4-(8-amino-3-((6R.8aR)-3-oxohexahydro-lH-oxazolo[3.4-a]pyrid in-6-ynimidazo [ 1.5-a]pyrazin- 1 -yl)-N-(4-(trifluoromethynpyridin-2-ynbenzamide

A mixture of compound 4-(8-((2,4-dimethoxybenzyl)amino)-3- ((6R,8aR)-3- oxohexahydro- lH-oxazolo[3 ,4-a]pyridin-6-yl)imidazo[ 1 , 5-a]pyrazin- 1 -yl)-N-(4- (trifluoromethyl)pyridin-2-yl)benzamide (40 mg crude, 0.06 mmol) in 1 mL of trifluoroacetic acid was stirred at 90°C for 2 h, and concentrated in vacuo. After purificationby prep-HPLC, 4-(8-amino-3-((6R,8aR)-3 -oxohexahydro -lH-oxazolo[3,4- a]pyridin-6-yl)imidazo[ 1 , 5-a]pyrazin- 1 -yl)-N-(4-(trifluoromethyl)pyridin-2- yl)benzamide (2 mg, yield 25.6%) was obtained. 1H MR (400 MHz, CD ₃ OD): δ= 8.61 ~ 8.63 (m, 2 H), 8.16 (d, J= 8.4 Hz, 2 H), 7.90 (d, J = 8.0 Hz, 2 H), 7.84 (d, J = 6.0 Hz, 1 H), 7.44 (d, J = 4.8 Hz, 1 H), 7.04 (d, J = 5.6 Hz, 1 H), 4.51 (t, J = 8.0 Hz, 1 H), 3.96 ~ 4.06 (m, 3 H), 3.67 (s, 1 H), 3.50 ~ 3.54 (m, 1 H), 2.28 ~ 2.42 (m, 2 H), 2.11 ~ 2.20 (m, 1 H), 1.76 - 1.80 (m, 1 H).

LCMS Method: WUXIAB01.M

Retention time: 2.455 min

(M+H)+ m/z : 538.2.

Example 3:

4-(8-amino-3-((6R,8aS)-2-methyl-3-oxooctahydroimidazo[l,5-a] pyridin-6- yl)imidazo[ 1 , 5-a]pyrazin- 1 -yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide.

(a) (2S.5RVbenzyl5-(8-amino-l-(4-((4-(trifluoromethvnpyridin-2- yOcarbamoyDphenyOimidazo [ 1.5 -a]pyrazin-3 -yl)-2-(methoxymethyl)piperidine- 1-carboxylate To a degassed mixture of (2S,5R)-benzyl 5-(8-amino-l-bromoimidazo[l,5-a]pyrazin-3- yl) -2-(methoxymethyl)piperidine-l-carboxylate (50 mg, 0.105 mmol), 4-(4,4,5,5- Tetramethyl-[l,3,2]dioxaborolan-2-yl)-N-(4-trifluoromethyl-p yridin-2-yl)-benzamide (41 mg, 0.105 mmol) and K ₂ C0 ₃ (44 mg, 0.316 mmol) in dioxane/H ₂ 0 (6 mL, 3 : 1) was added Pd(dppf)Cl ₂ under N ₂ . The mixture was heated to 100 °C for 1 hour. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated, and the residue was purified on silica gel column chromatograph (PE:EA= 100% ~ 70%) to give (2S,5R)-benzyl 5-(8-amino-l-(4-((4-(trifluoromethyl)pyridin-2- yl)carbamoyl)phenyl)imidazo [l,5-a]pyrazin-3-yl)-2-(methoxymethyl)piperidine-l- carboxylate (55 mg, yield: 72%).

MS (EI): M/Z (M+l): 660.25. (Condition: 0-60AB_2MIN; R.T. : 1.216)

(b) 4-(8-amino-3-((3R.6S)-6-(hydroxymethynpiperidin-3-ynimidazo[ 1.5-a]pyrazin- l-yl)-N-(4-(trifluoromethynpyridin-2-ynbenzamide

A mixture of (2S,5R)-benzyl 5-(8-amino-l-(4-((4-(trifluoromethyl)pyridin-2- yl)carbamoyl) phenyl)imidazo[ 1 , 5-a]pyrazin-3 -yl)-2-(methoxymethyl)piperidine- 1 - carboxylate (300 mg, 0.455 mmol) from Step a in dichloromethane (3 mL ) was added BBr ₃ (608.7 mg, 2.274 mmol) at -78 °C. The mixture was stirred at -78 °C for 7 hours. The reaction mixture was quenched with CH ₃ OH at -78 °C and adjusted to basic pH with NaHC0 ₃ . The mixture was then extracted with dichloromethane/ Propan-2- ol(3 : l,50mLx5). The combined organic layer was washed with brine 3 times, dried over anhydrous sodium sulfate and evaporated to give 4-(8-amino-3-((3R,6S)-6- (hydroxymethyl)piperidin-3 -yl)imidazo [ 1 , 5 -a]pyrazin- 1 -yl)-N-(4- (trifluoromethyl)pyridin-2-yl)benzamide (220 mg, yield 93%).

MS (EI): M/Z (M+l): 512.19. (Condition: 0-60AB_2MIN; R.T. : 1.025)

(c) (2S.5R)-5-(8-amino-l-(4-((4-(trifluoromethyl)pyridin-2- yl)carbamoyl)phenyl)imidazo[1.5-a]pyrazin-3-yl)-2-(hydroxyme thyl)-N- methylpiperidine- 1 -carboxamide

To a mixture of 4-(8-amino-3-((3R,6S)-6-(hydroxymethyl)piperidin-3-yl)imidaz o[l,5-a] pyrazin-l-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (70 mg, 0.137 mmol) in tetrahydrofuran was added methylcarbamic chloride (12.8 g, 0.137 mmol) and triethylamine (41.5 g, 0.411 mmol) at 0 °C. The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated to afford the crude product, which was purified by prep HPLC to give (2S,5R)-5-(8-amino-l-(4-((4- (trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl) imidazo [ 1 , 5 -a]pyrazin-3 -yl)-2-

(hydroxymethyl)-N-methylpiperidine-l-carboxamide (11.42 mg, 15% yield). 1H MR (400 MHz, CD ₃ OD): δ= 8.64 - 8.60 (m, 2H), 8.21 - 8.15 (m, 2H), 7.87 (d, J=8.3 Hz, 2H), 7.81 (d, J=6.0 Hz, IH), 7.46 - 7.43 (m, IH), 7.03 (d, J=5.8 Hz, IH), 4.26 (d, J=14.3 Hz, IH), 4.09 - 4.01 (m, IH), 3.84 - 3.77 (m, IH), 3.75 - 3.68 (m, IH), 3.59 (d, J=3.5 Hz, IH), 3.53 (dd, J=4.6, 14.2 Hz, IH), 2.60 (s, 3H), 2.33 - 2.19 (m, 2H), 2.13 - 2.02 (m, IH), 1.75 - 1.64 (m, IH). MS (ESI): M/Z (M+l): 569.22.

(d) 4-(8-amino-3-((6R.8aS)-2-methyl-3-oxooctahydroimidazo[1.5-a] pyridin-6- yl)imidazo[ 1.5-a]pyrazin- 1 -yn-N-(4-(trifluoromethynpyridin-2-ynbenzamide

To a mixture of (2S,5R)-5-(8-amino-l-(4-((4-(trifluoromethyl)pyridin-2- yl)carbamoyl)phenyl) imidazo [1,5 -a]pyrazin-3 -yl)-2-(hydroxymethyl)-N- methylpiperidine-l-carboxamide (15 mg, 0.026 mmol) in tetrahydrofuran was added SOCI ₂ (15.56 mg, 0.132 mmol) at 0 °C. The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated to afford the crude product, which was purified by prep HPLC to give 4-(8-amino-3-((6R,8aS)-2-methyl-3- oxooctahydroimidazo [ 1 , 5 -a]pyridin-6-yl)imidazo [ 1 , 5 -a]pyrazin- 1 -yl)-N-(4- (trifluoromethyl)pyridin-2-yl)benzamide (4.66 mg, 32 yield).1H NMR (400 MHz, CD ₃ OD): δ= 8.66 - 8.60 (m, 2H), 8.20 (d, J=8.3 Hz, 2H), 7.94 (d, J=5.8 Hz, IH), 7.87 (d, J=8.3 Hz, 2H), 7.45 (d, J=4.5 Hz, IH), 7.09 (d, J=5.8 Hz, IH), 5.04 (t, J=8.7 Hz, IH), 4.52 (t, J=8.5 Hz, IH), 4.30 - 4.15 (m, 2H), 3.79 - 3.68 (m, IH), 3.67 - 3.58 (m, IH), 3.07 - 2.99 (m, 3H), 2.33 (d, J=12.3 Hz, IH), 2.22 (dd, J=3.0, 13.1 Hz, IH), 2.06 - 1.93 (m, IH), 1.90 - 1.77 (m, IH). MS (ESI): M/Z (M+l): 551.21.

Example 4:

4-(8-amino-3-((6R.8aS)-3-oxooctahydroindolizin-6-yl)imidazo[ 1.5-a]pyrazin-l-yn-N- (4-(trifluoromethy0pyridin-2-yl)benzamide

Pd(dppf)Cl ₂ (23.32 mg, 0.029 mmol) was added to a stirred mixture of 4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-N-(4-(trifluoromethyl)p yridin-2-yl)benzamide (224 mg, 0.571 mmol), potassium phosphate tribasic (303 mg, 1.428 mmol) and (6R, 8aS)-6-(8-amino- 1 -bromoimidazo[ 1 , 5-a]pyrazin-3 -yl)hexahydro indolizin-3 (2H)- one (lOOmg, 0.286 mmol) in 1,4-Dioxane (8 ml) and Water (1 ml). The mixture was degassed back-filled with N ₂ and stirred at 80 °C for 3 h. and concentrated. The residue was purified by column chromatography on silica gel (ISCO, 40g), eluting with DCM/MeOH (20/l)to give 4-(8-amino-3-((6R,8aS)-3-oxooctahydroindolizin-6-yl) imidazo [ 1 , 5 -a]pyrazin- 1 -yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (125 mg, 0.233 mmol, 82 % yield) as a yellow solid. LCMS data: R _t 1.21min; m/z 536.25 (M+H) ⁺ ; 1H MR (CDC1 ₃ , 500 Hz): delta 8.98 (1H, br s), 8.76 (1H, br, s), 8.52 (1H, d, J = 5.5 Hz), 8.10 (1H, d, J = 8 Hz), 7.87 (2H, d , J = 8 Hz), 7.34 (1H, d, J = 5 Hz), 7.16 (1H, d, J = 5 Hz), 5.24 (2H, br s), 4.47 (1H, d, J= 14 Hz), 3.61-3.67 (1H, m), 3.04-3.16 (2H, m), 2.50 ((2H, t, J = 9 Hz), 2.11-2.37 (5H, m), 1.70-1.77 (1H, m), 1.41-1.49 (1H, m).

Example 5:

4-(8-amino-3-((6R.8aS)-3-oxooctahydroindolizin-6-yl)imidazo[ 1.5-a]pyrazin-l-yn-N-

(4-cyclopropoxypyridin-2-yl)benzamide

4-(8-amino-3-((6R,8aS)-3-oxooctahydroindolizin-6-yl)imidazo[ l,5-a]pyrazin-l-yl)-N- (4-cyclopropoxypyridin-2-yl)benzamide was prepared following the procedure described for example 4. LCMS data: R _t 1.11 min; m/z 524.33 (M+H) ⁺ ; 1H MR (CDCI ₃ , 500 Hz): 8.26 (1H, d, J = 4 Hz), 8.09 (1H, d, J =5.5 Hz), 8.08 (2H, d , J = 8 Hz), 7.82 (2H, d , J = 8 Hz), 7.32 (1H, d, J = 5.5 Hz), 7.11 (1H, d, J = 5 Hz), 6.74 (1H, dd, J= 5 and 2.5 Hz), 5.16 (1H, br s), 4.43 (1H, d, J= 14 Hz), 3.89-3.93 (1H, m), 3.59-3.65 (1H, m), 3.03-3.13 (2H, m), 2.47 ((2H, t, J = 9 Hz), 2.09-2.39 (5H, m), 1.67-1.75 (1H, m), 1.39-1.47 (1H, m), 0.84-0.93 (4H, m).

Example 6:

4-(8-amino-3-((6R.8aS)-3-oxooctahydroindolizin-6-yl)imidazo[ 1.5-a]pyrazin-l-yn-N-

(pyridin-2-yObenzamide

4-(8-amino-3-((6R,8aS)-3-oxooctahydroindolizin-6-yl)imidazo[ l,5-a]pyrazin-l-yl)-N-

(pyridin-2-yl)benzamide was prepared following the proceduredescribe for example 4. LCMS data: R _t 1.22 min; m/z 468.29 (M+H) ⁺ ; 1H NMR (CDC1 ₃ , 500 Hz): = 8.84 (1H, br, s), 8.44 (1H, d, J = 8.5 Hz), 8.35 (1H, d, J = 4 Hz), 8.09 (2H, d , J = 8 Hz), 7.85 (2H, d , J = 8 Hz), 7.82 (1H, dd, J = 9 and 7.5 Hz), 7.33 (1H, d, J =5 Hz), 7.15 (1H, d, J= 5 Hz), 7.13 (1H, dd, J = 6.5 and 5.5 Hz), 5.28 (1H, br s), 4.47 (1H, d, J= 14 Hz), 3.61- 3.66 (1H, m), 3.51 (2H, br s), 3.04-3.16 (2H, m), 2.49 ((2H, t, J = 9 Hz), 1.41-2.36 (7H, m).

Example 7:

4-(8-amino-3-((6R.8aS)-3-oxooctahydroindolizin-6-yl)imidazo[ 1.5-a]pyrazin-l-yn-N-

(4-cyclobutylpyridin-2-yl)benzamide

4-(8-amino-3-((6R,8aS)-3-oxooctahydroindolizin-6-yl)imida zo[l,5-a]pyrazin-l-yl)-N- (4-cyclobutylpyridin-2-yl)benzamide was prepared following the standard procedure in example 29. LCMS data: R _t 1.16 min; m/z 522.40 (M+H) ⁺ ; MR (CDC1 ₃ , 500 Hz):8.65 (1H, br s), 8.37 (1H, d, J = 8.5 Hz), 8.19 (1H, br s), 8.09 (2H, d , J = 8 Hz), 7.85 (2H, d , J = 8 Hz), 7.70 (1H, dd, J = 8.5 and 2.5 Hz), 7.34 (1H, d, J =5 Hz), 7.18 (1H, d, J= 5 Hz), 5.16 (1H, br s), 4.47 (1H, d, J= 14 Hz), 3.61-3.66 (2H, m), 3.04-3.16 (2H, m), 2.51 ((2H, t, J = 9 Hz), 1.41-2.51 (7H, m).

Example 8:

4-(8-amino-3-((6R.8aS)-3-oxooctahydroindolizin-6-yl)imidazo[ 1.5-a]pyrazin-l-yn-N-

(5-methylthiazol-2-yl)benzamide

4-(8-amino-3-((6R,8aS)-3-oxooctahydroindolizin-6-yl)imidazo[ l,5-a]pyrazin-l-yl)-N- (5-methylthiazol-2-yl)benzamide was prepared following the standard procedure describe for example 4. LCMS data: R _t 1.24 min; m/z 488.29 (M+H) ⁺ ; 1H NMR (CDC1 ₃ , 500 Hz): delta= 8.13 (1H, d, J = 8 Hz), 7.87 (1H, d, J = 8 Hz), 7.34 (1H, d, J = 5 Hz), 7.17 (1H, d , J = 5 Hz), 7.09 (1H, br s), 4.47 (1H, d, J= 12 Hz), 3.49-3.70 (2H, m), 3.06-3.17 (2H, m), 1.37-2.53 (9H, m).

Example 9:

4-(8-amino-3-((6S.8aR)-3-oxooctahydroindolizin-6-yl)imidazo[ 1.5-a]pyrazin-l-yn-N-

(pyridin-2-yObenzamide

4-(8-amino-3-((6S,8aR)-3-oxooctahydroindolizin-6-yl)imidazo[ l,5-a]pyrazin-l-yl)-N- (pyridin-2-yl)benzamide was prepared follow the standard procedure describe for example 4. LCMS data: R _t 1.05 min; m/z 468.20 (M+H) ⁺ ; 1H MR (CDC1 ₃ , 500 Hz): delta = 8.84 (1H, br, s), 8.44 (1H, d, J = 8.5 Hz), 8.35 (1H, d, J = 4 Hz), 8.09 (2H, d , J = 8 Hz), 7.84 (2H, d , J = 8 Hz), 7.82 (1H, dd, J = 9 and 7.5 Hz), 7.32 (1H, d, J =5 Hz), 7.15 (1H, d, J= 5 Hz), 7.13 (1H, dd, J = 6.5 and 5.5 Hz), 5.30 (1H, br s), 4.47 (1H, d, J= 14 Hz), 3.61-3.66 (1H, m), 3.04-3.15 (2H, m), 2.49 ((2H, t, J = 9 Hz), 1.41-2.36 (7H, m).

Example 10 and 11:

4-(8-amino-3 -(Y6S.8aS)-3 -oxooctahydroindolizin-6-yl)imidazo[ 1.5-a]pyrazin- 1 -yl)-N-

(4-(trifluoromethyDpyridin-2-yl)benzamide and 4-(8-amino-3-(Y6R.8aR)-3- oxooctahydroindolizin-6-yl)imidazo[ 1.5 -ajpyrazin- 1 -yD-N-(4-(trifluoromethyl)pyridin-

2-yl)benzamide

(a) cis-3-oxooctahydroindolizine-6-carboxylic acid LiOH (0.826 ml, 1.653 mmol) was added to a stirred mixture of cis-methyl 3- oxooctahydroindolizine-6-carboxylate (163 mg, 0.826 mmol) in Tetrahydrofuran (4 ml) and the mixture stirred at room temperature for 1 h. The mixture was then acidified with 1 N HC1. and concentrated to give cis-3-oxooctahydroindolizine-6-carboxylic acid. LCMS data: R _t 0.35 min; m/z 184.11 (M+H) ⁺ .

(b) cis-N-((3-chloropyrazin-2-yl)methyn-3-oxooctahydroindolizine -6-carboxamide

HATU (377 mg, 0.991 mmol) was added to a stirred, mixture of cis-3- oxooctahydroindolizine-6-carboxylic acid (151 mg, 0.826 mmol) at °C. DIPEA (0.433 ml, 2.478 mmol) in DMF (2ml) was then added followed by(3-chloropyrazin-2- yl)methanamine hydrochloride (164 mg, 0.909 mmol) and the mixture was stirred at room temperature for 1 h. and concentrated. The residue was purified by column chromatography on silica gel (Isco 40g column), eluting with CH2C12/MeOH (30/1) to give cis-N-((3-chloropyrazin-2-yl)methyl)-3-oxooctahydroindolizin e -6-carboxamide (185 mg, 0.599 mmol, 72.5 % yield) as a white solid. LCMS data: R _t 1.08 min; m/z 309.10 (M+H) ⁺ ; 1H MR (CDC1 ₃ , 500 Hz): delta = 8.43 (1H, t, J = 4.5 and 2.5 Hz), 8.30 (1H, br s), 7.46 (1H, br s), 4.89-4.93 (1H, m), 4.52-4.57 (m, 2), 3.57-3.59 (m, l)„ 3.00 (1H, br d, J = 14.5 Hz), 2.71 (1H, br s), 2.30-2.72 (4H, m), 1.69-1.82 (4H, m), 1.49-1.55 m, l).

(c) cis-6-(8-chloroimidazo[1.5-a]pyrazin-3-yl)hexahydroindolizin -3(2H)-one

POCl ₃ (0.326 ml, 3.50 mmol) was added to a stirred, mixture of cis-N-((3- chloropyrazin-2-yl)methyl)-3-oxooctahydroindolizine-6-carbox amide (180 mg, 0.583 mmol) at 0 °C in Acetonitrile (5 ml). DMF (0.045 ml, 0.583 mmol) was then added, the mixture stirred at room temperature overnight and quenched with iced water and solid NaHC03. The mixture was extracted with DCM, and the organic layer concentrated.. The residue was purified by column chromatography on silica gel (ISCO, 40 g column), eluting with CH ₂ Cl ₂ /MeOH (30/1) to give cis-6-(8-chloroimidazo[l,5- a]pyrazin-3-yl)hexahydroindolizin-3(2H)-one (10 mg) as a yellow oil. LCMS data: R _t 1.14 min; m/z 291.1 (M+H) ⁺ .

(d) cis-6-( 1 -bromo-8-chloroimidazo[ 1.5-a]pyrazin-3 -yOhexahydroindolizin-3 (2HV one

BS (8.26 mg, 0.046 mmol) was added to a stirred mixture of cis-6-(8- chloroimidazo[l,5-a]pyrazin-3-yl)hexahydroindolizin-3(2H)-on e (30mg, 0.031 mmol) in Acetonitrile (5 ml) and the mixture was stirred at room temperature for 1 h. The reaction was quenched with sat. NaHC0 ₃ , exctracted with DCM, dried and concentrated. The residue was purified by column chromatography on silica gel (ISCO, 40 g column) (30/1) to give cis-6-(l-bromo-8-chloroimidazo [l,5-a]pyrazin-3-yl)hexahydroindolizin- 3(2H)-one (10 mg, 0.027 mmol, 87 % yield). LCMS data: R _t 0.97 min; m/z 369.98 and 370.99 (M+H) ⁺ .

(e) cis-6-(8-amino- 1 -bromoimidazo[ 1.5-a]pyrazin-3 -yDhexahydroindolizin-3 (2H)- one

A stirred mixture of cis-6-(l-bromo-8-chloroimidazo[l,5-a]pyrazin-3-yl) hexahydroindolizin-3(2H)-one (10 mg, 0.027 mmol) in 15 mL of 2N H ₃ in 2-propanol was heated in a sealed tube at 100 °C overnight and concentrated. The residue was purified by column chromatography on silica gel (ISCO, 40g), eluting with CH ₂ Cl ₂ /MeOH (12/1) to give cis-6-(8-amino-l-bromoimidazo [l,5-a]pyrazin-3- yl)hexahydroindolizin-3(2H)-one (6 mg, 0.017 mmol, 63.3 % yield) as a white solid. LCMS Data: R _t 0.97 min; m/z 350.0, and 352.0 (M+H) ⁺ .

(f) 4-(8-amino-3 -(Y6S.8aS)-3 -oxooctahydroindolizin-6-yl)imidazo[ 1.5-a]pyrazin- 1 - yl)-N-(4-(trifluoromethynpyridin-2-yl)benzamide and 4-(8-amino-3- (Y6R.8aRV 3 -oxooctahydroindolizin-6-ynimidazo [ 1.5 -ajpyrazin- 1 -yl)-N-(4- (trifluoromethyl)pyridin-2-yl)benzamide

Pd(dppf)CH ₂ Cl ₂ (3.50 mg, 4.28 μιηοΐ) was added to a stirred mixture of 4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-N-(4-(trifluoromethyl)p yridin-2-yl)benzamide (16.80 mg, 0.043 mmol), cis-6-(8-amino-l-bromoimidazo [l,5-a]pyrazin-3- yl)hexahydroindolizin-3(2H)-one (15 mg, 0.043 mmol) and Potassium Phosphate Tribasic (45.5 mg, 0.214 mmol) in 1,4-Dioxane (8 ml) and Water (1 ml). The mixture was degassed, back-filled with N ₂ and stirred at 85°C for 3 h. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (ISCO, 40 g, column), eluting with (DCM/2N H ₃ in MeOH, 30/1) to give 4-(8-amino- 3 -((cis)-3 -oxooctahydroindolizin-6-yl) imidazo [ 1 , 5 -a]pyrazin- 1 -yl)-N-(4-

(trifluoromethyl)pyridin-2-yl)benzamide (21.1 mg, 0.039 mmol, 92 % yield) as a yellow solid, which was separated on chiral HPLC (4.6 x 250mm ChiralCel AD, 2.1 mL/min, 100 bar, 70% MeOH(0.2% DEA1/C02, 35 C, peak one retention time 3.33 min, peak two 5.24 min) ) to give 4-(8-amino-3-((6S,8aS)-3-oxooctahydroindolizin-6- yl)imidazo[ 1 ,5-a]pyrazin- 1 -yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (10.2 mg, 0.019 mmol, 48.6 % yield) followed by 4-(8-amino-3-((6R,8aR)-3- oxooctahydroindolizin-6-yl)imidazo[ 1 ,5-a] pyrazin- 1 -yl)-N-(4-(trifluoromethyl)pyridin- 2-yl)benzamide (9.7 mg, 0.018 mmol, 46.2 % yield). Spectra data for 4-(8-amino-3- ((6S,8aS)-3-oxooctahydroindolizin -6-yl)imidazo[l,5-a]pyrazin-l-yl)-N-(4- (trifluoromethyl)pyridin-2-yl)benzamide: LCMS Data: R _t 1.23 min; m/z 536.2 (M+H) ⁺ ; 1H MR (CDC1 ₃ , 500 Hz):9.14 (lH, br s), 8.76 (IH, s), 8.51 (IH, d, J = 5 Hz), 8.06 (2H, d , J = 8 Hz), 7.87 (2H, d , J = 8 Hz), 7.34 (IH, d , J = 5 Hz), 7.22 (IH, d , J = 5 Hz), 7.07 (IH, d , J = 5 Hz), 5.37 (2H, br s), 4.48 (IH, d, J= 14 Hz), 3.62-3.68 (IH, m), 3.42 (IH, br s), 3.21QH, dd, J = 13.5, 4 Hz), 1.72-2.48 (9H, m).

Spectra data for 4-(8-amino-3-((6R,8aR)-3-oxooctahydroindolizin-6-yl) imidazo[l,5- a]pyrazin-l-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide : LCMS Data: R _t 1.23 min; m/z 536.2 (M+H) ⁺ ; 1H MR (CDC1 ₃ , 500 Hz): 9.11 (IH, br s), 8.76 (IH, s), 8.51 (IH, d, J = 5 Hz), 8.06 (2H, d , J = 8 Hz), 7.87 (2H, d , J = 8 Hz), 7.34 (IH, d , J = 5 Hz), 7.22 (IH, d , J = 5 Hz), 7.08 (IH, d , J = 5 Hz), 5.34 (2H, br s), 4.48 (IH, d, J= 14 Hz), 3.62- 3.68 (IH, m), 3.43 (IH, br s), 3.21QH, dd, J = 13.5, 4 Hz), 1.72-2.52 (9H, m).

Following the procedure described for example 4, the following examples were prepared:

Exact

Retention

Example Structure IUPAC Name Mass

time (min) ΓΜ+ΗΓ

4-(8-amino-3-((6R,8aS)-3- oxohexahydro- 1 H- oxazolo[3,4-a]pyridin-6-

Example 12 yl)imidazo[ 1 , 5-a]pyrazin- 1 - 556.2 2.40 yl)-3-fluoro-N-(4-

(trifluoromethyl)pyridin-2- yl)benzamide

4-(8-amino-3-((6S,8aR)-3- oxohexahydro- 1 H- oxazolo[3,4-a]pyridin-6-

Example 13 yl)imidazo[ 1 , 5-a]pyrazin- 1 - 556.2 2.40 yl)-3-fluoro-N-(4- (trifluoromethyl)pyridin-2- yl)benzamide

^* ""V-<r ^F 4-{8-amino-3-[(6R,8aS)-3- oxooctahydroindolizin-6- yl]imidazo[ 1 , 5-a]pyrazin- 1 -

Example 69 580.2 2.57 yl}-3-ethoxy-N-[4-

O (trifluoromethyl)pyridin-2- yljbenzamide

4-{8-amino-3- [(3R,7R,9aS)-3-methyl-4- o ^N oxooctahydropyrido[2, 1 - c][l,4]oxazin-7-

Example 70 Γ 566.2 2.51 yl]imidazo[ 1 , 5-a]pyrazin- 1 - yl}-N-[4- (trifluoromethyl)pyridin-2- yljbenzamide

4-{8-amino-3-[(6R,8aS)-3-

^N J ^F

oxooctahydroindolizin-6- yl]imidazo[ 1 , 5-a]pyrazin- 1 -

Example 71 642.2 2.96 yl } -3 -(benzyloxy)-N- [4-

(trifluoromethyl)pyridin-2- yljbenzamide """V-<r ^F 4-{8-amino-3-[(6R,8aS)-3- N J ^F

oxooctahydroindolizin-6-

J ) yl]imidazo[ 1 , 5-a]pyrazin- 1 -

Example 72 602.2 2.63 yl } -3 -(difluoromethoxy)-N- [4-(trifluoromethyl)pyridin- 2-yl]benzamide

4-{8-amino-3- [(2S,6R,8aR)-2-hydroxy-3- oxooctahydroindolizin-6-

Example 73 yl]imidazo[ 1 , 5-a]pyrazin- 1 - 552.2 2.40 yl}-N-[4- (trifluoromethyl)pyridin-2- yljbenzamide

O°H yljbenzamide

Example 78

4-(8-amino-3 -(Y6R.8aR)-3 -oxohexa hydrooxazolo [4.3 -c] [ 1.4]oxazin-6-yl )imidazo [1.5- ajpyrazin- 1 -yl)-N-(4-(trifluoromethynpyridin-2-ynbenzamide

(a) (2R.5R)-tert-butyl S-rr ert-butyldiphenylsilvnoxy^methvn- -rS-rr ^-dimethoxy benzyl) amino)- 1 -(4-((4-(trifluoromethynpyridin-2-yncarbamoyl)phenyl)imidazo [1.5- a]pyrazin-3-yl)morpholine-4-carboxylate

To (2R,5R)-tert-butyl-2-(l-bromo-8-((2,4-dimethoxybenzyl)amino) imidazo[l,5- a]pyrazin-3-yl)-5-(((tert-butyldiphenylsilyl)oxy)methyl)morp holine-4-carboxylate (0.25 g, 0.306 mmol) and 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-N-(4-(triflu oro methyl)pyridin-2-yl)benzamide (0.144 g, 0.918 mmol) in 1,4-Dioxane (6 ml) and Water (0.2 ml) was added, K ₃ P0 ₄ (0.195 g, 14.63 mmol) and Pd(pddf)C12 (0.025 g, 0.031 mmol) and stirred at 80 °C overnight. The reaction mixture was diluted with EtOAc and filtered through celite. The filtrate was washed with water (3 x 80 mL). The organic phase was dried over MgS0 ₄ and evaporated to dryness. The crude was purified by column chromatography (using 30-60%EtOAc in Hex.) to give (2R,5R)-tert-butyl 5- (((tert-butyldiphenylsilyl) oxy)methyl)-2-(8-((2,4-dimethoxybenzyl)amino)- 1 -(4-((4- (trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)imidazo [ 1 , 5 -a]pyrazin-3 - yl)morpholine-4-carboxylate (0.216 g, 70%). LCMS: [M+H] ⁺ : 1002.89, Rt= 2.86 min.

(b) 4-(8-amino-3 -(Y2R.5 S)-5-(hydroxymethyl)morpholin-2-yl)imidazo[ 1.5-a]pyrazin- 1 - yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide

(2R,5R)-tert-butyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)- 2-(8-((2,4- dimethoxybenzyl)amino)- 1 -(4-((4-(trifluoromethyl)pyridin-2- yl)carbamoyl)phenyl)imidazo[l,5-a]pyrazin-3-yl)morpholine-4- carboxylate (0.5g, 0.499 mmol) was dissolved in 3 mL TFA and 0.5 mL H ₂ 0. The mixture was heated at 80 °C for 3h, and concentrated. The residue was purified by column chromatography (3-20% MeOH in DCM) to give 4-(8-amino-3-((2R,5S)-5-(hydroxymethyl)morpholin-2- yl)imidazo[ 1 , 5-a]pyrazin- 1 -yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (204 mg, 80%). LCMS: [M+H]+: 514.07, Rt= 1.01 min,).

(c)4-(8-amino-3 -(Y6R.8aR)-3 -oxohexa hydrooxazolo [4.3 -c] [ 1.4]oxazin-6- yl )imidazo [ 1.5 -a] pyrazin- 1 -yn-N-(4-(trifluoromethyl)pyridin-2-ynbenzamide

4-(8-amino-3 -((2R, 5 S)-5-(hydroxymethyl)morpholin-2-yl)imidazo[ 1 , 5-a]pyrazin- 1 -yl)- N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (12 mg, 0.023 mmol) was dissolved in 2 mL of Dichloromethane,and the this was added N-ethyl-N-isopropylpropan-2-amine ((9 mg, 0.070 mmol) and l, l '-Carbonyldiimidazole (3.8 mg, 0.023 mmol) at 0 °C. The mixture was stirred for 30 min and concentrated. The residue was purified using reverse phase column (TFA:CH3CN: H ₂ 0 system) to give 4-(8-amino-3-((6R,8aR)-3 -oxohexa hydrooxazolo [4, 3 -c] [ 1 ,4]oxazin-6-yl)imidazo [1,5 -a]pyrazin- 1 -yl)-N-(4- (trifluoromethyl)pyridin-2-yl)benzamide (6 mg, 48%). LCMS: [M+H] ⁺ : 818.31, Rt= 1.03 min.

Btk enzyme activity Assay Methods

BTK enzymatic activity was determined with the LANCE (Lanthanide Chelate Excite) TR-FRET (Time-resolved fluorescence resonance energy transfer) assay. In this assay, the potency (IC ₅₀ ) of each compound was determined from an eleven point (1 :3 serial dilution; final compound concentration range in assay from 1 μΜ to 0.017 nM) titration curve using the following outlined procedure. To each well of a black non- binding surface Corning 384-well microplate (Corning Catalog #3820), 5 nL of compound (2000 fold dilution in final assay volume of 10 μΐ.) was dispensed, followed by the addition of 7.5 μΐ, of lx kinase buffer (50 mM Hepes 7.5, 10 mM MgCl ₂ , 0.01% Brij-35, 1 mM EGTA, 0.05% BSA & 1 mM DTT) containing 5.09 pg/μΐ, (66.67 pM) of BTK enzyme (recombinant protein from baculovirus-transfected S/9 cells: full-length BTK, 6HIS-tag cleaved). Following a 60 minute compound & enzyme incubation, each reaction was initiated by the addition of 2.5 μΐ. lx kinase buffer containing 8 μΜ biotinylated "A5" peptide (Biotin-EQEDEPEGDYFEWLE-NH2), and 100 μΜ ATP. The final reaction in each well of 10 μΐ. consists of 50 pM ΛΒΤΚ, 2 μΜ biotin-A5- peptide, and 25 μΜ ATP. Phosphorylation reactions were allowed to proceed for 120 minutes. Reactions were immediately quenched by the addition of 20 uL of lx quench buffer (15 mM EDTA, 25 mM Hepes 7.3, and 0.1% Triton X-100) containing detection reagents (0.626 nM of LANCE-Eu-W1024-anti-phospho Tyrosine antibody, PerkinElmer and 86.8 nM of Streptavidin-conjugated Dylight 650,

Dyomics/ThermoFisher Scientific). After 60 minutes incubation with detection reagents, reaction plates were read on a PerkinElmer En Vision plate reader using standard TR- FRET protocol. Briefly, excitation of donor molecules (Eu-chelate:anti-phospho- antibody) with a laser light source at 337 nm produces energy that can be transferred to Dylight-650 acceptor molecules if this donor: acceptor pair is within close proximity. Fluorescence intensity at both 665 nm (acceptor) and 615 nm (donor) are measured and a TR-FRET ratio calculated for each well (acceptor intensity/donor intensity). IC ₅₀ values were determined by 4 parameter robust fit of TR-FRET ratio values vs. (Log ₁₀ ) compound concentrations.

The following Table B provides specific IC50 values for all the examples. The IC50 values set forth below were determined according to Assay method described above.

Table B

Example IC50 BTK Example IC50 BTK Example IC50 BTK activity activity activity value (nM) value (nM) value (nM)

5.5 0.638 4.53

1 28 54

15.6 1 .90 0.302

2 29 55

7.2 0.845 1 .76

3 30 56

0.10 0.096 0.285

4 31 57

0.24 0.208 4.07

5 32 58

2.0 0.172 0.13

6 33 59

61 2.45 12.8

7 34 60

3.5 1 .12 5.92

8 35 61

194 0.984 2.47

9 36 62

14.7 0.393 0.167

10 37 63

15.3 1 .92 0.449

11 38 64

0.083 0.1 1766 0.109

12 39 65 1.25 0.22546 0.149

13 40 66

0.115 3.978 0.508

14 41 67

0.208 0.5181 0.089

15 42 68

0.198 0.12658 0.162

16 43 69

0.313 0.095495 0.130

17 44 70

0.165 1.7327 10.7

18 45 71

0.184 0.530299 0.480

19 46 72

0.189 0.168 0.455

20 47 73

0.213 0.13658 0.928

21 48 74

0.411 0.1103 7.27

22 49 75

0.115 0.2632 4.58

23 50 76

0.448 1.5877 7.57

24 51 77

0.536 0.1272 24.9

25 52 78

1.49 0.5042

26 53

1.11

27