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Title:
NOVEL HETEROARYL AND HETEROCYCLE COMPOUNDS, COMPOSITIONS AND METHODS
Document Type and Number:
WIPO Patent Application WO/2014/015523
Kind Code:
A1
Abstract:
The invention relates to novel heteroaryl and heterocycle compounds and pharmaceutical compositions comprising them, uses and methods thereof for inhibiting the activity of PI3k and for treating inflammatory and autoimmune disorders diseases and cancer.

Inventors:
SU WEI-GUO (CN)
DAI GUANGXIU (CN)
XIAO KUN (CN)
JIA HONG (CN)
VENABLE JENNIFER DIANE (US)
BEMBENEK SCOTT DAMIAN (US)
Application Number:
PCT/CN2012/079290
Publication Date:
January 30, 2014
Filing Date:
July 27, 2012
Export Citation:
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Assignee:
HUTCHISON MEDIPHARMA LTD (CN)
SU WEI-GUO (CN)
DAI GUANGXIU (CN)
XIAO KUN (CN)
JIA HONG (CN)
VENABLE JENNIFER DIANE (US)
BEMBENEK SCOTT DAMIAN (US)
International Classes:
A61K31/407; C07D471/04; A61K31/437; A61K31/52; A61P1/00; A61P1/18; A61P3/00; A61P3/10; A61P7/00; A61P9/00; A61P9/10; A61P11/00; A61P11/06; A61P13/08; A61P13/12; A61P17/00; A61P17/06; A61P19/02; A61P19/04; A61P19/08; A61P21/04; A61P25/00; A61P29/00; A61P35/00; A61P35/02; A61P37/00; A61P37/08; C07D473/34
Domestic Patent References:
WO2011130342A12011-10-20
WO2008000410A12008-01-03
WO2003063800A22003-08-07
Attorney, Agent or Firm:
ZHONGZI LAW OFFICE (26 Pinganli Xidajie Xicheng District, Beijing 4, CN)
Download PDF:
Claims:
What claimed is:

1. A compound of formula I-l :

and/or its enantiomers, diasteromers, tautomers, or pharmaceutically acceptable salts thereof, wherein:

Ring A, and X and Y together form a ring selected from II-l, II-2 or II-3

II I II-2 II-3

Z = N or CH;

L = NR5 or O;

R is hydrogen, deuterium (D), optionally substituted alkyl, optionally substituted cycloalkyl, -(CR'R")n-heterocycle , -(CR'R")n-aryl, -(CR'R")n-heteroaryl, - (CR'R")n-C(0)NR R" , -(CR'R")n-S(0)pNR'R" , wherein heterocycle, aryl and heteroaryl independently are optionally substituted with one or more groups selected from the group consisting of halo, -OH, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkoxyl, optionally substituted heterocycle, -NR'R" , -CN, -CF3 and -S02 R'; R2 and R3 are each independently hydrogen, deuterium, halo, -CN, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -NR'R" , -(CR'R")n-C(0)R', -(CR'R")n-C(0)OR', -(CR'R")n-C(0)NR R", - (CR'R")n-S(0) pR or -(CR'R")n-S(0) pN R'R";

R4 is hydrogen, deuterium, halo, -OH, -CN, -N02, -CF3, -OR', -NR'R", optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, - (CR'R")n-C(0)NR R" , optionally substituted heterocycle, optionally substituted aryl or optionally substituted heteroaryl;

R5 is hydrogen, deuterium and optionally substituted alkyl;

or R3, R5 and the atoms they are attached to form an optionally substituted 3-12 membered mono-, bi- or tricyclic saturated or partially unsatuarated

heterocyclic ring;

R' and R" are each independently hydrogen, deuterium, halo, -CN, -OH,

optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted heterocycle; optionally substituted aryl; optionally substituted heteroaryl;

or R', R" and the nitrogen or carbon atom they are both attached to form an

optionally substituted 3-7 membered heterocycle;

each of m and n is 0, 1, 2, or 3;

each of p is 1 or 2;

W is a heteroaryl or heterocycle, wherein heteroaryl and heterocycle

independently are optionally substituted with one or more groups selected from halo,deuterium, -CN, -OH, -CF3, -NR'R", -NR'COR", -NR'CONR'R", - NR'S(0)pR", -(CR'R")n-C(0)R\ -(CR'R")n-C(0)OR , -(CR'R")n- C(0)NR'R", -(CR'R")n-S(0)pR\ -(CR'R")n-S(0) pNR R", optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted heterocycle, optionally substituted aryl and optionally substituted heteroaryl;

provided that when ring A, X and Y together form II-l and Z = N, R3, R5 and the atoms they are attached to must form an optionally substituted 3-12 membered mono-, bi- or tricyclic saturated or partially unsaturated optionally substituted heterocyclic ring.

2. At least one compound of claim 1, and/or its enantiomers, diasteromers, tautomers, or pharmaceutically acceptable salts thereof, wherein,

Ring A, X and Y together form a ring of said II- 1;

Z = N;

R3, R5 and the atoms they are attached to form an optionally substituted 4-6

membered mono saturated or partially unsatuarated heterocyclic ring.

3. At least one compound of claim 1, and/or its enantiomers, diasteromers, tautomers, or pharmaceutically acceptable salts thereof, wherein,

Ring A, X and Y together form a ring of said II- 1, II-2 or II-3; Z = CH;

R2 and R3 are each independently hydrogen, deuterium, halo, -CN, optionally substituted CI.CJO alkyl, optionally substituted C2-Cio alkenyl, optionally substituted C2-Cio alkynyl;

R5 is hydrogen, deuterium and alkyl;

or R3, R5 and the atoms they are attached to form an optionally substituted 4-6 membered mono saturated or partially unsatuarated heterocyclic ring.

4. At least one compound of claim 3, and/or its enantiomers, diasteromers, tautomers, or pharmaceutically acceptable salts thereof, wherein R2 and R3 are each independently H, methyl and ethyl, wherein methyl and ethyl independently are optionally substituted with one or more halogen, -CN and -CF3.

5. At least one compound of any one of claims 1, 3 or 4, and/or its enantiomers,

diasteromers, tautomers, or pharmaceutically acceptable salts thereof, wherein R5 = H.

6. At least one compound of any one of claims 1-5, and/or its enantiomers, diasteromers, tautomers, or pharmaceutically acceptable salts thereof, wherein R3, R5 and the atoms they are attached to form a hterocycle selected from III-l to III-7, which can be optionally substituted with one or more groups selected from halo, -OH, -CN, oxo, - S02 R', optionally substituted alkyl and optionally substituted alkoxyl.

111-1 III-2 III-3 III-4 III-5 III-6 W-7

7. At least one compound of any one of claims 1-6, and/or its enantiomers, diasteromers, tautomers, or pharmaceutically acceptable salts thereof, wherein R1 is hydrogen, optionally substituted Ci.Cio alkyl, optionally substituted C3-Ci2 cycloalkyl,

(CR'R")n-heterocycle, (CR'R")n-aryl, (CR'R")n-heteroaryl, wherein heterocycle, aryl and heteroaryl independently are optionally substituted with halo, -OH, optionally substituted Q.Cio alkyl, optionally substituted C3.Ci2 cycloalkyl, optionally

substituted Q.Cio alkoxyl, optionally substituted heterocycle, -NR'R" , -CN, -CF3 and -S02R'..

8. At least one compound of any one of claims 1-7, and/or its enantiomers, diasteromers, tautomers, or pharmaceutically acceptable salts thereof, wherein R4 is hydrogen, halo, -OH, -CN, -N02, -CF3, -OR', -NR'R", optionally substituted Ci.Cio alkyl, optionally substituted C3-Ci2 cycloalkyl, optionally substituted C2-Cio alkenyl, optionally substituted C2_Ci0 alkynyl, - (CR'R")n-C(0)NR R" , optionally substituted 3-12 membered heterocycle, optionally substituted aryl or optionally substituted heteroaryl.

9. At least one compound of any one of claims 1-8, and/or its enantiomers, diasteromers, tautomers, or pharmaceutically acceptable salts thereof, wherein m = 0, 1 or 2.

10. At least one compound of any one of claims 1-9, and/or its enantiomers, diasteromers, tautomers, or pharmaceutically acceptable salts thereof, wherein W is selected from IV-1, IV-2, IV-3, IV-4, IV-5, IV-6, IV-7 and IV-8, which is optionally substituted with halo, -D, -CN, -OH, -CF3, -NR'R", -(CR'R")n-C(0)NR'R", -NR'COR", - NR'CONR'R", -NR'S(0)nR", -NR'S(0)n R'R" , -(CR'R")n-C(0)R', -(CR'R")n- S(0)nR', -(CR'R")n-S(0) pNR R", optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted alkoxyalkoxy, optionally substituted heterocycle, optionally substituted aryl and optionally substituted heteroary;

IV-7 iv-8

11. At least one compound of any one of claim 10, and/or its enantiomers, diasteromers, tautomers, or pharmaceutically acceptable salts thereof, wherein IV-1, IV-2, IV-3, IV-4, IV-5, IV-6, IV-7 or IV-8 is optionally substituted with halo, -CN, -CF3, - NR'R", -(CR'R")n-C(0)NR'R", -NR'COR", d-Cio alkyl, C2-Ci0 alkenyl, C2-Ci0 alkynyl, C3.Ci2 cycloalkyl, -(CR'R")n-S(0)pR', heterocycle and heteroary, wherein alkyl, alkenyl, alkynyl, heterocycle and heteroary can be optionally substituted with halo, -CN, -OH, -CF3, -OR' and -NR'R".

12. At least one compound selected from compounds 1 to 188 and/or at least one its enantiomers, diasteromers, tautomers, or pharmaceutically acceptable salt thereof.

13. A composition comprising at least one compound of any one of claims 1-12, and/or at least one pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

14. A method of modulating the activity of a PI3K kinase comprising contacting the

kinase with one or more compounds of any one of claim 1-12, and/or its enantiomers, diasteromers, tautomers, or pharmaceutically acceptable salts thereof.

15. A method of treating a disease in a patient in recognized need of said treatment, wherein said disease is associated with abnormal expression or activity of a PI3K kinase, comprising administrating to said patient a therapeutically effective amount of any one or more compounds of claims 1-12, and/or its enantiomers, diasteromers, tautomers, or pharmaceutically acceptable salts thereof.

16. A method of claim 15, wherein the said disease is immune-based disease or cancer.

17. The method of claim 16, wherein said immune-based disease is rheumatoid arthritis, COPD, multiple sclerosis, asthma, glomerulonephritis, lupus, or inflammation related to any of the aforementioned; wherein said cancer is lymphoma or acute myeloid leukemia, multiple myelomia and chronic lymphocytic leukemia.

18. The method of any one of claims 14-17, wherein the said compound and/or its enantiomers, diasteromers, tautomers, or pharmaceutically acceptable salts thereof is administered in combination with another kinase inhibitor that inhibits a kinase activity other than a PI3K kinase.

19. A use of at least one compound of any one of claims 1-12, and/or its enantiomers, diasteromers, tautomers, or pharmaceutically acceptable salts thereof, in the manufacture of a medicament for inhibiting the activity of PI3K.

20. A use of at least one compound of any one of claims 1-12, and/or its enantiomers, diasteromers, tautomers, or pharmaceutically acceptable salts thereof, in the manufacture of a medicament for treating inflammatory and autoimmune disorders diseases or cancer responsive to inhibition of PI3K.

Description:
Novel Heteroaryl and Heterocycle Compounds, Compositions and Methods

FIELD OF THE INVENTION

This invention relates generally to the field of medicine and, more specifically, to novel heteroaryl and heterocycle compounds and pharmaceutical compositions comprising them, uses and methods thereof for inhibiting the activity of PI 3 K and for treating inflammatory and autoimmune disorders diseases and cancer.

BACKGROUND OF THE INVENTION

Phosphoinositide 3-kinases (PI 3-kinases or PI 3 Ks) are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking. After exposure of cells to various biological stimuli, PI 3 Ks primarily phosphorylate phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2, PIP2) at the 3'-OH position of the inositol ring to generate phosphatidylinositol- 3,4,5 - trisphosphate (PtdIns(3,4,5)P3, PIP3) which has an important role as second messengers by working as a docking platform for lipid-binding domains, such as the pleckstrin homology (PH) domains of various cellular proteins. These include kinases (such as 3- phosphoinositide-dependent protein kinase 1 (PDK1) and protein kinase B (PKB)/Akt) that trigger downstream kinase cascades, and guanine-nucleotide exchange factors (such as Vav and P-Rex) that control the activity of small GTPases (T Ruckle, M. K. et al. Nature Reviews Drug Discovery, 2006, 5, 903-9018).

Based on sequence homology and lipid substrate specificity, the PI 3 K family is divided into three classes, I, II, and III. The most studied and the focus of this invention, the class I PI 3 Ks, are heterodimeric proteins, each containing a smaller regulatory domain and a larger 110 kDa catalytic domain which occur in four isoforms differentiated as pi 10a, pi 10β, ρΐ ΐθγ and ρΐ ΐθδ (T. J. Sundstrom. et al Org. Biomol. Chem., 2009, 7, 840-850). Among them, pi 10a, pi 10β and pi 105 together, termed as the class IA PI 3 K, bind to p85 regulatory subunit and are primarily activated by protein tyrosine kinase- coupled receptors (RTK) and/or Ras proteins, whereas ΡΙ 3 Κγ as the sole class IB member, binds to one of two noncatalytic subunits, plOl or p87, is activated by G-protein coupled receptors (GPCRs) through direct interaction with G-protein β γ dimers and Ras proteins, which are widely implicated in various aspects of immune function and regulation.

All four class I catalytic PI 3 K isoforms show a characteristic expression pattern in vivo, pi 10a and pi 10β are ubiquitously expressed, while pi 10 γ and pi 105 are found predominantly in leukocytes, endothelial cells and smooth muscle cells (T. J. Sundstrom. et al Org. Biomol. Chem., 2009, 7, 840-850). Deletion of the class IA isoform pi 10a or β induces embryonic lethality (E9.5-E10) ( Bi L, Okabe I. et al . J Biol Chem, 1999, 274: 10963-8.; Bi L, Okabe I. et al. Mamm Genome. 2002, 13, 169-72) pi ΙΟγ-deficient mice develop and reproduce normally, although they have suboptimal immune responses because of defects in T-cell activation as well as in neutrophil and macrophage migration.The loss of pi 10δ mice are also viable and fertile but exhibit significant defects in T, B cell activation (A Ghigo. et al. BioEssays 2010, 32: 185-196).

Dysregulation and overactivation of the PI 3 K/AKT pathway has been firmly established in cancer cells. In principle, modulating PI 3 K and thus controlling PIP3 levels should regulate AKT activity and ultimately suppress tumor growth.The expression of ΡΙ 3 Κδ is generally restricted to hematopoietic cell types. The pi 105 isoform is

constitutively activated in B cell tumors. Genetic and pharmacologic approaches that specifically inactivate the pi 10δ isoform have demonstrated its important role for the treatment of B cell malignancy (B. J. Lannutti. et al. Blood. 2011, 117, 591-594).

Previous studies have shown that CAL-101, a potent and selective pi 105 inhibitor, has broad antitumor activity against cancer cells of hematologic origin. (Lannutti B. J. Am Soc Hematol. 2008; 1 12. Abstract 16; Flinn I. W. et al. J. Clin.Oncol. 2009; 27(A3543))

In addition to cancer, PI 3 K has also been suggested as a target for inflammatory and autoimmune disorders. The isoforms pi 106 and pi 10γ are mainly expressed in cells of the immune system and contributes to innate and adaptive immunity, pi 105 and pi 10γ regulate diverse immune cell function. For example, inhibition of p 110δ leads to suppression of B-cell activation and function, suppression of T-lymphocyte proliferation, T-cell trafficking, and Thl -Th2 differentiation and Treg function. Inhibition of both pi 10δ and pi 10γ results in inhibition of neutrophil (leukocyte) chemotaxis, inhibition of mast cell activation, intact macrophage phagocytosis and endothelium activation.

Inhibition of pi lOg could activate microglial (C. Rommel, et al. Current Topics in Microbiology and Immunology, 2010, 1, 346, 279-299). So iso form-specific pi 105 or pi 10γ inhibitors are expected to have therapeutic effects on these diseases without interfering with general PI 3 K signaling critical to the normal function of other cellular systems, pi 105 and pi 10γ supporting the hypothesis that pi 105 alone, pi 10γ alone or dual-blockade of both, all present a unique therapeutic opportunity in that

pharmacological inhibition, but the two PI 3 K isoforms simultaneously may yield more superior clinical results in the treatment of a variety of complex immune-mediated inflammatory diseases. In the case of RA, Phosphoinositide 3-kinases (PI 3 Ks), most notably ΡΙ 3 Κδ and ΡΙ 3 Κγ, have crucial and specific roles at all stages of disease progression: in antigen signalling in B and T cells, and in signalling downstream of FcRs, cytokine receptors and chemokine receptors in mast cells, macrophages, neutrophils and synoviocytes (C. Rommel, et al. Nature Reviews Immunology, 2007, 7, 191- 201) .Although the pathogenesis of RA is not yet completely understood, chemokines and other chemoattractants have been detected in the inflamed joint and are responsible for the recruitment of leukocytes into the joints. Amongst these, neutrophils constitute the most abundant population and are capable of inducing inflammatory response and tissue damage (T Riickle, M. K. et al. Nature Reviews Drug Discovery, 2006, 5, 903-9018). Blockade of hematopoietic ΡΙ 3 Κγ and/or ΡΙ 3 Κδ can potently suppresses neutrophil chemotaxis and, in turn, the progression of joint inflammation and cartilage erosion.

Novel compounds are disclosed which in some instances are inhibitors of PI 3 Ks kinase activity including pi 10δ, pi 10γ, pi 10α and pi 10β. These compounds therefore have potential therapeutic benefic in the treatment of a variety of diseases associated with inappropriate pi 10δ, pi 10γ, pi 10a and pi 10β activity, such as cancer, inflammatory, allergic and autoimmune diseases and leukemia etc, in particular systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), allergic disorders, respiratory diseases like asthma and chronic obstructive pulmonary disease (COPD), multiple sclerosis, all pathologic conditions whose onset and/or progression is driven by an inflammatory insult, such as myocardial infarction and cancer.

SUMMARY OF THE INVENTION

The present invention relates to compounds of formula I-l:

and/or its enantiomers, diasteromers, tautomers or pharmaceutically acceptable salts thereof, wherein all substituents are as defined in the detailed description.

The invention provides pharmaceutical compositions comprising at least one compound of formula I-l and/or at least one pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

In one aspect, the invention provides methods of inhibiting the activity of PI 3 K comprising administering a therapeutically effective amount of at least one compound of formula I-l and/or at least one pharmaceutically acceptable salt thereof to the subject in need thereof.

In one aspect, the invention provides a method of treating inflammatory and autoimmune disorders diseases or cancer responsive to inhibition of PI 3 K in a subject, comprising administering a therapeutically effective amount of at least one compound of formula I-l and/or at least one pharmaceutically acceptable salt thereof. In one aspect, the invention also provides a use of at least one compound and/or at least one pharmaceutically acceptable salt described herein in the manufacture of a medicament for inhibiting the activity of PI 3 K.

In one aspect, the invention also provides a use of at least one compound and/or at least one pharmaceutically acceptable salt described herein in the manufacture of a medicament for treating inflammatory and autoimmune disorders diseases or cancer responsive to inhibition of PI 3 K.

In one aspect, the subject can be human.

DETAILED DESCRIPTION OF THE INVENTION

Provided is at least one compound of formula I- 1 :

and/or its enantiomers, diasteromers, tautomers or pharmaceutically acceptable salts thereof, wherein

Ring A, and X and Y together form a ring selected from II- 1 to II-3 :

II-l Π-2 II-3

Z = N or CH;

L = NR 5 or O; R 1 is hydrogen, deuterium, optionally substituted alkyl, optionally substituted cycloalkyl, -(CR'R") n -heterocycle , -(CR'R") n -aryl, -(CR'R") n -heteroaryl, - (CR'R") n -C(0)NR R", -(CR'R") n -S(0) p NR R", wherein heterocycle, aryl and heteroaryl independently are optionally substituted with one or more groups selected from the group consisting of halo, -OH, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkoxyl, optionally substituted heterocycle, -NR'R", -CN, -CF 3 and -S0 2 R';

R 2 and R 3 are each independently hydrogen, deuterium, halo, -CN, optionally

substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -NR'R", -(CR'R") n -C(0)R\ -(CR'R") n -C(0)OR , -(CR'R") n -C(0)NR R", - (CR'R") n -S(0) p R or -(CR'R") n -S(0) P N R R";

R 4 is hydrogen, deuterium, halo, -OH, -CN, -N0 2 , -CF 3 , -OR', -NR'R", optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, - (CR'R") n -C(0)NR R", optionally substituted heterocycle, optionally substituted aryl or optionally substituted heteroaryl;

R 5 is hydrogen, deuterium and optionally substituted alkyl;

or R 3 , R 5 and the atoms they are attached to form an optionally substituted 3-12 membered mono-, bi- or tricyclic saturated or partially unsatuarated heterocyclic ring;

R' and R" are each independently hydrogen, deuterium, halo, -CN, -OH,

optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted heterocycle; optionally substituted aryl; optionally substituted heteroaryl;

or R', R" and the nitrogen or carbon atom they are both attached to form an

optionally substituted 3-7 membered heterocycle;

each of m and n is 0, 1, 2, or 3;

each of p is 1 or 2; W is a heteroaryl or heterocycle, wherein heteroaryl and heterocycle

independently are optionally substituted with one or more groups selected from halo, deuterium, -CN, -OH, -CF 3 , -NR'R", -NR'COR", -NR'CONR'R", -NR'S(0) p R", -(CR'R") n -C(0)R', -(CR'R") n -C(0)OR , -(CR'R") n - C(0)NR'R", -(CR'R") n -S(0) p R\ -(CR'R") n -S(0) p NR R", optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted heterocycle, optionally substituted aryl and optionally substituted heteroaryl;

provided that when ring A, X and Y together form II-l and Z = N, R 3 , R 5 and the atoms they are attached to must form an optionally substituted 3-12 membered mono-, bi- or tricyclic saturated or partially unsaturated optionally substituted heterocyclic ring.

Wherein each optionally substituted group above for which the substituent(s) is (are) not specifically designated, can be unsubstituted or independently substituted with, for example, one or more, such as one, two, or three, substituents independently chosen from halo, -OH, -CN, -CF 3 , -S0 2 R', -NR R", alkyl, alkenyl, alkynyl, alkoxyalkoxy, cycloalkyl, heterocycle, aryl and heteroaryl, in which alkoxy, cycloalkyl, heterocycle, aryl and heteroaryl is optionally substituted with one or more groups selected from halo, - OH, -CN, -CF 3 , -S0 2 R', -NR R", alkyl, alkenyl, alkynyl, alkoxyalkoxy, cycloalkyl, heterocycle, aryl and heteroaryl.

Preferably, the each optionally substituted group can be unsubstituted or

independently substituted with, for example, one or more, such as one, two, or three, substituents independently chosen from halogen, -OH, -CN, -CF , -S0 2 R', -NR R", Q. C 10 alkyl (preferably Ci.C 6 alkyl, more preferably C1.C4 alkyl ), C 2- Cio alkenyl (preferably C 2- C 6 alkenyl, more preferably C 2- C 4 alkenyl), C 2- C 10 alkynyl (preferably C 2- C 6 alkynyl, more preferably C 2- C 4 alkynyl), Ci.Cio alkoxyalkoxy (preferably C 2- C 6 alkoxyalkoxy, more preferably C 2- C 4 alkoxyalkoxy), C 3 .Ci 2 cycloalkyl, 3-12 membered heterocycle, aryl and heteroaryl, in which alkoxy, cycloalkyl, heterocycle, aryl and heteroaryl is optionally substituted with one or more groups selected from halo, -OH, -CN, -CF 3 , -S0 2 R', - NR R", alkyl, alkenyl, alkynyl, alkoxyalkoxy, cycloalkyl, heterocycle, aryl and heteroaryl.

Preferbly, R 1 is hydrogen, optionally substituted Ci.Cio alkyl (preferably Ci.C 6 alkyl, more preferably Ci.C 4 alkyl ), optionally substituted C 3- Ci 2 cycloalkyl, (CR'R") n - heterocycle, (CR'R") n -aryl, (CR'R") n - heteroaryl, wherein heterocycle, aryl and heteroaryl independently are optionally substituted with halo, -OH, optionally substituted Ci.Cio alkyl (preferably Ci.C 6 alkyl, more preferably Ci.C 4 alkyl ), optionally substituted C 3- C 12 cycloalkyl, optionally substituted Q.Cio alkoxyl, optionally substituted heterocycle, -NR'R" , -CN, -CF 3 and -S0 2 R'.

More preferbly, R 1 is hydrogen, Ci.C 4 alkyl, C 3- Ci 2 cycloalkyl, (CR'R") n -aryl and (CR'R") n -heteroaryl, wherein alkyl, cycloalkyl, aryl and heteroaryl can be optionally substituted with halo, -CN and alkoxyl. n is 0 or 1.

In some embodiments, R 1 is hydrogen, methyl, /-propyl, cyclobutyl, benzyl, phenyl, 1,1-difluoro-ethyl, trifluoroethyl, fluorophenyl, difluorophenyl, chlorophenyl, cyanophenyl, methoxyphenyl, methylphenyl, phenyl-S0 2 CH 3

Preferbly, R 2 and R 3 are each independently hydrogen, deuterium, halo, -CN, optionally substituted Ci.Cio alkyl (preferably Ci.Ce alkyl, more preferably Ci.C 4 alkyl), optionally substituted C 2 -Cio alkenyl (preferably C 2 .C 6 alkenyl, more preferably C 2 .C 4 alkenyl), optionally substituted C 2 .Cio alkynyl (preferably C 2 .C 6 alkynyl, more preferably C 2 .C 4 alkynyl).

More preferably, R 2 and R 3 are each independently hydrogen, deuterium, halo, -CN, Ci.Cio alkyl, Ci.Cio haloalkyl, Ci.Cio hydroxylalkyl, Ci.Ci 0 alkoxylalkyl and Ci.Cio aminoalkyl, wherein alkyl, haloalkyl, hydroxylalkyl, alkoxylalkyl and aminoalkyl can be optionally substituted with one or more groups selected from halo, -CN, and -CF 3 .

In some embodiments, R 2 and R 3 are each independently hydrogen, methyl and ethyl, wherein methyl and ethyl independently are optionally substituted with one or more groups selected from halo, -CN, and -CF 3 .

Preferbly, R 4 is hydrogen, deuterium, halo, -OH, -CN, -N0 2 , -CF 3 , -OR', -NR'R", optionally substituted Ci.Cio alkyl (preferably Ci.C 6 alkyl, more preferably Ci_C 4 alkyl ), optionally substituted C 3- Ci 2 cycloalkyl, optionally substituted C 2- Cio alkenyl (preferably C 2- C 6 alkenyl, more preferably C 2- C 4 alkenyl), optionally substituted C 2- Ci 0 alkynyl (preferably C 2 .C 6 alkynyl, more preferably C 2 .C 4 alkynyl), - (CR'R") n -C(0)NR R" , optionally substituted 3-12 membered heterocycle, optionally substituted aryl or optionally substituted heteroaryl, wherein alkyl, cycloalkyl, alkenyl, alkynyl, heterocycle, aryl or heteroaryl can be optionally substituted with one or more groups selected from halogen , -OH, -OR', -NR'R", alkyl, -C(0)NR'R", and heterocycle.

More preferably, R 4 is hydrogen, deuterium, halo, -OH, -CN, -N0 2 , -CF 3 , -OR', - NR'R", Ci.Cio alkyl (preferably Ci.C 6 alkyl, more preferably d.C 4 alkyl ), C 3- Ci 2 cycloalkyl, C 2- Ci 0 alkenyl (preferably C 2- C 6 alkenyl, more preferably C 2- C 4 alkenyl), C 2- Cio alkynyl (preferably C 2 .C 6 alkynyl, more preferably C 2 .C 4 alkynyl), Ci_Ci 0 haloalkyl, d-do hydroxylalkyl, Ci.Cio alkoxylalkyl and Ci.Ci 0 aminoalkyl, - (CR'R") n - C(0)NR R" , 3-12 membered heterocycle, aryl or heteroaryl, wherein alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, hydroxylalkyl, alkoxylalkyl, aminoalkyl, heterocycle, aryl or heteroaryl can be optionally substituted with halo and d.Cio alkyl (preferably Ci.C 6 alkyl, more preferably Ci-C 4 alkyl ).

In some embodiments, R 4 is hydrogen, halo, -CN, hydroxymethyl, methoxylmethyl, methyl, ethyl, cyclopropyl, vinyl, ethynyl, -C(0)NH 2 , 1 -methyl- lH-pyrazolyl.

R 5 is hydrogen, deuterium and optionally substituted Q.Qo alkyl (preferably Ci_C 6 alkyl, more preferably Ci.C4 alkyl).

In some embodiments, R 5 is hydrogen, methyl, ethyl, ^-propyl, /-propyl, «-butyl, i- butyl, i-butyl, each of which is optionally substituted.

Preferbly, R 3 , R 5 and the atoms they are attached to form an optionally substituted 3- 12 membered mono-, bi- or tricyclic saturated or partially unsatuarated optionally substituted heterocyclic ring, wherein heterocyclic ring contains one or more, preferably one or two heteroatoms selected from N, O, and S and is optionally substituted with one or more groups selected from halo, -OH, optionally substituted Ci.Cio alkyl (preferably Ci.C 6 alkyl, more preferably Ci.C 4 alkyl), optionally substituted Ci.Cio alkoxyl, -CN, oxo and -S0 2 R'. More preferably, said alkyl and alkoxyl can be further optionally substituted with one or more groups selected from halo, -OH, -NR'R" and Ci-Qo alkoxyl.

3 5

In some embodiments, R , R and the atoms they are attached to form a 4-6 membered mono- saturated or partially unsatuarated heterocyclic ring, which contains one or more, preferably one or two heteroatoms selected from N, O, and S and is optionally substituted with one or more groups selected from halo, -OH, optionally substituted Ci.C 10 alkyl, optionally substituted Ci.Cio alkoxyl, -CN, oxo and -S0 2 K wherien alkyl and alkoxyl can be further optionally substituted with one or more groups selected from halogen, -OH, -NR'R" and CI.CJO alkoxyl.

In some embodiments, R 3 , R 5 and the atoms they are attached to form an heterocycle selected from III-l to III-7, which can be optionally substituted with halo, -OH, -CN, oxo, -S0 2 R', optionally substituted alkyl and optionally substituted alkoxyl, wherien alkyl and alkoxyl can be further optionally substituted with halo, -OH, -NR'R" and alkoxyl.

111-1 III-2 I II -3 III-4 III-5 III-6 IH-7

In some embodiments, R 3 , R 5 and the atoms they are attached to form a heterocycle selected from III-l to III-7, which can be optionally substituted with halo, -OH and methoxyl.

Preferbly, R' and R" are each independently hydrogen, deuterium, halo, -CN, -OH, optionally substituted C 10 alkyl (preferably C \ .Ce alkyl, more preferably Q ^ alkyl), optionally substituted C3.C cycloalkyl or optionally substituted heterocycle; or R', R" and the nitrogen or carbon atom they are both attached to form an optionally substituted 3-7 membered heterocycle.

In some embodiments, W is selected from IV-1, IV-2, IV-3, IV-4, IV-5, IV-6, IV-7 and IV-8, which is optionally substituted with halo, -D, -CN, -OH, -CF 3 , -NR'R", - (CR'R") n -C(0)NR'R", -NR'COR", -NR'CONR'R", -NR'S(0)nR", -NR'S(0)nNR'R" , - (CR'R") n -C(0)R\ -(CR'R") n -S(0)nR', -(CR'R") n -S(0) p NR R", optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted alkoxyalkoxy, optionally substituted heterocycle, optionally substituted aryl and optionally substituted heteroary, wherein alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, heterocycle, aryl and heteroary can be optionally substituted with halo, -CN, -OH, -CF 3 , -OR', -NR'R", alkyl and heterocycle.

IV-l IV-2 IV-3 IV-4 IV-5 IV-6

IV-7

In some embodiments, W is selected from IV-1, IV-2, IV-3, IV-4, IV-5, IV-6, IV-7 and IV-8, which is optionally substituted with halo, -CN, -CF 3 , -NR'R", -(CR'R") n - C(0)NR'R", -NR'COR", Ci-Cio alkyl, C 2 -C 10 alkenyl, C 2 -Ci 0 alkynyl, C3.C 12 cycloalkyl, -(CR'R") n -S(0) p R', heterocycle and heteroary, wherein alkyl, alkenyl, heterocycle and heteroary can be optionally substituted with halo, -CN, -OH, -CF 3 , -OR' and -NR'R".

In some embodiments, W is selected from IV-1, IV-2, IV-3, IV-4, IV-5, IV-6, IV-7 and IV-8, which is optionally substituted with halo, -CN, -CF 3 , -NH 2 , -S(0)CH 3 , - C(0)CH 3 , -C(0)NH 2 , -C(0)NHCH 3 , -C(0)N(CH 3 ) 2 , -NHCOCH 3 , ethenyl, - CH≡CCH 2 OH, morpholinyl, 1H- pyrazolyl, pyridyl, pyrimidyl, wherein pyridyl and pyrimidyl can be optionally substituted with methyl, halo, -NH 2 or methoxyl..

In some embodiments, m is 0, 1, or 2.

In some embodiments, Z = N.

In some embodiments, Z = CH. In some embodiments, ring A, X and Y together form a ring of said II-2 or II-3, Z = CH. R 2 and R 3 are each independently H, methyl and ethyl, wherein methyl and ethyl independently are optionally substituted with one or more groups selected from halo, -CN and -CF 3 ; and R 5 is hydrogen, deuterium and Ci-Cio alkyl.

In some embodiments, ring A, X and Y together form a ring of said II- 1, II-2 and II-3,

Z=N or CH, preferably, R 2 is H. R 3 , R 5 and the atoms they are attached to form a 3-12 membered mono-, bi- or tricyclic saturated or partially unsaturated heterocyclic ring which contains one or more, preferably one or two heteroatoms selected from N, O, and S and is optionally substituted with one or more groups selected from, halo, -OH, optionally substituted Ci-Cio alkyl(preferably Ci.C 6 alkyl, more preferably C1.C4 alkyl), optionally substituted Q.C 10 alkoxyl, -CN, oxo and -S0 2 R' . In some embodiments, wherien alkyl and alkoxyl can be further optionally substituted with one or more groups selected from halo, -OH, -NR'R" and C1.C10 alkoxyl.

In some embodiments, ring A, X and Y together form a ring of said II- 1, Z = N. R 3 , R 5 and the atoms they are attached to form a 4-6 membered mono-, bi- or tricyclic saturated or partially unsaturated heterocyclic ring which contains one or more, preferably one or two heteroatoms selected from N, O, and S and is optionally substituted.

In some embodiments, ring A, X and Y together form a ring of said II- 1, Z = N. R 3 , R 5 and the atoms they are attached to form a 4-6 membered monocyclic saturated heterocyclic ring which contains one or more, preferably one or two heteroatoms selected from N, O, and S and is optionally substituted and R 2 = H.

Also provided is at least one compound selected frome compounds 1-188 and/or at least one pharmaceutically acceptable salt thereof.

Also provided is at least one compound selected from compounds 1 to 188 and/or at least one its enantiomers, diasteromers, tautomers, or pharmaceutically acceptable salt thereof

Also provided is a composition comprising at least one compound and/or at least one pharmaceutically acceptable salt described herein and at least one pharmaceutically acceptable carrier. Also provided is a method of inhibiting the activity of PI 3 K comprising contacting the receptor with an effective amount of at least one compound and/or its enantiomers, diasteromers, tautomers, or pharmaceutically acceptable salts thereof described herein.

Also provided is a method of treating inflammatory and autoimmune disorders diseases or cancer responsive to inhibition of PI3K comprising administering to a subject in need thereof an effective amount of at least one compound and/or its enantiomers, diasteromers, tautomers, or pharmaceutically acceptable salts thereof described herein.

Also provided is a use of at least one compound and/or its enantiomers, diasteromers, tautomers, or pharmaceutically acceptable salts thereof described herein in the manufacture of a medicament for inhibiting the activity of PI3K.

Also provided is a use of at least one compound and/or its enantiomers, diasteromers, tautomers, or pharmaceutically acceptable salts thereof described herein in the manufacture of a medicament for treating inflammatory and autoimmune disorders diseases or cancer responsive to inhibition of PI3K.

Preferably, the said immune-based disease is rheumatoid arthritis, COPD, multiple sclerosis, asthma, glomerulonephritis, lupus, or inflammation related to any of the aforementioned, and the said cancer is lymphoma or acute myeloid leukemia, multiple myelomia and chronic lymphocytic leukemia.

Preferably, the said compound described herein is administered in combination with another kinase inhibitor that inhibits a kinase activity other than a P¾K kinase.

Definitions

As used in the present specification, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise. The following abbreviations and terms have the indicated meanings throughout:

A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONH 2 is attached through the carbon atom.

The term "alkyl" herein refers to a C 1-10 straight or branched hydrocarbon. Preferably "alkyl" refers to a straight or branched hydrocarbon, containing 1-6 carbon atoms. More prepferably "alkyl" refers to a straight or branched hydrocarbon, containing 1-4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, rc-propyl, /-propyl, «-butyl, z ' -butyl, and t-butyl. "Hydroxylalkyl" refers to the alkyl which is substituted with OH. "Haloalkyl " refers to the alkyl which is substituted with halogen. "Alkoxylalkyl" refers to the alkyl which is substituted with alkoxy. "Aminoalkyl" refers to the alkyl which is substituted with NR a R b , R a and R b can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl.

By "alkoxy" is meant a straight or branched alkyl group of the indicated number of carbon atoms attached through an oxygen bridge. Alkoxy groups will usually have from 1 to 10 carbon atoms attached through the oxygen bridge. Preferably "alkoxy" refers to a straight or branched alkoxy, wherein the alkyl portion contains 1-6 carbon atoms. More prepferably "alkoxy" refers to a straight or branched alkoxy, wherein the alkyl portion contains 1-4 carbon atoms. Examples of alkyl groups include, but not limited to, methoxy, ethoxy, propoxy, z ' -propoxy, «-butoxy, s-butoxy, t-butoxy, pentoxy, 2-pentyloxy, i- pentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, and the like.

The term "alkenyl" herein refers to a C 2-10 straight or branched hydrocarbon, containing one or more C=C double bonds. Preferably "alkenyl" refers to a C 2-6 straight or branched hydrocarbon, containing one or more C=C double bonds. More prepferably "alkenyl" refers to a C 2- 4 straight or branched hydrocarbon, containing one or more C=C double bonds. Examples of alkenyl groups include, but are not limited to, vinyl, 1- propenyl, and 1-butenyl.

The term "alkynyl" herein refers to a C 2- i 0 straight or branched hydrocarbon, containing one or more C≡C triple bonds. Preferably "alkynyl" refers to a C 2-6 straight or branched hydrocarbon, containing one or more C≡C triple bonds. More preferably "alkynyl" refers to a C 2- 4 straight or branched hydrocarbon, containing one or more C≡C triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, 1- propynyl, and 1-butynyl.

The term "cycloalkyl" refers to a saturated and partially unsaturated monocyclic or bicyclic hydrocarbon group having 3 to 12 carbons. The ring may be saturated or have one or more double bonds (i.e. partially unsaturated), but not fully conjugated. Examples W

of bicycle cycloalkyl groups include, but are not limited to octahydropentalene, decahydronaphthalene, bicyclo[3.2.0]heptane, octahydro-lH-indene. Examples of single cycle cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

Cycloalkyl also includes 3- to 12-membered monocyclic or bicyclic carbocyclic ring fused with a 5- and 6-membered aromatic ring, and the point of the attachment is on the cycloalkyl ring.

"Aryl" encompasses: 5- and 6-membered C5 -6 carbocyclic aromatic rings, for example, benzene; bicyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, naphthalene; and tricyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, fluorene.

Aryl also includes 5- and 6-membered C5 -6 carbocyclic aromatic rings fused to a 5- to 7-membered non-aromatic carbocyclic or heterocyclic ring containing one or more heteroatoms selected from N, O, and S, or a 3- to 12- membered cycloalkyl. The point of the attachment is on the carbocyclic aromatic rings.

Bivalent radicals formed from substituted benzene derivatives and having the free valences at ring atoms are named as substituted phenylene radicals. Bivalent radicals derived from univalent polycyclic hydrocarbon radicals whose names end in "-yl" by removal of one hydrogen atom from the carbon atom with the free valence are named by adding "-idene" to the name of the corresponding univalent radical, e.g., a naphthyl group with two points of attachment is termed naphthylidene. Aryl, however, does not encompass or overlap in any way with heteroaryl, separately defined below. Hence, if one or more carbocyclic aromatic rings are fused with a heterocyclic aromatic ring, the resulting ring system is heteroaryl, not aryl, as defined herein.

The term "halo" includes fluoro, chloro, bromo, and iodo, and the term "halogen" includes fluorine, chlorine, bromine, and iodine.

The term "heteroaryl" refers to 5- to 8-membered aromatic, monocyclic rings containing one or more, for example, from 1 to 4, or, in some embodiments, from 1 to 3, or, in some embodiments, from 1 to 2, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon; In some embodiments monocyclic "heteroaryl" refers to 5- to 6-member aromatic containing one or more heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon.

8- to 12-membered bicyclic rings containing one or more, for example, from 1 to 6, or, in some embodiments, from 1 to 5, or, in some embodiments, from 1 to 4, or, in some other embodiments, from 1 to 3, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one heteroatom is present in an aromatic ring; In some embodiments "heteroaryl" refer to 9- to 10-member bicyclic aromatic rings containing one or more heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one heteroatom is present in an aromatic ring, and

11- to 14-membered tricyclic rings containing one or more, for example, from 1 to 6, or in some embodiments, from 1 to 5, or, in some embodiments, from 1 to 4, or, in some embodiments, from 1 to 3, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one heteroatom is present in an aromatic ring.

Heteroaryl also includes 5- to 6-membered heterocyclic aromatic ring fused to a 5- to 7-membered heterocyclic ring containing one or more heteroatoms selected from N, O, and S, or a 5- to 7-membered cycloalkyl ring, the point of the attachment is on the heterocyclic aromatic ring.

When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is not more than 1. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolinyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothienyl, furyl, benzofuryl,

benzoimidazolinyl, indazolyl, indolyl, triazolyl, quinolinyl, quinoxalinyl, pyrido[3,2- if]pyrimidinyl, quinazolinyl, naphthyridinyl, benzothiazolyl, benzoxazolyl, purinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, imidazolopyridinyl, imidazolopyrimidinyl, imidazolotriazinyl, triazolopyridinyl, triazolopyrimidinyl and triazolotriazinyl.

Bivalent radicals derived from univalent heteroaryl radicals whose names end in "-yl" by removal of one hydrogen atom from the atom with the free valence are named by adding "-idene" to the name of the corresponding univalent radical, e.g., a pyridyl group with two points of attachment is a pyridylidene. Heteroaryl does not encompass or overlap with aryl as defined above.

Substituted heteroaryl also includes ring systems substituted with one or more oxide substituents, such as pyridinyl N-oxides.

The terms "heterocycle" refers to 3- to 12-membered monocyclic, bicyclic and tricyclic rings containing one or more, for example, from 1 to 5, or, in some embodiments, from 1 to 4, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon; The rings may be saturated or partially unsaturated (i.e. have one or more double bonds), but not fully conjugated.

Heterocycle also includes 5- to 7-membered heterocyclic ring containing one or more heteroatoms selected from N, O, and S fused with a 5- and 6-membered carbocyclic aromatic ring or a 5- to 6-membered heterocyclic aromatic ring, and the point of the attachment is on the cycloalkyl ring. The point of the attachment may be on a carbon or heteroatom in the heterocyclic ring. The heterocycle can be substituted by oxo.

Suitable heterocycles include, but not limited to, azetidinyl, pyrrolidinyl,

imidazolidinyl, pyrazolidinyl, piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, oxazolidinyl,

thiazolidinyl and thiomorpholinyl. By "optional" or "optionally" is meant that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example,

"optionally substituted alkyl" encompasses both "unsubstituted alkyl" and "substituted alkyl" as defined below. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically non- feasible and/or inherently unstable.

The term "substituted", as used herein, means that any one or more hydrogens on the designated atom or group is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded. When a substituent is oxo (i.e., =0) then 2 hydrogens on the atom are replaced. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation from a reaction mixture, and subsequent formulation as an agent having at least practical utility. Unless otherwise specified, substituents are named into the core structure. For example, it is to be understood that when (cycloalkyl)alkyl is listed as a possible substituent, the point of attachment of this substituent to the core structure is in the alkyl portion.

Compounds described herein include, but are not limited to, their optical isomers, racemates, and other mixtures thereof. In those situations, the single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates or mixtures of diastereomers. Resolution of the racemates or mixtures of diastereomers can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral high-pressure liquid chromatography (HPLC) column. In addition, such compounds include R- and S- forms of compounds with chiral centers. Such compounds also include crystal forms including polymorphs and clathrates. Similarly, the term "salt" is intended to include all isomers, racemates, other mixtures, R- and S -forms, tautomeric forms and crystal forms of the salt of the compound. The invention includes also pharmaceutically acceptable salts of the compounds represented by Formula 1-1, preferably of those described below and of the specific compounds exemplified herein, and methods using such salts.

A "pharmaceutically acceptable salt" is intended to mean a salt of a free acid or base of a compound represented by Formula 1-1 that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S. M. Berge, et al., "Pharmaceutical Salts", J. Pharm. Sci., 1977, 66: 1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley- VCH and VHCA, Zurich, 2002.

Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response. A compound of Formula 1-1 may possess a sufficiently acidic group, a sufficiently basic group, or both types of functional groups, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-l,4-dioates, hexyne-1,6- dioates, benzoates, chlorobenzoates, methyl benzoates, dinitrobenzoates,

hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates, methane-sulfonates, propanesulfonates, naphthalene- 1 -sulfonates, naphthalene-2-sulfonates, and mandelates.

If the compound of Formula I- 1 contains a basic nitrogen, the desired

pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a

pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as mandelic acid, citric acid, or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cirmamic acid, a sulfonic acid, such as laurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, any compatible mixture of acids such as those given as examples herein, and any other acid and mixture thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary level of skill in this technology.

If the compound of Formula 1-1 is an acid, such as a carboxylic acid or sulfonic acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide, alkaline earth metal hydroxide, any compatible mixture of bases such as those given as examples herein, and any other base and mixture thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary level of skill in this technology. Illustrative examples of suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, carbonates, bicarbonates, primary, secondary, and tertiary amines, and cyclic amines, such as benzylamines, pyrrolidines, piperidine, morpholine, and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

A "solvate," such as a "hydrate," is formed by the interaction of a solvent and a compound. The term "compound" is intended to include solvates, including hydrates, of compounds. Similarly, "salts" includes solvates, such as hydrates, of salts. Suitable solvates are pharmaceutically acceptable solvates, such as hydrates, including

monohydrates and hemi-hydrates. As used herein the terms "group", "radical" or "fragment" are synonymous and are intended to indicate functional groups or fragments of molecules attachable to a bond or other fragments of molecules.

The term "active agent" is used to indicate a chemical substance which has biological activity. In some embodiments, an "active agent" is a chemical substance having pharmaceutical utility.

The terms "treating" or "treatment" or "alleviation" refers to administering at least on compounds /or at least one pharmaceutically acceptable salt described herein to a subject to slow down (lessen) an undesired physiological change or disorder, such as the developmnt or spread of inflammation or cancer. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of disease state, and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those with the condition or disorder.)

The term "effective amount" means an amount or dose of a P^K-inhibiting agent sufficient to generally bring about a therapeutic benefit in patients in need of treatment for a disease, disorder, or condition mediated by PI 3 K activity. Effective amounts or doses of the active agents of the present invention may be ascertained by routine methods such as modeling, dose escalation studies or clinical trials, and by taking into

consideration routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease, disorder, or condition, the subject's previous or ongoing therapy, the subject's health status and response to drugs, and the judgment of the treating physician. An exemplary dose is in the range of from about 0.0001 to about 200 mg of active agent per kg of subject's body weight per day, preferably about 0.001 to 100 mg/kg/day, or about 0.01 to 35 mg/kg/day, or about 0.1 to 10 mg/kg daily in single or divided dosage units (e.g., BID, TID, QID). For a 70-kg human, an illustrative range for a suitable dosage amount is from about 0.05 to about 7 g/day, or about 0.2 to about 5 g/day. Once improvement of the patient's disease, disorder, or condition has occurred, the dose may be adjusted for maintenance treatment. For example, the dosage or the frequency of administration, or both, may be reduced as a function of the symptoms, to a level at which the desired therapeutic effect is maintained. Of course, if symptoms have been alleviated to an appropriate level, treatment may cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.

The term "inhibition" indicates a decrease in the baseline activity of a biological activity or process. "Inhibition of PI 3 K activity" refers to a decrease in the activity of PI 3 K as a direct or indirect response to the presence of at least one at least one compound and/or at least one pharmaceutically acceptable salt described herein, relative to the activity of PI 3 K in the absence of the at least one compound and/or the at least one pharmaceutically acceptable salt thereof. The decrease in activity may be due to the direct interaction of the at least one compound and/or at least one pharmaceutically acceptable salt described herein with PI 3 K, or due to the interaction of the at least one compound and/or at least one pharmaceutically acceptable salt described herein, with one or more other factors that in turn affect PI 3 K activity. For example, the presence of at least one compound and/or at least one pharmaceutically acceptable salt described herein, may decrease PI 3 K activity by directly binding to the PI 3 K, by causing (directly or indirectly) another factor to decrease PI 3 K activity, or by (directly or indirectly) decreasing the amount of PI 3 K present in the cell or organism.

In addition, the active agents of the invention may be used in combination with additional active ingredients in the treatment of the above conditions. The additional active ingredients may be coadministered separately with an active agent of Formula 1-1 or included with such an agent in a pharmaceutical composition according to the invention. In an exemplary embodiment, additional active ingredients are those that are known or discovered to be effective in the treatment of conditions, disorders, or diseases mediated by PI 3 K activity, such as another PI 3 K modulator or a compound active against another target associated with the particular condition, disorder, or disease. The combination may serve to increase efficacy (e.g., by including in the combination a compound potentiating the potency or effectiveness of an active agent according to the invention), decrease one or more side effects, or decrease the required dose of the active agent according to the invention.

The active agents of the invention are used, alone or in combination with one or more additional active ingredients, to formulate pharmaceutical compositions of the invention. A pharmaceutical composition of the invention comprises: (a) an effective amount of at least one active agent in accordance with the invention; and (b) a pharmaceutically acceptable excipient.

A "pharmaceutically acceptable excipient" refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of a agent and that is compatible therewith. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

Delivery forms of the pharmaceutical compositions containing one or more dosage units of the active agents may be prepared using suitable pharmaceutical excipients and compounding techniques known or that become available to those skilled in the art. The compositions may be administered in the inventive methods by a suitable route of delivery, e.g., oral, parenteral, rectal, topical, or ocular routes, or by inhalation.

The preparation may be in the form of tablets, capsules, sachets, dragees, powders, granules, lozenges, powders for reconstitution, liquid preparations, or suppositories.

Preferably, the compositions are formulated for intravenous infusion, topical

administration, or oral administration.

For oral administration, the active agents of the invention can be provided in the form of tablets or capsules, or as a solution, emulsion, or suspension. To prepare the oral compositions, the active agents may be fonnulated to yield a dosage of, e.g., from about 5 mg to 5 g daily, or from about 50 mg to 5 g daily, in single or divided doses. For example, a total daily dosage of about 5 mg to 5 g daily may be accomplished by dosing once, twice, three, or four times per day. Oral tablets may include the active ingredient(s) mixed with compatible

pharmaceutically acceptable excipients such as diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like. Exemplary liquid oral excipients include ethanol, glycerol, water, and the like. Starch, polyvinyl -pyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are exemplary disintegrating agents. Binding agents may include starch and gelatin. The lubricating agent, if present, may be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.

Capsules for oral administration include hard and soft gelatin capsules. To prepare hard gelatin capsules, active ingredient(s) may be mixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsules may be prepared by mixing the active ingredient with water, an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di- glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.

Liquids for oral administration may be in the form of suspensions, solutions, emulsions or syrups or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may optionally contain: pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose,

carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.

The active agents of this invention may also be administered by non-oral routes. For example, compositions may be formulated for rectal administration as a suppository. For parenteral use, including intravenous, intramuscular, intraperitoneal, or subcutaneous routes, the agents of the invention may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms may be presented in unit-dose form such as ampules or disposable injection devices, in multi-dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre- concentrate that can be used to prepare an injectable formulation. Illustrative infusion doses range from about 1 to 1000 μg/kg/minute of agent admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.

For topical administration, the agents may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle. Another mode of administering the agents of the invention may utilize a patch formulation to affect transdermal delivery.

Active agents may alternatively be administered in methods of this invention by inhalation, via the nasal or oral routes, e.g., in a spray formulation also containing a suitable carrier.

The compounds described herein, and/or the pharmaceutically acceptable salts thereof, can be synthesized from commercially available starting materials by methods well known in the art. The following schemes illustrate methods for most of compound preparation. In each of the schemes, R 1 , R 2 , R 3 , R 4 , R 5 and W are as defined herein.

Scheme I

Z=C,N,0 orS(0)m heme II

Scheme III

Scheme IV

X= alogen or R1 Scheme V

X=halogen or absent

Scheme VI

The compounds thus obtained can be further modified at their peripheral positions to provide the desired compounds. Synthetic chemistry transformations are described, for example, in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons ( 1995) and subsequent editions thereof.

EXAMPLES

The examples below are intended to be purely exemplary and should not be considered to be limiting in any way. Efforts have been made to ensure accuracy with respect to numbers used (for example, amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric. All MS data were checked by agilent 6120 or agilent 1 100. All NMR data were generated using a Varian 400-MR machine. All reagents, except intermediates, used in this invention are commercially available. All compound names except the reagents were generated by Chemdraw 10.0.

In the following examples, the abbreviations below are used:

4AMS 4A Molecular sieves

aq. aqueous solution

ADP Adenosine diphosphate

ATP Adenosine triphospahte

«-BuOH «-butanol

BOP benzotriazol- 1 -yloxytris(dimethylamino)-phosphonium

hexafluorophosphate

CHAPS 3-[(3-Cholamidopropyl)dimethylammonio]propanesulfonate cone. concentrated

DAST diethylaminosulfur trifluoride

dba dibenzylideneacetone

DBU l,8-diazabicyclo[5.4.0]undec-7-ene

DCM dichloromethane

DHP 3,4-dihydro-2H-pyran DIEA N,N-diisopropylethylamine

DMA NN-dimethylacetamide

DMF Ν,Ν-dimethylformamide

DPPA diphenylphosphoryl azide

dppf 1 , 1 '-bis(diphenylphosphino)ferrocene

DTT DL-Dithiothreitol

EDC l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

EGTA Glycol-bis-(2-aminoethylether)-N,N,N',N'-tetraacetic acid

EtOAc ethyl acetate

g gram(s)

h hour(s)

HATU 2-(lH-7-azabenzotriazol-l-yl)-l, 1 ,3, 3-tetramethyl uronium hexafluorophosphate methanaminium

HBTU 2-( 1 H-B enzotriazole- 1 -yl)- 1 , 1 ,3 ,3 -Tetramethyluronium

hexafluorophosphate

HEPES 4-(2-Hydroxyethyl)-l-piperazineethanesulfonic acid m-CPBA 3-chloroperoxybenzoic acid

MeOH methanol

mg milligram(s)

min minute(s)

mL milliliter(s)

NCS N-chlorosuccinimide

PE petroleum ether

r.t. room temperature

Selectfluor l-chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)

SEM 2-(trimethylsilyl)ethoxymethyl

TBAF tetrabutyl ammonium fluoride

TBSC1 i-butylchlorodimethylsilane

TEA triethylamine TFA trifluoroacetic acid

THF tetrahydrofuran

THP tetrahydropyran

TLC thin-layer chromatography

TMS trimethylsilyl

TsOH 7-toluenesulfonic acid

Intermediate 1: Methyl 3-chloro-lH-pyrrole-2-carboxylate

At 55 - 60 U C with vigorous stirring to a mixture of NCS (107 g, 800 mmol) in THF (250 mL) in a 2 L flask was added 5-methyl-3,4-dihydro-2H-pyrrole (8.3 g, 100 mmol) in one- portion. After addition, the reaction spontaneously heated to reflux for about 5 min, then reacted at 60 - 70 °C for another 1.5 hours. After cooled to r.t., hexane (300 mL) and water (300 mL) were added to the mixture. The organic layer was separated, collected and concentrated. The residue was used in the next step without further purification.

To a mixture of the crude 4,4-dichloro-5-(trichloromethyl)-3,4-dihydro-2H-pyrrole (240 g, 941 mmol) in MeOH (2 L) in an ice-bath was added a solution of NaOMe (324 g, 6 mol) in MeOH (1.5 L) drop-wise over an hour. After addition, the mixture was stirred at r.t. for another one hour. Then 2N HC1 aq. was added to adjust its pH to 2 and the resulting was stirred at room temperature for 15 minutes. The mixture was concentrated and diluted with EtOAc (2.5 L) and water (2 L). The organic layer was separated, concentrated and purified by column chromatography eluting with EtOAc/PE and then crystallize upon standing. Methyl 3-chloro-lH-pyrrole-2-carboxylate was obtained as an orange solid (91.3 g, yield: 61%). MS (m/z): 160.1 (M+H) + . Ή NMR (400 MHz, DMSO-d 6 ) δ 12.05 (s, 1H), 6.98 (m, 1H), 6.21 (t, J= 2.6 Hz, 1H), 3.75 (s, 3H). Intermediate 2: Ethyl 3-bromo-lH-pyrrole-2-carboxylate

To a solution of ethyl 3-amino-lH-pyrrole-2-carboxylate hydrochloride (953 mg, 5.0 mmol) in 48% HBr aq. (3 mL, 26.0 mmol) and water (20 mL) was added NaN0 2 (966 mg, 14.0 mmol) in water (3 mL) at -5 °C. The resulting mixture was then stirred at -5 °C for another 30 minutes. CuBr (2.01 g, 14.0 mmol, fine powder) was added portion-wise at this temperature, and the mixture was stirred at r.t. for 30 minutes and refluxed for 2 hours. The reaction mixture was then extracted with EtOAc. The organic layer was separated, concentrated and purified by flash column chromatography, eluting with EtOAc/PE to afford ethyl 3-bromo-lH-pyrrole-2-carboxylate as a yellow solid (562 mg, yield: 52%). MS (m/z): 218.0, 220.0 (M+H) + . Ή NMR (400 MHz, DMSO- d 6 ) δ 9.22 (s, 1H), 6.86 (t, J= 2.8 Hz, 1H), 6.34 (t, J= 2.8 Hz, 1H), 4.36 (q, J= 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H).

Intermediate 3: l-Amino-3-chloro-lH-pyrrole-2-carboxamide

To a mixture of 60% NaH (12 g, 0.3 mol) in DMF (100 mL) at 0 U C was added methyl 3- chloro-lH-pyrrole-2-carboxylate (32 g, 0.2 mol) in DMF (100 mL) dropwise over one hour. After stirred at 0 °C for another 2.5 hours, to the light brown mixture was added a solution of 0-(2,4-dinitrophenyl)hydroxylamine (48 g, 0.24 mol) in DMF (100 mL) slowly over 30 minutes. The reaction was stirred at 0 °C for 2.5 hours and warmed to room temperature overnight. The mixture was quenched by Na 2 S 2 0 3 aq. and extracted with EtOAc and washed with 10% LiCl aq. The organic layer was separated, concentrated and purified by flash column chromatography eluting with MeOH/water to give methyl l-amino-3-chloro-lH-pyrrole-2-carboxylate as a yellow solid (30 g, yield: 86%). MS (m/z): 174.9 (M+H) + .

A mixture of methyl l-amino-3-chloro-lH-pyrrole-2-carboxylate (30 g, 0.172 mol) in 7N NH 3 /MeOH (300 mL) was allowed to heat to 130 °C in a sealed tube overnight. After concentrated, the residue was purified by flash column chromatography over silica gel eluting with EtOAc/PE to give l-amino-3-chloro-lH-pyrrole-2-carboxamide as a white solid (16 g, yield: 58%). MS (m/z): 160.1 (M+H) + .

Intermediate 4: l-amino-3-bromo-lH-pyrrole-2-carboxamide

To a solution of 60% NaH (2.88 g, 72 mmol) in dry DMF (90 mL) was drop-wise added a solution of ethyl 3-bromo-lH-pyrrole-2-carboxylate (13.08 mg, 60 mmol) in dry DMF (30 mL) at 0-5 °C over 30 min, then the reaction was stirred at 0-5 °C for 30 min.

Subsequently, 0-(2,4-dinitrophenyl)hydroxylamine (14.34 g, 72 mmol) in dry DMF (30 mL) was added drop-wise and the reaction was stirred at r.t. for another 16 hours. The mixture was poured into water and extracted with EtOAc. The combined layers were washed with brine, concentrated and purified by flash column chromatography eluting with PE/EA to afford ethyl l-amino-3-bromo-lH-pyrrole-2-carboxylate as a yellow oil (12.5 g, yield: 89%). MS (m/z): 233.0, 235.0 (M+H) + .

A mixture of ethyl l-amino-3-chloro-lH-pyrrole-2-carboxylate (12.5 g, 53.6 mol) in 7N NH 3 /MeOH (80 mL) was heat at 130 °C overnight in a sealed tube. After concentration, the residue was purified by flash column chromatography eluting with MeOH/H 2 0, and further purified by flash column chromatography over silica gel eluting with EtOAc/PE to give l-amino-3-bromo-lH-pyrrole-2-carboxamide as a yellow solid (6.0 g, yield: 55%). MS (m/z): 203.9, 205.9 (M+H) + . 1H NMR (400 MHz, DMSO- d 6 ) 6 7.71 (s, 1H), 7.47 (s, 1H), 6.89 (d, J= 2.9 Hz, 1H), 6.47 (s, 2H), 6.09 (d, J= 2.9 Hz, 1H).

Intermediate 5: l-amino-3-cyclopropyl-lH-pyrrole-2- carboxamide

To a solution of CuBr (7.25 g, 50 mmol) and Cs 2 C0 3 (16.25 g, 50 mmol) in DMF (150 mL) was added cyclopropylacetylene (3.3 g, 50 mmol) at r.t. under N 2 , the reaction was stirred at 120 °C for 15 min, then ethyl isocyanoacetate(l 1.4 g, 100 mmol) in DMF (20 mL) was added drop-wise and the reaction was stirred at 120 °C for 2 h. The mixture was concentrated and purified by flash column chromatography to give ethyl 3-cyclopropyl- lH-pyrrole-2-carboxylate as a white soild (4.0 g, yield: 49.9%). MS (m/z): 180.1 (M+H) + .

To a mixture of NaH(210 mg, 60%, 5.25 mmol) in DMF (10 mL) was added ethyl 3- cyclopropyl-lH-pyrrole-2-carboxylatemethyl (626 mg, 3.5 mol) in DMF (8 mL) dropwise at 0 °C, the reaction was stirred at °C for 1 h, then 0-(2,4- dinitrophenyl)hydroxylamine(836 mg, 4.2 mmol) in DMF(5 mL) was added dropwise, the reaction was continued at 0 °C for 2 h. The mixture was poured into water and extracted with EtOAc, the organic layers were washed with brine, dried over Na 2 S0 4 , concentrated and purified by flash column chromatography to give ethyl l-amino-3- cyclopropyl-lH-pyrrole-2-carboxylate as a yellow solid (679 mg). MS (m/z): 195.1 (M+H) + .

Ethyl l-amino-3 -cyclop ropyl-lH-pyrrole-2-carboxylate(679 mg, 3.5 mmol) was dissolved in MeOH(5 mL), 5 mL of aq. LiOH solution (I N ) was added, the reaction was stirred at reflux for 1 h. The mixture was concentrated, the resulting aqueous mixture was adjusted to pH~7.0 using 1 N HCl, then extracted with EtOAc, the organic layer was dried over Na 2 S0 4 , concentrated to give the crude product l-amino-3- cyclopropyl-lH-pyrrole-2-carboxylic acid(581 mg) which was used in the next step without further purification.

The mixture of l-amino-3-cyclopropyl-lH-pyrrole-2-carboxylic acid(581 mg, about 3.5 mmol), NH 4 C1(1855 mg, 35 mmol), HATU(1330 mg, 3.5 mmol) and DIPEA(2 mL, 11.5 mmol) in DMF(4 mL) was stirred at r.t. overnight. The reaction mixture was poured into water, extracted with EtOAc, dried over Na 2 S0 4 , concentrated and purified by flash column chromatography to give the title product(166 mg, yield:28%) as a white solid. MS (m/z): 166.1 (M+H) + .

Intermediate 6 and 7: l-amino-3-(methoxymethyl)-lH-pyrrole-2-carboxamide and

2-ethyl -methyl l-amino-lH-pyrrole-2,3-dicarboxylate

Intermediate 6 Intermediate 7

These intermediates were prepared according to the procedure of Intermediate 5 using the corresponding reagents and intermediates under appropriate conditions that will be recognized by one skilled in the art.

Example 1: Synthesis of Compounds 1-58 and Compounds 141-153

Compound 1

(S)-4-(2-(4-oxo-3-phenyl-3,4-dihydropyrrolo[l,2-f] [l,2,4]triazin-2-yl)pyrrolidin-l- yl)-7H-pyrrolo [2,3-d] pyrimidine-5-carbonitrile

Scheme

Compound 1

Step 1 - 1 (S)-tert-butyl 2-(2-carbamoyl- lH-pyrrol- 1 -ylcarbamoyl) pyrrolidine- 1 - carboxylate (lb)

To a solution of la (3.0 g, 24.0 mmol) and (5)-l-(tert-butoxycarbonyl)pyrrolidine- 2- carboxylic acid (7.1 g, 28.8 mmol) in THF (150 mL ) was added EDC (5.52 g, 28.8 mmol). The reaction mixture was stirred at room temperature for 3.5 hours, then the mixture was diluted in water and extracted with EtOAc three times. The combined organic layers were separated, dried over anhydrous Na 2 S0 4 , filtered and concentrated to afford lb as a white solid (4.6 g, yield: 60%). MS (m/z): 322.7 (M+H) + . It was used in the next step without further purification

Step 1-2 (£ tert-butyl 2-(4-oxo-3,4-dihydropyrrolo[l,2-fJ[l,2,4]triazin-2-yl) pyrrolidine- 1 -carboxylate (lc)

1 c

Ethanol (50 ml) was added to lb (3.1 g, 9.6 mmol), then to the mixture was added a solution of KOH (2.88 g, 49.6 mmol) in water (50 mL). The reaction mixture was heated to 100 °C for 3 days. After cooling to room temperature, the reaction mixture was diluted in water and adjusted to pH=3-4 with IN HCI aq. A precipitate was filtered off and dried to afford lc as a white solid (1.7 g, yield: 58%). MS (m/z): 304.7 (M+H) +

Step 1-3 (S)-tert-butyl 2-(4-oxo-3-phenyl-3,4-dihydropyrrolo[l,2-fJ[ 1,2,4] triazin-2-yl) pyrrolidine- 1-carboxylate (Id)

A mixture of lc (604 mg, 2.0 mmol), phenylboronic acid (0.49 g, 4.0 mmol), 4AMS (2 g), Cu(OAc) 2 (0.73 g, 4.0 mmol) and Pyridine (0.8 mL, 10.0 mmol) in dry DCM (30 mL) was stirred for 18 hours at room temperature under dry air atmosphere. The mixture was concentrated in vacuo and purified by flash column chromatography eluting with

MeOH/water to get Id as a white solid (150 mg, yield: 20%). MS (m/z): 380.7 (M+H) +

Step 1-4 (5)-3-phenyl-2-(pyrrolidin-2-yl)pyrrolo[l,2-fj[l,2,4]triazin -4 (3H)-one hydrochloride (le)

A solution of Id (150 mg, 0.395 mmol) in 6NHC1 / MeOH (20 mL) was stirred for 2.5 hours at room temperature, then concentrated under reduced pressure to afford le as a yellow oil which was used directly in next step without further purification.

Step 1-5 (S)-4-(2-(4-oxo-3-phenyl-3,4-dihydropyrrolo[l,2-f] [l,2,4]triazin-2-yl) pyrrolidin-l-yl)- H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (Compound 1)

Compound 1

A mixture of le (30 mg, 0.095 mmol), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5- carbonitrile (22 mg, 0.128 mmol) and TEA (0.05 ml, 0.360 mmol) in n-BuOH (3 mL) was stirred at reflux for 1.5 h. The reaction mixture was concentrated and purified by flash column chromatography eluting with MeOH/DCM to afford Compound 1 as a white solid (29 mg, yield: 64%). MS (m/z): 422.6 (M+H) + . 1H NMR (400 MHz, DMSO- d 6 ) δ: 12.81 (s, 1H), 8.27 - 8.26 (m, 2H), 7.70 (m, 1H), 7.64 - 7.41 (m, 5H), 6.88 (dd, J = 4.3, 1.7 Hz, 1H), 6.47 (dd, J= 4.3, 2.7 Hz, 1H), 4.68 (m, 1H), 4.10 (m, 1H), 3.92 (m, 1H), 2.23 (m, 2H), 2.06 - 1.83 (m, 2H).

The following Compounds 2-58 and Compounds 141-153 and Compound 186-188 were prepared according to the procedure of Compound 1 using the corresponding reagents and intermediates under appropriate conditions that will be recognized by one skilled in the art:

LC/MS

Structure NMR

+

, DMSO-d 6 ) δ: 8.29 (s, IH),

7.42 (m, 5H), 6.88 (m, IH), , IH), 4.20 (m, IH), 4.02 (m, .16 (m, IH), 2.02 - 1.91 (m,

DMSO-d 6 ) δ: 12.96 (br, IH), 7.31 (m, 5H), 6.88 (m, IH), , 0.5 H), 4.67(m, 0.5 H), 4.33 .5H), 3.89 (m, 0.5 H), 3.76(m, 1.98-1.89 (m, 3H). DMSO-d 6 ) δ: 8.17 (m, 2H), 7.53 - 7.32 (m, 3H), 6.87 (m, 32 (m , 0.5H), 4.66 (m, 0.5H), (m, 0.5H), 3.89 (m, 0.5H), -2.21 (m, IH), 1.97-1.88 (m,

DMSO-d 6 ) δ: 8.37-8.16 (m, H), 6.90 (m, IH), 6.48 (m, H), 4.09 (m, IH), 3.92 (m, ), 2.05-1.96 (m, 2H).

DMSO-d 6 ) δ: 12.86 (s, IH), .50 (m, 5H), 6.90 (s, IH), 6.49 , IH), 4.09 (m, IH), 3.92 (m, H), 2.06-1.97 (m, 2H).

Ή NMR (400 MHz, DMSO-d 6 ) δ: 8.24 (m, IH),

8.20 - 8.09 (m, IH), 7.88 - 7.70 (m, IH), 7.59 (m,

432.7 3H), 7.45 (m IH), 6.89 (m, IH), 6.47 (m, IH), 5.33 (m, 0.5H), 4.66-4.60 (m, 0.5H), 4.31 (m, 0.5H), 4.04 (m, 0.5H), 3.89 (m, 0.5H), 3.66 (m, 0.5H),

19

20

21

Ή NMR (400 MHz,DMSO-d 6 ) δ: 8.28 (s, IH), 8.26 (s, IH), 7.74 (d, J= 7.7 Hz, IH), 7.64 - 7.48

22 (m, 5H), 6.89 (d, J = 2.8 Hz, IH), 6.54 - 6.43 (m,

IH), 4.69 (m, IH), 4.10 (m, IH), 3.94 (m, IH), 2.30 (m, IH), 2.21 (m, IH), 2.07 - 1.90 (m, 2H). ,

, ,

,

. Ή NMR (400 MHz, CD 3 OD) δ 8.22 (s, IH), 7.93 (s, IH), 7.72 (m, IH), 7.64 - 7.51 (m, 3H), 7.40 - 7.29 (m, IH), 7.30 - 7.17 (m, IH), 6.28 (d, J= 3.2 Hz, IH), 5.29 (m, IH), 4.60 (m, IH), 4.24 (m, IH), 2.63 - 2.53 (m, IH), 2.20 (m , IH).

8

Ή NMR (400 MHz, DMSO-d 6 ) δ 8.21 (s, IH), 8.13 (s, IH), 7.56 (m, 6H), 6.70 (s, IH), 5.15 (m, IH), 4.15 (m, 2H), 2.68 (m, IH), 2.23 (m, IH).

H NMR (400 MHz, DMSO-d 6 ) δ 8.32 (m, IH), 8.17 (m, IH), 7.86-7.42 (m, 6H), 6.57 (m, IH), 5.61 (m, 0.5H), 4.88 (s, IH), 4.57 (m, 0.5H), 4.36 (m, 0.5H), 4.16 (m, 0.5H), 2.97 (m, 2H). 58

141

142

143

144

145

! H NMR (400 MHz, DMSO-d 6 ) δ: 8.22-8.12 (m,

2H), 7.64-7.49 (m, 6H), 6.61-6.55 (m, 1H), 5.34-

146 4.60 (m, 1H), 4.33-4.10 (m, 1H), 3.84-3.65 (m,

1H), 2.26 (m, 1H), 1.95 (m, 3H). -d 6 ) δ: 8.17 (s, 1H), 1-7.53 (m, 6H), 7.17 1H), 4.67 (m, 1H),

147 2.24 (m, 2H), 2.00 (m,

'H NMR (400 MHz, DMSO-d 6 ) δ: 11.62 (s, 1H), 8.19 (s, 1H), 7.73 - 7.50 (m, 6H), 7.18 (m, 1H),

148 6.70 (m, 1H), 5.03 (m, 1H), 4.19 (m, 1H), 4.08 (m,

1H), 2.75 - 2.67 (m, 1H), 2.25 - 2.16 (m, 1H).

1 : compound was purified by flash column chromatography

2 and 3 : compounds were purified by preparative TLC

Example 2: Synthesis of Compounds 59-69 and Compounds 155-162 Compound 59

(5)-4-(2-(5-chloro-3-(2,2-difIuoroethyl)-4-oxo-3,4-dihydropy rrolo[l,2- f][l,2,4]triazin-2-yl)azetidin-l-yl)-7H-pyrrolo[2,3-d]pyrimi dine-5-carbonitrile Scheme

Compound 59

Step 2-1 (S)-tert-butyl 2-(5-chloro-3-(2,2-difluoroethyl)-4-oxo-3,4-dihydropyrrolo [1,2- fj[ 1 ,2,4]triazin-2-yl azetidine- 1 -carboxylate (2b)

To a mixture of 2a (740 mg, 2.28 mmol) (2a was prepared according to the procedure of Example 1 using l-amino-3-chloro-lH-pyrrole-2-carboxamide and (5)-azetidine-2- carboxylic acid instead of la and (S')-l-(tert-butoxycarbonyl) pyrrolidine-2-carboxylic acid) and Cs 2 C0 3 (1.6 g, 4.92 mmol) in DMF (7 mL) was added 2-bromo-l , l- difluoroethane (0.4 mL, 5.02 mmol). The reaction was heated to 50 °C for one hour and 120 °C for another 1.5 hours. Then the mixture was diluted with water and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over MgS0 4 , filtered and concentrated to give the crude product which was further purified by flash column chromatography eluting with EtOAc/PE. 230 mg of 2b was obtained (yield: 26%) and HOmg of 2a were recovered. MS (m/z): 289.0 (M-Boc+H) + . Step 2-2 (5)-2-(azetidin-2-yl)-5-chloro-3-(2,2-difluoroethyl)pyrrolo[ l,2-fJ[ 1,2,4] triazin- 4(3H)-one hydrochloride 2c)

To a mixture of 2b (230 mg, 0.59 mmol) in MeOH (2 mL) was added cone. HCI aq. (2 mL), then the reaction was stirred at room temperature for about 3 hours. After concentration, 2c was obtained as a pale yellow solid which was used in the next step without further purification. MS (m/z): 289.0 (M+H) + .

Step 2-3 (5)-4-(2-(5-chloro-3-(2,2-difluoroethyl)-4-oxo-3,4-dihydropy rrolo[ l,2-fJ

[ 1 ,2,4]triazin-2-yl)azetidin- 1 -yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (59)

Compound 59

A mixture of 2c (0.59 mmol), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (105 mg, 0.59 mmol) and TEA (0.41 mL, 2.95 mmol) in n-BuOH (9 mL) was heated at 130 °C for 2 hours. After concentration, the residue was washed with water and dried, then purified by preparative TLC and Compound 59 as a pale yellow solid was obtained (160mg, yield: 63%). MS (m/z): 431.1 (M+H) + . J H NMR (400 MHz, DMSO-d 6 ) δ: 12.94 (s, 1H), 8.32 (m, 2H), 7.67 (s, 1H), 6.67 (s, 1H), 6.45 (t, J = 55.2 Hz, 1H), 5.87 (m, 1H), 4.67 (m, 2H), 4.52 - 4.26 (m, 2H), 3.01 (m, 1H), 2.72 (m, 1H). The following Compounds 60-69 and Compounds 155-162 were prepared according to the procedure of Compound 59 using the corresponding reagents and intermediates under appropriate conditions that will be recognized by one skilled in the art:

LC/MS

Structure NMR

+

J

,

Example 3: Synthesis of Compounds 70 and 71

Compound 70

4-((25',4R)-2-(5-chloro-4-oxo-3-phenyl-3,4-dihydropyrrolo[l, 2-f] [l,2,4]triazin-2-yl)- 4-hydroxypyrrolidin-l-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carb onitrile

Scheme

Compound 70

Synthesis of Compound 70 was carried out according to the procedure of Example 1 and the following Step 3-3 using l-amino-3-chloro-lH-pyrrole-2-carboxamide as the starting material. Compound 70 was got as a pale yellow solid. MS (m/z): 472.6 (M+H) + ; 1H NMR (400 MHz, CD 3 OD) δ: 8.29 (s, 1H), 7.99 (s, 1H), 7.80 (d, J= 7.1 Hz, 1H), 7.67 - 7.61 (m, 1H), 7.58 (d, J= 3.1 Hz, 2H), 7.41 (d, J = 6.7 Hz, 1H), 7.35 - 7.25 (m, 1H), 6.46 (d, J= 2.8 Hz, 1H), 4.99 (m, 1H), 4.67 (m, 1H), 4.34 (dd, J= 10.7, 4.1 Hz, 1H), 4.01 (d, J = 10.8 Hz, 1H), 2.33 (m, 1H), 2.20 - 2.11 (m, 1H).

Step 3-3 (25 , ,4i?)-tert-butyl 2-(5-chloro-4-oxo-3,4-dihydropyrrolo[l,2-fj[l,2,4]t yl)-4-(tetrahydro-2H-pyran-2-yloxy)pyrrolidine- 1 -carboxylate (3c)

To a solution of 3b (610 mg, 1.72 mmol) in DCM (30 mL) was added DHP (173 mg, 2 mmol) and TsOH-H 2 0 (65 mg, 0.34 mmol). The reaction mixture was stirred at room temperature for 5 hours. The resulting mixture was concentrated and purified by column chromatography eluting with EtOAc/PE to afford Compound 3c as a pale yellow oil (730 mg, yield: 97%). MS (m/z): 438.7 (M+H) +

Compound 71 was prepared according to the procedure of Compound 70 using the corresponding reagents and intermediates under appropriate conditions that will be recognized by one skilled in the art:

LC/MS

Structure NMR

+

Ή NMR (400 MHz, DMSO-d 6 ) δ 8.29 (m, 3H), 7.73 (d, 1H), 7.62 - 7.46 (m, 5H), 6.56 (m, 1H), 4.53 (m, 1H), 4.20 (m, 1H), 4.15 (m, 1H), 3.77 (m, 1H), 2.22 (m, 1H), 2.07 - 1.95 (m, 1H).

Example 4: Synthesis of Compound 72

Compound 72

5-chloro-2-((2S,4R)-4-methoxy-l-(9H-purin-6-yl)pyrrolidin-2- yl)-3- phenylpyrrolo[l,2-fJ [l,2,4]triazin-4(3H)-one

Scheme

Step 4-1 was carried out according to the procedure in Example 1.

Step 4-2 5-chloro-2-((2,S',4i?)-4-methoxy-l-(9-(tetrahydro-2H-pyran-2 -yl)-9H-purin -6- yl)pyrrolidin-2-yl -3-phenylpyrrolo[ 1 ,2-f] [ 1 ,2,4]triazin-4(3H)-one (4b)

Silver oxide (72 mg, 0.33 mmol) and methyl iodide (62 mg, 0.44 mmol) were added to a solution of 4a (56 mg, 0.1 1 mmol) in acetone (10 mL) at room temperature. The reaction mixture was stirred in the dark at 60 °C overnight. Then the reaction mixture was filtered and the filtrate was concentrated in vacuo to provide the crude 4b without further purification which is used in the next step reaction. MS (m/z): 547 (M+H) +

Step 4-3 5-chloro-2-((2S,4R)-4-methoxy- 1 -(9H-purin-6-yl)pyrrolidin-2-yl)-3-phenyl pyrrolo[ 1 ,2-fJ [ 1 ,2,4]triazin-4(3H)-one (72)

To a solution of 4b (60 mg, 0.1 1 mmol) in MeOH (2 mL) was added conc.HCl aq (2 mL). The resulting mixture was stirred at 50 °C for one hour. Then the reaction was

concentrated and 7NNH 3 in MeOH (5 mL) was added. After concentration in vacuo, the crude product was purified by preparative TLC eluting with MeOH/DCM to afford Compound 72 as a pale yellow solid (16mg, yield: 31%). MS (m/z): 462.9 (M+H) + ; Ή NMR (400 MHz, DMSO-d 6 ) δ: 8.23 - 8.08 (m, 2H), 7.73 - 7.40 (m, 6H), 6.53 (m, 1H), 5.29 (m, 1H), 4.64 - 4.51 (m, 1H), 4.12 (m, 2H), 3.09 (s, 3H), 2.33 (m, 1H), 2.00 (m, 1H).

Example 5: Synthesis of Compound 73 and 74

Compound 73

5-chloro-2-((2S,4S)-4-fluoro-l-(9H-purin-6-yl)pyrrolidin-2-y l)-3-phenylpyrrolo[l,2- f] [l,2,4]triazin-4(3H)-one

Scheme

Compound 73

Step 5-1 (25,45)-tert-butyl 2-(5-chloro-4-oxo-3,4-dihydropyrrolo[l,2-f][l,2,4]triazin -2- yl)-4-fluoropyrrolidine- 1 -carbox late (5 a)

3b 5a

To a solution of 3b (400 mg, 1.13 mmol) in DCM (50 mL) was added DAST (726 mg, 4.52 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for one hour, then at room temperature for another one hour. LC-MS showed the starting material disappeared, then NaHCC"3 aq. (10 mL) was added and extracted with DCM three times. The organic layers were combined, dried over Na 2 SC"4 and concentrated to give Compound 5a which was used in the next step without further purification. MS (m/z): 257 (M-Boc+H) +

Steps 5-2 to 4 were carried out according to the procedure of Example 1. Compound 73 was got as a white solid. MS (m/z): 451.1 (M+H) + ; 1H NMR (400 MHz, DMSO-d 6 ) δ: 8.38 - 8.10 (m, 3H), 7.68 (m, 2H), 7.60 (m, 1H), 7.55 (m, 1H), 7.46 (s, 1H), 6.54 (s, 1H), 5.34 (m, 1H), 4.88 - 4.34 (m, 1H), 4.24 - 3.93 (m, 2H), 2.24 (m, 2H). Compound 74 was prepared according to the procedure of Compound 73 using the corresponding reagents and intermediates under appropriate conditions that will be recognized by one skilled in the art:

LC/MS

Structure NMR 8

-

Example 6: Synthesis of Compounds 75-84

Compound 75

3-(l-(9H-purin-6-yIamino)ethyI)-8-chloro-2-(3-fluorophenyl)p yrroIo[l,2-a] pyrazin- l(2H)-one

Scheme

Compound 75 Step 6-1 methyl 3-chloro-l- 2-oxobutyl)-lH-pyrrole-2-carboxylate (6b)

To a solution of 6a (4.8 g, 30.0 mmol) in DMF (40 mL) was added 60% NaH (1.2 g, 30.0 mmol) at 0-5 °C and stirred at 0-5 °C for 30 minutes. Then l-bromobutan-2-one (5.0 g, 33 mmol) was added and stirred at room temperature for 2 hours. After concentration in vacuo, the residue was used in the next step without further purification. MS (m/z): 230.1 (M+H) +

Step 6-2 8-chloro-3-ethylpyrrolo[l,2-a]pyrazin-l(2H)-one (6c)

6b

A mixture of the obtained 6b (30.0 mmol) in 7M NH 3 / MeOH (80 mL) was stirred in a sealed tube at 130 °C for 16 hours. After concentration, the residue was purified by flash column chromatography eluting with MeOH/H 2 0 to afford 6c as a white solid (2.67 g, yield: 45%). MS (m/z): 197.1 (M+H) +

Step 6-3 8-chloro-3-ethyl-2-(3-fluorophenyl)pyrrolo[l,2- 6d) ,

6c 6d

A mixture of 6c (1.97 g, 10.0 mmol), 3-fluorophenylboronic acid (2.80 g, 20.0 mmol), 4AMS (24 g), Cu(OAc) 2 , (3.63 g, 20.0 mmol) and pyridine (3.96 g, 50.0 mmol) in dry DCM (80 mL) was stirred under dry air at room temperature for 16 hours. The mixture was filtered through celite and washed with MeOH/DCM. The filtrate was concentrated and purified by flash column chromatography eluting with MeOH/DCM to afford 6d as a yellow solid (1.53 g, yield: 53%). MS (m/z): 291.0 (M+H) +

Step 6-4 8-chloro-2-(3-fluorophenyl)-3-( 1 -hydroxyethyl)pyrrolo[ 1 ,2-a]pyrazin- 1 (2 H)-one (6e)

To a solution of 6d (1.53 g, 5.26 mmol) in dioxane (25 mL) was added Se0 2 (584 mg, 5.26 mmol) and stirred under reflux for one hour. After concentration, the residue was purified by flash column chromatography eluting with EtOAc/PE to afford 6e as a yellow solid (1.60 g, yield: 99%). MS (m/z): 307.0 (M+H) +

Step 6-5 3-(l-azidoethyl)-8-chloro-2-(3-fluorophenyl)pyrrolo[l,2-a]py razin-l(2H)- one (6f)

To a solution of 6e (1.60 g, 5.2 mmol) in THF (30 mL) was added DPPA (2.86 g, 10.4 mmol) and DBU (1.58 g, 10.4 mmol), then the mixture was stirred at 50-60 °C overnight. After concentration, the residue was purified by flash column chromatography eluting with EtOAc/PE to afford 6f as a yellow oil (680 mg, yield: 39%). MS (m/z): 332.0 (M+H) +

Step 6-6 3-(l-aminoethyl)-8-chloro-2-(3-fluorophenyl)pyrrolo[l,2-a]py razin-l(2H)- one (6g)

To a mixture of 6f (680 mg, 2.05 mmol) in THF (20 mL) was added PPh 3 (1.08 g, 4.10 mmol) and the reaction was stirred at room temperature for 10 minutes. Then cone.

ΝΗ 3 Ή 2 0 aq. (5 mL) was added and the reaction was stirred at 50-60 °C for another 4 hours. The reaction mixture was concentrated in vacuo and the residue was purified by flash column chromatography eluting with MeOH/H 2 0 to afford 6g as a white solid (320 mg, yield: 51%). MS (m/z): 306.1 (M+H) +

Step 6-7 3-(l-(9H-purin-6-ylamino)ethyl)-8-chloro-2-(3-fluorophenyl)p yrrolo[l ,2-a] pyrazin-l(2H -one (75)

Compound 75

A mixture of 6g (61 mg, 0.20 mmol), 6-chloro-9H-purine (37 mg, 0.24 mmol) and TEA (40 mg, 0.40 mmol) in n-BuOH (1 mL) was stirred under nitrogen at reflux for 16 hours. The reaction mixture was concentrated in vacuo, and the residue was purified by flash column chromatography eluting with MeOH/H 2 0 to afford Compound 75 as a yellow solid (44.4 mg, yield: 50%). MS (m/z): 424.1 (M+H) + . Ή NMR (400 MHz, DMSO-d 6 ) δ: 8.03-7.94 (m, 2H), 7.79 (s, 1H), 7.47 (s, 2H), 7.35-7.12 (m, 3H), 7.00 (s, 2H), 6.60 (s, 1H), 4.81 (m, 1H), 1.35 (br, 3H).

The following Compounds 76-84 were prepared according to the procedure of

Compound 75 using the corresponding reagents and intermediates under appropriate conditions that will be recognized by one skilled in the art: NMR

J

, ,

,

Example 7: Synthesis of Compounds 85-89

Compound 85

3-(l-(9H-purin-6-ylamino)propyl)-8-chloro-2-(3-fluorophenyl) pyrrolo[l,2- a] pyrazin-1 (2H)-one

Scheme

Compound 85

Step 7-1 methyl 3-chloro-l- 2-oxopropyl)-lH-pyrrole-2-carboxylate (7b)

To a solution of 6a (5.85 g, 36.7 mmol) in DMF (70 mL) was added 60% NaH (1.61 g, 40.3 mmol) at 0-5 °C and stirred at 0-5 °C for 30 minutes. Then a solution of 1- bromopropan-2-one (7.54 g, 55 mmol) in DMF (10 mL) was added dropwise at 0-5 °C, and the reaction was stirred at room temperature for 30 minutes. After concentration in vacuo, the residue 7b was used in the next step without further purification.

Step 7-2 8-chloro-3-methylpyrrolo[l,2-a]pyrazin-l(2H)-one (7c)

A mixture of obtained 7b (36.7 mmol) in 7M NH 3 in MeOH (80 mL) was stirred in a sealed tube at 130 °C for 16 hours. After concentration in vacuo, the residue was purified by flash column chromatography eluting with MeOH/DCM to afford 7c as a yellow solid (3.59 g, yield: 54%). MS (m/z): 183.1 (M+H) +

Step 7-3 8-chloro-2- 3-fluorophenyl)-3-methylpyrrolo[l,2-a]pyrazin-l(2H)-one (7d)

7c 7d

A mixture of 7c (910 mg, 5.0 mmol), 3-fluorophenylboronic acid (1.40 g, 10.0 mmol), 4AM S (25g), Cu(OAc) 2 , (1.82 g, 10.0 mmol) and pyridine (1.98 g, 25.0 mmol) in dry DCM (80 mL) was stirred under dry air at room temperature for 16 hours. The mixture was filtered through celite and washed with MeOH/DCM. The filtrate was concentrated and the residue was purified by flash column chromatography eluting with MeOH/H 2 0 to afford 7d as a yellow solid (1.38 g, yield: 83%). MS (m z): 277.1 (M+H) +

Step 7-4 8-chloro-2-(3 -fluorophenyl)- 1 -oxo- 1 ,2-dihydropyrrolo [ 1 ,2-a]pyrazine-3 - carbaldehyde (7

To a solution of 7d (1.38 g, 5.0 mmol) in dioxane (30 mL) was added Se0 2 (1.11 g, 10 mmol) and the reaction was stirred at reflux for 2 hours. The mixture was diluted with EtOAc, and filtered through celite. The filtratewas collected, concentrated and purified by flash column chromatography eluting with EtOAc/PE to afford 7e as a yellow solid (1.45 g, yield: 100%). MS (m z): 291.0 (M+H) +

Step 7-5 8-chloro-2-(3-fluorophenyl)-3-(l-hydroxypropyl)pyrrolo[l,2-a ]pyrazin- 1(2H)- one (7f)

To a solution of 7e (1.01 g, 3.5 mmol) in dry THF (50 mL) was added 3M EtMgBr in THF (7 mL, 21 mmol) at 0-5 °C and the reaction was stirred at room temperature for 30 minutes. The mixture was poured into sat. NH 4 C1 aq. and extracted with EtOAc. The organic layer was collected, concentrated and purified by flash column chromatography eluting with EtOAc/PE to afford 7f as a yellow solid (1.06 g, yield: 94%). MS (m/z): 321.0 (M+H) +

Step 7-6 3-(l-azidopropyl)-8-chloro-2-(3-fluorophenyl)pyrrolo[l,2-a]p yrazin- l(2H)-one (7g)

To a solution of 7f (1.06 g, 3.3 mmol) in THF (50 mL) was added DPPA (1.82 g, 6.6 mmol) and DBU (1.0 g, 6.6 mmol), then the reaction was stirred at 50-60 °C overnight. After concentration in vacuo, the residue was purified by flash column chromatography eluting with EtOAc/PE to afford 7g as a yellow oil (853 mg, yield: 75%). MS (m/z): 346.1 (M+H) +

Step 7-7 3-( 1 -aminopropyl)-8-chloro-2-(3-fluorophenyl)pyrrolo[ 1 ,2-a]pyrazin- 1 (2H)- one (7h)

To a mixture of 7g (853 mg, 2.46 mmol) in THF (10 mL) was added PPh 3 (1.293 g, 4.92 mmol) and conc.NH 3 -H 2 0 aq. (4.2 mL), then the reaction was stirred at 50-60 °C for 16 hours. After concentration in vacuo, the residue was purified by flash column

chromatography eluting with MeOH/H 2 0 to afford 7h as a yellow solid (600 mg, yield: 76%). MS (m/z): 320.1 (M+H) +

Step 7-8 3-(l-(9H-purin-6-ylamino)propyl)-8-chloro-2-(3-fluorophenyl) pyrrolo[l,2-a] pyrazin-l(2H)-one (85)

Com pound 85

A mixture of 7h (143 mg, 0.45 mmol), 6-chloro-9H-purine (77 mg, 0.50 mmol) and TEA (136 mg, 1.35 mmol) in n-BuOH (2 mL) was stirred under nitrogen at reflux for 16 hours. The reaction mixture was concentrated in vacuo. The residue was purified by flash column chromatography eluting with MeOH/H 2 0 and further purified by preparative TLC eluting with MeOH/DCM to afford Compound 85 as a yellow solid (16.1 mg, yield: 8.2%). MS (m/z): 438.1 (M+H) + . 'H NMR (400 MHz, DMSO-d 6 ) 5: 8.00-7.97 (m, 2H), 7.41-7.40 (m, 2H), 7.25-7.23 (m, 1H), 7.13-7.07 (m, 2H), 7.03-6.94 (m, 2H), 6.48-6.47 (m, 1H), 1.93- 1.84 (m, 1H), 1.75-1.68 (m, 1H), 0.85-0.82 (m, 3H).

The following Compounds 86-89 were prepared according to the procedure of

Compound 85 using the corresponding reagents and intermediates under appropriate conditions that will be recognized by one skilled in the art: LC/MS

StmCtUre (M+H)÷ ^

8

Example 8: Synthesis of Compounds 90-92

Compound 90

4-amino-6-(l-(8-methyl-l-oxo-2-phenyl-l,2-dihydropyrrolo[l,2 -a]pyrazin-3- yl)ethylamino)pyrimidine-5-carbonitrile

Scheme

Step 8-1 (Z)-ethyl -ethoxy-2-nitroacrylate (8a)

8a

A mixture of ethyl 2-nitroacetate (26.6 g, 200 mmol) and triethoxymethane (44.5 g, 300 mmol) in acetic anhydride (51.5 g, 500 mmol) was stirred at 100 °C for 16 hours. After concentration, the residue was further distilled under reduced pressure to afford 8a as a yellow oil (30.3 g, yield: 82%). MS (m/z): 190 (M+H) + . Step 8-2 methyl l-(l,3-diethoxy-2-nitro-3-oxopropyl)-3-methyl-lH-pyrrole-2- carboxylate (8b)

To a solution of methyl methyl 3-methyl-lH-pyrrole-2-carboxylate (13.33 g, 96 mmol) in THF (160mL) was added 60% NaH (5.76 g, 192 mmol) at 0-5 °C under nitrogen. The mixture was stirred at 0-5 °C for half an hour. Then 8a (27.27 g, 144 mmol) was added and the reaction was stirred at room temperature for one hour. Then the mixture was diluted with EtOAc and brine. The organic layer was collected, concentrated and purified by flash column chromatography eluting with EtOAc/PE to afford 8b as a yellow oil (24.6 g, purity: 60%).

Step 8-3 methyl l-(2-amino-l,3-diethoxy-3-oxopropyl)-3-methyl-lH-pyrrole-2- carboxylate (8c)

To a solution of 8b (21.3 g, 65 mmol) in MeOH (400 mL) was added CoCl 2 » 6H 2 0 (30.9 g, 130 mmol) followed by NaBH 4 (12.3 g, 32.4 mmol) in small portions. H 2 was evolved and the reaction was stirred at room temperature for one hour. 10% HCl aq. was added to dissolve the black precipitate and MeOH was removed by evaporation. Concentrated ΝΗ 3 ·Η 2 0 aq. was added and the mixture was extracted with EtOAc. The organic layer was dried and concentrated in vacuo to afford an orange oil which was purified by flash column chromatography eluting with EtOAc/PE to give 8c as a yellow oil (9.56 g). MS (m/z): 299 (M+H) + .

Step 8-4 ethyl 4-ethoxy-8-methyl-l-oxo-l,2,3,4-tetrahydropyrrolo[l,2-a]pyra zine -3- carboxylate (8d)

A solution of the obtained 8c (9.56 g) in toluene (180 mL) was heated at reflux under nitrogen for 40 hours. The mixture was concentrated and the residue was purified by flash column chromatography eluting with EtOAc/PE to give 8d as a brown oil (1.85 g, yield: 10%). MS (m/z): 267 (M+H) + .

Step 8-5 ethyl 8-meth l-l-oxo-l,2-dihydropyrrolo[l,2-a]pyrazine-3-carboxylate (8e)

To a solution of 8d (1.85 g, 6.9 mmol) in dry THF (40 mL) cooled in an ice-bath was added 60% NaH (210 mg, 7.0 mmol) and stirred at 0-5 °C for 30 minutes. MeOH was added and followed by water. The mixture was extracted with EtOAc three times. The organic layers were combined and concentrated, the residue was purified by flash column chromatography eluting with PE/EA to give 8e as a white solid (1.60 g, yield: 100%). MS (m/z): 221 (M+H) + .

Step 8-6 3-(hydroxymethyl)-8-methylpyrrolo[l,2-a]pyrazin-l(2H)-one (8f)

To a solution of 8e (110 mg, 0.50 mmol) in THF (5 mL) was added 1M BH 3 /THF (5 mL, 5 mmol) at 0-5 °C and stirred at room temperature for one hour. Water was added to quench the reaction. The mixture was diluted with EtOAc and brine. The organic layer was collected and concentrated. The residue as a white solid (65 mg, yield: 74%) was used in the next step without further purification. MS (m/z): 179 (M+H) + .

Step 8-7 3-((tert-butyldimethylsilyloxy)methyl)-8-methylpyrrolo[l,2-a ]pyrazin- 1(2H) - one (8g)

To a solution of 8f (1.78 g, 10 mmol) in dry THF (60 mL) was added 60% NaH (600 mg, 20 mmol) and the reaction was stirred at room temperature for 20 minutes. Then to the mixture was added tert-butylchlorodimethylsilane (3 g, 20 mmol) and the mixture was stirred at room temperature for another 40 minutes. The reaction was quenched by MeOH, and diluted with EtOAc and brine. The organic layer was collected, concentrated and purified by flash column chromatography eluting with EtOAc/PA to give 8g as a white solid (1.12 g, yield: 38%). MS (m/z): 293 (M+H) + .

Step 8-8 3-((tert-butyldimethylsilyloxy)methyl)-8-methyl-2-phenylpyrr olo[l,2-a] pyrazin-l(2H)-o

A mixture of 8g (1.03 g, 3.52 mmol), phenylboronic acid (860 mg, 7.04 mmol), diacetoxycopper (1.28 g, 7.04 mmol), pyridine (1.39 g, 17.61 mmol) and 4AMS (15 g) in DCM (60 mL) was stirred at room temperature under dry air for 16 hours. Then the reaction mixture was diluted with DCM and MeOH and filtered through celite. The filtrate was collected, concentrated and purified by flash column chromatography eluting with MeOH/H 2 0 to give 8h as a white solid (950 mg, yield: 73%). MS (m/z): 369 (M+H) + .

Step 8-9 3-(hydroxymethyl)-8-methyl-2-phenylpyrrolo[l,2-a]pyrazin-l(2 H)-one (8i)

To a solution of 8h (950 mg, 2.58 mmol) in THF (10 mL) was added TBAF»3H 2 0 (814 mg, 2.58 mmol) and stirred at room temperature for 15 minutes. The mixture was diluted with EtOAc and washed with brine. The organic layer was collected, dried and concentrated to give 8i as a yellow oil (585 mg, yield: 89%). MS (m/z): 255 (M+H) + .

Step 8-10 8-methyl-l-oxo-2-phenyl-l,2-dihydropyrrolo[l,2-a]pyrazine-3- carbaldehyde (¾)

To a solution of 8i (585 mg, 2.30 mmol) in DCM (30 mL) was added Mn0 2 (3.0 g, 34.4 mmol) and the reaction was stirred at room temperature overnight. The mixture was filtered through celite. The filtrate was concentrated and purified by flash column chromatography eluting with EtOAc/PE to give 8j as a white solid (366 mg, yield: 63%). MS (m/z): 252.7 (M+H) + . Step 8-11 3-(l-hydroxyethyl)-8-methyl-2-phenylpyrrolo[l,2-a]pyrazin-l( 2H)-one (8k)

To a solution of 8j (366 mg, 1.45 mmol) in THF (30mL) was added 2M CH 3 MgI in Et 2 0 (1.45 mL, 2.9 mmol) at -78 °C and stirred for 30 minutes. The mixture was quenched by adding 10 mL of saturated NH 4 C1 aq.and extracted with EtOAc. The organic layer was collected and concentrated to afford 8k as a yellow solid (349 mg, yield: 89.7%), which was used in the next step without further purification. MS (m/z): 269 (M+H) + .

Step 8-12 3-(l-azidoeth l)-8-methyl-2-phenylpyrro -a]pyrazin-l(2H)-one (81)

To a solution of 8k (349 mg, 1.3 mmol) in THF (20 mL) was added DPPA (716 mg, 2.6 mmol) at 0-5 °C, followed by DBU (396 mg, 2.6 mmol) at 0-5 °C. The mixture was stirred at room temperature under nitrogen for 16 hours. The mixture was concentrated and purified by flash column chromatography eluting with EtOAc/PE to give 81 as a white solid (160 mg, yield: 42%). MS (m/z): 294 (M+H) + .

Step 8-13 3-(l-aminoethyl)-8-methyl-2-phenylpyrrolo[l,2-a]pyrazin-l(2H )-one (8m)

To a solution of 81 (160 mg, 0.54 mmol) in THF (5 mL) was added triphenylphosphine (286 mg, 1.09 mmol) and cone. ΝΗ 3 · H 2 0 aq. (1 mL), then the reaction was stirred at 50 C for 2 hours. The mixture was concentrated and purified by flash column chromatography eluting with MeOH/water to give 8m as a yellow solid (120 mg, yield: 82.6%). MS (m z): 268 (M+H) + .

Step 8-14 4-amino-6-(l-(8-methyl-l-oxo-2-phenyl-l,2-dihydropyrrolo[ l,2-a]pyrazin- 3- yl) ethylamino)pyrimidine- 5 -carbonitrile (90)

A mixture of 8m (40 mg, 0.15 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (28 mg, 0.18 mmol) and triethylamine (30 mg, 0.3 mmol) in n-BuOH (1 mL) was reacted under N 2 at reflux for 16 hours. The precipitate was collected by filtration, washed with cold n- BuOH and dried to afford Compound 90 as a white solid (38.2 mg, yield: 55%). MS (m z): 386 (M+H) + . Ή NMR (400 MHz, DMSO-d 6 ) δ: 7.72 (s, 1H), 7.43 (d, J= 7.2 Hz, 1H), 7.36 (m, 3H), 7.24 (m, 4H), 7.10 (s, 2H), 6.37 (s, 1H), 4.73 (m, 1H), 2.38 (s, 3H), 1.26 (d, J= 6.7 Hz, 3H).

The following Compounds 91 and 92 were prepared according to the procedure of Compound 90 using the corresponding reagents under appropriate conditions that will be recognized by one skilled in the art:

LC/MS

# Structure NMR

+

91 Ή NMR (400 MHz, DMSO-d 6 ) δ: 8.06 - 8.02 (m,

2H), 7.81 (s, 1H), 7.36 - 7.08 (m, 8H), 6.34 (s, 1H), 4.78 (s, 1H), 2.37 (s, 3H), 1.31 (d, J= 6.7 Hz, 3H).

Example 9: Synthesis of Compound 93

Compound 93

3-(l-(9H-purin-6-ylamino)ethyl)-8-(l-methyl-lH-pyrazol-4-yl) -2-phenylpyrrolo [1,2- a]pyrazin-l(2H)-one

compound 93

Step 9-1 8-bromo-3-ethylpyiTolo[l,2-a]pyrazin-l(2H)-one (9b

9a 9b To a solution of 9a (900 mg, 4.4 mmol) in anhydrous DMF (30 mL) was added 60% NaH (246 mg, 6.2 mmol.) at 0 °C. The resulting mixture was stirred at 0 °C for 30min, then 1- bromobutan-2-one (3.3g, 22 mmol.) was added and the reaction was stirred at room termperature overnight. Then the solvent was removed in vacuo and the residue was dissolved in 7M NH 3 in MeOH (50 mL). The resulting mixture was stirred at 130 °C in a sealed tube for 24 hours. The reaction was cooled to room temperature and the solvent was removed in vacuo. The obtained residue was purified by flash column

chromatography eluting with EtOAc/PE to give compound 9b as a yellow solid (700 mg, yield: 66%). MS (m/z): 241 (M+H) +

Step 9-2 8-bromo-3-ethyl-2-phenylpyrrolo[l,2-a]pyrazin-l(2H)-one (9c)

A mixture of 9b (700 mg, 2.92 mmol), phenylboronic acid (71 1 mg, 5.84 mmol), 4AMS (3 g), Cu(OAc) 2 (1.06 g, 5.84 mmol) and Pyridine (1.15 g, 14.6 mmol) in dry DCM (30 mL) was stirred overnight at room temperature under dry air. The mixture was filtered through celite and the filtrate was concentrated and purified by flash column

chromatography eluting with MeOH/water to afford 9c as a yellow solid (520 mg, yield: 56%). MS (m z): 317 (M+H) +

Step 9-3 3-ethyl-8-(l-methyl-lH-pyrazol-4-yl)-2-phenylpyrrolo[l,2-a]p yrazin-l(2H) -one (9d)

To a mixture of 9c (500 mg, 1.58 mmol) in 1,4-dioxane (30 mL) and water (3mL) was added l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazole (362 mg, 1.74 mmol), Pd(PPh 3 ) 4 (91 mg, 0.079 mmol) and K 2 C0 3 (545 mg, 3.95 mmol). The resulting mixture was heated at reflux under N 2 for 1.5 hours. Then the solvent was removed in vacuo and water was added. The mixture was extracted with DCM three times. The organic layers were combined and concentrated to give the crude product which was purified by flash column chromatography eluting with EtOAc/PE to give 9d as a yellow solid (300 mg, yield: 60%). (m/z): 319 (M+H) +

Steps 9-4 to 7 3-(l-(9H-purin-6-ylamino)ethyl)-8-(l-methyl-lH-pyiazol-4-yl) -2- phenylpyrrolo[ 1 ,2-a]pyrazin- 1 (2H)-one (93)

Compound 93

Steps 9-4 to 7 were carried out according to the procedure of Example 6 using 9d instead of 6d. Compound 93 was obtained as a white solid. MS (m/z): 451.9 (M+H) + ; 1H NMR (400 MHz, CD 3 OD) δ: 8.18 (s, 1H), 8.04 (s, 1H), 7.99 (s, 1H), 7.90 (s, 1H), 7.51 (s, 1H), 7.47 - 7.39 (m, 1H), 7.36 (d, J= 2.2 Hz, 1H), 7.35 - 7.31 (m, 1H), 7.24 m, 1H), 7.18 (m, 1H), 6.92 (m, 1H), 6.82 (m, 1H), 5.02 (m, 1H), 3.82 (s, 3H), 1.50 (d, J= 6.8 Hz, 3H).

Example 10: Synthesis of Compounds 94-97 and Compounds 163-164

Compound 94

( 1 S)-4-(2-(4-oxo-3-phenyl-3,4-dihydropyrrolo[l,2-f] [l,2,4]triazin-2-yl)pyrrolidin-l- yl)-7H-py rrolo [2,3-d] py rimidine-5-carboxamide

10a Compound 94

Step 10- 1 0S 4-(2-(4-oxo-3-phenyl-3 ,4-dihydropyrrolo[ 1 ,2-fJ [ 1 ,2,4]triazin-2-yl) pyrrolidin-l-yl)-7H^yrrolo[2,3-d]pyrimidine-5-carboxylic acid (10a)

10a

Step 10-1 was carried out according to the procedure of Example 1 using 4-chloro-7H- pyrrolo[2,3-d]pyrimidine-5-carboxylic acid instead of 4-chloro-7H- pyrrolo[2,3- d]pyrimidine- 5-carbonitrile.

Step 10-2 0S 4-(2-(4-oxo-3-phenyl-3,4-dihydropyrrolo[ 1 ,2-fJ[ 1 ,2,4]triazin-2-yl) pyrrolidin-l-yl)- -pyrrolo[2,3-d]pyrimidine-5-carboxamide (94)

0a Compound 94

10a ( 123 mg, 0.28 mmol) was dissolved in DMF (10 mL) and to the solution was added HATU (117 mg, 0.31 mmol) and NH 4 C1 (300 mg, 5.6 mmol). The resulting mixture was stirred at room temperature overnight. The reaction was quenched by water and extracted with DCM three times. The organic layers were combined and concentrated to give the crude product which was purified by preparative TLC eluting with

DCM/MeOH to give compound 94 as a white solid (49 mg, yield: 40%). MS (m/z): 440.7

(M+H) + ; 1H NMR (400 MHz, DMSO-d 6 ) 6: 12.08 (s, 1H), 8.22 (s, 1H), 7.90 - 7.70 (m, 2H), 7.65 - 7.43 (m, 6H), 7.28 (s, 1H), 6.90 (s, 1H), 6.50 (s, 1H), 4.63 (m, 1H), 4.04 (m, 1H), 3.85 (m, 1H), 2.12 (m, 2H), 1.93 (m, 1H), 1.76 (m, 1H).

The following Compounds 95-97 and Compounds 163-164 were prepared according to the procedure of Compound 94 using the corresponding reagents and intermediates under appropriate conditions that will be recognized by one skilled in the art:

LC/MS

# Structure , NMR

+

,

,

Example 11: Synthesis of Compounds 98-104 and Compound 165 Compound 98

(Ay)-3-phenyl-2-(l-(5-vinyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl) pyrrolidin-2-yl) pyr

Compound 98 Step 11-1 (5)-2-(l-(5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyr rolo[2,3-d] pyrimidin-4-yl)pyrrolidin-2-yl)-3-phenylpyrrolo[l,2-f][l,2,4 ]triazin-4(3H)-one (11a)

Step 11-1 was carried out according to the procedure of Example 1 using 4-chloro-5- iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]p yrimidine instead of 4- chloro-7H- pyrrolo[2,3-d]pyrimidine- 5-carbonitrile.

Step 11-2 (S)-3-phenyl-2-(l-(7-((2-(trimethylsilyl)ethoxy)methyl)-5-vi nyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)pyrrolo[l,2-f][ l,2,4]triazin-4(3H)-one (1

To a solution of 1 la (70 mg, 0.11 mmol) in DMF/EtOH/H 2 0 (4 mL/1 mL/1 mL) were added 4,4,5,5-tetramethyl-2-vinyl-l,3,2-dioxaborolane(51 mg, 0.33 mmo), Pd(OAc) 2 (1.2 mg, 0.006 mmol), PPh 3 (2.8 mg, 0.011 mmol) and Na 2 C0 3 (70 mg, 0.66 mmol). Under N 2 , the reaction mixture was heated at 100 °C overnight. Then the solvent was removed in reduced pressure and the residue was purified by flash column chromatography eluting with MeOH/water to give 1 lb as a yellow solid (20 mg, yield: 33%).

Step 11-3 (S)-3-phenyl-2-(l-(5-vinyl-7H-pyiTolo[2,3-d]pyrimidin-4-yl)p yrrolidin-2- yl)pyrrolo[l,2-f][l,2,4]triazin-4(3H)-one (98)

11 b Compound 98

1 lb (20 mg, 0.036 mmol) was dissolved in TFA (3 mL) cooled in the ice bath. The resulting mixture was stirred at room temperature for 2 hours. Then the solvent was removed in vacuo. The residue was dissolved in MeOH (1 mL) and 7NNH 3 in MeOH (1 mL) was added. The mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue was purified by flash column chromatography eluting with MeOH/water to give compound 98 as a white solid (7 mg, yield: 46%). MS (m/z): 423.7 (M+H) + ; 'H NMR (400 MHz, CDC1 3 ) δ: 7.79 (m, 1H), 7.60-7.52 (m, 3H), 7.28 (s, 1H), 7.23 (m, 2H), 7.08-7.02 (m, 2H), 6.95-6.88 (m, 1H), 6.51-6.40 (m, 1H), 5.48 (m, 1H), 5.17 (m, 1H), 4.96 (m, 1H), 4.05 - 3.94 (m, 1H), 3.76 (m, 1H), 2.26 (m, 1H), 2.05 (m, 2H), 1.91-1.82 (m, 1H).

The following Compounds 99-104 and Compound 165 were prepared according to the procedure of Compound 98 using the corresponding reagents and intermediates under appropriate conditions that will be recognized by one skilled in the art:

NMR

'H NMR (400 MHz, DMSO-d 6 ) δ: 8.18 (s, 1H), 7.88 - 7.66 (m, 3H), 7.64 - 7.47 (m, 5H), 7.13 (d, J = 10.0 Hz, 1H), 6.95 - 6.84 (m, 1H), 6.51 (dd, J= 4.2, 2.7 Hz, 1H), 4.75 (t, J= 6.6 Hz, 1H), 3.17-3.15 (m, 1H), 3.04 (m, 1H), 1.80 (m, 1H), 1.49-1.46 (m, 1H), 1.20 (m, 2H).

,

Example 12: Synthesis of Compounds 105

Compound 105

(S)-4-(2-(5-ethynyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[l,2-f] [l,2,4]t

yl)azetidin-l-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitr ile

Scheme

Compound 55 12a Compound 105

Step 12-1 (S)-4-(2-(4-oxo-3-phenyl-5-((trimethylsilyl)ethynyl)-3,4-dih ydropyrrolo [1,2-f] [ 1 ,2,4]triazin-2-yl)azetidin- 1 -yl)-7H-pyrrolo[2,3 -d]pyrimidine-5-carbonitrile ( 12a)

Compound 55 12a

To a mixture of Compound 55 (84 mg, 0.173 mmol), Pd(PPh 3 ) 2 Cl 2 (8 mg, 0.0116 mmol) and Cul (2.2 mg, 0.0116 mmol) in DMF (4 mL) was added Et 3 N (0.36 mL, 2.6 mmol) and ethynyltrimethylsilane (44 mg, 0.448 mmol). The reaction was heated under N 2 at 90 °C for 4 hours, then the mixture was cooled to room temperature, filtered and

concentrated. The residue was further purified by flash column chromatography eluting with MeOH/water to get 12a (60 mg, yield: 69%). MS (m/z): 505 (M+H) + . Step 12-2 (5)-4-(2-(5-ethynyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[l,2-f] [l,2,4]triazin -2- yl)azetidin-l-yl)-7H-pyirolo[2,3-d]pyrimidine-5-carbonitrile (105)

12a Compound 105

To a solution of 12a (60 mg, 0.12 mmol) in DMF (2 mL) was added 1.0 M TBAF in THF (0.15 mL, 0.15 mmol). After 20 minutes, the reaction mixture was diluted in water and extracted with EtOAc three times. The combined organic layers were dried, filtered and concentrated to give the crude product which was purified by flash column

chromatography eluting with MeOH/water to afford Compound 105 as a white solid (2.0 mg, yield: 4%). MS (m/z): 433.2 (M+H) + . 1H NMR (400 MHz, CD 3 OD) δ: 8.22 (s, 1H), 7.94 (s, 1H), 7.74 (d, J= 7.6 Hz, 1H), 7.66 - 7.59 (m, 1H), 7.58 - 7.51 (m, 2H), 7.35 (m, 2H), 6.64 (d, J= 2.8 Hz, 1H), 5.33 (dd, J= 9.5, 5.2 Hz, 1H), 4.62 (m, 1H), 4.26 (m, 1H), 3.52 (s, 1H), 2.67 - 2.51 (m, 1H), 2.02 (m, 1H).

Example 13: Synthesis of Compound 106

Compound 106

(-S -4-(2-(7-fluoro-4-oxo-3,4-dihydropyrrolo[l,2-f] [l,2,4]triazin-2-yl)pyrroIidin-l-yI) -7H-pyrrolo [2,3-d] pyrimidine-5-carbonitrile

Scheme

Compound 1

Step 13-1 (£)-teit-butyl 2-(7-fiuoro-4-oxo-3,4-dihydropyrrolo[l,2-f][l,2,4]triazin-2- yl) pyrrolidine- 1 -carboxylate (13a)

To a solution of lc (80 mg, 0.263 mmol) in MeCN (15ml) was added Selectfluor (100 mg, 0.263 mmol), then the reaction was stirred at room temperature under N 2 atmosphere overnight. The mixture was diluted in water and extracted with EtOAc three times. The combined organic layers were washed with brine and concentrated. The residue was purified by flash column chromatography eluting with MeOH/water to get 13a as a white solid (51mg, yield: 60%). MS (m/z): 322.8 (M+H) +

Step 13-2 (5)-7-fluoro-2-(pyrrolidin-2-yl)pyrrolo[l,2-f][l,2,4]triazin -4(3H)-one hydrochloride (13

A solution of 13a (51 mg, 0.16 mmol) in 6NHC1 in MeOH (15 mL) was stirred for 2 hours at room temperature, then concentrated under reduced pressure to afford 13b as a yellow oil which was used directly in next step without further purification. MS (m/z): 222.8 (M+H) +

Step 13-3 0S 4-(2-(7-fluoro-4-oxo-3 ,4-dihydropyrrolo[ 1 ,2-f] [ 1 ,2,4]triazin-2-yl) pyrrolidin- 1 -yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile ( 106)

Compound 106

A mixture of 13b (0.16 mmol), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonitrile (28 mg, 0.16 mmol) and TEA (0.08 mL, 0.58 mmol) in n-BuOH (5 mL) was stirred at reflux for 2 hours. The reaction mixture was concentrated and purified by flash column chromatography eluting with MeOH/water to afford Compound 106 as a white solid (27 mg, yield: 62%). MS (m/z): 364.7 (M+H) + . Ή NMR (400 MHz, DMSO-d6) δ: 13.07 - 12.72 (m, 1H), 11.76 (s, 1H), 8.30 (s, 1H), 8.13 (s, 1H), 6.77 (m, 1H), 6.31 - 6.09 (m, 1H), 5.1 1 (m, 1H), 4.28 (m, 1H), 3.94 (m, 1H), 2.40 - 2.30 (m, 1H), 2.18 - 2.02 (m, 3H).

Example 14: Synthesis of Compound 107

Compound 107

(5)-4-(2-(7-fluoro-3-isobutyl-4-oxo-3,4-dihydropyrrolo[l,2-f J [l,2,4]triazin-2- yl)pyrrolidin-l-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitri le

Scheme

Compound 107

Step 14-1 (5)-tert-butyl 2-(7-fluoro-3-isobutyl-4-oxo-3,4-dihydropyrrolo[l,2-f][ 1,2,4] triazin-2-yl)pyrrolidine- 1 -carboxylate (14a)

To a mixture of 13a (200 mg, 0.62 mmol) and Cs 2 C0 3 (403 mg, 1.24 mmol) in DMF (5 rtiL) was added l-bromo-2-methylpropane (170 mg, 1.24 mmol), then the reaction was heated to 80 °C for 2 hours. The mixture was diluted with water and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over MgS0 4 , filtered, concentrated and purified by flash column chromatography eluting with MeOH/water to give 14a (50 mg, yield: 21%). MS (m/z): 278.8 (M-Boc+H) + .

Step 14-2 (5)-7-fluoro-3-isobutyl-2-(pyiTolidin-2-yl)pyrrolo[l,2-f][l, 2,4]triazin-4(3H) - one hydrochloride (14b)

To a mixture of 14a (50 mg, 0.132 mmol) in MeOH (5 mL) was added cone. HC1 aq (5 mL), then the reaction was stirred at room temperature for 2 hours. After concentration under reduced pressure, 14b was obtained as a yellow oil which was used directly in the next step without further purification. MS (m/z): 278.8 (M+H) +

Step 14-3 (5 -4-(2-(7-fluoro-3-isobutyl-4-oxo-3,4-dihydropyrrolo[l,2-fJ[l ,2,4]triazin -2- yl)pyrrolidin- 1 -yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile ( 107)

Compound 107

A mixture of 14b (0.132 mmol), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5- carbonitrile (24 mg, 0.132 mmol) and TEA (0.09 mL, 0.66 mmol) in n-BuOH (10 mL) was heated at reflux for 2 hours. The reaction mixture was concentrated purified by flash column chromatography eluting with MeOH/water to afford compound 107 as a slight yellow solid (17 mg, yield: 31%). MS (m/z): 420.7 (M+H) + . 1H-NMR (400 MHz, DMSO-d 6 ) δ: 8.29 (s, 1H), 8.03 (s, 1H), 6.77 (t, J= 5.1 Hz, 1H), 6.16 (t, J= 4.0 Hz, 1H), 5.50 (m, 1H), 4.26 (m, 1H), 4.15 - 4.08 (m, 2H), 3.69 (m, 1H), 2.37 - 2.01 (m, 5H), 1.00 (d, J= 6.6 Hz, 3H), 0.93 (d, J= 6.5 Hz, 3H).

Example 15: Synthesis of Compounds 108-109 and Compounds 166-176

Compound 108

(.yj- -il-ie-amino-S-ie-methox p ridin-S- ^p rimidin^- ^azetidin- - ^-S-chloro- 3-phenylpyrrolo[l,2-f] [l,2,4]triazin-4(3H)-one

Scheme

Compound 108

A mixture of 15a (50 mg, 0.106 mmol) (15a was prepared according to the procedure of Example 1), 2-methoxy-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (28 mg, 0.116 mmol), Pd(dppf) 2 Cl 2 (9 mg, 0.0106 mmol) and a 2 C0 3 (23 mg, 0.212 mmol) in dioxane (20 mL) and water (2 mL) was heated at 130 °C under N 2 atmosphere for 3 hours. Then the mixture was filtered, concentrated and purified by flash column

chromatography eluting with MeOH/water to give Compound 108 as a white solid (30 mg, yield: 56%). MS (m/z): 500.6 (M+H) + 1H NMR (400 MHz, DMSO-d 6 ) δ: 8.18 - 7.39 (m, 8H), 7.29 (d, J= 6.4 Hz, 2H), 6.73 - 6.57 (m, 1H), 5.82 (s, 2H), 4.50 (m, 1H), 3.81 (s, 3H), 3.22 - 3.08 (m, 2H), 2.24 (m, 1H), 1.75 (m, 1H).

The following Compound 109 and Compounds 166-176 were prepared according to the procedure of Compound 108 using the corresponding reagents and intermediates under appropriate conditions that will be recognized by one skilled in the art:

LC/MS

# Structure NMR

(M+H) +

Ή NMR (400 MHz, CD 3 OD) δ 8.72 (s, 1H), 8.61 (s, 1H), 8.28 (m, 1H), 8.10 (m, 1H), 7.97 (m, 1H),

109 539.8 7.89 (m, 2H), 7.73 (m, 2H), 7.26 (m, 1H), 6.82 (m,

1H), 5.64 (m, 1H), 4.29 (s, 3H), 3.78 (m, 1H), 3.49 - 3.46 (m, 1H), 2.29 (m, 4H).

Ή NMR (400 MHz, CDC1 3 ) δ: 12.06 (s, 1H), 8.70 (s, 2H), 8.39 (s, 1H), 7.76 (m, 1H), 7.68 - 7.60 (m, 1H), 7.57 - 7.49 (m, 2H), 7.28 (m, 1H), 7.24 (m,

166 526.3 1H), 6.43 (m, 1H), 5.32 (s, 2H), 5.06 (m, 1H), 3.39

(m, 1H), 3.24 (m, 1H), 2.00 (m, 4H).

, ,

IH), 3.39-3.33 (m, 2H), 2.89 - 2.83 (m, IH).

Example 16: Synthesis of Compounds 110 and 111

Compound 110 (,y)-4-(2-(4-oxo-3-phenyl-3,4-dihydropyrrolo[l,2-f| [l,2,4]triazin-2-yl)pyrrolidin-l- yl)-lH-pyrazolo[3,4-d]pyrimidine-3-carbonitrile

Scheme

A mixture of Compound 12 (120 mg, 0.25 mmol), Zn(CN) 2 (480 mg, 4.09 mmol), dppf (120 mg, 0.22 mmol), Pd 2 (dba) 3 (120 mg, 0.13 mmol) and Zinc powder (120 mg, 1.83 mmol) in DMA (4 mL) was heated at 110 °C for one hour. After concentration, the residue was diluted with DCM and washed with water. The organic layer was separated, concentrated and purified by preparative TLC to give Compound 110 as a white solid (9 mg, yeild: 9%). MS (m/z): 423.7 (M+H) + . 1H NMR (400 MHz, DMSO-d 6 ) δ 8.02 (s, 1H), 7.74 (m, 1H), 7.65 - 7.46 (m, 5H), 6.88 (m, 1H), 6.47 (m, 1H), 4.68 (m, 1H), 4.14 (m, 1H), 3.91 (m, 1H), 2.31 (m, 1H), 2.17 (m, 1H), 2.02 (m, 1H), 1.92 (m, 1H).

Compound 111 was prepared according to the procedure of Compound 110 using the corresponding reagents and intermediates under appropriate conditions that will be recognized by one skilled in the art:

LC/MS

Structure NMR

i n

Example 17: Synthesis of Compounds 112 and 113

Compound 112 (.y)-4-(2-(4-oxo-3-phenyl-3,4-dihydropyrrolo[l,2-f] [l,2,4]triazin-2-yl)pyrrolidin-l- yl)-lH-pyrazolo[3,4-d]pyrimidine-3-carbonitrile

A mixture of 17a (60 mg, 0.13 mmol) (17a was prepared according to the procedure of Example 1), Zn(CN) 2 (600 mg, 5.13 mmol) and Pd(PPh 3 ) 4 (120 mg, 0.10 mmol) in DMF (5 mL) was heated in the microwave at 180 °C for 30 minutes. After concentration, the residue was purified by preparative TLC and Compound 112 as a white solid was obtained (5.4 mg, yeild: 10%). MS (m/z): 423.8 (M+H) + . Ή NMR (400 MHz, DMSO-d 6 ) δ 8.23 (m, 2H), 7.61 (m, 6H), 7.05 (m, 1H), 5.32 (m, 0.5H), 4.69 (m, 0.5H), 4.34 (m, 0.5H), 4.10 (m, 0.5H), 3.90 (m, 0.5H), 3.70 (m, 0.5H), 2.26 (m, 1H), 2.00 (m, 2H), 1.89 (m, 1H).

Compound 113 was prepared according to the procedure of Compound 112 using the corresponding reagents and intermediates under appropriate conditions that will be recognized by one skilled in the art:

LC/MS

Structure NMR

+

Ή NMR (400 MHz, DMSO-d 6 ) 5 8.12 (s, 1H), 7.99 (s, 1H), 7.78 (m, 1H), 7.71-7.45 (m, 5H), 7.04 (m, 1H), 4.64 (m, 1H), 4.09 (m, 1H), 3.90 (m, 1H), 2.24 (m, 2H), 2.02-1.83 (m, 2H)

Example 18: Synthesis of Compound 114

Compound 114

(S)-5-chloro-2-(l-(2-morpholino-9H-purin-6-yl)azetidin-2-yl) -3-phenylpyrrolo[l,2- f][l,2,4]triazin-4(3H)-one

Scheme

14

Step 18-1 ( l S)-2-(azetidin-2-yl)-5-chloro-3-phenylpyrrolo[l,2-f][l ,2,4]triazin-4(3H) -one hydrochloride (18

To a mixture of 18a (185 mg, 0.462 mmol) (18a was prepared according to the procedure of Example 1) in MeOH (1 mL) was added cone. HCI (1 mL) at r.t. The mixture was stirred at r.t for 30min. The mixture was concentrated to give 18b as a brown solid which was used in the next step without purification. Steps 18-2 and 18-3 (S)-5-chloro-2-(l-(2-morpholino-9H-purin-6-yl)azetidin-2-yl) -3 phenylpyrrolo[ 1 ,2-fj [ 1 ,2,4]triazin-4(3H)-one (18c)

To a mixture of 18-b (0.462 mmol) in n-BuOH (5 mL) were added 2,6-dichloro-9H- purine (87 mg, 0.462 mmol) and DIEA (298 mg, 2.31 mmol) at r.t. The mixture was stirred at 80 °C for 3h, then morpholine (1 mL) was added, the mixture was stirred at 130 °C overnight. The reaction was concentrated and purified by flash column

chromatography to afford Compound 1 14 as a yellow solid (180 mg, 77%). Yield: MS (m/z): 503.8 (M+H) + . 'H NMR (400 MHz, DMSO-d 6 ) δ 12.26 (s,lH), 7.71 (s, 1H), 7.64 (s, 1H), 7.59 - 7.46 (m, 4H), 7.39 (d, J= 6.6 Hz, 1H), 6.61 (d, J= 2.6 Hz, 1H), 5.05 (s, 1H), 4.05 (s, 2H), 3.63 - 3.45 (m, 8H),2.65 - 2.54 (m, 1H), 2.27 - 2.13 (m, 1H).

Example 19: Synthesis of Compound 115-118 and 154

Compound 115

7-(l-(9H-purin-6-ylamino)ethyl)-3-chloro-6-phenylimidazo[l,2 -c]pyrimidin-5(6H)- one

Scheme

Compound 1 15

Step 19-1. 5-acetyl-4-hydroxy-2H-l,3-thiazine-2,6(3H)-dione (19b)

1 9a 19b

The mixture of 19a (20.8 g, 200 mmol), KSCN (20.0 g, 206 mmol), Ac 2 0 (20.0 mL) and AcOH (80 mL) was stirred at r.t. overnight. Then H 2 0 (100 mL) was added and extracted with DCM: MeOH=9: l, the organic layer was dried and concentrated to give 19b as a yellow solid which was used in the next step without further purification (2.0 g, yield: 53%)

Step 19-2. 6-methyl-l-phenylpyrimidine-2,4(lH,3H)-dione (19c)

19b 1 9c

To a solution of 19b (20 g, 106 mmol) in DMF (15 mL) was added aniline (9.2 mL) at r.t., the reaction was stirred at reflux until 20b disappeared by TLC. The mixture was concentrated, the residue was washed with EtOH, and filtered to give 19c as a yellow solid (880 mg, yield: 40.7%). MS (m/z): 203.1 (M+l) + .

Step 19-3. 4-a

19c 19d

The solution of 19c (7.29 g, 36 mmol) in CH 3 CN (120 mL) was purged by NH 3 for 5 min, then BOP (20.7 g, 46.8 mmol) and DBU (8.21 g, 54 mmol) were added, the reaction was stirred overnight. The mixture was filtered to give 19d was as a white solid (7.24 g). MS (m/z): 201.7 (M+l) + .

Step 19-4. 7-methyl-6-phenylimidazo[l,2-c]pyrimidin-5(6H)-one (19e)

19d 19e

To a solution of 19d (7.24 g, 36 mmol) in EtOH (100 mL) was added 40% 2- chloroacetaldehyde in water (17.8 mL, 108 mmol), the reaction was stirred at 100 °C overnight. The mixture was concentrated and purified by flash column chromatography to give 19e as a white solid (6.2 g, yield: 77%). MS (m/z): 225.9 (M+l) + .

Step 19-5. 3-chloro-7-methyl-6-phenylimidazo[l,2-c]pyrimidin-5(6H)-one (19f)

19e 1 9f

19e (2.25 g, 10 mmol) and NCS (700 mg, 5.26 mmol) were dissolved in DMF (10 mL), the reaction was stirred at r.t. for 3 h. The mixture was poured into H 2 0 (100 mL), and extracted with EtOAc, the organic layers were washed with brine, dried over anhydrous Na 2 S0 4 and concentrated. The resulting residue was washed with MeOH to give 19f as a white solid (600 mg, yield: 23%). MS (m/z): 260.1 (M+l) + .

Step 19-6. 3-chloro-5-oxo-6-phenyl-5,6-dihydroimidazo[l,2-c]pyrimidine- 7- carbaldehyde (19g)

19f (600 mg, 2.3 mmol) and Se0 2 (257 mg, 2.3 mmol) were dissolved in dioxane (20 mL), the reaction was stirred at reflux overnight, then concentrated and purified by flash column chromatography to give 19g as a white solid (250 mg, yield: 39%). MS (m/z): 274.1 (M+l) + .

Step 19-7. 3-chloro-7-(l-hydroxyethyl)-6-phenylimidazo[l,2-c]pyrimidin- 5(6H)-one (19h)

To a solution of 19g (250 mg, 0.9 mmol) in THF (10 mL) cooled to -78 °C was added MeMgBr (3M in ether, 1.2 mL) dropwise under N 2 , the reaction was stirred at -78 °C for 30min. Then MeOH (3 mL) was added dropwise, the resulting mixture was concentrated and purified by flash column chromatography to give 19h as a white solid (220 mg, yield: 83%). MS (m/z): 290.1 (M+l) + .

Step 19-8. 7-(l-azidoeth l)-3-chloro-6-phenylimida -c]pyrimidin-5(6H)-one (19i)

To a solution of 19h (200 mg, 0.69 mmol) in THF (20 mL) was added DPPA (630 mg, 2.29 mmol), followed by DBU (300 mg, 1.97 mmol) at r.t., the reaction was stirred at reflux for 3 h, then concentrated and purified by flash column chromatography to give 19i as a yellow oil(130 mg, yield: 59.9%). MS(m/z): 315.1 (M+l) + .

Step 19-9. 7-(l-aminoethyl)-3-chloro-6-phenylimidazo[l,2-c]pyrimidin-5( 6H)-one (19j)

To a solution of 19i (130 mg, 0.4 mmol) in THF (10 mL) was added ΝΗ 3 Ή 2 0 (25% aq., 1 mL), followed by PPh 3 (200 mg, 0.76 mmol), the reaction was stirred at r.t. for 30min, then warmed to 60 °C for another 2 hours. The mixture was concentrated and purified by flash column chromatography to give 19j as a white solid (60 mg, yield: 50%). MS (m/z): 288.9 (M+l) + .

Step 19-10. 7-(l-(9H-purin-6-ylamino)ethyl)-3-chloro-6-phenylimidazo[l,2 -c] pyrimidin-5(6H)-one (115)

Compound 115

To a solution of 19j (30 mg, 0.104 mmol) in n-BuOH (3 mL) were added DIEA (0.052 mL, 0.312 mmol) and 6-chloro-9H-purine (19.3 mg, 0.125 mmol), the reaction was stirred at 130 °C overnight. The mixture was concentrated and purified by preparative thin layer chromatography to give Compound 115 as a white solid (3.6 mg, yield: 9%). MS (m/z): 406.9 (M+l) + . 1H NMR (400 MHz, CD 3 OD) δ: 8.06 (s, 1H), 7.96 (s, 1H), 7.59 - 7.47 (m, 3H), 7.38 (t, J= 7.3 Hz, 1H), 7.27-7.24 (m, 2H), 6.76 (s, 1H), 4.93-4.89 (m, 1H), 1.47 (d, J= 6.7 Hz, 3H).

The following Compounds 116-1 18 and Compound 154 were prepared according to the procedure of Compound 1 15 using the corresponding reagents and intermediates under appropriate conditions that will be recognized by one skilled in the art:

LC/MS

# Structure NMR (s, 1 H), - 7.51 (m,

116 6.88 (s,

57 (m, 1H),

(s, 1H),

117 (s, 1H),

, 3H).

Example 20: Synthesis of Compounds 119-121

Compound 119

3-(l-(9H-purin-6-yIamino)ethyI)-7-chloro-2-phenylpyrrolo[l,2 -c]pyrimidin-l(2H)- one

Scheme

Step 20-1. 2-(benzyloxycarbonylaniino)-2-hydroxyacetic acid (20b)

20a 20b

To a mixture of 20a (7.55 g, 50 mmol) in Et 2 0 (80 mL) was added 2-oxoacetic acid-lH 2 0 (5.05 g, 55 mmol), the reaction was stirred at r.t. overnight. The mixture was concentrated in vacuo to give 20b as a white solid which was used in the next step without further purification.

Step 20-2. Methyl 2-(benzyloxycarbonylamino)-2-methoxyacetate (20c)

20b 20c

To a solution of 20b (about 11.25 g, 50 mmol) in MeOH (150 mL) was added concentrated sulfuric acid (2 mL) dropwise at 0 °C. After the addition, the reaction mixture was stirred at r.t. for 90 h, then poured into the iced sat. NaHC0 3 aq. (300 mL), the resulting mixture was extracted with EtOAc, the organic layers were dried over anhydrous Na 2 S0 4 , concentrated and purified by column chromatography to give 20c as a white solid (12 g, yield: 95%). MS (m/z): 275.7 (M+23) + .

Step 20-3. Methyl 2-(benzyloxycarbonylamino)-2-(diethoxyphosphoryl)acetate (20d)

20c 20d

To a solution of 20c (12 g, 47.4 mmol) in toluene (60 mL) was added PBr 3 (12.8 g, 47.4 mmol) at 70 °C, the reaction was stirred at 70 °C for 20 h, then triethyl phosphate (7.87 g, 47.4 mmol) was added dropwise and stirred at 70 °C for another 2 h. The mixture was concentrated, diluted with EtOAc, and washed with sat. NaHC0 3 aq.. The organic layers were dried over anhydrous Na 2 S0 4 , filtered and concentrated. The resulting residue was dissolved in EtOAc, petroleum ether was added with vigorous stirring, then filtrated to give 20d as a white solid (8 g, yield: 47%).

Step 20-4. Methyl l-oxo-l ,2-dihydropyrrolo[l,2-c]pyrimidine-3-carboxylate (20e)

To a solution of 20d (8 g, 22.3 mmol) in DCM (80 mL) was added 1,1,3,3- tetramethylguanidine (2.44 g, 21.2 mmol) at r.t, the reaction was stirred at r.t for 15min, then a solution of lH-pyrrole-2-carbaldehyde (1.92 g, 20.2 mmol) in DCM (5 mL) was added dropwise at -30 °C, the reaction mixture was stirred at -30 °C for 45 min, then warmed to r.t. and stirred for 48 h. The mixture was concentrated and purified by column chromatography to give 20e as a white solid (2 g, yield: 51%). MS (m/z): 192.9 (M+l) + .

. Methyl l-oxo-2-phenyl- 1 ,2-dihydropyrrolo[ 1 ,2-c]pyrimidine-3-carboxylate

20 e 20f

To a solution of 20e (576 mg, 3 mmol) in DCM (20 mL) was added phenylboronic acid (732 mg, 6 mmol), copper(II) acetate (1.08 g, 6 mmol), pyridine (1.18 g, 15 mmol) and 4A molecular sieve at r.t., the reaction was stirred at r.t. for 20h. The mixture was filtered, concentrated and purified by column chromatography to give 20f as a white solid (650 mg, yield: 81%). MS (m/z): 268.8 (M+l) + .

Step 20-6. l-oxo-2-phenyl-l,2-dihydropyrrolo[l,2-c]pyrimidine-3-carboxy lic acid (20g)

To a solution of 20f (1 g, 3.73 mmol) in EtOH (30 mL) and THF (30 mL) was added NaOH aq. (1 1.19 mL, IN) at 0 °C, the reaction was stirred at 0 °C for 30min. The mixture was concentrated, diluted with H 2 0 (10 mL), adjusted to pH=6 with HC1 aq. (IN) and concentrated in vacuo to give 20g as a brown solid which was used in the next step without further purification. MS (m/z): 254.7 (M+l) + .

I l l Step 20-7. N-methoxy-N-methyl-l-oxo-2-phenyl-l,2-dihydropyrrolo[l,2-c] pyrimidine - 3-carboxamide (2

To a solution of 20g (about 950 mg, 3.73 mmol) in DMF (10 mL) were added DIE A (1.44 g, 11.19 mmol) and HBTU (1.70 g, 4.48 mmol), the mixture was stirred at r.t for 5 min, then Ν,Ο-dimethylhydroxylamine hydrochloride (438 mg, 4.48 mmol) was added, the reaction was stirred at r.t overnight. The mixture was concentrated and purified by column chromatography to give 20h as a white solid (550 mg, yield: 50%). MS (m/z): 297.7 (M+l) + .

Step 20-8. 3-acetyl- -phenylpyrrolo[l,2-c]pyrimidin-l(2H)-one (20i)

To a solution of 20h (550 mg, 1.85 mmol) in THF (5 mL) was added a solution of Methylmagnesium bromide in Et 2 0 ( 1.23 mL, 3N) at 0 °C under N 2 , the reaction was stirred at 0 °C for lh. The mixture was quenched with sat. NH 4 C1 aq., concentrated and purified by column chromatography to give 20i as a yellow solid (220 mg, yield: 47%). MS (m/z): 252.7 (M+l) + .

Step 20-9. 3-(l-aminoethyl)-2-phenylpyrrolo[l,2-c]pyrimidin-l(2H)-one (20j)

20i 20j To a solution of 20i (50.4 mg, 0.2 mmol) in EtOH (6 mL) were added ammonium acetate (550 g, 7.1 mmol) and sodium cyanoborohydride (126 mg, 2 mmol), the reaction was stirred at 130 °C for 2 h under Microwave condition, then another part of ammonium acetate (550 g, 7.1 mmol) and sodium cyanoborohydride (126 mg, 2 mmol) was added, the reaction was stirred at 90 °C for 20 h. After cooling to r.t, aq. HC1 (0.5 mL, 1 N) was added, the mixture was stirred for 30 min, followed by cone. ΝΗ 3 Ή 2 0 (3 mL), the mixture was stirred for 10 min, then NaBH 4 (30 mg, 0.79 mmol) was added, the mixture was stirred for another 30 min. The mixture was concentrated and purified by flash column chromatography to give 20j as a yellow solid (32 mg, yield: 63%). MS (m/z): 236.7 (M-16) + .

Step 20-10. 3-(l-(9H-purin-6-ylamino)ethyl)-2-phenylpyrrolo[l,2-c]pyrimi din-l(2H) - one (Compound 119)

Compound 119

To a solution of 20j (40 mg, 0.158 mmol) in n-BuOH (8 mL) was added 6-chloro-9H- purine (29 mg, 0.190 mmol) and DIEA (61 mg, 0.474 mmol) at r.t., the reaction was stirred at 130 °C overnight. The mixture was concentrated and purified by flash column chromatography to give Compound 119 as a yellow solid (lOmg, yield: 17%). MS (m/z): 371.6 (M+l) + . 'H NMR (400 MHZ, DMSO-d 6 ) δ 8.05 (s, 1H), 7.97 (s, 1H), 7.72 (s, 1H), 7.66 (s, 1H), 7.57 - 7.30 (m, 6H), 6.71 (s, 1H), 6.63 (s, 1H), 6.29 (s, 1H), 4.78 (s, 1H), 1.32 (d, J= 6.5 Hz, 3H).

The following Compounds 120 and 121 were prepared according to the procedures of Compound 112 using the corresponding reagents and intermediates under appropriate conditions that will be recognized by one skilled in the art: 7.80 (s, 1H),

39 (m, 4H),

120 1H), 6.65 (s,

1H), 1.29 (d, J

8.03 (s, 1H), H), 7.54 - 7.25

121 , 6.31 (s, 1H),

, J= 6.4 Hz,

Example 21: Synthesis of Compounds 122-129

Compounds 122 and 123

3-(l-(9H-purin-6-ylamino)ethyl)-7-chloro-2-phenylpyrrolo[l,2 -c]pyrimidin-l(2H)- one and 3-(l-(9H-purin-6-ylamino)ethyl)-7-chloro-2-phenylpyrrolo [1,2-c] pyrimidin-l(2H)-one

To a solution of Compound 119 (60 mg, 0.16 mmol) in DMF (3 mL) was added NCS (21 mg, 0.16 mmol) at r.t., the reaction was stirred at 70 °C for 30 min, then another part of NCS (6 mg, 0.045 mmol) was added, the reaction was stirred at 70 °C for another 30 min. The mixture was concentrated and purified by flash column chromatography to give Compound 122 as a white solid (15 mg, yield: 23%) and Compound 123 as a white solid (5 mg, yield: 7.7%)). Compound 122: MS (m/z): 406.1 (M+l) + . 1H NMR (400 MHz, DMSO-d 6 ) δ 8.03 (s, 1H), 7.89 (s, 1H), 7.69 (s, 1H), 7.56 (s, 1H), 7.56 - 7.34 (m, 5H), 6.64 - 6.55 (m, 2H), 6.25 (d, J= 3.7 Hz, 1H), 4.87 - 4.57 (m, 1H), 1.28 (d, J= 6.6 Hz, 3H). Compound 123: MS (m/z): 405.7 (M+l) + . 1H NMR (400 MHz, CD 3 OD) δ 7.90 (s, 1H), 7.83 (s, 1H), 7.49 (d, J= 3.2 Hz, 1H), 7.46 (d, J= 7.6 Hz, 1H), 7.42 - 7.35 (m, 2H), 7.28 (t, J= 7.1 Hz, 1H), 7.03 (t, J= 7.4 Hz, 1H), 6.77 (s, 1H), 6.65 (d, J= 3.0 Hz, 1H), 1.49 (d, J= 6.7 Hz, 3H).

The following Compounds 124- 129 were prepared according to the procedures of Compound 122 and 123 using the corresponding reagents and intermediates under appropriate conditions that will be recognized by one skilled in the art:

# Structure LC/MS MR

+

,

,

Example 22: Synthesis of Compound 130

Compound 130

4-amino-6-((3-chloro-5-oxo-6-phenyl-5,6-dihydroimidazo [1 ,2-c] pyrimidin-7- yl)methoxy)pyrimidine-5-carbonitrile

Scheme

Step 22-1. 3-chloro-7-(hydroxymethyl)-6-phenylimidazo[l,2-c]pyrimidin-5 (6H) -one (22a)

To a solution of 19g (1 g, 3.66 mmol) in EtOH (15 mL) was added NaBH 4 (277 mg, 7.33 mmol) at 0 °C, the reaction was stirred for 0.5h at 0 °C. The mixture was quenched by water, then concentrated and purified by flash column chromatography to give 22a as a yellow solid (930 mg, yield: 92%). MS (m/z): 276.1 (M+l) + .

Step 22-2. 4-chloro-6-((3-chloro-5-oxo-6-phenyl-5,6-dihydroimidazo[l,2- c]pyrimidin -7- yl)methoxy)pyrimidine-5-carbonitrile (22b)

To a mixture of 22a (55 mg, 0.2 mmol) in THF (2 mL) was added NaH (16 mg 0.4 mmol) at 0 °C, the mixture was stirred at 0 °C for 30 min, then 4,6-dichloropyrimidine-5- carbonitrile (42 mg 0.24 mmol) was added, the reaction was stirred at 0 °C- r.t for 2 h. The mixture was quenched by MeOH, concentrated and purified by flash column chromatography to give 22b as a yellow solid (50 mg, yield: 60%). MS (m/z): 412.9 (M+l) + .

Step 22-3. 4-((3-chloro-5-oxo-6-phenyl-5,6-dihydroimidazo[l,2-c]pyrimid in-7- yl)methox -6-(4-methoxybenzylamino)pyrimidine-5-carbonitrile (22c)

22b 22c

To a mixture of 22b (50 mg, 0.12 mmol) in dioxane (5 mL) was added DIEA (62 mg, 0.48 mmol) and >-methoxylbenzylamine (65.7 mg, 0.48 mmol) at r.t. The

mixture was stirred at 120 °C overnight, then concentrated and purified by flash column chromatography to give 22c as a yellow solid (48 mg, yield: 78%). MS (m/z): 513.8 (M+l) + .

Step 22-4. 4-amino-6-((3-chloro-5-oxo-6-phenyl-5,6-dihydroimidazo[l,2-c ]pyrimidin -7- yl)methoxy)pyrimidine-5-carbonitrile (Compound 130)

22c Compound 130

The mixture of 22c (48 mg 0.094 mmol) in TFA (2 mL) was stirred at 80 °C for 3h. The mixture was concentrated, diluted with MeOH, and neutralized with ammonium hydroxide, the resulting mixture was concentrated and purified by flash column chromatography to give Compound 130 as a yellow solid (8 mg, yield: 22%). MS

(m/z): 394.0 (M+l) + . ! H NMR (400 MHz, DMSO-d 6 ) δ 8.06 (s, 1H), 7.94 (s, 1H), 7.81 (s, 2H), 7.50 - 7.38 (m, 5H), 6.95 (s, 1H), 4.98 (s, 2H).

Example 23: Synthesis of Compound 131

Compound 131

7-((9H-purin-6-yloxy)methyl)-3-chloro-6-phenylimidazo[l,2-c] pyrimidin-5(6H)-o ne

Step 23-1. 3-chloro-6-phenyl-7-((9-(tetrahydro-2H-pyran-2-yl)-9H-purin- 6-yloxy) methyl)imidazo[l,2-c]pyrimidin-5(6H)-one (23a)

To a mixture of 22a (15 mg, 0.055 mmol) in THF (2 mL) was added NaH (4.4 mg, 0.11 mmol) at 0 °C, the mixture was stirred at 0 °C for 30 min, then 6-chloro-9- (tetrahydro- 2H-pyran-2-yl)-9H-purine (19 mg 0.082 mmol) was added, the reaction was stirred at 0 °C - r.t for lh. The reaction was quenched by MeOH and concentrated to give 23 a as a brown solid which was used in the next step without further purification. MS (m/z): 477.8 (M+l) + .

Step 23-2. 7-((9H-purin-6-yloxy)methyl)-3-chloro-6-phenylimidazo[l,2-c] pyrimidin- 5(6H)-one (Compound 131)

To a mixture of 23a (about 26 mg, 0.054 mmol) in EtOH (3 mL) was added

pyridinium toluene-4-sulphonate (68.4 mg 0.273 mmol) at r.t., the reaction was stirred at 80 °C for lh. The mixture was concentrated and purified by flash column

chromatography to give Compound 131 as a yellow solid (5 mg, yield: 24%). MS (m/z): 393.9 (M+l) + . 'H NMR (400 MHz, CD 3 OD) δ 8.25 (s, 1H), 8.23 (s, 1H), 7.70 (s, 1H), 7.49 - 7.34 (m, 3H), 7.30 - 7.20 (m, 3H), 6.93 (s, 1H), 5.18 (s, 2H).

Example 24: Synthesis of Compound 132

Compound 132

5-fluoro-2-((2S,4S)-4-fluoro-l-(9H-purin-6-yI)pyrroIidin-2-y I)-3-phenyIpyrroIo[l,2- f] [l,2,4]triazin-4(3H)-one

Scheme

Compound 132

Compound 132 was prepared according to the procedures of Example 1 and the following Steps 24- 1 and 2. Compound 132 was got as a white solid. MS (m/z): 434.8 (M+H) + ; Ή NMR (400 MHz, CD 3 OD) δ: 8.27 (s, 1H), 8.16 - 7.93 (m, 2H), 7.65 - 7.49 (m, 4H), 7.10 (m, 1H), 6.22 (m, 1H), 5.41 (s, 0.5H), 5.28 (m, 0.5H), 4.32 (m, 2H), 3.98 (m, 1H), 2.58 - 2.44 (m, 1H), 2.32 - 2.14 (m, 1H).

Steps 24-1 and 2 (2S,4S)-tert-butyl 4-fluoro-2-(5-fluoro-4-oxo-3,4-dihydropyrrolo[l ,2-fl [ 1 ,2,4]triazin-2- l)pyrrolidine- 1 -carboxylate (24c)

To a solution of 24a (400 mg, 2.94 mmol) and (2S,4S)- l-(tert-butoxycarbonyl)-4- fluoropyrrolidine-2-carboxylic acid (889 mg, 3.82 mmol) in THF (35 mL) was added EDC (729 mg, 3.82 mmol). The reaction mixture was stirred at r.t. for 2 hours, then the solvent was removed in vacuo and water was added. The mixture was extracted with EtOAc three times. The organic layers were combined, died over anhydrous Na 2 S0 4 and concentrated to give 24b. 24b was dissolved in 7NNH 3 in MeOH (100 mL) and the mixture was stirred in a sealed tube at 130 U C overnight. The solvent was removed in vacuo and the residue was purified by flash column chromatography eluting with EtOAc/PE to give 24c as a white solid (110 mg , yield: 11%). MS (m/z): 341 (M+H) +

Example 25: Synthesis of Compound 133

Compound 133

(S)-4-(2-(5-ethyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[l,2-fJ [l,2,4]triazin-2- yl)azetidin-l-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile

Scheme

Compound 55 25a Compound 133

Step 1 (S)-4-(2-(4-oxo-3-phenyl-5-vinyl-3 ,4-dihydropyrrolo[ 1 ,2-f][ 1 ,2,4]triazin-2-yl) azetidin-l-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (25a)

Compound 55 25a

A mixture of Compound 55 (308 mg, 0.632 mmol), 4,4,5, 5-tetramethyl- 2 -vinyl- 1,3,2- dioxaborolane (200 mg, 1.265 mmol), Pd(dppf) 2 Cl 2 (52 mg, 0.0632 mmol) and Na 2 C0 3 (201 mg, 1.896 mmol) in dioxane (20 mL) and water (2 mL) was reacted at 130 C under N 2 atmosphere in a microwave oven for 30 min. Then the mixture was filtered, concentrated and purified by flash column chromatography eluting with MeOH/DCM to give 25a as a slight yellow solid (120 mg, yield: 44%). MS (m/z): 435.1 (M+H) + .

Step 2 ( l S -4-(2-(5-ethyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[l,2-f][l,2, 4]triazin-2-yl) azetidin-l-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (Compound 133)

25a Compound 133

To a solution of 25a (60 mg, 0.138 mmol) in methanol (10 mL) was added Pd/C (6 mg), the mixture was stirred at r.t. under H 2 atmosphere for 2.5 hours, then the mixture was filtered, concentrated and purified by flash column chromatography eluting with

MeOH/water to give Compound 133 as a white solid (41 mg, yield: 68%). MS (m/z): 436.8 (M+H) + . 1H NMR (400 MHz, DMSO-d 6 ) δ 8.31 (s, 2H), 7.78 - 7.42 (m, 6H), 6.47 (s, 1H), 5.13 (m, 1H), 4.41 (m, 1H), 4.20 (m, 1H), 2.88 (q, J= 7.4 Hz, 2H), 2.68 (m, 1H), 2.14 (m, 1H), 1.21 (t, J= 7.5 Hz, 3H).

Example 26: Synthesis of Compound 134-137

Compound 134

(5 -2-(l-(2-aminopyrazolo[l,5-a] [1,3,5] triazin-4-yl)pyrrolidin-2-yl)-5-chloro-3- phenylpyrrolo[l,2-fj[l,2,4]triazin-4(3H)-one

Scheme

Compound 134

Step 26-1 4-chloro-2-(methylsulfonyl)pyrazolo[l,5-a][l,3,5]triazine (26b)

T m-CPBA CI ^ N ^S \

N Y ,Ν ^ Ν

26a 26b

To a solution of 26a (250 mg, 1.25 mmol) in 20 mL of dry DCM was added m-CPBA

(473 mg, 2.75 mmol) and stirred at r.t. for 16 hours. The solution was used forward next step without further purification.

Step 26-2 (S)-5-chloro-2-( 1 -(2-(methylsulfonyl)pyrazolo[ 1 ,5-a] [ 1 ,3 ,5]triazin-4-yl) pyrroli

To the solution 26b was added 26c (63 mg, 0.18 mmol) (26c was prepared according to the procedure of Example 1) and DIEA (78 mg, 0.60 mmol), then the mixture was stirred at r.t. overnight. The mixture was concentrated and purified by flash column

chromatography eluting with MeOH/H 2 0 to afford 26d as a yellow solid (85 mg, yield: 49%). MS (m/z): 511.0 (M+H) + .

Step 26-3 (.S)-2-(l-(2-aminopyrazolo[l,5-a][l,3,5]triazin-4-yl)pyrroli din-2-yl)-5- chloro- 3-phenylpyrrolo[ l -f][l,2,4]triazin-4(3H)-one (Compound 134)

26d Com pound 134

To a solution of 26d (82 mg, 0.16 mmol) in 5 mL of THF was added 4 mL of 7NN¾ in MeOH, then the mixture was stirred at r.t. overnight. After concentration, the residue was purified by flash column chromatography, eluting with MeOH/H 2 0, and further purified by preparative TLC, eluting with MeOH/DCM = 1/80, to give Compound 134 as a white solid (28.8 mg, yield: 40%). MS (m z): 448.1 (M+H) + . Ή NMR (400 MHz, DMSO-d 6 ) δ 7.93-7.78 (m, 2H), 7.63-7.54 (m, 5H), 6.62-6.36 (m, 3H), 5.70-5.59 (m, 1H), 4.71-4.31 (m, 1H), 3.89 (m, 1H), 3.68 (m, 1H), 2.12-1.74 (m, 4H).

The following Compounds 135-137 was prepared according to the procedure of

Compound 134 using the corresponding reagents and intermediates under appropriate conditions that will be recognized by one skilled in the art:

LC/MS

Structure NMR

(M+H) + DMSO-d 6 ) δ: 7.90 (s, 1H),

, 2H), 6.82 (s, 1H), 6.60 , 4.33 (m, 1H), 4.21 (m, .46 (m, 1H).

DMSO-d 6 ) δ: 7.98-7.77 , 5H), 6.61-6.55 (m, 3H), .98-4.81 (m, 1H), 4.28- .90 (m, 2H).

DMSO-d 6 ) δ: 7.69 (m, 3H), 5.88 - 5.61 (m, 1H), 4.06 (m, 2H), 2.68 (m,

Example 27: Synthesis of Compound 138

Compound 138

(5)-2-(l-(4-amino-l,3,5-triazin-2-yl)pyrrolidin-2-yl)-5-chlo ro-3-phenylpyrrolo[l,2- f] [l,2,4]triazin-4(3H)-one

Com pou nd 1 38

2,4-dichloro-l,3,5-triazine(45 mg, 0.3 mmol) was added to 2 mL of ΝΗ 3 Ή 2 0 aq., the reaction was stirred at -20 °C for 10 min, then filtered, washed with water and dried to give 4-chloro- l,3,5-triazin-2-amine (18 mg, yield: 46%) as a yellow solid which was used in the next step without further purification. MS (m/z): 131.0 (M+H) + .

(^-2-(l-(4-amino- l,3,5-triazin-2-yl)pyrrolidin-2-yl)-5-chloro-3-phenylpyrrolo [l,2- fJ[l,2,4]triazin-4(3H)-one was prepared with 4-chloro-l,3,5-triazin-2-amine as the material according to the procedure of Example 1 from le to Compound 1. MS (m/z): 409.1 (M+H) + . 'H NMR (400 MHz, CD 3 OD) δ: 8.02 (d, J= 1.6 Hz, 1H), 7.81 (d, J= 7.6 Hz, 1H), 7.64-7.54 (m, 3H), 7.42-7.39( m, 1H), 7.37-7.35 (m, 1H), 6.50-6.49 (m, 1H), 4.67^.64 (m, 1H), 3.81-3.73 (m, 1H), 3.59-3.53 (m, 1H), 2.20-2.08 (m, 2H), 1.97 - 1.85 (m, 2H).

Example 28: Synthesis of Compounds 139-140

Compound 139

(S)-2-(l-(9H-purin-6-yl)pyrrolidin-2-yl)-4-oxo-3-phenyl-3,4- dihydropyrrolo[l,2- fJ[l,2,4]triazine-5-carboxamide

Compound 139

Step 28-1 (iS)-2-ethyl 3 -methyl l-(l-(tert-butoxycarbonyl)pyrrolidine-2-carboxamido)- lH-pyrrole-2,3-dicarboxylate (28a)

To a mixture of Intermediate 7 (500 mg, 2.36 mmol) in THF (40 mL) were added BOC-L-Proline (557 mg 2.59 mmol) and EDC (497 mg 2.59 mmol) at r.t. The reaction was stirred at r.t overnight. The mixture was concentrated and purified by flash chromatography to afford 28a as a yellow oil (800 mg, yield: 83%). MS (m/z): 410.5 (M+l) + .

Step 28-2 (S)-tert-butyl 2-(5-carbamoyl-4-oxo-3,4-dihydropyrrolo[l,2-f][l,2,4]triazin -2- yl)pyrrolidine-l-carbox late (28b)

28a 28b

The mixture of 28a (800 mg 1.96 mmol) in a solution of NH 3 in MeOH (7N, 50 mL) was stirred at 130°C for 36 h in a sealed tube. The reaction was concentrated and purified by chromatography to afford 28b as a yellow solid (580 mg, yield: 75%). MS (m/z): 348.5 (M+l) + .

Compound 139 was prepared from 28b according to the procedure of Example 1.

MS (m/z): 442.2 (M+l) + . 'H NMR (400 MHz, DMSO-d 6 ) δ 9.22 (s, 1H), 8.23 - 8.18 (m, 1.5H), 8.10(s, 0.5H), 7.87 - 7.42 (m, 6H), 7.35 (s, 1H), 6.95(s, 0.5H), 6.92(s, 0.5H), 5.37-5.25(m, 0.5H), 4.74-4.45 (m, 0.5H), 4.38 - 4.26 (m, 0.5H), 4.15-4.01(m, 0.5H), 3.94-3.84(m, 0.5H), 3.74- 3.63 (m, 0.5H), 2.35 - 2.21 (m, 2H), 2.01-1.93(m, 1H), 1.90- 1.82 (m, 1H). Compound 140 was prepared according to the procedure of Compound 139 using the corresponding reagents and intermediates under appropriate conditions that will be recognized by one skilled in the art.

Structure LC/MS NMR

+

Ή NMR (400 MHz, DMSO-d 6 ) δ 9.2 (s, 1H), 8.29 (s, 1H), 8.27 (s, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.65 - 7.52 (m, 5H), 7.35 (s, 1H), 6.96 (d, J = 2.9 Hz, 1H), 4.67 (dd, J = 8.0, 3.5 Hz, 1H), 4.16 - 4.05 (m, 1H), 3.94 (m, 1H), 2.32 - 2.19 (m, 2H), 2.04 - 1.92 (m, 2H).

Example 29 : Synthesis of Compounds 177-179

Compound 177

(5)-2-(l-(9H-purin-6-yl)pyrrolidin-2-yl)-5-(hydroxymethyl)-3 -phenylpyrrolo[l,2- f] [l,2,4]triazin- -one

Compound 149 Compound 177

To a solution of Compound 149 (30 mg, 0.068 mmol) in CH 2 C1 2 (1 mL) was added TFA (2 mL) at 0°C, the reaction was stirred at r.t. for 30 min, then concentrated at r.t.. The residue was dissolved in MeOH (2 mL), and treated with IN KOH (2 mL), then stirred at r.t. for another 1 h. The mixture was adjusted to pH =7.0, then concentrated and purified by chromatography to give the title compound as a white solid (2.2 mg, yield: 41%). MS (m/z): 429.6 (M+l) + Ή NMR (400 MHz, CD 3 OD) δ 8.21 (s, 1H), 8.14 (s, 1H), 7.95(s,0.5H), 7.91(s,0.5H), 7.69-7.43 (m, 4H), 7.37 (br, 1H), 7.17(s,0.5H), 7.09(s,0.5H), 6.43(s,0.5H), 6.40(s,0.5H), 5.51 (br, 0.5H), 4.48 (s, 2H), 4.31 (br, 0.5H), 4.09 (br, 0.5H), 3.92 (br, 0.5H), 3.71 (br, 0.5H), 2.29- 1.88 (m, 4H). The following Compounds 178-179 were prepared according to the procedure of Compound 177 using the corresponding reagents and intermediates under appropriate conditions that will be recognized by one skilled in the art.

u

178

179

Example 30 : Synthesis of Compounds 180-184

Compound 180

(»y)-2-(l-(5-(2-aminopyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrim idin -4-yl)azetidin-2-yI)- 5-fluoro-3-phenylpyrroIo[l,2-f][l,2,4]triazin-4(3H)-one

Step 30-1 5-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[ 2,3-d] pyrimidin-5-yl)pyrimidin-2-amine (3 Ob)

To a solution of 30a (409 mg, 1 mmol) in 1,4-dioxane/water (10 mL / 1 mL) was added 2-aminopyrimidin-5-ylboronic acid (139 mg, 1 mmol), Pd(dppf)Cl 2 (81.6mg, 0.1 mmol) and K 2 C0 3 (414 mg, 3 mmol). Under N 2 , the reaction mixture was heated at 100 °C for 2 h. Then the solvent was removed in reduced pressure and the residue was purified by flash column chromatography eluting with MeOH/DCM to give 30b as a yellow solid (310 mg, yield: 82.4%). MS (m/z): 377.1 (M+H) +

Steps 30-2 to 4 ( -2-(l-(5-(2-aminopyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin -4- yl)azetidin-2-yl)-5-fluoro-3-phenylpyrrolo[l,2-f][l,2,4]tria zin-4(3H)-one (Compound 180)

Com pound 180

A mixture of 30c (64 mg 0.2 mmol) (The intermediate was synthesized according to the procedure of Example 1), 30b (68 mg, 0.18 mmol) and Et 3 N (80 mg, 0.8 mmol) in n- BuOH (2 mL) was stirred at 100 °C for 1 h. The reaction solution was concentrated and the residue was dissolved in TFA (3 mL).The resulting mixture was stirred at r.t. for 30 min. Then the solvent was removed in vacuo. To the residue was added a solution of NH 3 in MeOH (7N, 3 mL). The mixture was stirred at r.t. for 30 min. The solvent was evaporated and the residue was purified by flash column chromatography eluting with MeOH/water to give Compound 180 as a white solid (37 mg, yield: 37.4%). MS (m/z): 495.1 (M+H) + ; 1H MR (400 MHz, DMSO-d 6 ) δ: 12.00 (s, 1H), 8.37 (s, 2H), 8.23 (s, 1H), 7.66 - 7.57 (m, 1H), 7.57 - 7.48 (m, 4H), 7.43 (d, J= 2.7 Hz, 1H), 7.32 (d, J= 2.4 Hz, 1H), 6.65 (s, 2H), 6.49 (d, J= 3.2 Hz, 1H), 5.06 - 5.00 (m, 1H), 3.18 (m, 1H), 3.13 - 2.99 (m, 1H), 2.40 (m, 1H), 1.73 (m, 1H).

Compounds 181-184 were prepared according to the procedure of Compound 180 using the corresponding reagents and intermediates under appropriate conditions that will be recognized by one skilled in the art:

Ή MR (400 MHz, CD 3 OD) δ: 8.75 (s, 2H), 8.23 (s, 1H), 7.55 (m, 4H), 7.33 (m, 3H), 6.32

181 (m, 1H), 5.13 (m, 1H), 4.03 (s, 3H), 3.38 (m,

1H), 3.20 (m, 1H), 2.32 (m, 1H), 1.81 (m, 1H).

Ή NMR (400 MHz, CD 3 OD) δ 8.26 (d, J = 2.0 Hz, 1H), 8.19 (s, 1H), 7.83 (dd, J= 8.5, 2.3 Hz, 1H), 7.54 (m, 2H), 7.47 (d, J= 1.1 Hz, 2H),

7.35 - 7.30 (m, 1H), 7.26 (d, J= 7.5 Hz, 1H),

182 7.17 (s, 1H), 6.84 (d, J= 8.5 Hz, 1H), 6.31 (d, J

= 3.2 Hz, 1H), 5.12 - 5.00 (m, 1H), 3.91 (s,

3H), 3.38 - 3.31 (m, 1H), 3.17 (m, 1H), 2.30 - 2.19 (m, 1H), 1.81 - 1.69 (m, 1H).

H NMR (400 MHz, CD 3 OD) δ: 8.17 (s, 1H), 8.04 (s, 1H), 7.64 - 7.47 (m, 5H), 7.37 - 7.24 (m, 2H), 7.10 (s, 1H), 6.63 (d, J= 8.5 Hz, 1H),

183 6.31 (d, J= 3.1 Hz, 1H), 5.08 - 5.03 (m, 1H),

3.36 (m, 2H), 2.24 (m, 1H), 1.76 (m, 1H).

Ή NMR (400 MHz, DMSO-d 6 ) δ: 9.27 (s, 2H), 8.33 (s, 1H), 7.89 (s, 1H), 7.55 (m, 6H), 6.51

184 (d, .7 = 2.6 Hz, lH), 5.14 (m, 1H), 3.17 (m, 2H),

2.46 (m, 1H), 1.68 (m, 1H).

Example 31: Synthesis of Compound 185 Compound 185

( 1 S)-2-(l-(5-acetyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)azet idin-2-yl)-5-chloro-3- phenylpyrrolo[l,2-f] [l,2,4]triazin-4(3H)-one

Scheme

31b

A mixture of 3 la (60 mg, 0.09 mmol) (The intermediate was synthesized according to the procedure of Example 1), Cul (10 mg, 0.05mmol), Pd(PPh 3 ) 2 Cl 2 (50 mg, 0.05mmol), DIEA (0.2 mL) and (trimethylsilyl)acetylene (0.5 mL) were stirred at r.t. in DMF (5 mL) under N 2 for 3 h. The mixture was diluted with DCM and washed with water three times and brine once, dried over Na 2 S0 4 , filtered and concentrated. The residue was purified by flash chromatography to give 31b as a brown solid (30 mg, yield: 52%).

Step 31-2

31 b Com pound 185

Cooled in ice-batch, to 3 lb (30 mg, 0.046 mmol) was added TFA (5 mL) and the mixture was stirred 0.5 h at 0 °C, then 1.5 h at r.t.. The reaction mixture was concentrated and the resulting residue was diluted with MeOH (10 mL). Then Cone. ΝΗνΗ?0 aq. (5 mL) was added and the mixture was stirred for another 2 h. After concentration, the residue was purified by chromatography eluting with MeOH/water to give Compound 185 as a solid (12 mg, yield: 56%). MS (m/z): 460.2 (M+H) + ; 1H NMR (400 MHz, DMSO-d 6 ) δ: 12.41 (s, 1H), 8.21 (s, 1H), 8.14 (s, 1H), 7.67 - 7.52 (m, 5H), 7.49 - 7.43 (m, 1H), 6.64 (m, 1H), 5.00 (m, 1H), 4.33 - 4.23 (m, 1H), 3.75 (m, 1H), 2.49 - 2.44 (m, 1H), 2.40 (s, 3H), 1.89 - 1.79 (m, 1H).

Example 32:

Kinase Inhibition assays of ρ110α/ρ85α, ρ110β/ρ85α, ρ110δ/ρ85α and ρΐΐθγ

PI 3 K kinases including pi 10α/ρ85α, pi 10δ/ρ85α and pi 10γ are purchased from

Invitrogen, and pi 10β/ρ85α is from Millipore.

Primary screening data and IC50 values are measured using Transcreener™ KINASE Assay (Bellbrook, Catalog # 3003-1 OK). The assay can be carried out according to the procedures suggested by the manufacturer. It is a universal, homogenous, high

throughput screening (HTS) technology using a far-red, competitive fluorescence polarization immunoassay based on the detection of ADP to monitor the activity of enzymes that catalyze group transfer reactions. Briefly, the Transcreener KINASE Assay is designed as a simple two-part, endpoint assay.

In the first step, the 25ul kinase reaction is performed by preparing a reaction mixture containing 5ul test compound (2%DMSO final concentration), lOul kinase, buffer (50mM HEPES, lOOmM NaCl, ImM EGTA, 0.03% CHAPS, 3mM MgCl 2 , and freshly supplemented ImM DTT), and lOul 30uM PIP2 / lOuM ATP. The plate is sealed and incubated for 80min at room temperature. Next, 25ul ADP detection mix is added per well. The plate is sealed again and incubated for 60min at room temperature, and then measure fluorescence polarization by Tecan Infinite F500 Reader.

Data is analyzed and IC50S are generated using the add-in software for Microsoft Excel, Xlfit™ (version 2.0). IH%= (ADP amount under 2%DMSO- ADP amount under test compound) / ADP amount under 2%DMSO.

In vitro activity data:

18.0 71.9 0.477 97.8

56.9 78.1 0.265 90.7

24.6 5.4 72.0 0.312 100

25.1 87.3 0.085 100

9.2 60.3 100

30.9 53.2 100

24.0 75.7 0.287 100

7.5 68.6 97.4

-1.3 30.4 94.3

8.9 21.2 7.7

36.9% 81.9 0.273 99.2

8.3% 14.1 17.7

80.9 93.7 0.034 98.6 0.004 >100 0.001

20.3 88.7 0.091 93.3 0.012 >100 0.002

82.6 0.100 92.7 0.051 >100 0.003

-0.3 49.9 92.2 0.032 >100 0.014

-1.5 18.5 72.5 0.271 >100 0.084

-20.5 51.3 74.1 0.094 >100 0.009

-17.7 35.3 81.5 0.153 >100 0.016

54.5 96.7 0.013 94.8 0.008 >100 0.001

-3.1 63.7 71.9 0.212

-2.5 12.4 84.6 0.203 96.8 0.029

-6.6 24.7 61.2 94.1 0.057

6.4 60.9 90.8 0.035 99.1

30.6 83.3 0.089 81.2

-3.3 54.8 93.5 0.01 1 > 100 0.003

20.7 16.5 94.2

19.8 6.5 74.0

80.2 0.066 > 100 0.021 91.7 0.006

71.8 79.8 0.186 91.2 0.005 > 100 -0.001

35.1 66.0 96.6 0.019 > 100 0.002 46.7 74.3 0.302 95.2 0.005 >100 0.001

71.9 0.795 80.9 0.172 100

33.8 68.1 > 100 0.014

47.3 84.7 0.152 > 100 0.026

69.7 0.501 86.1 0.058 98.4 0.004

-4.8 8.9 8.4

4.4 89.3 0.149 >100 0.029

-7.4 89.1 0.293 80.1 0.343

8.8 89.3 0.107 87.2 0.1 10

-1 1.0 86.4 0.035 68.8

26.0 1 1.9 90.1 0.207

23.8 99.5 0.067 97.6 0.008

21.7 83.9 0.287 91.1 0.156

37.1 88.3 0.239 98.2 0.013

45.5 97.6 0.073 >100 0.005

34.7 45.8 73.6 0.392

3.2 29.5 69.0 0.325

7.9 45.1 73.9 0.309

7.1 42.2 >100 0.039 95.4 0.039

93.7 0.061 >100 0.081 97.7

32.6 78.8 0.251 89.9 0.041 98.9 0.003

52.6 50.6 >100 0.078 >100 0.014

75.6 63.6 >100 0.014 > 100 0.012

71.3 0.188 61.0 98.1 0.007

52.1 73.8 0.078 98.5 0.028

13.0 57.8 68.8 99.9 0.009

41.6 92.1 0.220 >100 0.025 99.1 0.003

>100 0.031 >100 0.009 >100 0.001

13.5 49.5 91.6 0.088

33.6 69.5 0.420 92.7 0.016 >100 0.003

>100 0.025 >100 0.003 >100 0.001 75 69.3 0.096 97.3 0.008 99.1 0.003

76 82.0 0.104 93.9 0.010 98.8 0.004

77 88.2 0.058 85.5 0.034 99.5

78 92.4 0.026 91.2 0.018 98.2

79 96.3 0.006 91.6 0.016 99.0

80 58.9 83.5 0.046 >100 0.007

81 79.0 0.217 87.9 0.070 >100 0.006

8 2 56.4 78.6 0.194 98.7

83 42.7 78.6 0.309 97.3

84 -3.5 59.3 75.9 0.032 >100 0.004

85 27.4 74.7 0.311 87.8 0.030 >100 0.001

86 17.8 86.5 0.172 76.4 0.139 99.0 0.002

87 90.8 0.049 >100 0.008

88 94.7 0.058 98.0 0.014 93.2

89 96.1 0.017 94.8 0.016 >100

90 93.1 0.024 95.7 0.034 >100

91 48.3 78.3 0.222 93.5 0.034 >100 0.005

92 31.8 65.2 95.7 0.020 >100 0.003

93 5.4 53.7 77.6 0.244

94 36.3 53.5 >100 0.022 >100

95 82.0 0.036 >100 0.007 97.6 0.001

96 73.4 0.169 94.3 0.071 97.3 0.024

97 45.1 84.6 0.144 55.1

98 16.2 15.2 87.9 0.099 88.4

99 78.8 0.147 94.2 0.006 >100 0.003

100 89.8 0.006 >100 0.005 >100 0.001

101 47.8 81.6 0.138 >100 0.016 >100 0.003

102 92.3 0.061 >100 0.014 > 100 0.001

103 >100 0.046 98.2 0.019 99.7 0.001

104 >100 0.017 >100 0.003 >100 <0.0005

105 16.0 90.4 0.080 90.0 0.015 106 61.9 41.1 86.8 0.232

107 34.5 71.8 0.153 98.6 0.005

108 26.9 90.0 0.199 75.9 0.097

109 61.0 98.3 0.192 99.8 0.004

1 10 23.9 38.7 72.8

111 39.0 67.2 93.9 0.045

1 12 34.5 96.4 0.231 94.6 0.026

1 13 28.3 74.9 0.244 >100 0.043 99.3 0.006

1 14 86.4 0.159 4.3 93.7 0.027

115 80.2 0.143 91.7 0.003 >100 0.002

116 >100 0.128 96.9 0.045 >100 0.005

117 >100 0.038 >100 0.043 >100 0.005

1 18 19.1 5.2 77.5 0.471

1 19 47.8 85.6 0.239 94.3

120 74.7 0.237 85.9 0.295 >100

121 63.9 >100 0.105 92.7

122 88.3 0.051 >100 0.008 >100 0.003

123 47.9 67.9 94.6 0.022

124 95.0 0.022 >100 0.012 98.0 0.002

125 95.7 0.006 94.0 0.003 >100 0.001

126 90.9 0.025 >100 0.020 >100 0.001

127 7.0 71.3 0.307 >100 0.057 99.2 0.005

128 40.3 87.8 0.086 96.2 0.010 99.0 0.001

129 17.8 33.3 97.8 0.018

130 32.9 20.8 96.2 0.136

131 15.1 -9.7 62.0

132 74.5 0.338 >100 0.070 >100 0.009

133 11.5 65.9 88.1 0.172

134 59.2 >100 0.030 >100 0.005

135 20.6 >100 0.012 74.5 0.05136 27.6 95.0 0.042 83.5 0.124 137 35.9 89.3 0.013 96.8 0.036

138 42.3 95.0 0.075 >100 0.012

139 18.0 46.5 64.8

140 15.0 82.3 0.116 >100 0.051

141 28.2 92.3 0.151 >100 0.005

142 13.5 75.5 0.390 81.1 0.298

143 63.0 82.3 0.095 88.8 0.070

144 62.5 94.1 0.044 >100 0.005

145 55.5 >100 0.009 >100 0.002

146 77.9 0.120 97.3 0.009 >100 0.001

147 65.3 94.3 0.004 >100 0.001

148 19.5 83.0 0.173 86.7 0.044

149 -35.9 74.2 0.348 95.9 0.052

150 31.5 92.6 0.092 >100 0.003

151 11.4 22.8 52.4

152 54.4 79.3 0.287 99.2 0.005

153 56.5 85.8 0.165 >100 0.011

154 56.7 93.7 0.040 97.6 0.003

155 56.0 94.9 0.133 96.4 0.023

156 42.2 64.0 83.4 0.169

157 39.5 79.9 0.280 >100 0.021

158 71.1 0.473 >100 0.046 >100 0.006

159 32.8 20.4 85.0 0.127

160 11.4 34.3 80.2 0.140

161 15.3 -8.4 45.7

162 83.2 0.137 97.7 0.006 >100 0.001

163 -3.2 0.6 31.3

164 22.9 64.9 62.3

165 71.3 0.400 >100 0.002 >100 0.001

166 >100 0.017 >100 0.002 97.2 0.001

167 42.3 >100 0.021 >100 0.005 168 98.8 0.047 95.1 0.015 >100 0.001

169 -21.1 31.2 88.0 0.004

170 4.6 66.5 96.1 0.005

171 25.2 75.3 0.130 96.6 0.005

172 38.2 79.8 0.297 99.6 0.002

173 25.7 48.7 96.3 0.004

174 97.7 0.023 94.0 0.031 >100 0.001

175 90.9 0.078 87.6 0.105 99.5 0.001

176 16.8 58.3 97.1 0.005

177 17.0 79.8 0.089 97.1 0.030

178 1.5 7.6 82.3 0.211

179 51.5 97.9 0.015 >100 0.002

180 92.8 0.041 98.7 0.002 >100 <0.00046

181 95.9 0.023 >100 0.004 >100 <0.00046

182 93.3 0.062 94.9 0.007 >100 <0.00046

183 77.2 0.331 >100 0.005 >100 <0.00046

184 >100 0.038 98.4 0.008 >100 0.0005

185 45.9 99.0 0.005 >100 0.006