RELATED APPLICATIONS

This application claims the benefit of, and priority to, U.S. provisional application No. 62/207,039, filed August 19, 2015, the entire contents of which are incorporated herein by reference in its entirety.

FIELD

This invention relates to the field of protein kinases and inhibitors thereof. In particular, the invention relates to inhibitors of mammalian target of rapamycin (mTOR) signaling pathways, and methods of their use.

BACKGROUND

The mammalian target of rapamycin, mTOR, is a protein kinase that integrates both extracellular and intracellular signals of cellular growth, proliferation, and survival. Given its central role in cellular growth, proliferation and survival, it is perhaps not surprising that mTOR signaling is frequently dysregulated in cancer and other diseases (Bjomsti and Houghton Rev Cancer 2004, 4(5), 335-48; Houghton and Huang Microbiol Immunol 2004, 279, 339-59; Inoki, Corradetti et al. Nat Genet 2005, 37(1), 19-24).

mTOR is a member of the PIKK (PI3K-related Kinase) family of atypical kinases which includes ATM, ATR, and DNAPK, and its catalytic domain is homologous to that of PI3K. Dysregulation of PI3K signaling is a common function of tumor cells. In general, mTOR inhibition may be considered as a strategy in many of the tumor types in which PI3K signaling is implicated.

Inhibitors of mTOR may be useful in treating a number of cance s, including the following: breast cancer ( agata, Lan et al., Cancer Cell 2004, 6(2), 117-27: Pandolfi N. Engl, J. Med. 2004, 351(22), 2337-8; Nahta, Yu et al. Nat. Clin. Praci. Oncol. 2006, 3(5), 269-280); antle cell lymphoma (MCL) (Dal Col, Zancai et al. Blood 2008, 1 1 .1 (10), 5142-51); renal cell carcinoma (Thomas, Tran et al. Nat Med 2006, 12(1 ), 122-7; Atkins, Hidalgo et al. J. Clin. Oncol. 2004, 22(5), 909-18; Motzer, Hudes et al. J. Clin. Oncol. 2007, 25(25), 3958-64); acute myelogenous leukemia (AML) (Sujobert, Bardet et al. Blood 2005, 106(3), 1063-6; Billottet, Grandage et al. Oncogene 2006, 25(50), 6648-6659; Tamburini, Elie et al. Blood 2007, 110(3), 1025-8); chronic myelogenous leukemia (CML) (Skorski, Bellacosa et al. Embo J. 1997, 16(20), 6151- 61 : Bai, Quyang et al. Blood 2000, 96(13), 4319-27; Mickey and Cotter Biol ( ^" hem

2006, 281 (5), 2441 -50); diffuse large B cell lymphoma (DLBCL) (Uddin, Hussain et al. Blood 2006, 108( 13), 4178-86); several subtypes of sarcoma (Hernando, Charytonowicz et al. Nat. Med. 2007, 13(6), 748-53; Wan and Helman Oncologist

2007, 12(8), 1007-18); rhabdomyosarcoma (Cao, Yu et al Cancer Res 2008, 68(19), 8039-8048; Wan, Shen et al. Neoplasia 2006, 8(5), 394-401); ovarian cancer (Shayesteh, Lu et al. Nat. Genet. , 1999, 21(1), 99-102; (Lee, Choi et al. Gynecol. Oncol. 2005, 97(1 ) 26-34); endometrial tumors (Obata, Morland et al . Cancer Res. 1998, 58( 10), 2095-7; Lu, Wu et al , Clin. Cancer Res. 2008, 14(9), 2543-50); non small cell lung carcinoma (NSCLC) (Tang, He et al. Lung Cancer 2006, 51(2), 181-91 ; Marsit, Zheng et ai. Hum. Pathol. 2005, 36(7), 768-76); small cell, squamous, large cell and adenocarcinoma (Massion, Taflan et al. Am. J. Respir. Crit. Care Med. 2004, 170(10), 1088-94); lung tumors in general ( okubo, Gemma et al. Br. J. Cancer 2005, 92(9), 171 1-9; Pao, Wang et al. Pub Library of Science Med 2005, 2(1), el7); colorectal tumors (Velho, Oliveira et al. Eur. J. Cancer 2005, 41 (1 1), 1649-54; Foukas, Claret et al. Nature, 2006, 441 (7091), 366-370), particularly those that display microsatellite instability (Goel, Arnold et ai. Cancer Res. 2004, 64(9), 3014-21 ; Nassif, Lobo et al. Oncogene 2004, 23(2), 617-28), KRAS-mutated colorectal tumors (Bos. Cancer Res. 1989. 49(17), 4682-9; Fearon Ann. N Y. Acad Sci 1995, 768, 101-10); gastric carcinomas (Byun, Cho et al. Int. J. Cancer 2003, 104(3), 318-27); hepatocellular tumors (Lee, Soung et al . Oncogene 2005, 24(8), 1477-80); liver tumors (Hu, Huang et al. Cancer 2003, 97(8), 1929-40; Wan, Jiang et al. Cancer Res. Clin. Oncol. 2003, 129(2), 100-6); primary melanomas and associated increased tumor thickness (Guldberg, thor Straten et al. Cancer Res. 1997, 57(1 7), 3660-3; Tsao, Zhang et al. Cancer Res. 2000, 60(7), 1800-4; \\ hi Ionian. Zhou et ai. Int. J. Cancer 2002, 99( 1), 63- 7; Goel, Lazar et al. J. Invest. Dermatol. 126(1), 2006, 154-60); pancreatic tumors (Asano, Yao et al. Oncogene 2004, 23(53), 8571 -80); prostate carcinoma (Cairns, Okami et al. Cancer Res. 1997, 57(22), 4997-5000; Gray, Stewart et al. Br. J. Cancer 1998, 78(10), 1296-300; Wang, Parsons et ai. Clin. Cancer Res. 1998, 4(3), 81 1-5; Whang, Wu et al. Pro Natl. Aca. Sci. USA 1998, 95(9), 5246-50; Majumder and Sellers Oncogene 2005, 24(50) 7465-74; Wang, Garcia et al. Proc. Natl. Acad. Sci. USA 2006, 103(5), 1480-5; (Lu, Ren et ai. Int. J. Oncol. 2006, 28(1), 245-51 ; Mulholland, Dedhar et al. Oncogene 25(3), 2006, 329-37; Xin, Teitell et al. Proc. Natl. Acad. Sci. USA 72006, 03(20), 7789-94; Mikhaiiova, Wang et al Adv. Exp. Med. Biol. 2008, 617, 397-405; Wang, Mikhailova et al. Oncogene 2008, 27(56), 7106-7117); thyroid carcinoma, particularly in the anaplastic subtype (Garcia-Rostan, Costa et al. Cancer Res. 2005, 65(22), 10199-207); follicular thyroid carcinoma (Wu, Mambo et al. J. Clin. Endocrinol. Me tab. 2005, 90(8), 4688-93); anaplastic large cell lymphoma (ALCL); hamartomas, angiomyelo lipomas, T ^' SC-associated and sporadic lymphangioleiomyomatosis: Cowden's disease (multiple hamaratoma syndrome) (Bissler, McCormack et al. N. Engl. J. Med. 2008, 358(2), 140-151); sclerosing hemangioma (Randa M. S. Amin. Pathology International 2008, 58(1), 38-44); Peutz- Jeghers syndrome (PJS); head and neck cancer (Gupta, McKenna et al. Clin. Cancer Res. 2002, 8(3), 885-892); neurofibromatosis (Ferner R.E. Eur. J. Hum. Genet. 2006, 15(2), 131-138; Sabatini Nat. Rev. Cancer 2006, 6(9), 729-734; Johannessen, Johnson et al. Current Biology 2008, 18(1), 56-62); macular degeneration; macular edema; myeloid leukemia; systemic lupus; and autoimmune lymphoproliferative syndrome (ALPS).

Recently, it has been reported that inhibitors of mTO may be useful in the treatment of viral infections and diseases associated therewith (US 2012/0190676; CA 2825825).

There is a great unmet medical need for agents that more safely, effectively, and reliably treat cancers (for example those listed above), as well as viral infections, from HIV to the common cold. This includes a major need for better agents to treat human cytomegalovirus (where current agents suffer from significant toxicity and lack of efficacy), herpes simplex virus (where current agents are beneficial but provide incomplete relief), influenza A (where resistance to current agents is rampant), and hepatitis C virus (where many patients die from poor disease control). It further includes a major need for agents that work across a spectrum of viruses, facilitating their clinical use without necessarily requiring identification of the underlying pathogen.

SUMMARY

In brief, the present invention is directed to compounds having activity as mTOR inhibitors, including mTORCl and mTORC2, including stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and the use of such compounds to inhibit mTOR and to tliereby treat any of a variety of conditions or diseases in which modulation of the rapamycin signaling pathway provides a therapeutic benefit .

In one aspect of the invention, compounds having the following structure of Formula I are provided:

1 and pharmaceutically acceptable salts, hydrates, solvates, or stereoisomers thereof, wherein:

R ¹ is Ci-ealkyl optionally substituted with one or more R ', C2- ₆ alkenyl optionally substituted with one or more R', Ci-ealkynyl optionally substituted with one or more R', N(R ⁵ )(R ⁶ ), OR ⁵ , a 3 to 8 membered carbocyclic ring optionally substituted with one or more R', or a 3 to 8 membered heterocyclic ring optionally substituted with one or more R ⁷ ;

R ⁵ and R ⁶ are each independently H, C _h alky! optionally substituted with one or more R ⁷ , Ci-ealkenyl optionally substituted with one or more R ⁷ , C ₂ . ₆ alkyny3 optionally substituted with one or more R', a 3 to 8 membered carbocyclic ring optionally substituted with one or more R ⁷ , or a 3 to 8 membered heterocyclic ring optionally substituted with one or more R', heteroaryi optionally substituted with one or more R', or aryl optionally substituted with one or more R ⁷ , or

R ⁵ and R ^b , together with the nitrogen to which they are attached, form an N- heterocyclic ring containing between 3 and 8 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R' ;

R is Ci- ₆ alky3, Ci-ealkenyl, i ^" >.,<..'¾ikyn> !. Ci-ehaloalkyl, halogen, -CN, oxo, -OR, -N(R) ₂ , -C(0)R, -C(0)OR, -OC(0)R -C(0)N(R) ₂ , -NRC(0)R

-NRC(0)N(R) _2, -OC(0)N(R) ₂ , -NRC(Q)QR, -S(0) . R. -S(0) ₂ N(R) ₂ , -N RS(0) . R.

-C ;., a! kvi-OR. -C ₁ .. ₆ alkyl- (R) ₂ , -Ci. ₆ alkyl-C(0)R, -Ci.. ₆ alkyl-C(0)OR,

-Ci _-6 a]ky3-0-C(0)R -C _! _ ₆ alkyl-C(0)N(R) ₂ , -d^alkyl-NRCiOJR, -Ci_ ₆ a]ky3-S(0) ₂ R, -Ci_ ₆ alkyl-NRC(0)N(R) ₂ , -C _1-6 alkyl-NRC(0)0R, -C,_ ₆ alkyl-0C(0)N(R) ₂ , -Ci _-6 alkyl-S(0) ₂ N(R)2, -Ci _-6 alkyl-NRS(0) ₂ R, aryl, or heterocyclyl;

R ² is Ci- ₆ alkyl optionally substituted with one or more R'°, C ₂ - ₆ alkenyl optionally substituted with one or more R ^lU , N(R ⁸ )(R ), a 3 to 8 membered carbocyclic ring optionally substituted with one or more R ¹⁰ , or a 3 to 8 membered heterocyclic ring optionally substituted with one or more R ^lU , heteroaryl optionally substituted with one or more R ¹⁰ , or aryl optionally substituted with one or more R ¹⁰ ;

R ⁵ and R ⁹ are each independently H, d-ealky! optionally substituted with one or more R'°, Cj-ealkenyl optionally substituted with one or more R ⁱ⁰ , C^alkynyl optionally substituted with one or more R ¹⁰ . a 3 to 8 membered carbocyclic ring optionally substituted with one or more R ^l0 , a 3 to 8 membered heterocyclic ring optionally substituted with one or more R" ^J , heteroaryl optionally substituted with one or more R ¹⁰ , or aiyl optionally substituted with one or more R ¹⁰ , or

R ^K and R ⁹ , together with the nitrogen to which they are attached, form an N- heterocyclic ring containing between 3 and 8 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R ¹ ";

R ¹⁰ is C ₂ .. ₆ alkenyl, Ci-ealkyny!, halogen, -CN, oxo, -OR, -N(R) ₂ , -C(0)R, -C(0)OR, -OC(0)R -C(0)N(R) ₂ , -NRC(0)R

-NRC(0)N(R) _2, -OC(0)N(R) ₂ , -NRC(0)OR, -S(0) ₂ R, -S(C)) ₂ N(R) ₂ , -MRS(0) ₂ R,

··( ^■ ; ...alk I -OR. -C, _-6 alkyi-N(R) ₂ , -C;_6alkyl-C(Q)R, ^• ( ^'• .,aiky! -( {() )R.

~C ₁ . ₆ alky3-0-C(0)R -( ^•• ..,a!kyl-C(( ⁾ )\( R) .. -Ci- ₆ alkyl-NRC(0)R, -Ci. ₆ alky3-S(0) ₂ R, -Ci _-6 alkyl-NRC(0)N(R) ₂ , -C _1-6 alkyl-NRC(0)OR, -Ci _-6 alkyl-OC(0) (R) ₂ ,

-Ci. ₆ alkyl-S(0) ₂ N(R)2 ₅ -C ₁ - ₆ aikyl-NRS(0) ₂ R, aryl, or heterocyclyl:

R ³ is H, halogen, -CN, Ci-ealkyl, Ci-ehaloalkyi, or -OR;

R ⁴ is H, halogen, -CN, C _f .alk> !. Ci_ ₆ haloalkyl, -N(R) ₂ , -OR, -C(0)N(R) ₂ , -Ci-ealkyl-OR, 3 to 8 membered carbocyclic ring, or 3 to 8 membered heterocyclic ring;

A is aiyl or heteroaryl, wherein A is optionally substituted by one or more R ^{1 1} ;

R" is Ci-ealkyl, C ₂ . ₆ alkenyi, C ₂ .. ₆ alkynyl, Ci-Jialoalkyl, halogen, -CN, oxo, -OR, -N(R) ₂ , -C(0)R, -C(0)OR, -OC(0)R -C(0)N(R) ₂ , -NRC(0)R

-NRC(0)N(R) _2, -OC(0)N(R) ₂ , -MRC(0)OR, -S(0) ₂ R, -S(0) ₂ N(R) ₂ , -NRS(())2R,

-Ci-ealkyl-OR, -C _1-6 alkyi-N(R) ₂ , -C; ,.alk> l-Ci OOR.

-( ^• ;.,alk> i-0-C(0)R -C . ,,aik l-C(0)N( R ) .- -C ₁ .6alkyl-NRC(0)R, -Ci..6alkyl-S(0) ₂ R, -Ci- ₆ alky3-NRC(0)N(R) ₂ , -Ci- ₆ alkyl-NRC(0)OR, -Ci- ₆ alky3-OC(0)N(R) ₂ ,

-C]- ₆ alkyi-S(0) ₂ N(R) ₂ , -C!. ₆ aikyl-NRS(0) ₂ R, aryl, or heterocyclyl; and each R is independently H, C _h alky!, Ci-ehaloalkyl, 3 to 6 membered carbocyclic ring, or 3 to 6 membered heterocyclic ring.

In one aspect of the invention, compounds having the following structure of Formula I-a are provided

I-a and pharmaceutically acceptable salts, hydrates, solvates, or stereoisomers thereof, wherein:

and R ^" are each independently H, Ci-ealkyl optionally substituted with one or more R', Ci-ealkeny] optionally substituted with one or more R', Ci-ealkynyl optionally- substituted with one or more R'', heteroaryl optionally substituted with one or more R ^? , or aryi optionally substituted with one or more R', or

R ³ and R ⁶ , together with the nitrogen to which they are attached, form a heterocyclic ring containing between 3 and 8 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R ⁷ ;

R ⁷ is ( ^" ; ..,a!kyl . C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, Ci-ehaloalkyl, -OR, -N(R) ₂ , -NRC(0)R -NRC(0)N(R) _2, -OC(0)N(R) ₂ , -NRC(0)OR, -C^alkyl-OR, -C;_ ₆ alkyl-N(R) ₂ ,

-C(0)N(R) ₂ , -C;. ₆ alkyl-C(0)N(R) ₂ , -C _w alkyl-NRC(0)R, ar 4, or heterocyclyl;

R* ⁵ and R ^y , together with the nitrogen to which they are attached, form a heterocyclic ring containing between 3 and 8 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R ^l0 ;

R ⁱ⁰ is C]- ₄ alkyl, Ci. ₄ haloalkyl, -OR, -N(R) ₂ , -NRC(0)R -NRC(0)N(R) _2,

-OC(0)N(R) ₂ , -NRC(0)OR, -( ^'• ...aikyl-OK . -Ci. ₆ alkyl-N(R) ₂ , -C(0)N(R) ₂ ,

-Ci _-6 alky3-C(0)N(R) ₂ , or -C ₁ . ₆ alkyl-NRC(0)R ;

A is aryi or heteroaryl, wherein A is optionally substituted by one or more R ¹¹ ; R ^u is halogen, -CN, Ci-ealkyl, C ₂ - ₆ alkenyl, Ci-ealkynyi, Cj-ehaloalkyi, oxo, -OR, - (R) ₂ , ~C(Q)R, ~C(Q)OR, -C(0)N(R) ₂ , -NRC(0)R -NRC(0)N(R) ₂ , -OC(0)N(R) ₂ , -NRC(0)OR, -S(0) ₂ R, -S(0) ₂ N(R) ₂ , -NRS(0) ₂ R -Ci_ ₆ alkyl-OR, -Ci- ₆ alkyl-N(R) ₂ ,

-C ₁ . ₆ alkyl-NRC(0)R, -Ci. ₆ alkyl-S(0) ₂ R, -Ci.. ₆ aikyl-NRS(0) ₂ R aryl, or heterocyclyl; and

each R is independently H, Ci-ealkyl, Ci-ehaloalkyl, 3 to 6 membered carbocyclic ring, or 3 to 6 membered heterocyclic ring.

In one aspect of the invention, compounds having the following structure of Formula II are provided:

II and pharmaceutically acceptable salts, hydrates, solvates, or stereoisomers thereof, wherein:

R ¹ is Ci-eaikyl optionally substituted with one or more R' , C ₂ _ ₆ aikenyl optionally substituted with one or more R ⁷ , C ₂ .ealkyny3 optionally substituted with one or more R ⁷ , N(R ⁵ )(R ⁶ ), OR ³ , a 3 to 8 membered carbocyclic ring optionally substituted with one or more R'', or a 3 to 8 membered heterocyclic ring optionally substituted with one or more R ⁷ ;

R and R ⁶ are each independently H, ^' _: ...nlk% i optionally substituted with one or more R ⁷ , C ₂ _ ₆ alkenyl optionally substituted with one or more R ⁷ , C ₂ _ ₆ alkynyl optionally substituted with one or more R', a 3 to 8 membered carbocyclic ring optionally substituted with one or more R ^' , or a 3 to 8 membered heterocyclic ring optionally substituted with one or more R', heteroarv'l optionally substituted with one or more R ⁷ , or aryi optionally substituted with one or more R ⁷ , or

R ⁵ and R ⁶ , together with the nitrogen to which they are attached, form an N- heterocyclic ring containing between 3 and 8 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R' ; R' is Ci-ealkyl, C _2-6 alkenyl, C ₂ _ ₆ alkynyl, Ci-ehaloalkyi, halogen, -CN, oxo, -OR, - (R) ₂ , -C(0)R, -C(0)OR, OC(0)R -C(G)N(R) ₂ , -NRC(0)R

-NRC(0)N(R) _2, -OC(0)N(R) ₂ , -NRC(0)OR, -S(0) ₂ R, ~S(0) ₂ N(R) ₂ , -NRS(0) ₂ R, -Ci-galkyl-OR, -C,. ₆ alkyi-N(R) ₂ ,

-C ₁ . ₆ alkyl-0-C(0)R -Ci. ₆ alkyl-C(0)N(R) ₂ , -Ci.. ₆ alkyl-NRC(Q)R, -C;. ₆ alky3-S(Q) ₂ R, -Ci- ₆ alky3-NR.C(0)N(R) ₂ , -Ci- ₆ a3kyl- RC(0)OR, -Ci- ₆ aIky3-OC(0)N(R) ₂ ,

-C i- ₆ alkyl-S(0) ₂ N(R) ₂ , -Ci- ₆ alkyl-NRS(0) ₂ R, aryl, or heterocyclyl;

R ² is Ci -eaikyl optionally substituted with one or more R'°, C -ealkenyl optionally substituted with one or more R ¹⁰ , N(R ⁸ )(R ⁹ ), a 3 to 8 membered earbocyclie ring optionally substituted with one or more R ¹⁰ , or a 3 to 8 membered heterocyclic ring optionally substituted with one or more R" ^J , heteroaryl optionally substituted with one or more R ¹⁰ , or aiyl optionally substituted with one or more R ¹⁰ ;

R ^K and R are each independently H, optionally substituted with one or more R ^l0 , Ci-ealkenyl optionally substituted with one or more R'", C ₂ - ₆ alkynyl optionally substituted with one or more R ¹⁰ , a 3 to 8 membered earbocyclie ring optionally substituted with one or more R'°, a 3 to 8 membered heterocyclic ring optionally substituted with one or more R ^lU , heteroaryl optionally substituted with one or more R ^k ', or aiyl optionally substituted with one or more R ¹⁰ , or

and R ⁹ , together with the nitrogen to which they are attached, form an N- heterocyclic ring containing between 3 and 8 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R ^l0 ;

R ^lC" is Ci-ealkyi, C _2- ealkenyl, C ₂ _ ₆ alkynyl, Ci -ehaloalkyl, halogen, -CN, oxo, -OR, -N(R) ₂ , -C(0)R, -C(0)OR, OC(0)R -C(0)N(R) ₂ , -NRC(0)R

-NRC(0)N(R) _2, -OC(0)N(R) ₂ , -NRC(0)OR, -S(0) ₂ R, -S(0) ₂ N(R) ₂ , -NRS(0) ₂ R, -Ci-galkyl-OR, -Ci. ₆ alkyi-N(R) ₂ , -Ci. ₆ alkyl-C(0)OR,

-C]- ₆ alkyl-0-C(0)R -Ci- ₆ alkyl-C(0)N(R) ₂ , ^• C ;. _! ,a!k s i-N RC(0)R. ^•• ( ^•• ,.alk> ! -SiO) .R. -C ₁ . ₆ alky3-NRC(0)N(R) ₂ , -C ₁ . ₆ a3kyl-NRC(0)OR, -C ₁ . ₆ alky3-OC(0)N(R) ₂ ,

-C _1-6 alkyl-S(0) ₂ N(R) ₂ , -Ci_ ₆ alkyl-NRS(0) ₂ R, aryl, or heterocyclyl;

R ³ is H, halogen, -CN, C _h alky!, C;. ₆ haloalkyl, or -OR;

R ⁴ is H, halogen, -CN, CV ₆ aikyi, Ci-ehaloalkyi, -N(R) ₂ , -OR, -C(0)N(R) ₂ ,

-Ci-ealkyl-OR, 3 to 8 membered earbocyclie ring, or 3 to 8 membered heterocyclic ring;

A is ary] or heteroaiyl, wherein A is optionally substituted by one or more R ¹¹ ;

R ¹¹ is Ci-eaikyi, C _2-6 alkenyl, C _2-6 alkynyl, Ci-ehaloalkyl, halogen, -CN, oxo, -OR, -N(R) ₂ , -C(0)R, -C(0)OR, OC(0)R -C(0)N(R) ₂ , -NRC(0)R _, -NRC(0)N(R) _2, -QC(Q)N(R) ₂ , -NRC(Q)QR, -S(i)) .R. -S(0) ₂ N(R) ₂ , -NRS(0) >R.

-( ^• ;.,a!k> i-OR. -C ₁ .. ₆ alkyl- (R) ₂ , -C; .,-.a!k> l-C(G)R. -Ci.. ₆ alkyl-C(0)OR,

-Ci _-6 a]ky3-0-C(0)R -C _! _ ₆ alkyl-C(0)N(R) ₂ , -C^kyl-NRCiOJR, -Ci_ ₆ a]ky3-S(0) ₂ R, -Ci_ ₆ alkyl-NRC(0)N(R) ₂ , -C _1-6 alkyl-NRC(0)OR, -C,_ ₆ alkyl-OC(0)N(R) ₂ ,

~Ci. ₆ alkyi-S(0) ₂ N(R) ₂ , -Ci.6alkyl-NRS(0) ₂ R, aryl, or heterocyclyl; and

each R is independently H, Ci- ₆ alkyl, ( ^' ...haloalk) !. 3 to 6 mem be red carbocyclic ring, or 3 to 6 membered heterocyclic ring.

In one aspect of the invention, compounds having the following stmcture of Formula l!~a are provided

and pharmaceutically acceptable salts, hydrates, solvates, or stereoisomers thereof, wherein:

R ³ and R ^D are each independently H, C _h alky! optionally substituted with one or more R', C ₂ .. ₆ alkenyl optionally substituted with one or more R', C ₂ .. ₆ alkynyl optionally substituted with one or more R', heteroaryl optionally substituted with one or more R ⁷ , or aryi optionally substituted with one or more R ⁷ , or

R ⁵ and R ⁶ , together with the nitrogen to which they are attached, form a heterocyclic ring containing between 3 and 8 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R' ;

R ⁷ is Ci- ₆ alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _]-6 haloalkyl, -OR, -N(R) ₂ , -NRC(0)R -NRC(0)N(R) _2i -OC(0)N(R) ₂ , -NRC(0)OR, -Ci.. ₆ aikyl~OR, -( _: .,.aik> 1- N(R) ₂ , -C(0)N(R) ₂ , -C ₁ . ₆ alkyl-C(O)N(R) ₂ , -C ₁ . ₆ alky]-NR.C(0)R, atyl, or heterocyclyl; s and R ⁹ , together with the nitrogen to which they are attached, form a heterocyclic ring containing between 3 and 8 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R ^" : R ⁱ⁰ is C, . ₄ alkyL Ci.Aaloalkyl, -OR, -N(R) ₂ , -NRC(0)R -NRC(0)N(R) _2, -OC(0)N(R) ₂ , -NRC(0)OR, -( ^'• ...aikyl-OK . -( ^ ...a!kyl Ai K) -. -C(0)N(R) ₂ ,

-Ci _-6 a]ky3-C(0)N(R) ₂ , or -C ₁ . ₆ alkyl-NRC(0)R ;

A is aryl or heteroaryl, wherein A is optionally substituted by one or more R ¹¹ ; R ^{1 1} is halogen, -CN, Ci-ealkyl, C ₂ -6alkenyi, C ₂ .&alkynyi, Ci-ehaloalkyl, oxo, -OR, -N(R) ₂ , -C(0)R, -C(0)OR, -C(0)N(R) ₂ , -NRC(0)R -NRC(0)N(R) _2,

-OC(0)N(R) ₂ , -NRC(0)OR, -S(0) ₂ R, -S(0) ₂ N(R) ₂ , -NRS(0) ₂ R -d-ealkyl-OR, -Ci-6alkyl-N(R) _¾ -Ci-6alkyl-C(0)R, -C ₁ - ₆ alkyl-C(0)OR, -Ci _-6 alkyl-C(0)N(R) ₂ , -C ₁ .. ₆ alkyl-NRC(0)R, -C _I .. ₆ alkyl-S(0) ₂ R, -C ₁ . ₆ alkyl-NRS(0) ₂ R_ _, aryl, or heterocyclyl; and

each R is independently H, C _h alky!, Ci -ehaloalkyl, 3 to 6 membered carbocyclic ring, or 3 to 6 membered heterocyclic ring.

In another aspect, a pharmaceutical composition is provided comprising a compound having the structure of Formula I, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier, diluent or excipient. In another aspect, a pharmaceutical composition is provided comprising a compound having the structure of Formula I-a, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier, diluent or excipient. In another aspect, a pharmaceutical composition is provided comprising a compound having the structure of Formula II, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier, diluent or excipient. In another aspect, a pharmaceutical composition is provided comprising a compound having the structure of Formula Π-a, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier, diluent or excipient. In further embodiments, the pharmaceutical composition further comprises one or more additional biologically active agents. In more specific embodiments, the additionally biologically active agents is selected from the group consisting of anticancer drugs; cyctotoxins, cell cycle arresting drugs; and cytostatic drugs, or a combination of these agents. In other embodiments, the one or more additional biologically active agents is selected from the group consisting of antiviral drags; DNA gyrase inhibitors, protease inhibitors, polymerase inhibitors, or a combination of these agents. In other embodiments, the one or more additional biologically active agents is selected from the group consisting of immunomodulator drugs; interferon, steroid, cox inhibitor, or a combination of these agents. In one embodiment, the additionally biologically active agent is an anticancer drug selected from, the group consisting of paclitaxel, doxorubicin, vincristine, actinomycin D, altretamine, asparaginase, bleomycin, busulphan, cabazitaxel, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, cytarabine, dacarbazine, daunorubicm, docetaxel, epirubicin, etoposide, fludarabine, fluorouracil, gemcitabine, hydroxyurea, idarabicin, ifosfamide, irinotecan, lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitozantrone, oxaliplatin, procarbazine, steroids, streptozocin, taxotere, tamozolomide, thioguanine, thiotepa, tomudex, topotecan, treosulfan, uracil-tegufur, vinblastine, vindesine; agents targeting immune modualtors such as PD-1, PDL-1, and IDO l, e.g. nivolumab, pembrolizumab, MPDL3280A, and MEDI4736; agents targeting DNA repair deficiency, e.g. olaparib; agents targeting receptor tyrosine kinases such as EGFR, ERBB2, c-MET, VEGFR2, and IGFR1, e.g. erlotinib, necitumumab, traztuzamab, pertuzamab, lapatsnib, crizotinib, cabozantinib, onartuamab, ramucirumab, or bevacizumab; agents tarting hormone receptors such as the androgen and estrogen receptors, e.g. enzalutamide, abiraterone, or tamoxifen; agents targeting the MAP kinase or PI3K-AKT pathways, e.g. cobimetinib, vemurafenib, and everolimus; Her2 (ErbB2) pathway blockers such as lapatinib, trastuzumab, and Kadyzla; rnTOR blockers such as raiapogs {e.g., sirolimus); mTORC l/mTORCl inhibitors; Angiogenesis or VEGFR pathway blockers such as avastin, nexavar or sutent; Aromatase modulators such as exemtesane or femora; Androgen signaling modulators such as enzalutamide, bicalutamide; and B-RAF blockers such as Tafinlar or Zelboraf.

In one aspect, a method of inhibiting mTOR in a warm-blooded animal is provided, comprising administering to the animal an effective amount of a compound having the structure of Formula I, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound. In another aspect, a method of inhibiting mTOR in a warm-blooded animal is provided, comprising administering to the animal an effective amount of a compound having the structure of Formula I-a, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound. In another aspect, a method of inhibiting mTOR in a warm-blooded animal is provided, comprising administering to the animal an effective amount of a compound having the structure of Formula II, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound. In another aspect, a method of inhibiting mTOR in a warm-blooded animal is provided, comprising administering to the animal an effective amount of a compound having the structure of Formula Il-a, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound.

In one aspect, a method of treating cancer in a warm-blooded animal in need thereof is provided, comprising administering to the animal an effective amount of a compound having the structure of Formula I, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound. In another aspect, a method of treating cancer in a warm-blooded animal in need thereof is provided, comprising administering to the animal an effective amount of a compound having the structure of Formula I-a, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound. In another aspect, a method of treating cancer in a warm-blooded animal in need thereof is provided, comprising administering to the animal an effective amount of a compound having the structure of Formula II, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound. In another aspect, a method of treating cancer in a warm-blooded animal in need thereof is provided, comprising administering to the animal an effective amount of a compound having the structure of Formula Il-a, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound.

In one aspect, a method of treating or preventing a respirator}' vims infection in a warm-blooded animal in need thereof is provided, comprising administering to the animal an effective amount of a compound having the structure of Formula I, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound. In another aspect, a method of treating or preventing a respirator}- virus infection in a warm-blooded animal in need thereof is provided, comprising administering to the animal an effective amount of a compound having the structure of Formula I-a, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound. In another aspect, a method of treating or preventing a respiratory virus infection in a warm-blooded animal in need thereof is provided, comprising administering to the animal an effective amount of a compound having the structure of Formula II, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound. In another aspect, a method of treating or preventing a respirator],' virus infection in a warm-blooded animal in need thereof is provided, comprising administering to the animal an effective amount of a compound having the structure of Formula Il-a, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound.

In one aspect, a method of treating or preventing inflammation in a warmblooded animal in need thereof is provided, comprising administering to the animal an effective amount of a compound having the structure of Formula I, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound. In another aspect, a method of treating or preventing inflammation in a warm-blooded animal in need thereof is provided, comprising administering to the animal an effective amount of a compound having the structure of Fonnula I-a, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound. In another aspect, a method of treating or preventing inflammation in a warm-blooded animal in need thereof is provided, comprising administering to the animal an effective amount of a compound having the structure of Formula II, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound. In another aspect, a method of treating or preventing inflammation in a warm-blooded animal in need thereof is provided, comprising administering to the animal an effective amount of a compound having the structure of Fonnula Il-a, or a stereoisomer, pharmaceutically acceptable sale or prodrug thereof, or a pharmaceutical composition comprising such compound.

These and other aspects of the invention will be apparent upon reference to the following detailed description.

DETAILED DESCRIPTION

In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments of the invention. However, one skilled in the art will understand that the invention may be practiced without these details.

Unless the context requires otherwise, throughout the present specification and claims, the word "comprise" and variations thereof, such as, "comprises" and "comprising ^" ' are to be construed in an open, inclusive sense, that is as "including, but not limited to".

Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

"Amino" refers to the -NH ₂ radical .

"Cyano" refers to the -CN radical.

"Hydroxy" or "hydroxyl" refers to the -OH radical.

"Imino" refers to the =NH substituent.

"Nitro" refers to the -NO?, radical.

"Oxo" refers to the =0 substituent.

"Thioxo" refers to the =S substituent.

"Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, which is saturated or unsaturated (i.e., contains one or more double and/or triple bonds), having from one to twelve carbon atoms -12 alkyl), preferably one to eight carbon atoms (Cj-Cg alkyl) or one to six carbon atoms (Ci-Ce alkyl), and which is attached to the rest of the molecule by a single bond, e.g. , methyl, ethyl, «-propyl, 1 -methylethyl (/SO-propyl), «-but l, «-pentyl, 1, 1-dimethylethyl (f-butyl), 3-methylhexyl, 2-methylhexyl, ethenyl, prop-l-enyl, but-l-enyl, pent-l-enyl, penta-l ,4-dienyl, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted.

"Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, which is saturated or unsaturated (i.e. , contains one or more double and/or triple bonds), and having from one to twelve carbon atoms, e.g. , methylene, ethylene, propylene, H-butylene, ethenylene, propenylene, tt-butenylene, propynylene, w-butynylene, and the like. The alkylene chain is attached to the rest of the molecule through a single or double bond and to the radical group through a single or double bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkylene chain may be optionally substituted.

"Alkoxy" refers to a radical of the formula -OR ₃ where R _a is an alkyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted.

"Alkylamino" refers to a radical of the formula -NHR _a or -NRaR _a where each R, is, independently, an alkyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkylamino group may be optionally substituted.

"Thioalkyl" refers to a radical of the formula -SR ₃ where R _a is an alkyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, a thioalkyl group may be optionally substituted.

"Aryl" refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring. For purposes of this invention, the aryi radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system., which may include fused or bridged ring systems. Aryl radicals include, but are not limited to, and radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, os-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals that are optionally substituted.

'Aralkyl" refers to a radical of the fonnula -R _b ~R _G where R is an alkylene chain as defined above and R is one or more aryl radicals as defined above, for example, benzyl, diphenylmethyl and the like. Unless stated otherwise specifically in the specification, an aralkyl group may be optionally substituted.

"Cycloalkyl" or "carbocyclic ring" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, having from three to fifteen carbon atoms, preferably having from three to ten carbon atoms, and which is saturated or unsaturated and attached to the rest of the molecule by a single bond. Monocyclic radicals include, for example, cyclopropyi, cyclobutyl, cyclopentyi, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic radicals include, for example, adamantyi, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1Jheptanyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkyl group may be optionally substituted.

"Cycloalkylalkyl" refers to a radical of the formula -¾¾ where ¾ is an alkylene chain as defined above and R _g is a cycloalkyl radical as defined above. Unless stated otherwise specifically in the specification, a cycloalkylalkyl group may be optionally substituted.

"Fused" refers to any ring structure described herein which is fused to an existing ring structure in the compounds of the invention. When the fused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atom on the existing ring structure which becomes part of the fused heterocyclyl ring or the fused heteroaryl ring may be replaced with a nitrogen atom.

' ^" Halo ^" ' or "halogen" refers to bromo, chioro, fluoro or iodo.

"Haioaikyl" refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyL and the like. Unless stated otherwise specifically in the specification, a haloalkyl group may be optionally substituted.

"Heterocyclyl" or "heterocyclic ring" refers to a stable 3- to 18-membered non-aromatic ring radical which consists of two to twelve carbon atoms and from one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical may be a monocyclic, bicyciic, tricyclic or tetracyclic ring system, which may include fused, bridged, or spiro ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized; and the heterocyclyl radical may be partially or fully saturated. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyi, thienyl[l ,3]dithianyl, decahydroisoquinolyl, imidazo!inyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuciidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiarnorpholimyl, 1-oxo-thiomorpholinyl, and 1, 1-dioxo-tm^morpholinyl . Unless stated otherwise specifically in the specification, Unless stated otherwise specifically in the specification, a heterocyclyl group may be optionally substituted. "N-heterocyclyl" refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical . Unless stated otherwise specifically in the specification, a N-heterocyclyl group may be optionally substituted.

"Heterocyclyl alkyl" refers to a radical of the formula -¾ _e where ¾ is an alkylene chain as defined above and ¾ is a heterocyclyl radical as defined above, and if the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be attached to the alkyl radical at the nitrogen atom. Unless stated otherwise specifically in the specification, a heterocyclylalkyl group may be optionally substituted.

"Heteroaryl" refers to a 5- to 14-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and at least one aromatic ring. For purposes of this invention, the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxoiyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazoiyi, benzo [ )][!, 4] dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxoiyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, mdazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyi, oxazolyl, oxiranyl, 1-oxidopyridinyi, 1 -oxidopy rimidinyl, 1 -oxidopyrazinyl, 1 -oxidopyridazinyl, 1 -phenyl- lH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinoiinyl, quinuciidinyl, isoquinolmyi, tetany droquinolinyl, thiazolyi, thiadiazoiyl, triazolyl, tetrazoiyl, triazinyl, and thiophenyl (i.e. , thienyl). Unless stated otherwise specifically in the specification, a heteroaryl group may be optionally substituted.

' ^" N-heteroaryi" refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. Unless stated otherwise specifically in the specification, an N-heteroaryl group may be optionally substituted.

"Heteroarylalkyl" refers to a radical of the formula -R _¾ R _f where R _¾ is an alkvlene chain as defined above and Rf is a heteroaryl radical as defined above. Unless stated otherwise specifically in the specification, a heteroarylalkyl group may be optionally substituted.

The term "substituted" used herein means any of the above groups (i.e., alkyi, alkvlene, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and or heteroarylalkyl) wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atoms such as, but not limited to: a halogen atom such as F, CL Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, and ester groups: a sulfur atom in groups such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; a silicon atom in groups such as trialkylsilyl groups, dialkylary 1 sily 1 groups, alkyldiarylsilyl groups, and triaiylsilyl groups; and other heteroatoms in various other groups. "Substituted" also means any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g. , a double- or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles. For example, "substituted" includes any of the above groups in which one or more hydrogen atoms are replaced with -NR _¾ R _h , -NR _g C(=0)R _h , -NR _g C(=0)NR _g R _h ,

-N R,C( <)}<)¾. -NR _g SOiR _h , -OC(==0)NR _g R _h , -OR _g , -SR _g , -SOR _g , -S0 ₂ R _g , -OS0 ₂ R _g , -S0 ₂ OR _g , =NS0 ₂ R _g , and -SQ ₂ NR _g Ri,. "Substituted" also means any of the above groups in which one or more hydrogen atoms are replaced with -C(=0)R _g , -C(=0)OR _g , -CH ₂ S0 ₂ Rg, -CH ₂ S0 ₂ NR _g R _h , -(CH ₂ CH ₂ 0) _MG Rg, -(CH ₂ CH ₂ 0) ₂ _i _G Rg, -(()CH ₂ CH ₂ )i-ioRg and -(OCH ₂ CH ₂ ) ₂ -ioRg. In the foregoing, R _g and Rh are the same or different and independently hydrogen, alkyi, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl . "Substituted" further means any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyi, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cvcloalkyL cvcloalkylalkvl, haloaikyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl group. The above non-hydrogen groups are generally referred to herein as "substituents" or "non-hydrogen substituents". In addition, each of the foregoing substituents may also be optionally substituted with one or more of the above substituents.

"Prodrug" is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologicaliy active compound of the invention. Thus, the term "prodrug" refers to a metabolic precursor of a compound of the invention that is pharmaceutically acceptable. A prodrug may be inactive when administered to a subject in need thereof, but is converted in vivo to an active compound of the invention. Prodrugs are typically rapidly transformed in vivo to yield the parent compound of the invention, for example, by hydrolysis in blood. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). A discussion of prodrugs is provided in Higuchi, T., et al., A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, Ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

The term "prodrug" is also meant to include any covalently bonded carriers, which release the active compound of the invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of the invention may be prepared by modifying functional groups present in the compound of the invention in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound of the invention. Prodrugs include compounds of the invention wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the compound of the invention is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol or amide derivatives of amine functional groups in the compounds of the invention and the like.

The invention disclosed herein is also meant to encompass the in vivo metabolic products of the disclosed compounds. Such products may result from, for example, the oxidation, reduction, hydrolysis, amidation, esterification, and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the invention includes compounds produced by a process comprising administering a compound of this invention to a mammal for a period of time sufficient to yield a metabolic product thereof. Such products are typically identified by administering a radiolabelled compound of the invention in a detectable dose to an animal, such as rat, mouse, guinea pig, monkey, or to human, allowing sufficient time for metabolism, to occur, and isolating its conversion products from the urine, blood or other biological samples.

"Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

' ^" Mammal' ¹ includes humans and both domestic animals such as laboratory animals and household pets (e.g. , cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wildlife and the like.

"Optional" or "optionally" means that the subsequently described event or circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, "optionally substituted aryl" means thai the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.

"Pharmaceutically acceptable carrier, diluent or excipient" includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.

"Pharmaceutically acceptable salt" includes both acid and base addition salts. "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor- 10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecyS sulfuric acid, ethane- 1 ,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, gly colic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-l,5-disulfonic acid, naphthalene-2-sulfonic acid, 1 -hydroxy -2 -naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, '-toluenesulfonic acid, trifluoroacetic acid, undecyienic acid, and the like.

"Pharmaceutically acceptable base addition salt" refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamme, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.

Often crystallizations produce a solvate of the compound of the invention. As used herein, the term "solvate" refers to an aggregate that comprises one or more molecules of a compound of the invention with one or more molecules of solvent. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present invention may exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms. The compound of the invention may be true solvates, while in other cases, the compound of the invention may merely retain adventitious water or be a mixture of water plus some adventitious solvent.

A "pharmaceutical composition" refers to a formulation of a compound of the invention and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, e.g. , humans. Such a medium includes all pharmaceutically acceptable earners, diluents or excipients therefor.

"Effective amount" or "therapeutically effective amount" refers to that amount of a compound of the invention which, when administered to a mammal, preferably a human, is sufficient to inhibit mTOR. The amount of a compound of the invention which constitutes a "therapeutically effective amount" will vary depending on the compound, the condition and its severity, the manner of administration, and the age of the mammal to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.

"Treating" or "treatment" as used herein covers the treatment of the disease or condition of interest in a mammal, preferably a human, having the disease or condition of interest, and includes:

(i) preventing the disease or condition from occurring in a mammal, in particular, when such mammal is predisposed to the condition but has not yet been diagnosed as having it;

(li) inhibiting the disease or condition, i.e. , arresting its development;

(iii) relieving the disease or condition, i.e., causing regression of the disease or condition; or

(iv) relieving the symptoms resulting from the disease or condition, i.e. , relieving pain without addressing the underlying disease or condition. As used herein, the terms "disease" and "condition" may be used interchangeably or may be different in that the particular malady or condition may not have a known causative agent (so that etiology has not yet been worked out) and it is therefore not yet recognized as a disease but only as an undesirable condition or syndrome, wherein a more or less specific set of symptoms have been identified by clinicians. The compounds of the invention, or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomenc forms that may be defined, in terms of absolute stereochemistry, as (R)~ or (S)- or, as (D)- or (L)- for amino acids. The present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and ($)-, or (D)- and (L)~ isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefmic double bonds or other centres of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.

A "stereoisomer" refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present invention contemplates various stereoisomers and mixtures thereof and includes "enantiomers", which refers to two stereoisomers whose molecules are nonsuperimposeable mirror images of one another.

A "tautomer" refers to a proton shift from one atom of a molecule to another atom of the same molecule. The present invention includes tautomers of any said compounds.

As noted above, in one embodiment of the present invention, compound having activity as mTOR inhibitors are provided, the compounds having the following structure of Formula I:

I and pharmaceutically acceptable salts, hydrates, solvates, or stereoisomers thereof, wherein:

R ¹ is C j-ealkyl optionally substituted with one or more R ⁷ , C^-ealkenyl optionally substituted with one or more R ⁷ , C j-eaikynyl optionally substituted with one or more R ^? , N(R ³ )(R ^D ), OR ^'1 , a 3 to 8 membered carbocvclic ring optionally substituted with one or more R ', or a 3 to 8 membered heterocyclic ring optionally substituted with one or more R ⁷ ;

R ^" and R° are each independently H, Ci-ealkyl optionally substituted with one or more R', C ₂ - ₆ alkenyl optionally substituted with one or more R', C ₂ - ₆ alkynyl optionally substituted with one or more R ⁷ , a 3 to 8 membered carbocvclic ring optionally substituted with one or more R', or a 3 to 8 membered heterocyclic ring optionally substituted with one or more R ⁷ , heteroaryl optionally substituted with one or more R ⁷ , or aryl optionally substituted with one or more R , or

R ³ and R ⁶ , together with the nitrogen to which they are attached, fonn an N- heterocyclic ring containing between 3 and 8 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R ';

R' is Ci-ealkyl, Ci-ealkenyl, C ₂ - ₆ alkynyl, Ci-ghaloalkyl, halogen, -CN, oxo, -OR, -N(R) ₂ , -C(())R, -C(0)OR, ()C(())R -C(0)N(R) ₂ , -NRC(0)R

~NRC(0)N(R) _2, -OC(0) (R) ₂ , -NRC(0)OR, -S(0) ₂ R, -S(Q) ₂ N(R) ₂ , -NRS(0) ₂ R,

-( ^" : .,-.a!k> l-OK. -C ^alky!-V R) .. -Ci.. ₆ alkyl-C(0)R, -C; ..,a!kyl-C(( ⁾ )( ⁾ R.

-Ci _-6 alkyl-0-C(0)R ~C;. ₆ a!kyl-C(0)N(R) ₂ ,

-Ci-6alkyl-NRC(0)N(R) ₂ , -C _]-6 alkyi-NRC(0)OR, -Ci _-6 alkyl-0C(0)N(R) ₂ ,

-C ₁ .. ₆ alkyl-S(0) ₂ N(R) ₂ , -Ci. ₆ alkyl-NRS(0) ₂ R, aryl, o heterocyclyl:

R ² is Ci-ealkyl optionally substituted with one or more R ^l0 , C ₂ - ₆ alkenyl optionally substituted with one or more R ^llj , N(R ⁸ )(R ), a 3 to 8 membered carbocvclic ring optionally substituted with one or more R ¹⁰ , or a 3 to 8 membered heterocyclic ring optionally substituted with one or more R'°, heteroaryl optionally substituted with one or more R ¹⁰ , or aryl optionally substituted with one or more R ¹⁰ ;

R ⁵ and R ⁹ are each independently H, C _h alky 1 optionally substituted with one or more R'°, C ₂ - ₆ alkenyl optionally substituted with one or more R ⁱ⁰ , C ₂ _ ₆ alkynyl optionally substituted with one or more R ¹⁰ . a 3 to 8 membered carbocyclic ring optionally substituted with one or more R ^l0 , a 3 to 8 membered heterocyclic ring optionally substituted with one or more R'°, heteroaryl optionally substituted with one or more R ¹⁰ , or aryl optionally substituted with one or more R ¹⁰ , or R ⁸ and R ⁹ , togettier with the nitrogen to which they are attached, form an

N-heterocyclic ring containing between 3 and 8 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R ¹⁰ ;

R ^llj is Ci- ₆ alkyl, C ₂ _ ₆ alkenyl, Ci-ealkynyl, Ci-ehaloalkyl, halogen, -CN, oxo, -OR, -N(R) ₂ , -C(0)R, ··( ( O)OR. OC(0)R -C(0)N(R) ₂ , -NRC(0)R

~NRC(0) (R_) _2, ~0C(Q)N(R} ₂ , A RC (O)OR. -S(0) ₂ R, -S(0) ₂ N(R) ₂ , -NRS(G) ₂ R,

-C i-ealkyl-OR, -C i- ₆ alkyl-N(R) ₂ , -Ci- ₆ alkyl-C(0)R, -C ₁ - ₆ alky]-C(0)OR,

-Ci-6alkyl-0-C(0)R -C^alkyl-C(0)N(R) ₂ , -Ci-6alkyl-NRC(0)R, -C;- ₆ alkyl--Si0) ₂ R, -C ₁ .. ₆ alkyl-NRC(0)N(R) ₂ , -( ^' _; .,. i k ! A R( ^' { 0 ) ) R . -( ^' _: . ,a! k v ! -( )( ^' ( 0 }N ( R )...

-C ₁ . ₆ a]kyl-S(0) ₂ N(R) ₂ , -C _h alky] -NRS(0) ₂ R, aryl, or heterocyclyl ;

R ³ is H, halogen, -CN, C _h alky!, Ci-ehaloalkyi, or -OR;

R ⁴ is H, halogen, -CN, C _h alky!, ( ^•• ,.haloalk> I. -N(R) ₂ , -OR, -C(0)N(R) ₂ , ~Ci-6alky3-OR, 3 to 8 membered carbocycSic ring, or 3 to 8 membered heterocyclic ring;

A is aryl or heteroarv'l, wherein A is optionally substituted by one or more R ^{1 1} ; R ^{i J} is Ci-ealkyi, C _2-6 alkenyl, C ₂ _ ₆ alkynyl, Ci -ehaloalkyl, halogen, -CN, oxo, -OR, -N(R_) ₂ , -C(0)R, -C(0)OR, OC(0)R -C(0)N(R) ₂ , -NRC(0)R

-NRC(0)N(R) _2, -OC(0)N(R) ₂ , -NRC(0)OR, -S(0) ₂ R, -S(0) ₂ N(R) ₂ , -NRS(0) ₂ R,

-Ci-galkyl-OR, -Ci. ₆ alkyi-N(R) ₂ ,

-C]-6alkyl-0-C(0)R -Ci-6alkyl-C(0)N(R) ₂ , -i ^' ;.,,alk s i-N RC(0)R. ^•• ( ^•• .,alk> ! -SiO) .R. ~C ₁ . ₆ alky3-NR.C(0)N(R) ₂ , -C ₁ . ₆ a3kyl-NRC(0)OR, -C ₁ . ₆ alky3-0C(0)N(R) ₂ ,

-C _1-6 alky3-S(0) ₂ N(R) ₂ , -Ci_ ₆ alkyl-NRS(0) ₂ R, aryl, or heterocyclyl; and

each R is independently H, Ci-ealkyl, Ci-ehaloalkyl, 3 to 6 membered carbocyclic ring, or 3 to 6 membered heterocyclic ring.

In further embodiments, R ¹ is Ci-jalkyl optionally substituted with one or more R ⁷ , C ₂ .. ₃ alkenyl optionally substituted with one or more R ', C ₂ .. ₃ alkynyl optionally substituted with one or more R', N(R ⁵ )(R ⁶ ), OR ⁵ , a 3 to 6 membered carbocyclic ring optionally substituted with one or more R ^' ', or a 3 to 6 membered heterocyclic ring optionally substituted with one or more R' ;

R and R ⁶ are each independently H, C - >alkyi optionally substituted with one or more R ⁷ , C >. a!kein ! optionally substituted with one or more R ⁷ , Cj-nalkynyl optionally substituted with one or more R' , a 3 to 6 membered carbocyclic ring optionally substituted with one or more R', or a 3 to 6 membered heterocyclic ring optionally substituted with one or more R', heteroaryi optionally substituted with one or more R', or and optionally substituted with one or more R ⁷ , or

R ⁵ and R ^b , together with the nitrogen to which they are attached, form an N- heterocyclic ring containing between 3 and 6 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R'; and

is Ci-4alkyl, C _2- 4alkenyl, Cwhaloalkyl, -OR, -N(R) ₂ ,

-C(0)N(R) ₂ , -NRC(0)R -NRC(0)N(R) ₂ , -N R( ^' ( ⁽⁾ } ⁽⁾ ! -OC(0)N(R) ₂ ,

-Ci. ₂ alkyl-OR, -C _]-2 alkyi-N(R) ₂ , -C]- ₃ alkyi-C(0)N(R) ₂ , -Ci. ₃ alkyl-NRC(0)R, aryl, or heterocyclyl. In further embodiments, R ¹ is optionally substituted with one or more

R , C ₂ - ₃ alkenyl optionally substituted with one or more R', C ₂ . ₃ alkynyl optionally substituted with one or more R ⁷ , N(R ⁵ )(R ^t> ), OR ³ , a 4 to 6 membered carbocyclic ring optionally substituted with one or more R', or a 4 to 6 membered heterocyclic ring optionally substituted with one or more R';

R ⁵ and R ⁶ are each independently H, Ci_ ₃ alkyl optionally substituted with one or more R', C ₂ _ ₃ alkenyl optionally substituted with one or more R', C ₂ _ ₃ alkynyl optionally substituted with one or more R ⁷ , a 4 to 6 membered carbocyclic nng optionally substituted with one or more R ⁷ , or a 4 to 6 membered heterocyclic ring optionally substituted with one or more R , heteroaryi optionally substituted with one or more R', or aryl optionally substituted with one or more R', or

R ⁵ and R ⁶ , together with the nitrogen to which they are attached, form an N- heterocyclic ring containing between 4 and 6 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R'; and

R ⁷ is Ci_ ₃ alkyl, C _2-3 alkenyl, C _2-3 alkynyl, -OR, -N(R) ₂ , -C(0)N(R) ₂ , -NRC(0)R -NRC(G)N(R) _¾ ~C.. ₂ alkyl-OR, -C.. ₂ alky3-N(R) ₂ , -C _I .. ₂ alkyl-C(0) (R) ₂ ,

-Ci _-2 alkyl-NR.C(0)R, aiyl, or heterocyclyl.

In other further embodiments, R ^! is Ci-3alkyl optionally substituted with one or more R', C _2- 3alkenyl optionally substituted with one or more R', C _2- 3alkynyl optionally substituted with one or more R ⁷ , N(R ³ )(R ⁶ ), OR ¹ , a 6 membered carbocyclic ring optionally substituted with one or more R ', or a 6 membered heterocyclic ring optionally substituted with one or more R ⁷ ;

R ³ and R ^D are each independently H, C _h alky! optionally substituted with one or more R ⁷ , C _2-3 aikenyl optionally substituted with one or more R ⁷ , C _2-3 aikynyl optionally substituted with one or more R', a 5 to 6 membered carbocyclic ring optionally substituted with one or more R , or a 5 to 6 membered heterocyclic ring optionally substituted with one or more R', heteroarv'l optionally substituted with one or more R ⁷ , or aryi optionally substituted with one or more R ⁷ , or

R ⁵ and R ⁶ , together with the nitrogen to which they are attached, form an N- heteroeyclic ring containing 6 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R'; and

R ⁷ is methyl, -OR, -N(R) ₂ , -C(0)N(R) ₂ , -NRC(0)R -NRC(0)N(R) ₂ ,

-C;. ilkyi-OR. -Ci.. ₂ alkyl-N(R) ₂ , ~C ₁ . ₂ alkyl-C(0)N(R) ₂ , -(\ ,.aik> l-\ RC(0)R . aryl, or heterocyclyl.

In further embodiments, R ² is N(R ⁸ )(R ⁹ ), a 4 to 6 membered carbocyclic ring optionally substituted with one or more R ¹⁰ , or a 4 to 6 membered heterocyclic ring optionally substituted with one or more R ¹⁰ ;

R ⁸ and R ⁹ , together with the nitrogen to which they are attached, form an N- heterocyclic ring containing between 4 and 6 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R ^lC' ; and

R ^l0 is Ci_ ₆ alkyl, C ₂ „ ₆ aikenyl, C ₂ - ₆ alkynyL Ci- ₆ haloalkyL oxo, -OR, -N(R) ₂ , -C(0)N(R) ₂ , -NRC(0)R -NRC(0)N(R) _2, -OC(0)N(R) ₂ , -NRC(0)OR,

-C _1-6 alkyl-OR, -C _1-6 alkyl-N(R) ₂ , -Ci_ ₆ alkyl-C(0)N(R.) ₂ , or -C ₁ . ₆ alkyl-NRC(0)R. In other further embodiments, R ² is N(R ⁸ )(R ⁹ ), a 5 to 6 membered carbocyclic ring optionally substituted with one or more R ¹⁰ , or a 5 to 6 membered heterocyclic ring optionally substituted with one or more R ¹⁰ ;

R ⁸ and R ⁹ , together with the nitrogen to which they are attached, form an N- heterocyclic ring containing between 5 and 6 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R ^lC' ; and

R ^l0 is Ci_ ₆ alkyl, C ₂ „ ₆ aikenyl, C ₂ - ₆ aikyny3, Ci- ₆ haloalkyL oxo, -OR, -N(R) ₂ , -C(0)N(R) ₂ , -NRC(0)R -NRC(0) (R) _2i -OC(0)N(R) ₂ , ~NRC(0)OR,

-O-ealkyl-OR, -Ci- ₆ alkyl-N(R) ₂ , -Ci- ₆ alkyl-C(0)N(R) ₂ , or -C ₁ . ₆ alkyl-NRC(0)R.

In other further embodiments, R ² is N(R ⁸ )(R ⁹ ), a 6 membered carbocyclic ring optionally substituted with one or more R ¹⁰ , or 6 membered heterocyclic ring optionally substituted with one or more R ¹⁰ ;

?7 R ⁸ and R ⁹ , together with the nitrogen to winch they are attached, form an N- heterocyclic ring containing 6 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R ¹⁰ ; and

R ¹⁰ is Ci-ealkyl, C;. ₆ haloalkyl, oxo, -OR, -N(R) ₂ , -C(0)N(R) ₂ , -NRC(0)R -NRC(0)N(R)2, -OC(0)N(R) ₂ , -NRC(0)OR, ^•• ( ^' _; . _i ,aik> i- R. -C . ,.aik> l-\(R)...

-Ci-6alky3-C(0)N(R) ₂ , or -C .,,aik> !-N Ci Om

In other embodiments, R ¹⁰ is Ci-ealkyl, oxo, -OR, -N(R) ₂ .

In other embodiments, R ³ is H or halogen. In further embodiments R ³ is H or F. In still further embodiments R ³ is H. In other embodiments, R ⁴ is H, halogen, Ci ^alkyl, Ci-chaloalkyl, -OR,

-C(0)N(R) ₂ , -Ci-ealkyl-OR, 3 to 8 membered carbocyclic ring, or 3 to 8 membered heterocyclic ring. In further embodiments, R ⁴ is H, F, CI, Br, methyl, ethyl, -CH ₂ OH, -OR, or -CH ₂ OR, -C(0)N(R) ₂ . In otlier further embodiments, R ⁴ is H, F, CI, methyl, ethyl, -CH ₂ OH, CH ₂ OMe, or -OCH ₃ . In other specific embodiments, R ⁴ is H or F. In further embodiments R ⁴ is H.

As noted above, in one embodiment of the present invention, compound having activity as mTOR inhibitors are provided, the compounds having the following structure of Formula I-a:

and pharmaceutically acceptable salts, hydrates, solvates, or stereoisomers thereof, wherein:

R ³ and R ⁶ are each independently H, i ^" ;.,<.a!kyi optionally substituted with one or more R ⁷ , C ₂ - ₆ alkenyl optionally substituted with one or more R ⁷ , C ₂ - ₆ alkynyl optionally substituted with one or more R', heteroaryi optionally substituted with one or more R', or aryl optionally substituted with one or more R ⁷ , or

R ⁵ and R\ together with the nitrogen to which they are attached, form a heterocyclic ring containing between 3 and 8 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R' ;

R ⁷ is Ci-ealkyl, C _2-6 alkenyl, C _2-6 alkynyl, Ci- ₆ haloalkyl, -OR, -N(R) ₂ , -NRC(0)R ~ RC(0)N(R) ₂ . -OC(0) (R) ₂ , -NRC(0)OR, -C^alkyl-OR, -Ci- ₆ alkyl- (R) ₂ ,

-C(0)N(R) ₂ , -C;- ₆ alkyl-C(0)N(R) ₂ , aryl, or heterocyclyl;

IV and IV. together with the nitrogen to which they are attached, form a heterocyclic ring containing between 3 and 8 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R ^lC' ;

R ^: " is d_ ₄ alkyl, C ^' _: . ,haloalk> I. -OR, -N(R) ₂ , -NRC(0)R -NRC(0)N(R) _2, -OC(0)N(R) ₂ , ~NRC(G)QR, -C ,,aik U~i)R. -C ₁ - ₆ alkyl-N(R) ₂ , -C(0)N(R) ₂ ,

-C ₁ - ₆ alkyl-C(0) (R) ₂ , or -Ci- ₆ alkyl-NRC(0) ;

A is aryl or heteroaryi, wherein A is optionally substituted by one or more R ^{i J} ;

R ^u is halogen, -CN, C ₂ - ₆ alkenyl, C ₂ .. ₆ alkynyl, Ci-rJialoalkyl, oxo, -OR, -N(R) ₂ , -C(0)R, -C(0)OR, -C(0)N(R) ₂ , -NRC(0)R -NRC(0)N(R) _2,

-OC(0)N(R) ₂ , -NRC(0)OR, -S(()) ₂ R -S(0) ₂ N(R) ₂ , -NRS(0) ₂ R -Ci-ealkyl-OR,

-C, _-6 alkyl-N(R) ₂ , -Ci. ₆ aikyl-C(0)OR, -C _{] -6} alkyl-C(0)N(R) ₂ , ~C ₁ . ₆ alky3-NR.C(0)R, -C _! . ₆ alkyl-S(0) ₂ R -C ; ,,ai !-.> !-\ RS(0) . aiyl, or heterocyclyl; and

each R is independently H, Ci-ealkyl, Ci-ehaloalkyl, 3 to 6 membered carbocyclic ring, or 3 to 6 membered heterocyclic ring.

In another embodiment of Formula I or Formula I-a, A is phenyl optionally substituted by one or more R ¹ ' , benzimidazolyl optionally substituted by one or more R ^a , indolyl optionally substituted by one or more R ¹¹ , pyridiny] optionally substituted by one or more R ¹¹ , pyrimidinyl optionally substituted by one or more R ¹¹ , indazoiyl optionally substituted by one or more R ¹¹ , thiazolyl optionally substituted by one or more R ^{1 1} , imidazolyl optionally substituted by one or more R ¹ ' , pyrazolyl optionally substituted by one or more R ⁿ , triazolyl optionally substituted by one or more R ¹¹ , tetrazoiyi optionally substituted by one or more R ^{! 1} , oxazolyl optionally substituted by- one or more R ^u , furanyl optionally substituted by one or more R", thiophenyl optionally substituted by one or more R ^{1 1} , thiaziazolyl optionally substituted by one or more R ¹¹ , or pyrrolyl optionally substituted by one or more R ¹¹ . In a further embodiment, A is phenyl optionally substituted by one or more R ^u , pyridinyl optionally substituted by one or more R ^{1 !} , pyrimidinyl optionally substituted by one or more R ¹¹ , or indazolyi optionally substituted by one or more R ^{L L} .

In another embodiment of Formula I or Formula I-

In another embodiment of Formula 1 or Formula 1-a, R ² is -N(R ⁸ )(R ⁹ ) and I ^s and R ⁹ , together with the nitrogen to which they are attached, form an N-heterocyclic ring selected from the group consisting of:

wherein each N -heterocyclic ring is independently optionally substituted by one or more R

In another embodiment of Formula ΐ or Formula ΐ-a, R ² is selected from the group consisting of:

 , and

In another further embodiment of Formula 1 or Formula 1-a, R" is selected from "oup consisting of:

In another further embodiment of Formula I or Formula I-a, R~ is an optionally substituted 3 to 8 membered heterocyclic ring selected from the group consisting of:

In another embodiment of Formula I or Formula I-a, R ² is selected from the group consisting of:

In another embodiment of Formula I or Foimula I-a, R ⁷ is selected from the group consisting of:

In another embodiment of Formula I or Formula I-a, is an optionally substituted 3 to 8 membered carbocvclic ring selected from the group consisting of:

In another embodiment of Formula 1 or Formula I-a, R ^" is N(R )(R ) and R and are each independently H, i ^" _; .,<.a!kyi optionally substituted with one or more R ¹⁰ , a 3 to 8 membered carbocvclic ring optionally substituted with one or more R'°, or a 3 to 8 membered heterocyclic ring optionally substituted with one or more R'°. In a further embodiment of Formula I or Formula I-a, R ² is selected from the group consisting of:

In another embodiment of Formula I or Formula I-a, R is \(K )(R") and R and R ⁶ , together with the nitrogen to which they are attached, form an N-heterocyclic ring selected from the group consisting of:

wherein each N-heterocyclic ring is independently optionally substituted by one or more R ^llj . In a further embodiment of Formula I or Formula I-a, R ¹ is selected from the group consisting of:

wherein each N-heterocyclic ring is independently optionally substituted by one or more R ^? ,

In another further embodiment of Formula I or Formula I-a, R ¹ is selected from the group consisting of:

wherein each N-heterocyclic ring is independently optionally substituted by one or more R' _.

In anotlier embodiment of Formula I or Formula I-a, R ¹ is an optionally substituted 3 to 8 membered heterocyclic ring selected from the group consisting of:

wherein each 3 to 8 membered heterocyclic ring is independently optionally substituted by one or more R ⁷ In another embodiment of Formula 1 or Formula I-a, R ¹ is -N(R ^J )(R ^b ) and 1 ^Λ and R ⁶ are each independently H, Ci-ealkyi optionally substituted with one or more R ⁷ , or a 3 to 8 membered heterocyclic ring optionally substituted with one or more R ⁷ , wherein R ¹ is selected from the group consisting of:

o ; and In another embodiment of Formula I or Formula I-a, R ¹ is C _h alky] optionally substituted with one or more R ^? , wherein R ¹ is selected from the group consisting of:

O and

In more specific embodiments, the compound having the structure of Formula I or Formula I-a is selected from the group consisting of compounds 1 to 31.

As noted above, in one embodiment of the present invention, compound having activity as mTOR inhibitors are provided, the compounds having the following structure of Formula II:

II and pharmaceutically acceptable salts, hydrates, solvates, or stereoisomers thereof, wherein:

R ^! is C _h alky! optionally substituted with one or more R , C ₂ - ₆ alkenyl optionally substituted with one or more R', Ci-ealkynyl optionally substituted with one or more R', N(R ³ )(R ⁶ ), OR ⁵ , a 3 to 8 membered carbocyclic ring optionally substituted with one or more R', or a 3 to 8 membered heterocyclic ring optionally substituted with one or more R ⁷ :

R ⁵ and R ⁶ are each independently H, Ci-ealkyl optionally substituted with one or more R , C ₂ - ₆ aikenyl optionally substituted with one or more R , C ₂ _ ₆ aikynyl optionally substituted with one or more R ⁷ , a 3 to 8 membered carbocyclic ring optionally substituted with one or more R ⁷ , or a 3 to 8 membered heterocyclic ring optionally substituted with one or more R , heteroaryl optionally substituted with one or more R' , or aryl optionally substituted with one or more R', or

R ⁵ and R ⁶ , together with the nitrogen to which they are attached, form an N- heterocyclic ring containing between 3 and 8 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R ' ;

R ⁷ is Cj-eaikyl, Cj-ealkenyl, Ca-ealkynyl, Ci-ehaloalkyi, halogen, -CN, oxo, -OR, ~N(R) ₂ , -C(0)R, -C(())()R . OC(0)R -C(0)N(R) ₂ , -NRC(0)R

~ RC(0)N(R) ₂ . ~OC(0) (R) ₂ , -NRC(0)OR, -S(0) ₂ R, -S(0) ₂ N(R) ₂ , -NRS(0) ₂ R, -Ci-ealkyl-OR, -Ci alkyl-N(R) ₂ , -Ci-6alkyl-C(0)R, -Ci-6alkyl-C(0)OR,

-( ^• ;.,a!k> i-0-C(0)K -C . ,,aik> l-C(0)N( R ) .- -Ci-6alkyl-S(0) ₂ R, -Ci _-6 a]ky3-NRC(0)N(R) ₂ , -C _1-6 alkyl-NRC(0)OR, -Ci _-6 a]kyl-OC(0)N(R) ₂ ,

-Ci- ₆ alkyl-S(0) ₂ N(R) ₂ , -C;. ₆ alkyl-NRS(0) ₂ R, aryl, or heterocyclyl;

R ² is Ci-ealkyl optionally substituted with one or more R ¹⁰ , C _2-6 aikenyl optionally substituted with one or more R'°, N(R ^S )(R ⁹ ), a 3 to 8 membered carbocyclic ring optionally substituted with one or more R ¹⁰ , or a 3 to 8 membered heterocyclic ring optionally substituted with one or more R ^lC" , heteroaryl optionally substituted with one or more R ¹⁰ , or aryl optionally substituted with one or more R ^{! 0} ;

R ⁸ and R ⁹ are each independently H, Ci-ealkyl optionally substituted with one or more R ^l0 , C _2-6 alkenyl optionally substituted with one or more R'°, C ₂ _ealkynyl optionally substituted with one or more R ^! ", a 3 to 8 membered carbocyclic ring optionally substituted with one or more R ⁱ⁰ , a 3 to 8 membered heterocyclic ring optionally substituted with one or more R ^lC' , heteroaryl optionally substituted with one or more R ¹⁰ , or aryl optionally substituted with one or more R ^K ', or

R ⁸ and R ⁹ , together with the nitrogen to winch they are attached, form an N- heterocyclic ring containing between 3 and 8 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R'";

R'° is Ci-eaikyi, C _2-6 alkenyl, C _2-6 alkynyl, Ci-ehaloalkyl, halogen, -CN, oxo, -OR, ( !<)... -C(0)R, -C(())()R . OC(0)R -C(0)N(R) ₂ , -NRC(0)R _, -NRC(0)N(R) _2, -OC(0)N(R) ₂ , -NRC(Q)QR, -SiO hR. -S(0) ₂ N(R) ₂ , -NRS(0) >R.

-( ^• ;.,a!k> i-OR. -C ₁ .. ₆ alkyl- (R) ₂ , -C; .,-.a!k> l-C(G)R. -Ci.. ₆ alkyl-C(0)OR,

-Ci _-6 a]ky3-0-C(0)R -C _! _ ₆ alkyl-C(0)N(R) ₂ , -d^alkyl-NRC(0)R, -Ci. ₆ alkyl-S(0) ₂ R, -Ci_ ₆ alkyl-NRC(0)N(R) ₂ , -C _1-6 alkyl-NRC(0)OR, -d-ealkyl-OC(0)N(R) ₂ ,

~d. ₆ alky3-S(0) ₂ N(R) ₂ , -Ci.. ₆ aikyl-NRS(G) ₂ R, aryl or heterocyciyl;

R ³ is H, halogen, -CN, d-ealkyl, d-ehaloalkyl, or -OR;

R ⁴ is H, halogen, -CN, d-ealkyl, d-ehaloalkyl, -N(R) ₂ , -OR, -C(0)N(R) ₂ , -Ci-ealkyl-OR, 3 io 8 membered carbocyclic ring, or 3 to 8 membered heterocyclic ring:

A is aryl or heteroaryl, wherein A is optionally substituted by one or more R ¹¹ ; R ¹¹ is d-ealkyl, d-ealkenyl, d-ealkynyl, d-ehaloalkyl, halogen, -CN, oxo, -OR, -N(R) ₂ , -C(())R, -C(0)OR, ()C(())R -C(0)N(R) ₂ , -NRC(0)R

-NRC(0)N(R) _2, -OC(0)N(R) ₂ , -NRC(0)OR, -S(0) ₂ R, -S(0) ₂ N(R) ₂ , -NRS(0) ₂ R,

-d-ealkyl-OR, -C _; . _f .a!kyi-\( R) .. -C .,.alk> !-C(0)R . -d-6alkyl-C(0)OR,

-d-6alkyl-0-C(0)R -Ci-ealkyl -C(0)N(R) ₂ , -Ci- ₆ alkyl-NRC(0)R, -d- ₆ alkyl-S(0) ₂ R, -d-ealkyl-NRC(0)N(R) ₂ , -d _-6 alkyi-NRC(0)OR, -d-ealkyl-OC(0)N(R) ₂ ,

-d-ealkyl-S(0) ₂ N(R) ₂ , ~d. ₆ alkyl-NRSiO) ₂ R, aryl, or heterocyciyl: and

each R is independently H, d-ealkyl, d-ehaloalkyl, 3 to 6 membered carbocyclic ring, or 3 to 6 membered heterocyclic ring.

In further embodiments, R ^! is d^alkyl optionally substituted with one or more R', Cj-nalkenyl optionally substituted with one or more R', d-salkynyl optionally substituted with one or more R ^? , N(R ³ )(R ^D ), OR ³ , a 3 to 6 membered carbocyclic ring optionally substituted with one or more R', or a 3 to 6 membered heterocyclic ring optionally substituted with one or more R';

R ⁵ and R ⁶ are each independently H, C _h alky! optionally substituted with one or more R', d-salkenyl optionally substituted with one or more R', d-salkynyl optionally substituted with one or more R', a 3 to 6 membered carbocyclic ring optionally substituted with one or more R ⁷ , or a 3 to 6 membered heterocyclic ring optionally substituted with one or more R', heteroaryl optionally substituted with one or more R', or aryl optionally substituted with one or more R', or

R ⁵ and R ⁶ , together with the nitrogen to which they are attached, form an N- heterocyclic ring containing between 3 and 6 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R'; and

R is Ci-ealkyl, C ₂ ^alkenyl, C ₂ -»alkynyl, Ci. ₄ haloalkyl, -OR, ~N(R) ₂ , -C(0)N(R) ₂ , -NRC(0)R -S RC( 0)N( R ) . - \ Ri (O sOR. -OC(0)N(R) ₂ , -i _: . ,a!k> i- OR . -C ₁ . ₂ a3kyl-N(R) ₂ , -C ₁ .3alky3-C(0)N(R) ₂ , -C _: . :a!ky!-N RC(0)R. :uy k or lieterocyciyl.

In further embodiments, R ¹ is C _h alky! optionally substituted with one or more R', C ₂ -3aikenyl optionally substituted with one or more R', C ₂ -3alkynyl optionally substituted with one or more R' , N(R ⁵ )(R ^t '), OR ³ , a 4 to 6 mem be red carbocyclic ring optionally substituted with one or more R ', or a 4 to 6 membered heterocyclic ring optionally substituted with one or more R ⁷ ;

R and R ^" are each independently H, ( ^' ;. -.all-.} i optionally substituted with one or more R', C _2-3 alkenyl optionally substituted with one or more R', C _2-3 alkynyl optionally substituted with one or more R ^? , a 4 to 6 membered carbocyclic ring optionally substituted with one or more R' , or a 4 to 6 membered heterocyclic ring optionally substituted with one or more R , heteroaryl optionally substituted with one or more R', or aryl optionally substituted with one or more R ', or

R ⁵ and R ⁶ , together with the nitrogen to winch they are attached, form an N- heterocyclic ring containing between 4 and 6 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R'; and

R ⁷ is C _M alkyl, C _2-3 alkenyl, C _2-3 alkynyl, -OR, -N(R) ₂ , -C(0)N(R) ₂ , -NRC(0)R ~NRC(0)N(R)2, ^•• ( ^'• . ^• aiky! -OR. ^• ( ^'• . ^• alky! -Ni R ; .. -C ₁ _ ₂ aikyl~C(0)N(R)2,

~Ci. ₂ alky3-NR.C(0)R, aryl, or heterocyclyl.

In other further embodiments, R ¹ is optionally substituted with one or more R ⁷ , C ₂ .. ₃ aikenyl optionally substituted with one or more R ⁷ , C ₂ .. ₃ aikynyl optionally substituted with one or more R ⁷ , N(R ⁵ )(R ^t> ), OR ³ , a 6 membered carbocyclic ring optionally substituted with one or more R ⁷ , or a 6 membered heterocyclic ring optionally substituted with one or more R' :

R and R ⁶ are each independently H, ( ^" i . ^lkyi optionally substituted with one or more R ⁷ , C ₂ _ ₃ alkenyl optionally substituted with one or more R ⁷ , C ₂ _ ₃ alkynyl optionally substituted with one or more R', a 5 to 6 membered carbocyclic ring optionally substituted with one or more R', or a 5 to 6 membered heterocyclic ring optionally substituted with one or more R', heteroaryl optionally substituted with one or more R ⁷ , or aryl optionally substituted with one or more R ⁷ , or

R ⁵ and R ^D , together with the nitrogen to which they are attached, form an N- heterocyclic ring containing 6 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R'; and R. is methyl, -OR, -N(R) ₂ , -C(0)N< R ) .. -NRC(0)R -NRC(0)N(R) _2,

-C;. i!kyi-OR. -C _: ,.a!k> !-\( R) .. ~C ₁ . ₂ alkyl-C(0)N(R) ₂ , -(\ ,.aik> l-\ RC(0)R . aryl, or heterocyclyl.

In further embodiments, R ² is N(R ⁸ )(R ⁹ ), a 4 to 6 membered carbocyclic ring optionally substituted with one or more R ¹⁰ , or a 4 to 6 membered heterocyclic ring optionally substituted with one or more R ¹⁰ ;

R ⁸ and R ⁹ , together with the nitrogen to which they are attached, form an N- heterocyclic ring containing between 4 and 6 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R'"; and

R ⁱ⁰ is Ci- ₆ alkyl, C ₂ . ₆ alkenyl, C _2-6 alkynyl, Ci. ₆ haloalkyl, oxo, -OR, -N(R) ₂ ,

-C(0)N(R) ₂ , -NRC(0)R -NRC(0)N(R) _2, -OC(0)N(R) ₂ , -NRC(Q)QR,

-( ^" : .,-.a!k> l-OK. ~C ₁ . ₆ alkyl-N(R) ₂ , -Ci- ₆ alkyl-C(0)N(R) ₂ , or -( ^•• ..,aikyl-\ RC(0)R.

In other further embodiments, R ² is N(R )(R ⁹ ), a 5 to 6 membered carbocyclic ring optionally substituted with one or more R ¹⁰ , or a 5 to 6 membered heterocyclic ring optionally substituted with one or more R ¹⁰ ;

R ⁸ and R ⁹ , together with the nitrogen to which they are attached, form an N- heterocyclic ring containing between 5 and 6 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R ^" : and

R ⁱ⁰ is Ci- ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ - ₆ alkynyl, Ci- ₆ haloalkyl, oxo, -OR, -N(R) ₂ , -C(0)N(R) ₂ , -NRC(())R -NRC(0)N(R) _2, -OC(0)N(R) ₂ , -NRC(0)OR,

-( ^• ;.,alk> i-OR. -C ₁ .. ₆ alkyl- (R) ₂ , -C ₁ . ₆ alkyl-C(0)N(R) ₂ , or -C _I .. ₆ aikyl~NRC(0)R,

In other further embodiments, R ² is N(R°)(R ⁹ ), a 6 membered carbocyclic ring optionally substituted with one or more R ¹⁰ , or 6 membered heterocyclic ring optionally substituted with one or more R ¹⁰ ;

R ⁸ and R ⁹ , together with the nitrogen to which they are attached, form an N- heterocyclic ring containing 6 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R ¹⁰ ; and

R ⁱ⁰ is Ci- ₆ alkyl, d-ehaloalkyl, oxo, -OR, -N(R) ₂ , -C(0)N(R) ₂ , -NRC(0)R -NRC(0)N(R) ₂ , -OC(0)N(R) _¾ -NRC(0)OR, -Ci-ealkyl-OR, -Ci- ₆ alkyl-N(R) ₂ ,

-C]-6alkyl-C(0)N(R) ₂ . or -Ci-6alkyl-NRC(0)R.

In other embodiments, R ¹ " is C _h alky!, oxo, -OR, -N(R) ₂ . In other embodiments, R ³ is H or halogen. In further embodiments R' is H or F. In still further embodiments R' is H.

In other embodiments, R ⁴ is H, halogen, Ci -eaikyl, Ci-ehaloaikyl, -OR,

-C(0)N(R) ₂ , -Ci-eaikyl-OR, 3 to 8 membered carbocyclic ring, or 3 to 8 membered heterocyclic ring. In further embodiments, R ⁴ is H, F, CI, Br, methyl, ethyl, ( I i Ό! i. -OR, or -CH ₂ OR, -C(0)N(R) ₂ . In other further embodiments, R ⁴ is H, F, CI, methyl, ethyl, -CH ₂ OH, CH ₂ OMe, or -OCH3. In other specific embodiments, R ⁴ is H or F. In further embodiments R ¹ is H.

As noted above, in one embodiment of the present invention, compound having activity as mTOR inhibitors are provided, the compounds having the following structure of Formula Il-a:

and pharmaceutically acceptable salts, hydrates, solvates, or stereoisomers thereof, whe rein :

R ³ and R ⁶ are each independently H, Ci-ealkyl optionally substituted with one or more R ⁷ , Ci-ealkenyl optionally substituted with one or more R ⁷ , Ci-ealkynyl optionally substituted with one or more R', heteroaryi optionally substituted with one or more R', or and optionally substituted with one or more R ⁷ , or

R ⁵ and R ⁶ , together with the nitrogen to which they are attached, form a heterocyclic ring containing between 3 and 8 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R' ;

R ⁷ is Ci-ealkyl, C _2-6 alkenyl, C _2-6 a]kyny], C _1-6 haloalky], -OR, ~N(R) ₂ , -NRC(0)R -NRC(0)N(R) _2. -OC(0)N(R) ₂ , -NRC(0)OR, -C^alkyl-OR, -Ci- ₆ aikyl-N(R) ₂ ,

-C(0)N(R) ₂ , -Ci.. ₆ aikyl~C(0)N(R)2, -Ci.. ₆ alkyl"NRC(0)R, aiyl, or heterocyclyl; R ⁸ and R ⁹ , together with the nitrogen to which they are attached, form a heterocyclic ring containing between 3 and 8 ring atoms, wherein the heterocyclic ring is optionally substituted with one or more R'";

R ¹⁰ is Ci. ₄ alkyl, C^haloalkyl, -OR, -N(R) ₂ , -NRC(0)R -NRC(0)N(R) _2,

-OC(0)N(R) ₂ , -NRC(0)OR, -Ci.. ₆ aikyl~OR, -C _{: ;} ,aik> 1 -N{R) ··. -C(0)N(R) ₂ ,

-Ci- ₆ alky3-C(0)N(R) ₂ , or -C . _; ,alk U-\ C(0)K ;

A is aryl or heteroaiyl, wherein A is optionally substituted by one or more R ¹¹ ;

R ^{i J} is halogen, -CN, Cj-ealkyl, C^alkenyi, C ₂ _ ₆ alkynyl, Ci-ehaloalkyi, oxo, -OR, -N(R) ₂ , -C(0)R, -( (O)OR. -C(0)N(R) ₂ , -NRC(0)R -NRC(0)N(R) _2, -OC(0)N(R) ₂ , -NRC(0)OR, -S(0) ₂ R, -S(0) ₂ N(R) ₂ , -NRS(0) ₂ R -Ci_ ₆ alkyl-OR, -Ci- ₆ alkyl-N(R) ₂ ,

-C _)-6 aikyl-NRC(0)R, -C ₁ . ₆ aikyl-S(0) ₂ R, -Ci _-6 alkyl~NRS(0) ₂ R aryl, or heterocyclyl; and

each R is independently H, Ci-ealkyl, Ci-ehaloalkyl, 3 to 6 membered carbocyclic ring, or 3 to 6 membered heterocyclic ring.

In another embodiment of Formula II or Fonnula I-a, A is phenyl optionally- substituted by one or more R ⁿ , benzimidazolyl optionally substituted by one or more R' ¹ , indoiyi optionally substituted by one or more R ¹¹ , pyridinyl optionally substituted by one or more R ¹¹ , pyrimidinyl optionally substituted by one or more R ¹¹ , indazolyl optionally substituted by one or more R ^{1 !} , thiazolyl optionally substituted by one or more R ¹¹ , imidazolyl optionally substituted by one or more R ⁿ , pyrazolyl optionally substituted by one or more R ^u , triazolyl optionally substituted by one or more R ¹ ', tetrazolyl optionally substituted by one or more R ^a , oxazolyl optionally substituted by one or more R ¹¹ , furanyl optionally substituted by one or more R ¹¹ , thiophenyl optionally substituted by one or more R", thiaziazoiyl optionally substituted by one or more R ^{1 1} , or pyrrolyl optionally substituted by one or more R". In a further embodiment, A is phenyl optionally substituted by one or more R ^{1 !} , pyridinyl optionally substituted by one or more R ¹¹ , pyrimidinyl optionally substituted by one or more R ^{i !} , or indazolyl optionally substituted by one or more R".

In another embodiment of Formula II or Fonnula I-a, A is:

In another embodiment of Formula II or Formula Il-a, R ² is -N(R ⁸ )(R ⁹ ) and R ⁸ and R ⁹ , together with the nitrogen to which they are attached, form an N-heterocyclic ring selected from the group consisting of:

, and wherein each N-heterocyclic ring is independently optionally substituted by one

10

or more R.

In another embodiment of Formula II or Formula Il-a, R ^" is selected from the group consisting of:

53



In another further embodiment of Formula II or Formula II- a. R is selected from the group consisting of:

In another further embodiment of Formula II or Formula Il-a, R" is an optionally substituted 3 to 8 membered heterocyclic ring selected from the group consisting of:



In another embodiment of Formula II or Formula Il-a, R is selected from the group consisting of:

In another embodiment of Formula II or Formula Il-a, R ^" is an optionally substituted 3 to 8 membered carbocyclic ring selected from the group consisting of:

In another embodiment of Formula II or Formula Il-a, R ² is N(R ⁸ )(R ⁹ ) and R ⁸ and R ⁹ are each independently H, C _h alky! optionally substituted with one or more R ^l0 , a 3 to 8 membered carbocyclic ring optionally substituted with one or more R'°, or a 3 to 8 membered heterocyclic ring optionally substituted with one or more R ¹⁰ . In a further embodiment of Formula II or Formula Il-a, R ² is selected from the group consisting of:

In another embodiment of Formula II or Formula ll-a, R ^J is -N(R ⁵ )(R ⁶ ) and R and R° ^' ,, ttooggeetthheerr wwiitthh tthhee nniittrrooggeenn ttoo wwhhkich they are attached, form an N-heterocyclic ring selected from the group consisting of:

wherein each N -heterocyclic ring is independently optionally substituted by one or snore R'° In a further embodiment of Formula II or Formula Il-a, R ¹ is selected from, th

wherein each N -heterocyclic ring is independently optionally substituted by one or more R' _.

In another further embodiment of Formula 11 or Formula Il-a, R ^! is selected from the group consisting of:

wherein each N-heterocyciic ring is independently optionally substituted by one or more R' _.

In another embodiment of Formula II or Formula Il-a, R ¹ is an optionally substituted 3 to 8 mernbered heterocyclic ring selected from the group consisting of:

wherein each 3 to 8 mernbered heterocyclic ring is independently optionally substituted by one or more R ⁷ _.

In another embodiment of Formula II or Formula Il-a, R ¹ is N( ^'" )( K ^i- ) and R ⁵ and R ⁶ are each independently H, Cj-ealkyl optionally substituted with one or more R ⁷ , or a 3 to 8 mernbered heterocyclic ring optionally substituted with one or more R ^? , wherein R ¹ is selected from the group consisting of:

o ; and

In another embodiment of Formula II or Formula Il-a, ¹ is Cj-ealkyl optionally substituted with one or more R ⁷ , wherein R ^! is selected from the group consisting of:

In more specific embodiments, the compound having the structure of Formula II or Formula Il-a is selected from the group consisting of compounds 32 to 39.

It is understood that any embodiment of the compounds having the structure of

Formula I, I-a, II, or Il-a, as set forth above, and any specific substituent set forth herein for a A, R', R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , or R ^{! 1} group in the compounds of structure I, I-a, II, or II -a, respectively, as set forth above, may be independently- combined with oilier embodiments and/or substituents of compounds of structure I, I-a, II, or Il-a, respectively, to form embodiments of the inventions not specifically set forth above. In addition, in the event that a list of substituents is listed for any particular substituent in a particular embodiment and/or claim, it is understood that each individual substituent may be deleted from the particular embodiment and/or claim and that the remaining list of substituents will be considered to be within the scope of the invention.

Pharmaceutical Compositions and Methods of Treatment

For the purposes of administration, the compounds of the present invention may be administered to a patient or subject as a raw chemical or may be formulated as pharmaceutical compositions. Pharmaceutical compositions of the present invention generally comprise a compound of the invention and a pharmaceutically acceptable carrier, diluent or excipient. The compound is present in the composition in an amount which is effective to treat a particular disease or condition of interest, as described herein, and preferably with acceptable toxicity to the patient. The activity of compounds can be determined by one skilled in the art, for example, as described in the Example below. Appropriate concentrations and dosages can be readily determined by one skilled in the art.

In another embodiment, a pharmaceutical composition is provided comprising a compound having the structure of Formula I, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier, diluent or excipient. In another embodiment, a pharmaceutical composition is provided comprising a compound having the structure of Formula I-a, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier, diluent or excipient. In another embodiment, a pharmaceutical composition is provided comprising a compound having the structure of Formula IT, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier, diluent or excipient. In another embodiment, a pharmaceutical composition is provided comprising a compound having the structure of Formula Tl-a, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier, diluent or excipient. In further embodiments, the pharmaceutical composition further comprises one or more additional biologically active agents. In more specific embodiments, the additionally biologically active agents is selected from the group consisting of anticancer drugs; cyctotoxins, cell cycle arresting drags; and cytostatic drags, or a combination of these agents. In other embodiments, the one or more additional biologically active agents is selected from, the group consisting of antiviral drugs; DNA gyrase inhibitors, protease inhibitors, polymerase inhibitors, or a combination of these agents. In other embodiments, the one or more additional biologically active agents is selected from the group consisting of immunomodulator drugs; interferon, steroid, cox inhibitor, or a combination of these agents.

In another embodiment, a method of inhibiting mTOR in a warm-blooded animal is provided, comprising administering to the animal an effective amount of a compound having the structure of Formula I, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound. In another embodiment, a method of inhibiting mTOR in a warm-blooded animal is provided, comprising administering to the animal an effective amount of a compound having the structure of Formula I-a, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound. In another embodiment, a method of inhibiting mTOR in a warm-blooded animal is provided, comprising administering to the animai an effective amount of a compound having the structure of Formula II, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound. In another embodiment, a method of inhibiting mTOR in a warm-blooded animai is provided, comprising administering to the animal an effective amount of a compound having the stracture of Formula Il-a, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound.

In another embodiment, a method of treating a disease state associated with dysregulation of the mTOR pathway is provided, comprising administering to the animal an effective amount of a compound having the structure of Formula I, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound. In another embodiment, a method of treating a disease state associated with dysregulation of the mTOR pathway is provided, comprising administering to the animal an effective amount of a compound having the structure of Formula I-a, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound. In another embodiment, a method of treating a disease state associated with dysregulation of the mTOR pathway is provided, comprising administering to the animal an effective amount of a compound having the stracture of Formula II, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound. In another embodiment, a method of treating a disease state associated with dysregulation of the mTOR pathway is provided, comprising administering to the animal an effective amount of a compound having the stracture of Formula Il-a, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound.

In a further embodiment, the disease state associated with dysregulation of the mTOR pathway is selected from the group consisting of autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, infection, antiviral, antibacterial, vaccine adjuvant, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplantation rejection, graft rejection and lung injuries.

In a further embodiment, the disease state associated with dysregulation of the mTOR pathway is a viral infection. In one embodiment, the viral infection is by a virus from the herpesviridae family of viruses. In one embodiment the viral infection is by a herpesviridae viras selected from the group consisting of herpes simplex viras (HSV) types 1 and 2, varicella-zoster virus, cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus 6 (variants A and B), human herpesvirus 7, human herpesvirus 8 (Kaposi's sarcoma - associated herpesvirus, KSHV), and cercopithecine herpesvirus 1 (B virus). In one embodiment the viral infection is by a virus selected from human cytomegalovirus and herpes simplex virus- 1.

In one embodiment, the viral infection is by a virus from the paramyxovindae family of viruses. In one embodiment, the viral infection is by a paramyxoviridae viras selected from the group consisting of Respiratory syncytial viras (RSV), mumps, measles, human parainfluenza viruses such as Parainfluenza Virus Type 3 (PIV3), Human metapneumovirus, Hendra viras (HeV), Nipah viras ( iV), and Cedar Virus.

In one embodiment, the viral infection is by a viras from the picornaviridae family of viruses. In one embodiment, the viral infection is by a picornaviridae viras selected from the group consisting of Human rhino vims 16 (HRV-16), Human enterovirus. Hepatitis A viras, Coxsackie virus (including type A24 variant CA24v), Echovims, and Poliovirus.

In one embodiment, the viral infection is by a virus from the orthomyxoviridae family of viruses. In one embodiment, the viral infection is by a orthomyxoviridae vims selected from the group consisting of Avian influenza (pathogenic strain (H5N1)), and Swine influenza including influenza C and the subtypes of influenza A known as HlNl , H1N2, H2N1, H3N1 , H3N2, and H2N3.

In one embodiment, the viral infection is by a viras from the retroviridae family of viruses. In one embodiment, the viral infection is by a retroviridae viras selected from the group consisting of human immunodeficiency virus (HTV-1).

In one embodiment, the viral infection is by a virus from the papiliomaviridae family of viruses. In one embodiment, the viral infection is by a papiliomaviridae viras selected from the group consisting of human papillomavirus (HPV).

In one embodiment, the viral infection is by a vims from the adenoviridae family of viruses. In one embodiment, the viral infection is by a adenoviridae viras selected from the group consisting of human adenovirus (Adenovirus serotype 14.)

In one embodiment, the viral infection is by a viras from the poxviridae family of viruses. In one embodiment, the viral infection is by a poxviridae viras selected from the group consisting of Human orthopoxviruses, Monkeypox viras, Variola (VARV), including smallpox (Variola major virus) and Alastrim (Variola minor vims)), Cowpox (CPX), and Vaccinia (VACV or VV) vimses.

In one embodiment, the viral infection is by a vims from the polyomaviridae family of vimses.

In one embodiment, the viral infection is by a vims causing viral hemorrhagic fever. In one embodiment, the vims causing viral hemorrhagic fever is selected from the group consisting of arenaviruses, filoviruses, bunyaviruses, and flaviviruses including Bundibugyo virus (BDBV), Sudan vims (SUDV), Tai ^' Forest vims (TAFV) and Ebola vims (EBOV, formerly Zaire Ebola vims), Marburg, Lassa, Crimean-Congo, Seoul viruses, Lassa fever vims, Lujo vims and Argentine hemorrhagic fever. In one embodiment, the virus causing viral hemorrhagic fever is a South American Haemorrhagic Fever vims selected from the group consisting of Chapare, Guananto, Junin, Machupo, Sabia, Hantaviras hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS).

In one embodiment, the viral infection is by a virus from the flaviviridae family of vimses. In one embodiment, the viral infection is by a flaviviridae vims selected from the group consisting of Yellow fever, tick-borne encephalitis virus (TBEV), Kyasanur Forest disease virus, Omsk hemorrhagic fever vims, hepatitis B vims (HBV), hepatitis C vims (HCV), Dengue vimses (DEN-1, DEN-2, DEN- 3 and DEN-4), West Nile vims.

In one embodiment, the viral infection is by a vims from the togaviridae family of vimses. In one embodiment, the viral infection is by a togaviridae vims selected from the group consisting of Eastern. Equine Encephalitis vims, Venezuelan equine encephalitis vims, Western equine encephalitis vims, zoonotic alphaviruses (Chikungunya virus, Semiiki Forest virus complex), and arbovirus.

In one embodiment, the viral infection is by a virus from the coronavindae family of vimses. In one embodiment, the viral infection is by a eoronaviridae vims selected from the group consisting of a SARS-associated coronavirus (SARS-CoV) and MERS (Middle East Respiratory Syndrome, MERS-CoV).

In one embodiment, the viral infection is by a virus from the bunyaviridae family of vimses. In one embodiment, the viral infection is by a bunyaviridae vims selected from the group consisting of Rift Valley fever. In another embodiment, the compounds of the present invention can be administered in combination with other antiviral drags, antiviral treatments, vaccines, or supportive, prophylactic or preventative measures.

In a further embodiment, the disease state associated with dysregulation of the mTOR pathway is associated with immunomodulation. In one embodiment, the immunomodulation is selected from the group consisting of immunosuppression, regulation of immune cells, including neutrophils, mast cells, natural killer cells, γδ T cells, macrophages, dendritic cells (DCs), T cells, and B cells. In one embodiment, the method of treating immunomodulation is associated with the reduction of inflammatory cytokine signaling, such as through the activation of the TLR pathways. In one embodiment, the method of treating immunomodulation is associated with the reduction of NF-KB, IF -a and -β and increasing of IL-10 and IL-12. In one embodiment, the method of treating immunomodulation is associated with the immunosuppressive treatment of solid and bone marrow transplantation, hematopoietic stem cell transplantation, organ transplantation, cell transplantation (e.g. islet grafts) and treatment of autoimmune disease. In one embodiment, the method of treating immunomodulation is associated with the improvement of memor ' T cell generation and enhanced vaccine responses.

In another embodiment, a method of treating cancer in a warm-blooded animal in need thereof is provided, comprising administering to the animal an effective amount of a compound having the structure of Formula I, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound. In another embodiment, a method of treating cancer in a warm-blooded animal in need thereof is provided, comprising administering to the animal an effective amount of a compound having the structure of Formula I-a, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound. In another embodiment, a method of treating cancer in a warm-blooded animal in need thereof is provided, comprising administering to the animal an effective amount of a compound having the structure of Formula II, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound. In another embodiment, a method of treating cancer in a warm-blooded animal in need thereof is provided, comprising administering to the animal an effective amount of a compound having the structure of Formula Il-a, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound.

In a further embodiment, the cancer is associated with dysregulation of the PI3K pathway. In another further embodiment, the cancer is selected from the group consisting of breast cancer; antle ceil lymphoma; renal cell carcinoma; acute myelogenous leukemia (AML); chronic myelogenous leukemia (CML); diffuse large B cell lymphoma (DLBCL); sarcoma; rhabdomyosarcoma; ovarian cancer; endometrial tumors; non small cell lung carcinoma (NSCLC); small cell, squamous, large cell and adenocarcinoma; lung cancer; colon cancer; colorectal tumors; KRAS-mutated colorectal tumors; gastric carcinomas; hepatocellular tumors; liver tumors; primary melanomas; pancreatic tumors; prostate carcinoma; thyroid carcinoma; follicular thyroid carcinoma; anaplastic large cell lymphoma (ALCL); hamaratomas, angiomyeloiipomas, TSC-associated and sporadic iymphangioleiomyomatosis: Cowden's disease (multiple hamaratoma syndrome); sclerosing hemangioma; Peutz- Jeghers syndrome (PJS); head and neck cancer; neurofibromatosis; macular degeneration; macular edema; myeloid leukemia; systemic lupus; and autoimmune iymphoproliferative syndrome (ALPS).

In another embodiment, a method of treating or preventing a respiratory virus infection in a warm-blooded animal in need thereof is provided, comprising administering to the animal an effective amount of a compound having the staicture of Formula I, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound. In another embodiment, a method of treating or preventing a respiratory virus infection in a warm-blooded animal in need thereof is provided, comprising administering to the animal an effective amount of a compound having the structure of Formula I -a, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound. In another embodiment, a method of treating or preventing a respiratory virus infection in a warm-blooded animal in need thereof is provided, comprising administering to the animal an effective amount of a compound having the structure of Formula II, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound. In another embodiment, a method of treating or preventing a respiratory virus infection in a warm-blooded animal in need thereof is provided, comprising administering to the animal an effective amount of a compound having the structure of Formula II-a, or a stereoisomer, pharmaceutically acceptabie sait or prodrug thereof, or a pharmaceutical composition comprising such compound.

In another embodiment, a method of treating or preventing inflammation in a warm-blooded animal in need thereof is provided, comprising administering to the animal an effective amount of a compound having the structure of Formula I, or a stereoisomer, pharmaceutically acceptabie salt or prodrug thereof, or a pharmaceutical composition comprising such compound. In another embodiment a method of treating or preventing inflammation in a warm-blooded animal in need thereof is provided, comprising administering to the animal an effective amount of a compound having the structure of Formula I-a, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound. In another embodiment, a method of treating or preventing inflammation in a warm-blooded animal in need thereof is provided, comprising administering to the animal an effective amount of a compound having the structure of Formula II, or a stereoisomer, pharmaceutically acceptabie sait or prodrug thereof, or a pharmaceutical composition comprising such compound. In another embodiment, a method of treating or preventing inflammation i a warm-blooded animal in need thereof is provided, comprising administering to the animal an effective amount of a compound having the structure of Formula Il-a, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising such compound.

Administration of the compounds of the invention, or their pharmaceutically acceptabie salts, in pure form or in an appropriate pharmaceutical composition, can be carried out via any of the accepted m odes of adm inistration of agents for serving similar utilities. The pharmaceutical compositions of the invention can be prepared by combining a compound of the invention with an appropriate pharmaceutically acceptable carrier, diluent or excipient, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols. Typical routes of administering such pharmaceutical compositions include, without limitation, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal, and intranasal. The term, parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. Pharmaceutical compositions of the invention are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient. Compositions that will be administered to a subject or patient take the form of one or more dosage units, where for example, a tablet may be a single dosage unit, and a container of a compound of the invention in aerosol form may hold a plurality of dosage units. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy and Science, 2000). The composition to be administered will, in any event, contain a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, for treatment of a disease or condition of interest in accordance with the teachings of this invention.

A pharmaceutical composition of the invention may be in the form of a solid or liquid. In one aspect, the carner(s) are particulate, so that the compositions are, for example, in tablet or powder form.. The carrier(s) may be liquid, with the compositions being, for example, an oral symp, injectable liquid or an aerosol, which is useful in, for example, mhaiatory administration.

When intended for oral administration, the pharmaceutical composition is preferably in either solid or liquid form, where semi-solid, semi-liquid, suspension and gel forms are included within the forms considered herein as either solid or liquid.

As a solid composition for oral administration, the pharmaceutical composition may be formulated into a powder, granule, compressed tablet, pill, capsule, chewing gum, wafer or the like form. Such a solid composition will typically contain one or more inert diluents or edible carriers. In addition, one or more of the following may be present: binders such as carboxymethylcellulose, ethyl cellulose, microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, Primogel, com starch and the like; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; a flavoring agent such as peppermint, methyl salicylate or orange flavoring; and a coloring agent.

When the pharmaceutical composition is in the form of a capsule, for example, a gelatin capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or oil.

The pharmaceutical composition may be in the form of a liquid, for example, an elixir, syrup, solution, emulsion or suspension. The liquid may be for oral administration or for deliver}' by injection, as two examples. When intended for oral administration, preferred composition contain, in addition to the present compounds, one or more of a sweetening agent, preservatives, dye/colorant and flavor enhancer. In a composition intended to be administered by injection, one or more of a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer and isotonic agent may be included.

The liquid pharmaceutical compositions of the invention, whether they be solutions, suspensions or other like form, may include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer's solution, isotonic sodium chloride, fixed oils such as synthetic mono or diglycerides which may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Physiological saline is a preferred adjuvant. An injectable pharmaceutical composition is preferably sterile.

A liquid pharmaceutical composition of the invention intended for either parenteral or oral administration should contain an amount of a compound of the invention such that a suitable dosage will be obtained.

The pharmaceutical composition of the invention may be intended for topical administration, in which case the carrier may suitably comprise a solution, emulsion, ointment or gel base. The base, for example, may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, bee wax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers. Thickening agents may be present in a pharmaceutical composition for topical administration. If intended for transdermal administration, the composition may include a transdermal patch or iontophoresis device.

The pharmaceutical composition of the invention may be intended for rectal administration, in the form, for example, of a suppository, which will melt in the rectum and release the drag. The composition for rectal administration may contain an oleaginous base as a suitable nonirritating excipient. Such bases include, without limitation, lanolin, cocoa butter and polyethylene glycol. The pharmaceutical composition of the in v ention may include various materials, which modify the physical form, of a solid or liquid dosage unit. For example, the composition may include materials that form a coating shell around the active ingredients. The materials that form the coating shell are typically inert, and may be selected from, for example, sugar, shellac, and other enteric coating agents. Alternatively, the active ingredients may be encased in a gelatin capsule.

The pharmaceutical composition of the invention in solid or liquid form may include an agent that binds to the compound of the invention and thereby assists in the delivery of the compound. Suitable agents that may act in this capacity include a monoclonal or polyclonal antibody, a protein or a liposome.

The pharmaceutical composition of the invention may consist of dosage units that can be administered as an aerosol. The term aerosol is used to denote a variety of systems ranging from those of colloidal nature to systems consisting of pressurized packages. Deiiveiy may be by a liquefied or compressed gas or by a suitable pump system that dispenses the active ingredients. Aerosols of compounds of the invention may be delivered in single phase, bi-phasic, or tri-phasic systems in order to deliver the active ingredient(s). Deiiveiy of the aerosol includes the necessary container, activators, valves, subcontainers, and the like, which together may form a kit. One skilled in the art, without undue experimentation may determine preferred aerosols.

The pharmaceutical compositions of the invention may be prepared by methodology well known in the pharmaceutical art. For example, a pharmaceutical composition intended to be administered by injection can be prepared by combining a compound of the invention with sterile, distilled water so as to form a solution. A surfactant may be added to facilitate the formation of a homogeneous solution or suspension. Surfactants are compounds that non-covalently interact with the compound of the invention so as to facilitate dissolution or homogeneous suspension of the compound in the aqueous deliver}' system.

The compounds of the invention, or their pharmaceutically acceptable salts, are administered in a therapeutically effective amount, which will vary depending upon a variety of factors including the activity of the specific compound employed; the metabolic stability and length of action of the compound; the age, body weight, general health, sex, and diet of the patient; the mode and time of administration; the rate of excretion; the drug combination; the severity of the particular disorder or condition; and the subject undergoing therapy. In certain embodiments, a typical dosage of the substantially impermeable or substantially systemicaily non-bioavailable, compound may be between about 0.2 nig per day and about 2 g per day, or between about I mg and about 1 g per day, or between about 5 mg and about 500 mg, or between about 10 mg and about 250 mg per day, or between about 50 mg and about 200 mg, or between about 100 mg and about 150 mg, which is administered to a subject in need of treatment.

The frequency of administration of the compounds and compositions described herein may vary from once-a-day (QD) to twice-a-day (BID) or thrice-a-day (TID), etc., the precise frequency of administration varying with, for example, the patient's condition, the dosage, etc.

Compounds of the invention, or pharmaceutically acceptable derivatives thereof, may also be administered simultaneously with, prior to, or after administration of one or more other therapeutic agents. Such combination therapy includes administration of a single pharmaceutical dosage formulation which contains a compound of the invention and one or more additional active agents, as well as administration of the compound of the invention and each active agent in its own separate pharmaceutical dosage formulation. For example, a compound of the invention and the other active agent can be administered to the patient together in a single oral dosage composition such as a tablet or capsule, or each agent administered in separate oral dosage formulations. Where separate dosage formulations are used, the compounds of the invention and one or more additional active agents can be administered at essentially the same time, i.e., concurrently, or at separately staggered times, i.e., sequentially; combination therapy is understood to include all these regimens.

It is understood that in the present description, combinations of substituents and/or variables of the depicted formulae are permissible only if such contributions result in stable compounds.

It will also be appreciated by those skilled in the art that in the process described herein the functional groups of intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include hydroxy, amino, rnercapto and carboxylic acid. Suitable protecting groups for hydroxy include trialkyisilyl or diary lalkylsilyl (for example, f-butyldimethylsilyl, f-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for rnercapto include -C(0)-R" (where R" is alkyl, aryl or arylalkyl), >-methoxybenzyl, trityl and the like. Suitable protecting groups for car oxyiic acid include alkyl, aryl or arylalkyl esters. Protecting groups may be added or removed in accordance with standard techniques, which are known to one skilled in the art and as described herein. The use of protecting groups is described in detail in Green, T.W. and P.G.M. Wutz, Protective Groups in Organic Synthesis (1999), 3rd Ed., Wiley. As one of skill in the art would appreciate, the protecting group may also be a polymer resin such as a Wang resin. Rink resin or a 2-chlorotrityl-chloride resin.

It will also be appreciated by those skilled in the art, although such protected derivatives of compounds of this invention may not possess pharmacological activity as such, they may be administered to a mammal and thereafter metabolized in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as ^" 'prodrugs". All prodrugs of compounds of this invention are included within the scope of the invention.

Furthermore, all compounds of the invention which exist in free base or acid form can be converted to their pharmaceutically acceptable salts by treatment with the appropriate inorganic or organic base or acid by methods known to one skilled in the art. Salts of the compounds of the invention can be converted to their free base or acid form by standard techniques.

The following Examples illustrate various methods of making compounds of this invention, i.e., compounds of structure (I) or (II), or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof: it is understood that one skilled in the art may be able to make these compounds by similar methods or by combining other methods known to one skilled in the art. It is also understood that one skilled in the art would be able to make, in a similar manner as described below, other compounds of structures (I) or (II) not specifically illustrated below by using die appropriate starting components and modifying the parameters of the synthesis as needed. In general, starting components may be obtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, etc. or synthesized according to sources known to those skilled in the art {see, e.g., Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition (Wiley, December 2000)) or prepared as described in this invention. General Schemes 1-111 describe methods that were used to prepare compounds of the invention. The general methods described in these schemes can also be used to prepare additional compounds of the invention.

Scheme I

Scheme III

The following examples are provided for purposes of illustration, not limitation. EXAMPLE I

Preparation of {5-(5.7-bis((S)-3-methylmoipholino)-l .8-naphthyridin-2-yl)-2- methoxyphenyTjmethanol

Compound 1,1. 7-amino-l ,8-naphthyridme-2,4-dioL Pyridine-2,6-diamine (10,9 g, 99.9 mmol) and diethyl malonate (16, 1 mL, 105,8 mmol) were suspended in diphenyi ether (30 mL), The reaction was heated at 150 °C for 0,5 hours where upon the mixture became a homogeneous solution. The reaction was then refluxed for 2 hours, then cooled to room temperature, poured into water (300 mL) and extracted with ethyl acetate (300 mL). The organic phase was dried over MgS0 ₄ , filtered and concentrated. The residual gel was heated at 220 °C under reduced pressure (100 mTorr) for 2 hours where the mixture solidified. The reaction was cooled to room temperature and the solids were washed with ethyl alcohol and filtered to give compound 1.1 as a yellow- solid (9,72 g, 55 %). m/z (ES+) 178 (M+H) ⁺ .

Compound 1.2. 5,7-dichloro-l,8-naphthyridin-2-amine. 7~Amino-i,8~naphthyridine- 2,4-diol (compound 1.1 , 7.00 g, 39.5 mmo3) was suspended in acetic anhydride (80 mL), then heated at reflux for 18 hours. The reaction was cooled to room temperature, llie solids were filtered, washed with water and dried under reduced pressure to give 7.11 g of the intermediate as a yellow solid, m/z (ES+) 220 (M+H) ⁺ . The intermediate solid was suspended in POCI ₃ (55 mL) and refluxed for 2 hours. The solvent was removed under reduced pressure and the residue was carefully quenched by pouring onto ice/water (400 mL). The resulting mixture was heated to near boiling for 5 hours then cooled and the black solids were removed by filtration . The filtrate was carefully brought to pi ! with aqueous sodium hydroxide (2 M). The resulting solids were filtered, washed with water and dried under reduced pressure to obtain compound 1.2 (4.03 g, 48%). m/z (ES+) 214 (M+H) ^" ,

Compound 1.3. 5,7-dichloro-l,8-naphthyridin-2-oS. 5,7-dichloro-l,8-naphthyridin-2- amine (compound 1.2, 1.007 g, 4.70 mmoi) was dissolved in TFA (40 mL), then cooled 0 °C. Sodium nitrite (1.623 g, 23.5 mmol) was added portion-wise at 0 °C with stirring. The mixture was allowed to warm to room temperature and stirred for 16 hours. The solvent was removed under reduced pressure and the residue was dissolved in water (20 niL), stirred for 5 minutes then carefully brought to pH =7 with NaOH (2 M). The resulting precipitated solids were filtered, washed with water and dried under reduced pressure to give compound 1.3 (864 mg, 85%). m/z (ES+) 215 (M+H)~.

Compound 1.4. (i?)~5-ch!oro-7~(3-methyImorp oIino)~1 ,8~naphthyrid!5i-2~ol. 5,7- dichloro-l,8-naphthyridin-2-ol (compound 1.3, 1.07 g, 4.97 mrnol) was suspended in (5)-3-me1hylmorpholine (5 mL), then heated at 90 °C for 16 hours. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (S1O ₂ ; 1 % MeOH in dichloromethane) to give compound 1.4 as a yellow solid (720 mg, 52%). m/z (ES+) 280 (M+H) ⁺ .

Compound 1.5. (7?)-4-(4,7-dichloro-l ,8-naphthyridin-2-yI)-3-methylmorpholine. (i?)- -chloro-7-(3-methylmo holino)-l ,8-na hthyridin-2-ol (compound 1.4, 720 mg, 2.57 mmol) was dissolved in phosphoryl chloride (25 mL), then heated at reflux for 16 hours. The solvent was removed under reduced pressure and the residue was carefully quenched by pouring onto ice/water (20 mL). The mixture was carefully brought to pH=6 by slow portion-wise addition of aqueous Na ₂ C0 ₃ (2M). The mixture was exacted with EtOAc (3 x 30 mL) and the combined organics were washed with brine, dried over MgSCH, filtered and concentrated. The residue was purified by flash chromatography (Si0 ₂ ; 0-50 % EtOAc m hexanes) to give compound 1.5 as a yellow solid (506 mg, 66%). m/z (ES+) 298 (M+H) ⁺ .

Compound 1.6. (S)-(5-(5-chloro-7-(3-methylmorpholino)-l,8-naphthyridin-2-y l)-2- methoxyphenyl)methanol. To (i?)-4-(4,7-dichloro-l,8-naphthyricUn-2-yi)-3- methylmorpholine (compound 1.5, 27 mg, 0.091 mmol) in ethyl alcohol toluene (2 mL/2 mL) was added (2-metlioxy-5~(4,4,5,5-tetramethyl- l,3,2-dioxaboroian~2- yl)phenyl)methanol (26 mg, 0.098 mmol), tetrakis(triphenylphosphine)palladium ( 10 mg, 0.009 mmol) and potassium carbonate solution (2 M, 0.09 mL, 0.18 mmol). The mixture was sparged with argon for 10 minutes and then stirred to 80 °C for 18 h. The reaction was cooled to room temperature and filtered through Celite®. The filtrate was concentrated and purified by preparative TLC (Si0 ₂ ; 90% EtOAc, 10% hexanes) to give compound 1.6 as a yellow foam (25 rng, 69%). m/z { I S } 400 (Μ+Ή) ⁺ .

Compound 1. (5-(5,7-bis((iS)-3-methylmorpholino)-l,8-naphthyridin-2-yl)- 2- methoxyphenyi)methanol. (5)-(5-(5<:ωοΓθ-7-(3^6^^ο Ηο1ϊηο)-1,8-η3 Κ^ΓΪά-η- 2-yl)-2-methoxyphenyl)methanol (compound 1.6, 175 mg, 0.44 mmol), (S}-3- methy]mo holine (2.3 mL, 22 mmol), 2-dicyclohexylphosphino-2',6'- diisopropoxybiphenyl (RuPhos) (41 mg, 0.088 mmol), (2-dicyclohexylphosphino-2',6'- diisopropoxy- 1 , 1 '-biphenyl) j 2-(2'-amino- 1 , 1 '-biphenyl)]palladium(Il) methanesulfonate (RuPhos-Pd-G3) (80 mg, 0.088 mmol), 4A molecular sieve ( 100 mg) and sodium tert- butoxide (85 mg, 0.88 mmol) were suspended in dioxane (7 mL). The mixture was sparged with argon for 10 minutes and then stirred at 90 °C for 16 hours. The reaction mixture was filtered through Celite® and the filtrate was concentrated. The residue was purified by preparative TLC (Si02; 80% ethyl acetate, 20% hexanes) to give compound 1 as a foam (110 mg, 53%). m/z, (ES+) 465 (M+H) ⁺ .

EXAMPLE 2

Preparation of 3-(5.7^Ϊ5 (.5 ^ι )-3-ηΐ6ί1ιν1ηΐθφΗο1 ηο)- 1 ,8-naphthyridm-2- yl)phenyl)methanol

Compound 2. (3-(5,7-bis((S)-3-methylmorpholino)-l,8-naphthyridin-2-yl)ph enyl) methanol. Compound 2 was prepared using standard chemical manipulations. Procedures were similar to those used for preparation of compound 1 with the exception of using (3-(hydroxymethyl)phenyl)boronic acid in place of (2-methoxy-5~(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)methanol in the Suzuki reaction, m/z (ES+) 435 (M i l s .

EXAMPLE 3

Preparation of (3S3 »S)-4.4'-(7-(pyridin-4-yl)-l .8-naphthyridme-2,4-diyl)bis(3- m eth y Ιτηοφΐιοΐ ine)

Compound 3. (35,3 ¾ ⁷ )-4,4'-(7-(pyridin-4-yl)-l,8-naphthyridine-2,4-diyl)bi s(3- methylmorpholine). Compound 3 was prepared using standard chemical manipulations. Procedures were similar to those used for preparation of compound 1 with the exception of using pyridin-4-ylboronic acid in place of (2-methoxy-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-}'l)phenyl)methanol in the Suzuki reaction, m/z (ES+) 406 ( M i l) .

EXAMPLE 4 (TBV- Preparation of N-(4-{5.7-bis(iS -3-methylmorpholino)-l.S-naphthyridin-2- yl)benzyl)memanesulfonamide

Compound 4. 7V-(4-(5,7-bis((S)-3-methylmorpholino)-l,8-naphthyridin-2- yI)benzyl)methanesulfonamide. Compound 4 was prepared using standard chemical manipulations. Procedures were similar to those used for preparation of compound 1 with the exception of using (4-(metliylsulfonamidomethyl)phenyl)boronic acid in place of (2-methoxy-5 -(4,4,5,5 -tetramethyl -1,3 ,2-dioxaborolan-2-yl)phenyl)metlianoi in the Suzuki reaction, m/z (ES+) 512 (M+H) ⁺ . EXAMPLE 5

Preparation of 3-{5.7-bis((S)-3-methviiTiorpho¾ino)-1.8-naphtliyndm-2-yl)- N- methy Ibenzami de

Compound 5, 3-(5,7-bis((S)-3-methylmorpholino)-l,8-naphthyridin-2-yl)-N- methylbenzamide. Compound 5 was prepared using standard chemical manipulations. Procedures were similar to those used for preparation of compound 1 with the exception of using (3-(methylcarbamoyl)phenyl)boronic acid in place of (2-methoxy-5-(4,4,5,5- tetramethyl-L3,2"dioxaborolan~2-yl)phenyl)methanol in the Suzuki reaction, m/z (ES+) 462 ( M - ! 1) .

EXAMPLE 6

Preparation of 6-{5,7-bis((S)-3-methylmoq3holino)- 1.8-naphthyridin-2-yl)isoindolin- i - one

Compound 6. 6-(5,7-bis((S)-3-methylmorpholino)-l,8-naphthyridin-2- yl}isoindolm~l-one. Compound 6 was prepared using standard chemical manipulations. Procedures were similar to those used for preparation of compound 1 with the exception of 6-(4,4,5,5~tetraniethyi-l,3,2-dioxaboroiaii-2-yi)isoindolin- l-one in place of (2- methoxy-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pheny l)methanol in the Suzuki reaction, m/z (ES+) 460 (M+H) ⁺ .

EXAMPLE 7

Preparation of ?)-4- 7-(4-methoxy henyl)-2-((5)-3-methylmoφholino)-1.8- ηα 1ινήάϊη-4-ν1)-3-ηΐ6ΐ1ιν1ιηοφ1ΐο1ίη6

Compound 7. (i?)-4-(7-(4-metho.xyphenyl)-2-((S)-3-methylmorpholino)-l,8- naphthyridin-4-yl)-3-methylmorpholine. Compound 7 was prepared using standard chemical manipulations. Procedures were similar to those used for preparation of compound 1 with the exception of using (4-methoxyphenyl)boronic acid in place of (2- methoxy-5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl)methanol in the Suzuki reaction, m/z (ES+) 435 (Μ+Ή) ^" .

EXAMPLE 8

Preparation of (3-(5-(8-oxa-3-azabicyclo| ^" 3.2. l ^" |octan-3-yl)-7-((5)-3- memylmonjliolino)-i.8-naphthyridin-2-vi)phenyl)m.ethanol

Compound 8. (3-(5-(8-oxa-3-azabicyclo[3.2.1joctan-3-yl)-7-((S)-3- methylmorpholino)-l,8-napht yridin-2"yl)phenyl)methano!. Compound 8 was prepared using standard chemical manipulations and procedures similar to those used for preparation of compound 1 with the exception of using (3- (hydroxymethyl)phenyl)boronic acid in place of (2-methoxy-5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenyl)methanol in the Suzuki reaction and 8~oxa~3~ azabicyclo[3.2.1 ]octane in place of (<S)-3-methylmorpholine in the Buchwald coupling reaction, m/z (ES+) 447 (M+H) ⁺ .

EXAMPLE 9

Preparation of (5-(5-(8-oxa-3-azabicyclof 3.2.1 ]octan-3-yl)-7-(( S)-3- methylmorpholino)- 1 -naphthvridiii-2-yl)-2-methoxyphenyi)methanol

Compound 9. (5-(5-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-7-((S)-3- methylmorpholino)-l,8-naphthyridin-2-yl)-2-methoxyphenyl)met hanol. Compound 9 was prepared using standard chemical manipulations and procedures similar to those used for preparation of compound 1 with the exception of using 8-oxa-3- azabicyclo[ 3.2.1] octane in place of (S)-3-methylmorpholine in the Buchwald coupling reaction, m/z (ES+) 477 (M+H) ⁺ .

EXAMPLE 10

Preparation of 3-(7-{4-methoxy henyl)-2-((S -3-methylmoφholmo)-l .8-naplit.hyridm-

4-yl)-8-oxa-3-azabicyclo[3.2. I joctane

Compound 10. 3-(7-(4-methoxyphenyl)-2-((S)-3-methylmorpholino)-l,8- naphthyridm~4~yI)~8~oxa-3~azabkydo[3,2.1] octane. Compound 10 was prepared using standard chemical manipulations and procedures similar to those used for preparation of compound 1 with the exception of using (4-methoxyphenyl)boronic acid in place of (2-methoxy-5-(4,4,5,5-tetrame1hy]-l,3,2-dioxaboro]an-2-yl)ph eny])metlianol in the Suzuki reaction and 8-oxa-3-azabicyclo[3.2.1]octane in place of (S)-3- methylmorpholine in the Buchwaid coupling reaction, m/z (ES+) 447 (Μ+Ή) ^" .

EXAMPLE 1 1

Preparation of ( 1Κ.55)-8-(7-(4-ηΐ6ΐ1ιοχΛφ1ΐ6ην1)-2-((8)-3-ηΐ6� � ν1ηΐθ Ηο1ίηο)-1.8- iiaphthyridin-4-yl)-3-oxa-8-azabicvcloi3.2. Hoctane

Compound 11. (lR,5S)-8-(7-(4-methoxyphenyl)-2-((S)-3-methylmorpholino)-l, 8- naphthyridin-4-yl)-3-oxa-8-azabicyclo[3.2.1] octane. Compound 11 was prepared using standard chemical manipulations and procedures similar to those used for preparation of compound 1 with the exception of using (4-methoxyphenyl)boronic acid in place of (2-methoxy-5 -(4,4,5 ,5 -tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)phenyl)methanol in the Suzuki reaction and (l i,5<S)-3-oxa-8-azabicyclo[3.2.1]octane in place of (<S)-3- methylmorpholine in the Buchwald coupling reaction, nvz (ES+) 447 (M+H) ⁺ .

EXAMPLE 12

Preparation of (5-(5.7-άίιηοφηο1ίηο-1.8-ηαρ ίηνΓΪάίη-2^

12

Compound 12, (5-(5,7-dimorphoIino-l,8-naphthyridin-2-yI)-2- methoxyphenyl)methanol. Compound 12 was prepared using standard chemical manipulations and procedures similar to those used for preparation of 1 with the exception of using morpholine in place of (S)-3-methylmorpholine. nvz (ES+) 437 (M+H) ⁺ .

EXAMPLE 13

Preparation of 4,4'-(7-phenyl- 1.8-naphthyridme-2,4-diyl)dimorpholine

13

Compound 13. 4,4'-(7-phenyl-l ,8-naphthyridine-2,4-diyl)dimorphoIine. Compound 13 was prepared using standard chemical manipulations and procedures similar to those used for preparation of 1 with the exception of using morpholine in place of (S)-3- methylmorpholine and phenyl boronic acid instead of (2-methoxy-5-(4,4,5,5- tetramethyi-L3,2"dioxaboroian~2-yl)phenyi)methaiiol in the Suzuki reaction, m/z (ES+) 377 ( M - ! 1) .

EXAMPLE 14

Preparation of 2-((4-(5 ^^Ϊ5((5)-3^6ΐην1ΐΏθφ1ιο1ϊ ο)-1.8-ηα 1ι11ιν άϊιι-2- yi)benzy¾)amino)ethanol

Compound 14.1. (4-(5,7-bis((S)-3-methylmorpholino)-l,8-naphthyridin-2- yl)phenyl)methanol. Compound 14.1 was prepared using standard chemical manipulations and procedures similar to those used for preparation of compound 1 with the exception of using (4-(hydroxymethyl) phenyl) boronic acid instead of (2-methoxy-

5-(4 4,5,54etramethyl-l ,3,2-dioxaboroLan-2~yl)phenyl)methanol in the Suzuki reaction. m/z (ES+) 435 ( M l 0 .

Compound 14.2. 4-(5,7-bis((S)-3-methylmorpholino)-l,8-naphthyridin-2- yl)benzaldehyde. (4-(5,7-bis((¾-3-methyimoipholino)- l,8-naphthyridin-2- yl)phenyl)methanoi. (compound 14.1, 80 mg, 0.18 mmol) and manganese dioxide ( 1 18 mg, 6.9 mmol) were suspended in chloroform/acetonitrile (3 mL/3 mL). The reaction was stirred at 60 °C for 3 hours and then filtered through Celite®. The filtrate was concentrated and the residue was purified by preparative TLC (SiO _? .: 70% ethyl acetate, 30% hexanes) to give compound 14.2 as a foam (60 nig, 78%),

14.2 14

Compound 14. 2-((4-(5,7-bis((S)-3-methylmorpholino)-l,8-naphthyridin-2- yl)benzyl)amino)ethanol. To a mixture of 4-(5,7-bis((<S)-3-methylmo jholino)-l,8- naphthyridin-2-yl)benzaidehyde (compound 14.2, 60 nig, 0.14 mmol) in dichloroethane (2 niL), was added ethanolamine (30 μΐ,, 0.50 mmol). The mixture was stirred for 30 minutes, then sodium triacetoxyborohydride (38 mg, 0.18 mmol) and acetic acid (1 1iL, 0.18 mmol) were added. The reaction was stiired at 50 °C for 16 hours, then the solvent was removed. The residue was purified by preparative TLC (Si0 ₂ ; ethyl acetate, 4% MeOH, 1% ammonium hydroxide) to give compound 14 (24 mg, 36%). nv'z (ES+) 478 (M+H) ^" \

EXAMPLE 15

Preparation of l-(4-(5-(8-oxa-3-azabicyclol 3.2. i]oc¾an-3-yl)-7-((,S)-3- methylmorpholino)-l,8-naphtliyridin-2-yl)benzyl)azetidin-3-o l

15

Compound 15. l -(4-(5-(8-o.xa-3-azabicyclo[3.2.1]octan-3-yl)-7-((S)-3- methy!inorphoSino)-l,8-naphthyridin-2~yl)benzyI)azetidin-3-o l, Compound 15 was prepared using standard chemical manipulations and procedures similar to those used for preparation of compound 14 with the exception of using 8-oxa-3- azabicyclo[3.2.1]octane in place of (5)~3-methylmorpholme in the Buchwald coupling reaction and azetidin-3-ol in place of ethanolamine in the reductive animation, m/z (ES+) 502 (M l !) .

EXAMPLE 16

Preparation of (4-(5-(8-oxa-3-azabicycloF3.2.1 loctan-3-yl)-7-(ffl-3- me†hylmorpholino)-1.8-naphthyridin-2-yl)phenyl)methanol

Compound 16. (4-(5-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-7-((S)-3- methylmorpholino)-l,8-naphthyridin-2-yl)pheny])methanol. Compound 16 was prepared using standard chemical manipulations and procedures similar to those used for preparation of compound 14,1 with the exception of using 8-oxa-3- azahicyelo [3.2.1] octane in place of (<S)-3-methylmorpholine in the Buchwald coupling reaction, m/z (ES+) 447 (M+H) ⁺ .

EXAMPLE 17

Preparation of N-(4-(5-(8-oxa-3-azabicyclo[3.2. l]octan-3-yl)-7-((.S)-3- metliy lmorpholino) -1.8 -naphthv ridin -2-yl)benzyl) -2-methoxyethanamine

Compound 17. jV-(4-(5-(8-oxa-3-azabicyclo [3,2.1 |octan-3-yl)-7-((S)-3- methySmorphoSino}-l,8-naphthyridin-2-yl)benzyI)-2-methoxyeth ananiine.

Compound 17 was prepared using standard chemical manipulations and procedures similar to those used for preparation of compound 14 with the exception of using 8-oxa- 3-azabicycloj 3.2.1 joctane in place of (5)-3-methylmorpholine in the Buchwald coupling reaction and 2-methoxyethanamine in place of ethanolamine in the reductive animation, nv'z (ES+) 504 (M+H) ⁺ .

EXAMPLE 18

Preparation of 2-(f 4-(5-(8-oxa-3-azabicvclor3.2.1 loctan-3-vj -7-iiS)-3- methylmorpholinoj-l ,8-naphthyridin-2-yl)benzyl)amino)ethanol

18

Compound 18. 2-((4-(5-(8-oxa-3-azabicyclo [3.2.1] octan-3-yl)-7-((S)-3- methylmorpholino)-l,8-naphthyridin-2-yl)benzyl)amino)ethanol . Compound 18 was prepared using standard chemical manipulations and procedures similar to those used for preparation of compound 14 with the exception of using 8-oxa-3- azabicyclo[3.2.1]octane in place of (S)-3-methylmorpholine in the Buchwald coupling reaction, m/z (ES+) 490 (M+H) ⁺ . EXAMPLE 19

Preparation of (35.3'5)-4.4'-(7-(4-(ηιοφ1ιο1ίηοηΐ6ΐ1ιν1)ρ1ΐ 6ηνΠ-1.8-ηαρ1ιί1ινηάϊιΐ6-2.4- diy1)bis(3-methylmorpholine)

Compound 19. (3S,3'S)-4,4 ^! -(7-(4-{morphol!nomethy!)phenyl)~l,8-5iaphthyridine~ 2,4-diyl)bis(3-methylmorpholine). Compound 19 was prepared using standard chemical manipulations and procedures similar to those used for preparation of compound 14 with the exception of using morpholine in place of ethanolamine in the reductive animation, m/z (ES+) 504 (M+H) ⁺ . EXAMPLE 20

Preparation of 6-(5-(8-oxa-3-azabicyclo[3■2■l]octa -3-yl)-7-((i.S ^r )-3-methylmoφholino - 1.8-naphthyridin-2-yl )isoindolin- 1 -one

Compound 20. 6-(5-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-7-((S)-3- methylmorpholino)-l ,8-naphthyridin-2-y])isoindolin-l-one. Compound 20 was prepared using standard chemical manipulations and procedures similar to those used for preparation of compound 1 with the exception of using 6-(4,4,5,5-tetramethyl-l,3,2- dioxabofolan-2-yl)isoindolin-l-one in place of (2-methoxy-5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenyl)methanol in the Suzuki reaction and 8-oxa-3- azahicyelo [3.2.1] octane in place of (<S)-3-methylmorpholine in the Buchwald coupling reaction, m/z (ES+) 472 (M+H) ⁺ .

EXAMPLE 21

Preparation of (5-(7-((2 ?.6ά -2,6-dimethylmoφhojino)-5- ( _t -3-methyjmoφholino)- l,8-naphth\'ridin-2-yl)-2-methoxyphenyl)methaaol

Compound 21.1. 5-chloro-7-((2if,6S)-2,6-dimethylmorpholino)-l,8-naphthyridi n-2- o!. To a solution of 5,7-dichloro-l,8-naphthyridin-2-ol (compound 1.3, 1.00 g, 4.65 mmol) in dioxane (35 mL) was added (2i?,6,S 2,6-dimethylmorpholine (806 rng, 7.00 mmol) and DIEA ( 1.22 mL, 7.00 mmol). The resulting solution was stirred for 24 hours at 60 °C, then concentrated under reduced pressure. ^' The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1 :2) as the eluent to give compound 21.1 as a light yellow solid (980 mg, 72%).

Compound 21. (5-(7-((2i?,6 _i S ^T )-2,6-diniethy!niorpho!ino)-5-(( ₁ y)-3- methylmorpholino)-l,8-naphthyridin-2-y])-2-methoxypheny])met hanol. Compound 21 was prepared using standard chemical manipulations. Procedures were similar to those used for preparation of compound 1 with the exception of using (3- (hydroxymethyl)-4-meilioxyp3ienyi)boronic acid in place of (2-methoxy-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)memanol in the Suzuki reaction. Additionally, the title compound was purified by prep-HPLC with the following conditions: Column, XBridge Prep Shield RP18 OBD Column, 19* 150 mm, 5 μηι; mobile phase, water with 10 mmoi NH4HCO3 and acetonitriie (34% ACN up to 54% in 8 min); detector, UV 254 rail. This gave compound 21 (9.5 mg, 3%). m/z (ES+) 479 ( M i l) .

EXAMPLE 22

Preparation of 5-(5 ^^Ϊ8((27?.65 -2.6-άϊηΐ6ΰιν1ηΐθ 1ιο1ΐηο -1,8-ηα 1ιί1ινήάΐη-2-ν1 -2- methoxyphenyl)methanol

Compound 22,1. 5,7-bis((2i?,6S)-2,6-dimethylmorpholino)-l,8-naphthyridin-2- ol.

Into a round-bottom flask, was placed 5,7-dichloro-l,8-naphthyridin-2-ol (compound 1.3, 210mg, 0.98 mmol) and (2 ?,65 ^' )-2,6-dimethylmorpholine (6 mL). The resulting solution was stirred overnight at 130 °C under nitrogen, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1 :5) as the eluent to obtain compound 22.1 as a light yellow solid (310 mg, 85%).

Compound 22.2, (2R,2 'R,6S,6 'S)-4,4'-(7-chloro-l,8-naphthyridine-2,4-diyl)bis(2,6- dimethy!morpholine). Into a round-bottom flask, was placed 5,7-bis((2i?,65)-2,6- άί^6Λ>'1ηιοφ1ιοΗηο)-1,8-ηα ΗΐΗ>'πάίη-2-ο1 (compound 22.1 , 398 mg, 1.07 mmol) and phosphoryl chloride ( 10 mL). The resulting solution was stirred overnight at 100 °C, and then concentrated under reduced pressure. The residue was carefully quenched by- very slow addition of sodium, bicarbonate (sat., 30 mL). The resulting mixture was extracted with ethyl acetate (3 x 80 mL) and the combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1 :5) as the eluent to obtain compound 22.2 as a light yellow solid (277 mg, 66%).

Compound 22. (5-(5,7-bis((2/?,6iS)-2,6-dimethylmorpholino)-l,8-naphthyrid in-2- yl)-2-methoxyphenyl)methanol. To a solution of (2i?,2 ?,65',6S)-4,4'-(7-chloro-l,8- η3ρΗώνπάϊη6-2,4^ϊν1^Ϊ8(2,6-άηη6^^ο 1ιο1ϊη6) (compound 22.2, 105 mg, 0.27 mmol) in toluene (4 mL) and EtOH (4 mL) was added (3-(hydroxymethyl)-4- methoxyphenyl)boronic acid (62 mg, 0.34 mmol), tetrakis(triphenylphosphine)palladium (31 mg, 0.027 mmoi) and sodium carbonate (58 mg, 0.55 mmol). The resulting mixture was stirred overnight at 90 °C under nitrogen, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate to obtain impure product. The product was further purified by Prep-HPLC with the following conditions (Prep-HPLC-043): Column, XBridge Prep Shield RPI 8 OBD Column, 19* 1 0 mm, 5μηι, 13 nm; mobile phase, Water with 10 mmol NH ₄ HCO ₃ and acetonitrile (40.0% ACN up to 56.0% in 8 min); Detector, 254 nm. This yielded compound 22 as a light yellow solid (20.7 m, 16%) . m/z (ES+) 493 (M+H) ⁺ . EXAMPLE 23

Preparation of (5 (2^6ΐηοχν-5-(5-(3-Γη6ΐην1ΐΏθφ1ιο1ί ο -7-( ϊ 6Γ3ζίη-1-νΠ-1.8- naphthyridin-2-yj)pheny¾)methanol

Compound 23.1. 5-c !oro-7-(piperazin-l-yl)-l,8-naphi yridin-2-o!. Compound 23.1 was prepared usmg standard chemical manipulations. Procedures were similar to those used for preparation of compound 1.4 with the exception of using piperazine in place of (2 ?,65)~2,6-dimethylmoq3holme.

23.2

Compound 23.2. 4,7-dichloro-2-(piperazin-l-yl)-l,8-naphthyridine. Compound 23.2 was prepared from compound 23.1 using standard chemical manipulations starting and procedures were similar to those used for preparation of compound 1.5.

Compound 23.3. tert-butyl 4-(4,7-dichloro-l,8-naphthyridin-2-yl)piperazine-l carboxylate. To a solution of 4,7-dichloro-2-(piperazin-l-y])-l,8-naphthyridin (compound 23.2, 300 mg, 1.06 mmol) in dichloromethane (30 niL) was added triethylamine (223 μΐ,, 1.60 mmol) and di-tert-butyl dicarbonate (252 mg, 1.15 mmol). The resulting mixture was stirred overnight at room temperature. The mixture was washed with brine (20 mL) and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by- silica gel column chromatography (petroleum ether/ethyl acetate, 2: 1) as the eluent to give compound 23.3 as a yellow solid (310 mg, 76%).

23.4

Compound 23.4. (S)-tert-buty\ 4-(7-(3-(hydroxymethyl)-4-methoxyphenyl)-4-(3- methylmorpholino)-l,8-naphthyridin-2-yl)piperazine-l-carboxy Iate. Compound 23.4 was prepared from compound 23.3 using standard chemical manipulations and procedures were similar to those used for preparation of compound 1.5, with the exception of using (3-(hydroxymethyl)-4-methoxyphenyl)boronic acid in place of (2- methoxy-5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)phenyl)methanol in the Suzuki reaction.

23.4

Compound 23. (S)-(2-methoxy-5-(5-(3-methylmorpholino)-7-(piperazin-l-yl)- l,8- naphthyridin-2-yl)phenyl)methanol. To a solution of (S)-re n~huty\ 4-(7-(3- (hydrox}Tnethyl)-4-memoxyphenyl)-4-(3-methy

yl)piperazine-l-carboxylate (compound 23.4, 20 mg, 0.036 mmo!) in dichloromethane (2 ml.) was added trifluoroacetic acid (0.5 mL). The resulting solution was stirred overnight at room temperature, then concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-043): Column, XBridge Prep Shield RP18 OBD Column, 19* 150 mm, 5 μιη; mobile phase, water with 10 mrnol NH4HCO3 and ACN (16% ACN up to 40% in 8 min); detector, UV 254 nm. This gave compound 23 as a yellow solid (5 m, 31%). m/z (ES+) 450 ( M · H) .

EXAMPLE 24

Preparation of (35 ^l .3 'S -4.4'-(7-(4-methoxy'-2-methylphenyl)-1.8-naphtliyridine-2.4- diy1)bis(3-methylmorpholine)

Compound 24.1. 7-Methoxy-l ,8-naphthyridine-2,4-diol. A mixture of 6- methoxypyridin-2-amine (10.45 g, 84.18 mrnol), dimethyl malonate (9.62 mL, 84.18 mrnol) and diphenyl ether (30 mL) in a 250 3 -neck flask equipped with a Dean-Stark trap was purged with nitrogen. Tire mixture was heated at 150 °C for 3 hours, then 170 °C for 18 hours. The mixture was cooled and additional dimethyl malonate (4.8 mL, 42 mrnol) was added and then the mixture heated at 170 °C for an additional 2.5 hours. The mixture was cooled and additional dimethyl malonate (2.4 mL, 21 mrnol) was added and the mixture was heated at 170 °C for an additional 2 hours. The mixture was cooled and additional dimethyl malonate (2.4 mL, 21 mrnol) was added and then the mixture was heated at 180 °C for 1 hour and 190 °C for 2 hours. The reaction mixture was then heated at 230 °C (internal solution temp = 175 °C) for 12 hours. The solution was allowed to cool slowly, then ethyl acetate (60 mL) was slowly added with stirring. The resulting solids were filtered and washed with ethyl acetate (2 x 40 mL) and dried to obtain the crade product as a brown solid (14.09 g). The solids were heated to reflux with ethyl acetate (75 mL) for 8 hours, and then stirred at room temperature for 10 hours. The solids were filtered and washed with ethyl acetate. A slurry of the resulting solids in hot DMSO (50 mL) was made. The mixture was cooled to -70 °C, then ethyl acetate (300 mL) was slowly added until no additional product was precipitating. The solids were filtered to obtain a brown powder (8.41 g, 52%), Ether (500 mL) was added to the filtrate resulting in additional precipitation. Additional ether (500 mL) was added and the resulting solids were filtered. The additional solids obtained (2.30 g, -80% pure) was heated with DMSO (20 mL) for 10 minutes, then ethyl acetate (150 mL) was slowly added and the mixture was stirred at room temperature for 30 minutes. The solids were filtered and washed with ether (100 mL) to obtain a brown solid (821 mg, 5.1%). Additional solids precipitate upon ether addition and were filtered to obtain additional clean product (285 mg, 1 .7%). The total amount of clean product obtained (9.52 g, 59%).

Compound 24.2. 2,4-Dichloro-7-methoxy-l,8-naphthyridine. A solution of phosphoryl chloride (5 mL, 54 mmol) and dioxane (7.5 mL) in a 100 mL 3 -neck round bottom flask was heated to 60 °C. A suspension of 7-methoxy-l ,8-naphthyridine-2,4- diol (compound 24.1, 3.00 g, 15.6 mmol) in dioxane (5 mL) was added in portions over 45 minutes. The vial containing the suspension was rinsed with dioxane (2.5 mL) and phosphoryl chloride (10 mL, 107 mmol) and added to the reaction. The mixture was stirred at 60 °C for an 1 hour after scaffold addition. Additional phosphoryl chloride ( 15 mL, 161mmol) was added and the mixture heated at 60 °C for 1.5 hours, then at 70 °C for 1 hour. The mixture was cooled and concentrated under reduced pressure. The residue was carefully quenched into ice water (250 mL) and then saturated sodium bicarbonate was added slowly until a pH ~7 was attained and diluted with dichloromethane (300 mL). The insoluble solids were removed by filtration through Celite®. The layers were separated and the aqueous was extracted with additional dichloromethane (3 x 100 mL) , The combined organ ic ¹ ; were dried ( .Vt -SO ;). filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanes to 25% ethyl acetate in hexanes) to obtain compound 24,2 as a white solid (2.16 g, 61%).

Compound 24.3, (S)-4-(4-Chloro-7-methoxy-l,8-naphthyridin-2-yl)-3- methylmorpholine. 2,4-Dichloro-7-methoxy-l,8-naphthyridine (compound 24.2, 365 mg, 1 .6 mmol) was suspended in (S)-3-methylmorpholine (5 mL) at 100 °C for 16 hours. The solvent was removed under reduced pressure and the residue was purified by- silica gel column chromatography (ethyl acetate/he xanes, 3 :7) as the eiuent to give compound 24.3 as a white solid (405 mg, 86%).

Compound 24.4. (3S,3 'S)-4,4'-(7-Methoxy-l,8-naphthyridine-2,4-diyl)bis(3- methylmorpholine). (S)-4-(4-Ch]oro-7-methoxy- l ,8-naphthyridin-2-yl)-3- methylmorpholine (compound 24.3, 107 mg, 0.364 mmol), (5)-3-methylmorpholine (2.0 mL, 18 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos) (35 mg, 0,074 mmol), (2-dicyc]ohexylphosphino-2',6'-diisopropoxy-l, l '-biphenyl)[2-(2'- amino-l, l '-biphenyl)]palladium(II) methanesulfonate (RnPhos-Pd-G3) (62 rng, 0.074 mmol), 4A molecular sieves (80 mg) and sodium ferf-butoxide (71 mg, 0.74 mmol) were suspended in dioxane (5 mL) , The mixture was sparged with argon for 10 minutes and then stirred at 90 °C for 16 hours. The reaction mixture was cooled, then filtered through Celite® and the filtrate was concentrated. The residue was purified by preparative TLC (silica; 40% ethyl acetate in hexanes) to give compound 24.4 as a foam (130 mg, 96%). m/z (ES+) 359 (M i l) .

Compound 24.5. 5,7-Bis((S)-3-methylmorpholino)-1.,8-naphthyridin-2-ol. (35,33)- 4,4'-(7-methoxy- 1 ,8-naphthyridine-2,4-diyl)bis(3-methylmorpholine) (compound 24.4, 323 mg, 0.90 mmol) was dissolved in hydrobromic acid (48% aqueous solution). The reaction was heated at 80 °C for 30 minutes, then cooled and carefully neutralized by slow addition of sodium hydroxide (10 M, 4.5 ml) and sodium carbonate (1 M) to pH = 4. The mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were dried (Na ₂ S0 ₄ ), filtered and concentrated to give compound 24.5 as a foam (305 mg, yield 98%). m/z (ES+) 345 (M+H) ⁺ .

Compound 24.6. (3S,3 iS)-4,4'-(7-Chloro-l,8-naphthyridine-2,4-diyl)bis(3- methylmorpholine). 5,7-Bis((/S 3-methylmorpholino)-l,8-naphftyridin-2-ol (compound 24.5, 50 mg, 0.14 mmol) was dissolved in phosphoryl chloride (1 mL) and heated at 100 °C for 3 hours. The solvent was removed under reduced pressure and the residue was carefully neutralized by slow addition of sodium carbonate (1 M) _. The mixture was extracted by ethyl acetate (3 x 10 mL) and the combined organics were washed with brine (10 mL), dried over Na ₂ S0 ₄ , filtered, and concentrated to give compound 24.6 as a foam (50 mg, 96%). tn/z (ES+) 363 (M+H) ⁺ .

Compound 24. (3^3 ¾^-4,4 ^, -(7-(4-ineihoxy-2~niethy!phe!iyS)-l,8-naphthyridine-2, 4- diyl)bis(3-methylmorpholine). To a solution of (3^,3 '<S)-4,4'-(7-chloro- 1,8- naphthyridine-2,4-diyl)bis(3~methylmoq3lioline (compound 24.6, 24 mg, 0.059 mmol) in ethanol/toluene (1: 1)(2 mL) was added aqueous potassium carbonate (120 μΕ, 2 M, 0.24 mmol), tetrakis(triphenylphosphine)palladium (6 mg, 0.005 mmol) and (4- methoxy-2-methylphenyl)boronic acid (15 mg, 0.090 mmol). The resulting mixture was sparged with argon for 10 minutes and then stirred at 90 °C for 16 hours under nitrogen. The mixture was cooled, filtered and the filtrate was concentrated. The residue was punfied by with preparative HPLC to obtain compound 24 as a white solid (14.1 mg, 52%). m/z (ES+) 449 (M+H) ⁺

EXAMPLE 25

Preparation of (4-(5.7-bis((5')-3-methylmo holino)-1.8-na hthyridin-2-

25 Compound 25. (4-(5,7-bis((S)-3-methylmorpholino)-l,8-naphthyridin-2- yl)p eny!){morpholino)methanone. Compound 25 was prepared using standard chemical manipulations and procedures similar to those used for preparation of compound 24, except (4-(moipholine-4-carbonyl)phenyl)boronic acid was used in place of (4-methoxy-2-methylphenyl)boronic acid in the Suzuki reaction, m/z (ES+) 518 ( M i l) .

EXAMPLE 26

Preparation of (3-(5.7-¾8{( ^ι -3- 6Φν1ιτίοφ1ιο1ίηο)- 1 ,8-naphthyridin-2- yl)phenyl)(morpho¾ino)methanone

Compound 26. (3-(5,7-bis((S)-3-methylmorpholino)-l,8-naphthyridin-2- yl)p eny!)(morpholino)methanone. Compound 26 was prepared using standard chemical manipulations and procedures similar to those used for preparation of compound 24, except (3-(moipholine-4-carbonyl)phenyl)boronic acid was used in place of (4-methoxy-2-methylphenyl)boronic acid in the Suzuki reaction, m/z (ES+) 518 ( M i l) .

EXAMPLES 27 & 28

Preparation of {5V(5-(7-(3.6-dihydro-2H-pyran-4-yl)-5-(3-methyimorpho¾ino) -1.8- naphthyridin-2-yl)-2-methoxyphenyl)metha.nol & (.SV(5-(5-(3.6-dihydro-2H-pyran-4- yl)-7-(3-methylmorpholino)-l,8-ira^

Compound 27,1 and compound 28.1. 7-chloro-5-(3,6-dihydro-2H-pyran-4-yl)-l,8- naphthyridin-2-ol and 5-chloro-7-(3,6-dihydro-2H-pyran-4-yl)-l,8-naphthyridin-2- ol. To a solution of 5,7-dichloro-l,8-naphthyridin-2-ol (compound 1.3, 4.00 g, 18.6 mmo3) in DMA (90 mL) and water (5 mL) was added 2-(3,6-dihydro-2H-pyran-4-yl)- 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (2.80 g, 13.3 mmol), sodium carbonate (4.00 g, 37.7 mmol), [l, l'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (2.00 g, 2.73 mmol). The resulting mixture was stirred for 2 hours at 100 °C under nitrogen. The mixture was cooled, diluted with ethyl acetate (500 mL) and washed with 10% aqueous sodium chloride (500 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (dichloromethane/methanol, 30: 1) as the eluent to obtain a mixture of compounds 27.1 and 28.1 (2.0 g) as a light yellow solid.

Compound 27.2 and compound 28.2. (»S)-5-(3,6-dihydro-2H-pyran-4-yl)-7-(3- methylmorpholino)-l ,8-napht yridin-2"Ol and (»S)-7-(3,6-dihydro-2H-pyran-4-yl)-

5~(3~met y!morp etmo)~l,8~naphthyridin-2~eL To a solution containing a mixture of 7-chloro-5-(3,6-dihydro-2H-pyran-4-yl)-l,8-naphthyridin-2-ol (compound 27.1 ) and 5- chloro-7-(3,6-dih}'dro-2H-pyran-4-yl)-l,8-naphthyridin-2-ol (compound 28.1) (800 mg, 3.05 mmol) in 1,4- dioxane ( 10 mL) was added (2-dicyclohexylphosphino-2',6'- diisopropoxy- l, l'-bipheny])[2-(2'-amino-l, -bipheny])]palladium(II) methanesulfonate (RuPhos-Pd-G3) (254 mg, 0.30 mmol), 2-dicyclohexylphosphino-2',6'- diisopropoxybiphenyl (RuPhos)( 142 mg, 0.30 mmol), sodium ferf-butoxide (583 mg, 6.10 mmol) and (S)-3-methylmorpholine (3.1 1 g, 30.7 mmol). The resulting mixture was stirred for 2 hours at 90 °C under nitrogen, then cooled. The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol, 30: 1) as the eluent to obtain a mixture of compounds 27.2 and 28.2 as a light yellow solid (600 mg).

Compound 27.3 and compound 28.3. (S)-4-(7-ChIoro-4-(3,6-dihydro-2H-pyran-4- yl)-l,8-naphthyridin-2-yl)-3-methylmorpholine and (S)-4-(7-chloro-2-(3,6-dihydro- 2H-pyran-4-yl)-l,8-naphthyridin-4-yl)-3-methylmorpholine. A mixture of (S}-5-

(3,6-dihydro-2H-pyran-4-yl)-7-(3-methylmo holino)-l ,8-naphthyridin-2-ol (compound 27.2), (5)-7-(3,6^^(ΐΓθ-^-ρ} ⁷ κιη-4^1)-5-(3-ηΐ6ΐ1ΐ}Ίηιοφ1ιο1ίηο)-1, 8- naphthyridin-2-ol (compound 28.2) (500 mg, 1 ,52 mmol) and phosphoryl chloride (30 mL) was stirred for 3 hours at 70 °C. The resulting mixture was concentrated under reduced pressure. The residue was carefully quenched with water/ice (100 mL) and the resulting mixture was extracted with ethyl acetate (2 x lOOmL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Tire residue was purified by silica gel column chromatography with dichloromethane/methanol (50: 1) as the eluent to obtain a mixture of compounds 27.3 and 28.3 as a light yellow solid (350 mg).

Compound 27 and compound 28. (S)-(5-(7-(3,6-dihydro-2H-pyran-4-yl)-5-(3- methylmorpholino)-l,8-naphthyridin-2-yl)-2-methoxyphenyl)met hanol and (S)-(5- (5-(3,6-dihydro-2H-pyran-4-yl)-7-(3-methyImorphoIino)-l ,8-naphthyridin-2-yl)-2- methoxyphenyl)methanol. To a mixture of (5)-4-(7-chloro-4-(3,6-dihydro-2H-pyran- 4-yl)-l,8-naphthyridin-2-yl)-3-methylmo holine (compound 27.3) and (,S)~4~(7-chloro- 2-(3 ,6-dihydro-2H-pyran-4-yi)- 1 ,8-naphthyridin- -yl)-3 -ηιεΐΐινΐηιοφΐιοϋηε (compound 28.3) (90 mg, 0.26 mmol) in toluene (5 mL), ethanol (5 mL) was added (3- (hydroxymethyl)-4-metlioxyphenyl)boronic acid (60 mg, 0.33 mmol), sodium carbonate (60 mg, 0.57 mmol), and tetrakis(triphenylphosphine)pal3adiiim (80 mg, 0.07 mmol). Tire resulting mixture was stirred for 2 hours at 90 °C under nitrogen . The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane/methanol (30: 1) to obtain the mixture of products. Further purified by Prep-HPLC with the following conditions was performed: Column, XBridge Prep Shield RP 18 QBD Column, 19* 150 mm, 5μΐϊΐ, 13 nm; mobile phase, water with 0.1% formic acid and ACN (7.0% ACN up to 25.0% in 1 min); Detector, UV 254nm. This gave (5 -(5-(7-(3,6-dihydro-2H-pyΓan-4-yl)-5-(3-methy]mo holino)-l ,8-naphthyridin- 2-yl)-2-methoxyphenyl)methanol as a yellow solid (compound 27, 1.8 mg) and (S)-(5- (5~(3,6~dihydro~2H^yran-4-yi)-7-p^

methoxyphenyl)methanol as a yellow solid ((compound 28, 2.0 mg). m/z (ES+) 448 (M+H) ⁺ observed for both compounds.

EXAMPLE 29

Preparation of ffl- 5- 4-(3.6-dihydro-2H-pyran-4-yl)-7- 3-methylmoφholino)-1.8- naphthyridin-2-yl)-2-methoxyphenyl)methanol

Compound 29.1. 2,7-Dichloro-4-(3,6-dihydro-2H-pyran-4-yl)-l,8-naphthyridine . A mixture of 7-chloro-5-(3,6-dihydro-2H-pyran-4-yl)-l,8-naphthyridin-2-ol (compound 27.1, 500 mg, 1.90 mmol) and phosphoryl chloride (15 mL) was stirred at 70°C for 4 hours under nitrogen. The resulting mixture was concentrated under reduced pressure and the residue was then carefully quenched by the addition of water/ice (10 mL). The pH was carefully adjusted to 7 with sodium bicarbonate (sat.). The resulting mixture was extracted with ethyl acetate (5 x 40 mL) and the combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by a silica gel column chromatography with ethyl acetate/petroleum ether (2: 1) as the eluent to obtain compound 29.1 as a yellow solid (200 mg, 37%).

Compound 29.2. (5-(7-Chloro-4-(3,6-dihydro-2H-pyran-4-yl)-l,8-naphthyridin- 2- yl)-2-methoxyphenyl)methanol. To a solution of 2,7-dichloro-4-(3,6-dihydro-2H- pyran~4-yl)~l,8~naphthyridine (compound 29.1, 100 mg, 0.36 mmol) in EtOH (5 mL) and toluene (5 mL) was added (3-(hydroxymemyl)-4-methoxyphenyl)boronic acid (65 mg, 0.36 mmol), tetrakis(triphenylphosphine)palladium (83 mg, 0.072 mmol), and sodium carbonate (76 mg, 0.72 mmol). The reaction mixture was stirred for 2 hours at 90°C under nitrogen. The resulting mixture was concentrated under reduced pressure. The residue was purified by a silica gel column chromatography with ethyl acetate/petroleum ether (1 : 1) as the eiuent to obtain compound 29.2 as a yellow solid ( 120 mg, 87%).

Compound 29. (S)-(5-(4-(3,6-dihydro-2H-pyran-4-yl)-7-(3-methylmorpholino) -l,8- naphthyridin-2-yl)-2-methoxyphenyl)methanol. To a solution (5-(7-chloro-4-(3,6- dihydro-2H-pyran-4-yl)- 1 ,8-naphthyridin-2~yi)-2~m.ethoxyphenyl)methanol (compound 29.2, 100 mg, 0.26 mmol, 1.00 equiv) in 1,4-dioxane ( 10 mL) was added (S)-3- methylmorpholine (263 mg, 2.60 mmol), (2-dicyclohexylphosphino-2',6'-diisopropoxy- l, l '-biphenyl)[2-(2'-amino-l, l '-biphenyl)]palladium(II) methanesulfonate (RuPhos-Pd- G3) (22 mg, 0.026 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos) (1 1 mg, 0.026 mmol), and sodium tert-butoxide (50 rng, 0.52 mmol). The reaction mixture was stirred for 2 hours at 90°C under nitrogen, then cooled and diluted with ethyl acetate (100 mL). The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Column, XBridge Prep Shield R 18 OBD Column, 19* 150 mm, 5μηι,13 nm; mobile phase, water with 10 mmol NH4HCQ3 and ACN (30.0% ACN up to 46.0% in 8 min): Detector, 254 nm. This yielded compound 29 as a yellow solid (5 ,4 mg, 5%). m/z (ES+) 448 (M+Hf.

EXAMPLE 30

Preparation of (5-(5.7-Bis((S)-3-methylmorpholino)-L8-naphthyridin-2-yl)-2- methoxyphenyl)methanol

Compound 30. ( _i S ^, )-(2-methoxy-5-(S-(3-methyImorpholino)-7-(tetrahydro-2 H- pyran-4-yl)-l,8-naphthyridin-2-yl)phenyl)methanol. To a solution of (>S)-(5-(7-(3,6- dihydro-2H-pyrall-4-yl)-5-(3-methylmoφholino)-l,8-na hthyridin-2-yl)-2- methoxyphenyi)methanol (compound 27, 80 mg, 0.18 mmol) in ethyl acetate (20 mL) under nitrogen was carefully added palladium/carbon (10 % d) (100 mg). The system was purged with nitrogen, then hydrogen was introduced to the system. The resulting solution was stirred for 2 hour at room temperature, then evacuated and purged with nitrogen. The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Column, XBridge Prep Shield RP18 OBD Column, 19* 150 mm, 5 μηι, 13 nm; mobile phase, water with 10 mmol NH ₄ HCO ₃ and ACN (32.0% ACN up to 39.0% in 8 min); Detector, 254 nm. This yielded compound 30 as a light yellow solid (9.3 mg, 12%). m/z (ES+) 450 (M+H) ⁺ . EXAMPLE 31

Preparation of (5')- 2-ι 6ΐ1ιοχν-5-(7- 3-ι 6ΐ1ιν1ηιοφ1ιο1ίηο -5-(ίείΓ3ΐινάΓθ-2^ νΓ3 -4- yD- 1 ,8-naphthyridin-2-yl)phenyj)methanol

31 Compound 31, (i> ^T )-{2-methox ~5-(7-{3~methyImorpho!ino)-5-(tetrahydro-2H- pyran-4-y!)-l,8-!iaphthyridin-2-y!)pheny!)inethanoS. To a solution of (5)-(5-(5-(3,6- dihydro-2H-pyran-4-yl)-7-i3~m.eth.ylm

methoxyphenyPmethanol (compound 28, 50 mg, O i l mmol) in ethyl acetate (20 niL) under nitrogen was carefully added palladium/carbon (10 % Pd) (30 mg). The system was purged with nitrogen, then hydrogen was introduced to the system. The resulting solution was stirred for 2 hour at room temperature, then evacuated and purged with nitrogen. The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Column, XBridge Prep Shield P18 QBD Column, 19* 150 mm, 5 μιη, 13 nm; mobile phase, water with 10 mmol NH4HCO3 and ACN (32.0% ACN up to 39.0% in 8 min); Detector, 254 nm . This yielded compound 31 as a yellow solid (2.1 mg, 4%). /z (ES+) 450 { M i l s .

EXAMPLE 32

Preparation of 5-(5 7-6Ϊ5((5)-3^6ΐ1ιν1ηΐθ Ηο1ϊηο -Τ6-η3ρΗΐ1ΐνΓίάϊη-2-ν1)-2- methoxyphenyl) methanol

no

Compound 32,1. 6~chIoro-2~(2~ethoxy~2-oxoethyI)nkotimc acid. To a solution of potassium fert-buioxide (8.80 g, 78.4 mmol) in 2-propanol (100 mL) was added ethyl 3- oxobutanoate (4.00 g, 30.7 mmol) drop-wise. The resulting solution was stirred for 1 h at room, temperature. This was followed by the addition of 2,6~dicli3oropyridme~3- carboxylic acid (5.00 g, 26.0 mmol) and Cu(OAc) ₂ (950 mg, 5.23 mmol). The resulting mixture was stirred overnight at 80 °C under nitrogen, then concentrated under reduced pressure. The pH of the solution was carefully adjusted to 3-4 with aqueous HC1 (2M), then the mixture was extracted with ethyl acetate (3 x 100 mL) and the combined organic extracts were dried (NaiSCX- , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography with dichioromethane/methanol (20: 1) as the eluent to obtain compound 32.1 as a yellow solid (4.2 g, 66%).

Compound 32.2. 2-chloro-l,6-naphthyridine-5,7(6H,8H)-dione. To a solution of 6- chioro~2-(2-ethoxy~2-oxoethyl)nicotinic acid (compound 32.1, 1.00 g, 4.10 mmol) in tetrahydrofuran (30 mL) was added triethylamine (0,77 mL, 5.5 mmol). The solution was cooled to 0 °C and chloro(ethoxy)methanone (0.50 mL, 5.2 mmol) was added drop- wise with stirring. The resulting solution was stirred for 1 hour at 0 °C, then 25% ammonium hydroxide (2.53 mL, 16.4 mmol) was added. The resulting mixture was concentrated under reduced pressure and the residue was diluted with water (30 mL). The pH of the solution was adjusted to 6.5-7.5 with 6 M hydrogen chloride and the resulting solution was stirred for 1 hour at 0 °C. The precipitated solids were collected by filtration to obtain compound 32.2 as a yellow solid (440 mg, 50%).

Compound 32.3. 2,5,7- Trichloro-l,6-naphthyridine. To a 50-mL round-bottom flask, was added 2-chloro-l,6-naphthyridine-5,7(6H,8H)-dione (compound 32.2, 800 mg, 4.07 mmol) and phenylphosphonic dichloride (10 niL). The resulting solution was stirred for 5 hours at 140 °C under nitrogen. The reaction mixture was cooled to room temperature, then carefully quenched by slow addition to ice water ( 100 mL). The resulting mixture was extracted with ethyl acetate (2 x 100 mL) and the combined organics were dried (NaiSO,.), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1 : 100) as the eluent to obtain compound 32.3 as a white solid (500 mg, 53%).

Compound 32.4. (5-(5,7-Dichloro-l,6-naphthyridin-2-yl)-2- methoxyphenyl)methanol. To a solution of 2,5,7-trichloro-l,6-naphthyridirie

(compound 32.3, 1.00 g, 4.28 mmol) in ethanol/toluene (1 : 1 (40 mL) was added sodium carbonate (910 mg, 8.59 mmol), tetrakis(triphenylphosphine)palladium (250 mg, 0.22 mmol) and (3-(hydroxymethyl)-4-methoxyphenyl)boronic acid (780 mg, 4.29 mmol). The resulting mixture was stirred for 2 hours at 90 °C under nitrogen. The mixture was cooled, and the precipitating solids were collected by filtration to obtain compound 32.4 as a white solid (1.0 g, 70%).

Compound 32.5. (5)-(5-(7-Chloro-5-(3-methylmorpholino)-l,6-naphthyridin-2-y l)-

2-methoxyphenyl)methanoI. Into a 10-mL round-bottom flask, was placed (5-(5,7- dicliloro-l,6-naphthyridin-2-yl)-2-methoxyphenyl)metlianol (compound 32.4, 40 mg, 0.12 mmol,) and (,S)-3-methylm(^holine (0.3 mL). The resulting solution was stirred under nitrogen overnight at 100 °C, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether ( 1 : 1 ) as the eluent to obtain compound 32.5 as a yellow oil (20 mg, 42%).

Compound 32. (5-(5,7-bis((S)-3-methylmorpholino)-l,6-naphthyridin-2-yl)-2 - methoxyphenyl)methanol. To a solution of (5)-(5-(7-οΜθΓθ-5-(3-ηΐ6Λ}Ίηιοφ^Πηο)- l,6-naplithyridin-2-yl)-2-methoxyphenyl)methano3 (compound 32.5, 80 mg, 0.20 mmol) in dioxane (2.5 mL) was added (2-dicyclohexylphosphino-2',6'-diisopropoxy- 1, 1 '-biphenyl)[2-(2'-amino-l, 1 '-biphenyl)]palladium(II) methanesulfonate (RuPhos-Pd- G3) (33 mg, 0.040 mmol), 2~dicyclohexyiphosphino-2' 6'~diisopropoxybiphenyl (RuPhos) (19 mg, 0.040 mmol), (,S)-3-methylrnc^holine (206 mg, 2.04 mmol) and sodium feri-butoxide (38 mg, 0.40 rnmol). The resulting mixture was stirred for 2 hours at 100 °C under nitrogen, then cooled and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether ( 1 :2) as the eluent to obtain the product in an impure form. The product was additionally purified by Prep-HPLC with the following conditions (Prep-HPLC-043): Column, XBridge Shield RP 1 8 OBD Column, 5 μηι, 19* 150 mm; mobile phase, water with 10 mrnoi NH ₄ HCO ₃ and acetonitrile (43% ACN up to 58% in 8 min); detector, UV 254 am. This yielded compound 32 as a yellow solid ( 13.1 mg, 14%). m/z (ES+) 465 ( W W) .

EXAMPLE 33

Preparation of 2-metho y-5- 5- ffl-3-me1nylmoφholino)-7- _l .S -2-methyl iperidin-l - vD- 1.6-naphthyridin-2-yl)phenyl)methanol

Compound 33, (2-methoxy-5-(5-((S)-3-methylmorpholino)-7-((iS)-2- methylpiperidin-l-yl)-l,6-naphthyridin-2-yl)phenyl)methanol. Compound 33 was prepared using standard chemical manipulations and procedures similar to those used for preparation of compound 32, except (<S)-2-methylpiperidine was used in place of (,S)-3-methylmorpholine in the Buchwaid coupling reaction, m/z (ES+) 463(Μ+Ή) ⁺ .

EXAMPLE 34

Preparation of (2-methoxy-5-(7-((5V3-methylmoipholino)-5-((^-2-methylpiperi din- l- yl)- 1.6-naphthy ridin-2-yl)phenyl)methanol

Compound 34, (2-methoxy-5-(7-((S)-3-methylmorpholino)-5-((S)-2- inethySpiperid!n~l-yI)~l,6~naphthyridin-2-yl)pheny!}methanoI . Compound 34 was prepared using standard chemical manipulations and procedures similar to those used for preparation of compound 32, except (5)-2-methylpiperidine was used in place of (<S)-3-methylmorpholine in the S^Ar reaction, m/z (ES+) 463(M+H) ^"r .

EXAMPLE 35

Preparation of (5-(5.7-bis((A -2-memylpiperidin- l-yl)-1.6-naphthyridm-2-yl)-2- methoxyphenyl)methaaol

Compound 35. (5-(5,7-bis((S)-2-methylpiperidin-l-yl)-l,6-naphthyridin-2-y l)-2- methoxyphenyl)methanol. Compound 35 was prepared using standard chemical manipulations and procedures similar to those used for preparation of compound 32, except (<S)-2-methylpiperidine was used in place of (i.S)~3~¾mi:hy3rnorphoime in the 8 ΑΓ and Buchwald reactions, m/z (ES+) 461(M+H) ⁺ .

EXAMPLE 36

Preparation of (3-S'.3 'S)-4.4'-(2-(4-methoxyphenyl)- L6-naphthyridine-5J-diyl)bis(3- methylmorpholine)

Compound 36. (3S,3 'S)-4,4^2-(4-methoxyphenyl)-l,6-naphthyridine-5,7- diyl)bis(3-methyImorphoIine). Compound 36 was prepared using standard chemical manipulations and procedures similar to those used for preparation of compound 32, except (4-methoxyphenyi)boronic acid was used in place of (3-(hydroxymethyl)-4- methoxyphenyijboronic acid in the Suzuki reaction, m/z (ES+) 435 (M+H) ⁺ .

EXAMPLE 37

Preparation of (3-(5 J-bis(( _i S')-3-methvimorpho¾ino)-1.6-naphthyridin-2- yDphenypmethanol

Compound 37. (3-(5,7-bis((S)-3-methylmorpholino)-l,6-naphthyridin-2- yl)phenyl)methanol. Compound 37 was prepared using standard chemical manipulations and procedures similar to those used for preparation of compound 32, except (3~(hydroxymethyi)phenyi)boronic acid was used in place of (3- (hydroxymethyl)-4-methoxyphenyl)boronic acid in the Suzuki reaction, m/z (ES+) 435 (M+H) ⁺ . EXAMPLE 38

Preparation of 3 -( 5.7-bi s((»S)-3 -methylmorpholino) - 1.6-naphthyridin-2-vD-N- methy Ibenzami de

Compound 38, 3-(5,7-bis((S)-3-methylmorpholino)-l,6-naphthyridin-2-yl)-A ^r - methylbenzamide. Compound 38 was prepared using standard chemical manipulations and procedures similar to those used for preparation of compound 32, except (3- (methylcarbamoyl)phenyl)boronic acid was used in place of (3-(hydroxymethyl)-4- methoxyphenyl)boronic acid in the Suzuki reaction , m/z (ES+) 462 (M+H) ^" EXAMPLE 39

Preparation of (5-(5 ^-άίηιοφΗοΙϊηο-Ι.ό-ηα ΗΐΙινήάίη^-νΠ^-ηΐΒΐηοχν ΙΐΒηνΡηιοίΙιαηοΙ

Compound 39. (5-(5,7-dimorpholino-l,6-naphthyridin-2-yl)-2- methoxyphenyl)methanol. Into a round-bottom flask, was placed a solution of (5-(5,7- dichloro-l,6-naphth}'ridin-2-yl)-2-methoxyphenyl)methanol (compound 32.4, 64 rng, 0.19 mmol) and morpholine (2.5 mL). The resulting solution was stirred for 30 hours at 130 °C under nitrogen, cooled and concentrated under reduced pressure. The crude product was purified by Prep-HPL

EXAMPLE 40

mTOR Biochemical Assay

Half-maximal inhibitor}' concentration (ICjo) of the mTOR human enzyme was determined for each compound by monitoring the extent of phosphorylation of human p70 S6 kinase residue Thr389 in the presence or absence of mTOR inhibitor. The phosphorylation of Thr389 by mTOR was monitored through the use of a commercially available, europium-based, time-resolved fluorescence resonance energy transfer (TRFRET) assay, e.g. LANCE ® technology from Perkin Elmer or equivalent. Recombinant human mTOR enzyme was pre-incubated across a range of mTOR- inhibitor concentrations to give a dose response curve for the inhibitor compound. After incubation of mTOR with inhibitor compound, an appropriately emission dye labeled synthetic peptide containing the residues surrounding Thr38 of human p70 S6K, e.g. the Ultra ULight' ^M ~p7G S6K (Thr389) Peptide or equivalent was added to the compound/enzyme mix for 2 hours. The extent of phosphorylation of Thr389 residues was then quantitated with an europium-anti-phospho-p70 S6K (Thr389) antibody, such as mouse monoclonal antibody labeled with the LANCE® Europium W1024-ITC chelate or equivalent. The resulting fluorescent signal was obtained by using a TR- FRET reader, such as the Tecan Ml 000 Plate reader in TR-FRET mode (ex. 320 nm em. 665 nm). The IC ₅₀ values are summarized below in Table 1, wherein IC ₅₀ less than 0.1 μΜ are categorized as group A, IC50 between 0.1 and 1 μΜ are categorized as group B, and IC ₅ 0 values above 1 μΜ are categorized as group C.

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EXAMPLE 40

mTOR Cell-based ELISA

The cellular half-maximal effective concentration (EC ₅₀ ) was determined by monitoring the extent of mTOR phosphorylation of 4E-BP1 residues Thr37 Thr46 when human A549 ceils are incubated in the presence or absence of mTOR inhibitor compounds. A549 cells are seeded in multi-well plates the day before compound treatment. Serial dilutions of the compounds in tissue culture medium are added to replicate wells of the cells and incubated for 1 hour. After compound treatment, the cells are lysed, and the lysate is transferred to a plate coated with a rabbit anti-4EBP phospho-Thr37/Thr46 capture antibody. Following a 2 hour mcubation, a matched 4E-BP1 mouse detection antibody is added for 1 hour. This is follow ed by a 30 minute incubation with anti- mouse IgG, HRP-conjugated antibody. Signal is generated by the addition of a chemiluminescent HRP substrate. The resulting signal is quantitated with a luminometer, such as the Tecan Ml 000 plate reader. The EC50 values are summarized below in Table 2, wherein EC5 ₀ less than 0.1 μΜ are categorized as group A, EC5 ₀ between 0.1 and 1 μΜ are categorized as group B, and EC50 values greater than 1 μΜ are categorized as group C.

Table 2

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EXAMPLE 40

mTOR Comparative Data

Compounds in this disclosure are potent mTor inhibitors as exemplified by the biochemical inhibition (IC ₅₀ ) and cellular inhibition potency (EC ₅₀ ) data presented in Table 3 for structures ID # 1 and #32. In addition, these compounds were found to have desirable biochemical kinase selectivity versus PI3K across important isoforms alpha, beta and delta as shown in Table 3 as IC5 ₀ S > 0.5 μΜ. This selectivity is desirable to avoid potential off-target effects caused by inhibition of PI3K which might limit the therapeutic index and utility of mTor inhibitors. This selectivity was unexpected since the ATP -competitive binding sites for mTor and PI3K are very similar and most published mTor inhibitors show a lack of PI3K selectivity. The selectivity of the disclosed series was especially surprising in light of the poor selectivity of a structurally similar series of mTor inhibitors exemplified by structure AA which displays PI3K inhibition activity across isoforms and potent inhibition (<0.1 μΜ against the alpha and delta isoforms). The described series in this application shows a remarkable potency for mTor and selectivity against the closely related kinase PI3K.

Table 3

All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification are incorporated herein by reference, in their entirety to the extent not inconsistent with the present description.

Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically in this disclosure. Such equivalents are intended to be encompassed in the scope of the following claims.

From the foregoing it will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the appended claims.