NZ625447B2

NZ625447B2 - Thienopyrimidine inhibitors of atypical protein kinase c

Info

Publication number: NZ625447B2
Application number: NZ625447A
Authority: NZ
Inventors: Bruce D Dorsey; Keith S Learn; Emma L Morris; Gregory R Ott; Jonathan R Roffey; Christelle N Soudy; Jason C Wagner
Original assignee: Cancer Research Technology Limited; Ignyta Inc
Priority date: 2011-11-23
Filing date: 2012-11-19
Publication date: 2016-01-06

Abstract

The present disclosure provides a compound of formula (I) or a salt thereof, wherein R1, R2, R3, R4, R5, R6, A, G, M, Q and X are as defined herein. A compound of formula (I) and its salts have a PKC inhibitory activity, and may be used to treat proliferative disorders such as cancer. Examples of compounds of formula (I) are: (S)-3-Phenyl-N*1*-(2-pyridin-4-yl-7-[1,2,3]triazol-1-yl-thieno[3,2-d]pyrimidin-4-yl)-propane-1,2-diamine; (S)-N*1*-[7-(2-Cyclopropyl-ethyl)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl]-3-phenyl-propane-1,2-diamine; (E)-3-[4-((S)-2-Amino-3-phenyl-propylamino )-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-7-yl]-acrylic acid tert-butyl ester and 4-((S)-2-Amino-3-phenyl-propylamino)-2-pyridin-4-yl-thieno[3,2-d]pyrimidine-7-carboxylic acid dimethyl amide. compounds of formula (I) are: (S)-3-Phenyl-N*1*-(2-pyridin-4-yl-7-[1,2,3]triazol-1-yl-thieno[3,2-d]pyrimidin-4-yl)-propane-1,2-diamine; (S)-N*1*-[7-(2-Cyclopropyl-ethyl)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl]-3-phenyl-propane-1,2-diamine; (E)-3-[4-((S)-2-Amino-3-phenyl-propylamino )-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-7-yl]-acrylic acid tert-butyl ester and 4-((S)-2-Amino-3-phenyl-propylamino)-2-pyridin-4-yl-thieno[3,2-d]pyrimidine-7-carboxylic acid dimethyl amide.

Description

WO 78126 THIENOPYRIMIDINE TORS OF ATYPICAL PROTEIN KINASE C BACKGROUND OF THE INVENTION PKCL and PKCQ (accession numbers NM_002740 and NM_002744 respectively) together deﬁne the atypical sub-class of the protein kinase C (PKC) family. The aPKCs are structurally and functionally ct from the other PKC sub-classes, classic/conventional and novel, as their catalytic activity is not dependent on diacylglycerol and calcium (Ono, Y., Fujii, T., Ogita, K., Kikkawa, U., Igarashi, K., and Nishizuka, Y. (1989). n kinase C zeta subspecies from rat brain: its structure, expression, and properties. Proc Natl Acad Sci U S A 86, 3099-3103). Structurally, PKCL and PKCQ contain a C-terminal serine/threonine kinase domain (AGC class) and an N- terminal regulatory region containing a Phox Bem 1 (FBI) domain involved in mediating n:protein interactions critical for aPKC function. At the amino acid level the aPKCs share 72% overall gy, however, the kinase domains share 84% identity and differ in the active site by just a single amino acid. This striking homology suggests an ATP- competitive ligand would not be expected to exhibit significant aPKC m selectivity.

The aPKCs have been implicated in a diverse number of signalling pathways, demonstrating both redundant and distinct signalling functions. Both isoforms have emerged as central players in the mechanisms that regulate the establishment and maintenance of cellular polarity in multiple cell types (reviewed in Suzuki, A., and Ohno, S. (2006). The KC system: lessons in polarity. J Cell Sci 119, 979-987). Genetic dissection of their ﬁlnctions using knockout mice have also revealed preferential roles for PKCQ in the regulation ofNF-kB signalling es, M., Sanz, L., Martin, P., Duran, A., Braun, U., Garcia, J.F., o, F., eco, M.T., Rennert, RD, and Moscat, J. (2001). Targeted disruption of the zetaPKC gene results in the impairment of the NF- kappaB pathway. Mol Cell 8, 771-780), and PKCL in insulin secretion and action (Farese, R.V., Sajan, M.P., Yang, H., Li, P., Mastorides, S., Gower, W.R., Jr., Nimal, S., Choi, C.S., Kim, S., Shulman, G.I., et al. (2007). Muscle-speciﬁc ut of PKC-lambda impairs glucose transport and induces metabolic and diabetic syndromes. J Clin Invest I I 7, 2289-2301). In addition, both isoforms have been implicated in the pathogenesis of cancer making a strong case for the inhibition of the aPKCs as a novel therapeutic avenue.

PKCL is a known oncogene in non-small cell lung cancer (NSCLC). In one study it was shown to be overexpressed in 69% ofNSCLC cases at the n level. Consistent with this, the PKCL gene (PRKCI residing on chromosome 3q26) was shown to be ampliﬁed in 36.5% ofNSCLC tumours examined, including 96% of the squamous cell oma sub-type (Regala, R.P., Weems, C., Jamieson, L., Khoor, A., Edell, E.S., Lohse, C.M., and Fields, A.P. (2005b). al protein kinase C iota is an oncogene in human non-small cell lung cancer. Cancer Res 65, 8905-8911). Ampliﬁcation of 3q26 has also been reported in 44% of ovarian cancers, including >70% of serous epithelial ovarian cancers where 3q26 ampliﬁcation is translated into increased PKCL protein expression.

Moreover, increased PKCL expression is associated with poor prognosis in NSCLC and ovarian cancer where it may serve as a diagnostic biomarker of aggressive disease (Eder, A.M., Sui, X., Rosen, D.G., Nolden, L.K., Cheng, K.W., Lahad, J.P., Kango-Singh, M., Lu, K.H., Wameke, C.L., Atkinson, E.N., et al. (2005). Atypical PKCiota contributes to poor prognosis through loss of apical-basal ty and cyclin E overexpression in ovarian cancer. Proc Natl Acad Sci U S A 102, 125 24; Zhang, L., Huang, J., Yang, N., Liang, S., Barchetti, A., Giannakakis, A., Cadungog, M.G., O'Brien-Jenkins, A., rio, M., Roby, K.F. et al. (2006). Integrative genomic analysis of protein kinase C (PKC) family identiﬁes PKCiota as a biomarker and potential oncogene in ovarian carcinoma. Cancer Res 66, 4627-4635). 3q26 ampliﬁcations have been observed in many other s including oesophageal squamous cell carcinoma (Yang, Y.L., Chu, J.Y., Luo, M.L., Wu, Y.P., Zhang, Y., Feng, Y.B., Shi, Z.Z., Xu, X., Han, Y.L., Cai, Y., et al. (2008). Ampliﬁcation of PRKCI, located in 3q26, is associated with lymph node metastasis in esophageal squamous cell oma. Genes Chromosomes Cancer 47, 127- 136) and breast cancer (Kojima, Y., Akimoto, K., Nagashima, Y., Ishiguro, H., Shirai, S., Chishima, T., Ichikawa, Y., Ishikawa, T., Sasaki, T., Kubota, Y., et al. . The overexpression and altered zation of the atypical protein kinase C lambda/iota in breast cancer correlates with the ogic type of these tumors. Hum Pathol 39, 824- 831) suggesting that PKCL may also participate in the pathogenesis of these diseases.

In NSCLC the primary function of PKCL is to drive transformed growth via a Racl / PAK/ MEK/ ERK signalling axis. However, PKCL also functions in NSCLC al, resistance to chemotherapy, and invasion via distinct pathways (reviewed in Fields, AR, and Regala, RP. . Protein kinase C iota: human oncogene, prognostic marker and therapeutic . Pharmacol Res 55, 487-497). In ovarian cancer transformed growth is correlated with lated lial cell polarity and increased cycle E expression (Eder et al., 2005) suggesting that PKCL can inﬂuence the cancer phenotype through multiple mechanisms. Compelling evidence has emerged to t that inhibition of PKCL may be a useful therapeutic approach to combat tumours characterised by increased PKCL expression. In transgenic models, mice with elevated PKCL activity in the colon are more susceptible to carcinogen-induced colon carcinogenesis, and expression of a kinase-dead mutant of PKCL blocks the transformation of intestinal cells by oncogenic Ras (Murray, N.R., Jamieson, L., Yu, W., Zhang, J Gokmen-Polar, Y., Sier, D., Anastasiadis, P., Gatalica, Z., Thompson, EA, and Fields, AP. (2004). Protein kinase Ciota is required for Ras transformation and colon carcinogenesis in vivo. J Cell Biol 164, 797-802). Finally, genetic or cological inhibition of PKCL by a gold derivative — aurothiomalate (ATM) — blocks the growth of NSCLC cells in soft agar and significantly decreases tumour volume in xenograft models ofNSCLC(Regala, R.P., Thompson, EA, and Fields, AP. (2008). Atypical protein kinase C iota expression and aurothiomalate sensitivity in human lung cancer cells. Cancer Res 68, 895; Regala, R.P., Weems, C., Jamieson, L., Copland, J.A., Thompson, EA, and Fields, A.P. (2005a). Atypical protein kinase Ciota plays a al role in human lung cancer cell growth and tumorigenicity. J Biol Chem 280, 3 1 109-31 1 15).

Despite the high degree of rity between aPKC isoforms, the role of PKCE; in cancer is ct from that of PKCL. PKCQ plays a role in NSCLC cell survival by phosphorylating and antagonising the pro-apoptotic effects of Bax in response to ne (Xin, M., Gao, F., May, W.S., Flagg, T., and Deng, X. (2007). Protein kinase Czeta abrogates the proapoptotic ﬁanction of Bax through phosphorylation. J Biol Chem 282, 21268-21277). PKCE; activity has also been linked to resistance t a wide range of cytotoxic and genotoxic agents. For instance, in human leukaemia cells, overexpression of PKCE; confers resistance t l-[3-D-arabinofuranosylcytosine (ara-C), daunorubicin, etoposide, and mitoxantrone-induced apoptosis enko, R., Poirson-Bichat, F., ey, C., Belon, J.P., Garrido, C., Solary, E., and Bettaieb, A. (2002). Atypical protein kinase C zeta as a target for ensitization of tumor cells. Cancer Res 62, 821; P10, 1., Hernandez, H., Kohlhagen, G., Lautier, D., Pommier, Y., and Laurent, G. (2002).

Overexpression of the atypical protein kinase C zeta s topoisomerase II catalytic activity, cleavable complexes formation, and nduced cytotoxicity in monocytic U937 leukemia cells. J Biol Chem 277, 31407-31415). Furthermore, inhibition of PKCE; activity through expression of a kinase-dead mutant sensitises leukaemia cells to the cytotoxic effects of etoposide both in vitro and in viva (Filomenko et al., 2002). Atypical protein kinase C regulates dual pathways for ation of the oncogenic coactivator SRC-3/AIB1. Mol Cell 29, 465-476), and both of these proteins have been postulated to play a role in tamoxifen resistance in breast cancer (Ioms, E., Lord, C.J., and th, A.

. Parallel RNAi and compound screens identify the PDKl pathway as a target for tamoxifen sensitization. Biochem J 41 7, 361-370; Osborne, C.K., Bardou, V., Hopp, T.A., ss, G.C., Hilsenbeck, S.G., Fuqua, S.A., Wong, J., Allred, D.C., Clark, G.M., and Schiff, R. . Role of the estrogen receptor coactivator AIBl (SRC-3) and HER-2/neu in tamoxifen resistance in breast cancer. J Natl Cancer Inst 95, 353-361). er these studies suggest that inhibition of PKCQ activity may have beneficial therapeutic effects by acting as a chemosensitiser to a wide array of commonly used chemotoxic agents in the clinic.

Further evidence that small molecule inhibition of PKCE; could have important therapeutic benefits has recently emerged from tumour models that link PKCE; signalling to the mTOR pathway. PKCE; is constitutively activated in ular ma and has been identified as a novel target for the anti-CD20 therapeutic antibody rituximab (Leseux, L., Laurent, G., Laurent, C., Rigo, M., Blanc, A., Olive, D., and Bezombes, C. (2008).

PKC zeta mTOR pathway: a new target for rituximab therapy in follicular ma.

Blood 1 I I Rituximab inhibits follicular lymphoma proliferation by targeting a , 285-291).

PKCC-MAPK-mTOR pathway, suggesting that PKCE; is both a target of Rituximab, and a key regulator of its' anti-leukaemic effect. Regulation of the mTOle7OS6K pathway by PKCE; has also been ated in the transition of prostate cancer cells to an androgen- independent state (Inoue, T., Yoshida, T., Shimizu, Y., shi, T., Yamasaki, T., Toda, Y., Segawa, T., Kamoto, T., Nakamura, E., and Ogawa, O. (2006). Requirement of androgen-dependent activation of protein kinase Czeta for androgen-dependent cell proliferation in LNCaP Cells and its roles in transition to androgen-independent cells. Mol Endocrinol 20, 3053-3069). Finally, mice containing a homozygous deletion of Par4, a negative regulator of PKCQ, exhibit greatly enhanced PKCQ activity. These mice spontaneously develop s of the prostate and trium, and potentiate Ras- induced lung carcinogenesis consistent with a role for PKCQ in lung cancer (Garcia-Cao, 1., Duran, A., Collado, M., cosa, M.J., Martin-Caballero, J., Flores, J.M., Diaz- Meco, M.T., Moscat, J., and Serrano, M. (2005). Tumour-suppression activity of the ptotic regulator Par4. EMBO Rep 6, 577-5 83; Joshi, J., Femandez-Marcos, P.J., Galvez, A., Amanchy, R., Linares, J.F., Duran, A., Pathrose, P., Leitges, M., Canamero, M., Collado, M., et al. (2008). Par-4 inhibits Akt and suppresses Ras-induced lung genesis. EMBO J 2 7, 2181-2193).

A need exists for aPKC inhibitors for use as pharmaceutical agents.

SUMMARY OF THE INVENTION The ion provides a nd of formula (I) R3 | R4 \ R2 R6 A \ \ X N G or a salt f, wherein R1, R2, R3, R4, R5, R6, A, G, M, Q and X are as deﬁned herein.

A compound of formula (I) and its salts have aPKC inhibitory ty, and may be used to treat aPKC-dependent disorders or conditions.

The present invention ﬁarther provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with at least one pharmaceutically acceptable carrier, diluent, or excipient therefor.

In another aspect, the present invention provides a method of treating a subject ing from an aPKC-dependent disorder or condition comprising: stering to the subject a compound of formula (I) or a pharmaceutically acceptable salt thereof.

The present invention ﬁarther provides a method of treating a proliferative disorder in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE ION 1. Deﬁnitions " as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass reasonable variations of the value, such as, for example, ::lO% from the specified value. For example, the phrase “about 50” encompasses reasonable variations of 50, such as ::lO% of the numerical value 50, or from 45 to 55.

"Alkyl" or “alkyl group” refers to a monoradical of a branched or ched saturated hydrocarbon chain. Examples include, but are not limited to, methyl, ethyl, n- propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, tert-butyl, isobutyl, etc. Alkyl groups typically contain l-lO carbon atoms, such as 1-6 carbon atoms or 1-4 carbon atoms, and can be tuted or unsubstituted.

“Alkylene” or “alkylene group” refers to a cal of a branched or unbranched saturated hydrocarbon chain. es include, but are not limited to, methylene (—CH2—), the ethylene s (—CH(CH3)— and 2—), the propylene isomers (— CH(CH3)CH2—, —CH(CH2CH3)—, —C(CH3)2—, and —CH2CH2CH2—), etc. ne groups typically contain l-lO carbon atoms, such as 1-6 carbon atoms, and can be substituted or unsubstituted.

“Alkenyl” or “alkenyl group” refers to a monoradical of a branched or unbranched hydrocarbon chain containing at least one double bond. Examples include, but are not limited to, ethenyl, 3-buten-l-yl, 2-ethenylbutyl, and 3-hexen-l-yl. Alkenyl groups lly contain 2-10 carbon atoms, such as 2-6 carbon atoms or 2-4 carbon atoms, and can be tuted or unsubstituted.

“Alkynyl” or “alkynyl group” refers to a monoradical of a branched or unbranched hydrocarbon chain containing at least one triple bond. Examples include, but are not limited to, ethynyl, 3-butyn- l -yl, yl, 2-butyn- l -yl, and 3-pentyn- l -yl.

Alkynyl groups typically contain 2-10 carbon atoms, such as 2-6 carbon atoms or 2-4 carbon atoms, and can be substituted or unsubstituted.

“Aryl” or “aryl group” refers to phenyl and 7-15 membered dical bicyclic or tricyclic hydrocarbon ring systems, including bridged, spiro, and/or fused ring systems, in which at least one of the rings is aromatic. Aryl groups can be substituted or unsubstituted. Examples include, but are not limited to, naphthyl, indanyl, l,2,3,4-tetrahydronaphthalenyl, 9-tetrahydro-5H— ycloheptenyl, and 6,7,8,9-tetrahydro-5H-benzocycloheptenyl. An aryl group may contain 6 (i.e., phenyl) or 9 to 15 ring atoms, such as 6 (i.e., phenyl) or 9-11 ring atoms, e.g., 6 (i.e., phenyl), 9 or 10 ring atoms.

“Arylene” or ne group” refers to a phenylene (—C6H4—) or a 7-15 membered diradical bicyclic or tricyclic hydrocarbon ring systems, including bridged, spiro, and/or fused ring systems, in which at least one of the rings is aromatic. Arylene groups can be substituted or unsubstituted. For example, an arylene group may contain 6 (i.e., phenylene) or 9 to 15 ring atoms; such as 6 (i.e., phenylene) or 9-11 _ 6 _ ring atoms; e.g., 6 (i.e., phenylene), 9 or 10 ring atoms. An arylene group can also include ring s tuted on ring carbons with one or more —OH functional groups (which may ﬁarther tautomerize to give a ring C=O group).

“Arylalkyl” or “arylalkyl group” refers to an alkyl group in which a hydrogen atom is replaced by an aryl group, wherein alkyl group and aryl group are as preViously deﬁned (i.e., arylalkyl—). Arylalkyl groups can be substituted or unsubstituted.

Examples include, but are not limited to, benzyl (C6H5CH2—).

“Cycloalkyl” or “cycloalkyl group” refers to a monoradical omatic carbocyclic ring system, which may be saturated or unsaturated, substituted or unsubstituted, and may be monocyclic, bicyclic, or tricyclic, and may be bridged, spiro, and/or fused.

Examples include, but are not limited to, cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, norbomyl, enyl, bicyclo[2.2.l]hexane, o[2.2. l]heptane, bicyclo[2.2. l]heptene, bicyclo[3 . l . l]heptane, bicyclo[3 .2. l]octane, bicyclo[2.2.2]octane, o[3.2.2]nonane, bicyclo[3.3. l]nonane, and bicyclo[3.3.2]decane. The cycloalkyl group may contain from 3 to 10 ring atoms, such as 3 to 7 ring atoms (e.g., 3 ring atoms, 5 ring atoms, 6 ring atoms, or 7 ring atoms).

“Cycloalkylalkyl” or “cycloalkylalkyl group” refers to an alkyl group in which a hydrogen atom is replaced by a cycloalkyl group, wherein alkyl group and cycloalkyl group are as usly defined (i.e., cycloalkylalkyl—). lkylalkyl groups can be substituted or unsubstituted. Examples include, but are not limited to, exylmethyl (C6H11CH2—).

“Haloalkyl” or “haloalkyl group” refers to alkyl groups in which one or more hydrogen atoms are replaced by halogen atoms. Haloalkyl includes both ted alkyl groups and unsaturated alkenyl and alkynyl groups, such as for example —CF3, — CHFZ, —CH2F, 3, —CHFCF3, —CH2CF3, —CF2CH3, 3, —CF2CF2CF3, —CF2CH2CH3, CF—CFz, CCl—CHZ, CBr—CHZ, , C=C-CF3, — CHFCHZCHg and —CHFCH2CF3.

“Halogen” includes ﬂuorine, chlorine, bromine and iodine atoms.

“Heteroaryl” or “heteroaryl group” refers to (a) 5 and 6 membered clic aromatic rings, which contain, in addition to carbon atom(s), at least one heteroatom, such as nitrogen, oxygen or sulfur, and (b) 7-15 membered bicyclic and tricyclic rings, which contain, in addition to carbon atom(s), at least one heteroatom, such as nitrogen, oxygen or sulfur, and in which at least one of the rings is aromatic. _ 7 _ Heteroaryl groups can be substituted or unsubstituted, and may be bridged, spiro, and/or fused. Examples include, but are not limited to, 2,3-dihydrobenzofuranyl, l ,2-dihydroquinolinyl, 3 ,4-dihydroisoquinolinyl, l ,2,3 ,4-tetrahydroisoquinolinyl, l,2,3,4-tetrahydroquinolinyl, benzoxazinyl, benzthiazinyl, chromanyl, furanyl, 2- furanyl, 3-furanyl, imidazolyl, olyl, isothiazolyl, oxadiazolyl, yl, pyridinyl, 2-, 3-, or 4-pyridinyl, pyrimidinyl, 2-, 4-, or 5-pyrimidinyl, pyrazolyl, pyrrolyl, 2- or 3-pyrrolyl, pyrazinyl, pyridazinyl, 3- or 4-pyridazinyl, 2-pyrazinyl, l, nyl, 3- thienyl, tetrazolyl, thiazolyl, thiadiazolyl, triazinyl, triazolyl, pyridinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, naphthyridinyl, inyl, phthalazinyl, purinyl, alloxazinyl, benzimidazolyl, benzofuranyl, benzofurazanyl, 2H-l-benzopyranyl, benzothiadiazine, benzothiazinyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, cinnolinyl, furopyridinyl, indolinyl, indolizinyl, indolyl, or 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 3H- indolyl, quinazolinyl, quinoxalinyl, isoindolyl, isoquinolinyl, lO-aza- tricyclo[6.3 . l .0*2,7*]dodeca-2(7),3,5-trienyl, lZ-oxa-lO-azatricyclo [6.3. l .0*2,7*]dodeca-2(7),3,5-trienyl, lZ-aza-tricyclo[7.2. l .0*2,7*]dodeca- ,5-trienyl, l0-aza-tricyclo[6.3.2.0*2,7*]trideca-2(7),3,5-trienyl, 2,3,4,5- tetrahydro- l o [d]azepinyl, l ,3 ,4,5 -tetrahydro-benzo [d]azepinonyl, l ,3 ,4,5 -tetrahydro-benzo [b] azepinonyl, 2,3 ,4,5 -tetrahydro-benzo [c]azepin- l - onyl, l,2,3,4-tetrahydro-benzo[e][l,4]diazepinonyl, 2,3,4,5-tetrahydro-lH- benzo[e] [ l zepinyl, 5 -tetrahydrooxa-benzocycloheptenyl, 2,3 ,4,5- tetrahydro- l H-benzo [b] azepinyl, 1 ,2,4,5 -tetrahydro-benzo [e] [ l ,3 ] diazepin-3 -onyl, 3 ,4-dihydro-2H-benzo [b] [l ,4]dioxepinyl, 3 ,4-dihydro-2H-benzo[f] [ l ,4]oxazepin— -onyl, 6,7,8,9-tetrahydrothiaaza-benzocycloheptenyl, 5,5-dioxo-6,7,8,9- tetrahydro-S-thiaaza-benzocycloheptenyl, and 2,3,4,5-tetrahydro- f][l,4]oxazepinyl. For example, a heteroaryl group may contain 5, 6, or 8- ring atoms. As another example, a heteroaryl group may contain 5 to 10 ring atoms, such as 5, 6, 9, or 10 ring atoms.

“Heteroarylalkyl” or “heteroarylalkyl group” refers to an alkyl group in which a hydrogen atom is ed by a heteroaryl group, wherein alkyl group and heteroaryl group are as preViously deﬁned (i.e., heteroarylalkyl—). Heteroarylalkyl groups can be substituted or unsubstituted. Examples include, but are not d to, the \ CH32 2 I \ \ / / or | or \ N C / | H2 N N/ pyridinylmethyl isomers ( ) “Heterocycloalkyl” or ocycloalkyl group” refers to 3-15 membered clic, bicyclic, and tricyclic non-aromatic rings, which may be saturated or unsaturated, can be substituted or unsubstituted, may be bridged, spiro, and/or ﬁJsed, and which contain, in addition to carbon atom(s), at least one heteroatom, such as nitrogen, oxygen, sulfur or phosphorus. Examples include, but are not limited to, tetrahydroﬁlranyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, olinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl, isoindolinyl, lO morpholinyl, thiomorpholinyl, homomorpholinyl, peridyl, homopiperazinyl, thiomorpholinyl-S-oxide, thiomorpholinyl-S,S-dioxide, pyrrolidinyl, tetrahydropyranyl, piperidinyl, tetrahydrothienyl, homopiperidinyl, homothiomorpholinyl-S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, opyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl, ydrothienyl-5 -oxide, tetrahydrothienyl-S,S- dioxide, homothiomorpholinyl-S-oxide, quinuclidinyl, 2-oxa yclo[2.2.l]heptane, 8-oxaaza-bicyclo[3.2. l]octane, 3,8-diaza- bicyclo[3.2. ne, 2,5-diaza-bicyclo[2.2. l]heptane, 3,8-diazabicyclo [3.2. l]octane, 3,9-diaza-bicyclo[4.2.l]nonane, 2,6-diaza- bicyclo[3.2.2]nonane, xaphosphinane 4-oxide, [l,4]azaphosphinane 4-oxide, [l,2]oxaphospholane 2-oxide, phosphinane l-oxide, [l,3]azaphospholidine 3- oxide, and [l,3]oxaphospholane 3-oxide. A heterocycloalkyl group may contain, in addition to carbon atom(s), at least one nitrogen, oxygen, or sulfur. For example, a heterocycloalkyl group may contain, in addition to carbon atom(s), at least one nitrogen or oxygen. A heterocycloalkyl group may contain, in on to carbon atom(s), at least one en. A heterocycloalkyl group may contain from 3 to 10 ring atoms. A heterocycloalkyl group may contain from 3 to 7 ring atoms.

A heterocycloalkyl group may contain from 5 to 7 ring atoms, such as 5 ring atoms, 6 ring atoms, or 7 ring atoms. Unless otherwise indicated, the foregoing heterocycloalkyl groups can be C- attached or N—attached where such is possible and results in the creation of a stable structure. For example, piperidinyl can be piperidin-l-yl ached) or piperidinyl (C-attached).

“Heterocycloalkylene” or “heterocycloalkylene group” refers to diradical, 3-15 membered monocyclic, bicyclic, or tricyclic non-aromatic ring systems, which may be saturated or unsaturated, can be substituted or unsubstituted, may be bridged, spiro, and/or fused, and which contain, in addition to carbon atom(s), at least one heteroatom, such as nitrogen, oxygen, sulfur or phosphorus. Examples include, but are not limited to, the azridinylene isomers H H ACIDHZ or /AN\ or \H or £N (EH2 \ H C H2? 2 \ ( ). The heterocycloalkylene group may contain, in addition to carbon atom(s), at least one nitrogen, oxygen, or sulfur. The heterocycloalkylene group may contain, in addition to carbon ), at least one nitrogen or oxygen. The heterocycloalkylene group may contain, in on to carbon atom(s), at least one nitrogen. For example, a heterocycloalkylene group may contain from 3 to 10 ring atoms; such as from 3 to 7 ring atoms. A heterocycloalkylene group may contain from 5 to 7 ring atoms, such as 5 ring atoms, 6 ring atoms, or 7 ring atoms. Unless ise indicated, the foregoing heterocycloalkylene groups can be C- attached and/or N—attached where such is possible and results in the creation of a stable structure. A cycloalkylene group can also include ring systems substituted on ring s with one or more —OH ﬁanctional groups (which may further tautomerize to give a ring C=O group) and/or tuted on a ring sulfur atom by one (1) or two (2) oxygen atoms to give S=O or 802 groups, respectively, and/or substituted on a ring phosphorus by an oxygen atom to give P=O.

“Heterocycloalkylalkyl” or “heterocycloalkylalkyl group” refers to an alkyl group in which a hydrogen atom is replaced by a heterocycloalkyl group, wherein alkyl group and heterocycloalkyl group are as previously deﬁned (i.e., heterocycloalkylalkyl—). Heteroycloalkylalkyl groups can be substituted or unsubstituted. es include, but are not limited to, idinylmethyl (C4H8NCH2—). 2012/065831 “Pharmaceutically acceptable” refers to physiologically tolerable als, which do not typically e an allergic or other untoward reaction, such as gastric upset, dizziness and the like, when administered to a human. aceutical composition” refers to a composition that can be used to treat a e, condition, or disorder in a human.

“Pseudohalogen” refers to —OCN, —SCN, —CF3, and —CN.

“Stable” or “chemically stable” refers to a compound that is sufﬁciently robust to be isolated to a useful degree of purity from a reaction mixture. The present invention is directed solely to the preparation of stable compounds. When lists of alternative substituents include members which, owing to valency requirements, chemical stability, or other reasons, cannot be used to substitute a particular group, the list is intended to be read in t to include those members of the list that are suitable for substituting the particular group. For example, R1 can be C1_6alkyl optionally substituted by 1-13 R19; when R1 is , the methyl group is optionally substituted by 1—3 R19.

“Therapeutically effective amount” refers to an amount of a compound sufficient to inhibit, halt, or cause an improvement in a disorder or condition being treated in a particular subject or subject population. For example in a human or other mammal, a therapeutically effective amount can be determined experimentally in a laboratory or clinical setting, or may be the amount required by the guidelines of the United States Food and Drug Administration, or equivalent foreign agency, for the particular disease and subject being treated. It should be appreciated that determination of proper dosage forms, dosage amounts, and routes of administration is within the level of ordinary skill in the pharmaceutical and medical arts.

“Treatment” refers to the acute or prophylactic diminishment or alleviation of at least one m or characteristic associated or caused by a disorder being treated. For example, treatment can include shment of several symptoms of a er or complete eradication of a disorder. 11. Compounds The nds of the t invention are defined by the following numbered Embodiments. When a higher numbered Embodiment refers back to multiple us lower numbered Embodiments in the alternative and contains a new limitation not present _ 11 _ in the lower numbered Embodiments, the higher numbered Embodiment is intended to be an s description of each and every one of the alternatives. For example, if Embodiment 2 refers back to ment l and contains a limitation not present in ment l, Embodiment 3 referes back Embodiments l or 2 and contains a limitation(s) not present in Embodiments l or 2, and Embodiment 4 refers back to any of Embodiments 1-3 and contains a limitation(s) not present in Embodiments l, 2 or 3, then Embodiment 4 is ed to be an explicit description of a genus having the limitations of Embodiments l and 4, an explicit description of a genus having the limitations of Embodiments l, 2 and 4, an explicit description of a genus having the limitations of Embodiments l, 3 and 4, and an explicit description of a genus having the limitations of Embodiments l, 2, 3 and 4. By way of example, if Embodiment l is a compound of a (I) deﬁning R1, R2 and R3 ndently as alkyl or aryl, and ment 2 is a compound of ment l defining R1 as alkyl, and Embodiment 3 is a nd of Embodiments l or 2 deﬁning R2 as alkyl, and Embodiment 4 is a compound of any of Embodiments l-3 deﬁnining R3 as alkyl, then Embodiment 4 is an explicit description of a genus having the limitations of Embodiments l and 4 (i.e., a compound of formula (I) in which R1 and R2 are alkyl or aryl, and R3 is alkyl), an explicit description of a genus having the limitations of Embodiments l, 2 and 4 (i.e., a compound of formula (I) in which R2 is alkyl or aryl, and R1 and R3 are alkyl), an it description of a genus having the limitations of Embodiments l, 3 and 4 (i.e., a compound of formula (I) in which R1 is alkyl or aryl, and R2 and R3 are alkyl), and an explicit description of a genus having the limitations of ments l, 2, 3 and 4 (i.e., a compound of a (I) in which R1, R2 and R3 are alkyl). It should be noted in this regard that when a higher numbered Embodiment refers to a lower numbered Embodiment and ns limitations for a group(s) not present in the lower numbered Embodiment, the higher numbered Embodiment should be interpreted in context to ignore the missing group(s). For example, if Embodiment l recites a compound of formula (I) in which A is NR“, 0, or S, Embodiment 2 recites a compound of Embodiment l in which A is O or S, and Embodiment 3 recites a compound of Embodiments l or 2 in which R11 is alkyl, then Embodiment 3 defines a genus having the limitations of Embodiments l and 3 and a genus having the limitation of Embodiments l, 2 and 3. In the genus defined by the limitations of Embodiments l, 2 and 3, A cannot be NR“; therefore this genus should be interpreted to ignore and omit the Embodiment 3 def1ntion of R11 = alkyl.

Embodiment l. A compound of formula (I) _ 12 _ R3 | R4 N\R2 R6 A c3” /l X N G or a salt form thereof, wherein A is NR11,O,or S; R1, R2, R11, and R17 are independently chosen from H, C1_6alkyl optionally substituted by 1-13 R19, kenyl optionally substituted by 1-11 R19, C2- 6alkynyl optionally substituted by 1-9 R19, C6_11aryl ally substituted by 1-11 R19, C7_16arylalkyl optionally tuted by 1-19 R19, C3_11cycloalkyl optionally substituted by 1-21 R19, C4_17cycloalkylalkyl optionally substituted by 1—32 R19, 3—15 membered heterocycloalkyl optionally substituted by 1-28 R19, 4-21 membered heterocycloalkylalkyl optionally tuted by 1-40 R19, 5-15 membered heteroaryl optionally substituted by 1-15 R19, 6-21 membered heteroarylalkyl optionally substituted by 1-27 R19, and —OR20; R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, R16, and R18 are independently chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C2_6alkenyl optionally tuted by 1-11 R19, C2_6alkynyl optionally substituted by 1—9 R19, C6_11aryl optionally substituted by 1-11 R19, C7_16arylalkyl optionally tuted by 1—19 R19, C3.1 1oyoloalkyl optionally substituted by 1—21 R19, c4- 17cycloalkylalkyl optionally substituted by 1—32 R19, 3—15 ed heterocycloalkyl optionally substituted by 1-28 R19, 4-21 rnernbered heterocycloalkylalkyl optionally substituted by 1-40 R19, 5-15 ed heteroaryl optionally substituted by 1-15 R19, 6-21 rnernbered heteroarylalkyl optionally substituted by 1—27 R19, halogen, —CN, —C(=O)R20, —C(=O)OR2°, — C(=O)NR22R23, —C(=O)C(=O)R2°, —C(=NR25)R2°, 25)NR22R23, — C(=NOH)NR22R23, —C(=NOR26)R20, —C(=NNR22R23)R20, — C(=NNR24C(=O)R21)R2°, —C(=NNR24C(=O)OR21)R2°, —C(=S)NR22R23, —NC, —\102, —NR22R23, —NR24NR22R23, —N=NR24, —NR24OR26, —NR24C(=O)R2°, — \R24C(=O)C(=O)R2°, —NR24C(=O)OR21, —NR24C(=O)C(=O)OR21, — \R24C(=O)NR22R23, —NR24C(=O)NR24C(=O)R2°, — \R24C(=O)NR24C(=O)OR2°, —NR24C(=NR25)NR22R23, — \R24C(=O)C(=O)NR22R23, —NR24C(=S)R2°, —NR24C(=S)OR2°, — \R24C(=S)NR22R23, (=O)2R21,—NR24S(=O)2NR22R23, — \R24P(:O)R28R28’ —NR24P(=O)(NR22R23)(NR22R23), _ \R24P(=O)(OR20)(OR20), —NR24P(=O)(SR2°)(SR2°), —OR20, —OCN, — OC(=O)R2°, —OC(=O)NR22R23, )OR2°, —OC(=NR25)NR22R23, — OS(=O)R2°, —OS(=O)2R2°, —OS(=O)20R20, —OS(=O)2NR22R23, — OP(=O)R28R28, —OP(=O)(NR22R23)(NR22R23), —OP(=O)(OR20)(OR20), — OP(=O)(SR2°)(SR2°), —Si(R24)3 — , —SCN, —S(=O)nR20, —S(=O)20R2°, —sogR27, S(=O)2NR22R23, —S(=O)NR22R23, —SP(=O)R28R28, — SP(=O)(NR22R23)(NR22R23), —SP(=O)(OR2°)(OR2°), )(SR2°)(SR20), — P(=O)R28R28, —P(=O)(NR22R23)(NR22R23), —P(=O)(OR2°)(OR2°), and — P(=O)(SR2°)(SR2°); any ole and R2, R1 and R3, R1 and R5, R1 and R11, R4 and R11, R6 and R11, and R16 and R17 can, together with the atoms linking them, form a 3-15 ered heterocycloalkyl optionally substituted by 1-28 R19 or a 5-15 membered heteroaryl optionally substituted by 1-15 R19; WO 78126 any of R3 and R6, R7 and R8, R9 and R10, R12 and R13, and R14 and R15 can, together with the atoms linking them, form a ryl optionally substituted by 1-11 R19, C3_11cycloalkyl optionally substituted by 1—21 R19, 3—15 membered heterocycloalkyl optionally substituted by 1-28 R19 or a 5-15 membered heteroaryl optionally substituted by 1-15 R19; R3 and R5 or R4 and R6 can together form a double bond; any of R3 and R4, and R5 and R6 can together form =0, =NR20, =NOR20, or =8; R19 at each occurrence is independently chosen from C1_6alkyl optionally tuted by 1-13 R39, C2_6alkenyl optionally substituted by 1-11 R39, C2- 6alkynyl optionally substituted by 1-9 R39, C6_11aryl optionally substituted by 1-11 R39, C7_16arylalkyl optionally substituted by 1-19 R39, C3_11cycloalkyl optionally substituted by 1-21 R39, C4_17cycloalkylalkyl optionally substituted by 1-32 R39, 3-15 membered heterocycloalkyl ally substituted by 1-28 R39, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40 R39, 5-15 membered heteroaryl ally substituted by 1-15 R39, 6-21 membered heteroarylalkyl optionally substituted by 1-27 R39, halogen, —CN, —C(=O)R30, —C(=O)OR3°, —C(=O)NR32R33, —C(=O)C(=O)R3°, —C(=NR35)R3°, — C(=NR35)NR32R33, —C(=NOH)NR32R33, —C(=NOR36)R3°, —C(=NNR32R33)R30, —C(=NNR34C(=O)R31)R30, R34C(=O)OR31)R3°, —C(=S)NR32R33, —NC, —\102, —NR32R33, —NR34NR32R33, —N=NR34, =NR30, , —NR340R36, — \R34C(=0)R3°, —NR34C(=O)C(=O)R3°, —NR34C(=O)OR31, — \R34C(=O)C(=O)OR31, —NR34C(=O)NR32R33, (=O)NR34C(=O)R3°, — \R34C(=O)NR34C(=O)OR3°, —NR34C(=NR35)NR32R33, — \R34C(=O)C(=O)NR32R33, —NR34C(=S)R3°, —NR34C(=S)OR3°, — \R34C(=S)NR32R33, —NR34S(=O)2R31, —NR34S(=O)2NR32R33, — \R34P(:O)R38R38’ —NR34P(=O)(NR32R33)(NR32R33), _ \R34P(=O)(OR30)(OR30), —NR34P(=O)(SR3°)(SR3°), —0R3°, =o, —OCN, — OC(=O)R3°, —OC(=O)NR32R33, —OC(=O)OR3°, —OC(=NR35)NR32R33, — OS(=O)R3°, )2R30, —OS(=O)20R3°, —OS(=O)2NR32R33, — OP(=O)R38R38, —OP(=O)(NR32R33)(NR32R33), —OP(=O)(OR30)(OR30), — OP(=O)(SR3°)(SR3°), —Si(R34)3 — , —SCN, =s, —S(=O)HR3°, —S(=O)20R3°, sogR”, —S(=O)2NR32R33, —S(=O)NR32R33, —SP(=O)R38R38, — (NR32R33)(NR32R33), —SP(=O)(OR30)(OR30), —SP(=O)(SR3°)(SR30), — 2012/065831 P(=O)R38R38, —P(=O)(NR32R33)(NR32R33), —P(=O)(OR3°)(OR3°), and — P(=O)(SR3°)(SR3°); 21 24 25 26 27 30 31 34 35 36 R ,R ,R ,R ,R ,R ,R ,R ,R ,R ,R andR7ateachoccurrence1s3 - independently chosen from H, C1_6alkyl optionally substituted by 1-13 R49, C2- 6alkenyl optionally substituted by 1-11 R49, C2_6alkynyl optionally substituted by 1—9 R49, C6_11aryl optionally substituted by 1-11 R49, rylalkyl optionally substituted by 1-19 R49, C3_11cycloalkyl optionally tuted by l- 21 R49, C4_17cycloalkylalkyl optionally substituted by 1—32 R49, 3—15 membered heterocycloalkyl optionally substituted by 1-28 R49, 4-21 membered heterocycloalkylalkyl optionally substituted by 1—40 R49, 5—15 membered heteroaryl optionally substituted by 1-15 R49, and 6-21 membered heteroarylalkyl optionally substituted by 1-27 R49; R28 and R38 at each occurrence is independently chosen from C1_6alkyl optionally substituted by 1-13 R49, C2_6alkenyl optionally substituted by 1-11 R49, C2- 6alkynyl optionally tuted by 1-9 R49, C6_11aryl optionally substituted by 1-11 R49, C7_16arylalkyl optionally substituted by 1-19 R49, C3_11cycloalkyl optionally substituted by 1-21 R49, C4_17cycloalkylalkyl optionally substituted by 1—32 R49, 3—15 ed heterocycloalkyl optionally tuted by 1-28 R49, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40 R49, 5-15 membered heteroaryl optionally substituted by 1-15 R49, and 6-21 membered heteroarylalkyl optionally substituted by 1-27 R49; R22, R23, R32 and R33 at each occurrence is independently chosen from H, C1_6alkyl optionally tuted by 1-13 R59, C2_6alkenyl optionally substituted by 1-11 R59, C2_6alkynyl optionally substituted by 1-9 R59, C6_11aryl optionally substituted by 1-11 R59, rylalkyl ally substituted by 1-19 R59, ca 11cycloalkyl optionally substituted by 1-21 R59, C4_17cycloalkylalkyl optionally substituted by 1-32 R59, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R59, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40 R59, 5-15 membered heteroaryl optionally substituted by l- 15 R59, and 6-21 membered heteroarylalkyl optionally substituted by 1-27 R59; or any R22 and R23 and/or R32 and R33 may form, er with the nitrogen atom to which they are ed, a 3-15 membered cycloalkyl optionally substituted by 1-28 R69 or a 5-15 membered heteroaryl optionally substituted by 1-15 R69; _ l6 _ R39, R49, R59 and R69 at each occurrence is independently chosen from C1_6all<yl optionally tuted by 1-13 R79, C2_6alkenyl optionally substituted by 1-11 R79, C2_6alkynyl optionally substituted by 1-9 R79, C6_11aryl optionally substituted by 1-11 R79, C7_16arylalkyl optionally substituted by 1-19 R79, c3_ 11cycloalkyl optionally substituted by 1-21 R79, C4_17cycloalkylalkyl optionally substituted by 1-32 R79, 3-15 membered heterocycloalkyl ally substituted by 1-28 R79, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40 R79, 5-15 membered heteroaryl optionally substituted by l- R79, 6-21 membered heteroarylalkyl optionally substituted by 1-27 R79, halogen, —CN, —C(=O)R70, —C(=O)OR7°, —C(=O)NR72R73, —C(=O)C(=O)R7°, —C(=NR75)R7°, —C(=NR75)NR72R73, —C(=NOH)NR72R73, —C(=NOR76)R7°, — C(=NNR72R73)R7°, —C(=NNR74C(=O)R71)R7°, —C(=NNR74C(=O)OR71)R7°, — R72R73, —NC, —N02, —NR72R73, —NR74NR72R73, —N=NR74, =NR70, =NOR70, R76, —NR74C(=O)R7°, —NR74C(=O)C(=O)R7°, — NR74C(=O)OR71, —NR74C(=O)C(=O)OR71, —NR74C(=O)NR72R73, — =O)NR74C(=O)R7°, —NR74C(=O)NR74C(=O)OR7°, — =NR75)NR72R73, —NR74C(=O)C(=O)NR72R73, —NR74C(=S)R70, — NR74C(=S)OR7°, —NR74C(=S)NR72R73, —NR74S(=O)2R71, — NR74S(=O)2NR72R73, —NR74P(=O)R78R78, —NR74P(=O)(NR72R73)(NR72R73), _ NR74P(=O)(OR7°)(OR70), —NR74P(=O)(SR7°)(SR7°), —0R7°, =o, —OCN, — OC(=O)R7°, —OC(=O)NR72R73, —OC(=O)OR7°, —OC(=NR75)NR72R73, — OS(=O)R7°, —OS(=O)2R7°, )20R7°, —OS(=O)2NR72R73, — OP(=O)R78R78, )(NR72R73)(NR72R73), —OP(=O)(OR70)(OR70), — OP(=O)(SR7°)(SR7°), —Si(R7“)3 , —SCN, =s, —S(=O)HR7°, —S(=O)20R7°, — sogR”, —S(=O)2NR72R73, —S(=O)NR72R73, —SP(=O)R78R78, — SP(=O)(NR72R73)(NR72R73), —SP(=O)(OR70)(OR70), —SP(=O)(SR7°)(SR70), — P(=O)R78R78, (NR72R73)(NR72R73), —P(=O)(OR7°)(OR7°), and — P(=O)(SR7°)(SR7°); R70, R71, R74, R75 , R76 and R77 at each occurrence is independently chosen from H, C1_6alkyl optionally substituted by 1-13 R89, C2_6alkenyl ally substituted by 1-11 R89, C2_6alkynyl ally substituted by 1-9 R89, C6_11aryl optionally substituted by 1-11 R89, C7_16arylalkyl optionally substituted by 1-19 R89, c3- 11cycloalkyl optionally substituted by 1-21 R89, C4_17cycloalkylalkyl optionally substituted by 1-32 R89, 3-15 membered heterocycloalkyl optionally _ 17 _ WO 78126 substituted by 1-28 R89, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40 R89, 5-15 membered heteroaryl optionally substituted by l- R89, and 6-21 membered heteroarylalkyl optionally substituted by 1-27 R89; R72 and R73 at each occurrence is independently chosen from H, C1_6alkyl optionally substituted by 1-13 R99, C2_6alkenyl ally tuted by 1-11 R99, C2_6alkynyl optionally substituted by 1-9 R99, C6_11aryl optionally substituted by 1-11 R99, C7_16arylalkyl optionally substituted by 1-19 R99, c3- 11cycloalkyl optionally tuted by 1-21 R99, C4_17cycloalkylalkyl optionally substituted by 1-32 R99, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R99, 4-21 ed heterocycloalkylalkyl optionally substituted by 1-40 R99, 5-15 membered heteroaryl optionally substituted by l- R99, and 6-21 membered heteroarylalkyl optionally substituted by 1-27 R99; or any R72 and R73 may form, together with the nitrogen atom to which they are attached, a 3-15 membered heterocycloalkyl optionally substituted by 1-28 R109 or a 5-15 membered aryl optionally substituted by 1-15 R109; R78 at each occurrence is independently chosen from C1_6alkyl optionally substituted by 1-13 R89, C2_6alkenyl optionally substituted by 1-11 R89, C2- 6alkynyl optionally substituted by 1-9 R89, C6_11aryl optionally substituted by 1-11 R89, C7_16arylalkyl optionally substituted by 1-19 R89, C3_11cycloalkyl optionally substituted by 1-21 R89, C4_17cycloalkylalkyl optionally tuted by 1—32 R89, 3—15 membered heterocycloalkyl optionally substituted by 1-28 R89, 4-21 membered heterocycloalkylalkyl optionally tuted by 1-40 R89, -15 membered heteroaryl optionally substituted by 1-15 R89, and 6-21 membered heteroarylalkyl optionally substituted by 1-27 R89; R79, R89, R99 and R109 at each occurrence is independently chosen from C1_6alkyl optionally substituted by 1-13 halogen, C2_6alkenyl, kynyl, C6_11aryl, C7- 16arylalkyl, ycloalkyl, C4_17cycloalkylalkyl, 3-15 membered heterocycloalkyl, 4-21 membered heterocycloalkylalkyl, 5-15 membered heteroaryl, 6-21 membered heteroarylalkyl, halogen, —CN, —C(=O)R110, — C(=O)OR110, —C(=O)NR110R110, _C(:O)C(:O)R110’ —C(=NR110)R110, _ C(=NR110)NR110R110, —C(=NOH)NR110R110, —C(=NOR110)R110, _ C(=NNR110R110)R110, —C(=NNR110C(=O)R110)R110, _ C(=NNR110C(=O)OR110)R110, —C(=S)NR110R110,—NC, —N02, R110’ _ NRIIONRIIORIIO _N:NR110 :NRIIO O _NR1100R110 _ _ 18 _ =0)R“°, —NR“°C(=O)C(=O)R“°, —NR“°C(=0)0R“°, — \R“°C(=0)C(=0)0R“0, —NR“°C(=0)NR“°R“0, — \Rl1°C(=O)NR“°C(=O)R“°, (=0)NR11°C(=0)0R“0, — \R110C(=NR110)NR110R110, —NR110C(=O)C(=O)NR110R110, C(=S)R110, —\IR110C(=S)OR110, C(=S)NR110R110, —NRUOS(=O)2R110, _ \RUOS(=O)2NR110R110, —NR110P(=O)R111R111, _ \Rl10P(=O)(NR110R110)(NR110R110), —NR110P(=O)(OR110)(OR110), _ \R11°P(=O)(SR11°)(SR110), —0R“°, =0, —OCN, —OC(=O)R“0, — 0C(=0)NR“°R“°, —0C(=0)0R“°, —0C(=NR“°)NR“°R“°, —OS(=O)R“°, — OS(=O)2R“°, —OS(=O)20R“°, —OS(=O)2NR“°R“°, —OP(=O)R1“R“1, — OP(=O)(NR110R110)(NR110R110), —OP(=O)(OR110)(OR110), _ OP(=O)(SR“°)(SR“°), —Si(R“°)3 — , —SCN, =s, —S(=O)nR“0, —S(=O)20R“°, SOgRllO, —S(=O)2NR110R110, —S(=O)NR110R110, —SP(=O)R111R111, _ SP(=O)(NR110R110)(NR1IORUO), )(OR110)(OR110), _ SP(=O)(SR110)(SR110), —P(=O)R111R111, (NR110R1 10)(NR110R1 10), _ P(=0)(0R“°)(0R“°), and (SR“0)(SR“0); R110 at each occurrence is independently chosen from H, C1_6alkyl and €1 haloalkyl; R111 at each occurrence is independently chosen from C1_6alkyl and C1_6-haloalkyl; and n at each occurrence is independently chosen from 0, l, and 2.

Embodiment 2. The compound of Embodiment 1, wherein A is NR“, 0, or Embodiment 3. The compound of ment 1, wherein A is NR11 or O.

Embodiment 4. The compound of Embodiment 1, wherein A is NR“.

Embodiment 5. The compound of Embodiment 1, wherein A is O.

Embodiment 5. The compound of Embodiment 1, wherein A is S.

Embodiment 6. The compound of any of Embodiments 1-5, wherein M-Q-X is a group of formula OI' Embodiment 7. The compound of any of Embodiments 1-5, wherein M-Q-X R4§/7 I is a group of formula and the compound of formula (I) is a compound of R3 '1] R4 \ R2 R6 A S /ﬂ \ \ N G formula (la) (la).

Embodiment 8. The compound of any of Embodiments 1-5, wherein M-Q-X is a group of a and the compound of formula (I) is a compound of R3 '1] R4 \ R2 R9 R6 A s N G formula (1b) (1b).

Embodiment 9. The compound of any of ments 1-8, wherein G is a group of formula ment 10. The compound of any of Embodiments 1-8, wherein G is a group of formula Embodiment ll. group of formula and the compound of formula (I) is a compound of R3 '1] R4 \ R2 R6 A Q’M / IN R12 X \N R R15 / N formula (Ic) (1c).

Embodiment 12. The compound of any of Embodiments 1-8, wherein G is a and the compound of a (I) is a compound of / N\O* formula (Id) (Id).

Embodiment 13. The compound of any of Embodiments 1-8, wherein G is a and the compound of formula (I) is a compound of formula (Ie) (1e).

Embodiment 14. The compound of any of Embodiments 1-5, wherein M-Q-X S,\' 7 I R \\ R R is a group of a G is a group of formula and the , , compound of formula (I) is a compound of formula (If) R3 '1] R4 \R2 R6 A S / \ 1N 13 \ R N \ R I R15 / N (It).

Embodiment 15. The nd of any of Embodiments 1-5, wherein M-Q-X 7 , R \ R8 R14 is a group of formula G is a group of formula and the , , compound of formula (I) is a compound of formula (1g) R3 '1] R4 \R2 R6 A S / 12 \ |N \ R13 R |\ + R15 / \O, (lg). ment 16. The compound of any of Embodiments 1-5, wherein M-Q-X is a group of formula G is a group of formula and , , the compound of formula (I) is a compound of formula (1h) R3 '1] R4 \R2 R6 A R10 / / IN R \ R S N \ R15 / (1h). ment 17. The compound of any of Embodiments 1-5, wherein M-Q-X \ R is a group of formula G is a group of formula and , , the compound of formula (I) is a compound of formula (Ii) R3 | R4 N\R2 R6 A R10 / / IN R12 S \N R I N+ R15 / \O, (11).

Embodiment 18. The compound of any of ments 1-5, wherein M-Q-X \ \, is a group of formula G is a group of formula compound of formula (I) is a compound of formula (Ij) R3 '1] R4 \ R2 R6 A S / R7 IN R16 \N \ 17 —— R R8 \ /N (11'). ment 19. The compound of any of Embodiments 1-5, wherein M-Q-X is a group of formula G is a group of formula nd of formula (I) is a compound of formula (1k) R3 '1] R4 \ R2 R9 R6 / N 16 R10 / R S N \ N’R1 7 (1k).

Embodiment 20. The compound of any of Embodiments l-l9, wherein R1, R2, and R11 are independently chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C2_6alkenyl optionally substituted by 1-11 R19, C2_6alkynyl optionally substituted by 1-9 R19, C6_11aryl optionally substituted by 1-11 R19, C7_16arylalkyl optionally substituted by l- 19 R19, C3_11cycloalkyl optionally tuted by 1-21 R19, C4_17cycloalkylalkyl optionally substituted by 1-32 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R19, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40 R19, 5-15 membered aryl optionally substituted by 1-15 R19, 6-21 nlenlbered heteroarylalkyl optionally substituted by 1-27 R19, and —OR20; R3, R4, R5, and R6 are independently chosen from H, C1_6alkyl ally substituted by 1-13 R19, C2_6alkenyl optionally substituted by 1-11 R19, C2_6alkynyl optionally substituted by 1-9 R19, C6_11aryl optionally substituted by 1-11 R19, C7_16arylalkyl ally substituted by 1-19 R19, ycloalkyl optionally substituted by 1-21 R19, ycloalkylalkyl optionally substituted by 1-32 R19, 3-15 ed heterocycloalkyl optionally substituted by 1-28 R19, 4-21 ered heterocycloalkylalkyl optionally substituted by 1-40 R19, 5-15 membered heteroaryl optionally substituted by 1-15 R19, 6-21 membered heteroarylalkyl optionally substituted by 1-27 R19, halogen, —CN, —C(=O)R2°, —C(=O)OR2°, —C(=O)NR22R23, —C(=O)C(=O)R2°, —C(=NR25)R2°, —C(=NR25)NR22R23, H)NR22R23, —C(=NOR26)R2°, — C(=NNR22R23)R2°, —C(=NNR24C(=O)R21)R2°, —C(=NNR24C(=O)OR21)R2°, — C(=S)NR22R23, —NC, —N02, —NR22R23, —NR24NR22R23, 4, —NR24OR26, — NR24C(=O)R2°, —NR24C(=O)C(=O)R2°, —NR24C(=O)OR21, —NR24C(=O)C(=O)OR21, — NR24C(=O)NR22R23, —NR24C(=O)NR24C(=O)R2°, —NR24C(=O)NR24C(=O)OR2°, — NR24C(=NR25)NR22R23, —NR24C(=O)C(=O)NR22R23, —NR24C(=S)R2°, —NR24C(=S)OR2°, —NR24C(=S)NR22R23, —NR24S(=O)2R21,—NR24S(=O)2NR22R23, —NR24P(=O)R28R28, — NR24P(=O)(NR22R23)(NRZZRB), (=O)(OR20)(OR20), (=O)(SR20)(SR20), — ORZO, —OCN, —OC(=O)R2°, —OC(=O)NR22R23, )OR2°, —OC(=NR25)NR22R23, — OS(=O)R2°, —OS(=O)2R2°, —OS(=O)20R20, —OS(=O)2NR22R23, —OP(=O)R28R28, — (NR22R23)(NR22R23), —OP(=O)(OR2°)(OR20), —OP(=O)(SR20)(SR20), —Si(R24)3 — SCN, —S(=O)nR2°, —S(=O)20R20, —SOgR27, —S(=O)2NR22R23, —S(=O)NR22R23, — SP(=O)R28R28, —SP(=O)(NR22R23)(NR22R23), —SP(=O)(OR20)(OR20), — SP(=O)(SR20)(SR20), —P(=O)R28R28, —P(=O)(NR22R23)(NR22R23), —P(=O)(OR2°)(OR2°), and —P(=O)(SR20)(SR20); alternatively, R3 and R6 can, together with the atoms linking them, form a C6_11aryl optionally substituted by 1-11 R19, C3_1lcycloalkyl optionally substituted by 1-21 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R19 or a 5-15 membered heteroaryl optionally substituted by 1-15 R19; atively R3 and R5 or R4 and R6 can together form a double bond; alternatively any of R3 and R4, and R5 _ 26 _ and R6 can together form =0, =NR20, =NOR20, or =8; and alternatively any of R1 and R2, R1 and R3, R1 and R5, R1 and R11, R4 and R11, and R6 and R11 can, together with the atoms linking them, form a 3-15 membered heterocycloalkyl optionally tuted by 1-28 R19 or a 5-15 membered heteroaryl optionally substituted by 1-15 R19.

Embodiment 21. The compound of any of Embodiments l-l9, wherein R1, R2, and R11 are independently chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C2_6alkenyl optionally substituted by 1-11 R19, kynyl optionally tuted by 1-9 R19, C6_11aryl optionally tuted by 1-11 R19, C7_16arylalkyl optionally tuted by l- 19 R19, C3_11cycloalkyl optionally substituted by 1-21 R19, C4_17cycloalkylalkyl optionally substituted by 1-32 R19, 3-15 membered heterocycloalkyl ally substituted by 1-28 R19, 4-21 membered heterocycloalkylalkyl ally substituted by 1-40 R19, 5-15 membered heteroaryl optionally substituted by 1-15 R19, 6-21 membered heteroarylalkyl optionally tuted by 1-27 R19, and —OR20; R3, R4, R5, and R6 are independently chosen from H, kyl optionally substituted by 1-13 R19, kenyl optionally substituted by 1-11 R19, C2_6alkynyl optionally substituted by 1-9 R19, C6_11aryl optionally substituted by 1-11 R19, C7_16arylalkyl optionally substituted by 1-19 R19, C3_11cycloalkyl optionally substituted by 1-21 R19, C4_17cycloalkylalkyl optionally substituted by 1-32 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R19, 4-21 membered heterocycloalkylalkyl optionally tuted by 1-40 R19, 5-15 membered heteroaryl optionally substituted by 1-15 R19, 6-21 membered heteroarylalkyl optionally substituted by 1-27 R19, halogen, —CN, —C(=O)R2°, —C(=O)OR2°, —C(=O)NR22R23, —C(=O)C(=O)R2°, —C(=NR25)R2°, —C(=NR25)NR22R23, —C(=NOH)NR22R23, —C(=NOR26)R2°, — C(=NNR22R23)R2°, —C(=NNR24C(=O)R21)R2°, —C(=NNR24C(=O)OR21)R2°, — C(=S)NR22R23, —NC, —N02, —NR22R23, —NR24NR22R23, —N=NR24, —NR24OR26, — NR24C(=O)R2°, —NR24C(=O)C(=O)R2°, —NR24C(=O)OR21, —NR24C(=O)C(=O)OR21, — =O)NR22R23, —NR24C(=O)NR24C(=O)R2°, —NR24C(=O)NR24C(=O)OR2°, — =NR25)NR22R23, —NR24C(=O)C(=O)NR22R23, —NR24C(=S)R2°, —NR24C(=S)OR2°, (=S)NR22R23, —NR24S(=O)2R21,—NR24S(=O)2NR22R23, —NR24P(=O)R28R28, — NR24P(=O)(NR22R23)(NRZZRB), —NR24P(=O)(OR20)(OR20), —NR24P(=O)(SR20)(SR2°), — ORZO, —OCN, —OC(=O)R2°, —OC(=O)NR22R23, —OC(=O)OR2°, —OC(=NR25)NR22R23, — R2°, —OS(=O)2R2°, —OS(=O)20R20, —OS(=O)2NR22R23, —OP(=O)R28R28, — OP(=O)(NR22R23)(NR22R23), —OP(=O)(OR2°)(OR20), —OP(=O)(SR20)(SR20), —Si(R24)3 — SCN, —S(=O)nR2°, —S(=O)20R20, —SOgR27, —S(=O)2NR22R23, —S(=O)NR22R23, — SP(=O)R28R28, —SP(=O)(NR22R23)(NR22R23), —SP(=O)(OR20)(OR20), — _ 27 _ WO 78126 SP(=O)(SR20)(SR20), R28R28, —P(=O)(NR22R23)(NR22R23), —P(=O)(OR2°)(OR2°), and —P(=O)(SR20)(SR20); alternatively, R3 and R6 can, together with the atoms linking them, form a C6_10aryl optionally substituted by 1-6 R19, C3_10cycloalkyl optionally substituted by 1-6 R19, 3-10 membered heterocycloalkyl optionally substituted by 1-6 R19 or a 5-10 membered heteroaryl optionally substituted by 1-6 R19; alternatively R3 and R5 or R4 and R6 can together form a double bond; atively any of R3 and R4, and R5 and R6 can together form =0; and alternatively any of R1 and R2, R1 and R3, R1 and R5, R1 and R11, R4 and R11, and R6 and R11 can, together with the atoms linking them, form a 3-15 membered heterocycloalkyl optionally tuted by 1-22 R19 or a 5-15 membered heteroaryl ally substituted by 1-15 R19.

Embodiment 22. The compound of any of Embodiments l-l9, wherein R1, R2, and R11 are independently chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C2_6alkenyl optionally substituted by 1-11 R19, C2_6alkynyl optionally substituted by 1-9 R19, ryl optionally substituted by 1-11 R19, C7_16arylalkyl optionally substituted by l- 19 R19, C3_11cycloalkyl optionally substituted by 1-21 R19, C4_17cycloalkylalkyl optionally substituted by 1-32 R19, 3-15 membered heterocycloalkyl ally substituted by 1-28 R19, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40 R19, 5-15 membered heteroaryl optionally substituted by 1-15 R19, 6-21 ed arylalkyl optionally substituted by 1-27 R19, and —OR20; R3, R4, R5, and R6 are independently chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C2_6alkenyl ally substituted by 1-11 R19, C2_6alkynyl optionally substituted by 1-9 R19, C6_11aryl ally substituted by 1-11 R19, C7_16arylalkyl optionally substituted by 1-19 R19, C3_11cycloalkyl optionally substituted by 1-21 R19, C4_17cycloalkylalkyl optionally substituted by 1-32 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R19, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40 R19, 5-15 membered heteroaryl ally tuted by 1-15 R19, 6-21 membered arylalkyl optionally substituted by 1-27 R19, halogen, —CN, —C(=O)R2°, —C(=O)OR2°, —C(=O)NR22R23, —NC, —N02, — NRZZR”, —NR24OR26, —NR24C(=O)R2°, —NR24C(=O)OR21, —NR24C(=O)NR22R23, — =O)2R21, —NR24S(=O)2NR22R23, —OR2°, —OCN, —OC(=O)R2°, —OC(=O)NR22R23, — OC(=O)OR2°, —OS(=O)R2°, —OS(=O)2R2°, —OS(=O)20R2°, —OS(=O)2NR22R23, — OP(=O)R28R28, —OP(=O)(OR20)(OR20), —Si(R24)3, —SCN, —S(=O)nR2°, —S(=O)20R20, — SOsR27, —S(=O)2NR22R23, —S(=O)NR22R23, —P(=O)R28R28, —P(=O)(NR22R23)(NR22R23), and —P(=O)(OR20)(OR20); alternatively, R3 and R6 can, together with the atoms linking them, form a C6_10aryl optionally substituted by 1-6 R19, C3_10cycloalkyl optionally _ 28 _ substituted by 1-6 R19, 3-10 membered heterocycloalkyl optionally substituted by 1-6 R19 or a 5-10 membered heteroaryl optionally substituted by 1-6 R19; alternatively R3 and R5 or R4 and R6 can together form a double bond; alternatively any of R3 and R4, and R5 and R6 can together form =0; and alternatively any of R1 and R2, R1 and R3, R1 and R5, R1 and R11, R4 and R11, and R6 and R11 can, together with the atoms g them, form a 3-15 membered heterocycloalkyl optionally substituted by 1-22 R19 or a 5-15 membered heteroaryl optionally tuted by 1-15 R19.

Embodiment 23. The compound of any of Embodiments l-l9, wherein R1, R2, and R11 are independently chosen from H, C1_6alkyl optionally substituted by 1-6 R19, kenyl optionally substituted by 1-6 R19, C2_6alkynyl optionally substituted by 1-6 R19, C6_11aryl optionally substituted by 1-6 R19, C7_16arylalkyl optionally substituted by 1-6 R19, C3_11cycloalkyl ally substituted by 1-6 R19, C4_17cycloalkylalkyl optionally substituted by 1-6 R19, 3-15 ed heterocycloalkyl optionally substituted by 1-6 R19, 4-21 membered cycloalkylalkyl optionally substituted by 1-6 R19, 5-15 membered heteroaryl optionally tuted by 1-6 R19, 6-21 membered heteroarylalkyl optionally substituted by 1-6 R19, and —OR20; R3, R4, R5, and R6 are independently chosen from H, C1_6alkyl optionally substituted by 1-6 R19, C2_6alkenyl optionally substituted by 1-6 R19, C2_6alkynyl optionally substituted by 1-6 R19, C6_11aryl optionally substituted by 1-6 R19, C7_16arylalkyl optionally substituted by 1-6 R19, C3_11cycloalkyl ally substituted by 1-6 R19, C4_17cycloalkylalkyl optionally substituted by 1-6 R19, 3—15 membered heterocycloalkyl ally substituted by 1-6 R19, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-6 R19, 5-15 membered heteroaryl optionally tuted by 1-6 R19, 6-21 membered arylalkyl optionally substituted by 1-6 R19, halogen, —CN, — C(=O)R2°, —C(=O)OR2°, NR22R23, —NC, —N02, —NR22R23, —NR24OR26, — NR24C(=O)R2°, —NR24C(=O)OR21, —NR24C(=O)NR22R23, —NR24S(=O)2R21, — NR24S(=O)2NR22R23, ORZO, OCN, R2°, OC(—O)NR22R23, —OC(=O)OR2°, — OS(=O)R2°, —OS(=O)2R2°, —OS(=O)20R20, )2NR22R23, —OP(=O)R28R28, — OP(=O)(OR20)(OR2°), —Si(R24)3, —SCN, —S(=O)nR20, —S(=O)20R2°, —SOgR27, — S(=O)2NR22R23, —S(=O)NR22R23, —P(=O)R28R28, —P(=O)(NR22R23)(NR22R23), and — P(=O)(OR20)(OR20); alternatively, R3 and R6 can, together with the atoms linking them, form a C6_10aryl optionally substituted by 1-6 R19, C3_10cycloalkyl optionally substituted by 1-6 R19, 3-10 membered heterocycloalkyl optionally substituted by 1-6 R19 or a 5-10 membered heteroaryl optionally tuted by 1-6 R19; alternatively R3 and R5 or R4 and R6 can together form a double bond; alternatively any of R3 and R4, and R5 and R6 can _ 29 _ W0 2013/078126 er form =0; and alternatively any of R1 and R2, R1 and R3, R1 and R5, R1 and R11, R4 and R11, and R6 and R11 can, together with the atoms linking them, form a 5-15 ed heterocycloalkyl ally substituted by 1-6 R19 or a 5-15 membered heteroaryl optionally substituted by 1-6 R19.

Embodiment 24. The compound of any of Embodiments l-l9, n R1, R2, and R11 are independently chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C2_6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl optionally substituted by 1-3 R19, ryl optionally substituted by 1-3 R19, rylalkyl optionally substituted by 1-3 R19, C3_11cycloalkyl optionally tuted by 1-3 R19, C4_17cycloalkylalkyl optionally substituted by 1-3 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R19, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-3 R19, 5-15 membered heteroaryl optionally substituted by 1-3 R19, 6-21 membered heteroarylalkyl optionally substituted by 1-3 R19, and —OR20; R3, R4, R5, and R6 are independently chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C2_6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl optionally substituted by 1-3 R19, C6_11aryl optionally substituted by 1-3 R19, C7_16arylalkyl optionally substituted by 1-3 R19, C3_11cycloalkyl optionally tuted by 1—3 R19, ycloalkylalkyl optionally substituted by 1—3 R19, 3—15 membered heterocycloalkyl ally substituted by 1-3 R19, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-3 R19, 5-15 membered heteroaryl optionally tuted by 1-3 R19, 6-21 membered heteroarylalkyl optionally substituted by 1-3 R19, halogen, —CN, — C(=O)R2°, —C(=O)OR2°, —C(=O)NR22R23, —NC, —N02, 23, —NR24OR26, — NR24C(=O)R2°, —NR24C(=O)OR21, —NR24C(=O)NR22R23, (=O)2R21, — NR24S(=O)2NR22R23, ORZO, OCN, OC(—O)R2°, OC(—O)NR22R23, —OC(=O)OR2°, — OS(=O)R2°, —OS(=O)2R2°, —OS(=O)20R20, —OS(=O)2NR22R23, —OP(=O)R28R28, — OP(=O)(OR20)(OR2°), —Si(R24)3, —SCN, —S(=O)nR20, —S(=O)20R2°, —sogR27, — S(=O)2NR22R23, —S(=O)NR22R23, —P(=O)R28R28, —P(=O)(NR22R23)(NR22R23), and — P(=O)(OR20)(OR20); alternatively, R3 and R6 can, together with the atoms g them, form a C6_10aryl optionally substituted by 1-3 R19, C3_10cycloalkyl optionally substituted by 1-3 R19, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R19 or a 5-10 membered heteroaryl optionally substituted by 1-3 R19; alternatively R3 and R5 or R4 and R6 can together form a double bond; alternatively any of R3 and R4, and R5 and R6 can together form =0; and alternatively any of R1 and R2, R1 and R3, R1 and R5, R1 and R11, R4 and R11, and R6 and R11 can, together with the atoms linking them, form a 5-15 membered heterocycloalkyl optionally substituted by 1-3 R19 or a 5-15 membered aryl optionally substituted by 1-3 R19. ment 25. The compound of any of Embodiments l-l9, wherein R1, R2, and R11 are independently chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C2_6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl ally substituted by 1-3 R19, C6_11aryl optionally tuted by 1-3 R19, C3_11cycloalkyl optionally substituted by 1-3 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-15 membered heteroaryl optionally substituted by 1-3 R19, and —OR20; R3, R4, R5, and R6 are independently chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C2_6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl optionally tuted by 1-3 R19, C6_11aryl optionally substituted by 1-3 R19, C3_11cycloalkyl optionally substituted by 1-3 R19, 3-15 membered cycloalkyl optionally substituted by 1-3 R19, 5-15 membered heteroaryl optionally substituted by 1—3 R19, halogen, —CN, —C(=O)R20, OR2°, — C(=O)NR22R23, —NC, —N02, —NR22R23, —NR24OR26, (=O)R2°, —NR24C(=O)OR21, — NR24C(=O)NR22R23, —NR24S(=O)2R21, (=O)2NR22R23, —OR2°, —OCN, — OC(=O)R2°, —OC(=O)NR22R23, )OR2°, —OS(=O)R2°, —OS(=O)2R2°, — OS(=O)20R2°, —OS(=O)2NR22R23, —OP(=O)R28R28, —OP(=O)(OR20)(OR20), —Si(R24)3, — SCN, —S(=O)nR2°, —S(=O)20R20, —SOgR27, —S(=O)2NR22R23, —S(=O)NR22R23, — P(=O)R28R28, —P(=O)(NR22R23)(NR22R23), and —P(=O)(OR2°)(OR2°); alternatively, R3 and R6 can, together with the atoms linking them, form a C6_10aryl ally substituted by l- 3 R19, C3_10cycloalkyl optionally substituted by 1-3 R19, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R19 or a 5-10 ed heteroaryl optionally substituted by 1-3 R19; alternatively R3 and R5 or R4 and R6 can together form a double bond; alternatively any of R3 and R4, and R5 and R6 can together form =0; and alternatively any of R1 and R2, R1 and R3, R1 and R5, R1 and R11, R4 and R11, and R6 and R11 can, together with the atoms linking them, form a 5-15 membered heterocycloalkyl optionally substituted by 1-3 R19 or a 5-15 ed heteroaryl optionally substituted by 1-3 R19.

Embodiment 26. The compound of any of Embodiments l-l9, wherein R1, R2, and R11 are independently chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C2_6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl optionally substituted by 1-3 R19, C6_11aryl optionally substituted by 1-3 R19, C3_11cycloalkyl optionally substituted by 1-3 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-15 membered aryl ally substituted by 1-3 R19, and —OR20; R3, R4, R5, and R6 are independently chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C2_6alkenyl _ 31 _ 2012/065831 optionally substituted by 1-3 R19, C2_6alkynyl optionally substituted by 1-3 R19, C6_11aryl optionally substituted by 1-3 R19, C3_11cycloalkyl ally substituted by 1-3 R19, 3-15 ed heterocycloalkyl optionally substituted by 1-3 R19, 5-15 membered heteroaryl optionally substituted by 1—3 R19, halogen, —CN, —C(=O)R20, OR2°, — C(=O)NR22R23, —N02, —NR22R23, —NR24C(=O)R2°, (=O)2R21,—OR2°, —OC(=O)R2°, —S(=O)nR20, and —S(=O)2NR22R23; atively, R3 and R6 can, together with the atoms linking them, form a C6_10aryl optionally substituted by 1-3 R19, C3_10cycloalkyl optionally substituted by 1-3 R19, 3-10 membered heterocycloalkyl ally substituted by 1-3 R19 or a 5-10 membered aryl optionally substituted by 1-3 R19; atively R3 and R5 or R4 and R6 can together form a double bond; alternatively any of R3 and R4, and R5 and R6 can together form =0; and alternatively any of R1 and R2, R1 and R3, R1 and R5, R1 and R11, R4 and R11, and R6 and R11 can, together with the atoms linking them, form a 5-15 membered heterocycloalkyl optionally substituted by 1-3 R19 or a 5-15 membered heteroaryl optionally substituted by 1-3 R19.

Embodiment 27. The compound of any of Embodiments l-l9, n R1, R2, and R11 are independently chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C6_11aryl optionally substituted by 1-3 R19, ycloalkyl optionally substituted by 1-3 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R19, and 5-15 ed heteroaryl optionally substituted by 1-3 R19; R3 R5 and R6 are , R4, , independently chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C6_11aryl optionally substituted by 1-3 R19, C3_11cycloalkyl optionally substituted by 1-3 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-15 membered heteroaryl optionally substituted by 1—3 R19, halogen, —CN, —C(=O)R20, —C(=O)OR2°, — C(=O)NR22R23, —N02, —NR22R23, —NR24C(=O)R2°, —NR24S(=O)2R21,—OR2°, —OC(=O)R2°, —S(=O)nR20, and —S(=O)2NR22R23; alternatively, R3 and R6 can, together with the atoms linking them, form a C6_10aryl optionally substituted by 1-3 R19, C3_10cycloalkyl optionally substituted by 1-3 R19, 3-10 ed heterocycloalkyl optionally substituted by 1-3 R19 or a 5-10 membered heteroaryl optionally substituted by 1-3 R19; alternatively R3 and R5 or R4 and R6 can together form a double bond; and alternatively any of R1 and R2, R1 and R3, R1 and R5, R1 and R11, R4 and R11, and R6 and R11 can, together with the atoms linking them, form a 5-15 membered heterocycloalkyl optionally substituted by 1-3 R19 or a 5-15 membered heteroaryl optionally substituted by 1-3 R19.

Embodiment 28. The compound of any of Embodiments l-l9, n R1, R2, and R11 are ndently chosen from H and C1_6alkyl optionally substituted by 1-3 _ 32 _ R19; R3, R4, R5, and R6 are ndently chosen from H, kyl optionally substituted by 1-3 R19, C6_11aryl optionally substituted by 1-3 R19, C3_11cycloalkyl optionally tuted by 1-3 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R19, -15 membered aryl optionally substituted by 1-3 R19, halogen, —CN, —C(=O)R20, — C(=O)OR2°, —C(=O)NR22R23, —N02, —NR22R23, (=O)R20, —NR24S(=O)2R21,—OR2°, —OC(=O)R20, —S(=O)nR20, and —S(=O)2NR22R23; alternatively, R3 and R6 can, together with the atoms linking them, form a C6_10aryl optionally substituted by 1-3 R19, C3- 10cycloalkyl optionally tuted by 1-3 R19, 3-10 membered heterocycloalkyl ally substituted by 1-3 R19 or a 5-10 membered heteroaryl ally substituted by 1-3 R19; alternatively R3 and R5 or R4 and R6 can together form a double bond; and alternatively any of R1 and R2, R1 and R3, R1 and R5, R1 and R11, R4 and R11, and R6 and R11 can, together with the atoms linking them, form a 5-15 membered heterocycloalkyl optionally substituted by 1-3 R19 or a 5-15 membered heteroaryl optionally substituted by 1-3 R19.

Embodiment 29. The compound of any of Embodiments l-l9, n R1, R2, and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-3 R19; R3, R4, R5, and R6 are independently chosen from H, C1_6alkyl ally substituted by 1-3 R19, C6_11aryl optionally substituted by 1-3 R19, C3_11cycloalkyl optionally substituted by 1-3 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R19, -15 membered heteroaryl optionally substituted by 1-3 R19, halogen, —CN, —C(=O)R20, — C(=O)OR2°, —C(=O)NR22R23, —N02, —NR22R23, —NR24C(=O)R20, —NR24S(=O)2R21,—OR2°, —OC(=O)R2°, —S(=O)nR2°, and —S(=O)2NR22R23; alternatively, any of R1 and R2, R1 and R3, R1 and R5, R1 and R11, R4 and R11, and R6 and R11 can, er with the atoms linking them, form a 5-15 membered heterocycloalkyl optionally substituted by 1-3 R19.

Embodiment 30. The compound of any of Embodiments l-l9, wherein R1, R2, and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-3 R19; R3, R4, R5, and R6 are independently chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C6_10aryl optionally substituted by 1-3 R19, C3_7cycloalkyl optionally tuted by 1-3 R19, 3-7 membered heterocycloalkyl optionally substituted by 1-3 R19, -6 membered heteroaryl optionally substituted by 1-3 R19, halogen, —CN, —C(=O)R20, — C(=O)OR2°, —C(=O)NR22R23, —N02, 23, —NR24C(=O)R20, —NR24S(=O)2R21,—OR2°, —OC(=O)R2°, —S(=O)nR2°, and —S(=O)2NR22R23; alternatively, any of R1 and R2, R1 and R3, R1 and R5, R1 and R11, R4 and R11, and R6 and R11 can, together with the atoms linking them, form a 5-7 membered heterocycloalkyl optionally substituted by 1-3 R19.

Embodiment 3 l. The compound of any of Embodiments l-l9, wherein R1, R2, and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-3 R19; R3, R4, R5, and R6 are ndently chosen from H, C1_6alkyl optionally substituted by 1—3 R19, halogen, —CN, —C(=O)R2°, —C(=O)OR2°, NR22R23, —NOg, —NR22R23, — NR24C(=O)R2°, —NR24S(=O)2R21,—OR2°, —OC(=O)R2°, —S(=O)nR2°, and —S(=O)2NR22R23; alternatively, R3 and R6 can, together with the atoms linking them, form a C6_10aryl optionally substituted by 1-3 R19, C3_10cycloalkyl optionally substituted by 1-3 R19, 3-lO membered heterocycloalkyl optionally substituted by 1-3 R19 or a 5-10 membered heteroaryl optionally substituted by 1-3 R19; alternatively R3 and R5 or R4 and R6 can together form a double bond; and atively any of R1 and R2, R1 and R3, R1 and R5, R1 and R11, R4 and R11, and R6 and R11 can, together with the atoms linking them, form a 5-15 membered heterocycloalkyl optionally substituted by 1-3 R19 or a 5-15 membered heteroaryl optionally substituted by 1-3 R19.

Embodiment 32. The compound of any of ments l-l9, wherein R1, R2, and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-3 R19; R3, R4, R5, and R6 are ndently chosen from H, C1_6alkyl optionally substituted by 1—3 R19, halogen, —CN, —C(=O)R2°, —C(=O)OR2°, NR22R23, —NOg, —NR22R23, — NR24C(=O)R2°, —NR24S(=O)2R21,—OR2°, —OC(=O)R2°, —S(=O)nR2°, and 2NR22R23; alternatively, any of R1 and R2, R1 and R3, R1 and R5, R1 and R11, R4 and R11, and R6 and R11 can, together with the atoms linking them, form a 5-15 membered heterocycloalkyl optionally substituted by 1-3 R19.

Embodiment 33. The compound of any of ments l-l9, wherein R1, R2, and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-3 R19; R3, R4, R5, and R6 are independently chosen from H, C1_6alkyl optionally substituted by 1—3 R19, halogen, —CN, —C(=O)R2°, —C(=O)OR2°, —C(=O)NR22R23, —NOg, —NR22R23, — NR24C(=O)R2°, —NR24S(=O)2R21,—OR2°, —OC(=O)R2°, —S(=O)nR2°, and —S(=O)2NR22R23; alternatively, any of R1 and R2, R1 and R3, R1 and R5, R1 and R11, R4 and R11, and R6 and R11 can, er with the atoms linking them, form a 5-7 membered heterocycloalkyl optionally substituted by 1-3 R19. ment 34. The compound of any of Embodiments l-l9, wherein R1, R2, and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-3 R19; R3, R4, R5, and R6 are independently chosen from H, C1_6alkyl optionally tuted by 1—3 R19, halogen, —CN, —C(=O)R2°, —C(=O)OR2°, —C(=O)NR22R23, —NOg, —NR22R23, — =O)R2°, —NR24S(=O)2R21,—OR2°, —OC(=O)R2°, —S(=O)nR2°, and —S(=0)2NR22R23; _ 34 _ alternatively, any of R1 and R2, R1 and R3, R1 and R5, R1 and R11, R4 and R11, and R6 and R11 can, together with the atoms linking them, form a 5-6 membered heterocycloalkyl ally substituted by 1-3 R19.

Embodiment 35. The compound of any of Embodiments l-l9, wherein R1, R2, and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-3 R19; R3, R4, R5, and R6 are ndently chosen from H, C1_6alkyl optionally substituted by 1—3 R19, halogen, —CN, —C(=O)R2°, —C(=O)OR2°, —C(=O)NR22R23, —NOg, —NR22R23, — =O)R2°, —NR24S(=O)2R21,—OR2°, —OC(=O)R2°, —S(=O)nR2°, and —S(=O)2NR22R23; alternatively any of R1 and R2, R1 and R3, R1 and R5, R1 and R11, R4 and R11, and R6 and R11 can, together with the atoms linking them, form a 3-15 membered heterocycloalkyl optionally substituted by 1-3 R19 or a 5-15 membered heteroaryl optionally substituted by 1—3 R19.

Embodiment 36. The compound of any of Embodiments l-l9, wherein R1, R2, and R11 are independently chosen from H and C1_6alkyl optionally tuted by 1-3 R19; R3, R4, R5, and R6 are independently chosen from H, C1_6alkyl optionally substituted by 1—3 R19, halogen, —CN, —C(=O)R2°, —C(=O)OR2°, —C(=O)NR22R23, —NOg, —NR22R23, — NR24C(=O)R2°, —NR24S(=O)2R21,—OR2°, —OC(=O)R2°, —S(=O)nR2°, and 2NR22R23; altematively any of R1 and R2, R1 and R3, R1 and R5, R1 and R11, R4 and R11, and R6 and R11 can, together with the atoms linking them, form a 5-15 membered heterocycloalkyl ally substituted by 1-3 R19 or a 5-15 membered heteroaryl ally substituted by 1—3 R19.

Embodiment 37. The compound of any of Embodiments l-l9, wherein R1, R2, and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-3 R19; R3, R4, R5, and R6 are independently chosen from H, C1_6alkyl ally substituted by 1—3 R19, halogen, —CN, R2°, —C(=O)OR2°, —C(=O)NR22R23, —NOg, —NR22R23, — NR24C(=O)R2°, —NR24S(=O)2R21,—OR2°, —OC(=O)R2°, nR2°, and —S(=O)2NR22R23; altematively any of R1 and R2, R1 and R3, R1 and R5, R1 and R11, R4 and R11, and R6 and R11 can, together with the atoms linking them, form a 5-15 membered heterocycloalkyl ally substituted by 1-3 R19.

Embodiment 38. The compound of any of Embodiments l-l9, wherein R1, R2, and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-3 R19; R3, R4, R5, and R6 are independently chosen from H, C1_6alkyl optionally substituted by 1—3 R19, halogen, —CN, —C(=O)R2°, —C(=O)NR22R23, —NR22R23, —NR24C(=O)R20, — NR24S(=O)2R21,—OR20, —S(=O)nR20, and —S(=O)2NR22R23; alternatively any of R1 and R2, _ 35 _ R1 and R3, R1 and R5, R1 and R11, R4 and R11, and R6 and R11 can, together with the atoms linking them, form a 5-15 membered heterocycloalkyl optionally substituted by 1-3 R19.

Embodiment 39. The compound of any of Embodiments 1-19, wherein R1, R2, and R11 are ndently chosen from H and C1_6alkyl optionally substituted by 1-13 R19, C2_6alkenyl optionally substituted by 1-11 R19, C2_6alkynyl optionally substituted by l- 9 R19, C6_11aryl optionally substituted by 1-11 R19, C7_16arylalkyl ally substituted by 1-19 R19, ycloalkyl optionally substituted by 1-21 R19, C4_17cycloalkylalkyl optionally substituted by 1-32 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R19, 4-21 membered heterocycloalkylalkyl ally substituted by 1-40 R19, 5- 15 membered aryl optionally substituted by 1-15 R19, 6-21 membered heteroarylalkyl optionally tuted by 1-27 R19, and —OR20; R3, R4, R5, and R6 are independently chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C2_6alkenyl optionally substituted by 1-11 R19, C2_6alkynyl optionally substituted by 1-9 R19, C6_11aryl optionally substituted by 1-11 R19, C7_16arylalkyl optionally substituted by 1-19 R19, C3- 11cycloalkyl optionally substituted by 1-21 R19, ycloalkylalkyl optionally substituted by 1-32 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R19, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40 R19, 5-15 membered aryl optionally substituted by 1-15 R19, 6-21 membered heteroarylalkyl optionally substituted by 1—27 R19, halogen, —CN, —C(=O)R20, —C(=O)OR2°, —C(=O)NR22R23, —N02, —NR22R23, and —OR20; alternatively, R3 and R6 can, together with the atoms linking them, form a C6_11aryl ally substituted by 1-11 R19, C3_11cycloalkyl optionally tuted by 1-21 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R19 or a 5-15 membered heteroaryl optionally substituted by 1-15 R19; alternatively R3 and R5 or R4 and R6 can together form a double bond; alternatively any of R3 and R4, and R5 and R6 can together form =0, =NR20, , or =8; and alternatively any of R1 and R2, R1 and R3, R1 and R5, R1 and R11, R4 and R11, and R6 and R11 can, together with the atoms linking them, form a 3-15 ed heterocycloalkyl optionally substituted by 1-28 R19 or a 5-15 membered heteroaryl optionally substituted by 1-15 R19.

Embodiment 40. The compound of any of Embodiments 1-19, wherein R1, R2, and R11 are independently chosen from H and C1_6alkyl ally substituted by 1-13 R19, C2_6alkenyl optionally substituted by 1-11 R19, C2_6alkynyl optionally substituted by l- 9 R19, C6_11aryl optionally substituted by 1-11 R19, C7_16arylalkyl optionally substituted by 1-19 R19, C3_11cycloalkyl optionally substituted by 1-21 R19, C4_17cycloalkylalkyl optionally substituted by 1-32 R19, 3-15 membered cycloalkyl optionally substituted by 1-28 R19, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40 R19, 5- membered aryl optionally substituted by 1-15 R19, 6-21 membered heteroarylalkyl optionally tuted by 1-27 R19, and —OR20; R3, R4, R5, and R6 are independently chosen from H, C1_6alkyl optionally substituted by 1-1 3 R19, C2_6alkenyl optionally substituted by 1-11 R19, C2_6alkynyl optionally substituted by 1-9 R19, C6_11aryl optionally substituted by 1-11 R19, C7_16arylalkyl optionally substituted by 1-19 R19, C3- 11cycloalkyl ally substituted by 1-21 R19, C4_17cycloalkylalkyl optionally substituted by 1-32 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R19, 4-21 ed heterocycloalkylalkyl optionally substituted by 1-40 R19, 5-15 membered heteroaryl optionally substituted by 1-15 R19, 6-21 membered heteroarylalkyl ally substituted by 1-27 R19, halogen, —CN, —C(=O)NR22R23, —N02, 23, and —OR20; atively, R3 and R6 can, together with the atoms linking them, form a C6_11aryl optionally substituted by 1-11 R19, C3_11cycloalkyl optionally substituted by 1-21 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R19 or a 5-15 membered heteroaryl optionally substituted by 1-15 R19; alternatively R3 and R5 or R4 and R6 can together form a double bond; alternatively any of R3 and R4, and R5 and R6 can er form =0, =NR20, =NOR20, or =8; and alternatively any of R1 and R2, R1 and R3, R1 and R5, R1 and R11, R4 and R11, and R6 and R11 can, together with the atoms linking them, form a 3-15 membered heterocycloalkyl optionally substituted by 1-28 R19 or a 5-15 membered heteroaryl optionally substituted by 1-15 R19.

Embodiment 41. The compound of any of Embodiments l-l9, wherein R1, R4, R5, R6, and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-13 R19; R2 is chosen from H, C1_6alkyl ally substituted by 1-13 R19, C7- 16arylalkyl optionally substituted by 1-19 R19, and 6-21 membered heteroarylalkyl optionally substituted by 1-27 R19; R3 is chosen from H, C1_6alkyl optionally substituted by l- l 3 R19, C7_16arylalkyl optionally substituted by l- l 9 R19, ycloalkylalkyl optionally substituted by 1-32 R19, and 6-21 ed heteroarylalkyl optionally substituted by 1-27 R19; alternatively, R3 and R6 can, together with the atoms g them, form a C3- 10cycloalkyl optionally substituted by 1-6 R19; alternatively R3 and R4 can together form =0; and atively any of R1 and R2, R1 and R3, R1 and R5, R1 and R11, R4 and R11, and R6 and R11 can, together with the atoms linking them, form a 3-15 membered heterocycloalkyl optionally substituted by 1-22 R19.

Embodiment 42. The compound of any of Embodiments l-l9, wherein R1, R4, R5, R6, and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-13 R19; R2 is chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C7- 16arylalkyl optionally substituted by 1-19 R19, and 6-21 ed arylalkyl optionally substituted by 1-27 R19; R3 is chosen from H, C1_6alkyl optionally substituted by l- l 3 R19, C7_16arylalkyl optionally substituted by l- l 9 R19, ycloalkylalkyl optionally substituted by 1-32 R19, and 6-21 membered heteroarylalkyl ally substituted by 1-27 R19; alternatively, R3 and R6 can, er with the atoms linking them, form a C3- 10cycloalkyl optionally substituted by 1-6 R19; alternatively R3 and R4 can er form =0; and alternatively any of R1 and R2, R1 and R3, R1 and R5, R4 and R11, and R6 and R11 can, together with the atoms linking them, form a 3-15 membered heterocycloalkyl optionally substituted by 1-22 R19.

Embodiment 43. The compound of any of Embodiments l-l9, wherein R1, R4, R5, R6, and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-13 R19; R2 is chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C7- 16arylalkyl ally substituted by 1-19 R19, and 6-21 membered heteroarylalkyl ally tuted by 1-27 R19; R3 is chosen from H, C1_6alkyl optionally substituted by l- l 3 R19, C7_16arylalkyl optionally substituted by l- l 9 R19, ycloalkylalkyl optionally substituted by 1-32 R19, and 6-21 membered heteroarylalkyl optionally substituted by 1-27 R19; atively, R3 and R6 can, together with the atoms linking them, form a C3- 6cycloalkyl optionally substituted by 1-6 R19; and alternatively any of R1 and R2, R1 and R3, R1 and R5, R1 and R11, R4 and R11, and R6 and R11 can, together with the atoms linking them, form a 3-15 membered heterocycloalkyl ally substituted by 1-22 R19.

Embodiment 44. The compound of any of Embodiments l-l9, wherein R1, R4, R5, R6, and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-13 R19; R2 is chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C7- 16arylalkyl optionally substituted by 1-19 R19, and 6-21 membered heteroarylalkyl ally substituted by 1-27 R19; R3 is chosen from H, C1_6alkyl optionally substituted by l- l 3 R19, C7_16arylalkyl optionally substituted by l- l 9 R19, C4_17cycloalkylalkyl optionally substituted by 1-32 R19, and 6-21 membered heteroarylalkyl optionally substituted by 1-27 R19; alternatively, R3 and R6 can, together with the atoms linking them, form a C3_ 6cycloalkyl optionally substituted by 1-6 R19; and alternatively any of R1 and R2, R1 and R3, R1 and R5, R4 and R11, and R6 and R11 can, together with the atoms linking them, form a 3-15 membered heterocycloalkyl optionally substituted by 1-22 R19.

Embodiment 45. The compound of any of Embodiments l-l9, wherein R1, R4, R5, R6, and R11 are independently chosen from H and C1_6alkyl optionally substituted W0 2013/078126 by 1-13 R19; R2 is chosen from H, C1-6alkyl optionally substituted by 1-13 R19, C7- 16arylalkyl ally substituted by 1-19 R19, and 6-21 membered heteroarylalkyl optionally substituted by 1-27 R19; R3 is chosen from H, C1-6alkyl optionally substituted by l- l 3 R19, C7_16arylalkyl optionally substituted by l- l 9 R19, ycloalkylalkyl optionally substituted by 1-32 R19, and 6-21 membered heteroarylalkyl optionally substituted by 1-27 R19; alternatively, R3 and R6 can, together with the atoms linking them, form a C3- 6cycloalkyl optionally substituted by 1-6 R19.

Embodiment 46. The compound of any of Embodiments l-l9, wherein R1 and R11 are independently chosen from H and C1-6alkyl optionally substituted by 1-13 R19; R4, R5, and R6 are H; R2 is chosen from H, C1-6alkyl optionally substituted by 1-13 R19, C7- 16arylalkyl optionally substituted by 1-19 R19, and 6-21 membered arylalkyl optionally substituted by 1-27 R19; R3 is chosen from H, C1_6alkyl optionally tuted by l- l 3 R19, rylalkyl optionally substituted by l- l 9 R19, C4-17cycloalkylalkyl optionally substituted by 1-32 R19, and 6-21 membered heteroarylalkyl optionally substituted by 1-27 R19; alternatively R3 and R6 can, together with the atoms g them, form a C3- 6cycloalkyl optionally substituted by 1-6 R19; alternatively R3 and R4 can together form =0; and alternatively any of R1 and R2, R1 and R3, R1 and R5, R1 and R11, R4 and R11, and R6 and R11 can, together with the atoms linking them, form a 3-15 membered heterocycloalkyl optionally substituted by 1-22 R19.

Embodiment 47. The compound of any of Embodiments l-l9, wherein R1 and R11 are independently chosen from H and C1_6alkyl optionally tuted by 1-13 R19; R4, R5, and R6 are H; R2 is chosen from H, C1-6alkyl ally tuted by 1-13 R19, C7- 16arylalkyl optionally substituted by 1-19 R19, and 6-21 membered heteroarylalkyl ally substituted by 1-27 R19; R3 is chosen from H, C1-6alkyl optionally substituted by l- l 3 R19, C7_16arylalkyl optionally substituted by l- l 9 R19, C4_17cycloalkylalkyl optionally substituted by 1-32 R19, and 6-21 membered heteroarylalkyl ally substituted by 1-27 R19; alternatively R3 and R6 can, together with the atoms linking them, form a C3- 6cycloalkyl optionally substituted by 1-6 R19; alternatively R3 and R4 can together form =0; and alternatively any of R1 and R2, R1 and R3, R1 and R5, R4 and R11, and R6 and R11 can, together with the atoms linking them, form a 3-15 membered heterocycloalkyl optionally tuted by 1-22 R19.

Embodiment 48. The compound of any of Embodiments l-l9, wherein R1, R2, and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-13 R19; R4, R5, and R6 are H; R3 is chosen from H, C1-6alkyl optionally substituted by 1-13 WO 78126 R19, C7_16arylalkyl optionally substituted by 1-19 R19, ycloalkylalkyl optionally substituted by 1-32 R19, and 6-21 membered heteroarylalkyl optionally substituted by 1-27 R19; alternatively R3 and R6 can, together with the atoms linking them, form a C3- 6cycloalkyl optionally substituted by 1-3 R19; and alternatively any of R1 and R2, R1 and R3, R1 and R5, R1 and R11, R4 and R11, and R6 and R11 can, together with the atoms linking them, form a 3-15 membered heterocycloalkyl optionally substituted by 1-22 R19.

Embodiment 49. The compound of any of Embodiments l-l9, wherein R1, R2, and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-13 R19; R4, R5, and R6 are H; R3 is chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C7_16arylalkyl optionally substituted by 1-19 R19, C4_17cycloalkylalkyl optionally substituted by 1-32 R19, and 6-21 membered heteroarylalkyl optionally substituted by 1-27 R19; alternatively R3 and R6 can, together with the atoms g them, form a C3_ 6cycloalkyl optionally substituted by 1-3 R19; and alternatively any of R1 and R2, R1 and R3, R1 and R5, R4 and R11, and R6 and R11 can, together with the atoms g them, form a 3-15 membered heterocycloalkyl optionally substituted by 1-22 R19.

Embodiment 50. The compound of any of Embodiments l-l9, wherein R1, R2, and R11 are independently chosen from H and kyl optionally substituted by 1-13 R19; R4, R5, and R6 are H; R3 is chosen from H, C1_6alkyl ally tuted by 1-13 R19, C7_16arylalkyl optionally substituted by 1-19 R19, C4_17cycloalkylalkyl optionally substituted by 1-32 R19, and 6-21 membered heteroarylalkyl optionally tuted by 1-27 R19; alternatively R3 and R6 can, together with the atoms linking them, form a C3_ 6cycloalkyl ally substituted by 1-3 R19.

Embodiment 51. The compound of any of Embodiments l-l9, wherein R1 and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-13 R19; R2 is chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C7_16arylalkyl optionally substituted by 1-19 R19, and 6-21 membered heteroarylalkyl optionally substituted by 1-27 R19; R3 is chosen from H, kyl optionally substituted by 1-13 R19, rylalkyl optionally tuted by 1-19 R19, ycloalkylalkyl optionally substituted by 1-10 R19, and 6-21 membered heteroarylalkyl optionally substituted by 1-27 R19; R4, R5, and R6 are H; alternatively R3 and R6 can, together with the atoms linking them, form a C3- 6cycloalkyl optionally substituted by 1-3 R19; alternatively R3 and R4 can together form =0; and alternatively any of R1 and R2, R1 and R3, R1 and R5, R1 and R11, and R4 and R11 can, together with the atoms linking them, form a 3-15 membered heterocycloalkyl optionally substituted by 1-22 R19. _ 40 _ Embodiment 52. The compound of any of Embodiments l-l9, wherein R1 and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-13 R19; R2 is chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C7_16arylalkyl optionally substituted by 1-19 R19, and 6-21 membered heteroarylalkyl optionally substituted by 1-27 R19; R3 is chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C7_16arylalkyl optionally substituted by 1-19 R19, C6_10cycloalkylalkyl optionally substituted by 1-10 R19, and 6-21 membered heteroarylalkyl optionally substituted by 1-27 R19; R4, R5, and R6 are H; alternatively R3 and R6 can, together with the atoms g them, form a C3_ 6cycloalkyl optionally substituted by 1-3 R19; alternatively R3 and R4 can together form =0; and alternatively any of R1 and R2, R1 and R3, R1 and R5, and R4 and R11 can, together with the atoms linking them, form a 3-15 membered cycloalkyl optionally substituted by 1-22 R19.

Embodiment 53. The compound of any of Embodiments l-l9, n R1, R4, R5, R6, and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-13 R19; R2 is chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C7- lzarylalkyl optionally tuted by 1-6 R19, and 6-10 ed heteroarylalkyl optionally tuted by 1-6 R19; R3 is chosen from H, C1_6alkyl optionally tuted by l- l 3 R19, C7_16arylalkyl optionally substituted by l- l 9 R19, C6_10cycloalkylalkyl optionally substituted by 1-10 R19, and 6-21 membered heteroarylalkyl optionally substituted by 1-27 R19; atively R3 and R6 can, together with the atoms linking them, form a C3- alkyl optionally substituted by 1-3 R19; and alternatively any of R1 and R2, R1 and R3, R1 and R5, R1 and R11, and R4 and R11 can, together with the atoms linking them, form a 3-15 membered heterocycloalkyl optionally substituted by 1-22 R19. ment 54. The compound of any of Embodiments l-l9, wherein R1, R4, R5, R6, and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-13 R19; R2 is chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C7- alkyl optionally substituted by 1-6 R19, and 6-10 membered heteroarylalkyl optionally substituted by 1-6 R19; R3 is chosen from H, C1_6alkyl optionally substituted by l- l 3 R19, C7_16arylalkyl optionally substituted by l- l 9 R19, C6_10cycloalkylalkyl optionally substituted by 1-10 R19, and 6-21 membered heteroarylalkyl optionally substituted by 1-27 R19; alternatively R3 and R6 can, together with the atoms linking them, form a C3- 6cycloalkyl optionally substituted by 1-3 R19; and alternatively any of R1 and R2, R1 and R3, R1 and R5, and R4 and R11 can, together with the atoms linking them, form a 3-15 membered heterocycloalkyl optionally substituted by 1-22 R19. _ 41 _ W0 2013/078126 2012/065831 Embodiment 55. The compound of any of Embodiments l-l9, wherein R1, R4, R5, R6, and R11 are independently chosen from H and kyl optionally substituted by 1-13 R19; R2 is chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C7- lzarylalkyl optionally substituted by 1-6 R19, and 6-10 membered arylalkyl optionally substituted by 1-6 R19; R3 is chosen from H, C1_6alkyl optionally substituted by l- l 3 R19, C7_16arylalkyl optionally substituted by l- l 9 R19, C6_10cycloalkylalkyl optionally substituted by 1-10 R19, and 6-21 membered heteroarylalkyl optionally substituted by 1-27 R19; atively R3 and R6 can, together with the atoms linking them, form a C3_ 6cycloalkyl optionally substituted by 1-3 R19.

Embodiment 56. The compound of any of Embodiments l-l9, wherein R1 and R11 are ndently chosen from H and C1_6alkyl ally tuted by 1-13 R19; R2 is chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C7_12arylalkyl optionally substituted by 1-6 R19, and 6-10 membered heteroarylalkyl optionally substituted by 1-6 R19; R3 is chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C7_16arylalkyl optionally substituted by 1-19 R19, C6_10cycloalkylalkyl optionally substituted by 1-10 R19, and 6-21 ed heteroarylalkyl optionally substituted by 1-27 R19; R4, R5, and R6 are H; atively R3 and R6 can, together with the atoms linking them, form a C3- 6cycloalkyl optionally substituted by 1-3 R19; alternatively R3 and R4 can together form =0; and alternatively any of R1 and R2, R1 and R3, R1 and R5, R1 and R11, and R4 and R11 can, together with the atoms g them, form a 3-15 membered heterocycloalkyl optionally substituted by 1-22 R19.

Embodiment 57. The compound of any of Embodiments l-l9, wherein R1 and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-13 R19; R2 is chosen from H, C1_6alkyl ally substituted by 1-13 R19, C7_12arylalkyl optionally substituted by 1-6 R19, and 6-10 membered arylalkyl optionally substituted by 1-6 R19; R3 is chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C7_16arylalkyl optionally substituted by 1-19 R19, C6_10cycloalkylalkyl optionally substituted by 1-10 R19, and 6-21 membered heteroarylalkyl optionally substituted by 1-27 R19; R4, R5, and R6 are H; alternatively R3 and R6 can, together with the atoms linking them, form a C3_ 6cycloalkyl optionally substituted by 1-3 R19; alternatively R3 and R4 can together form =0; and alternatively any of R1 and R2, R1 and R3, R1 and R5, and R4 and R11 can, together with the atoms g them, form a 3-15 membered heterocycloalkyl optionally substituted by 1-22 R19. ment 58. The compound of any of ments l-l9, wherein R1, R2, and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-13 R19; R3 is chosen from H, C1_6alkyl optionally tuted by 1-13 R19, C7_16arylalkyl optionally substituted by 1-19 R19, C6_10cycloalkylalkyl optionally substituted by 1-10 R19, and 6-21 membered heteroarylalkyl optionally substituted by 1-27 R19; R4, R5, and R6 are H; alternatively R3 and R6 can, together with the atoms linking them, form a C3- 6cycloalkyl; and alternatively any of R1 and R2, R1 and R3, R1 and R5, R1 and R11, and R4 and R11 can, together with the atoms linking them, form a 3-15 membered heterocycloalkyl optionally tuted by 1-22 R19.

Embodiment 59. The compound of any of Embodiments l-l9, wherein R1, R2, and R11 are independently chosen from H and C1_6alkyl optionally tuted by 1-13 R19; R3 is chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C7_16arylalkyl optionally substituted by 1-19 R19, C6_10cycloalkylalkyl optionally substituted by 1-10 R19, and 6-21 membered heteroarylalkyl ally substituted by 1-27 R19; R4, R5, and R6 are H; alternatively R3 and R6 can, together with the atoms linking them, form a C3- 6cycloalkyl; and alternatively any of R1 and R2, R1 and R3, R1 and R5, and R4 and R11 can, together with the atoms linking them, form a 3-15 membered heterocycloalkyl optionally substituted by 1-22 R19.

Embodiment 60. The compound of any of Embodiments l-l9, wherein R1, R2, and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-13 R19; R3 is chosen from H, C1_6alkyl optionally tuted by 1-13 R19, C7_16arylalkyl optionally substituted by 1-19 R19, C6_10cycloalkylalkyl optionally substituted by 1-10 R19, and 6-21 membered heteroarylalkyl optionally substituted by 1-27 R19; R4, R5, and R6 are H; alternatively R3 and R6 can, together with the atoms linking them, form a C3- alkyl.

Embodiment 61. The compound of any of Embodiments l-l9, wherein R1, R4, R5, R6, and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-13 R19; R2 is chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C7- alkyl optionally substituted by 1-6 R19, and 6-10 membered heteroarylalkyl optionally substituted by 1-6 R19; R3 is chosen from H, C1_6alkyl optionally substituted by 1-13 R19, rylalkyl ally substituted by 1-9 R19, C6_7cycloalkylalkyl optionally substituted by 1-6 R19, and 6-11 membered heteroarylalkyl optionally substituted by 1-7 R19; alternatively R3 and R6 can, er with the atoms linking them, form a C3_ 6cycloalkyl; and alternatively any of R1 and R2, R1 and R3, R1 and R5, R1 and R11, and R4 _ 43 _ and R11 can, together with the atoms linking them, form a 3-7 membered heterocycloalkyl ally substituted by 1-11 R19.

Embodiment 62. The nd of any of Embodiments l-l9, wherein R1, R4, R5, R6, and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-13 R19; R2 is chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C7- 11arylalkyl optionally substituted by 1-6 R19, and 6-lO membered heteroarylalkyl optionally substituted by 1-6 R19; R3 is chosen from H, C1_6alkyl ally substituted by 1-13 R19, C7_11arylalkyl optionally substituted by 1-9 R19, C6_7cycloalkylalkyl optionally substituted by 1-6 R19, and 6-11 membered heteroarylalkyl optionally substituted by 1-7 R19; alternatively R3 and R6 can, er with the atoms linking them, form a C3- 6cycloalkyl; and alternatively any of R1 and R2, R1 and R3, R1 and R5, and R4 and R11 can, er with the atoms linking them, form a 3-7 membered heterocycloalkyl optionally substituted by 1-1 1 R19.

Embodiment 63. The compound of any of ments l-l9, wherein R1, R4, R5, R6, and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-13 R19; R2 is chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C7- 11arylalkyl optionally substituted by 1-6 R19, and 6-lO membered heteroarylalkyl optionally substituted by 1-6 R19; R3 is chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C7_11arylalkyl optionally substituted by 1-9 R19, C6_7cycloalkylalkyl optionally substituted by 1-6 R19, and 6-11 membered heteroarylalkyl optionally substituted by 1-7 R19; alternatively R3 and R6 can, together with the atoms linking them, form a C3_ 6cycloalkyl.

Embodiment 64. The compound of any of ments l-l9, n R1, R2, and R11 are independently chosen from H and kyl optionally substituted by 1-13 R19; R3 is chosen from H, C1_6alkyl ally substituted by 1-13 R19, C7_11arylalkyl optionally substituted by 1-9 R19, C6_7cycloalkylalkyl optionally substituted by 1-6 R19, and 6-11 membered heteroarylalkyl optionally substituted by 1-7 R19; R4, R5, and R6 are H; atively R3 and R6 can, together with the atoms linking them, form a C3- 6cycloalkyl; alternatively R3 and R4 can together form =0; and alternatively any of R1 and R2, R1 and R3, R1 and R5, R1 and R11, and R4 and R11 can, together with the atoms linking them, form a 3-7 ed heterocycloalkyl optionally substituted by 1-11 R19.

Embodiment 65. The nd of any of Embodiments l-l9, wherein R1, R2, and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-13 R19; R3 is chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C7_11arylalkyl _ 44 _ optionally substituted by 1-9 R19, C6_7cycloalkylalkyl optionally substituted by 1-6 R19, and 6-11 membered heteroarylalkyl optionally substituted by 1-7 R19; R4, R5, and R6 are H; alternatively R3 and R6 can, together with the atoms linking them, form a C3- 6cycloalkyl; alternatively R3 and R4 can together form =0; and alternatively any of R1 and R2, R1 and R3, R1 and R5, and R4 and R11 can, together with the atoms linking them, form a 3-7 membered heterocycloalkyl optionally substituted by 1-1 1 R19.

Embodiment 66. The compound of any of Embodiments l-l9, wherein R1, R2, and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-13 R19; R3 is chosen from H, kyl optionally substituted by 1-13 R19, C7_11arylalkyl optionally substituted by 1-9 R19, C6_7cycloalkylalkyl ally substituted by 1-6 R19, and 6-11 membered arylalkyl optionally substituted by 1-7 R19; R4, R5, and R6 are H; alternatively R3 and R6 can, together with the atoms linking them, form a C3_ 6cycloalkyl; atively R3 and R4 can together form =0.

Embodiment 67. The compound of any of Embodiments l-l9, wherein R1, R4, R5, R6, and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-13 R19; R2 is chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C7- 11arylalkyl optionally substituted by 1-6 R19, and 6-lO ed heteroarylalkyl optionally substituted by 1-6 R19; R3 is chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C7_11arylalkyl optionally substituted by 1-9 R19, C6_7cycloalkylalkyl optionally tuted by 1-6 R19, and 6-11 ed heteroarylalkyl optionally substituted by 1-7 R19; alternatively R3 and R6 can, together with the atoms linking them, form a ropyl group optionally substituted by 1-3 R19; and alternatively any of R1 and R3 , R1 and R5 , R1 and R11, and R4 and R11 can, together with the atoms linking them, form a 3-7 membered heterocycloalkyl optionally substituted by 1-1 1 R19.

Embodiment 68. The compound of any of Embodiments l-l9, wherein R1, R4, R5, R6, and R11 are independently chosen from H and C1_6alkyl ally substituted by 1-13 R19; R2 is chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C7- 11arylalkyl optionally substituted by 1-6 R19, and 6-lO membered heteroarylalkyl optionally substituted by 1-6 R19; R3 is chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C7_11arylalkyl optionally substituted by 1-9 R19, C6_7cycloalkylalkyl optionally substituted by 1-6 R19, and 6-11 ed heteroarylalkyl optionally substituted by 1-7 R19; alternatively R3 and R6 can, together with the atoms linking them, form a cyclopropyl group optionally substituted by 1-3 R19; and alternatively any of R1 and R3, R1 and R5, and R4 and R11 can, together with the atoms linking them, form a 3-7 membered heterocycloalkyl optionally substituted by 1-1 1 R19.

Embodiment 69. The compound of any of Embodiments l-l9, wherein R1, R4, R5, R6, and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-13 R19; R2 is chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C7- 11arylalkyl optionally tuted by 1-6 R19, and 6-10 membered heteroarylalkyl ally substituted by 1-6 R19; R3 is chosen from H, C1_6alkyl ally substituted by 1-13 R19, C7_11arylalkyl optionally substituted by 1-9 R19, C6_7cycloalkylalkyl optionally substituted by 1-6 R19, and 6-11 membered arylalkyl optionally substituted by 1-7 R19; alternatively R3 and R6 can, together with the atoms linking them, form a cyclopropyl group optionally substituted by 1-3 R19.

Embodiment 70. The compound of any of Embodiments l-l9, wherein R1, R2, and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-13 R19; R3 is chosen from H, C1_6alkyl ally tuted by 1-13 R19, C7_11arylalkyl optionally substituted by 1-9 R19, C6_7cycloalkylalkyl ally substituted by 1-6 R19, and 6-11 membered heteroarylalkyl optionally substituted by 1-7 R19; R4, R5, and R6 are H; alternatively R3 and R6 can, together with the atoms linking them, form a cyclopropyl group; and alternatively any of R1 and R3, R1 and R5, R1 and R11, and R4 and R11 can, together with the atoms linking them, form a 3-7 membered cycloalkyl optionally substituted by 1-1 1 R19.

Embodiment 71. The compound of any of Embodiments l-l9, wherein R1, R2, and R11 are ndently chosen from H and C1_6alkyl optionally substituted by 1-13 R19; R3 is chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C7_11arylalkyl optionally substituted by 1-9 R19, C6_7cycloalkylalkyl optionally tuted by 1-6 R19, and 6-11 membered heteroarylalkyl ally substituted by 1-7 R19; R4, R5, and R6 are H; alternatively R3 and R6 can, together with the atoms linking them, form a cyclopropyl group; and alternatively any of R1 and R3, R1 and R5, and R4 and R11 can, together with the atoms linking them, form a 3-7 membered heterocycloalkyl optionally substituted by 1-11 R19.

Embodiment 72. The compound of any of Embodiments l-l9, wherein R1, R2, and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-13 R19; R3 is chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C7_11arylalkyl optionally substituted by 1-9 R19, C6_7cycloalkylalkyl optionally substituted by 1-6 R19, and 6-11 membered heteroarylalkyl optionally substituted by 1-7 R19; R4, R5, and R6 are _ 46 _ 2012/065831 H; alternatively R3 and R6 can, together with the atoms linking them, form a cyclopropyl group.

Embodiment 73. The compound of any of Embodiments l-l9, n R1, R4, R5, R6, and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-3 R19; R2 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C7_11arylalkyl optionally substituted by 1-3 R19, and 6-10 membered heteroarylalkyl optionally substituted by 1-3 R19; R3 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C7_11arylalkyl optionally substituted by 1-9 R19, C6_7cycloalkylalkyl optionally substituted by 1-6 R19, and 6-11 membered heteroarylalkyl optionally substituted by 1-7 R19; and alternatively any of R1 and R2, R1 and R3, R1 and R5, R1 and R11, and R4 and R11 can, together with the atoms linking them, form a 3-7 ed heterocycloalkyl optionally substituted by 1—3 R19.

Embodiment 74. The compound of any of Embodiments l-l9, wherein R1, R4, R5, R6, and R11 are independently chosen from H and C1_6alkyl optionally tuted by 1-3 R19; R2 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C7_11arylalkyl optionally substituted by 1-3 R19, and 6-10 membered heteroarylalkyl optionally substituted by 1-3 R19; R3 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C7_11arylalkyl optionally substituted by 1-9 R19, C6_7cycloalkylalkyl optionally substituted by 1-6 R19, and 6-11 membered heteroarylalkyl optionally substituted by 1-7 R19; and alternatively any of R1 and R2, R1 and R3, R1 and R5, and R4 and R11 can, together with the atoms linking them, form a 3-7 ed heterocycloalkyl optionally substituted by 1-3 R19. ment 75. The compound of any of Embodiments l-l9, wherein R1, R4, R5, R6, and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-3 R19; R2 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C7_11arylalkyl optionally substituted by 1-3 R19, and 6-10 ed heteroarylalkyl optionally substituted by 1-3 R19; R3 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C7_11arylalkyl optionally substituted by 1-9 R19, C6_7cycloalkylalkyl ally substituted by 1-6 R19, and 6-11 membered heteroarylalkyl optionally substituted by 1-7 R19; and alternatively any of R1 and R2, R1 and R3, R1 and R5, R1 and R11, and R4 and R11 can, together with the atoms g them, form a 3-7 ed heterocycloalkyl optionally substituted by 1—3 R19.

Embodiment 76. The compound of any of Embodiments l-l9, wherein R1, R2, and R11 are independently chosen from H and C1_6alkyl ally substituted by 1-3 _ 47 _ WO 78126 R19; R3 is chosen from H, C1_6alkyl optionally tuted by 1-3 R19, C7_11arylalkyl optionally substituted by 1-9 R19, C6_7cycloalkylalkyl optionally substituted by 1-6 R19, and 6-11 membered heteroarylalkyl optionally substituted by 1-7 R19; R4, R5, and R6 are Embodiment 77. The nd of any of Embodiments l-l9, wherein R1, R2, R4, R5, R6, and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-3 R19; R3 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C7_11arylalkyl optionally substituted by 1-3 R19, C6_7cycloalkylalkyl optionally substituted by 1-3 R19, and 6-11 membered heteroarylalkyl optionally substituted by 1-3 R19; and alternatively any of R1 and R3, R1 and R5, R1 and R11, and R4 and R11 can, together with the atoms linking them, form a 3-7 membered heterocycloalkyl optionally substituted by 1—3 R19. ment 78. The compound of any of Embodiments l-l9, wherein R1, R2, R4, R5, R6, and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-3 R19; R3 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C7_11arylalkyl optionally substituted by 1-3 R19, cloalkylalkyl optionally substituted by 1-3 R19, and 6-11 membered heteroarylalkyl ally substituted by 1-3 R19; and alternatively any of R1 and R3, R1 and R5, and R4 and R11 can, together with the atoms linking them, form a 3-7 membered heterocycloalkyl optionally substituted by 1-3 R19.

Embodiment 79. The compound of any of Embodiments l-l9, wherein R1, R2, R4, R5, R6, and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-3 R19; R3 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C7_11arylalkyl optionally substituted by 1-3 R19, C6_7cycloalkylalkyl optionally substituted by 1-3 R19, and 6-11 ed heteroarylalkyl optionally substituted by 1-3 R19.

Embodiment 80. The compound of any of Embodiments l-l9, wherein R1, R2, and R11 are ndently chosen from H and kyl optionally substituted by 1-3 R19; R3 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C7_11arylalkyl optionally substituted by 1-3 R19, C6_7cycloalkylalkyl optionally substituted by 1-3 R19, and 6-11 membered heteroarylalkyl optionally substituted by 1-3 R19; R4, R5, and R6 are H; and atively any of R1 and R3, R1 and R5, R1 and R11, and R4 and R11 can, together with the atoms linking them, form a 5-7 membered heterocycloalkyl optionally substituted by 1—3 R19.

Embodiment 81. The compound of any of Embodiments l-l9, wherein R1, R2, and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-3 _ 48 _ 2012/065831 R19; R3 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C7_11arylalkyl optionally substituted by 1-3 R19, C6_7cycloalkylalkyl optionally tuted by 1-3 R19, and 6-11 membered heteroarylalkyl optionally substituted by 1-3 R19; R4, R5, and R6 are H; and alternatively any of R1 and R3, R1 and R5, and R4 and R11 can, together with the atoms linking them, form a 5-7 membered heterocycloalkyl optionally substituted by 1-3 R19. ment 82. The compound of any of Embodiments l-l9, wherein R1, R2, and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-3 R19; R3 is chosen from H, C1_6alkyl ally tuted by 1-3 R19, C7_11arylalkyl optionally substituted by 1-3 R19, C6_7cycloalkylalkyl optionally substituted by 1-3 R19, and 6-11 membered heteroarylalkyl optionally substituted by 1-3 R19; R4, R5, and R6 are Embodiment 83. The compound of any of Embodiments l-l9, wherein R1, R2, and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-3 R19; R3 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C7_11arylalkyl optionally substituted by 1-3 R19, C6_7cycloalkylalkyl optionally substituted by 1-3 R19, and 6-11 membered heteroarylalkyl optionally substituted by 1-3 R19; R4, R5, and R6 are H; alternatively any of R1 and R3, R1 and R5, and R4 and R11 can, together with the atoms linking them, form a 5-6 membered cycloalkyl optionally substituted by 1-3 R19; and alternatively R1 and R11 can, together with the atoms linking them, form a 5-7 membered heterocycloalkyl optionally substituted by 1-3 R19.

Embodiment 84. The compound of any of Embodiments l-l9, wherein R1, R2, and R11 are independently chosen from H and kyl ally substituted by 1-3 R19; R3 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C7_11arylalkyl optionally tuted by 1-3 R19, C6_7cycloalkylalkyl optionally substituted by 1-3 R19, and 6-11 membered heteroarylalkyl optionally substituted by 1-3 R19; R4, R5, and R6 are H; alternatively any of R1 and R3, R1 and R5, and R4 and R11 can, together with the atoms linking them, form a 5-6 membered heterocycloalkyl ally substituted by 1-3 R19.

Embodiment 85. The nd of any of Embodiments l-l9, wherein R1, R2, and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-3 R19; R3 is chosen from H, C1_6alkyl optionally tuted by 1-3 R19, C7_11arylalkyl ally substituted by 1-3 R19, C6_7cycloalkylalkyl optionally substituted by 1-3 R19, and 6-11 membered heteroarylalkyl optionally substituted by 1-3 R19; R4, R5, and R6 are H; alternatively any of R1 and R3, and R4 and R11 can, together with the atoms linking _ 49 _ them, form a 5 membered heterocycloalkyl optionally substituted by 1-3 R19; alternatively R1 and R5 can, together with the atoms linking them, form a 5-6 membered heterocycloalkyl optionally tuted by 1-3 R19; and alternatively R1 and R11 can, together with the atoms g them, form a 6-7 membered heterocycloalkyl optionally substituted by 1—3 R19.

Embodiment 86. The nd of any of Embodiments l-l9, wherein R1, R2, and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-3 R19; R3 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C7_11arylalkyl optionally substituted by 1-3 R19, C6_7cycloalkylalkyl optionally substituted by 1-3 R19, and 6-11 membered heteroarylalkyl optionally substituted by 1-3 R19; R4, R5, and R6 are H; atively any of R1 and R3, and R4 and R11 can, together with the atoms linking them, form a 5 membered heterocycloalkyl optionally substituted by 1-3 R19; alternatively R1 and R5 can, together with the atoms linking them, form a 5-6 membered heterocycloalkyl optionally tuted by 1-3 R19.

Embodiment 87. The compound of any of Embodiments l-l9, wherein R1 and R11 are independently chosen from H and C1_6alkyl ally substituted by 1-3 R19; R2 is chosen from H, kyl ally tuted by 1-3 R19, and C7_11arylalkyl optionally substituted by 1-3 R19; R3 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C7_11arylalkyl optionally substituted by 1-3 R19, cloalkylalkyl ally substituted by 1-3 R19, and 6-11 membered heteroarylalkyl optionally substituted by 1-3 R19; R4, R5, and R6 are H; alternatively any of R1 and R3, and R4 and R11 can, together with the atoms linking them, form a 5 membered heterocycloalkyl optionally substituted by 1-3 R19; alternatively R1 and R5 can, together with the atoms g them, form a 5-6 membered heterocycloalkyl optionally substituted by 1-3 R19; and alternatively R1 and R11 can, together with the atoms linking them, form a 6-7 membered heterocycloalkyl optionally substituted by 1-3 R19.

Embodiment 88. The compound of any of Embodiments l-l9, wherein R1 and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-3 R19; R2 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, and C7_11arylalkyl optionally substituted by 1-3 R19; R3 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C7_11arylalkyl optionally substituted by 1-3 R19, C6_7cycloalkylalkyl optionally substituted by 1-3 R19, and 6-11 membered heteroarylalkyl optionally substituted by 1-3 R19; R4, R5, and R6 are H; alternatively any of R1 and R3, and R4 and R11 can, together with the atoms linking them, form a 5 membered heterocycloalkyl optionally substituted by 1-3 R19; alternatively R1 and R5 can, together with the atoms linking them, form a 5-6 membered heterocycloalkyl optionally substituted by 1-3 R19.

Embodiment 89. The compound of any of Embodiments l-l9, wherein R1 and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-3 R19; R2 is H; R3 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C7_11arylalkyl optionally substituted by 1-3 R19, C6_7cycloalkylalkyl optionally substituted by 1-3 R19, and 6-11 membered heteroarylalkyl optionally substituted by 1-3 R19; R4, R5, and R6 are H; alternatively R1 and R5 can, together with the atoms linking them, form a 5-6 membered heterocycloalkyl optionally substituted by 1-3 R19; and alternatively R1 and R11 can, together with the atoms linking them, form a 6-7 membered cycloalkyl optionally substituted by 1-3 R19.

Embodiment 90. The compound of any of Embodiments l-l9, wherein R1 and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-3 R19; R2 is H; R3 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, rylalkyl ally substituted by 1-3 R19, C6_7cycloalkylalkyl optionally substituted by 1-3 R19, and 6-11 membered heteroarylalkyl ally substituted by 1-3 R19; R4, R5, and R6 are H; alternatively R1 and R5 can, together with the atoms linking them, form a 5-6 membered heterocycloalkyl optionally substituted by 1-3 R19.

Embodiment 91. The compound of any of Embodiments l-l9, wherein R1, R2, and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-3 R19; R3 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C7_11arylalkyl optionally substituted by 1-3 R19, cloalkylalkyl optionally substituted by 1-3 R19, and 6-11 ed heteroarylalkyl optionally tuted by 1-3 R19; R4, R5, and R6 are H; alternatively R1 and R5 can, together with the atoms g them, form a 5-6 ed heterocycloalkyl optionally substituted by 1-3 R19; and alternatively R1 and R11 can, together with the atoms linking them, form a 6-7 membered heterocycloalkyl optionally substituted by 1-3 R19.

Embodiment 92. The nd of any of Embodiments l-l9, wherein R1, R2, and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-3 R19; R3 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C7_11arylalkyl optionally substituted by 1-3 R19, cloalkylalkyl optionally substituted by 1-3 R19, and 6-11 membered heteroarylalkyl optionally substituted by 1-3 R19; R4, R5, and R6 are H; alternatively R1 and R5 can, together with the atoms linking them, form a 5-6 membered heterocycloalkyl optionally substituted by 1-3 R19. _ 51 _ 2012/065831 Embodiment 93. The compound of any of Embodiments l-l9, wherein R1, R2, and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-3 R19; R3 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C7_11arylalkyl optionally substituted by 1-3 R19, cloalkylalkyl optionally substituted by 1-3 R19, and 6-11 membered arylalkyl optionally tuted by 1-3 R19; R4, R5, and R6 are H; alternatively R1 and R5 can, together with the atoms linking them, form a 5-6 membered heterocycloalkyl optionally substituted by 1-3 R19; and alternatively R1 and R11 can, together with the atoms linking them, form a 6-7 membered cycloalkyl optionally tuted by 1-3 R19.

Embodiment 94. The compound of any of ments l-l9, wherein R1, R2, and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-3 R19; R3 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C7_11arylalkyl optionally substituted by 1-3 R19, cloalkylalkyl optionally substituted by 1-3 R19, and 6-11 membered heteroarylalkyl ally substituted by 1-3 R19; R4, R5, and R6 are H; alternatively R1 and R5 can, er with the atoms linking them, form a 5-6 membered cycloalkyl optionally substituted by 1-3 R19.

Embodiment 95. The compound of any of Embodiments l-l9, wherein R1 and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-3 R19; R2 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, and C7_11arylalkyl optionally substituted by 1-3 R19; R3 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, rylalkyl optionally substituted by 1-3 R19, C6_7cycloalkylalkyl optionally substituted by 1-3 R19, and 6-11 membered heteroarylalkyl optionally tuted by 1-3 R19; R4, R5, and R6 are H; alternatively R1 and R5 can, together with the atoms linking them, form a 5-6 membered heterocycloalkyl optionally substituted by 1-3 R19; and alternatively R1 and R11 can, together with the atoms linking them, form a 6-7 membered heterocycloalkyl optionally tuted by 1-3 R19.

Embodiment 96. The compound of any of Embodiments l-l9, wherein R1 and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-3 R19; R2 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, and C7_11arylalkyl optionally substituted by 1-3 R19; R3 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C7_11arylalkyl optionally substituted by 1-3 R19, C6_7cycloalkylalkyl optionally substituted by 1-3 R19, and 6-11 membered heteroarylalkyl optionally substituted by 1-3 R19; R4, R5, and R6 are H; alternatively R1 and R5 can, together with the atoms linking them, form a 5-6 membered heterocycloalkyl optionally substituted by 1-3 R19. _ 52 _ Embodiment 97. The compound of any of Embodiments l-l9, wherein R1, R2, R4, R5, R6, and R11 are H; R3 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C7_11arylalkyl optionally substituted by 1-3 R19, C6_7cycloalkylalkyl optionally tuted by 1-3 R19, and 6-11 membered heteroarylalkyl optionally tuted by 1-3 R19; alternatively R1 and R5 can, together with the atoms linking them, form a 5-6 membered heterocycloalkyl ally substituted by 1-3 R19; and alternatively R1 and R11 can, together with the atoms linking them, form a 5-7 membered heterocycloalkyl optionally substituted by 1-3 R19.

Embodiment 98. The compound of any of Embodiments l-l9, wherein R1, R2, R4, R5, R6, and R11 are H; R3 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C7_11arylalkyl optionally substituted by 1-3 R19, C6_7cycloalkylalkyl ally substituted by 1-3 R19, and 6-11 membered heteroarylalkyl optionally substituted by 1-3 R19; alternatively R1 and R5 can, together with the atoms g them, form a 5-6 membered heterocycloalkyl optionally substituted by 1-3 R19.

Embodiment 99. The compound of any of Embodiments l-l9, wherein R1, R2, R4, R5, R6, and R11 are H; R3 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C7_11arylalkyl optionally substituted by 1-3 R19, C6_7cycloalkylalkyl optionally substituted by 1-3 R19, and 6-11 membered heteroarylalkyl optionally substituted by 1-3 R19; alternatively R1 and R5 can, together with the atoms linking them, form a 5 membered heterocycloalkyl optionally substituted by 1-3 R19; and atively R1 and R11 can, together with the atoms linking them, form a 6 membered heterocycloalkyl optionally tuted by 1—3 R19.

Embodiment 100. The compound of any of Embodiments l-l9, wherein R1, R2, R4, R5, R6, and R11 are H; R3 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C7_11arylalkyl optionally substituted by 1-3 R19, C6_7cycloalkylalkyl ally substituted by 1-3 R19, and 6-11 membered heteroarylalkyl optionally substituted by 1-3 R19; alternatively R1 and R5 can, together with the atoms linking them, form a 5 ed cycloalkyl optionally substituted by 1-3 R19.

Embodiment 101. The compound of any of Embodiments l-l9, wherein R1, R2, R4, R5, R6, and R11 are H; R3 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, benzyl optionally substituted by 1-3 R19, oalkylalkyl ally substituted by 1-3 R19, and 6-7 membered heteroarylalkyl optionally substituted by 1-3 R19; alternatively R1 and R5 can, together with the atoms linking them, form a idinyl group optionally substituted by 1-3 R19; and alternatively R1 and R11 can, er with the atoms linking them, form a piperidinyl group optionally substituted by 1-3 R19.

Embodiment 102. The compound of any of Embodiments 1-19, wherein R1, R2, R4, R5, R6, and R11 are H; R3 is chosen from H, C1_6alkyl optionally tuted by 1-3 R19, benzyl optionally substituted by 1-3 R19, C7cycloalkylalkyl optionally substituted by 1-3 R19, and 6-7 membered heteroarylalkyl optionally substituted by 1-3 R19; alternatively R1 and R5 can, together with the atoms linking them, form a idinyl group ally substituted by 13 R19. ment 103. The compound of any of Embodiments 1-19, wherein R1, R2, R4, R5, R6, and R11 are H; R3 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, benzyl ally substituted by 1-3 R19, oalkylalkyl optionally substituted by 1-3 R19, and 6-7 membered arylalkyl optionally substituted by 1-3 R19; alternatively R1 and R5 can, together with the atoms linking them, form a idinyl group; and atively R1 and R11 can, together with the atoms linking them, form a piperidinyl group.

Embodiment 104. The compound of any of Embodiments 1-19, wherein R1, R2, R4, R5, R6, and R11 are H; R3 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, benzyl optionally substituted by 1-3 R19, C7cycloalkylalkyl optionally substituted by 1-3 R19, and 6-7 membered heteroarylalkyl optionally tuted by 1-3 R19; alternatively R1 and R5 can, together with the atoms linking them, form a pyrrolidinyl group.

Embodiment 105. The compound of any of Embodiments 1-19, wherein R1, R2, R4, R5, R6, and R11 are H; R3 is benzyl optionally substituted by 1-3 R19; alternatively R1 and R5 can, together with the atoms linking them, form a pyrrolidinyl group; and alternatively R1 and R11 can, together with the atoms linking them, form a piperidinyl group.

Embodiment 106. The compound of any of Embodiments 1-19, wherein R1, R2, R4, R5, R6, and R11 are H; R3 is benzyl optionally substituted by 1-3 R19; alternatively R1 and R5 can, together with the atoms linking them, form a pyrrolidinyl group.

Embodiment 107. The compound of any of Embodiments 1-19, wherein R1, R2, R4, R5, R6, and R11 are H; R3 is benzyl; alternatively R1 and R5 can, together with the atoms linking them, form a pyrrolidinyl group; and alternatively R1 and R11 can, together with the atoms linking them, form a piperidinyl group. 2012/065831 Embodiment 108. The compound of any of ments l-l9, wherein R1, R2, R4, R5, R6, and R11 are H; R3 is benzyl; alternatively R1 and R5 can, together with the atoms linking them, form a pyrrolidinyl group.

Embodiment 109. The compound of any of Embodiments 1-108, wherein R7, R8, R9, and R10 are independently chosen from H, C1_6alkyl ally substituted by 1-13 R19, kenyl optionally tuted by 1-11 R19, kynyl optionally substituted by l- 9 R19, C6_11aryl optionally substituted by 1-11 R19, C7_16arylalkyl optionally substituted by 1-19 R19, C3_11cycloalkyl optionally substituted by 1-21 R19, C4_17cycloalkylalkyl optionally substituted by 1-32 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R19, 4-21 membered heterocycloalkylalkyl optionally tuted by 1-40 R19, 5- membered heteroaryl optionally substituted by 1-15 R19, 6-21 membered heteroarylalkyl ally substituted by 1-27 R19, halogen, —CN, —C(=O)R20, — C(=O)OR2°, —C(=O)NR22R23, —C(=O)C(=O)R2°, —C(=NR25)R2°, 25)NR22R23, — C(=NOH)NR22R23, —C(=NOR26)R20, —C(=NNR22R23)R2°, —C(=NNR24C(=O)R21)R20, — C(=NNR24C(=O)OR21)R2°, —C(=S)NR22R23, —NC, —N02, —NR22R23, R22R23, — N=NR24, —NR24OR26, —NR24C(=O)R2°, —NR24C(=O)C(=O)R2°, —NR24C(=O)OR21, — NR24C(=O)C(=O)OR21, —NR24C(=O)NR22R23, —NR24C(=O)NR24C(=O)R2°, — NR24C(=O)NR24C(=O)OR2°, —NR24C(=NR25)NR22R23, —NR24C(=O)C(=O)NR22R23, — NR24C(=S)R2°, —NR24C(=S)OR2°, —NR24C(=S)NR22R23, —NR24S(=O)2R21, — NR24S(=O)2NR22R23, _NR24P(:O)R28R28’ (=O)(NR22R23)(NR22R23), _ NR24P(=O)(OR2°)(OR20), —NR24P(=O)(SR2°)(SR2°), —OR20, —OCN, —OC(=O)R2°, — OC(=O)NR22R23, —OC(=O)OR2°, —OC(=NR25)NR22R23, —OS(=O)R2°, —OS(=O)2R2°, — OS(=O)20R2°, —OS(=O)2NR22R23, —OP(=O)R28R28, —OP(=O)(NR22R23)(NR22R23), — OP(=O)(OR20)(OR2°), —OP(=O)(SR2°)(SR2°), —Si(R24)3 ,—SCN, —S(=O)nR2°, — S(=O)20R20, —SOgR27, —S(=O)2NR22R23, —S(=O)NR22R23, —SP(=O)R28R28, — SP(=O)(NR22R23)(NR22R23), —SP(=O)(OR2°)(OR2°), —SP(=O)(SR20)(SR20), —P(=O)R28R28, —P(=O)(NR22R23)(NR22R23), —P(=O)(OR20)(OR20), and —P(=O)(SR20)(SR20); alternatively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms g them, form a C6_11aryl optionally substituted by 1-11 R19, C3_11cycloalkyl optionally substituted by 1-21 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R19 or a 5-15 membered heteroaryl optionally substituted by 1-15 R19.

Embodiment 110. The compound of any of Embodiments 1-108, wherein R7, R8, R9, and R10 are independently chosen from H, kyl optionally substituted by 1-13 _ 55 _ R19, C2_6alkenyl ally substituted by l-ll R19, C2_6alkynyl optionally substituted by l- 9 R19, C6_11aryl optionally substituted by l-ll R19, C7_16arylalkyl optionally substituted by 1-19 R19, C3_1lcycloalkyl optionally substituted by 1-21 R19, C4_17cycloalkylalkyl optionally substituted by l-32 R19, 3-15 membered heterocycloalkyl optionally substituted by l-28 R19, 4-21 membered heterocycloalkylalkyl ally substituted by l-40 R19, 5- membered heteroaryl ally substituted by l-lS R19, 6-21 membered heteroarylalkyl optionally substituted by l-27 R19, halogen, —CN, —C(=O)R20, — R2°, NR22R23, —NC, —N02, —NR22R23, —NR24OR26, —NR24C(=O)R2°, — =O)OR21, —NR24C(=O)NR22R23, —NR24S(=O)2R21, —NR24S(=O)2NR22R23, —OR2°, — OCN, —OC(=O)R2°, —OC(=O)NR22R23, —OC(=O)OR2°, —OS(=O)2R20, )20R2°, — OS(=O)2NR22R23, —S(=O)nR2°, and 2NR22R23; alternatively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a C6_11aryl optionally substituted by l-ll R19, ycloalkyl optionally substituted by l-2l R19, 3-15 membered heterocycloalkyl optionally substituted by l-28 R19 or a 5-15 membered heteroaryl optionally substituted by l-lS R19.

Embodiment 111. The compound of any of Embodiments l-108, wherein R7, R8, R9, and R10 are ndently chosen from H, C1_6alkyl optionally substituted by l-6 R19, C2_6alkenyl optionally substituted by l-6 R19, C2_6alkynyl optionally substituted by l-6 R19, C6_11aryl optionally tuted by l-6 R19, C7_16arylalkyl optionally substituted by l-6 R19, C3_11cycloalkyl optionally substituted by l-6 R19, ycloalkylalkyl optionally substituted by l-6 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-6 R19, 4-21 membered heterocycloalkylalkyl optionally substituted by l-6 R19, 5-15 membered heteroaryl optionally substituted by l-6 R19, 6-21 membered heteroarylalkyl optionally substituted by 1-6 R19, halogen, —CN, —C(=O)R20, —C(=O)OR2°, —C(=O)NR22R23, —NC, — N02, —NR22R23, —NR24OR26, —NR24C(=O)R2°, —NR24C(=O)OR21, (=O)NR22R23, — NR24S(=O)2R21, —NR24S(=O)2NR22R23, —OR2°, —OCN, —OC(=O)R2°, —OC(=O)NR22R23, — OC(=O)OR2°, —OS(=O)2R2°, —OS(=O)20R2°, —OS(=O)2NR22R23, —S(=O)nR2°, and — S(=O)2NR22R23; alternatively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms g them, form a C6_11aryl ally substituted by l-6 R19, C3- 11cycloalkyl optionally tuted by l-6 R19, 3-15 membered heterocycloalkyl optionally substituted by l-6 R19 or a 5-15 membered heteroaryl optionally substituted by 1-6 R19.

Embodiment 112. The compound of any of Embodiments l-108, wherein R7, R8, R9, and R10 are independently chosen from H, C1_6alkyl optionally substituted by l-4 R19, C2_6alkenyl optionally substituted by l-4 R19, C2_6alkynyl optionally substituted by l-4 R19, C6_10aryl optionally tuted by 1-4 R19, C7_11arylalkyl optionally substituted by 1-4 R19, C3_7cycloalkyl optionally substituted by 1-4 R19, C4_gcycloalkylalkyl optionally substituted by 1-4 R19, 3-7 membered heterocycloalkyl optionally substituted by 1-4 R19, 4-8 membered heterocycloalkylalkyl optionally substituted by 1-4 R19, 5-6 membered heteroaryl optionally substituted by 1-4 R19, 6-21 membered heteroarylalkyl optionally substituted by 1-4 R19, halogen, —CN, R20, —C(=O)OR2°, —C(=O)NR22R23, —NC, — N02, —NR22R23, —NR24OR26, —NR24C(=O)R2°, —NR24C(=O)OR21, —NR24C(=O)NR22R23, — NR24S(=O)2R21, —NR24S(=O)2NR22R23, —OR2°, —OCN, —OC(=O)R2°, —OC(=O)NR22R23, — OC(=O)OR2°, —OS(=O)2R2°, —OS(=O)20R2°, )2NR22R23, —S(=O)nR2°, and — S(=O)2NR22R23; alternatively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a ryl ally substituted by 1-4 R19, C3- 7cycloalkyl optionally substituted by 1-4 R19, 3-7 membered heterocycloalkyl optionally substituted by 1-4 R19 or a 5-6 membered heteroaryl optionally substituted by 1-4 R19.

Embodiment 113. The compound of any of Embodiments 1-108, wherein R7, R8, R9, and R10 are ndently chosen from H, C1_6alkyl optionally tuted by 1-3 R19, C2_6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl optionally tuted by 1-3 R19, C6_10aryl optionally substituted by 1-3 R19, C7_11arylalkyl optionally substituted by 1-3 R19, C3_7cycloalkyl optionally substituted by 1—3 R19, C4_gcycloalkylalkyl optionally substituted by 1-3 R19, 3-7 ed heterocycloalkyl optionally substituted by 1-3 R19, 4-8 ed heterocycloalkylalkyl optionally substituted by 1-3 R19, 5-6 ed heteroaryl optionally substituted by 1-3 R19, 6-21 membered heteroarylalkyl optionally substituted by 1—3 R19, halogen, —CN, —C(=O)R20, —C(=O)OR2°, —C(=O)NR22R23, —NC, — N02, —NR22R23, —NR24OR26, —NR24C(=O)R2°, —NR24C(=O)OR21, —NR24C(=O)NR22R23, — =O)2R21, —NR24S(=O)2NR22R23, —OR2°, —OCN, —OC(=O)R2°, —OC(=O)NR22R23, — OC(=O)OR2°, —OS(=O)2R2°, —OS(=O)20R2°, —OS(=O)2NR22R23, —S(=O)nR2°, and — S(=O)2NR22R23; alternatively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a C6_10aryl optionally substituted by 1-3 R19, C3- 7cycloalkyl optionally substituted by 1-3 R19, 3-7 membered heterocycloalkyl optionally substituted by 1-3 R19 or a 5-6 membered heteroaryl optionally substituted by 1-3 R19.

Embodiment 114. The compound of any of Embodiments 1-108, wherein R7, R8, R9, and R10 are independently chosen from H, C1_6alkyl optionally tuted by 1-3 R19, C2_6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl optionally substituted by 1-3 R19, C6_10aryl optionally substituted by 1-3 R19, rylalkyl optionally substituted by 1-3 R19, cloalkyl optionally tuted by 1-3 R19, C4_gcycloalkylalkyl optionally substituted by 1-3 R19, 3-7 membered heterocycloalkyl optionally substituted by 1-3 R19, 4-8 ed heterocycloalkylalkyl optionally substituted by 1-3 R19, 5-6 membered heteroaryl optionally substituted by 1-3 R19, 6-21 membered heteroarylalkyl ally substituted by 1-3 R19, halogen, —CN, —C(=O)R20, —C(=O)OR2°, —C(=O)NR22R23, —NOg, — NRZZR”, —NR24C(=O)R20, —NR24C(=O)OR21, —NR24C(=O)NR22R23, —NR24S(=O)2R21,— NR24S(=O)2NR22R23, —OR20, )R2°, )NR22R23, —OS(=O)2R2°, — OS(=O)2NR22R23, —S(=O)nR2°, and —S(=O)2NR22R23; alternatively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a C6_10aryl optionally substituted by 1-3 R19, C3_7cycloalkyl optionally substituted by 1-3 R19, 3-7 membered heterocycloalkyl optionally substituted by 1-3 R19 or a 5-6 membered heteroaryl ally substituted by 1-3 R19.

Embodiment l 15. The compound of any of Embodiments 1-108, wherein R7, R8, R9, and R10 are independently chosen from H, C1_6alkyl ally substituted by 1-3 R19, C2_6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl optionally substituted by 1-3 R19, C6_10aryl optionally substituted by 1-3 R19, C7_11arylalkyl optionally substituted by 1-3 R19, C3_7cycloalkyl ally substituted by 1—3 R19, C4_gcycloalkylalkyl optionally substituted by 1-3 R19, 3-7 membered heterocycloalkyl ally substituted by 1-3 R19, 4-8 membered heterocycloalkylalkyl optionally substituted by 1-3 R19, 5-6 membered heteroaryl optionally substituted by 1-3 R19, 6-21 membered heteroarylalkyl optionally substituted by 1-3 R19, halogen, —CN, —C(=O)R20, —C(=O)OR2°, —C(=O)NR22R23, —NOg, — , (=O)R20,—NR24S(=O)2R21, —OR2°, —S(=O)nR2°, and —S(=O)2NR22R23; alternatively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a C6_10aryl optionally substituted by 1-3 R19, C3_7cycloalkyl ally substituted by 1-3 R19, 3-7 ed heterocycloalkyl optionally substituted by 1-3 R19 or a 5-6 membered heteroaryl optionally substituted by 1-3 R19.

Embodiment 116. The nd of any of Embodiments 1-108, wherein R7, R8, R9, and R10 are ndently chosen from H, C1_6alkyl, C2_6alkenyl, C2_6alkynyl, C6- loaryl, C7_11arylalkyl, C3_7cycloalkyl, C4_gcycloalkylalkyl, 3-7 membered heterocycloalkyl, 4-8 membered heterocycloalkylalkyl, 5-6 membered heteroaryl, 6-21 membered heteroarylalkyl, halogen, —CN, —C(=O)R20, —C(=O)OR2°, —C(=O)NR22R23, —NOg, — NRZZR”, —NR24C(=O)R20,—NR24S(=O)2R21, —OR2°, —S(=O)nR2°, and —S(=O)2NR22R23; alternatively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a C6_10aryl, C3_7cycloalkyl, 3-7 membered heterocycloalkyl or a 5-6 membered heteroaryl.

Embodiment 117. The compound of any of Embodiments l-108, wherein R7, R8, R9, and R10 are independently chosen from H, C1_6alkyl optionally substituted by l-3 R19, C2_6alkenyl ally substituted by l-3 R19, C2_6alkynyl optionally substituted by l-3 R19, C6_10aryl ally substituted by l-3 R19, C7_11arylalkyl optionally substituted by l-3 R19, C3_7cycloalkyl optionally substituted by 1-3 R19, C4_gcycloalkylalkyl optionally substituted by 1-3 R19, 3-7 membered heterocycloalkyl optionally substituted by 1-3 R19, 4-8 membered heterocycloalkylalkyl optionally tuted by l-3 R19, 5-6 membered heteroaryl optionally substituted by l-3 R19, 6-21 ed heteroarylalkyl optionally substituted by 1-3 R19, halogen, —CN, —C(=O)R20, —C(=O)NR22R23, —NOg, —NR22R23, — NR24S(=O)2R21, —OR2°, —S(=O)nR2°, and —S(=O)2NR22R23; alternatively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a ryl optionally substituted by 1-3 R19, cloalkyl optionally substituted by l-3 R19, 3-7 membered cycloalkyl optionally substituted by l-3 R19 or a 5-6 ed heteroaryl optionally substituted by l-3 R19.

Embodiment 118. The nd of any of Embodiments l-108, wherein R7, R8, R9, and R10 are ndently chosen from H, C1_6alkyl optionally substituted by l-3 R19, C2_6alkynyl optionally substituted by l-3 R19, C6_10aryl optionally substituted by l-3 R19, C3_7cycloalkyl optionally substituted by 1-3 R19, 3-7 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-6 membered heteroaryl optionally substituted by l-3 R19, halogen, —CN, —C(=O)R20, —C(=O)NR22R23, —NOg, —NR22R23, —NR24S(=O)2R21, — ORZO, —S(=O)nR20, and —S(=O)2NR22R23; alternatively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a C6_10aryl optionally substituted by 1-3 R19, C3_7cycloalkyl optionally substituted by l-3 R19, 3-7 membered heterocycloalkyl optionally substituted by l-3 R19 or a 5-6 membered heteroaryl optionally substituted by 1-3 R19.

Embodiment 119. The nd of any of Embodiments l-108, wherein R7, R8, R9, and R10 are independently chosen from H, C1_6alkyl optionally substituted by l-3 R19, C2_6alkynyl optionally substituted by l-3 R19, C6_10aryl optionally substituted by l-3 R19, C3_7cycloalkyl optionally substituted by 1-3 R19, 3-7 membered cycloalkyl optionally substituted by 1-3 R19, 5-6 membered heteroaryl optionally substituted by l-3 R19, n, —CN, —C(=O)R20, —C(=O)NR22R23, —NOg, —NR22R23, —NR24S(=O)2R21, — ORZO, —S(=O)nR20, and —S(=O)2NR22R23; atively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms g them, form a C3_7cycloalkyl optionally substituted by 1-3 R19, or a 3-7 membered heterocycloalkyl optionally substituted by 1-3 R19.

Embodiment 120. The compound of any of Embodiments 1-108, wherein R7, R8, R9, and R10 are independently chosen from H, C1_6alkyl, C2_6alkynyl, C6_10aryl, C3_ 7cycloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, halogen, —CN, — C(=O)R2°, —C(=O)NR22R23, —N02, 23, —NR24S(=O)2R21, —OR20, —S(=O)nR20, and — S(=O)2NR22R23; alternatively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a C3_7cycloalkyl, or a 3-7 membered heterocycloalkyl.

Embodiment 121. The compound of any of Embodiments 1-108, wherein R7, R8, R9, and R10 are independently chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C2_6alkenyl optionally substituted by 1-11 R19, kynyl optionally tuted by l- 9 R19, ryl optionally substituted by 1-11 R19, C7_16arylalkyl ally substituted by 1-19 R19, C3_1lcycloalkyl ally substituted by 1-21 R19, C4_17cycloalkylalkyl optionally substituted by 1-32 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R19, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40 R19, 5- membered heteroaryl optionally substituted by 1-15 R19, 6-21 membered arylalkyl optionally substituted by 1-27 R19, halogen, —CN, —C(=O)R20, — C(=O)OR20, —C(=O)NR22R23, —N02, —NR22R23, and —OR20; alternatively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a C6_11aryl optionally substituted by 1-11 R19, C3_11cycloalkyl ally substituted by 1-21 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R19 or a 5-15 membered heteroaryl optionally substituted by 1-15 R19.

Embodiment 122. The compound of any of Embodiments 1-108, wherein R7, R8, R9, and R10 are independently chosen from H, C1_6alkyl optionally substituted by 1-13 R19, kenyl optionally tuted by 1-11 R19, C2_6alkynyl optionally substituted by l- 9 R19, C6_11aryl optionally substituted by 1-11 R19, C7_16arylalkyl optionally substituted by 1-19 R19, C3_1lcycloalkyl optionally substituted by 1-21 R19, C4_17cycloalkylalkyl optionally substituted by 1-32 R19, 3-15 membered cycloalkyl optionally substituted by 1-28 R19, 4-21 membered cycloalkylalkyl optionally tuted by 1-40 R19, 5- 15 membered heteroaryl optionally substituted by 1-15 R19, 6-21 membered arylalkyl ally substituted by 1—27 R19, halogen, —CN, —C(=O)NR22R23, —N02, —NR22R23, and —OR20; alternatively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a C6_11aryl optionally substituted by 1-11 R19, C3_11cycloalkyl optionally substituted by 1-21 R19, 3-15 membered heterocycloalkyl _ 60 _ optionally substituted by 1-28 R19 or a 5-15 membered heteroaryl optionally substituted by 1-15 R19.

Embodiment 123. The compound of any of Embodiments 1-108, n R7, R8, R9, and R10 are independently chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C2_6alkenyl optionally substituted by 1-11 R19, kynyl ally substituted by l- 9 R19, ryl optionally substituted by 1-11 R19, C7_16arylalkyl optionally substituted by 1-19 R19, ycloalkyl optionally substituted by 1-21 R19, 3—15 membered heterocycloalkyl optionally substituted by 1-28 R19, 5-15 membered heteroaryl ally substituted by 1-15 R19, 6-2l ed heteroarylalkyl optionally substituted by 1-27 R19, halogen, —CN, —C(=O)R20, —C(=O)NR22R23, —NR22R23, —NR24C(=O)R20, and —OR20; alternatively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a C6_11aryl optionally substituted by 1-11 R19, C3_11cycloalkyl optionally substituted by 1-21 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R19 or a 5-15 membered aryl optionally substituted by 1-15 R19.

Embodiment 124. The compound of any of Embodiments 1-108, wherein R7, R9, and R10 are ndently chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C2_6alkenyl ally substituted by 1-11 R19, C2_6alkynyl optionally substituted by 1-9 R19, C6_11aryl optionally substituted by 1-11 R19, C7_16arylalkyl optionally substituted by l- 19 R19, C3_1lcycloalkyl optionally substituted by 1-21 R19, 3—15 membered heterocycloalkyl optionally substituted by 1-28 R19, 5-15 membered heteroaryl optionally substituted by 1-15 R19, 6-2l membered heteroarylalkyl ally substituted by 1-27 R19, halogen, —CN, —C(=O)R20, —C(=O)NR22R23, —NR22R23, —NR24C(=O)R20, and —OR20; R8 is chosen from H, kyl optionally tuted by 1-13 R19, C2_6alkenyl optionally substituted by 1-11 R19, C2_6alkynyl optionally substituted by 1-9 R19, C7_16arylalkyl optionally substituted by 1-19 R19, C3_11cycloalkyl ally substituted by 1-21 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R19, 6-2l membered heteroarylalkyl ally substituted by 1-27 R19, halogen, —CN, —C(=O)R20, — C(=O)NR22R23, —NR22R23, —NR24C(=O)R20, and —OR20; alternatively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a C6_11aryl optionally substituted by 1-11 R19, C3_11cycloalkyl optionally substituted by 1-21 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R19 or a 5-15 membered heteroaryl optionally substituted by 1-15 R19.

Embodiment 125. The compound of any of Embodiments 1-108, wherein R7 and R10 are independently chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C2- _ 6l _ 6alkenyl optionally substituted by l-ll R19, C2_6alkynyl optionally tuted by l-9 R19, 1'yl ally substituted by l-ll R19, C7_16a1'ylalkyl optionally substituted by l-l9 R19, C3_11cycloalkyl optionally substituted by l-2l R19, 3-15 membered heterocycloalkyl optionally substituted by l-28 R19, 5-15 membered heteroaryl ally substituted by l- R19, 6-21 membered heteroarylalkyl optionally substituted by l-27 R19, halogen, —CN, —C(=O)R2°, —C(=O)NR22R23, —NR22R23, —NR24C(=O)R20, and —OR20; R8 and R9 are independently chosen from C1_6alkyl optionally substituted by l-l3 R19, C2_6alkenyl optionally substituted by l-ll R19, C2_6alkynyl optionally substituted by l-9 R19, C6_11a1'yl optionally substituted by l-ll R19, C7_16a1'ylalkyl optionally substituted by l-l9 R19, C3- 11cycloalkyl optionally substituted by l-2l R19, 3-15 membered heterocycloalkyl optionally substituted by l-28 R19, 5-15 membered heteroaryl optionally substituted by l- R19, 6-21 ed heteroarylalkyl optionally substituted by l-27 R19, halogen, —CN, —C(=O)R2°, —C(=O)NR22R23, —NR22R23, —NR24C(=O)R2°, and —OR20;altematively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a 1'yl optionally substituted by l-ll R19, C3_11cycloalkyl ally substituted by l-21 R19, 3-15 membered cycloalkyl optionally substituted by l-28 R19 or a 5-15 membered heteroaryl optionally tuted by l-lS R19.

Embodiment 126. The compound of any of Embodiments l-108, wherein R7 and R10 are independently chosen from H, C1_6alkyl optionally substituted by l-l3 R19, C2- 6alkenyl ally substituted by l-ll R19, C2_6alkynyl optionally substituted by l-9 R19, C6_11a1'yl optionally substituted by l-ll R19, C7_16a1'ylalkyl optionally substituted by l-l9 R19, C3_11cycloalkyl optionally substituted by l-2l R19, 3-15 membered heterocycloalkyl optionally substituted by l-28 R19, 5-15 membered heteroaryl optionally substituted by l- R19, 6-21 membered heteroarylalkyl optionally substituted by l-27 R19, halogen, —CN, —C(=O)R2°, —C(=O)NR22R23, —NR22R23, —NR24C(=O)R2°, and —OR20; R8 is chosen from C1_6alkyl optionally substituted by l-l3 R19, C2_6alkenyl optionally substituted by l-ll R19, C2_6alkynyl optionally tuted by l-9 R19, C7_16arylalkyl optionally substituted by l-l9 R19, C3_11cycloalkyl ally substituted by l-2l R19, 3-15 membered heterocycloalkyl optionally substituted by l-28 R19, 6-21 membered heteroarylalkyl optionally substituted by 127 R19, n, —CN, —C(=O)R2°, —C(=O)NR22R23, —NR22R23, —NR24C(=O)R20, and —OR20; R9 is chosen from C1_6alkyl optionally substituted by l-l3 R19, C2_6alkenyl optionally tuted by l-ll R19, C2_6alkynyl optionally substituted by l-9 R19, C6_11a1'yl optionally substituted by l-ll R19, C7_16a1'ylalkyl ally substituted by l-l9 R19, C3_ oalkyl optionally substituted by l-2l R19, 3-15 membered heterocycloalkyl _ 62 _ optionally substituted by l-28 R19, 5-15 membered heteroaryl optionally substituted by l- R19, 6-21 membered heteroarylalkyl optionally tuted by l-27 R19, halogen, —CN, R2°, —C(=O)NR22R23, —NR22R23, (=O)R2°, and —OR20; alternatively, either or both of R7 and R8, and/or R9 and R10, can, er with the atoms linking them, form a C6_11aryl optionally tuted by l-ll R19, C3_11cycloalkyl optionally substituted by l-2l R19, 3-15 membered heterocycloalkyl optionally substituted by l-28 R19 or a 5-15 membered heteroaryl optionally substituted by l-lS R19.

Embodiment 127. The compound of any of Embodiments l-108, wherein R8 and R9 are independently chosen from H, C1_6alkyl optionally substituted by l-l3 R19, C2- 6alkenyl optionally substituted by l-ll R19, C2_6alkynyl optionally tuted by l-9 R19, ryl optionally substituted by l-ll R19, C7_16arylalkyl optionally substituted by l-l9 R19, C3_11cycloalkyl optionally substituted by l-2l R19, 3-15 membered heterocycloalkyl optionally substituted by l-28 R19, 5-15 membered aryl optionally substituted by l- R19, 6-21 membered heteroarylalkyl optionally substituted by l-27 R19, halogen, —CN, —C(=O)R2°, —C(=O)NR22R23, —NR22R23, —NR24C(=O)R20, and —OR20; R7 and R10 are independently chosen from C1_6alkyl optionally substituted by l-l3 R19, C2_6alkenyl optionally substituted by l-ll R19, C2_6alkynyl ally tuted by l-9 R19, C6_11aryl optionally substituted by l-ll R19, C7_16arylalkyl optionally substituted by l-l9 R19, C3- 11cycloalkyl optionally substituted by l-2l R19, 3-15 membered cycloalkyl optionally substituted by l-28 R19, 5-15 membered heteroaryl optionally substituted by l- R19, 6-21 membered heteroarylalkyl ally substituted by l-27 R19, halogen, —CN, —C(=O)R2°, —C(=O)NR22R23, —NR22R23, —NR24C(=O)R2°, and —OR20;altematively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a C6_11aryl optionally substituted by l-ll R19, C3_11cycloalkyl optionally substituted by l-2l R19, 3-15 ed heterocycloalkyl ally substituted by l-28 R19 or a 5-15 membered heteroaryl optionally substituted by l-lS R19.

Embodiment 128. The compound of any of Embodiments l-108, wherein R8 is chosen from H, C1_6alkyl optionally substituted by l-l3 R19, C2_6alkenyl optionally substituted by l-ll R19, C2_6alkynyl optionally substituted by l-9 R19, C7_16arylalkyl optionally substituted by l-l9 R19, C3_11cycloalkyl optionally substituted by l-2l R19, 3-15 membered heterocycloalkyl optionally substituted by l-28 R19, 6-21 membered heteroarylalkyl optionally substituted by l-27 R19, halogen, —CN, —C(=O)R20, — C(=O)NR22R23, —NR22R23, —NR24C(=O)R20, and —OR20; R9 is chosen from H, C1_6alkyl optionally substituted by l-l3 R19, C2_6alkenyl optionally substituted by l-ll R19, C2- _ 63 _ 2012/065831 6alkynyl optionally substituted by l-9 R19, C6_11aryl optionally tuted by l-ll R19, C7- 16arylalkyl optionally substituted by l-l9 R19, C3_11cycloalkyl optionally substituted by l- 21 R19, 3-15 membered heterocycloalkyl optionally substituted by l-28 R19, 5-15 membered heteroaryl optionally substituted by 1-15 R19, 6-21 membered heteroarylalkyl optionally tuted by 1-27 R19, halogen, —CN, —C(=O)R2°, —C(=O)NR22R23, —NR22R23, —NR24C(=O)R20, and —OR20; R7 and R10 are independently chosen from C1_6alkyl optionally substituted by l-l3 R19, C2_6alkenyl optionally substituted by l-ll R19, C2- 6alkynyl optionally substituted by l-9 R19, C6_11aryl optionally substituted by l-ll R19, C7- 16arylalkyl optionally substituted by l-l9 R19, C3_11cycloalkyl optionally substituted by l- 21 R19, 3-15 membered heterocycloalkyl optionally substituted by l-28 R19, 5-15 ed heteroaryl ally substituted by 1-15 R19, 6-21 membered heteroarylalkyl optionally substituted by 1-27 R19, halogen, —CN, —C(=O)R2°, NR22R23, 23, —NR24C(=O)R20, and —OR20;altematively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a C6_11aryl optionally substituted by l-ll R19, C3_11cycloalkyl optionally substituted by l-2l R19, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R19 or a 5-15 membered heteroaryl optionally substituted by 1-15 R19.

Embodiment 129. The compound of any of Embodiments l-108, wherein R7, R8, R9, and R10 are independently chosen from H, C1_6alkyl optionally tuted by l-3 R19, C2_6alkenyl optionally substituted by l-3 R19, C2_6alkynyl optionally substituted by l-3 R19, C6_11aryl optionally substituted by l-3 R19, C7_16arylalkyl optionally substituted by l-3 R19, C3_11cycloalkyl optionally substituted by 1-3 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-15 ed heteroaryl optionally substituted by 1-3 R19, 6-21 ed arylalkyl optionally substituted by l-3 R19, halogen, —CN, — C(=O)R20, —C(=O)NR22R23, —NR22R23, —NR24C(=O)R20, and —OR20; atively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a C6_11aryl optionally substituted by l-3 R19, C3_11cycloalkyl optionally substituted by l-3 R19, 3-15 membered heterocycloalkyl optionally substituted by l-3 R19 or a 5-15 membered heteroaryl optionally substituted by 1-3 R19.

Embodiment 130. The compound of any of Embodiments l-108, wherein R7, R9, and R10 are independently chosen from H, C1_6alkyl optionally substituted by l-3 R19, C2_6alkenyl optionally substituted by l-3 R19, C2_6alkynyl optionally tuted by l-3 R19, C6_11aryl ally substituted by l-3 R19, C7_16arylalkyl optionally substituted by l-3 R19, C3_11cycloalkyl optionally substituted by l-3 R19, 3-15 ed heterocycloalkyl _ 64 _ optionally substituted by 1-3 R19, 5-15 membered heteroaryl optionally substituted by 1-3 R19, 6-21 membered heteroarylalkyl optionally substituted by 1-3 R19, halogen, —CN, — , —C(=O)NR22R23, —NR22R23, —NR24C(=O)R20, and —OR20; R8 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C2_6alkenyl ally substituted by 1-3 R19, C2_6alkynyl optionally tuted by 1—3 R19, C7_16arylalkyl optionally substituted by 1—3 R19, C3_11cycloalkyl optionally substituted by 1-3 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R19, 6-21 membered heteroarylalkyl optionally substituted by 1—3 R19, halogen, —CN, —C(=O)R2°, —C(=O)NR22R23, —NR22R23, —NR24C(=O)R20, and — ORZO; alternatively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a ryl optionally substituted by 1-3 R19, C3_11cycloalkyl optionally substituted by 1-3 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R19 or a 5-15 membered heteroaryl ally tuted by 1-3 R19.

Embodiment 13 l. The compound of any of Embodiments 1-108, wherein R7 and R10 are independently chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C2- 6alkenyl optionally substituted by 1-3 R19, kynyl ally substituted by 1-3 R19, ryl optionally substituted by 1-3 R19, C7_16arylalkyl optionally substituted by 1-3 R19, C3_11cycloalkyl optionally substituted by 1-3 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-15 membered heteroaryl optionally substituted by 1-3 R19, 6-21 membered heteroarylalkyl optionally substituted by 1-3 R19, halogen, —CN, — C(=O)R2°, —C(=O)NR22R23, 23, —NR24C(=O)R20, and —OR20; R8 and R9 are ndently chosen from C1_6alkyl optionally substituted by 1-3 R19, C2_6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl optionally substituted by 1-3 R19, C6_11aryl optionally substituted by 1-3 R19, C7_16arylalkyl optionally substituted by 1-3 R19, C3- oalkyl optionally substituted by 1-3 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-15 membered heteroaryl optionally tuted by 1-3 R19, 6-21 membered arylalkyl optionally substituted by 1-3 R19, halogen, —CN, —C(=O)R20, — C(=O)NR22R23, —NR22R23, —NR24C(=O)R20, and —OR20; alternatively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a C6_11aryl optionally substituted by 1-3 R19, C3_11cycloalkyl ally substituted by 1-3 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R19 or a 5-15 membered heteroaryl optionally substituted by 1-3 R19. ment 132. The compound of any of Embodiments 1-108, wherein R7 and R10 are independently chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C2- 6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl optionally substituted by 1-3 R19, _ 65 _ C6_11aryl optionally substituted by 1-3 R19, rylalkyl optionally substituted by 1-3 R19, C3_11cycloalkyl optionally tuted by 1-3 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-15 membered heteroaryl optionally substituted by 1-3 R19, 6-21 membered arylalkyl optionally tuted by 1-3 R19, halogen, —CN, — C(=O)R20, —C(=O)NR22R23, —NR22R23, —NR24C(=O)R20, and —OR20; R8 is chosen from C1- 6alkyl optionally substituted by 1—3 R19, C2_6alkenyl optionally substituted by 1—3 R19, C2- 6alkynyl optionally substituted by 1—3 R19, rylalkyl optionally substituted by 1—3 R19, C3_11cycloalkyl optionally substituted by 1-3 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R19, 6-21 membered heteroarylalkyl optionally substituted by 1-3 R19, halogen, —CN, —C(=O)R2°, —C(=O)NR22R23, —NR22R23, —NR24C(=O)R20, and — ORZO; R9 is chosen from kyl optionally substituted by 1-3 R19, C2_6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl optionally substituted by 1-3 R19, C6_11aryl optionally substituted by 1-3 R19, C7_16arylalkyl optionally substituted by 1-3 R19, C3_11cycloalkyl optionally substituted by 1-3 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-15 membered heteroaryl ally substituted by 1-3 R19, 6-21 membered arylalkyl optionally substituted by 1—3 R19, halogen, —CN, —C(=O)R2°, — C(=O)NR22R23, —NR22R23, —NR24C(=O)R20, and —OR20; alternatively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a C6_11aryl optionally substituted by 1-3 R19, ycloalkyl optionally substituted by 1-3 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R19 or a 5-15 membered heteroaryl optionally substituted by 1-3 R19. ment 133. The compound of any of Embodiments 1-108, wherein R8 and R9 are independently chosen from H, C1_6alkyl optionally tuted by 1-3 R19, C2- 6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl optionally substituted by 1-3 R19, C6_11aryl optionally substituted by 1-3 R19, C7_16arylalkyl optionally substituted by 1-3 R19, C3_11cycloalkyl optionally substituted by 1-3 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-15 membered heteroaryl ally substituted by 1-3 R19, 6-21 membered heteroarylalkyl optionally substituted by 1-3 R19, n, —CN, — C(=O)R2°, —C(=O)NR22R23, —NR22R23, —NR24C(=O)R20, and —OR20; R7 and R10 are independently chosen from kyl ally substituted by 1-3 R19, C2_6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl optionally substituted by 1-3 R19, C6_11aryl optionally substituted by 1-3 R19, C7_16arylalkyl optionally substituted by 1-3 R19, C3- 11cycloalkyl optionally substituted by 1-3 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-15 ed heteroaryl optionally substituted by 1-3 R19, 6-21 _ 66 _ membered heteroarylalkyl optionally tuted by 1-3 R19, halogen, —CN, —C(=O)R20, — C(=O)NR22R23, —NR22R23, —NR24C(=O)R20, and —OR20; atively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a C6_11aryl ally substituted by 1-3 R19, ycloalkyl optionally substituted by 1-3 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R19 or a 5-15 membered heteroaryl optionally substituted by 1-3 R19.

Embodiment 134. The compound of any of ments 1-108, wherein R8 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C2_6alkenyl optionally substituted by 1—3 R19, C2_6alkynyl optionally substituted by 1—3 R19, C7_16arylalkyl optionally tuted by 1-3 R19, C3_11cycloalkyl optionally substituted by 1-3 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R19, 6-21 membered heteroarylalkyl optionally substituted by 1—3 R19, halogen, —CN, —C(=O)R2°, — C(=O)NR22R23, 23, —NR24C(=O)R20, and —OR20; R9 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C2_6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl optionally substituted by 1-3 R19, C6_11aryl optionally substituted by 1-3 R19, C7_16arylalkyl optionally substituted by 1-3 R19, C3_11cycloalkyl optionally substituted by 1-3 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-15 membered heteroaryl optionally substituted by 1-3 R19, 6-21 membered arylalkyl optionally substituted by 1-3 R19, n, —CN, R2°, —C(=O)NR22R23, —NR22R23, —NR24C(=O)R20, and — ORZO; R7 and R10 are independently chosen from C1_6alkyl optionally substituted by 1-3 R19, C2_6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl optionally substituted by 1-3 R19, C6_11aryl optionally substituted by 1-3 R19, C7_16arylalkyl optionally substituted by 1-3 R19, C3_11cycloalkyl optionally substituted by 1-3 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-15 ed heteroaryl optionally substituted by 1-3 R19, 6-21 membered heteroarylalkyl optionally substituted by 1-3 R19, halogen, —CN, — , —C(=O)NR22R23, —NR22R23, —NR24C(=O)R20, and —OR20; alternatively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a C6_11aryl optionally tuted by 1-3 R19, C3_11cycloalkyl optionally substituted by 1-3 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R19 or a 5-15 membered heteroaryl optionally substituted by 1-3 R19.

Embodiment 135. The nd of any of ments 1-108, n R7, R8, R9, and R10 are independently chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C2_6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl optionally substituted by 1-3 R19, C6_10aryl optionally substituted by 1-3 R19, C7_11arylalkyl optionally substituted by 1-3 _ 67 _ WO 78126 R19, C3_1ocycloalkyl optionally substituted by 1-3 R19, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-10 membered heteroaryl optionally substituted by 1-3 R19, 6-ll membered heteroarylalkyl optionally substituted by 1-3 R19, n, —CN, — C(=O)R20, —C(=O)NR22R23, —NR22R23, —NR24C(=O)R20, and —OR20; alternatively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a C6_10aryl optionally substituted by 1-3 R19, C3_10cycloalkyl optionally substituted by 1-3 R19, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R19 or a 5-10 membered aryl optionally substituted by 1-3 R19.

Embodiment 136. The nd of any of Embodiments 1-108, wherein R7, R9, and R10 are independently chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C2_6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl ally substituted by 1-3 R19, C6_10aryl optionally substituted by 1-3 R19, C7_11arylalkyl optionally substituted by 1-3 R19, C3_10cycloalkyl optionally substituted by 1-3 R19, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-10 membered heteroaryl optionally substituted by 1-3 R19, 6-ll membered heteroarylalkyl optionally substituted by 1-3 R19, halogen, —CN, — C(=O)R20, —C(=O)NR22R23, —NR22R23, —NR24C(=O)R20, and —OR20; R8 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C2_6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl optionally tuted by 1—3 R19, C7_11arylalkyl optionally substituted by 1—3 R19, C3_1ocycloalkyl optionally substituted by 1-3 R19, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R19, 6-ll ed heteroarylalkyl optionally substituted by 1-3 R19, n, —CN, R2°, NR22R23, —NR22R23, —NR24C(=O)R20, and — ORZO; alternatively, either or both of R7 and R8, and/or R9 and R10, can, er with the atoms linking them, form a ryl ally substituted by 1-3 R19, C3_10cycloalkyl optionally substituted by 1-3 R19, 3-10 membered heterocycloalkyl ally substituted by 1-3 R19 or a 5-10 membered heteroaryl optionally substituted by 1-3 R19.

Embodiment 137. The compound of any of Embodiments 1-108, wherein R7, R8, R9, and R10 are independently chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C2_6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl optionally substituted by 1-3 R19, C6_10aryl optionally tuted by 1-3 R19, C3_10cycloalkyl optionally substituted by l- 3 R19, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-10 membered heteroaryl optionally substituted by 1—3 R19, halogen, —CN, —C(=O)R2°, —C(=O)NR22R23, — NRZZRB, —NR24C(=O)R20, and —OR20; alternatively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a C6_10aryl optionally substituted by 1-3 R19, C3_1ocycloalkyl optionally substituted by 1-3 R19, 3-10 membered _ 68 _ 2012/065831 heterocycloalkyl optionally substituted by 1-3 R19 or a 5-10 ed heteroaryl optionally substituted by 1-3 R19.

Embodiment 138. The compound of any of Embodiments 1-108, wherein R7, R9, and R10 are independently chosen from H, kyl optionally substituted by 1-3 R19, C2_6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl optionally substituted by 1-3 R19, C6_10aryl optionally substituted by 1-3 R19, C3_10cycloalkyl optionally substituted by 1-3 R19, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-10 membered heteroaryl optionally substituted by 1—3 R19, halogen, —CN, —C(=O)R2°, —C(=O)NR22R23, — NRZZRB, —NR24C(=O)R20, and —OR20; R8 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C2_6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl optionally substituted by 1-3 R19, C3_1ocycloalkyl optionally tuted by 1-3 R19, 3-10 membered heterocycloalkyl optionally tuted by 1-3 R19, halogen, —CN, R20, — C(=O)NR22R23, —NR22R23, —NR24C(=O)R20, and —OR20; alternatively, either or both of R7 and R8, and/or R9 and R10, can, er with the atoms linking them, form a C6_10aryl optionally substituted by 1-3 R19, C3_10cycloalkyl optionally tuted by 1-3 R19, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R19 or a 5-10 ed heteroaryl optionally substituted by 1-3 R19.

Embodiment 139. The compound of any of ments 1-108, wherein R7 and R10 are independently chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C2- 6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl optionally substituted by 1-3 R19, C6_10aryl optionally substituted by 1-3 R19, C3_10cycloalkyl optionally substituted by 1-3 R19, 3-10 membered cycloalkyl optionally substituted by 1-3 R19, 5-10 membered heteroaryl optionally substituted by 1—3 R19, n, —CN, —C(=O)R2°, —C(=O)NR22R23, — NRZZRB, —NR24C(=O)R20, and —OR20; R8 and R9 are independently chosen from C1_6alkyl optionally substituted by 1-3 R19, C2_6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl optionally substituted by 1-3 R19, ryl optionally substituted by 1-3 R19, C3- locycloalkyl optionally substituted by 1-3 R19, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-10 membered heteroaryl optionally substituted by 1-3 R19, halogen, —CN, —C(=O)R20, —C(=O)NR22R23, —NR22R23, (=O)R20, and —OR20; alternatively, either or both of R7 and R8, and/or R9 and R10, can, er with the atoms linking them, form a C6_10aryl optionally substituted by 1-3 R19, C3_10cycloalkyl optionally substituted by 1-3 R19, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R19 or a 5-10 membered heteroaryl optionally substituted by 1-3 R19. 2012/065831 Embodiment 140. The compound of any of Embodiments 1-108, wherein R7 and R10 are independently chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C2- 6alkenyl ally tuted by 1-3 R19, C2_6alkynyl optionally substituted by 1-3 R19, C6_10aryl optionally substituted by 1-3 R19, C3_10cycloalkyl optionally substituted by 1-3 R19, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-10 ed heteroaryl optionally substituted by 1—3 R19, n, —CN, —C(=O)R2°, —C(=O)NR22R23, — NRZZRB, —NR24C(=O)R20, and —OR20; R8 is chosen from C1_6alkyl optionally substituted by 1-3 R19, C2_6alkenyl ally substituted by 1-3 R19, C2_6alkynyl optionally substituted by 1-3 R19, C3_1ocycloalkyl optionally substituted by 1-3 R19, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R19, halogen, —CN, —C(=O)R20, — C(=O)NR22R23, —NR22R23, —NR24C(=O)R20, and —OR20; R9 is chosen from C1_6alkyl optionally substituted by 1-3 R19, C2_6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl optionally tuted by 1-3 R19, C6_10aryl optionally tuted by 1-3 R19, C3- locycloalkyl optionally substituted by 1-3 R19, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-10 membered heteroaryl optionally substituted by 1-3 R19, n, —CN, —C(=O)R20, —C(=O)NR22R23, —NR22R23, —NR24C(=O)R20, and —OR20; alternatively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a C6_10aryl optionally substituted by 1-3 R19, C3_10cycloalkyl optionally substituted by 1-3 R19, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R19 or a 5-10 membered heteroaryl optionally substituted by 1-3 R19.

Embodiment 141. The compound of any of Embodiments 1-108, wherein R8 and R9 are independently chosen from H, C1_6alkyl ally substituted by 1-3 R19, C2- 6alkenyl ally substituted by 1-3 R19, C2_6alkynyl ally substituted by 1-3 R19, C6_10aryl optionally tuted by 1-3 R19, C3_10cycloalkyl optionally substituted by 1-3 R19, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-10 membered heteroaryl optionally substituted by 1-3 R19, halogen, —CN, —C(=O)R2°, —C(=O)NR22R23, — NRZZRB, —NR24C(=O)R20, and —OR20; R7 and R10 are independently chosen from C1_6alkyl optionally substituted by 1-3 R19, C2_6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl optionally substituted by 1-3 R19, C6_10aryl optionally substituted by 1-3 R19, C3- locycloalkyl ally substituted by 1-3 R19, 3-10 ed heterocycloalkyl ally substituted by 1-3 R19, 5-10 membered heteroaryl ally substituted by 1-3 R19, halogen, —CN, —C(=O)R20, —C(=O)NR22R23, —NR22R23, —NR24C(=O)R20, and —OR20; alternatively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a C6_10aryl optionally substituted by 1-3 R19, C3_10cycloalkyl optionally _ 70 _ substituted by 1-3 R19, 3-10 membered cycloalkyl optionally tuted by 1-3 R19 or a 5-10 membered heteroaryl optionally substituted by 1-3 R19.

Embodiment 142. The compound of any of Embodiments 1-108, wherein R8 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C2_6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl optionally substituted by 1-3 R19, C3_10cycloalkyl ally substituted by 1-3 R19, 3-10 membered heterocycloalkyl ally substituted by 1—3 R19, halogen, —CN, —C(=O)R2°, —C(=O)NR22R23, —NR22R23, —NR24C(=O)R20, and — ORZO; R9 is chosen from H, C1_6alkyl ally tuted by 1-3 R19, C2_6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl optionally tuted by 1-3 R19, C6_10aryl optionally substituted by 1-3 R19, C3_10cycloalkyl ally tuted by 1-3 R19, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-10 membered heteroaryl optionally substituted by 1-3 R19, halogen, —CN, —C(=O)R20, —C(=O)NR22R23, —NR22R23, —NR24C(=O)R20, and —OR20; R7 and R10 are independently chosen from C1_6alkyl optionally substituted by 1-3 R19, C2_6alkenyl optionally substituted by 1-3 R19, kynyl optionally substituted by 1-3 R19, C6_10aryl optionally tuted by 1-3 R19, C3- 10cycloalkyl optionally substituted by 1-3 R19, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-10 membered heteroaryl optionally substituted by 1-3 R19, halogen, —CN, —C(=O)R20, —C(=O)NR22R23, —NR22R23, —NR24C(=O)R20, and —OR20; alternatively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a C6_10aryl optionally substituted by 1-3 R19, C3_10cycloalkyl optionally substituted by 1-3 R19, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R19 or a 5-10 membered heteroaryl optionally substituted by 1-3 R19.

Embodiment 143. The compound of any of Embodiments 1-108, wherein R7, R8, R9, and R10 are independently chosen from H, C1_6alkyl, kenyl, C2_6alkynyl optionally substituted by 1-3 R19, C6_10aryl optionally substituted by 1-3 R19, C3- 10cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aryl, halogen, —CN, —C(=O)R2°, —C(=O)NR22R23, —NR22R23, —NR24C(=O)R2°, and —OR20; alternatively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a C6_10aryl optionally tuted by 1-3 R19, C3_10cycloalkyl optionally substituted by 1-3 R19, 3-10 ed heterocycloalkyl optionally substituted by 1-3 R19 or a 5-10 membered heteroaryl optionally substituted by 1-3 R19.

Embodiment 144. The compound of any of Embodiments 1-108, wherein R7, R9, and R10 are independently chosen from H, C1_6alkyl, C2_6alkenyl, C2_6alkynyl optionally substituted by 1-3 R19, C6_10aryl optionally substituted by 1-3 R19, C3- _ 71 _ WO 78126 locycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl, halogen, —CN, R2°, —C(=O)NR22R23, —NR22R23, —NR24C(=O)R2°, and —OR20; R8 is chosen from H, C1_6alkyl, C2_6alkenyl, C2_6alkynyl optionally substituted by 1—3 R19, C3_1ocycloalkyl, 3— membered heterocycloalkyl, n, —CN, —C(=O)R20, —C(=O)NR22R23, —NR22R23, — NR24C(=O)R20, and —OR20; alternatively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a C6_10aryl ally substituted by 1-3 R19, C3_1ocycloalkyl optionally substituted by 1-3 R19, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R19 or a 5-10 membered heteroaryl optionally substituted by 1—3 R19.

Embodiment 145. The compound of any of Embodiments 1-108, wherein R7, R8, R9, and R10 are independently chosen from H, C1_6alkyl, C2_6alkenyl, C2_6alkynyl optionally tuted by 1-3 R19, C6_10aryl, C3_10cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl, halogen, —CN, —C(=O)R20, —C(=O)NR22R23 , —NR22R23, —NR24C(=O)R20, and —OR20; alternatively, either or both of R7 and R8, and/or R9 and R10, can, er with the atoms linking them, form a ryl, C3_10cycloalkyl, 3- membered heterocycloalkyl or a 5-10 membered heteroaryl.

Embodiment 146. The compound of any of Embodiments 1-108, wherein R7, R9, and R10 are ndently chosen from H, C1_6alkyl, C2_6alkenyl, C2_6alkynyl optionally substituted by 1-3 R19, C6_1oaryl, C3_1ocycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl, halogen, —CN, —C(=O)R20, —C(=O)NR22R23 , —NR22R23, —NR24C(=O)R20, and —OR20; R8 is chosen from H, C1_6alkyl, C2_6alkenyl, C2_ 6alkynyl optionally tuted by 1—3 R19, C3_1ocycloalkyl, 3—10 membered heterocycloalkyl, halogen, —CN, —C(=O)R20, NR22R23, —NR22R23, —NR24C(=O)R20, and —OR20; alternatively, either or both of R7 and R8, and/or R9 and R10, can, er with the atoms linking them, form a C6_10aryl, C3_10cycloalkyl, 3-10 membered heterocycloalkyl or a 5-10 membered heteroaryl.

Embodiment 147. The compound of any of Embodiments 1-108, wherein R7, R8, R9, and R10 are independently chosen from H, C1_6alkyl, C2_6alkenyl, C2_6alkynyl, C6- , C3_10cycloalkyl, 3-10 ed heterocycloalkyl, 5-10 membered heteroaryl, halogen, —CN, —C(=O)R20, —C(=O)NR22R23, —NR22R23, —NR24C(=O)R20, and —OR20; alternatively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a C6_10aryl, C3_10cycloalkyl, 3-10 membered heterocycloalkyl or a 5-10 membered heteroaryl.

Embodiment 148. The compound of any of Embodiments l-108, wherein R7, R9, and R10 are ndently chosen from H, kyl, C2_6alkenyl, kynyl, C6_10aryl, ycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl, halogen, — CN, —C(=O)R20, —C(=O)NR22R23, —NR22R23, —NR24C(=O)R2°, and —OR20; R8 is chosen from H, C1_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_10cycloalkyl, 3-10 ed heterocycloalkyl, halogen, —CN, —C(=O)R20, —C(=O)NR22R23, —NR22R23, —NR24C(=O)R20, and —OR20; alternatively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a C6_10aryl, C3_10cycloalkyl, 3-10 membered heterocycloalkyl or a 5-10 membered heteroaryl. ment 149. The compound of any of Embodiments l-108, wherein R7, R8, R9, and R10 are independently chosen from H, C1_6alkyl optionally substituted by l-3 R19, kenyl optionally substituted by l-3 R19, C2_6alkynyl optionally substituted by l-3 R19, phenyl optionally substituted by l-3 R19, cloalkyl optionally substituted by l-3 R19, 3-6 membered cycloalkyl optionally substituted by 1-3 R19, 5-6 membered heteroaryl optionally substituted by 1-3 R19, halogen, —CN, —C(=O)R2°, —C(=O)NR22R23, — NRZZRB, —NR24C(=O)R20, and —OR20; atively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a phenyl optionally substituted by 1-3 R19, C3_6cycloalkyl optionally substituted by 1-3 R19, 3-6 membered cycloalkyl optionally substituted by l-3 R19 or a 5-6 membered aryl optionally substituted by l- 3 R19.

Embodiment 150. The compound of any of Embodiments l-108, wherein R7, R9, and R10 are independently chosen from H, C1_6alkyl optionally substituted by l-3 R19, C2_6alkenyl optionally substituted by l-3 R19, C2_6alkynyl optionally substituted by l-3 R19, phenyl optionally substituted by l-3 R19, C3_6cycloalkyl optionally substituted by l-3 R19, 3-6 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-6 membered heteroaryl optionally tuted by 1-3 R19, halogen, —CN, R2°, —C(=O)NR22R23, — NRZZRB, —NR24C(=O)R20, and —OR20; R8 is chosen from H, C1_6alkyl optionally substituted by l-3 R19, C2_6alkenyl optionally substituted by l-3 R19, C2_6alkynyl optionally substituted by 1-3 R19, C3_6cycloalkyl optionally substituted by 1-3 R19, 3-6 membered heterocycloalkyl optionally substituted by l-3 R19, halogen, —CN, —C(=O)R20, — C(=O)NR22R23, —NR22R23, —NR24C(=O)R20, and —OR20; alternatively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a phenyl optionally substituted by 1-3 R19, C3_6cycloalkyl optionally substituted by 1-3 R19, 3-6 membered heterocycloalkyl optionally substituted by 1-3 R19 or a 5-6 membered heteroaryl optionally tuted by 1-3 R19.

Embodiment 15 l. The compound of any of Embodiments 1-108, wherein R7 and R10 are independently chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C2- 6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl optionally substituted by 1-3 R19, phenyl optionally substituted by 1-3 R19, C3_6cycloalkyl optionally tuted by 1-3 R19, 3-6 ed heterocycloalkyl optionally substituted by 1-3 R19, 5-6 membered heteroaryl optionally substituted by 1—3 R19, halogen, —CN, —C(=O)R2°, NR22R23, — NRZZRB, —NR24C(=O)R20, and —OR20; R8 and R9 are independently chosen from C1_6alkyl ally tuted by 1-3 R19, C2_6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl optionally substituted by 1-3 R19, phenyl optionally substituted by 1-3 R19, C3_6cycloalkyl ally substituted by 1-3 R19, 3-6 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-6 membered heteroaryl optionally substituted by 1-3 R19, halogen, —CN, — C(=O)R20, —C(=O)NR22R23, 23, —NR24C(=O)R20, and —OR20; alternatively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a phenyl optionally substituted by 1-3 R19, C3_6cycloalkyl optionally substituted by 1-3 R19, 3-6 ed heterocycloalkyl optionally substituted by 1-3 R19 or a 5-6 membered heteroaryl optionally substituted by 1-3 R19.

Embodiment 152. The compound of any of Embodiments 1-108, wherein R7 and R10 are independently chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C2- 6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl ally substituted by 1-3 R19, phenyl optionally substituted by 1-3 R19, C3_6cycloalkyl optionally substituted by 1-3 R19, 3-6 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-6 membered heteroaryl optionally substituted by 1—3 R19, halogen, —CN, —C(=O)R2°, —C(=O)NR22R23, — NRZZRB, —NR24C(=O)R20, and —OR20; R8 is chosen from C1_6alkyl optionally substituted by 1-3 R19, C2_6alkenyl optionally substituted by 1-3 R19, kynyl ally substituted by 1-3 R19, cloalkyl optionally substituted by 1-3 R19, 3-6 membered heterocycloalkyl optionally substituted by 1-3 R19, halogen, —CN, —C(=O)R20, — C(=O)NR22R23, —NR22R23, —NR24C(=O)R20, and —OR20; R9 is chosen from C1_6alkyl optionally substituted by 1-3 R19, C2_6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl optionally substituted by 1-3 R19, phenyl optionally substituted by 1-3 R19, C3_6cycloalkyl optionally substituted by 1-3 R19, 3-6 membered heterocycloalkyl optionally tuted by 1-3 R19, 5-6 membered heteroaryl optionally substituted by 1-3 R19, halogen, —CN, — C(=O)R20, —C(=O)NR22R23, —NR22R23, (=O)R20, and —OR20; alternatively, either _ 74 _ WO 78126 or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a phenyl optionally substituted by 1-3 R19, C3_6cycloalkyl optionally substituted by 1-3 R19, 3-6 membered cycloalkyl optionally substituted by 1-3 R19 or a 5-6 membered heteroaryl ally tuted by 1-3 R19.

Embodiment 153. The compound of any of Embodiments 1-108, wherein R7, R8, R9, and R10 are independently chosen from H, C1_6alkyl, kenyl, C2_6alkynyl optionally substituted by 1-3 R19, , C3_6cycloalkyl, 3-6 membered heterocycloalkyl, -6 membered aryl, halogen, —CN, —C(=O)R20, —C(=O)NR22R23, —NR22R23, — =O)R20, and —OR20; alternatively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a phenyl, C3_6cycloalkyl, 3-6 membered heterocycloalkyl or a 5-6 membered heteroaryl.

Embodiment 154. The compound of any of Embodiments 1-108, wherein R7, R9, and R10 are independently chosen from H, C1_6alkyl, C2_6alkenyl, C2_6alkynyl optionally substituted by 1-3 R19, phenyl, C3_6cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halogen, —CN, —C(=O)R20, —C(=O)NR22R23, —NR22R23, — NR24C(=O)R20, and —OR20; R8 is chosen from H, C1_6alkyl, C2_6alkenyl, C2_6alkynyl optionally substituted by 1-3 R19, C3_6cycloalkyl, 3-6 membered heterocycloalkyl, halogen, —CN, —C(=O)R2°, —C(=O)NR22R23, —NR22R23, —NR24C(=O)R2°, and —OR20; alternatively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a phenyl, C3_6cycloalkyl, 3-6 membered cycloalkyl or a 5-6 membered heteroaryl.

Embodiment 155. The compound of any of ments 1-108, wherein R7 and R10 are independently chosen from H, C1_6alkyl, C2_6alkenyl, C2_6alkynyl optionally substituted by 1-3 R19, , C3_6cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halogen, —CN, —C(=O)R20, —C(=O)NR22R23, —NR22R23, — NR24C(=O)R20, and —OR20; R8 and R9 are independently chosen from C1_6alkyl, C2- 6alkenyl, kynyl optionally substituted by 1-3 R19, phenyl, C3_6cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halogen, —CN, —C(=O)R20, — C(=O)NR22R23, —NR22R23, —NR24C(=O)R20, and —OR20; alternatively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a phenyl, C3- 6cycloalkyl, 3-6 membered cycloalkyl or a 5-6 membered heteroaryl. ment 156. The compound of any of Embodiments 1-108, wherein R7 and R10 are independently chosen from H, C1_6alkyl, C2_6alkenyl, C2_6alkynyl optionally substituted by 1-3 R19, phenyl, C3_6cycloalkyl, 3-6 ed heterocycloalkyl, 5-6 _ 75 _ membered heteroaryl, halogen, —CN, —C(=O)R20, —C(=O)NR22R23, —NR22R23, — NR24C(=O)R20, and —OR20; R8 is chosen from C1_6alkyl, kenyl, kynyl optionally substituted by 1-3 R19, C3_6cycloalkyl, 3-6 membered heterocycloalkyl, halogen, —CN, —C(=O)R20, —C(=O)NR22R23, —NR22R23, —NR24C(=O)R2°, and —OR20; R9 is chosen from C1_6alkyl, C2_6alkenyl, C2_6alkynyl ally substituted by 1-3 R19, phenyl, C3- 6cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halogen, —CN, — C(=O)R20, NR22R23, —NR22R23, —NR24C(=O)R20, and —OR20; alternatively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a phenyl, cloalkyl, 3-6 membered heterocycloalkyl or a 5-6 membered heteroaryl.

Embodiment 157. The compound of any of Embodiments 1-108, wherein R7, R8, R9, and R10 are independently chosen from H, C1_6alkyl, kenyl, C2_6alkynyl, phenyl, C3_6cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halogen, —CN, —C(=O)R20, —C(=O)NR22R23, —NR22R23, —NR24C(=O)R20, and —OR20; alternatively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a phenyl, C3_6cycloalkyl, 3-6 membered heterocycloalkyl or a 5-6 membered heteroaryl.

Embodiment 158. The compound of any of Embodiments 1-108, wherein R7, R9, and R10 are independently chosen from H, C1_6alkyl, C2_6alkenyl, C2_6alkynyl, phenyl, C3_6cycloalkyl, 3-6 membered cycloalkyl, 5-6 ed heteroaryl, halogen, —CN, —C(=O)R2°, —C(=O)NR22R23, —NR22R23, —NR24C(=O)R2°, and —OR20; R8 is chosen from H, C1_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, 3-6 membered heterocycloalkyl, halogen, —CN, —C(=O)R20, —C(=O)NR22R23, —NR22R23, —NR24C(=O)R20, and —OR20; alternatively, either or both of R7 and R8, and/or R9 and R10, can, er with the atoms linking them, form a phenyl, C3_6cycloalkyl, 3-6 membered heterocycloalkyl or a 5-6 membered aryl.

Embodiment 159. The compound of any of ments 1-108, wherein R7, R8, R9, and R10 are independently chosen from H, C1_6alkyl, kynyl, phenyl, C3- 6cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halogen, —CN, — C(=O)R20, —C(=O)NR22R23, —NR22R23, —NR24C(=O)R20, and —OR20; alternatively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a C3_6cycloalkyl or a 3-6 ed heterocycloalkyl.

Embodiment 160. The compound of any of ments 1-108, wherein R7, R9, and R10 are independently chosen from H, C1_6alkyl, C2_6alkynyl, phenyl, C3_ 6cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halogen, —CN, — _ 76 _ WO 78126 C(=O)R20, NR22R23, —NR22R23, —NR24C(=O)R20, and —OR20; R8 is chosen from H, C1_6alkyl, C2_6alkynyl, C3_6cycloalkyl, 3-6 membered heterocycloalkyl, halogen, —CN, — C(=O)R20, —C(=O)NR22R23, —NR22R23, —NR24C(=O)R20, and —OR20; alternatively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a C3_6cycloalkyl or a 3-6 membered heterocycloalkyl. ment 161. The compound of any of Embodiments 1-108, wherein R7, R8, R9, and R10 are independently chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C2_6alkenyl optionally substituted by 1-11 R19, C2_6alkynyl optionally substituted by 1-9 R19, C6_11aryl optionally substituted by 1-11 R19, C3_11cycloalkyl optionally tuted by 1-21 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R19, 5-15 membered heteroaryl optionally substituted by 1-15 R19, halogen, —CN, —C(=O)NR22R23, and —NR22R23; alternatively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a C6_11aryl optionally substituted by 1-11 R19, C3- 11cycloalkyl optionally substituted by 1-21 R19, 3-15 membered heterocycloalkyl optionally tuted by 1-28 R19 or a 5-15 membered heteroaryl optionally substituted by 145 R19. ment 162. The compound of any of Embodiments 1-108, wherein R7, R9, and R10 are independently chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C2_6alkenyl optionally substituted by 1-11 R19, C2_6alkynyl optionally substituted by 1-9 R19, C6_11aryl ally substituted by 1-11 R19, C3_11cycloalkyl optionally substituted by 1-21 R19, 3-15 ed heterocycloalkyl optionally substituted by 1-28 R19, 5-15 membered heteroaryl optionally substituted by 1-15 R19, halogen, —CN, —C(=O)NR22R23, and —NR22R23; R8 is chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C2- 6alkenyl optionally substituted by 1-11 R19, C2_6alkynyl optionally tuted by 1-9 R19, C3_11cycloalkyl optionally substituted by 1-21 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R19, halogen, —CN, —C(=O)NR22R23, and —NR22R23; alternatively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a C6_11aryl optionally substituted by 1-11 R19, C3_11cycloalkyl optionally tuted by 1-21 R19, 3-15 membered cycloalkyl optionally substituted by 1-28 R19 or a 5-15 membered heteroaryl optionally substituted by 1-15 R19.

Embodiment 163. The compound of any of Embodiments 1-108, wherein R7 and R8 are independently chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C2- 6alkenyl optionally tuted by 1-11 R19, C2_6alkynyl optionally substituted by 1-9 R19, C6_11aryl optionally substituted by 1-11 R19, C3_11cycloalkyl ally substituted by 1-21 _ 77 _ WO 78126 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R19, 5-15 membered heteroaryl optionally substituted by 1-15 R19, halogen, —CN, —C(=O)NR22R23, and — ; alternatively, R7 and R8 can, er with the atoms linking them, form a C6- 11aryl optionally substituted by 1-11 R19, or a 5-15 membered heteroaryl optionally substituted by l-lS R19.

Embodiment 164. The compound of any of ments l-108, wherein R7 is chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C2_6alkenyl optionally substituted by 1-11 R19, C2_6alkynyl optionally substituted by 1-9 R19, C6_11aryl optionally substituted by 1-11 R19, C3_11cycloalkyl optionally substituted by 1-21 R19, 3-15 membered cycloalkyl ally substituted by 1-28 R19, 5-15 membered heteroaryl optionally substituted by l-lS R19, halogen, —CN, —C(=O)NR22R23, and —NR22R23; R8 is chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C2_6alkenyl optionally substituted by 1-11 R19, C2_6alkynyl optionally substituted by 1-9 R19, C3_11cycloalkyl optionally substituted by 1-21 R19, 3-15 membered heterocycloalkyl ally substituted by 1-28 R19, halogen, — CN, —C(=O)NR22R23, and —NR22R23; alternatively, R7 and R8 can, together with the atoms linking them, form a C6_11aryl optionally substituted by 1-11 R19, or a 5-15 membered aryl optionally substituted by 1-15 R19.

Embodiment 165. The compound of any of Embodiments l-108, wherein R9 and R10 are ndently chosen from H, C1_6alkyl optionally tuted by 1-13 R19, C6- 11aryl optionally substituted by 1-11 R19, and —C(=O)NR22R23; alternatively, R9 and R10 can, together with the atoms g them, form a C3_11cycloalkyl optionally substituted by 1-21 R19, or a 3-15 membered heterocycloalkyl optionally substituted by 1-28 R19.

Embodiment 166. The compound of any of Embodiments l-108, wherein R7, R8, R9, and R10 are independently chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C2_6alkenyl optionally substituted by 1-11 R19, kynyl optionally substituted by 1- 9 R19, C6_11aryl optionally substituted by 1-11 R19, ycloalkyl optionally substituted by 1-21 R19, 5-15 membered heteroaryl optionally substituted by 1-15 R19, halogen, —CN, —C(=O)NR22R23, and —NR22R23; alternatively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a C3_11cycloalkyl optionally tuted by 1-21 R19, a C6_11aryl optionally substituted by 1-11 R19, a 5-15 membered heteroaryl optionally tuted by 1-15 R19, or a 3-15 membered heterocycloalkyl optionally substituted by 1-28 R19.

Embodiment 167. The compound of any of Embodiments l-108, wherein R7, R9, and R10 are independently chosen from H, C1_6alkyl optionally substituted by 1-13 R19, _ 78 _ C2_6alkenyl optionally substituted by 1-11 R19, C2_6alkynyl optionally substituted by 1-9 R19, C6_11aryl optionally substituted by 1-11 R19, C3_11cycloalkyl optionally substituted by 1-21 R19, 5-15 membered heteroaryl optionally substituted by 1-15 R19, halogen, —CN, — C(=O)NR22R23, and —NR22R23; R8 is chosen from H, kyl optionally substituted by l- 13 R19, kenyl optionally substituted by 1-11 R19, C2_6alkynyl optionally substituted by 1-9 R19, C3_11cycloalkyl optionally substituted by 1-21 R19, halogen, —CN, — C(=O)NR22R23, and 23; alternatively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a C3_11cycloalkyl optionally tuted by 1-21 R19, a C6_11aryl optionally substituted by 1-11 R19, a 5-15 membered heteroaryl optionally substituted by 1-15 R19, or a 3-15 membered heterocycloalkyl ally substituted by 1-28 R19. ment 168. The compound of any of ments 1-108, wherein R7 and R8 are independently chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C2- 6alkenyl optionally substituted by 1-11 R19, C2_6alkynyl optionally substituted by 1-9 R19, C6_11aryl optionally tuted by 1-11 R19, C3_11cycloalkyl optionally substituted by 1-21 R19, 5-15 membered heteroaryl optionally substituted by 1-15 R19, n, —CN, — C(=O)NR22R23, and —NR22R23; alternatively, R7 and R8 can, together with the atoms g them, form a C6_1laryl optionally substituted by 1-11 R19, or a 5-15 membered heteroaryl optionally substituted by 1-15 R19.

Embodiment 169. The compound of any of Embodiments 1-108, wherein R7 is chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C2_6alkenyl optionally substituted by 1-11 R19, C2_6alkynyl optionally substituted by 1-9 R19, C6_11aryl optionally substituted by 1-11 R19, C3_11cycloalkyl optionally substituted by 1-21 R19, 5-15 membered heteroaryl optionally substituted by 1-15 R19, halogen, —CN, —C(=O)NR22R23, and — NRZZRB; R8 is chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C2_6alkenyl optionally substituted by 1-11 R19, C2_6alkynyl optionally tuted by 1-9 R19, C3- 11cycloalkyl optionally tuted by 1-21 R19, n, —CN, —C(=O)NR22R23, and — NRZZRB; atively, R7 and R8 can, together with the atoms linking them, form a C6- 11aryl optionally substituted by 1-11 R19, or a 5-15 membered heteroaryl optionally substituted by 1-15 R19.

Embodiment 170. The compound of any of Embodiments 1-108, wherein R9 and R10 are independently chosen from H, C1_6alkyl optionally substituted by 1-13 R19, and —C(=O)NR22R23; alternatively, R9 and R10 can, together with the atoms linking them, form a C3_11cycloalkyl optionally substituted by 1-21 R19, or a 3-15 membered heterocycloalkyl optionally substituted by 1-28 R19.

Embodiment 171. The compound of any of Embodiments 1-108, wherein R7 is chosen from H, C1_6alkyl optionally tuted by 1-13 R19, and halogen; R8 is chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C2_6alkenyl optionally substituted by 1-11 R19, kynyl ally substituted by 1-9 R19, C6_11aryl optionally substituted by 1-11 R19, C3_11cycloalkyl optionally substituted by 1-21 R19, 5-15 membered heteroaryl optionally substituted by 1-15 R19, halogen, —CN, —C(=O)NR22R23, and —NR22R23; alternatively, R7 and R8 can, together with the atoms linking them, form a C6_11aryl optionally substituted by 1-11 R19, or a 5-15 membered heteroaryl optionally substituted by 145 R19.

Embodiment 172. The compound of any of Embodiments 1-108, wherein R7 is chosen from H, C1_6alkyl optionally tuted by 1-13 R19, and halogen; R8 is chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C2_6alkenyl optionally substituted by 1-11 R19, C2_6alkynyl optionally substituted by 1-9 R19, C3_11cycloalkyl optionally substituted by 1-21 R19, halogen, —CN, —C(=O)NR22R23, and —NR22R23; alternatively, R7 and R8 can, together with the atoms linking them, form a C6_11aryl optionally substituted by 1-11 R19, or a 5-15 membered heteroaryl ally substituted by 1-15 R19. ment 173. The compound of any of Embodiments 1-108, wherein R9 is chosen from H and C1_6alkyl optionally substituted by 1-13 R19; R10 is chosen from H, C1- 6alkyl ally substituted by 1-13 R19, and —C(=O)NR22R23; alternatively, R9 and R10 can, together with the atoms linking them, form a C3_11cycloalkyl optionally substituted by 1-21 R19, or a 3-15 membered heterocycloalkyl optionally substituted by 1-28 R19.

Embodiment 174. The compound of any of Embodiments 1-108, wherein R9 is C1_6alkyl optionally substituted by 1-13 R19; R10 is chosen from H, C1_6alkyl optionally substituted by 1-13 R19, and NR22R23; alternatively, R9 and R10 can, together with the atoms linking them, form a C3_11cycloalkyl optionally substituted by 1-21 R19, or a 3- membered heterocycloalkyl optionally substituted by 1-28 R19.

Embodiment 175. The compound of any of Embodiments 1-174, wherein R12, R13, R14, and R15 are independently chosen from H, kyl optionally substituted by 1- 13 R19, C2_6alkenyl optionally substituted by 1-11 R19, C2_6alkynyl ally substituted by 1-9 R19, ryl optionally tuted by 1-11 R19, C7_16arylalkyl optionally substituted by 149 R19, C3.1 1cycloalkyl optionally substituted by 1—21 R19, c4_ _ 80 _ 17cycloalkylalkyl optionally substituted by 1-32 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R19, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40 R19, 5-15 membered heteroaryl optionally substituted by 1-15 R19, 6- 21 membered heteroarylalkyl optionally substituted by 1-27 R19, halogen, —CN, — 2°, —C(=O)OR2°, NR22R23, —C(=O)C(=O)R2°, —C(=NR25)R2°, — C(=NR25)NR22R23, —C(=NOH)NR22R23, —C(=NOR26)R2°, —C(=NNR22R23)R20, — C(=NNR24C(=O)R21)R2°, —C(=NNR24C(=O)OR21)R2°, —C(=S)NR22R23, —NC, —N02, — NRZZR”, —NR24NR22R23, —N=NR24, —NR24OR26, —NR24C(=O)R2°, —NR24C(=O)C(=O)R20, —NR24C(=O)OR21,—NR24C(=O)C(=O)OR21, —NR24C(=O)NR22R23, — NR24C(=O)NR24C(=O)R2°, —NR24C(=O)NR24C(=O)OR2°, —NR24C(=NR25)NR22R23, — NR24C(=O)C(=O)NR22R23, —NR24C(=S)R2°, —NR24C(=S)OR2°, —NR24C(=S)NR22R23, — NR24S(=O)2R21, —NR24S(=O)2NR22R23, —NR24P(=O)R28R28, — NR24P(=O)(NR22R23)(NRZZRB), —NR24P(=O)(OR20)(OR20), (=O)(SR20)(SR20), — ORZO, —OCN, —OC(=O)R2°, —OC(=O)NR22R23, —OC(=O)OR2°, R25)NR22R23, — OS(=O)R2°, —OS(=O)2R2°, —OS(=O)20R20, —OS(=O)2NR22R23, —OP(=O)R28R28, — OP(=O)(NR22R23)(NR22R23), —OP(=O)(OR2°)(OR20), —OP(=O)(SR20)(SR20), —Si(R24)3 — SCN, —S(=O)nR2°, 20R20, —SOgR27, —S(=O)2NR22R23, —S(=O)NR22R23, — SP(=O)R28R28, —SP(=O)(NR22R23)(NR22R23), —SP(=O)(OR20)(OR20), — SP(=O)(SR20)(SR20), —P(=O)R28R28, —P(=O)(NR22R23)(NR22R23), —P(=O)(OR2°)(OR2°), and —P(=O)(SR20)(SR20); alternatively, either or both of R12 and R13, and/or R14 and R”, can, together with the atoms linking them, form a C6_11aryl optionally substituted by 1-11 R19, C3_1lcycloalkyl optionally substituted by 1-21 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R19 or a 5-15 membered heteroaryl optionally substituted by 1—15 R19.

Embodiment 176. The compound of any of ments l-l74, wherein R12, R13, R14, and R15 are independently chosen from H, C1_6alkyl optionally substituted by l- 13 R19, C2_6alkenyl optionally substituted by 1-11 R19, C2_6alkynyl optionally substituted by 1-9 R19, C6_11aryl optionally substituted by 1-11 R19, C7_16arylalkyl ally substituted by 1-19 R19, C3_1lcycloalkyl optionally substituted by 1-21 R19, C4_ oalkylalkyl optionally substituted by 1-32 R19, 3-15 membered heterocycloalkyl ally substituted by 1-28 R19, 4-21 membered cycloalkylalkyl ally tuted by 1-40 R19, 5-15 membered heteroaryl optionally tuted by 1-15 R19, 6- 21 membered heteroarylalkyl optionally substituted by 1-27 R19, halogen, —CN, — C(=O)R2°, —C(=O)OR2°, —C(=O)NR22R23, —NC, —N02, —NR22R23, —NR24NR22R23, — _ 81 _ N=NR24, —NR24OR26, (=O)R2°, —NR24C(=O)OR21, (=O)NR22R23, — NR24S(=O)2R21, —NR24S(=O)2NR22R23, —NR24P(=O)R28R28, — NR24P(=O)(NR22R23)(NR22R23), —NR24P(=O)(OR20)(OR2°), —OR2°, —OCN, )R2°, )NR22R23, —OC(=O)OR2°, —OS(=O)R2°, )2R2°, —OS(=O)20R2°, — OS(=O)2NR22R23, —OP(=O)R28R28, —OP(=O)(NR22R23)(NR22R23), —OP(=O)(OR20)(OR20), —SCN, —S(=O)nR2°, —S(=O)20R20, —SOgR27, 2NR22R23, —S(=O)NR22R23, — P(=O)R28R28, —P(=O)(NR22R23)(NR22R23), and —P(=O)(OR2°)(OR2°); alternatively, either or both of R12 and R13, and/or R14 and R”, can, together with the atoms linking them, form a C6_11aryl optionally substituted by 1-11 R19, C3_11cycloalkyl ally substituted by l- 21 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R19 or a 5-15 membered heteroaryl optionally substituted by 1-15 R19.

Embodiment 177. The nd of any of Embodiments 1-174, wherein R12, R13, R14, and R15 are independently chosen from H, C1_6alkyl optionally substituted by 1-6 R19, C2_6alkenyl optionally substituted by 1-6 R19, C2_6alkynyl optionally substituted by 1-6 R19, ryl optionally substituted by 1-6 R19, C7_16arylalkyl optionally substituted by 1-6 R19, C3_11cycloalkyl optionally substituted by 1-6 R19, C4_17cycloalkylalkyl optionally substituted by 1-6 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-6 R19, 4-21 ed heterocycloalkylalkyl optionally substituted by 1-6 R19, 5-15 membered heteroaryl optionally substituted by 1-6 R19, 6-21 ed heteroarylalkyl optionally substituted by 1-6 R19, halogen, —CN, —C(=O)R20, —C(=O)OR2°, —C(=O)NR22R23, —NC, — N02, —NR22R23, —NR24NR22R23, —N=NR24, —NR24OR26, (=O)R2°, — NR24C(=O)OR21, —NR24C(=O)NR22R23, —NR24S(=O)2R21,—NR24S(=O)2NR22R23, — NR24P(=O)R28R28, —NR24P(=O)(NR22R23)(NRZZRB), —NR24P(=O)(OR20)(OR20), —OR20, — OCN, )R2°, —OC(=O)NR22R23, —OC(=O)OR2°, —OS(=O)R2°, —OS(=O)2R20, — OS(=O)20R2°, —OS(=O)2NR22R23, —OP(=O)R28R28, —OP(=O)(NR22R23)(NR22R23), — OP(=O)(OR20)(OR2°), —SCN, —S(=O)nR2°, —S(=O)20R2°, —sogR27, —S(=O)2NR22R23, — S(=O)NR22R23, —P(=O)R28R28, —P(=O)(NR22R23)(NR22R23), and —P(=O)(OR20)(OR2°); alternatively, either or both of R12 and R13, and/or R14 and R”, can, together with the atoms linking them, form a C6_11aryl optionally substituted by 1-6 R19, ycloalkyl optionally substituted by 1-6 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-6 R19 or a 5-15 membered heteroaryl optionally substituted by 1-6 R19.

Embodiment 178. The compound of any of Embodiments 1-174, wherein R12, R13, R14, and R15 are independently chosen from H, C1_6alkyl optionally substituted by 1-6 R19, C2_6alkenyl optionally substituted by 1-6 R19, kynyl optionally substituted by 1-6 _ 82 _ 2012/065831 R19, C6_11aryl optionally substituted by 1-6 R19, C7_16arylalkyl optionally substituted by 1-6 R19, C3_11cycloalkyl optionally substituted by 1-6 R19, C4_17cycloalkylalkyl optionally substituted by 1-6 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-6 R19, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-6 R19, 5-15 membered aryl optionally substituted by 1-6 R19, 6-21 ed heteroarylalkyl optionally substituted by 1-6 R19, halogen, —CN, —C(=O)R20, —C(=O)OR2°, —C(=O)NR22R23, —N02, — NRZZR”, —NR24C(=O)R20, —NR24C(=O)OR21, —NR24C(=O)NR22R23, —NR24S(=O)2R21,— =O)2NR22R23, —OR20, —OC(=O)R2°, —OC(=O)NR22R23, —OC(=O)OR2°, — S(=O)nR2°, —S(=O)20R2°, —SOgR27, —S(=O)2NR22R23, —S(=O)NR22R23, —P(=O)R28R28, — P(=O)(NR22R23)(NR22R23), and —P(=O)(OR20)(OR20); alternatively, either or both of R12 and R13, and/or R14 and R”, can, together with the atoms g them, form a C6_11aryl optionally substituted by 1-6 R19, C3_11cycloalkyl optionally substituted by 1-6 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-6 R19 or a 5-15 membered heteroaryl optionally substituted by 1-6 R19.

Embodiment 179. The compound of any of Embodiments l-l74, wherein R12, R13, R14, and R15 are independently chosen from H, C1_6alkyl optionally substituted by 1-3 R19, kenyl optionally substituted by 1-3 R19, C2_6alkynyl ally substituted by 1-3 R19, C6_11aryl optionally substituted by 1-3 R19, C7_16arylalkyl optionally tuted by 1-3 R19, C3_11cycloalkyl optionally substituted by 1-3 R19, C4_17cycloalkylalkyl optionally substituted by 1-3 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R19, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-3 R19, 5-15 membered heteroaryl optionally substituted by 1-3 R19, 6-21 membered heteroarylalkyl ally substituted by 1-3 R19, halogen, —CN, —C(=O)R20, —C(=O)OR2°, NR22R23, —N02, — NRZZR”, —NR24C(=O)R20, —NR24C(=O)OR21, —NR24C(=O)NR22R23, —NR24S(=O)2R21,— =O)2NR22R23, —OR20, —OC(=O)R2°, —OC(=O)NR22R23, —OC(=O)OR2°, — S(=O)nR2°, —S(=O)20R2°, 7, 2NR22R23, —S(=O)NR22R23, R28R28, — P(=O)(NR22R23)(NR22R23), and —P(=O)(OR20)(OR20); alternatively, either or both of R12 and R13, and/or R14 and R”, can, together with the atoms linking them, form a C6_11aryl optionally tuted by 1-3 R19, C3_11cycloalkyl optionally substituted by 1-3 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R19 or a 5-15 membered heteroaryl optionally substituted by 1-3 R19. ment 180. The compound of any of Embodiments l-l74, wherein R12, R13, R14, and R15 are independently chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C2_6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl optionally substituted by 1-3 _ 83 _ R19, C6_11aryl optionally substituted by 1-3 R19, C3_11cycloalkyl optionally substituted by l- 3 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-15 membered heteroaryl optionally substituted by 1—3 R19, n, —CN, R2°, —C(=O)OR2°, — C(=O)NR22R23, —N02, —NR22R23, —NR24C(=O)R2°, —NR24C(=O)OR21, — NR24C(=O)NR22R23, (=O)2R21, —NR24S(=O)2NR22R23, —OR2°, —OC(=O)R2°, — OC(=O)NR22R23, —OC(=O)OR2°, —S(=O)nR2°, —S(=O)20R2°, —SOgR27, —S(=O)2NR22R23, — S(=O)NR22R23, —P(=O)R28R28, —P(=O)(NR22R23)(NR22R23), and —P(=O)(OR20)(OR2°); alternatively, either or both of R12 and R13, and/or R14 and R”, can, er with the atoms linking them, form a C6_11aryl optionally tuted by 1-3 R19, C3_11cycloalkyl optionally substituted by 1-3 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R19 or a 5-15 ed heteroaryl optionally substituted by 1-3 R19.

Embodiment 181. The compound of any of Embodiments l-l74, wherein R12, R13, R14, and R15 are independently chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C2_6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl optionally substituted by 1-3 R19, C6_10aryl optionally substituted by 1-3 R19, C3_7cycloalkyl optionally substituted by l- 3 R19, 3-7 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-6 membered heteroaryl optionally substituted by 1—3 R19, halogen, —CN, —C(=O)R2°, —C(=O)OR2°, — C(=O)NR22R23, —NOg, —NR22R23, —NR24C(=O)R2°, —NR24C(=O)OR21, — NR24C(=O)NR22R23, —NR24S(=O)2R21, —NR24S(=O)2NR22R23, —OR2°, —OC(=O)R2°, — OC(=O)NR22R23, —OC(=O)OR2°, nR2°, —S(=O)20R2°, —SOgR27, —S(=O)2NR22R23, — S(=O)NR22R23, —P(=O)R28R28, (NR22R23)(NR22R23), and —P(=O)(OR20)(OR2°); alternatively, either or both of R12 and R13, and/or R14 and R”, can, er with the atoms linking them, form a C6_10aryl optionally tuted by 1-3 R19, C3_7cycloalkyl optionally substituted by 1-3 R19, 3-7 ed heterocycloalkyl optionally tuted by 1-3 R19 or a 5-6 membered heteroaryl optionally substituted by 1-3 R19.

Embodiment 182. The compound of any of Embodiments l-l74, wherein R12, R13, R14, and R15 are independently chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C2_6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl optionally tuted by 1-3 R19, C6_11aryl optionally substituted by 1-3 R19, C7_16arylalkyl optionally substituted by 1-3 R19, C3_11cycloalkyl optionally substituted by 1-3 R19, C4_17cycloalkylalkyl optionally substituted by 1-3 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R19, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-3 R19, 5-15 membered heteroaryl optionally substituted by 1-3 R19, 6-21 membered heteroarylalkyl ally tuted by 1—3 R19, halogen, —CN, R20, —C(=O)NR22R23, —NOg, —NR22R23, — _ 84 _ NR24C(=O)R2°, —NR24S(=O)2R21, —OR2°, —S(=O)nR2°, and —S(=O)2NR22R23; alternatively, either or both of R12 and R13, and/or R14 and R”, can, together with the atoms linking them, form a C6_11aryl optionally substituted by 1-3 R19, C3_11cycloalkyl optionally substituted by 1-3 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R19 or a 5-15 membered heteroaryl optionally substituted by 1-3 R19.

Embodiment 183. The compound of any of Embodiments 1-174, wherein R12, R13, R14, and R15 are independently chosen from H, C1_6alkyl optionally substituted by 1-3 R19, kenyl optionally tuted by 1-3 R19, C2_6alkynyl ally substituted by 1-3 R19, C6_11aryl optionally substituted by 1-3 R19, C3_11cycloalkyl ally substituted by 1- 3 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-15 membered heteroaryl optionally substituted by 1—3 R19, halogen, —CN, —C(=O)R2°, —C(=O)NR22R23, — N02, —NR22R23, —NR24C(=O)R20, —NR24S(=O)2R21,—OR2°, —S(=O)nR20, and — S(=O)2NR22R23; alternatively, either or both of R12 and R13, and/or R14 and R”, can, together with the atoms linking them, form a C6_11aryl optionally substituted by 1-3 R19, C3_11cycloalkyl optionally substituted by 1-3 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R19 or a 5-15 membered heteroaryl optionally substituted by 1-3 R19.

Embodiment 184. The nd of any of Embodiments 1-174, wherein R12, R13, and R15 are H; R14 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C2- 6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl optionally substituted by 1-3 R19, C6_11aryl optionally tuted by 1-3 R19, ycloalkyl optionally substituted by 1-3 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-15 membered heteroaryl optionally substituted by 1—3 R19, halogen, —CN, —C(=O)R2°, —C(=O)NR22R23, — N02, —NR22R23, —NR24C(=O)R20, —NR24S(=O)2R21,—OR2°, nR20, and — S(=O)2NR22R23; alternatively, either or both of R12 and R13, and/or R14 and R”, can, er with the atoms linking them, form a C6_11aryl optionally tuted by 1-3 R19, C3_11cycloalkyl optionally substituted by 1-3 R19, 3-15 membered heterocycloalkyl optionally tuted by 1-3 R19 or a 5-15 membered heteroaryl ally substituted by 1-3 R19.

Embodiment 185. The compound of any of Embodiments 1-174, wherein R12, R13, and R14 are H; R15 is chosen from H, C1_6alkyl optionally tuted by 1-3 R19, C2- 6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl optionally substituted by 1-3 R19, C6_11aryl optionally tuted by 1-3 R19, C3_11cycloalkyl optionally substituted by 1-3 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-15 membered _ 85 _ heteroaryl optionally substituted by 1—3 R19, halogen, —CN, R2°, NR22R23, — N02, 23, —NR24C(=O)R20, —NR24S(=O)2R21,—OR2°, —S(=O)nR20, and — S(=O)2NR22R23; alternatively, either or both of R12 and R13, and/or R14 and R”, can, together with the atoms linking them, form a C6_11aryl optionally substituted by 1-3 R19, C3_11cycloalkyl optionally substituted by 1-3 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R19 or a 5-15 membered heteroaryl optionally substituted by 1-3 R19.

Embodiment 186. The compound of any of Embodiments 1-174, wherein R12, R13, and R15 are H; R14 is chosen from H, C1_6alkyl optionally tuted by 1-3 R19, C2- 6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl optionally substituted by 1-3 R19, C6_11aryl ally substituted by 1-3 R19, ycloalkyl optionally substituted by 1-3 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-15 membered heteroaryl optionally substituted by 1—3 R19, halogen, —CN, —C(=O)R2°, —C(=O)NR22R23, — N02, —NR22R23, (=O)R20, —NR24S(=O)2R21,—OR2°, —S(=O)nR20, and — S(=O)2NR22R23. ment 187. The compound of any of Embodiments 1-174, wherein R12, R13, and R14 are H; R15 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C2- 6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl optionally substituted by 1-3 R19, ryl optionally substituted by 1-3 R19, C3_11cycloalkyl optionally substituted by 1-3 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-15 membered heteroaryl optionally substituted by 1—3 R19, halogen, —CN, —C(=O)R2°, —C(=O)NR22R23, — N02, —NR22R23, —NR24C(=O)R20, —NR24S(=O)2R21,—OR2°, —S(=O)nR20, and — S(=O)2NR22R23.

Embodiment 188. The compound of any of Embodiments 1-174, wherein R12, R13, R14, and R15 are independently chosen from H, C1_6alkyl optionally tuted by 1-3 R19, C2_6alkenyl optionally substituted by 1-3 R19, kynyl optionally substituted by 1-3 R19, C6_10aryl optionally substituted by 1-3 R19, C3_7cycloalkyl optionally substituted by 1- 3 R19, 3-7 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-6 membered heteroaryl optionally substituted by 1-3 R19, halogen, —CN, —C(=O)R2°, —C(=O)NR22R23, — N02, 23, —NR24C(=O)R20, (=O)2R21,—OR2°, —S(=O)nR20, and — S(=O)2NR22R23; alternatively, either or both of R12 and R13, and/or R14 and R”, can, together with the atoms linking them, form a C6_10aryl ally substituted by 1-3 R19, C3_7cycloalkyl optionally substituted by 1-3 R19, 3-7 membered heterocycloalkyl optionally substituted by 1-3 R19 or a 5-6 membered heteroaryl optionally substituted by l- 3 R19.

Embodiment 189. The compound of any of Embodiments l-l74, wherein R12, R13, and R15 are H; R14 is chosen from H, C1_6alkyl ally substituted by 1-3 R19, C2- 6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl optionally substituted by 1-3 R19, C6_10aryl optionally substituted by 1-3 R19, C3_7cycloalkyl optionally tuted by 1-3 R19, 3-7 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-6 membered heteroaryl optionally substituted by 1—3 R19, halogen, —CN, —C(=O)R2°, —C(=O)NR22R23, — N02, —NR22R23, —NR24C(=O)R20, —NR24S(=O)2R21,—OR2°, —S(=O)nR20, and — S(=O)2NR22R23; alternatively, either or both of R12 and R13, and/or R14 and R”, can, together with the atoms linking them, form a C6_10aryl optionally substituted by 1-3 R19, C3_7cycloalkyl optionally substituted by 1-3 R19, 3-7 membered heterocycloalkyl optionally substituted by 1-3 R19 or a 5-6 membered heteroaryl optionally substituted by l- 3 R19.

Embodiment 190. The compound of any of Embodiments l-l74, wherein R12, R13, and R14 are H; R15 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C2- 6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl optionally tuted by 1-3 R19, C6_10aryl optionally substituted by 1-3 R19, cloalkyl optionally substituted by 1-3 R19, 3-7 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-6 ed heteroaryl optionally substituted by 1—3 R19, halogen, —CN, —C(=O)R2°, —C(=O)NR22R23, — N02, —NR22R23, —NR24C(=O)R20, —NR24S(=O)2R21,—OR2°, —S(=O)nR20, and — S(=O)2NR22R23; atively, either or both of R12 and R13, and/or R14 and R”, can, together with the atoms linking them, form a C6_10aryl optionally substituted by 1-3 R19, C3_7cycloalkyl ally substituted by 1-3 R19, 3-7 membered heterocycloalkyl optionally substituted by 1-3 R19 or a 5-6 membered heteroaryl optionally substituted by l- 3 R19. ment 191. The nd of any of Embodiments l-l74, wherein R12, R13, and R15 are H; R14 is chosen from H, C1_6alkyl ally substituted by 1-3 R19, C2- 6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl optionally tuted by 1-3 R19, C6_10aryl optionally substituted by 1-3 R19, C3_7cycloalkyl optionally substituted by 1-3 R19, 3-7 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-6 membered heteroaryl optionally substituted by 1-3 R19, halogen, —CN, —C(=O)R2°, —C(=O)NR22R23, — N02, —NR22R23, —NR24C(=O)R20, —NR24S(=O)2R21,—OR2°, nR20, and — S(=O)2NR22R23. _ 87 _ Embodiment 192. The compound of any of Embodiments 1-174, wherein R12, R13, and R14 are H; R15 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C2- 6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl optionally substituted by 1-3 R19, C6_10aryl optionally substituted by 1-3 R19, C3_7cycloalkyl optionally substituted by 1-3 R19, 3-7 membered cycloalkyl optionally substituted by 1-3 R19, 5-6 membered heteroaryl optionally substituted by 1-3 R19, halogen, —CN, —C(=O)R2°, —C(=O)NR22R23, — N02, —NR22R23, —NR24C(=O)R20, —NR24S(=O)2R21,—OR2°, —S(=O)nR20, and — S(=O)2NR22R23. ment 193. The compound of any of Embodiments 1-174, wherein R12, R13, R14, and R15 are independently chosen from H, kyl optionally substituted by 1-3 R19, halogen, —NR22R23, —NR24C(=O)R20, —NR24C(=O)NR22R23, —OR2°, and — S(=O)2NR22R23.

Embodiment 194. The compound of any of Embodiments 1-174, wherein R12, R13, R14, and R15 are ndently chosen from H, C1_6alkyl optionally substituted by 1-3 R19, halogen, —NR22R23, —NR24C(=O)R20, and —NR24C(=O)NR22R23.

Embodiment 195. The compound of any of Embodiments 1-174, n R12, R13, and R15 are H; R14 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, halogen, —NR22R23, —NR24C(=O)R20, —NR24C(=O)NR22R23, —OR20, and 2NR22R23.

Embodiment 196. The compound of any of ments 1-174, wherein R12, R13, and R15 are H; R14 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, — NRZZR”, —NR24C(=O)R20, and —NR24C(=O)NR22R23.

Embodiment 197. The compound of any of Embodiments 1-174, wherein R12, R13, and R14 are H; R15 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, halogen, 23, —NR24C(=O)R20, —NR24C(=O)NR22R23, —OR20, and 2NR22R23.

Embodiment 198. The compound of any of Embodiments 1-174, n R12, R13, and R14 are H; R15 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, and halogen.

Embodiment 199. The nd of any of Embodiments 1-174, wherein R12, R13, R14, and R15 are independently chosen from H and kyl optionally substituted by 1-3 R19.

Embodiment 200. The compound of any of Embodiments 1-174, wherein R12, R13, R14, and R15 are independently chosen from H, C1_6alkyl, halogen, —NR22R23, — NR24C(=O)R2°, —NR24C(=O)NR22R23, —OR2°, and —S(=0)2NR22R23.

Embodiment 201. The compound of any of Embodiments l-l74, wherein R12, R13, R14, and R15 are independently chosen from H, C1_6alkyl, halogen, —NR22R23, — NR24C(=O)R2°, and (=O)NR22R23.

Embodiment 202. The compound of any of Embodiments l-l74, wherein R12, R13, and R15 are H; R14 is chosen from H, C1_6alkyl, halogen, —NR22R23, —NR24C(=O)R20, — NR24C(=O)NR22R23, —OR20, and 2NR22R23.

Embodiment 203. The compound of any of Embodiments l-l74, wherein R12, R13, and R15 are H; R14 is chosen from H, kyl, —NR22R23, —NR24C(=O)R20, and — NR24C(=O)NR22R23.

Embodiment 204. The compound of any of Embodiments l-l74, wherein R12, R13, and R14 are H; R15 is chosen from H, C1_6alkyl, halogen, —NR22R23, —NR24C(=O)R20, — NR24C(=O)NR22R23, —OR20, and —S(=O)2NR22R23.

Embodiment 205. The compound of any of ments l-l74, wherein R12, R13, and R14 are H; R15 is chosen from H, C1_6alkyl, and halogen.

Embodiment 206. The compound of any of Embodiments l-l74, wherein R12, R13, R14, and R15 are independently chosen from H and C1_6alkyl.

Embodiment 207. The compound of any of Embodiments l-l74, wherein R12, R13, R14, and R15 are independently chosen from H, C1_6alkyl optionally substituted by l- 13 R19, C2_6alkenyl optionally substituted by 1-11 R19, C2_6alkynyl ally tuted by 1-9 R19, C6_11aryl optionally substituted by 1-11 R19, C7_16arylalkyl optionally substituted by 1-19 R19, C3_11cycloalkyl optionally substituted by 1-21 R19, C4_ oalkylalkyl optionally substituted by 1-32 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R19, 4-2l membered heterocycloalkylalkyl optionally substituted by 1-40 R19, 5-15 membered heteroaryl optionally substituted by 1-15 R19, 6- 2l membered heteroarylalkyl optionally substituted by 1-27 R19, halogen, —CN, — C(=O)R2°, —C(=O)OR2°, —C(=O)NR22R23, —N02, 4x11821123, and —OR20; alternatively, either or both of R12 and R13, and/or R14 and R”, can, together with the atoms linking them, form a C6_11aryl ally substituted by 1-11 R19, C3_11cycloalkyl optionally substituted by 1-21 R19, 3-15 ed heterocycloalkyl optionally substituted by 1-28 R19 or a 5-15 membered aryl optionally substituted by 1-15 R19. ment 208. The compound of any of Embodiments l-l74, wherein R12, R13, R14, and R15 are independently chosen from H, C1_6alkyl optionally substituted by l- 13 R19, C2_6alkenyl optionally substituted by 1-11 R19, C2_6alkynyl optionally substituted by 1-9 R19, C6_11aryl optionally substituted by 1-11 R19, C7_16arylalkyl optionally _ 89 _ substituted by 1-19 R19, C3.1 1cycloalkyl optionally substituted by 1-21 R19, c4_ 17cycloalkylalkyl optionally substituted by 1-32 R19, 3-15 ed heterocycloalkyl optionally substituted by 1-28 R19, 4-21 membered cycloalkylalkyl optionally substituted by 1-40 R19, 5-15 membered heteroaryl optionally substituted by 1-15 R19, 6- 21 membered heteroarylalkyl optionally substituted by 1-27 R19, halogen, —CN, — R22R23, —N02, 23, and —OR20; alternatively, either or both of R12 and R13, and/or R14 and R”, can, together with the atoms linking them, form a C6_11aryl optionally tuted by 1-11 R19, C3_11cycloalkyl optionally substituted by 1-21 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R19 or a 5-15 membered heteroaryl optionally substituted by 1-15 R19.

Embodiment 209. The compound of any of Embodiments 1-174, wherein R12, R13, R14, and R15 are independently chosen from H, halogen, —NR22R23, (=O)R20, — NR24C(=O)NR22R23, —OR20, and —S(=O)2NR22R23.

Embodiment 210. The compound of any of Embodiments 1-174, wherein R12, R13, R14, and R15 are independently chosen from H, halogen, —NR22R23, —NR24C(=O)R20, and —NR24C(=O)NR22R23. ment 211. The compound of any of Embodiments 1-174, wherein R12, R13, and R15 are H; R14 is chosen from H, halogen, —NR22R23, —NR24C(=O)R20, — NR24C(=O)NR22R23, —OR20, and —S(=O)2NR22R23.

Embodiment 212. The compound of any of Embodiments 1-174, wherein R12, R13, and R15 are H; R14 is chosen from H, —NR22R23, —NR24C(=O)R20, and — NR24C(=O)NR22R23.

Embodiment 213. The nd of any of Embodiments 1-174, wherein R12, R13, and R14 are H; R15 is chosen from H, halogen, —NR22R23, —NR24C(=O)R20, — NR24C(=O)NR22R23, —OR20, and —S(=O)2NR22R23.

Embodiment 214. The nd of any of Embodiments 1-174, wherein R12, R13, and R14 are H; R15 is chosen from H and halogen.

Embodiment 215. The compound of any of Embodiments 1-174, n R12, R13, R14, and R15 are H.

Embodiment 216. The compound of any of Embodiments 1-215, n R17 is chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C2_6alkenyl optionally substituted by 1-11 R19, C2_6alkynyl optionally substituted by 1-9 R19, C6_11aryl optionally substituted by 1-11 R19, C7_16arylalkyl optionally substituted by 1-19 R19, C3_1lcycloalkyl _ 90 _ optionally substituted by 1-21 R19, C4_17cycloalkylalkyl optionally substituted by 1-32 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R19, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40 R19, 5-15 membered heteroaryl optionally substituted by 1-15 R19, 6-21 membered heteroarylalkyl optionally substituted by 1-27 R19, and —OR20; R16 and R18 are independently chosen from H, C1_6alkyl optionally tuted by 1-13 R19, kenyl optionally substituted by 1-11 R19, C2- 6alkynyl optionally substituted by 1-9 R19, C6_11aryl optionally substituted by 1-11 R19, C7- 16arylalkyl optionally substituted by 1-19 R19, ycloalkyl optionally tuted by l- 21 R19, C4_17cycloalkylalkyl optionally substituted by 1—32 R19, 3—15 membered heterocycloalkyl optionally substituted by 1-28 R19, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40 R19, 5-15 membered heteroaryl optionally substituted by l- R19, 6-21 membered heteroarylalkyl optionally substituted by 1-27 R19, n, —CN, —C(=O)R2°, —C(=O)OR2°, —C(=O)NR22R23, —C(=O)C(=O)R2°, —C(=NR25)R2°, — C(=NR25)NR22R23, —C(=NOH)NR22R23, —C(=NOR26)R2°, R22R23)R20, — C(=NNR24C(=O)R21)R2°, —C(=NNR24C(=O)OR21)R2°, —C(=S)NR22R23, —NC, —N02, — NRZZR”, —NR24NR22R23, —N=NR24, —NR24OR26, —NR24C(=O)R2°, —NR24C(=O)C(=O)R20, (=O)OR21,—NR24C(=O)C(=O)OR21, —NR24C(=O)NR22R23, — NR24C(=O)NR24C(=O)R2°, —NR24C(=O)NR24C(=O)OR2°, —NR24C(=NR25)NR22R23, — NR24C(=O)C(=O)NR22R23, —NR24C(=S)R2°, —NR24C(=S)OR2°, —NR24C(=S)NR22R23, — NR24S(=O)2R21, —NR24S(=O)2NR22R23, —NR24P(=O)R28R28, — NR24P(=O)(NR22R23)(NRZZRB), —NR24P(=O)(OR20)(OR20), —NR24P(=O)(SR20)(SR20), — ORZO, —OCN, —OC(=O)R2°, —OC(=O)NR22R23, )OR2°, —OC(=NR25)NR22R23, — OS(=O)R2°, —OS(=O)2R2°, —OS(=O)20R20, —OS(=O)2NR22R23, )R28R28, — (NR22R23)(NR22R23), —OP(=O)(OR2°)(OR20), —OP(=O)(SR20)(SR20), —Si(R24)3 — SCN, —S(=O)nR2°, —S(=O)20R20, —sogR27, 2NR22R23, —S(=O)NR22R23, — SP(=O)R28R28, —SP(=O)(NR22R23)(NR22R23), —SP(=O)(OR20)(OR20), — SP(=O)(SR20)(SR20), —P(=O)R28R28, —P(=O)(NR22R23)(NR22R23), —P(=O)(OR2°)(OR2°), or —P(=O)(SR20)(SR20); atively, R16 and R17 can, together with the atoms linking them, form a 3-15 membered heterocycloalkyl optionally substituted by 1-28 R19 or a 5-15 membered heteroaryl optionally substituted by 1-15 R19.

Embodiment 217. The compound of any of Embodiments 1-215, wherein R17 is chosen from H and C1_6alkyl optionally tuted by 1-13 R19; R16 and R18 are independently chosen from H, C1_6alkyl optionally substituted by 1-1 3 R19, kenyl optionally tuted by 1-11 R19, C2_6alkynyl optionally substituted by 1-9 R19, C6_11aryl _ 91 _ optionally substituted by 1-11 R19, C7_16a1'ylalkyl optionally substituted by 1-19 R19, C3- 11cycloalkyl optionally substituted by 1-21 R19, C4_17cycloalkylalkyl optionally substituted by 1-32 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R19, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40 R19, 5-15 membered heteroaryl optionally substituted by 1-15 R19, 6-21 membered heteroarylalkyl optionally tuted by 1—27 R19, halogen, —CN, —C(=O)R20, —C(=O)OR2°, —C(=O)NR22R23, — C(=O)C(=O)R2°, —C(=NR25)R2°, —C(=NR25)NR22R23, —C(=NOH)NR22R23, — C(=NOR26)R2°, —C(=NNR22R23)R2°, —C(=NNR24C(=O)R21)R20, — C(=NNR24C(=O)OR21)R2°, —C(=S)NR22R23, —NC, —N02, 23, —NR24NR22R23, — , R26, (=O)R2°, —NR24C(=O)C(=O)R2°, —NR24C(=O)OR21, — NR24C(=O)C(=O)OR21, —NR24C(=O)NR22R23, —NR24C(=O)NR24C(=O)R2°, — NR24C(=O)NR24C(=O)OR2°, —NR24C(=NR25)NR22R23, —NR24C(=O)C(=O)NR22R23, — NR24C(=S)R2°, —NR24C(=S)OR2°, —NR24C(=S)NR22R23, —NR24S(=O)2R21, — NR24S(=O)2NR22R23, _NR24P(:O)R28R28’ —NR24P(=O)(NR22R23)(NR22R23), _ NR24P(=O)(OR2°)(OR20), —NR24P(=O)(SR2°)(SR2°), —OR20, —OCN, —OC(=O)R2°, — OC(=O)NR22R23, —OC(=O)OR2°, —OC(=NR25)NR22R23, —OS(=O)R2°, )2R2°, — OS(=O)20R2°, —OS(=O)2NR22R23, —OP(=O)R28R28, )(NR22R23)(NR22R23), — OP(=O)(OR20)(OR2°), )(SR2°)(SR2°), —Si(R24)3 ,—SCN, —S(=O)nR2°, — S(=O)20R20, —SOgR27, —S(=O)2NR22R23, —S(=O)NR22R23, —SP(=O)R28R28, — SP(=O)(NR22R23)(NR22R23), —SP(=O)(OR2°)(OR2°), —SP(=O)(SR20)(SR20), —P(=O)R28R28 u —P(=O)(NR22R23)(NR22R23), —P(=O)(OR20)(OR20), or —P(=O)(SR20)(SR20); alternatively, R16 and R17 can, together with the atoms linking them, form a 3-15 membered heterocycloalkyl optionally substituted by 1-28 R19 or a 5-15 membered heteroaryl optionally substituted by 1-15 R19.

Embodiment 218. The compound of any of Embodiments 1-215, wherein R17 is chosen from H and C1_6alkyl optionally substituted by 1-3 R19; R16 and R18 are independently chosen from H, C1_6alkyl optionally substituted by 1-1 3 R19, C2_6alkenyl ally substituted by 1-11 R19, C2_6alkynyl optionally substituted by 1-9 R19, C6_11a1'yl optionally substituted by 1-11 R19, C7_16a1'ylalkyl ally substituted by 1-19 R19, C3_ 11cycloalkyl optionally tuted by 1-21 R19, C4_17cycloalkylalkyl ally substituted by 1-32 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R19, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40 R19, 5-15 membered aryl optionally substituted by 1-15 R19, 6-21 membered heteroarylalkyl optionally substituted by 1—27 R19, n, —CN, —C(=O)R20, —C(=O)OR2°, —C(=O)NR22R23, — _ 92 _ C(=O)C(=O)R2°, —C(=NR25)R2°, —C(=NR25)NR22R23, —C(=NOH)NR22R23, — C(=NOR26)R2°, —C(=NNR22R23)R2°, —C(=NNR24C(=O)R21)R20, — C(=NNR24C(=O)OR21)R2°, —C(=S)NR22R23, —NC, —N02, —NR22R23, R22R23, — N=NR24, —NR24OR26, —NR24C(=O)R2°, —NR24C(=O)C(=O)R2°, —NR24C(=O)OR21, — NR24C(=O)C(=O)OR21, —NR24C(=O)NR22R23, —NR24C(=O)NR24C(=O)R2°, — NR24C(=O)NR24C(=O)OR2°, —NR24C(=NR25)NR22R23, —NR24C(=O)C(=O)NR22R23, — NR24C(=S)R2°, —NR24C(=S)OR2°, —NR24C(=S)NR22R23, —NR24S(=O)2R21, — NR24S(=O)2NR22R23, —NR24P(=O)R28R28, (=O)(NR22R23)(NR22R23), _ NR24P(=O)(OR2°)(OR20), —NR24P(=O)(SR2°)(SR2°), —OR20, —OCN, —OC(=O)R2°, — OC(=O)NR22R23, —OC(=O)OR2°, —OC(=NR25)NR22R23, —OS(=O)R2°, —OS(=O)2R2°, — OS(=O)20R2°, —OS(=O)2NR22R23, —OP(=O)R28R28, —OP(=O)(NR22R23)(NR22R23), — OP(=O)(OR20)(OR2°), —OP(=O)(SR2°)(SR2°), —Si(R24)3 ,—SCN, —S(=O)nR2°, — S(=O)20R20, —SOgR27, —S(=O)2NR22R23, —S(=O)NR22R23, —SP(=O)R28R28, — SP(=O)(NR22R23)(NR22R23), —SP(=O)(OR2°)(OR2°), —SP(=O)(SR20)(SR20), —P(=O)R28R28 u —P(=O)(NR22R23)(NR22R23), —P(=O)(OR20)(OR20), or —P(=O)(SR20)(SR20); alternatively, R16 and R17 can, together with the atoms linking them, form a 3-15 membered heterocycloalkyl optionally substituted by 1-28 R19 or a 5-15 membered heteroaryl optionally substituted by 1-15 R19. ment 219. The compound of any of Embodiments 1-215, wherein R17 is chosen from H and kyl; R16 and R18 are ndently chosen from H, kyl optionally substituted by 1-13 R19, C2_6alkenyl ally substituted by 1-11 R19, C2_ 6alkynyl optionally substituted by 1-9 R19, C6_11aryl optionally substituted by 1-11 R19, C7- 16arylalkyl optionally substituted by 1-19 R19, C3_11cycloalkyl ally substituted by l- 21 R19, C4_17cycloalkylalkyl optionally substituted by 1—32 R19, 3—15 membered heterocycloalkyl optionally substituted by 1-28 R19, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40 R19, 5-15 membered heteroaryl ally tuted by l- R19, 6-21 membered heteroarylalkyl optionally substituted by 1-27 R19, halogen, —CN, —C(=O)R2°, —C(=O)OR2°, —C(=O)NR22R23, —C(=O)C(=O)R2°, —C(=NR25)R2°, — C(=NR25)NR22R23, —C(=NOH)NR22R23, —C(=NOR26)R2°, —C(=NNR22R23)R20, — C(=NNR24C(=O)R21)R2°, —C(=NNR24C(=O)OR21)R2°, —C(=S)NR22R23, —NC, —N02, — NRZZR”, —NR24NR22R23, —N=NR24, —NR24OR26, —NR24C(=O)R2°, (=O)C(=O)R20, (=O)OR21,—NR24C(=O)C(=O)OR21, —NR24C(=O)NR22R23, — NR24C(=O)NR24C(=O)R2°, (=O)NR24C(=O)OR2°, —NR24C(=NR25)NR22R23, — NR24C(=O)C(=O)NR22R23, —NR24C(=S)R2°, —NR24C(=S)OR2°, —NR24C(=S)NR22R23, — _ 93 _ NR24S(=O)2R21, —NR24S(=O)2NR22R23, —NR24P(=O)R28R28, — NR24P(=O)(NR22R23)(NRZZRB), —NR24P(=O)(OR20)(OR20), —NR24P(=O)(SR20)(SR20), — ORZO, —OCN, —OC(=O)R2°, —OC(=O)NR22R23, —OC(=O)OR2°, —OC(=NR25)NR22R23, — OS(=O)R2°, —OS(=O)2R2°, —OS(=O)20R20, )2NR22R23, )R28R28, — OP(=O)(NR22R23)(NR22R23), —OP(=O)(OR2°)(OR20), —OP(=O)(SR20)(SR20), —Si(R24)3 — SCN, —S(=O)nR2°, —S(=O)20R20, —SOgR27, —S(=O)2NR22R23, —S(=O)NR22R23, — SP(=O)R28R28, —SP(=O)(NR22R23)(NR22R23), —SP(=O)(OR20)(OR20), — SP(=O)(SR20)(SR20), —P(=O)R28R28, —P(=O)(NR22R23)(NR22R23), —P(=O)(OR2°)(OR2°), or —P(=O)(SR20)(SR20); alternatively, R16 and R17 can, together with the atoms linking them, form a 3-15 membered heterocycloalkyl optionally substituted by 1-28 R19 or a 5-15 membered heteroaryl optionally substituted by 1-15 R19.

Embodiment 220. The compound of any of Embodiments 1-215, wherein R17 is chosen from H and C1_6alkyl; R16 and R18 are independently chosen from H, C1_6alkyl optionally tuted by 1-6 R19, C2_6alkenyl ally substituted by 1-6 R19, kynyl optionally substituted by 1-6 R19, ryl optionally tuted by 1-6 R19, C7_11arylalkyl optionally substituted by 1-6 R19, C3_10cycloalkyl optionally substituted by 1-6 R19, 3-10 membered heterocycloalkyl optionally substituted by 1-6 R19, 5-10 membered heteroaryl optionally substituted by 1-6 R19, halogen, —CN, —C(=O)R20, —C(=O)OR2°, — C(=O)NR22R23, C(=O)R20, —NC, —N02, —NR22R23, —NR24NR22R23, —N=NR24, — NR24OR26, —NR24C(=O)R20, —NR24C(=O)C(=O)R2°, —NR24C(=O)OR21, — NR24C(=O)C(=O)OR21, —NR24C(=O)NR22R23, —NR24C(=O)NR24C(=O)R2°, — NR24C(=O)NR24C(=O)OR2°, —NR24C(=O)C(=O)NR22R23, —NR24S(=O)2R21, — NR24S(=O)2NR22R23, ORZO, OCN, OC(—O)R2°, OC(—O)NR22R23, —OC(=O)OR2°, — OS(=O)R2°, —OS(=O)2R2°, —OS(=O)20R20, —OS(=O)2NR22R23, —SCN, —S(=O)nR20, — S(=O)20R20, —sogR27, —S(=O)2NR22R23, and —S(=O)NR22R23; alternatively, R16 and R17 can, together with the atoms g them, form a 3-10 membered heterocycloalkyl optionally substituted by 1-6 R19 or a 5-10 membered heteroaryl optionally substituted by 1-6 R19.

Embodiment 221. The compound of any of Embodiments 1-215, wherein R17 is chosen from H and C1_6alkyl; R16 and R18 are independently chosen from H, kyl optionally substituted by 1-3 R19, C2_6alkenyl optionally substituted by 1-1 R19, C2_6alkynyl optionally substituted by 1-3 R19, C6_10aryl optionally substituted by 1-3 R19, C7_11arylalkyl ally substituted by 1-3 R19, C3_10cycloalkyl optionally substituted by 1-3 R19, 3-10 membered cycloalkyl optionally substituted by 1-3 R19, 5-10 membered heteroaryl _ 94 _ optionally substituted by 1—3 R19, halogen, —CN, —C(=O)R20, —C(=O)OR2°, — C(=O)NR22R23, —C(=O)C(=O)R20, —NC, —NOg, —NR22R23, —NR24NR22R23, —N=NR24, — NR24OR26, —NR24C(=O)R20, —NR24C(=O)C(=O)R2°, (=O)OR21, — NR24C(=O)C(=O)OR21, —NR24C(=O)NR22R23, —NR24C(=O)NR24C(=O)R2°, — NR24C(=O)NR24C(=O)OR2°, —NR24C(=O)C(=O)NR22R23, —NR24S(=O)2R21, — NR24S(=O)2NR22R23, ORZO, OCN, R2°, OC(—O)NR22R23,—OC(=O)OR2°,— OS(=O)R2°, —OS(=O)2R2°, —OS(=O)20R20, —OS(=O)2NR22R23, —SCN, —S(=O)nR20, — S(=O)20R20, —SOgR27, —S(=O)2NR22R23, and —S(=O)NR22R23; alternatively, R16 and R17 can, together with the atoms linking them, form a 3-10 membered heterocycloalkyl optionally substituted by 1-3 R19 or a 5-10 membered heteroaryl optionally substituted by 1—3 R19. ment 222. The compound of any of Embodiments 1-215, wherein R17 is chosen from H and C1_6alkyl; R16 and R18 are independently chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C6_10aryl optionally substituted by 1-3 R19, C7_11arylalkyl optionally substituted by 1-3 R19, C3_10cycloalkyl optionally substituted by 1-3 R19, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-10 membered heteroaryl optionally substituted by 1—3 R19, halogen, —CN, —C(=O)R20, —C(=O)OR2°, — C(=O)NR22R23, —NC, —NOg, 23, —NR24NR22R23, —NR24C(=O)R2°, — NR24C(=O)OR21, —NR24C(=O)NR22R23, —NR24S(=O)2R21, —NR24S(=O)2NR22R23, —OR2°, — OCN, )R2°, —OC(=O)NR22R23, —OC(=O)OR2°, —OS(=O)R2°, —OS(=O)2R20, — OS(=O)20R2°, —OS(=O)2NR22R23, —SCN, —S(=O)nR20, —S(=O)20R2°, —SOgR27, — S(=O)2NR22R23, and —S(=O)NR22R23; alternatively, R16 and R17 can, together with the atoms g them, form a 3-10 ed cycloalkyl optionally substituted by 1-3 R19 or a 5-10 membered heteroaryl optionally substituted by 1-3 R19.

Embodiment 223. The compound of any of ments 1-215, wherein R17 is chosen from H and C1_6alkyl; R16 and R18 are independently chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C6_10aryl optionally substituted by 1-3 R19, C7_11arylalkyl optionally substituted by 1-3 R19, C3_10cycloalkyl optionally tuted by 1-3 R19, 3-10 membered cycloalkyl optionally substituted by 1-3 R19, 5-10 membered heteroaryl optionally tuted by 1—3 R19, halogen, —CN, —C(=O)R20, —C(=O)OR2°, — C(=O)NR22R23, —NC, —NOg, —NR22R23, —NR24C(=O)R20, —NR24C(=O)OR21, — NR24C(=O)NR22R23, —NR24S(=O)2R21, —OR2°, —OCN, —OC(=O)R2°, —OC(=O)NR22R23, — SCN, —S(=O)nR2°, —S(=O)20R20, —503R27, —S(=O)2NR22R23, and —S(=O)NR22R23; alternatively, R16 and R17 can, together with the atoms linking them, form a 3-10 _ 95 _ membered heterocycloalkyl optionally substituted by 1-3 R19 or a 5-10 membered heteroaryl optionally substituted by 1-3 R19.

Embodiment 224. The compound of any of Embodiments 1-215, wherein R17 is chosen from H and kyl; R16 and R18 are independently chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C6_10aryl optionally substituted by 1-3 R19, rylalkyl optionally substituted by 1-3 R19, ycloalkyl optionally substituted by 1-3 R19, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-10 membered heteroaryl optionally substituted by 1—3 R19, n, —CN, —C(=O)R20, —C(=O)NR22R23, —NC, — N02, —NR22R23, —NR24C(=O)R20, —NR24C(=O)OR21,—NR24S(=O)2R21, —OR2°, — S(=O)nR20, and —S(=O)2NR22R23; alternatively, R16 and R17 can, together with the atoms g them, form a 3-10 ed heterocycloalkyl optionally substituted by 1-3 R19 or a 5-10 ed heteroaryl optionally substituted by 1-3 R19.

Embodiment 225. The compound of any of Embodiments 1-215, wherein R17 is chosen from H and C1_6alkyl; R16 and R18 are ndently chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C6_10aryl optionally substituted by 1-3 R19, C7_11arylalkyl optionally substituted by 1-3 R19, C3_10cycloalkyl optionally substituted by 1-3 R19, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-10 membered heteroaryl optionally substituted by 1—3 R19, halogen, —CN, —C(=O)R20, —C(=O)NR22R23, —NOg, — NRZZR”, —NR24C(=O)R20, —NR24S(=O)2R21,—OR2°, —S(=O)nR20, and —S(=O)2NR22R23; alternatively, R16 and R17 can, together with the atoms g them, form a 3-10 membered heterocycloalkyl optionally substituted by 1-3 R19 or a 5-10 membered heteroaryl optionally substituted by 1-3 R19.

Embodiment 226. The compound of any of Embodiments 1-215, wherein R17 is H; R16 and R18 are independently chosen from H, C1_6alkyl ally substituted by 1-3 R19, C6_10aryl optionally substituted by 1-3 R19, C7_11arylalkyl optionally substituted by 1-3 R19, C3_1ocycloalkyl optionally substituted by 1-3 R19, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-10 membered heteroaryl ally substituted by 1-3 R19, halogen, —CN, —C(=O)R20, —C(=O)NR22R23, —NOg, —NR22R23, —NR24C(=O)R2°, — NR24S(=O)2R21, —OR20, —S(=O)nR20, and 2NR22R23; alternatively, R16 and R17 can, together with the atoms linking them, form a 3-10 membered heterocycloalkyl optionally substituted by 1-3 R19 or a 5-10 membered heteroaryl ally substituted by 1-3 R19.

Embodiment 227. The nd of any of Embodiments 1-215, wherein R17 is chosen from H and C1_6alkyl; R16 and R18 are ndently chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C6_10aryl, C7_11arylalkyl, C3_10cycloalkyl, 3-10 membered _ 96 _ heterocycloalkyl, 5-10 membered heteroaryl, n, —CN, —C(=O)R20, —C(=O)NR22R23 , —N02, —NR22R23, —NR24C(=O)R20, —NR24S(=O)2R21,—OR2°, —S(=O)nR20, and — S(=O)2NR22R23; alternatively, R16 and R17 can, together with the atoms g them, form a 3-10 membered heterocycloalkyl or a 5-10 membered heteroaryl.

Embodiment 228. The compound of any of Embodiments 1-215, wherein R17 is H; R16 and R18 are independently chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C6_10aryl, C7_11arylalkyl, ycloalkyl, 3-lO membered heterocycloalkyl, 5-10 membered heteroaryl, halogen, —CN, —C(=O)R20, NR22R23, —N02, 23, — NR24C(=O)R2°, —NR24S(=O)2R21, —OR2°, —S(=O)nR2°, and —S(=O)2NR22R23; alternatively, R16 and R17 can, er with the atoms linking them, form a 3-10 membered heterocycloalkyl or a 5-10 membered aryl.

Embodiment 229. The compound of any of Embodiments 1-215, wherein R17 is chosen from H and C1_6alkyl; R16 and R18 are independently chosen from H, C1_6alkyl optionally tuted by 1-3 R19, halogen, —CN, —C(=O)R20, —C(=O)NR22R23, —N02, — , —NR24C(=O)R20, —NR24S(=O)2R21,—OR2°, —S(=O)nR20, and —S(=O)2NR22R23; alternatively, R16 and R17 can, together with the atoms linking them, form a 3-10 membered heterocycloalkyl or a 5-10 membered heteroaryl.

Embodiment 230. The compound of any of Embodiments 1-215, wherein R17 is H; R16 and R18 are independently chosen from H, C1_6alkyl optionally substituted by 1-3 R19, halogen, —CN, —C(=O)R20, NR22R23, —N02, 23, —NR24C(=O)R2°, — NR24S(=O)2R21, —OR20, —S(=O)nR20, and —S(=O)2NR22R23; alternatively, R16 and R17 can, together with the atoms linking them, form a 3-10 membered heterocycloalkyl or a 5-10 membered heteroaryl.

Embodiment 23 l. The compound of any of Embodiments 1-215, wherein R17 is chosen from H and C1_6alkyl; R16 and R18 are independently chosen from H, C1_6alkyl optionally substituted by 1-3 R19, halogen, —CN, —C(=O)R20, —C(=O)NR22R23, —N02, — , —NR24C(=O)R20, —NR24S(=O)2R21,—OR2°, —S(=O)nR20, and —S(=O)2NR22R23.

Embodiment 232. The nd of any of Embodiments 1-215, wherein R17 is H; R16 and R18 are independently chosen from H, C1_6alkyl optionally substituted by 1-3 R19, halogen, —CN, —C(=O)R20, —C(=O)NR22R23, —N02, —NR22R23, —NR24C(=O)R2°, — NR24S(=O)2R21, —OR2°, —S(=O)nR2°, and —S(=O)2NR22R23.

Embodiment 233. The compound of any of Embodiments 1-215, wherein R17 is chosen from H and C1_6alkyl; R16 and R18 are independently chosen from H, C1_6alkyl optionally substituted by 1-3 R19, halogen, and —OR20. _ 97 _ Embodiment 234. The compound of any of Embodiments 1-215, wherein R17 is H; R16 and R18 are independently chosen from H, C1_6alkyl ally substituted by 1-3 R19, halogen, and —OR20. ment 235. The compound of any of Embodiments 1-215, wherein R17 is H; R16 and R18 are independently chosen from H, C1_6alkyl optionally tuted by 1-3 R19, and halogen.

Embodiment 236. The nd of any of Embodiments 1-215, wherein R17 is H; R16 and R18 are independently chosen from H, kyl, and halogen.

Embodiment 237. The compound of any of Embodiments 1-215, wherein R16, R17, and R18 are independently chosen from H and C1_6alkyl.

Embodiment 238. The compound of any of Embodiments 1-215, wherein R17 is chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C2_6alkenyl optionally substituted by 1-11 R19, C2_6alkynyl ally substituted by 1-9 R19, ryl optionally substituted by 1-11 R19, C7_16arylalkyl optionally substituted by 1-19 R19, C3_11cycloalkyl optionally substituted by 1-21 R19, C4_17cycloalkylalkyl ally substituted by 1-32 R19, 3-15 membered cycloalkyl optionally substituted by 1-28 R19, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40 R19, 5-15 membered heteroaryl optionally substituted by 1-15 R19, 6-21 ed heteroarylalkyl optionally substituted by 1-27 R19, and —OR20; R16 and R18 are independently chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C2_6alkenyl optionally substituted by 1-11 R19, C2- 6alkynyl optionally substituted by 1-9 R19, C6_11aryl optionally substituted by 1-11 R19, C7- 16arylalkyl optionally substituted by 1-19 R19, C3_11cycloalkyl optionally substituted by l- 21 R19, ycloalkylalkyl optionally substituted by 1—32 R19, 3—15 membered heterocycloalkyl optionally substituted by 1-28 R19, 4-2l membered cycloalkylalkyl optionally substituted by 1-40 R19, 5-15 membered heteroaryl optionally substituted by l- R19, 6-21 membered heteroarylalkyl optionally substituted by 1-27 R19, halogen, —CN, —C(=O)R2°, —C(=O)OR2°, NR22R23, —N02, 4x11821123, and —OR20; alternatively, R16 and R17 can, together with the atoms linking them, form a 3-15 membered heterocycloalkyl optionally substituted by 1-28 R19 or a 5-15 membered heteroaryl optionally substituted by 1-15 R19.

Embodiment 239. The nd of any of Embodiments 1-215, wherein R17 is chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C2_6alkenyl optionally substituted by 1-11 R19, C2_6alkynyl optionally substituted by 1-9 R19, C6_11aryl optionally substituted by 1-11 R19, C7_16arylalkyl optionally substituted by 1-19 R19, C3_11cycloalkyl _ 98 _ optionally substituted by 1-21 R19, C4_17cycloalkylalkyl optionally substituted by 1-32 R19, 3-15 membered heterocycloalkyl optionally tuted by 1-28 R19, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40 R19, 5-15 membered heteroaryl optionally substituted by 1-15 R19, 6-21 membered heteroarylalkyl ally substituted by 1-27 R19, and —OR20; R16 and R18 are independently chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C2_6alkenyl optionally tuted by 1-11 R19, C2- yl optionally substituted by 1-9 R19, C6_11aryl optionally substituted by 1-11 R19, C7- 16arylalkyl optionally substituted by 1-19 R19, C3_11cycloalkyl optionally substituted by l- 21 R19, C4_17cycloalkylalkyl optionally substituted by 1—32 R19, 3—15 membered heterocycloalkyl optionally substituted by 1-28 R19, 4-2l membered heterocycloalkylalkyl optionally substituted by 1-40 R19, 5-15 membered heteroaryl optionally substituted by l- R19, 6-21 membered arylalkyl optionally substituted by 1-27 R19, halogen, —CN, —C(=O)NR22R23, —N02, 23, and —OR20; alternatively, R16 and R17 can, together with the atoms g them, form a 3-15 membered heterocycloalkyl optionally substituted by 1-28 R19 or a 5-15 membered heteroaryl optionally substituted by 1-15 R19.

Embodiment 240. The compound of any of Embodiments 1-215, wherein R17 is H; R16 and R18 are independently chosen from H and C1_6alkyl optionally substituted by 1—3 R19.

Embodiment 241. The compound of any of Embodiments 1-215, wherein R17 is H; R16 and R18 are independently chosen from H and C1_6alkyl.

Embodiment 242. The compound of any of Embodiments 1-215, wherein R17 is H; R16 and R18 are independently chosen from H and C1_4alkyl.

Embodiment 243. The compound of any of Embodiments 1-215, wherein R17 is H; R16 and R18 are independently chosen from H and C1_3alkyl.

Embodiment 244. The compound of any of Embodiments 1-215, wherein R17 is H; R16 and R18 are independently chosen from H and methyl.

Embodiment 245. The compound of any of Embodiments 1-215, n R16, R17, and R18 are H.

Embodiment 246. The compound of any of Embodiments 1-240, wherein R19 at each occurrence is independently chosen from kyl ally substituted by 1-13 R39, C2_6alkenyl optionally substituted by 1-11 R39, kynyl optionally substituted by l- 9 R39, C6_11aryl optionally substituted by 1-11 R39, C7_16arylalkyl optionally substituted by 1-19 R39, C3_1lcycloalkyl optionally tuted by 1-21 R39, C4_17cycloalkylalkyl _ 99 _ WO 78126 ally substituted by 1-32 R39, 3-15 membered heterocycloalkyl ally substituted by 1-28 R39, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40 R39, 5- membered aryl optionally substituted by 1-15 R39, 6-21 membered heteroarylalkyl optionally substituted by 1-27 R39, halogen, —CN, —C(=O)R30, — C(=O)OR3°, —C(=O)NR32R33, —C(=O)C(=O)R3°, —C(=NR35)R3°, —C(=NR35)NR32R33, — C(=NOH)NR32R33, —C(=N0R36)R3°, —C(=NNR32R33)R3°, —C(=NNR34C(=O)R31)R30, — C(=NNR34C(=0)0R31)R3°, —C(=S)NR32R33, —NC, —N02, —NR32R33, —NR34NR32R33, — N=NR34, =NR30, =N0R30, R36, —NR34C(=0)R3°, —NR34C(=O)C(=O)R3°, — NR34C(=O)OR31, (=O)C(=O)OR31, —NR34C(=O)NR32R33, — NR34C(=O)NR34C(=O)R3°, —NR34C(=O)NR34C(=O)OR3°, —NR34C(=NR35)NR32R33, — NR34C(=O)C(=O)NR32R33, —NR34C(=S)R3°, (=S)0R3°, —NR34C(=S)NR32R33, — NR34S(=O)2R31, —NR34S(=O)2NR32R33, —NR34P(=0)R38R38, — NR34P(=O)(NR32R33)(NR32R33), —NR34P(=O)(OR30)(OR30), —NR34P(=O)(SR30)(SR30), — 0R”, :0, —OCN, —OC(=O)R3°, —OC(=O)NR32R33, —OC(=O)OR3°, —OC(=NR35)NR32R33, —OS(=O)R3°, —OS(=O)2R3°, —OS(=O)20R3°, —OS(=O)2NR32R33, —OP(=O)R38R38, — OP(=O)(NR32R33)(NR32R33), —OP(=O)(OR3°)(OR30), —OP(=O)(SR30)(SR30), —Si(R34)3 — SCN, =s, —S(=O)HR3°, 20R3°, —sogR37, —S(=O)2NR32R33, —S(=O)NR32R33, — SP(=O)R38R38, —SP(=O)(NR32R33)(NR32R33), —SP(=O)(OR30)(OR30), — SP(=O)(SR30)(SR30), —P(=O)R38R38, (NR32R33)(NR32R33), —P(=O)(OR3°)(OR3°), and —P(=O)(SR30)(SR3°).

Embodiment 247. The compound of any of Embodiments 1-240, wherein R19 at each occurrence is independently chosen from C1_6alkyl optionally tuted by 1-6 R39, kenyl optionally substituted by 1-6 R39, C2_6alkynyl optionally substituted by 1-6 R39, C6_11aryl optionally substituted by 1-6 R39, C7_16arylalkyl optionally substituted by 1-6 R39, ycloalkyl optionally substituted by 1-6 R39, C4_17cycloalkylalkyl optionally substituted by 1-6 R39, 3-15 membered heterocycloalkyl optionally substituted by 1-6 R39, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-6 R39, 5-15 membered heteroaryl ally substituted by 1-6 R39, 6-21 membered heteroarylalkyl optionally substituted by 1-6 R39, halogen, —CN, —C(=O)R3°, —C(=O)OR3°, —C(=O)NR32R33, — (=O)R3°, —C(=NR35)R3°, —C(=NR35)NR32R33, —C(=NOH)NR32R33, — C(=N0R36)R3°, —C(=NNR32R33)R3°, —C(=NNR34C(=O)R31)R30, — C(=NNR34C(=0)0R31)R3°, —C(=S)NR32R33, —NC, —N02, —NR32R33, —NR34NR32R33, — N=NR34, =NR30, =N0R30, —NR340R36, —NR34C(=0)R3°, —NR34C(=O)C(=O)R3°, — NR34C(=O)OR31, —NR34C(=O)C(=O)OR31, —NR34C(=O)NR32R33, — - 100 — =O)NR34C(=O)R3°, —NR34C(=O)NR34C(=O)OR3°, —NR34C(=NR35)NR32R33, — NR34C(=O)C(=O)NR32R33, —NR34C(=S)R3°, —NR34C(=S)OR3°, —NR34C(=S)NR32R33, — NR34S(=O)2R31, —NR34S(=O)2NR32R33, —NR34P(=0)R38R38, — NR34P(=O)(NR32R33)(NR32R33), —NR34P(=O)(OR30)(OR30), —NR34P(=O)(SR30)(SR30), — 0R”, =0, —OCN, —OC(=O)R3°, —OC(=O)NR32R33, )OR3°, —OC(=NR35)NR32R33, —OS(=O)R3°, )2R3°, —OS(=O)20R3°, —OS(=O)2NR32R33, —OP(=O)R38R38, — OP(=O)(NR32R33)(NR32R33), —OP(=O)(OR3°)(OR30), )(SR30)(SR30), —Si(R34)3 — SCN, =s, —S(=O)HR3°, —S(=O)20R3°, —sogR37, —S(=O)2NR32R33, —S(=O)NR32R33, — SP(=O)R38R38, )(NR32R33)(NR32R33), —SP(=O)(OR30)(OR30), — SP(=O)(SR30)(SR30), —P(=0)R38R38, —P(=O)(NR32R33)(NR32R33), —P(=O)(OR3°)(OR3°), and —P(=O)(SR30)(SR3°).

Embodiment 248. The compound of any of Embodiments 1-240, n R19 at each occurrence is independently chosen from kyl optionally substituted by 1-6 R39, C2_6alkenyl optionally substituted by 1-6 R39, C2_6alkynyl ally substituted by 1-6 R39, C6_11aryl optionally substituted by 1-6 R39, C7_16arylalkyl optionally substituted by 1-6 R39, C3_11cycloalkyl optionally substituted by 1-6 R39, C4_17cycloalkylalkyl optionally substituted by 1-6 R39, 3-15 membered heterocycloalkyl optionally substituted by 1-6 R39, 4-2l membered cycloalkylalkyl optionally substituted by 1-6 R39, 5-15 membered heteroaryl optionally substituted by 1-6 R39, 6-2l membered heteroarylalkyl optionally substituted by 1-6 R39, halogen, —CN, —C(=O)R30, —C(=O)OR3°, —C(=O)NR32R33, — C(=O)C(=O)R3°, —NC, —N02, 33, —NR34NR32R33, —NR34OR36, —NR34C(=O)R3°, — NR34C(=O)C(=O)R3°, —NR34C(=O)OR31, —NR34C(=O)C(=O)OR31, —NR34C(=O)NR32R33, —NR34C(=O)NR34C(=O)R3°, —NR34C(=O)NR34C(=O)OR3°, —NR34C(=NR35)NR32R33, — =O)C(=O)NR32R33, —NR34S(=O)2R31, —NR34S(=O)2NR32R33, —OR3°, =o, —OCN, — OC(=O)R3°, —OC(=O)NR32R33, —OC(=O)OR3°, —OC(=NR35)NR32R33, —Si(R34)3, —SCN, =s, —S(=O)HR3°, —S(=O)20R3°, —sogR37, —S(=O)2NR32R33, —S(=O)NR32R33, — P(=0)R38R38, —P(=O)(NR32R33)(NR32R33), —P(=O)(OR3°)(OR3°), and —P(=O)(SR3°)(SR30).

Embodiment 249. The compound of any of Embodiments 1-240, wherein R19 at each occurrence is independently chosen from C1_6alkyl optionally substituted by 1-3 R39, C2_6alkenyl optionally tuted by 1-3 R39, C2_6alkynyl optionally substituted by 1-3 R39, C6_11aryl optionally substituted by 1-3 R39, C7_16arylalkyl ally substituted by 1-3 R39, C3_11cycloalkyl optionally substituted by 1-3 R39, C4_17cycloalkylalkyl optionally substituted by 1-3 R39, 3-15 ed heterocycloalkyl ally substituted by 1-3 R39, 4-2l membered heterocycloalkylalkyl optionally substituted by 1-3 R39, 5-15 membered - lOl - heteroaryl optionally substituted by 1-3 R39, 6-21 ed heteroarylalkyl optionally substituted by 1—3 R39, halogen, —CN, —C(=O)R3°, —C(=O)OR3°, —C(=O)NR32R33, — C(=O)C(=O)R3°, —NC, —N02, —NR32R33, —NR34NR32R33, —NR34OR36, —NR34C(=O)R3°, — NR34C(=O)C(=O)R3°, —NR34C(=O)OR31, —NR34C(=O)C(=O)OR31, —NR34C(=O)NR32R33, —NR34C(=O)NR34C(=O)R3°, —NR34C(=O)NR34C(=O)OR3°, —NR34C(=NR35)NR32R33, — NR34C(=O)C(=O)NR32R33, —NR34S(=O)2R31, —NR34S(=O)2NR32R33, —0R3°, =0, —OCN, — OC(=O)R3°, —OC(=O)NR32R33, —OC(=O)OR3°, —OC(=NR35)NR32R33, 4)3, —SCN, =s, —S(=O)HR3°, —S(=O)20R3°, —sogR37, —S(=O)2NR32R33, —S(=O)NR32R33, — P(=O)R38R38, (NR32R33)(NR32R33), —P(=O)(OR3°)(OR3°), and —P(=O)(SR3°)(SR3°).

Embodiment 250. The compound of any of Embodiments 1-240, wherein R19 at each occurrence is independently chosen from C1_6alkyl optionally substituted by 1-3 R39, C2_6alkenyl optionally substituted by 1-3 R39, C2_6alkynyl optionally substituted by 1-3 R39, C6_10aryl optionally substituted by 1-3 R39, C7_11arylalkyl optionally substituted by 1-3 R39, C3_10cycloalkyl optionally substituted by 1-3 R39, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R39, 5-10 membered heteroaryl optionally substituted by 1-3 R39, halogen, —CN, —C(=O)R30, —C(=O)OR30, —C(=O)NR32R33, —C(=O)C(=O)R3°, —NC, — N02, —NR32R33, —NR34NR32R33, —NR340R36, (=0)R30, —NR34C(=0)C(=0)R3°, — NR34C(=O)OR31, —NR34C(=O)C(=O)OR31, —NR34C(=O)NR32R33, — =O)NR34C(=O)R3°, —NR34C(=O)NR34C(=O)OR3°, —NR34C(=NR35)NR32R33, — NR34C(=O)C(=O)NR32R33, —NR34S(=O)2R31, —NR34S(=O)2NR32R33, —0R3°, =o, —OCN, — OC(=O)R3°, )NR32R33, —OC(=O)OR3°, —OC(=NR35)NR32R33, 4)3, —SCN, =s, —S(=O)HR3°, —S(=O)20R3°, —sogR37, —S(=O)2NR32R33, —S(=O)NR32R33, — P(=O)R38R38, (NR32R33)(NR32R33), —P(=O)(OR3°)(OR3°), and —P(=O)(SR3°)(SR3°).

Embodiment 251. The compound of any of Embodiments 1-240, wherein R19 at each occurrence is ndently chosen from C1_6alkyl optionally substituted by 1-3 R39, C2_6alkenyl optionally substituted by 1-3 R39, C2_6alkynyl optionally substituted by 1-3 R39, ryl optionally substituted by 1-3 R39, C7_11arylalkyl optionally substituted by 1-3 R39, C3_10cycloalkyl optionally substituted by 1-3 R39, 3-10 membered heterocycloalkyl ally substituted by 1-3 R39, 5-10 membered heteroaryl ally substituted by 1-3 R39, halogen, —CN, —C(=O)R30, —C(=O)OR30, NR32R33, —N02, —NR32R33, — NR34C(=0)R3°, —NR34C(=O)OR31, (=O)NR32R33, —NR34S(=O)2R31, — NR34S(=O)2NR32R33, —0R3°, =o, )R30, —OC(=O)NR32R33, —Si(R34)3, =s, — S(=O)nR30, —S(=O)20R3°, 7, —S(=O)2NR32R33, —S(=O)NR32R33, —P(=O)R38R38, — P(=O)(NR32R33)(NR32R33), —P(=O)(OR3°)(OR3°), and —P(=O)(SR3°)(SR3°). _ 102 _ Embodiment 252. The compound of any of Embodiments 1-240, wherein R19 at each occurrence is independently chosen from C1_6alkyl optionally substituted by 1-3 R39, C2_6alkenyl optionally substituted by 1-3 R39, C2_6alkynyl optionally substituted by 1-3 R39, C6_10aryl optionally substituted by 1-3 R39, C7_11arylalkyl ally substituted by 1-3 R39, C3_1ocycloalkyl optionally substituted by 1-3 R39, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R39, 5-10 membered heteroaryl optionally substituted by 1-3 R39, halogen, —CN, —C(=O)R30, OR30, —C(=O)NR32R33, —NOg, —NR32R33, — NR34C(=0)R3°, (=O)OR31, —NR34C(=O)NR32R33, —NR34S(=O)2R31, — NR34S(=O)2NR32R33, —0R3°, =o, —OC(=O)R30, —OC(=O)NR32R33, —Si(R34)3, =s, — S(=0),,R30, —S(=O)2NR32R33, and —S(=O)NR32R33.

Embodiment 253. The compound of any of ments 1-240, wherein R19 at each occurrence is independently chosen from C1_6alkyl optionally substituted by 1-3 R39, C2_6alkenyl optionally substituted by 1-3 R39, C2_6alkynyl optionally substituted by 1-3 R39, C6_10aryl optionally substituted by 1-3 R39, C7_11arylalkyl optionally substituted by 1-3 R39, C3_1ocycloalkyl optionally substituted by 1-3 R39, 3-10 ed heterocycloalkyl optionally substituted by 1-3 R39, 5-10 ed heteroaryl optionally substituted by 1-3 R39, halogen, —CN, —C(=O)R30, —C(=O)OR30, —C(=O)NR32R33, —NOg, —NR32R33, — NR34C(=0)R3°, —NR34C(=O)NR32R33, —NR34S(=O)2R31, —NR34S(=O)2NR32R33, —OR3°, =o, —OC(=O)R30, )NR32R33, —Si(R34)3, =s, ,,R3°, and —S(=O)2NR32R33.

Embodiment 254. The compound of any of ments 1-240, wherein R19 at each occurrence is independently chosen from C1_6alkyl optionally substituted by 1-3 R39, C2_6alkenyl optionally substituted by 1-3 R39, C2_6alkynyl ally substituted by 1-3 R39, C6_10aryl optionally substituted by 1-3 R39, rylalkyl optionally substituted by 1-3 R39, C3_6cycloalkyl optionally substituted by 1-3 R39, 3-6 ed heterocycloalkyl optionally substituted by 1-3 R39, 5-6 ed heteroaryl optionally substituted by 1-3 R39, halogen, —CN, —C(=O)R30, —C(=O)OR30, —C(=O)NR32R33, —NOg, —NR32R33, — NR34C(=0)R3°, —NR34C(=O)NR32R33, (=O)2R31, —NR34S(=O)2NR32R33, —OR3°, =o, —OC(=O)R30, —OC(=O)NR32R33, —Si(R34)3, =s, —S(=0),,R3°, and —S(=O)2NR32R33.

Embodiment 255. The compound of any of Embodiments 1-240, wherein R19 at each ence is independently chosen from C1_6alkyl optionally substituted by 1-3 R39, C6_10aryl optionally substituted by 1-3 R39, C7_11arylalkyl ally substituted by 1-3 R39, C3_6cycloalkyl optionally substituted by 1-3 R39, 3-6 membered heterocycloalkyl optionally substituted by 1-3 R39, 5-6 membered heteroaryl optionally substituted by 1-3 R39, halogen, —CN, —C(=O)R30, —C(=O)OR30, —C(=O)NR32R33, —NOg, —NR32R33, — - 103 — NR34C(=O)R3°, —NR34S(=O)2R31, —OR3°, =0, —OC(=O)R3°, —OC(=O)NR32R33, —Si(R34)3, —S(=O)HR30, and —S(=O)2NR32R33.

Embodiment 256. The compound of any of Embodiments 1-240, wherein R19 at each occurrence is independently chosen from C1_6alkyl optionally tuted by 1-3 R39, C6_10aryl optionally substituted by 1-3 R39, C7_11arylalkyl optionally substituted by 1-3 R39, C3_6cycloalkyl optionally substituted by 1-3 R39, 3-6 membered heterocycloalkyl optionally substituted by 1-3 R39, 5-6 membered heteroaryl optionally substituted by 1-3 R39, halogen, —CN, —C(=O)R30, —C(=O)NR32R33, —NR32R33, —NR34C(=O)R3°, — NR34S(=O)2R31, —0R3°, =o, —S(=O)HR3°, and —S(=O)2NR32R33.

Embodiment 257. The compound of any of Embodiments 1-240, wherein R19 at each occurrence is independently chosen from C1_6alkyl optionally substituted by 1-3 R39, C6_10aryl optionally substituted by 1-3 R39, C7_11arylalkyl optionally substituted by 1-3 R39, C3_6cycloalkyl optionally substituted by 1-3 R39, 3-6 ed heterocycloalkyl ally substituted by 1-3 R39, 5-6 membered heteroaryl optionally substituted by 1-3 R39, halogen, —CN, —C(=O)R30, —C(=O)NR32R33, —NR32R33, —NR34C(=O)R30, —OR30, and ment 258. The compound of any of Embodiments 1-240, wherein R19 at each occurrence is independently chosen from C1_6alkyl, C6_10aryl, C7_11arylalkyl, C3- alkyl, 3-6 membered heterocycloalkyl, 5-6 ed heteroaryl, halogen, —CN, — C(=O)R3°, —C(=O)NR32R33, —NR32R33, —NR34C(=O)R30, —OR3°, and :0.

Embodiment 259. The compound of any of Embodiments 1-240, n R19 at each occurrence is independently chosen from C1_6alkyl, C6_10aryl, C7_11arylalkyl, C3- alkyl, 3-6 membered cycloalkyl, 5-6 membered heteroaryl, halogen, — C(=O)R3°, —C(=O)OR3°, —C(=O)NR32R33, —NR32R33, and —OR30.

Embodiment 260. The compound of any of Embodiments 1-240, wherein R19 at each ence is independently chosen from C1_6alkyl optionally substituted by 1-13 R39, C2_6alkenyl optionally substituted by 1-11 R39, kynyl optionally substituted by l- 9 R39, ryl ally substituted by 1-11 R39, C7_16arylalkyl optionally substituted by 1-19 R39, C3_11cycloalkyl optionally substituted by 1-21 R39, C4_17cycloalkylalkyl optionally tuted by 1-32 R39, 3-15 membered heterocycloalkyl ally substituted by 1-28 R39, 4-2l membered heterocycloalkylalkyl optionally substituted by 1-40 R39, 5- l5 membered heteroaryl optionally substituted by 1-15 R39, 6-2l membered heteroarylalkyl optionally substituted by 1—27 R39, halogen, —CN, —C(=O)NR32R33, —NOg, —NR32R33, and —OR3°. — 104 — Embodiment 261. The compound of any of Embodiments 1-240, wherein R19 at each occurrence is independently chosen from C1_6alkyl optionally substituted by 1-13 R39.

Embodiment 262. The compound of any of Embodiments 1-240, wherein R19 at each occurrence is independently chosen from C1_6alkyl optionally substituted by 1-3 R39, C6_10aryl optionally substituted by 1-3 R39, C3_6cycloalkyl optionally substituted by l- 3 R39, 3-6 ed heterocycloalkyl optionally substituted by 1-3 R39, 5-6 membered heteroaryl optionally tuted by 1-3 R39, halogen, —C(=O)OR30, —NR32R33, and —OR30.

Embodiment 263. The nd of any of Embodiments 1-240, wherein R19 at each occurrence is independently chosen from kyl ally substituted by 1-3 R39, phenyl optionally substituted by 1-3 R39, C3_6cycloalkyl optionally substituted by 1-3 R39, 3-6 membered heterocycloalkyl optionally substituted by 1-3 R39, 5-6 membered heteroaryl optionally tuted by 1-3 R39, halogen, —C(=O)OR30, —NR32R33, and —OR30.

Embodiment 264. The compound of any of Embodiments 1-240, wherein R19 at each occurrence is independently chosen from C1_6alkyl, phenyl optionally tuted by 1-3 R39, C3_6cycloalkyl, 3-6 membered heterocycloalkyl optionally substituted by 1-3 R39, 5-6 membered heteroaryl, halogen, —C(=O)OR30, —NR32R33, and —OR30.

Embodiment 265. The nd of any of Embodiments 1-240, wherein R19 at each occurrence is independently chosen from C1_6alkyl, phenyl optionally substituted by 1 R39, C3_6cycloalkyl, 3-6 membered heterocycloalkyl optionally substituted by 1 R39, -6 membered heteroaryl, halogen, —C(=O)OR30, 33, and —OR30.

Embodiment 266. The compound of any of Embodiments 1-240, wherein R19 at each occurrence is independently chosen from C1_6alkyl, phenyl, C3_6cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halogen, —C(=O)OR30, 33, and —OR30.

Embodiment 267. The compound of any of Embodiments l-266, wherein R20, R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H, C1_6alkyl optionally substituted by 1-6 R49, C2_6alkenyl optionally substituted by 1-6 R49, C2_6alkynyl optionally tuted by 1-6 R49, C6_11aryl optionally substituted by 1-6 R49, C7_16arylalkyl optionally substituted by 1-6 R49, ycloalkyl optionally substituted by 1-6 R49, C4_17cycloalkylalkyl optionally substituted by 1-6 R49, 3- l5 membered heterocycloalkyl optionally substituted by 1-6 R49, 4-2l membered heterocycloalkylalkyl ally tuted by 1-6 R49, 5-15 membered heteroaryl optionally substituted by l-6 R49, and 6-21 membered heteroarylalkyl optionally tuted by 1-6 R49.

Embodiment 268. The compound of any of Embodiments l-266, wherein R20, R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H, C1_6alkyl ally substituted by l-6 R49, C2_6alkenyl optionally substituted by l-6 R49, C2_6alkynyl optionally substituted by l-6 R49, C6_10aryl optionally substituted by l-6 R49, C7_11arylalkyl ally substituted by l-6 R49, C3_10cycloalkyl optionally substituted by l-6 R49, 3-10 membered heterocycloalkyl optionally substituted by 1-6 R49, and 5-10 membered heteroaryl optionally substituted by l-6 R49.

Embodiment 269. The compound of any of Embodiments l-266, wherein R20, R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H, C1_6alkyl optionally substituted by 1-3 R49, C2_6alkenyl ally substituted by l-3 R49, C2_6alkynyl optionally substituted by 1-3 R49, C6_10aryl optionally substituted by l-3 R49, C7_11arylalkyl ally substituted by 1-3 R49, C3_10cycloalkyl optionally substituted by 1-3 R49, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R49, and 5-10 membered heteroaryl optionally substituted by 1-3 R49.

Embodiment 270. The compound of any of Embodiments l-266, wherein R20, R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H, C1_6alkyl optionally substituted by 1-3 R49, C6_10aryl optionally substituted by 1-3 R49, C7_11arylalkyl ally substituted by 1-3 R49, C3_10cycloalkyl optionally substituted by 1-3 R49, 3-10 membered heterocycloalkyl optionally tuted by 1-3 R49, and 5-10 ed heteroaryl optionally substituted by 1-3 R49.

Embodiment 271. The compound of any of Embodiments l-266, wherein R20, R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H, C1_6alkyl optionally substituted by 1-3 R49, C6_10aryl optionally substituted by 1-3 R49, C7_11arylalkyl optionally substituted by 1-3 R49, C3_6cycloalkyl ally substituted by 1-3 R49, 3-6 membered heterocycloalkyl optionally substituted by 1-3 R49, and 5-6 membered heteroaryl ally tuted by 1-3 R49.

Embodiment 272. The compound of any of Embodiments l-266, wherein R20, R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is ndently chosen from H, C1_6alkyl optionally substituted by 1-3 R49, phenyl optionally substituted by 1-3 R49, benzyl optionally substituted by 1-3 R49, C3_6cycloalkyl optionally substituted by 1-3 R49, 3-6 membered heterocycloalkyl optionally tuted by 1-3 R49, and 5-6 membered heteroaryl optionally substituted by 1-3 R49.

Embodiment 273. The compound of any of Embodiments l-266, wherein R20, R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H, kyl optionally substituted by l-3 R49, phenyl optionally substituted by 1-3 R49, benzyl optionally substituted by 13 R49, C3_6cycloalkyl, 3-6 membered heterocycloalkyl, and 5-6 ed heteroaryl.

Embodiment 274. The compound of any of Embodiments l-266, wherein R20 at each occurrence is independently chosen from H, C1_6alkyl ally substituted by l-3 R49, phenyl ally substituted by l-3 R49, benzyl optionally substituted by l-3 R49, C3- 6cycloalkyl, 3-6 membered heterocycloalkyl, and 5-6 membered heteroaryl; R21, R24, R25 , R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H and C1_6alkyl optionally substituted by l-3 R49. ment 275. The compound of any of Embodiments l-266, wherein R20 at each occurrence is independently chosen from H, C1_6alkyl optionally substituted by l-3 R49, phenyl optionally substituted by l-3 R49, benzyl ally substituted by l-3 R49, C3- 6cycloalkyl, 3-6 membered heterocycloalkyl, and 5-6 membered heteroaryl; R21, R24, R25 , R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H and C1_6alkyl.

Embodiment 276. The compound of any of Embodiments l-266, wherein R20 at each occurrence is independently chosen from H, C1_6alkyl optionally substituted by l-3 R49, phenyl optionally substituted by l-3 R49, benzyl optionally substituted by l-3 R49, C3- 6cycloalkyl, 3-6 membered cycloalkyl, and 5-6 membered aryl; R21, R24, R25 , R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is H.

Embodiment 277. The compound of any of Embodiments l-266, wherein R20, R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H and C1_6alkyl optionally substituted by l-6 R49.

Embodiment 278. The compound of any of Embodiments l-266, n R20, R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H and C1_6alkyl.

Embodiment 279. The compound of any of Embodiments l-266, wherein R20, R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H, C1_6alkyl optionally substituted by l-3 R49, C6_10aryl optionally substituted by l-3 R49, cloalkyl optionally tuted by l-3 R49, 3-6 ed heterocycloalkyl optionally substituted by l-3 R49, and 5-6 membered heteroaryl optionally substituted by l-3 R49.

Embodiment 280. The compound of any of Embodiments l-266, wherein R20 R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H, C6_10aryl optionally substituted by l-3 R49, cloalkyl optionally tuted by l-3 R49, 3-6 membered heterocycloalkyl optionally substituted by l-3 R49, and 5-6 ed heteroaryl optionally substituted by l-3 R49.

Embodiment 28 l. The compound of any of Embodiments l-266, wherein R20 R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H, C1_6alkyl optionally substituted by l-3 R49, phenyl optionally substituted by l-3 R49, C3_6cycloalkyl optionally tuted by l-3 R49, 5-6 membered cycloalkyl optionally substituted by l-3 R49, and 5-6 membered heteroaryl optionally substituted by l-3 R49.

Embodiment 282. The compound of any of Embodiments l-266, wherein R20 R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H, phenyl optionally substituted by l-3 R49, C3_6cycloalkyl optionally substituted by l-3 R49, 5-6 membered heterocycloalkyl ally substituted by l-3 R49, and 5-6 membered heteroaryl ally substituted by l-3 R49.

Embodiment 283. The compound of any of Embodiments l-266, wherein R20 R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H, kyl, phenyl optionally substituted by l-3 R49, C3_6cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl.

Embodiment 284. The compound of any of Embodiments l-266, wherein R20 R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H, phenyl ally substituted by l-3 R49, C3_6cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl.

Embodiment 285. The compound of any of Embodiments l-266, wherein R20 R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H, C1_6alkyl, phenyl optionally substituted by l-3 R49, cyclopropyl, 5 membered heterocycloalkyl, and 5 membered heteroaryl.

Embodiment 286. The compound of any of Embodiments l-266, wherein R20 R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H, phenyl optionally substituted by l-3 R49, cyclopropyl, 5 ed heterocycloalkyl, and 5 membered aryl.

Embodiment 287. The compound of any of Embodiments l-266, wherein R20 R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H, C1_6alkyl, phenyl optionally substituted by 1 R49, C3_6cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl.

Embodiment 288. The compound of any of ments 1-266, wherein R20, R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H, phenyl optionally substituted by 1 R49, C3_6cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered aryl.

Embodiment 289. The compound of any of Embodiments 1-266, wherein R20, R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H, C1_6alkyl, phenyl, C3_6cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl.

Embodiment 290. The compound of any of ments 1-266, wherein R20, R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is ndently chosen from H, phenyl, C3_6cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered aryl.

Embodiment 291. The compound of any of Embodiments 1-266, wherein R20, R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H, C1_6alkyl, phenyl, cyclopropyl, 5 membered heterocycloalkyl, and 5 membered heteroaryl.

Embodiment 292. The compound of any of Embodiments 1-266, wherein R20, R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H, phenyl, cyclopropyl, 5 membered heterocycloalkyl, and 5 membered heteroaryl. ment 293. The compound of any of Embodiments 1-266, n R20 at each occurrence is independently chosen from H, C1_6alkyl optionally substituted by 1-3 R49, C6_10aryl optionally substituted by 1-3 R49, C3_6cycloalkyl optionally substituted by l- 3 R49, 3-6 membered heterocycloalkyl optionally substituted by 1-3 R49, and 5-6 membered heteroaryl optionally substituted by 1-3 R49; R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H and C1_6alkyl ally substituted by 1-3 R49.

Embodiment 294. The compound of any of ments 1-266, wherein R20 at each occurrence is independently chosen from H, C6_1oaryl optionally substituted by 1-3 R49, C3_6cycloalkyl optionally substituted by 1-3 R49, 3-6 ed heterocycloalkyl ally substituted by 1-3 R49, and 5-6 membered heteroaryl optionally substituted by -lO9- 1—3 R49; R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H and C1_6alkyl optionally tuted by 1-3 R49.

Embodiment 295. The compound of any of Embodiments 1-266, wherein R20 at each occurrence is independently chosen from H, C1_6alkyl optionally substituted by 1-3 R49, phenyl optionally substituted by 1-3 R49, C3_6cycloalkyl optionally tuted by 1-3 R49, 5-6 membered heterocycloalkyl optionally substituted by 1-3 R49, and 5-6 membered heteroaryl optionally substituted by 1-3 R49; R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is ndently chosen from H and C1_6alkyl optionally substituted by 1—3 R49.

Embodiment 296. The compound of any of ments 1-266, wherein R20 at each occurrence is independently chosen from H, phenyl optionally substituted by 1-3 R49, C3_6cycloalkyl optionally substituted by 1-3 R49, 5-6 membered heterocycloalkyl optionally substituted by 1-3 R49, and 5-6 membered heteroaryl optionally substituted by 1—3 R49; R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H and C1_6alkyl optionally substituted by 1-3 R49. ment 297. The compound of any of Embodiments 1-266, n R20 at each occurrence is independently chosen from H, C1_6alkyl, phenyl optionally substituted by 1-3 R49, C3_6cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl; R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H and C1_6alkyl optionally tuted by 1-3 R49.

Embodiment 298. The compound of any of Embodiments 1-266, wherein R20 at each occurrence is independently chosen from H, phenyl optionally substituted by 1-3 R49, C3_6cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl; R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H and C1_6alkyl optionally substituted by 1-3 R49.

Embodiment 299. The compound of any of Embodiments 1-266, wherein R20 at each occurrence is independently chosen from H, C1_6alkyl, phenyl ally substituted by 1-3 R49, cyclopropyl, 5 membered heterocycloalkyl, and 5 membered heteroaryl; R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is ndently chosen from H and C1_6alkyl optionally tuted by 1-3 R49.

Embodiment 300. The compound of any of Embodiments 1-266, n R20 at each occurrence is independently chosen from H, phenyl optionally substituted by 1-3 R49, cyclopropyl, 5 membered cycloalkyl, and 5 membered heteroaryl; R21, R24, R25 , -llO- R26, R27, R30, R31, R34, R35, R36 and R37 at each ence is ndently chosen from H and C1_6alkyl optionally substituted by 1-3 R49.

Embodiment 301. The compound of any of Embodiments 1-266, wherein R20 at each occurrence is independently chosen from H, C1_6alkyl, phenyl optionally substituted by 1 R49, C3_6cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl; R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H and C1_6alkyl optionally substituted by 1-3 R49.

Embodiment 302. The compound of any of Embodiments 1-266, wherein R20 at each occurrence is independently chosen from H, phenyl optionally substituted by 1 R49, cloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl; R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H and C1_6alkyl optionally tuted by 1-3 R49.

Embodiment 303. The compound of any of Embodiments 1-266, wherein R20 at each occurrence is independently chosen from H, C1_6alkyl, phenyl, C3_6cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl; R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H and C1_6alkyl optionally substituted by 1-3 R49. ment 304. The nd of any of Embodiments 1-266, wherein R20 at each occurrence is independently chosen from H, phenyl, C3_6cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 ed heteroaryl; R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H and C1_6alkyl optionally substituted by 1—3 R49.

Embodiment 305. The compound of any of ments 1-266, wherein R20 at each occurrence is independently chosen from H, C1_6alkyl, phenyl, cyclopropyl, 5 membered heterocycloalkyl, and 5 membered heteroaryl; R21, R24, R25 , R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H and C1_6alkyl optionally substituted by 1-3 R49.

Embodiment 306. The compound of any of Embodiments 1-266, n R20 at each occurrence is independently chosen from H, phenyl, cyclopropyl, 5 membered heterocycloalkyl, and 5 ed heteroaryl; R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H and C1_6alkyl optionally substituted by 1—3 R49.

Embodiment 307. The compound of any of Embodiments 1-266, n R20 at each occurrence is ndently chosen from H, C1_6alkyl optionally substituted by 1-3 - lll - R49, C6_10aryl optionally substituted by l-3 R49, C3_6cycloalkyl ally substituted by l- 3 R49, 3-6 membered heterocycloalkyl optionally substituted by 1-3 R49, and 5-6 membered heteroaryl optionally substituted by 1-3 R49; R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H and C1_6alkyl.

Embodiment 308. The compound of any of Embodiments 1-266, wherein R20 at each occurrence is independently chosen from H, C6_1oaryl optionally substituted by l-3 R49, C3_6cycloalkyl optionally substituted by l-3 R49, 3-6 membered heterocycloalkyl optionally substituted by l-3 R49, and 5-6 membered aryl optionally substituted by 13 R49; R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each ence is independently chosen from H and C1_6alkyl.

Embodiment 309. The compound of any of Embodiments 1-266, wherein R20 at each occurrence is independently chosen from H, C1_6alkyl optionally substituted by l-3 R49, phenyl optionally substituted by l-3 R49, C3_6cycloalkyl optionally substituted by l-3 R49, 5-6 membered heterocycloalkyl ally substituted by l-3 R49, and 5-6 membered heteroaryl optionally substituted by l-3 R49; R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H and C1_6alkyl.

Embodiment 310. The compound of any of Embodiments l-266, wherein R20 at each occurrence is ndently chosen from H, phenyl optionally substituted by l-3 R49, C3_6cycloalkyl optionally tuted by l-3 R49, 5-6 membered heterocycloalkyl ally substituted by l-3 R49, and 5-6 membered heteroaryl optionally substituted by 13 R49; R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H and kyl.

Embodiment 3 l l. The compound of any of Embodiments l-266, wherein R20 at each occurrence is independently chosen from H, C1_6alkyl, phenyl optionally substituted by l-3 R49, C3_6cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl; R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H and C1_6alkyl.

Embodiment 312. The compound of any of Embodiments l-266, wherein R20 at each occurrence is independently chosen from H, phenyl optionally substituted by l-3 R49, C3_6cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl; R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is ndently chosen from H and C1_6alkyl. ment 3 13. The compound of any of Embodiments l-266, wherein R20 at each occurrence is independently chosen from H, kyl, phenyl optionally 2012/065831 substituted by 1-3 R49, cyclopropyl, 5 membered heterocycloalkyl, and 5 membered heteroaryl; R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H and C1_6alkyl.

Embodiment 314. The nd of any of Embodiments 1-266, n R20 at each occurrence is independently chosen from H, phenyl ally substituted by 1-3 R49, cyclopropyl, 5 membered heterocycloalkyl, and 5 membered heteroaryl; R21, R24, R25 , R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H and C1_6alkyl.

Embodiment 315. The compound of any of Embodiments 1-266, wherein R20 at each occurrence is independently chosen from H, C1_6alkyl, phenyl optionally substituted by 1 R49, C3_6cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl; R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H and C1_6alkyl.

Embodiment 3 16. The compound of any of Embodiments 1-266, wherein R20 at each occurrence is independently chosen from H, phenyl optionally substituted by 1 R49, C3_6cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered aryl; R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H and C1_6alkyl.

Embodiment 3 17. The compound of any of ments 1-266, wherein R20 at each occurrence is independently chosen from H, C1_6alkyl, phenyl, C3_6cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl; R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H and C1- 6alkyl.

Embodiment 318. The compound of any of Embodiments 1-266, wherein R20 at each occurrence is independently chosen from H, phenyl, C3_6cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered aryl; R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H and C1_6alkyl.

Embodiment 3 19. The nd of any of Embodiments 1-266, wherein R20 at each occurrence is ndently chosen from H, kyl, phenyl, cyclopropyl, 5 membered heterocycloalkyl, and 5 membered heteroaryl; R21, R24, R25 , R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H and C1_6alkyl.

Embodiment 320. The compound of any of Embodiments 1-266, wherein R20 at each occurrence is independently chosen from H, phenyl, ropyl, 5 membered -ll3- 2012/065831 heterocycloalkyl, and 5 membered aryl; R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H and C1_6alkyl.

Embodiment 321. The compound of any of Embodiments 1-266, wherein R20 at each occurrence is ndently chosen from H, C1_6alkyl optionally substituted by 1-3 R49, C6_10aryl ally substituted by 1-3 R49, C3_6cycloalkyl optionally substituted by 1- 3 R49, 3-6 membered heterocycloalkyl optionally substituted by 1-3 R49, and 5-6 membered aryl optionally substituted by 1-3 R49; R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is H.

Embodiment 322. The compound of any of Embodiments 1-266, wherein R20 at each occurrence is independently chosen from H, C6_1Oaryl optionally substituted by 1-3 R49, C3_6cycloalkyl optionally substituted by 1-3 R49, 3-6 membered heterocycloalkyl optionally substituted by 1-3 R49, and 5-6 membered heteroaryl optionally substituted by 13 R49; R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is H.

Embodiment 323. The compound of any of Embodiments 1-266, wherein R20 at each occurrence is independently chosen from H, C1_6alkyl optionally tuted by 1-3 R49, phenyl optionally substituted by 1-3 R49, C3_6cycloalkyl optionally substituted by 1-3 R49, 5-6 membered heterocycloalkyl optionally substituted by 1-3 R49, and 5-6 membered heteroaryl optionally substituted by 1-3 R49; R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is H.

Embodiment 324. The compound of any of Embodiments 1-266, wherein R20 at each occurrence is independently chosen from H, phenyl optionally substituted by 1-3 R49, C3_6cycloalkyl optionally tuted by 1-3 R49, 5-6 membered heterocycloalkyl optionally substituted by 1-3 R49, and 5-6 membered aryl optionally substituted by 13 R49; R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is H.

Embodiment 325. The nd of any of ments 1-266, wherein R20 at each occurrence is independently chosen from H, C1_6alkyl, phenyl optionally substituted by 1-3 R49, C3_6cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl; R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each ence is H.

Embodiment 326. The compound of any of Embodiments 1-266, wherein R20 at each ence is independently chosen from H, phenyl optionally substituted by 1-3 R49, C3_6cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl; R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is H. ment 327. The compound of any of Embodiments 1-266, wherein R20 at each occurrence is independently chosen from H, C1_6alkyl, phenyl optionally substituted by 1-3 R49, cyclopropyl, 5 membered heterocycloalkyl, and 5 membered heteroaryl; R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is H.

Embodiment 328. The compound of any of Embodiments 1-266, wherein R20 at each occurrence is independently chosen from H, phenyl optionally substituted by 1-3 R49, cyclopropyl, 5 ed heterocycloalkyl, and 5 membered heteroaryl; R21, R24, R25 , R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is H.

Embodiment 329. The nd of any of Embodiments 1-266, wherein R20 at each occurrence is independently chosen from H, C1_6alkyl, phenyl optionally substituted by 1 R49, C3_6cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl; R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is H.

Embodiment 330. The compound of any of Embodiments 1-266, wherein R20 at each occurrence is independently chosen from H, phenyl optionally substituted by 1 R49, C3_6cycloalkyl, 5-6 ed heterocycloalkyl, and 5-6 membered heteroaryl; R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each ence is H. ment 33 l. The compound of any of Embodiments 1-266, wherein R20 at each ence is independently chosen from H, C1_6alkyl, phenyl, C3_6cycloalkyl, 5-6 ed heterocycloalkyl, and 5-6 membered heteroaryl; R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is H. ment 332. The compound of any of Embodiments 1-266, wherein R20 at each occurrence is independently chosen from H, phenyl, C3_6cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl; R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is H.

Embodiment 333. The nd of any of ments 1-266, wherein R20 at each occurrence is independently chosen from H, C1_6alkyl, phenyl, cyclopropyl, 5 membered heterocycloalkyl, and 5 membered heteroaryl; R21, R24, R25 , R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is H.

Embodiment 334. The compound of any of Embodiments 1-266, wherein R20 at each occurrence is independently chosen from H, phenyl, cyclopropyl, 5 membered heterocycloalkyl, and 5 membered aryl; R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is H.

Embodiment 335. The compound of any of Embodiments 1-266, wherein R20, 21 24 25 26 27 30 31 34 35 36 R ,R ,R ,R ,R ,R ,R ,R ,R ,R andR37ateachoccurrence1sH.- -llS- Embodiment 336. The compound of any of Embodiments 1-335, wherein R28 and R38 at each occurrence is independently chosen from C1_6alkyl optionally substituted by 1-13 R49, C2_6alkenyl optionally substituted by 1-11 R49, C2_6alkynyl optionally substituted by 1-9 R49, C6_11aryl optionally substituted by 1-11 R49, C7_16arylalkyl optionally substituted by 1-19 R49, C3_11cycloalkyl optionally substituted by 1-21 R49, C4- 17cycloalkylalkyl optionally substituted by 1-32 R49, 3-15 membered cycloalkyl optionally substituted by 1-28 R49, 4-21 ed heterocycloalkylalkyl ally substituted by 1-40 R49, 5-15 membered heteroaryl optionally tuted by 1-15 R49, and 6-21 ed heteroarylalkyl optionally substituted by 1-27 R49.

Embodiment 337. The compound of any of Embodiments 1-335, wherein R28 and R38 at each occurrence is independently chosen from kyl optionally tuted by 1-3 R49, C2_6alkenyl ally substituted by 1-3 R49, C2_6alkynyl optionally substituted by 1-3 R49, ryl optionally substituted by 1-3 R49, C7_16arylalkyl optionally substituted by 1—3 R49, C3_1lcycloalkyl optionally substituted by 1—3 R49, C4_17cycloalkylalkyl optionally substituted by 1-3 R49, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R49, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-3 R49, 5-15 membered heteroaryl optionally substituted by 1-3 R49, and 6-21 membered heteroarylalkyl optionally substituted by 1-3 R49.

Embodiment 338. The compound of any of Embodiments 1-335, wherein R28 and R38 at each occurrence is independently chosen from C1_6alkyl optionally substituted by 1-3 R49, C2_6alkenyl optionally substituted by 1-3 R49, C2_6alkynyl optionally substituted by 1-3 R49, C6_10aryl ally substituted by 1-3 R49, C7_11arylalkyl optionally substituted by 1-3 R49, C3_10cycloalkyl optionally substituted by 1-3 R49, 3-10 membered heterocycloalkyl ally substituted by 1-3 R49, and 5-10 membered heteroaryl optionally substituted by 1-3 R49.

Embodiment 339. The compound of any of Embodiments 1-335, wherein R28 and R38 at each occurrence is independently chosen from C1_6alkyl optionally substituted by 1-3 R49, C6_10aryl optionally substituted by 1-3 R49, C7_11arylalkyl optionally substituted by 1-3 R49, C3_10cycloalkyl ally substituted by 1-3 R49, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R49, and 5-10 membered heteroaryl optionally substituted by 1-3 R49. ment 340. The compound of any of Embodiments 1-335, wherein R28 and R38 at each occurrence is independently chosen from C1_6alkyl, C6_10aryl, C7_ -ll6- 11arylalkyl, C3_10cycloalkyl, 3-10 membered heterocycloalkyl, and 5-10 membered heteroaryl.

Embodiment 341. The compound of any of Embodiments 1-335, wherein R28 and R38 at each occurrence is ndently chosen from C1_6alkyl, ryl, and C7_ 11arylalkyl.

Embodiment 342. The compound of any of Embodiments 1-335, wherein R28 and R38 at each occurrence is independently chosen from C1_6alkyl, phenyl, and benzyl. ment 343. The compound of any of Embodiments 1-335, wherein R28 and R38 at each ence is independently chosen from C1_6alkyl and C6_10aryl.

Embodiment 344. The compound of any of Embodiments 1-335, wherein R28 and R38 at each occurrence is independently chosen from C1_6alkyl and phenyl.

Embodiment 345. The compound of any of Embodiments 1-335, wherein R28 and R38 at each occurrence is C1_6alkyl optionally substituted by 1-3 R49.

Embodiment 346. The compound of any of Embodiments 1-335, wherein R28 and R38 at each occurrence is C1_6alkyl.

Embodiment 347. The compound of any of Embodiments 1-346, wherein R22, R23, R32 and R33 at each occurrence is ndently chosen from H, C1_6alkyl optionally substituted by 1-13 R59, C2_6alkenyl optionally substituted by 1-11 R59, C2_6alkynyl optionally substituted by 1-9 R59, C6_11aryl optionally substituted by 1-11 R59, C7- 16arylalkyl optionally substituted by 1-19 R59, C3_11cycloalkyl optionally tuted by 1- 21 R59, C4_17cycloalkylalkyl optionally substituted by 132 R59, 345 membered heterocycloalkyl optionally tuted by 1-28 R59, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40 R59, 5-15 membered heteroaryl optionally substituted by 1- 15 R59, and 6-21 membered heteroarylalkyl optionally substituted by 1-27 R59; alternatively, any R22 and R23 and/or R32 and R33 may form, together with the nitrogen atom to which they are attached, a 3-15 membered cycloalkyl optionally substituted by 1-28 R69 or a 5-15 membered heteroaryl optionally substituted by 1-15 R69. ment 348. The compound of any of ments 1-346, wherein R22, R23, R32 and R33 at each occurrence is independently chosen from H, C1_6alkyl optionally substituted by 1-3 R59, C2_6alkenyl optionally substituted by 1-3 R59, C2_6alkynyl optionally substituted by 1-3 R59, ryl optionally substituted by 1-3 R59, C7_16arylalkyl optionally substituted by 1-3 R59, C3_11cycloalkyl optionally substituted by 1-3 R59, C4_ 17cycloalkylalkyl optionally substituted by 1-3 R59, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R59, 4-21 membered heterocycloalkylalkyl ally substituted by 1-3 R59, 5-15 membered heteroaryl optionally substituted by 1-3 R59, and 6- 21 membered heteroarylalkyl optionally tuted by 1-3 R59; alternatively, any R22 and R23 and/or R32 and R33 may form, together with the nitrogen atom to which they are attached, a 3-15 membered heterocycloalkyl optionally substituted by 1-3 R69 or a 5-15 membered aryl optionally substituted by 1-3 R69.

Embodiment 349. The nd of any of Embodiments 1-346, wherein R22, R23, R32 and R33 at each occurrence is independently chosen from H, C1_6alkyl optionally substituted by 1-3 R59, C2_6alkenyl optionally substituted by 1-3 R59, C2_6alkynyl optionally substituted by 1-3 R59, C6_10aryl optionally substituted by 1-3 R59, C7_11arylalkyl ally substituted by 1-3 R59, C3_10cycloalkyl optionally substituted by 1-3 R59, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R59, and 5-10 membered heteroaryl optionally tuted by 1-3 R59; alternatively, any R22 and R23 and/or R32 and R33 may form, together with the nitrogen atom to which they are attached, a 3-10 membered heterocycloalkyl optionally substituted by 1-3 R69 or a 5-10 membered heteroaryl optionally substituted by 1-3 R69.

Embodiment 350. The nd of any of ments 1-346, wherein R22, R23, R32 and R33 at each ence is independently chosen from H, C1_6alkyl optionally substituted by 1-3 R59, C2_6alkenyl ally substituted by 1-3 R59, C2_6alkynyl optionally substituted by 1-3 R59, C6_10aryl optionally substituted by 1-3 R59, C7_11arylalkyl optionally substituted by 1-3 R59, C3_10cycloalkyl optionally substituted by 1-3 R59, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R59, and 5-10 membered heteroaryl optionally substituted by 1-3 R59.

Embodiment 35 l. The compound of any of Embodiments 1-346, n R22, R23, R32 and R33 at each occurrence is independently chosen from H, C1_6alkyl optionally substituted by 1-3 R59, C6_10aryl optionally tuted by 1-3 R59, C7_11arylalkyl optionally tuted by 1-3 R59, C3_10cycloalkyl optionally substituted by 1-3 R59, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R59, and 5-10 membered heteroaryl optionally substituted by 1-3 R59; alternatively, any R22 and R23 and/or R32 and R33 may form, together with the en atom to which they are attached, a 3-10 membered heterocycloalkyl optionally substituted by 1-3 R69 or a 5-10 ed heteroaryl optionally substituted by 1-3 R69.

Embodiment 352. The compound of any of Embodiments 1-346, wherein R22, R23, R32 and R33 at each occurrence is independently chosen from H, C1_6alkyl optionally substituted by 1-3 R59, C6_10aryl optionally substituted by 1-3 R59, C7_11arylalkyl optionally substituted by 1-3 R59, C3_10cycloalkyl optionally tuted by 1-3 R59, 3-10 membered cycloalkyl optionally substituted by 1-3 R59, and 5-10 ed heteroaryl optionally substituted by 1-3 R59.

Embodiment 353. The compound of any of Embodiments 1-346, wherein R22, R23, R32 and R33 at each occurrence is independently chosen from H, C1_6alkyl, C6_10aryl, rylalkyl, C3_10cycloalkyl, 3-10 membered heterocycloalkyl, and 5-10 membered aryl; alternatively, any R22 and R23 and/or R32 and R33 may form, together with the en atom to which they are attached, a 3-lO membered heterocycloalkyl or a 5-10 membered heteroaryl.

Embodiment 354. The compound of any of Embodiments 1-346, wherein R22, R23, R32 and R33 at each occurrence is independently chosen from H, C1_6alkyl, ryl, C7_11arylalkyl, ycloalkyl, 3-10 membered heterocycloalkyl, and 5-10 membered heteroaryl.

Embodiment 355. The compound of any of Embodiments 1-346, wherein R22, R23, R32 and R33 at each ence is independently chosen from H, C1_6alkyl optionally substituted by 1-3 R59, C6_1oaryl optionally substituted by 1-3 R59, and 5-10 membered aryl optionally substituted by 1-3 R59.

Embodiment 356. The compound of any of Embodiments 1-346, wherein R22, R23, R32 and R33 at each occurrence is independently chosen from H, ryl optionally substituted by 1-3 R59, and 5-10 membered heteroaryl optionally substituted by 1-3 R59.

Embodiment 357. The compound of any of Embodiments 1-346, wherein R22, R23, R32 and R33 at each occurrence is independently chosen from H, phenyl optionally substituted by 1-3 R59, and 5-6 membered heteroaryl optionally substituted by 1-3 R59.

Embodiment 358. The compound of any of Embodiments 1-346, wherein R22, R23, R32 and R33 at each occurrence is independently chosen from H, phenyl ally substituted by 1-3 R59, and 6 membered heteroaryl optionally substituted by 1-3 R59.

Embodiment 359. The compound of any of Embodiments 1-346, wherein R22, R23, R32 and R33 at each occurrence is independently chosen from H, phenyl optionally substituted by 1 R59, and 6 membered heteroaryl optionally substituted by 1 R59.

Embodiment 360. The compound of any of Embodiments 1-346, wherein R22 at each occurrence is independently chosen from H, C1_6alkyl optionally substituted by 1- 13 R59, kenyl optionally substituted by 1-11 R59, C2_6alkynyl optionally substituted by 1-9 R59, C6_11aryl optionally substituted by 1-11 R59, C7_16arylalkyl optionally - ll9 - 2012/065831 substituted by 1—19 R59, C3_11cycloalkyl optionally substituted by 1—21 R59, c4_ 17cycloalkylalkyl optionally substituted by 1-32 R59, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R59, 4-21 ed heterocycloalkylalkyl optionally substituted by 1-40 R59, 5-15 membered heteroaryl optionally substituted by 1-15 R59, and 6-21 membered heteroarylalkyl ally substituted by 1-27 R59; R23, R32 and R33 at each ence is independently chosen from H and C1_6alkyl; alternatively, any R22 and R23 and/or R32 and R33 may form, together with the nitrogen atom to which they are attached, a 3-15 membered heterocycloalkyl optionally substituted by 1-28 R69 or a 5-15 ed heteroaryl optionally tuted by 1-15 R69.

Embodiment 361. The compound of any of Embodiments 1-346, wherein R22 at each occurrence is independently chosen from H, kyl ally substituted by 1-3 R59, C2_6alkenyl optionally substituted by 1-3 R59, C2_6alkynyl optionally substituted by 1-3 R59, C6_11aryl optionally substituted by 1-3 R59, C7_16arylalkyl optionally substituted by 1-3 R59, C3_11cycloalkyl ally substituted by 1-3 R59, C4_17cycloalkylalkyl optionally substituted by 1-3 R59, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R59, 4-21 membered cycloalkylalkyl optionally substituted by 1-3 R59, 5-15 membered heteroaryl optionally substituted by 1-3 R59, and 6-21 membered heteroarylalkyl optionally tuted by 1-3 R59; R23 , R32 and R33 at each occurrence is independently chosen from H and C1_6alkyl; alternatively, any R22 and R23 and/or R32 and R33 may form, together with the nitrogen atom to which they are attached, a 3-15 membered heterocycloalkyl optionally substituted by 1-3 R69 or a 5-15 ed heteroaryl optionally substituted by 1-3 R69.

Embodiment 362. The compound of any of Embodiments 1-346, wherein R22 at each occurrence is independently chosen from H, C1_6alkyl optionally substituted by 1-3 R59, C2_6alkenyl optionally substituted by 1-3 R59, kynyl optionally substituted by 1-3 R59, C6_10aryl optionally substituted by 1-3 R59, C7_11arylalkyl optionally substituted by 1-3 R59, C3_10cycloalkyl optionally substituted by 1-3 R59, 3-10 membered cycloalkyl optionally tuted by 1-3 R59, and 5-10 membered heteroaryl optionally substituted by 1-3 R59; R23, R32 and R33 at each occurrence is independently chosen from H and C1_6alkyl; alternatively, any R22 and R23 and/or R32 and R33 may form, together with the nitrogen atom to which they are attached, a 3-10 membered heterocycloalkyl optionally substituted by 1-3 R69 or a 5-10 membered heteroaryl optionally substituted by 1-3 R69.

Embodiment 363. The compound of any of Embodiments 1-346, wherein R22 at each occurrence is independently chosen from H, C1_6alkyl optionally substituted by 1-3 R59, C2_6alkenyl optionally substituted by 1-3 R59, C2_6alkynyl optionally substituted by 1-3 R59, C6_10aryl optionally substituted by 1-3 R59, C7_11arylalkyl ally substituted by 1-3 R59, C3_10cycloalkyl optionally substituted by 1-3 R59, 3-10 membered heterocycloalkyl optionally tuted by 1-3 R59, and 5-10 membered heteroaryl optionally substituted by 1-3 R59; R23, R32 and R33 at each ence is independently chosen from H and C1_6alkyl.

Embodiment 364. The compound of any of Embodiments 1-346, wherein R22 at each occurrence is independently chosen from H, C1_6alkyl optionally substituted by 1-3 R59, C6_10aryl optionally substituted by 1-3 R59, C7_11arylalkyl ally substituted by 1-3 R59, C3_10cycloalkyl optionally substituted by 1-3 R59, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R59, and 5-10 membered heteroaryl optionally substituted by 1-3 R59; R23, R32 and R33 at each occurrence is independently chosen from H and C1_6alkyl; atively, any R22 and R23 and/or R32 and R33 may form, together with the nitrogen atom to which they are attached, a 3-lO membered heterocycloalkyl optionally substituted by 1-3 R69 or a 5-10 membered heteroaryl optionally tuted by 1-3 R69.

Embodiment 365. The compound of any of ments 1-346, n R22 at each occurrence is independently chosen from H, C1_6alkyl optionally substituted by 1-3 R59, C6_10aryl optionally substituted by 1-3 R59, C7_11arylalkyl optionally substituted by 1-3 R59, C3_10cycloalkyl optionally substituted by 1-3 R59, 3-10 membered cycloalkyl optionally substituted by 1-3 R59, and 5-10 membered heteroaryl optionally substituted by 1-3 R59; R23, R32 and R33 at each occurrence is independently chosen from H and C1_6alkyl.

Embodiment 366. The compound of any of Embodiments 1-346, wherein R22 at each occurrence is independently chosen from H, C1_6alkyl, C6_1oaryl, C7_11arylalkyl, C3- 10cycloalkyl, 3-lO ed heterocycloalkyl, and 5-10 ed heteroaryl; R23, R32 and R33 at each occurrence is independently chosen from H and C1_6alkyl; alternatively, any R22 and R23 and/or R32 and R33 may form, together with the nitrogen atom to which they are attached, a 3-10 membered heterocycloalkyl or a 5-10 membered heteroaryl.

Embodiment 367. The compound of any of Embodiments 1-346, wherein R22 at each occurrence is independently chosen from H, C1_6alkyl, C6_1oaryl, C7_11arylalkyl, C3- 10cycloalkyl, 3-lO membered heterocycloalkyl, and 5-10 membered heteroaryl; R23, R32 and R33 at each occurrence is independently chosen from H and C1_6alkyl.

Embodiment 368. The compound of any of ments 1-346, wherein R22 at each occurrence is independently chosen from H, kyl optionally substituted by 1-3 R59, C6_10aryl optionally substituted by 1-3 R59, and 5-10 ed heteroaryl optionally -lZl- tuted by l-3 R59; R23 R32 and R33 at each occurrence is independently chosen from H and C1_6alkyl. ment 369. The compound of any of Embodiments l-346, wherein R22 at each occurrence is independently chosen from H, C6_10aryl optionally substituted by l-3 R59, and 5-10 membered heteroaryl optionally tuted by l-3 R59; R23, R32 and R33 at each occurrence is independently chosen from H and C1_6alkyl.

Embodiment 370. The compound of any of Embodiments l-346, n R22 at each occurrence is independently chosen from H, phenyl optionally substituted by l-3 R59, and 5-6 membered heteroaryl optionally substituted by l-3 R59; R23, R32 and R33 at each occurrence is independently chosen from H and C1_6alkyl.

Embodiment 371. The compound of any of Embodiments l-346, wherein R22 at each occurrence is independently chosen from H, phenyl optionally substituted by l-3 R59, and 6 membered heteroaryl optionally substituted by l-3 R59; R23, R32 and R33 at each occurrence is ndently chosen from H and kyl.

Embodiment 372. The compound of any of Embodiments l-346, wherein R22 at each occurrence is independently chosen from H, phenyl optionally substituted by 1 R59, and 6 membered heteroaryl optionally substituted by 1 R59; R23, R32 and R33 at each occurrence is independently chosen from H and C1_6alkyl.

Embodiment 373. The compound of any of Embodiments l-346, n R22 at each occurrence is independently chosen from H, C1_6alkyl optionally substituted by 1- 13 R59, C2_6alkenyl optionally substituted by l-ll R59, C2_6alkynyl optionally substituted by l-9 R59, C6_11aryl optionally substituted by l-ll R59, C7_16arylalkyl optionally substituted by 149 R59, C3.1 alkyl ally substituted by 1—21 R59, c4_ 17cycloalkylalkyl ally substituted by l-32 R59, 3-15 membered heterocycloalkyl optionally substituted by l-28 R59, 4-21 membered heterocycloalkylalkyl ally substituted by l-40 R59, 5-15 membered heteroaryl optionally substituted by l- l 5 R59, and 6-21 ed heteroarylalkyl optionally substituted by l-27 R59; R23, R32 and R33 at each occurrence is H; alternatively, any R22 and R23 and/or R32 and R33 may form, er with the nitrogen atom to which they are attached, a 3-15 membered heterocycloalkyl optionally substituted by l-28 R69 or a 5-15 membered heteroaryl optionally substituted by 145 R69.

Embodiment 374. The compound of any of Embodiments l-346, wherein R22 at each occurrence is independently chosen from H, C1_6alkyl optionally substituted by l-3 R59, C2_6alkenyl optionally substituted by l-3 R59, C2_6alkynyl optionally substituted by l-3 2012/065831 R59, C6_11aryl optionally substituted by 1-3 R59, C7_16arylalkyl optionally substituted by 1-3 R59, C3_11cycloalkyl optionally substituted by 1-3 R59, ycloalkylalkyl optionally substituted by 1-3 R59, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R59, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-3 R59, 5-15 membered heteroaryl optionally substituted by 1-3 R59, and 6-21 membered heteroarylalkyl optionally substituted by 1-3 R59; R23, R32 and R33 at each occurrence is H; alternatively, any R22 and R23 and/or R32 and R33 may form, er with the nitrogen atom to which they are attached, a 3-15 ed heterocycloalkyl optionally substituted by 1-3 R69 or a -15 membered heteroaryl optionally substituted by 1-3 R69. ment 375. The compound of any of Embodiments 1-346, wherein R22 at each occurrence is independently chosen from H, C1_6alkyl optionally tuted by 1-3 R59, C2_6alkenyl optionally substituted by 1-3 R59, C2_6alkynyl optionally substituted by 1-3 R59, C6_10aryl optionally substituted by 1-3 R59, C7_11arylalkyl optionally substituted by 1-3 R59, C3_10cycloalkyl optionally substituted by 1-3 R59, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R59, and 5-10 membered heteroaryl ally tuted by 1-3 R59; R23, R32 and R33 at each occurrence is H; alternatively, any R22 and R23 and/or R32 and R33 may form, together with the nitrogen atom to which they are attached, a 3-10 membered heterocycloalkyl optionally substituted by 1-3 R69 or a 5-10 membered heteroaryl optionally substituted by 1-3 R69.

Embodiment 376. The compound of any of Embodiments 1-346, wherein R22 at each occurrence is independently chosen from H, kyl optionally substituted by 1-3 R59, C2_6alkenyl optionally substituted by 1-3 R59, C2_6alkynyl optionally substituted by 1-3 R59, C6_10aryl optionally substituted by 1-3 R59, C7_11arylalkyl optionally substituted by 1-3 R59, ycloalkyl optionally substituted by 1-3 R59, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R59, and 5-10 membered heteroaryl optionally substituted by 1-3 R59; R23, R32 and R33 at each ence is H.

Embodiment 377. The compound of any of Embodiments 1-346, wherein R22 at each occurrence is ndently chosen from H, C1_6alkyl optionally substituted by 1-3 R59, C6_10aryl optionally substituted by 1-3 R59, C7_11arylalkyl optionally substituted by 1-3 R59, C3_10cycloalkyl optionally substituted by 1-3 R59, 3-10 membered heterocycloalkyl ally substituted by 1-3 R59, and 5-10 membered heteroaryl optionally tuted by 1-3 R59; R23, R32 and R33 at each occurrence is H; alternatively, any R22 and R23 and/or R32 and R33 may form, together with the nitrogen atom to which they are attached, a 3-10 membered heterocycloalkyl optionally substituted by l-3 R69 or a 5-10 membered heteroaryl optionally substituted by l-3 R69.

Embodiment 378. The compound of any of Embodiments l-346, wherein R22 at each occurrence is independently chosen from H, C1_6alkyl optionally substituted by l-3 R59, C6_10aryl optionally substituted by l-3 R59, rylalkyl optionally substituted by l-3 R59, C3_10cycloalkyl optionally substituted by l-3 R59, 3-lO membered heterocycloalkyl optionally tuted by l-3 R59, and 5-10 membered heteroaryl optionally substituted by l-3 R59; R23, R32 and R33 at each ence is H.

Embodiment 379. The compound of any of Embodiments l-346, wherein R22 at each occurrence is ndently chosen from H, kyl, C6_1oaryl, C7_11arylalkyl, C3- 10cycloalkyl, 3-lO membered cycloalkyl, and 5-10 ed heteroaryl; R23, R32 and R33 at each occurrence is H; alternatively, any R22 and R23 and/or R32 and R33 may form, together with the nitrogen atom to which they are attached, a 3-lO ed cycloalkyl or a 5-10 membered heteroaryl.

Embodiment 380. The compound of any of ments l-346, wherein R22 at each occurrence is independently chosen from H, C1_6alkyl, C6_10aryl, C7_11arylalkyl, C3_ 10cycloalkyl, 3-lO membered heterocycloalkyl, and 5-10 membered heteroaryl; R23, R32 and R33 at each occurrence is H.

Embodiment 38 l. The compound of any of Embodiments l-346, wherein R22 at each occurrence is independently chosen from H, C1_6alkyl optionally substituted by l-3 R59, C6_10aryl optionally substituted by l-3 R59, and 5-10 membered heteroaryl optionally substituted by l-3 R59; R23, R32 and R33 at each occurrence is H.

Embodiment 382. The compound of any of Embodiments l-346, wherein R22 at each occurrence is independently chosen from H, C6_1oaryl ally substituted by l-3 R59, and 5-10 membered heteroaryl optionally substituted by l-3 R59; R23, R32 and R33 at each occurrence is H.

Embodiment 383. The compound of any of Embodiments l-346, wherein R22 at each occurrence is independently chosen from H, phenyl optionally substituted by l-3 R59, and 5-6 membered heteroaryl optionally substituted by l-3 R59; R23, R32 and R33 at each occurrence is H.

Embodiment 384. The compound of any of Embodiments l-346, wherein R22 at each ence is independently chosen from H, phenyl optionally substituted by l-3 R59, and 6 membered heteroaryl optionally substituted by l-3 R59; R23, R32 and R33 at each occurrence is H.

Embodiment 385. The compound of any of Embodiments 1-346, wherein R22 at each occurrence is independently chosen from H, phenyl optionally substituted by 1 R59, and 6 membered heteroaryl optionally substituted by 1 R59; R23, R32 and R33 at each occurrence is H.

Embodiment 386. The compound of any of Embodiments 1-346, wherein R22, R23, R32 and R33 at each occurrence is independently chosen from H and C1_6alkyl.

Embodiment 387. The nd of any of Embodiments 1-346, wherein R22, R23, R32 and R33 at each ence is H.

Embodiment 388. The compound of any of Embodiments 1-346, n R22, R23, R32 and R33 at each ence is independently chosen from H and C1_6alkyl optionally substituted by 1-13 R59; alternatively, any R22 and R23 and/or R32 and R33 may form, together with the nitrogen atom to which they are attached, a 3-l5 membered heterocycloalkyl optionally substituted by 1-28 R69 or a 5-15 membered heteroaryl optionally substituted by 1-15 R69.

Embodiment 389. The compound of any of Embodiments 1-346, n R22, R23, R32 and R33 at each occurrence is independently chosen from H and C1_6alkyl optionally tuted by 1-6 R59; alternatively, any R22 and R23 and/or R32 and R33 may form, together with the nitrogen atom to which they are attached, a 3-l5 membered heterocycloalkyl optionally substituted by 1-6 R69 or a 5-15 membered heteroaryl optionally substituted by 1-6 R69.

Embodiment 390. The compound of any of Embodiments 1-346, n R22, R23, R32 and R33 at each occurrence is independently chosen from H and C1_6alkyl optionally substituted by 1-6 R59; atively, any R22 and R23 and/or R32 and R33 may form, together with the nitrogen atom to which they are attached, a 3-lO membered heterocycloalkyl optionally substituted by 1-6 R69 or a 5-10 membered heteroaryl optionally substituted by 1-6 R69.

Embodiment 391. The compound of any of Embodiments 1-346, wherein R22, R23, R32 and R33 at each ence is ndently chosen from H and C1_6alkyl optionally substituted by 1-6 R59; alternatively, any R22 and R23 and/or R32 and R33 may form, together with the nitrogen atom to which they are attached, a 3-6 membered heterocycloalkyl optionally substituted by 1-6 R69 or a 5-6 membered heteroaryl optionally substituted by 1-6 R69.

Embodiment 392. The compound of any of Embodiments 1-346, n R22, R23, R32 and R33 at each occurrence is independently chosen from H and C1_6alkyl optionally; alternatively, any R22 and R23 and/or R32 and R33 may form, together with the nitrogen atom to which they are attached, a 3-6 membered heterocycloalkyl or a 5-6 membered heteroaryl.

Embodiment 393. The compound of any of Embodiments 1-392, n R39, R49, R59 and R69 at each occurrence is independently chosen from C1_6alkyl ally substituted by l-l3 R79, C2_6alkenyl optionally substituted by l-ll R79, kynyl optionally substituted by l-9 R79, C6_11aryl optionally substituted by l-ll R79, C7- 16arylalkyl optionally tuted by l-l9 R79, C3_11cycloalkyl optionally substituted by l- 21 R79, C4_17cycloalkylalkyl optionally substituted by 132 R79, 3—15 membered heterocycloalkyl optionally substituted by l-28 R79, 4-21 membered heterocycloalkylalkyl optionally substituted by l-40 R79, 5-15 membered heteroaryl optionally substituted by l- R79, 6-21 membered heteroarylalkyl optionally substituted by l-27 R79, halogen, —CN, —C(=O)R7°, —C(=O)OR7°, —C(=O)NR72R73, —C(=O)C(=O)R7°, 75)R7°, — C(=NR75)NR72R73, —C(=NOH)NR72R73, —C(=NOR76)R7°, —C(=NNR72R73)R70, — C(=NNR74C(=O)R71)R7°, —C(=NNR74C(=O)OR71)R7°, —C(=S)NR72R73, —NC, —N02, — NR72R73, —NR74NR72R73, —N=NR74, =NR70, =NOR70, —NR74OR76, —NR74C(=0)R70, — NR74C(=O)C(=O)R7°, —NR74C(=O)OR71, —NR74C(=O)C(=O)OR71, —NR74C(=O)NR72R73, (=O)NR74C(=O)R7°, —NR74C(=O)NR74C(=O)OR7°, —NR74C(=NR75)NR72R73, — NR74C(=O)C(=O)NR72R73, —NR74C(=S)R7°, (=S)OR7°, —NR74C(=S)NR72R73, — =O)2R71, —NR74S(=O)2NR72R73, —NR74P(=O)R78R78, — NR74P(=O)(NR72R73)(NR72R73), —NR74P(=O)(OR70)(OR70), —NR74P(=O)(SR70)(SR70), — OR70, =o, —OCN, —OC(=O)R7°, —OC(=O)NR72R73, )OR7°, —OC(=NR75)NR72R73, —OS(=O)R7°, —OS(=O)2R7°, —OS(=O)20R7°, —OS(=O)2NR72R73, —OP(=O)R78R78, — OP(=O)(NR72R73)(NR72R73), —OP(=O)(OR7°)(OR70), —OP(=O)(SR70)(SR70), —Si(R74)3 — SCN, =s, —S(=O)HR7°, —S(=O)20R7°, —sogR77, —S(=O)2NR72R73, NR72R73, — SP(=O)R78R78, —SP(=O)(NR72R73)(NR72R73), —SP(=O)(OR70)(OR70), — SP(=O)(SR70)(SR70), —P(=O)R78R78, —P(=O)(NR72R73)(NR72R73), —P(=O)(OR7°)(OR7°), and —P(=O)(SR70)(SR7°). ment 394. The compound of any of Embodiments l-392, wherein R39, R49, R59 and R69 at each occurrence is independently chosen from C1_6alkyl ally substituted by l-6 R79, C2_6alkenyl ally substituted by l-6 R79, C2_6alkynyl optionally substituted by l-6 R79, C6_11aryl optionally substituted by l-6 R79, C7_16arylalkyl optionally substituted by l-6 R79, C3_11cycloalkyl optionally substituted by 1-6 R79, C4- oalkylalkyl optionally substituted by 1-6 R79, 3-15 membered heterocycloalkyl optionally substituted by 1-6 R79, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-6 R79, 5-15 membered heteroaryl optionally substituted by 1-6 R79, 6-21 membered heteroarylalkyl optionally substituted by 1-6 R79, halogen, —CN, —C(=O)R70, — C(=O)OR7°, —C(=O)NR72R73, —C(=O)C(=O)R7°, —C(=NR75)R7°, —C(=NR75)NR72R73, — C(=NOH)NR72R73, —C(=NOR76)R7°, —C(=NNR72R73)R7°, —C(=NNR74C(=O)R71)R70, — C(=NNR74C(=O)OR71)R7°, —C(=S)NR72R73, —NC, —N02, —NR72R73, —NR74NR72R73, — , =NR70, =NOR70, —NR74OR76, —NR74C(=0)R7°, (=O)C(=O)R7°, — NR74C(=O)OR71, —NR74C(=O)C(=O)OR71, —NR74C(=O)NR72R73, — =O)NR74C(=O)R7°, —NR74C(=O)NR74C(=O)OR7°, —NR74C(=NR75)NR72R73, — NR74C(=O)C(=O)NR72R73, —NR74C(=S)R7°, (=S)OR7°, —NR74C(=S)NR72R73, — NR74S(=O)2R71, —NR74S(=O)2NR72R73, —NR74P(=O)R78R78, — NR74P(=O)(NR72R73)(NR72R73), —NR74P(=O)(OR70)(OR70), —NR74P(=O)(SR70)(SR70), — OR70, =o, —OCN, —OC(=O)R7°, —OC(=O)NR72R73, —OC(=O)OR7°, —OC(=NR75)NR72R73, —OS(=O)R7°, —OS(=O)2R7°, —OS(=O)20R7°, —OS(=O)2NR72R73, —OP(=O)R78R78, — OP(=O)(NR72R73)(NR72R73), —OP(=O)(OR7°)(OR70), —OP(=O)(SR70)(SR70), —Si(R74)3 — SCN, =s, —S(=O)HR7°, —S(=O)20R7°, —sogR77, —S(=O)2NR72R73, —S(=O)NR72R73, — SP(=O)R78R78, —SP(=O)(NR72R73)(NR72R73), —SP(=O)(OR70)(OR70), — SP(=O)(SR70)(SR70), —P(=O)R78R78, —P(=O)(NR72R73)(NR72R73), —P(=O)(OR7°)(OR7°), and —P(=O)(SR70)(SR7°). ment 395. The compound of any of Embodiments 1-392, wherein R39, R49, R59 and R69 at each occurrence is independently chosen from C1_6alkyl ally substituted by 1-6 R79, C2_6alkenyl optionally substituted by 1-6 R79, C2_6alkynyl optionally substituted by 1-6 R79, C6_11aryl optionally substituted by 1-6 R79, rylalkyl ally substituted by 1-6 R79, C3_11cycloalkyl optionally substituted by 1-6 R79, 3-15 membered heterocycloalkyl optionally substituted by 1-6 R79, 5-15 membered heteroaryl optionally substituted by 1-6 R79, halogen, —CN, —C(=O)R7°, —C(=O)OR7°, —C(=O)NR72R73, — C(=O)C(=O)R7°, —NC, —N02, —NR72R73, —NR74NR72R73, —N=NR74, =NR70, =NOR70, — NR74OR76, (=O)R7°, —NR74C(=O)C(=O)R7°, —NR74C(=O)OR71, — =O)C(=O)OR71, —NR74C(=O)NR72R73, —NR74C(=O)NR74C(=O)R7°, — NR74C(=O)NR74C(=O)OR7°, —NR74C(=NR75)NR72R73, —NR74C(=O)C(=O)NR72R73, — NR74S(=O)2R71, —NR74S(=O)2NR72R73, —NR74P(=O)R78R78, — NR74P(=O)(NR72R73)(NR72R73), (=O)(OR7°)(OR7°), —0R7°, =o, —OCN, — OC(=O)R7°, —OC(=O)NR72R73, —OC(=O)OR7°, R75)NR72R73, —OS(=O)R7°, — - 127 — OS(=O)2R7°, —OS(=O)20R7°, —OS(=O)2NR72R73, —OP(=O)R78R78, — OP(=O)(NR72R73)(NR72R73), —OP(=O)(OR7°)(OR7°), —Si(R74)3 ,—SCN, =s, —S(=O)nR7°, 20R7°, 7, —S(=O)2NR72R73, —S(=O)NR72R73, —SP(=O)R78R78, — SP(=O)(NR72R73)(NR72R73), —SP(=O)(OR7°)(OR7°), —SP(=O)(SR70)(SR7°), —P(=O)R78R78, —P(=O)(NR72R73)(NR72R73), and —P(=O)(OR70)(OR70).

Embodiment 396. The compound of any of Embodiments 1-392, wherein R39, R49, R59 and R69 at each occurrence is independently chosen from C1_6alkyl ally substituted by 1-6 R79, C2_6alkenyl optionally substituted by 1-6 R79, C2_6alkynyl optionally substituted by 1-6 R79, C6_10aryl optionally substituted by 1-6 R79, C7_11arylalkyl optionally substituted by 1-6 R79, C3_10cycloalkyl optionally substituted by 1-6 R79, 3-10 membered heterocycloalkyl ally substituted by 1-6 R79, 5-10 membered heteroaryl optionally tuted by 1-6 R79, halogen, —CN, —C(=O)R7°, —C(=O)OR7°, —C(=O)NR72R73, — C(=O)C(=O)R7°, —NC, —N02, —NR72R73, —NR74NR72R73, —N=NR74, =NR70, =NOR70, — NR74OR76, —NR74C(=O)R7°, —NR74C(=O)OR71,—NR74C(=O)NR72R73, —NR74S(=O)2R71, — NR74S(=O)2NR72R73, —NR74P(=O)R78R78, —NR74P(=O)(NR72R73)(NR72R73), _ NR74P(=O)(OR7°)(OR7°), OR70, —o, OCN, 0C(—0)R70, )NR72R73, — OC(=O)OR7°, R75)NR72R73, )R7°, —OS(=O)2R7°, —OS(=O)20R7°, — OS(=O)2NR72R73, )R78R78, —OP(=O)(NR72R73)(NR72R73), —OP(=O)(OR70)(OR70), —Si(R74)3 , —SCN, =s, —S(=O)HR7°, —S(=O)20R7°, —SOgR77, —S(=O)2NR72R73, — S(=O)NR72R73, —P(=O)R78R78, —P(=O)(NR72R73)(NR72R73), and —P(=O)(OR7°)(OR7°). ment 397. The compound of any of Embodiments 1-392, wherein R39, R49, R59 and R69 at each occurrence is independently chosen from C1_6alkyl optionally substituted by 1-3 R79, C2_6alkenyl optionally substituted by 1-3 R79, C2_6alkynyl optionally substituted by 1-3 R79, C6_10aryl ally substituted by 1-3 R79, C7_11arylalkyl optionally substituted by 1-3 R79, C3_10cycloalkyl optionally substituted by 1-3 R79, 3-10 membered heterocycloalkyl optionally tuted by 1-3 R79, 5-10 membered heteroaryl optionally tuted by 1—3 R79, halogen, —CN, —C(=O)R7°, —C(=O)OR7°, —C(=O)NR72R73, —NC, — N02, —NR72R73, —NR74NR72R73, —NR74OR76, —NR74C(=0)R70, —NR74C(=0)0R71, — NR74C(=O)NR72R73, —NR74S(=O)2R71, (=O)2NR72R73, —0R7°, =o, —OCN, — OC(=O)R7°, —OC(=O)NR72R73, —OC(=O)OR7°, —OS(=O)2NR72R73, —Si(R74)3 — , —SCN, S(=O)nR7°, —S(=O)2NR72R73, —S(=O)NR72R73, —P(=O)R78R78, (NR72R73)(NR72R73), and —P(=O)(OR70)(OR70).

Embodiment 398. The compound of any of Embodiments 1-392, wherein R39, R49, R59 and R69 at each occurrence is independently chosen from C1_6alkyl optionally substituted by 1-3 R79, C2_6alkenyl optionally substituted by 1-3 R79, C2_6alkynyl optionally tuted by 1-3 R79, C6_1oaryl optionally substituted by 1-3 R79, C7_11arylalkyl optionally substituted by 1-3 R79, C3_1ocycloalkyl optionally substituted by 1-3 R79, 3-10 membered cycloalkyl optionally substituted by 1-3 R79, 5-10 membered heteroaryl optionally substituted by 1-3 R79, halogen, —CN, —C(=O)R7°, —C(=O)OR7°, —C(=O)NR72R73, —NOg, — NR72R73, —NR74OR76, —NR74C(=0)R70, —NR74C(=0)0R71, —NR74C(=O)NR72R73, — NR74S(=O)2R71, —NR74S(=O)2NR72R73, —0R7°, =o, —OC(=O)R7°, )NR72R73, — OS(=O)2NR72R73, —S(=O)HR7°, and —S(=O)2NR72R73. ment 399. The compound of any of ments 1-392, wherein R39, R49, R59 and R69 at each occurrence is independently chosen from C1_6alkyl optionally substituted by 1-3 R79, C2_6alkenyl optionally substituted by 1-3 R79, C2_6alkynyl optionally substituted by 1-3 R79, C6_10aryl optionally substituted by 1-3 R79, C7_11arylalkyl optionally substituted by 1-3 R79, C3_1ocycloalkyl ally tuted by 1-3 R79, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R79, 5-10 membered aryl optionally substituted by 1-3 R79, halogen, —CN, —C(=O)R7°, —C(=O)OR7°, NR72R73, —NOg, — NR72R73, —NR74C(=O)R7°, —NR74C(=O)NR72R73, —NR74S(=O)2R71, —0R7°, =o, — R7°, and 2NR72R73.

Embodiment 400. The compound of any of Embodiments 1-392, wherein R39, R49, R59 and R69 at each occurrence is independently chosen from C1_6alkyl ally substituted by 1-3 R79, C6_1oaryl optionally substituted by 1-3 R79, C7_11arylalkyl optionally substituted by 1-3 R79, C3_10cycloalkyl optionally substituted by 1-3 R79, 3-10 membered heterocycloalkyl ally substituted by 1-3 R79, 5-10 membered heteroaryl optionally substituted by 1-3 R79, halogen, —CN, —C(=O)R7°, OR7°, —C(=O)NR72R73, —NOg, — NR72R73, —NR74C(=O)R7°, —NR74C(=O)NR72R73, —NR74S(=O)2R71, —0R7°, =o, — S(=O)nR7°, and —S(=O)2NR72R73.

Embodiment 401. The compound of any of Embodiments 1-392, wherein R39, R49, R59 and R69 at each occurrence is independently chosen from C1_6alkyl optionally substituted by 1-3 R79, C6_1oaryl optionally substituted by 1-3 R79, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R79, 5-10 membered heteroaryl optionally substituted by 1-3 R79, —CN, and —C(=O)R70.

Embodiment 402. The compound of any of Embodiments 1-392, wherein R39, R49, R59 and R69 at each occurrence is independently chosen from C1_6alkyl optionally substituted by 1-3 R79, phenyl optionally substituted by 1-3 R79, 5-6 membered heterocycloalkyl optionally substituted by 1-3 R79, 5-9 membered heteroaryl optionally substituted by 1—3 R79, —CN, and R70. ment 403. The compound of any of Embodiments 1-392, wherein R39, R49, R59 and R69 at each occurrence is independently chosen from C1_6alkyl optionally substituted by 1 R79, phenyl, 6 membered heterocycloalkyl optionally tuted by 1 R79, -9 membered heteroaryl optionally substituted by 1-3 R79, —CN, and —C(=O)R70.

Embodiment 404. The compound of any of Embodiments 1-392, wherein R39 at each occurrence is independently chosen from C1_6alkyl and 5-9 ed heteroaryl optionally substituted by 1-3 R79; R59 and R69 at each occurrence is independently C1- 6alkyl; R49 at each ence is independently chosen from kyl optionally substituted by 1 R79, phenyl, 6 membered heterocycloalkyl optionally substituted by 1 R79, membered heteroaryl optionally substituted by 1-3 R79, —CN, and —C(=O)R7O.

Embodiment 405. The compound of any of ments 1-392, wherein R39, R49, R59 and R69 at each occurrence is independently chosen from C1_6alkyl, phenyl, 5-6 membered heterocycloalkyl, 5-9 membered heteroaryl, —CN, and —C(=O)R70.

Embodiment 406. The compound of any of Embodiments 1-392, wherein R39, R49, R59 and R69 at each occurrence is independently chosen from C1_6alkyl, phenyl, 5-6 membered heterocycloalkyl, and 5-9 membered heteroaryl.

Embodiment 407. The compound of any of Embodiments 1-392, wherein R39, R49, R59 and R69 at each occurrence is independently chosen from kyl optionally substituted by 1-13 R79.

Embodiment 408. The compound of any of Embodiments 1-392, wherein R39, R49, R59 and R69 at each occurrence is independently chosen from C1_6alkyl optionally tuted by 1-6 R79.

Embodiment 409. The nd of any of ments 1-392, wherein R39, R49, R59 and R69 at each occurrence is independently chosen from C1_6alkyl optionally substituted by 1—3 R79.

Embodiment 410. The compound of any of Embodiments 1-392, wherein R39, R49, R59 and R69 at each occurrence is independently C1_6all<yl. -l30- WO 78126 Embodiment 411. The compound of any of Embodiments 1-410, n R70, R71, R74, R75, R76 and R77 at each occurrence is independently chosen from H, C1_6alkyl optionally substituted by 1-13 R89, C2_6alkenyl optionally substituted by 1-11 R89, C2- 6alkynyl optionally substituted by 1-9 R89, C6_11aryl optionally tuted by 1-11 R89, C7- 16arylalkyl optionally substituted by 1-19 R89, C3_11cycloalkyl optionally substituted by 1- 21 R89, C4_17cycloalkylalkyl optionally substituted by 1—32 R89, 3—15 membered heterocycloalkyl optionally substituted by 1-28 R89, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40 R89, 5-15 membered heteroaryl ally tuted by 1- R89, and 6-21 membered heteroarylalkyl optionally substituted by 1-27 R89.

Embodiment 412. The compound of any of Embodiments 1-410, wherein R70, R71, R74, R75, R76 and R77 at each occurrence is independently chosen from H, C1_6alkyl optionally substituted by 1-6 R89, kenyl optionally substituted by 1-6 R89, C2_6alkynyl optionally substituted by 1-6 R89, C6_10aryl optionally substituted by 1-6 R89, C7_11arylalkyl optionally substituted by 1-6 R89, C3_10cycloalkyl optionally substituted by 1-6 R89, 3-10 membered heterocycloalkyl optionally substituted by 1-6 R89, and 5-10 membered heteroaryl optionally substituted by 1-6 R89.

Embodiment 413. The compound of any of Embodiments 1-410, wherein R70, R71, R74, R75, R76 and R77 at each occurrence is independently chosen from H, C1_6alkyl optionally substituted by 1-3 R89, C2_6alkenyl optionally substituted by 1-3 R89, C2_6alkynyl optionally substituted by 1-3 R89, C6_10aryl optionally substituted by 1-3 R89, C7_11arylalkyl ally substituted by 1-3 R89, C3_10cycloalkyl optionally substituted by 1-3 R89, 3-10 membered heterocycloalkyl ally substituted by 1-3 R89, and 5-10 ed heteroaryl optionally substituted by 1-3 R89. ment 414. The nd of any of Embodiments 1-410, wherein R70, R71, R74, R75, R76 and R77 at each ence is independently chosen from H, C1_6alkyl optionally substituted by 1-3 R89, C6_10aryl optionally substituted by 1-3 R89, C7_11arylalkyl optionally substituted by 1-3 R89, C3_10cycloalkyl optionally substituted by 1-3 R89, 3-10 membered heterocycloalkyl ally substituted by 1-3 R89, and 5-10 membered heteroaryl optionally tuted by 1-3 R89.

Embodiment 415. The compound of any of Embodiments 1-410, wherein R70, R71, R74, R75, R76 and R77 at each occurrence is independently chosen from H, C1_6alkyl, C6_10aryl, C7_11arylalkyl, C3_10cycloalkyl, 3-10 membered heterocycloalkyl, and 5-10 membered heteroaryl.

Embodiment 416. The compound of any of Embodiments 1-410, wherein R70, R71, R74, R75, R76 and R77 at each occurrence is independently chosen from H, C1_6alkyl ally substituted by 1-3 R89, phenyl optionally substituted by 1-3 R89, benzyl optionally substituted by 1-3 R89, cloalkyl optionally substituted by 1-3 R89, 5-6 membered heterocycloalkyl optionally substituted by 1-3 R89, and 5-6 membered heteroaryl optionally tuted by 1-3 R89.

Embodiment 417. The compound of any of Embodiments 1-410, wherein R70, R71, R74, R75, R76 and R77 at each ence is ndently chosen from H, C1_6alkyl, phenyl, benzyl, C5_6cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl.

Embodiment 418. The compound of any of Embodiments 1-410, wherein R70, R71, R74, R75, R76 and R77 at each occurrence is independently chosen from H, C1_6alkyl, phenyl, , C5_6cycloalkyl, 5-6 membered heterocycloalkyl optionally substituted by 1-3 R89, and 5-6 ed heteroaryl.

Embodiment 419. The compound of any of ments 1-410, wherein R70, R71, R74, R75, R76 and R77 at each ence is independently chosen from H, C1_6alkyl, , benzyl, C5_6cycloalkyl, 5-6 membered heterocycloalkyl optionally substituted by 1 R89, and 5-6 membered heteroaryl.

Embodiment 420. The compound of any of Embodiments 1-410, wherein R70, R71, R74, R75, R76 and R77 at each occurrence is independently chosen from H, C1_6alkyl, and 5-6 membered heterocycloalkyl optionally substituted by 1-3 R89.

Embodiment 421. The compound of any of ments 1-410, wherein R70, R71, R74, R75, R76 and R77 at each occurrence is independently chosen from H, C1_6alkyl, and 5-6 membered heterocycloalkyl optionally substituted by C1_6alkyl.

Embodiment 422. The compound of any of Embodiments 1-410, wherein R70, R71, R74, R75, R76 and R77 at each occurrence is independently chosen from H, C1_6alkyl, and 5-6 membered heterocycloalkyl.

Embodiment 423. The compound of any of Embodiments 1-410, wherein R70 at each occurrence is independently chosen from H, C1_6alkyl, and 5-6 membered heterocycloalkyl optionally substituted by 1-3 R89; R71, R74, R75, R76 and R77 at each occurrence is H.

Embodiment 424. The compound of any of ments 1-410, wherein R70 at each occurrence is independently chosen from H, C1_6alkyl, and 5-6 membered heterocycloalkyl optionally substituted by kyl; R71, R74, R75, R76 and R77 at each occurrence is H.

Embodiment 425. The nd of any of Embodiments l-4lO, wherein R70 at each occurrence is independently chosen from H, C1_6alkyl, and 5-6 membered heterocycloalkyl; R71, R74, R75, R76 and R77 at each occurrence is H.

Embodiment 426. The compound of any of Embodiments l-4lO, wherein R70, R71, R74, R75, R76 and R77 at each occurrence is independently chosen from H and C1- 6alkyl.

Embodiment 427. The compound of any of Embodiments l-4lO, wherein R70, 71 74 75 76 R R R R and R77 at each occurrence 1s H.- , , , Embodiment 428. The compound of any of ments l-427, wherein R72 and R73 at each occurrence is ndently chosen from H, kyl optionally substituted by 1-13 R99, C2_6alkenyl optionally substituted by 1-11 R99, C2_6alkynyl optionally substituted by 1-9 R99, C6_11aryl ally substituted by 1-11 R99, C7- 16arylalkyl optionally tuted by 1-19 R99, C3_11cycloalkyl optionally substituted by l- 21 R99, ycloalkylalkyl optionally substituted by 1—32 R99, 3—15 membered heterocycloalkyl optionally substituted by 1-28 R99, 4-2l membered heterocycloalkylalkyl optionally substituted by 1-40 R99, 5-l5 membered heteroaryl optionally substituted by l- 15 R99, and 6-21 membered heteroarylalkyl optionally substituted by 1-27 R99; alternatively, any R72 and R73 may form, together with the nitrogen atom to which they are attached, a 3-15 membered heterocycloalkyl optionally substituted by 1-28 R109 or a 5-15 membered heteroaryl optionally substituted by 1-15 R109.

Embodiment 429. The nd of any of Embodiments l-427, wherein R72 and R73 at each ence is independently chosen from H, C1_6alkyl optionally substituted by 1-6 R99, C2_6alkenyl ally substituted by 1-6 R99, kynyl optionally substituted by 1-6 R99, C6_11aryl optionally substituted by 1-6 R99, C7_16arylalkyl optionally substituted by 1-6 R99, C3_11cycloalkyl optionally substituted by 1-6 R99, C4- 17cycloalkylalkyl optionally substituted by 1-6 R99, 3-15 membered heterocycloalkyl optionally substituted by 1-6 R99, 4-2l membered heterocycloalkylalkyl ally substituted by 1-6 R99, 5-l5 membered heteroaryl optionally substituted by 1-6 R99, and 6- 2l membered heteroarylalkyl optionally substituted by 1-6 R99; alternatively, any R72 and R73 may form, together with the nitrogen atom to which they are attached, a 3-15 -l33- membered heterocycloalkyl optionally tuted by l-6 R109 or a 5-15 membered heteroaryl optionally substituted by l-6 R109.

Embodiment 430. The compound of any of Embodiments l-427, wherein R72 and R73 at each occurrence is independently chosen from H, C1_6alkyl optionally substituted by l-3 R99, kenyl optionally tuted by l-3 R99, kynyl optionally substituted by l-3 R99, ryl optionally substituted by l-3 R99, C7_16arylalkyl optionally tuted by l-3 R99, C3_11cycloalkyl optionally substituted by l-3 R99, C4- 17cycloalkylalkyl optionally substituted by l-3 R99, 3-15 membered heterocycloalkyl optionally substituted by l-3 R99, 4-21 membered heterocycloalkylalkyl optionally substituted by l-3 R99, 5-15 membered heteroaryl optionally substituted by l-3 R99, and 6- 21 membered heteroarylalkyl optionally substituted by l-3 R99; alternatively, any R72 and R73 may form, together with the nitrogen atom to which they are attached, a 3-15 membered cycloalkyl optionally substituted by l-3 R109 or a 5-15 ed aryl optionally substituted by l-3 R109.

Embodiment 431. The compound of any of Embodiments l-427, wherein R72 and R73 at each occurrence is independently chosen from H, kyl optionally substituted by l-3 R99, C2_6alkenyl optionally substituted by l-3 R99, C2_6alkynyl optionally substituted by l-3 R99, C6_10aryl optionally substituted by l-3 R99, C7_11arylalkyl optionally substituted by l-3 R99, ycloalkyl optionally substituted by l-3 R99, 3-10 membered heterocycloalkyl ally substituted by l-3 R99, and 5-10 membered heteroaryl optionally substituted by l-3 R99; alternatively, any R72 and R73 may form, together with the nitrogen atom to which they are attached, a 3-10 membered heterocycloalkyl optionally tuted by l-3 R109 or a 5-10 membered heteroaryl optionally tuted by 1_3 R109 Embodiment 432. The compound of any of Embodiments l-427, wherein R72 and R73 at each occurrence is independently chosen from H, C1_6alkyl optionally substituted by l-3 R99, C6_10aryl optionally substituted by l-3 R99, C7_11arylalkyl optionally substituted by l-3 R99, C3_10cycloalkyl optionally substituted by l-3 R99, 3-10 membered heterocycloalkyl optionally substituted by l-3 R99, and 5-10 membered heteroaryl optionally substituted by l-3 R99; alternatively, any R72 and R73 may form, together with the nitrogen atom to which they are attached, a 3-10 membered heterocycloalkyl optionally substituted by l-3 R109 or a 5-10 membered heteroaryl optionally substituted by 1_3 R109 —134— Embodiment 433. The compound of any of Embodiments l-427, wherein R72 and R73 at each occurrence is ndently chosen from H, C1_6alkyl optionally substituted by l-3 R99, phenyl optionally substituted by l-3 R99, benzyl optionally substituted by l-3 R99, C5_6cycloalkyl optionally substituted by l-3 R99, 5-6 membered heterocycloalkyl optionally substituted by l-3 R99, and 5-6 membered heteroaryl optionally substituted by l-3 R99; alternatively, any R72 and R73 may form, together with the en atom to which they are attached, a 5-6 membered heterocycloalkyl optionally substituted by l-3 R109 109 or a 5-6 membered heteroaryl optionally substituted by l-3 R . ment 434. The compound of any of ments l-427, wherein R72 and R73 at each occurrence is independently chosen from H, kyl optionally substituted by l-3 R99, phenyl optionally tuted by l-3 R99, benzyl ally substituted by l-3 R99, C5_6cycloalkyl optionally substituted by l-3 R99, 5-6 ed heterocycloalkyl optionally substituted by l-3 R99, and 5-6 membered heteroaryl optionally substituted by l-3 R99.

Embodiment 435. The compound of any of Embodiments l-427, wherein R72 and R73 at each occurrence is ndently chosen from H, C1_6alkyl, phenyl, benzyl, C5_ 6cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered aryl; alternatively, any R72 and R73 may form, together with the nitrogen atom to which they are attached, a 5- 6 membered heterocycloalkyl or a 5-6 membered heteroaryl.

Embodiment 436. The compound of any of Embodiments l-427, wherein R72 and R73 at each occurrence is independently chosen from H, C1_6alkyl, phenyl, benzyl, C5_ 6cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl.

Embodiment 437. The compound of any of Embodiments l-427, wherein R72 and R73 at each occurrence is independently chosen from H, C1_6alkyl optionally substituted by l-3 R99, phenyl optionally substituted by l-3 R99, and benzyl ally substituted by 13 R99.

Embodiment 438. The compound of any of Embodiments l-427, wherein R72 and R73 at each occurrence is independently chosen from H and kyl optionally substituted by 13 R99.

Embodiment 439. The compound of any of Embodiments l-427, wherein R72 and R73 at each occurrence is independently chosen from H, C1_6alkyl, phenyl, and benzyl.

Embodiment 440. The compound of any of Embodiments l-427, wherein R72 and R73 at each occurrence is independently chosen from H and C1_6alkyl. -l35- Embodiment 441. The compound of any of ments 1-427, wherein R72 and R73 at each occurrence is H.

Embodiment 442. The compound of any of Embodiments l-44l, wherein R78 at each occurrence is independently chosen from C1_6alkyl optionally substituted by 1-13 R89, kenyl ally substituted by 1-11 R89, C2_6alkynyl optionally substituted by l- 9 R89, C6_11aryl optionally substituted by 1-11 R89, C7_16arylalkyl optionally substituted by 1—19 R89, C3_11cycloalkyl optionally substituted by 1—21 R89, C4_17cycloalkylalkyl optionally substituted by 1-32 R89, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R89, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40 R89, 5- ed heteroaryl optionally substituted by 1-15 R89, and 6-21 membered heteroarylalkyl ally substituted by 1-27 R89. ment 443. The compound of any of Embodiments l-44l, n R78 at each ence is independently chosen from C1_6alkyl optionally substituted by 1-3 R89, C2_6alkenyl optionally substituted by 1-3 R89, C2_6alkynyl optionally substituted by 1-3 R89, C6_11aryl optionally substituted by 1-3 R89, C7_16arylalkyl optionally substituted by 1-3 R89, C3_11cycloalkyl optionally substituted by 1-3 R89, C4_17cycloalkylalkyl optionally substituted by 1-3 R89, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R89, 4-21 ed heterocycloalkylalkyl optionally substituted by 1-3 R89, 5-15 membered heteroaryl optionally substituted by 1-3 R89, and 6-21 membered heteroarylalkyl optionally substituted by 1-3 R89.

Embodiment 444. The compound of any of Embodiments l-44l, wherein R78 at each occurrence is independently chosen from C1_6alkyl optionally substituted by 1-3 R89, C2_6alkenyl optionally tuted by 1-3 R89, C2_6alkynyl optionally substituted by 1-3 R89, C6_10aryl optionally substituted by 1-3 R89, C7_11arylalkyl optionally substituted by 1-3 R89, C3_10cycloalkyl ally substituted by 1-3 R89, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R89, and 5-10 ed heteroaryl optionally substituted by 1—3 R89.

Embodiment 445. The compound of any of Embodiments l-44l, wherein R78 at each occurrence is ndently chosen from C1_6alkyl ally substituted by 1-3 R89, C6_10aryl optionally substituted by 1-3 R89, C7_11arylalkyl optionally substituted by 1-3 R89, C3_10cycloalkyl optionally substituted by 1-3 R89, 3-10 membered cycloalkyl optionally substituted by 1-3 R89, and 5-10 membered heteroaryl optionally substituted by 1—3 R89. — 136 — Embodiment 446. The compound of any of Embodiments l-44l, wherein R78 at each occurrence is independently chosen from C1_6alkyl optionally substituted by 1-3 R89, phenyl ally substituted by 1-3 R89, benzyl optionally substituted by 1-3 R89, C3- 6cycloalkyl ally substituted by 1-3 R89, 3-6 membered heterocycloalkyl optionally substituted by 1-3 R89, and 5-6 membered aryl optionally substituted by 1-3 R89.

Embodiment 447. The compound of any of Embodiments l-44l, wherein R78 at each occurrence is independently chosen from C1_6alkyl, phenyl, benzyl, C3_6cycloalkyl, 3-6 ed heterocycloalkyl, and 5-6 membered heteroaryl.

Embodiment 448. The compound of any of ments l-44l, wherein R78 at each ence is independently chosen from C1_6alkyl optionally substituted by 1-3 R89, phenyl optionally substituted by 1-3 R89, and benzyl optionally substituted by 1-3 R89.

Embodiment 449. The compound of any of ments l-44l, wherein R78 at each occurrence is independently chosen from C1_6alkyl, phenyl, and benzyl.

Embodiment 450. The compound of any of Embodiments l-44l, wherein R78 at each occurrence is kyl optionally substituted by 1-3 R89.

Embodiment 45 l. The compound of any of Embodiments l-44l, wherein R78 at each occurrence is C1_6alkyl.

Embodiment 452. The compound of any of ments 1-45 1 wherein R79, R89, R99 and R109 at each occurrence is independently chosen from C1_6alkyl ally substituted by 1-13 halogen, C2_6alkenyl, C2_6alkynyl, C6_11aryl, C7_16arylalkyl, C3_ 11cycloalkyl, C4_17cycloalkylalkyl, 3-l5 membered heterocycloalkyl, 4-21 membered heterocycloalkylalkyl, 5-l5 membered heteroaryl, 6-21 membered heteroarylalkyl, halogen, —CN, —C(=O)R“°, —C(=0)0R“°, —C(=0)NR“°R“°, —C(=O)C(=O)R“°, — C(=NR110)R110, —C(=NR110)NR110R110, —C(=NOH)NR110R110, —C(=NOR110)R110, _ C(=NNR110R110)R110, —C(=NNR110C(=O)R110)R110, R110C(=O)OR110)R110, _ C(=S)NR110R110, —NC, —N02, —NR110R110, —NR110NR110R110, —N=NR110, =NR110, =\IOR110, 0R110, —NR110C(=O)R110, —NR110C(=O)C(=O)R110, —NR110C(=O)OR110, —\IR“0C(=0)C(=0)0R“°, —NR“0C(=0)NR“°R“°, —NR11°C(=0)NR“°C(=0)R“0, — l\ R110C(=O)NR110C(=O)OR110, —NR110C(=NR110)NR110R110, _ l\ R110C(=O)C(=O)NR110R110, —NR110C(=S)R110, —NR110C(=S)OR110, _ l\ R110C(=S)NR110R110, —NRUOS(=O)2R110, —NRUOS(=O)2NR110R110, _ l\ R110P(=O)R111R111, —NR110P(=O)(NR110R110)(NR110R110), —NR110P(=O)(OR110)(OR110), —\IR11°P(=0)(SR“°)(SR“°), —0R“°, =o, —OCN, )R“°, —0C(=0)NR“°R“°, — - 137 — OC(=O)OR“°, —0C(=NR“°)NR“°R“°, —OS(=O)R“°, )2R“°, )20R“°, — OS(=O)2NR110R110, —OP(=O)R111R111, —OP(=O)(NR110R110)(NR110R110), _ OP(=O)(OR“°)(OR“0), —OP(=O)(SR“°)(SR“°), —Si(R“°)3 — , —SCN, =s, nR“0, S(=O)20R110, —803R110, —S(=O)2NR110R110, —S(=O)NR110R110, —SP(=O)R111R111, _ SP(=O)(NR110R110)(NR110R110), —SP(=O)(OR110)(OR110), —SP(=O)(SR110)(SR110), _ P(=O)R111R111, —P(=O)(NR110R110)(NR110R110), —P(=O)(OR110)(OR110), and _ P(=O)(SR“0)(SR“0).

Embodiment 453. The compound of any of ments 1-45 1 wherein R79, R89, R99 and R109 at each occurrence is independently chosen from C1_6alkyl optionally substituted by 1-6 halogen, C2_6alkenyl, C2_6alkynyl, C6_11aryl, C7_16arylalkyl, C3- 11cycloalkyl, C4_17cycloall<ylalkyl, 3-15 membered heterocycloalkyl, 4-l5 membered heterocycloalkylalkyl, 5-l5 membered heteroaryl, 6-15 membered heteroarylalkyl, halogen, —CN, —C(=O)R“°, —C(=0)0R“°, —C(=0)NR“°R“°, —C(=O)C(=O)R“°, —NC, — N02, —NR110R110, —NR110NR110R110, —NR1100R110, —NR110C(=O)R110, _ NR“°C(=0)C(=0)R“0, —NR“°C(=0)0R“0, —NR“°C(=O)C(=O)OR“°, — NR110C(=O)NR110R110, —NR110C(=O)NR110C(=O)R110, —NR110C(=O)NR110C(=O)OR110, _ NR110C(=O)C(=O)NR1IORUO, _NRIIOS(:O)2R110’ —NRUOS(=O)2NR110R110, _ NR110P(=O)R111R111, —NR110P(=O)(NR110R110)(NR110R110), —NR110P(=O)(OR110)(OR110), —0R“°, =o, —OCN, —0C(=0)R“°, —0C(=0)NR“°R“0, )OR“°, )R“°, — OS(=O)2R“°, —OS(=O)20R“°, —OS(=O)2NR“°R“°, —0P(=0)R“1R“1, — 0P(=0)(NR“°R11°)(NR110R110), —OP(=O)(OR“°)(OR“°), —Si(R“°)3, —SCN, =s, — S(=O)nR110, —S(=O)20R110, —SOgR110, —S(=O)2NR110R110, —S(=O)NR110R110, _ P(=O)R111R111, —P(=O)(NR110R110)(NR110R110), and —P(=O)(OR110)(OR110).

Embodiment 454. The compound of any of Embodiments 1-45 1 wherein R79, R89, R99 and R109 at each occurrence is independently chosen from C1_6alkyl ally substituted by 1-3 n, C2_6alkenyl, C2_6alkynyl, C6_10aryl, C7_11arylalkyl, C3- 10cycloalkyl, C4_17cycloall<ylalkyl, 3-10 ed heterocycloalkyl, 4-10 membered heterocycloalkylalkyl, 5-10 membered heteroaryl, 6-10 membered heteroarylalkyl, halogen, —CN, —C(=O)R“°, —C(=0)0R“°, —C(=0)NR“°R“°, —NC, —N02, —NR“0R“°, — RIIO’ —NR110C(=O)R110, —NR110C(=O)OR110, —NR110C(=O)NR110R110, _ NR110C(=O)NR110C(=O)R110, _NRIIOS(:O)2R110’ —NRUOS(=O)2NR110R110, _ NR110P(=O)R111R111, —NR110P(=O)(NR110R110)(NR110R110), —NR110P(=O)(OR110)(OR110), —0R“°, =o, —OCN, —0C(=0)R“°, —0C(=0)NR“°R“°, —OS(=O)2NR“°R“°, — -l38- OP(=O)R111R111, )(NR110R110)(NR1IORUO), —SCN, =S, —S(=O)nR110, _ S(=O)2NR110R110, —S(=O)NR110R110, —P(=O)R111R111, and —P(=O)(NR110R110)(NR110R110).

Embodiment 455. The nd of any of Embodiments 1-45 1 wherein R79, R89, R99 and R109 at each occurrence is independently chosen from C1_6alkyl optionally substituted by 1-3 halogen, C2_6alkenyl, C2_6alkynyl, C6_10aryl, C7_11arylalkyl, C3- locycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl, halogen, —CN, —C(=O)R110, —C(=O)OR110, —C(=O)NR110R110, —N02, —NR110R110, —NR1100R110, _ NR110C(=O)R110, —NR110C(=O)NR110R110, (=O)2R110, _NRIIOS(:O)2NR110R110’ _ OR”, :0, —OCN, —OC(=O)R“0, —S(=O)nR“0, —S(=O)2NR“°R“°, and —S(=0)NR“0R“0.

Embodiment 456. The compound of any of Embodiments 1-45 1 wherein R79, R89, R99 and R109 at each occurrence is independently chosen from C1_6alkyl optionally substituted by 1-3 halogen, C2_6alkenyl, C2_6alkynyl, phenyl, benzyl, C3_6cycloalkyl, 3-6 membered cycloalkyl, 5-6 membered heteroaryl, halogen, —CN, R110, — C(=O)OR110,—C(=O)NR110R110,—N02, —NR110R110, —NR110C(=O)R110, _ NR110C(=O)NR110R110, (=O)2R110, —NRUOS(=O)2NR110R110, —OR110, :0, _ S(=O)nR“°, and 2NR“°R“°.

Embodiment 457. The compound of any of Embodiments 1-45 1 wherein R79, R89, R99 and R109 at each occurrence is ndently chosen from C1_6alkyl optionally substituted by 1-3 halogen, C2_6alkenyl, C2_6alkynyl, phenyl, benzyl, C3_6cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halogen, —CN, —C(=O)R110, — C(=O)OR110, NR110R110, —NR110R110, —NR110C(=O)R110, _NRIIOS(:O)2R110’ _ OR”, :0, —S(=O)nR“0, and —S(=O)2NR“°R“°.

Embodiment 458. The compound of any of Embodiments 1-45 1 wherein R79, R89, R99 and R109 at each occurrence is independently chosen from C1_6alkyl optionally substituted by 1-3 halogen, phenyl, , C3_6cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halogen, —CN, —C(=O)R110, —C(=O)OR110, — C(=O)NR110R110, —NR110R110, , :0, —S(=O)nR110, and —S(=O)2NR110R110.

Embodiment 459. The compound of any of Embodiments 1-45 1 wherein R79, R89, R99 and R109 at each occurrence is independently chosen from C1_6alkyl optionally substituted by 1-3 n, halogen, and —NR110R110.

Embodiment 460. The compound of any of Embodiments 1-45 1 wherein R79, R89, R99 and R109 at each occurrence is independently chosen from C1_6alkyl, n, and _NR110R110 -l39- Embodiment 461. The compound of any of Embodiments l-451, wherein R79, R89, R99 and R109 at each ence is independently chosen from C1_6alkyl and — NRUORUO.

Embodiment 462. The compound of any of Embodiments l-451, wherein R79, R89, R99 and R109 at each occurrence is —NR110R110.

Embodiment 463. The compound of any of Embodiments l-451, wherein R79, R89, R99 and R109 at each occurrence is C1_6alkyl.

Embodiment 464. The nd of any of Embodiments l-451, n R79 at each occurrence is independently chosen from C1_6alkyl and —NR110R110; R89, R99 and R109 at each occurrence is C1_6alkyl.

Embodiment 465. The compound of any of Embodiments l-451, wherein R79 at each occurrence is independently chosen from C1_6alkyl and —NR110R110; R89, R99 and R109 at each ence is —NR110R110.

Embodiment 466. The compound of any of Embodiments l-451, wherein R79 at each occurrence is R110; R89, R99 and R109 at each occurrence is C1_6alkyl.

Embodiment 467. The nd of any of Embodiments l-466, wherein R110 at each occurrence is independently chosen from H, C1_6alkyl and C1_6-haloalkyl.

Embodiment 468. The compound of any of Embodiments l-466, wherein R110 at each occurrence is independently chosen from H and C1_6alkyl. ment 469. The compound of any of Embodiments l-466, wherein R110 at each occurrence is C1_6alkyl.

Embodiment 470. The nd of any of Embodiments l-466, wherein R110 at each occurrence is H.

Embodiment 471. The compound of any of Embodiments l-470, wherein R111 at each occurrence is independently chosen from C1_6alkyl and C1_6-haloalkyl.

Embodiment 472. The compound of any of Embodiments l-470, wherein R111 at each ence is C1_6alkyl.

Embodiment 473. The compound of any of Embodiments l-470, wherein R111 30 at each occurrence is C1_6-haloalkyl. —140— Embodiment 474. The compound of any of ments 1-473, wherein n at each occurrence is independently chosen from 0, l, and 2.

Embodiment 475. The nd of any of Embodiments 1-473, wherein n at each occurrence is independently chosen from 0 and 2.

Embodiment 476. The compound of any of Embodiments 1-473, wherein n at each occurrence is independently chosen from 1 and 2.

Embodiment 477. The compound of any of Embodiments 1-473, wherein n at each occurrence is independently chosen from 0 and l.

Embodiment 478. The compound of any of Embodiments 1-473, n n at each occurrence is 0.

Embodiment 479. The compound of any of ments 1-473, n n at each occurrence is l.

Embodiment 480. The compound of any of Embodiments 1-473, wherein n at each occurrence is 2.

Embodiment 48 l. The compound of any of Embodiments 1-480, wherein neither R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, nor R28 contain either of the following chemical moieties W W Ho\ J J Z Z or ; wherein W is O or S, and Z is N or C.

Embodiment 482. The compound of any of Embodiments 1-48 1 wherein neither R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, nor R28 is: R301 (a) ; where W is O or S; J is O, NH or NCH3; and R301 is hydrogen or alkyl; —141— WO 78126 (b) 302 ; Where W is O or S; Y2 is absent, N, or CH; Z is N or CH; R302 and R304 are independently hydrogen, hydroxyl, or an aliphatic group; provided that if R302 and R304 are both present, one of R302 or R304 must be hydroxyl and if Y2 is absent, R304 must be hydroxyl; and R303 is hydrogen or aliphatic group; W W W HO\Z)KY}Z Ho\ JR}: Z Ho\Z)KY)vZ w w w HO\Z)J\Y}IZ HO\ )k )7, HO\ )k )1 Z Y Z Y K2 U1 “K21 9 9 9 w w \Y)7Z HO\ A )2 Z Y k)|1 | 1 1 l 1 , ;Where W is O or S; Y1 and 21 are independently N, C or CH; or R201 NH2 R202 A)72 203 | (d) 212 211 Where Z is N or CH; Y2 is absent, N, or CH; W is O or S; R211 and R212 are independently selected from hydrogen or aliphatic group; R201, R202 and R203 are independently selected from hydrogen, hydroxyl, amino, halogen, alkoxy, niino, dialkylaniino, CF3, CN, N02, sulfonyl, acyl, aliphatic group, substituted aliphatic group, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted cyclic; wherein for the purpose of this Embodiment, the following deﬁnitions apply: —142— an aliphatic group is a non-aromatic moiety that may be saturated (e.g. single bond) or contain one or more units of unsaturation, e.g., double and/or triple bonds; an aliphatic group may be straight chained, branched or cyclic, contain carbon, hydrogen or, optionally, one or more heteroatoms and may be substituted or unsubstituted; "acyl" refers to hydrogen, alkyl, partially saturated or ﬁllly saturated cycloalkyl, partially saturated or fully ted heterocycle, aryl, and heteroaryl substituted carbonyl groups; "alkoxy" es linear or ed oxy-containing radicals each haVing alkyl portions of one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms; and "heterocyclic" refers to saturated, partially unsaturated and rated heteroatom-containing ringshaped radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen; Embodiment 483. The compound of any of Embodiments 1-482, wherein A is not S.

Embodiment 484. The compound of any of Embodiments 1-483, n R1 is not —OR20.

Embodiment 485. The compound of any of Embodiments l-484, wherein R8 is not tetrahydrofuranyl substituted by 4 or 5 R19.

Embodiment 486. The compound of any of Embodiments l-484, wherein R8 is 3/0 O\ 2 T T not wherein T1 is R39; T2, T3, and T5 are independently chosen from R30, R30, —C(=O)NR32R33, —C(=O)OR3°, —C(=NR35)NR32R33, —S(=O)R3°, — S(=O)2R30, 20R3°, 2NR32R33, —P(=O)R38R38, —P(=O)(NR32R33)(NR32R33), — P(=O)(OR30)(OR30), and —P(=O)(SR30)(SR30); and T4 is R”. —143— W0 2013/078126 Embodiment 487. The compound of any of Embodiments 1-484, wherein R8 is T3/O O\T2 not wherein T1 is hydrogen, ﬂuoro, azido, amino, hydroxyl, C1_ galkoxy, mercapto, or C1_3alkylthio; T2, T3, and T5 are independently chosen from R30, — C(=O)R3°, NR32R33, —C(=O)OR30, —C(=NR35)NR32R33, —S(=O)R3°, —S(=O)2R30, — S(=O)20R30, —S(=O)2NR32R33, —P(=O)R38R38, —P(=O)(NR32R33)(NR32R33), — P(=O)(OR30)(OR30), and (SR30)(SR30); and T4 is hydrogen, azido, methyl, hydroxymethyl, or ﬂuoromethyl.

Embodiment 488. The compound of any of Embodiments 1-487, wherein R10 is not —CN.

Embodiment 489. The compound of any of Embodiments 1-488, wherein none of R1 and R2, R1 and R3, R1 and R5, or R1 and R11, together with the atoms linking them, form a cycloalkyl optionally substituted by one or more R19 or a heteroaryl optionally tuted by one ore more R19.

Embodiment 490. The compound of any of Embodiments 1-488, wherein R1 and R11 do not, together with the atoms linking them, form a heterocycloalkyl optionally substituted by one or more R19 or a heteroaryl optionally tuted by one or more R19.

Embodiment 491. The compound of any of Embodiments 1-490, wherein neither R7 nor R10 is H, or neither R8 nor R9 is H.

Embodiment 492. The compound of Embodiment 491, wherein neither R7 nor R10 is H.

Embodiment 493. The nd of Embodiment 491, wherein neither R8 nor R9 is H.

Embodiment 494. The nd of any of Embodiments 1-493, wherein neither R3 and R4 nor R5 and R6 together form =0, =NR20, =NOR20, or =S. ment 495. The compound of any of Embodiments l-494, wherein neither R3 and R4 nor R5 and R6 together form =0.

Embodiment 496. The compound of any of Embodiments 1-495, wherein (a) when R1 is H, R2 is neither aryl optionally substituted by one or more R19 nor aryl optionally substituted by one or more R19, —144— (b) when R2 is H, R1 is neither optionally substituted by one or more R19 nor heteroaryl optionally substituted by one or more R19, (c) R3, R4, R5, and R6 are not —NHR22, —NHR23, —SOZNHR22, —SOZNHR23, — C(=O)NHR22, or —C(=O)NHR23, wherein R22 and R23 are either aryl optionally substituted by one or more R59 or heteroaryl optionally substituted by one or more R59, and (d) R3, R4, R5, and R6 do not contain a group of formula —NHR, —SOZNHR, or — HR, wherein R is optionally substituted aryl, or optionally substituted aryl.

Embodiment 497. The nd of any of Embodiments 1-496, wherein the R3 l: B R4 \R2 H'Tl/ R5 o\ 6 A NH R «it wit group of formula does not together form a group of formula B is an optionally substituted aryl, or ally substituted heteroaryl; Q is a C1_4alkylidene chain in which each methylene unit of said Q is substituted by R2 and R2,, and up to two non-adjacent methylene units of said Q are optionally and independently replaced by —SOz or —C(=O); each R2 is independently selected from H, —OH, C1_10alkyl, €1-10 tic, (€1-10 aliphatic)-NH-(C1_10 aliphatic); -O-(C1_10 aliphatic); -NH2, -NH(C1_10 aliphatic), -N(C1_10 aliphatic)2, -C(=O)R, aryl, or aryl, wherein said aliphatic, aryl, or heteroaryl is optionally substituted; each R2, is independently selected from H and an optionally substituted C140 aliphatic group; and R is selected from an optionally substituted group selected from €1-10 aliphatic, aryl, aralkyl, heteroaryl, and heteroaralkyl; wherein for the purpose of this Embodiment, the following deﬁnitions apply: "alkylidene chain" refers to a straight or branched carbon chain that may be fully saturated or have one or more units of un tion and has two points of ment to the rest of the molecule; —145— "aliphatic" or "aliphatic group" means a straight-chain or branched, tuted or unsubstituted C1-C8 hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic C3-C8 hydrocarbon or bicyclic Cg-Cn hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule wherein any individual ring in said bicyclic ring system has 3-7 members.

Embodiment 498. The compound of any of Embodiments 1-497, wherein R8 is neither aryl optionally tuted by one or more R19 nor heteroaryl optionally substituted by one or more R19.

Embodiment 499. The compound of any of Embodiments 1-498, n: (a) when R9 is —NH2, R10 is not —C(=O)NH2; (b) when R9 is S)NHCOPh, R10 is not —C(=O)OR20, wherein R20 is alkyl optionally substituted by R49; and (c) R9 and R10 do not, together with the atoms g them, form a group of O R MH hw HN H N / / f O O formula or wherein R19 is as deﬁned herein.

Embodiment 500. The compound of any of Embodiments 1-499, wherein: (a) when R9 is —NH2, R10 is not —C(=O)NH2; and (b) R9 and R10 do not, together with the atoms linking them, form a group of O R H >LNH HN H N / / f O O a or wherein R is as deﬁned herein.

Embodiment 501. The compound of any of Embodiments 1-500, wherein R9 and R10 do not, together with the atoms linking them, form a group of a o R H H o H%;o or wherein R19 is as deﬁned herein.

Embodiment 502. The compound of any of Embodiments 1-501, wherein neither R1 and R2 nor R1 and R3, together with the atoms linking them, form a heterocycloalkyl optionally substituted by one or more R19 or a heteroaryl optionally substituted by one or more R19, wherein R19 is as deﬁned herein.

Embodiment 503. The compound of any of Embodiments 1-502, wherein R10 is not —CN, aryl optionally substituted by one or more R19, heterocycloalkyl optionally substituted by one or more R19, or heteroaryl optionally substituted by one or more R19, wherein R19 is as deﬁned herein.

Embodiment 504. The compound of any of Embodiments l-503, n R9 is neither —NH2 nor —OH when R10 is —C(=O)R20, OR20, or —C(=O)NR22R23, wherein R20, R22, and R23 are as deﬁned herein.

Embodiment 505. The compound of any of Embodiments 1-504, wherein when (a) R9 is chosen from H, C1-C6alkyl, C3-C7cycloalkyl and -(CH2)n1-R411 wherein the subscript nl is an integer of from 0 to 3 and R411 is selected from C1-C6alkoxy, C1- C6alkylthio, mono- or -C6alkyl)amino, amino, phenyl, pyridyl, furanyl, pyrrolyl, olyl, oxazolyl, isoxazolyl, triazolyl, olyl, thiazolyl, pyrazolyl, and thienyl, wherein each of the rings is ally substituted with from 1 to 3 substituents ed from halogen, N3, N02, CN, C1-C6alkyl, OR412,N(R412)2, C02R412 and CON(R412)2, wherein each R412 is independently H or lkyl; and (b) R10 is chosen from —R401, —OR401, —SR401, —N(R410)R401, —C(=O)R401, and — CH(OH)R401, wherein R410 is selected from H, C1-C6alkyl and C(=O)C1-C6alkyl; and R401 is chosen from H, halo, CN, N02, N3, C1-C6alkyl, C3-C7cycloalkyl, -C(R413)=C(R413)2, — CECR413 or -(CH2)n2-R414; wherein each R413 is independently ed from H, F, Cl, Br, CN, C1-C6alkyl, C3-C7cycloalkyl, (CH2)n2-R414 and C(O)-(CH2)n2-R414; and wherein each ipt n2 is independently an integer of from 0 to 3 and each R414 is ndently selected from C1-C6alkoxy, C1-C6alkylthio, mono- or di-(Cl-C6)alkylamino, amino, phenyl, pyridyl, ﬁlranyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, thiazolyl, pyrazolyl, and thienyl, n each of the rings is optionally substituted with from 1 to 3 substituents selected from n, N02, N3, CN, (C1-C6)alkyl, OR415, N(R415)2, C02R415 and CON(R415)2, wherein each R415 is independently H or C1-C6alkyl; and wherein any alkyl or lkyl portions of R401 are optionally substituted with from one to ﬁve F substituents; R1 and R11 do not, together with the atoms linking them, form a 6-7 membered heterocycloalkyl optionally substituted by one or more R19, wherein R19 is as deﬁned ment 506. The nd of any of Embodiments 1-504, wherein when (a) R9 is chosen from H, C1-C6alkyl, C3-C7cycloalkyl and -(CH2)n1-R411 wherein the ipt nl is an integer of from 0 to 3 and R411 is selected from lkoxy, C1- lthio, mono- or di-(Cl-C6alkyl)amino, amino, phenyl, pyridyl, furanyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, thiazolyl, pyrazolyl, and thienyl, wherein each of the rings is optionally substituted with from 1 to 3 substituents selected from halogen, N3, N02, CN, C1-C6alkyl, OR412,N(R412)2, C02R412 and CON(R412)2, wherein each R412 is independently H or C1-C6alkyl; and (b) R10 is chosen from —R401, —OR401, —SR401, —N(R410)R401, —C(=O)R401, and — CH(OH)R401, wherein R410 is selected from H, C1-C6alkyl and C(=O)C1-C6alkyl; and R401 is chosen from H, halo, CN, N02, N3, lkyl, C3-C7cycloalkyl, -C(R413)=C(R413)2, — CECR413 or -(CH2)n2-R414; wherein each R413 is independently selected from H, F, Cl, Br, CN, C1-C6alkyl, C3-C7cycloalkyl, (CH2)n2-R414 and CH2)n2-R414; and wherein each subscript n2 is independently an integer of from 0 to 3 and each R414 is independently ed from C1-C6alkoxy, C1-C6alkylthio, mono- or di-(Cl-C6)alkylamino, amino, phenyl, pyridyl, l, pyrrolyl, imidazolyl, yl, isoxazolyl, triazolyl, tetrazolyl, thiazolyl, pyrazolyl, and thienyl, wherein each of the rings is optionally substituted with from 1 to 3 substituents selected from halogen, N02, N3, CN, (C1-C6)alkyl, OR415, N(R415)2, C02R415 and CON(R415)2, wherein each R415 is independently H or C1-C6alkyl; and wherein any alkyl or cycloalkyl portions of R401 are optionally substituted with from one to ﬁve F substituents; R1 and R11 do not, together with the atoms linking them, form a 6-7 membered heterocycloalkyl optionally substituted by 1-4 R403 wherein each R403 is independently chosen from C1-C6alkyl, C3-C7cycloalkyl, -(CH2)n4-R419 and -C(O)-(CH2)n4-R419; wherein the subscript n4 is an integer of from 0 to 4 and each R419 is independently selected from C1-C6alkoxy, C1-C6alkylthio, mono- or di-(C1-C6)alkylamino, amino, phenyl, pyridyl, ﬁlranyl, pyrrolyl, olyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, thiazolyl, pyrazolyl, and thienyl, wherein each of the rings is optionally substituted with from 1 to 3 substituents selected from halogen, N3, N02, CN, C1-C6alkyl, , 0)2, C02R420 and CON(R420)2, wherein each R420 is independently H or C1-C6alkyl; and wherein any alkyl or lkyl portions of R403 are optionally substituted with from one to ﬁve F substituents.

Embodiment 507. The nd of any of Embodiments 1-504, wherein R1 and R11 do not, together with the atoms linking them, form a 6-7 membered heterocycloalkyl optionally substituted by 1-4 R403, wherein each R403 is independently chosen from C1-C6alkyl, C3-C7cycloalkyl, -(CH2)n4-R419 and -C(O)-(CH2)n4-R419; wherein the subscript n4 is an integer of from 0 to 4 and each R419 is independently selected from C1-C6alkoxy, lkylthio, mono- or di-(Cl-C6)alkylamino, amino, phenyl, pyridyl, ﬁlranyl, yl, imidazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, thiazolyl, pyrazolyl, and thienyl, wherein each of the rings is optionally substituted with from 1 to 3 substituents selected from halogen, N3, N02, CN, C1-C6alkyl, -OR420, -N(R420)2, C02R420 and CON(R420)2, wherein each R420 is independently H or lkyl; and wherein any alkyl or cycloalkyl portions of R403 are optionally substituted with from one to ﬁve F substituents.

Embodiment 508. The compound of any of ments 1-504, wherein R1 and R11 do not, together with the atoms linking them, form a 6-7 membered heterocycloalkyl optionally substituted by one or more R19, wherein R19 is as deﬁned herein.

The above Embodiments include salts of acidic and basic compounds of formula (I). Preferably, the salts are ceutically acceptable. Pharmaceutically acceptable acid addition salts of basic compounds of formula (I) include, but are not limited to, salts derived from nic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, and phosphorus, as well as the salts derived from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, dioic acids, aromatic acids, and aliphatic and aromatic sulfonic acids. Such salts thus include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulﬁte, bisulﬁte, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, caprylate, isobutyrate, e, malonate, succinate, suberate, te, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, and methanesulfonate. See, for example, Berge et al., "Pharmaceutical " J. of Pharmaceutical Science, 1977; 66: 1-19.

Acid addition salts may be ed by contacting a compound of formula (I) with a sufficient amount of the desired acid to e the salt in the conventional manner. The free base form of the compound of formula (I) may be rated by contacting the salt form with a base and isolating the free base in the conventional manner.

Pharmaceutically acceptable base salts of acidic compounds of a (I) are formed with metals or amines, such as alkali and alkaline earth metal hydroxides, or of organic amines. Examples of metals used as cations e, but are not limited to, sodium, potassium, magnesium, and calcium. Examples of suitable amines include, but are not limited to, N,N'- dibenzylethylenediamine, chloroprocaine, choline, nolamine, ethylenediamine (ethane-l,2-diamine), N—methylglucamine, and procaine.

See, for example, Berge et al., "Pharmaceutical Salts," J. of Pharmaceutical Science, 1977; 66: l - l 9.

Base salts may be prepared by contacting a nd of formula (I) with a sufficient amount of the desired base to produce the salt in the conventional manner. The acid form of the compound of a (I) may be regenerated by contacting the salt form with an acid and isolating the acid in a conventional manner.

Some compounds of the present invention may exist as stereoisomers, including enantiomers, diastereomers, and geometric s. Geometric isomers include compounds of the present invention that have alkenyl groups, which may exist as entgegen or zusammen conformations, in which case all geometric forms thereof, both entgegen and zusammen, cis and trans, and mixtures f, are within the scope of the t invention. Some compounds of the present invention have cycloalkyl groups, which may be substituted at more than one carbon atom, in which case all geometric forms thereof, both cis and trans, and mixtures f, are within the scope of the present invention. All of these forms, including (R), (S), epimers, diastereomers, cis, trans, syn, anti, (E), (Z), tautomers, and mixtures thereof, are included in the compounds of the present ion.

The compounds of the present invention may be in any physical form, including amorphous or crystalline solids in any polymorphic form, in any state of purity.

Crystalline polymorphic forms include ated forms as well as solvated forms, such as hydrated forms.

III. Pharmaceutical Compositions The present invention further provides pharmaceutical compositions comprising a compound of any of the above Embodiments (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof), together with a pharmaceutically acceptable excipient therefor. For preparing a ceutical composition from a compound of the present invention, pharmaceutically acceptable ents can be either solid or liquid. An excipient can be one or more nces which may act as, e.g., a carrier, diluent, ﬂavoring agent, binder, preservative, tablet disintegrating agent, or an encapsulating material. The pharmaceutical composition may contain two or more compounds of the present invention (e. g., two different salt forms of a compound of formula (I), may be used together in the same ceutical composition). Preferably, the pharmaceutical composition contains a therapeutically effective amount of a compound of formula (I) or a ceutically acceptable salt form thereof. In one embodiment, the composition contains an amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof effective to treat an al protein kinase C (aPKC)-dependent disorder or condition. Preferably, a compound of the present invention will cause a decrease in symptoms or disease indicia associated with an aPKC-dependent er as measured quantitatively or qualitatively. The ition may also contain, in addition to a nd of formula (I) or a pharmaceutically able salt form f and a ceutically acceptable excipient, another therapeutic nd, such as a compound useful in the treatment of cancer.

A nd of the present invention can be formulated as a ceutical composition in any delivery form, such as a syrup, an elixir, a suspension, a powder, a granule, a tablet, a capsule, a lozenge, a troche, an aqueous solution, a cream, an ointment, a , a gel, an emulsion, etc. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Preferably, the pharmaceutical composition is a tablet or capsule. In one embodiment, the pharmaceutical composition is a tablet. In another embodiment, the pharmaceutical composition is a capsule.

In powders, the excipient may be a ﬁnely divided solid in a mixture with a finely divided active component (i.e., nd of the present invention). In tablets, the active component may be mixed with an excipient having the necessary binding properties in suitable proportions and compacted in the shape and size desired. Suitable excipients include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, - lSl - starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter, and the like.

The pharmaceutical composition preferably contains from 1% to 95% (w/w) of the active compound (i.e., compound of the present invention). More preferably, the pharmaceutical composition contains from 5% to 70% (w/w) of the active compound.

For preparing suppositories, a low g wax, such as a mixture of fatty acid glycerides or cocoa butter, may be melted and the active component dispersed homogeneously therein, as by stirring. The molten homogeneous mixture may then be poured into convenient sized molds, allowed to cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions.

Formulations suitable for parenteral administration, such as, for example, by intravenous, intramuscular, intradermal, and subcutaneous routes, include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain antioxidants, s, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and nonaqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. In the practice of this invention, compositions can be administered, for example, by enous infusion, orally, topically, intraperitoneally, esically or intrathecally. The formulations of compounds can be presented in unit-dose or multi-dose sealed containers, such as es and vials. Injection solutions and suspensions can be ed from sterile powders, es, and tablets of the kind previously described.

A compound of the t invention, alone or in combination with other suitable components, can be made into aerosol ations (e.g., they can be "nebulized") to be administered via inhalation. Aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodiﬂuoromethane, propane, nitrogen, and the like.

Pharmaceutically acceptable excipients are determined in part by the particular composition being administered, as well as by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of pharmaceutical compositions of the present invention (see, e.g., ton: The Science and ce ofPharmacy, 20th ed., Gennaro et al. Eds., Lippincott ms and Wilkins, 2000).

The ty of active component in a pharmaceutical composition may be varied or adjusted from, e.g., 1 mg to 1,000 mg, 5 mg to 500 mg, 10 mg to 300 mg, or 25 mg to 250 mg, according to the ular application and the desired size of the dosage form. - l52 - The dose administered to a subject is ably sufﬁcient to induce a ial therapeutic response in the subject over time. The beneﬁcial dose can vary from subject to subject ing upon, e. g., the subject’s condition, body weight, surface area, and side effect susceptibility. Administration can be accomplished via single or divided doses.

IV. Method of Treatment In another aspect, the present invention provides a method of treating an aPKC- dependent disorder or condition in a subject comprising: administering to the subject a compound of formula (I) as deﬁned in any of the above Embodiments or a pharmaceutically acceptable salt form thereof. In another aspect, the present invention provides a compound of a (I) as deﬁned in any of the above Embodiments or a pharmaceutically acceptable salt form thereof for use in treating an aPKC-dependent disorder or condition in a subject. In another aspect, the present invention provides a compound of formula (I) as deﬁned in any of the above ments or a pharmaceutically acceptable salt form thereof for use in the ation of a medicament for treating an aPKC-dependent disorder or condition in a t. Preferably, the compound is administered to the subject as a pharmaceutical composition comprising a pharmaceutically acceptable excipient. ably, the compound is administered to the subject in a pharmaceutically acceptable amount. In one embodiment, the aPKC- dependent ion or disorder is cancer. In another embodiment, the aPKC-dependent condition is selected from non-small cell lung cancer (NSCLC), squamous cell carcinoma (e.g., oesophageal squamous cell carcinoma), leukaemia, prostate , non-Hodgkin’s lymphoma (e. g., follicular lymphoma), endometrial cancer, lung cancer and breast cancer.

The aPKC-dependent disorder or condition can be treated prophylactically, acutely, or chronically using compounds of the present invention, depending on the nature of the disorder or condition. lly, the subject in each of these methods is human, although other s can also beneﬁt from the administration of a compound of the present invention.

In another embodiment, the present invention provides a method of ng a erative disorder in a subject, comprising administering to the subject a compound of formula (I) as deﬁned in any of the above Embodiments or a pharmaceutically acceptable salt form thereof. In another aspect, the present invention provides a compound of formula (I) as deﬁned in any of the above Embodiments or a pharmaceutically acceptable salt form thereof for use in treating a proliferative disorder in a subject. In r aspect, the present invention provides a compound of a (I) as deﬁned in any of the above Embodiments or a pharmaceutically acceptable salt form thereof for use in the preparation of a medicament for treating a proliferative disorder in a t. Preferably, the compound is administered to the t in a pharmaceutical composition comprising a ceutically acceptable ent. Preferably, the compound is administered to the subject in a pharmaceutically acceptable amount. In certain embodiments, the proliferative disorder is aPKC-dependent. In certain embodiments, the proliferative disorder is cancer. In n embodiments, the proliferative disorder is selected from non- small cell lung cancer (NSCLC), squamous cell carcinoma (e.g., oesophageal squamous cell carcinoma), leukaemia, prostate cancer, non-Hodgkin’s ma (e. g., follicular lymphoma), endometrial cancer, lung cancer and breast cancer.

The proliferative disorder can be d prophylactically, acutely, or chronically using a compound of the present invention, depending on the nature of the disorder or condition. Typically, the subject in each of these methods is human, although other mammals can also benefit from the administration of a compound of the present invention.

In therapeutic applications, the compounds of the present invention can be prepared and administered in a Wide variety of oral and parenteral dosage forms. Thus, the compounds of the present invention can be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or eritoneally. Also, the compounds described herein can be administered by inhalation, for example, asally. Additionally, the compounds of the present invention can be administered transdermally. In another embodiment, the nds of the present invention are delivered orally. The compounds can also be delivered ly, bucally or by ation. ination of the proper dosage for a particular situation is Within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the stances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired. A typical dose is about 1 mg to about 1,000 mg per day, such as about 5 mg to about 500 mg per day. In certain embodiments, the dose is about 10 mg to about 300 mg per day, such as about 25 mg to about 250 mg per day. —154— V. Chemistry Abbreviations For convenience, the following common abbreviations are used herein: LCMS for Liquid Chromatography-Mass ometry.

HPLC for High Pressure Liquid Chromatography.

NMR for Nuclear Magnetic Resonance.

RT for Retention Time.

M1 for lar Ion h for hours min for minutes A1C13 for ium chloride BBr3 for boron mide Boc for tert-butoxycarbonyl cataCXium C for trans-Bis(acetato)bis[o-(di-o-tolylphosphino)benzyl] dipalladium(II).

C82C03 for cesium carbonate CuI for copper(I)iodide DAST for diethylaminosulfur triﬂuoride DBU for azabicyclo(5 .4.0)undecene DMAP for 4-(dimethylamino) pyridine DCE for l,l-dichloroethane or ethylidene chloride DCM for dichloromethane or methylene chloride DEA for diethanolamine DIPEA for N,N,-di-isopropyethylamine, Hunig’s base DMA for N,N-dimethylacetamide DMF for N,N-dimethylformamide DMSO for dimethylsulfoxide.

Eth for triethylamine EtOH for ethyl alcohol, ethanol HCl for hydrochloric acid H2804 for sulﬁaric acid KOH for potassium hydroxide MW for microwave mCPBA for meta-Chloroperoxybenzoic acid MeOH for methyl alcohol, methanol WO 78126 \/lo(CO)6 for Molybdenum hexacarbonyl VIP-BH4 for macroporous triethylammonium methyl polystyrene borohydride \aOH for sodium hydroxide \32C03 for sodium ate \aZSO4 for sodium sulphate \aOAc for sodium acetate \aOtBu for sodium t-butoxide \MP for l-methylpyrrolidinone \MM for N—methylmorpholine Pd(dba)2 for Bis(dibenzylideneacetone)palladium Pd(OAc)2 for Palladium ate Pd(Ph3)4 for is(triphenylphosphine)palladium Pd(PPh3)2Clg for Bis(triphenylphosphine)palladium(II) dichloride POCl3 for phosphorus oxychloride PPh3 for triphenylphosphine PS-TsCl for polystyrene sulfonyl chloride PS-PPhg-Pd for polystyrene triphenylphosphine-Pd(O) SCX-2 for a silica-based sorbent with a chemically bonded propylsulfonic acid onal group TBAF for Tetra-n-butylammonium ﬂuoride TBDMS for tert—butyldimethylsilyl TCA for trichloroacetic acid TFA for triﬂuoroacetic acid THF for tetrahydrofuran TMS azide for trimethylsilyl azide Xantphos for 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene XPhos for clohexylphosphino-2’,4’,6’-triisopropylbiphenyl Proton NMR spectra are recorded using a Bruker AMX-300 NMR machine at 300 MHz or a Bruker Avance NMR machine at 400 MHz. Shifts are reported in ppm values relative to an internal standard of tetramethylsilane (TMS) or residual protic solvent. The following abbreviations are used to describe the splitting patterns: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (double-doublet), dt (double-triplet), br (broad).

LCMS Methods Samples analysed by High Performance Liquid Chromatography-Mass Spectrometry employed the following conditions.

Method 1 Method 1 employed Gilson 306 pumps, Gilson 811C mixer, Gilson 806 manometric module, and Gilson UV/VIS 152 or at 254 nm wavelength. The mass spectrometer was a Finnigan AQA and the column used was a Waters SunFire, 5 um pore size, C18 of dimensions 50 x 4.60 mm. The ion volume was 10 ul.

The mobile phase consisted of a mixture of water and acetonitrile containing 0.1% formic acid. The eluent ﬂow rate was 1.5 mL/min, using 95% water: 5% itrile, changed linearly to 5% water: 95% acetonitrile over 5.5 minutes and then maintained at this mixture for 2 minutes.

Method 2 Method 2 ed Waters 515 pumps, a Waters 2525 mixer and a Waters 2996 diode array detector. The detection was performed between 210 nm and 650 nm. The mass ometer was a Waters micromass ZQ and the column used was a Waters SunFire, 5 um pore size, C18 of dimensions 50 x 4.60 mm. The injection volume was 10 ul.

The mobile phase consisted of a mixture of water and acetonitrile containing 0.1% formic acid. The eluent ﬂow rate was 1.5 mL/min, using 95% water: 5% acetonitrile, changed linearly to 5% water: 95% acetonitrile over 5.5 minutes and then maintained at this mixture for 2 minutes.

Method 3 Method 3 employed Waters 515 pumps, a Waters 2525 mixer and a Waters 2487 UV detector (single wavelength 254 nm). The mass ometer was a Waters micromass ZQ and the column used was a Waters SunFire, 5 um pore size, C18 of dimensions 50 x 4.60 mm. The injection volume was 10 ul.

The mobile phase ted of a mixture of water and itrile containing 0.1% formic acid. The eluent ﬂow rate was 1.5 mL/min, using 95% water: 5% acetonitrile, changed linearly to 5% water: 95% acetonitrile over 5.5 minutes and then maintained at this mixture for 2 minutes.

Method 4 Method 4 employed Waters 515 pumps, a Waters 2545 mixer with valves directing to the different columns and a Waters 2996 diode array detector. The detection was performed between 210 nm and 650 nm. The mass spectrometer used was a Waters 3100 which detected masses between 100 and 700 g/mol. The column used was a XBridge, 5 micron pore size, C18, 50x4.60 mm.The injection volume was 10 ul of a solution (around 1mg/ml). The ﬂow rate was 1.5 mL/min and the mobile phases of water pH 10 0.03% ammonium hydroxide) (3 ) and itrile 0.03% ammonium hydroxide (3 ml/101) .The elution was started at 95% water: 5% acetonitrile ramping up to 5% water:95% acetonitrile over 5.50 minutes. The eluent level was returned to the starting conditions of 95% water: 5% acetonitrile over 6 seconds. These conditions were held for 1.4 minutes to allow equilibration of the column before the next sample was injected. The run lasted 7 minutes in total.

Method 5 Method 5 employed Waters 515 pumps, a Waters 2525 mixer with valves directing to the ent columns and a Waters 2487 UV detector. The detection was done between at 254 nm. The mass spectrometer used was a Waters micromass ZQ which detected masses between 100 and 700g/mol. The column used was a e, 5 micron pore size, C18 column of dimensions 50x4.60 mm was used. The injection volume was 10uL of a solution (around 1mg/mL). The ﬂow rate was 1.5 mL/min and the mobile phases of water and methanol contained 0.1% formic acid. The elution was started at 85% water:15% methanol ramping up to 15% water:85% ol over 4.5 minutes, these conditions were held for 1 minute before the eluent level was ed to the ng conditions of 85% water: 15% methanol over 6 seconds. These conditions were held for 1.4 minutes to allow equilibration of the column before the next sample was injected. The run lasted 7 s in total.

Method 6 Method 6 employed Waters 515 pumps, a Waters 2545 mixer with valves directing to the different columns and a Waters 2996 diode array detector. The detection was done between 210 nm and 650 nm. The mass spectrometer used was a Waters 3100 which detected masses between 100 and 700g/mol. The column used was a XBridge, 5 micron pore size, C18 ,50x4.60 mm. The injection volume was 10uL of a solution (around 1mg/mL). The ﬂow rate was 1.5 mL/min and the mobile phases of water pH 10 0.03% ammonium hydroxide) (3 ml/101) and ol0.03% ammonium hydroxide (3 ml/101) .The elution was started at 85% water: 15% methanol ramping up to 15% water:85% ol over 4.5 minutes. These conditions were held for 1 minute before the eluent level was returned to the starting conditions of 85% water: 15% ol over 6 seconds.

WO 78126 These conditions were held for 1.4 minutes to allow equilibration of the column before the next sample was injected. The run lasted 7 minutes in total.

Method 7 Method 7 employed Waters 515 pumps, a Waters 2545 mixer with valves directing to the different columns and a Waters 2487 UV detector. The detection was done n at 254nm. The mass spectrometer used was a Waters micromass ZQ which detected masses between 100 and 700g/mol. The column used was a SunFire, 5 micron pore size, C18 column of dimensions 50x4.60 mm was used. The injection volume was 10uL of a solution (around 1mg/mL). The ﬂow rate was 1.5 mL/min and the mobile phases of water and methanol contained 0.1% formic acid. The elution was started at 85% water:15% methanol ramping up to 15% water:85% methanol over 4.5minutes., these conditions were held for 1 minute before the eluent level was returned to the starting conditions of 85% water: 15% methanol over 6 seconds. These conditions were held for 1.4 minutes to allow bration of the column before the next sample was injected. The run lasted 7 minutes in total.

Method 8 Method 8 employed Waters 515 pumps, a Waters 2525 mixer with valves directing to the different columns and a Waters 2487 UV detector. The detection was done between at 254nm. The mass spectrometer used was a Waters micromass ZQ which detected masses between 100 and 700g/mol. The column used was a SunFire, 5 micron pore size, C18 column of ions 50x4.60 mm was used. The injection volume was 10uL of a solution (around 1mg/mL). The ﬂow rate was 1.5 mL/min and the mobile phases of water and methanol contained 0.1% formic acid. The elution was started at 85% water:15% methanol ramping up to 15% water:85% ol over 3 s., these conditions were held for 2.5 minute before the eluent level was returned to the starting ions of 85% water: 15% methanol over 6 seconds. These conditions were held for 1.4 minutes to allow equilibration of the column before the next sample was injected.The run lasted 7 minutes in total.

Method 9 Method 9 employed Waters 515 pumps, a Waters 2545 mixer with valves directing to the different columns and a Waters 2487 UV or. The detection was done between at 254nm. The mass spectrometer used was a Waters micromass ZQ which detected masses n 100 and 700g/mol. The column used was a e, 5 micron pore size, C18 ,50x4.60 mm.The injection volume was 10uL of a solution (around 1mg/mL). The ﬂow rate was 1.5 mL/min and the mobile phases of water pH 10 0.03% ammonium hydroxide) (3 ml/101)and methanol0.03% um hydroxide (3 ml/101) .The n was started at 85% water: 15% methanol ramping up to 15% water:85% methanol over 4.5 minutes. These conditions were held for 1 minute before the eluent level was returned to the starting conditions of 85% water: 15% methanol over 6 seconds. These conditions were held for 1.4 minutes to allow equilibration of the column before the next sample was inj ected.The run lasted 7 minutes in total.

Method 10 LCMS results were obtained on either of two instruments. LCMS analysis was performed on a Waters Aquity Ultra Performance LC with a 2.1 mm x 50 mm Waters Aquity UPLC BEH C18 1.7 um column. The target column temperature was 45°C, with a run time of two (2) s, a ﬂow rate of 0.600 mL/min, and a solvent mixture of 5% (0.1% formic acid/water):95% (acetonitrile/0.1% formic acid). The mass spectrometry data was acquired on a Micromass LC-ZQ 2000 quadrupole mass spectrometer.

Alternatively, LCMS is was performed on a Bruker Esquire 200 ion trap.

Preparative HPLC Methods Samples puriﬁed by Mass Spectrometry directed High Performance Liquid tography employed the following conditions.

MethodA Method A employed Waters 515 pumps, a Waters 2525 mixer and a Waters 2487 UV detector (single wavelength 254 nm). The mass ometer was a Waters micromass ZQ and the column used was a Waters SunFire, 5 um pore size, C18 of dimensions 50 x 19mm. The injection volume was up to 500 uL of solution at a maximum concentration of 50 mg/mL. The mobile phase ted of a e of water and acetonitrile containing 0.1% formic acid. The eluent ﬂow rate was 25 mL/min using 95% water, 5% acetonitrile, changing linearly over 5.3 minutes to 95% acetonitrile, 5% water, and maintaining for 0.5 minutes.

Method B Method B employed Waters 515 pumps a Waters 2545 mixer with valves directing to the different columns and a Waters 2996 diode array or. The detection was performed between 210 nm and 650 nm. The mass spectrometer used was a Waters 3100 which detected masses between 100 and 700 g/mol. The column used was a XBridge, 5 micron pore size, C18, 50x19 mm. The injection volume was chosen by the user and can be up to 500uL of the solution (max 50mg/mL). The ﬂow rate was 25mL/min and the mobile phases of water pH 10 0.03% ammonium hydroxide (3 m1/101)and acetonitrile 0.03% ammonium hydroxide (3 ml/101) .The elution was started at 95% 5% acetonitrile ramping up to 5% water:95% itrile over 5 .30 minutes. The eluent level was returned to the starting conditions of 95% water: 5% acetonitrile over 0.6 minutes.

These conditions were held for 1.4 minutes to allow equilibration of the column before the next sample was injected. The run lasted 7 minutes in total.

Analﬂical HPLC Methods MethodX Method X employs gradient elution (0 to 100%) itrile ining 0.1% triﬂuoroacetic acid):water (containing 0.1% triﬂuoroacetic acid) over ﬁve minutes on a 4.6 X 75 mm (2.5 micron) Zorbax XDB-C8 column at 2.5 ml/min on an Agilent 1100 series HPLC.

Synthesis Several methods for the chemical synthesis of 4-substituted(pyridinyl)- thieno[2,3-d]pyrimidine compounds (“4PT23P compounds”) and 4-substituted(pyridin- 4-yl)—thieno[3,2-d]pyrimidine compounds 2P compounds”) of the present invention are described herein. These and/or other well known methods may be d and/or adapted in known ways in order to facilitate the synthesis of additional compounds within the scope of the present invention. Unless otherwise stated, nds are of commercial origin or readily synthesized by standard methods well known to one skilled in the art of organic synthesis.

It is understood that the examples and embodiments described herein are for rative purposes only and that various ations or changes in light thereof will be suggested to persons skilled in the art and are to be ed within the spirit and purview of this invention. Speciﬁc chemical transformations are listed in the ensuing schemes and one d in the art appreciates that a variety of different reagents may be used in place of those . Common replacements for such reagents can be found in texts such as “Encyclopedia of Reagents for Organic Synthesis” Leo A. Paquette John Wiley & Son Ltd (1995) or “Comprehensive Organic Transformations: A Guide to Functional Group Preparations” Richard C. Larock. Wiley-VCH and “Strategic Applications ofNamed Reactions in c Synthesis” Kurti and Czako, Elsevier, 2005 and references cited therein. 4PT23P compounds In one approach, compounds of formula [F-l] (where A = NH or N alkyl) are prepared by reacting a compound of formula [F-2] (where X is a halogen such as chlorine or sulfonate) with a compound of formula [F-3] (where A is NH or NH2 and Z on the al nitrogen is H, alkyl or a suitable nitrogen protecting group, such as Boc, Alloc, Cbz or Fmoc) in a suitable solvent such as DMF in the presence of a suitable base such as triethylamine. 1 9 R X R3 I? / / R4 NxRZ IN R R10 13 R5 S \N R R9 R6 A I R15 /N / 12 / N R R 14 I R \ R13 S N \ [F-2] R15 /N A/\/N\Z [F4] [F-3] The reaction is suitably conducted at an elevated temperature for example 40 0C. Where Z is a suitable nitrogen protecting group, such as Boc, Alloc, Cbz or Fmoc, compounds of a [F-l] are prepared by a suitable deprotection reaction. For example: where Z is a Boc protecting group reaction with an acid such as TFA in a suitable solvent such as DCM. The reaction is suitably conducted at ambient temperature. In one approach, nds of a [F-l] (where A is O) are prepared by reacting a compound of a [F-2] (where X is a halogen such as chlorine or sulfonate) with a compound of formula [F-2] (where A = OH and Z on the terminal nitrogen is H, alkyl or a suitable nitrogen protecting group, such as Boc, Alloc, Cbz or Fmoc) in a suitable t such as DMA in the presence of a suitable base such as sodium hydride. The on is suitably conducted at ambient temperature. Where Z is a suitable nitrogen protecting group, such as Boc, Alloc, Cbz or Fmoc, compounds of formula [F-l] are prepared by a suitable deprotection reaction. For example: where Z is a Boc protecting group reaction with an acid such as TFA in a suitable solvent such as DCM. The reaction is suitably conducted at ambient temperature. -l62- In one approach, compounds of formula [F-2] (where X is a n such as chlorine) are prepared by reacting a compound of formula [F-4] with a suitable halogenating agent such as phosphorous oxychloride. The reaction is suitably conducted at elevated temperature such as 125 0C. nds of formula [F-2] (where X is a ate) are prepared by reacting a compound of formula [F-4] with a suitably substituted sulfonyl chloride such as 2,4,6-triisopropylbenzenesulfonyl chloride in a suitable solvent such as DMA in the presence of a le base such as triethylamine and a catalytic amount of DMAP. The reaction is suitably conducted at ambient temperature. 9 OH Rlo/JfklNR R12 S \N R R15 /N [F-4] In one approach, compounds of formula [F-4] are prepared by reacting a compound of formula [F-S] (where Rx is an alkyl group such as methyl or ethyl) with a compound of formula [F-6] in a suitable solvent such as dioxane with a suitable base such as potassium-tert-pentylate. The reaction is suitably conducted at ambient temperature.

R9 O'RX NC R13 R10 / 0 I R15 / N S NH2 R14 [F-5] [F-G] In one ch, compounds of formula [F-S] are prepared by reacting a ketone derivative of formula [F-7] (where RXI and RX2 are H, alkyl, aryl or form a cyclic saturated ring) with a cyanoacetic acid derivative of formula [F-8] (where RX is an alkyl group such as methyl or ethyl) with tal sulphur in the presence of a base such as line in a suitable solvent such as ethanol. The reaction is suitably ted at an ed temperature for example 80-90 0C.

R NOV0 RXQEO 0\ [F-7] [F-8] In one approach, compounds of formula [F-3] (where A is OH) are prepared by reacting a compound of formula [F-9] (where Z on the terminal nitrogen is H, alkyl or a -l63- WO 78126 suitable nitrogen protecting group, such as Boc, Alloc, Cbz or Fmoc) with a reducing agent such as borane-THF complex in a suitable solvent such as THF. The reaction is suitably conducted at low temperature for example 0 0C. In one approach, compounds of formula [F-3] (where A is NHZ) are prepared by reacting a compound of a [F-lO] (where Z on the terminal nitrogen is H, alkyl or a suitable nitrogen ting group, such as Boc, Alloc, Cbz or Fmoc) with a reducing agent such as borane-THF complex in a suitable solvent such as THF. The reaction is suitably conducted at low temperature for e 0 0C. In one approach, compounds of formula [F-lO] are prepared by reacting compounds of formula [F-9] with Boc anhydride in the presence of a suitable base such as pyridine, ammonium carbonate in a suitable solvent such as dioxane. The reaction is suitably conducted at t temperature.

An example of a method as described above is illustrated in the following scheme. o) 9 0H o R x1 R9 10 R12 R / / N _> O R —> | 13 X2 \ R R R10 / \ S N |\ S NH2 R15 /N [F-7] [F 5] R14 [F-4] R9 CI R9 O’S‘b / ﬂ“ R12 R10 13 \ R / N R12 N R / I |\ \ R13 R15 /N S N \ N [F-11] R14 R15 / [F-121R14 R3 F51 A/\/N\Z\ R‘ﬁ:N N\ R2 A/\/ Z [P3] [F-3] RFSRe A #wa R12 8 \N R13 [F-1] General synthesis of 2-amin0-4,5-substitued—thiophene—3-carb0xylic acid ethyl esters of general formula [F-5] (Scheme A1) 2-amino-4,5-substitued-thiophenecarboxylic acid ethyl esters of general formula [F-S] were synthesised by a cyclisation reaction with cyano-acetic acid ethyl ester of general a [F-8], a substituted ketone of general formula [F-7] and elemental sulphur in the presence of line in a polar protic solvent such as ethanol at reﬂux (scheme A1). -l65- Scheme Al O ORX x1 )8 R 8 2 O RX2 —, 0 R1O’2f NC NH2 [F-7] O‘Rx [F-5] [F-8] Synthesis of 2-Amino-1 ,4-Dioxa-spiro[6.6]4,5,6,7-tetrahydro-benzo[b]thiophene carboxylic acid ethyl ester [AA-1] 0 l o 0 EOQfO \J S NH2 [AA-1] To a mixture of 1,4-Dioxa-spiro[4.5]decanone (1.56 g, 10 mmol), cyano-acetic acid ethyl ester (1.13 g, 10 mmol) and elemental sulphur (320 mg, 10 mmol) in ethanol (20 ml) was added rnorpholine (870 mg, 10 mmol). The reaction was heated at reﬂux overnight. The e was left to cool down and a itate formed which was recovered by ion and washed with cold ethanol (40 ml), then dried under reduced pressure to give the title compound (2.1 g ,76 %) which was used without further puriﬁcation. LCMS method: 3, RT: 5.24 min, MI: 284 [M+l]. 1H NMR (300MHz, DMSO): 4.21 (m, 1H), 4.17 (q, 2H), 4.01 (m, 1H,), 3.82 (m, 2H,), 3.08 (m, 1H), 2.68 (m, 1H), 1.91(m, 4H), 1.21 (t, 3H).

Synthesis of 2-amino-6,6-dimethyl-4,5,6,7-tetrahydro-benzo[b]thiophenecarboxylic acid ethyl ester [AA-2] o O: q]: _, 0 ; 3/ \l S NH2 [AA-2] WO 78126 To a mixture of 4,4-Dimethyl-cyclohexanone, acetic acid ethyl ester and tal sulphur in ethanol was added morpholine. The reaction was reﬂux overnight.

The mixture was left to cool down and a precipitate appeared. The solid was recovered by ﬁltration and to give the title compound as a yellow solid. LCMS method: 3, RT: 5.64 min, MI: 254 [M+l].

Synthesis of o-4,7-dihydro-5H-thieno[2,3-c]thiopyrancarboxylic acid ethyl ester [AA-3] O l 55 O _, s S 3fO S NH2 [AA-3] To a mixture of tetrahydro-thiopyranone, cyano-acetic acid ethyl ester and elemental sulphur in ethanol was added morpholine. The reaction was reﬂux overnight.

The mixture was left to cool down and a precipitate appeared. The solid was recovered by ﬁltration and to give the title compound as a yellow solid. LCMS method: 3, RT: 5.78 min, MI: 244 [M+l].

Synthesis of 2-amino-4,7-dihydro-5H-thieno[2,3-c]pyrancarboxylic acid ethyl ester [AA-4] O l O _, o O S NH2 [AA-4] To a mixture of tetrahydro-pyranone, cyano-acetic acid ethyl ester and elemental sulphur in ethanol was added line. The reaction was reﬂux overnight.

The mixture was left to cool down and a precipitate appeared. The solid was recovered by filtration and to give the title compound as a yellow solid. LCMS method: 3, RT: 5.86 min, MI: 228 [M+l]. -l67- General synthesis of 5, tituted 2-pyridinyl—thieno [2, 3-d] pyrimidinols of general formula [F-4] e A2) 4,5-substitutedamino-thiophene-3 -carboxylic acid alkyl esters of general formula [F-5] were subjected to a cyclisation reaction with 4-cyanopyridine of general formula [F-6] in the presence of a ed alkoxide base such as potassium-tert-pentylate 1.7M in toluene or potassium-tert-butoxide in a dry non-aprotic solvent such as dioxane or THF at ambient temperature.

Scheme A2 NC R13 R15 /N R9 OH 9 0 R R14 \N R12 [F-6] R10 / / Q | R 8' / R13 Rx __. s N NH |\ potassium tert-pentylate R15 / N Dry Dloxane' 14 [F-5] [F-4] Synthesis of 2-pyridinyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidinol [AA-5] [AA-5] To a solution of 4-cyanopyridine (1.25 g, 12 mmol) in dry dioxane (10 ml) was added 2-amino-4,5,6,7-tetrahydro-benzo[b]thiophenecarboxylic acid ethyl ester (2.25 g,10 mmol) followed by potassium-tert—pentylate 1.7M in toluene (12 ml, 20 mmol). The reaction mixture was stirred at room temperature ght. After completion the itate formed was ﬁltered and washed with diethyl ether. The residue was used without any further puriﬁcation in the next step. LCMS method: 1, RT: 3.54 min, MI: 284 [M+l]. 1H 1 H NMR (300MHz, DMSO): 8.56 (d,2H), 8.12 (d,2H), 2.90 (m,2H), 2.67 (m,2H), 1.76 (m,4H).

The ing compounds were prepared according to the general synthesis shown in scheme A2: O HO I\ \ NH. —» | N s s [AA-6] 7-methylpyridinyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidinol [AA-6] was prepared by reaction of 2-aminomethyl-4,5,6,7-tetrahydro-benzo[b]thiophene carboxylic acid ethyl ester, opyridine, potassium-tert-pentylate 1.7M in toluene and dioxane at room temperature to give the title compound as an off-white solid. LCMS method: 1, RT: 3.68min, MI: 298 [M+l]. o HO o “N _.

\ / \ @N NH2 —> | N s s [AA-7] 2-pyridinyl-5 ,6,7,8,9, l 0-hexahydro-l l-thia-l ,3-diaza-cycloocta[a]indenol [AA-7] was prepared by reaction of 2-amino-4,5,6,7,8,9-hexahydro-cycloocta[b]thiophene carboxylic acid ethyl ester, 4-cyanopyridine, ium-tert-pentylate l.7M in toluene and dioxane at room temperature to give the title compound as an off-white solid. LCMS method: 1, RT: 3.72 min, MI: 312 [M+l].

O HO \”HQN | \ NH2 | N s s [AA-8] dinyl-6,7,8,9-tetrahydro-5H-lO-thia-l,3-diaza-benzo[a]azulenol [AA-8] was prepared by on of 2-amino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene carboxylic acid ethyl ester, 4-cyanopyridine, potassium-tert-pentylate l.7M in toluene and dioxane at room temperature to give the title compound as a yellow solid. LCMS method: 2, RT: 3.87 min, MI: 298 [M+l]. o [0 OH K O —> / o O / | \\ S 3 NH2 \ [AA-1] [AA-9] -l69- WO 78126 l,4-Dioxa-spiro [7.7] pyridinyl-5 ,6,7,8-tetrahydro-benzo [4,5 ]thieno [2,3 -d]pyrimidin- 4-ol [AA-9] was prepared by reaction of 2-Amino-l,4-Dioxa-spiro[6.6]4,5,6,7-tetrahydro- benzo[b]thiophenecarboxylic acid ethyl ester [AA-l], 4-cyanopyridine, potassium-tert- pentylate 1.7M in toluene and e at room ature to give the title compound as a yellow solid. LCMS method: 3, RT: 2.80 min, MI: 342 [M+1]. 0 HO 0 “N ..

/ \ /N | \ \ NH2 —> | N s s [AA-2] [AA-10] 7,7-dimethylpyridinyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidinol [AA-10] was ed by reaction of 2-amino-6,6-dimethyl-4,5,6,7-tetrahydro- benzo[b]thiophenecarboxylic acid ethyl ester [AA-2], 4-cyanopyridine, potassium-tert- pentylate l.7M in toluene and dioxane at room temperature to give the title compound as an off-white solid. LCMS method: 3, RT: 4.24 min, MI: 312 [M+1].

IS\ ﬂ/OYN NH2 o ﬁ/o [AA-11] 4-hydroxypyridinyl-5,8-dihydro-6H-pyrido[4',3':4,5]thieno[2,3-d]pyrimidine carboxylic acid tert-butyl ester [AA-l l] was prepared by reaction of o-4,7-dihydro- SH-thieno[2,3-c]pyridine-3,6-dicarboxylic acid 6-tert-butyl ester 3-ethyl ester, 4- cyanopyridine, potassium-tert-pentylate l.7M in toluene and dioxane at room temperature to give the title compound as an off-white solid. LCMS method: 1, RT: 3.50 min, MI: 384 [M+1].

[AA-4] ] 2-pyridinyl-5,8-dihydro-6H-pyrano[4',3':4,5]thieno[2,3-d]pyrimidinol [AA-l2] was prepared by reaction of 2-amino-4,7-dihydro-5H-thieno[2,3-c]pyrancarboxylic acid ethyl ester [AA-4], 4-cyanopyridine, potassium-tert-pentylate l.7M in toluene and -l70- dioxane at room temperature to give the title compound as a yellow solid. LCMS : 3, RT: 3.50 min, MI: 286 [M+l].

|\NH2 —> [AA-3] [AA-13] 2-pyridinyl-5 ,8-dihydro-6H-thiopyrano [4',3 ':4 ,5 ]thieno [2,3 -d]pyrimidinol [AA- 1 3] was prepared by reaction of 2-amino-4,7-dihydro-5H-thieno[2,3-c]thiopyrancarboxylic acid ethyl ester [AA-3], 4-cyanopyridine, potassium-tert-pentylate l.7M in toluene and dioxane at room temperature to give the title compound as a yellow solid. LCMS method: 2, RT: 314 min, MI: 302 [M+l].

QYN I \ NH2 —> N O o [AA-1 4] (4-Hydroxypyridinyl-5,8-dihydro-6H-pyrido[4',3':4,5]thieno[2,3-d]pyrimidinyl)- phenyl-methanone [AA-l4] was prepared by reaction of 2-Aminobenzoyl-4,5,6,7- tetrahydro-thieno[2,3-c]pyridinecarboxylic acid ethyl ester, 4-cyanopyridine, potassium-tert-pentylate l.7M in toluene and THF at room temperature to give the title compound as a yellow solid. LCMS method: 3, RT: 3.02 min, MI: 389[M+l].

O HO V ’VQN/ | \ \ NH2 —> | N S S [AA-1 5] ylpyridinyl-thieno[2,3-d]pyrimidinol [AA-l5] was prepared by reaction of ethyl 2-aminomethylthiophenecarboxylate, 4-cyanopyridine, potassium-tert- pentylate l.7M in toluene and THF at room temperature to give the title nd as a yellow solid. LCMS : 3, RT: 2.56 min, MI: 244[M+l].

O HO \’N»@N | \ NH2 —> | N s s [AA-16] - l7l - -isobutylpyridinyl-thieno[2,3-d]pyrimidinol [AA- 1 6] was prepared by reaction of 2-aminoisobutyl-thiophenecarboxylic acid ethyl ester, opyridine, potassium-tert-pentylate 1.7M in toluene and dioxane at room temperature to give the title compound as a brown solid. LCMS method: 2, RT: 3.14 min, MI: 286 [M+1].

[AA-17] -ethylmethylpyridinyl-thieno[2,3-d]pyrimidinol [AA-l7] was prepared by reaction of 2-aminoethylmethyl-thiophenecarboxylic acid ethyl ester, 4- cyanopyridine, potassium-tert-pentylate l.7M in toluene and dioxane at room temperature to give the title compound as a brown solid. LCMS method: 2, RT: 3.26 min, MI: 272 [M+1]. 6-ethylpyridinyl-thieno [2, 3-d] pyrimidinol [AA-l8] was prepared by reaction of 2-aminoethyl-thiophenecarboxylic acid ethyl ester, 4-cyanopyridine, potassium-tert- pentylate l.7M in e and e at room temperature to give the title compound as a brown solid. LCMS method: 2, RT: 3.15 min, MI: 258 [M+1].

|\ NH2 [AA-19] ,6-dimethylpyridinyl-thieno[2,3-d]pyrimidinol [AA-l9] was prepared by reaction of 2-amino-4,5-dimethyl-thiophenecarboxylic acid ethyl ester, 4- cyanopyridine, ium-tert-pentylate l.7M in toluene and dioxane at room temperature to give the title compound as a yellow solid. LCMS method: 3, RT: 3.05 min, MI: 258 [M+1]. -l72- [AA-20] 4-hydroxymethylpyridinyl-thieno [2, 3-d]pyrimidinecarboxylic acid amide [AA-20] was prepared by reaction of 2-aminocarbamoylmethyl-thiophene carboxylic acid ethyl ester, 4-cyanopyridine, potassium-tert-pentylate 1.7M in e and e at room temperature to give the title compound as a brown solid. LCMS method: 2, RT: 3.02 min, MI: 287 [M+l].

|\NH2 —» [AA-21] 6-isopropylpyridinyl-thieno[2,3-d]pyrimidinol [AA-21] was prepared by reaction of oisopropyl-thiophenecarboxylic acid ethyl ester, 4-cyanopyridine, potassium-tert-pentylate l.7M in toluene and dioxane at room temperature to give the title compound as a brown solid. LCMS method: 2, RT: 3.29 min, MI: 272 [M+l].

|\ NH2 [AA-22] 6-methylphenylpyridinyl-thieno[2,3-d]pyrimidinol [AA-22] was prepared by reaction of 2-aminomethylphenyl-thiophenecarboxylic acid ethyl ester, 4- cyanopyridine, potassium-tert-pentylate l.7M in toluene and dioxane at room temperature to give the title compound as a yellow solid. LCMS method: 2, RT: 3.79 min, MI: 320 [M+l].

Br Br O H O O..N ’— V HQN I \ \ NH2 —> I N S S [AA-23] -(4-bromo-phenyl)pyridinyl-thieno[2,3-d]pyrimidinol [AA-23] was prepared by reaction of 2-amino(4-bromo-phenyl)-thiophenecarboxylic acid ethyl ester, 4- - l73 - cyanopyridine, potassium-tert-pentylate 1.7M in toluene and dioxane at room temperature to give the title compound as a brown solid. LCMS method: 2, RT: 4.16 min, MI: 384-3 86 [M+l].

General synthesis of 5,6 substituted 4-amin0pyridinyl-thien0[2,3-d]pyrimidines of general formula [F-l] (Scheme A3) ,6-substituted 2-pyridinyl-thieno[2,3-d]pyrimidinol derivatives of general formula [F-4] were reacted in an activation step using a chlorinating reagent such as phosphorus oride or phosphorous hloride to yield the 5,6-substituted 4- chloropyridinyl-thieno[2,3-d]pyrimidine derivatives of general formula [F-l l], which were d with primary or secondary amine derivative of general formula [F-l3] at t temperature. After reaction work up, lly by a liquid-liquid extraction or puriﬁcation by acidic ion ge catch-release, the crude reaction product was purified by reverse phase preparative HPLC.

Scheme A3 R3 F5 R4 N\R2 R9 OH R9 0' A 12 12 12 R10 / /|N R R R 13 13 i)Amine[F-13] 13 s \N R RﬂJfklN R1Qf\INRRG |\ P003 8 \N p R E‘3N'DMA S \N R —> —> |\ R15 /N R15 /N R15 /N R14 R14 R14 [F4] [F-11] [F4] Synthesis of 4-chloropyridinyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine [AA-24] [AA-5] [AA-24] 2-pyridinyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidinol [AA-5] (l g, 3.6 mmol) was stirred in POC13 (lO ml,lO9 mmol) at reﬂux at 125 CC overnight. The mixture was allowed to cool down to room temperature and the excess of POC13 was removed under reduced pressure. The e was carefully poured into ice-water and the solution —174— was basiﬁed with a saturated solution of sodium hydrogen carbonate (50 ml) and the product was ted into DCM (2x25 ml). The combined extracts were dried with magnesium sulfate, ﬁltered and evaporated under reduced pressure to yield the title compound as a yellow-orange solid, which was was used without ﬁarther puriﬁcation.

LCMS method: 2, RT: 5.46 min, MI: 302 [M+l]. sis ofN,N—dimethyl-N'-(2-pyridinyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidinyl)-ethane- l ,2-diamine [l] [AA-24] [1] To a solution of 4-chloropyridinyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3- midine (50mg, 0.166 mmol) [AA-24] in DMA (1 ml) was added N,N— dimethylethylenediamine (20ul, 0. 166 mmol) followed by Eth (32 ul, 0.232 mmol) and the mixture was d at room temperature for 2 hours. The reaction mixture was loaded onto a SCX-2 cartridge, and washed with ol. The product was released from the cartridge using a solution of 2M ammonia / methanol. The ammonia / methanol eluent was concentrated under reduced pressure and the crude product was puriﬁed by preparative HPLC (method A) to yield to the title compound. LCMS method: 2,: RT: 2.lmin, MI: 354 [M+l]. 1H NMR (300MHz, DMSO): 8.70 (d,2H) 8.20 (d,2H), 3.7 (m,2H), 2.9 (m,2H), 2.8 (m,2H), 2.6 (m,2H), 2.3 (s,6H), l.8 (m,4 H).

The following compounds were ed according to the general synthesis shown in scheme A3: Amine terisation [F- 13] method: 2, RT: [AA-24] E 2.05 min, MI: 340 [M+l] method: 2, RT: ’ \ 3 .

[AA-24] HN NH 2.13 min, MI: 352 [M+l] -l75- W0 2013/078126 Ex HU) Characterisation 1H NMR (300MHz, DMSO): 8.70 (d,2H) 8.20 (d,2H), 4 method: 2, RT: (m,2H), 3.8 (m,2H), 2.15 min, MI: 3.2 (m,2H), 3 (m,2H), 380 [M+1] 2.9 (m,4H), 2.1 (m,2H), 1.9 (m,2H), 1.7 (m,2H), 0.8 (s,3H) method: 2,RT: .—..gN3 2.10 min, MI: 340 [M+1] method: 2, RT: 2.33 min, MI: 400 [M+1] : 2, RT: 2.46 min, MI: 455 [M+1] method: 2, RT: .—..gN3 2.20 min, MI: 366 [M+1] method: 2, RT: 2.23 min, MI: 380[M+1] 1H NMR (300MHz, DMSO): 8.8 (d,2H), 8.2 (d,2H), 3.4 method: 2, RT: (m,2H), 3.2 (m,2H), 0 2.30 min, MI: 3.1 (m,2H), 2.90 380 [M+1] , 2.68 (m,2H) , 1.9 , 1.13 (d,6H) method: 2, RT: 2.10 min, MI: 338 [M+1] General synthesis of 5,6 substituted 4-aminopyridinyl—thieno[2,3-d]pyrimidine derivatives of general formula [F-l] (Scheme A4) ,6 substituted 4-chloropyridinyl-thieno[2,3-d]pyrimidine derivatives of general a [F-l l] were reacted with N—Boc protected primary or secondary diamine derivatives of general formula [F-l3] at ambient ature. After reaction work up, typically by a liquid-liquid extraction or puriﬁcation by acidic ion exchange catch-release, the N—Boc derivatives were deprotected under acidic conditions with a strong acid such as TFA, TCA, methanesulfonic acid, HCl or H2S04 in a solvent such as DCM, DCE, THF, EtOH or MeOH and the crude reaction product was puriﬁed by reverse phase preparative HPLC Scheme A4 R3 '3 R9 Cl R4 NxRZ / / I35 IN R R10 R R6 A \ R13 S N \ / 12 I R [F43] R10 / IN 1 5 /N \ R13 R S i. Amines, Et3N,DMA N \ R14 —> I /N ii. TFA, DCM [F-11] [F-1] Synthesis ofN* l *-(2-pyridinyl-5 ,6,7,8-tetrahydro-benzo[4,5]thieno[2,3 -d]pyrimidin yl)-ethane-l ,2-diamine [l2] [AA-24] [12] To a solution of 4-chloropyridinyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidine (50 mg, 0.166 mmol) ] in DMA (1 ml) was added (2-amino-ethyl)— carbamic acid tert-butyl ester (28 ul, 0.182 mmol) ed by Eth (32 ul, 0.232 mmol) the mixture was stirred at room temperature for 2 hours. The t was extracted with DCM (1 ml) and washed with brine (2 ml). To the organic phase was added TFA (1 ml) -l77- and the mixture was stirred at room temperature for 1 hour. After completion the mixture was loaded onto a SCX-2 cartridge and washed with methanol. The product was released from the cartridge using a on of 2M ammonia / methanol. The ammonia /methanol eluent was concentrated under reduced pressure and the crude product was puriﬁed by preparative HPLC (method A) to yield to the title compound. LCMS : 2, RT: 2.07min, MI: 326 [M+1]. 1H NMR (300MHz, DMSO): 8.70 (d,2H)., 8.28 (d,2H), 3.88 (m,2H), 3.14 (m,2H), 2.94 , 2.78 (m,2H), 1.84 (m,4H).

The following compounds were prepared according to the general synthesis shown in Scheme A4: Amine Characterisation [F - 1 3] 1H NMR (300MHz, DMSO): method; 2, 8.7 , 8.2 (d,2H), 3.9 b°C\N/\/NH2 RT: 2.05 min, (m,2H), 3.1 (m,2H), 3 (m,2H), MI: 340 2.8 (m,2H), 2.45 (s,3H) 1.8 [M+1] (m,4H) method: 2, RT: 2.10 min, MI: 366 [M+1] method: 2, RT: 2.17 min, MI: 340 [M+1] method: 2, RT: 2.35 min, MI: 382 [M+1] method: 2, RT: 2.18 min, MI: 354 [M+1] method: 2, RT: 2.13 min, MI: 364 [M+1] General synthesis of 5,6-substituted—(2,4,6-triisopropyl-benzenesulfonic acid)- 2- pyridinyl—thien0[2,3-d]pyrimidinyl ester derivatives of general a [F-12] (Scheme A5) Compounds were prepared by the reaction of 5,6-substituted 2-pyridinylthieno [2,3-d]pyrimidinol derivatives of general formula [F-4] (described in scheme A2) with 2,4,6-triisopropylbenzenesulfonyl chloride in halogenated solvent such as DCM or a polar aprotic solvent such as DMA, DMF, NMP with a tertiary alkylamine base such as Eth, DIPEA or NMM and a catalytic amount of DMAP.

Scheme A5 R9 OH #04ng/ N R12 S N \ R15 /N R13 DMAP,Et3N,DMA R15 /N [F-4] [F-12] Synthesis of 2,4,6-triisopropyl-benzenesulfonic acid 2-pyridinyl-5,6,7,8-tetrahydro- benzo[4,5]thieno[2,3-d]pyrimidinyl ester [AA-25].

OH ,0 Cl/Sf \N o S N \ | DMAP,Et3N,DMA [AA-5] To a solution of 2-pyridinyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidinol (l g, 3.5 mmol) [AA-5] in DCM (10 ml) was added 2,4,6- triisopropylbenzenesulfonyl chloride (1.3 g, 4.2 mmol), Eth (l .5 ml, 10.5 mmol) and DMAP (6 mg, 0.05 mmol). The e was d for at room temperature for one hour.

After completion the mixture was diluted with water and the product was extracted into DCM (2X2 ml). The combined extracts were dried with magnesium sulfate, ﬁltered and evaporated under reduced pressure to yield the title compound as a brown solid, which was used without ﬁarther puriﬁcation in the next step. LCMS : 3, RT: 6.23 min, MI:550[M+1].

The following compounds were ed according to the general synthesis shown in scheme A5: [AA-6] 2,4,6-triisopropyl-benzenesulfonic acid 7-methylpyridinyl-5,6,7,8-tetrahydro- benzo[4,5]thieno[2,3-d]pyrimidinyl ester [AA-26] was prepared by reaction of 7- methylpyridinyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidinol , triisopropyl benzene sulfonyl chloride, Eth, DMAP and DCM at room temperature to give the desired compound as a brown solid. LCMS method: 3, RT: 6.34 min, MI: 564 [M+l]. | ——> S N/ \ [AA-7] 2,4,6-triisopropyl-benzenesulfonic acid 2-pyridinyl-5 ,9, l 0-hexahydro-l l-thia-l ,3- diaza-cycloocta[a]indenyl ester [AA-27] was prepared by reaction of 2-pyridinyl- ,6,7,8,9, l 0-hexahydro-l l-thia- l ,3-diaza-cycloocta[a]indenol [AA-7], 2,4,6- triisopropylbenzenesulfonyl chloride, Eth, DMAP and DCM at room temperature to give the desired compound as a brown solid. LCMS method: 3, RT: 6.47 min, MI: 578 [M+l].

/ \N I __> S N/ [AA-8] 2,4,6-triisopropyl-benzenesulfonic acid 2-pyridinyl-6,7,8 rahydro-5H- l O-thia- l ,3 - diaza-benzo[a]azulenyl ester [AA-28] was prepared by reaction of 2-pyridinyl- 6,7,8,9-tetrahydro-5H-lO-thia- l ,3-diaza-benzo[a]azulenol [AA-8], 2,4,6- propylbenzenesulfonyl de, Eth, DMAP and DCM at room temperature to give the title compound as a brown solid. LCMS method: 3, RT: 6.39 min, MI: 564 [M+l].

[AA-9] [AA-29] 2,4,6-triisopropyl-benzenesulfonic acid l,4-Dioxa-spiro[7.7]pyridinyl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidinol ester [AA-29] was prepared by reaction of l,4-Dioxa-spiro[7.7]—2-pyridinyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidinol [AA-9], 2,4,6-triisopropylbenzenesulfonyl chloride, Eth, DMAP and DCM at room temperature to give the desired compound as a brown solid. LCMS method: 3, RT: 6.56 min, MI: 608 [M+l].

W” —> S N/ \ [AA-10] 2,4,6-triisopropyl-benzenesulfonic acid 7,7-dimethylpyridinyl-5,6,7,8-tetrahydro- benzo[4,5]thieno[2,3-d]pyrimidinyl ester [AA-30] was prepared by reaction of 7,7- dimethylpyridinyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidinol [AA- 10], 2,4,6-triisopropyl benzenesulfonyl chloride, Eth, DMAP and DCM at room temperature to give the desired compound as a brown solid. LCMS method: 3, RT: 6.37 min, MI: 578 [M+l]. s Nka lO triisopropyl-benzenesulfonic acid 2-pyridinyl-5,8-dihydro-6H-pyrano [4',3':4,5]thieno [2,3-d]pyrimidinyl ester [AA-31] was prepared by reaction of 2- pyridinyl-5,8-dihydro-6H-pyrano[4',3':4,5]thieno[2,3-d]pyrimidinol [AA-12], 2,4,6- triisopropylbenzenesulfonyl chloride, Eth, DMAP and DCM at room temperature to give the desired nd as a brown solid. LCMS method: 3, RT: 6.29 min, MI: 552 [M+l].

S N/ \ [AA-13] 2,4,6-triisopropyl-benzenesulfonic acid 2-pyridinyl-5,8-dihydro-6H-thiopyrano [4',3':4,5]thieno[2,3-d]pyrimidinyl ester [AA-32] was prepared by reaction of 2- nyl-5 , 8-dihydro-6H-thiopyrano [4',3 ' :4,5 ]thieno [2,3 -d]pyrimidinol [AA- 1 3 ] , 2,4,6-triisopropyl benzene yl chloride, Eth, DMAP and DCM at room temperature to give the desired compound as a brown solid. LCMS method: 3, RT: 6.58 min, MI: 568 [M+1].

[AA-1 4] [AA-33] lO 2,4,6-Triisopropyl-benzenesulfonic acid 7-benzoylpyridinyl-5,6,7,8-tetrahydro- pyrido[4',3':4,5]thieno[2,3-d]pyrimidinyl ester [AA-33] was prepared by reaction of (4- Hydroxypyridinyl-5,8-dihydro-6H-pyrido[4',3':4,5]thieno[2,3-d]pyrimidinyl)— phenyl-methanone [AA-l4], 2,4,6-triisopropyl e sulfonyl chloride, Eth, DMAP and DCM at room temperature to give the desired compound as a brown solid. LCMS method: 3, RT: 6.67 min, MI: 655 [M+1]. 2,4,6-triisopropyl-benzenesulfonic acid 5-isobutylpyridinyl-thieno[2,3-d]pyrimidin- 4-yl ester [AA-34] was prepared by on of 5-Isobutylpyridinyl-thieno[2,3- d]pyrimidinol [AA-l6], 2,4,6-triisopropylbenzenesulfonyl chloride, Eth, DMAP and DCM at room temperature to give the desired compound as a brown solid. LCMS method: 3, RT: 6.36 min, MI: 552 [M+l].

/ \N I _> S N/ \ [AA-17] [AA-35] triisopropyl-benzenesulfonic acid 5-ethylmethylpyridinyl-thieno[2,3- d]pyrimidinyl ester [AA-35] was prepared by reaction of 5-ethylmethylpyridin yl-thieno[2,3-d]pyrimidinol [AA-l7], 2,4,6-triisopropylbenzenesulfonyl chloride, Eth, DMAP and DCM at room temperature to give the desired compound as a brown solid.

LCMS : 3, RT: 6.29 min, MI: 538 [M+l].

M?“ —» S N/ [AA-18] WO 78126 2,4,6-triisopropyl-benzenesulfonic acid 6-ethylpyridinyl-thieno[2,3-d]pyrimidinyl ester [AA-3 6] was prepared by reaction of 6-ethylpyridinyl-thieno[2,3-d]pyrimidin- 4-ol [AA-18], 2,4,6-triisopropylbenzenesulfonyl chloride, Eth, DMAP and DCM at room temperature to give the desired compound as a brown solid. LCMS method: 3, RT: 6.22 min, MI: 524 [M+1].

/ I _> S N \ [AA-19] 2,4,6-triisopropyl-benzenesulfonic acid 5,6-dimethylpyridinyl-thieno[2,3- d]pyrimidinyl ester [AA-3 7] was ed by reaction of 5,6-dimethylpyridinyl- thieno[2,3-d]pyrimidinol [AA-l9], 2,4,6-triisopropylbenzenesulfonyl chloride, Eth, DMAP and DCM at room ature to give the desired compound as a brown solid.

LCMS method: 3, RT: 6.18 min, MI: 524 [M+1]. 2,4,6-triisopropyl-benzenesulfonic acid 6-carbamoylmethylpyridinyl-thieno[2,3- d]pyrimidinyl ester [AA-3 8] was prepared by reaction of 4-hydroxymethyl pyridinyl-thieno[2,3-d]pyrimidinecarboxylic acid amide [AA-20], 2,4,6- triisopropylbenzenesulfonyl chloride, Eth, DMAP and DCM at room temperature to give the desired nd as a brown solid. LCMS method: 3, RT: 6.12 min, MI: 553 [M+1]. triisopropyl-benzenesulfonic acid 6-isopropylpyridinyl-thieno[2,3- d]pyrimidinyl ester [AA-3 9] was prepared by reaction of 6-isopropylpyridinyl- thieno[2,3-d]pyrimidinol [AA-21], triisopropylbenzenesulfonyl chloride, Eth, DMAP and DCM at room temperature to give the desired compound as a brown solid.

LCMS method: 3, RT: 6.24 min, MI: 538 [M+1].

SN |\ [AAQZ] 2,4,6-triisopropyl-benzenesulfonic acid 6-methylphenylpyridinyl-thieno[2,3- d]pyrimidinyl ester [AA-40] was prepared by reaction of 6-methylphenylpyridin- 4-yl-thieno[2,3-d]pyrimidinol [AA-22], 2,4,6-triisopropylbenzenesulfonyl chloride, Eth, DMAP and DCM at room temperature to give the desired compound as a brown solid. LCMS method: 3, RT: 6.55 min, MI: 586 [M+1]. 2,4,6-triisopropyl-benzenesulfonic acid romo-phenyl)pyridinyl-thieno[2,3- d]pyrimidinyl ester [AA-41] was prepared by reaction of 5-(4-bromo-phenyl)—2- pyridinyl-thieno[2,3-d]pyrimidinol [AA-23], 2,4,6-triisopropylbenzenesulfonyl chloride, Eth, DMAP and DCM at room temperature to give the desired compound as a brown solid. LCMS method: 3, RT: 6.66 min, MI: 651 [M+1].

General synthesis of 5,6 substituted 4-aminopyridinyl-thieno[2,3-d]pyrimidine derivatives of general formula [F-l] (Scheme A6) ,6-substituted-(2,4,6-triisopropyl-benzenesulfonic acid)- 2-pyridinyl- thieno[2,3-d] pyrimidin yl ester derivatives of general formula [F-lZ] [prepared in scheme A5] were reacted with a primary or secondary amino derivative of general formula [F-l3] in a polar aprotic solvent such as DMA, DMF, NMP in the presence of a tertiary amine base such as Eth, DIPEA or NMM at t ature. After reaction work up, typically by a liquid-liquid extraction or puriﬁcation by acidic ion ge catch- release, the N—Boc derivatives were ected under acidic ions with a strong acid such as TFA, TCA, methanesulfonic acid, HCl or H2804 in a solvent such as DCM, DCE, THF, EtOH or MeOH and the crude reaction product was puriﬁed by reverse phase preparative HPLC Scheme A6 R3 E R4 ‘R2 \\S @5 R9 0 A R1wa‘33 [F-13] RRe R12 i.Amines, Et3N,DMA / / IN R12 13 _> 13 \ R S \N R \ ii. TFA,DCM s N \ | | R15 /N R15 /N R14 R14 [F-12] [F4] (2-pyridinyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidinyl)-(R)-pyrrolidin- 3 -yl-amine [19] _, 2 II S N \ To a solution of 2,4,6-triisopropyl-benzenesulfonic acid 2-pyridinyl-5,6,7,8- ydro-benzo[4,5]thieno[2,3-d]pyrimidinyl ester (60 mg, 0.110 mmol) [AA-25] in DMA (1 ml) was added (R)—(+)Bocaminopyrrolidine (23 mg, 0.121 mmol) followed by Eth (30 ul, 0.220 mmol) and the mixture was stirred at room temperature for 2 hours.

Water (1 ml) was added and the mixture was extracted with DCM (2 x ml), the ts were combined and washed with brine (2 m1). To the c phase was added TFA (1 ml) and the mixture was stirred at room temperature for 1 hour. After completion the mixture was loaded onto a SCX-2 dge and washed with methanol. The product was released from the cartridge using a solution of 2M ammonia / methanol. The ammonia / methanol eluent was concentrated under reduced pressure and the crude product was puriﬁed by preparative HPLC (method B) to yield to the desired compound. LCMS method: 4, RT: 4.43 min, MI: 352 [M+l]. 1H NMR (300MHz, DMSO): 8.70 (d,2H), 8.24 (d,2H), 3.53 (m,2H), 3.33 (m,lH), 3.22 (m,2H), 3.03 , 2.81 (m,2H), 2.34 (m,lH), 2.10 (m,lH), 1.83 (m,4H).

The following compounds were prepared according to the general synthesis shown in scheme A6: Ex SM Amine Characterisation H N .,, /boc method: 4, RT: 4.14 [AA-25] 2 \N \_/ min, MI: 352 [M+1] H method: 2, RT: 2.32 21 [AA-26] N\bOC min,MI:340[M+1] HZN method: 2, RT: 273 22 [AA 26] HN\bOC min, MI: 354 [M+1] HZN/\E(/S) method: 2, RT; 2.66 23 [AA 26] HN\bOC min, MI: 354 [M+1] Ex SM Amine Characterisation : 2, RT: 2.36 24 [AA-27] /\/H\ H2N bOC min, MI: 354 [M+1] H2N/\5(/S) method: 2, RT: 2.68 [AA-27] HN\bOC min, MI: 368 [M+1] H2Nﬁg method: 2, RT: 2.57 26 [AA-27] HN\bOC min, MI: 368 [M+1] method: 3, RT: 2.16 27 [AA-33] /\/H \ H2N bOC min, MI: 431 [M——1] method: 2, RT: 2.37 28 [AA-34] /\/H \ H2N bOC min, MI: 328 [M——1] method: 2, RT: 29 [AA-34] H138) 2.41min, MI: 342 [h4+1] H2N (R) method: 2, RT: 2.51 [AA-34] HN‘boc min, MI: 342 [M+1] HZNM : 2, RT: 2.30 31 [AA-35] HN‘boc min, MI: 328 [M+1] H2N method: 2, RT: 2.32 32 [AA-35] HN\bOC min, MI: 328 [M+1] method: 2, RT: 2.01 33 [AA-36] /\/H \ H2N bOC min, MI: 300 [M+1] 14,1156 method: 2, RT: 2.12 34 [AA-36] HN\bOC min, MI: 314 [M+1] H2N method: 2, RT: 2.12 [AA-36] HN‘boc min, MI: 314 [M+1] method: 2, RT: 1.92 36 [AA-37] /\/H\ H2N bOC min, MI: 300 [M+1] HZNM method: 2, RT: 2.08 37 [AA-37] HN\bOC min, MI: 314 [M+1] Ex SM Characterisation method: 2, RT: 2.52 38 [AA-37] min, MI: 314 [M+1] method: 2, RT: 1.60 39 [AA-38] min, MI: 329 [M--1] : 2, RT: 2.07 40 [AA-39] min, MI: 314 [M--1] method: 2, RT: 2.16 41 [AA-39] min, MI: 328 [M+1] 1H NMR (300MHz, DMSO): 8.7 (d, 8.42 (s, HCOOH, method: 3, RT: 1.48 1H) 42 ] H N/\/ \boc 8.26 (d, 2H), min, MI: 384 [M+1] 3.94(bs,2H), 3.86 ), m, 2H), 3.30 (m, 2H), 3.22 (m, 4H), method: 3, RT: 2.33 43 [AA-30] min, MI: 354 [M+1] method: 3, RT: 2.07 44 [AA-32] min, MI: 344 [M+1] method: 3, RT: 1.81 45 [AA-31] min, MI: 328 [M+1] General synthesis of 5,6 substituted opyridinyl—thieno[2,3-d]pyrimidine derivatives of general formula [F-l] (Scheme A7) Compounds were sised starting from an N—Boc protected amino acid derivative of general formula [F-14] which was converted to a primary carboxamide derivative of general formula [F-15] by reaction with di-tert-butyl dicarbonate in the presence of a base such as pyridine or 2,6-1utidine and ammonium carbonate in an anhydrous solvent such as dioxane, THF or diethylether. The resultant primary carboxamide derivative was reduced to the amino derivativeof general formula [F-16] with a borane reducing agent such as BH3.THF or BH3.SMe2 in an anhydrous solvent such as 2012/065831 THF, dioxane or diethylether. The resultant amino derivative was then reacted with a 5,6- substituted-(2,4,6-triisopropyl-benzenesulfonic acid)- dinyl-thieno[2,3- d]pyrin1idinyl ester [F-12] [prepared in scheme A5] in a polar aprotic solvent such as DMA, DMF, NMP in the ce of a tertiary amine base such as Eth, DIPEA or NMM at ambient temperature. After reaction work up, typically by a liquid-liquid tion or puriﬁcation by acidic ion exchange catch-release, the N—Boc derivatives were deprotected under acidic conditions with a strong acid such as TFA, TCA, methanesulfonic acid, HCl or H2804 in a solvent such as DCM, DCE, THF, EtOH or MeOH and the crude reaction product was puriﬁed by reverse phase preparative HPLC.

SchemeA7 o (>4 o 24 0 (>4 y BocZO,Pyridine, Y Y HN R4 HN ammonium carbonate, R4 HN BH3_THF R4 R3)E’OH _> R3 —> R3 drydioxane )E’NHZ NH2 0 o [F-14] [F-15] [F-16] R9 0 “o 1 / 12 R3 I? / N R R10 R4 N\ I 13 R2 S \N R |\ I35 /N RR6 A 14 R10 / / IN R12 [F-12] S \N R _, I R15 /N i. Et3N,DMA R14 " [F-1] II.TFA,DCM ((S)- l-carban10yl-2—p-tolyl-ethyl)-carban1ic acid tert-butyl ester [AA-42]. -l9l- O 54 o ov0 WH? HN OH NH2 0 o [AA-42] To a stirred solution of (S)tert-butoxycarbonylaminop-tolyl-propionic acid (560 mg, 2 mmol), ne (100 ul, 1.2 mmol) and di-tert—butyl onate (568 mg, 2.6 mmol) in dry dioxane (4 ml) was added um carbonate (240 mg, 2.5 mmol). The mixture was stirred for 4 hours at room temperature. Ethylacetate was added and the mixture was washed with water and a solution of 5% H2804. The combined organic phases were dried with magnesium sulfate, ﬁltered and evaporated to provide the title compound as a white solid. LCMS method: 2, RT: 3.69 min, MI: 279 [M+1].

[(S)amino- l -(4-methyl-benzyl)-ethyl]-carbamic acid tert-butyl ester [AA-43] 0% x H?o o W v0 NH2 NH2 [AA-42] [AA-43] A 1M solution of BH3 in THF (15 ml, 15mmol) was added dropwise to ((S)—l- oylp-tolyl-ethyl)-carbamic acid tert-butyl ester [AA-42] (560 mg, 2mmol), the on was stirred overnight at room temperature then subsequently hydrolysed by slow addition of excess of 10% acetic acid/MeOH (30 ml) and stirred at room temperature for a further 2 hours. The solvent was removed under reduced pressure the residue dissolved in ol and passed h a SCX-2 cartridge and washed with methanol. The product was released from the cartridge using a solution of 2M ammonia / methanol. The solvent was evaporated to provide the title compound as a white solid. LCMS method: 2, RT: 2.42min, MI: 265 [M+1].

[(S)- l -carbamoyl(2-methoxy-phenyl)-ethyl]-carbamic acid tert-butyl ester [AA-44] -l92- 2012/065831 Oyo Oyo H HN OH NH /O 2 o /o o [AA-44] To a d solution of (S)tert-butoxycarbonylamino(2-methoxy-phenyl)- propionic acid (998 mg, 3.3 mmol), pyridine (300 ul, 3.6 mmol) and di-tert-butyl dicarbonate (1 .16g, 5.32 mmol) in dry dioxane (10 ml) was added ammonium carbonate (512 mg, 5.32 mmol). The mixture was stirred for 4 hours at room temperature.

Ethylacetate was added and after washings with water and a solution of 5% H2804. The ed organic phases were dried with magnesium e, ﬁltered and evaporated to provide the title compound as a white solid. LCMS method: 4, RT: 3.09 min, MI: 295 [M+l].

[(S)amino(2-methoxy-benzyl)—ethyl]-carbamic acid tert-butyl ester [AA-45] [AA-44] [AA-45] A 1M solution of BH3 in THF (15 ml, 15mmol) was added dropwise to [(S) carbamoyl(2-methoxy-phenyl)-ethyl]-carbamic acid tert-butyl ester [AA-44] (980 mg, 3.32 mmol), the solution was stirred overnight at room temperature then subsequently ysed by slow addition of excess of 10% acetic eOH (30 ml) and stirred at room temperature for a further 2 hours. The solvent was removed under reduced pressure the residue dissolved in methanol and passed through a SCX-2 cartridge and washed with methanol. The product was released from the dge using a solution of 2M ammonia / methanol. The solvent was evaporated to provide the title compound as a white solid.

LCMS method: 2, RT: 2.40min, MI: 281 [M+l]. 2012/065831 (S)(4-methyl-benzyl)-3 -(2-pyridinyl-5 ,6,7, 8-tetrahydro-benzo [4,5 ]thieno [2,3 - d]pyrimidinyl)-propylamine [46] o v 94 2'SINN ox0 \mN HN [AAN-Z5] H | N \ 2 | i. MA [AA_43] SJU ii. TFA,DCM [46] To a solution of 2,4,6-triisopropyl-benzenesulfonic acid 2-pyridinyl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidinyl ester (100 mg, 0.182 mmol) [AA-25] in DMA (2 ml) was added [(S)amino(4-methyl-benzyl)-ethyl]-carbamic acid tert-butyl ester [AA-43] (58 mg, 0.218 mmol) followed by Eth (76 ul, 0.546 mmol), the mixture was stirred at room temperature for 2 hours. Then the product was extracted with DCM (2 ml) and washed with brine (3 ml). To the organic phase was added TFA (2 ml) and the mixture was stirred at room temperature for 1 hour. After completion the mixture was loaded onto a SCX-2 cartridge and washed with methanol. The product was released from the cartridge using a solution of 2M ammonia / methanol. The a / methanol eluent was concentrated under reduced pressure and the crude product was puriﬁed by preparative HPLC (method B) to yield to the title compound. LCMS : 4, RT: 4.85 min, MI: 430 [M+1]. 1H NMR (300MHz, DMSO): 8.64 (d,2H), 7.99 (d,2H), 7.18 (m,4H), 3.89 (m,2H), 3.49 (m,2H), 2.98 (m,1H), 2.94 (m,2H), 2.78 (m,2H), 2.31 (s,3H), 1.83 (m,4H).

The ing compounds were prepared according to the general sis shown in Scheme A7: method: 3, RT: 2.47 min, MI: 446 [M+1] —194— m>< (/1Z Amino acid [F- 14] Characterisation method: 3, RT: 2.64 J; 00 [AA-25] min, MI: 430 [M+1] method: 3, RT: 2.66 L [AA'ZS] min, MI: 446 [M+1] method: 3, RT: 2.76 kl] [AA-25] min, MI: 434 [M+1] method: 3, RT: 2.56 kl] H [AA-25] min, MI: 434 [M+1] : 3, RT: 2.87 kl] [AA'ZS] min, MI: 466 [M+1] method: 3, RT: 2.65 kl] U.) [AA'ZS] min, MI: 430 [M+1] method: 3, RT: 2.53 kl] [AA-25] min, MI: 446 [M+1] method: 3, RT: 2.23 kl] ] min, MI: 432 [M+1] method: 3, RT: 1.87 kl] ON [AA-25] min, MI: 417 [M+1] method: 3, RT: 1.98 kl] \] [AA-25] min, MI: 417 [M+1] -m>< (/1Z Amino acid [F- l 4] Characterisation method: 3, RT: 2.18 min, MI: 417 [M+l] method: 3, RT: 2.26 min, MI: 423 [M+l] I method: 3, RT: 2.44 min, MI: 396 [M+l] method: 3, RT: 2.59 min, MI: 472 [M+l] method: 3, RT: 2.21 min, MI: 380 [M+l] method: 4, RT: 4.60 min, MI: 455 [M+l] I method: 4, RT: 4.55 O'\ J; min, MI: 464 [M+l] General synthesis of (S)—3-(2 or 3-hydr0xy-phenyl)—N*1*-(2-pyridinyl—5,6,7,8-tetra hy dro-benz0[4,5]thien0[2,3-d]pyrimidinyl)-pr0 pane-1,2-diamine derivatives of general formula [F-18] (Scheme A8) Compounds were synthesised starting from (S)(2 or 3-methoxy-phenyl)-N"< l *- (2-pyridinyl-5 ,6,7,8-tetrahydro-benzo [4,5 ]thieno [2,3 -d]pyrimidinyl)-propane- l ,2- diamine derivatives of general a [F-l7] ibed in scheme A7) by a de- methylation reaction with a Lewis acid such as BBrg or A1C13 in a nated solvent such as DCM or DCE at low on temperature. After reaction work up, typically by a liquid-liquid extraction or puriﬁcation by acidic ion exchange catch-release, the crude reaction product was d by reverse phase preparative HPLC.

SchemeA8 NH = OH S N / BBr,DCM3 I S N/ / a I [F-17] [F-18] Synthesis of 2-[(S)amino(2-pyridinyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidinylamino)—propyl]-phenol [65] S BB ,DCM N / r3 I 8 N/ / a I

[65] To a on of (S)(2-methoxy-phenyl)-N* l *-(2-pyridinyl-5,6,7,8- lO tetrahydro-benzo[4,5]thieno[2,3-d] pyrimidinyl)-propane-l,2-diamine [49] (30 mg, 0.06 mmol) in DCM (1 ml) at -30°C was added dropwise a on of l M BBrg in DCM (180 ul, 0.180 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at - °C for 1 hour and then stirred overnight at room temperature. The crude reaction mixture was concentrated under reduced pressure and then puriﬁed by preparative HPLC (method A) to yield to the title compound. LCMS : 3, RT: 2.28 min, MI: 432 [M+l].

The following compounds were prepared according to the general sis shown in Scheme A8: method: 3, RT: 2.34 min, MI: 432 [M+l] General synthesis of 5,6 substituted 4-aminopyridinyl—thieno[2,3-d]pyrimidine derivatives of general formula [F-l] (Scheme A9) -l97- Compounds were synthesised starting from the hloride or hydrobromide salt of an 0t-amino acid carboxamide derivative of general formula [F-l9] which was converted to the free base by reaction with a base such as Eth or DIPEA in a nated solvent such as DCM or DCE. The resultant free base was then reduced to a diamino derivative of general formula [F-20] by on with a borane reducing agent such as BH3.THF or BH3.SMe2 in an anhydrous solvent such as THF, dioxane or diethylether. The resultant diamino derivative [F-20] was then reacted with a 5,6-substituted-(2,4,6- triisopropyl-benzenesulfonic acid)- 2-pyridinyl-thieno[2,3-d]pyrimidinyl ester of general formula [F-lZ] [prepared in scheme A5] in a polar aprotic solvent such as DMA, DMF, NMP in the presence of a tertiary amine base such as Eth, DIPEA or NMM at ambient temperature. After reaction work up, typically by a liquid-liquid extraction or puriﬁcation by acidic ion exchange catch-release the crude reaction t was purified by reverse phase preparative HPLC.

Scheme A9 R4 \R2 5R3; R%R6 A R10 / / IN R12 HzN R4 IEt3N,DCM HZN s R3):R \N |\ R3 15 /N NHz R IIBH3.THF O 14 HCI reflux R [F-19] [F-20] [F-1] sis of (S)phenyl-propane-l,2-diamine [AA-46] H2N H i.Et3N,DCM H2N H 2 NH2 0 ii.BH3.THF reﬂux [AA-46] To a sion of (S)aminophenyl-propionamide hydrochloride , 2.7 mmol) in DCM (5 ml) was added Eth (3 80ul, 2.7 mmol). The suspension was stirred for 2h at room temperature, the resulting solid was filtered and the filtrate was concentrated under reduced pressure to yield to a white solid to which was added dropwise a 1M solution of BH3 in THF (20 ml, 20mmol) the on was stirred overnight at reﬂux. After -l98- WO 78126 cooling the solution was hydrolysed by slow addition of excess of 10% acetic acid/MeOH (30ml) and reﬂuxed for a ﬁarther 2 hours. The solvent was removed under reduced pressure, the residue dissolved in methanol and passed through a SCX-2 cartridge and washed with methanol. The product was released from the cartridge using a solution of 2M ammonia / ol. The solvent was evaporated to provide the title compound as a white solid. LCMS method: 1, RT: 0.36min, MI: 151 [M+1].

Synthesis of (S)—N*1*-(2-pyridinyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidinyl)-butane- 1 ,2-diamine [67] NH S 2 Et3N,DMA [AA-46] [67] NJ\©/ N To a solution of 2,4,6-triisopropyl-benzenesulfonic acid 2-pyridinyl-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidinyl ester [AA-25] (100 mg, 0.180 mmol) in DMA (2 ml) was added (S)phenyl-propane-1,2-diamine [AA-46] (30 mg, 0.180 mmol) followed by Eth (50 ul, 0.36 mmol), the e was d at room ature for 2 hours. After completion the mixture was loaded onto a SCX-2 cartridge and washed with methanol. The product was released from the cartridge using a solution of 2M ammonia / methanol. The ammonia / methanol eluent was concentrated under reduced pressure and the crude product was puriﬁed by ative HPLC d A) to yield to the title nd. LCMS method: 4, RT: 2.51 min, MI: 416 [M+1]. 1H NMR (300MHz, DMSO): 8.64 (d,2H), 7.95 (d,2H), 7.36 (m,5H), 3.92 (m,2H), 3.46 (m,2H), 2.92 (m,1H), 2.91 (m,2H), 2.79 (m,2H), 1.83 (m,4H).

The following compounds were prepared according to the general synthesis shown in Scheme A9: PCT/U82012/065831 SM Carboxamide m>< Characterisation [F-12] [F-19] 1H NMR (300MHz, DMSO): 8.7(d,2H), method: 2, 8.2 (d,2H), 3.9 RT: 2.16 min, (m,1H), 3.6 (m,1H), MI: 354 3.3 , 1.8 [M+1] (m,4H), 1.6 (m,2H), 1 (I, 3H) method: 2, RT: 2.94 min, MI: 430 [M+1] method: 2, RT: 2.72 min, \l O MI: 430 [M+1] 1H NMR (300MHz, DMSO): 8.67 (d,2H), method: 3, 7.9 (d,2H), 7.3 RT: 2.54 min, (m,5H), 3.9 (m,2H), MI: 416 3.53 (m,2H), 2.92 [M+1] (m,1H), 2.91 (m,2H), 2.79 (m,2H), 1.83 (m,4H) : 3, RT: 2.52 min, MI: 521 [M+1] method: 3, RT: 2.53 min, \1 U.) MI: 521 [M+1] method: 2, \1 J; RT: 2.31 min, MI: 419 SM Carboxamide Ex Characterisation [F-12] method: 2, RT: 2.56 min, MI: 404 [M+1] method: 2, RT: 2.95 min, \l ON MI: 444 [M+1] method: 3, RT: 2.77 min, \l \1 MI: 444 [M+1] method: 3, RT: 2.37 min, \l 00 MI: 474 [M+1] method: 3, RT: 2.37 min, MI: 474 [M+1] : 3, RT: 2.59 min, MI: 434 [M+1] method: 3, RT: 2.60 min, 00 >—‘ MI: 434 [M+1] method: 3, RT: 2.23 min, MI: 418 [M+1] SM Carboxamide EX Characterisation [13—12] [F-19] method: 3, ; RT: 2.27 min, 83 [AA-31] MI' 418 [M+l] General synthesis of 5,6 substituted 4-aminopyridinyl—thieno[2,3-d]pyrimidine derivatives of general formula [F-l] (Scheme A10) , 6-substituted 2-pyridiny1—thieno [2, 3-d] pyrimidinol derivatives of general a [F-4] [prepared in scheme A2] were ted to a activation reaction by on with a solid supported sulfonyl chloride tive such as benzenesulfonyl choride on polystyrene resin in a polar c solvent such as DMA, DMF, NMP in the presence of a ry amine base such as Eth, DIPEA or NMM with a catalytic amount ofDMAP at ambient temperature. Excess reagents and reactants were removed by ﬁltration and washing the polystyrene resin with solvents such as DCM, DMF, THF. The polymer supported reagent of l formula [F-2l] was then reacted with an N—Boc protected diamino derivative of general formula [F-l3] in a polar aprotic solvent such as DMA, DMF, NMP in the ce of a tertiary amine base such as Eth, DIPEA or NMM at ambient temperature. The resin was ﬁltered through a PTFE frit and washed with a solvent such as DCM or ethylacetate, the ﬁltrate was combined and after reaction work up, typically by a liquid-liquid extraction or puriﬁcation by acidic ion exchange catch-release, the N—Boc derivatives were deprotected under acidic conditions with a strong acid such as TFA, TCA, methanesulfonic acid, HCl or H2804 in a solvent such as DCM, DCE, THF, EtOH or MeOH and the crude reaction product was puriﬁed by reverse phase preparative HPLC.

Scheme A10 P8 P8 R9 OH Rng/IKIN/ Q.0 R Q 12 9 O’ \\ R 13 ,O O S N \ Cl/S“ / I O 10 / N R12 R | ———> R13 R s N \ 14 DMAP,Et3N,DMA | R [F-21] R15 / N [F-4] [F-13] R R6 i. Amines, Et N,DMA Rwy/fl/ N R12 —3_, 13 \ R ii. TFA,DCM S \ [F-1] R15 Synthesis of yrene ted esulfonic acid 2-pyridinyl-6,7,8,9- tetrahydro-SH- l 0-thia-l ,3 -diaza-benzo [a]azulenyl ester [AA-47] z ? 2 /o OH ,0 o \‘ Cl/s; 0 / \N I ’Q_—> / \N / / S N \ S N | DMAP,Et3N,DMA | /N /N [AA-8] [AA-47] 2-pyridinyl-6,7,8 ,9-tetrahydro-5H- l 0-thia- l ,3 -diaza-benzo [a] azulenol [AA- 8] (70mg, 0.241 mmol) and PS-TSCl (70mg, 0.241 mmol) were placed into sealed ﬁlter cartridge. DMA was added (2 ml) followed by Eth (100 ul, 0.723 mmol) and DMAP (1.5 mg, 0.001 mmol). The reaction mixture was shaken for 3 hours at room temperature and then the resin was ﬁltered, through a PTFE frit. The resin was washed with DCM to yield to the polystyrene supported benzenesulfonic acid 2-pyridinyl-6,7,8,9-tetrahydro-5H- -thia-l za-benzo[a]azulenyl ester [AA-77] which was used in the next step without further puriﬁcation.

Synthesis ofN"< 1 *-(2-pyridinyl-6,7,8,9-tetrahydro-5Hthia-1,3-diaza- benzo[a]azulenyl)-ethane-1 ,2-diamine [84] >\:\< NH s”O HN/\/ 2 o’ v / | S N/ \ S N/ \ I I /N [AA-47] [84] The polystyrene supported benzenesulfonic acid 2-pyridinyl-6,7,8,9-tetrahydro- 5Hthia-l,3-diaza-benzo[a]azulenyl ester [AA-47] (70 mg, 0.24 mmol) was placed in a ﬁlter cartridge and DMA (2 ml) was added followed by Boc-ethylenediamine (39 mg, 0.241 mmol) and Eth (67 ul, 0.482 mmol). The reaction was shaken overnight at room temperature. The resin was ﬁltered through a PTFE frit and washed with ethylacetate. The ﬁltrate was concentrated under reduced pressure and the crude t was dissolved in DCM (2 ml) and TFA (2 ml) was added and the e was stirred at room temperature for 1 hour. After completion the mixture was loaded onto a SCX-2 cartridge and washed with methanol. The product was released from the cartridge using a solution of 2M ammonia / methanol. The ammonia / methanol eluent was concentrated under reduced pressure and the crude product was d by preparative HPLC (method A) to yield to the title nd. LCMS : 2, RT: 3.22 min, MI: 340 [M+l].

The following compounds were prepared according to the general sis shown in Scheme A10: Characterisation 1H NMR (300MHz, method: 2, DMSO): 8.72 (d,2H), RT: 2.26 8.25 (d,2H), 3.62 min, MI: (m,2H), 3.44 (m,4H), 366 [M+1] 3.06 (m,2H), 3.03 (m,4H), 1.88 (m,2H), 1.64 (m,4H) —204— terisation method: 2, 380 [M+1] method: 2, 430 [M+1] method: 2, 354 [M+1] 1H NMR (300MHz, DMSO): 8.71 (d,2H), method: 2, 8.26 , 3.83 RT: 2.26 (m,1H), 3.75 (m,1H), mm, MI: 3.62 (m,1H), 3.09 354 [M+1] (m,2H), 2.98 (m,2H), 1.89 (m,2H), 1.66 (m,4H), 1.21 (d,3H) method: 2, 517 [M+ 1] method: 2, 362 [M+1] method: 2, 402 [M+1] method: 2, 467 [M+1] Characterisation method: 2, RT: 1.90 min, MI: 312 [M+1] method: 2, RT: 1.91 min, MI: 326 [M+1] method: 2, RT: 2.32 min, MI: 441 [M+1] General synthesis of pyridyl substituted 4-amin0pyridinyl-thien0[2,3- d]pyrimidine tives of general formula [F-l] (Scheme All) A chloro-5,6,7,8-tetrahydro-enzo [4,5] thieno [2,3-d]pyrimidine derivative of general formula [F-21] was reacted with primary and secondary amino derivative of l formula [F-13] in a polar aprotic solvent such as DMA, DMF, NMP in the presence of a tertiary amine base such as Eth, DIPEA or NMM at ambient temperature.

Following reaction work up, typically by a liquid-liquid extraction or puriﬁcation by acidic ion exchange catch-release, the amino derivative of general formula [F-23] was reacted with pyridyl boronic acids or boronate esters of general formula [F-24] in the presence of a ium st such as Pd(PPh3)4 or Pd(PPh3)2C12 a base such as Eth, KOH, N32C03 0r NaOH in a polar solvent such as EtOH, THF, DMA or dioxane at high temperature either by heating thermally or using a microwave reactor. ing on work up, typically by a liquid-liquid extraction or puriﬁcation by acidic ion exchange catch-release the crude reaction product was puriﬁed by reverse phase preparative HPLC.

Scheme A11 R3 I? 9 4 N\ 2 R CI R R R10 / /JN\ R 6 A Amines, MA S \N CI [F-22] [F-231 R R6 / N R12 ArB(OR)2, Pd(Ph3P)4 N \ ——> R15 / N MW, EtOH, 15min, 150°C [F-1] Synthesis of [2-(2—chloro-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidinyla mino)-ethyl]-carbamic acid tert-butyl ester [AA-49] CI HNNNYO \N \N | | S N/J\C| s N/J\CI 0% [AA-48] [AA-49] To a solution of 2,4-dichloro-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine [AA-48] (100mg, 0.387mmol) in DMA (5 ml) was added Boc-ethylenediamine (62 mg, 0.387mmol) followed by Eth (l 10 ul, 0.774 mmol), the mixture was stirred at room temperature for 2 hours. Then the product was extracted with DCM (2x10 ml) and washed with brine (2x10 ml). The combined organic phases were dried with magnesium sulfate, ﬁltered and ated to provide a brown solid. The residue was used without ﬁarther puriﬁcation in the next step. LCMS method: 1, RT: 6.26 min, MI: 383 [M+l]. sis ofN* l *-[2-(3-ﬂuoro-pyridinyl)-5 ,6,7,8-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidinyl] -ethane- l ,2-diamine [97] NH O /\/NH2 HN Y “N \ o ArB(OR)2, Pd(Ph3P)4 \ N N X NACI | MW, EtOH, 15min, 150°C 8 N’ \ TFA, DCM / N [AA-49] [97] F A ave vial was charged with [2-(2-chloro-5,6,7,8-tetrahydro- benzo[4,5]thieno[2,3-d]pyrimidinylamino)-ethyl]-carbamic acid tert-butyl ester [AA- 49] (80mg, 0.210 mmol), 3-ﬁuoropyridineboronic acid hydrate (3 8mg, 0.24 mmol), tetrakis (triphenyl phosphine) palladium (12 mg, 0.01 mmol), N32C03 (2M in water, 300ul, 0.6 mmol) and EtOH (1ml). The reaction was heated to 150°C for 15 minutes under microwave irradiation. The mixture was then d through a plug of silica, washed with methanol and the ﬁltrate was concentrated under reduced pressure. To a solution of the crude product in DCM (2 ml) was added TFA (2 ml) and the mixture was stirred at room temperature for 1 hour. After completion the mixture was loaded onto a SCX-2 dge and washed with ol. The product was released from the cartridge using a solution of2M ammonia / methanol. The ammonia / methanol eluent was concentrated under reduced pressure and the crude product was puriﬁed by ative HPLC (method A) to yield to the title compound. LCMS method: 2, RT: 2.41 min, MI: 344 [M+1].

The following compounds were ed according to the general synthesis shown in Scheme A11: Boron1c acid Amine Character1sat1on [F24] [F 13] method: 2, RT. 2.64 m1n, MI: 344 [M+1] 1H NMR (300MHz, DMSO): 8.677 , 8.26 (d,1H), method: 2, RT: 8.34 (s,1H), 3.83 2.56 m1n, MI: (m,1H), 3.75 358 [M+1] (m,1H), 3.62 (m,1H), 2.91 (m,2H), 2.79 (m,2H), 1.66 Boronic acid Amine Characterisation [F24] [F 13] —_(m4H) 1.21 (d3H) method: 2, RT: 2.52 min, MI: 358 [M+1] 1H NMR (300MHz, DMSO): 8.64 (d,1H), 8.53 (d,1H), 7.83 (m,1H), 7.26 method: 2, RT: , 3.92 101 - 2.79 min, MI: (m,2H), 3.46 434 [M+1] (m,2H), 2.92 (m,1H), 2.91 (m,2H), 2.79 (m,2H), 1.83 (m,4H) method: 4, RT: 102 ; - 4.22 min, MI: 446 [M+1] Synthesis of 4-[4-((S)Amin0phenyl—pr0pylamin0)-5,6,7,8-tetrahydr0- benzo[4,5]thieno[2,3-d]pyrimidin-Z-yl]-pyridinol [103] (Scheme A12) Scheme A12 QIKNHN/\5/\©NH2 N/V\© BBr3,DCM S N“ 3 —>QI:NNH \0 53

[103] To a solution of 1*-[2-(3-methoxy-pyridinyl)-5,6,7,8-tetrahydro- benzo[4,5]thieno[2,3-d]pyrimidinyl]phenyl-propane- 1 ,2-diamine (prepared according to the general sis shown in scheme A11) [102] (30 mg, 0.06 mmol) in DCM (1 m1) cooled to -30°C was added dropwise a solution of 1 M BBr3 in DCM (180 ul, 0.180 mmol) under nitrogen. The reaction mixture was stirred at -30°C for 1 hour and stirred overnight at room temperature. The residue was concentrated under reduced pressure and then dissolved in DMSO and d by preparative HPLC (method B) to yield to the title nd. LCMS method: 4, RT: 4.43 min, MI: 432 [M+l]. 1H NMR (300MHz, DMSO): 8.30 (d,lH), 8.10 (d,lH), 7.81 d,lH), 7.28 (m,5H), 3.46 (m,2H), 3.40 (m,1H), 2.96 (m,2H), 2.79 (m,4H), 1.83 (m,4H).

General synthesis of 1-[4-(2-amino-ethylamin0)pyridinyl-5,8-dihydr0-6H— pyrido[4',3':4,5]thien0[2,3-d]pyrimidin-7—yl]-alkylan0ne derivatives of general formula [ [F-26] (Scheme A13) 4-benzenesulfonyloxypyridinyl-5,8-dihydro-6H-pyrido[4',3':4,5]thieno[2,3- d]pyrimidinecarboxylic acid tert—butyl ester [AA-11] (described in scheme A2) was subjected to an activation by on with a solid supported sulfonyl chloride derivative such as benzenesulfonyl choride on yrene in a polar aprotic solvent such as DMA, DMF, NMP in the presence of a tertiary amine base such as Eth, DIPEA or NMM with a tic amount ofDMAP at ambient temperature. Excess reagents and reactants were removed by ﬁltration and washing the polystyrene resin with a solvent such as DCM, DMF, THF. The polymer supported reagent was then reacted with (2-amino-ethyl)- carbamic acid allyl ester in a polar aprotic solvent such as DMA, DMF, NMP in the presence of a tertiary amine base such as Eth, DIPEA or NMM at ambient ature.

The resin was ﬁtred through a PTFE frit and washed with a solvent such as DCM or cetate, the ts were combined and after reaction work up, typically by a liquid- liquid extraction or puriﬁcation by acidic ion exchange catch-release, the N—Boc derivative was deprotected under acidic conditions with a strong acid such as TFA, TCA, methanesulfonic acid, HCl or H2S04 in a solvent such as DCM, DCE, THF, EtOH or MeOH to give pyridinyl-5,6,7,8-tetrahydro-pyrido[4',3':4,5]thieno[2,3- d]pyrimidinylamino)-ethyl]-carbamic acid allyl ester [AA-50]. Reaction of pyridin yl-5,6,7,8-tetrahydro-pyrido[4',3':4,5]thieno[2,3-d]pyrimidinylamino)-ethyl]-carbamic acid allyl ester [AA-50] with an acyl chloride derivative of general formula [F-27] in a polar aprotic solvent such as DMA, DMF, NMP in the presence of a tertiary amine base such as Eth, DIPEA or NMM gave the N—acylated [F-25] derivative which was subjected to an N—allyl ection reaction with polymer supported ium, polymer supported borohydride in DCM, MeOH and water to give the corresponding amino derivates [F-26] .

Following reaction work up, typically by a liquid-liquid tion or puriﬁcation by acidic ion ge catch-release the crude reaction product was puriﬁed by e phase preparative HPLC.

Scheme A13 i. PS-SOZCI, DMAP, Et3N, DMA 0Y0 0 NH ii. HZNwNJKO/V I >/'—N H HN EtNDMA HN / \ N iii. TFA, DCM I [AA-111 [AA-50] / N J/NH J/NH DMA RX HN PS-PPhS-Pd, MP-BH4 o)"N / \ N DCM:MeOH:HZO \N 0 | )L . s N/ (5.4.1).

RX CI | /hi] [F-27] [F-25] [F--26] Synthesis of polystyrene supported 4-benzenesulfonyloxypyridinyl-5,8-dihydro-6H- pyrido[4',3':4,5]thieno[2,3-d]pyrimidinecarboxylic acid tert-butyl ester [AA-51] >Lo)‘ 9\ :0 OH O 0’be s N/ |\ /N /s|NJ\O [AA-11] [AA-51] 2-pyridinyl-6,7,8 ,9-tetrahydro-5H- 1 O-thia- 1 ,3 -diaza-benzo [a] azulenol [AA- 11] (700mg, 1.83 mmol) and PS-TSCl (1.2 g, 2.92 mmol) were placed into ﬁlter cartridge closed with a stopper. DMA (10 ml) was added followed by Eth (510 ul, 3.66 mmol) and DMAP (11 mg, 0.09 mmol). The reaction was shaken for 3 hours at room temperature and then the resin was ﬁltered through a PTFE frit. The resin was washed with DCM (6 ml) to yield to the polystyrene supported 4-benzenesulfonyloxypyridinyl-5,8-dihydro-6H- pyrido[4',3':4,5] thieno [2,3-d]pyrimidinecarboxylic acid tert-butyl ester [AA-51], which was used in the next step without further puriﬁcation.

Synthesis of [2-(2-pyridinyl-5,6,7,8-tetrahydro-pyrido[4',3':4,5]thieno[2,3-d]pyrimidin- 4-ylamino)-ethyl]-carbamic acid allyl ester [AA-50] PS 9’ /0 I >LO ’ O \O\ HN OM—Qf _,HN / m S N/ \ S N/ \ I I /N /N [AA-51] [AA-50] To the polystyrene supported 4-benzenesulfonyloxypyridinyl-5,8-dihydro- 6H-pyrido[4',3':4,5] thieno [2,3-d]pyrimidinecarboxylic acid tert-butyl ester [AA-51] placed into a ﬁlter cartridge was added DMA (2 ml) followed by allyl-N-(2- aminoethyl)carbamate hydrochloride (397 mg, 2.2 mmol) and Eth (510 ul, 3.66 mmol).

The reaction was shaken overnight at room temperature. The resin was ﬁltered through a PTFE frit and washed with ethylacetate (6 ml) followed by DCM (6 ml). The extracts were combined and evaporated under reduced pressure. The crude reaction product was dissolved in DCM (25 ml) and washed with sodium en carbonate (20 ml) then brine (20 ml), dried with magnesium sulfate, ﬁltered and ated under d pressure to provide an orange solid. To a solution of the crude product in DCM (5 ml) was added TFA (5 ml) and the mixture was stirred at room temperature for 1 hour. After tion the mixture was loaded onto a SCX-2 cartridge and washed with methanol. The product was released from the dge using a solution of 2M ammonia / methanol. The a / methanol eluent was concentrated under reduced pressure and the crude product was used without further puriﬁcation in the next step. LCMS method: 1, RT: 4.23 min, MI: 411 [M+l].

Synthesis of (2,2-dimethyl-propionyl)pyridinyl-5,6,7,8-tetrahydro- pyrido[4',3':4,5]thieno[2,3-d]pyrimidinylamino]-ethyl} -carbamic acid allyl ester [AA- —212— To a solution of [2-(2-pyridinyl-5,6,7,8-tetrahydro-pyrido[4',3':4,5]thieno[2,3- d]pyrimidinylamino)-ethyl]-carbamic acid allyl ester [AA-50] (50mg, 0.121 mmol) in DMA (1 ml) at -10°C were added trimethylacetyl chloride (16 ul, 0.133 mmol) and N,N,— di-isopropyethylamine (60 ul, 0.363 mmol). The mixture was stirred overnight. After completion the reaction e was treated with water (2 ml) and brine (2 ml) and ted with DCM (3 ml). The organics were evaporated under vacuum and the crude product was used without further ation in the next step.

Synthesis of 1-[4-(2-amino-ethylamino)pyridinyl-5,8-dihydro-6H- pyrido [4',3 ':4,5 ]thieno [2,3 -d]pyrimidinyl]-2,2-dimethyl-propanone [104] in]NQfN —>\iNPSPPh-,Pd MPBH DCM: MeOH:H20 “1&0“ (5- 4- 1) NQfNV [AA—52] [104] “1&0“ To a solution of {2-[7-(2,2-dimethyl-propionyl)pyridinyl-5,6,7,8-tetrahydro- pyrido[4',3':4,5] thieno[2,3-d]pyrimidinylamino]-ethyl}-carbamic acid allyl ester [AA- 52] (50mg, 0.121 mmol) in DCM:MeOH:HgO (5:4:1) (2 ml) in a ﬁlter cartridge were added PS-PPhg-Pd (18mg, 0.002 mmol) and MP-BH4 (116mg, 0.363 mmol). The on was shaken for 2h after then the solution was ﬁltered through NaZSO4 plug. The ﬁltrate was trated under reduced pressure and the crude residue was puriﬁed by preparative HPLC (method A) to yield to the title compound. LCMS method: 2, RT: 2.26 min, MI: 411 [M+1].

The following compounds were prepared according to the general synthesis shown in Scheme A13: Acid chloride Ex SM terisation [F-27] 0 : 2 RT: 1.83 min ’ ’ [AA—52] )L CI MI: 369 [M+1] 0 method: 2 RT: 1.97 min ’ ’ [AA—52] \JKCI MI: 383 [M+1] : 2, RT: 2.02 min, [AA—52] CI MI: 397 [M+1] method: 2, RT: 2.01 min,.

[AA—52] CI MI: 395 [M+1] method: 2, RT: 2.13 min, [AA52] MI. 409 [M+1] method: 2, RT: 2.32 min, [AA52] MCI MI: 411 [M+1] | 0 method. 2, RT. 1.66 min, [AA—52] /N$CI MI: 412 [M+1] General sis of N*1*-(7-alkyl-Z-pyridinyl-5,6,7,8-tetrahydr0- pyrid0[4',3':4,5]thien0[2,3-d]pyrimidinyl)—ethane-1,2-diamine derivatives of general formula [F-28] (Scheme A14) [2-(2-pyridinyl-5,6,7,8-tetrahydro-pyrido[4',3':4,5]thieno[2,3-d]pyrimidin ylamino)-ethyl]-carbamic acid allyl ester [AA-50] was reacted in reductive amination reaction with aldehyde derivative of l formula [F-30] and a solid supported borohydride reagent in acetic acid and a polar protic solvent such as MeOH or EtOH. The N—alkylated derivative of general formula [F-29] was subjected to an N—allyl deprotection reaction with polymer supported palladium, polymer ted borohydride in DCM, MeOH and water to provide the amino derivative [F-28]. Following reaction work up, —214— typically ﬁltration h a PTFE frit followed by by a liquid-liquid extraction or puriﬁcation by acidic ion exchange catch-release the crude reaction product was puriﬁed by reverse phase preparative HPLC.

Scheme A14 HN%N “2-301 RXL HN RXCHO, MP—BH4 / \ N S N/ \ S N/ \ I Acetic acid,MeOH I / N / N [AA-50] [F-29] PS-PPhs-Pd, MP—BH4 RX DCM:MeOH:H20 I (5:4:1) s N/ \ [F-28] sis of [2-(7-ethylpyridinyl-5,6,7,8-tetrahydro-pyrido[4',3':4,5]thieno[2,3- d]pyrimidinylan1ino)-ethyl]-carban1ic acid allyl ester [AA-53] HN%N \N ] / N [AA—53] To a solution of [2-(2-pyridinyl-5,6,7,8-tetrahydro-pyrido[4',3':4,5]thieno[2,3- d]pyrimidinylan1ino)-ethyl]-carban1ic acid allyl ester [AA-50] (50mg, 0.121 mmol) in MeOH (1 ml) in a ﬁlter cartridge were added MP-BH4 (144mg, 0.290 mmol) followed by acetaldehyde (4 ul, 0.075 mmol) and acetic acid (7 ul, 0.121 mmol). The on was shaken overnight at room temperature and then ﬁltered through a PTFE frit. The ﬁltrate was evaporated under reduced pressure and the resulting residue was dissolved in 2012/065831 methanol and the mixture was loaded onto a SCX-2 cartridge and washed with methanol.

The product was released from the cartridge using a solution of 2M a / methanol.

The ammonia / methanol eluent was concentrated under reduced pressure to yield the title compound which was used without further puriﬁcation in the next step.

Synthesis ofN* 1 *-(7-ethylpyridinyl-5,6,7,8-tetrahydro-pyrido[4',3':4,5]thieno[2,3- d]pyrimidinyl)-ethane-1,2-diamine [1 12] S “no 8:13 [AA-53] [112] To a solution of ethylpyridinyl-5,6,7,8-tetrahydropyrido[4',3':4,5]— [2,3-d]pyrimidinylamino)-ethyl]-carbamic acid allyl ester [AA-53] (50mg, 0.121 mmol) in DCM:MeOH:H2O (5:4: 1) (2 ml) in a ﬁlter cartridge were added PS-PPhg-Pd (18mg, 0.002 mmol) and MP-BH4 (116mg, 0.363 mmol). The reaction was shaken for 2h after completion the solution was ﬁltered through NazSO4 plug. The ﬁltrate was concentrated under reduced pressure and the residue puriﬁed by preparative HPLC (method A) to yield to the title compound. LCMS method: 2, RT: 1.89 min, MI: 355 [M+1].

The following compounds were prepared according to the general synthesis shown in Scheme A14: Aldehyde Ex SM Characterisation [F-30] 0 : 2 RT: 1.96 min ’ ’ 1 13 [AA-50] )L H MI: 341 [M+1] : 2, RT: 1.61 min, 114 [AA 50 M_ 1 H MI:383[M+1] General synthesis of lkyl-piperazinyl)pyridinyl-5,6,7,8-tetrahydr0- benzo[4,5]thien0[2,3-d]pyrimidine derivatives of general formula [F-31] (Scheme A15) 4-piperazin- l pyridinyl-5 ,6,7,8-tetrahydro-benzo [4,5 ]thieno [2,3 - d]pyrimidine [3] was subjected to a ive amination reaction with aldehyde derivatives of general formula [F-30] and a solid supported borohydride t in acetic acid and a polar protic solvent such as MeOH or EtOH to yield the ted derivative [F-27].

Following reaction work up, typically by a liquid-liquid extraction or puriﬁcation by acidic ion exchange catch-release the crude reaction product was puriﬁed by reverse phase preparative HPLC.

Scheme A15 H F EN] [N] N N [F-30] \ N \ N | i) RXCHO, MP-BH4 | / / S N \ —> S N \ I I ii) Acetic acid, MeOH / N [p-31] Synthesis of 4-(4-benzyl-piperazin- l -yl)—2-pyridinyl-5 ,6,7,8-tetrahydrobenzo [4,5]thieno[2,3-d]pyrimidine [l 15] H N EN] [N] S N/ |\ —> S N/ |\ /N /N

[115] To a solution of 4-piperazin-l-ylpyridinyl-5,6,7,8-tetrahydro- benzo[4,5]thieno[2,3-d]pyrimidine [3] (50mg, 0.142 mmol) in MeOH (2 ml) in a ﬁlter cartridge were added MP-BH4 (170mg, 0.341 mmol), p-anisaldehyde (ll ul, 0.09 mmol) and acetic acid (8 ul, 0.142 mmol). The reaction was shaken overnight at room temperature and then ﬁltered h a PTFE frit. The ﬁltrate was evaporated under 2012/065831 reduced pressure and the resulting residue was dissolved in ol and the mixture was loaded onto a SCX-2 cartridge and washed with methanol. The product was released from the cartridge using a solution of 2M ammonia / methanol. The ammonia / methanol eluent was concentrated under reduced pressure and puriﬁed by preparative HPLC (method A) to yield to the title compound. LCMS method: 2, RT: 2.61 min, MI: 456 [M+l]. 1H NMR (300MHz, DMSO): 8.70 (d,2H), 8.22 (d,2H), 7.21 , 7.15 (d,2H), 3.47 (m,7H), 2.90 (m,5H), 2.54 (s,2H), 2.28 (s,3H), 1.87 (br s, 2H), 1.73 (br s, 2H).

The ing compounds were prepared according to the general sis shown in Scheme A15: Aldehyde Characterisation [F - 3 0] method: 2, RT: 2.56 min, MI: 442 [M+1] method: 2, RT: 2.77 min, MI: 520 [M+1] method: 2, RT: 2.3 min, MI: 443 [M+1] method: 2, RT: 2.22 min, MI: 380 [M+1] method: 2, RT: 2.32 min, MI: 443 [M+1] 1H NMR (300MHz, DMSO): 8.72 (d,2H), 8.24 (d,2H), 8.17 (s,1H), 7,73 method: 2, RT: 2.97 (d.2H), 7,58 (d.2H), 3,66 min, MI: 510 (s.2H), 3.51 (m,4H), 2.9 [M+1] (m,4H), 2.61 (m,2H), 2.53 (m,2H), 1.87 (m,2H), 1.74 (m,2H) Aldehyde Characterisation [F-30] method: 2, RT: 2.72 min, MI: 476 : 2, RT: 2.78 min, MI: 476 1H NMR (300MHz, DMSO): 8.68 (d,2H), 8.22 method: 2, RT: 2.76 (d,2H), 8.16 (s,1H), 7.34 min, MI: 476 (m,4H), 3.45 (s,2H), 3.48 [M+1] (m,4H),2.87 (m,4H),2.57 (m,2H), 2.53 (m,2H), 1.87 (m,2H), 1.73 (m,2H) 1H NMR (300MHz, DMSO): 8.68 (d,2H), 8.22 method: 2, RT: 2.19 (d,2H), 3.48 (m,4H), 2.87 min, MI: 366 (m,4H), 2.57 (m,2H), 2.53 [M+1] (m,2H), 2.28 (s,3H), 1.87 (d,2H), 1.72 (d,2H) method: 2, RT: 2.41 min, MI: 458 [M+1] method: 2, RT: 2.83 min, MI: 520 [M+1] method: 2, RT: 2.57 min, MI: 520 [M+1] method: 2, RT: 2.32 min, MI: 408 [M+1] 1H NMR z, method: 2, RT: 2.23 DMSO): 8.69 (d,2H), 8.53 min, MI: 443 (s,1H), 8.48 , 8.23 [M+1] (d,2H), 7.75 (m,1H), 7.35 Aldehyde Characterisation [F-30] (m1H) 358 (m2H) 348 (m,4H), 2.88 (m,4H), 2.59 (m,2H), 2.53 (m,4H), 1.87 (m,2H), 1.73 (m,2H) method: 2, RT: 3.28 131 [3] \ min,MI: 520 N / [M+1] method: 2, RT: 2.57 132 [3] @H min, MI: 456 [M+1] method: 2, RT: 2.30 \i min, MI: 394 [M+1] O method: 2 RT: 2.32 YkH , min, MI: 408 [M+1] l synthesis of 5,6 substituted 4-alkoxy-Z-pyridinyl—thieno[2,3-d]pyrimidine derivatives of general formula [F-32] e A16) 4-chloropyridinyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrirnidine [AA-24] was ted to a philic substitution reaction with an amino alcohol or N- Boc protected arnino alcohol of general formula [F-33] in the presence of a strong base such as NaH, KH or LDA in the presence of an anhydrous polar aprotic solvent such as DMA, DMF or NNP. After reaction work up, typically by a liquid-liquid extraction or lO puriﬁcation by acidic ion exchange catch-release, the N—Boc derivative was deprotected under acidic conditions with a strong acid such as TFA, TCA, rnethanesulfonic acid, HCl or H2804 in a solvent such as DCM, DCE, THF, EtOH or MeOH and the crude reaction product was d by reverse phase preparative HPLC.

Scheme A16 R3 '3 R4 N\R2 6 o C' R [F-33] | |. NaH, ROH, DMA I /N ii. TFA,DCM /N [AA-24] [F-32] .

Synthesis of dimethyl-[2-(2-pyridinyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidinyloxy)-ethyl]-amine [1 3 5] CI O/\/N\ Q II \N Q II \N s N/ |\ —> s / N [1&0/ N [AA-24] [135] To a mixture of 4-chloropyridinyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidine [AA-24] (80 mg, 0.280 mmol) and 2-dimethylaminoethanol (34 ul, 0.340 mmol) in DMA (1 ml) was added NaH (13 mg, 0.560 mmol). The reaction mixture was allowed to stir at room temperature for 2 hours and after completion the e was diluted with water and the product was extracted into DCM (2x2 ml). The combined organic phases were dried with magnesium sulfate, ﬁltered and evaporated under reduced re and the crude product was puriﬁed by preparative HPLC (method A) to yield to the title nd. LCMS method: 2, RT: 2.20 min, MI: 355 [M+l]. 1H NMR (300MHz, DMSO): 8.70 (d,2H), 8.22 (d,2H), 3.1 (m,2H), 2.9 (m,2H), 2.75 (m,2H), 2.65 (m,2H), 2.34 , 1.83 (m,4H).

Synthesis ofmethyl-[2-(2-pyridinyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidinyloxy)-ethyl]-amine [ 1 3 6] CI O/\/NH2 \N \N l Q / :l' / S N \ —> S N \ I I / N / N [AA-24] [136] To a mixture of 4-chloropyridinyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidine ] (80 mg, 0.280 mmol) and tert-butyl-N—2-hydroxyethylcarbamate (53 ul, 0.340 mmol) in DMA (1 ml) was added NaH (13 mg, 0.560 mmol). The reaction mixture was allowed to stir at room temperature for 2 hours and after completion the mixture was diluted with water and the product was extracted into DCM (2x2 ml). The ed organic phases were dried with magnesium sulfate, ﬁltered and ated under . To a solution of the crude product in DCM (1 ml) was added TFA (1 ml) and the e was stirred at room temperature for 1 hour. After completion the mixture was loaded onto a SCX-2 cartridge and washed with methanol. The product was released from the cartridge using a solution of 2M ammonia / methanol. The ammonia / methanol eluent was concentrated under reduced pressure and the product was puriﬁed by preparative HPLC (method A) to yield to the title compound. LCMS method: 2, RT: 2.16 min, MI: 327 [M+l]. 1H NMR (300MHz, DMSO): 8.70 (d,2H), 8.3 (d,2H), 2.96 (m,2H), 2.8 (m,2H), 2.56m,2H), 2.45(m,2H), 1.81 (m,4H).

The following compounds were prepared according to the general synthesis shown in Scheme A16: EX Characterisation [F33] method: 2, RT. 2.83 min, MI: 341 [M+1] method: 2, RT: 2.45 min, MI: 383 [M+1] method: 2, RT: 2.20 min, MI: 353 [M+1] method: 2, RT: 2.20 min, MI: 353 [M+1] method: 2, RT: 2.29 min, MI: 367 [M+1] method: 2, RT: 2.60 min, MI: 417 [M+1] 2012/065831 Alcohol Characterisation [F-33] method: 2, RT: 2.56 min, MI: 417 [M+1] method: 2, RT: 2.22 min, MI: 341 [M+1] method: 2, RT: 2.88 min, MI: 341 [M+1] method: 2, RT: 2.52 min, MI: 383 [M+1] method: 2, RT: 3.47 min, MI: 403 [M+1] method: 2, RT: 2.37 min, MI: 369 [M+1] method: 2, RT: 2.31 min, MI: 355 [M+1] method: 2, RT: 2.32 min, MI: 355 [M+1] method: 2, RT: 2.40 min, MI: 369 [M+1] method: 2, RT: 2.21 min, MI: 339 [M+1] method: 2, RT: 2.27 min, MI: 367 [M+1] 2012/065831 Alcohol Characterisation [F-33] method: 2 RT: 227 min, MI: 367 [M+1] method: 2, RT: 2.49 min, MI: 403 [M+1] General synthesis of 5,6 substituted 4-a]k0xy-Z-pyridinyl—thien0[2,3-d]pyrimidines [F-32] (Scheme A17) 2,4,6-triisopropyl-benzenesulfonic acid 2-pyridinyl-5,6,7,8-tetrahydro- benzo[4,5]thieno[2,3-d]pyrimidinyl ester [AA-25] was ted to a nucleophilic tution reaction with a N—Boc protected amino alcohol of general formula F-33] in the presence of a strong base such as NaH, KH or LDA in the presence of an anhydrous polar aprotic solvent such as DMA, DMF or NNP. After reaction work up, typically by a liquid- liquid extraction or puriﬁcation by acidic ion exchange catch-release, the N—Boc derivative was deprotected under acidic conditions with a strong acid such as TFA, TCA, methanesulfonic acid, HCl or H2804 in a solvent such as DCM, DCE, THF, EtOH or and the crude reaction product was d by e phase preparative HPLC.

Scheme A17 [F-33] / N i. NaH,ROH,DMA \ s \ ii. TFA,DCM [F-32] Synthesis of (S)— l -cyclohexyl(2-pyridinyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidinyloxy)-ethylamine [ l 5 6] \N NH2 8 N/ \ To a mixture of 2,4,6-triisopropyl-benzenesulfonic acid 2-pyridinyl-5,6,7,8- ydro-benzo[4,5]thieno[2,3-d]pyrimidinyl ester [AA-25] (100 mg, 0.185 mmol) and N—Boc-L-cyclohexylglycinol (67 mg, 0.278 mmol) in DMA (1 ml) was added NaH (13 mg, 0.560 mmol). The reaction mixture was allowed to stir at room temperature for 2 hours and after completion the mixture was diluted with water and the product was ted into DCM (2x2 ml). The ed organic phases were dried with magnesium sulfate, ﬁltered and evaporated under reduced pressure. The crude product was dissolved in DCM (1 ml) and TFA (1 ml) was added and the mixture was stirred at room temperature for 1 hour. After completion the e was loaded onto a SCX-2 cartridge and washed with methanol. The product was released from the cartridge using a solution of2M ammonia / methanol. The ammonia / methanol eluent was concentrated under reduced pressure and the t was d by preparative HPLC (method A) to yield to the title compound. LCMS method: 2, RT: 2.62 min, MI: 409 [M+1]. 1H NMR (300MHz, DMSO): 8.7 (d,2H), 8.3 (d,2H), 4.7 , 4.5 (m,2H), 3 (m,2H), 2.9 (m,2H), 1.81 (m,4H), 1.7 (m,3H), 1.6 (m,3H), 1.2 (m,4H).

The following compounds were prepared according to the general synthesis shown in Scheme A17: Alcohol Characterisation [F-33] 1H NMR (300MHz, DMSO): 8.7 (d,2H), 8.3 (d,2H), 4.7 method: 2, RT: (m,2H), 4.5 (m,2H), 3.2 (m,2H), 2.82 min, MI: 2.8 (m,2H), 1.81 (m,4H), 1.7 423 [M+1] (m,4H), 1.6 (m,2H), 1.4 (m,2H), 1.2 (m,2H), 0.9 (m,2H) Alcohol Ex SM Characterisation [F-3 3] method: 2, RT: 158 [AA-25] = 2.82 min, MI: 456 [M+1] General synthesis of 5,6 substituted 4-alkoxypyridinyl—thieno[2,3-d]pyrimidine derivatives of general formula [F-32] (Scheme A18) Compounds were synthesised ng from an N—Boc protected amino acid of general formula [F-34] which was converted to a primary alcohol derivative of l formula [F-35] by reduction with a borane reducing agent such as BH3.THF or BH3.SMe2 in an anhydrous t such as THF, dioxane or diethylether. The resultant aminoalcohol derivative [F-35] was then reacted with a 5,6-substituted-(2,4,6-triisopropyl- benzenesulfonic acid)- dinyl-thieno[2,3-d]pyrimidinyl ester [AA-25] [prepared in scheme A5] in the presence of a strong base such as NaH, KH or LDA in the presence of an anhydrous polar c solvent such as DMA, DMF or NNP. After reaction work up, typically by a liquid-liquid extraction or puriﬁcation by acidic ion exchange catch- release, the N-Boc derivative was deprotected under acidic conditions with a strong acid such as TFA, TCA, methanesulfonic acid, HCl or H2S04 in a solvent such as DCM, DCE, THF, EtOH or MeOH the crude reaction t was puriﬁed by reverse phase preparative HPLC.

Scheme A18 R3 E Rj:R4 \R2 $4 R6 O 0 $4 HN | R BH3.THF \ HN 8 3 —> R4 N R |\ |. NaH,DMA 0°C R3)<—OH /N 0 ii. TFA,DCM [F-34] [F-35] [F32] Synthesis of [(S)hydroxy(4-methoxy-benzyl)-ethyl]-carbamic acid tert-butyl ester [AA-54] H BHyTHF HN 0 c0 OH [AA-54] A 1M solution of BH3 in THF (1.7 ml, 1.7 mmol) was added dropwise to a stirred solution of (S)tert-butoxycarbonylamino(4-methoxy-phenyl)-propionic acid (200 mg, 0.678 mmol) in dry THF (2.5 ml) at 0°C. The mixture was d for 2 hours at 0°C then hydrolysed by slow addition of excess of 10% acetic acid/MeOH (5 ml) and stirred at room temperature for a r 2 hours. The solvent was removed under reduced pressure the residue was dissolved in ethylacetate (5 ml) and washed with saturated sodium bicarbonate (2x5 ml) and brine (2x5 ml). The combined organic phases were dried with magnesium sulfate, ﬁltered and ated under reduced pressure to provide the title compound as a white solid which was used without further ation in the next step.

LCMS method: 1, RT: 2.82 min, MI: 441 [M+1].

Synthesis of (S)(4-methoxy-benzyl)(2-pyridinyl-5,6,7,8-tetrahydro-benzo [4,5]thieno [2,3-d]pyrimidinyloxy)-ethylamine [159] I O o 0 HI?’ \N NH2 0 H —> I | S N \ “59] KO“ [AA-54] To a solution of 2,4,6-triisopropyl-benzenesulfonic acid 2-pyridinyl-5,6,7,8- tetrahydro-benzo [4,5]thieno[2,3-d]pyrimidinyl ester ] (50 mg, 0.091 mmol) in DMA (1 ml) was added [(S)amino(4-methyl-benzyl)-ethyl]-carbamic acid tert-butyl ester [AA-54] (31 mg, 0.110 mmol) followed by NaH (4 mg, 0.110 mmol), the mixture was stirred at room temperature for 2 hours. After tion the product was extracted with DCM (2 ml) and washed with brine (3 ml). To the organic phase was added TFA (2 ml) and the mixture was stirred at room temperature for 1 hour. After completion the mixture was loaded onto a SCX-2 cartridge and washed with methanol. The t was released from the cartridge using a solution of 2M ammonia / methanol. The a / methanol eluent was concentrated under reduced pressure and the crude product was d by preparative HPLC (method A) to yield to the title compound. LCMS method: 2, RT: 2.61 min, MI: 447 [M+l]. 1H NMR z, DMSO): 8.7 (d,2H), 8.1 (d,2H), 7.2 (d,2H), 6.9 (d,2H), 4.7 (m,lH), 4.5 (m,lH), 3.8 (s,3H), 3.6 (m,2H), 2.9 (m,lH), 2.8 (m,2H), 2.7 (m,2H),1.81 .

The following compounds were prepared according to the general synthesis shown in Scheme A18: Amino acid Ex SM Characterisation. . method: 2, RT: 2.77 min, MI: 467 [M+1] method: 2, RT: 2.81 min, MI: 467 [M+1] method: 2, RT: 2.62 min, MI: 435 [M+1] method: 2, RT: 2.69 min, MI: 435 [M+1] method: 2, RT: 2.70 min, MI: 435 [M+1] method: 2, RT: 2.70 min, MI: 435 [M+1] I Amino acid Characterlsatlon. . method: 2, RT: 2.71 min, MI: 431 [M+1] method: 2, RT: n, MI: 431 [M+1] method: 2, RT: 2.71 min, MI: 423 [M+1] method: 2, RT: 2.71 min, MI: 447 [M+1] method: 2, RT: 2.58 min, MI: 423 [M+1] method: 2, RT: 2.76 min, MI: 495 [M+1] method: 2, RT: 3.04 min, MI: 467 [M+1] method: 2, RT: 2.81 min, MI: 467 [M+1] method: 2, RT: 2.76 min, MI: 431 [M+1] Amino acid Ex SM terisation. . method: 2, RT: 2.19 min, MI: 407 [M+l] method: 2, RT: 2.87 min, MI: 473 [M+l] method: 2, RT: 2.82 min, MI: 473 [M+l] method: 2, RT: 2.37 min, MI: 381 [M+l] method: 2, RT: 2.38 min, MI: 381 [M+l] method: 2, RT: 2.59 min, MI: 447 [M+l] General synthesis of substituted 4-amino-2—pyrazolylyl-thien0[2,3-d]pyrimidine derivatives of general formula [F-35] (Scheme A19) A 2,4-dichloro-5,6,7,8-tetrahydro-enzo [4,5] thieno [2,3-d]pyrimidine of l formula [F-2l] was reacted with primary and secondary amino tive of general formula [F-l3] in a polar aprotic solvent such as DMA, DMF, NMP in the presence of a tertiary amine base such as Eth, DIPEA or NMM at ambient temperature. Following reaction work up, typically by a liquid-liquid extraction or puriﬁcation by acidic ion exchange catch-release, the amino derivative of general a [F-23] were reacted with pyrazolyl boronic acids or boronate esters of general formula [F-36] in the presence of a palladium catalyst such as Pd(PPh3)4 or Pd(PPh3)2Clg a base such as Eth, KOH, N32C03 or NaOH in a polar solvent such as EtOH, THF, DMA or dioxane at high temperature either by heating thermally or using a microwave reactor. After reaction work up, lly by a liquid-liquid tion or puriﬁcation by acidic ion exchange catch-release, the N—Boc derivative was deprotected under acidic conditions with a strong acid such as TFA, TCA, methanesulfonic acid, HCl or H2S04 in a solvent such as DCM, DCE, THF, EtOH or MeOH the crude reaction product was puriﬁed by reverse phase preparative HPLC.

Scheme A19 R CI R R6 A [F-36] R / [F-13] I / / s N :IN'R17 R10 / IN Amines, Et3N,DMA R10 / IN ArB(OR)2,Pd(Ph3P)4 \ A \ A S S 18 N N C' N 0' MW,EtOH,15min, 150°C R [F-22] [F-23] [F-35] sis of [2-(2-chloro-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidinyla mino)-ethyl]—carbamic acid tert-butyl ester [AA-49] CI HNNNYO I1 I‘“ N/ N/J\CI 0% S CI 8 [AA-48] [AA-49] To a solution of chloro-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine [AA-48] (100mg, 0.387mmol) in DMA (5 ml) was added Boc-ethylenediamine (62 mg, 0.387mrnol) followed by Et3N (l 10 ul, 0.774 mmol), the mixture was stirred at room temperature for 2 hours. Then the product was extracted with DCM (2x10 ml) and washed with brine (2x10 ml). The ed organic phases were dried with magnesium sulfate, ﬁltered and evaporated under d pressure to provide a brown solid. The e was used without further puriﬁcation in the next step. LCMS method: 1, RT: 6.26 min, MI: 383 [M+l].

Synthesis ofN* l * - [2-( l H-Pyrazolyl)-5 ,6,7, 8-tetrahydro-benzo [4,5 ]thieno [2,3 - d]pyrimidinyl]—ethane- l ,2-diamine [l 8 l] -23l- HN/VNY,1; —> QﬁNENHN/\/NH2 NACI [AA-49] [181] A microwave vial was charged with [2-(2-chloro-5,6,7,8-tetrahydro- benzo[4,5]thieno[2,3-d]pyrimidinylamino)-ethyl]-carbamic acid tert-butyl ester [AA- 49] (40mg, 0.17 mmol), 1H-pyrazoleboronic acid (23 mg, 0.20 mmol), is (triphenyl ine) ium (10 mg, 0.008 mmol), N32C03 (2M in water, 180ul, 0.6 mmol) and EtOH (1ml). The reaction was heated to 150°C for 15 minutes under microwave irradiation. The mixture was then ﬁltered through a plug of silica, washed with methanol and the ﬁltrate was concentrated under reduced pressure. To a solution of the crude product in DCM (2 ml) was added TFA (2 ml) and the mixture was stirred at room temperature for 1 hour. After completion the mixture was loaded onto a SCX-2 cartridge and washed with methanol. The product was released from the cartridge using a solution of2M ammonia / methanol. The ammonia / methanol eluent was concentrated under reduced pressure and the crude product was puriﬁed by preparative HPLC (method A) to yield to the title nd. LCMS method: 2, RT: 2.20 min, MI: 315 [M+1], 1H NMR (300MHz, DMSO): 8,41 (s,1H), 8,20 (s,2H), 6.80 (t,1H), 3,74 , 3,06 (m,2H), 2,94 (m,2H), 2,74 (s,2H), 2,53 (s,2H), 1,81 (s,4H).

The ing compounds were ed according to the general synthesis shown in Scheme A19: Boronic acid Amine Characterisation [F36] [F 13] 1H NMR (300MHz, DMSO): 8,37 (s,1H), 6,87 (t,1H), method: 2, RT: 3,73 , 3,15 2.32 min, MI: (m,2H), 3,03 343 [M+1] (m,2H), 2,97 (s,2H), 2,74 (s,2H), 2,49 (s,6H), 1,84 (s,4H) method: 2, RT: 2.52 min, MI: 405 [M+1] Boronic acid Amine SM Characterisation [F36] [F-13] (PH method: 2, RT.

HO \N 184 [AA-48] \ 2.65 min, MI: 433 [M+1] 1H NMR (300MHz, DMSO): 8,20 method: 2, RT: (s,2H), 3,51 (m,4H), 185 [AA-48] 2.30 min, MI: 3,19 (m,4H), 2,88 341 [M+1] (m,4H), 1,87 (m,2H), 1,78 (m,2H) 1H NMR (300MHz, DMSO): 8,17 (s,2H), 3,87 (m,2H), method: 2, RT: 3,74 , 3,38 2.31 min, MI: (m,2H), 3,1 1 355 [M+1] (m,2H), 2,84 (m,2H), 1,88 (m,2H), 1,77 (m,2H) method: 2, RT: 2.21 min, MI: 329 [M+1] : 2, RT: ﬂAA-42 2.26 min, MI: 329 [M+1] method: 2, RT: 2.27 min, MI: 341 [M+1] 1H NMR (300MHz, method: 2, RT: DMSO): 8,97 n, MI: (s,1H), 3,51 (m,6H), 369[M+1] 2,84 (m,6H), 1,88 (m,2H), 1,77 (m,2H) method: 2, RT: 2.48min, MI: 383[M+1] Boronic acid Amine SM Characterisation [F36] [F-l3] (PH method: 2, RT: ,8 \ “‘ HO \ 5“ n, MI: 357[M+l] (le method: 2, RT: ,3 \ N [AA-48] “0 \ I 2.37min, MI: (PH method: 2, RT: ,8 \ [AA-48] HO \ 5V 2.41min, MI: 369[M+l] (PH method: 2, RT: HO’B \ [AA-48] \ 2.27min, MI: 329[M+l] method: 7, RT: [AA-48] 3.76min, MI: 43 l [M+l] 4PT32P compounds In one approach, nds of formula [G-lOO] (where A = NH or N alkyl) are prepared by reacting a compound of formula [G-lOZ] (Where X is a halogen such as chlorine or a sulfonate) with a compound of formula ] (Where A is NH or NHz and Z on the terminal nitrogen is H, alkyl or a suitable nitrogen protecting group, such as Boc, Alloc, Cbz or Fmoc) in a suitable solvent such as DMF in the presence of a suitable base such as triethylamine. —234— s / N\ 2 7 N R12 R R R‘grl R13 R5 N \ 6 A R l R 15 /N 7S/NR12 H R R14 \\I R13 A/\/N\2 [6-102] R |\ R15 /N 3] [ca-100] The reaction is suitably conducted at an elevated temperature for example 40 0C. Where Z is a suitable nitrogen protecting group, such as Boc, Alloc, Cbz or Fmoc, compounds of formula [G-lOO] are ed by a suitable deprotection reaction. For example: where Z is a Boc protecting group reaction with an acid such as TFA in a suitable solvent such as DCM. The reaction is suitably conducted at ambient ature. In one approach, compounds of a [G-lOO] (where A = O) are prepared by reacting a compound of formula [G-lOZ] (where X is a halogen such as chlorine or sulfonate) with a compound of formula [G-lO3] (where A is OH and Z on the terminal nitrogen is H, alkyl or a suitable en protecting group, such as Boc, Alloc, Cbz or Fmoc) in a suitable solvent such as DMA in the presence of a le base such as sodium hydride. The reaction is suitably ted at ambient temperature. Where Z is a suitable nitrogen protecting group, such as Boc, Alloc, Cbz or Fmoc, compounds of formula [G-lOO] are prepared by a suitable deprotection reaction. For example: where Z is a Boc protecting group reaction with an acid such as TFA in a suitable solvent such as DCM. The reaction is suitably conducted at ambient temperature.

In one approach, compounds of formula [G-lO2] (where X is a halogen such as chlorine) are prepared by reacting a compound of formula [G-lO4] with a suitable halogenating agent such as phosphorous oxychloride. The reaction is suitably conducted at elevated temperature such as 125 0C. nds of formula [G-102] (where X is a sulfonate) are prepared by reacting a compound of formula [G-lO4] with a suitably substituted sulfonyl chloride in a suitable t such as DMA in the presence of a le base such as triethylamine and a catalytic amount of DMAP. The reaction is ly ted at ambient temperature.

R7 \8 / IN R12 \N R R8 I R15 / N [G-104] In one approach, compounds of formula [G-lO4] are prepared by reacting a compound of formula ] (where Rd is an alkyl group such as methyl or ethyl) with a compound of formula [G-lO6] in a suitable solvent such as dioxane with a suitable base such as potassium-tert-pentylate. The reaction is suitably conducted at ambient temperature. 0 R12 IRX 1 NC R13 S O \ \ I I /N 8 NH2 R R14 [G-105] [G-106] In another approach compounds of formula ] are prepared by reacting a compound of ] with a compound of formula ] in a suitable solvent such as methanol with a le protic acid such as hydrogen chloride. The reaction is suitably conducted at elevated temperature. Full aromatisation to yield nds of formula [G- 104] is achieved by reaction with an oxidising agent such as 2,3-dichloro-5,6- dicyanobenzoquinone in a suitable solvent such as dichloromethane. The on is suitably conducted at ambient temperature. 0 R12 R OHC NHZ \ \8| | /N 8 NH2 R 14 [G-107] [G-108] In one approach, compounds of a [G-lO3] (where A is OH) are prepared by reacting a compound of formula ] (where Z on the terminal nitrogen is H, alkyl or a suitable nitrogen ting group, such as Boc, Alloc, Cbz or Fmoc) with a reducing agent such as borane-THF complex in a suitable solvent such as THF. The reaction is suitably conducted at low temperature for example 0 0C. In one approach, compounds of formula [G-lO3] (where A is NHZ) are prepared by reacting a compound of formula [G- 110] (Where Z on the terminal nitrogen is H, alkyl or a suitable nitrogen protecting group, such as Boc, Alloc, Cbz or Fmoc) with a reducing agent such as borane-THF complex in a suitable t such as THF. The reaction is suitably ted at low temperature for example 0 0C. In one approach, compounds of a [G-l 10] are prepared by reacting compounds of formula [G-lO9] with Boc anhydride in the presence of a suitable base such as pyridine, ammonium carbonate in a suitable solvent such as dioxane. The reaction is suitably conducted at ambient temperature.

[G-109] ] An example of a method as described above is illustrated in the following scheme.

,RX1 s O R7 \\ N’H OH R8 |l| 3 / 7 N R \ \Nl [G-5] —> R8 | 7 NH2 [G-104] R \ I R8 2 [6-112] R3 E R‘ﬁ: / H ‘R2 A/\/ ‘z RR6 A [G-103] H /\/N\ 3 / Z N R12 A \ ' \ R13 [6-103] N \ R l R15 /N [6-100] 2012/065831 General synthesis of 6, 7 -substituted 2-pyridinyl—thieno [3,2-d]pyrimidinol, of general formula [G-104] (Scheme B1) A 4,5-substitutedAmino-thiophenecarboxylic acid alkyl ester tive, of l formula [G-lO5] (wher Rx = alkyl such as methyl or ethyl) was subjected to a cyclisation on with a 4-cyanopyridine derivative of general formula [G-lO6] in the presence of a hindered alkoxide base such as potassium-tert-pentylate l.7M in toluene or potassium-tert-butoxide in a dry non-aprotic solvent such as dioxane or THF at ambient temperature, to yield the 6, 7 -substituted 2-pyridinyl-thieno [3,2-d]pyrimidinol tive of formula [G- l 04].

Scheme B1 [6-106] 8\ potassium tert--penty|ate R8 Dry Dioxane R15 Synthesis of 6-methylpyridinyl-thieno [3,2-d]pyrimidinol [BB-01] O OH 8 O/ S \ N \ l —> \ I NH2 N \ [BB-01] To a solution of 4-cyanopyridine (552 mg, 5.3 mmol) in dry dioxane (10 ml) was added 3-aminomethyl-thiophenecarboxylic acid methyl ester (1 g, 5.84 mmol) followed by potassium-tert-pentylate l.7M in toluene (6.9 ml, 11.7 mmol). The reaction mixture was stirred at room ature overnight. After completion the precipitate formed was ﬁltered and washed with diethyl ether. The residue was used without any WO 78126 further puriﬁcation in the next step. LCMS method: 3, RT: 2.44 min, MI: 244 [M+1]. 1H NMR (300MHz, DMSO): 2.60 (s,3H), 7.23 (d,1H), 8.05 (m,2H), 8.76 (m,2H).

The following compounds were prepared according to the l synthesis shown in scheme Bl : O OH 8 O/ S \ N \ I a \ I NH2 N \ [B B-02] methylpyridinyl-thieno[3,2-d]pyrimidinol [BB-02] was ed by reaction of 3-amino-4,5-dimethyl-thiophenecarboxylic acid methyl ester, 4- cyanopyridine, potassium-tert-pentylate l.7M in toluene and dioxane at room temperature to give the title nd as a yellow solid. LCMS method: 3, RT: 3.05min, MI: 258 [M+1].

O OH 8 O/ S \ N \ I ’ \ I NH2 N \ [B B-03] 6-tert-butylpyridinyl-thieno[3,2-d]pyrimidinol [BB-03] was prepared by reaction of 3-aminotert-butyl-thiophenecarboxylic acid methyl ester, 4- cyanopyridine, potassium-tert-pentylate l.7M in toluene and dioxane at room temperature to give the title compound as an off-white solid. LCMS method: 3, RT: 3.02 min, MI: 286 [M+1].

O OH 8 O/ S \ | —> \ l NH2 N |\ Br Br [BB-04] 7-(4-bromo-phenyl)pyridinyl-thieno[3,2-d]pyrimidinol [BB-04] was prepared by reaction of 3-amino(4-bromo-phenyl)-thiophenecarboxylic acid methyl ester, 4-cyanopyridine, potassium-tert-pentylate l.7M in toluene and dioxane at room temperature to give the title compound as a yellow solid. LCMS method: 3, RT: 4.11 min, MI: 384-386 [M+l].

O OH \ l \ l NH2 N \ [BB-05] ylpyridinyl-thieno[3,2-d]pyrimidinol [BB-05] was prepared by reaction of 3-aminomethyl-thiophenecarboxylic acid methyl ester, 4-cyanopyridine, potassium-tert-pentylate l.7M in toluene and dioxane at room temperature to give the title compound as a yellow solid. LCMS method: 1, RT: 3.09 min, MI: 243 [M+l].

O OH 8 O/ S \ I ’ \ I NH2 N \ [BB-06] 6-phenylpyridinyl-thieno[3,2-d]pyrimidinol [BB-06] was prepared by reaction of 3-aminophenyl-thiophenecarboxylic acid methyl ester, 4-cyanopyridine, potassium-tert-pentylate l.7M in toluene and dioxane at room temperature to give the title compound as an off-white solid. LCMS method: 1, RT: 3.46 min, MI: 306 [M+l]. 0 OH \ l \ l NH2 N \ [BB-07] 6-(4-tert-butyl-phenyl)pyridinyl-thieno[3,2-d]pyrimidinol [BB-07] was prepared by reaction of 3-amino(4-tert-butyl-phenyl)-thiophenecarboxylic acid methyl ester, opyridine, potassium-tert-pentylate l.7M in toluene and dioxane at room temperature to give the title nd as an off-white solid. LCMS method: 1, RT: 4.78 min, MI: 362 [M+l]. —240— o OH 8 / S \ O N NH2 N \ [BB-O8] 2-(2-Chloro-pyridinyl)-thieno[3,2-d]pyrimidinol [BB-08] was prepared by reaction of methyl 3-aminothiophene-carboxylate, 2-Chloropyridinecarbonitrile, potassium-tert-pentylate 1.7M in e and THF at room temperature to give the title compound as a pale yellow solid. LCMS method: 8, RT: 3.32 min, MI: 264 [M+1].

O OH S O/ S \N | —> I NH2 N \ CI CI [BB-09] 9-Chloro(2-chloro-pyridinyl)-benzo[4,5]thieno[3,2-d]pyrimidinol [BB-09] was prepared by on of 3-Aminochloro-benzo[b]thiophenecarboxylic acid methyl ester opyridine, potassium-tert-pentylate l.7M in toluene and THF at room temperature to give the title compound as an off-white solid. LCMS method: 2, RT: 3.6 min, MI: 314 [M+1].

[B 8-1 0] 2-Pyridinyl-pyrido[3',2':4,5]thieno[3,2-d]pyrimidinol [BB-10] was prepared by reaction of ethyl 3-aminothieno[2,3-b]pyridinecarboxylate, 4-cyanopyridine, potassium-tert-pentylate l.7M in toluene and THF at room temperature to give the title compound as an te solid. LCMS method: 2, RT: 2.57 min, MI: 281 [M+1].

[BB-11] —241— 7,9-Dimethylpyridinyl-pyrido[3',2':4,5]thieno[3,2-d]pyrimidinol [BB-l l] was prepared by reaction of ethyl 3-amino-4,6-dimethylthieno[2,3-b]pyridine carboxylate, 4-cyanopyridine, potassium-tert-pentylate 1.7M in toluene and THF at room ature to give the title compound as an off-white solid. LCMS method: 2, RT: 3.07 min, MI: 309[M+l].

O OH 3 / S \ N \ | —» W NH2 N \ [BB-13] 2-Pyridinyl-thieno[3,2-d]pyrimidinol [BB-l3] was prepared by on of methyl 3-aminothiophene-carboxylate, 4-pyridinecarbonitrile, potassium-tert-pentylate l.7M in toluene and THF at room temperature to give the title compound as a pale yellow solid: LCMS method B: 1.98 min, 100%, 230.00 [M+H] General synthesis of 6, 7 -substituted 2-pyridinyl—thieno [3,2-d]pyrimidinol, of general formula [G-104] (Scheme B2) An 4,5-substitutedamino-thiophenecarboxylic acid amide derivative of general formula ] was subjected to a cyclisation reaction with an isonicotinaldehyde tive of general formula [G-108] in the presence of 4M en chloride in dioxane in a suitable solvent such as methanol. The reaction is ly conducted at an elevated temperature for example 140 0C in a ave reactor for 20minutes. Full aromatisation is subsequently achieved with 2,3-dichloro-5,6- dicyanobenzoquinone in a suitable solvent such as dichloromethane at ambient temperature, to yield the 6, 7 -substituted 2-pyridinyl-thieno [3,2-d]pyrimidinol, of general a [G-104].

Scheme B2 —242— R12 R13 / \ OHC N R14 OH S R 7 NH2 R | S \ 12 \ [G-108] N R \ | NH —> / R13 R8 2 N \ R I /N i) ol / HCI dioxane 140 C R ii) 2,3—dichIoro-5,6-dicyanobenzoquinone, DCM [(5407] [G-104] Synthesis of 2-(3-Fluoro-pyridinyl)-thieno[3,2-d]pyrimidinol [BB-l4] O OH 8 S \ N \ | NH2 —> H \ | NH2 N \ H H I [B-14] A microwave Vial was charged with 3-amino-thiophenecarboxylic acid amide (2 g, 14.07 mmol), oisonicotinaldehyde (0.85 ml, 8.52 mmol), hydrogen chloride 4M in dioxane (0.7 ml, 2.81 mmol) and methanol (20 ml). The reaction mixture was heated to 140°C for 20 s under microwave irradiation. After completion, the mixture was concentrated under reduced pressure. To a solution of the crude product in dichloromethane (20 ml) was added 2,3-dichloro-5,6-dicyanobenzoquinone (3.2 g, 14.07).

The mixture was stirred at room temperature for 18 hours. After tion, the precipitate formed was ﬁltered and washed with methanol. The residue was used without any ﬁarther puriﬁcation in the next step. LCMS method: 5, RT: 3.39 min, MI: 248 [M+l].

NMR 1H (DMSO, 300MHz): 13.03 (s, 1H), 8.80 (d, 1H), 8.62 (dd, 1H), 8.27 (d,lH), 7.80 (t, 1H), 7.52 (d, 1H).

The following compounds were prepared ing to the general synthesis shown in scheme B2: 2-(2-Chloroﬂuoro-pyridinyl)-thieno [3 ,2-d]pyrimidinol [BB- 1 5] —243— O OH 3 S 0/ F \l —> \ l‘N NH2 N |\ [BB-1 5] A microwave vial was charged with 3-amino-thiophenecarboxylic acid amide (1.3 g, 9.3 mmol), roﬂuoroformylpyridine (1g, 5.6 mmol), concentrated hydrogen chloride (1 drop) and methanol (10 ml). The reaction mixture was heated to 120 0C for 20 minutes under ave irradiation. After completion, the e was concentrated under reduced pressure. To a solution of the crude product in romethane (20 ml) was added 2,3-dichloro-5,6-dicyanobenzoquinone (2.3 g, 9.3 mmol). The mixture was stirred at room temperature for 18 hours. After completion, the precipitate formed was ﬁltered and washed with methanol. The residue was used without any ﬁlrther puriﬁcation in the next step. LCMS method: 8, RT: 3.20 min, MI: 281-283 [M+l]. 1H NMR (DMSO, 300MHz): 8.68 (1H, d), 8.27 (1H, d), 7.96 (1H, d), 7.51 (1H, 2-(2-Chloroﬁuoro-pyridinyl)-thieno [3 ,2-d]pyrimidinol [BB-15 a] O OH \ l —> \ / CI NH2 N \ [BB-1 5a] A microwave vial was charged with 3-amino-thiophenecarboxylic acid amide (0.5 g, 3.5 mmol), 2-Chloroﬂuoroformylpyridine (0.75 g, 2.12 mmol), 1.25 N en chloride (1 drop) and methanol (4 ml). The reaction mixture was heated to 120 0C for 20 minutes under ave irradiation. After completion, the mixture was concentrated under reduced pressure. To a solution of the crude product in dichloromethane (5 ml) was added 2,3-dichloro-5,6-dicyanobenzoquinone (800 mg, 3.5 mmol). The mixture was stirred at room temperature for 18 hours. After completion, the precipitate formed was ﬁltered and washed with methanol. The residue was used without any r puriﬁcation in the next step. LCMS method: 8, RT: 3.21 min, MI: 281-283 —244— [M+l]. 1H NMR (DMSO) 13.09 (1H, s, br), 8.46 (1H, d), 8.29 (1H, d), 7.83 (1H, t), 7.51 (1H, d). 2-(3 -Chloro-pyridinyl)-thieno [3 ,2-d]pyrimidinol [BB-15b] o OH old —»8 / of.S \ O N CI NH2 N \ [BB-15b ] A microwave vial was charged with 3-amino-thiophenecarboxylic acid amide (l g, 7.03 mmol), 3-Chloro-pyridinecarbaldehyde (0.6 g, 4.24 mmol), 2.5 N hydrogen chloride in ethanol (0.56 mL, 1.4 mmol) and ethanol (10 ml). The reaction mixture was heated to 140 0C for 20 minutes under microwave ation. After completion, the precipitate formed was ﬁltered and washed with DCM then methanol. The residue was puriﬁed by ﬂash column chromatography (SiO2, MeOH : DCM elution) to ﬁve the title compound (0.52g, 47% yield). LCMS method: 10, MI: 264 [M+l].

General synthesis of 7-halo substitutedpyridinyl-thien0[3,2-d]pyrimidinol of general formula ] (Scheme B321) A 6 -substituted 2-pyridinyl-thieno ]pyrimidinol tive of general formula [G-l 12] was brominated at the C7 position in the presence of a halogenating agent such as Brz, N—Bromosuccinimide, Phosphorus(V) oxybromide, and an acidic reagent such as acetic acid. Or chlorinated at the C7 position in the presence of a halogenating agent such as rosuccinimide and an acidic reagent such as acetic acid to give the corresponding 7-halo substitutedpyridinyl-thieno[3,2-d]pyrimidinol derivative of general formula [G-l 13], Scheme B3a.

Scheme B321 —245— 3 / N R12 S / N \ I \ R13 N \ H I R15 /N [G-112] [G-113] Synthesis of 7-bromomethylpyridinyl-thieno[3,2-d]pyrimidinol [BB-16] OH OH 8 \N Br2 S \N \ l —> , \ l N \ aceticacid N \ I chloroform Br I /N /N [BB-O1] [BB-16] A solution of bromine (1.2 ml, 23.2 mmol) in chloroform (10ml) was added to a ng solution of 6-tert-butylpyridinyl-thieno[3,2-d]pyrimidinol [BB-01] (2.84 g, 11.6 mmol) in chloroform (15ml) acetic acid (15ml) at 0°C. The e was allowed to warm to room ature and stirred over night. After completion the resulting solid was d and washed with chloroform and diethylether to yield the title compound as a yellow solid. LCMS : 4, RT: 2.14 min, MI: 322-324 [M+1]. 1H NMR (300MHz, DMSO): 8.76 (m, 2H), 8.05 (m, 2H), 2.60 (s, 3H).

The following compounds were prepared according to the general synthesis shown in scheme B3 a: Synthesis of 7-Bromo(3-ﬂuoro-pyridinyl)-thieno[3,2-d]pyrimidinoHl [BB-17] 8 8 \ N F Br, \N H \ I \ N/ N \ acetic acid, 80° C, 18hours H I [BB-14] [BB-17] Bromine (1.2 ml, 24.27 mmol) was added to a stirring solution of 2-(3-Fluoro- pyridinyl)-thieno[3,2-d]pyrimidinol [BB-14] (2.00 g, 8.09 mmol) in acetic acid (20ml) at ambient temperature. The mixture was heated to 80°C and stirred over night under reﬂux conditions. After completion, 10% sodium thiosulphate solution (5ml) was added and the resulting solid was ﬁltered and washed with water and ethyl acetate to yield the title compound as a colourless solid. LCMS method: 6, RT: 4.33 min, MI: 326-238 [M+1]. NMR 1H (DMSO, 300MHz): 7.82 (dd, 1H), 8.47 (s, 1H), 8.63 (d, 1H), 8.81 (s, 1H), 13.28 (bs, lH).

Synthesis of 7-Chloropyridinyl-thieno[3,2-d]pyrimidinol [BB-l8] OH OH \ l ——> l / \ / N \ N \ I C' I /N /N [BB-13] [BB-18] To a stirred suspension of 2-Pyridinyl-thieno[3,2-d]pyrimidinol [BB-l3] (0.5g, 2.18 mmol) in AcOH (10 ml) was added NCS , 10.9 mmol) and the reaction heated to 80 0C. After 18hr further NCS (0.58 g, 4.36 mmol) was added and the e was left to stir at 80 CC for a ﬁlrther another 24 hr. The reaction mixture was cooled and evapourated under reduced pressure and the resulting e suspended in H20 and the solid formed was collected by ﬁltration, to give the title compound (0.4g, 70% yield) which was used without further puriﬁcation: LCMS method B: 4.16 min, 64%, 263.95 [M+H] sis of 7-Bromotert-butylpyridinyl-thieno[3,2-d]pyrimidinol [BB-l9] OH OH 8 \N S \N \ | —’ \ | / / N \ N \ /N Br I [BB-03] [BB-19] A solution of bromine (60 uL, 1.17 mmol) in chloroform (1 ml) was added to a stirring solution of 6-tert-Butylpyridinyl-thieno[3,2-d]pyrimidinol [BB-03] (0.33 g, 1.17 mmol) in form (4 ml) and acetic acid (5 ml) at 0°C. The mixture was allowed to warm to room temperature and stirred over night. After completion the resulting solid was ﬁltered and washed with chloroform and diethylether to yield the title compound as a yellow solid. LCMS method: 3, RT: 4.22 min, MI: 364-366 [M+1].

Synthesis of 7-Bromopyridinyl-thieno[3,2-d]pyrimidinol [BB-20] —247— OH OH cf 8 P“ \ \ N/ \ N/ \ I Br I / N / N [BB-13] [BB-20] To a stirred suspension of 2-Pyridinyl-thieno[3,2-d]pyrimidinol [BB-l3] (20g, 87.2 mmol) in AcOH (400 ml) was added Brz (20 ml). The mixture was left to stir 80 CC for 24 hr then an additional Brz (10ml) was added and the mixture was left to stir 80 °C for a r 24 hours. The reaction mixture was cooled and poured into HzO-ice e, and the yellow precipitate was collected by ﬁltration and washed with satutated sodium metabisulfite, then H20 followed by EtZO, to give the title compound as a pale yellow solid (24.1 g, 90% . LCMS method: 8, RT: 3.28 min, MI: 307—309 [M+1]. 1H NMR (DMSO) 8.99 (2H, d), 8.49 (1H, s), 8.42 (2H, d).

General synthesis of 6-halo substitutedpyridinyl—thien0[3,2-d]pyrimidinol derivative of general formula [G—116] (Scheme B3b) A 7 -substituted 2-pyridinyl-thieno [3,2-d]pyrimidinol derivative of general a [G-l 15] was brominated at the C6 position in the presence of a halogenating agent such as Brz, N—Bromosuccinimide, orus(V) oxybromide, and an acidic reagent such as acetic acid. Or nated at the C6 position in the presence of a halogenating agent such as N—chlorosuccinimide and an acidic reagenet such as acetic acid to give the corresponding 6-halo substitutedpyridinyl-thieno[3,2-d]pyrimidinol derivative of general formula [G-l 16], Scheme B3b.

Scheme B3b «r R: a Mr R8 NR15 | /N :ﬁR R14 R14 [G-115] [G-1 16] Synthesis of 6-Bromomethylpyridinyl-thieno[3,2-d]pyrimidinol [BB-21] OH OH 8 \ S N —> \ N \ l N \ WWN \ I I /N /N ] [BB-21] A solution of bromine (600 uL, 4.1mmol) in form (30ml) was added to a stiring solution of 7-methylpyridinyl-thieno[3,2-d]pyrimidinol [BB-05] (lg, .030 mmol) in chloroform (20ml) acetic acid (15ml) at 0°C. The mixture was allowed to warm to room ature and stirred over night. After tion the resulting solid was filtered and washed with chloroform and diethylether to yield the title compound as a yellow solid, which was used without further puriﬁcation in the next step: LCMS method B, Purity: 98%, RT: 3.85min, MI: 321-323.

General synthesis of 4PT32P derivatives of general formula [G-100] e B4) 4PT32P derivatives of general formula [G-100] were prepared by the reaction of a 6, 7 -substituted 2-pyridinyl-thieno [3,2-d]pyrimidinol, of general formula [G-104] (described in scheme Bl & B2) with 2,4,6-triisopropylbenzenesulfonyl chloride in a polar aprotic solvent such as DMA, DMF, NMP with a tertiary alkylamine base such as Eth, DIPEA or NMM and a catalytic amount of DMAP. The ediate 6,7-substituted- (2,4,6-triisopropyl-benzenesulfonic acid)- 2-pyridinyl-thieno[3,2-d]pyrimidinyl ester, of general formula [G-l l l] was isolated and then reacted with a primary or secondary amino tive, of general formula [G-l 17], in a polar aprotic solvent such as DMA, DMF, NMP in the presence of a tertiary amine base such as Eth, DIPEA or NMM at ambient ature [Method A]. After reaction work up, typically by a liquid-liquid extraction or puriﬁcation by acidic ion exchange catch-release, the N-Boc derivatives were deprotected under acidic conditions with a strong acid such as TFA, TCA, methanesulfonic acid, HCl or H2804 in a solvent such as DCM, DCE, THF, EtOH or MeOH and the crude reaction product was puriﬁed by e phase preparative HPLC. 4PT32P derivatives of general formula [G-100] were prepared by the on of a 6, 7 - substituted 2-pyridinyl-thieno [3,2-d]pyrimidinol, of general a [G-104] (described in scheme B 1, B2 & B3) with 2,4,6-triisopropylbenzenesulfonyl chloride in a polar aprotic solvent such as DMA, DMF, NMP with a tertiary alkylamine base such as Eth, DIPEA or NMM and a tic amount ofDMAP then used crude and reacted further with a primary or secondary amino derivative, of general formula [G-l 17], in a polar aprotic solvent such as DMA, DMF, NMP in the presence of a tertiary amine base such as Eth, DIPEA or NMM at ambient temperature [Method B] without further puriﬁcation. After reaction work up, typically by a liquid-liquid extraction or ation by acidic ion ge catch-release, the N—Boc derivatives were deprotected under acidic conditions with a strong acid such as TFA, TCA, methanesulfonic acid, HCl or H2804 in a solvent such as DCM, DCE, THF, EtOH or MeOH and the crude reaction product was puriﬁed by reverse phase preparative HPLC. 4PT32P derivatives of general formula [G- 100] were prepared by the reaction of a 6, 7 -substituted 2-pyridinyl-thieno [3,2- d]pyrimidinol of general formula [G-lO4] with a chlorination reagent such as orus oxychloride to give compounds of general formula ] and then reacted with a primary or secondary amino derivative, of general formula [G-l 17], in a polar aprotic solvent such as DMA, DMF, NMP in the presence of a ry amine base such as Eth, DIPEA or NMM at ambient temperature d C]. After on work up, typically by a liquid-liquid extraction or puriﬁcation by acidic ion exchange catch-release, the N—Boc derivatives were deprotected under acidic conditions with a strong acid such as TFA, TCA, methanesulfonic acid, HCl or H2804 in a solvent such as DCM, DCE, THF, EtOH or MeOH and the crude reaction product was puriﬁed by reverse phase preparative HPLC.

Scheme B4 MethodA R4 N\R2 i. Amine, EtsN,DMA R5 OH R [G-117] 8 \N R12 R12 R7 R8 I IN \N I —> R7 \ 13 \ R13 R N/ \ N/ ii. TFA,DCM \N I 8 8 R |\ R /N R15 /N R15 R15 [G-1 04] [G-111] [G-100] Method B OH 6 A 8 |\N R12 ,E13N,DMA S / 7 N R12 / R13 \ | \ R13 N \ N \ R8 | ii) Amine, EtsN,DMA R8 I :4N R15 [G-117] R15 / N R R14 iii) TFA, DCM [G-104] [G-100] Method C i. Amine, EisN,DMA OH CI R [G-117 1 I\N R12 POCI3 S IN R12 R7 8 —>R7 \ |\N \ \ 13 N/ R13 ii. TFA, DCM \ N/ \N R I R |\ R15 /N R15 R15 R14 R14 [G-104] [G-112] [G-100] MethodA Synthesis of 2,4,6-triisopr0py1—benzenesulfonic acid 7-br0rnomethy1—2-pyridiny1— thien0[3,2-d]pyrirnidiny1 ester ] OH O,8;\O \ / \ N \ N/ Br l |\ /N Br /N [BB-16] [BB-22] To a solution of 7-brorn0rnethy1—2-pyridiny1—thieno[3,2-d]pyrirnidin01 [BB-16] (3.76 g, 11.6 mmol) in DCM (15 ml) was added 2,4,6- propylbenzenesulfonyl chloride (4.25 g, 23.2 mmol), Eth (2.2 ml, 23.2 mmol) and DMAP (27 mg, 0.22 mmol). The mixture was d for one hour. After completion the e was diluted with water and the product was extracted into DCM (2x10 ml). The combined organic phases were dried (MgSO4), ﬁltered and evaporated under reduced pressure to e the title compound as a brown solid. The crude was used without further puriﬁcation in the next step. LCMS : 3, RT: 6.36 min, MI: 588-590 [M+l].

Synthesis of (S)—N* l *-(7-bromomethylpyridinyl-thieno[3,2-d]pyrimidinyl) phenyl-propane- l ,2-diamine [300] [AA-46] HZN ; HN é 8 NH2 Et3N,DMA B: N/ | :N [BB-22] [300] To a solution of 2,4,6-triisopropyl-benzenesulfonic acid 7-bromomethyl pyridinyl-thieno[3,2-d]pyrimidinyl ester [BB-22] (2.5 g, 4.24 mmol) in DMA (5 ml) was added (S)—3-phenyl-propane-l,2-diamine [AA-46] (700 ul, 4.66 mmol) followed by Eth (1.1 ml, 8.48 mmol), the mixture was stirred at room ature for 2 hours. After completion the e was loaded onto a SCX-2 cartridge and washed with methanol.

The product was released from the cartridge using a solution of 2M ammonia / methanol.

The ammonia / methanol eluent was concentrated under reduced pressure and the crude product was puriﬁed by preparative HPLC (method A) to yield to the title compound.

LCMS method: 4, RT: 4.07 min, MI: 454-456 [M+l]. 1H NMR (300MHz, DMSO): 8.69 (d,2H), 8.06 (d,2H), 7.32 (m,5H), 3.86 (m,lH), 3.37 (m,2H), 2.77 (m,2H), 2.59 (s,3H) Synthesis of 2,4,6-Triisopropyl-benzenesulfonic acid 6-phenylpyridinyl-thieno[3,2- d]pyrimidinyl ester [BB-23] \ —> N \ [BB-06] ] To a solution of 6-Phenylpyridinyl-thieno[3,2-d]pyrimidinol [BB-06] (671 mg, 2.2 mmol) in DCM (5 ml) was added 2,4,6-triisopropylbenzenesulfonyl chloride (710 mg, 2.64 mmol) were added Eth (920 ul, 6.6 mmol) and DMAP (14 mg, 0.11 mmol).

The mixture was stirred for one hour. After completion the mixture was diluted with water and the product was extracted into DCM (2x2 ml). The ed organic phases were dried with magnesium sulfate, ﬁltered and evaporated to provide 2,4,6-Triisopropyl- benzenesulfonic acid 6-phenylpyridinyl-thieno[3 ,2-d]pyrimidinyl ester [BB-16] as a brown solid. The crude was used without ﬁarther puriﬁcation in the next step. LCMS method: 3, RT: 6.12 min, MI: 572 [M+1].

Synthesis of 6-phenylpiperazinylpyridinyl-thieno [3 ,2-d]pyrimidine [3 01] S \N \ l N \ [BB-23] [301] To a on of 2,4,6-triisopropylbenzenesulfonic acid 6-phenylpyridinyl- thieno[3,2-d]pyrimidinyl ester [BB-23] (60 mg, 0.105 mmol) in DMA (1 ml) was added piperazine (10 mg, 0.115 mmol) followed by Eth (30 ul, 0.210 mmol) the mixture was stirred at room temperature for 2 hours. The crude reaction mixture was extracted with DCM (1 ml) and washed with brine (2 ml) and the extracts were loaded onto a SCX-2 dge and washed with methanol. The product was ed from the cartridge using a WO 78126 2012/065831 solution of 2M ammonia / methanol. The ammonia / methanol eluent was concentrated under d pressure and the crude product was puriﬁed by preparative HPLC (method A) to yield to the desired compound. LCMS method: 2, RT: 2.20 min, MI: 374 [M+l]. 1H NMR (300MHz, DMSO): 8.73 (dd,2H), 8.27 (dd,2H), 8 (s,lH), 7.91 (d,2H), 7.51 (m,3H), 4.06 (m,4H), 3.04 (m,4H).

The following 6,7-substituted-(2,4,6-triisopropyl-benzenesulfonic acid)- 2-pyridinyl- thieno[3,2-d]pyrimidinyl esters of general formula [G-111] were prepared: Synthesis of 2,4,6-triisopropylbenzenesulfonic acid 6-tert-butylpyridinyl-thieno[3,2- d]pyrimidinyl ester [BB-24]. \ l N*G\ [BB-03] [BB-24] To a solution of 6-tert-butylpyridinyl-thieno[3,2-d]pyrimidinol [BB-03] (630 mg, 2.2 mmol) in DCM (5 ml) was added 2,4,6-triisopropylbenzenesulfonyl chloride (710 mg, 2.64 mmol), Eth (920ul, 6.6 mmol) and DMAP (14 mg, 0.110 mmol). The mixture was stirred for one hour. After tion the e was diluted with water and the product was extracted into DCM (2x2 ml). The combined organic phases were dried ), ﬁltered and evaporated under reduced pressure to provide the title compound as a brown solid. The crude was used without ﬁarther purification in the next step. LCMS method: 3, RT: 6.25 min, MI: 551 [M+l]. —254— N/ \ [BB-02] [BB-25] 2,4,6-triisopropyl-benzenesulfonic acid methylpyridinyl-thieno[3,2- d]pyrimidinyl ester [BB-25] was prepared by reaction of methylpyridinyl- thieno[3,2-d]pyrimidinol [BB-02], 2,4,6-triisopropylbenzenesulfonyl chloride, Eth, DMAP and DCM at room temperature to give the desired compound as a brown solid.

LCMS method: 3, RT: 6.33 min, MI: 524 [M+1].

N/ |\ [BB-05] [BB-26] 2,4,6-triisopropyl-benzenesulfonic acid ylpyridinyl-thieno[3,2- d]pyrimidinyl ester [BB-26] was prepared by reaction of 7-methylpyridinyl- thieno[3,2-d]pyrimidinol [BB-05], 2,4,6-triisopropylbenzenesulfonyl chloride, Eth, DMAP and DCM at room temperature to give the desired compound as a brown solid.

LCMS method: 3, RT: 6.15 min, MI: 510 [M+1].

WO 78126 8 \N ——> \ l N \ Br Br [BB-04] [BB-27] triisopropyl-benzenesulfonic acid 7-(4-bromo-phenyl)pyridinylthieno [3,2-d]pyrimidinyl ester [BB-27] was prepared by reaction of 7-(4-bromophenyl )pyridinyl-thieno[3,2-d]pyrimidinol [BB-04], 2,4,6- triisopropylbenzenesulfonyl chloride, Eth, DMAP and DCM at room temperature to give the desired compound as a brown solid. LCMS method: 3, RT: 6.69 min, MI: 650 [M+1].

Synthesis of 2,4,6-Triisopropyl-benzenesulfonic acid 7-bromotert-butylpyridinylthieno [3,2-d]pyrimidinyl ester [BB-29] 8 \N \ l —> N \ Br l/N [BB-19] ] 2,4,6-Triisopropyl-benzenesulfonic acid 7-bromotert-butylpyridinyl- thieno[3,2-d]pyrimidinyl ester [BB-28] was prepared by reaction of 7-Bromotert- butylpyridinyl-thieno[3,2-d]pyrimidinol [BB-l9], 2,4,6-triisopropyl benzene sulfonyl chloride, Eth, DMAP and DCM at room temperature to give the desired compound as a brown solid. LCMS : 3, RT: 6.56min, MI: 630-632 [M+1].

Synthesis of (S)—N*1*-(2-pyridinyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidinyl)-butane- 1 ,2-diamine [3 02] H2N H NH2 HN ] \N ““2 \ | N \ MA /N [BB-26] [302] To a solution of 2,4,6-triisopropyl-benzenesulfonic acid 7-methylpyridinyl- thieno[3,2-d]pyrimidinyl ester [BB-26] (100 mg, 0.196 mmol) in DMA (2 ml) was added (S)phenyl-propane-1,2-diamine [AA-46] (32 mg, 0.216 mmol) followed by Eth (55 ul, 0.392 mmol), the mixture was stirred at room temperature for 2 hours. After completion the mixture was loaded onto a SCX-2 dge and washed with methanol.

The ammonia / ol eluent was concentrated under reduced pressure and the crude product was puriﬁed by ative HPLC (method B) to yield to the title compound.

LCMS method: 4, RT: 3.70 min, MI: 376 [M+l]. 1H NMR (300MHz, DMSO): 8.68 (dd,2H), 8.10 (dd,2H), 7.80 (s,lH), 7.34 (m,5H), 3.87 (m,lH), 3.39 (m,2H), 2.79 (m,2H), 2.41 (s,3H).

(S)-N* 1 * -(7-bromotert-butylpyridinyl-thieno [3 ,2-d]pyrimidinyl)-3 -(2- methoxy-phenyl)—propane- 1 ,2-diamine [303] 0?,O [AA-45] s \N NH2 \ l N \ Br l/N [BB-29] [303] To a solution of 2,4,6-triisopropyl-benzenesulfonic acid 7-bromotert-butyl pyridinyl-thieno[3,2-d]pyrimidinyl ester [BB-29] (173 mg, 0.275 mmol) in DMA (2 ml) was added [(S)amino(2-methoxy-benzyl)-ethyl]-carbamic acid tert-butyl ester [AA-45] (85 mg, 0.302 mmol) followed by Eth (120 ul, 0.825 mmol), the mixture was stirred at room temperature for 2 hours. The crude reaction mixture was extracted with DCM (2 ml) and washed with brine (3 ml). To the organic phase was added TFA (2 ml) and the mixture was d at room temperature for 1 hour. After completion the mixture was loaded onto a SCX-2 cartridge and washed with methanol. The product was released from the cartridge using a solution of 2M ammonia / methanol. The a / methanol eluent was concentrated under reduced pressure and the crude product was puriﬁed by preparative HPLC d A) to yield to the title compound. LCMS method: 4, RT: 3.79 min, MI: 526-528 [M+l].

Method B Owe»? [M NH I., 2 \ N F c| \ H O NH2 8 \ I S \ / —> N F \N F N \ H \ | | / .. . . \ / ||. 4M HCI In dloxane Br I DMAP,Et3N,DCM N \ N N \ Br I [BB-17]

[304] Synthesis of (S)—N*1*-[7-Bromo(3-ﬂuoro-pyridinyl)-thieno[3,2-d]pyrimidinyl]- yl-propane- 1 mine [3 04] To a solution of 7-Bromo(3-ﬂuoro-pyridinyl)-thieno[3,2-d]pyrimidinol [BB-17] (2.0 g, 6.13 mmol) in DCM (40 ml) was added 2,4,6-triisopropylbenzenesulfonyl chloride (2.2 g, 7.36 mmol), triethylamine (2.6 ml, 18.40 mmol) and DMAP (75 mg, 0.613 mmol). The on was stirred at room temperature for 4hours. ((S)Aminobenzylethyl )-carbamic acid tert—butyl ester (1.84 g, 7.36 mmol) was added and the mixture was stirred at room temperature for 18 hours. The crude on mixture was extracted with DCM (150 ml), washed with brine (100 ml) the combined organic phases were dried (MgSO4), ﬁltered and ated under reduced pressure to provide a crude gum which was titrutated with ether to provide the N—Boc protected intermediated as a pale white solid. The N—Boc protected intermediate was taken up in a 4M solution of HCl / e (10 ml) and the mixture was stirred at room temperature overnight. After completion the mixture was loaded onto a SCX-2 cartridge and washed with ol. The t was released from the cartridge using a solution of 2M ammonia / methanol. The ammonia / methanol eluent was concentrated under reduced pressure followed by trituration in ether to yield the desired compound. LCMS method: 9, RT: 5.34 min, MI: 458-460 [M+l]. 1H NMR (MeOD, 300 MHz): 8.61 (d, 1H), 8.52 (dd, 1H), 8.18 (s, 1H), 8.02 (m, 1H), 7.32 (m, 5H), 3.99 (m, 2H), 3.77 (m, 1H), 3.06 (d, 2H).

Synthesis of (R)[2-(2-Chloroﬂuoro-pyridinyl)-thieno[3,2-d]pyrimidin ylamino]-pyrrolidine- l -carboxylic acid tert-butyl ester [BB-3 l] 1» t N \ —> I I / N / N CI CI [BB-15] [BB-31] To a stirred suspension of hloroﬂuoro-pyridinyl)-thieno[3,2- d]pyrimidinol [BB-l5] (l.46g, 5.18 mmol) and DMAP (63mg, 0.518 mmol) in DCM (10 ml) was added triethylamine (l .6 ml, 114 mmol) followed by 2,4,6- Triisopropylbenzenesulfonyl chloride (2.35 g, 7.77 mmol). The reaction mixture was d at room temeperature for lhr, during which time the solution became clear. The crude reaction mixture was evapourated under reduced pressure, then the residue was dissolved in DMA (10 ml) and triethylamine (l .6 ml, 114 mmol) followed by (R)-(+)-l- Bocaminopyrrolidine (450 uL, 7.77 mmol) added and the mixture was left to stir at room temeperature for l8hr. The mixture was partitioned between (DCM:H20) and organic phase separated and evaporated under reduced pressure to give a pale brown oil, which was puriﬁed by normal phase chromatography (SiO2, ethyl acetate: exane elution) to give the title compound (1 .7lg, 73% yield: LCMS method 3: 4.70 min, 95%, 450.06 [M+H]; 1H NMR (MeOD) 8.40 (1H, d), 8.05 (1H, d), 8.03 (1H, d), 7.44 (1H, d), 4.80 (1H, m), 3.87-3.77 (1H, m), 3.59—3.42 (2H, m), 3.40 (1H, dd), 3.36-3.26 (1H, m), 2.18-2.09 (1H, m), 1.46 (9H, s).

Synthesis of [2-(2-Chloro-pyridinyl)-thieno[3,2-d]pyrimidinylamino]- pyrrolidinecarboxylic acid tert-butyl ester[ BB-32] LN) 2 OH HN N \ ——> N \ I I / N / N CI CI [BB-08] [BB-32] To a stirred suspension of hloro-pyridinyl)-thieno[3,2-d]pyrimidinol [BB-08] (2.69g, 10.2 mmol) and DMAP (125mg, 1 mmol) in DCM (30 ml) was added triethylamine (3.1 ml, 22.4 mmol) followed by 2,4,6-Triisopropylbenzenesulfonyl chloride (4.6g, 15.3 mmol). The reaction mixture was stirred at room temeperature for 1hr. The crude reaction mixture was evapourated under reduced pressure, then the residue was ved in DMA (30 ml) and ylamine (3.1 ml, 22.4 mmol) ed by (R)-(+) Bocaminopyrrolidine (2.6 ml, 15.3 mmol) added and the mixture was left to stir at room temeperature for 18hr. The crude reaction mixture was partitioned between 20) and organic phase separated, dried (MgSO4), ﬁltered and evaporated under reduced pressure to give a pale brown oil, which was puriﬁed by normal phase chromatography (SiOz, ethyl acetate: cyclohexane elution) to give the title compound (2.2g, 50% yield: LCMS method 3: 4.81 min, 85%, 432.07 [M+H]; 1H NMR (DMSO) 8.54 (1H, dd), 8.29 (1H, d), 8.28 (1H, s), 8.21 (1H, d), 7.51 (1H, d), 4.89-4.80 (1H, m), 3.79-3.67 (1H, m), 3.51-3.25 (3H, m), 2.30-2.19 (1H, m), 2.07-2.01 (1H, m), 1.40 (9H, s).

OH HN S \ N S F \ N F H \ | H | / \ / N \ N Br I Br | / N / N [BB-17] [BB-33] { l l [7-bromo(3 -ﬂuoro-pyridinyl)-thieno [3 ,2-d]pyrimidin ylamino]-ethyl}-carbamic acid tert-butyl ester [BB-33] was prepared by reaction of 7- Bromo(3-ﬂuoro-pyridinyl)-thieno[3,2-d]pyrimidinol [BB-l7], DMAP, triethylamine, Triisopropylbenzenesulfonyl chloride in DCM, followed by reaction with ((S)-l-Aminomethylphenyl-ethyl)-carbamic acid tert-butyl ester to give the title compound: LCMS method B, RT: n, MI: 558-560 OH HN S \ S N \ N H | —> \ H \ | / / N \ N Br I Br | / N / N [BB-20] [BB-34] [l-Benzyl(7-bromopyridinyl-thieno [3 ,2-d]pyrimidinylamino)-ethyl]- carbamic acid tert-butyl ester [BB-34] was prepared by reaction of of 7-Bromopyridin- 4-yl-thieno[3,2-d]pyrimidinol [BB-20], DMAP, triethylamine, 2,4,6- Triisopropylbenzenesulfonyl chloride in DCM, followed by reaction with ((S)-l- Aminomethylphenyl-ethyl)-carbamic acid utyl ester to give the title compound: LCMS method 3: 4.39 min, 95%, 542.04 [M+H]; 1H NMR (DMSO) 8.70 (2H, d), 8.39 (1H, s), 8.20 (2H, d), .22 (5H, m), 6.83 (1H, d), 4.09-4.06 (1H, m), 3.78-3.71 (1H, m), 3.51 (1H, m), 2.82-2.78 (2H, m), 1.23 (7H, s), 0.88 (2H, s). -26l- o %» S \N Br \ IN/ \ [BB-21] [BB-35] (R)(6-Bromomethylpyridinyl-thieno[3,2-d]pyrimidinylamino)- pyrrolidine-l-carboxylic acid tert-butyl ester [BB-35] was prepared by reaction of of 6- Bromomethylpyridinyl-thieno[3,2-d]pyrimidinol [BB-21], DMAP, triethylamine, 2,4,6-Triisopropylbenzenesulfonyl chloride in DCM, followed by reaction with )-l-Bocaminopyrrolidine to give the title compound: LCMS method 3 RT: 4.77min, MI: 490-492 [BB-17] [BB-36] (R)[7-Bromo(3-ﬂuoro-pyridinyl)-thieno[3,2-d]pyrimidinylamino]- pyrrolidine-l-carboxylic acid utyl ester [BB-3 6] was prepared by reaction of of 67- Bromo(3-ﬂuoro-pyridinyl)-thieno[3,2-d]pyrimidinol [BB-l7], DMAP, triethylamine, 2,4,6-Triisopropylbenzenesulfonyl de in DCM, followed by reaction with )-l-Bocaminopyrrolidine to give the title compound: LCMS method 3 RT: 4.49min, MI: 494-496 Method C OH CI M HN/\;:/ @N H N POCI3,100 C @N 2 :le NHz / / ——> \ / N \ N \ \ Br I Et3N, DMA §fNN Br I I / N / N Br / N [BB-20] [BB-38] [305] Synthesis of 7-Bromochloropyridinyl-thieno[3,2-d]pyrimidine (BB-3 8) 7-Bromopyridinyl-thieno[3,2-d]pyrimidinol [BB-20] (12 g, 38.9 mmol) was suspended in phosphorus oxychloride (120 ml) and the suspension heated to 110 0C. After 1 hour the reaction e was allowed to cool then phosphorus oxychloride removed under reduced pressure and the residue azeotroped with toluene. The pH was adjusted to pH 8 by the cautious addition of 2M NaOH and the mixture was left to stir at room temperature for 18 hours and the pale brown solid was collected by ﬁltration, washed with water and dried under reduced pressure to give the title nd which was used in the next step without r puriﬁcation. LCMS : 5, RT: 5.68 min, MI: 327 [M+l]. lHNMR (300MHz, DMSO) 8.92 (2H, dd), 8.88 (1H, s), 8.50 (2H, dd).

Synthesis of (S)-N* l *-(7-Bromopyridinyl-thieno[3,2-d]pyrimidinyl)-propane- l,2-diamine [305] To a solution of Bromochloropyridinyl-thieno[3,2-d]pyrimidine [BB-3 8] (100 mg, 0.307 mmol) in DMA (2 ml) was added S-(-)-l,2-diaminopropane dihydrochloride (50 mg, 0.308 mmol) followed by Eth (128 ul, 0.921 mmol), and the mixture stirred at room temperature for 18 hours. After completion the mixture was loaded onto a SCX-2 cartridge and washed with methanol. The product was released from the cartridge using a solution of 2M ammonia / methanol. The ammonia / methanol eluent was concentrated under reduced re and the crude product was puriﬁed by ative HPLC (method A) to yield the title nd. LCMS method: 3, RT: 2.25 min, MI: 364- 366 [M+l]. lHNMR (300MHz, DMSO): 8.74 (2H, dd), 8.41 (1H, s), 8.38 (1H, s), 8.34 (dd, 2H), 3.72 (m, 2H), 3.46 (m, 1H), 1.21 (s, 3H).

Synthesis of 7-chlorochloropyridinyl-thieno[3,2-d]pyrimidine (BB-39) 8 \N POCI3,100C \N \ l N \ N/ Et3N, DMA CI l [BB-18] [BB-39] [306 ] To a stirred solution of 7-Chloropyridinyl-thieno[3,2-d]pyrimidinol [BB- 18] (0.2 g, 0.78 mmol) in DMF (2 ml) was added POC13 (40 uL) and the RM stirred at 80 °C for 48 hours. The reaction mixture was cooled and poured into ice-water and the dark brown solid was collected by ﬁltration to give the title compound which was used without r ation: LCMS method B 5.29 min, 281.89 [M+H].

Synthesis of (S)—N*1*-(7-Chloropyridinyl-thieno[3,2-d]pyrimidinyl)phenyl- propane-1,2-diamine [306] To a stirred suspension of 7-chlorochloropyridinyl-thieno[3,2- midine [BB-39] (0.5g, 0.18 mmol) in DMA (1 ml) was added ((S)aminomethyl- 2-phenyl-ethyl)-carbamic acid tert-butyl ester (30 mg, 0.19 mmol) and triethylamine (50 uL, 0.36 mmol). The mixture was left to stir at room temeperature for 18hr then the crude reaction mixture was loaded onto an SCX cartridge and washed with methanol. The product was released from the cartridge using a on of 2M a / methanol. The ﬁltrate was rated under reduced pressure and the crude reaction product was puriﬁed by preparative HPLC (method B) to give the title compound :LCMS method 5: 33.06 min, 85%, 396.04 [M+H]; 1H NMR (DMSO, 300MHz): 9.00 (1H, s), 8.67 (2H, d), 8.33 (2H, s), 7.99 (2H, d), 7.36 (5H, m), 3.96 (1H, d), 3.60 (1H, m), 3.53 (1H, m), 3.01 (1H, dd), 2.84 (1H, dd), 2.49 (2H, m).

The following compounds were prepared according to the general synthesis shown in Scheme B3: Characterisation method: 2, RT: 2.11 min, MI: 342 [M+1] method: 2, RT: 2.15 min, MI: 342 [M+1] method: 3, RT: 1.91 min, MI: 300 [M+1] Ex SM Method Characterisation method: 3, RT: 2.41 min, MI: 426 [M+1] method: 2, RT: 2.03 min, MI: 328 [M+1] method: 2, RT: 1.88 min, 312 [BB-26] MI: 312 [M+1] method: 2, RT: 2.15 min, 313 [BB-23] MI: 348 [M+1] method: 4, RT: 3.18 min, 314 [BB-13] MI: 362 [M+1] method: 10, RT: 1.57 min, 315 [BB-13] MI: 406 [M+1], method: 10, RT: 1.23 min, 316 [BB-13] MI: 312 [M+1], method: 10, RT: 1.10 min, 317 ] MI: 298 [M+1] , method: 10, RT: 1.07 min, 318 [BB-13] MI: 298 [M+1] , Amine Characterisation [G-1 17] method: 10, RT: 0.99 min, [BB-13] MI: 314 [M+1] , method: 10, RT: 1.11 min, [BB-13] MI: 355 [M+1] , method: 10, RT: 1.16 min, [BB-13] MI: 316 [M+1] , method: 10, RT: 1.31 min, MI: 332 [M+1] , method: 10, RT: 1.87 min, MI: 396 [M+1] , method: 4, RT: 3.32 min, [BB-24] MI: 418 [M+1] method: 3, RT: 2.30 min, MI: 390 [M+1] method: 3, RT: 2.73 min, [BB-27] MI: 513 [BB-22] [M+1] Amine Ex SM Method Characterisation [G-1 17] method: 3, RT: 2.72 min, 327 [BB-27] MI: 513 [M+1] 1H NMR (300MHz, DMSO): 8.73 (d,2H), 8.30 method: 4, (d,2H), 4.88 RT: 4.11 min, (m,1H), 3.41 328 [BB-22] MI: 390-392 (m,2H), 3.15 [M+1] (m,1H), 3.06 , 2.6 (s,3H), 2.24 (m,1H), 1.97 (HLlH) : 4, RT: 4.43 min, 329 [BB-22] MI: 454-456 [M+1] method: 4, RT: 3.79 min, 330 [BB-22] MI: 378-380 [M+1] method: 4, RT: 3.78 min, 331 [BB-22] MI: 378-380 [M+1] method: 4, RT: 4.26 min, 332 [BB-22] MI: 390-392 [M+1] method: 3, RT: 4.18 min, 333 ] MI: 406-408 [M+1] method: 4, RT: 4.42 min, 334 [BB-29] MI: 496-498 [M+1] PCT/U82012/065831 Amine Characterisation [G-l 17] method: 4, RT: 4.94 min, [BB-29] MI: 496-498 [M+1] 1H NMR (DMSO, 300MHz): 8.70 method: 4, (2H, dd), 8.36(1H, RT: 3.82 min, s), 8.11 (2H, dd), [BB-20] MI: 440-442 7.25 (m, 5H), 3.79 [M+1] (dd, 1H), 3.30 (m, 1H), 2.70 (m, 2H), 2.50 (m, 2H) : 4, RT: 4.49 min, [BB-21] MI: 454 [M+1] method: 3, RT: 2.49 min, MI: 365.9 [BB-20] [M+1] : 4, RT: 4.87 min, MI: 379.98 [BB-20] [M+1] method: 3, RT: 2.49 min, MI: 391.92 [BB-21] [M+1] method: 4, RT: 4.99 min, MI: 392.01 [BB-20] [M+1] EX SM Method Characterisation method: 3, RT: 1.97 min, MI: 391.92 342 ] [M+1] method: 3, RT: 2.16 min, MI: 392 343 [BB-20] [M+1] method: 3, RT: 2.34 min, 344 [BB-20] MI: 364-366 [M+1] : 3, RT: 2.28 min, 345 [BB-20] MI: 364-366 [M+1] method: 3, RT: 2.57 min, 346 [BB-20] MI: 406-408 [M+1] method: 3, RT: 2.39 min, 347 [BB-20] MI: 392-394 [M+1] method: 3, RT: 2.64 min, 348 [BB-20] MI: 446-448 [M+1] method: 3, RT: 1.78 min, 349 [BB-20] MI: 350-352 [M+1] method: 3, RT: 1.89 min, 350 [BB-20] MI: 376-378 [M+1] Characterisation 1H NMR (DMSO, 300MHz): 8.96 (2H, 5, br), 8.83 method: 8, (2H, d), 8.54 (1H, RT: 1.88 min, d), 8.48 (2H, dd), MI: 376-378 8.45 (1H, s), 4.95 [M+1] (1H, m), 3.70 (1H, m), 3.28 (3H, m), 2.35 (1H, m), 2.15 (1H, m) 1H NMR (DMSO, 300 MHZ): 8.69(1H, d), 8.57 (1H, dd), 8.50 (1H, method: 6, s), 8.06 (1H, m), RT: 4.95 min, [BB-17] 4.80 (1H, m), 3.87- MI: 394-396 3.77 (1H, m), 3.59- [M+1] 3.42 (2H, m), 3.40 (1H, dd), 3.36-3.26 (1H, m), .09 (1H, m) method: 5, RT: 2.02 min, [BB-14] MI: 304 [M+1] 1H NMR (DMSO, 300 MHZ): 8.70(1H, d), 8.56 (1H, dd), 8.40 (1H, method: 5, s), 8.07 (1H, m), [BB-14] RT: 2.06 min, 7.52 (1H,d), 4.78 MI: 316 (1H, m), 3.49 (1H, [M+1] m), 3.32 (1H, m), 3.23 (2H, m), 2.26 (1H, m), 2.09 method: 5, RT: 3.02 min, [BB-14] MI: 380 [M+1] method: 5, [BB-20] RT: 3.13 min, MI: 440-442 [M+1] Characterisation 1H NMR (DMSO) 8.37 (1H, d), 8.32 (1H, d), 8.23 (1H, d), 8.06 (1H, t), method: 8, 7.50 (1H, d), 4.74- RT: 4.70 min, 4.69 (1H, m), 3.78- MI: 448-450 3.61 (1H, m), 3.49- [M+l] 3.41 (1H, m), 3.35— 3.25 (2H, m), 2.26- 2.15 (1H, m), 2.08- General synthesis of 6,7—substituted—4 amin0pyridinyl—thien0[3,2-d] pyrimidines e B4) 6, 7 -substituted 2-pyridinyl-thieno [3,2-d]pyrimidinol, of general a [G-lO4] red in scheme B l) were subjected to a activation reaction by reaction with a solid supported yl chloride derivative such as benzene sulfonyl choride on polystyrene in a polar c solvent such as DMA, DMF, NMP in the presence of a tertiary amine base such as Eth, DIPEA or NMM with a catalytic amount ofDMAP at ambient temperature. Excess reagents and reactants were removed by ﬁltration and washing the polystyrene resin with ts such as DCM, DMF, THF. The polymer supported reagent, of general a [G-118], was then reacted with a primary or secondary amino derivative, of l formula [G-l 17], in a polar aprotic solvent such as DMA, DMFor NMP in the presence of a tertiary amine base such as Eth, DIPEA or NMM at ambient temperature. The resin was ﬁtered through a PTFE frit, washed with a solvent such as DCM and the ﬁltrate and combined washings were loaded onto an acidic ion exchange catch release cartridge, which was washed with an organic solvent such as methanol and then the product was released with methanolic ammonia solution and the crude product was puriﬁed by reverse phase ative HPLC. The N—Boc derivatives were deprotected under acidic conditions with a strong acid such as TFA, TCA, methanesulfonic acid, HCl or H2804 in a solvent such as DCM, DCE, THF, EtOH or MeOH and the crude reaction mixture was puriﬁed by acidic ion exchange catch-release or reverse phase preparative HPLC.

Scheme B4 -27l- R I 0 PS R4imR2 "‘3 i. Amines Et3NDMA CI’S; o \‘ O [G- 117] S / SR / 7 N R12 R \ ' \ R13 \ ii TFADCM 3NDMA N \ \N [G-104] ] [ca-100] Synthesis of polystyrene supported benzenesulfonic acid 6-(4-tert-butyl-phenyl) nyl-thieno[3,2-d]pyrimidinyl ester [BB-40] Pb? Q0 \I:“ who I DMAP, Et3N,DMA [BB-07] [BB-40] 6-(4-tert-butyl-phenyl)pyridinyl-thieno[3,2-d]pyrimidinol [BB-07] (60mg, 0.167 mmol) and PS-TSCl (120mg, 0.250 mmol) were placed into ﬁlter cartridge closed with a stopper. DMA was added (2 ml) followed by Eth (70 ul, 0.5 mmol) and DMAP (1.1 mg, 0.009 mmol).The reaction was shaken for 3 hours at room temperature and then the polymer was ﬁltered (after removing the stopper). The resin was washed with DCM to yield to the polystyrene supported benzenesulfonic acid 6-(4-tert-butyl-phenyl)pyridin- 4-yl-thieno[3 ,2-d]pyrimidinyl ester. sis of 6-(4-tert-butyl-phenyl)[l,4]diazepan-l-ylpyridinyl-thieno[3,2- d]pyrimidine [356] 3’0 LEgMDMA H ’3’ NH O \3 |\N H \ II N N/ \ ii.TFA,DCM H>—<S N/ |\ ] [356] To the polystyrene supported benzenesulfonic acid 6-(4-tert-butyl-phenyl) pyridinyl-thieno[3,2-d]pyrimidinyl ester [BB-40] placed into a ﬁlter cartridge was added DMA (2 ml) followed by homopiperazine (20 mg, 0.2 mmol) and Eth (70 ul, 0.5 mmol). The reaction was shaken overnight at room temperature. The resin was ﬁltered and washed with cetate and the mixture was loaded onto a SCX-2 cartridge and washed with methanol. The product was ed from the cartridge using a solution of 2M ammonia / methanol. The ammonia / methanol eluent was concentrated under reduced pressure and the crude product was puriﬁed by preparative HPLC (method A) to yield to the title compound. LCMS method: 2, RT: 2.66 min, MI: 444 [M+l]. 1H NMR (300MHz, DMSO): 8.68 , 8.22 (d,2H), 7.82 (s,lH), 7.8 (d,2H), 7.52 (d,2H), 4.22 (m,2H), 4.15 (m,2H), 3.28 (m,2H), 3.06 (m,2H), 2.13 (m,2H), 1.32 (s,9H).

The following compounds were prepared according to the general synthesis shown in Scheme B4: Characterisation 2, RT: 2.67 min, MI: 430 nu+u 2, RT: 2.73 min, MI: 418 nu+u method: 2, RT: 2.67 min, MI: 418 nu+u Characterisation 1H NMR (300MHz, DMSO): 8.76 (m,2H), 8.33 , 7.94 (s,1H), 4.22 (m,1H), 4.09 , 3.74 (m,2H), 3.41 (m,2H), 2.43 (s,3H), 1.95 (m,2H) 1H NMR (300MHz, DMSO): 8.72 (m,2H), 8.35 (m,2H), 8.16 (m,1H), 7.93 (s,1H), 4.02 (m,4H), 2.96 (m,4H), 2.44 (s,3H) method: 2, RT: 1.89 min, MI: 300 [M+1] —274— Characterisation 1H NMR z, DMSO): 8,72 (d,2H), 8,27 , 7,97 (s,1H), 7,90 (d,2H), 7,49 (m,3H), 4,21 (m,2H), 4,11 (m,2H), 3,33 (m,2H), 3,08 (m,2H), 2,1 (m,2H) method: 2, RT: 1.76 min, 286[M+1] method: 2, RT: 2.57 min, MI: 446 [M+1] 1H NMR (300MHz, DMSO): 8.86 (dd,1H), 8.77 (m,3H), 8.41 (m,2H), 7.69 (dd,1H), 3.86 (m,2), 3.10 (m,2H) Characterisation 1H NMR (300MHz, method: DMSO): 8.97 (dd,1H), 2, RT: 8.76 , 8.34 1.92 mm, (m,2H), 7.65 (dd,1H), MI: 362 4.07 (m,4), 3.18 [M+1] , 2.93 (m,2H) 1H NMR (300MHz, method: DMSO): 8.87 (dd,1H), 2, RT: 8.79 (m,3H), 8.44 1.89 mm, (m,2H), 7.69 (dd,1H), MI: 337 3.80 (m,2), 3.48(m,1H),1.26(d,3H) method: 2, RT: 2.17 mm, MI: 391 method: 2, RT: 2.19 mm, MI: 365 3 85 BB—09 method:— Characterisation 1H NMR (300MHz, DMSO): 8.78 (dd,2H), 8.40 (dd,2H), 8.18 (m,lH), 7.69 (dd,2H), 4.04 (m,4), 2.98 (m,4H) General synthesis of 6 or 7 aryl substituted-4PT32P tives, of general formula [G-120] and [G-122] e BS) The 7-brornosubstitutedpyridinyl-thieno[3,2-d]pyrimidine derivative, of general formula [G-l 19] or the 6-bromosubstitutedpyridinyl-thieno[3,2- d]pyrimidine derivative, of general formula ] were reacted in a Suzuki type reaction utilising a suitable boronic acid or boronic ester, of general formula [G-123], a palladium catalyst such as Pd(PPh3)4 or 3)2Clz a base such as Eth, KOH, N32C03 or NaOH in a polar solvent such as EtOH, THF, DMA or dioxane at high temperature either by heating thermally or using a microwave reactor. After reaction work up, typically by a liquid-liquid extraction or puriﬁcation by acidic ion ge catch-release, the N-Boc derivatives were deprotected under acidic conditions with a strong acid such as TFA, TCA, methanesulfonic acid, HCl or H2S04 in a solvent such as DCM, DCE, THF, EtOH or MeOH and the crude on product was puriﬁed by reverse phase preparative HPLC.

Scheme B5 R R 3 3 R I R | 5 RR6R‘ﬁN‘RZA RR6R4j: N\R2A S / S 7 N R12 [G423] / 7 N R12 R \ I 13 R \ | 13 \N R \ ArB(OR)2,F’d(F’l13|:’)4 \N R Br ' Ar | R15 /N MW, EtOH,15min,150°C R15 /N R14 R14 [G119] [G120] 1 1 R3 E R3 E R: \R2 R4 \R2 R6 A S / [6-123] 8 / N R12 Ar \ ArB(OR)2,Pd(Ph3P)4 \NI R13 R | R15 MW, EtOH,15min, 150°C R15 /N [G-1211R R14 [G-122] Synthesis of (S)—N* l *-[6-methyl(2H-pyrazol-3 -pyridinyl-thieno[3 ,2- d]pyrimidinyl] phenyl-propane- l ,2-diamine [3 8 8] H)2/ \ E H S \ N NH2 \ I An Pd(Ph3P)4 N \ B r | / N MW, EtOH, 15min,150°C

[300] [388] A microwave vial was charged with (S)—N* l *-(7-bromomethylpyridinyl- thieno[3,2-d]pyrimidinyl)—3-phenyl-propane-l,2-diamine [300] (50mg, 0.100 mmol), lH-pyrazole-S-boronic acid (13mg, 0.115 mmol), tetrakis (triphenyl phosphine) palladium (ll mg, 0.009 mmol), N32C03 (2M in water, 100ul, 0.2 mmol) and EtOH (2 ml). The reaction was heated to 150°C for 15 s under microwave irradiation. The mixture was then ﬁltered through a plug of silica, washed with methanol and the ﬁltrate was concentrated under reduced pressure. The crude reaction product was dissolved in DCM (2 ml) and TFA (2 ml) was added and the mixture was stirred at room temperature for 1 hour.

After completion the mixture was loaded onto a SCX-2 cartridge and washed with methanol. The product was released from the cartridge using a solution of 2M ammonia / methanol. The ammonia / methanol eluent was concentrated under reduced pressure and the crude product was puriﬁed by preparative HPLC (method B) to yield to the title compound. LCMS : 4, RT: 3.71 min, MI: 442 [M+l]. 1H NMR (DMSO, 300MHz): 8.67 (d,2H), 8.06 (d,2H), 8.30 (d,lH), 7.88 (d,lH), 7.33 (m,5H), 3.88 (m,lH), 3.41 (m,2H), 2.93 (m,2H), 2.83 (s,3H).

Synthesis of [7-Methyl(2H-pyrazolyl)pyridinyl-thieno[3,2-d]pyrimidinyl]- (R)-pyrrolidinyl-amine [3 89] Br \8 |\N ArB(OR)2,Pd(Ph3P)4 N \ | MW, EtOH,15min,150°C [BB-35] [389] A microwave vial was charged with (6-Bromomethylpyridinyl- thieno[3,2-d]pyrimidinylamino)-pyrrolidinecarboxylic acid tert-butyl ester [BB-35] (100mg, 0.200 mmol), 1H-pyrazoleboronic acid (26mg, 0.23 mmol), tetrakis (triphenyl phosphine) ium (31 mg, 0.02 mmol), N32C03 (2M in water, 200ul, 0.4 mmol) and EtOH (2 ml). The reaction was heated to 150°C for 15 minutes under microwave irradiation. The mixture was then ﬁltered through a plug of silica, washed with methanol and the e was concentrated under reduced re. The crude reaction product was dissolved in DCM (2 ml) and TFA (2 ml) was added and the e was stirred at room ature for 1 hour. After completion the mixture was loaded onto a SCX-2 cartridge and washed with methanol. The product was released from the cartridge using a solution of2M ammonia / ol. The ammonia / ol eluent was concentrated under reduced pressure and the crude product was puriﬁed by preparative HPLC (method B) to yield to the title nd. LCMS method: 2, RT: 2.43min, MI: 378. 1H NMR (DMSO, 300MHz): 8.28 (dd,1H), 8.73 (dd,2H), 8.35 (dd,2H), 7.95 (d,lH), 4.93 (m,lH), 3.48(m,lH), 3.25 (m,lH), 3.l7m,lH), 3.l4(m,lH), 2.61 (s,3H), 2.28 (M,1H), 2.05 (m,lH).

The following compounds were prepared according to the general sis shown in Scheme B5: Boronic acida e SM Characterisation. .

[G-123] 1H NMR (DMso, 300MHz) 8.72 method: 4, B OH( )2 (2H, d) 856(1H, - , RT: 326 mm,. s, br), 8.43 (3H, m, 390 [336] " l MI: 428 br), 8.12 (2H, dd), HN / [M+1] 7.78 (1H, d, br), 7.34 (5H, m), 3.91 (1H, m), 3.45 (2H, m 2.82 , 2H, m method: 4, N RT: 3.30 min 391 [336] ’ MI 442 N \\ [M+1] 1H NMR (DMso, 300MHz): 8.66 (2H, d), 8.38 (1H, B(OH)2 method: 4, s, br), 8.22 (1H, s), RT: 3.65 min 8.00 (2H d) 7.30 392 [336] W 9 9 9 M1457 (6H, m), 3.85 (1H, 0 [M+1] m, br), 3.34 (2H, m), 2.73 (2H, t), 2.43 (3H, s), 2.25 3H, s . method: 3, RT‘ 2 25 min 393 [336 ] - - , MI: 428 [M+1] method: 3, RT‘ 2 81 min 394 [336 ] - - , MI: 484 [M+1] 1H NMR (DMso, 300MHz): 8.72 (2H, dd), 8.50 (1H, B(0H)2 8, hr), 8.39 (1H, 8) method: 3, 8.29 (1H, s), 8.12 395 [336] \\ RT: 2.92 mm, (2H, dd), 7.72 (1H, MI. 458 s), 7.35 (4H, m), [M+1] 7.20 (1H, s), 3.91 (1H, d), 3.48 (1H, d), 2.84 (1H, m), 2.49 (2H, m), 2.29 3H, s PCT/L S2012/065831 Boronic acida Example SM Characterlsatlon. .

[G-123] 1H NMR (DMSO, 300MHz): 8.68 (2H, dd), 8.61 (1H, s, br), 8.30 (1H, s), B(OH)2 method: 3, 8.25 (1H, s), 8.06 MI: 458 \ d), 7.35 (4H, m), [M+1] 7.06 (1H, d), 3.95 (1H, d), 3.52 (1H, m), 2.93 (1H, m), 2.49 (2H, m), 2.40 3H, s B(OH)2 method: 3, HN RT: 2.53 min 397 [336 ] \\ 3 MI: 427 [M+1] B(OH)2 method: 3, ,— RT: 2.47 min 398 [336] ’ 427[M+1] method: 5, RT: 4 82 min 399 [336 ] ‘ ‘ 3 MI: 500 [M+1] method: 5, RT: 2.95 min 400 [336 ] 3 MI: 430 [M+1] method: 5, RT: 3 68 min 401 [336 ] ‘ ‘ 3 MI: 428 [M+1] 1H NMR (DMSO, 300MHz): 8.80 B(OH)2 (1H, s, br), 8.68 / (2H, d), 8.48 (1H, / method: 5’ ): 838011: 5): RT: 3 98 min 402 [336] M1: 462 ’ 8.05 (2H, d), 7.63 [M+1] (2H, d), 7.47 (2H, m), 7.35 (4H, m), 3.94 (1H, d), 3.50 (2H, m), 2.94 (1H, dd 2.82 , 1H, dd 1H NMR (DMSO, B(OH)2 ). 8.76 method: 5 (2H, dd), 8.68 (1H, N RT: 1 97 mm 403 [351] ’ / d), 8.44 (1H, s), HN / M1364 [M+1] 8.38 (2H, dd), 8.31 (1H, s), 7.79 (1H, d 7.37 , 1H, d , PCT/L S2012/065831 Boronic acida Example SM Characterlsatlon. .

[G-123] .01 (1H, m), 3.60 (1H, dd), 3.29 (2H, m), 2.49 (2H, m), 2.32 (1H, m), 2.15 (1H, m) method: 5, RT: 3.13 min, 404 [336] MI: 432 [M+1] 1H NMR (DMSO, 300MHz): 8.66 (2H, dd), 8.46 (1H, s, br), 8.34 (1H, s), 8.01 (2H, dd), 7.95 B(0H)2 method: 6, (1H, s), 7.35 (5H, — RT: 5.99 min, 405 [336] m), 6.81 (1H, d), MI: 428 6.47 (1H, dd), 3.91 [M+1] (2H, d, br), 3.51 (2H, m), 2.91 (1H, dd), 2.81 (1H, dd), 1.64 (1H, m), 0.85 (2H, m), 0.56 (2H, B(0H)2 : 5, — RT: 4.28 min, 406 [336] MI: 444 [M+1] 1H NMR (DMSO, 300MHz): 8.66 (2H, dd), 8.32 (1H, s), 8.10 (1H, s), method: 6, 8.04 (2H, dd), 7.36 \ ,B(OH)2 RT: 5.95 min, (5H, m), 6.88 (1H, MI: 402 dd), 6.00 (1H, m), [M+1] 3.91 (2H, d, br), 3.49 (3H, m), 2.88 (1H, dd), 2.81(1H, dd), 1.97 (2H, dd), 1.92 (1H, dd). method: 5, 99O I .3“ RT: 3.26 min, 408 [336] l MI: 388 [M+1] 1H NMR (DMSO, 300MHz): 8.83 B(OH)2 (1H, s), 8.67 (2H, method: 5, d), 8.41 (1H, s), RT: 4.01 min, 8.36 (1H, s), 8.17 409 [336] MI: 456 (2H, t), 7.97 (2H, Tl [M+1] d), 7.38 (5H, m), 4.00 (1H, m), 3.64 (2H, m), 3.08 (1H, dd 2.89 , 1H, dd.

PCT/L S2012/065831 Boronic acida Example SM Characterisation [G- 123] B(OH)2 method: 5, RT: 2.24 min, 410 [336] MI: 439 [M+1] method: 5, RT: 3.02 min, 411 [336] MI: 442 [M+1] method: 5, RT: 4.01 min, 412 [336] MI: 442 [M+1] 1H NMR (DMSO, 300MHz): 8.66 (2H, d), 8.37 (1H, B(OH)2 method: 5, s), 8.02 (2H, d), RT: 3.36 min, 7.59 (1H, s), 7.35 413 [336] MI: 402 (5H, m), 3.93 (1H, [M+1] m), 3.52 (2H, m), 2.93 (1H, dd), 2.82 (1H, dd), 2.38 (2H, m 1.00 , 3H, m method: 5, RT: 2.96 min, 414 [BB-39a] MI: 428 [M+1] 1H NMR (DMSO, 300MHz): 8.72 (1H, s), 8.70 (2H, : 5, d), 8.39 (1H, s), RT: 3.07 min, 8.34 (1H, s), 8.03 415 [336] MI: 442 (2H, d), 7.81 (1H, [M+1] d), 7.37 (5H, m), 3.92 (3H, s), 3.56 (3H, m), 2.93 (1H, dd), 2.77 (1H, m) 1H NMR (DMSO, 300MHz): 8.73 (d, 1H), 8.57 (d, 1H), 8.43 method: 5, [BB-33 ] (s, 1H), 8.24 RT: 3.42 min, 416 (s, 1H), 8.03 (m, MI: 446 1H), 7.74 [M+1] (s, 1H), 7.27 (m, 5H), 3.70 (m, 1H), 2.75 (m, 1H), 2.64 m, 1H . 1H NMR (DMSO, method: 6, 300MHz): 8.67 RT: 6.53 min, 417 (3H, d, br), 8.42 MI: 438 (1H, s), 8.30 (2H, [M+1] s), 8.12 (2H, d), PCT/L S2012/065831 Boronic acida Example SM Characterisation [G- 123] 8.00 (2H, d), 7.53 (2H, t), 7.40-7.37 (5H, m), 4.00 (1H, m), 3.58 (2H, m), 3.00 (1H, dd), 2.86-2.81 1H, m . 1H NMR (DMSO, 300MHz): 8.69 (2H, d), 8.64 (1H, s, br), 8.35 (1H, s), 8.27 (2H, s, br), method: 5, 8.03 (2H, d), 7.42- RT: 3.48 min, 7.36 (5H, m), 6.95 418 [336] MI: 468 (1H, s), 4.00 (1H, [M+1] d, br), 3,71-3.58 (2H, m), 3.13 (1H, dd), 2.84 (1H, dd), 2.03-1.98 (1H, m), 0.98-0.92 (2H, m), 0.78-0.73 2H, m method: 6, RT: 5.23 min, 419 MI: 445 [M+1] 1H NMR (DMSO, 300MHz): 8.26 (s,1H), 8.70 , 8.53 method: 5, (d,1H), 7.96 RT: 5.61 min, (s,1H), 7.91 420 MI: 445 (m,1H), 7.30 [M+1] (m,5H), 6.83 (d,1H), 6.68 (d,1H), 3.66 (m,1H), 2.74 (m,2H), 2.62 (m,2H) : 5, RT: 4.32 min, 421 MI: 514 [M+1] method: 5, RT: 3.4 min, MI: 458 [M+1] PCT/L 065831 Boronic acida Example Characterisation [G-123] B(OI )2 method: 5, / RT: 3.03 min, MI: 457 ] [M+1] B(O I )2 method: 5, RT: 3.61 min, 424 [BB-33] MI: 486 [M+1] B(OI )2 method: 5, RT: 3.7 min, MI: 486 [M+1] method: 5, 426 0&2OI [3" RT: 4.02 min, MI: 446 [M+1] EOI s“ method: 5, RT: 2.51 min, MI: 485 [M+1] 1H NMR (MeOD, 300MHz): 8.58 (d, 1H), 8.52 method: 5, (s, 1H), 8.49 RT: 3.44 min, (d, 1H), 7.93 MI: 475 (m, 1H), 7.32 (m, [M+1] 5H), 3.95 (m, 2H), 3.77 (m, 1H), 3.03 (m, 2H), 2.43 (s, 3H), 2.27 s, 3H .

B(OI 3’ method: 5, RT: 2.64 min, 429 \ / MI: 457 z [M+1] lOE method: 5, RT: 4.21 min, MI: 474 [M+1] PCT/L S2012/065831 Boronic acida Example SM Characterisation [G- 123] 1H NMR (DMSO, 300MHz): 8.62(m,2H), 8.52 (”$20I3’ . (TILZH), ' 5: 8.08(dd,1H), 7.8 RT: 4.12 mm, 431 [BB-33] (dd’lH)’ MI: 462 [M+1] 7.48(dd,1H), 7.35 (m,5H), 4.03 (m,2H), 3.93 (m,2H), 3.76 m,1H method: 5, RT: 4.07 min, 432 ] MI: 446 [M+1] method: 5, RT: 4.02 min, 433 [BB-33] MI: 470 [M+1] method: 5, RT: 4.11 min, 434 [BB-33] MI: 456 [M+1] B(OH)2 method: 5, RT: 2.51 min, 435 [BB-33] MI: 475 [M+1] method: 4, RT: 5.49 min, 436 [334] MI: 512 [M+1] method: 4, RT: 3.82 min, 437 [334] MI: 484 [M+1] method: 4, RT: 4.24 min, 438 [300] MI: 471 [M+1] 1H NMR (DMSO, . 300MHz): Rﬁeghggﬁi’n 8.59(dd,2H), 8.53 439 [300] ' ' ’ (d,1H), 8.36(d,2H), MI: 483 7.86(d,2H), [M+1] 7.33(m,5H), 7.25 d,1H 3.81 PCT/L S2012/065831 Boronic acida Example SM terisation [G- 123] (s,3H), 3.45 (m,2H), 2.81 (m,3H), 2.44 (s,3H) method: 4, RT: 4.49 min, LLO [300] MI: 540 [M+1] method: 4, RT: 5.35 min, 441 [334] MI: 524 [M+1] method: 4, RT: 5.51 min, LLN [334] MI: 512 [M+1] method: 4, RT: 4.79 min, 443 [334] MI: 513 [M+1] method: 4, RT: 4.57 min, LLL [334] MI: 509 [M+1] method: 4, RT: 5.07 min, 445 [334] MI: 484 [M+1] 1H NMR (DMSO, 300MHz): 8.62 (dd,2H), 7.90 (dd,2H), 7.46 (m,1H), 7.29 method: 4, (m,5H), 7.27 RT: 4.80 min, 446 [300] (m,1H), 7.16 MI: 528 (m,1H), 3.84 [M+1] (m,2H), 3.16 (d,6H), 2.92 (m,2H), 2.81 (m,1H), 2.65 (m,1H), 2.53 s,3H PCT/L S2012/065831 Boronic acida Example SM Characterisation [G- 123] E!OIr method: 4, RT: 5.72 min, 447 [BM MI: 514 [M+1] method: 4, RT: 4.45 min, 448 [BM MI: 523 [MH] 1H NMR (DMSO, 300MHz): 8.62 (dd,2H), 7.90 method: 4, 29OI )2 (dd,2H), 757 RT: 4.51 min, , 734 LLC [mm M1: 452 (m,5H), 3.5 [M+1] (mJH), 2.92 (m,2H), 2.81 , 2.65 (mJHL2665H) B(OH)2 method: 4, RT: 4.59 min, L£11 0 [mm MI: 496 [MH] method: 4, EOI)2 RT: 5.51 min, 451 [334] MI: 494 [MH] method: 4, RT: 5.02 min, EOIs“ L£11 N [mm MI: 554 [M+1] 92OI NV method: 4, CI RT: 4.41 min, 453 [mm MI: 516 [MH] method: 4, RT: 4.12 min, 454 [mm MI: 512 [MH] method: 4, RT: 4.74 min, 455 [BM MI: 554 [MH] WO 78126 PCT/L S2012/065831 Boronic acida e SM Characterisation [G-123] B(OH)2 method: 4, 0\ RT: 3.45 min, MI: 483 §%z/Iz\$’/\Lm [M+1] method: 4, RT: 3.73 min, MI: 487 [M+1] 1H NMR (DMSO, 300MHz): 8.6 (dd,2H), 7.85 (dd,2H), 7.34 B(OH)2 method: 4, (m,5H), 717 RT: 5.03 min, (m’1H)’ 703 M1: 524 (m,2H),3.5 (m,1H), [M+1] 2.92 (m,2H), 2.81 (m,2H), 2.53 (d, 6H), 2.65 (m,1H), 2.41 (s,3H), 2.3 (s,3H) B(OH)2 method: 4, RT: 3.49 min, 459 \ MI: 467 [M+1] 1H NMR (DMSO, ): 8.62 (dd,2H), 7.92 (dd,2H), 7.44 B( OI )2 method: 4., Em,1H;, 7.28m,5H 7.32 RT: 5.13 mm, 460 (m,2H), 719 M1: 544 CI (m,2H), 3.5 [M+1] (m,1H), 2.92 (m,2H), 2.81 (m,2H), 2.65 (m,1H), 2.53 (d, 6H), 2.42 (s,3H) B(OI )2 method: 4, RT: 5.14 min, MI: 524 [M+1] PCT/L S2012/065831 Boronic acid Example Characterisation [G- 123] : 4, B(OH) RT: 4.91 min, 463 [300] MI: 530 [M+1] method: 4, /O RT: 4.73 min, 464 [300 ] F MI: 550 F [M+1] 1H NMR (DMSO, 300MHz): 8.6 (dd,2H), 8.28 (dd,1H), 7.82 method: 4, (dd,2H), 7.72 RT: 3.96 min, (m,1H), 7.34 465 [300 ] MI: 483 (ma5H), 7.15 (m,1H), 3.82 [M+1] (s,3H), 3.5 (m,3H), 2.93 (m,1H), 2.82 (m, 1H), 2.43 (s,3H) method: 4, RT: 4.24 min, 466 [300 ] MI: 512 [M+1] method: 4, RT: 4.35 min, 467 [300 ] MI: 500 [M+1] : 4, RT: 3.83 min, 468 [334 ] MI: 484 [M+1] : 3, RT: 2.26 min, 469 [BB41 ] MI: 392 [M+1] “site of attachment to thieno pyrimidine core. b Clapham, Kate M.; Batsanov, Andrei S.; Bryce, Martin R.; Tarbit, Brian, Organic and Biomolecular Chemistry, 2009, V01. 7, p. 2155 — 216 General synthesis of 7-amid0-4PT32P derivatives of general formula [G-128] (Scheme B6) A 7 -unsubstituted 2-pyridinyl-thieno [3,2-d]pyrimidinol of general formula [G-124] was nitrated at the C-7 position by reaction with a nitrating agent such as ﬁlming nitric acid in concentrated sulphuric acid to yield the corresponding 7-nitro-substituted 4PT32P derivative of general formula [G-125]. The 7-nitro-4PT32P derivative was then d to the corresponding 7-amino PT32P ative of general formaula [G-126] by hydrogenation reaction under an atmosphere of en in the presence of a catalyst such as palladium on activated charcoal. Amide formation was med by reaction with an acyl chloride, of general formula [G-129] with the 7-amino-4PT32P derivative ] to yield the corresponding 7 substituted 4PT32P derivative of general formula [G- 127]. The intermediate 7 -amidosubstituted 4PT32P derivative of general formula [G- 127] was then reacted with 2,4,6-triisopropylbenzenesulfonyl chloride in a polar aprotic solvent such as DMA, DMF, NMP with a tertiary alkylamine base such as Eth, DIPEA or NMM and a catalytic amount of DMAP, and the ediate 7-amido-substituted- (2,4,6-triisopropyl-benzenesulfonic acid)- 2-pyridinyl-thieno[3,2-d]pyrimidinyl ester was used crude and reacted further with a primary or secondary amino derivative, of general formula [G-l 17], in a polar aprotic solvent such as DMA, DMF, NMP in the presence of a ry amine base such as Eth, DIPEA or NMM at ambient temperature.

After reaction work up, typically by a liquid-liquid extraction or purification by acidic ion exchange catch-release, the N—Boc derivatives were deprotected under acidic conditions with a strong acid such as TFA, TCA, esulfonic acid, HCl or H2804 in a solvent such as DCM, DCE, THF, EtOH or MeOH and the crude reaction product was puriﬁed by reverse phase preparative HPLC.

Scheme B6 -29l- %RHNO34/HZSO R7if\S / N DMF) if i DIPEA RX Cl R1 \ DMA 53; “L [G-129] :5 R i) 2,4,6—triisopropyl benzene sulfonyl chloride OH TEA, DMAP, DCM R6 A S / 12 Amine 7 N R R I S 12 \ / [G-117] \ R13 7 N R o N \ R \ 13 R | O \N' \ y” / N l R15 N Rx R15 / N II) TFA, DCM 14 H R R14 [G-127] [G-l 28] Synthesis of 7-nitroPyridin—4-yl-thieno[3,2-d]pyrimidin—4-ol [BB-40] \ |\N ’ N \ ] [BB-40] To a stirred solution of 2-Pyridinyl-thieno[3,2-d]pyrimidin—4-ol [BB-l3] (5g, 21.8 mmol) in concentrated sulfuric acid (50 ml) at 0 CC was added fuming nitric acid (5 ml) dropwise. The reaction mixture was left to stir at 0 CC for lhr then the mixture was poured onto ice and left to stir at room temperature overnight. The pale yellow precipitate was collected by ﬁltration, and washed with H20 followed by THF, to yield the title compound as a pale yellow solid (1.84g, 31% yield) which was used in the next step t further ation: LCMS method 3, 2.94 min, 100%, 274.97 [M+H] Synthesis of 7-Aminopyridinyl-thieno[3,2-d]pyrimidinol [BB-41] 0“ OH c?\ | ——> , w\ l , N \ N \ [BB-40] [BB-41] opyridinyl-thieno[3,2-d]pyrimidinol [BB-40] , 15.5 mmol) was dissolved in 2:3 mixture of MeOH-DMF (500 ml) and ﬁltered h a PTFE phase separation frit to remove any undissolved solids. The ﬁltrate was then loaded onto an H- cube with a ﬂow rate of lml/min [using a paladium on actiavted charcoal cartridge at room temerature and an atmospheric pressure of H2]. The crude on mixture was evapourated under d pressure to remove the MeOH and the ing DMF solution was poured onto an an SCX cartridge, which was washed with MeOH followed by NH3:MeOH. The methanolic ammonia ﬂush was concentrated in vacuo to provide the title compound as a brown solid (1 .5 g, 40% yield) which was used in the next step without further puriﬁcation: LCMS method 3, 2.35 min, 100%, 244.99 [M+H] Synthesis of Cyclopentanecarboxylic acid [2-pyridinyl((R)-pyrrolidinylamino)- thieno[3,2-d]pyrimidinyl]-amide [470] OH §rNIN HN’E) / N ——>E§N g” [BB-41] [BB-42] [470] 7-Aminopyridinyl-thieno[3,2-d]pyrimidinol [BB-41] (100 mg, 0.42 mmol) was dissolved in DMA (2 ml) and DIPEA (l50 uL). The reaction mixture was cooled to 0°C and a mixture of cyclopentane carbonyl chloride (100 uL, 0.84 mmol) in DMA (1 ml) was added and the reaction was left to stir at 0°C for 2 hours. The mixture was treated with water (1 ml) and left to stir for 2 hours at room temperature. The crude reaction e was extracted with DCM (2 ml) and washed with brine (3 ml) and the organic extract was then loaded on a SCX-2 cartridge, which was washed with MeOH followed by NH3:MeOH. The methanolic ammonia ﬂush was concentrated under reduced pressure to provide cyclopentanecarboxylic acid (4-hydroxypyridinyl-thieno[3,2- d]pyrimidinyl)-amide [BB-42] which was used crude in the next step. To a solution of crude cyclopentanecarboxylic acid (4-hydroxypyridinyl-thieno[3,2-d]pyrimidin yl)-amide [BB-42] (70 mg, 0.21 mmol), DMAP (3 mg), TEA (60 ml, 0 .42 mmol) in DMA (5 ml) was added 2,4,6-triisopropylbenzenesulfonyl de (77 mg, 0.25 mmol). The mixture was left to stir at room temeperature overnight. A mixture of (R)-(+)Bocaminopyrrolidine (40 ml, 0.21 mmol) in DMA (1 ml) was added and the mixture was left to stir at room temeoperature for 24 hours. Water was added and the reaction mixture was extracted with DCM and the extract was dried (MgSO4), ﬁltered and evaporated under reduced pressure. The crude product was dissolved in DCM (2 ml) and TFA (1 ml) was added, the mixture was left to stir at room temeperature for 1 hour then the crude reaction mixture was loaded on to a SCX-2 dge, which was washed with MeOH ed by NHgiMeOH. The methanolic a ﬂush was concentrated in vacuo and the residue was purified by preparative LC-MS to e the title compound.

LCMS method 5, 2.71 min, 409 [M+H].

The following compounds were prepared according to the general synthesis shown in Scheme B6: Amine JL Example SM . .

RX CI Characterisation [F 1 17] [F-129] LCMS 1’00 0 method 5, SJ CI 3.00 mm,. ( R 2 411 [M+H] LCMS boc\ NH method 5, < ) CI 4.01 min, 475 [M+H] LCMS 3°C CI method 5, ( SJR 3.09 min, 2 423 [M+H] O LCMS hemN CI method 5, 4.39 min, 487 [M+H] Amine JL Example Rx CI Characterisation [F 1 17] [F-129] LCMS method 5, 3.91 min, 473 [M+H] General synthesis of xy-substituted 4PT32P derivative of general a [G- 130] (Scheme B7) The Polystyrene supported benzenesulfonic acid 6,7 subsituted-Z-pyridinyl- [3,2-d]pyrimidinyl ester of l formula [G-118] [prepared in scheme B5] was subjected to a nucleophilic substitution reaction with an amino alcohol, of general formula [G-l3 l], in the presence of a strong base such as NaH, KH or LDA in an anhydrous polar aprotic solvent such as DMA, DMF or NMP. After reaction work up, typically ﬁltration of the resin through a PTFE frit followed by a -liquid extraction or puriﬁcation by acidic ion exchange catch-release, the N—Boc derivatives were deprotected under acidic conditions with a strong acid such as TFA, TCA, methanesulfonic acid, HCl or H2804 in a solvent such as DCM, DCE, THF, EtOH or MeOH and the crude reaction product was puriﬁed by reverse phase preparative HPLC.

Scheme B7 3 F3 N 2 (9‘ PS R4 \R 0,8“ i. ROH, NaH, DMA R5 6 o S 1, [G-131] / g 12 7 N R / 7 N R R \ | 13 R \ | 13 \N R \ II.TFA,DCM.. \N R R8 I R8 I /N 15 /N R R R14 R14 [G-118] [G-130] Synthesis of 7-methylpyridinyl((R)- l -pyrrolidinylmethoxy)-thieno[3,2- d]pyrimidine [476] \ I —> _> N / \ I \ / \ I / N / N [BB'05] [BB-43] [476] 7-methylpyridinyl-thieno[3,2-d]pyrimidinol ] (70 mg, 0.28 mmol) and PS-TSCl (210 mg, 0.45 mmol) were placed into ﬁlter cartridge closed with a stopper.

DMA (2 ml) was added followed by Eth (70 ul, 0.5 mmol) and DMAP (1.1 mg, 0.009 mmol). The reaction was shaken for 3 hours at room temperature and then the r was ﬁltered through a PTFE frit. The resin was washed with DCM, DMA, DCM to yield to the intermediate polystyrene supported benzenesulfonic acid 7-methylpyridinyl- thieno[3,2-d]pyrimidinyl ester [BB-43], which was used in the next step without ﬁlrther puriﬁcation.

Polymer ted benzenesulfonic acid 7-methylpyridinyl-thieno[3,2- d]pyrimidinyl ester ] (0.280 mmol) was placed in a ﬁlter cartridge and DMA (2 ml) was added, followed by (R)-(+)-l-bocpyrrolidinemethanol (68 ul, 0.340 mmol) and NaH (14 mg, 0.340 mmol). The reaction was shaken overnight at room temperature.

The resin was d through a PTFE frit and washed with ethylacetate. The ﬁltrates were combined and trated under reduced pressure. The crude product was dissolved in DCM (2 ml) and TFA (2 ml) was added and the mixture was stirred at room temperature for 1 hour. After completion the e was loaded onto a SCX-2 cartridge and washed with methanol. The product was released from the cartridge using a solution of 2M ammonia / methanol. The ammonia / methanol eluent was concentrated under reduced pressure and the crude product was d by preparative HPLC (method A) to yield to the title compound. LCMS method: 2, RT: 1.91 min, MI: 313 [M+l].

The following compounds were prepared according to the general synthesis shown in scheme B7: Example SM Characterisation [G-131] : 2, RT: 3.47 min, MI: 447 [M+1] 477 ] “he method: 2, RT: 3.29 min, MI: 397 [M--l] 478 ”“0 ] Wm) method: 2, RT: 2.28 min, MI: 397 [M--l] 479 [BB-09] b°° 480 [BB-05] b°°fif} method: 2, RT: 1.95 min, MI: 327 [M+1] 481 [BB-05] method: 2, RT: 2.80 min, MI: 377 [M+1] 0'o0 482 [BB-05] K method: 2, RT: 2.80 min, MI: 377 [M+1] 483 [BB-05] )V 7 method: 2, RT:1.92min, MI:313 [M+1] 484 [BB-05] (R): 7 method: 2, RT: 1.91 min, MI: 313 [M+1] General synthesis of 7-arylaminosubstituted-4PT32P derivatives of general formula [F-132] e B8) The 7-br0mosubstitutedpyridin—4-yl-thieno[3,2-d]pyrimidine derivative of general formula [G-l 19] was involved in a Buchwald type reaction utilising a suitable amine, of general formula [G-l33], a palladium catalyst such as )2 0r Pd(OAc)2, a ligand such as Xantphos and a base such as NaOtBu or CS2C03 in a polar solvent such as dioxane or a combination of dioxane and DMA at high temperature either by heating thermally or using a microwave reactor. After on work up, typically by a liquidliquid extraction or puriﬁcation by acidic ion exchange catch-release, the N—Boc derivatives were deprotected under acidic conditions with a strong acid such as TFA, TCA, methanesulfonic acid, HCl or H2S04 in a solvent such as DCM, DCE, THF, EtOH or MeOH and the crude reaction product was puriﬁed by preparative reverse phase HPLC.

Scheme B8 3 3 R5 I I N\R2 RB N\R2 R5 RnyNH, Pd(dba)2, R5 R6 A os, NaOtBu R6 A S / S 7 N R12 [G'I| 33] / 7 N R12 R \ | R R13 —> \ | \ \ R13 N \ MW, Dioxane-DMA, N \ Br l 15min, 150°C RX’N. I R15 / N Ry R15 / R14 R14 [Cu-119] [Cu-132] Synthesis -((S)Aminophenyl-propyl)-N*7*-phenylpyridinylthieno ]pyrimidine-4,7-diamine [485] HN/\a/\©- HN ; PhNHZ, Pd(dba)2, S S m \N NH2 Xantphos, NaOtBu \N 2 \ l —> \ I N/ \ N/ \ | MW, Dloxane-DMA,.

Br l / N 15min, 150°C Q/HN / N

[485] A microwave vial was charged with (S)—N*1*-(7-bromomethylpyridinyl- thieno[3,2-d]pyrimidinyl)phenyl-propane-1,2-diamine [336] (100mg, 0.227 mmol), aniline (27ul, 0.295 mmol), Pd(dba)2 (7 mg, 0.011 mmol), Xantphos (13 mg, 0.023 mmol), NaOtBu (45 mg, 0.454 mmol), DMA (few drops) and dioxane (1 ml). The reaction was heated to 150°C for 15 minutes under microwave irradiation. The mixture was then loaded onto a SCX-2 cartridge and washed with methanol. The product was released from the cartridge using a solution of 2M ammonia / methanol. The ammonia / methanol eluent was concentrated under reduced pressure and the crude product was puriﬁed by preparative HPLC (method B) to yield the title compound. LCMS method: 4, RT: 4.38 min, MI: 453 [M+1]. 1H NMR (300MHz, DMSO): 8.68 (2H, d), 8.41 (1H, s, br), 8.24 (2H, d), 8.17 (1H, s), 7.34 (9H, m), 6.87 (1H, t), 3.89 (1H, m, br), 3.40 (2H, t), 2.78 (2H, The following compounds were prepared according to the general synthesis shown in Scheme B8: Example Characterisation method: 5, RT: 3.06 min, MI: 454 [M+1] 1H NMR (300, MHZ, DMSO): 9.07 (1H, s), 8.76 (2H, d), 8.54 (2H, d), 8.39 (2H, t), 8.26 method: 5, RT: (1H, d), 7.66 (1H, 1.60 min, MI: t), 7.35 (1H, d), 390 [M+1] 6.84 (1H, t), 4.90 (1H, m), 3.44 (2H, m), 3.09 (2H, m), 2.25 (1H, m), 1.88 (1H, m) 1H NMR (300, MHz, DMSO): 9.02 (1H, s), 8.67 (2H, s,br), 8.61 (2H, d), : 5, RT: 8.25 (1H, s), 8.18 3.33 min, MI: (2H, d), 7.35 (5H, 455 [M+1] m), 6.98 (2H, t), 3.95 (1H, m), 3.49 (2H, m), 2.93 (1H, m), 2.81 (1H, m) method: 5, RT: 3.22 min, MI: 455 [M+1] method: 5, RT: 3.29 min, MI: 458 [M+1] 1H NMR (300, method: 5, RT: MHz, MeOD): 8.62 4.15 min, MI: (d, 1H), 8.53 (s, 471 [M+1] 1H), 8.51 (d, 1H), 8.12 (m, 1H), 7.33 2012/065831 (m, 10H), 3.95 (m, 2H), 3.76 (m, 1H), 3.04 (m, 2H). method: 5, RT: 3.89 min, MI: 421 [M+1] method: 5, RT: 3.64 min, MI: 425 [M+1] method: 5, RT: 1.19 min, MI: 408 [M+1] method: 5, RT: 2.08 min, MI: 408 [M+1] method: 5, RT: 3.07 min, MI: 412 [M+1] method: 5, RT: 2.82 min, MI: 398 [M+1] 1H NMR (300, MHZ, MeOD): 8.6 (1H, d), 8.52 (1H, d), 8.48 (1H, s), method: 5, RT: 8.27 (1H, m), 7.23 3.95 min, MI: (2H, d), 7.35 (1H, 421 [M+1] d), 6.92 (1H,m), 4.9 (1H, m), 3.44 (2H, m), 3.09 (2H, m), 2.25 (1H, m), 1.88 (1H,m) method: 5, RT: 3.69 min, MI: 425 [M+1] 1H NMR (300, method: 5, RT: MHz, MeOD): 8.61 3.8 min, MI: 425 (1H, d), 8.53 (1H, [M+1] d), 8.49 (1H, s), 8.28 (1H, m), 7.24 (2H, d), 7.34 (1H, d), 6.91 (lH,m), 4.91 (1H, m), 3.44 (2H, m), 3.08 (2H, m), 2.27 (1H, m), 1.88 (lH,m) General synthesis of 7-alkynyl-substituted-4PT32P and 6-alkynyl substituted- 4PT32P derivatives of general formula [F134] & ] (Scheme B9) The 7-Bromosubstitutedamino(3-substituted-pyridinyl)-thieno[3 ,2- d]pyrimidine derivative of general formula [G-l 19] or 6 -Bromosubstitutedamino (3-substituted-pyridinyl)-thieno[3,2-d]pyrimidine derivative of general formula [G-lZl] was involved in a Sonogashira coupling reaction utilising a suitable terminal alkyne, of general formula ], in the presence of copper(I)iodide with Pd(PPh3)2Clz as catalyst, triphenylphosphine as , and a base such as Eth, or DEA in a polar solvent such as DMA or DMF at a high temperature either by heating thermally or using a microwave reactor. After reaction work up, typically by a liquid-liquid extraction or puriﬁcation by acidic ion exchange catch-release, the N—Boc derivatives were deprotected under acidic conditions with a strong acid such as TFA, HCl in a solvent such as DCM, DCE or 1,4- dioxane or by catch and release sulfonic acidic resins such as polymer ted toluene ic acid. In the case of silyl protected acetylenes, a further ection using lM TBAF in THF was used prior to the acid mediated ge of the Boc group and the crude reaction mixtures were puriﬁed by preparative reverse phase HPLC.

Scheme B9 -30l- 2012/065831 R3 I? R3 4 2 R R \R2 R5 ::N\ R: R6 A E \3 / IN R12 x—[G-_136]H ,5 / R7 13 —> R7 \N R \ Pd(Ph3P)22,CI Br I /N Cu| DZEA DMA, MW, R14 15min,150°C R14 [CI-119] [G-134] R3 F51 R3 4 N\ 2 E R R R4 \R2 R5 l [Cu-136] R5 R6 A R6 A S XTH / IN R12 S / R12 B IN r \ 13 X _— \ 13 \N R \ Pd(Ph3P)ZC|2, \N R R8 I 8 | R R15 /N PPha, Cul, DEA R15 /N DMA, MW, R14 14 15min, 150°C R [CI-121] [Cu-135] Synthesis of 4-[4-((S)Arnin0pheny1—pr0py1arnin0)—2-(3-ﬂuor0-pyridiny1)— thieno [3 ,2-d]pyrirnidiny1] -but-3 -yn01 [5 01] Ij/NHZ HN HO HN S \N _ F \N \ l —> / / N \ \ N Br I/N Pd(Ph3P)ZC|2, PPha, Cul, DEA | MW, DMF, 15min, 150°C ii. MP-TsOH, MeOH [BB-33] H0 [501] A microwave Vial was charged with {(S)—1-Benzy1—2-[7-br0rno-2—(3-ﬂuoro- pyridiny1)—thieno[3,2-d]pyrirnidinylarnino]-ethy1}-carbarnic acid tert-butyl ester [BB-33] (100 mg, 0.179 mmol), 3-butynol (15 uL, 0.197 mmol), bis(triphenylphosphine)palladiumchloride (13 mg, 0.018 mmol), copper(I)Iodide (3.4 mg, 0.018 mmol), triphenylphosphine (9.4 mg, 0.036 mmol), diethylamine (0.28 ml, 2.686 mmol) and DMF (1 ml). The reaction mixture was heated to 150°C for 15 s under microwave irradiation. After completion, the product was extracted with ethyl acetate (2 x 2 ml), washed with brine (2 ml) and the combined organic phases were dried (MgSO4), ﬁltered and ated under reduced pressure. The crude product was dissolved in DCM (2 ml) and TFA (1 ml) was added, the e was stirred at room temeperature for 1 hour then the crude product was loaded onto an SCX cartridge and the cartridge was washed with methanol then the product was eleuted with 2M ammonia / methanol. The eluent was concentrated under reduced pressure and the crude mixture puriﬁed by preparative HPLC (method A) to yield the title compound: LCMS : 7, RT: 3.15 min, MI: 448 [M+1]. 1H NMR (300, MHz, DMSO): 8.69 (d, 1H), 8.55 (d, 1H), 8.28 (s, 1H), 7.90 (m, 1H), 7.24 (m, 5H), 4.92 (bs, 1H), 3.62 (m, 2H), 2.78 (m, 1H), 2.62 (m, 2H).

Synthesis of 2-Methyl[7-methylpyridinyl((R)-pyrrolidinylamino)- thieno[3,2-d]pyrimidinyl]-butynol [5 02] S \N Br \ I N/ \ [BB-35] [502] A ave vial was charged with (R)(6-Bromomethylpyridinyl- thieno[3,2-d]pyrimidinylamino)-pyrrolidinecarboxylic acid tert-butyl ester [BB-35] (60 mg, 0.13 mmol), 2-methylbutynol (51 uL, 0.53 mmol), bis(triphenylphosphine)palladiumchloride (93 mg, 0.13 mmol), copper(I)Iodide (25 mg, 0.13 mmol), triphenylphosphine (70 mg, 0.26 mmol), diethylamine (0.2 ml, 1.9 mmol) and DMF (1 ml). The reaction mixture was heated to 150°C for 10 minutes under microwave irradiation. After completion, the product was extracted with ethyl acetate (2 x 2 ml), washed with brine (2 ml) and the combined organic phases were dried (MgSO4), ﬁltered and evaporated under reduced pressure. The crude product was dissolved in DCM (2 ml) and TFA (1 ml) was added, the mixture was stirred at room temeperature for 1 hour then the crude t was loaded onto an SCX cartridge and the cartridge was washed with methanol then the product was eleuted with 2M ammonia / methanol. The eluent was trated under reduced pressure and the crude mixture puriﬁed by preparative HPLC (method A) to yield the title compound. LCMS method 5, 2.83 min, 394 [M+H].

The ing compounds were prepared according to the general synthesis shown in Scheme B9: Terminal alkyne EX Characterisation [G- l 3 6] method. 5 RT. n, MI: 394 [M+l] method: 5, RT: 3.28min, MI: 458 [M+l] method: LC-MSl5QC, RT: .93min, MI: 500 [M+l] 1H NMR (300MHz, DMSO): 8.68 (1H, d), method: 5, RT: 3.02min, 8-56(1H, dd), 8.38 (lH, MI: 434 [M+1] s), 7.89 (1H, m), 7.24 (5H,m) 4.35 (2H, s), 3.67 (2H, m), 3.25 (2H, m), 2.77 (1H, m), 2.58 (1H, 1H NMR (300MHz, MeOD): 8.62 (d, 1H), 8.53 (d, method: 5, RT: 3.55min, 1H)» 8-47 (8» 1H)» 8-20 MI'474[M+1] (S, 1H), 7.98011, 1H), 7.31 (m, 5H), 4.62 (s, 2H), 3.95 (m, 2H), 3.74 (m, 1H), 3.02 (d, 2H), 255 (m 2H) 235 (m 1H NMR (300 MHz DMSO) 8.68 (d,1H), 8.53 (d,1H), method: 5, RT: 3.32min, 8.35 (s,lH), 7.84 MI: 448 [M+l] (dd,1H), 7.25 (m, 5H), 4.62 ,3.7l (m,lH), 3.45 (m,2H), 2.80 —304_ - Terminal alkyne SM Charactensanon. .

[G- 1 3 6] II6 1H NMR (300, MHz, : LC-MS 1 5QC, RT: DMSO): 8.68 (d,1H), 8.53 (d,1H), 8.31 (s,1H), .58m111, MI: 462 [M+1] 7.91 (t,1H), 7.25 (m,5H), 3.68 (m,1H), 2.75 (m,2H) 2.60 1HNMR(DMSO, 300MHz). 8.77(1H, s, b1), 8.68 (2H, d), 8.37 method: 6, RT: 4.87mi11, (1H, s, b1), 8.29 (1H, s), MI: 444 [M+1] 8.00 (2H, d), 7.36(5H, m), 3.93 (1H, d, b1), 3.50 (2H, m), 2.93 (1H, dd), 2.82 (1H, m), 1.53 (6H, method: 5, RT: 4.01mi11, MI: 442 [M+1] V/ : 5, RT: 3.41mm, MI: 426 [M+1] 1H NMR (DMSO, 300 MHz) 8.75 (2H, s, b1), 1Hﬁifli‘écﬁf1’ﬁi2'84mm’ 8.37 (1H, t), 8.30 (1H, s), 8.13 (2H, s, b1), 7.39 (5H, m), 4.70 (1H, q), 3.93 (1H, dd), 3.65 (2H, m), 3.13 (1H, dd), 1.45 (3H, d) 1H NMR (DMSO, 300MHz) 8.75 (2H, d), 8.66 (1H, d), 8.35 (2H, method: 5, RT: 2.10mi11, ] d), 4.98 (1H, m), 3.60 MI: 380 [M+1] (1H, m), 3.31 (2H, m), 2.35 (2H, m), 2.12 (2H, 1H NMR (DMSO, ) 8.68 (2H, d), 8.37 (1H, s), 8.01 (2H, method: 5, RT: 2.59mi11, - ] I d), 7.36 (5H, m), 4.40 MI: 416 [M+1] (2H, s), 3.95 (2H, m), 3 4.9 (2H, m), 2.95 (1H, I 1H NMR (DMSO, 300MHz) 8.69 (2H, d), 8.27 (1H, s, b1), 8.21 method: 5, RT: 2.16mi11, (1H, s), 8.11 (2H, d), MI: 443 [M+1] 7.33—7.26 (5H, m), 3.82 (1H, m), 3.30 (2H, m), 2.71 (2H, m), 1.44 (6H, Terminal alkyne SM terlsanon. .

[G- 1 3 6] 1H NMR (DMSO, 300MHz): 8.75 (2H, d), H 8.59 (1H, s), 8.34 (2H, method: 5, RT: 1.83min, d), 4.91 (1H, m), 4.70 > .0S MI: 366 [M+1] (1H, m), 3.46 (1H, m), 3.23 (1H, m) 3.16 (1H, m), 2.27 (1H, m), 2.07 2H, m 1.46 , 3H, d 1H NMR (DMSO, 300MHz): 8.68 (2H, d), H 8.46 (1H, s), 8.24 (1H, method: 5, RT: n, [336 ] % s), 8.05 (2H, d), 7.33 MI: 428 [M+1] (5H, m), 3.89 (1H, m), 2.91 (1H, m), 2.81 (1H, m), 1.29 (3H, s), 1.27 (3H, s) H/// method 6, 4.79 min, 398 [M+H] 1H NMR (DMSO, H 300MHz): 8.69 (2H, d), method: 5, RT: 3.48min, 8.36 (1H, s), 8.05 (2H, V d), 7.35-7.29 (5H, m), MI: 458 [M+1] / 3.87 (1H, m), 3.45 (3H, s), 2.79-2.71 (2H, m), 1.53 6H, s 1H NMR (DMSO, 300MHz): 8.68 (2H, d), 8.47 (1H, s), 8.32 (1H, H s), 8.27 (1H, s), 8.05 é method: 5, RT: 3.17min, (2H, d), 7.35—7.29 (5H, MI: 444 [M+1] 0H m), 4.48 (1H, t), 3.88 (1H, 61, br), 3.41 (2H, m), 2.89—2.77 (2H, m), 1.77- 1.67 (2H, m), 1.08 (3H, (DMSO,300MHZ): 8.67 (2H, d), 8.51 (1H, s, br), 8.31 (1H, s), 8.05 (2H, H d), 7.36-7.28 (5H, m), method. 6, RT. 6.22m11’1, é 4.40 (1H, dd), 3.89 (1H, MI: 486 [M+1] m), 3.42 (2H, m), 2.81 (2H, m), 1.72 (2H, m), 1.43 (1H, m), 1.31 (2H, m), 1.04 (3H, m), 0.89 (3H, t) /Hé method: LC—Ms15QC, RT: .80min, MI: 458 [M+1] method: 5, RT: 3 .60min, MI: 472 [M+1] : 5, RT: 3 .70min, MI: 472 [M+1] 1H NMR (DMSO,300 MHZ): 8.67 (2H, d), 8.52 (1H, s, br), 8.30 (1H, s), 8.26 (1H, s), 8.03 (2H, method: 5, RT: 3 .46min, d), 7.38-7.31 (5H, m), MI: 458 [M+1] 4.54 (1H, t), 3.90 (1H, m), 3.49 (2H, m), 2.90- 2.81(2H, m), 1.71-1.56 (4H, m), 0.97 (3H, s) 1H NMR (DMSO,300 MHZ): 8.02 ( dd,1H), 8.21 (bs,1H), 8.70 (d,1H), 8.55 (d,1H), 8.47 method: 5, RT: 2.44min, (s,1H), 4.64 (q,1H), 3.88 MI: 384 [M+1] (m,1H), 3.66 (m,2H), 3.12 (m,2H), 2.24 ( m,1H), 2.19 , 1.43 1H NMR (DMSO 300MHz). 8.,70(1H s, br), 8.68 (2H, d), 8.35 (1H, s), 8.29 (1H, s), method: 5, RT: 3 .48min, 8.00 (2H, d), 7.36-7.33 MI: 470 [M+1] (5H, m), 3.93 (1H, d, br), 3.46-3.41 (2H, m), 2.92 (1H, dd), 2.79—2.75 (1H, m), 2.00 1.90 (4H, m), 1H NMR (DMSO 300MHz). 9.0,6(1H s, br), 8.67 (2H, d), 8.64 (1H, m), 8.60 (1H, s), 8.38 (1H, s), 8.01 (2H, method: 5, RT: 3 .27min, d), 7.89 (1H, t), 7.72 MI: 463 [M+1] (1H, d), 7.47—7.34 (6H, m), 4.02—3.97 (1H, m), 3.59—3.50 (2H, m), 3.03(1H, dd), .77 1H NMR (DMSO 300MHz). 8.83 (1H, s, br), 8.67 (2H, d), 8.54 method: 5, RT: 4.00min, (1H, s), 8.37 (1H, s), MI: 480 [M+1] 8.04 (2H, d), 7.71 (1H, t), 7.53-7.48 (1H, m), 7.41-7.28 (6H, m), 3.97— 3.94 1H,m,3.50-3.46 (2H, m), 2.95 (1H, dd), 2.84-2.77 (1H, m) 1H NMR (DMSO,300 MHZ): 8.79 (1H, s, br), 8.67 (2H, d), 8.28 (3H, d), 7.98 (2H, d), 7.40- method: 5, RT: 2.67min, 7.34 (5H, m), 3.97 (1H, MI: 430 [M+1] d, br), 3.64 (2H, t), 3.54- 3.48 (2H, m), 3.01 (1H, dd), 2.84 (1H, m), 2.63 1H NMR (DMSO,300 MHz). 8.69 (2H, d), 8.39 (1H, s), 8.28 (2H, d), 8.06 (2H, d), 7.35-7.28 method: 5, RT: 2.89min, (5H, m), 6.41 (1H, s, br), MI: 442 [M+1] 3.86 (1H, m), 2.86 (2H, m), 2.78-2.72 (2H, m), 1.13 (2H, t), 1.04 (2H, 1H NMR (DMSO,300 MHZ): 8.85 (1H, s, br), 8.67 (2H, d), 8.33 (1H, s), 8.29 (2H, s, br), 7.98 method: 5, RT: 2.74min, (2H, d), 7.41-7.36 (5H, MI: 430 [M+1] m), 4.68 (1H, q), 3.97 (1H, d, br), 3.62-3.51 (2H, m), 2.93 (1H, dd), 2.84 (1H, dd), 1.45 (3H, 1H NMR (DMSO,300 MHZ): 8.87 (1H, s, br), 8.67 (2H, d), 8.33 (1H, s), 8.29 (2H, s, br), 7.97 method: 5, RT: 2.76min, (2H, d), 7.41-7.36 (5H, MI: 430 [M+1] m), 4.68 (1H, q), 3.97 (1H, d, br), 3.64-3.52 (2H, m), 2.93 (1H, dd), 2.84 (1H, dd), 1.45 (3H, 1H NMR (DMSO, ): 8.76 (1H, s, br), 8.67 (2H, d), 8.35 (2H, s), 8.25 (1H, s), : 5, RT: 2.84min, 7.99 (2H, d), 7.39-7.32 MI: 444 [M+1] (5H, m), 3.96 (1H, d, br), 3.61 (2H, t), 3.51-3.46 (2H, m), 2.97 (1H, dd), 2.82 (1H, dd), 2.55 (2H, 2012/065831 Terminal alkyne SM Characterlsanon. .

[G-136] 1H NMR H (DMSO,300MHZ): 8.77 (1H, s ,br), 8.66 (2H, d), 8.30 (2H, s, br), 8.26 method: 5, RT: 2.93min, (1H, s), 7.98 (2H, d), MI: 444 [M+1] 7.40—7.34 (5H, m), 3.96- 3.90 (2H, m), 3.60-3.49 (2H, m), 3.00 (1H, dd), 2.86—2.82 (1H, m), 2.63 1H, dd 1.29 , 3H, d 1H NMR (DMSO,300 MHZ): 8.68 (2H, d), 8.24 e é (2H, s, br), 8.09 (2H, d), method: 5, RT: 3.08min, 7.32—7.25 (5H, m), 4.67 MI: 458 [M+1] (1H, s), 3.80 (1H, d, br), OH 3.28 (2H, m), .67 (2H, m), 2.58 (2H, s), 1.34 6H, s . 1H NMR (DMSO, 300 MHZ): 8.67 (2H, d), 8.31 f (2H, s), 8.01 (2H, d), method: 5, RT: 1.44min, 7.38-7.31 (5H, m), 3.93 / MI: 429 [M+1] (1H, d, br), 3.63 (2H, s), boc 3.48-3.40 (2H, m), 2.93 (1H, dd), 2.80 (1H, dd), 2.45 3H, s 1H NMR (MeOD, 300MHz): 8.61 (2H, d), 8.25 (2H, d), 8.10 (1H, H s), 7.37-7.27 (5H, m), method: 5, RT: 3.18min, 4.01-3.98 (1H, m), 3.58- OH MI: 456 [M+1] 3.52 (2H, m), 2.86 (2H, dd), 2.65—2.55 (2H, m), 2.42—2.32 (2H, m), 1.99- 1.92 2H, m 1H NMR (MeOD, 300 MHz): 8.58 (2H, d), 8.35 (2H, s), 8.13 (2H, d), 8.03 (1H, s), 741—735 method: 5, RT: 6.43min, [BB-34] (5H, m), 4.13 (1H, dd), MI: 444 [M+1] 4.05 (1H, q), 3.92—3.89 OH (1H, m), 3.70 (1H, dd), 3.11 (1H, dd), 3.00 (1H, dd), 2.66 (2H, d), 1.41 3H, d 1H NMR (MeOD, 9 ): 8.65 (2H, dd), / 8.29 (1H, s), 8.25 (2H, / method: 5, RT: 2.82min, dd), 7.41-7.35 (5H, m), MI: 386 [M+1] 4.09 (1H, dd), 3.86 (1H, s), 3.76-3.63 (2H, m), .97 2H, d h 1H NMR (DMSO, \l. 300MHz): 8.66 (2H, d), / method: 5, RT: 2.98min, 8.54 (1H, s, br), 8.31 MI: 400 [M+1] (2H, s), 8.04 (2H, d), 7.93 (1H, s), 7.34 (5H, m) 673 (1H t) 535 (2H, d), 3.80 (2H, m), 3.50 (2H, m), 2.99 (1H, dd), 2.65 (1H, dd) method: 5, RT: 2.77min, MI: 452 [M+1] C Li-Mei Wei, Li-Lan Wei, Wen-Bin Pan and Ming-Jung Wu Tetrahedron Letters, 2003 vol. 44, , p. 595 — 597 Emme, Ingo; Bruneau, ian; Dixneuf, Pierre H.; Militzer, Hans-Christian; Meijere, Armin de; Synthesis, 2007 vol. 22 , p. 3574 — 358 e Dinges, Juergen; Albert, Daniel H.; Arnold, Lee D.; th, Kimba L.; Akritopoulou-Zanze, Irini; Bousquet, Peter F.; Bouska, Jennifer J .; Cunha, George A.; en, Steven K.; Diaz, Gilbert J .; Djuric, Stevan W.; et al.

Journal of Medicinal Chemistry, 2007 vol. 50, No. 9 , p. 2011 — 2029 f Bradbury, Barton J .; Baumgold, Jesse; Jacobson, Kenneth A.

Journal of Medicinal Chemistry, 1990 vol. 33, No. 2 , p. 741 — 748 g Derived from TBDMS protected acetylene. h Derived from TMS protected acetylene.

General synthesis of ﬂuoro-alkynyl—7—4PT32P derivatives of general formula [G-134], e B10) The 7-Bromosubstitutedamino(3-substituted-pyridinyl)-thieno[3 ,2- d]pyrimidine derivative of general formula [G-119] was involved in a Sonogashira coupling reaction utilising a suitable terminal propargylic or homopropargylic l, of general formula [G-136], in the presence of (I)iodide with Pd(PPh3)2C12 as st, triphenylphosphine as ligand, and a base such as Eth, or DEA in a polar t such as DMA or DMF at a high temperature either by heating thermally or using a microwave reactor. After on work up, typically by a liquid-liquid extraction or puriﬁcation by acidic ion ge catch-release, the intermediate was purified by column chromatography to give the acetylenic intermediate. This was involved in a ﬂuorination reaction utilising ylamino)sulfur triﬂuoride in a chlorinated solvent such as chloroform or DCM at low temperature. After reaction work up, typically by a liquid- liquid extraction, the N—Boc derivatives were deprotected under acidic conditions with a strong acid such as TFA, HCl in a solvent such as DCM, DCE or 1,4-dioxane or by catch and release sulfonic acidic resins such as polymer supported toluene sulfonic acid and the crude reaction product was puriﬁed by reverse phase preparative HPLC. 2012/065831 Scheme B10 R1 3 '31 R3 . i) Pd(Ph3P)2C|2, PPh3, Cul, DEA 5 N R‘ﬁj‘kR2 2 DMA, MW, 15min, 150°C R R st 6 A R6 R _ XTH[GI-136] S / 12 S N / 12 7 R 7 N R R 13 R | —’ I 13 \ \ \ R \N R N \ \ I Br | ii) DAST, CHCI3, 0 °C / N / N // R15 R14 X R14 [G-1 19] [6-134] Synthesis of (S)—N* l *-[7-(3 -Fluoro-but- l -ynyl)pyridinyl-thieno[3 ,2-d]pyrimidin yl]-3 -phenyl-propane-l ,2-diamine [544] /\© i) Pd(Ph3P)2C|2, PPh3, Cul, DEA HZNj/\© DMA, MW, 15min, 150°C HN \ I “00 OH / N/Jb' B. Eilﬁéik‘élf'r 0 °C // /N [BB-34] [544] A microwave vial was charged with [(S)-l-Benzyl(7-bromopyridinyl- thieno[3,2-d]pyrimidinylamino)-ethyl]-carbamic acid tert-butyl ester [BB-34] (100 mg, 0.185 mmol), (S)-(-)Butynol (59 uL, 0.740 mmol), Bis(triphenylphosphine)palladiumchloride (13 mg, 0.018 mmol), (I)Iodide (4 mg, 0.019 mmol), triphenylphosphine (10 mg, 0.036 mmol), diethylamine (0.28 ml, 2.686 mmol) and DMF (0.8 ml). The reaction mixture was heated under microwave irradiation then the crude product isolated by liquid-liquid extraction and puriﬁed by column tography (0-5% MeOH:DCM) to provide the desired propargylic alcohol which was dissolved in CHC13 (2 ml) and cooled to 0 oC DAST (100 ul, 0.82 mmol) was edded and the mixture stirred for 2 hours at 0 CC. The reaction mixture was quenched with ice, basiﬁed with NaHC03 and the crude t extracted into DCM, then loaded onto a phase separation cartridge. The DCM solution was cooled to 0 °C and TFA added. After 2 hours the reaction mixture was loaded onto an SCX cartridge and washed with MeOH then the product eluted with 2M ammonia / methanol. The a / methanol eluent -3ll- was concentrated under reduced pressure and the crude product was puriﬁed by preparative HPLC (method A) to yield the title compound.

LCMS method: 5, RT: 3.32 min, MI: 432 [M+1]. 1H NMR (DMSO, ): 8.87 (1H, s, br), 8.67 (2H, d), 8.50 (1H, s), 8.28 (2H, s), 7.99 (2H, d), 7.39-7.33 (5H, m), 5.75 (1H, dq), 3.97-3.92 (1H, m), .45 (2H, m), 2.93-2.77 (2H, m), 1.68 (3H, dd).

The following compounds were prepared according to the general synthesis shown in scheme B10: Alkyne EX Characterisation [G-136] 1H NMR (DMSO, 300MHz): 8.68 (2H, d), 8.60 (1H, s, br), 8.53 (1H, s), 8.28 (1H, s), 8.03 (2H, d), 7.37- method: 5, RT: 7-30 (5H, m), 5.52 n, MI: 418 (1H, 8)» 5-37 (1H, s), [M+1] 3.90 (1H, d, br), 3.47— 3.39 (2H, m), 2.91— 2.75 (2H, m) 1H NMR (DMSO, 300MHz): 8.68 (2H, d), 8.32 (1H, s), 8.27 (1H, s), 8.03 (2H, d), 7.37-7.30 (5H, m), 4.71 (1H, t), 4.56 (1H, method: 5, RT: t), 3.88 (1H, d, br), 2.93min, MI: 432 3.46 (2H, m), 3.01 [M+1] (1H, t), 2.93 (1H, t), 2.84-2.78 (2H, m) Synthesis of 7 (S)Phenyl-N*1*—[2-pyridinyl-7—(3H-[1,2,3]triazol—4-yl)—thien0[3,2- d]pyrimidinyl]-pr0pane-1,2-diamine [547] (Scheme B11) Scheme B11 2012/065831 BocHNm HZNj/\© i) Pd(Ph3P)2C|2, PPh3, Cul, DEA HN DMA, MW, 15min, 150°C 8 \ N | :—SiMe3 \ \ / N/ N \ \ —» | ii) TMS azide, Cul, DMF, 100°C B N/ r | , N / N iii) TFA, DCM I / HN\N [BB-34] [547] Synthesis of (S)—3-Phenyl-N* l *-[2-pyridinyl(3H-[l ,2,3]triazolyl)-thieno[3,2- d]pyrimidinyl]-propane-l ,2-diamine [547] A microwave vial was charged with [(S)-l-Benzyl(7-bromopyridinyl- thieno[3,2-d]pyrimidinylamino)-ethyl]-carbamic acid utyl ester [BB-34] (60 mg, 0.114 mmol), (TMS)-acetylene (65 uL, 0.456 mmol), Bis(triphenylphosphine)palladiumchloride (9 mg, 0.012 mmol), copper (I) iodide (3 mg, 0.012 mmol), nylphosphine (7 mg, 0.024 mmol), diethylamine (0.2 ml) and DMF (0.8 ml). The reaction mixture was heated under microwave irradiation then the crude product isolated by liquid-liquid extraction.

To a d solution of the crude acetylene and copper (I) iodide (2mg, 0.006 mmol) in DMF (2ml) was added TMS azide (30 uL, 0.226 mmol) and the reaction mixture heated to 100 CC. After 18 hours the reaction mixture was loaded onto an SCX cartridge and washed with MeOH then the product eluted with 2M ammonia / methanol and evaporated. The crude product was dissolved in DCM (2ml) and TFA added (2ml), and after 5 hours the reaction mixture again loaded onto an SCX cartridge and washed with MeOH then the product eluted with 2M ammonia / ol. The ammonia / methanol eluent was concentrated under reduced pressure and the crude product was puriﬁed by ative HPLC (method A) to yield the title compound. LCMS method: 5, RT: 2.80 min, MI: 429 [M+l]. 1H NMR (DMSO, 300MHz): 8.78 (1H, s), 8.69 (2H, d), 8.53 (1H, s), 8.36 (1H, s, br), 8.10 (2H, d), 7.39-7.33 (5H, m), 3.95 (1H, m), 3.51 (2H, m), 2.95-2.93 (1H, m), 2.74 (1H, m).

General synthesis of aryl—ethynylsubstituted-4PT32P derivatives of general formula [G-138] (Scheme B12) The 7-Bromo-4PT32P derivative, of general formula [G-l 19], was involved in a Sonogashira coupling reaction utilising a protected acetylene, in the presence of -3l3- copper(I)iodide with 3)2Clg as catalyst, triphenylphosphine as a ligand, and a base such as Eth, or DEA in a polar solvent such as DMA or DMF at a high temperature either by heating thermally or using a microwave reactor. After on work up, typically by a liquid-liquid extraction or puriﬁcation by acidic ion exchange catch-release, the ted acetylene was deprotected using a le source of ﬂuoride such as TBAF, and then subjected to a second Sonogashira with the appropriate bromide, of l formula [G-l37]. After reaction work up, typically by a liquid-liquid extraction, the N-Boc derivatives were deprotected under acidic conditions with a strong acid such as TFA, HCl in a solvent such as DCM, DCE or l,4-dioxane or by catch and release sulfonic acidic resins such as polymer supported toluene sulfonic acid and the crude reaction product was puriﬁed by reverse phase preparative HPLC.

Scheme B12 1 1 R3 '3 R3 I? R4 Nsz i) Pd(Ph3P)2C|2, PPh3, Cul, DEA R4 N\R2 R5 DMA, MW, 15min, 150°C R5 6 A A _ R6 R _ TBDMS S S / / 7 N R12 7 N R12 R R \ | ’ 13 \ | R13 \N R \ ii) TBAF, THF,0°C N \ Br | | / N 15 /N R15 iii) Pd(Ph3P)2C|2, PPh3, Cul, DEA // R R _ 0 R14 DMA, MW, 15mm, 150 0, Ar [ca-119] Ar—Br [6-137] [G-138] sis of (S)—3-Phenyl-N* l *-(2-pyridinylthiazolylethynyl-thieno[3,2- d]pyrimidinyl)-propane-l ,2-diamine [548] BocHNm HZNj/\© i) Pd(Ph3P)2C|2, PPh3, Cul, DEA HN DMA, MW, 15min, 150°C | : TBDMS \ / Br | ii) TBAF, THF, 0 °c / N / N // iii) Pd(Ph3P)2C|2, PPh3, Cul, DEA DMA, MW, 15min, 150°C, / [BB-34] SJ [548] 8|§\ A microwave vial was charged with [(S)benzyl(7-bromopyridinyl- thieno[3,2-d]pyrimidinylamino)-ethyl]-carbamic acid tert-butyl ester [BB-34] (500 mg, 0.925 mmol), tert-butyldimethylsilylacetylene (700 uL, 3.7 mmol), bis(triphenylphosphine)palladiumchloride (65 mg, 0.093 mmol), copper (I) iodide (18 mg, 0.093 mmol), nylphosphine (50 mg, 0.186 mmol), diethylamine (0.2 ml) and DMF (0.8 ml). The on mixture was heated under microwave irradiation at 150 CC for 10 min then the crude reaction mixture was partitioned between (DCM:H20) and organic phase separated, dried (MgSO4), d and evaporated under reduced pressure. The crude reaction product was dissolved in THF (15ml), cooled to 0 OC and TBAF (1M in THF, 1.1ml, 1.06 mmol) added. After 3 hours the crude reaction mixture was partitioned between (DCM:H20) and organic phase ted, dried (MgSO4), ﬁltered and evaporated under reduced re and used crude in the second Sonogashira coupling. To the crude on product (100 mg, 0.2 mmol) was added 4-bromothiazole (74 ul, 0.84 mmol), dichlorobis(triphenylphosphine)-palladium(II) (15 mg, 0.021 mmol), PPh3 (11 mg, 0.042 mmol) ,CuI (4mg, 0.021 mmol) and diethylamine-DMF (1 :4, 1 ml) and then mixture was heated under microwave irradiation at 150 CC for 10 min. The crude reaction mixture was partitioned between (DCM:H20) and organic phase separated, dried (MgSO4), ﬁltered and evaporated under reduced pressure. The crude reaction product was dissolved in DCM (2 ml) and TFA (1 ml) was added and the mixture was stirred at room temperature for 2 hours then the reaction mixture was loaded onto an SCX cartridge and washed with MeOH then the product eluted with 2M ammonia / methanol. The ammonia / ol eluent was concentrated under reduced pressure and the crude product was puriﬁed by preparative HPLC (method A) to yield the title compound. LCMS method: 5, RT: 3.05 min, MI: 469 [M+1]. 1H NMR (MeOD, 300MHz) 9.08 (1H, d), 8.58 (2H, d), 8.28 (2H, d), 8.27 (1H, s), 8.00 (1H, d), 7.36-7.24 (5H, m), 3.97 (1H, dd), 3.54-3.47 (2H, m), 2.84-2.81 (2H, m).

The following compounds were prepared ing to the general synthesis shown in Scheme B12: Arylhalide Ex SM Characterisation. .

[G- l 3 7] 1H NMR (MeOD, 300MHz): 8.61 (2H, d), 8.44 (1H, s), 8.28 (1H, s), 8.23 (2H, d), 7.71 (1H, s), 7.42—7.38 (5H, : 5, RT: 3.03min, m)» 6-63 UH» S)» 4-15 MI: 452 [M+1] (1H, dd), 3.96-3.89 (1H, m), 3.73 (1H, dd), 3.14— 3.03 (2H, m).

General sis of 7-amido substituted-4PT32P derivatives of general formula [G- 139] (Scheme B13) The 7-bromo-4PT32P derivative, of general a [G-l 19], was involved in a carbonylation type reaction utilising a suitable amine, of general formula [G-l40], a carbonyl source such as molybdenum hexacarbonyl, a palladium catalyst such as cataCXium C, a ligand such as tri-tert-butylphosphonium uoroborate and a base such as DBU in a polar solvent such as dioxane at high temperature either by heating thermally or using a microwave reactor. After reaction work up, typically by a liquid- liquid extraction or puriﬁcation by acidic ion exchange release the crude reaction product was puriﬁed by reverse phase preparative HPLC Scheme B13 '3 1 R3 R3 II? R4 N\R2 Rx\ ,H R RR6R:i:‘R2 N [G-140] S / N R12 S 7 / R13 thxaa Ium HBF R7 \N R3 Mo(CO)6,DBU Dioxane,20min, 140°C [G-1 19] [G-139] Synthesis of 4-((S)Aminophenyl-propylamino)pyridinyl-thieno[3,2- d]pyrimidinecarboxylic acid dimethylarnide [550] -3l6- 2012/065831 MeZNH, CataCXium C, S \N tBu3PHBF4 \N \ I —> \ / / N \ N \ Br | Mo(CO)6, DBU, \N | Dioxane, 20min, 140°C / N / N / O

[550] A microwave vial was charged with (S)—N*1*-(7-bromomethylpyridinyl- thieno[3,2-d]pyrimidinyl)phenyl-propane-1,2-diamine [336] (50mg, 0.114 mmol), dimethylamine (2M in THF, 570111, 1.14 mmol), CataCXium C (10 mg, 0.010 mmol), tri- tert-butylphosphonium tetraﬂuoroborate (6 mg, 0.020 mmol), DBU (51 ul, 0.342 mmol), molybdenum hexacarbonyl (30mg, 0.114 mmol) and dioxane (0.5 ml). The reaction was heated to 1400C for 15 minutes under microwave irradiation. The e was then loaded onto a SCX-2 dge and washed with methanol. The product was released from the cartridge using a on of 2M a / methanol. The ammonia / methanol eluent was concentrated under reduced pressure and the crude product was puriﬁed by preparative HPLC (method B) to yield the title compound. LCMS method: 5, RT: 2.28 min, MI: 433 [M+1]. 1H NMR (300MHz, DMSO): 8.68 (2H, d), 8.26 (2H, s), 8.04 (2H, d), 7.31 (5H, m), 3.81 (1H, d, br), 3.33 (1H, m), 2.67 (3H, m), 1.29 (3H, s), 1.25 (3H, s).

The following compounds were prepared according to the general synthesis shown in Scheme B 1 3: Characterisation method:8, RT: 3.59 min, MI: 447 [M+1] method:8, RT: 552 2.80 min, MI: 461 [M+1] method: 6, RT: 553 5.12 min, MI: 419 [M+1] -3l7- 8 , 8.77 (s,1H).8.72 (d,2H), 8.2 (s,1H), 7.33 method:5, RT: (m,5H), 3.91 554 3.32min, MI: 433 (m,2H), 3.48 [M+1] (m,2H), 3.42 (m,1H), 2.88 (m,2H), 1.27 (t,3H) 1H NMR (300MHz, DMSO): 8.76 (s,1H)., 8.73 , 8.26 (s,1H), 7.97 method:5, RT: (d,2H), 7.34 555 3.64min, MI: 447 (m,5H), 4.11 [M+1] (sep,1H), 3.91 (m,2H), 3.48 (m,2H), 3.42 (m,1H), ,6H) 1H NMR (300MHz, DMSO): 8.72 (d,2H), 8.29 (s,1H), 7.89 (d,2H), 7.33 :5, RT: (m,5H), 3.90 556 3.43min, MI: 445 (m,1H), 3.47 [M+1] (m,2H), 2.95 (m,2H), 2.76 (m,1H), 0.85 (m,2H), 0.65 (m,2H) 1H NMR (300MHz, DMSO): 8.73 (s,1H).8.70 (d,2H), method:5, RT: 8.27 , 7.99 3.95min, MI: 461 (d,2H), 7.31 [M+1] (m,5H), 3.86 (m,1H), 3.42 (m,2H), 2.81 (m,2H), 1.49 (s,9H) Synthesis of (E)[4-((S)Arninopheny1—propy1arnino)pyridiny1—thieno[3,2- d]pyrirnidiny1]—acry1ic acid tert-butyl ester [558] (Scheme B14) S \ \ N —> N/ N \ / Br | O / N OH [BB-34] [558] A microwave vial was charged with [(S)Benzyl(7-bromopyridinyl- thieno[3,2-d]pyrimidinylamino)-ethyl]-carbamic acid tert-butyl ester [BB-34] (50mg, 0.091 mmol), tert-butyl acrylate (27ul, 0.182 mmol), palladium acetate (2 mg, 0.009 mmol), tri-tert-butylphosphonium tetraﬂuoroborate (3 mg, 0.010 mmol), sodium acetate (15mg, 0.182 mmol) and DMF (1 ml). The reaction was heated to 1500C for 30 minutes under microwave irradiation. The mixture was then loaded onto a SCX-2 cartridge and washed with ol. The product was released from the cartridge using a solution of 2M a / methanol. The ammonia / methanol eluent was concentrated under reduced pressure and the crude product was dissolved in DCM (2 ml) and TFA (1 ml) was added and the e was stirred at room temperature for 1 hour. After completion the mixture was loaded onto a SCX-2 cartridge and washed with ol. The product was released from the cartridge using a solution of 2M ammonia / methanol. The ammonia / methanol eluent was concentrated under reduced re and the crude product was puriﬁed by preparative HPLC (method B) to yield the title compound. LCMS method: 5, RT: 2.98 min, MI: 432 [M+1]. 1H NMR (300MHz, DMSO): 8.84 (1H, s, br), 8.65 (2H, d), 8.53 (1H, s), 7.94 (2H, d), 7.78 (1H, d, J = 15Hz), 7.34 (5H, m), 7.25 (1H, d, J=15Hz), 3.94 (1H, d, br), 3.62 (2H, m), 3.01 (1H, dd), 2.85 (1H, m).

Synthesis of (7-Ethynylpyridinyl-thieno[3,2-d]pyrimidinyl)-(R)-pyrrolidinyl- amine (559) (Scheme B15) HN HN \3 \N | i) Pd(Ph3P)4, MW, EtOH,15min,150 °C \3 \N N \ \ | ii) TBAF, C N Br | /N // /N

[559] A microwave vial was charged with (7-Bromopyridinyl-thieno[3,2- d]pyrimidinyl)-(R)-pyrrolidinyl-amine [351] (70mg, 0.186 mmol), 2-[(tert-Butyl- dimethyl-silanyl)-ethynyl] boronic acid pinacol ester (100mg, 0.372 mmol), tetrakis (triphenyl phosphine) palladium (22 mg, 0.019 mmol), N32C03 (2M in water, 200ul, 0.4 mmol) and EtOH (1 ml). The on was heated to 150°C for 15 minutes under ave irradiation. The mixture was then loaded onto a SCX-2 cartridge and washed with methanol. The product was released from the cartridge using a solution of 2M ammonia / methanol. The ammonia / methanol eluent was concentrated under reduced pressure and the crude product ved in THF (2ml), cooled to 0 OC and TBAF (190ul, 1M in THF, 0.372 mmol) added. After 18 hours the reaction mixture was concentrated under reduced pressure and the crude reaction mixture was partitioned between (DCM:H20) and organic phase separated, dried (MgSO4), ﬁltered and evaporated under d pressure and the residue puriﬁed by preparative HPLC (method B) to yield to the title compound. LCMS method: 5, RT: 1.87 min, MI: 322 [M+1]. 1H NMR (DMSO, 300MHz): 8.59 (2H, d), 8.52 (1H, s), 8.45 (2H, d), 4.93 (1H, dd), 4.48 (1H, s), 3.68 (1H, m), 3.09 (1H, m), 2.49 (2H, m), 2.35 (1H, m), 2.16 (1H, m).

Synthesis of 4-((S)Aminophenyl-propylamino)pyridinyl-thieno[3,2- d]pyrimidinecarbonitrile (560) (Scheme B16) i) Cu(|)CN, DMA, 150 °C 8 \ N S \ N ——’.. \ l \ | u) TFA, DCM, 0 co N \ N \ | // / N B r I / N N [BB-34] [560] A round bottomed ﬂask was charged with [(S)Benzyl(7-bromopyridin yl-thieno[3,2-d]pyrimidinylamino)-ethyl]-carbamic acid tert—butyl ester [BB-34] (50mg, 0.093 mmol), copper cyanide (25mg, 0.279 mmol) and DMA (2 ml). The reaction was heated to 150°C for 18 hours. The crude on mixture was partitioned between (DCM:H20) and organic phase separated, dried ), ﬁltered and ated under reduced pressure to a volume of 2 ml. The mixture was cooled to 0 OC and TFA (2 ml) was added. After 18 hours the solution was loaded onto a SCX-2 cartridge and washed with methanol. The product was released from the cartridge using a solution of 2M a / methanol. The a / ol eluent was trated under reduced pressure and the crude t was puriﬁed by preparative HPLC (method B) to yield to the title compound. LCMS method: 5, RT: 2.75 min, MI: 387 [M+l].

Synthesis of (S)Phenyl-N* 1 * -(7-pyrazolylpyridinyl-thieno [3 ,2-d]pyrimidin yl)-propane-1,2-diamine (561) (Scheme B17) jA© HN Pyrazole, Cul, CSZCO3 s \ N \S \ I Nab | :N DMF, MW, 190 °c I :N w / N

[336] [561] A microwave vial was charged with (S)—N*1*-(7-Bromopyridinyl- thieno[3,2-d]pyrimidinyl)phenyl-propane-1,2-diamine [336] (50mg, 0.111 mmol), pyrazole (12 mg, 0.555 mmol), copper iodide (5 mg, 0.022 mmol), caesium carbonate (73 mg, 0.222 mmol) and DMF (1 ml). The reaction was heated to 190°C under microwave irradiation for 5 minutes. The solution was then loaded onto a SCX-2 cartridge and washed with methanol. The product was released from the cartridge using a solution of 2M ammonia / methanol. The ammonia / methanol eluent was concentrated under reduced pressure and the crude product was puriﬁed by preparative HPLC (method B) to yield to the title compound. LCMS method: 5, RT: 3.11 min, MI: 428 [M+l]. 1H NMR (DMSO) 8.71 (1H, d), 8.65 (2H, d), 7.95 (2H, d), 7.84 (1H, s), 7.76 (1H, s), 7.38 (5H, m), 6.68 (1H, t), 3.94 (1H, m), 3.57 (2H, m), 2.97 (1H, dd), 2.84 (1H, m).

Synthesis of (S)Phenyl-N* 1 yridinyl[1,2,3]triazolyl-thieno[3 ,2- midinyl)-propane-1 ,2-diamine (562) (Scheme B l 8) i) 1,2,3-Triazole, Cul, C32C03 2m OH DMF, MW, 240 °C HN S \ ..

H POCI 110 Co N \ I ——>)3, S \ \ |\N | ii)Amine, TEA, DMA B N/ \ / N I W’N /N N / [BB-20] [562] A microwave vial was charged with 7-bromopyridinyl-thieno[3,2- d]pyrimidinol [BB-20] (0.13g, 0.42 mmol), 1,2,3-triazole (56 mg, 0.811 mmol), copper iodide (6 mg, 0.033 mmol), caesium carbonate (106 mg, 0.324 mmol) and DMF (1 ml).

The reaction was heated to 240°C under microwave irradiation for 2 hours. The solution was then loaded onto a SCX-2 cartridge and washed with ol. The product was released from the cartridge using a solution of 2M ammonia / methanol. The a / methanol eluent was concentrated under reduced pressure and the crude product suspended in POC13 and heated to reﬂux. After 1 hour the on mixture was cooled, trated and azeotroped with toluene twice. The residue was basiﬁed with a 2M solution ofNaOH and the product extracted into DCM (x2). The combined organics were dried (MgSO4), ﬁltered and evaporated under reduced pressure. The crude product was dissolved in DMA (2 ml) and triethylamine (174 ul, 1.257 mmol) and Phenyl- propane-1,2-diamine (75mg, 0.503 mmol) was added. After 18 hours the solution was loaded onto a SCX-2 cartridge and washed with methanol. The t was released from the cartridge using a solution of 2M ammonia / methanol. The ammonia / methanol eluent was concentrated under reduced pressure and the crude product puriﬁed by preparative HPLC (method B) to yield to the title compound. LCMS method: 17, RT: 2.91 min, MI: 429 [M+1]. 1H NMR (300 MHz, DMSO) 9.23 (1H, s), 8.70 (2H, d), 8.69 (1H, s), 8.07 (2H, d), 8.04 (1H, s), 7.33 (5H, m), 3.92 (1H, m), 3.45 (2H, m), 2.82 (2H, m).

Synthesis of (S)-N*1*-[7-(2-Cyclopropyl-ethyl)pyridinyl-thieno[3,2-d]pyrimidin yl]phenyl-propane-1,2-diamine (563) (Scheme B19) H2N H2N l l l I>—\ o \ B, l I l HN ‘o HN s \ N i) Pd(Ph3P)4, MW, EtOH, 15min, 150 °C \ N \ | \8 | / / N \ | ii) H2, Pd/C (5%), EtOH, HCOOH, 50 °c N \ Br | / N / N

[563] A microwave vial was d with (S)—N*1*-(7-Bromopyridinyl- thieno[3,2-d]pyrimidinyl)phenyl-propane-1,2-diamine [336] (50mg, 0.114 mmol), transcyclopropylvinylboronic acid pinacol ester (44mg, 0.228 mmol), tetrakis (triphenyl phosphine) palladium (13 mg, 0.011 mmol), N32C03 (2M in water, 200ul, 0.4 mmol) and EtOH (1 ml). The reaction was heated to 150°C for 15 minutes under microwave irradiation. The mixture was then loaded onto a SCX-2 cartridge and washed with methanol. The product was released from the cartridge using a solution of 2M ammonia / methanol. The a / ol eluent was concentrated under d pressure and the crude product taken up in EtOH, Pd/C (5%, 10 mg) added followed by a few drops of formic acid and the reaction mixture stirred under an atmosphere of hydrogen at 50 °C for 18 hours. The suspension was d through celite, concentrated under reduced pressure and puriﬁed by preparative HPLC (method B) to yield to the title compound. LCMS method: 5, RT: 4.23 min, MI: 430 [M+1]. 1H NMR (DMSO, 300MHz) 8.66 (2H, d), 8.41 (1H, s), 8.34 (1H, s), 8.02 (2H, s), 7.79 (1H, d), 7.35 (5H, m), 3.92 (1H, m), 3.49 (2H, m), 2.91 (4H, m), 1.63 (2H, m), 0.76 (1H, m), 0.40 (2H, m), 0.06 (2H, m). sis of (S)—N* 1 *-[7-Bromo(1-oxy-pyridinyl)-thieno[3 ,2-d]pyrimidinyl]-3 - phenyl-propane-1,2-diamine (564) (Scheme B20) BocHNm m i) mCPBA, DCM, 0 °C 3 \ N S \ —..——’ \ I \ | /N II)TFA,DCM N/ \ N \ Br I I /N: 7 Br O [5641 [BB-34] To a stirred suspension of [(S)benzyl(7-bromopyridinyl-thieno[3,2- d]pyrimidinylamino)-ethyl]-carbamic acid tert-butyl ester [BB-34] (100mg, 0.185 W0 78126 mmol), in DCM (2ml) at 0 CC was added mCPBA (35mg, 0.204 mmol). After 18 hours the reaction diluted with DCM (10 ml) and the e washed with saturated solution of Na2S03 (2 x 10 ml) then H20 (10 ml) and ﬁnally brine (10 ml), dried (MgSO4), ﬁltered and evapourated under reduced pressure and the crude product was puriﬁed by column chromarography (0-5% MeOH:DCM) to provide the desired reaction intermediate. This was taken up in 4N HCl in dioxane (2 ml) and stirred at room temeperature for 2 hours.

The crude reaction mixture was loaded onto a SCX-2 dge and washed with methanol.

The t was released from the cartridge using a solution of 2M ammonia / methanol.

The ammonia / methanol eluent was concentrated under reduced re and the crude product was puriﬁed by preparative HPLC (method B) to yield to the title compound.

LCMS method: 5, RT: 2.81 min, MI: 456-458 [M+l]. 1H NMR (MeOD, 300MHz) 8.53 (1H, s), 8.31 (q, 4H), 8.10 (1H, s), 7.38-7.31 (5H, m), 4.06-4.03 (1H, m), 3.64-3.60 (1H, m), 3.31-3.29 (1H, m), 2.93 (2H, m).

Synthesis of (S)—N* 1 *-[2-(1-Oxy-pyridinyl)(2H-pyrazolyl)-thieno[3 ,2- d]pyrimidinyl] phenyl-propane- 1 ,2-diamine (5 65) (Scheme B21) BOCHNj/\© HzNjA© HN HN i) mCPBA, DCM, 0 °C S \N 8 ii) Pd(Ph3P)4, MW, EtOH,15min,150 °C \N \ | | / \ / N \ ,OH N \ Br I HN/N @—\ I + /N B \OH E \ /N\O, ”') TFA, DCM [BB-34] [565] To a stirred suspension of [(S)benzyl(7-bromopyridinyl-thieno[3,2- d]pyrimidinylamino)-ethyl]-carbamic acid tert-butyl ester ] , 0.37 mmol), in DCM (2ml) at 0 CC was added mCPBA (70mg, 0.408 mmol). After 18 hours the on was diluted with DCM (10 ml) and the mixture washed with saturated solution of Na2S03 (2 x 10 ml) then H20 (10 ml) and ﬁnally brine (10 ml), dried (MgSO4), ﬁltered and evapourated under d pressure. To the crude reaction product was added 1H- Pyrazoleboronic acid (50mg, 0.444 mmol), Pd(PPh3)4 (43mg, 0.037 mmol), N32C03 (2M in water, 200ul, 0.4 mmol) and EtOH (2 ml) and the mixture was heated to 150°C for minutes under microwave irradiation. The mixture was then loaded onto a SCX-2 cartridge and washed with methanol. The product was released from the cartridge using a solution of 2M ammonia / methanol. The ammonia / methanol eluent was concentrated —324— under reduced pressure. This was suspended in 4N HCl:dioxine (2 ml) and stirred at room temeperature for 18 hours. The ion mixture was evaporated under reduced pressure and the residue dissolved in MeOH, loaded onto a SCX-2 cartridge and washed with methanol. The product was released from the cartridge using a solution of 2M ammonia / methanol. The ammonia / methanol eluent was concentrated under reduced pressure and the crude product was puriﬁed by preparative HPLC (method B) to yield to the title compound. LCMS method: 5, RT: 3.08 min, MI: 444 [M+l]. 1H NMR (DMSO, 300MHz) 8.38 (1H, s, br), 8.23 (2H, d), 8.07 (2H, d), 7.83 (1H, s), 7.35-7.29 (6H, m), 3.87 (1H, m), 3.48-3.45 (2H, m), 2.90-2.83 (2H, m).

General sis of 0-substituted 4PT32P derivatives of general formula [G- 143] (Scheme B22) 2-Pyridinyl-thieno[3,2-d]pyrimidinol, of general formula ], was involved in a chlorination reaction using phosphorus oxychloride, then nitrated at the 7- position using a combination of ﬁlming nitric acid and concentrated sulphuric acid, to give nds of general formula [G-l42]. The nitro group was subsequently reduced under a dissolving metal reduction using iron and hydrochloric acid, and ﬁnally reacted with an N—Boc protected primary or secondary amine derivative, of general formula [G-l 17], in a polar c solvent such as DMA, DMF, NMP in the presence of a tertiary amine base such as Eth, DIPEA or NMM at ambient temperature. After reaction work up, lly by a liquid-liquid extraction, the N—Boc derivatives were deprotected under acidic conditions with a strong acid such as TFA, HCl in a solvent such as DCM, DCE or l,4- dioxane or by catch and release sulfonic acidic resins such as r supported toluene sulfonic acid and the crude on product was puriﬁed by reverse phase preparative HPLC.

Scheme B22 OH .I) POCI3, E?N\R2 i) Fe, HCI, s / 7 N R12 80°C 8 EtOH, 40 °C R I R7\ / \ \ R13 —> R13 —> N \ \8 I II) HNO3, ii) Amine, TEA, DMA R15 / N H2804, 40 °c OzN [G-117] R14 iii) TFA, DCM [G 141]_ [G-142] [(3-1 43] Synthesis of 4-Chloronitropyridinyl-thieno[3,2-d]pyrimidine [BB-44] {iriG—ﬁii)HN03, HMSO 40°C 3 i)POCI3, 80°C \N [BB-20] ] dinyl-thieno[3,2-d]pyrimidinol [BB-20] (5g, 21 .8mmol) was heated to 80 0C in phosphorus oxychloride (50 ml) for 30 minutes. The reaction mixture was allowed to cool to room temperature then evapourated under reduced pressure and the crude product was zeotroped with toluene. The residue was trituration with a mixture of diethyl ether and 2N NaOH and the solid formed was was collected by ﬁltration and washed with water followed by ether to yield the title compound as a beige solid which was used in the next step without further puriﬁcation: LCMS method: 17, RT: 4.91 min, MI:248[M+1].

To a on of 4-Chloropyridinyl-thieno[3,2-d]pyrimidine (4g, 15.9 mmol) in sulphuric acid (10ml) was added nitric acid (lml) and the reaction mixture heated to 40 0C. After 2 hours the solution was cooled to 0 0C then added to vigorously stirred ice- water, and the resulting precipitate was collected by ﬁltration and washed with water to yield the title compound as a yellow solid which was used in the next step without further puriﬁcation: LCMS method: 5, RT: 4.54 min, MI: 293 [M+l]. 1H NMR (DMSO, 300MHz) 9.83 (1H, s), 9.01 (2H, d), 8.65 (2H, d).

Synthesis ofN*4*-((S)Aminophenyl-propyl)pyridinyl-thieno[3,2- d]pyrimidine-4,7-diamine [566] \3 \N | I) Fe HCI EtOH 40°C N/ \ | II) Amine TEA DMA O2N xN A DCM [BB-44] [566] To a stirred suspension of 4-chloronitropyridinyl-thieno[3,2-d]pyrimidine [BB-44] (1g, 3.42 mmol) and iron powder (770mg, 13.7mmol) in EtOH (20ml) at 40 CC was added concentrated HCl (20ml) dropwise. After 20 minutes the reaction mixture was loaded onto a SCX-2 cartridge and washed with methanol. The product was released from the cartridge using a solution of 2M ammonia / methanol. The ammonia / methanol eluent was concentrated under reduced pressure to give a brown solid. LCMS method: 18, RT: 3.38 min, MI:263[M+1].

To a solution of 4-Chloroaminopyridinyl-thieno[3,2-d]pyrimidine (130 mg, 0.476 mmol) in DMA (1 ml) was added ((S)Aminobenzyl-ethyl)-carbamic acid tert-butyl ester (143 mg, 0.571 mmol) followed by triethylamine (200 ul, 1.43 mmol), and the mixture stirred at room temperature for 18 hours. The crude on mixture was partitioned between (DCM:H20) and organic phase ted, dried (MgSO4), ﬁltered and ated under reduced pressure and the crude product was loaded onto a phase separation dge and washed with methanol. The product was released from the cartridge using a solution of 2M ammonia / methanol. The ammonia / methanol eluent was concentrated under reduced pressure to give a brown solid. The crude reaction product was dissolved in DCM (2 ml) and TFA (2 ml) was added and the mixture was stirred at room temperature for 1 hour then the mixture was loaded onto a SCX-2 dge and washed with methanol. The t was ed from the cartridge using a solution of 2M ammonia / methanol. The ammonia / methanol eluent was concentrated under d pressure and the crude product was puriﬁed by preparative HPLC (method A) to yield the title compound. LCMS method: 6, RT: 4.62 min, MI: 377 [M+l]. 1H NMR (DMSO) 8.67 (2H, d), 8.16 (2H, d), 7.92 (1H, s), 7.28 (5H, m), 6.49 (1H, s), 5.29 (2H, s, br), 3.79 (1H, m), 3.28 (2H, m), 2.69 (2H, m).

The following compounds were prepared according to the general synthesis shown in Scheme B22: Amine Example SM Characterisation. .

[G- 1 17] 567 [BB-44] (RS—7 .

AnN : 6, RT: 3.90 111111, MI: 313 [M+1] General synthesis of 7-heteroaryl-substituted 4PT32P derivatives of general a [G-145] (Scheme B23) 2012/065831 The 7-bromo-substituted 4PT32P tive, of general formula [G-l 19], was involved in a Heck type reaction utilising a suitable oleﬁn, of general formula [G-l46], a palladium catalyst such as palladium acetate, a ligand such as tri-t-butyl phosphonium tetrafluoroborate and a base such as sodium acetate in a polar solvent such as DMF at high temperature either by heating thermally or using a microwave reactor. The generated oleﬁn derivative, of general formula [G-l44], was then cyclised using either para- toluenesulfonylhydrazide or N—hydroxyltoluenesulfonamide to e either the corresponding pyrazole or isoxazole respectively. After reaction work up, typically by a liquid-liquid extraction, the N—Boc derivatives were deprotected under acidic conditions with a strong acid such as TFA, HCl in a t such as DCM, DCE or l,4-dioxane or by catch and release sulfonic acidic resins such as polymer supported toluene sulfonic acid and the crude reaction t was purified by e phase preparative HPLC Scheme B23 1 1 R3 E R3 B R4 ‘R2 RXCHZCH2,Pd(OAc)2, R4 “\R2 R5 tBu3PHBF4 R6 A s [G-146] 7 N R12 R12 R \ I ’ \ R13 13 N \ NaOAc,DMF, R Br | 30min,150°C I R15 /N /N R14 R14 [G-1 19] ] i) N-hydroxyItoluenesulfonamide para-toluenesulfonylhydrazide EtOH,8OC ii) TFA, DCM [G-145] Synthesis of (E)[4-((S)—2-Arninopheny1—propy1arnino)pyridiny1—thien0[3,2- d]pyrirnidiny1]—acrylic acid tert-butyl ester [BB-45] ﬂ/OIO ﬂ/onfo mm HNj/\© S \ N i) 1-butenone, Pd(OAc)2, tBuaPHBF4 \ N \ | / NaOAc, DMF, 30min, 150°C / N \ \ Br | | / N / N [BB-34] [BB-45] A microwave Vial was charged with -Benzy1—2-(7-br0rnopyridiny1— thien0[3,2-d]pyrirnidiny1arnin0)-ethyl]-carbarnic acid tert-butyl ester [BB-34] (50mg, 0.091 mmol), tert-butyl acrylate (27ul, 0.182 mmol), palladium acetate (2 mg, 0.009 mmol), tri-tert-butylphosphonium tetraﬂuoroborate (3 mg, 0.010 mmol), sodium acetate (15mg, 0.182 mmol) and DMF (1 ml). The reaction was heated to 1500C for 30 minutes under microwave irradiation. The mixture was then loaded onto a SCX-2 cartridge and washed with methanol. The product was ed from the cartridge using a solution of 2M ammonia / methanol. The ammonia / methanol eluent was concentrated under reduced pressure and the crude product was d by preparative HPLC (method B) to yield the title compound. LCMS method: 5, RT: 2.98 min, MI: 432 [M+1]. 1H NMR z, DMSO): 8.84 (1H, s, br), 8.65 (2H, d), 8.53 (1H, s), 7.94 (2H, d), 7.78 (1H, d, J = 15Hz), 7.34 (5H, m), 7.25 (1H, d, J=15Hz), 3.94 (1H, d, br), 3.62 (2H, m), 3.01 (1H, dd), 2.85 (1H, m).

Synthesis of (S)-N*1*-[7-(5-Methyl-isoxazolyl)pyridinyl-thieno[3,2-d]pyrimidin- 3-phenyl-propane-1,2-diamine [568] \ﬁOYOHN j/\© HZN HN i) N-hydroxyl-4—toluenesulfonamide, s \N EtOH, 80°C 3 l \ N N/ —. \ \ / | ii) TFA, DCM N \ / /N | N/ /N o c', / [BB-45] [568] N-hydroxyltoluenesulfonamide (128 mg, 0.74 mmol) was added to a stirred suspension of (E)—3-[4-((S)Aminophenyl-propylamino)pyridinyl-thieno[3,2- d]pyrimidinyl]-acrylic acid tert-butyl ester [BB-45] (90mg, 0.166mmol) in l (2 ml) and the reaction mixture heated to 90°C. After 2 hours the mixture was loaded onto a SCX-2 cartridge and washed with methanol. The product was released from the cartridge using a solution of 2M ammonia / methanol. The ammonia / ol eluent was concentrated under reduced pressure and the crude product was dissolved in DCM (2 ml) and TFA (2 ml) was added and the mixture stirred at room temperature for 1 hour. After completion the mixture was loaded onto a SCX-2 cartridge and washed with ol.

The ammonia / methanol eluent was concentrated under reduced pressure and the crude product was puriﬁed by preparative HPLC d B) to yield the title compound. LCMS method: 5, RT: 3.36 min, MI: 443 [M+1]. 1H NMR (300MHz, DMSO): 8.70 (2H, d), 8.66 (1H, s), 8.50 (1H, s, br), 8.11 (2H, d), 7.33 (5H, m), 7.24 (1H, s), 3.89 (1H, m), 3.39 (2H, m), 2.77 (2H, m), 2.55 (3H, s).

The following compounds were ed according to the general synthesis shown in Scheme B23: Oleﬁn Ex SM Reactant Characterisation. .

[G- 146] [BB- para- 34] toluenesulfonylhydrazide [BB- N—hydroxyl 34] toluenesulfonamide . 1H NMR (300MHz, DMSO): 8.71 (2H, d), 8.35 : (1H, s), 8.26 (1H, s,br), [BB- para— 8.11 (2H, d), 3 4] toluenesulfonylhydrazide : 7 .3 8-7 .29 (5H, m), 7.09 (1H, s), 3.89 (1H, m), 2.82 (2H, m), 2.69 (2H, q), 1.27 (3H, t).

[BB- N—hydroxyl 34] toluenesulfonamide .

General synthesis of 2-Amin0-pyridyl-substituted-4PT32P derivatives of general formula [G-148], ], [G-150] & [G—151] (Scheme B24) The 2-chloropyridyl 4PT32P derivative of general formula [G-l47] was involved in a Buchwald type reaction utilising a suitable amine, of general formula [G-l33], a palladium catalyst such as Pd(dba)2 or )2, a ligand such as Xantphos and a base such as NaOtBu or C82C03 in a polar solvent such as dioxane or a combination of dioxane and DMA at high temperature either by heating thermally or using a microwave reactor, to yield aminopyridyl 4PT32P tive of l a [G-l48], method A.

After reaction work up, typically by a liquid-liquid extraction or puriﬁcation by acidic ion exchange catch-release, the intermediate was puriﬁed by column chromatography and the N—Boc tives were deprotected under acidic conditions with a strong acid such as TFA, HCl in a solvent such as DCM, DCE or l,4-dioxane or by catch and release sulfonic acidic resins such as polymer supported toluene sulfonic acid and the crude reaction product was puriﬁed by e phase preparative HPLC. The 2-chloropyridyl 4PT32P derivative of general formula ] was involved in a Buchwald type reaction utilising a suitable amide, of general a [G-152], a palladium catalyst such as Pd(dba)2 or Pd(OAc)2, a ligand such as Xantphos and a base such as NaOtBu or C82C03 in a polar solvent such as e or a combination of dioxane and DMA at high temperature either by heating thermally or using a microwave reactor, to yield aminopyridyl 4PT32P derivative of general formula [G-l49], method B. After reaction work up, typically by a -liquid extraction or puriﬁcation by acidic ion exchange catch-release, the intermediate was puriﬁed by column chromatography and the N—Boc derivatives were deprotected under acidic conditions with a strong acid such as TFA, HCl in a solvent such as DCM, DCE or 1,4-dioxane or by catch and release sulfonic acidic resins such as polymer supported toluene sulfonic acid and the crude reaction product was puriﬁed by reverse phase preparative HPLC. The 2-chloropyridyl 4PT32P derivative of general formula [G-l47] was involved in a ld type reaction ing a suitable urea, of general formula [G-153], a palladium catalyst such as Pd(dba)2 or Pd(OAc)2, a ligand such as 2-Dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl and a base such as NaOtBu or C82C03 in a polar solvent such as dioxane or a combination of dioxane and DMA at high ature either by heating thermally or using a microwave reactor, to yield aminopyridyl 4PT32P derivative of general formula [G-lSO], method C. After reaction work up, typically by a liquid-liquid extraction or puriﬁcation by acidic ion exchange catch-release, the intermediate was d by column chromatography and the N—Boc derivatives were deprotected under acidic conditions with a strong acid such as TFA, HCl in a t such as DCM, DCE or l,4-dioxane or by catch and release sulfonic acidic resins such as polymer supported toluene sulfonic acid and the crude reaction product was puriﬁed by reverse phase preparative HPLC. The 2-chloropyridyl 4PT32P derivative of general formula [G-l47] was involved in a Buchwald type reaction utilising a le sulfonamide, of general a [G-154], a palladium catalyst such as Pd(dba)2 or Pd(OAc)2, a ligand such as 2-Dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl and a base such as NaOtBu or C82C03 in a polar solvent such as dioxane or a combination of dioxane and DMA at high temperature either by heating thermally or using a microwave reactor, to yield yridyl 4PT32P derivative of general formula [G-lS 1], method D. After reaction work up, typically by a liquid-liquid extraction or purification by acidic ion exchange catch-release, the intermediate was purified by column chromatography and the N-Boc derivatives were deprotected under acidic conditions with a strong acid such as TFA, HCl in a solvent such as DCM, DCE or l,4-dioxane or by catch and e sulfonic acidic resins such as polymer supported e sulfonic acid and the crude reaction product was purified by reverse phase preparative HPLC Scheme B24 MethodA R1 R3 N R4Rj: \R2 R6 A RXRyNH,Pd(dba)2, S / Xantphos,NaOtBu 7 N R12 R \ I 3] \ CI N \ —> R8 | MW, Dioxane—DMA, R15 / N 15min,150°C [G-147] MethodB R3 F51 4 N\ 2 R5Rj: R6 A RXCONH2,Pd(dba)2, S / 12 os, NaOtBu 7 N R \ I [G-152] \ CI R8 I MW, Dioxane—DMA, R15 / N 15min 150°C [G-147] MethodC 1 R3 F5 4 N\ 2 R R R5 RXRyNCONHZ, Pd(dba)2, SRB/A Xantphos, NaOtBu R12 [G-153] MW, Dioxane—DMA, 15min,150°C [G-147] Method D R3 F5 4 N\ 2 RR6Rj: A RXSOZNH2,Pd(dba)2, Xantphos, NaOtBu S 12 R7 R ] \ IN R \N C| R8 I ,5 ,N MW, Dioxane—DMA, R 15min, 150°C [G-147] [ca-151] MethodA —334_ WO 78126 Synthesis of Phenylamino-pyridinyl)-thieno[3,2-d]pyrimidinyl]-(R)-pyrrolidin- 3-yl-amine [573] HN (E) I) PhNHZ, Pd(dba)2, Xantphos, NaOtBu, HN S \N \ I MW, Dioxane-DMA, 15min, 150°C 8 N/ CI \ \ I .. / H I II) TFA, DCM N \ / N I [BB-32] [573] A microwave vial was charged with (R)[2-(2-Chloro-pyridinyl)-thieno[3,2- d]pyrimidinylamino]-pyrrolidinecarboxylic acid tert-butyl ester [BB-32] (50mg, 0.116 mmol), Aniline (22ul, 0.232 mmol), Pd(dba)2 (4 mg, 0.006 mmol), Xantphos (7 mg, 0.012 mmol), NaOtBu (23 mg, 0.232 mmol), DMA (few drops) and dioxane (1 ml). The reaction was heated to 150°C for 15 minutes under microwave irradiation. The reaction mixture was partitioned between DCM and saturated NH4Cl (50%) and the organic phase separated, dried (MgSO4), ﬁltered and evaporated under reduced pressure. The crude reaction product was dissolved in DCM (2 ml) and TFA (2 ml) was added and the e d at room temperature for 2 hours. The reaction mixture was loaded onto a SCX-2 cartridge and washed with methanol. The product was ed from the cartridge using a on of 2M ammonia / methanol. The ammonia / methanol eluent was concentrated under reduced pressure and the crude product was puriﬁed by preparative HPLC (method B) to yield the title compound. LCMS method: 5, RT: 2.16 min, MI: 389 [M+1]. 1H NMR (300MHz, DMSO): 9.40 (1H, s), 8.40 (1H, d), 8.36 (1H, s), 8.27 (1H, d), 8.20 (1H, d), 7.94 (1H, s), 7.74 (2H, d), 7.67 (1H, d), 7.48 (1H, d), 7.27 (2H, t), 6.88 (1H, t), 4.94-4.85 (1H, m), 3.66 (1H, dd), 3.39-3.19 (3H, m), 2.34-2.30 (1H, m), 2.17-2.10 (1H, m).

Method B sis of Furancarboxylic acid {4-[4-((R)-pyrrolidinylamino)-thieno[3,2- d]pyrimidinyl]-pyridinyl} -amide [5 74] yo i) Pd(dba)2, Xantphos, NaOtBu N > MW, Dioxane-DMA, 15min, 1500c H [BB-32] [574] A microwave vial was charged with (R)[2-(2-Chloro-pyridinyl)-thieno[3,2- midinylamino]-pyrrolidine-l-carboxylic acid tert-butyl ester [BB-32] (50mg, 0.11 mmol), furancarboxamide (mg, 0.23 mmol), Pd(dba)2 (4 mg, 0.006 mmol), Xantphos (7 mg, 0.012 mmol), NaOtBu (23 mg, 0.23 mmol), DMA (few drops) and dioxane (1 ml). The reaction was heated to 150°C for 15 minutes under microwave irradiation. The reaction e was partitioned between DCM and saturated NH4Cl (50%) and the organic phase separated, dried (MgSO4), ﬁltered and evaporated under reduced pressure. The crude reaction product was dissolved in DCM (2 ml) and TFA (2 ml) was added and the mixture stirred at 0 CC for 2 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in 10% HCOOH:MeOH and loaded onto an SCX cartridge which was washed with MeOH and the product was released from the cartridge using a on of 2M ammonia / ol. The ammonia / methanol eluent was concentrated under reduced pressure. The crude product was d by preparative HPLC (method B) to yield the title compound. LCMS method: , RT: 3.04 min, MI: 407 [M+1]. 1H NMR (DMSO) 9.86 (1H, s), 9.09 (1H, s), 8.44 (1H, d), 8.29 (1H, s), 8.21 (1H, d), 8.06 (1H, dd), 7.53 (1H, d), 4.88 (1H, m), 4.52 (1H, dd), 4.04-3.97 (1H, m), 3.88-3.82 (1H, m), 3.52 (1H, dd), 3.29-3.15 (3H, m), 2.34-1.89 (4H, Method C sis of l-Phenyl {4- [4-((R)-pyrrolidin-3 -ylamino)-thieno [3 ,2-d]pyrimidinyl] - pyridinyl} -urea [5 75] (Dy—o L“) % ZI \ Z 68:<ZI [BB-32] A microwave vial was charged with (R)[2-(2-chloro-pyridinyl)-thieno[3,2- midinylamino]-pyrrolidinecarboxylic acid tert-butyl ester [BB-32] (100mg, 0.23 mmol), N—phenylurea (38 mg, 0.278 mmol), Pd(dba)2 (11 mg, 0.012 mmol), 2- dicyclohexylphosphino-2'-(N,N—dimethylamino)biphenyl (9 mg, 0.023 mmol), CS2C03 (106 mg, 0.32 mmol), DMA (few drops) and dioxane (0.5 ml). The reaction was heated to 180°C for 10 minutes under microwave irradiation. The reaction mixture was partitioned between DCM and NH4Cl (50%) and the organic phase collected then loaded onto a SCX- 2 dge and washed with methanol. The product was released from the cartridge using a solution of 2M ammonia / methanol. The ammonia / methanol eluent was concentrated under reduced pressure and the crude product dissolved 4N HCl:dioxane (2 ml) and stirred at room ature for 4 hr. The reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in 10% MeOH and loaded onto an SCX cartridge which was washed with MeOH and the product was released from the cartridge using a solution of 2M ammonia / methanol. The ammonia / methanol eluent was concentrated under reduced pressure. The crude product was puriﬁed by preparative HPLC (method B) to yield the title compound. LCMS : 5, RT: 3.05 min, MI: 432 [M+1]. 1H NMR (MeOD) 8.46 (1H, s), 8.39 (1H, d), 8.36 (1H, s), 8.07 (1H, d), 7.96 (1H, dd), 7.53 (2H, dd), 7.49 (1H, d), 7.33 (2H, t), 7.08 (1H, t), 5.04 (1H, m), 3.87 (1H, d), 3.63-3.45 (3H, m), 2.58-2.49 (1H, m), 2.40-2.29 (1H, m).

Method D Synthesis ofN— {4-[4-((R)-Pyrrolidinylamino)-thieno[3 ,2-d]pyrimidinyl]-pyridin yl} -benzenesulfonamide [576] yo H L“) L”) HN HN \ \ N/ CI N/ N\ ’1 | | ”S /N /N O Q [BB-32] A microwave vial was charged with (R)[2-(2-Chloro-pyridinyl)-thieno[3,2- d]pyrimidinylamino]-pyrrolidinecarboxylic acid tert-butyl ester [BB-32] (100mg, 0.23 mmol), benzenesulfonamide (44 mg, 0.278 mmol), Pd(dba)2 (11 mg, 0.012 mol), 2- Dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (9 mg, 0.023 mmol), CS2C03 (106 mg, 0.32 mmol), DMA (few drops) and e (0.5 ml). The on was heated to 180°C for 10 minutes under microwave irradiation. The reaction mixture was partitioned between DCM and NH4Cl (50%) and the c phase collected then loaded onto a SCX- 2 cartridge and washed with methanol. The product was released from the dge using a solution of 2M ammonia / methanol. The ammonia / methanol eluent was concentrated under reduced pressure and the crude product dissolved 4N HCl:dioxane (2 ml) and stirred at room temeperature for 4 hr. The reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in 10% HCOOH:MeOH and loaded onto an SCX cartridge which was washed with MeOH and the product was released from the cartridge using a solution of 2M ammonia / methanol. The ammonia / methanol eluent was concentrated under reduced pressure. The crude product was puriﬁed by preparative HPLC (method B) to yield the title compound. LCMS : 5, RT: 2.74 min, MI: 453 [M+1]. 1H NMR (DMSO) 8.41 (1H, d), 8.21 (1H, s), 8.10 (1H, d), 7.92-7.89 (2H, m), 7.75 (1H, dd), 7.55-7.50 (5H, m), 4.85-4.80 (1H, m), 3.60 (1H, dd), 3.43-3.25 (3H, m), 2.38- 2.31 (1H, m), 2.19-2.11 (1H, m).

The following nds were prepared according to the general sis shown in Scheme B24: method: 5, le RT: 1.85 577 A [BB-32] YN . mm, MI: 391 [M+1] 1H NMR (DMSO, 300MHz): 9.15 (1H, s), 8.49 (2H, d), 8.30 (1H, s), 8.20 (1H, d), 8.07 method: 5, (1H, d), 7.97 RT: 2.78 (1H, s), 7.64 min, MI: (1H, d), 7.54 411[M+1] (1H, d), 6.71 (1H, dd), 4.90- 4.88 (1H, m), 3.55 (1H, dd), 3.31-3.15 (3H, m), 2.37-2.30 (1H, m), 2.15 (1H, m) 1H NMR (MeOD, 300MHz): 8.32 (2H, s), 8.11 (1H, d), 8.08 (1H, d), 7.53 (2H, dd), 7.45 : 5, (1H, d), 7.40 RT: 2.81 (1H, d), 7.27 min, MI: (2H, t), 6.95 407 [M+1] (1H, t), 4.90 (1H, m), 3.73 (1H, dd), 3.56- 3.29 (3H, m), 2.51-2.44 (1H, m), 2.32-2.30 (1H, m). 1H NMR (MeOD, 300MHz): 8.85 (1H, d), 8.40 method: 5, (1H, d), 8.29 RT: 4.37 (1H, d),8.23 min, MI: (1H, dd), 8.11 409 [M+1] (1H, d), 8.02 (1H, d), 7.91- 7.88 (3H, m), 7.68 (1H, d), 7.50 (1H, d), 4.93-4.87 (1H, m), 3.78 (1H, dd), 3.62-3.43 (3H, m), 2.56- 2.45 (1H, m), 2.40—2.30 (1H, (MeOD, 300MHz): 8.84 (1H, s), 8.31 (1H, d), 7.99 (1H, d), 7.95 (1H, dd), 7.43 method: 7, (1H, d), 4.92- RT: 1.90 4.89 (1H, m), min, MI: 3.54 (1H, dd), 384 [M+1] 3.23-3.20 (1H, m), 3.15-3.10 (2H, m), 3.08 (6H, s), 2.41- 2.37 (1H, m), 2.09-2.02 (1H, 1H NMR (MeOD, 300MHz): 8.25 (1H, d), 8.06 (1H, s), 8.00 (1H, d), 7.84 : 7, (1H, dd), 7.42 RT: 3.40 (1H, d), 4.93- min, MI: 4.89 (1H, m), 412 [M+1] 3.51 (1H, Cdd), 3.18- 3.09 (2H, m), 2.41-2.37 (1H, m), 2.07-2.05 (1H, m), 1.43 (9H, s). 1H NMR method: 7, (MeOD, RT: 2.26 300MHz): 8.27 min, MI: (1H, d), 8.04 370 [M+1] (1H, s), 7.99 (1H, d), 7.85 (1H,dd), 7.43 (1H, d), 4.93- 4.89 (1H, m), 3.48 (1H, dd), 3.26-3.22 (1H, m), 3.12-3.08 (1H, m), 3.04 (1H, dd), 2.90 (3H, s), 2.41- 2.34 (1H, m), 2.06-1.99 (1H, 1H NMR (DMSO, 300MHz): 9.15 (1H, s), 8.75 (1H, s), 8.32 (1H, d), 8.19 (1H, d), 7.89 (1H, d), 7.51 (1H, d), 4.79- method: 7, 4.75 (1H, m), RT: 2.48 .44 (2H, min, MI: m), 3.21 (1H, 424 [M+1] dd), 3.07-3.02 (4H, m), 2.31- 2.21 (1H, m),2.02-1.97 (1H, m), 1.60- 1.50 (2H, m), 1.49-1.41 (4H, m), 1.40-1.35 (2H, m). 1H NMR (MeOD, 300MHz): 9.52 (1H, d), 8.49 method: 5, (1H, s), 8.30 RT: 2.41 (1H, dd), 8.20 min, MI: (1H, d), 8.16 409 [M+1] (1H, d), 8.10 (1H, d), 7.54 (1H, t), 7.47 (1H, d), 4.95- 4.88 (1H, m), —341— WO 78126 3.76 (1H, dd), 3.61-3.50 (3H, m), 2.53-2.46 (1H, m), 2.36- 2.31 (1H, m).

(DMSO, 300MHz): 8,39 (d,1H).8.14 (d,1H), 8 (d,1H), 7.56 (s,1H), 7.45 method: 6, (m,1H), 7.43 (m,1H), 7.31 .68min, (m,2H), 7.16 MI: 417 (m,1H), 5.07 [M+1] (m,1H), 4.82 , 3.24 (m,1H), 3.12 (m,2H), 2.24 (m,1H), 2.03 (m,1H), 1.43 (d,3H) method: 6, RT: 5.7mm, MI: 417 [M+1] 1H NMR (DMSO, 300MHz): 8.46 (m,1H).8.33 , 8.03 (s,1H), 7.81 method: 6, (m,1H), 7.53 , 7.47 .22min, (m,1H), 7.44 MI: 405 (m,1H), 4.85 [M+1] (m,1H), 3.66 (m,1H), 3.18 (m,1H), 3.15 (m,2H), 2.31 (m,1H), 2.09 (m,1H) method: 6, 1H NMR RT: (DMSO, .93min, 300MHz): 8.31 (d,1H).8.15 (d,1H)., 7.98 (d,1H), 7.57 , 7.44 (M,1H), 7.36 (m,2H), 7.28 (m,2H), 7.16 (m,1H), 4.83 (m,1H), 3.51 (m,1H), 3.25 (m,2H), 3.10 (m,2H), 2.26 (m,1H), 2.04 (m,1H), 1.76 (q,2H), 0.90 (t,3H) : 6, .95min, MI: 431 [M+1] method: 6, .49min, MI: 433 [M+1] —343— method: 10, RT: 1.61 min, MI: 367 [M+1], method: 10, RT: 1.82 min, MI: 403 [M+1], method: 10, RT: 1.52 min, MI: 381 [M+1], method: 10, RT: 1.53 min, MI: 390 [M+1], method: 10, RT: 2.26 min, MI: 466 [M+1], method: 10, RT: 1.39 min, MI: 475 [M+1], : 10, RT: 1.28 min, MI: 488 [M+1], method: 10, RT: 1.71 min, MI: 415 [M+1], method: 10, RT: 1.44 min, MI: 487 [M+1], method: 10, RT: 1.76 min, MI: 414 [M+1], method: 10, RT: 1.86 min, MI: 414 [M+1], 2012/065831 method: 10, RT: 1.45 min, MI: 472 [M+1], method: 10, RT: 1.71 min, MI: 415 [M+1], method: 10, RT: 1.89 min, MI: 496 [M+1], method: 10, RT: 1.39 min, MI: 472 [M+1], method: 10, RT: 1.85 min, MI: 496 [M+1], method: 10, RT: 1.35 min, MI: 529 [M+1], method: 10, RT: 1.35 min, MI: 469 [M+1], I method: 10, RT: 1.60 min, MI: 419 [M+1], method: 10, RT: 2.28 min, MI: 471 [M+1], method: 10, RT: 2.33 min, MI: 471 [M+1], —345— method: 10, RT: 1.90 [BB-32] . mm, MI: 435 [M+1], 1H NMR (MeOD) 8.10 (1H, d), 7.99 (1H, d), 7.67 (2H, dd), 7.47 (1H, d), 7.33- method:5, 7.24 (3H, m), RT: 3.05 7.01 (1H, t), [BB-39b] . mm, MI.. 4.95-4.89 (1H, 407 [M+1] m), 3.76 (1H, dd), 3.64-3.55 (1H, m), 3.50- 3.40 (1H, m), 2.53-2.44 (1H, m), 2.37-2.31 (1H, m). method: 10, RT: 1.49 [BB-32] . mm, MI: 515 [M+1], method: 10, RT: 1.93 [BB 32- ] min, MI: 502 [M+1], 1H NMR (MeOD) 8.38 (1H, s), 8.17 (1H, d), 8.07 (1H, d), 7.90 (1H, dd), 7.48 (1H, d), 4.99- method:7, 4.97 (1H, m), RT: 2.28 3.86 (1H, dd), ] . mm, MI: 3.62-3.56 (1H, 417 [M+1] m), 3.50-3.46 (2H, m), 2.89- 2.86 (1H, m), .51 (1H, m), 2.37-2.32 (1H, m),1.19- 1.16 (2H, m), 1.03-0.99 (2H, (MeOD) 7.99 (2H, d), 7.48 (1H, s), 7.41 (2H, d), 4.92- 4.89 (1H, m), 3.70-3.65 (1H, method:7, m), 3.52 (1H, RT: 2.21 dd), 3.31—3.29 min, MI: (1H, m), 3.20— 395 [M+1] 3.13 (2H, m), 2.40-2.36 (1H, m), 2.09—2.04 (3H, m), 1.81- 1.78 (2H, m), 1.68-1.66 (1H, m), .41 (2H, m), 1.30— 1.26 (3H, m). 1H NMR (MeOD) 8.29 (1H, s), 8.19 (1H,d), 8.07 (1H, d), 7.90 (1H, d), 7.49 method:7, (1H, d), 5.01— RT: 2.07 4.95 (1H, m), min, MI: 3.86 (1H, dd), 391 [M+1] 3.63-3.57 (1H, m), 3.52—3.47 (2H, m), 3.20 (3H, s), 2.59- 2.51 (1H, m), 2.38-2.32 (1H, 1H NMR (MeOD) 8.03 (1H, d), 8.00 method:7, (1H, d), 7.52 RT: 1.60 (1H, s), 7.45 min, MI: (1H, dd), 7.42 397 [M+1] (1H, d), 4.96- 4.94 (1H, m), 4.00-3.94 (3H, m), 3.65-3.55 —347— (3H, m), 3.40— 3.34 (2H, m), 3.29-3.19(1H, m), 2.45-2.38 (1H, m), 2.16- 2.13 (1H, 3—2.00 (2H, m), 1.61- 1.54 (2H, m). method: 5, RT: 1.87 min, MI: 355 [M+1] method: 10, RT: 1.67 min, MI: 440 [M+1], Method: 10, RT: 1.84 min, MI: 437 [M+1], Method: 10, RT: 1.62 min, MI: 496 [M+1], Method: 10, RT: 2.56 min, MI: 555 [M+1], Synthesis of 2- {(R)[2-(2-Pheny1arnino-pyridiny1)—thieno[3,2-d]pyrirnidin- 4y1amin0]pyrrolidiny1}-acetamide [63 1] S \ NKU0\ A sealed tube containing [2-(2-Phenylamino-pyridinyl)-thieno[3,2-d]pyrimidin- 4-yl]-(R)-pyrrolidinyl-amine [573] (261 mg, 0.67 mmol) was charged with iodoacetamide (150 mg, 0.81 mmol), cesium carbonate (0.88g, 2.7 mmol) and acetonitrile (7.0 mL) was heated at 70°C until complete. Partitioning between dichloromethane and sat aq. NaHCO3, sepration of the organic layer, drying (MgSO4), ﬁltration, concentration and puriﬁcation by RP-HPLC, acetonitrile/water gradient provided the title compound as a yellowish solid (106 mg, 35% yield). HPLC: method: 10, RT: 1.61 min, MI: 446 [M+1].

General synthesis of substituted 4-amino-2—pyrazolylyl-thien0[3,2-d]pyrimidine derivatives of l formula [F-156] e B25) An 4,5-substitutedamino-thiophenecarboxylic acid amide derivative of general formula [G-107] was subjected to a cyclisation reaction with an pyrazole aldehyde derivative of general formula [G-157] in the ce of 4M hydrogen chloride in dioxane in a le solvent such as methanol. The reaction is suitably conducted at an elevated temperature for e 140 0C in a microwave reactor for 20 minutes. Full aromatisation is subsequently achieved with 2,3-dichloro-5,6-dicyanobenzoquinone in a suitable solvent such as dichloromethane at ambient temperature, to yield the 6, 7 - substituted 2-pyrazolylyl-thieno [3,2-d]pyrimidinol, of l formula [G-155]. The corresponding 6, 7 -substituted 2-pyrazolylyl-thieno [3,2-d]pyrimidinol, of general formula [G-155] was d with 2,4,6-triisopropylbenzenesulfonyl de in a polar aprotic solvent such as DMA, DMF, NMP with a tertiary alkylamine base such as Eth, DIPEA or NMM and a catalytic amount ofDMAP and used crude and reacted further with a y or secondary amino derivative, of general formula [G-117]. After reaction work up, typically by a liquid-liquid extraction or puriﬁcation by acidic ion exchange catch- release, the N—Boc derivatives were deprotected under acidic ions with a strong acid such as TFA, TCA, methanesulfonic acid, HCl or H2804 in a solvent such as DCM, DCE, THF, EtOH or MeOH and the crude on product was d by reverse phase preparative HPLC.

Scheme B25 —349— SOZCI o R16 / R17 R3 I? S R4j:N‘R25 \N ReA S R16 {6-157] R )DMAP, Et3N, 7 NH2 | \ R S \ / R17 DMA 7 N R16 NH \ I s 2 R i)Methanol / HCI ii))Amine, Et3N, N / 17 8 N—R dioxane 140 C R DMA 18 \Nl [G-1 17] ii) 2,3—dichloro-5,6- [(3-155] [CS—107] dicyanobenzoquinone, iii) DCM. TFA [G-156] Synthesis of 2-(5-Methyl-1H-pyrazolyl)-thieno[3,2-d]pyrimidinol [BB-46] O OH H \l 2 H _. \ 'N/ / NH2 H [NH H \N [BB-46] A microwave Vial was charged with 3-amino-thiophenecarboxylic acid amide (0.25 g, 1.76 mmol), 3-methyl-1H-pyrazolecarbaldehyde (165 mg, 1.5 mmol), hydrogen de 4M in dioxane (7 l, 0.03 mmol) and methanol (2 ml). The reaction mixture was heated to 140 0C for 20 minutes under microwave irradiation. After completion, the mixture was concentrated under reduced pressure. To a solution of the crude product in dichloromethane (3 ml) was added 2,3-dichloro-5,6- dicyanobenzoquinone (440 mg, 1.93 mmol). The mixture was d at room temperature for 18 hours. After tion, the precipitate formed was ﬁltered and washed with methanol. The residue was used without any ﬁarther puriﬁcation in the next step. LCMS : 8, RT: 2.48 min, MI: 233 [M+1]. 1H NMR (DMSO) 12.38 (1H, br s), 8.36 (1H, s), 8.16 (1H, d), 7.35 (1H, d), 2.56 (3H, s).

Synthesis of Methyl- 1 H-pyrazolyl)-thieno [3 ,2-d]pyrimidinyl]-(R)-pyrrolidin- 3-yl-amine [633] [B B-46] [633] To a solution of ethyl-1H-pyrazolyl)—thieno[3,2-d]pyrimidinol [BB- 46] (0.28 mg, 1.2 mmol) in DMA (10 ml) was added 2,4,6-triisopropylbenzenesulfonyl de (438 mg, 1.45 mmol), triethylamine (0.34 ml, 2.4 mmol) and DMAP (16 mg, 0.12 mmol). The solution was stirred at room temperature for 4 hours then (R)-(+)Boc aminopyrrolidine (220 mg, 1.2 mmol) was added and the mixture was stirred at room temperature for 18 hours. Water was added and the mixture was extracted with DCM (50 ml), washed with brine (50 ml) and dried (MgSO4), d and evapourated under reduced pressure. The crude reaction product was dissolved in DCM (5 ml) and TFA (2 ml) was added and the mixture stirred at room temeperature for 2 hours. After completion the mixture was loaded onto a SCX-2 cartridge and washed with methanol. The product was released from the cartridge using a on of 2M ammonia / methanol. The ammonia / methanol eluent was concentrated under reduced pressure followed by trituration in ether and the crude product was puriﬁed by preparative HPLC (method B) to yield the title compound. LCMS method: 6, RT: 3.80 min, MI: 301 [M+1].

N* 1 * - [2-(5 l- 1 H-pyrazolyl)-thieno [3 ,2-d]pyrimidinyl] -3 -(S)-phenyl-propane- 1,2-diamine [634] was prepared according to the above procedure from 2-(5-Methyl-1H- pyrazolyl)-thieno[3,2-d]pyrimidinol ] and ((S)—1-Aminomethylphenyl- ethyl)-carbamic acid tert-butyl ester to give the title compound: LCMS method: 6, RT: 3.65 min, MI: 365 [M+1].

[BB-46] [634] VI. Biology PKCL ICEALsaY Assays are based on the ability of PKCI to phosphorylate a commercially available peptide substrate in vitro. The peptide substrate is FAM-PKCS pseudopeptide derived peptide, and ses the amino acid ce 5FAM-ERMRPRKRQGSVRRRV-NH2.

Recombinant, ﬁlll-length human PKCI expressed in Sf21 insect cells is also commercially available. Recombinant, kinase-domain human PKCL is expressed and puriﬁed in-house.

The procedure below explains how dose response curves for inhibitors of PKCI are ed. The screen described is for a 384 well format but the assay can be adapted to 1536 or other formats as required.

Compounds to be tested are dissolved in 100% DMSO. Compounds are d as required to give a ﬁnal concentration of 4% DMSO (v/v) in the assay. lul is plated into 384 well black low-binding ﬂat bottomed assay plates which are used ately.

Dilutions and additions of compound to assay plates are carried out using Matrix WellMate® and Matrix PlateMate® Plus liquid handling systems.

On the day of the screen PKCI / substrate working solution, and ATP working solution, are prepared in buffer containing 20mM tris-HCl pH7.5, 10mM MgClz, 0.01% Triton X100, 250uM EGTA and 1mM DTT. The ﬁnal concentration of PKCI used varies ing on the batch of protein but is typically 15pM. The ﬁnal concentration of e substrate in the assay is 100nM. ATP is used at a ﬁnal concentration of 150uM or 25uM in the assays containing full-length or -domain PKCL respectively, which corresponds to ﬁve times or equal to the KMAPP for ATP for each enzyme, respectively.

The ﬁnal buffer concentration in the assay is 18mM tris-HCl pH7.5, 9mM MgClz, 0.009% Triton X100, 225uM EGTA and 0.9mM DTT. Relevant controls are included, namely no compound and no enzyme. 5ulPKC1/ substrate working solution at 30pM and 200nM, respectively, is added to the wells, followed by 4ul ATP g solution at 375uM or 62.5uM for full-length or kinase-domain PKCL respectively, using a 16 channel Matrix pipette. The reaction is allowed to incubate for 60 minutes at room temperature, before the reaction is stopped and developed by the addition of 20ul IMAPTM pment reagent (Molecular Devices). IMAP development reagent consists of 0.25% (v/v) IMAP progressive binding reagent, 17% (v/v) IMAP progressive g buffer A and 3% (v/v) IMAP progressive binding buffer B. The plates are then ted for 2 hours at room temperature before being read using an appropriate plate reader, for example a Molecular s HT Analyst or a BMG Pherastar. Plates are read using a ﬂuorescence polarisation protocol with excitation at 485nm and emission at 530nm, and dichroic mirror at 505nm.

Percentage inhibition values are calculated from ﬂuorescence polarisation , using the no compound and no enzyme control values as 0% and 100% inhibition, respectively. IC50 determination is performed with ExcelFit software (IDBS) using curve fit 205. Z’ factors are determined for each plate tested and are all above 0.5.

Results Biological data for the Example compounds is presented in the ing table.

Activities are set forth as follows: IC50 in IMAP assay against full length PKCi at 150 uM ATP: A = < 100 nM B = 100 nM to 1,000 nM C = 1,000 nM to 10,000 nM D = 10,000 nM to 40,000 nM IC50 in IMAP assay against kinase domain PKCi at 25 uM ATP: A* = < 100 nM B* = 100 nM to 1,000 nM C* = 1,000 nM to 10,000 nM D* = 10,000 nM to 40,000 nM -_I—— N,N—Dimethyl-N'-(2-pyridinyl- 8—tetrahydro- benzo[4,5]thieno[2, 3 -d]pyrimidinyl)-ethane-1,2- (R)-N*1*-(2-Pyridinyl-5,6,7, 8-te trahydro-benzo[4,5]thieno[2,3 - d]pyrimidinyl)-propane- 1 ,2- diamine 4-P1perazinylpyridinyl-5, 6 , 7, 8-tetrahydro-benzo[4,5 ]thieno[2, 3 -d]pyrimidine B * / 4-(4-Methy1-[1 ,4]diazepan- 2- pyridiny1—5 ,6,7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidine (S)-N*1*-(2-Pyridiny1—5,6,7,8-te trahydro—benz0[4,5]thien0[2,3 - d]pyrimidiny1)-pr0pane- 1 ,2- diamine (R)Methy1sulfanyl-N* 1 *-(2- pyridiny1—5,6,7, ahydr0- 4,5]thien0[2,3 -d]pyrimidin- 4-y1)-butane- 1 ,Z-diamine (R)-3 -(1H-Ind01-3 -y1)-N*1*-(2- pyridiny1—5 ,6,7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y1)-pr0pane- 1 ,Z-diamine 4-((S)-3 -Methy1-piperazin—1-y1) pyridiny1—5 ,6,7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidine 4-((3R,5 S)-3 ,5 -Dimethy1-piperazin- 1-y1)pyridiny1-5 ,6,7, 8- tetrahydro—benz0[4, 5 ]thien0[2, 3 - d]pyrimidine —354— 4-((2R,5 S)-2,5 -Dimethy1-piperazin- 1-y1)pyridiny1-5 ,6,7, 8- tetrahydro—benz0[4, 5 ]thien0[2, 3 - d]pyrimidine (18,2S)-N—(2-Pyridiny1—5 , 6, 7, 8-t etrahydro—benz0[4,5]thien0[2,3 - midiny1) -cyclopropane- 1 ,Z-diamine N*1*-(2-Pyridiny1-5,6,7,8-tetrah ydIO-benzo[4,5]thien0[2,3 - d]pyrimidiny1)-ethane- 1 ,2- diamine N—Methyl-N'-(2-pyridiny1- ,6,7,8—tetrahydr0- benz0[4,5]thien0[2,3-d] pyrimidiny1)-ethane- 1 ,Z-diamine 4-[1,4]Diazepany1pyridin y1-5 , 6,7, 8-tetrahydr0- 4,5]thien0[2,3 -d]pyrimidine N*1*-Methy1-N*1*-(2-pyridin y1-5 , 6,7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y1)-ethane-1,2-diamine mX t (R)Methy1—N* 1 *-(2-pyridin yl-5,6,7,8—tetrahydr0- 1 ON benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y1)-pentane- 1 ,Z-diamine (R)-N* 1 *-(2-Pyridiny1—5,6,7, 8-te trahydro—benz0[4,5]thien0[2,3 - 1 \] d]pyrimidiny1)-butane- 1 ,2- diamine DJ * 4-(1 S,4S)-2,5-Diaza— bicyclo[2.2.1]hepty1pyridin—4- ,_. 8 yl-5,6,7,8—tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidine (2-Pyridinyl-5, 6,7, 8-tetrahydr0- 19 4,5]thien0[2,3 -d]pyrimidin- 4-y1)-(R)-pyrrolidin-3 -y1-amine I'O (2-Pyridinyl-5, 6,7, 8-tetrahydr0- NO benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y1)-(S)-pyrrolidin-3 -y1-amine 03 * N*1*-(7-Methy1pyridiny1- ,6, 7, ahydr0- N 1 benz0[4,5]thien0[2,3 - d]pyrimidiny1)-ethane-1 ,2- diamine (S)-N*1*-(7-Methy1—2-pyridiny1- ,6,7,8—tetrahydr0- benz0[4,5]thien0[2,3 imidin- 4-y1)-pr0pane- 1 ,Z-diamine mX Activit I. (R)-N*1*-(7-Methy1pyridin yl-5,6,7,8—tetrahydr0- N U.) benz0[4,5]thien0[2,3 -d]pyrimidin- pr0pane- 1 ,Z-diamine I.03 N*1*-(2-Pyridiny1—5,6,7,8,9,10- hexahydro—l 1-thia—1,3 -diaza— cycloocta[a]inden-4 -y1)-ethane-1,2- diamine (S)-N*1*-(2-Pyridiny1-5,6,7, 8,9, -hexahydr0-1 1-thia—1,3 -diaza- cycloocta[a]indeny1)-pr0pane- 1 ,Z-diamine (R)-N*1*-(2-Pyridiny1—5,6,7,8,9, -hexahydr0-1 1-thia—1,3 -diaza- cycloocta[a]indeny1)-pr0pane- 1 ,Z-diamine Amin0-ethy1amin0) ny1-5, 8-dihydr0-6H- N \1 pyrid0[4',3':4,5]thien0[2,3- d]pyrimidiny1] -pheny1— methanone I.Cd N* 1 *-(5-Isobuty1pyridiny1-thi N 00 en0[2,3 -d]pyrimidiny1)-ethane- 1,2-diamine I.Cd 1*-(5-Is0buty1pyridin NO yl-thien0[2,3-d]pyrimidin-4—y1)_ propane- 1 ,Z-diamine mX Activit I. (R)-N* 1 * -(5 -Is0buty1pyridin U.) 0 en0[2,3-d]pyrimidin-4—y1)_ propane- 1 ,Z-diamine I.O as (S)-N*1*-(5-Ethy1—6-methy1 pyridiny1—thien0[2,3 - d]pyrimidiny1)-pr0pane- 1 ,2- diamine I.Uas 1*-(5-Ethy1—6-methyl ny1—thien0[2,3 - d]pyrimidiny1)-pr0pane- 1 ,2- diamine N*1*-(6-Ethy1pyridiny1- 33 thien0[2, 3 -d]pyrimidiny1)- ethane- 1,2-diamine I.O as 1*-(6-Ethy1—2-pyridinyl- thien0[2, 3 -d]pyrimidiny1)- propane- 1 ,Z-diamine I.O as (R)-N* 1 *-(6-Ethy1—2-pyridiny1- thien0[2, 3 -d]pyrimidiny1)- propane- 1 ,Z-diamine I.Dd N*1*-(5,6-Dimethy1pyridin U.) 0'\ yl-thien0[2, 3 -d]pyrimidin-4—y1)_ ethane- 1,2-diamine I. (S)-N*1*-(5,6-Dimethy1pyridin- U.) \1 4-y1-thien0[2,3 -d]pyrimidinyl)- propane- 1 ,Z-diamine (R)-N* 1* -(5 ,6-Dimethy1pyridin- 4-y1-thien0[2,3 -d]pyrimidinyl)- propane- 1 ,Z-diamine 4-(2-Amin0-ethy1amin0)methy1— 2-pyridinyl-thien0[2,3 - d]pyrimidinecarb0xylic acid amide N* 1*-(6-Is0pr0py1pyridiny1— thien0[2, 3 -d]pyrimidiny1)- ethane- 1,2-diamine (R)-N* 1*-(6-Is0pr0pylpyridin yl-thien0[2, 3 -d]pyrimidin-4—y1)_ propane- 1 ,Z-diamine N*1*-1,4-Dioxa—spir0[7.7]— (2- pyridiny1—5,6,7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y1)-pr0pane- 1 ,Z-diamine N*1*-(7,7-Dimethy1pyridin y1-5 , 6,7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- ethane-1,2-diamine N*1*-(2-Pyridiny1-5 , 8-dihydr0- 6H-thiopyran0[4',3 ':4,5]thien0[2,3 - d]pyrimidiny1)-ethane-1 ,2- diamine N*1*-(2-Pyridiny1-5 , dr0- 6H-pyran0[4',3 ':4,5]thien0[2,3 - midiny1)-ethane-1 ,2- diamine WO 78126 S—ructure (S)-N*1*-(2-Pyridiny1-5,6,7, 8- tetrahydro—benz0[4, 5 ]thien0[2, 3 - d]pyrimidinyl)-3 -p-t01y1- propane- 1 ,Z-diamine (S)-3 -(4-Meth0xy-pheny1)-N*1* - (2-pyridin—4-y1—5 ,6, 7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y1)-pr0pane- 1 mine (S)-N*1*-(2-Pyridiny1-5,6,7, 8- tetrahydro—benz0[4, 5 ]thien0[2, 3 - d]pyrimidiny1)-3 -m-t01y1— propane- 1 ,Z-diamine (S)-3 -(2-Meth0xy-pheny1)-N*1* - (2-pyridin—4-y1—5 ,6, 7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y1)-pr0pane- 1 ,Z-diamine (S)(4-F1u0r0-pheny1)-N*1*-(2- pyridinyl-5 ,6,7, ahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y1)-pr0pane- 1 ,Z-diamine (S)(2-F1u0r0-pheny1)-N*1*-(2- pyridinyl-5 ,6,7, 8-tetrahydr0- benz0[4,5]thien0[2,3 imidin- 4-y1)-pr0pane- 1 ,Z-diamine (R)-3 -Naphthaleny1-N* 1 * -(2- pyridinyl-5 ,6,7, ahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y1)-pr0pane- 1 ,Z-diamine mX Activit I. (S)-N*1*-(2-Pyridiny1-5,6,7, 8- tetrahydro—benz0[4, 5 ]thien0[2, 3 - kl] U.) d]pyrimidinyl)-3 t01y1- propane- 1 ,Z-diamine (S)-3 -(3 -Meth0xy-pheny1)-N*1* - (2-pyridin—4-y1—5 ,6, 7, 8-tetrahydr0- J; benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y1)-pr0pane- 1 ,Z-diamine 4-[(S)Amin0(2-pyridinyl- ,6,7,8—tetrahydr0- 4,5]thien0[2,3 -d]pyrimidin- 4-y1amino)-pr0py1] -phen01 (S)-3 -Pyridiny1—N*1*-(2- pyridinyl-5 ,6,7, ahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y1)-pr0pane- 1 ,Z-diamine I. (S)-3 -Pyridin-3 -y1-N*1*-(2- pyridinyl-5 ,6,7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y1)-pr0pane- 1 ,Z-diamine I. (S)-3 -Pyridiny1—N*1*-(2- nyl-5 ,6,7, 8-tetrahydr0- kl] 00 benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y1)-pr0pane- 1 ,Z-diamine 1*-(2-Pyridiny1-5,6,7, 8- tetrahydro—benz0[4, 5 0[2, 3 - kl] O d]pyrimidiny1)-3 -thiaz01y1- propane- 1 ,Z-diamine (S)-4,4-Dimethy1—N* 1 * -(2-pyridin- 4-y1-5,6,7,8—tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y1)-pentane- 1 ,Z-diamine (R)Benz0[b]thiophen—3 -y1- N*1*-(2-pyridiny1—5,6,7, 8- tetrahydro—benz0[4, 5 ]thien0[2, 3 - d]pyrimidiny1)-pr0pane- 1 ,2- diamine (R)- 1-Piperidiny1methy1-(2- nyl-5 ,6,7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y1)-amine (S)-3 -(1H-Ind01-3 -y1)-N*1*-(2- pyridinyl-5 ,6,7, ahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y1)-pr0pane- 1 ,Z-diamine (S)-3 -(2-Meth0xy-pheny1)-N*1* - (2-pyridiny1—5 , 8-dihydr0-6H- thiopyran0[4',3 thien0[2,3 - d]pyrimidiny1)-pr0pane- 1 ,2- diamine 2-[(S)Amin0(2-pyridinyl- 8—tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y1amino)-pr0py1] -phen01 3 - [(S)Amin0-3 -(2-pyridiny1- ,6, 7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y1amino)-pr0py1] -phen01 -T—— (S)-3 -Pheny1-N*1* r1d1ny1— ,6, 7, ahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- pr0pane- 1 ,Z-diamine (S)-N* 1 *-(2-Pyridiny1—5,6,7,8—te trahydro—benz0[4,5]thien0[2,3 - d]pyrimidiny1)-butane- 1 ,2- diamine (S)-N*1*-(7-Methy1—2-pyridiny1- ,6, 7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y1)-3 -pheny1—pr0pane-1,2- diamine (R)Phenyl-N* 1*-(2-pyridiny1- 6,7,8,9-tetrahydr0-5Hthia—1,3- diaza-benz0[a] -4—y1)_ propane- 1 ,Z-diamine (R)Pheny1-N* 1* -(2-pyridiny1— ,6, 7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y1)-pr0pane- 1 ,Z-diamine [4-((S)Amin0-3 -pheny1— propylamino)pyridiny1-5 , 8 - dihydr0-6H- pyrid0[4',3':4,5]thien0[2,3- d]pyrimidiny1] -pheny1— [4-((R)Amin0-3 -pheny1— propylamino)pyridiny1-5 , 8 - dihydr0-6H- pyrid0[4',3':4,5]thien0[2,3- d]pyrimidiny1] -pheny1— methanone 4-((S)Amin0pheny1— propylamin0)methy1—2-pyridin- 4-y1-thien0[2,3-d]pyrimidine carboxylic acid amide mX Activit I. (S)-N*1*-(6-Is0pr0pylpyridin \] kl] yl-thien0[2,3 -d]pyrimidiny1)-3 - phenyl-propane- amine I.B (S)-3 -Pheny1-N*1* -(2-pyridiny1— ,6,7,8,9,10-hexahydr0thia-1,3 - \] ON diaza—cycloocta[a]indenyl)- propane- 1 ,Z-diamine I. (S)-N*1*-(7,7-Dimethy1pyridin- ,6,7,8—tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y1)-3 -pheny1- propane- 1 ,Z-diamine (S)-3 -Pheny1-N*1*-*-1,4-Dioxa— spir0[7.7] - (2-pyridiny1-5,6,7,8— 78 tetrahydro—benz0[4, 5 ]thien0[2, 3 - d]pyrimidiny1)-pr0pane- 1 ,2- diamine I. (R)-3 -Pheny1-N*1*-*-1,4-Dioxa- spir0[7.7] - (2-pyridiny1-5,6,7,8— tetrahydro—benz0[4, 5 ]thien0[2, 3 - d]pyrimidiny1)-pr0pane- 1 ,2- diamine (S)-3 -Pheny1-N*1* -(2-pyridiny1— ,8—dihydr0-6H- thiopyran0[4',3':4,5] thien0[2, 3 -d]pyrimidiny1)- propane- 1 ,Z-diamine (R)Pheny1-N* 1* -(2-pyridiny1— ,8—dihydr0-6H- 00 1 thiopyran0[4',3':4,5] thien0[2, 3 -d]pyrimidiny1)- propane- 1 mine I. (S)-3 -Pheny1-N*1* -(2-pyridiny1— hydr0-6H- 00N pyran0[4',3':4,5]thien0[2,3 - d]pyrimidiny1)-pr0pane- 1 ,2- diamine (R)Pheny1-N* 1* -(2-pyridiny1— hydr0-6H- pyran0[4',3':4,5]thien0[2,3 - d]pyrimidiny1)-pr0pane- 1 ,2- diamine N*1*-(2-Pyridiny1-6,7,8,9- tetrahydro—SH- 1 0-thia— 1 ,3 -diaza— benz0[a]azuleny1)-ethane- 1 ,2- diamine 4-Piperaziny1pyridiny1- 6,7,8,9-tetrahydr0-5Hthia—1,3- diaza-benz0[a] azulene 4-[1,4]Diazepany1pyridiny1 -6,7,8,9-tetrahydr0-5Hthia—1,3- benz0[a] azulene (S)-3 'Phenyl—N* 1*-(2-pyridiny1- 6,7,8,9-tetrahydr0-5Hthia—1,3- diaza-benz0[a] azulen-4—y1)_ propane- 1 mine (S)-N*1*-(2-Pyridiny1-6,7,8,9- tetrahydro—SH- 1 0-thia— 1 ,3 -diaza— benz0[a] azuleny1)-pr0pane- 1 ,2- diamine (R)-N*1*-(2-Pyridin—4-y1—6,7, 8,9- tetrahydro—SH- 1 0-thia— 1 ,3 -diaza— a] azuleny1)-pr0pane- 1 ,2- diamine 2012/065831 ActiVit Structure 4-((S)Amin0pheny1— propylamino)pyridiny1-5,8- dihydr0-6H- pyrid0[4',3':4,5]thien0[2,3- d]pyrimidinecarb0xy1ic acid tert- bu 1 ester N*1*-(6-Methy1—5-pheny1 pyridiny1—thien0[2,3 - d]pyrimidiny1)-ethane-1 ,2- 4-[1,4]Diazepany1methy1—5 - phenyl-Z-pyridiny1-thien0[2,3 - d]pyrimidine -(4-Br0m0-pheny1) [1,4] diazepany1pyridiny1- thien0[2 , 3 -d]pyrimidine -Methy1—4-piperaziny1 pyridiny1—thien0[2,3 - d]pyrimidine 4-[1,4]Diazepanylmethy1—2- pyridiny1—thien0[2,3 - d]pyrimidine 2012/065831 -_I—— Am1n0-pr0pylam1n0) pyridiny1-5,8-dihydr0-6H- pyrid0[4',3':4,5]thien0[2,3- d]pyrimidinecarb0xylic acid tertbutyl ester N*1* - [2-(3 -F1u0r0-pyridiny1)- ,6, 7, 8-tetrahydr0- benz0[4,5]thien0[2,3 imidin- 4-y1]—ethane-1,2-diamine N*1*-[2-(2-F1u0r0-pyridinyl)- ,6,7,8—tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y1]—ethane-1,2-diamine (S)-N*1*-[2-(3-F1u0r0-pyridin yl)-5,6,7,8—tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y1] -pr0pane- 1 ,Z-diamine (R)-N*1*-[2-(3 0-pyridin y1)-5 , 6,7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y1] -pr0pane- 1 ,Z-diamine (S)-N*1*-[2-(3-F1u0r0-pyridin y1)-5 , 6,7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y1] -3 -pheny1—pr0pane-1,2- diamine (S)-N*1* - [2-(3 -Meth0xy-pyridin—4- y1)-5 , 6,7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y1] -3 -pheny1—pr0pane-1,2- diamine Ex —Activit 4- [4- ((S)Amin0-3 -pheny1— propylamino)-5 , 6 ,7 , 8-tetrahydr0- 4,5]thien0[2,3 -d]pyrimidin- 2-y1] -pyridin-3 -01 1- [4-(2-Amin0-ethylamin0) pyridiny1-5 , 8-dihydr0-6H- pyrid0[4',3':4,5]thien0[2,3- d]pyrimidiny1] -2,2-dimethy1- propan0ne 1-[4-(2-Amin0-ethylamin0) pyridiny1-5, 8-dihydr0-6H- [4',3':4,5]thien0[2,3- d]pyrimidiny1] -ethan0ne 1- [4-(2-Amin0-ethylamin0) pyridiny1-5 , 8-dihydr0-6H- [4',3':4,5]thien0[2,3- d]pyrimidiny1] -pr0pan0ne 1-[4-(2-Amin0-ethylamin0) pyridiny1-5, 8-dihydr0-6H- pyrid0[4',3':4,5]thien0[2,3- d]pyrimidiny1] methy1—pr0pan0ne [4-(2-Amin0-ethy1amin0) pyridiny1-5, 8-dihydr0-6H- pyrid0[4',3':4,5]thien0[2,3- d]pyrimidinyl]-cyclopr0py1— methanone [4-(2-Amin0-ethy1amin0) pyridiny1-5, 8-dihydr0-6H- pyrid0[4',3':4,5]thien0[2,3- d]pyrimidiny1] -cyclobutyl- methanone 1- [4-(2-Amin0-ethylamin0) pyridiny1-5 , 8-dihydr0-6H- pyrid0[4',3 thien0[2,3 - d]pyrimidiny1] -pentan— 1 -0ne 1-[4-(2-Amin0-ethylamin0) pyridiny1-5, 8-dihydr0-6H- pyrid0[4',3':4,5]thien0[2,3- d]pyrimidiny1]—2- dimethylamino—ethanone N*1*-(7-Ethy1pyridiny1- ,6, 7, 8-tetrahydr0- pyrid0[4',3 ':4,5]thien0[2,3 - d]pyrimidiny1)-ethane-1 ,2- Diamine N*1*-(7-Methy1pyridiny1- ,6, 7, 8-tetrahydr0- pyrid0[4',3 thien0[2,3 - d]pyrimidiny1)-ethane-1 ,2- diamine N*1*-(7-Is0buty1pyridiny1- ,6, 7, 8-tetrahydr0- [4',3 ':4,5]thien0[2,3 - d]pyrimidiny1)-ethane-1 ,2- diamine 4- Methy1—benzyl)-piperazin- 1-y1]pyridiny1-5,6,7,8— tetrahydro—benz0[4,5]thien0[2,3 - d]pyrimidine 4-(4-Benzy1-piperaziny1) pyridinyl-5 ,6,7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidine WO 78126 D* Br 4- [4-(4-Br0m0-benzy1)-piperazin y1]pyridiny1-5 ,6,7, 8- tetrahydro—benz0[4, 5 ]thien0[2, 3 - d]pyrimidine 2-Pyridin—4-y1(4-pyridin ylmethyl-piperaziny1)-5 ,6,7, 8- tetrahydro—benz0[4, 5 ]thien0[2, 3 - d]pyrimidine 4-(4-Ethy1-piperaziny1) pyridiny1—5 ,6,7, ahydr0- benz0[4,5]thien0[2,3 -d]pyrimidine 2-Pyridin—4-y1(4-pyridin ylmethyl-piperaziny1)-5 ,6,7, 8- tetrahydro—benz0[4, 5 ]thien0[2, 3 - d]pyrimidine 13* F 2-Pyridin—4-y1—4-[4-(4- triﬂuoromethyl-benzyl)-piperazin- 1-y1]-5,6,7,8—tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidine 4-Ch10r0-benzy1)-piperazin-1 - y1]pyridiny1-5 ,6,7, 8- tetrahydro—benz0[4, 5 ]thien0[2, 3 - d]pyrimidine 4-[4-(2-Ch10r0-benzy1)-piperazin-1 - y1]pyridiny1-5 ,6,7, 8- tetrahydro—benz0[4, 5 ]thien0[2, 3 - d]pyrimidine 4- [4-(3 -Ch10r0-benzy1)-piperazin y1]pyridiny1-5 ,6,7, 8- tetrahydro—benz0[4, 5 0[2, 3 - d]pyrimidine C* | 4-(4-Methy1-piperaziny1) pyridiny1—5 ,6,7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidine 3 - Pyridiny1-5 ,6,7, 8- tetrahydro—benz0[4, 5 ]thien0[2, 3 - d]pyrimidiny1)-piperazin ylmethyl]-phen01 4- [4-(3 -Br0m0-benzy1)-piperazin y1]pyridiny1-5 ,6,7, 8- tetrahydro—benz0[4, 5 ]thien0[2, 3 - midine 4- [4- (6-Br0m0-pyridin-3 - ylmethy1)-piperazin- 1-y1] pyridiny1—5 ,6,7, 8-tetrahydr0- benz0[4,5]thien0[2,3 - d]pyrimidine 2012/065831 4-(4-Buty1-piperaziny1) pyridinyl-5 ,6,7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidine 2-Pyridin—4-y1(4-pyridin-3 - ylmethyl-piperaziny1)-5 ,6,7, 8- tetrahydro—benz0[4, 5 ]thien0[2, 3 - d]pyrimidine 4- [4- (3 -Br0m0-pyridin y1)-piperazin- 1-y1] pyridinyl-5 ,6,7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidine 4-(4-Phenethy1-piperaziny1) pyridinyl-5 ,6,7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidine 4-(4-Pr0py1—piperaziny1) pyridinyl-5 ,6,7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidine 4-(4-Isobutyl-piperaziny1) nyl-5 ,6,7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidine Dimethyl-[2-(2-pyridiny1— ,6,7,8—tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y10xy)-ethy1] -amine 2-(2-Pyridinyl-5,6,7,8- ydro—benz0[4,5]thien0[2,3 - d]pyrimidiny10xy)-ethylamine Methyl-[2-(2-pyridiny1—5,6,7,8— tetrahydro—benz0[4,5]thien0[2,3 - d]pyrimidiny10xy)-ethy1] -amine (S)-3 -Methy1— 1 -(2-pyridiny1— ,6, 7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y10xymethy1)-buty1amine 2-Pyridiny1((R)-pyrrolidin-3 - yloxy)-5 ,6,7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidine —374— Ex Activit 2-Pyridin—4-y1((S)-pyrrolidin-3 - yloxy)-5 ,6,7, ahydr0- benz0[4,5]thien0[2,3 -d]pyrimidine 4-(Piperidin-3 -y10xy)pyridin yl-5,6,7,8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidine (R)Pheny1— 1 ridin—4-y1— ,6, 7, 8-tetrahydr0- benz0[4,5]thien0[2,3 imidin- 4-y10xymethy1)-ethylamine (S)Pheny1(2-pyridiny1- ,6, 7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y10xymethyl)-ethy1amine (S)Methy1—2-(2-pyridiny1— ,6, 7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y10xy)-ethy1amine (R)Methy1—2-(2-pyridiny1- ,6, 7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y10xy)-ethy1amine (R)-3 -Methy1— 1 -(2-pyridiny1- ,6, 7, 8-tetrahydr0- 4,5]thien0[2,3 -d]pyrimidin- 4-y10xymethy1)-buty1amine Ex —Activit (R)-1 -Pheny1—2-(2-pyridin—4-y1— ,6, 7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y10xy)-ethy1amine (R)Methy1— 1 ridiny1- ,6, 7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y10xymethyl)-pr0py1amine (R)(2-Pyridiny1-5 , 6, 7, 8- tetrahydro—benz0[4, 5 ]thien0[2, 3 - d]pyrimidiny10xymethyl)- propylamine (S)(2-Pyridiny1—5,6,7, 8- tetrahydro—benz0[4, 5 ]thien0[2, 3 - d]pyrimidiny10xymethy1)- propylamine (S)Methy1—1-(2-pyridiny1— ,6, 7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y10xymethyl)-pr0py1amine 4-(Azetidin-3 -y10xy)pyridiny1 -5,6,7,8—tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidine 2-Pyridiny1((R)pyrrolidin- th0xy)-5 , 6,7, ahydr0- benz0[4,5]thien0[2,3 -d]pyrimidine Ex t 2-Pyridiny1((S)pyrrolidin- 2-y1meth0xy)-5 , 6,7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidine (S)Pheny1(2-pyridiny1- ,6, 7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y10xy)-ethy1amine (S)Cyclohexy1(2-pyridiny1— ,6, 7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- y)-ethy1amine (S)Cyclohexy1(2-pyridiny1— ,6, 7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- ymethyl)-ethy1amine (S)(1H-Ind01—3 -y1)(2-pyridin— 4-y1-5 ,6,7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y10xymethyl)-ethy1amine (S)(4-Meth0xy-benzyl)(2- pyridinyl-5 ,6,7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y10xy)-ethy1amine (S)Naphthaleny1methy1—2-(2- pyridinyl-5 ,6,7, 8-tetrahydr0- 4,5]thien0[2,3 -d]pyrimidin- 4-y10xy)-ethy1amine (S)Naphthaleny1methy1—2-(2- pyridinyl-5 ,6,7, ahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y10xy)-ethy1amine (S)- 1 u0r0-benzy1)(2- pyridinyl-5 ,6,7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y10xy)-ethy1amine (S)(3 -F1u0r0-benzyl)(2- pyridinyl-5 ,6,7, 8-tetrahydr0- 4,5]thien0[2,3 -d]pyrimidin- 4-y10xy)-ethy1amine (S)(2-F1u0r0-benzy1)(2- pyridinyl-5 ,6,7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y10xy)-ethy1amine (S)(3 -Methy1—benzy1)(2- pyridinyl-5 ,6,7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y10xy)-ethy1amine (S)(4-Methy1—benzyl)(2- pyridinyl-5 ,6,7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- y)-ethy1amine (R)-3 -Pheny1— 1 -(2-pyridin—4-y1— ,6, 7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y10xymethyl)-pr0py1amine Ex —Activit (S)(2-Pyridiny1—5 ,6,7, 8- tetrahydro—benz0[4, 5 ]thien0[2, 3 - d]pyrimidiny10xy)thiophen-2 - ylmethyl-ethylamine (R)(4-Meth0xy-benzy1)(2- pyridinyl-5 ,6,7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y10xy)-ethy1amine (R)(2-Pyridiny1-5 , 6, 7, 8- tetrahydro—benz0[4, 5 ]thien0[2, 3 - d]pyrimidiny10xy)thiophen-2 - yl-ethylamine (S)(4-Br0m0-benzy1)(2- pyridinyl-5 ,6,7, 8-tetrahydr0- benz0[4,5]thien0[2,3 imidin- 4-y10xy)-ethy1amine (R)- 1-Naphthaleny1methy1(2- pyridinyl-5 ,6,7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y10xy)-ethy1amine (R)Naphthaleny1methy1(2- pyridinyl-5 ,6,7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- y)-ethy1amine (S)(2-Methy1—benzyl)(2- pyridinyl-5 ,6,7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y10xy)-ethy1amine HX —Activit (1H-Imidaz01y1methy1) (2-pyridin—4-y1—5 ,6, 7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y10xy)-ethy1amine (R)Benz0[b]thiophen—3 - ylmethyl-Z-(Z-pyridiny1—5 ,6,7, 8- tetrahydro—benz0[4, 5 ]thien0[2, 3 - d]pyrimidiny10xy)-ethylamine (S)Benz0[b]thiophen-3 - ylmethyl-Z-(Z-pyridiny1—5 ,6,7, 8- tetrahydro—benz0[4, 5 ]thien0[2, 3 - d]pyrimidiny10xy)-ethylamine 4-((R)Piperidiny1meth0xy) pyridinyl-5 ,6,7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidine Piperidiny1meth0xy) pyridinyl-5 ,6,7, 8-tetrahydr0- 4,5]thien0[2,3 -d]pyrimidine (S)(3 -Meth0xy-benzy1)(2- pyridinyl-5 ,6,7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y10xy)-ethy1amine N*1*-[2-(1H-Pyraz01—4-y1)-5,6,7, 8- tetrahydro—benz0[4, 5 ]thien0[2, 3 - d]pyrimidiny1] -ethane- 1 ,2- diamine N*1*-[2-(3 ,5-Dimethy1-1H- 1y1)-5 , 6,7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- ethane-1,2-diamine (S)-3 -Pheny1-N*1*-[2-(1H-pyraz01- 4-y1)-5 ,6,7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y1] -pr0pane- 1 ,Z-diamine (S)-N*1* - [2-(3 ,5 -Dimethy1-1H- pyraz01y1)-5 , 6,7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y1] -3 -pheny1—pr0pane-1,2- diamine 4-Piperaziny1—2-(1H-pyraz01—4- y1)-5 , 6,7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidine 4-[1,4]Diazepany1(1H- pyraz01y1)-5 , 6,7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidine 1*-[2-(1H-Pyraz01yl)- ,6, 7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y1] -pr0pane- 1 ,Z-diamine Structure (R)-N*1*-[2-(1H-Pyraz01y1)- ,6, 7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y1] -pr0pane- 1 ,Z-diamine -Pyraz01y1)-5 ,6,7, 8- tetrahydro—benz0[4, 5 0[2, 3 - d]pyrimidiny1] -(R)-pyrr01idin-3 - yl-amine 2-(3 , 5 hy1-1H-pyraz01y1)- 4-piperazin- 1-y1-5 , 6,7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidine 4-[1,4]Diazepany1(3 ,5 - dimethyl-1H-pyraz01y1)-5 ,6, 7, 8- tetrahydro—benz0[4, 5 ]thien0[2, 3 - d]pyrimidine (S)-N*1*-[2-(3 ,5-Dimethy1-1H- pyraz01y1)-5 , 6,7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y1] -pr0pane- 1 ,Z-diamine 1*-[2-(3 ,5-Dimethy1— 1H- pyraz01y1)-5 , 6,7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y1] -pr0pane- 1 ,Z-diamine 13* H [2-(3 , 5 -Dimethy1-1H-pyraz01y1)- ,6, 7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y1] -(R)-pyrr01idin-3 ine N*1*-[2-(1-Methy1-1H-pyraz01 y1)-5 , 6,7, 8-tetrahydr0- benz0[4,5]thien0[2,3 -d]pyrimidin- 4-y1]—ethane-1,2-diamine 4-((S)-3 -Benzy1-piperaziny1) (1H-pyraz01y1)-5,6,7,8- tetrahydro—benz0[4, 5 ]thien0[2, 3 - d]pyrimidine Name A (S)—N*1*-(7-Brorno methylpyridinyl- thieno [3 ,2-d]pyrirnidin y1)-3 -pheny1—pr0pane- 1 ,2- diamine C* 6-Pheny1—4-piperaziny1- dinyl-thieno [3 ,2- d]pyrimidine (S)—N*1*-(7-Methy1—2- pyridiny1—thieno[3 ,2- rnidinyl) phenyl-propane-l ,2- diamine Activit ure Name (S)—N*1*-(7-Brorno tert-butyl-Z-pyridinyl- thieno[3 ,2-d]pyrirnidin yl)(2-rnethoxy-phenyl) propane-1,2-diarnine (S)-N*1*-[7-Brorn0(4- methyl-thiazol-S-yl)— [3 ,2-d]pyrirnidin y1]-3 -pheny1—pr0pane- 1 ,2- diamine (S)—N*1*-(7-Brorno pyridiny1—thieno[3 ,2- d]pyrirnidinyl)- propane-1,2-diarnine (S)—N*1*-(7-Chloro pyridiny1—thieno[3 ,2- d]pyrirnidinyl) phenyl-propane-l ,2- diamine U* (S)—N*1*-(6-tert-Butyl pyridiny1—thieno[3 ,2- d]pyrirnidiny1)- propane-1,2-diarnine U* (R)—N* 1 *-(6-tert-Butyl pyridiny1—thieno[3 ,2- rnidiny1)- propane-1,2-diarnine N*1*-(6,7-Dimethyl pyridiny1—thieno[3,2— d]pyrirnidiny1)-ethane- 1 ,2-diamine Structure Name N*1*-[7-(4-Brorn0- phenyl)pyridiny1— thieno[3 ,2-d]pyrirnidin yl]—ethane-1 ,2-diarnine N* 1 *-(6-tert-Butyl ny1—thieno[3,2— d]pyrirnidiny1)-ethane- 1 ,2-diamine (7-Methy1—2-pyridiny1— thieno[3,2-d]pyrirnidin yl)-(R)-pyrr01idiny1— amine N*1*-(6-Pheny1—2- pyridiny1—thieno[3,2— d]pyrirnidiny1)-ethane- 1 ,2-diamine (S)—3-Pheny1—N*1*-(2- pyridiny1—thieno[3 ,2- d]pyrirnidinyl)- propane-1,2-diarnine ((3 S ,4S)Benzy1—4- ﬂuoro-pyrrolidin-3 -y1)-(2- ny1—thieno [3 ,2- d]pyrirnidiny1)-arnine Structure Name (R)-Piperidin-3 -y1-(2- pyridiny1— thieno[3,2-d]pyrirnidin yl)-arnine (2-Pyridinyl-thieno[3,2- d]pyrirnidinyl)—(R)- pyrrolidin-3 -yl-arnine (R)(2-Pyridinylthieno [3,2-d]pyrirnidin rr01idin-3 -y1arnine (3S,4S)(2-Pyridinyl- thieno[3,2-d]pyrirnidin o)-pyrrolidinol 2-[(R)(2-Pyridiny1— thieno[3,2-d]pyrirnidin ylarnino)-pyrrolidin- 1-y1]-acetarnide Structure Name ((3S,4R)—4-Fluor0- pyrrolidin-3 -y1)- (2-pyridiny1—thieno[3,2- rnidinyl)-arnine 32 1 [2'(3-Ch10r0-pyridin yl)-thieno[3,2_ d]pyrirnidinyl]_(R)_ pyrrolidin-3 -y1—arnine (S)-N*1*-[2-(3-Chloropyridinyl )-thieno[3 ,2- d]pyrirnidiny1]—3- -propane-l ,2- diamine (S)—N*1*-(6-tert-Butyl pyridiny1—thieno[3 ,2- d]pyrirnidinyl) phenyl-propane-l ,2- diamine (S)-N*1*-(6,7-Dirnethyl- 2-pyridiny1—thieno[3 ,2- d]pyrirnidinyl) phenyl-propane-l ,2- diamine (S)-N*1*-[7-(4-Br0rno- phenyl)pyridiny1— [3 ,2-d]pyrirnidin y1]-3 -pheny1—pr0pane- 1 ,2- 326 diamine t Structure Name (R)-N*1*-[7-(4-Brorno- phenyl)pyridiny1— [3 ,2-d]pyrirnidin y1]-3 1—pr0pane- 1 ,2- 327 diamine (7-Brornornethyl pyridiny1—thieno[3,2- d]pyrirnidinyl)—(R)- 328 pyrrolidin-3 -yl-arnine (R)-N*1*-(7-Brorno methylpyridinyl- thien0[3 ,2-d]pyrirnidin y1)-3 -pheny1—pr0pane- 1 ,2- diamine (R)-N*1*-(7-Brorno methylpyridinyl- thien0[3 ,2-d]pyrirnidin y1)-pr0pane-1 ,2-diarnine (S)—N*1*-(7-Brorno methylpyridinyl- thien0[3 ,2-d]pyrirnidin y1)-pr0pane-1 rnine (7-Brornornethyl pyridiny1—thieno[3,2- d]pyrirnidinyl)-(S)- 332 pyrrolidin-3 -yl-arnine N*1*-(7-Brornotertbuty1pyridiny1 thien0[3 ,2-d]pyrirnidin yl)—ethane-1 ,2-diarnine t Structure Name (S)—N*1*-(7-Brorno tert-butyl-Z-pyridinyl- thien0[3 ,2-d]pyrirnidin y1)-3 -pheny1—pr0pane- 1 ,2- diamine (R)-N*1*-(7-Brorno tert-butyl-Z-pyridinyl- thien0[3 ,2-d]pyrirnidin y1)-3 -pheny1—pr0pane- 1 ,2- diamine (S)—N*1*-(7-Brorno pyridiny1—thieno[3 ,2- d]pyrirnidinyl) phenyl-propane-l ,2- diamine 1*-(6-Brorno methylpyridinyl- [3 ,2-d]pyrirnidin y1)-3 -pheny1—pr0pane- 1 ,2- 2-(7-Br0rnopyridin yl-thieno[3 ,2-d]pyrimidin- 4-y1arnin0)-acetarnide N'-(7-Brornopyridin yl-thieno[3 ,2-d]pyrimidin- 4-y1)-N,N—dirnethyl- ethane-1 ,2-diarnine (6-Brornornethyl pyridiny1—thieno[3,2— d]pyrirnidinyl)—(R)- pyrrolidin-3 -yl-arnine Structure Name (7-Br0rnopyridiny1— thien0[3,2-d]pyrirnidin y1)-(S)pyrr01idin- 2-y1rnethy1—arnine (7-Br0rnopyridiny1— thien0[3,2-d]pyrirnidin y1)-(R)-1 -pyrr01idin- 342 2-y1rnethy1—arnine (7-Br0rnopyridiny1— thien0[3,2-d]pyrirnidin yl)—(R)-piperidinyl- amine 343I (7-Br0rnopyridiny1— thien0[3,2-d]pyrirnidin yl)—(S)—pyrrolidinyl- amine 344I N—(7-Brornopyridin eno[3 yrimidin- 4-y1)-N'-rnethy1—ethane- 1 ,2-diamine 345- (S)—N*1*-(7-Brorno pyridiny1—thieno[3 ,2- d]pyrirnidinyl) 346 methyl-pentane- 1 ,2- diamine Structure Name (S)—N*1*-(7-Brorno ny1—thieno[3 ,2- rnidinyl) methyl-butane- 1 ,2- 347I diamine (S)—N*1*-(7-Brorno pyridiny1—thieno[3 ,2- d]pyrirnidinyl) 348I cyclohexyl-propane- 1 ,2- diamine N*1*-(7-Brorn0 pyridiny1—thieno[3,2— d]pyrirnidiny1)-ethane- 349I 1 ,2-diamine 7-Brorn0piperaziny1- 2-pyridinyl-thieno[3,2- d]pyrirnidine 350I A (7-Br0rnopyridiny1— thien0[3,2-d]pyrirnidin yl)-(R)-pyrr01idiny1— amine C [7-Brorno(3-ﬂuoropyridiny1 thien0[3,2-d]pyrirnidin yl]—(R)-pyrrolidinyl- amine ActiVit Structure Name (S)-N*1*-[2-(3-F1uoro- pyridinyl)-thieno[3 ,2- d]pyrirnidinyl]— e-1,2-diarnine [2-(3 -F1u0r0-pyridinyl)- thien0[3,2-d]pyrirnidin yl]-(R)-pyrrolidinyl- 354 amine (S)-N*1*-[2-(3-F1uoro- pyridinyl)-thieno[3 ,2- d]pyrirnidiny1]—3- 355 phenyl-propane-l ,2- diamine 6-(4-tert-Buty1—phenyl)—4- [1,4]diazepany1—2- ny1—thieno[3,2— d]pyrimidine 6-(4-tert-Buty1—phenyl)—4- piperaziny1—2-pyridin- 4-y1-thieno[3,2- d]pyrimidine U* (R)-N* 1 *-[6-(4-tert-Butylphenyl ridiny1— thien0[3 ,2-d]pyrirnidin yl] -pr0pane- 1 ,2-diarnine U* (S)-N*1*-[6-(4-tert-Butylphenyl )pyridiny1— thien0[3 ,2-d]pyrirnidin yl] -pr0pane- 1 ,2-diarnine Structure Name N*1*-[6-(4-tert-Butyl- phenyl)pyridiny1— thien0[3,2-d]pyrirnidin hane-1 ,2-diarnine (S)—N*1*-(7-Methy1—2- pyridiny1—thieno[3,2— d]pyrirnidinyl)- propane-1,2-diarnine 03 * 4-[1,4]Diazepany1—7- methylpyridinyl- thien0[3 ,2-d]pyrirnidine * 7-Methylpiperazin ylpyridin—4-y1— thien0[3 ,2-d]pyrirnidine O* (7-Methy1—2-pyridiny1— thien0[3,2-d]pyrirnidin yl)—(S)—pyrrolidinyl- 364 amine O* N*1*-Methyl-N*1*-(7- methylpyridinyl- thien0[3 ,2-d]pyrirnidin y1)-ethane-1,2-diarnine U* 1*-(6-Pheny1—2- pyridiny1—thieno[3,2— rnidinyl)- propane-1,2-diarnine ActiVit Structure Name * (S)—N* 1 *-(6-Pheny1—2— pyridiny1—thieno[3 ,2- d]pyrirnidinyl)- propane-1,2-diarnine O* 4-[1,4]Diazepany1—6- phenylpyridin—4-yl- thien0[3 ,2-d]pyrirnidine O* (R)-N* 1 *-(7-Methy1—2- pyridiny1—thieno[3 ,2- d]pyrirnidinyl)- propane-1,2-diarnine * N* 1 * -(7-Methy1—2- pyridiny1—thieno[3 ,2- d]pyrirnidiny1)-ethane- 1,2-diamine 03 * 9-Chloro[1,4]diazepany1—2-pyridiny1— benzo[4,5]thieno[3,2- d]pyrimidine 03 * (S)—N*1*-(9-Chloro pyridiny1— benzo[4,5]thieno[3,2- d]pyrirnidinyl) -propane-l ,2- diamine 03 * (S)—N*1*-(9-Chloro ny1— 4,5]thieno[3,2- d]pyrirnidinyl)- propane-1,2-diarnine Structure Name I.B* (R)-N*1*-(9-Chloro pyridiny1— 4,5]thieno[3,2- d]pyrirnidinyl)- propane-1,2-diarnine I.C* N* 1 *-(2-Pyridinyl- pyrid0[3',2':4,5]thien0[3,2- rnidiny1)-ethane- 1,2-diamine IID* 4-Piperaziny1—2- pyridiny1— pyrid0[3',2':4,5]thien0[3,2- d]pyrimidine IIC* 4-[1,4]Diazepany1—2- pyridiny1— pyrid0[3',2':4,5]thien0[3,2- d]pyrimidine C* (S)—N* 1 *-(2-Pyridin—4-yl- pyrid0[3',2':4,5]thien0[3,2- d]pyrirnidinyl)- propane-1,2-diarnine D* (R)-N* 1 * -(2-Pyridin—4-yl- pyrid0[3',2':4,5]thien0[3,2- d]pyrirnidinyl)- propane-1,2-diarnine Structure Name IC* 7,9-Dirnethy1—4-piperaziny1—2-pyridiny1— pyrid0[3',2':4,5]thien0[3,2- d]pyrimidine C* 4-[1,4]Diazepany1—7,9- dimethyl-Z-pyridinylpyrid0 [3',2':4,5]thien0[3,2- d]pyrimidine B* (S)-N* 1 -Dimethy1— 2-pyridinyl- pyrid0[3',2':4,5]thien0[3,2- rnidinyl)- propane-1,2-diarnine C* (R)-N* 1 *-(7,9-Dirnethyl- 2-pyridinyl- pyrid0[3',2':4,5]thien0[3,2- d]pyrirnidinyl)- propane-1,2-diarnine C* oropyridiny1— benzo[4,5]thieno[3,2- d]pyrirnidinyl)—(R)- pyrrolidin-3 -yl-arnine C* N*1*-(9-Chlor0 pyridiny1— benzo[4,5]thieno[3,2- d]pyrirnidinyl)-N * 1 * - methyl-ethane-1,2- diamine Structure Name B* N*1*-(9-Chloro pyridiny1— benzo[4,5]thieno[3,2- 3 86 d]pyrirnidiny1)-ethane- amine 9-Chlor0piperaziny1- 2-pyridinyl- benzo[4,5]thieno[3,2- d]pyrimidine (S)—N*1*-[6-Methy1—7- (2H-pyraz01—3- y1)pyridinyl- [3 ,2-d]pyrirnidin y1]-3 -pheny1—pr0pane- 1 ,2- diamine [7-Methy1—6-(2H-pyrazol- 3-y1)pyridiny1— thieno[3,2-d]pyrirnidin 389 )-pyrrolidinyl- amlne (S)Pheny1—N*1*-[7- (2H-pyraz01—3 -y1) pyridiny1—thieno[3 ,2- 390 d]pyrirnidiny1]— propane-1,2-diarnine (S)-N* 1 *-[7-(2-Methy1— 2H-pyraz01—3-y1)—2- pyridiny1—thieno[3 ,2- 391 d]pyrirnidiny1]—3- phenyl-propane-l ,2- diamine Structure Name C N*1*-[7-(3,5-Dirnethy1— isoxazoly1)pyridin yl-thieno[3 ,2-d]pyrimidin- 392I 4-y1]-3 -pheny1—pr0pane- 1 ,2-diamine (S)Pheny1—N*1*-[7- (1H-pyraz01—4- y1)pyridinyl- thieno [3 ,2-d]pyrirnidin 393I yl] -pr0pane- 1 ,2-diarnine C (S)—N* 1 *-[7-(1-Isobuty1— 1H-pyrazoly1)—2- pyridiny1—thieno [3 ,2- 394 d]pyrirnidiny1]—3 - -propane-l ,2- diamine C (S)-N* 1 *-[7-(4-Methy1— thiophen-Z-yl)—2-pyridin- 4-y1-thien0[3 ,2- d]pyrirnidiny1]—3- phenyl-propane-l ,2- diamine (S)-N* 1 *-[7-(3-Methy1— thiophen-Z-yl)—2-pyridin- 4-y1-thien0[3 ,2- 396 d]pyrirnidiny1]—3- phenyl-propane-l ,2- diamine Pheny1—N* 1 *-[2- n—4-y1—7-(1H-pyrrol- 2-yl)—thieno[3 ,2- 397I d]pyrirnidinyl] - propane-1,2-diarnine - Structure Name Pheny1—N* 1 * - [2- pyridin—4-y1—7-(1H-pyrroly1)-thieno [3 ,2- d]pyrirnidinyl] - e-l rnine (S)-N*1* - {7- [(tert-Butyl- dimethyl-silanyl)- ethynyl] pyridiny1— thieno [3 ,2-d]pyrirnidin yl} -3 -pheny1—pr0pane- 1 ,2- diamine (S)-N*1*-[7-(3-Methoxy- propyny1)pyridin yl-thieno [3 ,2-d]pyrimidin- 4-y1] -3 -pheny1—pr0pane- 1 ,2-diamine (S)—N* 1 *-(7-Pentyny1— 2-pyridinyl-thieno [3 ,2- d]pyrirnidinyl)-3 - phenyl-propane-l ,2- diamine (S)—3-Pheny1—N*1*-(7- phenylethynyl-Z-pyridin- 4-y1-thien0[3 ,2- d]pyrirnidinyl)- propane-1,2-diarnine Structure Name [7-(2H-Pyraz01—3-yl) pyridiny1—thieno[3,2— d]pyrirnidinyl]—(R)- pyrrolidin-3 -yl-arnine (S)—N*1*-[7-((E) Methoxy-propenyl)—2- ny1—thieno[3 ,2- 404 d]pyrirnidiny1]—3- phenyl-propane-l ,2- diamine (S)—N*1*-[7-((E)-2— Cyclopropyl-Vinyl) pyridiny1—thieno[3 ,2- 405 rnidiny1]—3- phenyl-propane-l ,2- diamine (S)-N*1*-[7-((E)-3,3- Dimethyl-buteny1) pyridiny1—thieno [3 ,2- 406 d]pyrirnidiny1]—3 - phenyl-propane-l ,2- diamine Pheny1—N*1*-[7- ((Z)-pr0penyl)pyridin- 4-y1-thien0[3 ,2- d]pyrirnidiny1]— propane-1,2-diarnine (S)—3-Pheny1—N*1*-(2- pyridiny1—7-Viny1- thien0[3,2-d]pyrirnidin y1)-propane-1 ,2-diarnine -400— Structure Name (S)-N*1*-[7-(4-F1uoro- phenyl)pyridiny1— [3 ,2-d]pyrirnidin y1]-3 -pheny1—pr0pane- 1 ,2- 409I e C (S)—3-Pheny1—N*1*-(2- pyridiny1—7-pyridin yl-thieno[3 ,2-d]pyrimidin- 410 4-y1)-pr0pane-1 ,2-diarnine C (S)-N* 1 *-[7-(1-Methy1— 1H-pyrazoly1)—2- pyridiny1—thieno [3 ,2- d]pyrirnidinyl] -3 - phenyl-propane-l ,2- diamine C (S)-N*1*-[7-(5-Methyl- ﬁJran-Z-yl)pyridiny1- thieno[3 ,2-d]pyrirnidin 412 y1]-3 -pheny1—pr0pane- 1 ,2- diamine A (S)—N*1*-(7-Cyclopropy1— 2-pyridiny1—thieno[3 ,2- d]pyrirnidinyl) 413 phenyl-propane-l ,2- diamine (R)Pheny1—N* 1 * - [7- (1H-pyraz01—3 -y1) pyridiny1—thieno [3 ,2- 414I rnidinyl] - propane-l ,2-diarnine —401— Structure Name C (S)-N*1*-[7-(1-Methyl- 1H-pyraz01—3 -y1) pyridiny1—thieno [3 ,2- 415 d]pyrirnidiny1]—3 - -propane-l ,2- diamine A (S)-N*1*-[2-(3-F1uoropyridiny1 )—7-(1H- pyraz01-3 -y1)-thien0 [3 ,2- 416 d]pyrirnidiny1]—3- phenyl-propane-l ,2- (S)—3-Pheny1—N*1*-(7- phenylpyridin—4-yl- thien0[3 yrirnidin 417I y1)-pr0pane-1 ,2-diarnine (S)-N*1*-[7-(5- Cyclopropyl- 1 H-pyrazoly1)pyridinyl- thieno [3 ,2-d]pyrirnidin 418I y1]-3 -pheny1—pr0pane- 1 ,2- diamine (S)-N*1*-[2-(3-F1uoropyridiny1 pyrrol-Z-yl)-thieno[3 ,2- 419I d]pyrirnidiny1]—3- phenyl-propane-1,2- diamine (S)-N*1*-[2-(3-F1uoropyridiny1 )—7-(1H- pyrrolyl)-thieno[3 ,2- 420I d]pyrirnidiny1]—3- phenyl-propane-l ,2- diamine —402— Structure Name (S)-N*1*-[2-(3-F1uoro- pyridinyl)—7-(5- triﬂuoromethyl-ZH- pyrazolyl)-thieno[3 ,2- d]pyrirnidiny1]—3- phenyl-propane-l ,2- diamine (R)-N* 1 *-[2-(3 o- pyridinyl)pyrirnidin- -y1-thieno[3 ,2- I d]pyrirnidiny1]—3- phenyl-propane-l ,2- diamine (R)-N* 1 *-[2-(3 -F1uoro- pyridin—4-y1)—7-pyridin yl-thieno[3 ,2-d]pyrimidin- 423I 4-y1]-3 1—pr0pane- 1 ,2-diamine {4-[4-((R)-2—Arnino phenyl-propylarnino)(3- ﬂuoro-pyridiny1)- thieno[3,2-d]pyrirnidin 424I yl] -pheny1} -rnethan01 {3-[4-((R)-2—Amino phenyl-propylarnino)(3- ﬂuoro-pyridiny1)- 425 thieno[3,2-d]pyrirnidin yl] -pheny1} -rnethan01 (R)-N* 1 *-[2-(3 -F1uoropyridinyl ran-3 -y1- thieno [3 ,2-d]pyrirnidin 426 yl]-3 -pheny1—pr0pane- 1 ,2- diamine -403— Structure Name (R)-N*1*-[7-(4- Aminomethyl-pheny1) (3-ﬂuoro-pyridiny1)— thieno[3 ,2-d]pyrirnidin 427 y1]-3 -pheny1—pr0pane- 1 ,2- diamine (R)-N*1*-[7-(3,5- Dimethyl-isoxazolyl)- 2-(3-ﬂu0ro-pyridinyl)- 428I thieno[3 ,2-d]pyrirnidin y1]-3 1—pr0pane- 1 ,2- diamine (R)-N* 1 *-[2-(3 -F1uoro- pyridin—4-y1)pyridin yl-thieno[3 ,2-d]pyrimidin- 429pheny1—pr0pane- 1 ,2-diamine (R)-N* 1 *-[7-(4-F1uoropheny1 )(3-ﬂuoropyridinyl )-thieno[3 ,2- d]pyrirnidiny1]—3propane-l ,2- diamine (R)-N* 1 *-[2-(3 -F1uoro- pyridiny1)thi0phen- 3-y1-thieno[3 ,2- d]pyrirnidiny1]—3- phenyl-propane-l ,2- diamine (R)-N* 1 *-[2-(3 -F1uoro- pyridiny1)furany1- thieno[3 ,2-d]pyrirnidin y1]-3 -pheny1—pr0pane- 1 ,2- diamine —404— ure Name (S)-N*1*-[2-(3-F1uoro- pyridinyl)0-tolyl- thieno[3 ,2-d]pyrirnidin y1]-3 -pheny1—pr0pane- 1 ,2- diamine C (S)-N*1*-[2-(3-F1uoropyridin —4-y1)—7-pheny1— [3 ,2-d]pyrirnidin 434I y1]-3 -pheny1—pr0pane- 1 ,2- diamine C S)—N*1*-[7-(4- Aminornethyl-ﬁlran-Z- y1)(3-ﬂu0ro-pyridin yl)-thien0[3 ,2- 435I d]pyrirnidiny1]—3- phenyl-propane-l ,2- diamine (S)—N*1*-[6-tert-Buty1—7- (3-ﬂuoro-phenyl) pyridiny1—thieno[3 ,2- d]pyrirnidiny1]—3- phenyl-propane-l ,2- diamine C (S)—N* 1 * - [6-tert-Buty1—7- (1H-pyraz01—4-y1) pyridiny1—thieno [3 ,2- d]pyrirnidinyl] -3 - phenyl-propane-l ,2- diamine C (S)-N*1*-[7-(6-F1uoropyridin rnethy1—2- pyridiny1—thieno[3 ,2- d]pyrirnidiny1]—3- 438 phenyl-propane-l ,2- diamine —405— Structure Name (S)-N*1*-[7-(4-Methoxy- pyridin—3-y1)rnethy1—2- pyridiny1—thieno[3 ,2- d]pyrirnidiny1]—3- phenyl-propane-l ,2- diamine (S)-N*1*-[7-(2- Isopropoxymethoxyphenyl )—6-rnethyl pyridiny1—thieno[3 ,2- d]pyrirnidiny1]—3- phenyl-propane-l ,2- diamine (S)—N*1*-[6-tert-Buty1—7- (3 -rneth0xy-phenyl) pyridiny1—thieno[3 ,2- d]pyrirnidiny1]—3- phenyl-propane-l ,2- diamine 1*-[6-tert-Buty1—7- r0-phenyl) pyridiny1—thieno[3 ,2- d]pyrirnidiny1]—3- phenyl-propane-l ,2- diamine (S)—N*1*-[6-tert-Buty1—7- (6-ﬂuoro-pyridiny1) pyridiny1—thieno[3 ,2- d]pyrirnidiny1]—3- phenyl-propane-l ,2- diamine ure Name (S)-N*1*-[7-(3-Arnino- phenyl)tert-butyl pyridiny1—thieno[3 ,2- rnidiny1]—3- 444I phenyl-propane-l ,2- (S)—N*1*-(6-tert-Butyl furan-3 -y1—2-pyridiny1— thieno[3 ,2-d]pyrirnidin 445I y1)-3 -pheny1—pr0pane- 1 ,2- diamine (S)-N* 1 *-[7-(5-F1u0r0 isopropoxy-pheny1) pyridinyl- 446I thieno[3 ,2-d]pyrirnidin y1]-3 -pheny1—pr0pane- 1 ,2- diamine C (S)—N*1*-[6-tert-Buty1—7- (5-methy1—thiopheny1)— 2-pyridiny1—thieno[3 ,2- 447 d]pyrirnidiny1]—3- phenyl-propane-l ,2- diamine C (S)—N*1*-[6-tert-Buty1—7- (4-rnethy1arnino-phenyl)- 2-pyridiny1—thieno[3 ,2- d]pyrirnidiny1]—3- 448 phenyl-propane-l ,2- diamine C (S)—N*1*-(6-Methy1—7- phenylpyridin—4-yl- thieno[3 ,2-d]pyrirnidin 449 y1)-3 -pheny1—pr0pane- 1 ,2- diamine —407— 2012/065831 Structure Name (S)-N*1*-[7-(2-Methoxy- -methy1—phenyl) methylpyridinyl- 450 thieno[3,2-d]pyrirnidin y1]-3 -pheny1—pr0pane- 1 ,2- diamine (S)—N*1*-(6-tert-Butyl phenylpyridin—4-yl- thieno[3 ,2-d]pyrirnidin 45 1 y1)-3 -pheny1—pr0pane- 1 ,2- (S)-N*1*-[7-(2-Chloro triﬂuorornethyl-phenyl) methylpyridinyl- 452 thieno[3 ,2-d]pyrirnidin y1]-3 -pheny1—pr0pane- 1 ,2- diamine (S)-N*1*-[7-(2-Chloro methoxy-phenyl) methylpyridinyl- 453 thieno[3 ,2-d]pyrirnidin y1]-3 -pheny1—pr0pane- 1 ,2- (S)-N*1*-[7-(2,6- Dimethoxy-phenyl) methylpyridinyl- thieno[3 ,2-d]pyrirnidin y1]-3 -pheny1—pr0pane- 1 ,2- diamine (S)-N*1*-[7-(2-Isobutoxy- 6-methoxy-phenyl) pyridinyl- 455 thieno[3 ,2-d]pyrirnidin y1]-3 -pheny1—pr0pane- 1 ,2- diamine Structure Name (S)-N*1*-[7-(3-Methoxy- n—4-y1)rnethy1—2- pyridiny1—thieno[3 ,2- d]pyrirnidiny1]—3- phenyl-propane-l ,2- diamine (S)-N*1*-[7-(2,4- Dimethyl-thiazol-S-y1) methylpyridinyl- thieno[3 ,2-d]pyrirnidin y1]-3 -pheny1—pr0pane- 1 ,2- diamine (S)-N*1*-[7-(2- Isopropoxy-S-rnethy1— phenyl)—6-rnethyl pyridiny1—thieno[3 ,2- d]pyrirnidiny1]—3- phenyl-propane-l ,2- diamine (S)-N*1*-[6-Methyl(2- methyl-pyridinyl) pyridiny1—thieno[3 ,2- d]pyrirnidiny1]—3- phenyl-propane-l ,2- diamine (S)-N* 1 *-[7-(5-Ch10r0 poxy-pheny1) methylpyridinyl- 460I thieno[3 ,2-d]pyrirnidin y1]-3 -pheny1—pr0pane- 1 ,2- diamine I (S)-N*1* - [7-(5 -tert-Butyl- oxy-phenyl) methylpyridinyl- thieno[3 yrirnidin y1]-3 -pheny1—pr0pane- 1 ,2- diamine -409— Structure Name (S)—N* 1 *-[7-(5 -Isopropy1— 2-methoxy-phenyl) methylpyridinyl- 462 thieno[3 ,2-d]pyrirnidin y1]-3 -pheny1—pr0pane- 1 ,2- diamine (S)-N* 1 5-Ch10r0 ethoxy-phenyl)methyl- 2-pyridiny1—thieno[3 ,2- 463I d]pyrirnidiny1]—3- phenyl-propane-l ,2- diamine (S)-N*1*-[7-(2-Methoxy- -triﬂuor0rnethyl-pheny1)- 6-methylpyridinyl- [3 ,2-d]pyrirnidin 464I y1]-3 1—pr0pane- 1 ,2- diamine (S)-N*1*-[7-(2-Methoxy- pyridin—3-y1)rnethy1—2- pyridiny1—thieno[3 ,2- 465I d]pyrirnidiny1]—3- phenyl-propane-l ,2- diamine (S)-N*1*-[7-(2,5- Dimethoxy-phenyl) methylpyridinyl- 466 thieno[3 ,2-d]pyrirnidin y1]-3 -pheny1—pr0pane- 1 ,2- diamine (S)-N* 1 *-[7-(5-F1u0r0 methoxy-phenyl) pyridinyl- 467 thieno[3 ,2-d]pyrirnidin y1]-3 -pheny1—pr0pane- 1 ,2- diamine —410— 2012/065831 ure Name C (S)—N*1*-[6-tert-Buty1—7- (2H-pyraz01—3 -y1) pyridiny1—thieno[3 ,2- d]pyrirnidiny1]—3- phenyl-propane-l ,2- diamine [7-Methy1—6-(2-methyl- 2H-pyrazol y1)pyridinylthieno [3,2-d]pyrirnidin yl]-(R)-pyrrolidinyl- amine Cyclopentanecarboxylic acid [4-((S)arnin0 -propylamino) pyridiny1—thieno[3,2— d]pyrimidinyl]-amide 2,2-Dimethy1—N—[2- pyridinyl((R)- pyrrolidin-3 -ylarnino)- thieno[3,2-d]pyrirnidin yl] -butyrarnide N—[4-((S)—2-Arnino phenyl-propylamino) pyridiny1—thieno[3,2— d]pyrirnidiny1]—2,2- dimethyl-butyrarnide Structure Name Cyclohcxanecarboxylic acid [2-pyridinyl ((R)-pyrr01idin ylamino)-thicno[3,2- 473I d]pyrirnidiny1]—arnidc Cyclohcxanecarboxylic acid [4-((S)- n0phcnylpropylarnino )pyridin 474I yl-thicno[3 ,2-d]pyrirnidin- 7-y1] -arnidc Cyclopcntanecarboxylic acid [2-pyridinyl ((R)-pyrr01idin ylamino)-thicno[3,2- 475I d]pyrirnidiny1]—arnidc D* 7-Mcthy1—2-pyridinyl- 4-((R)pyrr01idin ylrncthoxy)-thicno[3 ,2- 476 d]pyrirnidinc D* (R)(9-Chlor0pyridin- 4-y1—bcnz0[4,5]thicno[3,2- rnidin 477I yloxymcthyl)phcny1— cthylarninc D* 9-Chlor0pyridinyl ((R)- 1 1idin—2- ylrncthoxy)- 478 benzo[4,5]thieno[3,2- d]pyrirnidinc Structure Name 9-Chlor0pyridinyl ((S)— 1 -pyrr01idin ylrnethoxy)- benzo[4,5]thieno[3,2- d]pyrimidine 7-Methy1—2-pyridinyl- 4-((S)pyrr01idin hoxy)-thieno[3 ,2- d]pyrimidine (S)(7-Methy1—2-pyridin- 4-y1-thieno[3,2- d]pyrirnidin yloxymethyl)pheny1— rnine (R)(7-Methy1—2- pyridiny1—thieno[3,2— d]pyrirnidin yloxymethyl)pheny1— ethylarnine 7-Methy1—2-pyridinyl- 4-((S)-pyrrolidinyloxy)- [3 ,2-d]pyrirnidine 7-Methy1—2-pyridinyl- 4-((R)-pyrrolidin yloxy)-thieno[3,2- d]pyrimidine N*4*-((S)Amino phenyl-propyl)—N*7*- phenylpyridin—4-ylthieno [3,2-d]pyrirnidine- 4,7-diarnine —413— Structure Name A N*4*-((S)Amino phenyl-propyl)pyridin- 4-y1-N*7*-pyridinyl- 486 thieno[3,2-d]pyrirnidine- 4,7-diarnine C 2-Pyridiny1—N*7*- pyridin—2-yl-N*4*-(R)- pyrrolidiny1—thieno[3,2- d]pyrimidine-4,7-diamine N*4*-((S)Amino phenyl-propyl)pyridin- 4-y1-N*7*-pyrirnidiny1— 488I thieno[3,2-d]pyrirnidine- 4,7-diarnine C N*4*-((S)Amino phenyl-propyl)pyridin- 4-y1-N*7*-pyrirnidiny1— 489 thieno[3,2-d]pyrirnidine- arnine A N*4*-((S)Amino -propyl)—N*7*-(5- -isoxazol-3 -y1) 490 pyridiny1—thieno[3,2— d]pyrimidine-4,7-diamine C N*4*-((S)Amino phenyl-propyl)— 2-(3-ﬂu0ro-pyridinyl)- 491 N*7*-pheny1—thieno[3,2- d]pyrimidine-4,7-diamine —414— - Structure Name 2-(3 -F1u0r0-pyridiny1)- pyrrolidiny1—N*7*-rn— tolyl-thieno[3,2— d]pyrimidine-4,7-diamine N*7*-(4-Fluoro-phenyl)- 2-(3-ﬂuoropyridinyl )-N*4*-(R)- pyrrolidiny1—thieno[3,2- d]pyrimidine-4,7-diamine 2-(3 -F1u0r0-pyridiny1)- N*7*-pyridiny1-N*4*- (R)-pyrr01idin-3 -y1- thieno[3,2-d]pyrirnidine- 4,7-diarnine 2-(3 -F1u0r0-pyridiny1)- N*7*-pyridinyl-N*4*- (R)-pyrr01idin-3 -y1- thieno[3,2-d]pyrirnidine- 4,7-diarnine 2-(3 -F1u0r0-pyridiny1)- -rnethy1—isoxazol- 3-y1)-N*4*-(R)-pyrrolidin- 3-y1-thieno[3,2- d]pyrirnidine- 4,7-diarnine —415— ure Name 2-(3 -F1u0r0-pyridiny1)- N*7*-isoxazoly1-N*4*- (R)-pyrr01idin-3 -y1— 497 thieno[3,2-d]pyrirnidine- 4,7-diarnine C 2-(3 -F1u0r0-pyridiny1)- N*4*-(R)-pyrr01idinyl- N*7*-o-tolyl-thieno[3,2- d]pyrimidine-4,7-diamine C N*7*-(3-F1uoro-pheny1)- ‘. 2-(3-ﬂuoro- pyridinyl)-N*4*-(R)- pyrrolidiny1—thieno[3,2- 499 d]pyrimidine-4,7-diamine N*7*-(2-Fluoro-phenyl)- uoropyridinyl )-N*4*-(R)- pyrrolidiny1—thieno[3,2- d]pyrimidine-4,7-diamine 4-[4-((S)Arnino phenyl-propylarnino)(3- ﬂuoro-pyridiny1)- thieno[3,2-d]pyrirnidin yl]—but-3 -yn01 ure Name y1—4-[7-rnethyl pyridinyl((R)- pyrrolidin-3 -ylarnin0)- thien0[3,2-d]pyrirnidin yl]—butyn01 2-Methy1—4-[6-rnethyl pyridinyl((R)- pyrrolidin-3 -ylarnin0)- 503 thien0[3,2-d]pyrirnidin yl]—butyn01 4-[4-((S)Arnin0 phenyl-propylamino) methylpyridinyl- thien0[3,2-d]pyrirnidin 504 yl]methy1—butyn01 4-[4-((S)Arnin0 phenyl-propylamino) tert-butyl-Z-pyridinylthien0 [3,2-d]pyrirnidin 505 yl]methy1—butyn01 3-[4-((S)Arnin0 phenyl-propylarnino)(3- pyridiny1)- 506 thien0[3,2-d]pyrirnidin y1]-propyn01 1-[4-((S)Arnino phenyl-propylarnino)(3- ﬂuoro-pyridiny1)- thien0[3,2-d]pyrirnidin 507 ylethynyl]-cyclobutanol —417— Structure Name (S)[4-((S)Arnino phenyl-propylarnino)(3- ﬂuoro-pyridiny1)- thieno[3,2-d]pyrirnidin yl]—butyn01 4-[4-((S)Arnino phenyl-propylarnino)(3- ﬂuoro-pyridiny1)- thieno[3,2-d]pyrirnidin yl]methy1—butyn01 4-[4-((S)Arnino phenyl-propylamino) pyridiny1—thieno[3,2— d]pyrirnidiny1]—2- methyl-but—3-ynol (S)-N*1*-[7-(3,3- Dimethyl-butyny1)—2- pyridiny1—thieno [3 ,2- rnidinyl] -3 - phenyl-propane-l ,2- diamine 1*-(7- Cyclopropylethynyl-Z- pyridiny1—thieno[3 ,2- rnidinyl) phenyl-propane-l ,2- diamine Structure Name A 4-[4-((S)Arnino phenyl-propylamino) pyridiny1—thieno[3,2— d]pyrimidiny1]—but 513 yn01 II 2-Methy1—4-[2-pyridin y1—4-((R)—pyrr01idin y1amino)-thieno[3,2- d]pyrimidiny1]—but A 3-[4-((S)Arnino phenyl-propylamino) pyridiny1—thieno[3,2— 515 d]pyrirnidiny1]-prop yn01 C 1*-[7-(3-Arnino methyl-butyny1) pyridiny1—thieno [3 ,2- d]pyrirnidiny1] -3 - 516 phenyl-propane- 1 ,2- diamine A (S)—4-[2-Pyridiny1—4- ((R)-pyrr01idin y1amino)-thieno[3,2- d]pyrimidiny1]—but yn01 —419— Structure Name (S)-N"< 1 *-[7-(3 1— butyny1)pyridin yl-thieno [3 ,2-d]pyrirnidin- 4-y1] -3 -pheny1—pr0pane- 1 ,2-diamine 4-[2-(3 -F1uoro-pyridin yl)((R)-pyrrolidin ylamino)-thieno[3,2- rnidiny1]—2- methyl-butyn- 2_01 (S)-N*1*-[7-(3-Methoxyrnethy1-butyny1) pyridiny1—thieno [3 ,2- rnidiny1]—3 - 520 phenyl-propane-l ,2- diamine S)[4-((S)Arnino phenyl-propylamino) pyridiny1—thieno [3 ,2- d]pyrirnidiny1]—pent 521 ynol (S)[4-((S)Arnino phenyl-propylamino) pyridiny1—thieno[3,2- d]pyrirnidiny1]—4- 522 methyl-hept— 1 -yn-3 -01 —420— Structure Name (S)[4-((S)-2—Arnino phenyl-propylamino) pyridiny1—thieno [3 ,2- d]pyrirnidiny1]—3 - methyl-pent— 1 -yn-3 -01 (S)[4-((S)Arnino phenyl-propylamino) ny1—thieno [3 ,2- d]pyrirnidiny1]—3 ,4- dirnethyl-pentyn-3 -01 1- [4-(2-Arnin0-3 -pheny1— propylarnino)pyridin yl-thieno [3 ,2-d]pyrimidin- 7-y1]-3 -ethy1—pentyn-3 - (S)[4-((S)Amino phenyl-propylamino) pyridiny1—thieno [3 ,2- rnidiny1]—hex yn-3 -01 (S)[2-(3 -F1uoro- pyridiny1)—4- ((R)-pyrrolidin ylamino)-thieno[3,2- d]pyrimidinyl]-but ynol —421— Structure Name (S)Arnino phenyl-propylamino) ny1—thieno[3,2— d]pyrirnidinylethynyl]- cyclopentanol (S)—3-Pheny1—N*1*-(2- pyridiny1—7-pyridin ylethynyl-thieno [3 ,2- d]pyrirnidinyl)- propane-1,2-diarnine (S)-N*1*-[7-(2—F1uoro- phenylethyny1)pyridin- 4-y1-thien0[3 ,2- d]pyrirnidiny1]—3- phenyl-propane-l ,2- diamine 4-[4-((S)Arnino phenyl-propylamino) pyridiny1—thieno[3,2— d]pyrimidinyl]-but yn01 1-[4-((S)Arnino phenyl-propylamino) pyridiny1—thieno[3,2— d]pyrirnidinylethynyl]- cyclopropanol —422— Structure Name (S)[4-((S)Amino phenyl-propylamino) pyridiny1—thieno[3,2— midinyl]-but ynol (R)[4-((S)—2-Arnino phenyl-propylamino) pyridiny1—thieno[3,2— d]pyrimidinyl]-but ynol -[4-((S)Arnino phenyl-propylamino) pyridiny1—thieno[3,2— d]pyrirnidiny1]-pent yn01 A 5-[4-((S)Arnino phenyl-propylamino) pyridiny1—thieno[3,2— d]pyrirnidiny1]-pent ynol -[4-((S)Arnino -propylamino) pyridiny1—thieno[3,2— d]pyrirnidiny1]—2- methyl-pent—4-ynol —423— Structure Name (S)-N*1*-[7-(3- Methylamino-prop yny1)pyridinyl- thieno [3 ,2-d]pyrirnidin 538I y1]-3 -pheny1—pr0pane- 1 ,2- diamine A 1-[4-((S)Arnino phenyl-propylamino) ny1—thieno[3,2— d]pyrirnidinylethynyl]- 539 cyclobutanol (S)[4-((S)Amino -propylamino) pyridiny1—thieno[3,2— d]pyrirnidiny1]-pent 540I ynol A (S)—N* 1 *-(7-Ethyny1 pyridiny1—thieno[3 ,2- d]pyrirnidinyl) 541 -propane-l ,2- diamine A (S)—3-Pheny1—N* 1 * -(7- propyny1pyridin yl-thieno [3 ,2-d]pyrimidin- 542 4-y1)-pr0pane-1 ,2-diarnine C (6-Ethyny1—7-rnethyl pyridiny1— thieno[3,2-d]pyrirnidin yl)-(R)-pyrr01idiny1— 543 amine Structure Name A (S)-N*1*-[7-((R) Fluoro-butyny1)—2- ny1—thieno [3 ,2- d]pyrirnidiny1]—3 - phenyl-propane-l ,2- diamine (S)-N*1*-[7-(3-F1uoro- propyny1)pyridin yl-thieno [3 ,2-d]pyrimidin- 4-y1] -3 -pheny1—pr0pane- 1 ,2-diamine (S)-N*1*-[7-(4-F1uoro- butyny1)pyridin_4_ eno [3 ,2-d]pyrirnidine A (S)Pheny1—N*1*-[2- ; pyridiny1—7-(2H- [1 ,2,3]triaz01—4-y1)- 547 [3 ,2-d]pyrirnidin yl] -pr0pane- 1 ,2-diarnine (S)—3-Pheny1—N*1*-(2- pyridinylthiazol ylethynyl-thieno [3 ,2- d]pyrirnidinyl)- propane-1,2-diarnine —425— ActiVit Structure Name (S)Phcny1—N* 1 * - [7- (1H-pyraz01—3-ylcthyny1)- 2-pyridinyl-thicno [3 ,2- d]pyrirnidiny1]— 549 c-l ,2-diarninc 4-((S)Arninophcny1— propylarnino)pyridin cno[3,2— 550 d]pyrirnidinccarboxylic acid dirncthylarnidc 4-((S)Arninophcny1— propylarnino)pyridin yl-thicno[3,2— 551 d]pyrirnidinccarboxylic acid propylarnidc 4-((S)Arninophcny1— propylarnino)pyridin yl-thicno[3,2— 552 rnidinccarboxylic acid dicthylarnidc 4-((S)Arninophcny1— propylarnino)pyridin yl-thicno[3,2— 553 rnidinccarboxylic acid methylarnidc 4-((S)Arninophcny1— propylarnino)pyridin yl-thicno[3,2— 554 d]pyrirnidinccarboxylic acid cthylarnidc 4-((S)Arninophcny1— propylarnino)pyridin yl-thicno[3,2— 555 d]pyrirnidinccarboxylic acid isopropylarnidc Structure Name Arninophcny1— propylarnino)pyridin yl-thicno[3,2— 556 d]pyrirnidinccarboxylic acid cyclopropylarnide Arninophcny1— propylarnino)pyridin cno[3,2— 557 d]pyrirnidinccarboxylic acid tert-butylarnidc (E)[4-((S)Arnino phenyl-propylamino) pyridiny1—thicno[3,2— 558 d]pyrirnidiny1]—acrylic acid (7-Ethyny1—2-pyridinylthicn0 [3,2-d]pyrirnidin yl)-(R)-pyrr01idiny1— amine 559l 4-((S)Arninophcny1— propylarnino)pyridin yl-thicno[3,2— 560 d]pyrirnidinc carbonitrilc (S)—3-Phcny1—N* 1 * -(7- pyrazoly1—2-pyridin yl-thicno [3 ,2-d]pyrirnidin- 4-y1)-pr0panc-1 ,2-diarninc —427— Structure Name Pheny1—N*1*-(2- pyridinyl [1 riazoly1— 562I thieno [3 ,2-d]pyrirnidin y1)-pr0pane-1 ,2-diarnine C 1*-[7-(2- Cyclopropyl-ethy1) pyridiny1—thieno[3 ,2- 563 d]pyrirnidiny1]—3- phenyl-propane-l ,2- diamine C S)-N*1*-[7-Brorno(1- oxy-pyridin- 4-y1)-thien0 [3 ,2- d]pyrirnidiny1] pheny1—pr0pane-1 ,2- diamine C (S)-N*1*-[2-(1-Oxy- pyridiny1)—7- (2H-pyraz01—3 -y1)- 565 thieno [3 ,2-d]pyrirnidin y1]-3 -pheny1—pr0pane- 1 ,2- diamine N*4*-((S)Amino phenyl-propyl)— 2-pyridinyl-thieno[3,2- d]pyrimidine-4,7-diamine C 2-Pyridiny1—N*4*-(R)- pyrrolidiny1—thieno[3,2- d]pyrimidine-4,7-diamine Structure Name (S)-N*1*-[7-(5-Methyl- isoxazol-3 -y1)pyridin yl-thieno[3 ,2-d]pyrimidin- 4-y1]-3 -pheny1—pr0pane- 1 ,2-diamine A (S)-N* 1 5 -Methy1— 1H-pyraz01—3- y1)pyridinyl- thieno [3 ,2-d]pyrirnidin y1]-3 -pheny1—pr0pane- 1 ,2- diamine C (S)-N* 1 *-[7-(5-Ethy1— isoxazol-3 -pyridin eno[3 ,2-d]pyrimidin- 4-y1]-3 -pheny1—pr0pane- 1 ,2-diamine A (S)-N* 1 *-[7-(5 -Ethy1-2H- pyrazoly1)pyridin yl-thieno[3 ,2-d]pyrimidin- 4-y1]-3 -pheny1—pr0pane- 571I 1 ,2-diamine (S)-N*1*-(7-Isoxazol ylpyridin—4-y1— thieno[3 ,2-d]pyrirnidin y1)-3 -pheny1—pr0pane- 1 ,2- diamine C [2-(2-Pheny1arninopyridiny1 )-thieno[3,2- d]pyrirnidinyl]—(R)- idin-3 -yl-arnine Structure Name c Furan-Z-carboxylic acid {4-[4-((R)-pyrr01idin—3- ylamino)-thicno[3,2- 574 d]pyrirnidiny1] -pyridin- 2-y1} -amidc 1 -Phcny1—3- {4-[4-((R)- pyrrolidin-3 -y1arnin0)- thicno [3 ,2-d]pyrirnidin 575I yl]-pyridin-Z-y1}-urca N— {4-[4-((R)-Pyrrolidin ylarnino)- thicno[3,2-d]pyrirnidin yl] -pyridiny1} - 576I benzcncsulfonarnide {2-[2-(Pyrazin ylarnino)-pyridiny1]— thicno[3,2-d]pyrirnidin yl} -(R)-pyrr01idin-3 -y1— 577I amine (S)-Tctrahydr0-furan-2— carboxylic acid {4-[4- ((R)-pyrr01idin o)-thicno[3,2- 578I d]pyrirnidiny1]-pyridin- 2-y1}-amidc C [2-(5-F1u0r0 phenylarnino-pyridin yl)-thicn0[3,2- rnidinyl]—(R)- pyrrolidin-3 -y1-arninc Structure Name II {2-[S-Fluoro-Z-(pyrazin-Z- ylarnino)-pyridiny1]— thien0[3,2-d]pyrirnidin yl} -(R)-pyrr01idin-3 -y1— amine C 1,1-Dirnethy1—3-{4-[4- ((R)-pyrrolidin-3 - no)-thieno [3 ,2- 581 d]pyrirnidiny1] -pyridin- 2-y1} -urea C 1-tert-Buty1—3- {4-[4-((R)- pyrrolidin-3 -y1arnin0)- thieno [3 ,2-d]pyrirnidin 582 ridin-Z-y1}-urea C 1-Methy1—3- {4-[4-((R)— pyrrolidin-3 -y1arnin0)- thieno [3 ,2-d]pyrirnidin 583 ridin-Z-y1}-urea C Piperidinecarb0xylic acid {4-[4-((R)—pyrrolidiny1arnin0)-thieno [3 ,2- 584 d]pyrirnidiny1] -pyridin- 2-y1} -arnide {2-[3-F1uor0(pyrazin ylarnino)-pyridiny1]— thien0[3,2-d]pyrirnidin yl} -(R)-pyrr01idin-3 -y1— amine WO 78126 Structure Name {2-[2-((R)-1 -Pheny1- ethylarnino)—pyridiny1]- thieno [3 ,2-d]pyrirnidin yl} -(R)-pyrr01idin-3 -y1— 586I amine {2-[2-((S)Pheny1— ethylarnino)—pyridiny1]- thieno [3 ,2-d]pyrirnidin yl} -(R)-pyrr01idin-3 -y1— 587I amine {2-[2-(6-Methy1— pyridazinylarnino)- pyridiny1]—thieno[3,2- d]pyrirnidinyl} -(R)- 588I pyrrolidin-3 -yl-arnine C ((S)Pheny1— propylarnino)-pyridin yl] -thieno [3 ,2- d]pyrirnidinyl} -(R)- pyrrolidin-3 -yl-arnine C {2-[2-((R)-1 -Pheny1- propylarnino)-pyridin yl] -thieno [3 ,2- d]pyrirnidinyl} -(R)- pyrrolidin-3 -yl-arnine C (S){4-[4-((R)- Pyrrolidin-3 -ylarnin0)- thien0[3,2-d]pyrirnidin ridin-Z-ylarnino} - propan-Z-ol —432— ure Name C {4-[4-((R)- Pyrrolidin-3 -ylarnin0)- thieno[3,2-d]pyrirnidin yl]-pyridin-Z-ylarnino} - 592I propan-Z-ol C (R)Pheny1—2- {4-[4- ((R)-pyrrolidin-3 - ylarnino)-thieno [3 ,2- 593 d]pyrirnidiny1] -pyridin- 2-y1arnino} -ethan01 C [2-(2-Cyc10propylamino- pyridiny1)-thieno[3,2- d]pyrirnidiny1]—(R)— pyrrolidin-3 -yl-arnine enecarboxylic acid {4-[4-((R)—pyrrolidin- 3-ylarnino)-thieno[3,2- d]pyrirnidiny1] -pyridin- 595I 2-y1} -amide 3-Methoxy-N— {4-[4-((R)- pyrrolidin-3 -ylarnino)- thieno[3,2-d]pyrirnidin yl] -pyridinyl} - 596I benzarnide C {2- [2- (Cyclopropylrnethyl- amino)—pyridinyl] - thieno[3,2-d]pyrirnidin yl} -(R)-pyrr01idin-3 -y1— amine Structure Name Benzylamino- pyridiny1)-thieno[3,2- d]pyrirnidinyl]—(R)- pyrrolidin-3 -y1-arnine Cyclopropanecarboxylic acid {4-[4-((R)—pyrrolidin- 3-y1arnin0)-thien0[3,2- rnidiny1] -pyridin- 2-y1} -arnide {2-[2-(Pyridin ylarnino)-pyridiny1]— thien0[3,2-d]pyrirnidin yl} -(R)-pyrr01idin-3 -y1— amine (5 -Pheny1—pyridin ylarnino)-pyridiny1]— thien0[3,2-d]pyrirnidin yl} -(R)-pyrr01idin-3 -y1— amine {2-[2-(5 -M0rph01iny1— pyridin-Z-ylamino)- pyridiny1]—thieno[3,2-d] pyrimidiny1} -(R)- pyrrolidin-3 -y1-arnine —434— Structure Name (2-{2-[5-(4-Methy1— piperaziny1)- pyridin-Z-ylarnino] - pyridiny1} -thieno [3 ,2- d]pyrirnidinyl)—(R)- pyrrolidin-3 nine 6- {4-[4-((R)—Pyrrolidin ylamino)-thieno[3,2- d]pyrirnidiny1] -pyridin- 2-y1arnino} -nicotin0nitrile (2- {2-[3-(4-Methy1— piperaziny1)- phenylamino]-pyridin yl} -thieno [3 ,2- d]pyrirnidinyl)—(R)- pyrrolidin-3 -yl-arnine 3- {4-[4-((R)—Pyrrolidin o)-thieno[3,2- d]pyrirnidiny1] -pyridin- 2-ylamino} -benz0nitrile 4- {4-[4-((R)—Pyrrolidin ylamino)-thieno[3,2- d]pyrirnidiny1] in- 2-ylamino} -benz0nitrile —435— Ex Structure Name {2- [2-(4-Piperidin-1 -y1- phenylarnino)-pyridin yl]—thien0[3,2- d]pyrirnidinyl} -(R)- pyrrolidin-3 -yl-arnine 6- {4-[4-((R)—Pyrrolidin ylamino)-thieno[3,2- d]pyrirnidiny1] -pyridin- 2-y1arnino} -nicotin0nitrile N,N—Dirnethyl {4-[4- ((R)-pyrrolidin ylamino)-thieno[3,2- rnidiny1] -pyridin- 2-y1arnino} - benzenesulfonarnide (R)-Pyrrolidinyl- {2-[2- (4-pyrrolidin- 1 thy1— phenylarnino)-pyridin y1]-thien0 [3 ,2-]pyrirnidin- 4-y1} -amine (2- {2-[3-(Pr0pane sulfonyl)—phenylarnino] - pyridiny1} -thieno [3 ,2- d]pyrirnidinyl)—(R)- idin-3 -yl-arnine 2012/065831 Structure Name (4-Methy1—piperaziny1)- (4- {4-[4-((R)-pyrr01idin ylarnino)-thieno [3 ,2- d]pyrirnidiny1] -pyridin- 2-y1arnino} -pheny1)- methanone (4-Irnidazol ylrnethyl-phenylamino)- pyridinyl] -thieno [3 ,2- d]pyrirnidinyl} -(R)- pyrrolidin-3 -y1— amine Pyrazinecarboxylic acid {4-[4-((R)-pyrr01idin—3- ylamino)-thieno[3,2- d]pyrirnidiny1] -pyridin- 2-y1} -amide (R)-Pyrrolidinyl- {2-[2- (4-thiopheny1— phenylarnino)-pyridin yl]—thien0[3,2- midiny1} -arnine (R)-Pyrrolidinyl- {2-[2- (4-thi0phen-3 -y1— phenylarnino)-pyridin yl]—thien0[3,2- d]pyrimidiny1} -arnine —437— ure Name 4-F1uor0-N— {4-[4-((R)— pyrrolidin ylamino)-thieno[3,2- d]pyrirnidiny1] -pyridin- 2-y1} -benzarnide [2-(3-F1u0r0 phenylarnino-pyridin- 4-y1)-thien0[3,2- d]pyrirnidinyl]— (R)-pyrr01idin-3 -yl-arnine 4-(4-Methy1—piperazin y1>-N- {4- [4-<<R>- idin-3 -ylarnino)- thieno [3 ,2-d]pyrirnidin yl] inyl} - benzarnide 4-M0rph01iny1—N—{4- [4-((R)-pyrrolidin ylamino)-thieno[3,2- d]pyrirnidiny1] -pyridin- 2-y1} -benzarnide Cyclopropanesulfonic acid {4-[4-((R)-pyrr01idin—3- ylamino)-thieno[3,2- 622I d]pyrirnidiny1] -pyridin- 2-y1} -amide I [2-(2-Cyclohexy1arnino- pyridiny1)-thieno[3,2- d]pyrirnidinyl]—(R)- 623 pyrrolidin-3 -yl-arnine 2012/065831 Structure Name N— {4-[4-((R)-Pyrr01idin ylamino)-thicno[3,2- d]pyrirnidiny1] -pyridin- 2-y1} -mcthancsulfonarnidc (R)-Pyrrolidinyl- {2-[2- (tetrahydro-pyran ylarnino)-pyridiny1]— [3,2-d]pyrirnidin yl} -arninc C [2-(2-Isopropylarnino- pyridiny1)- thicn0[3,2-d]pyrirnidin 626 yl]-(R)-pyrr01idiny1— amine Thiophcnccarboxylic acid {4-[4-((3 S,4S)—4- hydroxy-pyrrolidin-3 - no)-thicno [3 ,2- d]pyrirnidiny1] -pyridin- 2-y1} -amidc Thiophcnccarboxylic acid {4- [4-((R)— 1 -rncthy1— pyrrolidin-3 -y1arnin0)- thicno [3 ,2-d]pyrirnidin yl] -pyridinyl} -arnidc -439— Structure Name Thiophcnccarboxylic acid {4-[4-((3 S,4S)— 1 - oylrncthyl hydroxy-pyrrolidin-3 - ylarnino)-thicno [3 ,2- d]pyrirnidiny1] -pyridin- 2-y1} -amidc Thiophcnccarboxylic acid (4- {4-[(S)arnino (4-triﬂu0rorncthylphenyl )—pr0py1arnino] - thicno [3 ,2-d]pyrirnidin yl} -pyridiny1)—amidc 2- {(R)[2-(2- Phenylarnino-pyridin- 4-y1)-thicno[3 ,2- d]pyrimidinylamino] - pyrrolidinyl} -acctarnidc [2-(5 -Mcthy1—1H-pyrazol- thicn0[3,2- d]pyrirnidinyl]—(R)- pyrrolidin-3 -yl-arninc —440— Structure (S)-N* l *-[2-(5 l- lH-pyrazol yl)-thieno [3 ,2- d]pyrimidinyl] -3 - phenyl-propane-l ,2- diamine Preferably, a compound of the present invention (i.e., a compound of formula (I) or a salt thereof) has an IC50 in an IMAP assay against ﬁlll length PKCL at 150 uM ATP of < 40 uM. In one embodiment, a compound of the present invention has an IC50 in an IMAP assay t ﬁlll length PKCL at 150 uM ATP of 40 uM — lO uM. More preferably, a compound of the present invention has an IC50 in an IMAP assay against ﬁlll length PKCL at 150 uM ATP of 10 uM — 1 uM. In one embodiment, a compound of the present invention has an IC50 in an IMAP assay against full length PKCL at 150 uM ATP of 1 uM — 0.1 uM. More preferably, a compound of the t invention has an IC50 in an IMAP assay t ﬁlll length PKCL at 150 uM ATP of < 0.1 uM.

Preferably, a compound of the present invention (i.e., a compound of formula (I) or a salt thereof) has an IC50 in an IMAP assay against kinase domain PKCL at 25 uM ATP of < 40 uM. In one embodiment, a compound of the present invention has an IC50 in an IMAP assay against kinase domain PKCL at 25 uM ATP of 40 uM — lO uM. More preferably, a compound of the present invention has an IC50 in an IMAP assay against kinase domain PKCL at 25 uM ATP of 10 uM — 1 uM. In one embodiment, a compound of the present invention has an IC50 in an IMAP assay against kinase domain PKCL at 25 uM ATP of 1 uM — 0.1 uM. More preferably, a compound of the present invention has an IC50 in an IMAP assay against kinase domain PKCL at 25 uM ATP of < 0.1 uM.

As those skilled in the art will iate, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore understood that Within the scope of the appended claims, the invention may be practiced otherwise than as cally described herein, and the scope of the invention is intended to encompass all such variations. —441— Each publication referenced herein is orated by reference in its entirety for all purposes. —442— 2012/065831 Additional Preferred Embodiments of the present invention include: l. A compound of formula (I) R3 If R4 \ R2 R6 A at“ /l X N G or a salt form f, wherein A is NR11,O,or S; S,\' \ ‘I M-Q-X is a group of formula R1, R2, R11, and R17 are independently chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C2_6alkenyl optionally substituted by 1-11 R19, C2- 6alkynyl optionally substituted by 1-9 R19, C6_11aryl ally substituted by 1-11 R19, C7_16arylalkyl optionally substituted by 1-19 R19, C3_11cycloalkyl optionally substituted by 1-21 R19, C4_17cycloalkylalkyl optionally substituted by 1—32 R19, 3—15 membered heterocycloalkyl optionally substituted by 1-28 R19, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40 R19, —443— -15 membered heteroaryl optionally tuted by 1-15 R19, 6-21 membered heteroarylalkyl optionally tuted by 1-27 R19, and —OR20; R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, R16, and R18 are independently chosen from H, C1_6alkyl optionally tuted by 1-13 R19, kenyl optionally substituted by 1-11 R19, C2_6alkynyl optionally substituted by 1—9 R19, C6_11aryl optionally substituted by 1-11 R19, C7_16arylalkyl optionally substituted by 1—19 R19, C3.1 1cycloalkyl optionally substituted by 1-21 R19, c4- oalkylalkyl optionally substituted by 1—32 R19, 3—15 membered heterocycloalkyl ally substituted by 1-28 R19, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40 R19, 5-15 membered heteroaryl optionally substituted by 1-15 R19, 6-21 ed heteroarylalkyl optionally substituted by 1—27 R19, halogen, —CN, —C(=O)R20, —C(=O)OR2°, — C(=O)NR22R23, C(=O)R2°, —C(=NR25)R2°, —C(=NR25)NR22R23, — C(=NOH)NR22R23, —C(=NOR26)R20, —C(=NNR22R23)R20, — C(=NNR24C(=O)R21)R2°, —C(=NNR24C(=O)OR21)R2°, —C(=S)NR22R23, —NC, —\102, —NR22R23, —NR24NR22R23, —N=NR24, —NR24OR26, —NR24C(=O)R2°, — \R24C(=O)C(=O)R2°, (=O)OR21, —NR24C(=O)C(=O)OR21, — \R24C(=O)NR22R23, —NR24C(=O)NR24C(=O)R2°, — \R24C(=O)NR24C(=O)OR2°, —NR24C(=NR25)NR22R23, — \R24C(=O)C(=O)NR22R23, —NR24C(=S)R2°, (=S)OR2°, — \R24C(=S)NR22R23, —NR24S(=O)2R21,—NR24S(=O)2NR22R23, — \R24P(:O)R28R28’ —NR24P(=O)(NR22R23)(NR22R23), _ \R24P(=O)(OR20)(OR20), —NR24P(=O)(SR2°)(SR2°), —OR20, —OCN, — OC(=O)R2°, —OC(=O)NR22R23, —OC(=O)OR2°, —OC(=NR25)NR22R23, — OS(=O)R2°, —OS(=O)2R2°, —OS(=O)20R20, —OS(=O)2NR22R23, — OP(=O)R28R28, —OP(=O)(NR22R23)(NR22R23), —OP(=O)(OR20)(OR20), — OP(=O)(SR2°)(SR2°), 4)3 — , —SCN, —S(=O)nR20, —S(=O)20R2°, —SOgR27, S(=O)2NR22R23, —S(=O)NR22R23, —SP(=O)R28R28, — SP(=O)(NR22R23)(NR22R23), —SP(=O)(OR2°)(OR2°), —SP(=O)(SR2°)(SR20), — P(=O)R28R28, —P(=O)(NR22R23)(NR22R23), —P(=O)(OR2°)(OR2°), and — P(=O)(SR2°)(SR2°); any ole and R2, R1 and R3, R1 and R5, R1 and R11, R4 and R11, R6 and R11, and R16 and R17 can, together with the atoms linking them, form a 3-15 membered —444— heterocycloalkyl optionally substituted by 1-28 R19 or a 5-15 membered heteroaryl ally substituted by 1-15 R19; any of R3 and R6, R7 and R8, R9 and R10, R12 and R13, and R14 and R15 can, together with the atoms linking them, form a C6_11aryl optionally substituted by 1-11 R19, C3_1lcycloalkyl optionally substituted by 1-21 R19, 3—15 membered heterocycloalkyl optionally substituted by 1-28 R19 or a 5-15 ed heteroaryl ally substituted by 1-15 R19; R3 and R5 or R4 and R6 can together form a double bond; any of R3 and R4, and R5 and R6 can together form =0, =NR20, =NOR20, or =8; R19 at each occurrence is independently chosen from C1_6alkyl optionally substituted by 1-13 R39, C2_6alkenyl ally substituted by 1-11 R39, C2- 6alkynyl ally substituted by 1-9 R39, C6_11aryl optionally substituted by 1-11 R39, C7_16arylalkyl optionally tuted by 1-19 R39, C3_11cycloalkyl optionally substituted by 1-21 R39, ycloalkylalkyl optionally substituted by 1—32 R39, 3—15 ed heterocycloalkyl optionally substituted by 1-28 R39, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40 R39, -15 membered aryl optionally tuted by 1-15 R39, 6-21 membered heteroarylalkyl optionally substituted by 1-27 R39, halogen, —CN, —C(=O)R30, —C(=O)OR3°, —C(=O)NR32R33, C(=O)R3°, —C(=NR35)R3°, — 5)NR32R33, —C(=NOH)NR32R33, —C(=NOR36)R3°, —C(=NNR32R33)R30, —C(=NNR34C(=0)R31)R3°, —C(=NNR34C(=O)OR31)R3°, —C(=S)NR32R33, —NC, —\102, —NR32R33, —NR34NR32R33, —N=NR34, =NR30, =N0R30, —NR340R36, — \R34C(=0)R3°, —NR34C(=O)C(=O)R3°, —NR34C(=O)OR31, — \R34C(=O)C(=O)OR31, —NR34C(=O)NR32R33, —NR34C(=O)NR34C(=O)R3°, — \R34C(=O)NR34C(=O)OR3°, —NR34C(=NR35)NR32R33, — \R34C(=O)C(=O)NR32R33, —NR34C(=S)R3°, —NR34C(=S)OR3°, — \R34C(=S)NR32R33, —NR34S(=O)2R31, —NR34S(=O)2NR32R33, — \R34P(:O)R38R38’ —NR34P(=O)(NR32R33)(NR32R33), _ \R34P(=O)(OR30)(OR30), —NR34P(=O)(SR3°)(SR3°), —0R3°, =o, —OCN, — OC(=O)R3°, —OC(=O)NR32R33, —OC(=O)OR3°, —OC(=NR35)NR32R33, — OS(=O)R3°, —OS(=O)2R30, —OS(=O)20R3°, —OS(=O)2NR32R33, — OP(=O)R38R38, —OP(=O)(NR32R33)(NR32R33), —OP(=O)(OR30)(OR30), — OP(=O)(SR3°)(SR3°), —Si(R34)3 — , —SCN, =s, —S(=0)nR3°, —S(=O)20R3°, SOsR37, —S(=O)2NR32R33, —S(=O)NR32R33, —SP(=O)R38R38, — - 445 — SP(=O)(NR32R33)(NR32R33), —SP(=O)(OR30)(OR30), —SP(=O)(SR3°)(SR30), — P(=O)R38R38, —P(=O)(NR32R33)(NR32R33), —P(=O)(OR3°)(OR3°), and — SR3°)(SR3°); 21 24 25 26 27 30 31 34 35 36 R ,R ,R ,R ,R ,R ,R ,R ,R ,R ,R ateachoccurrence1s- independently chosen from H, C1_6alkyl optionally substituted by 1-13 R49, C2- 6alkenyl optionally substituted by 1-11 R49, C2_6alkynyl optionally substituted by 1—9 R49, C6_11aryl optionally substituted by 1-11 R49, rylalkyl optionally substituted by 1-19 R49, ycloalkyl optionally substituted by l- 21 R49, C4_17cycloalkylalkyl optionally substituted by 1—32 R49, 3—15 membered heterocycloalkyl optionally substituted by 1-28 R49, 4-21 membered heterocycloalkylalkyl optionally substituted by 1—40 R49, 5—15 membered heteroaryl optionally substituted by 1-15 R49, and 6-21 membered heteroarylalkyl optionally substituted by 1-27 R49; R28 and R38 at each occurrence is independently chosen from kyl optionally substituted by 1-13 R49, C2_6alkenyl optionally substituted by 1-11 R49, C2- 6alkynyl ally substituted by 1-9 R49, C6_11aryl optionally substituted by 1-11 R49, C7_16arylalkyl optionally substituted by 1-19 R49, C3_11cycloalkyl optionally substituted by 1-21 R49, C4_17cycloalkylalkyl optionally substituted by 1—32 R49, 3—15 ed heterocycloalkyl optionally substituted by 1-28 R49, 4-21 ed heterocycloalkylalkyl optionally substituted by 1-40 R49, -15 membered aryl optionally substituted by 1-15 R49, and 6-21 ed heteroarylalkyl optionally substituted by 1-27 R49; R22, R23, R32 and R33 at each occurrence is independently chosen from H, C1_6alkyl optionally substituted by 1-13 R59, C2_6alkenyl ally substituted by 1-11 R59, kynyl optionally substituted by 1-9 R59, C6_11aryl optionally substituted by 1-11 R59, C7_16arylalkyl optionally substituted by 1-19 R59, c3- 11cycloalkyl optionally substituted by 1-21 R59, C4_17cycloalkylalkyl ally substituted by 1-32 R59, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R59, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40 R59, 5-15 membered heteroaryl optionally substituted by l- R59, and 6-21 membered heteroarylalkyl optionally substituted by 1-27 R59; or any R22 and R23 and/or R32 and R33 may form, together with the nitrogen atom to which they are attached, a 3-15 membered heterocycloalkyl optionally substituted by 1-28 R69 or a 5-15 membered heteroaryl optionally substituted by l - l 5 R69; R39, R49, R59 and R69 at each occurrence is ndently chosen from C1_6alkyl optionally substituted by 1-13 R79, C2_6alkenyl optionally substituted by 1-11 R79, C2_6alkynyl optionally substituted by 1-9 R79, ryl optionally tuted by 1-11 R79, C7_16arylalkyl optionally substituted by 1-19 R79, c3- 11cycloalkyl optionally substituted by 1-21 R79, C4_17cycloalkylalkyl optionally substituted by 1-32 R79, 3-15 rnernbered heterocycloalkyl optionally substituted by 1-28 R79, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40 R79, 5-15 membered heteroaryl optionally substituted by l- R79, 6-21 membered heteroarylalkyl optionally substituted by 1-27 R79, n, —CN, —C(=O)R70, —C(=O)OR7°, —C(=O)NR72R73, —C(=O)C(=O)R7°, —C(=NR75)R7°, —C(=NR75)NR72R73, —C(=NOH)NR72R73, —C(=NOR76)R7°, — C(=NNR72R73)R7°, —C(=NNR74C(=O)R71)R7°, —C(=NNR74C(=O)OR71)R7°, — C(=S)NR72R73, —NC, —N02, —NR72R73, —NR74NR72R73, 4, =NR70, =NOR70, —NR74OR76, —NR74C(=O)R7°, —NR74C(=O)C(=O)R7°, — NR74C(=O)OR71, —NR74C(=O)C(=O)OR71, —NR74C(=O)NR72R73, — NR74C(=O)NR74C(=O)R7°, —NR74C(=O)NR74C(=O)OR7°, — NR74C(=NR75)NR72R73, —NR74C(=O)C(=O)NR72R73, —NR74C(=S)R70, — NR74C(=S)OR7°, —NR74C(=S)NR72R73, —NR74S(=O)2R71, — NR74S(=O)2NR72R73, —NR74P(=O)R78R78, —NR74P(=O)(NR72R73)(NR72R73), _ NR74P(=O)(OR7°)(OR70), (=O)(SR7°)(SR7°), —0R7°, =o, —OCN, — OC(=O)R7°, —OC(=O)NR72R73, —OC(=O)OR7°, —OC(=NR75)NR72R73, — OS(=O)R7°, —OS(=O)2R7°, )20R7°, —OS(=O)2NR72R73, — OP(=O)R78R78, )(NR72R73)(NR72R73), —OP(=O)(OR70)(OR70), — (SR7°)(SR7°), —Si(R7“)3 — , —SCN, =s, —S(=O)nR7°, —S(=O)20R7°, SOgR77, —S(=O)2NR72R73, —S(=O)NR72R73, —SP(=O)R78R78, — SP(=O)(NR72R73)(NR72R73), —SP(=O)(OR70)(OR70), )(SR7°)(SR70), — 78R78, —P(=O)(NR72R73)(NR72R73), —P(=O)(OR7°)(OR7°), and — P(=O)(SR7°)(SR7°); R70, R71, R74, R75 , R76 and R77 at each occurrence is independently chosen from H, C1_6alkyl optionally substituted by 1-13 R89, C2_6alkenyl ally substituted by 1-11 R89, C2_6alkynyl optionally substituted by 1-9 R89, C6_11aryl optionally substituted by 1-11 R89, C7_16arylalkyl optionally substituted by 1-19 R89, c3- _ 447 — WO 78126 11cycloalkyl optionally substituted by 1-21 R89, C4_17cycloalkylalkyl optionally tuted by 1-32 R89, 3-15 membered heterocycloalkyl ally substituted by 1-28 R89, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40 R89, 5-15 membered heteroaryl optionally substituted by l- R89, and 6-21 membered heteroarylalkyl optionally substituted by 1-27 R89; R72 and R73 at each occurrence is independently chosen from H, C1_6alkyl optionally tuted by 1-13 R99, C2_6alkenyl optionally substituted by 1-11 R99, C2_6alkynyl optionally substituted by 1-9 R99, C6_11aryl optionally substituted by 1-11 R99, C7_16arylalkyl optionally substituted by 1-19 R99, c3- 11cycloalkyl optionally substituted by 1-21 R99, C4_17cycloalkylalkyl optionally substituted by 1-32 R99, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R99, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40 R99, 5-15 membered heteroaryl optionally tuted by l- R99, and 6-21 membered heteroarylalkyl optionally substituted by 1-27 R99; or any R72 and R73 may form, together with the nitrogen atom to which they are attached, a 3-15 ed heterocycloalkyl optionally substituted by 1-28 R109 or a 5-15 membered heteroaryl optionally substituted by 1-15 R109; R78 at each occurrence is independently chosen from C1_6alkyl optionally substituted by 1-13 R89, C2_6alkenyl optionally substituted by 1-11 R89, C2- 6alkynyl optionally tuted by 1-9 R89, C6_11aryl optionally substituted by 1-11 R89, C7_16arylalkyl ally substituted by 1-19 R89, C3_11cycloalkyl optionally substituted by 1-21 R89, C4_17cycloalkylalkyl optionally substituted by 1—32 R89, 3—15 membered heterocycloalkyl optionally tuted by 1-28 R89, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40 R89, 5-15 ed aryl optionally substituted by 1-15 R89, and 6-21 membered arylalkyl optionally substituted by 1-27 R89; R79, R89, R99 and R109 at each occurrence is independently chosen from C1_6alkyl optionally substituted by 1-13 halogen, C2_6alkenyl, C2_6alkynyl, C6_11aryl, C7- 16arylalkyl, C3_11cycloalkyl, C4_17cycloalkylalkyl, 3-15 membered heterocycloalkyl, 4-21 membered heterocycloalkylalkyl, 5-15 membered heteroaryl, 6-21 membered heteroarylalkyl, n, —CN, —C(=O)R110, — C(=O)OR“0, —C(=0)NR“°R“0, C(=O)R“°, —C(=NR“°)R“°, — C(=NR110)NR110R110, —C(=NOH)NR110R110, —C(=NOR110)R110, _ C(=NNR110R110)R110, —C(=NNR110C(=O)R110)R110, _ C(=NNR110C(=O)OR110)R110, —C(=S)NR110R110, —NC, —N02, R110, _ 77777 RHONRUORUO, _N:NR1 10’ ZNRUO, , —NR1100R110, (=O)R110, —NR110C(=O)C(=O)R110, C(=O)OR110, _R110C(=O)C(=O)OR110, —NR110C(=O)NR110R110, _R“°C(=0)NR“°C(=0)R“0, —NR“°C(=0)NR11°C(=0)0R“0, —R110C(=NR110)NR110R110, —NR110C(=O)C(=O)NR1IORUO, C(=S)R110, —\IR110C(=S)OR110, —NR110C(=S)NR110R110, —NRUOS(=O)2R110, _ thlOS(:O)ZNR110R110’ —NR110P(=O)R111R111, _ l\R110P(=O)(NR110R110)(NR110R110), —NR110P(=O)(OR110)(OR110), _ I\R“°P(=O)(SR11°)(SR110), —0R“°, =0, —OCN, —OC(=O)R“0, — 0C(=0)NR“°R“°, —0C(=0)0R“°, —0C(=NR“°)NR“°R“°, —OS(=O)R“°, — OS(=O)2R“°, —OS(=O)20R“°, —OS(=O)2NR“°R“°, —OP(=O)R1“R“1, — OP(:O)(NR110R1 10)(NR110R1 10), —OP(=O)(OR110)(OR110), _ OP(=O)(SR“°)(SR“°), —Si(R“°)3 — , —SCN, =s, —S(=O)nR“0, —S(=O)20R“°, SOgRllO, —S(=O)2NR110R110, NR110R110, —SP(=O)R111R111, _ SP(=O)(NR1IORUOXNRUORUO), )(OR110)(OR110), _ SP(=O)(SR110)(SR110), —P(=O)R111R111, —P(=O)(NR110R110)(NR110R110), _ P(=0)(0R“°)(0R“°), and —P(=O)(SR“0)(SR“0); R110 at each occurrence is independently chosen from H, C1_6alkyl and €1 haloalkyl; R111 at each occurrence is independently chosen from C1_6alkyl and C1_6-haloalkyl; n at each occurrence is independently chosen from 0, l, and 2. 2. A compound as deﬁned in Preferred Embodiment 1, wherein A is NR“. 3. A compound as deﬁned in Preferred Embodiments l or 2, wherein G is a group of —449— WO 78126 4. A compound as deﬁned in Preferred ment 3, wherein G is a group of formula and the compound of formula (I) is a compound of formula R3 If R4 \ R2 R6 A [M / N R12 Q\ l \ R13 X N \ R15 / N (1c) (1c).

A compound as defined in any of Preferred Embodiments 1-4, wherein R1, R2, and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-3 R19; R3, R4, R5, and R6 are independently chosen from H, C1_6alkyl ally substituted by 1-3 R19, halogen, —CN, —C(=O)R20, —C(=O)OR2°, —C(=O)NR22R23, —N02, —NR22R23, — NR24C(=O)R2°, —NR24S(=O)2R21,—OR2°, —OC(=O)R2°, —S(=O)nR2°, and —S(=O)2NR22R23; alternatively, R3 and R6 can, together with the atoms linking them, form a C6_10aryl optionally substituted by 1-3 R19, ycloalkyl optionally tuted by 1-3 R19, 3-10 ed heterocycloalkyl optionally substituted by 1-3 R19 or a 5-10 membered heteroaryl optionally substituted by 1-3 R19; alternatively R3 and R5 or R4 and R6 can together form a double bond; and alternatively any of R1 and R2, R1 and R3, R1 and R5, R1 and R11, R4 and R11, and R6 and R11 can, together with the atoms linking them, form a 5-15 membered heterocycloalkyl optionally substituted by 1-3 R19 or a 5-15 membered heteroaryl ally substituted by 1-3 R19. 6. A compound as defined in any of Preferred Embodiments 1-4, wherein R1, R2, and R11 are independently chosen from H and C1_6alkyl ally substituted by 1-3 R19; R3, R4, R5, and R6 are independently chosen from H, C1_6alkyl optionally substituted by 1-3 R19, halogen, —CN, —C(=O)R20, —C(=O)NR22R23, —NR22R23, —NR24C(=O)R2°, — NR24S(=O)2R21,—OR20, —S(=O)nR20, and —S(=O)2NR22R23; alternatively any of R1 and R2, R1 and R3, R1 and R5, R1 and R11, R4 and R11, and R6 and R11 can, together with the atoms WO 78126 linking them, form a 5-15 membered heterocycloalkyl optionally substituted by 1-3 R19. 7. A compound as deﬁned in any of Preferred Embodiments 1-4, wherein R1, R4, R5 R6, and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-13 R19; R2 is chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C7_16arylalkyl optionally substituted by 1-19 R19, and 6-21 membered heteroarylalkyl optionally substituted by 1-27 R19; R3 is chosen from H, C1_6alkyl optionally tuted by 1-13 R19, C7_16arylalkyl optionally tuted by l- l 9 R19, C4_17cycloalkylalkyl optionally substituted by 1-32 R19, and 6-21 membered arylalkyl optionally substituted by 1-27 R19; alternatively, R3 and R6 can, together with the atoms linking them, form a C3- 10cycloalkyl optionally substituted by 1-6 R19; alternatively R3 and R4 can together form =0; and alternatively any of R1 and R2, R1 and R3, R1 and R5, R1 and R11, R4 and R11, and R6 and R11 can, together with the atoms linking them, form a 3-15 membered heterocycloalkyl optionally substituted by 1-22 R19. 8. A compound as deﬁned in any of Preferred Embodiments 1-4, wherein R1, R4, R5 R6, and R11 are independently chosen from H and C1_6alkyl ally substituted by 1-3 R19; R2 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C7_11arylalkyl optionally substituted by 1-3 R19, and 6-10 membered heteroarylalkyl optionally substituted by 1-3 R19; R3 is chosen from H, C1_6alkyl optionally tuted by 1-3 R19, C7_11arylalkyl optionally substituted by 1-9 R19, C6_7cycloalkylalkyl optionally substituted by 1-6 R19, and 6-11 ed heteroarylalkyl optionally substituted by 1-7 R19; and alternatively any of R1 and R2, R1 and R3, R1 and R5, R1 and R11, and R4 and R11 can, together with the atoms linking them, form a 3-7 membered heterocycloalkyl optionally tuted by 1—3 R19. 9. A compound as deﬁned in any of Preferred Embodiments 1-8, wherein R7, R8, R9, and R10 are independently chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C2- 6alkenyl ally substituted by 1-3 R19, C2_6alkynyl optionally tuted by 1-3 R19, C6_10aryl optionally substituted by 1-3 R19, C7_11arylalkyl optionally substituted by 1-3 R19, C3_7cycloalkyl optionally substituted by 1-3 R19, C4_gcycloalkylalkyl optionally tuted by 1-3 R19, 3-7 membered heterocycloalkyl optionally substituted by 1-3 R19, 4-8 membered heterocycloalkylalkyl optionally substituted by 1-3 R19, 5-6 membered heteroaryl optionally substituted by 1-3 R19, 6-21 membered heteroarylalkyl optionally substituted by 1—3 R19, n, —CN, —C(=O)R20, —C(=O)OR2°, NR22R23, —NC, — N02, —NR22R23, —NR24OR26, —NR24C(=O)R2°, (=O)OR21, —NR24C(=O)NR22R23, — NR24S(=O)2R21, —NR24S(=O)2NR22R23, —OR2°, —OCN, —OC(=O)R2°, —OC(=O)NR22R23, — OC(=O)OR2°, —OS(=O)2R2°, —OS(=O)20R2°, —OS(=O)2NR22R23, —S(=O)nR2°, and — S(=O)2NR22R23; alternatively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a C6_10aryl optionally substituted by 1-3 R19, C3- 7cycloalkyl optionally substituted by 1-3 R19, 3-7 membered cycloalkyl optionally substituted by 1-3 R19 or a 5-6 membered heteroaryl optionally substituted by 1-3 R19.

. A compound as deﬁned in any of red Embodiments 1-8, wherein R7, R8, R9, and R10 are independently chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C2- 6alkynyl ally substituted by 1-3 R19, C6_10aryl optionally substituted by 1-3 R19, C3- 7cycloalkyl ally tuted by 1-3 R19, 3-7 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-6 ed heteroaryl optionally substituted by 1-3 R19, halogen, —CN, —C(=O)R20, —C(=O)NR22R23, —N02, —NR22R23, —NR24S(=O)2R21, —OR2°, — S(=O)nR20, and 2NR22R23; alternatively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a C3_7cycloalkyl optionally substituted by 1-3 R19, or a 3-7 membered heterocycloalkyl optionally substituted by 1-3 R19. ll. A compound as deﬁned in any of Preferred Embodiments 1-8, wherein R7, R8, R9, and R10 are independently chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C2- yl optionally substituted by 1-11 R19, C2_6alkynyl optionally substituted by 1-9 R19, C6_11aryl optionally substituted by 1-11 R19, C7_16arylalkyl optionally substituted by 1-19 R19, C3_11cycloalkyl optionally substituted by 1-21 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R19, 5-15 membered heteroaryl optionally substituted by l- R19, 6-21 membered heteroarylalkyl optionally substituted by 1-27 R19, halogen, —CN, —C(=O)R2°, —C(=O)NR22R23, —NR22R23, —NR24C(=O)R2°, and —OR20; alternatively, either or both of R7 and R8, and/or R9 and R10, can, er with the atoms linking them, form a C6_11aryl optionally tuted by 1-11 R19, C3_11cycloalkyl optionally substituted by 1-21 R19, 3-15 membered heterocycloalkyl ally tuted by 1-28 R19 or a 5-15 ed heteroaryl optionally substituted by 1-15 R19. 12. A compound as deﬁned in any of Preferred Embodiments 1-8, wherein R7 and R10 are independently chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C2_6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl ally substituted by 1-3 R19, C6_11aryl optionally substituted by 1-3 R19, C7_16arylalkyl optionally substituted by 1-3 R19, C3- 11cycloalkyl optionally tuted by 1-3 R19, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-15 membered heteroaryl optionally substituted by 1-3 R19, 6-21 membered heteroarylalkyl optionally substituted by 1-3 R19, halogen, —CN, —C(=O)R20, — 2012/065831 C(=O)NR22R23, —NR22R23, —NR24C(=O)R20, and —OR20; R8 and R9 are independently chosen from C1_6alkyl optionally substituted by 1-3 R19, C2_6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl optionally substituted by 1-3 R19, C6_11aryl optionally substituted by 1-3 R19, C7_16arylalkyl optionally substituted by 1-3 R19, C3_11cycloalkyl optionally substituted by 1-3 R19, 3-15 membered heterocycloalkyl optionally tuted by 1-3 R19, -15 membered heteroaryl optionally substituted by 1-3 R19, 6-21 membered heteroarylalkyl optionally substituted by 1—3 R19, halogen, —CN, —C(=O)R2°, — C(=O)NR22R23, —NR22R23, —NR24C(=O)R20, and —OR20; alternatively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a C6_11aryl optionally tuted by 1-3 R19, C3_11cycloalkyl optionally tuted by 1-3 R19, 3-15 ed heterocycloalkyl optionally substituted by 1-3 R19 or a 5-15 ed aryl ally substituted by 1-3 R19. 13. A compound as deﬁned in any of Preferred Embodiments 1-8, wherein R7, R8, R9, and R10 are independently chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C2- 6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl optionally substituted by 1-3 R19, C6_10aryl optionally substituted by 1-3 R19, C7_11arylalkyl optionally substituted by 1-3 R19, C3_10cycloalkyl optionally substituted by 1-3 R19, 3-10 membered heterocycloalkyl optionally tuted by 1-3 R19, 5-10 membered heteroaryl optionally substituted by 1-3 R19, 6-ll ed heteroarylalkyl optionally substituted by 1-3 R19, halogen, —CN, — C(=O)R20, —C(=O)NR22R23, —NR22R23, —NR24C(=O)R20, and —OR20; alternatively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a C6_10aryl optionally substituted by 1-3 R19, C3_10cycloalkyl optionally substituted by 1-3 R19, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R19 or a 5-10 ed aryl optionally substituted by 1-3 R19. 14. A compound as deﬁned in any of Preferred Embodiments 1-8, wherein R7, R8, R9, and R10 are independently chosen from H, C1_6alkyl optionally tuted by 1-3 R19, C2- 6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl ally substituted by 1-3 R19, phenyl optionally substituted by 1-3 R19, C3_6cycloalkyl optionally substituted by 1-3 R19, 3-6 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-6 membered heteroaryl optionally substituted by 1-3 R19, halogen, —CN, —C(=O)R2°, —C(=O)NR22R23, — NRZZRB, —NR24C(=O)R20, and —OR20; alternatively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a phenyl ally substituted by 1-3 R19, C3_6cycloalkyl optionally substituted by 1-3 R19, 3-6 membered heterocycloalkyl —453— optionally substituted by 1-3 R19 or a 5-6 membered heteroaryl optionally substituted by l- 3 R19.

. A compound as deﬁned in any of Preferred Embodiments 1-14, n R12, R13, R14, and R15 are independently chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C2_6alkenyl optionally tuted by 1-3 R19, C2_6alkynyl ally substituted by 1-3 R19, C6_10aryl optionally substituted by 1-3 R19, C3_7cycloalkyl optionally substituted by 1-3 R19, 3-7 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-6 membered heteroaryl optionally substituted by 1—3 R19, halogen, —CN, —C(=O)R2°, —C(=O)OR2°, — C(=O)NR22R23, —NOg, —NR22R23, (=O)R2°, —NR24C(=O)OR21, — NR24C(=O)NR22R23, —NR24S(=O)2R21, —NR24S(=O)2NR22R23, —OR2°, —OC(=O)R2°, — OC(=O)NR22R23, —OC(=O)OR2°, nR2°, —S(=O)20R2°, —SOsR27, —S(=O)2NR22R23, — S(=O)NR22R23, —P(=O)R28R28, —P(=O)(NR22R23)(NR22R23), and —P(=O)(OR20)(OR2°); atively, either or both of R12 and R13, and/or R14 and R”, can, together with the atoms linking them, form a C6_10aryl optionally substituted by 1-3 R19, C3_7cycloalkyl optionally substituted by 1-3 R19, 3-7 membered heterocycloalkyl optionally substituted by 1-3 R19 or a 5-6 membered heteroaryl optionally substituted by 1-3 R19. 16. A compound as deﬁned in any of Preferred Embodiments 1-14, wherein R12, R13, R14, and R15 are ndently chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C2_6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl optionally tuted by 1-3 R19, C6_10aryl optionally substituted by 1-3 R19, C3_7cycloalkyl optionally substituted by 1-3 R19, 3-7 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-6 membered heteroaryl optionally substituted by 1—3 R19, halogen, —CN, —C(=O)R2°, —C(=O)NR22R23, — N02, —NR22R23, —NR24C(=O)R20, —NR24S(=O)2R21,—OR2°, —S(=O)nR20, and — S(=O)2NR22R23; alternatively, either or both of R12 and R13, and/or R14 and R”, can, together with the atoms linking them, form a C6_10aryl optionally substituted by 1-3 R19, C3_7cycloalkyl optionally substituted by 1-3 R19, 3-7 membered cycloalkyl optionally substituted by 1-3 R19 or a 5-6 membered heteroaryl optionally substituted by l- 3 R19. 17. A compound as deﬁned in any of Preferred Embodiments 1-14, wherein R12, R13, and R14 are H; R15 is chosen from H, C1_6alkyl ally substituted by 1-3 R19, C2- 6alkenyl optionally tuted by 1-3 R19, kynyl optionally substituted by 1-3 R19, C6_10aryl optionally substituted by 1-3 R19, C3_7cycloalkyl optionally substituted by 1-3 R19, 3-7 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-6 membered heteroaryl optionally substituted by 1—3 R19, halogen, —CN, R2°, —C(=O)NR22R23, — _ 454 _ N02, —NR22R23, (=O)R20, —NR24S(=O)2R21,—OR2°, —S(=O)nR20, and — S(=O)2NR22R23. 18. A compound as deﬁned in any of Preferred Embodiments 1-14, wherein R12, R13, R14, and R15 are independently chosen from H, halogen, —NR22R23, —NR24C(=O)R20, — NR24C(=O)NR22R23, —OR20, and —S(=O)2NR22R23. 19. A compound as deﬁned in any of Preferred ments 1-14, wherein R12, R13, and R15 are H; R14 is chosen from H, halogen, —NR22R23, —NR24C(=O)R20, — NR24C(=O)NR22R23, —OR20, and —S(=O)2NR22R23.

. A compound as deﬁned in any of Preferred Embodiments 1-3 or 5-19, wherein R17 is chosen from H and C1_6alkyl; R16 and R18 are independently chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C6_10aryl optionally tuted by 1-3 R19, C7_11arylalkyl optionally tuted by 1-3 R19, C3_10cycloalkyl optionally substituted by 1-3 R19, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-10 membered heteroaryl optionally tuted by 1—3 R19, halogen, —CN, —C(=O)R20, —C(=O)OR2°, — C(=O)NR22R23, —NC, —N02, —NR22R23, —NR24C(=O)R20, —NR24C(=O)OR21, — NR24C(=O)NR22R23, —NR24S(=O)2R21, —OR2°, —OCN, —OC(=O)R2°, )NR22R23, — SCN, —S(=O)nR2°, —S(=O)20R20, —SOgR27, —S(=O)2NR22R23, and —S(=O)NR22R23; alternatively, R16 and R17 can, together with the atoms linking them, form a 3-10 membered cycloalkyl optionally substituted by 1-3 R19 or a 5-10 membered heteroaryl optionally substituted by 1-3 R19. 21. A compound as deﬁned in any of Preferred Embodiments 1-3 or 5-19, wherein R17 is chosen from H and C1_6alkyl; R16 and R18 are independently chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C6_10aryl optionally substituted by 1-3 R19, C7_11arylalkyl optionally substituted by 1-3 R19, C3_10cycloalkyl optionally substituted by 1-3 R19, 3-10 membered heterocycloalkyl optionally tuted by 1-3 R19, 5-10 membered heteroaryl optionally substituted by 1—3 R19, halogen, —CN, R20, —C(=O)NR22R23, —N02, — NRZZR”, —NR24C(=O)R20, —NR24S(=O)2R21,—OR2°, —S(=O)nR20, and —S(=O)2NR22R23; atively, R16 and R17 can, together with the atoms linking them, form a 3-10 membered heterocycloalkyl optionally substituted by 1-3 R19 or a 5-10 membered heteroaryl optionally substituted by 1-3 R19. 22. A nd as deﬁned in any of red Embodiments 1-3 or 5-19, wherein R17 is H; and R16 and R18 are independently chosen from H and C1_6alkyl optionally substituted by 1—3 R19. —455— WO 78126 23. A compound as deﬁned in any of Preferred Embodiments 1-3 or 5-19, wherein R17 is H; and R16 and R18 are independently chosen from H and C1_6alkyl. 24. A compound as deﬁned in any of Preferred ments 1-23, wherein R19 at each occurrence is independently chosen from C1_6alkyl optionally tuted by 1-3 R39, C2_6alkenyl optionally tuted by 1-3 R39, C2_6alkynyl optionally substituted by 1-3 R39, C6_10aryl optionally substituted by 1-3 R39, C7_11arylalkyl optionally substituted by 1-3 R39, C3_10cycloalkyl optionally substituted by 1-3 R39, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R39, 5-10 membered heteroaryl optionally substituted by 1-3 R39, halogen, —CN, R30, —C(=O)OR30, —C(=O)NR32R33, —N02, —NR32R33, — NR34C(=0)R3°, (=O)NR32R33, —NR34S(=O)2R31, —NR34S(=O)2NR32R33, —OR3°, =o, )R30, —OC(=O)NR32R33, —Si(R34)3, =s, —S(=0),,R3°, and —S(=O)2NR32R33.

. A compound as deﬁned in any of Preferred Embodiments 1-23, wherein R19 at each occurrence is ndently chosen from C1_6alkyl optionally substituted by 1-3 R39, C6_10aryl optionally substituted by 1-3 R39, rylalkyl ally substituted by 1-3 R39, C3_6cycloalkyl optionally substituted by 1-3 R39, 3-6 membered heterocycloalkyl optionally substituted by 1-3 R39, 5-6 membered heteroaryl optionally substituted by 1-3 R39, halogen, —CN, R30, —C(=O)NR32R33, —NR32R33, —NR34C(=0)R3°, — NR34S(=O)2R31, —0R3°, =o, —S(=0),,R3°, and —S(=O)2NR32R33. 26. A compound as deﬁned in any of Preferred Embodiments 1-23, wherein R19 at each occurrence is independently chosen from C1_6alkyl optionally substituted by 1-3 R39, C6_10aryl optionally substituted by 1-3 R39, C3_6cycloalkyl optionally substituted by 1-3 R39, 3-6 membered heterocycloalkyl optionally substituted by 1-3 R39, 5-6 membered heteroaryl optionally substituted by 1-3 R39, halogen, —C(=O)OR30, —NR32R33, and —OR30. 27. A compound as deﬁned in any of Preferred Embodiments 1-23, wherein R19 at each occurrence is independently chosen from C1_6alkyl, phenyl optionally substituted by 1-3 R39, C3_6cycloalkyl, 3-6 membered heterocycloalkyl optionally substituted by 1-3 R39, -6 membered heteroaryl, halogen, —C(=O)OR30, —NR32R33, and —OR30. 28. A compound as deﬁned in any of red Embodiments 1-27, n R20, R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H, C1_6alkyl optionally substituted by 1-6 R49, C2_6alkenyl optionally tuted by 1-6 R49, C2_6alkynyl optionally substituted by 1-6 R49, C6_10aryl optionally substituted by 1-6 R49, C7_11arylalkyl optionally substituted by 1-6 R49, C3_10cycloalkyl ally substituted by 1-6 R49, 3-10 membered heterocycloalkyl optionally substituted by 1-6 R49, and 5-10 membered heteroaryl ally substituted by 1-6 R49.

WO 78126 29. A compound as deﬁned in any of Preferred Embodiments l-27, wherein R20, R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H, C1_6alkyl ally substituted by 1-3 R49, phenyl optionally substituted by 1-3 R49, benzyl ally substituted by 1-3 R49, C3_6cycloalkyl optionally tuted by 1-3 R49, 3-6 membered heterocycloalkyl optionally tuted by 1-3 R49, and 5-6 membered heteroaryl optionally substituted by 1-3 R49.

. A compound as deﬁned in any of Preferred Embodiments l-27, wherein R20, R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H, C1_6alkyl optionally substituted by 1-3 R49, ryl optionally substituted by 1-3 R49, C3_6cycloalkyl optionally substituted by 1-3 R49, 3-6 ed heterocycloalkyl optionally substituted by 1-3 R49, and 5-6 membered heteroaryl optionally tuted by 1-3 R49. 3 l. A compound as deﬁned in any of Preferred Embodiments l-27, wherein R20, R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is ndently chosen from H, C1_6alkyl optionally substituted by 1-3 R49, phenyl optionally substituted by 1-3 R49, C3_6cycloalkyl optionally tuted by 1-3 R49, 5-6 membered heterocycloalkyl optionally substituted by 1-3 R49, and 5-6 ed heteroaryl ally substituted by 1-3 R49. 32. A compound as deﬁned in any of Preferred Embodiments l-27, wherein R20 at each ence is independently chosen from H, C1_6alkyl optionally substituted by 1-3 R49, phenyl optionally substituted by 1-3 R49, C3_6cycloalkyl optionally substituted by 1-3 R49, 5-6 membered heterocycloalkyl optionally substituted by 1-3 R49, and 5-6 membered heteroaryl optionally substituted by 1-3 R49; R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H and C1_6alkyl. 33. A compound as deﬁned in any of Preferred Embodiments l-32, wherein R28 and R38 at each occurrence is independently chosen ﬁom C1_6alkyl optionally substituted by l- 3 R49, C2_6alkenyl optionally substituted by 1-3 R49, C2_6alkynyl optionally substituted by 1-3 R49, C6_10aryl optionally substituted by 1-3 R49, C7_11arylalkyl optionally substituted by 1—3 R49, C3_10cycloalkyl optionally substituted by 1—3 R49, 340 membered heterocycloalkyl optionally substituted by 1-3 R49, and 5-10 membered heteroaryl optionally substituted by 1-3 R49. 34. A compound as deﬁned in any of Preferred Embodiments l-33, wherein R22, R23 R32 and R33 at each occurrence is independently chosen from H, C1_6alkyl, C6_10aryl, C7_ —457— 11arylalkyl, C3_10cycloalkyl, 3-10 membered heterocycloalkyl, and 5-10 membered heteroaryl.

. A compound as deﬁned in any of Preferred Embodiments l-33, wherein R22 at each occurrence is independently chosen from H, C1_6alkyl optionally substituted by 1-3 R59, C2_6alkenyl optionally substituted by 1-3 R59, C2_6alkynyl optionally substituted by 1-3 R59, C6_10aryl optionally substituted by 1-3 R59, C7_11arylalkyl optionally substituted by 1-3 R59, C3_10cycloalkyl optionally substituted by 1-3 R59, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R59, and 5-10 membered heteroaryl optionally substituted by 1-3 R59; R23, R32 and R33 at each occurrence is independently chosen from H and C1_6alkyl; alternatively, any R22 and R23 and/or R32 and R33 may form, together with the nitrogen atom to which they are attached, a 3-lO membered heterocycloalkyl optionally substituted by 1-3 R69 or a 5-10 membered heteroaryl optionally substituted by 1-3 R69. 36. A compound as deﬁned in any of red ments l-33, wherein R22 at each occurrence is independently chosen ﬁom H, phenyl optionally substituted by 1 R59, and 6 membered heteroaryl optionally substituted by 1 R59; R23, R32 and R33 at each occurrence is independently chosen from H and C1_6alkyl. 37. A compound as deﬁned in any of Preferred Embodiments 1-36, wherein R39, R49, R59 and R69 at each occurrence is independently chosen from C1_6alkyl optionally substituted by 1-3 R79, kenyl optionally substituted by 1-3 R79, C2_6alkynyl optionally substituted by 1-3 R79, C6_10aryl optionally substituted by 1-3 R79, C7_11arylalkyl optionally substituted by 1-3 R79, C3_10cycloalkyl optionally substituted by 1-3 R79, 3-lO membered heterocycloalkyl optionally substituted by 1-3 R79, 5-10 membered heteroaryl ally tuted by 1—3 R79, halogen, —CN, —C(=O)R7°, —C(=O)OR7°, NR72R73, —N02, — 3, —NR74C(=O)R7°, —NR74C(=O)NR72R73, —NR74S(=O)2R71, —0R7°, =o, — S(=O)nR7°, and —S(=O)2NR72R73. 38. A nd as deﬁned in any of Preferred Embodiments l-37, wherein R39, R49, R59 and R69 at each occurrence is ndently chosen from kyl, phenyl, 5-6 membered cycloalkyl, 5-9 membered heteroaryl, —CN, and R70. 39. A compound as deﬁned in any of Preferred Embodiments 1-38, wherein R70, R71, R74, R75, R76 and R77 at each occurrence is independently chosen from H, kyl optionally substituted by 1-3 R89, C6_10aryl optionally substituted by 1-3 R89, C7_11arylalkyl optionally substituted by 1-3 R89, C3_10cycloalkyl optionally substituted by 1-3 R89, 3-lO membered heterocycloalkyl optionally substituted by 1-3 R89, and 5-10 ed heteroaryl optionally substituted by 1-3 R89. 40. A compound as deﬁned in any of Preferred Embodiments 1-38, wherein R70, R71, R74, R75, R76 and R77 at each occurrence is independently chosen from H, C1_6alkyl, and 5- 6 membered heterocycloalkyl. 41. A compound as deﬁned in any of Preferred Embodiments l-40, wherein R72 and R73 at each occurrence is independently chosen from H, C1_6alkyl optionally substituted by l-3 R99, C2_6alkenyl optionally substituted by l-3 R99, kynyl optionally substituted by l-3 R99, C6_10aryl optionally substituted by l-3 R99, C7_11arylalkyl optionally substituted by 13 R99, C3_10cycloalkyl ally substituted by 13 R99, 3—10 membered heterocycloalkyl optionally tuted by l-3 R99, and 5-10 membered heteroaryl optionally substituted by l-3 R99; atively, any R72 and R73 may form, together with the nitrogen atom to which they are attached, a 3-10 ed heterocycloalkyl optionally substituted by l-3 R109 or a 5-10 membered heteroaryl optionally substituted by 1_3 R109 42. A compound as deﬁned in any of Preferred Embodiments l-40, wherein R72 and R73 at each occurrence is independently chosen from H, C1_6alkyl, , benzyl, C5- 6cycloalkyl, 5-6 membered cycloalkyl, and 5-6 membered heteroaryl; alternatively, any R72 and R73 may form, together with the nitrogen atom to which they are attached, a 5- 6 membered heterocycloalkyl or a 5-6 membered heteroaryl. 43. A compound as deﬁned in any of Preferred Embodiments 1-42, wherein R78 at each occurrence is independently chosen from C1_6alkyl optionally substituted by 1-3 R89, C2_6alkenyl optionally substituted by l-3 R89, C2_6alkynyl optionally substituted by l-3 R89, C6_10aryl optionally substituted by l-3 R89, C7_11arylalkyl ally substituted by l-3 R89, C3_10cycloalkyl optionally substituted by l-3 R89, 3-10 membered cycloalkyl optionally substituted by 1-3 R89, and 5-10 membered heteroaryl optionally substituted by 13 R89. 44. A compound as deﬁned in any of red Embodiments l-42, wherein R78 at each occurrence is ndently chosen from C1_6alkyl, phenyl, benzyl, C3_6cycloalkyl, 3- 6 membered heterocycloalkyl, and 5-6 membered aryl. 45. A nd as deﬁned in any of Preferred Embodiments 1-44, wherein R79, R89, R99 and R109 at each occurrence is independently chosen from C1_6alkyl optionally substituted by l-3 halogen, C2_6alkenyl, C2_6alkynyl, C6_10aryl, C7_11arylalkyl, C3- locycloalkyl, 3-10 ed heterocycloalkyl, 5-10 membered heteroaryl, halogen, —CN, —C(=O)R110, —C(=O)OR110, —C(=O)NR110R110, —N02, —NR110R110, —NR1100R110, _ —459— NR110C(:O)R110, —NR110C(:O)NR110R110, _NR110S(:O)2R1 10’ _NR1 IOS(:O)2NR1 10R1 10’ _ 0R1“), =0, —OCN, —0C(=0)R“°, —S(=O)nR“0, —S(=O)2NR“°R“°, and —S(=0)NR“0R“0. 46. A compound as deﬁned in any of Preferred ments 1-45, wherein R110 at each ence is independently chosen from H, C1_6a1ky1 and C1_6-haloa1ky1. 47. A compound as deﬁned in any of Preferred Embodiments 1-46, wherein R at each occurrence is independently chosen from C1_6a1ky1 and C1_6-haloa1ky1.

Claims

WHAT IS CLAIMED IS: l. A compound of formula (I) R3 I? R4 \ R2 R6 A \ \ X N G or a salt form thereof, wherein A is NR11,O,or S; \ \I M-Q-X is a group of formula 10 R1, R2, R11, and R17 are ndently chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C2_6alkenyl optionally substituted by 1-11 R19, C2_ 6alkynyl optionally substituted by 1-9 R19, C6_11aryl optionally substituted by 1-11 R19, C7_16arylalkyl optionally substituted by 1-19 R19, C3_11cycloalkyl optionally substituted by 1-21 R19, C4_17cycloalkylalkyl optionally substituted 15 by 1—32 R19, 3—15 membered heterocycloalkyl optionally substituted by 1-28 R19, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40 R19, 5-15 membered heteroaryl optionally substituted by 1-15 R19, 6-21 membered heteroarylalkyl optionally substituted by 1-27 R19, and —OR20; R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, R16, and R18 are independently chosen from H, C1_6alkyl optionally substituted by 1-13 R19, C2_6alkenyl optionally substituted by 1-11 R19, C2_6alkynyl optionally substituted by 1—9 R19, C6_11aryl optionally substituted by 1-11 R19, C7_16arylalkyl optionally substituted by 1—19 R19, C3.1 1cycloalkyl optionally substituted by 1-21 R19, c4- 17cycloalkylalkyl ally substituted by 1—32 R19, 3—15 membered heterocycloalkyl optionally substituted by 1-28 R19, 4-21 membered 10 heterocycloalkylalkyl optionally substituted by 1-40 R19, 5-15 membered heteroaryl optionally tuted by 1-15 R19, 6-21 membered heteroarylalkyl optionally substituted by 1—27 R19, halogen, —CN, —C(=O)R20, —C(=O)OR2°, — C(=O)NR22R23, —C(=O)C(=O)R2°, —C(=NR25)R2°, 25)NR22R23, — )NR22R23, —C(=NOR26)R20, —C(=NNR22R23)R20, — 15 C(=NNR24C(=O)R21)R2°, —C(=NNR24C(=O)OR21)R2°, —C(=S)NR22R23, —NC, —\102, 23, —NR24NR22R23, —N=NR24, —NR24OR26, (=O)R2°, — \R24C(=O)C(=O)R2°, —NR24C(=O)OR21, (=O)C(=O)OR21, — \R24C(=O)NR22R23, —NR24C(=O)NR24C(=O)R2°, — \R24C(=O)NR24C(=O)OR2°, —NR24C(=NR25)NR22R23, — 20 \R24C(=O)C(=O)NR22R23, (=S)R2°, —NR24C(=S)OR2°, — \R24C(=S)NR22R23, —NR24S(=O)2R21,—NR24S(=O)2NR22R23, — \R24P(:O)R28R28’ —NR24P(=O)(NR22R23)(NR22R23), _ \R24P(=O)(OR20)(OR20), —NR24P(=O)(SR2°)(SR2°), —OR20, —OCN, — R2°, —OC(=O)NR22R23, —OC(=O)OR2°, —OC(=NR25)NR22R23, — 25 OS(=O)R2°, —OS(=O)2R2°, —OS(=O)20R20, —OS(=O)2NR22R23, — OP(=O)R28R28, —OP(=O)(NR22R23)(NR22R23), —OP(=O)(OR20)(OR20), — OP(=O)(SR2°)(SR2°), —Si(R24)3 — , —SCN, nR20, —S(=O)20R2°, —SOgR27, S(=O)2NR22R23, —S(=O)NR22R23, —SP(=O)R28R28, — SP(=O)(NR22R23)(NR22R23), —SP(=O)(OR2°)(OR2°), —SP(=O)(SR2°)(SR20), — 30 P(=O)R28R28, —P(=O)(NR22R23)(NR22R23), —P(=O)(OR2°)(OR2°), and — P(=O)(SR2°)(SR2°); any ole and R2, R1 and R3, R1 and R5, R1 and R11, R4 and R11, R6 and R11, and R16 and R17 can, together with the atoms linking them, form a 3-15 membered heterocycloalkyl optionally substituted by 1-28 R19 or a 5-15 membered heteroaryl optionally substituted by 1-15 R19; any of R3 and R6, R7 and R8, R9 and R10, R12 and R13, and R14 and R15 can, er with the atoms linking them, form a C6_11aryl optionally substituted by 1-11 R19, C3_1lcycloalkyl optionally substituted by 1-21 R19, 3—15 membered heterocycloalkyl optionally substituted by 1-28 R19 or a 5-15 membered heteroaryl optionally substituted by 1-15 R19; R3 and R5 or R4 and R6 can er form a double bond; any of R3 and R4, and R5 and R6 can er form =0, =NR20, =NOR20, or =8; 10 R19 at each occurrence is independently chosen from C1_6alkyl optionally substituted by 1-13 R39, C2_6alkenyl optionally substituted by 1-11 R39, C2- 6alkynyl optionally substituted by 1-9 R39, C6_11aryl optionally substituted by 1-11 R39, C7_16arylalkyl optionally substituted by 1-19 R39, ycloalkyl optionally substituted by 1-21 R39, C4_17cycloalkylalkyl optionally substituted 15 by 1—32 R39, 3—15 membered heterocycloalkyl optionally substituted by 1-28 R39, 4-21 ed heterocycloalkylalkyl optionally substituted by 1-40 R39, 5-15 membered heteroaryl optionally substituted by 1-15 R39, 6-21 membered heteroarylalkyl optionally substituted by 1-27 R39, halogen, —CN, —C(=O)R30, —C(=O)OR3°, —C(=O)NR32R33, —C(=O)C(=O)R3°, —C(=NR35)R3°, — 20 C(=NR35)NR32R33, —C(=NOH)NR32R33, —C(=NOR36)R3°, —C(=NNR32R33)R30, —C(=NNR34C(=0)R31)R3°, —C(=NNR34C(=O)OR31)R3°, —C(=S)NR32R33, —NC, —\102, —NR32R33, R32R33, —N=NR34, =NR30, =N0R30, —NR340R36, — =0)R3°, —NR34C(=O)C(=O)R3°, —NR34C(=O)OR31, — \R34C(=O)C(=O)OR31, —NR34C(=O)NR32R33, —NR34C(=O)NR34C(=O)R3°, — 25 \R34C(=O)NR34C(=O)OR3°, —NR34C(=NR35)NR32R33, — \R34C(=O)C(=O)NR32R33, (=S)R3°, (=S)OR3°, — \R34C(=S)NR32R33, —NR34S(=O)2R31, —NR34S(=O)2NR32R33, — \R34P(:O)R38R38’ —NR34P(=O)(NR32R33)(NR32R33), _ \R34P(=O)(OR30)(OR30), —NR34P(=O)(SR3°)(SR3°), —0R3°, =o, —OCN, — 30 OC(=O)R3°, —OC(=O)NR32R33, —OC(=O)OR3°, R35)NR32R33, — OS(=O)R3°, —OS(=O)2R30, —OS(=O)20R3°, —OS(=O)2NR32R33, — OP(=O)R38R38, —OP(=O)(NR32R33)(NR32R33), —OP(=O)(OR30)(OR30), — OP(=O)(SR3°)(SR3°), —Si(R34)3 — , —SCN, =s, —S(=0)nR3°, —S(=O)20R3°, SOsR37, —S(=O)2NR32R33, —S(=O)NR32R33, —SP(=O)R38R38, — - 463 — SP(=O)(NR32R33)(NR32R33), —SP(=O)(OR30)(OR30), —SP(=O)(SR3°)(SR30), — P(=O)R38R38, —P(=O)(NR32R33)(NR32R33), —P(=O)(OR3°)(OR3°), and — SR3°)(SR3°); 20 21 24 25 26 27 30 31 34 35 36 R ,R ,R ,R ,R ,R ,R ,R ,R ,R ,R andR37ateachoccurrence1s- independently chosen from H, C1_6alkyl optionally substituted by 1-13 R49, C2- 6alkenyl optionally substituted by 1-11 R49, C2_6alkynyl optionally substituted by 1—9 R49, C6_11aryl optionally substituted by 1-11 R49, C7_16arylalkyl optionally substituted by 1-19 R49, C3_11cycloalkyl optionally tuted by l- 21 R49, ycloalkylalkyl optionally substituted by 1—32 R49, 3—15 ed 10 heterocycloalkyl optionally substituted by 1-28 R49, 4-21 membered heterocycloalkylalkyl optionally substituted by 1—40 R49, 5—15 membered heteroaryl optionally substituted by 1-15 R49, and 6-21 membered heteroarylalkyl optionally substituted by 1-27 R49; R28 and R38 at each occurrence is independently chosen from C1_6alkyl optionally 15 substituted by 1-13 R49, C2_6alkenyl optionally substituted by 1-11 R49, C2- 6alkynyl optionally substituted by 1-9 R49, C6_11aryl optionally substituted by 1-11 R49, C7_16arylalkyl optionally substituted by 1-19 R49, C3_11cycloalkyl optionally substituted by 1-21 R49, ycloalkylalkyl optionally tuted by 1—32 R49, 3—15 membered heterocycloalkyl optionally substituted by 1-28 20 R49, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40 R49, 5-15 membered heteroaryl optionally substituted by 1-15 R49, and 6-21 ed heteroarylalkyl optionally substituted by 1-27 R49; R22, R23, R32 and R33 at each occurrence is independently chosen from H, kyl optionally substituted by 1-13 R59, C2_6alkenyl optionally substituted by 1-11 25 R59, kynyl optionally tuted by 1-9 R59, C6_11aryl optionally substituted by 1-11 R59, C7_16arylalkyl optionally substituted by 1-19 R59, c3- 11cycloalkyl optionally substituted by 1-21 R59, C4_17cycloalkylalkyl optionally substituted by 1-32 R59, 3-15 membered heterocycloalkyl ally substituted by 1-28 R59, 4-21 membered heterocycloalkylalkyl optionally 30 substituted by 1-40 R59, 5-15 membered heteroaryl optionally substituted by l- 15 R59, and 6-21 membered arylalkyl optionally substituted by 1-27 R59; or any R22 and R23 and/or R32 and R33 may form, together with the nitrogen atom to which they are attached, a 3-15 membered heterocycloalkyl optionally —4o4— substituted by 1-28 R69 or a 5-15 membered aryl optionally substituted by l - l 5 R69; R39, R49, R59 and R69 at each occurrence is independently chosen from C1_6alkyl optionally tuted by 1-13 R79, C2_6alkenyl optionally substituted by 1-11 R79, C2_6alkynyl optionally substituted by 1-9 R79, C6_11aryl optionally substituted by 1-11 R79, C7_16arylalkyl optionally substituted by 1-19 R79, c3- oalkyl ally substituted by 1-21 R79, C4_17cycloalkylalkyl optionally substituted by 1-32 R79, 3-15 rnernbered heterocycloalkyl optionally substituted by 1-28 R79, 4-21 membered heterocycloalkylalkyl optionally 10 substituted by 1-40 R79, 5-15 membered heteroaryl optionally substituted by l- 15 R79, 6-21 ed heteroarylalkyl optionally substituted by 1-27 R79, halogen, —CN, —C(=O)R70, —C(=O)OR7°, —C(=O)NR72R73, —C(=O)C(=O)R7°, —C(=NR75)R7°, —C(=NR75)NR72R73, —C(=NOH)NR72R73, —C(=NOR76)R7°, — C(=NNR72R73)R7°, —C(=NNR74C(=O)R71)R7°, —C(=NNR74C(=O)OR71)R7°, — 15 C(=S)NR72R73, —NC, —N02, —NR72R73, —NR74NR72R73, —N=NR74, =NR70, =NOR70, —NR74OR76, —NR74C(=O)R7°, —NR74C(=O)C(=O)R7°, — NR74C(=O)OR71, —NR74C(=O)C(=O)OR71, (=O)NR72R73, — NR74C(=O)NR74C(=O)R7°, —NR74C(=O)NR74C(=O)OR7°, — NR74C(=NR75)NR72R73, —NR74C(=O)C(=O)NR72R73, —NR74C(=S)R70, — 20 NR74C(=S)OR7°, —NR74C(=S)NR72R73, —NR74S(=O)2R71, — NR74S(=O)2NR72R73, (=O)R78R78, —NR74P(=O)(NR72R73)(NR72R73), _ NR74P(=O)(OR7°)(OR70), —NR74P(=O)(SR7°)(SR7°), —0R7°, =o, —OCN, — OC(=O)R7°, —OC(=O)NR72R73, —OC(=O)OR7°, —OC(=NR75)NR72R73, — OS(=O)R7°, —OS(=O)2R7°, —OS(=O)20R7°, —OS(=O)2NR72R73, — 25 R78R78, —OP(=O)(NR72R73)(NR72R73), )(OR70)(OR70), — OP(=O)(SR7°)(SR7°), —Si(R7“)3 , —SCN, =s, —S(=O)HR7°, —S(=O)20R7°, — SOgR77, —S(=O)2NR72R73, —S(=O)NR72R73, —SP(=O)R78R78, — SP(=O)(NR72R73)(NR72R73), —SP(=O)(OR70)(OR70), —SP(=O)(SR7°)(SR70), — P(=O)R78R78, (NR72R73)(NR72R73), —P(=O)(OR7°)(OR7°), and — 30 P(=O)(SR7°)(SR7°); R70, R71, R74, R75 , R76 and R77 at each occurrence is ndently chosen from H, C1_6alkyl optionally substituted by 1-13 R89, C2_6alkenyl optionally substituted by 1-11 R89, kynyl optionally substituted by 1-9 R89, C6_11aryl optionally substituted by 1-11 R89, C7_16arylalkyl optionally substituted by 1-19 R89, c3- _ 465 — oalkyl optionally substituted by 1-21 R89, C4_17cycloalkylalkyl optionally substituted by 1-32 R89, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R89, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40 R89, 5-15 membered heteroaryl optionally substituted by l- 15 R89, and 6-21 membered heteroarylalkyl optionally substituted by 1-27 R89; R72 and R73 at each occurrence is independently chosen from H, C1_6alkyl optionally substituted by 1-13 R99, C2_6alkenyl optionally substituted by 1-11 R99, C2_6alkynyl optionally substituted by 1-9 R99, C6_11aryl optionally substituted by 1-11 R99, C7_16arylalkyl optionally substituted by 1-19 R99, c3- 10 11cycloalkyl optionally substituted by 1-21 R99, C4_17cycloalkylalkyl optionally substituted by 1-32 R99, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R99, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40 R99, 5-15 ed heteroaryl optionally substituted by l- 15 R99, and 6-21 ed heteroarylalkyl optionally substituted by 1-27 R99; 15 or any R72 and R73 may form, together with the nitrogen atom to which they are attached, a 3-15 ed heterocycloalkyl optionally substituted by 1-28 R109 or a 5-15 ed heteroaryl optionally substituted by 1-15 R109; R78 at each occurrence is independently chosen from kyl optionally substituted by 1-13 R89, kenyl optionally substituted by 1-11 R89, C2- 20 6alkynyl optionally substituted by 1-9 R89, C6_11aryl optionally substituted by 1-11 R89, C7_16arylalkyl optionally substituted by 1-19 R89, C3_11cycloalkyl optionally substituted by 1-21 R89, C4_17cycloalkylalkyl optionally tuted by 1—32 R89, 3—15 membered cycloalkyl optionally substituted by 1-28 R89, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40 R89, 25 5-15 membered heteroaryl optionally substituted by 1-15 R89, and 6-21 membered heteroarylalkyl optionally substituted by 1-27 R89; R79, R89, R99 and R109 at each occurrence is independently chosen from C1_6alkyl ally substituted by 1-13 halogen, C2_6alkenyl, C2_6alkynyl, C6_11aryl, C7- 16arylalkyl, C3_11cycloalkyl, C4_17cycloalkylalkyl, 3-15 membered 30 heterocycloalkyl, 4-21 membered heterocycloalkylalkyl, 5-15 membered aryl, 6-21 ed heteroarylalkyl, halogen, —CN, —C(=O)R110, — C(=O)OR“0, —C(=0)NR“°R“0, C(=O)R“°, —C(=NR“°)R“°, — C(=NR110)NR110R110, —C(=NOH)NR110R110, —C(=NOR110)R110, _ C(=NNR110R110)R110, —C(=NNR110C(=O)R110)R110, _ C(=NNR110C(=O)OR110)R110, —C(=S)NR110R110, —NC, —N02, —NR110R110, _ 77777 RHONRUORUO, _N:NR1 10’ ZNRUO, ZNORUO, —NR1100R110, _R110C(=O)R110, —NR110C(=O)C(=O)R110, —NR110C(=O)OR110, _R110C(=O)C(=O)OR110, —NR110C(=O)NR110R110, _R“°C(=0)NR“°C(=0)R“0, —NR“°C(=0)NR11°C(=0)0R“0, —R110C(=NR110)NR110R110, —NR110C(=O)C(=O)NR1IORUO, —NR110C(=S)R110, 0C(=S)OR110, —NR110C(=S)NR110R110, —NRUOS(=O)2R110, _ thlOS(:O)ZNR110R110’ P(=O)R111R111, _ P(=O)(NR110R110)(NR110R110), —NR110P(=O)(OR110)(OR110), _ 10 I\R“°P(=O)(SR11°)(SR110), —0R“°, =0, —OCN, —OC(=O)R“0, — 0C(=0)NR“°R“°, )0R“°, —0C(=NR“°)NR“°R“°, )R“°, — OS(=O)2R“°, —OS(=O)20R“°, —OS(=O)2NR“°R“°, —OP(=O)R1“R“1, — OP(:O)(NR110R1 10)(NR110R1 10), —OP(=O)(OR110)(OR110), _ (SR“°)(SR“°), —Si(R“°)3 — , —SCN, =s, —S(=O)nR“0, —S(=O)20R“°, 15 SOgRllO, —S(=O)2NR110R110, —S(=O)NR110R110, —SP(=O)R111R111, _ SP(=O)(NR1IORUOXNRUORUO), —SP(=O)(OR110)(OR110), _ SP(=O)(SR110)(SR110), —P(=O)R111R111, —P(=O)(NR110R110)(NR110R110), _ P(=0)(0R“°)(0R“°), and —P(=O)(SR“0)(SR“0); R110 at each occurrence is independently chosen from H, C1_6alkyl and €1 20 haloalkyl; R111 at each occurrence is independently chosen from C1_6alkyl and C1_6-haloalkyl; n at each occurrence is independently chosen from 0, l, and 2. 2. A compound as deﬁned in claim 1, wherein A is NR“. 25 3. A compound as deﬁned in claims 1 or 2, wherein G is a group of formula 4. A compound as deﬁned in claim 3, wherein G is a group of formula and the compound of formula (I) is a compound of formula (Ic) R3 '1] R4 \R2 R6 A /M / N R12 Q\ I \ R13 X N \ R15 / N (1c). 5. A compound as defined in any of claims 1-4, wherein R1, R2, and R11 are ndently chosen from H and C1_6alkyl ally substituted by 1-3 R19; R3, R4, R5, and R6 are ndently chosen from H, C1_6alkyl optionally substituted by 1-3 R19, halogen, —CN, —C(=O)R20, —C(=O)OR2°, —C(=O)NR22R23, —N02, —NR22R23, — NR24C(=O)R2°, —NR24S(=O)2R21,—OR2°, —OC(=O)R2°, —S(=O)nR2°, and —S(=O)2NR22R23; alternatively, R3 and R6 can, together with the atoms linking them, form a C6_10aryl 10 optionally substituted by 1-3 R19, C3_10cycloalkyl optionally substituted by 1-3 R19, 3-10 membered heterocycloalkyl optionally tuted by 1-3 R19 or a 5-10 membered heteroaryl optionally tuted by 1-3 R19; atively R3 and R5 or R4 and R6 can together form a double bond; and alternatively any of R1 and R2, R1 and R3, R1 and R5, R1 and R11, R4 and R11, and R6 and R11 can, together with the atoms linking them, form a 5-15 15 membered heterocycloalkyl ally substituted by 1-3 R19 or a 5-15 membered heteroaryl optionally substituted by 1-3 R19. 6. A compound as defined in any of claims 1-4, wherein R1, R4, R5, R6, and R11 are independently chosen from H and C1_6alkyl optionally substituted by 1-3 R19; R2 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C7_11arylalkyl optionally substituted by 20 1-3 R19, and 6-10 membered heteroarylalkyl optionally substituted by 1-3 R19; R3 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C7_11arylalkyl optionally substituted by 1-9 R19, C6_7cycloalkylalkyl optionally substituted by 1-6 R19, and 6-11 membered heteroarylalkyl optionally substituted by 1-7 R19; and alternatively any of R1 and R2, R1 and R3, R1 and R5, R1 and R11, and R4 and R11 can, together with the atoms linking them, form a 3-7 membered heterocycloalkyl ally tuted by 1-3 R19. 7. A compound as deﬁned in any of claims 1-6, wherein R7, R8, R9, and R10 are independently chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C2_6alkynyl optionally substituted by 1-3 R19, C6_10aryl ally substituted by 1-3 R19, C3- 7cycloalkyl optionally substituted by 1-3 R19, 3-7 ed heterocycloalkyl optionally substituted by 1-3 R19, 5-6 membered heteroaryl optionally substituted by 1-3 R19, halogen, —CN, —C(=O)R20, —C(=O)NR22R23, —N02, —NR22R23, —NR24S(=O)2R21, —OR2°, — 10 S(=O)nR20, and —S(=O)2NR22R23; alternatively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a C3_7cycloalkyl optionally substituted by 1-3 R19, or a 3-7 membered heterocycloalkyl optionally substituted by 1-3 R19. 8. A compound as deﬁned in any of claims 1-6, wherein R7, R8, R9, and R10 are 15 independently chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C2_6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl optionally substituted by 1-3 R19, C6_10aryl optionally substituted by 1-3 R19, C7_11arylalkyl optionally substituted by 1-3 R19, C3- locycloalkyl optionally substituted by 1-3 R19, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-10 membered heteroaryl ally substituted by 1-3 R19, 6-11 20 membered heteroarylalkyl optionally substituted by 1-3 R19, halogen, —CN, —C(=O)R20, — C(=O)NR22R23, —NR22R23, —NR24C(=O)R20, and —OR20; alternatively, either or both of R7 and R8, and/or R9 and R10, can, together with the atoms linking them, form a ryl optionally substituted by 1-3 R19, C3_10cycloalkyl ally substituted by 1-3 R19, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R19 or a 5-10 membered 25 heteroaryl optionally substituted by 1-3 R19. 9. A compound as deﬁned in any of claims 1-8, wherein R12, R13, R14, and R15 are independently chosen from H, C1_6alkyl ally substituted by 1-3 R19, C2_6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl optionally substituted by 1-3 R19, C6_10aryl optionally substituted by 1-3 R19, C3_7cycloalkyl optionally substituted by 1-3 R19, 3-7 30 membered heterocycloalkyl optionally substituted by 1-3 R19, 5-6 membered aryl optionally substituted by 1-3 R19, halogen, —CN, —C(=O)R20, —C(=O)OR2°, — C(=O)NR22R23, —N02, 23, —NR24C(=O)R2°, —NR24C(=O)OR21, — NR24C(=O)NR22R23, —NR24S(=O)2R21, —NR24S(=O)2NR22R23, —OR2°, —OC(=O)R2°, — OC(=O)NR22R23, )OR2°, —S(=O)nR2°, —S(=O)20R2°, —SOgR27, —S(=O)2NR22R23, — - 469 — S(=O)NR22R23, —P(=O)R28R28, —P(=O)(NR22R23)(NR22R23), and —P(=O)(OR20)(OR2°); alternatively, either or both of R12 and R13, and/or R14 and R”, can, together with the atoms linking them, form a C6_10aryl optionally substituted by 1-3 R19, C3_7cycloalkyl optionally substituted by 1-3 R19, 3-7 ed heterocycloalkyl optionally substituted by 1-3 R19 or a 5-6 membered aryl optionally tuted by 1-3 R19. 10. A compound as deﬁned in any of claims 1-8, n R12, R13, and R14 are H; R15 is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C2_6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl optionally substituted by 1-3 R19, C6_10aryl optionally substituted by 1-3 R19, C3_7cycloalkyl optionally substituted by 1-3 R19, 3-7 membered 10 heterocycloalkyl optionally substituted by 1-3 R19, 5-6 membered heteroaryl optionally substituted by 1—3 R19, halogen, —CN, —C(=O)R20, —C(=O)NR22R23, —N02, —NR22R23, — NR24C(=O)R2°, (=O)2R21, —OR2°, —S(=O)nR2°, and —S(=0)2NR22R23. ll. A compound as deﬁned in any of claims 1-3 or 5-10, wherein R17 is H; and R16 and R18 are independently chosen from H and C1_6alkyl. 15 12. A compound as deﬁned in any of claims 1-1 1, wherein R19 at each occurrence is independently chosen from C1_6alkyl optionally substituted by 1-3 R39, C6_10aryl ally substituted by 1-3 R39, rylalkyl optionally substituted by 1-3 R39, C3_6cycloalkyl optionally substituted by 1-3 R39, 3-6 membered cycloalkyl optionally substituted by 1-3 R39, 5-6 membered heteroaryl optionally substituted by 1-3 R39, halogen, —CN, — 20 C(=O)R3°, —C(=O)NR32R33, —NR32R33, —NR34C(=0)R3°, —NR34S(=O)2R31,—OR3°, =o, — S(=O)nR30, and —S(=O)2NR32R33. 13. A compound as deﬁned in any of claims 1-12, wherein R20, R21, R24, R25, R26, R27, R30, R31, R34, R35, R36 and R37 at each occurrence is independently chosen from H, C1- 6alkyl optionally substituted by 1-3 R49, phenyl optionally substituted by 1-3 R49, benzyl 25 ally substituted by 1-3 R49, C3_6cycloalkyl ally substituted by 1-3 R49, 3-6 membered heterocycloalkyl ally substituted by 1-3 R49, and 5-6 membered heteroaryl ally substituted by 1-3 R49. 14. A compound as deﬁned in any of claims 1-13, wherein R22, R23, R32 and R33 at each occurrence is independently chosen from H, C1_6alkyl, C6_10aryl, C7_11arylalkyl, C3_ 30 10cycloalkyl, 3-10 membered heterocycloalkyl, and 5-10 membered heteroaryl. 15. A nd as deﬁned in any of claims 1-14, wherein R39, R49, R59 and R69 at each occurrence is independently chosen from C1_6alkyl optionally substituted by 1-3 R79, C2_6alkenyl optionally substituted by 1-3 R79, C2_6alkynyl optionally substituted by 1-3 R79, C6_10aryl optionally tuted by 1-3 R79, C7_11arylalkyl optionally substituted by 1-3 R79, ycloalkyl optionally substituted by 1-3 R79, 3-10 ed heterocycloalkyl optionally substituted by 1-3 R79, 5-10 membered heteroaryl optionally substituted by 1-3 R79, halogen, —CN, —C(=O)R70, —C(=O)OR7°, —C(=O)NR72R73, —N02, —NR72R73, — NR74C(=O)R7°, —NR74C(=O)NR72R73, —NR74S(=O)2R71, —0R7°, =o, —S(=O)HR7°, and — S(=O)2NR72R73. 16. A compound as deﬁned in any of claims 1-15, wherein R70, R71, R74, R75, R76 and R77 at each occurrence is independently chosen from H, kyl ally substituted by

1-3 R89, C6_10aryl optionally tuted by 1-3 R89, rylalkyl optionally substituted by 1—3 R89, C3_1ocycloalkyl optionally substituted by 1—3 R89, 3—10 membered 10 heterocycloalkyl ally substituted by 1-3 R89, and 5-10 membered heteroaryl ally substituted by 1-3 R89. 17. A compound as deﬁned in any of claims 1-16, wherein R72 and R73 at each occurrence is independently chosen from H, C1_6alkyl, phenyl, benzyl, C5_6cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl; alternatively, any R72 and R73 15 may form, together with the nitrogen atom to which they are attached, a 5-6 ed heterocycloalkyl or a 5-6 membered heteroaryl. 18. A compound as deﬁned in any of claims 1-17, wherein R78 at each ence is independently chosen from C1_6alkyl, phenyl, benzyl, C3_6cycloalkyl, 3-6 membered heterocycloalkyl, and 5-6 membered heteroaryl. 20 19. A compound as deﬁned in any of claims 1-18, wherein R79, R89, R99 and R109 at each occurrence is independently chosen from C1_6alkyl optionally substituted by 1-3 n, C2_6alkenyl, C2_6alkynyl, C6_10aryl, C7_11arylalkyl, C3_10cycloalkyl, 3-10 membered cycloalkyl, 5-10 membered heteroaryl, halogen, —CN, —C(=O)R110, — C(=O)OR110,—C(=O)NR110R110,—N02, _NR110R110’ _NR1100R110’ —NR110C(=O)R110, _ 25 NR110C(=O)NR110R110, _NRIIOS(:O)2R110’ _NRIIOS(:O)2NR110R110’ —OR110, :0, —OCN, —OC(=O)R“0, —S(=O)nR“0, —S(=O)2NR“°R“°, and —S(=0)NR“°R“0. 20. A compound as deﬁned in any of claims 1-19, wherein R110 at each occurrence is independently chosen from H, C1_6alkyl and C1_6-haloalkyl; and R111 at each occurrence is independently chosen from C1_6alkyl and C1_6-haloalkyl.