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    公开号:AU2008237660A1
    申请号:U2008237660
    申请日:2008-04-10
    公开日:2008-10-23
    发明作者:Iriny Botrous；Yufeng Hong；Hui Li；Kevin Kun-Chin Liu；Seiji Nukui；Min Teng；Eileen Valenzuela Tompkins；Chunfeng Yin
    申请人:Pfizer Inc；
    IPC主号:A61K31-496
    专利说明:
    WO 2008/125945 PCT/IB2008/000862 NOVEL 3-AMIDO-PYRROLO[3,4-C]PYRAZOLE-5(1H, 4H,6H) CARBALDEHYDE DERIVATIVES This application claims the benefit of U. S. Provisional Application No. 60/911,462 5 filed April 12, 2007, U. S. Provisional Application No. 61/035,519 filed March 11, 2008, and U.S. Provisional Application No. 61/040,115 filed March 27, 2008, the contents of which are hereby incorporated by reference in their entireties. FIELD OF THE INVENTION 10 The present invention relates to novel compounds, to pharmaceutical compositions comprising the compounds, as well as to the use of the compounds in medicine and for the preparation of a medicament which acts on the human protein kinase C enzyme, and in particular the beta II isoform (pkcpl1). BACKGROUND OF THE INVENTION 15 Protein kinase C (PKC) is a superfamily of lipid-activated Ser/Thr kinases involved in multiple signal transduction pathways. There are thirteen PKC-isoforms that have been identified and are classified according to their regulation by cellular signaling molecules such as diacylglycerol, phospholipids, and calcium. The protein kinase C isozymes, alpha, beta (two splice variants PKCBI and PKCRII) and gamma, require 20 membrane phospholipids, calcium and diacylglycerolphorbol esters for full activation. The delta, epsilon, eta, and theta forms of PKC are calcium-independent in their mode of activation. The zeta and lambda forms of PKC are independent of both calcium and diacylglycerol and are believed to require only membrane phospholipids for their activation. 25 The tissue-specific expression and activation of PKC-isoforms suggests that individual PKC-isoforms might be potential therapeutic targets. For diabetes, activation of PKC-beta has been demonstrated in tissues of diabetic animals and has been implicated in the development of microvascular abnormalities related to the hyperglycemic state. Genetic polymorphisms have been identified in the 5'-flanking 30 upstream region of the PKCR gene in Japanese patients with type II diabetes. This PKCB genetic variation was associated with a significant increase in the susceptibility to develop diabetic vascular complications and macrovascular diseases such as coronary heart disease.
    WO 2008/125945 PCT/IB2008/000862 -2 In a large case-control study at the Joslin Diabetes Center, additional polymorphisms were identified in the PKCR promoter region that had an association with type I diabetes mellitus (duration <24 years) and a greater risk for development of diabetic nephropathy. Administration of PKCB1 inhibitors such as ruboxistaurin mesylate 5 (LY333531, Lilly) in diabetic animal models, was shown to prevent or ameliorate the hemodynamic changes and vascular damage associated with diabetic nephropathy, diabetic peripheral neuropathy, and diabetic retinopathy. Way, K.J. et al, Diabet.Med. 18: 945-959 (2001); Vinik, A., Expert Opin. Investiq.Druqs 14: 1547-1559 (2005). Together with additional data from phase II and phase III clinical studies of ruboxistaurin 10 mesylate for treatment of diabetes and diabetic microvascular complications, there is a building body of evidence to support the rationale that PKCB can function as a molecular target for diabetic complications and for the development of selective- PKCB inhibitors as potential therapeutic agents. The compounds of the present invention are protein kinase C beta |1 inhibitors, 15 and are therefore believed to be useful in the treatment of conditions associated with diabetes mellitius and its complications, cancer, ischemia, inflammation, central nervous system disorders, cardiovascular disease and dermatological disease. 20 SUMMARY OF THE INVENTION The present invention is directed to compounds or pharmaceutically acceptable salts or solvates of Formula (1), R7 8 0 2 ,N N X R3 Nj
    R
    6 NH
    R
    4 R5 0 R1 (1) 25 wherein: Xis C or N; WO 2008/125945 PCT/IB2008/000862 -3 Z
    R
    1 is selected from an aryl or A wherein ring A is a 5 to 6 membered heterocyclyl containing Z, wherein Z is an 0, S or N heteroatom which is adjacent to the point of attachment, and wherein R 1 is optionally further substituted with 0 to 3 R 9 groups and wherein two of the R 9 groups may optionally cyclize to form an aryl or a 5-6 5 membered heterocyclyl ring containing N or S fused to the aryl or heterocyclyl to which it is attached;
    R
    2 is H or C1-C 6 alkyl optionally further substituted with 0 to 3 R 9 groups;
    R
    3 may be attached to any unsaturated carbon on the ring and is selected from H, C 1
    -C
    6 alkyl or halide, or perfluoroalkyl; 10 R 4 and R 5 are each independently selected from H, Ra-O-Rb, C 1
    -C
    8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, -(Rd)m-(C 3 -C1 2 cycloalkyl), -(Rd)m-aryl, -(Rd)m-(3-15 membered heterocyclyl), -(Rd)m-(C1-C 6 perfluoroalkyl), -(Rd)m-halide, -(Rd)m-CN, -(Rd)m-C(O)Ra, (Rd)m-C(O)ORa, -(Rd)m-C(O)NRaRb, -(Rd)m-ORa, -(Rd)m-OC(O)Ra, -(Rd)m-OC(O)NRaR, (Rd)m-0-S(O)Ra, -(Rd)m-OS(0) 2 Ra, -(Rd)m-OS(0) 2 NRaR b, -(Rd)mOS(O)NRaRb, -(Rd)_ 15 NO 2 , -(Rd)m-NRaRb, -(Rd)m-N(Ra)C(O)Rb, -(Rd)m-N(Ra)C(O)ORb, -(Rd)m-N(RC)C(O)NRaRb, -(Rd)m-N(Ra)S(O) 2 Rb, -(Rd)m-N(Ra)S(O)Rb, -(Rd)mSRa (Rd)m-S(O)Ra, -(Rd)m-S(O) 2 Ra, (Rd)mS(O)NRaRb, -(Rd)m-S(O) 2 NRaRb, -(Rd)m0-(Re)m-NRaRb or -(Rd)m-NRa-(Re)-ORb, or R 4 and R 5 may together cyclize to form a 3- to- 5- membered spiro-cycloalkyl; wherein any of the said C3-C12 cycloalkyl, aryl, heterocycyl, or heteroaryl are 20 independently optionally further substituted by 0 to 3 R 9 groups;
    R
    6 is selected from H, Ra-O-Rb, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, -(Rd),_ (C3-C12 cycloalkyl), -(Rd)m-aryl, -(Rd)m-(3-15 membered heterocyclyl), -(Rd)m-(C1-C 6 perfluoroalkyl), -(Rd)m-halide, -(Rd)m-CN, -(Rd)m-C(O)Ra, -(Rd)m-C(O)ORa, -(Rd), C(O)NRaRb, -(Rd)m-ORa, -(Rd)mOC(O)Ra, -(Rd)mOC(O)NRaRb, -(Rd)m-O-S(O)Ra, -(Rd) 25 OS(O) 2 Ra, -(Rd)m-OS(0) 2 NRaRb, -(Rd)m-OS(O)NRaRb', -(Rd)m-NO 2 , -(Rd)m-NRaRb, -(Rd)m N(Ra)C(O)Rb, -(Rd)m-N(Ra)C(O)ORb, -(Rd)m-N(Rc)C(O)NRaRb, -(Rd)m-N(Ra)S(O) 2 Rb' (Rd)m-N(Ra)S(O)Rb, -(Rd)m-SRa, -(Rd)mS(O)Ra, -(Rd)m-S(O) 2 Ra, -(Rd)m-S(O)NRaR b (Rd)m-S(O) 2 NRRb', -(Rd)m-O-(R)m-NRaRb or -(Rd)m-NRa-(Re)-ORb; or R6 may together with R 4 cyclize to form a 4- to 7- membered heterocyclyl ring fused to the piperazine or 30 piperadine to which they are attached; and wherein any of the said alkyl, alkenyl, WO 2008/125945 PCT/IB2008/000862 -4 alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl may independently be further substituted with 0 to 3 R 9 groups; each R 7 and R 8 are each independently Cr1C2 alkyl or can together cyclize to form a cyclopropyl or cyclobutyl; 5 each R 9 is independently selected from H, Ra-O-Rb, C1C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, -(Rd)m-(C3-C1 2 cycloalkyl), -(Rd)m-aryl, -(Rd)m-(3-15 membered heterocyclyl), -(Rd)m(i-C 6 perfluoroalkyl), -(Rd m-halide, -(Rd)m-CN, -(Rd)mC(O)R", (Rd)m-C(O)OR", -(Rd)m-C(O)NRaR, -(Rd)m-ORa, -(Rd)m-OC(O)Ra, -(Rd)m-OC(O)NRaRb, (Rd)m-O-S(O)Ra, -(Rd)m-OS(O) 2 Ra, -(Rd)m-OS(O) 2 NRaRb, -(Rd)m-OS(O)NRaRb, -(Rd)m 10 NO 2 , -(Rd)m-NRaRb, -(Rd)m-N(Ra)C(O)R, -(Rd)m-N(Ra)C(O)OR', -(Rd)m-N(R)C(O)NR"Rb, -(Rd)m-N(Ra)S(O) 2 Rb, -((Rd)m-N(Ra)S(O)Rb, -(Rd)m-SRa, -(Rd)m-S(O)Ra, -(Rd)m-S(O) 2 Ra (Rd)mS(O)NRaRb, -(Rd)m-S(O) 2 NRaRb' -(Rd)m-O-(R)m-NRaRb or -(Rd)m-NRa-(Re)-ORb; and wherein any of the said alkyl, alkenyl, alkynyl, Rd, Re, C3-C12 cycloalkyl, aryl or 3-15 membered heterocyclyl are independently optionally further substituted by 1-3 groups 15 selected from -halide, C1C6 alkyl, CrC6 perfluoroalkyl, Cr 1
    C
    6 alkoxyl, Cr 1
    C
    6 alkylamino, CN or oxo; each R", Rb and Rc is independently selected from H, CrC 6 perfluoroalkyl, C1C8 alkyl, C2-C8 alkenyl, -(C1C3 alkylene)m-(C 3
    -C
    8 cycloalkyl), -(C1C3 alkylene)m-(C 3
    -C
    8 cycloalkenyl), C2-C8 alkynyl, -(C1C3 alkylene)m-aryl, or -(C1C3 alkylene)m-(3-8 member 20 heterocyclyl), and each R", Rb and Rc is independently optionally further substituted by 0 to 3 groups selected from halide, hydroxyl, -CN, Cr1C6 alkyl, C1C6 perfluoroalkyl, C1C6 alkoxyl and C1C6 alkylamino; or, when connected to the same nitrogen, Ra and Rb may optionally form a -(3-8 membered heterocyclyl), and the said ring is optionally further substituted by 0 to 3 groups selected from halide, hydroxyl, -CN, C1C6 alkyl, Cr1C6 25 perfluoroalkyl, C1C6 alkoxyl or C1C6 alkylamino; each Rd and Re is independently -(C1C3 alkylene)-, -(C2-C5 alkenylene)-,or -(C2 C5 alkynylene)-; each m is independently 0 or 1; and with the proviso that R 2 , R 3 , R 4 and R 5 are not all H 30 In one embodiment of the invention, R 7 and R 8 are both methyl. In another embodiment of the invention, X is N. In an alternative embodiment of the invention, X is C and is attached to R 3 . In one embodiment of the invention, Z is N.
    WO 2008/125945 PCT/IB2008/000862 -5 In still another embodiment of the invention, R 3 is fluoro. In an alternative embodiment of the invention, R 3 is H, and at least one of R 2 , R 4 or R 5 is a C 1
    -C
    6 alkyl. In yet another embodiment of the invention, R1 is an aryl. In an alternative embodiment of the invention, R 1 is a pyridine. 5 In one embodiment of the invention, R 2 or R 4 is methyl. In another embodiment of the invention, R 6 together with R 4 cyclizes to form a 4 to 7- membered heterocyclyl ring fused to the piperazine to which they are attached and wherein the said heterocyclyl may independently be further substituted. xx 10 In another embodiment, wherein R 1 is a 6-membered heterocyclyl. In a further aspect of this embodiment, R 1 is a pyridine or a piperazine. In another embodiment, R 1 is a 5-membered heterocyclyl. In a further aspect of this embodiment, R 1 is selected from the group consisting of oxazole, isoxazole, thiazole or imidazole. 15 In another embodiment, R 2 or R 4 is methyl. In another embodiment, R 6 is -(Rd)m-(3-15 membered heterocyclyl). In a further aspect of this embodiment, R 6 is -(Rd)mtetrahydropyran. In a still further aspect of this embodiment, R 6 is tetrahydro-2H-pyran-4-ylmethyl. In an alternative embodiment, R 6 is -( Rd)m-ORa 20 In another embodiment, R 2 is -CH 3 in (S) configuration. In a further aspect of this embodiment, Rd is a -(C 1
    -C
    3 alkylene)- and Ra is either H or methyl. The invention includes the following compounds or pharmaceutically acceptable salts thereof: N-(5-((2R,5S)-2,5-dimethyl-1 -((tetrahydro-2H-pyran-4-yl)methyl)piperazine-4-carbonyl) 25 6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)picolinamide; N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H-pyran-4-yl)piperazin-1 -yl]carbonyl}-6,6 dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-5-fluoropyridine-2-carboxamide; N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H-pyran-4-ylmethyl)piperazin-1 -yl]carbonyl} 6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-5-ethylisoxazole-3 30 carboxamide; N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H-pyran-4-ylmethyl)piperazin-1 -yl]carbonyl} 6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-y)-2,4-dimethyl-1,3-oxazole-5 carboxamide; WO 2008/125945 PCT/IB2008/000862 -6 N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H-pyran-4-ylmethyl)piperazin-1 -yl]carbonyl} 6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-2-methyl-1,3-thiazole-4 carboxamide; N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H-pyran-4-ylmethyl)piperazin-1 -yl]carbonyl} 5 6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-2-ethyl-4-methyl-1,3-oxazole 5-carboxamide; 1 -cyclobutyl-N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H-pyran-4-ylmethyl)piperazin-1 yl]carbonyl}-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-1 H-imidazole-4 carboxamide; 10 N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H-pyran-4-ylmethyl)piperazin-1 -yl]carbonyl} 6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-1 -isopropyl-1 H-imidazole-4 carboxamide; N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H-pyran-4-ylmethyl)piperazin-1 -yl]carbonyl} 6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-2-ethyl-1,3-oxazole-4 15 carboxamide; N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H-pyran-4-yl)piperazin-1 -yl]carbonyl}-6,6 dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-5-morpholin-4-ylpyridine-2 carboxamide; and N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H-pyran-4-ylmethyl)piperazin-1-yl]carbonyl} 20 6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-5-(trifluoromethyl)pyridine-2 carboxamide. The invention is further directed to a pharmaceutical composition comprising an effective amount of a compound according to any of the preceding claims, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 25 The present invention further includes methods of treating diabetes mellitus and its complications, cancer, ischemia, inflammation, central nervous system disorders, cardiovascular disease, Alzheimer's disease and dermatological disease pression, viral diseases, inflammatory disorders, or diseases in which the liver is a target organ, the method comprising administering to a mammal an effective amount of a compound 30 having Formula I above, or a pharmaceutically acceptable salt thereof. In another aspect of the invention, the method of treating is directed to ophthalmic complications. In a still further aspect of the invention, the diabetic complications comprise diabetic retinopathy (including diabetic macular edema), nephropathy and neuropathy.
    WO 2008/125945 PCT/IB2008/000862 -7 DEFINITIONS As used herein, the terms "comprising" and "including" are used in their open, non-limiting sense. The term "alkyl", as used herein, unless otherwise indicated, includes saturated 5 monovalent hydrocarbon radicals having straight or branched moieties. The term "alkenyl", as used herein, unless otherwise indicated, includes alkyl moieties having at least one carbon-carbon double bond wherein alkyl is as defined above and including E and Z isomers of said alkenyl moiety. The term "alkynyl", as used herein, unless otherwise indicated, includes alkyl 10 moieties having at least one carbon-carbon triple bond wherein alkyl is as defined above. The term "alkoxy", as used herein, unless otherwise indicated, includes O-alkyl groups wherein alkyl is as defined above. The term "amino", as used herein, unless otherwise indicated, is intended to 15 include the
    -NH
    2 radical, and any substitutions of the N atom. The terms "halogen" and "halo", as used herein, unless otherwise indicated, represent chlorine, fluorine, bromine or iodine. The term "trifluoromethyl", as used herein, unless otherwise indicated, is meant to 20 represent a -CF 3 group. The term "perfluoroalkyl", as used herein, is meant to represent an alkyl group in which all hydrogens attached to the carbons have been replaced by fluorine, such as
    CF
    3 , CF 2
    -CF
    3 , C(CF 2
    )(CF
    2 ) and so on. The term "trifluoromethoxy", as used herein, unless otherwise indicated, is meant 25 to represent a -OCF 3 group. The term "cyano", as used herein, unless otherwise indicated, is meant to represent a -CN group. The term "CH 2 Cl 2 ", as used herein, unless otherwise indicated, is meant to represent dichloromethane. 30 The term "C3-C12 cycloalkyl" or "C5-C8 cycloalkyl", as used herein, unless otherwise indicated, refers to a non-aromatic, saturated or partially saturated, monocyclic or fused, spiro or unfused bicyclic or tricyclic hydrocarbon referred to herein containing a total of from 3 to 12 carbon atoms, or 5-8 ring carbon atoms, respectively.
    WO 2008/125945 PCT/IB2008/000862 -8 Exemplary cycloalkyls include rings having from 3-10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and adamantyl. Illustrative examples of cycloalkyl are derived from, but not limited to, the following: FA,> 5 0 ,0,0,/ ,and The term "aryl", as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl. 10 The term "(3-15)-membered heterocycyl", "(3-8)-membered heterocyclyl", "(6-10) membered heterocyclyl", or "(4 to 10)-membered heterocyclyl", as used herein, unless otherwise indicated, includes aromatic and non-aromatic heterocyclic groups containing one to four heteroatoms each selected from 0, S and N, wherein each heterocyclic group has from 3-15, 3-8, 6-10, or 4 to 10 atoms, respectively, in its ring system, and 15 with the proviso that the ring of said group does not contain two adjacent 0 or S atoms. Non-aromatic heterocyclic groups include groups having only 3 atoms in their ring system, but aromatic heterocyclic groups must have at least 5 atoms in their ring system. The heterocyclic groups include benzo-fused ring systems. An example of a 3 membered heterocyclic group is aziridine, an example of a 4 membered heterocyclic 20 group is azetidinyl (derived from azetidine). An example of a 5 membered heterocyclic group is thiazolyl, an example of a 7 membered ring is azepinyl, and an example of a 10 membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, 25 thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2 pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, WO 2008/125945 PCT/IB2008/000862 -9 pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3 azabicyclo[4.1.0]heptanyl, 3H-indolyl and quinolizinyl. Heterocycles include monocyclic and polycyclic aromatic ring structures, with "(5-12)-membered heteroaryls" referring to those that are heterocycles having 5 to 12 atoms in their ring system(s). Examples of 5 "(5-12)-membered heteroaryls" are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, 10 quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups, as derived from the groups listed above, may be C-attached or N-attached where such is possible. For instance, a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole may be imidazol-1-yl (N-attached) or imidazol-3-yl (C-attached). The above-mentioned heterocyclic groups 15 may be optionally substituted on any ring carbon, sulfur, or nitrogen atom(s) by one to two oxo, per ring. An example of a heterocyclic group wherein 2 ring carbon atoms are substituted with oxo moieties is 1,1-dioxo-thiomorpholinyl. Other Illustrative examples of 4 to 10 membered heterocyclic are derived from, but not limited to, the following: 0 H N N N N Nl111 N H 0 H H H 20N NH N N 20 S. 0 H H 0 -0 N 0 N N N / / H H H WO 2008/125945 PCT/IB2008/000862 -10 N~ ()01 H 00 oNH NNO and The term "(12-15)-membered heterocyclyl", as used herein, unless otherwise indicated, includes aromatic and non-aromatic heterocyclic groups that are in a partially fused or spirocyclic configuration and which contain at least one N and optionally additional 1 to 5 5 heteroatoms each selected from 0, S and N, wherein the heterocyclic group has from 12 to 15 atoms, respectively, in its system, and with the proviso that any ring of said group does not contain two adjacent 0 or S atoms. The heterocyclic groups include tricyclic fused ring and spirocyclic systems. An example of a 13-membered tricyclic heterocyclic group is 3,4-dihydropyrazino[1,2-a]benzimidazole and an example of a 15 10 membered spirocyclic heterocyclic group is 3,4-dihydro-1'H-spirochromene. Unless otherwise indicated, the term "oxo" refers to =0. A "solvate" is intended to mean a pharmaceutically acceptable solvate form of a specified compound that retains the biological effectiveness of such compound. Examples of solvates include compounds of the invention in combination with water, 15 isopropanol, ethanol, methanol, DMSO (dimethylsulfoxide), ethyl acetate, acetic acid, or ethanolamine. The phrase "pharmaceutically acceptable salt(s)", as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds of Formula 1. The compounds of Formula I that are basic in nature are 20 capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds of Formula I are those that form non-toxic acid addition salts, i.., salts containing pharmacologically acceptable anions, such as the acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium 25 edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edislyate, estolate, esylate, ethylsuccinate, fumarate, gluceptate, gluconate, glutamate, WO 2008/125945 PCT/IB2008/000862 - 11 glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phospate/diphosphate, polygalacturonate, salicylate, stearate, 5 subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodode, and valerate salts. The term "treating", as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term 10 "treatment", as used herein, unless otherwise indicated, refers to the act of treating as "treating" is defined immediately above. The phrase "therapeutically effective amount", as used herein, refers to that amount of drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by a researcher, veterinarian, 15 medical doctor or other. The term "substituted" means that the specified group or moiety bears one or more substituents. The term "unsubstituted" means that the specified group bears no substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted by one or more substituents. 20 In accordance with convention, in some structural formula herein, the carbon atoms and their bound hydrogen atoms are not explicitly depicted e.g., represents a methyl group, represents an ethyl group, represents a cyclopentyl group, etc. The convention ,denoted the point of attachment to the remainder of R the compound, and the convention denotes that the R substituent may be 25 attached at any of the available atoms on the given structure, here shown as a WO 2008/125945 PCT/IB2008/000862 -12 X 2 R3 R 6 cyclohexyl, unless otherwise indicated. In the particular embodiment, R 4
    R
    5 R3 may be attached at any of the heteroatoms of the heterocycle, including X if X is C. R7O R8 O2N N-Boc In the particular pyrazolo intermediate embodiment, H 2 N , the acyl group may be attached to either of the two nitrogens of the fused pyrazole ring. 5 Certain compounds of Formula I may have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of the compounds of Formula I and mixtures thereof, are considered to be within the scope of the invention. With respect to the compounds of Formula I, the invention includes the use of a racemate, one or more enantiomeric forms, one or more diastereomeric forms, 10 or mixtures thereof. The compounds of Formula I may also exist as tautomers. This invention relates to the use of all such tautomers and mixtures thereof. Certain functional groups contained within the compounds of the present invention can be substituted for bioisosteric groups, that is, groups which have similar spatial or electronic requirements to the parent group, but exhibit differing or improved 15 physicochemical or other properties. Suitable examples are well known to those of skill in the art, and include, but are not limited to moieties described in Patini et al., Chem. Rev, 1996, 96, 3147-3176 and references cited therein. The subject invention also includes isotopically-labelled compounds, which are identical to those recited in Formula I, but for the fact that one or more atoms are 20 replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18o, 170 3 1P, 32 P, 35S 18 F, and 36 C1, respectively. Compounds of the present invention and 25 pharmaceutically acceptable salts or solvates of said compounds which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labelled compounds of the present invention, for WO 2008/125945 PCT/IB2008/000862 - 13 example those into which radioactive isotopes such as 3 H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon 14, i.e., 1 4 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2 H, can 5 afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of Formula I of this invention thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available 10 isotopically labeled reagent for a non-isotopically labeled reagent. The term "mmol", as used herein, unless otherwise indicated, is intended to mean millimole. The term "equiv", as used herein, unless otherwise indicated, is intended to mean equivalent. The term "mL", as used herein, unless otherwise indicated, is intended to mean milliliter. The term "U", as used herein, unless otherwise indicated, is 15 intended to mean units. The term "mm" as used herein, unless otherwise indicated, is intended to mean millimeter. The term "g", as used herein, unless otherwise indicated, is intended to mean gram. The term "kg", as used herein, unless otherwise indicated, is intended to mean kilogram. The term "h", as used herein, unless otherwise indicated, is intended to mean hour. The term "min", as used herein, unless otherwise indicated, is 20 intended to mean minute. The term "pL", as used herein, unless otherwise indicated, is intended to mean microliter. The term "pM", as used herein, unless otherwise indicated, is intended to mean micromolar. The term "pm", as used herein, unless otherwise indicated, is intended to mean micrometer. The term "M", as used herein, unless otherwise indicated, is intended to mean molar. The term "N", as used herein, unless 25 otherwise indicated, is intended to mean normal. The term "nm", as used herein, unless otherwise indicated, is intended to mean nanometer. The term "nM", as used herein, unless otherwise indicated, is intended to mean nanoMolar. The term "amu", as used herein, unless otherwise indicated, is intended to mean atomic mass unit. The term "'C", as used herein, unless otherwise indicated, is intended to mean Celsius. The term 30 "m/z", as used herein, unless otherwise indicated, is intended to mean, mass/charge ratio. The term "wt/wt", as used herein, unless otherwise indicated, is intended to mean weight/weight. The term "v/v", as used herein, unless otherwise indicated, is intended to mean volume/volume. The term "mL/min", as used herein, unless otherwise indicated, WO 2008/125945 PCT/IB2008/000862 - 14 is intended to mean milliliter/minute. The term "UV", as used herein, unless otherwise indicated, is intended to mean ultraviolet. The term "APCI-MS", as used herein, unless otherwise indicated, is intended to mean atmospheric pressure chemical ionization mass spectroscopy. The term "HPLC", as used herein, unless otherwise indicated, is 5 intended to mean high performance liquid chromatograph. The chromatography was performed at a temperature of about 20 'C, unless otherwise indicated. The term "LC", as used herein, unless otherwise indicated, is intended to mean liquid chromatograph. The term "LCMS", as used herein, unless otherwise indicated, is intended to mean liquid chromatography mass spectroscopy. The term "TLC", as used herein, unless otherwise 10 indicated, is intended to mean thin layer chromatography. The term "SFC", as used herein, unless otherwise indicated, is intended to mean supercritical fluid chromatography. The term "sat" as used herein, unless otherwise indicated, is intended to mean saturated. The term "aq" as used herein, is intended to mean aqueous. The term "ELSD" as used herein, unless otherwise indicated, is intended to mean 15 evaporative light scattering detection. The term "MS", as used herein, unless otherwise indicated, is intended to mean mass spectroscopy. The term "HRMS (ESI)", as used herein, unless otherwise indicated, is intended to mean high-resolution mass spectrometry (electrospray ionization). The term "Anal.", as used herein, unless otherwise indicated, is intended to mean analytical. The term "Calcd", as used herein, 20 unless otherwise indicated, is intended to mean calculated. The term "N/A", as used herein, unless otherwise indicated, is intended to mean not tested. The term "RT" or "rt" as used herein, unless otherwise indicated, is intended to mean room temperature. The term "Mth.", as used herein, unless otherwise indicated, is intended to mean Method. The term "Celite*", as used herein, unless otherwise indicated, is intended to mean a 25 white solid diatomite filter agent commercially available from World Minerals located in Los Angeles, California USA. The term "Eg.", as used herein, unless otherwise indicated, is intended to mean example. The term "Ki", as used herein, unless otherwise indicated, is intended to mean values of enzyme inhibition constant. The term "Ki app", as used herein, unless 30 otherwise indicated, is intended to mean Ki apparent. The term "IC50", as used herein, unless otherwise indicated, is intended to mean concentrations required for at least 50% enzyme inhibition.
    WO 2008/125945 PCT/IB2008/000862 -15 Other aspects, advantages, and features of the invention will become apparent from the detailed description below. DETAILED DESCRIPTION AND EMBODIMENTS OF THE INVENTION The following reaction Schemes illustrate the preparation of the compounds of 5 the present invention. Unless otherwise indicated, R 1 through R 1 2 and Ra through Re in the reaction schemes and the discussion that follows are as defined above. Detailed Description Compounds of Formulas I can be made following the synthetic routes in Scheme 1 through Scheme 5. In the following schemes and examples, the terms, "BOC", "Boc" 10 or "boc" means N-tert-butoxycarbonyl, "BOP" means benzotriazol-1 yloxytris(dimethylamino)phosphonium hexafluorophosphate, "DCM" means CH 2
    CI
    2 , DIPEA (also known as Hunig's base) means diisopropyl ethyl amine, "DMA" means dimethyl amine, "DMF" means dimethyl formamide, "DMSO" means dimethylsulfoxide, "Me" means methyl - CH 3 , "Et" means -CH 2
    CH
    3 , "MTBE" means methyl t-butyl ether, 15 TEA means triethyl amine, TFA means trifluoro acetic acid, THF means tetrahydrofuran and "SEM" means 2-(trimethylsilyl)ethoxymethyl, "HATU" means 2-(7-Aza-1 H benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate. Scheme 1 (Pyrrolo[3,4-C]pyrazole Intermediates)
    R
    7
    R
    8 R 7
    R
    8
    R
    7
    R
    8 RR , NC, R7RCX NC ""N XCO2H
    H
    2 N COOH H C0 2 H o H(A Boc.1c |( ) (B) I(C) R7 R 8
    R
    7 R8 C N CO 2
    CH
    3 N-Boc Boc NC I(D) (E)
    R
    7 RR6R H R8tB 2 C N N N-Boc HN N-Boc 20
    H
    2 N I(F)
    H
    2 N I(G) Scheme 1 illustrates the synthesis of the intermediates I(A) through |(G), which are useful in preparation of compounds of Formula 1. The amino group of the WO 2008/125945 PCT/IB2008/000862 -16 substituted amino acid I(A) is alkylated to give compound I(B). This can typically be done by treating compound I(A) with an alkylating agent in the presence of a base. An activated electrophilic double bond moiety is a commonly used alkylating reagent. A typical reaction condition of alkylating I(A) with an activated electrophilic double bond 5 moiety is to treat I(A) with the activated double bond moiety in the presence of a strong base. Subsequent aqueous work up affords compound I(B). The amino group of compound (B) is then protected with a boc group to give compound I(C). This can typically be done by treating compound I(B) with Boc agent in the presence of a base. A typical condition is to treat compound l(B) with (Boc) 2 0 in the presence of Me 4 NOH in 10 MeCN as a solvent. The carboxylic acid group of compound I(C) is then converted into a methyl ester of compound I(D). A typical condition of converting the carboxylic acid group into the methyl ester group is to treat I(C) with methyl iodide in DMF in the presence of a base. Compound I(D) then undergoes an intramolecular aldol condensation to give compound (E). This can typically be done by treating compound 15 I(D) with a strong base in an aprotic solvent. A typical condition is to treat compound I(D) with t-BuOK in toluene. Subsequent aqueous workup gives compound I(E). Compound I(E) then undergoes a 2+3 cyclization with a hydrazine moiety to form compound I(F). A typical condition of the cyclization is to reflux compound l(E) with hydrazine and acetic acid in EtOH. The free base pyrazole nitrogen of compound (F) is 20 then acylated to give compound (G). A typical condition of the acylation is to treat compound I(F) with chloro ethyl carbonate in THF. As indicated in the above structure for l(G), the acyl group can be attached to either of the nitrogens of the pyrazole. More detailed synthetic conditions to intermediate (G) of Scheme 1 can be found in U.S. Patent Application Publication No. 2003/0171357 and PCT Publication WO 25 02/12242, the disclosures of which are incorporated herein by reference. Scheme 2 (Routes A through D) WO 2008/125945 PCT/IB2008/000862 -17 EtOOC R R HN N-Boc
    H
    2 N (G) EtOOCEtOOC HNEt N-Boc HN NH 111(A) HN O 11(A) HN R1 [COOEt] R 7 EtOOC R7 R EtOOC R 7
    R
    8 EtOOCN NH H 0 eNHtl( HN N< HN;J HN N 111(B) Het He t HN O 11(B) HN 11(D) H R7 R 8 OOEt) R1 R N 0 Het 7 EtOOC R
    H
    2 N 111(D) R R 8 HNHN IN NB C Het CI HN 0 HN 0 11(C) R 111(c) R 7 A H R 7 R8 N N Of HN 0 Het R1 Scheme 2 illustrates several routes through which compounds of Formula I can be made from intermediate l(G). The substituents R 1 , R 7 and R3 are as defined in Formula I above. The term "Het" is the piperazine or piperidine heterocyclic group as
    R
    2 R3 RG 5 defined by R 4
    R
    5 . In one route of Scheme 2, compound (G) undergoes a nucleophilic reaction with an R 1 electrophile moiety. This nucleophilic reaction can be any acylation carried out by an amine functionality. A typical acylation reaction condition is to treat compound l(G) with an acylating agent such as R 1 -COCI, in the presence of a base such as 2 equivalents of DIPEA, in a solvent such as dichloromethane. The 10 reaction mixture is stirred at a temperature between 0 0 C and room temperature for about 12 hours. Subsequent aqueous workup gives compound II(A). The Boc group on the pyrrole nitrogen of compound II(A) is then removed to give compound II(B). This can WO 2008/125945 PCT/IB2008/000862 -18 typically be done by treating 11(A) with a strong acid. A typical reaction condition is to treat compound II(A) with 4N HCI in dioxane and DCM. Subsequent aqueous workup affords compound II(B). The pyrrole NH of compound II(B) is then converted to the chloroformate ll(C). This can typically be done by using phosgene, triphosgene, or 5 some other equivalent. A typical reaction condition is to treat II(B) with 2 equivalents of triphosgene in DCM at 0 0 C for four hours. Subsequent mild basic workup with saturated NaHCO 3 and purification gives compound II(C). Compound II(C) is then treated with a nucleophile moiety. The nucleophile can be any amine that can react with the electrophile ll(C). A typical reaction involves treating 11(C) with a nucleophile such as 10 1.5 equivalents of an amine in the presence of 1 equivalent of base such as DIPEA in a solvent such as THF. Subsequent deprotection of ethoxy carbonyl group in a protic solvent, such as methanol, in the presence of base, such as TEA, followed by purification gives a compound of Formula 1. Alternatively, compound II(B) can then undergo a nucleophilic reaction with a Het 15 electrophile to give compound 11(D). The nucleophilic reaction carried out for this transformation can be an acylationn. An acylation reaction of 11(B) to give ll(D) is carried out by treating compound II(B) with an acylating reagent in the presence of base. A typical reaction condition is to mix compound II(B) with an excess of base, such as DIPEA in DCM, followed by addition of the resulting solution to an acylchloride at 0CC. 20 The reaction is stirred for about 2 hours at room temperature and subsequent aqueous workup gives compound II(D). The ethoxycarbonyl protecting group on the pyrazole nitrogen of compound 11(D) is removed to give a compound of Formula 1. This can typically be done by treating a compound II(D) with a base. A typical reaction condition is to treat compound lIl(B) in a protic solvent, such as methanol, in the presence of 25 base, such as TEA, or to treat a compound II(D) in MeOH in the presence of 2-3 equivalents of NaOH at room temperature. Subsequent aqueous workup affords a compound of Formula 1. In an alternate route of Scheme 2, the Boc group on the pyrrole nitrogen is removed to give compound lIl(A). The reaction can typically be carried out by treating 30 compound (G) with a strong acid. A typical reaction condition is to treat compound l(G) with 4N HCI in dioxane and DCM. Subsequent aqueous workup affords compound lIl(A). Compound 1il(A) can then undergo a nucleophilic reaction with a Het electrophile to give compound Il(B). Because the -NH 2 group attached to the pyrazole in WO 2008/125945 PCT/IB2008/000862 - 19 compound 1il(A) is less reactive than the pyrrole nitrogen of Il(A), the transformation of Ill(A) to Ill(B) can be carried out without protecting the pyrazole -NH 2 group of compound li1(A). The nucleophilic reaction carried out for this transformation can be an acylation, Relative mild reaction conditions are preferred to achieve reaction selectivity. 5 An acylation reaction of Ill(A) to give Il(B) is carried out by treating compound i1(A) with an acylating reagent in the presence of base. A typical reaction condition is to mix compound I1(A) with an excess of base, such as DIPEA in DCM, and adding the resulting solution to an acyl chloride at 00C. The reaction mixture is held at 00C for about two hours and subsequent aqueous workup gives compound lIl(B). 10 Compound Ill(B) then undergoes a nucleophilic reaction with an R 1 electrophile moiety. This nucleophilic reaction can be an acylation that an amine functionality carries out. A typical acylation reaction condition is to treat compound 1il(B) with an acylating agent, such as RCOCI in the presence of a base, such as 2 equivalents of DIPEA, in a solvent, such as 1,2-dichloroethane. Subsequent aqueous workup gives compound 15 il(C). The ethoxycarbonyl protecting group on the pyrazole nitrogen of compound lIl(C) is removed, typically with a base, to give the free base of compounds of Formula 1. A typical reaction condition is to mix compound lIl(C) with TEA in a protic solvent, such as methanol, followed by purification to give a compound of Formula 1. Alternatively, the ethoxycarbonyl protecting group on the pyrazole nitrogen of 20 compound Il(B) is removed to give the free base compound 1il(D). This can typically be done by treating compound 1il(B) with a base. A typical reaction condition is to reflux compound 1il(B) in dioxane and DCM in the presence of 2-3 equivalents of LiOH. Subsequent aqueous workup affords compound lIl(D). Compound Ill(D) then undergoes a nucleophilic reaction with an R 1 electrophile moiety. This nucleophilic 25 reaction can be an acylation that an amine functionality carries out. A typical acylation reaction condition is to treat compound Il(D) with an acylating agent, such as R 1 -COCI, in the presence of a base, such as 2 equivalents of DIPEA, in a solvent such as dichloromethane. The reaction mixture is stirred for four hours and subsequent aqueous workup and purification gives a compound of Formula 1. 30 In a method similar to Route B described above, compounds of Formula I can also be synthesized by the following method in Scheme 3.
    WO 2008/125945 PCT/IB2008/000862 - 20 Scheme 3 (Route E) route E H R 7
    R
    8 SEM RR SEM R R8 H R 7 R8 H R 7 R8 N-B c ~ N N N N_ _ N-0 S N-Boc N-Boc N N-Boc N NH -et
    H
    2 N I(F) H 2 N IV(A) HN 0 IV(B) HN 0 IV(C) HN 0 I R1 R1 R1 Scheme 4 (Piperazine Intermediates) Rz=C1-C 5 alkyl 0 Rz Rz z'ko V(E) RZ 0Q OH Boc 2 O HnOH Na T Bnr OH NH 2 HC V
    H
    2 N _ NaOH I~ NaH THF N HATU, CHCI 2 Bri-N, HN 0 Dioxane, H 2 0 Boc 0 Boc 0 Boc V(A) V(B) V(C) V(F) Bn Bn Bn HCI-dioxane Rz O / EtaN, xylene 0 N Rz 1. LiAIH 4 N Rz HCI-dioxane Bn-NH HN 2. Boc 2 O N a N "X N HC VH BocH V(G) V(H) V(I) V(J) 0 0 HMeOH -O
    NH
    2
    NH
    2 HCI 5 V(D) V(E) Intermediate V(B) was prepared by mixing a solution of V(A) (267 g, 3 mol) in dioxane (6 L), H 2 0 (3 L) and 1 M NaOH (3 L) and cooling in an ice-water bath. Boc 2 O (720 g, 3 mol) was added at 0-10 0C and stirring was continued at room temperature 10 overnight. The solvent was removed in vacuum. 3 L of H 2 0 was added to dissolve the residue. The resulting solution was cooled to 0-5 0C and acidified with 1 N HCI to pH = 3. The resulting solution was extracted with ethyl acetate (1.5 Lx3). The organic phases were combined, dried over Na 2
    SO
    4 and concentrated to give compound V(B) (465 g, 82%) as a white solid. (Ra = CH 3 : 1 H NMR (400 MHz, CDC1 3 ) 6 11.30(br, 1H), 6.90(br, 15 0.5H), 5.10(br, 0.5H), 4.50-4.00(m, 1H), 1.40(m, 12H)) In the next step, the intermediate V(C) was subsequently prepared by suspending NaH (200 g, 5 mol) in 2.5 L of dry THF and cooling the mixture to -10-0 *C. A solution of V(B) (94.5 g, 0.5 mol) in 800 mL of dry THF was added dropwise at -10-0 *C. After the addition, the mixture was stirred at -10-0 0C for 30 minutes. Then BnBr 20 (478 mL, 4 mol) was added dropwise at -10-0 0C. The reaction mixture was stirred at rt WO 2008/125945 PCT/IB2008/000862 -21 for 60 hours. The mixture was poured into 3 L of ice water carefully. The resulting solution was washed with 1.5 L of diethyl ether. The aqueous phase was acidified with 2 N aq. HCI to pH = 3-4 at 0-5 *C and extracted with diethyl ether (1.5 Lx2). The combined organic layers were dried over Na 2
    SO
    4 and evaporated in vacuum to give compound 5 V(C) (115 g, 84%) as a yellow solid. (RZ=CH 3 : 1 H NMR (400 MHz, CDCl3) 6 9.50(br, 1H), 7.38(m, 5H), 4.63-3.95(m, 3H), 1.51(m, 12H)). In a separate reaction, the intermediate reagent V(E) was prepared by suspending V(D) (100 g, 1.12 mol) in 1 L of MeOH. The mixture was cooled to 0-5 *C. 50 mL of SOC1 2 was added dropwise at 0-5 *C. The reaction mixture was then stirred at 10 rt for 24 hours. The mixture was evaporated in vacuum to give compound V(E) (141 g, 90%) as a white solid. Interemdiate V(F) was prepared from V(C) and V(E). Compound V(C) (100 g, 0.358 mol) and DIPEA (138 g, 1.07 mol) were dissolved in 900 mL of DMF. The mixture was cooled to 0-10 0C. Then HATU (150 g, 0.394 mol) was added to the mixture 15 portionwise at 0-10 0C. The resulting mixture was stirred at 0-10 0C for 10 minutes. Compound V(E) (55 g, 0.394 mol) was added portionwise at 0-10 0. The reaction mixture was stirred at rt overnight. The solvent was removed in vacuum and the residue was dissolved in 500 mL of water. The resulting mixture was extracted with ethyl acetate (300 mLx3). The organic phases were combined, dried over Na 2
    SO
    4 and concentrated 20 in vacuum. The residue was purified by chromatography via silica gel eluted with petroleum ether/ethyl acetate (50:1-10:1) to give compound V(F) (100 g, 76%) as a yellow oil. Compound V(F) (100 g, 0.274 mol) was dissolved in 2 L of 4 N HCI (g)/dioxane at 0-5 *C. The mixture was stirred at rt overnight and concentrated in vacuum to give 25 compound V(G) (85 g, 100%) as a colorless syrup. (RZ=CH 3 : 1 H NMR (400 MHz, D20) 6 7.41(m, 5H), 4.38(m, 1H), 4.14(m, 2H), 3.93(m, 1H), 3.69(s, 3H), 1.44(d, J= 6.8 Hz, 3H), 1.35(d, J= 7.2 Hz, 3H)). In the next step, V(G) (75 g, 0.25 mol) and Et 3 N (41.7 mL, 0.3 mol) were suspended in 1500 mL of xylene. The mixture was stirred at rt for 30 minutes. Then 30 DMAP was added as catalyst and the mixture was heated to reflux for 48 hours. The solvent was removed in vacuum and the residue was purified by chromatography on silica gel eluted with petroleum ether/ethyl acetate (50:1-10:1) to give compound V(H) (47 g, 81%) as a brown oil. (Rz=CH 3 : 1 H NMR (400 MHz, CDC13) 6 7.71(br, 1H), WO 2008/125945 PCT/IB2008/000862 -22 7.33(m, 5H), 5.16(d, J=14.8 Hz, 1H), 4.13(m, 2H), 3.86(m, 1H), 1.59(d, J= 12.8 Hz, 3H), 1.38(d, J= 8.8 Hz, 3H)). LiAIH 4 (31 g, 0.82 mol) was suspended in 200 mL of dry THF. A solution of compound V(H) (47 g, 0.203 mol) in 600 mL of dry THF was added dropwise. After the 5 addition, the mixture was heated to reflux overnight. The reaction mixture was cooled to 0-5 0C and diluted with 300 mL of THF. 190 mL of 20% aqueous NaOH was added dropwise to the reaction mixture. After the addition, the mixture was stirred at room temperature for 30 minutes. (Boc) 2 0 (66.5 g, 0.31 mol) was added to the mixture. The mixture was stirred at rt overnight. The solvent was removed in vacuum and the residue 10 was purified by chromatography via silica gel eluted with petroleum ether/ethyl acetate (100:1) to give compound V(J) (48 g, 77%) as a pale yellow liquid. (Rz=CH 3 : 1 H NMR (400 MHz, CDC13) 6 7.36(m, 5H), 4.19(m, 1H), 3.67(m, 2H), 3.47(m, 1H), 3.33(m, 1H), 2.97(m, 1H), 2.72(m, 1H), 2.27(d, J=25.6 Hz, 1H), 1.48(s, 9H), 1.36(d, J= 6.4 Hz, 3H), 0.99(d, J= 7.2 Hz, 3H)). 15 In the final step, V(I) (48 g, 0.158 mol) was dissolved in 1500 mL of 4 N HCI (g)/dioxane and the resulting solution was stirred at rt overnight. The solvent was removed in vacuum and the residue was triturated with 500 mL of diethyl ether. The solid formed was filtered and the filter cake was washed with 50 mL of diethyl ether, then dried in vacuum to give V(J) (37 g, 100%) as a white solid. (RZ=CH 3 : 1 H NMR 20 (400 MHz, CDCl3) 6 7.42(s, 5H), 4.82(d, J=17.6 Hz, 1H), 4.10(d, J=17.6 Hz, 1H), 3.71 2.98(m, 6H), 1.56(d, J= 8.0 Hz, 3H), 1.20(d, J= 8.8 Hz, 3H).) Spirocyclic piperazine derivatives such as in Example A2, can be prepared using analogous methods to the above scheme, wherein R' is a C 2
    -C
    5 alkyl.
    WO 2008/125945 PCT/IB2008/000862 - 23 Scheme 5 (Bicyclic Piperazine Intermediates) 0 0 O-CH, OCH3 BOP/-PrNet 2 /DCM HC~ldioxane ~HOJ N 0 NN H CIH VI(B) boc N VI(A) Vi(C)
    O-CH
    3 0 N O NEt 3 /MeOH N LiAIH 4 /THF N NC O N
    H
    3 C
    CH
    3 CH 3 VI(D) VI(E) VI(F) The intermediate VI(C) was prepared by mixing N-(tert-Butoxycarbonyl)-D alanine VI(B) (114.23 g, 0.0.603 mol), methyl L-prolinate VI(A) (100 g, 0.603 mol), BOP 5 (291.72 g, 0.66 mol), and dichloromethane (1.5 L) in a 2 L flask. DIPEA (193 g, 1.5 mol) was added dropwise under stirring and cooling on a water bath. The reaction mixture was stirred overnight at room temperature and evaporated. Water (1 L), ethyl acetate (400 mL), and ether (400 mL) were added. After extraction, the organic layer was separated. The aqueous one was washed with ether (300 mL). The combined extracts 10 were washed with 1 M HCI (1 L), water (1 L), 10% K 2
    CO
    3 (2 x 1 L), dried with anhydrous Na 2
    SO
    4 , and evaporated. A viscous oil VI(C) (110 g, 61%) was obtained. The intermediate VI(C) (110 g, 0.366 mol) was treated with 4 M HCI in dioxane (-400 mL). The solution was kept for 16 h at room temperature and evaporated. The oily residue was washed with ether (2 x 500 mL). The ether was decanted, and the oil VI(D) 15 was dried in vacuum. Intermediate VI(D) was dissolved in absolute methanol (700 mL). Triethylamine (105 mL, 0.75 mol) was added to pH -8-9. The reaction mixture was stirred overnight at room temperature. The solution was evaporated. The solid residue was stirred in dichloromethane/ethyl acetate mixture (1:1, 600 mL), and the obtained mixture was 20 washed with 40% aqueous potash (500 mL). The aqueous layer was subjected to extraction with dichloromethane/ethyl acetate mixture (1:1, 2 x 300 mL). The combined extracts were dried with potash and evaporated. The solid residue was treated with ether (400 mL). The resulting mixture was kept for 2 h at room temperature, then overnight at 4 *C. The formed crystals were washed with cold ether (100 mL) and WO 2008/125945 PCT/IB2008/000862 -24 vacuum-dried to afford VI(E) (48.1 g, 78.08%). 1 H NMR spectrum is attached (see LJMT0165-07_AdditionalQCData folder). Intermediate VI(E) (48.1 g, 0.286 mol) was suspended in THF (600 mL). This suspension was added to a solution of LiAIH 4 (27.2 g, 0.715 mol) in THF (300 mL) in a 5 flow of argon under stirring and heating at such a rate that the solvent simmer. After this, the reaction mixture was refluxed for 15 h, cooled to room temperature, and treated with 5 M NaOH (200 mL). The organic layer was separated, and the curds-like residue was washed with ether (3 x 100 mL.). The combined extracts were dried with anhydrous K2CO3 and evaporated. The liquid residue was distilled in vacuum (72-75 0C/10 mmHg). 10 Yield: 75.2% (30.1 g). Satisfactory C, H, N-analysis was obtained. EXAMPLES The invention will now be described in reference to the following examples. These examples are not to be regarded as limiting the scope of the present invention, but shall only serve in an illustrative manner. The examples and preparations provided below 15 further illustrate and exemplify the compounds of the present invention and methods of preparing such compounds. It is to be understood that the scope of the present invention is not limited in any way by the scope of the following examples and preparations. In the following examples molecules with a single chiral center, unless otherwise noted, exist as a racemic mixture. Those molecules with two or more chiral 20 centers, unless otherwise noted, exist as a racemic mixture of diastereomers. Single enantiomers/diastereomers may be obtained by methods known to those skilled in the art. The structures of the compounds are confirmed by either elemental analysis or NMR, where peaks assigned to the characteristic protons in the title compound are 25 presented where appropriate. 1 H NMR shift ( 6 H) are given in parts per million (ppm) down field from an internal reference standard. Unless otherwise shown, NMR data is provided in Table 1 below. EXAMPLE Al: N-(6,6-Dimethyl-5-((3S,8aS)-3-methyl-octahdropyrrolo[1,2-alpyrazine 2-carbonyl)-1,4,5,6-tetrahvdropyrrolo[3,4-cpvrazol-3-yl)picolinamide WO 2008/125945 PCT/IB2008/000862 -25 0 c o >OEt -- R0 OEt BocN N + N Io-N N HCI HN N BocN N C C Dioxane HN AA1() NH 2 A1(IV) O 0 O~tNH trphosgene O0OEt 1. DIPEA, CH 2 Cl 2 N N N N _
    DIPEACH
    2 Cl 2 C1 N N + NH 2. Et 3 N, CH 3 0H N HN N 92% n 50% HN N Al0 A1(V) A1(VI) Intermediate A(Ill): 5-tert-Butyl1-ethyl6,6-dimethyl-3-(picolinamido)pyrrolo[3,4 c]pyrazole-1, 5(4H,6H)-dicarboxylate 5 To a solution of 5-tert-butyl 1-ethyl 3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4 c]pyrazole-1,5-dicarboxylate, A1(l), (7.32g, 22.56 mmol) and DIPEA (12mL) in CH 2
    CI
    2 (60mL), picolinoyl chloride hydrochloride, A1(II), (4.82g, 27.07mmol) was added slowly. The reaction was stirred at room temperature for 2 hrs. The reaction mixture was diluted with CH 2
    CI
    2 (50mL), washed with water (2 X 30mL), sat. NaCI (brine), and dried 10 over MgSO 4 , filtered and concentrated to give A1(lII) ( 9.12g, 94 % yield). 1 H NMR (400 MHz, CDCl 3 -d) 6 ppm 1.39 - 1.50 (m, 2 H) 1.49 - 1.58 (m, 10 H) 1.72 (s, 3 H) 1.78 (s, 3 H) 4.63 (q, J=7.07 Hz, 2 H) 4.81 (d, J=19.45 Hz, 2 H) 7.46 - 7.58 (m, 1 H) 7.82 - 7.97 (m, 1 H) 8.25 (dd, J=7.71, 3.41 Hz, 1 H) 8.73 (dd, J=9.60, 4.55 Hz, 1 H). Intermediate A1(IV): Ethyl 6,6-dimethyl-3-(picolinamido)-5,6-dihydropyrrolo[3,4 15 c]pyrazole-1 (4H)-carboxylate dihydrochloride Intermediate Al(Ill) was dissolved in 4N HCI in 1,4,dioxane ( 80mL). The reaction was stirred at room temperature for 16 hr. The solvent was concentrated to give Al (IV) (8.97g, 99 % yield). 1 H NMR (400 MHz, CD 3 0D) ppm 1.52 (t, J=7.20 Hz, 3 H) 1.78 (s, 6 H) 4.60 (q, J=7.24 Hz, 2 H) 4.85 (s, 2 H) 7.60 - 7.74 (m, 1 H) 8.00 - 8.12 20 (m, 1 H) 8.23 (d, J=7.83 Hz, 1 H) 8.69 - 8.84 (m, 1 H). Intermediate Al(V): Ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-(picolinamido)-5,6 dihydropyrrolo[3,4-c]pyrazole-1 (4H)-carboxylate To a cooling bath (0*C) of A1(IV) (5.0g, 12.43 mmol) and DIPEA (11mL) in
    CH
    2
    CI
    2 (50mL), triphosgene (9.22g, 31.08 mmol) in CH 2
    CI
    2 (20mL) was added slowly. 25 The reaction was stirred at room temperature for 2hrs. The reaction mixture was diluted WO 2008/125945 PCT/IB2008/000862 -26 with CH 2 C1 2 (50mL), washed with water (2X5OmL), sat. NaCl (brine) dried over MgSO 4 and concentrated. The residue was dissolved in minimal amount of acetone and water was added to precipitate. The compound was filtered and washed with water to give A1(V) (4.48g, 92% yield). 1 H NMR (400 MHz, DMSO-d 6 ) 5 ppm 1.40 (t, J=7.07 Hz, 3 H) 5 1.69 (s, 6 H) 4.51 (q, J=7.07 Hz, 2 H) 5.03 (s, 2 H) 7.76 (dd, J=7.45, 4.93 Hz, 1 H) 8.04 8.17 (m, I H) 8.18 - 8.32 (m, 1 H) 8.78 (d, J=4.80 Hz, 1 H) 12.15 (s, 1 H). Compound Al: N-(6,6-Dimethyl-5-((3S,8aS)-3-methyl-octahydropyrrolo[1,2-a]pyrazine 2-carbonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)picolinamide A solution of Al (IV) (4.48g, 11.4mmol), (3S,8aS)-3-methyl-octahydropyrrolo[1,2 10 a]pyrazine (2.40g, 17.1mmol), and DIPEA (7mL) in THF ( 50mL) was heated to 800C for 2hrs. THF was concentrated. The reaction mixture was dissolved in CH 3 0H (30mL) and Et 3 N (30mL) then stirred at room temperature for 16 hrs. The residue was purified by HPLC (10%ACN(.1%AcOH)-30%ACN(0.1% AcOH)) to give the title compound Al( 3.01g, 62 % yield). 15 EXAMPLE A2: N-(5-ff(8S)-6,8-dimethyl-6,9-diazaspiro[4.51dec-9-yllcarbonyl}-6,6 dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-cpvrazol-3-yl)pyridine-2-carboxamide 0 O0Et O O aq.NaOH NH N% amine -N N MeOH N I N NlNn /*. /:) N N - / QCf-D H/'z S N H N N / N HN HN N N 0 A1(V) A2(1) A2 The intermediate of A2(I), was prepared from A1(V) in a manner analogous to the preparation of Al above, except (8S)-6,8-dimethyl-6,9-diazaspiro[4,5]decane was 20 substituted in place of Al (VI). To the resulting suspension of A2(l) (668 mg, 1.28 mmol) in 30 mL methanol was added sodium hydroxide (3 mL of 10% solution in methanol). After stirring at room temperature for 30 minutes, the solvent was removed in vacuo. Purification as in example Al afforded the title compound A2 as a white solid (254 mg, 29%). 25 EXAMPLES A3 - A141 Examples A3 through A141 were prepared using methods analogous to Examples Al and A2 above. EXAMPLE A142: N-(5-((2R,5S)-1-(3-fluoropropyl)-2,5-dimethylpiperazine-4-carbonyl) 6,6-dimethyl-1,4,5,6-tetrahvdropyrrolo[3,4-cpvrazol-3-vl)picolinamide WO 2008/125945 PCT/IB2008/000862 - 27 OH 3 C CH 3 O
    OH
    3 C CH 3 0 N H 3 cCH3 N A1(v) A142(I A142(II) 1. TEA, THF 85CC r 3 C CH 3 A N N~OH 11C-N3 A142N Intermediate Al142(II): Ethyl 5-((2S,5R)-2,5-dimethylpiperazine-1 -carbonyl)-6,6 dimethyl-3-(picolinamido)-5,6-dihydropyrrolo[3,4-c]pyrazole-1 (4H)-carboxylate To a sealed tube was added the piperazine A142(I) (1.0g, 2.4 mmol, 1.0 equiv), 5 tetrahydrofuran (50.0 mL), the Al1(V) (0.627 g, 2.93 mmol, 1.2 equiv) and DIPEA (1 .27 mL, 7.32 mmol, 3.0 equiv). The tube was heated to 85 0 C overnight. The reaction was allowed to cool to rt and then concentrated. The resulting residue was then redissolved in dichloromethane (50 mL) and washed with saturated aqueous sodium bicarbonate (2 x 20 mL). The collected organic was dried over sodium sulfate, filtered and 10 concentrated to afford a light orange solid. This material (1.1g, 1.9 mmol, 1 equiv) was then taken up in dioxane (5 mL) and 4 M HCI in dioxane (4.83 mL, 19.3 mmol, 10 equiv) was added. The resulting solution was allowed to stir at room temperature for 15 minutes. The dioxane removed in vacuo and the residue was redissolved in dichloromethane (20 mL) and washed with saturated sodium bicarbonate (10 mL). The 15 collected organic was dried over sodium sulfate, filtered and concentrated to afford the desired product, A142(II). The crude product was subjected to the next step without further purification (see next step for overall reaction yield). MS (ESI+) m/z 465.4 1 H NMR (300 MHz, DMSO-de) 6 ppm 0.97 (dd, J=1 1.68, 6.03 Hz, 6 H) 1.40 (t, J=7.06 Hz, 3 H) 1.61 (s, 3 H) 1.69 (s, 3 H) 2.25 (d, J=10.93 Hz, 1 H) 2.85 (in, 3 H) 3.01 - 3.14 (in, 1 20 H) 3.56 (s, 2 H) 4.49 (q, J=7.03 Hz, 2 H) 4.82 (d, J=4.33 Hz, 2 H) 7.71 - 7.79 (in, 1 H) 8.05 -8.16 (in, 1 H) 8.18 -8.26 (in, 1 H) 8.77 (d, J=3.96 Hz, 1 H) 12.15 (s, 1 H) WO 2008/125945 PCT/IB2008/000862 -28 Compound A142: N-(5-((2R,5S)-l-(3-fluoropropyl)-2,5-dimethylpiperazine-4-carbonyl) 6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)picolinamide To a microwave vial was added A142(II) (0.200 g, 0.426 mmol, 1.0 equiv), triethylamine (0.148 mL, 1.06 mmol, 2.5 equiv), 1-bromo-3-fluoropropane (0.090 g, 5 0.639 mmol, 1.5 equiv) and tetrahydrofuran (1.5 mL). The resulting reaction mixture was heated in the MW at 1500C for 1 hour. The crude reaction was concentrated in vacuo and taken up in methanol and trimethylamine (6 mL-6 mL) and stirred at rt for 16 hours. The reaction mixture was then concentrated again and the resulting residue dissolved in dichloromethane (50 mL) and washed with saturated aqueous sodium 10 bicarbonate. The collected organic was dried over sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography. Eluted with methanol in dichloromethane (0-> 1% methanol) to afford the desired product A142 in 23% yield as an off white solid over two steps. EXAMPLES A143 - A144: 15 Examples A143 and A144 were prepared using methods analogous to Example A142 above. EXAMPLE A145: : N-(5-((2R,5S)-2,5-dimethyl-1-(2(tetradhydro-2H-pyran-4 yl)ethvl)piperazine-4-carbonyl)-6,6-dimethyl-1,4,5,6-tetrahvdropyrrolo[3,4-clpyrazol-3 yl)picolinamide oHac CH3 0 OH 3 c CH 3 H3Cc0cN 3 o 1. NaCNBH 4
    H
    3 C',, N N< HN X + AcOH,MeOH N 2. TEA, MeOH 0 N N N A145 20 A142(l) To a 100 mL round bottom flask was added A142(ll) (0.100 g, 0.213 mmol, 1.0 equiv), methanol (3.0 mL), tetrahydropyranyl-4-acetaldehyde (0.041 g, 0.319 mmol, 1.5 equiv) and acetic acid (0.013 mL, 0.213 mmol, 1.0 equiv). After 1 hour, sodium cyanoborohydride (0.022 g, 0.341 mmol, 1.6 equiv) was added and the reaction was 25 allowed to stir at rt for 16 hours. Triethylamine (3 mL) was added to the reaction and it was allowed to stir at rt for another 16 hours. Concentrated the reaction, diluted with dichloromethane (5 mL) and washed with saturated sodium sulfate (2 mL) and brine (2 WO 2008/125945 PCT/IB2008/000862 -29 mL). Dried collected organic over sodium sulfate, filtered and concentrated. The crude product was purified on preparative HPLC (0.1% HOAc) to afford 60 mg of the desired product A145 in 53% yield as a white solid. EXAMPLES A146-A164: 5 Examples A146 through A164 were prepared using methods analog to Examples Al, A142 and A145 above. EXAMPLE B1: Pyridine-2-carboxylic acid [5-(1-cyclobutyl-4-fluoro-piperidine-4 carbonyl)-6,6-dimethyl-1,4,5,6-tetrahVdro-pVrrolo[3,4-clpvrazol-3-vll-amide S>=O F 2Et F Co 2 H OEt BI(II) o 6 M aqueous HCI SO 2 CI Na(OAc) 3 BH N refuxing (100 *C) N HCI refluxing H HOAc, CH 2
    CI
    2 B1(1) B1(1ll) B1(IV) C0 2 CI i 3 c r-C30N HN N-cO 2 Et 1) DIPEA,
    CH
    2 CI2 N HCI HN 0 2)1 M NaOH, N K + HN~) M eOH N Meo N B1(V) B1(VI) BI 10 Intermediate B1(111): 1-Cyclobutyl-4-fluoro-piperidine-4-carboxylic acid ethyl ester To a 250 mL round bottle was added compound B1_ () ethyl 4-fluoropiperidine-4 carboxylate, hydrochloride (1.25 g, 5.91 mmol, 1.0 eq), CH 2
    CI
    2 (40 mL), cyclobutanone B1(11) (1.30 g, 7.68 mmol, 1.30 eq), and glacial HOAc (0.338 mL, 5.91 mmol, 1.0 eq). After stirring at rt for 5 to 10 min, sodium triacetoxyborohydride (2.00 g, 9.45 mmol, 1.60 15 eq) was added in one portion. A cloudy solution was obtained. The reaction mixture was stirred at rt for 2 h. To the reaction mixture, 100 mL aqueous NaOH (1 M) was added, and the resulting suspension was stirred at rt for 10 min. The reaction was extracted with EtOAc (150 mL). The organic layer was collected, washed with brine (200 mL), dried over Na 2
    SO
    4 , filtered, and concentrated to afford the desired product, 20 BI(111), as a colorless oil. The crude product was cleaned and subjected to the next step without purification (see next step for the overall reaction yield). 1 H NNR (400 MHz, CDCl 3 , ppm) 6 1.28 (t, J = 7.20 Hz, 3H), 1.64-1.73 (m, 2H), 1.82-1.99 (m, 4H), 2.01-2.21 (m, 6H), 2.72-2.80 (m, 3H), 4.22 (q, J = 7.2 Hz, 2H); 19 F NMR (376 Hz, CDCl 3 , ppm) 6 166.83.
    WO 2008/125945 PCT/IB2008/000862 - 30 Intermediate B1(IV): 1-Cyclobutyl-4-fluoro-piperidine-4-carboxylic acid hydrochlorite The intermediate B1(lll) (crude, 5.91 mmol) was dissolved in 10 mL 6 M aqueous HCL. The colorless solution was warmed to 100 'C and refluxed under N 2 . After 2h, the reaction mixture was cooled to rt. The solvent was removed and a yellow solid was 5 obtained. The solid was washed with 10 mL EtOAc, and dried under vacuum to afford 1.20 g of the desired product B1 (IV) as a white solid in 85 % yield over two steps. The product was subjected to next step without further purification. 1 H NNR (400 MHz, DMSO-d 6 , ppm) 6 1.63-1.78 (m, 2H), 2.10-2.16 (m, 4H), 2.35-2.45 (m, 4H), 2.82-2.88 (m, 2H), 3.29-3.32 (m, 2H), 3.66-3.70 (m, 1H), 11.63 (br s, 1H), 13.68 (br s, 1H); 1 9 F 10 NMR (376 Hz, DMSO-d 6 , ppm) 6 -166.31. Compound B1: Pyridine-2-carboxylic acid [5-(1 -cyclobutyl-4-fluoro-piperidine-4 carbonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yI]-amide The crude starting material B1 (IV) (0.673 mmol) was dissolved in 10 mL SOCl 2 . The obtained pale yellow suspension was warmed to 80 0C and refluxed under N 2 for 1 15 h. At this point, the reaction turned into clear pale yellow solution. The reaction mixture was cooled to rt. The solvent was removed under reduced pressure to afford the acyl chloride B1 (V) as a yellow solid in quantitative yield. To a 100 mL RB were added the acyl chloride B1(V) (crude, 0.673 mmol, 1.3 eq), compound ethyl 6,6-dimethyl-3-[(pyridin-2-ylcarbonyl)amino]-5,6-dihydropyrrolo[3,4 20 c]pyrazole-2(4H)-carboxylate, B1(VI), (189 mg, 0.518 mmol, 1.0 eq), and 13 mL
    CH
    2
    CI
    2 . The resulting suspension was stirred at rt for 5 min under N 2 . DIPEA (0.354 ml, 2.07 mmol, 4.0 eq) was added slowly and one can see that lots of smoke was generated. After being stirred at rt for 1 h, the reaction was quenched with brine (50 mL), extracted with EtOAC (50 mL), dried over Na 2
    SO
    4 , and concentrated. The crude 25 coupling product was subjected to next deprotection step. To a solution of crude coupling product in 10 mL MeOH was added 1.5 mL 1.0 M aqueous NaOH dropwise at rt. A yellow clear solution was obtained. The LC-MS indicated that the reaction was complete in 30 min. The reaction was diluted with 50 mL EtOAc, and washed with brine (50 mL). The organic layer was collected, dried over 30 Na 2
    SO
    4 , filtered, and concentrated to give the crude product. The crude product was purified on preparative HPLC (0.1 % HOAc) to afford 80 mg of the desire product, B1, in 28% yield as a white solid over two steps.
    WO 2008/125945 PCT/IB2008/000862 - 31 EXAMPLE B2: Pyridine-2-carboxylic acid {5-[4-fluoro-1 -(tetrahydro-pyran-4-yl) piperidine-4-carbonyll-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-cpvrazol-3-yl}-amide 0 Q=0 FO 2 Et F CO 2 H OEt B2(II) 6 M aqueous HCI SO 2 CI Na(OAc) 3 BH N refuxing (100 *C) N HCI refluxing HCI HOAc, CH 2
    CI
    2 B2(1) 6 B2(11) B2(IV)
    H
    3 C CH 3 C0 2 CI H 3 C CH 3 0 HN N-C2Et 1) DIPEA, CH 2
    CI
    2 F K) Cl0 N HICI HN 2)1 M NaOH, N 0 0 B2(V) B2(VI) B2 Intermediate B2(111): 4-Fluoro-1-(tetrahydro-pyran-4-yl)-piperidine-4-carboxylic acid 5 ethyl ester To a 250 mL RB were added compound B2(1) ethyl 4-fluoropiperidine-4 carboxylate, hydrochloride (1.25 g, 5.91 mmol, 1.0 eq), CH 2
    CI
    2 (20 mL), 4 oxotetrahydropyranone (II) (0.61 mL, 6.50 mmol, 1.10 eq), and glacial HOAc (0.340 mL, 5.91 mmol, 1.0 eq). After being stirred at rt for 5 to 10 min, sodium 10 triacetoxyborohydride (2.02 g, 9.45 mmol, 1.60 eq) was added in one portion. A cloudy solution was obtained. After being stirred at rt for 12 h, the reaction mixture was diluted with 150 mL Et 2 0 and 200 mL NaOH (1 M aqueous). The resulting suspension was stirred at rt for 1 h. The organic layer was collected, washed with 200 mL brine, dried over Na 2
    SO
    4 , filtered, and concentrated to afford 320 mg of the desired product, 4 15 fluoro-1 -(tetrahydro-pyran-4-yl)-piperidine-4-carboxylic acid ethyl ester B2(11) in 21 % yield as a colorless oil. 1 H NNR (400 MHz, CDCl 3 , ppm) 6 1.30 (t, J = 7.08, 3H), 1.56 1.66 (m, 2H), 1.74-1.78 (m, 2H), 1.94-2.21 (m, 4H), 2.46-2.55 (m, 3H), 2.82-2.85 (m, 2H), 3.38 (ddd, J = 1.52, 11.84, 11.84, 2H), 4.03 (dd, J = 4.28, 11.08, 2H), 4.24 (q, J= 7.05 Hz, 2H); 19 F NMR (376 Hz, CDCl 3 , ppm) 6 -166.94.
    WO 2008/125945 PCT/IB2008/000862 -32 Intermediate B2(IV): 4-Fluoro-1-(tetrahydro-pyran-4-yl)-piperidine-4-carboxylic acid hydrochlorite To a vial were added B2([ll) (260 mg, 1.0 mmol) and 8 mL aqueous HCI (6.0 M). A colorless solution was obtained. The solution was stirred at rt for 5 min and was 5 warmed to 100 0C. The mixture was refluxing at 100 6C for 2 h and a pale orange solution was obtained. The reaction was then cooled to rt, and the solvent was removed under reduced pressure to afford a yellow solid. The solid was washed with 2 x 3 mL EtOAc to afford the 260 mg of the desired product, 4-fluoro-1 -(tetrahydro-pyran-4-yl) piperidine-4-carboxylic acid hydrochlorite B2(IV), as a yellow solid in 97 % yield. 1 H 10 NNR (400 MHz, DMSO-d 6 , ppm) 6 1.70-1.80 (m, 2H), 2.02-2.05 (m, 2H), 2.14-2.20 (m, 2H), 2.41-2.59 (m, 2H), 2.97-3.09 (m, 2H), 3.29 (dd, J = 11.33, 11.33 Hz, 2H), 3.39-3.53 (m, 3H), 3.96 (dd, J= 3.78, 11.08 Hz, 2H), 11.19 (s, 1H), 13.76 (s, 1H); 19 F NMR (376 Hz, DMSO-d 6 , ppm) 6 -166.57. Compound B2: Pyridine-2-carboxylic acid {5-[4-fluoro-1 -(tetrahydro-pyran-4-yl) 15 piperidine-4-carbonyl]-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl}-amide Intermediate B2(IV)(240 mg, 0.896 mmol) was dissolved in 10 mL SOCI 2 . The suspension was warmed to 80 0C. After stirring the mixture at 80 0C for 1 h, the suspension became a clear pale yellow solution indicating that the reaction was done. The mixture was cooled to rt and the solvent was removed under reduced pressure to 20 afford 257 mg (100 %) of the desired product, acyl chloride B2(V), as a white solid. To a 100 mL RB were added acyl choride B2(V) (257 mg, 0.896 mmol, 1.5 eq), compound B2(VI) ethyl 6,6-dimethyl-3-[(pyridin-2-ylcarbonyl)amino]-5,6 dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate (219 mg, 0.598 mmol, 1.0 eq), and 13 mL CH 2 Cl 2 . The resulting suspension was stirred at rt for 5 min under N 2 . DIPEA 25 (0.408 ml, 2.39 mmol, 4.0 eq) was added slowly to generate smoke. After stirring the reaction at rt for 1 h, the reaction was quenched with brine (20 mL), extracted with
    CH
    2 Cl 2 (50 mL), dried over Na 2
    SO
    4 , and concentrated. The crude product was dissolved in 10 mL MeOH. At rt, 1.5 mL of 1 M aqueous NaOH was added dropwise. LC-MS indicated that the reaction was complete in 5 to 10 min. The reaction was 30 diluted with 100 mL EtOAc, and washed with 100 mL brine. The organic solvent was collected, dried over Na 2
    SO
    4 , filtered, and concentrated to give a crude final product. The crude product was purified by preparative HPLC to give us 200 mg of the desired product, B2 as a partial HOAc salt, in 47 % yield over two steps.
    WO 2008/125945 PCT/IB2008/000862 - 33 EXAMPLE B3: 3,4-Dichloro-N-[5-(4-fluoro-1-methyl-piperidine-4-carbonyl)-6,6-dimethyl 1,4,5,6-tetrahydro-pyrrolo[3,4-clpyrazol-3-vll-benzamide 0
    CH
    3 Z0 2 Et C1 - 3 CH3 H
    H
    3 C N 3C DF N N HN ' NIN 0 1)D F 0 HN H 3 CH / CI 2) aq.NaOH-MeOH
    H
    3 C CI B3 C1 5 DIEA (0.220 mL, 1.66 mmol) and 3-(3,4-Dichloro-benzoylamino)-6,6-dimethyl 5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-1-carboxylic acid ethyl ester (221 mg, 0.51 mmol) were added to a solution of 4-Fluoro-1-methyl-piperidine-4-carbonyl chloride (0.51 mmol) in CH 2 Cl 2 (10 mL). The reaction was stirred at RT for 4h. The mixture was quenched with H 2 0 (30 mL), extracted with CHC1 3 (2x30 mL). The organic layers were 10 dried over MgSO 4 and concentrated to give the title compound as brown color oil which was used without further purification. ESI (MNa*): 564.10. The above oil was taken into MeOH (5 mL) and NaOH (1N, 3 mL) was added. The mixture was stirred at RT for 2 h, concentrated and purified by reverse phase HPLC to give a white solid B3 (15 mg, 6%). 15 EXAMPLE B4: Example B4 was prepared using methods analogous to Example B above. EXAMPLE C1: N-(5-{[(2S,5R)-4-ethyl-2,5-dimethylpiperazin-1-yllcarbonyll-6,6-dimethyl 1,4,5,6-tetrahydropyrrolo[3,4-clpyrazol-3-yl)pvrazine-2-carboxamide I C 0 H0 1) HCI/Diox H3CiaN.H
    H
    3 C )'-N O NaH, THF H N 2) phosgene C 3 c CH3 H 3 CN>CH3
    H
    3 '~ /H c ~ , -CH 3 0N/ -CH 3 C(V
    NH
    2 EtOCOCI HN O CH 3 THF, DIPEA C1(1) C1(11) O HN O CH 3 aiI CII) 0C1 (III)Y HHN3Ca C 33LiOH, MeOHH THF, DIPEA H 3 C ~ ~ H HCC 1(V) O .C1(VI)
    N
    2 c -~N 20 WO 2008/125945 PCT/IB2008/000862 -34 Intermediate C1(1I): 5-tert-Butyl 1-ethyl 3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4 c]pyrazole-1,5-dicarboxylate To a 0 0C solution of 5-tert-butyl 1-ethyl 3-amino-6,6-dimethyl-4,6 dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate, C1(1) (16.2 g, 49.9 mmol) in THF (100 5 mL) was added NaH (2.4 g, 59.9 mmol) in 3 portions. The reaction was stirred for 15 min in an ice bath, then ethyl chloroformate (6.5 g, 59.9 mmol) was added over 10 min. The reaction was warmed to room temperature and stirred for 16h, then quenched with
    NH
    4 Cl (sat) and extracted with EtOAc (2 x 50 mL). The combined extracts were washed with brine then dried (MgSO 4 ) filtered and concentrated to give the desired compound 10 C1(1) (19.8 g, 99%). Mass spectrum: Calcd for C1 8
    H
    29
    N
    4 0 6 (M+H): 397. Found 397. Intermediate Cl(Ill): Ethyl 5-(chlorocarbonyl)-3-[(ethoxycarbonyl)amino]-6,6-dimethyl 5,6-dihydropyrrolo[3,4-c]pyrazole-1 (4H)-carboxylate To a solution of C1(ll)(19.8 g, 49.9 mmol) in dioxane (20 mL) was added HCI (60 mL, 4M in dioxane). The reaction was stirred at room temperature for 3h then 15 concentrated and dried under vacuum. The HCI salt of ethyl 3-[(ethoxycarbonyl)amino] 6,6-dimethyl-5,6-dihydropyrrolo[3,4-c]pyrazole-1 (4H)-carboxylate was taken up in
    CH
    2 Cl 2 (60 mL). DIPEA (16.1 g, 125 mmol) was added and the reaction mixture was cooled in an ice bath. Phosgene (30 mL, 20% in toluene) was added slowly then the reaction was warmed to room temperature and run overnight. The reaction was 20 concentrated then taken up in EtOAc (100 mL) and water (100 mL). The aqueous phase was extracted with EtOAc (2 x 25 mL) then the combined organic extracts were washed with brine, dried (MgSO 4 ), filtered and concentrated. The crude material was purified by silica gel column chromatography using CH 2
    CI
    2 -2% 7N NH 3 /MeOH in CH 2 Cl 2 to give the title compound C1(111) as a white solid (9.58 g, 54%). Mass spectrum: Calcd for 25 C 1 4
    H
    20
    CIN
    4 0 5 (M+H): 359. Found 359. Intermediate C1(V): Ethyl 3-[(ethoxycarbonyl)amino]-6,6-dimethyl-5-{[4-ethyl(2S, 5R) 2,5-dimethylpiperazin-1 -yl]carbonyl}-5,6-dihydropyrrolo[3,4-c]pyrazole-1 (4H)-carboxylate To a sealed tube was added N-ethyl (2S, 5R)-2,5-dimethylpiperazine C1 (IV), DIPEA and THF followed by C1(111). The tube was sealed and placed in an oil bath at 30 80 0C and heated for 16 h. The reaction was cooled to room temperature then concentrated. This resulting material C1(V) was carried on forward without further purification.
    WO 2008/125945 PCT/IB2008/000862 - 35 Intermediate Cl(VI): 5-{[(2S,5R)-4-ethyl-2,5-dimethylpiperazin-1-yl]carbonyl}-6,6 dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine To a microwave vial was added C1(V), MeOH and LIOH. The reaction was heated at 110 0C in the microwave for 20 min. The crude reaction mixture was 5 concentrated and taken up in THF. The insoluble material was filtered off and the filtrate was concentrated to give the title compound C1 (VI). This material was used further without purification. Compound Cl: N-(5-{[(2S,5R)-4-Ethyl-2,5-dimethylpiperazin-1-yl]carbonyl}-6,6 dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)pyrazine-2-carboxamide 10 A 2 mL THF suspension of C1(VI) (240 mg, 0.7 mmol) was added to a solution of pyrazine-2-carbonyl chloride (213 mg, 2 eq) and diisopropylethyl amine (0.5 mL, 3 eq) in 3 mL THF. After stirring at room temperature for 3 hours, the solvent was removed in vacuo. Purification as in example Al afforded the title compound C1 as a white solid (16 mg, 5%). 15 EXAMPLES C2 - C8: Examples C2 to C8 were prepared using methods analogous to Example C1 above. EXAMPLE D1: Currently no embodiments were prepared using Route D as shown in Scheme 2 above, although it is expected that one skilled in the art can use route D as described above to 20 prepare many compounds of the invention. EXAMPLE El: N-(6,6-Dimethyl-5-f[(3S,8aS)-3-methylhexahydropyrrolo[1,2-alpyrazin 2(1 H)-yllcarbonyl}-1,4,5,6-tetrahydropyrrolo[3,4-clpvrazol-3-yl)-3-ethylisoxazole-5 carboxamide 0
    HCH
    3 E N3 CH H HA CH 3 CI4 CH HHACo SEM, N N-' N ,N N-Boc SEM N-Boc N H NH N CR CH 3 HN 0 HN 0 HN E1(VI) N
    X=CO
    2 Et:EI(Q) 0 0 = H: E1(11) N C N C 25 = SEM: EI(IIl-2) E1(IV) E1(V) El Intermediate El(11): tert-Butyl 3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole 5(1 H)-carboxylate WO 2008/125945 PCT/IB2008/000862 -36 Reagent 5-tert-butyl 1-ethyl 3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4 c]pyrazole-1,5-dicarboxylate, E1(l),(10.97g, 33.9mmol) was dissolved in MeOH (200mL) after which NaOH (5eq, 169mmol) was added. After stirring the mixture at room temperature for 3h, the starting material disappeared. After removal of MeOH, add H 2 0 5 and AcOEt was added, and the product was extracted with AcOEt and dried over Na 2
    SO
    2 followed by concentration to afford El (II). Intermediate El(111-2): tert-Butyl 3-amino-6,6-dimethyl-1-{[2 (trimethylsilyl)ethoxy]methyl}-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1 H)-carboxylate Me 3 Si Me 3 Si 0-- H3 0HHCC N I N-Boc N N-Boc
    H
    2 N E(III-2)
    H
    2 N E(II-1) 10 To the mixture of the intermediate El (1) (87g), methylene chloride (1.74L) and diisopropylethylamine (87g) at 00C were added 2-(trimethylsilyl)ethoxymethyl chloride (63g) drop wise at 00C (1 hour addition). The reaction mixtures were stirred at room temperature over night. The reaction was a light brown solution. Then the mixture was concentrated to give a light yellow/brown oil and the residue was mixed with ethyl 15 acetate and the salts were filter off. The mixture was purified with silica gel (2:1 to 1:1 EtOAc/Hexane with 0.5% of TEA) to afford the regioisomers E1(111-2) (24g, >90% purity by HPLC) and E(ll-1) (10g, >98% purity by HPLC). 1 H NMR (400 MHz, CD30D) ppm 0.03 (s, 9H) 0.88 (t, J=8.2 Hz, 2H) 1.48 and 1.53 (s, 4.5H each, a total of 9H), 1.70 (s, 3H), 1.72 (s, 3H), 3.56-3.62 (m, 2H), 4.24-4.26 (m, 2H), 5.16 (s, 2H). 20 Intermediate E1(VII): N-(6,6-Dimethyl-5-{[(3S,8aS)-3-methylhexahydropyrrolo[l,2 a]pyrazin-2(l H)-yl]carbonyl}-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yI)-3 ethylisoxazole-5-carboxam ide A 0.25 M solution of SEM-Boc protected aminopyrrolopyrazole, El (111-2) was 25 prepared using anhydrous DMF as solvent. A 0.25 M solution of 3-ethylisoxazole-5 carboxylic acid was prepared using anhydrous DMF as solvent. A fresh 0.5 M solution of o-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyl uronium hexafluorophosphate (HATU) was prepared in anhydrous DMF. To the reaction tube were added 320 ptL (0.08 mmol, 1 equiv, 0.25M) of the 3-ethylisoxazole-5-carboxylic acid DMF solution WO 2008/125945 PCT/IB2008/000862 -37 prepared, 320 plL (0.080 mmol, 1 equiv, 0.25M) of SEM-Boc protected aminopyrrolopyrazole DMF solution prepared, and 40 pL (0.288 mmol, 3.6 equiv) neat TEA followed by the 160 pL (0.080 mmol, 1 equiv) of the HATU DMF solution. The reaction mixtures were stirred at 600C for 16h. Then the tube was allowed to cool to 5 room temperature. The solvents and volatiles from the tubes were removed in vacuo. To the residue were added 1 mL of EtOAc and 1 mL of 2M aqueous NaOH. After the tube was covered with Parafilm, the covered test tube was vigorously shaken until all residues have dissolved or the mixtures are completely homogenized. The agitation was stopped and the phases were allowed to separate completely. The supernatant 10 organic layer (EtOAc layer) of each test tube was transferred into its corresponding receiving tube. EtOAc (0.5 mL) was added to the tube and extracted the organic layers after the agitation of the mixtures and these procedures were repeated twice. The solvent (EtOAc) and volatiles from the receiving tube were removed in vacuo until they were dry. To the residue was added 0.6 mL (2.4 mmol, 30 equiv) of 4M HCI in dioxane 15 and the mixtures were stirred at room temperature for 2h. Then the solvent, volatiles and HCI from the tube were removed in vacuo. To the residue were added 500 pL anhydrous DMA, 70 ptL neat DIPEA (0.400 mmol, 5 equiv.). A 0.25 M solution of (3S,8aS)-3-methylhexahydropyrrolo[1,2-a]pyrazine-2(1 H)-carbonyl chloride, El (VI), in anhydrous CH 2
    CI
    2 was prepared. 20 Intermediate E1(VI): (3S,8aS)-3-methvlhexahvdropyrrolo[1,2-alpvrazine-2(1H)-carbonyl chloride Triphosgene (1.1 equiv.) was dissolved in DCM at 00C under N 2 in round bottom flask, and DIPEA (2 equiv.) was added dropwise to the stirred solution at 0 C under N 2 . The solution of (3S,8aS)-3-methyloctahydropyrrolo[1,2-a]pyrazine in CH 2
    CI
    2 was added 25 dropwise to the triphosgene reaction mixture at 00C under N 2 . After stirring for one hour at 0 C under N 2 , the reaction mixtures were warmed to room temperature and stirred for 16 hours under N 2 . The solvent was evaporated and dried in vacuum overnight at room temperature. The dried product El (VI) was utilized for the urea formation reaction without purification. 30 To the tube were added 385 piL (0.096 mmol, 1.2 equiv.) of El (VI), and the mixture was stirred at 400C for 20h. After removal of the solvent and volatiles in vacuo, 1340 tL of DMSO (containing 0.01% BHT) was added to each tube to reach a final WO 2008/125945 PCT/IB2008/000862 - 38 concentration of 0.0572 M and the mixtures were agitated to dissolve the product. In order to prepare the analytical sample, 5 ptL of the solution was removed, and the aliquot was diluted to 1.0 mL with 95:5 MeOH/H 2 0, and submit for LC-MS analysis. Crude reaction mixtures from plate 821-107-3930 were dissolved in 5 MeOH:DMSO:H20 (95:5:5) solution and analyzed utilizing analytical scale CO 2 SFC (UV/MS {APCI +}/ELSD detection). Analytical SFC method parameters would include; Column: Zymor/Pegasus (150X4.6mm, 5pm), linear Gradient: 5 to 50% Eluent A (MeOH) in 2.5 min. at 5.6ml/min (140 bar outlet pressure). The same crude reaction mixtures were purified utilizing preparative scale CO 2 10 SFC (UV detection {260nm}). Prep SFC method parameters would include: Column: Zymor/Pegasus (1 50X21.2mm, 5ptm), linear Gradient: 5 to 50% Eluent A (MeOH) in 5min. at 56 ml/min (140 bar outlet pressure). Products were dried, weighed and dissolved in DMSO at 30mM. Products were then analyzed using RP-HPLC (UV {260nm}/MS {APCI+} /ELSD detection). The HPLC 15 method parameters would include; Column: Peeke Scientific/HI-Q (C 1 8 , 50X4.6mm, 3 ptm), linear Gradient: 100% Eluent A (H 2 0 + 0.05%TFA) to 100% Eluent B (Acetonitrile + 0.05% TFA) in 1.75 min at 3 ml/min. All products, at least 85% pure by two or more HPLC detection methods with an NMR spectrum confirming a structure consistent with the molecular weight, were made 20 available for screening. EXAMPLES El through E14: All of Examples E2 through E14 utilized the same analytical and purification conditions as described in Example El above. EXAMPLE Fl: N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H-pyran-4-ylmethyl)piperazin 25 1 -vllcarbonvl}-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-clpvrazol-3-yl)-2-ethyl-4 methyl-1,3-oxazole-5-carboxamide WO 2008/125945 PCT/IB2008/000862 -39 CI uNC H 3 CHH OH 3 C , MH 3 e OH N CiNYNC -H ~ H..~ -oH MeH HONN' ' N OC c JC3 3 ,-OH, LieOH H N %H 3 HN O CH 3 THF, DIPEA HN OOCH 3
    NH
    2 F1(i) O F1(ii) O F1(iii) OH oH3C CH 3
    H
    3 3 H O O H H H Si-OH 3 1<Oy0
    H
    3 0< 3OO 3 /-- CH 3 ' N CH, 0 N~ SEM CI HC-CN 3LN O, 1)CAUH3 0 N H3 N 1) HATU, DIPEA, H, DIPEA, THF O /N C H3 N CHr F 1F () H NH 2 2) 4N HCI dioxane F1 H 3 c N F1(iv) Intermediate F1(ii): ethyl 5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H-pyran-4 ylmethyl)piperazin-1-yl]carbonyl}-3-[(ethoxycarbonyl)amino]-6,6-dimethyl-5,6 dihydropyrrolo[3,4-c]pyrazole-1 (4H)-carboxylate 5 To a sealed tube was added (2R,5S)-2,5-dimethyl-1-(tetrahydro-2H-pyran-4 ylmethyl)piperizine (2.1 g, 9.89 mmol), DIPEA (3.8 mL, 21.8 mmol) and THF (50 mL) followed by F1(i) (3.6 g, 9.89 mmol). The tube was sealed and placed in an oil bath at 90 *C and heated for 16 h. The reaction was cooled to room temperature and concentrated then triturated with MeOH in two batches to give the title compound F1(ij) 10 (4.89 g, 93%) as a white solid. Mass spectrum: Calcd for C2 6
    H
    42
    N
    6 0 6 (M+H): 535. Found 535. Intermediate F1(iii): 5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H-pyran-4 ylmethyl)piperazin-1 -yljcarbonyl}-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3 amine 15 To a sealed tube was added FL(ii) (4.0 g, 7.54 mmol) in a slurry of MeOH (75 mL) and LiOH (1.0 g, 42 mmol). The reaction was heated at 100 C for 16 h. The reaction was concentrated and taken up in THF (100 mL). The mixture was filtered through a bed of Celite and MgSO 4 then rinsed with THF (100 mL). The filtrate was concentrated to give 1.9 g (65%) of F1(ii) as a yellow solid. 1 H NMR (300 MHz, DMSO-d 6 ) 6 ppm 0.82 - 0.92 20 (m, 1 H), 0.92 - 1.00 (m, 6 H), 1.00 - 1.14 (m, 2 H), 1.48 (s, 3 H), 1.57 (s, 3 H), 1.69 (d, J=14.32 Hz, 2 H), 1.78 - 1.95 (m, 2 H), 2.27 - 2.48 (m, 3 H), 2.74 - 2.88 (m, 1 H), 2.94 3.15 (m, 2 H), 3.18 - 3.31 (m, 2 H), 3.70 - 3.93 (m, 2 H), 4.26 (s, 2 H), 4.96 (br. s., 2 H). Mass spectrum: Calcd for C 20 H34N 6
    O
    2 (M+H): 391. Found 391.
    WO 2008/125945 PCT/IB2008/000862 -40 Intermediate Fl(iv): 5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H-pyran-4 ylmethyl)piperazin-1 -yl]carbonyl}-6,6-dimethyl-1 -{[2-(trimethylsilyl)ethoxy]methyl} 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine To a OC solution of Fl(iii) (1.7 g, 4.35 mmol) in THF (30 mL) was added DIPEA (0.95 5 mL, 5.44 mmol) followed by [2-(chloromethoxy)ethyl](trimethyl)silane (0.81 mL, 4.57 mmol). The reaction was slowly warm to RT and stirred for 16h. The reaction was quenched with water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined extracts were washed with brine (50 mL) then dried (MgSO4), filtered and concentrated to provide the title compound F1(iv) (1.7 g, 65%) as a yellow solid. Mass spectrum: 10 Calcd for C 26
    H
    48
    N
    6
    O
    3 Si (M+H): 521. Found 521. Example Fl: N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H-pyran-4-ylmethyl)piperazin-1 yl]carbonyl}-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-2-ethyl-4-methyl 1,3-oxazole-5-carboxamide To a solution of 2-ethyl-4-methyl-1,3-oxazole-5-carboxylic acid (223 mg, 1.44 mmol) and 15 F1(iv) (500 mg, 0.960 mmol) in DMF (5 mL) was added DIPEA (0.52 mL, 2.88 mmol) followed by HATU (548 mg, 1.44 mmol). The reaction was stirred at 650C for 16 h then diluted with NaHCO 3 (sat) (10 mL) and extracted with MTBE (2 x 20 mL). The combined extracts were washed with brine (15 mL) then dried (MgSO 4 ), filtered and concentrated. The crude solid was taken up in CH 2
    CI
    2 (5 mL) and 4N HCI in dioxane (5 20 mL) was added. The reaction was stirred at RT for 5h. The reaction was concentrated then taken up in EtOAc (15 mL) and NaHCO 3 (sat) (15 mL) and extracted with EtOAc (2 x 10 mL). The combined extracts were washed with brine (15 mL) then dried (MgSO 4 ), filtered and concentrated. Preparative HPLC using 5-50% ACN/H 2 0 (0.1% AcOH) provided the title compound F1 as a white solid (35 mg, 6%). 25 EXAMPLES F2 - F60: Examples F2 to F60 were prepared using methods analogous to Example Fl1 above. EXAMPLE G1: 5-cyano-N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahvdro-2H-pyran-4 yl)piperazin-1 -vllcarbonyl}-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-cpyrazol-3 yl)pyridine-2-carboxamide WO 2008/125945 PCT/IB2008/000862 -41 OH H CH3 HO 0 H33OH3C CH 3 /OH3 H OH 3 C CH 3 -O N--CH3 H 3 N Zn(CN)2 H3C ko/XN N HN O Pd(PPh 3
    )
    4
    H
    3 C BN DMF k/ -- N
    NH
    2 DIPEA,
    CH
    2 Cl 2 GI(i) A1(i) Br 3C H 3 C CH 3
    O/-H
    3
    H
    3 C CH 3 fCH 3
    O
    3 C CH 3 f--CH 3 ON N HN N CI /N
    H
    3 C /I ZN HN 0 HCI/dioxane HN O triphosgene HN O DIPEA, CH 2 C1 2 N N N~ G1(ii) G1(iii) GI(iv) CN CN CN C H3C. NCH 3 OH 3 C CH 3 kN _NH
    H
    3 C.. N H |N 0 O N.-/CHk 3 1) DIPEA, CH 2 C1 2 HN 0 2)EtsN, CH 3 0H G1 N N ON Intermediate G1(i): tert-butyl 1-ethyl 3-{[(5-bromopyridin-2-yl)carbonyl]amino}-6,6 dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate To a solution of 5-bromopyridine-2-carboxylic acid (3.11 g, 15.4mmol) and 5-tert-butyl 1 5 ethyl 3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate (5.00g, 15.4mmol) in DCM (200mL) was added DIPEA (5.37mL, 30.8mmol) followed by HATU (7.03g, 18.5mmol). The reaction was allowed to run at 22oC overnight. The reaction mixture was diluted with NaHCO3, the layers separated, and the organic portion dried (MgSO4), filtered and concentrated. The crude solid was triturated with Et2O to yield 10 G1(i) as a pale yellow solid (2.8g, 15%). Mass Spectrum: Calcd for C21 H27BrN505 (M+H): 509. Found: 509. Intermediate G1(ii): 5-tert-butyl 1-ethyl 3-{[(5-cyanopyridin-2-yl)carbonyl]amino}-6,6 dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate. To a suspension of G1(ii) (2.80g, 5.51mmol) in DMF (40mL) was added Pd(PPh3)2 15 (0.636g, 0.551mmol) and Zn(CN)2 (0.647g, 5.51mmol). The solution evac/backfilled with argon x3, then heat to 80o0C for 2 hours. The reaction mixture was diluted with water and EtOAc, the aqueous layer extracted with EtOAc x2, the organic layer washed WO 2008/125945 PCT/IB2008/000862 -42 with water and brine, dried over MgSO4 and concentrated to give a bright yellow solid. The crude solid was triturated with Et2O to yield G1(ii) as a pale yellow solid (1.9g, 76%). Mass Spectrum: Calcd for C22H27N605 (M+H): 455. Found: 455. Intermediate G1 (iii): ethyl 3-{[(5-cyanopyridin-2-yl)carbonyl]amino}-6,6-dimethyl-5,6 5 dihydropyrrolo[3,4-c]pyrazole-1 (4H)-carboxylate. To a solution of G1(ii) (1.9g, 4.18mmol) in DCM (20mL) was added 20 mL HCI/dioxane solution. Reaction mixture was allowed to stir overnight at 22oC. The suspension was concentrated to yield G1(iii) a pale yellow solid (1.9g, 100%). Mass Spectrum: Calcd for C17H19N603 (M+H): 355. Found: 355. 10 Intermediate G1 (iv): ethyl 5-(chlorocarbonyl)-3-{[(5-cyanopyridin-2-yl)carbonyl]amino} 6,6-dimethyl-5,6-dihydropyrrolo[3,4-c]pyrazole-1 (4H)-carboxylate. To a solution of G1(iii) (1.90g, 4.45mmol) in DCM (50mL) was added DIPEA (2.30mL, 17.8mmol). The reaction mixture was cooled to -78o0C and triphosgene (0.924g, 3.11mmol) in a solution of DCM (30mL) was added dropwise with an addition funnel. 15 The reaction was stirred at -70oC for 15m then quenched with NaHCO3 (sat., aq.) and warmed to 22oC. The reaction mixture was diluted with water and the aqueous layer extracted with DCM x2. The organic layer was washed with water and brine, dried over MgSO4 and concentrated to give G1(iv) as a bright yellow solid (1.9g, 100%). Example G1: 5-cyano-N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H-pyran-4 20 yl)piperazin-1 -yl]carbonyl}-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3 yl)pyridine-2-carboxamide. To a solution of G1(iv) (0.250g, 0.600mmol) and (2R,5S)-2,5-dimethyl-1-(tetrahydro-2H pyran-4-yl)piperazine (0.238g, 1.20 mmol) in THF (4mL) was added DIPEA (0.5mL, 3.00mmol). The reaction was heated to 90C in a sealed tube overnight. Volatiles were 25 removed in vacuo and the residue was dissolved in MeOH (3 mL). TEA (3 mL) was added and the solution was stirred at 45oC for 3 hours. Solution was concentrated and the crude mixture was purified by preparative chromatography to yield G1 as a white powder (0.130g, 38%). 30 EXAMPLES G2-G3: Examples G2 to G3 were prepared using methods analogous to Example G1 above.
    WO 2008/125945 PCT/IB2008/000862 -43 EXAMPLE Hi: N-[5-({(2S,5R)-4-[(4-hydroxytetrahydro-2H-pyran-4-vl)methyll-2,5 dimethylpiperazin-1 -yl}carbonyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-cpyrazol-3 yllpyridine-2-carboxamide
    CH
    2 0N
    CH
    3 N CH m-CPBA H 3 C"' N Pd/C, H 2 O 3- H3C' N '
    CH
    2 Cl 2 O MeOH HI(i) MW, 1500C o 0 H1(ii) 0 H C CH 3 NciN 0 H 3 C CH 3
    N)CH
    3 N H NN N H3C,,.. N %
    H
    3 C N 0 N 1) DIPEA, CH2C2 N CH 3 N O N 2) Et 3 N, MeOH O O N 0 Q-O N HI(iii) A1(V) 0 H1 5 Intermediate H1(i): 1,6-dioxaspiro[2.5]octane A solution of 4-methylenetetrahydro-2H-pyran (1.00 g, 10.2 mmol) in CH 2
    CI
    2 (30 mL) was placed in an ice bath then meta-chloroperoxybenzoic acid (2.46 g, 14.3 mmol) was added in three portions. The reaction was slowly warmed to RT and stirred for 3h then quenched with 10% NaOH(aq) (10 mL) and extracted with CH 2
    CI
    2 (2 x 15 mL). The 10 combined extracts were dried (MgSO 4 ), filtered and concentrated to provide intermediate H1_(i) as a clear oil (607 mg, 52%). 1 H NMR (300 MHz, CHLOROFORM-d) 8 ppm 1.45 - 1.63 (m, 2 H), 1.76 - 1.99 (m, 2 H), 2.69 (s, 2 H), 3.71 - 3.95 (m, 4 H). Intermediate H1(ii): 4-{[(2R,5S)-4-benzyl-2,5-dimethylpiperazin-1-yl]methyl}tetrahydro 2H-pyran-4-ol 15 To a microwave vial was added 1,6-dioxaspiro[2.5]octane ( 259 mg, 2.3 mmol), (2S,5R) 1-benzyl-2,5-dimethylpiperazine (464 mg, 2.3 mmol) and 5 mL of MeOH. The vial was heated to 1500C for 2h in the microwave. The crude reaction was concentrated to provide intermediate H1(ii) (723 mg, 100%) 1 H NMR (300 MHz, CHLOROFORM-d) 5 ppm 0.92 (d, J=6.22 Hz, 3 H), 1.13 (d, J=5.84 Hz, 3 H), 1.35 - 1.45 (m, I H), 1.46 - 1.68 20 (m, 4 H), 1.83 (dd, J=1 1.30, 9.80 Hz, 1 H), 2.12 (d, J=13.94 Hz, 1 H), 2.36 - 2.53 (m, 3 H), 2.60 - 2.69 (m, 2 H), 2.85 (d, J=9.04 Hz, 1 H), 3.08 (d, J=13.38 Hz, I H), 3.71 - 3.82 WO 2008/125945 PCT/IB2008/000862 -44 (m, 4 H), 4.04 (d, J=13.38 Hz, 1 H), 7.10 - 7.47 (m, 5 H). Mass Spectrum: Calcd for
    C
    1 qH 30
    N
    2 0 2 (M+H): 318. Found: 318. Intermediate H1(iii): 4-{[(2R,5S)-2,5-dimethylpiperazin-1-yl]methyl}tetrahydro-2H-pyran 4-ol 5 To a nitrogen purged solution of H1ii (723 mg, 2.3 mmol) in MeOH (15 mL) was added Pd/C (72 mg, 0.07 mmol). The reaction was subject evacuation-backfill (3x) with H 2 gas then run overnight under an H 2 atmosphere. The completed reaction mixture was filtered through a bed of Celite, rinsed with CH 2 Cl 2 and MeOH then concentrated to give the title compound (500 mg, 97%) as a yellow-orange semi solid. Mass Spectrum: 10 Calcd for C 1 2
    H
    2 4
    N
    2 0 2 (M+H): 229. Found: 229. Compound H1: N-[5-({(2S,5R)-4-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]-2,5 dimethylpiperazin-1 -yl}carbonyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3 yl]pyridine-2-carboxamide. The title compound was prepared using methods analogous to Example Al above, 15 where 4-{[(2R,5S)-2,5-dimethylpiperazin-1-yl]methyl}tetrahydro-2H-pyran-4-ol was substituted in place of (3S,8aS)-3-methyloctahydropyrrolo[1,2-a]pyrazine. Table 1 provides a full listing of the compounds of the present invention and includes relevant H NMR data and Ki values as available Any of the above compounds of Formula I, can be converted into another 20 analogous compound by standard chemical manipulations. All starting materials, regents, and solvents are commercially available and are known to those of skill in the art unless otherwise stated. These chemical manipulations are known to those skilled in the art and include (a) removal of a protecting group by methods outlined in T. W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2nd Ed., John Wiley 25 and Sons, New York, 1991; (b) displacement of a leaving group (halide, mesylate, tosylate, etc) with a primary or secondary amine, thiol or alcohol to form a secondary or tertiary amine, thioether or ether, respectively; (c) treatment of primary and secondary amines with an isocyanate, acid chloride (or other activated carboxylic acid derivative), alkyl/aryl chloroformate or sulfonyl chloride to provide the corresponding urea, amide, 30 carbamate or sulfonamide; (d) reductive amination of a primary or secondary amine using an aldehyde. The compounds of the present invention may have asymmetric carbon atoms. Diastereomeric mixtures can be separated into their individual diastereomers on the WO 2008/125945 PCT/IB2008/000862 -45 basis of their physical chemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixtures into a diastereomric mixture by reaction with an appropriate optically active compound (e.g., alcohol), separating the 5 diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. All such isomers, including diastereomeric mixtures and pure enantiomers are considered as part of the invention. The compounds of Formula I that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such 10 salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the compound of Formula I from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt. The 15 acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained. The desired acid salt can also be precipitated from a solution of 20 the free base in an organic solvent by adding to the solution an appropriate mineral or organic acid. Those compounds of Formula I that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline-earth metal salts and particularly, the sodium and 25 potassium salts. These salts are all prepared by conventional techniques. The chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds of Formula 1. Such non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium, calcium, and magnesium, 30 etc. These salts can easily be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they may also be prepared by mixing lower WO 2008/125945 PCT/IB2008/000862 -46 alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final 5 product. The compounds of the present invention are inhibitors of protein kinase C and preferably selectively inhibit beta-1, beta-2 and optionally alpha isozymes of protein kinase C. With respect to the beta-2 isozyme in particular, the compounds of the present invention have Ki values of less than 200 nM. 10 As an inhibitor of protein kinase C the compounds are useful in the treatment of conditions in which protein kinase C has demonstrated a role in the pathology. Conditions recognized in the art include: diabetes mellitus and its complications, cancer, ischemia, inflammation, central nervous system disorders, cardiovascular disease, Alzheimer's disease and dermatological disase. 15 Protein kinase C has been linked to several different aspects of diabetes. Excessive activity of protein kinase C has been linked to insulin signaling defects and therefore to the insulin resistance seen in Type il diabetes. Karasik, A. et al. J. Biol. Chem. 265: 10226-10231 (1990); Chen, K.S. et al. Trans.Assoc.Am.Physicians 104: 206-212 (1991); Chin, J.E. et al J. Biol. Chem. 268: 6338-6347 (1993). In addition, 20 studies have demonstrated a marked increase in protein kinase C activity in tissues known to be susceptible to diabetic complications when exposed to hyperglycemic conditions. Lee, T.S. et al., J. Clin. Invest. 83: 90-94 (1989); Lee, T.S. et al. Proc. NatI. Acad.Sci USA 86: 5141-5145 (1989); Craven, P.A. and DeRubertis, F.R. J. Clin. Invest. 83: 1667-1675 (1989); Wolf, B.A. J. Clin. Invest. 87: 1643-1648 (1991). 25 Protein kinase C activity has long been associated with cell growth, tumor promotion and cancer. Rotenberg, S.A. and Weinstein, I.B. Biochem. Mol.Aspects Sel. Cancer 1: 25-73 (1991). Ahamd et al., Molecular Pharmacology: 43, 858-862 (1993). It is known that inhibitors of protein kinase C inhibitors are effective in preventing tumor growth in animals. Meyer, T. et al. Int. J. Cancer 43: 851-856 (1989); Akinagaka, S. et 30 al. Cancer Res. 51: 4888-4892 (1991). More recently, the protein kinase CO inhibitor, Enzastauring (LY317615.HCI) was shown to have a direct tumor effect by inducement of apoptosis and suppression of proliferating cultured tumor cell, in particular on human glioblastoma and colon carcinoma. Graff et al, Cancer Res.16: 7462- 7469 (2005). The WO 2008/125945 PCT/IB2008/000862 -47 compounds of the present invention also act as multridrug reversal (MDR) agents making them effective compounds when administered in conjunction with other chemotherapeutic agents. Protein kinase C inhibitors have been shown to block inflammatory responses such 5 as neutrophil oxidative burst, CD3 down-regulation in T-lymphocytes, and phorbol induced paw edema. Towemy, B. et al. Biochem. Biophys. Res. Commun. 171: 1087 1092 (199)); Mulqueen, M.J. et al. Agents Actions 37: 85-89 (1992). Accordingly, as inhibitors of PKC, the present compounds are useful in treating inflammation. Protein kinase C activity plays a central role in the functioning of the central 10 nervous system. Huang, K.P. Trends Neurosci. 12: 425-432 (1989). In addition, protein kinase C inhibitors have been shown to prevent the damage seen in focal and central ischemic brain injury and brain edema. Hara, H. et al. J. Cereb.. Blood Flow Metab. 10: 646-653(1990); Shibata, S. et al. Brain Res. 594: 290-294 (1992). Protein kinase C has also been determined to be implicated in Alzheimer's disease. Shimohama, S. et al. 15 Neurology 43: 1407-1413 (1993). Accordingly, the compounds of the present invention are useful in treating Alzheimer's disease and ischemic brain injury. Protein kinase C activity also plays an important role in cardiovascular disease. Increased protein kinase C activity in the vasculature has been shown to cause increased vasoconstriction and hypertension. A known protein kinase C inhibitor prevented this 20 increase. Bilder, G.E. et al. J. Pharmacol. Exp. Ter. 252: 526-430 (1990). Because protein kinase C inhibitors demonstrate inhibition of the neutrophil oxidative burst, protein kinase C inhibitors are also useful in treating cardiovascular ischemia and improving cardiac function following ischemia. Muid, R.E. et al. FEBS Lett.293: 169-172 (1990); Sonoki, H. et al. Kokyu-To Junkan 37: 669-674 (1989). The role of protein kinase C in 25 platelet function has also been investigated and as shown elevated protein kinase C levels being correlated with increased response to agonists. Bastyr Ill, E.J. and Lu, J. Diabetes 42: (Suppl. 1) 97A (1993). PKC has been implicated in the biochemical pathway in the platelet-activity factor modulation of microvascular permeability. Kobayashi et al., Amer. Pius. Soc. H1214-H1220 (1994). Potent protein kinase C 30 inhibitors have been demonstrated to affect agonist-induced aggregation in platelets. Toullec, D. et al. J. Biol. Chem. 266: 15771-15781 (1991). Protein kinase C inhibitors also block agonist-induced smooth muscle cell proliferation. Matsumoto, H. and Sasaki, WO 2008/125945 PCT/IB2008/000862 -48 Y. Biochem. Biophys, Res. Commun. 158: 105-109 (1989). Therefore, the present compounds are useful in treating cardiovascular disease, atherosclerosis and restenosis. Abnormal activity of protein kinase C has also been linked to dermatological disorders such as psoriasis. Horn, F. et al. J. Invest. Dermatol. 88: 220-222 (1987); 5 Raynaud, F. and Evain-Brion, D. Br. J. Dermatol. 124: 542-546 (1991). Psoriasis is characterized by abnormal proliferation of keratinocytes. Known protein kinase C inhibitors have been shown to inhibit keratinocyte proliferation in a manner that parallels their potency as PKC inhibitors. Hegemann, L. et al. Aarch. Dermatol. Res. 283: 456-460 (1991); Bollag, W.B. et al. J. Invest. Dermatol. 100: 240-246 (1993). Accordingly, PKC 10 inhibitors are useful in treating psoriasis. The compounds of the invention are also isozyme-selective. The compounds preferentially inhibit protein kinase C beta-1 and beta-2 isozyme and optionally the alpha isozyme, over the remaining protein kinase C isozymes, i.e., gamma, delta, epsilon, zeta nad eta. Accordingly, compounds of the present invention inhibit beta-1 and beta-2 15 isozymes of protein kinase C, and optionally the alpha isozyme at much lower concentrations with minimal inhibition of the other PKC isozymes. The compounds of the present invention are particularly useful in treating those disease states in which protein kinase C isozyme beta-1, beta-2, and optionally alpha, are associated. For example, the elevated blood glucose levels found in diabetes leads to an 20 isozyme-specific elevation of the beta-2 isozyme in vascular tissues. Proc. Natl Acad. Sci. USA 89: 11059-11065 (1992). A diabetes-linked elevation of the beta isozyme in human plateles has been correlated with their altered response to agonists. Bastyr III, E.J. and Lu, J. Diabetes 42: (Suppl 1) 97A (1993). The human vitamin D receptor has been shown to be selectively phosphorylated by protein kinase C beta. This 25 phosphorylation has been linked to alterations in the functioning of the receptor. Hsieh et al, Proc. NatI. Acad. Sci. USA 88: 931509319 (1991); Hsieh et al. J. Biol. Chem. 268: 15118-15126 (1993). In addition, recent work has shown that the beta-2 isozyme is responsible for erythroleukemia cell proliferation while the alpha isozyme is involved in megakaryocyte differentiation in these same cells. Murray et al., J. Biol. Chem. 268: 30 15847-15853 (1993). In addition to the beta-1 and beta-2 isozymes discussed above, the protein kinase C alpha isozyme has been shown to have potential in the treatment of nephropathy: a PKC-alpha knockout mouse having STZ-induced diabetes showed improved WO 2008/125945 PCT/IB2008/000862 -49 nephropathy. Menne et al, Diabetes 53: 2101-2109 (2005). PKC alpha was implicated in heart contractility, Braz et al. Nature Medicine 10: 248-254 (2004); and also in the regulation of Akt activation and eNOS phosphorylation in endothelial cells. Partovian & Simons, Cellular Signalling 16: 951-957 (2004). 5 ASSAY Protein Kinase C beta 2 (PKCPII) catalyzes the production of ADP from ATP that accompanies the phosphoryl transfer to the PKC Pseudosubstrate peptide (A -> S, RFARKGSLRQKNV). This transfer is coupled to the oxidation of p-NADH through the 10 activities of Pyruvate Kinase (PK) and Lactate Dehydrogenase (LDH). p-NADH conversion to NAD+ is monitored by the decrease in absorbance at 340 nm (e = 6.22 cm-imM- 1 ) using a Molecular Devices SPECTRA max PLUS spectrophotometer. A typical assay was carried out on a 96-well, clear microtiter plate in a Molecular Devices spectrophotometer for 20 minutes at 300C in 0.1 mL of assay buffer containing 15 50 mM HEPES, pH 7.4, 5 nM PKC, 23 units of pyruvate kinase, 33 units of lactate dehydrogenase, 0.15 mM peptide, 0.1 mM ATP, 1 mM DTT, 4 mM PEP, 8 mM MgCl 2 , 0.3 mM NADH, 60 mM CaCl 2 , 10 mg/mL PS, 50 ng/mL PMA, 7.5% DMSO and from about 10,000 nM to 0.169 nM compound inhibitor. Stock solutions of 3-sn-phosphatidyl L-serine (PS) and phorbol-1 2-myristate-1 3-acetate (PMA) were sonicated for 30 20 seconds just prior to addition to assay buffer and assays were initiated by the addition of 100 pM ATP. Steady-state kinetic parameters for the bi-bi kinase reaction were determined at saturating phospho-acceptor peptide substrate concentration (0.15 mM) by fitting initial velocity data to the Michaelis-Menten equation, 25 v = Vmax[S]/(Km + [S]) where v is the measured initial velocity, Vmax is the maximal enzyme velocity, [S] is the ATP substrate concentration, and KM is the Michealis constant for ATP. Enzyme 30 turnover values (kcat) were calculated according to kcat = Vmax[E], where [E] is the total enzyme concentration. Enzyme inhibition constants (apparent Ki values) were determined by fitting initial velocities at variable inhibitor concentrations to a model for WO 2008/125945 PCT/IB2008/000862 -50 ATP competitive inhibition based on the Morrison equation). Morrison, J.F., Biochim. Biophys Acta 185: 269-286 (1969). PHARMACEUTICAL COMPOSITIONs/FORMULATIONS, DOSAGING AND MODES OF ADMINISTRATION 5 Methods of preparing various pharmaceutical compositions with a specific amount of active compound are known, or will be apparent, to those skilled in this art. In addition, those of ordinary skill in the art are familiar with formulation and administration techniques. Such topics would be discussed, e.g. in Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, current ed., Pergamon Press; and Remington's 10 Pharmaceutical Sciences, current ed., Mack Publishing, Co., Easton, PA. These techniques can be employed in appropriate aspects and embodiments of the methods and compositions described herein. The following examples are provided for illustrative purposes only and are not meant to serve as limitations of the present invention. The compounds of Formula I may be provided in suitable topical, oral and 15 parenteral pharmaceutical formulations for use in the treatment of PKCpIl mediated diseases. The compounds of the present invention may be administered orally as tablets or capsules, as oily or aqueous suspensions, lozenges, troches, powders, granules, emulsions, syrups or elixirs. The compositions for oral use may include one or more agents for flavoring, sweetening, coloring and preserving in order to produce 20 pharmaceutically elegant and palatable preparations. Tablets may contain pharmaceutically acceptable excipients as an aid in the manufacture of such tablets. As is conventional in the art these tablets may be coated with a pharmaceutically acceptable enteric coating, such as glyceryl monostearate or glyceryl distearate, to delay disintegration and absorption in the gastrointestinal tract to provide a sustained 25 action over a longer period. Formulations for oral use may be in the form of hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. They may also be in the form of soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, 30 liquid paraffin or olive oil. Aqueous suspensions normally contain active ingredients in admixture with excipients suitable for the manufacture of an aqueous suspension. Such excipients may be a suspending agent, such as sodium carboxymethyl cellulose, methyl cellulose, WO 2008/125945 PCT/IB2008/000862 - 51 hydroxypropylmethyl cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; a dispersing or wetting agent that may be a naturally occurring phosphatide such as lecithin, a condensation product of ethylene oxide and a long chain fatty acid, for example polyoxyethylene stearate, a condensation product of ethylene 5 oxide and a long chain aliphatic alcohol such as heptadecaethylenoxycetanol, a condensation product of ethylene oxide and a partial ester derived from a fatty acid and hexitol such as polyoxyethylene sorbitol monooleate or a fatty acid hexitol anhydrides such as polyoxyethylene sorbitan monooleate. The pharmaceutical compositions may be in the form of a sterile injectable 10 aqueous or oleagenous suspension. This suspension may be formulated according to know methods using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation may also be formulated as a suspension in a non toxic perenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents 15 that may be employed are water, Ringers solution and isotonic sodium chloride solution. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition fatty acids such as oleic acid find use in the preparation of injectables. The compounds of Formula I may also be administered in the form of 20 suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at about 25 Celsius but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and other glycerides. For topical use preparations, for example, creams, ointments, jellies solutions, or 25 suspensions, containing the compounds of the present invention are employed. The compounds of Formula I may also be administered in the form of liposome delivery systems such as small unilamellar vesicles, large unilamellar vesicles and multimellar vesicles. Liposomes can be formed from a variety of phospholipides, such as cholesterol, stearylamine or phosphatidylcholines. 30 Dosage levels of the compounds of the present invention are of the order of about 0.5 mg/kg body weight to about 100 mg/kg body weight. A preferred dosage rate is between about 30 mg/kg body weight to about 100 mg/kg body weight. It will be understood, however, that the specific dose level for any particular patient will depend WO 2008/125945 PCT/IB2008/000862 -52 upon a number of factors including the activity of the particular compound being administered, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy. To enhance the therapeutic activity of the 5 present compounds they may be administered concomitantly with other orally active antidiabetic compounds such as the sulfonylureas, for example, tolbutamide and the like. For administration to the eye, a compound of the present invention is delivered in a pharmaceutically acceptable ophthalmic vehicle such that the compound is maintained 10 in contact with the ocular surface for a sufficient time period to allow the compound to penetrate the cornea and/or sclera and internal regions of the eye, including, for example, the anterior chamber, posterior chamber, vitreous body, aqueous humor, vitreous humor, cornea, iris/ciliary's, lens, choroid/retina and sclera. The pharmaceutically acceptable ophthalmic vehicle may be an ointment, vegetable oil, or 15 an encapsulating material. A compound of the invention may also be injected directly into the vitreous humor or aqueous humor. The compounds of the invention, and pharmaceutically acceptable salts thereof, may be administered for the treatment of ophthalmic diseases such as age-related macular degeneration (both wet and dry 'AMD'), glaucoma, diabetic retinopathies 20 (including diabetic macular edema), choroidal neovascular membrane (CNV), uveitis, myopic degeneration, ocular tumors, entral retinal vein occlusion, rubeosis, ocular neovascularization, central serous retinopathy, ocular surface discus such as dry eye, central retinal artery occlusion, cystoid macular edema and other retinal degenerative disease. 25 The compounds may be formulated as a depot preparation. Such long-acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) intramuscular injection or by the above mentioned subtenon or intravitreal injection. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. 30 Within particularly preferred embodiments of the invention, the compounds may be prepared for topical administration in saline (combined with any of the preservatives and antimicrobial agents commonly used in ocular preparations), and administered in eyedrop form. The solution or suspension may be prepared in its pure form and WO 2008/125945 PCT/IB2008/000862 - 53 administered several times daily. Alternatively, the present compositions, prepared as described above, may also be administered directly to the cornea. Within preferred embodiments, the composition is prepared with a muco adhesive polymer which binds to cornea. Thus, for example, the compounds may be 5 formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion-exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. A pharmaceutical carrier for hydrophobic compounds is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and 10 an aqueous phase. The cosolvent system may be a VPD co-solvent system. VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol. The VPD co-solvent system (VPD:5W) contains VPD diluted 1:1 with a 5% dextrose in water solution. This co-solvent system dissolves 15 hydrophobic compounds well, and itself produces low toxicity upon systemic administration. Naturally, the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics. Furthermore, the identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of polysorbate 80; the fraction size of 20 polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars or polysaccharides may be substituted for dextrose. Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are known examples of delivery vehicles 25 or carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity. Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials have been established and are known by 30 those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.
    WO 2008/125945 PCT/IB2008/000862 -54 The pharmaceutical compositions also may comprise suitable solid- or gel-phase carriers or excipients. Examples of such carriers or excipients include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols. 5 Some of the compounds of the invention may be provided as salts with pharmaceutically compatible counter ions. Pharmaceutically compatible salts may be formed with many acids, including hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free-base forms. 10 The preparation of preferred compounds of the present invention is described in detail in the following examples, but the artisan will recognize that the chemical reactions described may be readily adapted to prepare a number of other compounds of the invention. For example, the synthesis of non-exemplified compounds according to the invention may be successfully performed by modifications apparent to those skilled 15 in the art, e.g., by appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by making routine modifications of reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the invention. 20 Table 1 The following Table 1 depicts Ki, structure, nomenclature, and NMR data of the embodiments of the Invention. Unless otherwise specifically exemplified, compounds in Table 1 were synthesized starting from commercially available materials or by known methods using routine modifications of the above described examples. While the 25 invention has been illustrated by reference to specific embodiments, those skilled in the art will recognize that additional variations and modifications may be made through routine experimentation and practice of the invention. Thus, the invention is intended not to be limited by the foregoing description, but to be defined by the appended claims and their equivalents. The foregoing detailed description.and examples have been 30 given for clarity of understanding only.
    WO 2008/125945 PCT/IB2008/000862 - 55 PKCb Ex. Ki No. Structure (nM) 1H NMR Chiral O N 3 N N N 0 Y I/ 1H NMR (400 MHz, DMSO-d6) d ppm 1.13 -1.26 N (m, 3 H) 1.26 - 1.36 (m, 1 H) 1.61 (d, J=14.40 Hz, N 0 6 H) 1.64 - 1.79 (m, 2 H) 1.82 - 2.04 (m, 4 H) 2.24 Al ( >CH, N 29.2 (dd, J=10.48, 3.16 Hz, 1 H) 2.69 - 2.83 (m, 2 H) 'N2.94 (t, J=7.58 Hz, 1 H) 3.22 - 3.45 (m, 2 H) 3.86 (d, J=2.02 Hz, 1 H) 4.44 - 4.71 (m, 2 H) 7.63 7.82 (m, 1 H) 7.99 - 8.10 (m, 1 H) 8.17 (d, J=7.83 N-(6,6-dimethyi-5-((3S,8aS)-3-nethyl- Hz, 1 H) 8.74 (d, J=4.55 Hz, 1 H). octahydropyrroloji ,2-a]pyrazine-2-carbonyl) 1 ,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-, yl)picolinamide___________________________ Chiral
    CH
    3 OCH NN a ,N I1H NMR (400 MHz, DMSO-d6) ppm 1.03 (3 H, d, N O -N a J=6.06 Hz), 1.31 (1 H, d, J=5.81 Hz), 1.57 (6 H, - H N-_ s), 1.66 (4 H, s), 1.89 (3 H, d, J=1.77 Hz), 2.09 (3 A2/ N 3.05 H, d, J=1.52 Hz), 2.16 (1 H, d, J18.19 Hz), 2.60 N 2.67 (1 H, in), 2.86 (1 H, d, J=1 1.87 Hz), 3.31 (21
    OH
    3 H, s), 4.59 - 4.70 (2 H, in), 7.68 (1 H, none), 8. 10 N-(5-{[(8S)-6,8-dimethyl-6,9-diazaspiro[4.5]dec- 8.15 (2 H, i), 8.72 (1 H, d, J=4.30 Hz). 9-yl]carbonyl}-6,6-dimethyl-1,4,5,6 tetrahydropyrrolo[3,4-c]pyrazol-3-yl)pyridine-2 carboxamide Chiral OH IH 1 H NMR (400 MHz, CDC3) d ppm 1.31 - 2.25 A3 3.5 (, 13 H), 2.52 - 2.63 ( , 1 H), 2.75 -3.18 ( , 5 2.7(13 ),286(3,6,J118.H)8.3 2 H s), 3.35 - 3.48 (, H), 3.92-4.58 (in, 3 H), 6.80-7.65 (m, 14 H), 9.53(s, br, 1 H). N-(5-((3S,8aS)-3-benzyl-octahydropyrrolo[1,2 a]pyrazine-2-carbonyl)-6,6-dimethyl-1,4,5,6 tetrahydropyrrolo[3,4-c]pyrazol-3-yI)-3 I__ phenoxybenzainile ______________________ Chiral CH H H N 1 H NMR (400 MHz, MeOD) 6 ppm: 1.65 (s, 3 H), 3 3. 1.72 (s, 3 H), 2.29 (s, 3 H), 2.34 - 2.46 (m, 2 H), CN 2.55 (dd, J=1 1.24, 4.67 Hz, 1 H), 2.62 -2.73 (in, 1 A4 N / H), 2.89 (dd, J=13.26, 8.46 Hz, 1 H), 3.09 (dd, A4N146 J=13.39, 6.32 Hz, 1 H), 3.16 - 3.26 (in, 1 H), 3.36
    H
    3 -6 - 3.45 (in, 1 H), 3.79 (s, 1 H), 4.39 (b, 1 H), 4.59 (b, 1 H), 7.11 -7.19 (m, 1 H), 7. 2 - 7.28 (m, 4 H), 7.40-7.53 (m, 2 H), 7.90.-8.00 (, 2 H), 8.15 (s, (S)-N-(5-(3-benzyl- c -methylpiperazine-4- 1 H). carbonyl)-6,6-dimethyl-2,4,5,6 tetrahydropyrrolo[3,4-c]pyrazo-3 y p)benzo[blthiophene-2-carboxamide WO 2008/125945 PCT/IB2008/000862 - 56 PKCb Ex. Ki No. Structure (nM) 1H NMR Chiral 1 H NMR (400 MHz, MeOD) d ppm: ppm: 1.56 (s,
    OH
    3 N 3 H), 1.63 (s, 3 H), 2.21 (s, 3 H), 2.26 - 2.39 (m, 2 NH), 2.46 (dd, J=1 1.62, 4.80 Hz, 1 H), 2.54 -2.64 N (m, 1 H), 2.80 (dd, J=13.26, 8.46 Hz, 1 H), 2.99 N 189 (dd, J=13.39, 6.32 Hz, 1 H), 3.07 - 3.16 (m, 1 H), 3.27 - 3.36 (m, 1 H), 3.69 (b, 1 H), 4.30 (d, J=12.63 Hz, 1 H), 4.51 (d, J=13.14 Hz, 1 H), 7.02 m - 7.11 (m, 1 H), 7.12 - 7.19 (m, 4 H), 7.43 (t, J=7.45 Hz, 2 H), 7.48 - 7.56 (m, 1 H), 7.86 (d, (S)-N-(5-(3-benzyl-1 -inethylpiperazine-4- J=7.33 Hz, 2 H). carbonyl)-6,6-dimethyl-1,4,5,6 I tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzamide Chiral CH,
    OH
    3 t N 1 H NMR (400 MHz, MeOD) d ppm: 1.55 (s, 3 H), N 1.63 (s, 3 H), 2.22 (s, 3 H), 2.29 - 2.40 (m, N J=1 1.37, 3.03 Hz, 2 H), 2.48 (dd, J=1 1.49, 4.93 Hz, 1 H), 2.55 - 2.65 (m, 1 H), 2.79 (dd, J=13.39, A6 ~ ,187 8.34 Hz, 1 H), 2.99 (dd, J=13.39, 6.06 Hz, 1 H), 3.06 - 3.16 (m, 1 H), 3.29 - 3.36 (m, 1 H), 3.69 (b, 1 H), 4.27 (d, J=11.87 Hz, 1 H), 4.48 (d, J=13.39 Hz, 1 H), 7.05 - 7.12 (m, 2 H), 7.13 - 7.19 (m, 4 (S)-N-(5-(3-benzyl-1-inethylpiperazine-4- H), 7.67 (d, J=4.29 Hz, 1 H), 7.76 - 7.84 (m, 1 H). carbonyl)-6,6-dimethy-1,4,5,6 tetra hydro pyrro lo[3,4-c] pyrazol-3-yI)th ioph ene 2-carboxamide Chiral 0 CH CH 3 N N 1 H NMR (400 MHz, DMSO-D6) d ppm 1.38 - 1.85 (N %(mn, J=24.76 Hz, 6 H) 2.68 - 2.82 (in, 3 H) 2.83 N 3.06 (in, 3 H) 3.09 - 3.55 (in, 4 H) 3.95 - 4.27 (in, N No A7 cl'H 3 N 124 1 H)4.27-4.62(m,2H)6.51 (s,1 H)7.03-7.35 / 0 0 0 (in, 6 H) 7.44 (t, J=7.83 Hz, I H) 7.62 (d, J=7.83 'N/ 0Hz, 1 H) 7.69 -7.90 (m, 2H) 9.56 -10.03 (m, 1 H) (S)-N-(5-(3-benzyl-1 -methylpiperazine-4- 11.16 (s, 1 H). carbonyl)-6,6-dimethyl-1,4,5,6 tetrahydropyrrolo[3,4-c]pyrazol-3 yl)benzofuran-2-carboxamide ______________________ Chiral
    OH
    3 OH N 1H NMR (400 MHz, DMSO-d6) d ppm 1.43 - 1.71 (m, 6 H) 2.55 -2.67 (-, J=12.38 Hz, 1 H) 2.71 N N N 2.86 (m, 5 H) 3.37 (s, 4 H) 4.44 - 4.67 ( ,, 2 H) A8 N0 78.1 715 (d, J=8.08 Hz, 2 H) 7.25 (d, J5.31 Hz, 3 H) 7163 - 7.76 (m, 1 H) 7.81 - 7.93 (3H , 1 H) 8.08 (d, CH / J=8.08 Hz, 1 H) 8.10 -8.25 (in, 2 H) 8.59 (d, J=8.59 Hz, 1 H) 9.41 - 9.95 (, 1 H) 10.89 (s, 1 (S)-N-(5-(3-benzyl-1 -i1ethylpiperazine-4- H). carbonyl)-6,6-dimethyl-1,4,5,6 tetra hyd ropyrrolo[3,4-c] pyrazol-3-yI)q uin ol ine-2 carboxamide WO 2008/125945 PCT/IB2008/000862 - 57 PKCb Ex. Ki No. - Structure (nM) 1H NMR 3CH N CH N N N NH NMR (400 MHz, CDCla) 6 ppm 1.38 (s, 3 H), 1.57 (s, 3 H), 2.38 - 2.47 (m, 4 H), 2.52 - 2.63 (m, A9 /159 1 H), 2.89 - 2.98 (m, 2 H), 3.15 - 3.33 (m, 2 H), CH, 4.35 - 4.41 (m, 1 H), 4.77 (d, J = 16 Hz, 1 H), N-(6,6-dinethyl-5-(1 -methyi-3- 4.91 (d, J = 16 Hz), 6.95-7.66 (m, 14 H), 9.52(s, phenylpiperazine-4-carbony)-1 ,4,5,6- br, 1 H). tetrahydropyrrolo[3,4-c]pyrazol-3-yI)-3 phenoxybenzamide ______________________ N-N CH H N / o 1 H NMR (400 MHz, MeOD) 6 ppm 1.34 (s, 3 H), S1.59 (s, 3 H), 2.93 - 3.03 (m, 2 H), 3.12 - 3.25 (m, A10 0 55.9 3 H), 3.47 (d, J = 12 Hz, 1 H), 4.12 - 4.17 (m, 1 N H), 4.82 (d, J = 12 Hz, 1 H), 4.97 (d, J = 12 Hz), N-(6,6-dimethyl-5-(2-phenyipiperazine-1 - 7.02-7.75 (m, 14 H). carbonyl)-1 ,4,5,6-tetrahydropyrrolo[3,4 _____ clpyrazol-3-yi)-3-phenoxybenzamide ____ 0 CH CH3 1H NMR (400 MHz, DMSO-D6) d ppm 1.75 (none, 1 H) 1.89 - 1.99 (m, 1 H) 2.02 - 2.24 (m, 2 N NH) 2.73 - 2.88 (m, 1 H) 2.90 - 3.08 (m, 2 H) 3.48 All N 739 (dd, J=42.95, 12.13 Hz, 2 H) 4.53 - 4.83 (m, 2 H) 0 7.76 (t, J=6.95 Hz, 1 H) 7.87 - 7.99 (m, 1 H) 8.13 N-(6,6-diiethyl-5-(octahydropyrrolo[1 ,2- (d, J=7.33 Hz, 1 H) 8.24 (d, J=8.08 Hz, 2 H) 8.55 a]pyrazine-2-carbonyl)-1,4,5,6- 8.79 (m, J=8.08 Hz, 1 H) 10.64 (s, 1 H) 12.58 (s, 1 tetrahydropyrrolo[3,4-c]pyrazol-3-yI)quinoline-2- H). carboxamide Chiral 0 CH CH3 H N 1H NMR (400 MHz, CDC13) d ppm 0.82 - 0.89 (m, J=8.72, 6.69 Hz, 7 H) 1.50 - 1.88 (m, J=30.57 Hz, N 13 H) 2.82 - 3.13 (m, 2 H) 3.56 (s, 1 H) 3.80 - 4.00 A12 N N103 (m, J=5.05 Hz, 1 H) 4.57 (s, 1 H) 4.72 (d, J=12.88 Hz, 1 H) 7.60 (t, J=7.45 Hz, 1 H) 7.75 (t, J=7.33
    H,
    3 Hz, 1 H) 7.85 (d, J=8.08 Hz, 1 H) 8.11 (d, J=8.59 N-(5-((3S,8aS)-3-isobutyl-octahydropyrrolo[1,2- Hz, 1 H) 8.23 - 8.39 (m, 2 H) 10.48 (s, 1 H). a]pyrazine-2-carbonyl)-6,6-dimethyl-1,4,5,6 tetrahydropyrrolo[3,4-c]pyrazol-3-yI)quinoline-2 carboxamide Chiral 1 H NMR (400 MHz, DMSO-D6) d ppm 1.21 - 1.30 0 CH OH 3 (m, 1 H) 1.42 (s, 3 H) 1.48 (s, 3 H) 1.61 - 1.69 (m, 2 H) 1.71 - 1.79 (m, 1 H) 1.89 (d, J=8.84 Hz, 1 H) N N 2.05 (dd, J=10.86, 3.54 Hz, 1 H) 2.25 - 2.34 (m, 1 N NH) 2.71 - 2.79 (m, 1 H) 2.80 - 2.90 (m, 3 H) 2.97 A13 N N27.7 (dd, J=13.14, 8.08 Hz, 1 H) 3.29 - 3.41 (m, 1 H) 0 3.75 - 3.84 (m, J=2.02 Hz, 1 H) 4.17 (d, J=13.14 1I Hz, 1 H) 4.50 (d, J=12.88 Hz, 1 H) 6.98 - 7.07 (m, - 1 H) 7.08 - 7.18 (m, 4 H) 7.64 - 7.68 (m, 1 H) 7.76 - 7.84 (m, 1 H) 8.02 (d, J=7.83 Hz, 1 H) 8.13 (d, a]pyrazine-2-carbonyl)-6,6-dimethyl-1,4,5,6- J=8.84 Hz, 1 H) 8.16 (d, J=8.59 Hz, 1 H) 8.54 (d, tetrahydropyrrolo[3,4-c]pyrazol-3-yI)quinoline-2- J=8.34 Hz, 1 H). carboxamide WO 2008/125945 PCT/IB2008/000862 - 58 PKCb Ex. Ki No. [ Structure (nM) 1H NMR Chiral O CH
    CH
    3 N N1H NMR (500 MHz, D20) d ppm 1.47 (s, 1 H) 1.52 (s, 1 H) 1.59 (s, 3 H) 1.64 (s, 3 H) 1.76 (s, 2 NC,, N ~H) 2.04 (s, 2 H) 2.90 (d, J=4.94 Hz, 1 H) 3.08 (s, 1 N N16.1 H) 3.77 (d, J=15.66 Hz, 4 H) 3.84 (s, 1 H) 4.48 (s, 2 H) 7.09 - 7.20 (m, 5 H) 7.22 - 7.29 (m, 3 H) 7.34 - 7.40 (m, 3 H) 7.49 (dd, J=12.50, 8.65 Hz, 3 H) 10.87 (s, 1 H). N-(5-((3S,8aS)-3-benzyl-octahydropyrrolo[1,2 a]pyrazine-2-carbonyl)-6,6-dimethyl-1,4,5,6 tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzam ide O CH CH N fN N 1H NMR (400 MHz, CDCl3) d ppm 1.23 - 1.36 (m, 1 H) 1.59 - 1.67 (m, J=2.02 Hz, 6 H) 1.67 - 1.81 I (m, 3 H) 1.91 - 2.05 (m, 1 H) 2.08 (q, J=8.42 Hz, 1 A15 N 136 H) 2.16 - 2.29 (m, 1 H) 2.50 - 2.68 (m, 1 H) 2.85 3.05 (m, 3 H) 3.47 (d, J=12.63 Hz, 1 H) 3.57 (d, N-(6,6-dimethyl-5-(octahydropyrrolo[1,2- J=12.13 Hz, 1 H) 4.50 - 4.77 (m, 2 H) 7.37 (t, a]pyrazine-2-carbonyl)-1,4,5,6- J=7.58 Hz, 2 H) 7.46 (t, J=7.20 Hz, 1 H) 7.81 (d, tetra hydropyrrolo[3,4-c] pyrazo-3-y)thiophen e- J=7.58 Hz, 2 H) 9.46 (s, 1 H). 2-carboxamide
    CH
    3
    CH
    3 N N iH NMR (500 MHz, D20) d ppm 1.58 (s, 10 H) N 2.36 (s, 1 H) 2.49 (d, J=6.04 Hz, 2 H) 2.98 (s, 2 H) A16 N 113 4.51 (s, 2 H) 7.02 (d, J=8.24 Hz, 3 H) 7.14 (s, 3 H) 7.36 - 7.40 (m, 3 H) 7.44 - 7.47 (m, 1 H) 7.55 (s, 2 N-(5-(1-(2-hydroxyethyl)piperazine-4-carbonyl)- H) 7.73 (s, 1 H) 10.89 (s, 1 H) 12.39 (s, 1 H). 6,6-dimethyl-1 ,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yi)-3-phenoxybenzamide Chiral CH, CH N A 0 H ; 0 1 H NMR (500 MHz, D20) d ppm 1.47 (s, 1 H) 1.52 (s, 1 H) 1.59 (s, 3 H) 1.64 (s, 3 H) 1.76 (s, 2 1 NH) 2.04 (s, 2 H) 2.90 (d, J=4.94 Hz, 1 H) 3.08 (s, 1 Al 7, /16.1 H) 3.77 (d, J=15.66 Hz, 4 H) 3.84 (s, 1 H) 4.48 (s, 2 H) 7.09 - 7.20 (m, 5 H) 7.22 - 7.29 (m, 3 H) 7.34 - 7.40 (m, 3 H) 7.49 (dd, J=12.50, 8.65 Hz, 3 H) N-(5-((3S,8aS)-3-benzyl-octahydropyrrolo[1 ,2- 10.87 (s, 1 H). a]pyrazine-2-carbonyl)-6,6-dimethyl-1,4,5,6 tetrahydropyrrolo[3,4-c]pyrazol-3-yi)-3 methoxybenzamide Chiral
    OCH
    3 N 0 H QN 0 1 H NMR (500 MHz,D20) d ppm 1.47 (s, 1 H) 1.51 'N (s, 1 H) 1.59 (s, 3 H) 1.63 (s, 3 H) 1.76 (s, 2 H) - N 2.03 (s, 2 H) 2.90 (s, 1 H) 3.08 (s, 1 H) 3.78 (d, 018 "' 0( 30.2 J=6.59 Hz, 6 H) 4.48 (d, J=14.28 Hz, 2 H) 6.98 A18 N', (dd, J=11.81, 8.79 Hz, 3 H) 7.18 (d, J=7.42 Hz, 3 O-CH3H) 7.21 - 7.29 (in, 3 H) 7.84 (d, J=8.52 Hz, 1 H) 7.94 (t, J=9.34 Hz, 2 H) 9.83 (s, 1 H) 10.70 (s, 1 N-(5-((3S,8aS)-3-benzyl-octahydropyrrolo[1,2- H). a]pyrazine-2-carbonyl)-6,6-dimethyl-1,4,5,6 tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-4 methoxybenzamide I_______________I_______ WO 2008/125945 PCT/IB2008/000862 - 59 PKCb Ex. Ki No. Structure (nM) 1H NMR Chiral CH, CHC N, O - N \/ ~.- P/'0 1H NMR (500 MHz, D20) d ppm 1.49 (d, J=16.21 N N- C Hz, 2 H) 1.60 (s, 3 H) 1.65 (s, 3 H) 1.78 (s, 1 H) 2.03 (s, 2 H) 2.90 (s, 1 H) 2.94 (s, 1 H) 3.66 (s, 1 N 91.4 H) 3.79 (s, 1 H) 4.48 (s, 2 H) 7.17 (d, J=7.69 Hz, 3 H) 7.21 - 7.29 (m, 3 H) 7.36 - 7.42 (m, 2 H) 7.45 (s, 2 H) 7.49 (d, J=2.20 Hz, 3 H) 7.73 (d, J=7.69 N-(5-((3S,8aS)-3-benzyl-octahydropyrrolo[1,2- Hz, 1 H) 9.82 (s, I H) 10.99 (s, 1 H). a~pyrazine-2-carbonyl)-6,6-diinethyl-1,4,5,6 tetra hyd ro pyrro lo[3,4-c] pyrazol-3-yI)-2 chlorobenzamide Chiral CH CH, N, OH N 0 N N 0 1H NMR (500 MHz,D20) d ppm 1.47 (s, 1 H) 1.51 (s, 1 H) 1.59 (s, 3 H) 1.64 (s, 3 H) 1.77 (s, 2 H) C N N-b F2.03 (s, 2 H) 2.56 (s, 1 H) 2.88 (d, J=13.73 Hz, 1 2 0 IF 50.8 H) 2.95 (d, J=8.52 Hz, 1 H) 3.07 (s, 1 H) 3.80 (s, 1 N H) 4.48 (s, 2 H) 7.18 (t, J=8.24 Hz, 3 H) 7.23 (s, I H) 7.24 - 7.30 (m, 4 H) 7.39 (s, 1 H) 7.56 (s, 1 H) 7.63 (d, J=8.24 Hz, 1 H) 9.83 (s, 1 H) 11.03 (s, 1 a]pyrazine-2-carbonyl)-6,6-dimethyl-14,5,6-H). tetrahydropyrrolo[3,4-c]pyrazol-3-yI)-2,3 difluorobenzamide Chiral CH, CH 'I..N N Ct NO o 1 H NMR (500 MHz, D20) d ppm 1.47 (s, 1 H) N N F1.51 (s, 1 H) 1.59 (s, 3 H) 1.64 (s, 3 H) 1.77 (s, 2 H) 2.04 (s, 2 H) 2.56 (s, 1 H) 2.90 (s, 1 H) 3.47 (s, A21 ~53.2 2 H) 3.66 (s, 1 H) 3.80 (s, 1 H) 4.44 (s, 1 H) 4.50 (d, J=14.01 Hz, 1 H) 7.18 (t, J=7.83 Hz, 3 H) 7.24 (s, 1 H) 7.26 (dd, J=12.77, 5.63 Hz, 5 H) 7.53 (s, 1 N-(5-((3S,8aS)-3-benzyl-octahydropyrrolo[1,2- H) 7.59 (s, 1 H) 9.83 (s, 1 H) 10.84 (s, 1 H). a]pyrazine-2-carbonyl)-6,6-dimethyl-1,4,5,6 tetra hyd ro pyrro lo[3,4-c] pyrazo1-3-yI)-2 I_ fluorobenzamide CH N NH 3 N N 1H NMR (500 MHz, D20) d ppm 1.45 (s, 1 H) A22 N 28 1.60 (s, 5 H) 1.89 (s, 1 H) 2.06 (s, 1 H) 3.54 (s, 10 A22 C28.9 H) 3.71 (s, 1 H) 3.80 (s, 1 H) 4.57 (s, 2 H) 7.50 (t, J=7.97 Hz, 1 H) 7.61 (s, 1 H) 7.90 (s, 1 H) 7.98 (s, 3-chloro-N-(6,6-dimethyl-5- 1 H) 11.03 (s, 1 H). (octahydropyrrolo[1,2-a]pyrazine-2-carbonyl) 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3 yl)benzamide WO 2008/125945 PCT/IB2008/000862 - 60 PKCb Ex. Ki No. Structure (nM) 1H NMR CH O NO CH IN N 1H NMR (500 MHz, 020) d ppm 1.45 (s, H) N ( 1.59 (s, 6 H) 1.90 (s, 2 H) 2.06 (s, 1 H) 2.86 (s, 1 A2C 55.9 H) 2.94 (s, 1 H) 3.55 (s, 6 H) 3.64 (s, H) 3.72 (s, 1 H) 4.61 (s, 2 H) 7.78 (d, J=7.69 Hz, 1 H) 8.05 (s, 6-chloro-N-(6,6-dimethyl-5- 1 H) 8.07 (d, J=15.38 Hz, 1 H) 10.64 (s, 1 H). (octahydropyrrolo[1,2-a]pyrazine-2-carbony) 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3 yl)picolinamide Chra CH H , OON N N N N' N N I H NMR (500 MHz,D20) d ppm 1.45 (s, 1 H) 1.59 N ( (s, 6 H) 1.90 (s, 2 H) 2.06 (s, 1 H) 2.86 (s, 1 H) A25 N 42.9 3.55 (s, 7 H) 3.65 (s, 1 H) 3.80 (s, 1 H) 4.63 (s, 2 H) 7.66 (dd, J=6.59, 5.49 Hz, I H) 8.02 - 8.10 (in, N-(6,6-dimethyl-5-(octahydropyrrolo[1,2- 2 H) 8.69 (d, J=4.40 Hz, 1 H) 10.77 (s, 1 H). a]pyrazine-2-carbonyl)- -1,4,5,6 tetrahydropyrrolo[3,4-c]pyrazol-3 yr)picoinamide Chiral CH OH 3 hN CH N / N N 1 H NMR (400 MHz, DMSO-d6) d ppm 1.55 (d, N J=15.41 Hz, 2 H) 1.68 (d, J14.65 Hz, 4 H) 1.77 1.90 (s, 2 H) 1.92-2.21 (in, 2 H) 2.59 -2.74 (, A25 ~5. H29(28.8 1 H) 2.84 -2.98 ( s, 1 H) 3.04-3.22 (, 3 H) 3.65 N / t N - 3.78 (in, 4 H) 3.84 -3.98 (in, 1 H) 4.54 -4.74 (in, 2 H) 7.19-7.27 (in, 2 H) 7.28- 7.41 (i, 3 H) 8.11 N-(5-((3S,8aS)-3-benzyl-octahydropyrrolo[11,2- (d, J=6.06 Hz, 1 H) 8.35 (d, J8.59 Hz, 1 H) 8.83 a]pyrazine-2-carbonyl)-6,6-dinethyl-1,4,5,6- 8.94 ( , 2 H) 9.59 (s, H) 9.96 (s, 1 H). tetra hyd ropyrro(o[3,4-c]pyrazo(-3-yI)-s1 7 naphthyridine-2-carboxamide________________________
    OH
    3 Chiral 2C)86 d J44 z H) 107 (,1 ) 0 N IN 1 H NMR (400 MHz, DMSO-d6) d ppm 1.35 (s, 1 = H) 1.50 (s, 2 H) 1.53- 1.59 ( z, 4 H) 1.60-1.68 .N (m, 2 H) 1.69- 1.81 (, J 1 5.16 Hz, 2 H) 1.85 0 -N (dd, J=13.77, 6.69 Hz, 1 H) 1.99 (d, J=9.35 Hz, 1 A26 N 8 69.3 H) 2.12 (dd, J=10.61, 3.54 Hz, 3 H) 2.8832.9 (in, 4 H) 3.03 - 3.17 (, 1 H) 3.45 (d, J=17.43 Hz, 1 H) 3.80 -3.91 (m, 1 H) 4.01 (s, 3 H) 4.15 -4.23 N-(5-((3S,8aS)-3-benzyl-octahydropyrrolo[1,2- (d, H)4.46 (d, J= 12.88 Hz, 1 H) 7.08 (s, 1 H) a]pyrazine-2-carbonyl)-6,6-dimethyl-1,4,5,6- 7.16 (dd, 1 H) 7.20-7.30 (in, 4 H) 7.45 (s, 1 H). tetra hyd ro pyrro lo[3,4-] pyrazo-3-yi)- 1 -methyl Chiral 01 3 IN 1H NMR (400 MHz, CD30d) d ppm 1.35 (d, N OJ=6.80 Hz, 3 H) 1.41 - 1.55 (m, 1 H) 1.66 - 1.96 A27 C 0 35.1 (m, 9 H) 2.03 -2.26 (m, 2 H) 2.40-2.51 (in, 1 H) 2.88 - 3.08 (, 3 H) 3.43-3.52 (, 1 H) 3.92 4.01 (n, , H) 4.52 -4.82 ( s, 2 H) 7.49- 7.65 (in, (m3 H) .6 (d, J=12.88z, HzH). 70s,1H N-(6,6-dimethyl-5-((3S,8aS)-3-methyl octahydropyrrolo[1,2-a]pyrazine-2-carbonyl) 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3 yl)benzainide WO 2008/125945 PCT/IB2008/000862 - 61 PKCb Ex. Ki No. Structure (nM) IH NMR OH
    CH
    3 N Chiral N N 21H NMR (400 MHz, CD3D) d ppm 0.95 (t, N N J=7.30 Hz, 3 H) 1.32 - 1.48 (in, 3 H) 1.63 -2.03 -n o (mn, J=31.73 Hz, 12 H) 2.08 -2.19 (in, 1 H) 2.36 A28 <(N- CH / 96.1 2.45 (mn, 1 H) 2.93 - 3.08 (in, 3 H) 3.52 (d, J=9.57 Hz, 1 H) 3.83 -3.91 (mn, 1 H) 4.50 -4.61 (in, 1 H) 4.73 - 4.83 (in, 1 H) 7.47 - 7.67 (in, 3 H) 7.95 (d, N-(6,6-dimethyl-5-((3S,8aS)-3-propyl- J=7.55 Hz, 3 H). octahydropyrrolo[1,2-a]pyrazine-2-carbonyl) 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3 yl)benzamide CH HN 0 N - NJ X 0H NMR (400 MHz, DMSO-d6) d ppm 1.11 (d, /N N- J=5.81 Hz, 6 H) 1.64 (s, 6 H) 2.93 -3.12 (in, 2 H) A29OH 3 ND 77.6 3.38 - 3.51 (m, J=12.13 Hz, 4 H) 4.64 (s, 2 H) 7.64 -7.79 (mi, 1 H) 8.05 -8.13 (m, 1 H) 8.15 CH 3 8.22 (i, 1 H) 8.76 (d, J=4.55 Hz, 1 H). N-(5-(2,6-dimethylpiperazine-4-carbonyl)-6,6 dimethyl-1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yI)picolinamide CH, Chiral O N N N
    CH
    3 / 1H NMR (500 MHz, D20) d ppm 1.07 (s, 1 H) A30 N22.9 1.19 (s, 1 H)1.56(s,4H)1.62(s,4H)1.82(s,2 H) 1.99 (s, 1 H) 3.45 (s, 9 H) 4.54 (s, 2 H) 7.79 (s, CI 1 H)7.93 (s, 2 H) 11.12 (s, 1 H). 3,5-dichloro-N-(6,6-dimethyl-5-((3S,8aS)-3 methyl-octahydropyrrolo[1,2-a]pyrazine-2 carbonyl)-1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yI)benzamide CH Chiral N C/ CI N NCC, Chiral O N 0C 1H NMR (400 MHz, DMSO-d6) d ppm 1.22 (d, NN J=6.82 Hz, 3 H) 1.27 - 1.40 (n, J=9.98, 6.95 Hz, 1 H) 1.62 (d, J=15.66 Hz, 6 H) 1.68 -1.81 (in, 3 H) A1Cle N21. 1.84 -2.12 (in, 3 H) 2.29 (s, 1 H) 2.80 (t, J=10.74 A32 C/a N 2F. (~J Hz, 2 H) 2.94 (t, J=7.58 Hz, 1 H) 3.83 (s, 1 H) 4.36 - 4.68 (in, 2 H) 7.54 (t, J=7.83 Hz, 1 H) 7.66 3-chloro-N-(6,6-dimethyl-5-((3S,8aS)-3-methyl- (d, J=8.08 Hz, 1 H) 7.95 (d, J=7.58 Hz, 1 H) 8.04 octahydropyrrolo[1,2-a]pyrazine-2-carbonyl)- (s, 1 H) 11.06 (s, 1 H). 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3 ______yI)benzainide Chiral O HH 'N N 01H NMR (400 MHz, DMSO-d6) d ppm 1.16- 1.24 H, N F(=, 3 H) 1.26 1.37 (, 1 H) 1.62 (d, J=13.89 Hz, (,6 H) 1.64-1.77 ( , 3 H) 1.97 (d, J=8.84 Hz, 3 H) A32 N 92.4 2.12- (2.29 (, H) 2.69 -2.83 (, 2 H) 2.89 2.99 ( , 1 H) 3.83 (d, J5.05 Hz, H) 4.56 (s, 2 N-(6,6-dimethyl-5-((3S,8aS)-3-methyl- H) 7.23 - 7.38 (m, 2 H) 7.49 - 7.80 (m, 2 H) 10.87 otahydropyrrolo[1J,2-a]pyrazine-2-carbonyl)- (s, 1 H). 1J,4,5,6-tetrahydropyrrolo[3,4-=]pyrazol-3-yI)-2 fluorobenzamide WO 2008/125945 PCT/IB2008/000862 - 62 PKCb Ex. Ki No. Structure (nM) 1H NMR CH, CH N Chiral 0 f N O N N F 1 H NMR (400 MHz, DMSO-d6) d ppm 1.22 (d, CH3 J=6.57 Hz, 3 H) 1.35 (d, 1 H) 1.62 (d, J14.91 Hz, A33 N J 827 6H) 1.66-1.77 (i, 3 H) 1.86- 2.13 (i, 3 H) 2.15 - 2.36 (in, 1 H) 2.69 - 3.06 (in, 3 H) 3.82 (s, 1 H) ci 4.36 - 4.68 (in, 2 H) 7.40 (t, J=9.22 Hz, 1 H) 7.55 5-chloro-N-(6,6-dimethyl-5-((3S,8aS)-3-methyl- 7.74 (m, 2 H) 11.03 (s, 1 H). octahydropyrrolo[1,2-a]pyrazine-2-carbonyl) 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-2 _____ fiuorobenzainide CH H Chiral N 1 H NMR (400 MHz, DMSO-d6) d ppm 1.22 (d, N N J=6.57 Hz, 3 H) 1.29- 1.35 ( , 1 H) 1.52 1.74 8CH 3 c (, 9 H) 1.81 - 2.05 (m, 4 H) 2.14 -2.31 (m, 1 H) A34 21.9 2.79 (d, J=10.61 Hz, 2H)2.92 (s, H) 3.82 (s, 1 F H) 4.31 -4.63 (m, 2 H) 7.56 (t, J=8.84 Hz, 1 H) 3-chloro-N-(6,6-diinethyl-5-((3S,8aS)-3-methyl- 7.88 - 8.11 (in, 1 H) 8.23 (dd, J=7.07, 2.27 Hz, 1 octahydropyrrolo[1,2-a]pyrazine-2-carbonyl)- H) 11.06 (s, 1 H). 1 ,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-y)-4 fluorobenzamide
    CH
    3 N Chiral ON O N H "IN Ca N1H NMR (400 MHz, DMSO-d6) d ppm 1.18 -1.40
    C<N>~CH
    3 I (, 4 H) 1.55-.1.75 (in, 9 H) 1.81 -2.04 (i, 3 H) A35 N( 176 2.16 - 2.27 (, 1 H) 2.69 - 2.83 (, 2 H) 2.92 (t, F J=7.58 Hz, 1 H) 3.84 (s, 1 H) 4.37 -4.78 (s, 2 H) F F 7.59 (t, J9.09 Hz, 1 H) 7.84- 8.14 (i, 2 H) 11.14 N-(6,6-diinethyl-5-((3S,8aS)-3-methyl- (s, 1 H) 12.42 (s, 1 H). octahydropyrroloji ,2-a]pyrazine-2-carbonyl) 1 ,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yI)-2 fluoro-5-(trfluoromethyl)benzamide CH N Chiral 0O N N N0 N N- 1 H NMR (400 MHz, DMSO-d6) d ppm 1.22 (d,
    CH
    3 /Ci J=6.57 Hz, 3 H) 1.27-1.41 (i, 1 H) 1.55-1.76 A36 N- 13.9 (i, 9 H) 1.80-2.27 (i, 4 H) 2.68-3.01 (, Cl J=53.05 Hz, 3 H) 3.78 (s, 1 H) 4.48 (d, J=5.05 Hz, 3,4-dichloro-N-(6,6-dimethyl-5-((3S,8aS)-3- 2 H) 7.45m-e7.78 (, 3 H) 11.29 (s, 1 H). methyl-octahydropyrrolo[1,2-a]pyrazine-2 carbonyl)-1,4,5,6-tetrahydropyrrolo[3,4 f c]pyrazol-3-y)benzamide
    CH
    3 Chiral 0 1 N / 0 1H NMR (400 MHz, DMSO-d6) d ppm 1.22 (d, N N F J=6.57 Hz, 3 H) 1.26 - 1.34 (in, 1 H) 1.45 -1.76 CHCI A373 F /b 5 (in, 9 H) 1. 79 -2.04 (in, 4 H) 2.22 (dd, J=10.48, A37 NF 155 3.41 Hz, 1 H) 2.67 -2.83 (in, 2 H) 2.90 -3.02 (in, F -1 H) 3.84 (s, 1 H) 4.42 - 4.64 (in, 2 H) 7.79 (d, N-(6,6-dimethyl-5-((3S,8aS)-3-methyl- J=8.34 Hz, 1 H) 7.97 (dd, J=8.34, 2.02 Hz, 1 H) octahydropyrrolo[1,2-a]pyrazine-2-carbonyl)- 8.25 (d, J=2.02 Hz, 1 H) 11.15 (s, 1 H). 1c,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yI)-2 fluoro-6-(trifluoromethyl)benzamide WO 2008/125945 PCT/IB2008/000862 -63 PKCb Ex. Ki . No. Structure (nM) 1H NMR CHC N Chiral O N O N 1H NMR (400 MHz, DMSO-d6) d ppm 1.19 - 1.27 N N: c(m, 3 H) 1.25 - 1.38 (m, 1 H) 1.63 (d, J=11.62 Hz, / H 6 H) 1.66 - 1.76 (m, 3 H) 1.79 - 1.96 (m, 3 H) 2.18 A38 N- F _181 - 2.25 (m, 1 H) 2.67 - 2.84 (m, 2 H) 2.87 - 3.01 (m, 1 H) 3.82 (dd, J=6.44, 2.15 Hz, 1 H) 4.39 - 4.57 2-chloro-N-(6,6-dimethyl-5-((3S,8aS)-3-methyl- (m, 2 H) 7.20 - 7.44 (m, 2 H) 7.48 - 7.59 (m, 1 H) octahydropyrrolo[1,2-a]pyrazine-2-carbony)- 11.31 (s, 1 H) 12.41 (s, 1 H). 1 ,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-y)-6 fluorobenzamide H C, OH N Chiral N 1 0 N N -1 H NMR (400 MHz, DMSO-d6) d ppm 1.07 (d, CH, J=6.06 Hz, 3 H) 1.56 -1.75 (in, 6 H) 1.83 -2.22 A39 N H (i, 4 H) 3.01 - 3.68 (, 8 H) 3.77 - 3.88 (m, 3 H) 4.49 -4.71 (in, 2 H) 7.15 (dd, J=8.08, 2.53 Hz, 1 CT P3 H) 7.42 (t, J=7.83 Hz, 1 H) 7.46 - 7.62 (in, 2 H) N-(6,6-dimethyl-5-((3S,8aS)-3-methyl- 10.98 (s, 1 H). octahydropyrrolo[1,2-a]pyrazine-2-carbonyl) 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-3 methoxybenzamide CH3
    CH
    3 N N Chiral O NO Nhra N 1 H NMR (400 MHz, DMSO-d6) d ppm 1.06 (d,
    OH
    3 / J=6.06 Hz, 2 H) 1.33 (d, J=7.07 Hz, 1 H) 1.52 N40 N 32.7 1.6(m, 6H) 1.81 -2.20 (m, 4H) 3.02 -3.60 (m, A40 8 H) 3.79 - 3.91 (i, 3 H) 4.49 - 4.78 (, 2 H) 7.04 c-66dmehl5((S8S- -meHyl (d, J=8.84 Hz, 2 H) 7.98 (d, J=8.59 Hz, 2 H) 10.80 N-(6,6-dimethyl-5-((3S,8aS)-3-methyl-(s1H) octahydropyrrolo[1,2-a]pyrazine-2-carbonyl) 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-4 methoxybenzamide CH Chiral N CH, N 1H NMR (400 MHz, DMSO-d6) d ppm 1.06 (d, / N F J=6.06 Hz, 2 H) 1.33 (d, J=7.33 Hz, 1 H) 1.61 A41 NF 45.4 1.80 (i, 6 H) 1.88 -2.24 (i, 4 H) 3.02 - 3.86 (, OkF 8 H) 4.54 - 4.77 (in, 2 H) 7.51 (d, J=8.34 Hz, 2 H) N-(6,6-dimethyl-5-((3S,8aS)-3-methyl- 7.99 -8.19 (i, 2 H) 11.12 (s, 1 H). octahydropyrrolo[1,2-a]pyrazine-2-carbonyl) 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-4 (trifluoromethoxy)benzamide Chiral oCH CH N N CH, 1 H NMR (400 MHz, MeOD) d ppm 1. 11 -1.25 (in, N N C ''C N 2 H) 1.44 (s, 1 H) 1.69 (s, 3 H) 1.76 (s, 3 H) 2.05 AN H 3 N N 2.20 (, 2 H) 2.26 (s, 3 H) 3.02 (s, 1 H) 3.15 A42 N N' 67.9 3.27 (in, 2 H) 3.15 - 3.28 (in, 2 H) 3.34 - 3.45 (in, 0 CHJ= 12.38 Hz, 2 H) 3.57 (s, 2 H) 3.78 - 3.91 (in, 1 H) O4.07 (s, 3 H) 4.64-4.75 (i, 2 H) 6.66 (s, 1 H) N-(6,6-dimethyl-5-((3S,8aS)-3-methyl- 7.54 (s, 2 H). octahydropyrrolo[1,2-a]pyrazine-2-carbonyl) 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl) I 1 ,3-dimethyl-1 H-pyrazole-5-carboxamide _________________________ WO 2008/125945 PCT/IB2008/000862 - 64 PKCb Ex. Ki No. Structure (nM) 1H NMR Chiral o CH 3
    CH
    3 NN N 1H NMR (400 MHz, MeOD) d ppm 1.17 (s, 2 H) 1.41 (s, 1 H) 1.60 - 1.82 (m, 6 H) 2.14 (s, 2 H) N-./'CH N 2.26 (s, 2 H) 2.66 (s, 2 H) 2.92 - 3.05 (m, 1 H) A43 N 135 3.12 - 3.27 (m, 2 H) 3.34 - 3.43 (m, 1 H) 3.48 [S 3.64 (m, 1 H) 3.76 (d, J=53.56 Hz, 1 H) 4.59 0 4.79 (m, 2 H) 7.45 (s, 2 H) 8.53 (s, 1 H) 9.03 (s, 1 N-(6,6-diinethyl-5-((3S,8aS)-3-methyl- H). octahydropyrrolo[1 ,2-a]pyrazine-2-carbonyl) 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3 yl)thiazole-5-carboxamide Chiral o
    CH
    3 CH, N N NN 1H NMR (400 MHz, MeOD) d ppm 1.34 (d, J=6.82 N CH 3 S Hz, 3 H) 1.73 (d, J=15.92 Hz, 6 H) 1.81 - 2.02 (m, A44 N N43.5 3 H) 2.24 - 2.46 (m, 1 H) 2.58 (s, 1 H) 2.86 - 3.21 (m, 4 H) 3.48 (d, J=12.38 Hz, 1 H) 3.95 (s, 1 H) N-(6,6-dimethyl-5-((3S,8aS)-3-methyl- 4.58 (s, 5 H) 8.42 (s, 1 H) 9.08 (s, 1 H). octahydropyrrolo[1,2-a]pyrazine-2-carbonyl) 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3 yl)thiazole-4-carboxamide Chiral o CH CH, N "N N N 1H NMR (400 MHz, DMSO-d6) d ppm 1.06 (d, N CH 3 J=5.81 Hz, 2 H) 1.33 (d, J=7.07 Hz, 1 H) 1.55 A45 N _0 104 1.73 (m, 6 H) 1.84 - 2.23 (m, 4 H) 2.94 - 3.49 (m, o F8 H) 4.46 - 4.75 (m, 2 H) 7.50 - 7.75 (m, 2 H) 7.86 F - 8.12 (m, 2 H) 11.22 (s, 1 H). N-(6,6-dimethyl-5-((3S,8aS)-3-methyl octahydropyrrolo[1,2-a]pyrazine-2-carbonyl) 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-y)-3 (trifluoromethoxy)benzamide CH 3 N 1 H NMR (400 MHz, DMSO-d6) d ppm 1.05 (d, N / %J=5.81 Hz, 3 H) 1.17 (s, 1 H) 1.24 (d, J=6.32 Hz, N 3 H) 1.60 (s, 3 H) 1.68 (s, 3 H) 2.65 (t, J=11.62 SN362 Hz, 1 H) 2.75 - 2.91 (m, 1 H) 3.18 - 3.38 (m, 3 H) CH 3 N 4.73 (d, J=7.58 Hz, 2 H) 7.63 - 7.75 (m, J=1.77 o Hz, 1 H) 8.08 (d, J=6.32 Hz, 1 H) 8.15 (d, 1 H) 8.72 (s, 1 H) 8.86- 9.06 (in, 1 H) 9.34 (s, 1 H) N-(5-(2,5-dimethylpiperazine-1 -carbonyl)-6,6- 10.79 (s, 1 H). dimethyl-1,4,5,6-tetrahydropyrrolo[3,4 clpyrazol-3-yl)picolinamide N N O H 3 1 H NMR (400 MHz, DMSO-d6) d ppm 0.93 - 1.19 N0 N (m, 3H) 1.57 -1.74 (m, 6H) 1.84 -2.21 (m, 4H) A47 IN065.5 3.02 - 3.77 (in, 8 H) 3.85 - 3.98 (in, 3 H) 4.55 CH3 4.77 (in, 2 H) 7.18 -7.35 (in, 1 H) 7.53 -7.72 (in, N-(6,6-dimethyl-5-((3S,8aS)-3-methyl octahydropyrrolo[1,2-a]pyrazine-2-carbonyl) 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-5 methoxypicolinamide WO 2008/125945 PCT/IB2008/000862 - 65 PKCb Ex. Ki No. Structure (nM) 1H NMR C
    CH
    3 N, C hiral N N N N 1 H NMR (400 MHz, DMSO-d6) d ppm 0.85 - 1.14 A48 NN 0 688 2.86- 3.14 (m, 3 H) 3.26-3.74 (, 5 H) 3.89
    OH
    3 4.00 (in, 3 H) 4.00 -4.16 (in, 1 H) 4.49 -4.69 (in, cl 2 H) 7.43-7.61 (i, 2 H) 7.76 (s, 1 H) 11.15 (s, 2 4-chloro-N-(6,6-dimethyl-5-((3S,8aS)-3-methyl- H). octahydropyrrolo[1,2-a]pyrazine-2-carbonyl) 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-3 methoxybenzamide CH CH3 N Chiral O N N IN 1 H NMR (400 MHz, DMSO-d6) d ppm 0.91 - 1.18
    >CH
    3 a(in, 3 H) 1.56 -1.67 (in, 6 H) 1.79 -2.08 (in, 4 H) A49 NN 53.6 2.88-3.15 (m,3H) 3.17-3.72 (m H) 4.34 - 4.71 (in, 2 H) 7.35 - 7.64 (in, 1 H) 7.88 - 8.00 (in, F 1 H)8.11 -8.26 (i, 1 H) 11.13 (s, 1 H) 11.25 (s, 1 3-chloro-N-(6,6-dimethyl-5-((3S,8aS)-3-methyl- H). octahydropyrrolo[1,2-a]pyrazine-2-carbonyl) 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-y)-4 _____fluorobenzamide CH C3N Chiral N 1H NMR (400 MHz, DMSO-d6) d ppm 0.99 (d, ~-N~. 0 N J=5.81 Hz, 3 H) 1.08 - 1.23 (in, 6 H) 1.43 -1.70 (m, 4 H) 1.96 - 2.10 (m, 3 H) 2.60 - 2.74 (m, 2 H) A50 N- 82.1 2.81 - 3.10 (m, 4 H) 3.23 - 3.76 (m, 4 H) 4.45 4.76 (m, 2 H) 7.45 - 7.56 (m, 1 H) 7.89 - 8.03 (m, 2H 3 1 H) 8.55 (d, J=5.05 Hz, 1 H) 10.51 - 10.91 (s, 1 N-(6,6-diinethyl-5-((3S,8aS)-3-ethyl- H). octahydropyrrolo[1 ,2-a]pyrazine-2-carbony) 1 ,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-y)-5 ethylpicolinainide Chiral o OH -H 3 -N N OH 3 1H NMR (400 MHz, MeOD) d ppm 1.21 (d, J6.06 N Hz, 3 H) 1.46 (d, J=7.83 Hz, 1 H) 1.73 (s, 2 H) CN OH 3 .- N1.75 (d, J=8.34 Hz, 3 H) 1.81 (s, 3 H) 2.05 -2.22 A51 N '.20.9 (in, 1 H) 2.21 - 2.35 (in, 2 H) 2.44 (s, 3 H) 2.60 (s, 5N H 3 3 H) 3.11 - 3.27 (7, J=3.54 Hz, 1 H) 3.36 - 3.50 0 (m, 2 H) 3.50 - 3.68 (m, 2 H) 3.82 - 3.99 (m, 1 H) N-(6,6-dimethyl-5-((3S,8aS)-3-methyl- 4.90 (s, 2 H) 7.36 (s, 1 H) 7.82 (s, 1 H). octahydropyrrolo[1 ,2-a]pyrazine-2-carbonyl) 1 ,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yI) 4,6-dimethylpicolinamide I I WO 2008/125945 PCT/IB2008/000862 - 66 PKCb Ex. Ki No. Structure (nM) 1H NMR Chiral O CH, CH 3 N N HN N CH, N H, N N OH1H NMR (400 MHz, MeOD) d ppm 1.10 - 1.22 (i, CN OH, -C 3 H)1.35 -1.46 (m, 2H) 1.64 -1.82 (m, 6H) 2.03 A52 N NNCH3 149 -2.15 (, 2 H) 2.18-2.25 (i, 2 H) 3.01 -3.13 (i, 3 H) 3.29 - 3.43 (in, 2 H) 3.44 - 3.65 (in, 3 H) 3.82 0 - 3.90 (, 6 H) 4.72 (s, 2 H) 6.55 (s, 1 H). N-(6,6-dimethyl-5-((3S,8aS)-3-methyl octahydropyrrolo[1,2-a]pyrazine-2-carbonyl) 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl) 1,5-dimethyl-1 H-pyrazole-3-carboxamide CH 0C a N Chiral ~N '/ 0 1 H NMR (400 MHz, DMSO-d6) d ppm 0.99 -1.16 NC, N-J (in, 3 H) 1. 16 - 1.32 (in, 6 H) 1. 50 - 1.82 (in, 2 H) A5 N'N' 66.3 1.85 -2.06 (in, 2 H) 2.07 -2.19 (in, 3 H) 2.62 A53 H 2.84 (m, 2 H) 2.86C-H3.15 (, 4 H) 3.36-3.63 (m, 2 H) 3.98 -4.13 (m, 2H) 7.81 - 7.98 (m, 1 H) 8.04 N-(6,6-dimethyl-5-((3S,8aS)-3-methyl- -8.16 (i, 1 H) 8.61 (d, J=1.52 Hz, 1 H). octahydropyrrolo[1,2-a]pyrazine-2-carbonyl) 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-y)-4 ethylpicolinamide
    CH
    3 Chiral 0 N_ N
    OH
    3 ra S 1 H NMR (400 MHz, DMSO-d6) d ppm 0.98 - 1.11 NICH (m,3 H) 1.17- 1.40 (m, 2H) 1.61 - 1.78 (mn,2 H) A54 N C 49.9 1.84-2.09(m,6H)2.83-3.18(m,4H)3.42 -~ 3.63 (in, 4 H) 5.18 -5.46 (in, 2 H) 7.44 -7.77 (in, N-(66-diethy-5-(3SaS)--metyl-2 H) 7.94 -8.37 (in, 2 H) 10.64 -11.47 (in, 2 H). N-(6,6-dimnethyl-5-((3S,8aS)-3-mnethyl octahydropyrrolo[1,2-a]pyrazine-2-carbonyl) 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3 yl)benzo[d]thiazole-2-carboxamide Chiral N N H1H NMR (400 MHz, DMSO-d6) d ppm 0.80 - 0.92 N CL. N OH 3 (in, I H) 1.00 -1.14 (m, 2 H) 1.15 -1.39 (m, 9 H) A N 177 1.50 (s, 2 H) 1.57 - 1.85 (m, 2 H) 1.86 - 2.09 (m,2 H) 2.83 - 3.22 (m, 4 H) 3.33 - 3.76 (m, 2 H) 3.96 4.29 (m, 3 H) 4.37-4.80 ( , 2 H) 5.24 (s, 1 H) 0 5.30- 5.81 (, 1 H) 7.51 - 7.83 (m, 1 H). N-(6,6-diNMethyl-5-((3S,8aS)-3-M-ethyl octahydropyrrolo[1 ,2-a]pyrazine-2-carbonyl) 1(,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-ym)-4 _____ sopropylthiazole-2-carboxainide____ Chiral IN OH 3 N N H 3 A55N0 N N 1 H NMR (500 MHz, D20) d ppm 0.84 (s, 2 H) e1N - 1.09 (s, 2H) 1.38 (s, 1 H) 1.57 (s, 9H) 1.62 (s, 9 A56 18.1 H) 1.78 (s, 2 H) 2.06 (s, 3 H) 3.03 (s, 2 H) 3.74 (s, 1 H) 4.01 (s, 1 H) 4.65 (s, 1 H) 7.65 (s, 1 H) 8.07 N-(5-((3S,8aS)-3-(cyclohexylmethyl)- (s, 3 H) 8.69 (s, 1 H) 10.77 (d, J=2.75 Hz, 1 H). octahydropyrrolo[1,2-a]pyrazine-2-carbonyl) 6,6-dimethy1-1 4,5,6-tetrahydropyrrolo[3,4 i]pyrazol-3-yI)icoxinamide WO 2008/125945 PCT/IB2008/000862 - 67 PKCb Ex. Ki No. Structure (nM) 1H NMR N CH 3 Chiral N C O 0 C N N C
    CH
    3 1 H NMR (500 MHz, 020) d ppm 1.21 (s, 4 H) A57_e 1.N87. (s, 5H) 1.55 (s, 5H) 1.63 (s, 5H) 2.09 (s, 3 A57 N87.4 H) 3.01 (s, 2 H) 3.35 (s, 1 H) 4.59 (s, 2 H) 7.50 (s, (S)--chlro-N(5-3,3-imetyl-1 H) 7.96 (s, 1 H) 9.70 (s, 1 H) 11.00 (s, 1 H). (S)-3-chloro-N-(5-(3,3-dimethyl octahydropyrrolo[1,2-a]pyrazine-2-carbonyl) 6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yl)benzamide Chiral o CH CH3 )-N N CH N % 1 H NMR (400 MHz, DMSO-d 6 ) d ppm 1.05 (d, CHN CN CH, N J=6.06 Hz, 3 H) 1. 13 - 1.30 (in, 2 H) 1.54 -1.78 A58 N N )Cl 35.3 (m,6H) 1.86-2.02 (m,2H) 2.62 (s,3H) 2.95 3.20 (in, 6 H) 3.95 -4.15 (in, 2 H) 4.53 -4.77 (in, o 2 H) 7.91 -8.17 (i, 1 H) 10.97 (s, 2 H). 2-chloro-N-(6,6-dimethyl-5-((3S,8aS)-3-methyl octahydropyrrolo[1,2-a]pyrazine-2-carbonyl) 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yI)-6 methylpyrimidine-4-carboxamide Chiral o CH CH3 N -N N 0' =6.06 Hz, 3 H) 1. 17 -1.31 (,J75,7.58 Hz, 2 %'/ HNR(0 ~,DS-6 (i, J .5 (d N N O'H C( CH, N ' N H) 1.38 -1.46 (m, J=4.29 Hz, 1 H) 1.61 (s, 3H) A59 N CH 3 N N OCH, 1.69 (s, 3 H) 1.84 - 1.98 (m, J=7.58 Hz, 1 H) 2.02 N 0 - 2.21 (in, 2 H) 2.98 -3.13 (mn, 2 H) 3.38 -3.50 (in, 0 ~2 H) 3.64 (d, J=57.35 Hz, 2 H) 3.98 (s, 3 H) 4.06 N-(6,6-dimethyl-5-((3S,8aS)-3-methyl- (s, 3 H) 4.54-4.74 (i, 2 H) 7.05 (s, 1 H) 10.72 (s, octahydropyrrolo[1,2-a]pyrazine-2-carbonyl)- 1 H). 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl) 2,6-dimethoxypyrimidine-4-carboxamide Chiral o N-N
    CH
    3 N W /- CH~1H NMR (400 MHz, DMSO-d6) d ppm 0.90 - 1.30 N87~'N-~(i, 4 H) 1.40 - 1.67 (, J=22.74 Hz, 6 H) 1.61 - )32.15 (s, 6 H) 2.67-3.14 ( , J54.06 Hz, 3 H) A60 17.1 3.33- 3.87 (, 3 H) 4.55 (s, 2 H) 7.65 (t, J7.71 N CH, Hz, 1 H) 7.98 (d, J7.58 Hz, 1 H) 8.20 (d, J7.58 3-cyano-N-(6,6-dii3ethyl-5-((3S,8aS)-3-methyl- Hz, 1 H) .8.35 (s, 1 H) 11. 11 (s, H) 12.47 (s, 1 octahydropyrrolo[1,,2-a]pyrazine-2-carbonyl)- H). 12,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3 yI)benzamide ____ WO 2008/125945 PCT/IB2008/000862 - 68 PKCb Ex. Ki No. Structure (nM) 1H NMR S CH 3 N, O OH N r N' Chiral N N CH 3 / H NMR (400 MHz, DMSO-d6) d ppm 1.11 -1.38 -(m, 7H) 1.51 -16 m )16 .7(,6H A61 (N 23.8 2.61 - 3.03 (i, 5 H) 3.83 (s, 1 H) 4.56 (s, 2 H) CH,7.33 (s, 2 H) 7.91 (d, J=7.58 Hz, 2 H) 10.80 (s, 1 N-(6,6-dimethyl-5-((3S,8aS)-3-methyl octahydropyrrolo[1,2-a]pyrazine-2-carbonyl) 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-y)-4 ethylbenzamide Chiral O N 0 A62 NN CH3 CH ,N Chira N N1 H NMR (500 MHz, D20) d ppm 1.04 (s, 2 H) N CH - I-131.20 (s, 2 H) 1.56 (s, 4 H) 1.58 - 1.66 (in, 6 H) A62 / O 3 50.8 1.83 (s, 2 H) 2.01 (s, 2 H) 2.24 (s, 5 H) 3.41 (s, 1 clmF H) 4.55 (s, 2 H) 7.21 (s, 1 H) 7.80 (s, 1 H) 7.90 (s, N-(6,6-dimethyl-5-((3S,8aS)-3-methyl- 1 H) 10.83 (s, 1 H). octahydropyrrolo[1,2-a]pyrazine-2-carbonyl) 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-y)-4 fluoro-3-methylbenzamide Chiral CH HN N 1 H NMR (400 MHz, DMSO-d6) d ppm 1.22 (d, O N 0 J=6.57 Hz, 3 H) 1.26 - 1.36 (mn, J=10.61, 6.57 Hz,
    O
    3 N F1 H) 1.62 (d, J=1 3.64 Hz, 6 H) 1.66 - 1.76 (mn, 3 A63 N /3 F 65.4 H) 1.80 -1.88 (m, 1 H) 1.91 - 2.02 (m, 1 H) 2.20 A63(dd, J=10.48, 3.16 Hz, 1 H) 2.67-2.84 (, 2 H) 2.89 - 3.00 (in, 1 H) 3.83 (s, 1 H) 4.34 - 4.67 (in, 2 N-(6,6-dimethyl-5-((3S,8aS)-3-methyl- H) 7.16 - 7.36 (m, 1 H) 7.46 (s, 1 H) 7.61 (s, 1 H) octahydropyrrolo[1,2-a]pyrazine-2-carbonyl)- 11.07 (s, 1 H). 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl) 2,3-difluorobenzamide Chiral 0C-4 N NH N- 1H NMR (400 MHz, DMSO-d6) d ppm 1.10 (s, 5 (N, 7 H) 1.39-1.91 (m, 13 H) 2.99 -3.18 (m, 1 H)4.04 15.9 (q, J=5.31 Hz, 3 H) 4.33 - 4.74 (, J=8.72, 8.72 o Hz, 4 H) 7.83 (s, 2 H) 10.60 (s, 1 H) 12.33 (s, 1 N-(6,6-dimethy1-5-((3S,8aS)-3-H1ethyl- H). octahydropyrrolo[1 ,2-a]pyrazine-2-carbonyl) 1 ,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yI) 2,3-dihydrobenzofuran-5-carboxamide ____ Chiral 0 OH N N N 1H NMR (400 MHz, DMSO-d6) d ppm 0.95- 1.28 . (m,3 H) 1.54 (s, 6 H) 1.68 - 2.03 (m, 4 H) 2.20 A65 N /3 OCH 3 54.5 2.37 (-, 3 H) 2.79 - 3.64 (s, 8 H) 4.3 (s, 2 H) 7.32 (s, 2 H) 7.73 (d, J15.41 Hz, 2 H) 10.78 (s, 2 N-(6,6-dimethyl-5-((3S,8aS)-3-methyl- H) 12.40 (s, 1 H). octahydropyrrolo[1,2-a]pyrazine-2-carbonyl) 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-y)-3 2,3-dhydrmethylbenzamiderboxa WO 2008/125945 PCT/IB2008/000862 -69 PKCb Ex. Ki No. Structure 1(nM) H NMR Chiral CH H 3 N OH1N 1H NMR (400 MHz, DMSO-d6) d ppm 1.18- 1.26 (m, J=6.57, 6.57 Hz, 3 H) 1.25 - 1.33 (m, 1 H) 1.55 - 1.64 (m, J=13.39 Hz, 6 H) 1.74 (d, J=5.05 A66 6 N 122 Hz, 3 H) 1.79 - 2.06 (m, 4 H) 2.20 (dd, J=10.48, N 3.41 Hz, 1 H) 2.62 - 2.96 (m, 4 H) 3.83 (s, 1 H) 4.56 (s, 2 H) 7.82 (s, 2 H) 8.02 (d, J=9.35 Hz, 1 H) N 11.20 (s, 1 H) 12.49 (s, 1 H). 4-cyano-N-(6,6-dimethyl-5-((3S,8aS)-3-nethyl octahydropyrroloji ,2-a]pyrazine-2-carbonyl) 1 ,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-y)-2 fluorobenzamide Chiral A6 CH 3 N 5 o -,1H NMR (400 MHz, DMSO-d6) d ppm 1.14- 1.36 Nt 0(in, 4 H) 1.47 -1.80 (in, 9 H) 1.80 - 2.03 (in, 3 H) A6 rC 3 N 24 2.22 (dd, J=10 0 61, 3.28 Hz, 1 H) 2.69 - 2.85 (in,2 N6 NH 2. H) 2.87 - 3.01 (in, 1 H) 3.85 (s, 1 H) 4.42 - 4.71 C N(in, 2 H) 8.00 - 8.34 (in, 2 H) 8.80 (s, 1 H) 12.24 CI (d, J=211.96 Hz, 1 H). 5-chloro-N-(6,6-dimethyl-5-((3S,8aS)-3-methy octahydropyrrolo[1,2-a]pyrazine-2-carbonyl) 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3 yl)picolinamide Chiral N CH 3 ON NC O CH IN N 1 H NMR (500 MHz, D20) d ppm 1.09 (s, 2 H) A68 l- N21.3 1.54 -1.63 (in, 14 H) 1.84 (s, 2 H) 1.99 (s, 2 H) A68 C N 21. Oi 4.56 (s, 2 H) 4.61 (s, 1 H) 7.80 (s, 2 H) 8.07 (s, 1 H) 8.67 (s, 2 H). 4-chloro-N-(6,6-dimethyl-5-((3S,8aS)-3-methyl octahydropyrrolo[1,2-a]pyrazine-2-carbonyl) 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3 yl)picolinamide Chiral O N NN N 1H NMR (500 MHz, DMSO-d6) d ppm 0.77 -13 J=7.55 Hz, 1 H) 0.85 (t, J=7.42 Hz, 3 H) 1.26 (d, N J=10.99 Hz, 1 H) 1.58 (s, 4 H) 1.62 - 1.69 (m, 6 H) N 1.72 (d, J=7.42 Hz, 2 H) 1.79 (s, 1 H) 1.90 (s, 1 H) A69 67.8 1.97 (d, J=8.79 Hz, H) 2.18 (d, J3.57 Hz, 1 H) rCH N 3 2.70 - 2.79 (m, 2 H) 2.90 (d, J2 10.99 Hz, 2 H) 3.60 (s, 1 H) 4.43 (s, 1 H) 4.59 (s, 1 H) 7.51 (d, J=7.14 Hz, 2 H) 7.57 (s, 1 H) 7.98 (d, J7.69 Hz, N-(5-((3S,8aS)-3-ethyl-octahydropyrrolo[1 ,2- 2 H). a]pyrazine-2-carbony3)-6,6-dimethyl-14,5,6 tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzamide WO 2008/125945 PCT/IB2008/000862 - 70 PKCb Ex. Ki No. Structure (nM) IH NMR Chiral O N H3 N 0 'No -4/ IH NMR (400 MHz, CD3OD) d ppm 0.96 (t, N J=7.43 Hz, 3 H) 1.12 -1.22 (in, 1 H) 1.34- 1.49 N ~~(m, 1 H) 1.65 -2.02 (m, 11 H) 2.04 -2.16 (m, 1 H) A7c C1 3 7Nb6. 2.38 (dd, J=10. 95, 3.90 Hz, 1 H) 2.90 - 3.08 (in, 3 A70 NN.C N H) 3.47 - 3.57 (in, 1 H) 3.72 - 3.81 (in, 1 H) 4.57 4.67 (in, 1 H) 4.79 - 4.86 (in, 1 H) 7.63 (dd, J=7.55, 4.78 Hz, 1 H) 7.96 - 8.09 (in, 1 H) 8.21 (d, N-(5-((3S,8aS)-3-ethyl-octahydropyrrolo[1,2- J=7.55 Hz, 1 H) 8.71 (d, J=4.78 Hz, 1 H). a]pyrazine-2-carbonyl)-6,6-dimethyl-1,4,5,6 tetrahydropyrrolo[3,4-c]pyrazol-3 yl)picolinamide CH H3 NChiral 0 N N, I 1H NMR (400 MHz, CD3OD) dppm 0.95 (t, N N J=7.43 Hz, 3 H) 1.33 - 1.49 (in, 1 H) 1.65 -2.02 (in, 12 H) 2.11 (q,J=8.81 Hz, 1 H) 2.37 (dd, A7 C 3 J=1 1.20, 3.90 Hz, 1 H) 2.89 - 3.07 (in, 3 H) 3.47 A1N_ CpC 4. 3.56 (in, 1 H) 3.66 - 3.82 (in, 1 H) 4.48 - 4.60 (in, CI 1 H) 4.72 - 4.82 (in, 1 H) 7.52 (t, J=7.93 Hz, 1 H) 7.62 (d, J=7.93 Hz, 1 H) 7.89 (d, J=7.93 Hz, 1 H) 3-chloro-N-(5-((3S,8aS)-3-ethyl- 7.98 (s, 1 H). octahydropyrrolo[1,2-a]pyrazine-2-carbonyl) 6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yl)benzamide Chiral A72 CHC) F 1 H NMR (500 MHz, DMSO-d6) d ppm 0.85 (t, N J=7.42 Hz, 3 H) 1.26 (d, J10.16 Hz, 1 H) 1.57 (S F 3 H) 1.64 - 1.73 (m, 7 H) 1.88 (s, 2 H) 1.96 (d, A72 N4 3 105 J=8.79 Hz, 1 H) 2.18 (dd, J=10.71, 3.30 Hz, 1 H) H 2.7 - 2.79 (m, 2 H) 2.90 (d, J10.71 Hz, 3 H) 2.99 (s, 1 H) 3.40 (s, 1 H) 4.43 (d, J=12.64 Hz, 1 H)=4.61(,5 =6 Hz, 1 H) 7. 1 ( q, J=4.78 Hz, 2 N-(5-((3S,8aS)-3-ethyl-octahydropyrrolo[1,2- H) 7.57 (d, J=2. Hz, 1 H) 1 (, 1.37 H),. a]pyrazine-2-carbonyl)-6,6-dimethyl-17. (d, J=. Hz, 1 H) 7. (, H tetra hyd ropy rrolo[3,4-c] pyrazol-3-yI)-2 fluorobenzamide ______________________ Chiral CF7.
    (
    3 N 1 H NMR (500 MHz, DMSO-d6) d ppm 0.85 (t, J=7.42 Hz, 3 H) 1.27 (s, 1 H) 1.58 (s, 4 H) 1.62 N 7 1.69 (, 6 H) 1.72 (d, J7.14 Hz, 2 H) 1.79 (s, 1 53 H) 1.90 (s, 2 H) 1.97 (d, J=8.52 Hz, I H) 2.19 (d, .0 J=10.71 Hz, 1 H) 2.90 (d, J=10.99 Hz, 2 H) 3.59 . (s, 2 H) 4.43 (s, 1 H) 4.60 (d, J=12.91 Hz, 1 H) F 7.29 - 7.37 ( , 2 H) 8.06 (dd, J=8.24, 5.49 Hz, 2 N-(5-((3S,8aS)-3-ethyl-octahydropyrrolo[1 ,2- H). a]pyrazine-2-carbonyl)-6,6-dinethy-1,4,5,6 tetra hyd ro pyrro lo [3,4-c] pyrazol-3-yI)-4 fluorobenzamide WO 2008/125945 PCT/IB2008/000862 - 71 PKCb Ex. Ki No. Structure (nM) IH NMR Chiral o CH CH, (N N N CI 1 H NMR (400 MHz, DMSO-d 6 ) d ppm 1.21 (d, nl NJ=6.57 Hz, 3H) 1.24-1.36(in,l1H) 1.57 (s, 3H) CN Z CH3 S 1.61 (s, 3H) 1.63 -1.77 (m, 2H) 1.84 (s, 1 H) A74 N N 10.4 1.98(d,J=7.83Hz, 1 H)2.21 (d,J=8.34Hz, 1 H) 2.70 - 2.85 (in, 2 H) 2.92 (t, J=7.71 Hz, 1 H) 3.27 0 3.44 (mn, 2 H) 3.75 - 3.88 (in, 1 H) 4.37 - 4.60 (in, 4,5-dichloro-N-(6,6-dimethyl-5-((3S,8aS)-3- 2 H). methyl-octahydropyrrolo[1,2-a]pyrazine-2 carbonyl)-1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yl)thiazole-2-carboxamide Chiral 0 CHCH 3 1 H NMR (400 MHz, DMSO-d 6 ) d ppm 1.03 -1.16 NN C/- H- ( n, 1 H) 1.23 (d, J=6.57 Hz, 3 H) 1.30 (dd, N -3 N J=0.9 6.44 Hz, 1 H) 1.59 (s, 3 H) 1.63 (s, 3 H) OCH Ha N 6 A75 N N 56.9 1569 -1.77 (m,3H)1.80-1.89 (m, J=9.09 Hz, 1 N CH 3 H)1.93-2.04 (m, 1 H) 2.19-2.27 (, 1 H)2.55 0 (s, 3 H) 2.71 (s, 3 H) 2.74 -2.84 (in, 2 H) 2.93 (t, N-(6,6-dimethyl-5-((3S,8aS)-3-methyl- J=7.71 Hz, 1 H) 3.83 (s, 1 H) 4.46 - 4.70 (i, 2 H) octahydropyrrolo[1,2-a]pyrazine-2-carbonyl)- 7.84 (s, 1 H). 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl) 2,6-di methylpyri midine-4-carboxa mide Chiral O CHCH 1 H NMR (400 MHz, DMSO-d) d ppm 1.24 (d, )N N J=6.57 Hz, 3 H) 1.25 - 1.39 (in, J=1 6.67 Hz, 1 H) I 1.58 (s, 3H) 1.62 (s, 3H) 1.64 -1.76 (m, 2H) N CH 3 N_ N 1.80-1.88(m, 1 H)1.98(q,J8.59Hz, 1 H)2.22 A76 N 13.9 (dd, J=10.48, 3.41 Hz, 1 H) 2.45-2.57 (m, 2 H) 2.72 -2.84 (in, 2 H) 2.93 (t, J=7.71 Hz, 1 H) 3.85 0 (d, J=7.07 Hz, 1 H) 4.46 - 4.74 (in, 2 H) 6.85 (d, N-(6,6-dimethyl-5-((3S,8aS)-3-methyl- J=3.28 Hz, 1 H) 7.06 (t, J=3.16 Hz, 1 H) 7.90 (s, 1 octahydropyrrolo[1,2-a]pyrazine-2-carbonyl)- H) 8.24 (s, 1 H) 9.29 (s, 1 H). 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)H pyrrolo[1,2-f]pyrimidine-3-carboxamide O 3 N Chiral N jN 1 H NMR (400 MHz, DMSO-d6) d ppm 0.96 (d, .J=5.81 Hz, 3 H) 1.19 - 1.34 (m, 1 H) 1.58 (s, 3 H) N N 1.60-1.66 ( , 1 H) 1.67 (s, 3 H) 1.69-1.80 (in, 2
    CH
    3 O1. H) 1.97-2.12 (in, 2 H) 2.34 (t, J=10.48 Hz, 1 H) A77 UN 77.8 2.90 - 3.05 (m, 3 H) 3.19-3.25 (in, 1 H) 3.27 3.41 (m, 1 H) 4.66 (q, 2 H) 7.65- 7.72 (, 1 H) 8.02-8.10 (in, 1 H) 8.16 (d, 1 H) 8.72 (d, J=4.55 N-(6,6-dimethyl-5-((3S,8aR)-3-iJethyl- Hz, 1 H) 10.12 11.38 (, 1 H) 11.50 - 12.80 (m, octahydropyrrolofI7,2-a]pyrazine-2-carbonyl)- 1 H). 1 ,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3 yI)picolinamide ____ ______________________ WO 2008/125945 PCT/IB2008/000862 -72 PKCb Ex. Ki No. Structure 1H NMR CH3 C h ira l N OO N N 1H NMR (500 MHz, D20) d ppm 1.57 (s, 7 H) f ~ 1.62 (s, 2 H) 1.73 (s, 2 H) 1.83 (s, 1 H) 2.'01 (s, 2 A78 N N 165 H) 3.56 (s, 1 H) 3.70 (s, 1 H) 3.78 (s, 1 H) 4.54 (s, 2 H) 4.66 (s, 2 H) 7.65 (s, 2 H) 8.03 (s, 4 H) 8.69 N-(5-((3R,8aS)-3-(hydroxymethyl)- (s, 2 H) 10.36 (s, 1 H) 11.23 (s, 1 H). octahydropyrrolo[1,2-a]pyrazine-2-carbonyl) 6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yl)picolinamide
    CH
    3 O NO A7 CH N N /- 0 N N 1 H NMR (500 MHz, D20) d ppm 0.90 (s, 5 H) 1.48 A79 H 3 )-79.6 (s, 1 H) 1.61 (s, 11 H) 1.90 (s, 1 H) 2.83 (s, 3H) N N 4.60 (s, 2 H) 7.65 (s, 2 H) 8.04 (s, 2 H) 8.10 (s,1 N3 H) 8.69 (s, 2H).
    CH
    3 N-(5-(2-ethyl-1 -methylpiperazine-4-carbonyl) 6,6-dimethyl- 1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yl)picolinamide CH Chiral N N 3 OH N N- O 3 01H NMR (500 MHz, 020) d ppm 0.81 (s, 10 H) e1 N C~O _H3 19 1.10 (s, 2 H) 1.29 (s, 1 H) 1.59 (s, 8 H) 1.65 (s, 4 /8 2 H) 1.92 (s, 2 H) 4.65 (s, 2 H) 7.65 (s, 2 H) 8.04 (s, 2 H) 8.11 (s, 1 H) 8.68 (s, 1 H). N-(5-((3S,8aR)-3-((S)-sec-butyl) octahydropyrrolo[1,2-a]pyrazine-2-carbonyl) 6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yl)picolinamide N CH 3 Chiral N C/ O N-_ N N 3CH, N NJ CH,1H NMR (500 MHz, D20) d ppm 1.12 (s, 3 H) A81 N N125 1.19 (s, 2 H) 1.36 (s, 4 H) 1.54 (s, 5 H) 1.59 (s, 7 l"/ H) 1.92 (s, 1 H) 2.94 (s, 1 H) 4.59 (s, 3 H) 7.65 (s, 2 H) 8.04 (s, 2H) 8.11 (s, 1 H) 8.68 (s, 1 H). (S)-N-(5-(3,3-dimethyl-octahydropyrrolo[1,2 a]pyrazine-2-carbonyl)-6,6-dimethyl-1,4,5,6 tetrahydropyrrolo[3,4-c]pyrazol-3 yl)picolinamide N CH 3 Chiral N
    OCH
    3 0 N 3N N N CH 31 H NMR (500 MHz, D20) d ppm 1.00 (s, 4 H) A82 N N818 1.12 (s, 17 H) 1.52 (s, 2 H) 1.57 (s, 2 H) 1.61 (s, 2 / NH) 1.65 (s, 3 H) 3.84 (s, 1 H) 4.48 (s, 1 H) 4.70 (s, 1 H) 7.65 (s, 1 H) 8.06 (s, 3 H) 8.69 (s, 1 H). N-(5-((3R,8aS)-3-((R)-1 -tert-butoxyethyl) octahydropyrrolo[1,2-a]pyrazine-2-carbonyl) 6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yI)picolinamide ______________________ WO 2008/125945 PCT/IB2008/000862 -73 PKCb Ex. Ki No. Structure 1H NMR Chiral CH3 H CH N
    H
    3 N -N N O N N 1 H NMR (500 MHz,D 2 O) d ppm 0.85 (s, 5 H) 1.00 A.5 HN(d, J=5.49 Hz, 5 H) 1.59 (d, J=14.28 Hz, 10 H) A83 CH, N 9.5 1.65 (s, 4 H) 4.63 (s, 3 H) 7.65 (s, 2 H) 8.04 (s, 2 0 /H) 8.10 (s, 2 H) 8.68 (s, 2 H). N-(5-((2R,5S)-2-(2-hydroxyethyl)-5-methyl-1 propylpiperazine-4-carbonyl)-6,6-dimethyl 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3 yl)picolinamide CH N 3 H Chiral N N- ( ' CH 3 N CH3 NOH, 1 H NMR (500 MHz, D20) d ppm 0.79 (d, J=6.59 A84N Hz, 8 H) 1.06 (s, 1 H) 1.48 (s, 3 H) 1.57 (s, 6 H) A84N 139 1.64 (s, 2 H) 2.01 (s, 2 H) 4.13 (s, 1 H) 4.34 (s, 1 H) 4.66 (s, 2 H) 7.65 (s, 2 H) 8.03 (s, 2 H) 8.10 (s, 0 2 H) 8.68 (s, 2 H) 10.33 (s, 1 H). N-(5-((3S,7R,8aS)-3-((S)-sec-butyl)-7-hydroxy octahydropyrrolo[1,2-a]pyrazine-2-carbonyl) 6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yl)picolinamide OH N 30 X N Ohiral N H O H 3 1 H NMR (400 MHz, DMSO-d6) d ppm 1.23 (d, A85 ' 152 H) 1.90-2.02 (i, 1 H) 2.21 (dd, J=10.61,3.28 N Hz, 1 H) 2.67 - 2.82 (in, 2 H) 2.92 (t, 1 H) 3.83 (d, J=8.59 Hz, 1 H) 4.48 -4.66 (i, 2 H) 8.37 (d, 0 J=8.59 Hz, I H) 8.79 (dd, J=8.59, 2.53 Hz, 1 H) N-(6,6-dimethyl-5-((3S,8aS)-3-methyl- 9.44 (d, J=2.53 Hz, 1 H). octahydropyrrolo[1,2-a]pyrazine-2-carbonyl) 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-y)-5 nitropicolinamide CH 3 N OON Chiral 0 N 3 N 1 H NMR (400 MHz, DMSO-d6) d ppm 1.23 (d, J=6.57 Hz, 3 H) 1.30 (dd, J=10.61, 6.57 Hz, 1 H) 0,, I1 F N 1.60 (s, 3H) 1.63 (s, 3H) 1.68 -1.77 (m, 3H) A86 1.80- 1.88 (, 1 H) 1.95 -2.04 (, 1 H) 2.22 (dd, A86 74. 10.61, 3.54 Hz, 1 H) 2.68 -2.85 (in, 2 H) 2.85 F 3.01 (in, 1 H) 3.70 - 3.90 (in, 1 H) 4.41 - 4.69 (in, 2 H) 8.03 - 8.28 (in, 1 H) 8.65 (d, J=1.77 Hz, I H) N-(6,6-dimethyl-5-((3S,8aS)-3-methyl- 10.86 (s, 1 H) 11.98-12.37 (i, 1 H). octahydropyrrolo[1,2-a]pyrazine-2-carbonyl) 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl) _____3,5-difluoropicolinamide WO 2008/125945 PCT/IB2008/000862 - 74 PKCb Ex. Ki No. Structure (nM) 1H NMR Chiral N 1H)1.57(s,3H)1.62(s,3H)1.65-1.77(m,2 C He ~.. H) 1.78 -1.87 (m, 1 H) 1.97 (q,J=8.59 Hz, 1 H) A87 CH N 32.3 2.23 (dd, J10.48, 3.41 Hz, 1 H) 2.71 -2.82 (n, 2
    OH
    3 H) 2.86 - 2.98 (in, 2 H) 3.05 (s, 6 H) 3.31 (s, 1 H) 3.84 (d, J=2.78 Hz, 1 H) 4.40 - 4.75 (in, 2 H) 6.81 (dd, J=5.81, 2.78 Hz, 1 H) 7.34 (d, J=2.78 Hz, 1 N-(6,6-dimethyl-5-((3S,8aS)-3-methyl- H) 8.22 (d, J5.81 Hz, 1 H). octahydropyrrolo[1,2-a]pyrazine-2-carbonyl) 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-4 (dimethylamino)picolinamide Chiral oOCH H 3 1 H NMR (400 MHz, DMSO-d6) d ppm 1.25 (d,. /N NC N J=6.57 Hz, 3 H) 1.27 -1.38 (in, 1 H) 1.61 (s, 3 H) L /, % 1.65 (s, 3 H) 1.66 - 1.79 (in, J=10.36 Hz, 2 H) A8 N OH 3 )" C H, 1.80 -1.89 (in, 1 H) 1.94 -2.07 (in, 1 H) 2.24 (dd, A88 N ; N 17.8 J=10.61, 3.79 Hz, 1 H) 2.75-2.86 (m, 2 H) 2.93 0 (t, J=9.35 Hz, 1 H) 3.34 - 3.43 (in, 2 H) 3.87 (s, 1 0 H) 4.52 - 4.75 (in, 2 H) 7.73 - 7.81 (in, 1 H) 7.92 N-(6,6-dimethyl-5-((3S,8aS)-3-methyl- (t, J7.45 Hz, 1 H) 8.14 (d, J8.34 Hz, 1 H) 8.21 octahydropyrrolo[1,2-a]pyrazine-2-carbonyl)- 8.30 (m, 2 H) 8.65 (d, J=8.59 Hz, 1 H). 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3 yl)quinoline-2-carboxamide Chiral O CH H 3 1 H NMR (400 MHz, DMSO-d 6 ) d ppm 0.94 - 1.05 0H 3 W (m, 6 H) 1.58 (s, 3 H) 1.67 (s, 3 H) 2.00 (dd, N N NJ111,93Hz 1 H) 2.37 -2.45 (mn,2 H) 2.74 N (dd, J=11.24, 2.65 Hz, 1 H) 2.88 (dd, J=14.15, A89 N 15.7 7.58 Hz, 1 H)3.01 -3.11 (, 2 H) 3.22-3.42 (m,
    OH
    3 ; N- 1 H) 4.65 (s, 2H) 5.15 (d, J=10.1 1 Hz, 1 H) 5.21 0 (d, J= 16.93 Hz, 1 H) 5.80 - 5.95 (in, 1 H) 7.70 (dd, N-(5-((+/-)-trans-1-allyl-2,5-dimethylpiperazine- 8.0 (in , 1 H) 8. J .2 Hz, 1 H). 4-carbonyl)-6,6-dimethyl-1,4,5,6 tetrahydropyrrolo[3,4-c]pyrazol-3 yl)picolinamide
    CH
    3
    OCH
    3 NN N 1H NMR (400 MHz, CD3OD-d4) d ppm 0.92 (t, N J=7.43 Hz, 3 H) 1.40 - 1.54 (m, 2 H) 1.64 -1.97 N (, 10 H) 2.13 - 2.40 (, 3 H) 2.56 -2.71 (m, 1 H) A90 H107 3.04 - 3.22 (m, 3 H) 3.36-3.47 (m, 1 H) 4.76 N / 4.86 (d, 2 H) 7.49 7.71 ( , 1 H) 7.94.-78.10 (, 1 H) 8.21 (d, J7.81 Hz, 1 H) 8.71 (d, J=4.78 Hz, N-(5-((3S,8aR)-3-ethyl-octahydropyrrolo[1 ,2- 1 H). a]pyraHzine-2-carbonyl)-6,6-dimethyl-1N4,5,6 tetra hyd ropyrro lo [3,4-c]pyrazo3 -3 yI)picolinainide ____________________________ WO 2008/125945 PCT/IB2008/000862 -75 1PKCb Ex. Ki No. Structure (nM) 1H NMR CH H, N N Chiral O N 1H NMR (400 MHz, DMSO-d6) d ppm 1.22 (d, N J=6.57 Hz, 3 H) 1.24 - 1.37 (in, 1 H) 1.57 (s, 3 H) N CH301.61 (s, 3 H) 1.63-1.78 (i, 2 H) 1.78-1.88 (i, 1 KYCH N H) 1.97 (q, J=8.67 Hz, 1 H) 2.21 (dd, J=10.48, A91 20.3 3.41 Hz, 1 H) 2.65 -2.83 (i, 2 H) 2.91 (t, 1 H) IN 3.33 (d, J=9.60 Hz, 2 H) 3.82 (s, 1 H) 4.42 - 4.67 Br (in, 2 H) 8.07 (d, J=8.34 Hz, 1 H) 8.31 (dd, 5-bromo-N-(6,6-dimethyl-5-((3S,8aS)-3-methyl- J8.34, 2.27 Hz, 1 H) 8.85 (d, J=2.27 Hz, 1 H) octahydropyrrolo[1,2-a]pyrazine-2-carbonyl)- 10.83 (s, 1 H) 12.07 (s, 1 H). 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3 yl)picolinamide CH, CH ,N, Chiral O /N Ohial 1 H NMR (400 MHz, DMSO-d6) d ppm 1.22 (d, J=6.82 Hz, 3 H) 1.24 -1.35 (in, 1 H) 1.57 (s, 3 H) N C, N % 1.61 (s, 3 H) 1.63 -1.77 (in, 2 H) 1.79 - 1.88 (in, 1 A92 /0.N H) 1.92 -2.01 (in, 1 H) 2.21 (dd, J=10.48, 3.41)I A92 N 203 Hz, 1 H) 2.70 - 2.83 (in, 2 H) 2.85 - 2.97 (in, 1 H) F 3.33 (dd, J=12.25, 2.40 Hz, 2 H) 3.75 - 3.90 (in, 1 N-(6,6-dimethyl-5-((3S,8aS)-3-methyl- H) 4.45 -4.70 (i, 2 H) 7.85 - 8.02 (i, 1 H) 8.22 octaydrpyrrlo[,2-apyrzine2-crbonl)-(dd, J=8.84, 4.55 Hz, 1 H) 8.72 (d, J=2.78 Hz, 1 octahydropyrrolo[1,2-a]pyrazine-2-carbonyl)- H) 10.74 (s, 1 H) 12.13 (s, 1 H). 1 ,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-5 fluoropicolinamide CH H, ON YN 'N 1 H NMR (400 MHz, DMSO-d 6 ) d ppm 0.98 (d, N 0 J=6.06 Hz, 6 H) 1.58 (s, 3 H) 1.67 (s, 3 H) 2.03 CH3 CH 3 N 2.18 (, 1 H) 2.33 - 2.47 (m, 4 H) 2.74- 2.88 (m, A93 N /N 63.6 2,H) 3.05 (d, J=9.85 Hz, 2 H) 3.25 (s, 3 H) 3.39 /-j 3.49 (in, 3 H) 4.66 (s, 2 H) 7.65 - 7.80 (in, 1 H) OF + 4 Jp. 8.00 -8.12 (in, 1 H) 8.17 (d, J=8.08 Hz, 1 H) 8.66 N-(5-(+/-)-trans-1 -(2-methoxyethyl)-2,5- -8.83 (i, 1 H). dimethylpiperazine-4-carbonyl)-6,6-dimethyl 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3 .yl)picolinamide O CHa CH NN_ N'H NMR (400 MHz, DMSO-d 6 ) d ppm 0.99 (dd,6 C N N N
    OH
    3 % H) 1.58 (s, 3H) 1.63 (dd, 1 H) 1.67 (s, 3H) 1.95 N OH 3 ..- N . 2.09 (in, 1 H) 2.39 - 2.47 (in, 2 H) 2.70 -2.82 (in, N 1 H)2.86-2.99(m, 1 H)3.01 -3.15(m,J=7.83 .O N A94 CH3N 23.8 Hz, 3 H) 3.22 (s, 2 H) 3.33 (s, 4 H) 4.66 (s, 2 H) 0 5.11 - 5.28 (m, 1 H) 5.87 (d, J=15.16 Hz, 1 H) N-(5-((+/-)-trans-1-(3-methoxypropyl)-2,5- 7.70 (dd, 1 H) 8.08 (t, J=7.45 Hz, 1 H) 8.17 (d, dimethylpiperazine-4-carbonyl)-6,6-dimethyl- J=7.83 Hz, 1 H) 8.73 (d, J=4.04 Hz, 1 H). 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3 yI)picolinamide ____ _______________________ WO 2008/125945 PCT/IB2008/000862 -76 PKCb Ex. Ki No. Structure (nM) IH NMR CH CH 3 , CH N N IN It 'H~ NMR (400 MHz, DMSO-d6) d ppm 1.00 (d, CH; CH 3 N J5.81 Hz, 9 H) 1.58 (s, 3 H) 1.68 (s, 3 H .94 N0 2.10 (in, 1 H) 2.30 - 2.46 (in, J=30.57 Hz, 2 H) A95IN A95 N9. 11 2.78 (s, 1 H) 3.02 -3.14 (in, 2 H) 3.33 (s, 2 H) OH4.66 (s, 2 H) 7.66 -7.73 (in, 1 H) 8.03 -8.11 (in, 1 CHH) 8.17 (d, J=7.58 Hz, 1 H) 8.74 (d, J=4.29 Hz, 1 N-(5-((+/-)-trans-1 -ethyl-2,5-dimethylpiperazine- H). 4-carbonyl)-6,6-dimethyl-1,4,5,6 tetrahydropyrrolo[3,4-c]pyrazol-3 yl)picolinamide o CH 3
    CH
    3 N'i N 'H NMR (400 MHz, DMSO-d 6 ) d ppm 0.95 (d,
    OH
    3 N N~ J=6.32 Hz, 3 H) 0.97 (d, J=6.06 Hz, 3 H) 1.58 (s, CH H H)1.68(s,3H)2.03-2.12(m, 1 H)2.16(s,3 A96 C'H N N H) 2.33 (t, J=10.74 Hz, 1 H) 2.37- 2.45 (, 1 H) A96 CH 28,2 2.65 -2.70 (in, 1 H) 2.70 - 2.76 (in, 1 H) 2.95 0 3.06 (in, 3 H) 4.67 (q, 2 H) 7.65 - 7.73 (in, 1 H) N-(6,6-dimethyl-5-((+/-)-trans-1,2,5- 8.04-8.11 (i, 1 H) 8.17 (d, J=7.83 Hz, 1 H) 8.73 trimethylpiperazine-4-carbonyl)-1,4,5,6- (d, J=4.80 Hz, 1 H). tetrahydropyrrolo[3,4-c]pyrazol-3 yl)picolinamide o CH3CH 3 CHNMR (400 MHz, DMSO-d 6 ) d ppm 0.86 (d, CHIN OHA IN L J=6.32 Hz, 3 H) 0.97 (d, J=2.53 Hz, 3 H) 0.98 (d, r CH 3 -N J=2.27 Hz, 3 H) 1.05 (d, J=6.57 Hz, 3 H) 1.58 (s, A97 CH 3 N 3 H) 1.67 (s, 3 H) 1.97- 2.05 (i, 1 H)2.31 -2.41 A97 9.2 (in, 1 H) 2.54 - 2.57 (in, 1 H) 2.57 - 2.62 (in, 1 H) r N) 2.65 -2.74 (in, 1 H) 2.95 -3.08 (in, 2 H) 3. 10 0 3.19 (in, 1 H) 4.66 (s, 2 H) 7.70 (dd, J=6.44, 4.93 N-(5-((+/-)-trans-1-isopropyl-2,5- Hz, 1 H) 8.04-8.11 (i, 1 H) 8.17 (d, J=7.83 Hz, 1 dimethylpiperazine-4-carbonyl)-6,6-dimethyl- H) 8.74 (d, J=4.55 Hz, 1 H). 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3 yl)picolinamide 0 CH CIH OH C I IN N lH NMR (400 MHz, DMSO-d 6 ) d ppm 0.03 - 0.13 ,111 O-Cll N (in, 2 H) 0.39 -0.54 (in, 2 H) 0.78 -0.89 (in, 1 H) 3 ~0.97 (d, J=6.06 Hz, 3 H) 1.00 (d, J=6.06 Hz, 3 H) 11158 (s, 2 H) 1.68 (s, 3 H) 2.05 -2.21 (in, 2 H) A98 N 2.34 -2.47 (i, 2 H) 2.96 (dd, J=1 1.37, 2.78 Hz, 1 0 H) 3.01 - 3.11 (in, 2 H) 4.66 (d, J=4.04 Hz, 2 H) N-(5-((+/-)-trans-1-(cyclopropylmethyl)-2,5- 7.66-7.76(m, 1 H) 8.03-8.11 (i, 1 H)8.17 (d, dimethylpiperazine-4-carbonyl)-6,6-dimethyl- J=7.83 Hz, 1 H) 8.73 (d, J=4.29 Hz, 1 H). 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3 yl)picolinamide o
    CH
    3 CH3
    CH
    3 NN / N 'H NMR (400 MHz, DMSO-d) d ppm 0.94- 0.98 SN (in, 2 H) 1.00 (d, J=6.06 Hz, 3 H) 1.04 (d, J=6.06 N O)-H 3 iHz, 3 H) 1.58 (s, 3 H) 1.67 (s, 3 H) 2.00 -2.18 (in, A99 N N 19.9 2 H) 2.32 -2.46 (i, 2 H) 2.80-2.90 (i, 1 H) 3.05 - 3.17 (in, 2 H) 3.67 -3.79 (in, 1 H) 4.65 (s, 2 H) 0 7.70 (dd, 1 H) 8.03 -8.12 (in, 1 H) 8.17 (d, J=7.58 N-(5-(1-(3-hydroxypropyl)-2,5- Hz, 1 H) 8.73 (d, J=4.29 Hz, 1 H). dimethylpiperazine-4-carbonyl)-6,6-dimethyl 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3 yI)picolina ide ________________________ WO 2008/125945 PCT/IB2008/000862 -77 PKCb Ex. Ki No. Structure (nM) 1H NMR
    CH
    3 OC H N N 1 0H NMR (400 MHz, CD30) d ppm 0.97 (d, IN J=6.80 Hz, 6 H) 1.33 - 1.48 (in, 1 H) 1.63-1.99 (in, N C 10H)1.99 -2.21 (in, 1 H) 2.26 -2.39 (m, 2H) 2.90 Al100 /14.1 - 3.07 (m, 2H) 3.19 -3.27 (m, 1 H) 3.44 -3.51 (in, N O CH! 1 H) 3.55 - 3.63 (in, 1 H) 4.48 - 4.64 (in, 1 H) 4.89 - 4.94 (in, 1 H) 7.57 - 7.67 (in, 1 H) 7.98 - 8.06 (in, N-(5-((3S,8aS)-3-isopropyl- 1 H) 8.20 (d, J7.81 Hz, 1 H) 8.70 (d, J4.78 Hz, octahydropyrrolo[1,2-a]pyrazine-2-carbonyl)- 1 H). 6,6-dimethyl-1 ,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yl)picolinamide CH OCH N N N N 1H NMR (400 MHz, CD3OD) d ppm 0.97 (dd, N C F J=6.55, 3.27 Hz, 6 H) 1.34-1.46 (i, 1 H) 1.65 C6 0 1.96 (m, 10OH) 2.07 -2.16 (m, 1 H) 2.27 -2.39 (mn A101 N CH 3 148 2 H) 2.92 - 3.07 (i, 2 H) 3.21 - 3.27 (i, 1 H) 3.4 - 3.51 (in, 1 H) 3.56 - 3.63 (in, 1 H) 4.46 -4.56 (in, 1 H) 4.79 -4.87 (in, 1 H) 7.07 - 7.21 (in, 2 H) 7.84 2,4-difluoro-N-(5-((3S,8aS)-3-isopropyl octahydropyrrolo[1,2-a]pyrazine-2-carbonyl) 6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yl)benzamide CH N A102 N /5.9 (m, 1H), 2.25-2.40 (m, IH), 2.70-2.85 (m, 2H), -- 2.89-2.93 (in, 1 H), 3.05-3.25 (m, 2H), 3.40-3.50
    CH
    3 Fi, 1H), 3.65-3.90 (m, 2H), 4.05425 (m, 1H), F 4.60-4.85 (in, 2H), 6.93 (dd, J = 8.5Hz, J = 2,4-difluoro-N-(5-((2R,5S)-2-(2-hydroxyethyl)-5- 11.6Hz, IH), 7.01-7.10 (m, 1H), 8.05-8.20 (i, methyl-1-propylpiperazine-4-carbonyl)-6,6- 1 H), 9.00-9.10 (i, 1 H). dimethyl-1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yl)benzamide Chiral N CHCH, 1 H NMR (400 MHz, DMSO-d6) d ppm 1.21 (d, N J=6.57 Hz, 3 H) 1.23 - 1.35 (m, 1 H) 1.57 (s, 3 H) N s 1.60(s, 3H) 1.62-1.77 (m, 2 H) 1.78 - 1.87 (m, 1 Al103 C Nj -OH 3 n />-B 12.9 H) 1.96 (q,J=8.59 Hz, 1 H) 2.20 (dd, J=10.36, 4N 3.54 Hz, 1 H) 2.69 - 2.82 (m, 2 H) 2.86 - 2.96 (m, 1 H) 3.25 - 3.44 (m, J9.09 Hz, 2 H) 3.77 - 3.88 2-bromo-N-(6,6-dimethyl-5-((3S,8aS)-3-methyl- (, H) 1 .65 (m, H ) 8. 06 octahydropyrrolo[1,2-a]pyrazine-2-carbonyl)-, . , H). 1 ,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3 yl)thiazole-4-carboxamide ____________________________ WO 2008/125945 PCT/IB2008/000862 - 78 1PKCbI Ex. Ki No. Structure IH NMR CH
    CH
    3 N 0 'N ,N 1H NMR (400 MHz, DMSO-d6) d ppm 0.12 -0.25 N N(i, 1 H)0.66-0.84(m, 1 H)1.04(ddJ101.31,
    OH
    3 0 6.32 Hz, 3 H) 1.22 -1.38 (mn, 2 H) 1.58 (s, 3 H) Al 04N /N 837 1.64 (d, J=25.52 Hz, 3 H) 2.19 -2.43 (mn, 3 H) A042.64 (d, J=10.36 Hz, 1 H) 2.72-2.94 (, 3 H) 3.08 - 3.25 (mn, 1 H) 3.67 - 3.82 (in, 1 H) 4.44 N-(6,6-dimethyl-5-((3S,6aS,7aS,7bS)-3-methyl- 4.74 (i, 2 H) 7.64 - 7.73 (i, 1 H) 8.01 - 8.11 (i, octahydro-1H-3-aza-bicyclo[3.1.0]hex-1(5)- 1 H) 8.12-8.21 (i, 1 H) 8.66-8.76 (i, 1 H). eno[3,2-a]pyrazine-2-carbonyl)-1,4,5,6 tetrahydropyrrolo[3,4-c]pyrazol-3 yI)picolinamide o f N Chiral 0 N0 1 N 1H NMR (400 MHz, CD30) d ppm 1.40 (d, J=6.55 Hz, 3 H) 1.71 (s, 3 H) 1.74 (s, 3 H) 1.97 N N 2.09 (d, 1 H) 2.15- 2.46 (i, 3 H) 2.90 (d,
    CH
    3 2 0 d J J=10.83 Hz, 1 H) 2.98 - 3.25 (i, 3 H) 3.47 (d, AlN31 - 09 J=312.59 Hz, 1 H) 3.92 - 4.04 (m, 1 H) 4.65 -4.81 (m, 2 H) 5.02 - 5.24 (m, 1 H) 7.58-7.66 (, 1 H) F 7.99 - 8.06 (m, 1 H) 8.20 (d, J7.81 Hz, 1 H) 8.67 N-(5-((3S,7S,8aS)-7-fluoro-3-methyl- - 8.75 (in, 1 H). octahydropyrroloji ,2-a]pyrazine-2-carbonyl) 6,6-diiethyl-1,4,5,6-tetrahydropyrrolo[3,4 clpyrazol-3-yl)picolinamide
    CH
    3 NCH
    CH
    3 N ,H 1 H NMR (400 MHz, DMSO-d6) d ppm 0.85 (t, A105 F CH3 1 N J=7.33 Hz, 3 H) 0.97 (d, J5.31 Hz, 3 H) 0.99 (d, N OH 3 J=6.32 Hz, 3 H) 1.36- 1.49 (n, 2 H) 1.58 (s, 3 H) Al106 OH 3 N N 39.5 1.67 (s, 3 H) 1.95 (t, 1 H) 2.10 -2.22 (m , 1 H) 2.41 N< (d, J=6.57 Hz, 2 H) 2.52 - 2.64 (m, H) 2.79 (dd, 0 J=11.12, 2.78 Hz, 1 H) 3.02 - 3.14 (m, 2 H) 4.65 N-(5-(+/-)-trans-2,5-dinethyl-1 - (s, 2 H) 7.70 (dd, 1 H) 8.08 (t, 1 H) 8.17 (d, J=7.83 propylpiperazine-4-carbo7nyl)-6,6-d.iethyl- Hz, 1 H) 8.73 (d, J=4.29 Hz, 1 H). 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3 yl)picolinamide o CH 3
    CH
    3 OH 5 N N 1 NMR (400 MHz, DMSO-d 6 ) d ppm 0.06 (d, CH3 N/ N J=4.80 Hz, 2 H) 0.45 (dd, J=7.96, 3.66 Hz, 2 H) NA106 CI N F 0.76 - 0.88 (m, J4.55 Hz, 1 H) 0.96 (d, J5.81 =N3Hz, 3 H) 0.98 (d, J=5.81 Hz, 3 H) 1.59 (s, 3 H) A307 68.9 1.68 (s, 3 H) 2.04 -2.21 (, 2 H) 2.31 -2.45 (in, 2 0 F H) 2.88- 2.99 (i, 1 H) 3.00 - 3.09 (m, 2 H) 3.17 (d, J2 Hz0d, 1 H) .9 (, H) 7.0 (, J=7.83 N-(5-(+/-)-trans-1 -(cyclopropylmethyl)-2,5- (d, J=3.28 Hz, 1 H) .3 (, J=.9 Hz, 1 H) 7.6 7.8 dimethylpiperazine-4-carbonyl)-6,6-dimethyl- H), 10H.39 (, =.9 H). H .7 .4 m 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yI) 2,4-difluorobenzamide WO 2008/125945 PCT/IB2008/000862 - 79 PKCb Ex. Ki No. Structure (nM) 1H NMR O CH 3CH 3 oH3H 3 OHF CH /N NI N 'H NMR (400 MHz, DMSO-d 6 ) d ppm 0.92 (d, SN F J=6.32 Hz, 3 H) 1.03 (d, J=6.32 Hz, 3 H) 1.50 NJ OH 3 1.60 (m, 5 H) 1.67 (s, 3 H) 1.76 - 1.89 (m, 3 H) A108 N 742 1.92 - 2.07 (m, 1 H) 2.40 - 2.47 (m, 1 H) 2.53 2.58 (m, J=7.07 Hz, 1 H) 2.61 - 2.71 (m, 1 H) 2.91 0 F - 3.01 (m, 1 H) 3.00 - 3.13 (m, 1 H) 3.17 - 3.27 (m, N-(5-((+/-)-trans-1 -cyclobutyl-2,5- 2 H) 4.57 (s, 2 H) 7.20 (s, 1 H) 7.39 (s, 1 H) 7.73 dimethylpiperazine-4-carbonyl)-6,6-dimethyl- (s, 1 H) 10.89 (s, 1 H) 12.44 (s, 1 H). 1 ,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-y) 2,4-difluorobenzamide 0 CH 3
    CH
    3 fiN N 1 H NMR (400 MHz, DMSO-d 6 ) d ppm 0.84 - 0.90 N N OH 3 N /(n )09 .7(n )09 d 60 z N OH3 'N F H)1.18-1.33(m,2H)1.31-1.43(m,2H)1.58 CH3 (s, 3 H) 1.67 (s, 3 H) 1.91-1.98 (, 1 H) 2.11 A109 Nq 54.9 2.23 (i, 1 H) 2.34-2.44 (i, 1 H) 2.54 - 2.65 (i, 0 F 1 H) 2.76 (dd, J=11. 12, 2.78 Hz, 1 H) 3.05 (t, N-(5-((+/-)-trans-1-butyl-2,5-dimethylpiperazine- J=9.22 Hz, 1 H) 3.16 (s, 2 H) 4.59 (s, 2 H) 7.20 (t, 4-carbonyl)-6,6-dimethyl-1,4,5,6- J=7.71 Hz, 1 H) 7.39 (t, J9.47 Hz, 1 H) 7.68 tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-2,4- 7.82 (i, 1 H). difluorobenzamide o OH 3
    OH
    3 OH N N 1 H NMR (400 MHz, DMSO-de) d ppm 0.92 (d, F J=6.32 Hz, 3 H) 1.03 (d, J=6.32 Hz, 3 H) 1.50 N OH 3 1.60 (, 5 H) 1.67 (s, 3 H) 1.76 -1.89 (m, 3 H) 1.92 - 2.07 (, 1 H) 2.40 - 2.47 (m, 1 H) 2.53 A110 0 F 81.3 2.58 (m, J7.07 Hz, 1 H) 2.61 - 2.71 (, 1 H) 2.91 -3.01 (in, 1 H)3.00-3.13 (m, 1 H) 3.17-3.27 (, J=2 Hz7(, 2 H) .20 (s, 2 H) .9 (s, 2 H) 7.73(t N-(5-((+/-)-trans-J-(cyclopentylmethyl)-2,5- Hz, H) 7. (s, 1 H) 2.4 ( , 1 H) 7. diethylpiperazine-4-carbonyl)-6,6-dimethyl- (, 1 1 ,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yI) 2,4-difluorobenzamide
    CCH
    3 Ohira 0 N1 H NMR (400 MHz, DMSO-d6) d ppm 0.82 - 0.90 Chirl 0N (in, 3 H) 0.91 - 0.97 (in, 1 H) 1.03 (s, 3 H) 1.22 (d, J=6.57 Hz, 3 H) 1.58 (s, 3 H) 1.61 (s, 3 H) 1.78 N (dd, J10.61, 2.53 Hz, 1 H) 2.19 (dd, J10.36, 3.28 Hz, 1 H) 2.32 (dd, J=9.85, 8.34 Hz, 1 H) 2.71 A11 OH C F177 (d,J=10.36Hz, 1 H) 2.78 '6 J=12.38, 2.27 Hz, 1 H) 3.22 - 3.25 (in, 3 H) 3.38 (dd, J=8.08, 3.03 Hz, 2 H) 3.74 (d, J=3.54 Hz, 1 N-(5-((3S,7S,8aS)-7-methoxy-3,8,8-trimethyl- H) 4.58 (d, J3.54 Hz, H) 7.58 - 7.76 (n, 1 H) octahydropyrrolo[1,2-a]pyrazine-2-carbonyl)- 8.02 - 8.11 (i, 1 H) 8.11 - 8.20 (, 1 H) 8.72 (d, 6,6-dimethyl-1 4,5,6-tetrahydropyrrolo[3,4- J=4.29 Hz, 1 H). I__ clpyrazol-3-yI)picolinamide ______________________ OH OH3 N1 4 IH NMR (400 MHz, DMSO-d6) d ppm 1.14- 1.22 N (m,J7.07Hz, 3 H) 1.25- 1.46 (m, 2 H) 1.47 1.52 (m, 3 H) 1.54 (s, 3 H) 1.58 (s, 3 H) 1.60 A12 0 186 1.73 (-, 2 H) 1.75 - 1.85 (m, 3 H) 1.91 - 2.05 (-, S86.3 H) 2.06 - 2.31 (in, 1 H) 2.66 - 2.86 (m, 2 H) 2.86 - 3.01 (m, 1 H) 3.23 - 3.37 (m, 2 H) 3.40 - 3.53 (m, N-(6,6-dimethyl-5-((3S,8aS)-3-methyl- 1 H) 3.76 (s, 1 H) 3.86 - 4.03 (n, 2 H) 4.33 -4.57 octahydropyrrolo[1,2-a]pyrazine-2-carbonyl)- (s, 2 H). 1 ,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-y) tetra hydro-2H-pyran-2-carboxamide WO 2008/125945 PCT/IB2008/000862 - 80 PKCb Ex. Ki No. Structure (nM) 1H NMR Chiral 0 N I1H NMR (400 MHz, DMSO-d6) d ppm 0.96 (d, IN 'N /J=6.06 Hz, 3 H) 0.99 (d, J=6.06 Hz, 3 H) 1.59 (s, N 3 H) 1.68 (s, 3H) 1.92 -2.01 (in, 1 H) 2.08 -2.17 A113 CHC CH 3 N O13.9 (i, 1 H) 2.20 (s, 3 H) 2.35 (t, J=10.48 Hz, 1 H) /N _02.67 - 2.82 (in, J=9.09 Hz, 1 H) 2.95 - 3.12 (in, 2 CH 3 H) 4.59 -4.79 (in, 2 H) 7.65 - 7.79 (in, 1 H) 8.02 N-(66-dmetyl--((2,5S-1,,5-8.13 (in, 1 H) 8.13 -8.21 (in, 1 H) 8.74 (d, J=4.29 N-(6,6-dimethyi-5-((2R,5S)-1,2,5 trimethylpiperazine-4-carbonyl)-1,4,5,6- Hz, 1 H). tetrahydropyrrolo[3,4-c]pyrazol-3 yl)picolinamide Chiral O CH 3
    CH
    3 k-N N 1H NMR (400 MHz, DMSO-d6) d ppm 0.82-0.89 CH N ( ' N(in, 3 H) 0.92 -1.00 (in, 6 H) 1.43 -1.54 (in, 3 H)
    CH
    3 N CH 3 F 1.55- 1.66 (m,.3 H) 1.96-2.05 (i, 3 H)2.02 Al 14 CH 87.1 2.25 (, 2 H) 2.45-2.56 (i, 2 H) 2.65-2.87 (i, C H 3 2 H) 4.39 -4.68 (in, 2 H) 7.13 (t, J=7.58 Hz, 1 H) 0 F 7.32 (t, J=9.35 Hz, 1 H) 7.65 (q, J=7.58 Hz, 1 H) N-(6,6-dimethyl-5-{[(2S)-2,4,5,5- 10.83 (s, 1 H) 12.37 (s, 1 H). tetramethylpiperazin-1 -yl]carbonyl}-1,4,5,6 tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-2,4 difluorobenzamide 0 CH 3 OH H )-N F 1H NMR (400 MHz, DMSO-d 6 ) d ppm 0.90 - 1.04 N HI (in, J=6.06 Hz, 9 H) 1.58 (s, 3 H) 1.68 (s, 3 H) Al3 N 83.1 ) -2.35 (m, 1 H) 2.36 -2.42 (m, 1 H) 2.53 2.59 (-, 2 H) 2.69- 2.80 (, 2 H) 2.99 -3.11 (m, 0 F 2 H) 4.61 (s, 2 H) 7.20 (s, 1 H) 7.39 (s, 1 H) 7.74 N-(5-((+/-)-trans-1-ethyl-2,5-dimethylpiperazine- (s, 1 H) 10.90 (s, 1 H) 12.46 (s, 1 H). 4-carbonyl)-6,6-dimethyl-1H4,5,6 tetra hyd ropyrrolo[3,4-c] pyrazol-3-yI)-2,4 _____ ~difluorobenzamide ______________________ N 1 H NMR (400 MHz, DMSO-d6) d ppm 0.83 (t,
    O
    3 N F J=7.33 Hz, 3 H) 0.95 (d, J=5.56 Hz, 3 H) 0.98 (d, N H, J6.06 Hz, 3 H) 1.31 - 1.48 (m, 2 H) 1.58 (s, 3 H) .5-1.67 (s, 3 H) 1.95 (dd, J10.86, 9.35 Hz, H) 2.08 A116 OH 3 N87.3 -2.19 (m, 1 H) 2.31 -2.42 (m, 2 H) 2.54 - 2.60 (m, 0 F 1 H) 2.77 (dd, J=1 1.12, 2.53 Hz, 1 H) 3.00 -3.11 n , J=8.97, 8.97 Hz, 2 H) 4.59 (s, 2 H) 7.20 (t, N-(-((/-)tras-25-dmetyl-- 7.2 z, =.3 Hz, 7.3 (H) 7.6 z, =.5 Hz, 7.6 H) propylpiperazine-4-carbonyl)-6,6-dimethyl- J7.8 (, 1 H) 10.39 (s, 1H1.46 (, 1 H) . 1 ,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-y)- 78 m )1.0(,1H 24 s ) 2,4-difluorobenzamide I II WO 2008/125945 PCT/IB2008/000862 - 81 PKCb Ex. Ki No. Structure (nM) IH NMR o CH 3 CH N N 1 H NMR (400 MHz, DMSO-d 6 ) d ppm 0.95 (d, CHa N / -C .N F J=5.31 Hz, 3 H) 0.98 (d, J6.06 Hz, 3 H) 1.58(s, N Z'CH 3 3.H) 1.59 -1.64 (in, 2 H) 1.67 (s, 3 H) 1.90 - 2.01 A117 C H N 131 (m, 1 H)2.13-2.26(m, 1 H)2.32-2.44(m,2H)
    H
    3 ;q2.58 - 2.72 (in, 1 H) 2.72 - 2.82 (in, 1 H) 2.99 o F 3.11 (m,2 H) 3.22 (s, 3H) 3.27 -3.39 (m, 2H) 2,4-difluoro-N-(5-((+/-)-trans-1-(3- 4.59 (s, 2 H) 7.21 (t, 1 H) 7.39 (t, J=9.35 Hz, 1 H) methoxypropyl)-2,5-dimethylpiperazine-4- 7.70 - 7.84 (i, 1 H) 10.92 (s, 1 H) 12.46 (s, 1 H). carbonyl)-6,6-dimethyl-1,4,5,6 tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzamide Chiral o CH CH 3 NN, CH N N CH N 1 1 H NMR (400 MHz, DMSO-d6) d ppm 0.86 (t, CH:, N n 4 N 0J=7.07 Hz, 3 H) 0.94 (d, J=6.06 Hz, 3 H) 1. 10 (d, N CH 3 N J=6.57 Hz, 3 H) 1.52 (s, 3 H) 1.56 (s, 3 H) 1.83 (s, A118 149 3 H) 2.09-2.36 (i, 3 H) 2.49 (dd, J=1 1.24, 3.41 /H Hz, 1 H) 2.57 -2.74 (in, 2 H) 2.93 (dd, J=12.51, CH N 2.40 Hz, 1 H) 3.45-3.61 (i, 1 H) 4.44-4.66 (i, 2 H) 7.50 - 7.69 (in, 1 H) 7.89 -8.03 (in, 1 H) 8.05 N-(5-{[(2S,5S)-4-ethyl-2,5-dimethylpiperazin-1- - 8.16 (i, 1 H) 8.67 (d, J=4.04 Hz, 1 H). yl]carbonyl}-6,6-dimethyl-1,4,5,6 tetrahydropyrrolo[3,4-c]pyrazol-3-yl)pyridine-2 _____carboxamide Chiral 0OCH CH 3 N 1 H NMR (400 MHz, DMSO-d6) ppm 0.77 (t, CH N / N J=7.33 Hz, 3 H) 0.94 (d, J=6.06 Hz, 3 H) 1.11 (d, 30 J6.57 Hz, 3 H) 1.24 - 1.38 (, 3 H) 1.44 - 1.61 N, 1 H) 1.97 - 2.10 (m, 1 H) 2.16 - 2.35 (m, 2 H) A119 - 52.5 2.52 (dd, J= 10.86, 3.28 Hz, 2 H) 2.59 2.75 (n, 1
    CH
    3 N H) 2.94 (dd, J 12.51, 2.65 Hz, 1 H) 3.48-3.66 (in, 1 H) 4.31 -4.63 (in, 2 H) 7.49-7.70 (s, 1 H) N-(5-{[(2S,5S)-2,5-diiJethyl-4-propylpiperazin- 7.93-8.05 (in, 1 H) 8.08 8.15 (i, 1 H) 8.67 (d, 1-yl]carbonyl)-6,6-diiethyl-1,4,5,6- J=4.04 Hz, 1 H) 10.74 (s, 3 H) 12.09 (s, 1 H). tetra hyd ropyrrolo [3,4-c]pyrazol-3-yH)pyrid ine-2 carboxamide Chiral O CH H 3 N1
    OH
    3 N -N / NH NMR (400 MHz, DMSO-d6) d ppm 0.91 - 1.03 (, 9 H) 1.58 (s, 3 H) 1.67 (s, 3 H) 1.99 (dd, AH0 OH 3 NJ=10.99, 9.73 Hz, 1 H) 2.32 (dd, J12.88, 6.82 A0NN 19.5 Hz, 1 H) 2.37 - 2.44 (m, 2 H) 2.16 - 2.82 (m, 2 H) N 3.00 - 3.11 (i, 2 H) 4.66 (d, J=2.53 Hz, 2 H) 7.65 0 7.3 -. (mn, 1 H) 8.0-8.1 (, 1 H) 8.-82 (, N-(5-((2R,5S)-1-ethyl-2,5-dimethylpiperazine-4- -7 m 1 H) 8. d J 8412 Hz, 1 H) 81 82 m carbonyl)-6,6-di0ethyl-144,5,6- 1 H) . , 1 H). tetra hyd ropyrro lo[3,4-c]pyrazol-3 yI)picoinamide WO 2008/125945 PCT/IB2008/000862 - 82 PKCb Ex. Ki No. Structure (nM) 1H NMR Chiral 0 CH H CH ). 1 H NMR (400 MHz, DMSO-d 6 ) d ppm 0.85 (t, / J=7.33 Hz, 3 H) 0.93 - 1.04 (m, 6 H) 1.33 - 1.46 N CH(m, 2 H) 1.58 (s, 3 H) 1.67 (s, 3 H) 1.96 - 2.02 (m, A121 N N 14.6 1 H) 2.09 - 2.25 (m, J=5.31 Hz, 1 H) 2.37 - 2.46 (m, 2 H) 2.79 (dd, J=1 1.37, 2.78 Hz, 1 H) 3.00 N 3.14 (m, 3 H) 4.65 (s, 2 H) 7.70 (dd, J=6.82, 5.31 Hz, 1 H) 8.01 - 8.12 (m, 1 H) 8.13 - 8.24 (m, 1 H) N-(5-((2 R,5S)-2,5-dimethy1-1 -propylpiperazine- 8.73 (d, J=4.55 Hz, 1 H). 4-carbonyl)-6,6-dimethyl-1,4,5,6 tetrahydropyrrolo[3,4-c]pyrazol-3 yl)picolinamide Chiral o CHCH 3
    CH
    3 NILkN 'H NMR (400 MHz, DMSO-d 6 ) d ppm -0.04 - 0.14 N / N (in, 2 H) 0.40 -0.54 (in, 2 H) 0.84 (s, 1 H) 0.98 N ~ (dd, J=10.86, 6.06 Hz, 6 H) 1.58 (s, 3 H) 1.68 (s, 3 A122 N 13.3 H) 2.04-2.21 (i, 2 H) 2.56-2.73 (i, 1 H) 2.91 NN 3.01 (in, 1 H) 3.01 - 3.10 (in, 2 H) 3.41 - 3.56 (mn, r N 2 H) 4.66 (d, J=3.54 Hz, 2 H) 7.62 - 7.74 (in, 1 H) 0 7.99 -8.13 (m, 1 H) 8.14 -8.21 (in, 1 H) 8.73 (d, N-(5-((2R,5S)-1-(cyclopropylmethyl)-2,5- J=4.29 Hz, I H). dimethylpiperazine-4-carbonyl)-6,6-dimethyl 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3 yl)picolinamide Chiral S CH NMR (400 MHz, DMSO-d 6 ) d ppm 0.89 (t,
    CHC
    3 H J=7.20 Hz, 3 H) 0.98 (dd, J=10.48, 5.68 Hz, 6 H) CH3K(N N 1.21 - 1.34 ( m, 2 H) 1.32-1.45 (, 2 H) 1.58 (s, 3 N N(dJ1.,60,I H) 1.67 (s, 3 H) 1.97 (dd, J10.99, 9.22 Hz, 1 H) A23 13.3 2.12 - 2.24 (m, 1 H) 2.41 (d, J=6.57 Hz, 2 H) 2.56 N -2.67 (m, 1 H) 2.78 (dd, J=11.12, 2.78 Hz, 1 H) 2.99 - 3.11 (, 2 H) 4.65 (s, 2 H) 7.70 (dd, J6.95, 5.43 Hz, 1 H)8.01 - 8.12 (m, 1 H) 8.13 - 8.26 (, N-(5-((2R,5S)-1-butyl-2,5-diiethylpiperazine-4- 1 H) 8.73 (d, J=4.55 Hz, 1 H). carbonyl)-6,6-diinethyl-1,4,5,6 tetrahydropyrrolo[3,4-c]pyrazol-3 ______ ~~yI)picolinainide________________________ Chiral 0 CH 3
    CH
    3 CH N)-N 1 H NMR (400 MHz, DMSO-d6) d ppm 0.85 - 1.00 -N (in, 3 H) 1.11 (d, J=6.32 Hz, 3 H) 1.54 (d, J=15.16 NH N Hz, 8 H) 1.99 -2.15 (in, 1 H) 2.16 -2.34 (in, 2 H) rfNIJ 3 N6 0 2.52 (dd, J=1 1.24, 2.91 Hz, 1 H) 2.59 - 2.77 (in, 2 A124 143 H) 2.94 (d, J10.36 Hz, 1 H) 3.22 - 3.36 (, 4 H)
    C
    3 - N 3.54 (d, J=5.56 Hz, 1 H) 4.43 - 4.66 (in, 2 H) 7.42 - 7.74 (in, 1 H) 8.01 (t, J=7.71 Hz, 1 H) 8.06 -8.15 (in, 1 H) 8.67 (d,J=4.04 Hz, 1 H) 10.40 -11.17 N-(5-{[(2S,5S)-4-(3-methoxypropyl)-2,5- (i, 1 H) 12.09 (s, 1 H). dimethylpiperazin-1 -yI]carbonyl)-6,6-diethy 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3 yl)pyridine-2-carboxamide I II WO 2008/125945 PCT/IB2008/000862 -83 PKCb Ex. Ki No. Structure (nM) 1H NMR Chiral o CH 3
    OH
    3 1 H NMR (400 MHz, DMSO-d6) d ppm 0.80 (t, NH3 N / N J=7.45 Hz, 3 H) 1. 15 (d, J=6.57 Hz, 3 H) 1.24 N1.38(m, 1 H)1.54(d,J10.61 Hz,6H)1.81 (s,2 N OH, H) 2.07 (s, 3 H) 2.15 -2.32 (i, 1 H) 2.50 (d, A125 CH N N 93.9 J11.12 Hz, 1 H) 2.66-2.84 (m, 1 H) 3.03 (d, N J=12.63 Hz, 1 H) 3.57 - 3.73 (in, 1 H) 4.37 -4.59 0(in, 2 H) 7.47-7.78 (mn, 1 H) 8.01 (t, J=7.58 Hz, 1 N-(5-{[(2S,5S)-5-ethyl-2,4-dimethylpiperazin-1- H) 8.05- 8.17 (i, 1 H) 8.67 (d, J4.55 Hz, 1 H) yl]carbonyl}-6,6-dimethyl-1,4,5,6- 10.76 (s, 1 H). tetrahydropyrrolo[3,4-c]pyrazol-3-yl)pyridine-2 carboxamide ______________________ Chiral OH NN N 1 H NMR (400 MHz, DMSO-d6) d ppm 0.90 - 1.03 C 3N F (m, 9 H) 1.57 (s, 3 H) 1.66 (s, 3 H) 1.97 (dd, 9 J=10.99, 9.47 Hz, 1 H) 2.30 (dd, J13.01, 6.95 Al126 CH 3 -/N OHJ 3 =222.2 Hz, .H) 2.34 -2.43 (i, 2 H) 2.62 - 2.81 (, 2 H) N N 2.96-3.19 (, 2 H) 4.63 (s, 2 H) 7.92 8.04 (i, 1 0 H) 8.24 (dd, J=8.59, 4.55 Hz, 1 H) 8.73 (d, J1 .77 N-(5-((2R,5S)-1-ethyl-2,5-dii1ethylpiperazine-4- Hz, 1 H). carbonyl)-6,6-diinethyl-1,4,5,6 tetra hydropyrrolo[3,4-c]pyrazo1-3-yi)-5 fluoropicolinamide OH o OH NH / N1H NMR (400 MHz, DMSO-d6) d ppm 0.02 - 0.14 0 (m, 2 H) 0.38 -0.53 (m, 2 H) 0.75 -0.89 (d, 1 H) N 0.99 (d, J=6.32 Hz, 3 H) 1.61 (d, J=3.54 Hz, 6 H) Nl N713 2.13 (dd, J=13.14, 6.57 Hz, 1 H) 2.30 -2.39 (in, 1 2. , 1H) 2.43 -2.61 (m, 2 H) 2.82 -3.01 (m, 2 H) 3.23 (dd, J1 8.06, 13.77 Hz, 3 H) 4.61 (s, 2 H) 7.62 N-(5-(1-(cyclopropyliHethyl)-2- 7.76 (in, 1 H) 8.04- 8.10 (, 1 H) 8.13 -(8.20 (i, nethylpiperazine-4-carbonyl)-6,6-diiethyl- 1 H) 8.73 (d, J=4.29 Hz, 1 H). 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3 yl)picolinamide CH H oOH N N N O H NMR (400 MHz, DMSO-d6) d ppm 0.89 - 1.03 NN N H) 2.28 - 2.37 (in, 1 H) 2.37 - 2.47 (in, 1 H) 2.57 A128 ~ N N156 (dd, J=12.13, 8.84 Hz, 1 H) 2.65 -2.78 (in, 2 H) Al O8N CH /5 2.82 - 2.94 (, 1 H) 3.21 (t, J13.39 Hz, 2 H) 4.61 OH 3 (s, 2 H) 7.65 -7.74 (m, 1 H) 8.02 -8.11 (m, 1 H) 8.12 - 8.21 (m, 1 H) 8.73 (d, J=4.55 Hz, H) N-(5-(1-ethyl-2-methylpiperazine-4-carbonyl)- 10.82 (s, 1 H). 6,6-diiethyl-1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yl)picolinamide WO 2008/125945 PCT/IB2008/000862 - 84 PKCb Ex. Ki No. Structure (n M) 1H NMR CH CH3 Chiral 0 N S1H NMR (400 MHz, DMSO-d6) d ppm 1.03 (s, 3 ,-N 0-b H) 1.11 - 1.18 (m, 6 H) 1.66 (s, 3 H) 1.75 (s, 3 H) H OH 3 2.19 (s, 3 H) 2.26 - 2.35 (m, 1 H) 2.63 - 2.72 (m, 2 A29 3 N18.1 H) 2.95 (d, J=11.87 Hz, 1 H) 3.35 - 3.43 (m, 1 H) O H 3 -4.60 - 4.84 (m, 2 H) 7.65 - 7.87 (m, 1 H) 8.05 N-(6,6-dimethyl-5-{[(2S)-2,4,5,5- 8.18 (m, 1 H) 8.19 - 8.33 (m, 1 H) 8.82 (d, J=4.80 tetramethylpiperazin-1-y]carbonyl}-1,4,5,6- Hz, 1 H) 10.91 (s, 1 H). tetra hyd ropyrrolo[3,4-o]pyrazo1-3-yl)pyrid ine-2 carboxamide
    CH
    3 O N Chiral NC O N H NMR (400 MHz, DMSO-d6) d ppm 1.24 (d, NC3N J=6.57 Hz, 3 H) 1.25 -1.36 (in, 1 H) 1.61 (d, /0 J= 13.64 Hz, 6 H) 1.64 - 1.78 (in, 4 H) 1.80 - 1.86 A130 N - F A3 NF 31.5 (in, 1 H) 1.97 (q, 1 H) 2.17 - 2.27 (in, 1 H) 2.73 F 2.83 (in, 2 H) 2.87 - 2.98 (in, 1 H) 3.84 (s, 1 H) F 4.49 - 4.67 (in, 2 H) 8.34 (d, J=8.34 Hz, 1 H) 8.49 N-(6,6-dimethyl-5-((3S,8aS)-3-methyl- (d, J=9.35 Hz, 1 H) 9.13 (s, 1 H). octahydropyrrolo[1,2-a]pyrazine-2-carbonyl) 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-y)-5 I_ (trifluoromethyl)picolinamide
    CH
    3 OHN N al N 1 H NMR (400 MHz, DMSO-d6) d ppm 0.72 - 0.95 N (in, 3 H) 1.46 -1.60 (mn, 6 H) 1.73 -1.96 (in, 2 H) OH3 N C 1.99 -2.12 (in, 3 H) 2.31 - 2.54 (mn, 4 H) 2.59 Al.1..... C 1 2.79 (m, 1 H) 2.82 -3.03 (m, 2H) 4.44 -4.66 (in, A31N 37.2 2 H) 7.46 -7.73 (in, 1 H) 7.93 -8.03 (in, 1 H) 8.05 &,~- 8.18 (in, 1 H) 8.67 (d, J=4.29 Hz, 1 H) 10. 19 N-(5-((2R,5S)-2-ethyl-1,5-diinethylpiperazine-4- 11.03 (in, 1 H) 11.65 -12.26 (mn, J=36.13 Hz, 1 carbonyi)-6,6-diinethyl-1 ,4,5,6- H). tetrahydropyrrolo[3,4-c]pyrazol-3 yl)picolinamide
    CH
    3
    OH
    3 Chiral N N 1 H NMR (400 MHz, DMSO-d6) d ppm 0.52 - 0.69 N& , (m, 6H) 0.88 -1.21 (m, 2H) 1.26 (d,J=6.82 Hz, 3 6 N CH0N H) 1.28 -1.38 (in, 1 H) 1.54 -1.81 (in, 6 H) 1.99 A132 N 61.9 (q, J=8.67 Hz, 1 H) 2.19C-H2.34 (, 2 H) 2.40 (dd, J=13.39, 7.33 Hz, I H) 2.72 - 2.85 (in, 2 H) 2.93 (t, J=7.58 Hz, 1 H) 3.84 (s, 1 H) 4.52 - 4.74 (in, 2 N-(6,6-diethyl-5-((3S,8aS)-3-methyl- H) 7.69 (dd, J=6.82, 5.05 Hz, 1 H) 7.98 - 8.11 (i, octahydropyrrolo[1,2-a]pyrazine-2-carbonyl)- 1 H) 8.11 -8.20 (i, 1 H) 8.73 (d, J=4.29 Hz, 1 H). 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3 yl)picolinamide Chiral CH, 0OCH , 1 H NMR (400 MHz, DMSO-d6) ppm 1.01 (3 H, d, J=6.32 Hz), 1.53 (1 H, i), 1.5 (3 H, s), 1.67 (3 H, 31N. s), 1.68-1.77(2 H, n), 1.90(2 H, s), 2.10 -2.20 A133 4
    /
    3 N 8.58 (2 H, m), 2.22(3 H, s), 2.44 (1 H, dd, J=11.62, 3.54 Hz), 2.79 (1 H, d, J=12.13 Hz), 3.07(1 H, d,
    CH
    3 J=11.87 Hz), 7.68 (1 H, ddd, J=7.58, 4.80, 1.26 N-(5-{[(7S)-5,7-dimethyl-5,8-diazaspiro[3.5]non- Hz), 8.04 - 8.12 (2 H, i), 8.72 (1 H, d, J=4.29 Hz). 8-y1]carbonylH-6,6-dimethyl-1H4,5,6 tetra hyd ropyrrolo [3,4-] pyrazol-3-y)pyrid ine-2 carboxamide WO 2008/125945 PCT/IB2008/000862 -85 PKCb Ex. Ki No. Structure (nM) 1H NMR Chiral CH H 3 1H NMR (400 MHz, DMSO-d6) d ppm 0.82-0.89 CHCH N 0 (, 9 H) 0.98 (s, 3 H) 1.22- 1.31 (i, 2 H) 1.54(s, C ) N N-46N 3 H) 1.66 (s, 3 H) 2.l1O (s, 3 H) 2.24 - 2.35 (in, 1 CN Al134 N. 0.1 H) 2.81 - 2.93 (in, 2 H) 3.15-3.17 (in, 1 H) 4.34 CH 3 4.50 (in, 1 H) 4.66 -4.77 (in, 1 H) 7.65 - 7.75 (in, CH 1 H)8.03-8.12(m, 1 H)8.11 -8.24(m, 1 H)8.67 N-(5-{[(2S)-2-isopropyl-4,5,5-trimethylpiperazin- - 8.81 (m, 1 H). 1 -yl]carbonyl} 6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yl)pyridine-2 carboxamide Chiral
    OH
    3 N.
    CH
    3 O H 3 N 1 H NMR (400 MHz, DMSO-d6) d ppm 0.79 -0.89 NH q N (in, 9 H) 0.98 (s, 3 H) 1.22 -1.31 (in, 1 H) 1.54 (s, A135 3_ 512 3H)1.66(s,3H)2.10(s,3H)2.24-2.36(m, 1
    OH
    3 N. H) 2.54 -2.62 (in, 1 H) 2.81 - 2.94 (in, 2 H) 3.12 CH 3 3.19 (m, 1 H) 4.42 (s, 1 H) 4.68 (s, 1 H) 8.17-8.18 5-chloro-N-(5-{[(2S)-2-isopropyl-4,5,5- (i, 2 H) 8.79 (s, 1 H). trimethylpiperazin-1 -yl]carbonyl}-6,6-dimethyl 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3 yl)pyridine-2-carboxamide Chiral Y N 0 1H NMR (400 MHz, DMSO-d6) d ppm 0.86 (s, 3 N H) 1.07 (d, J=6.29 Hz, 3 H) 1.19 - 1.29 (m, 2 H) A136 CH N CH3 /N5736 1.42 -1.75 (, 8 H) 2.36-2.45 ( , 1 H) 2.54 N )2.62 (8, 1 H) 2.63-2.80 (i, 2 H) 3.10 (s, 2 H) 3.78 - 3.87 (m , 1 H) 4.63 -4.75 (m , 1 H) 7.60 N-(5-{[(3S,8aS)-3,8a- 7.76 ( -, 1 H) 7.98 - 8.23 ( -, 2 H) 8.71 (s, 1 H). diinethyihexahydropyrroloj ,2-a]pyrazin-2(1 H) yl~carbonyl}-6,6-dirnethyl-1,4,5,6 tetra hyd ropyrroIo [3,4-c]py razol-3-yI)pyridine-2 carboxamide Chiral a CH CH, OH-1 3 ( N N N 1H NMR (300 MHz, DMSO-d6) d 0.95 - 1.00 (n, 4 9 H) 1.58 (s, 3 H) 1.59 - 1.66 (m, 1 H) 1.67 (s, 3 H) N 1.H0 N 2 3)1. (s, 3 H) 1.97-2.01 (, 1 H) 2.15 - 2.30 (m, 1 H) 2.40 - 2.42 (m, 2 H) 2.67 - 2.71 (m, 1 H) 2.76 2.81 (m, 1 H) 3.01 - 3.14 (), 2 H) 3.22 (s, 3 H) .0 N 3.32 - 3.36 (i, 3 H) 4.65 (s, 2 H) 7.68 -7.72 (i, 1
    OH
    3 IH) 8.05 -8.10 (m, 1 H) 8.13 -8.20 (m, 1 H) 8.73 N-(5-{[(2S,5R)-4-(3-methoxypropyl)-2,5- 8.73 (, 1 H) 10.9 (bs, 1 H). dinethylpiperazin-1 -y]carbonyl-6,6-dimethyl 1,4,5,6-tetrahydropyrrol[3,4-c]pyrazol-3 yl)pyridine-2-carboxainide. ___________________________ WO 2008/125945 PCT/IB2008/000862 - 86 PKCb Ex. Ki No. Structure (nM) 1H NMR Chiral CH, O Nt NN 0 1H NMR (400 MHz, MeOD) d ppm 1.18 (d, J= 6.04, 3 NN H) 1.26 (s, 3 H) 1.69 (s, 3H), 1.75-1.86(m, 4H) 1.95 CH, 2. 10 (in, 3 H) 2.80-2.97 (mn, 2H) 3.10-3.19 (in, 1 H) A138 CH /29.3 3.21-3.28(m, 1H)3.35-3.44(m, 1H)3.52-3.55(m, 1H) 3.77-3.93 (m,1I H) 4.64-4.68 (mn, 1 H) 4.88 - 4.97 (in, 1 F H) 7.74 - 7.91 (in, 1 H) 8.25-8.28 (in, 1 H) 8.61 (d, N-(5-{[(3S,8aS)-3,8a- J=2.77Hz, 1 H). dimethylhexahydropyrrolo[1,2-a]pyrazin-2(1 H) yl]carbonyl}-6,6-dimethyl-1,4,5,6 tetrahydropyrrolo[3,4-c]pyrazol-3-y)-5 fluoropyridine-2-carboxamide Chiral CH CH N - 01 H NMR (400 MHz, MeOIJ) d ppm 0.93 (t, J=7.43 Hz, C H N ; F N. ~ , , , ( n 3 H ) 1 .80 (s , 3 H ) 1 .8 2 - 1 .9 2 (i n , 2 H )1. 8 ( , 3 H N.6 -H1.77(,2 ) .0(s,3H3H)-1 1.82,1 - 1.92(,H) CH N/ A139 N 75.2 2.65-2.77 (, 2 H) 3.00-3.12 (i, 2 H) 3.22-3.29 (m )3.34 - 3.45 (in, 1 H) 3.77 - 3.88 (in, 1 H) 4.53 F - 4.66 (in, 2 H) 7.74 - 7.91 (in, 1 H) 8.27 (dd, J=8.81, N-(5-{[(3S,8aS)-3-ethyl-8a- 4.53 Hz, 1 H) 8.61 (d, J2.77 Hz, 1 H). methylhexahydropyrrolo[1,2-a]pyrazin-2(1 H) yl]carbonyl}-6,6-dimethyl-1,4,5,6 tetrahydropyrrolo[3,4-c]pyrazo-3-yl)-5 fluoropyridine-2-carboxamide Chiral OH H I- JN 1H NMR (400 MHz, MeOD) d ppm 0.95-1.05 (, 2H) NC H N1 1.10-1.22 (, 5H) 1.38-1.43 (, 3H), 1.73 (s, 3H) 1.78 A140 2 0 26.8 (s, 3 H) 2.16-2.26 (i, 1 H) 2.67 (s, 3 H) 2.70-2.81 (i, H29. N 1 H) 2.90-3.10 (m, 3H) 3.40-3.60 (mi, 2 H) 4.75-4.90 (, 2H) 6.47 (s, 1 H). 5-cyclopropyi-N-(6,6-diinethyl-5-{[(2S,5R) 2,4,5-tri7Hethylpiperazin-1 -yI]carbony.5-1-4,5,6 tetrahydropyrrolo[3,4-c]pyrazol-3-yI)isoxazole 3-carboxamide 0 -11 3 C OH 3
    H
    3 C,,, N N N Nl L.CH3 / ~H 1 H NMR (300 MHz, DMSO-d 6 ) ppm 0.89- 1.09 (in, 6 CN 0 N H) 1.50- 1.83 (in, 9 H) 1.89-2.02 (, J=9.42 Hz, 1 H) 2.16 - 2.28 (m, 1 H) 2.44 (d, J=6.78 Hz, 3 H) 2.75 (m, Al741 23.6 2 H) 3.10 (m, 2 H) 4.66 (s, 2 H) 7.63-7.75 (, 1 H) 8.02- 8.12 (in, H) 8.13 - 8.23 (i, 1 H) 8.73 (d, J=4.14 Hz, 1 H) 10.32 - 11.39 (m, 1 H) 12.28 (d, N-(5-((2R,5S)-4-(3-cyanopropyl)-2,5- J146.37 Hz, 1 H). diinethylpiperazine-4-carbonyl)-6,6-dimethyl 1 ,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3 yI)picolinamide__________________________ WO 2008/125945 PCT/IB2008/000862 -87 PKCb Ex. Ki No. Structure (nM) IH NMR oH 3 C CH 3
    H
    3 C,' N N NH o N HH %N A14.3CH 3 N H NMR (300 MHz, DMSO-d 6 ) ppm 1.04 (n, 6 H) 0 N 1.72 (in, 8 H) 1.93 - 2.07 (in, 1 H) 2.27 (d, J=5.09 Hz, Al 42 434 1 H) 2.44 (s, 2H) 2.78 (m, 2H) 3.11 (m, 2H) 4.36 -N 4.48 (in, 1 H) 4.51 - 4.61 (in, 1 H) 4.68 (in, 2 H) 7.70 (s, 1 H) 8.12 (d, J=25.05 Hz, 2 H) 8.73 (s, 1 H) 10.87 N-(5((2,5S-l -3-fuorpropl)-,5-(d, J=267.50 Hz, 1 H) 12.29 (d, J=144.86 Hz, 1 H) N-(5-((2R,5S)--iet--( (tetooraydo-2 dimethylpiperazine-4-carbonyl)-6,6-dimethyl 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3 yl)picolinamide H 3 C CH 3
    H
    3 C,' NN NMR (300 MHz, CHLOROFORM-d) ppm 1.01 (, " 'C / NH 3 H) 1.12 (d, J=6.03 Hz, 3 H) 1.25 (in, 3 H) 1.65 (in, 2
    CH
    3 ~N N, H) 1.73 (s, 3 H) 1.81 (s, 3 H) 2.04 (in, 2 H) 2.17 (s, 1 H) 2.52 (in, 2 H) 2.67 -2.80 (in, 1 H) 2.81 - 2.93 (in, 1 Al143 1.9 H) 3.12 (dd, J= 11.40, 1.79 Hz, 1 H) 3.39 (in, 3 H) 3.97 (dd, J= 10.93, 3.01 Hz, 2 H) 4.73 (in, 2 H) 7.52 (dd, N J=6.50, 4.80 Hz, 1 H) 7.88 -7.98 (in, 1 H) 8.26 (d, N-(5-((2R,5S)-2,5-dimethyl-1-((tetrahydro-2H- J=7.72 Hz, 1 H) 8.62 (d, J=4.14 Hz, 1 H) 10.38 (s, 1 pyran-4-yd)iethyl)piperazine-4-carbonyl)-6,6- H). dimethyl-1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yl)picolinamide
    H
    3 C CH 3
    H
    3 ,,' N 2 'N N' N / N H H 3CC H
    -
    N k O l'H 3 -N 1 H NMR (300 MHz, DMSO-de) 6 ppm 0.99 (in, 6 H) CCN N 1.59 (m, 8H) 1.88 -2.05 (m, 1 H) 2.13 -2.29 (m, 1 H) Al144 38.3 2.43 (d, J=6.59 Hz, 2 H) 2.65 (d, J=5.84 Hz, 1 H) 2.79 0N (d, J=9.61 Hz, 1 H) 3.09 (in, 3 H) 3.35 (in, 3 H) 4.65 (s, I 2 H) 7.70 (s, 1 H) 8.12 (in, 2 H) 8.73 (d, 1 H) 10.87 (d, N-(5-((2R,5S)-1-(4-cyanobutyl)-2,5- J=266.37 Hz, 1 H) 12.29 (d, J=147.31 Hz, 1 H). dimethylpiperazine-4-carbonyl)-6,6-dimethyl 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3 yl)picolinamide ______________________________ 0
    H
    3 C CH,
    H
    3 C,,. NlN / lH 1 H NMR (300 MHz, DMSO-d 6 ) 8 ppm 0.91 - 1.05 (m , 6 O N H)1.05 - 1.26 (m,2H 1.35 (t, J7.91 Hz, 2H)1.41 0 N 1.72 (m, 7H) 1.99 (d, J8.10OHz, 1 H) 2.17 -2.31 (in, A145 00 17.6 2 H) 2.41 (d, J=6.40 Hz, 2 H) 2.61 -2.83 (m, 3 H) 2.99 - N -3.13 (m, 2 H) 3.19 - 3.29 (m, 2 H) 3.74- (3.86 (i, 2 H) 4.65 (s, 2 H) 7.66-7.70 (in, 1 H) 8.08 (, 1 H) 8.18 (i, 1 H) 8.73 (s, 1 H) 10.87 (d, J269.38 Hz, 1 H) N-(5-((2R,5S)-2,5-dimethyl-1 -(2(tetradhydro- 12.28 (d, J=149.76 Hz, 1 H). 2H-pyran-4-yI)ethyl)piperazine-4-carbonyl)-6,6 dimethyl-1 ,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yI iolnmie____ WO 2008/125945 PCT/IB2008/000862 -88 PKCb Ex. Ki No. Structure (nM) IH NMR oH 3 C CH 3
    H
    3 C,, N N Na NH O H N N /-J"H H N H NMR (300 MHz, DMSO-d 6 ) 8 ppm 1.07 (d, J=5.84 o N Hz, 3 H) 1.32 (d, J=5.84 Hz, 3 H) 1.62 (s, 3 H) 1.65 1.81 (in, 5 H) 1.81 - 1.99 (in, 2 H) 2.69 -2.99 (in, 2 H) A146 1.7 3.30 (s, H) 3.36-3.55 (i, 3 H) 3.80 (i, 1 H) 3.97 (d, INJ=9.04 Hz, 2 H) 4.72 (d, J=1 .88 Hz, 2 H) 7.70 (in, 1 H) 8.05 - 8.18 (in, 2 H) 8.73 (d, J=0.75 Hz, 1 H) 9.47 (s, 1 N-(5-((2R,5S)-2,5-dimethyl-1 -(tetrahydro-2H- H) 10.87 (s, 1 H) pyran-4-yl)piperazine-4-carbonyl)-6,6-dimethyl 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3 yl)picolinamide
    OH
    3 C CH 3 H3C".(- N
    H
    3 C "NH 1 H NMR (300 MHz, DMSO- Qs 8 1.06 (d, J=5.84 Hz, N-.-/-CH, 3 H) 1.23 - 1.28 (in, 1 H) 1.32 (d, J=4.33 Hz, 3 H) 1.62 H N0 (s, 3 H) 1.69 (s, 3 H) 2.04 -2.19 (in, 1 H) 2.59 -2.81 A14 (in, 1 H) 2.59 - 2.81 (in, 1 H) 2.83 - 2.98 (in, 1 H) 3.05 A147 N' 0 ~ N10 - 3.20 (in, 1 H) 3.21 - 3.46 (in, 4 H) 3.21 - 3.46 (in, 1 'I H) 3.54 - 3.71 (in, 2 H) 3.72 - 3.81 (in, 1 H) 3.81 - 3.91 N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydrofuran- (m, 1 H) 4.63 - 4.80 (i, 2 H) 7.65 - 7.74 (i, 1 H) 7.99 3-ylmethyl)piperazin-1-yl]carbonyl}-6,6- -81 i,1H .9(,J09 z )87 d dimethyl-1,4,5,6-tetrahydropyrrolo[3,4- J=4.52 Hz, 1 H) 9.56 (br. s., 1 H) 10.86 (s, 1 H). c]pyrazol-3-yI)pyridine-2-carboxamide CH CH3 N..N F H NMR (300 MHz, CHLOROFORM-d) S ppm 1.06 (d, N, O0 N' J=6.03 Hz, 3 H), 1.20 (d, J=5.84 Hz, 3 H), 1.73 (s, 3 Ci. H), 1.81 (s, 3 H), 2.15 - 2.32 (m, 1 H), 2.65 -2.80 (m, 2 A148 O 3 N48.3 H), 2.80 - 2.91 (in, 1 H), 3.00 - 3.14 (in, 1 H), 3.24 1.7 3.41 (s, 1 H), 3.59 - 3.91 (m, 2 H), 4.57 - 4.83 (m, 2 J H), 7.47 - 2 H) 4 H), 7.63 8H, H) 7.87 - 7.99 H H), 8.27 (d, J=7.91 Hz, 1 H), 8.63 (d, J=4.14 Hz, 1 H), N-(5-{[(2S,5R)-2,5-dimethyl-4-(1 ,3-oxazol-4- 10.36 (s, 1 H). ylmethyl)piperazin-1 -yI]carbonyi}-6,6-dimethyl 1 ,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3 _____yI)pyridine-2-carboxamide 0H 3 0 O H 3
    H
    3 C"- NN NH NJ.$CH3 1 H NMR (300 MHz, DMSO-d 6 ) 5 0.95 - 1.07 (in, 6 H) HN 0 1.33 -154 (m,2H) 1.33 -1.54 (m, 1 H) 1.54 - 1.63 (m, 3 H) 1.67 (br.s., 4 H) 2.11 -2.22 (m, 1 H) 2.
    A149 N <10 2.91 (m, 1 H) 2.68 -2.91 (m, 2 H) 3.06 - 3.20 (in, 3 H) 3.06 - 3.20 (m, H) 3.20 - 3.28 (m, 1 H) 3.88 (d, J=9.04 Hz, 2 H) 4.02 -4.18 (, 0 H) 4.56 -4.71 (i, 2 F H) 7.93-8.04 (m , 1 H) 8.19 8.29 (i, 1 H) 8.69 8.79 N-(5-J((2S,5R)-2,5-dimethY=44(tetrahydro-2H- (in, 1 H). pyran-4-yI)piperazin-1 -yI]carbonyl}-6,6 dimethyl-1 ,4,5,6-tetrahydropyrrolo[3,4 1 c]pyrazol-3-yl)-5-fluoropyridine-2-carboxamide I WO 2008/125945 PCT/IB2008/000862 -89 PKCb Ex. Ki No. Structure (n M) IH NMR
    OH
    3 C CH 3 N N NH HO- ,,,. N N CH 3 1 H NMR (300 MHz, DMSO-d 6 ) 80.96 (d, J6.03 Hz, 3
    H
    3 C HN6 H) 1.37-1.52 (m, 1 H) 1.59 (s, 3 H) 1.63-1.77 (i, 1 H) 1.67 (s, 3H) 1.86 -1.92 (m, 2H) 1.92 -1.99 (m, 1 A15 N 42.0 H) 2.11 - 2.23 (m, 4H) 2.66 -2.79 (m, 1 H) 2.98 -3.15 A150 N (in, 1 H) 2.98 -3.15 (in, 1 H) 3.38 -3.50 (in, 2 H) 3.38 -3.50 (in, 1 H) 4.57 -4.73 (in, 2 H) 7.65 - 7.76 (in, 1 N-(5-((2R,5S)-2-(2-hydroxyethyl)-1,5- H) 8.04-8.13 (m, 1 H) 8.13-8.22 (i, 1 H) 8.73 (d, dimethylpiperazine-4-carbonyl)-6,6-dimethyl- J=4.52 Hz, 1 H) 10.86 (br. s., 1 H). 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3 yl)picolinamide _____(Isomer A)I
    OH
    3 C CH 3 -NkN NH 1H NMR (300 MHz, DMSO-d 6 ) 5 1.19 (d, J=6.59 Hz, 3 ,NJ CH 3 H) 1.42 - 1.55 (m, 1 H) 1.61 (d, J=10.93 Hz, 6 H) 1.70
    H
    3 . H -1.82 (m, 1 H) 1.87 - 1.96 (m, 2 H) 1.99 -2.11 (m, 1 42. 51H) 2.15 (s, 3 H) 2.20 2.32 (-, 1 H) 2.77 H 2.90 (-, 1 1N 152 H) 3.06 - 3.14 (m, 1 H) 3.24-3.40 (, 1 H) 3.40 - 3.55 -m, 1 H) 3.40 - 3.55 (i, 1 H) 3.58 - 3.72 (i, 1 H) 4.51 N-(5-((2S,5S)-2-(2-hydroxyethyl)-1H5- -84.67 (i, 2 H) 7.65- 87.74 , (m, 1 H) 8.03-8.12 (, 1 d imethylpi pe razine-4-ca rbonyl)-6,6-diimnethyl- H) 8.12 - 8.19 (in, 1 H) 8.73 (d, J=4.71 Hz, 1 H) 10.82 1J,4,5,6-tetrahydropyrro=o[3,4-c]pyrazol-3- (br. s., 1 H). yI)picolinainide (Isomer B) 0 NN NH
    H
    3 C' H'N O N CH 3 1 H NMR (300 MHz, DMSO-d 6 ) 8 0.94 (d, J=5.84 Hz, 6 HN6 H) 0.98 - 1.08 (m, 5 H) 1.08 - 1.23(,2 H) 1.49 - 1.59 (-, 1 (m 1.59 - 1.76 (, 3 H) 1.92 -2.04(,2H)2.17 A152 N 76.2 - 2.31 (-, 1 H) 2.71 - 2.86 (-, 1 H) 3.08 - 3.19 (-, 1 H) 3.19 - 3.29 (m, 3 H) 3.76 - 3.92 (m, 2 H) 4.69-4.88 (in, 2 H) 7.64 - 7.78 (i, 1 H) 8.03 - 8.12 (m, 1 H) 8.12 N-(5'-{[(2S,5R)-2,5-diiethyl-4-(tetrahydro-2H- - 8.23 (n, 1 H) 8.73 (d, J=4.14 Hz, 1 H) 11.00 (br. s., 1 pyran-4-yliethyl)piperazin-1 -yI]carbonyl)-4',5'- H) 12.01 (br. s., 1 H). dihydro-1 H-spiro[cyclopropane-1,6' pyrrolo[3,4-c]pyrazol]-3'-yI)pyridine-2 carboxamide____________________________
    OH
    3 C CH 3 NH 1H NMR (300 MHz, CHLOROFORM- ) 6 1.04 (d, H r 0 - J6.22 Hz, 3 H) 1.14 (d, J=6.22 Hz, 3 H) 1.39 (s, 3 H) H HN 1.72 (s,3H) 1.81 (s, 3 H) 1.92 - 2.04 (m, 1 H) 2.41 .
    3 2.51 (m, 1 H) 2.52 -2.65 (m, 1 H) 2.52 - 2.65 (m, 1 H) Al 53 H N 2.68 - 2.76 (m, 1 H) 2.76 -2.85 (m, 1 H) 3.13 - 3.24 I (m, 1 H) 3.41 - 3.73 (m, 1 H) 4.28 -4.38 (m, 2 H) 4.48 (d, J=5.65 Hz, 1 H) 4.55 (d, J=5.65 Hz, 1 H) 4.65 N-[5-({(2SS-,-i~methyl-4-[(3in-- 4.75 (in, 2 H) 7.49 - 7.58 (in, 1 H) 7.89 - 8.00 (in, 1 H) intylroetnl-,-iethyl-ipeazin-- 8.28 (d, J=7.91 Hz, 1 H) 8.64 (d;* J=4.52 Hz, 1 H) tetrahydropyrrolo[3,4-c]pyrazol-3-y]pyridHine-2- 10.33 (s, 1 H). carboxamide WO 2008/125945 PCT/IB2008/000862 -90 PKCb Ex. Ki No. Structure (nM) 1H NMR
    OH
    3 C CH 3 kN NH
    H
    3 C'. N N CH 3 1 H NMR (400 MHz, MeOD) 8 1.00-1.02 (i, 6 H) 1.08 HO HN 0 1.18 (i, 3 H) 1.50-1.60 (i, 2 H) 1.66 (s, 3 H) 1.69 (s, A154 CH 3 N3 H) 2.07-2.10 (i, 1 H) 2.41 -2.49 (i, 1 H) 2.51 0N 25.1 2.52 (in, 2 H) 2.72 -2.82 (in, 2 H) 3.05 -3.11 (in, 1 H) 1 3.12 -3.22 (in, 1 H) 3.70 -3.76 (in, 1 H) 4.71 - 4.72 N-[5-({(2S,5R)-4-[(1 R)-3-hydroxy-1- (i, 2 H) 7.51 -7.54 (i, 1 H) 7.91 -7.95 (i, 1 H) 8.10 methylpropyl]-2,5-dimethylpiperazin-1- -8.12 (i, 1 H) 8.60-8.61 (m, 1 H). yl}carbonyl)-6,6-dimethyl-1,4,5,6 tetrahydropyrrolo[3,4-c]pyrazol-3-yl]pyridine-2 carboxainide 0H 3 C OH 3
    H
    3 C0'r XN NH N..-OH3 1H NMR (400 MHz, MeOD) 8 0.99-1.01 (m, 6 H) 1.15 HN6 01.17 (m, 3 H) 1.44 - 1.56 (m, 2 H) 1.58 (s, 3 H) 1.60 (s, A H 3 3 H) 1.91 - 1.99 (m, I H) 2.23 - 2.29 (m, 1 H) 2.43 N 43.3 2.50 (m, 2 H) 2.89 - 2.96 (m, 2 H) 3.04 - 3.10 (m, 2 H) 3.69 - 3.77 (m, 1 H) 4.68 - 4.84 (m, 2 H) 7.50 - 7.53 N-[5-(( (2S,5R)-4-[(2 S)-3-hydroxy-1H- (i, 1 H) 7.90 - 7.94 (i, 1 H) 8.10-8.11 (i, 1 H) 8.59 nethylpropyl]-2,5-dinethylpiperazin-1 - - 8.60 (m, 1 H). yIlcarbonyl)-6,6-diinethyl-1,4,5,6 tetra hyd ropyrro lo [3,4-c] pyrazol-3-yi] pyrid ine-2 carboxamide OH3C CH3 N NH
    H
    3 C'. N "' FN 1 H NMR (400 MHz, MeOD) 0.98-1.01 (i, 6 H) 1.60 N H 3 /-/' C3H N60 (s, 3 H) 1.69 (s, 3 H) 2.08 -2.13 (in, 1 H) 2.37 -2.43 A156 HO-Y'- (in, 1 H) 2.47 - 2.53 (in, 2 H) 2.89 -2.97 (in, 2 H) 3.04 -~N 108 - 3.14 (m, 2H) 3.44 -3.47 (m, 2H) 3.50 -3.61 (m, 4 H) 4.68 -4.76 (in, 2 H) 7.51 - 7.54 (in, 1 H) 7.91 7.95 (m, 1 H) 8.10 -8.12 (in, 1 H) 8.59 -8.60 (in, 1 N-[5-({(2S,5R)-4-[2-(2-hydroxyethoxy)ethylJ- H). 2,5-dimethylpiperazin-1 -yI}carbonyl)-6,6 diy)ethyl-1,4,5,6-tetrahydropyrrolo[3,4 ctpyrazol-3-y c]ppyrridazne-2-carboxa mide O OH CH 3 CH N 0-, %C r 1 H NMR (300 MHz, DMSO-d6) ppm 0.88- 1.07 (m , 6 N H), 1.58 (s, 3 H), 1.67 (s, 3 H), 2.10 (t, J10.0 Hz, 1 H), 2.32 - 2.48 (m, 3 H),2.75 - 2.91 (m, 2 H), 3.06 (dd, A157 N 38.8 J=9.2, 1.5 Hz, 2 H), 3.25 (s, 3 H), 3.39 - 3.46 (m, 2 H), 4.66 (s, 2 H), 7.64-7.77 (m, 1 H), 8.03 -8.13 (m, 1 H), 8.14- 8.24 (m, 1 H), 8.69 - 8.80 (i, I H), 10.86 (br. s., N(5-{[(2S,5R)-4-(2-inethoxyethyl)-2,5- 1 H), 12.18 (br. s., 1 H) diinethylpiperazin-1 -yI]carbonyl}-6,6-dimethyl 1 ,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3 yI)pyridine-2-carboxaiide WO 2008/125945 PCT/IB2008/000862 - 91 PKCb Ex. Ki No. Structure (nM) IH NMR O CH CH 3 H N
    CH
    3 N O 0 CH N 1 H NMR (400 MHz, MeOD) 8 ppm 0.79 (d, J6.4 HZ, ~3H), 1.03 (d, J=6.0 Hz, 3H), 1.07 (d, J=6.0 Hz, 3H), A158 N1.60 (s, 3H), 1.70 (s, 3H), 1.96- 2.07 (, 2H), 2.15 Al 58 50.4 2.19 (in, 1 H), 2.49 -2.56 (in, 2H), 2.76 -2.83 (in, 2H), " 1 3.07 - 3.14 (mn, 3H), 3.44 - 3.46 (in, 2H), 4.73 -4.79 N-[5-({(2S,5R)-4-[(2S)-3-hydroxy-2- (m, 2H), 7.51 - 7.54 (i, 1 H), 7.91 - 7.95 (i, 1 H), 8.09 methylpropyl]-2,5-dimethylpiperazin-1- 8.11 (i, 1H), 8.59-8.61 (i, 1H). yl}carbonyl)-6,6-dimethyl-1,4,5,6 tetrahydropyrrolo[3,4-c]pyrazol-3-yl]pyridine-2 carboxainide ___ ________________________ 0 O H . O H 3 OHCN fN 'ZN OH 3 N.....O H NMR (400 MHz, MeOD) 8 ppm 0.76 (d, J=6.8 HZ, 0 N3H), 1.00 - 1.02 (, 6H), 1.60 (, 3H), 1.69 (s, 3H), 1.88- 1.97 ( , 2H), 2.02 - 2.07 (m, 1 H), 2.44- 2.49 50N(i.4 , 2H), 2.69- 2.72 (im, 1 H), 2.97-3.00 (in, 1 H), 3.08 .0 - 3.10 (m, 2H), 3.40 - 3.48 (m, 2H), 4.72 - 4.78 (, N-[5-(((2S,5R)-4-[(2R)-3-hydroxy-2- 2H), 7.50-7.53 (m, IH), 7.91 -7.95 (m, 1H), 8.10 inethylpropyl]-2,5-dinethylpiperazin-1-- 8.12 (m, 1H), 8.59 - 8.60 (m, 1H). yI~carbonyl)-6,6-diinethyl-1,4,5,6 tetra hyd ropyrro lo[3,4-c]pyrazol-3-y]pyrid in e-2 carboxamide.
    H
    3 O CH 3 H O O N 0 N NI ~ NH 1 H NMR (400 MHz, MeOD) 8 ppm 1.07- 1.16 (in, 6 H) 1.70 (s, 3 H) 1.72 - 1.80 ( , 5 H) 2.47 (s, 3 H) 2.54 (s, A160 ( H 3 O-('0 24.9 3 H) 2.60 (d, J=6.55 Hz, 2 H) 2.89 - 3.00 (m, 2 H) 3.13 N- NCH 3 - 3.37 (m, 2 H) 3.48-3.52 (m, 1 H) 3.64 (t, J=6.17 Hz, 2 H) 4.59 - 84.62 (i, 2 H) N-(5-{[(2S,5R)-4-(3-hydroxypropyl)-2,5 d imethyl pipe razin- 1 -yI]carbonyl}-6,6-dimethyl 1 ,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-y) 2,4-dimethyl-1,3-oxazole-5-carboxamide 0H 3 C CH 3 N NH CH,/-N F ZN NHC H 3 1H NMR (400 MHz, MeOD) 8 ppm 1.04- 1.15 (m, 6 N H) 1.70 (s, 3 H) 1.79 (s, 3 H) 2.20-2.30(1 H) 2.41 A10 2.53 (in, 1 H) 2.54- 2.75 (i, 2 H) 2.87 - 3.05 (m, 1 H) HO N 38.8 3.10- 3.28 (m, 3 H) 3.64- 3.76 (m , 2 H) 4.74- 4.85 (n, 2 H) 7.75 - 7.92 (m, H) 8.27- 8.29 (i, 1 H) 8.61 (d, F J=2.77 Hz, 1 H) 5-fluoro-N-(5-((2R,5S)- -(2-hydroxyethyl)-2,5 dimethylpiperazine-4-carbonyl)-6,6-dimethyl 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3 yl)picolinamidecarboxamide WO 2008/125945 PCT/IB2008/000862 - 92 PKCb Ex. Ki No. Structure (nM) 1H NMR 3NN 0 yNt /H N- 1H NMR (400 MHz, MeOD) 6ppm 1.11 -1.13 (in, 6 H) N CH3 N X~ 1.65 -1.83 (m, 8H) 2.11 -2.24 (m, 1 H) 2.43 -2.52 A162 H 3 C'".N (i, 1 H) 2.56- 2.69 (m, 2 H) 2.90-3.00 (in, 1 H) 3.10 F 21.7 - 3.30 (in, 3 H) 3.63 (t, J=6.04 Hz, 2 H) 4.81 (s, 2 H) 7.74 - 7.89 (in, I H) 8.25-8.30 (in, 1 H) 8.57-8.63 (in, 1 OH H) 5-fluoro-N-(5-{[(2S,5R)-4-(3-hydroxypropyl) 2,5-dimethylpiperazin-1-yl]carbonyl}-6,6 dimethyl-1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yl)pyridine-2-carboxamide NN y NO N CH N
    (
    3 ~ /r 1H NMR (400 MHz, MeOD) 8 ppm 1.06 - 1.13 (m, 6 H) 1.68 - 1.84 (m, 8 H) 2.10 - 2.19 (m, 1 H) 2.37 - 2.48 1F24.5 (m, 1 H) 2.54 - 2.65 (m, 2 H) 2.75-2.93 (m, 2H) 3.11 3.26 (m, 2 H) 3.34 (s, 3H) 3.40-3.50 (i, 2 H) 4.73 4.85 (n, 2 H) 7.74 - 7.91 (m, 1 H) 8.25-8.33 ( m, H) 8.60-8.62 (in, 1 H) 5-fluoro-N-(5-{[(2S,5R)-4-(3-inethoxypropyl) 2,5-diinethylpiperazin-1 -yI]carbonyl)-6,6 dimethyl-1 ,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yl)pyridine-2-carboxamide NN A164 HC"iIIN~j 2.67 (in, 3 H) 2.95 -3.05 (in, 2 H) 3.13 - 3.25 (in, 2 H) F 56.9 3.37 (s, 3H) 3.53 - 3.61 (in, 2 H) 4.75 - 4.86 (in, 2 H) 7.76 - 7.89 (in, 1 H) 8.27-8.32 (in, 1 H) 8.60-8.64 (in, 1 H ' -H) 5-fluoro-N-(5-{[(2S,5R)-4-(2-methoxyethyl)-2,5 dimethylpiperazin-1 -yl]carbonyl}-6,6-dimethyl 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3 yl)pyridine-2-carboxamide
    H
    3 C CH 3 N NH F 1 H NMR (400 MHz, DMSO-d6, ppm) 6 1.68 (s, 6H), _ o1.53-3.03 (br m, 12 H), 2.57-3.10 (br s, 3H), 4.96 (s, N2.673m, 3 H) 2.95 , 3.0 (, 2 H 7.56, 7.80 H) N 7H), 8.16 (d, J = 7.80 Hz, 1H), 8.74 (d, 8.8 Hz, Bi7N5 3 2H), 7.67-7.71 (in, 1H), 8.08 (dd;, = 7.6 4.80 Hz, 1H), 10.42 (s, 0.5 H), 11.33 (s, 0.5H), 12.06 (s, 0.5H), Pyridine-2-carboxylic acid [5-(1 -cyclobutyl-4- 12.59 (s, 0.5H). fluoro-piperidine-4-carbonyi6,6-dimethyl 1 ,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-y] amide ____________________________ WO 2008/125945 PCT/IB2008/000862 - 93 PKCb Ex. Ki No. Structure (nM) 1H NMR CH CH 3 0 N, 1H NMR (400 MHz, DMSO-d6, ppm) 6 1.41-1.51 (in, N ,N 2H), 1.65-1.71 (in, 2H), 1.68 (s, 6H), 1.93-2.02 (in, F N 0 3H), 2.07-2.14 (in, 2H), 2.42-2.54 (in, 2H), 2.83-2.86 ( N (i, 2H), 3.27 (dd, J = 10.56, 10.56 Hz, 2H), 3.88 (dd, J B2 N89.8 = 3.27,11.04 Hz, 2H), 4.96 (d, J = 4.28 Hz, 2H), 7.70 0 ~(ddd, J = 1.26, 4.80,,7.56 Hz, 1 H), 8.08 (ddd, J = 1.76, 7.56, 7.56 Hz, 1 H), 8.16 (d, J = 7.56 Hz, 1 H), 8.73 (d, Pyridine-2-carboxylic acid {5-[4-fluoro-1- J = 4.03 Hz, 1H) (one pyrazole N-H and one amide N (tetrahydro-pyran-4-yl)-piperidine-4-carbonyl]- H are missing due to deuterium exchange); 19F NMR 6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4- (376 Hz, DMSO-d6, ppm) 6 -16 c]pyrazol-3-yi}-amide CH3 N,N NOO O H N N NF IN 1 HNMR (400 MHz, MeOD) d ppm 8.12 -8.17 (m, 1 H) 7.86 - 7.92 (in,, 1 H) 7.69 - 7.77 (in, 1 H) 5.07 (d, 63 /N C 67.4 J=4.80 Hz, 2 H) 4.61 - 4.66 (in, 2 H) 3.55 - 3.66 (in, 2 1 ~H) 2.98 (s, 3 H) 2.34 - 2.59 (in, 2 H) 1.80 -1.84 (in, 5
    CH
    3 0! H) 1.78 (s, 3 H). 3,4-dichloro-N-{5-[(4-fluoro-1 -methylpiperidin 4-yl)carbonyl]-66-dimethyl-1456 tetrahydropyrrolo[34-c]pyrazol-3-yl)benzamide 0
    H
    3 Q CH 3 N N N 1 H NMR (300 MHz, DMSO-d6) d ppm 1.68 (s, 6 H) HC- N 1 1.91 - 2.08 (m, 1 H) 1.91 - 2.08 (m, 2H) 2.10 -2.17 B4" N NT (in, 3 H) 2.20 (s, 3 H) 2.62 - 2.68 (in, 1 H) 2.68 -2.75 B4 H3CNT 0 (in, 1 H) 4.89 - 5.00 (in, 2 H) 7.66 - 7.72 (in, 1 H) 8.04 N-{5-[(4-fluoro-1-methylpiperidin-4- -8.11 (i, 1 H) 8.04-8.11 (i, 1 H) 8.14-8.19 (i, 1 yl)carbonyl]-6,6-dimethyl-1,4,5,6- H) 8.70-8.75 (i, 1 H) 10.85 (br. s., 1 H) tetrahydropyrrolo[3,4-c]pyrazol-3-yl}pyridine-2 carboxamide Chiiral CH
    OH
    3 0 N 11 ;N 1 H NMR (400 MHz, DMSO-d6) ppm 0.95 - 1.00 (11 H, CHCH, N 0 i), 1.59(3 H, s), 1.68(3 H, s), 1.88(3 H, s), 1.99(1 , CN28.6 dd, J1 1.08, 9.32 Hz), 2.27-2.37 (2 H, i), 2.37-2.44 (2 H, in), 2.66- 2.78 (2 H, i), 3.01 -3.10(2 H, in), d4.65 (2 H, d, J=3.53 Hz), 8.80 - 8.83 (1 H, i), 8.94 (1 N-(5-{[(2S,7R)-4-ethyl-2,5-dimethylpiperazin-1- H, d, J=2.27 Hz), 9.31 (1 H, d, J=1.26 Hz). yI]oarbonyl}-6,6-dimethyl-1,4,5,6 tetrahydropyrrolo[3,4-c]pyrazol-3-yJ)pyrazine-2 carboxamide
    OH
    3 O OH 3
    OH
    3 ,,.(-N /NH N CA 0 1H NMR (400 MHz, CHLOROFORM-d) 5 ppml.08 1.20(m, 6 H), 1.75 (s, 3 H) 1.84 (s, 3 H) 2.10 -2.20 02 OH 3 4(, 1 H) 2.30-2.40 (, 4 H) 2.55 (s, 3 H) 2.56 (s, 3H)
    H
    3 1 50.3 2.64- 2.74 (m, 1 H) 2.78-2.86 (m,, 1 H) 3.00-3.10(, (1 H) 3.25-3.35 (m, 1 H) 4.68 (d, J = 9.60 Hz, 1 H) 4.83 H)3 8.70 - .75 (, 1 H) .85 (br. s. 1HH N-(6,6-dimethyl-5-{[(2S,5R)-2,4,5-(dJ=9.0H,1)855(,I) trimethylpiperazin-1 -yI]carbony}-1 ,4,5,6 tetra hyd ro pyrro lo[3,4-c]pyrazo1-3-yl)-2,4 dimethyl-1c,3-oxazole-5-carboxamide
    II
    WO 2008/125945 PCT/IB2008/000862 -94 PKCb Ex. Ki No. Structure (nM) 1H NMR
    OH
    3 C CH 3 N NH
    OH
    3 , N / N H 1 H NMR (400 MHz, CHLOROFORM-d) ppm 1.00 CH3 N 1.11 (i, 6 H) 1.67 (s, 3H), 1.74 (s, 3H)2.10-2.25 (,
    OH
    3 3 03 2 H) 2.31 (s, 3 H) 2.65 - 2.72 (in, I H) 2.70 (s, 3H) /N 35.1 2.75 -2.80 (in, 1 H) 2.92 - 3.00 (in, 1 H) 3.20 -3.35 SA~ (in, 1 H) 4.62 (d, J=12.80 Hz, 1 H) 4.72 (d, J=12.80
    OH
    3 Hz, 1 H) 8.03 (s, 1 H) 9.58 (brs, 1 H) N-(6,6-dimethyl-5-{[(2S,5R)-2,4,5 trimethylpiperazin-1-yl]carbonyl}-1,4,5,6 tetrahydropyrrolo[3,4-c]pyrazo-3-yl)-2-methyl 1 ,3-thiazole-4-carboxainide _______________________
    OH
    3 C OH 3
    OH
    3 , -N I N N OH 3
    OH
    3 N 0 1H NMR (400 MHz, CHLOROFORM-d) 6 ppm 0.98 043 1.11 (m, 6 H) 1.65 (s, 3 H)1.74 (s, 3 H) 1.94 - 2.02 (m, O4CH 3 N 45.1 1 H) 2.10 - 2.30 (, 1 H) 2.22 (s, 3H) 2.50-2.60 ( , 1 31 H) 2.62 - 2.73 (m, 4 H) 2.80 - 2.95 (m, 1 H) 3.12 - 3.20 0-// (m, 1 H) 4.53 (d, J=13.60 Hz, 1 H) 4.67 (d, J=13.60 N-(6,6-dimethyl-5-{[(2S,5R)-2,4,5- Hz, 1 H) 7.72 (s, 1 H) 9.35 (brs, 1 H). trimethylpiperazin-1-y]carbonyl-1,4,5,6 tetra hyd ropyrro lo[3,4-c] pyrazol-3-yi)-5-inethyl 1,3-oxazole-4-carboxamide OH3C CH 3 N NH
    CH
    3 , N / N CH 3 N 1H NMR (400 MHz, CHLOROFORM-d) 6 ppm 0.98 CH 3 N 1.02 (m, 6 H) 1.66 (s, 3 H) 1.74 (s, 3 H) 2.00 -2.06 O4
    OH
    3 (in, 1 H) 2.18 - 2.23 (m, 1 H) 2.23 (s, 3H) 2.52 -2.60 o 46.5 (, 4 H) 2.69 -2.73 (m, 1 H) 2.91- 2.95 (m, 1 H) 3.17 N -- j 3.23 (m, 1 H) 4.60 (d, J=13.60 Hz, 1 H) 4.74 (d, N-(6,6-dimethyl-5-{[(2S,5R)-2,4,5- J13.60 Hz, H) 7.80 (s, 1 H) 8.64 (brs, 1 H) trimethylpiperazin-1 -yl]carbonyl}-1,4,5,6 tetrahydropyrrolo[3,4-c]pyrazo-3-yl)-4-methyl 1,3-oxazole-5-carboxamide
    OH
    3 C CH 3 N NH
    CH
    3 , N I N N 1H NMR (400 MHz, OHLOROFORM-d) 6 ppm 0.98 /H N H 1.03 (in, 6 H)1.32 (t, J = 7.6 Hz, 3 H) 1.65 (s, 3 H) 1.74 06 CH H 3 25. (s, 3H) 1.99 -2.07 (m, 1 H) 2.15 -2.24 (in, 4 H) 2.47 0 25.7 (s, 3 H) 2.54 -2.62 (in, 1 H) 2.69 - 2.80 (in, 3H) 2.91 N ~2.95 (in, 1 H) 3.12 -3.25 (in, 1 H) 4.56 -4.73 (in, 2 H)
    CH
    3 8.30 (s, 1 H) N-(6,6-dimethyl-5-{[(2S,5R)-2,4,5 trimethylpiperazin-1 -yl]carbonyl}-1,4,5,6 tetrahydropyrrolo[3,4-c]pyrazol-3-y)-2-ethyl-4 methyl-i ,3-oxazoie-5-carboxamide WO 2008/125945 PCT/IB2008/000862 - 95 PKCb Ex. Ki No. Structure (nM) 1H NMR
    OH
    3 C CH 3 N NH CH3, N ' N CH N1H NMR (400 MHz, CHLOROFORM-d) S ppm 0.98 /N 3 N 0 1.02 (m, 6 H) 1.26 (t, J = 7.6 Hz, 3 H) 1.65 (s, 3 H) 07 1.73 (s, 3 H) 1.95 - 2.05 (m, 1 H) 2.12 - 2.23 (m, 4 H) 66.4 2.53 - 2.58 (m, 1 H) 2.69 - 2.73 (m, 1 H) 2.89 - 2.93 (m, 1 H) 3.09 - 3.23 (m, 3 H) 4.51 (d, J=13.60 Hz, 1 H) N-(6,6-dimethyl-5-{[(2S,5R)-2,4,5- 4.65 (d, J=13.60 Hz, 1 H) 7.73 (s, 1 H) 9.25 (brs, 1 H) trimethylpiperazin-1 -yI]carbony}-1,4,5,6 tetra hydropyrro lo[3,4-c] pyrazol-3-y)-5-ethyl 1,3-oxazole-4-carboxamide
    OH
    3 C CH 3 /N NH
    CH
    3 , N NH N CH 3 CH3 CH N O CH N 0 1 H NMR (400 MHz, CHLOROFORM-d) 8 ppm 1.03 H 3 1. 19 (m, 10OH) 1.66 -1.74 (m, 6H) 1.99 -2.06 (s, 1 08-"N H) 2.20 -2.60 (in, 5 H) 2.70 -2.90 (in, 2 H) 2.95 C8 N 0/- 25 3.05 (in, 1 H), 3.30-3.42 (in, 1 H) 4.60 (d, J= 13.60 Hz, ) > 1 H) 4.73 (d, J= 13.60 Hz, 1 H) 8.10 (s, 1 H) 9.90 (brs, 2-cyclopropyl-N-(6,6-dimethyl-5-{[(2S,5R) 2,4,5-trimethylpiperazin-1 -yl]carbonyl}-1,4,5,6 tetrahydropyrrolo[3,4-c]pyrazo-3-y)-1, 3 oxazole-4-carboxamide Chiral 'N CH 3 N H 0 N N--T CH, 1H NMR (500 MHz, D20) d ppm 1.03 (s, 2 H) 1.20 (t, El N 61.6 J=7.42 Hz, 7 H) 1.54 - 1.63 (m, 6 H) 1.84 (s, 2 H) 02.20 (s, 2 H) 2.79 (d, J7.42 Hz, 3 H) 3.05 (s, 1 H) 4.50 (s, 3 H)6.66 (s, 1 H) 11.05 (s, 1 H). N-(6,6-dimethyl-5-((3S,8aS)-3-methyl octahydropyrrolo[1 ,2-a]pyrazine-2-carbonyl) 1 ,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yI)-5 ethylisoxazole-3-carboxamide I Chiral 0 CH 3 CH3 O N N N CH 3 1 H NMR (500 MHz, D20) d ppm 1.09 (s, 2 H) 1.54 E2 N N :72.9 1.63 (s, 11 H) 1.81 (s, 2 H) 1.97 (s, 1 H) 3.41 (s, 9 H) 4.54 (s, 1 H) 4.61 (s, 1 H) 8.63 (s, H) 9.07 (s, 1 H). 0 N-(6,6-dimethyl-5-((3S,8aS)-3-methyl octahydropyrrolo[1,2-a]pyrazine-2-carbonyl) 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-5 methylpyrazine-2-carboxamide I WO 2008/125945 PCT/IB2008/000862 - 96 PKCb Ex. Ki No. Structure (nM)_ 1H NMR Chiral O N OH CH, 1H NMR (400 MHz, DMSO-d6) d ppm 1.24 (d, J=6.57 0 N Hz, 3 H) 1.25 - 1.37 (m, 1 H) 1.60 (s, 3 H) 1.64 (s, 3 H) N 1.66 - 1.78 (m, 2 H) 1.79 - 1.88 (m, 1 H) 1.97 (q, J=8.76 Hz, 1 H) 2.23 (dd, J=10.36, 3.54 Hz, 1 H) 2.72 E3 5.51 - 2.83 (m, 2 H) 2.88 - 2.96 (m, 1 H) 3.36 (dd, J=12.51, 2.40 Hz, 2 H) 3.79 - 3.91 (m, 1 H) 4.54 - 4.73 (m, 2 H) 7.76 (t, J=7.45 Hz, 1 H) 7.86 - 7.95 (m, 1 H) 8.12 (d, J=7.83 Hz, 1 H) 8.20 - 8.27 (m, 2 H) 8.63 (d, J=8.59 N-(6,6-dimethyl-5-((3S,8aS)-3-methyl- Hz, 1 H) 10.90 (s, 1 8.27 (, 2 H) 8.63 (d, J-H) octahydropyrrolo[1,2-a]pyrazine-2-carbonyl)- H,1H 09 s )1.7(,1H 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3 yl)isoguinoline-3-carboxamide Chiral N N CH3 CH0 1 H NMR (400 MHz, DMSO-d6) d ppm 1.24 (d, J=6.82 o N Hz, 3 H) 1.26 - 1.36 (m, 1 H) 1.60 (s, 3 H) 1.64 (s, 3 H) N N OH, 1.66 - 1.78 (m, 2 H) 1.79 - 1.87 (m, 1 H) 1.97 (q, E4 6.17 J=8.67 Hz, 1 H) 2.22 (dd, J=10.48, 3.41 Hz, 1 H) 2.71 -2.85 (m, 2 H) 2.86 - 3.00 (m, 1 H) 3.35 - 3.40 (m, 2 H) 3.80 - 3.90 (m, 1 H) 4.52 - 4.77 (m, 2 H) 8.10 (d, J=6.06 Hz, 1 H) 8.38 (d, J=8.34 Hz, 1 H) 8.80 -'8.93 N-(6,6-dimethyl-5-((3S,8aS)-3-inethyl- (m, 2 H) 9.56 (s, 1 H). octahydropyrrolo[1 ,2-a]pyrazine-2-carbonyl) 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl) 1,6-naphthyridine-2-carboxamide Chiral N OH 3 o NO N C1H NMR (500 MHz, D20) d ppm 1.09 (s, 2 H) 1.30 (t, J=6.73 Hz, 4 H) 1.56 (s, 4 H) 1.62 (s, 5 H) 1.81 (s, 2 E5 0 /37.5 H) 1.97 (s, 2 H) 3.40 (s, 5 H) 4.05 (q, J=6.78 Hz, 3 H)
    H
    3 4.54 (s, 2 H) 7.07 (s, 1 H) 7.35 (s, 1 H) 7.46 (s, 3 H) 10.82 (s, 1 H). N-(6,6-dimethyl-5-((3S,8aS)-3-methyl octahydropyrrolo[1,2-a]pyrazine-2-carbonyl) 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-3 ethoxybenzamide Chiral IN CH 3 N
    CH
    3 N H NMR (500 MHz, D20) d ppm 0.67 (s, 2 H) 0.92 (s, N5 CH3 3 H) 1.04 (s, 2 H) 1.21 (s, 2 H) 1.55 (d, J=12.91 Hz, 9 E8 ,N 6.81 H) 1.89 (s, 2 H) 2.01 (s, 1 H) 2.28 (s, 1 H) 2.72 (s, I H) N 2.85 (s, 2 H) 3.05 (s, 1 H) 3.42 (s, 4 H) 4.51 (s, 2 H) 6.24 - 6.52 (m, 1 H). 3-cyclopropyl-N-(6,6-dimethyl-5-((3S,8aS)-3 methyl-octahydropyrrolo[1,2-a]pyrazine-2 carbonyl)-1,4,5,6-tetrahydropyrrolo[3,4 clpyrazol-3-yl)-1H-pyrazole-5-carboxamide
    I
    WO 2008/125945 PCT/IB2008/000862 - 97 PKCb Ex. Ki No. Structure (nM) 1H NMR Chiral ~N CH 3 N/ CH, 1 H NMR (400 MHz, DMSO-d6) d ppm 1.23 (d, J=5.81 0 N Hz, 3H) 1.26-l1.41 (in, 1 H) 1.61 (s, 3H)l1.65 (s, 3H) E N N1 67-1.84 (i, J =6.06 Hz, 4 H) 1.3-2 11 (i, 1 H) N71. 2.15 -2.33 (in, 1 H) 2.75 - 2.87 (in, 2 H) 2.90 - 3.01 E7 / / 2.5 (in, 1 H) 3.24 -3.40 (in, 2 H) 3.80 -3.96 (in, 1 H) 4.53 N -4.75 (in, 2 H) 7.98 -8.05 (in, 1 H) 8.18 -8.25 (in, 1 H) 8.26- 8.33 (in, 1 H) 9.54 (s, I H) 11.65 -12.21 (in, N-(6,6-dimethyl-5-((3S,8aS)-3-methyl- 1 H) 12.54 (s, I H). octahydropyrrolo[1,2-a]pyrazine-2-carbonyl) 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3 yl)quinoxaline-2-carboxamide Chiral CH O N NC CH C E8
    CH
    3 N N .. 1 H NMR (500 MHz, D20) d ppm 1.06 (s, 2 H) 1. 19 (s, E8 118 2 H) 1.56 (s, 4 H) 1.58 -1.65 (in, 5 H) 1.83 (s, 1 H) E8N 1.99 (s, 1 H) 3.42 (s, 8H) 4.02 (s, 3H)4.51 (s,2H1 N-., 7.05 (s, 1 H) 7.45 (s, 1 H) 10.87 (s, 1 H). N-(6,6-dimethyl-5-((3S,8aS)-3-methyl octahydropyrrolo[ 1,2-a]pyrazine-2-carbonyl) 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-1 methyl-1H-pyrazole-5-carboxamide Chiral N CH 3 N/ CH 3 N CH, 1H NMR (500 MHz, D20) d ppm 1.06 (s, 2 H) 1.20 (s, H H) 1 54-1.63 (m, 11 H) 1.82 (s, 2 H) 2.00 (s, 2 H)
    H
    3 SH 3 . 6 - 2.73 (m, 5 H) 3.12 (s, 1 H) 4.52 (s, 1 H) 4.58 (s, 1 H) 8.24 (s, 1 H). N-(6,6-dimethyl-5-((3S,8aS)-3-methyl octahydropyrrolo[1 ,2-a]pyrazine-2-carbonyl) 11,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yH)-2 _____methylthiazole-4-carboxamide Chiral ,N CH 3 CH N N N N CH 3 1H NMR (500 MHz, D20) d ppm 1.05 (s, 1 H) 1.20 (s, E9 N 10.6 12 H) 1.55 (s, 4 H) 1.57-1.65 (s, 4 H) 1.84 (s, 2 H) N 1.99 (s, 1 H) 3.41 (s, 7 H) 3.95 (s, 3 H) 4.50 (s, 2 H) CH CH, 6.95 (s, 1 H) 10.74 (s, 1 H). 3-tert-butyi-N-(6,6-dimethyl-5-((3S,8aS)-3 methyl-octahydropyrrolo[12-a]pyrazine-2 carbonyl)-1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-y)-1 -methyl-i H-pyrazole-5 carboxamide WO 2008/125945 PCT/IB2008/000862 - 98 PKCb Ex. Ki No. Structure (nM) IH NMR Chiral .N CH 3 O , N O ,
    CNCH
    3 1H NMR (500 MHz, D20) d ppm 1.09 (s, 2 H) 1.21 (s, Eli N O 28.9 2 H) 1.53 - 1.62 (m, 12 H) 1.82 (s, 2 H) 2.00 (s, 2 H) Y 2.30 (s, 6 H) 4.47 (s, 3 H) 10.57 (s, 1 H).
    CH
    3 N-(6,6-dimethyl-5-((3S,8aS)-3-methyl octahydropyrrolo [ ,2-a]pyrazine-2-carbonyl) 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl) 2,4-dimethyloxazole-5-carboxamide Chiral ,N CH 3 0 N NN CH 3 1 H NMR (500 MHz, D20) d ppm 0.89 (d, J=4.94 Hz, 2 E12 /58.6 H) 0.91 (s, 1 H) 1.07 (d, J=5.22 Hz, 5 H) 1.22 (s, 2 H) N 5.6 1.55 (s, 5 H) 1.61 (s, 6 H) 1.83 (s, 2 H) 1.99 (s, 2 H) 2.17 (s, 2 H) 4.49 (s, 3 H) 6.59 (s, 1 H) 11.01 (s, 1 H). 5-cyclopropyl-N-(6,6-dimethyl-5-((3S,8aS)-3 methyl-octahydropyrrolo[1,2-a]pyrazine-2 carbonyl)-1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yl)isoxazole-3-carboxamide Chiral ,N CH 3 o N F N CH 3 1H NMR (500 MHz, D20) d ppm 1.01 (s, 2 H) 1.20 (d, E13 F 135 J=14.28 Hz, 3 H) 1.28 (s, 1 H) 1.57 (s, 10 H) 1.86 (s, 1 F H) 2.05 (s, 1 H) 2.71 (s, 1 H) 4.56 (s, 2 H) 7.21 (s, 1 H) 7.59 (s, 1 H) 11.38 (s, 1 H) 12.50 (s, 1 H). N-(6,6-dimethyl-5-((3S,8aS)-3-methyl octahydropyrrolo[1,2-a]pyrazine-2-carbonyl) 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl) 2,3,6-trifluorobenzamide CH CH N O CH N N N CH N 1 H NMR (400 MHz, CDCI3-d) d ppm 1.29 - 1.40 (mn, 3 C'H',H), 1.33 (t, J = 7.5Hz, 3H), 1.63 - 2.14 (in, 11 H), 2.26 E14 OH 3 157 - 2.46 (in, 1 H), 2.72 - 3.06 (in, 6 H), 3.48 - 3.63 (in, 1 H), 3.90-4.05 (in, 1 H), 4.53 - 4.84 (in, 2 H), 6.92 (s, 1 1 0 H), 10.05 (brs, 1 H) 10.54 (brs, 1 H). N-(6,6-dimethyl-5-((3S,8aS)-3-methyl octahydropyrrolo[1,2-a]pyrazine-2-carbonyl) 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-3 ethylisoxazole-5-carboxamide WO 2008/125945 PCT/IB2008/000862 - 99 PKCb Ex. Ki No. Structure (nM) IH NMR
    ---
    3 C CH 3 HF 3 CCH ~~ H-C N 0 N 'H NMR (300 MHz, DMSO-d 6 ) 8 ppm 0.95 (d, J=5.27 Hz, 3 H), 1.00 (d, J=5.84 Hz, 3 H), 1.06 - 1.20 (m, 2 Fl 0 H), 1.29 (t, J=7.54 Hz, 3 H), 1.48 - 1.73 (m, 10 H), 1.92 H )= N22.4 - 2.00 (m, 2 H), 2.37 (s, 3 H), 2.39 - 2.46 (m, 2 H), 2.72 H 3 - 2.89 (m, 3 H), 3.01 - 3.18 (m, 2 H), 3.20 - 3.30 (m, 2 N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H- H), 3.82 (d, J=9.04 Hz, 2 H), 4.53 (s, 2 H), 10.66 (s, 1 pyran-4-ylmethyl)piperazin-1 -yI]carbonyl}-6,6- H), 12.16 (br. s., 1 H). dimethyi-1 ,4,5,6-tetrahydropyrroio[3,4 c~pyrazoi-3-yl)-2-ethyl-4-methy-1 ,3-oxazole-5 carboxamide
    CH
    3 N~3 N, N
    H
    3 C. CH NH N / 1 H NMR (500 MHz, DMSO-d6) 8 0.87 - 1.07 (i, 6 H) F2 >N 784 1.51-1.61 (m,4H)1.61 -1.76H(3,6H)1.91 (s,3H) o H3C ( ~ N2.00 -2.12 (in, 2 H) 3.00 -3.16 (in, 4 H) 3.20 -3.30 H3 H 3 C (in, 2 H) 4.54 -4.77 (mn, 2 H) 7.82 (s, 1 H).
    H
    3 C N-(5-{[(2S,5R)-4-(3-methoxypropyl)-2,5 dimethylpiperazin-1-yl]carbonyl}-6,6-dimethyl 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl) 2,6-dimethylpyrimidine-4-carboxamide
    CH
    3 Cj- 3 C- N, N N N 93" N -Cb NH 1 H NMR (500 MHz, DMSO-d6) 8 0.96 - 1.09 (in, 3 H) 1.09 -1.22 (mn, 4 H) 1.52 -1.63 (in, 4 H) 1.63 -1.70 F3 N~ (in, 4 H) 1.72 -1.80 (in, 1 H) 1.79 -1.88 (in, 1 H) 2.89 (/ 625 - 3.11 (in, 5 H) 3.11 -3.29 (mn, 4 H) 4.68 (br. s., 2 H) 0 8.71 - 8.87 (in, 1 H) 8.87 - 8.99 (in, 1 H) 9.20 - 9.33
    H
    3 C (m, 1 H). N-(5-{[(2S,5R)-4-(3-methoxypropyl)-2,5 dimethylpiperazin-1-yl]carbonyl}-6,6-dimethyl 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3 yl)pyrazine-2-carboxamide
    CH
    3 H N bN HC.CHb NH H3C". N- CHIO NHCH 3 1 H NMR (500 MHz, DMSO-d6) 6 0.90 - 0.96 (m, 3 H) N. / 0.96 -1.05 (in, 3 H) 1. 10 -1.22 (in, 3 H) 1.52 -1.58 F4 N'3. (in, 3 H) 1.58 -1.64 (in, 3 H) 1.64 -1.68 (in, 3 H) 2.97 H H3 -3.06 (in, 2 H) 3.05 -3.15 (mn, 3 H) 3.14 -3.25 (m, 4
    H
    3 C H) 3.90 -4.05 (m, 4 H) 4.47 -4.65 (i, 2 H) 6.87 - 6.99 3-ethyl-N-(5-{[(2S,5R)-4-(3-methoxypropyl)- (i, 1 H). 2,5-dimethylpiperazin-1-yl]carbonyl}-6,6 dimethyl-1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yl)-1 -methyl-1 H-pyrazole-5 carboxamide WO 2008/125945 PCT/IB2008/000862 -100 PKCb Ex. Ki No. Structure (nM) 1H NMR
    CH
    3 H Nj~ N H3C3CHNH N HN F5 0 N
    H
    3 OC>O~N O3" N -Hb N H 3 1 H NMR (500 MHz, DMSO-d6) 6 0.93 - 1.03 (in, 3 H) FS 0 - 71. 1.41.10 (mn, 3 H) 1.10 -1.18 (in, I H) 1.51 -1.62 /N7. (m, 4H) 1.62 -1.68 (m, 3H) 1.69 -1.82 (m, 2H) 2.35 0 H 3 C (br. s., 3 H) 2.82 -2.97 (in, 3 H) 2.95 -3. 10 (in, 2 H)
    H
    3 C 3.10 -3.20 (in, 2 H) 3.23 (s, 2 H) 4.50 -4.63 (in, 2 H). N-(5-{[(2S,5R)-4-(3-methoxypropyl)-2,5 dimethylpiperazin-1-yl]carbonyl}-6,6-dimethyl 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl) 2,4-dimethyl-1,3-oxazole-5-carboxamide
    CH
    3 H N3C N H3C_. CH, NH -N CH3 NH 2-ethyl-N-(5-{[(2S,5R)-4-(3-mnethoxypropyl)-4.1(n2H) 2,5-dimnethylpiperazin-1 -yI]carbonyl}-6,6 dimnethyl-1 ,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yi)-4-mnethyl-1 ,3-oxazole-5 N 0 CH,1 H NMR (500 MHz, DMSO-d6) 5 0.93 - 1.03 (m, 3 H) 01.0 - 1.10 (m, 3 H) 1.10 -r 1.8(, 1 H) 1.5 - 1.6 2 F6~1. (m 43. H) 1.62 -.6(, 3 H) 1. 9 - .82 (m, 2 H) 2. 35 7 m 0~br . 3 H) 2.2 - 2.7 (m, 3 H) 2.5 - 310 (m, 2 H) CH3 3.05 (m, 2 H) 3.05 - 3.13 (m, 2 H) 3.21 (s, 2 H) 4.45 carboxamide
    CH
    3 H N3 N N
    H
    3 O.( CH NH 1 H NMR (500 MHz, DMSO-d6) 6 0.94 - 1.02 (m, 3 H)
    H
    3 C 1.02 - 1.11 (m, 3 H) 1.56 (br. s., 3 H) 1.64 (br. s., 3 H) F7 67.1 1.67 - 1.81 (m, 2 H) 1.91 (s, 3 H) 2.08 - 2.12 (m, 2 H) osN CH 3 2.13 (s, 3 H) 2.26 - 2.29 (m, 2 H) 2.31 (s, 3 H) 2.94 p (none, 4 H) 3.08 - 3.19 (m, 2 H) 3.19 - 3.25 (m, 1 H) 2-(3,5-dimethylisoxazol-4-yl)-N-(5-{[(2S,5R)-4- 4.41 -4.59 (m, 2 H) 10.64 (br. s., 1 H). (3-methoxypropyl)-2,5-dimethylpiperazin-1 yl]carbonyl}-6,6-dimethyl-1,4,5,6 tetrahydropyrrolo[3,4-c]pyrazol-3-yl)aceta mide CH 3 H N N N CH3
    H
    3 C2ObN HPI ON-HON H 3 1 H NMR (500 MHz, DMSO-d6) 6 0.96 - 1.06 (in, 3 H) F8 0 --N 95.6 1.53 - 1.62 (in, 3 H) 1.62 -1.70 (in, 4 H) 1.70 -1.86 (in, 4 H) 1.91 (s, 3 H) 3.03 - 3.26 (in, 7 H) 3.70 - 3.92
    H
    3 C 0(in, 2 H) 4.49 - 4.68 (in, 2 H) 8.45 (br. s., 1 H). N-(5-{[(2S,5R)-4-(3-methoxypropyl)-2,5 dimethylpiperazin-1 -yl]carbonyl}-6,6-dimethyl 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-4 methyl-1,3-oxazole-5-carboxamide WO 2008/125945 PCT/IB2008/000862 - 101 PKCb Ex. Ki No. Structure (nM) 1H NMR CH N O N N0 CH N N 0 N CH3 N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H pyran-4-ylmethyl)piperazin-1-yl]carbonyl}-6,6 dimethyl-1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yi)-1 -methyl-1 H-imidazole-4 carboxamide N ' C N / C CHS N N CH N 1 H NMR (500 MHz, DMSO-d 6 ) 6 ppm 0.99 - 1.06 (m, 3 F10 CH 3 22.6 H), 1.06 - 1.27 (m, 5 H), 1.44 - 1.77 (m, 3.8232.64 (s, 3 H), 3.80 - 3.89 (m, 2 H), 4.52 - 4.62 (m, 2 H), 10.58 0 10.65 (m, 1 H) N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H pyran-4-ylmethyl)piperazin-1 -yl]carbonyl}-6,6 dimethyl-1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yl)-2,4-dimethyl-1,3-thiazole-5 carboxamide CH H N' N o N 0 C N C CHN NNH NMR (500 MHz, DMSO-d 6 ) 5 ppm 0.95 (d, J=6.11 CHHz, 5 H), 1.00 (d, J=5.84 Hz, 3 H), 1.06 - 1.17 (m, 3 29.8 H), 1.48 - 1.71 (m, 10 H), 1.92 - 1.98 (m, 2 H), 2.17 2.27 (m, 2 H 2.77 - 2.85 (m, 1 -43.77 - 3.86 (m, 3 N-(5-{[(2S,5R)-2,5-diethyl-4-H), 4.56 (s, 2 H), 6.66 (s, 1 H) (ttar-Hpyran-4-ylmethyl)piperazin-1 -yIcroyl66 ycabnI66dimethyl-1 ,4,5,6-eradoprl[34 terchrpyrzol-3-I),4-imetyl-1 ,13-thisazole 3-carboxamide o N CN N CH NMR (500 MHz, DMSO-d 6 ) 5 ppm 1.00 - 1.07 (m, 6 F2CH3 CH H), 5.08 1.022 (m, 2 H), 3.47 , 1. 73 (m, 10 H), 2.18 (s, 33.0 3 H), 3.78 - 3.90 (m, 3 H), 4.00 (s, 3 H), 4.51 - 4.64 (m, 2 H), 6.85 (d, J=1.30 Hz, 1 H), 10.69 - 10.80 (m, 1 H) N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H pyran-4-ylmethyl)piperazin-1 -yl]carbony}-6,6 dimethyl-1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yl)-1,3-dimethyl-1H-pyrazole-5 carboxamide WO 2008/125945 PCT/IB2008/000862 -102 PKCb Ex. Ki No. Structure (nM) 1H NMR CH N orN N O CH '. NN CH CH N N O 3 ' CH 3 'H NMR (500 MHz, DMSO-d 6 ) 8 ppm 0.97 (d, J=3.85 F13 5341.1 Hz, 3 H), 1.01 (d, J=6.04 Hz, 3 H), 1.04 -1.20 (m, 2 H), 1.48 - 1.73 (in, 10 H), 1.93 -2.02 (in, 2 H), 2.68 (s, o 3 H), 3.76 - 3.87 (in, 3 H), 4.57 (s, 2 H), 6.70 (s, 1 H) N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H pyran-4-ylmethyl)piperazin-1 -yl]carbonyl}-6,6 dimethyl-1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yl)-5-methylisoxazole-3 carboxamide CH3 N CH N N /-CH 3 N C F14~C N H /H NMR (500 MHz, DMSO-d 6 ) S ppm 0.92 - 0.97 (m, 3 NC OH, 3H 3 H), 1.03 (d, J=0.48 Hz, 3 H), 1.05 - 1.17 (m, 2 H), 1.26 F14 20.0 - 1.34 (m, 3 H), 1.46 - 1.72 (m, 10 H), 1.92 - 2.00 (m, 2 H), 2.68 (s, 3 H), 2.74 - 2.88 (m, 1 H), 3.75 - 3.88 (m, 2 o H), 4.38 - 4.48 (m, 2 H), 4.51 - 4.57 (m, 2 H), 6.81 N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H- 6.86 (m, 1 H) pyran-4-ylmethyl)piperazin-1 -yI]carbonyl}-6,6 dimethyl-1 ,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yl)-1 -ethyl-3-methyl-1 H-pyrazole-5 carboxamide CH CH3 N, N o 0 N o CH N N CH 3 N O F1N H 3 H NMR (500 MHz, DMSO-d 6 ) 5 ppm 0.84 - 1.06 (m, 6 52.1 H), 1.17 - 1.28 (m, 3 H), 1.46 - 1.77 (m, 10 H), 3.69 3.94 (m, 2 H), 4.48 - 4.69 (m, 2 H), 8.33 - 8.51 (m, 1 H) N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H pyran-4-ylmethyl)piperazin-1-yl]carbonyl}-6,6 dimethyl-1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yI)-5-ethyl-1,3-oxazole-4 carboxamide
    CH
    3 N OH N 0C N 0 N CH3 N NC '..No 3 1 H NMR (500 MHz, DMSQ-d 6 ) 5 ppm 0.98- 1,10 (in, 3 F1625.8 3.91 (in, 3 H), 3.95 (s, 3 H), 4.55 - 4.80 (in, 2 H), 6.71 0 6.87 (in, J=2.98, 1.59, 0.70, 0.70 Hz, 1 H), 7.74 - 7.93 N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H- (i, H) pyran-4-ylmethyl)piperazin-1-yl]carbonyl}-6,6 dimethyl-1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yl)-1-methyl-1H-pyrazole-3 carboxamide WO 2008/125945 PCT/IB2008/000862 -103 PKCb Ex. Ki No. Structure (nM) 1H NMR H CHN N F 0 N 0 N CH N NN N 1 H NMR (500 MHz, DMSO-d 6 )56ppm 0.69- 0.74 (in, 2
    CH
    3 H), 0.92 - 0.98 (in, 5 H), 0.99 - 1.02 (in, 3 H), 1.04 F17 19.4 1.20 (in, 2 H), 1.46 -1.74 (in, 10 H), 1.91 -1.99 (in, 2 o6 H), 2.82 (d, J=14.15 Hz, 1 H), 3.78 - 3.90 (in, 2 H), 3-cyclopropyl-N-(5-{[(2S,5R)-2,5-dimethyl-4- 4.57 (s, 2 H) (tetrahydro-2H-pyran-4-ylmethyl)piperazin-1 yl]carbonyl}-6,6-dimethyl-1,4,5,6 tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-1 H pyrazole-5-carboxamide CH , O NO CHN a. - 1 H NMR (500 MHz, DMSO-d 6 ) 8 ppm 0.92 - 0.97 (in, 3 Cl1N N F18 N CH 3
    CH
    3 H), 0.99-1.03 (m,3H), 1.04-1.18(m,2 H), 1.24(t, 32.1 J=7.49 Hz, 3 H), 1.51 - 1.73 (in, 10 H), 1.92 - 1.98 (in, 2 H), 2.69 -2.76 (in, 2 H), 2.78 - 2.85 (in, 1 H), 3.71 o 3.92 (i, 3 H), 4.47-4.63 (i, 1 H), 7.24 (s, 1 H) N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H pyran-4-ylmethyl)piperazin-1 -yl]carbonyl}-6,6 dimethyl-1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yl)-3-ethylisoxazole-5-carboxamide C N N O N C1NM DMN N 6 N/, 0 1 H NR(500 MHz, DSd6 ppm 0.94 - 0.99 (in, 3 C1 H 3 CH, H), 1.00 -1.03 (in, 3 H), 1.05 -1.18 (in, 2 H), 1.23 F1926.5 1.30 (, 3 H), 1.50- 1.75 (m, 10 H), 1.93-2.08 (, 2 H), 2.80 - 2.88 (in, 3 H), 3.78 - 3.88 (in, 2 H), 4.49 o 4.65 (i, 2 H), 6.65- 6.79 (i, I H) N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H pyran-4-ylmethyl)piperazin-1 -yl]carbonyl}-6,6 dimethyl-1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yl)-5-ethylisoxazole-3-carboxamide
    OH
    3 N OCH N O 0 rN N CH N CH 3 NCH O N F20 3
    CH
    3 1 H NMR(500 MHz, DMSO-d6)6ppm0.97-1.08(i, 3 F019.7 H), 1. 13 - 1.28 (in, 3 H), 1.52 - 1.73 (in, 10 H), 2.32 O2.39 (i, 3 H), 3.77 - 3.92 (i, 3 H), 4.53 -4.65 (i, 2 H) N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H pyran-4-ylmethyl)piperazin-1-yl]carbonyl}-6,6 dimethyl-1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yl)-2,4-dimethyl-1,3-oxazole-5 Harboxamide NMR_(500_M_ z,_DMSO-d)ppm0.69-0.74(m,2 WO 2008/125945 PCT/IB2008/000862 -104 PKCb Ex. Ki No. Structure (nM) 1H NMR CH O N N O
    CH
    3 N F1 N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H pyran-4-ylmethyl)piperazin-1-yl]carbonyl}-6,6 dimethyl-1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yl)-3-methylisoxazole-5 N CH H NMR (500 MHz, DMSO-de) 6 ppm 0.97 - 1.10 (in, 3 0H N 0 F223 H), 1.10 - 1.28 (m, 5 H), 1.50 - 1.77 (m, 10 H), 2.26 12.37 (m, 3 H), 3.81 - 3.90 (m, 2 H), 4.55 - 4.68 (m, 2 o H), 7.14 - 7.19 (m, 1 H) N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H pyran-4-ylmethyl)piperazin-1 -yI]carbonyl}-6,6 dimethyl-1 ,4,5,6-tetrahydropyrrolo[3,4 c] pyrazol-3-y I)--methylis,5oxadzo lecarboxamide CH CH 3 N O C N N CH 3 N CH 3 1H NMR (500 MHz, DMSO-d 6 ) 6 ppm 0.92 - 0.99 (m, 3 F22 3 H), 1.00 - 1.03 (m, 3 H), 1.06 - 1.20 (m, 2 H), 1.48 1.75 (m, 10 H), 1.91 - 2.08 (m, 2 H), 3.77 - 3.88 (m, 3 o H), 4.53 - 4.63 (m, 2 H) N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H pyran-4-ylmethyl)piperazin-1 -yl]carbonyl}-6,6 dimethyl-1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yl)-4-methyl-1 ,2,5-oxadiazole-3 carboxamide CH N CH N CH N N 0 CH C~pN N. 0 N CH H NMR (500 MHz, DMSO-d 6 ) 5 ppm 0.90 - 1.01 (m, 3 F233 CH,33 H), 1.00 - 1.06 (m, 3 H), 1.07 - 1.20 (m, 2 H), 1.23 1.28 (m, 1 H), 1.48 - 1.74 (m, 1 H), 3.77 - 3.88 (m, 3 o H), 4.50 - 4.63 (m, 2 H) N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H pyran-4-ylmethyl)piperazin-1 -yl]carbonyl)-6,6 dimethyl-1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yI)-2,5-dimethyl-1,3-oxazole-4 carboxamide oH NO F24L C<a N a H NMR (500 MHz, DMSO-de) 6 ppm 0.91 - 0.98 (mn, 6 F24 C 3
    CH
    3 H), 0.98 - 1.02 (mn, 3 H), 1.04 - 1.18 (mn, 2 H), 1.46 59.4 1.60 (mn, 5 H), 1.60 -1.73 (in, 7 H), 1.92 -1.99 (in, 2 H), 2.77 - 2.85 (in, 2 H), 3.76 - 3.86 (in, 2 H), 4.50 N-(5{[(2,5R-2,5dimthyl4-(ttraydro2H-4.61 (in, 2 H), 6.70 - 6.76 (in, 1 H) carboxamide ________________________ WO 2008/125945 PCT/IB2008/000862 -105 IPKCbr Ex. Ki No. Structure IH NMR OCH N N CH N N N N / S NMR (500 MHz, DMSO-d6) 5 ppm 0.93 - 0.97 (in, 3 N CH 3 CH, H), 0.98-1.03 (m, 3 H), 1.05-1.18 (i, 2 H), 1.36 (t, F25 J=7.62 Hz, 3 H), 1.49-1.73 (i, 10 H), 1.92- 1.99 (i, 2 H), 2.79 -2.86 (in, 1 H), 3.02 -3.11 (in, 1 H), 3.75 o6 3.88 (in, 3 H), 4.04 - 4.15 (mn, 2 H), 4.55 - 4.69 (in, 2 N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H- H), 8.36 (d, J1.37 Hz, 1 H) pyran-4-ylmethyl)piperazin-1 -yl]carbonyl}-6,6 dimethyl-1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yl)-2-ethyl-1,3-thiazole-4 carboxamide 0 CH OH 3 _N o-H NH NMR (300 MHz, DMSO-d 6 ) S ppm 0.95 (d, J5.46 Hz, 3 H), 1.00 (d, J=6.03 Hz, 3 H), 1.05 - 1.26 ( , 2 F26 N H), 1.47 - 1.78 (i, 10 H), 1.91 -2.00 (i, 2 H), 2.32 62 12.8 2.47 ( m, 2 H), 2.82 (d, J=9.04 Hz, 1 H), 3.00 - 3.19 (-, 2 H), 3.20- 3.30 (in, 2 H), 3.74 - 3.91 (, 2 H), 4.63 (s, F 2 H), 7.92 - 8.05 (in, 1 H), 8.17 - 8.32 (i, 1 H), 8.73 (d, N-(5-{[(2S,5R)-2,5-diinethyl-4-(tetrahydro-2H- J=2.45 Hz, 1 H), 10.79 (br. s., 1 H), 12.22 (br. s., 1 H) pyran-4-ylinethyl)piperazin-1 -yI]carbonyl}-6,6 dimethyl-1 ,4,5,6-tetrahydropyrrolo[3,4 ___ c] pyrazol-3-yi)-5-fluoropridine-2-carboxamide. O CH CH 3 CH N N N - CH3 N N OH 3 H NMR (300 MHz, DMSO-d 6 ) 5 ppm 0.97 (d, J=4.71 O N Hz, 3 H), 1.01 (d, J=6.03 Hz, 3 H), 1.06 - 1.25 (in, 2 F27 -~N 217 H), 1.45 -1.77 (in, 10 H), 1.92 - 2.05 (in, 2 H), 2.34 6o 21. 2.47 (in, 5 H), 2.80 - 2.91 (in, 1 H), 3.05 - 3.20 (in, 2 0 OH 3 " H), 3.21 - 3.30 (in, 2 H), 3.82 (d, J=9.23 Hz, 2 H), 4.65 N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H- (s, 2 H), 7.52 (d, J4.14 Hz, 1 H), 8.02 (s, 1 H), 8.57 pyran-4-ylmethyl)piperazin-1-yl]carbonyl}-6,6- (d, J=4.90 Hz, 1 H) diinethyl-1 ,4,5,6-tetrahydropyrrolo[3,4 cjpyrazol-3-yI)-4-inethylpyridine-2 _____carboxamide. o OH OH 3 o N NH NMR (300 MHz, DMSO-d 6 ) 5 ppm 0.95 (d, J=5.46 Hz, 3 H), 1.01 (d, J=6.03 Hz, 3 H), 1.05 - 1.24 (m, 2 H), 1.47 - 1.75 (m, 10 H), 1.91 - 1.99 (m, 2 H), 2.32 F02.7 2.47 (m, 2 H), 2.75 ( 2.90 (i, 1 H), 3.03 -3.18 (i, 2 0 H), 3.22 - 3.30 (m, 2 H), 3.82 (d, J=10.55 Hz, 2 H),
    OH
    3 4.03 (s, 3 H), 4.63 (s, 2 H), 7.10 (d, J=8.29 Hz, 8 H), N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H- 7.74 (d, J=7.16 Hz, 1 H), 7.94 (t, J=7.82 Hz, 1 H), pyran-4-ylmethyl)piperazin-1 -y]carbonylJ-6,6- 10.41 (br. s., 1 H), 12.56 (br. s., 1 H). dimethyl-1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-y)-6-methoxypyridine-2 carboxamide WO 2008/125945 PCT/IB2008/000862 - 106 PKCb Ex. Ki No. Structure (nM) 1H NMR 0 CH CH, C C N N HN ~ ,' OH~/~N 0 N 1 H NMR (300 MHz, DMSO-d 6 ) 8 ppm 0.96 (d, J=4.33 Hz, 3 H), 1.01 (d, J=6.03 Hz, 3 H), 1.06 - 1.23 (in,2 F29N H), 1.45-1.75(m, 10 H), 1.91 -2.01 (m,2 H), 2.38 F2I <10 2.48 (in, 2 H), 2.77 -2.94 (in, 1 H), 3.04 -3.19 (in, 2 .0 H), 3.21 - 3.31 (in, 2 H), 3.76 - 3.87 (in, 2 H), 3.93 (s, 3
    OH
    3 H), 4.64 (s, 2 H), 7.54 -7.68 (in, 1 H), 8.13 (d, J=8.85 N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H- Hz, 1 H), 8.39 (d, J=2.64 Hz, 1 H). pyran-4-ylmethyl)piperazin-1-yl]carbonyl}-6,6 dimethyl-1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yl)-5-methoxypyridine-2 carboxainide.____________________________ 0 OH OH 3 CHJ-Ck 0 N 1 H NMR (300 MHz, DMSO-de) 8 ppm 0.95 (d, J=5.65 F30 ~N Hz, 3 H), 1.01 (d, J=6.03 Hz, 3 H), 1.06 - 1.28 (m, 2 0 1 H), 1.46 - 1.76 (m, 10 H), 1.89 - 2.01 (m, 2 H), 2.29 <0 1 2.47 (m, 2 H), 2.76 - 2.89 (m, 1 H), 3.02 - 3.19 (m, 2 H), 3.20 - 3.30 (m, 2 H), 3.75 - 3.90 (m, 2 H), 4.63 (s, 2 5-chloro-N-(5-{[(2S,5R)-2,5-diiHethyl-4- H), 8.11 - 8.28 (n, 2 H), 8.79 (d, J1.88 Hz, H) (tetrahydro-2H-pyran-4-ylmethyl)piperazin-1 yI]carbonyl}-6,6-dimethyl-1,4,5,6 tetra hyd ropyrrolo [3,4-c]pyrazol-3-yI)pyrid ine-2 carboxamide 0 CH CH 3 CHC N N N OH NN N NJ OH 3 1 H NMR (300 MHz, DMSO-d6) 6 ppm 0.95 (d, J=5.46 0 N Hz, 3 H), 1.00 (d, J=5.84 Hz, 3 H), 1.05 - 1.25 (in, 2 F31 -- N H), 1.48- 1.81 (m, 10 H), 1.91 -2.02 (m, 2 H), 2.32 3-1 .19 (n2H)3.033(i,2H,36-.7i,2.48 (mn, 2 H), 2.61 (s, 3 H), 2.75 - 2.90 (in, 1 H), 3.03 OH 3 H), 4.66 (s, 2 H), 7.40 - 7.71 (in, 1 H), 7.80 - 8.16 (in 2 N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H- H) pyran-4-ylmethyl)piperazin-1--y]carbonyl}-6,6 dimethyl-1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yI)-6-methylpyridine-2 carboxamide 0 OH OH 3 0 N 'H NMR (300 MHz, DMSO-d 6 ) 8 ppm 0.96 (d, J=4.33 Hz, 3 H), 1.00 (d, J=6.03 Hz, 3 H), 1.05 - 1.24 (m, 2 F32 N H), 1.48 - 1.79 (m, 10 H), 1.92 - 2.03 (m, 2 H), 2.35 0 s- / 12.8 2.47 (m, 2 H), 2.75 (s, 3 H), 2.78 - 2.90 (i, 1 H), 3.02 HH 3 3.17 (in, 2 H), 3.20-3.30 (in, 2 H), 3.75 - 3.88 (, 2 N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H- H), 4.60 (s, 2 H), 8.35 (s, 1 H pyran-4-ylinethyl)piperazin-1 -yl~carbonyl)-6,6 dimethyl-1 ,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yI)-2-inethyl-1 ,3-thiazole-4 carboxamide WO 2008/125945 PCT/IB2008/000862 -107 PKCb Ex. Ki No. Structure (nM) IH NMR O CH CH 3 CHCN N CHo N 1 H NMR (300 MHz, DMSO-d 6 ) 6 ppm 0.96 (d, J5.27 Hz, 3 H), 1.01 (d, J=5.84 Hz, 3 H), 1.04 - 1.19 (in, 2 F33 N H), 1.49- 1.79 (i, 10 H), 1.91 -2.00 (i, 2 H), 2.42 (s, 0 I26.4 3 H), 2.44 - 2.47 (mn, 2 H), 2.75 -2.88 (in, 1 H), 3.01 3.19 (in, 2 H), 3.20 - 3.29 (in, 2 H), 3.77 - 3.89 (in, 2 CH, H), 4.64 (s, 2 H), 7.83 - 7.94 (in, 1 H), 8.06 (d, J=7.72 N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H- Hz, 1 H), 8.57 (d, J1.32 Hz, 1 H). pyran-4-ylmethyl)piperazin-1 -yl]carbonyl}-6,6 dimethyl-1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yl)-5-methylpyridine-2 carboxamide 0 CH OH 3 OH - NN 'N Nj OH 3 NH NMR (300 MHz, DMSO-de) 8 ppm 0.95 (d, J=4.52 N Hz, 3 H), 1.01 (d, J=6.03 Hz, 3 H), 1.04 - 1.12 (m, 2 H), 1.18 (t, J=7.54 Hz, 3 H), 1.47 - 1.76 (m, 10 H), 1.91 F34 N OH 3 <0 -2.01 (i, 2 H), 2.35-2.47 (n, 2 H), 2.53 - 2. 61 (m, , 2 0 1 H), 2.73-2.90 (n, 1 H), 3.00- 3.17 ( -, 2 H), 3.18
    HH
    3 3.30 (s, 2 H), 3.82 (d, J=9.23 Hz, 2 H), 4.00 (s, 3 H), N-(5-{[(2 S, 5R)-2,5-d iiethyl-4- tetraa hyd ro-2HH- 4.55 (s, 2 H), 6.92 (s, 1 H), 10.80 (s, 1 H), 12.47 (br. pyran-4-ylinetl)piperazin-1 -yI]carbonyl}-6,6- s., 1 H). dimethyl-1 ,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yI)-3-ethyl-1 -methyl-i H-pyrazole-5 carboxamide O CH CH CHC O N F34 j~/N'H 3 H), 1. 11 (d, J=6.03 Hz, 3 H), 1. 15 - 1.34 (in, 2 H), F35 M-CH3 47.9 1.57 -1.86 (m, 10OH), 1.97 -2.11 (m, 2H), 2.47 -2.70 F350 <N~ (in, 3 H), 2.86 -2.96 (in, 1 H), 3.11 - 3.22 (in, 1 H), N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H- 3.35 - 3.50 (i, 2 H), 3.88 - 3.96 (i, 2 H), 3.98 (s, 3 H), pyran-4-ylmethyl)piperazin-1-yl]carbonyl}-6,6- 4.68 (s, 2 H), 7.77 (s, 1 H), 7.82 (s, 1 H). dimethyl-1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yI)-1-methyl-1 H-imidazole-5 carboxamide. O OH OH 3 N o N 'H NMR (300 MHz, DMSO-d 6 ) 6 ppm 0.95 (d, J=5.46 Hz, 3 H), 1.00 (d, J=6.03 Hz, 3 H), 1.06 - 1.28 (m, 2 F)611 (, 624 H), 1.45 - 1.80 (m, 10 H), 1.93-1.98 (m,2H), 2.31 0 N<10 2.47 (m, 2 H), 2.76 - 2.88 (m, 1 H), 3.01 - 3.19 (m, 4 eH3 H), 3.72 (s, 3 H), 3.77 - 3.88 (in, 2 H), 4.57 (s, 2 H), N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H- 7.76 (s, 1 H), 7.85 (s, 1 H), 10.08 (br. s., 1 H). prn-4-ylinethyl)piperazin-1 -yI]carbonyl}-6,6 dimethyl-1s,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yl)-1 -methyl-i H-imidazole-4 carboxamide WO 2008/125945 PCT/IB2008/000862 - 108 PKCb Ex. Ki No. Structure (nM) 1H NMR O CH CH, N N N CH Cj 'N o N 1 H NMR (300 MHz, DMSO-d6) 6 ppm 0.95 (d, J=5.46 Hz, 3 H) 1.00 (d, J=5.84 Hz, 3 H) 1.04 -1.29 (in, 2 H) F37 0 N I 14.1 1.50-1.69 (i, 10 H) 1.72 -2.02 (m,6 H) 2.29-2.46 (mn, 4 H) 2.75 - 2.89 (mn, 1 H) 2.98 - 3.20 (mn, 4 H) 3.82 (d, J=10.93 Hz, 2 H) 4.58 (s, 2 H) 4.66 -4.92 (in, 1 H) 1-cyclobutyl-N-(5-{[(2S,5R)-2,5-dimethyl-4- 7.91 (s, 1 H) 8.09 (s, 1 H). (tetrahydro-2H-pyran-4-ylmethyl)piperazin-1 yl]carbonyl}-6,6-dimethyl-1,4,5,6 tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-1 H _____imidazole-4-carboxamide O OH OH 3 /N o N 1 H NMR (300 MHz, DMSO-d 6 ) 8 ppm 0.95 (d, J=5.65 Hz, 3 H), 0.99 (d, J=6.22 Hz, 3 H), 1.03 - 1.27 (m, 2 F38 <9,N 238 H), 1.42 (s, 3 H), 1.45 (s, 3 H), 1.50 -1.77 (in, 10 H), 1N.1 1.87 - 1.99 (m, 2 H), 2.33 - 2.46 (m, 2 H), 2.77 -2.8 (m, 1 H), 3.02 - 3.29 (m, 4 H), 3.76 - 3.87 (m, 2 H),
    OH(
    3 4.43 - 4.54 (H, 1 H), 4.58 (s, 2 H), 7.90 (s, 1 H), 8.03 N-(5-{[(2S,5R)-2,5-di7ethyl-4-(tetrahydro-2H- (d, J=1.13 Hz, 1 H). pyran-4-ylinethyl)piperazin-1 -yl]carbonyl}-6,6 diinethyl-1 ,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yI)-1-isopropyl-1 H-iinidazole-4 carboxamide O CH CH OH NN N OH N o N ~Ti 1 H NMR (300 MHz, DMSO-d 6 ) 6 ppm 1.01 (d, J=5.09 F3 Hz, 6 H), 1.07 - 1.19 (in, 2 H), 1.28 (t, J=7.54 Hz, 3 H), F38 O6' 0 a 14.9 1.45 -1.81 (in, 10 H), 1.83 -2.06 (in, 2 H), 2.28 -2.46 (in, 2 H), 2.79 - 2.88 (in, 3 H), 2.90 - 3.22 (in, 4 H), CH, 3.83 (d, J=9.23 Hz, 2 H), 4.60 (s, 2 H), 8.69 (s, 1 H) N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H pyran-4-ylmethyl)piperazin-1-yl]carbonyl}-6,6 dimethyl-1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yI)-2-ethyl-1H,3-ixazole-4 carboxainide____________________________ o CH OH 3 /_-C o N 1 H NMR (300 MHz, DMSO-d 6 ) 6 ppm 0.93-1.06 ( , 6 H), 1.04-1.17 (d, 4 H), 1.16-1.28 (, J6.40, 1.88 F40 15.7 Hz, 2 H), 1.46 1.77 (, 10 H), 1.82 - 2.03 (m, 2 H), 2.11 - 2.24 (m, 1 H), 2.32 - 2.46 (m, 1 H), 2.63 - 2.99 (m, 2 H), 3.03 - 3.25 (m, 4 H), 3.83 (d, J=9.61 Hz, 2 2-oyclopropyl-N-(5-4[(2S,5R)-2,5-dimethyl-4- H), 4.59 (s, 2 H), 8.62 (s, 1 H). (tetrahydro-2H-pyran-4-ylmethyl)piperazin-( yl~carbonyl}-6,6-dimethyl-1,4,5,6 tetra hyd ropyrrolo[3,4-c]pyrazol-3-y)-1, 3 oxazole-4-carboxamide WO 2008/125945 PCT/IB2008/000862 -109 PKCb Ex. Ki No. Structure (n) IH NMR o CH CH 3 C H N N / I N 1 H NMR (300 MHz, DMSO-d 6 ) 5 ppm 0.97 (d, J=2.07 o NCH Hz, 4 H), 1.01 (d, J=6.03 Hz, 3 H), 1.07 -1.22 (in, 2 CH NN H), 1.45 -1.61 (in, 5 H), 1.61 - 1.76 (in, 5 H), 1.91 (s, 1 F41 CH NH), 1.95 (d, J=3.77 Hz, 1 H), 2.53-2.57 (, 1 H), 2.62 6o 3<j 17 (s, 2 H), 2.69 (s, 2 H), 2.83 (d, J=5.46 Hz, 1 H), 3.07 N-(5{[(SS)-25-dmethl-4(terahdro2H-(s, 1 H), 3.12 (d, J= 11.49 Hz, 2 H), 3.24 (d, J=5.46 Hz, N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H-1 H), 3.26 - 3.30 (, 2 H), 3.82 (d, J9.04 Hz, 2 H), pyran-4-ylmethyl)piperazin-1-yl]carbonyl}-6,6- 4.56 (s, 1 H), 8.44 (s, 1 H). dimethyl-1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yl)-5-methyl-1,3-oxazole-4 carboxamide o CH CH 3 CHCN N NH NMR (300 MHz, DMSO-d 6 ) S ppm 1.02 (d, J=5.09 Hz, 6 H), 1.17 (s, 3 H), 1.60 (s, 6 H), 1.68 (s, 5 H), F42 1.91 (s, 2 H), 2.39 (s, 2 H), 2.78 (d, J=4.52 Hz, 1 H), 6. 3.15 (s, 1 H), 3.26 (s, 2 H), 3.81 (s, 3 H), 4.61 (s, 2 H), 7.47- 7.62 (, 3 H), 7.98 (d, J=7.35 Hz, 2 H), 10.92 N-(5-{[(2S,5R)-2,5-dimethyl44-(tetrahydro-2H- (s, I H) pyran-4-ylmethyl)piperazin-1 -yI]carbonyl)-6,6 dimethyl-1 ,4,5,6-tetrahydropyrrolo[3,4 clpyrazol-3-y)benzamide o CH CH 3 CH NN N N CH 3 NH NMR (300 MHz, DM - 6 ) ppm 0.95 (d, J=5.65 O N Hz, 3 H), 1.00 (d, J6.03 Hz, 3 H), 1.04- 1.24 ( , 2 z, H), 1.43 (t, J=7.25 Hz, 3 H), 1.48- 1.76 ( , 10 H), 1.85 F43 6 -2.01 (, 2 H), 2.37 - 2.46 ( , J=10.36 Hz, 2 H), 2.82 1(dd, J10.93, 2.45 Hz, 1 H), 2.99- 3.18 ( , 2 H), 3.18 73.28 (i, 2 H), 3.82 (d, J=9.23 Hz, 2 H), 4.24 (q,
    (H
    3 J=6.97 Hz, 2 H), 4.58 (s, 2 H), 6.82 (s, 1 H), 7.90 N-(5-{[(2 S, 5R)-2,5-d imethyl-4- (tetra hydro-2H- H), 10.29 (br. s., 1 H), 12.13 (br. s., 1 H). pyran-4-ylmethyl)piperazin-1 -yI]carbonyl)-6,6 dimethyl-1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yI)-1-ethyl-1 H-pyrazole-3 carboxamide o CH CH CH N N N F 43H NMR (300 MHz, DMSO-6) 5 ppm 0.96 (d, J3.20 o0 N Hz, 3 H), 1.*01 (d, J=6.03 Hz, 3 H), 1.06 -1.25 (in, 2 H), 1.48 -1.80 (in, 4 H), 1.59 (s, 3 H), 1.68 (s, 3 H), F44 .- <10 1.92 - 2.02 (in, 2 H), 2.38 (s, 3 H), 2.40 -2.47 (in, 2 H), 6- ~2.75 -2.90 (in, 1 H), 3.01 - 3.19 (in, 2 H), 3.19 -3.28 0 CH3 (in, 2 H), 3.82 (d, J=9.42 Hz, 2 H), 4.58 (s, 2 H), 7.31 H 3 7.45 (m, 2 H), 7.72 - 7.86 (, 2 H), 10.82 (s, 1 H), N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H- 12.28 (br. s., 1 H pyran-4-ylmethyl)piperazin-1-yl]carbonyl}-6,6 dimethyl-1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-y)-3-methylbenzamide3 WO 2008/125945 PCT/IB2008/000862 -110 PKCb Ex. Ki No. Structure (nM) IH NMR o CH CH, NN OH NN , N-)-C NN H NMR (300 MHz, DMSO-d 6 ) 8 ppm 0.95 (d, J=5.84 NHz, 3 H), 1.01 (d, J6.03 Hz, 3 H), 1.05- 1.22 (i, 2 o N H), 1.46 -1.79 (in, 4 H), 1.58 (s, 3 H), 1.67 (s, 3 H), F45 CH,1.86- 1.96 (, 2 H), 2.38 (s, 3 H), 2.41 -2.47 (i, 2 H), 6-OH 6. 2.76 - 2.85 (in, 1 H), 3.01 - 3.19 (in, 2 H), 3.21 - 3.28 0 6(in, 2 H), 3.82 (d, J=8.48 Hz, 2 H), 4.56 (s, 2 H), 7.28 (d, J=7.54 Hz, 2 H), 7.32 - 7.48 (in, 2 H), 10.76 (br. s., N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H- 1 H), 12.27 (br. s., 1 H). pyran-4-ylmethyl)piperazin-1-yi]carbonyl}-6,6 dimethyl-1,4,5,6-tetrahydropyrrolo[3,4 I c]pyrazol-3-yi)-2-methylbenzamide O CH CH 3 CH N N NCH H NH NMR (300 MHz, DMSO-d 6 ) 6 ppm 0.95 (d, J=5.65 o N Hz, 3 H), 1.00 (d, J6.03 Hz, 3 H), 1.06-1.22 (i, 2 F46 H), 1.47 -1.84 (in, 4 H), 1.58 (s, 3 H), 1.68 (s, 3 H), b0 1 11.2 1.91 - 2.01 (m,2 H), 2.30 -2.48 (mn,2H), 2.76 -2.87 0. (in, I H), 3.01 - 3.19 (in, 2 H), 3.19 -3.29 (in, 2 H), 3.72 - 3.91 (in, 2 H), 4.58 (s, 2 H), 7.18 - 7.48 (in, 2 H), F 7.89 - 8.30 (in, 2 H), 10.98 (s, 1 H), 12.43, (br. s., 1 H). N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H pyran-4-ylmethyl)piperazin-1-yl]carbonyl}-6,6 dimethyl-1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yi)-4-fluorobenzamide O CH CH, LNN oCOHCH 3 CH N / _N 1 H NMR (300 MHz, DMSO-d 6 ) 8 ppm 0.95 (d, J=5.84 NJ-CH 06Hz, 3 H), 1.00 (d, J=6.03 Hz, 3 H), 1.05 - 1.22 (in, 2 o N H), 1.47 - 1.80 (in, 4 H), 1.59 (s, 3 H), 1.68 (s, 3 H), F47 10 1.91 - 1.99 (in, 2 H), 2.35 - 2.47 (in, 2 H), 2.76 - 2.86 06I (in, 1 H), 3.01 - 3.18 (in, 2 H), 3.20 -3.28 (in, 2 H), 0F 3.74 - 3.89 (in, 2 H), 4.59 (s, 2 H), 7.38 - 7.49 (in, I H), N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H- 7.50 - 7.62 (i, 1 H), 7.73 - 7.91 (i, 2 H), 11.05 (s, 1 pyran-4-ylmethyl)piperazin-1-yl]carbonyl}-6,6- H), 12.23 (br. s., 1 H). dimethyl-1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yI)-3-fluorobenzamide o CH CH 3 NN C NH NMR (300 MHz, DMSO-d 6 ) 8 ppm 0.95 (d, J5.65 Hz, 3 H), 1.00 (d, J=6.03 Hz, 3 H), 1.05 - 1.23 (in, 2 H), 1.47 - 1.76 (in, 4 H), 1.59 (s, 3 H), 1.68 (s, 3 H), F48 0 43 1.90 - 1.99 (in, 2 H), 2.33 -2.50 (in, 2 H), 2.74 - 2.90 ON 243 (in, 1 H), 3.01 - 3.18 (in, 2 H), 3.18 -3.28 (in, 2 H), 4-cyano-N-(5-{[(2S,5R)-2,5-dimethyl-4- 3.82 (d, J=10.36 Hz, 2 H), 4.59 (s, 2 H), 7.93 -8.04 (tetrahydro-2H-pyran-4-ylimethyl)piperazin-1- (m, 2 H), 8.07-8.18 (i, 2 H), 11.22 (s, 1 H), 12.42 (br. yl]carbonyl}-6,6-dimethyl-1,4,5,6- s., 1 H). tetrahydropyrrolo[3,4-c]pyrazol-3 yI)benzamide.
    WO 2008/125945 PCT/IB2008/000862 - 111 IPKCb Ex. Ki No. Structure (nM) IH NMR o CH CH 3 N N CH N cH(j KN 1 H NMR (300 MHz, DMSO-d 6 ) 5 ppm 0.95 (d, J=5.65 NHz, 3 H), 1.00 (d, J=6.03 Hz, 3 H), 1.05- 1.26 (i, 2 0 NH), 1.44 -1.80 (m, 4H), 1.59 (s, 3H), 1.68 (s, 3H), F49 25.6 1.91 - 2.00 (in, 2 H), 2.34 - 2.48 (in, 2 H), 2.75 - 2.88 6- (in, 1 H), 3.02 -3.18 (in, 2 H), 3.20 - 3.27 (in, 2 H), 0 CN 3.82 (d, J=9.80 Hz, 2 H), 4.60 (s, 2 H), 7.67 - 7.79 (in, CN 1 H), 8.05 (d, J=7.72 Hz, 1 H), 8.28 (d, J=7.91 Hz, 1 3-cyano-N-(5-{[(2S,5R)-2,5-dimethyl-4- H), 8.42 (s, 1 H), 11.19 (s, 1 H), 12.50 (br. s., I H). (tetrahydro-2H-pyran-4-ylmethyl)piperazin-1 yl]carbonyl}-6,6-dimethyl-1,4,5,6 tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzamide 0 CH CH 3 N 3N CHCCH N Nj CH N 1 H NMR (300 MHz, DMSO-d 6 ) I ppm 0.90- 1.02 (in, 6 0 NH), 1.59 (s, 3 H), 1.68 (s, 3 H), 1.82-1.94 (s, 1 H), (m, 1 H), 2.01 - 2.13 ( m, 2 H), 2.16 (s, 3 H), 2.27-2.40 (m, 1 H), 9. 2.70 (dd, J= 1. 11,2.45Hz, 1 H), 2.91-3.09 (in, 2 H), 4.48 - 4.81 (i, 2 H), 7.75 (t, J4.80 Hz, 1 H), 9.03 (d, N-(6,6-dimethyl-5-{[(2S,5R)-2,4,5- J4.71 Hz, 2 H), 10.84 (br. s., 1 H), 12.46 (br. s., 1 H). triinethylpiperazin-1-y]carbonyl}-1,4,5,6 tetrahydropyrroio[3,4-c]pyrazol-3-yI)pyrimidine _____2-carboxamide
    OH
    3 C CH 3 HN 0 1H NMR (300 MHz, DMSO-de) 6 0.99 - 1.14 (m, 3 H) S1.159-1.28 (, 3 H) 1.28 1.40, 3 H), 1.50-1.73 96 20 . N ( m, 6 H) 1.73-1.83 (i, 1 H) 1.84 2.06 (, 2 H) 2.67 <10 -2.88 (in, 3 H) 2.88-3.03 (in, 1 H) 3.24 -3.36 (m, 2 H) 3.56 - 3.72 (in, 3 H) 3.72 - 3.89 (in, 4 H) 3.90 - 4.09 CH, (i, 4 H) 4.63 -4.80 (i, 1 H) 7.92 (d, J8.10 Hz, 1 H) N-(5-{2S,5R)-2,5-diiJethyl-4-(tetrahydro-2H- 8.05 (d, J7.54 Hz, 1 H) 8.60 (br. s., 1 . H). pyran-4-yI)piperazin-i -yI]carbonyl)-6,6 dimethyl-1 ,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yI)-5-ethylpyridine-2-carboxamide
    OH
    3 C CH 3 H N -NH 3C". N N _ CH'3 HN 0 SN 1 H NMR (300 MHz, DMSO-d 6 ) 6 1.00 - 1.14 (m, 8 H) F52 1.14 - 1.31 (m, 3 H) 1.14 - 1.31 (m, 2 H) 1.51 - 1.63 IN <10 (m, 6 H) 1.63 - 1.81 (m, 8 H) 3.69 - 3.84 (m, 6 H) 3.85 - 4.04 (i, 4 H) 4.56- (4.74 (i, 2 H) 7.46 (d, J=8.85 Hz, 1 H) 7.96 (d, J=8.48 Hz, 1 H) 8.37 (d, J=2.45 Hz, 1 H). N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H pyran-4-yi)piperazin-1 -yI]carbonyl)-6,6 dimethyl-1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-y)-5-morpholin-4-ylpyridine-2 carboxainide ________________________ WO 2008/125945 PCT/IB2008/000862 -112 PKCb Ex. Ki No. Structure 1H NMR
    OH
    3 C CH 3 N NH H3C"-. N HN /3 A1H NMR (300 MHz, DMSO-d 6 ) 5 0.99 - 1.15 (m, 3 H) HN 0 1.23 - 1.41 (m, 3 H) 1.62 (br. s., 3 H) 1.69 (br. s., 4 H) F53 1.72 - 1.81 (m, 2 H) 1.81 - 1.90 (m, 2 H) 1.91 - 2.00 0 ~ N 24.0 (m, 1 H) 2.69 - 2.86 (m, 2 H) 2.86 - 3.05 (m, 2 H) 3.40 I - 3.52 (m, 4 H) 3.68 - 3.87 (m, 1 H) 3.89 - 4.03 (m, 2 N H) 4.63 - 4.74 (m, 2 H) 8.03 - 8.13 (m, 1 H) 9.06 - 9.19 N-(5-{[(2S,5R)-2,5-diiethyl-4-(tetrahydro-2H- (im, 1 H) 9.42 (s, 1 H). pyran-4-yI)piperazin-1 -yI]carbonyl}-6,6 dimethyl-1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yl)pyrimidine-4-carboxamide
    OH
    3 C CH 3 H N NH
    H
    3 C. N N N .JCH3 HN O HN 0 1 H NMR (300 MHz, DMSO-d 6 ) 6 0.94 - 1.12 (mn, 6 H) 00 - 1.51 (br. s., 3 H) 1.55 -1.63 (in, 5 H) 1.67 (br. s., 4 H) F54-N212 F54 IN 12.2 2.1 -. 22 (in, 1 H) 2.43 (s, 3 H) 2.69 -2.83 (in, 3 H) 2.83 - 2.94 (in, 1 H) 3.05 - 3.22 (in, 3 H) 3.05 -3.22 OH3 (in, I H) 3.82 - 3.95 (mn, 2 H) 4.56 -4.70 (in, 2 H) 7.88 N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H- (d, J=7.54 Hz, 1 H) 8.02 - 8.09 (m, 1 H) 8.58 (s, 1 H). pyran-4-yl)piperazin-1 -yl]carbonyl}-6,6 dimethyl-1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yl)-5-methylpyridine-2 carboxainide 0H 3 C OH 3
    H
    3 C'. NN IN N_-~.CH3 HN 0 1 H NMR (300 MHz, DMSO-d 6 ) 8 0.94 - 1.08 (m, 6 H) N 1.40 -1.53 (m, 2 H) 1.54 -1.62 (m, 4 H) 1.62 - 1.74 F55 <12 (2 , 4H 2.22 ( 1.12 ( s, 4 H) 2.12. - 2.2 (m, H)2.69 - 2.81 (, 2 H) 2.81 - 2.91 (m, 1 H) 3.06 - 3.22 (, 3 m 1 H) 3.84 - 3.99 (m, 5 H) 4.60 - 4.71 (m, 2 H) 7.62 (d, 0 5(, m(dh 3 J=8.29 Hz, 1 H) 8.14 (d, J=8.48 Hz, 1 H) 8.39 (s, 1 H). pyran-4-yI)piperazin-1 -yI]carbonyl)-6,6 diinethyl-1 ,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yI)-5-inethoxypyridine-2 carboxamide OHC OH 3 kN NH
    H
    3 CO. N N N -JCH3 HN O 1H NMR (300 MHz, DMSO-d 6 ) 60.91 - 1.18 (i, 6 H) 0 1. 19 -1.41 (in, 2 H) 1.43 -1.63 (in, 6 H) 1.63 -1.84 F56 N (, 7 H) 2.01 -2.18 (m, 1 H) 2.18-2.35 (m, 1 H) 2.68 N.~ ~ <1 2.79 (in, 1 H) 2.79 -2.99 (in, 2 H) 3.53 -3.68 (in, 1 ci H) 3.79 -4.02 (in, 2 H) 4.53 -4.77 (in, 2 H) 8.05 - 8.25 5-chloro-N-(5-{[(2S,R)-2,5-dimethyl-4- (i, 2 H) 8.79 (br. s., 1 H). (tetrahydro-2H-pyran-4-y)piperazin-1 yi]carbonyl -6,6-dimethyl-1o4,5,6 tetrahydropyrrolo[3,4-c]pyrazol-3-y)pyridine-2 carboxamide WO 2008/125945 PCT/IB2008/000862 -113 PKCb Ex. Ki No. Structure (nM) 1H NMR
    OH
    3 C CH 3 N
    H
    3 C'. N NH N CH3 1 H NMR (300 MHz, DMSO-d 6 ) 6 0.89 - 0.99 (i, 3 H) F57 F5 N 52.7 (m, 6H) 1.88 -2.02 (m, 2H) 2.34 -2.46 (m, 3H) 2.76 -2.90 (in, 1 H) 3.14 - 3.19 (in, 3 H) 3.76 -3.88 (in, 3 o N,,) H) 4.59 - 4.71 (in, 2 H) 8.72 - 8.85 (in, 1 H) 8.86 -9.01 N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H- (i, 1 H) 9.21 - 9.35 (i, 1 H). pyran-4-ylmethyl)piperazin-1-yl]carbonyl}-6,6 dimethyl-1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yl)pyrazine-2-carboxamide
    OH
    3 C OH 3 kN NH
    H
    3 C". N N HH NMR (300 MHz, DMSO-d 6 ) 6 0.91 - 0.98 (in, 4 H) HN 01.01 (d, J=5.84 Hz, 3 H) 1.42 -1.55 (in, 3 H) 1.55 F58 N133 1.62 (m, 4 H) 1.62-1.81 (m, 6 H) 1.85-2.00 (m, 3 H) h-N 2.77 -2.89 (in, 1 H) 2.95 -3.19 (in, 4 H) 3.75 -3.89 o (m, 3 H) 4.52 -4.71 (m, 2 H) 7.68- 7.81 (m, 1 H) 8.90 N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H- 9.08 (m, 2 H). pyran-4-ylmethyl)piperazin-1-yl]carbonyl}-6,6 dimethyl-1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yl)pyrimidine-2-carboxamide
    OH
    3 C CH 3 XN NH
    H
    3 C'.. N / N3 N > H3 N O CH O3" H3C NCH3HN 0 1H NMR (300 MHz, DMSO-d 6 ) 6 1.01 (d, J=6.03 Hz, 3
    OH
    3 H) 1.09 -1.18 (m, 1H) 1.18 -1.27 (m, 2H) 1.28 -1.40 F59 0 2 (in, 4 H) 1.47 - 1.53 (in, 3 H) 1.59 (s, 3 H) 1.65 (s, 3 H) 20~ 1.86 -2.00 (m, 1 H) 2.02 -2.11 (in, 1 H) 2.12 (s, 3H)
    H
    3 C 2.31 (s, 3 H) 2.73 -2.91 (in, 3 H) 2.91 - 3.07 (in, 2 H) 2-(3,5-dimethylisoxazol-4-y)-N-(5-{[(2S,5R)- 3.77 - 3.89 (m, 3 H) 4.46 - 4.60 (m, 2 H) 6.35 - 6.66 2,5-dimethyl-4-(tetrahydro-2H-pyran-4- (i, 1 H) 9.95- 10.18 (i, 1 H) 10.62- 10.78 (i, 1 H). ylmethyl)piperazin-1-yl]carbonyl}-6,6-dimethyl 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3 yl)acetamide
    OH
    3
    COH
    3 kN NH
    H
    3 C. N HN O N-~+H3 N 01 H NMR (300 MHz, CHLOROFORM-d) 6 0.94 - 1.23 b N (in, 6 H) 1.23 -1.46 (in, 4 H) 1.71 -1.85 (in, 9 H) 1.84 F60 0 4.17 -2.02(m, 1 H)3.09-3.25(m, 1 H)3.28-3.41 (m, 1 H) 3.41 - 3.51 (in, 2 H) 3.88 - 4.02 (in, 4 H) 4.64 -4.87 F FF (in, 2 H) 8.11 - 8.30 (in, 1 H) 8.33 - 8.53 (in, 1 H) 8.90 FFF N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H- (s, 1 H) 10.29 (br. s., 1 H). pyran-4-ylmethyl)piperazin-1-yl]carbonyl}-6,6 dimethyl-1,4,5,6-tetrahydropyrrolo[3,4 c]pyrazol-3-yi)-5-(trifluoromethyl)pyridine-2 carboxa1DideH NMR_(300_M_ zDMSO-de)0.89-.99(m,3H) WO 2008/125945 PCT/IB2008/000862 -114 PKCb Ex. Ki No. Structure (nM) IH NMR
    OH
    3 C CH 3 kN NH
    H
    3 C". N N CH 3 HN 0 1H NMR (300 MHz, DMSO-d) 60.87 -1.13 (i, 6 H) .00 -N 1.26 - 1.40 (m, 1 H) 1.40 - 1.54 (mn, 2 H) 1.54 - 1.63 G1 I 10 (in, 3 H) 1.63 -1.77 (mn, 4 H) 2.06 -2.27 (mn, 2 H) 2.68 - 2.94 (in, 3 H) 3.04 - 3.20 (in, 4 H) 3.79 - 3.95 (mn, 2 ON H) 4.52 - 4.76 (in, 2 H) 8.29 (d, J=8.1 0 Hz, 1 H) 8.59 5-cyano-N-(5-{[(2S,5R)-2,5-dimethyl-4- (d, J=9.61 Hz, 1 H) 9.19 (br. s., 1 H). (tetrahydro-2H-pyran-4-yl)piperazin-1 yl]carbonyl}-6,6-dimethyl-1,4,5,6 tetrahydropyrrolo[3,4-c]pyrazol-3-yl)pyridine-2 carboxamide X~N NH
    H
    3 O". N IN
    H
    3 0 H HN 0 1H NMR (300 MHz, DMSO-d 6 ) 8 0.97 - 1.12 (m, 3 H) 1.19 - 1.33 (m, 3 H) 1.61 (s, 3 H) 1.69 (s, 3 H) 2.66 G2 N 28.7 2.81 (m, 6 H) 2.81 - 2.96 (m, 2 H) 3.12- 3.19 (m , 1 H) 4.65-4.78 (m, 2 H) 6.54 (s, 1 H) 8.25 (d, J8.10 Hz, 1 H) 8.59 (dd, J=8.19, 1.98 Hz, 1 H) 9.20 (d, J1.32 Hz, ON 1 H) 11.05 (br. s., 1 H). 5-cyano-N-(6,6-dimethyl-5-{[(2S,5R)-2,4,5 trimethylpiperazin-1 -yI]carbonyl}-1 ,4,5,6 tetra hyd ropyrro lo[3,4-c] py razo1-3-yI)py rid in e-2 carboxamide
    OH
    3 C CH 3 NNH
    H
    3 C'.. N / N
    H
    3 N 5-cyanoN--diehyl5{(2,R-245 HN 0 1 H NMR (300 MHz, DMSO-de) 6 0.91 - 1.09 (m, 8 H) 1.09 - 1.25 (m, 2 H) 1.49 - 1.62 (in, 4 H) 1.62 - 1.81 G3 7 (m, 6 H) 1.86-2.02 (i, 3 H) 2.34 - 2.47 (m, 2 H) 2.76 S- 2.91 (m, 1 H) 3.00 -3.21 (, 3 H) 3.77- 3.95 (i, 2 ON H) 4.58 -4.75 (i, 2 H) 8.29 (d, J=7.91 Hz, 1 H) 8.59 5-cyano-N-(5-[(2S,5R)-2,5-dimethyl-4- (d, J=6.03 Hz, 1 H) 9.20 (br. s., 1 H). (tetra hyd ro-2H-pyra n-4-ylmnethyl) pi perazin- 1 yI]carbonyl}-6,6-dimethyl-1,4,5,6 tetrahydropyrrolo[3,4-c]pyrazol-3-yI)pyridine-2 carboxamide 0 OH CH 3 HC -N /NH N N H NMR (300 MHz, DMSO-d 6 ) ppm 0.97 (d, J=5.27 0 N Hz, 3 H), 1.04 (d, J=6.03 Hz, 3 H), 1.25 1.47 (, 2 00 H), 1.52 1.75 (, 8 H), 2.07 2.26 (in, 2 H), 2.36 H1iN NA 2.47 (m, 1 H), 2.53 - 2.62 (m, 2 H), 2.99 - 3.12 (m, 1 0 H), 3.16 (d, J=8.48 Hz, 1 H), 3.23 - 3.31 (in, 1 H), 3.52 - 3.69 (in, 4 H), 4.10 (s, 1 H), 4.53 - 4.74 (in, 2 H), 7.64 N-[5-({(2SHR)-4-[(4-hydroxytetrahydro-2H- -47.76 (i, 1 H), 8.09 (t, J6.97 Hz, 1 H), 8.13 - 8.22 pyran-4-y)methyl]-2,5-dimethyl pipe razin-1- (d, 1 H, 8.74 (d, )3.77 Hz, 1 H). yI~carbonyl)-6,6-dimethyl-1,4,5,6 tetra hydro pyrrolo[3,4-o] pyrazol-3-yl] pyrid in e-2 carboxamide II NA = Not available. NT = Not tested.
    权利要求:
    Claims (15)
    [1] 1. A compound or pharmaceutically acceptable salt or solvate of Formula (I), R7 8 0 N N X R3 NH R 4 R5 O- _R1 5 wherein: X is C or N; Z A R 1 is selected from an aryl or wherein ring A is a 5 to 6 membered heterocyclyl containing Z, wherein Z is an 0, S or N heteroatom which is adjacent to the 10 point of attachment, and wherein R1 is optionally further substituted with 0 to 3 R 9 groups and wherein two of the R 9 groups may optionally cyclize to form an aryl or a 5-6 membered heterocyclyl ring containing N or S fused to the aryl or heterocyclyl to which it is attached; R 2 is H or C1-C6 alkyl optionally further substituted with 0 to 3 R 9 groups; 15 R3 may be attached to any unsaturated carbon on the ring and is selected from H, C 1 -C 6 alkyl or halide, or perfluoroalkyl; R 4 and R 5 are each independently selected from H, RaO-Rb, C1-C8 alkyl, C2-C8 alkenyl, C2-C alkynyl, -(Rd)m-(C 3 -Ci 2 cycloalkyl), -(Rd)m-aryl, -(Rd)m-(3-15 membered heterocyclyl), -(Rd)m-(C1C 6 perfluoroalkyl), -(Rd)m-halide, -(Rd)m-CN, -(Rd)m-C(O)Ra _ 20 (Rd)m-C(O)ORa, -(Rd)m-C(O)NRaRb, -(Rd)m-ORa, -(Rd)m-OC(O)Ra, -(Rd)m-OC(O)NRaRb, (Rd)m-O-S(O)Ra, -(Rd)m-OS(0)
    [2] 2 Ra, -(Rd)m-OS(O) 2 NRaRb, -(Rd)m-OS(O)NRaRb, -(Rd) NO 2 , -(Rd)m-NRaRb, -(Rd)m-N(Ra)C(O)Rb, -(Rd)m-N(Ra)C(O)ORb, -(Rd)m-N(R)C(O)NRaRb, -(Rd)m-N(Ra)S(O) 2 Rb, -(Rd)m-N(Ra)S(O)Rb, -(Rd)m-SRa, -(Rd)m-S(O)Ra, -(Rd)m-S(O) 2 Ra, (Rd)m-S(O)NRaRb, -(Rd)m-S(O) 2 NRaRb, -(Rd)m0-(Re)m-NRaRb or -(Rd)m-NRa-(Re)-ORb, 25 or R 4 and R 5 may together cyclize to form a 3- to- 5- membered spiro-cycloalkyl; WO 2008/125945 PCT/IB2008/000862 -116 wherein any of the said C3-C12 cycloalkyl, aryl, heterocyclyl, or heteroaryl are independently optionally further substituted by 0 to 3 R 9 groups; R 6 is selected from H, RaO-Rb, C-C alkyl, C2-C8 alkenyl, C2-C8 alkynyl, -(R d)m (C3-C12 cycloalkyl), -(Rd)m-aryl, -(Rd)m-(3-15 membered heterocyclyl), -(Rd)m-(C1-C6 5 perfluoroalkyl), -(Rd)m-halide, -(Rd)m-CN, -(Rd)m-C(O)Ra, -(Rd)m-C(O)ORa, -(Rd)m C(O)NRaRb, -(Rd)m-ORa, -(Rd)m.-OC(O)Ra, -(Rd)m-OC(O)NRaRb, -(Rd)m-OS(O)Ra, -(Rd)m OS(O) 2 Ra, -(Rd)m-OS(O) 2 NRaRb, -(Rd)m-OS(O)NRaRb, -(Rd)m-NO 2 , -(Rd)m-NRaRb, -(Rd)m N(Ra)C(O)Rb, -(Rd)m-N(Ra)C(O)ORb, -(Rd)m-N(Rc)C(O)NRaRb, -(Rd)m-N(Ra)S(O) 2 Rb, (Rd)m-N(Ra)S(O)Rb, -(Rd)m-SRa, -(Rd)m-S(O)Ra, -(Rd)m-S(O) 2 Ra, -(Rd)m-S(O)NRaRb', 10 (Rd)m-S(O) 2 NRaRb, -(Rd)m-0-(Re)m-NRaRb or -(Rd)m-NRa-(Re)-ORb; or R 6 may together with R 4 cyclize to form a 4- to 7- membered heterocyclyl ring fused to the piperazine or piperadine to which they are attached; and wherein any of the said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl may independently be further substituted with 0 to 3 R 9 groups; 15 each R 7 and R 8 are each independently C1-C2 alkyl or can together cyclize to form a cyclopropyl or cyclobutyl; each R 9 is independently selected from H, R"-O-Rb, C1-C8 alkyl, C2-C8 alkenyl, C2-Ca alkynyl, -(Rd)m-(C3-C 12 cycloalkyl), -(Rd)m-aryl, -(Rd)m-(3-15 membered heterocyclyl), -(Rd)m-(C1-C 6 perfluoroalkyl), -(Rd)m-halide, -(Rd)m-CN, -(Rd)m-C(O)Ra, 20 (Rd)m-C(O)ORa, -(Rd)m-C(O)NRaRb, -(Rd)m-ORa, -(Rd)m-OC(O)Ra, -(Rd)m-OC(O)NRaRb, (Rd)m-O-S(O)Ra, -(Rd)m-OS(O) 2 Ra, -(Rd)m-OS(O) 2 NRaRb, -(Rd)m-OS(O)NRaRb, -(Rd)m NO 2 , -(Rd)m-NRaRb, -(Rd)m-N(Ra)C(O)Rb, -(Rd)m-N(Ra)C(O)ORb', -(Rd)m-N(R)C(O)NRaRb, -(Rd)m-N(Ra)S(O) 2 R, -(Rd)m-N(Ra)S(O)R , -(Rd)m.SR a d(Rd)m-S(O)Ra, -(Rd)m-S(O) 2 Ra _ (Rd)m-S(O)NRaRb, -(Rd)m-S(0) 2 NRaRb, -(Rd)m-O-(Re)m-NRaRb or -(Rd)m-NRa-(Re)-ORb; 25 and wherein any of the said alkyl, alkenyl, alkynyl, Rd, Re, C3-C12 cycloalkyl, aryl or 3-15 membered heterocyclyl are independently optionally further substituted by 1-3 groups selected from -halide, C1C6 alkyl, C1C6 perfluoroalkyl, CrC 6 alkoxyl, Cr 1 C 6 alkylamino, CN or oxo; each Ra, Rb and Rc is independently selected from H, C 1 -C 6 perfluoroalkyl, C1-C8 30 alkyl, C2-C8 alkenyl, -(C1C3 alkylene)m-(C 3 -C cycloalkyl), -(C1C3 alkylene)m-(C 3 -C8 cycloalkenyl), C2-C8 alkynyl, -(C1C3 alkylene)m-aryl, or -(C1C3 alkylene)m-(3-8 member heterocyclyl), and each R", Rb and Rc is independently optionally further substituted by 0 to 3 groups selected from halide, hydroxyl, -CN, C1C6 alkyl, C1C6 perfluoroalkyl, C1C6 WO 2008/125945 PCT/IB2008/000862 -117 alkoxyl and C1-C6 alkylamino; or, when connected to the same nitrogen, Ra and Rb may optionally form a -(3-8 membered heterocyclyl), and the said ring is optionally further substituted by 0 to 3 groups selected from halide, hydroxyl, -CN, C1-C6 alkyl, C1-C6 perfluoroalkyl, C1-C6 alkoxyl or C1-C6 alkylamino; 5 each Rd and Re is independently -(C 1 -C 3 alkylene)-, -(C2-C5 alkenylene)-,or -(C2 C5 alkynylene)-; each m is independently 0 or 1; and with the proviso that R 2 , R 3 , R 4 and R 5 are not all H. 10 2. The compound or pharmaceutically acceptable salt according to claim 1, wherein R 7 and R 8 are both methyl.
    [3] 3. The compound or pharmaceutically acceptable salt according to claim 1, wherein X is N. 15
    [4] 4. The compound or pharmaceutically acceptable salt according to claim 1, wherein R 1 is a pyridine or a piperazine.
    [5] 5. The compound or pharmaceutically acceptable salt according to claim 1, wherein R 1 20 is a 5-membered heterocyclyl.
    [6] 6. The compound or pharmaceutically acceptable salt according to claim 5, wherein R 1 is selected from the group consisting of oxazole, isoxazole, thiazole or imidazole. 25
    [7] 7. The compound or pharmaceutically acceptable salt according to any of the preceding claims, wherein R 2 or R 4 is methyl.
    [8] 8. The compound or pharmaceutically acceptable salt according to any of the preceding claims, wherein R 6 is -(Rd)m-(3-15 membered heterocyclyl). 30
    [9] 9. The compound or pharmaceutically acceptable salt according to claim 8, wherein R 6 is -(Rd)mtetrahydropyran. WO 2008/125945 PCT/IB2008/000862 -118
    [10] 10. The compound or pharmaceutically acceptable salt according to claim 9, wherein R 6 is tetrahyd ro-2H-pyran-4-ylmethyl.
    [11] 11. The compound orpharmaceutically acceptable salt according to any of the 5 preceding claims, wherein R 2 is -CH 3 in (S) configuration.
    [12] 12. The compound or pharmaceutically acceptable salt according to claims any of the preceding claims wherein R 6 is -( Rd)m-ORa. 10
    [13] 13. A compound or pharmaceutically acceptable salt selected from the group consisting of: N-(5-((2R,5S)-2,5-dimethyl-1 -((tetrahydro-2H-pyran-4-yl)methyl)piperazine-4-carbonyl) 6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)picolinamide; N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H-pyran-4-yl)piperazin-1 -yl]carbonyl}-6,6 15 dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-5-fluoropyridine-2-carboxamide; N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H-pyran-4-ylmethyl)piperazin-1 -yl]carbonyl} 6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-5-ethylisoxazole-3 carboxamide; N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H-pyran-4-ylmethyl)piperazin-1 -yl]carbonyl} 20 6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-y)-2,4-dimethyl-1,3-oxazole-5 carboxamide; N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H-pyran-4-ylmethyl)piperazin-1 -yl]carbonyl} 6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-2-methyl-1,3-thiazole-4 carboxamide; 25 N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H-pyran-4-ylmethyl)piperazin-1 -yl]carbonyl} 6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-2-ethyl-4-methyl-1,3-oxazole 5-carboxamide; 1 -cyclobutyl-N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H-pyran-4-ylmethyl)piperazin-1 yl]carbonyl}-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-1 H-imidazole-4 30 carboxamide; N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H-pyran-4-ylmethyl)piperazin-1 -yl]carbonyl} 6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-1-isopropyl-1 H-imidazole-4 carboxamide; WO 2008/125945 PCT/IB2008/000862 -119 N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H-pyran-4-ylmethyl)piperazin-1 -yl]carbonyl} 6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-2-ethyl-1,3-oxazole-4 carboxamide; N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H-pyran-4-yl)piperazin-1 -yl]carbonyl}-6,6 5 dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-5-morpholin-4-ylpyridine-2 carboxamide; and N-(5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H-pyran-4-ylmethyl)piperazin-1-yl]carbonyl} 6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-y)-5-(trifluoromethyl)pyridine-2 carboxamide. 10
    [14] 14. A pharmaceutical composition comprising an effective amount of a compound according to any of the preceding claims, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
    [15] 15 15. A method of treating diabetes mellitus and its complications, cancer, ischemia, inflammation, central nervous system disorders, cardiovascular disease, Alzheimer's disease and dermatological disease pression, viral diseases, inflammatory disorders, or diseases in which the liver is a target organ, the method comprising administering to a mammal an effective amount of a compound according to any of the preceding claims, 20 or a pharmaceutically acceptable salt thereof.
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    法律状态:
    2012-04-19| FGA| Letters patent sealed or granted (standard patent)|
    优先权:
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    US91146207P| true| 2007-04-12|2007-04-12||
    US60/911,462||2007-04-12||
    US3551908P| true| 2008-03-11|2008-03-11||
    US61/035,519||2008-03-11||
    US4011508P| true| 2008-03-27|2008-03-27||
    US61/040,115||2008-03-27||
    PCT/IB2008/000862|WO2008125945A2|2007-04-12|2008-04-10|3-amido-pyrrolo [3, 4-c] pyrazole-5carbaldehyde derivatives as inhibitors of protein kinase c|
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