MX2008007036A - Pyrimidine derivatives for the treatment of abnormal cell growth - Google Patents

Abstract

The present invention relates to a compound of the Formula (I) or a pharmaceutically acceptable salt thereof, wherein Ar is a group of Formula (II) and salts thereof. Such pyrimidine derivatives are useful in the treatment of abnormal cell growth, such as cancer, in mammals. This invention also relates to a method of using such compounds in the treatment of abnormal cell growth in mammals, especially humans, and to pharmaceutical compositions containing such compounds.

Description

DERIVATIVES OF PYRIMIDINE FOR THE TREATMENT OF ABNORMAL CELLULAR GROWTH FIELD OF THE INVENTION This invention relates to novel pyrimidine derivatives which are useful in the treatment of abnormal cell growth, such as cancer, in mammals. This invention also relates to a method of using said compounds in the treatment of abnormal cell growth in mammals, especially humans, and to pharmaceutical compositions containing said compounds. BACKGROUND OF THE INVENTION It is known that a cell can become cancerous by virtue of the transformation of a portion of its DNA into an oncogene (i.e., a gene that, on activation, leads to the formation of malignant tumor cells). Many oncogenes encode proteins that are aberrant tyrosine quipases capable of causing cell transformation. Alternatively, overexpression of a normal proto-oncogenic tyrosine kinase may also result in proliferative disorders, sometimes resulting in a malignant phenotype. Tyrosine quinases are enzymes that extend the cell membrane and possess an extracellular binding domain for growth factors such as epidermal growth factor, a transmembrane domain, and an intracellular portion that functions as a kinase to phosphorylate specific tyrosine residues in proteins. and therefore to influence cell proliferation. Other receptor tyrosine kinases include c-erbB-2, c-met, tie-2, PDGFr, FGFr, and VEGFR. It is known that such kinases are frequently expressed aberrantly in common human cancers such as breast cancer, gastrointestinal cancer such as colon, rectal or stomach cancer, leukemia, and ovarian, bronchial or pancreatic cancer. It has also been shown that the epidermal growth factor receptor (EGFR), which possesses tyrosine kinase activity, is mutated and / or overexpressed in many human cancers such such as brain, lung, squamous, bladder, gastric, breast, head and neck, esophageal, gynecological and thyroid tumors. Accordingly, it has been recognized that inhibitors of receptor tyrosine kinases are useful as selective inhibitors of the growth of mammalian cancer cells. For example, erbstatin, a tyrosine kinase inhibitor, selectively attenuates the growth in nude nude mice of a transplanted human breast carcinoma expressing epidermal growth factor receptor tyrosine kinase (EGFR) but has no effect on the growth of another carcinoma that does not express the EGF receptor. In this way, selective inhibitors of certain receptor tyrosine kinases are useful in the treatment of abnormal cell growth, in particular cancer, in mammals. In addition to receptor tyrosine kinases, selective inhibitors of certain non-receptor tyrosine kinases, such as FAK (focal adhesion kinase), Ick, src, abl or serine / threonine kinases (eg, cyclin-dependent kinases), are useful in the treatment of abnormal cell growth, in particular cancer, in mammals. FAK is also known as the Protein-Tyrosine Kinase 2, PTK2. The following refers to FAK inhibitors: Convincing evidence suggests that FAK, a cytoplasmic non-receptor tyrosine kinase, plays an essential role in signal cell transduction pathways (Clark and Brugge 1995, Science 268: 233-239) and its Aberrant activation is associated with an increase in the metastatic potential of tumors (Owens et al 1995, Cancer Research 55: 2752-2755). FAK was originally identified as a 125 kDa protein highly tyrosine phosphorylated in cells transformed by v-Src. It was later discovered that FAK was a tyrosine kinase that is located in focal adhesions, which are points of contact between cultured cells and their underlying substrate and sites of intense tyrosine phosphorylation. FAK is phosphorylated and, therefore, activated in response to the binding of the extracellular matrix (EMC) to integrins. Recently, studies have shown that an increase in FAK mRNA levels accompanied the invasive transformation of tumors and the attenuation of FAK expression (through the use of antisense oligonucleotides) induces apoptosis in tumor cells (Xu et al 1996 , Cell Growth and Diff. 7: 413- 418). In addition to expressing itself in most tissue types, FAK is found at elevated levels in most human cancers, particularly in highly invasive metastases. Various compounds, such as styrene derivatives, have also been shown to possess tyrosine kinase inhibitory properties. Five publications of European Patent, namely EP 0 566 226 A1 (published on October 20, 1993), EP 0 602 851 A1 (published on June 22, 1994), EP 0 635 507 A1 (published on January 25, 1995). ), EP 0 635 498 A1 (published January 25, 1995), and EP 0 520 722 A1 (published December 30, 1992), refer to certain bicyclic derivatives, in particular quinazoline derivatives, as possessors of properties anti-cancer that result from its tyrosine kinase inhibitory properties. In addition, World Patent Application WO 92/20642 (published on November 26, 1992), refers to certain bis-mono and bicyclic aryl and heteroaryl compounds as tyrosine kinase inhibitors that are useful in inhibiting abnormal cell proliferation. The World Patent Applications WO96 / 16960 (published June 6, 1996), WO 96/09294 (published March 6, 1996), WO 97/30034 (published August 21, 1997), WO 98/02434 (published January 22, 1998), WO 98/02437 (published January 22, 1998), and WO 98/02438 (published January 22, 1998), also refer to substituted bicyclic heteroaromatic derivatives as inhibitors of tyrosine kinase that are useful for the same purpose. In addition, the following list of publications refers to bis-mono and bicyclic aryl and heteroaryl compounds which may optionally be used as tyrosine kinase inhibitors: WO 03/030909, WO 03/032997, U.S. Patent Application Ser. 2003/0181474, U.S. Patent Application No. 2003/0162802, U.S. Patent No. 5,863,924, WO 03/078404, U.S. Patent No. 4,507,146, WO 99/41253, WO 01/72744, WO 02/48133, U.S. Patent Application No. 2002/156087, WO 02/102783, and WO 03/063794. U.S. Patent Application Serial No. 10 / 734,039, filed December 11, 2003 (Attorney Docket No. PC25339A) refers to a broad class of novel pyrimidine derivatives that are kinase inhibitors, and more specifically, FAK inhibitors. In addition, the U.S. Patent Application Serial No. 10 / 733,215, presented on 11 December 2003 (Attorney Docket No. PC25937A) relates more specifically to a subset of pyrimidine derivatives, ie those which carry a 5-aminooxindole, which are tyrosine kinase inhibitors, and more particularly, FAK inhibitors. Compounds such as these are useful in the treatment of abnormal cell growth. The following refers to Aurora-2 inhibitors: Many kinases are involved in regulatory cascades for cells in which their substrates may include other kinases whose activities are regulated by the phosphorylation state. Finally, the activity of some downstream effector is modulated by the phosphorylation resulting from the activation of said pathway. The serine / threonine (S / T) kinase family includes members discovered at all stages of various signaling cascades, including those involved in the control of cell growth, migration, differentiation and secretion of hormones, phosphorylation of transcription factors that gives as a result gene expression, muscle contraction, glucose metabolism, control of cellular protein synthesis, and altered cell cycle regulation. A family of mitotic serine / threonine kinases is the Aurora family (AUR) kinase. It has been discovered that the AUR kinase family is essential for providing signals that initiate and advance mitosis. It has been discovered that Aurora kinases are overexpressed in tumor types, including colon cancer, breast cancer, and leukemia. Two primary isoforms of Aurora kinases have been identified and designated as form A and B. Aurora A is also known as Aurora-2 (AUR2), STK6, ARK1, Aurora / kinase related to IPL1, while Aurora B is also known as Aurora 1 or AUR1. Aurora kinases have been characterized and identified in U.S. Patent Nos. 5,962,312 and 5,972,676 (a division of the '312 patent) which refer to Aurora 1 (AUR-1) and Aurora-2 (AUR-2) polypeptides, nucleic acids encoding said polypeptides, cells, tissues and animals containing said nucleic acids, antibodies to said polypeptides, assays using said polypeptides, and methods that relate to all of the foregoing. Overexpression of Aurora kinases, especially Aurora-2, in tumor cells provides an attractive target for drug intervention and the potential for significant opportunity to control cell division in many types of cancer, and in particular for colon cancer and breast cancer. We have now identified new heteroaromatic Aurora kinase inhibitors that are able to modulate (reduce) this activity of Aurora kinases in cancer cells. Accordingly, there is a need for additional selective inhibitors of certain receptor and non-receptor tyrosine kinases, useful in the treatment of abnormal cell growth, such as cancer, in mammals. The present invention provides novel pyrimidine derivatives which are kinase inhibitors and inhibitors of non-receptor tyrosine kinases, for example, FAK, Pyk, HgK, Aurora-1 and Aurora-2, and are useful in the treatment of abnormal cell growth.

SUMMARY OF THE INVENTION The present invention relates to a compound of formula I: where Ar is III or a pharmaceutically acceptable salt thereof, wherein K is C (R1) or N M is C (H) or N; Q is C (D) or N; D is a substituent selected from the group consisting of hydrogen, halogen, -CF3, -N02, -CN, -alkyl (d-C6), -alkenyl (C2-C6), -alkynyl (C2-C6), - perfluorinated (C2-C6) alkyl, perfluorinated (C2-C6) alkenyl, perfluorinated (C3-C6) alkynyl, -cycloalkyl (C3-C), -cycloalkenyl (C5-C10), -cycloalkyl (C6) -C10), -bicycloalkenyloylCß-do), heterocyclyl (C6-C? 0), -heterocycloalkyl (d-C10), -heterobicycloalkyl (C6-C9), -heterobicycloalkenyl (C6-C9) , -aryl (C6-C10), -heteroaryl (C? -C9), perfluorinated -aryl (C6-C10), -heteroaryloid-Cg), -NR3R4, -OR5, -C (0) R5, -C02R5, -CONR3R4, -SR6, -SOR6, -SOzR6, -S02NR3R4, -NHCOR5, -NR3CONR3R4, and -NR3S02R6, wherein said substituents D -alkyl (d-C6), -alkenyl (C2-C6), - (C2-C6) alkynyl, (C3-C7) cycloalkyl, (C5-C10) cycloalkenyl, (C6-C10) -bicycloalkyl, (C6-C10) -bicycloalkenyl, -heterocyclyl (d-C9), - heterocycloalkenyl (d-C10), -heterobicycloalkyl (C6-C9), -heterobicycloalkenyl (C6-C9), -aryl (C6-C10) ), heteroaryl (d-C9), -NR3R4, -OR5, -C (0) R5, -C02R5, -CONR3R4, -SR6, -SOR6, -S02R6, -S02NR3R4, -NHCOR5, -NR3CONR3R4, and -NR3S02R6 are optionally substituted with one to three substituents independently selected from the group consisting of hydrogen, halogen, -CF3, -N02, -CN, -alkyl (d-C6), -alkenyl (C2-C6), -alkynyl (C2- C6), -CR3 = N-NR3R4, -CR3 = N-0R5, -CR3 = N-NR3C (0) R3, -CR3 = N-NR3C (0) OR5, -NR3R4, -OR5, -cycloalkyl (C3- C7), -heterocyclyl (C2-C9), -C02R5, -CONR3R4, -SR6, -SOR6, -S02R6, -S02NR3R4, -NHCOR5, -NR3CONR3R4, and -NR3SOzR6, and wherein each of said substituents -alk (D-C6), -alkenyl (C2-C6), -alkyl (C2-C6), -cycloalkyl (C3-C7), -cycloalkenyl (C5-C10), -bicycloalkyl (C6-C10) ), -bicycloalkenyl (C6-C10), -heterocyclyl (CrC9), - heterocycloalkenyl (dC? o). heterobicycloalkyl (C6-C8), -hetero-cycloalkenyl (C6-C9), -aryl (C6-C10), and -heteroaryl (C1-C9) is optionally interrupted by one to three elements independently selected from the group consisting of - C (R3) = C (R3) -, -C (O) -, - (C = N-R3) -, - (C = N-NR3R4) -, -0 = NNC (O) -R5, -C = NNC (0) OR3, - (C = CR3R4) -, - (C = C (R3) 0 (O) -NR3R4)) -, - (C = C (R3) C (0) OR6) -, - S02-, -S-, -O- and -NR3-; R1 and R2 are identical or different and are independently selected from the group consisting of hydrogen, halogen, -CF3, -N02, -CN, -alkyl (C, -C6), -alkenyl (C2-C6), -alkynyl ( C2-C6), -perfluorinated (C2-C6) alkyl, -alkenyl (C2-C6) perfluorinated, -alkynyl (C3-C6) perfluorinated, -cycloalkyl (C3-C7), -cycloalkenyl (C5-do), -bicycloalkyl (C6-C10), -bicycloalkenyl (C6-C10), -heterocyclyl (C2-C9), -heterocycloalkenyl (C2-C10), -terobicycloalkyl (C6-C9), - heterobicyclocloalkenyl (C6-C9), -aryl (C6-C10), -heteroaryl-d-Cg), -aryl (C6-C10) perfluorinated, -heteroaryl (C1-C9) perfluorinated, -OR5 , -C (0) R5, -C02R5, -CONR3R4, -SR6, -SOR6, -S02R6, -S02NR3R4, -NHCOR5, -NR3CONR3R4, wherein said -alkyl (C, -C6), -alkenyl (C2- C6), -alkynyl (C2-C6), -cycloalkyl (C3-C7), -cycloalkenyl (C5-C10), -bicycloalkyl (C6-C10), bicycloalkenyl (C6-C10), -heterocyclyl (C2-C9) ), -heterocycloalkenyl (C2-C? 0), -heterobicycloalkyl (C6-C9), -heterobicycloalkenyl (C6-C9), -aryl (C6-C10) and -heteroaryloid-Cg) can be optionally substituted with from one to three residues independently selected between R5 and R6, and wherein n is an integer from 0 to 4; Re is a substituent selected from the group consisting of hydrogen, perfluorinated (C2-C6) alkyl, perfluorinated (C2-C6) alkenyl, perfluorinated (C3-C6) alkynyl, -NR3R4, -OR5, -C (0) R5, -C02R5, -CONR3R4, -SR6, -SOR6, -SOzR6, -S02NR3R4, -NHCOR5, -NR3CONR3R4, -NR3S02R6, -cycloalkyl (C3-C), -cycloalkenyl (C5-C10), -bicycloalkyl (C6-) C10), -bicycloalkenyl (C6-C? O), -heterocyclylCyC Cg), -heterocycloalkenylofd-do). -heterobicycloalkyl (C6-Cg), heterobicycloalkenyl (C6-Cg), -aryl (C6-C0), -heteroaryloylCG), -aryl (C6-C10) -fluorinated, -heteroaryl (C, -Cg) perfluorinated; wherein said substituents are Re-alkyl (d-C6) -cycloalkyl (C3-C7), -cycloalkenyl (C5-C10), -bicycloalkyl (C6-C10), -bicycloalkenyl (C6-C10), -heterocyclid-Cg) , -heterocyclealkenylofCrC ^), -heterobicycloalkyl (C6-Cg), -heterobicycloalkenyl (C6-C9), -aryl (C6-C10) and -heteroaryl (d-Cg) are optionally substituted with one to three independently selected residues between the group consisting of hydrogen, halogen, -alkyl (d-C6), -CN, - NR3R4, -OR5, -cycloalkyl (C3-C7), -heterocyclyl (C2-C9), -C02R5, -S02NR3R4, -NR3S02R6, -S02R6 and -CONR3R4; each RF is a substituent independently selected from the group consisting of hydrogen, -alkyl (d-C6),-perfluorinated (C2-C6) alkyl,-perfluorinated (C2-C6) alkenyl, -perfluorinated (C3-C6) alkynyl , -cycloalkyl (C3-C7), -cycloalkenyl (C5-do). -bicycloalkyl (C6-C10), bicycloalkenyl (C6-C? o), -heterocyclyl (C2-C9), -heterocycloalkenyl (C2-C10), heterobicycloalkyl (C6-Cg), -heterobicycloalkenyl (C6-Cg) ), -0-alkyl (d-C6), -0-cycloalkyl (C3-C7), -O-heterocyclyloid-Cg), -NR3R4, -SR6, -SOR6, -S02R6, -C02R5, -CONR3R4, -S02NR3R4 , -NHCOR5, -NR3CONR3R4, and -NR3S02R6; wherein said substituents RF -alkylidene-Ce). -cycloalkyl (C3-C7), -cycloalkenyl (C5-C10), -bicycloalkyl (C6-C10), -bicycloalkenyl (C6-C10), -heterocyclyl (C2-Cg), -heterocycloalkenyl (C2-C10) > -heterobicycloalkyl (C6-Cg), -heterobicycloalkenyl (C6-C9), -O-alkyl (d-C6), -0-cycloalkyl (C3-C7), -0-heterocyclyl (C2-C9), -NR3R4, - SR6, -SOR6, -S02R6, -C02R5, -CONR3R4, -S02NR3R4, -NHCOR5, -NR3CONR3R4, and -NR5S02R6 are optionally substituted with one to three residues independently selected from the group consisting of hydrogen, halogen, -CF3, - CN, -alkyloid-Ce), -NR3R4, -OR5, -cycloalkyl (C3-C7), -heterocyclyl (C2-C9), -COzR5, and -CONR3R4; each RG is a substituent independently selected from the group consisting of hydrogen, -alkyl (d-C6), -alkenyl (C2-C6), -alkynyl (C2-C6), -alkyl (C2-C6) perfluorinated, - perfluorinated (C2-C6) alkenyl, perfluorinated (C3-C6) alkynyl, (C3-C7) cycloalkyl, (C5-C, o), -bicycloalkyl (C6-C10), -bicycloalkenyl (C6-) C10), -heterocyclyl (C2-C9), -heterocycloalkenyl (C2-C10), -heterobicycloalkyl (C6-Cg), -heterobicycloalkenyl (C6-C9), -C02R5, and -CONR3R4, wherein said substituents RG -alkyloid -Cß), -alkenyl (C2-C6), -alkynyl (C2-C6), -cycloalkyl (C3-C7), -cycloalkenyl (C5-C? O), -bicycloalkyl (C6-C10), -bicycloalkenyl (C6) -C 0), -heterocyclyl (C2-C9), -heterocycloalkenyl (C2-C10), -heterobicycloalkyl (C6-C9), and -heterobicycloalkenyl (C6-Cg), are optionally substituted with from one to three residues independently selected from the group consisting of hydrogen, halogen, -CF3, -N02, -CN, -alkyl (C1-C6), -alkenyl (C2-C6), -alkyne lo (C2-C6), -CR3 = N-NR3R4, -CR3 = N-OR5, -CR3 = N-NR3C (0) R3, -CR3 = N-NR3C (0) OR5, -NR3R4, -OR5, - cycloalkyl (C3-C7), -heterocyclyl (C2-C9), -COzR5, -CONR3R4, -SR6, -SOR6, -SOzR6, - S02NR3R4, -NHCOR5, -NR3CONR3R4, and -NR3S02R6, wherein said alkyl (D-C6) -a! Quenyl (C2-C6) and -alkynyl (C2-C6) alkyl moieties may be optionally substituted with one of three r-, 10 R groups; RE and RH can be taken together with the atom (s) to which they are attached to form a -heterocyclyl (C2-Cg), -heterocycloalkenyl (C2-C10), -heterobicycloalkyl (C6-C9), heterobicycloalkenyl (C6-C9), wherein said -heterocyclyl (C2-Cg), -heterocycloalkenyl (C2-C10), -heterobicycloalkyl (C5-C? o) and -hetero-bicycloalkenyl (C6-C10) are optionally interrupted by one to three elements independently selected from the group consisting of -C (R3) = C (R3) -, -C (O) -, - (C = N -R3) -, - (C = N- NR3R4) -, -C = NNC (0) -R5, -C = NNC (0) OR3, - (C = CR3R4) -, - (C = C (R3) C (0) -NR3R4)) -, - (C = C (R3) C (0) OR6) -, -S02-, -S-, -O- and -NR3-, and wherein said -heterocyclyl (C2-C9), -heterocycloalkenyl (C2-C) 0), -teroalkyl (C5-C? 0) and -heterobicycloalkenyl (C6-C10) is optionally substituted with one to three residues independently selected from the group consisting of hydrogen, halogen, -CF3, -N02, -CN, -alkyl (d-C6), -alkenyl (C2-C6), -alkynyl (C2-C6), -CR3 = N-NR3R4, -CR3 = N-OR5, -CR3 = N -NR3C (0) R3, -CR3 = N-NR3C (0) OR5, -NR3R4, -OR5, -cycloalkyl (C3-C7), -heterocyclyl (C2-C9), -C02R5, -CONR3R4, -SR6, - SOR6, -S02R6, -S02NR3R4, -NHCOR5, -NR 3CONR3R4, and -NR3S02R6; RH is a substituent selected from the group consisting of: (a) hydrogen; (b) -aryl (C6-C? o) or -heteroaryl (d-Cg), optionally substituted with one to three residues independently selected from the group consisting of halogen, hydroxy, -alkyl (d-C6), -alkyl (C1-C6) -P (0) (0-(C1-C6) alkyl) 2, -cycloalkyl (C3-C10), -aryl (C6-C10), -heterocyclyl (C2-C9), -heteroaryl (d-Cg), -NR3R4, -NHS02-alkyl (C, -C6), -NHS02-a "cloalkyl (C3-C6), -N (alkyl (C6)) (S? 2-alkyl (C C6) )), -N (C6 alkyl) (S02-cycloalkyl (C3-C6)), -N (cycloalkyl (C3-C6)) (S02- alkyloylC ^ Ce)), -N (cycloalkyl (C3-C6) )) (S02-cycloalkyl (C3-C6)), -0-alkyl (C, -C6), -0-S02-alkylene (d-C6), -0-S02-cycloalkyl (C3-C6), -C (0) -alkyl (d-C6), -C (0) CF3, -C (O) -cycloalkyl (C3-C10), -C (O) -aryl (C6-C10), -C (0) ) -heterocyclyl (C2-C9), -C (0) 0-alkyl (d-C6), -C (0) 0-cycloalkyl (C3-C10), -C (O) O-aryl (C6-C10), -C (0) 0-heterocyclyl (C2-C9), -C (0) 0-heteroaryl (C? -C9), -C (0) -alkyl (C1-C6) -0-alkyl (C1-C6), -S02-alkyl ( C C6), -S02-cycloalkyl (C3-C6), -S02CF3, - S02NH2, -SO2NH-alkyl (C6), -S02NH-cycloalkyl (C3-C6), -S02N (alkyl (C, -C6)) 2, S02N (alkyl (d-C6)) (cycloalkyl) (C3-C6)), -S02N ((C3-C6) cycloalkyl) 2 and -S02NR3R4, wherein said (C6-C10) aryl or -heteroaryloid-Cg) are optionally interrupted by one to three selected elements between the group consisting of -S-, -O-, -N-, -NH- and -NR11, and wherein said -aryl (C6-C10) or -heteroaryl (CrCg) are optionally condensed to a moiety -cycloalkyl (C3-C10) or -heterocyclyl (C2-Cg), and wherein said residues -cycloalkyl (C3-C10) or -heterocyclyl (C2-Cg) are optionally substituted with one to three elements selected from the group consisting of halogen, hydroxy, -alkyl (d-C6), -alkyl (d-C6) -P (0) (0 -alkyl (C? -C6)) 2, -cycloalkyl (C3-C10) , -arylCe-do), -heterocyclyl (C2-C9), -heteroaryl (d-Cg), -NR3R4, -NHS02-alkyl (d-C6), -NHS02-cycloalkyl (C3-C6), -Nalk d-CeJKSO alkyloid-Ce)), -Nalkyl d-CßJXSOz-cycloalkyloylCa-Ce)), -Nicicloalqui Cs-CßJJ ÍSO alkyloylC Ce)), -N ((C3-C6) cycloalkyl) (S02-cycloalkyl (C3-C6)) t -O-alkyl (d-C6), -0-S02-alkyl (d-C6), - 0-S02-cycloalkyl (C3-C6), -C'OJ-alkyloid-Ce), -C (0) CF3, -C (O) -cycloalkyl (C3-C10), -C (O) -aryl (C6-C10), -C (0) -heterocyclyl (C2-C9), -CiOJ-heteroaryloid-Cg), -C (0) 0 -alkyl (C, -C6), -C (O) O-cycloalkyl (C3-C10), -C (O) O-aryl (C6-C10), -C (0) 0-heterocyclyl (C2-C9), -C (0) 0-heteroaryl (C? -C9) , -C (0) -alkyl (d-C6) -0-alkyl (C? -C6), -S02-alkyl (C6), -S02-cycloalkyl (C3-C6), -S02CF3, -S02NH2, -S02NH-alkyl (d-C6), -S02NH-cycloalkyl (C3-C6), -S02N ((C1-C6) alkyl) 2, -S02N ((C, -C6) alkyl) (cycloalkyl) (C3-C6)), -S02N ((C3-C6) cycloalkyl) and -S02NR3R4; (c) -cycloalkyl (C3-C7), -cycloalkenyl (C5-C10), -bicycloalkyl (C6-C10), -bicycloalkenyl (C6-C10), -heterocyclyl (C2-C9), -heterocycloalkenyl (C2-C10) , heterobicycloalkyl (C6-C9), -heterobicycloalkenyl (C6-C9) and -alkyl-CJJ-heterocyclyloyl CrCg), optionally substituted with one to three residues independently selected from the group consisting of halogen, hydroxy, -alkyl (C? -C6) ), -alkyl (C? -C6) -P (0) (0-alk (d-C6)) 2, -cycloalkyl (C3-C10), -aryl (C6-C10), -heterocyclyl ( C2-C9), -he'-arylaryl (d-C9), -NR3R4, -NS02-alkyloid-Ce), -NHS02-cycloalkyl (C3-C6), -Nalkyl-CeJKSOalkyloxyCrCe)), -N'alqui C! - C6)) (S02-cycloalkyl (C3-C6)), -N ((C3-C6) cycloalkyl (S02- (C1-C6) alkyl), -N (C3-C6) alkylcycloalkyl) (S02- (C3-C6) cycloalkyl, -0-alkyl (d-C6), -0-S02-alkyl (C, -C6), -O-SOz-alkylCCrE), -0-S02- cycloalkyl (C3-C6), -CioJ-alkyloid-Ce), -C (0) CF3, -C (O) -cycloalkyl (C3-C10), -C (O) -aryl (C6-C10), - C (0) -heterocyclyl (C2-C9), -C (0) -heteroaryl (d-C9), -C (0) 0-alkyl (d-C6), -C (0) 0- cycloalkyl (C3-C10), -C (O) O-aryl (C6-C10), -C (0) 0-heterocyclyl (C2-C9), -C (0) 0-heteroaryl (d-C9) , -C (0) -alkyl (C, -C6) -0-alkyl (C, -C6), -S02-alkyl (d-C6), -S02-cycloalkyl (C3-C6). -S02CF3, -S02NH2, -S02NH-alkyl (C, -C6), -S02NH-cycloalkyl (C3-C6), -S02N (alkyl (C6)) 2, -S02N (((C, -C6) alkyl )) ((C3-C6) cycloalkyl, -S02N (C3-C6) cycloalkyl) and -S02NR3R4, wherein said - (C3-C7) cycloalkyl, (C5-C10) cycloalkenyl, -bicycloalkyl (C6-C10), -bicycloalkenyl (C6-C10), -heterocyclyl (C2-C9), -heterocycloalkenyl (C2-C10), -heterobicycloalkyl (C6-Cg), -heterobicycloalkenyl (C6-C9) and -alkyl (d-C6) -heterocyclyl (C2-C9) are optionally interrupted by one to three elements selected from the group consisting of -C (R3) = C (R3) -, -C (0) -, - (C = N-R3) -, - (C = N-NR3R4) -, -C = NNC (0) -R5, -C = NNC (0) OR3, - (C = CR3R4) -, - (C = C (R3) C (0) -NR3R4)) -, - (C = C (R3) C (0) OR6) -, -S02-, -S-, -O- and -NR3-, and wherein said substituents - (C3-C7) cycloalkyl, - (C5-C10) cycloalkenyl, -bicycloalkyl (C6-C10), -bicycloalkenyl (C6-C10), -heterocyclyl (C2- C9), -heterocycloalkenyl (C2-C0), -heterobicycloalkyl (C6-C9), -heterobicycloalkenyl (C6-C9) are optionally fused to a (C6-C10) aryl or -heteroaryl (d-Cg), optionally substituted with one to three residues independently selected from the group consisting of halogen, hydroxy, -alkyl (d-C6), -alkyl-Ce- (oxy-alky-Ce)) ^ -cycloalkyl (C3-C10), -aryl (C6-C10), -heterocyclyl (C2-C9), -heteroaryl (dC), -NR3R4, -NHS02-(C1-C6) alkyl, -NHS02-cycloalkyl (C3-C6), -N (alkyl (C, -C6)) (S02-alkyl (C6C6)), -N ((C1-C6) alkyl) (S02.Cycloalkyl (C3-C6)) I -N ((C3-C6) cycloalkyl) (S02- alkyl (d-C6)), -N ((C3-C6) cycloalkyl) (S02-cycloalkyl (C3-C6)), -O-alkylofC ^ Ce), -0-S02-a alkyl (C C6), -0-S02-cycloalkyl (C3-C6). -C (0) -alkyl (d-C6), -C (0) CF3, -C (O) -cycloalkyl (C3-C10), -C (O) -aryl (C6-C10), -C (0) -heterocyclyl (C2-C9), -C (0) 0 -alkyl (d-C6), -C (O) O-cycloalkyl (C3-C10), -C (O) O-aryl (C6-) C10), -C (0) 0-heterocyclyl (C2-C9), -CINO-heteroaryloid-Cg), -C (0) -alkyl (C, -C6) -0-alkyl (d-C6), -S02 -alkyl (C C6), -S02-cycloalkyl (C3-C6). -S02CF3 >; -S02NH2, -S02NH- (d-C6) alkyl, -S02NH-cycloalkyl (C3-C6), -S02N (alk (d-C6)) 2, -S02N ((C, -C6) alkyl) (cycloalkyl) (C3-C6)), -S02N ((C3-C6) cycloalkyl) and -S02NR3R4; (d) -alkyl (CrC6), perfluorinated (C2-C6) alkyl, perfluorinated (C2-C6) alkenyl, and perfluorinated (C3-C6) alkynyl, wherein said -alkyl (d-C6) is optionally substituted with one to three residues selected from the group consisting of halogen, hydroxy, -alkyl (d-C6), -alkenyl (C2-) Cß), -alkynyl (C2-C6), -alkyl'd-CeH-'OKO-alkyD-Ce) ^, -NR3R4, -NHS02-alkyl (d-C6), -NHS02-cycloalkyl (C3-C6) , -Nalkalid-d MSOü-alkyloid-Cg)), -N (alkyl (d-C6)) (S02-cycloalkyl (C3-C6)), -N ((C3-C6) cycloalkyl) (S02-alkyl) (d-C6)), -N ((C3-C6) cycloalkyl) (S02-cycloalkyl (C3-C6)), -NHCYOJ-alkyMd-Ce), -NHC (0) -cycloalkyl (C3-C6), - NHC (0) -heterocyclyl (C2-C9), -NHC (O) -aryl (C6-C10), -NHC (0) -heteroaryl (d-C9), -N-phenylcycline-JCIOX-AlkyloCrCß), -N ( (C 1 -C 6) alkyl) C (0) -cycloalkyl (C 3 -C 6), -N (C 1 -C 6 alkyl) C (0) -heterocyclic (C 2 -C 9), -N (alkyl ( C C6)) C (0) -aryl (C6-C1o) > -Nalkyl d-Ce ^ CÍOHieteroariloíd-Cg), -0-alkyl (d-C6), -0-S02-alkyl (C, -C6), -0-S02-cycloalkyl (C3-C6), -C (0 ) -alkyl (d-C6), -C (0) CF3, -C (0) -cycloalkyl (C3-C10), -C (O) -aryl (C6-C10), -C (0) - heterocyclyl (C2-C9), -CYOJ-heteroaryloid-Cg), -C (0) 0-alkyl (C, -C6), -C (O) O-cycloalkyl (C3-C10), -C (0) 0 -aryl (C6-C? o), -C (0) 0-heterocyclyl (C2-C9), -C (0) 0-heteroaryl (C C9), -dOJ-alkyD-Ce? -O-alkyl d-Cß), -S02-alkyl (d-C6), -S02-cycloalkyl (C3-C6), -S02CF3 > -S02NH2, -S02NH-alkyl (CrC6), -S02NH-cycloalkyl (C3-C6), -S02N (alkyl (d-C6)) 2, -S02N (alkyl (C, -C6)) (cycloalkyl (C3-C6) )), -S02N ((C3-C6) cycloalkyl) 2 and -S02NR3R4, wherein said -alkyl (d-C6) is optionally interrupted by one to three elements independently selected from the group consisting of-C ( O), -S02, -S-, -O-, and -NR11; and wherein each substituent, residue, or element RH (b) - (d) is optionally substituted with one to three radicals independently selected from the group consisting of hydrogen, halogen, hydroxy, -CF3, -N02, -CN, -alkyl (d-C6), -alkenyl (C2-C6), -alkynyl (C2-C6), -cycloalkyl (C3-C), -cycloalkenyl (C5-C10), -bicycloalkyl (C6-C10), -bicycloalkenyl (C6-C10), -heterocyclic (C2-C9), -heterocycloalkenyl (C2-C10), -heterobicycloalkyl (C6-C9), heterobicycloalkenyl (C6-C9), -aryl (C6-C10), - heteroaryl (d-Cg), -0-alkyl (d-C6), -O-cycloalkyl (C3-C7), -0-heterocyclyl (C2-Cg), -CR3 = N-NR3R4, -CR3 = N-OR5 , -CR3 = N-NR3C (0) R3, - CR3 = N-NR3C (0) OR5, -NR3R4, -SR6, -SOR6, -S02R6, -C02R5, -CONR3R4, - S02NR3R4, -NHCOR5, - NR3CONR3R4, and -NR3S02R6; A is a ring system selected from the group consisting of -cycloalkyl (C3-C? 0), -cycloalkenyl (C5-C10), -heterocyclyl (C2-C10), -heterocycloalkenyl (C2-C10), -aryl (C6-C10) and -heteroaryl (C2-C9), wherein said -cycloalkyl (C3) -C10), -cycloalkenyl (C5-C? O), -heterocyclyl (C2-C10), -heterocycloalkenyl (C2-C10), -aryl (C6-C10) and -heteroaryl (C2-C9) of said ring A are optionally interrupted by one to three elements selected from the group consisting of -C (R3) = C (R3) -, -C (O) -, - (C = N -R3) -, - (C = N-NR3R4 ) -, -C = NNC (0) -R5, -C = NNC (0) OR3, - (C = CR3R4) -, - (C = C (R3) C (0) -NR3R4)) -, - ( C = C (R3) C (0) OR6) -, -S02-, -S-, -O- and -NR3-, and wherein said ring system A is optionally substituted with one to three independently selected substituents between the group consisting of hydrogen, halogen, -CF3, -N02, -CN, -alkyl (d-C6), -alkenyl (C2-C6), -alkynyl (C2-C6), -CR3 = N-NR3R4, - CR3 = N-OR5, -CR3 = N-NR3C (0) R3, -CR3 = N-NR3C (0) OR5, -NR3R4, -OR5, -cycloalkyl (C3-C7), -cycloalkenyl (C5-do), -bicycloalkyl (C6-C10), -bicycloalkenyl (C6-C10), -heterocyclyl (C2-C9), -heterocycloalkenyl (C2-C10), -heterobicycloalkyl (C6-C9), -heterobicycloalkenyl (C6-Cg), -aryl (C6-C10), -heteroaryloid-Cg), -C (0) R5, -C02R5, -CONR3R4, -SR6, -SOR6, -S02R6, -S02NR3R4, -NHCOR5, -NR3CONR3R4, and -NR3S02R6; Z1 and Z2 are identical or different and are independently selected from the group consisting of -C-, -CR7- and -N-, wherein each R7 is the same or different; Y1 and Y2 are equal or different and are independently selected from the group consisting of -CR7- and -N-, wherein each R7 is the same or different; L1 and L2 are each independently a linking group selected from the group consisting of -CR8R9-, -C (R3) = C (R3) -, -C (O) -, - (C = N -R3) -, - (C = N-NR3R4) -, - (C = N-NOR5) -, -C = CR3R4) -, - (C = C (R3) C (0) -NR3R4)) -, - (C = C ( R3) C (0) OR6) -, -NC (0) R8-, -S02, -S-, -O- and -NR3, wherein L1 is not -C (R8) = C (R8) - or -C = C- when Z1 or Y1 is N, and L2 is not -C (R3) = C (R3) - or -C = C- when Z2 or Y2 is N; q is an integer from 0 to 3; L1 and a substituent of A, or L2 and a substituent of A can be taken together to form a -cycloalkyl (C5-C7), -cycloalkenyl (C5-C? 0), -heterocyclic (C2-C9) ), -heterocycloalkanoyl (C2-C10), -aryl (C6-C10) and -heteroaryl (d-Cg), in which each of said -cycloalkyl (C5-C7), -c C5alkyl (C5-C6), -heterocyclic (C2-C9), -heterocycloalkenyl (C2-C10), -aryl (C6-C10) and -heteroaryl (d-C9) is optionally interrupted by one to three elements independently selected from the group consisting of -C (R3) = C (R3) -, -C (O) -, - (C = N -R3) -, - (C = N- NR3R4 ) -, - (C = N-NOR5) -, - (C = CR3) -, - (C = C (R3) C (0) -NR3R)) - > - (C = C (R3) C (0) OR6) -, -S02-, -S-, -O- and -NR3-, and in which each of said -cycloalkyl (C3-C7), -cycloalkenyl (C3-C10), -heterocyclyl (C2-C9) and -heterocycloalkenyl (C2-C10) is optionally substituted with one to three substituents independently selected from the group consisting of halogen, -CF3, -CN, -N02, -alkyl (d-C6), -OR16, -C (0) OR16, -OC (0) R16, -OC ( 0) OR16, -N (R16) 2, -NR16C (0) R16, -S02R16, -S02N (R16) 2 and -NR16S02R16; X and W are the same or different and each is independently selected from the group consisting of -CR8R9-, -NR12-, -C (O) -, - (C = NR3) -, - (C = N-NR3R4) - , - (C = NN-OR5) -, - (C = CR3R4) -, - (C = C (R3) C (0) -NR3R4)) -, - (C = C (R3) C (0) OR6 ) -, -S-, -S (O) -, -S (0) 2-, -S (0) (NR3R4) -, and -O-, in which one or more adjacent carbons or heteroatoms selected from X , Y1, Y2, or W are optionally condensed to a ring system selected from the group consisting of -cycloalkyl (C3-C7), -heterocyclic (C2-Cg), -aryl (C6-C10), and -heteroaryl (d-C9), wherein each of said -cycloalkyl (C3-C), -heterocyclyl (C2-C9), -aryl (C6-C? 0) is optionally interrupted by one to three selected elements independently between the group consisting of -C (R3) = C (R3) -, -C (O) -, - (C = N -R3) -, - (C = N-NR3R4) -, - (C = N -NOR5) -, - (C = CR3) -, - (C = C (R3) C (0) -NR3R4)) -, - (C = C (R3) C (0) OR6) -, -S02- , -S-, -O- and -NR3-, and in which each of said ring systems -cycloalkyl (C3-C7), -heterocyclyl (C2) -C9), -aryl (C6-C? 0), and -heteroaryl (d-Cg) are optionally substituted with one to three substituents selected from the group consisting of hydrogen, hydroxyl, halogen, -CF3, -CN , -N02, -alkyl (d-C6), -NH-alkylene (d-C6), -NH-cycloalkyl (C3-C7), -NH-heterocyclyl (C2-C9), -NH-aryl (C6-C10), -NH-heteroaryl (d-C9), -Nalkyl-Ce) ^, -N ((C3-C7) cycloalkyl), -N ((C2-C9)) 2-heterocyclyl. -N (aryl (C6-C10)) 2, -N (heteroaryl (d-C9)) 2, -0-alkyl (C1-C6), -0-cycloalkyl (C3-C7), -0-heterocycline Cl (C2-C9), -O-aryl (C6-C10), -O-heteroaryloid-Cg), -cycloalkyl (C3-C7), -heterocyclyl (C2-C9), -C02H, - C (0) (alkyl (C, -C6)), -S02H, -S02 (alkyl (d-C6)), -S02NH2 > -S02NH (alkyl (CrC6)), -S02N ((C1-C6) alkyl) 2, -NHS02 (alkyl (d-C6)), and -NalkyKd-Cß ^ SOzyalkyloid-Ce)); Y1 together with W, Y2 together with W, Y1 together with X, Y2 together with X, X together with W, or L together with And they can form a -cycloalkyl (C5-C7), -cycloalkenyl (C5-C10), -heterocyclyl (C2-Cg) and -heterocycloalkenyl (C2-C10), wherein each of said -cycloalkyl (C5-C7) , -cycloalkenyl (C5-C10), -heterocyclyl (C2-Cg) and -heterocycloalkenyl (C2-C10) is optionally interrupted by one to three elements independently selected from the group consisting of -C (R3) = C (R3) -, -C (O) -, - (C = N -R3) -, - (C = N-NR3R4) -, -C = NNC (0) -R5, -C = NNC (0) OR3, - (C = CR3R4) -, - (C = C (R3) C (0) -NR3R4)) -, - (C = C (R3) C (0) OR6) -, -S02-, -S-, -O- and -NR3-, and wherein each of said -cycloalkyl (C3-C7), -c (C3-do), -heterocyclyl (C2-Cg) and -heterocycloalkenyl (C2-C10) is optionally substituted with one to three substituents independently selected from the group consisting of halogen, -CF3, -CN, -N02, - alkyl (d-C6), -OR16, -C (0) OR16, -OC (0) R, 6, -OC (0) OR16, -N (R16) 2, -NR16C (0) R16, -S02R16, -S02N (R16) 2 and -NR16S02R16; W together with another W, X together with another X, L1 together with another L1, or L2 together with another L2 can form a -cycloalkyl (C3-C7), -cycloalkenyl (C5-C? O), -heterocyclyl (C2- Cg), -heterocycloalkenyl (C2-C10), -aryl (C6-C10) or -heteroaryl (d-Cg), wherein each of said -cycloalkyl (C3-C), -cycloalkenyl (C5) -do), -heterocyclyl (C2-Cg) and -heterocycloalkenyl (C2-C10) is optionally interrupted by one to three elements independently selected from the group consisting of -C (R3) = C (R3) -, -C ( O) -, - (C = N-R3) -, - (C = N-NR3R4) -, -C = NNC (0) -R5, -C = NNC (0) OR3, - (C = CR3R4) - , - (C = C (R3) C (0) -NR3R4)) -, - (C = C (R3) C (0) OR6) -, -S02-, -S-, -O- and -NR3- , and wherein each of said -cycloalkyl (C3-C), -cycloalkenyl (C3-C10), -bicycloalkyl (C6-C10), -bicycloalkenyl (C6-C10), -heterocyclyl (C2-C9) , -heterocycloalkenyl (C2-C10), -heterobicycloalkyl (C5-C10), -heterobicycloalkenyl (C6-C10), -aryl (C6-C? 0) and -heteroaryl (d-Cg) is optionally substituted with one to three substitute listeners independently selected from the group consisting of halogen, -CF3 >; -CN, -N02, -alkyl (d-C6), -OR16, -C (0) OR16, -OC (0) R16, -OC (0) OR16, -N (R16) 2, -NR16C ( 0) R16, -S02R16, -S02N (R16) 2y-NR16S02R16; R3 and R4 are each independently a substituent selected from the group consisting of hydrogen, -alkyl (d-C6), -cycloalkyl (C3-C7), -bicycloalkyl (C5-Cn), heterocyclyl (C2-C9), -aryl (C6-C10), -heteroaryl (d-C9), -C02H, -C (0) (alkyl (d-C6)), C (0) (heterocycloalkyl (C2-Cg)), -C (0) OR 8, -C (0) NR 8 R 9, and -S 2 (alkyl (C Cß)); wherein said substituents -alkyl (d-C6), -cycloalkyl (C3-C7), -bicycloalkyloyl-di). -heterocyclyl (C2-C9), -aryl (C6-C10), -heteroaryl (d-Cg), -C (0) (alkyl (d-C6)), -C (0) (heterocycloalkyl (C2-C9) ) and - S02 (alkyl (CrC6)) are optionally substituted with from one to three selected residues independently from the group consisting of amino, hydrogen, hydroxyl, halogen, -CF3, -CN, -N02, = 0, = S, = NR8, -C (0) NR5R6, -alkyl (d-C6), -NH- alkyl (d-C6), -NR8C (0) R9, -NR8CONR8R9-NH-cycloalkyl (C3-C7), -NH-heterocyclyl (C2-C9), -NH-aryl (C6-C10), -NH-heteroar (C, -Cg), -N (C (C 6) alkyl) 2, -N ((C 3 -C 7) cycloalkyl) 2, -N (heterocyclyl (C 2 -C 9)) 2, -N (aryl (C 6) -C, 0)) 2, -N (heteroaryl (d-C9)) 2, -0-alkyl (C, -C6), -0-cycloalkyl (C3-C7), rO-heterocyclyl (C2) -Cg), -O-aryl (C6-C? O), -0-heteroaryl (C? -C9), -cycloalkyl (C3-C7), -heterocyclyl (C2-C9), -C02H, C (0) (alkyl (d-C6)), -S02H, -S02 (alkyl (C, -Cβ)), -S02NH2, -S02NH (alkyl (d-C6)), -S02N (alkyl (d-C6)) 2, -NHS02 (alkyl (d-C6)). -Nalkalk-CeJJSOz'alkylide-Cß)), -NHS02NR8R9, wherein R3 and R4 when attached to the same nitrogen atom can form a (C2-C9) -heterocyclyl optionally substituted with one to three substituents independently selected from the group consisting of hydrogen, halogen, -CF3t -N02, -CN, -alkyl (C, -C6), -alkenyl (C2-C6), -alkynyl (C2-C6), -CR5 = N-NR5R6, -CR5 = N-OR10, -CR5 = N-NR5C (0) R10, -CR5 = N-NR5C (0) OR10, -NR5R6, -OR5, -cycloalkyl (C3-C7), -heterocyclyl (C2-C9) , -C02R5, -CONR5R6, -SR6, -SOR6, -SOzR6, -S02NR5R6, -NHCOR5, -NR5CONR5R6 and -NR5S02R6; R5 is a substituent selected from the group consisting of hydrogen, -alkyl (d-C6), -alkenyl (C2-C6), -cycloalkyl (C3-C7), -cycloalkenyl (C5-C7), -heterocyclyl (C2) -Cg), -aryl (C6-C10), -heteroaryl (d-C9), -C02H, -C (0) (alkyl (d-C6)), and -P (0) (OR16) 2, in the which said -alkyl (d-C6), -cycloalkyl (C3-C7), -heterocyclyl (C2-C9), -aryl (Cß-C? o). -heteroaryloid-Cg), and -C (0) (alkyl (d-C6)), and substituents are optionally substituted with one to three residues independently selected from the group consisting of hydrogen, hydroxyl, halogen, -CF3, -CN , -N02, -alkyl (CrC6), -NH-alkyl (d-C6), -NH-cycloalkyl (C3-C7), -NH-heterocyclyl (C2-C9), -NH-aryl ( C6-C, 0), -NH-heteroaryl (d-Cg), -N (alkyl (C, -C6)) 2, -N ((C3-C7) cycloalkyl) 2, -N (heterocyclyl (C2-C9) )) 2, -N (ar! (C6-C? O)) 2, -N'heteroaril'CrCgJfe, -0-alkylo (d-C6), -0-cycloalkyl (C3-C7), - 0-heterocyclyl (C2-C9), -O-aryl (C6-C10), -O-heteroaryl (d-Cg), -cycloalkyl (C3-C7), -heterocyclyl (C2-C9), -C02H, -C (0) (alkyl (C, -C6)), -S02H, -S02 (alkyl (d-C6)), -S02NH2, -SOzNHalkyl-Ce)), -S02N (alkyl (d-C6)) 2, - NHS 2 2 (alkyl (d-C6)), and -Nalkyl-JJSOzalkyloyl -Ce)); R6 is a substituent selected from the group consisting of hydrogen, -alkyl (d-CB), -cycloalkyl (C3-C7), -heterocyclyl (C2-Cg), -aryl (C6-C10), -heteroaryloid-Cg), -C02H, - C (0) (alkyl (d-C6)), and -S02 ((C? -C6) alkyl), wherein said substituents -alkyl (d-C6), -cycloalkyl (C3-C7) , -heterocyclyl (C2-Cg), -aryl (C6-C10), -heteroaryl (d-Cg), -C (0) (alkyl (d-C6)), and -S02 (alkyl (C) ? -C6)) are optionally substituted with from one to three moieties independently selected from the group consisting of hydrogen, hydroxyl, halogen, -CF3, -CN, -N02, -alkyl (d-C6), -NH-alkyl (d -C6), -NH-cycloalkyl (C3-C7), -NH-heterocyclyl (C2-C9), -NH-aryl (C6-C10), -NH-heteroaryl (d-Cg), -N (alkyl (d-C6)) 2, -N ((C3-C7) cycloalkyl) 2, -N (heterocyclyl (C2-Cg)) 2, -N (aryl (C6-C10)) 2, -N (heteroaryl (C1-Cg)) 2- -0-alkyl (C6), -0-cycloalkyl (C3-C7), -0-heterocyclyl (C2-C9), -O-aryl (C6-C10) , -O-heteroaryloid-Cg), -cycloalkyl (C3-C7), -heterocyclyl (C2-C9), -COzH, -C (0) (alkyl (d-C6)), -S02H, -S02 (alkyl ( CrC6)), -S02NH2, -S02NH (alkyl (d-C6)), -S02N ((C1-C6) alkyl) 2 > -NHS02 (alkyl (d-C6)), and -N'alkyl'd-d JSOjalkyl-Ce)); R7 is a substituent selected from the group consisting of hydrogen, halogen, -N02, -CF3, -CN, -NR10R10, -C (O) NR10R10, -OR10, -C02R10, -C (0) R1 °, -SR10, -SOR10, -S02R10, -SO2NR10R10, -NHCOR10, -NR10CONR10R10, -NR10SO2R10, -P (0) (OR16) 2, -alkyl (d-C6), -alkyl (C, -C6), -alkenyl (C2- C6), -alkynyl (C2-C6), -perfluorinated (C2-C6) alkyl,-perfluorinated (C2-C6) alkenyl, -perfluorinated (C3-C6) alkyl, -cycloalkyl (C3-C), -cycloalkenyl (C3-C10), -bicycloalkyl (C6-C10), -bicycloalkenyl (C6-C10), -heterocyclyl (C2-Cg), -heterocycloalkenyl (C2-C10), -heterobicycloalkyl (C5-C10), -heterobicycloalkenyl (C6-C10), - aryl (C6-C? o), -heteroaryloid-Cg), perfluorinated (C6-C10) -aryl, -heteroaryl (d-Cg) perfluorinated, wherein said substituents -alkyl (d-C6), -alkenyl (C2-C6), -alkynyl (C2-C6), -cycloalkyl (C3-C7), -cycloalkenyl (C3-C10), -bicycloalkyl (C6-C10), bicycloalkenyl (C6-C10), -heterocyclyl (C2- C9), - heterocycloalkenyl (Cz-C10), -heterobicycloalkyl (C5-C10). -heterobicycloalkenyloylCß-Cio), and -aryl (C6-C10), -heteroarilofd-Cg) are optionally substituted with one to three moieties independently selected from the group consisting of hydrogen, hydroxyl, halogen, -CF3, -CN, -N02 , -alkyl (d-C6), -NH-Clycyl-Cß), -NH-cycloalkyl (C3-C7), -NH-heterocyclyl (C2-C9), -NH-aryl (C6-C10), - NH-heteroaryl (C? -C9), -N (alkyl (dC6)) 2, -N ((C3-C7) cycloalkyl) 2, -N (heterocyclyl (C2-C9)) 2t -N (aryl ( C6-C10)) 2, -O-alkyloid-Ce), -0-cycloalkyl (C3-C7). -0-heterocyclyl (C2-Cg), -O-aryl (C6-C10), -O-heteroaryloid-Cg), -cycloalkyl (C3-C7), -heterocyclyl (C2-C9), -C02H, - C (0) (alkyl (C, -C6)), -S02H, -SOZalkyl-Ce)), -S02NH2, -S02NH (alkyl (d-C6)), -S02N (alkyl (d-C6)) 2, -NHS02 ((C1-C6) alkyl) > and -N (alkyl (C, -C6)) S02 (alkyl (d-C6)); R8 and R9 are each independently a substituent selected from the group consisting of hydrogen, halogen, -alkyl (d-C6), -alkyl (C2-C6) perfluorinated, -cycloalkyl (C3-C7), -cycloalkenyl (C5-C) ?), -bicycloalkyl (C6-C10), -bicycloalkenyl (C6-C? 0), -heterocyclyl (C2-C9), -heterocycloalkenyl (C2-C10), -heterobicycloalkyl (C6-Cg), -heterobicycloalkenyl (C6) -Cg), -aryl (C6-C10), -heteroaryl (C? -Cg), -aryl (C6-C10) perfluorinated, -heteroaryl (d-Cg) perfluorinated, C02H, -C (0) alkyl (CrC6) , OR10, S02 (alkyl (d-C6)) and P (0) (OR16) 2, wherein said substituents alkyl (C? -C6), -cycloalkyl (C3-C), -cycloalkenyl (C5-C10) , -bicycloalkyl (C6-C10), bicycloalkenyl (C6-C? 0), -heterocyclyl (C2-Cg), -heterocycloalkenyl (C2-C10), -heterobicycloalkyl (C6-C9), -heterobicycloalkenyl (C6-C9), -aryl (C6-C10), -heteroaryl (d-C9), -CÍOXalq? iloid-Ce)), and -S02 ((C1-C6) alkyl) are optionally substituted with from one to three residues independently selected from the group with It is composed of hydrogen, hydroxyl, halogen, -CF3, -CN, -NO2, -alkyl (d-C6), -NH-alkyl (C? -C6), -NH-cycloalkyl (C3-C7), -NH-heterocyclyl (C2-C9), -NH-aryl (C6-C10), -NH-heteroaryloid-Cg), -N (alkyl (d-C6)) 2, -N (cycloalkyl (C3-C7) )) 2, -N (heterocyclyl (C2-C9)) 2, -N (aryl (C6-C10)) 2, -N (heteroaryl (d-Cg)) 2, -0-alkyl (d-C6), -0-cycloalkyl (C3-C7), -0-heterocyclyl (C2-C9), -0-aryl (C6-C? O), -O-heteroaryl (d-Cg), -cycloalkyl (C3-C7), -heterocyclyl (C2-C9), -C02H, -C (0) (alkyl (d-C6)), -S02H, -SOZ-phenyloid-Cß)), -S02NH2, -SOzNHyalkyloid-Cß), - SOzN'alqui d-Cß));, -NHS02 (alkyl (C, -C6)), and -Nalkyl d-CßMSOzyalkylofC)); R8 and R9 when attached to the same carbon atom can be joined to form a (C3-C7) cycloalkyl, (C5-C10) cycloalkenyl, (C6-C10) -bicycloalkyl, (C6-C10) -bicycloalkenyl, -heterocyclyl (Cz-Cg), -heterocycloalkenyl (C2-C10), -heterobicycloalkyl (C6-C9), heterobicycloalkenyl (C6-C9), -aryl (C6-C10), or -heteroaryloid-Cg), wherein each of the above-cycloalkyl (C3-C), -cycloalkenyl (C5-C10), -bicycloalkyl (C6-C10), -bicycloalkenyl (C6-C10), -heterocyclyl (C2-C9), -heterocycloalkenyl (C2-C10), -heterobicycloalkyl (C6-Cg), heterobicycloalkenyl (C6-Cg), -aryl (C6-C10) and -heteroaryl (d-Cg) is optionally substituted with one to three substituents independently selected from the group consisting of halogen, -CF3, -CN, -N02, -alkyl (C, -C6), -OR16, -C (0) OR16, -OC (0) R6, -OC (0) OR16, -N (R16) 2l -NR16C (0) R16, -S02R16, -S02N (R16) 2 and -NR16S02R16; R10 and R11 are each independently a substituent selected from the group consisting of hydrogen, -alkyl (C, -C6),-perfluorinated (C2-C6) alkyl, -cycloalkyl (C3-C7), -cycloalkenyl (C5-C? or), -cycloalkyl (C6-C10), -bicycloalkenyl (C6-C? o), -heterocyclyl (C2-Cg), -heterocycloalkenyl (C2-C10), -heterobicycloalkyl (C6-C9), - heterobicycloalkenyl (C6-C9), -aryl (C6-C10), -heteroaryl (d-Cg), perfluorinated -aryl (C6-C? 0), -heteroaryloid-Cg) perfluorinated, -C02H, -C (0) ( alkyl (CrC6)), -S02 (alkyl (d-C6)) and -P (0) (OR16) 2, wherein said substituents -alkyl (d-C6), -cycloalkyl (C3-C7), -heterocyclyl (C2-C9), -aryl (C6-C10), -heteroarilofd-Cg), -C (0) (alkyl (d-C6)), and -S02 ((C1-C6) alkyl) are optionally substituted with one to three residues independently selected from the group consisting of hydrogen, hydroxyl, halogen, -CF3, -CN, -N02, -alkyl (d-C6), -NH-alkyl (d-C6), -NH-cycloalkyl (C3-C7), -NH-heterocyclyl (C2-C9), -NH-aryl (C6-C10), -NH-heter oaryloid-Cg), -N (alkyl (d-C6)) 2, -N ((C3-C7) cycloalkyl) 2, -N (heterocyclyl (C2-C9)) 2, -N (aryl (C6-C10) ) 2, -N (heteroaryl (d-C9)) 2, -0-alkyl (C, -C6), -O-cycloalkyl (C3-C7), -0-heterocyclyl (C2-C9) ), -O-aryl (C6-C10), -O-he'eroaryl (d-Cg), -cycloalkyl (C3-C7), -heterocyclyl (C2-C9), -C02H, -C (0) (alkyl) (d-C6)), -S02H, -S02 (alkyl (d-C6)), -S02NH2 >; -S02NH (alkyl (C6)), -S02N (alkyl (d-C6)) 2, -NHS02 (alkyl (d-C6)), and -N (alkyl (C6)) S02 (alkyl) (CrC6)); R12 is a substituent selected from the group consisting of hydrogen, -alkyl (C? -C6), -cycloalkyl (C3-C7), -heterocyclyl (C2-C9), -aryl (C6-C10), -heteroaryl ( C, -C9), -C (0) R15, -C (0) OR15, -C (0) N (R15) 2, -C (0) NR15C (0) NR15 and -S02 (R15) 2, in that said substituents -alkyl (d-C6), -cycloalkyl (C3-C7), -heterocyclyl (C2-C9), -arl (C6-C10) and -heteroaryloid-Cg) are optionally substituted with one to three residues independently selected from the group consisting of halogen, -CF3, -CN, -N02l -alkyloid-Cß), -OR16, -0 (O) OR16, -OC (0) R16, -OC (0) OR16 , -N (R16) 2, -NR16C (0) R16, -SOzR16, -S02N (R16) 2 and -NR16S02R16; R13 is a substituent selected from the group consisting of hydrogen, -alk? or (d- C6), -C (0) H, -C (0) - ((C6) alkyl), -alkyl (d-C6) -OR14, -alkyl (C1-C6) -N (R16) 2 and -P (0) (OR16) 2; R14 is a substituent selected from the group consisting of hydrogen, -alkyl (C C6) and -P (0) (OR16) 2; R15 is a substituent independently selected from the group consisting of hydrogen, -alkyl (C, -C6), -cycloalkyl (C3-C7), -heterocyclyl (C2-C9), -aryl (C6-C10), and -heteroaryl ( d-C9), wherein said -alkyl (C C6), -cycloalkyl (C3-C7), -heterocyclyl (C2-Cg), -aryl (C6-C10), and -heteroaryl (C? -Cg ) are optionally substituted with from one to three residues independently selected from the group consisting of halogen, -CF3, -CN, -N02, -alkyl (d-C6), -OR16, -C (0) (R16) 2 , -C (0) OR16, -OC (0) R16, -N (R16) 2, -NR16C (0) R16, -S02R16, -S02N (R16) 2 and -NR16S02R16; Two groups R15 when they are attached to the same nitrogen atom can form a (C2-Cg) heterocyclyl optionally substituted with one to three substituents independently selected from the group consisting of hydrogen, halogen, -CF3, -N02, -CN, - alkyl (C, -C6), -alkenyl (C2-C6), -alkynyl (C2-C6), -CR16 = NN (R16) 2, -CR16 = N-OR16, -CR16 = N-NR16C (0 ) R16, -CR3 = N-NR16C (0) OR16, -N (R16) 2, -OR16, -cycloalkyl (C3-C7), -heterocyclyl (C2-C9), -C02R16, -CON (R16) 2, -SR16, -SOR16, -S02R16, -S02N (R16) 2, -NHCOR16, -NR16CON (R16) 2 and -NR16S02R16; R16 is a substituent independently selected from the group consisting of hydrogen, -alkyl (d-C6), -cycloalkyl (C3-C7), -heterocyclyl (C2-C9), -aryl (C6-C10), and -heteroaryl (C) , -C9); Two R 6 groups when linked to the same nitrogen atom can form a (C 2 -Cg) -heterocyclyl optionally substituted with one to three substituents independently selected from the group consisting of halogen, -CF 3, -N0 2, -CN, - alkyl (d-C6), -cycloalkyl (C3-C), -heterocyclyl (C2-C9), -aryl (C6-C? 0), and -heteroaryl (d-C9); m is an integer from 1 to 4; and p is an integer from 1 to 4. The present invention also relates to a compound of formula II wherein Ar is a bicyclic fused ring system comprising at least one ring attached via a bridging bridge at least one saturated, unsaturated or aromatic ring selected from the group consisting of -cycloalkyl (C3-C10), -cycloalkenyl ( C5-C10), -heterocyclyl (C2-C10), -heterocycloalkenyl (C2-C10), -aryl (C6-C10) and -heteroaryl (C2-Cg), wherein Ar is optionally substituted with one to five substituents independently selected from the group consisting of hydrogen, halogen, -CF3, -N02, -CN, -alkyl (d-C6), -alkenyl (C2-C6), -alkynyl (C2-C6), -CR3 = N-NR3R4 , -CR3 = N-0R5, -CR3 = N-NR3C (0) R3, -CR3 = N-NR3C (0) OR5, -NR3R4, -OR5, -cycloalkyl (C3-C7), -heterocyclyl (C2-C9) ), -C (0) R5, -C02R5, -CONR3R4, -SR6, -SOR6, -S02R6, -S02NR3R4, -NHCOR15, -NR3CONR3R4, and -NR3S02R6; and one or more adjacent carbons or heteroatoms of said ring linked via a bridged bond or said saturated, unsaturated or aromatic ring are optionally fused to a ring system selected from the group consisting of -cycloalkyl (C3-C), -heterocyclyl ( C2-C9), -aryl (C6-C10), and -heteroaryloid-Cg), wherein said ring systems -cycloalkyl (C3-C7), -heterocyclyl (C2-Cg), -aryl (C6-C10) , and (C 1 -C 9 heteroaryl) are optionally substituted with one to three substituents selected from the group consisting of hydrogen, hydroxyl, halogen, -CF 3, -CN, -N02, -alkyl (C C6), -NH-alkylofd -Cß), -NH-cycloalkyl (C3-C7), -NH-heterocyclyl (C2-C9), -NH-aryl (C6-C? 0), -NH-heteroaryl (C? -Cg), -N ( alkyl (CrC6)) 2, N ((C3-C7) cycloalkyl) 2, -N (heterocyclic (C2-Cg)) 2, -N (aryl (C6-C10)) 2, -0-alkyl (d-C6), -0-cycloalkyl (C3-C7), -0-heterocyclyl (C2-C9), -0-aryl (C6-C? O), -O-heteroaryloid-Cg ), -cycloalkyl (C3-C7), -heterocyclyl (C2-C9), -C02H, -C (0) (alkyl (C? -C6)), -S02H, -SOzfalkyloid-Ce)), -S02NH2, - S02NH (alkyl (d-C6)), -S02N ((alkyl (d-C6)) 2, -NHS? 2 (alkyl (d-C6)), and -N (alkyl (C, -C6)) S02 ( alkyl (d-C6)), and K, M and Q are as defined above; R1 to R16 are as defined above; Z and Z2 are as defined above; Y1 and Y2 are as defined above; L and L2 are as defined above; q is as defined above; X is as defined above; W is as defined above; m is as defined above; n is as defined above; and p is as defined above. Unless otherwise indicated, the compounds of formula I and II are collectively referred to collectively as "the compounds of the invention." In one embodiment, M is N. In another embodiment, Q is C (D). In another embodiment, at least one ring linked by a bridging link is selected from the group consisting of a ring system 2.1.1, 2.2.1, 2.2.2, 3.2.1, 3.2.2 and 3.3.2. In another embodiment, Q is C (D) and D is selected from the group consisting of hydrogen, halogen, -OR5, -CF3, -N02, -CN, -alkyl (d-C6), -alkenyl (C2- C6), - (C2-C6) -alkynyl, - perfluorinated (C2-C6) alkyl, - perfluorinated (C2-C6) alkenyl, - perfluorinated (C3-C6) alkynyl, wherein said substituents D -alkyl (d) -C6), -alkenyl (C2-Cß), -alkynyl (C2-C6), are optionally substituted with one to three substituents independently selected from the group consisting of hydrogen, halogen, -CF3, -N02, -CN, - alkyl (d-C6), -alkenyl (C2-C6), -alkyl (C2-C6), -CR3 = N-NR3R4, -CR3 = N-OR5, -CR3 = N-NR3C (0) R3, -CR3 = N-NR3C (0) OR5, -NR3R4, -OR5, -cycloalkyl (C3-C7), -C02R5, -CONR3R4, -SR6, -SOR6, -S02R6, -S02NR3R4, -NHCOR5, -NR3CONR3R4, and -NR3S02R6. In another embodiment, Q is C (D) and D is selected from the group consisting of -cycloalkyl (C3-C7), -cycloalkenyl (C5-C10), -bicycloalkyl (C6-C10), -bicycloalkenyl (C6-C10) , -heterocyclyl (d-C9), -heterocycloalkenylofd-do), -heterobicycloalkyl (C6-C9), heterobicycloalkenyl (C6-C9), -aryl (C6-C10), and -heteroaryl (d-Cg), wherein said substituents D-cycloalkyl (C3-C7), -cycloalkenyl (C5-do). -bicycloalkyl (C6-C10), -bicycloalkenyl (C6-C10), -heterocyclyl (C? -Cg),. -heterocycloalkenyloid-do). -heterobicycloalkyl (C6-C9), heterobicycloalkenyl (C6-Cg), -arylCi-do), and -heteroaryl (d-Cg) are optionally substituted with one to three substituents independently selected from the group consisting of hydrogen, halogen, - CF3, -N02, -CN, -alkyl (d-C6), -alkenyl (C2-C6), -alkynyl (C2-C6), -CR3 = N-NR3R4, -CR3 = N-OR5, -CR3 = N -NR3C (0) R3, -CR3 = N-NR3C (0) OR5, -NR3R4, -OR5, -cycloalkyl (C3-C7), -heterocyclyl (C2-Cg), -C02R5, -CONR3R4, -SR6, - SOR6, -S02R6, -S02NR3R4, -NHCOR5, -NR3CONR3R4, and -NR3S02R6. In another embodiment, Q is C (D) and D is selected from the group consisting of -NR3R4, -OR5, -C (0) R5, -C02R5, -CONR3R4, -SR6, -SOR6, -S02R6, -S02NR3R4, -NHCOR5, -NR3CONR3R4, and -NR3S02R6, wherein said substituents D-NR3R4, -OR5, -C (0) R5, -C02R5, -CONR3R4, -SR6, -SOR6, -S02R6, -S02NR3R4, -NHCOR5, -NR3CONR3R4, and -NR3S02R6 are optionally substituted with one to three substituents independently selected from the group consisting of hydrogen, halogen, -CF3, -N0, -CN, -alkyl (d-C6), -alkenyl (C2- C6), -alkynyl (C2-C6), -CR3 = N-NR3R4, -CR3 = N-0R5, -CR3 = N-NR3C (0) R3, -CR3 = N-NR3C (0) OR5, -NR3R4, -OR5, -cycloalkyl (C3-C7), -heterocyclyl (C2-C9), -C02R5, -CONR3R4, -SR6, -SOR6, -S02R6, -S02NR3R4, -NHCOR5, -NR3CONR3R4, and -NR3S02R6. In another embodiment, Q is C (D) and D is selected from the group consisting of hydrogen, halogen, hydroxy, -CF3, -N02, -CN, and -alkyl (d-C6), wherein said substituent D- alkylofd-Cß) is optionally substituted with one to three substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, -CF3, -N02, -CN, and -alkyl (d-C6). In another embodiment, Q is C (D) and D is selected from the group consisting of hydrogen, halogen, hydroxy, -CF3, -N02, and -CN. In another embodiment, Q is C (D) and D is -alkyl (d-C6) optionally substituted with one to three substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, -CF ,, -N02, -CN, and -alqu¡lo (d-C6).

In a preferred embodiment, Q is C (D) and D is selected from the group consisting of halogen, -CF3, and -N02. In another preferred embodiment, Q is C (D) and D is -alkyl (d-C6) optionally substituted with one to three halogen substituents. In a more preferred embodiment, Q is C (D) and D is -CF3. In another embodiment, K is C (R1). In another embodiment, K is C (R1) and R1 is selected from the group consisting of hydrogen, halogen, -CF3, -N02, -CN, -alkyl (C, -C6), -alkenyl (C2-C6), - C2-C6 alkynyl, perfluorinated (C2-C6) alkyl, perfluorinated (C2-C6) alkenyl, perfluorinated (C3-C6) alkynyl, -cycloalkyl (C3-C), -heterocyclyl (C2-C9), -aryl (C6-C10), -heteroaryl (d-C9), -OR5, -C (0) R5, -C02R5, -CONR3R4, -SR6, -SOR6, -S02R6, -S02NR3R4, -NHCOR5, -NR3CONR3R4, -NR3S02R6, and In another embodiment, K is C (R1) and R1 is selected from the group consisting of -alkyl (d-Cß) -alkenyl (C2-C6), -alkynyl (Cz-C6), -alkyl (Cz-C6) perfluorinated , -alkenyl (C -C6) perfluorinated, perfluorinated (C3-C6) alkynyl, -cycloalkyl (C3-C7), -heterocyclyl (C2-C9), -aryl (C6-do). and -heteroaryl (d-Cg). In another embodiment, K is C (R1) and R1 is selected from the group consisting of -OR5, -C (0) R5, -C02R5, CONR3R4, -SR6, -SOR6, -S02R6, -S02NR3R4, -NHCOR5 -NR3CONR3R4 , and -NR3S02R6. In another embodiment, K is In another embodiment, K is C (R1) and R1 is selected from the group consisting of hydrogen, halogen, hydroxy, -CF3, -N02, and -CN. In another embodiment, K is C (R1) and R1 is hydrogen. In another embodiment, M is N, K is C (H) and K is C (H). In another embodiment, M is N, K is C (H), Q is C (CF3) and K is C (H). In another embodiment, R2 is selected from the group consisting of hydrogen, halogen, -CF3, -N02, -CN, -alkyl (d-C6), -alkenyl (C2-C6), -alkynyl (C2-C6) , -cycloalkyl (C3-C7), -heterocyclyl (C2-C9), -aryl (C6-C10), -heteroaploid-Cg), -NR3R4, -OR5, -C (0) R5, -C02R5, -CONR3R4, -SR6, -SOR6, -S02R6, -S02NR3R4, -NHCOR5, -NR3CONR3R4, -NR3S02R6, and In another embodiment, R is selected from the group consisting of -alkyloid-Cß), -alkenyl (C2-C6), -alkynyl (C2-C6), -cycloalkyl (C3-C7), -heterocyclyl (C2-C9), -aryl (C6-C10), and -heteroaryl (d-C9), wherein said -alkyl (d-C6), -alkenyl (C2-C6), -alkynyl (C2-C6) -, -cycloalkyl (C3-C), -cycloalkenyl (C5-C0), -aryl (C6-C10) and -heteroaryloid-Cg) may be optionally substituted with one to three residues independently selected from R5 and R 'In another embodiment, R is selected from the group consisting of -NR R, -OR, -C (0) R -C02R- \ -CONR ^ R4, -SR °, -SOR ", -S02RD, -S02NRJR, > -NHCOR3, -NRJC0NRJR4, and -NRJS02Rb, In another embodiment, R2 is In a more preferred embodiment, R is In another preferred embodiment, R is R is hydrogen, and n is 0, In another preferred embodiment, R2 is RE is hydrogen, n is 0, and RH is -cycloalkyl (C3-C7). In another preferred embodiment, R2 is RE is hydrogen, n is 0, and RH is selected from the group consisting of -cyclopropyl, -cyclobutyl, -cyclopentyl, and -cydohexyl. In another embodiment, A is an (C6-C0) aryl, optionally substituted with one to three substituents independently selected from the group consisting of hydrogen, halogen, -CF3, -N02, -CN, -alkyl (d -C6), -alkenyl (C2-C6), -alkynyl (C2-C6), -CR3 = N-NR3R4, -CR3 = N-OR5, -CR3 = N-NR3C (0) R3, -CR3 = N- NR3C (0) OR5, -NR3R4, -OR5, -cycloalkyl (C3-C7), -heterocyclyl (C2-C9), -C (0) R5, -C02R5, -CONR3R4, -SR6, -SOR6, -S02R6, -S02NR3R4, -NHCOR15, -NR3CONR3R4, and -NR3S02R6. In another embodiment, A is - (C3-C10) cycloalkyl, optionally substituted with one to three substituents independently selected from the group consisting of hydrogen, halogen, -CF3, -N02, -CN, -alkyl (d-C6) ), -alkenyl (C2-C6), -alkynyl (C2-C6), -CR3 = N-NR3R4, -CR3 = N-OR5, -CR3 = N-NR3C (0) R3, -CR3 = N- NR3C (0) OR5, -NR3R4, -OR5, -cycloalkyl (C3-C7), - heterocyclyl (C2-C9), -C (0) R5, -C02R5, -CONR3R4, -SR6, -SOR6, -S02R6, -S02NR3R4, -NHCOR15, -NR3CONR3R4, and -NR3S02R6. In another embodiment, A is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl, optionally substituted with one to three substituents independently selected from the group consisting of hydrogen, halogen, -CF3 , -N02, -CN, -alkyl (C? -C6), -alkenyl (C2-C6), -alkynyl (C2-C6), -CR3 = N-NR3R4, -CR3 = N-OR5, -CR3 = N-NR3C (0) R3, -CR3 = N-NR3C (0) OR5, -NR3R4, -OR5, -cycloalkyl (C3-C7), -heterocyclyl (C2-C9), -C (0) R5, - C02R5, -CONR3R4, -SR6, -SOR6, -S02R6, -S02NR3R4, -NHCOR15, -NR3CONR3R4, and -NR3S02R6. In another embodiment, A is-(C5-C10) cycloalkenyl, optionally substituted with one to three substituents independently selected from the group consisting of hydrogen, halogen, -CF3, -N02, -CN, -alkyl (d-C6), -alkenyl (C2-C6), -alkynyl (C2-C6), -CR3 = N-NR3R4, -CR3 = N-OR5, -CR3 = N-NR3C (0) R3, -CR3 = N-NR3C (0) OR5, -NR3R4, -OR5, -cycloalkyl (C3-C7), -heterocyclyl (C2-C9), -C (0) R5, -C02R5, -CONR3R4, -SR6, -SOR6, -SOzR6, -S02NR3R4, - NHCOR15, -NR3CONR3R4, and -NR3S02R6. In another embodiment, A is selected from the group consisting of cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, and cyclodecenyl, optionally substituted with one to three substituents independently selected from the group consisting of hydrogen, halogen, -CF3, -N02, -CN, -alkyl (d-C6), -alkenyl (C2-C6), -alkynyl (C2-C6), -CR3 = N-NR3R4, -CR3 = N-OR5, -CR3 = N-NR3C ( 0) R3, -CR3 = N-NR3C (0) OR5, -NR3R4, -OR5, -cycloalkyl (C3-C7), -heterocyclyl (C2-C9). -C (0) R5, -C02R5, -CONR3R4, -SR6, -SOR6, -S02R6, -S02NR3R4, -NHCOR15, -NR3CONR3R4, and -NR3S02R6. In another embodiment, A is -heterocyclyl (C2-C10), optionally substituted with one to three substituents independently selected from the group consisting of hydrogen, halogen, -CF3, -N02, -CN, -alkyl (d-C6), -alkenyl (C2-C6), -alkynyl (C2-C6), -CR3 = N-NR3R4, - CR3 = N-OR5, -CR3 = N-NR3C (0) R3, -CR3 = N-NR3C (0) OR5, -NR3R4, -OR5, -cycloalkyl (C3-C7), - heterocyclyl (C2-C9), -C (0) R5, -C02R5, -CONR3R4, -SR6, -SOR6, -S02R6. -S02NR3R4, -NHCOR15, -NR3CONR3R4, and -NR3S02R6.

In another embodiment, A is -heterocycloalkenyl (C2-C10), optionally substituted with one to three substituents independently selected from the group consisting of hydrogen, halogen, -CF3, -N02, -CN, -alkyl (d-C6), alkenyl (C2-C6) -alkynyl (C2-C6), -CR 3 = N-NR3R4, -CR 3 = N-OR5, -CR 3 = N-NR 3 C (0) R3, -CR 3 = N-NR 3 C (0) OR5, -NR3R4, -OR5, (C3-C7) -heterocicl¡lo (C2-C9), -C (0) R5, -C02R5, -CONR3R4, -SR6, -SOR6, -S02R6, -S02NR3R4 , -NHCOR15, -NR3CONR3R4, and -NR3S02R6. In another embodiment, A is -heteroaryl (d-Cg), optionally substituted with one to three substituents independently selected from the group consisting of hydrogen, halogen, -CF3, -N02, -CN, -alkyl (d-C6), alkenyl (C2-C6) -alkynyl (C2-C6), -CR 3 = N-NR3R4, -CR 3 = N-OR5, -CR 3 = N-NR 3 C (0) R3, -CR 3 = N-NR 3 C (0) OR5, -NR3R4, -OR5, (C3-C7) cycloalkyl, (C2-C9), -C (0) R5, -C02R5, -CONR3R4, -SR6, -SOR6, -S02R6, -S02NR3R4, - NHCOR15, -NR3CONR3R4, and -NR3S02R6. In another embodiment, A is selected from the group consisting of oxazole, imidazole, thiazole, furyl, thienyl, pyrrole, pyridyl, pyrazyl, pyrimidyl, quinoline, isoquinoline, quinazoline, benzimidazole, and pyridopyrimidine, wherein each of said oxazole groups , imidazole, thiazole, furyl, thienyl, pyrrole, pyridyl, pyrazyl, pyrimidyl, quinoline, isoquinoline, quinazoline, benzimidazole, and pyridopyrimidine is optionally interrupted by one to three elements independently selected from the group consisting of -C (R3) = C (R3) -, -C (O) -, - (C = N-R3) -, - (C = N-NR3R4) -, - (C = N-NOR5) -, - (C = CR3) -, - (C = C (R3) C (0) -NR3R4)) -, - (C = C (R3) C (0) OR6) -, -S02-, -S-, -O- and -NR3-. In a preferred embodiment, A is selected from the group consisting of phenyl and naphthyl optionally substituted with one to three substituents independently selected from the group consisting of hydrogen, halogen, -CF3, -N02, -CN, -alkyloid-Cß), -alkenyl (C2-C6), -alkynyl (C2-C6), -CR3 = N-NR3R4, -CR3 = N-OR5, -CR3 = N-NR3C (0) R3, -CR3 = N-NR3C (0) OR5, -NR3R4, -OR5, -cycloalkyl (C3-C7), -heterocyclyl (C2-C9), -C (0) R5, -C02R5. -CONR3R4, -SR6, -SOR6, -S02R6, -S02NR3R4, -NHCOR15, -NR3CONR3R4, and -NR3S02R6. In a more preferred embodiment, A is phenyl. In one embodiment, Z1 and Z2 are -CR7-. In another embodiment, Y1 and Y2 are each -CH-.

In another embodiment, L1 and L2 are each independently -CR8R9-. In a preferred embodiment, q is 0. In another preferred embodiment, X and W are the same or different and each is independently selected from the group consisting of-CR8R9- and -NR12-. In another embodiment, X is selected from the group consisting of -S-, -S (O) -, -S (0) 2- and - S (0) NR3-. In another embodiment, X is -CR8R9-. In another embodiment, X is -C (O) -. In another embodiment, X is -C (= NR3) -. In another embodiment, X is -O-. In a preferred embodiment, X is -NR12-. In another preferred embodiment, X is -NR12- and m is 1. In another embodiment, R 2 is -C (0) R15. In another preferred embodiment, X is -NR12, m is 1, R12 is -C (0) R15, and R15 is an -alkyl (d-C6) optionally substituted with one to three residues independently selected from the group consisting of halogen , -CF3, -CN, -N02, -alkyl (C? -C6), -OR16, -C (0) (R16) 2, -C (0) OR16, -OC (0) R16, -N (R16) ) 2, -NR16C (0) R16, -S02R16, -S02N (R16) 2 and -NR16S02R16. In another preferred embodiment, X is -NR12, m is 1, R12 is -C (0) R15, and R15 is an -alkyl (d-C6) optionally substituted with one to three residues independently selected from the group consisting of halogen , -CF3, -CN and -N02. In another preferred embodiment, X is -NR12, m is 1, R12 is -C (0) R15, and R15 is an -alkyl (C, -C6) optionally substituted with one to three residues independently selected from the group consisting of -OR16, -C (0) (R16) 2, -C (0) OR16 and -O0 (O) R16. In another preferred embodiment, X is -NR12, m is 1, R12 is -C (0) R15, and R15 is an -alkyl (d-C6) optionally substituted with one to three residues independently selected from the group consisting of - N (R16) 2, -NR16C (0) R16, -SOzR16, -SOzN (R16) 2 and -NR16S02R16. In another preferred embodiment, X is -NR12, m is 1, R12 is -C (0) R15, and R1S is an -alkyl (d-C6) substituted with -N (R16) 2.

In another preferred embodiment, X is -NR12, m is 1, R12 is -C (0) R15, and R15 is an -alkyl (C6C) substituted with -NR16C (0) R16. In another preferred embodiment, X is -NR12, m is 1, R 2 is -C (0) R15, and R15 is an -alkyl (d-C6) substituted with -S02R16. In another preferred embodiment, X is -NR12, m is 1, R12 is -C (0) R15, and R15 is an - (C, -C6) alkyl substituted with -S02N (R16) 2. In another preferred embodiment, X is -NR12, m is 1, R12 is -C (0) R15, and R15 is an -alkyl (d-C6) substituted with -NR16S02R16. In another embodiment, W is selected from the group consisting of -S-, -S (O) -, -S (0) 2-, and -S (0) NR3-. In another embodiment, W is -CR8R9-. In another embodiment, W is -C (O) -. In another embodiment, W is -C = NR3. In another embodiment, W is -O-. In a preferred embodiment, another embodiment, W is -NR12-. In a more preferred embodiment, W is -CR8R9- and p is 2. In another embodiment, W is -CH2- and p is 2. In another preferred embodiment, Ar is selected from the group consisting of -aryl (C6-C10) and - heteroaryloid-Cg). In another embodiment, Ar is selected from the group consisting of: AND? another embodiment, Ar is selected from the group consisting of: In another embodiment, Ar is selected from the group consisting of: In another embodiment, Ar is selected from the group consisting of: In another preferred embodiment, Z1 and Z2 are each -CR7-. In another more preferred embodiment, Y1 and Y2 are each -CR7-, each R7 is the same or different, and each R7 is independently selected from the group consisting of hydrogen, halogen, -FC3, -N02, -CN, -alkyl ( d-Ce), -alkenyl (C2-C6), -alkynyl (C2-C6), -cycloalkyl (C3-C7), -heterocyclyl (C2-C9), -aryl (C6-C10), -heteroar ?? (d-Cg), -NR3R4, -OR5, -COR5, -COzR5, -CONR3R4, -SR6, -SOR6, -S02R6, -S02NR3R4, -NHCOR5, -NR5CONR3R4, and -NR3S02R6. In one embodiment, the invention relates to a compound selected from the group consisting of compounds 1 to 490 as described in the Examples section of this application. In a preferred embodiment, the compound is selected from the group consisting of:? - (3- { [2- (12,12-Dioxo-12? 6-thia-tricyclo [6.3.1.027] dodeca-2 (7), 3,5-trien-4-ylamino) -5-trifluoromethyl-β-rimidin-4-ylamino] -methyl) -pyridin-2-yl) -? / - methyl-methanesulfonamide; / V- (3- { [2- (10-Methanesulfonyl-10-aza-tricyclo [6.3.1.027] dodeca-2 (7), 3,5-trien-4-ylamino) -5-trifluoromethyl-p Rimidin-4-ylamino] -methyl] -pyridin-2-yl) -? / - methyl-methanesulfonamide; rV-Methyl -? / - (3- { [2- (10-trifluoroacetyl-10-aza-tricyclo [6.3.1.02 7] dodeca-2 (7), 3,5-trien-4-ylamino) - 5-Trifluoromethyl-pyrimidin-4-ylamino] -methyl) -pyridin-2-yl) -methanesulfonamide; ? / - (3- { [2- (10-Aza-tricyclo [6.3.1.027] dodeca-2 (7), 3,5-trien-4-ylamino) -5-trifluoromethyl-pyrimidin-4-ylamino ] -methyl) -pyridin-2-yl) - / V-methyl-methanesulfonamide; ? / - Methyl- / V- (3- { [2- (9-trifluoroacetyl-1, 2,3,4-tetrahydro-1,4-epiazan-naphthalen-6-ylamino) -5-trifluoromethyl-pyra 4-ylamino] -methyl) -pyridin-2-yl) -methanesulfonamide; ? / - Met.l- / V- (3- { [2- (1, 2,3,4-tetrahydro-1,4-epiazan-naphthalen-6-ylamino) -5-trifluoromethyl-pyrimidin-4 -ylamino] -methyl.} - pyrrn-2-yl) -methanesulfonamide; ? - (3- { [2- (9-Methanesulfonyl-1,2,3,4-tetrahydro-1,4-epiazan-naphthalen-6-ylamino) -5-trifluoromethyl-pyrimidin-4-ylamino] -methyl.} - pyridin-2-yl) - / V-methyl-methanesulfonamide, and pharmaceutically acceptable salts of each of the above compounds. In another preferred embodiment, the compound of the invention is selected from the group consisting of:? / -. { (1 / ?, 2R) -2- [2- (9-Acetyl- (1 S, 4R) -1,2,3,4-tetrahydro-1,4-epiazan-naphthalen-6-ylamino) -5- trifluoromethyl-pyrimidin-4-ylaminol-cyclopentyl} -acetamide, (+/-) - 6- (4-Cyclobutyl-lane-5-trifluoromethyl-pyrimidin-2-ylamino) -1, 2,3,4-tetrahydro-1, 4- epiazan-naphthalene-9-carboxylic acid, [(1S, 4R) -6- (4-Cyclobutyl-lane-5-trifluoromethyl-pyrimidin-2-ylamino) -1, 2,3,4-tetrahydro- 1,4-epiazan-naphthalen-9-yl] -cyclopropyl-methanone,? -. { 2- [6- (4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino) - (1S, 4R) -1, 2 > 3,4-tetrahydro-1,4-epiazan-naphthalen-9-yl] -2-oxo-ethyl) -? / - methyl-acetamide, 1 - [6- (4-Methylamino-5-trifluoromethyl-pyrimidin-2 -amino) - (1 R, 4 S) -1, 2,3,4-tetrahydro-1,4-epiazan-naphthalen-9-yl] -ethanone, (+/-) - 1 - [- 6- (4 -Metoxy-5-trifluoromethyl-pyrimidin-2-ylamino) -1,2,3,4-tetrahydro-1,4-epiazannaphthalen-9-yl] -ethanone, (+/-) - 1- [6- (4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -1,2,3,4-tetrahydro-1,4-epiazan-naphthalen-9-yl] -ethanone, (+/-) - / V4-Cyclobutyl -? / 2- (9-methanesulfonyl-1,2,3,4-tetrahydro-1,4-epiazan-naphthalen-6-yl) -5-trifluoromethyl-pyrimidin-2 , 4-diamine, (+/-) - 1- [6- (4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -1, 2,3,4-tetrahydro-1,4-epiazan-naphthalene- 9-yl] -2-methylamin-ethanone, Cyclopropyl- [6- (4-cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino) - (1R, 4S) -1, 2,3,4-tetrahydro- 1, 4-epiazan-naphthalen-9-yl] -methanone, 1- [6- (4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino) - (1S, 4R) -1.2 , 3,4-tetrahydro-1,4-epiazan-naphthalen-9-yl] -2-methoxy-ethanone, (+/-) - / V2- (9-Ethyl-1,2,3,4-tetrahydro- 1,4-epiazan-naphthalen-6-yl) -? / 4-methyl-5-trifluoromethyl-pyrimidine-2,4-diamine, (+/-) -? / 4-Cyclopropyl- / V2- (9 -ethyl-1,2,3,4-tetrahydro-1,4-epiazan-naphthalen-6-yl) -5-trifluoromethyl-pyrimidine-2,4-diamamine, (+/-) - ester of 2- [6- (4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -1,2,3,4-tetrahydro-1,4-epiazan-naphthalen-9-yl] -2-oxo acid -ethyl acetic, 2-Methyl-1 - [- 6- (4-propylamino-5-trifluoromethyl-pyrim din-2-ylamino) - (1 S, 4R) -1, 2,3,4-tetrahydro-1,4-epiazan-naphthalen-9-yl] -propan-1 -one, (+/-) -? / 4-Cyclobutyl-? 2-1, 2,3,4-tetrahydro-1,4-epiazan-naphthalen-6-yl-5-trifluoromethyl-pyrimidine-2,4-diamine, 6- (6-) -acrypropylamide 4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino) - (1S, 4R) -1, 2,3,4-tetrahydro-1,4-epiazan-naphthalene-9-carboxylic acid, (+/-) - 1 - [6- (4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -1, 2,3,4-tetrahydro-1,4-epiazan-naphthalen-9-yl] -ethanone, 2-Hydroxy -1 - [- 6- (4-cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino) - (1S, 4R) -1, 2,3,4-tetrahydro-1,4-epiazan-naphthalen-9-yl ] -etanone, 1 - [- 6- (4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) - (1S, 4; ") - 1.2 > 3,4-tetrahydro-1,4-epiazan-naphthalen-9-yl] -2-methylamino-ethanone, 1 - [- 6- (4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino) - (1S, 4R) -1,2,3,4-tetrahydro-1,4-epiazan-naphthalen-9-yl] -2-methylamino-ethanone, 1- [6- (4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino) - (1S, 4R) -1,2,3,4-tetrahydro-1,4-epiazan-naphthalen-9-yl] - 2-methylamino-ethanone, (+/-) - 2-Amino-1 - [- 6- (4-cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -1, 2,3,4-tetrahydro-1, 4-epiazan-naphthalen-9-yl] -ethanone, 2-Fluoro-1- (6- [4-cyclopropylammono-5-trifluoromethyl-pyrimidin-2-ylamino] - (1 S, 4 /?) - 1 , 2,3,4-tetrahydro-1,4-epiazan-naphthalen-9-yl) -ethanone,? / -. { 2 - [- 6- (4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino) - (1S, 4R) -1, 2,3,4-tetrahydro-1,4-epiazan-naphthalene-9- il] -2-oxo-ethyl) -? / - methyl-acetamide, 2-H -droxy-1 - [- 6- (4-cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino) - (1R, 4S) -1, 2,3,4-tetrahydro-1,4-epiazan-naphthalen-9-yl] -ethanone, / V-. { 2- [6- (4-Etylamino-5-trifluoromethyl-pyrimidin-2-ylammon) - (1S, 4R) -1, 2,3,4-tetrahydro-1,4-epiazan-naphthalene 9-yl] -2-oxo-ethyl) -acetamide, 2-Amino-1 - [- 6- (4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) - (1S, 4; *) - 1, 2,3,4-tetrahydro-1,4-epiazan-naphthalen-9-yl] -ethanone, 2-Amino-1 - [- 6- (4-cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino) - (1S, 4R) -1, 2,3,4-tetrahydro-1,4-epiazan-naphthalen-9-yl] -ethanone, (+/-) - 2-H-droxy-1 - [- 6- (4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino) - (1S, 4R) -1,2,3,4-tetrahydro-1,4-e? -iazan-naphthalen-9-yl] -ethanone , 2-Fluoro-1- [6- (4-Et-lamino-5-trifluoromethyl-pyrimidin-2-ylamino) - (1S, 4r:?) -1, 2 > 3,4-tetrahydro-, 4-epiazan-naphthalen-9-yl] -ethanone, 6- [4- (2-methoxy-ethylamino) -5-trifluoromethyl-pyrimidin-2-ylamino] - (1 S) isopropylamide , 4?) - 1, 2,3,4-tetrahydro-1,4-epiazan-naphthalene-9-carboxylic acid, 2-Fluoro-1-. { 6- [4- (2-methoxy-ethylamino) -5-trifluoromethyl-pyrimidin-2-ylamino] - (1S, 4R) -1, 2,3,4-tetrahydro-1,4-epiazan-naphthalene-9- il) -ethanone, 6- (4-cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino) - (1r?, 4S) - 1, 2,3,4-tetrahydro-1,4-epiazan-naphthalene acid ispropylamide -9-carboxylic acid, 2-Amino- 1 - [- 6- (4-cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino) - (1 R, 4S) -1, 2,3,4-tetrahydro-1, 4-epiazan-naphthalen-9-yl] -ethanone, 1- [6- (4-Etylamino-5-trifluoromethyl-pyrimidin-2-ylamino) - (1S, 4R) -1,2,3,4-tetrahydro-1,4-epiazan-naphthalene-9-yl ] -2-methoxy-ethanone, 1 - [- 6- (4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino) - (1S, 4:?) -1, 2,3,4-tetrahydro-1,4-epiazan-naphthalene-9 -yl] -2-methoxy-ethanone, (+/-) - 1-. { 6- [4- (1,3-Dihydro-pyrrol [3,4-c] pyridin-2-yl) -5-trifluoromethyl-pyrimidin-2-ylamino] -1, 2,3,4- tetrahydro-1,4-epiazan-naphthalen-9-yl) -ethanone, 6- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) - (1S, 4?) - 1, 2,3-Isopropylamide , 4-tetrahydro-1,4-epiazan-naphthalene-9-carboxylic acid, 6- (4-ethalamide-5-trifluoromethyl-pyrimidin-2-ylamino) - (1S, 4r "") - 1, 2,3,4-tetrahydro-1,4-epiazan-naphthalene-9-carboxylic acid, (+/-) - 1 - [6- (4-Cyclopropylamino-5-methyl-pyrimidin-2 -ylamino) -1, 2,3,4-tetrahydro-1,4-epiazan-naphthalen-9-yl] -ethanone, 1-. { 6- [4- (2-Methoxy-ethylamino) -5-trifluoromethyl-pyrimidin-2-ylamino] - (1S, 4 /;?) - 1,2,3,4-tetrahydro-1,4-epiazan-naphthalen-9-yl) -ethanone, 1- [6- (4-Etylamino-5-trifluoromethyl-pyrimidine -2-ylamino) - (1S, 4R) -1, 2,3,4-tetrahydro-1,4-epiazan-naphthalen-9-yl] -ethanone, 2-Methyl-1- [6- (4-methylamino -5-trifluoromethyl-pyrimidin-2-ylamino) - (1S, 4R) -1,2,3,4-tetrahydro-1,4-epiazan-naphthalen-9-yl] -propan-1-one, Ester 6- (4-Cyclobutylammon-5-trifluoromethylpyridyl-2-ylamine) - (1S, 4"?) - 1, 2,3,4-methyl ester -tetrahydro-1,4-epiazan-naphthalene-9-carboxylic acid, 2-methoxy-1- [6- (4-methalamine-5-trifluoromethyl-pyrimidin-2-ylamino) - (1S, 4?) -1,2,3,4-tetrahydro-1,4-epiazan-naphthalen-9-yl] -ethanone, 2-methoxy-1- { 6- [4- (2-methoxy-ethylamino) -5- trifluoromethyl-pyrimidin-2-ylamino] - (1S, 4f?) - 1, 2,3,4-tetrahydro-1,4-epiazan-naphthalen-9-yl) -ethanone, and pharmaceutically acceptable salts of each of the previous compounds In another preferred embodiment, the compound of the invention is selected from the group consisting of: 1- [6- (4-Cyclobutylamino-5-tritluoromethyl-pyrimidin-2-ylamino) - (1S, 4R) -1, 2,3,4-tetrahydro-1,4-epiazan-naphthalen-9-yl] - 2-hydroxy-ethanone, 2-Amino-1- [6- (4-cyclobutylammon-5-trifluoromethyl-pyrimidin-2-ylamino) - (1S, 4R) -1, 2,3,4-tetrahydro-1 , 4-epiazan-naphthalen-9-yl] -ethanone, l-te-IS-Chloro-2-cyclobutylamino-pyrimidin-1-ylamino-1-RIS-1-S-tetrahydro-1-epiazan-naphthalene-9 -l] -etanone,? / -. { 2- [6- (4-Cyclobutylammon-5-tnfluoromethyl-pyrimidin-2-ylannan) - (1S, 4R) -1,2,3,4-tetrahydro-1,4-epiazan-naphthalene -9-yl) -2-oxo-ethyl} -acetamide, 6- (4-cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino) - (1S, 2R) -1, 2,3,4-tetrahydro-1,4-epiazan-naphthalene- ethylamide 9-carboxylic, 1- [6- (4-Cyclobutylammon-5-trifluoromethyl-pyrimidin-2-ylamino) - (1S, 4R) -1, 2,3,4-tetrahydro-1,4-epiazan -naphthalen-9-yl] -2-methoxy-ethanone, [6- (4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino) - (1S, 4R) -1,2F3,4-tetrahydro-1, 4 -epiazan-naphthalen-9-yl] -cyclopropyl-methanone, 1- [6- (4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino) - (1S, 4R) -1,2,3,4-tetrahydro -1,4-epiazan-naphthalen-9-yl] -ethanone,? 4-Cyclobutyl -? / 2 - [(1 S, 4R) -1, 2,3,4-tetrahydro-1,4-epiazan -naphthalen-6-yl) -5-trifluoromethyl-pyrimidine-2,4-diamine, (+/-) - 1- [6- (4-C-cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -1 , 2,3,4-tetrahydro-1,4-epiazan-naphthalen-9-yl] -ethanone, 1- [6- (4-Cyclopropylamino-5-methyl-pyrimidin-2-ylamino) - (1S, 4 / * ") - 1,2,3,4-tetrahydro-1,4-epiazan-naphthalen-9-yl] -ethanone 1- [6- (4-Cyclopropylamino-5-fluoro-pyrimidin-2-ylamino) - ( 1 S, 4R) -1, 2,3,4 -tetrahydro-l, 4-epiazan-naphthalen-9-yl] -ethanone, 1- [6- (4-ethylamino-5-methyl-pyrimidin-2-ylammon) - (1 S, 4R) - 1, 2,3,4-tetrahydro-1,4-epiazannaphthalen-9-yl] -ethanone, 1- [6- (4-ethylamino-5-fluoro-pyrimidin-2-ylammon) - (1S, 4R) -1, 2,3,4-tetrahydro-1,4-epiazannaphthalen-9-yl] -ethanone, 1- [6- (4-Etylamino-5-chloro-pyrimide-2-ylamine) - (1 S, 4R) -1, 2,3,4-tetrahydro-1,4-epiazan-naphthalene 9-yl] -etanone, 1-. { 6- [5-Fluoro-4 - ((S) -2-methoxymethyl-pyrrolidin-1-yl) -pyrimidin-2-ylamino] - (1S, 4R) -1, 2,3,4-tetrahydro-1, 4-epiazan-naphthalen-9-yl) -ethanone,? / 4-Cyclobutyl-W2 - [(1R, 4S) -1, 2,3,4-tetrahydro-1,4-epiazan-naphthalene-6- il] -5-trifluoromethyl-pyrimidin-2,4-diamine, 1- [6- (4-Cyclobutyl-lane-5-methyl-pyrimidin-2-ylamino) - (1R, 4S) -1, 2,3,4-tetrahydro-1,4-epiazan-naphthalen-9-yl] -ethanone, 1- [6- (4-Cyclobutylamino-5-fluoro-pyrimidin-2-ylamino) - (1R, 4S) -1, 2,3,4-tetrahydro-1,4-epiazan-naphthalen-9-yl] -ethanone,? / -. { 2- [6- (4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylammon) - (1:?, 4S) -1,2,3,4-tetrahydro-1,4-epiazan-naphthalene -9-yl] -2-oxo-ethyl) -acetamide, [6- (4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino) - (1R, 4S) -1, 2,3-methyl ester, 4-tetrahydro-1,4-epiazan-naphthalen-9-yl] -acetic acid, 6- (4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino) - (1 R, 4S) -1, 2,3,4-tetrahydro-1,4-epiazan-naphthalen-9-yl] - (R) -pyrrolidin-2-yl-methanone, [6- (4-Cyclobutylamino-5-trifluoro-O-methyl-pyrimidine -2-ylamino) - (1R, 4S) -1,2,3,4-tetrahydro-1,4-epiazan-naphthalen-9-yl] -cyclopropyl-methanone, 1 - [6- (4-Cyclobutylamino-5 -trifluoromethyl-pyrimidin-2-ylamino) - (1 R, 4S) -1, 2,3,4-tetrahydro-1,4-epiazan-naphthalen-9-yl] -2-methoxy-ethanone, 6-Isopropylamide - (4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino) - (1Rl4S) -1, 2,3,4-tetrahydro-1,4-epiazan-naphthalene-9-carboxylic, 1- [6- (4 -Cyclobutyllamino-5-trifluoromethyl-pyrimidin-2-ylamino) - (1R, 4S) -1,2,3,4-tetrahydro-1,4-epiazan-naphthalen-9-yl] -2-m ethylamine-ethanone, 1- [6- (5-Chloro-4-cyclobutylamino-pyrimidin-2-ylamino) - (1R, 4S) -1, 2,3,4-tetrahydro-1,4-epiazannaphthalene-9 -yl] -ethanone, 1- [6- (4-Cyclobutylamino-5-fluoro-pyrimidin-2-ylamino) - (1R, 4S) -1,2,3,4-tetrahydro-1,4-epiazan - naphthalene-9-yl] -ethanone, 1- [6- (4-Cyclobutylamino-5-ethyl-pyrimidin-2-ylamino) - (1R, 4S) -1, 2,3,4-tetrahydro-1,4-epiazan-naphthalene-9-yl] -etanone, 1- [6- (4-Cyclobutylamido-5-methyl-pyrimidin-2-ylamino) - (1R, 4S) -1, 2,3,4-tetrahydro-1,4-epiazan- naphthalen-9-yl] -ethanone,? / 4-Cyclopropyl- / V2- (1R, 4S) -1, 2,3,4-tetrahydro-1,4-epiazan-naphthalen-6-yl-5-trifluoromethyl- pyrimidine-2,4-diamine,? / 4-Cyclopropyl- / V2 - [(1R, 4S) -9-methanesulfonyl-1,2,3,4-tetrahydro-1,4-epiazan-naphthalen-6-yl] -5-trifluoromethyl-pyrimidin-2,4-diamine, 1- [6- (4 -Cyclopropylammonium-5-trifluoromethyl-pyrimidin-2-ylamino) - (1R, 4S) -1,2,3,4-tetrahydro-1,4-epiazan-naphthalene-9-yl] -2-methoxy-ethanone , (+/-) - 1-. { 6- [4- (2-Methoxy-ethylamino) -5-trifluoromethyl-pyrimidin-2-ylamino] -1,2,3,4-tetrahydro-1,4-epiazan-naphthalen-9-yl) -ethanone, ( +/-) - 2- [6- (4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -1, 2,3,4-tetrahydro-1,4-epiazan-naphthalen-9-yl] -? /,? / - dimethyl acetamide, and pharmaceutically acceptable salts of each of the above compounds. The present invention also includes isotopically-labeled compounds, which are identical to those listed in formulas 1 and 2, but in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or number Mass that is normally found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, but not limited to, 2H, 3H, 13C, 14C, 15N, lSO, 170, 31P, P, S, F, and Cl, respectively. The compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as H and C are incorporated are incorporated, are useful in drug and / or substrate tissue distribution assays. Particularly preferred are tritiates, i.e., isotopes of 3H, and carbon-14, that is, 14C, for its ease of preparation and detectability. In addition, replacement with heavier isotopes such as deuterium, ie, 2H, can produce certain therapeutic advantages resulting from increased metabolic stability, for example increased in vivo half-life or reduced dosage requirements, and may even be preferred in some circumstances. The isotopically-labeled compounds of this invention and prodrugs thereof can generally be prepared by performing the procedures described in the schemes and / or in the Examples and Preparations below, substituting an isotopically non-labeled reagent for an isotopically readily available reagent. The present invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the invention. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, ie, salts containing pharmacologically acceptable anions, such as, but without limitation, the salts of chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate , ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1 '-methylene-b /' s- (2-hydroxy-3-naphthoate)]. The invention also relates to base addition salts of the compounds of the invention. The chemical bases which can be used as reagents for preparing pharmaceutically acceptable base salts of those compounds of the compounds of the invention which are acidic in nature are those which form non-toxic base salts with said compounds. Such non-toxic salts of bases include, but are not limited to, those obtained from said pharmacologically acceptable cations such as alkali metal cations (eg, potassium and sodium) and alkaline earth metal cations (eg, calcium and magnesium), ammonium salts or addition of water-soluble amines such as N-methylglucamine- (meglumine), and the lower alkanolammonium and other pharmaceutically acceptable organic amine base salts. The term "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 the present invention. The compounds of the present invention which are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. Acids which can be used to prepare pharmaceutically acceptable acid addition salts of said basic compounds are those which form non-toxic acid addition salts, ie, salts which contain pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide salts , nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate , glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1'-methylene-o / s- (2-hydroxy-3-naphthoate)]. The compounds of the present invention that include a basic moiety, such as an amino group, can form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above. This invention also encompasses pharmaceutical compositions containing prodrugs of compounds of the compounds of the invention. The compounds of the compounds of the invention having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs. Prodrugs include compounds in which a residue of amino acids, or a polypeptide chain of two or more (eg, two, three or four) amino acid residues that are covalently linked through peptide bonds to free amino, hydroxy or carboxylic acid groups of compounds of the invention. The amino acid residues include the 20 naturally occurring amino acids commonly designated by three-letter symbols and also include, 4-hydroxyproline, hydroxylysine, demosin, isodemosin, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine , homoserin, ornithine and sulfone methionine. Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters are covalently attached to the above substituents of the compounds of the invention via the carbonyl side chain carbon of the prodrug. This invention also encompasses compounds of the invention which contain protecting groups. A person skilled in the art will also understand that they can also be prepared compounds of the invention with certain protecting groups that are useful for purification or storage and can be removed prior to administration to a patient. The protection and deprotection of functional groups is described in "Protective Groups in Organic Chemistry", edited by J.W.F. McOmie, Plenum Press (1973) and "Protective Groups in Organic Synthesis", 3rd edition, T.W. Greene and P.G.M. Wuts, Wiley-lnterscience (1999). The compounds of this invention include all stereoisomers (e.g., cis and trans isomers) and all optical isomers of compounds of the invention (e.g., R and S enantiomers), as well as racemic, diastereomeric and other mixtures of such isomers.

The compounds, salts and prodrugs of the present invention can exist in various tautomeric forms, including the enol e mine form, and the keto and enamine form and geometric isomers and mixtures thereof. All of said tautomeric forms are included within the scope of the present invention. Tautomers exist as mixtures of a tautomeric set in solution. In solid form, usually a tautomer predominates. Even though a tautomer can be described, the present invention includes all the tautomers of the present compounds. The present invention also includes atropisomers of the present invention. Atropisomers refer to compounds of the invention that can be separated into isomers of restricted rotation. The compounds of this invention may contain olefin-like double bonds. When such linkages are present, the compounds of the invention exist in the form of cis and trans configurations and in the form of mixtures thereof. A "suitable substituent" is intended to indicate a chemically and pharmaceutically acceptable functional group, ie, a moiety that does not negate the biological activity of the compounds of the invention. Such suitable substituents can be routinely selected by those skilled in the art. Illustrative examples of suitable substituents include, but are not limited to halo groups, perfluoroalkyl groups, perfluoroalkoxy groups, alkyl groups, alkenyl groups, alkynyl groups, hydroxy groups, oxo groups, mercapto groups, alkylthio groups, alkoxy groups, aryl or heteroaryl groups, groups aryloxy or heteroaryloxy, aralkyl or heteroaralkyl, aralkoxy or heteroaralkoxy groups, HO-C (O) - groups, amino groups, alkyl- and dialkylamino groups, carbamoyl groups, alkylcarbonyl groups, alkoxycarbonyl groups, alkylaminocarbonyl groups, dialkylaminocarbonyl groups, arylcarbonyl groups, aryloxycarbonyl groups, alkylsulfonyl groups, groups Arsulfonyl and the like. Those skilled in the art will understand that many substituents can be substituted with additional substituents. Other examples of suitable substituents include those listed in the definition of compounds of the invention, including R1 through R12, as defined hereinbefore. The term "interrupted by" refers to compounds in which an element selected from the group consisting of -C (R3) = C (R3) -, -C (O) -, - (C = N-R3) -, - (C = N-NR3R4) -, -C = NNC (0) -R5, -C = NNC (0) OR3, - (C = CR3R4) -, - (C = C (R3) C (0) - NR3R4)) -, - (C = C (R3) C (0) OR6) -, -S02-, -S-, -O- and -NR3- is inserted into, for example, an acid system or a rings For example, if a substituent is a heterocyclic group, such as an azetidine group: The ring may be interrupted by, for example, a -C (O) - to form a pyrrolidinone group so that two atoms in the ring of the azetidine group are interrupted by the group - C (O) -. The compounds of the invention can harbor up to three such substitutions or interruptions. As used herein, the term "alkyl," as well as the alkyl moieties of other groups mentioned herein (e.g., alkoxy), may be linear or branched (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, fer-butyl); optionally substituted with 1 to 3 substituents suitable as defined above such as fluoro, chloro, trifluoromethyl, -alkoxy (d-C6), -aryloxy (C6-C10), trifluoromethoxy, difluoromethoxy or -alkyl (d-C6) . The expression "each of said alkyl" as used herein refers to any of the above alkyl moieties within a group of said alkoxy, alkenyl or alkylamino. Preferred alkyls include (d-C6) alkyl, more (C4-C6) alkyl is preferred, and methyl and ethyl are more preferred. As used herein, the term "halogen" includes fluoro, chloro, bromo or iodo or fluoride, chloride, bromide or iodide. As used herein, the term "alkenyl" means straight or branched chain unsaturated radicals of 2 to 6 carbon atoms, including, but not limited to, ethenyl, 1-propenyl, 2-propenyl (allyl), Iso-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like; optionally substituted with 1 to 3 substituents suitable as defined above such as fluoro, chloro, trifluoromethyl, -alkoxyid-Cß), -aryloxy (C6-C10), trifluoromethoxy, difluoromethoxy 0 -. 0 -alqu¡lo (d-C6). As used herein, the term "alkynyl" is used herein to mean straight or branched hydrocarbon chain radicals having a triple bond including, but not limited to, ethynyl, propynyl, butynyl, and the like; optionally replaced with 1 to 3 suitable substituents as defined above such as fluoro, chloro, -trifluoromethyl, -alcoxy (d-C6), -arithioxy (C6-C0), trifluoromethoxy, difluoromethoxy or -alkyl (C, -C6). The term "perfluorinated" refers to a compound that contains 4 or more fluorine groups. As used herein, the term "carbonyl" or "C (O)" (as used in phrases such as alkylcarbonyl, alkyl-C (O) - or alkoxycarbonyl) refers to the bonding of the residue > C = 0 to a second moiety such as an alkyl or amino group (ie, an amido group) .alkoxycarbonylamino (ie, alkoxy-C (O) -NH-) refers to an alkylcarbamate group.The carbonyl group is also defined equivalently in this document as C (O) .alkylcarbonylamino refers to groups such as acetamide, as used herein, the term "cycloalkyl" refers to a monocarbocyclic ring (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl. cyclooctyl, cyclononyl, cyclopentenyl, cyclohexenyl); optionally substituted with 1 to 3 suitable substituents as defined above such as fluoro, chloro, trifluoromethyl, -alkoxy- (d-C6), aryloxy- (C6-C10), trifluoromethoxy, difluoromethoxy or -alkyl- (d) -C6). As used herein, the term "cycloalkenyl" refers to a cycloalkyl as defined above and which further contains 1 or 2 double bonds. As used herein, the term "bicycloalkyl" refers to a cycloalkyl as defined above that is linked via a bridging link to a second carbocyclic ring (eg, bicyclo [2.2.1] heptanil, bicyclo [ 3,2,1] octanil and bicyclo [5,2,0] nonane, etc.).

As used herein, the term "bicycloalkenyl" refers to a bicycloalkyl as defined above and which further contains 1 or 2 double bonds. As used herein, the term "aryl" means aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, adenyl, and the like; optionally substituted with 1 to 3 suitable substituents as defined above. As used herein, the term "heteroaryl" refers to a heterocyclic aromatic group usually with a heteroatom selected from O, S and N in the ring, in addition to said heteroatom, the aromatic group may optionally have up to four N atoms. in the ring. For example, heteroaryl group includes pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, phenyl, furyl, imidazolyl, pyrrolyl, oxazolyl (e.g., 1,3-oxazolyl, 1,2-oxazolyl), thiazolyl (e.g. -thiazolyl, 1,3-thiazolyl), pyrazolyl, tetrazolyl, triazolyl (for example, 1,3-triazolyl, 1,4-triazolyl), oxadiazolyl (for example, 1,3-oxadiazolyl), thiadiazolyl (for example, 1,3,4-thiadiazolyl), quinolyl, isoquinolyl, benzothienyl, benzofuryl, indolyl, and the like; optionally substituted with 1 to 3 suitable substituents as defined above such as fluoro, chloro, trifluoromethyl, -alkoxyid-Cß), -aryloxy (C6-C10), trifluoromethoxy, difluoromethoxy or -alkyl (C? -Cβ). As used herein, the term "heteroatom" refers to an atom or group selected from N, O, S (0) n or NR, where n is an integer from 0 to 2 and R is a substituent group. The term "heterocyclic" as used herein refers to a cyclic group containing 1-9 carbon atoms and 1 to 4 heteroatoms. Examples of such rings include azetidinyl, tetrahydrofuranyl, midazolidínilo, pyrrolidine, piperidinyl, piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, thiomorpholinyl, tetrahydrothiazinyl, tetrahydro-thiadiazinyl, morpholinyl, oxetanyl, tetrahydrodiazinyl, oxazinyl, oxathiazinyl, indolinyl, isoindolinyl, quinuclidinyl, chromanyl, isochromanyl, benzoxazinyl, and Similar. Examples of such saturated or partially saturated monocyclic ring systems are tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyrrolidin-1-yl, pyrrolidin- 2-yl, pyrrolidin-3-yl, piperidin-1-yl, pyperidin-2-yl, piperidin-3-yl, piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, 1,3- oxazolidin-3-yl, isothiazolidine, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, thomorpholin-yl, 1,2-tetrahydrothiazin-2- I, 1, 3-tetrahydrothiazin-3-yl, tetrahydrothiadiazin-yl, morpholin-yl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, 1,4-oxazin-2-yl, 1,2,5-oxathiazin-4-yl and the like; which optionally contain 1 or 2 double bonds and optionally substituted with 1 to 3 suitable substituents as defined above such as fluoro, chloro, trifluoromethyl, -alkoxy (C? -C6), -aryloxy (Ce-C? o), trifluoromethoxy, difluoromethoxy or -alkyl (d-C6) As used herein, the term "heterobicycloalkyl" refers to a bicycloalkyl as defined above, wherein at least one of the carbon atoms in the ring has been replaced with at least one heteroatom (for example, tropane). As used herein, the term "heterobicycloalkenyl" refers to a heterobicycloalkyl as defined above and which further contains 1 or 2 double bonds. Heteroatoms of nitrogen as used herein refers to N =, > N and -NH; where -N = refers to a double bond of nitrogen; > N refers to a nitrogen containing two linking connections and -N refers to a nitrogen containing a bond. "Realization" as used herein refers to specific groupings of compounds or uses in separate subgenres. Said subgenres can be identified according to a particular substituent such as a specific R1 or R3 group. Other subgenres are identified according to combinations of various substituents, such as all compounds wherein R 2 is hydrogen and R 1 is -alkyloid-Cß).

The term "perfluoro" or "perfluoro" refers to a compound having 4 or more fluorine groups. The invention also relates to processes for preparing the compounds of the invention. In one embodiment, the invention relates to a process for preparing a compound of formula 1 comprising leaving a compound of formula react with a compound of formula to provide the compounds of the invention; wherein R17 is selected from the group consisting of R12 as defined and a protecting group. In another embodiment, the invention relates to a process for preparing the compounds of the invention which comprises leaving the compound of formula react with a compound of formula to provide the compounds of the invention wherein R 7 is as defined above. When preparing compounds of the invention according to the invention, it is within the judgment of a person skilled in the art to routinely select the shape of the intermediate compound that provides the best combination of characteristics for this purpose. Said characteristics include the melting point, solubility, processability and yield of the intermediate form and the resulting ease with which the product can be purified in isolation. The invention also relates to processes for preparing intermediate compounds that are useful for preparing the compounds of the invention. As indicated above, the invention also relates to the pharmaceutically acceptable salts of the compounds of the invention. The pharmaceutically acceptable salts of the compounds of the invention include the acid addition salts and bases thereof. Suitable acid addition salts are formed from acids that form non-toxic salts. Non-limiting examples of the suitable acid addition salts include the acetate salts, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisilate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybienate, hydrochloride / chloride, hydrobromide / bromide , hydroiodide / iodide, setionate, lactate, malate, maleate, malonate, mesylate, methyl sulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotao, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate. Suitable base salts are formed from bases that form non-toxic salts. Non-limiting examples of suitable base salts include the aluminum, arginine, benzathine salts, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc. Hemisal acids and bases can also be formed, for example, hemiste and hemicalcium salts. For a review of suitable salts, see Handbook of Pharmaceutical Salts: Properties. Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002). The methods for preparing pharmaceutically acceptable salts of compounds of the invention are known to one skilled in the art. The compounds of the invention can also exist in solvated and unsolvated forms. Accordingly, the invention also relates to the hydrates and solvates of the compounds of the invention. The term "solvate" is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is used when said solvent is water. A classification system currently accepted for organic hydrates is one that defines hydrates of isolated site, channel or coordinated to metal ions see Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed.

H. G. Brittaín, Marcel Dekker, 1995). Isolated site hydrates are hydrates in which the water molecules are isolated from direct contact with each other by intermediate organic molecules. In channel hydrates, water molecules rest in channels of the network where they are close to other water molecules. In hydrates coordinated to metal ions, the water molecules are bound to the metal ion. When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry regardless of moisture. When, however, the solvent or water binds weakly, as in channel solvates and hygroscopic compounds, the water / solvent content will depend on the conditions of moisture and dryness. In these cases, the normal will be no stoichiometry.

The invention also relates to prodrugs of the compounds of the invention. Thus, certain derivatives of compounds of the invention which may have little or no pharmacological activity per se may, when administered in or on the body, be converted into compounds of the invention having the desired activity, for example, by cleavage hydrolytic Said derivatives are referred to as "prodrugs". More information on the use of prodrugs can be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Híguchi and W. Stella) and Bíoreversible Carriers in Drug Design, Pergamon Press, 1987 (Ed. EB Roche , American Pharmaceutical Association). Prodrugs according to the invention can, for example, be produced by replacing appropriate functions present in the compounds of the invention with certain residues known to those skilled in the art as "pro-residues" as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985). Some non-limiting examples of prodrugs according to the invention include (i) where the compound of the invention contains a carboxylic acid function (-COOH), an ester thereof, for example, a compound in which the hydrogen of the function carboxylic acid of the compound of formula (I) is replaced with alkyl (d-Ce); (ii) wherein the compound of the invention contains an alcohol function (-OH), an ether thereof, for example, a compound in which the hydrogen of the alcohol function of the compound of the invention is replaced with alkanoyloxymethyl ( C? -C6); and (iii) wherein the compound of the invention contains a primary or secondary amino function (-NH2 or -NHR where R? H), an amide thereof, for example, a compound in which, as the case may be, one or both hydrogens of the amino function of the compound of the invention are replaced (n) with alkanoyld-Cß). Other examples of replacement groups according to the above examples and examples other types of prodrugs can be found in the references mentioned above. In addition, certain compounds of the invention may themselves act as prodrugs of other compounds of the invention.

Metabolites of compounds of the invention, i.e., compounds formed in vivo after drug administration are also included within the scope of the invention. Some examples of metabolites according to the invention include: (i) wherein the compound of the invention contains a methyl group, a hydroxymethyl derivative thereof (eg, -CH3-> -CH2OH): (ii) wherein the compound of the invention contains an alkoxy group, a hydroxy derivative thereof (for example, -OR7 -> -OH); (ii) wherein the compound of the invention contains a tertiary amino group, a secondary amino derivative thereof (eg, -NR3R4 -> -NHR3 or -NHR4); (iv) wherein the compound of the invention contains an aminonsecondary group, a primary derivative thereof (eg, -NHR3 -> -NH2); (v) wherein the compound of the invention contains a phenyl moiety, a phenol derivative thereof (eg, -Ph -> -PhOH); and (vi) wherein the compound of the invention contains an amide group, a carboxylic acid derivative thereof (eg, -CONH2 -> COOH). The compounds of the invention containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of the invention contains an alkenyl or alkenylene group, cis / trans (or Z / E) geometric isomers are possible. Where structural isomers are interconvertible through a low energy barrier, tautomeric isomerism ("tautomerism") can occur. This may take the form of proton tautomerism in compounds of the invention containing, for example, an imino, keto, or oxime group, or so-called valence tautomeria in compounds containing an aromatic moiety. From this it follows that a single compound can show more than one type of isomerism. Within the scope of the present invention are included all stereoisomers, geometric isomers and tautomeric forms of the compounds of the invention, including compounds that display more than one type of isomerism, and mixtures of one or more thereof.

Also included are acid addition salts or bases in which the counterion is optically active, for example, d-lactate or l-lysine, or racemic, for example, dl-tartrate or dl-arginine.

The cis / trans isomers can be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, high performance liquid chromatography (HPLC) chiral . Alternatively, the racemate (or a racemic precursor) can be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of the invention contains an acidic or basic moiety, a base or acid such such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture can be separated by chromatography and / or fractional crystallization and one or both diastereomers converted to the corresponding pure enantiomer (s) by means well known to one skilled in the art. The chemistry compounds of the invention (and the chiral precursors thereof) can be obtained in enantiomerically enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing 0 to 50% by volume of an alcohol solvent such as isopropanol, typically 2% to 20%, and 0 to 5% by volume of an alkylamine, typically 0.1% diethylamine. The concentration of the eluate produces the enriched mixture. When any racemate crystallizes, crystals of two different types are possible. The first type is the racemic compound (authentic racemate) mentioned above in which a homogeneous crystal form is produced which contains the two enantiomers in equimolar amounts. The second type is the racemic or conglomerate mixture in which two crystal forms are produced in equimolar amounts each comprising a single enantiomer. Although the two crystal forms present in a racemic mixture have identical physical properties, may have different physical properties compared to the real racemate. Racemic mixtures can be separated by known conventional techniques by those skilled in the art - see, for example, Stereochemistry of Organic Compounds by E. L Eliel and S. H. Wilen (Wiley, 1994). The invention also relates to methods for the treatment of abnormal cell growth in a mammal. In one embodiment, the invention relates to a method for treating abnormal cell growth in a mammal comprising administering to said mammal an amount of a compound of the invention that is effective to treat abnormal cell growth. In another embodiment, abnormal cell growth is cancer. In another embodiment, the cancer is selected from the group consisting of lung cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer , cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, fallopian tube carcinoma, endometrial carcinoma, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's disease, esophageal cancer, small bowel cancer, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, soft tissue sarcoma, cancer of the urethra, cancer of the penis, cancer of prostate, chronic or acute leukemia, lymphocytic lymphomas, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis carcinoma, neoplasms of the system central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, brainstem glioma, pituitary adenoma, or a combination of one or more of the above cancers. The invention also relates to methods for the treatment of cancerous solid tumors in a mammal. In one embodiment, the invention relates to the treatment of cancerous solid tumor in a mammal comprising administering to said mammal an amount of a compound of the invention that is effective to treat said cancerous solid tumor. In another embodiment, the cancerous solid tumor is from breast, lung, colon, brain, prostate, stomach, pancreas, ovary, skin (melanoma), endocrine, uterine, testicular, or bladder. In another embodiment, the invention relates to a method for the treatment of abnormal cell growth in a mammal comprising administering to said mammal a amount of a compound of the invention that is effective to treat abnormal cell growth together with an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, cell growth inhibitors, radiation, inhibitors of the cell cycle, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxics, anti-hormones, and anti-androgens. In yet another embodiment, the invention relates to a pharmaceutical composition comprising an effective amount of the compound of the invention, and a pharmaceutically acceptable carrier. In another embodiment, the invention relates to a pharmaceutical composition useful for treating abnormal cell growth in a mammal comprising an effective amount of the compound of the invention, and a pharmaceutically acceptable carrier. A particular aspect of this invention relates to methods of treating or preventing a condition that occurs with low bone mass in a mammal (including a human) which comprises administering to a mammal in need of such treatment an amount that treats a condition that it is presented with low bone mass of a compound of the invention or a pharmaceutically acceptable salt of said compound of the invention. This invention is particularly directed to methods such that the condition that presents with low bone mass is osteoporosis, fragility, an osteoporotic fracture, a bone defect, juvenile idiopathic bone loss, alveolar bone loss, mandibular bone loss, bone fracture, osteotomy, periodontitis or prosthetic growth inward. A particular aspect of this invention relates to methods of treating osteoporosis in a mammal (including a human) which comprises administering to a mammal in need of such treatment an osteoporosis treating amount of a compound of the invention or a pharmaceutically acceptable salt thereof. said compound. Another aspect of this invention relates to methods of treating a bone fracture or an osteoporotic fracture in a mammal comprising administering to a mammal in need of such treatment an amount that treats bone fracture or that treats fracture. osteoporotic of a compound of the invention or a pharmaceutically acceptable salt of said compound. The term "osteoporosis" includes primary osteoporosis, such as senile, postmenopausal and juvenile osteoporosis, as well as secondary osteoporosis, such as osteoporosis due to hyperthyroidism or Cushing's syndrome (due to the use of corticosteroids), acromegaly, hypogonadism, dysosteogenesis and hypophosphatasemia.

DETAILED DESCRIPTION OF THE INVENTION The compounds of the invention can be prepared by the following general procedures and by procedures described in detail in Section Experimental. Synthesis of 2,4-diamno pyrimidines Two non-limiting processes for preparing the 2,4-diamin pyrimidines of the invention are shown in Schemes 1 and 2. Scheme 1 shows a procedure for preparing 2,4-diamino pyrimidines where D is a group other than a trifluoromethyl group. Scheme 1 Scheme 2 shows a process for preparing 2,4-diamino-5-trifluoromethyl pyrimidines where the C-5 position of the pyrimidine is substituted with a trifluoromethyl group. Scheme 2 wherein said "R17" can be an R12 group as defined above or a protecting group. Non-limiting examples of protecting groups such as tert-butoxycarbonyl- (BOC), benzyloxycarbonyl- (CBZ), trifluoroacetamido- (TFA), or benzyl (Bn) as protecting groups as described by Green and Wutts, "Protective Groups in Organic Synthesis "Third Edition, Wiley Interscience. The protecting group can be removed at the appropriate time from the synthesis sequence so that the exposed deprotected atom can be further functionalized to prepare the compounds depicted in Scheme 3, where R17 can be an R12 group as defined above or another group that 12 may be further modified to provide R 'Scheme 3 The compounds of general formulas A, B and C are commercially available or can be prepared by known methods (see, for example, WO 2004056786, WO 2004056807, WO 2005023780, Ange andte Chemie, International Edition, 41 (22), (2002), Angewandte Chemie, International Edition, 43 (33), 4364-4366 (2004), Archiv der Pharmazie (Weínheim, Germany), 314 (1), 26-34 (1981), Bulletin of the Chemical Society of Japan , 59 (12), 3988-90 (1986), Chemical &Pharmaceutical Bulletin, 33 (6), 2313-22 (1985); Communications, 5, 143 (1966); Journal of Medicinal Chemistry, 31 (2), 433-44 (1988); Journal of Organic Chemistry, 49 (21), 4025-9 (1984); Journal of Organic Chemistry, 67 (23), 8043 (2002); Journal of Organic Chemistry, 55 (2), 405-6 (1990); Journal of Organic Chemistry, 60 (21), 6904-11 (1995); Journal of the American Chemical Society, 109 (18), 5393-403 (1987); Journal of the American Chemical Society, 125 (49), 15191-15199 (2003); Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), (15), 1647-54 (1976); Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), (8), 2013-16; (1979); Journal of the Chemical Society, Perkins Transactions I, 1981, 1846; March and Smith, Text Book on Organ Chemistry; Monatshefte fuer Chemie, 128 (3), 271-280 (1997); New Journal of Chemistry 29 (1), 42-56 (2005); Organic & Biomolecular Chemistry, 1 (21), 3787-3798 (2003); Synlett, (1), 58-60 (1998); Synlett, (7), 1103-1105 (1999); Synthesis, (11), 1755-1758 (2004); Synthetic Communications, 20 (12), 1877-84 (1990); Tetrahedron, 60 (16), 3611 (2004); U.S. Patent No. 4,761,413; U.S. Patent No. 6,605,610; Journal of the American Chemical Society 91 (24), 6775-8 (1969); Journal of the American Chemical Society, 91 (5), 1170-5 (1969); Journal of the American Chemical Society, 88 (18), 4289-90 (1966); and references cited in the above references). These compounds represented in Schemes 1-3 are also useful for the preparation of other similar ring systems and also larger and smaller rings for the compounds of formula C described below: Ring systems [2.2.1] where X is (CH2): 1,4-Dihydro-1,4-methano-naphthalene where X is Oxygen: 11 -Oxa-tricyclo [6.2.1.02'7] undeca-2,4,6,9-tetraene where X is NH: 1,4-Dihydro-1,4-epiazan-naphthalene where X is Sulfur: 11-Thia-tricyclo [6.2.1.027] undeca-2,4,6 > 9-tetrane Ring systems [2.2.2] where X and A are CH2: Tricyclo [6.2.2.0 '] dodeca-2,4,6,9-tetraene where X is N-Boc, A is CH2: 9-azatricyclo-methyl ester [6,2, 2.02 7] dodeca-2,4,6,11-tetraen-9-carboxylic acid where X is N, A is C = 0: 9-Aza-tricyclo [6.2,2,02'7] dodeca-2 , 4,6,11-tetraen-10-one As indicated above, the compounds of general formula C can be prepared by known procedures following the general procedure depicted in Scheme 4. Based on the known chemistry and the literature, a One skilled in the art of organic chemistry can prepare any of the compounds of general structural formula C. Scheme 4 By taking an intermediate from the above sequence, the following sequence of reactions can be applied (Scheme 5) to produce the amines functionalized differently desired.

Scheme 5 Alternatively, the aryl ring may already be functionalized and incorporated into the cycle addition sequence to prepare compounds of general formula C as depicted in Scheme 6, Scheme 6 D D where A is, for example, -CRßR9-, -C (O) -, -N (C02-R5) - or -N ((C (0) R12) -; and X is, for example, -N (C02) -R5) (for example, -N-Boc), -N ((C (0) R12) -, -N (TFA) - or -O- The compounds of formula D and the other reagents are commercially available. or they can be prepared by known methods (see references listed above.) Alternatively, the following reaction schemes can be used (Schemes 7a and 7b) to prepare compounds of general formula C (see references listed above): Scheme 7a Scheme 7b where an "Olefin" is defined as a group that contains a double bond or triple bond and R17 is as defined above. The amount of groups in the olefin can vary from 1 to 4 depending on the dienophile used. Non-limiting examples of ethylenic olefins are useful non-functionalized acyclic olefins, functionalized cyclic olefins, non-functionalized cyclic olefins, and functionalized cyclic olefins. Non-limiting examples of useful acetylenic olefins include substituted acetylenes and unsubstituted acetylenes. The compounds of general formula C can also be prepared by expanding the ring starting from a heterocycle by known procedures (see references listed above) as depicted in Scheme 8: Scheme 8 where X = N-Boc, N-TFA, or oxygen; "Y" = Na2S or H2N-Benzyl; Y = sulfur or N-R; Lg = leaving group (such as mesylate, tosylate); O = oxygen; DEAD = diethyl azodicarboxylate; and TPP = triphenyl phosphine. Alternatively, compounds of general formula C can be prepared by known methods (see references listed above) starting from a heteroalkane by ring expansion according to known procedures as depicted in Scheme 8: Scheme 9 where X = N-Boc, N-C02R or N-TFA; A = CH2, C = 0 or N-COzR; "Y" = Na2S or H2N-Benzyl; Y = sulfur or N-R; Lg = leaving group (such as mesylate, tosylate); O = oxygen; DEAD = diethyl azodicarboxylate; and TPP = triphenyl phosphine. Non-limiting procedures for functionalizing olefins include 2-3 dipolar cycloaddition reaction, aziridination reactions, cyclopropanation, decarboxylation, Dieckmann condensation, Diels-Alder reaction, eno reaction, epoxidation, Favorskii reaction, Friesdel Crafts reaction, halogenation, Heck reaction (to add additional carbon function), hetero-ene reaction, reductions of. hydride (for example, aldehydes, ketones, ester amides), hydroboration-oxidation of the olefin (to install a hydroxy group), Michael reaction, olefin metatasis, olefin osmilation to install cis diols, oxidation of the hydroxy group installed to ketone, and amine reduction of ketones with amines. The general procedure for functionalizing olefinic groups is depicted in Scheme 10 (where FG is a functional group) and are described in, for example, the references listed above.

Scheme 10 Alternatively, the compounds of the invention, where L1 = a binder of atoms and L2 = a bond or L = a bond and L2 = a binder of atoms, can be prepared by forming a compound of general formula C followed by reaction with 2, Suitable 5-substituted pyrimidine 5-diamine pyrimidine as depicted in Schemes 11 or 12. Scheme 11 where X can be -S-, -S02-, -O-, -NR17- or -CR8R9- as defined above.

Scheme 12 where X can be -S-, -S02-, -O-, -NR12- or -CR8R9- as defined above.

In Vitro and In Vivo Assays As indicated above, the compounds of the invention are useful as inhibitors of receptor tyrosine kinases such as, for example, FAK, Aurora-1, Aurora-2, HgK and Pyk. The following describes methods for determining the in vitro and in vivo activity of these receptor tyrosine kinase inhibitor compounds: In vitro activity of FAK: The in vitro activity of the compounds of the invention can be determined by the following procedure. More particularly, the following assay provides a method for determining which compounds of the compounds of the invention inhibit the tyrosine kinase activity of the FAK catalytic construct (410-689). The assay is an ELISA-based format, which measures the inhibition of poly-glu-tyr phosphorylation by FAK (410-689). The test protocol has three parts: I. Purification and cleavage of His-FAK (410-689) II. Activation of FAK410-689 (a.k.a. FAKcd) III. ELISA of FAKcd kinase Materials: agar-Ni-NTA (Qiagen) -column XK-16 (Amersham-Pharmacia) -Imidizol 300 mM -column Superdex 200 HiLoad 16/60 quality prep (Amersham Biotech.) Antibody: Py20 Antí-Phosphotyrosine Conjugate with HRP (Transduction labs) -FAKcd: Purification and self-activation TMB Microwell Peroxidase Substrate (Oncogene Research Products No. CL07) -BSA: Sigma No. A3294 -Tween-20: Sigma No. P1379 -DMSO: Sigma No. D-5879 -D-PBS: Gib No. 14190-037 Reagents for Purification: - Buffer A: 50 mM HEPES pH 7.0 NaCI 500 mM TCEP 0.1 mM Complete protease inhibitor cocktail TM (Roche) - Buffer B: 25 mM HEPES pH 7.0 NaCl 400 mM TCEP 0.1 mM - Buffer C: 10 mM HEPES pH 7.5 Ammonium sulphate 200 mM TCEP 0.1 mM Reagents for activation - FAK (410-689): 3 frozen aliquot tubes at 150 μl / tube for a total of 450 μl a 1.48 mg / ml (660 μg) -His-Src (249-524): -0.74 mg / ml stock solution in 10 mM HEPES, 200 mM (NH4) 2S04 - Src Reaction Buffer (Upstate Bíotech): Tris -HCl 100 mM pH7 2 MgCl2125 mM MnCl225 mM 2 mM EDTA Na3VO4250 μM 2 mM DTT-Mn2 + / ATP cocktail (Upstate Biotech) MnCI275 mM ATP 500 μM 20 mM MOPS pH 7.2 1 mM glycerol phosphate 25 mM EGTA 5 mM DTT 1 mM -ATP: stock solution 150 mM -MGCI2: 1 M stock solution -DTT: 1 M stock solution Reagents for FAKcd ELISA kinase -Posphorylation buffer: 50 mM HEPES, pH 7.5 125 mM NaCI MgCI2 48mM -Tape buffer: TBS + Tween-20 0.1%, - Blocking plug: Saline solution Tris buffer 3% BSA 0.05% Tween-20, filtered - Plate coating buffer: 50 mg / ml Poly-Glu-Tyr (Sigma No. P0275) in Phosphate Buffer Saline (DPBS).

-ATP: 0.1 M ATP in H20 or HEPES, pH 7 Note: ATP assay buffer: Prepare as ATP 75 μM in PBS, so that 80 μl in 120 μl reaction volume = final concentration of ATP 50 μM . I. Purification of His-FAKcd (410-689) 1. Resuspend 130 g of baculovirus cell paste containing the recombinant protein His-FAKcd410-689 overexpressed in 3 volumes (400 ml) of Buffer A. 2. Lyse cells with one step in a microfluidizer. 3. Remove cell debris by centrifugation at 4 ° C for 35 minutes at 14,000 rpm in a SorvalSLA-1500 rotor. 4. Transfer the supernatant to a clean tube and add 6.0 ml of Ni-NTA agarose (Qiagen).

. Incubate the suspension by gently stirring at 4 ° C for 1 hour. 6. Centrifuge the suspension at 700 x g in a swinging bucket rotor. 7. Discard the supernatant and resuspend the agarose beads in 20.0 ml of Buffer A. 8. Transfer the beads to an XK-16 column (Amersham-Pharmacia) connected to a FPLCTM. 9. Wash the agarose beads with 5 column volumes of Buffer A and elute from the column with stepwise gradient of Buffer A containing 300 mM Imidizol. 10. Perform a buffer exchange of the fractions eluted in Buffer B. After buffer exchange, gather the fractions and add thrombin at a ratio of 1: 300 (w / w) and incubate overnight at 13 ° C to remove the N-terminal His tag.

(HIS-FAK410-698? FAK410-689 (a.k.a. FAKcd)). 12. Add the reaction mixture back into the Ni-NTA column equilibrated with Buffer A and collect the flow through it. . 13. Concentrate the flow that passes through to 1.7 ml and load directly into a column Superdex 200 H i Load 16/60 prep quality balanced with Buffer C. The desired protein is eluted between 85-95 ml. 14. Separate the FAKcd protein in Aliquots and store frozen at -80 ° C.

II. activation of FAK 1. To 450 μl of FAK (410-689) at 1.48 mg / ml (660 μg) add the following: 30 μl of 0.037 mg / ml (1 μM) of His-Src (249-524) 30 μl of 7.5 mM ATP 12 μl of MgCl220 mM 10 μl of Mn2 + / ATP cocktail (UpState Biotech.) 4 μl of 6.7mM DTT 60 μl of Src Reaction Buffer (UpState Biotech.) 2. Incubate the reaction for at least 3 hours at room temperature At time t, almost all of the FAK (410-689) is phosphorylated once. The second phosphorylation is slow. At t 20 (t = 120 minutes), add 10 μl of 150 mM ATP. T0 = (Beginning) 90% of FAK (410-689) is phosphorylated only once (1 P04) T43 - (43 min) 65% is phosphorylated only once (1 P04), 35% is phosphorylated twice (2 P04) T90 = (90 min) 45% 1 P04, 55% 2 P04 T150 = 15% 1 P04, 85% 2 P04 T210 = < 10% 1 P04, > 90% 2 P04 desalted sample 3. Add 180 μl aliquots of the desalted material to a NiNTA column for centrifugation and incubate on a centrifugation column. 4. Centrifuge at 10k rpm (microfuge), for 5 minutes to isolate and collect flow through ( FAK (410-689) activated) and remove His-Src (captured in the column) III. FAKcd kinase ELISA 1. Coat 96-well Nunc MaxiSorp plates with poly-glu-tyr (pGT) at 10 ug / well: Prepare 10 μg / ml of pGT in PBS and aliquot 100 μl / well. Incubate the plates at 37 ° C overnight, aspirate the supernatant, wash the plates 3 times with Wash Buffer, and shake to dry before storing at 4 ° C. 2. Prepare stock solutions of the 2.5 mM compound in 100% DMSO. The stock solutions are subsequently diluted to 60x of the final concentration in 100% DMSO, and diluted 1: 5 in Kinase phosphorylation Buffer. 3. Prepare a working solution of ATP 75 μM in Kinase phosphorylation Buffer. Add 80 μl to each well for a final ATP concentration of 50 μM. 4. Transfer 10 μl of the diluted compounds (0.5 log serial dilutions) to each well of the pGT assay plate, processing each compound in triplicate in the same plate. 5. Dilute on ice, FAKcd protein at 1: 1000 in Kinase phosphorylation buffer. Dispense 30 μl per well. 6. Note: appropriate linearity and dilution should be predetermined for each batch of protein. The enzyme concentration selected should be such that the quantification of the test signal will be about 0.8-1.0 to OD450, and in the linear range of the reaction rate. 7. Prepare a control without ATP (noise) and a Control Without Compound (Signal): 8. (Noise) A row of white wells receives 10 μl of compounds diluted 1: 5 in DMSO, 80 μl of phosphorylation buffer (minus ATP) ), and 30 μl of FAKcd Solution. 9. (Signal) The control wells receive 10 μl of DMSO diluted 1: 5 (less Compound) in Kinase phosphorylation buffer, 80 μl of 75 μM ATP, and 30 μl of Enzyme FAKcd 1: 1000. 10. Incubate the reaction at room temperature for 15 minutes by gently shaking on a plate shaker. 11. Stop the reaction by suctioning off the reaction mixture and washing 3 times with wash buffer. 12. Dilute the phospho-tyrosine antibody conjugated with HRP (pY20HRP) to 0.250 μg ml (1: 1000 of stock solution) in blocking buffer. Dispense 100 μl per well, and incubate with stirring for 30 minutes at T.A. 13. Aspirate the supernatant and wash the plate 3 times with wash buffer. 14. Add 100 μl per well of TMB solution at room temperature to initiate color development. The color development is terminated after approximately 15-30 seconds by the addition of 100 μl of 0.09 M H2SO4 per well. 15. The signal is quantified by measuring the absorbance at 450 nm in the BioRad Microplate Reader or a microplate reader capable of reading OD450. 16. Inhibition of tyrosine kinase acti could result in a reduced absorbance signal. The signal is typically 0.8-1.0 OD units. The values are presented as IC50, concentration μM. Cell-based inducible FAK ELISA: Final protocol Materials: 96 well plates with goat anti-rabbit Reacti-Bind (Pierce Product No. 15135ZZ @ 115.00 USD) Rabbit polyclonal antibody FAKpY397 (Biosource No. 44624 @ 315 , 00 USD) ChromePure Rabbit IgG, complete molecule (Jackson Laboratories No. 001-000-003 @ 60/25 mg USD) Mouse Monoclonal Antibody UBI aFAK clone 2A7 (Upstate No. 05-182 @ 289.00 USD) IgG goat anti-mouse AffiniPure conjugated with peroxidase (Jackson Labs No. 115-035-146 @ 95/1, 5 ml USD) SuperBIock TBS (Pierce Product No. 37535ZZ @ 99 USD) Bovine Serum Albumin (Sigma No. A-9647 @ 117.95 / 100 g USD) TMB Peroxidase Substrate (Oncogene Research Products N ° CL07-100 ml @ 40.00 USD) Na3V04 Sodium Orthovanadate (Sigma No. S6508 @ 43.95 / 50 g USD) MTT Substrate (Sigma No. M-2128 @ 25.95 / 500 mg USD) Culture Media: DMEM + 10% FBS, P / S , Glu, 750 μg / ml Zeocin and 50 μg / ml Hygromycin (Zeocin Inogen No. R250-05 @ 725 USD and Inogen Hygromycin No. R220-05 @ 150 USD) Mifepristone Inogen No. H110-01 @ 125 USD Sediment Inhibitor of Protease CompleteTM without EDTA Boehringer Mannheim No. 1873580 FAK protocol based on cells for kinase dependent phosphoFAKY397 selecti Procedure: An inducible cell-based FAK assay was developed in ELISA format for the screening of chemical materials to identify specific tyrosine kinase inhibitors. The cell-based assay exploits the mechanism of the GeneSwitch ™ system (Inogen) to exogenously control the expression and phosphorylation of FAK and the kinase dependent autophosphorylation site on the Y397 moiety. Inhibition of kinase-dependent autophosphorylation in Y397 results in a reduced absorbance signal at OD450. The signal is typically 0.9 to 1.5 units at OD450 with noise within the range of 0.08 to 0.1 units of DO450. The values are presented as IC50, concentration in μM. On day 1, cultivate A431 »FAKwt in T175 flasks. The day before performing the cell-based FAK Assay, sow A431"FAKwt cells in culture media in 96-well bottom-U plates. Allow the cells to deposit at 37 ° C, 5% C02 for 6 days. at 8 hours before the induction of FAK. Prepare 10 μM Mifepristone stock solution in 100% Ethanol. The stock solution is subsequently diluted to 10x of the final concentration in Culture Media. Transfer 10 μl of this dilution (final concentration of 0.1 nM Mifepristone) to each well. Allow the cells to settle at 37 ° C, 5% C02 overnight (12 to 16 hours). In addition, prepare control wells without induction with Mifepristone for the expression and phosphorylation of FAK. On day 2, coat goat anti-rabbit plate (s) with 3.5 μg / ml of phospho-specific FAKpY397 polyclonal antibody prepared in TBS SuperBIock buffer, and allow to stir the plate (s) on a plate shaker at room temperature. environment for 2 hours. Optionally, the control wells can be coated with 3.5 μg / ml of control Capture antibody (complete rabbit IgG molecules) prepared in TBS SuperBIock. Remove by washing the excess FAKpY397 antibody 3 times using buffer. Block the plate (s) coated with Anti-FAKpY397 with 200 μl per well of Buffer 3% BSA / 0.5% Tween for 1 hour at room temperature on the plate shaker. While the plate (s) are blocked, prepare stock solutions of the 5 mM compound in 100% DMSO. The stock solutions are subsequently diluted in series at 100x of the final concentration in 100% DMSO. Prepare a 1:10 dilution using the 100X solution in Culture Media and transfer 10 μl of the appropriate compound dilutions to each well containing the A431 control cells not induced or induced with FAK for 30 minutes at 37 ° C, C02 al 5%. Prepare RIPA Lysis Buffer (50 mM Tris-HCl, pH 7.4, 1% NP-40, 0.25% Na-deoxycholate, 150 mM NaCl, 1 mM EDTA, 1 mM Na3V04, 1 mM NaF, and a CompleteTM protease inhibitor sediment without EDTA per 50 ml of solution). At the end of the 30 minutes of compound treatment, remove by washing the compound 3 times using TBS-T wash buffer. Strain the cells with 100 μl / well of RIPA buffer. To the coated plate, remove the blocking buffer and wash 3 times using TBS-T Wash Buffer. Using a 96-well automated microdispenser, transfer 100 μl of whole cell lysate (from step 6) to the plate (s) coated with the goat anti-rabbit FAKpY397 to capture phosphoFAKY397 proteins. Stir at room temperature for 2 hours. Remove by washing the unbound proteins 3 times using TBS-T Wash Buffer. Prepare 0.5 μg / ml (1: 2000 dilution) of UBI aFAK detection antibody in 3% BSA blocking buffer / 0.5% Tween. Dispense 100 μl of UBI aFAK solution per well and shake for 30 minutes at room temperature. Remove by washing the excess UBI aFAK antibody 3 times using TBS-T Wash Buffer. Prepare 0.08 μg / ml (1: 5000 dilution) of anti-mouse secondary antibody conjugated with peroxidase (Anti-2MHRP). Dispense 100 μl per well of the Anti-2MHRP solution and shake for 30 minutes at room temperature. Remove by washing the excess Anti-2MHRP antibody 3 times using TBS-T Wash Buffer. Add 100 μl per well of TMB substrate solution at room temperature to allow color development. Stop the TMB reaction with 100 μl per well of TMB Stop Solution (0.09 M H2SO4) and quantify the signal by absorbance measurement at 450 nm on the BioRad microplate reader. Additional FAK cellular assays are incorporated herein by reference from Pfizer Attorney Docket N °. PC11699 titled "INDUCIBLE FOCAL ADHESION KINASE CELL ASSAY". In a preferred embodiment, the compounds of the present invention have an in vitro activity as determined by a kinase assay, for example, as described in this document, less than 500 nM. Preferably, the compounds have an IC50 of less than 25 nM in the kinase assay, and more preferably less than 10 nM. In a further preferred embodiment, the compounds show an IC50 in a cell-based FAK Assay, for example, such as that described herein, of less than 1 μM, more preferably less than 100 nM, and most preferably less than 25 nM. In vitro activity of Aurora-2: The in vitro activity of the compounds of the invention can be determined by the following procedure. This assay measures the activity of recombinant Aurora-2 kinase (AUR2), specifically the phosphorylation of a peptide substrate, and the potency of the Aurora-2 kinase inhibitors. The product (phosphorylated peptide) is measured by the use of a scintillation proximity assay (SPA). The peptidic substrate is incubated with gamma 33P-ATP and enzyme and after the designated time the peptide is captured in a streptavidin SPA bead and the degree of phosphorylation is measured by scintillation counting. Inhibition is evaluated based on the ability of the inhibitor to reduce phosphorylation relative to the reaction without inhibitor. The Aurora-2 kinase used in the assay is a full-length human protein that incorporates an H-S6 sequence at the N-terminus to facilitate purification. The gene encoding this sequence was incorporated into a baculovirus and the virus was used to infect insect SF9 cells in culture. The recombinant protein was purified by nickel-agarose affinity chromatography by standard procedures. The reactions are carried out in a volume of 50 μl constituted by 25 ng of Aurora-2 protein, 50 mM Tris pH 8, 10 mM MgCl 2, 1 mM dithiothreitol, 0.1 mM NaV04, 0.02% Bovine Serum Albumin, 10 μM ATP, 33 P-ATP 0.03 μCi, and biotin- (LRRWSLG) 4 2 μM in wells of a 96-well microplate with transparent bottom and anti-junction surface (Wallac Isoplate Cat 1450-514). The compounds are initially dissolved in DMSO, then diluted in 50 mM Tris pH 8, 10 mM MgCl 2, 1 mM dithiothreitol, 0.1 mM NaVO, 0.02% Bovine Serum Albumin so that the addition of 5 μl to each well produces the desired final concentration. The reaction is carried out at room temperature for 45 min with gentle agitation, then stopped by the addition of 30 μL of Stop Buffer (0.3 mg streptavidin beads from SPA (Amersham), water: phosphate buffered saline 1: 1 (0.2 g / l KCl, 0.2 g / l KH2P04 , 8 g / l of NaCl, 1.15 g / l of Na2HP04), 0.5% Triton-X, 75 mM EDTA, 375 μM ATP). Cesium chloride (100 μl, 7.5 M) is added to each well, the beads are allowed to settle overnight and scintillation counts are performed in a Wallac Mycrobeta Trilux counter. For each one, a baseline correction is made to a zero time reaction. The potency of the compound is determined as the cntration of inhibitor that produces 50% inhibition relative to the control reaction (without compound), i.e., IC50. In vitro activity for HgK: 0 The in vitro activity of the compounds of the invention for HgK can be determined by the following procedure using purified recombinant GST-HGK (produced by baculovirus expression in insect cells) and with peptide No. 1345, KRTLRRKRTLRRKRTLRR produced by Sugen and New England Peptide (without biotin brand) as a substrate. The following reagents were also used: 15 Tris 100 mM MnCl 2 5 mM MgCl 2 5 mM NaCl 200 mM CHAPS 0.8 mM 20 DTT 1 mM 10 mM NaF 10% Glycerol ATP / Peptide mixture in HGK Buffer: eg 2 μM ATP (final assay cntration 1 μM) Peptide 1345A 40 μM (final assay cntration 20 μM) 1. Add 10 μl / well of a 384-well Whatman white plate (N ° 7701-3100) using a Titertek Multi-drop. 2. Add 0.5 μl of drug from an HTS compressed drug plate using a Tomtec liquid handler. 3. Prepare HGK enzyme in 400 nM HGK buffer (200 nM final assay cntration). Add 10 μl per well using 4. Apricot Soken. (Add only white buffer to control wells G and H 13-18) 5. Incubate at 37 ° C for one hour, or until the assay has developed to 70% at room temperature. Add 10 μl of Pro-mega 6. Luciferase reagent that has been diluted 1: 3 in a 100 mM Tris buffer, 5 mM MgCl 2, and is at room temperature. 7. Read the luminescence in an LJL analyst (Molecular Devices, Sunnyvale, CA). In vitro activity to inhibit osteoporosis and / or low bone mass: In addition, the following test (s) can be used to evaluate the ability of a compound of the present invention to inhibit osteoporosis and / or low bone mass, as described above. ^ (1) Effect of Test Compound on Body Weight. Body Composition v Bone Density in the Intact and Ovarectomized Agitated Rat Female This assay can be used to test the effects of a test compound on an aged, intact or ovariectomized rat (OVX) female model. Study Protocol 0 An operation of Sprague-Dawley rat females or OVX at 18 months of age is simulated, while a group of rats is necropsied on day 0 to serve as reference controls. One day after surgery, the rats are treated with vehicle or test compound. The vehicle or test compound is administered twice a week (Tuesday and Friday) by subcutaneous injection (sc), with the test compound being administered at an average dose of 10 5 milligrams per kilogram of body weight per day (10 mg / kg /day). All rats are given s.c. of 10 mg / kg of calcein (Sigma, St. Louis, MO) for fluorescence bone markers 2 and 12 days before the necropsy. On the day of necropsy, all rats under anesthesia with ketamine / xylazine are weighed and subjected to dual-energy x-ray absorptiometry (DXA, QDR-4500 / W, Hologic Inc., Waltham, MA) equipped with Rat Whole Body Sean software for the determination of lean body mass and fat. The rats are necropsied, then the autopsy is performed and blood is obtained by cardiac puncture. The distal femoral metaphysis and the femoral diaphysis of each rat are analyzed by means of peripheral quantitative computed tomography (pQCT), and the mineral content of the cortical and trabecular and total volumetric bone are determined. Peripheral quantitative computed tomography (pQCT) scan: extirpated femurs are scanned by a x-ray pQCT machine (Stratec XCT Research M, Norland Medical Systems, Fort Atkinson, Wl.) With a software version 5.40. A cross section of 1 millimeter (mm) in thickness from the metaphysis of the femur to 5.0 mm (proximal femoral metaphysis, a primary cancellous bone site) and 13 mm (femoral diaphysis, a cortical bone site) proximal to the distal end is taken with a voxel size of 0.10 mm. The cortical bone is defined and analyzed using mode 2 of contour and cortical mode 4. An external threshold setting of 340 mg / cm3 is used to distinguish cortical cortex from soft tissue and an internal threshold of 529 mg / cm3 to distinguish cortical bone along the endocortical surface. Trabecular bone is determined using mode 4 of skin with a threshold of 655 mg / cm3 to distinguish (sub) cortical bone from cancellous bone. An additional concentric shell of 1% of the defined cancellous bone is used to ensure that the (sub) cortical bone is removed from the analysis. The volumetric content, density and area are determined for trabecular and cortical bone (Jamsa T. et al., Bone 23: 155-161, 1998; Ke, HZ et al., Journal of Bone and Mineral Research, 16: 765- 773, 2001). Vaginal histology: vaginal tissue is fixed and included in paraffin. 5 micron sections are cut and stained with alcian blue stain. A histological examination of the thickness of the vaginal luminal epithelium and mucopolysaccharide (secreted cells) is performed. The experimental groups for the protocol are as follows: Group I: Reference controls Group II: Drill + Vehicle Group III: OVX + Vehicle Group IV: OVX + Test compound at 10 mg / kg / day (in Vehicle) (2) Fracture Cure Tests (a) Fracture Healing Effects Test After Systemic Administration Fracture Technique: 3-month-old Sprague-Dawley rats are anesthetized with Ketamine. An incision of 1 cm is made on the anteromedial side of the proximal part of the right tibia or femur. The following describes the tibial surgical technique. The incision is made through the bone, and a 1 mm, 4 mm hole is drilled proximal to the distal side of the tibial tuberosity and 2 mm medial to the anterior crest. An intramedullary fixation with nails is made with a 0.8 mm stainless steel tube (maximum load 36.3 N, maximum rigidity 61, 8 N / mm, tested under the same conditions as bones). Reaming of the medullary canal is not performed. A conventional closed fracture 2 mm above the tibioperion junction is produced by a three-point bend using an adjustable forceps specially designed with blunt mandibles. To minimize damage to the soft tissue, care is taken not to displace the fracture. The skin is closed with nylon monofilament sutures. The operation is performed under sterile conditions. X-rays of all fractures are taken immediately after fixation, and rats with fractures outside the specified diaphyseal area or with displaced fixations are excluded. The remaining animals are divided at random into the following groups with 10-12 animals per subgroup per time point to test fracture healing. The first group receives daily dosing of vehicle by tube (water: 100% Ethanol = 95: 5) at 1 ml / rat, while the others receive daily dosing per tube of 0.01 to 100 mg / kg / day of the compound to be tested (1 ml / rat) for 10, 20, 40 and 80 days. In days 10, 20, 40 and 80, 10-12 rats from each group are anesthetized with Ketamine and sacrificed by exsanguination. Tibioperoeres bones are removed by dissection and all soft tissue is removed. Bones of 5-6 rats are stored for each group in 70% ethanol for histological analysis, and bones of another 5-6 rats are stored for each group in a buffered Ringer's solution (+ 4 ° C, pH 7.4) for radiographs and biomechanical tests that are performed. Histological analysis: The procedures for histological analysis of fractured bone have been previously published by Mosekilde and Bak (The Effects of Growth Hormone on Fracture Healing in Rats: A Histological Description. Bone, 14: 19-27, 1993). In summary, the fracture site is sawed 8 mm on each side of the fracture line, included without decalcification in methymethacrylate, and frontal sections are cut in a Reichert-Jung Polycut microtome in 8 μm thickness. The mid-frontal sections stained with Masson's Trichrome (including tibia and fibula) are used for the visualization of the cellular and tissue response to the healing of fractures with and without treatment. The sections stained with Sirius red are used to demonstrate the characteristics of the callus structure and to differentiate between fibrous bone and lamellar bone at the fracture site. The following measurements are made: (1) fracture gap - measured as the shortest distance between the ends of cortical bone in the fracture, (2) callus length and callus diameter, (3) area of total bone volume of the callus , (4) bone tissue by area of tissue within the callus area, (5) fibrous tissue in the callus, and (6) area of cartilage in the callus. Biomechanical Analysis: Procedures for biomechanical analysis have been previously published by Bak and Andreassen (The Effects of Aging on Fracture Healing in Rats, Calcif Tissue Int 45: 292-297, 1989). In summary, radiographs of all fractures are taken before the biomechanical test. The mechanical properties of healing fractures are analyzed by a three or four point destructive bending procedure. Maximum load, stiffness, energy at maximum load, deviation at maximum load, and maximum stress are determined, (a) Effects Test on Fracture Cure After Local Administration Fracture technique: in the study, female beagle dogs or male dogs are used. approximately two years of age under anesthesia. Transverse radial fractures occur slowly and continuously bending at three points as described by Lenehan et al. (Lenehan, T. M .; Balligand, M .; Nunamaker, D.M .; Wood, F.E .: Effects of EHDP on Fracture Healing in Dogs, J Orthop Res 3: 499-507, 1985). A wire is pulled through the fracture site to ensure complete anatomical separation of the bone. Next, local delivery of prostaglandin agonists to the fracture site is achieved by slow release of the delivered compound by slow release pellets or by administration of the compounds in a suitable formulation such as a gel solution or suspension in paste for 10.15, or 20 weeks.

Histological analysis: The procedures for histological analysis of fractured bone have been previously published by Peter et al. (Peter, CP, Cook, WO, Nunamaker, DM, Provost, MT, Seedor, JG, Rodan, GA, Effects of alendronate on fracture healing and bone remodeling in dogs, J. Orthop, Res. 14: 74-70, 1996). and Mosekilde and Bak (The Effects of Growth Hormone on Fracture Healing in Rats: A Histological Description, Bone, 14: 19-27, 1993). In summary, after sacrifice, the fracture site is sawed 3 cm on each side of the fracture line, included without decalcification in methymethacrylate, and frontal sections are cut in a Reíchert-Jung Polycut microtome in 8 μm thickness. The mid-frontal sections stained with Masson's Trichrome (including tibia and fibula) are used for the visualization of the cellular and tissue response to the healing of fractures with and without treatment. The sections stained with Sirius red are used to demonstrate the characteristics of the callus structure and to differentiate between fibrous bone and lamellar bone at the fracture site. The following measurements are made: (1) fracture gap - measured as the shortest distance between the ends of cortical bone in the fracture, (2) callus length and callus diameter, (3) area of total bone volume of the callus , (4) bone tissue by area of tissue within the callus area, (5) fibrous tissue in the callus, (6) area of cartilage in the callus. Biomechanical analysis: Procedures for biomechanical analysis have been previously published by Bak and Andreassen (The Effects of Aging on Fracture Healing in Rats, Calcif Tissue Int 45: 292-297, 1989) and Peter et al. (Peter, C.P.; Cook, W.O .; Nunamaker, DM .; Provost, M. T .; Seedor, J.G .; Rodan, G.A. Effects of Alendronate On Fracture Healing And Bone Remodeling In Dogs. J. Orthop. Res. 14: 74-70,1996). In summary, radiographs of all fractures are taken before the biomechanical test. The mechanical properties of healing fractures are analyzed by a three or four point destructive bending procedure. Maximum load, rigidity, energy at maximum load, deviation at maximum load, and maximum stress are determined. Methods for treating abnormal cell growth in a mammal This invention also relates to a method for treating abnormal cell growth in a mammal, including a human, which comprises administering to said mammal an amount of a compound of the invention, as has previously defined, or a pharmaceutically acceptable salt, solvate or prodrug thereof, which is effective to treat abnormal cell growth. In one embodiment of this method, abnormal cell growth is cancer, including, but not limited to, lung cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous or intraocular melanoma, uterine cancer , ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, fallopian tube carcinoma, endometrial carcinoma, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, soft tissue sarcoma, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, bladder cancer, kidney or ureter cancer, renal cell carcinoma, carcinoma d e the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, or a combination of one or more of the above cancers. In one embodiment the method comprises administering to a mammal an amount of a compound of the invention that is effective to treat said cancerous solid tumor. In a preferred embodiment, the solid tumor is cancer of the breast, lung, colon, brain, prostate, stomach, pancreas, ovary, skin (melanoma), endocrine, uterine, testicular, and bladder. In another embodiment of said method, said abnormal cell growth is a benign proliferative disease, including, but not limited to, psoriasis, benign prostatic hypertrophy or restenosis. This invention also relates to a method for treating abnormal cell growth in a mammal comprising administering to said mammal an amount of a compound of the invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof, which is effective to treat abnormal cellular growth together with an antitumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, cell growth inhibitors, cycle inhibitors cellular, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxic, anti-hormones, and anti-androgens. This invention also relates to a pharmaceutical composition for the treatment of abnormal cell growth in a mammal, including a human, comprising an amount of a compound of the invention, as defined above, or a salt, solvate or prodrug of the same pharmaceutically acceptable, which is effective to treat abnormal cell growth, and a pharmaceutically acceptable carrier. In one embodiment of said composition, said abnormal cell growth is cancer, including, but not limited to, lung cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous or intraocular melanoma, uterine cancer , ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, fallopian tube carcinoma, endometrial carcinoma, carcinoma of the cervix, carcinoma of the uterus vagina, carcinoma of the vulva. Hodgkin's disease, esophageal cancer, small bowel cancer, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, soft tissue sarcoma, cancer of the urethra, cancer of the penis, cancer of prostate, chronic or acute leukemia, lymphocytic lymphomas, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis carcinoma, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, or a combination of one or more of the above cancers. In another embodiment of said pharmaceutical composition, said abnormal cell growth is a benign proliferative disease, including, but not limited to, psoriasis, benign prostatic hypertrophy or restenosis. This invention also relates to a method for treating abnormal cell growth in a mammal comprising administering to said mammal an amount of a compound of the invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof, which is effective to treat abnormal cell growth together with another anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, cell growth inhibitors, cycle inhibitors cellular, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxic, anti-hormones, and anti-androgens. The invention also includes a pharmaceutical composition for treating abnormal cell growth in which the composition includes a compound of the invention, as defined above, or a pharmaceutically acceptable salt, solvate or prodrug thereof, which is effective in treating abnormal cell growth. , and another anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, cell growth inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxic, anti-hormones, and anti-androgens. This invention also relates to a method for the treatment of a disorder associated with angiogenesis in a mammal, including a human, which comprises administering to said mammal an amount of a compound of the invention, as defined above, or a salt thereof. , solvate or prodrug thereof pharmaceutically acceptable, which is effective to treat said disorder together with one or more anti-tumor agents listed above. Such disorders include cancerous tumors such as melanoma; ocular disorders such as age-related macular degeneration, presumed ocular hystoplasmosis syndrome, and retinal neovascularization from proliferative diabetic retinopathy; rheumatoid arthritis; bone loss disorders such as osteoporosis, Paget's disease, hypercalcemia or humoral malignancy, hypercalcemia of matastatic tumors in the bone, and osteoporosis induced by treatment with glucocorticoids; coronary restenosis; and certain microbial infections including those associated with microbial pathogens selected from adenoviruses, hantaviruses, Borrelia burgdorferi, Yersinia spp., Bordetella pertussis, and group A Streptococcus. This invention also relates to a method for (and a pharmaceutical composition for) treating growth abnormal cell in a mammal comprising an amount of a compound of the invention, or a pharmaceutically acceptable salt, soivate or prodrug thereof, together with an amount of one or more substances selected from anti-aging agents. angiogenesis, inhibitors of signal transduction, and antiproliferative agents, amounts that together are effective in treating such abnormal cell growth. Anti-angiogenesis agents, such as inhibitors of MMP-2 (matrix metalloproteinase 2), inhibitors of MMP-9 (matrix metalloproteinase 9), and COX-II (cyclooxygenase II) inhibitors, together with a compound of the invention in the methods and pharmaceutical compositions described herein. Examples of useful COX-II inhibitors include CELEBREX ™ (celecoxib), Bextra (valdecoxib), paracoxib, Vioxx (rofecoxib), and Arcoxia (etoricoxib). Examples of useful matrix metalloproteinase inhibitors are described in WO 96/33172 (published October 24, 1996), WO 96/27583 (published March 7, 1996), European Patent Application No. 97304971, 1 (filed July 8, 1997), European Patent Application No. 99308617.2 (filed October 29, 1999), WO 98/07697 (published February 26, 1998), WO 98/03516 (published January 29, 1998), WO 98/34918 (published August 13, 1998). ), WO 98/34915 (published August 13, 1998), WO 98/33768 (published August 6, 1998), WO 98/30566 (published July 16, 1998), European Patent Publication No. 606,046 (published July 13, 1994), European Patent Publication No. 931,788 (published July 28, 1999), WO 90/05719 (published May 31, 1990), WO 99/52910 (published on May 21, 1999). October 1999), WO 99/52889 (published October 21, 1999), WO 99/29667 (published June 17, 1999), PCT International Application No. PCT / IB98 / 01113 (filed July 21, 1998), European Patent Application No. 99302232.1 (filed March 25, 1999), British Patent Application No. 9912961.1 (filed June 3, 1999), United States Provisional Application No. 60 / 148,464 (filed August 12, 1999), U.S. Patent No. 5,863,949 (issued January 26, 1999), U.S. Patent No. 5,861,510 (issued January 19, 1999) , and European Patent Publication No. 780,386 (published June 25, 1997), all of which are incorporated herein by reference in their entirety. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1. More preferred are those that selectively inhibit MMP-2 and / or MMP-9 relative to the other matrix metalloproteinases (ie MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13). Some specific examples of MMP inhibitors useful together with the compounds of the present invention are AG-3340, RO 32-3555, RS 13-0830, and the compounds listed in the following list: 3 - [[4- (4- fluoro-phenoxy) -benzenesulfonyl] - (1-hydroxycarbamoyl-cyclopentyl) -amino] -propionic; Hydroxyamide of 3-exo-3- [4- (4-fluoro-phenoxy) -benzenesulfonylamino] -8-oxa-bicyclo [3.2.1] octane-3-carboxylic acid; (2R, 3R) 1- [4- (2-Chloro-4-fluoro-benzyloxy) -benzenesulfonyl] -3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide; 4- [4- (4-Fluoro-phenoxy) -benzenesulfonyl-amino] -tetrahydro-pyran-4-carboxylic acid hydroxyamide; 3 - [[4- (4-Fluoro-phenoxy) -benzenesulfonyl] - (1-hydroxycarbamoyl-cyclobutyl) -amino] -propionic acid; Hydroxyamide of 4- [4- (4-chloro-phenoxy) -benzenesulfonylamino] -tetrahydro-pyran-4-carboxylic acid; 3- [4- (4-Chloro-phenoxy) -benzenesulfonylamino] -tetrahydro-pyran-3-carboxylic acid hydroxyamide; (2R, 3R) 1- [4- (4-Fluoro-2-methyl-benzyloxy) -benzenesulfonyl-3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide; 3 - [[4- (4-Fluoro-phenoxy) -benzenesulfonyl] - (1-hydroxycarbamoyl-1-methyl-ethyl) -amino] -propionic acid; 3 - ([4- (4-Fluoro-phenoxy) -benzenesulfonyl] - (4-hydroxycarbamoyl-tetrahydro-pyran-4-yl) -aminoj-propionic acid; 3-exo-3- [4- (4) hydroxyamide -chloro-phenoxy) -benzenesulfonylamino] -8-oxa-bicyclo [3.2.1] octane-3-carboxylic acid; Hydroxyamide 3-endo-3- [4- (4-fluoro-phenoxy) -benzenesulfonylamino] -8-oxa-bicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide; and Hydroxyamide of 3- [4- (4-fluoro-phenoxy) -benzenesulfonylamino] -tetrahydro-furan-3-carboxylic acid; And pharmaceutically acceptable salts, solvates and prodrugs of said compounds. VEGF inhibitors, eg, SU-11248, SU-5416 and SU-6668 (Sugen Inc. of South San Francisco, California, USA), can also be combined with a compound of the invention. VEGF inhibitors are described in, for example, WO 99/24440 (published May 20, 1999), PCT International Application No. PCT / IB99 / 00797 (filed May 3, 1999, 1999), in WO 95/21613 (published August 17, 1995), WO 99/61422 (published December 2, 1999), U.S. Patent No. 5,834,504 (issued November 10, 1998), WO 98/50356 (published November 12, 1998), U.S. Patent No. 5,883,113 (issued March 16, 1999), U.S. Patent No. 5,886,020 (issued March 23, 1999), U.S. Pat. United States No. 5,792,783 (issued August 11, 15, 1998), United States Patent No. US 6,653,308 (issued November 25, 2003), WO 99/10349 (published March 4, 1999), WO 97/32856 (published September 12, 1997), WO 97/22596 (published on 26). June 1997), WO 98/54093 (published December 3, 1998), WO 98/02438 (published January 22, 1998), WO 99/16755 (published April 8, 1999), and WO 98/02437 (published January 22, 1998), all of which are incorporated herein by reference in their entirety. Other examples of specific VEGF inhibitors are IM862 (Cytran Inc. of Kirkland, Washington, USA); Avastin, an anti-VEGF monoclonal antibody from Genentech, Inc. of South San Francisco, California; and angiozyme, a synthetic ribozyme from Ribozyme (Boulder, Colorado) and Chiron (Emeryville, California). Inhibitors of the ErbB2 receptor, such as GW-282974 (Glaxo Wellcome foot), and monoclonal antibodies AR-209 (Aronex Pharmaceuticals Inc. of The Woodlands, Texas, USA) and 2B-1 (Chiron) can be administered together with a compound of the invention. Such erbB2 inhibitors include Herceptin, 2C4, and pertuzumab. Such erbB2 inhibitors include those described in WO 98/02434 (published January 22, 1998), WO 99/35146 (published July 15, 1999), WO 99/35132 (published July 15, 1999), WO 98/02437 (published January 22, 1998), WO 97/13760 (published April 17, 1997). ), WO 95/19970 (published July 27, 1995), U.S. Patent No. 5,587,458 (issued December 24, 1996), and U.S. Patent No. 5,877,305 (issued March 2, 1995). 1999), each of which is incorporated herein by reference in its entirety. The ErbB2 receptor inhibitors useful in the present invention are also described in the Application Provisional of the United States N °. 60 / 117,341, filed on January 27, 1999, and on Application Provisional of the United States N °. 60 / 117,346, filed on January 27, 1999, that both are incorporated herein by reference in their entirety. Other receptor inhibitors ErbB2 include TAK-165 (Takeda) and GW-572016 (Glaxo-Wellcome). Various different compounds, such as styrene derivatives, have also been shown to possess tyrosine kinase inhibitory properties, and some of the tyrosine kinase inhibitors have been identified as inhibitors of the ErbB2 receptor. More recently, five European patent publications, specifically EP 0 566 226 A1 (published on October 20, 1993), EP 0 602 851 A1 (published on June 22, 1994), EP 0 635 507 A1 (published on January 25, 1995), EP 0 635 498 A1 (published on January 25, 1995), and EP 0 520 722 A1 (published December 30, 1992), refer to certain bicyclic derivatives, in particular quinazoline derivatives, which possess anti-cancer properties resulting from their tyrosine kinase inhibitory properties. In addition, World Patent Application WO 92/20642 (published November 26, 1992), refers to certain aryl and heteroaryl bis-mono compounds and bicyclics as tyrosine kinase inhibitors that are useful in inhibiting abnormal cell proliferation. The World Patent Applications WO96 / 16960 (published June 6, 1996), WO 96/09294 (published March 6, 1996), WO 97/30034 (published August 21, 1997), WO 98/02434 (published January 22, 1998), WO 98/02437 (published January 22, 1998), and WO 98/02438 (published January 22, 1998), also refer to derivatives substituted bicyclic heteroaromatics as tyrosine kinase inhibitors that are useful for the same purpose. Other patent applications that refer to anti-cancer compounds are the World Patent Application WO00 / 44728 (published August 3, 2000), EP 1029853A1 (published August 23, 2000), and WO01 / 98277 (published December 12, 2001) all of which are incorporated herein by reference in their entirety. Other antiproliferative agents that can be used with the compounds of the present invention include inhibitors of the enzyme farnesylprotein transferase and inhibitors of the tyrosine kinase receptor PDGFr, including the compounds described and claimed in the following U.S. Patent Applications: 09/221946 (filed on December 28, 1998); 09/454058 (filed December 2, 1999); 09/501163 (filed on February 9, 2000); 09/539930 (filed on March 31, 2000); 09/202796 (filed on May 22, 1997); 09/384339 (filed on August 26, 1999); and 09/383755 (filed August 26, 1999); and the compounds described and claimed in the following Provisional U.S. Patent Applications: 60/168207 (filed November 30, 1999); 60/170119 (filed December 10, 1999); 60/177718 (filed January 21, 2000); 60/168217 (filed on November 30, 1999), and 60/200834 (filed May 1, 2000). Each of the above patent applications and provisional patent applications is incorporated herein by reference in its entirety. A compound of the invention can be used with other agents useful for treating abnormal cell growth or cancer, including, but not limited to, agents capable of enhancing antitumor immune responses, such as CTLA4 (cytotoxic lymphocyte antigen 4) antibodies, and other agents capable of block CTLA4; and anti-proliferative agents such as other farnesylprotein transferase inhibitors, for example the famesylprotein transferase inhibitors described in the references cited in the "Background" section, supra. Specific CTLA4 antibodies that can be used in the present invention include those described in United States Provisional Application 60 / 113,647 (filed December 23, 1998) which is incorporated herein by reference in its entirety. A compound of the invention can be applied as an exclusive therapy or it can involve one or more different anti-tumor substances, for example those selected from, for example, mitotic inhibitors, for example vinblastine; alkylating agents, for example cis-platinum, oxaliplatin, carboplatin and cyclophosphamide; anti-metabolites, for example 5-fluorouracil, capecitabine, cytosine arabinoside and hydroxyurea, or, for example, one of the preferred anti-metabolites described in European Patent Application No. 239362 such as acid? / - (5 - [? / - (3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl) - / V-methylamino) -2-tenoyl) -L-glutamic; cell growth inhibitors; cell cycle inhibitors; intercalating antibiotics, for example adriamycin and bleomycin; enzymes, for example interferon; and anti-hormones, for example anti-estrogens such as Nolvadex (tamoxifen) or, for example, anti-androgens such as Casodex (4'-cyano-3- (4-fluorophenylsulfonyl) -2-hydroxy-2) -metl-3 '- (trifluoromethyl) propiononilide). The compounds of the present invention may be used alone or together with one or more of a variety of anti-cancer agents or treatment support agents. For example, the compounds of the present invention can be used with cytotoxic agents, for example, one or more selected from the group consisting of a camptothecin, irinotecan HCl (Camptosar), derecaline, SU-11248, epirubicin (Ellence), docetaxel (Taxotere). ), paclitaxel, rituximab (Rituxan) bevacizumab (Avastin), imatinib mesylate (Gleevac), Erbitux, gefitinib (Iressa), and combinations thereof. The invention also includes the use of the compounds of the present invention in conjunction with hormone therapy, for example, exemestane (Aromasin), Lupron, anastrozole (Arimidex), tamoxifen citrate (Nolvadex), Trelstar, and combinations thereof. In addition, the invention provides a compound of the present invention alone or together with one or more treatment support products, for example, a product selected from the group consisting of Filgrastim (Neupogen), ondansetron (Zofran), Fragmin, Procrit, Aloxi, Emend, or combinations thereof. Such joint treatment can be achieved by means of the simultaneous, sequential or separate dosing of the individual components of the treatment. The compounds of the invention can be used with antitumor agents, alkylating agents, antimetabolites, antibiotics, antitumor agents obtained from plants, camptothecin derivatives, tyrosine kinase inhibitors, antibodies, interferons, and / or biological response modifiers. In this regard, the following is a non-limiting list of examples of secondary agents that can be used with the compounds of the invention. • Alkylating agents include, but are not limited to, nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, melphalan, busulfan, mitobronitol, carboquone. thiotepa, ranimustine, nimustine, temozolomide, AMD-473, altretamine, AP-5280, apaziquone, brostallicin, bendamustine, carmustine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, mafosfamide, and mitolactol; alkylating compounds coordinated with platinum include but are not limited to cisplatin, carbopiatin, eptaplatin, lobaplatin, nedaplatin, oxaliplatin or satrplatin; • Antimetabolites include, but are not limited to, methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil (5-FU) alone or together with leucovorin, tegafur, UFT, doxifluridine, carmofur, cytarabine, cytarabine ocphosphate, enocythabin, S -1, gemcitabine, fludarabin, 5-azacytidine, capecitabine, cladribine, clofarabine, decitabine, eflornithine, ethynylcytidine, cytosine arabinoside, hydroxyurea, TS-1, melphalan, nelarabine, nolatrexed, ocphosphate, premetrexed disodium, pentostatin, pelitrexol, raltitrexed, triapine, trimetrexate, vidarabine, vincristine, vinorelbine; or for example, one of the preferred anti-metabolites described in European Patent Application No. 239362 such as W- (5- [V- (3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl) -W-methylamino] -2-tenoyl) -L-glutamic acid; • Antibiotics include but are not limited to: aclarubicin, actinomycin D, amrubicin, annamicin, bleomycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin, galarubicin, idarubicin, mitomycin C, nemorubicin, neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimalamer, streptozocin, valrubicin or zinostatin; • Hormone therapy agents, for example, exemestane (Aromasin), Lupron, anastrozole (Arimidex), doxercalciferol, fadrozole, formestane, anti-estrogens such as tamoxifen citrate (Nolvadex) and fulvestrant, Trelstar, toremifene, raloxifene, lasofoxifene, letrozole (Femara), or anti-androgens such as bicalutamide, flutamide, mifepristone, nilutamide, Casodex® (4'-cyano-3- (4-fluorophenylsulfonyl) -2-hydroxy-2-methyl-3 '- (trifluoromethyl) propionanilide) and combinations thereof; • Anti-tumor substances obtained from plants include, for example, those selected from mitotic inhibitors, for example vinblastine, docetaxel (Taxotere) and paclitaxel; • Cytotoxic topoisomerase inhibiting agents include one or more agents selected from the group consisting of aclarubicin, amonafide, belotecan, camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, diflomotene, irinotecan HCl (Camptosar), edecaline, epirubicin (Ellence), etoposide, exatecano, gimatecano, lurtotecano, mitoxantrone, pirarubicin, pixantrone, rubitecan, sobuzoxane, SN-38, tafluposide, and topotecan, and combinations thereof; • Immunological substances include interferons and many other immunity enhancing agents. The interferons include interferon alpha, interferon alpha-2a, interferon, alpha-2b, interferon beta, interferon gamma-1a or interferon gamma-n1. Other agents include PF3512676, filgrastim, (entinan, sizofilan, TheraCys, ubenimex, WF-10, aldesleukin, alemtuzumab, BAM-002, dacarbazine, daclizumab, denileuquine, gemtuzumab ozogamycin, britumomab, imiquimod, lenograstim, lentinan, melanoma vaccine ( Corixa), molgramostim, OncoVAX-CL, sargramostim, tasonermin, tecleuquine, timalase, tositumomab, Vulizizine, Z-100, epratuzumab, mummomab, oregovomab, pemtumomab, Provenge • Biological response modifiers are agents that modify defense mechanisms of living organisms or biological responses, such as survival, growth, or differentiation of tissue cells to direct them to have antitumor activity.These agents include krestin, lentinan, sizofiran, picibanil, or ubenimex; • Other anticancer agents include alitretinoin, ampligen, atrasentan bexarotene, bortezomib, bosentan, calcitriol, exisulínd, finasteride, fotemustine, ibandronic acid, m iltefosine, mitoxantron, l-asparaginase, procarbazine, dacarbazine, hydroxycarbamide, pegaspargase, pentostatin, tazarotne, TLK-286, Velcade, Tarceva, or tretinoin; • Other anti-angiogenic compounds include acitretin, fenretinide, thalidomide, zoledronic acid, angiostatin, aplidine, cilengtide, combretastatin A-4, endostatin, hafofuginone, rebimastat, removab, Revlimid, squalamine, ukraine and Vitaxin; • Compounds coordinated with platinum include but are not limited to, cisplatin, carboplatin, nedaplatin, or oxaliplatin; • Camptothecin derivatives include but are not limited to camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, irinotecan, SN-38, edecaline, and topotecan; • Tyrosine kinase inhibitors are Iressa or SU5416; • Antibodies include Herceptin, Erbitux, Avastin, or Rituximab; • Interferons include interferon alpha, interferon alfa-2a, interferon, alpha-2b, interferon beta, interferop gamma-1a or interferon gamma-n1; • Biological response modifiers are agents that modify the defense mechanisms of living organisms or biological responses, such as survival, growth, or differentiation of tissue cells to direct them to have antitumor activity. Such agents include krestin, lentinan, sizofiran, pikibanil, or ubenimex; and Other antitumor agents include mitoxantrone, l-asparaginase, procarbazine, dacarbazine, hydroxycarbamide, pentostatin, or tretinoin. "Abnormal cell growth," as used herein, unless otherwise indicated, refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes the abnormal growth of: (1) tumor cells (tumors) that proliferate by expressing a mutated tyrosine kinase or overexpressing a receptor tyrosine kinase; (2) benign and malignant cells of other proliferative diseases in which activation of aberrant tyrosine kinase occurs; (4) Any tumors that proliferate by receptor tyrosine kinases; (5) any tumors that proliferate by aberrant serine / threonine kinase activation; and (6) benign and malignant cells of other proliferative diseases in which aberrant serine / threonine kinase activation occurs. The compounds of the present invention are potent inhibitors of FAK. Aurora-1, Aurora-2 and HgK protein kinase kinases, and therefore all are adapted for therapeutic use as antiproliferative agents (eg, anticancer agents), antitumor agents (eg, effective against solid tumors), antiangiogenesis (eg, stop or prevent the proliferation of blood vessels) in mammals, particularly in humans. In particular, the compounds of the present invention are useful in the prevention and treatment of a variety of human hyperproliferative disorders such as malignant and benign tumors of the liver, kidney, bladder, breast, gastric, ovaries, colorectal, prostate, pancreas, lung, vulva, thyroid, hepatic carcinomas, sarcomas, glioblastomas, head and neck, and other hyperplastic conditions such as benign hyperplasia of the skin (eg, psoriasis) and benign prostatic hyperplasia (eg example, BPH). It is further expected that the compound of the present invention may possess activity against a range of leukemias and lymphoid malignancies. In a preferred embodiment of the present invention the cancer is selected from lung cancer, bone cancer, pancreatic cancer, gastric cancer, skin cancer, head or neck cancer, cutaneous or intraocular melanoma, cancer of the uterus, ovarian cancer, gynecological, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, fallopian tube carcinoma, endometrial carcinoma, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's disease, esophageal cancer, small bowel cancer, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, soft tissue sarcoma, cancer of the urethra, cancer of penis, squamous cell, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, bladder cancer, kidney or ureter cancer, renal cell carcinoma, c Renal pelvic arcinoma, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal cord tumors, brain, pituitary adenoma, or a combination of one or more of the above cancers. In a more preferred embodiment the cancer is selected from a solid tumor, such as, but not limited to, breast, lung, colon, brain (eg, glioblastoma), prostate, stomach, pancreas, ovaries, skin (melanoma), endocrine, uterine, testicular, and bladder. The compounds of the present invention may also be useful in the treatment of additional disorders in which aberrant expression of ligand / receptor activation or activation or signaling events related to various protein tyrosine kinases are involved. Said disorders may include neuronal, glial, astrocytic, hypothalamic, and other glandular, macrophage, epithelial, stromal, and blastocoelic in which the aberrant function, expression, activation, or signaling of the erbB tyrosine kinases are involved. In addition, the compounds of the present invention may have therapeutic utility in inflammatory, angiogenic and immunogenic disorders involving identified and as yet unidentified tyrosine kinases that are inhibited by the compounds of the present invention.

A particular aspect of this invention relates to methods of treating or preventing a condition that presents with low bone mass in a mammal (including a human) comprising administering to a mammal in need of such treatment an amount that treats a condition that it is presented with low bone mass of a compound of the invention or a pharmaceutically acceptable salt of said compound. This invention is particularly directed to such procedures in which the condition that presents with low bone mass is osteoporosis, fragility, an osteoporotic fracture, a bone defect, juvenile idiopathic bone loss, alveolar bone loss, mandibular bone loss, bone fracture, osteotomy , periodontitis or prosthetic growth inwards. A particular aspect of this invention relates to methods of treating osteoporosis in a mammal (including a human) comprising administering to a mammal in need of such treatment an osteoporosis treating amount of a compound of the invention or a pharmaceutically acceptable salt of said compound. Another aspect of this invention relates to methods of treating a bone fracture or an osteoporotic fracture in a mammal comprising administering to a mammal in need of such treatment an amount that treats a bone fracture or that treats an osteoporotic fracture of a compound of the invention. invention or a pharmaceutically acceptable salt of said compound. The term "osteoporosis" includes primary osteoporosis, such as senile osteoporosis, postmenopausal and juvenile, as well as secondary osteoporosis, such as osteoporosis due to hyperthyroidism or Cushing's syndrome (due to the use of corticosteroids), acromegaly, hypogonadism, dysosteogenesis and hypophosphatasemia. The term "treat", 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 said disorder or condition. The term "treatment", as used herein, unless otherwise indicated, refers to the act of treating as "treating" is defined immediately above.

The present invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined hereinbefore in association with a pharmaceutically acceptable adjuvant, diluent or carrier. The invention further provides a process for the preparation of a pharmaceutical composition of the invention comprising mixing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined hereinbefore with an adjuvant, diluent. or pharmaceutically acceptable vehicle. For the aforementioned therapeutic uses the dosage administered, of course, will vary with the compound employed, the mode of administration, the desired treatment and the indicated disorder. The daily dosage of the compound of formula (I) / salt / solvate (active ingredient) can be in the range of 1 mg to 1 gram, preferably 1 mg to 250 mg, more preferably 10 mg to 100 mg. The present invention also encompasses sustained release compositions. Procedures for Administering the Compounds of the Invention The administration of the compounds of the present invention (hereinafter referred to as "active compound (s)") can be made by any method that allows the delivery of the compounds to the site of action. These procedures include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, invasive or infusion), topical, and rectal administration. The amount of active compound administered will depend on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dose is in the range of about 0.001 to about 100 mg per kg of body weight per day, preferably about 1 to about 35 mg / kg / day, in single or divided doses. For a 70 kg human being, it would amount to about 0.05 to about 7 g / day, preferably about 0.2 to about 2.5 g / day. In some cases, dosage levels below the lower limit of the range mentioned above may be more than adequate, while in other cases, even higher doses can be used without causing any harmful side effects, provided that said higher doses are divided into several smaller doses first for administration throughout the day. The active compound can be applied as an exclusive therapy or it can include one or more different anti-tumor substances, for example those selected from, for example, mitotic inhibitors, for example vincblastin; alkylating agents, for example cis-platinum, carboplatin and cyclophosphamide; anti-metabolites, for example 5-fluorouracil, cytosine arabinoside and hydroxyurea, or, for example, one of the preferred anti-metabolites described in European Patent Application No. 239362 such as acid? - (5- [V- (3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl) -? - methylamino] -2-tenoyl) -glutamic; cell growth inhibitors; cell cycle inhibitors; intercalating antibiotics, for example adriamycin and bleomycin; enzymes, for example interferon; and anti-hormones, for example anti-estrogens such as Nolvadex® (tamoxifen) or, for example anti-androgens such as Casodex® ^ '- cyano-S - ^ - fluorophenylsulfoni ^ -hydroxy ^ -methyl-S' - (trifluoromethyl) ) propionanilide). Such joint treatment can be achieved by means of the simultaneous, sequential or separate dosing of the individual components of the treatment. The pharmaceutical composition can be, for example, in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution, suspension, for parenteral injection in the form of a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository. The pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient. In addition, they may include other agents, vehicles, medicinal or pharmaceutical adjuvants, etc. Exemplary forms of parenteral administration include solutions or suspensions of active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solution. Said dosage forms may be suitably buffered, if desired.

Suitable pharmaceutical carriers include diluents or inert fillers, water and various organic solvents. The pharmaceutical compositions may contain, if desired, additional ingredients such as flavors, binders, excipients and the like. Thus for oral administration, tablets containing various excipients, such as citric acid may be employed together with various disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and gum arabic. In addition, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tabletting purposes. Solid compositions of a similar type can also be used in capsules filled with soft and hard gelatin. Preferred materials, therefore, include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration the active compound therein can be combined with various sweetening or flavoring agents, coloring materials or dyes and, if desired, emulsifying agents or suspending agents, together with diluents such as water, ethanol , propylene glycol, glycerin, or combinations thereof. Processes are known for preparing various pharmaceutical compositions with a specific amount of active compound, or will be apparent to those skilled in the art. For examples, see Reminqton's Pharmaceutical Sciences. Mack Publishing Company, Easter, Pa., 15th Edition (1975). The examples and preparations given below further illustrate and exemplify the compounds of the present invention and methods for preparing said compounds. It should be appreciated 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 the molecules with a single chiral center, unless otherwise indicated, exist as a racemic mixture. Molecules with two or more chiral centers, unless otherwise indicated, exist in the form of a racemic mixture of diastereomers. Isolated enantiomers / diastereomers can be obtained by methods known to those skilled in the art.

EXAMPLES Where HPLC chromatography is mentioned in the preparations and examples below, the general conditions used, unless otherwise indicated, are as follows. The column used is a ZORBAX ™ RXC18 column (manufactured by Hewlett Packard) of 150 mm of travel and 4.6 mm of internal diameter. Samples are processed in a Hewlett Packard-1100 system. A solvent gradient procedure is used passing 100 percent ammonium acetate / acetic acid buffer (0.2 M) to 100 percent acetonitrile per 10 minutes. The system then continues in a washing cycle with 100 percent acetonitrile for 1.5 minutes and then 100 percent buffer solution for 3 minutes. The flow rate during this period is constant at 3 ml / minute. EXAMPLES General Procedures: HPLC Procedures Where HPLC chromatography is mentioned in the preparations and examples, the general conditions used, unless otherwise indicated, are as follows. The column used is a ZORBAX ™ Eclipse XDB-C8 column (manufactured by Agílent) of 150 mm of travel and 4.6 mm of internal diameter. Samples are processed in an Agilent 1100 series system. A solvent gradient procedure is used, passing 100-per-cent ammonium acetate / acetic acid buffer (0.2 M) to a mixture of 15 percent ammonium acetate buffer / acetic acid (0.2 M) and 85% acetonitrile. percent for 8 minutes and then to 100 percent acetonitrile for 1 minute. The system then continues in a wash cycle by passing 100% acetonitrile to 100 percent buffer solution for 2 minutes. The flow rate during this period is constant at 3 ml / minute. Then other specific procedures. Procedure A1 HPLC analyzes were obtained using a Reliasil BDX-C18 column (4.6 * 100 mm) with UV detection at 223 nm (Procedure A) or a Symmetry C18 column (4.6 * 250 mm) with UV detection at 254 nm (Method B) using a conventional solvent gradient program.

A = Water with 0.05% v / v Trifluoroacetic acid, B = Acetonitrile with 0.05% Trifluoroacetic acid v / v Procedure B1 A = Water with Trifluoroacetic acid 0.05% v / v, B = Acetonitrile with Trifluoroacetic acid 0.05% v / v Procedure A: Column: Xterra MS C 18 (4.6 X 50 mm, 3.5 μm). Gradient: H20 / CH3CN / 2% NH4OH in H20 of 85: 10: 5 at 0 min at 0: 95: 5 at 5 min at 2 ml / min. Procedure B: Column: Atlantis dC18 (4.6 X 50 mm, 5 μm). Gradient: HzO / CH3CN / 1% TFA in H20 from 85/10/5 to 25/70/5 in 5 min at 2 mi / min. Method C: Column: Xterra MS C8 (4.6 X 50 mm, 3.5 μm). Gradient: H20 / CH3CN / 2% NH4OH in H20 from 90/5/5 to 35/60/5 in 5 min at 2 ml / min. Method D: Column: Waters Symmetry C8 (4.6 X 50 mm, 4.6 μm). Gradient: H20 / CH3CN / 1% TFA in HzO of 94: 5: 1 at 0 min at 4: 95: 1 at 3.5 min, from 4: 95: 1 at 3.5 min at 4: 95: 1 at 4 min at 2 ml / min. Method E: Where HPLC chromatography is mentioned in the preparations and examples, the general conditions used, unless otherwise indicated, are as follows. The column used is a ZORBAX ™ Eclipse XDB-C8 column (manufactured by Agilent) of 150 mm of travel and 4.6 mm of internal diameter. Samples are processed in an Agilent 1100 system series. A solvent gradient procedure is used by passing 100 percent ammonium acetate / acetic acid buffer (0.2 M) to a mixture of 15 percent ammonium acetate buffer / acetic acid (0.2 M) and 85 percent acetonitrile. one hundred for 8 minutes and then 100% acetonitrile for 1 minute. The system then continues in a wash cycle by passing 100 percent acetonitrile to 100 percent buffer for 2 minutes. The flow rate during this period is constant at 3 ml / minute. Method F: Where LCMS chromatography is mentioned in the preparations and examples, the general conditions used, unless otherwise indicated, are as follows. The Gilson ™ 215 liquid manipulator is used, equipped with a Varian C8 column and Gilson HPLC pump. The chromatography system uses a binary solvent system consisting of an acid solution (consisting of 98 percent water, 1.99 percent acetonitrile and 0.01 percent formic acid) and a solution of acetonitrile (constituted by acetonitrile). 99.995 percent and 0.005 percent formic acid). A solvent gradient procedure is used by passing a mixture of 95 percent of the acid solution and 5 percent of the acetonitrile solution to a mixture of 80 percent acid solution and 20 percent acetonitrile solution for 1 minute, continuing to a mixture of 50 percent acid solution and 50 percent acetonitrile solution for a period of 1.3 minutes and continuing to 100 percent acetonitrile solution for 1.2 minutes. The system then continues an equilibrium cycle by passing 100 percent acetonitrile solution to a mixture of 95 percent acid solution and 5 percent acetonitrile for 0.2 minutes. The flow rate during this period is constant at 1 ml / minute. Procedure G: The reactions were purified on preparative HPLC of Shimadzu, using a steel column waters SunFire C18, 5 μm, 3.0 x 5.0 mm. The mobile phase, flow rate 18.0 ml / min, water (gradient 95 - 0%) and acetonitrile (gradient 5 - 100%) using 1% trifluoroacetic acid in water (2.0 ml / min) as modifier. Example 1 (+/-)? / - (3- { [2- (12,12-Dioxo-12? 6-thia-tricyclo [6.3.1.02-7] dodeca-2 (7), 3.5 -trien-4-ylamino) -5- trifluoromethyl-pyrimidin-4-ylamino] -methyl.} - pyridin-2-yl) -V-methyl-methanesulfonamide (1) Stage 1. 12,12-Dioxide of (+/-) 4-nitro-12-thia-tricyclo [6.3.1.0A '] dodeca-2 (7), 3,5-triene (C4): It was carefully dissolved 12 , 12-dioxide of 12-thia-tricyclo [6.3.1.02 '] dodeca-2 (7), 3,5-trine (C3) (see J. Chem. Soc, Perk. Trans. I, 1981 (7 ), 1846) (407 mg, 1.96 mmol) in 6.00 ml of H2SO4 was cooled and the resulting solution was cooled to -10 ° C (NaCl / ice bath). The resulting brown solution was treated in portions with KN03 (198 mg, 1.96 mmol) in such a way that the internal temperature of the reaction never exceeded -8 ° C. The reaction mixture was stirred at about -10 ° C for a further five minutes and poured into ice. The resulting cloudy ice mixture was stirred until all the ice was melted and the resulting aqueous mixture was washed with EtOAc. The combined organic phases were dried over MgSO4 and concentrated under reduced pressure to give compound C4 as a pale yellow solid (397 mg, 1.56 mmol, 80% yield). C11HHNO4S. GC / MS t.a. = 5.07 min; m / z 237, 189 (bp), 174, 161, 141, 128, 115, 1 H NMR (CDCl 3) d 8.30 (d, J = 8.3 Hz, 1H), 7.25 (s, 1H) , 7.56 (d.J = 8.3 Hz, 1H), 4.26 (dd, J = 10.7, 4.9 Hz, 2H), 2.68-2.60 (m, 2H), 2, 11-2.03 (m.H2), 1, 57-1, 52 (m, 1 H), 0.87-0.74 (m, 1 H) ppm. Step 2. (+/-) 12,12-Dioxo-12? 6-thia-tricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-trien-4-ylamine (C5): A mixture of compound C4 (397 mg (1.56 mmol), EtOH (3.00 ml) and cyclohexene (790 ml, 7.80 mmol) was carefully treated with palladium on carbon (832 mg, 0.780 mmol) and heated at 60 ° C. After three hours, the reaction mixture was allowed to cool to 25 ° C. and concentrated under reduced pressure The resulting residue was purified on silica (40% EtOAc in hexanes) to give compound C5 in the form of a white solid (78 mg, 0.358 mmol, 23%) .CNH ^ NO? S GC / MS ta = 2.94 min.m / z 159 (pe), 144, 130; 1H NMR (CDCl3) d 6, 69-6.67 (m, 2H), 4.06 (d.J = 5.2 Hz, 1H), 4.02 (d, J = 4.7 Hz, 1H), 2.56-2.51 (m. , 2H), 2.00-1.95 (m, 2H), 1.48-1.44 (m, 1H), 1.00--0.93 (m, 1H) ppm.

Step 3. (+/-) (4-Chloro-5-trifluoromethyl-pyrimidin-2-yl) - (12,12-dioxo-12? 6-thia-tricyclo [6.3.1.02 r] dodeca-2 (7) , 3,5-trien-4-yl) -amine (C6): A solution of 2,4-dichloro-5-trifluoromethylpyrimidine (78 mg, 0.358 mmol) and a mixture 1/1 (vol: vol) of f- BuOH and dichloroethane (400 ml) was cooled to 0 ° C, treated with a solution of ZnCl2 (715 ml, 0.715 mmol, 1.0 Molar in Et20) and stirred at 0 ° C for 30 minutes. The mixture was treated with a suspension of compound C5 in 1/1 of ibuOH / CH2Cl2 (800 ml) and then treated dropwise with diisopropylethylamine (125 ml, 0.715 mmol). After five minutes, the mixture was heated to 50 ° C. After 4 hours, the reaction mixture was allowed to cool to room temperature, 25 ° C, and concentrated under reduced pressure. The resulting residue was triturated with MeOH and the resultant was collected by filtration to give compound C6 as a white solid (52 mg, 0.129 mmol, 36%). C? 6H13CIF3N302S LCMS (Method F) m / z 402/404 (MH +); 'H NMR (D6-DMSO) d 10.8 (s.1H), 8.81 (s, 1H), 7.69 (s, 1H), 7.68 (d, J = 8.3 Hz, 1H ), 7.41 (d, J = 8.3 Hz, 1H), 4.42-4.37 (m, 2H), 2.39-2.24 (m, 2H), 1.94-1, 90 (m, 2H), 1.38-1.34 (m, 1H), 0.79-0.60 (m, 1H) ppm. Step 4. A mixture of compound C6 (51 mg, 0.126 mmol) and 1: 1 (vohvol) of t-BuOH / dichloroethane (500 μl) was added to a mixture of α- (3-aminomethyl-pyridin-2-yl). ) -? methyl-methanesulfonamide (38 mg, 0.139 mmol) and diisopropylethylamine (66 μl, 0.378 mmol). The reaction mixture was heated to 85 ° C in a sealed vial. After two hours, the hot reaction mixture was directly charged onto silica under reduced pressure, purified by chromatography (99: 1: 0.1 of CHCl3: CH3OH: NH4OH) and concentrated under reduced pressure, affording compound 1 in form of a white solid (13 mg, 0.0223 mmol, 18%). LC / MS (Method F) t.a. = 2.26 min; m / z 583.2, t.r. HPLC = 6.40 min. Example 2? / - (3- { [2- (10-Methanesulfonyl-10-aza-tricyclo [6.3.1.02,7] dodeca-2 (7), 3,5-trien-4-ylamino) -5 - trifluoromethyl-pyrimidin-4-ylamino] -methyl) -pyridin-2-yl) -? / - methyl-methanesulfonamide (2) Step 1. (+/-) 10-Methanesulfonyl- 4-nitro-10-aza-tricyclo [6.3.1.02,7] dodeca-2,4,6-triene (C7): 4-Nitro-10-aza-tricyclo [6.3.1.02,7] dodeca-2,4,6-triene (150 mg, 0.734 mmol) (see International Publication No. WO01 / 062736) was combined with pyridine ( 3.00 ml) and cooled to -10 ° C in a NaCl / ice bath. Methanesulfonyl chloride (74 μL, 0.954 mmol) was added slowly and the mixture will reach equilibrium at room temperature. (An orange change was observed.) After two hours, the reaction mixture was cooled to 0 ° C and water (500 μl) was carefully added. The mixture was concentrated under reduced pressure and the resulting orange solid was combined with a minimum amount of 99: 1: 0.1 of CHCl3: CH3OH: NH40. The resulting orange mixture was filtered and the solid phase was collected to give C7 as a white crystalline solid (56 mg, 0.230 mmol, 31% yield). The filtrates were purified on silica gel (99: 1: 0.1 of CHCl3: CH3OH: NH4OH), yielding an additional amount of compound C7. C, 2H14N204S CG / MS t.a. = 5.53 min, m / z 282 (Ml), 128, 122 (pe). 1 H NMR (D 6 -DMSO) d 8.16 (s, 1H), 8.10 (d J = 7.9 Hz, 1H), 7.54 (d, J = 7.9 Hz, 1H), 3 , 48-3.38 (m, 5H), 3.24-3.19 (m.2H). 2.54 (s 3 H). 2,27-2, 21 (m, 1H) ppm. Step 2. (+/-) 10-Methanesulfonyl-10-aza-tricyclo [6.3.1.02,7] dodeca-2,4,6-trien-4-ylamine (C8): A mixture of compound C7 (207 mg, 0.734 mmol) and 5: 4: 3 (vol: vol) dioxane / EtOH / H20 (5.00 ml.) was treated sequentially with NH4CI (157 mg, 2.94 mmol) and iron powder (205 mg. 3.67 mmol). The resulting mixture was heated to 80 ° C in a gentle flow of nitrogen. After three hours, the reaction mixture was allowed to cool to 25 ° C, diluted with EtOAc and H20 and filtered through diatomic earth. The resulting organic phase was collected, dried over MgSO4 and concentrated under reduced pressure to give compound C8. This compound was used without further purification. C12H16N202S LC / MS (Method F) 253.1 (MH +); 1 H NMR (D 6 -DMSO) d 6.89 (d, J = 7.8 Hz, 1H), 6.50 (s, 1H), 6.36 (d, J = 7.8 Hz, 1H), 4 , 92 (sa, 2H). 3.40-3.31 (m.2H). 3.18-3.13 (m, 2H). 3.02 (s a, 2H). 2.50 (s, 3H), 2.10-2.08 (m, 1H), 1.72-1.67 (d, J = 10.9 Hz, 1H) ppm. Stage 3: Was it combined? -. { 3 - [(2-Chloro-5-trifluoromethyl-pyrimidin-4-ylamino) -methyl] -pyridin-2-yl) -? methyl methanesulfonamide (247 mg, 0.624 mmol) (see WO 2005023780) with dioxane (1.00 ml), compound C8 (158 g, 0.624 mmol) and diisopropylethylamine (255 ml, 1.47 mmol) and the The mixture was heated to 110 ° C in a gentle flow of nitrogen. After sixteen hours, the mixture was concentrated under reduced pressure and the resulting residue was purified on silica (95: 5.0.5 of CHCl3: CH3OH: NH4OH), giving compound 2 as a white foam (61 mg, 0, 0997 mmol, 16%). C25H28F3N704S2 LC / MS (Method F) m / z 612.3 (MH *); 1 H NMR (D 6 -DMSO) d 8.22 (s, 1 H) ppm.

Example 3 (+/-)? / - Metl-? - (3- { [2- (10-trifluoroacetyl-10-aza-tricyclo [6.3.1.027] dodeca-2 (7), 3,5-trien-4-ylamino) -5-trifluoromethyl-pyrimidine -4-ylammon] -methyl.}. -pyridin-2-yl) -methanesulfonamide (3) A mixture of 1- (4-amino-10-aza-tricyclo [6.3.1.027] dodeca -2,4,6-trien-10-yl) -2,2,2-trifluoro-ethanone (158 g, 0.624 mmol) (see International Publications No. WO01 / 076576A2, WO01 / 062736A1, W099 / 35131 and European Patent No. EP 1078637), 1,4-dioxane (1.00 ml), A / -. { 3 - [(2-Chloro-5-trifluoromethyl-pyrimid-4-ylamino) -methyl] -pyridin-2-yl} -? / - Methyl-methanesulfonamide (247 mg, 0.624 mmol) and DIAE (255 mL, 1.47 mmol) was heated at 110 ° C in a gentle flow of nitrogen. After sixteen hours, the mixture was concentrated and the resulting residue was purified on silica (95: 5: 0.5 of CHCl3: CH3OH: NH4OH), yielding (+/-) V-methyl-V- (3-. { . [2- (10-trifluoroacetyl-10-aza-tricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-trien-4-ylammon) -5-trifluoromethyl-pyrimidine 4-ylamino] -methyl.} - pyridin-2-yl) -methanesulfonamide (3) as a white foam (78 mg, 0.124 mmol, 20%). C 26 H 25 F 6 N 703 S CLMS (Method F) 630.3 (MH +); 19 F NMR (D6-DMSO) d -60.38, -67.99 (1: 1 ratio) ppm. Example 4 (+/-)? - (3- { [2- (10-aza-tricyclo [6.3.1.02,7] dodeca-2 (7), 3,5-trien-4-ylamino) -5-trifluoromethyl-pyrimidin-4 -ylamino] -methyl.} - pyridin-2-yl) -? -methyl methanesulfonamide (4) A solution of compound 3 and tetrahydrofuran (2.00 ml) was treated with three crystals of benzythriethylammonium chloride and 40% aqueous NaOH (2.00 ml) and the resulting biphasic reaction mixture was heated at 70 ° C under a nitrogen atmosphere. After sixteen hours, the mixture was allowed to cool to 25 ° C. The organic phase was collected and the aqueous phase was washed with EtOAc. The combined organic phases were dried over MgSO4, concentrated under reduced pressure and purified on silica (92: 8: 0.8 of CHC13: CH3OH: NH4OH), yielding 32 g of compound 4 as a yellow foam). The yellow foam was dissolved in a minimum amount of CH 2 Cl 2 at ° C and 15 μl (0.0600 mmol) of 4.0 M HCl in 1,4-dioxane was added slowly. The resulting white suspension was stirred in a gentle stream of nitrogen for one hour and filtered to provide the hydrochloride salt form of compound 4 as a white solid (25 mg, 0.0474 mmol, 38%). C24H26F3N702S t.r. HPLC = 5.10 min; LC / MS (Procedure F) m / z 534.4 (MH +). Example 5 -Methyl- / V- (3- { [2- (9-trifluoroacetyl-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-6-ylamino) -5-trifluoromethyl-pyrim D-n-4-ylamino] -methyl) -pyridin-2-yl) -methanesulfonamide (5) Step 1. 2,2,2-Trifluoro-1- (1,2,3,4-tetrahydro- 1,4-epiazano-naphthalen-9-yl) -ethanone (C11): A solution of 1,2,3,4-tetrahydro-1,4-epiazano-naphthalene (see JOC, 1966 (31), 764) in Dry CH2CI2 (40.0 ml) and DIAE (1.92 ml, 11.0 mmol) was cooled to 0 ° C and treated with trifluoroacetic anhydride (1.55 ml (11.0 mmol). The reaction mixture slowly reached 25 ° C under nitrogen, and after 5 hours, the resulting green reaction mixture was cooled to 0 ° C and treated with 2.00 ml of water to inactivate any remaining anhydride. 1 N) and the phases were separated The aqueous phase was washed with CH 2 Cl 2 and the combined organic extracts were dried over MgSO 4 and concentrated under reduced pressure The resulting dark oil was treated with EtOAc, stirred with activated carbon, filtered through diatomaceous earth and concentrated under reduced pressure to provide C11 as a brown oil (1.65 g, 6.80 mmol, 68% yield). GC / MS t.a. = 2.22 min, m / z 241 (Ml), 213 (pe), 116; 19 F NMR (D 6 -DMSO) 5-71.50 ppm. Step 2. (+/-) 2,2,2-Trifluoro-1- (6-nitro-1, 2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl) -ethanone (C12) A solution of trifluoromethanesulfonic acid (1.20 ml, 13.6 mmol) and dichloromethane (7.00 ml) was cooled to 0 ° C and treated carefully with a solution of HN03 (300 ml, 6.80 mmol), time during which steam evolution and solid formation was observed.The resulting mixture was stirred for an additional fifteen minutes at 0 ° C, cooled to -78 ° C and treated dropwise with a solution of C11 (1.65 g, 6.80 mmol) in dry CH2Cl2 (10.0 mL). After stirring for 1 hour at -78 ° C, the mixture was warmed to 0 ° C and left to stand for one hour at 0 ° C. Then, the reaction mixture was carefully poured into water cooled with vigorously stirred ice and CH 2 Cl 2 was added after the ice melted. The resulting organic phase was collected and the aqueous phase was washed with CH2Cl2. The combined organic phases were dried over MgSO4 and concentrated under reduced pressure. The resulting oily residue was purified on silica (EtOAc at % in hexanes), providing C12 as a yellow foam (1.05 g, 3.69 mmol, 54% yield). C12H10F3NO APCI m / z 286.1 (M), 19 F NMR (D6-DMSO) 5-71, 55 ppm. Step 3. (+/-) 1- (6-Amino-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl) -2,2,2-trifluoro-ethanone (C13) ): Compound C13 was prepared in a manner similar to that described for compound C8 in Step 2 of Example 2 with the exception that 2,2,2-trifluoro-1- (6-nitro-1,2 was used. , 3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl) -ethanone (570 mg, 1.99 mmol) instead of compound C7, giving compound C13 as a brown-yellow foam (430 mg, 1.67 mmol, 84%). C HNFaNzO LC / MS (Method F) m / z 257.1 (MH *). 1 H NMR (D 6 -DMSO) d 6.98 (m (Coupling F), 1H), 6.57 (s (Coupling F), 1H), 6.31 (d, J = 7.9 Hz, 1H), 5.15 (br s, 2H) ppm. Step 4. Compound 5 was prepared in a manner similar to that described for compound 3 in Example 3 with the exception that 1- (6-amino-1,2,3,4-tetrahydro-1,4 was used. -epiazano-naphthalen-9-yl) -2,2,2-trifluoro-ethanone (180 mg, 0.700 mmol) in place of 1- (4-amine-10-aza-tricyclo [6.3.1.02,7-dododeca-2, 4,6-trien-10-yl) -2,2,2-trifluoro-ethanone, affording compound 5 in the form of a light yellow foam (180 mg, 0.700, 53% yield). C25H23F6N703S t.r. HPLC = 7.31 min, LC / MS (Method F) m / z 616.3 (MH +). Example 6 (+/-)? / - Methyl-W- (3- { [2- (1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-6-ylamino) -5-trifluoromethyl) -pyrimidin-4-ylamino] -methyl) -pyridin-2-yl) -methanesulfonamide (6) Compound 6 was prepared in a manner similar to that described for compound 4 in the Example 4 with the exception that compound 5 (8 mg, 0.0153 mmol) was used in place of compound 3, giving compound 6 as a white solid (8 mg, 0.0153 mmol, yield 7% ). C23H24F3N702S t.r. HPLC = 4.80 min; LC / MS (Method F) m / z 520.3 (MH *). Example 7? / - (3- { [2- (9-Methanesulfonyl-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-6-ylamino) -5- trifluoromethyl-pyrimidin- 4-ylamino] -methyl) -pyridin-2-yl) -? -methyl-methanesulfonamide (7) Step 1: (+/-) 6-Nitro-1,2,3,4-tetrahydro-1,4-epiazano-naphthalene (C14): Compound C14 was prepared in a manner similar to that described for compound 4 in Example 4 with the exception that compound C12 (480 mg, 1.68 mmol) was used in place of compound 3, giving compound C14 as a white solid (250 mg, 1.31 mmol, yield 78%). %). C, oH10N202 LCMS (Method F) m / z 191.1 (MH *); 'H NMR (CD3OD) d 8.08 (d, J = 7.9 Hz, 1H). 8.05 (s, 1H), 7.43 (d, J = 7.9 Hz, 1H) ppm. Step 2. (+/-) 9-Methanesulfonyl-6-nitro-1,2,3,4-tetrahydro-1,4-epipanane-naphthalene (C15): Compound C15 was prepared in a manner similar to that described for compound C7 in Step 2 of Example 2, with the exception that compound C14 (250 mg, 1.31 mmol) was used in place of 4-nitro-10-aza-tricyclo [6.3.1.02.7] dodeca -2,4,6-triene. The reaction afforded compound C15 as a beige crystalline solid (350 mg, 1.30 mmol, 99% yield). C? H12N204S. 1 H NMR (CD 3 OD) d 8.24 (s, 1 H), 8, 19 (d, J = 7, 7 Hz, 1 H), 7.58 (d, J = 7.7 Hz, 1 H), 2.48 (s, 3H) ppm. Step 3. (+/-) 9-Methanesulfonyl-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-6-ylamine (C16): Compound C16 was prepared in a similar manner to that described for compound C8 in Step 1 of Example 2, with the exception that compound C15 (350 mg, 1.30 mmol) was used in place of compound C7, giving compound C16 as a tan solid (269 mg, 1.12 mmol, 86% yield). C "H, 4N202S CG / MS t.a. = 4.72 min; m / z 238 (Ml), 210, 131 (pe); 1 H NMR (Dß-DMSO) d 6.94 (d, J = 7.9 Hz, 1H), 6.55 (s, 1H), 6.29 (d J = 7.9 Hz, 1H), 5.06 (sa, 2H), 2.18 (s 3 H) ppm. Step 3. Compound 7 was prepared in a manner similar to that described for the compound 3 in Example 3, with the exception that compound C16 (269 mg, 1.12 mmol) was used in place of 1- (4-amino-10-aza-tricyclo [6.3.1.02.7] dodeca-2 , 4,6-trien-10-yl) -2,2,2-trifluoro-ethanone, affording compound 7 in the form of such a foam (0.570 mmol, 342 mg, 61% yield). C24H26F3N204Sjt.r. HPLC = 6.43 min. Example 9? / - (3- { [2- (9-Methanesulfonyl-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-6-ylamino) -5- trifluoromethyl-pyrimidip-4- ilamino] -methyl) -pyridin-2-yl) -? -meti-methanesulfonamide (Enantiomer 2) (9) Compound 7 (racemate) from Example 7 was separated on a preparative Chiralpak AS HPLC column of 10 x 50 cm using a 3: 2 (vol: vol) mixture of heptane / ethanol as the mobile phase at a rate of 275 ml / min. . The eluent containing the slower eluting enantiomer was concentrated under reduced pressure to provide compound 9 as a white foam. C24H26F3N204S2 Prep. t.r. HPLC = 12.59 min; LC / MS (Method F) m / z 598.2 (MH *). Example 10 1- [4- (4-Cyclopropylamine-5-trifluoromethyl-pyrimidin-2-ylamino) -10-aza-tricyclo [6.3.1.02-7] dodeca-2 (7), 3,5-trien-10 -yl] -2-methoxy-ethanone (10) (Method A) Í0 Stage 1. (+/-) - 2,2,2-Trifluoro-1- (4-nitro-10-aza-tricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-trien- 10-yl) -ethanone (C17): A solution of 1- (10-aza-tricyclo [6.3.1.027] dodeca-2 (7), 3,5-trien-10-yl) -2,2,2- trifluoro-ethanone (49.9 g, 196 mmol) (4) (see O'Donnell et al., JOC, 2004 (69.7), 5756-59 and International Publications No. WO 04/063164 and WO 99 / 35131) in trifluoroacetic acid (TFA) (100 ml) was cooled in an acetone / ice bath and treated dropwise with fuming HN03 for 10 minutes. The resulting reaction mixture was stirred for 1 hour as the temperature of the ice bath increased at 0 ° C and then for an additional 1 hour. The ice bath was removed, the excess N02 was removed under a nitrogen atmosphere and the TFA was removed under reduced pressure. The resulting residue was poured into 300 ml of ice water and extracted with 3 x 200 ml of CH2Cl2. The combined organic phases were washed with saturated NaCl (1 x 100 ml) and saturated NaHCO 3 (1 x 100 ml). The organic phase was dried over MgSO4 and passed through a 200 g silica gel bed (230-400 mesh) eluting with CH2Cl2 (2000 mL). The resulting eluant was concentrated under reduced pressure to provide compound C1 as a yellow solid pale (55.4 g, 184 mmol, 94% yield). 1 H NMR (400 MHz, DMSO-D6) d ppm 2.1 (d, J = 11.2 Hz, 1 H) 2.3 (dd, J = 10.8, 5.4 Hz, 1 H) 3, 2 (dd, J = 12.9, 4.6 Hz, 1 H) 3.4 (d, J = 4.6 Hz, 2 H) 3.7 (m, 1 H) 3.8 (m, 1 H) 4.1 (d, J = 12.9 Hz. 1 H) 7.5 (t, J = 8.5 Hz, 1 H) 8.1 (d, J = 7.9 Hz, 1 H) 8.2 (dd, J = 10.8, 2.1 Hz, 1 H) ppm. Step 2. (+/-) 4-Nitro-10-aza-tricyclo [6.3.1.02,7] dodeca-2 (7), 3,5-triene (C18): A solution of the compound C17 (45, 4 g, 157 mmol) in tetrahydrofuran (THF) (300 ml) was treated dropwise with lithium hydroxide monohydrate (9.4 g, 224 mmol) in H20 (75 ml) for 10 minutes. The mixture was stirred for 1 hour at 25 ° C and the mixture was concentrated under reduced pressure. The resulting residue was treated with 250 ml of 1: 1 (vol: vol) of water saturated with concentrated NaCl: NH 4 OH and extracted with CH 2 Cl 2 (2 x 200 ml). The combined organic phases were dried over K2CO3 and concentrated under reduced pressure to give compound C18 as an orange solid (32 g, 155 mmol, 99% yield). Compound C18 was used without further purification. 1 H NMR (400 MHz, DMSO-D6) d ppm 1.7 (d, J = 0.4 Hz, 1 H) 1.9 (d, J = 10.4 Hz, 1 H) 2.3 (m. 1 H) 2.6 (dd, J = 12.3, 1, 9 Hz, 2 H) 2.9 (m, 2 H) 3.0 (d, J = 13.7 Hz, 2 H) 7, 4 (d, J = 7.9 Hz, 1 H) 8.0 (s, 1 H) 8.0 (dd, J = 8.1, 2.3 Hz, 1 H) ppm. Step 3. (+/-) 4-nitrium-10-aza-tricyclo [6.3.1.02,7] dodeca-2 (7), 3,5-trien-10-carboxylic acid ert-butyl ester (C19) ): To a solution of compound C18 (2.00 g, 9.78 mmol) in 10 ml of acetonitrile was added di-t-butyl dicarbonate (2.12 g, 9.78 mmol) and the resulting mixture it was stirred at 25 ° C for 2 hours. The mixture was concentrated under reduced pressure and the resulting residue was redissolved in ethyl acetate (50 ml) and washed with saturated sodium bicarbonate (2 x 25 ml) and brine (2 x 25 ml). The combined aqueous phases were extracted with ethyl acetate (50 ml) and the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The resulting yellow residue was chromatographed on silica gel (25% EtOAc: Hexanes) and concentrated under reduced pressure to give compound C19 as a colorless oil (2.7 g, 9.3 mmol, 95% yield). ). HPLC Tr 7.085 minutes; LC / MS (Method F) m / z 305.3 (MH *); 1 H NMR (400 MHz, DMSO-D 6) d ppm 1.1 (s, 9 H) 1.9 (d, J = 10.8 Hz, 1 H) 2.2 (m, 1 H) 3.1 ( m, 1 H) 3.2 (d J = 16.2 Hz, 3 H) 3.8 (m 2 H) 7.5 (dd, J = 11.4, 8.1 Hz, 1 H) 8.1 (ddd, J = 15.3. 8.1, 7.8 Hz, 2 H) ppm.

Step 4. (+/-) - 4-Amino-10-aza-tricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-trien-10- carboxylic acid (C20): A mixture of compound C19 (1.34 g, 4.27 mmol), ethanol (50 ml) and 10% Pd / C (134 mg) was charged to a hydrogenation vessel with Parr stirrer and the The resulting mixture was stirred at 310.26 kPa (45 psi) of H2 for 2 hours at about 25 ° C. The resulting mixture was filtered through Celite® and concentrated under reduced pressure to give compound C20 as a clear oil (1.2 g, 3.8 mmol, 89%). HPLC Tr 5.88; LC / MS (Method F) m / z 275.3 (MH *); 1 H NMR (400 MHz, DMSO-D6) d ppm 1.2 (d, J = 4.2 Hz, 9 H) 1.7 (d, J = 10.4 Hz, 1 H) 2.0 (m, 1 H) 2.9 (m, 3 H) 3, 1 (t, J = 11, 4 Hz, 1 H) 3.6 (m, 2 H) 4.8 (s, 2 H) 6.3 ( dd, J = 3.9, 2.3 Hz, 1 H) 6.4 (d, J = 4.2 Hz, 1 H) 6.8 (t, J = 7.5 Hz, 1 H) ppm. Step 5. 4- (4-Chloro-5-trifluoromethyl-pyrimidin-2-ylamino) -10-aza-tricyclo [6.3.1.02'7] dodeca-2 (7), 3, tert-butyl ester 5-trien-10-carboxylic acid (C21): A mixture of 5-trifluoromethyl-2,6-dichloropyrimidine (9.6 g, 44.4 mmol) and 180 ml of f-BuOH / DCE (1: 1) was cooled at 0 ° C under a nitrogen atmosphere, treated with ZnCl2 (53.3 ml, 1 M in Et20) and stirred for 1 hour at 0 ° C. The mixture was treated dropwise with a solution of compound C20 (11.6 g, 42.3 mmol) in 40 ml of 1: 1 (vol: vol) of '-BuOH / DCE and left to stir for 45 minutes. more at 0 ° C. Then, the resulting mixture was treated dropwise at 0 ° C with a solution of Et3N (7.4 ml, 53.3 mmol) in 10 ml of 1: 1 (vohvol) of t-BuOH / DCE and allowed to warm at 25 ° C. The mixture was stirred for a further 2 hours and concentrated under reduced pressure. The resulting green foam was dissolved in CH2Cl2, chromatographed on 500 g of silica gel (230-400 mesh) eluting with 17% EtOAc / hexane and concentrated under reduced pressure. The resulting viscous pale yellow oil (17 g) was dissolved in 60 ml of hexane and stirred for 2 hours, during which time the crystallization occurred. The resulting solids were collected by filtration, washed with cold hexane and dried to give compound C21 as a white solid (15.3 g, 33.8 mmol, 80% yield). HPLC tr 9.5 minutes; LC / MS (Method F) m / z 455.3 (MH *); 'H NMR (400 MHz, DMSO-D6) d ppm 1.2 (s, 9 H) 1.8 (d, J = 10.4 Hz, 1 H) 2.1 (m, 1 H) 3.0 (t J = 10.6 Hz. 1 H) 3.1 (s, 1 H) 3.1 (d, J = 12.5 Hz, 2 H) 3.7 (m, 2 H) 7.2 (dd) J = 11.0, 8.1 Hz, 1 H) 7.4 (m, 1 H) 7.5 (s, 1 H) 8.7 (s 1 H) 10.6 (s 1 H) ppm .

Step 6. (+/-) - (10-aza-tricyclo [6.3.1.027] dodeca-2 (7), 3,5-trien-4-yl) - (4-chloro-5-trifluoromethyl-pyrimid) hydrochloride ? n-2-yl) -amine (C22): A solution of compound C21 (1.0 g, 2.2 mmol) in 12 ml of HCl in 1,4-dioxane (4 N) was stirred at approximately 25 °. C for 30 minutes, during which time a white precipitate formed. The resulting solids were collected by filtration, washed with 1,4-dioxane (2 x 25 ml) and dried under reduced pressure to give compound C22 as a white solid (912 mg, 2.0 mmol, 91%). HPLC Tr 5.2 minutes; LC / MS (Method F) m / z 355.3 (MH *); 1 H NMR (400 MHz, DMSO-d 6) d 1.98 (d, J = 11 Hz, 2 H), 2.0 (m, 2 H), 2.9 (m, 4 H), 3.17 ( d, J = 9 Hz, 3 H), 3.2 (m, 4 H), 7.29 (m, 2 H) 7.30 (d, J = 4 Hz, 1 H) 7.57 (m, 2 H) 7.66 (br s, 2 H) 8.1 (s, 1 H) 8.77 (s, 1 H) 9.45 (br s, 2 H) 10.75 (s, 1 H) ppm. Step 7. (+/-) - 1- [4- (4-Chloro-5-trifluoromethyl-pyrimidin-2-ylammon) -10-aza-tricyclo [6.3.1.02,7] dodeca-2 (7) , 3,5-trien-10-yl] -2-methoxy-ethanone (C23): A mixture of methoxyacetyl chloride (140 mg, 1.53 mmol), methoxyacetic acid (120 mg, 1.53 mmol), DIEA (1.3 ml, 7.65 mmol) and 5 ml of 1,4-dioxane was stirred for 10 minutes at 25 ° C to perform the in situ generation of methoxyacetic anhydride. The C22 compound (460 mg, 1.17 mmol) was added to the previously formed anhydride and the mixture was stirred at 25 ° C for 1 hour. Then, the reaction mixture was partitioned between EtOAc (10 ml) and saturated NaHCO 3 (10 ml) and the phases were separated. The resulting organic phase was washed with brine (2 x 20 ml), dried over Na 2 SO 4 and concentrated under reduced pressure. The resulting residue was purified on silica gel using a gradient of 10-30% EtOAc / Hexanes to give compound C23 as a white solid (480 mg, 1.12 mmol, 96% yield). HPLC Tr 6.39 minutes; LC MS (Method F) m / z 427.8 (MH *).

Step 8. Compound C23 (100 mg, 234 μmol) was treated with cyclopropylamine (26 mg, 468 μmol) and DIEA (74 μl, 468 μmol) in 2 ml of 1,4-dioxane in a pressure vessel. The contents of the reactor were stirred at 90 ° C for 1 hour and the resulting brown solution was diluted with 5 mL of EtOAc and washed with water. The organic phase was collected, concentrated under reduced pressure and purified over silica gel (50% EtOAc / Hexanes) to provide compound 10 as a white solid (52.3 mg, 0.117 mmol, 50% yield). ). HPLC Tr 6.5 minutes; LC / MS (Method F) m / z 448.1 (MH *).

Example 11 (+/-) - 1- [4- (4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -10-aza-tricyclo [6.3.1.027] dodeca-2 (7), 3,5-trien-10-yl] -2,2-difluoro-ethanone (11) Step 1. (+/-) - 1- [4- (4-Chloro-5-trifluoromethyl-pyrimidine- 2-ylamino) -10-aza-tricycle [6.3.1.027] dodeca-2 (7), 3,5-trien-10-yl] -2,2-d-fluoro-ethanone (C24): A solution of compound C22 (1 g, 2.55 mmol) DMF (5 ml) was treated with diisopropylethylamine (880 μl, 5.00 mmol) and difluoroacetic acid (200 μl, 3.06 mmol) and stirred at room temperature for 5 minutes. 0- (7-Azabenzotriazol-1-yl) -? /,? /,? / ',? /' - tetramethyluronium hexafluorophosphate (HATU) (970 mg, 2.55 mmol) was added and the mixture was stirred at 25 ° C. ° C for 30 minutes. The mixture was poured into water (50 ml) and the resulting white precipitate was collected by filtration, washed with MeOH (20 ml) and dried under reduced pressure to give compound C24 as a white powder (920 mg, , 94 mmol, yield 76%). HPLC Tr 6.55 minutes; LC / MS (Method F) m / z 433.3, 434.6, 435.3 (MH *). Step 2. Compound 11 was prepared in a manner similar to that described for compound 10 in Step 8 of Example 10 with the exception that compound C24 (125 mg, 289 mmol) was used in place of compound C23, providing Compound 11 in the form of a white solid (53 mg, 116 mol% yield). HPLC Tr 6.76; APCI m / z 454.1 (MH *) Example 12 (+/-) - 1- [4- (4-Cyclopropylmethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -10-aza-tricyclo [6.3. 1.02,7] dodeca-2 (7) .3,5-trien-10-yl] -2,2,2-trifluoro-ethanone (12) Stage 1. (+/-) - 1 - [4- (4-Chlorine -5-trifluoromethyl-pyrimidin-2-ylamino) -10-aza-tricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-trien-10-yl] -2,2,2-trifluoro-ethanone (C25): A suspension of compound C22 (1 g, 2.55 mmol) in CHCl 3 (5 ml) was treated with DIEA (1.33 ml, 7.65 mmol) and trifluoroacetic anhydride (500 μl, 3.06 mmol) and the resulting solution was stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc (5 mL), washed with saturated NaHCO 3 (2 x 10 mL) and brine (2 x 10 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The resulting brown residue was purified on silica gel (30% EtOAc / Hexanes), affording the Compound C25 as a white solid (460 mg, 102 mmol, 40% yield). HPLC tr 7.7 minutes; APCI m / z 451.2; 1 H NMR (400 MHz, DMSO-d 6) d 1, 98 (d J = 11 Hz, 1 H), 2.2 (m, 1 H), 3.17 (d, J = 12 Hz, 2 H) , 3.23 (m, 2 H), 3.59 (d, J = 12 Hz, 1 H), 3.65 (s, 1 H), 4.04 (d, J = 13 Hz, 1 H) , 7.2 (m, 1 H), 7.4 (m, 1 H), 7.6 (sa, 1 H), 8.75 (d, J = 8 Hz, 1 H), 10.6 ( s, 1 H) ppm. Step 2. Compound 12 was prepared in a manner similar to that described for compound 10 in Step 8 of Example 10 by reacting compound C25 (153 mg, 324 mmol) with cyclopropylmethylamine (46 mg, 648 mmol), affording the compound 12 in the form of a white solid (99 mg, 0.204 mmol, 63%). HPLC Tr 7.735; APCI m / z 486.4 (MH *). EXAMPLE 13 Dichlorohydrate of (+/-) -? / 2- (10-aza-tricyclo [6.3.1.027] dodeca-2 (7), 3,5-trien-4-yl) -? R'- cyclopropyl-5-trifluoromethyl-pyrimidine-2,4-diamine (13) Compound 13 was prepared in a manner similar to that described for compound 10 in Example 10 by reacting compound C21 (2.0 g, 4.4 mmol) with cyclopropylamine (410 μl, 5.9 mmol) followed by removal of the BOC group under acidic conditions using hydrochloric acid in 3 N MeOH, affording compound 13 as an off-white solid (1.89 mg, 4.22 mmol). mmol, 96% yield). LC / MS (Method F) m / z 376.3 (MH *); 1 H NMR (400 MHz. DMSO-D 6) d ppm 0.8 (m, 4 H) 2.0 (d, J = 11.2 Hz, 2 H) 2.2 (d, J = 5.0 Hz, 1 H) 3.0 (d, J = 10.4 Hz. 4 H) 3.2 (t, J = 9.3 Hz, 4 H) 7.3 (d, J = 7.9 Hz. 2 H) 7 , 8 (s, 2 H) 8.5 (s 1 H) 9.7 (s 1 H) 11.3 (s, 1 H) ppm. Example 14 (+/-) -? / 4-Cyclopropyl-? R? - (10-pyridin-2-yl-10-aza-tricyclo [6.3.1.02'7] dodeca-2 (7), 3.5- trien-4-yl) -5-trifluoromethyl-pyrimidine-2,4-diamine (14) Compound 13 (290 mg, 645 μmol) was dissolved in DMSO (2 ml) in a screw-capped pressure tube of 15 ml and the resulting solution was treated with DIEA (431 μl, 2.48 mmol) and 2-fluoropyride (125 mg, 1.29 mmol). The reaction vessel was sealed and stirred at 130 ° C for 14 hours. The contents of the reactor were cooled to 25 ° C, poured into H20 (30 ml) and stirred for 1 hour, yielding an orange gummy residue. H20 was removed by decanting and the residue was purified on silica gel (40% EtOAc / Hexanes) to provide compound 14 in the form of a whitish powder (143 mg, 49% yield). HPLC Tr 6.57 minutes; LC / MS (Method F) m / z 453.3 (MH *). Example 15 (+/-) - [4- (4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -10-aza-tricyclo [6.3.1.02-7] dodeca-2 (7), 3.5- trien-10-yl] -pyridin-3-yl-methanone (15) A solution of compound 13 (200 mg, 446 μmol) and DIEA (124 μl, 880 μmol) in 1,4-dioxane (2 ml) was treated with a portion of nicotinoyl chloride hydrochloride (80 mg, 446 μmol). The mixture was stirred at room temperature for 4 hours and concentrated under reduced pressure. The resulting residue was purified on silica (3% CH3OH / CH2Cl2) to afford compound 15 as an off-white solid (52 mg, 20% yield). HPLC tr 5.7 minutes; LC / MS (Method F) m / z 427 (MH *). Example 16 (+/-) - 1- [4- (4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -10-aza-tricyclo [6.3.1.02] dodeca-2 (7), 3, 5-trien-10-yl] -2-dimethylamino-ethanone (16) Compound 16 was prepared in a manner similar to that described for compound 15 in Example 15 by reacting compound 13 (150 mg, 337 μmol) with N, N-dimethylglycine hydrochloride (127 mg, 337 μmol), affording compound 16 as a white solid (62 mg, 0.135 mmol, 40% yield). LC / MS (Procedure F) Tr 1.4 minutes; LC / MS (Method F) m / z 461.3 (MH *). EXAMPLE 17 Ethylamide of the acid (+/-) - 4- (4-cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -10-aza-tricyclo [6.3.1.02.7) dodeca-2 (7), 3,5-trien-10-carboxylic acid (17) Compound 17 was prepared in a manner similar to that described for compound 15 in Example 15 with the exception that ethyl isocyanate (42 μl, 337 μmol) was used in place of nicotinoyl chloride hydrochloride, providing compound 17 as a white solid (120 mg, 0.270 mmol, 80% yield). HPLC tr 6.1 minutes; LC / MS (Method F) m / z 447.3.

Example 18 (+/-) - 1-. { 4- [4- (3-Morpholin-4-yl-azetidin-1-yl) -5-trifluoromethyl-pyrimidin-2-ylamino] -10-aza-tricyclo [6.3.1.027] dodeca- 2 (7), 3,5-trien-10-μl} -etanone (18) Stage 1. (+/-) - 1- [4- (4-Chloro-5-trifluoromethyl-pyrimidin-2-ylamino) -10-aza-tricyclo [6.3.1.02'7] dodeca -2 (7), 3,5-trin-10-yl] -ethanone (C26): Compound C26 was prepared in a manner similar to that described for compound 10 in Step 7 of Example 10 by reacting Compound C22 (460 mg, 1.17 mmol) with acetic anhydride (91 μL, 1.17 mmol) to afford compound C26 as a light yellow solid (309 mg, 0.725 mmol, 62% yield). HPLC Tr 6.5 minutes; LC / MS (Method F) m / z 427.3 (MH *); 1 H NMR (400 MHz, DMSO-d 6) d 1.65 (s, 3 H), 1.84 (d, J = 11 Hz, 1 H), 2.18 (m.H.), 2.86 ( d, J = 3 Hz, 1 H), 3.127 (sa, 2H), 3.4 (d J = 6 Hz, 1 H), 3.57 (d, J = 12 Hz, 1 H), 4.03 ( d.J = 12 Hz. 1 H), 7.16 (dd, J = 8, 8 Hz, 1 H), 7.36 (d, J = 8 Hz, 1 H), 7.53 (d, J = 19 Hz, 1 H), 8.75 (s, 1 H), 10.58 (s, 1 H) ppm. Step 2. 1-Azetidin-3-yl-morpholine dichlorohydrate (C27): A sealed pressure tube was charged with 3-methanesulfonyloxy-azetidine-1-carboxylic acid ferrickeptide ester (5.00 g). , 19.9 mmol) (see Apderson, et al, JOC, 1972, 37, 3953), DMSO (10 ml), morpholine (5.4 g, 59.7 mmol) and DIEA (3.4 ml, 19, 9 mmol). The mixture was heated to 103 ° C. After 12 hours, EtOAc (50 ml) was added and the resulting mixture was filtered. The filtrate was washed with 2 x 100 ml of water and 2 x 100 ml of brine, dried over K2CO3 and concentrated. The resulting residue was purified on silica gel (75% EtOAc / Hexanes) and concentrated to give a clear oil (2.8 g). The oil was dissolved in 1.25 N HCl in MeOH and heated to reflux for 3 hours. The mixture was concentrated under reduced pressure and the resulting residue was triturated with pentane (20 ml) to afford compound C27 (2.0 g, 10.05 mmol, 50.5% yield). 1 H NMR (400 MHz, DMSO-d 6) d 1.91 (d, J = 41 Hz. 4 H). 2.93 (s a, 2 H). 3.41 (s a, 3 H). 4.04 (m. 3 H), 4.32 (m, 4H) ppm. Step 3. A mixture of compound C26 (200 mg, 503 μmol), DIEA (350 μl, 2.0 mmol) and compound C27 (154 mg, 503 μmol) in 1,4-dioxane (2 ml) was reacted at 90 ° C for 12 hours. The mixture was concentrated under reduced pressure and the resulting residue purified on a silica (2% CH3OH / CH CI2) to afford compound 18 as an off-white solid (120 mg, 0.236 mmol, 47% yield). LC / MS (Method F) Tr 1.7 minutes, LC / MS (Method F) m / z 503.3 (MH *). Example 19 vJ, Ethyl -? / 2- (10-ethyl-10-aza-tricyclo (6.3.1.027) dodeca-2 (7), 3,5-trien-4-yl) -5-trifluoromethyl- pyrimidine-2,4-diamine (19) Stage 1. Hydrochloride salt of (+/-) - 10-ethyl-4-nitro-10-aza-tricyclo [6.3.1.02'7] dodeca-2 (7), 3 , 5-triene (C28): To a stirred solution of compound C18 (500 mg, 2.43 mmol) in acetonitrile (10 ml) was added dropwise ethyl iodide (165 μl, 2.43 mmol) at 25 ° C. C. The reaction mixture was allowed to stir for 12 hours at 25 ° C, the resulting yellow precipitate was collected by filtration and dried to give compound C28 (540 mg, 1.38 mmol, 57% yield). HPLC Tr 3.11 minutes; LC / MS (Method F) m / z 231.3 (MH *); * H NMR (400 MHz, DMSO- g) d 1.04 (t, J = 7 Hz, 3 H), 2.09 (d, J = 11 Hz, 1 H), 2.23 (m, 1 H), 3.04 (m, 2 H), 3.35 (m, 4 H), 3.51 (m). sa, 2 H), 7.62 (d, J = 8 Hz, 1 H), 8.2 (m, 2 H) ppm, Stage 2. (+/-) - 10-Etl-10-aza -trip [6.3.1.02'7] dodeca-2 (7), 3,5-trien-4-ylamine (C29): A container of hydrogenation was charged Nation with Parr® shaker with compound C28 (1.2 g, 5.14 mmol), MeOH (15 ml), NaOH flakes (200 mg, 5.14 mmol) and 10% Pd / C (120 mg) and the contents of the reactor were stirred at 344.74 kPa (50 psi) of H2 for 14 hours at about 25 ° C. The reaction mixture was filtered through Celite® and concentrated to give compound C29 as a white solid. (860 mg, 83% yield). HPLC Tr 2.12 minutes; LC / MS (Method F) m / z 202.1; 1 H NMR (400 MHz, DMSO-d 6) d ppm 0.77 (t, J = 7.3 Hz, 3 H) 1.49 (d J = 10.0 Hz, 1 H) 2.01 (m, 1 H ) 2.17 (t, J = 9.3 Hz, 2 H) 2.23 (c, J = 7.3 Hz, 2 H) 2.65 (m, 2 H) 2.85 (s.2 H) ) 4.7 (s, 2 H) 6.23 (d, J = 7.9 Hz, 1 H) 6.34 (s, 1 H) 6.71 (d J = 7.9 Hz. 1 H ) ppm. Step 3. (+/-) - (4-Chloro-5-trifluoromethyl-pyrimidin-2-yl) - (10-ethyl-10-aza-tricyclo [6.3.1.02'7] dodeca-2 (7) hydrochloride salt ), 3,5-trien-4-yl) -amine (C30): Compound C30 was prepared in a manner similar to that described in Step 5 of Example 10 with the exception that compound C29 (860 mg , 4.27 μmol) in place of compound C20, giving the free base form of compound C30 (600 mg, 1.58 mmol, 37% yield). The free base form of compound C30 was dissolved in 1 N HCl in MeOH (5 ml), stirred for 1 hour and concentrated to give compound C30 (718 mg, 1.58 mmol, 100% yield). LC / MS (Method F) Tr 2.4 min; LC / MS (Method F) m / z 383.2 (MH +). Step 4. A mixture of compound C30 (173 mg, 412 mmol), 1,4-dioxane (2 ml), DIEA (215 μl, 1.23 mmol) and 2 M ethylamine in THF was stirred at 90 ° C for 12 hours. hours and concentrated. The resulting residue was purified on silica gel (6-8% CH3OH / CH2Cl2) to afford compound 19 as a light yellow solid (30 mg, 18% yield). HPLC Tr 5.48 minutes; LC / MS (Method F) m / z 392.3 (MH *). Example 20 (-) - 2-Methoxy-1-. { 4- [4- (2-methoxy-ethylamino) -5-trifluoromethyl-pyrimidin-2-ylamino-J- (1R, 8S) -10-aza-tricyclo [6.3.1.027] dodeca-2 (7), 3,5-trien-10-yl) -ethanone (20) Stage 1. (-) - 4-Nitro-10-aza-tricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-triene (C31): The racemic compound C18 (13.68 g, 67 mmol) was resolved by chemical chromatography using a 50/50 ethanol / heptane solution on a ChiralPak AD column (10 cm x 50 cm), flow rate 450 mL, , 84 g per injection. The optical rotation of each isolated enantiomer was calculated using a JASCO® polarimeter: Peak 1: Tr = 14.44 min. [α] D -12.93 ° (c = 0.0117, CH2Cl2), (-) - 4-Nitro-10-aza-tricyclo [6.3.1.02] dodeca-2 (7), 3,5-trinose ( C31) (6.5 g, 32.1 mmol, 96% yield) Peak 2: Tr = 20.56 min. [a] D + 12.85 ° (c = 0.0115, CH2Cl2), (+) - 4-Nitro-10-aza-tricyclo [6.3.1.02] dodeca-2 (7), 3.5-tr eno (C32) (6.5 g, 32.1 mmol, 96% yield). Step 2. (-) - (4-Iodo-phenyl) - (1 R, 8S) - (4-nitro-10-aza-tricycloI6.3.1.02, 7] dodeca-2 (7), 3,5-trien-10-yl) -methanone (C33): A mixture of compound C31 (1.3 g, 4.89 mmol) and 4-iodobenzoyl chloride (1 , 0 g, 4.89 mmol) in MeCN (10 mL) was stirred at 25 ° C for 2 hours. The resulting precipitate was collected by filtration, washed with cold MeCN (10 ml) and dried under reduced pressure to give compound C33 as a white solid (1.35 g, 2.88 mmol, 59% yield) . A 100 mg portion of compound C33 was recrystallized from hot ethanol. The resulting orthorhombic crystals were examined by monocrystal crystal X-ray crystallography and the results confirmed the structure shown for compound C33. 1 H NMR (400 MHz, DMSO-D6) d ppm 2.0 (t, J = 11.0 Hz, 1 H) 2.2 (d, J = 5.4 Hz, 1 H) 3.1 (dd, J = 12.0, 5.0 Hz, 1 H) 3.2 (s, 1 H) 3.4 (d, J = 18.3 Hz, 1 H) 4.4 (d, J = 12.0 Hz, 1 H) 6 , 6 (d, J = 4.6 Hz, 2 H) 7.4 (d, J = 7.9 Hz, 1 H) 7.5 (d, J = 7.9 Hz, 1 H) 7.7 (t, J = 8.1 Hz, 4 H) 8.0 (s, 1 H) 8.1 (m, 3 H) ppm. HPLC tr 6.9 minutes; [α] D21 -59.4 ° (c = 0.011, CH2Cl2); LC / MS (Method F) m / z 435 (MH *). Step 3. (-) - 2-Methoxy-1 - ((1R, 8S) -4-nitro-10-aza-tricyclo [6.3.1.02 7] dodeca-2 (7), 3,5-trien-10- 1) -etanone (C34): Compound 34 was prepared in a manner similar to that described for compound C23 in Step 7 of Example 10 with the exception that compound C31 (2.00 g, 9, 79 mmol) was added in place of the C22 compound, yielding the compound C34 as a white solid (1.68 g, 62% yield). 1 H NMR (400 MHz, DMSO-D 6) d ppm 2.0 (d, J = 11.2 Hz, 1 H) 2.2 (d, J = 5.4 Hz, 1 H) 2.9 (m, 3 H) 3.0 (dd, J = 12.7, 3.9 Hz, 2H) 3.4 (m, 2 H) 3.7 (m, 3H) 4.1 (d, J = 12.5 Hz, 1 H) 7.5 (dd, J = 16.6, 7.9 Hz, 1 H) 8.1 (m, 2 H) ppm. HPLC Tr 4.56 minutes; [ajD -12.27 ° (c = 0.010, CH2Cl2); LCMS (Method F) m / z 277.3 (MH +). Step 4. (-) - 1 - ((1R-8S) -4-amine-10-aza-tricyclo [6.3.1.027] dodeca-2 (7), 3,5-trien-10-yl) -2- methoxy-ethanone (C35): Compound 35 was prepared in a manner similar to that described for compound C21 in Step 5 of Example 10 with the exception that compound C34 (1.68 g, 6.07 mmol) was used. ) in place of compound C20, yielding compound C35 as a white solid (1.5 g, 6 mmol, 99%). 1 H NMR (400 MHz, DMSO-D6) d ppm 1.8 (d, J = 10.4 Hz, 1 H) 2.1 (m, 1 H) 2.8 (dd, J = 11, 4, 6 , 9 Hz, 1 H) 3.0 (s, 3 H) 3.0 (d, J = 5.8 Hz, 2 H) 3.3 (m.1 H) 3.5 (m, 1 H) 3.7 (m, 2 H) 4.0 (m, 1 H) 4.8 (s, 2 H) 6.3 (m, 1 H) 6.4 (dd, J = 23, 2 Hz, 1 H) 6.8 (dd, J = 19.9, 7.9 Hz, 1 H) ppm. HPLC Tr 3.054 minutes; [α] D -11.3 ° (c = 0.009, CH2Cl2); LC / MS (Method F) m / z 248.3 (MH *). Step 5. (-) - 1 - [4- (4-Chloro-5-trifluoromethyl-pyrimidin-2-ylamino) - (1 R, 8S) -10-aza-tricyclo [6.3.1.02,7] dodeca -2 (7), 3,5-trien-10-yl] -2-methoxy-ethanone (C36): A mixture of 5-trifluoromethyl-2,6-dichloropyrimidine (1.3 g, 6, 12 mmol) and 22 ml of (1: 1) (vol: vol) of f-BuOH / DCE was cooled to 0 ° C under a nitrogen atmosphere and treated with ZnCl2 (12.24 ml, 1 M in Et20). . The mixture was stirred for 1 hour at 0 ° C and then treated with compound C35 (1.5 g, 6.12 mmol). The contents of the reactor were stirred for a further 45 minutes at 0 ° C and then treated dropwise with Et3N (904 μL, 6.73 mmol). The reaction mixture was allowed to warm to 25 ° C, stirred for 2 hours. hours and concentrated under reduced pressure. The resulting residue was triturated with CH3OH, filtered and the filtrate was concentrated to dryness to give compound C36 as a white solid (1.6 g, 3.06 mmol, 50% yield). HPLC Tr 6.39 minutes; CUEM (Method F) m / z 427.8 (MH *); [] D = -10.2 °. Step 6. Compound 20 was prepared in a manner similar to that described for compound 10 in Step 8 of Example 10 by reacting compound C36 (250 mg, 585 μmol) with 2-methoxy-1-e'lamin (104 mg, 1.17 mmol), affording compound 20 as a white solid (66 mg, 24% yield). MS (Method F) Tr 1.9 minutes; LC / MS (Method F) m / z 466.3 (MH *). Example 21 (+) - 2-Methoxy-1-. { 4- [4- (2-methoxy-ethylamino) -5-trifluoromethyl-pyrimidin-2-ylammon] - (1S, 8R) -10-aza-tricyclo [6.3.1.02,7] dodeca-2 (7) , 3,5-trien-10-yl) -ethanone (21) Step 1: (+) - 2-Methoxy-1 - ((1S, 8R) -4-nitro-10-aza-tricyclo [6.3. 1.02'7] dodeca-2 (7), 3,5-trien-10-yl) -ethanone (C37): Compound C37 was prepared in a manner similar to that described for compound C34 in Step 7 of Example 10, with the exception that compound C32 (2.00 g, 9.79 mmol) was used in place of compound C22, yielding compound C37 as a pale yellow solid (1.68 g, 62%). 1 H NMR (400 MHz, DMSO-D6) d 2.0 (d, J = 11.2 Hz, 1 H) 2. 2 (d, J = 5.4 Hz, 1 H) 2.9 (m.3 H) 3.0 (dd, J = 12.7, 3.9 Hz. 2 H) 3.4 (m.2 H) 3.7 (m, 3 H) 4.1 (d, J = 12.5 Hz, 1 H) 7.5 (dd, J = 16.6, 7.9 Hz. 1 H) 8.1 (m. H) ppm. HPLC Tr 4.56 minutes; LC / MS (Method F) m / z 277.3 (MH *). Step 2. (+) - 1 - ((1S, 8R) -4-Amino-10-aza-tricyclo [6.3.1.0z'7] dodeca-2 (7), 3,5-trien-10-yl) -2-methoxy-ethanone (C38): Compound C38 was prepared in a manner similar to that described for compound C21 in Step 4 of Example 10 with the exception that compound C37 (1.68 g, , 07 mmol) in place of compound C19, giving compound C38 as a white solid (1.5 g, 6.0 mmol, 99% yield). 1 H NMR (400 MHz, DMSO-D 6) d ppm 1.8 (d, J = 10.4 Hz, 1 H) 2.1 (m, 1 H) 2.8 (dd J = 11.4, 6.9 Hz, 1 H) 3.0 (s, 3 H) 3.0 (d, J = 5.8 Hz. 2 H) 3. 3 (m, 1 H) 3.5 (m, 1 H) 3.7 (m 2 H) 4.0 (m, 1 H) 4.8 (s.2 H) 6.3 (m.1 H) 6.4 (m. dd, J = 23, 2 Hz, 1 H) 6.8 (dd, J = 19.9, 7.9 Hz, 1 H) ppm. HPLC Tr 3.05 minutes; [a] D + 12.05 °; LC / MS (Method F) m / z 248.3 (MH *). Step 3. (+) - 1 - [4- (4-Chloro-5-trifluoromethyl-pyrimidin-2-ylamino) - (1S, 8R) -10-aza-tricyclo [6.3.1.02.7 ] dodeca-2 (7), 3,5-trien-10-yl] -2-methoxy-ethanone (C39): Compound C39 was prepared in a manner similar to that described for compound C21 in Step 5 of Example 10 with the exception that compound C38 (1.5 g, 6.12 mmol) was used in place of compound C20, yielding compound C39 as a white solid (1.7 g, 51% yield). HPLC Tr 6.39 minutes; LC / MS (Method F) m / z 427.8 (MH *); [a] D = + 12.04 °. Step 4. Compound 21 was prepared in a manner similar to that described for compound 10 in Step 8 of Example 10 by reacting compound C39 (250 mg, 585 μmol) with 2-methoxy-1-ethylamine (104 mg, 1.17 mmol), affording compound 21 as a white solid (110 mg, 0.234 mmol, 40% yield). LC / MS (Method F) Tr 1.9 minutes; LC / MS (Method F) m / z 466.3 (MH *). Example 22 (+/-) - V4-Cyclobutyl -? / - (9-methanesulfonyl-1, 2,3,4-tetrahydro-1,4-epiazano-naphthalen-6-yl) -5-trifluoromethyl-pyrimidine -2,4-diamine (22) Step 1. (+/-) 6-Nitro-1, 2,3,4-tetrahydro-1,4-epivazane-naphthalene-9-carboxylic acid tert-butyl ester (C40) ): To a solution of (+/-) 6-nitro-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-trifluoroacetamide (16.65 g, 64.3 mmol) in 200 ml of THF was added dropwise a solution of LiOH monohydrate (5.4 g, 128.6 mmol) in 50 ml of water. The resulting mixture was stirred at 25 ° C for 1 hour and treated with di-f-butyl dicarbonate (21.1 g, 96.5 mmol). The resulting suspension was stirred for 2 hours at 25 ° C and concentrated under reduced pressure. Then, the resulting residue was partitioned between 100 ml of saturated NaCl and 3 x 100 ml of CHCl3. The combined organic phases were dried over MgSO4 and concentrated under reduced pressure. The resulting orange solid was passed through a pad of 250 g of silica gel (230-400 mesh) eluting with 5% EtOAc / hexanes, while collecting 250 ml fractions. Fractions containing the C40 compound were combined and concentrated to give the compound C40 racemate in form of a pale yellow solid (14.4 g, 50.2 mmol 78%). 1 H NMR (400 MHz, DMSO-d 6) d 1.18 (m, 2 H), 1.29 (s, 9 H), 2.04 (m, 2 H), 5.20 (m, 2 H) , 7.56 (m, 1 H), 8.08 (m, 1 H), 8.18 (m, 1 H) ppm.

Step 2. An amount of 200 g (0.685 mol) of compound C40 was resolved using chiral preparative chromatography under the following conditions: Column: ChiralCel OJ 10 x 50 cm; particle size: 20 μm; flow rate: 400 ml / min; Detection: UV 300 nm; Feeding concentration: 20 mg / ml in 50/50 of IPA / Heptane; injection volume: 106 ml / injection; mobile phase: 15/85 IPA / Heptane; Processing time: 17 min / injection. The injections were pooled and two fractions were collected for each injection, one for the enantiomer 1 isomer (-) and the other for the enantiomer 2 isomer (+). The separation provided the following enantiomers: 93.5 g of 6-nitro- (1S, 4R) -1,2,3,4-tetrahydro-1,4-epiazano-naphthalene-9-carboxylic acid fer-butyl ester ( C41) (the enantiomerically pure (-) isomer of the racemic compound C40). 1 H NMR (400 MHz. DMSO-d 6) d 1.21 (m.2 H), 1.29 (s.9 H), 2.04 (m, 2 H), 5.19 (m.2 H), 7.56 (d, J = 8 Hz, 1 H), 8.08 (m, 1 H), 8.18 (d, J = 3 Hz, 1 H) ppm. [a] D (CH2Cl2) = -14.0 °. 93.5 g of 6-nitro- (1R, 4S) -1, 2,3,4-tetrahydro-1,4-epiazano-naphthalene-9-carboxylic acid (C42) ferric-butyl ester (the isomer (+ enantiomerically pure of the racemate compound C40). 1 H NMR (400 MHz, DMSO-d 6) d 1.21 (m, 2 H), 1.30 (s, 9 H), 2.02 (m, 2 H), 5.19 (m, 2 H) , 7.56 (d, J - 8 Hz, 1 H), 8.07 (m, 1 H), 8.18 (d, J = 3 Hz, 1 H) ppm. [a] D (CH2Cl2) = + 12.9 °. Stage 3. Ferric-butyl acid ester (+/-) - 6-amino-1, 2,3,4-tetrahydro-1,4-epiazane-naphthalene-9-carboxylic acid (C43): Compound C43 was prepared in a manner similar to that described for compound C20 in Step 4 of Example 10 with the exception that Compound C40 (5.0 g, 17.2 mmol) was used in place of Compound C19, giving Compound C43 as a gray solid (4.4 g, 17.0 mmol, 99% yield) . 1 H NMR (400 MHz, DMSO) d 6.89 (d J = 7.75 Hz, 1 H), 6.51 (d, J = 1.56 Hz, 1 H), 6.27 (dd, J = 7.75 Hz. 1H). 4.94 (s.2H). 4.84 (t, J = 3 Hz. 1H), 1.92 (d, J = 7.26 Hz, 2H). 1.33 (s, 9H). 1.13 (d, J = 6.22 Hz, 2H); MS: 261.3 (MH *); HPLC tr: 5.9 min; HPLC purity: 100%. Step 4. (+/-) - 6- (4-Chloro-5-trifluoromethyl-pyrimidin-2-ylamino) -1,2,3,4-tetrahydro-1,4-epiazano-naphthalene tert-butyl ester -9-carboxylic acid (C44): Compound C44 was prepared from a similarly to that described for compound C21 in Step 5 of Example 10 with the exception that compound C43 (1.5 g, 5.76 mmol) was used in place of compound C20, providing compound C44 in the form of a white solid (2.14 g, 84%). Regiochemistry was confirmed by x-ray crystallography. 1 H NMR (400 MHz, DMSO) d 10.6 (s, 1H), 8.75 (s, 1H), 7.61 (s, 1H), 7.39 (dd, J = 3.95 Hz, 1H ), 7.25 (d, J = 8.31 Hz, 1H), 4.99 (d, J = 8.68 Hz, 2H), 1.97 (d, J = 8.3 Hz. 2H), 1.29 (s, 9H), 1.16 (d, J = 7.0 Hz, 2H). MS: 441.0 / 443.0 (MH *); HPLC tr; 8.50 min; purity by HPLC; 100% Stage 5. (+/-) - 6- (4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -1,2,3,4-tetrahydro-1,4-epiazano-butyl ether ester Naphthalene-9-carboxylic acid (C45): Compound C44 was prepared in a manner similar to that described for compound 10 in Step 8 of Example 10 by reacting compound C44 (0.4 g, 0.9 mmol) with Cyclobutylamine (0.16 g, 2.72 mmol) to give compound C45 as a white solid (2.88 g, 89%). 'H NMR (500 MHz, DMSO-d6) d 9.6 (s, 1 H), 8.179 (s, 1 H), 7.81 (s, 1 H), 7.38-7.37 (m, 1 H ), 6 7.2 (d, J = 8 Hz 1 H); 7.01 (d, J = 6.7 Hz, 1 H), 4.985 (t, J = 4 Hz, 2 H), 4.616 (m, 1 H), 2.28-2.14 (m.4 H), 2, 01 (m 2 H), 1.71-1.62 (m, 2 H), 1.33 (s, 9 H), 1.20 (m, 2 H); MS: 476.3 (MH +); HPLC tr: 8.8 mip; HPLC purity: 100%. Step 6. Dihydrochloride (+/-) - V4-cyclobutyl-? 2- (1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-6-yl) -5-trifluoromethyl-pyrimidin-2,4-diamine (C46): A solution of compound C45 (2.73 g, 5.74 mmol) and HCl (3 M in MeOH, 20 mL) was heated at 50 ° C. After 2 hours, the mixture was concentrated under reduced pressure, diluted with EtOAc and the resulting solid was collected by filtration to give compound C46 as a white solid (2.4 g, 93%). 'H NMR (400 MHz, DMSO-d6) d 10.9 (a.1 H), 9.6 (d, J = 7.9 Hz, 1 H), 9.37 (d, J = 7.9 Hz, 1 H), 8.39 (s, 1 H). 8.10 (a, 1 H), 7.77 (d.J = 1 Hz, 1 H). 7.52-7.50 (m, 1 H). 7.42 (d.J = 7.9 Hz, 1 H), 6.6 (a, 1 H). 5.21-5.18 (m, 2 H), 4.58-4.52 (m, 1 H), 2.27-2.14 (m, 6 H), 1.7-1.61 (m.2H). 1.37 (d, J = 8.3 Hz, 2 H); MS: 376.1 (MH +); HPLC Tr: 5.3 min; HPLC purity: 100%. Step 7. To a solution of compound C46 (75 mg, 0.17 mmol) and DIEA (65 mg, 0.5 mmol) in dichloromethane (4 ml) was added methanesuifonyl chloride (24 mg, 0.21 mmol). . After 20 min, the mixture was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography on silica gel (99: 1 CH2Cl2 / MeOH) to afford compound 22 as a white solid (65 mg, 86%). 1 H NMR (500 MHz, DMSO-d 6) d 9.7 (a, 1 H), 8.19 (s, 1 H), 7.87 (s, 1 H), 7.42 (m, 1 H) , 7.2 (d, J = 7.7 Hz, 1 H), 7.03 (d, J = 6.7 Hz, 1 H), 5.04 (s, 2 H), 4.61 (m , 1 H), 2.3 (s, 3 H), 2.25-2.12 (m, 6 H), 1.7 (m, 2 H), 1.3 (m, 2 H); MS: 454.0 (MH *); HPLC Tr: 7.11 min; HPLC purity: 100%. Example 23 (+/-) - 1- [6- (4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl ] -etanone (23) To a solution of compound C46 (75 mg, 0.17) and DIEA (65 mg, 0.5 mmol) in CH2Cl2 (4 ml) was added acetyl chloride (13.1 mg, 17 mmol). After 20 min, the mixture was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography on silica gel (98: 2 CH2Cl2 / MeOH) to afford compound 23 as a white solid (44 mg , 107 mmol, 63%). 1 H NMR (500 MHz. DMSO-d 6) d 9.6 (a, 1 H), 8.17 (s, 1 H), 7.8 (m, 1 H), 7.4 (m, 1 H) , 7.2 (m, 1 H), 7.0 (m, 1 H), 5.3-5.2 (m, 2 H), 4.6 (m, 1 H), 2.26-1 , 97 (m, 6 H), 1.9 (s, 3 H), 1.72-1.62 (m, 2 H), 1.3-1.16 (m, 2 H); MS: 418.1 (MH *); HPLC tr: 6.71 min; HPLC purity: 100%. Examples 24 to 28 The compounds of Examples 24 to 28 (Table 1) were prepared in a manner similar to that described for compound 23 in Example 23. Example 29 (+/- H6- (4-Cyclobutylamino-5-trifluoromethyl) -pyrimidin-2-ylamino) -1, 2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl] -pyrrolidin-1-yl-methanone (29) Stage 1. 4-Nitro-phenylester of acid (+/-) - 6- (4-cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -1,2,3,4-tetrahydro-1,4-epiazane-naphthalene-9-carboxylic acid (C47): Compound C47 was prepared in a manner similar to that described for compound 24 in Example 24 with the exception that 4-nitrophenyl chloroformate (0.45 g, 2.23 mmol) was used in place of methyl chloroformate to provide compound C47 in the form of a white solid (1.0 g, 83%). 1 H NMR (500 MHz, DMSO-d 6) d 9.6 (a.1 H), 8.26-8.23 (m.2 H). 8.18 (s, 1 H). 7.88 (a.1 H). 7.43 (a.1 H), 7.36 (d, J = 8.8 Hz, 2 H), 7.29 (d, J = 7.1 Hz, 1 H), 7.036 (d, J = 6.7 Hz, 1 H), 5.44 (a, 1 H) , 5.22 (a, 1 H), 4.6 (m.1 H), 2.24-2.10 (m, 6 H), 1.64 (a, 2 H), 1.33 (a , 2 H) ppm. MS: 541.4 (MH *); HPLC Tr: 8.5 min; HPLC purity: 100%. Step 2. A solution of compound C47 (90 mg, 0.17 mmol), pyrrolidine (18 mg, 0.25 mmol) and DIEA (43 mg, 0.33 mmol) in DMF (2 ml) was heated to 50 ° C. C. After 2 hours, the mixture was diluted with H20 and extracted with EtOAc. The combined organic phases were washed with water, dried over Na 2 SO 4 and concentrated under reduced pressure. The resulting residue was purified by 12S Instantaneous Biotage® (98: 2 CH2Cl2 / MeOH) to afford compound 29 as a white solid (34 mg, 43%). H NMR (500 MHz, DMSO-d6) d 9.5 (a, 1 H), 8.16 (s, 1 H). 7.74 (s, 1 H), 7.34 (m, 1 H), 7.15 (d J = 8.3 Hz, 1 H), 7.0 (d, J = 6.7 Hz, 1 H), 4.99 (s, 2 H), 4.6 (a, 1 H), 3.2 (a, 4 H), 2.25-2.11 (m 4 H), 2.04- 2.03 (m, 2 H), 1, 74-1.60 (m, 6 H), 1.17-1.15 (m, 2 H) ppm. MS: 473.5 (MH *) Example 30 (+/-) - 6- (4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -1, 2,3,4-tetrahydro cyclopropylamide -1,4-epiazane-naphthalene-9-carboxylic acid (30) Stage 1. 4-Nitro-phenylester of cyclopropyl-carbamic acid (C48): To a solution of cyclopropylamine (0.5 g, 8.7 mmol) and DIEA (2.2 g, 17.1 mmol) in THF (25 mL) was added 4-nitrophenyl chloroformate (1.7 g, 8.7 mmol). After 20 min, the reaction mixture was quenched with H20 and the phases were separated. The aqueous phase was extracted with EtOAc and the combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was crystallized from hexanes EtOAc to give compound C48 as a pale yellow solid (0.2 g, 0.87 mmol, 10% yield). 1 H NMR (400 MHz, DMSO-dβ) d 8.2 (m, 3 H), 7.3 (m, 2 H), 2.5 (m, 1 H), 0.6 (m, 2 H) , 0.4 (m.2 H) ppm. HPLC Tr: 5.2 min; HPLC purity: 100%. Step 2. A solution of compound C46 (0.1 g, 0.22 mmol), C48 (75 mg, 0.34 mmol) and DIEA (115 mg, 0.15 ml) in DMF (1 ml) was stirred at 25 ° C for 2 hours. Then, the mixture was partitioned between EtOAc and H20 and the phases were separated. The organic phase was washed with water, dried over Na 2 SO 4 and concentrated under reduced pressure. The resulting residue was purified by Biotage® Instantaneous 12S (99: 1 CH2Cl2 / MeOH), affording compound 30 as a white solid (73 mg, 71%). 1 H NMR (500 MHz, DMSO-dβ) d 9.5 (a, 1 H), 8.17 (s, 1 H), 7.74 (s, 1 H), 7.3 (m, 1 H) , 7.15 (d, J = 1 Hz, 1 H), 7.0 (1, J = 6.7 Hz, 1 H), 6.8 (d, J = 3.6 Hz, 1 H), 5.08 (s, 2 H), 4.6 (a, 1 H), 2.4 (m, 1 H), 2.28-2.13 (m, 4 H), 1.9 (m, 2 H) ), 1.7 (m, 2 H), 1.1 (m, 2 H), 0.5 (m, 2 H), 0.3 (m, 2 H) ppm. MS: 459.5 (MH *); HPLC tr: 6.63 min; HPLC purity: 100%. Example 31 (+/-) - 1- [6- (4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -1,2,3,4-tetrahydro-1,4-epiazane-naphthalene-9 -yl] -2-morpholin-4-yl-ethanone (31) To a solution of compound 28 (50 mg, 0.11 mmol) and DIEA (29 mg, 0.22 mmol) in THF 1 ° (2 ml) was added morpholine (38 mg, 0.22 mmol) and the resulting mixture was stirred for 2 days at about 25 ° C. Then, the mixture was partitioned between EtOAc and H20 and the phases were separated. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by 12 M instantaneous Biotage® (98: 2 CH2Cl2 / CH3OH) to afford compound 31 as a white solid (30 mg, 55%). 1 H NMR (500 MHz, DMSO-d 6) d 9.6 (m, i5 1 H), 8.18 (s, 1 H), 7.82 (d, J = 23 Hz. 1 H), 7.4 (m, 1 H), 7.2 (m, 1 H), 7.01 (m, 1 H), 5.5 (s, 1 H), .34 (s, 1 H), 4.6 (a, 1 H), 3.5 (s, 4 H), 3.1-3.0 (m, 2 H), 2.36-2.11 (m, 9 H) ), 1.95 (m.H.), 1.66 (m, 2 H), 1.25 (m, 2 H) ppm. MS: 503.2 (MH *); HPLC tr: 6.3 min; HPLC purity: 100%. EXAMPLE 32 Dihydrochloride of (+/-) - / V ¥ -cyclopropyl- / V2- (1, 2,3,4-tetrahydro-1,4-epiazano-naphthalen-6-yl) -5- 20 trifluoromethyl- pyrimidine-2,4-d-amines (32) Stage 1. (+/-) - 6- (4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -1,2,3-tert-butyl ester , 4-tetrahydro-1,4-epipane-naphthalene-9-carboxylic acid (C49): Compound C49 was prepared in a manner similar to that described for compound C45 in Step 5 of Example 22 by reacting compound C44 (0.5 g, 1.13 mmol) with cyclopropylamine (77 mg, 1.36 mmol), affording compound C49 as a white solid (0.41 g, 80%). 1 H NMR (400 MHz, DMSO-d 6) d 9.6 (a, 1 H), 8.15 (s, 1 H). 7.94 (1H). 7.52 (d, J = 8 Hz, 1 H), 7.15 (m, 2 H). 4.92 (d, J = 6 Hz, 2 H), 2.8 (m, 1 H). 1.95 (m 2 H). 1.28 (s.9 H). 1.14 (d.J = 8 Hz. 2 H), 0.74 (d, J = 7 Hz, 2 H). 0.65 (d, J = 3 Hz, 2 H) ppm. MS: 462.1 (MH *); HPLC Tr: 8.2 min; HPLC purity: 100%.

Step 2. Compound 32 was prepared in a manner similar to that described for compound C46 in Step 6 of Example 22 with the exception that compound C49 (0.38 g, 0.83 mmol) was used instead of compound C45, providing compound 32 as a white solid (0.36 g, 100%). 1 H NMR (500 MHz. DMSO-d 6) d 10.8 (a, 1 H), 9.47 (d, J-8 Hz, 1 H), 9.31 (d, J = 8 Hz. 1 H) , 8.4 (s, 1 H), 8.03 (s, 2 H), 1.7 (d, J = 7 Hz, 1 H), 7.42 (d, J = 8 Hz, 1 H) , 5.22 (m, 2 H), 4.8 (a, 1 H), 2.9 (m, 1 H), 2.2 (m, 2 H), 1.4 (m, 2 H), 0.83 (m, 2 H), 0.74 (m, 2 H) ppm. MS: 362.1 (MH *). Example 33 Dihydrochloride of (+/-) - V4-cyclopentyl- / V2- (1, 2,3,4-tetrahydro-1,4-epiazano-naphthalen-6-yl) -5-trifluoromethyl-pyrimidin-2,4 -diamine (33) Stage 1. Tert-butyl alcohol (+/-) - 6- (4-cyclopentylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -1,2,3,4-tetrahydro-1-tert-butyl ester , 4-epipane-naphthalene-9-carboxylic acid (C50): Compound C50 was prepared in a manner similar to that described for compound C44 in Step 4 of Example 22 by reacting compound C44 with cyclopentylamine (119 mg, 1.35 mmol) to give compound C50 as a white solid (0.38 g, 70%). 1 H NMR (400 MHz, DMSO-d 6) d 9.5 (a, 1 H), 8.14 (s, 1 H), 7.78 (s, 1 H), 7.33 (m, 1 H) , 7.15 (m, 1 H), 6.51 (m, 1 H). 4.93 (m, 2 H), 4.4 (m, 1 H), 1.9 (m, 4 H), 1.7 (m, 2 H), 1.54 (m, 4 H), 1, 29 (s, 9 H), 1.15 (m, 2 H) ppm. MS: 490.1 (MH *); HPLC Tr: 9.1 min; HPLC purity: 100%. Step 2. Compound 33 was prepared in a manner similar to that described for compound C46 in Example 22 with the exception that compound C50 (341 mg, 0.697 mmol) was used in place of compound C45, affording compound 33 in the form of a white solid (0.32 g, 100%). 1 H NMR (500 MHz, DMSO-d 6) d 10.7 (a, 1 H), 9.54 (d J = 8.3 Hz. 1 H). 9.4 (d, J = 7.7 Hz, 1 H), 8.38 (s, 1 H). 7.82 (s, 1 H), 7.55 (m, 1 H), 7.42 (m, 1 H). 5.2 (s, 2 H), 4.48 (m, 1 H), 2.27 (m, 2 H), 1.9 (m 2 H), 1.75-1, 62 (m, 4 H), 1.59-1.54 (m, 2 H). 1.39 (m, 2 H) ppm. MS: 390.1 (MH *). EXAMPLE 34 Dihydrochloride of (+/-) - / V'-methyl-? / 2- (1, 2,3,4-tetrahydro-1,4-epiazano-naphthalen-6-yl) -5- trifluoromethyl-pyrimidin- 2,4-diamine (34) Stage 1. Ferric-butyl acid ester (+/-) - 6- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -1, 2,3,4-tetrahydro-1,4-epiazano -naphthalene-9-carboxylic acid (C51): Compound C51 was prepared in a manner similar to that described for compound C45 in Step 5 of Example 22 by reacting compound C44 (1.0 g, 2.27 mmol) with methylamine (2.0 M solution in THF, 2.2 ml, 4.54 mmol), affording compound C51 as a white solid (0.85 g, 86%). 1 H NMR (500 MHz, DMSO-d 6) d 9.6 (a, 1 H), 8.16 (s, 1 H), 7.76 (m.H.), 7.48 (m, 1 H), 7 , 12 (m, 1 H), 7.12 (m, 1 H), 4.98 (s, 2 H), 2.92 (m, 3 H), 1.99 (m, 2 H), 1 , 33 (s, 9 H), 1.19 (m, 2 H); MS: 436.5 (MH *) ppm. HPLC Tr: 7.7 min; HPLC purity: 100%. Step 2. Compound 34 was prepared in a manner similar to that described for compound C46 in Step 6 of Example 22 with the exception that compound C51 (0.85 g, 1.95 mmol) was used instead of compound C45, providing compound 34 as a white solid (0.79 g, 99%). 1 H NMR (500 MHz, DMSO-d 6) d 11.02 (a, 1 H). 9.62 (m, 1 H), 9.37 (m, 1 H), 8.43 (s, 1 H), 8.25 (a, 1 H), 7.82 (m, 1 H), 7.62 (m, 1 H), 7.45 (m, 1 H), 5.22 (m, 2 H), 2.98 (d, J = 4 Hz, 3 H), 2.26 (m) , 2 H), 1.40 (m, 2 H) ppm. MS: 336.5 (MH *). EXAMPLE 35 (+/-) -? 4- (2-Methoxy-ethyl) -N% 4 &-methyl- / V2- (1,2,3,4-tetrahydro-1,4-epiazano-naphthalene-) dihydrochloride 6-yl) -5-trifluoromethyl-pyrimidin-2, 4-diamine (35) Stage 1. Tert-butyl acid ester (+/-) - 6-. { 4 - [(2-methoxy-ethyl) -methyl-amino] -5-trifluoromethyl-pyrimidin-2-ylamino) -1,2,3,4-tetrahydro-1,4-epiazane-naphthalene-9-carboxylic acid (C52): Compound C52 was prepared in a manner similar to that described for compound C45 in Step 5 of Example 22 by reacting Compound C44 (1.0 g, 2.27 mmol) with (2-methoxy-ethyl) ) -methyl-amine (0.4 g, 4.54 mmol), yielding compound C52 as a white solid (1.0 g, 89%). 1 H NMR (500 MHz, DMSO-d 6) d 9.67 (a, 1 H), 8.35 (s, 1 H), 7.7 (a, 1 H), 7.34 (m, 1 H) 7.19 (m.h. H). 4.99 (s.2 H), 3.77 (m, 2 H), 3.58 (m, 2 H), 3.25 (s, 3 H), 3.12 (s, 3 H), 2, 00 (m, 2 H). 1.33 (s, 9 H). 1.19 (m >; 2 H) ppm. MS: 494.5 (MH *); HPLC Tr: 8.4 min; HPLC purity: 100%. Step 2. Compound 35 was prepared in a manner similar to that described for compound C46 in Step 6 of Example 22 with the exception that compound C52 (0.85 g, 1.95 mmol) was used instead of compound C45, providing compound 35 in the form of a solid white (0.95 g, 100%). 1 H NMR (500 MHz, DMSO-d 6) d 10.6 (a, 1 H), 9.67 (m, 1 H), 9.37 (m, 1 H), 8.53 (s, 1 H) , 7.7 (s, 1 H), 7.51 (m, 1 H), 7.41 (m, 1 H), 5.2 (s, 2 H), 3.83 (m, 2 H) , 3.6 (m, 2 H), 3.25 (s, 3 H), 3.20 (s, 3 H). 2.28 (m, 2 H), 1.49 (m, 2 H) ppm. MS: 394.5 (MH *). Example 36 (+/-) - V * -ethyl- / V2- (1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-6-yl) -5-trifluoromethyl-pyrimidin-2-dihydrochloride , 4-diamine (36) Stage 1. (+/-) - Ethylamino-5-trifluoromethyl-2-ylamino) -1,2,3,4-tetrahydric acid tert-butyl ester -1,4-epiazano-naphthalene-9-carboxylic acid (C53): Compound C53 was prepared in a manner similar to that described for compound C45 in Step 5 of Example 22 by reacting compound C44 (1.0 g, 2.27 mmol) with ethylamine (4.54 mmol, 2.27 mL, 2.0 M solution in THF) to afford compound C53 as a white solid. (0.86 g, 84%). 1 H NMR (500 MHz, DMSO-d 6) d 9.6 (a, 1 H), 8.16 (s, 1 H), 7.77 (s, 1 H), 7.42 (m, 1 H) , 7.17 (m, 2 H), 4.96 (m, 2 H), 3.48 (m, 2 H), 2.0 (m, 2 H), 1.32 (s, 9 H), 1 , 17 (M. 5 H) ppm. MS: 450.5 (MH *); HPLC tr: 8.11 min; HPLC purity: 100%. Step 2. Compound 36 was prepared in a manner similar to that described for compound C46 in Step 6 of Example 22 with the exception that compound C53 (0.86 g, 1.9 mmol) was used instead of compound C45, providing compound 36 as a white solid (0.8 g, 99%). 1 H NMR (500 MHz, DMSO-d 6) d 11.0 (a.h. H). 9.64 (m, 1 H), 9.38 (m, 1 H). 8.44 (s, 1 H), 8.2 (a, 1 H), 7.8 (m, 1 H). 7.58 (m.I. H), 7.44 (m, 1 H). 5.23 (m 2 H), 3.5 (m, 2 H), 2.28 (m, 2 H), 1.39 (m, 2 H), 1.17 (m, 3 H) ppm. MS: 350.5 (MH *). Example 37 (+/-) - / V- (2-methoxy-ethyl) -V2- (1, 2,3,4-tetrahydro-1,4-epiazano-naphthalen-6-yl) -5-trifluoromethyl dihydrochloride -pyrimidine-2,4-diamine (37) Stage 1. (+/-) - 6- [4- (2-methoxy-ethylamino) -5-trifluoromethyl-pyrimidin-2-tert-butyl ester; lamino] -1,2,3,4-tetrahydro-1,4-epiazano-naphthalene-9-carboxylic acid (C54): Compound C54 was prepared in a manner similar to that described for compound C45 in Step 5 of Example 22 by reacting compound C44 (1.0 g, 2.27 mmol) with 2-methoxyethylamine (341 mg, 4.5 mmol), affording compound C54 as a white solid (1.0 g, 93%). %). 1 H NMR (500 MHz, DMSO-ds) d 9.6 (a, 1 H), 8.18 (s, 1 H), 7.8 (a, 1 H), 7.37 (m, 1 H), 7.18 (m , 1 H), 7.07 (m, 1 H), 4.98 (s, 2 H), 3.62 (m, 2 H), 3.55 (m, 2 H), 3.28 (s) , 3H), 1.98 (m, 2 H), 1.33 (s, 9 H), 1.19 (m, 2 H) ppm. MS: 480.5 (MH *): HPLC Tr: 7.8 min; HPLC purity: 100%. Step 2. Compound 37 was prepared in a manner similar to that described for compound C46 in Step 6 of Example 22 with the exception that the C54 compound (1.0 g, 2.1 mmol) was used instead. of compound C45, affording compound 36 as a white solid (0.92 g, 98%). 1 H NMR (500 MHz, DMSO-d 6) d 10.5 (a, 1 H), 9.4 (m, 1 H), 9.3 (m, 1 H), 8.3 (s, 1 H), 7 , 85 (s, 1 H), 7.56 (m, 1 H), 7.41 (m, 1 H), 5.2 (s, 2 H), 4.3 (a, 1 H), 3 , 63 (m, 2.H), 3.52 (m, 2 H), 3.27 (s, 3 H), 2.25 (m, 2 H), 1.40 (m, 2 H) ppm . MS: 380.5 (MH *). EXAMPLE 38 Dichloride of (+/-) - V, -isopropyl- / V2- (1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-6-yl) -5-trifluoromethyl-pyrimidin-2, 4-daytime (38) 38 Stage 1. Tere-butyl acid ester (+/-) - 6- (4-isopropylamido-5-trifluoromethyl-pyrimidin-2-ylamino) -1,2,3,4-tetrahydro-1,4-ep Azano-naphthalene-9-carboxylic acid (C55): Compound C55 was prepared in a manner similar to that described for compound C45 in Step 5 of Example 22 by reacting compound C44 (1.0 g, 2.27 mmol ) with isopropylamine (0.27 g, 4.5 mmol) to afford compound C55 as a white solid (0.73 g, 69%). ? NMR (500 MHz, DMSO-d6) d 9.58 (a, 1 H). 8.17 (1H). 7.73 (s, 1 H), 7.41 (m, 1 H), 7.19 (m, 1 H). 6.47 (m.h. H). 4.9 (m, 2 H), 4.4 (m, 1 H), 2.0 (m.2 H). 1.33 (s, 9 H), 1.23 (m, 6 H), 1.2 (m, 2 H) ppm. MS: 464.5 (MH *); HPLC Tr: 8.62 min; HPLC purity: 100%. Step 2. Compound 38 was prepared in a manner similar to that described for compound C46 in Step 6 of Example 22 with the exception that compound C55 was used. (0.72 g, 1.55 mmol) in place of compound C45, affording compound 38 as a white solid (0.67 g, 99%). 1 H NMR (500 MHz, DMSO-d 6) d 11.0 (a.h. H), 9.7 (m, 1 H), 9.4 (m, 1 H), 8.4 (s, 1 H), 7 , 6 (m, 2 H), 7.55 (m, 1 H), 7.44 (m, 1 H), 5.25 (m, 2 H), 4.4 (m, 1 H), 2 , 3 (m, 2 H), 1.4 (m, 2 H), 1.24 (m, 6 H) ppm. MS: 364.5 (MH *). Example 39 (+/-) - (4-Methoxy-5-trifluoromethyl-pyrimidin-2-yl) - (1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-6-yl) - amine (39) Compound 39 was prepared in a manner similar to that described for compound 46 in Step 6 of Example 22 with the exception that compound C44 (1.0 g, 2.23 mmol) was used instead of compound C45, affording compound 39 as a white solid (0.9 g, 98%). 1 H NMR (400 MHz, DMSO-d 6) d 10.3 (a, 1 H), 9.58 (m.hour), 9.31 (m, 1 H), 8.50 (s, 1 H), 7 , 86 (m, 1 H), 7.58 (m, 1 H), 7.36 (m, 1 H), 5.18 (m, 2 H), 4.01 (s, 3 H), 2 , 23 (m, 2 H), 1.35 (m, 2 H); MS: 335.6 (MH ") HPLC Tr ppm: 4.72 min; HPLC purity: 100% Example 40? F4-Cyclobutyl- / V2- (1S, 4 /:) - dichlorhydrate , 2,3,4-tetrahydro-1,4-epiazano-naphthalen-6-yl) -5-trifluoromethyl-pyrimidin-2,4-diamine (40) Step 1. Tert-butyl ester of 6-acid -amino- (1S, 4R) -1,2,3,4-tetrahydro-1,4-epivazan-naphthalene-9-carboxylic acid (C56): Compound 56 was prepared in a manner similar to that described for compound C20 in Step 4 of Example 10 with the exception that compound C41 (4.5 g, 15.5 mmol) was used in place of compound C19, affording compound C56 as an off-white solid (3.95 g, 98%). 'H NMR (400 MHz, DMSO-d6) 8 1.10 (m, 2 H), 1.29 (s, 9 H), 1.89 (m, 2 H), 4.81 (m, 2 H), 4.95 (sa, 2 H), 6.24 (m, 1 H), 6.48 (m, 1 H), 6.86 (m. 1 H) ppm, HPLC Tr = 5.95. HPLC = 100%. [a], C (0.01165) = -7.02 ° Stage 2. Tertiary-butyl acid 6- (4-chloro-5-trifluoromethyl-pyrimidin-2-ylamino) - (1S) , 4R) - 1,2,3,4-tetrahydro-1,4-epiazano-naft alen-9-carboxylic acid (C57): Compound C57 was prepared in a manner similar to that described for compound C21 in Step 5 of Example 10, with the exception that compound C56 (3.8 g, 14 g) was used. , 6 mmol) in place of compound C20, giving compound C57 as a white solid (4.76 g, 74%). * H NMR (400 MHz, DMSO-d6) d 1.17 (m, 2 H), 1.30 (s, 9 H), 1.97 (m, 2 H), 4.99 (m 2 H), 7.24 (m, 1 H), 7, 40 (m, 1 H), 7.61 (sa, 1 H), 8.76 (s, 1 H), 10.6 (s, 1 H) ppm. HPLC Tr = 8.49, Purity by HPLC = 100%. [aj, C (0.01035) = -14.8 °. Step 3. 6- (4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino) - (1S, 4R) -1,2,3,4-tetrahydro-1,4-tert-butyl ester α-naphthalene-9-carboxylic acid (C58): Compound 58 was prepared in a manner similar to that described for compound 10 in Step 8 of Example 12 by reacting compound C57 (1.1 g, 2.5 mmol) with cyclobutylamine (288 μl, 3.4 mmol) to give compound C58 as a white solid (998 mg, 84%). 1 H NMR (400 MHz, DMSO-d 6) d 1.17 (m, 2 H), 1.30 (s, 9 H), 1.66 (m, 2 H), 1.97 (m, 2 H) , 2.20 (m, 4 H), 4.50 (m, 1 H), 4.95 (m, 2 H), 6.99 (m, 1 H), 7.17 (m, 1 H) , 7.33 (m, 1 H), 7.78 (sa, 1), 8.15 (s, 1 H), 9.59 (s, 1 H) ppm. HPLC Tr = 8.77, Purity by HPLC = 100%. Step 4. Compound 40 was prepared in a manner similar to that described for compound C46 in Step 6 of Example 22 with the exception that compound C58 (938 mg, 1.98 mmol) was used in place of compound C45 , providing compound 40 as a bone-colored solid (911 mg, 82%). 1 H NMR (400 MHz, DMSO-d 6) d 1.37 (m, 2 H), 1.67 (m, 2 H). 2.20 (m, 6 H), 4.55 (m, 1 H), 5.18 (m, 2 H), 6.65 (sa, 1 H), 7.40 (m, 1 H), 7.52 (m, 1 H), 7.80 (m, 1 H), 7.89 (sa, 1 H), 8.34 (s 1 H). 9.31 (m, 1 H). 9.48 (m, 1 H). 10.63 (s a, 1 H) ppm. HPLC Tr = 5.62, Purity by HPLC = 100%.

Example 41 1- [6- (4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino) - (1S, 4R) -1,2,3,4-tetrahydro-1,4-epiazano-naphthalene -9-yl] -2-methylamino-ethanone (41) Step 1. (4-Chloro-5-trifluoromethyl-pyrimidin-2-ylH (1S) dihydrochloride, 4R) -1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-6-yl) -amine (C59): The compound C59 was prepared in a manner similar to that described for compound C22 in the Step 6 of Example 10 with the exception that compound C57 (1.0 g, 2.26 mmol) in 1,4-dioxane (2 ml) was used in place of compound C21, providing compound C59 in the form of a solid white (0.93 g, 100%). 1 H NMR (500 MHz. DMSO-d 6) d 10.84 (1 H), 9.27 (a, 2 H), 8.8 (1 H), 7.8 (s, 1 H) . 7.6 (m.H.) 7.44 (m, 1 H), .24 (m, 2 H), 2.23 (m, 2 H), 1.41 (m, 2 H) ppm. MS: 339.4 (MH *); HPLC Tr: 4.98 min; HPLC purity: 100%. Stage 2. Ferric acid butyl ester. { 2- [6- (4-chloro-5-trifluoromethyl-pyrimidin-2-ylamino) - (1S, 4R) -1, 2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl] - 2-oxo-ethyl} methyl-carbamic (C60): To a solution of W-methyl-α-f-Boc-sarcosine (0.41 g, 2.20 mmol) in CH 2 Cl 2 (5 ml) was added 1,3-diisopropylcarbodiimide ( 0.14 g, 1.1 mmol). After 1 hour, compound C59 (0.46 g, 1.10 mmol) was added, followed by the addition of DIEA (0.43 g, 3.30 mmol). After 30 min, the mixture was concentrated and the resulting residue was partitioned between EtOAc and saturated aqueous sodium bicarbonate. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were dried over Na 2 SO and concentrated under reduced pressure. The resulting residue was purified by 40 M instantaneous Biotage® (1: 1 hexanes / EtOAc) to give compound C60 as a white solid (0.55 g, 98%). 1 H NMR (400 MHz, DMSO-d < d) 10.65 (a, 1 H), 8.7 (s, 1 H), 7.6 (a, 1 H), 7.39 (m, 1 H), 7.26 (m, 1 H), 5.4-5.34 (m, 2 H), 4.02-3.94 (m, 2 H), 2.7-2.67 (m). m, 3 H), 2.92-1.92 (m, 2 H), 1.34, 1.17 (rotamers) (s, s, 9 H), 1.25-1.1 (m, 2 H) ppm. MS: 512.4 / 412.3 (MH *); HPLC Tr: 7.4 min; HPLC purity: 100%. Step 3. A solution of compound C60 (0.1 g, 0.2 mmol), cyclopropylamine (0.23 mg, 0.40 mmol) and DIEA (78 mg, 0.60 mmol) was heated to 90 ° C in a tube tightly closed. After 5 hours, the mixture was concentrated under reduced pressure and the resulting residue was partitioned between EtOAc and H20. The phases were separated and the organic phase was washed with water. Then, the organic phase was dried over Na 2 SO and concentrated under reduced pressure. The resulting residue was purified by 12M Instantaneous Biotage® (1: 1 hexanes / EtOAc) to give a white solid. The solid was dissolved in CH2Cl2 and TFA (0.23 g, 2.0 mmol) was added. After 20 min, the mixture was concentrated under reduced pressure. The resulting residue was dissolved in EtOAc and washed with saturated aqueous NaHCO3 and H20. The organic phase was dried over Na 2 SO and concentrated under reduced pressure to provide compound 41 as a white solid (60 mg, 70%). 1 H NMR (500 MHz, DMSO-d 6) d 9.71 (a.h. H), 8.18 (s, 1 H), 7.99 (m.hour). 7.57 (m.H.) 7.19 (m, 2 H). 5.34 (m 2 H), 3.32-3.12 (m 3 H), 2.85 (m, 1 H), 2.2 (s, 3 H), 2.06-1.93 (m, 2 H), 1.23 (m 2 H). 0.80 (m, 2 H), 0.68 (m.2 H) ppm. MS: 433.0 (MH *); HPLC Tr: 5.0 min; HPLC purity: 100%.

Example 42? Í-. { 2- [6- (4-Cyclopropylamino-5-trifluoromethyl] -pyrimidin-2-ylamino) - (1S, 4R) -1,2,3,4-tetrahydro-1,4-epiazane-naphthalene-9 -yl] -2-oxo-ethyl} -? / - methyl acetamide (42) To a solution of compound 41 (50 mg, 0.12 mmol) and DIEA (45 mg, 0.35 mmol) in THF (5 ml) was added acetic anhydride (12 mg 0.12 mmol). After 20 min, the mixture was concentrated under reduced pressure and the resulting residue was purified by 12 M instantaneous Biotage® (98: 2 CH2Cl2 / CH3OH) to afford compound 42 as a white solid (38 mg, 69% ). 1 H NMR (500 MHz. DMSO-d 6) d 9.7 (a, 1 H), 8.18 (s, 1 H), 8.01 (m, 1 H). 7.59 (m, 1 H), 7.2 (m, 2 H), 5.36-5.29 (m, 2 H), 4.01 (m, 2 H), 2.89, 2.69 ( s, s, 3 H), 2.85 (a.1 H), 2.09-1, 9 (m, 2 H), 1.98 (s, 3 H), 1.2 (m, 2 H) ), 0.8 (m, 2 H), 0.68 (m, 2 H) ppm. MS: 475.0 (MH *); HPLC Tr: 5.54 min; HPLC purity: 100%. Example 43 1- [6- (4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino) - (1S, 4R) -1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl ] -2-methylamino-ethanone (43) Step 1. Tert-butyl acid ester. { 2- [6- (4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino) - (1S, 4R) -1,2,3,4-tetrahydro-1,4-epipane-naphthalene-9-yl ] -2-oxo-ethyl) -methyl-carbamic acid (C61): Compound C61 was prepared in a manner similar to that described for compound C60 in Example 41 by reacting compound 40 (0.1 mg, 0.223 mmol) and / V-methyl- / Vr-Boc-sarcosine (84 mg g, 0.45 mmol), affording compound C61 as a white solid (0.1 g, 98%). 'H NMR (500 MHz, DMSO-d6) d 9.6 (a, 1 H). 8.2 (s, 1 H). 7.8 (a.1 H), 7.4 (m.1 H), 7.2 (m, 1 H), 7.02 (m, 1 H), 5.34 (m, 2 H), 4, 6 (a.1 H). 4.0 (m 1 H), 3.86 (m, 1 H), 2.6 (m 3 H), 2.25-1.9 (m 6 H), 1.7 (m, 2 H), 1, 37,1,2 (rotamers) (m, 9 H), 1,3 (m 2 H); MS: 547.5 / 447.4 (MH *); HPLC tr: 7.7 min; HPLC purity: 100%. Step 2. To a solution of C61 (0.18 g, 0.33 mmol) in CH2Cl2 (5 mL) was added TFA (0.15 g, 1.3 mmol). After 1 hour, the mixture was concentrated, the resulting residue was partitioned between EtOAc and saturated aqueous NaHCO3 and the phases were separated. The organic phase was washed with H20, dried over Na2SO4 and concentrated under reduced pressure to provide compound 43 as a white solid (0.12 g, 82%). ? NMR (500 MHz. DMSO-d6) d 9.61 (a, 1 H). 8.18 (s, 1 H), 7.6 (m, 1 H), 7.3 (m, 1 H), 7.2 (m.1 H), 7.0 (m, 1 H), 5.3 (m, 2) H), 4.6 (a, 1 H), 3.28 (m, 2 H), 2.25-1, 95 (m, 6 H), 2.2 (s, 3 H), 1.6 (m, 2 H), 1.2 (m, 2 H) ppm. MS: 447.4 (MH +); HPLC Tr: 5.5 min; HPLC purity: 100%. Example 44 / V-. { 2- [6- (4-Cyclobutylammon-5-trifluoromethyl-pyrimidin-2-ylamino) - (1S, 4 /:) - 1,2,3,4-tetrahydro-1,4-epiazano- naphthalen-9-yl] -2-oxo-ethyl) -V-methyl-acetamide (44) Compound 44 was prepared in a manner similar to that described for compound 42 in Example 42 with the exception that the compound 40 (70 mg, 0.16 mmol) in place of compound 41, affording compound 44 as an off-white solid (60 mg, 78%). 1 H NMR (500 MHz, DMSO-d 6) d 9.6 (a, 1 H), 8.18 (s, 1 H), 7.8 (m, 1 H), 7.4 (m.1 H), 7 , 2 (m, 1 H), 7.0 (m, 1 H), 5.36 (m, 2 H), 4.6 (a, 1 H), 4.1 (m, 1 H), 4 , 0 (m, 1 H), 2.9, 2.7 (rotamers) (s, s, 3 H), 2.2 (m, 6 H), 1.99 (m, 3 H), 1.69 ( m, 2 H), 1.2 (m, 2 H); MS: 489.0 (MH *) ppm. HPLC Tr: 6.0 min; HPLC purity: 100%. Example 45? { 2- [6- (4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino) - (1S, 4R) -1, 2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl] - 2-oxo-ethyl) -acetamide (45) Step 1.? / -. { 2- [6- (4-Chloro-5-trifluoromethyl-pyrimidin-2-ylamino) - (1 S, 4R) -1, 2,3,4-tetrahydro-1,4-epivazan-naphthalene-9-yl] -2-oxo-ethyl) -acetamide (C62): Procedure A. Compound C62 was prepared in a manner similar to that described for compound C60 in Example 41 by reacting compound C59 (0.92 mg, 2.23 mmol) and / V-acetyl glycipase (0.6 g, 2.25 mmol), affording compound C62 as an off-white solid (0.54 g, 55%). 1 H NMR (500 MHz. DMSO-d 6) d 10.68 (m.hour). 8.79 (s, 1 H), 8.03 (a.1 H), 7.68 (a, 1 H), 7.4 (m, 1 H), 7.3 (m, 1 H), 5.48-5.36 (m 2 H), 3.93 (m, 1 H), 3.73 (m, 1 H), 2.12 (m.h. H). 1.95 (m.H.) 1.82 (s 3 H). 1.28-1.11 (m, 2 H) ppm. MS: 442.0 / 439.9 (MH *); HPLC Tr: 5.6 min; HPLC purity: 100%. Method B. Alternatively, compound C62 can be prepared by adding a solution of compound C41 (37.9 g, 0.13 mol) in methanol (38 ml) to a solution of thionyl chloride (47.4 ml, 0.650 mol, 5 equiv.) In methanol (380 ml) under a nitrogen atmosphere at 25 ° C, mixing for 18 hours and concentrating under reduced pressure, yielding 6-nitre-1, 2,3,4-tetrahydro-1,4-epiazano-naphthalene HCl (C113) as a solid (33.1 g, 0.145 mol, 112% yield (excess yield due to residual methanol)): A mixture of n-acetylglucin (3.26 g, 0.028 mol, 1 equiv.), 6-chloro-2,4-dimethyloxy-s-triazine (CDMT) ) (4.69 g, 0.027 mol, 0.97 equiv.) And acetonitrile (50 mL) was cooled to 0 ° C and treated dropwise with? / -methylmorpholine (3.03 mL, 0.028 mol, 1 equiv.). After 2 hours, the mixture was treated with solid compound C113 (5.00 g, 0.028 mol) and the reaction mixture was allowed to warm to room temperature. After about 18 hours, the mixture was filtered, concentrated to about half the volume and treated with water with stirring. The resulting mixture was filtered and concentrated under reduced pressure, yielding? / - [2 - ((1S, 4R) -6- / vltro-1,2,3,4-tetrahydro-1,4-epiazano-naphthalene-9 -yl) -2-oxo-ethyl] -acetamide (CAB) (5.30 g, 0.018 mol, 83% yield). Compound C114 (4.2 g, 0.015 mol), 10% palladium on carbon moistened 50% with water (400 mg) and ethanol (40 ml) were charged to a Parr reactor and the contents of the reactor were treated with water. , 74 kPa (50 psi) of hydrogen at 40 ° C. After 1 hour, the mixture was filtered through celite at 40 ° C and concentrated to dryness, yielding? - [2 - ((1S, 4R) -6-amino-1, 2,3,4-tetrahydro- 1,4-epiazano-naphthalen-9-yl) -2-oxo-ethyl] -acetamide (C115) (3.43 g, 0.013 mol, 91% yield). A mixture of compound C115 (0.44 g, 17 mmol), zinc dibromide (0.43 g, 18 mmol, 1.1 equiv.), / -butanol (1.3 ml) and dichloroethane (1.32 ml) ) was stirred at room temperature for 30 minutes. Then, the mixture was treated with 2,4-dichloro-5-trifluoromethylpyrimidine (0.42 g, 18 mmol 1.1 equiv.) Followed by triethylamine (0.26 mL, 18 mmol, 1.1 equiv.). After 3 hours, the mixture was concentrated and the resulting residue was triturated with hexanes overnight. The resulting solids were collected by filtration to provide compound C62 (0.33 g, 075 mmol, 44% yield). Step 2. Compound 45 was prepared in a manner similar to that described in Step 8 of Example 10 by reacting compound C62 (0.10 g, 0.23 mmol) with cyclobutylamine (32 mg, 0.45 mmol) to afford compound 45 as a white solid (39 mg, 62%). ? NMR (400 MHz, DMSO-d6) d 9.6 (a, 1 H), 8.15 (s, 1 H), 8.0 (m, 1 H), 7.78 (m, 1 H), 7, 37 (m, 1 H), 7.19 (m, 1 H), 7.0 (m, 1 H), 5.39-5.3 (m, 2 H), 4.6 (m, 1 H), 3.9-3.8 (m) , 1 H), 3.7-3.6 (m, 1 H), 2.21-2.0 (m, 5 H), 1.9-1.8 (m, 1 H), 1.8 (s, 3 H), 1.67-1, 63 (m, 2 H), 1, 2-1.1 (m, 2 H) ppm. HPLC Tr: 8.82 min; HPLC purity: 100%. EXAMPLE 46 / V-isopropyl-V2- dihydrochloride. { (1S, 4R) -1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-6-yl} -5-trifluoromethyl-pyrimidine-2,4-diamine (46) Step 1. 6- (4-isopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino) - tert -butyl ester ( 1S, 4R) -1,2,3,4-tetrahydro-1,4-epiazano-naphthalene-9-carboxylic acid (C63): Compound C63 was prepared in a manner similar to that described for compound C58 in Step 3 of Example 40 with the exception that isopropylamine (0.16 g, 2.27 mmol) was used in place of cyclobutylamine to give compound C63 as an off-white solid (0.78 g, 74%). 1 H NMR (400 MHz. DMSO-d 6) d 9.5 (a, 1 H), 8.14 (s, 1 H), 7.69 (s, 1 H), 7.37 (m, 1 H) , 7.15 (m, 1 H), 6.44 (m, 1 H), 4.94 (m.2 H). 4.4 (m, 1 H), 1.9 (m, 2 H), 1.29 (s, 9 H), 1.2 (m, 6 H), 1.1 (m, 2 H); MS: 464.6 (MH *) ppm. HPLC Tr: 8.6 min; HPLC purity: 100%. Step 2. Compound 46 was prepared in a manner similar to that described for compound 40 in Step 4 of Example 40 with the exception that compound C63 (70 mg, 0.16 mmol) was used in place of compound C58 , providing compound 46 as a white solid (0.73 g, 99%). 1 H NMR (500 MHz, DMSO-d 6) d 10.8 (a, 1 H), 9.62 (m, 1 H), 9.36 (m, 1 H), 8.4 (s, 1 H), 7 , 7 (1 H), 7.6 (a, 1 H), 7.5 (m, 1 H), 7.43 (m, 1 H). 5.23 (m, 2 H). 4.4 (m.h. H). 4.4 (a, 1 H). 2.27 (m.2 H), 1.39 (m, 2 H), 1.24 (m, 6 H) ppm. MS: 364.5 (MH *). Example 47? / 4-ethyl-? / 2- dichloride. { (1S, 4R) -1, 2,3,4-tetrahydro-1,4-epiazano-naphthalen-6-yl) -5-trifluoromethyl-pyrimidine-2,4-diamine (47) Stage 1. Terc ester butyl 6- (4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) - (1S, 4R) -1,2,3,4-tetrahydro-1,4-epipane-naphthalene-9 -carboxylic (C64): Compound C64 was prepared in a manner similar to that described for compound C58 in Step 3 of Example 40 with the exception that ethylamine was used (2.0 M solution in tetrahydrofuran, 2.27 ml , 4.5 mmol) in place of cyclobutylamine, giving compound C64 as a white solid (1.0 g, 98%). 1 H NMR (500 MHz, DMSO-d 6) d 9.6 (a.1 H), 8.16 (s, 1 H), 7.7 (s, 1 H), 7.42 (m, 1 H) , 7.18 (m, 2 H), 4.97 (m, 2 H), 3.48 (m, 2 H), 1.99 (m 2 H), 1.32 (s, 9 H) . 1.17 (m, 5 H); MS: 450.5 (MH +) ppm. HPLC Tr: 8.0 min; HPLC purity: 100%. Step 2. Compound 47 was prepared in a manner similar to that described for compound 40 in Step 4 of Example 40 with the exception that compound C64 (1.0 g, 2.22 mmol) was used instead of Compound C58, affording compound 47 as a white solid (0.87 g, 93%). 1 H NMR (500 MHz, DMSO-d 6) d 10.8 (a.h.H), 9.55 (m, 1 H), 9.35 (m, 1 H), 8.4 (s, 1 H) , 8.21 (a, 1 H), 7.81 (m, 1 H), 7.58 (m, 1 H), 7.43 (m, 1 H), 5.22 (m, 2H), 3.5 (m, 2 H), 2.26 (m, 2 H), 1.4 (m, 2 H), 1.17 (m, 3 H); MS: 350.5 (MH *). Example 48 2-Amino-1- [6- (4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) - (1S, 4R) -1,2,3,4-tetrahydro-1,4-epiázano -naphthalen-9-yl] -ethanone (48) Compound 48 was prepared in a manner similar to that described for compound 43 in Step 2 of Example 43 by reacting compound 47 (0.15 g, 0.35 mmol ) with tert-butoxycarbonylaminoacetic acid (0.12 g, 0.71 mmol) to afford compound 48 as an amber solid (45 mg, 31%). 1 H NMR (500 MHz, DMSO-d 6 d) 9.6 (a, 1 H), 8.16 (s, 1 H), 7.78 (m, 1 H), 7.44 (m, 1 H) , 7.2 (m, 2 H), 5.32 (m, 2 H), 3.4 (m, 2 H). 3.32 (m, 2 H), 3.17 (m 2 H), 2.06-1.94 (m, 2 H), 1.23-1.17 (m, 5 H); MS: 407.0 (MH *) ppm. HPLC tr: 4.7 min; HPLC purity: 100%. EXAMPLE 49 Dihydrochloride of / v-propyl-W-IIIS-RJ-I-II-S-tetrahydro-1-phenazoline-naphthalene-e-methyl-S-trifluoromethyl-pyrimidine-2,4-diamine (49 ) Stage 1. 6- (4-Propylamino-5-trifluoromethyl-pyrimidin-2-ylamino) - (1S, 4R) -1,2,3,4-tetrahydro-1,4- tert-butyl ester epiazano-naphthalene-9-carboxylic acid (C65): Compound C65 was prepared in a manner similar to that described for compound C58 in Step 3 of Example 40 with the exception that propylamine (0.2 g, 3.4 mmol) was added in place of cyclobutylamine to give compound C65 as a white solid (1.0 g, 2.27 mmol). ^ NMR (500 MHz. DMSO-d6) d 9.6 (a, 1 H), 8.15 (s, 1 H), 7.78 (s 1 H), 7.41 (m, 1 H), 7.19 (m, 2 H), 4.97 (m 2 H), 3.39 (m, 2 H), 1.98 (m, 2 H), 1.6 (m, 2 H), 1.32 (s, 9 H), 1.17 (m, 2 H), 0.91 (m, 3 H); MS: 463.5 (MH *) ppm. HPLC Tr: 8.35 min; HPLC purity: 100%. Step 2. Compound 49 was prepared in a manner similar to that described for compound 40 in Step 4 of Example 40 with the exception that compound C65 (0.96 g, 2.1 mmol) was used instead of Compound C58, affording compound 49 as an off-white solid (0.88 g, 98%). 1 H NMR (500 MHz, DMSO-d 6) d 11.0 (a, 1 H). 9.62 (m 1 H), 9.37 (m, 1 H), 8.43 (s, 1 H), 8.3 (a, 1 H), 7.7 (s, 1 H), 7.61 (m, 1 HOUR). 7.44 (m.h. H), 5.2 (s, 2 H), 3.42 (m, 2 H), 2.28 (m, 2 H), 1.60 (m, 2 H), 1.4 (m. m, 2 H), 0.89 (m, 3 H) ppm. MS: 364.5 (MH *). Example 50? / 4- (2-Methoxy-ethyl) -? 2 - [(1 S, 4R) -1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-6-yl] - hydrochloride 5-Trifluoromethyl-pyrimidine-2,4-diamine (50) Step 1. 6- [4- (2-Methoxy-ethylamino) -5-trifluoromethyl-pyrimidin-2-ylamino] - tert -butyl ester 1S, 4R) -1, 2,3,4-tetrahydro-1,4-epiazano-paftalen-9-carboxylic acid (C66): Compound C66 was prepared in a manner similar to that described for compound C58 in Step 3 of Example 40 with the exception that 2-methoxyethylamine (256 mg, 3.4 mmol) was used in place of cyclobutylamine to give compound C66 as a pale syrup (1.02 g, 94%). 1 H NMR (500 MHz, DMSO-d 6) d 9.6 (a, 1 H). 8.18 (s, 1 H), 7.8 (a, 1 H), 7.37 (m, 1 H). 7.17 (m, 1 H), 7.07 (m, 1 H), 4.98 (s, 2 H), 3.6 (m 2 H), 3.51 (m 2 H), 3.28 (m. s, 3H), 1.99 (m, 2 H), 1.33 (s, 9 H), 1.19 (m, 2 H); MS: 480.5 (MH *); HPLC Tr: 7.76 min; HPLC purity: 100%. Step 2. Compound 50 was prepared in a manner similar to that described for compound 40 in Step 4 of Example 40 with the exception that compound C66 (1.0 g, 2.08 mmol) was used instead of Compound C58, affording compound 50 as an off-white solid (0.88 g, 94%). 1 H NMR (500 MHz, DMSO-d 6) d 10.8 (a, 1 H), 9.57 (m, 1 H). 9.36 (m.H.) 8.4 (s, 1 H). 8.07 (a, 1 H), 7.82 (s 1 H). 7.56 (m, 1 H), 7.41 (m, 1 H), 5.2 (s.2 H). 3.62 (m, 2 H), 3.52 (m, 2 H), 3.27 (s, 3 H), 2.27 (m, 2 H), 1, 4 (m, 2 H) ppm. MS: 380.5 (MH *). Example 51 / V * -cyclobutyl- / V- (1 /? 4S) - (1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-6-yl) -5-trifluoromethyl- dihydrochloride salt pyrimidine-2,4-diamine (51) Step 1. 6-Amino- (1R, 4S) -1,2,3,4-tetrahydro-1,4-epiazano-naphthalene-9-carboxylic acid tert-butyl ester (C67): Compound C67 was prepared from a manner similar to that described for compound C20 in fa Stage 4 of Example 10 with the exception that compound C42 (4.5 g, 15.5 mmol) was used in place of compound C19, providing compound C67 in the form of a whitish solid (3.59 g, 89%). 1 H NMR (400 MHz, DMSO-d 6) d 1.10 (m, 2 H). 1.29 (s, 9 H), 1.89 (m, 2 H), 4.81 (m, 2 H), 4.95 (s, 2 H), 6.24 (m 1 H), 6.48 (m, 1 H), 6.86 (m, 1 H) ppm. [a], C (0.01165) = + 5.82 °. Step 2. 6- (4-Chloro-5-trifluoromethyl-pyrimidin-2-ylamino) - (1R, 4S) -1,2,3,4-tetrahydro-1,4-epiazano-naphthalen tert-butyl acid ester -9-carboxylic acid (C68): Compound C68 was prepared in a manner similar to that described for compound C21 in Step 5 of Example 10 with the exception that compound C67 was used (3.4 g, 13.1 mmol) was added in place of compound C20 to give compound C68 as a white solid (4.68 g (81%). 1 H NMR (400 MHz, DMSO-d 6) d 1.17 (m, 2 H), 1 , 30 (s, 9 H), 1.97 (m, 2 H), 5.00 (m, 2 H), 7.24 (m, 1 H), 7.40 (m, 1 H), 7 , 61 (sa, 1 H), 8.75 (s, 1 H), 10.6 (s, 1 H) ppm, HPLC Tr = 8.49, HPLC Purity = 100%. [A], CIO .01015) = + 14.1 °. Stage 3. 6- (4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylammon) - (1R, 4S) -1,2,3,4-tetrahydro-1,4-epiazano tert-butyl ester Naphthalene-9-carboxylic acid (C69): Compound C69 was prepared in a manner similar to that described for compound C45 in Step 5 of Example 22 with the exception that compound C68 (1.1 g, 2 g) was used. , 5 mmol) in place of compound C44, yielding compound C69 as a white solid (, 17 g, 98%). ? NMR (400 MHz, DMSO-d6) d 1.17 (m, 2 H), 1.30 (s, 9 H), 1.66 (m, 2 H), 1.97 (m, 2 H), 2.20 (m, 4 H). 4.50 (m.H.) 4.95 (m, 2 H), 6.99 (m, 1 H), 7.17 (m, 1 H), 7.33 (m, 1 H). 7.78 (s a.1), 8.15 (s.1 H), 9.59 (s a, 1 H) ppm. HPLC Tr = 8.78, Purity by HPLC = 100%. Step 4. Compound 51 was prepared in a manner similar to that described for compound C46 in Step 6 of Example 22 with the exception that compound C69 (938 mg, 1.98 mmol) was used in place of compound C45 , providing compound 51 in the form of an off-white solid (1.08 g, >100%). 1 H NMR (400 MHz, DMSO-d < d) d 1.38 (m, 2 H). 1.66 (m, 2 H), 2.22 (m, 6 H), 4.58 (m, 1 H), 5.19 (m, 2 H), 7.05 (sa, 1), 7 , 39 (m, 1 H), 7.52 (m 1 H), 7.70 (s a. 1 HOUR). 7.81 (s, 1 H), 8.32 (s.1 H), 9.29 (m, 1 H), 9.42 (m.1 H). 10.25 (s a, 1 H) ppm. [a], C0.0059) CH2Cl2 = -8.3 °. HPLC Tr = 5.10, Purity by HPLC = 100%. EXAMPLE 52 - f4-Cyclopropyl-'V2- (1R, 4S) - (1, 2,3,4-tetrahydro-1,4-epiazano-naphthalen-6-yl) -5-trifluoromethyl-pyrimidin-2-dihydrochloride 4-diamine (52) Compound 52 was prepared in a manner similar to that described for compounds C45 and C46 in Steps 5 and 6, respectively, of Example 22 by reacting compound C68 (2.0 g, 4, 5 mmol) with cyclopropylamine (425 μl, 6.1 mmol) followed by treatment with methanolic HCl, affording compound 52 as a white solid (1.95 g, 99%). 1 H NMR (400 MHz, DMSO-d 6) d EYE (m, 2 H), 0 J 9 (m, 2 H), 1.36 (m, 2 H), 2.23 (m, 2 H), 2.87 ( m, 1), 5.18 (m, 2 H), 5.82 (br s, 1 H). 7.38 (m, 1 H), 7.67 (m, 1 H), 7.93 (s a.1 H). 8.01 (m, 1 H). 8.34 (s, 1 H), 9.26 (m, 1 H). 9.42 (m, 1 H), 10.65 (s a, 1 H) ppm. HPLC Tr = 4J0, Purity by HPLC = 100%. Examples 53 to 87 Examples 53 to 87 (Table 1) were prepared according to the procedures described in Example 23 or 52. Example 88 Methanesulfonic acid salt of? / - (2-. {6- [4- ( 2-methoxy-ethylamino) -5-trifluoromethyl-pyrimidin-2-ylamino] - (1R, 4S) -1, 2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl) -2-oxo -ethyl) -acetamide (88) A suspension of? Acetylglycine (182 mg, 1.56 mmol) in 10 ml of CH 2 Cl 2 was treated with diisopropylcarbodiimide (eDIC) (140 μl, 0.9 mmol) under nitrogen and the mixture was stirred for 1 hour at 25 ° C. The resulting suspension was treated with compound 57 (300 mg, 0.664 mmol) followed by DIEA (787 μl, 4.52 mmol) and stirred overnight at 25 ° C. The mixture was concentrated under reduced pressure and the resulting residue was partitioned between 1 x 25 ml of EtOAc and 3 x 20 ml of 50% saturated NaHCO 3. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The resulting pasty solid was dissolved in 3 ml of isopropanol, treated with methanesulfonic acid (43 μl, 0.664 mmol) and concentrated. The resulting pale foam was suspended in 10 ml of EtOAc and the mixture was stirred at 65 ° C for 1 hour. The resulting fine white solid was collected, washed with Et20 and dried. The solid was triturated a second time with hot EtOAc to Remove residual diisopropyurea to give compound 88 as a white solid (302 mg, 79%). HPLC Tr = 4.98, Purity by HPLC = 100%. MS for C22H25F3N603: [M + H] = 479.2. Example 89 Salt of α-methanesulfonic acid. { 2- [6- (4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino) - (1R, 4S) -1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl] - 2-oxo-ethyl) -acetamide (89) Compound 89 was prepared in a manner similar to that described for compound 88 in Example 88 by reacting compound 51 (500 mg, 1.13 mmol) and? / - acetylglycine (311 mg, 2.65 mol), affording compound 89 as a white solid (490 mg, 76%). HPLC Tr = 5.84, Purity by HPLC = 100%. MS for C 23 H 25 F 3 N 602: (M + H) = 475.3 EXAMPLE 90 Hydrochloride salt of / V-. {2- 2- (4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) - (1S, 4:? ) - 1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl] -2-oxo-ethyl) -rV-methyl-acetamide (90) Step 1.? / -. { 2- [6- (4-Chloro-5-trifluoromethyl-pyrimidin-2-ylamino) - (1 S, 4R) -1, 2,3,4-tetrahydro-1,4-epiazane-naphthalene-9- il] -2-oxo-ethyl) -A -methyl-acetamide (C70): A solution of compound C60 (0.37 g, 0J3) in HCl (4.0 M in 1,4-dioxane, 5 ml) was stirred at 25 ° C for 20 min and concentrated. The resulting white solid was dissolved in CH2Cl2 (5 ml) and treated with acetic anhydride (75 mg, 0J3 mmol) and DIEA (0.28 g, 2.19 mmof). After 20 min, the reaction was quenched with water, the phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were dried over Na2SO4 and concentrated to give compound C70 as a white solid (0.27 g, 82%). MS: 454.0 (MH *); HPLC Tr: 5.84 min; HPLC purity: 100%. Step 2. Compound C70 (125 mg, 0.276 mmol) was combined with ethylamine (96 μl, 0.52 mmol) and DIEA (250 μl, 1.44 mmol) in 3 ml of dioxane in a 15 ml screw-capped pressure tube under nitrogen. The mixture was heated to 90 ° C, stirred for 4 hours and cooled to 25 ° C. The mixture was diluted with 10 ml of CHCl3 to dissolve suspended solids and the solution was concentrated under reduced pressure. The resulting residue was chromatographed on 15 g of silica gel (230-400 mesh) eluting with 4% MeOH / CH 2 Cl 2 while collecting 9 ml fractions. Fractions containing compound 90 were combined and concentrated. The resulting white foam (132 mg) was dissolved in 3 mL of EtOAc and treated with 0.35 mL of 1 N HCl in Et20. The The solids were collected and dried to give compound 90 as an off-white solid (110 mg, 80%). HPLC Tr = 5.46, Purity by HPLC = 100%. EM for C22H25F3N602: [M + Hj = 463.3. Example 91 6- (4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino) - (1S, 4R) -1,2,3,4-tetrahydro-1,4-epiazane-naphthalene-9- methyl ester carboxylic (91) Compound 91 was prepared in a manner similar to that described for compound 24 in Example 24 by reacting compound 40 (140 mg, 0.313 mmol) and methyl chloroformate. (26 μl, 0.340 mmol), affording compound 91 as a white solid (101 mg, 74%). 1 H NMR (400 MHz, DMSO-dβ) d 1.18 (m.2 H), 1.64 (m.2 H). 2.05 (m, 2 H). 2.21 (m. 4 H). 3.49 (s, 3 H), 4.58 (m.h. H), 5.05 (s, 2 H), 6.98 (m, 1 H), 7.18 (m, 1 H), 7.35 (m, 1 H), 7J7 (m, 1 H), 8.15 (s.

H), 9.57 (s, 1 H) ppm. HPLC Tr = 7.66, Purity by HPLC = 100%. Example 92 6- (4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino) - (1R, 4S) -1, 2,3,4-tetrahydro-1,4-epiazano-naphthalene- methyl ester 9-carboxylic acid (92) Compound 92 was prepared in a manner similar to that described for compound 24 in Example 24 by reacting compound 51 (140 mg, 0.313 mmol) and methyl chloroformate. (26 μl, 0.340 mmol), affording compound 92 as a white solid (58 mg, 37%). 1 H NMR (400 MHz, DMSO-d 6) d 1.18 (m, 2 H), 1.64 (m, 2 H), 2.05 (m, 2 H), 2.21 (m, 4 H) . 3.49 (s, 3 H), 4.58 (m, 1 H), 5.05 (s, 2 H), 6.98 (m, 1 H), 7.18 (m, 1 H), 7, 35 (m, 1 H), 7.77 (m, 1 H), 8.15 (s, 1 H), 9.57 (s, 1 H) ppm. HPLC Tr = 7.66. Purity by HPLC = 100%. EXAMPLE 93 / V-Cyclobutyl-A ^ -i? -methanesulfonyl-yl S.4R) -1, 2,3,4-tetrahydro-1,4-epioazan-naphthalen-6-yl) -5-trifluoromethyl- pyrimidine-2,4-d-aminine (93) Compound 93 was prepared in a manner similar to that described for compound 22 in Example 22 by reacting compound 40 (140 mg, 0.313 mmol) and methanesulfonyl chloride (26). μl, 0.340 mmol), affording compound 93 as a white solid (61 mg, 43%). 1 H NMR (400 MHz, DMSO-d 6) d 1.26 (m, 2 H), 1.65 (m, 2 H), 2.22 (m.6 H). 2.26 (s. 3 H), 4.58 (m, 1 H). 5.01 (s, 2 H). 7.01 (m, 1 H). 7.23 (m.h. H). 7.38 (m, 1 H). 7.84 (m, 1 H). 8.16 (s, 1 H), 9.64 (s a, 1 H) ppm. HPLC Tr = 7.11, Purity by HPLC = 100%. Example 94 / V- Cyclobutyl-? II-? - methanesulfonyl-flR.sup.12-S-tetrahydro-1-epiphane-naphthalene-ei-S-trifluoromethyl-pyrimidine-2,4-diamine (94) Compound 94 was prepared in a manner similar to that described for compound 22 in Example 22 by reacting compound 51 (140 mg, 0.313 mmol) and methanesulfonyl chloride (26 μl, 0.340 mmol), affording compound 94 in the form of a white solid (61 mg, 43%). 1 H NMR (400 MHz, DMSO-d 6) d 1.26 (m.2 H). 1.65 (m, 2 H). 2.22 (m 6 H), 2.26 (s 3 H), 4.58 (m, 1 H). 5.01 (s, 2 H), 7.01 (m, 1 H), 7.23 (m, 1 H), 7.38 (m, 1 H), 7.84 (m, 1 H). 8.16 (s.1 H), 9.64 (s a, 1 H) ppm. HPLC Tr = 7.11. Purity by HPLC = 100%. Example 95 (+/-) - 1- [6- (4-lsopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -1,2,3,4-tetrahydro-1,4-epipane-naphthalene-9 -yl] -ethanone (95) Step 1. 6-Nitro-1,2,3,4-tetrahydro-1,4-epiazano-naphthalene hydrochloride (C71): A solution of compound C40 (3.67 g, 12.6 mmol) in HCl (1.25 M in MeOH, 10 ml) was heated at 50 ° C for 30 min and concentrated to give compound C71 as a pink solid (2.84 g, 100%). 1 H NMR (400 MHz, DMSO-d 6) d 9.89-9.71 (a, 2 H). 8.31 (d, J = 2.07 Hz, 1 H). 8.22 (dd, J = 2.07, 8.31 Hz, 1 H), 7.71 (d, J-8.3 Hz, 1 H), 5.34 (t, J = 3 Hz, 2 H). 2.35-2.24 (m 2 H). 1.46-1.33 (m, 2 H); 3 C NMR (100 MHz, DMSO-d 6) d 148.0, 147.8, 142.6, 124.8, 123.0, 117.3, 60J. 23.9 ppm. Step 2. (+/-) - 1- (6-Nitro-1,2,3,4-tetrahydro-1,4-epivazan-naphthalen-9-yl) -ethanone (C72): To a solution of compound C71 (3.0 g, 15.8 mmol) in EtOAc (30 mL) was added acetic anhydride (2.1 g, 20.5 mmol). After 30 min, the white precipitate formed. The solids were isolated by filtration to provide compound C72 as a white solid (3.3 g, 90%). 1 H NMR (500 MHz, DMSO-d 6) d 8.21 (d, J = 6.5 Hz, 1 H), 8.11 (d, J = 1.7 Hz, 1 H), 7.61-7.58 (m . 1 HOUR). d 5.54-5.51 (m, 2 H), 2.17-2.12 (m, 1 H), 2.03-1.96 (m, 1 H), 1.93 (s, 3 H), 1.35-1.18 (m, 2 H) ppm. HPLC Tr: 4.58 min; HPLC purity: 100%. MS: 232.3 (MH *) ppm.

Step 3. (+/-) - 1- (6-Amino-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl) -ethanone (C73): A suspension of compound C72 ( 3.3 g, 14.2 mmol) in EtOH (100 ml) was stirred on 10% Pd / C (0.33 g) with hydrogen at 310.25 kPa (45 psi) and at about 25 ° C. After 2 hours, the mixture was filtered through diatomaceous earth and the filtrate was concentrated to give compound C73 as a white solid (2.83 g, 97%). 1 H NMR (500 MHz, DMSO-d 6) d 6.90 (d, J = 7.7 Hz, 1 H), 6.53 (a, 1 H), 6.28 (d, J = 7.3 Hz , 1 H), 5.75-5.10 (m, 2 H), 4.97 (a.2H). 1.99-1.95 (m, 2 H), 1.87 (s, 3 H), 1.23-1.18 (m, 1 H). 1.13-1.10 (m, 1 H); HPLC Tr: 3.0 min; HPLC purity: 100%. MS: 203.2 (MH *) ppm. Step 4. (+/-) - 1 - [6- (4-Chloro-5-trifluoromethyl-pyrimidin-2-ylamino) -1, 2,3,4-tetrahydro-1,4-epivazine-naphthalene 9-yl] -ethanone (C74): To a solution of 2,4-dichloro-5- (trifluoromethyl) pyrimidine (5.5 g, 25.2 mmol) in f-BuOH / DCE (1: 1 (vol: vol), 200 ml) was added dropwise ZnCl 2 (1.0 M in Et 20, 30.3 ml, 30.3 mmol) at 0 ° C. After 1 hour, compound C73 (1.5 g, 5J6 mmol) was added followed by the dropwise addition of TEA (27J mmol, 3.8 ml). After 2 hours, the mixture was concentrated under reduced pressure and the resulting residue was partitioned between EtOAc and water. The phases were separated and the organic phase was washed with water. Then, the organic phase was dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was crystallized from EtOAc / hexanes to give compound C74 as a white solid (6.15 g, 64%). The regiochemistry was confirmed by x-ray crystallography. 1 H NMR (500 MHz, DMSO-d 6) d 10.6 (d, J = 10.3 Hz, 1 H), 8J8 (s, 1 H), 7.68-7.65 (a, 1 H), 7, 44-7.41 (m, 1 H), 7.9 (d, J = 8.3 Hz, 1 H), 5.37-5.31 (m, 2 H), 2.1-2.05 (m, 1 H), 1 , 98-1.93 (m, 1 H), 1.9 (d, J = 3.6 Hz, 3 H), 1.3-1.21 (m.H.), 1.20-1.15 ( m. 1 H) ppm. HPLC Tr: 6.4 min; HPLC purity: 100%. MS: 383.4 (MH *). Step 5. A solution of compound C74 (0.15 g, 0.39 mmol), isopropylamine (28 mg, 0.47 mmol) and DIEA (0.1 g, 0.08 mmol) in 1,4-d-oxane ( 2 ml) was heated at 90 ° C for 1 hour. Then, the reaction mixture was concentrated under reduced pressure. The resulting residue was partitioned between EtOAc and H20 and the phases were separated. The organic phase was washed with H20, dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was crystallized from EtOAc to provide compound 95 as a white solid (90 mg, 56%). 1 H NMR (500 MHz, DMSO-d 6) d 9.58 (a, 1 H), 8.17 (s, 1 H), 7.74 (d, J = 6 Hz, 1 H), 7.26 ( d, J = 8 Hz, 1 H), 7.2 (d, J = 8 Hz, 1 H), 6.46 (d, J = 8 Hz, 1 H), 5.30-5.26 (m, 2 H), 4.46-4.43 (m, 1 H), 2.08-2.03 (m, 1 H), 1.96-1.92 (m, 1 H), 1.9 (s 3 H), 1.29-1.14 (m, 8 H) ppm. HPLC Tr: 6.55 min; HPLC purity: 100%. MS: 406.3 (MH *). EXAMPLE 96 (+/-) - 6- [4- (1-Ethylcarbamoyl-azetidin-3-ylamino) -5-trifluoromethyl-pyrimidin-2-ylamino] -1,2,3,4-tetrahydro-1 acid ethylamide , 4-epiazane-naphthalene-9-carboxylic acid (96) Step 1. (+/-) - 3- [2- (9-acetyl-1,2,3,4-tetrahydro-1,4-) tert-butyl ester epiazano-naphthalen-6-ylammon) -5-trifluoromethyl-pyrimidin-4-ylammonyl] -zetidine-1-carboxylic acid (C88): A solution of compound C74 (2.47 g, 6.81 mmol ) and 1,4-dioxane (15 ml) was treated with DIEA (2.36 ml, 13.62 mmol) followed by the addition of 3-amino-azetidine-1-carboxylic acid tert-butyl ester (1.4 g, 8.18 mmol). The mixture was heated to 90 ° C and stirred for 12 hours. The mixture was diluted with EtOAc (25 ml) and H20 (25 ml), forming a biphasic mixture. The organic phase was collected, dried over Na 2 SO and concentrated under reduced pressure. The resulting yellow residue was purified on silica gel (60% EtOAc / Hexanes) to give compound C88 as a white solid (3.0 g, 85%). 1 H NMR (400 MHz, DMSO-D 6) d ppm 1.2 (m, 2 H) 1.3 (s, 9 H) 1.9 (m, 4 H) 2.0 (m, 1 H) 3, 9 (m, 2 H) 4.0 (d, J = 17.0 Hz, 2 H) 4.7 (d, J = 5.8 Hz, 1 H) 5.3 (m, 2 H) 7.2 ( d, J = 7.5 Hz, 1 H) 7.3 (m, 1 H) 7.4 (d, J = 5.4 Hz, 1 H) 7J (s, 1 H) 8, 2 (s, 1 H) 9.6 (s. 1 H) ppm. HPLC Tr = 6.55 minutes. LC / MS (Method F) m / z 519 (MH *). Step 2. Dihydrochloride of (+/-) - V * -azetidin-3-yl -? * 2- (1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-6-yl) -5-tri fluoromethyl-pyrimidine-2,4-d-amine (C89): Compound C88 (2J2 g, 5.25 mmol) and 3 N HCl in MeOH (15 mL) were combined and the mixture was refluxed for 12 hours. The mixture was concentrated under reduced pressure and dried in vacuo to give compound C89 as a white solid (2.33 g, 99%). HPLC Tr = 2.92 minutes. LC / MS (Method F) m / z 377 (MH +).

Step 3. Compound C89 (125 mg, 254 μmol) and 1,4-dioxane (1 ml) were combined and the mixture treated with ethyl isocyanate (36 mg, 508 μmol) and DIEA (176 μl, 1.01). mmol). The mixture was stirred at 25 ° C for 15 hours, diluted with EtOAc (4 ml) and partitioned in H20 (3 x 4 ml). The organic phase was collected, dried over Na2SO4 and concentrated. The resulting residue was purified on silica gel (5% CH3OH / CH2Cl2) to afford compound 96 as a solid yellow (35 mg, 26% yield). HPLC Tr = 4.92 minutes. CUEM (Procedure F) m / z 519 (MH *). EXAMPLE 97 (+/-) - 3- [2- (9-Acetyl-1, 2,3,4-tetrahydro-1,4-epiazano-naphthalen-6-ylamino) -5- Isopropylamide trifluoromethyl-pyrimidin-4-ylamino] -zetidine-1-carboxylic acid (97) Step 1. 1- trifluoroacetate salt. { 6- [4- (azetidin-3-ylamino) -5-trifluoromethyl-pyrimidin-2-ylamino] -1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl) -ethanone (C90) ): Compound C74 (1.5 g, 2.89 mmol) and 15 ml of 20% TFA in CHCl3 were reacted for 15 hours at about 25 ° C and concentrated to give compound C90 as an oil. viscous brown (1.5 g, 98% yield). 1 H NMR (400 MHz. DMSO-D 6) d 1.2 (m, 2 H) 1.9 (m, 4 H) 2.0 (m, 1 H) 3.9 (m, 2 H) 4.0 (d, J = 17.0 Hz, 2 H) 4.7 (d, J = 5.8 Hz, 1 H) 5.3 (m, 2 H) 7.2 (d, J = 7.5 Hz , 1 H) 7.3 (m, 1 H) 7.4 (d, J = 5.4 Hz. 1 H) 7J (s.1 H) 8.2 (s.1 H) 9.6 (s) , 1 H) ppm. HPLC tr 3.9 minutes. CUEM (Procedure F) m / z 419 (MH *). Step 2. A mixture of compound C90 (208 mg, 400 mmol), 1,4-dioxane (1 ml), DIEA (140 μl, 800 μmol) and isopropyl-isocyanate (60 mg) was stirred at 25 ° C for 2 hours. The mixture was diluted with 4 mL EtOAc and washed with saturated NaHCO 3 (2 x 4 mL) and brine (2 x 4 mL). The organic phase was collected, dried over Na 2 SO and concentrated to give compound 97 as an off-white solid (50 mg, 25% yield). LC / MS (Procedure F) Tr = 2.0 minutes. CUEM (Procedure F) m / z 504.3 (MH *). EXAMPLE 98 (+/-) - 3- [2- (9-Acetyl-1, 2,3,4-tetrahydro-1,4-epiazano-naphthalen-6-ylamino) -5-trifluoromethyl-pyrimidine ethyl ester -4-ylamino] -zetidine-1-carboxylic acid (98) Compound 98 was prepared in a manner similar to that described for compound 97 in Step 2 of Example 97 by reacting compound C90 (208 mg, 400 μmol ), 1,4-dioxane (1 ml), DIEA (140 μl, 800 μmol) and ethyl chloroformate (28 μl, 800 μmol), affording compound 98 as an off-white solid (50 mg, 25% yield) ). HPLC Tr = 5J8 minutes. CUEM (Procedure F) m / z 491.3 (MH *).

Example 99 (+/-) - 1- [6- (4-Cyclobutyloxy-5-trifluoromethyl-pyrimidin-2-ylamino) -1,2,3,4-tetrahydro-1,4-epiazane-naphthalene -9-μl] -ethanone (99) Compound C74 (125 mg, 326 μmol) was treated with DIEA (113 μl, 652 μmol) and cyclobutanol (47 mg, 652 μmol) and the pure mixture was heated to 130 °. C for 16 hours. The mixture was cooled to 25 ° C, diluted with EtOAc (5 mL) and washed with H20 (2 x 5 mL). The organic phase was dried over Na2SO4 and purified on silica gel (30% EtOAc / Hexanes) to provide compound 99 as a tan solid (38 mg, 28% yield). HPLC tr 7.1 minutes. CUEM (Procedure F) m / z 419.2 (MH *). Example 100 (-) - (4-Ethylsulfanyl-5-trifluoromethyl-pyrimidin-2-yl) - (1 S, 4R) - (1, 2,3,4-tetrahydro-1,4-epiazano-naphthalene hydrochloride salt -6-yl) -amine (100) Step 1. (-) - 6- (4-Ethylsulfanyl-5-trifluoromethyl-pyrimidin-2-ylamino) - (1S, 4R) -1, 2-tert-butyl ester , 3,4-tetrahydro-1,4-epipane-naphthalene-9-carboxylic acid (C91): A sealed pressure tube sealed to the flame was charged with 1,4-dioxane (5 ml) and the Compound C57 (700 mg, 1.59 mmol). Then, the mixture was treated with ethanethiol (118 mg, 1.9 mmol) followed by the addition of a 60% dispersion of sodium hydride in mineral oil (82 mg, 2.06 mmol). Then, the mixture was stirred at 50 ° C for 1.5 hours, diluted with EtOAc (10 ml) and washed with saturated NH 4 Cl (2 x 10 ml) and brine (2 x 10 ml). The organic phase was collected, dried over Na 2 SO and concentrated. The resulting residue was purified on silica gel (20% EtOAc / Hexanes) to afford compound C91 as a white solid (730 mg, 98% yield). 1 H NMR (400 MHz, DMSO-D 6) 1.2 (m, 3 H) 1.27 (m, 2 H) 1.3 (m, 9 H) 2.0 (d J = 7.5 Hz, 2 H) 3.2 (c J = 7.1 Hz, 2 H) 5.0 (s, 2 H) 7.2 (d, J = 7.9 Hz, 1 H) 7.3 (d, J = 7.5 Hz. 1 H) 7.7 (s, 1 H) 8.4 (s, 1 H) 10.1 (s, 1 H) ppm. HPLC Tr = 9.0 minutes; CUEM (Procedure F) m / z 467.3 (MH *). Step 2. A mixture of compound C91 (730 mg, 1.56 mmol) and 4 N HCl in 1,4-dioxane was stirred at 25 ° C for 1 hour, during which time a yellow precipitate formed. The solids were collected by filtration, washed with 1,4-dioxane and dried under reduced pressure to provide compound 100 as a yellow solid (554 mg, 95%). 1 H NMR (400 MHz, DMSO-D6) 1.3 (t J = 7.3 Hz, 3 H) 1.4 (d, J = 9.6 Hz. 2 H) 2.2 (d, J = 9.1 Hz, 2 H) 3.2 (c.J = 7.3 Hz, 2 H) 5.2 (d, J = 14.1 Hz, 2 H) 7.4 (d, J = 7.9 Hz, 1 H) 7.5 (d, J = 7.9 Hz, 1 H) 7.8 (s, 1 H) 8.5 (s, 1 H) 9.3 (s, 1 H) 9.4 (s, 1 H) 10.3 (s, 1 H) ppm. HPLC Tr = 6.6 minutes. CUEM (Procedure F) m / z 367.3 (MH *). Example 101 (-) - 1- [6- (4-Ethylsulfanyl-5-trifluoromethyl-pyrimidin-2-ylamino) - (1S, 4R) -1,2,3,4-tetrahydro-1,4-epiazano -naphthalen-9-yl] -ethanolam (101) A suspension of compound 100 (250 mg, 620 μmol) and CH 2 Cl 2 (5 ml) was treated with DIEA (270 μl, 1.55 mmol) followed by the addition of acetic anhydride. (126 μl, 1.24 mmol). The mixture was stirred at 25 ° C for 1 hour and concentrated under reduced pressure. The resulting residue was purified on silica gel (20% EtOAc / Hexanes) to provide compound 101 as a white solid (110 mg, 43% yield). HPLC Tr = 7.0 minutes. CUEM (Procedure F) m / z 409.3 (MH *). Example 102 / V - ((1 R, 2R) -2-Dimethylamine-cyclopentyl) - / V2 - [(1 R, 4S) -1, 2.3.4-tetrahydro-1,4-epiazano-naphthalen-6-yl ] -5-trifluoromethyl-pyrimidine-2,4-diamine (102) Step 1. (1R, 4S) -6- [4 - ((1R, 2R) -2-dimethylamino-cyclopentylamino) tert-butyl ester ) -5-trifluoromethyl-pyrimidin-2-ylamino] -1, 2,3,4-tetrahydro-1,4-epiazano-naphthalene-9-carboxylic acid (C92): To a suspension of compound C93 (918 mg, 4, 56 mmol) and Na 2 CO 3 (2.20 g, 20.74 mmol) in 1-methylene-2-pyrrolidinone (30 ml, anhydrous) was added compound C68 (1.83 g, 4, 15 mmol). The mixture was stirred at 70 ° C for 16 hours, cooled and poured into ice water (150 ml). The precipitate was removed by filtration, washed with water and dried in air. The resulting white solid was purified by flash column chromatography (90: 9: 1 elution of CHCl3 / MeOH / NH4OH) to give compound C92 as a white foamy solid (1.9 g, 86%). CUEM (Method F) Tr 1, 8 min, purity by HPLC (254 nM,> 95%) M + H = 533.5.

Step 2. HCl (g) was bubbled through EtOAc (10 mL) until steam evolution was observed. To a solution of C92 (1.9 g, 3.57 mmol) in EtOH (10 mL, absolute) was added the resulting solution and the mixture was stirred at 25 ° C for about 14 hours. The The mixture was concentrated under reduced pressure to provide compound 102 as an off-white solid (1.67 g, 3.30 mmol). CUEM (Method F) Tr 1.0 min purity by HPLC (254 nm, 90%). M + H = 433.5. EXAMPLE 103 1- Dihydrochloride salt. { 6- [4 - ((1R, 2R) -2-dimethylamino-cyclopentylamino) -5-trifluoromethyl-pyrimidin-2-ylamino] - (1R, 4S) -1, 2,3,4-tetrahydro-1, 4- epiazano-naphthalen-9-yl) -ethanone (103) A suspension of compound 102 (1.67 g, 3.30 mmol) in CH 2 Cl 2 (30 ml) was treated with TEA (2.30 ml, 16.52 mmol) and acetic anhydride and stirred at 25 ° C for 1 hour. The mixture was diluted with CH2Cl2 and washed with H20, NaHCO3 (aq sat.) And brine. The organic phase was collected, dried over Na 2 SO 4 and concentrated to give a foam, 1 H NMR (400 MHz, CD 3 OD) d 1.29-1.49, 1.5-1, 8, 1, 95-2.3 , 2.0, 2.25. 2.65-2.9. 4.6-4.7, 5.3-5.35. 5.45-5.50. 7.21-7.26, 7.31-7.37. 7.69-7.73, 8.1 CUEM (Method F) Tr 2.2 min Purity by HPLC (254 nm,> 95%) M + H = 475.4. The foam was converted to the dihydrochloride salt by the procedure described in Step 2 of Example 2, providing compound 103 as a white powder (1.7 g, 94%). CUEM (Method F) Tr 1.5 min, purity by HPLC > 90%, M + H = 475.3. EXAMPLE 104 / - ((IR ^ RJ ^ -Dimethylamino-cyclopenti-? / ^ L, 2,3,4-tetrahydro-1,4-epiazano-naphthalen-6-yl) -5-trifluoromethyl-pyrimidin-2,4 -diamine (104) Step 1. 6- [4 - ((1R, 2R) -2-dimethylamino-cyclopentylamino) -5-trifluoromethyl-pyrimidin-2-ylamino] -1,2-tert-butyl ester. 3,4-tetrahydro-1,4-epiazane-naphthalene-9-carboxylic acid (C94): Compound C94 was prepared in a manner similar to that described for compound C92 in Step 1 of Example 102 by reacting compound C44 ( 200 mg, 0.45 mmol) and (1R, 2R) - / V, / V-dimethyl-cyclopentane-1,2-diamine (63 mg, 0.49 mmol), affording compound C94 as a mixture of diastereomers in form of a solid chestnut (193 mg, 80%). CUEM (Procedure F) Tr 2.17 min Purity by HPLC (254 nm, >90%) M + H = 533.3. Step 2. Compound 104 was prepared in a manner similar to that described for compound 102 in Step 2 of Example 102 with the exception that compound C94 (90 mg, 1.69 mmol) was used in place of compound C92 . Purification by preparative HPLC provided Compound 104 as a mixture of diastereomers in the form of a white solid (55 mg, 75% yield). CUEM (Method F) Tr 1.2 min purity by HPLC (254 nm,> 95%). M + H = 433.3. Example 105 1 -. { 6- [4 - ((1 R, 2R) -2-Dimethylamino-cyclopentylamino) -5-trifluoromethyl-pyrimidin-2-ylammon] -1,2,4,4-tetrahydro-1,4-epiazane -naftalen-9-íl} -etanone (105) Compound 105 was prepared in a manner similar to that described for compound 103 in Example 103 with the exception that compound 104 (50 mg, 0.12 mmol) was used in place of compound 102. Purification by flash chromatography (Biotage) eluting with CH2Cl2 / MeOH / NH OH afforded compound 105 as a mixture of diastereomers in the form of a clear glass (25 mg, 44% yield). 1 H NMR (400 MHz. CD3OD) 1.2-1.5, 1.5-1.8, 2.0-2.2, 2.0, 2.25, 2.8-2.9, 4.6-4J, 5.3-5.4, 5.4-5.5, 7.2, 7.3-7.4. 7.7, 8.1. CUEM (Method F) Tr 1.1 min purity by HPLC (254 nm,> 95%). M + H = 475.3. EXAMPLE 106 / - ((IR ^ R ^ -Dimethylamino-cyclopentyl -A ^ -y? -methanesulfonyl-I ^. S ^ -tetrahydro-l ^ -epi-azano-naphthalen-6-yl) -5-trifluoromethyl -pyrimid-p-2,4-diamine (106) A solution of compound 104 (50 mg, 0.12 mmol) in DMF (1 ml) was treated with TEA (64 ml, 0.14 mmol) and methanesulfonyl chloride (11 mL, 0.14 mmol) and stirred at 25 ° C for 3 hours.

The mixture was poured into H20 and extracted with EtOAc. The combined organic phases were washed with water and brine, dried over Na 2 SO and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (Biotage) to afford compound 106 as a mixture of diastereomers in the form of a clear glass (25 mg, 44% yield). CUEM (Method F) Tr 1.6 min Purity by HPLC (254 nm,> 95%).

M + H = 511, 2. Example 107 N * - (C \ RI2R) -2-D-methylamino-cyclopentyl) - / V2- (1 S, 4R) -1, 2,3,4-tetrahydro-1,4-epiazano-naphthalene-6-yl- 5-Trifluoromethyl-pyrimidine-2,4-diamine (107) Step 1. (1S, 4R) -6- [4 - ((1R, 2f?) - 2-dimethylamino-cyclopentylamino) -5-trifluoromethyl-pyrimidin-2-ylamino] -1,2 tert -butyl ester 3,4-tetrahydro-1,4-epiazano-naphthalene-9-carboxylic acid (C95): Compound C95 was prepared in a manner similar to that described for compound C92 in Step 1 of Example 102 with the exception that used compound C57 (200 mg, 0.45 mmol) in place of compound C68, providing compound C95 as a mixture of diastereomers as a tan solid (126 mg, 52.5%). CUEM (Method F) Tr 1.8 min, Purity by HPLC (254 nm,> 90%). M + H = 533.3. Step 2. Compound 107 was prepared in a manner similar to that described for compound 102 in Step 2 of Example 102 with the exception that compound C95 (126 mg, 0.236 mmol) was used in place of compound C92, providing Compound 107 as a mixture of diastereomers in the form of a white solid (125 mg,> 100%). CUEM (Procedure F) Tr < 0.9, M + H = 433.3. Example 108 Sai dihydrochloride of 1-. { (1S, 4R) -6- [4 - ((1R, 2R) -2-Dimethylamino-cyclopentylamino) -5-trifluoromethyl-pyrimidin-2-ylamino] -1,2,3,4-tetrahydro-1, 4-epiazano-naphthalen-9-yl) -ethanone (108) Compound 108 was prepared in a manner similar to that described for compound 103 in Example 103 with the exception that compound 107 (125 mg, 0.288) was used. mmol) in place of compound 102. Purification by flash chromatography (Biotage) eluting with CH2Cl2 / MeOH / NH4OH provided an off-white foam. The foam was converted to the dihydrochloride salt by the procedure described in Step 2 of Example 102, affording compound 108 as a white solid (121 mg, 77%). ? NMR (400 MHz, dmso-d6) 1.1-1.3, 1, 5-1, 8, 1.8-2.2, 2.6-2.8, 3.8-4.0, 4 , 6-4.8, 5.3-5.4, 7.2-7.4, 7.6, 7.8, 8.3 ppm. CUEM (Method F) Tr 1.5 min, purity by HPLC (254 nm,> 95%). M + H = 475.2. Example 109? H (1 R, 2R) -2- [2- (1, 2,3,4-Tetrahydro-1,4-epiazano-naphthalen-6-ylamino) -5-trifluoromethyl-pyrimidin-4-ylam no] -cyclopentyl) -acetamide (109) Step 1. ((1R, 2R) -2-amino-cyclopentyl) -carbamic acid benzyl ester (C96): Compound C96 was prepared in a similar manner to described for compound 103 in the Example 103, with the exception that ((1R, 2R) -2-benzyloxycarbonyl-cyclopentyl) -carbamic acid tert -butyl ester (100 mg, 0.299 mmol) was used in place of compound 102, yielding compound C96 in the form of a white solid (92 mg, 100%). Step 2. ((1 ~, 2R) -2-Acetylamino-cyclopentyl) -carbamic acid benzyl ester (C97): Compound C97 was prepared in a manner similar to that described for compound 103 at Example 103, with the exception that compound C96 (92 mg, 0.299 mmol) was used in place of compound 102, giving compound C97 as a white solid (82 mg, 100%).

CUEM (Method F) Tr 1.8 min purity by HPLC (254 nm,> 95%). M + H = 277.3. Step 3.? / - ((1R, 2r * ") -2-Amine-cyclopentyl) -acetamide (C98): A mixture of compound C97 (82 mg, 0.3 mmol), MeOH and palladium on carbon (10%). %, catalytic) was stirred on a Parr® stirrer at 310.26 kPa (45 psi) of H2 for 16 hours at about 25 ° C. The mixture was filtered through celite and the solids were washed with copious amounts of MeOH. The combined filtrates were concentrated under reduced pressure to give Compound C98 as an off-white solid (40 mg, 94%) Step 4. Tert-butyl acid ester 6- [4 - ((1R, 2R) -2- acetylamino-cyclopentylamino) -5-trifluoromethyl-pyrimidin-2-ylamino] -1,2,3,4-tetrahydro-1,4-epiazane-naphthalene-9-carboxylic acid (C99): Compound C99 was prepared from a similarly to that described for compound 102 in Step 2 of Example 102 with the exception that compound C44 (144 mg, 0.321 mmol) was used in place of compound C92, providing compound C99 as a mixture of diastereomers in the form of a s Brown oil (55 mg, 36%). CUEM (Procedure F) Tr 2.6 min purity by HPLC (254 nm,> 95%) M + H = 547.3. Step 5. Compound 109 was prepared in a manner similar to that described for compound 102 in Step 2 of Example 102 by cleaving compound C99 (55 mg, 0.100 mmol) with HCl, affording compound 109 as a mixture of diastereomers in form of a white solid (50 mg, 96%). CUEM (Method F) Tr 1.0 min, purity by HPLC (254 nm, > 95%). M + H = 447.3.

Example 110? / -. { (1R, 2R) -2- [2- (9-Acetyl-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-6-ylamino) -5-trifluoromethyl-pyrimidin-4-ylamino] - cyclopentyl} -acetamide (110) Compound 110 was prepared in a manner similar to that described for compound 103 in Example 103, with the exception that compound 109 (50 mg, 0.096 mmol) was used in place of compound 102, providing Compound 110 as a mixture of diastereomers in the form of a white solid (37 mg, 78%). CUEM (Method F) Tr 1, 8 min, Purity by HPLC (254 nm,> 93%). M + H = 489.4. Example 111? -. { (1 R, 2R) -2- [2- (1, 2,3,4-Tetrahydro-1,4-epiazano-naphthalen-6-ylamino) -5-trifluoromethyl-pyrimidin-4-ylamino] -cyclohexyl} -acetamide (111) Step 1.? / - ((1R, 2R) -2-Amine-cyclohexyl) -acetamide (C100): A solution of (1R, 2R) -1,2-cyclohexanediamine (10.0 g, 87.9 mmol) and ethyl acetimidate (11.0 g, 88.8 mmol) in EtOH (350 mL) was heated to reflux for 18 hours under an atmosphere of dry nitrogen. The reaction mixture was cooled to 25 ° C and concentrated. The resulting white solid was dissolved in a 1: 1 mixture (vol: vol) of EtOH / H20, was buffered to pH = 7 and heated to reflux for 2 days. The mixture was cooled to about 25 ° C and 12 N HCl was added with cooling and stirring. The resulting viscous oil was redissolved in 50 ml of MeOH and stirred at about 25 ° C for 1 hour. The resulting mixture was filtered and concentrated. The resulting foamy solid was triturated with Et20 overnight. The resulting solids were collected by filtration, washed with Et20 (3 x 50 ml) and dried under reduced pressure to give compound C100 as a solid having a purity of about 80%. (17.2 g). Compound C100 was used without further purification CUEM (Method F) Tr 0.3 min, M + H = 157.1. M (cale.) 156.13. Step 2. 6- [4 - ((1R, 2 ~) - 2-acetylamino-cyclohexyllamine) -5-trifluoromethyl-pyrimidin-2-ylamino] -1-tert-butyl ester 2,3,4-tetrahydro-1,4-epiazano-naphthalene-9-carboxylic acid (C101): Compound C101 was prepared in a manner similar to that described for compound C92 in Step 1 of Example 102 by reacting the compound C44 (100 mg, 0.223 mmol) and compound C100 (49 mg, 0.250 mmol), affording compound C101 as a mixture of diastereomers as a white solid (91 mg, 0.163%). CUEM (Method F) Tr 2.8 min, purity by HPLC (254 nm,> 85%). M + H = 561.4. Step 3. Compound 111 was prepared in a manner similar to that described for compound 102 in Step 2 of Example 102 with the exception that compound C101 (91 mg, 73 mmol) was used in place of compound C92, providing compound 111 as a mixture of diastereomers in the form of a yellow solid (92 mg, 100%). CUEM (Method F) Tr 1.2 min, purity by HPLC (254 nm,> 95%), M + H = 461.3. Example 112 / V, - ((1 R, 2R) -2-Dimethylamino-cyclopentyl) -? - (9-methyl-1, 2,3,4-tetrahydro-1,4-epiazano-naphthalen-6-yl) -5-trifluoromethyl-pyrimidine-2,4-diamine (112) A solution of compound 111 (38 mg, 0.08 mmol) and MP-Carbonate (xs) (polymer supported carbonate) in MeOH (2 mL, anhydrous) was stirred at 25 ° C for 2 hours. The resulting mixture was filtered and the solids were washed with MeOH. The combined filtrates were added to paraformaldehyde (7 mg, 0.08 mmol) and the resulting solution was stirred at 25 ° C for 3 hours. The solution was treated with NaBH 4 (9 mg, 0.23 mmol), stirred at about 25 ° C for 16 hours and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (elution with CH2Cl2 / MeOH / NH OH) to provide compound 112 as a mixture of diastereomers as a white solid (6 mg, 17%). CUEM (Method F) Tr 1.0 min, Purity by HPLC (254 nm,> 95%). M + H = 447.4. Example 113? -. { (1R, 2R) -2- [2- (9-Methanesulfonyl-1,2,3,4-tetrahydro-1,4-epipana-naphthalen-6-ylamino) -5-trifluoromethyl-pyrimidin-4 -ylamino] -cyclopentyl) -acetamide (113) Compound 113 was prepared in a manner similar to that described for compound 106 in Example 106 with the exception that compound 111 (30 mg, 0.056 mmol) was used instead of compound 104, affording compound 113 as a mixture of diastereomers in the form of a white solid (21 mg, 71%). CUEM (Procedure F) Tr 2.0 min, purity by HPLC (254 nm, 92%). M + H = 525.3.

EXAMPLE 114 6- [4- (1,3-Dihydro-pyrrolI3,4-c] pyridin-2-yl) -5-trifluoromethyl-pyrimidin-2-ylamino] -1,3,3-tert-butyl ester 4-tetrahydro-1,4-epiazane-naphthalene-9-carboxylic acid (114) Stage 1. Tertiary-butyl ester of e- -lI.S-dihydro-pyrro ^ -cjpiridin ^ -i -S-trifluoromethyl-p. rimidin-2-ylamino] -1, 2,3,4-tetrahydro-1,4-epiazano-naphthalene-9-carboxylic acid (C103): The compound C103 was prepared in a manner similar to that described for compound C92 in Step 1 of Example 102 by reacting compound C44 (105 mg, 0.234 mol) and (1R, 2R) - / V, / V-dimethyl-cyclopentane- 1,2-diamine (C102) (see U.S. Patent No. 5,371,090) (28 g, 0.234), affording compound C103 as a white solid (108 mg, 88%). CUEM (Procedure F) Tr 2.8 min, Purity by HPLC (254 nm, 84%). M + H = 525.4. Step 2. Compound 114 was prepared in a manner similar to that described for compound C92 in Step 1 of Example 102, with the exception that compound C103 (108 mg, 0.206 mmol) was used in place of C68, providing Compound 114 in the form of a white solid (105 mg, 96%). CUEM (Procedure F) Tr 1, 8 min (polar procedure) Purity by HPLC (254 nm, 95%). M + H = 425.3. Example 115 1-. { 6- [4- (1,3-Dihydro-pyrrol [3,4-c] pyridin-2-yl) -5-trifluoromethyl-pyrimidin-2-ylamino] -1, 2,3,4 -tetrahydro-1,4-epiazano-naphthalen-9-yl) -ethanone (115) Compound 115 was prepared in a manner similar to that described for compound 103 in Example 103, with the exception that the compound was used 114 (105 mg, 0.196 mmol) in place of compound 102, affording compound 115 as a white solid (65 mg, 71%). CUEM (Method F) Tr 1.9 min, purity by HPLC (254 nm,> 95%). M + H = 467.3. Example 116? F * - ((1 R ^ R ^ -Morfolin ^ -yl-cyclopenti-? ^ - 0, 2,3,4-tetrahydro-1,4-epiazano-naphthalen-6-yl) -5-trifluoromethyl -pyrimidine-2,4-diamine (116) Step 1. 6- [4 - ((1R, 2R) -2-morpholin-4-yl-cyclopentylamino) -5-trifluoromethyl-pyrimidin-2-tert-butyl ester -ylamino] -1,2,3,4-tetrahydro-1,4-epiazano-naphthalene-9-carboxylic acid (C104): Compound C104 was prepared in a manner similar to that described for compound C92 in the Step 1 of Example 102, with the exception that 2-morpholin-4-yl-cyclopentylamine (38 mg, 0.223 mmol) was used in place of compound C68 to react with compound C44 (100 mg, 0.223 mmol), affording the Compound C104 as a mixture of diastereomers in the form of a white solid (130 mg, 100%). CUEM (Method F) Tr 1.9 min, purity by HPLC (254 nm,> 95%). M + H = 575.5. Step 2. Compound 116 was prepared in a manner similar to that described for compound 102 in Step 2 of Example 102, with the exception that compound C104 (130 mg, 0.223 mmol) was used in place of compound C92, providing compound 116 as a mixture of diastereomers in the form of a white solid (13 mg, 10%). CUEM (Method F) Tr 0.8 min, purity by HPLC (254 nm,> 95%). M + H = 475.3. Example 117 1- [6- (4-Etylamino-5-methyl-pyrimidin-2-ylamino) - (1S, 4R) -1,2,3,4-tetrahydro-1,4-epiazano-naphthalene- 9-yl] -ethanone (117) Step 1. 6-nitride- (1S, 4R) -1,2,3,4-tetrahydro-1,4-epiazano-naphthalene hydrochloride (C105): A mixture of Compound C41 (2.50 g, 8.61 mmol) and 4 N hydrogen chloride in 1,4-dioxane (100 mL, 400 mmol) was stirred at 25 ° C for 40 min. The mixture was concentrated and the resulting residue was dried under reduced pressure to provide compound C105 in the form of a brown syrup (1.99 g, 100%). 1 H NMR (500 MHz, DMSO-d 6) d 9.68 (sa, 2 H), 8.36 (d J = 1.5 Hz, 1 H), 8.26 (dd J = 8.0, 2.0 Hz, 1 H), 7J6 (d, J = 8.5 Hz, 1H), 5.38 (s, 2H), 3.36 (s, 2H), 2.32 (m, 2H), 1.45 (m, 2H). Step 2. 1- (6-Nitro- (1S, 4R) -1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl) -ethanone (C106): A mixture of the compound C105 ( 1.99 g, 8.61 mmol) and DIEA (2.22 g, 17.2 mmol) in CH2Cl2 (110 mL) was treated with acetyl chloride (1.01 g, 12.9 mmol) and stirred at 25 ° C for one night. The reaction mixture was diluted with CH2Cl2 (100 ml) and washed with saturated aqueous NaHCO3 (150 ml) and then with brine (150 ml). The organic phase was collected, dried over Na 2 SO, filtered and concentrated to dryness to give compound C106 as a brown syrup (1.82 g, 91%). 1 H NMR (500 MHz, CDCl 3) d 8.13 (m, 2H), 7.41 (m, 1H). 5.66 (m, 1H). 5.21 (m, 1H), 2.21 (m, 2H), 2.04 (m, 3H), 1.40 (m, 2H).

Step 3. 1- (6-Amino- (1S, 4R) -1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl) -ethanone (C107): A mixture of the compound C106 ( 1.82 g, 7.84 mmol) and 10% palladium on carbon (0J50 g, 50% by weight water) in MeOH (55 ml) was stirred under a hydrogen atmosphere 344.74 kPa (50 psi) during 1.5 hours at 25 ° C. Then, the reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated to dryness, yielding compound C107 as a white solid (1.60 g, 100%). 1 H NMR (500 MHz, CDCl 3) d 7.00 (m, 1H), 6.62 (dd, J = 14.0, 2.0 Hz, 1H), 6.44 (m, 1H), 5.44 (m , 1H), 4.97 (m, 1H), 3.65 (sa, 2H), 2.06 (m.2H), 1.99 (m, 3H), 1.40 (m, 1H), 1.29 (m. ,1 HOUR). Step 4. A mixture of compound C107 (0.196 g, 0.969 mmol), (2-chloro-5-methyl-pyrimidin-4-yl) -ethylamine (0.166 g, 0.969 mmol), f / s (dibenzyl idinacetone) dipalladium ( 0) (0.088 g, 0.097 mmol) and 2- (dicyclohexylphosphino) biphenyl (0.034 g, 0.097 mmol) in THF (1 ml) was treated with a 1 M solution of 6 μs (trimethylsilyl) amide lithium in THF (2.13 ml, 2, 13 mmol). The resulting mixture was heated in a microwave reactor at 140 ° C for 20 min. Then, the mixture was cooled to room temperature, diluted with MeOH (2 ml) and concentrated to dryness. The resulting residue was purified by preparative HPLC followed by chromatography (silica, 1: 9 MeOH / EtOAc). The eluents containing compound 117 were combined and concentrated. The resulting residue was lyophilized from acetonitrile / water to give compound 117 as a white solid (0.134 g, 41%). HPLC (Method B1) Tr = 4.21, Purity by HPLC = 100%. MS for C19H23N50: [M + H] = 388. Examples 118 to 125 The compounds of Examples 118 to 125 (Table 1) were prepared in a manner similar to that described for compound 117 in Step 4 of Example 117. Example 126 1- [6- (4-Etylamino-5-fluoro-pyrimidin-2-ylamino) - (1S, 4R) -1,2,3,4-tetrahydro-1,4-epiazano-naphthalene-9- il] -etanone (126) Step 1. (2-Chloro-5-fluoro-pyrimidin-4-yl) -ethylamine (C108): A mixture of 2,4-dichloro-5-fluoro-pyrimidine (4.95 g , 29.6 mmol), DIEA (7.64 g, 59.2 mmol) and a 2.0 M solution of EtNH2 in MeOH (14.8 mL, 29.6 mmol) was stirred at 50 ° C in a vessel. closed tightly for 20 hours. Then, the reaction mixture was cooled to 25 ° C and concentrated. The resulting residue was dissolved in EtOAc (200 ml) and washed with H20 (150 ml) and brine (150 ml). The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was triturated with hexanes to give compound C108 as an off-white solid (4.02 g, 77%). PF: 56-58 ° C. 1 H NMR (500 MHz, CDCl 3) d 7.86 (d, J = 3.0 Hz, 1H), 5.20 (br s, 1H), 3.57 (m, 1H), 1.29 (t J = 7.5 Hz, 3H) ppm. Step 2. A mixture of compound C107 (0.200 g, 1.00 mmol), C108 (0.187 g, 1.00 mmol), / ris (dibenzylidin acetone) dipalladium (0) (0.090 g, 0.100 mmol) and 2- (dicyclohexylphosphine) ) biphenyl (0.035 g, 0.100 mmol) in THF (1 ml) was stirred for 1 min at 25 ° C. A 1 M solution of 6 μs (trimethylsilyl) amide lithium in THF (2.20 ml, 2.20 mmol) was added and the mixture was heated in a microwave reactor at 140 ° C for 20 min. . Then, the resulting mixture was cooled to room temperature, diluted with MeOH (2 ml) and concentrated to dryness. The resulting residue was purified by chromatography (silica, 1: 1 EtOAc / hexanes to EtOAc) and then by preparative HPLC to provide compound 126 as a white solid (0.112 g, 33%). PF: 201-203 ° C. 1 H NMR (500 MHz, CDCl 3) d 7.66 (m, 1H). 7.65 (d.J = 1.3 Hz. 1H). 7.23 (m, 1H), 7.15 (m, 1H). 6.80 (d, J = 3.1 Hz, 1H), 5.52 (m, 1H), 5.04 (m, 1H), 4.91 (sa, 1H), 3.53 (m, 2H), 2 , 09 (m, 2H), 2.00 (s, 3H), 1.43 (m, 1H), 1.29 (m, 4H) ppm. Example 127 1- [6- (5-Fluoro-4-isopropylamino-pyrimidin-2-ylamino) - (1 S, 4R) -1, 2,3,4-tetrahydro-1,4-epiazano-naphthalene-9- il] -etanone (127) Stage 1. (2-Chloro-5-fluoro-pyrimidin-4-yl) -sopropylamine (C109): A mixture of 2,4-dichloro-5-fluoro-pyrimidine (5.01 g, 30.0 mmol), DIEA (7.93 g, 60 mmol) and isopropylamine (1 J7 g, 30.0 mmol) in EtOH (15 mL) was stirred at 50 ° C in a sealed container. for 21 hours. Then, the mixture was cooled to 25 ° C and concentrated. The resulting residue was dissolved in EtOAc (200 ml) and washed with H20 (200 ml) and brine (200 ml). The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by chromatography (silica, hexanes to 3: 1 CH2Cl2 / hexanes) to give compound C109 as a solid. yellow (4.67 g, 82%). PF: 55-57 ° C. 1 H NMR (500 MHz, CDCl 3) d 7.85 (d, J = 3.0 Hz. 1H). 5.31 (s a, 1H). 3.34 (m, 1H), 1.29 (d, J = 6.5 Hz, 6H) ppm .. Step 2. Compound 127 was prepared in a manner similar to that described for compound 126 in Step 2 of Example 126 with the exception that compound C109 (0.199 g, 1.0 mmol) was used in place of compound C108, giving compound 127 as a white solid (0.138 g, 39%). HPLC (Method B1) Tr = 3.81, Purity by HPLC = 99%. MS for C, 9H22FIN50: [M + H] = 356. Example 128 1- [6- (4-Cyclopropylamino-5-fluoro-pyrimidin-2-ylamino) - (1 S, 4R) -1, 2.3.4- tetrahydro-1,4-epiazano-naphthalen-9-yl] -ethanone (128) Step 1. (2-Chloro-5-fluoro-pyrimidin-4-yl) -cyclopropylamine (C110): A mixture of 2,4- dichloro-5-fluoro-pyrimidine (4.96 g, 29J mmol), DIEA (7.64 g, 59.4 mmol) and cyclopropylamine (1.69 g, 29J mmol) in EtOH (15 ml) was stirred at 50 ° C in a sealed container for 25 hours. The mixture was cooled to 25 ° C and concentrated. The resulting residue was dissolved in EtOAc (200 ml) and washed with H20 (150 ml) and brine (150 ml). The organic phase was collected, dried over Na 2 SO 4 and concentrated under reduced pressure. The resulting residue was triturated with hexanes to give compound C110 as an off-white solid (4.97 g, 89%). PF: 83-85 ° C. 1 H NMR (500 MHz, CDCl 3) d 7.89 (m, 1 H), 5.42 (br s, 1 H), 2.90 (m, 1 H), 0.93 (m, 2 H), 0.63 (m , 2H) ppm. Step 2. Compound 128 was prepared in a manner similar to that described for compound 126 in Step 2 of Example 126 with the exception that compound C110 was used. (0.197 g, 1.0 mmol) in place of compound C108, affording compound 128 as a white solid (0.033 g, 8%). HPLC (Method B1) Tr = 10.1, Purity by HPLC = 85%. MS for C19H20FIN5O: [M + H] = 354. Example 129 1- [6- (4-Cyclobutylamine-5-fluoro-pyrimidin-2-ylamino) - (1 S, 4R) -1, 2, 3,4-tetrahydro-1,4-epiazane-naphthalen-9-yl] -ethanone (129) Step 1. (2-Chloro-5-fluoro-pyrimidin-4-yl) -cyclobutylamine (C111): A mixture of 2,4-dichloro-5-fluoro-pyrimidine (4.89 g, 29.3 mmol), DIEA (7J9 g, 58.6 mmol) and cyclobutylamine (2.08 g, 29.3 mmol) in EtOH (15 mL) was stirred at 50 ° C in a sealed container for 21 hours.

Then, the mixture was cooled to 25 ° C and concentrated. The resulting residue was dissolved in EtOAc (200 ml) and washed with H2O (200 ml) and brine (200 ml). The organic phase was collected, dried over Na 2 SO 4, and concentrated under reduced pressure. The resulting residue was purified by chromatography (silica, hexanes to 3: 1 CH2Cl2 / hexanes) to give compound C111 as a yellow solid (4.57 g, 82%). PF: 63-65 ° C. 1 H NMR (500 MHz, CDCl 3) d 7.87 (m, 1 H), 5.33 (s a, 1H), 4.61 (m, 1H), 2.46 (m.2H). 1.96 (m, 2H), 1.81 (m, 2H) ppm. Step 2. Compound 129 was prepared in a manner similar to that described for compound 126 in Step 2 of Example 126 with the exception that compound C111 was used. (0.210 g, 1.0 mmol) in place of compound C108, affording compound 129 as an off-white solid (0.125 g, 38%). HPLC (Procedure B1) Tr = 11, 1, Purity by HPLC = 99% MS for C20H22FIN5O: [M + H] = 368. Examples 130 to 355 Examples 130 to 355 (Table 2) were prepared by specific procedures of the examples described above or by methods known to those skilled in the art. Example 356 (+/-) - 1- [6- (4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -1,2,3,4-tetrahydro-1,4-epiazane-naphthalene-9 -yl] -propan-2-one (356) A solution of compound C46 (92 mg, 0.22 mmol) and DIEA (115 mg, 0.89 mmol) in DMF (2 ml) was stirred at 29 ° C for 12 hours. The reaction mixture was partitioned between EtOAc and H20 and the phases were separated. The organic phase was collected, washed with water, dried over Na 2 SO 4 and concentrated under reduced pressure. Purification of the resulting residue by 12S Instantaneous Biotage® (99: 1 CH2Cl2 / CH3OH) provided compound 356 as a brown solid (50 mg, 52%).

'H NMR (500 MHz, DMSO-d6) d 9.5 (s, 1 H), 8.2 (s, 1 H), 7J (s, 1 H), 7.3 (m, 1 H), 7.1 (d.J = 8 Hz. 1 H), 7.0 (d, J = 7 Hz, 1 H), 4.6 (a, 1 H), 4.17 (t, J = 4 Hz. 2 H), 2.95 (m, 2 H) ), 2.2 (m, 2 H), 2.15 (m. 2 H), 2.01 (s, 3 H), 1.90 (m, 2 H), 1.7-1.6 (m, 2 H). 1.09 (m.2H) ppm. MS: 432.5 (MH *).

Example 357 (+/- H6- (4-Cyclobutyl-lane-5-trifluoromethyl-pyrimidin-2-ylamino) -1, 2,3,4-tetrahydro-1,4-epiazane-naphthalen-9-yl acid dihydrochloride ] -acetic (357) Stage 1. Tert-butyl ester of the acid (+/- H6- (4-cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -1, 2,3,4-tetrahydro-1, 4 -epiazano-naphthalen-9-yl] -acetic (C112): To a solution of compound C46 (1.0 g, 2.23 mmol) and DIEA (0.86 g, 6 J mmol) in THF (10 ml) and DMF (10 ml) was added tert-butyl bromoacetic acid ester (0.48 g, 2.45 mmol) After 2 hours, the reaction mixture was partitioned between EtOAc and H20 and the phase was separated. The organic phase was collected and the aqueous phase was extracted with EtOAc The combined organic phases were washed with H20, dried over Na2SO4 and concentrated under reduced pressure Purification of the resulting residue by Bimotage® Instant 40M (97: 3 CH2Cl2 / CH3OH) gave compound C112 as a white solid (0.93 g, 85%). 1 H NMR (400 MHz, DMSO-d6) d 9.54 (a, 1 H), 8.14 (s. 1 H), 7 J (1 H), 7,3 (m, 1 H), 7,12 (d, J = 8 Hz, 1 H), 6,9 (m, 1 H), 4,5 (a, 1 H), 4.2 (t, J = 4 Hz, 2H), 2J (m, 2 H), 2.18-2.12 (m, 4 H), 1.97 (m, 2 H) , 1.67-1, 58 (m, 2 H), 1.33 (s, 9 H), 1.0 (m, 2 H); MS: 490.3 (MH *). Step 2. A solution of HCl (4 N in dioxane, 10 ml) and compound C112 (0.19 g, 0.388 mmol) was stirred at about 25 ° C for 4 hours. Then, the mixture was concentrated to give compound 357 as a white solid (0.19 g, 100%). 1 H NMR (400 MHz, DMSO-de) d 1.63 (a, 1 H), 8.3 (s, 1 H), 7.87 (m, 1 H), 7.81 (a, 1 H) 7.6 (m, 1 H), 7.5 (m.H.). 5.3 (m, 2 H), 4.5 (m, 1 H). 4.0 (s, 1 H), 3.6 (m, 2 H), 2.4 (m, 2 H), 2.1 (m, 4 H), 1.7 (m 2 H), 1.47 (m, 2 H) ppm. HPLC tr: 4J2 min; HPLC purity: 100%. MS: 434.2 (MH *). Example 361 (+/-) - 2- [6- (4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -1,2,3,4-tetrahydro-1,4-epiázano -naphthalen-9-yl] -? / - methyl-acetamide (358) A solution of compound 357 (0.19 g, 0.37 mmol) in thionyl chloride (0.22 g, 1.86 mmol) was heated at 50 ° C. After 2 hours, the mixture was concentrated and the residue was dissolved in THF (5 ml). The resulting solution was treated with DIEA (0.15 g, 1.12 mmol), methylamine (2.0 M in THF, 0.37 mL, 0J5 mmol) was added and stirred for 2 hours at about 25 ° C. The mixture of The reaction was quenched with water and extracted with EtOAc. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. Purification of the resulting residue by Biotage® Instantaneous 12S (98: 2 CH2Cl2 / CH3OH) gave compound 358 as a brown solid (45 mg, 27%). 1 H NMR (500 MHz, DMSO-d 6 d) 9.6 (a, 1 H), 8.1 (s, 1 H), 7.7 (s, 1 H), 7.6 (a, 1 H) , 7.4 (d, J = 7 J Hz, 1 H), 7.19 (d, J = 7.7 Hz, 1 H), 7.05 (d, J = 6 Hz, 1 H), 4, 6 (a, 1 H). 4.2 (a, 2 H), 2J (a, 2 H), 2.6 (d, J = 5 Hz, 3 H), 2.24-2.11 (m, 6 H), 1.64-1, 60 (m, 2 H), 1.15 (a.2 H) ppm. HPLC Tr: 5.6 min; HPLC purity: 100%. MS: 447.3 (MH *). Examples 359 to 362 Examples 359 to 362 (Table 3) were prepared in a manner similar to that described for compound 356 in Example 356. Example 363-417 Examples 363-417 (Table 4) were prepared by the general procedure which is described below: A solution of the appropriate aryl chloride (0.2 mmol), the appropriate amine (0.3 mmol) and DIEA (0.4 mmol) in 1,4-dioxane (1 ml) was stirred at 90 ° C for one night. The reaction mixture was concentrated and the resulting residue was dissolved in DCE (2 ml). The resulting solution was treated with polystyrene benzaldehyde resin (2 equiv.) And stirred overnight. The mixture was filtered and concentrated. The resulting residue was dissolved in DMSO (1 ml), filtered and concentrated to give the products. Example 418 Salt of trifluoroacetic acid of 5-chloro- / V4-cyclobutyl-? 2-9-methanesulfonyl-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-6-yl) -pyrimidine-2,4-diamine (418) 418 To an 8 ml reaction vial were added 2,4,5-trichloro-pyrimidine (0.5 M in DMSO), cyclobutylamine (0.5 M in DMSO, 160 μl) and DIEA (pure, 30 μl). . The vial was capped and the contents were stirred at 25 ° C for 22 h. The reaction mixture was concentrated in Genevac, providing 3,3-cyclobutylamino-2,5-dichloro-pyrimidine. The solid was treated with compound C76 (0.5 M in DMSO, 160 μl), concentrated in Genevac and the resulting residue treated with EtOAc (160 μl). The vial was capped and the contents were stirred at 75 ° C for 22.5 hours. Then, the reaction mixture was concentrated in Genevac. The resulting crude product was dissolved in DMSO and purified by HPLC to provide compound 418 (11.9 mg, 35%). IQPA CLEM: Retention time: 3.00 min (Procedure A), Observed mass: 419.99 'M + HJ. Examples 419-482 Examples 419-482 (Table 5) were prepared in a manner similar to that described for compound 421 in Example 421. Examples 483-490 Examples 483-490 (Table 6) were prepared by the general procedure which is described below. To an 8 ml vial were added compound C74 (1 ml, 0.05 M in NMP, 50 μmol), azetidine-3-carboxylic acid (300 μl, 0.5 M in NMP, 150 μmol) and pure DIEA. and the contents of the vial were added at 80 ° C overnight. The mixture was concentrated in Genevac and the contents of the vial were treated with DCE (3 ml) and a saturated solution of NH CI (2 ml). The vials were shaken with vortex formation, centrifuged and the upper phase (2 ml) was removed, leaving a residue. To the vial a saturated solution of additional NaHCO3 (2 ml) was added. The vial was vortexed, centrifuged, a portion of 2700 μl was removed from the mixture and transferred to the clean vial. The contents of the clean vial were concentrated, providing the crude product. CUEM (Procedure F) product: Tr = 196 s. Exact mass 447.1. The contents of the vial were treated with the appropriate amine (0.5 M in DMF, 200 μl), HBTU (0.25 M in DMF, 400 μl) and pure DIPEA (50 μl) and stirred at 25 ° C for one week. night. The crude product was dissolved in DCE, washed with a saturated solution of NH 4 Cl and a saturated solution of NaHCO 3 and concentrated. Then, the resulting residue was purified by HPLC to provide the product. The scope of the present invention is not limited by the specific embodiments described herein. In fact, various modifications of the invention in addition to those described herein will be apparent to those skilled in the art from the foregoing description and the accompanying figures. Said modifications are intended to be within the scope of the appended claims. All patents, applications, publications, test procedures, bibliography and other materials cited in this document are incorporated herein by reference in their entirety.

Table 1. Examples 24 to 28, 53 to 87 and 118-125. fifteen twenty fifteen twenty I5 twenty fifteen twenty fifteen twenty fifteen twenty fifteen twenty fifteen twenty twenty fifteen twenty fifteen twenty fifteen twenty twenty fifteen twenty fifteen twenty 10 fifteen twenty fifteen twenty fifteen twenty fifteen twenty twenty fifteen twenty fifteen twenty fifteen twenty fifteen twenty Table 2. Examples 130-355. 15 20 fifteen twenty fifteen twenty fifteen twenty fifteen twenty fifteen twenty fifteen twenty fifteen twenty fifteen twenty twenty fifteen twenty twenty fifteen twenty Table 3. Examples 359-362. fifteen twenty Table 4. Examples 363-417. fifteen twenty twenty twenty fifteen twenty fifteen twenty fifteen twenty fifteen twenty fifteen twenty Table 5. Examples 419-482. 15 20 fifteen twenty fifteen twenty fifteen twenty Table 6. Examples 483-490. fifteen twenty

Claims (15)

1. A compound of formula I: where Ar is III or a pharmaceutically acceptable salt thereof, wherein K is C (R1) or N M is C (H) or N; Q is C (D) or N; D is a substituent selected from the group consisting of hydrogen, halogen, -CF3, -N02, -CN, -alkenyl (C2-C6), -alkynyl (C2-C6), -alkyl (C2-C6) perfluorinated, -alkenyl (C2-C6) perfluorinated, -alkynyl (C3-C6) perfluorinated, -cycloalkyl (C3-C7) , -cycloalkenyl (C5-C10). -bicycloalkyl (C6-C10), -bicycloalkenyl (C6-C? 0), -heterocyclylamide CrCg), -heterocycloalkenylofCt-Cio), -heterobicycloalkyl (C6-C9), -heterobicycloalkenyl (C6-C9), -aryl (C6-C10). - perfluorinated heteroaryl (C? -C9), perfluorinated (C6-C10) -aryl, -heteroaryloid-Cg, -NR3R4, -OR5, -C (0) R5. -C02R5 - - > 3, -, - > 3? -, 4 CONRJR \ -SR °, -SOR °, -S02R °, -S02NRJR *. -NHCOR ', -NRJCONRJR, 1 and -NRJS02Rb, in which said substituents D - (C, -C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) -alkynyl, - (C3-C7) -cycloalkyl, -cycloalkenyl (C-C? o), -bicycloalkyl (C6) -C10) -bicycloalkenyl (C6-C10), -heterocyclylamide CrCg), -heterocycloalkenyl (C1-C10), -heterobicycloalkyl (C6-C9), -heterobicycloalkenyl (C6-C9), -aryl (Cß-C, o), -heteroaryl (CrC9) ), -NR3R4, -OR5. -C (0) R5, -C02R5. -CONR3R4, -SR6. -SOR6, -S02R6. -S02NR3R4, -NHCOR5, -NR3C0NR3R4, and -NR3S02R6 are optionally substituted with one to three substituents independently selected from the group consisting of hydrogen, halogen, -CF3, -N02, -CN, -alkyl (C6), -alkenyl (C2-C6), -alkynyl (C2-C6), -CR3 = N-NR3R4, -CR3 = N-OR5, -CR3 = N-NR3C (0) R3, -CR3 = N-NR3C (0) OR5, -NR3R4, -OR5, -cycloalkyl (C3-C7), -heterocyclyl (C2-C9), -C02R5. -CONR3R4, -SR6. -SOR6, -S02R6, -S02NR3R4, -NHCOR5, -NR3CONR3R4, and -NR3S02R6, and wherein each of said substituents -alkyloid-Ce), -alkenyl (C2-C6), -alkynyl (C2-C6), -cycloalkyl (C3-C7). -cycloalkenyl (C5-C10), -bicycloalkyl (C6-C10), -bicycloalkenyl (C6-C10), -heterocyclylid-Cg), -heterocycloalkenyl (C10), heterobicycloalkyl (C6-C9), -heterobicycloalkenyl (C6) -C9), -aryl (C6-C? 0), and -heteroaryl (C? -C9) is optionally interrupted by one to three elements independently selected from the group consisting of -C (R3) = C (R3) - , -C (O) -. - (C = N-R3) -. - (C = N-NR3R4) -. -C = NNC (0) -R5, -C = NNC (0) OR3, - (C = CR3R4) -, - (C = C (R3) C (0) -NR3R4)) -, - (C = C (R3) C (0) OR6) -. -S02-. -S-, -O- and -NR3-; R1 and R2 are the same or different and are independently selected from the group consisting of hydrogen, halogen, -CF3, -N02, -CN, -alkyl (C? -C6), -alkenyl (C2-C6), -alkyne (C2-C6), perfluorinated (C2-C6) alkyl, perfluorinated (C2-C6) alkenyl, perfluorinated (C3-C6) alkynyl, (C3-C7) cycloalkyl, (C5-C10) cycloalkenyl , -bicycloalkyl (C6-C10), -bicycloalkenyl (C6-C10), -heterocyclyl (C2-C9), -heterocycloalkenyl (C2-C10), -heterobicycloalkyl (C6-C9), -dolebicycloalkenyl (C6-C9), - aryl (C6-C10), -heteroaryloid-Cg), perfluorinated (C6-C10) -aryl, -heteroaryloyl CrCg) perfluorinated, -OR5, -C (0) R5. -C02R5, -CONR3R4, -SR6, -SOR6. -S02R6. - S02NR3R4, -NHCOR5, -NR3CONR3R4, wherein said -alkyl (C, -C6). -alkenyl (C2-C6). - (C2-C6) alkyl-cycloalkyl (C3-C7), -cycloalkenyl (C5-C? 0), -bicycloalkyl (C6-C? 0), bicycloalkenyl (C6-C10), -heterocyclyl (C2-C9), -heterocycloalkenyl (C2-C10), -heterobicycloalkyl (C6-C9), -heterobicycloalkenyl (C6-C9), -aryl (C6-C? 0), -heteroaryloid-Cg) can optionally being substituted with one to three residues independently selected from R5 and R6, and wherein n is an integer from 0 to 4; RE is a substituent selected from the group consisting of hydrogen, perfluorinated (C2-C6) alkyl, perfluorinated (C2-C6) alkyl, perfluorinated (C3-C6) alkynyl. -NR3R4. -OR5, -C (0) R5, -C02R5, -CONR3R4, -SR6. -SOR6, -S02R6, -S02NR3R4, -NHCOR5, -NR3CONR3R4, -NR3S02R6-alkyloid-Ce), cycloalkyl- (C3-C7), -cycloalkenyl- (C5-C10), -bicycloalkyl (C6-C10), bicycloalkenyl ( C6-C10), -heterocyclyl (C? -Cg), -heterocycloalkenyl (C? -Cto), -heterobicycloalkyl (C6-Cg), -heterobicycloalkenyl (C6-Cg), -aryl (C6-C10), -heteroaryloid- Cg), perfluorinated -aryl (C6-C10), -heteroaryl (C1-Cg) perfluorinated; wherein said substituents RE -alkyl (C? -C6) -cycloalkyl (C3-C7), -cycloalkenyl (C5-C10). -bicycloalkyl (C6-C10), -bicycloalkenyl (C6-C? 0). -heterocyclylamino CrCg), -heterocycloalkenyloylC C ^), -heterobicycloalkyl (C6-C9), -heterobicycloalkenyl (C6-C9), -aryl (C6-C10) and -heteroaryloid-Cg) are optionally substituted with one to three independently selected residues between the group consisting of hydrogen, halogen, -alkyl (C? -C6), -CN, -NR3R4, -OR5. -cycloalkyl (C3-C7). -heterocyclic (C2-C9), -C02R5. -S02NR3R4. -NR3S02R6 -S02R6 and -CONR3R4; wherein R3 and R4 of said group -CONR3R4 can be taken together with the atoms to which they are attached to form a -heterocyclyl (C2-C9); each RF is a substituent independently selected from the group consisting of hydrogen, -alkyloid-Cß), -perfound (C2-C6) perfluorinated,-perfluorinated (C2-C6) alkenyl, -perfluorinated (C3-C6) alkynyl. -cycloalkyl (C3-C7), -cycloalkenyl (C5-C10), -bicycloalkyl (C6-C10), bicycloalkenyl (C6-C10), -heterocyclyl (C2-C9), -heterocycloalkenyl (C2-C10), -heterobicycloalkyl ( C6-C9), -heterobicycloalkenyl (C6-Cg), -O-alkylCt-Cß), -0-cycloalkyl (C3-C7). -O-heterocyclyl (C? -Cg), -NR3R4, -SR6, -SOR6, -S02R6, -C02R5. -CONR3R4. -S02NR3R4. -NHCOR5. -NR3CONR3R4. and -NR3S02R6; wherein said substituents RF -alkyl (C? -C6), -cycloalkyl (C3-C7), - cycloalkenyl (C3-C10), -bicycloalkyl (C6-C10), -bicycloalkenyloylCe-do). -heterocyclyl (C2-C9), -heterocycloalkenyl (C2-C10), -heterobicycloalkyl (C6-C9), -heterobicycloalkenyl (C6-C9), -O-alkyl (C6), -0-cycloalkyl (C3-C7) , -0-heterocyclyl (C2-C9), -NR3R4. -SR6, -SOR6, -S02R6, -C02R5, -CONR3R4, -S02NR3R4, -NHCOR5, -NR3CONR3R4, and -NR5S02R6 are optionally substituted with one to three residues independently selected from the group consisting of hydrogen, halogen, -CF3, -CN, -alkyl (C, -C6), -NR3R4. -OR5, -cycloalkyl (C3-C7), -heterocyclyl (C2-C9), -C02R5, and -CONR3R4; each RG is a substituent independently selected from the group consisting of hydrogen, -alkyl (d-C6), -alkenyl (C2-C6), -alkyl (C2-C6), -alkyl (C2-C6) perfluorinated , - perfluorinated (C2-C6) alkenyl, - perfluorinated (C3-C6) alkyl, - (C3-C7) cycloalkyl, (C5-C10) cycloalkenyl, - (C6-C10) bicycloalkyl, - (C6-C10) -bicycloalkenyl , -heterocyclyl (C2-C8), -heterocycloalkenyl (C2-C10), -heterobicycloalkyl (C6-C9), -heterobicycloalkenyl (C6-C9), -C02R5, and -CONR3R4; wherein said substituents RG -alkyl CrCß), -alkenyl (C2-C6), -alkynyl (C2-C6), -cycloalkyl (C3-C7), -cycloalkenyl (C5-C10), -bicycloalkyl (C6) -do), -b-cycloalkenyl (C6-do). -heterocyclyl (C2-Cg), -heterocycloalkenyl (C2-C? o), -heterobicycloalkyl (C6-Cg), and -heterobicycloalkenyl (C6-C9), are optionally substituted with from one to three residues independently selected from the group constituted by hydrogen, halogen, -CF3, -N02, -CN, -alkyl (d-C6), -alkenyl (C2-C6), -alkynyl (C2-C6), -CR3 = N-NR3R4, -CR3 = N- OR5, -CR3 = N-NR3C (0) R3. -CR3 = N-NR3C (0) OR5. -NR3R4, -OR5, -cycloalkyl (C3-C7), -heterocyclyl (C2-C9), -C02R5, -CONR3R4. -SR6, -SOR6. -S02R6, -S02NR3R4. -NHCOR5, -NR3CONR3R4, and -NR3S02R6, wherein said RG moieties-C2-C6alkenyl and -alkynyl (C2-C6) may be optionally substituted with one to three R10 groups; RE and RH can be taken together with the atom (s) to which they are attached to form a -heterocyclyl (C2-C9), -heterocycloalkenyl (C2-C10), -heterobicycloalkyl (C6-Cg), heterobicycloalkenyl (C6-Cg), wherein said -heterocyclyl (C2-Cg), -heterocycloalkenyl (C2-C? 0), -heterobicycloalkyl (C5-C? O) and -heterobicycloalkenyl (C6-C? O) is optionally interrupted by one to three elements independently selected from the group consisting of -C (R3) = C (R3) -. -CO)-. - (C = N-R3) -, - (C = N-NR3R4) -, -C = N-N-C (0) -R5, -C = N-N-C (0) OR3. - (C = CR3R4) -, - (C = C (R3) C (0) -NR3R4)) -. - (C = C (R3) C (0) OR6) -, -S02-, -S-. -OR- and -NR3-. and in which said - heterocyclyl (C2-Cg), -heterocycloalkenyl (C2-C10), -heterobicycloalkyl (C5-C10) and heterobicycloalkenyl (C6-C10) is optionally substituted with one to three residues independently selected from the group consisting of hydrogen, halogen, - CF3, -N02, -CN, -alkyl (C, -C6), -alkenyl (C2-C6), -alkynyl (C2-C6), -CR3 = N-NR3R4. -CR3 = N-OR5, -CR3 = N-NR3C (0) R3. -CR3 = N-NR3C (0) OR5. -NR3R4. -OR5, -cycloalkyl (C3-C7), -heterocyclyl (C2-C9). -C02R5 -CONR3R4, -SR6, -SOR6, -S02R6, -S02NR3R4, -NHCOR5, -NR3CONR3R4. and -NR3S02R6; RH is a substituent selected from the group consisting of: (a) hydrogen; (b) -aryl (C6-C? o) or -heteroaryl (d-Cg), optionally substituted with from one to three residues independently selected from the group consisting of halogen, hydroxy, -alkyl (d-C6), -alkyl (C 1 -C 6) -P (0) (0-C 1 -C 6 alkyl) 2, -cycloalkyl (C 3 -C 10), -aryl (C 6 -C 0), heterocyclyl (C 2 -C 9), -heteroaryl ( d-C9), -NR3R4, -NHS02-alkyl (d-Cß), -NHS02-cycloalkyl (C3-C6), -Nfalqui d-CeJKSO? -alkyloid-Ce)), -N (alkyl (C, -C6 )) (S02-cycloalkyl (C3-C6)). N ((C3-C6) cycloalkyl (S02-alkyl (d-C6)), -N ((C3-C6) cycloalkyl) (S02-cycloalkyl (C3-Cß)), -O-alkyl (d-C6) , -0-S02-alkyl (d-C6). -0-S02-cycloalkyl (C3-Cß), -C (0) -alkyl (d-C6). -C (0) CF3, -C (O) -cycloalkyl (C3-d0), -C (O) -aryl (C6-C10), -C (0) -heterocyclyl (C2-C9), -C (0) ) -heteroaryl (d-C9). -C (0) 0-alkyl (C? -C6), -C (O) O-cycloalkyl (C3-C10), -C (O) O-aryl (C6-C10). -C (0) 0-heterocyclyl (C2-C9), -CINO-heteroaryloid-Cg), -CYO-alk-d-Cβ? -O-alkyloid-Cβ), -S02-alkyl (C, -C6) . -S02-cycloalkyl (C3-C6), -S02CF3, -S02NH2, -S02NH-alkyl (C? -C6). -S02NH-cycloalkyl (C3-C6). -S02N ((C1-C6) alkyl) 2, -S02N (alkyl (d-C6)) (cycloalkyl (C3-C6)), -S02N ((C3-C6) cycloalkyl) 2 and -S02NR3R4, wherein said -aryl (C6-C10) or -teroheteroyl (d-C9) are optionally interrupted by one to three elements selected from the group consisting of -S-, -O-, -N-, -NH - and -NR11, and wherein said -aryl (C6-do) or -heteroaryl (C? -Cg) are optionally fused to a -cycloalkyl (C3-C? o) or -heterocyclyl (C2-C9) moiety, wherein said residues -cycloalkyl (C3-C10) or -heterocyclyl (C2-Cg) are optionally substituted with from one to three elements selected from the group consisting of halogen, hydroxy, -alkyl (C, -C6), -alkyl (C1-Cβ) -P (0) (0-C 1 -C 6) -alkyl 2 -cycloalkyl (C 3 -C 10), -aryl (C 6 -C 10), -heterocyclyl (C 2 -C 9), -heteroaryloid-Cg ), -NR3R4, -NHSO alkyl (d-C6), -NHS02-cycloalkyl (C3-C6), -NalkkyKd-CßMSOalkyl-Ce)), -N (alkyl (C, -) C6)) (S02-cycloalkyl (C3-C6)). -N'cycloalkyl Qrd XSOralqui d-Cß)), -N ((C3-C6) cycloalkyl) (S02-cycloalkyl (C3-C6)), -0-alkyl (d-C6), -0-S02- alkyl (d-C6), -0-S02-cycloalkyl (C3-C6). -C (O) -alkyl (d-C6), -C (0) CF3, -C (O) -cycloalkyl (C3-C10). -C (O) -aryl (C6-C10), -C (0) -heterocyclyl (C2-C9), -C (0) -heteroaryl (d-Cg), -C (0) 0 -alkyl (C C6) ), -C (O) O-cycloalkyl (C3-C10), -C (O) O-aryl (C6-C10), -C (0) 0-heterocyclyl (C2-C9), -C (0) 0 -heteroaryl (d-C9), -C (0) -alkyl (C, -C6) -0-alkyl (C? -C6). -S02-alkyl (C, -C6), -S02-cycloalkyl (C3-C6), -S02CF3. -S02NH2. -S02NH-alkyl (C, -C6). -SOzNH-cycloalkyl (C3-C6), -S02N (alkyl (d-C6)) 2, -S02N (alkyl (d-C6)) (cycloalkyl (C3-C6)). S02N (cycloalkyl (C3-C6)) 2 and -S02NR3R4; (c) -cycloalkyl (C3-C7), -cycloalkenyl (C5-C10), -bicycloalkyl (C6-C10), -bicycloalkenyl (C6-C10), -heterocyclyl (C2-C9), -heterocycloalkenyl (C2-C10) , -heterobicycloalkyl (C6-C9), heterobicycloalkenyl (C6-C9) and -alkyl-C-Heterocyclyloid-Cg), optionally substituted with one to three residues independently selected from the group consisting of halogen, hydroxy, -alkyl (C, - C6), -alchi dd -PIOXO-alky Ci-Cß))., -cycloalkyl (C3-C10). -aryl (C6-C10), -heterocyclyl (C2-C9), -heteroaryl (C9), -NR3R4, -NS02-alkyl (d-C6), -NHS02-cycloalkyl (C3-C6), -Nalk d-CeJJSOSOalkyl-Ce)), -Nalkyl d-CeJXSO? -cycloalkyloyCrCß)), -N (cycloalkyl (C3-C6)) (S02-alkyl (C1-C6)), -N (cycloalkyl (C3-C6) ) (SOCycloalkyl (C3-C6)), -O-Cydyloid-Cß), -0-S02-alkyl (d-C6), -0-S02-alkyl (d-C6), -0-S02-cycloalkyl (C3-C6), -C (0) -alkyl (C, -C6). -C (0) CF3. -C (O) -cycloalkyl (C3-C10), -CÍOj-ariloíCe-do). -C (0) -heterocyclyl (C2-C9), -CYOJ-heteroaryloid-Cg), -C (0) 0 -alkyl (C, -C6). -C (O) O-cycloalkyl (C3-C10), -C (O) O-aryl (C6-C10), -C (0) 0-heterocyclyl (C2-C9), -C (0) 0-heteroaryl (D-C9), -dOJ-alkyD-CeJ-O-alkyloid-Ce), -S02alkyl (C, -C6). -S02-cycloalkyl (C3-C6), -S02CF3, -S02NH2, -S02NH-alkyl (C, -C6), -S02NH-cycloalkyl (C3-C6). -S02N (alkyl (d-C6)) 2, -SOaNalkali d-CßMcycloalkyloyl -Cβ), -S02N ((C3-Cβ) cycloalkyl) and -S02NR3R4, wherein said -3C7 cycloalkyl, - (C5-C10) cycloalkenyl, -bicycloalkyl (C6-C? 0), -bicycloalkenyl (C6-C? o), -heterocyclyl (C2-C9), -heterocycloalkenyl (C2-C1o), -heterobicycloalkyl (C6-Cg) , -heterobicycloalkenyl (C6-Cg) and -alki- Kd-CβJheterocyclylide-Cg) are optionally interrupted by one to three elements selected from the group consisting of -C (R3) = C (R3) -, -C (O) -, - (C = N-R3) -. - (C = N-NR3R h -C = NNC (0) -R5.C = NNC (0) OR3. - (C = CR3R4) -, - (C = C (R3) C (0) -NR3R4) ) -, - (C = C (R3) C (0) OR6) -. -S02-, -S-. -O- and -NR3-, and in which said substituents - (C3-C7) cycloalkyl, (C5-C10) -cycloalkenyl, (C5-C10) -bicycloalkyl. bicycloalkenyl (C6-C10), -heterocyclyl (C2-Cg), -heterocycloalkenyl (C2-C10), -heterobicycloalkyl (C6-Cg), -heterobicycloalkenyl (C6-Cg) are optionally fused to -aryl (C6-C10) or -heteroaryl (d-Cg), optionally substituted with one to three residues independently selected from the group consisting of halogen, hydroxy, -alkyl (d-C6), -alkyl (d-C6) -P (0) (O-alkyl ( C? -C6)) 2, -cycloalkyl (C3-C10), -aryl (C6-C10), -heterocyclyl (C2-C9), -heteroaryl (d-Cg). -NR3R4, -NHS02alkyl (d-C6), -NHS02-cycloalkyl (C3-C6), -N (alkyl (d-C6)) (S02-alkyl (d-C6)). -Nalkyl d-Cf KSO Cycloalkyloid-Ce)), -N ((C3-C6) cycloalkyl (S02-alkyl (C, -C6)). N (C3-C6) cycloalkyl (S02-cycloalkyl (C3-C6)), -O-alkyloid-Ce), -0-S02-alkyl (d-C6). -0-S02-cycloalkyl (C3-C6), -CioJ-alkyloid-Ce). -C (0) CF3. -C (O) -cycloalkyl (C3-C10). -CoJ-ariloíCe-do). -C (0) -heterocyclyl (C2-C9), -C (0) -heteroaryl (d-C9). -C (0) 0-alkyl (C, -C6). -C (0) 0-cycloalkyl (C3-C10), -C (O) O-aryl (C6-C10). -C (0) 0-heterocyclyl (C2-C9). -C (0) 0-he'eroaryl (C, -C9), -CioJ-alkyKd-CeJ-O-alkyloid-Ce), -S02-alkyl (C, -C6), -S02-cycloalkyl (C3-C6) ). -S02CF3, -SOzNH2, -S02NH-alkyloCrCe), -S02NH-cycloalkyl (C3-C6). -S02N (alkyl (d-C6)) 2, -S02N (alkyl (d-C6)) (cycloalkyl (C3-C6)). -S02N ((C3-C6) cycloalkyl) and -S02NR3R4; (d) -alkyl'd-Cß). -Calcyl (C2-C6) perfluorinated, perfluorinated (C2-C6) alkenyl, and perfluorinated (C3-C6) alkynyl, wherein said (C, -C6) alkyl is optionally substituted with from one to three residues selected from the group consisting of halogen, hydroxy , -alkio (C? -C6), -alkenyl (C2-C6), -alkynyl (C2-C6), -alk C CeI-PYOJtO-alqui C Cß) ^, -NR3R4. -NHS-2-alkyl (C, -C6). -NHS02-cycloalkyl (C3-C6), -N (C1-C6 alkyl) (S02-(C1-C6) alkyl), -N ((C, -C6) alkyl) (S02-cycloalkyl (C3-C6) )), -N ((C3-C6) cycloalkyl (S02-alkyl (d-C6)). -N ((C3-C6) cycloalkyl (S02-c? -Calkalkyl (C3-C6)), -NHC (0) -alkyl (d-C6), -NHC (0) -cycloalkyl (C3-C6). -NHC (0) -heterocyclyl (C2-C9), -NHC (O) -aryl (C6-C10), -NHCYOJ-heteroaryloid-Cg), -N ((C1-C6) alkyl) C (0 / -alkyl) (C 1 -C 6) -N (C 1 -C 6) alkyl) C (0) -cycloalkyl (C 3 -C 6), -N (alkyl (C, -Cβ)) C (0) -heterocyclyl (C 2 -C 9) , -N (alkyl (d-C6)) C (O) -aryl (C6-C10), -N (alkyl (d-C6)) C (0) -heteroaryl (d-C9), -O-alkyl ( d-Cß), -0-S02-alkyloCC), -0-S02-cycloalkyl (C3-C6). -CioJ-C1alkylalkyl). -C (0) CF3, -C (0) -cycloalkyl (C3-C10), -C (O) -aryl (C6-C10), -C (0) -heterocyclyl (C2-C9), -C (0) ) -heteroaryl (d-Cg), -C (0) 0-alkyl (d-C6). -C (O) O-cycloalkyl (C3-C10), -C (O) O-aryl (C6-C10), -C (0) 0-heterocyclyl (C2-C9). -C (0) 0- heteroaryl (d-C9), -CioJ-alky d-CβJ-O-C-alkyloid), -SOralkylofd-Cβ), -S02-cycloalkyl (C3-C6), -S02CF3, -S02NH2, -S02NH-alkyl (C , -C6), -S02NH-cycloalkyl (C3-C6), -S02N (alkyl (C, -C6)) 2, -S02N (alkyl (d-C6)) (cycloalkyl (C3-C6) )), -S02N ((C3-C6) cycloalkyl) 2 and -S02NR3R4, wherein said -alkyl (d-C6) is optionally interrupted by one to three elements independently selected from the group consisting of -C (O) , -S02, -S-, -O-, and -NR1 '; and wherein each substituent, residue, or element RH (b) - (d) is optionally substituted with one to three radicals independently selected from the group consisting of hydrogen, halogen, hydroxy, -CF3, -N02, -CN, -alkyl (d-C6), -alkenyl (C2-C6), -alkynyl (C2-C6), -cycloalkyl (C3-C), -cycloalkenyl (C5-C10), -bicicJoalkyl (Cß-C10), -bicycloalkenyl (C6-C10). -heterocyclyl (C2-C8), -heterocycloalkenyl (C2-C? 0), -heterobicycloalkyl (C6-C9), heterobicycloalkenyl (C6-Cg), -aryl (C6-C10), -heteroaryl (C, -C9) ), -O-alkyl (d-Cß), -O-cycloalkyl (C3-C7), -0-heterocyclyl (C2-C9), -CR3 = N-NR3R4, -CR3 = N-OR5. -CR3 = N-NR3C (0) R3, -CR3 = N-NR3C (0) OR5, -NR3R4. -SR6, -SOR6, -S02R6, -C02R5, -CONR3R4, -S02NR3R4, -NHCOR5, -NR3CONR3R4, and -NR3S02R6; A is a ring system selected from the group consisting of -cycloalkyl (C3-C10), -cycloalkenyl (C5-do), -heterocyclyl (C2-C10), -heterocycloalkenyl (C2-C10), -aryl (Cß-C10) and -heteroaryl (C2-C9), wherein said -cycloalkyl (C3-C) 0 0), -cycloalkenyl (Cs-C10), -heterocyclyl (C2-C10), -heterocycloalkenyl (C2-C10), -aryl (C6-C10) and -heteroaryl (C2-C9) of said ring A are optionally interrupted by one to three elements selected from the group consisting of -C (R3) = C (R3) -. -CO)-. - (C = N-R3) -. - (C = N-NR3R4) -, -C = N-N-C (0) -R5. -C = N-N-C (0) OR3. - (C = CR3R4) -, - (C = C (R3) C (0) -NR3R4)) -. - (C = C (R3) C (0) OR6) -. -S02-, -S-. -OR- and -NR3-. and wherein said ring system A is optionally substituted with one to three substituents independently selected from the group consisting of hydrogen, halogen. -CF3, -N02, -CN, -alkyl (C C6), -alkenyl (C2-C6), -alkynyl (C2-Cß), -CR3 = N-NR3R4, -CR3 = N-OR5. -CR3 = N- NR3C (0) R3, -CR3 = N-NR3C (0) OR5, -NR3R4, -OR5, -cycloalkyl (C3-C7). -cycloalkenyl (C5-C, 0). - bicycloalkyl (C6-C10), -bicycloalkenyl (C6-C10), -heterocyclyl (C2-C9), -heterocycloalkenyl (C2-C10), - heterobicycloalkyl (C6-Cg), -heterobicycloalkenyl (C6-C9), -aryl (C6-C? 0). -heteroaryl (d-Cg), - C (0) R5, -C02R5, -CONR3R4, -SR6. -SOR6 -S02R6. -S02NR3R4. -NHCOR5. -NR3CONR3R4. and -NR3S02R6; Z 'and Z2 are the same or different and are independently selected from the group consisting of -C-, -CR7- and -N-, wherein each R7 is the same or different; Y1 and Y2 are the same or different and are independently selected from the group consisting of -CR7- and -N-, wherein each R7 is the same or different; L1 and L2 are each independently selected from the group consisting of -CRßR9-, -C (R3) = C (R3) -. -CO)-. - (C = N-R3) -. - (C = N-NR3R4) -, - (C = N-NOR5) -, -C = CR3R4) -. - (C = C (R3) C (0) -NR3R4)) -, - (C = C (R3) C (0) OR6) -, -N-C (0) R8-, -S02. -S-, -O- and -NR3. wherein L1 is not -C (R8) = C (R8) -or -C = C- when Z1 or Y1 is N, and L2 is not -C (R3) = C (R3) - or -CsC- when Z2 or Y2 is N; q is an integer from 0 to 3; L1 and a substituent of A, or L2 and a substituent of A can be taken together to form a-C5-C7-cycloalkyl, -cycloalkenyl (C5-C10), -heterocyclyl (C2-Cg), -heterocycloalkenyl (C2) -C10) -aryl (C6-C10) and -heteroaryl (C-C9), in which each of said -cycloalkyl (C5-C), • C -cloalkenyl (C5-C10), -heterocyclyl (C2-Cg) , -heterocycloalkenyl (C2-C10), -aryl (Cß-C? o) and -heteroaryl (C1-Cg) is optionally interrupted by one to three elements independently selected from the group consisting of -C (R3) = C ( R3) -, -C (O) -, - (C = N-R3) -. - (C = N-NR3R4) -, -C = N-N-C (0) -R5. -C = N-N-C (0) OR 3, - (C = CR 3 R 4) -, - (C = C (R 3) C (0) -NR 3 R 4)) -. - (C = C (R3) C (0) OR6) -, -S02-, -S-, -O- and -NR3-. and wherein each of said -cycloalkyl (C3-C7), -cycloalkenyl (C3-C10), -heterocyclyl (C2-Cg) and -heterocycloalkenyl (C2-C10) is optionally substituted with one to three independently selected substituents between the group consisting of halogen, -CF3. -CN, -N02, -alkyloid-Cß). -OR16. -C (0) OR16, -OC (0) R16, -OC (0) OR16, -N (R16) 2. -NR16C (0) R16. -SOzR16. -S02N (R16) 2 and -NR16S02R16; X and W are the same or different and each is independently selected from the group consisting of -CR8Rβ-, -NR 12-, -C (O) -, - (C = NR 3) -. - (C = N-NR3R4) -. - (C = N-N-OR5) -. - (C = CR3R4) -. (C = C (R3) C (0) -NR3R4) -. - (C = C (R3) C (0) OR6) -, -S-. -SW)-. -S (0) 2-, -S (?? NR3R4) -ly -O-, wherein one or more adjacent carbons or heteroatoms selected from X, Y1, Y2, or W are optionally condensed to a selected ring system between the group constituted by -cycloalkyl (C3-C), -heterocyclyl (C2-Cg), -aryl (C6-C10). and - heteroaryl (d-C9), wherein each of said -cycloalkyl (C3-C7), -heterocyclyl (C2-C9), -aryl (C6-C10) is optionally interrupted by one to three elements independently selected from the group consisting of -C (R3) = C (R3) -, -C (O) -. - (C = N-R3) -. - (C = N-NR3R4) -, - (C = N-NOR5) -. - (C = CR3) -, - (C = C (R3) C (0) -NR3R4)) -. - (C = C (R3) C (0) OR6) -. -S02-, -S-, -O- and -NR3-, and in which each of said ring systems -cycloalkyl (C3-C7), -heterocyclyl (C2-Cg), -aryl (C6-C? 0), and -terole (d-Cg) are optionally substituted with one to three substituents selected from the group consisting of hydrogen, hydroxyl, halogen, -CF3, -CN, -N02, -alkyloid-Cβ). -NH-alkyl (C, -C6). -NH-cycloalkyl (C3-C7), -NH-heterocyclyl (C2-C9), -NH-aryl (Cß-C10). -NH-heteroaryl (d-Cg), -N (alkyl (d-C6)) 2, -N ((C3-C7) cycloalkyl) 2. -N (heterocyclyl (C2-Cg)) 2, -N (aryl (Cß-C10)) 2. -N (heteroaryl (d-Cg)) 2. -0-alkyl (d-C6), -0-cycloalkyl (C3-C). -0-heterocyclyl (C2-Cß). -0-aryl (C6-C? O). -O-heteroaryloid-Cg), -cycloalkyl (C3-C7), -heterocyclyl (C2-C9), -C02H, -C (0) (alkyl (C? -C6)). -S02H, -S02 (alkyl (d-C6)), -S02NH2, -S02NH (alkyl (C, -C6)), SOzNalkKd-Ce). -NHS? 2 (alkyl (d-C6)). and - N -alkyl-CeJJSOzalkyloid-Ce)); Y1 together with W, Y2 together with W, Y1 together with X, Y2 together with X. X together with W, or L together with And they can form a -cycloalkyl (C5-C7), -cycloalkenyl (C5-do). -heterocyclyl (C2-Cg) and -heterocycloalkenyl (C2-C10), wherein each of said -cycloalkyl (C5-C7), -cycloalkenyl (C5-C10), -heterocyclyl (C2-C9) and -heterocycloalkenyl ( C2-C? O) is optionally interrupted by one to three elements independently selected from the group consisting of -C (R3) = C (R3) -, -C (O) -. - (C = N-R3) -. - (C = N-NR3R4) -, -C = N-N-C (0) -R5. -C = N-N-C (0) OR3, - (C = CR3R4). - (C = C (R3) C (0) -NR3R4)) -, - (C = C (R3) C (0) OR6) -, -S02, -S-, -O- and -NR3-, and wherein each of said -cycloalkyl (C3-C7), -cycloalkenyl (C3-C? 0), -heterocyclyl (C2-C9) and -heterocycloalkenyl (C2-C10) is optionally substituted with one to three selected substituents independently from the group consisting of halogen, -CF3, -CN, -N02, -alkyl (d-C6), -OR16, -C (0) OR16, -OC (0) R16.-OC (0) OR16, - N (R16) 2, -NR16C (0) R16. -S02R16. -S02N (R16) 2 and -NR16S02R16; W together with another W, X together with another X, L1 together with another L1. or L2 together with another L2 can form a -cycloalkyl (C3-C7), -cycloalkenyl (C5-C? o), -heterocyclyl (C2-C9), -heterocycloalkenyl (C2- C10), -aryl (C6-C10) or -heteroaryloyl CrCg), wherein each of said -cycloalkyl (C3-C7), -cycloalkenyl (C5-C10), -heterocyclyl (C2-Cg) and -heterocycloalkenyl (C2) -C10) is optionally interrupted by one to three elements independently selected from the group consisting of -C (R3) = C (R3) -. -C (O) -, - (C = N-R3) -. - (C = N-NR3R4) -. -C = N-N-C (0) -Rs, -C = N-N-C (0) OR3, - (C = CR3R4) -, - (C = C (R3) C (0) -NR3R4)) -. - (C = C (R3) C (0) OR6) -. -S02 -S-, -O- and -NR3-. and wherein each of said -cycloalkyl (C3-C7), -cycloalkenyl (C3-C10), -bicycloalkyl (C6-C10), -b-cycloalkenyl (C6-C10), -heterocyclyl (C2-Cg), -heterocycloalkenyloylC? -do), -heterobicycloalkyl (C5-C10), -heterobicycloalkenyl (C6-C? o), -aryl (C6-C10) and -heteroaryl (C? -C9) is optionally substituted with one to three substituents independently selected from the group consisting of halogen, -CF3, -CN, -N02, -alkyl (C, -C6), -OR16, -C (0) OR16, -OC (0) R16, -OC (0) OR16 , -N (R16) 2, -NR16C (0) R16. -S02R16. -S02N (R16) 2y-NR16S02R16; R3 and R4 are each independently a substituent selected from the group consisting of hydrogen, -alkyl (d-C6), -cycloalkyl (C3-C7), -bicycloalkylofCs-C ,,,), heterocyclyl (C2-C9) ), -aryl (C6-C10), -heteroaryl (d-C9), -C02H, -C (0) (alkyl (d-Cß)), C (0) (heterocycloalkyl (C2-C9)), -C (0) OR8, -C (0) NR8R9. and -S02 (alkyl (d-C6)); wherein said substituents -alkyl (d-C6), -cycloalkyl (C-C), -bicycloalkyl (Cs-d?). -heterocyclyl (C2-C9), -aryl (C6-C? 0). -heteroaryl (d-C9). -C (0) (alkyl (d-C6)). -C (0) (heterocycloalkyl (C2-Cß)) and -S02 (alkyl (d-C6)) are optionally substituted with from one to three residues independently selected from the group consisting of amino, hydrogen, hydroxyl, halogen, -CF3, -CN, -N02, = 0, = S, = NR8, -C (0) NR5R6, -alkyl (d-C6). -NH-alkyl (C, -C6), -NRßC (0) R9. -NR8CONR8R9 -NH-cycloalkyl (C3-C7). -NH-het? RocicJilo (C2-C9). -NH-aryl (C6-C10), -NH-heteroaryl (d-Cg), -N (alkyl (d-C6)) 2, -N (cycloalkyl (C3-C7)) 2, -N (heterocyclyl (C2) -C9)) 2. -N (aryl (C6-C10)) 2, -N (heteroaryl (C, -C9)) 2. -0-alkyl (C? -C6), -0-cycloalkyl (C3-C7), -0-heterocyclyl (C2-C9). -O-aryl (C6-C, o), -0-heteroaryl (C1-C9), -cycloalkyl (C3-C7), -heterocyclyl (C2-C9), -C02H, C (0) (alkyl (d-) C6)), -S02H, -S02 (alkyl (d-C6)). -S02NH2, -S02NH (alkyl (d-C6)). -S02N (alkyl (C, -C6)) 2. -NHS02 (alkyl (d-C6)), -N (C1-C6 alkyl) S02 (C1-C6 alkyl) and, NHS02NR8R9, wherein R3 and R4 when attached to the same nitrogen atom can form a (C2-C9) heterocyclyl optionally substituted with one to three selected substituents independently from the group consisting of hydrogen, halogen, -CF3, -N02, -CN, -alkyl (d-C6), -alkenyl (C2-C6), -alkynyl (C2-C6). -CR5 = N-NR5R6. -CR5 = N-OR10. -CR5 = N-NR5C (0) R1 °, -CR5 = N-NR5C (0) OR10, -NR5R6. -OR5, -cycloalkyl (C3-C7), -heterocyclyl (C2-C9), -C02R5, -CONR5R6, -SR6, -SOR6, -S02R6, -S02NR5R6, -NHCOR5, -NR5CONR5R6y -NR5S02R6; R5 is a substituent selected from the group consisting of hydrogen, -alkyl (d-C6), -alkenyl (C2-C6), -cycloalkyl (C3-C7), -cycloalkenyl (C5-C7), -heterocyclyl (C2-C9) ), -aryl (C6-C10), -heteroaryl (C? -C9), -C02H, -C (0) (alkyl (C? -C6)), and -P (0) (0R16) 2, in the said -alkyl (C, -C6), -cycloalkyl (C3-C7), -heterocyclyl (C2-C9), -aryl (C6-C10), -heteroaryl (d-C9), -C (0) (alkyl) (C, -Oß)), and substituents are optionally substituted with one to three moieties independently selected from the group consisting of hydrogen, hydroxyl, halogen, -CF3, -CN, -N02, -alkyl (d-C6), - NH-alkyld-Ce), -NH-cycloalkyl (C3-C7), -NH-heterocyclyl (C2-C9), -NH-aryl (C6-C, o), -NH-heteroaryl (d-Cg), -N (alkyl (C, -C6)) 2, -N ((C3-C7) cycloalkyl) 2, -N (heterocyclyl (C2-C9)) 2, -N (aryl (C6-C? 0)) 2 , -N (heteroaryl (d-C9)) 2, -0-alkyl (d-C6), -0-cycloalkyl (C3-C7), -0-heterocyclyl (C2-C9), - O-aryl (C6-C10), -O-heteroaryl (C? -Cg). -cycloalkyl (C3-C7), -heterocyclyl (C2-C9). -C02H, -C (0) (alkyl (d-C6)), -S02H, -S02 ((C? -C6) alkyl). -S02NH2. -S02NH (alkyl (C, -C6)), -S02N (alkyl (d-C6)) 2, -NHS02 (alkyl (d-C6)), and -Nalkyl d-CeJJSO ^ alkyl-Cß)); R6 is a substituent selected from the group consisting of hydrogen, -alkyl (C6), -cycloalkyl (C3-C7), -heterocyclyl (C2-C9), -aryl (C6-C? O), -heteroaryl (d- Cg), -C02H, wherein said substituents -alkyl (d-C6), -cycloalkyl (C3-C7), -heterocyclyl (C2-C9), -aryl (C6-C10). -heteroaryloyl Cg), -CioXalkyloid-Cβ), and -S? 2 (alkyl (d-C6)) are optionally substituted with one to three residues independently selected from the group consisting of hydrogen, hydroxyl, halogen, - CF3. -CN, -N02 -alkyl (d-C6). -NH-alkyl (C, -C6), -NH-cycloalkyl (C3-C7), -NH-heterocyclyl (C2-C9), -NH-aryl (Cß-C10), -NH-heteroaryl (C? -C9) ). -N (-alkyl (d-C6)) 2, -N ((C3-C7) cycloalkyl) 2, -N ((C2-C9) heterocyclic) 2, -N ((C6-C10) aryl) 2. -N (heteroaryl (d-Cg)) 2. -O- alkyl'd-Ce), -0-cycloalkyl (C3-C7), -0-heterocyclyl (C2-Cg), -O-aryl (C6-C10). -0-heteroaryl (d-C9). -cycloalkyl (C3-C7), -heterocyclyl (C2-C9), -C02H, -C (0) (alkyl (d-C6)). -S0 H. -S02 (alkyl (C? -C6)). -S02NH2, -S02NH (alkyl (d-C6)), -S02N (alkyl (d-Cß)) 2. -NHS02 (alkyl (d-C6)). and -N (alkyl (C, - CeJJSOzíalquiloíC Ce)); R7 is a substituent selected from the group consisting of hydrogen, halogen, -N02, -CF3. -CN, -NR10R10. -C (O) NR10R10, -OR10. -C02R1 °. -C (0) R10. -SR10 -SOR10. -S02R10. -SO2NR10R10, -NHCOR10, -NR10CONR10R10, and -NR10SO2R10 and -P (0) (OR16) 2, -alkyl (d-C6). -alkyl (d-C6), -alkenyl (C-C6), -alkynyl (C2-C6). - perfluorinated (C2-C6) alkyl, perfluorinated (C2-C6) alkenyl, - perfluorinated (C3-C6) alkynyl, - (C3-C7) cycloalkyl, - cycloalkenyl (C -Ct0). b.cycloalkyl (C6-C? o). -bicycloalkenyl (C6-C? 0), -heterocyclyl (C2-C9), -heterocycloalkenyl (C2-C10), -heterobicycloalkyl (C5-C10), -heterobicycloalkenyl (C6-C10), -aryl (C6-C10) ), -heteroaryl (d-C9), perfluorinated (C6-C10) -aryl, -heteroaryl (C? -C9) perfluorinated, wherein said substituents -alkyl (C, -C6), -alkenyl (C2-C6) , -alkynyl (C2-C6), -cycloalkyl (C3-C7). -cycloalkyl (C3-C10). bicycloalkyl (C6-C? o), -bicycloalkenyl (C6-C10), -heterocyclyl (C2-C9), -heterocycloalkenyl (C2-C10), -heterobicycloalkyl (C5-C10). -heterobicycloalkenyl (Cß-C10), and -aryl (C6-C10), -heteroaryl (C? -C9) are optionally substituted with one to three residues independently selected from the group consisting of hydrogen, hydroxyl, halogen, -CF3, -CN, -N02l -alkyl (d-Cß), -NH-alkyl (d-C6), -NH-cycloalkyl (C3-C7), -NH-heterocyclyl (C2-C9), - NH-aryl (C6-C? 0), -NH-heteroaryl (d-Cg), -N (alkyl (d-C6)) 2. -N ((C3-C7) cycloalkyl) 2, -N (heterocyclyl (C2-C9)) 2. -N (aryl (C6-C? O)) 2. -NyheteroarylC CgJJ ?, -0-alkyl (C? -Cß). -0-cycloalkyl (C3-C7), -0-heterocyclyl (C2-Cg). -O-aryl (C6-C10), -O-heteroaryloid-Cg), -cycloalkyl (C3-C7). -heterocyclylCyC? -Cg), -C0HC (O) (alkyl0 (dC6)). -S02H, -S02 (alkyl (d-C6)). -S02NH2. -S02NH (alkyl? (D-C6)). -S02N (alkyl (d-C6)) 2, -NHS02 (alkyl (d-C6)), and -N (alkyl (d-C6)) S02 (alkyl (C Cß)); R8 and R9 are each independently a substituent selected from the group consisting of hydrogen, halogen, -alkyl (C, -C6),-perfluorinated (C2-C2) alkyl, -cycloalkyl (C3-C7), -cycloalkenyl (C5-) C? 0). -bicycloalkyl (C6-C10), -bicycloalkenyl (C6-C10), -heterocyclyl (C2-Cg). -heterocycloalkenyl (C2-C10), -heterobicycloalkyl (C6-C9), -heterobicycloalkenyl (C6-C9), -aryl (C6-C10). -heteroaryl (C? -C9), perfluorinated (C6-C10) -aryl, -heteroaryl (d-C?) perfluorinated, -C02H, -C (0) (alkyl (C, -C6)). -OR10, -S02 ((C1-C6) alkyl) and -P (0) (OR16) 2, wherein said substituents -alkyl (d-C6), -cycloalkyl (C3-C7), -c chloralkenyl (C5-C, o) > -bicycloalkyl (Cß-C10), bicycloalkenyl (C6-C10), -heterocyclyl (C2-Cg), -heterocycloalkenyl (C2-C10), -heterobicycloalkyl (C6-C9), -heterobicycloalkenyl (C6-Cg), -aryl ( C6-C10), -he'eroaryl (d-C8), -C (0) (alkyl (C? -C6)), and - S02 (alkyl (d-C6)) are optionally substituted with one to three residues independently selected from the group consisting of hydrogen, hydroxyl, halogen, -CF3, -CN, -N02, -alkyl (d-C6), -NH-alkyl (d-C6). -NH-cycloalkyl (C3-C7). -NH-heterocyclyl (C2-Cg), -NH-aryl (C6-C10), -NH-heteroaryl (C, -C9). -Nalkalk-Ce) ^, -N ((C3-C7) cycloalkyl), -N (heterocyclyl (C2-C9)) 2. -N (aryl (C6-C10)) 2, -N (heteroaryl (d-C9)) 2, -O-alkyl (d-Ce). -0-cycloalkyl (C3-C7). -0- (C2-C9) heterocyclyl, -O-aryl (C6-C10), -O-heteroaryl (d-Cg), -cycloalkyl (C3-C7), -heterocyclyl (C2-C9). -C02H, -C (0) (alkyl (d-C6)), -S02H, -S02 (alkyl (d-C6)). -S02NH2, -S? 2 NH (alkyl (C, -C6)), -S02N ((C, -C6) alkyl) 2, -NHS02 ((C, -C6) alkyl). and -N (alkyl (d-C6)) S02 (alkyl (C, -C6)); R8 and R9 when attached to the same carbon atom can be joined to form a (C3-C7) -cycloalkyl, -cycloalkenyl (C5-d0), -bicycloalkyl (C6-do), -bicycloalkenyl (C6-C10), -heterocyclyl (C2-Cg), -heterocycloalkenyl (C2-C10), -heterobicycloalkyl (C6-Cg), heterobicycloalkenyl (C6-Cg), -aryl (C6-C, 0), or -heteroaryl (d-C9), wherein each of the above-cycloalkyl (C3-C7), -cycloalkenyl (C5-do), -bicycloalkyl (Cß-C10), -bicycloalkenyl (C6-C10), -heterocyclyl (C2) -Cg), -heterocycloalkenyl (C2-C? O), -heterobicycloalkyl (C6-C9), heterobicycloalkenyl (C6-Cg), -aryl (C6-C? O) and -heteroaryl (C? -Cg) is optionally substituted with one to three substituents independently selected from the group consisting of halogen. -CF3 -CN -N02, -alkyl (d-C6), -OR16, -C (0) 0R1ß.-0C (0) R16.-0C (0) 0R16. -N (R16) 2, -NR16C (0) R16, -S02R16. -S02N (R16) 2 and -NR16S02R16; R10 to R11 are each independently a substituent selected from the group consisting of hydrogen, -alkyl (d-C6), -alkyl (C2-C6) perfluorinated, -cycloalkyl (C3-C7), -cycloalkenyl (C5-C10), -bicycloalkyl (C6-C10), -bicycloalkenyloylCe-do). -heterocyclyl (C2-C9), -heterocycloalkenyl (C2-C? o), -heterobicycloalkyl (C6-C9), -heterobicycloalkenyl (C6-C9), -aryl (C6-C10), -heteroaryl (d-C9), -aryl (C6-C? o) perfluorinated. -sheteroaryl (d-C8) perfluorinated, -C02H, -CiOJalkyloid-Cβ), -S02 (alkyl (d-C6)) and -P (0) (OR16) 2. wherein said substituents-alk (d-C6), -cycloalkyl (C3-C7), -heterocyclyl (C2-C9). -aryl (C6-C? 0). -heteroaryl (C? -C9), -C (0) (alkyl (d-C6)), and -S02 ((C1-C6) alkyl) are optionally substituted with from one to three residues independently selected from the group constituted by hydrogen, hydroxyl, halogen, -CF3, -CN, -N02, -alkyl (C? -C6). -NH-alkyl (d-C6). -NH-cycloalkyl (C3-C7). -NH- heterocyclyl (C2-C9). -NH-aryl (C6-C10), -NH-heteroaryloid-Cg). -N (alkyl (C, -Cβ)) 2. -N ((C3-C) cycloalkyl) 2, -N (heterocyclyl (C2-C9)) 2, -N (aryl (C6-C10)) 2. -N (heteroaryl (C, -C9)) 2. -0-alkyl (C, -C6). -O-cycloalkyl (C3-C7), -0-heterocyclyl (C2-C9). -0-aryl (C6-do), -0-heteroaryl (d-C9), -cycloalkyl (C3-C7), -heterocyclyl (C2-C9), -C02H, -C (0) (alkyl (d) -C6)), -S02H, -S02 (alkyl (d-C6)), -S02NH2, -S02NH (alkyl (C, -C6)), -S02N (alkyl (d-C6)) 2, -NHS02 (alkyl (C, -C6)). and -N (alkyl (d-C6)) S02 (alkyl (d-C6)); R12 is a substituent selected from the group consisting of hydrogen, -alkyl (C? -C6), -cycloalkyl (C3-C7), -heterocyclyl (C2-C9), -aryl (C6-C10). -heteroaryl (d-Cg). -C (0) R15, -C (0) OR15. -C (0) N (R15) 2. -C (0) NR15C (0) NR15 and -S02 (R15) 2, wherein said substituents -alkyl (d-C6), -cycloalkyl (C3-C), -heterocyclyl (C2-C9), -aryl ( C6-C10) and -heteroaryloid-Cg) are optionally substituted with one to three residues independently selected from the group consisting of halogen, -CF3. -CN -N02, -alqu¡lo (C, -C6), -OR16. -C (0) OR16, -OC (0) R16, -OC (0) OR16, -N (R16) 2. -NR16C (0) R16. -S02R16, -S02N (R16) 2 and -NR18S02R16; R13 is a substituent selected from the group consisting of hydrogen, -alkyl (C? -C6), -C (0) H, -CYOJ-alkylotd-Ce)), -alkyl (d-C6) -OR14. -alkyloid-CßJ-NRaFL, and -P (0) (OR16) 2; R14 is a substituent selected from the group consisting of hydrogen, -alkyl (d-C6) and -P (0) (OR16) 2; R15 is a substituent independently selected from the group consisting of hydrogen, -alkyl (d-C6), -cycloalkyl (C3-C7), -heterocyclyl (C2-C9), -aryl (Cß-C, 0), and -heteroaryl (d-C9), wherein said -alkyl (C? -C6), -cycloalkyl (C3-C), -heterocyclyl (C2-C9), -aryl (C6-C10), and -heteroaryl ( d-Cg) are optionally substituted with one to three residues independently selected from the group consisting of halogen, -CF3, -CN, -N02, -alkyl (C? -C6), -OR16, -C (0) (R16) ) 2, -C (0) OR16. -OC (0) R16.-N (R16) 2. -NR16C (0) R16. -S02R16. -S02N (R16) 2 and -NR16S02R16; two R15 groups when linked to the same nitrogen atom can form a (C2-Cg) heterocyclyl optionally substituted with one to three substituents independently selected from the group consisting of hydrogen, halogen, -CF3, -N02, -CN, - alkyl (C? -C6), -alkenyl (C2-C6), -alkynyl (C2-C6). -CR16 = N-N (R 6) 2. -CR16 = N-0R16. -CR16 = N- NR16C (0) R16, -CR3 = N-NR16C (0) OR16. -N (R16) 2, -OR16. -cycloalkyl (C3-C7). -heterocyclyl (C2-C9). -C02R16, -CON (R16) 2, -SR16. -SOR16, -S02R16, -S02N (R16) 2, -NHCOR16, -NR16CON (R16) 2 and -NR16S02R16; R16 is a substituent independently selected from the group consisting of hydrogen, -alkyloid-Cß), -cycloalkyl (C3-C7), -heterocyclyl (C2-C9), -aryl (C6-C10). and -heteroaryl (C, -C9); two R16 groups when attached to the same nitrogen atom can form a (C2-C9) heterocyclyl optionally substituted with one to three substituents independently selected from the group consisting of halogen, -CF3, -N02, -CN, -alkyl ( d-C6), -cycloalkyl (C3-C7), -heterocyclyl (C2-C9), -aryl (C6-C? o), and -heteroarilofd-Cg); m is an integer from 1 to 4; and p is an integer from 1 to 4.

2. A compound according to claim 1 wherein M is N.

3. A compound according to any one of the preceding claims wherein Q is C (D) and D is selected from the group consisting of hydrogen, halogen, hydroxy, -CF3, -N02l -CN, and -alkyl (d-C6) ), wherein said -alkyl (d-Cß) substituent D is optionally substituted with one to three substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, -CF3, -N02, -CN, and -alkyl ( d-C6).

4. A compound according to any one of the preceding claims wherein K is C (R1) and R1 is selected from the group consisting of hydrogen, halogen, hydroxy, -CF3, -N02, and -CN.

5. A compound according to any one of the preceding claims wherein M is N, K is C (H) and Q is C (CF3).

A compound according to any one of the preceding claims wherein R2 is wherein RE is hydrogen, n is 0, and RH is -cycloalkyl (C3-C10).

7. A compound according to any one of the preceding claims wherein A is an -aryl (C6-C10), optionally substituted with one to three substituents independently selected from the group consisting of hydrogen, halogen, -CF3, -N02, -CN, -alkyl (C, -C6), -alkenyl (C2-C6), -alkynyl (C2-C6), -CR3 = N-NR3R4, -CR3 = N-OR5. -CR3 = N-NR3C (0) R3. -CR3 = N-NR3C (0) OR5. -NR3R4, -OR5, -cycloalkyl (C3-C7), -heterocyclyl (C2-C9), -C (0) R5, -C02R5. -CONR3R4, -SR6, -SOR6. -S02R6, -S02NR3R4. -NHCOR15. -NR3CONR3R4. and -NR3S02R6.

8. A compound according to any one of the preceding claims wherein Z1 and Z2 are -CR7-, Y1 and Y2 are each -CH-, and L1 and L2 are each independently selected from the group consisting of -CR ß Rr-, 9

9. A compound according to any one of the preceding claims wherein W is -CR8R9 and p is 2.

10. A compound according to claim 61, wherein X is -NR12- and m is 1.

11. A compound according to any one of the preceding claims, wherein X is -NR12-, and R12 is a substituent selected from the group consisting of -C (0) R15, -C (0) OR15. -C (0) N (R15) 2, -C (0) NR15C (0) R15 and -S02R152

12. A compound according to any one of the preceding claims wherein R12 is -C (0) R15.

13. A compound selected from the group consisting of: 1- [6- (4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino) - (1S, 4R) -1, 2,3,4-tetrahydro -1, 4-epiazan-naphthalen-9-yl] -2-hydroxy-ethanone, 2-Amino-1 - [6- (4-cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino) - (1S, 4R ) -1, 2,3,4-tetrahydro-1,4-epiazan-naphthalen-9-yl] -ethanone, 1- [6- (5-Chloro-4-cyclobutylamino-pyrimidin-2-ylamino) - (1 S, 4 *?) - 1, 2,3,4-tetrahydro-1,4-epiazan-naphthalen-9-yl] -ethanone, / V-. { 2- [6- (4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino) - (1 S.4R) -1, 2,3,4-tetrahydro-1,4-epiazan-naphthalene-9-yl] -2-oxo-ethyl) -acetamide, 6- (4-cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino) - (1 S, 2R) -1, 2,3,4-tetrahydro-1-ethylamide, 4-epiazan-naphthalene-9-carboxylic acid, 1 - [6- (4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino) - (1 S), 4 /?) - 1, 2,3,4-tetrahydro-1,4-epiazan-naphthalen-9-yl] -2-methoxy-ethanone, [6- (4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2 -ylamino) - (1S, 4R) -1,2,3,4-tetrahydro-1,4-epiazan-naphthalen-9-yl] -cyclopropyl-methanone, 1- [6- (4-Cyclobutylamino-5-trifluoromethyl-pyrimidine -2-ylamino) - (1S, 4?) - 1,2,3,4-tetrahydro-1,4-epiazan-naphthalen-9-yl] -ethanone,? 4-Cyclobutyl -? / 2 - [(1 S, 4R) -1, 2,3,4-tetrahydro-1,4-epiazan-naphthalen-6-yl) -5-trifluoromethyl-pyrimidine-2,4-diamine, (+/-) - 1- [6- ( 4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -1, 2,3,4-tetrahydro-1,4-epiazan-naphthalen-9-yl] -ethanone, 1- [6- (4-Cyclopropylamino-5-methyl-pyrimidin-2-ylamino) - (1S, 4?) - 1,2,3,4-tetrahydro-1,4-epiazan-naphthalen-9-yl] -etanone, 1 - [6- (4-Cyclopropylamino-5-fluoro-pyrimidin-2-ylamino) - (1 S, 4R) -1, 2,3,4-tetrahydro-1,4-epiazan-naphthalene-9 -yl] -etanone, 1- [6- (4-ethylamino-5-methyl-pyrimidin-2-ylamino) - (1S, 4:?) - 1,2,3,4-tetrahydro-1,4-epiazan -naphthalen-9-yl] -ethanone, 1- [6- (4-ethylamino-5-fluoro-pyrimidin-2-ylamino) - (1S, 4R) -1,2,3,4-tetrahydro-1,4 -epiazan-naphthalen-9-yl] -ethanone, 1- [6- (4-ethylamino-5-chloro-pyrimidin-2-ylamino) - (1 S.4R) -1, 2,3,4-t-tetrahydro- 1,4-epiazan-naphthalen-9-yl] -ethanone, 1 -. { 6- [5-Fluoro-4 - ((S) -2-methoxymethyl-pyrroline-1-yl) -pyrimidin-2-ylamino] - (1 S, 4R) -1, 2,3,4-tetrahydro-1, 4 -epíazan-naftalen-9-il} -etanone,? / 4-Cyclobutyl- / V2 - [(1 R, 4S) -1, 2,3,4-tetrahydro-1,4-epiazan-naphthalen-6-yl] -5-trifluoromethyl-pyrimidin-2 , 4-diamine, 1 - [6- (4-Cyclobutylamino-5-methyl-pyrimidin-2-ylamino) - (1 R, 4S) -1, 2,3,4-tetrahydro-1,4-epiazan -naphthalen-9-yl] -etanone, 1- (6- (4-Cyclobutylamino-5-fluoro-pyrimidin-2-ylamino) - (1 R, 4S) -1, 2,3,4-t? trahydro- 1, 4-epiazan-naphthalen-9-yl] -ethanone, / V ^ -ie ^ -CyclobutylamincHS-trifluoromethyl-pyrimidin ^ -ylaminoHIR ^ SJ-ISS ^ -tetrahydro-1,4-epiazan-naphthalen-9-yl] -2-oxo-ethyl} -acetamide, methyl ester of the acid "e - ^ - cyclobutylamino-S-trifluoromethyl-pyrimidin ^ -ylaminoHI ^ S) -1, 2,3,4-tetrahydro-1,4-epirazan-naphthalen-9-yl] -ace Co, 6- (4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino) - (1?, 4S) -1,2,3,4-tetrahydro-1,4-epiazan-naphthalen-9-yl] - ( R) -pyrrolidin-2-yl-methanone, [6- (4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino) - (1R, 4S) -1,2,3,4-tetrahydro-1,4-epiazan- Naphthalen-9-yl] -cyclopropyl-methanone, 1 - [6- (4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino) - (1 R, 4S) -1, 2,3,4-tetrahydro-1 4- epiazan-naphthalene-9-yl] -2-methoxy-ethanone, 6- (4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino) - (1R, 4S) -1, 2,3,4-tetrahydro-1,4-epiazan-naphthalene-9-carboxylic acid, isopropyl-amide , 1- [6- (4-Cyclobutylammon-5-trifluoromethyl-pyrimidin-2-ylamino) - (1R, 4S) -1,2,3,4-tetrahydro-1,4-epiazan-naphthalene-9- il] -2-methylamino-ethanone, 1- [6- (5-Chloro-4-cyclobutylamino-pyrimidin-2-ylamino) - (1R.4S) -1,2,3,4-tetrahydro-1,4- epiazan-naphthalen-9-yl] -ethanone, 1- [6- (4-Cyclobutylamino-5-fluoro-pyrimidin-2-ylamino) - (1R.4S) -1,2,3,4-tetrahydro-1, 4-epiazan-naphthalen-9-yl] -ethanone, 1- [6- (4-Cyclobutylamino-5-ethyl-pyrimidin-2-ylamino) - (1R, 4S) -1,2,3,4-tetrahydro- 1,4-epiazan-naphthalen-9-yl] -ethanone, 1- [6- (4-Cyclobutylamino-5-methyl-pyrimidin-2-ylamino) - (1 4S) -1,2,3l4-tetrahydro-1 , 4-epiazan-naphthalen-9-yl] -ethanone,? 4-Cyclopropyl-? 2- (1 R, 4S) -1, 2,3,4-tetrahydro-1,4-epiazan-naphthalen-6-yl-5-trifluoromethyl-pyrimidine-2,4-diamine, V4-Cyclopropyl-v2 - [(1 R, 4S) -9-methanesulfonyl-1, 2,3,4-tetrahydro-1,4-epiazan-naphthalen-6-yl] -5-trifluoromethyl-pyrimidine-2,4-diamine, l-te ^ -Cyclopropylamino-S-trifluoromethyl-pyrimidin-4-aminoamiroy-SJ-I ^. S ^ -tetrahydro-l ^ -epiazan-naphthalen-9-yl] -2-methoxy-ethanone, (+/-) - 1. { 6- [4- (2-Methoxy-ethylamino) -5-trifluoromethyl-pyrimidin-2-ylamino] -1,2,3,4-tetrahydro-1,4-epiazan-naphthalen-9-yl) -ethanone, (+ / -) - 2- [6- (4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -1, 2,3,4-tetrahydro-1,4-epiazan-naphthalen-9-yl] - V, V -dimethyl acetamide, and pharmaceutically acceptable salts of each of the above compounds.

14. A method for treating abnormal cell growth in a mammal comprising administering to said mammal an amount of compound of any one of the preceding claims that is effective in treating abnormal cell growth.

15. A pharmaceutical composition comprising an effective amount of compound of any one of the preceding claims, and a pharmaceutically acceptable carrier.