MX2008005985A - Compounds and uses thereof iv - Google Patents

Abstract

This invention relates to novel compounds having the structural formula I below:and to their pharmaceutically acceptable salts, compositions and methods of use. These novel compounds provide a treatment or prophylaxis of cognitive impairment, Alzheimer Disease, neurodegeneration and dementia.

Description

COMPOUNDS IV AND USES OF THEMSELVES FIELD OF THE INVENTION The present invention relates to novel compounds, their pharmaceutical compositions. In addition, the present invention relates to therapeutic methods for the treatment and / or prevention of Aß-related pathologies such as Down syndrome and β-amyloid angiopathy, such as but not limited to cerebral amyloid angiopathy, hereditary cerebral hemorrhage, disorders associated with cognitive impairment, such as but not limited to MCI ("mild cognitive impairment"), Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear palsy or basal cortical degeneration.

BACKGROUND OF THE INVENTION Various groups identify and isolate aspartate proteinases that have β-secretase activity (Hussain et al., 1999; Lin et. al, 2000; Yan et. al, 1999; Sinha et. al., 1999 and Vassar et. al., 1999). The β-secretase is also known in Ref .: 192577 the literature as Asp2 (Yan et al., 1999), Beta-site APP unfolding enzyme (BACE) (Vassar et al., 1999) or memapsin 2 (Lin et al., 2000). BACE was identified using a number of experimental approaches such as EST database analysis (Hussain et al., 1999); cloning of expression (Vassar et al., 1999); identification of human homologs from public databases of predicted C. elegans proteins (Yan et al., 1999) and finally using an inhibitor to purify the human brain protein (Sinha et al., 1999). Thus, five groups that employ three different experimental approaches lead to the identification of the same enzyme, making a strong case that BACE is a β-secretase. Reference is also made to the patent literature: WO96 / 40885, EP871720, Patents of E.U.A. Nos. 5,942,400 and 5,744,346, EP855444, US 6,319,689, 099/64587, 099/31236, EP1037977, O00 / 17369, WO01 / 23533, O0047618, O00 / 58479, WO00 / 69262, O01 / 00663, O01 / 00665, US 6,313,268.

BACE was found to be a pepsin-like aspartic proteinase, the mature enzyme consists of the N-terminal catalytic domain, a transmembrane domain, and a small cytoplasmic domain. BACE has an optimal activity at pH 4.0-5.0 (Vassar et al, 1999) and is weakly inhibited by pepsin inhibitors such as pepstatin. It is also shown that the catalytic domain minus the transmembrane and the cytoplasmic domain have activity against the peptides of the substrate (Lin et al, 2000). BACE is a type 1 protein bound to the membrane that is synthesized as a partially active proenzyme, and is abundantly expressed in brain tissue. It is believed to represent the highest activity of the β-secretase, and it is considered to be the stage that limits the ratio in the production of the β-amyloid protein (Aβ). It is thus of special interest in the pathology of Alzheimer's Disease, and in the development of drugs as a treatment of Alzheimer's Disease. The Aβ or β-amyloid protein is the main constituent of the brain plaques which are characteristic of Alzheimer's disease (De Strooper et al, 1999). Aß is a 39-42 residue peptide formed by the specific unfolding of a class I transmembrane protein called APP, or amyloid precursor protein. The activity of the Aβ-secretase unfolds this protein between residues Met671 and Asp672 (numbering of the 770aa isoform of APP) to form the N-terminus of Aβ. A second splitting of the peptide is associated with the? -secretase to form the C terminal of the Aβ peptide. Alzheimer's Disease (AD) is estimated to affect more than 20 million people worldwide and is believed to be the most common form of dementia. Alzheimer's disease is a progressive dementia in which massive deposits of added protein break down amyloid-product plates and neurofibrillary tangles accumulated in the brain. Amyloid plaques are considered responsible for the mental decline seen in Alzheimer's patients. The probability of developing Alzheimer's disease increases with age, and as the population that ages in the developed world increases, this disease becomes a bigger and bigger problem. In addition to this, there is a familial link to Alzheimer's disease and consequently any individual who possesses the double mutation of the APP known as the Swedish mutation (in which the mutated APP forms a considerably better substrate for BACE) is much more likely to develop the AD, and also to develop it at an early age (see also US 6,245,964 and US 5,877,399 concerning transgenic rodents comprising the Swedish APP-S). Consequently, there is also a strong need to develop a compound that can be used in a prophylactic manner for these individuals.

The gene that encodes the APP is located on the chromosome 21, which is also the chromosome found as an extra copy in Down Syndrome. Patients with Down syndrome tend to acquire Alzheimer's Disease at an early age, with almost all those above 40 years of age, which shows Alzheimer-type pathology (Oyama et al., 1994). It is considered to be due to the extra copy of the APP gene found in these patients, which leads to overexpression of APP and therefore to increased levels of APPß which causes the high prevalence of Alzheimer's Disease observed in this population. Thus, BACE inhibitors may be useful to reduce Alzheimer-type pathology in patients with Down syndrome. Drugs that reduce or block BACE activity should therefore reduce Aß levels and levels of Aß fragments in the brain, or anywhere where Aß or fragments of the same deposit, and thus slow the formation of amyloid plaques and the progress of AD or other ills that involve the deposition of Aß or fragments thereof (Yankner, 1996, De Strooper and Konig, 1999). BACE is therefore an important candidate for the development of drugs as a treatment and / or prophylaxis of Aß-related pathologies such as Down syndrome and β-amyloid angiopathy, such as but not limited to cerebral amyloid angiopathy, hemorrhage Hereditary brain, disorders associated with cognitive impairment, such as but not limited to MCI ("mild cognitive impairment"), Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with such diseases as Alzheimer's disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear palsy or basal cortical degeneration. It would therefore be useful to inhibit the deposition of Aβ and portions thereof by inhibiting BACE through inhibitors such as the compounds provided herein. The therapeutic potential of inhibiting Aβ deposition has motivated many groups to isolate and characterize the secretase enzymes and to identify their potential inhibitors (see, for example, WO01 / 23533 A2, EP0855444, O00 / 17369, O00 / 58479, WO00 / 47618, WO00 / 77030, O01 / 00665, WO01 / 00663, WO01 / 29563, WO02 / 25276, US5,942,400, US65245,884, US6,221,667, US6,211,235, WO02 / 02505, WO02 / 02506, O02 / 02512, O02 / 02518, WO02 / 02520, WO02 / 14264, WO05 / 058311, WO 05/097767, US2005 / 0282826). The compounds of the present invention show improved properties compared to the potential inhibitors known in the art, for example, hERG selectivity improves.

BRIEF DESCRIPTION OF THE INVENTION Novel compounds of the invention are provided herein. structural formula I: I or a salt, tautomer or pharmaceutically acceptable in vivo hydrolysable precursor thereof, wherein: G is O, NR7 or CR8R9; R1 is H, C6_6alkyl, C6_6haloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C1_ aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl , cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4 or 5 R14; R2 is Q or -L-Q; or R1 and R2 together with the carbon atom to which they are attached form a cycloalkyl group of 3-14 members or heterocycloalkyl group of 3-14 members, each substituted by Cy2 and optionally substituted by 1, 2, 3, 4 or 5 A4; R, R, R5 and R are independently, H, CN, N02, OR, SRa, OC (0) Ra, OC (0) ORß, OC (0) NRcRa, C (0) Ra, C (0) ORD, C (0) NRcRa, NRcRd, NRA (0) Ra, NRA (0) ORb, NRcS (0) 2Rb, S (0) Ra, S (0) NRcRd, S (0) 2Ra, S (0) 2NRcRd, C? _10 alkyl, haloalkyl A-io, C2-? Alkenyl, C2_ alkynyl 0, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C1-io alkyl, C1-iohaloalkyl, C2-? 0 alkenyl, C2-? Alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 R14; R7 is H, C (0) Ra, C (0) ORb, C (0) NRcRd, S (0) Ra, S (0) 2Ra, C? -? Alkyl, C2-? Alkenyl, or C2_ alkynyl? _- cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C C _? alkyl, C2-?? alkenyl, C2_? alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl are each optionally substituted with 1, 2, 3, 4 or 5 R14; R8 and R9 are, independently, H, CN, N02, ORa, SRa, OC (0) Ra, OC (0) ORb, C (0) ORb, OC (0) NRcRd, NRcRd, NRcC (0) Ra, NRcC (O) 0Rb, NRcS (0) 2Rb, S (0) Ra, S (0) NRcRd, S (0) 2Ra, S (0) 2NRcRd, C? _? Alkyl, halo? C? -? Or, alkenyl C2_? O, C2_? Alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the alkyl A-io, haloalkyl A-io, alkenyl C2-? o, alkynyl C_? 0, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 R14; or R8 and R9 together with the carbon atom to which they are attached form a cycloalkyl group of 3-14 heterocycloalkyl members of 3-14 members, each optionally substituted by 1, 2 or 3 R14; R12 and R13 are each, independently, H, halo, C? -4 alkyl, C? _ Haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, N02, 0Ra ', SRa', C (0) Rb ', C (0) NRc'Rd ', C (0) ORa', OC (0) Rb ', OC (O) NRC' Rd ', NRc'Rd', NRcX (0) Rd ', NRc'C (0) ORa ', NRc'S (0) 2Rb', S (0) Rb ', S (0) NRc'Rd', S (0) 2Rb ', or S (0) 2NRc'Rd'; R14 is halo, C? - alkyl, C? _4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, N02, ORa ', SRa ', C (0) Rb', C (0) NRc'Rd ', C (0) ORa', OC (0) Rb ', OC (0) NRcRd', NRc'Rd ', NRcA (0) Rd ', NRC'C (O) ORa', NRC 'S (O) 2Rb', S (0) Rb ', S (0) NRc'Rd ', S (0) 2Rb', or S (0) 2NRc'Rd '; Q is aryl, cycloalkyl, heteroaryl or heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 Cy1 or A1; L is C2 -? - alkenylenyl, C2 -? Alkynynyl, ICR12R13, q ' (CR12R13) q? 0 (CR12R13) q2, (CR12R13) qlS (CR12R13) q2, (CR12R13) q? S02 (CR12R13) q2, (CR12R13) q? SO (CR12R13) q2, (CR12R13) q? CO (CR12R13) q2, (CR12R13) q? NRACR12R13) q2, or (CR12R13) qlCONRe (CR12R13) q2; Cy1 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 A2; Cy2 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 A3; A1 is halo, CN, N02, ORa, SRa, C (O) Rb, C (0) NRcRd, C (0) ORa, OC (0) Rb, OC (0) NRcRd, NRcRd, NRCC (O) Rd, NRcC (0) ORa, NRcS (0) Rb, NRcS (0) 2Rb, S (0) Rb, S (0) NRcRd, S (0) 2Rb, S (0) 2NRcRd, C 4 alkoxy, haloalkoxy C ? -, amino, alkylamino C? _4, dialkylamino C2-?, alkyl Cy-b, C2-6 alkenyl, C2_6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl, wherein each of C? _6 alkyl, C2_6 alkenyl, alkynyl C2__, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4 or 5 halo, C? -6 alkyl, C2-6 alkenyl, C2_6 alkynyl, C? - haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl , CN, N02, ORa, SRa, C (0) Rb, C (0) NRcRd, C (0) ORa, OC (0) Rb, 0C (0) NRcRd, NRcRd, NRcC (0) Rd, NRcC (0) ) 0Ra, NRcS (0) Rb, NRcS (0) 2Rb, S (0) Rb, S (0) NRcRd, S (0) 2Rb, or S (0) 2NRcRd; TO, A, and A are each independently, halo, CN, N02, 0Ra, SRa, C (0) Rb, C (0) NRcRd, C (0) ORa, OC (0) Rb, OC (0) NRcRd, NRcR, NRX (0) Rd, NRX (0) ORa, NRcS (0) Rb, NRcS (0) 2Rb, S (0) Rb, S (0) NRcRd, S (0) 2Rb, S (0) 2NRcRd, CX-4 alkoxy, C? _4 haloalkoxy, amino, C? _4 alkylamino, C2_s dialkylamino, C? _g alkyl, C2_6 alkenyl, C2_e alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl , wherein each of C 1 -C 6 alkyl, C 2 6 alkenyl, C 2-6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2, 3, 4 or 5 halo, C? _ alkyl, C2_6 alkenyl, C2_6 alkynyl, C? _4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, N02, ORa, SRa, C (0) Rb, C (0) NRcRd, C (0) ORa, 0C (0) Rb, OC (0) NRcRd, NRcRd, NRcC (0) Rd, NRcC (0) ORa, NRcS (0) Rb, NRcS (0) 2Rb, S (0) Rb, S (0) NRcRd, S (0) 2Rb, or S (0) 2NRcRd; Ra and Ra 'are each independently, H, C ?6 alkyl, C ?6 haloalkyl, C2-6 alkenyl C2-6, C2- alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C C _6 alkyl, C?-6 haloalkyl, C2_6 alkenyl, C2_6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C? -6 alkyl, C? -6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; Rb and Rb are each independently, H, C? _6 alkyl, C? -6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C? _6 alkyl, C? -6 haloalkyl, C2_6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C? -6 alkyl, haloalkyl Ae, C?-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; Rc and Rd are each independently, H, C?-C? Alkyl, C?-C halo haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C C-βalkyl, C? _6 haloalkyl, C2_6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C? -6 alkyl, C? _6 haloalkyl, C? -6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or Rc and Rd together with the N atom to which they are bonded form a 4, 5, 6 or 7 membered heterocycloalkyl group; Rc 'and Rd' are each, independently, H, C? _? Alkyl, C? -6 haloalkyl, C2_6 alkenyl, C2_6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C alquilo _ ?alkyl, C?-C halohaloalkyl, C C_6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C alquiloalkyl? -6, haloalkyl C6-6, haloalkyl C6-6, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or Rc 'and Rd' together with the N atom to which they are bonded form a 4, 5, 6 or 7 membered heterocycloalkyl group; Re is H, C? - alkyl, C? _ Haloalkyl, C2_4 alkenyl, C2- alkynyl, or CO- (C? _4 alkyl); q is 1, 2, 3, 4, 5 or 6; ql is 0, 1, 2 or 3; and q2 is 0, 1, 2 or 3; with the conditions: a) when G is NH or CH2; R2 is -L-Q; L is -CH2, -CH = CH- or -C = C-; and R1 is H or methyl, then Q is different from unsubstituted phenyl; and b) when G is NR7 or CR8R9; R7 is H, methyl, or phenyl optionally substituted by halo; R8 and R9 are each independently, H or methyl; R2 is Q; and R1 is H or methyl, then Q is aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each substituted by at least one Cy3 and optionally substituted by 1, 2 or 3 A4. In some embodiments, R1 is H, C? _6 alkyl, C? -6 haloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C? -6 alkyl, C? _6 haloalkyl, aryl, heteroaryl, arylalkyl , heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4 or 5 R14. In some embodiments, R1 is H, C6_6 alkyl, C6_6 haloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein C6_6alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, OH, C? -6 alkoxy, C? -6 haloalkoxy, C? _6 haloalkyl, C? _6 alkyl, C2_6 alkenyl, C2_6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl , heteroaryl and heterocycloalkyl.

In some embodiments, R1 is C6-6 haloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein the aryl, heteroaryl, arylalkyl or heteroarylalkyl is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, OH, alkoxy C? _6, C? _6 haloalkoxy, C? -6 haloalkyl, C? -6 alkyl, C2_6 alkenyl, C2_6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl. In some modalities, R2 is Q or -L-Q; and Q is aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally substituted by 1, 2 or 3 A1. In some embodiments, R2 is Q or -L-Q; and Q is aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each substituted by at least one Cy1 and optionally substituted by 1, 2 or 3 A1. In some embodiments, R2 is Q or -L-Q; and Q is aryl or heteroaryl, each substituted by at least one Cy1 and optionally substituted by 1, 2 or 3 A1. In some embodiments, R2 is Q or -L-Q; and Q is aryl substituted by at least one Cy1 and optionally substituted by 1, 2 or 3 A1. In some embodiments, R2 is Q or -L-Q; and Q is phenyl substituted by at least one Cy1 and optionally substituted by 1, 2 or 3 A1.

In some embodiments, R2 is Q or -L-Q; and Q is phenyl substituted by Cy1. In some embodiments, R2 is Q or -L-Q; Q is phenyl substituted by Cy1; and Cy1 is aryl or heteroaryl, each optionally substituted with 1, 2, 3, 4 or 5 A2. In some embodiments, R2 is Q or -L-Q; Q is phenyl substituted by Cy1; and Cy1 is aryl optionally substituted with 1, 2 or 3 substituents independently selected from halo, CN, OH, C? -6 alkoxy, C? -6 haloalkoxy, C? -6 haloalkyl, C? _6 alkyl, C2_g alkenyl, C2 alkynyl -6, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. In some embodiments, R2 is Q or -L-Q; Q is phenyl substituted by Cy1, wherein Cy1 is substituted at the meta position of the phenyl; and Cy1 is aryl optionally substituted with 1, 2 or 3 substituents independently selected from halo, CN, OH, alkoxy A-6, haloalkoxy C6-6, haloalkyl A-6, alkyl A-6, alkenyl C2_6, alkynyl C2_6, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. In some embodiments, R2 is Q. In some embodiments, R2 is -L-Q; and L is C2-? 0 alkenylenyl, C2-10 alkynynyl or (CR12R13) q.

In some embodiments, R2 is -L-Q; and L is C2-? 0 alkenylenyl, C2_? 0 alkynynyl or (CR12R13) q. In some embodiments, R2 is -L-Q; and L is (CR12R13) q. In some embodiments, R2 is -L-Q; L is (CR12R13) q; and q is 2. In some embodiments, R1 and R2 together with the carbon atom to which they bond form a cycloalkyl group of 3-14 members or heterocycloalkyl group of 3-14 members, each substituted by Cy2 and optionally substituted by 1, 2 or 3 A4; and Cy2 is aryl or heteroaryl, each optionally substituted with 1, 2, 3, 4 or 5 A3. In some embodiments, R1 and R2 together with the carbon atom to which they are attached form a cycloalkyl group of 3-14 members substituted by Cy2 and optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, OH, C? -6 alkoxy, Ci- 6 haloalkoxy, C? -6 haloalkyl, C? -alkenyl C2_6, alkynyl C2-6, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl; Cy2 is aryl or heteroaryl, each optionally substituted with 1, 2 or 3 A3; and A3 is aryl or heteroaryl, each optionally substituted with 1, 2 or 3 substituents independently selected from halo, CN, OH, C 1-6 alkoxy, C 1-6 haloalkoxy, C? -6 haloalkyl, C? -6 alkyl, C2- "alkenyl, C2_6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. In some embodiments, R1 and R2 together with the carbon atom to which they bond form a 3-14 membered cycloalkyl group substituted by Cy2 and optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, OH, alkoxy A -6, haloalkoxy C6-6, haloalkyl C6-6, C6-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl; Cy2 is phenyl substituted with 1 or 2 A3; and A3 is aryl or heteroaryl, each optionally substituted with 1, 2 or 3 substituents independently selected from halo, CN, OH, C? -6 alkoxy, C? _6 haloalkoxy, C? _6 haloalkyl, C? _6 alkyl, C2 alkenyl -6, C2_6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl. In some embodiments, R3, R4, R5 and R6 are independently, H, CN, C (0) Ra, C (0) ORb, C (0) NRcRd, C? -? Alkyl, haloalkyl A-io, C2-alkenyl -?, C2-? or alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the alkyl A-1, haloalkyl A-ioC,? al alkenyl, C2_ alqu alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 R14. In some embodiments, R3, R4, R5 and R6 are independently, H, CN, C (0) Ra, C (0) ORb, C (0) NRcRd, C? -? Alkyl, haloalkyl C? _? O, C2_? 0 alkenyl, C2-? al alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C? _? _ alkyl, C? _? 0 haloalkyl, C2_ alkenyl, alkynyl C2_? O, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 substituents independently selected from halo, C? - alkyl, C? _4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NRC 'Rd', NRcX (0) Rd ', NRc'C (0) 0Ra' and NRC'S (O) 2Rb '. In some embodiments, R3, R4, R5 and R6 are independently, H. In some embodiments, R4 is CN, C (0) Ra, C (0) ORb, C (0) NRcRd, C? _? Alkyl, haloalkyl C? _? 0, C2_? Alkenyl, C2_? Alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C1-io alkyl, C? _? halo haloalkyl, C2_? alkenyl, C2- o alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 substituents independently selected from halo, C? _4 alkyl, C? _4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NRc'Rd ', NRc'C (0) Rd', NRcX (0) 0Ra 'and NRC' S (O) 2Rb '. In some embodiments, G is O. In some embodiments, G is NR7 or CR8R9; and R7, R8 and R9 are each independently, H, C? -? - alkyl, Ci-? haloalkyl, C2_? alkenyl, C2-? or alkynyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl or heterocycloalkylalkyl. In some embodiments, R1 is C6-C6 haloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein the aryl, heteroaryl, arylalkyl or heteroarylalkyl is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, OH, alkoxy C? -6, C? _6 haloalkoxy, C? _6 haloalkyl, C? _6 alkyl, C2_6 alkenyl, C2_6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl; R is Q; and Q is aryl or heteroaryl, each optionally substituted by 1, 2 or 3 A1. Also provided herein are the novel compounds of structural formula II: II wherein: R1 is H, C6_6 alkyl, C6_6 haloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein C6_6alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, OH, C? -6 alkoxy, C? -6 haloalkoxy, C? _6 haloalkyl, C? -6 alkyl, C2-6 alkenyl, C2-6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. L is C4_4 alkylenyl; n is 0 or 1; and Cy3 is aryl or heteroaryl, each optionally substituted with 1, 2 or 3 substituents independently selected from halo, CN, OH, C6-6 alkoxy, C6-6 haloalkoxy-C6-6 haloalkyl, C6-6 alkyl, C2_6 alkenyl, C2-6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. In some embodiments, L is CH2CH2; and Cy3 is aryl optionally substituted with 1, 2 or 3 substituents independently selected from halo, CN, OH, C6_6 alkoxy, C6_6 haloalkoxy, C6_6 haloalkyl, C6_6 alkyl, C2_6 alkenyl, C2_ alkynyl 6, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. The novel compounds of the formula Illa or structural formula Illb are provided herein: Illa pib where: r is 0, 1, 2 or 3; and Cy 4 is aryl optionally substituted with 1, 2 or 3 substituents independently selected from halo, CN, OH, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 haloalkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. The novel compounds of formula IVa or structural formula IVb are provided herein: IVa IVb wherein: r is 0, 1, 2 or 3; and Cy 4 is aryl optionally substituted with 1, 2 or 3 substituents independently selected from halo, CN, OH, C 1-6 alkoxy, haloalkoxy A-6, C 1-6 haloalkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. Also provided herein are the novel compounds of structural formula V: or a salt, tautomer or pharmaceutically acceptable in vivo hydrolysable precursor thereof, wherein: R21 is H, C? -6 alkyl, C? _6 haloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C C-6 alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4 or 5 R29; R22 is Q or -L-Q; R23, R24, R25 and R26 are independently, H, Si (alkyl X-? O) 3, CN5 N02, 0Ra, SRa, 0C (0) Ra, OC (0) ORb, OC (0) NRcRd, C (0) ) Ra, C (0) ORb, C (0) NRcRd, NRcRd, NRCC (O) Ra, NRA (0) ORb, NRcS (0) 2Rb, S (0) R3, S (0) NRcRd, S (0 2Ra, S (0) 2NRcRd, alkyl d-10, haloalkyl C? -? Or, C2_? Alkenyl, C2_? Al alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the Ci-io alkyl, Ci-iohaloalkyl, C2-? 0 alkenyl, C2-? or alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl it is optionally substituted by 1, 2 or 3 R29; R27 and R28 are each independently, H, halo, C? _4 alkyl, C? - haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, N02, ORa ', SRa', C (0) Rb ', C (0) ) NRc'Rd ', C (0) ORa', OC (0) Rb ', OC (O) NRC' Rd ', NRc'Rd', NRc'C (0) Rd ', NRc'C (0) ORa ', NRC'S (0) 2Rb', S (0) Rb ', S (0) NRc'Rd', S (0) 2Rb ', or S (0) 2NRc'Rd'; R29 is halo, C? -4 alkyl, C? _4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, N02, ORa, SRa ', C (0) Rb', C (0) NRc'Rd ', C (0) ORa', OC (0) Rb ', OC (O) NRC' Rd ', NRc'Rd ', NRc'c (0) Rd', NRC 'C (O) ORa', NRC 'S (O) 2Rb', S (0) Rb ', S (0) NRc'Rd ', S (0) 2Rb', or S (0) 2NRc'Rd '; Q is aryl, cycloalkyl, heteroaryl or heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 Cy1 or A1; L is C2_? 0 alkenylenyl, C2_? Alkynynyl, (CR27R28) q, (CR27R28) q? O (CR27R28) q2, (CR27R28) qiS (CR27R28) q2, (CR27R28) qlS02 (CR2 R28) q2, (CR27R28) q? SO (CR27R28) q2, (CR27R28) q? CO (CR27R28) q2, (CR2 R28) qlNRACR27R28) q2, or (CR2 R28) q? CONRe (CR27R28) q2; Cy1 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 A2; A1 is halo, CN3 N02, OR3, SRa, C (0) Rb, C (0) NRcRd, C (0) ORa, OC (0) Rb, OC (0) NRcRd, NRcRd, NRcC (0) Rd, NRcC (0) ORa, NRcS (0) Rb, NRcS (0) 2Rb, S (0) Rb, S (0) NRcRd, S (0) 2Rb, S (0) 2NRcRd, C4 alkoxy, haloalkoxy C? , amino, alkylamino C? _, dialkylamino C2_s, C? -6 alkyl, C2_6 alkenyl, C2_6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl, wherein each of C? _6 alkyl, C2_? alkenyl, C2_6 alkynyl, arylalkyl , cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4 or 5 halo, C? -6 alkyl, C2-6 alkenyl, C2_6 alkynyl, C? -4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN , N02, ORa, SRa, C (O) Rb, C (0) NRcRd, C (0) ORa, OC (0) Rb, OC (0) NRcRd, NRcRd, NRcC (0) Rd, NRcC (0) ORa , NRcS (0) Rb, NRcS (0) 2Rb, S (0) Rb, S (0) NRcRd, S (0) 2Rb, or S (0) 2NRcRd; A2 is halo, CN, N02, ORa, SRa, C (0) Rb, C (0) NRcRd, C (0) ORa, OC (0) Rb, OC (0) NRcRd, NRcRd, NRcC (0) Rd, NRcC (0) ORa, NRCS (O) Rb, NRcS (0) 2Rb, S (0) Rb, S (0) NRcRd, S (0) 2Rb, S (0) 2NRcRd, alkoxy C? _4, haloalkoxy C? _, amino, alkylamino C? -, dialkylamino C2-s, C6_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein each of C6_6 alkyl, C2_6 alkenyl, C_6 alkynyl, arylalkyl, cycloalkylalkyl,. heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2, 3, 4 or 5 halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, haloalkyl C, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, N02, 0Ra, SRa, C (0) Rb, C (0) NRcRd, C (0) 0Ra, 0C (0) Rb, 0C (0) NRcRd, NRcRd, NRcC (0) Rd, NRcC ( 0) ORa, NRcS (0) Rb, NRcS (0) 2Rb, S (0) Rb, S (0) NRcRd, S (0) 2Rb, or S (0) 2NRcRd; Ra and Ra are each independently, H, C? _6 alkyl, C? -6 haloalkyl, C2_6 alkenyl, C2_? Alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein alkyl C ? -6, C? _6 haloalkyl, C2_6 alkenyl, C2_6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C? -6 alkyl, haloalkyl C? ? -6, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; Rb and Rb 'are each independently, H, C? _6 alkyl, C? _6 haloalkyl, C _6 alkenyl, C2_6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C? _6 alkyl, C? _6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl , cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C? -6 alkyl, C? _6 haloalkyl, C? -6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; Rc and Rd are each independently, H, C? -? Alkyl, C? --6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the alkyl A-io, haloalkyl C6-6, alkenyl C2_6, alkynyl C2-6, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 0H3 amino, halo, alkyl C? _6, C6_6 haloalkyl, C6_6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or Rc and Rd together with the N atom to which they are bonded form a 4, 5, 6 or 7 membered heterocycloalkyl group; Rc and Rd 'are each independently, H, alkyl A-io, C6-C6 haloalkyl, C2_6 alkenyl, C2_6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C? -? _ alkyl, haloalkyl A-6, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C? -6 alkyl, C? _6 haloalkyl, C? -6 haloalkyl, aryl, arylalkyl , heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or Rc and Rd 'together with the N atom to which they are bonded form a heterocycloalkyl group of 4, 5, 6 or 7 members; Re is H, C ?4 alkyl, C ?4 haloalkyl, C2_4 alkenyl, C2_4 alkynyl, or CO- (C ?_4 alkyl); q is 1, 2, 3, 4, 5 or 6; ql e s O, 1, 2 or 3; and q2 is 0, 1, 2 or 3; with the conditions: when R21, R23 and R24 are each H, and R22 is Q, then Q is aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each substituted by at least one Cy1 and optionally substituted by 1, 2 or 3 A1; and when R21, R22 and R23 are each H, R22 is -L-Q and L is -C = C-, then Q is different from unsubstituted phenyl.

In some embodiments, R21 is H, C? -6 alkyl, C? _5 haloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C? -6 alkyl, C? -6 haloalkyl, aryl, heteroaryl, Arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4 or 5 R29. In some embodiments, R21 is H, C? -6 alkyl, haloalkyl A-6, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein each C? -6 alkyl, haloalkyl Ae, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, OH, C? -6 alkoxy, C1-6 haloalkoxy, C? _6 haloalkyl, C? -6 alkyl, C2_6 alkenyl, C2_6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl , heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. In some embodiments, R21 is C? -6 alkyl or C? -6 haloalkyl, each optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, OH, C? -6 alkoxy, C? _6 haloalkoxy, haloalkyl C? -6, C? -6 alkyl, C2_6 alkenyl, C2_6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl In some embodiments, R .21 is C? -6 alkyl or haloalkyl C 1-6 'In some embodiments, R21 is haloalkyl CX-6. In some embodiments, R21 is trifluromethyl. In some embodiments, R21 is H. In some embodiments, R22 is Q or -L-Q; and Q is aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally substituted by 1, 2 or 3 A1. In some embodiments, R22 is Q or -L-Q; and Q is aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each substituted by at least one Cy1 and optionally substituted by 1, 2 or 3 A1. In some embodiments, R22 is Q or -L-Q; and Q is aryl or heteroaryl, each substituted by at least one Cy1 and optionally substituted by 1, 2 or 3 A. In some embodiments, R22 is Q or -L-Q; and Q is aryl substituted by at least one Cy1 and optionally substituted by 1, 2 or 3 A1. In some embodiments, R22 is Q or -L-Q; and Q is phenyl substituted by at least one Cy1 and optionally substituted by 1, 2 or 3 A1. In some embodiments, R22 is Q or -L-Q; and Q is phenyl substituted by Cy1. In some embodiments, R22 is Q or -L-Q; Q is phenyl replaced by Cy1; and Cy1 is aryl or heteroaryl, each optionally substituted with 1, 2, 3, 4 or 5 A2. In some embodiments, R22 is Q or -L-Q; Q is phenyl substituted by Cy1; and Cy1 is aryl optionally substituted with 1, 2 or 3 substituents independently selected from halo, CN, OH, C6-6 alkoxy, C6-6 haloalkoxy, C6-6 haloalkyl, C6-6 alkyl, C2-6 alkenyl, C2_6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. In some embodiments, R22 is Q or -L-Q; Q is phenyl substituted by Cy1, wherein Cy1 is substituted at the meta position of the phenyl; and Cy1 is aryl optionally substituted with 1, 2 or 3 substituents independently selected from halo, CN, OH, C6-6 alkoxy, haloalkoxy A-6, haloalkyl C6-6, C6-6 alkyl, C2-6 alkenyl, C2_6 alkynyl , arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. In some embodiments, R22 is Q. In some embodiments, R is -L-Q; and L is C2-? o alkenylenyl or (CR27R28) q. In some embodiments, R22 is -L-Q; and L is (CR27R28) q. In some embodiments, R23, R24, R25 and R26 are independently, H, CN, C (0) Ra, C (0) ORb, C (0) NRcRd, alkyl C? -? O, haloalkyl A-io, C2-? 0 alkenyl, C2_? 0 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the alkyl A-io, haloalkyl A-io , C2- [alpha] alkenyl, C2- [alpha] alkenyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 R29. In some embodiments, R23, R24, R25 and R26 are independently, H, Si (C? -10) alkyl, CN, C (0) Ra, C (0) ORb, C (0) NRcRd, alkyl A-io , haloalkyl C? _? 0, C2_? 0 alkynyl C2_? alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C? -? alkyl, haloalkyl C? _? , C2-? or alkenyl, C2-? or alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 substituents independently selected from halo, C? - alkyl, haloalkyl C ? -4, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NRc'Rd ', NRc'C (0) Rd', NRc'C (0) ORa 'and NRC' S (O) 2Rb '. In some embodiments, R23, R24, R25 and R26 are independently, H, Si (C? -? O) alkyl, CN, C? -? O alkyl, haloalkyl A-io, C2_? alkenyl, C2-? alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein each of alkyl A-io, haloalkyl A-io, alkenyl C2- C2_? 0 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 substituents independently selected from halo, OH, C? _4 alkoxy, C? _4 alkyl, C? _4 haloalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. In some embodiments, R23 and R24 are independently, H, alkyl A-io, haloalkyl Ci-io, alkenyl C2_? O, alkynyl C2 -? _, Aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl. In some embodiments, R23 and R24 are independently, H or Ci-i alkyl. In some embodiments, R25 and R2d are independently, H, Si (C? -? 0 alkyl) 3, CN, C (0) Ra, C (0) ORb, C (0) NRcRd, C? -? Alkyl, C? -? Haloalkyl, C2-? Alkenyl, C2_? Alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or Heterocycloalkylalkyl. Compounds are also provided herein novelties of structural formula VI SAW. In some embodiments, R? 21 is H, C? -6 alkyl or C? -6 haloalkyl, each optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, OH, C? -6 alkoxy, haloalkoxy C? ? -6, C? -6 haloalkyl, C? -6 alkyl, C2-6 alkenyl, C2-6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl. In some embodiments, R21 is C? -6 alkyl or haloalkyl Cl-6- In some embodiments, R21 is haloalkyl C? -6- In some embodiments, Q is aryl, cycloalkyl, heteroaryl or heterocycloalkyl, each substituted by at least one Cy1 and optionally substituted by 1, 2 or 3 A1. In some embodiments, Q is aryl substituted by at least one Cy1 and optionally substituted by 1, 2 or 3 A1. In some embodiments, Q is phenyl substituted by at least one Cy1 and optionally substituted by 1, 2 or 3 A1. In some embodiments, Q is phenyl substituted by minus one Cy1 in the meta position and optionally substituted by 1, 2 or 3 A1. In some embodiments, R21 is H, C? -6 alkyl or C? -6 haloalkyl, each optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, OH, C? -6 alkoxy, haloalkoxy C? 6, C? -6 haloalkyl, C? -6 alkyl, C2-6 alkenyl, C-6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. In some embodiments, R21 is H, C6-6 alkyl or C6-6 haloalkyl. In some embodiments, R21 is H. In some embodiments, R23 and R24 are independently, H or Ci-io-alkyl- The present invention further provides compositions comprising a compound of any of the formulas described herein, or a pharmaceutically acceptable salt, tautomer or hydrolysable precursor thereof, and at least one pharmaceutically acceptable carrier, diluent or excipient. The present invention further provides methods for modulating the activity of BACE comprising contacting the BACE with a compound of any of the formulas described herein or pharmaceutically acceptable salt, tautomer or hydrolysable precursor thereof. The present invention also provides methods for treating or preventing an Aβ-related pathology in a patient, comprising administering to the patient a therapeutically effective amount of a compound of any of the formulas described herein, or a pharmaceutically acceptable salt, tautomer, or hydrolysable precursor thereof in vivo. The present invention further provides a compound of any of the formulas described herein, or a pharmaceutically acceptable in vivo hydrolysable salt, tautomer or precursor described herein for use as a medicament. The present invention further provides a compound of any of the formulas described herein, or a pharmaceutically acceptable salt, tautomer or hydrolysable precursor thereof, described herein for the manufacture of a medicament.

DETAILED DESCRIPTION OF THE INVENTION The novel compounds of structural formula I are provided herein: I or a salt, tautomer or hydrolysable precursor in vivo pharmaceutically acceptable thereof. In some embodiments, G is 0, NR7 or CR8R9, or any subgroup thereof. In some modalities, G is 0. In some modalities, G is NR7 or CR8R9. In some embodiments, R1 is H, C? _ Alkyl, C? _6 haloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, or any subgroup thereof, wherein C? -6 alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4 or 5 R14, or any subgroup thereof. In some modalities, R1 is H, C? -6 alkyl, C? _6 haloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C? -6 alkyl, C? -6 haloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl , cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4 or 5 R14. In some embodiments, R1 is H, C6_6 alkyl, C6_6 haloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein C6_6alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, OH, C? _6 alkoxy, C? _6 haloalkoxy, C? -6 haloalkyl, C? _6 alkyl, C2_6 alkenyl, C2_6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. In some embodiments, R1 is C6-C6 haloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein the aryl, heteroaryl, arylalkyl or heteroarylalkyl is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, OH, alkoxy C? ~ 6, haloalkoxy C? _6, haloalkyl C? _6, C? -6 alkyl, C2-b alkenyl, C2_6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. In some modalities, R2 is Q or -L-Q. In some embodiments, R2 is Q. In some embodiments, R2 is -L-Q. In some embodiments, R1 and R2 together with the carbon atom to which they bond form a cycloalkyl group of 3-14 members or heterocycloalkyl group of 3-14 members, each substituted by Cy2 and optionally substituted by 1, 2, 3, 4 or 5 A4, or any subgroup thereof. In some embodiments, R1 and R2 together with the carbon atom to which they bond form a cycloalkyl group of 3-14 members or heterocycloalkyl group of 3-14 members, each substituted by Cy2 and optionally substituted by 1, 2 or 3 A4 . In some embodiments, R1 and R2 together with the carbon atom to which they bond form a cycloalkyl group of 3-14 members substituted by Cy2 and optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, OH, C? -6 alkoxy, C? -6 haloalkoxy, C? -6 haloalkyl, C? -6 alkenyl C2_6 alkenyl, C2_6 alkynyl , arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. In some embodiments, R3, R4, R5 and R6 are, independently, H, CN, N02, 0Ra, SRa, OC (O) Ra, OC (0) ORb, OC (0) NRcRd, C (0) Ra, C (0) ORb, C (0) NRcRd, NRcRd, NRCC (O) Ra, NRA (0) ORb, NRcS (0) 2Rb, S (0) Ra, S (0) NRcRd, S (0) 2Ra, S (0) 2NRcRd, alkyl A-io, haloalkyl C? -? Or, C2_? 0 alkenyl, C2_? 0 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, or any subgroup thereof, wherein the alkyl A-io, haloalkyl C? -? or, C2_? alkenyl, C2_? 0 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 R14 , or any subgroup thereof. In some embodiments, R3, R4, R5 and R6 are independently, H, CN, C (0) Ra, C (0) 0Rb, C (0) NRcRd, C? -? Alkyl, C? _10 haloalkyl, C2 alkenyl -? 0, C2-? 0 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the alkyl A-1, haloalkyl A-io, C2_? alkenyl, C2_? 0 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 R14. In some embodiments, R3, R4, R5 and R6 are independently, H, CN, C (0) Ra, C (0) ORb, C (0) NRcRd, C? -? Alkyl, C? -10 haloalkyl, alkenyl C2-? O, C2-? Alkynyl or aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, iocycloalkylalkyl or heterocycloalkylalkyl, wherein the alkyl A-io, haloalkyl A-io, alkenyl C2-? _, Alkynyl C2-? _, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 substituents independently selected from halo, C? _ alkyl, C? _ haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NRc > Rd ', NRc'C (0) Rd', NRc'C (0) ORa 'and NRc's (0) 2Rb'. In some embodiments, R3, R4, R5 and R6 are independently, H. In some embodiments, R7 is H, C (0) Ra, C (0) ORb, C (0) NRcRd, S (0) Ra, S ( 0) 2Ra, Ci-io alkyl, C2-? O alkenyl, C2-? O alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, or any subgroup thereof, wherein the alkyl A-io, C2_10 alkenyl, C2-? or alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl are each optionally substituted with 1, 2, 3, 4 or 5 R14, or any subset of the same. In some embodiments, R7 is H, C? _? 0 alkyl, C? -? Haloalkyl, C2-? 0 alkenyl, C2-? Or alkynyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl or heterocycloalkylalkyl. In some embodiments, R8 and R9 are independently, H, CN, N02, ORa, SRa, OC (0) Ra, OC (0) ORb, C (0) ORb, OC (0) NRcRd, NRcRd, NRcC (0) Ra, NRcC (0) ORb, NRcS (0) 2Rb, S (O) Ra, S (0) NRcRd, S (0) 2Ra, S (0) 2NRcRd, C? -? 0 alkyl, C? -? Haloalkyl? 0, C2-? O alkenyl, C2_? 0 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, or any subgroup thereof, wherein the alkyl A-io, haloalkyl C? -? Or , C2-10 alkenyl, C2_2 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 R14, or any subgroup thereof. In some embodiments, R8 and R9 together with the carbon atom to which they bond form a cycloalkyl group of 3-14 heterocycloalkyl members of 3-14 members, each optionally substituted by 1, 2 or 3 R14. In some embodiments, R12 and R13 are each independently, H, halo, C? _ Alkyl, C? _ Haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, N02, 0Ra ', SRa', C (0) Rb ' , C (0) NRc'Rd ', C (0) ORa', OC (0) Rb ', OC (0) NRC' Rd ', NRc'Rd', NRc'C (0) Rd ', NRC'C (0) 0Ra ', NRC' S (0) 2Rb ', S (0) Rb', S (0) NRc'Rd ', S (0) 2Rb', or S (0) 2NRc'Rd ', or any subgroup of them. In some embodiments, R14 is halo, C? _ Alkyl, C? _ Haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, N02, 0Ra ', SRa', C (0) Rb ', C (0) NRc'Rd ', C (0) 0Ra', 0C (0) Rb ', 0C (0) NRc'Rd', NRc'Rd ', NRc'C (0) Rd', NRc'C (0) 0Ra ', NRC'S ( 0) 2Rb ', S (0) Rb', S (0) NRc'Rd ', S (0) 2Rb', or S (0) 2NRc'Rd ', or any subgroup thereof. In some embodiments, Q is aryl, cycloalkyl, heteroaryl or heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 Cy1 or A1, or any subgroup thereof. In some embodiments, Q is aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally substituted by 1, 2 or 3 A1. In some embodiments, Q is aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each substituted by at least one Cy1 and optionally substituted by 1, 2 or 3 A1. In some embodiments, Q is aryl or heteroaryl, each substituted by at least one Cy1 and optionally substituted by 1, 2 or 3 A1. In some embodiments, Q is aryl substituted by at least one Cy1 and optionally substituted by 1, 2 or 3 A1. In some embodiments, Q is phenyl substituted by at least one Cy1 and optionally substituted by 1, 2 or 3 A1. In some embodiments, Q is phenyl substituted by Cy1. In some embodiments, Q is phenyl substituted by Cy1, wherein Cy1 is substituted at the meta position of the phenyl. In some embodiments, Q is aryl or heteroaryl, each optionally substituted by 1, 2 or 3 A1. In some embodiments, L is C2_? O-alkynylenyl C2-? O, (CR12R13) q, (CR12R13) qlO (CR12R13) q2, (CR12R13) qlS (CR12R13) q2, (CR12R13) qlS02 (CR12R13) q2, (CR12R13) q? SO (CR12R13) q2, (CR12R13) q? C0 (CR12R13) q2, (CR12R13) q? NRe (CR12R13) q2, or (CR12R13) q? CONRe (CR12R13) q2, or any subgroup thereof. In some embodiments, L is C2-? Alkenylenyl, C2-? Alkynynyl or o (CR12R13) q. In some modalities, L is (CR12R13) q. In some embodiments, Cy1 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, or any subgroup thereof, each optionally substituted with 1, 2, 3, 4 or 5 A2, or any subgroup thereof. In some embodiments, Cy1 is aryl or heteroaryl, each optionally substituted with 1, 2, 3, 4 or 5 A2. In some embodiments, Cy1 is aryl optionally substituted with 1, 2 or 3 substituents independently selected from halo, CN, OH, C6-6 alkoxy, haloalkoxy A-e, haloalkyl C6-6, alkyl A-β, C 2-6 alkenyl, C 2-6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. In some embodiments, Cy2 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, or any subgroup thereof, each optionally substituted with 1, 2, 3, 4 or 5 A3, or any subgroup thereof. In some embodiments, Cy2 is aryl or heteroaryl, each optionally substituted with 1, 2, 3, 4 or 5 A3. In some embodiments, Cy2 is aryl or heteroaryl, each optionally substituted with 1, 2 or 3 A3. In some embodiments, Cy2 is phenyl substituted with 1 or 2 A3. In some embodiments, A1 is halo, CN, N02, 0Ra, SRa, C (0) Rb, C (0) NRcRd, C (0) ORa, 0C (0) Rb, OC (0) NRcRd, NRcRd, NRcC ( 0) Rd, NRcC (0) ORa, NRcS (0) Rb, NRcS (0) 2Rb, S (0) Rb, S (0) NRcRd, S (0) 2Rb, S (0) 2NRcRd, alkoxy C? _4 , haloalkoxy A-, amino, alkylamino C? -, dialkylamino C2-8? C6_6alkyl, C2_6alkenyl, C2_6alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl, or any subgroup thereof, wherein each of C6_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4 or 5 halo, C? -6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C? _4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, N02, 0Ra, SRa, C (0) Rb, C (0) NRcRd, C (0) ORa, OC (0) Rb, 0C (0) NRcRd, NRcRd, NRcC (0) Rd, NRA (0) ORa, NRcS (0) Rb, NRcS (0) 2Rb, S (0) Rb, S (0) NRcRd, S (0) 2Rb, or S (0) 2NRcRd, or any subgroup thereof. In some embodiments, A2, A3, and A4 are each independently, halo, CN, N02, 0Ra, SRa, C (0) Rb, C (0) NRcRd, C (0) OR3, OC (0) Rb, OC (0) NRcRd, NRcRd, NRcC (0) Rd, NRcC (0) ORa, NRcS (0) Rb, NRcS (0) 2Rb, S (0) Rb, S (0) NRcRd, S (0) 2Rb, S (0) 2NRcRd, C 1 -4 alkoxy, C 1 -4 haloalkoxy, amino, C 1 -C 8 alkylamino, C 2-8 dialkylamino, C 6 alkyl, C 2 6 alkenyl, C 2 6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl , heteroaryl or heterocycloalkyl, or any subgroup thereof, wherein each of alkyl A-6, C2-6 alkenyl, C2-6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2, 3, 4 or 5 halo, C? -6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C? _ haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, N02, ORa, SRa, C (O) Rb , C (0) NRcRd, C (0) ORa, OC (0) Rb, OC (0) NRcRd, NRcRd, NRA (0) Rd, NRcC (0) ORa, NRc S (0) Rb, NRcS (0) 2Rb, S (0) Rb, S (0) NRcRd, S (0) 2Rb, or S (0) 2NRcRd, or any subgroup thereof. In some embodiments, A3 is aryl or heteroaryl, each optionally substituted with 1, 2 or 3 substituents independently selected from halo, CN, OH, C6-6 alkoxy, C6-6 haloalkoxy, C6-6 haloalkyl, C6-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. In some embodiments, Ra and Ra 'are each independently, H, C? -6 alkyl, C? _6 haloalkyl, C2_6 alkenyl, C2_6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, or any subgroup thereof, wherein the C? _6 alkyl, C? -6 haloalkyl, C2_6 alkenyl, C2_6 alkynyl? aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C? _6 alkyl, C? -6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl, or any subgroup of them. In some embodiments, Rb and Rb 'are each independently, H, C? -6 alkyl, C? _6 haloalkyl, C2_6 alkenyl, C2_? Alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, or any subgroup thereof, wherein the alkyl A-6, haloalkyl C? -6, alkenyl C2-6, alkynyl C2-6? aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C? -alkyl, C? -6 haloalkyl, haloalkyl A-6, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl, or any subgroup thereof. In some embodiments, R c and R d are each independently, H, alkyl A-io, haloalkyl C? -6, alkenyl C2_6, alkynyl C2_6, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, or any subgroup thereof, wherein the alkyl A-io, haloalkyl C6-6, C2_6 alkenyl, C2.6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo , C_6 alkyl, C6_6 haloalkyl, C6_6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl, or any subgroup thereof. In some embodiments, Rc and Rd together with the N atom to which they bond form a heterocycloalkyl group of 4, 5, 6 or 7 members. In some modalities, Rc 'and Rd' are each independently, H, C? -? - alkyl, C? --6 haloalkyl, C2-6 alkenyl, C2_6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, or any subgroup thereof, wherein the alkyl A-io, haloalkyl C6-6, alkenyl C2_6, alkynyl C2-6, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, alkyl C? _5, C? -6 haloalkyl, C? _6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl, or any subgroup thereof. In some embodiments, Rc 'and Rd together with the N atom to which they are linked form a 4, 5, 6 or 7 membered heterocycloalkyl group, or any subgroup thereof. In some embodiments, Re is H, C? _4 alkyl, C? _4 haloalkyl, C2_4 alkenyl, C2_4 alkynyl, or CO- (C? -4 alkyl), or any subgroup thereof. In some modalities, q is 1, 2, 3, 4, 5 or 6, or any subgroup thereof. In some modalities, q is 2. In some modalities, ql is 0, 1, 2 or 3, or any subgroup thereof. In some modalities, q2 is 0, 1, 2 or 3, or any subgroup of them. When G is NH or CH2, R2 is -L-Q, L is -CH2, -CH = CH-, or -C = C-, and R1 is H or methyl, however, then Q is different from unsubstituted phenyl. When G is NR7 or CR8R9, R7 is H, methyl, or phenyl optionally substituted by halo, R8 and R9 are each independently, H or methyl, R2 is Q, and R1 is H or methyl, however, then Q is aryl , cycloalkyl, heteroaryl, or heterocycloalkyl, each substituted by at least one Cy3 and optionally substituted by 1, 2 or 3 A4. In some embodiments, R2 is Q or -L-Q; and Q is aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally substituted by 1, 2 or 3 A1. In some embodiments, R2 is Q or -L-Q; and Q is aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each substituted by at least one Cy1 and optionally substituted by 1, 2 or 3 A1. In some embodiments, R2 is Q or -L-Q; and Q is aryl or heteroaryl, each substituted by at least one Cy1 and optionally substituted by 1, 2 or 3 A1. In some embodiments, R2 is Q or -L-Q; and Q is aryl substituted by at least one Cy1 and optionally substituted by 1, 2 or 3 A1. In some embodiments, R2 is Q or -L-Q; and Q is phenyl substituted by at least one Cy1 and optionally substituted by 1, 2 or 3 A1. In some embodiments, R2 is Q or -L-Q; and Q is phenyl substituted by Cy1. In some embodiments, R2 is Q or -L-Q; Q is phenyl substituted by Cy1; and Cy1 is aryl or heteroaryl, each optionally substituted with 1, 2, 3, 4 or 5 A2. In some modalities, R2 is Q or -L-Q; Q is phenyl substituted by Cy1; and Cy1 is aryl optionally substituted with 1, 2 or 3 substituents independently selected from halo, CN, OH, C6_6alkoxy, C6_6 haloalkoxy, C6_6haloalkyl, C6_6alkyl, C2_6alkenyl, C2_6alkynyl , arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. In some embodiments, R2 is Q or -L-Q; Q is phenyl substituted by Cy1, wherein Cy1 is substituted at the meta position of the phenyl; and Cy1 is aryl optionally substituted with 1, 2 or 3 substituents independently selected from halo, CN, OH, alkoxy A-6, haloalkoxy C? -6, haloalkyl C? _6, alkyl C? _6, alkenyl C2_6, alkynyl C2-6 , arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. In some embodiments, R2 is -L-Q; and L is C2_? alkenylenyl, C2-? alkynynyl or o (CR12R13) q.

In some embodiments, R2 is -L-Q; and L is C2-? 0 alkenylenyl, C2-10 alkynynyl or (CR12R13) q. In some embodiments, R2 is -L-Q; and L is (CR12R13) q. In some embodiments, R2 is -L-Q; L is (CR12R13) q; and q is 2. In some embodiments, R1 and R2 together with the carbon atom to which they bond form a cycloalkyl group of 3-14 members or heterocycloalkyl group of 3-14 members, each substituted by Cy2 and optionally substituted by 1, 2 or 3 A4; and Cy2 is aryl or heteroaryl, each optionally substituted with 1, 2, 3, 4 or 5 A3. In some embodiments, R1 and R2 together with the carbon atom to which they bond form a 3-14-membered cycloalkyl group substituted by Cy2 and optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, OH, alkoxy C ? -6, haloalkoxy C? -6, haloalkyl C? -6, C? -6 alkyl, C2_6 alkenyl, C2_6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl; Cy2 is aryl or heteroaryl, each optionally substituted with 1, 2 or 3 A3; and A3 is aryl or heteroaryl, each optionally substituted with 1, 2 or 3 substituents independently selected from halo, CN, OH, C 1-6 alkoxy, C? -6 haloalkoxy, C? -6 haloalkyl, C? _ Alkyl, C2-C2 alkenyl C2_6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. In some embodiments, R1 and R2 together with the carbon atom to which they bond form a 3-14 membered cycloalkyl group substituted by Cy2 and optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, OH, alkoxy , haloalkoxy C6-6, haloalkyl C6-6, C6-6alkenylC2_6 alkenyl, C2_6alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl; Cy2 is phenyl substituted with 1 or 2 A3; and A3 is aryl or heteroaryl, each optionally substituted with 1, 2 or 3 substituents independently selected from halo, CN, OH, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 haloalkyl, C 1-6 alkenyl, C 2-6 alkenyl , C2-6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. In some embodiments, R4 is CN, C (0) Ra, C (0) ORb, C (0) NRcRd, alkyl C? _? 0, haloalkyl C? _? 0, alkenyl C2_? O, alkynyl C2 _? _, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the alkyl X-io, haloalkyl C? -? o. C2_? alkenyl, C2-? 0 alkynyl, aryl, cycloalkyl, heteroaryl, Heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 substituents independently selected from halo, C 1 -ChaloalkylCi_alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NRc'Rd ', NRcX ( ) Rd ', NRcX (0) ORa' and NRC'S (0) 2Rb '. In some embodiments, G is NR7 or CR8R9; and R7, R8 and R9 are each independently, H, C? _? _ alkyl, C? -? halo or C2-? alkenyl, C2_? 0 alkynyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl or heterocycloalkyl alkyl. In some embodiments, R1 is C6-C6 haloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein the aryl, heteroaryl, arylalkyl or heteroarylalkyl is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, OH, alkoxy C? _6, C? -6 haloalkoxy, C? -6 haloalkyl, C? _6 alkyl, C2_6 alkenyl, C2_6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl; R2 is Q; and Q is aryl or heteroaryl, each optionally substituted by 1, 2 or 3 A1. Compounds are also provided herein novelties of structural formula II II or a salt, tautomer or pharmaceutically acceptable in vivo hydrolysable precursor thereof. In some embodiments, R1 is H, alkyl 0_6, haloalkyl 0-6, aryl, heteroaryl, arylalkyl or heteroarylalkyl, or any subgroup thereof, wherein the alkyl 0_6, aryl, heteroaryl, arylalkyl or heteroarylalkyl is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, OH, 0_6 alkoxy, 0_6 haloalkoxy, 0-6 haloalkyl, 0_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl , or any subgroup thereof. In some embodiments, L is 0-4 alkylenyl. In some embodiments, L is CH2CH2. In some embodiments, n is 0 or 1. In some embodiments, Cy3 is aryl or heteroaryl, each optionally substituted with 1, 2 or 3 substituents independently selected from halo, CN, OH, 0_6alkoxy, haloalkoxy 0-6, haloalkyl 0 -6, alkyl 0-6, C2-6 alkenyl, C2-6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl, or any subgroup thereof. In some embodiments, Cy3 is aryl optionally substituted with 1, 2 or 3 substituents independently selected from halo, CN, OH, 0_6 alkoxy, 0_6 haloalkoxy, 0-6 haloalkyl, 0_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl , heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. In some embodiments, L is CH2CH2; and Cy3 is aryl optionally substituted with 1, 2 or 3 substituents independently selected from halo, CN, OH, alkoxy 0-6, haloalkoxy 0-6, haloalkyl 0_6, alkyl -6, C2_6 alkenyl, C2_6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl , heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. The novel compounds of the formula Illa or structural formula Illb are provided herein: Ola Hlb or a salt, tautomer or hydrolysable precursor in vivo pharmaceutically acceptable thereof. In some embodiments, r is 0, 1, 2 or 3. In some embodiments, Cy 4 is aryl optionally substituted with 1, 2 or 3 substituents independently selected from halo, CN, OH, C 1-6 alkoxy, halo C 1-6 alkoxy, haloalkyl C6-6, alkyl A-β, C2-6 alkenyl, C2_6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl, or any subgroup thereof. The novel compounds of the formula are provided herein IVa IV or a salt, tautomer or pharmaceutically acceptable in vivo hydrolysable precursor thereof. In some embodiments, r is 0, 1, 2 or 3. In some embodiments, Cy 4 is aryl optionally substituted with 1, 2 or 3 substituents independently selected from halo, CN, OH, C 1-6 alkoxy, halo C 1-6 alkoxy, C6-6 haloalkyl, C6-6 alkyl, C2-6 alkenyl, C2_6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl, or any subgroup thereof. Also provided herein are the novel compounds of structural formula V: V or a salt, tautomer or pharmaceutically acceptable in vivo hydrolysable precursor thereof. In some embodiments, R21 is H, C? _6 alkyl, haloalkyl A-6, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, or any subgroup thereof, wherein C? -6 alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4 or 5 R29, or any subgroup thereof. In some embodiments, R21 is H, C? _6 alkyl, C? _6 haloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C? _6 alkyl, C? _6 haloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4 or 5 R29. In some embodiments, R21 is H, C? _6 alkyl, C? -6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein each of C? -6 alkyl, C? _ Haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, OH, C6-6 alkoxy, C6-6 haloalkoxy, C6-6 haloalkyl, C6-6 alkyl, C2-6 alkenyl, C2- alkynyl 6, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. In some embodiments, R21 is C? _6 alkyl or C? _6 haloalkyl, each optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, OH, C? _6 alkoxy, C? _6 haloalkoxy, haloalkyl A-6 , C 1 -C 6 alkyl, C 2 6 alkenyl, C 2-6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. In some embodiments, R21 is C? _6 alkyl or C? _6 haloalkyl. In some embodiments, R21 is haloalkyl C? -6- In some embodiments, R21 is trifluromethyl. In some embodiments, R21 is H. In some embodiments, R22 is Q or -L-Q. In some modalities, R22 is Q. In some modalities, R22 is -L-Q. In some embodiments, R23, R24, R2S and R26 are independently, H, Si (alkyl C? -? 0) 3, CN, N02, 0Ra, SRa, OC (0) Ra, OC (0) ORb, OC (0 ) NRcRd, C (0) Ra, C (0) ORb, C (0) NRcRd, NRcRd, NRcC (0) Ra, NRcC (0) ORb, NRcS (0) 2Rb, S (0) Ra, S (0) ) NRcRd, S (0) 2Ra, S (0) 2NRcRd, Ci-io alkyl, Ci-iohaloalkyl, C2-? O alkenyl, C2_? Al alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, or any subgroup thereof, wherein the C C-βalkyl, C?-βalkyl, C2_? alkenyl, C2- o alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 R29, or any subgroup thereof. In some embodiments, R23, R24, R25 and R26 are independently, H, CN, C (0) Ra, C (0) ORb, C (0) NRcRd, C alquilo-0 0 alkyl, haloalkyl A-io, C2 alkenyl -?, C2_? alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C? -? o alkyl, C? _? 0 haloalkyl, C2-? 0 alkenyl, C2 alkynyl -? 0, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 R29. In some embodiments, R23, R24, R25 and R26 are independently, H, Si (C? _? 0) 3 alkyl, CN, C (0) Ra, C (0) ORb, C (0) NRcRd, Ci- io, Ci-io haloalkyl, C2-io alkenyl, C2-? or alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C? -? o alkyl, C? -? haloalkyl? or, C2-? or alkenyl, C2-? or alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 substituents independently selected from halo, C? _ alkyl, haloalkyl C? _, Aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NRc'Rd ', NRc'C (0) Rd', NRc'C (0) ORa 'and NRC' S (O) 2Rb '. In some embodiments, R23, R24, R25, and R26 are independently, H, Si (C? _? 0) alkyl, CN, C? -? Alkyl, C? _? Haloalkyl, C2_? Alkenyl, C2_ alkynyl, Or, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein each of C? -? _ alkyl, haloalkyl A-io, C2_? alkenyl, C2_? alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 substituents independently selected from halo, OH, C? _ alkoxy, C? _ alkyl, C? _4 haloalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. In some embodiments, R23 and R24 are independently, H, Ci-io alkyl, C? _? Halo haloalkyl, C2- 0 0 alkenyl, C2_? 0 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl . In some embodiments, R23 and R24 are independently, H or C? _? 0 alkyl. In some embodiments, R25 and R26 are independently, H, Si (C? -? 0 alkyl) 3, CN, C (0) Ra, C (0) ORb, C (0) NRcRd, alkyl A-io, haloalkyl Ci -io, C2_? 0 alkenyl, C2_? alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl. In some embodiments, R27 and R28 are each independently, H, halo, C? -4 alkyl, C? - haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, N02, ORa ', SRa', C (0) Rb ', C (0) NRc'Rd', C (0) ORa ', OC (0) Rb', OC (O) NRC 'Rd', NRc'Rd ', NRcC (0) Rd', NRC 'C ( O) ORa ', NRC' S (O) 2Rb ', S (O) Rb', S (0) NRc'Rd ', S (0) 2Rb', or S (0) 2NRc'Rd ', or any subgroup thereof. In some embodiments, R29 is halo, C? - alkyl, C? _4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, N02, ORa ', SRa', C (0) Rb ', C (0) NRc'Rd ', C (0) ORa', 0C (0) Rb ', OC (0) NRc'Rd', NRc'Rd ', NRc'C (0) Rd', NRcA (0) ORa ', NRC'S (0) 2Rb ', S (0) Rb', S (0) NRc'Rd ', S (0) 2Rb', or S (O) 2NRc'Rd ', or any subgroup thereof. In some embodiments, Q is aryl, cycloalkyl, heteroaryl or heterocycloalkyl, or any subgroup thereof, each optionally substituted by 1, 2, 3, 4 or 5 Cy1 or A1. In some embodiments, Q is aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally substituted by 1, 2 or 3 A1. In some embodiments, Q is aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each substituted by at least one Cy1 and optionally substituted by 1, 2 or 3 A1. In some embodiments, Q is aryl or heteroaryl, each substituted by at least one Cy1 and optionally substituted by 1, 2 or 3 A1. In some embodiments, Q is aryl substituted by at least one Cy1 and optionally substituted by 1, 2 or 3 A1. In some embodiments, Q is phenyl substituted by at least one Cy1 and optionally substituted by 1, 2 or 3 A1. In some embodiments, Q is phenyl substituted by Cy1. In some embodiments, Q is phenyl substituted by Cy1. In some embodiments, Q is phenyl substituted by Cy1. In some embodiments, Q is phenyl substituted by Cy1, wherein Cy1 is substituted at the meta position of the phenyl. In some embodiments, L is C2_? Alkenylenyl, C2-? Alkynynyl, or, (CR27R28) q, (CR27R28) qlO (CR27R28) q2, (CR2R28) qlS (CR27R28) q2, (CR27R28) qlS02 (CR27R28) q2, (CR27R28) q? SO (CR27R28) q2, (CR27R28) q? CO (CR27R28) q2, (CR27R28) qlNRACR27R28) q2, or (CR27R28) q? CONRACR27R28) q2; or any subgroup thereof. In some embodiments, L is alkenylenyl C2-? O or (CR27R28) q. In some modalities, L is (CR2R28) q. In some embodiments, Cy1 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, or any subgroup thereof, each optionally substituted with 1, 2, 3, 4 or 5 A2, or any subgroup thereof. In some embodiments, Cy1 is aryl or heteroaryl, each optionally substituted with 1, 2, 3, 4 or 5 A2. In some embodiments, Cy1 is aryl optionally substituted with 1, 2 or 3 substituents independently selected from halo, CN, OH, C? -6 alkoxy, C? _6 haloalkoxy, C? -ha haloalkyl, C? _6 alkyl, C2_6 alkenyl, C2_6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. In some embodiments, A1 is halo, CN, N02, ORa, SRa, C (0) Rb, C (0) NRcRd, C (0) ORa, OC (0) Rb, OC (0) NRcRd, NRcRd, NRcC ( 0) Rd, NRcC (0) ORa, NRCS (O) Rb, NRcS (0) 2Rb, S (O) Rb, S (0) NRcRd, S (0) 2Rb, S (0) 2NRcRd, C 1 alkoxy- 4, C? -4 halo-haloalkoxy, amino, C? -4 alqu alkylamino, C dial_ dial dialkylamino, C? _ _ Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl, or any subgroup thereof, wherein each of alkyl C? -6, C2-6 alkenyl, C2-6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4 or 5 halo, C6-6alkyl, C2-6alkenyl, C2-6alkynylC haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, N02, 0Ra , SRa, C (0) Rb, C (0) NRcRd, C (0) ORa, OC (0) Rb, OC (0) NRcRd, NRcRd, NRcC (0) R, NRA (0) ORa, NRcS (0) ) Rb, NRcS (0) 2Rb, S (0) Rb, S (0) NRcRd, S (0) 2Rb, or S (0) 2NRcRd, or any subgroup thereof. In some embodiments, A2 is halo, CN, N02, 0Ra, SRa, C (0) Rb, C (0) NRcRd, C (0) ORa, OC (0) Rb, OC (0) NRcRd, NRcRd, NRA ( 0) Rd, NRA (0) ORa, NRcS (0) Rb, NRcS (0) 2Rb, S (0) Rb, S (0) NRcRd, S (0) 2Rb, S (0) 2NRcRd, alkoxy Cx_4, haloalkoxy C? _4, amino, alkylamino C? _4, dialkylamino C2-8? C? _ alkyl, C2_6 alkenyl, C2_6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, or any subgroup thereof, wherein each of C? -6 alkyl, C2_6 alkenyl, alkynyl C2__, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2, 3, 4 or 5 halo, C 1 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, haloalkyl C ? _, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, N02, ORa, SRa, C (0) Rb, C (0) NRcRd, C (0) ORa, OC (0) Rb, OC (0) NRcRd, NRcRd , NRcC (0) Rd, NRcC (0) ORa, NRcS (0) Rb, NRcS (0) 2Rb, S (O) Rb, S (0) NRcRd, S (0) 2Rb, or S (0) 2NRcRd, or any subgroup thereof In some embodiments, Ra and Ra are each independently, H, C? _6 alkyl, C? _6 haloalkyl, C2_6 alkenyl, C2_? Alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, or any subgroup thereof, wherein the C C_6 alkyl, C ?_6 haloalkyl, C2_6 alkenyl, C2_6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C? _6 alkyl, C? -6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl, or any subgroup thereof. In some embodiments, Rb and Rb 'are each independently, H, C? -6 alkyl, C? _6 haloalkyl, C2_6 alkenyl, C2_6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, or any subgroup thereof, wherein the C C_6 alkyl, C ?_6 haloalkyl, C2_6 alkenyl, C2_6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C? _6 alkyl, C? -6 haloalkyl, C? _6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl, or any subgroup thereof. In some embodiments, Rc and Rd are each independently, H, alkyl A-io, haloalkyl C6-6, C2-b alkenyl, C2_6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, or any subgroup thereof, wherein the alkyl A-io, haloalkyl C6-6, alkenyl C2_6, alkynyl C2-6, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C? -6 alkyl, C? _6 haloalkyl, haloalkyl A-6, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl, or any subgroup thereof. In some embodiments, Rc and Rd together with the N atom to which they are linked form a 4, 5, 6 or 7 membered heterocycloalkyl group, or any subgroup thereof. In some embodiments, Rc 'and R' are each independently, H, alkyl A-io, haloalkyl C6-6, alkenyl- ?, C2_6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, or any subgroup thereof, wherein the alkyl A-io, haloalkyl C6-6, C2-6 alkenyl, C2_6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C? _6 alkyl , C? -6 haloalkyl, C? _6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl, or any subgroup thereof. In some embodiments, Rc 'and Rd' together with the N atom to which they are attached form a 4, 5, 6 or 7 membered heterocycloalkyl group, or any subgroup thereof. In some embodiments, Re is H, C? _ Alkyl, C? - haloalkyl, C2_ alkenyl, C2_4 alkynyl, or CO- (C? -4 alkyl), or any subgroup thereof. In some modalities, q is 1, 2, 3, 4, 5 or 6, or any subgroup thereof. In some modalities, ql is 0, 1, 2 or 3, or any subgroup thereof. In some modalities, q2 is 0, 1, 2 or 3, or any subgroup thereof. When R21, R23 and R24 are each H, and R22 is Q, however, then Q is aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each substituted by at least one Cy and optionally substituted by 1, 2 or 3 A1. When R21, R23 and R24 are each H, R22 is -L-Q and L is - C = C-, however, then Q is different from unsubstituted phenyl. In some embodiments, R22 is Q or -L-Q; and Q is aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally substituted by 1, 2 or 3 A1. In some embodiments, R22 is Q or -L-Q; and Q is aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each substituted by at least one Cy1 and optionally substituted by 1, 2 or 3 A1. In some embodiments, R22 is Q or -L-Q; and Q is aryl or heteroaryl, each substituted by at least one Cy1 and optionally substituted by 1, 2 or 3 A1. In some embodiments, R22 is Q or -L-Q; and Q is aryl substituted by at least one Cy1 and optionally substituted by 1, 2 or 3 A1. In some embodiments, R22 is Q or -L-Q; and Q is phenyl substituted by at least one Cy1 and optionally substituted by 1, 2 or 3 A1. In some embodiments, R22 is Q or -L-Q; and Q is phenyl substituted by Cy1. In some embodiments, R22 is Q or -L-Q; Q is phenyl substituted by Cy1; and Cy1 is aryl or heteroaryl, each optionally substituted with 1, 2, 3, 4 or 5 A2. In some embodiments, R22 is Q or -L-Q; Q is phenyl substituted by Cy1; and Cy1 is optionally substituted aryl with 1, 2 or 3 substituents independently selected from halo, CN, OH, C? -alkoxy, C? -6 haloalkoxy, C? -6 haloalkyl, C? _6 alkyl, C2? alkenyl, C2-6 alkynyl, arylalkyl, cycloalkylalkyl , heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. In some embodiments, R22 is Q or -L-Q; Q is phenyl substituted by Cy1, wherein Cy1 is substituted at the meta position of the phenyl; and Cy 1 is aryl optionally substituted with 1, 2 or 3 substituents independently selected from halo, CN, OH, C 1-6 alkoxy, C 1-6 haloalkoxy, C? -6 haloalkyl, C? _6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl Arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. In some embodiments, R22 is Q. In some embodiments, R22 is -L-Q; and L is C2-? o alkenylenyl or (CR27R28) q. In some embodiments, R22 is -L-Q; and L is (CR27R28) q. In some embodiments, R23, R24, R25 and R26 are independently, H, CN, C (0) Ra, C (0) ORb, C (0) NRcRd, C? -10 alkyl, C1-10 haloalkyl, C2_ alkenyl? or, C2_? alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the alkyl A-1, haloalkyl Ci-io, C2_? alkenyl, C2_? 0 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 R29. In some modalities, R23, R24, R25 and R26 are independently, H, Si (C? -? _) Alkyl 3, CN, C (0) Ra, C (0) ORb, C (0) NRcRd, C? -10 alkyl, haloalkyl C? -? 0, C2_? 0 alkenyl, C2-? 0 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein Ci_io alkyl, C? -? haloalkyl, alkenyl C2_? O, C2_? 0 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 substituents independently selected from halo, C? _4 alkyl, C? - haloalkyl, aryl , cycloalkyl, heteroaryl, heterocycloalkyl, CN, NRC Rd ', NRcX (0) Rd', NRcX (0) ORa 'and NRC' S (O) 2Rb '. In some embodiments, R23, R24, R25 and R26 are independently, H, Si (C? _? 0) alkyl, CN, C? -? Alkyl, C? _? 0 haloalkyl, C2_? 0 alkenyl, C2_ alkynyl, or, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein each of alkyl X-io, haloalkyl X-io, C2_? alkenyl, C2-? al alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 0 3 substituents independently selected from halo, OH, C? _4 alkoxy, C? _4 alkyl, C? _ Haloalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. In some embodiments R 23 and R 2 are independently, H, C? -? - alkyl, C? _? _ Haloalkyl, C2-? 0 alkenyl, C2_? 0 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl , cycloalkylalkyl or heterocycloalkylalkyl. In some embodiments, R23 and R24 are independently, H or C? -? _ Alkyl. In some embodiments, R25 and R26 are independently, H, Si (C? _? O) alkyl, CN, C (0) Ra, C (0) ORb, C (0) NRcRd, C? -10 alkyl, haloalkyl C 1, C 2 alkenyl, C 2 0 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl. Also provided here are the Novel compounds of structural formula VI SAW or a salt, tautomer or pharmaceutically acceptable in vivo hydrolysable precursor thereof. In some embodiments, R21 is H, C? _6 alkyl or haloalkyl Ae, each optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, OH, C? -6 alkoxy, C? -6 haloalkoxy, haloalkyl C ? -6, C? _6 alkyl, C2_6 alkenyl, C2_6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, or any subgroup thereof. Other variables are as described above. In some embodiments, R21 is C? -6 alkyl or C? _6 haloalkyl. In some embodiments, R21 is haloalkyl C? _ 6. In some embodiments, R21 is H, C? -6 alkyl or C? -6 haloalkyl, or any subgroup thereof, each optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, OH, C6_6 alkoxy, C6_6 haloalkoxy, C6_6 haloalkyl, C6_6 alkyl, C2_6 alkenyl, C2-6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl, or any subgroup thereof. In some embodiments, R21 is H, C? _6 alkyl or C? _6 haloalkyl, or any subgroup thereof. In some embodiments, R21 is H. In some embodiments, Q is aryl, cycloalkyl, heteroaryl or heterocycloalkyl, or any subgroup thereof, each substituted by at least one Cy1 and optionally substituted by 1, 2 or 3 A1. In some embodiments, Q is aryl substituted by at least one Cy1 and optionally substituted by 1, 2 or 3 A1. In some embodiments, Q is phenyl substituted by at least one Cy1 and optionally substituted by 1, 2 or 3 A1. In some embodiments, Q is phenyl substituted by at least one Cy1 in the meta position and optionally substituted by 1, 2 or 3 A1. In some embodiments, R23 and R24 are independently H or C? _? 0 alkyl. The compounds of the invention include, for example: 3- (3'-methoxybiphenyl-3-yl) -3,4-dihydroisoquinolin-1-amine trifluoroacetate; 3- (3-bromophenyl) -3,4-dihydroisoquinolin-1-amine trifluoroacetate; 3-Biphenyl-3-yl-3,4-dihydroisoquinolin-1-amine trifluoroacetate; trifluoroacetate 3-Phenyl-3- (trifluoromethyl) -3,4-dihydroisoquinolin-1-amine; 3- (3'-Methoxybiphenyl-3-yl) -3- (trifluoromethyl) -3,4-dihydroisoquinol? n-l-amine trifluoroacetate; 3- (3-bromophenyl) -3- (trifluoromethyl) -3,4-dihydroisoquinolin-1-amine trifluoroacetate; 3- (3-Chlorophenyl) -3-phenyl-3,4-dihydroisoquinolin-1-amine trifluoroacetate; 3- (3'-Methoxybiphenyl-3-yl) -3-phenyl-3,4-dihydroisoquinolin-1-amine trifluoroacetate; 3- (3-bromophenyl) -3-phenyl-3,4-dihydroisoquinolin-1-amine trifluoroacetate; 3- (3'-Methoxybiphenyl-3-yl) -3-methyl-3,4-dihydroisoquinolin-1-amine trifluoroacetate; 3- (3-bromophenyl) -3-methyl-3,4-dihydroisoquinolin-1-amine; 3- (3-bromophenyl) -1- (ethylthio) -3-methyl-3,4-dihydroisoquinoline; 3-Biphenyl-3-yl-3-methyl-3,4-dihydroisoquinolin-1-amine trifluoroacetate; 3- [2- (3'-Methoxybiphenyl-3-yl) ethyl] -3-methyl-3,4-dihydroisoquinolin-1-amine trifluoroacetate; 3- [2- (3-bromophenyl) ethyl] -3-methyl-3,4-dihydroisoquinolin-1-amine trifluoroacetate; 3- [2- (3'-Methoxybiphenyl-3-yl) ethyl] -3-phenyl-3, -dihydroisoquinolin-1-amine trifluoroacetate; N- trifluoroacetate. { [L-Amino-3-phenyl-3- (trifluoromethyl) -3,4-dihydroisoquinolin-6-yl] methyl} methanesulfonamide; N- trifluoroacetate. { [L-Amino-3-phenyl-3- (trifluoromethyl) -3,4-dihydroisoquinolin-6-yl] methyl} acetamide; 6- (Aminomethyl) -3-phenyl-3- (trifluoromethyl) -3,4-dihydroisoquinolin-1-amine bis trifluoroacetate; 3-Phenyl-6- (1H-tetrazol-5-yl) -3- (trifluoromethyl) -3,4-dihydroisoquinoline-1-amine trifluoroacetate; l-Amino-3-phenyl-3- (trifluoromethyl) -3,4-dihydroisoquinoline-6-carboxylic acid trifluoroacetate; L-Amino-3-phenyl-3- (trifluoromethyl) -3,4-dihydroisoquinoline-6-carbonitrile HCl salt; l-Amino-3- (3'-methoxybiphenyl-3-yl) -3- (trifluoromethyl) -3,4-dihydroisoquinoline-6-carboxamide trifluoroacetate; l-Amino-3- (3-bromophenyl) -3- (trifluoromethyl) -3-dihydroisoquinoline-6-carboxamide trifluoroacetate; l-Amino-3- (3'-methoxybiphenyl-3-yl) -3- (trifluoromethyl) -3,4-dihydroisoquinoline-6-carboxylic acid trifluoroacetate; l-Amino-3- (3'-methoxybiphenyl-3-yl) -3- (trifluoromethyl) -3,4-dihydroisoquinoline-6-carbonitrile trifluoroacetate; l-Amino-3- (3-bromophenyl) -3- (trifluoromethyl) -3, -dihydroisoquinoline-6-carbonitrile; 2- [2- (3'-methoxybiphenyl-3-yl) ethyl] -2-methyl-1,2-dihydroquinazolin-4-amine trifluoroacetate; 2- [2- (3-bromophenyl) ethyl] -2-methyl-l, 2- trifluoroacetate dihydroquinazolin-4-amine; 2- (3 '-Bethoxybiphenyl-3-yl) -2-methyl-1,2-dihydroquinazolin-4-amine trifluoroacetate; 2- (3-bromophenyl) -2-methyl-1,2-dihydroquinazolin-4-amine trifluoroacetate; 4-Amino-2- [2- (3'-methoxybiphenyl-3-yl) ethyl] -2-methyl-1,2-dihydroquinazoline-7-carboxylic acid trifluoroacetate; 4-Amino-2- [2- (3-bromophenyl) ethyl] -2-methyl-1,2-dihydroquinazoline-7-carboxylic acid trifluoroacetate; 2- [2- (3'-Methoxybiphenyl-3-yl) ethyl] -1,2-dimethyl-1,2-dihydroquinazolin-4-anima trifluoroacetate; 2- [2- (3'-Methoxybiphenyl-3-yl) ethyl] -2-methyl-2H-l, 3-benzoxazin-4-amine trifluoroacetate; 2- [2- (3-bromophenyl) ethyl] -2-methyl-2H-1,3-benzoxazin-4-amine trifluoroacetate; 2- (3'-Methoxybiphenyl-3-yl) -2-methyl-2H-1,3-benzoxazin-4-amine trifluoroacetate; 2- (3-bromophenyl) -2-methyl-2H-l, 3-benzoxazin-4-amine; 2- (3-bromophenyl) -N-methoxy-2-methyl-2H-1,3-benzoxazin-4-amine trifluoroacetate; 2- (3-bromophenyl) -4-chloro-2-methyl-2H-l, 3-benzoxazine; 2- (3-bromophenyl) -2-methyl-2, 3-dihydro-4H-l, 3-benzoxazin-4-one; 3- (3 '-Metoxibiphenyl-3-yl) -1H- trifluoroacetate spiro [cyclohex-2-ene-1, 2'-quinazolin] -4'-amino; 3- (3'-Methoxybiphenyl-3-yl) -1'H-spiro [cyclohexane-1,2' -quinazolin] -4'-amino trifluoroacetate; 3-Methyl-5- (trimethylsilyl) thiophene-2-carbonitrile; 5- (3-bromophenyl) -2- (trimethylsilyl) -4,5-dihydrothieno [2,3-c] pyridin-7-amine; 5- (3-bromophenyl) -4,5-dihydrothieno [2, 3-c] pyridin-7-amine trifluoroacetate; trifluoroacetate 5- (3'-methoxybiphenyl-3-yl) -4,5-dihydrothieno [2,3-c] pyridin-7-amine; 5-Phenyl-5- (trifluoromethyl) -2- (trimethylsilyl) -4,5-dihydrothieno [2,3-c] pyridin-7-amine trifluoroacetate; 5-Phenyl-5- (trifluoromethyl) -4,5-dihydrothieno [2,3-c] pyridin-7-amine; 5- (3-bromophenyl) -5- (trifluoromethyl) -2- (trimethylsilyl) -4,5-dihydrothieno [2,3-c] pyridin-amine trifluoroacetate; 5- (3-bromophenyl) -5- (trifluoromethyl) -4,5-dihydrothieno [2,3-c] pyridin-7-amine trifluoroacetate; 5- (3'-Methoxybiphenyl-3-yl) -5- (trifluoromethyl) -4,5-dihydrothieno [2,3-c] pyridin-7-amine trifluoroacetate; or any subgroup thereof. The compounds of the present invention also include pharmaceutically acceptable salts, alternative salts, tautomers and in vivo hydrolysable precursors of the compounds of any of the formulas described in I presented. The compounds of the invention further include hydrates and solvates. The compounds of the invention can be used as medicaments. In some embonts, the present invention provides compounds of any of the formulas described herein, or pharmaceutically acceptable salts, tautomers or in vivo hydrolysable precursors thereof, for use as a medicament. In some embonts, the present invention provides compounds described herein for use as medicaments for treating or preventing an Aβ-related pathology. In some additional modalities, the pathology related to Aß is Down syndrome, an amyloid ß angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, a disorder associated with cognitive impairment, MCI ("mild cognitive impairment"), Alzheimer's disease, loss of memory, symptoms of attention deficit associated with Alzheimer's disease, neurodegeneration associated with Alzheimer's disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or basal cortical degeneration. In some embonts, the present invention provides compounds of any of the formulas described herein, or salts, tautomers or hydrolyzable precursors in living thereof pharmaceutically acceptable, in the manufacture of a medicament for the treatment or prophylaxis of pathologies related to Aß. In some additional embonts, pathologies related to Aß include such as Down syndrome and β-amyloid angiopathy, such as but not limited to cerebral amyloid angiopathy, hereditary cerebral hemorrhage, disorders associated with cognitive impairment, such as but not limited to MCI ( "mild cognitive impairment"), Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's disease or dementia including mixed vascular dementia and degenerative origin, dementia pre -senyl, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear palsy or basal cortical degeneration. In some embonts, the present invention provides a method for inhibiting BACE activity comprising contacting BACE with a compound of the present invention. BACE is considered to represent the highest activity of β-secretase, and it is considered to be the stage that limits the relationship in the production of β-amyloid protein (Aβ). In this manner, inhibiting BACE through inhibitors such as the compounds provided herein could be useful in inhibiting the deposition of Aβ and portions thereof. Because that the deposition of Aß and portions thereof is linked to diseases such as Alzheimer's Disease, BACE is an important candidate for the development of drugs as a treatment and / or prophylaxis of pathologies related to Aß such as Down syndrome and ß angiopathy -amiloid, such as but not limited to cerebral amyloid angiopathy, hereditary cerebral hemorrhage, disorders associated with cognitive impairment, such as but not limited to MCI ("mild cognitive impairment"), Alzheimer's disease, memory loss, deficit symptoms of attention associated with Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's disease or dementia that includes mixed vascular dementia and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical degeneration basal. In some embonts, the present invention provides a method for the treatment of Aβ-related pathologies such as Down syndrome and β-amyloid angiopathy, such as but not limited to cerebral amyloid angiopathy, hereditary cerebral hemorrhage, disorders associated with cognitive impairment, such as but not limited to MCI ("mild cognitive impairment"), Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's Disease or dementia including mixed vascular dementia of degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear palsy or basal cortical degeneration, which comprises administering to a mammal ( including a human) a therapeutically effective amount of a compound of any of the formulas described herein, or a salt, tautomer or pharmaceutically acceptable in vivo hydrolysable precursor thereof. In some embodiments, the present invention provides a method for the prophylaxis of Aß-related pathologies such as Down syndrome and β-amyloid angiopathy, such as but not limited to cerebral amyloid angiopathy, hereditary cerebral hemorrhage, disorders associated with cognitive impairment, such such as but not limited to MCI ("mild cognitive impairment"), Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's disease or dementia that includes mixed vascular dementia and of degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear palsy or basal cortical degeneration comprising administering to a mammal (including a human) an amount therapeutically effective of a compound of any of the formulas described herein or a pharmaceutically acceptable salt, tautomer or hydrolyzable in vivo precursors. In some embodiments, the present invention provides a method for treating or preventing Aβ-related pathologies such as Down syndrome and β-amyloid angiopathy, such as but not limited to cerebral amyloid angiopathy, hereditary cerebral hemorrhage, disorders associated with cognitive impairment, such such as but not limited to MCI ("mild cognitive impairment"), Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's disease or dementia that includes mixed vascular dementia and of degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear palsy or basal cortical degeneration when administered to a mammal (including a human) a compound of any of the formulas described herein or a salt, tautomer or hydrolysable precursors in vivo far maceutically acceptable and an agent that increases cognition and / or memory. In some embodiments, the present invention provides a method for treating or preventing Aß-related pathologies such as Down syndrome and β-amyloid angiopathy, such as such as but not limited to cerebral amyloid angiopathy, hereditary cerebral hemorrhage, disorders associated with cognitive impairment, such as but not limited to MCI ("mild cognitive impairment"), Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's disease or dementia that includes mixed vascular dementia and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear palsy or basal cortical degeneration when administered to a mammal (including a human) a compound of any of the formulas described herein or a salt, tautomer or pharmaceutically acceptable in vivo hydrolysable precursors thereof wherein the constituent members are provided herein, and a choline esterase inhibitor or anti-inflammatory agent. In some embodiments, the present invention provides a method for treating or preventing Aβ-related pathologies such as Down syndrome and β-amyloid angiopathy, such as but not limited to cerebral amyloid angiopathy, hereditary cerebral hemorrhage, disorders associated with cognitive impairment, as but not limited to MCI ("mild cognitive impairment"), Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's disease or dementia including mixed vascular dementia and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear palsy or basal cortical degeneration, or any other disease, disorder, or condition described herein, when administering to a mammal (including a human) a compound of the present invention, and an atypical antipsychotic agent. Atypical antipsychotic agents include, but are not limited to, Olanzapine (marketed as Zyprexa), Aripiprazole (marketed as Ability), Risperidone (marketed as Risperdal), Quetiapine (marketed as Seroquel), Clozapine (marketed as Clozaril), Ziprasidone (marketed as Geodon) and Olanzapine / Fluoxetine (marketed as Symbyax). In some embodiments, the mammal or human being treated with a compound of the present invention has been diagnosed with a particular disease or disorder, such as those described herein. In these cases, the treated mammal or human being needs such treatment. The diagnosis, however, does not need to be done previously.

The present invention also includes pharmaceutical compositions containing, as the active ingredient, one or more of the compounds of the invention herein together with at least one pharmaceutically acceptable carrier, diluent or excipient. When used for pharmaceutical compositions, medicaments, manufacture of a medicament, inhibit the activity of BACE, or treat or prevent pathologies related to Aß, the compounds of the present invention include the compounds of any of the formulas described herein, and salts , pharmaceutically acceptable in vivo hydrolysable tautomers and precursors thereof. The compounds of the present invention further include hydrates and solvates. The definitions set forth in this application are intended to clarify the terms used through this application. The term "in the present" means the complete application. As used in this application, the term "optionally substituted", as used herein, means that the substitution is optional and therefore possible for the atom or portion designated to be substituted. In the event of substitution it is then desired that such substitution means that any number of hydrogens in the designated atom or portion is replaced with a selection of the indicated group, with the proviso that the normal valence of the designated atom or portion is not exceeded, and that the substitution results in a stable compound. For example, if the methyl group (that is, CH3) is optionally substituted, then 3 hydrogens on the carbon atom can be replaced. Examples of suitable substituents include, but are not limited to: halogen, CN, NH2, OH, SO, S02, COOH, O-alkylC? _6, CH2OH, S02H, alkylC? -6, O-alkylC? -6, C (= 0) C1-6alkyl, C (= 0) O-alkylC? -6, C (= 0) NH2, C (= 0) NHalkylC? -6, C (= 0) N (alkylC? -6) 2, S02alkylC? -6, S02NHalkylC? -6, S02N (CixX2 alkyl, NH (C16 alkyl), N (C16 alkyl), NHC (= 0) C16 alkyl, NC (= 0) (C16 alkyl) 2, C5-6 aryl , OC5-6aryl, C (= 0) arylC5-6, C (= 0) 0arylC5-6, C (= 0) NHarylC5_6, C (= 0) N (arylC5-6) 2, S02arylC5-6, S02NHarylC5-6 , S02N (arylC5-6) 2, NH (arylC5-6), N (arylC5-6) 2, NC (= 0) arylC5-6, NC (= 0) (arylC5-6) 2, heterocyclylC5-S, OheterocyclylC5 -6, C (= 0) heterocyclylC5-6, C (= 0) OheterocyclylC5-6, C (= 0) NHheterocyclylC5-6, C (= 0) N (heterocyclylC5-6) 2, S02heterocyclylC5-6, S02NHheterocyclylC5-6, S02N (heterocyclylC5-6) 2, NH (heterocyclylC5-6), N (heterocyclylC5-6) 2, NC (= 0) heterocyclylC5-6, NC (= 0) (heterocyclylC5-6) 2. A variety of compounds in the present invention can exist in particular geometric or stereoisomeric forms. The present invention takes into account all these compounds, including cis and trans isomers, R and S enantiomers, diastereomers, isomers (D), isomers (L), racemic mixtures thereof, and other mixtures thereof, as covered within the scope of this invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. Such isomers, as well as mixtures thereof, are intended to be included in this invention. The compounds described herein may have asymmetric centers. The compounds of the present invention containing an asymmetrically substituted atom can be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis of optically active starting materials. When required, the separation of the racemic material can be achieved by methods known in the art. Many geometric isomers of olefins, C = N double bonds, and the like may also occur in the compounds described herein, and such stable isomers are contemplated in the present invention. The cis and trans geometric isomers of the compounds of the present invention are described and can be isolated as a mixture of isomers or as separate isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. When a bond to a substituent is shown to cross a bond connecting two atoms in the ring, then such Substituent can be linked to any atom in the ring. When a substituent is listed without indicating the atom by means of which such substituent is bonded to the rest of the compound of a given formula, then such a substituent may be linked by any atom in such a substituent. Combinations of substituents and / or variables are allowed only if such combinations result in compounds. As used herein, "alkyl", "alkylenyl" or "alkylene" used alone or as a subscript or superscript, is intended to include straight or branched chain saturated aliphatic hydrocarbon groups having from 1 to 12 carbon atoms or If a specific number of carbon atoms is provided then the specific number would be pretended. For example, "C C alkyl" means alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl. As used herein, "C ?_3 alkyl", if it is a terminal substituent or an alkylene (or alkylenyl) group that binds two substituents, is meant to specifically include straight, branched chain methyl, ethyl, and propyl. As used herein, "alkenyl" refers to an alkyl group having one or more double carbon-carbon bonds. Examples of alkenyl groups include ethenyl, propenyl, cyclohexenyl, and the like. The term "alkenylenyl" refers to an alkenyl group of divalent ligation. As used herein, "alkynyl" refers to an alkyl group having one or more triple carbon-carbon bonds. Examples of alkynyl groups include ethynyl, propynyl, and the like. The term "alkynynyl" refers to an alkynyl group of divalent ligation. As used herein, "aromatic" refers to hydrocarbyl groups having one or more carbon polyunsaturated rings having aromatic characters, (e.g., 4n + 2 delocalised electrons) and comprising up to 14 carbon atoms. As used herein, the term "aryl" refers to an aromatic ring structure made from 5 to 14 carbon atoms. The ring structures containing 5, 6, 7 and 8 carbon atoms will be single ring aromatic groups, for example, phenyl. The ring structures containing 8, 9, 10, 11, 12, 13, or 14 will be a polycyclic portion in which at least one carbon is common to any of two rings attached thereto (for example, the rings are "rings"). fused "), for example naphthyl. The aromatic ring can be substituted at one or more positions on the ring with such substituents as described above. He "aryl" also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two attached rings (the rings are "fused rings") wherein at least one of the rings is aromatic, for example, the other cyclic rings can be cycloalkyls, cycloalkenyls or cycloalkynyls. The terms broken, meta and para apply benzenes 1,2-, 1,3- and 1, -disubstituted, respectively. For example, the names 1, 2-dimethylbenzene and ortho-dimethylbenzene are synonymous. As used herein, "cycloalkyl" refers to non-aromatic cyclic hydrocarbons including cyclic alkyl, alkenyl, and alkenyl groups, which have the specific number of carbon atoms. Cycloalkyl groups may include mono or polycyclic groups (e.g., having rings or fused, 2, 3 or 4 rings). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnil, adamantyl, and the like. Also included in the definition of cycloalkyl are portions having one or more fused aromatic rings (that is, having a common bond with) to the cycloalkyl ring, for example, benzo derivatives of cyclopentane (i.e., indanyl), cyclopentene, cyclohexane, and similar. The term "cycloalkyl" further includes groups of 9 saturated rings, which have the specific number of carbon atoms. These may include polycyclic ponteados or fused systems. Preferred cycloalkyls have from 3 to 10 carbon atoms in their ring structure, and more preferably have 3, 4, 5, and 6 carbons in the ring structure. For example, "cycloalkyl XX" denotes such groups as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl As used herein, "cycloalkenyl" refers to hydrocarbyl groups containing rings having at least one carbon-carbon double bond in the ring, and having 3 to 12 carbon atoms As used herein, "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo. "Countraion" is used to represent a positively charged species or negatively small such as chlorine (Cl "), bromine (Br"), hydroxide (OH "), acetate (CH3COO"), sulfate (S042"), tosylate (CH3-phenyl-S03"), benezensulfonate (phenyl-S03" ), sodium ion (Na +), potassium (K +), ammonium (NH4 +), and the like. As used herein, the term "heterocyclic" or "heterocyclic" or "heterocycle" refers to a ring containing monovalent and divalent structures having one or more heteroatoms, independently selected from N, O, and S, as part of the structure of the ring and comprising 3 up to 20 atoms in the rings, more preferably rings of 3 to 7 members. The number of atoms formed in the heterocyclic ring occur in ranges in the present. For example, C5_? Heterocyclyl or refers to a ring structure comprising from 5 to 10 atoms formed in the ring wherein at least one of the atoms formed in the ring is N, O or S. The heterocyclic groups can be saturated or partially saturated or unsaturated, containing one or more double bonds, and the heterocyclic groups may contain more than one ring as in the case of polycyclic systems. The heterocyclic rings described herein may be substituted at the carbon atom or in a heteroatom if the resulting compound is stable. If specifically noted, the nitrogen in the heterocyclic can optionally be quaternized. It is understood that when the total number of S and O atoms in the heterocyclyl exceeds 1, then these heteroatoms are not adjacent to each other. Examples of heterocyclyls include, but are not limited to, lH-indazole, 2-pyrrolidonyl, 2H, 6H-1, 5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H- quinolizinyl, 6H-1, 2,5-thiadiazinyl, acridinyl, azabicyclo, azetidine, azeidine, aziridine, azocinyl, benzimidazolyl, benzodioxole, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinolinyl, diazepam, decahydroquinolinyl, 2H, 6H-1, 5, 2-dithiazinyl, dioxolane, furyl, 2,3-dihydrofuran, 2,5-dihydrofuran, dihydrofuro [2, 3-b] tetrahydrofuran, furanyl, furazanyl, homopiperidinyl, imidazolidino, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxirane, oxazolidinylperimidinyl, fenantridinyl, phenanthrolinyl, fenarsazinyl, phenazinyl, phenothiazinyl, phenoxyntinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, purinyl, pyranyl, pyrrolidinyl, pyrroline, pyrrolidin a, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, N-oxide-pyridinyl, pyridyl, pyrirnidinyl, pyrrolidinyl, dione pyrrolidinyl, pyrrolinyl, pyrrolyl, pyridine, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl , quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetramethylpiperidinyl, tetrahydroquinoline, tetrahydroisoquinolinyl, thiophane, thiotetrahydroquinolinyl, 6H-1, 2, 5-thiadiazinyl, 1,2,3-thiadiazolyl, 1, 2,4-thiadiazolyl, 1, 2, 5-thiadiazolyl, 1,3,4-thiadiazolyl, thiantrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenoyl, thiurane, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3-triazolyl, xanthenyl. As used herein, "heteroaryl" refers to an aromatic heterocycle having at least one ring heteroatom member such as sulfur, oxygen, or nitrogen. Heteroaryl groups include monocyclic and polycyclic systems (e.g., having 2, 3 or 4 fused rings). Examples of heteroaryl groups include without limitation, pyridyl (ie, pyridinyl), pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl (this is furanyl), quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, and the like. In some embodiments, the heteroaryl group has from 1 to about 20 carbon atoms, and in additional embodiments from about 3 to about 20 carbon atoms. In some embodiments, the heteroaryl group contains 3 to about 14, 4 to about 14, 3 to about of 7, or 5 to 6 atoms formed in the ring. In some embodiments, the heteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. In some embodiments, the heteroaryl group has 1 heteroatom. As used herein, "alkoxy" or "alkyloxy" represents an alkyl group as defined above with the indicated number of carbon atoms bonded through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, n-pentoxy, isopentoxy, cyclopropylmethoxy, allyloxy and propargyloxy. Similarly, "alkylthio" or "thioalkoxy" represents an alkyl group as defined above with the indicated number of carbon atoms bonded through a sulfur bridge. As used herein, the term "carbonyl" is recognized in the art and includes such portions as may be represented by the general formula: wherein X is a bond or represents an oxygen or sulfur, and R represents a hydrogen, an alkyl, an alkenyl, - (CH2) mR "or a pharmaceutically acceptable salt, R 'represents a hydrogen, an alkyl, an alkenyl or - (CH2) mR ", where m is an integer less than or equal to ten, and R" is alkyl, cycloalkyl, alkenyl, aryl, or heteroaryl. Where X is an oxygen and R and R 'are not hydrogen, the formula represents an "ester". Where X is an oxygen, and R is as defined above, the portion is referred to herein as a carboxyl group, and particularly when R 'is a hydrogen, the formula represents a "carboxylic acid." Where X is oxygen, and R 'is a hydrogen, the formula represents a "formate." In general, where the oxygen atom of the above formula is replaced by sulfur, the formula represents a "thiolcarbonyl" group. Where X is a sulfur and R and R 'is not hydrogen, the formula represents a "thiolyester." Where X is sulfur and R is hydrogen, the formula represents a "thiolcarboxylic acid." Where X is sulfur and R 'is hydrogen, the formula represents a "thiolformiate." On the other hand, where X is a bond, and R is not a hydrogen, the above formula represents a "ketone" group. Where X is a link, and R is Hydrogen, the above formula represents an "aldehyde" group.

As used herein, the term "sulfonyl" refers to a portion that can be represented by the general formula: where R is represented by, but not limited to hydrogen, alkyl, cycloalkyl, alkenyl, aryl, heteroaryl, aralkyl, or heteroaralkyl. As used herein, some substituents are described in a combination of two or more groups. For example, the expression of "C (= 0) cycloalkylC3-9Rd" is meant to refer to a structure: wherein p is 1, 2, 3, 4, 5, 6 or 7 (ie, C3_ cycloalkyl); the C3-g cycloalkyl is substituted by R; and the linking point of the "C (= 0) C3-9Rd cycloalkyl" is through the carbon atom of the carbonyl group, which is on the left of the expression. As used herein, the phrase "protecting group" means temporarily substituents that protect a potentially reactive functional group from undesired chemical transformations. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones respectively. The field of protective group chemistry has been reviewed (Greene, T. W .; Wuts, P.G.M. Protective Groups in Organic Synthesis, 3rd ed .; Wiley: New York, 1999). As used herein, "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation , allergic response, or other problem or complication, in a proportion with a reasonable benefit / risk ratio. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the described compounds wherein the parent compound is modified by making acid or basic salts thereof (ie, they also include counterions). Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkaline or organic salts of acidic residues such as carboxylic acids; and similar. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, of non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, phosphoric, and the like; and the prepared salts of organic acids such as lactic, maleic, citric, benzoic, methanesulfonic, and the like. The pharmaceutically acceptable salts of the present invention can be synthesized from the precursor compound containing an acidic or basic portion by conventional chemical methods. Generally, such salts can be prepared by reacting the basic or free acid forms of those compounds with a stoichiometric amount of the appropriate acid or base in water or in an organic solvent, or in a mixture of the two; nonaqueous medium similar to ether, ethyl acetate, ethanol, isopropanol, or acetonitrile can be used. As used herein, "in vivo hydrolysable precursors" means an in vivo hydrolysable ester (or cleavage) of a compound of any of the formulas described herein that contain a carboxy or hydroxy group. For example amino acid ester, esters of alkoxymethyl C? -6 methoxymethyl type; esters alkanoyloxymethyl C? _6 pivaloyloxymethyl type; C 1 -C 6 alkylcycloalkoxycarbonyloxy esters type 1-cyclohexylcarbonyloxyethyl, acetoxymethoxy, or cyclic phosphoramide esters. As used herein, "tautomer" means other structural isomers that exist in equilibrium resulting from the migration of a hydrogen atom. For example, tautomerism of keto-enol where the resulting compound has the properties of both ketone and an unsaturated alcohol. As used in the present "stable compound" and "stable structure" means to indicate a compound that is sufficiently robust to survive the isolate for a useful degree of purity of a reaction mixture and formulation into an effective therapeutic agent. The present invention also includes isotopically labeled compounds of the invention. An "isotopically" or "radiolabelled" compound is a compound of the invention where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic masses or mass number typically found in the nature (that is, it occurs naturally). Suitable radionuclides that can be incorporated into the compounds of the present invention include but are not limited to 2H (also written as D for deuterium), 3H (also written as T for tritium), 1 1C, 13C, 14C, 13N, 15N, 150, 170, 180, 18F3 35S, 36C1, 82Br, 75Br, 76Br, 77Br, 1231, 1241, 125I and 131I. The radionuclide that is incorporated in the instant labeled radioactive compounds should depend on the specific application of radioactive compound labeled. For example, for in vitro receptor labeling and competition assays, compounds that incorporate 3 H, 14 C, 82 Br, 125 I, 11 11, 5 S or are generally more useful. For the radio-image forming applications 1XC, 18F, 125I, 123I, 124I, 131I, 75Br, 76Br or 77Br are the most useful. It is understood that a "radiolabelled compound" is a compound that has incorporated at least one radionuclide. In some embodiments the radionuclide is selected from the group consisting of 3 H, 14 C, 125 I, 35 S and 82 Br. The anti-dementia treatment defined herein may be applied as a therapy alone or may involve, in addition to the compound of the invention, conventional chemotherapy. Such a treatment as a whole may be carried out in a manner of simultaneous, sequential or separate dosing of individual components of the treatment. Such combination products employ the compounds of this invention. Cognition enhancing agents, memory enhancing agents and choline esterase inhibitors include, but are not limited to, onepezil (Aricept), galantamine (Reminyl or Razadyne), rivastigmine (Exelon), tacrine (Cognex) and memantine (Namenda, Axura or Ebixa). Atypical anti-ipsychotic agents include, but are not limited to, olanzapine (marketed as Zyprexa), aripiprazole (marketed as Abilify), risperidone (marketed as Risperdal), quetiapine (marketed as Seroquel), clozapine (marketed as Clozaril), ziprasidone. (marketed as Geodon) and olanzapine / fluoxetine (marketed as Symbyax).

The compounds of the present invention can be administered orally, parenterally, buccally, vaginally, rectally, inhalation, insufflation, sublingually, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrametroxically, intravenously, epidurally, intrathecally, intracerebroventricularly and by injection into the joints. Doses depend on the route of administration, the severity of the disease, age and weight of the patient and other factors normally considered by the attending physician, when determining the individual regimen and dose level as the most appropriate for a particular patient. An effective amount of a compound of the present invention for use in the therapy of dementia is an amount sufficient to symptomatically relieve a warm-blooded animal, particularly a human, the symptoms of dementia, to slow down the progress of the dementia. dementia, or to reduce the risk of worsening in patients with symptoms of dementia. To prepare the pharmaceutical compositions of the compounds of this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, sachets and suppositories.

A solid carrier may be one or more substances, which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, linkers, or tablet disintegrating agents; these can also be in an encapsulating material. In the powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in the appropriate proportions and compacted in the desired shape and size. To prepare the suppository compositions, a low melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The homogeneous molten mixture is then emptied into conveniently sized molds and cooling and solidification is allowed. Suitable carriers include magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low melting wax, cocoa butter and the like. Some of the compounds of the present invention are capable of forming salts with various acids and bases Inorganic and organic salts and such salts are also within the scope of this invention. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, phosphoric, and the like; and the prepared salts of organic acids such as lactic, maleic, citric, benzoic, methanesulfonic, trifluoroacetate and the like. In some embodiments, the present invention provides a compound of any of the formulas described herein or a pharmaceutically acceptable salt thereof for the therapeutic treatment (including prophylactic treatment) of mammals including humans, is normally formulated in accordance with standard pharmaceutical practice. as a pharmaceutical composition. In addition to the compounds of the present invention, the pharmaceutical composition of this invention may also contain, or be co-administered (simultaneously or sequentially) with, one or more pharmacological agents of value in the treatment of one or more disease conditions referred to in the present. The term composition is intended to include the formulation of the active component or a pharmaceutically acceptable salt with a pharmaceutically acceptable carrier. For example, this invention can be formulated by means known in the art in the form of, for example, tablets, capsules, 1 aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols or nebulizers for inhalation and for parenteral use (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or emulsions sterile The liquid form compositions include solutions, suspensions and emulsions. The sterile water or propylene glycol-water solutions of the active compounds can be mentioned as an example of liquid preparations suitable for parenteral administration. The liquid compositions can also be formulated in the solution in an aqueous polyethylene glycol solution. Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired. Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose and other suspending agents known for the art of pharmaceutical formulation. . The pharmaceutical compositions can be in unit dosage form. In such form, the composition is divided into the unit doses containing the appropriate amounts of the active component. The unit dosage form can be a packaged preparation, the package contains discrete quantities of the preparations, for example, packed tablets, capsules and powders in vials or ampoules. The unit dosage form can also be a capsule, pouch, or tablet by itself, or it can be the appropriate number of any of these packaged forms. The compositions can be formulated for any route and suitable administration means. Pharmaceutically acceptable carriers or diluents include those used in formulations suitable for oral, rectal, nasal, topical (including buccal or sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) administration. The formulations can conveniently be presented in a unit dosage form and can be prepared by any of the methods known in the art of pharmacy. For solid compositions, conventional non-toxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, cellulose, cellulose derivatives, starch, magnesium stearate, sodium saccharine, talc, glucose, sucrose, magnesium carbonate, and the like. can be used Administered pharmaceutically liquid compositions can, for example, be prepared by dissolving, dispersing, etc., a active compound as defined above and optional pharmaceutical adjuvants in a carrier, such as, for example, water, aqueous saline dextrose, glycerol, ethanol, and the like, thereby to form a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH-buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine acetate sodium, sorbitan monolaurate, triethanolamine oleate, etc. Current methods for preparing such dosage forms are known, or will be apparent, to those skilled in the art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, 15th Edition, 1975. The compounds of the invention can be derived in various forms. As used herein "derivatives" of the compounds include salts (e.g., pharmaceutically acceptable salts), any complexes (e.g., inclusion complexes or clathrates with compounds such as cyclodextrins, or coordination complexes with metal ions such as Mn2 +. and Zn2 +), esters such as hydrolysable esters in vivo, free acids or bases, polymorphic forms of the compounds, solvates (e.g. hydrates), prodrugs or lipids, coupling partners and group protectors. By "prodrugs" is meant, for example, any compound that is converted in vivo into a biologically active compound. The salts of the compounds of the invention are preferably physiologically well tolerated and non-toxic. Many examples of salts are known to those skilled in the art. All salts are within the scope of this invention, and references for the compounds include the salt forms of the compounds. Compounds having acidic groups, such as carboxylate, phosphates or sulfates, can form salts with alkali or alkaline earth metals such as Na, K, Mg and Ca, and with organic amines such as triethylamine and Tris (2-hydroxyethyl) amine. The salts can be formed between the compounds with basic groups, for example amines, with inorganic acids such as hydrochloric acid, phosphoric acid or sulfuric acid, or organic acids such as acetic acid, citric acid, benzoic acid, fumaric acid, or tartaric acid . The compounds have both acidic and basic groups that can form internal salts. The acid addition salts can be formed with a wide variety of acids, both inorganic and organic. Examples of addition salts include salts formed with hydrochloric, hydriodic, phosphoric, nitric, sulfuric, citric, lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulfonic, toluenesulfonic, methanesulfonic, ethanesulfonic, naphthalenesulfonic, valeric, acetic, propanoic, butanoic, malonic, glucuronic and lactobionic acids. If the compound is anionic, or has a functional group which can be anionic (for example, COOH can be COO), then a salt can be formed with a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na + and K +, alkaline earth cations such as Ca2 + and Mg2 +, and other cations such as Al3 +. Examples of suitable organic cations include, but are not limited to, ammonium ion (ie, NH4 +) and substituted ammonium ions (eg, NH3R +, NH2R2 +, NHR3 +, NR4 +). Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine. and arginine. An example of a common quaternary ammonium ion is N (CH3) 4+. Where the compounds contain an amine function, they can form quaternary ammonium salts, for example by reaction with an alkylating agent according to methods well known to the skilled person. Such compounds of quaternary ammonium are within the scope of the invention.

The compounds containing an amine function can also form N. oxides. Reference is made herein to a compound containing an amine function also includes the oxide N. Where a compound contains various amine functions, one or more than one nitrogen atom is it can oxidize to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. The N oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (for example a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages . More particularly, the N-oxides can be made by the method of LW Deady (Syn.Comm. 1911, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example , in an inert solvent such as dichloromethane. The esters can be formed between carboxylic or hydroxyl acid groups present in the compound and an appropriate carboxylic acid or an alcohol reaction partner, using techniques well known in the art. The examples of esters are compounds that contain the group C (= 0) OR, wherein R is an ester substituent, for example, a C? -7 alkyl group, a C3-2o heterocyclic group, or a C5- or aryl group, preferably a C? _? Alkyl group; . Particular examples of ester groups include, but are not limited to, C (= 0) OCH3, C (= 0) OCH2CH3, C (= 0) OC (CH3) 3, and -C (= 0) 0Ph. Examples of acyloxy groups (reverse ester) are represented by 0C (= 0) R, wherein R is an acyloxy substituent, for example, a C? _? Alkyl group? , a C3_20 heterocyclic group, or a C5-20 aryl group, preferably a C? -7 alkyl group. Particular examples of acyloxy groups include, but are not limited to, 0C (= 0) CH3 (acetoxy), OC (= 0) CH2CH3, OC (= 0) C (CH3) 3, 0C (= 0) Ph, and 0C (= 0) CH2Ph. Derivatives which are prodrugs of the compounds are converted in vivo or in vitro to one of the precursor compounds. Typically, at least one of the biological activities of the compound will be reduced in the prodrug form of the compound, and can be activated by the conversion of the prodrug to release the compound or a metabolite thereof. Some prodrugs are esters of the active compound (eg, a physiologically active metabolically unstable ester). During metabolism, the ester group (-C (= 0) 0R) is split to provide the active drug. Such esters can be formed by esterification, for example, of any of the groups of carboxylic acid (-C (= 0) 0H) in the precursor compound, with, where appropriate, prior to the protection of any other reactive groups present in the parent compound, followed by deprotection if required. Examples of such metabolically unstable esters include those of the formula -C (= 0) 0R wherein R is: C? -7 alkyl (eg, Me, Et, -nPr, -iPr, -nBu, -sBu, iBu , tBu); C 1 - aminoalkyl (eg, aminoethyl; 2- (N, N-diethylamino) ethyl; 2 (4-morpholino) ethyl); and acyloxy-C 7 -alkyl (eg, acyloxymethyl; acyloxyethyl; pivaloyloxymethyl; acetoxymethyl; lacetoxyethyl; 1- (1-methoxy-1-methyl) ethyl-carbonyloxyethyl; 1- (benzoyloxy) ethyl; isopropoxy-carbonyloxymethyl; lysopropoxy-carbonyloxyethyl cyclohexylcarbonyloxymethyl, 1-cyclohexylcarbonyloxyethyl, cyclohexyloxycarbonyloxymethyl, 1-cyclohexyloxycarbonyloxyethyl (4-tetrahydropyranyloxy) carbonyloxymethyl, 1- (4-tetrahydropyranyloxy) carbonyloxyethyl (4-tetrahydropyranyl) carbonyloxymethyl; 1 (4-tetrahydropyranyl) carbonyloxyethyl). Also, some prodrugs are enzymatically active to provide the active compound, or a compound which, during the additional chemical reaction, provides the active compound (eg, as in ADEPT, GDEPT, LIDEPT, etc.). For example, the prodrug may be a derivative of sugar or another glycoside conjugate, or it may be a derivative of amino acid ester. Other derivatives include coupling partners of the compounds in which the compounds are linked to a coupling partner, for example, by chemically coupling the compounds or physically associating with them. Examples of coupling partners include a labeled or reporter molecule, a support substrate, a transport or carrier molecule, an effe, a drug, an antibody or an inhibitor. Coupling partners can be covalently linked to compounds of the invention by means of an appropriate functional group on the compound such as a hydroxyl group, a carboxyl group or an amino group. Other derivatives include formulating the compounds with liposomes. Where the compounds contain chiral centers, all individual optical forms such as enantiomers, epimers and diastereomers, as well as racemic mixtures of the compounds are within the scope of the invention. The compounds can exist in a number of different geometric and isomeric and tautomeric forms and references to compounds include all forms. For the avoidance of doubt, where a compound may exist in one of the various geometric or isomeric or tautomeric forms and only one is specifically described or shown, all others are nevertheless encompassed by the scope of this invention The amount of the compound to be administered will vary for the patient to be treated and will vary from about 100 ng / kg of body weight to 100 mg / kg of body weight per day and preferably will be from 10 pg / kg to 10 mg / kg per day. For example, doses can be easily ascertained by those skilled in the art of this disclosure and knowledge in the art. Thus, the skilled artisan can easily determine the amount of compound and additives, vehicles and / or optimal carriers in compositions and to be administered in methods of the invention. The compounds of the present invention have been shown to inhibit beta secretase activity (including BACE) in vitro. Beta secretase inhibitors have been shown to be useful in the formation of blockade or aggregation of Aβ peptide and therefore have a beneficial effect in the treatment of Alzheimer's disease and other neurodegenerative diseases associated with elevated levels and / or deposition of Aβ peptide. It is therefore believed that the compounds of the present invention can be used for the treatment of Alzheimer's disease and the disease associated with dementia. Therefore, the compounds of the present invention and their salts are expected to be active against age-related diseases such as Alzheimer's, as well as other pathologies. related to Aß such as Down syndrome and amyloid angiopathy b. It is expected that the compounds of the present invention should be more likely used in combination with a wide range of cognition deficit enhancing agents but should also be used as a single agent. Generally, the compounds of the present invention have been identified in one or both of the assays described below as having an IC50 value of 100 micromolar or less.

IGEN assay The enzyme is diluted 1:30 in 40 mM MES pH 5.0. The reserve substrate is diluted to 12 μM in 40 mM MES pH 5.0. The PALMEB solution is added to the substrate solution (1: 100 dilution). DMSO reserve solutions of the compounds or DMSO are only diluted to the desired concentration in 40mM MES pH 5.0. The assay is given in a 96-well Nunc PCR plate. The compound in DMSO (3 μL) is added to the plate then the enzyme is added (27 μL) and pre-incubated with the compound for 5 minutes. Then the reaction was started with substrate (30 μL). The final dilution of the enzyme is 1:60; The final concentration of the substrate is 6 μM (Km is 150 μM). After a 20-minute reaction at room temperature, the reaction is stopped by removing 10 μl of the mixture from reaction and diluted 1:25 in 0.20 M Tris pH 8.0. The compounds are added to the plate by hand then all the rest of the liquid handled is given by the CyBi well instrument. All antibodies and streptavidin-coated beads are diluted in PBS containing 0.5% BSA and 0.5% Tween20. The product is quantified by adding 50 μL of a 1: 5000 dilution of the neoepitope antibody to 50 μL of the 1:25 dilution of the reaction mixture. Then, 100 μL of PBS (0.5% BSA, 0.5% Tween20) containing 0.2 mg / ml of IGEN beads and a 1: 5000 dilution of rutinillated goat anti-rabbit antibody (Ru-Gar) is added. The final dilution of the neoepitope antibody is 1: 20,000, the final dilution of Ru-GAR is 1: 10,000 and the final concentration of beads is 0.1 mg / ml. The mixture is read on the IGEN instrument with the Cindy AB40 program after a 2 hour incubation at room temperature. The addition of DMSO is only used to define 100% activity. 20 μM of control inhibitor is used to define 0% of control activity and 100 nM inhibitor which defines 50% control of control activity in single introduction assays. The control inhibitor is also used in dose response assays with an IC50 of 100 nM.

Fluorescent assay The enzyme is diluted 1:30 in 40mM MES pH 5.0. The reserve substrate is diluted to 30 μM in 40 mM MES pH 5.0. The PALMEB solution is added to the substrate solution (1: 100 dilution). The enzyme and substrate reserve solutions are kept on ice until placed on the reserve plates. The Platemate-plus instrument is used to do all liquid handling. The enzyme (9 μL) is added to the plate then 1 μL of the compound in DMSO is added and pre-incubated for 5 minutes. When a dose response curve is tested for the compound, the dilutions are given in pure DMSO and the DMSO stock solutions are added as described above. The substrate (10 μL) is added and the reaction proceeds in the dark for 1 hour at room temperature. The assay occurs on an unlinked, low volume, round bottom surface of 384 Corning wells (Corning # 3676). The final dilution of the enzyme is 1: 60; The final concentration of the substrate is 15 μM (Km of 25 μM). The fluorescence of the product is measured in a Victor II plate reader with an excitation wavelength of 360 nm and an emission wavelength of 485 nm using the Edans peptide labeling protocol. The DMSO control defines 100% activity level and 0% activity is defined using 50 μM of the control inhibitor, which completely blocks the function of the enzyme. The control inhibitor is also used in dose response assays and has an IC50 of 95 nM.

Whole Cell Assay Beta-Secretase Generation of HEK-Fc33-1: The cDNA encoding the full-length BACE was fused in the structure with a three amino acid linker (Ala-Val-Thr) to the human IgGl portion of the fe of amino acids 104. The BACE-Fc construct was then cloned into a GFP / pGEN-IRES-neoK vector (a vector owned by AstraZeneca) for protein expression in mammalian cells. The expression vector was stably transfected in HEK-293 cells using a calcium phosphate method. The colonies were selected with 250 μg / mL of G-418. Cloning of limited dilution was performed to generate homogeneous cell lines. The clones were characterized by levels of expression of APP and Aβ secreted in the conditioned medium using an ELISA assay developed by this applicant. The secretion of Aβ from clone Fc33-1 BACE / Fc was moderated.

Cell Culture: HEK293 cells stably expressing human BACE (HEK-Fc33) were grown at 37 ° C in DMEM containing 10% heat inhibited FBS, 0.5 mg / mL antibiotic-antifungal solution, and 0.05 mg / mL of antibiotic G-418 selection.

Aβ40 Release Assay: Cells were harvested when they are between 80 to 90% of confluence. 100 μL of the cells were added at a cell density of 1.5 million / mL to a white 96-well culture plate with the transparent flat bottom (Costar 3610), or a flat-bottomed, transparent 96-well cell culture plate ( Costar 3595), which contains 100 μL of inhibitor in cell culture medium with DMSO at a final concentration of 1%. After the plate was incubated at 37 ° C for 24 h, 100 μL of the cell medium was transferred to a 96 well round-bottom plate (Costar 3365) to quantify the Aβ40 levels. Cell culture plates are saved for ATP assay as described in the ATP assay below. To each well of the round bottom plate, was added 50 μL of detection solution containing 0.2 μg / mL of the RaAß40 antibody and 0.25 μg / mL of the biotinylated 4G8 antibody (prepared in DPBS with 0.5% BSA and Tween-20 0.5%) and incubated at 4 ° C for at least 7 hours. Then a 50 μL solution (prepared in the same buffer as above) containing 0.062 μg / mL of ruthenilated goat anti-rabbit antibody and 0.125 mg / mL of streptavidin-coated Dynabeads per well was added. The plate was shaken at 22 ° C on the plate shaker for 1 hour, and then the plates were then measured for ECL counts on an IGEN M8 analyzer. Standard Aβ curves were obtained with a 2-fold serial dilution of an Aβ stock solution of known concentration in the same cell culture medium used in cell-based assays.

ATP assay: As indicated above, after transferring 100 μL of media from the cell culture plates for Aβ40 detection, the plates, which still contain cells, were saved for cytotoxicity assays when using the assay kit (ViaLight ™ Plus) of Cambrex BioScience that measures total cellular ATP. Briefly, 50 μL of cell lysis reagent was added to each well of the plates. Plates were incubated at room temperature for 10 minutes. Two minutes after the addition of 100 μL of reconstituted ViaLight ™ Plus reagent for ATP measurement, the luminescence of each well was measured on an LJL or Wallac Topcount plate reader.

BACE BACE Protocol Biacore3000 Instrument Preparation: BACE was evaluated on a Biacore3000 instrument by linking either an eptidic transition state isotope (TS1) or a revolved version of the peptide TS1 to the surface of a Biacore CM5 sensor chip. The surface of a CM5 sensor chip has 4 different channels that can be used to couple the peptides. The stirred KFES-statin-ETIAEVENV peptide was coupled to channel 1 and the TSI inhibitor KTEEISEVN-statin-VAEF was coupled to channel 2 of the same chip. The two peptides were dissolved at 0.2 mg / ml in 20 mM Na acetate pH 4.5, and then the solutions were centrifuged at 14K rpm to remove any of the particles. The carboxyl groups in the dextran layer were activated by injecting one by one a mixture of N-ethyl-N '(3-dimethylaminopropyl) -carbodiimide 0.5M (EDC) and N-hydroxysuccinimide 0.5M (NHS) at 5 μL / minute for 7 minutes. Then the control peptide stock solution was injected into channel 1 for 7 minutes at 5 μL / min, and then the remaining activated carboxyl groups were blocked by injecting 1M ethanolamine for 7 minutes at 5 μL / minute.

Test Protocol: The BACE Biacore test was given by diluting BACE up to 0.5 μM in an Na buffer solution pH 4.5 (running buffer minus DMSO). The diluted BACE was mixed with DMSO or a compound diluted in DMSO to a final concentration of 5% DMSO. The BACE / inhibitor mixture was incubated for 1 hour at 4 ° C, then injected onto channel 1 and 2 of the CM5 Biacore microplate at a ratio of 20 μL / minute. As BACE is linked to the chip, the signal was measured in response units (RU). The BACE linked to the TSI inhibitor in channel 2 gives a certain signal. The presence of a BACE inhibitor reduces the signal by binding the BACE and inhibiting the interaction with the peptide TSl in the microplate. Any link to channel 1 was nonspecific and subtracted from channel 2 responses. The DMSO control was defined as 100% and the effect of the compound was reported as a percentage of inhibition of the DMSO control.

HERG Assay Cell Cul tive Chinese hamster ovary (CHO) Kl cells expressing hERG described by (Persson, Carlsson, Duker, &Jacobson, 2005) were grown to a semi-confluence at 37 ° C in a humidified environment (C02 at 5%) in F-12 Ham medium containing L-glutamine, 10% fetal calf serum (FCS) and 0.6 mg / ml hygromycin (all from Sigma-Aldrich). Before use, the monolayer was washed using a previously warmed 1 ml aliquot (37 ° C) of Versene 1: 5,000 (Invitrogen). After aspiration of this solution the flask was incubated at 37 ° C in an incubator with an additional 2 ml of Versene 1: 5,000 for a period of 6 minutes. The cells were then removed from the bottom of the flask by puncture and then 10 ml of Dulbecco's buffered saline solution containing calcium (0.9 mM) and magnesium (0.5 mM) (PBS, Invitrogen) was added to the flask and aspirated into the flask. a 15 ml centrifuge tube before centrifugation (50 g, for 4 mins). The resulting supernatant was discarded and the pellet was gently resuspended in 3 ml of PBS. An aliquot of 0.5 ml of cell suspension was removed and the number of viable cells (based on the exclusion of triptan blue) was determined in an automated reader (Cedex; Innovatis) so that the volume of cellular re-suspension can be adjusted with PBS to give the desired final cell concentration. This is the cell concentration at this point in the assay that is cited when referring to this parameter. The CHO-Kvl.5 cells, which were used to adjust the voltage shutdown in IonWorks ™ HT, were maintained and prepared to be used in the same manner.

Electrophysiology The principles and operation of this device have been described by (Schroeder, Neagle, Trezise, &Worley, 2003). Briefly, the technology is based on a 384 well plate (PatchPlate ™) in which a log is attempted in each well using suction to the position and the cell is kept in a small hole separating two isolated fluid chambers. Once the seal has taken place, the solution on the underside of the PatchPlate ™ is changed to one that contains amphotericin B. This allows the cell membrane patch to cover the hole in each well and, in effect, allows it to make a record of a pierced whole cell patch fastener. An Ion Works ™ HT test instrument from Essen Instrument was used. There is no capacity for warmed solutions in this device therefore it was operated at room temperature (~ 21 ° C), as follows. The reservoir in the "Buffering" position was charged with 4 ml of PBS and in the "Cells" position with the CHO-hERG cell suspension described above. A 96-well plate (V-bottom, Greiner Bio-one) containing the compounds to be tested (at 3 times above their final test concentration) is placed in the "Plate 1" position and a PatchPlate ™ is secured in the PatchPlate ™ station. Each composite plate was placed in 12 columns to allow two 8-point concentration-effect curves to be constructed; the remaining two columns in the plate were taken with vehicle (final concentration 0.33% DMSO), to define the baseline of the test, and a higher maximum blocking concentration of cisapride (final concentration 10 μM) to define the level of inhibition at 100 %. The superior fluids (F domes) of IonWorks ™ HT are then added with 3.5 μl of PBS to each well of the PatchPlate ™ and the bottom side is perfused with an "internal" solution having the following composition (in mM): K- Gluconate 100, KCl 40, MgCl 2 3.2, EGTA 3 and HEPES 5 (all from Sigma-Aldrich, pH 7.25-7.30 using 10 M KOH). After priming and deburring, the electronic dome (dome E) then moves around the PatchPlate ™ performing the orifice test (this is applying a voltage pulse to determine if the hole in each well was opened). The F dome then dispenses 3.5 μl of the cell suspension described above in each well of the PatchPlate ™ and the cells are given 200 seconds to reach and seal the hole in each well. After this, the dome E moves around the PatchPlate ™ plate to determine the resistance of the seal obtained in each well. Next, the solution on the underside of the PatchPlate ™ was loaded for "access" of the solution having the following composition (in mM): KCl 140, EGTA 1, MgCl 2 1 and HEPES 20 (pH 7.25-7.30 using 10 M KOH) plus 100 μg / ml amphotericin B (Sigma-Aldrich). After allowing 9 for the joint perforation to take place, dome E moves around 48 wells of the PatchPlate ™ at a time APRA obtain hERG current measurements prior to the compound. The F dome then adds 3.5 μl of a solution from each well of the composite plate to 4 wells in the PatchPlate ™ (the final DMSO concentration was 0.33% in each well). This is achieved by moving from the most dilute well to the most concentrated well of the composite plate to minimize the impact of any compound carried. After approximately 3.5 minutes of incubation, the dome E then moves around all 384 wells of the PatchPlate ™ to obtain the hERG current measurements d after the compound. In this way, non-cumulative concentration-effect curves will occur where, with the condition that accepted criteria are reached in a sufficient percentage of wells (see below), the effect of each concentration of the test compounds was based on the record in 1 and 4 cells.

The hERG current before and after the compound was evoked by a single constant voltage pulse consisting of a period of 20 seconds maintained at -70 mV, a 160 ms step for -60 mV (to obtain a leak estimate), a 100 ms stage again at -70 mV, a 1 s phase for + • 40 mV, a 2 s stage for -30 mV and finally a 500 ms stage for -70mV. There was no binding of the membrane potential between the pre- and post-compound voltage pulses. The currents were subtracted from the leak based on the current estimate evoked during the + 10mV stage at the beginning of the voltage pulse protocol. Any voltage compensation in IonWorks ™ HT was adjusted in one of two ways. When determining the potency of the compound, a depolarizing voltage rise was applied to the CHO-Kvl.5 cells and the voltage noted at which there is an infection point in the induction current (this is the point at which the activation of the channel it was appreciated with a lifting protocol). The voltage at which this is presented is determined previously using the same voltage command in conventional electrophysiology and is found to be -15 mV (data not shown); in this way a compensation potential will be entered into the IonWorks ™ HT software using this value as a reference point. When determining the basic electrophysiological properties of hERG, any compensation was adjusted by determining the reverse potential of hERG tail current in IonWorks ™ HT, in comparison with that found in conventional electrophysiology (-82 mV; see Fig. lc) and then making the necessary compensation adjustment in the IonWorks ™ HT software. The current signal was shown at 2.5 kHz. The hERG current magnitude before and after the sweep was measured automatically from the signs of leakage subtraction by the IonWorks ™ HT software by taking an average of 40 ms of current during the initial standby period to -70 mV (line current). base) and subtract this from the peak of the tail current response. The acceptance criteria for the currents evoked in each well were: stamp resistance, price, sweep > 60 MO, tail current amplitude hERG price at sweep > 150 pA; resistance of the post-swept seal > 60 MO. The degree of inhibition of the hERG current was evaluated by dividing the hERG current subsequent to the sweep by the respective hERG current prior to the sweep for each well. The compounds of the present invention have been shown to inhibit beta secretase activity (including BACE) in vitro. Beta secretase inhibitors have been shown to be useful in blocking the formation or aggregation of the Aβ peptide and therefore have beneficial effects in the treatment of Alzheimer's disease and other neurodegenerative diseases associated with elevated levels and / or deposition of the Aβ peptide. . Therefore, it is considered that the compounds of the present invention can be used for the treatment of Alzheimer's disease and disease associated with dementia. Therefore, the compounds of the present invention and their salts are expected to be active against age-related diseases such as Alzheimer's, as well as other Aß-related pathologies such as Down syndrome and ßamiloid angiopathy. It is expected that the compounds of the present invention would be more likely to be used as simple agents but could also be used in combination with a wide range of agents that increase the deficit of cognition. The anti-dementia treatment defined herein may be applied as a single therapy or may involve, in addition to the compound of the invention, conventional chemotherapy. Such chemotherapy may include one or more of the following categories of agents: acetyl cholinesterase inhibitors, anti-inflammatory agents, agents that increase cognition and / or memory or atypical antipsychotic agents. Such joint treatment can be achieved by means of simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention.

Methods of Preparation The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereof as appreciated by those skilled in the art. Such methods include, but are not limited to, those described below. All references cited herein are hereby incorporated by reference in their entirety. The novel compounds of this invention can be prepared using the reactions and techniques described herein. The reactions are carried out in appropriate solvents for the reagents and materials used and are suitable for the transformations that are carried out. Also, in the description of the synthetic methods described below, it will be understood that all the proposed reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and work procedures, are chosen to be the standard conditions for that reaction, which should be easily recognized by one skilled in the art. This is understood by one skilled in the art of organic synthesis that the functionality present in various portions of the molecule must be compatible with the proposed reagents and reactions.

Such restrictions for substituents, which are not compatible with reaction conditions, are readily apparent to one skilled in the art and alternative methods should be used. The starting materials for the examples contained herein are either commercially available or are readily prepared by standard methods from known materials. For example, the following reactions are illustrations but not limitations of the preparation of some of the starting materials and examples used herein. The general procedures for making the compounds of the invention are as follows: The invention is now illustrated by the following non-limiting examples: I. The temperatures are given in degrees Celsius (° C); Unless stated otherwise, operations are carried out at room or room temperature, that is, at a temperature in the range of 18-25 ° C; II. The organic solutions were dried over anhydrous magnesium sulfate; the evaporation of the solvent was carried out using a rotary evaporator under reduced pressure (600-4000 Pascal, 4.5-30 mm Hg) with a bath temperature of up to 60 ° C; III. Chromatography means instant gel chromatography of silica; Thin layer chromatography (CCD) was carried out on silica gel plates; IV. In general, the course of reactions was followed by CCD or CLAR and the reaction times are given for illustration only; V. The melting points are not corrected and (desc) indicates decomposition; SAW. The final products have satisfactory proton nuclear magnetic resonance (NMR) spectra; VII. When given, the NMR data is in the form of delta values for the main diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300 MHz using deuterated chloroform (CDC13). ), dimethylsulfoxide (d6-DMSO) or dimethylsulfoxide / TFA (d6-DMSO / TFA) as solvent; Conventional abbreviations for the signal form are used; for AB spectrum the changes observed directly are reported; the coupling constants (J) are given in Hz; Ar designates an aromatic proton when such cession occurs; VIII. The reduced pressures are given as absolute pressures in pascals (Pa); the high pressures are given as pressures measured in bars; IX. The non-aqueous reactions were carried out under a nitrogen atmosphere; X. Solvent relations are given in volume: terms volume (v / v); and XI. Mass spectra (EM) were run using an automated system with chemical atmospheric pressure (APCI) or electro-ionization ionization (+ ES). Generally, only the spectra where the precursor masses are observed are reported. The lower mass main ion is reported for molecules where isotope splice results in multiple mass spectrum peaks (for example when chlorine is present).

XII. Commercial reagents were used without further purification. XIII. 1- (3-Bromo-phenyl) -2,2,2-trifluoro-ethanone was prepared according to Kogon, et al, Leibigs Ann. Chem., 1992, 879-881 using NBS as the brominating agent. The 1-hydroxybenzotriazole ammonium salt was prepared according to Bajusz, et. al., FEBS Letters, 1977, 76 (1), 91-2. 4- (3-Bromo-phenyl) -butan-2-one was prepared from 3- (3-bromo-phenyl) -propionic acid using standard Weinreb Amida chemistry, Nahm, et al, Tet. Lett., 1981, 3815-3818. 3- (3-Bromo-phenyl) -1-phenyl-propan-1-one was prepared from 3- (3-bromo-phenyl) -propionic acid using standard Weinreb Amida chemistry, Nahm, et al, Tet. Lett., 1981, 3815-3818. 4-Cyano-3-nitro-benzoic acid was prepared in accordance with the procedure found in US 2195076, with the exception of NMP used in place of quinoline. The 2-methylamino-benzonitrile was prepared according to Sebastien, et al, Synlett, 2002, 164-166. The 2- hydroxy-benzamidine was prepared according to Lepore, et al, Tet. Lett. 2002, 8777-8779. XIV. Mass spectra were recorded using either a Hewlett Packard 5988A mass spectrometer or a Quattro-1 MicroMass and are reported as m / z for the precursor molecular ion with their relative intensity. XV The ambient temperature refers to 20-25cC. XVI. CLAR CL-EM conditions: Column: Agilent Zorbax SB-C8 2mm ID X 50mm Flow: 1.4 mL / min Gradient: 95% A up to 90% B for 3 min. waiting 1 minute reducing up to 95% A for 1 minute and waiting 1 minute. Where A = 2% acetonitrile in water with formic acid 0.1% and B = 2% water in acetonitrile with formic acid 0.1%. UV-DAD 210-400 nm. XVII. The HPLC conditions of preparative reverse phase were: The compounds were purified using a Phenomenex Luna Cl 8 reverse phase column (250 X 21 mm, 10 micron particle size). One skilled in the art will appreciate that raw samples can be dissolved in methanol, DMF, or a wide range of acetonitrile / water mixtures with and without TFA, methanol, or DMF in concentrations ranging from dilute to concentrate. All purifications were run using 220nm wavelength for collected fractions. Retention time (tR) = min. Agilent 1 gradient (AGÍ): 0% acetonitrile with 0.1% TFA 3 min, rising 0-50% acetonitrile / water with 0.1% TFA for 12 min, waiting for 50% acetonitrile / water for 3 min, 50-100% acetonitrile / water with 0.1% TFA for 7 min, flow ratio 40 ml / min. Agilent 2 gradient (AG2): 10-100% acetonitrile / water with 0.1% TFA for 20 min, flow ratio of 40 mL / min. Agilent 3 gradient (AG3): 0% acetonitrile with 0.1% TFA 3 min, raising 0-100% acetonitrile / water with 0.1% TFA for 25 min, flow ratio of 40 ml / min. XVIII. Preparatory reverse phase CLAR conditions: Gilson int rumentation (215 Injector, 333 Pumps and 155 UV / Vis Detector): Reverse phase column Varies C8 (60 Angstrom irregular load in 8 mm particle size, 21 mm ID x 25 cm). The crude compounds were solubilized in dimethyl sulfoxide: methanol (~1: 1). Elution gradient made with 0.1% aqueous trifluoroacetic acid / acetonitrile (typically 25-75% acetonitrile for 30 min., 95% acetonitrile for 7 min.) Flow ratio at 22 mL / min, UV collection at 254 nm. Retention time (tR) = minutes. This method was used for examples 88-94.

XIX Normal phase chromatography conditions: Flash chromatography is used as a method for purification for selected intermediates. Instrument Isco CombiFlash Sq 16x: stationary phase columns RediSep Si02 pre-packed disposable (4, 12, 40, 120 sizes in gram) with gradient elution at 5-125 mL / min of selected bi-solvent mixture, UV detection (range 190-760 nm) or collection time, 0.1 mm flow path length cell phone . XX. Microwave heating instrumentation: One unit Personal Chemistry Smith Synthesizer (monomodal, 2.45 GHz, 300W max) was used for microwave heating of the reactions. XXI. Terms and abbreviations: The solvent mixture compositions are given as percentages of volume or volume ratios. In cases where the NMR spectrum are complex; only the diagnostic signals are reported, atm: atmospheric pressure; Boc: t-butoxycarbonyl; Cbz: benzyloxycarbonyl; DCM: methylene chloride; DIPEA: diisopropylethylamine; DMF: N; N-dimethyl formamide; DMSO: dimethyl sulfoxide; Et20: diethyl ether; EtOAc: ethyl acetate; h: hours; HPLC: high pressure liquid chromatography; minutes: min .; NMR: nuclear magnetic resonance; psi: pounds per square inch; TFA: trifluoroacetic acid; THF: tetrahydrofuran; ACN: acetonitrile; NMP: 1-methylpyrrolidin-2-one; DMPU: 1,3-dime t il t e t rahidropir imidin-2 (1 H) -one; LDA: di i sopropi lithium zanide Reaction scheme 1 , J ° Example 1 3- (3'-methoxybiphenyl-3-yl) -3,4-dihydroisoquinolin-1-amine trifluoroacetate (Reaction scheme # 1, B) To a crude 3- (3-bromophenyl) -3,4-dihydroisoquinoline-1-amine (Reaction Scheme # 1, A) (100 mg, 0.332 mmol) was added cesium carbonate (325.0 mg, 0.996 mmol), 3-methoxyphenylboronic acid (53.0 mg, 0.432 mmol), dichlorobis (triphenylphosphino) palladium (II) (12.0 mg, 0.0155 mmol), and 1,2-dimethoxyethane: water: ethanol (7: 3: 2, 2.0 mL). The reaction was microwaved for 15 minutes at 150 ° C after which the aqueous layer was removed and the organic solvents were removed under reduced pressure. Acetonitrile and water were added to the brown gum, the precipitate was removed, and the filtrate was purified using RP-CLAR AG2 (tR = 9.83 min). The combined purified fractions were lyophilized to give the title compound as a TFA salt (7.9 mg, 5%). A NMR (300 MHz, DMSO-d6 / TFA-d) d 3.43 - 3.46 (m, 1H), 3.83 - 3.86 (m, 4H), 5.10 (t, J = 7.1 Hz, 1H), 6.97 (dd, J = 8.1, 2.0 Hz, 1H), 7.18 -7.24 (m, 2H), 7.38 - 7.52 (m, 6H), 7.72 - 7.75 (m, 2H), 8.14 (d, J = 7.8 Hz, 1H), m / z (APCI +) MAL (329); tr = 2.18 min.

EXAMPLE 2 3- (3-Bromophenyl) -3,4-dihydroisoquinolin-1-amine trifluoroacetate (Reaction Scheme # 1, A) To an ice-cooled solution of 3-bromo-benzaldehyde in THF (10 mL) was added 1.06 M lithium hexamethyldisilyl azide in THF (8.05 mL, 8.54 mmol) and the stirred reaction was cooled for 2 hours. To a cooled THF solution - 78 ° C (10 mL) of 2-methyl-benzonitrile (1.01 mL, 8.54 mmol) and 1,3-dimethyl-tetrahydro-pyrimidin-2-one (1.55 mL, 12.80 mmol) was added 2.5M n-butyllithium in hexanes (3.41 mL, 8.54 mmol) for 5 minutes. After 20 minutes the previously made trimethylsilylimine was cannulated in the 2-methyl-benzonitrile anion for 10 minutes. The reaction was stirred in a -78 ° C bath for 20 minutes then warmed to room temperature. After 30 minutes the reaction was quenched with 1M HCl (10 mL) and the aqueous mixture was extracted three times with DCM. The organic layer was washed once with brine, dried over sodium sulfate, the solvent was removed under reduced pressure, and the resulting yellow oil was placed under high vacuum. Most of the material was carried forward as is and a small portion of the crude material, 100 mg, was dissolved in acetonitrile / water and purified by RP-CLAR AG2 (tR = 7.8 min). The combined purified fractions were lyophilized to give the title compound as a TFA salt (25.2 mg).

A NMR (300 MHz, DMSO-d6 / TFA-d) d 3.33 - 3.42 (m, 2H), 5.05 (t, J = 7.3 Hz, 1H), 7.32 - 7.41 (m, 2H), 7.47 (d, J = 7.5 Hz, 1H), 7.51 - 7.56 (m, 2H), 7.65 - 7.74 (m, 2H), 8.12 (d, J = 7.9 Hz, 1H), m / z (APCI +) M + l (301); tR = 1.89 min. The following compounds were prepared according to reaction scheme 1 using appropriate ketone or aldehyde starting material and boronic acid.

EXAMPLE 3 3-Biphenyl-3-yl-3,4-dihydroisoquinoline-1-amine trifluoroacetate XHRMN (300 MHz, DMSO-dg / TFA-d) d 3.42 - 3.45 (m, 2H), 5.11 (t, J = 6.9 Hz, 1H), 7.37 - 7.42 (m, 2H), 7.46 - 7.57 (m, 5H), 7.65-7.74 (m, 5H), 8.14 (d, J = 7.9 Hz, 1H), m / z (APCI +) M + l (299); tR = 2.15 min.

Example 4 3-Phenyl-3- (trifluoromethyl) -3,4-dihydroisoquinolin-1-amine trifluoroacetate A NMR (300 MHz, DMSO-d6 / TFA-d) d 3.82 (d, J = 16.1 Hz, 1H), 4.15 (d, J = 16.1 Hz, 1H), 7.35-7.50 (m, 4H), 7.59 ( d, J = 7.7 Hz, 3H), 7.70 (t, J = 7.5 Hz, 1H), 8.06 (d, J = 7.9 Hz, 1H), m / z (APCI +) M + l (291); tR = 1.49 min.

Example 5 3- (3'-methoxybiphenyl-3-yl) -3- (trifluoromethyl) -3,4-dihydroisoquinoline-1-amine trifluoroacetate A NMR (300 MHz, DMSO-d6 / TFA-d) d 3.84 - 3.89 (m, 4H), 4.32 (d, J = 16.2 Hz, 1H), 6.99 (dd, J = 8.0, 2.1 Hz, 1H), 7.14-7.20 (m, 2H), 7.37-7.75 (m, 7H), 7.85 (s, 1H), 8.09 (d, J = 7.9 Hz, 1H), m / z (APCI +) M + l (397); tR = 2.18 min Example 6 3- (3-Bromophenyl) -3- (trifluoromethyl) -3,4-dihydroisoquinolin-1-amine trifluoroacetate A NMR (300 MHz, DMSO-d6 / TFA-d) d 3.82 (d, J = 16.2 Hz, 1H), 4.21 (d, J = 16.2 Hz, 1H), 7.39 (t, J = 8.0 Hz, 1H) , 7.49 (t, J = 7.5 Hz, 1H), 7.61 (d, J = 7.3 Hz, 3H), 7.73 (t, J = 8.1 Hz, 1H), 7.83 (s, 1H), 8.08 (d, J = 7.8 Hz, 1H), m / z (APCI +) M + l (369); t R = 1.90 min.

Example 7 3- (3-Chlorophenyl) -3-phenyl-3,4-dihydroisoquinolin-1-amine trifluoroacetate ^ NMR (300 MHz, DMSO-d6 / TFA-d) d 4.01 (s, 2H), 7.28-7.47 (m, 10H), 7.53 (d, J = 7.4 Hz, 1H), 7.67 (t, J = 7.5 Hz, 1H), 8.03 (d, J = 7.9 Hz, 1H), m / z (APCI +) M + l (333); tR = 2.03 min.

EXAMPLE 8 3- (3'-methoxybiphenyl-3-yl) -3-phenyl-3,4-dihydroisoquinolin-1-amine trifluoroacetate A NMR (300 MHz5 DMSO-d6 / TFA-d) d 3.82 (s, 3H), 4.03 (d, J = 16.3 Hz, 1H), 4.15 (d, J = 16.2 Hz, 1H), 6.96 (dd, J = 8.1, 2.0 Hz, 1H), 7.12 - 7.19 (m, 2H), 7.28 - 7.48 (m, 9H), 7.56 -7.70 (m, 4H), 8.04 (d, J = 7.9 Hz, 1H), m / z (APCI +) M + l (405); tR = 2.39 min.

EXAMPLE 9 3- (3-Bromophenyl) -3-phenyl-3,4-dihydroisoquinolin-1-amine trifluoroacetate A NMR (300 MHz, CMSO-d6 / TFA-d) d 4.01 (s, 2H), 7.30 - 7.47 (m, 8H), 7.51 - 7.55 (m, 2H), 7.60 (s, 1H), 7.68 (t , J = 7.4 Hz, 1H), 8.03 (d, J = 7.8 Hz, 1H), m / z (APCI +) M + l (377); tR = 2.15 min.

Reaction scheme 2 EtSCN EXAMPLE 10 3- (3'-methoxybifinyl-3-yl) -3-methyl-3,4-dihydroisoquinolin-1-amine trifluoroacetate (Reaction scheme # 2, G) To 3- (3-bromofenyl) -3-methyl-3, 4-dihydroisoquinolin-1-amine (Reaction Scheme # 2, F) (50.0 mg, 0.159 mmol) was added cesium carbonate (155.0 mg, 0.476 mmol ), 3-methoxyphenylboronic acid (31.0 mg, 0.206 mmol), dichlorobis (trif enylphosphine) palladium (II) (6.0 mg, 0.008 mmol), and 1,2-dimethoxyethane: water: ethanol (7: 3: 2, 2.0) mL). The reaction was microwaved for 15 minutes at 100 ° C after which the aqueous layer was removed and the organic solvents were removed under reduced pressure. Acetonitrile: water: TFA (75: 25: 0.1), added to the brown gum, the precipitate was removed, and the filtrate was purified using RP-CLAR AG3 (tR = 13.6 min). The combined purified fractions were lyophilized to give the title compound as a TFA salt (40.3 mg, 56%). A NMR (300 MHz, DMSO-d6 / TFA-d) d 1.78 (s, 3H), 3.44 (d, J = 16.1 Hz, 1H), 3.80 - 3.85 (m, 4H), 6.96 (dd, J = 8.1 , 2.3 Hz, 1H), 7.12 - 7.18 (m, 2H), 7.35 - 7.53 (m, 6H), 7.61 - 7.67 (m, 2H), 8.04 (d, J = 7.8 Hz, 1H), m / z ( ES +) M + 1 (343); t R = 1.84 min.

Example 11 3- (3-Bromophenyl) -3-methyl-3,4-dihydroisoquinoline-1-amine (Reaction scheme # 2, To 3- (3-bromophenyl) -1- (ethylthio) -3-methyl-3,4-dihydroisoquinoline (Reaction Scheme # 2, E) (605 mg, 1.68 mmol) was added 1-hydroxybenzotriazole ammonium salt (766 mg, . 04 mmol), and DMF (5 mL). The reaction was placed in a bath 100 ° C for 5 hours. The solvent was removed under reduced pressure and the residues were taken in ethyl acetate. The organic layer was washed four times with saturated sodium bicarbonate. A white precipitate formed in the organic layer and completely filtered. The filter cake was washed with water and placed under high vacuum at 50 ° C providing the product as a white solid (145 mg, 27%). XHRMN (300 MHz, DMSO-d6 / TFA-d) d 1.71 (s, 3H), 3.41 (d, J = 16.2 Hz, 1H), 3.72 (d, J = 16.4 Hz, 1H), 7.26 (t, J = 7.9 Hz, 1H), 7.37-7.47; (m, 4H), 7.60-7.67 (m, 2H), 8.03 (d, J = 7.6 Hz, 1H), m / z (APCI +) M + l (315); tR = 1.87 min.

Example 12 3- (3-Bromophenyl) -1- (ethylthio) -3-methyl-3,4-dihydroisoquinoline (Reaction scheme # 2 To l-bromo-3- (l-chloro-l-methyl-2-phenylethyl) benzene (Reaction Scheme # 2, D) (775 mg, 2.50 mmol) was added tin (IV) chloride (0.342 mL, 2.92 mmol ) and ethyl thiocyanate (0.252 mL, 2.92 mmol). The pure reaction was placed in a 110 ° C bath for 5 minutes and quenched by adding DCM (20 mL) followed by sodium hydroxide, IN, until the aqueous layer remained basic. The aqueous layer was stirred and the organic layer was dried over sodium sulfate, the solvent was removed under reduced pressure, and the orange oil was placed under high vacuum overnight. The crude material was processed by chromatography on 20 g silica gel eluting with 30% DCM / hexanes. The solvent was removed from the combined fractions under reduced pressure to give the title compound as a semi-purified oil (794 mg). 1 H NMR (300 MHz, DMSO-d 6 / TFA-d) d 1.43 (t, J = 7.3 Hz, 3 H), 1.63 (s, 3 H), 3.31 - 3.50 (m, 4 H), 7.27 - 7.34 (m, 2 H ), 7.39-7.47 (m, 3H), 7.52-7.6 (m, 2H), 7.74-7.78 (m, 1H), m / z (ES +) M + 1 (360); tR = 2.93 min. l -Bromo-3- (l-chloro-l-methyl-2-phenylethyl) benzene (Reaction Scheme # 2, D) To a solution cooled in an ice bath 2- (3-bromophenyl) -1-phenylpropan-2-ol (Reaction scheme # 2, C) (3.70 g, 12.71 mmol) in DCM (50 mL) was inserted a tube of Teflon below the surface of the solvent and gas bubble of anhydrous hydrogen chloride in the solution. After 1 hour the addition was stopped and anhydrous sodium sulfate was added and filtered after 5 minutes. The solvent was removed from the filtrate under reduced pressure using a bath at room temperature and the resulting oil is placed under high vacuum. The material was processed by chromatography on silica gel 75 g eluting with 30% DCM / hexanes. The solvent was removed from the combined fractions under reduced pressure without heating to give the title compound as an oil (1.12g, 28%). A NMR (300 MHz, DMS0-d6) d 1.90 (s, 3H), 3.43 (s, 2H), 7.00 -7.03 (m, 2H), 7.19 - 7.23 (m, 3H), 7.33 (t, J = 7.9 Hz, 1H), 7.50-7.58 (m, 2H), 7.69 (t, J = 1.9 Hz, 1H). 141 2- (3-bromophenyl) -l-phenylpropan-2-ol (Reaction scheme # 2, C) To a room temperature solution of 3-bromobenzophenone (3.32 mL, 25.12 mmol) in THF (50 mL) was added 2.0 M benzylmagnesium chloride in THF (12.60 mL, 25.20 mmol) for 5 minutes. After 2 hours the reaction was quenched with saturated ammonium chloride. The ethyl acetate was added and the aqueous layer was removed. The organic layer was washed once with saturated ammonium chloride, once with brine, dried over sodium sulfate, and the solvent was removed under reduced pressure. The oil was processed by chromatography on 75g silica gel eluting first with a 0-15% step gradient of DCM in hexanes (5% steps) then 100% DCM. The solvent was removed from the combined purified fractions under reduced pressure to give the title compound as an oil (3.05 g, 42%). A NMR (300 MHz, 300 MHz, DMSOd6) d 1.39 (s, 3H), 2.93 (s, 2H), 7.00 - 7.05 (m, 2H), 7.12 - 7.16 (m, 3H), 7.23 (t, J = 7.9 Hz, IH), 7.34-7.40 (m, 2H), 7.55 (t, J = 1.8 Hz, 1H). The following compounds were prepared according to reaction scheme # 2 using the appropriate ketone starting material.

Example 13 3-Bifenyl-3-yl-3-methyl-3,4-dihydroisoquinolin-1-amino trifluoroacetate A NMR (300 MHz, DMSO-d6 / TFA-d) d 1.78 (s, 3 H), 3.44 (d, J = 16.2 Hz, 1 H), 3.83 (d, J = 16.3 Hz, 1 H), 7.35 - 7.52 ( m, 8H), 7.60-7.68 (m, 4H), 8.04 (d, J = 7.8 Hz, 1H), m / z (ES +) M + l (313); tR = 1.85 min.

EXAMPLE 14 3- [2- (3'-methoxybiphenyl-3-yl) ethyl] -3-methyl-3,4-d-__-thisoqu-iol_n-l-a__Lna trifluoroacetate X H NMR (300 MHz, DMSO-d 6 / TFA-d) d 1.37 (s, 3 H), 1.91 (t, J = 7.8 Hz, 2 H), 2.73 (t, J = 8.3 Hz, 2 H), 3.07 (d, J = 16.1 Hz, 1H), 3.22 (d, J = 16.2 Hz, 1H), 3.83 (s, 3H), 6.94 (dd, J = 8.0, 2.1 Hz, 1H), 7.14 - 7.20 (m, 3H), 7.33-7.40 (m, 2H), 7.45-7.74 (m, 6H), 8.08 (d, J = 7.8 Hz, 1H), m / z (APCI +) M + l (371); tR = 2.27 min.

Example 15 3- [2- (3-Bromophenyl) ethyl] -3-methyl-3,4-dihydroisoquinolin-1-amine trifluoroacetate The tertiary chloride intermediate required to make this compound was prepared using a biphasic mixture of anhydrous zinc chloride saturated 1: 1 in concentrated hydrochloric acid / chloroform. Thibblin et al, J. Am. Chem. Soc, 1977, 7926-7930. A NMR (300 MHz, DMSO-d6 / TFA-d) d 1.34 (s, 3H), 1.79 - 1.90 (m, 2H), 2.66 (t, J = 8.4 Hz, 2H), 3.04 (d, J = 16.2 Hz, 1H), 3.19 (d, J = 16.2 Hz, 1H), 7.17 -7.26 (m, 2H), 7.34 - 7.55 (m, 4H), 7.72 (t, J = 7.5 Hz, 1H), 8.08 (d , J = 7.8 Hz, 1H), m / z (APCI +) M + l (343); tR = 2.12 min.

Example 16 3- [2- (3'-methoxybiphenyl-3-yl) ethyl] -3-phenyl-3,4-dihydroisoquinoline-1-amine trifluoroacetate The tertiary chloride intermediate required to make this compound was prepared using a biphasic mixture of anhydrous zinc chloride saturated 1: 1 in concentrated hydrochloric acid / chloroform. Thibblin et al, J. Am. Chem. Soc, 1977, 7926-7930. A NMR (300 MHz, DMSO-d6 / TFA-d) d 2.31-2.44 (m, 2H), 2.57-2.78 (m, 2H), 3.60 (d, J = 16.1 Hz, 1H), 3.77 (d, J = 16.2 Hz, 1H), 3.83 (s, 3H), 6.95 (dd, J = 8.2, 1.8 Hz, 1H), 7.16 - 7.24 (m, 4H), 7.31 - 7.50 (m, 10H), 7.63 (t, J = 7.4 Hz, 1H), 8.02 (d, J = 7.8 Hz, 1H), m / z (APCI +) M + l (433); tR = 2.59 min.

Example 17 N- Trifluoroacetate. { [L-amino-3-phenyl-3- (trifluoromethyl) -3,4-dihydroisoquinolin-6-yl] methyl} methanesulfonamide (Reaction Scheme # 3, M) To an ice-cooled solution of crude 6- (aminomethyl) -3-phenyl-3- (trifluoromethyl) -3,4-dihydroisoquinolin-1-amine (Reaction scheme # 3, K) (50.0 mg, 0.157 mmol ) in DCM (1 mL) was added pyridine (15.2 uL, 0.188 mmol) and a solution of methanesulfonyl chloride (12.1 uL, 0.157 mmol) in DCM (1 mL). The reaction was warmed to room temperature and stirred 1 hour, and the solvent was removed under a stream of nitrogen. To the residue was added acetonitrile: water: TFA (75: 25: 0.1, 2 mL) and the mixture was purified using RP-CLAR AGÍ (tR = 12.1 min). The combined purified fractions were lyophilized to give the title compound as a TFA salt (25.2 mg, 31%). A NMR (300 MHz, DMSO-d6 / TFA-d) d 2.87 (s, 3H), 3.83 (d, J = 16.2 Hz, 1H), 4.14-4.23 (m, 3H), 7.38-7.46 (m, 4H) ), 7.58 (t, J = 7.6 Hz, 3H), 8.06 (d, J = 8.2 Hz, 1H), m / z (APCI +) M + l (398); tR = 1.61 min.

Example 18 N- Trifluoroacetate. { [L-amino-3-phenyl-3- (trifluoromethyl) -3,4-dihydroisoquinolin-6-yl] methyl} Acetamide (Reaction Scheme # 3, L) To an ice-cooled solution of crude 6- (aminomethyl) -3-phenyl-3- (trifluoromethyl) -3,4-dihydroisoquinolin-1-amine (Reaction scheme # 3, K) (100.0 mg, 0.313 mmol ) in DCM (1 mL) was added pyridine (30.3 uL, 0.376 mmol) and a solution of acetic anhydride (29.5 uL, 0.313 mmol) in DCM (1 mL). The reaction was warmed to room temperature and stirred 20 minutes, and the solvent was removed under a stream of nitrogen. To the residue was added acetonitrile: water: TFA (75: 25: 0.1, 2 mL) and the mixture was purified using RP-CLAR AGÍ (tR = 11.4 min). The combined purified fractions were lyophilized to give the title compound as a TFA salt (38.4 mg, 26%). A NMR (300 MHz, DMSO-d / TFA-d) d 1.91 (s, 3H), 3.81 (d, J = 16.2 Hz, 1H), 4.13 (d, J = 16.3 Hz, 1H), 4.30 (s, 2H), 7.33 (d, J = 8.1 Hz, 1H), 7.38 - 7.47 (m, 4H), 7.59 (d, J = 7.1 Hz, 2H), 8.03 (d, J = 8.2 Hz, 1H), m / z (APCI +) M + l (362); tR = 1.58 min.

EXAMPLE 19 6- (Aminomethyl) -3-phenyl-3- (trifluoromethyl) -3,4-dihydroisoquinolin-1-amine bistrifluoroacetate (Reaction scheme # 3, K) A salt HCl l-amino-3-phenyl-3- (trifluoromethyl) -3,4-dihydroisoquinoline-6-carbonitrile (Reaction Scheme # 3, H) (100.0 mg, 0.284 mmol) suspended in THF (2 mL) was added 1.0M lithium aluminum hydride in THF (1.14 mL, 1.14 mmol). After 2 hours the reaction was quenched with saturated aqueous sodium sulfate and partitioned between ethyl acetate / saturated sodium bicarbonate. The aqueous layer was removed and the organic layer was dried over sodium sulfate., the solvent was removed under reduced pressure, and the amber gum was placed under high vacuum (90 mg crude). A 40 mg portion was dissolved in acetonitrile: water: TFA (75: 25: 0.1, 2 mL) and purified using RP-CLAR AGÍ (tR = 9.8 min). The combined purified fractions were lyophilized to give the title compound as a bis-TFA salt (20.7 mg). A NMR (300 MHz, DMSO-d6 / TFA-d) d 3.85 (d, J = 16.1 Hz, 1H), 4.08-4.13 (m, 3H), 7.39-7.47 (m, 3H), 7.54-7.95 (m , 4H), 8.13 (d, J = 8.2 Hz, 1H), m / z (APCI +) M + l (320); tR = 0.45 min.

Example 20 3-Phenyl-6- (lH-tetrazol-5-yl) -3- (trifluoromethyl) -3,4-dihydroisoquinolin-1-amine trifluoroacetate (Reaction scheme # 3, T) To salt HCl l-amino-3-phenyl-3- (trifluoromethyl) -3,4-dihydroisoquinoline-6-carbonitrile (Reaction scheme # 3, H) (100.0 mg, 0.284 mmol) was added salt HCl triethylamine (117.0 mg, 0.853 mmol), sodium azide (55.0 mg, 0.853 mmol), and NMP (2.0 mL). The reaction was microwaved for 30 minutes at 150 ° C. The solvent was removed under reduced pressure and acetonitrile: water was added to the resulting gum and this was purified using RP-CLAR AGÍ (tR = 12.2 min). The combined purified fractions were lyophilized to give the title compound as a TFA salt (19.9 mg, 15%). A NMR (300 MHz, DMSO-de / TFA-d) d 3.93 (d, J = 16.2 Hz, 1H), 4.33 (d, J = 16.2 Hz, 1H), 7.35-7.46 (m, 3H), 7.63 ( d, J = 7.4 Hz, 2H), 8.11 (dd, J = 8.3, 1.4 Hz, 1H), 8.28 (d, J = 8.3 Hz, 1H), 8.33 (s, 1H), m / z (APCI +) M + l (359); tR = 1.72 min.

Example 21 l-amino-3-phenyl-3- (trifluoromethyl) -3,4-dihydroisoquinoline-6-carboxylic acid trifluoroacetate (Reaction scheme # 3, J) To salt HCl l-amino-3-phenyl-3- (trifluoromethyl) -3,4-dihydroisoquinoline-6-carbonitrile (Reaction scheme # 3, H) (50.0 mg, 0.142 mmol) was added 6N HCl (2 mL ) and the reaction was microwaved for 15 minutes at 150 ° C. The solvent was removed under reduced pressure and to the resulting gum was added acetonitrile: water: TFA (75: 25: 0.1, 2 mL) and this was purified using RP-CLAR AGÍ (tR = 11.9 min). The combined purified fractions were lyophilized to give the title compound as a TFA salt (33.8 mg, 53%). 1 H NMR (300 MHz, DMSOd 6 / TFA-d) d 3.87 (d, J = 16.2 Hz, 1H), 4.30 (d, J = 16.2 Hz, 1H), 7.35-7.46 (m, 3H), 7.60 (d, J = 7.2 Hz, 2H), 7.97 (dd, J = 8.2, 1.4 Hz, 1H), 8.18 (d, J = 8.5 Hz, 2H), m / z (APCI +) M + l (335); t R = 1.55 min.

EXAMPLE 22 L-amino-3-phenyl-3- (trifluoromethyl) -3,4-dihydroisoquinoline-6-carbonitrile HCl salt (Reaction scheme # 3, H) The HCl salt l-amino-3-phenyl-3- (tri f luoromet il) -3,4-dihydroi soquinol in- 6-carbonyl tri (Reaction scheme # 3, H) was prepared according to the scheme of reaction # 1 of 2, 2, 2-1 rif luoro- 1 -f eni 1-et anona and 2-methyl-terephononitrile. ARMN (300 MHz, DMSO-d6 / TFA-d) d 3.89 (d, J = 16.1 Hz, 1H), 4.23 (d, J = 16.3 Hz, 1H), 7.40-7.46 (m, 3H), 7.60 (d , J = 7.3 Hz, 2H), 7.98 (d, J = 8.2 Hz, 1H), 8.09 (s, 1H), 8.25 (d, J = 8.2 Hz, 1H), m / z (ES +) M + l ( 316); t R = 1.51 min.

Reaction Scheme 4 Example 23 l-amino-3- (3'-methoxybiphenyl-3-yl) -3- (rifluoromethyl) -3,4-dihydroisoquinoline-6-carboxamide trifluoroacetate (Reaction scheme # 4, R) A salt TFA of l-amino-3- (3-bromofenyl) -3- (trifluoromethyl) -3,4-dihydroisoquinoline-6-carboxamide (Reaction scheme # 4, Q) (55 mg, 0. 105 mmol)) was added potassium phosphate (65.0 mg, 0.307 mmol), 3-methoxyphenylboronic acid (30.0 mg, 0.200 mmol), dichlorobis (trifluorophosphine) palladium (II) (5.0 mg, 0.00667 mmol), and 1 , 2-dimethoxyethane: water: ethanol (7: 3: 2, 2.0 mL). The reaction was microwaved for 15 minutes at 100 ° C after which the aqueous layer was removed and the organic solvents were removed under reduced pressure. Acetonitrile and EMF were added to the brown gum, the precipitate was removed, and the filtrate was purified using RP-CLAR AG2 (tR = 8.2 min). The combined purified fractions were lyophilized to give the title compound as a TFA salt (50.7 mg, 88%). A NMR (300 MHz, DMSO-d6 / TFA-d) d 3.84 (s, 3H), 3.90 (d, J = 16.1 Hz, 1H), 4.36 (d, J = 16.3 Hz, 1H), 6.99 (dd, J = 8.2, 2.0 Hz, 1H), 7.13 - 7.20 (m, 2H), 7.40 (t, J = 8.0 Hz, 1H), 7.51 (t, J = 7.7 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.85-7.92 (m, 2H), 8.10 - 8.18 (m, 2H), m / z (APCI +) M + l (440); tR = 1.91 min.

Example 24 l-amino-3- (3-bromo-enyl) -3- (trifluoromethyl) -3,4-dihydroisoquinoline-6-carboxamide trifluoroacetate (Reaction scheme # 4,) To l-amino-3- (3-bromofenyl) -3- (trifluoromethyl) -3, 4- crude dihydroisoquinoline-6-carbonitrile (Reaction scheme # 4, N) (200.0 mg, 0.507 mmol) was added toluene (2 mL) and potassium trimethylsilanolate (98.0 mg, 0.76 mmol). The reaction was microwaved for 15 minutes at 150 ° C and the toluene was removed under reduced pressure. Acetonitrile: water: TFA (75: 25: 0.1, 2 mL) was added resulting in a precipitate. To this mixture was added 2 drops of TFA and the precipitate was stirred for 30 min, filtered, and placed under high vacuum at 50 ° C to give the product as a white TFA salt (65 mg, 24%). A NMR (300 MHz, DMSO-d6 / TFA-d) d 3.86 (d, J- 16.2 Hz, 1H), 4.26 (d, J = 16.5 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 7.58-7.65 (m, 2H), 7.84 (s, 1H), 7.92 (d, J = 9.4 Hz, 1H), 8.05 (s, 1H), 8.16 (d, J = 8.2 Hz, 1H), m / z (APCI +) M + l (412); tR = 1.62 min.

Example 25 l-amino-3- (3'-methoxybiphenyl-3-yl) -3- (trifluoromethyl) -3,4-dihydroisoquinoline-6-carboxylic acid trifluoroacetate (Reaction scheme # 4, A salt TFA l-amino-3- (3'-methoxybiphenyl-3-yl) -3- (trifluoromethyl) -3,4-dihydroisoquinoline-6-carbonityl (Reaction scheme # 4, 0) (30 mg, 0.056 mmol) was added with 6N HCl (2 mL) and the reaction was subjected to microwave for 15 minutes at 150 ° C. The solvent was removed under reduced pressure and the resulting gum was dissolved in acetonitrile / water and purified using RP-CLAR AG2 (tR = 8.2 min). The combined purified reactions were lyophilized to give the title compound as a TFA salt (10.5 mg, 34%). A NMR (300 MHz, DMSO-d5- / TFA-d) d 3.84 (s, 3H), 3.91 (d, J = 16.1 Hz, 1H), 4.45 (d, J = 16.2 Hz, 1H), 6.99 (dd) , J = 8.2, 2.3 Hz, 1H), 7.13 - 7.21 (m, 2H), 7.40 (t, J = 7.9 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.60 (d, J = 7.7 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.98 (d, J = 9.5 Hz, 1H), 8.19 - 8.23 (m, 2H), m / z (APCI +) M + l (441 ); tR = 2.04 min.

Example 26 L-amino-3- (3'-methoxybiphenyl-3-yl) -3- (trifluoromethyl) -3,4-dihydroisoquinoline-6-carbonitrile trifluoroacetate (Reaction scheme # 4, To crude l-amino-3- (3-bromofenyl) -3- (trifluoromethyl) -3,4-dihydroisoquinoline-6-carbonitrile (Reaction Scheme # 4, N) (200.0 mg, 0.507 mmol) was added carbonate of cesium (496.0 mg, 1,522 mmol), 3-methoxyphenylboronic acid (93.0mg, 0.609 mmol), dichlorobis (triphenylphosphino) palladium (II) (18.0 mg, 0.025 mmol), and 1,2-dimethoxyethane: water: ethanol (7: 3: 2, 2.0 mL ). The reaction was microwaved for 15 minutes at 150 ° C after which the aqueous layer was removed and the organic solvents were removed under reduced pressure. Acetonitrile / water was added to the brown gum, the precipitate was removed, and the filtrate was purified using RP-CLAR AG3 (tR = 14.3 min).

The combined purified fractions were lyophilized to give the title compound as a TFA salt (55.9 mg, 21%). A NMR (300 MHz, DMSO-d6 / TFA-d) d 3.85 (s, 1H), 3.93 (d, J = 16.2 Hz, 1H), 4.37 (d, J = 16. 3 Hz, 1H), 6.99 (dd, J = 8.1, 2.2 Hz, 1H), 7.13 - 7.21 (m, 2H), 7.41 (t, J = 8.0 Hz, 1H), 7.49 - 7.59 (m, 2H), 7.70 (d, J = 7.4 Hz, 1H), 7.84 (s, 1H), 8.00 (d, J = 8.2 Hz, 1H), 8.15 (s, 1H), 8.26 (d, J = 8.2 Hz, 1H), m / z (APCI +) M + l (422); tR = 2.14 min.

Example 27 1-Amino-3- (3-bromophenyl) -3- (trifluoromethyl) -3,4-dihydroisoquinoline-6-carbonitrile (Reaction scheme # 4, N) L-amino-3- (3-bromophenyl) -3- (trifluoromethyl) -3,4-dihydroisoquinoline-6-carbonitrile (Reaction scheme # 4, N) was prepared according to reaction scheme # 1 using 2-methyl-terephthalonitrile and 1- (3-bromo-phenyl) -2,2,2-trifluoro-ethanone. A NMR (300 MHz, DMSO-d6 / TFA-d) d 3.89 (d, J = 16.3 Hz, 1H), 4.26 (d, J = 16.3 Hz, 1H), 7.41 (t, J = 8.0 Hz, 1H) , 7.62 (t, J = 6.9 Hz, 2H), 7.82 (s, 1H), 8.01 (d, J = 9.2 Hz, 1H), 8.09 (s, 1H), 8.25 (d, J = 8.2 Hz, 1H) , m / z (APCI +) M + l (394); tR = 1.86 min.

Reaction scheme 5 Example 28 2- [2- (3'-methoxybiphenyl-3-yl) ethyl] -2-methyl-1,2-dihydroquinazolin-4-amine trifluoroacetate (Reaction scheme # 5, V) To crude 2- [2- (3-bromophenyl) ethyl] -2-methyl-1, 2-dihydroquinazolin-4-amine (Reaction Scheme # 5, U) (100 mg, 0.290 mmol) was added cesium carbonate. (284.0 mg, 0.871 mmol), 3-methoxyphenylboronic acid (53.0 mg, 0.349 mmol), dichlorobis (triphenylphosphino) palladium (II) (10.0 mg, 0.0145 mmol), and 1,2-dimethoxyethane: water: ethanol (7: 3) : 2, 2.0 mL). The reaction was microwaved for 15 minutes at 100 ° C after which the aqueous layer was removed and the organic solvents were removed under reduced pressure. Acetonitrile: water: TFA (75: 25: 0.1) was added to the brown gum, the precipitate was removed, and the filtrate was purified using RP-CLAR AG3 (tR = 14.3 min). The combined purified fractions were lyophilized to give the title compound as a TFA salt (42.5 mg, 30%). ARMN (300 MHz, DMSO-d6 / TFA-d) d 1.53 (s, 3H), 2.04-2.21 (m, 2H), 2.70-2.88 (m, 2H), 3.83 (s, 3H), 6.79 (t, J = 8.1 Hz, 1H), 6.86 (d, J = 8.1 Hz, 1H), 6.95 (dd, J = 7.9, 2.2 Hz, 1H), 7.15 - 7.22 (m, 3H), 7.34 - 7.50 (m, 5H), 7.85 (d, J = 8.1 Hz, 1H), m / z (APCI +) M + l (372); tR = 2.22 min.

EXAMPLE 29 2- [2- (3-Bromophenyl) ethyl] -2-methyl-1,2-dihydroquinazolin-4-amine trifluoroacetate Reaction mixture # 5, U) To crude HCl salt 2-aminobenzenecarboximidamide (Reaction scheme # 5, T) (1.00 g, 5.73 mmol) was added 4- (3-bromo-phenyl) -butan-2-one (0.866 g, 3.82 mmol) and ethanol (10 mL). The reaction was refluxed 18 hours and the solvent was removed under reduced pressure. The volume of the raw material was carried forward as it is while a portion, 100 mg, of the raw material was dissolved in acetonitrile: water: TFA (75: 25: 0.1, 2 mL) and purified using RP-CLAR AG3 (tR = 13.1 min). The combined purified fractions were lyophilized to give the title compound as a TFA salt (57.7 mg). A NMR (300 MHz, DMSO-de / TFA-d) d 1.50 (s, 3H), 1.98-2.14 (m, 2H), 2.63 - 2.81 (m, 2H), 6.76 - 6.86 (m, 2H), 7.20 - 7.28 (m, 2H), 7.36 - 7.49 (m, 3H), 7.85 (d, J = 8.1 Hz, 1H), m / z (APCI +) M + l (344); tR = 1.98 min.

Salt HCl 2-aminobenzenecarboximidamide (Reaction scheme # 5, T) To crude HCl salt 2-nitrobenzenecarboximidamide (Reaction scheme # 5, S) (4.79g, 23.75mmol) was added methanol (100 mL), palladium on carbon 10% (0.5g), and the reaction was charged with gas from hydrogen (50 PSI (3.515 kg / cm2)). The reaction was stirred on a Parr shaker for 20 minutes. The catalyst was filtered and the solvent was removed under reduced pressure to give a tan solid which was carried forward as is (6.0g). Salt of HCl 2-nor trobencencarboximidamide (Reaction scheme # 5, S) To a flask cooled in an ice bath containing solid 2-nitro-benzonitrile (5.00 g, 33.76 mmol) was added directly a THF solution of 1.0 M lithium hexamethyldisilylazide (40.5 mL, 40.5 mmol). The reaction was stirred cold for 10 minutes then warmed to room temperature. After 1.5 hours the reaction was carefully quenched with 2.0 M HCl in Et20 (50 mL). The supernatant was decanted and Et20 1 7 Additional (150 mL) was added followed by a few mL of EtOAc. After triturating for 30 min the solids were filtered and partitioned between EtOAc and IN aqueous HCl. The organic layer was washed three times with IN HCl and the combined aqueous layers were washed once with EtOAc. The aqueous solvent was removed under reduced pressure to give a brown solid which was carried forward as is. A NMR (300 MHz, DMSO-d6 / TFA-d) d 7.84 (d, J = 7.4 Hz, 1H), 7.90 - 8.03 (m, 2H), 8.36 (d, J = 8.1 Hz, 1H), m / z (ES +) M + l (166); tR = 0.67 min. The compounds below were prepared according to reaction scheme # 5 using the appropriate starting 2-nitro-benzonitrile and the subsequent ketone.

EXAMPLE 30 2- (3'-methoxybiphenyl-3-yl) -2-methyl-1,2-dihydroquinazolin-4-amine trifluoroacetate ARMN (300 MHz, DMSO-d6 / TFA-d) d 1.89 (s, 3H), 3.83 (s, 3H), 6.77 (t, J = 8.1 Hz, 1H), 6.95 - 7.03 (m, 2H), 7.13 - 7.19 (m, 2H), 7.36-7.50 (m, 4H), 7.56-7.60 (m, 1H), 7.76-7.78 (m, 2H), m / z (APCI +) M + l (344); tR = 2.04 min.

Example 31 2- (3-Bromophenyl) -2-methyl-1,2-dihydroquinazolin-4-amine trifluoroacetate A NMR (300 MHz, DMSO-d6 / TFA-d) d 1.82 (s, 3H), 6.79 (t, J = 7.3 Hz, 1H), 6.99 (d, J = 8.1 Hz, 1H), 7.34 (t, J = 7.8 Hz, 1H), 7.43 - 7.52 (m, 3H), 7.66 (t, J = 1.7 Hz, 1H), 7.78 (d, J = 8.1 Hz, 1H), m / z (APCI +) M + l (316); tR = 1.72 min.

EXAMPLE 32 4-Amino-2- [2- (3'-methoxybiphenyl-3-yl) ethyl trifluoroacetate] 2-methyl-l, 2-dihydroquinazolin-7-carboxyl A NMR (300 MHz, DMSO-dd / TFA-d) d 1.56 (s, 3H), 2.08 -2.22 (m, 2H), 2.74-2.86 (m, 2H), 3.83 (s, 3H), 6.94 (d , J = 8.1 Hz, 1H), 7.15 - 7.22 (m, 3H), 7.28 (dd, J = 8.4, 1.6 Hz, 1H), 7.37 (t, J = 7.8 Hz, 2H), 7.45 - 7.50 (m, 3H), 7.97 (d, J = 8.3 Hz, 1H), m / z (APCI +) M + 1 (416); tR = 2.13 min.

EXAMPLE 33 4-Amino-2- [2- (3-bromophenyl) ethyl] -2-methyl-1,2-dihydroquinazoline-7-carboxylic acid trifluoroacetate ARMN (300 MHz, DMSO-d6 / TFA-d) d 1.53 (s, 3H), 2.00 -2.15 (m, 1H), 2.65 - 2.79 (m, 1H), 7.20 - 7.30 (m, 3H), 7.36 - 7.44 (m, 3H), 7.97 (d, J = 8.4 Hz, 1H), m / z (APCI +) M + l (388); tR = 1.87 min.

Reaction scheme 6 EXAMPLE 34 2- [2- (3'-Methoxybiphenyl-3-yl) ethyl] -1,2-dimethyl-1,2-dihydroquinazolin-4-amine trifluoroacetate (Reaction scheme # 6, To crude 2- (methylamino) benzenecarboximidamide (113 mg, 0.757 mmol) (Reaction Scheme # 6, W) was added NMP (2.0 mL) followed by 4- (3-bromo-phenyl) -butan-2-one ( 172 mg, 0.757 mmol) and the reaction was microwaved for 30 min at 200 ° C. The NMP was removed under reduced pressure and 3-methoxyphenylboronic acid (172 mg, 1.36 mmol), cesium carbonate (740 mg, 2.27 mmol), dichlorobis (triphenylphosphino) palladium (II) (27 mg, 0.0379) was added to the crude mixture. mmol), and 1,2-dimethoxyethane: water: ethanol (7: 3: 2, 2.0 mL). The reaction was microwaved for 15 minutes at 100 ° C after which the aqueous layer was removed and the organic solvents were removed under reduced pressure. Acetonitrile: water: TFA (75: 25: 0.1), the gum was added to the gum, the precipitate was removed, and the filtrate was purified using RP-CLAR AGI (tR = 17.8 min). The combined purified fractions were lyophilized to give the title compound as a TFA salt (3.6 mg, 1%). A NMR (300 MHz, DMSO-d6 / TFA-d) d 1.53 (s, 3 H), 2.04 - 2.15 (m, 1 H), 2.30 - 2.45 (m, 1 H), 2.67 - 2.80 (m, 2 H), 2.95 (s, 3H), 3.83 (s, 3H), 6.89 - 7.02 (m, 3H), 7.16 - 7.28 (m, 3H), 7.37 (t, J = 7.7 Hz, 2H), 7.47 - 7.53 (m, 2H) ), 7.61 (t, J = 7.3 Hz, 1H), 7.93 (d, J = 6.2 Hz, 1H), m / z (ES +) M + l (386); tR = 2.14 min. 2- (Methylamino) benzenecarboximidamide (Reaction scheme # 6, W) To 2-methylamino-benzonitrile (100 mg, 0.757 mmol) was added potassium hydroxide (127 mg, 2.27 mmol), hydroxylamine hydrochloride (105 mg, 1.51 mmol), and methanol (2.0 mL). The reaction was refluxed for 18 hours after which the solvent was removed under reduced pressure and the residues were triturated with 10: 1: 1 EtOAc / DCM / MeOH. The salts were completely filtered and the solvent was removed from the filtrate under reduced pressure. To the solid brown was added EtOH (5 mL) and a non-weighed amount of Raney Nickel previously washed with EtOH. The reaction was charged with hydrogen gas (50 PSI (3.515 kg / cm2)), heated to 60 ° C, and stirred on a Parr shaker for 18 hours. The catalyst was removed and the solvent was removed from the filtrate under reduced pressure to give a greenish gum which was used as it is in the following reaction, m / z (ES +) M + 1 (150); tR - 0.36 min.

Reaction scheme 7 Example 35 2- [2- (3'-Methoxybiphenyl-3-yl) ethyl] -2-methyl-2H-1,3-benzoxazin-4-amine trifluoroacetate (Reaction scheme # 7, Z) A salt TFA - [2- (3-bromophenyl) et il] -2-met1-2H-1, 3-benzoxazin-4-amine (45 mg, 0.098 mmol) (Reaction Scheme # 7, Y) was added cesium carbonate (96 mg, 0.29 mmol), 3-methoxyphenylboronic acid (22 mg, 0.15 mmol), dichlorobis (triphenylphosphine) palladium (II) (3.4 mg, 0.0049 mmol), and 1,2-dimethoxyethane: water: ethanol (7: 3: 2, 2.0 mL). The reaction was microwaved during minutes at 100 ° C after which the aqueous layer was removed and the organic solvents were removed under reduced pressure. Acetonitrile: water: TFA (75: 25: 0.1) (2.0 mL) was added to the brown gum, the precipitate was removed, and the filtrate was purified using RP-CLAR AGÍ (tR = 16.7 min). The combined purified fractions were lyophilized to give the title compound as a TFA salt (48 mg, 101%). XH NMR (300 MHz, DMSOd6_ / TFA-d) d 1.69 (s, 3H), 2.29 (t, J- 8.3 Hz, 2H), 2.79-2.90 (m, 2H), 3.83 (s, 3H), 6.94 ( dd, J = 7.8, 2.2 Hz, 1H), 7.15 -7.22 (m, 4H), 7.29 (t, J = 8.1 Hz, 1H), 7.37 (td, J = 7.9, 2.1 Hz, 2H), 7.47 - 7.50 (m, 2H), 7.74 (dd, J = 15.7, 1.4 Hz, 1H), 8.10 (dd, J = 8.0, 1.3 H, 1H); m / z (APCI +) M + l (373); tR = 2.38 min.

Example 36 2- [2- (3-Bromophenyl) ethyl] -2-methyl-2H-l, 3-benzoxazin-4-amine trifluoroacetate (Reaction scheme # 7, Y) To 2-hydroxy-benzamidine (600 mg, 4.41 mmol) was added 4- (3-bromo-phenyl) -butan-2-one (1.00 g, 4.41 mmol), monohydrate of p-toluensul phonic acid (84 mg, 0.44 mmol), and toluene (15 mL). The reaction was equipped with a pre-filled Dean-Stark trap heated to reflux. After refluxing overnight the solvent was removed under reduced pressure and the solids placed under high vacuum. The Et20 was added and the solids were crushed for 1 hour and removed. The filtrate was removed from the solvent under reduced pressure, re-dissolved in ACN, and purified using RP-CLAR AGÍ (tR = 15.5 min). The combined purified fractions were lyophilized to give the title compound as a TFA salt (45 mg, 3%). m / z (ES +) M + 1 (345); tR = 1.88 min. eONH, Example 37 2- (3'-methoxybiphenyl-3-yl) -2-methyl-2H-l, 3-benzoxazin-4-amine trifluoroacetate (Reaction scheme # 8, EE) A crude 2- (3-bromo phenyl) -2-methyl-2H-l, 3-benzoxazin-4 -amine (Reaction Scheme # 8, DD) (70 mg, 0.162 mmol) was added cesium carbonate (211 mg, 0.216 mmol), 3-methoxyphenylboronic acid (49 mg, 0.32 mmol), dichlorobis (triphenylphosphino) palladium (II) (7.6 mg, 0.011 mmol), and 1,2-dimethoxyethane: water: ethanol (7: 3: 2, 2.0 mL). The reaction was microwaved for 15 minutes at 100 ° C after which the aqueous layer was removed and the organic solvents were removed under reduced pressure. Acetonitrile: water: TFA (75: 25: 0.1) (2.0 mL) was added to the brown gum, the precipitate was removed, and the filtrate was purified using RP-CLAR AGÍ (tR = 15.6 min). The combined purified fractions were lyophilized to give the title compound as a TFA salt (20 mg, 27%). 1U NMR (300 MHz, DMSOd6 / TFA-d) d 2.05 (s, 3H), 3.83 (s, 3H), 6.97 (dd, J = 8.1, 2.4 Hz, 1H), 7.11 - 7.22 (m, 3H), 7.35-7.49 (m, 4H), 7.59-7.64 (m, 1H), 7.70-7.75 (m, 2H), 7.99 (dd, J = 8.0, 1.3 Hz, 1H); m / z (APCI +) M + l (345); tR = 2.13 min.

Example 38 2- (3-Bromophenyl) -2-methyl-2H-1, 3-benzoxazin-4-amine (Reaction scheme # 8, DD) A salt TFA 2- (3-bromophenyl) -N-methoxy-2-methyl-2H-1, 3-benzoxazin-4-amine impure (Reaction scheme # 8, CC) (75 mg, 0.162 mmol) was added acetic acid (1.5 mL) and zinc powder (28 mg, 0.432 mmol). The reaction was stirred for 1 hour, the zinc was filtered off completely and the acetic acid was removed under reduced pressure. The solid was used as it is in the next reaction, m / z (APCI +) M + l (317); tR = 1.95 min.

Example 39 2- (3-Bromophenyl) -N-methoxy-2-methyl-2H-l, 3-benzoxazip-4-amine trifluoroacetate (Reaction scheme # 8, CC) A 2- (3-bromophenyl) -4-chloro-2-methyl-2H-l, 3-benzoxazine (Reaction scheme # 8, BB) (100 mg, 0.297 mmol) in DMF (1.0 mL) was added DIPEA (0.26 mL, 1.49 mmol) and methoxyamine hydrochloride (124 mg, 1.49 mmol). The reaction was placed in a 100 ° C bath for 10 hours and the DMF was removed under reduced pressure. The crude mixture was dissolved in acetonitrile: water: TFA (75: 25: 0.1) (4.0 mL) and purified using RP-CLAR AG2 (tR = 16.4 and 17.9 min). Two peaks with the same molecular weight were collected, combined, and lyophilized to give the title compound as a TFA salt (78 mg, 57%). 1 H NMR (300 MHz, DMSO-d 6 / TFA-d) d 1.78 (s, 3 H), 3.86 (s, 2.5 H), 3.93 (s, .5H), 6.86 (t, J = 8.2 Hz, 1H), 7.01 (d, J = 7.7 Hz, 1H), 7. 26 (d, J = 7.9 Hz, 1H), 7.37-7.42 (m, 2H), 7.52-7.54 (m, 2H), 8.03 (s, 1H); m / z (ES +) M + l (348).

Example 40 2- (3-Bromophenyl) -4-chloro-2-methyl-2H-l, 3-benzoxazine (Reaction Scheme # 8, BB) A 2- (3-bromophenyl) -2-methyl-2, 3-dihydro-4H-l, 3-benzoxazin-4-one (Reaction scheme # 8, AA) (5.OOg, 15.71 mmol) was added phosphorus oxychloride (III) (8.8 mL, 94.28 mmol) and 17! phosphorus chloride (V) (0.33 g, 1.57 mmol). The reaction was placed in a 50 ° C bath and stirred for 2 hours. The additional gold phosphide (V) chloride (0.33 g, 1.57 mmol) was added and the reaction was stirred 1 hour. Any remaining phosphorus (III) oxychloride was removed under reduced pressure and the resulting oil was added DCM / hexanes (1: 1, 25 mL). This solution was applied to silica gel 600 mL and eluted with DCM / hexanes (1: 1). The combined purified fractions were removed from solvent under reduced pressure to give the title compound as a pale oil (3.37g, 64%). A NMR (300 MHz, DMSO-d6) d 1.86 (s, 3 H), 7.10 - 7.14 (m, 2 H), 7.36 (t, J = 7.9 Hz, 1 H), 7.53 - 7.60 (m, 4 H), 7.68 (t, J = 1.8 Hz, 1H); m / z (ES +) M + l (336); tR = 2.75 min.

Example 41 2- (3-Bromofenyl) -2-methyl-2,3-dihydro-4H-l, 3-benzoxazin-4-one (Reaction scheme # 8, To salicylamide (10.00 g, 72.92 mmol) in toluene (50 mL) was added 3-bromoacetofenone (14.6 mL, 109.38 mmol) and p-toluenesulfonic acid monohydrate (1.39 g, 7.29 mmol). The reaction was equipped with a pre-filled Dean-Stark trap and refluxed overnight. The reaction was cooled to room temperature 17 then in an ice bath for 30 minutes. The resulting precipitate was filtered, washed with toluene, and placed under high vacuum at 75 ° C for 4 hours to give the title compound as a white solid (18.82g, 81%). XH NMR (300 MHz, DMSO-d6 / TFA-d) d 1.79 (s, 3H), 7.01 (dd, J = 15.0, 0.9 Hz, 1H), 7.10 (d, J = 7.8 Hz, 1H), 7.45 ( d, J = 8.0 Hz, 3H), 7.60 -7.62 (m, 2H), 7.65 (d, J = 1.7 Hz, 1H); m / z (ES +) M + l (318); tR = 2.13 rran.

Reaction scheme 9 Example 42 3- (3'-methoxybiphenyl-3-yl) -1'H-spiro [cyclohex-2-ene-1, 2'-quinazolin] -4'-amino trifluoroacetate (Reaction scheme # 9, JJ) To 3- (3'-methoxybiphenyl-3-yl) cyclohex-2-en-l-one (Reaction scheme # 9, HH) (100 mg, 0.36 mmol) was added 2-amino-benzamidine HCl salt (94mg) , 0.54 mmol) and EtOH (2.0 mL). The reaction was microwaved for 15 minutes at 100 ° C followed by 15 minutes at 150 ° C. The solvent was removed under reduced pressure, the residue was dissolved in acetonitrile: water: TFA (75: 25: 0.1) (2.0 mL), and purified using RP-HPLC AG2 (tR = 12.2 min). The combined purified fractions were lyophilized to give the title compound as a TFA salt (51 mg, 28%). ARMN (300 MHz, DMSO-d6 / TFA-d) d 1.85-1.97 (m, 1H), 2.02-2.24 (m, 1H), 2.38-2.46 (m, 1H), 2.54-2.61 (m, 2H), 2.96 (dd, J = 30.4, 17.4 Hz, 1H), 3.84 (s, 3H), 6.36 (d, J = 20.0 Hz, 1H), 6.79-6.97 (m, 3H), 7.21 - 7.27 (m, 2H) , 7.37-7.74 (m, 6H), 7.87 (dd, J = 7.0, 3.7 Hz, 1H); m / z (ES +) M + l (396); tR = 2.11 min. 3- (3 '-Metoxibifenyl-3-yl) ci clohex-2-en-l -one (Reaction Scheme # 9, HH) To 3- (3-bromophenyl) cyclohex-2-en-l-one (Reaction Scheme # 9, FF) (3.00 g 11.95 mmol) was added potassium phosphate (5.07 g, 23.89 mmol), 3-methoxyphenylboronic acid (2.18 g, 14.34 mmol), dichlorobis (triphenylphosphino) palladium (II) (0.42 g, 0.60 mmol), and 1,2-dimethoxyethane: water: ethanol (7: 3: 2, 10.0 mL). The reaction was heated in a J-Kem block at 80 ° C for 1 hour. The aqueous layer was removed and the organic solvent was removed under reduced pressure. To the resulting brown oil was added 30% EtOAc / hexanes and the solution was applied to 50 g of silica gel eluting with the same solvent system. The combined purified fractions were removed from the solvent under reduced pressure to give the title compound as a yellow oil (3.25g, 98%). A NMR (300 MHz, DMSO-d6) d 2.07 (quintet, J = 6.3 Hz, 2H), 2.40 (t, J = 6.7 Hz, 2H), 2.85 (t, J = 6.6 Hz, 2H), 3.84 (s) , 3H), 6.45 (s, 1H), 6.96 (ddd, J = 8.1, 2.5, 0.9 Hz, 1H), 7.25 - 7.30 (m, 2H), 7.39 (t, J = 8.1 Hz, 1H), 7.53 ( t, J = 7.7 Hz, 1H), 7.63-7.67 (m, 1H), 7.72-7.75 (m, 1H), 7.86 (t, J = 1.7 Hz, 1H); m / z (APCI +) M + l (279); tR = 2.65 min. 3- (3-bromo phenyl) cyclohex-2-en-l-one (Reaction scheme # 9, FF) To a cold solution -78 ° C of 1,3-dibromobenzene (10.3 mL, 84. 8 mmol) in THF (200 mL) was added 2.5M n-butyllithium (33.9 mL, 84.8 mmol) for 10 minutes. After cold stirring for 10 minutes, 3-ethoxy-cyclohex-2-enone (18.5 mL, 127.2 mmol) in THF (30 mL) was added dropwise over 5 minutes. After cold stirring for 30 minutes the reaction was warmed to room temperature and quenched with water (50 mL). The mixture was partitioned between Et20 / saturated NaCl and the aqueous layer was removed. The organic layer was washed three times with saturated NaCl, dried over MgSO 4, the solvent was removed under reduced pressure, and the residue placed under high vacuum to give the product as a yellow oil. (18.83g, 88%). A NMR (300 MHz, DMSO-d6) d 2.04 (quintet, J = 6.1 Hz, 2H), 2.38 (t, J = 6.3 Hz, 2H), 2.76 (t, J = 6.0 Hz, 2H), 6.36 (d , J = 1.4 Hz, 1H), 7.41 (td, J = 7.9, 1.2 Hz, 1H), 7.65 (td, J = 7.0, 1.0 Hz, 2H), 7.82 (d, J = 1.6 Hz, 1H); m / z (APCI +) M + 1 (251); tR = 2.36 min.

Example 43 3- (3'-Methoxybiphenyl-3-yl) -1'H-spiro [cyclohexane-1,2' -quinazolin] -4'-amino trifluoroacetate (Reaction scheme # 9, II) To 3- (3'-methoxybiphenyl-3-yl) cyclohex-2-en-l-one (Reaction scheme # 9, HH) (50 mg, 0.18 mmol) in MeOH (5 mL) was added Pd / C 10% (10 mg) and the reaction was charged with H2 (50 PSI (3.515 kg / cm2)). After stirring on a Parr shaker for 1.5 hours the catalyst was completely filtered and the organic solvent was removed under reduced pressure. To the resulting residue was added crude 2-amino-benzamidine HCl salt (75 mg, 0.43 mmol) and EtOH (2.0 mL). The reaction was microwaved for 20 minutes at 150 ° C. The solvent was removed under reduced pressure and the residue was dissolved in acetonitrile: water: TFA (75: 25: 0.1) (2.0 mL) and purified using RP-CLAR AG2 (tR = 13.0 min). The combined purified fractions were lyophilized to give the title compound as a TFA salt (19 mg, 21%). ARMN (300 MHz, DMSO-d6 / TFA-d) d 1.51 - 1.96 (m, 6H), 2.14 - 2.37 (m, 2H), 2.93 - 3.15 (m, 1H), 3.83 (s, 3H), 6.77 - 6.87 (m, 2H), 6.95 (dd, J = 8.1, 2.3 Hz, 1H), 7.11 - 7.25 (m, 3H), 7.35 - 7.52 (m, 5H), 7.84 (d, J = 8.3 Hz, 1H); m / z (APCI +) M + l (398); tR = 2.45 min.

Example 44 3-Methyl-5- (trimethylsilyl) thiophene-2-carbonitrile (Reaction scheme # 10, A) To a stirred solution -78 ° C of freshly prepared LDA (2.17 g, 20.30 mmol) in THF (20 mL) was slowly added 3-methylthiophen-2-carbonitrile (2.50 g, 20.30 mmol) in THF (10 mL) and the reaction was stirred at -78 ° C for 5 minutes. To this anion trimethylsilyl chloride (2.84 mL, 22.33 mmol) was slowly added and the reaction was stirred at -78 ° C for 30 minutes. The ice bath was stirred, warmed to room temperature and stirred an additional hour. The THF was removed under reduced pressure at room temperature to produce a bright yellow oil. The crude compound was purified using flash chromatography (neutral activated alumina, 10: 90 ether: hexanes) to give the title compound as a volatile, clear, colorless oil (2.52 g, 64%). NMR (300 MHz, DMSO-dd): d 0.34 (s, 9H); 2.43 (s, 3H); 6.95 (s, 1H). CLAR (Platform 3): 2.93 minutes, m / z (APCI) 237 M + 41.

Example 45 5- (3-Bromophenyl) -2- (trimethylsilyl) -4,5-dihydrothieno [2, 3-c] pyridin-7-amine (Reaction scheme # 10, B) In the first reaction vessel, to a stirred solution -10 ° C of 3-bromobenzaldehyde (0.12 mL, 1.02 mmol) in THF (2 mL) was added lithium bis (trimethylsilyl) amide (1.02 mL, 1.02 mmol) and the The reaction was stirred at 0 ° C for 2 hours. In the second reaction vessel, to a stirred solution -78 ° C of freshly prepared LDA (0.11 g, 1.02 mmol) in THF (2 mL) was slowly added DMPU (0.19 mL, 1.53 mmol) and Example 44 (0.20 g, 1.02 mmol) in THF (1 mL) and the anion was stirred at -78 ° C for 30 minutes. To this anion the preformed silylimine was added rapidly by cannula and the mixture was stirred at -78 ° C for 30 minutes. The mixture was warmed to 0 ° C and stirred in an additional 30 minutes. The reaction mixture was quenched with IN HCl, extracted with CH2C12 (3 X 20 mL) and dried over Na2SO4. The solvent was removed under reduced pressure to yield the crude title compound as an amber oil. (0.39 g, quantitative). At NMR (300 MHz, DMSOd6): d 0.37 (s, 9H); 1.97 (m, 2H); 4.96 (m, 1H); 7.12 (s, 1H), 7.45 (m, 4H); 10.26 (br s, 1H); 10.75 (br S, 1H). CLAR (Platform 3): 2.34 minutes, m / z (APCI) 279 M, 281 M + 2.

Example 46 5- (3-Bromophenyl) -4,5-dihydrothieno [2,3-c] pyridin-7-amine trifluoroacetate (Reaction scheme # 10, C) To a solution of crude Example 45 (0.39 g, 1.02 mmol) in THF (20 mL) tetrabutylammonium fluoride (1.50 mL, 1.53 mmol) was added and the mixture was stirred at room temperature for 18 hours. The THF was removed under reduced pressure to produce an amber colored syrup. To this was added EtOAc (50 mL) and washed with saturated Na 2 HCO 3 (2 X 25 mL) and brine (1 X 25 mL). After drying over Na 2 SO 4, the EtOAc was removed under reduced pressure to yield a yellow waxy solid. To this was added acetonitrile: water: TFA (75: 25: 0.1, 3 mL) and the resulting precipitate was removed. The filtrate was purified using RP-CLAR (Ret t time: 20.00 mins). The combined purified fractions were lyophilized to give the title compound as a white TFA salt (0.07 g, 40%). ? H NMR (300 MHz, DMSO-d6): d 3.28 (br m, 2H); 5.09 (dd, J = 8.4 Hz, 1H); 7.22 (d, J = 4.8 Hz, 1 H); 7.39 (m, 2 H); 7.57 (m, 1 H); 7.65 (s, 1 H); 8.17 (d, J = 4.8 Hz, 1H); 8.59 (br s, 1H); 9.50 (br s, 1H). CLAR (Platform 8): 1.58 minutes, m / z (APCI) 307 M, 309 M + 2. CLAR conditions Preparative inverse phase: The compounds were purified on a Phenomenex Luna Cl 8 reverse phase column (250 X 21 mm, 10 micron particle size). The crude compounds were solubiliZed in water acti on: TFA (75: 25: 0. 1) . An elution gradient (0% acetonitrile waiting for 10 mins, 0-50% acteonitrile for 12 mins, waiting for 50% acteonitrile for 3 mins, 50-100% acteonitrile for 7 mins, flow ratio at 40 ml / min , 220 nm) to provide the purified title compounds.

Example 47 5- (3'-methoxybiphenyl-3-yl) -4,5-dihydrothieno [2,3-c] pyridin-7-amine trifluoroacetate (Reaction scheme # 10, D) To a solution of Example 46 (0.007 g, 0.017 mmol) in 7: 3: 2 1, 2 -dime t oxiet an: water: ethanol (1 mL) was added potassium triphosphate (0.009 g, 0.04 mmol), acid 3-me t-oxy-phenyl-lboronic acid (0.005 g, 0.033 mmol), and dichlorobis (tri-phenyl-phosphono) palladium (II) (0.002 g, 0.002 mmol). The contents were sealed in a microwave reaction vessel and heated by microwave at 100 ° C for 10 minutes. The solvent was removed under reduced pressure until produce a black oil. To this was added acetonitrile: water: TFA (75: 25: 0.1, 3 mL) and the resulting precipitate was removed. The filtrate was purified using RP-CLAR (Ret time: 15.52 mins). The combined purified fractions were lyophilized to give the title compound as a white TFA salt (0.004 g, 57%). X H NMR (300 MHz, DMSO-d 6): d 3.36 (br m, 2H); 3.83 (s, 3H); 5.16 (dd, J = 6.6 Hz, 1H); 6.96 (d, J = 7.8 Hz, 1H); 7.22 (m, 3H); 7.40 (m, 2 H); 7.47 (t, J = 7.8 Hz, 1 H); 7.67 (d, J = 7.8 Hz, 1 H); 7.73 (s, 1H); 8.54 (d, J = 4.8 Hz, 1H); 8.44 (br s, 1H); 9.45 (br s, 1H). CLAR (Platform 3): 2.06 minutes, m / z (APCI) 335 M + l. CLAR conditions preparative reverse phase: The compounds were purified on a Phenomenex Luna Cl 8 reverse phase column (250 X 21mm, 10 micron particle size). The crude compounds were solubilized in acteonitrile: water: TFA (75: 25: 0.1). An elution gradient (0-50% acteonitrile for 12 mins, standby in 50% acteonitrile for 3 mins, 50-100% acteonitrile for 7 mins, flow ratio at 40 ml / min, 220 nm) to provide the purified title compounds . The additional compounds are shown in Table 1.

Table 1 Ex. Compound Chemistry NMR m / z M + l CL ionization (min) 48 Tr i f luoroacetate 4. NMR (300 MHz, DMSO- 369 (APCI +) 2 of 5-phen_l-5-dg / TET? -d) d 0.32 (s, (trifluoranethyl) - 9H), 3.74 (d, J = 16.8 2- (tr? met? l? l? l) - Hz, 1H), 4.19 (d, J = 4.5-16.8 Hz, 1H), 7.48 dihydrothieno [2,3- (m, 4H), 7.60 (m, c] p? pd? n-7-amin 2H), 9.02 (br s, 1H), 10.18 (s, 1H) 49 5-Fen L-5-4N NMR (300 MHz, DMSO-297 (APCI +) 1.65 (trifluoromethyl) -of / TFA-d) d 3.73 (d, 4.5- J = 17.1 Hz, 1H), 4.22 dihydrothieno [2,3- (d, J = 17.1 Hz, 1H), c] p? R? D? N-7-am? Na 7.27 (d, J = 5.1 Hz, 1H), 7.48 (m, 3H), 7.60 (m, 2H), 8.18 (d, J = 5.1 Hz, 1H), 8.99 (br s, 1H), 10.19 (s, 1H) 50 Trifluoroacetate 4i NMR (300 MHz, DMSO- 447, 449 2.20 of 5- (3- dg / TFA-d) d 0.34 (s, (APCI +) bromophen? l) -5- 9H), 3.75 (d, J = 17.1 (trifluoramethyl) - Hz, 1H), 4.23 (d, J = 2- (tr? met? ls? l? l) - 17.1 Hz, 1H ), 7.43 4.5- (m, 2H), 7.65 (m, dihydrothieno [2, 3- 2H), 7.82 (s, 1H), c] p? R? D? N-7-apu.na 9.03 ( br s, 1H), 10.23 (s, 1H) X Compound Chemistry NMR m / z M + l CL ionization (min) 51 Trif luoroacetate of XH NMR (300 MHz, DMSO- 375, 377 1.84 5- (3-bromofeml) -5- of / TFA-d) d 3.74 (d, (APCI +) (tpfluoromethyl) - J = 17.1 Hz, 1H ), 4.27 4.5- (d, J = 17.1 Hz, 1H), dihydrothieno [2, 3-7.27 (d, J = 5.1 Hz, c] p? Pd? N-7 -amine 1H), 7.44 (t, J = 8.1 Hz, 1H), 7.64 (m, 2H), 7.83 (s, 1H), 8.20 (d, J = 5.1 Hz, 10 1H), 9.03 (br s, 1H), 10.23 (s, 1H) 52 Tpfluoroacetate 4. NMR (300 MHz, DMSO- 2.10 - (3'-dg / TFA-d) d 3.78 (d, methox? B? Phen?) -3- J = 17.4 Hz, 1H), 3.84? L) -5- (s, 3H), 4.37 (d, J = (trifluoromethyl) - 17.4 Hz, 1H), 6.98 15 4.5- (d, J = 7.5 Hz, 1H), d hydrothieno [2.3- 7.17 (s, 1H), 7.21 c] p ? r? d? n-7-amine (d, J = 7.5 Hz, 1H), 7.31 (d, J = 5.1 Hz, 1H), 7.41 (t, J = 7.5 Hz, 1H), 7.56 (m, 20 2H), 7.73 (d, J = 7.5 Hz, 1H), 7.85 (s, 1H), 8.19 (d, J = 5.1 Hz, 1H), 8.73 (br s, 1H), 10.16 (s, 1H).

Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference (including, but not limited to, journal articles, US and non-US patents, patent application publications, international patent application publications, and the like) cited in the present application is incorporated herein by reference. reference in its entirety. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (83)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. A compound of the formula I or a salt, tautomer, or pharmaceutically acceptable in vivo hydrolysable precursor thereof, characterized in that: G is O, NR7 or CR8R9; R1 is H, C? -6 alkyl, haloalkyl C? _6, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C? -6 alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4 or 5 R14; R2 is Q or -L-Q; or R1 and R2 together with the carbon atom to which they are attached form a cycloalkyl group of 3-14 members or heterocycloalkyl group of 3-14 members, each substituted by Cy2 and optionally substituted by 1, 2, 3, 4 or 5 TO; R3, R4, R5 and R6 are, independently, H, CN, N02, ORa, SRa, OC (0) R, OC (0) ORb, OC (0) NRcRd, C (0) Ra, C (0) ORb , C (0) NRcRd, NRcRd, NRcC (0) Ra, NRcC (0) ORb, NRcS (0) 2Rb, S (0) Ra, S (0) NRcRd, S (0) 2R3, S (0) 2NRcR , Ci-io alkyl, Ci-io haloalkyl, C2-? 0 alkenyl, C2_? alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C? _? 0 alkyl, haloalkyl C C 10, C 2 0 alkenyl, C 2 0 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 R 14; R7 is H, C (0) R3, C (0) ORb, C (0) NRcRd, S (0) R3, S (0) 2R3, C? _? Alkyl, C2_? Alkenyl, C2_? Alkynyl? , cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C-io alkyl, alkenyl C2-? or alkynyl C2_? or, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl are each optionally substituted with 1, 2, 3, 4 or 5 R14; R8 and R9 are, independently, H, CN, N02, OR3, SRa, OC (0) R3, OC (0) ORb, C (0) ORb, OC (0) NRcRd, NRcRd, NRcC (0) R3, NRcC (0) ORb, NRcS (0) 2Rb, S (0) Ra, S (0) NRcRd, S (0) 2R3, S (0) 2NRcRd, C?-Α 0 alkyl, C? _? Halo haloalkyl, C2_ al alkenyl, C2_? Alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the alkyl C? -?, Ci-io haloalkyl, C2_? Alkenyl, C2-? Or alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 R14; or R8 and R9 together with the carbon atom to which they are attached form a cycloalkyl group of 3-14 members or heterocycloalkyl of 3-14 members, each optionally substituted by 1, 2 or 3 R14; R12 and R13 are each, independently, H, halo, C? _ Alkyl, C? _4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, N02, ORa ', SRa', C (0) Rb ', C ( 0) NRc > Rd ', C (0) ORa', OC (0) Rb ', OC (0) NRc'Rd', NRc'Rd ', NRC'C (O) Rd', NRcA (0) ORa ', NRc'S (0) ) 2Rb ', S (0) Rb', S (0) NRc'Rd ', S (0) 2Rb', or S (O) 2NRc'Rd '; R14 is halo, C4_4alkyl, C5_haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, N02, ORa, SRa ', C (0) Rb', C (0) NRc'Rd ', C (0) ) ORa ', OC (0) Rb', OC (O) NRC 'Rd', NRc'Rd ', NRc'C (0) Rd', NRcX (0) ORa ', NRC' S (O) 2Rb ', S (O) Rb ', S (0) NRc'Rd ', S (0) 2Rb', or S (0) 2NRc'Rd '; Q is aryl, cycloalkyl, heteroaryl or heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 Cy1 or A1; L I is alkenylenyl C2_? 0, alquinilenilo C2_? 0, (CR12R13) q, (CR12R13) qlo (CR12R13) q2, (CR12R13) q? S (CR12R13) q2, (CR12R13) q? S02 (CR12R13) q2, (CR12R13 ) qiSO (CR12R13) q2, (CR12R13) qiCO (CR12R13) q2, (CR12R13) q? NRe (CR12R13) q2, or (CR12R13) q? CONRe (CR12R13) q2; Cy1 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 A2; Cy2 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 A3; A1 is halo, CN, N02, 0Ra, SRa, C (0) Rb, C (0) NRcRd, C (0) ORa, OC (0) Rb, OC (0) NRcRd, NRcRd, NRA (0) Rd, NRA (0) ORa ,, NRcS (0) Rb, NRcS (0) 2Rb, S (0) Rb, S (0) NRcRd, S (0) 2Rb, S (0) 2NRcRd, C 4 alkoxy, haloalkoxy C? _, Amino, C? -4 alkylamino, C2_8 dialkylamino, C? -6 alkyl, C2_6 alkenyl, C2_6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl, wherein each of C? _6 alkyl, C2_6 alkenyl, C2_6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4 or 5 halo, C6_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C4_4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, N0, OR3, SRa, C (0) Rb, C (0) NRcRd, C (0) ORa, OC (0) Rb, OC (0) NRcRd, NRcRd, NRCC (O) Rd, NRcC ( 0) ORa, NRcS (0) Rb, NRcS (0) 2Rb, S (0) Rb, S (0) NRcRd, S (0) 2Rb, or S (0) 2NRcRd; A2, A3, and A4 are each, independently, halo, CN, N02, ORa, SRa, C (0) Rb, C (0) NRcRd, C (0) ORa, OC (0) Rb, OC (0) NRcRd, NRcRd, NRcC (0) Rd, NRA (0) ORa,, NRcS (0) Rb, NRcS (0) 2Rb, S (0) Rb, S (0) NRcRd, S (0) 2Rb, S (0) ) 2NRcRd, C 1 -4 alkoxy, C 1 -4 haloalkoxy, amino, C 4 alkyl alkylamino, C 2-8 dialkylamino, C 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein each of C

1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2, 3, 4 or 5 halo, C? -6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C? -4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, N02, 0Ra, SRa, C (0 ) Rb, C (0) NRcRd, C (0) 0Ra, 0C (0) Rb, OC (0) NRcRd, NRcR, NRA (0) Rd, NRA (0) 0Ra, NRCS (0) Rb, NRcS (0) ) 2Rb, S (0) Rb, S (0) NRcRd, S (0) 2Rb, or S (0) 2NRcRd; Ra and Ra 'are each, independently, H, C? _6 alkyl, C? _6 haloalkyl, C2_6 alkenyl, C2_6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C 6 alkyl, haloalkyl C 6, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C alkyl? -6, haloalkyl A-6, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; Rb and Rb 'are each, independently, H, C? -6 alkyl, C? _6 haloalkyl, C2_6 alkenyl, C2_6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C C-6 alkyl, C?-6 haloalkyl, C 2-6 alkenyl, C

2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C-alkyl ? 6, C? _6 haloalkyl, C? -6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; Rc and Rd are each, independently, H, C?-C? Alkyl, C?-C halo haloalkyl, C2__ alkenyl, C2__ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein alkyl C? _? _, C? _6 haloalkyl, C2_6 alkenyl, C2_6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C? -6 alkyl, C? _6 haloalkyl, C? -6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or Rc and Rd together with the N atom to which they bind form a heterocycloalkyl group of 4-, 5-, 6- or 7- members; Rc 'and Rd' are each, independently, H, C? -? Alkyl or, C? -? Haloalkyl, C2_6 alkenyl, C2_6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C? -? alkyl, C? _6 haloalkyl, C2_6 alkenyl, C2_6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C? -6 alkyl, C? _6 haloalkyl, C? -6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or Rc 'and Rd' together with the N atom to which they are bonded form a heterocycloalkyl group of 4-, 5-, 6- or 7-membered; Re is H, C? -4 alkyl, C? -4 haloalkyl, C2_4 alkenyl, C2_4 alkynyl, or CO- (C? _4 alkyl); q is 1, 2, 3, 4, 5 or 6; ql is 0, 1, 2 or 3; and q2 is 0, 1, 2 or 3; with the proviso that: a) when G is NH or CH2; R2 is -L-Q; L is -CH2, -CH = CH-, or -C = C-; and R1 is H or methyl, then Q is another unsubstituted phenyl; and b) when G is NR7 or CR8R9; R7 is H, methyl, or phenyl optionally substituted by halo; R8 and R9 are each, independently, H or methyl; R2 is Q; and R1 is H or methyl, then Q is aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each substituted by at least one Cy3 and optionally substituted by 1, 2 or 3 A4. 2. The compound according to claim 1, characterized in that R1 is H, C? _6 alkyl, C? _6 haloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C?-C alquilo alkyl, C halo-haloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4 or 5 R 14. 3. The compound according to claim 1, characterized in that R1 is H, C6 alkyl, C6_6 haloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein C6_6 alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, OH, C? -6 alkoxy, C? -6 haloalkoxy, C? -6 haloalkyl, C? _6 alkyl, C2_6 alkenyl, C2_6 alkynyl, arylalkyl, cycloalkylalkyl , heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. 4. The compound according to claim 1, characterized in that R1 is C6-6 haloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein the aryl, heteroaryl, arylalkyl or heteroarylalkyl is optionally substituted by 1, 2 or 3 substituents independently selected halo, CN, OH, C6_6 alkoxy, C6_6 haloalkoxy, C6_6 haloalkyl, C6_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. 5. The compound according to claim 1, characterized in that: R2 is Q or -L-Q; and Q is aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally substituted by 1, 2 or 3 A1. 6. The compound according to claim 1, characterized in that: R2 is Q or -L-Q; and Q is aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each substituted by at least one Cy1 and optionally substituted by 1, 2 or 3 A1. 7. The compound according to claim 1, characterized in that: R2 is Q or -L-Q; and Q is aryl or heteroaryl, each substituted by at least one Cy1 and optionally substituted by 1, 2 or 3 A1. 8. The compound according to claim 1, characterized in that: R2 is Q or -L-Q; and Q is aryl substituted by at least one Cy1 and optionally substituted by 1, 2 or 3 A1. 9. The compound according to claim 1, characterized in that: R2 is Q or -L-Q; and Q is phenyl substituted by at least one Cy1 and optionally substituted by 1, 2 or 3 A1. 10. The compound according to claim 1, characterized in that: R2 is Q or -L-Q; and Q is phenyl substituted by Cy1. 11. The compound according to claim 1, characterized in that: R2 is Q or -L-Q; and Q is phenyl substituted by Cy1; and Cy1 is aryl or heteroaryl, each optionally substituted with 1, 2, 3, 4 or 5 A2. 12. The compound according to claim 1, characterized in that: R2 is Q or -L-Q; and Q is phenyl substituted by Cy1; and Cy1 is aryl optionally substituted with 1, 2 or 3 substituents independently selected from halo, CN, OH, C? -6 alkoxy, C? _6 haloalkoxy, C? _6 haloalkyl, C? -6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. 13. The compound according to claim 1, characterized in that: R2 is Q or -L-Q; and Q is phenyl substituted by Cy1, wherein Cy1 is substituted at the meta position of the phenyl; and Cy1 is aryl optionally substituted with 1, 2 or 3 substituents independently selected from halo, CN, OH, C? -6 alkoxy, C? _6 haloalkoxy, C-6 haloalkyl, C? -6 alkyl, C2-6 alkenyl, alkynyl C2-6, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. The compound according to claim 1, characterized in that R is Q. 15. The compound according to claim 1, characterized in that: R2 is -L-Q; and L is C2-? o alkenylenyl, C2-alkynynylnyl or (CR12R13) q. 16. The compound according to claim 1, characterized in that: R2 is -L-Q; and L is (CR12R13) q. 17. The compound according to claim 1, characterized in that: R2 is -L-Q; and L is (CR12R13) q; and q is 2. 18. The compound according to claim 1, characterized in that: R1 and R2 together with the carbon atom to which it bonds form a cycloalkyl group of 3-14 members or group 4

3-14 membered heterocycloalkyl, each substituted by Cy2 and optionally substituted by 1, 2 or 3 A4; Cy2 is aryl or heteroaryl, each optionally substituted with 1, 2, 3, 4 or 5 A3. 19. The compound according to claim 1, characterized in that: R1 and R2 together with the carbon atom to which they are bound form a cycloalkyl group of 3-14 members substituted by Cy2 and optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, OH, C6-6 alkoxy, C6-6 haloalkoxy, C6-6 haloalkyl, C6-6 alkyl, C2_6 alkenyl, C2-6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl; Cy2 is aryl or heteroaryl, each optionally substituted with 1, 2 or 3 A3; and A3 is aryl or heteroaryl, each optionally substituted with 1, 2 or 3 substituents independently selected from halo, CN, OH, C6-6 alkoxy, C6-6 haloalkoxy, C6-6 haloalkyl, C6-6 alkyl, C2_6 alkenyl, C2_6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. 20. The compound according to claim 1, characterized in that: R1 and R2 together with the carbon atom to which they are bonded form a 3-14 membered cycloalkyl group substituted by Cy2 and optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, OH, C6-alkoxy, C6-6 haloalkoxy, C6-6 haloalkyl, C6-6 alkyl, C2_6 alkenyl, C2_6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. Cy2 is phenyl substituted with 1 or 2 A3; and A3 is aryl or heteroaryl, each optionally substituted with 1, 2 or 3 substituents independently selected from halo, CN3 OH, C6 alkoxy, C6-6 haloalkoxy, C6-6 haloalkyl, C6-6 alkyl, C2-6 alkenyl , C2_6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. 21. The compound according to claim 1, characterized in that R3, R4, R5 and R6 are, independently, H, CN, C (0) Ra, C (0) ORb, C (0) NRcRd, C alquilo alkyl- ? 0, haloalkyl C? _? O, C2-? Al alkenyl, C2-? Or alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C? _? Alkyl, haloalkyl C? ? -10, C2-10 alkenyl, C2_10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 R14. 22. The compound according to claim 1, characterized in that R3, R4, R5 and R6 are, independently, H, CN, C (0) Ra, C (0) ORb, C (0) NRcRd, C? -? 0 alkyl, haloalkyl d-xo, C2_10 alkenyl, C2-? _ Alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl , arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C?-10 alkyl, C? _? haloalkyl, C 2 - o alkenyl, C 2? 0 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 substituents independently selected from halo, C? _4 alkyl, C? -4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NRc'Rd ', NRc'C (0) Rd' , NRC C (0) ORa 'and NRC'S (0) 2Rb'. 23. The compound according to claim 1, characterized in that R3, R4, R5 and R6 are, independently, H. 24. The compound according to claim 1, characterized in that R4 is CN, C (O) Ra, C (0) ORb, C (0) NRcRd, C? -10 alkyl, C? -? Haloalkyl, C2-? 0 alkenyl, C2-? Or alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or Heterocycloalkylalkyl, wherein the C C-10 alkyl, C-10 haloalkyl, C2-10 alkenyl, C2- o alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 substituents independently selected from halo, C? -4 alkyl, C? _4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NRc'Rd ', NRc'C (0) R', NRc'C (0) ORa 'and NRc's (O) 2Rb '. 25. The compound according to claim 1, characterized in that G is O. 26. The compound according to claim 1, characterized in that: G is NR7 or CR8R9; and R7, R8 and R9 are each, independently, H, C? -? 0 alkyl, C? -? haloalkyl, C2-10 alkenyl, C2-10 alkynyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl or heterocycloalkylalkyl. 27 The compound according to claim 1, characterized in that: R 1 is C 1-6 haloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein the aryl, heteroaryl, arylalkyl or heteroarylalkyl is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, OH, C6-6 alkoxy, C6-6 haloalkoxy, C6-6 haloalkyl, 0-6 alkyl, C2-6 alkenyl, C2_6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclic alkali, , cycloalkyl, heteroary and heterocycloalkyl; R2 is Q; and Q is aryl or heteroaryl, each optionally substituted by 1, 2 or 3 A1. 28. The compound according to claim 1, characterized in that it has the structure of formula II: II wherein: R1 is H3, C6_6 alkyl, C6_6 haloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein C6_6 alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN3 OH3 C6-6 alkoxy, C6-6 haloalkoxy, C6-6 haloalkyl, C6-6 alkyl, C2-6 alkenyl, C2_6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. L is C4_4 alkylenyl; n is 0 or 1; Cy3 is aryl or heteroaryl, each optionally substituted with 1, 2 or 3 substituents independently selected from halo, CN, OH, C6-6 alkoxy, C6-6 haloalkoxy, C6-6 haloalkyl, C6-6 alkyl, C2_6 alkenyl, C2-6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. 29. The compound according to claim 28, characterized in that: L is CH2CH2; and Cy 3 is aryl optionally substituted with 1, 2 or 3 substituents independently selected from halo, CN, OH, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. 30. The compound according to claim 1, characterized in that it has the structure of the formula Illa or Illia, where: r is 0, 1, 2 or 3; and Cy 4 is aryl optionally substituted with 1, 2 or 3 substituents independently selected from halo, CN, OH, C 1-6 alkoxy, C 1-6 haloalkoxy, C? -6 haloalkyl, C? _6 alkyl, C2_6 alkenyl, C2_6 alkynyl, arylalkyl , cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. 31. The compound according to claim 1, characterized in that it has the structure of the formula IVa or formula IVb: IVa IVb wherein: r is 0, 1, 2 or 3; and Cy 4 is aryl optionally substituted with 1, 2 or 3 substituents independently selected from halo, CN, OH, C 1-6 alkoxy, C 1-6 haloalkoxy, C? -6 haloalkyl, C? _6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. 32. A compound of the formula V: V or a salt, tautomer, or pharmaceutically acceptable in vivo hydrolysable precursor thereof, characterized in that: R21 is H, C? _6 alkyl, C? _6 haloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C6_6 alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4 or 5 R29; R22 is Q or -L-Q; R23, R24, R25 and R26 are, independently, H, Si (C? -? O) alkyl, CN, N02, ORa, SRa, OC (0) Ra, OC (0) ORb, OC (0) NRcRd, C (0) Ra, C (0) ORb, C (0) NRcRd, NRcRd, NRcC (0) Ra, NRX (0) ORb, NRcS (0) 2Rb, S (0) Ra, S (0) NRcRd, S (0) 2Ra, S (0) 2NRcRd, C?-0 0 alkyl, C?-Halo halo haloalkyl, C C_10 alkenyl, C2_ alqu alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C? _? 0 alkyl, C? -? _ haloalkyl, C2_? alkenyl, C2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl , cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 R29; R27 and R28 are each, independently, H, halo, C? _4 alkyl, C? _4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, N02, ORa ', SRa', C (O) Rb ', C ( 0) NRc'Rd ', C (0) ORa', OC (0) Rb ', OC (O) NRC' Rd ', NRc'Rd', NRc'C (0) Rd ', NRcX (0) ORa' , NRc'S (0) 2Rb ', S (0) Rb', S (0) NRc'Rd ', S (0) 2Rb', or S (0) 2NRc'Rd '; R29 is Halo, C? -4 alkyl, C halo _ haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, N02, ORa ', SRaA C (0) Rb', C (0) NRc'Rd ', C (0) ) ORa ', OC (0) Rb', OC (O) NRC 'Rd', NRc'Rd ', NRc'C (0) Rd', NRC 'C (O) ORa', NRC 'S (O) 2Rb ', S (0) Rb', S (0) NRc'Rd ', S (0) 2Rb', or S (0) 2NRc'Rd '; Q is aryl, cycloalkyl, heteroaryl or heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 Cy1 or A1; L is alkenylenyl C2 _? _, C2_? Alkynynyl, (CR2R28) q, (CR2R28) q10 (CR27R28) q2, (CR27R28) qS (CR27R28) q2, (CR27R28) qlS02 (CR27R28) q2, (CR27R28) ) qiSO (CR27R28) q2, (CR27R28) q? CO (CR27R28) q2, (CR2 R28) q? NRA CR2 R28) q2, or (C CR27R28) q? CONRe (CR2 R28) q2; Cy1 is aryl, heteroaryl, cycloalkyl or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 A2; A1 is Halo, CN, N02, 0Ra, SRa, C (0) Rb, C (0) NRcRd, C (0) ORa, OC (0) Rb, OC (0) NRcRd, NRcRd, NRcC (0) Rd, NRcC (0) ORa, NRcS (0) Rb, NRcS (0) 2Rb, S (0) Rb, S (0) NRcRd, S (0) 2Rb, S (0) 2NRcRd, C 4 alkoxy, haloalkoxy C ? 4, amino, alkylamino C? _4, dialkylamino C2-b, C? -6 alkyl, C2-6 alkenyl, C2_6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl, wherein each of C? _6 alkyl, C2- alkenyl 6, C2_6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4 or 5 halo, C? -6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C? -4 haloalkyl, aryl, cycloalkyl, heteroaryl , heterocycloalkyl, CN, N02, 0Ra, SRa, C (0) Rb, C (0) NRcRd, C (0) 0Ra, 0C (0) Rb, 0C (0) NRcRd, NRcRd, NRcC (0) R, NRcC (0) ORa, NRcS (0) Rb, NRcS (0) 2Rb, S (0) Rb, S (0) NRcRd, S (0) 2Rb, or S (0) 2NRcRd; A2 is Halo, CN, N02, ORa, SRa, C (O) Rb, C (0) NRcRd, C (0) ORa, OC (0) Rb, OC (0) NRcRd, NRcRd, NRcC (0) Rd, NRcC (0) ORa, NRcS (0) Rb, NRcS (0) 2Rb, S (0) Rb, S (0) NRcRd, S (0) 2Rb, S (0) 2NRcRd, alkoxy d_4, haloalkoxy C? _4, amino, alkylamino C? _4, dialkylamino C2-b, C? -6 alkyl, C2_6 alkenyl, C2_6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein each of the alkyl6, C2_6 alkenyl, C2_6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2 , 3, 4 or 5 halo, alkyl d-6, alkenyl C2_6, alkynyl C2_6, haloalkyl C? _, Aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, N02, 0Ra, SRa, C (0) Rb, C (0) NRcRd, C (0) ORa, OC (0) Rb, OC (0) NRcRd, NRcR, NRcC (0) Rd, NRcC (0) ORa, NRcS (0) Rb, NRcS (0) 2Rb, S (0) Rb, S (0) NRcRd, S (0) 2Rb, or S (0) 2NRcRd; Ra and Ra are each, independently, H, alkyl d-6, haloalkyl d_6, alkenyl C2_6, alkynyl C2-6, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein alkyl d- C6-C6 haloalkyl, C2_6 alkenyl, C2_6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C? -alkyl, C? _6 haloalkyl, aryl , arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; Rb and Rb 'are each, independently, H, C? -6 alkyl, haloalkyl d_6, C2_6 alkenyl, C2_6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein alkyl d-6 / haloalkyl d-6, C2_6 alkenyl, C2_6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, d-6 alkyl, C? _6 haloalkyl, C_6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; Rc and Rd are each, independently, H, C? _ Alquilo alkyl, C? _6 haloalkyl, C2_6 alkenyl, C2_6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the alkyl d -?, haloalkyl C? _, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C? -6 alkyl, C6_6 haloalkyl, C6_6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or Rc and Rd together with the N atom to which they are bonded form a 4, 5, 6 or 7 membered heterocycloalkyl group; Rc 'and Rd' are each, independently, H, C? _ Alkyl, haloalkyl d-6, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C alquilo _ ?alkyl, C? _6 haloalkyl, C2_6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C? _ alquiloalkyl , C? -6 haloalkyl, d6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or Rc 'and Rd' together with the N atom to which they are bonded form a 4, 5, 6 or 7 membered heterocycloalkyl group; Re is H, alkyl d4, haloalkyl d-, C2_4 alkenyl, C2_4 alkynyl, or CO- (C4_4 alkyl); q is 1, 2, 3, 4, 5 or 6; ql is 0, 1, 2 or 3; and q2 is 0, 1, 2 or 3; with the proviso that: when R21, R23 and R24 are each H, and R22 is Q, then Q is aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each substituted by at least one Cy1 and optionally substituted by 1, 2 or 3 A1; and when R21, R23 and R24 are each H, R22 is -L-Q and L is - C = C-, then Q is different from unsubstituted phenyl. 33. The compound according to claim 32, characterized in that R21 is H, C? _6 alkyl, C? -6 haloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C? -6 alkyl, haloalkyl C? -6, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4 or 5 R29. 34. The compound according to claim 32, characterized in that R21 is H, C? _6 alkyl, C? -6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein each of d-6 alkyl, d6 haloalkyl, arylalkyl , heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, OH, C6_6 alkoxy, haloalkoxy d6, C6_6 haloalkyl, C6_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. 35. The compound according to claim 32, characterized in that R21 is C? _6 alkyl or C? -6 haloalkyl, each optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, OH, C? 6, haloalkoxy d-6, haloalkyl d6, C6-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. 36. The compound according to claim 32, characterized in that R21 is C? -6 alkyl or C? _6 haloalkyl. 37. The compound according to claim 32, characterized in that R21 is haloalkyl C? _6. 38. The compound according to claim 32, characterized in that R21 is trifluoromethyl. 39. The compound according to claim 32, characterized in that R21 is H. 40. The compound according to claim 32, characterized in that: R22 is Q or -L-Q; and Q is aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally substituted by 1, 2 or 3 A1. 41. The compound according to claim 32, characterized in that: R22 is Q or -L-Q; and Q is aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each substituted by at least one Cy1 and optionally substituted by 1, 2 or 3 A1. 42. The compound according to claim 32, characterized in that: R22 is Q or -L-Q; and Q is aryl or heteroaryl, each substituted by at least one Cy1 and optionally substituted by 1, 2 or 3 A1. 43. The compound according to claim 32, characterized in that: R22 is Q or -L-Q; and Q is aryl substituted by at least one Cy1 and optionally substituted by 1, 2 or 3 A1. 44. The compound according to claim 32, characterized in that: R22 is Q or -L-Q; and Q is phenyl substituted by at least one Cy1 and optionally substituted by 1, 2 or 3 A1. 45. The compound according to claim 32, characterized in that: R22 is Q or -L-Q; and Q is phenyl substituted by Cy1. 46. The compound according to claim 32, characterized in that: R22 is Q or -L-Q; Q is phenyl substituted by Cy1; and Cy1 is aryl or heteroaryl, each optionally substituted with 1, 2, 3, 4 or 5 A2. 47. The compound according to claim 32, characterized in that: R22 is Q or -L-Q; Q is phenyl substituted by Cy1; and Cy1 is aryl optionally substituted with 1, 2 or 3 substituents independently selected from halo, CN, OH, C6-6 alkoxy, haloalkoxy d-6, haloalkyl d-6 C6-6 alkyl, C2_6 alkenyl, C2-6 alkynyl , arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. 48. The compound according to claim 32, characterized in that: R22 is Q or -L-Q; Q is phenyl substituted by Cy1, wherein Cy1 is substituted at the meta position of the phenyl; and Cy1 is aryl optionally substituted with 1, 2 or 3 substituents independently selected from halo, CN, OH, C6 alkoxy, haloalkoxy d6, C6-6 haloalkyl, C6_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, arylalkyl, cycloalkylalkyl , heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. 49. The compound according to claim 32, characterized in that R22 is Q. 50. The compound according to claim 32, characterized in that: R22 is -L-Q; Y L is C2-10 alkenylenyl or (CR27R28) q. 51. The compound according to claim 32, characterized in that: R22 is -L-Q; and L is (CR27R28) q. 52. The compound according to claim 32, characterized in that R23, R24, R25 and R26 are, independently, H, CN, C (0) Ra, C (0) ORb, C (0) NRcRd, C alquilo alkyl ???, haloalkyl C? _10, C2-10 alkenyl, C2-? al alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein alkyl d-?, haloalkyl d-?, alkenyl C2-? O, C2_? Alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 R29. 53. The compound according to claim 32, characterized in that R23, R24, R25 and R26 are, independently, H, Si (C? .10 alkyl) 3, CN, C (0) Ra, C (0) ORb, C (0) NRcRd, C_? 0 alkyl, C? _? Haloalkyl, C2_? 0 alkenyl, C2-? Or alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein alkyl d -?, haloalkyl C? _? 0, C2_? alkenyl, C2-? alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 substituents independently selected from halo, C? _4 alkyl, C? - haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NRc'Rd ', NRc'C (0) Rd', NRc'C (0) ORa 'and NRC'S (0) 2Rb'. 54. The compound according to claim 32, characterized in that R23, R24, R25 and R26 are, independently, H, Si (C? _? O) alkyl, CN, alkyl d_?, Haloalkyl C? _? , C2_? 0 alkenyl, C2-? 0 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein each of C? _? o alkyl, C? -? haloalkyl, C2 - alkenyl ?, C2-? or alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 substituents independently selected from halo, OH, alkoxy d4, alkyl d4, haloalkyl d4, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. 55. The compound according to claim 32, characterized in that R23 and R24 are, independently, H, alkyl d-? O, haloalkyl C? _? O, C2_? Alkenyl, C2-? Al alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl. 56. The compound according to claim 32, characterized in that R23 and R24 are, independently, H or C? -? O alkyl. 57. The compound according to claim 32, characterized in that R25 and R26 are, independently, H, Si (C? -? O) alkyl, CN, C (0) Ra, C (0) ORb, C (0) ) NRcRd, C? _10 alkyl, C? -? Haloalkyl, C2_? 0 alkenyl, C2_? Alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl. 58. The compound according to claim 32, characterized in that it has the structure of formula VI: SAW. 59. The compound according to claim 58, characterized in that R21 is H, C? _6 alkyl or C? _6 haloalkyl, each optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, OH, C? -6 alkoxy , C6-haloalkoxy, C6-6 haloalkyl, C6-6 alkyl, C2-b alkenyl, C2_6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. 60. The compound according to claim 58, characterized in that R21 is C6-6 alkyl or d6 haloalkyl. 61. The compound according to claim 58, characterized in that R21 is haloalkyl C? -6. 62. The compound according to claim 58, characterized in that Q is aryl, cycloalkyl, heteroaryl or heterocycloalkyl, each substituted by at least one Cy1 and optionally substituted by 1, 2 or 3 A1. 63. The compound according to claim 58, characterized in that Q is aryl substituted by at least one Cy1 and optionally substituted by 1, 2 or 3 A1. 64. The compound according to claim 58, characterized in that Q is phenyl substituted by at least one Cy1 and optionally substituted by 1, 2 or 3 A1. 65. The compound according to claim 58, characterized in that Q is phenyl substituted by at least one Cy1 in the meta position and optionally substituted by 1, 2 or 3 A1. 66. The compound according to claim 62, characterized in that R21 is H, C? -6 alkyl or haloalkyl d-6, each optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, OH, C? -6 alkoxy, C? _6 haloalkoxy, d6 haloalkyl, C? _6 alkyl, C2_6 alkenyl, C2_6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl. 67. The compound according to claim 62, characterized in that R21 is H, alkyl d6 or haloalkyl d6. 68. The compound according to claim 62, characterized in that R21 is H. 69. The compound according to claim 58, characterized in that R23 and R24 are, independently, H or C? -? 0 alkyl. 70. A compound, characterized in that it is selected from: 3- (3'-Methoxybiphenyl-3-yl) -3,4-dihydroisoquinolin-1-amine trifluoroacetate; 3- (3-bromophenyl) -3,4-dihydroisoquinolin-1-amine trifluoroacetate; 3-Biphenyl-3-yl-3,4-dihydroisoquinolin-1-amine trifluoroacetate; 3-Phenyl-3- (trifluoromethyl) -3,4-dihydroisoquinolin-1-amine trifluoroacetate; 3- (3'-Methoxybiphenyl-3-yl) -3- (trifluoromethyl) -3,4-dihydroisoquinolin-1-amine trifluoroacetate; 3- (3-bromophenyl) -3- (trifluoromethyl) trifluoroacetate - 3, 4-dihydroisoquinolin-1-amine; 3- (3-Chlorophenyl) -3-phenyl-3,4-dihydroisoquinolin-1-amine trifluoroacetate; 3- (3'-Methoxybiphenyl-3-yl) -3-phenyl-3,4-dihydroisoquinolin-1-amine trifluoroacetate; 3- (3-bromophenyl) -3-phenyl-3,4-dihydroisoquinolin-1-amine trifluoroacetate; 3- (3'-Methoxybiphenyl-3-yl) -3-methyl-3, -dihydroisoquinolin-1-amine trifluoroacetate; 3- (3-bromophenyl) -3-methyl-3,4-dihydroisoquinolin-1-amine; 3- (3-bromophenyl) -1- (ethylthio) -3-methyl-3,4-dihydroisoquinoline; 3-Biphenyl-3-yl-3-methyl-3,4-dihydroisoquinolin-1-amine trifluoroacetate; 3- [2- (3'-Methoxybiphenyl-3-yl) ethyl] -3-methyl-3,4-dihydroisoquinolin-1-amine trifluoroacetate; 3- [2- (3-bromophenyl) ethyl] -3-methyl-3,4-dihydroisoquinolin-1-amine trifluoroacetate; 3- [2- (3'-Methoxybiphenyl-3-yl) ethyl] -3-phenyl-3,4-dihydroisoquinolin-1-amine trifluoroacetate; N- trifluoroacetate. { [L-Amino-3-phenyl-3- (trifluoromethyl) -3,4-dihydroisoquinolin-6-yl] methyl} methanesulfonamide; N- trifluoroacetate. { [l-Ammo-3-phenyl-3- (trifluoromethyl) -3,4-dihydroisoquinolin-6-yl] methyl} acetamide; 6- (Aminomethyl) -3-phenyl-3- bistrifluoroacetate (trifluoromethyl) -3,4-dihydroisoquinolin-1-amine; 3-Phenyl-6- (1H-tetrazol-5-yl) -3- (trifluoromethyl) -3,4-dihydroisoquinoline-1-amine trifluoroacetate; l-Amino-3-phenyl-3- (trifluoromethyl) -3,4-dihydroisoquinoline-6-carboxylic acid trifluoroacetate; HCl l-Amino-3-phenyl-3- (trifluoromethyl) -3,4-dihydroisoquinoline-6-carbonitrile salt; l-Amino-3- (3'-methoxybiphenyl-3-yl) -3- (trifluoromethyl) -3,4-dihydroisoquinoline-6-carboxamide trifluoroacetate; l-Amino-3- (3-bromophenyl) -3- (trifluoromethyl) -3,4-dihydroisoquinoline-6-carboxamide trifluoroacetate; l-Amino-3- (3'-methoxybiphenyl-3-yl) -3- (trifluoromethyl) -3,4-dihydroisoquinoline-6-carboxylic acid trifluoroacetate; l-amino-3- (3'-methoxybiphenyl-3-yl) -3- (trifluoromethyl) -3,4-dihydroisoquinoline-6-carbonitrile trifluoroacetate; l-Amino-3- (3-bromophenyl) -3- (trifluoromethyl) -3,4-dihydroisoquinoline-6-carbonitrile trifluoroacetate; 2- [2- (3'-methoxybiphenyl-3-yl) ethyl] -2-methyl-1,2-dihydroquinazolin-4-amino trifluoroacetate; 2- [2- (3-bromophenyl) ethyl] -2-methyl-1,2-dihydroquinazolin-4-amine trifluoroacetate; 2- (3'-Methoxybiphenyl-3-yl) -2-methyl-1,2-dihydroquinazolin-4-amine trifluoroacetate; 2- (3-bromophenyl) -2-methyl-1,2-dihydroquinazolin-4-amine trifluoroacetate;

4-Amino-2- [2- (3 '-methoxybiphenyl-3-yl) ethyl] -2-methyl-1,2-dihydroquinazoline-7-carboxylic acid trifluoroacetate; 4-Amino-2- [2- (3-bromophenyl) ethyl] -2-methyl-1,2-dihydroquinazoline-7-carboxylic acid trifluoroacetate; trifluoroacetate 2- [2- (3'-methoxybiphenyl-3-yl) ethyl] -1,2-dirnethyl-1,2-dihydroquinazolin-4-amine; trifluoroacetate 2- [2- (3'-methoxybiphenyl-3-yl) ethyl] -2-methyl-2H-l, 3-benzoxazin-4-amine; trifluoroacetate 2- [2- (3-bromophenyl) ethyl] -2-methyl-2H-l, 3-benzoxazin-4-amine; trifluoroacetate 2- (3'-methoxybiphenyl-3-yl) -2-methyl-2HA 1,3-benzoxazin-4-amine; 2- (3-bromophenyl) -2-methyl-2H-l, 3-benzoxazin-4-amine; trifluoroacetate 2- (3-bromophenyl) -N-methoxy-2-methyl-2Jf-1,3-benzoxazin-4-amine; 2- (3-bromophenyl) -4-chloro-2-methyl-2H-l, 3-benzoxazine; 2- (3-bromophenyl) -2-methyl-2, 3-dihydro-4H-l, 3-benzoxazin-4-one; trifluoroacetate 3- (3'-methoxybiphenyl-3-yl) -l'H-spiro [cyclohex-2-ene-l, 2'-quinazolin] -4'-amino; trifluoroacetate 3- (3'-methoxybiphenyl-3-yl) -1'H-spiro [cyclohexane-1,2' -quinazolin] -4'-amino; 3-Methyl-

5- (trimethylsilyl) thiophene-2-carbonitrile; 5- (3-bromophenyl) -2- (trimethylsilyl) -4,5-dihydrothieno [2,3- c] pyridin-7-amine; trifluoroacetate 5- (3-bromophenyl) -4,5-dihydrothieno [2,3-c] pyridin-7-amine; trifluoroacetate 5- (3'-methoxybiphenyl-3-yl) -4,5-dihydrothieno [2, 3-c] pyridin-7-amine; trifluoroacetate 5-Phenyl-5- (trifluoromethyl) -2- (trimethylsilyl) -4,5-dihydrothieno [2,3-c] pyridin-7-amine; 5-Phenyl-5- (trifluoromethyl) -4,5-dihydrothieno [2,3-c] pyridin-7-amine; trifluoroacetate 5- (3-bromophenyl) -5- (trifluoromethyl) -2- (trimethylsilyl) -4,5-dihydrothieno [2,3-c] pyridin-7-amine; trifluoroacetate 5- (3-bromophenyl) -5- (trifluoromethyl) -4,5-dihydrothieno [2, 3-c] pyridin-7-amine; trifluoroacetate 5- (3'-methoxybiphenyl-3-yl) -5- (trifluoromethyl) -4,5-dihydrothieno [2,3-c] pyridin-7-amine or a salt, an alternative salt, tautomer, or hydrolysable precursor pharmaceutically acceptable in vivo thereof. 71. A pharmaceutical composition, characterized in that it comprises as the active ingredient a therapeutically effective amount of the compound according to any of claims 1 to 70 in association with the pharmaceutically acceptable excipients, carriers or diluents. 72. The compound in accordance with any of the claims 1 to 70, or a pharmaceutically acceptable salt thereof, characterized in that it is for use as a medicament. 73. The use of a compound according to any of claims 1 to 70, as a medicament for treating or preventing a pathology related to Aß. 74. The use of a compound according to any of claims 1 to 70, as a medicament for treating or preventing an Aβ-related pathology, wherein the pathology related to Aß is Down syndrome, an amyloid ß angiopathy, amyloid angiopathy cerebral, hereditary cerebral hemorrhage, a disorder associated with cognitive impairment, MCI ("mild cognitive impairment"), Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with Alzheimer's disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or basal cortical degeneration. 75. The use of a compound according to any of claims 1 to 70 in the manufacture of a medicament for treating or preventing an Aβ-related pathology. 76. The use of a compound in accordance with any of claims 1 to 70 in the manufacture of a medicament for treating or preventing a pathology related to Aß, wherein the pathology related to Aß is Down syndrome, an amyloid ß angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, a disorder associated with cognitive impairment, MCI ("mild cognitive impairment"), Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with Alzheimer's disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or basal cortical degeneration. 77. A method for inhibiting BACE activity, characterized in that it comprises contacting the BACE with a compound according to any of claims 1 to 70. 78. A method for treating or preventing an Aβ-related pathology in a mammal, characterized in that it comprises administering to the patient a therapeutically effective amount of the compound according to any of claims 1 to 70. 79. The method according to claim 78, characterized in that the pathology related to Aß is Down Syndrome, an amyloid angiopathy, Amyloid angiopathy cerebral, hereditary cerebral hemorrhage, a disorder associated with cognitive impairment, MCI ("mild cognitive impairment"), Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with Alzheimer's disease, dementia mixed vascular origin, dementia of degenerative origin, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or basal cortical degeneration. 80. The method according to claim 78, characterized in that the mammal is a human. 81. A method for treating or preventing an Aβ-related pathology in a mammal, characterized in that it comprises administering to the patient a therapeutically effective amount of the compound according to any one of claims 1 to 70 and at least one agent that increases cognition, an agent that increases memory or inhibition of choline esterase. 82. The method according to claim 81, characterized in that the pathology related to Aß is Down syndrome, an ß amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, a disorder associated with cognitive impairment, MCI ("mild cognitive impairment"), Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with Alzheimer's disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or basal cortical degeneration. 83. The method according to claim 81, characterized in that the mammal is a human.