BACKGROUND OF THE INVENTION

The critical function of mitochondria in eukaryotic cells is now well defined (Henze, K., et al.Nature2003, 426, 127; Saraste, M. W.Science1999, 283, 1488; McBride, H. M., et al.Curr. Biol.2006, 16, R551; Newmeyer, D. D., et al. Cell 2003, 112, 481; Graier, W. F.Eur. J. Physiol.2007, 455, 375; Bras, M., et al. Biochemistry (Moscow) 2005, 70, 231; and Fiore, C., et al.Biochimie1998, 80, 13). Their essential role in energy metabolism through the production of adenosine-5′-triphosphate (ATP) is one of the main points which can affect the fate of cells (Saraste, M. W.Science1999, 283, 1488; and McBride, H. M., et al.Curr. Biol.2006, 16, R551). This ATP production is the result of conversion of ADP in mitochondrial complex V. This process involves protons transported from the inner mitochondrial membrane to the intermembrane space which is coupled with an electron flow through mitochondrial complexes I-IV. This process is called oxidative phosphorylation (OXPHOS). The decline in mitochondrial function is connected to aging, neurodegenerative diseases and many complex mitochondrial diseases (Markesbery, W. R., et al.Brain Pathol.1999, 9, 133; Calabrese, V., et al.Neurol. Sci.2005, 233, 145; Lin, M. T., et al.Nature2006, 443, 787; DiMauro, S., et al.Annu. Rev. Neurosci.2008, 31, 91; and Armstrong, J. S., et al.FASEB J.2010, 24, 2152). Currently there is a need for new compounds that protect mitochondrial function.

SUMMARY OF THE INVENTION

The invention provides compounds that protect the mitochondrial function. Accordingly the invention provides a compound of formula I:



wherein R1is hydrogen or C1-6alkyl;

R2is C1-20alkyl, C2-20alkenyl or C2-20alkynyl, wherein the C1-20alkyl, C2-20alkenyl and C2-20alkynyl are optionally substituted with one or more groups independently selected from —F, —Cl, —Br, —I, —ORa, —SRa, —N(Ra)2, oxo, —NO2and —CN;

R3is —OR5or —NR6R7;

R4is —OR8or —NR9R10;

R5is C3-10cycloalkyl or C1-8alkyl; wherein C3-10cycloalkyl and C1-8alkyl are optionally substituted with one or more groups independently selected from C1-4alkyl, C1-4haloalkyl, —F, —Cl, —Br, —I, —ORb, —SRb, —N(Rb)2, oxo, —NO2and —CN;

R6is C1-6alkyl, C2-6alkenyl or C2-6alkynyl, and wherein the C1-6alkyl, C2-6alkenyl and C2-6alkynyl are optionally substituted with one or more groups independently selected from —F, —Cl, —Br, —I, —ORc, —SRc, —N(Rc)2, oxo, —NO2and —CN; R7is C1-6alkyl, C2-6alkenyl or C2-6alkynyl, and wherein the C1-6alkyl, C2-6alkenyl and C2-6alkynyl are optionally substituted with one or more groups independently selected from —F, —Cl, —Br, —I, —ORd, —SRd, —N(Rd)2, oxo, —NO2and —CN; or R6and R7taken together with the nitrogen to which they are attached form a 3-10 membered heterocycle that is optionally substituted with one or more groups independently selected from C1-4alkyl, C1-4haloalkyl, —F, —Cl, —Br, —I, —ORe, —SRe, —N(Re)2, oxo, —NO2and —CN;

R8is C3-10cycloalkyl or C1-8alkyl; wherein C3-10cycloalkyl and C1-8alkyl are optionally substituted with one or more groups independently selected from C1-4alkyl, C1-4haloalkyl, —F, —Cl, —Br, —I, —ORf, —SRf, —N(Rf>, oxo, —NO2and —CN;

R9is C1-6alkyl, C2-6alkenyl or C2-6alkynyl, and wherein the C1-6alkyl, C2-6alkenyl and C2-6alkynyl are optionally substituted with one or more groups independently selected from —F, —Cl, —Br, —I, —ORg, —SRg, —N(Rg)2, oxo, —NO2and —CN; R10is C1-6alkyl, C2-6alkenyl or C2-6alkynyl, and wherein the C1-6alkyl, C2-6alkenyl and C2-6alkynyl are optionally substituted with one or more groups independently selected from —F, —Cl, —Br, —I, —ORh, —SRh, —N(Rh)2, oxo, —NO2and —CN; or R9and R10taken together with the nitrogen to which they are attached form a 3-10 membered heterocycle that is optionally substituted with one or more groups independently selected from C1-4alkyl, C1-4haloalkyl, —F, —Cl, —Br, —I, —ORi, —SRi, —N(Ri)2, oxo, —NO2and —CN;

each Rais independently hydrogen or C1-4alkyl; or two Rataken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each Rbis independently hydrogen or C1-4alkyl; or two Rbtaken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each Rcis independently hydrogen or C1-4alkyl; or two Rctaken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each Rdis independently hydrogen or C1-4alkyl; or two Rdtaken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each Reis independently hydrogen or C1-4alkyl; or two Retaken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each Rfis independently hydrogen or C1-4alkyl; or two Rftaken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each Rgis independently hydrogen or C1-4alkyl; or two Rgtaken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each Rhis independently hydrogen or C1-4alkyl; or two Rhtaken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; and

each Riis independently hydrogen or C1-4alkyl; or two Ritaken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

or a pharmaceutically acceptable salt thereof.

The invention also provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

The invention also provides a method for treating mitochondrial disease, neurodegenerative disease, cardiovascular disease, cancer or diabetes in an animal comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof to the animal.

The invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in medical therapy.

The invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof for the prophylactic or therapeutic treatment of mitochondrial disease, neurodegenerative disease, cardiovascular disease, cancer or diabetes.

The invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof to prepare a medicament for treating mitochondrial disease, neurodegenerative disease, cardiovascular disease, cancer or diabetes in an animal (e.g. a mammal such as a human).

The invention also provides processes and intermediates disclosed herein that are useful for preparing a compound of formula I or a salt thereof.

