Provided herein are compounds that inhibit HDAC6, a protein whose activity is associated with a variety of diseases (e.g., cancer, neurological disorders). Also provided are pharmaceutical compositions and kits comprising the compounds, and methods of treating HDAC6-related diseases and disorders (e.g., Alzheimer's disease, cancer) with the compounds in a subject, by administering the compounds and/or compositions described herein.

The present invention provides a compound having the structure:

##STR00001## wherein R.sub.1 is H or a protecting group; R.sub.2 and R.sub.3 are each independently H, halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkyl-C(O)NHR.sub.6, C.sub.1-C.sub.6 alkyl-C(O)OR.sub.6, wherein R.sub.6 is H, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl or C.sub.2-C.sub.6 alkynyl, or R.sub.2 and R.sub.3 combine to form a 3-7 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; and R.sub.4 and R.sub.5 are each independently halo.

The present invention relates to an improved asymmetric synthesis of azaspiro or diazaspiro compound (hereafter referred to as the compound 5, (5.sup.A) or (5.sup.N)) or their pharmaceutically acceptable salts and derivatives; through the formation of intermediate compounds 4, (4.sup.A) or (4.sup.N) respectively. The process comprises an unusual substrate specific highly diastereoselective as well as enantio-enriched 1-substituted 2-azaspiro[3.3]heptane or 1-substituted 2-diazaspiro[3.3]heptane compounds with high diastereoselectivity by addition of a cyclobutane carboxylate anion to a Davis-Ellman's imine, followed by reduction and cyclisation resulting in the selective formation of azaspiro or diazaspiro intermediate compound 4, (4.sup.A) or (4.sup.N); which on subsequently removing the sulfinyl group provides corresponding azaspiro or diazaspiro compound 5, (5.sup.A) or (5.sup.N) respectively.

The present invention relates to an improved asymmetric synthesis of azaspiro or diazaspiro compound (hereafter referred to as the compound 5, (5.sup.A) or (5.sup.N)) or their pharmaceutically acceptable salts and derivatives; through the formation of intermediate compounds 4, (4.sup.A) or (4.sup.N) respectively. The process comprises an unusual substrate specific highly diastereoselective as well as enantio-enriched 1-substituted 2-azaspiro[3.3]heptane or 1-substituted 2-diazaspiro[3.3]heptane compounds with high diastereoselectivity by addition of a cyclobutane carboxylate anion to a Davis-Ellman's imine, followed by reduction and cyclisation resulting in the selective formation of azaspiro or diazaspiro intermediate compound 4, (4.sup.A) or (4.sup.N); which on subsequently removing the sulfinyl group provides corresponding azaspiro or diazaspiro compound 5, (5.sup.A) or (5.sup.N) respectively.

Provided are novel compounds of Formula (I or Ia′): and pharmaceutically acceptable salts thereof, which are useful for treating a variety of diseases, disorders or conditions, associated with LSD1. Also provided are pharmaceutical compositions comprising the novel compounds of Formula (I or Ia′), pharmaceutically acceptable salts thereof, and methods for their use in treating one or more diseases, disorders or conditions, associated with LSD1.

Provided are novel compounds of Formula (I or Ia′): and pharmaceutically acceptable salts thereof, which are useful for treating a variety of diseases, disorders or conditions, associated with LSD1. Also provided are pharmaceutical compositions comprising the novel compounds of Formula (I or Ia′), pharmaceutically acceptable salts thereof, and methods for their use in treating one or more diseases, disorders or conditions, associated with LSD1.

Compounds of Formula (I), and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof, pharmaceutical compositions containing them, methods of making them, and methods of using them including methods for treating disease states, disorders, and conditions associated with MGL modulation, such as those associated with pain, psychiatric disorders, neurological disorders (including, but not limited to depression, major depressive disorder, treatment resistant depression, anxious depression, autism spectrum disorders, Asperger syndrome, and bipolar disorder), cancers and eye conditions:

##STR00001##

wherein R.sup.1, , R.sup.3, and L are as defined herein.

Compounds of Formula (I), and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof, pharmaceutical compositions containing them, methods of making them, and methods of using them including methods for treating disease states, disorders, and conditions associated with MGL modulation, such as those associated with pain, psychiatric disorders, neurological disorders (including, but not limited to depression, major depressive disorder, treatment resistant depression, anxious depression, autism spectrum disorders, Asperger syndrome, and bipolar disorder), cancers and eye conditions:

##STR00001##

wherein R.sup.1, , R.sup.3, and L are as defined herein.

The compounds of the invention as shown by general structure I, as shown below, are effective in treating filovirus infections.

##STR00001## X is selected from the group consisting of O and H; R.sup.1 is selected from (C.sub.6 to C.sub.10) aryl and (C.sub.2 to C.sub.9) heteroaryl, and R.sup.2 is selected from (C.sub.1 to C.sub.10) alkyl, (C.sub.1 to C.sub.10) alkenyl, (C.sub.1 to C.sub.10) alkynyl, (C.sub.3 to C.sub.10) cycloalkyl, and (C.sub.5 to C.sub.10) cycloalkenyl, and NR.sup.3aR.sup.3b is defined in the specification.

These compounds are effective in treating filovirii infections including Ebolavirus and Marburg virus.

The compounds of the invention as shown by general structure I, as shown below, are effective in treating filovirus infections.

##STR00001## X is selected from the group consisting of O and H; R.sup.1 is selected from (C.sub.6 to C.sub.10) aryl and (C.sub.2 to C.sub.9) heteroaryl, and R.sup.2 is selected from (C.sub.1 to C.sub.10) alkyl, (C.sub.1 to C.sub.10) alkenyl, (C.sub.1 to C.sub.10) alkynyl, (C.sub.3 to C.sub.10) cycloalkyl, and (C.sub.5 to C.sub.10) cycloalkenyl, and NR.sup.3aR.sup.3b is defined in the specification.

These compounds are effective in treating filovirii infections including Ebolavirus and Marburg virus.