[0001] This application claims the benefit of U.S. Provisional Patent

Application No. 62/430,812, filed December 6, 2016, the entire contents of which are hereby incorporated herein by reference.

BACKGROUND OF THE INVENTION

[0002] Multiple sclerosis (MS) is an inflammatory neurodegenerative disease of the central nervous system, characterized by myelin loss and degeneration of axons (see, Blakemore, et al, J. ofNeuroimmunology, 98, 69-76, 1999).

Activation and CNS infiltration of the peripheral immune system is typical in early stages of the disease, but can become less prevalent as disease progresses.

[0003] A hallmark of MS is loss of myelin, accompanied by the death of associated oligodendrocytes (see, Merrill, J.E. et al., Neuropathology and Applied Neurobiology, 25, 435-458, 1999). Myelin, which is produced by

oligodendrocytes, ensheathes axons and dramatically increases conduction velocity of neural impulses while providing trophic support to the neuron. Myelin is thought to regenerate early in disease, as oligodendroycte progenitor cells (OPCs) proliferate and generate new myelinating oligodendrocytes in response to demyelination events. As the disease progresses the regenerative capacity of the OPCs becomes less robust, and axons remain chronically demyelinated. Chronic demyelination is thought to underlie axon loss, as loss of trophic support combined with the metabolic stress of transmitting impulses along a demyelinated membrane can lead to a breakdown of axonal integrity and permanent damage to the demyelinated circuit. In addition, exposure of a demyelinated axon to an inflammatory milieu, including infiltrating immune cells and activated microglial cells, is also thought to produce permanent damage and axonal loss. Axon loss as a result of demyelination is thought to underlie long term disease progression and disability in MS patients (see, Compston, et al., he Lancet, Vol. 359, 1221-1231, 2002 and D. Kremer et al, Trends in Neurosciences, Vol. 39, No. 4, 246-263, 2016). [0004] The loss of remyelinating capacity in MS is not well understood, but is thought to involve a block in the differentiation capacity of OPCs, or the absence of a necessary signal present in the cell environment of the demyelinating lesion or in the demyelinated axons (see, R. Franklin et al, Nature Review s/Neuroscience, Vol. 9, 839-855, 2008). The OPC cell population is prevalent in MS patients, but fails to generate new myelin in response to demyelination. Thus, a compound that can promote differentiation and myelination of OPCs should function to restore this regenerative capacity and blunt or reverse the degenerative effects of MS (see, Stangel, M. et al, Progress in Neurobiology, 68, 361-376, 2002, Nairn, F. J. et al, Nature (Letter), published online 20 April 2015, doi: 10.1038/naturel4335). Such an agent could both increase the function of neurons and provide trophic support to enhance their survival (see, Mei, F. et al. Nature Medicine, Vol. 20, No. 8, 954- 961, 2014).

[0005] Leukodystrophies are degenerative white matter diseases characterized by dysmyelination or demyelination. Multiple genetic or metabolic disorders can lead to progressive white matter damage in pediatric or adult populations resulting in severe motor or cognitive deficits, mental retardation or death. A compound that can delay myelin damage or promote repair of demyelinated axons could significantly alter the course of leukodystrophies and improve their outcome. Such a compound could be also useful in combination with other therapies that can correct the disease-specific defect, metabolic, genetic or other, responsible for initiating or maintaining the disease in order to accelerate repair, restore function or prevent further damage.

[0006] Hypoxic-ischemic insults leading to reduced oxygenation and blood supply into the brain can cause severe damage to OPCs, and demyelination.

Periventricular leukomalacia is a condition characterized by toxic death of OPCs in the periventricular region and leading to severe dysmyelination and demyelination.

This pathology has been proposed as the root cause of cerebral palsy, a life-long debilitating CNS disorder characterized by various motor and/or cognitive deficits of variable intensity. A compound promoting differentiation of surviving OPCs and remyelination of damaged areas could be used for the treatment or prevention of cerebral palsy in vulnerable infant populations. [0007] Current therapies for MS are immunomodulatory in nature and do not directly promote repair. In addition, some of these immunomodulatory agents can leave patients vulnerable to opportunistic infection or neoplasia. Thus, there remains a need for compounds, such as those of the present invention, that can promote differentiation and myelination of OPCs and lead to the repair of demyelinated axons. Such a compound could also be useful in combination with existing or experimental immunmodulating and other relevant therapies to treat MS and other neurological and demyelinating diseases.

SUMMARY OF THE INVENTION

[0008] The present invention provides compounds or a pharmaceutically acceptable salt thereof and the methods, compositions and kits disclosed herein for treating or lessening the severity of, in a subject, a disease or disorder selected from a demyelinating disease, central pontine myelinolysis, a nerve injury disease or disorder, a leukoencephalopathy or a leukodystrophy. These compounds have the general formula I:

(I)

or a pharmaceutically acceptable salt thereof:

[0009] wherein:

[0010] R ¹ is selected from the group consisting of -NR ⁴ R ⁵ , -NR ⁴ -G°, -G -L -R ⁶ , -NR'-G^-L^R ⁶ , and G ² ;

[0011] R ⁴ and R ⁵ are each independently selected from the group consisting of hydrogen and Ci- ₄ alkyl;

[0012] G° is a C3- ₈ cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- ₄ alkyl, Ci _-4 haloalkyl, halogen, hydroxyl, oxo, cyano, -C(0)Ci _-4 alkyl, -C(0)C ₃ - ₆ cycloalkyl, -C(0)OCi _-4 alkyl, - C(0)OCi _-4 haloalkyl, -C(0)NH ₂ , -C(0)NH(Ci _-4 alkyl), -C(0)N(Ci _-4 alkyl)(Ci _-4 alkyl), -C(0)NH(-Ci _-6 alkylene-OCi _-4 alkyl), -C(0)N(Ci _-4 alkyl)(-Ci _-6 alkylene-OCi _-4 alkyl), -C(0)NH(-Ci _-6 alkylene-OH), -C(0)N(Ci _-4 alkyl)(-Ci _-6 alkylene-OH), -NH(-Ci_ ealkylene-OCi^alky ^NiCi^alky i-Ci-ealkylene-OCi^alky ^NHi-Ci-ealkylene- OH), -N(Ci. ₄ alkyl)(-Ci _-6 alkylene-OH), -C(0)Ci _-4 haloalkyl, -OCi _-4 alkyl, -Ci_ ₄ alkylene-OCi- ₄ alkyl, -Ci- ₆ alkylene-OH, -Ci- ₆ alkylene substituted by 2 groups independently selected from hydroxyl and -OC(0)Ci- ₄ alkyl, -Ci- ₄ alkylene-C(0)OCi- ₄ alkyl, -Ci _-4 alkylene-C(0)OH, -NHC(0)(Ci _-4 alkyl), -N(Ci _-4 alkyl)C(0)(Ci _-4 alkyl), - NH ₂ , -NH(Ci _-4 alkyl), and

[0013] G ¹ is a 4- to 8-membered monocyclic heterocycle containing a first nitrogen atom and optionally a second heteroatom independently selected from oxygen, nitrogen, and sulfur, and optionally containing one double bond and/or a Ci_ ₃ alkylene bridge between two non-adjacent ring atoms, G ¹ being connected to the parent molecular moiety through the first nitrogen atom and optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- ₄ alkyl, halogen, hydroxyl, and oxo;

[0014] G ^1A is a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a

bridge between two non-adjacent ring atoms, G ^1A being optionally substituted with 1- 4 substituents independently selected from the group consisting of C _h alky 1, Ci_ ₄ haloalkyl, halogen, hydroxyl, and oxo;

[0015] L ¹ is a bond, -Ci _-3 alkylene-, -C(O)-, -0-, or -NR ⁷ -, wherein R ⁷ is hydrogen or Ci- ₄ alkyl;

[0016] R ⁶ is (a) a 4- to 12-membered heterocycle containing 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the heterocycle being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- ₄ alkyl, -CH ₂ S(0) ₂ phenyl, halogen, hydroxyl, oxo, - OCi- ₄ alkyl, -Ci- ₆ alkylene-OCi- ₄ alkyl, and -Ci- ₆ alkylene-OH; or (b) a Cs-gcycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- ₄ alkyl, halogen, hydroxyl, -C(0)OCi- ₄ alkyl, -C(0)OH, oxo, -OCi- ₄ alkyl, -Ci- ₆ alkylene-OCi- ₄ alkyl, and -Ci- ₆ alkylene-OH;

[0017] G ² is a 5- to 12-membered heterocycle containing a first nitrogen atom and optionally 1-3 additional heteroatoms independently selected from oxygen, nitrogen, and sulfur, G ² being connected to the parent molecular moiety through the first nitrogen atom and optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- ₄ alkyl, Ci _-4 haloalkyl, halogen, hydroxyl, oxo, cyano, -Ci-ealkylene-cyano, -C(0)Ci _-4 alkyl, -C(0)-Ci _-6 alkylene-OCi _-4 alkyl, -C(0)-Ci_ ₆ alkylene-OH, -C(0)C ₃ - ₆ cycloalkyl, -C(0)OCi _-4 alkyl, -C(0)OCi _-4 haloalkyl, - C(0)NH ₂ , -C(0)NH(Ci _-4 alkyl), -C(0)N(Ci _-4 alkyl)(Ci _-4 alkyl), -C(0)NH(-Ci_

₆ alkylene-OCi _-4 alkyl), -C(0)N(Ci _-4 alkyl)(-Ci _-6 alkylene-OCi _-4 alkyl), -C(0)NH(-Ci_ ₆ alkylene-OH), -C(0)N(Ci _-4 alkyl)(-Ci _-6 alkylene-OH), -NH(-Ci _-6 alkylene-OCi. ₄ alkyl), -N(Ci _-4 alkyl)(-Ci _-6 alkylene-OCi _-4 alkyl), -NH(-Ci _-6 alkylene-OH), -N(Ci_ ₄ alkyl)(-Ci _-6 alkylene-OH), -C(0)Ci _-4 haloalkyl, -OCi _-4 alkyl, -OCi _-4 haloalkyl, -Ci_ ₆ alkylene-OCi _-4 alkyl, -Ci _-6 alkylene-OH, -Ci _-6 alkylene-NH ₂ , -Ci. ₆ alkylene-NH(Ci. ₄ alkyl), -Ci _-6 alkylene-N(Ci _-4 alkyl)(Ci _-4 alkyl), -0-Ci _-6 alkylene-NH ₂ , -O-Ci.

6alkylene-NH(Ci _-4 alkyl), -0-Ci- ₆ alkylene-N(Ci- ₄ alkyl)(Ci- ₄ alkyl), -0-Ci _-6 alkylene- OCi _-4 alkyl, -0-Ci _-6 alkylene-OH, -Ci _-4 alkylene-0-Ci _-4 alkylene-OCi _-4 alkyl, -Ci_ ₄ alkylene-0-Ci- ₄ alkylene-OH, -Ci- ₄ alkylene-C(0)OCi _-4 alkyl, -Ci _-4 alkylene- C(0)OH, -NHC(0)(Ci _-4 alkyl), -N(Ci _-4 alkyl)C(0)(Ci _-4 alkyl), -NH ₂ , -NH(Ci _-4 alkyl), -N(Ci _-4 alkyl)(Ci _-4 alkyl), -S(0)i _-2 Ci _-4 alkyl, -Ci. ₆ alkylene-S(0)i _-2 Ci _-4 alkyl, and a -Ci. ₆ alkylene substituted by 2 groups independently selected from hydroxyl, -OC(0)Ci_ ₄ alkyl, -OCi _-4 alkyl, -NH ₂ , -NH(Ci _-4 alkyl), and -N(Ci _-4 alkyl)(Ci _-4 alkyl);

[0018] R ² is selected from the group consisting of Ci _-4 alkyl, Ci _-4 haloalkyl, and - L ² -G ³ , R ² being connected to the parent molecular moiety through a carbon atom;

[0019] L ² is a bond or -Ci _-3 alkylene-;

[0020] G ³ is selected from the group consisting of phenyl, 5- to 8-membered monocyclic heterocyclyl, C5- ₆ cycloalkenyl, and Cs-gcycloalkyl, the 5- to 8-membered monocyclic heterocyclyl optionally containing one double bond, and the 5- to 8- membered monocyclic heterocyclyl and Cs-gcycloalkyl each optionally containing a Ci- ₃ alkylene bridge between two non-adjacent ring atoms, G ³ being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- ₄ alkyl, Ci _-4 haloalkyl, halogen, hydroxyl, oxo, cyano, -C(0)Ci _-4 alkyl, -C(0)C3_ ecycloalkyl, -C(0)OCi _-4 alkyl, -C(0)OCi _-4 haloalkyl, -C(0)NH ₂ , -C(0)NH(Ci_ ₄ alkyl), -C(0)N(Ci _-4 alkyl)(Ci _-4 alkyl), -C(0)Ci _-4 haloalkyl, -OCi _-4 alkyl, -OCi.

4haloalkyl, -NH ₂ , -NH(Ci _-4 alkyl), -N(Ci _-4 alkyl)(Ci _-4 alkyl), -S(0)i _-2 Ci _-4 alkyl, - S(0) ₂ NH ₂ , -S(0) ₂ NH(Ci _-4 alkyl), -S(0) ₂ N(Ci _-4 alkyl)(Ci _-4 alkyl), and G ¹⁰ , G ¹⁰ being a C3- ₆ cycloalkyl or a 4- to 8-membered monocyclic heterocycle containing 1 to 2 heteroatoms independently selected from nitrogen and oxygen, G being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- ₄ alkyl, Ci _-4 haloalkyl, halogen, hydroxyl, and oxo;

[0021] R ³ is selected from the group consisting of hydrogen, halogen, Ci- ₄ alkyl, and Ci _-4 haloalkyl;

[0022] R ⁸ is selected from the group consisting of C _h alky 1, Ci- ₆ haloalkyl, and - L ³ -G ⁴ ;

[0024] G ⁴ is selected from the group consisting of phenyl, 5- to 6-membered monocyclic heteroaryl, 5- to 8-membered monocyclic heterocyclyl, C5- ₆ cycloalkenyl, and C3- ₈ cycloalkyl, the 5- to 8-membered monocyclic heterocyclyl optionally containing one double bond, and the 5- to 8-membered monocyclic heterocyclyl and C3- ₈ cycloalkyl each optionally containing a bridge between two non- adjacent ring atoms, G ⁴ being optionally substituted with 1-4 substituents

independently selected from the group consisting of Ci- ₄ alkyl, Ci _-4 haloalkyl, halogen, hydroxyl, oxo, cyano, -C(0)Ci _-4 alkyl, -C(0)C ₃ - ₆ cycloalkyl, -C(0)OCi _-4 alkyl, - C(0)OCi _-4 haloalkyl, -C(0)NH ₂ , -C(0)NH(Ci _-4 alkyl), -C(0)N(Ci _-4 alkyl)(Ci _-4 alkyl), -C(0)Ci _-4 haloalkyl, -OCi _-4 alkyl, -OCi _-4 haloalkyl, -NH(Ci _-4 alkyl), -N(Ci _-4 alkyl)(Ci. ₄ alkyl), -S(0)i _-2 Ci _-4 alkyl, -S(0) ₂ NH ₂ , -S(0) ₂ NH(Ci _-4 alkyl), -S(0) ₂ N(Ci _-4 alkyl)(Ci. ₄ alkyl), and G ²⁰ , G ²⁰ being a C3- ₆ cycloalkyl or a 4- to 8-membered monocyclic heterocycle containing 1 to 2 heteroatoms independently selected from nitrogen and oxygen, G ²⁰ being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci _-4 alkyl, Ci _-4 haloalkyl, halogen, hydroxyl, and oxo;

[0025] provided that L ² is -Ci _-3 alkylene- when R ¹ is G ² , R ² is -L ² -G ³ , G ² is optionally substituted piperazinyl, G ³ is optionally substituted phenyl and R ⁸ is Ci_ ₆ alkyl; and provided that when R ¹ is -G^L^R ⁶ , R ² is -L ² -G ³ , G ¹ is optionally substituted azetidinyl, L ¹ is a bond, and G ³ is optionally substituted phenyl, then R ⁶ is (a).

[0026] In one aspect, the present invention provides compounds of formula (I).

[0027] Another aspect of the present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and therapeutically effective amounts of a compound of formula (I), or a pharmaceutically acceptable salt thereof. [0028] In another aspect, the invention provides compounds of formula (I), or a pharmaceutically acceptable salt thereof, which promote remyelination of demyelinated axons.

[0029] In another aspect, the invention provides compounds of formula (I), or a pharmaceutically acceptable salt thereof, which differentiate endogenous

oligodendrocyte precursor cells.

[0030] In another aspect, the invention provides methods of treating multiple sclerosis by administering to a patient in need thereof a therapeutically effective amount of a compound or composition of formula (I), or a pharmaceutically acceptable salt thereof.

[0031] In another aspect, the present invention provides a method of treating, preventing or ameliorating one or more symptoms of a subject with multiple sclerosis or another neurological disease.

[0032] In another aspect, the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of multiple sclerosis, the promotion of remyelination of demyelinated axons, or the differentiation of endogenous oligodendrocyte precursor cells.

[0033] In another aspect, the invention provides compounds of formula (I), or a pharmaceutically acceptable salt thereof, for use in treating multiple sclerosis, promoting remyelination of demyelinated axons, or differentiating endogenous oligodendrocyte precursor cells.

[0034] In another aspect, the invention provides compounds of formula (I), or a pharmaceutically acceptable salt thereof for treating or lessening the severity of, in a subject, a disease or disorder selected from a demyelinating disease, central pontine myelinolysis, a nerve injury disease or disorder, a leukoencephalopathy or a leukodystrophyin.

[0035] In another aspect, the invention provides compounds of formula (I), or a pharmaceutically acceptable salt thereof

[0036] In another aspect, the invention provides compounds of formula (I), or a pharmaceutically acceptable salt thereof can be employed in combination therapies, that is, the compounds and pharmaceutically acceptable compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures.

[0037] The present invention also features kits comprising compounds of formula I. DETAILED DESCRIPTION OF THE INVENTION

[0038] 1. Definitions

[0039] For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 ^th Ed. Additionally, general principles of organic chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," 5 ^th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0040] As described herein, compounds of the invention can optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention. As described herein, the variables in formula I encompass specific groups, such as, for example, alkyl and cycloalkyl. As one of ordinary skill in the art will recognize, combinations of substituents envisioned by this invention are those combinations that result in the formation of stable or chemically feasible compounds. The term

"stable," as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40°C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.

[0041] The phrase "optionally substituted" may be used interchangeably with the phrase "substituted or unsubstituted." In general, the term "substituted," whether preceded by the term "optionally" or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Specific substituents are described above in the definitions and below in the description of compounds and examples thereof. Unless otherwise indicated, an optionally substituted group can have a substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different at every position. A ring substituent, such as a heterocycloalkyl, can be bound to another ring, such as a cycloalkyl, to form a spiro-bicyclic ring system, e.g., both rings share one common atom. As one of ordinary skill in the art will recognize, combinations of substituents envisioned by this invention are those combinations that result in the formation of stable or chemically feasible compounds.

[0042] The compounds of the invention are defined according to the terms in the claims and the embodiments. The following definitions are provided as a general guide to understanding the claims and embodiments and are applicable where specific definitions are absent.

[0043] The term "alkyl" as used herein, means a straight or branched chain saturated hydrocarbon. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

[0044] The term "alkylene," as used herein, means a divalent group derived from a straight or branched chain saturated hydrocarbon. Representative examples of alkylene include, but are not limited to, -CH ₂ - -CH ₂ CH ₂ - -CH ₂ CH ₂ CH ₂ -, - CH ₂ CH(CH ₃ )CH ₂ - and -CH ₂ CH(CH ₃ )CH(CH ₃ )CH ₂ -.

[0045] The term "alkoxy" as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, and hexyloxy.

[0046] The term "aryl," as used herein, means phenyl or a bicyclic aryl. The bicyclic aryl is naphthyl, dihydronaphthalenyl, tetrahydronaphthalenyl, indanyl, or indenyl. The phenyl and bicyclic aryls are attached to the parent molecular moiety through any carbon atom contained within the phenyl or bicyclic aryl. [0047] The term "halogen" means a chlorine, bromine, iodine, or fluorine atom. [0048] The term "haloalkyl," as used herein, means an alkyl, as defined herein, in which one, two, three, four, five, six, or seven hydrogen atoms are replaced by halogen. For example, representative examples of haloalkyl include, but are not limited to, 2-fluoroethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2,2,2- trifluoro-l , l-dimethylethyl, and the like.

[0049] The term "haloalkoxy," as used herein, means an alkoxy group, as defined herein, in which one, two, three, four, five, or six hydrogen atoms are replaced by halogen. Representative examples of haloalkoxy include, but are not limited to, trifiuoromethoxy, difiuoromethoxy, 2,2,2-trifluoroethoxy, 2,2-difluoroethoxy, 2- fluoroethoxy, and pentafluoroethoxy.

[0050] The term "heteroaryl," as used herein, means an aromatic heterocycle, i.e., an aromatic ring that contains at least one heteroatom. A heteroaryl may contain from 5 to 12 ring atoms. A heteroaryl may be a 5- to 6-membered monocyclic heteroaryl or an 8- to 12-membered bicyclic heteroaryl. A 5-membered monocyclic heteroaryl ring contains two double bonds, and one, two, three, or four heteroatoms as ring atoms. Representative examples of 5-membered monocyclic heteroaryls include, but are not limited to, furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, and triazolyl. A 6- membered heteroaryl ring contains three double bonds, and one, two, three or four heteroatoms as ring atoms. Representative examples of 6-membered monocyclic heteroaryls include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl. The bicyclic heteroaryl is an 8- to 12-membered ring system having a monocyclic heteroaryl fused to an aromatic, saturated, or partially saturated carbocyclic ring, or fused to a second monocyclic heteroaryl ring. Representative examples of bicyclic heteroaryl include, but are not limited to, benzofuranyl, benzoxadiazolyl, 1 ,3-benzothiazolyl, benzimidazolyl, benzothienyl, indolyl, indazolyl, isoquinolinyl, naphthyridinyl, oxazolopyridine, quinolinyl, thienopyridinyl, 5,6,7,8-tetrahydroquinolinyl, and 6,7-dihydro-5H-cyclopenta[b]pyridinyl. The heteroaryl groups are connected to the parent molecular moiety through any substitutable carbon atom or any substitutable nitrogen atom contained within the groups. [0051] The term "cycloalkyl" as used herein, means a monocyclic all-carbon ring containing zero heteroatoms as ring atoms, and zero double bonds. Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The cycloalkyl groups described herein can be appended to the parent molecular moiety through any substitutable carbon atom.

[0052] The term "cycloalkenyl" as used herein, means a monocyclic non-aromatic all-carbon 5- to 6-membered ring containing zero heteroatoms as ring atoms and one double bond. Examples of cycloalkenyl include cyclopentenyl and cyclohexenyl. The cycloalkenyl groups described herein can be appended to the parent molecular moiety through any substitutable carbon atom.

[0053] The terms "heterocycle" or "heterocyclic" refer generally to ring systems containing at least one heteroatom as a ring atom where the heteroatom is selected from oxygen, nitrogen, and sulfur. In some embodiments, a nitrogen or sulfur atom of the heterocycle is optionally substituted with oxo. Heterocycles may be a monocyclic heterocycle, a fused bicyclic heterocycle, or a spiro heterocycle. The monocyclic heterocycle is generally a 4, 5, 6, 7, or 8-membered non-aromatic ring containing at least one heteroatom selected from O, N, or S. The 4-membered ring contains one heteroatom and optionally one double bond. The 5-membered ring contains zero or one double bond and one, two or three heteroatoms. The 6, 7, or 8-membered ring contains zero, one, or two double bonds, and one, two, or three heteroatoms.

Representative examples of monocyclic heterocycle include, but are not limited to, azetidinyl, azepanyl, diazepanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl , 4,5- dihydroisoxazol-5-yl, 3,4-dihydropyranyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxetanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, thiadiazolinyl,

thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1- dioxidothiomorpholinyl, thiopyranyl, and trithianyl. The fused bicyclic heterocycle is a 7-12-membered ring system having a monocyclic heterocycle fused to a phenyl, to a saturated or partially saturated carbocyclic ring, or to another monocyclic heterocyclic ring, or to a monocyclic heteroaryl ring. Representative examples of fused bicyclic heterocycle include, but are not limited to, l ,3-benzodioxol-4-yl, 1,3-benzodithiolyl, 3-azabicyclo[3.1.0]hexanyl, hexahydro-lH-furo[3,4-c]pyrrolyl, 2,3-dihydro-l,4- benzodioxinyl, 2,3-dihydro-l-benzofuranyl, 2,3-dihydro-l -benzothienyl, 2,3-dihydro- lH-indolyl, 5,6,7,8-tetrahydroimidazo[l,2-a]pyrazinyl, and 1,2,3,4- tetrahydroquinolinyl. Spiro heterocycle means a 4, 5-, 6-, 7-, or 8-membered monocyclic heterocycle ring wherein two of the substituents on the same carbon atom form a second ring having 3, 4, 5, 6, 7, or 8- members. Examples of a spiro heterocycle include, but are not limited to, l,4-dioxa-8-azaspiro[4.5]decanyl, 2-oxa-7- azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.3]heptanyl, and 8-azaspiro[4.5]decane. The monocyclic heterocycle groups of the present invention may contain an alkylene bridge of 1, 2, or 3 carbon atoms, linking two non-adjacent atoms of the group.

Examples of such a bridged heterocycle include, but are not limited to, 2,5- diazabicyclo[2.2. l]heptanyl, 2-azabicyclo[2.2. l]heptanyl, 2-azabicyclo[2.2.2]octanyl, and oxabicyclo[2.2.1]heptanyl. The monocyclic, fused bicyclic, and spiro heterocycle groups are connected to the parent molecular moiety through any substitutable carbon atom or any substitutable nitrogen atom contained within the group.

[0054] The term "oxo" as used herein refers to an oxygen atom bonded to the parent molecular moiety. An oxo may be attached to a carbon atom or a sulfur atom by a double bond. Alternatively, an oxo may be attached to a nitrogen atom by a single bond, i.e., an N-oxide.

[0055] Terms such as "alkyl," "cycloalkyl," "alkylene," etc. may be preceded by a designation indicating the number of atoms present in the group in a particular instance (e.g., "Ci-4alkyl," "C3- ₆ cycloalkyl," " C _h alky lene"). These designations are used as generally understood by those skilled in the art. For example, the

representation "C" followed by a subscripted number indicates the number of carbon atoms present in the group that follows. Thus, "C ₃ alkyl" is an alkyl group with three carbon atoms (i.e., n-propyl, isopropyl). Where a range is given, as in "CM," the members of the group that follows may have any number of carbon atoms falling within the recited range. A "Ci-4alkyl," for example, is an alkyl group having from 1 to 4 carbon atoms, however arranged (i.e., straight chain or branched). [0056] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Thus, included within the scope of the invention are tautomers of compounds of formula I. The structures also include zwitterioinc forms of the compounds or salts of formula I where appropriate.

[0057] 2. Compounds

[0058] In a first aspect of the invention are provided compounds of formula (I)

(I)

[0059] or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ³ , and R ⁸ are as defined herein.

[0060] In some embodiments, G° is a C3- ₈ cycloalkyl optionally substituted with 1- 4 substituents independently selected from the group consisting of C _h alky 1, Ci_ ₄ haloalkyl, halogen, hydroxyl, -OCi- ₄ alkyl, oxo, cyano, -C(0)Ci- ₄ alkyl, -C(0)OCi_ ₄ alkyl, -C(0)NH ₂ , -C(0)NH(Ci _-4 alkyl), -C(0)N(Ci _-4 alkyl)(Ci _-4 alkyl), -NHC(0)(Ci_ ₄ alkyl), -N(Ci _-4 alkyl)C(0)(Ci _-4 alkyl), -NH ₂ , -NH(Ci _-4 alkyl), and -N(Ci _-4 alkyl)(Ci. ₄ alkyl);

G ¹ is a 4- to 8-membered monocyclic heterocycle containing a first nitrogen atom and optionally a second heteroatom independently selected from oxygen and nitrogen, G ¹ being connected to the parent molecular moiety through the first nitrogen atom and optionally substituted with 1-4 substituents independently selected from the group consisting of Ci _-4 alkyl, Ci _-4 haloalkyl, halogen, hydroxyl, and oxo; G is a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from oxygen and nitrogen, G ^1A being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- ₄ alkyl, Ci- ₄ haloalkyl, halogen, hydroxyl, and oxo; L ¹ is a bond, or -C(O)-; R ⁶ is

(a) a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms

independently selected from oxygen, nitrogen, and sulfur, the heterocycle being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- ₄ alkyl, halogen, hydroxyl, oxo, and - OCi _-4 alkyl; or

(b) a C3- ₈ cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- ₄ alkyl, halogen, hydroxyl, oxo, and -OCi- ₄ alkyl;

G ² is a 5- to 12-membered heterocycle containing a first nitrogen atom and optionally 1-3 additional heteroatoms independently selected from oxygen and nitrogen, G ² being connected to the parent molecular moiety through the first nitrogen atom and optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- ₄ alkyl, Ci- ₄ haloalkyl, halogen, hydroxyl, oxo, cyano, -Ci- ₆ alkylene- cyano, -C(0)Ci _-4 alkyl, -C(0)OCi _-4 alkyl, -C(0)OCi _-4 haloalkyl, -C(0)NH ₂ , - C(0)NH(Ci _-4 alkyl), -C(0)N(Ci- ₄ alkyl)(Ci- ₄ alkyl), -NH(-Ci- ₆ alkylene-OCi- ₄ alkyl), - NiCi^alky i-Ci-ealkylene-OCi^alky ^NHi-Ci-ealkylene-O^^NiCi^alky i-Ci- ₆ alkylene-OH), -C(0)Ci- ₄ haloalkyl, -OCi- ₄ alkyl, -C _h alky lene- OCi _-4 alkyl, -C _h alky lene-OH, -C _h alky lene-NH ₂ , - Ci-ealkylene-NiCi^alkylXCi^alkyl), -C _M alk lene-C(0)OC _M alk l, - HCiOXd. ₄ alkyl), -N(C _M alkyl)C(0)(C _M alk l), -NH ₂ , -NH(Ci _-4 alkyl), -N(Ci _-4 alkyl)(Ci. ₄ alkyl), and a -Ci- ₆ alkylene substituted by 2 groups independently selected from hydroxyl, -OC(0)Ci _-4 alkyl, -OCi _-4 alkyl, -NH ₂ , -NH(Ci _-4 alkyl), and -N(Ci_ ₄ alkyl)(Ci _-4 alkyl); G ³ is selected from the group consisting of phenyl and C3- ₈ cycloalkyl, G ³ being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- ₄ alkyl, halogen, hydroxyl, oxo, and -OCi- ₄ alkyl; and

G ⁴ is selected from the group consisting of phenyl, 5- to 6-membered monocyclic heteroaryl, 5- to 8-membered monocyclic heterocyclyl, C5-6cycloalkenyl, and C3- gcycloalkyl, the Cs-gcycloalkyl optionally containing a bridge between two non-adjacent ring atoms, G ⁴ being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- ₄ alkyl, halogen, hydroxyl, oxo, and -OCi- ₄ alkyl. [0061] In some embodiments R ¹ is -NR ⁴ R ⁵ (i.e., formula (II)). In further embodiments, R ⁴ and R ⁵ are each independently Ci- ₄ alkyl (e.g., methyl).

(Π)

[0062] Further according to formula (II) are embodiments wherein R ² is Ci_ ₄ haloalkyl. In further embodiments of formula (II), R ³ is hydrogen. Further according to formula (II) are embodiments wherein R is -L -G ⁴ , L ³ is a bond, and G is optionally substituted Cs-gcycloalkyl. In one embodiment of formula (II), R ² is Ci_

3 8 3 4 3 4

₄ haloalkyl, R is hydrogen, R is -V-G V is a bond, and G is C3- ₈ cycloalkyl.

[0063] In other embodiments, R ¹ is -NR ⁴ -G° (i.e., formula (III)). In further embodiments, R ⁴ is hydrogen. In still other embodiments according to the foregoing, G° is a C5- ₇ cycloalkyl (e.g., cyclohexyl) optionally substituted with -N(Ci- ₄ alkyl)(Ci- ₄ alkyl) (e.g., -N(CH ₃ ) ₂ ). In some embodiments, G° is 4-dimethylaminocyclohexyl.

[0064] Further according to formula (III) are embodiments wherein R ² is -L ² -G ³ , L ² is a bond, and G ³ is optionally substituted C3- ₈ cycloalkyl (e.g., cyclopropyl). In further embodiments of formula (III), R ³ is halogen (e.g., fluoro). Further according to formula (III) are embodiments wherein R is -L -G ⁴ , L ³ is a bond, and G is optionally substituted Cs-gcycloalkyl. In one embodiment of formula (III), R ² is -L ² -

3 2 3 3 8 3

G , L is a bond, G is optionally substituted Cs.gcycloalkyl, R is halogen, R is -L - G ⁴ , L ³ is a bond, and G ⁴ is Cs-gcycloalkyl.

[0065] In other embodiments, R ¹ is -G -L -R ⁶ (i.e., formula (IV)), wherein G ¹ , L ¹ , and R ⁶ are as defined herein.

(IV)

[0066] G ¹ is a 4- to 8-membered monocyclic heterocycle containing a first nitrogen atom and optionally a second heteroatom independently selected from oxygen, nitrogen, and sulfur, and optionally containing one double bond and/or a Ci_ ₃ alkylene bridge between two non-adjacent ring atoms, G ¹ being connected to the parent molecular moiety (i.e., at the pyrimidine 6 position) through the first nitrogen atom and optionally containing one double bond and/or a Ci-3alkylene bridge between two non-adjacent ring atoms, G ¹ being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- ₄ alkyl, halogen, hydroxyl, and oxo. In some embodiments, G ¹ is a 4- to 8-membered monocyclic heterocycle containing 1 or 2 nitrogen atoms, the monocyclic heterocycle optionally containing one double bond and/or a bridge between two non-adjacent ring atoms, G ¹ being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- ₄ alkyl, halogen, hydroxyl, and oxo. In some embodiments, G ¹ contains one nitrogen atom. In other embodiments, G ¹ contains two nitrogen atoms. The heterocycles at G ¹ may be unsubstituted or substituted. For example, in some embodiments, G ¹ may be piperazinyl,

homopiperazinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, 2,5- diazabicyclo[2.2.1]heptanyl, 2,5-dihydro-lH-pyrrolyl, morpholino, or 1,2,3,6- tetrahydropyridinyl, each unsubstituted or substituted as described herein. In other embodiments, the piperazinyl, homopiperazinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,5-dihydro-lH-pyrrolyl, morpholino, or 1,2,3,6-tetrahydropyridinyl are optionally substituted with 1-4 substituents independently selected from 1 hydroxyl, 1-2 halogen, 1 oxo, and 1-4 Ci- ₄ alkyl groups. In some embodiments, pyrrolidinyl and/or piperidinyl is optionally substituted with halogen, 1 hydroxyl, or 1 oxo and the piperazinyl is optionally substituted with oxo. In some embodiments, G ¹ is piperazin-l-yl optionally substituted with oxo. In some embodiments, G ¹ may have a bridge between two non-adjacent ring atoms (e.g., 2,5-diazabicyclo[2.2.1]heptanyl). In other embodiments, G ¹ is without a Ci- ₃ alkylene bridge between two non-adjacent ring atoms. For example, non-limiting examples of G ¹ include piperazin-l-yl, 2-oxo-piperazin-l-yl, homopiperazin-l-yl, azetidin-l-yl, piperidin-l-yl, and 2,5-diazabicyclo[2.2.1]heptan-2-yl.

[0067] In further embodiments, G ¹ is a 4- to 6-membered monocyclic heterocycle containing a first nitrogen atom and optionally a second heteroatom independently selected from oxygen and nitrogen, and optionally containing one double bond and/or a Ci- ₃ alkylene bridge between two non-adjacent ring atoms, G ¹ being connected to the parent molecular moiety through the first nitrogen atom. In still further embodiments, G ¹ is piperazinyl, azetidinyl, morpholinyl, or piperidinyl.

[0068] In other embodiments, R ¹ is -NR ⁴ -G ^1A -L -R ⁶ (i.e., formula V).

[0069] In further embodiments of formula (V), R ⁴ is hydrogen.

[0070] G ^1A is a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a bridge between two non-adjacent ring atoms, G ^1A being optionally substituted with 1- 4 substituents independently selected from the group consisting of C _h alky 1, Ci_ ₄ haloalkyl, halogen, hydroxyl, and oxo. In some embodiments, G ^1A is a 4- to 8- membered monocyclic heterocycle containing 1 or 2 nitrogen atoms, the monocyclic heterocycle optionally containing one double bond and/or a bridge between two non-adjacent ring atoms, G ^1A being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- ₄ alkyl, Ci_ ₄ haloalkyl, halogen, hydroxyl, and oxo. In some embodiments, G ^1A contains one nitrogen atom. In other embodiments, G ^1A contains two nitrogen atoms. In some embodiments, G ^1A is a 6-membered monocyclic heterocycle containing 1 or 2 nitrogen atoms. In some embodiments, G ^1A is appended to NR ⁴ by a carbon ring atom of G ^1A . The heterocycles at G ^1A may be unsubstituted or substituted. For example, in some embodiments, G ^1A may be piperazinyl, homopiperazinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,5-dihydro-lH- pyrrolyl, oxetanyl, morpholino, tetrahydropyranyl, or 1,2,3,6-tetrahydropyridinyl, each unsubstituted or substituted as described herein. In other embodiments, the piperazinyl, homopiperazinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, 2,5- diazabicyclo[2.2.1]heptanyl, 2,5-dihydro-lH-pyrrolyl, oxetanyl, morpholino, tetrahydropyranyl, or 1,2,3,6-tetrahydropyridinyl are optionally substituted with 1-4 substituents independently selected from 1 hydroxyl, 1-2 halogen, 1 oxo, and 1-4 Ci_ ₄ alkyl groups. In some embodiments, pyrrolidinyl and/or piperidinyl is optionally substituted with halogen, 1 hydroxyl, or 1 oxo and the piperazinyl is optionally substituted with oxo. In some embodiments, G may have a bridge between two non-adjacent ring atoms (e.g., 2,5-diazabicyclo[2.2. l]heptanyl). In other embodiments, G ^1A is without a bridge between two non-adjacent ring atoms. For example, non-limiting examples of G ^1A include azetidin-3-yl, pyrrolidin- 3-yl, 3-hydroxy-pyrrolidin-3-yl, 3-fluoro-pyrrolidin-3-yl, piperidin-3-yl, piperidin-4- yl, 3-hydroxypiperidin-4-yl, 4-hydroxypiperidin-4-yl, 3-fluoropiperidin-4-yl, 4- fluoropiperidin-4-yl, 3,3-difluoropiperidin-4-yl, azepan-3-yl, 2,5-dihydro-lH-pyrrol- 3-yl, or l,2,3,6-tetrahydropyridin-4-yl.

[0071] In still further embodiments, G ^1A is a 4- to 6-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from oxygen and nitrogen, and optionally containing one double bond and/or a bridge between two non-adjacent ring atoms. In yet further embodiments, G ^1A is piperidinyl.

[0072] In some embodiments, R ⁶ is a 4- to 12-membered heterocycle containing 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the heterocycle being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- ₄ alkyl, -CH ₂ S(0) ₂ phenyl, halogen, hydroxyl, oxo, -OCi- ₄ alkyl, -Ci- ₆ alkylene-OCi- ₄ alkyl, and -C _h alky lene-OH.

[0073] In embodiments containing R ⁶ , the 4- to 12-membered heterocycle at R ⁶ may be a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a bridge between two non- adjacent ring atoms and being optionally substituted with 1-4 substituents

independently selected from the group consisting of Ci- ₄ alkyl, - CH ₂ S(0) ₂ phenyl, halogen, hydroxyl, oxo, -OCi- ₄ alkyl, -Ci- ₆ alkylene-OCi- ₄ alkyl, and -C _h alky lene-OH. In some embodiments, R ⁶ is a 4- to 6-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from oxygen and nitrogen sulfur, the heterocycle optionally containing one double bond and/or a Ci- ₃ alkylene bridge between two non-adjacent ring atoms and being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- ₄ alkyl, halogen, hydroxyl, oxo, and -OCi- ₄ alkyl. For example, in some embodiments, R ⁶ is an oxetanyl, a tetrahydrofuranyl, a tetrahydropyranyl, a morpholinyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 1 ,4-oxazepanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, a pyrrolidinyl, piperidinyl, thiomorpholinyl, a thietanyl, piperazinyl, or azetidinyl, each being optionally substituted as described herein. In other embodiments, R ⁶ is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, pyrrolidinyl, or thietanyl, each being optionally substituted with 1 -4 substituents independently selected from Ci- ₄ alkyl and oxo. In some embodiments, the oxetanyl,

tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, pyrrolidinyl, thietanyl, piperazinyl, and azetidinyl, are each optionally substituted with 1-4 substituents independently selected from halogen, Ci- ₄ alkyl and oxo. In some embodiments, the oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, pyrrolidinyl, thietanyl, and piperazinyl are each optionally substituted with Ci- ₄ alkyl, and the pyrrolidinyl, piperazinyl, and thietanyl further optionally substituted with 1-2 oxo groups. In other embodiments, R ⁶ is a 4- to 8-membered monocyclic heterocycle containing 1 oxygen atom (e.g., an oxetanyl, a tetrahydrofuranyl, a tetrahydropyranyl). In other embodiments, R ⁶ is a 4-membered monocyclic heterocycle containing 1 oxygen atom and optionally substituted with Ci- ₄ alkyl or -CH ₂ S(0) ₂ phenyl. In other embodiments, R ⁶ is a 4-membered monocyclic heterocycle containing 1 oxygen atom and optionally substituted with Ci- ₄ alkyl. In other embodiments, R ⁶ is a 4- to 8-membered monocyclic heterocycle containing 1 sulfur atom (e.g., thietanyl,

tetrahydrothiophenyl, tetrahydro-2H-thiopyranyl). In other embodiments, R ⁶ is a 4- membered monocyclic heterocycle containing 1 sulfur atom and optionally substituted with 1 -2 oxo groups. In other embodiments, R ⁶ is a 4- to 8-membered monocyclic heterocycle containing 1 nitrogen atom and optionally 1 oxygen atom or 1 sulfur atom (e.g., azetidinyl, pyrrolidinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, piperazinyl) and optionally substituted with oxo (e.g., 2- oxopyrrolidin-l-yl). The heterocycles of R ⁶ may be appended to the parent molecule (i.e., at L ¹ ) at any substitutable carbon atom or nitrogen atom of R ⁶ . Thus, in some embodiments, the oxygen-containing heterocycle is oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-3-yl, or tetrahydropyran-4-yl. In other embodiments, the sulfur- containing heterocycle is thietan-3-yl, tetrahydrothiophen-3-yl, tetrahydro-2H- thiopyran-3-yl, or tetahydro-2H-thiopyran-4-yl. In other embodiments, the heterocycle containing 1 nitrogen atom and optionally 1 oxygen or sulfur atom is e.g., piperidin-l-yl, morpholin-4-yl, azetidin-l-yl, piperazin-l-yl, 2-oxa-5- azabicyclo[2.2. l]heptan-5-yl, 6-oxa-3-azabicyclo[3.1. l]heptan-3-yl, 1 ,4-oxazepan-4- yl, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, 8-oxa-3-azabicyclo[3.2.1]octan-3-yl, thiomorpholin-4-yl, or 2-oxopyrrolidin-l -yl. In the embodiments of the invention, the oxygen- and sulfur-containing heterocycles may be unsubstituted or substituted as described herein. For example, the oxygen-containing heterocycle may be oxetan-3- yl, 3-methyloxetan-3-yl or 3-((phenylsulfonyl)methyl)oxetan-3-yl and the sulfur- containing heterocycle may be thietan-3-yl or l, l-dioxothietan-3-yl. In some embodiments, R ⁶ is oxetanyl, tetrahydrofuranyl, 1,4-dioxanyl, morpholino, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with 1-4 substituents independently selected from the group consisting of Ci-4alkyl, Ci_ 4haloalkyl, halogen, hydroxyl, oxo, and -OCi-4alkyl.

[0074] In embodiments containing R ⁶ , the 4- to 12-membered heterocycle at R ⁶ may be a 7- to 12-membered spiro heterocycle comprising a first ring and a second ring, the first ring being a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from nitrogen and oxygen and being attached to L ¹ , the second ring being a C3- ₈ cycloalkyl or a 4- to 8-membered monocyclic heterocycle containing 1-2 oxygen atoms wherein two atoms of the second ring are attached to one carbon of the first ring to form a spirocycle optionally substituted with 1-4 substituents independently selected from the group consisting of Ci-4alkyl, Ci_ 4haloalkyl, halogen, hydroxyl, and oxo. In some embodiments, the spirocyclic R ⁶ is optionally substituted with 1-4 substituents independently selected from the group consisting of Ci-4alkyl, -CH ₂ S(0)2phenyl, halogen, hydroxyl, oxo, - OCi-4alkyl, -Ci- ₆ alkylene-OCi-4alkyl, and -Ci- ₆ alkylene-OH. In some

embodiments, R ⁶ is a 7- to 12-membered spiro heterocycle consisting of the first ring and a second ring, as described herein. The first ring is attached to L ¹ through any substitutable carbon or nitrogen atom. In one embodiment, the first ring is attached to L ¹ through a nitrogen atom. The first ring of R ⁶ includes, but is not limited to, heterocycles such as azetidine, pyrrolidine, piperidine, azepane, morpholine, azocane, piperazine, and homopiperazine. In some embodiments, the first ring of R ⁶ is a 4- to 8-membered monocyclic heterocycle containing 1-2 nitrogen atoms or 1 nitrogen atom and 1 oxygen atom. For example, in some embodiments, the first ring is morpholino, piperazin-l-yl, or piperidin-l-yl. The second ring includes a C3- gcycloalkyl, e.g., cyclopropyl, cyclobutyl cyclopentyl. The second ring is formed by the attachment of two atoms of the second ring to a single carbon atom of the first ring such that the first ring and the second ring share one carbon atom in common. For example, in some embodiments, R ⁶ is 4-oxa-7-azaspiro[2.5]octanyl (e.g., 4-oxa-7- azaspiro[2.5]octan-7-yl).

[0075] In embodiments containing R ⁶ , the 4- to 12-membered heterocycle at R ⁶ may be a 7- to 12-membered fused bicyclic heterocycle (e.g., 2-oxa-5- azabicyclo[4.1.0]heptan-5-yl) containing 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur and being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- ₄ alkyl, Ci_ 4haloalkyl, halogen, hydroxyl, and oxo. In other embodiments, R ⁶ is a 7- to 12- membered fused bicyclic heterocycle containing 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur and being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- ₄ alkyl, Ci_

₄ haloalkyl, halogen, hydroxyl, oxo, -OCi- ₄ alkyl, -Ci- ₆ alkylene-OCi- ₄ alkyl, and -Ci- ₆ alkylene-OH. In some embodiments, the fused bicyclic heterocycle is a 7- 12- membered ring system having a monocyclic heterocycle, as defined herein, fused to another monocyclic heterocyclic ring. [0076] In embodiments containing R ⁶ , R ⁶ may be a 3- to 8-membered cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- ₄ alkyl, halogen, hydroxyl, -C(0)OCi- ₄ alkyl, -C(0)OH, and oxo. In other embodiments, R ⁶ is optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- ₄ alkyl, halogen, hydroxyl, -C(0)OCi _-4 alkyl, -C(0)OH, oxo, -OCi _-4 alkyl, -Ci _-6 alkylene-OCi _-4 alkyl, and -Ci- ₆ alkylene-OH. For example, in some embodiments, R ⁶ is cyclopropyl, cyclobutyl, or cyclopentyl, each being optionally substituted with -C(0)OCi-4alkyl, - C(0)OH, hydroxyl or 1-2 halogen. In one group of compounds, R ⁶ is cyclopropyl. In another group of compounds R ⁶ is cyclobutyl. In other embodiments, R ⁶ is 3,3- difluorocyclobutyl. In other embodiments, R ⁶ is a cyclobutane carboxylic acid. [0077] For example, R may be represented by the following formulas, wherein R ^6a and R ^6b are the optional R ⁶ substituents, respectively, for the 4-12 membered heterocycle or C3- ₈ cycloalkyl of R ⁶ and s is an integer from 0-4:

[0078] In embodiments wherein R ⁶ is an optionally substituted oxetan-3-yl, G ¹ may be represented by the following formulas, wherein R ^l is the optional G ¹ substituent and m is an integer from 0-4:

[0079] In embodiments wherein R is an optionally substituted oxetan-3-yl, G may be represented by the following formulas, wherein R ^l is the optional G ^1A substituent and m is an integer from 0-4:

[0080] In embodiments according to formulas (I) and (IV), L ¹ may be a bond, - Ci _-3 alkylene- (e.g., CH ₂ ), or -C(O)-.

[0081] G^R ⁶ may also be represented by the following formulas when L ¹ is a bond, wherein R ^l , R ^6a , R ^6b , m and s are as defined herein:

[0082] In embodiments according to formulas (I) and (IV), L ¹ may be -Ci_ 3alkylene- (e.g., CH ₂ ). For example, G^I^-R ⁶ may also be represented by the following fo ned herein:

[0083] In embodiments according to formulas (I) and (IV), L ¹ may be -C(O)-. For example, G^I^-R ⁶ may also be represented by the following formula when L ¹ a C(O), wherein R ^l , R ^6a , m and s are as defined herein.

[0084] -G -L -R ⁶ together may be 4-(oxetan-3-yl)piperazin-l-yl, 4-(3- methyloxetan-3-yl)piperazin-l -yl, 4-(tetrahydrofuran-3-yl)piperazin-l -yl, 4-(2- methyltetrahydrofuran-3-yl)piperazin-l-yl, 4-(tetrahydro-2H-pyran-3-yl)piperazin-l- yl, 4-(tetrahydro-2H-pyran-4-yl)piperazin-l-yl, 4-((3-methyloxetan-3- yl)methyl)piperazin-l-yl, 4-(oxetan-3-yl)-2-oxo-piperazin-l-yl, 4-(oxetan-3- y l)piperidin- 1 -y 1, 4-(2-oxopy rrolidin- 1 -y l)piperidin- 1 -y 1, 3 -(2-oxopy rrolidin- 1 - yl)piperidin-l-yl, 4-mo holinopiperidin-l-yl, (4-methylpiperazin-l-yl)piperidin-l-yl, 4-(3,3-difluoroazetidin-l-yl)piperidin-l-yl, 3-morpholinopyrrolidin-l-yl, 5-(oxetan-3- yl)-2,5-diazabicyclo[2.2. l]heptan-2-yl, 3-(oxetan-3-yl)azetidin-l-yl, 3-(pyrrolidin-l- yl)azetidin-l-yl, 3-(4-fluoropiperidin-l-yl)azetidin-l-yl, 3-morpholinoazetidin-l-yl, 3- methyl-3-mo holinoazetidin-l -yl, 3-(2-methylmorpholino)azetidin-l -yl, 3-(3- methy lmo holino)azetidin- 1 -y 1, dimethy lmorpholino)azetidin- 1 -y 1, 3 -(2,6- dimethylmorpholino)azetidin-l-yl, 3-(morpholine-4-carbonyl)azetidin-l-yl, 3- (pyrrolidine-l-carbonyl)azetidin-l-yl, 3-(l,4-oxazepan-4-yl)azetidin-l-yl, 3-(6-oxa-3- azabicyclo[3.1. l]heptan-3-yl)azetidin-l-yl, (3-(2-oxa-5-azabicyclo[2.2. l]heptan-5- yl)azetidin-l-yl, 3-(8-oxa-3-azabicyclo[3.2. l]octan-3-yl)azetidin-l-yl, 3-(3-oxa-8- azabicyclo[3.2.1]octan-8-yl)azetidin-l-yl, 3-(4-oxa-7-azaspiro[2.5]octan-7- yl)azetidin-l-yl, 3-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)azetidin-l-yl, 3- (morpholinomethy l)azetidin- 1 -y 1), 3 -( 1 , 1 -dioxidothiomorpholino)azetidin- 1 -y 1, 4- (thietan-3-yl)piperazin-l-yl, 4-(piperazin-l-yl)thietane 1,1-dioxide, 4-(oxetan-3-yl)-4- ( ¹ -oxidanyl)-4 ⁴ -piperazin-l-yl, or 4-(oxetan-3-yl)-l,4-diazepan-l-yl.

[0085] In other embodiments, -G^R ⁶ together may represent 3-(l- hydroxycyclobutyl)piperazin-l-yl; 4-cyclopropylpiperazin-l-yl; 4- cyclobutylpiperazin-l-yl; 4-cyclopentylpiperazin-l-yl; l-cyclopropylpiperidin-4-yl; 4-(3,3-difluorocyclobutyl)piperazin-l-yl; or 5-cyclopropyl-2,5- diazabicyclo[2.2. l]heptan-2-yl.

[0086] Further according to formula (IV) and the foregoing description are embodiments wherein R 2 is Ci 2 3 2 3

- ₄ alkyl, or -I -G ^J , is a bond, and G is optionally substituted Cs.gcycloalkyl (e.g., cyclopropyl). In further embodiments of formula (IV), R ³ is hydrogen, halogen (e.g., fluoro), or Ci- ₄ alkyl. Further according to formula (IV) are embodiments wherein R ⁸ is Ci- ₆ alkyl, Ci- ₆ haloalkyl (e.g., CF ₃ ), -L ³ - G ⁴ , L ³ is a bond, and G ⁴ is optionally substituted phenyl, 5- to 6-membered monocyclic heteroaryl (pyridinyl), 5- to 8-membered monocyclic heterocyclyl (e.g., tetrahydropyranyl), or Cs-gcycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or bicyclo[2.2. l]heptan-2-yl). In one embodiment of formula (IV), R ² is Ci-4alkyl, or -L ² -G ³ , L ² is a bond, and G ³ is optionally substituted C3- gcycloalkyl; R ³ is hydrogen, halogen, or Ci-4alkyl; R ⁸ is Ci- ₆ alkyl, Ci- ₆ haloalkyl, -L ³ - G ⁴ , L ³ is a bond, and G ⁴ is optionally substituted phenyl, 5- to 6-membered monocyclic heteroaryl, 5- to 8-membered monocyclic heterocyclyl, or Cs-gcycloalkyl. In further embodiments in combination with the foreg oing, G -L -R ⁶ is still further embodiments in combination with the foregoing, m is 0. In still further embodiments in combination v , or

[0087] In embodiments according to formulas (I) and (V), L ¹ may be -Ci_ 3alkylene- (e.g., CH2). For example, G^-L^R ⁶ may also be represented by the following formula when L ¹ is a CH ₂ , wherein R ^gl , R ^6a , m and s are as defined herein:

[0088] In other embodiments, R ¹ is G ² (i.e., formula (VI)), provided that L ² is Ci- ₃ alkylene- when G ² is optionally substituted piperazin-l-yl, G ³ is optionally substituted phenyl, and R ⁸ is Ci- ₆ alkyl.

(VI)

[0089] G ² is a 5- to 12-membered heterocycle containing a first nitrogen atom and optionally 1-3 additional heteroatoms independently selected from oxygen, nitrogen, and sulfur, G ² being connected to the parent molecular moiety (i.e., at the pyrimidine 6 position) through the first nitrogen atom and optionally substituted as described herein.

[0090] G ² may be substituted or unsubstituted. Optional G ² substituents include Ci- ₄ alkyl (e.g., methyl, ethyl, isopropyl), Ci _-4 haloalkyl (e.g., -CF ₃ , -CH ₂ CF ₃ , - CH ₂ CHF ₂ ), halogen (e.g., fluoro), hydroxyl, oxo, cyano, -Ci- ₆ alkylene-cyano, - C(0)Ci _-4 alkyl (e.g., -C(0)CH ₃ ), -C(0)-Ci _-6 alkylene-OCi _-4 alkyl, -C(0)-Ci_ ealkylene-OH, -C(0)OCi _-4 alkyl (e.g., -C(0)OCH ₃ , -C(0)OCH ₂ CH ₃ , - C(0)OC(CH ₃ ) ₃ ), -C(0)OCi _-4 haloalkyl (e.g., -C(0)OCH ₂ CF ₃ ), -C(0)NH ₂ , - C(0)NH(Ci _-4 alkyl) (e.g., -C(0)NHCH ₂ CH ₃ ), -C(0)N(Ci _-4 alkyl)(Ci _-4 alkyl) (e.g., - C(0)N(CH ₃ ) ₂ ), -C(0)NH(-Ci _-6 alkylene-OCi _-4 alkyl) (e.g., - C(0)NH(CH ₂ CH ₂ OCH ₃ )), -C(0)N(Ci _-4 alkyl)(-Ci _-6 alkylene-OCi _-4 alkyl) (e.g., - C(0)NCH ₃ (CH ₂ CH ₂ OCH ₃ )), -C(0)NH(-Ci _-6 alkylene-OH) (e.g., - C(0)NH(CH ₂ CH ₂ OH)), -C(0)N(Ci _-4 alkyl)(-Ci _-6 alkylene-OH) (e.g., - C(0)NCH ₃ (CH ₂ CH ₂ OH)), -NH(-Ci- ₆ alkylene-OCi- ₄ alkyl) (e.g., - NH(CH ₂ CH ₂ OCH ₃ )), -N(Ci _-4 alkyl)(-Ci _-6 alkylene-OCi _-4 alkyl) (e.g., - NCH ₃ (CH ₂ CH ₂ OCH ₃ )), -NH(-Ci _-6 alkylene-OH) (e.g., -NH(CH ₂ CH ₂ OH)), -N(Ci_ ₄ alkyl)(-Ci _-6 alkylene-OH) (e.g., -NCH ₃ (CH ₂ CH ₂ OH)), -C(0)Ci _-4 haloalkyl (e.g., - C(0)CF ₃ ), -OCi _-4 alkyl (e.g., -OCH ₃ ), -OCi _-4 haloalkyl, -Ci _-6 alkylene-OCi _-4 alkyl (e.g., -CH ₂ OCH ₃ , -CH ₂ CH ₂ OCH ₃ , -CH ₂ CH ₂ CH ₂ OCH ₃ ), -Ci _-6 alkylene-OH (e.g., - CH ₂ OH, -C (OH)(CH ₃ ) ₂ , -CH ₂ C(OH)(CH ₃ ) ₂ , -C(OH)(CH ₃ )CH(CH ₃ ) ₂ , -Ci.

6alkylene-NH ₂ , -Ci- ₆ alkylene-NH(Ci _-4 alkyl), -Ci- ₆ alkylene-N(Ci- ₄ alkyl)(Ci _-4 alkyl) (e.g., -CH ₂ CH ₂ -N(CH ₃ ) ₂ , -0-Ci _-6 alkylene-NH ₂ , -0-Ci _-6 alkylene-NH(Ci _-4 alkyl), - 0-Ci _-6 alkylene-N(Ci _-4 alkyl)(Ci _-4 alkyl), -0-Ci _-6 alkylene-OCi _-4 alkyl, -O-Ci. ₆ alkylene-OH, -Ci- ₄ alkylene-0-Ci- ₄ alkylene-OCi- ₄ alkyl, -Ci- ₄ alkylene-0-Ci- ₄ alkylene-OH, -Ci _-4 alkylene-C(0)OCi _-4 alkyl (e.g., -CH(CH ₃ )C(0)OCH ₃ ,- CH ₂ C(0)OCH ₂ CH ₃ -CH ₂ C(0)OCH ₂ CH ₃ ), -Ci _-4 alkylene-C(0)OH, -NHC(0)(Ci_ ₄ alkyl), -N(C _M alkyl)C(0)(C _M alkyl), -NH ₂ , -NH(Ci _-4 alkyl),

(e.g., -N(CH ₃ ) ₂ ), -S(0)i _-2 Ci _-4 alkyl, -Ci _-6 alkylene-S(0)i _-2 Ci _-4 alkyl, and a -Ci_

₆ alkylene substituted by 2 groups independently selected from hydroxyl, -OC(0)Ci_ ₄ alkyl, -OCi _-4 alkyl, -NH ₂ , -NH(Ci _-4 alkyl), and -N(Ci _-4 alkyl)(Ci _-4 alkyl) (e.g., - CH ₂ CH(OH)CH ₂ OCH ₂ CH ₃ ).

[0091] In some embodiments, G ² is optionally substituted with Ci- ₄ alkyl, Ci_ ₄ haloalkyl, halogen, hydroxyl, -N(Ci- ₄ alkyl)(-Ci- ₆ alkylene-OH), -Ci- ₆ alkylene-OCi- ₄ alkyl, -Ci- ₄ alkylene-C(0)OCi- ₄ alkyl, -N(Ci- ₄ alkyl)(Ci- ₄ alkyl), or a -Ci _-6 alkylene substituted by 2 groups independently selected from hydroxyl and -OCi-4alkyl.

[0092] In some embodiments containing G ² , the 5- to 12-membered heterocycle at G ² may be a 5- to 8-membered monocyclic heterocycle containing a first nitrogen atom and optionally 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a Ci- ₃ alkylene bridge between two non-adjacent ring atoms, G ² being connected to the parent molecular moiety through the first nitrogen atom and optionally substituted as described herein. In some embodiments, the 5- to 8-membered monocyclic heterocycle at G ² may have a Ci _-3 alkylene bridge between two non-adjacent ring atoms (e.g., 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 3- oxa-8-azabicyclo[3.2.1]octanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl). In other embodiments, the 5- to 8-membered monocyclic heterocycle at G ² is without a Ci_ ₃ alkylene bridge between two non-adjacent ring atoms. The heterocycles of G ² are appended to the parent molecule by a nitrogen atom in G ² (e.g., morpholin-4-yl, homomorpholin-4-yl, thiomorpholin-4-yl, 4-thiomorpholine 1,1 -dioxide, piperazin-1- yl, homopiperazin-l-yl, pyrrolidin-l-yl, piperidin-l-yl, azepan-l-yl, 2,5- diazabicyclo[2.2. l]heptan-2-yl, 6-oxa-3-azabicyclo[3.1. l]heptan-3-yl, 2-oxa-5- azabicyclo[2.2.1]heptan-5-yl, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, 8-oxa-3- azabicyclo[3.2.1]octan-3-yl). [0093] In further embodiments, G ² is a pyrrolidin-l-yl, piperidin-l-yl, morpholin- 4-yl, thiomo holin-4-yl, piperazin-l-yl, azepan-l-yl, azocan-l-yl, l,4-oxazepan-4-yl, 1,4-diazepan-l-yl, 1,5-diazocan-l-yl, l,5-oxazocan-5-yl, each optionally containing one double bond and/or a bridge between two non-adjacent ring atoms, G ² being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- ₄ alkyl, Ci _-4 haloalkyl, halogen, hydroxyl, oxo, cyano, -Ci_ ₆ alkylene-cyano, -C(0)Ci _-4 alkyl, -C(0)-Ci_ ₆ alkylene-OH, -C(0)OCi _-4 alkyl, -C(0)OCi _-4 haloalkyl, -C(0)NH ₂ , -C(0)NH(Ci_ ₄ alkyl), -C(0)N(Ci _-4 alkyl)(Ci _-4 alkyl), -C(0)NH(-Ci _-6 alkylene-OCi _-4 alkyl), - C(0)N(Ci _-4 alkyl)(-Ci _-6 alkylene-OCi _-4 alkyl), -C(0)NH(-Ci _-6 alkylene-OH), - C(0)N(Ci _-4 alkyl)(-Ci _-6 alkylene-OH), -NH(-Ci _-6 alkylene-OCi _-4 alkyl), -N(Ci- ₄ alkyl)(-Ci-6alkylene-OCi- ₄ alkyl), -NH(-Ci-6alkylene-OH), -N(Ci- ₄ alkyl)(-Ci- ₆ alkylene-OH), -C(0)Ci _-4 haloalkyl, -OCi _-4 alkyl, -OCi _-4 haloalkyl, -C _h alky lene- OCi _-4 alkyl, -Ci _-6 alkylene-OH, -C _h alky lene-NH ₂ , -Ci _-6 alkylene-NH(Ci _-4 alkyl), - Ci _-6 alkylene-N(Ci _-4 alkyl)(Ci _-4 alkyl), -0-Ci _-6 alkylene-NH ₂ , -0-Ci _-6 alkylene- NH(Ci _-4 alkyl), -0-Ci _-6 alkylene-N(Ci _-4 alkyl)(Ci _-4 alkyl), -O-Ci-ealkylene-OCi. ₄ alkyl, -0-Ci- ₆ alkylene-OH, -Ci- ₄ alkylene-0-Ci- ₄ alkylene-OCi _-4 alkyl, -Ci_ ₄ alkylene-0-Ci- ₄ alkylene-OH, -Ci- ₄ alkylene-C(0)OCi _-4 alkyl, -Ci _-4 alkylene- C(0)OH, -NHC(0)(Ci _-4 alkyl), -N(Ci _-4 alkyl)C(0)(Ci _-4 alkyl), -NH ₂ , -NH(Ci _-4 alkyl), -N(Ci _-4 alkyl)(Ci _-4 alkyl), -S(0)i _-2 Ci _-4 alkyl, -Ci. ₆ alkylene-S(0)i _-2 Ci _-4 alkyl, and a -Ci_ 6alkylene substituted by 2 groups independently selected from hydroxyl, -OC(0)Ci- ₄ alkyl, -OCi _-4 alkyl, -NH ₂ , -NH(Ci _-4 alkyl), and -N(Ci _-4 alkyl)(Ci _-4 alkyl).

[0094] In further examples, the optionally substituted G ² may be piperidin-l-yl, 3- fluoropiperidin-l-yl, 4-fluoropiperidin-l-yl, 3 -methoxy piperidin-l-yl, 3- (methoxymethyl)piperidin-l-yl, 4-(methoxymethyl)piperidin-l-yl, 4-methylpiperidin- 1-yl, 4-hydroxy-4-methylpiperidin-l-yl, l-acetylpiperidin-3-yl, 4- (ethoxycarbonyl)piperidin-l -yl, 4-(tert-butoxycarbonyl)piperidin-l -yl, 3- cyanopiperidin-l-yl, 4-cyanopiperidin-l-yl, 3-hydroxypiperidin-l-yl, 4- hydroxypiperidin-l-yl, 3-(hydroxymethyl)piperidin-l-yl, 4-(2- methoxyethyl)piperidin-l-yl, pyrrolidin-l-yl, 3-fluoropyrrolidin-l-yl, 3-(2- hy droxypropan-2-yl)pyrrolidin- 1 -yl, 3-hy droxy-3-methylpyrrolidin- 1 -yl, 4- methylpiperazin-l-yl, 4-ethylpiperazin-l-yl, 4-isopropylpiperazin-l-yl, 4-(tert- butyl)piperazin-l-yl, 3-(2-hydroxypropan-2-yl)piperazin-l-yl, 4- (ethoxy carbonyl)piperazin- 1 -yl, 4-(methoxy carbonyl)piperazin-l -yl, 4- acety lpiperazin- 1 -y 1, 2,4,5 -trimethy lpiperazin- 1 -y 1, 3,3 ,4-trimethy lpiperazin- 1 -y 1, piperazin- 1 -y 1, 3-(trifluoromethy l)piperazin- 1 -y 1, 4-(2-methoxy ethy l)piperazin- 1 -y 1, 4-(2,2,2-trifluoroethyl)piperazin-l-yl, 3,4,5-trimethylpiperazin-l-yl, 3-(2-hydroxy-3- methylbutan-2-yl)piperazin- 1 -yl, 2,5-dimethy lpiperazin- 1 -yl, 3,4-dimethylpiperazin- 1 -yl, 3-methylpiperazin-l-yl, 4-(2-hydroxy-2-methylpropyl)piperazin-l-yl, 3- (hydroxymethyl)-4-methy lpiperazin- 1 -yl, 3-(hydroxy methyl)piperazin- 1 -yl, 4-(tert- butoxycarbonyl)piperazin-l-yl, 2-oxopiperazin-l-yl, 3-methylpiperazin-l-yl, 4- (carboxymethyl)piperazin-l-yl, (3-methoxypropyl)piperazin-l-yl, 4-methyl-l,4- diazepan-l-yl, 4-acetyl-l,4-diazepan-l-yl, l,4-oxazepan-4-yl, morpholin-4-yl, 2,6- dimethylmorpholino, 2-(methoxymethyl)mo holino, 1,1-dioxidothiomorpholino, 6- oxa-3-azabicyclo[3.1. l]heptan-3-yl, 2-oxa-5-azabicyclo[2.2. l]heptan-5-yl, 3-oxa-8- azabicyclo[3.2.1]octan-8-yl, 8-oxa-3-azabicyclo[3.2.1]octan-3-yl, or 5-methyl-2,5- diazabicyclo[2.2. l]heptan-2-yl.

[0095] In some embodiments, G ² may be represented by the following formulas, wherein R ^2a is the optional G ² substituent and m is an integer between 0 and 4.

[0096] In other embodiments, the 5- to 12-membered heterocycle at G ² is a 7- to 12-membered spiro heterocycle comprising a first ring and a second ring, the first ring being a 4- to 8-membered monocyclic heterocycle containing the first nitrogen atom and optionally 1-3 additional heteroatoms independently selected from oxygen, nitrogen, and sulfur, G ² being connected to the parent molecular moiety through the first nitrogen atom, the second ring being a C3- ₈ cycloalkyl or a 4- to 8-membered monocyclic heterocycle containing 1-2 oxygen atoms wherein two atoms of the second ring are attached to one carbon of the first ring to form a spirocycle, and wherein G ² is optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- ₄ alkyl, halogen, hydroxy 1, and oxo. In some embodiments, G ² is a 7- to 12-membered spiro heterocycle consisting of the first ring and a second ring, as described herein. The first ring of the spiro heterocycle includes, but is not limited to, heterocycles such as azetidine, pyrrolidine, piperidine, azepane, morpholine, azocane, piperazine, and homopiperazine. In another embodiment, the first ring is a 4- to 8-membered monocyclic heterocycle containing 1 -2 nitrogen atoms or 1 nitrogen atom and 1 oxygen atom. In another embodiment, the first ring is a 4- to 6-membered monocyclic heterocycle containing 1 -2 nitrogen atoms. The first ring is attached to the parent molecule through a nitrogen atom (e.g., azetidin-l -yl, pyrrolidin-l-yl, piperazin-l-yl, or piperidin-l -yl). The second ring includes, but is not limited to, heterocycles such as oxetane, tetrahydrofuran, tetrahydropyran, dioxolane, etc. In some embodiments, the second ring has one oxygen atom. In other embodiments, the second ring has two oxygen atoms. In other embodiments, the second ring is a C3-8cycloalkyl, e.g., cyclopropyl, cyclobutyl cyclopentyl. The second ring is formed by the attachment of two atoms of the second ring to a single carbon atom of the first ring such that the first ring and the second ring share one carbon atom in common. For example, the second ring may be joined with the first ring at the 4-position of a first ring piperidin-l -yl or the 3 -position of a first ring azetidin-l -yl, pyrrolidin-l-yl, piperidin-l -yl, or piperazin-l -yl. In certain embodiments, G ² is l ,4-dioxa-8-azaspiro[4.5]decanyl, 2-oxa-6-azaspiro[3.5]nonanyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-5,8-diazaspiro[3.5]nonanyl, 2,5-dioxa-8- azaspiro[3.5]nonanyl, l -oxa-8-azaspiro[4.5]decanyl, 5-oxa-8-azaspiro[3.5]nonanyl, 2- oxa-6-azaspiro[3.4]octanyl, 6-oxa-2-azaspiro[3.4]octanyl, l-oxa-6- azaspiro[3.3]heptanyl, or 2-oxa-6-azaspiro[3.3]heptanyl, 2-oxa-8- azaspiro[4.5]decanyl, 2,6-diazaspiro[3.3]heptanyl, 2-oxa-7-azaspiro[4.4]nonanyl, 2- oxa-5-azaspiro[3.4]octanyl, l-oxa-9-azaspiro[5.5]undecanyl, where the 2,6- diazaspiro[3.3]heptanyl and 2-oxa-5,8-diazaspiro[3.5]nonanyl are optionally substituted with Ci- ₄ alkyl and/or oxo. Other embodiments include l,4-dioxa-8- azaspiro[4.5]decan-8-yl, 2-oxa-7-azaspiro[3.5]nonan-7-yl, 2-oxa-7- azaspiro[4.4]nonan-7-yl, 5-methyl-2-oxa-5,8-diazaspiro[3.5]nonan-8-yl, 2-oxa-6- azaspiro[3.4]octan-6-yl, 2-oxa-5-azaspiro[3.4]octan-5-yl, l -oxa-6- azaspiro[3.3]heptan-6-yl, 2-oxa-6-azaspiro[3.5]nonan-6-yl, 2,5-dioxa-8- azaspiro[3.5]nonan-8-yl, l-oxa-8-azaspiro[4.5]decan-8-yl, 5-oxa-8- azaspiro[3.5]nonan-8-yl, 6-oxa-2-azaspiro[3.4]octan-2-yl, 2-oxa-6- azaspiro[3.3]heptan-6-yl, 2-oxa-8-azaspiro[4.5]decan-8-yl, l-oxa-9- azaspiro[5.5]undecan-9-yl, 6-isopropyl-2,6-diazaspiro[3.3]heptan-2-yl, or 2,6- diazaspiro[3.3]heptan-2-yl. In further embodiments, G ² is selected from the group consisting of 2,6-diazaspiro[3.3]heptan-2-yl, 2-oxa-6-azaspiro[3.4]octan-6-yl, and 2- oxa-8-azaspiro[4.5]decan-8-yl. [0097] In other embodiments, the 5- to 12-membered heterocycle at G ² is a 7- to 12-membered fused bi cyclic heterocycle containing a first nitrogen atom and optionally 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, G ² being connected to the parent molecular moiety through the first nitrogen atom and optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- ₄ alkyl, halogen, hydroxyl, -OCi- ₄ alkyl, and oxo. In some embodiments, the fused bicyclic heterocycle is a 7-12-membered ring system having a monocyclic heterocycle, as defined herein, fused to another monocyclic heterocyclic ring. For example, in some embodiments,

, each being optionally substituted with 1-4 substituents selected from the group consisting of C _h alky 1 (e.g.,

being optionally substituted with one Ci- ₄ alkyl, halogen, or oxo. In some embodiments, G ² may be substituted with one substituent selected from the

foregoing group. For example, in some embodiments, G ^z is

[0098] Further according to formula (VI) are embodiments wherein R ² is -L ² -G ³ , L ² is a bond or and G ³ is optionally substituted phenyl or C3- gcycloalkyl (e.g., cyclopropyl). In further embodiments of formula (VI), R ³ is hydrogen or halogen (e.g., fluoro). Further according to formula (VI) are

embodiments wherein R ⁸ is Ci- ₆ alkyl or -L -G ⁴ , L ³ is a bond, and G ⁴ is optionally substituted C3- ₈ cycloalkyl. In one embodiment of formula (VI), R is -L ² -G ³ , L ² is a bond or -Ci- ₃ alkylene-, G ³ is optionally substituted phenyl or C3- ₈ cycloalkyl, R ³ is hydrogen or halogen, R is -L -G ⁴ , L ³ is a bond, and G ⁴ is C3- ₈ cycloalkyl.

[0099] R ² is selected from the group consisting of Ci- ₄ alkyl, Ci- ₄ haloalkyl, and - L ² -G ³ , R ² being connected to the parent molecular moiety through a carbon atom. In some embodiments, R ² is Ci- ₄ alkyl (e.g., methyl, ethyl, isopropyl) or

(e.g., CF ₃ ). In some embodiments, R ² is Ci- ₄ haloalkyl (e.g., CF ₃ ). In some

2 2 3 2 3

embodiments, R is -V-G 1 is a bond or -Ci- ₃ alkylene-, and G is selected from the group consisting of phenyl, 5- to 8-membered monocyclic heterocyclyl, C5- ₆ cycloalkenyl, and Cs-gcycloalkyl, the 5- to 8-membered monocyclic heterocyclyl optionally containing one double bond, and the 5- to 8-membered monocyclic heterocyclyl and C3- ₈ cycloalkyl each optionally containing a Ci- ₃ alkylene bridge between two non-adjacent ring atoms, G ³ being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- ₄ alkyl, Ci_ ₄ haloalkyl, halogen, hydroxyl, oxo, cyano, -C(0)Ci- ₄ alkyl, -C(0)C3- ₆ cycloalkyl, - C(0)OCi _-4 alkyl, -C(0)OCi _-4 haloalkyl, -C(0)NH ₂ , -C(0)NH(Ci _-4 alkyl), -C(0)N(Ci_ ₄ alkyl)(Ci _-4 alkyl), -C(0)Ci _-4 haloalkyl, -OCi _-4 alkyl, -OCi _-4 haloalkyl, -NH ₂ , -NH(Ci_ ₄ alkyl), -S(0)i _-2 Ci _-4 alkyl, -S(0) ₂ NH ₂ , -S(0) ₂ NH(Ci _-4 alkyl), -S(0)2N(Ci _-4 alkyl)(Ci _-4 alkyl), and G , G ^1U being a C ₃ - ₆ cycloalkyl or a 4- to 8- membered monocyclic heterocycle containing 1 to 2 heteroatoms independently selected from nitrogen and oxygen, G ¹⁰ being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- ₄ alkyl, Ci_ ₄ haloalkyl, halogen, hydroxyl, and oxo. In further embodiments, L ² is a bond or -Ci_ ₃ alkylene-, and G ³ is phenyl or Cs-gcycloalkyl (e.g., cyclopropyl, cyclohexyl) optionally substituted with 1-4 halogen. In further embodiments, L ² is a bond or -Ci_ ₃ alkylene-, and G ³ is phenyl optionally substituted with 1-4 halogen. In further embodiments, L ² is a bond and G ³ is Cs-gcycloalkyl. [00100] R ⁸ is selected from the group consisting of Ci- ₆ alkyl, Ci- ₆ haloalkyl, and - L -G ⁴ . In some embodiments, R ⁸ is Ci- ₆ alkyl (e.g., methyl, ethyl, isopropyl, isobutyl, tert-butyl, neopentyl). In other embodiments, R ⁸ is Ci-6haloalkyl (e.g., CF3). In other embodiments, R is -L -G ⁴ , L ³ is a bond or and G ⁴ is selected from the group consisting of phenyl, 5- to 6-membered monocyclic heteroaryl, 5- to 8- membered monocyclic heterocyclyl, C5- ₆ cycloalkenyl, and Cs-gcycloalkyl, the 5- to 8- membered monocyclic heterocyclyl optionally containing one double bond, and the 5- to 8-membered monocyclic heterocyclyl and Cs-gcycloalkyl each optionally containing a C _h alky lene bridge between two non-adjacent ring atoms, G ⁴ being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- ₄ alkyl, Ci _-4 haloalkyl, halogen, hydroxyl, oxo, cyano, -C(0)Ci- ₄ alkyl, -C(0)C ₃ - ₆ cycloalkyl, -C(0)OC _M alkyl, -C(0)OCi _-4 haloalkyl, -C(0)NH ₂ , - C(0)NH(Ci _-4 alkyl), -C(0)N(C _M alkyl)(C _M alk l), -C(0)Ci _-4 haloalkyl, -OC _M alkyl, -OCi _-4 haloalkyl, -NH(Ci _-4 alkyl), -N(Ci _-4 alkyl)(Ci _-4 alkyl), -S(0)i _-2 Ci _-4 alkyl, - S(0) ₂ NH ₂ , -S(0) ₂ NH(Ci _-4 alkyl), -S(0) ₂ N(Ci _-4 alkyl)(Ci _-4 alkyl), and G ²⁰ , G ²⁰ being a C3- ₆ cycloalkyl or a 4- to 8-membered monocyclic heterocycle containing 1 to 2 heteroatoms independently selected from nitrogen and oxygen, G ²⁰ being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- ₄ alkyl, Ci _-4 haloalkyl, halogen, hydroxyl, and oxo. In some embodiments, G ⁴ is selected from the group consisting of phenyl, 5- to 6-membered monocyclic heteroaryl, 5- to 8-membered monocyclic heterocyclyl, and C3- ₈ cycloalkyl, each optionally substituted. In some embodiments, G ⁴ is phenyl. In some embodiments, G ⁴ is pyridinyl (e.g., pyridin-2-yl). [00101] In some embodiments, G ⁴ is a 4- to 8-membered monocyclic heterocycle containing 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, optionally containing one double bond and/or a bridge between two non- adjacent ring atoms, wherein G ⁴ is attached at a ring carbon ring atom of G ⁴ or G ^B , and optionally substituted as described herein. In some embodiments, G ⁴ is tetrahydropyranyl (e.g., tetrhydropyran-4-yl). In some embodiments according to the foregoing, L is a bond.

[00102] In some embodiments, L is a bond and G ⁴ is C3- ₈ cycloalkyl optionally containing a C _h alky lene bridge between two non-adjacent ring atoms, G ⁴ being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- ₄ alkyl, and halogen. In further embodiments, G ⁴ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or bicyclo[2.2.1]heptan-2-yl, G ⁴ being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- ₄ alkyl and halogen. [00103] In another embodiment, the compounds of the present invention are selected from 2-cyclopropyl-5-fluoro-N-(5-((lr,3r)-3-fluorocyclobutyl)-lH- pyrazol-3- yl)-6-(4-(oxetan-3-yl)piperazin-l-yl)pyrimidin-4-amine; 2-cyclopropyl-5-fluoro-N-(5- ((ls,3s)-3-fluorocyclobutyl)-lH-pyrazol-3-yl)-6-(4-(oxetan-3 -yl)piperazin-l- yl)pyrimidin-4-amine; N-(5-(bicyclo[2.2.1]heptan-2-yl)-lH-pyrazol-3-yl)-2- cyclopropyl-5-fluoro-6-(4-(oxetan-3-yl)piperazin-l-yl)pyrirn idin-4-amine; N-(5- cyclobutyl-lH-pyrazol-3-yl)-2-cyclopropyl-5-fluoro-6-(4-(oxe tan-3-yl)piperazin-l- yl)pyrimidin-4-amine; N-(5-cyclopentyl-lH-pyrazol-3-yl)-2-cyclopropyl-5-fluoro-6- (4-(oxetan-3-yl)piperazin-l-yl)pyrimidin-4-amine; 2-cyclopropyl-5-fluoro-N-(5- ((ls,3s)-3-fluorocyclobutyl)-lH-pyrazol-3-yl)-6-(4-(3-methyl oxetan-3-yl)piperazin-l- yl)pyrimidin-4-amine; -(2-cyclopropyl-6-((5-(3,3-difluorocyclobutyl)-lH-pyrazol-3- yl)ainino)-5-fluoropyrimidin-4-yl)-[l,4'-bipiperidin]-3-ol; 2-cyclopropyl-N-(5-(3,3- difluorocyclobutyl)-lH-pyrazol-3-yl)-5-fluoro-6-(4-(oxetan-3 -yl)piperazin-l- yl)pyrimidin-4-amine; N-(5-(3,3-difluorocyclobutyl)-lH-pyrazol-3-yl)-2-ethyl-5- fluoro-6-(4-(3-methyloxetan-3-yl)piperazin-l-yl)pyrirnidin-4 -amine; and N-(5-(3,3- difluorocyclobutyl)-lH-pyrazol-3-yl)-5-fluoro-2-isopropyl-6- (4-(oxetan-3- y l)piperazin- 1 -y l)py rimidin-4-amine. [00104] In another embodiment, the compounds of formula I include isotope- labelled forms thereof. An isotope-labelled form of a compound of formula I is identical to this compound apart from the fact that one or more atoms of the compound have been replaced by an atom or atoms having an atomic mass or mass number which differs from the atomic mass or mass number of the atom which usually occurs in greater natural abundance. Examples of isotopes which are readily commercially available and which can be incorporated into a compound of formula I by well-known methods include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example ² H, H, ¹ C, ¹⁴ C, ¹⁵ N, ¹⁸ 0, ¹⁷ 0, ¹ P, 2P, ⁵ S, ¹⁸ F and ⁶ C1, respectively.

[00105] In another embodiment, a compound of formula I or a pharmaceutically acceptable salt thereof which contains one or more of the above-mentioned isotopes and/or other isotopes of other atoms is intended to be part of the present invention.

[00106] In another embodiment, the present invention features a compound of formula I and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

[00107] In another embodiment, an isotope-labelled compound of formula I can be used in a number of beneficial ways. In one embodiment, an isotope-labelled compound of formula I into which, for example, a radioisotope, such as H or ¹⁴ C, has been incorporated is suitable for a medicament and/or for substrate tissue distribution assays. In one embodiment, tritium ( H) and carbon-14 ( ¹⁴ C) are particularly preferred owing to simple preparation and excellent detectability.

[00108] In yet another embodiment, incorporation of heavier isotopes, for example deuterium ( ² H), into a compound of formula I have therapeutic advantages owing to the higher metabolic stability of this isotope-labelled compound. Higher metabolic stability translates directly into an increased in vivo half-life or lower dosages, which under most circumstances would represent a preferred embodiment of the present invention. An isotope-labelled compound of formula I can usually be prepared by carrying out the procedures disclosed in the synthesis schemes and the related description, in the example part and in the preparation part in the present text, replacing a non-isotope-labelled reactant by a readily available isotope-labelled reactant. [00109] In another embodiment, Deuterium ( ² H) can also be incorporated into a compound of formula I for the purpose of manipulating the oxidative metabolism of the compound by way of the primary kinetic isotope effect. The primary kinetic isotope effect is a change of the rate for a chemical reaction that results from exchange of isotopic nuclei, which in turn is caused by the change in ground state energies necessary for covalent bond formation after this isotopic exchange.

Exchange of a heavier isotope usually results in a lowering of the ground state energy for a chemical bond and thus causes a reduction in the rate-limiting bond breakage. If the bond breakage occurs in or in the vicinity of a saddle-point region along the coordinate of a multi-product reaction, the product distribution ratios can be altered substantially. For explanation: if deuterium is bonded to a carbon atom at a non- exchangeable position, rate differences of kM _/ ko = 2-7 are typical. If this rate difference is successfully applied to a compound of formula I that is susceptible to oxidation, the profile of this compound in vivo can be drastically modified and result in improved pharmacokinetic properties. For a further discussion, see S. L. Harbeson and R. D. Tung, Deuterium In Drug Discovery and Development, Ann. Rep. Med. Chem. 2011, 46, 403-417, incorporated in its entirety herein by reference.

[00110] When discovering and developing therapeutic agents, the person skilled in the art attempts to optimise pharmacokinetic parameters while retaining desirable in vitro properties. It is reasonable to assume that many compounds with poor pharmacokinetic profiles are susceptible to oxidative metabolism. In vitro liver microsomal assays currently available provide valuable information on the course of oxidative metabolism of this type, which in turn permits the rational design of deuterated compounds of formula I with improved stability through resistance to such oxidative metabolism. Significant improvements in the pharmacokinetic profiles of compounds of formula I are thereby obtained, and can be expressed quantitatively in terms of increases in the in vivo half-life (ti/2), concentration at maximum therapeutic effect (Cmax), area under the dose response curve (AUC), and bioavailability; and in terms of reduced clearance, dose and materials costs.

[00111] The following is intended to illustrate the above: a compound of formula I which has multiple potential sites of attack for oxidative metabolism, for example benzylic hydrogen atoms and hydrogen atoms bonded to a nitrogen atom, is prepared as a series of analogues in which various combinations of hydrogen atoms are replaced by deuterium atoms, so that some, most or all of these hydrogen atoms have been replaced by deuterium atoms. Half-life determinations enable favourable and accurate determination of the extent to which the improvement in resistance to oxidative metabolism has improved. In this way, it is determined that the half-life of the parent compound can be extended by up to 100% as the result of deuterium- hydrogen exchange of this type.

[00112] In another embodiment, deuterium-hydrogen exchange in a compound of formula I can be used to achieve a favourable modification of the metabolite spectrum of the starting compound in order to diminish or eliminate undesired toxic metabolites. For example, if a toxic metabolite arises through oxidative carbon- hydrogen (C-H) bond cleavage, it can reasonably be assumed that the deuterated analogue will greatly diminish or eliminate production of the unwanted metabolite, even if the particular oxidation is not a rate-determining step. Further information on the state of the art with respect to deuterium-hydrogen exchange may be found, for example in Hanzlik et al, J. Org. Chem. 55, 3992-3997, 1990, Reider et al, J. Org. Chem. 52, 3326-3334, 1987, Foster, Adv. Drug Res. 14, 1-40, 1985, Gillette et al, Biochemistry 33(10) 2927-2937, 1994, and Jarman et al. Carcinogenesis 16(4), 683- 688, 1993.

[00113] In another embodiment, the invention features a compound of formula I, wherein the compound or a pharmaceutically acceptable salt thereof, is selected from Table 1 below.

] Table 1. Compound Table

41

42

44











Table 2 Com ound Names IUPAC Nomenclature Cmpd. Compound Name

No.

5-chloro-N-(5-cyclobutyl-lH-pyrazol-3-yl)-2-cyclopropyl-6-(4 -

17 (oxetan-3-yl)piperazin-l-yl)pyrimidin-4-amine

N-(5-cyclopentyl-lH-pyrazol-3-yl)-2-cyclopropyl-5-fluoro-6-( 4-

18 (oxetan-3-yl)piperazin-l-yl)pyrimidin-4-amine

N-(5-cyclobutyl-lH-pyrazol-3-yl)-2-cyclopropyl-5-fluoro-6-(4 -

19 (oxetan-3-yl)piperazin-l-yl)pyrimidin-4-amine

5-chloro-2-cyclopropyl-N-(5-(3,3-difluorocyclobutyl)-lH-pyra zol-

20 3-yl)-6-(4-(oxetan-3-yl)piperazin-l-yl)pyrimidin-4-amine

N-(5-cyclobutyl-lH-pyrazol-3-yl)-5-fluoro-6-(4-(oxetan-3-

21 y l)piperazin- 1 -y l)-2-(trifluoromethy l)py rimidin-4-amine

N-(5-cyclobutyl-lH-pyrazol-3-yl)-5-fluoro-6-(3-

22 morpholinoazetidin- 1 -y l)-2-(trifluoromethy l)pyrimidin-4-amine

N-(5-cyclopropyl-lH-pyrazol-3-yl)-5-fluoro-6-(4-(oxetan-3-

23 y l)piperazin- 1 -y l)-2-(trifluoromethy l)py rimidin-4-amine

N-(5-cyclopentyl-lH-pyrazol-3-yl)-5-fluoro-6-(4-(oxetan-3-

24 y l)piperazin- 1 -y l)-2-(trifluoromethy l)py rimidin-4-amine

5-fluoro-6-(4-(oxetan-3-yl)piperazin-l-yl)-N-(5-(tetrahydro- 2H- pyran-4-yl)-lH-pyrazol-3-yl)-2-(trifluoromethyl)pyrimidin-4-

25 amine

5-fluoro-N-(5-(2-methylcyclopropyl)-lH-pyrazol-3-yl)-6-(4-

26 (oxetan-3-yl)piperazin-l-yl)-2-(trifluoromethyl)pyrimidin-4- amine

N-(5-cyclopropyl-lH-pyrazol-3-yl)-5-fluoro-2-methyl-6-(3-

27 morpholinoazetidin- 1 -y l)py rimidin-4-amine

N-(5-cyclobutyl-lH-pyrazol-3-yl)-5-fluoro-2-methyl-6-(3-

28 morpholinoazetidin- 1 -y l)py rimidin-4-amine

N-(5-(3,3-difluorocyclobutyl)-lH-pyrazol-3-yl)-5-fluoro-2-

29 methyl-6-(3-morpholinoazetidin- 1 -yl)pyrimidin-4-amine

N-(5-cyclopentyl-lH-pyrazol-3-yl)-5-fluoro-2-methyl-6-(3-

30 morpholinoazetidin- 1 -y l)py rimidin-4-amine

N-(5-cyclopropyl-lH-pyrazol-3-yl)-5-fluoro-2-methyl-6-(4-

31 (oxetan-3-yl)piperazin-l-yl)pyrimidin-4-amine

N-(5-cyclobutyl-lH-pyrazol-3-yl)-5-fluoro-2-methyl-6-(4-(oxe tan-

32 3-y l)piperazin- 1 -y l)pyrimidin-4-amine

N-(5-(3,3-difluorocyclobutyl)-lH-pyrazol-3-yl)-5-fluoro-2-

33 methyl-6-(4-(oxetan-3-yl)piperazin- 1 -yl)pyrimidin-4-amine

N-(5-cyclopentyl-lH-pyrazol-3-yl)-5-fluoro-2-methyl-6-(4-

34 (oxetan-3-yl)piperazin-l-yl)pyrimidin-4-amine

2- cyclopropyl-N-(5-ethyl-lH-pyrazol-3-yl)-5-fluoro-6-(4-(oxeta n-

35 3- yl)piperazin-l-yl)pyrimidin-4-amine

2-cyclopropyl-5-fluoro-N-(5-isopropyl-lH-pyrazol-3-yl)-6-(4-

36 (oxetan-3-yl)piperazin-l-yl)pyrimidin-4-amine

2-cyclopropyl-N-(5-cyclopropyl-lH-pyrazol-3-yl)-5-fluoro-6-( 4-

37 (oxetan-3-yl)piperazin-l-yl)pyrimidin-4-amine

2-cyclopropyl-5-fluoro-N-(5-isobutyl-lH-pyrazol-3-yl)-6-(4-

38 (oxetan-3-yl)piperazin-l-yl)pyrimidin-4-amine

39 N-(5-(tert-butyl)-lH-pyrazol-3-yl)-2-cyclopropyl-5-fluoro-6- (4- Cmpd. Compound Name

No.

(oxetan-3-yl)piperazin-l-yl)pyrimidin-4-amine

2-cyclopropyl-N-(5-(3,3-difluorocyclobutyl)-lH-pyrazol-3-yl) -5-

40 fluoro-6-(4-(oxetan-3-yl)piperazin-l-yl)pyrimidin-4-amine

N-(5-(bicyclo[2.2.1]heptan-2-yl)-lH-pyrazol-3-yl)-2-cyclopro pyl-

41 5-fluoro-6-(4-(oxetan-3-yl)piperazin-l-yl)pyrimidin-4-amine

2-cyclopropyl-N-(5-ethyl-lH-pyrazol-3-yl)-5-fluoro-6-(4-(3-

42 methy loxetan-3 -y l)piperazin- 1 -y l)py rimidin-4-amine

2-cyclopropyl-5-fluoro-N-(5-isopropyl-lH-pyrazol-3-yl)-6-(4- (3-

43 methy loxetan-3 -yl)piperazin- 1 -yl)pyrimidin-4-amine

2-cyclopropyl-N-(5-cyclopropyl-lH-pyrazol-3-yl)-5-fluoro-6-( 4-

44 (3 -methy loxetan-3 -yl)piperazin- 1 -yl)pyrimidin-4-amine

2-cyclopropyl-5-fluoro-N-(5-isobutyl-lH-pyrazol-3-yl)-6-(4-( 3-

45 methy loxetan-3 -yl)piperazin- 1 -yl)pyrimidin-4-amine

N-(5-(tert-butyl)-lH-pyrazol-3-yl)-2-cyclopropyl-5-fluoro-6- (4-(3-

46 methy loxetan-3 -yl)piperazin- 1 -yl)pyrimidin-4-amine

2-cyclopropyl-N-(5-(3,3-difluorocyclobutyl)-lH-pyrazol-3-yl) -5- fluoro-6-(4-(3-methyloxetan-3-yl)piperazin-l-yl)pyrimidin-4-

47 amine

N-(5-(bicyclo[2.2.1]heptan-2-yl)-lH-pyrazol-3-yl)-2-cyclopro pyl-

5-fluoro-6-(4-(3-methyloxetan-3-yl)piperazin-l-yl)pyrimid in-4-

48 amine

N-(5-(3,3-difluorocyclobutyl)-lH-pyrazol-3-yl)-2-ethyl-5-flu oro-

49 6-(4-(oxetan-3-yl)piperazin- 1 -yl)pyrimidin-4-amine

N-(5-cyclopentyl-lH-pyrazol-3-yl)-2-ethyl-5-fluoro-6-(4-(oxe tan-

50 3-y l)piperazin- 1 -y l)pyrimidin-4-amine

N-(5-cyclobutyl-lH-pyrazol-3-yl)-2-ethyl-5-fluoro-6-(4-(oxet an-

51 3-y l)piperazin- 1 -y l)pyrimidin-4-amine

N-(5-(3,3-difluorocyclobutyl)-lH-pyrazol-3-yl)-2-ethyl-5-flu oro-

52 6-(4-(3-methyloxetan-3-yl)piperazin-l-yl)pyrimidin-4-amine

N-(5-cyclopentyl-lH-pyrazol-3-yl)-2-ethyl-5-fluoro-6-(4-(3-

53 methy loxetan-3 -yl)piperazin- 1 -yl)pyrimidin-4-amine

N-(5-cyclobutyl-lH-pyrazol-3-yl)-2-ethyl-5-fluoro-6-(4-(3-

54 methy loxetan-3 -yl)piperazin- 1 -yl)pyrimidin-4-amine

N-(5-(3,3-difluorocyclobutyl)-lH-pyrazol-3-yl)-5-fluoro-2-

55 isopropyl-6-(4-(oxetan-3-yl)piperazin-l-yl)pyrimidin-4-amine

N-(5-cyclobutyl-lH-pyrazol-3-yl)-5-fluoro-2-isopropyl-6-(4-

56 (oxetan-3 -y l)piperazin- 1 -y l)pyrimidin-4-amine

N-(5-cyclopentyl-lH-pyrazol-3-yl)-5-fluoro-2-isopropyl-6-(4-

57 (oxetan-3 -y l)piperazin- 1 -y l)pyrimidin-4-amine

N-(5-cyclopropyl-lH-pyrazol-3-yl)-5-fluoro-2-isopropyl-6-(4-

58 (oxetan-3 -y l)piperazin- 1 -y l)pyrimidin-4-amine

N-(5-(bicyclo[2.2.1]heptan-2-yl)-lH-pyrazol-3-yl)-5-fluoro-2 -

59 isopropyl-6-(4-(oxetan-3-yl)piperazin-l-yl)pyrimidin-4-amine

N-(5-(3,3-difluorocyclobutyl)-lH-pyrazol-3-yl)-5-fluoro-2- isopropyl-6-(4-(3-methyloxetan-3-yl)piperazin-l-yl)pyrimidin -4-

60 amine Cmpd. Compound Name

No.

N-(5-cyclobutyl-lH-pyrazol-3-yl)-5-fluoro-2-isopropyl-6-(4-( 3-

61 methy loxetan-3 -y l)piperazin- 1 -y l)py rimidin-4-amine

N-(5-cyclopentyl-lH-pyrazol-3-yl)-5-fluoro-2-isopropyl-6-(4- (3-

62 methy loxetan-3 -yl)piperazin- 1 -yl)pyrimidin-4-amine

N-(5-cyclopropyl-lH-pyrazol-3-yl)-5-fluoro-2-isopropyl-6-(4- (3-

63 methy loxetan-3 -yl)piperazin- 1 -yl)pyrimidin-4-amine

N-(5-(bicyclo[2.2.1]heptan-2-yl)-lH-pyrazol-3-yl)-5-fluoro-2 - isopropyl-6-(4-(3-methyloxetan-3-yl)piperazin-l-yl)pyrimidin -4-

64 amine

1- (4-(2-cyclopropyl-6-((5-(3,3-difluorocyclobutyl)-lH-pyrazol- 3- yl)amino)-5-fluoropyrimidin-4-yl)piperazin-l-yl)-3-ethoxypro pan-

65 2- ol

2-((l-(2-cyclopropyl-6-((5-(3,3-difluorocyclobutyl)-lH-pyraz ol-3- yl)amino)-5-fluoropyrimidin-4-yl)piperidin-4-

66 y l)(methy l)amino)ethan- 1 -ol

2-cyclopropyl-N-(5-(3,3-difluorocyclobutyl)-lH-pyrazol-3-yl) -5- fluoro-6-(2-((4-methy lpiperazin- 1 -

67 yl)methyl)mo holino)pyrimidin-4-amine

2-(4-(2-cyclopropyl-6-((5-(3,3-difluorocyclobutyl)-lH-pyrazo l-3-

68 yl)amino)-5-fluoropyrimidin-4-yl)piperazin- 1 -yl)cy clopentan- 1 -ol

2-cyclopropyl-N-(5-(3,3-difluorocyclobutyl)-lH-pyrazol-3-yl) -6-

69 (4-(dimethylamino)piperidin- 1 -yl)-5-fluoropyrirnidin-4-amine

2-cyclopropyl-N-(5-(3,3-difluorocyclobutyl)-lH-pyrazol-3-yl) -5- fluoro-6-(6-isopropyl-2,6-diazaspiro[3.3]heptan-2-yl)pyrimid in-4-

70 amine

l'-(2-cyclopropyl-6-((5-(3,3-difluorocyclobut l)-lH-pyrazol-3-

71 yl)amino)-5-fluoropyrimidin-4-yl)-[l,4'-bipiperidin]-3-ol

2-cyclopropyl-N-(5-(3,3-difluorocyclobutyl)-lH-pyrazol-3-yl) -5-

72 fluoro-6-(4-(pyrrolidin-l -yl)piperidin-l -yl)pyrimidin-4-amine

2-cyclopropyl-N-(5-(3,3-difluorocyclobutyl)-lH-pyrazol-3-yl) -5-

73 fluoro-6-(2-oxa-8-azaspiro[4.5]decan-8-yl)pyrimidin-4-amine

2-cyclopropyl-N-(5-(3,3-difluorocyclobutyl)-lH-pyrazol-3-yl) -5-

74 fluoro-6-(2-oxa-6-azaspiro[3.4]octan-6-yl)pyrimidin-4-amine

6-chloro-2-cyclopropyl-5-fluoro-N-(5-((lr,3r)-3-

76 fluorocyclobutyl)-lH-pyrazol-3-yl)pyrimidin-4-amine

6-chloro-2-cyclopropyl-5-fluoro-N-(5-((ls,3s)-3-

77 fluorocyclobutyl)-lH-pyrazol-3-yl)pyrimidin-4-amine

2-cy clopropy 1-5 -fluoro-N-(5 -(( 1 r,3r)-3 -fluorocy clobuty 1)- 1 H-

78 pyrazol-3-yl)-6-(4-(oxetan-3-yl)piperazin-l-yl)pyrimidin-4-a mine

2-cy clopropy 1-5 -fluoro-N-(5 -(( 1 r,3r)-3 -fluorocy clobuty 1)- 1 H- pyrazol-3-yl)-6-(4-(3-methyloxetan-3-yl)piperazin-l-yl)pyrir nidin-

79 4-amine

2-cyclopropyl-5-fluoro-N-(5-((ls,3s)-3-fluorocyclobut l)-lH-

80 pyrazol-3-yl)-6-(4-(oxetan-3-yl)piperazin-l-yl)pyrimidin-4-a mine

81 2-cyclopropyl-5-fluoro-N-(5-((ls,3s)-3-fluorocyclobut l)-lH- Cmpd. Compound Name

No.

pyrazol-3-yl)-6-(4-(3-methyloxetan-3-yl)piperazin-l-yl)pyrim idin- 4-amine

2-cyclopropyl-N-(5-(3,3-difluorocyclobutyl)-lH-pyrazol-3-yl) -5-

82 fluoro-6-(4-methoxy-[ 1 ,4'-bipiperidin] - 1 '-y l)py rimidin-4-amine

(l-(2-cyclopropyl-6-((5-(3,3-difluorocyclobutyl)-lH-pyrazol- 3- yl)amino)-5-fluoropyrimidin-4-yl)piperidin-4-

83 yl)(morpholino)methanone

2-cyclopropyl-N4-(5-(3,3-difluorocyclobutyl)-lH-pyrazol-3-yl )-5- fluoro-N6-(l-((tetrahydrofuran-3-yl)methyl)piperidin-4-

84 yl)pyrimidine-4,6-diamine

6-(4-((l ,4-dioxan-2-yl)methyl)piperazin-l -yl)-2-cyclopropyl-N-

(5-(3,3-difluorocyclobutyl)-lH-pyrazol-3-yl)-5-fluoropyri midin-4-

85 amine

2-cyclopropyl-N4-(5-(3,3-difluorocyclobutyl)-lH-pyrazol-3-yl )- N6-(4-(dimethylamino)cyclohexyl)-5-fluoropyrimidine-4,6-

86 di amine

ethyl 2-(4-(2-cyclopropyl-6-((5-(3,3-difluorocyclobut l)-lH- pyrazol-3-yl)amino)-5-fluoropyrimidin-4-yl)piperazin-l-

87 yl)propanoate

2-cyclopropyl-N-(5-(3,3-difluorocyclobutyl)-lH-pyrazol-3-yl) -5-

88 fluoro-6-(4-(2,2,2 rifluoroethyl)piperazin-l-yl)pyrimidin-4-amine

2-cyclopropyl-N-(5-(3,3-difluorocyclobutyl)-lH-pyrazol-3-yl) -5-

89 fluoro-6-(4-(3-methoxypropyl)piperazin-l-yl)pyrimidin-4-amin e

2-cyclopropyl-N-(5-(3,3-difluorocyclobutyl)-lH-pyrazol-3-yl) -5-

90 fluoro-6-(4-(oxetan-3-yl)piperidin-l-yl)pyrimidin-4-amine

2-cyclopropyl-N-(5-(3,3-difluorocyclopentyl)-lH-pyrazol-3-yl )-5-

91 fluoro-6-(4-(oxetan-3-yl)piperazin- 1 -yl)pyrimidin-4-amine

2-cyclopropyl-N-(5-(3,3-difluorocyclopentyl)-lH-pyrazol-3-yl )-5- fluoro-6-(4-(3-methyloxetan-3-yl)piperazin-l-yl)pyrimidin-4-

92 amine

2-cyclopropyl-5-fluoro-6-(4-(oxetan-3-yl)piperazin-l-yl)-N-( 5-

93 (trifluoromethy 1)- 1 H-py razol-3 -y l)py rimidin-4-amine

2-cyclopropyl-5-fluoro-6-(4-(3-methyloxetan-3-yl)piperazin-l -yl)-

94 N-(5-(trifluoromethyl)-lH-pyrazol-3-yl)pyrimidin-4-amine

2-cyclopropyl-5-fluoro-N-(5-neopentyl-lH-pyrazol-3-yl)-6-(4-

95 (oxetan-3 -y l)piperazin- 1 -y l)pyrimidin-4-amine

2-cyclopropyl-5-fluoro-6-(4-(3-methyloxetan-3-yl)piperazin-l -yl)-

96 N-(5-neopentyl-lH-pyrazol-3-yl)pyrimidin-4-amine

2-cyclopropyl-5-fluoro-N-(5-neopentyl-lH-pyrazol-3-yl)-6-(4-

97 (oxetan-3-yl)piperidin-l-yl)pyrimidin-4-amine

2-cyclopropyl-N-(5-(3,3-dimethylcyclobutyl)-lH-pyrazol-3-yl) -5-

98 fluoro-6-(4-(oxetan-3-yl)piperazin- 1 -yl)pyrimidin-4-amine

2-cyclopropyl-N-(5-(3,3-dimethylcyclobutyl)-lH-pyrazol-3-yl) -5- fluoro-6-(4-(3-methyloxetan-3-yl)piperazin-l-yl)pyrimidin-4-

99 amine

100 2-cyclopropyl-N-(5-(3,3-dimethylcyclobutyl)-lH-pyrazol-3-yl) -5- Cmpd. Compound Name

No.

fluoro-6-(4-(oxetan-3-yl)piperidin-l-yl)pyrimidin-4-amine

2-cyclopropyl-N-(5-(3,3-difluorocyclopentyl)-lH-pyrazol-3-yl )-5-

101 fluoro-6-(4-(oxetan-3-yl)piperidin-l-yl)pyrimidin-4-amine

Salts. Compositions. Uses. Formulation. Administration and Additional Agents

Pharmaceutically acceptable salts and compositions

[00115] As discussed herein, the compounds of formula 1 of the present invention and the methods, compositions and kits disclosed herein are useful for the treatment of neurodegenerative or neurological diseases or disorders related to axonal damage, demyelinating diseases, central pontine myelinolysis, nerve injury diseases or disorders, metabolic diseases, mitochondrial diseases, metabolic axonal degeneration, a leukoencephalopathy or a leukodystrophy. In one embodiment, said

neurodegenerative or neurological diseases or disorders related to axonal damage, demyelinating diseases, central pontine myelinolysis, nerve injury diseases or disorders, metabolic diseases, mitochondrial diseases, metabolic axonal degeneration, a leukoencephalopathy or a leukodystrophy include, but are not limited to spinal cord injur}', stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital hypomyelination, encephalomyelitis, acute disseminated

encephalomyelitis, central pontine myelolysis, hypoxic demyelination, ischemic demyelination, neuromyelitis optics, adrenoleukodystrophy, Alexander's disease, Niemann-Pick disease. Pelizaeus Merzbacher disease, periventricular leukomalatia. globoid cell leucodystrophy (Krabbe's disease), Wallerian degeneration, optic neuritis, transverse myelitis, amylotrophic lateral sclerosis (Lou Gehrig's diseae), Huntington's disease, Alzheimer's disease, Parkinson's disease, Tay-Sacks disease, Gaucher's disease, Hurler Syndrome, traumatic brain injury, post radiation injury, neurologic complications of chemotherapy, neuropathy, acute ischemic optic neuropathy, neuromyelitis optica, vitamin B12 deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, Leber's hereditary optic atrophy /Leber congenital amaurosis, Marchiafava-Bignami syndrome, metachromatic

leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, schizophrenia, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paraparesis human T-lvmphotropic virus 1 (HTLV- 1 ) associated myelopathy, essential tremor or osmotic hyponatremia.

[00116] In another embodiment, the compounds of formula I of th e present invention and the methods, compositions and kits disclosed herein are useful for treating, preventing or ameliorating one or more symptoms of multiple sclerosis or another neurodegenerative disease selected from auditor}- impairment, optic neuritis, decreased visual acuity, diplopia, nystagmus, ocular dysmetria, intemuclear ophthalmoplegia, movement and sound phosphenes, afferent pupillary defect, paresis, monoparesis, paraparesis, hemiparesis, quadraparesis, plegia, paraplegia, hemiplegia, tetraplegia, quadraplegia, spasticity, dysarthria, motor dysfunction, walking impairment, muscle atrophy, spasms, cramps, hypotonia, clonus, myoclonus, myokymia, restless leg syndrome, gait disturbances, footdrop, dysfunctional reflexes, paraesthesia, anaesthesia, neuralgia, neuropathic and neurogenic pain, L'hermitte's, proprioceptive dysfunction, trigeminal neuralgia, ataxia, intention tremor, dysmetria, vestibular ataxia, vertigo, speech ataxia, dy stonia, disability progression,

dy sdi adoch ok i ties i a. frequent micturation, bladder spasticit ', flaccid bladder, detrusor- sphincter dyssynergia, erectile dysfunction or anorgasmy,

[00117] Accordingly, in another aspect of the invention, pharmaceutically acceptable compositions are provided, wherein these compositions comprise any of the compounds as described herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents. In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or vehicles.

[00118] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. A "pharmaceutically acceptable salt" means any non-toxic salt or salt of an ester of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof. As used herein, the term "inhibitorily active metabolite or residue thereof means that a metabolite or residue thereof is also useful for treating or lessening the severity of, in a subject, a disease or disorder selected from neurodegenerative or neurological diseases or disorders related to axonal damage, demyelinating diseases, central pontine myelinolysis, nerve injury diseases or disorders, metabolic diseases, mitochondrial diseases, metabolic axonal degeneration, a leukoencephalopathy or a leukodystrophy.

[00119] Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences , 1977, 66, 1-19, incorporated herein by reference.

Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3- phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (Ci-4 alkyl) ₄ salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersable products may be obtained by such quaternization.

Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[00120] As described herein, the pharmaceutically acceptable compositions of the invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the

pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention. Some examples of materials which can serve as

pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene- poly oxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as com starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;

powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

[00121] In another aspect, the invention features a pharmaceutical composition comprising the compound of the invention and a pharmaceutically acceptable carrier.

[00122] In another aspect, the invention features a pharmaceutical composition comprising a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof of the compounds of formula I and one or more

pharmaceutically acceptable carriers or vehicles.

Uses of Compounds and Pharmaceutically Acceptable Salts and Compositions

[00123] In one embodiment, the methods described herein also provide a method of promoting oligodendrocyte proliferation, differentiation or survival comprising contacting oligodendrocytes with a compound of formula I or a composition thereof.

[00124] In another embodiment, a method of the present invention comprises promoting oligodendrocyte proliferation, differentiation or survival. In another embodiment, a method of the present invention comprises promoting oligodendrocyte proliferation, differentiation or survival with a compound of formula I or a composition thereof. In another embodiment, a method of the present invention is useful for treating or lessening the severity of a disease or disorder selected from a disease or disorder associated with a lack of oligodendrocyte proliferation, differentiation or survival comprising administering a therapeutically effective amount of the compounds of formula I or compositions thereof to a subject in need thereof.

[00125] In another embodiment, a method of the present invention comprises promoting myelination by contacting neuronal cells, oligodendrocyte cells or oligodendrocyte precursor cells. In one embodiment, a method of the present invention comprises promoting myelination by contacting neuronal cells, oligodendrocyte cells or oligodendrocyte precursor cells with a compound of formula I or a composition thereof.

[00126] In another embodiment, a method of the present invention comprises promoting survival of cells of the nervous system. In another embodiment, a method of the present invention comprises promoting survival of cells of the nervous system comprising contacting the cells with a compound or composition of formula I. In one embodiment, the cells of the nervous system comprise brain cells, cortical neurons, oligodendroctyes or oligodendrocyte precursor cells.

[00127] In another embodiment, a method of the present invention is useful for treating or lessening the severity of a disease or disorder selected from a disease or condition associated with demyelination comprising administering a therapeutically effective amount of the compounds of formula I or compositions thereof to a subject in need thereof. In one embodiment, the disease or condition associated with demyelination is a CNS disorder or a CNS demyelinating disease as described herein. In one embodiment, the disease is multiple sclerosis.

[00128] In another embodiment, the subject has, or is at risk of having, multiple sclerosis. The subject with multiple sclerosis can be at any stage of treatment or disease. In one embodiment, the subject with multiple sclerosis has one or more of: benign multiple sclerosis, relapsing remitting multiple sclerosis, quiescent relapsing remitting multiple sclerosis, active relapsing remitting multiple sclerosis, primary progressive multiple sclerosis, or secondary progressive multiple sclerosis, clinically isolated syndrome, or clinically defined multiple sclerosis. In one embodiment, the t pe of multiple sclerosis is primary progressive multiple sclerosis. In another embodiment, the type of multiple sclerosis is relapsing-remitting multiple sclerosis. In yet another embodiment, the type of multiple sclerosis is secondary progressive multiple sclerosis. In still a further embodi ment, the type of multiple sclerosis is progressive relapsing multiple sclerosis. In another embodiment, the subject is asymptomatic. In another embodiment, the subject has one or more multiple sclerosis-like symptoms, such as those having clinically isolated syndrome or clinically defined multiple sclerosis. In yet other embodiments, the subject has one or more multiple sclerosis relapses.

100129| In another embodiment, the subject has a relapsing form of multiple sclerosis such as relapsing remitting multiple sclerosis or relapsing secondary progressive multiple sclerosis. In one embodiment, the subject has relapsing remitting multiple sclerosis and has one or more ongoing clinical exacerbations. In another embodiment, the subject has relapsing remitting multiple sclerosis and one or more subclinical activities. In one embodiment, the clinical exacerbation or subclinical activity is shown by gadolinium enhancement of white matter lesions using T 1 T2 magnetic resonance imaging. In another embodiment, the clinical exacerbation or subclinical activity is shown by development of new or enlarged white matter lesions on magnetic resonance imaging of the brain or spinal cord. In one embodiment, the development of new or enlarged white matter lesions is monitored by T1/T2 magnetic resonance imaging. In another embodiment, the development of new or enlarged white matter lesions is monitored by Proton Density magnetic resonance imaging. In yet another embodiment, the development of new or enlarged white matter lesions is monitored by MTR magnetic resonance imaging. See also, Gaitan, M. I. and Reich, D. S. (2014) MRI in Diagnosis and Disease Monitoring, in Multiple Sclerosis and CNS Inflammatory Disorders (eds L. M. Samkoff and A. D. Goodman), John Wiley & Sons, Ltd., Chichester, UK.

doi: 10.1002/9781118298633. ch4 which is incorporated herein in its entirety by reference.

[00130] In another embodiment, the clinical exacerbations or subclinical activities are monitored by a f unctional readout such as ambulators changes (gait changes, sway changes, etc.), T25W changes and/or EDSS changes. In another embodiment, the clinical exacerbations or subclinical activities are monitored by a visual evoked potential assay, a visual acuity assay or a measurement of optic nerve thickness. In another embodiment, the clinical exacerbations or subclinical activities are monitored by a myelin labelling assay.

[00131] In another embodiment, the subject with multiple sclerosis can be at any stage of treatment or disease and treatment with compounds of formula I of the present invention result in improvement of the disease or symptoms. In one embodiment, improvement in the disease or symptoms is evidenced by a reduction or disappearance of one or more white matter lesions in the brain. In another embodiment, improvement in the disease or symptoms is evidenced by improved function such as improved ambulation, improved gait, reduced sway, improved T25W scores or improved EDSS scores. In another embodiment, improvement in the disease or symptoms is evidenced by improvements in a visual acuity assay or a visual evoked potential assay. In another embodiment, improvement in the disease or symptoms is evidenced by enhanced optic nerve thickness. In another embodiment, improvement in the disease or symptoms is evidenced by increased myelination in a myelin labelling assay. [00132] In another embodiment, the compounds of formula I of the present invention and the methods, compositions and kits disclosed herein are useful for promoting myelin regeneration in progressive demyelinating diseases. In one embodiment, the compounds of formula I of the present invention and the methods, compositions and kits disclosed herein are useful for promoting myelin regeneration in primary progressive multiple sclerosis. In another embodiment, the compounds of formula I of the present invention and the methods, compositions and kits disclosed herein are useful for promoting myelin regeneration in secondary progressive multiple sclerosis. In another embodiment, the compounds of formula I of the present invention and the methods, compositions and kits disclosed herein are useful for promoting myelin regeneration in relapsing-remitting multiple sclerosis. In another embodiment, the compounds of formula I of the present invention and the methods, compositions and kits disclosed herein are useful for promoting myelin regeneration in progressive relapsing multiple sclerosis.

[00133] In yet another embodiment, the compounds of formula I of the present invention and the methods, compositions and kits disclosed herein are useful for promoting remyelination at the cellular level wherein oligodendrocyte cells are stimulated to regenerate or differentiate. In another embodiment, the compounds of formula I of the present invention and the methods, compositions and kits disclosed herein are useful for promoting remyelination at the cellular level wherein oligodendrocyte cells are stimulated to remyelinate axons.

[00134] In another embodiment, the compounds of formula I of the present invention and the methods, compositions and kits disclosed herein are useful for promoting remyelination at the cellular level whereby oligodendrocyte cells are stimulated to regenerate or differentiate thereby treating demyelinating diseases or disorders. In yet another embodiment, the compounds of formula I of the present invention and the methods, compositions and kits disclosed herein are useful for promoting

remyelination at the cellular level whereby axons are remyelinated by

oligodendrocyte cells thereby treating demyelinating diseases or disorders.

[00135] In another embodiment, the compounds of formula I of the present invention and the methods, compositions and kits disclosed herein are useful for inducing endogenous oligodendrocytes or oligodendrocyte precursor cells to contact an axon and produce myelin. [00136] In another aspect, the present invention provides a method of treating or lessening the severity of, in a subject, a disease or disorder selected from a demyelinating disease, central pontine myelinolysis, a nerve injury disease or disorder, a leukoencephalopathy or a leukodystrophy comprising administering an effective amount of a compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the compounds of formula I.

[00137] In one aspect, the present invention provides a method of treating or lessening the severity of, in a subject, a disease or disorder selected from spinal cord injury, stroke, multiple sclerosis, progressive multifocal

congenital hypomyelination, encephalomyelitis, acute disseminated

encephalomyelitis, central pontine myelolysis, hypoxic demyelination, ischemic demyelination. neuromyelitis optics, adrenoleukodystrophy, Alexander's disease, Niemann-Pick disease, Pelizaeus Merzbacher disease, periventricular leukomalatia, globoid cell ieucodystrophy ( Krabbe's disease). Wallerian degeneration, optic neuritis. transverse myelitis, amyotrophic lateral sclerosis (Lou Gehrig ^' s diseae). Huntington's disease, Alzheimer's disease, Parkinson's disease, Tay-Sacks disease, Gaucher ^" s disease, Hurler Syndrome, traumatic brain injury, post radiation injur}-, neurologic complications of chemotherapy, neuropathy, acute ischemic optic neuropathy, neuromyelitis optica, vitamin B12 deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornz eig syndrome, Leber's hereditary optic atrophy Leber congenital amaurosis. M arch i afa v a- B i gn ami syndrome, metachromatic

leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia. Bell's palsy, schizophrenia, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paraparesis human T-lymphotropic virus 1 ( HTLV- 1 ) associated myelopathy, essential tremor or osmotic hyponatremia comprising administering an effective amount of a compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the compounds of formula I.

[00138] In another aspect, the present invention provides a method of treating, preventing or ameliorating one or more symptoms of multiple sclerosis or another neurodegenerative disease selected from auditory impairment, optic neuritis, decreased visual acuity, diplopia, nystagmus, ocular dysmetria, internuclear ophthalmoplegia, movement and sound phosphenes. afferent pupillary defect, paresis, monoparesis, paraparesis, hemi paresis, quadraparesis. plegia. paraplegia, hemiplegia. tetraplegia, quadraplegia, spasticity, dysarthria, motor dysfunction, walking impairment, muscle atrophy, spasms, cramps, hypotonia, clonus, myoclonus, myokymia, restless leg syndrome, gait disturbances, footdrop, dysfunctional reflexes, paraesthesia, anaesthesia, neuralgia, neuropathic and neurogenic pain, L'hermitte's, proprioceptive dysfunction, trigeminal neuralgia, ataxia, intentio tremor, dysmetria, vestibular ataxia, vertigo, speech ataxia, dystonia, disability progression,

d s d i ad och ok i n es i a. frequent micturation. bladder spasticity, flaccid bladder, detrusor- sphincter dyssynergia, erectile dysfunction or anorgasmy comprisin administering an effective amount of a compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the compounds of formula I.

[00139] In yet another aspect, the present invention provides a method of treating or lessening the severity of, in a subject, a disease or disorder selected from a demyelinatin disease, central pontine myelinolysis, a nerve injury disease or disorder, a leukoencephalopathy or a leukodystrophy comprising administering an effective amount of a compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the compounds of formula I with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound or pharmaceutical composition.

[00140] In another aspect, the present invention provides a method of treating or lessening the severity of, in a subject, a disease or disorder selected from spinal cord injur}', stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital hypomyelination, encephalomyelitis, acute disseminated

encephalomyelitis, central pontine myelolysis, hypoxic demyelination, ischemic demyelination, neuromyelitis optics, adrenoleukodystrophy, Alexander's disease, Niemann-Pick disease. Pelizaeus Merzbacher disease, periventricular leukomalatia. globoid cell leucodystrophy (Krabbe's disease), Wallerian degeneration, optic neuritis, transverse myelitis, amylotrophic lateral sclerosis (Lou Gehrig's diseae), Huntington's disease, Alzheimer's disease, Parkinson's disease, Tax -Sacks disease, Gaucher's disease, Hurler Syndrome, traumatic brain injury, post radiation injury, neurologic complications of chemotherapy, neuropathy, acute ischemic optic neuropathy, neuromyelitis optica, vitamin B12 deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, Leber's hereditary optic atrophy /Leber congenital amaurosis, Marchiafava-Bignami syndrome, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia. Bell's palsy, schizophrenia, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paraparesis uman T-lymphotropic virus 1 (HTLV-1 ) associated myelopathy, essential tremor or osmotic hyponatremia comprising administering an effective amount of a compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the compounds of formula I with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound or pharmaceutical composition.

[00141] In another aspect, the present invention provides a method of treating or lessening the severity of, in a subject, a type of multiple sclerosis selected from primary progressive multiple sclerosis, relapsing-remitting multiple sclerosis, secondaiy progressive multiple sclerosis or progressive relapsing multiple sclerosis. In one aspect, the type of multiple sclerosis is primary progressive multiple sclerosis. In another aspect, the t pe of multiple sclerosis is relapsing-remittin multiple sclerosis. In yet another aspect, the type of multiple sclerosis is secondary progressive multiple sclerosis. In still a further aspect, the type of multiple sclerosis is progressive relapsing multiple sclerosis.

[00142] In another aspect, the present invention provides a method for treating, preventing or ameliorating one or more symptoms of multiple sclerosis or another neurodegenerative disease selected from auditory impairment, optic neuritis, decreased visual acuity, diplopia, nystagmus, ocular dysmetria. intemiiclear ophthalmoplegia, movement and sound phosphenes, afferent pupillary defect, paresis, monoparesis, paraparesis, hemiparesis, quadraparesis, plegia, paraplegia, hemiplegia, tetraplegia, quadraplegia, spasticity, dysarthria, motor dysfunction, walking impairment, muscle atrophy, spasms, cramps, hypotonia, clonus, myoclonus, myokymia, restless leg syndrome, gait disturbances, footdrop, dysfunctional reflexes, paresthesia, anaesthesia, neuralgia, neuropathic and neurogenic pain, L'hermitte's, proprioceptive dysfunction, trigeminal neuralgia, ataxia, intention tremor, dysmetria, vestibular ataxia, vertigo, speech ataxia, dy stonia, disability progression,

d sdi adoch ok i ties i a. frequent micturation, bladder spasticit ', flaccid bladder, detrusor- sphincter dyssynergia, erectile dysfunction or anorgasmy comprising administerin an effective amount of a compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the compounds of formula I with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound or pharmaceutical composition.

Manufacture of Medicaments

[00143] In one aspect, the present invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in treating or lessening the severity of, in a subject, a disease or disorder selected from a demyelinating disease, central pontine myelinolysis, a nerve injury disease or disorder or a leukoencephalopathy.

[00144] In another aspect, the present invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in treating or lessening the severity of, in a subject, a disease or disorder selected from spinal cord injury, stroke, multiple sclerosis, progressive multifocal

leukoencephalopathy, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelolysis, hypoxic demyelination. ischemic demyelination, neuromyelitis optics, adrenoleukodystrophy, Alexander's disease, Niemann-Pick disease, Pelizaeus Merzbacher disease, periventricular leukomalatia. globoid cell leucodystrophy (Krabbe's disease). Wallerian degeneration, optic neuritis, transverse myelitis, amylotrophic lateral sclerosis (Lou Gehrig's diseae), Huntington's disease, Alzheimer's disease, Parkinson's disease, Tay -Sacks disease. Gaucher's disease, Hurler Syndrome, traumatic brain injury, post radiation injury, neurologic complications of chemotherapy, neuropathy, acute ischemic optic neuropathy, neuromyelitis optica, vitamin B12 deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, Leber's hereditary optic atrophy Leber congenital amaurosis, Marchiafava-Bignami syndrome, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, schizophrenia, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic parapares i s uman T-lymphotropic virus 1 (HTLV- 1 ) associated myelopathy, essential tremor or osmotic hyponatremia.

[00145] In another aspect, the present invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in treating, preventing or ameliorating one or more symptoms of multiple sclerosis or another neurodegenerative disease selected from auditory impairment, optic neuritis, decreased visual acuity, diplopia, nystagmus, ocular dysmetria, intern uclear ophthalmoplegia, movement and sound phosphenes. afferent pupillar - defect, paresis, monoparesis, paraparesis, hemiparesis, quadraparesis, plegia, paraplegia, hemiplegia, tetraplegia, quadraplegia, spasticity, dysarthria, motor dysfunction, walking impairment, muscle atrophy, spasms, cramps, hypotonia, clonus, myoclonus, myokymia, restless leg syndrome, gait disturbances, footdrop, dysfunctional reflexes, pallesthesia, anaesthesia, neuralgia, neuropathic and neurogenic pain, L'hermitte's, proprioceptive dy sfunction, trigeminal neuralgia, ataxia, intention tremor, dysmetria, vestibular ataxia, vertigo, speech ataxia, dystonia, disability progression, dysdiadochokinesia, frequent micturation, bladder spasticity, flaccid bladder, detrusor- sphincter dy ssy nergia. erectile dysfunction or anorgasmy.

[00146] In yet another aspect, the present invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament in combination with one or more additional therapeutic agents administered concurrentl with, prior to, or subsequent to treatment with the compound or pharmaceutical composition.

[00147] In one aspect, the present invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in treating or lessening the severity of, in a subject, a disease or disorder selected from a demy elinating disease, central pontine myelinolysis, a nerve injury disease or disorder or a leukoeiicephalopathy with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound or pharmaceutical composition.

[00148] In another aspect, the present invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in treating or lessening the severity of, in a subject, a disease or disorder selected from spinal cord injury, stroke, multiple sclerosis, progressive multifocal

leukoencephalopathy, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomy elitis, central pontine my eloly sis, hypoxic demy elination. ischemic demyelination, neuromyelitis optics, adrenoleukodystrophy, Alexander's disease, Niemann-Pick disease, Pelizaeus Merzbacher disease, periventricular leukomalatia. globoid cell leucody strophy (Krabbe's disease). Wallerian degeneration, optic neuritis, transverse myelitis, amy otrophic lateral sclerosis (Lou Gehrig's diseae), Huntington's disease, Alzheimer's disease. Parkinson's disease. Tay- Sacks disease, Gaucher's disease, Hurler Syndrome, traumatic brain injur ', post radiation injury, neurologic complications of chemotherapy, neuropathy, acute ischemic optic neuropathy, neuromyelitis optica, vitamin B 12 deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, Leber's hereditary optic atrophy/Leber congenital amaurosis, Marchiafava-Bignami syndrome, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia. Bell's palsy, schizophrenia, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paraparesis human T-lvmphotropic virus 1 (HTLV-1 ) associated myelopathy, essential tremor or osmotic hyponatremia in combination with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound or pharmaceutical composition.

[00149] In another aspect, the present invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in treatin or lessening the seventy of, in a subject, a t pe of multiple sclerosis selected from primary progressive multiple sclerosis, relapsing-remitting multiple sclerosis, secondary progressive multiple sclerosis or progressive relapsing multiple sclerosis. In one aspect, the type of multiple sclerosis is primary progressive multiple sclerosis. In another aspect, the t pe of multiple sclerosis is relapsing-remitting multiple sclerosis. In yet another aspect, the type of multiple sclerosis is secondar ' progressive multiple sclerosis. In still a further aspect, the type of multiple sclerosis is progressive relapsing multiple sclerosis.

[00150] In yet another aspect, the present the present invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in treating, preventing or ameliorating one or more symptoms of multiple sclerosis or another neurodegenerative disease selected from auditory impairment, optic neuritis, decreased visual acuity, diplopia, nystagmus, ocular dysmetria, iiitemuclear ophthalmoplegia, movement and sound phosphenes, afferent pupillary defect, paresis, monoparesis, paraparesis, hemiparesis, quadraparesis, piegia, paraplegia, hemiplegia, tetraplegia, quadraplegia, spasticity, dysarthria, motor dysfunction, walking impairment, muscle atrophy, spasms, cramps, hypotonia, clonus, myoclonus, myokymia, restless le syndrome, gait disturbances, footdrop.

dysfunctional reflexes, paraesthesia, anaesthesia, neuralgia, neuropathic and neurogenic pain, L'herniitte's, proprioceptive dysfunction, trigeminal neuralgia, ataxia, intention tremor, dysmetria, vestibular ataxia, vertigo, speech ataxia, dystonia, disability progression, dysdiadochokinesia, frequent micturation, bladder spasticity, flaccid bladder, detrusor- sphincter dyssynergia, erectile dysfunction or anorgasmyin combination with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound or pharmaceutical composition.

Administration of Pharmaceutically acceptable salts and Compositions

[00151] In certain embodiments of the invention an "effective amount" of the compound, a pharmaceutically acceptable salt thereof or pharmaceutically acceptable composition is that amount effective for treating or lessening the severity of, in a subject, a disease or disorder selected from one or more of a demyelinating disease, central pontine myelinolysis, a nerve injury disease or disorder or a

leukoencephalopathy.

[00152] The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease, the particular agent, its mode of administration, and the like. The compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression "dosage unit form" as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts. The term "patient", as used herein, means an animal, preferably a mammal, and most preferably a human [00153] The pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally,

intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the disease being treated. In certain embodiments, the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

[00154] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol,

polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[00155] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S. P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[00156] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. [00157] In order to prolong the effect of a compound of the invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming

microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[00158] Compositions for rectal or vaginal administration are preferably

suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[00159] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[00160] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.

[00161] The active compounds can also be in microencapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[00162] Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms are prepared by dissolving or dispensing the compound in the proper medium.

Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

Additional Therapeutic Agents

[00163] It will also be appreciated that the the compounds of formula I of the present invention and the methods, compositions and kits disclosed herein can be employed in combination therapies, that is, the compounds and pharmaceutically acceptable compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated." Additional appropriate therapeutic agents or approaches are described generally in The Merck Manual, Nineteenth Edition, Ed. Robert S. Porter and Justin L. Kaplan, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., 2011, and the Food and Drug

Administration website, www.fda.gov, the entire contents of which are hereby incorporated by reference.

[00164] In one embodiment, the additional therapeutic agents is an

immunomodulatory agent, such as an IFN-β 1 molecule including but not limited to an interferon beta la (Avonex®, Rebif®) or an interferon beta lb (Betaseron®, Betaferon®, Extavia®). Immunomodulatory agents also include other interferons and fragments, analogues, homologues, derivatives, and natural variants thereof with substantially similar biological activity to interferon beta la molecules.

[00165] In another embodiment, the additional therapeutic agent is a polymer of glutamic acid, lysine, alanine and tyrosine such as glatiramer acetate (Copaxone®).

[00166] In another embodiment, the additional therapeutic agent is an antibody or fragment thereof against alpha-4 integrin (e.g., natalizumab (Tysabri®)).

[00167] In another embodiment, the additional therapeutic agent is an

anthracenedione molecule such as mitoxantrone (Novantrone®).

[00168] In another embodiment, the additional therapeutic agent is a sphingosine 1- phosphate receptor modulator such as fingolimod (Gilenya®) and those described in WO 2012/109108 the entire contents of which is hereby incorporated by reference.

[00169] In another embodiment, the additional therapeutic agent is a dimethyl fumarate such as an oral dimethyl fumarate (Tecfidera®).

[00170] In another embodiment, the additional therapeutic agent is an antibody to the alpha subunit of the IL-2 receptor of T cells such as daclizumab (Zenapax®).

[00171] In another embodiment, the additional therapeutic agent is an antibody against CD52 such as alemtuzumab (Lemtrada®).

[00172] In another embodiment, the additional therapeutic agent is an inhibitor of a dihydroorotate dehydrogenase such as teriflunomide (Aubagio®).

[00173] In another embodiment, the additional therapeutic agent is an antibody to CD20 such as ocrelizumab, rituximab or ofatumumab.

[00174] In another embodiment, the additional therapeutic agent is a corticosteroid such as, but not limited to methylprednisolone, Depo-Medrol®, Solu-Medrol®, Deltasone®, Delta-Cortef®, Medrol®, Decadron® or Acthar®.

[00175] In another embodiment, the additional therapeutic agent is an anti-VLA4 antibody, such as Natalizumab (Tysabri®) or a related VLA-4 antibodies such as those described in US 5,840,299, US 6,602,503, Sanchez-Madrid et al, (1986) Eur. J. Immunol 16: 1343-1349; Hemler et al, (1987) J Biol. Chem. 2: 11478-11485; Issekutz et al. (1991) J Immunol 147: 109 (TA-2 mab); Pulido et al. (1991) J Biol. Chem. 266: 10241-10245; and U.S. Pat. No. 5,888,507 the entire contents of each patent or publication hereby incorporated by reference in their entirety.

[00176] In another embodiment, the additional therapeutic agent is a LINGO- 1 antagonist (e.g., an antibody against LINGO (e.g., LINGO-1, LINGO-2, LINGO-3, LINGO-4) or a Nogo receptor-1 (NgRl) modulator and compositions thereof such as those disclosed in WO2004/085648, WO2006/002437, WO2007/008547,

WO2007/025219, WO2007/064882, WO2007/056161, WO2007/133746,

WO2007/098283, WO2008/086006, WO2009/061500, WO2010/005570,

WO2010/062904, WO 2013/173364, WO2014/058875, each of which is hereby incorporated by reference in its entirety.

[00177] In another embodiment, the additional therapeutic agent is a TAJ modulator, such as those disclosed in WO2006/017673, which is hereby incorporated by reference in its entirety.

[00178] In another embodiment, the additional therapeutic agent is a TrkA antagonist such as those disclosed in WO2008/013782 or a TrkB antagonist such as those disclosed in WO2009/048605, each of which is hereby incorporated by reference in its entirety.

[00179] In another embodiment, the additional therapeutic agent is a sclerostin modulator such as those disclosed in WO2013/063095, which is hereby incorporated by reference in its entirety.

[00180] In another embodiment, the additional therapeutic agent is an autotaxin (ATX) inhibitor or LPA receptor antagonist, such as those described in

WO2015048301, WO2015042053, WO2015042052, WO2015008230,

WO2015008229, WO2014202458, WO2014139882, WO2014133112,

WO2014097151, WO2014110000, WO2014/081756, WO2014/081752,

WO2014/048865, WO2014168824 , WO2014143583, WO2014139978,

WO2013/186159, WO2012/024620, WO2012/166415, WO2012078593,

WO2012078805, WO2012024620,WO2013070879, WO2013/061297,

WO2013/054185, WO2014/018881, WO2014/018887, WO2014/018891,

WO2014/025708, W02104/025709, WO2014/152725, WO2012028243,

WO2012005227, WO2011/159635, WO2011/159550, WO2011116867,

WO2011053948, WO2011041729, WO2011041694, WO2011041462,

WO2011041461, WO2011017561, WO2011017350, WO2010115491,

WO2011006569, WO20110141761, WO2010112124, WO2010112116,

WO2010077883, WO2010077882, WO2010068775, WO2010063352,

WO2010051031, WO2010051030, WO2009046841, WO2009046842,

WO2009046804, WO2009023854, WO2009/135590, WO2008/014286, WO 2010/141768, US2006/194850, US 2003/114505, US 2004/122236, US 2006/194850, US 6964945, US2005/0256160, US 2006/148830, US 2008/0293764,

US2010/0249157, the disclosure of each patent application and patent hereby incorporated by reference in its entirety.

[00181] In another embodiment, the additional therapeutic agent is a Nox4 modulator such as those described in WO2013/037499, which is hereby incorporated by reference in its entirety.

[00182] In another embodiment, the additional therapeutic agent is a remyelinating antibody such as rHIgM22.

[00183] In another embodiment, the additional therapeutic agent is dalfampridine (Ampyra®)

[00184] In another embodiment, the additional therapeutic agent is a death receptor 6 (DR6) antagonist, a p75 antagonist or a combination thereof such as those disclosed in US 8894999 and WO2014106104 each of which is incorporated herein by reference in its entirety.

[00185] In another embodiment, the additional therapeutic agent is Cethrin™.

[00186] In another embodiment, the additional therapeutic agent is an activin receptor modulator such as those described in WO2015/001352, which is hereby incorporated by reference in its entirety.

[00187] In another embodiment, the additional therapeutic agent is a GLP-1 like peptide or a derivative of GLP-1 like peptides such as those disclosed in

WO2015/000942, WO2014/202727, WO2012/140117, WO2012/062803, WO 2012/062804, WO2011/080102 and WO2009/030771, each of which is incorporated herein by reference in its entirety. In another embodiment, the GLP-1 derivative is Liraglutide or Semaglutide.

[00188] In another embodiment, the additional therapeutic agent is a RXR modulator such as those disclosed in US2015/0038585 and WO2013056232 each of which is incorporated herein by reference in its entirety. In another embodiment, the RXR modulator is HX630.

[00189] In another embodiment, the additional therapeutic agent is an activator of the NRF2/KE AP 1 / ARE pathway such as those disclosed in WO2014/197818 which is hereby incorporated by reference in its entirety. [00190] In another embodiment, the additional therapeutic agent is a PPAR agonist such as those disclosed in WO2014/165827 which is hereby incorporated by reference in its entirety.

[00191] In another embodiment, the additional therapeutic agent is an inhibitor of HDAC4 such as those disclosed in WO2013/080120 which is hereby incorporated by reference in its entirety.

[00192] In another embodiment, the additional therapeutic agent is a gamma secretase inhibitor such as DAPT.

[00193] In another embodiment, the additional therapeutic agent is an antipsychotic medication such as quetiapine.

[00194] In another embodiment, the additional therapeutic agent is a thyroid hormone.

[00195] In another embodiment, the additional therapeutic agent is a thyroid translocator protein (TSPO) such as etifoxine.

[00196] In another embodiment, the additional therapeutic agent is insulin-like growth factor 1 (IGF-1).

[00197] In another embodiment, the additional therapeutic agent is an anticholinergic such as benzatropine.

[00198] In another embodiment, the additional therapeutic agent is an antihistamine/anti cholinergic such as clemastine or clemastine fumarate.

[00199] In another embodiment, the additional therapeutic agent is one that removes antiaquaporin by plasmapheresis.

[00200] In another embodiment, the additional therapeutic agent is a hyaluronan inhibitor or antagonist such as those described in WO2015023691, which is hereby incorporated by reference in its entirety.

[00201] In another embodiment, the additional therapeutic agent is a hyaluronidase inhibitor such as a PH20 inhibitor or those described in

WO2013/102144, WO2011/133862, and WO2010/007729 each of which is hereby incorporated by reference in its entirety.

[00202] In another embodiment, the additional therapeutic agent is a Toll-Like Receptor-2 (TLR-2) inhibitor. [00203] In another embodiment, the additional therapeutic agent is a

Semaphorin 3A antagonist or antibody such as those disclosed in WO2014123186, which is hereby incorporated by reference in its entirety.

[00204] In another embodiment, the additional therapeutic agent is a CXCR2 inhibitor or antagonist.

[00205] In another embodiment, the additional therapeutic agent is a

Semaphorin 3F agonist.

[00206] In another embodiment, the additional therapeutic agent is a Wnt polypeptide or Wnt inhibitor such as those disclosed in WO 2013/040309 and WO 2012/097093, each of which is hereby incorporated by reference in its entirety.

[00207] In another embodiment, the additional therapeutic agent is a mitochondrial pore modulator such as Olesoxime.

[00208] In another embodiment, the additional therapeutic agent is a PSA NCAM antagonist, a CXCR2 inhibitor or antagonist, a MRF agonist, a GM-98 agonist, a Tcf4 inhibitor, a retinoid, a neuregulin 1-erbB signaling modulator, a zpfl91 activator, an miR219 activator, an miR338 activator or an miR138 activator.

[00209] In certain embodiments, the additional agent is an immunomodulatory agent such as an IFN-β 1 molecule which is administered intravenously, subcutaneously or intramuscularly. In one embodiment, the IFN-β 1 molecule is administered at 20-45 microgram once a week by intramuscular injection. In another embodiment, the IFN- β 1 molecule is administered at 20-30 microgram three times a week by intramuscular injection. In another embodiment, the IFN-β 1 molecule is administered at 40-50 micrograms once a week, by subcutaneous injection.

[00210] In another embodiment, the IFN-β 1 molecule is administered in an amount of between 10 and 50 μg intramuscularly three times a week.

[00211] In another embodiment, the IFN-β 1 molecule is administered in an amount of between 10 and 50 μg intramuscularly every five to ten days.

[00212] In another embodiment, the IFN-β 1 molecule is administered in an amount between 200 and 600 μg every other day by subcutaneous injection. In one embodiment, the IFN-β 1 molecule is an interferon β-lb (Betaseron®, Betaferon®, or Extavia®). [00213] These combinations are useful for treating or lessening the severity of, in a subject, the diseases described herein including neurodegenerative diseases such as multiple sclerosis. These combinations are also useful in the kits described herein.

[00214] It will also be appreciated that the the compounds of formula I of the present invention and the methods, compositions and kits disclosed herein can be employed in combination therapies to not only treat or lessen the severity of, in a subject, the diseases described herein but may also be used in symptom management. Those additional agents include those useful for treating symptoms such as bladder problems (e.g., Botox®, DDAVP Nasal Spray®, Detrol®, Ditropan®, Ditropan XL®, Enablex®, Flomax®, Hytrin®, Minipress®, Oxytrol®, Pro-Banthine®, Sanctura®, Tofranil®, Vesicare®); infections (Bactrim®, Septra®, Cipro®, Macrodantin®, Hiprex®, Pyridium®); bowel dysfunction (Colace®, Dulcolax®, Enemeez®, Fleet enema, Mineral oil, Metamucil®, Milk of Magnesia®, glycerin suppositories);

depression (Cymbalta®, Effexor®, Paxil®, Prozac®, Wellbutrin®, Zoloft®);

dizziness and vertigo (Antivert®); emotional changes (Nuedexta®), Fatigue

(Amantadine®, Provigil®, Prozac®), itching (Atarax®); pain (Dilantin®, Elavil®, Klonipin®, Neurontin®, Pamelor®, Aventyl®, Tegetrol®); sexual problems

(Cialis®, Levitra®, Papaverine®, MUSE®, Prostin VR®, Viagra®); spasticity (Dantrium®, Gablofen®, Klonipin®, Lioresal®, Valium®, Zanaflex®); tremors (Laniazid®, Nydrazid®, Klonopin®, Rivotril®); and walking or gait difficulties (Ampyra®).

[00215] The amount of additional therapeutic agent present in or with the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

[00216] In another aspect, the present invention features a kit comprising a compound and/or pharmaceutical composition of formula I of the present invention and instructions for use thereof.

[00217] In another embodiment, the kits of the present invention further comprise one or more additional therapeutic agent(s). In another embodiment, the additional therapeutic agent is selected from an immunomodulatory agent, such as an IFN-β 1 molecule including but not limited to an interferon beta la (Avonex®, Rebif®) or an interferon beta lb (Betaseron®, Betaferon®, Extavia®).

[00218] In another embodiment, the additional therapeutic agent is a polymer of glutamic acid, lysine, alanine and tyrosine such as glatiramer acetate (Copaxone®).

[00219] In another embodiment, the additional therapeutic agent is an antibody or fragment thereof against alpha-4 integrin (e.g., natalizumab (Tysabri®)).

[00220] In another embodiment, the additional therapeutic agent is an

anthracenedione molecule such as mitoxantrone (Novantrone®).

[00221] In another embodiment, the additional therapeutic agent is a sphingosine 1- phosphate receptor modulator such as fingolimod (Gilenya®) and those described in WO 2012/109108 the entire contents of which is hereby incorporated by reference.

[00222] In another embodiment, the additional therapeutic agent is a dimethyl fumarate such as an oral dimethyl fumarate (Tecfidera®).

[00223] In another embodiment, the additional therapeutic agent is an antibody to the alpha subunit of the IL-2 receptor of T cells such as daclizumab (Zenapax®).

[00224] In another embodiment, the additional therapeutic agent is an antibody against CD52 such as alemtuzumab (Lemtrada®).

[00225] In another embodiment, the additional therapeutic agent is an inhibitor of a dihydroorotate dehydrogenase such as teriflunomide (Aubagio®).

[00226] In another embodiment, the additional therapeutic agent is an antibody to CD20 such as ocrelizumab, rituximab or ofatumumab.

[00227] In another embodiment, the additional therapeutic agent is a corticosteroid such as, but not limited to methylprednisolone, Depo-Medrol®, Solu-Medrol®, Deltasone®, Delta-Cortef®, Medrol®, Decadron® or Acthar®.

[00228] In another embodiment, the additional therapeutic agent is one or more compounds useful for treating symptoms of the disease such as bladder problems (e.g., Botox®, DDAVP Nasal Spray®, Detrol®, Ditropan®, Ditropan XL®, Enablex®, Flomax®, Hytrin®, Minipress®, Oxytrol®, Pro-Banthine®, Sanctura®, Tofranil®, Vesicare®); infections (Bactrim®, Septra®, Cipro®, Macrodantin®, Hiprex®, Pyridium®); bowel dysfunction (Colace®, Dulcolax®, Enemeez®, Fleet enema, Mineral oil, Metamucil®, Milk of Magnesia®, glycerin suppositories);

depression (Cymbalta®, Effexor®, Paxil®, Prozac®, Wellbutrin®, Zoloft®); dizziness and vertigo (Antivert®); emotional changes (Nuedexta®), Fatigue

(Amantadine®, Provigil®, Prozac®), itching (Atarax®); pain (Dilantin®, Elavil®, Klonipin®, Neurontin®, Pamelor®, Aventyl®, Tegetrol®); sexual problems (Cialis®, Levitra®, Papaverine®, MUSE®, Prostin VR®, Viagra®); spasticity (Dantrium®, Gablofen®, Klonipin®, Lioresal®, Valium®, Zanaflex®); tremors (Laniazid®, Nydrazid®, Klonopin®, Rivotril®); or walking or gait difficulties (Ampyra®).

[00229] In another embodiment, the kits of the present invention are drawn to kits wherein the compounds or the pharmaceutical compositions of the present invention and the one or more additional therapeutic agent(s) are in separate containers.

[00230] In another embodiment, the kits of the present invention are drawn to kits wherein the compounds or the pharmaceutical compositions of the present invention and the one or more additional therapeutic agent(s) are in the same container.

[00231] In another embodiment, the container is a bottle, vial, or blister pack, or combination thereof.

SCHEMES AND EXAMPLES

The compounds of the invention may be readily prepared by known methods and by using the following methods, schemes and examples. Illustrated below in Scheme A through Scheme Q are general methods for preparing the compounds of the present invention. Compounds were named using either IUPAC nomenclature or the nomenclature used in ChemBioDraw Ultra (Version 12.0.2.1076, CambridgeSoft®). EXAMPLES

General methods. ^X H NMR (obtained on a Bruker 400MHz Advance III QNP probe 1H/13C/19F or a Bruker 300MHz Advance I QNP probe 1H/13C/19F) spectra were obtained as solutions in an appropriate deuterated solvent such as dimethyl sulfoxide- d ₆ (DMSO-D6 or DMSO-d6). Mass spectra (MS) were obtained using a Waters Acquity UPLC-MS system equipped with a Waters 3100 mass detector and one of the following HPLC (High Performance Liquid Chromatography) or UPLC (Ultra Performance Liquid Chromatography) methods: UPLC method A: Mobile phase A: water (0.1 % trifluoroacetic acid). Mobile phase B: acetonitrile (0.1 % trifluoroacetic acid). Column: Waters Acquity CSH C18, 2.1 x 50 mm, 1.7 μηι particle size. Flow rate = 0.6 mL/min, injection volume = 2 μί, and column temperature = 25 °C. 5%-95% Phase B 1.4 minutes.

UPLC method B: Mobile phase A: water (0.1 % trifluoroacetic acid). Mobile phase B: acetonitrile (0.1 % trifluoroacetic acid). Column: Waters Acquity CSH CI 8, 2.1 x 50 mm, 1.7 μηι particle size. Flow rate = 0.6 mL/min, injection volume = 2 μΐ _^ , and column temperature = 25 °C. Gradient 10-60% phase B overl.4 minutes.

UPLC method C: Mobile phase A: water (0.1 % trifluoroacetic acid). Mobile phase B: acetonitrile (0.1 % trifluoroacetic acid). Column 4.6 x 100mm Sunfire CI 8 column. Flow rate = 1.5 mL/min. Gradient 2-98% phase B over 3.8 minutes.

UPLC method D: Mobile Phase A: 95 % water [50 mM ammonium formate pH 9] : 5% acetonitrile. Mobile Phase B: acetonitrile. Column: Waters Acquity BEH C8, 2.1 x 50 mm, 1.7 μηι particle size. Flow rate=0.6ml/min ; Injection Volume: 2 μΐ _^ . Gradient 5-95% phase B over 1.4 minutes.

Normal phase silica gel flash chromatography was performed using pre-packed Isco RediSepRf regular or high performance (Isco Gold) columns as well as specialty capped silicagel columns such as Isco Gold Amine, Isco Gold Diol, Isco Gold Cyano as specified in the Examples. Reverse phase chromatography was performed using pre-packed Isco RediSepRf reverse phase columns such as Isco C18 and Isco Gold C18Aq. Pyridine, dichloromethane (CH ₂ C1 ₂ or DCM), tetrahydrofuran (THF), dimethylformamide (DMF), acetonitrile (ACN), methanol (MeOH), and 1,4-dioxane were from Baker or Aldrich and in some cases the reagents were Aldrich Sure-Seal bottles kept under dry nitrogen. All reactions were stirred magnetically unless otherwise noted.

[00232] The following definitions describe terms and abbreviations used herein

DCM dichloromethane

DMA diemethylacetamide

EtOAc/EA ethyl acetate

Hex hexanes

HEP heptanes

HPLC high-performance liquid chromatography

LCMS liquid chromatography-mass spectrometry ESI-MS electrospray ionization mass spectrometiy

TLC thin layer chromatography

DMF N,N-dimethylformamide

DMSO dimethylsulfoxide

THF tetrahydrofuran

Et ₃ N triethylamine

NMP N-methylpyrrolidone

HOAc acetic acid

TFA trifluoroacetic acid

ACN acetonitrile

DCM dichloromethane

DCE dichloroethane

DMA dimethylacetamide

N2 nitrogen

R ./RT/rt room temperature

AT ambient temperature

MeOH methanol

EtOH ethanol

t-BuOH ^-butanol

t-BuONa sodium t-butoxide

Pd/C palladium on carbon

SnAr nucleophilic aromatic substitution mechanism t-BuXPhos Palladacycle chloro(2-di-t-butylphosphino-2' biphenyl) [2-(2-aminoethyl)phenyl]palladium(

Pd ₂ (dba) ₃ tris(dibenzylideneacetone)dipalladium

ISCO flash chromatography system

Si0 ₂ silica gel

MP-TMT macroporous polystyrene-bound trimecaptotriazine PL-HCO ₃ MP SPE polymer supported bicarbonate resin RBF round-bottom flask

Cmpd Compound

HSQC Heteronuclear Single Quantum Coherence

COSY Correlation spectroscopy SPE Solid phase extraction

Preparation of non-commercial intermediates

[00233] All intermediates used in the synthesis of the final compounds were purchased commercially, with the exception of the intermediates described below in Examples 1 and 2.

EXAMPLE 1

Preparation of 4.5.6-trichloro-2-cvclopropyl-pyrimidine (Int-1)

(a) NaOMe, MeOH, 80 °C; (b) POCl ₃ , 90 °C

Preparation of 5-chloro-2-cvclopropyl-4-hvdroxy-lH-pyrimidin-6-one

[00234] To a solution of cyclopropanecarboxamidine (hydrochloride salt) in methanol (5 mL) was added sodium methoxide (16.4 mL of 0.5 M, 8.200 mmol) followed by dimethyl 2-chloropropanedioate (approximately 1.366 g, 1.047 mL, 8.200 mmol). The reaction mixture was heated to 80 °C for approximately 2 hours. The reaction was cooled to room temperature and partially concentrated until a solid appeared. The reaction mixture was acidified with ammonium chloride and dichloromethane was added. The resulting mixture was filtered and the precipitate was washed with diethyl ether to provide 5-chloro-2-cyclopropyl-4-hydroxy-lH- pyrimidin-6-one (458 mg, 30%) as an off white solid. ^X H NMR (400 MHz, DMSO- d6) δ 12.46 (s, 1H), 7.31 - 6.93 (m, 1H), 1.89 (m, 1H), 1.06 (m, 4H) ppm. ESI-MS m/z calc. 186.0196, found 187.06 (M+l) ⁺ ; Retention time: 0.44 minutes.

Preparation of 4.5.6-trichloro-2-cvclopropyl-pyrimidine (Int-1)

lnt-1

[00235] A mixture of 5-chloro-2-cyclopropyl-4-hydroxy-lH-pyrimidin-6-one (458 mg, 2.455 mmol) and phosphorus oxy chloride (1.5 mL, 16.09 mmol) was heated to 90 °C for approximately 4 hours. An additional portion of phosphorus oxy chloride (0.5 mL) was added after the first two hours. The reaction mixture was poured into a solution of 0.5M sodium hydroxide at room temperature (exotherm). After cooling, the mixture was extracted with dichloromethane and passed through a phase separation cartridge. The collected organic layer was concentrated and the residue was purified by silica gel chromatography (12 g column; 0-75% ethyl

acetate/heptane) to give 4,5,6-trichloro-2-cyclopropyl-pyrimidine (357 mg, 65%) as a white solid. ^X H NMR (400 MHz, DMSO-c 6) δ 2.22-2.18 (m, 1H), 1.21 - 1.14 (m, 2H), 1.06 - 0.99 (m, 2H) ppm. ESI-MS m/z calc. 221.95183, found 225.02 (M+l) ⁺ ; Retention time: 0.97 minutes. EXAMPLE 2

(a) n-BuLi, -78 °C, CH ₃ CN, THF; (b) hydrazine, CH ₃ C0 ₂ H, EtOH, 80 °C.

Preparation of 3-(3.3-difluorocvclopentyl)-3-oxo-propanenitrile

[00236] A solution of «-butyllithium (15 mL of 2.5 M, 37.50 mmol) in anhydrous tetrahydrofuran (50 mL) was cooled to -78 °C. Acetonitrile (2 mL, 38.29 mmol) was added dropwise and the mixture was stirred at -78 °C for 30 minutes. Methyl 3,3-difluorocyclopentanecarboxylate (2500 mg, 15.23 mmol) was added dropwise at -78 °C. The reaction was stirred at the same temperature for 1 hour, then was warmed to room temperature for 1 hour. Water was added to the reaction mixture, and the pH was adjusted to 3 by adding 1 N HC1 solution. The resulting mixture was extracted with ethyl acetate (3 X 150 mL). The combined organic fractions were washed with brine (1 X 50 mL), water (2 X 50 mL), dried over sodium sulfate and concentrated to dryness. Purification by silica gel chromatography under ELSD detection (80g column; 0-100% ethyl acetate/heptane) provided 3-(3,3- difluorocyclopentyl)-3-oxo-propanenitrile (1600 mg, 46%). ^l NMR (400 MHz, CDC1 ₃ ) δ 3.56 (d, J = 2.8 Hz, 2H), 3.44 - 3.28 (m, 1H), 2.55 - 2.10 (m, 4H), 2.14 - 1.90 (m, 1H) ppm. ESI-MS m/z calc. 173.06522, found 182.29 (M+l) ⁺ ; Retention time: 0.55 minutes. Preparation of 5-(3.3-difluorocvclopentyl)-lH-pyrazol-3-amine (Int-2)

lnt-2

[00237] 3-(3,3-difluorocyclopentyl)-3-oxo-propanenitrile (1000 mg, 5.775 mmol) was treated with hydrazine (30 mL of 1 M, 30.00 mmol) (1M in ACN) and acetic acid (1.7 mL, 29.89 mmol) in ethanol (30 mL). The reaction was stirred at 80 °C for 3 hours, then the solvent was evaporated. The residue was dissolved in dichloromethane and treated with a saturated aqueous sodium bicarbonate solution, then filtered through an SPE filter and the filtrate was concentrated to provide 5-(3,3- difluorocyclopentyl)-lH-pyrazol-3-amine (1.03 g, 81%). ^X H NMR (300 MHz, CDCI ₃ ) δ 5.47 (d, J = 0.6 Hz, 1H), 3.82 - 3.71 (m, 1H), 3.27 (tdd, J = 10.0, 8.1, 6.8 Hz, 1H), 2.62 - 2.40 (m, 1H), 2.46 - 2.01 (m, 4H), 1.92 - 1.82 (m, 1H) ppm. ESI-MS m/z calc. 187.0921, found 188.14 (M+l) ⁺ ; Retention time: 0.52 minutes.

Scheme A: General Route A for Preparation of Compounds of Formula I

Compounds of the invention may be prepared as generally outlined in Scheme A, where R ² , R ³ , R ⁴ , R ⁵ , and R ⁸ are as described herein. The general process illustrated in the foregoing scheme may also be used where R ¹ is -NR ⁴ -G°, -G^I^-R ⁶ , -NR ⁴ - G^-I^-R ⁶ , or G ² .

EXAMPLE 3

Preparation of N-(5-cvclopentyl-lH-pyrazol-3-yl)-2-cvclopropyl-5-fluoro-6-r 4- (oxetan-3-yl)piperazin-l-yllpyrimidin-4-amine (Compound 18)

Cmpd 18

(a) DIPEA, DCM; (b) i-BuXPhos Palladacycle, NaOtBu, tBuOH, 1,4-dioxane, 80 °C,

3 hours. Preparation of 4-chloro-2-cvclopropyl-5-fluoro-6-[4-(oxetan-3-yl)piperazin- l- yllpyrimidine (ID-3a)

[00238] A microwave vial was charged with 4,6-dichloro-2-cyclopropyl-5- fluoro-pyrimidine (1.0 g, 4.8 mmol), dichloromethane (10 mL),

diisopropylethylamine (2.0 mL, 11 mmol) and l-(oxetan-3-yl)piperazine (758 mg, 5.33 mmol) in that order. The reaction was stirred at room temperature for 2 hours and was then partitioned between saturated aqueous sodium bicarbonate (80 mL) and dichloromethane (80 mL). The organic phase was separated and the aqueous phase was re-extracted with dichloromethane (50 mL). The combined organics were dried on magnesium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography (40 g column; 0-100% ethyl acetate/heptane) to give 4- chloro-2-cyclopropyl-5-fluoro-6-[4-(oxetan-3-yl)piperazin-l- yl]pyrimidine (1.49 g, 97%) as a white solid. ^l H NMR (400 MHz, CDC1 ₃ ) δ 4.67 - 4.50 (m, 4H), 3.81 - 3.66 (m, 4H), 3.51 - 3.37 (m, 1H), 2.39 - 2.26 (m, 4H), 1.94 (tt, J = 8.0, 4.9 Hz, 1H), 0.97 - 0.82 (m, 4H) ppm. ESI-MS m/z calc. 312.11533, found 313.0 (M+l) ⁺ ;

Retention time: 0.53 minutes.

Preparation of N-(5-cvclopentyl-lH-pyrazol-3-yl)-2-cvclopropyl-5-fluoro-6-[ 4- (oxetan-3-yl)piperazin-l-yllpyrimidin-4-amine (Compound 18)

Cmpd 18

[00239] A 5 ml vial was charged with 5-cyclopentyl-lH-pyrazol-3-amine (17.3 mg, 0.1144 mmol), chloro(2-di-t-butylphosphino-2',4',6'-tri-i-propyl-l, -biphenyl)[2- (2-aminoethyl)phenyl] palladium(II) (ί-BuXPhos Palladacycle) (8 mg, 0.01165 mmol) and sodium ter f-butoxide (30 mg, 0.3122 mmol) under nitrogen and then treated with 4-chloro-2-cyclopropyl-5-fluoro-6-[4-(oxetan-3-yl)piperazin- l-yl]pyrimidine (32 mg, 0.1023 mmol) in 1,4-dioxane (0.5 mL) and fert-butanol (1.5 mL) under nitrogen. The reaction was stirred at 70 °C for 1 hour. Ethyl acetate and water were added, the aqueous layer was extracted with ethyl acetate and the combined organic layers were concentrated. The crude material was purified by silica gel chromatography (12g Gold column (ISCO); 0-10% methanol/dichloromethane). After concentration, the product was triturated with diethyl ether, sonicated and the ether was decanted to provide N-(5-cyclopentyl-lH-pyrazol-3-yl)-2-cyclopropyl-5-fluoro-6-[ 4-(oxetan-3- yl)piperazin-l-yl]pyrimidin-4-amine 18 (18.2 mg, 40%). ^X H NMR (400 MHz,

DMSO-c¾) δ 11.90 (s, 1H), 8.92 (s, 1H), 6.36 (s, 1H), 4.54 (t, J = 6.5 Hz, 2H), 4.46 (t, J = 6.1 Hz, 2H), 3.58 (s, 4H), 3.47 - 3.39 (m, 1H), 3.05 - 2.94 (m, 1H), 2.33 (m, 4H), 1.98 (s, 2H), 1.89 - 1.51 (m, 7H), 0.85 (m, 4H) ppm. ESI-MS m/z calc. 427.24957, found 428.36 (M+l) ⁺ ; Retention time: 0.55 minutes.

[00240] Using the general synthetic scheme outlined in Scheme A and the experimental procedures listed above for intermediates in Examples 1 and 2 and compound 18 in Example 3, the following compounds can be prepared: 1-23 and 26. heme B: General Route B for Preparation of Compounds of Formula I

Compounds of the invention may also be prepared as generally outlined in Scheme B, where R ² , R ³ , R ⁴ , R ⁵ , and R ⁸ are as described herein. The general process illustrated in the foregoing scheme may also be used where R ¹ is -NR ⁴ -G°, -G^I^-R ⁶ , -NR ⁴ - G ^1A -L -R ⁶ , or G ² .

EXAMPLE 4

Preparation of 2-cvclopropyl-N-(5-(3.3-difluorocvclobutyl)-lH-pyrazol-3-yl) -5- fluoro-6-(4-(oxetan-3-yl)piperazin-l-yl)pyrimidin-4-amine (Compound 40)

Cmpd 40

(a) i. aminopyrazole, DIPEA, 1,4-dioxane, 150 °C, microwave, 1 hour; ii. amine, DIPEA, 160 °C, microwave, 45 mins.

Preparation of of 2-cvclopropyl-N-(5-(3.3-difluorocvclobutyl)-lH-pyrazol-3-yl) -5- fluoro-6-(4-(oxetan-3-yl)piperazin-l-yl)pyrimidin-4-amine (Compound 40):

Cmpd 40

[00241] A solution of 5-(3,3-difluorocyclobutyl)-lH-pyrazol-3-amine, 4,6- dichloro-2-cyclopropyl-5-fluoro-pyrimidine and diisopropylethylamine (250 μί) in 1,4-dioxane (2 mL) was heated to 150 °C in a microwave for 1 hour. The crude solution of 6-chloro-2-cyclopropyl-N-[5-(3,3-difluorocyclobut l)-lH-pyrazol-3-yl]-5- fluoro-pyrimidin-4-amine was treated with l-(oxetan-3-yl)piperazine and

diisopropylethylamine (250 μί) in 1,4-dioxane and heated to 160 °C in a microwave for 45 minutes. To the reaction was then added 2 more equivalents of l-(oxetan-3- yl)piperazine and heating was continued at 170 °C in a microwave for 1 hour. The solvent was evaporated and the sample was dissolved in a small amount of dimethylsulfoxide and purified by reverse phase HPLC using an acetonitrile/water gradient with a trifluoroacetic acid modifier. The pure trifiuoroacetic acid salt was neutralized by passing through a PL-HCO ₃ MP SPE cartridge (100 mg, loading level 1.8 mmol/g) to provide, after concentration, 2-cyclopropyl-N-(5-(3,3- difluorocyclobutyl)-lH-pyrazol-3-yl)-5-fluoro-6-(4-(oxetan-3 -yl)piperazin-l- yl)pyrimidin-4-amine (Cmpd 40). ^X H NMR (400 MHz, Methanol-^) δ 6.27 (s, 1H), 4.85 - 4.71 (m, 4H), 4.05 (p, J = 6.3 Hz, 1H), 3.95 - 3.87 (m, 4H), 3.48 - 3.32 (m, 1H), 3.10 - 2.94 (m, 1H), 2.98 - 2.90 (m, 1H), 2.94 (s, 2H), 2.81 - 2.64 (m, 2H), 2.02 (tt, J = 7.8, 4.9 Hz, 1H), 1.07 - 0.93 (m, 4H) ppm. ESI-MS m/z calc. 449.47, found 450.32 (M+l) ⁺ ; Retention time: 0.55 minutes.

[00242] Using the general synthetic scheme outlined in Scheme B and the experimental procedures listed above in Example 4, the following compounds can be prepared: 24, 25, 27-39 and 41-64.

Scheme C: General Route C for Pre aration of Compounds of Formula I

Compounds of the invention may also be prepared as generally outlined in Scheme C, where R ² , R ³ , R ⁴ , R ⁵ , and R ⁸ are as described herein. The general process illustrated in the foregoing scheme may also be used where R ¹ is -NR ⁴ -G°, -G^I^-R ⁶ , -NR ⁴ - i^-L'-R ⁶ , or

EXAMPLE 5

Preparation of 2-cvclopropyl-N-r5-(3.3-difluorocvclopentyl)-lH-pyrazol-3-yl l-5- fluoro-6-[4-(oxetan-3-yl)-l-piperidyllpyrimidin-4-amine (Compound 101)

ID-5a

(a) DIPEA, Nal, DMF, 1 10 °C, overnight; (b) Nal, DMF, 180 °C, microwave, 45 mins.

Preparation of 6-chloro-2-cvclopropyl-N-[5-(3.3-difluorocvclopentyl)-lH-pyr azol-3- yll -5 -fluoro-pyrimidin-4-amin -5a)

ID-5a

[00243] A solution of 5-(3,3-difluorocyclopentyl)-lH-pyrazol-3-amine (420 mg, 1.917 mmol), 4,6-dichloro-2-cyclopropyl-5-fluoro-pyrimidine (400 mg, 1.932 mmol), diisopropylethylamine (2 mL, 11.48 mmol), and sodium iodide (300 mg, 2.001 mmol) in dimethylformamide (5 mL) was heated to 110 °C overnight. The residue was dissolved in dichloromethane and treated with water, and filtered through Isolute® SPE Phase separator and concentrated to provide crude product. The crude product was purified by silica gel chromatography (80g column; 0-100% ethyl

acetate/heptane) to provide 6-chloro-2-cyclopropyl-N-[5-(3,3-difluorocyclopentyl)- lH-pyrazol-3-yl]-5-fluoro-pyrimidin-4-amine, ID-5a (460 mg, 60%). i NMR (400 MHz, CDCI ₃ ) δ 6.51 (s, 1H), 3.47 - 3.33 (m, 1H), 2.67 - 2.51 (m, 1H), 2.42 - 2.17 (m, 2H), 2.21 - 2.06 (m, 1H), 2.07 (s, 2H), 2.07 - 1.88 (m, 1H), 1.17 - 1.00 (m, 4H) ppm. ESI-MS m/z calc. 357.0968, found 358.21 (M+l) ⁺ ; Retention time: 0.83 minutes. Preparation of 2-cvclopropyl-N-[5-(3.3-difluorocvclopentyl)-lH-pyrazol-3-yl l-5- fluoro-6-r4-(oxetan-3-yl)-l-piperidyllpyrimidin-4-amine (Compound 101)

[00244] A solution of 6-chloro-2-cyclopropyl-N-[5-(3,3-difluorocyclopentyl)- lH-pyrazol-3-yl]-5-fluoro-pyrimidin-4-amine (50 mg, 0.1166 mmol), 4-(oxetan-3- yl)piperidine (30 mg, 0.2124 mmol), sodium iodide (50 mg, 0.3336 mmol) and diisopropylethylamine (100 μί, 0.5741 mmol) in dimethylformamide (2 mL) was heated to 180 °C in a microwave for 45 minutes. The reaction mixture was filtered and purified by reverse phase HPLC using an acetonitrile/water gradient with a trifluoroacetic acid modifier. The pure trifluoroacetic acid salt was neutralized by passing through a PL-HCO ₃ MP SPE cartridge (500 mg, loading level 1.8 mmol/g) to provide, after concentration, 2-cyclopropyl-N-[5-(3,3-difluorocyclopentyl)-lH- pyrazol-3-yl]-5-fluoro-6-[4-(oxetan-3-yl)-l-piperidyl]pyrimi din-4-amine, 101 (26.4 mg, 44%). 'H NMR (400 MHz, CDC1 ₃ ) δ 12.03 (s, 1H), 6.97 (s, 1H), 5.65 (s, 1H), 4.52 (d, J = 13.5 Hz, 1H), 4.30 (ddd, J = 12.9, 3.7, 1.9 Hz, 1H), 4.07 - 3.99 (m, 1H), 3.86 (td, J = 12.5, 11.7, 5.1 Hz, 1H), 3.76 - 3.58 (m, 3H), 3.60 - 3.45 (m, 1H), 3.39 (dt, J = 17.3, 9.2 Hz, 1H), 3.12 (t, J = 10.9 Hz, 1H), 3.01 - 2.90 (m, 1H), 2.66 - 2.44 (m, 2H), 2.31 (ddd, J = 32.4, 16.3, 9.3 Hz, 3H), 2.07 - 1.83 (m, 2H), 1.80 - 1.65 (m, 1H), 1.51 - 1.35 (m, 1H), 1.06 - 0.88 (m, 4H) ppm. ESI-MS m/z calc. 462.2355, found 463.47 (M+l) ⁺ ; Retention time: 0.68 minutes.

[00245] Using the general synthetic scheme outlined in Scheme C and the experimental procedures listed above in Example 5, the following compounds can be prepared: 65-77 and 82-100.

EXAMPLE 6

Preparation of of 2-cvclopropyl-5-fluoro-N-(5-((ls.3s)-3-fluorocvclobutyl)-lH- pyrazol-3-yl)-6-(4-(oxetan-3-yl)piperazin-l-yl)pyrimidin-4-a mine (Compound 80)

(a) DIPEA, Nal, DMF, 110 °C, overnight; (b) Nal, DMF, 180 °C, microwave, 45 mins.

Preparation of 6-chloro-2-cvclopropyl-5-fluoro-N-(5-((ls.3s)-3-fluorocvclob utyl)-lH- pyrazol-3-yl)pyrimidin-4-amine (Compound 77) and 6-chloro-2-cvclopropyl-5- fluoro-N-(5-((lr.3r)-3-fluorocvclobut^l)-lH-pyrazol-3-yl)pyr irnidin-4-amine

(Compound 76)

[00246] A solution of 5-(3-fluorocyclobutyl)-lH-pyrazol-3-amine (580 mg,

3.738 mmol), 4,6-dichloro-2-cyclopropyl-5-fluoro-pyrimidine (800 mg, 3.864 mmol), diisopropylethylamine (2 mL, 11.48 mmol) and sodium iodide (700 mg, 4.670 mmol) in dimethylformamide (5 mL) was heated to 110 °C overnight. The reaction mixture was added drop wise to water and stirred for 30 minutes, filtered and the cake was washed with water and dried. The crude product was purified by silica gel chromatography (80g column; 0-100% ethyl acetate/heptane to provide two isomers. HSQC and COSY confirmed that the first eluting peak (Peak 1) is the trans isomer (Cmpd 76), and the second eluting peak (Peak 2) is the cis isomer (Cmpd 77). Peak 1 : 6-chloro-2-cyclopropyl-5-fluoro-N-(5-((lr,3r)-3-fluorocyclob utyl)-lH-pyrazol-3- yl)pyrimidin-4-amine, 86 (106 mg, 8%). ^X H NMR (300 MHz, CDC1 ₃ ) δ 6.42 (s, 1H), 5.29-5.10 (m, 1H), 3.64 (s, 2H), 3.53 (dq, J = 9.8, 4.8 Hz, 1H), 2.76 - 2.39 (m, 3H), 2.01 (dq, J = 8.1, 5.0, 4.1 Hz, 1H), 1.17 (s, 1H), 0.99 (ddt, J = 10.8, 8.1, 2.8 Hz, 4H) ppm. ESI-MS m/z calc. 325.09058, found 326.19 (M+l) ⁺ ; Retention time: 0.77 minutes. Peak 2: 6-chloro-2-cyclopropyl-5-fluoro-N-(5-((ls,3s)-3-fluorocyclob ut l)- lH-pyrazol-3-yl)pyrimidin-4-amine, 87 (85 mg, 6%). ^l H NMR (400 MHz, CDC1 ₃ ) δ 6.52 (s, 1H), 5.08-4.94 (m, 1H), 3.63 - 3.43 (m, 1H), 2.99 (tt, J = 9.8, 7.5 Hz, 1H), 2.84 (dtt, J = 13.0, 9.6, 4.6 Hz, 2H), 2.78 - 2.50 (m, 1H), 2.50 - 2.30 (m, 2H), 2.11 (tt, J = 8.2, 4.7 Hz, 1H), 1.08 (ddt, J = 21.3, 5.8, 3.9 Hz, 4H) ppm. ESI-MS m/z calc. 325.09058, found 326.19 (M+l) ⁺ ; Retention time: 0.76 minutes.

Preparation of 2-cvclopropyl-5-fluoro-N-(5-((ls.3s)-3-fluorocvclobutyl)-lH- pyrazol- 3 -yl)-6-(4-(oxetan-3-yl)piperazin- 1 -yl)pyrimidin-4-amine (Compound 80)

[00247] 6-Chloro-2-cy clopropy 1-5 -fluoro-N-(5 -(( 1 s,3 s)-3-fluorocy clobuty 1)- 1 H- pyrazol-3-yl)pyrimidin-4-amine (15 mg, 0.04605 mmol), l-(oxetan-3-yl)piperazine (15 mg, 0.1055 mmol), sodium iodide (10 mg, 0.06671 mmol) and diisopropyl ethylamine (50 μί, 0.2871 mmol) were dissolved in dimethylformamide (2 mL) and the mixture was heated to 180 °C in the microwave for 45 minutes. The reaction mixture was filtered and the filtrate was purified by reverse phase HPLC (0-100% water/acetonitrile with 0.1% trifluoroacetic acid modifier). The pure product

(trifluoroacetic acid salt) was dissolved in dichloromethane, treated with a saturated sodium bicarbonate solution and and filtered through an Isolute ^® SPE Phase separator. The filtrate was concentrated to provide 2-cyclopropyl-5-fluoro-N-(5-((ls,3s)-3- fluorocyclobutyl)-lH-pyrazol-3-yl)-6-(4-(oxetan-3-yl)piperaz in-l-yl)pyrimidin-4- amine, 80 (9.8 mg, 45%). ^X H NMR (400 MHz, Chloroform-d) δ 11.03 (s, 1H), 7.10 (d, J = 3.4 Hz, 1H), 6.01 (s, 1H), 5.32 (s, 1H), 4.91 (m, 1 H), 4.64 (d, J = 5.5 Hz, 2H), 4.27 (d, J = 5.6 Hz, 2H), 3.80 - 3.73 (m, 4H), 3.57 (ddt, J = 10.1, 8.9, 4.5 Hz, 1H), 2.79 - 2.62 (m, 1H), 2.66 - 2.53 (m, 2H), 2.48 - 2.41 (m, 4H), 1.99 (tt, J = 8.0, 4.8 Hz, 1H), 1.39 (s, 3H), 1.06 - 0.88 (m, 4H) ppm. ESI-MS m/z calc. 431.22452, found 432.45 (M+l) ⁺ ; Retention time: 0.53 minutes.

[00248] Using the general synthetic scheme outlined in Scheme C and the experimental procedures listed above in Example 6, the following compounds can be prepared: 78, 79 and 81. [00249] In Table 3 below, the LC/MS methods used are as follows:

UPLC method A: Mobile phase A: water (0.1 % trifluoroacetic acid). Mobile phase B: acetonitrile (0.1 % trifluoroacetic acid). Column: Waters Acquity CSH CI 8, 2.1 x 50 mm, 1.7 μηι particle size. Flow rate = 0.6 mL/min, injection volume = 2 μί, and column temperature = 25 °C 5%-95% Phase B 1.4 minutes.

UPLC method B: Mobile phase A: water (0.1 % trifluoroacetic acid). Mobile phase B: acetonitrile (0.1 % trifluoroacetic acid). Column: Waters Acquity CSH CI 8, 2.1 x 50 mm, 1.7 μηι particle size. Flow rate = 0.6 mL/min, injection volume = 2 μΐ _^ , and column temperature = 25 °C. Gradient 10-60% phase B overl.4 minutes.

UPLC method C: Mobile phase A: water (0.1 % trifluoroacetic acid). Mobile phase B: acetonitrile (0.1 % trifluoroacetic acid). Column 4.6 x 100mm Sunfire C18 column. Flow rate = 1.5 mL/min. Gradient 2-98% phase B over 3.8 minutes.

UPLC method D: Mobile Phase A: 95 % water [50 mM ammonium formate pH 9] : 5% acetonitrile. Mobile Phase B: acetonitrile. Column: Waters Acquity BEH C8, 2.1 x 50 mm, 1.7 μηι particle size. Flow rate=0.6ml/min ; Injection Volume: 2 μΐ _^ .

Gradient 5-95% phase B over 1.4 minutes.

[00250] Table 3: Analytical Data

ASSAYS FOR DETECTING AND MEASURING REMYELINA TION PROPERTIES OF COMPOUNDS In vivo Mouse Cuprizone Assay:

[00251] Cuprizone Feeding Protocol:

[00252] 2 month old female C57BL/6 mice (Stock Number: 000664) are purchased from Jackson Labs and fed for 4-10 months with a 0.2% cuprizone chow (provided by Research Diets, Product # Dl 0020701R, Description AIN-76A Rodent Diet with 0.2% cuprizone) using cuprizone purchased from Sigma (Cat# 14690-

100G). Chow is provided ad libitum, and refreshed every 4 days to ensure stability of the cuprizone. Mice are maintained on this diet for 4 -10 months before initiation of the experiments.

[00253] Dosing and PK:

[00254] 1) 24 hours prior to the start of dosing, 6 to 10 mice are switched from cuprizone chow to normal chow (Picolab rodent diet 20 EXT IRR 5053, irradiated) without added cuprizone. These mice are maintained on normal chow throughout the course of dosing.

[00255] 2) 6 to 10 mice per group are randomized into new cages such that mice that are housed in one cage during the cuprizone diet are not housed together in one dose group during the study.

[00256] 3) Mice can be dosed with compound in one of two regimens:

Regimen A: mice are dosed QD or BID for 14 days via oral gavage. Regimen B: mice are dosed QD or BID for 14 days via IP injection. However, other dosing schedules and/or routes of administration may also be used.

[00257] 4) On the last day of dosing, dried blood spots are collected at multiple time points following the last dose. Often this is 30 minutes, 2, 6 and 24 hours following the final dose on day 14 via the tail vein.

[00258] Perfusion and sectioning:

[00259] 1) The day after the last day of dosing, mice are transcardially perfused with 12 ml of PBS (Sigma, P4417) followed by 20 ml of 3.2% paraformaldehyde in PBS (Electron Microscopy Sciences # 15714-S). The brains are removed via standard dissection techniques and each is postfixed in 3.2% paraformaldehyde (20 ml) for 24- 48 hours at room temperature in sealed scintillation vials.

[00260] 2) Serial 50 micron sections are collected through the anterior posterior extent of the brain, from just behind the olfactory bulb, through visual cortex using a vibrating microtome, the V-STAR (described in International Publication No. WO 2013/012799 and US Patent number US 8,967,024 both of which are incorporated herein by reference in their entirety). Sections are collected in phosphate buffered saline (PBS). Vibratome speed is set to 1.1 mm/s and amplitude is set to 0.8 mm.

[00261] 3) A series of every 24th section is removed for staining yielding 5 sections per brain.

[00262] Staining:

[00263] 1) Tissue sections are stained using an automated system for processing blots (hereinafter the "blotinator") (described in WO2011/087646 and US Patent numbers US 8,337,754 and US 8,679,406 each of which is incorporated herein by reference in its entirety). Brain sections are placed in the blotinator plate and bathed in PBS. The blotinator applies primary antibodies (MOG and MBP together) and Hoechst nuclear stain for 12 hours at room temperature with constant shaking.

[00264] The following stains sre diluted in blocking buffer (described below):

[00265] Hoechst nuclear stain (0.5 mg/ml)(bisBenzimide H 33342

trihydrochloride Sigma # 33342).

[00266] Myelin basic Protein (MBP) antibody (Abeam Cat # ab7349) is diluted at a 1 :750 ratio in blocking buffer).

[00267] Myelin Oligodendrocyte Glycoprotein (MOG) (R&D systems Cat # AF2439) is diluted at a 1 :250 ratio in blocking buffer. [00268] Antibodies are diluted in blocking buffer, which consists of 0.3% Triton X-100 (Sigma Cat # 234729), 0.02% Sodium Azide (Sigma Cat# S2002) and 8% fetal bovine serum in PBS (Sigma Cat# F2442).

[00269] 2) The blotinator washes the samples 4 times for 5 minutes each with a wash buffer (0.2% Triton X-100 in PBS).

[00270] 3) The blotinator applies secondary antibodies diluted in blocking buffer and incubates them for 2 hours with constant shaking.

[00271] Alexa 488 donkey anti-rat secondary (Life technologies Cat# A-21208) is diluted at 1 : 1000 in blocking buffer.

[00272] Alexa 568 donkey anti-goat secondary (Life technologies Cat# A- 11057) is diluted at 1 : 1000 in blocking buffer.

[00273] Antibodies are also diluted in blocking buffer described above.

[00274] 4) The samples are then washed 4 times for 5 minutes each with wash buffer (0.2% Triton X-100 in PBS).

[00275] 5) All 5 sections are mounted on a slide (Fisherbrand Superfrost Plus microscope slide Cat# 12-550-15) and coverslip with 50 microliters Fluormount (Sigma cat# F4680-25ml) in preparation for scanning.

[00276] Scanning:

[00277] Images are scanned using an Olympus CS120 flourescent scanning microscope. Entire sections are scanned at lOx magnification, with 500 millisecond exposures for the 488 and 568 nanometer fluorescent channels. The Hoechst signal is detected using a 100 millisecond exposure.

[00278] In vivo Myelin Detection Software:

[00279] A custom algorithm, developed in house, is used to quantify the amount of new myelin in mice that has been demyelinated with cuprizone and subsequently is treated with compounds. Conceptually, the software subtracts a mature myelin marker from a pan-myelin (young and old myelin) marker, and measures the area of the remaining "new" myelin. Myelin oligodendrocyte glycoprotein ("MOG") is specific to old myelin, while myelin basic protein ("MBP") is a pan myelin marker, expressed in more immature myelin as well as more mature myelin. This process accounts for the variability inherent in the demyelination process, in which some animals experience more demyelination than others. It more accurately measures myelin generated in response to compound treatment.

[00280] The algorithm is written using Definiens Tissue Studio and Definiens Developer XD. There are several steps to the algorithm, each of which is discussed below.

[00281] Three channels of information for each sample are loaded. The intensity levels of the three images are summed, and the resulting image is used to determine the "tissue" area. Subsequent analyses are done exclusively on the tissue area.

[00282] The MOG channel is loaded and the Definiens "Auto Threshold" function is used to distinguish MOG positive regions from background. Regions of putative white matter with areas < 50 pixels are returned to the tissue class. Thus, remaining white matter tracts that resist demyelination from cuprizone are excluded from subsequent analyses.

[00283] The ratio of MBP signal to MOG signal is calculated. This consists of the mean MBP intensity value divided by the mean MOG intensity value over the entirety of the image. This MBP: MOG ratio is used to normalize the intensity between the MBP and MOG channels. The normalized MOG signal multiplied by 0.5 is subtracted from the MBP signal, creating a new image, "MBP-MOG". The "Auto Threshold" function is used on the MBP-MOG image, and the 'new' myelin consisting of pixels with intensities above the threshold is delineated. Regions of putative new myelin with areas <2 pixels are returned to the tissue class, and the number of pixels positive for "new" myelin is measured.

[00284] The algorithm returns the area of the tissue and the MBP positive, MOG negative 'new' myelin. Each section is normalized by area relative to its comparable tissue (e.g., the first). Most anterior sections are normalized relative to other first anterior sections. The 5 normalized MBP+/MOG- areas are summed, yielding a total positive area per sample. This yields a representation of myelin synthesis over the whole extent of the brain, excluding the olfactory bulb and the cerebellum.

[00285] Compound of the present invention may be tested in the in vivo Mouse Cuprizone assay described above.

[00286] In vitro Myelination Assay [00287] Compounds were screened for their ability to induce myelination using a primary rat mixed cortical cell culture assay, which contains neurons,

oligodendrocyte precursor cells, oligodendrocytes, astrocytes and microglia. The assay quantifies myelination by measuring myelin basic protein (MBP)

immunofluorescent positive myelin strands from images taken using a Cellomics Array Scan (model Arrayscan VTI HCS Reader) or a Molecular Devices Image Xpress (model IXM XL) high content imager. The myelin strands were quantitated using a custom created myelin detection software program. Test compounds were dissolved in DMSO to make a 10 mM initial stock solution. Dilutions were made in myelination medium to obtain the final solutions for the assay and were tested in primary rat mixed cortical cells at selected doses.

[00288] Primary rat mixed cortical cells were prepared from harvested cerebral cortices from postnatal day 1 (PI) rats (PI Rat CD® IGS pups) were purchased from Charles River) in Complete Dissociation Medium, wherein the meninges were removed and the cortical tissue chopped with a razor blade into ~1 mm ³ pieces.

Tissue from 1-3 pups was collected and placed into 15 ml conical tubes in a total volume of 5 ml of Complete Dissociation Medium. Activated papain (3 ml) was added to each 15 ml conical tube and tissue was incubated at 37°C for 30 minutes. After the 30 minute incubation, DNase (Sigma D4527; 75 μΐ of a 1 mg/ml stock) was added to each tube, followed by mechanical trituration using a 2 ml serological pipette and autopipettor to gently dissociate the tissue. Following trituration, larger tissue pieces were allowed to settle by gravity, and the supernatant containing dissociated cells was transferred to a 50 ml conical tube with 4 ml of trypsin inhibitor. Cells were pelleted by centrifugation, resuspended in myelination medium and filtered through a 40 μιτι filter. Cells were then seeded in 96-well plates (BD Biosciences, Black, PDL- coated, Cat. No. 356640) or in some cases in 384-well plates at 87,500-95,000 cells/well in a final volume of 200μ1 of Myelination Medium in the presence or absence of compound and cultured for 14 days in a humidified 37°C incubator with 5% CO2. Half the medium was removed and replaced with fresh medium containing IX compound on days 6 and 10. Using a Biotek automatic plate washer (model Biomek® FXP Laboratory Automation Workstation), cells were fixed with 4% paraformaldehyde on day 14, washed with PBS and blocked in 5% normal goat serum (Vector Laboratories, S-1000) in 0.1% PBS-TritonX-100 (PBST) for 1 hour. Cells were stained with 1 :500 anti-MBP (Covance, cat #SMI99) primary antibody in 1% normal goat serum in 0.1% PBST for 2 hours at room temperature followed by 2 washes with PBST. A final incubation in secondary antibody (1 : 1000, Invitrogen, Alexa-488 anti-mouse IgG2b) and 1 : 10,000 Hoechst dye in 1% normal goat serum in 0.1 % PBST was performed for 2 hours at room temperature. Plates were washed with PBS and then scanned on a Cellomics Array Scan using a 10X objective (25 images per well) or the Image Xpress using a 10X objective (9 image per well). Images were analyzed using Vertex myelin detection software (described below) to quantify total MBP myelin pixels per well. Fold myelin pixels above background at two concentrations (1.0 μΜ and 10.0 μΜ) relative to baseline of no added compound are reported below in Table 4. Standard deviation for each compound concentration was calculated using all replicates and using a standard deviation formula commonly used in the art.

[00289] One of skill in the art would recognize that for this type of primary neuronal mixed cell assay variability between different assay runs is to be expected even though the protocol is the same for each assay run. For instance, variability may be due to small differences in cell viability, cell density, age of the animals, etc.

[00290] Vertex Myelin Detection Software:

[00291] The Vertex myelin detection software was used to quantify the amount of myelin wrapping axons in a digital image that was obtained from our in-house microscope. Conceptually, the software identified and traced MBP positive ridge like structures in the image that were indicative of myelinating axons. A confounding factor in the analysis was the large debris fields typically occurring in the images. These fields resulted from the assay conditions required to achieve myelination. Special care was taken to ensure that noise in the image induced by the debris field was appropriately suppressed so that the signal that arose from the myelination could be recovered. The software was written in the Jython programming language and made significant utilization of the Fiji image analysis toolkits (see, Schindelin, J.; Arganda-Carreras, I. & Frise, E. et al, "Fiji: an open-source platform for biological- image analysis", Nature Methods 9(7): 676-682, 2012). There were several steps to the algorithm, each of which are discussed below.

[00292] Initially the image was loaded and converted to a 256-bit grey scale representation. Image contrast was enhanced by performing standard histogram stretching. The saturation parameter for the enhancement was set at 0.35, meaning the upper and lower 3.5% of the distribution of the gray scale values present in the image were removed prior to enhancement. The Frangi[2] vesselness measure, which computes the likelihood of a pixel belonging to a ridge-like structure, was applied to the resulting image (see, Frangi AF, Niessen WJ, Vincken KL, Viergever MA

"Multiscale vessel enhancement filtering", Proceedings of Medical Image Computer- Assisted Intervention (MICCAI), Lecture notes in computer science 1496: 130-137, 1998). The Frangi process created a "vessel likeness image" which was then converted to a binary image mask. The threshold of the Frangi measure for conversion to the mask was adjusted so that appropriate regions of the input image were selected. Once the mask was created, morphological closing was applied to remove small holes. Small structures were removed from the mask by deleting regions containing less than 40 connected pixels. The resulting mask overlaps regions of the original image that had a high likelihood of containing myelin strands.

[00293] Morphological skeletonization was applied to the binary mask and the resulting image was then converted to a graph data structure. Each node of the graph represented a pixel of the image. Owing to the skeletonizaiton process, each node was connected to at most 4 neighboring pixels. Nodes connected to one other node indicated the end of a myelin strand ("end nodes"); nodes connected to exactly two other nodes indicated a pixel contained in a myelin strand ("myelin node"); while nodes connected to 3 or 4 other nodes indicated regions where myelin strands intersect ("join nodes"). Neighboring 'myelin nodes' that were adjacent to the same "join node" were merged into longer strands of myelin. This process was done in a greedy fashion. The longest strand of myelin originating from an "end node" in the graph was identified. If this strand terminated in an end node the strand was extracted from the graph. If the strand terminated at a "join node" then it was joined with one of the other myelin strands adjacent to the same join node. The largest angle between the growing strand and all other strands adjacent to the join node was determined. If this angle was greater or equal to 140 degrees, then the growing strand and the strand that made this large angle were merged into one strand. The two strands that were merged were removed from being adjacent to the "join node". If the angle was less than 140 degrees, the growing strand was extracted from the graph and removed as being adjacent to the join node. The entire process was repeated until all strands were removed from the graph. Various geometric properties of the strand such as length and maximum curvature were computed from the number of pixels in the strand and the connectivity of the graph.

[00294] Before a putative myelin strand was quantified as myelin it was subjected to several quality control measures. The strand needed to be of a sufficient length (at least greater than 40 pixels). To ensure the strand was not overly curved, the ratio of the geometric distance between strand endpoints to the length of the strand needed to be greater than or equal to 0.8. Finally, to ensure the strand was not overly thick, the gray scale gradient at each point on the strand in the directions orthogonal to the strand direction needed to decay sufficiently rapidly. Specifically, the gray scale needed to decrease by 25% from the gray scale value of pixel intersected by the orthogonal line and the putative myelin strand. This decrease needed to occur within 5 pixels. If a strand passes all quality checks it was quantified as myelin.

[00295] Reagent and media preparation and animal source for the in vitro

Myelination Assay

[00296] lOx Dissociation Media (DM): lOx DM was prepared on a 1 liter scale by combining 900 mM Na2S04, 300 mM K2S04, 58 mM MgC12, 2.5 mM CaC12, 10 mM HEPES and 20 mL of a phenol red solution (0.5%). The pH was adjusted with . IN NaOH by eye until orange-red. The solution was then sterilized by Alteration through a 0.2uM filter (prewashed with 100 ml of deionized sterile water which was discarded prior to filtration of the DM media solution.

[00297] lOx KyMg Stock: KyMg stock was prepared on a 200 mL scale as follows. To a 250 mL flask was added 190 mL of water, 1 mL of phenol red (Sigma P0290), stock, 1.75 mL of IN NaOH, 378 mg of kynurenic acid, and 2 mL 500 mM HEPES. The mixture was then sonicated to dissolve the kynurenate and then MgC12 (4.1 ml of a 4.9 M solution) was added. The pH was adjusted to 7.4 by adding up to 1 ml of 0.1N NaOH and the mixture sterilized by filtration through a prewashed nylon filter

[00298] Complete dissociation medium (DM): 5 mL Ky Mg to 45 mL IX DM media

[00299] Papain Enzyme Solution (Worthinaton Biochemical. LK003178): A 10 units/mL stock solution was made fresh the day of dissection by adding lmL of lOmM NaOH and Complete Dissociation Medium to one vial of papain (-100 units) to give a 10 units/mL final concentration. The papain was activated at 37 °C for 10- 15 minutes prior to use.

[00300] Trypsin Inhibitor Solution : 9.6mL of Complete Dissociation Medium was added to 100 mg of trypsin inhibitor (type II-O; Sigma T-9253) and the mixture was sonicated. The pH was adjustedto -5.75 using IN NaOH and pH strips. Aliquots (4 mL) were measured out and and stored at -20 °C.

[00301] DNase I Solution lmg/mL): Added 25 mL DMEM/F12 medium (Corning, 10-092-CM) to 20 KU DNAse I (Sigma D4527) and aliquoted into one time use aliquots stored at -20° C.

Myelination Medium:

DMEM (Invitrogen, Cat #11960-051)

1 :50 B27 (Invitrogen, Cat #17504-044)

1% FBS (HyClone)

2 mM Glutamax (1 : 100) (Cat # Gibco 25030081)

Pen Strep (1 : 100) 10,000 units/mL (Cat # Gibco 15140122)

PDGF/FGF 0.3 ng/mL each (3 uL per 100 mL; PeproTech, cat #100-13 A and cat #100-18B

Myelination medium was made fresh the day of use from a stock bottle of DMEM containing pencillin/streptomycin and Glutamax, which was stored at 4° C for up to one month. On the day of use, 1 :50 B27, 1% FBS and 0.3ng/mL of PDGF and FGF were added to the DMEM containing pencillin/streptomycin and Glutamax.

[00302] Other in vitro and in vivo assays and models known in the art may also be used to show induction of remyelination in response to treatment with compounds such as those of the present invention (see, Nairn, F. J. et al., Nature (Letter), published online 20 April 2015, doi: 10.1038/naturel4335 and Macklin, W.B. et al, Developmental Cell, 32, pp 447-458 (2015))

[00303] The activities of the compounds below were determined by testing groups of compounds in different test batches. Compounds with no asterisk were part of one in vitro assay testing batch. Compound numbers indicated with an asterisk were all part of a different in vitro assay test batch. Compounds in Table 4 below have between less than 1 fold to greater than 10,000 fold myelin pixels above background at two concentrations (1.0 μΜ and 10.0 μΜ) relative to baseline of no added compound. Table 4. Remyelination in vitro data.

Cmpd

10 uM Score 1 uM Score No.

45 - -

46 - ++

47 + ++

48 - ++

49 + ++

50 + ++

51 - ++

52 + ++

53 + ++

54 + ++

55 - ++

56 + -

57 - -

58 - +

59 - -

60 - +++

61 - -

62 - +

63 - -

64 - +++

65 + +++

66 - -

67 - ++

68 - +++

69 - +++

70 - ++

71 - -

72 - ++

73 +++ ++

74 ND ND

75 +++ ++

76 - +

77 + -

78 - +++

79 - ++

80 - +++

81 - +++

82 - ++

83 - +++

84 - ++

85 - ++

86 - +++

87 - +++

88 - ++

89 - +++ Cmpd

10 uM Score 1 uM Score

No.

90 - ++

91 - +++

92 - +++

93 + +

94 + +

95 - +++

96 - +++

97 - +

98 + ++

99 - +++

100 ++ ++

101 + +

Fold relative to baseline Activity

ND not determined

<1

>1 to lOx +

>10 to lOOx ++

> 100 to lOOOx +4

>1000 to 10,000x ++4

[00304] All publications and patents referred to in this disclosure are incorporated herein by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Should the meaning of the terms in any of the patents or publications incorporated by reference conflict with the meaning of the terms used in this disclosure, the meaning of the terms in this disclosure are intended to be controlling. Furthermore, the foregoing discussion discloses and describes merely exemplary embodiments of the invention. One skilled in the art will readily recognize from such discussion and from the accompanying drawings and claims, that various changes, modifications and variations can be made therein without departing from the spirit and scope of the invention as defined in the following claims.