NZ788753A

NZ788753A - Pyrimidin-2-ylamino-1H-pyrazols as LRRK2 inhibitors for use in the treatment of neurodegenerative disorders

Info

Publication number: NZ788753A
Application number: NZ788753A
Authority: NZ
Inventors: Vicente Fidalgo Javier De; Anthony A Estrada; Jianwen A Feng; Joseph P Lyssikatos; Zachary K Sweeney
Original assignee: Denali Therapeutics Inc
Priority date: 2016-06-16
Filing date: 2017-06-15
Publication date: 2022-07-01

Abstract

The present disclosure relates generally to LRRK2 inhibitors, or a pharmaceutically acceptable salt, deuterated analog, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof, and methods of making and using thereof.

Description

PYRIMIDINYLAMINO-1H-PYRAZOLS AS LRRK2 INHIBITORS FOR USE IN THE TREATMENT OF NEURODEGENERATIVE DISORDERS CROSS REFERENCE TO RELATED APPLICATIONS This application is a divisional application of New Zealand ation no. 748936, the entire disclosure of which is incorporated herein by reference. This application claims the benefit under 35 U.S.C. §119(e) to U.S. Provisional Application Numbers 62/350,876 filed June 16, 2016, 62/417,151 filed November 3, 2016, ,581 filed March 24, 2017, and 62/510,711 filed May 24, 2017, and all of which are incorporated by reference.

FIELD The present disclosure relates generally to novel heteroaryl-substituted dines and their use as therapeutic agents, for example, as inhibitors of LRRK2.

BACKGROUND egenerative diseases, such as Parkinson’s disease, amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, Lewy body dementia, and Huntington’s e affect millions of people. Parkinson’s disease is a chronic, progressive motor system disorder characterized by selective degeneration and cell death of dopaminergic s in the substantial nigra region of the brain. This leaves patients with impaired ability to direct and control their movements. The cause of the disease was generally considered to be sporadic and unknown, but significant advancements in understanding have been made in the last 15 years.

The genetic basis for the disease and ated pathogenic isms have led ation of the gene ng leucine-rich repeat kinase 2 (LRRK2) protein and its association with hereditary Parkinson’s disease (Paisan-Ruiz et al., Neuron, Vol. 44(4), 2004, 601-607). LRRK2 is a member of the ROCO protein family and shares five conserved domains with all other family members. Many mis-sense mutations to the LRRK2 gene have been linked with autosomal dominant Parkinson’s disease in familial studies (Trinh and Farrar, Nature Reviews in Neurology, Vol. 9, 2013, 445-454; Paisan-Ruiz et al., J.

Parkinson’s Disease, Vol. 3, 2013, 85-103). The most common pathogenic mutation, G2019S, occurs in the highly conserved kinase domain of LRRK2 (See Gilks et al., , Vol 365, 2005, 415-416). In vitro studies indicate Parkinson’s disease-associated on leads to increased LRRK2 activity and a decreased rate of GTP hydrolysis (Guo et al., Experimental Cell Research, Vol. 313(16), 2007, 670). This evidence suggests the kinase and GTPase activities of LRRK2 are important for pathogenesis and the LRRK2 kinase domain may regulate overall LRRK2 function (See Cookson, Nat. Rev. Neurosci., Vol. 11, 2010, 791-797).

While progress has been made in this field, there s a need for ed inhibitors of the LRRK2 receptor which are useful for treatment of various neurodegenerative diseases, such as son’s disease, Alzheimer’s disease and amyotrophic lateral sclerosis.

DESCRIPTION Provided herein are compounds that are useful as inhibitors of LRRK2. The disclosure also provides compositions, including pharmaceutical compositions, kits that include the compounds, and methods of using (or stering) and making the compounds. The disclosure further provides compounds or compositions thereof for use in a method of treating a disease, disorder, or condition that [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson is mediated, at least in part, by LRRKZ. Moreover, the disclosure provides uses of the compounds or compositions thereof in the manufacture of a medicament for the treatment of a disease, disorder, or condition that is mediated, at least in part, by LRRKZ.

In one embodiment, provided is a compound of formula I: HN N R3 R1‘N \ R4 R5 1 or a pharmaceutically acceptable salt, deuterated , prodrug, stereoisomer, or a mixture of stereoisomers thereof, wherein: R1 is optionally substituted cycloalkyl or, when R5 is -CR55‘R6R7 where R5a is optionally substituted triazol-2—yl, R1 is optionally substituted cycloalkyl or C1_6 alkyl ally tuted with halo, R2 is halo, cyano, optionally substituted C1-6 alkyl, optionally tuted C1-6 alkenyl, optionally substituted C1-6 alkynyl, optionally tuted cycloalkyl, optionally substituted C1-6 alkoxy, optionally substituted cycloalkoxy, optionally substituted C1.6 alkylthio, optionally substituted C1—6 alkylsulfonyl, -C(O)R10, or -C(O)N(R“)(R12), R3 is optionally substituted C1-6 alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkoxy, optionally substituted C1.6 alkylthio, ally substituted C1—6 alkylsulfonyl, or -N(R”)(R12); R4 is hydrogen or halo, R5 is hydrogen, halo, cyano, optionally tuted C1.6 alkyl, optionally substituted C1—6 alkenyl, optionally substituted C1.6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, ally substituted heteroaryl, optionally substituted C1.6 alkylthio, optionally substituted C1—6 alkylsulfonyl, -C(O)R10, or -C(O)N(R“)(R12), R6 and R7 are each independently H or optionally tuted C1—6 alkyl, each R10 is independently optionally substituted C1_6 alkyl or optionally substituted C1_6 alkoxy, R11 and R12 are each independently hydrogen, optionally substituted C1_6 alkyl, optionally substituted cycloalkyl, or R11 and R12 together form an optionally substituted heterocyclyl group.

In one embodiment, provided is a compound of formula II: HTAN/IXR21 D / \ (R22)m AN ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson or a pharmaceutically acceptable salt, deuterated , prodrug, stereoisomer, or a mixture of stereoisomers thereof, wherein: R20 is halo, cyano, C1—6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1_6 koxy, cycloalkyl, cycloalkoxy, cycloalkylalkyl, cycloalkylalkoxy, or -C(O)R23, R21 is optionally substituted cycloalkyl, heteroaryl, C1-6 alkoxy, -S-C1.6 alkyl, or )(R25), m is 0,1, 2, 3, or 4, each R22 is independently halo, cyano, C1—6 alkyl, C1-6 haloalkyl, C1_6 hydroxyalkyl, C1_6 alkoxyalkyl, C1_6 cyanoalkyl, C1_6 aminoalkyl, C1_6 alkylsulfonyl, C1_6 alkylsulfonylalkyl, cycloalkyl, cyanocycloalkyl, cycloalkylalkyl, cyclyl, heterocyclylalkyl, eterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkylheteroarylalkyl, heteroarylcycloalkyl, alkylheteroarylcycloalkyl, amido, amidoalkyl, or -C(O)R26, wherein each C1_6 alkyl, C1_6 haloalkyl, C1_6 hydroxyalkyl, C1_6 alkoxyalkyl, C1_6 cyanoalkyl, C1_6 lkyl, C1_6 alkylsulfonyl, C1_6 alkylsulfonylalkyl, cycloalkyl, cyanocycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, alkylheterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, eteroarylalkyl, heteroarylcycloalkyl, and alkylheteroarylcycloalkyl is ally substituted, or two R22 together with the atom to which they are attached form a cycloalkyl or heterocyclyl, wherein each cycloalkyl and heterocyclyl is optionally substituted, R23 is C1_6 alkyl, C1_6 alkoxy, -N(R27)2, or cyclyl, wherein each C1_6 alkyl, C1_6 alkoxy and cyclyl is optionally substituted, R24 and R25 are each independently en or optionally substituted C1—6 alkyl, or R24 and R25 together with the atom to which they are ed form an optionally substituted cyclyl, R26 is C1_6 alkyl or heterocyclyl, wherein C1-6 alkyl, C1-6 haloalkyl, and heterocyclyl is independently optionally substituted with one or more substituents selected from halo, cyano, hydroxy, C1—6 alkoxy, and C1—6 alkylsulfonyl, each R27 is independently H or optionally substituted C1—6 alkyl, and A is a heterocyclyl or heteroaryl ring ﬁlSCd to the le.

In some embodiments, the compound is in Table 1A, 1B, 2A or 2B, or is a pharmaceutically acceptable salt, deuterated analog, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers thereof.

In another embodiment, provided is a pharmaceutical composition comprising a compound as shown in Table 1A, 1B, 2A or 2B, or a pharmaceutically acceptable salt, deuterated analog, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

In another embodiment, provided is a method for treating a disease or condition mediated, at least in part, by LRRKZ, the method comprising administering an effective amount of the pharmaceutical compcDJn comprising a compound as shown in Table 1A or Table 1B, or a pharmaceutically [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson acceptable salt, deuterated analog, prodrug, tautomer, isomer, or a e of stereoisomers f, and a pharmaceutically acceptable carrier, diluent, or excipient, to a subject in need f.

In another ment, provided is a pharmaceutical composition comprising a compound as shown in Table 1A or Table 1B, or a pharmaceutically acceptable salt, deuterated analog, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers thereof, and a pharmaceutically acceptable r, diluent, or excipient.

In another embodiment, provided is a method for treating a disease or condition mediated, at least in part, by LRRKZ, the method comprising administering an effective amount of the pharmaceutical composition comprising a compound as shown in Table 1A or Table 1B, or a pharmaceutically acceptable salt, deuterated analog, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers thereof, and a pharmaceutically acceptable carrier, diluent, or excipient, to a t in need thereof. In another embodiment, provided is a method for treating a disease or condition mediated, at least in part, by LRRKZ, the method comprising stering an effective amount of the pharmaceutical composition comprising a compound as shown in Table 1A, 1B, 2A or 2B, or a pharmaceutically acceptable salt, deuterated analog, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers thereof, and a pharmaceutically acceptable carrier, diluent, or excipient, to a subject in need f.

The description herein sets forth exemplary embodiments of the present technology. It should be recognized, r, that such description is not intended as a tion on the scope of the present disclosure but is instead provided as a description of exemplary embodiments. 1. Definitions As used in the present specification, the ing words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

A dash (“-”) that is not between two s or symbols is used to indicate a point of attachment for a tuent. For example, -C(O)NH2 is ed through the carbon atom. A dash at the front or end of a chemical group is a matter of convenience, chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line or a dashed line drawn through a line in a structure indicates a specified point of attachment of a group. Unless chemically or structurally required, no directionality or stereochemistry is indicated or implied by the order in which a chemical group is written or named.

The prefix “CH” indicates that the following group has from u to v carbon atoms. For example, “C1-6 alkyl” indicates that the alkyl group has from 1 to 6 carbon atoms.

Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or ter per se. In certain embodiments, the term “about” includes the indicated amount :: 10%. In other embodiments, the term “about” includes the indicated amount :: 5%. In certairger embodiments, the term “about” includes the indicated amount :: 1%. Also, to the term “about includes description of “X”. Also, the singular forms “a” and “the” include plural references [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson ation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson unless the context clearly dictates otherwise. Thus, e.g., reference to “the compound” includes a ity of such nds and reference to “the assay” includes reference to one or more assays and lents thereofknown to those skilled in the art.

“Alkyl” refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C140 , 1 to 8 carbon atoms (i.e., C14; alkyl), 1 to 6 carbon atoms (i.e., C1-6 alkyl) or 1 to 4 carbon atoms (i.e., C1-4 alkyl). Examples of alkyl groups e , ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2- hexyl, l and ylpentyl. When an alkyl residue having a specific number of carbons is named by chemical name or identified by molecular formula, all positional isomers having that number of carbons may be encompassed, thus, for example, “butyl” includes n-butyl (i.e. -(CH2)3CH3), sec-butyl (i.e. -CH(CH3)CH2CH3), isobutyl (i.e. -CH2CH(CH3)2) and tert-butyl (i.e. -C(CH3)3), and “propyl” includes n-propyl (i.e. -(CH2)2CH3) and isopropyl (i.e. -CH(CH3)2). n commonly used alternative chemical names may be used. For example, a divalent group such as a nt “alkyl” group, a divalent “aryl” group, etc., may also be referred to as an “alkylene” group or an “alkylenyl” group, an “arylene” group or an “arylenyl” group, respectively. Also, unless indicated explicitly otherwise, where combinations of groups are referred to herein as one moiety, e.g. arylalkyl or aralkyl, the last mentioned group contains the atom by which the moiety is attached to the rest of the molecule.

“Alkenyl” refers to an alkyl group containing at least one -carbon double bond and having from 2 to 20 carbon atoms (i.e., C240 alkenyl), 2 to 8 carbon atoms (i.e., C24; alkenyl), 2 to 6 carbon atoms (i.e., C2.6 alkenyl) or 2 to 4 carbon atoms (i.e., C2-4 alkenyl). Examples of alkenyl groups include ethenyl, propenyl, butadienyl (including l,2-butadienyl and l,3-butadienyl).

“Alkynyl” refers to an alkyl group containing at least one carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C240 alkynyl), 2 to 8 carbon atoms (i.e., C2—8 alkynyl), 2 to 6 carbon atoms (i.e., C2-6 alkynyl) or 2 to 4 carbon atoms (i.e., C2-4 alkynyl). The term “alkynyl” also includes those groups having one triple bond and one double bond.

“Alkoxy” refers to the group “alkyl-O-”. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy and 1,2- dimethylbutoxy.

“Alkoxyalkyl” refers to the group “alkyl-O-alkyl”.

“Alkylthio” refers to the group “alkyl-S-”.

“Alkylsulfinyl” refers to the group “alkyl-S(O)-”.

“Alkylsulfonyl” refers to the group “alkyl-S(O)2-”. sulfonylalkyl” refers to -alkyl-S(O)2-alkyl.

“Acyl” refers to a group -C(O)Ry, n Ry is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroayl, aryl, alkyl, or heteroaryl, each of which may be optionally substituted, as defined [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson herein. Examples of acyl include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl and benzoyl.

“Amido” refers to both a “C-amido” group which refers to the group -C(O)NRyRZ and an “N- amido” group which refers to the group -NRyC(O)RZ, wherein Ry and RZ are independently en, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally tuted, as defined herein, or Ry and RZ are taken er to form a cycloalkyl or heterocyclyl, each of which may be optionally substituted, as defined herein.

“Amidoalkyl” refers to refers to an alkyl group as defined above, wherein one or more en atoms are replaced by an amido group.

“Amino” refers to the group -NRyRZ wherein Ry and RZ are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted, as defined herein.

“Aminoalkyl” refers to the group “-alkyl-NRyRZ,” wherein Ry and RZ are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted, as defined herein.

“Amidino” refers to )(NRZZ), wherein Ry and RZ are independently hydrogen, alkyl, alkenyl, alkynyl, lkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be ally substituted, as defined herein.

“Aryl” refers to an aromatic carbocyclic group having a single ring (e.g. monocyclic) or multiple rings (e.g. bicyclic or tricyclic) including ﬁlSCd systems. As used herein, aryl has 6 to 20 ring carbon atoms (i.e., C640 aryl), 6 to 12 carbon ring atoms (i.e., C6—12 aryl), or 6 to 10 carbon ring atoms (i.e., C6—10 aryl). Examples of aryl groups include phenyl, naphthyl, ﬂuorenyl and anthryl. Aryl, however, does not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are ﬁlSCd with a heteroaryl, the resulting ring system is heteroaryl. If one or more aryl groups are ﬁlSCd with a heterocyclyl, the resulting ring system is heterocyclyl.

“Arylalkyl” or “Aralkyl” refers to the group “aryl-alkyl-”.

“Carbamoyl” refers to both an “O-carbamoyl” group which refers to the group -O-C(O)NRyRZ and an “N-carbamoyl” group which refers to the group -NRyC(O)ORZ, wherein Ry and RZ are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be ally substituted, as defined herein. xyl ester” or “ester” refer to both RX and R", wherein RX is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted, as defined herein.

“Cyanoalkyl” refers to refers to an alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a cyano group. [0040B “Cycloalkyl” refers to a saturated or lly unsaturated cyclic alkyl group having a single ring or le rings including ﬁlSCd, bridged and spiro ring systems. The term “cycloalkyl” includes [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson lkenyl groups (i.e. the cyclic group having at least one double bond) and carbocyclic fused ring systems having at least one sp3 carbon atom (i.e., at least one non-aromatic ring). As used herein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C340 lkyl), 3 to 12 ring carbon atoms (i.e., C342 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C340 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3—8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C3-6 cycloalkyl). Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2. anyl, bicyclo[2.2.2]octanyl, adamantyl, norbomyl, decalinyl, 7,7-dimethyl-bicyclo[2.2. l]heptanyl and the like. r, the term cycloalkyl is intended to encompass any non-aromatic ring which may be ﬁlSCd to an aryl ring, regardless of the attachment to the remainder of the molecule. Still ﬁthher, cycloalkyl also includes “spirocycloalkyl” when there are two positions for substitution on the same carbon atom, for e spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5] undecanyl.

“Cycloalkoxy” refers to “-O-cycloalkyl.” “Cycloalkylalkyl” refers to the group “cycloalkyl-alkyl-.” “Cycloalkylalkoxy” refers to “-O-alkyl-cycloalkyl.” “Guanidino” refers to -NRyC(=NRZ)(NRyRZ), wherein each Ry and RZ are independently hydrogen, alkyl, alkenyl, l, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted, as defined herein.

“Hydrazino” refers to -NHNH2.

“Imino” refers to a group -C(NRy)RZ, wherein Ry and RZ are ach independently en, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted, as d herein.

“Imido” refers to a group —C(O)NRyC(O)RZ, wherein Ry and RZ are each independently hydrogen, alkyl, l, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be ally substituted, as defined herein.

“Halogen” or “halo” refers to atoms occupying group VIIA of the periodic table, such as ﬂuoro, chloro, bromo, or iodo.

“Haloalkyl” refers to an ched or branched alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen. For example, where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and oalkyl refer to alkyl substituted with two (“di”) or three (“tri” halo groups, which may be, but are not necessarily, the same halogen. Examples of haloalkyl include triﬂuoromethyl, diﬂuoromethyl, ﬂuoromethyl, trichloromethyl, 2,2,2-triﬂuoroethyl, ﬂuoroethyl, 3-bromoﬂuoropropyl, bromoethyl and the like.

“Haloalkoxy” refers to an alkoxy group as defined above, wherein one or more hydrogen atoms Deplaced by a halogen.

[Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson “Hydroxyalkyl” refers to an alkyl group as deﬁned above, wherein one or more hydrogen atoms are replaced by a hydroxy group. oalkyl” refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatomic group, provided the point of attachment to the remainder of the molecule is through a carbon atom. The term oalkyl” includes unbranched or branched saturated chain having carbon and heteroatoms. By way of example, 1, 2, or 3 carbon atoms may be independently replaced with the same or different heteroatomic group. atomic groups include, but are not d to, -NRy-, -O-, -S-, -S(O)-, -S(O)2-, and the like, wherein Ry is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted, as defined herein. Examples of heteroalkyl groups include ethers (e.g., -CH20CH3, -CH(CH3)OCH3, 20CH3, -CH2CH20CH2CH20CH3, etc.), thioethers (e.g., -CH2$CH3, -CH(CH3)SCH3, -CH2CH2$CH3, -CH2CH2$CH2CH2$CH3, etc.), sulfones (e.g., -CH2$(O)2CH3, -CH(CH3)S(O)2CH3, -CH2CH2$(O)2CH3, 2$(O)2CH2CH20CH3, etc.), and amines (e.g., -CH2NRyCH3, -CH(CH3)NRyCH3, -CH2CH2NRyCH3, -CH2CH2NRYCH2CH2NRYCH3, etc., where Ry is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted, as d herein). As used herein, heteroalkyl includes 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms, and l to 3 heteroatoms, l to 2 atoms, or 1 heteroatom. oaryl” refers to an aromatic group having a single ring, multiple rings or multiple ﬁlSCd rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulﬁir. As used , heteroaryl includes 1 to 20 ring carbon atoms (i.e., C140 heteroaryl), 3 to 12 ring carbon atoms (i.e., C342 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C34; heteroaryl), and l to 5 ring heteroatoms, l to 4 ring heteroatoms, l to 3 ring heteroatoms, l to 2 ring heteroatoms, or 1 ring heteroatom ndently selected from nitrogen, oxygen and sulﬁir. In certain instances, heteroaryl includes 5-10 membered ring systems, 5-7 membered ring systems, or 5-6 membered ring systems, each independently having 1 to 4 ring heteroatoms, l to 3 ring atoms, l to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen and sulﬁir. Examples of heteroaryl groups include acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzoﬁiranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthoﬁJranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzoﬁJranyl, dibenzothiophenyl, ﬁJranyl, isothiazolyl, imidazolyl, indazolyl, l, indazolyl, isoindolyl, isoquinolyl, isoxazolyl, naphthyridinyl, zolyl, oxazolyl, l-oxidopyridinyl, opyrimidinyl, l-oxidopyrazinyl, l-oxidopyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, inyl, lidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, and triazinyl. Examples of the ﬁJsed-heteroaryl rings include, but are not limited to, benzopyrazog,5-a]pyridinyliazolyl, quinolinyl, isoquinolinyl, b]thiophenyl, indazolyl, d]imidazolyl, and imidazo[l,5-a]pyridinyl, where the heteroaryl can be bound via either ring [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson of the ﬁlSCd system. Any aromatic ring, having a single or multiple ﬁlSCd rings, containing at least one heteroatom, is considered a heteroaryl regardless ofthe attachment to the remainder of the molecule (i.e., through any one of the ﬁlSCd rings). Heteroaryl does not encompass or overlap with aryl as deﬁned above.

“Heteroarylalkyl” refers to the group “heteroaryl-alkyl-.” “Heterocyclyl” refers to a saturated or partially unsaturated cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulﬁJr. The term “heterocyclyl” includes heterocycloalkenyl groups (i.e. the cyclyl group haVing at least one double bond), bridged-heterocyclyl groups, ﬁised-heterocyclyl groups and spiro-heterocyclyl groups. A heterocyclyl may be a single ring or multiple rings wherein the multiple rings may be ﬁlSCd, bridged or spiro, and may se one or more oxo (=0) or N—oxide (-O') moieties. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of the attachment (i.e., can be bound through a carbon atom or a heteroatom). Further, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring may be fused to an aryl or heteroaryl ring, regardless of the ment to the remainder ofthe molecule. As used herein, heterocyclyl has 2 to 20 ring carbon atoms (i.e., C2_20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C2_12 heterocyclyl), 2 to 10 ring carbon atoms (i.e., C210 heterocyclyl), 2 to 8 ring carbon atoms (i.e., C2_8 heterocyclyl), 3 to 12 ring carbon atoms (i.e., C3_12 heterocyclyl), 3 to 8 ring carbon atoms (i.e., C34; heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C3_6 heterocyclyl), having 1 to 5 ring heteroatoms, l to 4 ring heteroatoms, l to 3 ring heteroatoms, l to 2 ring atoms, or 1 ring heteroatom ndently selected from nitrogen, sulﬁJr or oxygen. Examples of heterocyclyl groups include azetidinyl, yl, benzodioxolyl, benzo[b][l,4]dioxepinyl, l,4-benzodioxanyl, benzopyranyl, ioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, l[l,3]dithianyl, decahydroisoquinolyl, nyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, linyl, octahydroindolyl, droisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydroﬁerl, tetrahydropyranyl, anyl, tetrahydroquinolinyl, thiophenyl (i.e. thienyl), tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, l-oxo-thiomorpholinyl and l,l-dioxo-thiomorpholinyl. The term “heterocyclyl” also includes heterocyclyl” when there are two positions for substitution on the same carbon atom. Examples of the spiro-heterocyclyl rings include bicyclic and tricyclic ring systems, such as 2-oxaazaspiro[3.5]nonanyl, 6-azaspiro[3.4]octanyl and 6-oxa-l-azaspiro[3.3]heptanyl.

Examples of the ﬁJsed-heterocyclyl rings include, but are not d to, l,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl and isoindolinyl, where the heterocyclyl can be bound Via either ring of the ﬁlSCd system. [0056 “Heterocyclylalkyl” refers to the group “heterocyclyl-alkyl-”.

[Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson The term “leaving group” refers to an atom or a group of atoms that is displaced in a chemical reaction as stable species taking with it the bonding electrons. The non-limiting examples of a leaving group include, halo, methanesulfonyloxy, p-toluenesulfonyloxy, romethanesulfonyloxy, nonaﬂuorobutanesulfonyloxy, (4-bromo-benzene)sulfonyloxy, (4-nitro-benzene)sulfonyloxy, (2-nitrobenzene )-sulfonyloxy, (4-isopropyl-benzene)sulfonyloxy, (2,4,6-tri-isopropyl-benzene)-sulfonyloxy, (2,4,6-trimethyl-benzene)sulfonyloxy, (4-tert-butyl-benzene)sulfonyloxy, benzenesulfonyloxy, (4- methoxy-benzene)sulfonyloxy, and the like. ” refers to the group -CRy(=NOH) wherein Ry is hydrogen, alkyl, alkenyl, l, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted, as deﬁned herein.

“Sulfonyl” refers to the group -S(O)2Ry, where Ry is hydrogen, alkyl, l, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted, as defined herein. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl and toluenesulfonyl.

“Sulfinyl” refers to the group -S(O)Ry, where Ry is en, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be ally substituted, as defined herein. Examples of sulfinyl are methylsulfinyl, ethylsulfinyl, phenylsulfinyl and toluenesulfinyl.

“Sulfonamido” refers to the groups -SOzNRyRZ and zRZ, where Ry and RZ are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted, as defined herein.

The terms “optional” or “optionally” means that the subsequently described event or stance may or may not occur and that the description includes instances where said event or circumstance occurs and instances in which it does not. Also, the term “optionally tuted” refers to any one or more hydrogen atoms on the ated atom or group may or may not be replaced by a moiety other than hydrogen.

The term ituted” used herein means any of the above groups (e.g., alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, and/or heteroalkyl) wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atom such as, but not limited to alkyl, alkenyl, alkynyl, , alkylthio, acyl, amido, amino, amidino, aryl, aralkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, lkyl, cycloalkylalkyl, ino, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, cyclyl, heterocyclylalkyl, hydrazine, hydrazone, imino, imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, sulfinic acid, ic acid, sulfonamido, thiol, thioxo, N—oxide, or -Si(Ry)3 wherein each Ry is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, lkyl, aryl, heteroaryl, or heterocyclyl. alkynygkylene,[0064 n one embodiment, “substituted” includes any ofthe above groups (e.g., alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, and/or ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson alkyl) in which one or more hydrogen atoms are ed with -NRth, -NRgC(=O)Rh, -NRgC(=O)NRth, -NRgC(=O)ORh, -NRgsoth, -OC(=O)NRth, -0Rg, -SRg, -SORg, , -OSOzRg, g, =NSOzRg, and -SOzNRth. “Substituted” also means any of the above groups in which one or more hydrogen atoms are replaced with -C(=O)Rg, -C(=O)0Rg, -C(=O)NRth, -CH2S02Rg, -CH2S02NRth. In the foregoing, Rg and R11 are the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and/or heteroarylalkyl. “Substituted” ﬁthher means any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylamino, kyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N—heterocyclyl, heterocyclylalkyl, heteroaryl, and/or heteroarylalkyl group. In addition, each of the foregoing substituents may also be optionally substituted with one or more ofthe above substituents.

Polymers or r indefinite structures arrived at by defining substituents with ﬁthher substituents appended ad infinitum (e.g., a substituted aryl having a substituted alkyl which is itself substituted with a substituted aryl group, which is ﬁthher substituted by a tuted alkyl group, etc.) are not intended for inclusion herein. Unless otherwise noted, the maximum number of serial substitutions in nds bed herein is three. For example, serial substitutions of substituted aryl groups with two other substituted aryl groups are limited to tituted aryl)substituted aryl) substituted aryl. Similarly, the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 ﬂuorines or heteroaryl groups having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to the d artisan. When used to modify a chemical group, the term “substituted” may describe other chemical groups defined herein. Unless speciﬁed otherwise, where a group is described as optionally substituted, any tuents ofthe group are lves unsubstituted. For example, in some embodiments, the term ituted alkyl” refers to an alkyl group having one or more substituents including hydroxy, halo, alkoxy, acyl, oxo, amino, cycloalkyl, cyclyl, aryl and heteroaryl. In other embodiments, the one or more substituents may be ﬁthher substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted. In other embodiments, the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.

Any compound or structure given herein, is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted herein, except that one or more atoms are ed by an atom having a selected atomic mass or mass . es of isotopes that can be incorporated into the disclosed compounds e isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, ﬂuorine, chlorine and iodine, such as 2H, 3H, 11C, 13C, 14C, BQN, 15O, 17O, 18O, 31P, 32P, 35S, 18F, 36Cl, 123I and 125I, respectively. Various isotopically labeled compoun s ofthe present disclosure, for example those into which radioactive isotopes such as 3H, 13C [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson and 14C are orated. Such isotopically labelled compounds may be useﬁil in lic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.

The sure also includes “deuterated analogs” of compounds described herein in which from 1 to n hydrogens ed to a carbon atom is/are replaced by deuterium, in which n is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and are thus useﬁil for increasing the half-life of any compound when stered to a mammal, particularly a human. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing ng materials in which one or more hydrogens have been replaced by deuterium.

Deuterium labelled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, lism and excretion (ADME). Substitution with r es such as deuterium may afford certain therapeutic ages resulting from greater metabolic stability, for example increased in viva half-life, reduced dosage requirements and/or an improvement in eutic index. An 18F, 3H, 11C labeled compound may be useﬁil for PET or SPECT or other imaging studies. Isotopically labeled compounds ofthis disclosure and prodrugs f can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a otopically labeled t. It is understood that deuterium in this context is regarded as a substituent in a compound described herein.

The concentration of such a heavier isotope, speciﬁcally deuterium, may be deﬁned by an isotopic enrichment factor. In the nds ofthis disclosure any atom not speciﬁcally designated as a particular isotope is meant to represent any stable isotope ofthat atom. Unless otherwise stated, when a position is designated speciﬁcally as “H” or “hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition. Accordingly, in the compounds of this disclosure any atom speciﬁcally designated as a deuterium (D) is meant to represent deuterium.

In many cases, the compounds of this disclosure are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.

Provided are also pharmaceutically able salts, hydrates, solvates, tautomeric forms, stereoisomers and prodrugs of the compounds described . “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other als which are useﬁil in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use. biolog1ca[0072the term aceutically acceptable salt” of a given compound refers to salts that retain theeffectiveness and properties of the given compound and which are not biologically or ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson otherwise undesirable. “Pharmaceutically acceptable salts” or “physiologically acceptable salts” include, for example, salts with inorganic acids and salts with an organic acid. In addition, if the compounds described herein are ed as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by ving the free base in a suitable c solvent and treating the on with an acid, in accordance with conventional procedures for preparing acid on salts from base compounds. Those skilled in the art will recognize various tic methodologies that may be used to prepare nontoxic pharmaceutically able addition salts.

Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulﬁJric acid, nitric acid, phosphoric acid and the like. Salts derived from organic acids include acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, ﬁimaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid and the like. Likewise, pharmaceutically acceptable base addition salts can be ed from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, ium, lithium, um, ammonium, calcium and magnesium salts. Salts derived from organic bases e, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines (i.e., NH2(alkyl)), dialkyl amines (i.e., yl)2), trialkyl amines (i.e., N(alkyl)3), substituted alkyl amines (i.e., NH2(substituted alkyl)), di(substituted alkyl) amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl) amines (i.e., N(substituted alkyl)3), alkenyl amines (i.e., NH2(alkenyl)), dialkenyl amines (i.e., HN(alkenyl)2), trialkenyl amines (i.e., N(alkenyl)3), substituted alkenyl amines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl) amines (i.e., HN(substituted alkenyl)2), tri(substituted alkenyl) amines (i.e., N(substituted alkenyl)3, mono-, di- or tri- cycloalkyl amines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, oalkyl)3), mono-, di- or tri- arylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3) or mixed amines, etc. Speciﬁc examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N—ethylpiperidine and the like.

The term “hydrate” refers to the complex formed by the ing of a compound described herein and water.

A “solvate” refers to an association or complex of one or more solvent molecules and a compound ofthe sure. Examples of solvents that form solvates include, but are not d to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethylacetate, acetic acid and ethanolamine.

Some of the compounds exist as tautomers. Tautomers are in equilibrium with one another. For example, amide ning nds may exist in equilibrium with imidic acid tautomers. Regardless utomer is shown and regardless of the nature of the equilibrium among tautomers, the compoun s are understood by one of ordinary skill in the art to comprise both amide and imidic acid [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson tautomers. Thus, the amide containing compounds are understood to include their imidic acid tautomers.

Likewise, the imidic acid containing compounds are understood to include their amide tautomers.

The compounds of the invention, or their pharmaceutically able salts include an asymmetric center and may thus give rise to omers, reomers, and other isomeric forms that may be deﬁned, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids. The present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional llization. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable lly pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for e, chiral high pressure liquid chromatography . When the compounds described herein n ic double bonds or other centres of geometric asymmetry, and unless speciﬁed otherwise, it is intended that the compounds include both E and Z geometric isomers.

A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present invention contemplates s stereoisomers and mixtures thereof and es “enantiomers,” which refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another.

“Diastereomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

“Prodrugs” means any compound which es an active parent drug according to a structure described herein in vivo when such g is administered to a mammalian subject. Prodrugs of a compound bed herein are prepared by modifying ﬁinctional groups present in the compound described herein in such a way that the modifications may be cleaved in vivo to release the parent nd. Prodrugs may be prepared by modifying ﬁinctional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds described herein wherein a hydroxy, amino, carboxyl, or sulﬂlydryl group in a compound described herein is bonded to any group that may be cleaved in vivo to regenerate the free hydroxy, amino, or sulﬂlydryl group, respectively. Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate and benzoate derivatives), amides, guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl) ofhydroxy ﬁinctional groups in nds described herein and the like. Preparation, selection and use of prodrugs is discussed in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 ofthe A.C.S. Symposium Series, “Design of Prodrugs,” ed. H.

Bundgaard, Elsevier, 1985, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which are hereby incorporated by refuze in their entirety.

[Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson As used herein, “pharmaceutically acceptable carrier” or “pharmaceutically able excipient” or “excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antiﬁJngal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions. 2. Compounds Provided herein are compounds that are useﬁil as inhibitors of LRRKZ.

In one embodiment, provided is a compound of formula I: HN N R3 R1\N \ R4 R5 1 or a pharmaceutically acceptable salt, deuterated analog, prodrug, stereoisomer, or a mixture of isomers thereof, wherein: R1 is optionally substituted cycloalkyl or, when R5 is -CR55‘R6R7 where R5a is ally tuted triazol-2—yl, R1 is optionally substituted cycloalkyl or C1-6 alkyl optionally substituted with halo, R2 is halo, cyano, optionally tuted C1-6 alkyl, ally substituted C1-6 alkenyl, optionally substituted C1-6 alkynyl, optionally substituted cycloalkyl, optionally substituted C1-6 alkoxy, optionally substituted cycloalkoxy, optionally substituted C1.6 alkylthio, optionally substituted C1—6 alkylsulfonyl, -C(O)R10, or -C(O)N(R“)(R12), R3 is ally substituted C1-6 , optionally substituted cycloalkyl, optionally substituted lkoxy, optionally substituted C1.6 alkylthio, ally substituted C1—6 alkylsulfonyl, or -N(R”)(R12); R4 is hydrogen or halo, R5 is hydrogen, halo, cyano, optionally substituted C1_6 alkyl, ally substituted C1_6 alkenyl, optionally substituted C1_6 alkynyl, ally substituted cycloalkyl, optionally substituted heterocyclyl, optionally tuted heteroaryl, optionally tuted C1_6 alkylthio, optionally substituted C1_6 alkylsulfonyl, -C(O)R10, or -C(O)N(R“)(R12), R6 and R7 are each independently H or optionally substituted C1_6 alkyl, each R10 is independently optionally substituted C1-6 alkyl or optionally substituted C1—6 alkoxy, R11 and R12 are each independently hydrogen, optionally substituted C1-6 alkyl, optionally substitD lkyl, or R11 and R12 together form an optionally substituted heterocyclyl group.

[Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson In one embodiment, provided is a compound of formula I represented by formula Ia: or a pharmaceutically acceptable salt, deuterated analog, prodrug, stereoisomer, or a mixture of stereoisomers thereof, wherein R2, R3 and R4 are as defined herein, and: R1 is optionally tuted cycloalkyl or C1-6 alkyl optionally substituted with halo, R6 and R7 are each independently hydrogen or C1-6 alkyl optionally substituted with halo, and R8 and R9 are each independently hydrogen, cyano, halo, optionally tuted C1—6 alkyl, ally substituted C1.6 alkoxy, or optionally substituted heteroaryl.

In certain embodiments, R6 and R7 are methyl.

In n embodiments, R8 and R9 are hydrogen.

In certain embodiments, at least one of R8 and R9 is hydrogen.

In certain embodiments, R1 is optionally substituted cyclopropyl or ally substituted cyclobutyl.

In certain embodiments, R1 is cycloalkyl independently substituted with one or more halo, hydroxy, cyano, or heteroaryl.

In certain embodiments, R1 is cyclopropyl, cyclobutyl, hydroxycylobutyl, cyanocylobut yl, triazol-2yl-cyclobut-3 -yl, triazol-l-yl-cyclobutyl, or ﬂuorocyclobut—3-yl.

In certain ments, R1 is CD3, ethyl, or propyl.

In certain embodiments, R2 is halo, cyano, C1_6 alkyl optionally substituted with halo.

In certain embodiments, R2 is bromo.

In certain embodiments, R2 is -CF3.

In n embodiments, R3 is optionally substituted cycloalkyl, optionally substituted C1_6 alkoxy, or -N(R11)(R12).

In certain embodiments, R3 is cyclopropyl, methoxy, l,l-diﬂuoroethy-2—ylamino, cyclopropylamino, -NH(CH3), or -NH(CH2CH3).

In certain ments, R4 is en.

In certain embodiments, R5 is cyano, ally substituted C1-6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally tuted heteroaryl, optionally substituted C1.6 alkylsulfonyl, -C(O)R10, or (R”)(R12).

In certain embodiments, R5 is cyano, -C(O)R10, -C(O)N(R11)(R12), C1-6 alkylsulfonyl, acyl, heteroq optionally substituted with C1-6 alkyl, cycloalkyl optionally substituted with one to three oxo orC1-6 alky substituted with one to three halo, C1-6 alkyl, C1-6 alkyl substituted with , heterocyclyl optionally [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson cyano, hydroxyl, alkylsulfonyl, heterocyclyl, hydroxy, alkoxy, or heteroaryl, or C1_6 cycloalkyl substituted with cyano, aminocarbonyl, or alkoxycarbonyl. In certain embodiments, R5 is cyano, - C(O)R10, -C(O)N(R”)(R12), C1-6 alkylsulfonyl, acyl, heteroaryl optionally substituted with C1-6 alkyl, heterocyclyl ally substituted with C1-6 alkyl, C1-6 alkyl substituted with cyano, hydroxyl, alkylsulfonyl, heterocyclyl, hydroxy, alkoxy, or heteroaryl, or C1.6 cycloalkyl substituted with cyano, aminocarbonyl, or alkoxycarbonyl.

In certain ments, R5 is 2-(triazolyl)propan-2—yl, 2-pyrimidin-2—ylpropanyl, N,N— dimethylamido, 2-methylpropanyl, sulfonyl, cyano, 2-hydroxypropan-2—yl, carbonyl, 5- pyrrolidin-2—oneyl, l-(triazolyl)ethyl, 2-methylsulfonylpropanyl, 5-methyl-l,3-oxazol yl)pyrazolyl, 3-methyloxetanyl, l-cyano-cycloprop-2—yl, pyrrolidin-2—oneyl, l,l-dioxo-l,2— thiazolidin-2—yl, 7-methyl-5,6-dihydropyrrolo[l,2-a]imidazolyl, l-ethoxycarbonyl-cyclopropyl, l- aminocarbonyl-cycloprop-2—yl, 7-methyl-5 ,6-dihydropyrrolo[ l ,2—b] [ l ,2,4]t1iazolyl, 2-methoxypropan- 2-yl, 2-cyanopropan-2—yl, 3-methyloxolan-2—oneyl, oxabicyclo[3.l.0]hexanoneyl, l-methylpyrrolidinone-yl , cyclopropyl, l-ethyl-4,4-diﬂuoropipeiidyl, 4,4-diﬂuoropipe1idyl, or 2-methyll-oxo-cyclopent-2 —yl. In certain embodiments, R5 is 2-(tiiazolyl)propanyl, 2-pyiimidinylpropan- 2-yl, N,N-dimethylamido, 2-methylpropanyl, methylsulfonyl, cyano, 2-hydroxypropan-2—yl, methylcarbonyl, 5-methylpyrrolidinoneyl, l-(triazolyl)ethyl, ylsulfonylpropan-2—yl, 5- methyl-l,3-oxazolyl)pyrazolyl, 3-methyloxetanyl, l-cyano-cycloprop-2—yl, pyrrolidin-2—one yl, l,l-dioxo-l,2-thiazolidin-2—yl, 7-methyl-5,6-dihydropyrrolo[l,2-a]imidazolyl, l-ethoxycarbonylcyclopropyl , l-aminocarbonyl-cyclopropyl, 7-methyl-5 ,6-dihydropyrrolo [ l ,2-b] [ l ,2,4]t1iazolyl, 2-methoxypropan-2—yl, 2-cyanopropan-2—yl, 3-methyloxolan-2—oneyl, oxabicyclo[3.1.0]hexanone- 3-yl, or l-methyl-pyrrolidinone-yl.

In n embodiments, R1 is cycloalkyl independently substituted with one or more hydroxy, cyano, or heteroaryl, R2 is halo or C1-6 ﬂuoroalkyl, R3 is (R12) or C1_6 alkoxy, and R4 is hydrogen.

In certain embodiments, certain nds provided herein are surprisingly brain penetrant.

In certain embodiments, the compounds further have an MDRl-MDCK efﬂuX ratio of less than or equal to about ﬁve. In certain embodiments, these nds are of a Ia or Ib.

In one embodiment, provided is a compound of a I represented by formula Ib: HN N N ‘N— ,N— H30 CH3 or a pharmaceutically able salt, deuterated analog, prodrug, stereoisomer, or a mixture of stereoﬁers thereof, wherein: R is optionally substituted cycloalkyl or C1-6 alkyl optionally substituted with halo, [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson R2 is halo, cyano, ally substituted C1_6 alkyl, optionally substituted C1_6 alkenyl, optionally substituted C1-6 alkynyl, optionally substituted cycloalkyl, optionally substituted C1-6 alkoxy, optionally substituted cycloalkoxy, ally substituted C1.6 alkylthio, optionally substituted C1—6 alkylsulfonyl, 10, or -C(O)N(R“)(R12), R10 is optionally substituted C1-6 alkyl or optionally substituted C1—6 alkoxy, and each R11 and R12 are independently hydrogen, optionally substituted C1.6 alkyl, optionally substituted cycloalkyl, or R11 and R12 together form an optionally substituted heterocyclyl group.

In certain embodiments, R1 is optionally substituted cyclopropyl.

In certain embodiments, R1 is cyclopropyl.

In certain embodiments, R1 is methyl optionally substituted with halo.

In certain embodiments, R1 is -CD3.

In certain embodiments, R1 is -CF3.

In certain embodiments, R2 is halo, cyano, or C1-6 alkyl ally substituted with halo.

In certain embodiments, R2 is bromo.

In n embodiments, R2 is -CF3.

In n embodiments, R12 is optionally substituted C1_6 alkyl.

In certain embodiments, R12 is ethyl.

In certain embodiments, is optionally substituted cyclopropyl or methyl optionally substituted with halo, R2 is halo, cyano, or C1_6 alkyl optionally substituted with halo, and R12 is optionally substituted C1—6 alkyl.

In one embodiment, provided is a compound of formula II: ”TR| 20 HNAN/ R21 / |—\\ 22 ’N (R )m N or a pharmaceutically able salt, deuterated analog, prodrug, stereoisomer, or a e of stereoisomers f, wherein: R20 is halo, cyano, C1_6 alkyl, C1_6 haloalkyl, C1_6 alkoxy, C1_6 haloalkoxy, cycloalkyl, cycloalkoxy, cycloalkylalkyl, cycloalkylalkoxy, or -C(O)R23, R21is optionally substituted cycloalkyl, aryl, C1_6 alkoxy, -S-C1_6 alkyl, or -N(R24)(R25), m is 0,1, 2, 3, or 4, each R22 is ndently halo, cyano, C1_6 alkyl, C1_6 haloalkyl, C1_6 hydroxyalkyl, C1_6 alkoxyalkyl, C1_6 cyanoalkyl, C1_6 lkyl, C1_6 alkylsulfonyl, C1_6 alkylsulfonylalkyl, cycloalkyl, cyanocycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, alkylheterocyclylalkyl, aryl, arylalkyl, heteroD heteroarylalkyl, alkylheteroarylalkyl, heteroarylcycloalkyl, alkylheteroarylcycloalkyl, amido, amidoalkyl, or -C(O)R26, wherein each C1_6 alkyl, C1_6 haloalkyl, C1_6 hydroxyalkyl, C1_6 alkoxyalkyl, C1_6 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson ation] Sarah.Wilkinson ed set by Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson cyanoalkyl; C1_6 aminoalkyl; C1_6 alkylsulfonyl; C1_6 alkylsulfonylalkyl; cycloalkyl; cyanocycloalkyl; cycloalkylalkyl; heterocyclyl; heterocyclylalkyl; alkylheterocyclylalkyl; aryl; arylalkyl; aryl; heteroarylalkyl; alkylheteroarylalkyl; heteroarylcycloalkyl; and alkylheteroarylcycloalkyl is optionally substituted; or two R22 together with the atom to which they are attached form a cycloalkyl or heterocyclyl; wherein each cycloalkyl and heterocyclyl is optionally substituted; R23 is C1_6 alkyl; C1_6 alkoxy; -N(R27)2; or heterocyclyl; wherein each C1-6 alkyl; C1-6 alkoxy and heterocyclyl is optionally substituted; R24 and R25 are each independently H or optionally substituted C1—6 alkyl; or R24 and R25 together with the atom to which they are attached form an optionally substituted cyclyl; R26 is C1_6 alkyl or heterocyclyl; wherein C1-6 alkyl; C1-6 haloalkyl; and heterocyclyl is independently ally substituted with one or more substituents selected from halo; cyano; hydroxy; C1-6 alkoxy; and C1—6 alkylsulfonyl; each R27 is independently H or optionally substituted C1—6 alkyl; and A is a heterocyclyl or heteroaryl ring ﬁlSCd to the pyrazole.

In one embodiment; ring A contains additional heteroatoms. In one ment; ring A ns only the bridgehead en shared with the pyrazole ring.

In one embodiment; ed is a compound of formula IIA: VN‘” 11A or a pharmaceutically acceptable salt; deuterated analog; prodrug; stereoisomer; or a mixture of stereoisomers thereof; wherein R20; R21; R22 and m are as deﬁned herein.

In one embodiment; provided is a compound of formula IIB: HNJ\\N R21 (R22)m IIB or a pharmaceutically acceptable salt; deuterated analog; prodrug; stereoisomer; or a mixture of stereoisomers thereof; wherein R20; R21; R22 and m are as deﬁned herein.

[Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson ed set by Sarah.Wilkinson ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson In one embodiment, provided is a compound of a IIA-a: R22 IIA-a or a pharmaceutically able salt, deuterated analog, prodrug, stereoisomer, or a mixture of stereoisomers f, wherein R20, R21, R22 and m are as deﬁned herein.

In one embodiment, ed is a compound of formula IIA-b: R22 N—[(1 R22 IIA-b or a pharmaceutically acceptable salt, deuterated analog, prodrug, stereoisomer, or a mixture of stereoisomers thereof, wherein R20, R21, R22 and m are as defined herein.

In certain embodiments, R20 is halo, cyano, C1_6 alkyl, or C1_6 haloalkyl. In certain embodiments, R20 is C1_6 haloalkyl. In certain embodiments, R20 is C1_6 haloalkyl.

In certain embodiments, R21 is optionally tuted cycloalkyl or -N(R24)(R25). In certain embodiments, R21 is optionally substituted cycloalkyl, C1_6 alkoxy or -N(R24)(R25).

In certain embodiments, R22 is independently halo, cyano, C1—6 alkyl, C1—6 haloalkyl, C1_6 yalkyl, C1_6 alkoxyalkyl, C1_6 cyanoalkyl, C1_6 aminoalkyl, C1_6 alkylsulfonyl, C1_6 alkylsulfonylalkyl, cycloalkyl, cyanocycloalkyl, cycloalkylalkyl, cyclyl, heterocyclylalkyl, alkylheterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkylheteroarylalkyl, heteroarylcycloalkyl, alkylheteroarylcycloalkyl, amido, amidoalkyl, or -C(O)R26, wherein each C1_6 alkyl, C1_6 haloalkyl, C1_6 hydroxyalkyl, C1_6 alkoxyalkyl, C1_6 cyanoalkyl, C1_6 aminoalkyl, C1_6 alkylsulfonyl, C1_6 alkylsulfonylalkyl, cycloalkyl, cyanocycloalkyl, cycloalkylalkyl, cyclyl, heterocyclylalkyl, alkylheterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkylheteroarylalkyl, heteroarylcycloalkyl, and alkylheteroarylcycloalkyl is optionally substituted.

In certain ments, R22 is independently halo, cyano, C1-6 alkyl, or heteroaryl.

In n embodiments, two R22 together with the atom to which they are attached form a cycloalkyl or heterocyclyl, wherein each cycloalkyl and heterocyclyl is ally substituted. In certain embodiments, two R22 together with the atom to which they are attached form a heterocyclyl.

[Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson In one embodiment, provided is a compound of formula III: N 111 or a pharmaceutically acceptable salt, deuterated analog, prodrug, stereoisomer, or a mixture of isomers thereof, wherein: n is 0 or 1, R30 is halo, cyano, C1—6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1_6 haloalkoxy, cycloalkyl, cycloalkoxy, lkylalkyl, cycloalkylalkoxy, or -C(O)R33, R31 is optionally substituted C1-6 alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkoxy, optionally substituted C1_6 alkylthio, optionally substituted C1_6 alkylsulfonyl, or - N(R35)(R36); R32 is hydrogen, halo, cyano, optionally substituted C1_6 alkyl, optionally substituted C1_6 alkenyl, optionally substituted C1_6 alkynyl, optionally tuted C1_6 haloalkyl, optionally substituted C1_6 alkoxy, optionally tuted C1-6 haloalkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted C1-6 alkylthio, optionally substituted C1-6 alkylsulfonyl, 34, or -C(O)N(R35)(R36), R33 is C1_6 alkyl, C1_6 alkoxy, -N(R35)(R36), or heterocyclyl, wherein each C1_6 alkyl, C1-6 alkoxy, and heterocyclyl is optionally substituted, R34 is optionally tuted C1-6 alkyl or ally substituted C1—6 alkoxy, and R35 and R36 are each independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted cycloalkyl, or R35 and R36 together form an optionally tuted heterocyclyl group.

In one embodiment, provided is a compound of formula IIIA: HNAN| / R32 N—N b\:N IIIA or a pharmaceutically acceptable salt, deuterated analog, prodrug, stereoisomer, or a mixture of stereoisomers thereof, wherein: no is halo, cyano, C1—6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1_6 haloalkoxy, cycloalkyl, cycloalkoxy, cycloalkylalkyl, cycloalkylalkoxy, or -C(O)R33, [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson R31 is ally tuted C1_6 alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkoxy, optionally substituted C1.6 alkylthio, optionally substituted C1—6 alkylsulfonyl, or - N(R35)(R36); R32 is hydrogen, halo, cyano, optionally tuted C1-6 alkyl, optionally substituted C1—6 alkenyl, ally substituted C1.6 alkynyl, optionally substituted C1-6 haloalkyl, optionally substituted C1—6 alkoxy, optionally substituted C1-6 haloalkoxy, ally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted C1-6 hio, optionally tuted C1-6 alkylsulfonyl, -C(O)R34, or -C(O)N(R35)(R36), R33 is C1_6 alkyl, C1_6 alkoxy, -N(R35)(R36), or heterocyclyl, wherein each C1_6 alkyl, C1-6 alkoxy, and heterocyclyl is optionally substituted; R34 is optionally substituted C1-6 alkyl or ally tuted C1—6 alkoxy, R35 and R36 are each independently hydrogen, optionally substituted C1-6 alkyl, optionally and substituted cycloalkyl, or R35 and R36 together form an optionally substituted heterocyclyl group.

In one embodiment, provided is a compound of formula IIIB: HNAN| / N_l'\l R32 N IIIB or a pharmaceutically acceptable salt, ated , prodrug, stereoisomer, or a mixture of stereoisomers thereof, wherein: R30 is halo, cyano, C1—6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1_6 haloalkoxy, cycloalkyl, cycloalkoxy, cycloalkylalkyl, cycloalkylalkoxy, or -C(O)R33, R31 is ally substituted C1-6 alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkoxy, optionally substituted C1.6 alkylthio, ally substituted C1—6 alkylsulfonyl, or - N(R35)(R36); R32 is hydrogen, halo, cyano, optionally substituted C1-6 alkyl, optionally substituted C1—6 l, optionally substituted C1.6 alkynyl, optionally substituted C1-6 haloalkyl, optionally substituted C1—6 , optionally substituted C1-6 haloalkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted C1-6 alkylthio, optionally substituted C1-6 alkylsulfonyl, -C(O)R34, or -C(O)N(R35)(R36), R33 is C1_6 alkyl, C1_6 alkoxy, -N(R35)(R36), or cyclyl, wherein each C1_6 alkyl, C1-6 alkoxy and heterocyclyl is optionally substituted, D4 is optionally substituted C1-6 alkyl or optionally substituted C1—6 alkoxy, and [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson R35 and R36 are each independently hydrogen, optionally substituted C1_6 alkyl, ally substituted cycloalkyl, or R35 and R36 together form an optionally substituted heterocyclyl group.

In certain embodiments, R30 is halo, cyano, C1-6 alkyl, or C1_6 haloalkyl. In certain embodiments, R30 is C1-6 haloalkyl. In certain embodiments, R30 is C1_6 haloalkyl.

In n embodiments, R31 is optionally substituted cycloalkyl, C1-6 alkoxy or )(R36).

In n embodiments, R31 is optionally substituted cycloalkyl or -N(R35)(R36). In certain embodiments, R31 is cycloalkyl or -N(R35)(R36). In n embodiments, R31 is -N(R35)(R36).

In certain embodiments, R32 is hydrogen, halo, cyano, C1—6 alkyl, C1-6 alkenyl, C1_6 alkynyl, C1_6 haloalkyl, C1_6 alkoxy, C1_6 haloalkoxy, cycloalkyl, cyclyl, heteroaryl, C1—6 alkylthio, C1—6 alkylsulfonyl, -C(O)R34, or (R35)(R36). In certain embodiments, R32 is hydrogen, halo, cyano, optionally substituted C1.6 alkyl, optionally substituted C1—6 haloalkyl, optionally substituted C1—6 alkoxy, or optionally substituted C1-6 haloalkoxy. In certain embodiments, R32 is hydrogen. In certain embodiments, R32 is halo. In n embodiments, R32 is methyl.

In one embodiment, provided is a compound of formula IVA: (R45)n IVA or a pharmaceutically acceptable salt, ated analog, prodrug, stereoisomer, or a mixture of stereoisomers thereof, wherein: W is O, (R47) or N(R46), R40 is halo, cyano, optionally substituted C1-6 alkyl, ally substituted C1-6 alkenyl, optionally substituted C1_6 alkynyl, optionally substituted cycloalkyl, optionally substituted C1_6 , optionally substituted cycloalkoxy, optionally tuted C1_6 alkylthio, optionally substituted C1_6 alkylsulfonyl, -C(O)R48, or -C(O)N(R49)(R50), R41 is optionally substituted C1_6 alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkoxy, optionally substituted C1_6 hio, optionally substituted C1_6 alkylsulfonyl, or -N(R49)(R50); R42 is optionally substituted cycloalkyl or C1-6 alkyl optionally substituted with halo, R43 is en or halo, R44 is H or C1_3 alkyl optionally substituted with halo, each R45 independently is halo, oxo, or optionally substituted C1-3 alkyl, n is l, 2, 3, or 4, D6 and R47 are independently H, halo, optionally substituted C1.3 alkyl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl, [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson R48 is ally tuted C1_6 alkyl or optionally substituted C1_6 alkoxy, and R49 and R50 are each independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted cycloalkyl, or R49 and R50 together form an optionally substituted heterocyclyl group.

In one embodiment, provided is a compound of formula IVA-a: HN N R41 R42 \ R43 (R45)n IVA-a or a pharmaceutically able salt, deuterated analog, prodrug, stereoisomer, or a mixture of stereoisomers thereof, wherein W, R43, R44, R45, and n are as deﬁned herein, and: R40 is halo or C1_6 haloalkyl, R41 is -N(R49)(R50), R42 is optionally substituted cyclopropyl, R49 is hydrogen, and R50 is optionally substituted C1—6 alkyl.

In one embodiment, the compound is not (4-cyclopropyl(triﬂuoromethyl)pyrimidin yl)amino)-3 -methyl- lH-pyrazol- l -yl)pyrrolidinone, 3 4-cyclopropyl-5 - (triﬂuoromethyl)pyrimidin-2—yl)amino)methyl- lH-pyrazol- l -yl)-3 -methylpyrrolidinone, 3 -(4-((4- cyclopropyl-5 -(triﬂuoromethyl)pyrimidinyl)amino)-5 -methyl- lH-pyrazol- l -yl)pyrrolidinone, or 3 - -cyclopropyl-5 -(triﬂuoromethyl)pyrimidinyl)amino)-3 -methyl- lH-pyrazol- l -yl)-3 - methylpyrrolidinone, or a stereoisomer thereof.

In one embodiment, provided is a compound of formula IVA-b: RQN \ R43 N— O (R45)n IVA-b or a pharmaceutically acceptable salt, deuterated analog, prodrug, stereoisomer, or a mixture of stereoisomers thereof, wherein W, R43, R44, R45, and n are as defined herein, and: R40 is halo or C1_6 kyl, R41 is -N(R49)(R50), D2 is optionally tuted cyclopropyl, R49 is hydrogen, and [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson R50 is optionally substituted C1_6 alkyl.

In one embodiment, provided is a compound of a IVB: or a pharmaceutically acceptable salt, deuterated , prodrug, stereoisomer, or a mixture of isomers thereof, wherein: R40 is halo, cyano, optionally substituted C1_6 alkyl, optionally substituted C1_6 alkenyl, optionally substituted C1_6 alkynyl, optionally substituted cycloalkyl, optionally substituted C1_6 alkoxy, optionally substituted cycloalkoxy, optionally substituted C1_6 alkylthio, optionally substituted C1_6 alkylsulfonyl, -C(O)R48, or -C(O)N(R49)(R50), R41 is optionally substituted C1-6 alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkoxy, optionally substituted C1.6 hio, optionally substituted C1—6 alkylsulfonyl, or -N(R49)(R50); R42 is optionally tuted cycloalkyl or C1-6 alkyl optionally substituted with halo, R43 is hydrogen or halo, each R44 is ndently H or C1-3 alkyl optionally substituted with halo, each R45 independently is halo, oxo, or optionally substituted C1-3 alkyl, n is l, 2, 3, or 4, R46 is H, halo, optionally tuted C1.3 alkyl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl, R48 is optionally substituted C1-6 alkyl or ally substituted C1—6 alkoxy, and R49 and R50 are each independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted lkyl, or R49 and R50 together form an optionally substituted heterocyclyl group.

[Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson In one embodiment, provided is a compound of formula IVB-a: )LN/jR‘w/ HN N R41 R4%/R43 R44 _/ (R45)n/LN R46 IVB-a or a pharmaceutically acceptable salt, deuterated analog, prodrug, stereoisomer, or a mixture of stereoisomers thereof, wherein R43, R44, R45, R46, and n are as deﬁned herein, and: R40 is halo or C 1-6 haloalkyl, R41 is -N(R49)(R50), R42 is optionally substituted cyclopropyl, R49 is hydrogen, and R50 is optionally tuted C 1—6 alkyl.

In one embodiment, the compound is not 5 —(4w(4~{ethylanilno)— 5 v(trifluoron'iethylprrin'iidin—Zw 3;} am ino)—5 —methyl , lH~pyrazol ~ l ~yi )v i. ~m ethylpiperi d in— e, 5 ~(4 ~{4—(ethylamin o)~5 - {trifluorome Lhylﬁwrémidin —2~yiamino}~3«16:111in — lI-I~p.yrazol — l ~yi)— i~me thylpipen dinwﬁ—0n {3, 5 —( 3 ~ meihyl4443-41111": thylamino ) "5 "(triﬂuoroﬁ ~(5—metl1yl"4as:4~(methylamin0::6{mu uor‘omethy 1):)yi‘imidinQ _ ylamino} lH—pyrazol~ l —yl)piperidin—2—onemethyl)pyr‘imidin~2—ylamlno)— lI—lwpyrazoln l vy l)plp€i’l£ll£1'2~ one, N 4—ethyl~N2- {5 —methyi , I {(8)4 —oxotan~3 —yl ~pi pori din—3 gal)—1H—pymzoi—4-—yl}—5 —triﬁum‘omethyi - pyrimidine—2,4~diamine, N4~ethyl ~N2~ {3 ~ methyl ~l {(3} l —oxetan—3 per&din—3 ~yi)—1H— l~4—yl}~ unit} uoron'ietliylupyi’imidine"2,4udiamine, Milne tl'iyLN” ~ [5 amethylu 14(8)»? writethylmpiperidinu?) ~yl )_ lI-Eu pyrazol~4—yl} ~5 luoromethyl~133'i'imidine—2,4—diamine, or N4wethyl—N 2—{ 3 “Illeﬂ'lzyr’l' l —((S) — l lv pi peri din—3 —yl)— 1 H—pymzol—dmylj —5 —tri thyi —pyrimidine—2,4—diami no, or a stereoisomer thereof In one embodiment, the compound is not 5-(4-((4-cyclopropyl(triﬂuoromethyl)pyrimidin yl)amino)-3 -methyl- azol- l -yl)- l -ethylpiperidinone, 5 -(4-((4-cyclopropyl-5 - (triﬂuoromethyl)pyrimidin-2—yl)amino)methyl- lH-pyrazol- l -yl)- l -ethylpiperidin-2—one, 5 -(4-((4- cyclopropyl-5 -(triﬂuoromethyl)pyrimidinyl)amino)-3 -methyl- lH-pyrazol- l -yl) - l lpiperidin one, 5 -(4-((4-cyclopropyl-5 -(triﬂuoromethyl)pyrimidinyl)amino)-5 -methyl- lH-pyrazol- l -yl)- l - ethylpiperidinone, N-(5-chloro- l -(4,4-diﬂuoro- l -(oxetan-3 -yl)piperidin-3 -yl)- lH-pyrazolyl) cyclopropyl-5 -(triﬂuoromethyl)pyrimidinamine , or 5 -(4-((4-cyclopropyl-5 - oromethyl)pyrimidin-2—yl)amino)methyl- lH-pyrazol- l -yl)- l -ethylpiperidin-2—one, 5 -(4-((4- cyclopropyl-5 uoromethyl)pyrimidinyl)amino)-5 -methyl- lH-pyrazol- l -yl) - l -methylpiperidin one, or a stereoisomer thereof. ation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson In one embodiment, provided is a nd of formula IVB-b: )L/lN \ HN N R41 R42\N \ R43 R44 N’R46 R44 \-/ (R45)n IVB-b or a pharmaceutically acceptable salt, deuterated analog, prodrug, stereoisomer, or a e of stereoisomers thereof, wherein R43, R44, R45, R46, and n are as deﬁned herein, and: R40 is halo or C1_6 haloalkyl, R41 is -N(R49)(R50), R42 is optionally tuted cyclopropyl, R49 is hydrogen, and R50 is optionally substituted C1—6 alkyl.

In one embodiment, provided is a compound of formula V: AXN \ HN N R61 \R63 V or a pharmaceutically acceptable salt, deuterated analog, prodrug, stereoisomer, or a mixture of stereoisomers thereof, n: R60 is halo, cyano, optionally substituted C1-6 alkyl, ally substituted C1-6 alkenyl, optionally tuted C1-6 alkynyl, optionally substituted cycloalkyl, optionally substituted C1-6 alkoxy, optionally substituted cycloalkoxy, optionally substituted C1.6 alkylthio, optionally substituted C1—6 alkylsulfonyl, 64, or -C(O)N(R65)(R66), R61 is optionally substituted C1-6 alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkoxy, optionally substituted C1.6 alkylthio, optionally substituted C1—6 alkylsulfonyl, or -N(R65)(R66); R62 is hydrogen or halo, R63 is hydrogen, halo, cyano, optionally substituted C1-6 alkyl, optionally substituted C1—6 alkenyl, optionally substituted C1.6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally tuted heteroaryl, optionally substituted C1.6 alkylthio, optionally tuted C1—6 alkylsEhyl, -C(O)R64, or -C(O)N(R65)(R66), R64 is independently optionally substituted C1_6 alkyl or optionally substituted C1_6 alkoxy, [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson R65 and R66 are each independently hydrogen, optionally substituted C1_6 alkyl, optionally substituted cycloalkyl, or R65 and R66 together form an ally substituted heterocyclyl group.

In one embodiment, the compound is not NZ43~cyciopmpylvi~methyl~l H-pyrazol~4—yl)~N4~ methyl —5 ~(Lréﬁuoromethyl)pyrimidi113~2,4~diamine, N2~(5 ~cyel opropyl — l ~me Lbyl~ l l~4—yl)~N4~ methyl—5 "a:iriﬂuormnethyl)pyrimidine~2,4udiamine_ l"(3~cyclopmpylu4~{4_(metliylaiminoaut?u {trilluoromethy midinvZ~ylamino)— lH—pyrazol— l ﬁll—2'anothylpropanvlwl, l~(3 —e:yclopropyl~4—(4— {ethyiam ino)—5 vftrifluoromethyl)pyrimidiii—Zvylamino}l zol~l —yl)~2~m etbylpropan—Zvoi, 2-(3- cyclopropyl(4-(methylamino)-5 -(triﬂuoromethyl)pyrimidin-2—ylamino)- lH-pyrazol- l -yl) methylpropanenitrile, orZuE44:5~chlor’o—4umetl'ioxyupyrimidind—ylzm1ino)~3ncyclopiopylu pyrazolm l uyl}_2u wpropionitrilo, or a stereoisomer thereof.

In one embodiment, provided is a compound as shown in Table 1A or a pharmaceutically acceptable salt, deuterated analog, prodrug, stereoisomer, or a mixture of stereoisomers thereof.

Table 1A [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson Structure [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 0. Structure . Structure k NH 24 0% ”N N \ F N—N Nfﬁ\ F HN N NH HN N NH (Second eluting isomer) [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson No. urC No. Structure [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson Structure HN NH / K HN H / K HN NH / K HN NH / K (F1rst elutmg 1somer) HN NH / K (Second elutlng 1somer) [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson No. StructurC No. Structure (First g isomer) [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson No. Structure SecOnd e1u.Ung .1 S0meA” ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson N0. Str.uCtu r.e (Second eluting isomer) [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson N \ F HN N N—N 0 NYI / HN N NH Y5 K (Second eluting isomer) (First eluting isomer) [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson Structure FN‘ HNAN/ \ ,NII.

EN HNAN/ \N’NIIIM\\ 4:"! HNXN/| \ ’NII.

N GWK§ 200 F HN N/ N/\ V» H F N-N (ﬁrst eluting isomer) (second g isomer) [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson DumEN (ﬁrst eluting isomer) HN N N/ (ﬁrst g isomer) A?» H (ﬁrst eluting isomer) [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson Structure 215 Br )L/ /\ Dun—EN (second eluting isomer) (ﬁrst g isomer) DIIIIEN , second eluting isomer) ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson 101431 In some embodiments. the compound is in Table I Bor is a phatrnaceutically acceptable salt. prodrug. tautomer. stereoisomer. or a mixture of stereoisomers thereof Table I B No. Structure No. Structure 34 71 57 75 68 77 69 78 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson Structure N0. Structure [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson Structure Structure [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson (Second eluting isomer) (First eluting isomer) [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson Structure Structure (SecOnd e1u.Ung .m0meA” (Second eluting isomer) [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson (First eluting isomer) (First g isomer) ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson (First g isomer) [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson ed set by Sarah.Wilkinson Structure Structure (Sec0nd e1u.Ung .m0mc\U (First eluting isomer) [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson In one embodiment, a compound may be selected from those compounds in Table 1A. Also ed within the sure are pharmaceutically acceptable salts, prodrugs, stereoisomers, or a mixture of stereoisomers thereof. In certain embodiments, provided are compounds of Table 1A for use in the methods described herein.

In one embodiment, a compound may be selected from those compounds in Table 1B. Also included within the disclosure are pharmaceutically acceptable salts, prodrugs, isomers, or a mixture of stereoisomers thereof. In certain embodiments, provided are compounds of Table 1B for use in the methods described herein.

Speciﬁc stereoisomers plated include the following in Table 2A and Table 2B.

Table 2A [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson Structure Structure Structure [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson F F [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson Structure Structure Structure [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson or a pharmaceutically acceptable salt, deuterated analog, g, stereoisomer, or a mixture of stereoisomers thereof.

Table 2B [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson or a pharmaceutically acceptable salt, deuterated analog, prodrug, stereoisomer, or a mixture of stereoisomers thereof.

In one embodiment, a compound may be selected from those compounds in Table 2A. Also included within the disclosure are pharmaceutically able salts, gs, stereoisomers, or a mixture of stereoisomers thereof. In one embodiment, a compound may be selected from those compounds in Table 2B. Also included within the disclosure are pharmaceutically acceptable salts, deuterated analogs, prodrugs, isomers, or a mixture of stereoisomers thereof. In certain embodiments, provided are compounds of Table 2A for use in the methods described herein. In n embodiments, provided are compounds of Table 2B for use in the methods described herein. 3. Treatment s and Uses “Treatment” or “treating” is an approach for ing beneficial or desired results including clinical results. Beneficial or desired clinical results may include one or more ofthe following: a) inhibiting the disease or ion (e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent ofthe disease or condition), b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., izing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and/or preventing or delaying the spread (e.g., metastasis) of the disease or condition), and/or c) relieving the disease, that is, g the regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of r medication, ng the progression of the disease, increasing the quality of life and/or prolonging survival.

“Prevention” or “preventing” means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to p. Compounds may, in some embodiments, be administered to a subject ding a human) who is at risk or has a family history ofthe disease or condition.

“Subject” refers to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation or experiment. The methods described herein may be useful in human therapy and/or veterinary applications. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human. [0151DThe term “therapeutically effective amount” or “effective amount” of a compound described herein or a pharmaceutically acceptable salt, deuterated analog, tautomer, stereoisomer, mixture of [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson stereoisomers, g, or ated analog thereofmeans an amount ient to effect treatment when administered to a subject, to provide a therapeutic benefit such as amelioration of symptoms or slowing of disease progression. For example, a therapeutically effective amount may be an amount sufficient to decrease a symptom of a disease or condition of as described herein. The therapeutically ive amount may vary depending on the subject, and disease or condition being treated, the weight and age of the subject, the severity of the e or ion, and the manner of administering, which can readily be determined by one of ordinary skill in the art.

The methods described herein may be applied to cell populations in viva or ex viva. “In viva” means within a living individual, as within an animal or human. In this context, the methods described herein may be used therapeutically in an individual. “Ex viva” means outside of a living individual.

Examples of ex vivo cell populations include in viira cell cultures and biological s including ﬂuid or tissue samples obtained from individuals. Such samples may be obtained by methods well known in the art. Exemplary biological ﬂuid samples include blood, cerebrospinal ﬂuid, urine, and . In this context, the compounds and compositions described herein may be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions bed herein may be used ex viva to determine the optimal schedule and/or dosing of administration of a compound of the present disclosure for a given indication, cell type, individual, and other parameters. Information gleaned from such use may be used for experimental purposes or in the clinic to set protocols for in viva treatment. Other ex vivo uses for which the nds and compositions described herein may be suited are described below or will become apparent to those skilled in the art.

The selected compounds may be ﬁthher characterized to examine the safety or tolerance dosage in human or non-human subjects. Such ties may be ed using commonly known methods to those skilled in the art.

LRRK2 has been ated with the transition from mild cognitive impairment to Alzheimer’s disease, L-Dopa induced dyskinesia (Hurley et al., Eur. J, Neurosci., Vol. 26, 2007, 7), CNS disorders associated with neuroprogenitor cell proliferation and ion, and regulation of LRRK2 may have utility in improving neurological outcomes following ischemic injury, and stimulating restoration of CNS ﬁll’lCthl’l following neuronal injury such as ischemic stroke, traumatic brain injury, or spinal cord injury (Milosevic et al., Neurodegen., Vol. 4, 2009, 25, See Zhang et al., J. Neurosci. Res. Vol. 88, 2010, 3275-3281), Parkinson’s disease, Alzheimer’s e, multiple sclerosis, and HIV-induced dementia (See Milosevic et al., Mol. Neurodegen., Vol. 4, 2009, 25), , breast, prostate (e.g. solid tumor), blood and lung cancer, and acute myeologenouse leukemia (AML), mas and leukemias (See Ray et al., J. Immunolo., Vol. 230, 2011, 109), multiple myeoloma (Chapman et al., Nature, Vol. 471, 2011, 467-472), papillary renal and thyroid omas, multiple myeloma (Chapman et al., Nature, Vol. 471, 2011, 2), diseases ofthe immune , including rheumatoid arthritis, ic lupus erythegsus autoimmune hemolytic anemia, pure red cell aplasia, idiopathic thrombocytopenic pupurav(ITP), ans syndrome, vasculitis, bullous skin disorders, type 1 es mellitus, Sjogren’s syndrome, [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson Delvic’s disease, and inﬂammatory myopathies (Nakamura et al., DNA Res. Vol. 13(4), 2006, 169-183, See Engel et al., Pharmacol. Rev. Vol. 63, 2011, 127-156, Homam et al., J. Clin. Neuromuscular e, Vol. 12, 2010, 91-102), ankylosing spondylitis and leprosy infection (DAnoy et al., PLoS Genetics, Vol. 6(12), 2010, e1001195, 1-5, see Zhang et al., N. Eng. J. Med. Vol. 361, 2009, 2609-2618), alpha- synucleinopathies, taupathies (See Li et al., 2010 Neurodegen. Dis. Vol. 7, 2010, 265-271), Gaucher disease (See Westbroek et al., Trends. Mol. Med. Vol. 17, 2011, 485-493), tauopathy diseases characterized by hyperphosphorylation of Tau such as argyrophilic grain disease, Pick’s disease, corticobasal degeneration, progressive supranuclear palsy, and inherited frontotemporal dementia and parkinsonism linked to chromosome 17 (See Goedert, M and Jakes, R, Biochemica et Biophysica Acta, Vol. 1739, 2005, 240-250), diseases characterized by diminished ne levels such as withdrawal symptoms/relapse ated with drug addiction (See Rothman et al., og. Brain Res., Vol. 172, 2008, 385), microglial proinﬂammatory responses (See Moehle et al., J. Neuroscience Vol. 32, 2012, 1602- 1611), Crohn’s disease pathogenesis (see Barrett et al., Nature Genetics, Vol. 40, 2008, 955-962), and amyotrophic l sclerosis (ALS).

It is suggested that increased LRRK2 ty may be characteristic of ALS. Signiﬁcantly elevated levels of LRRK2 mRNA have been observed in fibroblasts ofNiemann-Pick Type C (NPC) disease ts, indicating abnormal LRRK2 ﬁmction may play a role in lysosomal disorders.

In another aspect, the present disclosure relates to a method of treating a disease or condition ed, at least in part, by LRRK2. In particular, the disclosure provides methods for preventing or treating a disorder associated with LRRK2 in a mammal, comprising the step of administering to said mammal a therapeutically effective amount of a compound of Table 1A or Table 1B or therapeutic preparation of the present sure. In some ments, the disease or condition ed, at least in part, by LRRK2 is a neurodegenerative disease, for example, a central nervous system (CNS) disorder, such as Parkinson's disease (PD), Alzheimer's e (AD), dementia (including Lewy body dementia and ar dementia), amyotrophic lateral sclerosis (ALS), age related memory ction, mild cognitive impairment (e.g., including the transition from mild cognitive impairment to Alzheimer’s disease), argyrophilic grain disease, lysosomal disorders (for example, Niemann-PickType C e, Gaucher disease) corticobasal degeneration, progressive supranuclear palsy, inherited frontotemporal ia and parkinsonism linked to chromosome 17 (FTDP-17), withdrawal symptoms/relapse associated with drug ion, L-Dopa induced dyskinesia, Huntington's disease (HD), and HIV- associated dementia (HAD). In other embodiments, the disorder is an ischemic disease of organs including but not limited to brain, heart, kidney, and liver.

In some other embodiments, the disease or condition mediated, at least in part, by LRRK2 is cancer. In certain specific embodiments, the cancer is thyroid, renal (including papillary renal), , lung, blood, and prostate cancers (e.g. solid tumor), leukemias (including acute enous leukemia (AMLgr lymphomas. In some embodiments, the cancer is kidney cancer, breast , prostate cancer, ood cancer, papillary cancer, lung cancer, acute myelogenous leukemia, or multiple myeloma.

[Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson In other embodiments, the tly disclosed compounds are used in methods for treatment of inﬂammatory disorders. In some embodiments, the disorder is an inﬂammatory disease ofthe intestines, such as Crohn’s disease or tive colitis (both generally known together as inﬂammatory bowel disease). In other embodiments, the inﬂammatory disease is leprosy, amyotrophic lateral sclerosis, toid arthritis, or ankylosing spondylitis. In some embodiments, the inﬂammatory disease is leprosy, Crohn’s disease, inﬂammatory bowel disease, ulcerative colitis, ophic l sclerosis, rheumatoid arthritis, or ankylosing spondylitis.

In other embodiments, the presently disclosed compounds are used in s for ent of multiple sis, systemic lupus erythematosus, autoimmune hemolytic anemia, pure red cell a, idiopathic thrombocytopenic purpura (ITP), Evans syndrome, vasculitis, bullous skin ers, type 1 diabetes mellitus, Sjogren’s syndrome, Devic’s disease, and inﬂammatory myopathies.

Other embodiments e methods for enhancing ive memory of a subject, the method comprising administering an ive amount of a composition comprising the compound of Table 1A, Table 1B, Table 2A or Table 2B to a subject in need thereof.

Other ments include use of the presently disclosed compounds in therapy. Some embodiments include their use in the treatment of a neurodegenerative disease, cancer, or an inﬂammatory disease.

In other embodiments, provided are the presently disclosed compounds for use in the treatment of Alzheimer’s disease, L-Dopa induced dyskinesia, Parkinson’s disease, dementia, ALS, kidney cancer, breast cancer, prostate cancer, blood cancer, papillary cancer, lung cancer, acute myelogenous leukemia, multiple myeloma, leprosy, Crohn’s disease, inﬂammatory bowel disease, ulcerative s, amyotrophic lateral sis, rheumatoid arthritis, or ankylosing spondylitis.

In other ments, provided is the use of the presently disclosed compounds for the manufacture of a medicament for treating a neurodegenerative disease, cancer, or an atory disease.

In other embodiments, provided is the use of the presently disclosed compounds for the manufacture of a medicament for treating Alzheimer’s disease, L-Dopa induced dyskinesia, Parkinson’s disease, dementia, amyotrophic lateral sis, kidney cancer, breast cancer, prostate cancer, blood cancer, papillary cancer, lung cancer, acute myelogenous leukemia, multiple a, leprosy, Crohn’s disease, inﬂammatory bowel e, ulcerative colitis, amyotrophic lateral sclerosis, rheumatoid arthritis, or ankylosing spondylitis.

The term “trauma” as used herein refers to any physical damage to the body caused by violence, accident, fracture etc. The term “ischemia” refers to a cardiovascular disorder characterized by a low oxygen state usually due to the obstruction of the arterial blood supply or inadequate blood ﬂow leading to hypoxia in the tissue. The term “stroke” refers to cardiovascular disorders caused by a blood clot oﬁding in the brain, most commonly caused by an interruption in the ﬂow of blood in the brain as from c ot blocking a blood vessel, and in certain embodiments of the disclosure the term stroke refers [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson to ischemic stroke or hemorrhagic stroke. The term “myocardial infarction” refers to a cardiovascular disorder characterized by localized necrosis resulting from obstruction of the blood supply.

In certain embodiments, the t disclosure relates to compounds for inhibiting cell death, wherein the compounds are shown in Table 1A, Table 1B, Table 2A or Table 2B. In certain embodiments, the compounds of the present disclosure are inhibitors of cell death. In any event, the compounds of the present disclosure preferably exert their effect on ting cell death at a concentration less than about 50 micromolar, more preferably at a tration less than about 10 micromolar, and most preferably at a tration less than 1 micromolar. 4. Kits Provided herein are also kits that include a compound of the disclosure, or a pharmaceutically acceptable salt, deuterated analog, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, and suitable packaging. In one embodiment, a kit ﬁthher includes instructions for use. In one aspect, a kit includes a compound of the disclosure, or a pharmaceutically acceptable salt, deuterated analog, er, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, and a label and/or instructions for use of the compounds in the treatment ofthe indications, including the diseases or conditions, described herein.

Provided herein are also articles of cture that include a compound described herein or a ceutically acceptable salt, deuterated analog, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof in a suitable container. The container may be a vial, jar, ampoule, preloaded syringe, and intravenous bag.

. Pharmaceutical itions and Modes of Administration nds ed herein are usually administered in the form of pharmaceutical compositions. Thus, provided herein are also pharmaceutical compositions that contain one or more of the compounds bed herein or a pharmaceutically acceptable salt, deuterated analog, er, stereoisomer, mixture of stereoisomers, prodrug, or ated analog thereof and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants and excipients. Suitable pharmaceutically acceptable es may include, for example, inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, tion enhancers, solubilizers and adjuvants. Such itions are prepared in a manner well known in the pharmaceutical art. See, e.g., ton’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. , and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (GS. Banker & C.T. Rhodes, Eds).

The pharmaceutical compositions may be administered in either single or multiple doses. The ceutical composition may be administered by various methods including, for example, rectal, , intranasal and transdermal . In certain embodiments, the pharmaceutical composition may be administered by intra-arterial ion, intravenously, intraperitoneally, parenterally, intramuscularly, subcutDJusly, orally, topically, or as an inhalant.

[Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson One mode for administration is parenteral, for example, by inj ection. The forms in which the pharmaceutical compositions bed herein may be incorporated for administration by injection include, for example, aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.

Oral administration may be another route for administration of the compounds described herein. Administration may be via, for example, e or enteric coated tablets. In making the pharmaceutical compositions that include at least one compound described herein or a pharmaceutically acceptable salt, ated analog, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, the active ient is y diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, ons, solutions, syrups, ls (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile inj ectable ons, and sterile packaged powders.

Some examples of suitable excipients e e, dextrose, sucrose, ol, mannitol, starches, gum acacia, calcium phosphate, alginates, anth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, e water, syrup, and methyl cellulose. The formulations can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil, wetting agents, fying and ding agents, preserving agents such as methyl and propylhydroxy- benzoates, sweetening agents, and ﬂavoring agents.

The compositions that include at least one compound described herein or a ceutically acceptable salt, deuterated analog, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof can be ated so as to provide quick, sustained or delayed release ofthe active ingredient after administration to the subject by employing procedures known in the art.

Controlled release drug delivery systems for oral administration include c pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations.

Transdermal patches may be used to provide continuous or discontinuous SlOl’l of the compounds described herein in controlled amounts. Transdermal patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

For preparing solid itions such as tablets, the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a neous mixture of a compound described herein or a pharmaceutically acceptable salt, ated , tautomer, stereoisomer, mixture of isomers, prodrug, or deuterated analog thereof. When referring to theneformulation compositions as homogeneous, the active ingredient may be dispersed evenly [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson throughout the ition so that the composition may be readily ided into y ive unit dosage forms such as tablets, pills and capsules.

The tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can e an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and es of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

Compositions for inhalation or insufﬂation may e solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as bed herein. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. In other embodiments, compositions in pharmaceutically acceptable ts may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be ed to a facemask tent, or intermittent positive pressure breathing machine. Solution, sion, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner. 6. Dosing The specific dose level of a compound ofthe present application for any particular subject will depend upon a variety of factors ing the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease in the subject undergoing therapy. For e, a dosage may be expressed as a number of milligrams of a nd described herein per kilogram ofthe subject’s body weight (mg/kg). Dosages of between about 0.1 and 150 mg/kg may be appropriate. In some embodiments, about 0.1 and 100 mg/kg may be appropriate. In other embodiments a dosage of n 0.5 and 60 mg/kg may be appropriate. In some embodiments, a dosage of from about 0.0001 to about 100 mg per kg of body weight per day, from about 0.001 to about 50 mg of compound per kg of body weight, or from about 0.01 to about 10 mg of compound per kg of body weight may be appropriate. Normalizing ing to the subject’s body weight is ularly USCﬁll when adjusting dosages between subjects of widely disparate size, such as occurs when using the drug in both children and adult humans or when converting an effective dosage in a non-human subject such as dog to a dosage suitable for a human subject.

The daily dosage may also be described as a total amount of a compound described herein adminged per dose or per day. Daily dosage of a compound of Table 1A, Table 1B, Table 2A or Table may be between about 1 mg and 4,000 mg, n about 2,000 to 4,000 , between [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson about 1 to 2,000 mg/day, between about 1 to 1,000 mg/day, n about 10 to 500 , between about 20 to 500 mg/day, between about 50 to 300 mg/day, between about 75 to 200 mg/day, or between about 15 to 150 mg/day.

When stered orally, the total daily dosage for a human subject may be between 1 mg and 1,000 mg, n about 1,000-2,000 mg/day, n about 10-500 mg/day, between about 50-300 mg/day, between about 75-200 mg/day, or between about 100-150 .

The nds ofthe present ation or the compositions thereofmay be administered once, twice, three, four, or more times daily, using any suitable mode described above.

In a particular embodiment, the method ses administering to the subject an initial daily dose of about 1 to 800 mg of a compound described herein and increasing the dose by increments until clinical efﬁcacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. The dosage can be increased daily, every other day, twice per week, or once per week. 7. Combination Therapy In another aspect of the disclosure the compounds can be administered in combination with other agents, including (but not limited to) compounds that are apoptosis inhibitors, PARP poly(ADP- ribose) rase inhibitors, Src inhibitors, agents for the treatment of cardiovascular disorders, hypertension, hypercholesterolemia and type II diabetes, anti-inﬂammatory agents, anti-thrombotic agents, ﬁbrinolytic agents, anti-platelet agents, lipid reducing agents, direct thrombin inhibitors, glycoprotein IIb/IIIa receptor inhibitors, calcium channel blockers, drenergic receptor blocking agents, cyclooxygenase (e.g., COX-1 and COX-2) inhibitors, angiotensin system inhibitor (e.g., angiotensin-converting enzyme (ACE) inhibitors), renin inhibitors, and/or agents that bind to cellular adhesion molecules and inhibit the ability of white blood cells to attach to such molecules (e.g., polypeptides, polyclonal and monoclonal antibodies).

In other embodiments, the compounds of the present disclosure can be administered in combination with an additional agent having activity for treatment of a neurodegenerative disease. For example, in some embodiments the compounds are administered in combination with one or more additional therapeutic agents useﬁil for treatment of Parkinson’s e. In some embodiments, the additional therapeutic agent is L-dopa (e.g., Sinemet®), a dopaminergic agonist (e.g. Ropinerol or Pramipexole), a ol-O-methyltransferase (COMT) inhibitor (e.g. Entacapone), a amine oxidase (MAO) inhibitor (e.g., line or rasagiline) or an agent which increases dopamine release (e.g., Zonisamide).

The present sure also provides combinations oftwo or more compounds that inhibit cellular necrosis (e.g., a compound as disclosed herein and an additional agent for ting necrosis).

The present disclosure also provides combinations of one or more compounds that inhibit cellular necrosis ed with one or more additional agents or compounds (e.g., other therapeutic compounds for tren a disease, condition, or infection).

[Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 8. Synthesis of the Compounds The compounds may be prepared using the methods disclosed herein and routine modiﬁcations thereof, which will be nt given the disclosure herein and methods well known in the art.

Conventional and well-known synthetic methods may be used in addition to the teachings herein. The synthesis oftypical nds described herein may be accomplished as described in the following es. If available, reagents may be purchased commercially, e.g., from Sigma h or other chemical suppliers.

The compounds of the disclosure may be prepared using methods disclosed herein and routine modiﬁcations f which will be apparent given the disclosure herein and s well known in the art. Conventional and well-known synthetic methods may be used in addition to the teachings . The synthesis of the compounds described herein may be accomplished as described in the following examples. If available, ts may be purchased commercially, e.g. from Sigma Aldrich or other chemical suppliers.

The compounds ofthis disclosure can be prepared from readily available starting materials using, for e, the following general s and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. onally, as will be nt to those skilled in the art, conventional protecting groups may be necessary to prevent certain ﬁinctional groups from undergoing undesired reactions. Suitable protecting groups for various ﬁinctional groups as well as suitable conditions for protecting and deprotecting particular ﬁinctional groups are well known in the art. For example, numerous protecting groups are described in Wuts, P. G. M., Greene, T. W., & Greene, T. W. (2006). 's protective groups in organic synthesis. n, N.J., Interscience, and references cited therein.

Furthermore, the compounds ofthis disclosure may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or ed as pure stereoisomers, i.e., as individual enantiomers or reomers or as stereoisomer-enriched mixtures. All such isomers (and enriched mixtures) are included within the scope of this disclosure, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active ng materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for e, chiral column tography, chiral resolving agents, and the like.

The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materigre available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin,aUSA), chem (Torrance, California, USA), Emka—Chemce or Sigma (St. Louis, Missouri, [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Wilkinson [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson USA). Others may be prepared by procedures or obvious modiﬁcations thereof, described in rd reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's try of Carbon Compounds, Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989) organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5th Edition, 2001), and Larock's Comprehensive c Transformations (VCH hers Inc., 1989).

The terms “solvent,” “inert organic solvent” or “inert solvent” refer to a solvent inert under the conditions of the reaction being bed in conjunction therewith (including, for e, benzene, toluene, acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, pyridine and the like). Unless specified to the contrary, the solvents used in the reactions of the present disclosure are inert organic solvents, and the reactions are carried out under an inert gas, ably nitrogen.

The term “q.s.” means adding a quantity ient to achieve a stated ﬁll’lCthl’l, e.g., to bring a solution to the desired volume (i.e., 100%).

It will also be appreciated that in each of the above schemes, the addition of any substituent may result in the production of a number of isomeric products (including, but not limited to, enantiomers or one or more diastereomers) any or all of which may be isolated and puriﬁed using conventional techniques. When enantiomerically pure or enriched nds are desired, chiral chromatography and/or enantiomerically pure or enriched starting materials may be employed as conventionally used in the art or as described in the Examples.

General Synthesis The following General Reaction Scheme I illustrates a general method of making the compounds disclosed herein.

SchemeI R2 NH2 N \ NI \ A /I + —> / HN N R3 x N R3 (Y) (Z) G Referring to General Reaction Scheme I, compounds of formula (X) are ed by coupling of a tuted pyrimidine of formula OK) with an amine of formula (Z), n R2, R3, ring B and m are defined as in any of the formulas provided herein or by the specific compounds exemplified in Table 1A, Table 1B, Table 2A or Table 2B, and X is a leaving group. In certain embodiments, X is halo.

Appropriate compounds of formula OK) or (Z) can be prepared according to the more specific methods described in the Examples which follow or by methods known to one of skill in the art. Coupling of compcﬂ: of formula OK) and (Z) in presence of an acid, provides a compound of formula (X). In some s, the acid is toluene sulfonic acid or triﬂuroacetic acid. In some [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson embodiments, coupling of compounds of a OK) and (Z) in the presence of a base provides a compound of a (X). In some embodiments, the base is triethylamine.

In one embodiment, ed is a method of preparing a compound of a (X) comprising coupling a compound of formula OK) with a compound of formula (Z) under conditions to provide the compound of formula (X), wherein R1, R2, R3, ring B and m are defined as in any of the formulas provided herein or by the specific compounds exemplified in Table 1A, Table 1B, Table 2A or Table 2B, and X is a g group. In certain embodiments, X is halo.

When not commercially available, amines of a (Z) can be prepared from commercially available ng materials. For example, in certain embodiments, amines of formula (Z) can be prepared from reducing the corresponding nitro substituted compound. The amines of a (Z) are typically ﬁinctionalized prior to the coupling with the substituted pyrimidine of formula (Y). Where a certain stereoisomer is desired (e.g., a cis- or trans- isomer of formula III, IIIA, or IIIB), a single stereoisomer of the corresponding amine may be ed prior to coupling with the substituted pyrimidine of formula (Y). Each of the cis- and trans- isomers can be prepared by selectively inverting the stereochemistry prior to the installation of the cyano moiety on the cyclobutyl ring. In certain embodiments, amines of formula (Z) are prepared via l,3-dipolar cycloaddition reactions using appropriately ﬁinctionalized ng materials. Further ﬁmctionalization or ﬁinctional group interconversion may be performed before or after the cycloaddition reaction.

In certain embodiments, compounds of formula Ia can be prepared according to Scheme II.

Scheme 11 _\ 0 R8 X \ R8 R8 R O I \ R7 /N\ /N\ HN —> N —> N N R9 2-2 R7 N R9 R R9 2-1 2-3 R2 2-5 ACEN \ R2 1 A / R, 3 R1N x N R \ N \ ‘ l N\ R8 N\ R8 (Y) ,N\ NI \ R6 N\ / R6 R N R9 R7 \N/ [0199D Referring to General Reaction Scheme II, compounds of formula (2-3) can be prepared by coupling appropriately substituted triazole (2-1) with appropriately substituted ester (2-2). Conversion of [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson the ester of compound (2-3) to the noketone compound (2-4) can be lished under substitution reaction conditions using a strong base (e.g., butyllithium) and acetonitrile. Contacting compound (2-4) with an appropriately substituted ine (2-5) or salt thereof, provides an amine of formula (2-6). Coupling of the amine of formula (2-6) with the appropriately substituted pyrimidine of formula (Y) can be accomplished according to Scheme 1, thus providing the compounds of formula Ia.

The following examples are included to trate specific embodiments of the disclosure.

It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques to ﬁmction well in the practice of the disclosure, and thus can be ered to constitute specific modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope ofthe disclosure.

General Experimental Methods: All non-aqueous reactions were d out in ried or ﬂame-dried glassware under nitrogen atmosphere. All chemicals were purchased from commercial vendors and used as is, unless otherwise specified. ons were magnetically d and monitored by thin layer chromatography (TLC) with 250nm pre-coated silica gel , visualized either with UV, or in an iodine chamber. Flash column chromatography was performed using silica gel (100—200 mesh). Chemical shifts are reported relative to chloroform (57.26), methanol (53.31), or DMSO (62.5 0) for 1H NMR. HPLC analysis was performed on Shimadzu 20AB HPLC system with a photodiode array detector and Luna-C18(2) mm, 5um column at a ﬂow rate of 1.2 mL/min with a gradient solvent Mobile phase A (MPA, H20+0.037 % (v/v) TFA): Mobile phase B (MPB, ACN+0.018 % (v/v) TFA) (0.01 min, 10% MPB, 4 min, 80% MPB, 4,9 min, 80% MPB, 4.92 min, 10% MPB, 5.5 min, 10% MPB). LCMS was detected under 220 and 254 nm or used evaporative light scattering (ELSD) ion as well as positive electrospray ionization (MS). reparative HPLC was performed by either acidic or neutral condition. Acidic: Luna C18 100X30 mm, 5pm, MPA: HCl/HzO=0.04%, or formic acid/HzO=0.2% (v/v), MPB: ACN. Neutral: Waters Xbridge 150X25, 5um, MPA: 10mM NH4HC03 in H20, MPB: ACN. Gradient for both conditions: 10% of MPB to 80% ofMPB within 12 min at a ﬂow rate of 20 mL/min, then 100% MPB over 2 min, 10% MPB over 2 min, UV detector. SFC analysis was performed on Thar analytical SFC system with a UV/Vis detector and series of chiral columns including AD-3, AS- H, OJ-3, OD-3, AY-3 and IC-3, 4.6x 100mm, 3um column at a ﬂow rate of 4 mL/min with a gradient solvent Mobile phase A (MPA, C02): Mobile phase B (MPB, MeOH+0.05 % (v/v) IPAm) (0.01 min, % MPB, 3 min, 40% MPB, 3.5 min, 40% MPB, 3.56-5 min, 10% MPB). SFC preparative was performed on Thar 80 ative SFC system with a UV/Vis detector and series of chiral preparative columncluding AD-H, AS-H, OJ-H, OD-H, AY-H and IC-H, 30X250 mm, 5um column at a ﬂow rate [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Wilkinson ation] Sarah.Wilkinson Unmarked set by Wilkinson of 65 mL/min with a gradient solvent Mobile phase A (MPA, C02): Mobile phase B (MPB, MeOH+0.1 % (v/v) NH3H20) (0.01 min, 10% MPB, 5 min, 40% MPB, 6 min, 40% MPB, 61-10 min, 10% MPB).

Compounds were named by using either ChemBioDraw Ultra 13.0 or chemaxon.

CompoundPreparation Where the preparation of ng materials is not described, these are commercially available, known in the literature or readily obtainable by those skilled in the art using standard procedures. Where it is stated that compounds were prepared analogously to earlier es or intermediates, it will be appreciated by the skilled person that the reaction time, number of equivalents of reagents and temperature can be modiﬁed for each speciﬁc reaction and that it may be necessary or ble to employ different work-up or puriﬁcation techniques. Where reactions are carried out using microwave irradiation, the microwave used is a Biotage tor. The actual power supplied varies during the course of the reaction in order to maintain a constant temperature.

EXAMPLE 1 Synthesis of N4-ethyl-N2-[1-(3-isocyanocyclobutyl)—5-methyl-pyrazolyl]-5— (triflu0r0methyl)pyrimidine-2,4-diamine (26) 3-(benzyloxy)cyclobutanol: To a stirring solution of yloxycyclobutanone (125 g, 709.38 mmol) in MeOH (1.5 L) was added NaBH4 (26.84 g, 709.38 mmol) portionwise at -20°C under N2 over a period of 4 h. After addition, the mixture was d to warm to 25 OC and stirred for 30 min.

The mixture was added with water (50 mL) and stirred for 30 min. The mixture was concentrated under reduced pressure to give a residue. (Two batches of the same scale were combined to workup.) The residue was puriﬁed by silica gel column chromatography (PE:EtOAc = 6: 1) to afford (1S,3S) (benzyloxy)cyclobutanol as a colorless oil. 1-(3-(benzyloxy)cyclobutyl)nitr0-lH-pyrazole: To a mixture of (1S,3S) (benzyloxy)cyclobutanol (250 g, 1.40 mol) and 4-nitro-1H-pyrazole (158.3 g, 1.40 mol) in THF (5 L) was added PPh3 (477.37 g, 1.82 mol) and DIAD (368.02 g, 1.82 mol, 353.87 mL) dropwise at 0°C under N2, After addition, the mixture was stirred at 25 0C for 16 h. The mixture was concentrated in reduced pressure to give a residue. The residue was triturated with PE:EtOAc=2: 1 (2 L) and ﬁltered.

The ﬁlter cake was washed with PE: EtOAc= 2: 1 (2 X 1 L) and the combined e were concentrated to afford a crude product. The crude product was puriﬁed by silica gel column chromatography (PE: EtOAc = 6: 1) to afford 1-((1R,3R)(benzyloxy)cyclobutyl)nitro-1H-pyrazole as a white solid.

LCMS: RT 0.851 min, m/z = 274.2 [M+H]+. 1H NMR (400 MHz, CDC13) 5 8.15 (s, 1H), 8.12 (s, 1H), 7.29-7.41 (m, 5H), 4.92-4.99 (m, 1H), 4.49 (s, 2H), 4.41-4.47 (m, 1H), .84 (m, 4H). 1-(3-(benzy10xy)cycl0butyl)chl0r0nitr0-1H-pyrazole: To a solution of 1-((1R,3R) (benzyloxy)cyclobutyl)nitro-1H-pyrazole (80 g, 292.73 mmol) in THF (1.6 L) was added LiHMDS (1 M, 567.90 mL) dropwise at -75 0C under N2 over a period of 1 h. After addition, the mixture was stirred for 1 Ipn the solution of 2,2,2-hexachloroethane (83.16 g, 351.28 mmol) in THF (200 mL) was added rop wise at -78°C. The mixture was stirred at -78 OC and stirred for 1 h. The mixture was poured [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson into aqueous NH4Cl (1.5 L). The organic phase was separated and the aqueous phase was extracted with EtOAc (2 X 500 mL). The combined organic phase was washed with brine (1 L), dried with anhydrous Na2SO4, ﬁltered and concentrated under d pressure. The residue was puriﬁed by silica gel column chromatography (PE: EtOAc = 10: 1) to afford 1-((1R,3R)(benzyloxy)cyclobutyl) chloronitro-1H-pyrazole as a white solid. 1H NMR (400 MHz, CDCl3) 5 8.21 (s, 1H), 7.29-7.41 (m, 5H), 5.16-5.24 (m, 1H), 4.50 (s, 2H), 4.42-4.47 (m, 1H), 2.81-2.89 (m, 2H), 2.61-2.70 (m, 2H). 1-(3-(benzyloxy)cyclobutyl)—5-methylnitro-1H—pyrazole: To a mixture of 1-((1R,3R) (benzyloxy)cyclobutyl)chloronitro-1H-pyrazole (65 g, 211.22 mmol), 2,4,6-trimethyl-1,3,5,2,4,6- trioxatriborinane (212.12 g, 844.90 mmol, 235.69 mL) and Na2C03 (44.78 g, 422.45 mmol) in 1,4- e (1.5 L) and H20 (150 mL) was added Pd(dppf)Cl2.CH2Cl2 (27.6 g, 33.80 mmol) at 25 0C under N2. The mixture was then heated to 100 OC and stirred for 40 h. The e was cooled to 25 OC and trated under reduced pressure to dryness. The residue was dissolved in PE: EtOAc = 2: 1 (2 L), then added with anhydrous Na2SO4 (100 g), celite (100 g) and stirred for 30 min. The mixture was ﬁltered through a pad of celite. The ﬁlter cake was washed with PE: EtOAc = 2: 1 (2 X 1 L) and the ﬁltrate was concentrated under reduced pressure to give a residue. The residue was puriﬁed by silica gel column chromatography (PE: EtOAc = 10: 1) to afford 1-((1R,3R)(benzyloxy)cyclobutyl)methyl nitro-1H-pyrazole as a white solid. LCMS: RT 0.844 min, m/z = 288.2 [M+H]+. 3—(5-methylnitr0-1H-pyrazolyl)cyclobutanol: To a solution of 1-((1R,3R) (benzyloxy)cyclobutyl)methylnitro-1H-pyrazole (59.5 g, 207.09 mmol) in DCM (1.2 L) was added BC13 (1 M, 621.27 mL) dropwise at 0°C under N2 over a period of 2 h. The mixture was then stirred at 0 0C for 1 h. The mixture was poured into ice-water (600 mL). The aqueous phase was ted with DCM (2 X 600 mL). The combined organic phase was washed with aqueous NaHC03 (500 mL), brine (500 mL), dried with anhydrous Na2SO4, d and concentrated under reduced pressure. (Four batches of the same scale were combined to workup) The residue was puriﬁed by silica gel column chromatography (PE: EtOAc = 1: 1) to afford (1R,3R)(5 -methylnitro-1H-pyrazol lobutanol as white solid. 1H NMR (400 MHz, CDCl3) 5 8.10 (br d, J=4.63 Hz, 1H), 4.98-5.03 (m, 1H), 4.70-4.82 (m, 1H), 2.85-2.97 (m, 2H), 2.59-2.66 (m, 3H), .58 (m, 2H), 2.38 (br s, 1H). 1-(3-i0docyclobutyl)methylnitr0-1H-pyrazole: To a mixture of (1R,3R)(5-methyl nitro-1H-pyrazolyl)cyclobutanol (70 g, 354.99 mmol), PPh3 (139.66 g, 532.49 mmol) and imidazole (36.25 g, 532.49 mmol) in THF (1.2 L) was added the on of 12 (135.15 g, 532.49 mmol) in THF (200 mL) dropwise at 0 0C under N2. After that the mixture was stirred at 25 0C for 16 h. The mixture was poured into ice-water (500 mL). The aqueous phase was extracted with EtOAc (2 X 300 mL). The ed organic phase was washed with brine (500 mL), dried with anhydrous Na2SO4, ﬁltered and concentrated under reduced pressure. The residue was puriﬁed by silica gel column chromatography (PE: EtOAc = 10: 1) to afford 1-((1R,3R)-3 -iodocyclobutyl)-5 -methylnitro-1H-pyrazole as white solid. 1HN 00 MHz, CDCl3) 5 8.14 (s, 1H), 4.61-4.83 (m, 1H), 4.12-4.34 (m, 1H), 3.09-3.36 (m, 4H), 2.61 (ﬁgs.

[Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 3-(5-methylnitr0-pyrazolyl)cyclobutanecarbonitrile: To a solution of l-(3- iodocyclobutyl)methylnitro-pyrazole (2 g, 6.51 mmol) in DMF (30 mL) was added KCN (2.5 g, 39.06 mmol) at 0°C. Then the mixture was stirred at 70°C for 2 days. The mixture was diluted with water (60 mL), extracted with EtOAc (4 x 20 mL). The combined organic layers were washed with water (2 x 50 mL), brine (50 mL), dried over Na2SO4, ﬁltered and concentrated. The crude product was d by silica gel column chromatography (PEzEtOAc = 1:0 to 1:1) to give 3-(5 -methylnitro- pyrazol-l-yl)cyclobutanecarbonitrile as a yellow solid. LCMS: RT 1.066 min, m/z = 207.3 [M+H]+. 1H NMR (400 MHz, CDCl3) 5 ppm 8.16 (s, 1 H), 5.11 (quin, J=7.81 Hz, 1 H), 3.32 - 3.47 (m, 1 H), 3.08 - 3.21 (m, 2 H), 2.85 - 2.95 (m, 2 H), 2.67 (s, 3 H), 1.59 (s, 1 H). 3-(4-amin0-5—methyl-pyrazolyl)cyclobutanecarbonitrile: To a mixture of 3-(5-methyl nitro-pyrazolyl)cyclobutanecarbonitrile (200 mg, 969.93 umol), NH4Cl (259 mg, 4.85 mmol) in the mixture of EtOH (4.8 mL) and H20 (1.2 mL) was added Fe (270 mg, 4.85 mmol) at 15°C. The mixture was stirred at 80°C for 2 h. The mixture was ﬁltered and the ﬁltrate was concentrated under reduced pressure. The residue was diluted with water (10 mL), ted with EtOAc (10 x 5 mL). The combined c layers were dried over Na2SO4, d and concentrated to give 3-(4-amino-5 -methyl- pyrazol-l-yl)cyclobutanecarbonitrile. LCMS: RT 0.101 min, m/z = 177.2 . ro-N-ethyl-S-(trifluoromethyl)pyrimidinamine: To a solution of 2,4-dichloro (triﬂuoromethyl)pyrimidine (70 g, 322.61 mmol) in THF (1.4 L) was added a solution of mine (32 g, 709.74 mmol, 46.37 mL) in THF (100 mL) dropwise at 0°C under N2 over a period of l h. After addition, the mixture was stirred at 25 °C for l h. The mixture was ﬁltered and concentrated under reduced re to afford a residue. The residue was triturated with DCM (200 mL) and ﬁltered. The ﬁltrate was recrystallizated with n-heptane (600 mL) and MTBE (400 mL). The precipitated phase was syrup. The liquid was ded. The syrup residue was puriﬁed by silica gel column chromatography (PEzEtOAc = 20: 1) to afford 2-chloro-N-ethyl-5 -(triﬂuoromethyl)pyrimidinamine as a white solid. 1H NMR (400 MHz, CDC13): 5 8.22-8.27 (m, 1H), 5.40 (br s, 1H), 3.56-3.65 (m, 2H), 1.29 (t, J=7.22 Hz, 3H). HPLC: RT: 2.68 min.

N4—ethyl-N2-[1-(3-isocyanocyclobutyl)methyl-pyrazol-4—yl] (trifluoromethyl)pyrimidine-2,4-diamine: A mixture of 1-(3-isocyanocyclobutyl)methyl-pyrazol amine (170 mg, 964.70 umol), 2-chloro-N-ethyl(triﬂuoromethyl)pyrimidinamine (217 mg, 964.70 umol,), p-TsOH.H20 (55 mg, 289.41 umol) in 1,4-dioxane (10 mL) was stirred at 90°C for 2 h. The mixture was concentrated under reduced re. The residue was diluted with water (20 mL), extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over Na2SO4, ﬁltered and concentrated. The crude product was puriﬁed by prep-TLC (DCM:MeOH = 15 : l) to give yl-N2-[1-(3-isocyanocyclobutyl)methyl-pyrazolyl] (triﬂuoromethyl)pyrimidine-2,4-diamine. 1H NMR (400 MHz, CDCl3) 5 ppm 8.10 (s, 1 H), 7.65 - 7.93 (m, 1U15 - 6.60 (m, 1 H), 4.91 - 5.15 (m, 2 H), 3.44 - 3.55 (m, 2 H), 3.23 - 3.35 (m, 1 H), 3.07 - 3.21 [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson (m, 2 H), 2.75 - 2.89 (m, 2 H), 2.20 (s, 3 H), 1.61 (br s, 1 H), 1.25 (t, J=7.1Hz, 3 H). HPLC: RT: 1.73 min. MS: m/z = 366.2 [M+H]+.

EXAMPLE 2 Synthesis of [9] N4-ethyl-N2-[1-(2H3))methyl[2-(2H—1,2,3-triazolyl)propan-Z-yl]-1H-pyrazol yl](triflu0r0methyl)pyrimidine-2,4-diamine (34) Ethyl 2-methyl(2H—1,2,3-triazolyl)propanoate: To a mixture of 2H-triazole (20 g, 289.56 mmol) in DMF (200 mL) was added t—BuOK (48.74 g, 434.34 mmol) at 0°C. After the addition, ethyl 2-bromomethy1-propanoate (78.63 g, 434.34 mmol) was added dropwise at 0 0C, then the mixture was stirred at 25 0C for 3 h. The mixture was poured into ter (70 mL) and stirred for 5 min. The aqueous phase was extracted with EtOAc (3 X 300 mL). The ed organic phase was washed with brine (2 X 200 mL), dried with anhydrous Na2SO4, d and concentrated under reduced pressure. The residue was puriﬁed by silica gel column chromatography (PEzEtOAc = 3: 1) to give ethyl yl(1H-1,2,3-triazolyl)propanoate and isomer ethyl 2-methyl(2H-1,2,3-triazol yl)propanoate. LCMS: RT 0.565 min, m/z = 184.1 [M+H]+. 1H NMR (400 MHz, CDC13): 5 ppm 7.64 (s, 2 H), 4.12 — 4.18 (m, 2 H), 1.95 (s, 6 H), 1.18 (t, J=7.28 Hz, 3 H). Undesired isomer, ethyl 2-methyl- 2-(1H-1,2,3-triazolyl)propanoate. 1H NMR (400 MHz, CDC13)I 5 ppm7.70 (d, J=6.40 Hz,2 H), 4.14 — 4.19 (m, 2 H), 1.94 (s, 6 H), 1.20 (t, J=7.28 Hz, 3 H). 4-Methyl0x0(2H-1,2,3-triazolyl)pentanenitrile: To a mixture of MeCN (96.88 mg, 2.36 mmol) in THF (10 mL) was added n-BuLi (2.5 M, 0.94 mL) dropwise at -78°C under N2. After 0.5 h, ethyl y1(2H-1,2,3-triazoly1)propanoate (200 mg, 2.36 mmol) was added se over 1 h at -78 0C, then the reaction was stirred at -78 0C for 2 h. The mixture was poured into ice-water (20 mL) and stirred for 5 min. The mixture was adjusted to pH = 5~6 by HCl (1 M). The aqueous phase was extracted with ethyl acetate EtOAc (3 X 10 mL). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na2SO4, ﬁltered and concentrated. The residue was puriﬁed by silica gel column chromatography ( PEzEtOAc = 10:1 to 1:1) to give 4-methy1oxo(2H-1,2,3-triazol yl)pentanenitrile. LCMS: RT 0.945 min, m/z = 179.1 [M+H]+. 1H NMR (400 MHz, CDC13): 5 ppm 7.76 (s, 1 H), 3.11 (s, 2 H), 1.90 (s, 6 H). 1-(2H3)Methyl[2-(2H—1,2,3-triazolyl)pr0panyl]-1H-pyrazolamine: To a solution of 2 (250 mg, 1.4 mmol), trideuteriomethylhydrazine (512.4 mg, 4.2 mmol 2HC1, 3 equiv) in EtOH (20 mL) was added dropwise TEA (992 mg, 9.8 mmol, 1.36 mL, 7 equiv) at 0 °C. After addition, the e was stirred at 95 0C for 4 h. The on mixture was concentrated to get a residue, which was d with H20 (5 mL) and extracted with EtOAc (3 X 5 mL), dried over Na2SO4, ﬁltered and concentrated under reduced pressure to give 1-(2H3)methy1[2-(2H-1,2,3-triazoly1)propanyl]-1H- pyrazolamine. LCMS: RT 0.236 min, m/z = 210.2 [M+H]+. 1H NMR (400 MHz, CDCl3)I 5 ppm 7.61 (s, 1 H), 5.25 (s, 1 H), 3.39 (br s, 1 H), 2.05 (s, 3 H).

N4-Ethyl-N2-[1-(2H3)methyl[2-(2H—1,2,3-triazol-Z-yl)propanyl]-1H-pyrazolyl] (trifluoromethyl)pyrimidine-2,4-diamine: To a solution of 1-(2H3)methyl[2-(2H-1,2,3-triazol [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson yl)propanyl]-1H-pyrazolamine (100 mg, 477.85 umol) and 2-chloro-N-ethyl oromethyl)pyrimidinamine (107.8 mg, 477.85 umol) in 1,4-dioxane (10 mL) was added p-TsOH (24.69 mg, 143.36 umol). The mixture was stirred at 90 0C for 3 h. The reaction e was concentrated under reduced pressure. The residue was diluted with H20 (5 mL) and adjusted to pH = 8-9 with aq. NaHC03 and extracted with EtOAc (3 X 8 mL). The ed organic layers were washed with brine (10 mL), dried over , ﬁltered and concentrated under reduced re. The residue was puriﬁed by prep-TLC (PEzEtOAc = 1:1) and trituration with n-heptane to give N4-ethyl-N2-[l- (2H3)methyl-3 -[2-(2H-1,2,3 -triazolyl)propanyl]-1H-pyrazol-5 -yl] -5 -(triﬂuoromethyl)pyrimidine- 2,4-diamine. 1H NMR (400 MHz, CDCl3)I 5 ppm 8.10 (s, 1 H), 7.62 (s, 2 H), 6.73 (br s, 1 H), 6.03 (s, 1 H), 5.15 (br s, 1 H), 3.35 - 3.44 (m, 2 H), 2.11 (s, 6 H), 1.18 — 1.21 (t, J=7.28 Hz, 3 H). HPLC: RT 2.24 min, m/z: 399.2 [M+H]+.

EXAMPLE 3 Synthesis of N2-[2-cyclopr0pyl[1-methyl(triaz01—2—yl)ethyl]pyrazolyl]-N4-ethyl (triflu0r0methyl)pyrimidine-2,4-diamine (78) 4-methyl0x0(triazol-Z-yl)pentanenitrile: To a mixture of 2H-triazole (20 g, 289.56 mmol) in DMF (200 mL) was added t—BuOK (48.74 g, 434.34 mmol) in one portion at 0°C under N2.

After addition, methyl 2-bromomethyl-propanoate (78.63 g, 434.34 mmol, 56.16 mL) was added dropwise. The mixture was stirred at 25 0C for 3 h. The residue was poured into ice-water (700 mL) and stirred for 5 min. The aqueous phase was extracted with EtOAc (3 X300 mL). The ed organic phase was washed with brine (2 X 100 mL), dried over anhydrous Na2SO4, ﬁltered and concentrated under reduced pressure. The residue was puriﬁed by silica gel column chromatography OAc =10:l to 3: 1) to give methyl 2-methyl(triazolyl)propanoate as a yellow oil. 1H NMR (400 MHz, CDCl3)I 5 ppm 7.649 (s, 2H), 3.701 (s, 3 H), 1.963 (s, 6 H). 4-methyl0x0(triazol-Z-yl)pentanenitrile: To a solution of CH3CN (485.21 mg, 11.82 mmol) in THF (20 mL) was added dropwise n-BuLi (2.5 M, 4.73 mL) at -78 0C over 10 min. After addition, the mixture was stirred at this temperature for 50 min, and then methyl yl(triazol yl)propanoate (l g, 5.91 mmol) was added se at -78 OC. The resulting e was stirred at -78 0C for 2 h. The reaction e was poured into ice-water (50 mL), adjusted to pH=5-6 with HCl (1N) and extracted with EtOAc (3 X 20 mL). The combined organic layers were washed with brine (10 mL), dried over , ﬁltered and concentrated under reduced re. The residue was puriﬁed by silica gel column chromatography (PE: EtOAc = 10:1 to 1: 1) to give 4-methyloxo(triazol yl)pentanenitrile as a yellow solid. 1H NMR (400 MHz, CDCl3)I 5 ppm 7.761 (s, 2H), 3.106 (s, 2 H), 1.904 (s, 6 H). 2-cyclopr0pyl[1-methyl(triaz01—2—yl)ethyl]pyrazolamine: To a mixture of 4-methyl- 3-oxo(triazolyl)pentanenitrile (400 mg, 2.24 mmol) and cyclopropylhydrazine dihydrochloride was(974.6q 6.72 mmol) in EtOH (10 mL) was added HCl (12 M, 560 uL) at 25°C under N2.The mixturest1rre at 90 0C for 12 h. The mixture was concentrated. The residue was poured into aq. NaHC03 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson (10 mL) and stirred for 5 min. The aqueous phase was extracted with EtOAc (3 X 5 mL). The combined organic phase was dried with anhydrous Na2SO4, ﬁltered and concentrated under reduced re. The residue was puriﬁed by LC (PE: EtOAc = 1/ 1) to give 2-cyclopropyl[1-methyl(triazol yl]pyrazolamine as a yellow oil. 1H NMR: (400 MHz, CDCl3)I 5 ppm 7.756-7.722 (d, J = 13.6 Hz, 1 H), 7.616 (s, 1 H), 2.041 (s, 6 H), 1.139~1.100 (m, 2 H), 1.022-1.004 (m, 2 H).

N2-[2-cyclopr0pyl[1-methyl(triazolyl)ethyl]pyrazolyl]-N4-ethyl u0r0methyl)pyrimidine-2,4-diamine: A mixture of 2-cyclopropyl[1-methyl(triazol yl)ethyl]pyrazolamine (77 mg, 331.5 umol), 2-chloro-N-ethyl(triﬂuoromethyl)pyrimidinamine (74.79 mg, 331.5 umol) and p-TsOH.H20 (31.53 mg, 165.75 umol) in 1,4-dioxane (10 mL) was stirred at 90 0C for 3 h under N2. The reaction mixture was quenched by sat. NaHC03 (10 mL) and extracted with EtOAc (2 X 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, ﬁltered and concentrated under reduced pressure. The residue was d by prep-TLC (SiOz, PEzEtOAc = 1: 1) and ﬁthher puriﬁcation by prep-HPLC (FA) to give N2-[2-cyclopropyl[1-methyl (triazolyl)ethyl]pyrazolyl]-N4-ethyl(triﬂuoromethyl)pyrimidine-2,4-diamine. 1H NMR (400 MHz, CDCl3)I 5 8.13 (s, 1H), 7.62 (s, 2H), 7.30 (br s, 1H), 6.13 (s, 1H), 5.18 (br s, 1H), 3.38-3.47 (m, 2H), 3.24 (tt, J= 3.59, 6.95 Hz, 1H), 2.10 (s, 6H), 1.24 (t, J: 7.22 Hz, 3H), 1.09-1.21 (m, 4H). HPLC: RT 2.61 min. MS: m/z: 422.3 [M+H]+.

EXAMPLE 4 Synthesis of (3S)— and (3R)—3-[1-cyclopr0pyl-5—[[4-(ethylamin0)(triflu0r0methyl)pyrimidin yl]amin0]pyrazolyl]methyl-tetrahydrofuran-Z-one (143 and 144) Tert—butyl N-(l-methylcycl0pr0pyl)carbamate: To a mixture of sodium (5.34 g, 232.32 mmol) in diethyl carbonate (50 mL) was added a solution oftetrahydroﬁJranone (20 g, 232.32 mmol) in diethyl carbonate (25 mL) at 100 0C over a period of 3 h. The mixture was cooled to 20 OC and quenched by ice sat. NH4Cl, then adjusted to pH=5 by adding 1N HCl. The aqueous phase was extracted with EtOAc (3 X 30 mL). The combined organic phase was washed with brine (2 X 20 mL), dried over anhydrous Na2SO4, ﬁltered and trated under reduced pressure. The residue was puriﬁed by silica gel column chromatography (PE: EtOAc = 10:1 to 0: 1) to give ethyl 2- oxotetrahydroﬁJrancarboxylate as a light yellow oil. 1H NMR (400 MHz, CDCl3)I 5 ppm 4.49 (td, J = 8.47, 5.52 Hz, 1 H), 4.34 (dt, J= 8.69, 7.45 Hz, 1 H), 4.24 - 4.30 (m, 2 H), 3.55 (dd, J: 9.35, 7.59 Hz, 1 H), 2.69 (dq, J= 13.07, 7.57 Hz, 1 H), 2.51 (dddd, J= 13.08, 9.32, 7.59, 5.52 Hz, 1 H), 1.32 (t, J: 7.09 Hz, 3 H).

Ethyl 3-methyl0x0-tetrahydr0furancarboxylate: To a on of ethyl 2- oxotetrahydroﬁJrancarboxylate (6.9 g, 43.63 mmol) in THF (150 mL) was added NaH (1.92 g, 47.99 mmol, 60% purity) at 0 0C over 30 min. After addition, the e was d at 20 0C for 30 min, and then MeI (9.29 g, 65.45 mmol, 4.07 mL) was added dropwise at 0 0C over 30 min. The ing mixture was st' at 20 0C for 10.5 h. The reaction mixture was poured into aqueous sat. NH4Cl solution at 0 OC ancgracted with EtOAc (3 X 50 mL). The combined organic layers were washed with brine (30 [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson mL), dried over anhydrous Nast4, ﬁltered and concentrated under reduced pressure. The residue was puriﬁed by silica gel column chromatography (PE: EtOAc = 20:1 to 1: 1) to give ethyl 3-methyloxotetrahydroﬁJrancarboxylate as a yellow oil. 1H NMR (400 MHz, CDCl3)I 5 ppm 4.32 - 4.44 (m, 2 H) 4.24 (q, J= 7.20 Hz, 2 H), 2.76 (ddd, J: 13.01, 7.06, 4.19 Hz, 1 H), 2.20 (dt, J= 13.23, 8.38 Hz, 1 H), 1.54 (s, 3 H), 1.30 (t, J: 7.17 Hz, 3 H). 3—(3-methyl-Z-oxo-tetrahydrofuranyl)—3-0x0-pr0panenitrile: To a solution of CH3CN (1.2 g, 30.03 mmol, 1.58 mL) in THF (50 mL) was added dropwise n-BuLi (12.01 mL, 2.5 M) at -78 0C over 30 min under N2. After addition, the mixture was stirred at this temperature for 30 min. The suspension mixture was added dropwise to a on of ethyl 3-methyloxo-tetrahydroﬁ1ran carboxylate (4.7 g, 27.30 mmol) in THF (50 mL) at -78 0C for 30 min. The resulting mixture was warmed to -40 OC and stirred at -40 0C for 1.5 h. The reaction mixture was ed by addition of sat.

NH4Cl at 0 OC, and then adjusted to pH=4-5 with 1N HCl and extracted with EtOAc (3 X 50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Nast4, ﬁltered and trated under reduced re to give 3-(3 -methyloxo-tetrahydrofuran-3 -yl)oxo- propanenitrile as a yellow solid, which was used in next step t further puriﬁcation. 1H NMR (400 MHz, CDCl3)I 5 ppm 4.29 - 4.46 (m, 2 H), 3.79 - 4.12 (m, 2 H), 3.03 (ddd, J=13.40, 7.55, 6.17 Hz, 1 H), 2.10 (dt, J=13.73, 7.14 Hz, 1 H), 1.60 (s, 3 H). 3-(5-amin0cyclopropyl-pyraz01yl)methyl-tetrahydrofuran-Z-one: A mixture of 3- (3-methyloxo-tetrahydroﬁJranyl)oxo-propanenitrile (200 mg, 1.2 mmol) and cyclopropylhydrazine ochloride salt (174 mg, 1.2 mmol) in i-PrOH (5 mL) was stirred at 50 0C for 16 h under N2. The reaction solution was adjusted to pH=7 with sat. NaHCOg, extracted with EtOAc (3 X 5 mL). The organic layers were combined, washed with brine (5 mL), dried over anhydrous Nast4, ﬁltered and concentrated under reduced pressure. The crude product was puriﬁed by prep-TLC (DCMzMeOH = 10: 1) to give 3-(5-aminocyclopropyl-pyrazolyl)methyl-tetrahydroﬁ1ranone as a yellow oil. 1H NMR (400 MHz, CDCl3)I 5 ppm 5.47 (s, 1 H), 4.24 - 4.41 (m, 2 H), 3.76 - 3.94 (br, 2 H), 3.04 - 3.14 (m, 1 H), 2.89 - 3.02 (m, 1 H), 2.12 - 2.28 (m, 1 H), 1.53 (s, 3 H), 0.95 - 1.04 (m, 4 H). (3S) and (3R) N2-[5—cyclopr0pyl[3-(triazol-Z-yl)cyclobutyl]pyrazolyl]-N4-ethyl (trifluoromethyl)pyrimidine-2,4-diamine: To a solution of 3-(5-aminocyclopropyl-pyrazolyl) methyl-tetrahydroﬁ1ranone (90 mg, 406.76 umol) in 1,4-dioxane (5 mL) was added 2-chloro-N-ethyl- -(triﬂuoromethyl)pyrimidinamine (91.77 mg, 406.76 umol) and p-TsOH (14.01 mg, 81.35 umol).

The mixture was stirred at 90 0C for 10 h. The reaction solution was ed to pH=7 with sat.NaHC03, extracted with EtOAc (3 X 5 mL). The organic layers were ed, washed with brine (5 mL), dried over anhydrous Nast4, ﬁltered and trated under reduced pressure. The crude product was puriﬁed by prep-TLC (PE: EtOAc = 1: 1) to give a mixtures of enantiomers, which were separated by [0227 irst eluting isomer: 1H NMR (400 MHz, CDCl3)I 5 ppm 8.09 (s, 1 H), 7.16 (br s, 1 H), 6.55 (s,1 .17 (br s, 1 H), 4.20 - 4.32 (m, 2 H), 3.48 - 3.57 (m, 2 H), 3.12 - 3.20 (m, 1 H), 2.93 (ddd, J: [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 12.58, 6.49, 4.02 Hz, 1 H), 2.19 (dt, J= 12.58, 8.52 Hz, 1 H), 1.53 (s, 3 H), 1.24 (t, J: 7.22 Hz, 3 H), 1.02 - 1.13 (m, 4 H). HPLC: RT: 2.33 min. MS: m/z: 411.2 [M+H]+.

Second eluting isomer: 1H NMR (400 MHz, CDCl3)I 5 ppm 8.17 (d, J: 0.75 Hz, 1 H), 7.28 (br s, 1 H), 6.62 (s, 1 H), 5.26 (br s, 1 H), 4.28 - 4.42 (m, 2 H), 3.55 - 3.66 (m, 2 H), 3.17 - 3.28 (m, 1 H), 3.01 (ddd, J: 12.61, 6.46, 4.02 Hz, 1 H), 2.26 (dt, J= 12.55, 8.47 Hz, 1 H), 1.53 - 1.64 (m, 3 H), 1.32 (t, J: 7.22 Hz, 3 H), 1.10 - 1.21 (m, 5 H). HPLC: RT: 2.33 min. MS: m/z: 411.2 [M+H]+.

EXAMPLE 5 Synthesis of yclopropyl((4-(ethylamino)(trifluoromethyl)pyrimidinyl)amino)—1H- pyrazolyl)pyrrolidinone (153) l-cyclopropyl-1H-pyrazole-3,5-diamine: A mixture of propanedinitrile (6.15 g, 93.09 mmol) and cyclopropylhydrazine (9 g, 62.06 mmol, 2HCl salt) in i-PrOH (10 mL) was heated at 105 0C for 5 h. The reaction solution was cooled to 0 OC, adjusted to pH = 7 with sat. , concentrated under reduced pressure. The crude product was d by silica gel column chromatography (DCMzMeOH = 30:1 to 10: 1) to give 1-cyclopropylpyrazole-3,5-diamine as a brown syrup. 1H NMR (400 MHz, CDCl3)Z 5 ppm 4.88 (s, 1 H), 3.80 (br s, 2 H), 2.98 (tt, J= 6.89, 3.47 Hz, 1 H), 2.84 (br s, 2 H), 1.05 (dq, J= 7.86, 3.70 Hz, 2 H), 0.93 - 1.00 (m, 2 H).

N-(S-aminocyclopropyl-1H-pyrazolyl)—4-chlorobutanamide: To a solution of 1- cyclopropylpyrazole-3,5-diamine (2.25 g, 16.28 mmol) and TEA (3.29 g, 32.56 mmol) in DCM (200 mL) was added dropwise 4-chlorobutanoyl chloride (2.07 g, 14.65 mmol) at 0 0C for 30 min. The mixture was stirred at 0 0C for 30 min and stirred at 15 0C for 1 h. The reaction mixture was diluted with H20 (50 mL) and extracted with DCMzi-PrOH (V:V = 3: 1, 3 X 30 mL). The combined organic layers were dried over NazSO4, ﬁltered and concentrated under reduced pressure. The residue was puriﬁed by silica gel column chromatography (PEzEtOAc = 10:1 to 0: 1) to give mino ropyl-pyrazolyl)chloro-butanamide as a yellow oil. 1H NMR (400 MHz, CDCl3)I 5 ppm 7.97 (br s, 1 H), 5.94 (s, 1 H), 3.90 (br s, 2 H), 3.63 (t, J: 6.21 Hz, 2 H), 3.08 (tt, J=6.82, 3.59 Hz, 1 H), 2.49 (t, J: 7.09 Hz, 2 H), 2.16 (quin, J= 6.62 Hz, 2 H), 0.93 -1.13(m, 4 H). 1-(5-aminocyclopropyl-1H-pyrazolyl)pyrrolidin-2—one: To a solution -amino- 1-cyclopropyl-pyrazolyl)chloro-butanamide (1.3 g, 5.36 mmol) in THF (390 mL) was added NaH (536 mg, 13.40 mmol, 60% purity) at 0 0C over 10 min. After addition, the mixture was stirred at 0 0C for 20 min, and then stirred at 15 0C for 1.5 h. The reaction e was quenched by addition of aq.

NH4Cl (100 mL) at 0 OC, and then ted with DCM:i-PrOH (V:V = 3:1, 3 X 100 mL). The combined organic layers were dried over NazSO4, ﬁltered and concentrated under reduced pressure. The residue was d by silica gel column chromatography (PEzEtOAc = 10:1 to 0: 1) to give 1-(5-amino cyclopropyl-pyrazol-3 -yl)pyrrolidinone as an off-white solid. 1H NMR (400 MHz, CDCl3)I 5 ppm 6.10 (s, 1 H), 3.89 (t, J: 7.06 Hz, 4 H), 3.10 (tt, J= 6.86, 3.61 Hz, 1 H), 2.52 (t, J: 8.05 Hz, 2 H), 2.11 (quin,D7.61 Hz, 2 H), 1.06 - 1.12 (m, 2 H), 1.00 - 1.06 (m, 2 H).

[Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 1-(1-cyclopr0pyl((4-(ethylamin0)(trifluoromethyl)pyrimidinyl)amin0)—1H- pyraz01yl)pyrr01idin0ne: To a solution of 1-(5-aminocyclopropyl-pyrazolyl)pyrrolidin one (180 mg, 872.77 umol) and 2-chloro-N-ethyl(triﬂuoromethyl)pyrimidinamine (197 mg, 872.77 umol) in 1,4-dioxane (10 mL) was added p-TsOH.H2O (45 mg, 261.83 umol). The mixture was stirred at 90 °C for 12 h. The reaction mixture was diluted with H20 (30 mL) and adjusted to pH = 8-9 with aq.

NaHC03 (10 mL) at 0 °C and extracted with EtOAc (3 X 30 mL). The combined c layers were washed with brine (10 mL), dried over Na2SO4, ﬁltered and concentrated under reduced pressure. The residue was puriﬁed by prep-HPLC (FA) to give 1-(1-cyclopropyl((4-(ethylamino) (triﬂuoromethyl)pyrimidinyl)amino)-1H-pyrazolyl)pyrrolidinone. 1H NMR (400 MHz, CDCl3)I ppm 8.16 (s, 1 H), 7.35 (br s, 1 H), 7.22 (s, 1 H), 5.27 (br s, 1 H), 3.93 (t, J: 7.06 Hz, 2 H), 3.62 - 3.73 (m, 2 H), 3.19 - 3.27 (m, 1 H), 2.56 (t, J: 8.16 Hz, 2 H), 2.09 - 2.20 (m, 2 H), 1.34 (t, J: 7.28 Hz, 3 H), 1.15 - 1.20 (m, 2 H), 1.09 - 1.15 (m, 2 H). HPLC: RT 2.11 min. MS: m/z: 396.2 [M+H]+.

EXAMPLE 6 sis of N2-[3-cyclopr0pyl(1,1-dioxothietanyl)pyrazolyl]-N4—ethyl (trifluor0methyl)pyrimidine-2,4-diamine (110) ycl0pr0pylnitr0-pyrazolyl)thietane 1,1-di0xide: To a mixture of 3-cyclopropyl- 4-nitro-1H-pyrazole (500 mg, 3.26 mmol) in DMF (15 mL) was added NaH (156 mg, 3.91 mmol, 60% purity) at 0 °C under N2. The mixture was d at 20 °C for 30 min, then treated with 3-bromothietane 1,1-dioxane (1.01 g, 3.26 mmol) and d at 20 °C for 15.5 h. The mixture was poured into ice-water (30 mL) and ted with EtOAc (3 X 15 mL). The combined organic phase was washed with brine (3 X 15 mL), dried over anhydrous Na2SO4, ﬁltered and concentrated under reduced pressure. The residue was puriﬁed by silica gel column chromatography (PEzEtOAc = 1:0 to 3:1), to give 3-(3-cyclopropyl nitro-pyrazolyl)thietane 1,1-dioxide as a yellow oil. 3-cyclopr0pyl(1,1-di0x0thietanyl)pyrazol-4—amine: To a solution of 3-(3-cyclopropyl- 4-nitro-pyrazolyl)thietane 1,1-dioxide (160 mg, 621.91 umol) in EtOH (8 mL) and H20 (2 mL) was added Fe (174 mg, 3.11 mmol) and NH4Cl (166 mg, 3.11 mmol, 108.71 uL) at 20°C. The reaction e was heated at 70°C for 2 h, then concentrated under reduced pressure. The residue was washed with a mixture solvent of DCM and MeOH (10 mL, 10:1), ﬁltered and the e was trated under reduced pressure to give 3-cyclopropyl(1,1-dioxothietanyl)pyrazolamine as a brown oil.

N2-[3-cyclopr0pyl(1,1-dioxothietanyl)pyraz01—4-yl]-N4—ethyl (trifluoromethyl)pyrimidine-2,4-diamine: To a solution of 3-cyclopropyl(1,1-dioxothietan yl)pyrazolamine (100 mg, 439.99 umol) and 2-chloro-N-ethyl(triﬂuoromethyl)pyrimidinamine (99 mg, 439.99 umol) in 1,4-dioxane (5 mL) was added p-TsOH (15 mg, 88 umol). The reaction solution was stirred at 80°C for 1h. The mixture was adjusted to pH=7 with sat.NaHC03, extracted with EtOAc (3 X 5 mL). The combined organic layers were washed with brine (5 mL), dried over ous Na2SHPLCgutral)ltered and concentrated under d re. The crude product was puriﬁed by prep- to give N2-[3-cyclopropyl(1,1-dioxothietanyl)pyrazolyl]-N4-ethyl [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson (triﬂuoromethyl)pyrimidine-2,4-diamine. 1H NMR (400 MHz, CDC13)I 5 8.16 (s, 1 H), 8.12 (br s, 1 H), 6.62 - 7.03 (m, 1 H), 5.15 (br s, 1 H), 5.07 (br s, 1 H), 4.66 (br s, 2 H), 4.58 (br s, 2 H), 3.58 (br d, J: .90 Hz, 2 H), 1.67 - 1.78 (m, 1 H), 1.32 (br t, J: 6.78 Hz, 3 H), 0.91 - 0.98 (m, 2 H), 0.81 - 0.90 (m, 2 H). HPLC: RT: 1.92 min. MS: m/z = 417.2 [M+H]+.

EXAMPLE 7 Synthesis of (1R,5S)[l-cyclopropyl-S-[[4-(ethylamin0)—5-(triflu0r0methyl)pyrimidin no]pyrazolyl]0xabicyclo[3.1.0]hexan0ne (162) Methyl (1R,5S)0x00xabicyclo[3.1.0]hexanecarb0xylate: Na (8.27 g, 359.52 mmol) was added into MeOH (500 mL) and the mixture was stirred at 20 0C for 3 h until the Na dissolved.

Dimethyl propanedioate (50 g, 378.44 mmol) was added at 0 0C, after 30 min, (2S) (chloromethy1)oxirane (31.51 g, 340.6 mmol) was added at 20 0C under N2. The mixture was stirred at 90 0C for 12 h. The e was concentrated under reduced pressure at 45 OC. The residue was poured into ice-water (100 mL) and stirred for 5 min. The s phase was extracted with EtOAc (3 X 300 mL). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, ﬁltered and concentrated under reduced pressure. The residue was puriﬁed by silica gel column chromatography (PE: EtOAc = 100:1 to 5: 1) to give methyl (1R,5S)oxooxabicyclo[3.1.0]hexanecarboxylate as an oil. 1H NMR (400 MHz, CDC13): 5 ppm 4.35 (dd, J = 9.37, 4.74 Hz, 1 H), 4.18 (d, J = 9.48 Hz, 1 H), 3.79 (s, 3 H), 3.33 - 3.40 (m, 1 H), 2.74 (dt, J = 7.94, 5.18 Hz, 1 H), 2.07 (dd, J = 7.94, 4.85 Hz, 1 H), 1.39 (t, J = 5.07 Hz, 1 H). 3-[(1R,5S)—2-0x00xabicyclo[3.1.0]hexan-l-yl]propanenitrile: To a mixture of MeCN (1.45 g, 35.22 mmol) in THF (20 mL) was added n-BuLi (2.5 M, 14.09 mL) at -78 0C under N2. After 1 h the mixture was added into the on of methyl (1R,5S)oxo oxabicyclo[3.1.0]hexanecarboxylate (5 g, 32.02 mmol) in THF (30 mL) at -78 0C, then the mixture was stirred at -78 0C for 2 h. The mixture was poured into aq. NH4C1 (30 mL) and stirred for 5 min and adjusted the pH=3 with diluted HCl (1N). The aqueous phase was extracted with EtOAc (3 X 30 mL).

The combined organic phase was washed with brine (30 mL), dried over anhydrous Na2SO4, ﬁltered and concentrated under reduced re. The residue was puriﬁed by silica gel column chromatography (PE: MTBE = 50: 1 to 0: 1) to give 3-oxo[(1R, 5S)oxooxabicyclo [3.1.0] hexanyl] propanenitrile as a white solid. 1H NMR (400 MHz, CDC13): 5 ppm 4.25 - 4.47 (m, 3 H), 4.03 - 4.15 (m, 1 H), 3.02 (dt, J = 7.99, 5.26 Hz, 1 H), 2.19 (dd, J = 8.16, 4.41 Hz, 1 H), 1.58 - 1.65 (m, 1 H).

(IR, 5S)(5-amin0cyclopr0pyl-pyraz01—3-yl)—3—oxabicyclo[3.1.0]hexan0ne: To a mixture of 3-oxo[(1R,5S)oxooxabicyclo[3.1.0]hexany1]propanenitri1e (800 mg, 4.84 mmol) in i-PrOH (20 mL) was added cyclopropylhydrazine dihydrochloride salt 8 mg, 4.36 mmol) in one portion at 25 0C under N2. The mixture was d at 50 0C for 12 h. The mixture was poured into aq. NaHC03 (50 mL) and stirred for 10 min. The aqueous phase was extracted with DCM/DDH (3: 1, 3 X 20mL). The combined organic phase was washed with brine (20 mL), dried with ous Na2SO4, d and concentrated under reduced pressure. The residue was puriﬁed by prep- [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson TLC (SiO2, DCMzMeOH = 20: 1) to give (1R,5S)(5-aminocyclopropyl-pyrazolyl) oxabicyclo[3.1.0]hexanone as a brown oil. LCMS: RT 0.370 min, m/z = 220.2 [M+H]+. 1H NMR (400 MHz, CDC13)25 ppm 5.76 (s, 1 H), 4.38 (dd, J = 9.15, 4.74 Hz, 1 H), 4.20 (d, J = 9.26 Hz, 1 H), 3.83 (br s, 2 H), 3.06 (tt, J = 6.89, 3.58 Hz, 1 H), 2.61 (dt, J = 7.72, 4.63 Hz, 1H),1.81 (dd, J = 7.72, 4.41 Hz, 1 H), 1.24 (t, J = 4.74 Hz, 1 H), 0.94 - 1.11 (m, 4 H). (1R,5S)—1-[l-cyclopropyl-S-[[4-(ethylamin0)—5-(triflu0r0methyl)pyrimidin yl]amino]pyrazolyl]0xabicyclo[3.1.0]hexan0ne: To a mixture of (1R,5S)(5-amino cyclopropyl-pyrazolyl)oxabicyclo[3.1.0]hexanone (150 mg, 684.18 umol) and ro-N-ethyl- -(triﬂuoromethyl)pyrimidinamine (154.35 mg, 684.18 umol) in 1,4-dioxane (5 mL) was added p- TsOH.H2O (26.03 mg, 136.84 umol) in one portion at 20 0C under N2. The mixture was stirred at 90 0C for 12 h. The mixture was poured into aq. NaHC03 (30 mL) and stirred for 10 min. The aqueous phase was extracted with EtOAc (3 X 20 mL).The combined organic phase was washed with brine (30 mL), dried with anhydrous Na2SO4, ﬁltered and concentrated under reduced pressure. The residue was puriﬁed by prep-HPLC al condition) to give (1R,5S)[1-cyclopropyl[[4-(ethylamino) (triﬂuoromethyl)pyrimidinyl]amino]pyrazol-3 -yl]oxabicyclo[3.1.0]hexanone. 1H NMR (400 MHz, I 5 ppm 8.10 (s, 1 H), 7.13 (br s, 1 H), 6.87 (s, 1 H), 5.16 (br s, 1 H), 4.35 (dd, J = 9.22, 4.71 Hz, 1 H), 4.18 (d, J = 9.29 Hz, 1 H), 3.49 - 3.64 (m, 2 H), 3.07 - 3.19 (m, 1 H), 2.57 - 2.68 (m, 1 H), 1.81 (dd, J = 7.72, 4.45 Hz, 1 H), 1.22 - 1.30 (m, 4 H), 0.98 - 1.12 (m, 3 H), 1.09 (br s, 1 H). HPLC: reaction time: 2.17 min. MS: m/z: 409 [M+H]+. sis of (1R,3R)—3-(5-((4—(ethylamin0)(trifluoromethyl)pyrimidin-Z-yl)amin0)—1H-pyraz01 yl)cyclobutanecarbonitrile (181) 3—[2-(3-benzyloxycycl0butylidene)hydrazin0]propanenitrile: A mixture of 3- oxycyclobutanone (10 g, 56.75 mmol) and 3-hydrazinopropanenitrile (4.83 g, 56.75 mmol) in EtOH (150 mL) was stirred at 20 0C for 16 h. The mixture was concentrated under reduced pressure to afford 3-[2-(3-benzyloxycyclobutylidene)hydrazino]propanenitrile (13.81 g, crude) as a yellow oil.

LCMS: RT 0.686 min, m/z = 244.2 [M+H]+. 2-(3-benzyloxycycl0butyl)pyrazolamine: To a mixture of 3-[2-(3- benzyloxycyclobutylidene)hydrazino]propanenitrile (13.81 g, 56.76 mmol) in t—BuOH (130 mL) was added t-BuONa (5.45 g, 56.76 mmol) under N2. The mixture was d at 110 0C for 3 h. The mixture was poured into ice-water (100 mL) and extracted with EtOAc (2 X 100 mL). The organic phase was adjusted to pH=3 by 2N HCl and washed with water (3 X 100 mL). The aqueous phase was adjusted to pH = 8 by 6 N NaOH, extracted with EtOAc (3 X 100 mL), washed with brine (100 mL), dried over ous Na2SO4, ﬁltered and concentrated to afford enzyloxycyclobutyl)pyrazol-3 -amine as a yellow oil. LCMS: RT 0.625 min, m/z = 244.2 [M+H]+. [0242 in0pyrazolyl)cyclobutanol: To a solution of 2-(3-benzyloxycyclobutyl)pyrazol aminepg, 20.55 mmol) in DCM (200 mL) was added BC13 (1 M, 8.02 mL) at 0 0C under N2. The [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson mixture was stirred at 20 0C for 2 h. The mixture was poured into saturated NaHC03 (200 mL) and the aqueous phase was concentrated under reduced pressure. The residue was washed with OH (vzv = 10: 1, 100 mL), ﬁltered and the ﬁltrate was concentrated under reduced pressure to afford 3-(5- aminopyrazolyl)cyclobutanol as a yellow oil. LCMS: RT 0.096 min, m/z = 154.1 [M+H]+. (1S,3S)—3—(5-((4-(ethylamin0)(triflu0r0methyl)pyrimidinyl)amino)-1H-pyrazol yl)cyc10butan01 and (1R,3R)-3—(5-((4-(ethylamin0)—5-(triflu0r0methyl)pyrimidinyl)amin0)-1H- pyrazolyl)cyclobutanol: To a mixture of 3-(5-aminopyrazolyl)cyclobutanol (2.2 g, 14.36 mmol) in NMP (22 mL) was added 2-chloro-N-ethyl-5 uoromethyl)pyrimidinamine (2.59 g, 11.49 mmol) and p-TsOH.H2O (819.59 mg, 4.31 mmol) in one portion at 20 0C under N2. The mixture was then heated to 100 OC and stirred for 16 h. The mixture was cooled to 20 OC, poured into water (150 mL) and ed to pH = 7-8 by aqueous NaHCOg. The aqueous phase was extracted with EtOAc (3 X 50 mL). The combined c phase was washed with brine (50 mL), dried over anhydrous Na2SO4, ﬁltered and concentrated under d pressure to give a residue. The residue was puriﬁed by silica gel column chromatography (DCMzMeOH = 30: 1) to afford a mixture of (1S,3S)(5-((4-(ethylamino) oromethyl)pyrimidinyl)amino)-1H-pyrazolyl)cyclobutanol and (1R,3R)-3 -(5 -((4- amino)-5 -(triﬂuoromethyl)pyrimidinyl)amino)-1H-pyrazolyl)cyclobutanol as a yellow gum. (1S,3S)—3—(5-((4-(ethylamin0)(triflu0romethyl)pyrimidinyl)amin0)-1H-pyrazol yl)cyclobutyl methanesulfonate (1R,3R)—3-(5-((4—(ethylamin0)(triflu0r0methyl)pyrimidin yl)amin0)—1H-pyrazolyl)cyclobutyl methanesulfonate: To a mixture of (18,3S)(5-((4- (ethylamino)-5 -(triﬂuoromethyl)pyrimidinyl)amino)-1H-pyrazolyl)cyclobutanol and (1r,3r)-3 -(5 - ((4-(ethylamino)(triﬂuoromethyl)pyrimidinyl)amino)-1H-pyrazolyl)cyclobutano (2 g, 5.84 mmol) in DCM (40 mL) was added TEA 4 mg, 7.01 mmol) and MsCl (802.77 mg, 7.01 mmol) at 0 0C under N2. The mixture was then stirred at 0 0C for another 1 h. The mixture was added with water (10 mL) and stirred for 3 min. The organic phase was separated, washed with brine (10 mL), dried over anhydrous Na2SO4, ﬁltered and concentrated under reduced pressure to give a e. The residue was puriﬁed by silica gel column chromatography (DCMzMeOH = 30: 1) to afford a mixture of (1 8,3 S)-3 -(5 -((4-(ethylamino)-5 -(triﬂuoromethyl)pyrimidinyl)amino)-1H-pyrazolyl)cyclobutyl methanesulfonate and (1R,3R)-3 -(5-((4-(ethylamino)-5 -(triﬂuoromethyl)pyrimidinyl)amino)- 1H- pyrazol-l-yl)cyclobutyl methanesulfonate as a yellow oil. (1R,3R)—3-(5-((4-(ethylamin0)(triflu0r0methyl)pyrimidin-Z-yl)amin0)-1H—pyrazol yl)cyclobutanecarbonitrile: To a mixture of (1S,3S)(5-((4-(ethylamino) (triﬂuoromethyl)pyrimidinyl)amino)-1H-pyrazolyl)cyclobutyl methanesulfonate and )(5- ((4-(ethylamino)-5 -(triﬂuoromethyl)pyrimidinyl)amino)-1H-pyrazolyl)cyclobutyl methanesulfonate (200 mg, 475.73 umol) in DMSO (4 mL) was added 18-crown-6 (12 mg, 47.57 umol) and NaCN (140 mg, 2.85 mmol) at 20°C under N2. The e was then heated to 120 OC and extracgwith EtOAc (3 X 20 mL). The combined organic phase was washed with brine (20 mL), driedstirred 8 h. The mixture was cooled to 20 OC and poured into water (50 mL). The aqueous phase was [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson over anhydrous , ﬁltered and concentrated under reduced pressure to give a residue. The residue was d by prep-HPLC (FA) to give product, which was ﬁthher d by prep-TLC (PEzEtOAc = 1: 1) to afford (1R,3R)(5-((4-(ethylamino)(triﬂuoromethyl)pyrimidinyl)amino)-1H-pyrazol yl)cyclobutanecarbonitrile and a byproduct 2-(6,7-dihydro-5,7-methanopyrazolo[1,5-a]pyrimidin-4(5H)- yl)-N-ethyl(triﬂuoromethyl)pyrimidinamine. (1R,3R)(5-((4-(ethylamin0)(triflu0r0methyl)pyrimidin-Z-yl)amin0)-1H—pyraz01—1- lobutanecarbonitrile. 1H NMR (400 MHz, CDCl3)I 5 8.08 (s, 1H), 7.57 (d, J: 1.76 Hz, 1H), 7.08 (br s, 1H), 6.19 (d, J: 1.76 Hz, 1H), 5.16 (br s, 1H), 5.06 (quin, J= 7.87 Hz, 1H), 3.36-3.48 (m, 2H), 3.24-3.36 (m, 1H), 3.06-3.18 (m, 2H), 2.73-2.84 (m, 2H), 1.20 (t, J: 7.22 Hz, 3H). LCMS: RT: 0.652 min. MS: m/z: 352.1 [M+H]+.

EXAMPLE 9 Synthesis of N2—(1-((1r,3r)—3-(2H—1,2,3-triazol-Z-yl)cyclobutyl)-1H—pyraz01yl)-N4-ethyl (trifluor0methyl)pyrimidine-2,4-diamine (182) and N2-(1-((1r,3r)—3-(1H—1,2,3-triazol yl)cyclobutyl)—1H-pyrazol-S-yl)—N4-ethyl(triflu0r0methyl)pyrimidine-2,4-diamine (183) N2—(1-((1R,3R)(2H-1,2,3-triazolyl)cyclobutyl)—1H-pyrazolyl)—N4-ethyl (trifluor0methyl)pyrimidine-2,4-diamine and N2-(1-((1R,3R)—3—(1H-1,2,3-triaz01—1-yl)cyclobutyl)— 1H-pyraz01yl)—N4-ethyl(triflu0r0methyl)pyrimidine-2,4-diamine: To a mixture of (1S,3S)(5- ((4-(ethylamino)-5 -(triﬂuoromethyl)pyrimidinyl)amino)-1H-pyrazolyl)cyclobutyl methanesulfonate and (1R,3R)-3 -(5-((4-(ethylamino)-5 -(triﬂuoromethyl)pyrimidinyl)amino)- 1H- pyrazol-l-yl)cyclobutyl methanesulfonate (300 mg, 713.59 umol) in DMF (5 mL) was added K2C03 (148 mg, 1.07 mmol) and 2H-triazole (74 mg, 1.07 mmol) in one portion at 20 0C under N2. The mixture was then heated to 120 OC and stirred for 8 h. The mixture was cooled to 20 OC and poured into water (50 mL). The aqueous phase was extracted with EtOAc (3 X 20 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous NazSO4, ﬁltered and concentrated under reduced pressure. The e was separated by prep-HPLC (FA condition) to afford N2-(1-((1R,3R)(2H- 1,2,3-triazolyl)cyclobutyl)-1H-pyrazol-5 -yl)-N4-ethyl-5 -(triﬂuoromethyl)pyrimidine-2,4-diamine and N2-(1-((1R,3R)-3 -(1H- 1,2,3 -triazolyl)cyclobutyl)-1H-pyrazol-5 4-ethyl-5 - (triﬂuoromethyl)pyrimidine-2,4-diamine.

N2—(1-((1R,3R)(2H-1,2,3-triazolyl)cyclobutyl)—1H-pyrazolyl)—N4-ethyl (trifluor0methyl)pyrimidine-2,4-diamine (182). 1H NMR (400MHz, CDCl3)I 5 8.11 (s, 1H), 7.64 (s, 2H), 7.61 (d, J: 1.88 Hz, 1H), 6.83 (br s, 1H), 6.29 (d, J: 1.76 Hz, 1H), 5.50 (tt, J= 4.49, 8.69 Hz, 1H), .17-5.27 (m, 1H), 5.13 (br s, 1H), 3.39-3.51 (m, 2H), 3.25-3.36 (m, 2H), 3.01-3.14 (m, 2H), 1.21 (t, J: 7.22 Hz, 3H). LCMS: RT: 0.706 min. MS: m/z: 394.3 [M+H]+.

N2—(1-((1R,3R)(1H-1,2,3-triazolyl)cyclobutyl)—1H-pyrazolyl)—N4-ethyl (trifluor0methyl)pyrimidine-2,4-diamine (183). 1H NMR (400MHz, CDCl3)I 5 8.10 (s, 1H), 7.74 (s, 1H), 7nd, J= 1.63 Hz, 1H), 7.60 (s, 1H), 6.70 (br s, 1H), 6.28 (d, J: 1.76 Hz, 1H), 5.36-5.45 (m, 1H), [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson .27 (m, 1H), 5.14 (br s, 1H), 3.37-3.53 (m, 2H), 3.31 (ddd, J: 5.77, 8.31,13.65 Hz, 2H), .23 (m, 2H), 1.22 (t, J: 7.22 Hz, 3H). LCMS: RT: 0.660 min. MS: m/z: 394.2 [M+H]+.

EXAMPLE 10 Synthesis of N2-(5-cyclopr0pylpyrazinyl-pyrazolyl)—N4-ethyl (trifluor0methyl)pyrimidine-2,4-diamine (105) 2—(4-nitr0pyrazolyl)pyrazine: To a solution of 4-nitro-1H-pyrazole (1 g, 8.84 mmol) in DMF (20 mL) was added NaH (424 mg, 10.61 mmol, 60% purity) at 0 0C under N2. The mixture was stirred at 0 0C for 1 h. Then 2-chloropyrazine (1.01 g, 8.84 mmol, 790.99 uL) was added at 0 OC and the mixture was heated to 80 OC and stirred for 12 h. The mixture was cooled to 20 OC, quenched by cold aqueous sat. NH4Cl solution (60 mL). The aqueous phase was extracted with EtOAc (3 X 20 mL). The combined organic phase was washed with brine (3 X 15 mL), dried over anhydrous Na2SO4, ﬁltered and concentrated under reduced pressure. The residue was puriﬁed by silica gel column chromatography (PEIEtOAc = 10:1 to 0: 1) to give 2-(4-nitropyrazolyl)pyrazine as a light-yellow solid. 1H NMR (400 MHz, DMSO-dQ: 5 ppm 9.54 (s, 1 H), 9.31 (d, J: 1.13 Hz, 1 H), 8.81 (d, J: 2.51 Hz, 1 H), 8.70 - 8.74 (m, 1 H), 8.71 (s, 1 H), 8.69 (dd, J: 2.45, 1.32 Hz, 1 H). 2—(5-chl0r0nitr0-pyrazolyl)pyrazine: To a solution of 2-(4-nitropyrazolyl)pyrazine (0.78 g, 4.08 mmol) in THF (15 mL) was added LiHMDS (1 M, 4.49 mmol, 4.49 mL) at -78 0C under N2. The mixture was stirred at -78 0C for 30 min, then a solution of 1,1,1,2,2,2-hexachloroethane (1.06 g, 4.49 mmol, 508.45 uL) in THF (10 mL) was added at -78 0C under N2 and the mixture was stirred for 3.5 h. The mixture was quenched by cold aqueous sat. NH4Cl (30 mL). The aqueous phase was extracted with EtOAc (3 X 10 mL). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, d and concentrated. The residue was puriﬁed by silica gel column chromatography OAc = 10:1 to 1: 1) to give 2-(5-chloronitro-pyrazolyl)pyrazine as a white solid. LCMS: RT 1.066 min. MS m/z = 226.0 [M+H]+. 2—(5-cyclopr0pylnitr0-pyrazolyl)pyrazine: To a mixture of 2-(5-chloronitro-pyrazol- 1-yl)pyrazine (200 mg, 886.56 umol) and ropylboronic acid (380 mg, 4.43 mmol) in 1,4-dioxane (10 mL) was added KF (154 mg, 2.66 mmol) and Pd(dppf)Cl2.CH2Cl2 (145 mg, 177.31 umol) at 20 0C under N2. The mixture was heated to 110 OC and stirred for 12 h. The mixture was cooled to 20 OC and d. The residue was added with water (15 mL). The aqueous phase was extracted with EtOAc (3 X 8 mL). The combined c phase was washed with brine (8 mL), dried over anhydrous , d and concentrated. The residue was puriﬁed by silica gel column chromatography (PEzEtOAc = :1 to 0:1) to give 2-(5-cyclopropylnitro-pyrazolyl)pyrazine. 1H NMR (400 MHz, CDCl3)I 5 ppm 9.08 (s, 1 H), 8.71 (d, J: 2.38 Hz, 1 H), 8.56 - 8.61 (m, 1 H), 8.29 (s, 1 H), 2.36 (tt, J= 8.52, 5.79 Hz, 1 H), 1.07 - 1.17 (m, 2 H), -0.17 (tt, J= 8.96, 5.91 Hz, 2 H). 5-cyclopropylpyrazinyl-pyrazolamine: To a solution of 2-(5-cyclopropylnitro- pyrazpylmyrazine (240 mg, 1.04 mmol) in EtOH (16 mL) and H20 (4 mL) was added NH4Cl (277mmg, 5. mol) and Fe (290 mg, 5.19 mmol) at 20 OC. The mixture was heated to 80 OC and stirred for 2 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson h. The mixture was cooled to 20 OC, ﬁltered and concentrated under reduced pressure. The residue was washed with DCM:MeOH (10 mL, v:v = 10: 1), ﬁltered and concentrated under reduced re to give -cyclopropylpyrazinyl-pyrazolamine as a brown oil. LCMS: RT 0.711 min. MS m/z = 202.1 [M+H]+.

N2—(5-cyclopr0pylpyrazinyl-pyraz01—4-yl)—N4-ethyl(triflu0r0methyl)pyrimidine- 2,4-diamine: To a mixture of 5-cyclopropylpyrazinyl-pyrazolamine (100 mg, 496.95 umol) and 2-chloro-N-ethyl(triﬂuoromethyl)pyrimidinamine (112 mg, 496.95 umol) in 1,4-dioxane (5 mL) was added p-TsOH.HzO (34 mg, 198.78 umol) at 20 OC. The e was heated to 90 OC and d for 2 h. The mixture was cooled to 20 OC, added with water (10 mL) and ed to pH = 7-8 by sat. NaHCOg. The aqueous phase was extracted with EtOAc (3 X 8 mL). The combined organic phase was washed with brine (2 X 5 mL), dried over anhydrous NazSO4, ﬁltered and concentrated. The residue was puriﬁed by silica gel column chromatography (PEzEtOAc = 10:1 to 0:1) to give N2-(5 -cyclopropyl- 1-pyrazinyl-pyrazolyl)-N4-ethyl(triﬂuoromethyl)pyrimidine-2,4-diamine. 1H NMR (400 MHz, MeOD): 5 ppm 9.08 (s, 1 H), 8.55 (s, 2 H), 8.04 (br s, 2 H), 3.53 (q, J = 6.82 Hz, 2 H), 2.16 - 2.34 (m, 1 H), 1.20 (br t, J = 7.03 Hz, 3 H), 0.91 (br d, J = 6.90 Hz, 2 H), 0.55 (br d, J = 4.77 Hz, 2 H). HPLC: RT: 2.06 min. MS: m/z: 391.2 [M+H]+.

EXAMPLE 11 Synthesis of (3S)[3-cyclopr0pyl[[4-(methylamin0)(trifluoromethyl)pyrimidin yl]amino]pyrazol-l-yl]methyl-tetrahydrofuran0ne and (3R)—3-[3-cyclopr0pyl[[4- (methylamin0)—5-(triflu0r0methyl)pyrimidinyl]amino]pyrazol-l-yl]methyl-tetrahydrofuran- 2-0ne (113 and 122) 3-(3-cyclopr0pylnitr0-pyrazolyl)tetrahydrofuran0ne: To a solution of 3- cyclopropylnitro-1H-pyrazole (1 g, 6.53 mmol) in DMF (10 mL) was added NaH (313 mg, 7.84 mmol, 60% purity) at 0°C under N2. The e was stirred at 20 0C for 30 min, then treated with 3- bromotetrahydrofuranone (1.19 g, 7.18 mmol, 670 uL) and stirred for 15.5 h. The mixture was poured into ice-water (20 mL) and extracted with EtOAc (3 X 10 mL). The combined organic phase was washed with brine (3 X 10 mL), dried over ous NazSO4, ﬁltered and concentrated under reduced pressure.

The residue was puriﬁed by silica gel column chromatography (PEzEtOAc =1 :0 to 1:1) to give 3-(3- cyclopropylnitro-pyrazolyl)tetrahydrofuranone as a yellow oil. 1H NMR (400 MHz, CDCl3)I 5 8.31 (s, 1 H), 4.96 (t, J: 9.16 Hz, 1 H), 4.65 (td, J= 8.88, 3.45 Hz, 1 H), 4.39 - 4.51 (m, 1 H), 2.95 (dq, J = 13.25, 8.92 Hz, 1 H), 2.77 - 2.87 (m, 1 H), 2.56 - 2.65 (m, 1 H), 1.01 - 1.09 (m, 2 H), 0.93 - 1.01 (m, 2 H). LCMS: RT 0.746 min, m/z = 252.1 . 3-(3-cyclopr0pylnitr0-pyrazolyl)methyl-tetrahydrofuran-Z-one: To a solution of 3- (3 -cyclopropylnitro-pyrazolyl)tetrahydrofuranone (780 mg, 3.29 mmol) in THF (15 mL) was added LDA (4.93 mmol, 2 M, 2.47 mL) at -78 0C under N2. The mixture was stirred at -78 0C for 30 min, tlgreated with MeI (700 mg, 4.93 mmol, 307 uL) at -78 OC and warmed to 0 OC and d for 1.5 h. e mixture was poured into sat. NH4Cl (15 mL) and extracted with EtOAc (3 X 5 mL). The [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Wilkinson None set by Sarah.Wilkinson ation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson combined organic phase was washed with brine (5 mL), dried over anhydrous , ﬁltered and concentrated under reduced pressure. The residue was puriﬁed by silica gel column chromatography (PEzEtOAc = 1:0 to 1: 1) to give 3-(3-cyclopropylnitro-pyrazolyl)methyl-tetrahydroﬁ1ranone as a colorless oil. 1H NMR (400 MHz, I 5 8.40 (s, 1 H), 7.27 (s, 1 H), 4.55 (td, J= 8.53, 5.77 Hz, 1 H), 4.38 - 4.48 (m, 1 H), 3.12 - 3.22 (m, 1 H), 2.56 - 2.65 (m, 1 H), 2.49 (ddd, J: 13.49, 7.59, 5.90 Hz, 1 H), 1.84 (s, 3 H), 1.00 - 1.09 (m, 2 H), 0.90 - 1.00 (m, 3 H). LCMS: RT 0.746 min, m/z = 252.1 [M+H]+. 3-(4-amin0-3—cyclopropyl-pyrazolyl)—3-methyl-tetrahydrofuran-Z-one: To a solution of 3-(3-cyclopropylnitro-pyrazolyl)methyl-tetrahydroﬁJranone (555 mg, 2.21 mmol) in MeOH (15 mL) was added Pd-C (10%, 220 mg) under N2. The suspension was degassed under reduced pressure and purged with Hz for three times. The mixture was stirred under H2 (15 psi) at 20°C for 2 h. The mixture was ﬁltered and the ﬁltrate was concentrated under reduced pressure to give 3-(4- amino-3 -cyclopropyl-pyrazolyl)-3 -methyl-tetrahydrofuranone as a yellow oil. 1H NMR (400 MHz, CDCl3)I 5 7.18 (s, 1 H), 4.43 - 4.51 (m, 1 H), 4.30 - 4.39 (m, 1 H), 3.25 (ddd, J: 13.05, 7.53, 5.02 Hz, 1 H), 2.91 (br s, 2 H), 2.36 (dt, J= 13.43, 7.47 Hz, 1 H), 1.72 (s, 3 H), 1.62 - 1.70 (m, 1 H), 0.82 - 0.90 (m, 2 H), 0.79 (ddd, J: 7.81, 4.99, 2.38 Hz, 2 H). -[3-cyclopr0pyl[[4-(methylamin0)—5-(triflu0r0methyl)pyrimidin no]pyrazol-l-yl]methyl-tetrahydrofuran-Z-one and (3R)[3-cyclopr0pyl[[4- (methylamin0)—5-(triflu0r0methyl)pyrimidin-Z-yl]amino]pyrazol-l-yl]methyl-tetrahydrofuran- 2-0ne: A mixture of ro-N-methyl(triﬂuoromethyl)pyrimidinamine (143 mg, 677.95 umol) and 3-(4-aminocyclopropyl-pyrazolyl)methyl-tetrahydrofuranone (150 mg, 677.95 umol) in 1,4-dioxane (10 mL) was added p-TsOH.H20 (40 mg, 203.39 umol) at 20 0C under N2 and stirred at 90 0C for 4 h. The mixture was poured into ice-water (10 mL) and extracted with EtOAc (3 X 8 mL). The combined organic phase was washed with brine (8 mL), dried over anhydrous Na2804, ﬁltered and concentrated under reduced pressure. The residue was puriﬁed by prep-TLC (SiOz, PEzEtOAc = 1:1) to give 3-[3-cyclopropyl[[4-(methylamino)(triﬂuoromethyl)pyrimidinyl]amino]pyrazol yl]methyl-tetrahydrofuranone. The enantiomers were separated by SFC to provide (3 S)[3- cyclopropyl[[4-(methylamino)-5 -(triﬂuoromethyl)pyrimidinyl]amino]pyrazolyl]-3 -methyltetrahydroﬁJranone and (3R)[3 propyl[[4-(methylamino)-5 -(triﬂuoromethyl)pyrimidin yl]amino]pyrazolyl]methyl-tetrahydrofuranone.

First eluting isomer - 1H NMR (400 MHz, CDCl3)I 5 8.28 (br s, 1 H), 8.13 (br s, 1 H), 7.08 (br s, 1 H), 5.25 (br s, 1 H), 4.47 (br d, J: 7.53 Hz, 1 H), 4.38 (td, J= 8.38, 4.83 Hz, 1 H), 3.31 (br s, 1 H), 3.11 (br s, 3 H), 2.43 (dt, J= 13.52, 7.48 Hz, 1 H), 1.78 (s, 3 H), 1.67 - 1.75 (m, 1 H), 0.77 - 0.95 (m, 4 H). HPLC: RT: 2.00 min. MS: m/z = 397.2 [M+H]+.

Second eluting isomer - 1H NMR (400 MHz, CDCl3)I 5 8.28 (br s, 1 H), 8.13 (br s, 1 H), 7.08 (br s, D 5.25 (br s, 1 H), 4.47 (br d, J: 7.40 Hz, 1 H), 4.33 - 4.42 (m, 1 H), 3.32 (br s, 1 H), 3.11 (br s, [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson 3 H), 2.37 - 2.49 (m, 1H), 1.78 (s, 3 H), 1.67 - 1.76 (m, 1H), 0.79 - 0.94 (m, 4 H). HPLC: RT: 2.00 min.

MS: m/z = 397.2 [M+H]+.

Synthesis of 2-[4-[[4-(ethylamin0)—5-(triflu0r0methyl)pyrimidinyl]amino]-3—methyl-pyrazol yl]methyl-cyclopentan0ne (194) 2-(4-br0m0methyl-pyrazolyl)cyclopentan0ne and 2-(4-br0m0methyl-pyrazol yl)cyclopentan0ne: To a solution of 4-bromomethyl-1H-pyrazole (10 g, 62.11 mmol) in DMF (60 mL) was added NaH (3.23 g, 80.75 mmol, 60% purity) at 0 oC and stirred at 15 0C for 1 h. Then 2- chlorocyclopentanone (8.84 g, 74.53 mmol, 7.43 mL) was added to the mixture and stirred at 15 0C for 15 h. The reaction mixture was quenched by addition aq. NH4Cl (300 mL) at 0°C, and then extracted with EtOAc (3 X 100 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, ﬁltered and concentrated under reduced re. The residue was puriﬁed by silica gel column chromatography (PEzMTBE = 2:1 to 1: 1) to give the mixture of 2-(4-bromomethyl- pyrazolyl)cyclopentanone and 2-(4-bromomethyl-pyrazolyl)cyclopentanone as a yellow gum.

LCMS: RT 2.119 min, m/z = 243.1 [M+H]+. 2—(4-brom0methyl-pyrazolyl)methyl-cyclopentanone and 2-(4-br0m0-5—methylpyrazolyl )methyl-cyclopentanone: To a mixture of 2-(4-bromomethyl-pyrazol yl)cyclopentanone and 2-(4-bromo-5 -methyl-pyrazolyl)cyclopentanone (6.5 g, 26.74 mmol) in THF (30 mL) was added LiHMDS (1 M, 34.76 mL) and stirred at -78 0C for 1 h. Mel (4.93 g, 34.76 mmol, 2.16 mL) was then added at -78 OC and stirred at 15 0C for 15 h. The on mixture was quenched by on of saturated aq. NH4Cl (200 mL) at 0°C, and then extracted with EtOAc (3 X 70 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, ﬁltered and concentrated under d pressure. The residue was puriﬁed by silica gel column chromatography (PEzEtOAc = 4:1 to 2:1) to give the mixture of 2-(4-bromomethyl-pyrazolyl)methyl-cyclopentanone) and2-(4- bromomethyl-pyrazol-l-yl)methyl-cyclopentanone as a yellow gum. LCMS: RT 0.747 min, m/z = 257.1 . utyl N-[3-methyl(1-methyloxo-cyclopentyl)pyraz01yl]carbamate and tertbutyl N-[5-methyl(1-methyl0x0-cyclopentyl)pyrazolyl]carbamate: A mixture of 2-(4-bromomethyl-pyrazolyl)methyl-cyclopentanone and 2-(4-bromo-5 -methyl-pyrazolyl)methyl- entanone (160 mg, 622.26 umol), NHzBoc (437 mg, 3.73 mmol), t-BuONa (120 mg, 1.24 mmol) and [2-(2-aminoethyl)phenyl]-chloro-palladium,ditert-butyl-[2-(2,4,6- triisopropylphenyl)phenyl]phosphane (107 mg, 155.57 umol) in THF (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 0C for 2 h under N2. The reaction mixture was ﬁltered and the ﬁltrate was concentrated under reduced re. The residue was puriﬁed by prep- HPLC (neutral) to give tert—butyl N—[3 -methyl(1-methyloxo-cyclopentyl)pyrazolyl]carbamate and te tyl N—[5 -methyl(1-methyloxo-cyclopentyl)pyrazolyl]carbamate as a yellow gum.

LCM : 1.203 min, m/z = 294.3 [M+H]+.

[Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 2-(4-aminomethyl-pyrazolyl)methyl-cyclopentanone: A solution of tert-butyl N-[3- methyl(1-methyloxo-cyclopentyl)pyrazolyl]carbamate (80 mg, 272.7 umol) in HCl/EtOAc (3 mL) was stirred at 0 0C for l h. The reaction mixture was concentrated under reduced pressure to give 2- (4-aminomethyl-pyrazolyl)methyl-cyclopentanone as a yellow solid. LCMS: RT 1.032 min, m/z = 194.2 [M+H]+. 2-[4-[[4-(ethylamin0)—5-(trifluoromethyl)pyrimidin-Z-yl]amino]methyl-pyrazolyl] methyl-cyclopentanone: 2-(4-aminomethyl-pyrazolyl)methyl-cyclopentanone (55 mg, 284.61 umol), ro-N-ethyl(triﬂuoromethyl)pyrimidinamine (64 mg, 284.61 umol) and TEA (86 mg, 853.84 umol, 118.84 uL) were taken up into a microwave tube in n-BuOH (1 mL). The sealed tube was heated at 110 0C for 1h under microwave. The mixture was trated under reduced pressure. The residue was puriﬁed by prep-HPLC (neutral) and prep-TLC OAc = 1:1) to give 2-[4-[[4- (ethylamino)-5 uoromethyl)pyrimidinyl]amino] -3 -methyl-pyrazolyl]methylcyclopentanone. 1H NMR (400 MHz, CHLOROFORM-d): 5 ppm 8.12 (br s, 2 H), 6.66 (br s, 1 H), 5.15 (br s, 1 H), 3.58 (br s, 2 H), 2.90 - 3.07 (m, 1 H), 2.38 - 2.58 (m, 2 H), 2.24 (s, 3 H), 2.04 - 2.19 (m, 2 H), 1.88 - 2.00 (m, 1 H), 1.58 (s, 3 H), 1.31 (br t, J = 7.09 Hz, 3 H). HPLC: Retention Time: 2.557 min. MS: (M+H+) m/z: 383.2.

EXAMPLE 13 Synthesis of (S)(4-((4-(ethylamin0)(triflu0r0methyl)pyrimidin-Z-yl)amin0)methyl-1H- pyrazolyl)—3-(flu0r0methyl)dihydrofuran-2(3H)-0ne and (R)—3-(4-((4-(ethylamin0) (trifluoromethyl)pyrimidinyl)amin0)—3-methyl-1H—pyrazolyl)(flu0r0methyl)dihydr0furan- 2(3H)—0ne (216 and 217) 3-(hydroxymethyl)(3—methylnitr0-1H-pyrazolyl)dihydr0furan-2(3H)—0ne: To a mixture of 3-(3-methylnitro-pyrazolyl)tetrahydroﬁ1ranone (2 g, 9.47 mmol) in THF (25 mL) was added LiHMDS (1 M, 12.31 mL) at -78 0C under N2, and then the mixture was stirred at -78 0C for 0.5 h.

A solution of paraformaldehyde (1.02 g, 11.37 mmol) in THF (1 mL) was then added to the on mixture and then the mixture was stirred at 10 0C for 2.5 h. The reaction was quenched by addition aq. sat. NH4Cl (150 mL) at 0 OC, and then ted with EtOAc (3 X 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, d and concentrated under reduced pressure.

The residue was puriﬁed by silica gel column chromatography (PE: EtOAc = 2:1 to l: 1) to give 3- (hydroxymethyl)(3-methylnitro-pyrazol-l-yl)tetrahydroﬁiranone as a white solid. LCMS: RT 0.497 min, m/z = 242.1 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d): 5 8.54 (s, 1H), 4.59 - 4.48 (m, 2H), 4.20 - 4.07 (m, 2H), 3.07 - 2.98 (m, 1H), 2.95 - 2.86 (m, 2H), 2.55 (s, 3H). 3—(flu0r0methyl)—3-(3-methylnitr0-1H-pyrazolyl)dihydrofuran-2(3H)-0ne: To a solution of 3-(hydroxymethyl)(3 -methylnitro-pyrazolyl)tetrahydroﬁ1ranone (1.1 g, 4.56 mmol) in DCM (30 mL) was added DAST (5.88 g, 36.48 mmol, 4.82 mL) at 0 0C, then the mixture was extracgwith EtOAc (3stirred 0 0C for 15 h. The mixture was quenched by addition aq. sat. NaHC03 (200 mL) at 0°C, and X 70 mL). The combined organic layers were washed with brine (70 mL), ation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson dried over Na2SO4, d and concentrated under reduced pressure. The residue was puriﬁed by silica gel column chromatography (PEzEtOAc = 3:1 to 1: 1) to give 3-(ﬂuoromethyl)(3-methylnitropyrazolyl )tetrahydrofuranone as a white solid. LCMS: RT 0.576 min, m/z = 244.1 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d): 5 8.56 (s, 1H), 4.96 - 4.74 (m, 2H), 4.59 - 4.49 (m, 2H), 3.30 - 3.20 (m, 1H), 2.95 - 2.86 (m, 1H), 2.55 (s, 3H). 3-(4-amin0-3—methyl-1H—pyrazolyl)(flu0r0methyl)dihydr0furan-2(3H)—one:A mixture of 3-(ﬂuoromethyl)(3-methylnitro-pyrazolyl)tetrahydroﬁ1ranone (0.7 g, 2.88 mmol), Fe (804 mg, 14.39 mmol) and NH4Cl (770 mg, 14.39 mmol) in EtOH (8 mL) and H20 (2 mL) was stirred at 70 0C for 2 h. The reaction mixture was concentrated under reduced re, the residue was diluted with DCMzMeOH (50 mL, ratio=10:1 ), ﬁltered and concentrated under reduced pressure to give 3-(4- aminomethyl-pyrazolyl)-3 -(ﬂuoromethyl)tetrahydroﬁ1ranone as a brown solid. LCMS: RT 0.087 min, m/z = 214.1 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d): 5 7.30 (s, 1H), 4.89 - 4.66 (m, 2H), 4.52 - 4.40 (m, 2H), 3.31 (br dd, J: 6.2, 13.2 Hz, 1H), 2.87 - 2.80 (m, 1H), 2.21 - 2.15 (m, 3H).

(R)—3-(4-((4-(ethylamin0)—5-(triflu0r0methyl)pyrimidin-Z-yl)amin0)—3-methyl-1H- pyrazolyl)—3-(flu0r0methyl)dihydr0furan-2(3H)-0ne and (4-((4-(ethylamin0) (trifluoromethyl)pyrimidin-Z-yl)amin0)methyl-1H-pyrazolyl)—3-(fluoromethyl)dihydrofuran- 0ne: A mixture of 3-(4-aminomethyl-pyrazolyl)(ﬂuoromethyl)tetrahydroﬁ1ranone (0.2 g, 938.05 umol), 2-chloro-N-ethyl(triﬂuoromethyl)pyrimidinamine (190 mg, 844.24 umol) and p- TsOH.H20 (71 mg, 375.22 umol) in 1,4-dioxane (3 mL) was stirred at 90 0C for 6 h under N2. The reaction mixture was quenched by addition aq. sat. NaHC03 (60 mL) at 0 OC, and then extracted with EtOAc (3 X 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, d and concentrated under reduced pressure. The residue was d by silica gel column chromatography (PE: EtOAc = 3:1 to 1:1) to give desired compound as a brown oil, which was separated by SFC.

SFC, first eluting isomer: 1H NMR (400 MHz, CHLOROFORM-d): 5 8.30 (br s, 1H), 8.12 (s, 1H), 7.01 - 6.61 (m, 1H), 5.32 - 5.06 (m, 1H), 4.91 - 4.68 (m, 2H), 4.54 - 4.37 (m, 2H), 3.64 - 3.53 (m, 2H), 3.32 (br s, 1H), 2.92 - 2.79 (m, 1H), 2.26 (s, 3H), 1.33 (br t, J = 7.0 Hz, 3H). HPLC: Retention Time: 2.02 min. MS: (M+H+) m/z = 403.3.

SFC, second eluting isomer: 1H NMR (400 MHz, CHLOROFORM-d): 5 8.30 (br s, 1H), 8.12 (s, 1H), 7.01 - 6.61 (m, 1H), 5.32 - 5.06 (m, 1H), 4.91 - 4.68 (m, 2H), 4.54 - 4.37 (m, 2H), 3.64 - 3.53 (m, 2H), 3.32 (br s, 1H), 2.92 - 2.79 (m, 1H), 2.26 (s, 3H), 1.33 (br t, J = 7.0 Hz, 3H). HPLC: Retention Time: 1.99 min. MS: (M+H+) m/z = 403.3.

[Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson EXAMPLE 14 Synthesis of N2-[5-ch10r0[(3S)—1-ethyl-4,4-diflu0r0piperidyl]pyrazolyl]-N4-ethyl (triflu0r0methyl)pyrimidine-2,4-diamine and N2-[5-ch10r0[(3R)—1-ethyl-4,4-diflu0r0 piperidyl]pyrazolyl]-N4-ethyl(trifluoromethyl)pyrimidine-2,4-diamine (204 and 205) tert-butyl 3-(4-nitr0pyrazolyl)—4-0x0-piperidinecarb0xylate: To a solution of tert- butyl 3-bromooxo-piperidinecarboxylate (20 g, 71.91 mmol) and 4-nitro-1H-pyrazole (8.94 g, 79.10 mmol) in DMF (100 mL) was added K2C03 (19.88 g, 143.81 mmol) at 20°C under N2. The mixture was stirred at 20 0C for 16 h. The mixture was poured into ice-water (300 mL) and extracted with EtOAc (3 X 100 mL). The combined organic phase was washed with brine (3 X 100 mL), dried over anhydrous Na2SO4, ﬁltered and concentrated under reduced pressure. The residue was puriﬁed by silica gel column chromatography (PEzEtOAc = 1:0 to 3: 1) to give tert-butyl 3-(4-nitropyrazolyl)oxo- dine-l-carboxylate as a yellow oil. LCMS: RT 1.306 min, m/z = 255.2 [M-56]+. 1H NMR (400 MHz, CDCl3)I 5 8.22 - 8.27 (m, 1 H), 8.12 (s, 1 H), 4.97 (dd, J: 10.85, 6.34 Hz, 1 H), 4.75 (br s, 1 H), 4.43 (br s, 1 H), 3.64 (brt,J= 11.86 Hz, 1 H), 3.30 (br d, J: 5.77 Hz, 1 H), 1.41 - 1.58 (m, 9 H), 1.41- 1.58 (m, 2 H). tert—butyl 4,4-diflu0r0(4-nitr0pyrazolyl)piperidinecarb0xylate: To a solution of tert-butyl itropyrazolyl)oxo-piperidinecarboxylate (1 g, 3.22 mmol) in DCM (10 mL) was added DAST (2.6 g, 16.11 mmol, 2.13 mL) at -78°C under N2. The mixture was stirred at 20 0C for 16 h. The mixture was poured into ice cold sat. NaHC03 (15 mL) and extracted with EtOAc (3 X mL). The combined organic phase was washed with brine (5 mL), dried over anhydrous Na2SO4, ﬁltered and concentrated under reduced pressure. The residue was puriﬁed by silica gel column chromatography (PEzEtOAc = 1:0 to 3: 1) to give utyl 4,4-diﬂuoro-3 -(4-nitropyrazol yl)piperidinecarboxylate as a white solid. LCMS: RT 1.335 min, m/z = 277.1 [M-56]+. 1H NMR (400 MHz, CDCl3)I 5 8.30 (s, 1 H), 8.13 (s, 1 H), 4.52 (ddq, J= 14.23, 9.60, 4.65, 4.65, 4.65 Hz, 1 H), 4.39 (br s, 1 H), 4.10 (br s, 1 H), 3.66 (br t, J: 11.36 Hz, 1 H), 3.30 (br t, J: 11.42 Hz, 1 H), 2.26 - 2.42 (m, 1 H), 1.95 - 2.18 (m, 1 H), 1.37 - 1.57 (m, 9 H). tert—butyl 3-(5-chl0r0nitro-pyrazolyl)-4,4-diflu0r0-piperidinecarb0xylate: To a on of tert-butyl 4,4-diﬂuoro(4-nitropyrazolyl)piperidinecarboxylate (740 mg, 2.23 mmol) in THF(10 mL) was added dropwise LiHMDS (1 M, 3.34 mmol,3.34 mL) at -78 0C under N2.

The reaction was stirred at -78 0C for 1 h. Then 1,1,1,2,2,2-hexachloroethane (1.05 g, 4.45 mmol, 504.49 uL) in THF (5 mL) was added dropwise and the mixture was stirred at -78 0C for 1 h. The mixture was poured into sat. NH4Cl (15 mL) and extracted with EtOAc (3 X 5 mL). The combined organic phase was washed with brine (5 mL), dried over anhydrous Na2SO4, ﬁltered and trated under d pressure. The residue was d by silica gel column chromatography (PEzEtOAc = 1:0 to 3: 1) to give tert-butyl 3-(5 -chloronitro-pyrazolyl)-4,4-diﬂuoro-piperidinecarboxylate as a yellow oil.

LCMﬁ‘ 1.352 min, m/z = 311.2 [M-56]+. 1H NMR (400 MHz, CDCl3)I 5 8.22 (s, 1 H), 4.59 - 4.72 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson (m, 1 H), 4.00 - 4.16 (m, 2 H), 3.81 - 3.90 (m, 1 H), 3.55 (br d, J: 9.03 Hz, 1 H), 2.38 - 2.54 (m, 1 H), 1.96 - 2.15 (m, 1 H), 1.39 - 1.56 (m, 9 H). hlor0nitr0-pyrazolyl)—4,4-diflu0r0-piperidine : The mixture of tert-butyl 3-(5- chloronitro-pyrazolyl)-4,4-diﬂuoro-piperidinecarboxylate (1.8 g, 4.91 mmol) in HCl/EtOAc (40 mL) was stirred at 20 0C for 2 h. The reaction mixture was concentrated under reduced pressure and the mixture was adjusted to pH = 7-8 with sat. aq. NaHC03, Then the aqueous phase was extracted with EtOAc (3 X 15 mL), dried over anhydrous Na2SO4, ﬁltered and concentrated under reduced pressure to give 3-(5-chloronitro-pyrazolyl)-4,4-diﬂuoro-piperidine as a light yellow solid. 1H NMR (400 MHz, CHLOROFORM-d): 5 8.17 - 8.32 (m, 1 H), 4.57 - 4.81 (m, 1 H), 3.59 (br dd, J: 13.68, 4.89 Hz, 1 H), 3.36 (br dd, J: 13.93, 4.02 Hz, 1 H), 3.14 - 3.27 (m, 1 H), 2.98 - 3.11 (m, 1 H), 2.37 (br s, 1 H), 2.14 - 2.34 (m, 1 H). 3-(5-chl0r0nitr0-pyrazolyl)ethyl-4,4-difluoro-piperidine: To a mixture of 3-(5- chloronitro-pyrazolyl)-4,4-diﬂuoro-piperidine (0.5 g) and acetaldehyde (2.07 g, 18.75 mmol, 2.63 mL) in MeOH (10 mL) was added NaBHgCN (589 mg, 9.38 mmol) and stirred for 15 min.

Then CH3COOH (1. 13 g, 18.75 mmol, 1.07 mL) was added to the solution at 20 OC and the mixture was stirred at 20 0C for 1 h. The e was adjusted to pH = 7-8 with sat. aq. NaHC03 and the aqueous phase was extracted with EtOAc (3 X 15 mL). The ed organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, ﬁltered and concentrated under reduced pressure. The residue was puriﬁed by silica gel column chromatography (PE : EtOAc = 100 : 1 to 0 : 1) to give 3-(5-chloro nitro-pyrazolyl)ethyl-4,4-diﬂuoro-piperidine as a yellow oil. LCMS: RT 0.939 min, m/z = 295.1 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) 5: 8.19 - 8.33 (m, 1 H), 4.78 - 4.95 (m, 1 H), 3.10 - 3.22 (m, 2 H), 2.97 - 3.06 (m, 1 H), 2.57 - 2.67 (m, 2 H), 2.39 - 2.51 (m, 1 H), 2.22 - 2.36 (m, 1 H), 2.12 - 2.21 (m, 1 H), 1.13 (t, J: 7.22 Hz, 3 H). 5-ch10r0(1-ethyl-4,4-difluor0piperidyl)pyrazolamine: To a mixture of 3-(5-chloro- o-pyrazolyl)ethyl-4,4-diﬂuoro-piperidine (0.15 g, 509.02 umol) in EtOH (4 mL) and H20 (1 mL) was added Fe (142 mg, 2.55 mmol) and NH4Cl (136 mg, 2.55 mmol, 88.98 uL) at 20 OC. Then the mixture was d at 80 0C for 1 h. The reaction mixture was ﬁltered and the ﬁltrate was trated under reduced pressure. The crude was washed with DCM : MeOH (V : V = 10 : 1) (30 mL), d and the ﬁltrate was trated under reduced pressure to give 5-chloro(1-ethyl-4,4-diﬂuoro piperidyl)pyrazolamine as a red solid. LCMS: RT 1.150 min, m/z = 265.1 [M+H]+. chlor0[(3S)ethyl-4,4-diflu0r0piperidyl]pyrazolyl]-N4-ethyl (trifluor0methyl)pyrimidine-2,4-diamine and N2-[5-chlor0[(3R)—1-ethyl-4,4-diflu0r0 piperidyl]pyrazolyl]-N4-ethyl(triflu0r0methyl)pyrimidine-2,4-diamine: To a mixture of 5- chloro(1-ethyl-4,4-diﬂuoropiperidyl)pyrazolamine (0.13 g, 491.12 umol) and 2-chloro-N-ethyl- ﬂuoromethyl)pyrimidinamine (110 mg, 491 . 12 umol) in 1,4-dioxane (3 mL) was added p- TsOHD) (25 mg, 147.33 umol) at 20 OC and the mixture was stirred at 90 0C for 5 h. The e was adjusted to pH = 7-8 with sat. aq. NaHC03 and the aqueous phase was extracted with EtOAc (3 X 5 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson mL). The combined organic phase was washed with brine (8 mL), dried over anhydrous Na2S04, ﬁltered and trated under reduced pressure. The residue was puriﬁed by prep-TLC (SiOz, EtOAc) to give desired compound as a white syrup, which was further separated by SFC to give N2-[5-chloro[(3 S) ethyl-4,4-diﬂuoro-3 -piperidyl]pyrazolyl]-N4-ethyl(triﬂuoromethyl)pyrimidine-2,4-diamine as a white syrup and N2-[5-chloro[(3R)ethyl-4,4-diﬂuoropiperidyl]pyrazolyl]-N4-ethyl (triﬂuoromethyl)pyrimidine-2,4-diamine.

SFC, first eluting isomer: 1H NMR (400 MHz, CHLOROFORM-d): 5 8.23 (br s, 1 H), 8.13 (s, 1 H), 6.72 (br s, 1 H), 5.14 (br s, 1 H), 4.64 - 4.79 (m, 1 H), 3.48 - 3.64 (m, 2 H), 3.14 (br d, J: 8.41 Hz, 2 H), 2.99 (br d, J: 10.67 Hz, 1 H), 2.60 (q, J= 7.15 Hz, 2 H), 2.35 - 2.50 (m, 1 H), 2.04 - 2.34 (m, 2 H), 1.27 (t, J: 7.22 Hz, 3 H), 1.13 (t, J: 7.15 Hz, 3 H). HPLC: RT: 1.116 mm MS: m/z = 454.4 [M+H]+. SFC: ion Time: 1.621 min.

SFC, second g isomer: 1H NMR (400 MHz, CHLOROFORM-d): 5 8.23 (br s, 1 H), 8.14 (s, 1 H), 6.71 (br s, 1 H), 5.13 (br s, 1 H), 4.60 - 4.81 (m, 1 H), 3.49 - 3.61 (m, 2 H), 3.15 (br d,J= 8.28 Hz, 2 H), 2.99 (br d, J: 11.80 Hz, 1 H), 2.60 (q, J= 7.15 Hz, 2 H), 2.43 (br t, J: 12.05 Hz, 1 H), 2.06 - 2.33 (m, 2 H), 1.27 (t, J: 7.22 Hz, 3 H), 1.13 (t, J: 7.15 Hz, 3 H). HPLC: Retention Time: 1.108 min. MS: m/z = 454.4 [M+H]+. SFC: Retention Time: 1.785 min.

Synthesis of (1S,2R)—2-[4-[(5-br0m0meth0xy-pyrimidinyl)amino]-3—cyclopropyl-pyrazol-lyl ]cyclopropanecarbonitrile and (1R,ZS)[4-[(5-brom0meth0xy-pyrimidinyl)amin0] ropyl-pyrazol-l-yl]cyclopropanecarbonitrile (213 and 214) 3-cyclopr0pylnitr0vinyl-pyrazole: To a mixture of 3-cyclopropylnitro-1H-pyrazole (7 g, 45.71 mmol) and benzyl triethyl ammonium chloride (1.04 g, 4.57 mmol) in 1,2-dichloroethane (50 mL) was added NaOH (9.14 g, 228.55 mmol) and water (9 mL) at 20 0C under N2. The mixture was stirred at 80 0C for 8 h. The reaction mixture was ﬁltered and the ﬁltrate was concentrated. The crude product was puriﬁed by silica gel column chromatography (PE: EtOAc= 100:1 to 1: 1) to give 3- cyclopropylnitrovinyl-pyrazole as a yellow solid. 1H NMR (400 MHz, I 5 ppm 8.23 (s, 1 H), 6.87 (dd, J: 15.55, 8.71 Hz, 1 H), 5.70, (d, J: 15.66 Hz, 1 H), 5.06 (d, J: 8.60 Hz, 1 H), 2.53 - 2.68 (m, 1 H), 0.97 - 1.11 (m, 4 H).

Ethyl (1S,2R)—2-(3-cyclopr0pyl-4—nitr0-pyrazolyl)cyclopropanecarboxylate and ethyl (1S,ZS)(3-cyclopr0pylnitr0-pyrazolyl)cyclopr0panecarboxylate: To a mixture of 3- cyclopropylnitrovinyl-pyrazole (4.7 g, 26.23 mmol) and 3-[3-(2-carboxymethyl-propyl)phenyl]- 2,2-dimethyl-propanoic acid,rhodiorhodium (200 mg, 262.31 umol) in DCM (100 mL) was added dropwise ethyl oacetate (17.96 g, 157.39 mmol) in DCM (30 mL) at 20 0C under N2 for 3 h. The mixture was stirred at 20 0C for 12 h. The mixture was concentrated. The residue was puriﬁed by silica gel column chromatography ( PE: EtOAc= 100: 1 to 1: 1) to give ethyl (1S*,2R*)(3-cyclopropyl nitro-ppzolyl)cyclopropanecarboxylate and ethyl (1S* ,2S * )(3 -cyclopropylnitro-pyrazolyl)cyc opropanecarboxylate as a brown oil.

[Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson (1S*,2R*)(3-cycl0pr0pylnitr0-pyrazolyl)cyclopropanecarboxylate: 1H NMR (400 MHz, CDCl3)I 5 8.15 (s, 1 H), 4.12 - 4.37 (m, 1 H), 3.97 - 4.07 (m, 2 H), 3.90 (td, J= 7.50, 5.71 Hz, 1 H), 2.43 - 2.71 (m, 1 H), 2.13 - 2.37 (m, 1 H), 1.88 - 2.07 (m, 1 H), 1.59 (td, J= 8.06, 6.46 Hz, 1 H), 1.23 - 1.36 (m, 1 H), 1.17 (t, J: 7.15 Hz, 3 H), 0.84 - 1.06 (m, 4 H). (1S*,2S*)(3-cycl0pr0pylnitr0-pyrazolyl)cyclopropanecarboxylate: 1H NMR (400 MHz, CDCl3)I 5 8.18 (s, 1 H), 4.08 - 4.32 (m, 3 H), 3.98 (ddd, J: 7.97, 4.89, 3.07 Hz, 1 H), 2.50 - 2.65 (m, 1 H), 2.30 (ddd, J: 9.54, 6.27, 3.01 Hz, 1 H), 1.79 (dt, J= 9.91, 5.21 Hz, 1 H), 1.65 (dt, J= 8.03, .96 Hz, 1 H), 1.24 - 1.36 (m, 4 H), 0.92 - 1.10 (m, 4 H). (1S,2R)—2-(3-cyclopropylnitro-pyrazolyl)cyclopr0panecarboxylic acid: To a mixture of ethyl (1S,2R)(3-cyclopropylnitro-pyrazolyl)cyclopropanecarboxylate (2.2 g, 8.29 mmol) in 1,4-dioxane (20 mL) was added HCl (2 M, 20 mL) at 20 0C under N2. The mixture was stirred at 60 0C for 12 h. The mixture was concentrated to give (1S,2R)(3-cyclopropylnitro-pyrazol yl)cyclopropanecarboxylic acid as a brown solid. 1H NMR (400 MHz, DMSO): 5 8.84 (s, 1 H), 4.01 - 4.10 (m, 1 H), 2.39 - 2.46 (m, 1 H), 2.02 - 2.10 (m, 1 H), 1.98 (q, J= 6.03 Hz, 1 H), 1.46 - 1.55 (m, 1 H), 0.93 - 1.07 (m, 2 H), 0.76 - 0.89 (m, 2 H). (1S,2R)—2-(3-cycl0pr0pylnitr0-pyrazolyl)cyclopr0panecarboxamide: To a mixture of (1S,2R)(3 -cyclopropylnitro-pyrazolyl)cyclopropanecarboxylic acid (2 g, 8.43 mmol), NH4Cl (2.71 g, 50.59 mmol) and DIPEA (6.54 g, 50.59 mmol) in DMF (20 mL) was added HATU (6.41 g, 16.86 mmol) at 20 0C under N2. The mixture was stirred at 20 0C for 4 h. The mixture was poured into ice-water (100 mL). The aqueous phase was ted with EtOAc (3 X 50 mL). The ed organic phase was washed with brine (3 X 50 mL), dried with anhydrous Na2SO4, ﬁltered and concentrated under reduced pressure to give (1S,2R)(3 propylnitro-pyrazolyl)cyclopropanecarboxamideas a brown solid. 1H NMR (400 MHz, DMSO): 5 8.67 (s, 1 H), 7.65 (br s, 1 H), 6.87 (br s, 1 H), 3.81 - 3.98 (m, 1 H), 2.38 - 2.47 (m, 1 H), 2.04 (q, J= 7.57 Hz, 1 H), 1.93 (q, J= 5.73 Hz, 1 H), 1.37 (td, J= 8.05, .95 Hz, 1 H), 1.21 - 1.29 (m, 1 H), 0.94 - 1.01 (m, 2 H), 0.78 - 0.84 (m, 1 H). (1S, 2R)—2—(3-cyclopr0pyl-4—nitr0-pyrazolyl) cyclopropanecarbonitrile: To a mixture of (1S, 2R)(3-cyclopropylnitro-pyrazolyl) cyclopropanecarboxamide (1.7 g, 7.2 mmol) in EtOAc (80 mL) was added T3P (18.32 g, 28.79 mmol, 17.12 mL, 50% purity) at 20 0C under N2. The mixture was stirred at 75 0C for 12 h. The mixture was poured into aq. NaHC03 (200 mL). The aqueous phase was extracted with EtOAc (3 X 50 mL). The combined organic phase was washed with brine (150 mL), dried with anhydrous , ﬁltered and concentrated under reduced pressure.

The residue was d by silica gel column chromatography (PE: EtOAc = 100: 1 to 1: 1) to give (1S,2R)(3-cyclopropylnitro-pyrazolyl)cyclopropanecarbonitrile as a white solid. LCMS: RT 1.20 min, m/z = 219.2 [M+H]+. 1H NMR (400 MHz, CDCl3)I 5 8.26 (s, 1 H), 3.90 - 4.09 (m, 1 H), 2.62 (tt, J=8.05, 5.29 Hz, 1 H), 2.10 - 2.20 (m, 1 H), 2.01 (dt, J= 9.43, 6.64 Hz, 1 H), 1.75 (dt, J= 9.26, 7.39 Hz,1u.00-1.11(m,4H).

[Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson (IS, 2R)—2-(4-aminocyclopr0pyl-pyrazolyl)cyclopropanecarbonitrile: To a mixture of (1S,2R)(3-cyclopropylnitro-pyrazolyl)cyclopropanecarbonitrile (0.8 g, 3.67 mmol) and Fe (1.02 g, 18.33 mmol) in EtOH (20 mL) and water (5 mL) was added NH4Cl (981 mg, 18.33 mmol) at 20 0C under N2.The mixture was stirred at 75 0C for l h. The mixture was ﬁltered and the e was concentrated. The residue was washed with DCM: MeOH (10:1, 3 X 10 mL), ﬁltered and the e was concentrated under reduced pressure to give (1S, 2R)(4-aminocyclopropyl-pyrazolyl) cyclopropanecarbonitrile (0.75 g, crude) as a brown oil. LCMS: RT 0.81 min, m/z = 189.3 [M+H]+. 1H NMR (400 MHz, CDCl3)Z 5 6.97 - 7.15 (m, 1 H), 3.74 - 3.91 (m, 1 H), 2.03 (q, J= 6.25 Hz, 1 H), 1.80 (dt, J= 9.43, 6.42 Hz, 1 H), 1.64 - 1.74 (m, 1 H), 1.54 - 1.63 (m, 1 H), 0.78 - 0.93 (m, 4 H). )—2-[4-[(5-br0m0methoxy-pyrimidin-Z-yl)amin0]cyclopropyl-pyrazol-l- yl]cyclopropanecarbonitrile and (1R,ZS)[4-[(5-brom0-4—methoxy-pyrimidin-Z-yl)amin0] cyclopropyl-pyrazol-l-yl]cyclopropanecarbonitrile: To a mixture of (1S,2R)(4-amino cyclopropyl-pyrazolyl)cyclopropanecarbonitrile (0.1 g, 531.27 umol) and 5-bromochloro methoxy-pyrimidine (119 mg, 531.27 umol) in 1,4-dioxane (2 mL) was added p-TsOH.H20 (30 mg, 159.38 umol) at 20 0C under N2. The mixture was stirred at 85 0C for 4 h. The e was poured into aq. NaHC03 (5 mL) and extracted with EtOAc (3 X 5 mL). The combined organic phase was washed with brine (10 mL), dried with anhydrous , ﬁltered and concentrated under d pressure. The residue was puriﬁed by silica gel column tography (PEzEtOAc = 100:1 to 1:1) and separated by SFC to give (1S,2R)[4-[(5-bromomethoxy-pyrimidinyl)amino]cyclopropyl-pyrazol yl]cyclopropanecarbonitrile and (1R,2S)[4-[(5 -bromomethoxy-pyrimidinyl)amino] cyclopropyl-pyrazolyl]cyclopropanecarbonitriles.

SFC, first eluting isomer: 1H NMR (400 MHz, CDCl3)I 5 8.23 (s, 1 H), 8.01 (s, 1 H), 6.76 (br s, 1 H), 4.05 (s, 3 H), 3.85 - 3.97 (m, 1 H), 2.11 (q, J= 6.27 Hz, 1 H), 1.88 (dt, J= 9.29, 6.46 Hz, 1 H), 1.60 - 1.78 (m, 2 H), 0.84 - 0.97 (m, 4 H). LCMS: reaction time: 1.475 min. MS: [M+H]+m/z: 375.2.

SFC, first eluting isomer: 1H NMR (400 MHz, CDCl3)I 5 8.22 (s, 1 H), 8.01 (s, 1 H), 6.77 (br s, 1 H), 4.05 (s, 3 H), 3.86 - 3.96 (m, 1 H), 2.11 (q, J= 6.27 Hz, 1 H), 1.88 (dt, J= 9.29, 6.53 Hz, 1 H), 1.61 - 1.77 (m, 2 H), 0.85 - 0.97 (m, 4 H). LCMS: reaction time: 1.465 min. MS: [M+H]+ m/z: 375.2.

The other compounds of Table 1A, 1B, 2A and 2B were, or can be, prepared according to the Examples above and/or l ures described herein using the approporiate starting materials.

Example 16 Biochemical Assay of the Compounds Materials: 0 LRRK2 G2019S enzyme 0 Substrate (LRRKtide) D 0 ATP 0 TR-FRET dilution buffer [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson o pLRRKtide antibody 0 384-well assay plate 0 DMSO Enzyme reaction ions 0 50 mM Tris pH 7.5, 10 mM MgClz, 1mM EGTA, 0.01% Brij-35, 2 mM DTT 0 5 nM LRRK2 o 134 uM ATP 0 60 minute reaction time o 23 OC reaction temperature 0 10 uL total on volume Detection reaction conditions 0 1X TR-FRET dilution buffer 0 10 mM EDTA 0 2 nM antibody 0 23 OC reaction temperature 0 10 uL total reaction volume Compounds were prepared by initially diluting to 1 mM with DMSO. 35 [LL of reference compound solution, 35 uL of test compound solution, and 35 uL HPE were successively added to the source plate (3 84-well assay plate, e). The plates were centrifuged at 2500 rpm for 1 minute and sealed in foil. POD was used to perform a 3.162 fold serial dilution and 100 nL of nce compound solution, test compound solution, HPE and ZPE were transferred to assay . The assay plate was centrifuged at 2500 rpm for 1 minute, and sealed with foil.

To m the enzyme reaction, 5 uL of LRRKtide substrate and kinase mixture in assay buffer was added to all wells of the assay plate. The plate was centriﬁJged to concentrate the mixture at the bottom of the wells. The assay plate was incubated at 23 0C for 20 minutes. Following incubation, 5 uL of 2X ATP in assay buffer was added to each well, and plates were centrifuged to concentrate the mixture at the bottom of the wells. The plate was incubated at 23 0C for 60 minutes.

To perform the detection ofthe on, EDTA completely mixed in TR-FRET dilution buffer was added to antibody reagent. 10 uL of detection reagent was added to all wells of each well ofthe assay plate and the plate was centriﬁJged to concentrate the mixture at the bottom of the wells. The plate was then incubated at 23 0C for 60 minutes. Plates were read on Perkin Elmer Envision 2104 instrument in TR-FRET mode using a 340 nm excitation filter, 520 nm ﬂuorescence emission filter, and 490 or 495 nm terbium emission filter.

Several ofthe compounds disclosed herein were tested according to the above methods and found to exhibit an LRRK2 G2019S IC50 as indicated in Table 3. In the table below, activity is ed as follD In the table below, activity is provided as follows: +++ = IC50 less than 30 nM, ++ = IC50 between 30 nM and 60 nM, + = ICso greater than 60 nM.

[Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson Table 3 LRRK2 MS LRRK2 MS 2o No.

TR-FRET ICso (nM) [M+1]+ TR-FRET ICso (nM) [M+1]+ 396.2 I» 4; 399.2 396.3 35A 366.2 353.1 35B 366.2 353.1 DJ \1 349.0 392.1 38 366.1 n 378.1 39A 384.2 378.1 4;O 352.2 n 325.1 41 352.1 n 409 42 350.1 -1—11—11— HO 409.1 43 364.1 - 389.1 44 363.3 389.1 45 349.2 .hw 389.1 46 399.2 396.2 48 375.2 395.2 50 331.1 O\ 341.2 52A 338.1 \] 341.1 52B 338.2 409.2 54A 380.2 -000 350.2 54B 380.1 355.2 57 396.2 - 378.1 58 362.1 - 404.2 59 390.2 404.3 60 333.1 - 404.2 61 380.2 - 387.3 62 343.2 - 366.2 63 346.1 - 366.1 64A 381.1 - 468.2 64B 381.1 - 468.2 65 381.1 -WNNNNNNNNNNW OCOOQQUI-PN1— 371.2 66 376.1 371.2 67 343.2 n- 352.1 68 411.3 I. 410.1 69 408.2 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson LRRK2 MS LRRK2 MS \1\1\1\1\1\1\1\1\12O . N0.

TR-FRET ICso (nM) [M+1]+ TR-FRET ICso (nM) [M+1]+ \]O\M4>UJN1—*O 398.2 104 411.2 410.2 105 391.2 332.1 106 489.3 400.1 107 378.3 368.3 108 411.2 409.1 109 273.2 404.1 110 417.25 408.2 111 401.1 00 422.3 112 391.1 \l0 421.1 113 397.2 346.2 114 423.1 oo 423.0 115 423.1 00 399.2 116 434.4 oo WNH 399.2 117 405.3 0000 LII-P 380.2 118 380.2 413.1 119 371.2 424.3 120 382.2 0000 \] 354.2 121 489.3 00 415.2 122 397.2 359.2 123 391.2 382.1, 384.0 124 371.2 @0000 ,_1 374.3 125 385.2 [\J 434.4 126 433.8 DJ 390.1, 392.1 127 436.3 LII-P 394.2 128 419.2 390.1, 392.1 129 410.2 429.1 130 384.2 0\] 434.2 131 380.2 385.1 132 391.1 391.3 133 338.1 385.2 134 371.2 434.2 135 355.2 382.1, 384 136 410.2 382.2 137 T.1. 408.2 ation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson LRRK2 MS LRRK2 MS TR-FRET ICso (nM) [M+1]+ TR-FRET ICso (nM) [M+1]+ 408.2 172 434.3 433.1 173 388.2 443.1, 445.2 174 388.3 392.2 175 374.2 394.2 176 374.3 411.2 177 419.3 411.2 178 419.3 383.3 179 343.3 418.2,420.2 180 ++ 343.2 418.2, 420.2 181 352.1 393.1 182 394.3 1— 4; C 410.2 183 394.2 ,_1 421.1, 423.1 184 386.2 421.1, 423.1 185 386.2 378.2 186 374.3 396.2 187 390.1, 392.1 432.2 188 394.2 397.2 189 394.2 397.2 190 345.1 ++ 419.2, 421.2 191 385.3 408.1 192 399.3 442.1, 444.1 193 ++ 374.3 408.2, 410.1 194 383.2 408.1, 410.1 195 369.2 409 196 434.4 395.1 197 434.4 378.3 198 420.4 409.3 199 ++ 420.4 433.2 200 406.4 433.2 201 406.4 395.2 202 440.4 425.3 203 440.4 396.3 204 454.4 434.3 205 454.4 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson LRRK2 TR-FRET ICso (nM) Example 17 Metabolic stability Metabolic stability of compounds was evaluated in human liver microsomes (from Corning or XenoTech, LLC) using a 96-well plate assay format. Compounds were incubated at 37° C at 1 uM ﬁnal concentration in the microsomal matrix (0.5 mg/mL total protein) in the presence or absence ofNADPH cofactor. An NADPH regenerating system, comprised , MgClz, isocitric acid, and isocitrate dehydrogenase, was used in the assay. Enzymatic reactions were conducted for 0, 5, 10, 20, 30, or 60 min before ation by addition of acetonitrile ning tolbutamide and lol internal standards (100 ng/mL). After g for 10 min, plates were subjected to centriﬁigation (4000 rpm at 4° C) for 20 min and supernatants were mixed 1:3 with HPLC grade water. s were analyzed by LC-MS/MS using appropriate MRM transitions for each analyte and internal standard (IS). Analyte/IS peak area ratios were used to determine t compound ing at each time point. Intrinsic clearance (Clint, expressed as mL-min'lomg'l) was calculated from the ﬁrst order elimination constant (k, min'l) oftest article decay and the volume of the incubation. These values were scaled to intrinsic organ clearance (Clint) using human specific scaling factors (48.8 mg microsomal protein per g liver, 25.7 g liver per kg body weight). Organ Clim was subsequently converted to hepatic clearance (CLhep, mLomin-10kg-1) using the well-stirred model of hepatic elimination, where Qh is human hepatic blood ﬂow (20.7 mLomin- 1 .

CL1lep is the projected human clearance in the liver based on the above in vitro assay. A lower value is indicative of less compound being removed by the liver. Surprisingly, compounds having a C5- le attachment to the aminopyrimidine core resulted in a lower clearance (i.e., improved ity) as compared to compounds having a C4-pyrazole attachment to the aminopyrimidine core, without a significant change in potency.

[Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson Table 4 Compound Structure LRRK2 Human liver No. TR-FRET ICso microsomes CLhep (nM) (mL/min/kg) (First eluting isomer) [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson Compound ure LRRK2 Human liver N0. TR-FRET ICso microsomes CLhep (nM) (mL/min/kg) [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Wilkinson Unmarked set by Wilkinson Compound ure LRRKZ Human liver No. TR-FRET IC50 microsomes CL]Jep (nM) (mL/min/kg) Example 18 MDRl-MDCK Permeability The blood brain barrier (BBB) separates circulating blood from the extracellular ﬂuid of the central nervous system (CNS). The e membrane permeability (Papp) and MDRl (P-glycoprotein) substrate efﬂux potential were determined using the MDRl-MDCK cell line as an in vitro model of the effective bility of a compound through the BBB. A bidirectional assay was conducted in pre- plated MDRl-MDCK cells using a 12 or 96-well plate in the absence or presence ofMDRl inhibitor (GF120918 or Valspodar). Assays were run in duplicate in transport buffer (HBSS, pH 7.4) for 90 or 120 min (minutes) at 37° C, using a test article concentration of 1 uM. Monolayer integrity was conﬁrmed using Lucifer yellow, and riate positive controls for passive permeability and MDRl transport were included in each experiment. Following incubation, samples from donor and receiver compartments were removed and quenched with acetonitrile containing an appropriate internal standard (IS). Protein was precipitated by centriﬁigation for 10 min at 3220 g, and supematants were diluted in ultra-pure water (if necessary) prior to analysis by LC-MS/MS using riate MRM transitions for analytes and IS. Papp (apparent permeability expressed in cm/sec [centimeter/second]) values were calculated according to the following equation: P ( ) —dCR x VR VR CR = — —x— app cm/sec or dt (Area x CA) Area x Time Co where VR is the solution volume in the receiver chamber (apical or basolateral side), Area is the surface area for the insert membrane), Time is incubation time expressed in seconds, CR is the peak area ratio (analyte/IS) in the receiver r, CA is the e of the initial and final concentrations in the donor chamber, and C0 is the initial peak area ratio in the donor chamber. Papp was determined in both the apical to basolateral (A—>B) and basolateral to apical (B—>A) ions. yer efﬂux ratios (ER) were derived using the following equation: Papp (B —> A) ER =—[Papp D (A —> B) [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson Compounds with an MDRl-MDCK efﬂuX ratio of less than or equal to ﬁve are likely to trate ability to cross the blood-brain-barrier.

Compounds having the 1,2,3-triazole tuent were surprisingly brain ant as compared to molecules having a 1,2,4-triazole moiety.

Table 5 Compound Structure LRRKZ Human liver N0. TR-FRET microsomes CLhep (mL/min/kg) [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson Compound ure LRRKZ Human liver No. TR-FRET microsomes ICSO (11M) CLhep (mL/min/kg) Unless otherwise deﬁned, all technical and scientiﬁc terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this ion belongs.

The inventions illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not speciﬁcally disclosed herein. Thus, for example, the terms “comprising”, “including,” “containing”, etc. shall be read expansively and without limitation. onally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of ing any equivalents of the es shown and described or portions thereof, but it is recognized that various modiﬁcations are possible within the scope of the invention claimed.

Thus, it should be understood that gh the present invention has been speciﬁcally thediscloqy preferred embodiments and optional features, modiﬁcation, improvement and variation ofinven ions embodied therein herein disclosed may be resorted to by those skilled in the art, and that [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson such modiﬁcations, improvements and variations are considered to be within the scope of this invention.

The als, methods, and examples provided here are representative of preferred embodiments, are exemplary, and are not intended as tions on the scope ofthe invention.

The invention has been described broadly and generically herein. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part ofthe invention. This includes the c description of the invention with a proviso or negative limitation removing any subject matter from the genus, regardless of r or not the excised material is speciﬁcally recited In addition, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby bed in terms of any dual member or subgroup ofmembers of the Markush group.

All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety, to the same extent as if each were incorporated by reference individually. In case of conﬂict, the present ication, including definitions, will control.

It is to be understood that while the disclosure has been described in conjunction with the above embodiments, that the foregoing description and examples are intended to illustrate and not limit the scope of the disclosure. Other aspects, advantages and modifications within the scope of the disclosure will be apparent to those skilled in the art to which the disclosure pertains. 1004017871

Claims

What is claimed is:

1. A compound of formula I: or a pharmaceutically acceptable salt, deuterated analog, prodrug, stereoisomer, or a mixture of stereoisomers thereof, wherein: R1 is optionally substituted cycloalkyl; R2 is halo, cyano, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally tuted C2-6 alkynyl, optionally substituted cycloalkyl, optionally substituted C1-6 alkoxy, optionally substituted cycloalkoxy, optionally substituted C1-6 alkylthio, optionally substituted C1-6 alkylsulfonyl, 10, or -C(O)N(R11)(R12); R3 is optionally substituted C1-6 alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkoxy, optionally substituted C1-6 alkylthio, optionally substituted C1-6 alkylsulfonyl, or -N(R11)(R12); R4 is hydrogen or halo; R5 is optionally substituted cyclyl; each R10 is independently optionally substituted C1-6 alkyl or optionally substituted C1-6 alkoxy; R11 and R12 are each independently hydrogen, optionally substituted C1-6 alkyl, or optionally substituted cycloalkyl.

2. The compound of claim 1, wherein R1 is optionally substituted cyclopropyl or optionally substituted cyclobutyl.

3. The compound of claim 2, wherein R1 is cycloalkyl ndently tuted with one or more halo, hydroxy, cyano, or heteroaryl.

4. The compound of claim 3, n R1 is cyclopropyl, cyclobutyl, hydroxycylobutyl, cyanocylobutyl, triazol-2yl-cyclobutyl, triazolyl-cyclobutyl, or cyclobutyl.

5. The nd of any of the preceding claims, n R2 is halo, cyano, C1-6 alkyl optionally substituted with halo.

6. The compound of claim 5, wherein R2 is bromo.

7. The compound of claim 5, wherein R2 is -CF3.

8. The compound of any preceding claim, wherein R3 is optionally substituted lkyl, ally substituted C1-6 alkoxy, or -N(R11)(R12). 1004017871

9. The compound of any preceding claim, wherein R3 is cyclopropyl, methoxy, 1,1- difluoroethyylamino, cyclopropylamino, -NH(CH3), or -NH(CH2CH3).

10. The compound of any preceding claim, wherein R4 is hydrogen.

11. The nd of any preceeding claim, wherein R5 is heterocyclyl substituted with C1-6 alkyl.

12. The compound of 11, wherein R5 is heterocyclyl having an oxo group and tuted with C1-6 alkyl.

13. The compound of claim 12, wherein R5 is 5-methylpyrrolidinoneyl, 3- methyloxetanyl, idinoneyl, 1,1-dioxo-1,2-thiazolidinyl, 3-methyloxolanoneyl, oxabicyclo[3.1.0]hexanoneyl, 1-methyl-pyrrolidinone-yl, 1-ethyl-4,4-difluoropiperidyl, 4,4- difluoropiperidyl, or 2-methyloxo-cyclopentyl.

14. The compound of claim 13, wherein R5 is 5-methylpyrrolidinoneyl.

15. The compound of any preceding claim, n R1 is cycloalkyl independently substituted with one or more hydroxy, cyano, or heteroaryl; R2 is halo or C1-6 fluoroalkyl; R3 is -N(R11)(R12) or C1-6 ; and R4 is H.

16. A compound according to claim 1, or a pharmaceutically acceptable salt, ated analog, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers thereof, selected from: No. Structure N F HN N NH 143 N O (First eluting isomer) 1004017871 N F HN N NH 144 N O (Second eluting isomer) (First eluting isomer) (Second eluting isomer) N F HN N NH 155 N O (First eluting isomer) N F HN N NH 156 N O d eluting isomer) 1004017871 N F HN N O 160 N O (First eluting isomer) N F HN N O 161 N O d eluting isomer) 1004017871

17. A compound according to claim 1, or a pharmaceutically acceptable salt, ated analog, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers thereof, selected from: Structure 1004017871 Structure

18. A compound according to claim 1 having the structure: N F HN N NH N O or a pharmaceutically acceptable salt, stereoisomer, or a e of stereoisomers thereof.

19. A compound according to claim 1 having the structure: 1004017871 or a pharmaceutically acceptable salt, stereoisomer, or a mixture of stereoisomers f.

20. A pharmaceutical composition comprising a compound of any preceding claim, or a pharmaceutically acceptable salt, deuterated analog, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers f, and a pharmaceutically acceptable carrier, diluent, or excipient.

21. Use of a compound of any one of claims 1-19 or a deuterated analog, prodrug, tautomer, stereoisomer, or a mixture of isomers thereof, for the manufacture of a medicament for the treatment of a neurodegenerative disease, , or an inflammatory disease; or Alzheimer’s disease, LDopa induced dyskinesia, Parkinson’s disease, dementia, ALS, kidney cancer, breast cancer, prostate , blood cancer, papillary cancer, lung cancer, acute enous leukemia, multiple myeloma, leprosy, Crohn’s disease, matory bowel disease, ulcerative colitis, amyotrophic lateral sclerosis, rheumatoid arthritis, or ankylosing spondylitis.

22. The use of claim 21, wherein the disease or condition is a neurodegenerative disease.

23. The use of claim 22, wherein the neurodegenerative disease is Parkinson’s disease or dementia.

24. The use of claim 21, wherein the disease or condition is a central nervous system (CNS) disorder.

25. The use of claim 24, wherein the CNS disorder is Alzheimer’s disease or L-Dopa induced dyskinesia.

26. The use of claim 21, wherein the disease or condition is a cancer.

27. The use of claim 26, wherein the cancer is kidney cancer, breast cancer, te cancer, blood cancer, papillary cancer, lung , acute myelogenous ia, or multiple myeloma.

28. The use of claim 21, wherein the disease or condition is an inflammatory disease.

29. The use of claim 28, wherein the inflammatory disease is leprosy, Crohn’s disease, inflammatory bowel disease, ulcerative colitis, amyotrophic lateral sclerosis, rheumatoid arthritis, or ankylosing spondylitis.

30. Use of the pharmaceutical composition of claim 20 in the ation of a medicament for enhancing ive memory in a subject in need thereof.