NZ788756A

NZ788756A - Pyrimidin-2-ylamino-1H-pyrazols as LRRK2 inhibitors for use in the treatment of neurodegenerative disorders

Info

Publication number: NZ788756A
Application number: NZ788756A
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 ATIONS This application is a divisional application of New Zealand application 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. ional Application Numbers 62/350,876 filed June 16, 2016, 62/417,151 filed November 3, 2016, 62/476,581 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 Neurodegenerative diseases, such as son’s disease, amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, Lewy body dementia, and Huntington’s disease affect ns of people. Parkinson’s e is a chronic, progressive motor system disorder characterized by selective degeneration and cell death of dopaminergic neurons in the substantial nigra region of the brain. This leaves patients with impaired ability to direct and control their nts. The cause of the disease was generally considered to be sporadic and n, but significant advancements in understanding have been made in the last 15 years.

The genetic basis for the disease and associated pathogenic mechanisms have led exploration of the gene encoding e-rich repeat kinase 2 (LRRK2) n 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 nt Parkinson’s disease in familial studies (Trinh and Farrar, Nature Reviews in Neurology, Vol. 9, 2013, 4; Paisan-Ruiz et al., J. Parkinson’s Disease, Vol. 3, 2013, 85-103).

The most common pathogenic on, G2019S, occurs in the highly ved kinase domain of LRRK2 (See Gilks et al., , Vol 365, 2005, 415-416). In vitro studies te Parkinson’s disease-associated mutation leads to increased LRRK2 activity and a decreased rate of GTP hydrolysis (Guo et al., mental Cell Research, Vol. 313(16), 2007, 3658-3670). 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, 7).

While progress has been made in this field, there remains a need for improved inhibitors of the LRRK2 receptor which are useful for treatment of various neurodegenerative diseases, such as Parkinson’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 administering) 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 ionNone 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 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 analog, prodrug, stereoisomer, or a mixture of stereoisomers thereof, wherein: R1 is optionally tuted cycloalkyl or, when R5 is R6R7 where R5a is optionally substituted 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, optionally substituted C1-6 alkenyl, optionally substituted C1-6 alkynyl, ally tuted cycloalkyl, optionally substituted C1-6 alkoxy, optionally substituted cycloalkoxy, ally 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, optionally substituted C1—6 alkylsulfonyl, or -N(R”)(R12); R4 is hydrogen or halo, R5 is hydrogen, halo, cyano, ally substituted C1.6 alkyl, optionally substituted C1—6 alkenyl, ally substituted C1.6 l, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally 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 substituted C1—6 alkyl, each R10 is independently optionally substituted C1_6 alkyl or optionally tuted C1_6 alkoxy, R11 and R12 are each ndently hydrogen, ally 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 [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 or a ceutically acceptable salt, deuterated analog, prodrug, isomer, or a mixture of stereoisomers thereof, 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, R21 is optionally substituted cycloalkyl, heteroaryl, C1-6 alkoxy, -S-C1.6 alkyl, or -N(R24)(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, ycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, alkylheterocyclylalkyl, aryl, kyl, 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, heterocyclyl, heterocyclylalkyl, alkylheterocyclylalkyl, aryl, arylalkyl, heteroaryl, 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 lkyl 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 ndently hydrogen or optionally substituted C1—6 alkyl, or R24 and R25 together with the atom to which they are attached form an ally tuted heterocyclyl, 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 pyrazole.

In some ments, the nd is in Table 1A, 1B, 2A or 2B, or is a pharmaceutically acceptable salt, deuterated analog, prodrug, tautomer, stereoisomer, or a mixture of isomers f.

In another embodiment, provided is a pharmaceutical composition comprising a compound as shown in Table 1A, 1B, 2A or 2B, or a ceutically acceptable salt, ated 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 sing a nd as shown in Table 1A or Table 1B, or a pharmaceutically [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 acceptable salt, ated analog, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers f, and a pharmaceutically acceptable carrier, diluent, or excipient, to a subject in need thereof.

In another embodiment, provided is a pharmaceutical composition sing 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 ent.

In another embodiment, provided is a method for treating a disease or ion mediated, at least in part, by LRRKZ, the method sing 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, er, stereoisomer, or a mixture of stereoisomers f, 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 sing administering an effective amount of the pharmaceutical composition comprising a nd 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 thereof.

The description herein sets forth exemplary ments of the present technology. It should be recognized, however, 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 following 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 letters or symbols is used to indicate a point of attachment for a substituent. For example, -C(O)NH2 is attached 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 e, “C1-6 alkyl” indicates that the alkyl group has from 1 to 6 carbon atoms. nce to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter 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 rger embodiments, the term “about” es 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 [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] 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 nd” includes a plurality of such compounds and reference to “the assay” includes nce to one or more assays and equivalents 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 alkyl), 1 to 8 carbon atoms (i.e., C14; , 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 include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, tyl, neopentyl, hexyl, 2- hexyl, 3-hexyl and 3-methylpentyl. 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), tyl (i.e. -CH(CH3)CH2CH3), isobutyl (i.e. -CH2CH(CH3)2) and tert-butyl (i.e. -C(CH3)3), and l” es n-propyl (i.e. -(CH2)2CH3) and isopropyl (i.e. 3)2).

Certain commonly used alternative chemical names may be used. For example, a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, etc., may also be referred to as an “alkylene” group or an enyl” 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-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 l, 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 yl” also includes those groups having one triple bond and one double bond.

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

“Alkylsulfonylalkyl” refers to -alkyl-S(O)2-alkyl.

“Acyl” refers to a group y, wherein Ry is hydrogen, alkyl, l, alkynyl, cycloalkyl, ayl, aryl, heteroalkyl, 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] 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 Wilkinson herein. Examples of acyl include formyl, acetyl, cyclohexylcarbonyl, exylmethyl-carbonyl and benzoyl. ” refers to both a do” 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 hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be ally substituted, as defined herein, or Ry and RZ are taken together 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 hydrogen atoms are ed 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 tuted, as defined herein.

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

“Aryl” refers to an aromatic yclic group having a single ring (e.g. monocyclic) or multiple rings (e.g. ic or tricyclic) including ﬁlSCd s. 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, lkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted, as defined .

“Carboxyl ester” or “ester” refer to both -OC(O)RX and -C(O)OR", wherein RX is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted, as defined .

“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 partially unsaturated cyclic alkyl group having a single ring or multiple rings including ﬁlSCd, bridged and spiro ring systems. The term “cycloalkyl” includes [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson cycloalkenyl 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 lkyl), or 3 to 6 ring carbon atoms (i.e., C3-6 cycloalkyl). Monocyclic groups include, for e, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2. l]heptanyl, 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, less 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 example 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, cyclyl, aryl, heteroalkyl, or aryl, each of which may be ally substituted, as defined herein.

“Hydrazino” refers to -NHNH2.

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

“Imido” refers to a group —C(O)NRyC(O)RZ, wherein 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.

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

“Haloalkyl” refers to an unbranched 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 trihaloalkyl refer to alkyl substituted with two (“di”) or three (“tri” halo groups, which may be, but are not necessarily, the same n. Examples of kyl include triﬂuoromethyl, diﬂuoromethyl, ﬂuoromethyl, trichloromethyl, 2,2,2-triﬂuoroethyl, 1,2-diﬂuoroethyl, 3-bromoﬂuoropropyl, l,2—dibromoethyl and the like.

“Haloalkoxy” refers to an alkoxy group as defined above, n 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 [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 “Hydroxyalkyl” refers to an alkyl group as deﬁned above, n one or more hydrogen atoms are replaced by a hydroxy group.

“Heteroalkyl” 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 ment to the der of the molecule is through a carbon atom. The term “heteroalkyl” includes unbranched or branched saturated chain having carbon and heteroatoms. By way of e, 1, 2, or 3 carbon atoms may be independently replaced with the same or different heteroatomic group. Heteroatomic groups include, but are not limited to, -NRy-, -O-, -S-, -S(O)-, -S(O)2-, and the like, wherein Ry is en, alkyl, l, alkynyl, lkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted, as defined herein. Examples of heteroalkyl groups include ethers (e.g., -CH20CH3, 3)OCH3, -CH2CH20CH3, 20CH2CH20CH3, etc.), thioethers (e.g., -CH2$CH3, -CH(CH3)SCH3, -CH2CH2$CH3, -CH2CH2$CH2CH2$CH3, etc.), sulfones (e.g., -CH2$(O)2CH3, 3)S(O)2CH3, -CH2CH2$(O)2CH3, -CH2CH2$(O)2CH2CH20CH3, etc.), and amines (e.g., -CH2NRyCH3, -CH(CH3)NRyCH3, -CH2CH2NRyCH3, -CH2CH2NRYCH2CH2NRYCH3, etc., where Ry is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be ally substituted, as defined 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 heteroatoms, or 1 atom.

“Heteroaryl” 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 herein, aryl 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 independently 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 heteroatoms, 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, azolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzoﬁJranyl, dibenzothiophenyl, ﬁJranyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, yl, l-oxidopyridinyl, l-oxidopyrimidinyl, l-oxidopyrazinyl, l-oxidopyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, inyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, and nyl. Examples of the heteroaryl rings include, but are not d to, benzopyrazog,5-a]pyridinyliazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[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 ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson ation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by 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 p with aryl as deﬁned above.

“Heteroarylalkyl” refers to the group “heteroaryl-alkyl-.” “Heterocyclyl” refers to a saturated or partially rated 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 comprise one or more oxo (=0) or N—oxide (-O') moieties. Any non-aromatic ring ning 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 attachment 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 cyclyl), having 1 to 5 ring heteroatoms, l to 4 ring heteroatoms, l to 3 ring heteroatoms, l to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulﬁJr or oxygen. Examples of heterocyclyl groups include azetidinyl, azepinyl, benzodioxolyl, benzo[b][l,4]dioxepinyl, nzodioxanyl, yranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, ﬁJranonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, azinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, lidinyl, lidinyl, ydroﬁerl, tetrahydropyranyl, trithianyl, tetrahydroquinolinyl, thiophenyl (i.e. l), tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, l-oxo-thiomorpholinyl and l,l-dioxo-thiomorpholinyl. The term “heterocyclyl” also includes “spiroheterocyclyl” 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 7-azaspiro[3.5]nonanyl, 2-oxaazaspiro[3.4]octanyl and 6-oxa-l-azaspiro[3.3]heptanyl.

Examples of the ﬁJsed-heterocyclyl rings include, but are not limited to, l,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, nyl 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] 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 term “leaving group” refers to an atom or a group of atoms that is displaced in a al reaction as stable species taking with it the bonding electrons. The non-limiting examples of a leaving group include, halo, esulfonyloxy, enesulfonyloxy, triﬂuoromethanesulfonyloxy, nonaﬂuorobutanesulfonyloxy, (4-bromo-benzene)sulfonyloxy, (4-nitro-benzene)sulfonyloxy, robenzene )-sulfonyloxy, (4-isopropyl-benzene)sulfonyloxy, (2,4,6-tri-isopropyl-benzene)-sulfonyloxy, (2,4,6-trimethyl-benzene)sulfonyloxy, t-butyl-benzene)sulfonyloxy, benzenesulfonyloxy, (4- methoxy-benzene)sulfonyloxy, and the like.

“Oxime” refers to the group NOH) wherein Ry is hydrogen, alkyl, alkenyl, l, cycloalkyl, cyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted, as deﬁned herein. nyl” refers to the group -S(O)2Ry, where Ry is hydrogen, alkyl, alkenyl, 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 esulfonyl.

“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 optionally substituted, as defined herein. Examples of sulfinyl are sulfinyl, ethylsulfinyl, phenylsulfinyl and toluenesulfinyl.

“Sulfonamido” refers to the groups -SOzNRyRZ and -NRySOzRZ, 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 circumstance may or may not occur and that the ption includes instances where said event or circumstance occurs and instances in which it does not. Also, the term “optionally substituted” refers to any one or more hydrogen atoms on the designated atom or group may or may not be replaced by a moiety other than hydrogen.

The term “substituted” used herein means any of the above groups (e.g., alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, aryl, and/or heteroalkyl) wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atom such as, but not d to alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl, aralkyl, azido, carbamoyl, yl, carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanadino, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, ine, hydrazone, imino, imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, sulfinic acid, sulfonic acid, sulfonamido, thiol, thioxo, N—oxide, or )3 wherein each Ry is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, aryl, 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 [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 alkyl) in which one or more hydrogen atoms are replaced with -NRth, -NRgC(=O)Rh, =O)NRth, -NRgC(=O)ORh, th, -OC(=O)NRth, -0Rg, -SRg, -SORg, -SOzRg, -OSOzRg, -SOzORg, =NSOzRg, and -SOzNRth. ituted” 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 en, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, cyclyl, 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, mino, thioalkyl, aryl, aralkyl, cycloalkyl, lkylalkyl, 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 similar indefinite ures 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 substituted heteroalkyl group, etc.) are not ed for inclusion herein. Unless otherwise noted, the m number of serial substitutions in compounds described herein is three. For e, serial substitutions of substituted aryl groups with two other substituted aryl groups are limited to ((substituted 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 aryl groups having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to the skilled artisan. When used to modify a chemical group, the term ituted” may describe other chemical groups defined herein. Unless speciﬁed otherwise, where a group is described as optionally substituted, any substituents ofthe group are themselves 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, heterocyclyl, 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, cyclyl, aryl, or heteroaryl, each of which is unsubstituted.

Any compound or structure given herein, is also intended to represent unlabeled forms as well as ically labeled forms of the compounds. Isotopically labeled compounds have structures depicted herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the sed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, ﬂuorine, chlorine and , 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 e those into which radioactive isotopes such as 3H, 13C [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson [Annotation] Sarah.Wilkinson None set by Wilkinson [Annotation] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson and 14C are incorporated. Such isotopically labelled compounds may be useﬁil in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon on ed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.

The disclosure also includes “deuterated analogs” of compounds described herein in which from 1 to n hydrogens attached 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 administered to a mammal, particularly a human. See, for example, Foster, “Deuterium e 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 starting materials in which one or more hydrogens have been replaced by deuterium. ium labelled or substituted therapeutic compounds of the sure may have improved DMPK (drug metabolism and cokinetics) properties, relating to distribution, metabolism and ion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic ity, for example increased in viva half-life, reduced dosage requirements and/or an improvement in therapeutic index. An 18F, 3H, 11C labeled compound may be useﬁil for PET or SPECT or other imaging studies. Isotopically d 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 non-isotopically labeled reagent. It is understood that deuterium in this context is ed 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 compounds ofthis disclosure any atom not speciﬁcally designated as a ular 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 ium.

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 r thereto.

Provided are also pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, stereoisomers and prodrugs of the compounds described herein. “Pharmaceutically able” or “physiologically acceptable” refer to nds, salts, compositions, dosage forms and other materials which are useﬁil in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use. biolog1ca[0072the term “pharmaceutically acceptable salt” of a given compound refers to salts that retain theeffectiveness and properties of the given compound and which are not biologically or [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 otherwise undesirable. “Pharmaceutically acceptable salts” or ologically acceptable salts” include, for example, salts with inorganic acids and salts with an organic acid. In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a on of the acid salt. Conversely, if the product is a free base, an on salt, particularly a pharmaceutically able addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid on salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts.

Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts d 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, nic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, ﬁimaric acid, tartaric acid, citric acid, c acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid and the like. Likewise, pharmaceutically able base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of e only, sodium, potassium, m, aluminum, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines (i.e., NH2(alkyl)), dialkyl amines (i.e., HN(alkyl)2), trialkyl amines (i.e., N(alkyl)3), substituted alkyl amines (i.e., bstituted alkyl)), di(substituted alkyl) amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl) amines (i.e., tituted 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, N(cycloalkyl)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 combining of a compound described herein and water.

A “solvate” refers to an ation or complex of one or more solvent molecules and a nd ofthe disclosure. Examples of solvents that form solvates include, but are not limited to, water, panol, ethanol, methanol, dimethylsulfoxide, ethylacetate, acetic acid and ethanolamine.

Some of the nds exist as tautomers. Tautomers are in equilibrium with one another. For example, amide containing nds may exist in equilibrium with imidic acid ers. Regardless ofwhiqutomer 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] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone 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 Wilkinson tautomers. Thus, the amide containing compounds are understood to include their imidic acid tautomers.

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

The compounds of the invention, or their pharmaceutically acceptable salts include an tric center and may thus give rise to enantiomers, diastereomers, and other stereoisomeric 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. lly 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 crystallization. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography . When the compounds described herein contain olefinic 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 various stereoisomers and mixtures thereof and es “enantiomers,” which refers to two isomers whose molecules are nonsuperimposable mirror images of one another.

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

“Prodrugs” means any compound which releases an active parent drug according to a structure described herein in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound described herein are prepared by modifying ﬁinctional groups present in the compound bed herein in such a way that the modifications may be cleaved in vivo to e the parent compound. Prodrugs may be prepared by modifying ﬁinctional groups t 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, yl, or sulﬂlydryl group in a compound described herein is bonded to any group that may be d 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, ates (e.g., N,N-dimethylaminocarbonyl) ofhydroxy ﬁinctional groups in compounds 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 , “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 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 As used herein, aceutically acceptable carrier” or aceutically 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 tional media or agent is atible with the active ingredient, its use in the eutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions. 2. Compounds Provided herein are nds 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 stereoisomers f, 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 optionally substituted with halo, R2 is halo, cyano, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkenyl, optionally substituted C1-6 alkynyl, optionally substituted cycloalkyl, ally 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 lkoxy, optionally substituted C1.6 alkylthio, optionally substituted C1—6 ulfonyl, or -N(R”)(R12); R4 is hydrogen or halo, R5 is en, halo, cyano, optionally substituted C1_6 alkyl, optionally substituted C1_6 alkenyl, optionally substituted C1_6 alkynyl, optionally substituted cycloalkyl, optionally tuted heterocyclyl, optionally 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 substituted C1_6 alkyl, each R10 is independently ally substituted C1-6 alkyl or optionally substituted C1—6 , R11 and R12 are each independently hydrogen, optionally substituted C1-6 alkyl, ally substitD cycloalkyl, 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] 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 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 en, cyano, halo, optionally substituted C1—6 alkyl, optionally substituted C1.6 alkoxy, or optionally substituted aryl.

In certain embodiments, R6 and R7 are methyl.

In certain 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 optionally substituted cyclobutyl.

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

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

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

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

In certain embodiments, R2 is bromo.

In certain embodiments, R2 is -CF3.

In certain 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 2CH3).

In n embodiments, R4 is hydrogen.

In n embodiments, R5 is cyano, optionally substituted C1-6 alkyl, optionally substituted cycloalkyl, optionally tuted heterocyclyl, optionally substituted heteroaryl, ally substituted C1.6 alkylsulfonyl, -C(O)R10, or -C(O)N(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 ally substituted with one to three oxo orC1-6 alky substituted with one to three halo, C1-6 alkyl, C1-6 alkyl tuted with , heterocyclyl optionally [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] 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 cyano, hydroxyl, alkylsulfonyl, heterocyclyl, hydroxy, alkoxy, or heteroaryl, or C1_6 cycloalkyl tuted 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 optionally substituted with C1-6 alkyl, C1-6 alkyl substituted with cyano, hydroxyl, alkylsulfonyl, cyclyl, hydroxy, alkoxy, or aryl, or C1.6 cycloalkyl substituted with cyano, aminocarbonyl, or alkoxycarbonyl.

In certain embodiments, R5 is 2-(triazolyl)propan-2—yl, 2-pyrimidin-2—ylpropanyl, N,N— dimethylamido, 2-methylpropanyl, methylsulfonyl, cyano, oxypropan-2—yl, methylcarbonyl, 5- methylpyrrolidin-2—oneyl, l-(triazolyl)ethyl, 2-methylsulfonylpropanyl, 5-methyl-l,3-oxazol yl)pyrazolyl, 3-methyloxetanyl, o-cycloprop-2—yl, pyrrolidin-2—oneyl, oxo-l,2— thiazolidin-2—yl, 7-methyl-5,6-dihydropyrrolo[l,2-a]imidazolyl, xycarbonyl-cyclopropyl, l- arbonyl-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, 2-methylsulfonylpropan-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 yl-pyrrolidinone-yl.

In certain ments, R1 is cycloalkyl independently substituted with one or more hydroxy, cyano, or heteroaryl, R2 is halo or C1-6 ﬂuoroalkyl, R3 is -N(R”)(R12) or C1_6 , and R4 is hydrogen.

In certain embodiments, certain compounds ed 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 compounds are of formula 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 acceptable 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] 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 Unmarked set by Sarah.Wilkinson R2 is halo, cyano, optionally substituted C1_6 alkyl, optionally substituted C1_6 alkenyl, optionally substituted C1-6 l, optionally substituted cycloalkyl, optionally substituted C1-6 alkoxy, optionally substituted lkoxy, optionally substituted C1.6 hio, optionally substituted C1—6 alkylsulfonyl, -C(O)R10, or -C(O)N(R“)(R12), R10 is optionally tuted C1-6 alkyl or optionally substituted C1—6 alkoxy, and each R11 and R12 are independently hydrogen, optionally substituted C1.6 alkyl, optionally tuted cycloalkyl, or R11 and R12 together form an optionally substituted heterocyclyl group.

In certain embodiments, R1 is optionally substituted ropyl.

In certain embodiments, R1 is cyclopropyl.

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

In certain embodiments, R2 is bromo.

In certain embodiments, R2 is -CF3.

In certain ments, 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 acceptable salt, deuterated analog, prodrug, isomer, or a mixture of stereoisomers thereof, wherein: R20 is halo, cyano, C1_6 alkyl, C1_6 haloalkyl, C1_6 alkoxy, C1_6 haloalkoxy, cycloalkyl, cycloalkoxy, cycloalkylalkyl, lkylalkoxy, or -C(O)R23, R21is optionally substituted cycloalkyl, heteroaryl, C1_6 , -S-C1_6 alkyl, or -N(R24)(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 ulfonylalkyl, cycloalkyl, cyanocycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, alkylheterocyclylalkyl, aryl, arylalkyl, D 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 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 cyanoalkyl; C1_6 aminoalkyl; C1_6 alkylsulfonyl; C1_6 ulfonylalkyl; cycloalkyl; cyanocycloalkyl; cycloalkylalkyl; heterocyclyl; heterocyclylalkyl; alkylheterocyclylalkyl; aryl; kyl; heteroaryl; heteroarylalkyl; eteroarylalkyl; 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; n 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 heterocyclyl; 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 one embodiment; ring A contains additional heteroatoms. In one embodiment; ring A contains only the bridgehead nitrogen shared with the pyrazole ring.

In one embodiment; provided is a compound of formula IIA: VN‘” 11A or a ceutically acceptable salt; deuterated analog; prodrug; stereoisomer; or a e of stereoisomers thereof; n 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 ceutically acceptable salt; ated analog; prodrug; stereoisomer; or a e 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 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 In one embodiment, provided is a compound of a IIA-a: R22 IIA-a or a ceutically acceptable salt, deuterated analog, prodrug, stereoisomer, or a mixture of isomers thereof, wherein R20, R21, R22 and m are as deﬁned herein.

In one embodiment, provided 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 n embodiments, R20 is C1_6 haloalkyl.

In n embodiments, R21 is optionally substituted lkyl or -N(R24)(R25). In certain embodiments, R21 is ally 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, lkylalkyl, heterocyclyl, heterocyclylalkyl, alkylheterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkylheteroarylalkyl, heteroarylcycloalkyl, and alkylheteroarylcycloalkyl is optionally substituted.

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

In certain embodiments, two R22 together with the atom to which they are ed form a lkyl or heterocyclyl, wherein each cycloalkyl and heterocyclyl is optionally substituted. In certain embodiments, two R22 together with the atom to which they are attached form a heterocyclyl. 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] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson In one embodiment, provided is a compound of formula III: N 111 or a pharmaceutically acceptable salt, ated analog, prodrug, stereoisomer, or a mixture of stereoisomers 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, cycloalkylalkyl, cycloalkylalkoxy, or -C(O)R33, R31 is optionally substituted C1-6 alkoxy, optionally substituted cycloalkyl, optionally tuted lkoxy, optionally substituted C1_6 alkylthio, optionally substituted C1_6 alkylsulfonyl, or - N(R35)(R36); R32 is hydrogen, halo, cyano, ally substituted C1_6 alkyl, optionally substituted C1_6 alkenyl, optionally substituted C1_6 alkynyl, optionally tuted C1_6 haloalkyl, optionally tuted C1_6 alkoxy, optionally tuted C1-6 haloalkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally tuted 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 substituted C1-6 alkyl or optionally substituted C1—6 alkoxy, and R35 and R36 are each independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted lkyl, or R35 and R36 together form an optionally substituted 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 , 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 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 R31 is optionally 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 alkenyl, optionally substituted C1.6 alkynyl, optionally substituted C1-6 haloalkyl, optionally substituted C1—6 alkoxy, ally substituted C1-6 haloalkoxy, optionally substituted cycloalkyl, ally substituted heterocyclyl, optionally tuted 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 heterocyclyl, wherein each C1_6 alkyl, C1-6 alkoxy, and heterocyclyl is optionally substituted; R34 is optionally substituted C1-6 alkyl or ally substituted C1—6 alkoxy, R35 and R36 are each independently hydrogen, optionally substituted C1-6 alkyl, optionally and substituted cycloalkyl, or R35 and R36 er form an optionally substituted heterocyclyl group.

In one ment, provided is a nd of formula IIIB: HNAN| / N_l'\l R32 N IIIB or a pharmaceutically acceptable salt, deuterated analog, prodrug, stereoisomer, or a mixture of stereoisomers f, 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 optionally substituted C1-6 alkoxy, optionally substituted cycloalkyl, optionally substituted lkoxy, ally 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 l, optionally substituted C1.6 alkynyl, optionally substituted C1-6 haloalkyl, optionally substituted C1—6 alkoxy, optionally substituted C1-6 haloalkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, ally 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 , -N(R35)(R36), or heterocyclyl, wherein each C1_6 alkyl, C1-6 alkoxy and heterocyclyl is optionally tuted, D4 is optionally substituted C1-6 alkyl or optionally substituted C1—6 alkoxy, and [Annotation] Sarah.Wilkinson None set by 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 ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson R35 and R36 are each independently hydrogen, optionally substituted C1_6 alkyl, optionally 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 n embodiments, R30 is C1-6 haloalkyl. In certain ments, R30 is C1_6 haloalkyl.

In certain embodiments, R31 is optionally substituted cycloalkyl, C1-6 alkoxy or -N(R35)(R36).

In certain embodiments, R31 is optionally tuted cycloalkyl or )(R36). In certain ments, R31 is cycloalkyl or -N(R35)(R36). In certain 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, heterocyclyl, heteroaryl, C1—6 alkylthio, C1—6 alkylsulfonyl, -C(O)R34, or -C(O)N(R35)(R36). In certain embodiments, R32 is hydrogen, halo, cyano, optionally substituted C1.6 alkyl, ally substituted C1—6 haloalkyl, optionally substituted C1—6 alkoxy, or optionally substituted C1-6 haloalkoxy. In certain embodiments, R32 is en. In certain embodiments, R32 is halo. In certain embodiments, R32 is methyl.

In one ment, provided is a compound of formula IVA: (R45)n IVA or a pharmaceutically acceptable salt, deuterated analog, prodrug, stereoisomer, or a mixture of stereoisomers thereof, wherein: W is O, C(R46)(R47) or N(R46), R40 is halo, cyano, optionally substituted C1-6 alkyl, optionally tuted C1-6 alkenyl, optionally substituted C1_6 alkynyl, optionally substituted cycloalkyl, optionally substituted C1_6 alkoxy, optionally substituted cycloalkoxy, optionally tuted C1_6 alkylthio, optionally substituted C1_6 alkylsulfonyl, 48, or -C(O)N(R49)(R50), R41 is optionally substituted C1_6 alkoxy, optionally substituted cycloalkyl, optionally tuted cycloalkoxy, optionally substituted C1_6 alkylthio, optionally substituted C1_6 alkylsulfonyl, or -N(R49)(R50); R42 is optionally substituted cycloalkyl or C1-6 alkyl optionally substituted with halo, R43 is hydrogen 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, ally substituted C1.3 alkyl, optionally substituted cycloalkyl, or ally 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 ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson R48 is optionally substituted C1_6 alkyl or optionally substituted C1_6 alkoxy, and R49 and R50 are each ndently hydrogen, optionally substituted C1-6 alkyl, ally substituted cycloalkyl, or R49 and R50 together form an optionally substituted cyclyl group.

In one embodiment, provided is a compound of formula IVA-a: HN N R41 R42 \ R43 (R45)n IVA-a 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 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 3-(4-((4-cyclopropyl(triﬂuoromethyl)pyrimidin no)-3 -methyl- lH-pyrazol- l rrolidinone, 3 -(4-((4-cyclopropyl-5 - (triﬂuoromethyl)pyrimidin-2—yl)amino)methyl- lH-pyrazol- l -yl)-3 -methylpyrrolidinone, 3 -(4-((4- cyclopropyl-5 uoromethyl)pyrimidinyl)amino)-5 -methyl- lH-pyrazol- l -yl)pyrrolidinone, or 3 - -cyclopropyl-5 -(triﬂuoromethyl)pyrimidinyl)amino)-3 -methyl- azol- 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 , and: R40 is halo or C1_6 haloalkyl, R41 is -N(R49)(R50), D2 is optionally substituted cyclopropyl, R49 is hydrogen, and [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 R50 is optionally substituted C1_6 alkyl.

In one embodiment, provided is a compound of formula IVB: or a pharmaceutically acceptable salt, deuterated analog, prodrug, stereoisomer, or a mixture of stereoisomers f, wherein: R40 is halo, cyano, optionally substituted C1_6 alkyl, optionally substituted C1_6 alkenyl, optionally substituted C1_6 l, 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 alkylthio, ally substituted C1—6 alkylsulfonyl, or -N(R49)(R50); R42 is optionally substituted lkyl or C1-6 alkyl ally substituted with halo, R43 is hydrogen or halo, each R44 is independently 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 substituted C1.3 alkyl, optionally substituted cycloalkyl, or optionally substituted cyclyl, R48 is optionally substituted C1-6 alkyl or optionally substituted C1—6 , 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 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 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, ated 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 substituted 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— '2.wone, 5 ~(4 thylamin o)~5 - {trifluorome Lhylﬁwrémidin —2~yiamino}~3«16:111in — lI-I~p.yrazol — l ~yi)— i~me thylpipen 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)— yrazoln 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— pyrazol~4—yl}~ unit} uoron'ietliylupyi’imidine"2,4udiamine, Milne N” ~ [5 lu 14(8)»? writethylmpiperidinu?) ~yl )_ lI-Eu pyrazol~4—yl} ~5 —ti’lfluoromethyl~133'i'imidine—2,4—diamine, or N4wethyl—N 2—{ 3 “Illeﬂ'lzyr’l' l —((S) — l amethylv pi peri din—3 —yl)— 1 ol—dmylj —5 —tri ﬂmromethyi —pyrimidine—2,4—diami no, or a stereoisomer thereof In one embodiment, the nd is not 5-(4-((4-cyclopropyl(triﬂuoromethyl)pyrimidin yl)amino)-3 l- azol- l -yl)- l -ethylpiperidinone, 5 -(4-((4-cyclopropyl-5 - oromethyl)pyrimidin-2—yl)amino)methyl- lH-pyrazol- l -yl)- l -ethylpiperidin-2—one, 5 4- cyclopropyl-5 -(triﬂuoromethyl)pyrimidinyl)amino)-3 -methyl- lH-pyrazol- l -yl) - l -methylpiperidin 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 - (triﬂuoromethyl)pyrimidin-2—yl)amino)methyl- lH-pyrazol- l -yl)- l -ethylpiperidin-2—one, 5 -(4-((4- cyclopropyl-5 -(triﬂuoromethyl)pyrimidinyl)amino)-5 -methyl- lH-pyrazol- l -yl) - l -methylpiperidin one, or a isomer thereof.

[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] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson In one embodiment, provided is a compound 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 mixture 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 substituted cyclopropyl, R49 is hydrogen, and R50 is ally 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 , prodrug, stereoisomer, or a mixture of stereoisomers thereof, wherein: R60 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)R64, or -C(O)N(R65)(R66), R61 is optionally substituted C1-6 alkoxy, ally substituted cycloalkyl, ally substituted lkoxy, optionally substituted C1.6 alkylthio, ally substituted C1—6 alkylsulfonyl, or -N(R65)(R66); R62 is en 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, ally substituted heteroaryl, optionally substituted C1.6 alkylthio, optionally substituted C1—6 alkylsEhyl, -C(O)R64, or -C(O)N(R65)(R66), R64 is independently optionally substituted C1_6 alkyl or ally substituted C1_6 alkoxy, [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] 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 optionally substituted heterocyclyl group.

In one embodiment, the compound is not NZ43~cyciopmpylvi~methyl~l H-pyrazol~4—yl)~N4~ methyl —5 uoromethyl)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 l)pyrimidinvZ~ylamino)— lH—pyrazol— l ﬁll—2'anothylpropanvlwl, l~(3 —e:yclopropyl~4—(4— {ethyiam ino)—5 luoromethyl)pyrimidiii—Zvylamino}l H-pyrazol~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 methylwpropionitrilo, or a stereoisomer thereof.

In one embodiment, provided is a compound as shown in Table 1A or a ceutically 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 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 [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 ed set by Sarah.Wilkinson 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] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson 0. ure . 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] 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 No. StructurC No. 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] 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] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson No. StructurC No. Structure (First eluting isomer) [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] 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 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson No. Structure SecOnd e1u.Ung .1 S0meA” [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 [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 Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson N0. Str.uCtu r.e (Second g isomer) [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] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.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] 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 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 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 Wilkinson DumEN (ﬁrst eluting isomer) HN N N/ (ﬁrst eluting isomer) A?» H (ﬁrst eluting isomer) [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 HN N N� t)-==N t> ••••==N (first eluting isomer) (second clutin, ·.g isomer) 21.'i Br 210 A.A/, HN N N� /, F H N \ r �� N-N, � F t> II 11:=N t> ••••==N (second c utmg isomer),j • (first eluting isomer) 211 N�: A .. � . .-- HN N � "" t>• •••==N (First c u mg isomer),J t· (second c utmg isomer),J · 217 212 Br A ..AN� NXFFF N , o" HNAN N� � \ N-N N-Nr+-fo t)-== N F' �b (first eluting isomer) (second eluting isomer) --= -----1 2-1 - NXFFF HN)lN NH l> :N � N-N N d eluting isomer) \--<'\ �/\ \,, N, [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 MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson 101431 In some embodiments. the compound is in Table I Bor is a phatrnaceutically able 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] 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 Structure N0. Structure [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 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 ation] Sarah.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 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] Wilkinson Unmarked set by Sarah.Wilkinson Structure Structure (SecOnd e1u.Ung .m0meA” (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 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 (First eluting ) (First eluting isomer) [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] 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 (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 ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson Structure Structure (Sec0nd e1u.Ung U (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 ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Wilkinson In one embodiment, a compound may be selected from those compounds in Table 1A. Also included within the disclosure are pharmaceutically acceptable salts, prodrugs, stereoisomers, or a mixture of isomers 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 nds in Table 1B. Also included within the disclosure are pharmaceutically acceptable salts, prodrugs, stereoisomers, or a mixture of stereoisomers f. In n embodiments, provided are compounds of Table 1B for use in the methods described herein.

Speciﬁc stereoisomers contemplated 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 Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by 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 ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson F F [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] 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] Wilkinson None set by 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.

Table 2B ation] 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 Sarah.Wilkinson [Annotation] Sarah.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 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] 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 acceptable salts, prodrugs, stereoisomers, or a mixture of stereoisomers thereof. In one embodiment, a nd may be selected from those compounds in Table 2B. Also ed within the disclosure are pharmaceutically acceptable salts, deuterated analogs, prodrugs, stereoisomers, or a mixture of stereoisomers thereof. In certain embodiments, provided are compounds of Table 2A for use in the s described herein. In certain embodiments, provided are compounds of Table 2B for use in the methods bed herein. 3. Treatment s and Uses “Treatment” or “treating” is an approach for obtaining beneficial or desired results including al results. Beneficial or desired clinical results may include one or more ofthe following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent ofthe disease or condition), b) g or arresting the development of one or more clinical ms associated with the disease or condition (e.g., stabilizing 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, causing the sion of al symptoms (e.g., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another medication, delaying the progression of the disease, sing the quality of life and/or prolonging survival.

“Prevention” or “preventing” means any treatment of a disease or ion that causes the clinical symptoms of the e or condition not to develop. Compounds may, in some embodiments, be stered to a subject (including 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.

The term “therapeutically effective amount” or “effective amount” of a compound described herein or a pharmaceutically acceptable salt, deuterated , tautomer, stereoisomer, mixture of ation] 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 stereoisomers, prodrug, or deuterated analog thereofmeans an amount sufficient to effect treatment when stered to a t, to provide a therapeutic benefit such as amelioration of symptoms or slowing of disease progression. For e, a therapeutically effective amount may be an amount sufficient to decrease a symptom of a disease or condition of as described . The therapeutically effective amount may vary ing on the t, and disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, 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 tions in viva or ex viva. “In viva” means within a living dual, 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 samples including ﬂuid or tissue samples obtained from individuals. Such s may be obtained by methods well known in the art. Exemplary biological ﬂuid samples include blood, cerebrospinal ﬂuid, urine, and saliva. In this context, the compounds and compositions described herein may be used for a variety of purposes, ing therapeutic and experimental purposes. For example, the compounds and compositions described herein may be used ex viva to determine the optimal schedule and/or dosing of administration of a compound of the t disclosure for a given indication, cell type, dual, 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 compounds and compositions described herein may be suited are described below or will become nt 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 properties may be ed using commonly known methods to those skilled in the art.

LRRK2 has been associated with the transition from mild cognitive impairment to Alzheimer’s disease, L-Dopa induced dyskinesia (Hurley et al., Eur. J, Neurosci., Vol. 26, 2007, 171-177), CNS ers associated with neuroprogenitor cell proliferation and migration, and regulation of LRRK2 may have utility in improving neurological outcomes following ischemic injury, and stimulating restoration of CNS ﬁll’lCthl’l following al 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 disease, le sclerosis, and HIV-induced dementia (See Milosevic et al., Mol. Neurodegen., Vol. 4, 2009, 25), kidney, breast, prostate (e.g. solid tumor), blood and lung cancer, and acute myeologenouse leukemia (AML), lymphomas and leukemias (See Ray et al., J. lo., Vol. 230, 2011, 109), multiple myeoloma (Chapman et al., Nature, Vol. 471, 2011, 467-472), papillary renal and thyroid carcinomas, le myeloma (Chapman et al., Nature, Vol. 471, 2011, 467-472), diseases ofthe immune system, including rheumatoid arthritis, systemic lupus erythegsus autoimmune hemolytic anemia, pure red cell aplasia, idiopathic thrombocytopenic pupurav(ITP), ans me, vasculitis, bullous skin ers, type 1 diabetes mellitus, Sjogren’s syndrome, [Annotation] 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 ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked 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 egen. Dis. Vol. 7, 2010, 265-271), Gaucher disease (See oek et al., . 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 t, M and Jakes, R, Biochemica et Biophysica Acta, Vol. 1739, 2005, 240-250), diseases characterized by diminished dopamine levels such as withdrawal symptoms/relapse associated 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 ophic lateral sis (ALS).

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

In another aspect, the present disclosure relates to a method of treating a disease or condition mediated, at least in part, by LRRK2. In particular, the disclosure es 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 disclosure. In some embodiments, the disease or condition mediated, at least in part, by LRRK2 is a neurodegenerative disease, for example, a central nervous system (CNS) disorder, such as son's e (PD), Alzheimer's disease (AD), ia (including Lewy body dementia and cascular dementia), amyotrophic l sclerosis (ALS), age related memory dysﬁJnction, mild cognitive impairment (e.g., including the transition from mild cognitive impairment to Alzheimer’s disease), philic grain disease, lysosomal disorders (for example, Niemann-PickType C disease, Gaucher disease) corticobasal degeneration, progressive supranuclear palsy, inherited frontotemporal ia and parkinsonism linked to chromosome 17 (FTDP-17), withdrawal symptoms/relapse associated with drug addiction, 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 n specific embodiments, the cancer is thyroid, renal (including ary renal), breast, lung, blood, and prostate cancers (e.g. solid tumor), leukemias (including acute myelogenous leukemia (AMLgr mas. In some embodiments, the cancer is kidney cancer, breast cancer, prostate cancer, ood cancer, papillary cancer, lung cancer, acute myelogenous leukemia, or multiple myeloma.

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

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

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

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

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

In other embodiments, provided is the use of the presently disclosed compounds for the manufacture of a medicament for treating a neurodegenerative disease, cancer, or an inﬂammatory 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, son’s disease, dementia, amyotrophic lateral sclerosis, 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 colitis, amyotrophic lateral sclerosis, rheumatoid arthritis, or ankylosing spondylitis.

The term “trauma” as used herein refers to any al damage to the body caused by violence, accident, re 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 ation] 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 Wilkinson to ischemic stroke or hemorrhagic stroke. The term “myocardial infarction” refers to a cardiovascular disorder characterized by localized necrosis resulting from ction of the blood supply.

In certain embodiments, the present disclosure relates to compounds for ting 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 t disclosure preferably exert their effect on inhibiting cell death at a concentration less than about 50 micromolar, more preferably at a concentration less than about 10 micromolar, and most preferably at a concentration 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 able salt, deuterated analog, tautomer, stereoisomer, mixture of isomers, 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 manufacture that include a compound bed herein or a ceutically acceptable salt, deuterated analog, er, 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. . ceutical itions and Modes of Administration Compounds provided herein are usually stered in the form of pharmaceutical compositions. Thus, provided herein are also pharmaceutical compositions that contain one or more of the compounds described herein or a pharmaceutically acceptable salt, deuterated analog, tautomer, stereoisomer, e of stereoisomers, prodrug, or deuterated analog thereof and one or more pharmaceutically acceptable vehicles ed from carriers, adjuvants and excipients. Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and nts. Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985), 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 pharmaceutical composition may be administered by s methods including, for example, rectal, buccal, intranasal and transdermal routes. In certain embodiments, the pharmaceutical composition may be administered by intra-arterial injection, intravenously, eritoneally, parenterally, intramuscularly, subcutDJusly, orally, topically, or as an inhalant.

[Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] 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 One mode for administration is parenteral, for example, by inj . The forms in which the pharmaceutical compositions described herein may be incorporated for administration by ion 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. stration may be via, for example, capsule or enteric coated tablets. In making the pharmaceutical compositions that include at least one compound described herein or a pharmaceutically acceptable salt, deuterated analog, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a e, 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 al, which acts as a vehicle, r or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid ), ointments containing, for e, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile inj ectable solutions, and sterile packaged powders.

Some examples of suitable excipients e lactose, se, e, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, m silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The ations can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifying and suspending agents, preserving agents such as methyl and propylhydroxy- benzoates, sweetening , and ﬂavoring agents.

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

Controlled e 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 ll’lﬁlSlOl’l of the compounds described herein in controlled amounts. Transdermal patches may be constructed for uous, pulsatile, or on demand delivery of pharmaceutical agents.

For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a ceutical excipient to form a solid preformulation ition containing a homogeneous mixture of a compound described herein or a pharmaceutically acceptable salt, deuterated analog, tautomer, stereoisomer, mixture of isomers, prodrug, or deuterated analog thereof. When referring to theneformulation compositions as neous, the active ingredient may be dispersed evenly 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 throughout the composition so that the composition may be readily subdivided into equally 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 ing the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can include 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 als can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

Compositions for inhalation or insufﬂation may include solutions and suspensions in pharmaceutically acceptable, aqueous or organic ts, or es thereof, and powders. The liquid or solid itions may contain suitable pharmaceutically acceptable excipients as described 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 solvents may be nebulized by use of inert gases. zed solutions may be inhaled ly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, 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 nd ofthe t application for any particular subject will depend upon a variety of factors including 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 ation and the severity of the particular disease in the subject oing therapy. For example, a dosage may be expressed as a number of rams of a compound described herein per kilogram ofthe subject’s body weight (mg/kg). s 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 between 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. izing according to the subject’s body weight is particularly 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 ive dosage in a man 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 bed herein adminged per dose or per day. Daily dosage of a nd of Table 1A, Table 1B, Table 2A or Table may be between about 1 mg and 4,000 mg, between about 2,000 to 4,000 mg/day, between [Annotation] Sarah.Wilkinson None set by 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 about 1 to 2,000 mg/day, between about 1 to 1,000 mg/day, between about 10 to 500 mg/day, between about 20 to 500 mg/day, between about 50 to 300 , between about 75 to 200 mg/day, or between about 15 to 150 mg/day.

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

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

In a particular ment, the method comprises 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. ents of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. The dosage can be sed daily, every other day, twice per week, or once per week. 7. Combination y In another aspect of the disclosure the compounds can be administered in combination with other agents, including (but not limited to) nds that are apoptosis inhibitors, PARP poly(ADP- ribose) polymerase inhibitors, Src inhibitors, agents for the treatment of cardiovascular disorders, ension, hypercholesterolemia and type II diabetes, anti-inﬂammatory , anti-thrombotic agents, ﬁbrinolytic agents, anti-platelet agents, lipid reducing agents, direct in inhibitors, glycoprotein IIb/IIIa receptor inhibitors, calcium channel blockers, beta-adrenergic or blocking agents, cyclooxygenase (e.g., COX-1 and COX-2) inhibitors, ensin 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 sure 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 disease. In some embodiments, the additional therapeutic agent is L-dopa (e.g., Sinemet®), a nergic agonist (e.g. Ropinerol or Pramipexole), a catechol-O-methyltransferase (COMT) inhibitor (e.g. Entacapone), a L-monoamine oxidase (MAO) inhibitor (e.g., selegiline or line) or an agent which increases dopamine release (e.g., Zonisamide).

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

The present disclosure also provides combinations of one or more compounds that inhibit cellular necrosis combined 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 apparent 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 sis cal compounds described herein may be accomplished as described in the following examples. If ble, reagents may be purchased commercially, e.g., from Sigma Aldrich or other chemical suppliers.

The compounds of the disclosure may be prepared using methods disclosed herein and routine modiﬁcations thereof which will be apparent given the disclosure herein and methods well known in the art. tional and nown 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, reagents may be purchased commercially, e.g. from Sigma Aldrich or other chemical suppliers.

The compounds ofthis disclosure can be prepared from readily ble starting materials using, for example, the following general methods and procedures. It will be iated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other s conditions can also be used unless ise 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.

Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain onal groups from undergoing undesired reactions. Suitable protecting groups for various ﬁinctional groups as well as suitable conditions for protecting and deprotecting ular 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). Greene's tive groups in organic synthesis. Hoboken, 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 diastereomers or as stereoisomer-enriched mixtures. All such stereoisomers (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 starting materials or selective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be ted using, for example, chiral column chromatography, chiral resolving agents, and the like.

The ng als 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 Unmarked set by Sarah.Wilkinson [Annotation] Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson USA). Others may be prepared by procedures or obvious modiﬁcations thereof, described in standard nce texts such as Fieser and Fieser's Reagents for Organic sis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and mentals ier 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 Organic Transformations (VCH Publishers Inc., 1989).

The terms nt,” “inert organic solvent” or “inert solvent” refer to a solvent inert under the conditions of the reaction being described in conjunction ith (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 d out under an inert gas, preferably nitrogen.

The term “q.s.” means adding a quantity sufficient 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 tuent 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 compounds 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 .

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 prepared by coupling of a substituted dine of formula OK) with an amine of formula (Z), wherein R2, R3, ring B and m are defined as in any of the formulas provided herein or by the ic 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 a OK) or (Z) can be prepared according to the more specific s described in the es which follow or by methods known to one of skill in the art. Coupling of : of formula OK) and (Z) in presence of an acid, provides a compound of formula (X). In some diments, the acid is toluene sulfonic acid or triﬂuroacetic acid. In some ation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] 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 MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson embodiments, coupling of compounds of formula OK) and (Z) in the presence of a base es a compound of formula (X). In some embodiments, the base is triethylamine.

In one embodiment, provided is a method of preparing a compound of formula (X) comprising coupling a compound of formula OK) with a compound of a (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 ed 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 ments, X is halo.

When not commercially available, amines of formula (Z) can be prepared from commercially available starting materials. For example, in certain embodiments, amines of a (Z) can be prepared from reducing the corresponding nitro substituted compound. The amines of formula (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- stereoisomer of formula III, IIIA, or IIIB), a single stereoisomer of the corresponding amine may be prepared prior to coupling with the substituted dine of formula (Y). Each of the cis- and trans- stereoisomers can be prepared by selectively inverting the chemistry 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 starting 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 on 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] 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 MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson the ester of compound (2-3) to the (x-cyanoketone compound (2-4) can be accomplished under substitution reaction conditions using a strong base (e.g., butyllithium) and acetonitrile. Contacting compound (2-4) with an appropriately substituted hydrazine (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 ing the compounds of formula Ia.

EXAMPLES The following examples are ed to demonstrate ic embodiments of the disclosure.

It should be appreciated by those of skill in the art that the ques disclosed in the examples which follow represent techniques to ﬁmction well in the practice of the sure, and thus can be considered 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 oven-dried or ﬂame-dried glassware under nitrogen atmosphere. All chemicals were purchased from commercial vendors and used as is, unless otherwise specified. Reactions were magnetically stirred 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 is was performed on Shimadzu 20AB HPLC system with a photodiode array detector and Luna-C18(2) 2.0X50mm, 5um column at a ﬂow rate of 1.2 mL/min with a gradient t 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) detection as well as ve electrospray ionization (MS). Semi-preparative 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 is was performed on Thar ical SFC system with a UV/Vis detector and series of chiral columns ing 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 nt 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 preparative 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] 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 MigrationNone set by Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson of 65 mL/min with a gradient solvent Mobile phase A (MPA, C02): Mobile phase B (MPB, MeOH+0.1 % (v/v) ) (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 starting materials is not described, these are commercially ble, 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 examples or intermediates, it will be appreciated by the skilled person that the reaction time, number of equivalents of ts and temperature can be modiﬁed for each speciﬁc reaction and that it may be necessary or desirable to employ different work-up or puriﬁcation techniques. Where reactions are carried out using microwave ation, the microwave used is a Biotage tor. The actual power supplied varies during the course of the on 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 allowed 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 d 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 e of ) (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 7 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 ﬁltrate 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), 2.63-2.84 (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) se at -75 0C under N2 over a period of 1 h. After addition, the mixture was stirred for 1 Ipn the solution of 1,1,1,2,2,2-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 [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 into aqueous NH4Cl (1.5 L). The c phase was ted 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 reduced 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), .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- dioxane (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 mixture was cooled to 25 OC and concentrated 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 d 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 trated 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]+. ethylnitr0-1H-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 s phase was extracted with DCM (2 X 600 mL). The combined organic phase was washed with aqueous NaHC03 (500 mL), brine (500 mL), dried with anhydrous Na2SO4, ﬁltered and concentrated under reduced pressure. (Four batches of the same scale were combined to workup) The residue was puriﬁed by silica gel column tography (PE: EtOAc = 1: 1) to afford (1R,3R)(5 -methylnitro-1H-pyrazol yl)cyclobutanol 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), 2.47-2.58 (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 solution of 12 5 g, 532.49 mmol) in THF (200 mL) dropwise at 0 0C under N2. After that the e was stirred at 25 0C for 16 h. The mixture was poured into ter (500 mL). The aqueous phase was extracted with EtOAc (2 X 300 mL). The combined organic phase was washed with brine (500 mL), dried with anhydrous Na2SO4, ﬁltered and trated under reduced pressure. The residue was puriﬁed by silica gel column tography (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. ation] 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 ation] 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 c layers were washed with water (2 x 50 mL), brine (50 mL), dried over Na2SO4, ﬁltered and concentrated. The crude product was puriﬁed 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 trated under reduced pressure. The residue was diluted with water (10 mL), extracted with EtOAc (10 x 5 mL). The combined organic layers were dried over Na2SO4, ﬁltered and concentrated to give 3-(4-amino-5 -methyl- pyrazol-l-yl)cyclobutanecarbonitrile. LCMS: RT 0.101 min, m/z = 177.2 . 2-ch10ro-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 ethanamine (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 pressure to afford a residue. The residue was ated with DCM (200 mL) and ﬁltered. The ﬁltrate was tallizated with n-heptane (600 mL) and MTBE (400 mL). The precipitated phase was syrup. The liquid was discarded. The syrup residue was puriﬁed by silica gel column chromatography OAc = 20: 1) to afford 2-chloro-N-ethyl-5 uoromethyl)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,), .H20 (55 mg, 289.41 umol) in oxane (10 mL) was stirred at 90°C for 2 h. The mixture was concentrated under reduced pressure. 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 N4-ethyl-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 ation] Sarah.Wilkinson None set by 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 (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]+. sis 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 on, 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 ice-water (70 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 (2 X 200 mL), dried with anhydrous Na2SO4, ﬁltered and concentrated under reduced pressure. The residue was puriﬁed by silica gel column chromatography OAc = 3: 1) to give ethyl 2-methyl(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 2-methy1(2H-1,2,3-triazoly1)propanoate (200 mg, 2.36 mmol) was added dropwise 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 d 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 mixture was stirred at 95 0C for 4 h. The reaction mixture was concentrated to get a e, which was diluted 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). [0217DN4-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 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 yl)propanyl]-1H-pyrazolamine (100 mg, 477.85 umol) and 2-chloro-N-ethyl (triﬂuoromethyl)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 mixture was concentrated under reduced re. 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 combined organic layers were washed with brine (10 mL), dried over Na2SO4, ﬁltered and concentrated under reduced pressure. The residue was puriﬁed by prep-TLC OAc = 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]+.

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 c phase was washed with brine (2 X 100 mL), dried over anhydrous Na2SO4, ﬁltered and concentrated under d pressure. The residue was puriﬁed by silica gel column chromatography (PEzEtOAc =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 on 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 2-methyl(triazol yl)propanoate (l g, 5.91 mmol) was added dropwise at -78 OC. The resulting mixture was d at -78 0C for 2 h. The reaction mixture 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 Na2SO4, ﬁltered and trated under reduced pressure. The e 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 ation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed 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 (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 pressure. The residue was puriﬁed by prep-TLC (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 (triflu0r0methyl)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 d pressure. The residue was puriﬁed by prep-TLC (SiOz, PEzEtOAc = 1: 1) and ﬁthher puriﬁcation by prep-HPLC (FA) to give N2-[2-cyclopropyl[1-methyl olyl)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 solution 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 mixture was stirred 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 e was st' at 20 0C for 10.5 h. The reaction mixture was poured into s 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 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 mL), dried over anhydrous Nast4, ﬁltered and concentrated under reduced pressure. The residue was puriﬁed by silica gel column tography (PE: EtOAc = 20:1 to 1: 1) to give ethyl yloxotetrahydroﬁJrancarboxylate as a yellow oil. 1H NMR (400 MHz, 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 d at this temperature for 30 min. The suspension mixture was added dropwise to a solution of ethyl 3-methyloxo-tetrahydroﬁ1ran carboxylate (4.7 g, 27.30 mmol) in THF (50 mL) at -78 0C for 30 min. The ing mixture was warmed to -40 OC and stirred at -40 0C for 1.5 h. The reaction mixture was quenched by addition of sat.

NH4Cl at 0 OC, and then adjusted to pH=4-5 with 1N HCl and ted with EtOAc (3 X 50 mL). The combined organic layers were washed with brine (20 mL), dried over ous Nast4, ﬁltered and concentrated under reduced pressure to give 3-(3 -methyloxo-tetrahydrofuran-3 -oxo- propanenitrile as a yellow solid, which was used in next step without 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, 3, 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 dihydrochloride 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 adjusted to pH=7 with sat.NaHC03, 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 d pressure. The crude product was d 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] 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 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 1-(1-cyclopropyl((4-(ethylamino)(trifluoromethyl)pyrimidinyl)amino)—1H- pyrazolyl)pyrrolidinone (153) opropyl-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. NaHCOg, concentrated under reduced pressure. The crude product was puriﬁed 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, 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 robutanoyl 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 e was puriﬁed by silica gel column chromatography (PEzEtOAc = 10:1 to 0: 1) to give N—(5-amino cyclopropyl-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 m, 4 H). 1-(5-aminocyclopropyl-1H-pyrazolyl)pyrrolidin-2—one: To a solution ofN-(5-amino- opropyl-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 d at 0 0C for 20 min, and then stirred at 15 0C for 1.5 h. The reaction mixture was quenched by addition of aq.

NH4Cl (100 mL) at 0 OC, and then extracted with DCM:i-PrOH (V:V = 3:1, 3 X 100 mL). The combined c layers were dried over NazSO4, ﬁltered and trated under d pressure. The residue was puriﬁed 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 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 Wilkinson 1-(1-cyclopr0pyl((4-(ethylamin0)(trifluoromethyl)pyrimidinyl)amin0)—1H- pyraz01yl)pyrr01idin0ne: To a on 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 Synthesis of N2-[3-cyclopr0pyl(1,1-dioxothietanyl)pyrazolyl]-N4—ethyl (trifluor0methyl)pyrimidine-2,4-diamine (110) 3—(3-cycl0pr0pylnitr0-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 stirred at 20 °C for 30 min, then treated with 3-bromothietane 1,1-dioxane (1.01 g, 3.26 mmol) and stirred at 20 °C for 15.5 h. The mixture was poured into ice-water (30 mL) and extracted with EtOAc (3 X 15 mL). The combined c 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 OAc = 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 oxide (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 mixture was heated at 70°C for 2 h, then concentrated under reduced pressure. The e was washed with a mixture solvent of DCM and MeOH (10 mL, 10:1), ﬁltered and the ﬁltrate was concentrated 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 on 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 ed 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 anhydrous Na2SHPLCgutral)ltered and concentrated under reduced pressure. 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] 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 (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 yl]amino]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, - (chloromethy1)oxirane (31.51 g, 340.6 mmol) was added at 20 0C under N2. The e was stirred at 90 0C for 12 h. The mixture was concentrated under reduced pressure at 45 OC. The e was poured into ice-water (100 mL) and d for 5 min. The aqueous 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 solution of methyl (1R,5S)oxo yclo[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 ted 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 pressure. The residue was puriﬁed by silica gel column chromatography (PE: MTBE = 50: 1 to 0: 1) to give 3-[(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 (632.28 mg, 4.36 mmol) in one portion at 25 0C under N2. The mixture was stirred 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 anhydrous Na2SO4, ﬁltered and concentrated under reduced pressure. The residue was puriﬁed by prep- [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] 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 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 2-chloro-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 c phase was washed with brine (30 mL), dried with anhydrous Na2SO4, ﬁltered and concentrated under reduced pressure. The residue was puriﬁed by prep-HPLC (neutral condition) to give (1R,5S)[1-cyclopropyl[[4-(ethylamino) (triﬂuoromethyl)pyrimidinyl]amino]pyrazol-3 -yl]oxabicyclo[3.1.0]hexanone. 1H NMR (400 MHz, CDCl3)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]+.

EXAMPLE 8 Synthesis 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- benzyloxycyclobutanone (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 e 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 stirred 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 ed 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 anhydrous Na2SO4, d and trated to afford enzyloxycyclobutyl)pyrazol-3 -amine as a yellow oil. LCMS: RT 0.625 min, m/z = 244.2 [M+H]+. [0242 -(5-amin0pyrazolyl)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 Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson ation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson e was stirred at 20 0C for 2 h. The mixture was poured into saturated NaHC03 (200 mL) and the aqueous phase was trated under reduced pressure. The residue was washed with DCMzMeOH (vzv = 10: 1, 100 mL), ﬁltered and the ﬁltrate was trated 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 -(triﬂuoromethyl)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 adjusted to pH = 7-8 by aqueous NaHCOg. The aqueous phase was extracted with EtOAc (3 X 50 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, ﬁltered and concentrated under reduced 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) (triﬂuoromethyl)pyrimidinyl)amino)-1H-pyrazolyl)cyclobutanol and (1R,3R)-3 -(5 -((4- (ethylamino)-5 -(triﬂuoromethyl)pyrimidinyl)amino)-1H-pyrazolyl)cyclobutanol as a yellow gum. )—3—(5-((4-(ethylamin0)(triflu0romethyl)pyrimidinyl)amin0)-1H-pyrazol yl)cyclobutyl methanesulfonate )—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 (709.14 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 c phase was separated, washed with brine (10 mL), dried over anhydrous Na2SO4, d and concentrated under reduced pressure to give a residue. 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 (1R,3R)(5- ((4-(ethylamino)-5 uoromethyl)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 mixture 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] 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 over anhydrous Na2S04, d and concentrated under reduced pressure to give a residue. The residue was puriﬁed by prep-HPLC (FA) to give product, which was ﬁthher puriﬁed 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. )(5-((4-(ethylamin0)(triflu0r0methyl)pyrimidin-Z-yl)amin0)-1H—pyraz01—1- yl)cyclobutanecarbonitrile. 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 lobutyl)—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 n 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 residue was separated by prep-HPLC (FA condition) to afford ((1R,3R)(2H- triazolyl)cyclobutyl)-1H-pyrazol-5 -yl)-N4-ethyl-5 uoromethyl)pyrimidine-2,4-diamine and N2-(1-((1R,3R)-3 -(1H- 1,2,3 -triazolyl)cyclobutyl)-1H-pyrazol-5 -yl)-N4-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 .

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 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 .18-5.27 (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), 3.11-3.23 (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 uor0methyl)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% ) 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 , ﬁltered and concentrated under reduced pressure. The residue was puriﬁed by silica gel column tography OAc = 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). hl0r0nitr0-pyrazolyl)pyrazine: To a on 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 (PEzEtOAc = 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 cyclopropylboronic 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 ﬁltered. The e was added with water (15 mL). The s phase was extracted with EtOAc (3 X 8 mL). The combined organic phase was washed with brine (8 mL), dried over anhydrous Na2SO4, ﬁltered and concentrated. The e 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 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 h. The e 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 pressure 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- amine: 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 oxane (5 mL) was added p-TsOH.HzO (34 mg, 198.78 umol) at 20 OC. The mixture was heated to 90 OC and stirred for 2 h. The mixture was cooled to 20 OC, added with water (10 mL) and adjusted to pH = 7-8 by sat. . 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 on of 3- ropylnitro-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 mixture was stirred at 20 0C for 30 min, then treated with 3- bromotetrahydrofuranone (1.19 g, 7.18 mmol, 670 uL) and d 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 anhydrous NazSO4, ﬁltered and trated 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 [M+H]+. 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 e 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 stirred 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 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 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 1: 1) to give 3-(3-cyclopropylnitro-pyrazolyl)methyl-tetrahydroﬁ1ranone as a colorless oil. 1H NMR (400 MHz, CDCl3)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 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 e was ﬁltered and the ﬁltrate was concentrated under reduced pressure to give 3-(4cyclopropyl-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). (3S)—3-[3-cyclopr0pyl[[4-(methylamin0)—5-(triflu0r0methyl)pyrimidin yl]amino]pyrazol-l-yl]methyl-tetrahydrofuran-Z-one and (3R)[3-cyclopr0pyl[[4- lamin0)—5-(triflu0r0methyl)pyrimidin-Z-yl]amino]pyrazol-l-yl]methyl-tetrahydrofuran- 2-0ne: A mixture of 2-chloro-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 ed 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 -[3 -cyclopropyl[[4-(methylamino)-5 -(triﬂuoromethyl)pyrimidin no]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 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 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]+.

EXAMPLE 12 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 pressure. The residue was puriﬁed by silica gel column tography (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 thyl-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 d at 15 0C for 15 h. The reaction mixture was quenched by addition 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 , ﬁltered and trated under reduced 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 [M+H]+. 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- cyclopentanone (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 d at 90 0C for 2 h under N2. The reaction mixture was ﬁltered and the ﬁltrate was concentrated under reduced pressure. The e 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] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] 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 on 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), 2-chloro-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 ave. The mixture was trated under reduced pressure. The residue was puriﬁed by prep-HPLC (neutral) and prep-TLC (PEzEtOAc = 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 ethylnitro-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 reaction mixture and then the e 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 extracted with EtOAc (3 X 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, ﬁltered 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 gwith 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 ed organic layers were washed with brine (70 mL), [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Wilkinson [Annotation] 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, ﬁltered and concentrated under reduced pressure. The residue was puriﬁed by silica gel column tography (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 pressure, 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, FORM-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 (S)-3—(4-((4-(ethylamin0) (trifluoromethyl)pyrimidin-Z-yl)amin0)methyl-1H-pyrazolyl)—3-(fluoromethyl)dihydrofuran- 2(3H)—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 c layers were washed with brine (20 mL), dried over Na2SO4, ﬁltered and concentrated under reduced pressure. The e was puriﬁed by silica gel column chromatography (PE: EtOAc = 3:1 to 1:1) to give desired nd 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] 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 EXAMPLE 14 Synthesis of 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) utyl 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 e 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- piperidine-l-carboxylate as a yellow oil. LCMS: RT 1.306 min, m/z = 255.2 +. 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 3-(4-nitropyrazolyl)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 d by silica gel column chromatography (PEzEtOAc = 1:0 to 3: 1) to give tert-butyl 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). utyl 3-(5-chl0r0nitro-pyrazolyl)-4,4-diflu0r0-piperidinecarb0xylate: To a solution 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 d 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 reduced pressure. The residue was puriﬁed 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] Wilkinson None set by Sarah.Wilkinson ation] Sarah.Wilkinson ionNone 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). 3—(5-chlor0nitr0-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 d 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 s phase was extracted with EtOAc (3 X 15 mL), dried over anhydrous Na2SO4, d 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 d at 20 0C for 1 h. The mixture was ed to pH = 7-8 with sat. aq. NaHC03 and the aqueous phase was extracted with EtOAc (3 X 15 mL). The combined 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 stirred at 80 0C for 1 h. The reaction mixture was ﬁltered and the ﬁltrate was concentrated under reduced pressure. The crude was washed with DCM : MeOH (V : V = 10 : 1) (30 mL), ﬁltered and the ﬁltrate was concentrated 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]+.

N2-[5-chlor0[(3S)ethyl-4,4-diflu0r0piperidyl]pyrazolyl]-N4-ethyl (trifluor0methyl)pyrimidine-2,4-diamine and N2-[5-chlor0[(3R)—1-ethyl-4,4-diflu0r0 dyl]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- -(triﬂuoromethyl)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 mixture 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 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] 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 ted 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 eluting 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: ion Time: 1.108 min. MS: m/z = 454.4 [M+H]+. SFC: Retention Time: 1.785 min.

EXAMPLE 15 Synthesis of (1S,2R)—2-[4-[(5-br0m0meth0xy-pyrimidinyl)amino]-3—cyclopropyl-pyrazol-lyl ]cyclopropanecarbonitrile and (1R,ZS)[4-[(5-brom0meth0xy-pyrimidinyl)amin0] cyclopropyl-pyrazol-l-yl]cyclopropanecarbonitrile (213 and 214) opr0pylnitr0vinyl-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 e was concentrated. The crude t 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 hodiorhodium (200 mg, 262.31 umol) in DCM (100 mL) was added dropwise ethyl 2-diazoacetate (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] 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 (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). )—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 extracted with EtOAc (3 X 50 mL). The combined organic phase was washed with brine (3 X 50 mL), dried with anhydrous Na2SO4, ﬁltered and trated under reduced pressure to give (1S,2R)(3 -cyclopropylnitro-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 e 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% ) 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 s phase was extracted with EtOAc (3 X 50 mL). The combined organic phase was washed with brine (150 mL), dried with anhydrous Na2SO4, ﬁltered and concentrated under reduced re.

The residue was puriﬁed 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 . 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). 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] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.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 e was stirred at 75 0C for l h. The e was ﬁltered and the ﬁltrate was concentrated. The residue was washed with DCM: MeOH (10:1, 3 X 10 mL), ﬁltered and the ﬁltrate 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). (1S,2R)—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 .H20 (30 mg, 159.38 umol) at 20 0C under N2. The mixture was stirred at 85 0C for 4 h. The mixture 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 NazSO4, d and concentrated under reduced pressure. The residue was puriﬁed by silica gel column chromatography (PEzEtOAc = 100:1 to 1:1) and ted 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, 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 g isomer: 1H NMR (400 MHz, 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 general procedures 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 [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 ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson o pLRRKtide antibody 0 ll assay plate 0 DMSO Enzyme reaction conditions 0 50 mM Tris pH 7.5, 10 mM MgClz, 1mM EGTA, 0.01% 5, 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 reaction 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 lly 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, Labcyte). The plates were fuged 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 reference compound solution, test nd solution, HPE and ZPE were erred to assay plates. The assay plate was centrifuged at 2500 rpm for 1 minute, and sealed with foil.

To perform the enzyme on, 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 reaction, EDTA completely mixed in T 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 trate 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 ing to the above methods and found to exhibit an LRRK2 G2019S IC50 as indicated in Table 3. In the table below, activity is provided 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] 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 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 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] Sarah.Wilkinson None set by Sarah.Wilkinson ation] 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 [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed 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 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 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 ed 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. tic reactions were conducted for 0, 5, 10, 20, 30, or 60 min before termination by addition of acetonitrile containing tolbutamide and labetalol internal standards (100 ng/mL). After shaking for 10 min, plates were ted 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 percent compound remaining 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 sic 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 0kg-1).

CL1lep is the projected human clearance in the liver based on the above in vitro assay. A lower value is indicative of less nd being removed by the liver. Surprisingly, compounds having a C5- pyrazole attachment to the aminopyrimidine core resulted in a lower clearance (i.e., improved stability) as compared to nds 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 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 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] Wilkinson MigrationNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ed set by Sarah.Wilkinson Compound Structure 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 Sarah.Wilkinson ation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson [Annotation] Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson ionNone set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson Unmarked set by Sarah.Wilkinson Compound Structure 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 passive membrane permeability (Papp) and MDRl (P-glycoprotein) ate efﬂux potential were determined using the MDRl-MDCK cell line as an in vitro model of the effective permeability of a compound through the BBB. A bidirectional assay was conducted in pre- plated MDRl-MDCK cells using a 12 or l 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 ﬁigation for 10 min at 3220 g, and supematants were d in ultra-pure water (if necessary) prior to analysis by LC-MS/MS using appropriate MRM tions 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 sed in seconds, CR is the peak area ratio (analyte/IS) in the receiver chamber, CA is the average 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 teral (A—>B) and teral to apical (B—>A) directions.

Monolayer 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] 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 Compounds with an MDRl-MDCK efﬂuX ratio of less than or equal to ﬁve are likely to demonstrate y to cross the blood-brain-barrier.

Compounds having the 1,2,3-triazole substituent were surprisingly brain penetrant as compared to molecules having a 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 Sarah.Wilkinson ation] Sarah.Wilkinson ed set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson None set by Sarah.Wilkinson [Annotation] Sarah.Wilkinson MigrationNone set by Wilkinson [Annotation] Wilkinson Unmarked set by Sarah.Wilkinson Compound Structure LRRKZ Human liver No. TR-FRET microsomes ICSO (11M) CLhep (mL/min/kg) Unless otherwise , 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 invention 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 ively and without limitation.

Additionally, the terms and sions 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 excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modiﬁcations are le within the scope of the invention claimed.

Thus, it should be understood that although the present invention has been speciﬁcally thediscloqy preferred ments 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 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 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 materials, methods, and examples provided here are representative of preferred embodiments, are exemplary, and are not intended as limitations 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 generic description of the invention with a proviso or negative tion removing any subject matter from the genus, regardless of whether or not the excised material is speciﬁcally d herein.

In addition, where features or aspects of the invention are described in terms of Markush groups, those d in the art will recognize that the invention is also y described in terms of any dual member or subgroup ofmembers of the Markush group.

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

It is to be understood that while the disclosure has been bed 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. 1004017995

Claims

What is claimed is:

1. A compound having the structure: or a pharmaceutically acceptable salt, deuterated analog, g or stereoisomer, or a mixture of stereoisomers thereof.

2. A pharmaceutical composition comprising the compound claim 1, or a pharmaceutically acceptable salt, deuterated analog, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

3. Use of a compound of claim 1 or a deuterated analog, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers f, for the manufacture of a medicament for treating a neurodegenerative disease, , an inflammatory disease, Alzheimer’s disease, L-Dopa induced dyskinesia, Parkinson’s disease, dementia, amyotrophic lateral sclerosis (ALS), kidney , breast cancer, prostate cancer, blood cancer, papillary , lung cancer, acute myelogenous leukemia, multiple myeloma, leprosy, s disease, inflammatory bowel disease, tive colitis, amyotrophic lateral sclerosis, toid arthritis, or ankylosing spondylitis..

4. The use of claim 3, wherein the disease or condition is a neurodegenerative disease.

5. . The use of claim 4, wherein the neurodegenerative disease is Parkinson’s disease or dementia.

6. The use of claim 3, wherein the disease or condition is a central s system (CNS) disorder.

7. The use of claim 6, wherein the CNS disorder is Alzheimer’s e or L-Dopa induced dyskinesia.

8. The use of claim 3, wherein the e or condition is a cancer. 1004017995

9. The use of claim 8, n the cancer is kidney cancer, breast cancer, prostate cancer, blood cancer, papillary cancer, lung cancer, acute myelogenous leukemia, or multiple myeloma.

10. The use of claim 3, wherein the disease or condition is an matory disease.

11. The use of claim 10, wherein the inflammatory disease is leprosy, Crohn’s disease, inflammatory bowel disease, ulcerative colitis, amyotrophic lateral sclerosis, rheumatoid tis, or sing spondylitis.

12. Use of the pharmaceutical composition of claim 2 in the preparation of a medicament for enhancing cognitive memory in a subject in need thereof.