Potassium channel modulators

Abstract

Provided are novel compounds of Formula (I): and pharmaceutically acceptable salts thereof, which are useful for treating a variety of diseases, disorders or conditions which can be affected by potassium channel modulation. Also provided are pharmaceutical compositions comprising the novel compounds of Formula (I), pharmaceutically acceptable salts thereof, and methods for their use in treating one or more diseases, disorders or conditions, associated with potassium channels.

Description

POTASSIUM CHANNEL MODULATORS BACKGROUND

[0001] Among the ion channels, potassium channels are the largest and most diverse, being found in a variety of animal cells such as nervous, muscular, glandular, immune, reproductive, and epithelial tissue. These channels allow the flow of potassium in and / or out of the cell under certain conditions. These channels are regulated, e.g., by calcium sensitivity, voltage-gating, second messengers, extracellular ligands, and ATP-sensitivity.

[0002] Dysfunction of potassium channels, as well as other ion channels, generates loss of cellular control and results in altered physiological functioning and disease conditions.

[0003] Because of their ability to modulate ion channel function and / or regain ion channel activity in acquired or inherited channel opathies, potassium channel modulators are being used in the pharmacological treatment of a wide range of pathological diseases and have the potential to address an even wider variety of therapeutic indications.

[0004] The small conductance calcium-activated potassium channels (SK channel) are a subfamily of Ca<com:Sup>2+< / com:Sup>-activated K<com:Sup>+< / com:Sup> channels and the SK channel family contains 4 members - SK1, SK2, SK3, and SK4 (often referred to as intermediate conductance). The physiological roles of the SK channels have been especially studied in the nervous system, where for example they are key regulators of neuronal excitability and of neurotransmitter release, and in smooth muscle, where they are crucial in modulating the tone of vascular, broncho- tracheal, urethral, uterine or gastro-intestinal musculature.

[0005] Given these implications, small molecule modulators of potassium ion channels could have potentially powerful influence in the modulation and control of numerous consequences of a variety of conditions. SUMMARY

[0006] Disclosed are compounds and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, which are useful in the treatment of diseases associated with the modulation of ion channels, such as potassium ion channels. (See e.g., Table 2). Such compounds include those of structural Formula I: [Image disponible dans le document PDF, Image available in the PDF document] ) or a pharmaceutically acceptable salt thereof, wherein each of R<com:Sup>1< / com:Sup>, R<com:Sup>3< / com:Sup>, R<com:Sup>5< / com:Sup>, R<com:Sup>4a< / com:Sup>, R<com:Sup>4b< / com:Sup>, X<com:Sup>1< / com:Sup>, X<com:Sup>2< / com:Sup>, and A are defined and described herein.

[0007] Compounds described herein, and pharmaceutically acceptable compositions thereof, are useful for treating a variety of diseases, disorders or conditions, associated with the modulation of potassium channels. Such diseases, disorders, or conditions include those described herein. BRIEF DESCRIPTION OF THE FIGURES

[0001] FIG. 1 is a diagram illustrating the effect of Compound 359 following oral (PO) dosing on harmaline induced tremor.

[8000] FIG. 2 is a diagram illustrating the <com:Math><semantics>%<annotation encoding="application / x-tex">\%< / annotation>< / semantics>< / com:Math>SK2 SC<com:Sub>100< / com:Sub> of Compound 359 compared with chlorzoxazone (CHZ). DETAILED DESCRIPTION 1. General Description of Compounds of the Invention

[0009] In certain embodiments, provided herein is a compound of Formula I: [Image disponible dans le document PDF, Image available in the PDF document] (I); or a pharmaceutically acceptable salt thereof, wherein: [Image disponible dans le document PDF, Image available in the PDF document] ring A is selected from <com:Math><semantics>X1<annotation encoding="application / x-tex">X^{1}< / annotation>< / semantics>< / com:Math> is selected from <com:Math><semantics>C(Ra)<annotation encoding="application / x-tex">C(R^{a})< / annotation>< / semantics>< / com:Math> and N; <com:Math><semantics>X2<annotation encoding="application / x-tex">X^2< / annotation>< / semantics>< / com:Math> is selected from <com:Math><semantics>C(Rb)<annotation encoding="application / x-tex">C(R^b)< / annotation>< / semantics>< / com:Math> and N, wherein <com:Math><semantics>X1<annotation encoding="application / x-tex">X^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X2<annotation encoding="application / x-tex">X^2< / annotation>< / semantics>< / com:Math> are not simultaneously nitrogen; each of R<com:Sup>a< / com:Sup> and R<com:Sup>b< / com:Sup> is independently selected from hydrogen, halo, -CN, optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub> alkyl, optionally substituted -O-(C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub> alkyl), -OH, -NH<com:Sub>2< / com:Sub>, optionally substituted -NH(C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub> alkyl), optionally substituted -N(C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub> alkyl)<com:Sub>2< / com:Sub>, optionally substituted -S-(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C4<annotation encoding="application / x-tex">C_4< / annotation>< / semantics>< / com:Math> alkyl), and optionally substituted -S(<com:Math><semantics>O<annotation encoding="application / x-tex">O< / annotation>< / semantics>< / com:Math>)<com:Sub>2< / com:Sub>-<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C4<annotation encoding="application / x-tex">C_4< / annotation>< / semantics>< / com:Math> alkyl; each R<com:Sup>1< / com:Sup>, if present, is independently selected from halo, -CN, optionally substituted <com:Math><semantics>−C1−C6<annotation encoding="application / x-tex">-C_1-C_6< / annotation>< / semantics>< / com:Math> alkyl, optionally substituted <com:Math><semantics>−O1−C4<annotation encoding="application / x-tex">-O_1-C_4< / annotation>< / semantics>< / com:Math> alkyl, optionally substituted -NH(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C4<annotation encoding="application / x-tex">C_4< / annotation>< / semantics>< / com:Math> alkyl), optionally substituted -N(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C4<annotation encoding="application / x-tex">C_4< / annotation>< / semantics>< / com:Math> alkyl)<com:Sub>2< / com:Sub>, optionally substituted -S-<com:Math><semantics>(C1−C4 alkyl)<annotation encoding="application / x-tex">(C_1-C_4 \text{ alkyl})< / annotation>< / semantics>< / com:Math>, optionally substituted -S(O)-<com:Math><semantics>(C1−C4 alkyl)<annotation encoding="application / x-tex">(C_1-C_4 \text{ alkyl})< / annotation>< / semantics>< / com:Math>, and optionally substituted <com:Math><semantics>−S(O)2−C1−C4<annotation encoding="application / x-tex">-S(O)_2-C_1-C_4< / annotation>< / semantics>< / com:Math> alkyl; each R<com:Sup>2< / com:Sup> is independently selected from halo, -CN, optionally substituted C<com:Sub>3< / com:Sub>-C<com:Sub>6< / com:Sub> cycloalkyl, optionally substituted <com:Math><semantics>−C1−C6<annotation encoding="application / x-tex">-C_1-C_6< / annotation>< / semantics>< / com:Math> alkyl, optionally substituted <com:Math><semantics>−O−(C1−C4<annotation encoding="application / x-tex">-O-(C_1-C_4< / annotation>< / semantics>< / com:Math> alkyl), optionally substituted -NH(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C4<annotation encoding="application / x-tex">C_4< / annotation>< / semantics>< / com:Math> alkyl), optionally substituted -S-(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C4<annotation encoding="application / x-tex">C_4< / annotation>< / semantics>< / com:Math> alkyl), optionally substituted <com:Math><semantics>−S(O)−(C1−C4 alkyl)<annotation encoding="application / x-tex">-S(O)-(C_1-C_4 \text{ alkyl})< / annotation>< / semantics>< / com:Math>, and optionally substituted <com:Math><semantics>−S(O)2−C1−C4 alkyl<annotation encoding="application / x-tex">-S(O)_2-C_1-C_4 \text{ alkyl}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is selected from halo, <com:Math><semantics>−C(=O)NH2<annotation encoding="application / x-tex">-C(=O)NH_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OH<annotation encoding="application / x-tex">-OH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−CN<annotation encoding="application / x-tex">-CN< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−(C0−C4)<annotation encoding="application / x-tex">-(C_0-C_4)< / annotation>< / semantics>< / com:Math> alkylene)- carbocyclyl, -(C<com:Sub>0< / com:Sub>-C<com:Sub>4< / com:Sub> alkylene)-heteroaryl, -(C<com:Sub>0< / com:Sub>-C<com:Sub>4< / com:Sub> alkylene)-heterocyclyl, -(C<com:Sub>0< / com:Sub>-C<com:Sub>4< / com:Sub> alkylene)-aryl, <com:Math><semantics>−N(R6)<annotation encoding="application / x-tex">-N(R^6)< / annotation>< / semantics>< / com:Math>-carbocyclyl, <com:Math><semantics>−N(R6)<annotation encoding="application / x-tex">-N(R^6)< / annotation>< / semantics>< / com:Math>-heterocyclyl, <com:Math><semantics>−N(R6)<annotation encoding="application / x-tex">-N(R^6)< / annotation>< / semantics>< / com:Math>-heteroaryl, <com:Math><semantics>−N(R6)<annotation encoding="application / x-tex">-N(R^6)< / annotation>< / semantics>< / com:Math>-aryl, <com:Math><semantics>−N(R6)<annotation encoding="application / x-tex">-N(R^6)< / annotation>< / semantics>< / com:Math>-aryl, <com:Math><semantics>−N(R6)<annotation encoding="application / x-tex">-N(R^6)< / annotation>< / semantics>< / com:Math>-aryl, <com:Math><semantics>−N(R6)<annotation encoding="application / x-tex">-N(R^6)< / annotation>< / semantics>< / com:Math>-aryl, <com:Math><semantics>−N(R6)<annotation encoding="application / x-tex">-N(R^6)< / annotation>< / semantics>< / com:Math>-aryl, <com:Math><semantics>−N(R6)<annotation encoding="application / x-tex">-N(R^6)< / annotation>< / semantics>< / com:Math>-aryl, <com:Math><semantics>−N(R6)<annotation encoding="application / x-tex">-N(R^6)< / annotation>< / semantics>< / com:Math>-aryl, <com:Math><semantics>−N(R6)<annotation encoding="application / x-tex">-N(R^6)< / annotation>< / semantics>< / com:Math>-aryl, <com:Math><semantics>−N(R6)<annotation encoding="application / x-tex">-N(R^6)< / annotation>< / semantics>< / com:Math> <com:Math><semantics>O(C0−C4 alkyl)<annotation encoding="application / x-tex">O(C_0-C_4 \text{ alkyl})< / annotation>< / semantics>< / com:Math> carbocyclyl, <com:Math><semantics>−O(C0−C4 alkylene)<annotation encoding="application / x-tex">-O(C_0-C_4 \text{ alkylene})< / annotation>< / semantics>< / com:Math> heterocyclyl, <com:Math><semantics>−O(C0−C4 alkylene)<annotation encoding="application / x-tex">-O(C_0-C_4 \text{ alkylene})< / annotation>< / semantics>< / com:Math> heteroaryl, <com:Math><semantics>−<annotation encoding="application / x-tex">-< / annotation>< / semantics>< / com:Math> <com:Math><semantics>O(C0−C4 alkylene)<annotation encoding="application / x-tex">O(C_0-C_4 \text{ alkylene})< / annotation>< / semantics>< / com:Math>aryl, <com:Math><semantics>−S(C0−C4 alkylene)<annotation encoding="application / x-tex">-S(C_0-C_4 \text{ alkylene})< / annotation>< / semantics>< / com:Math>carbocyclyl, <com:Math><semantics>−S(C0−C4 alkylene)<annotation encoding="application / x-tex">-S(C_0-C_4 \text{ alkylene})< / annotation>< / semantics>< / com:Math>heterocyclyl, - <com:Math><semantics>S(C0−C4 alkylene)<annotation encoding="application / x-tex">S(C_0-C_4 \text{ alkylene})< / annotation>< / semantics>< / com:Math>heteroaryl, <com:Math><semantics>−S(C0−C4 alkylene)<annotation encoding="application / x-tex">-S(C_0-C_4 \text{ alkylene})< / annotation>< / semantics>< / com:Math>aryl, <com:Math><semantics>−S(O)(C0−C4 alkylene)<annotation encoding="application / x-tex">-S(O)(C_0-C_4 \text{ alkylene})< / annotation>< / semantics>< / com:Math>carbocyclyl, <com:Math><semantics>−<annotation encoding="application / x-tex">-< / annotation>< / semantics>< / com:Math> <com:Math><semantics>S(O)(C0−C4)<annotation encoding="application / x-tex">S(O)(C_0-C_4)< / annotation>< / semantics>< / com:Math> alkylene)heterocyclyl, <com:Math><semantics>−S(O)(C0−C4)<annotation encoding="application / x-tex">-S(O)(C_0-C_4)< / annotation>< / semantics>< / com:Math> alkylene)heteroaryl, <com:Math><semantics>−S(O)(C0−C4)<annotation encoding="application / x-tex">-S(O)(C_0-C_4)< / annotation>< / semantics>< / com:Math> alkylene)aryl, <com:Math><semantics>−S(O)2(C0−C4<annotation encoding="application / x-tex">-S(O)_2(C_0-C_4< / annotation>< / semantics>< / com:Math> alkylene)carbocyclyl, <com:Math><semantics>−S(O)2(C0−C4<annotation encoding="application / x-tex">-S(O)_2(C_0-C_4< / annotation>< / semantics>< / com:Math> alkylene)heterocyclyl, <com:Math><semantics>−<annotation encoding="application / x-tex">-< / annotation>< / semantics>< / com:Math> <com:Math><semantics>S(O)2(C0−C4 alkylene)<annotation encoding="application / x-tex">S(O)_2(C_0-C_4 \text{ alkylene})< / annotation>< / semantics>< / com:Math>heteroaryl, <com:Math><semantics>−S(O)2(C0−C4 alkylene)<annotation encoding="application / x-tex">-S(O)_2(C_0-C_4 \text{ alkylene})< / annotation>< / semantics>< / com:Math>aryl, <com:Math><semantics>−O−(C1−C4 alkyl)<annotation encoding="application / x-tex">-O-(C_1-C_4 \text{ alkyl})< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NH(C1−C4 alkylene)<annotation encoding="application / x-tex">-NH(C_1-C_4 \text{ alkylene})< / annotation>< / semantics>< / com:Math> alkyl), <com:Math><semantics>−S−(C1−C4 alkyl)<annotation encoding="application / x-tex">-S-(C_1-C_4 \text{ alkyl})< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(O)−(C1−C4 alkyl)<annotation encoding="application / x-tex">-S(O)-(C_1-C_4 \text{ alkyl})< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(O)2−(C1−C4 alkyl)<annotation encoding="application / x-tex">-S(O)_2-(C_1-C_4 \text{ alkyl})< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>−C1−C6 alkyl<annotation encoding="application / x-tex">-C_1-C_6 \text{ alkyl}< / annotation>< / semantics>< / com:Math>, wherein each instance of said heterocyclyl, carbocyclyl, heteroaryl, aryl, alkylene, and alkyl are optionally substituted; or R<com:Sup>3< / com:Sup> and R<com:Sup>a< / com:Sup> or R<com:Sup>3< / com:Sup> and R<com:Sup>b< / com:Sup> taken together with the atoms they are attached form an optionally substituted 5-6 membered heterocyclyl or carbocyclyl; R<com:Sup>4a< / com:Sup> is selected from fluoro and -CF<com:Sub>3< / com:Sub>; R<com:Sup>4b< / com:Sup> is selected from hydrogen and fluoro; <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is selected from hydrogen and optionally substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C4<annotation encoding="application / x-tex">C_4< / annotation>< / semantics>< / com:Math> alkyl; each R<com:Sup>6< / com:Sup> is independently selected from hydrogen and optionally substituted C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub> alkyl; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9; n is 1, 2 or 3; o is 1 or 2; and p is 1, 2, 3 or 4, provided the compound of Formula I is not [Image disponible dans le document PDF, Image available in the PDF document] , or a pharmaceutically acceptable salt thereof. 2. Compounds and Definitions

[0010] The terms "halo" and "halogen" as used herein refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I).

[0011] The term "alkyl" used alone or as part of a larger moiety, such as "alkoxy", "haloalkyl", "aralkyl", "heteroaralkyl" and the like, means saturated straight-chain or branched monovalent hydrocarbon radical. Unless otherwise specified, an alkyl group typically has 1-6 carbon atoms, i.e., <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkyl. As used herein, a "<com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkyl" group is means a radical having from 1 to 6 carbon atoms in a linear or branched arrangement.

[0012] The term "haloalkyl" includes mono, poly, and perhaloalkyl groups where the halogens are independently selected from fluorine, chlorine, bromine, and iodine.

[0013] "Alkoxy means an alkyl radical attached through an oxygen linking atom, represented by <com:Math><semantics>−O<annotation encoding="application / x-tex">-O< / annotation>< / semantics>< / com:Math>-alkyl. For example, "<com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math>alkoxy" includes methoxy, ethoxy, proproxy, and butoxy.

[0014] The term "aryl" used alone or as part of a larger moiety as in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to an aromatic monocyclic or bicyclic carbon ring system having, unless otherwise specified, a total of 6 to 14 ring members. The term "aryl" may be used interchangeably with the term "aryl ring", "aryl group", "aryl moiety," or "aryl radical". Also included within the scope of the term "aryl", as it is used herein, is a group in which an aromatic carbon ring is fused to one or more carbocyclyl rings, e.g., tetrahydronaphthalenyl. In certain embodiments of the present disclosure, "aryl" refers to an aromatic ring system which includes, but is not limited to, phenyl (abbreviated as "Ph"), naphthyl and the like. It will be understood that when specified, optional substituents on an aryl group (e.g., in the case of an optionally substituted aryl or aryl which is optionally substituted) may be present on any substitutable position, i.e., any ring carbon substituted with hydrogen.

[0015] The term "carbocyclyl" (also referred to herein as "carbocycle" or "cycloaliphatic", as used herein, means a monocyclic, bicyclic (e.g., a bridged or spiro bicyclic ring), polycyclic (e.g., tricyclic), or fused hydrocarbon ring system that is completely saturated or that contains one or more units of partial unsaturation, but where there is no aromatic ring. Cycloalkyl is a completely saturated carbocycle. Monocyclic carbocyclyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, and cyclooctyl. Bridged bicyclic carbocyclyl groups include, without limitation, bicyclo[3.2.1]octane, bicyclo[2.2.1]heptane, bicyclo[3.1.0]hexane, and the like. Spiro bicyclic carbocyclyl groups include, e.g., spiro[3.6]decane, spiro[4.5]decane, and the like. Fused carbocyclyl rings include, e.g., decahydronaphthalene, octahydropentalene, and the like. It will be understood that when specified, optional substituents on a carbocyclyl (e.g., in the case of an optionally substituted carbocyclyl or carbocyclyl which is optionally substituted) may be present on any substitutable position and, include, <com:Math><semantics>e.g.<annotation encoding="application / x-tex">e.g.< / annotation>< / semantics>< / com:Math>, the position at which the carbocyclyl group is attached.

[0016] The term "heteroaryl" used alone or as part of a larger moiety as in "heteroarylalkyl", "heteroarylalkoxy", or "heteroarylaminoalkyl", refers to a 5-10 -membered aromatic radical containing 1-4 heteroatoms selected from N, quaternary ammonium cation, O, and S, and includes, for example, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl" ring", "heteroaryl group", or "heteroaromatic". Nonlimiting examples include indolyl, indazolyl, benzimidazolyl, benzthiazolyl, pyrrolopyridinyl, quinolyl, quinazolinyl, and quinoxalinyl. It will be understood that when specified, optional substituents on a heteroaryl group may be present on any substitutable position (carbon and nitrogen).

[0017] The term "heterocyclyl" means a 3-12 membered (e.g., a 4-, 5-, 6- and 7- membered) saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S. It can be mononcyclic, bicyclic (e.g., a bridged, fused, or spiro bicyclic ring), or tricyclic. The terms "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic moiety", and "heterocyclic radical", are used interchangeably herein. A heterocyclyl ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, terahydropyranyl, pyrrolidinyl, pyridinonyl, pyrrolidonyl, piperidinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, 3- azabicyclo[3.1.0]hexanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 1-azaspiro[4.5]decane, and tetrahydropyrimidinyl. The term "heterocyclyl" also includes, e.g., unsaturated heterocyclic radicals fused to another unsaturated heterocyclic radical or aryl or heteroaryl ring, such as for example, tetrahydronaphthyridine, indolinone, dihydropyrrolotriazole, imidazopyrimidine, quinolinone, dioxaspirodecane. It will also be understood that when specified, optional substituents on a heterocyclyl group may be present on any substitutable position and, include, e.g., the position at which the heterocyclyl is attached (e.g., in the case of an optionally substituted heterocyclyl or heterocyclyl which is optionally substituted).

[0018] The term "spiro" refers to two rings that share one ring atom (e.g., carbon).

[0019] The term "fused" refers to two rings that share two adjacent ring ring atoms.

[0020] The term "bridged" refers to two rings that share at least three ring atoms.

[0021] As described herein, compounds herein may contain "optionally substituted" moieties. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent that results in the formation of stable or chemically feasible compounds. The term "stable", as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0022] In one embodiment, suitable substituents for an optionally substituted alkyl, carbocyclyl, heterocyclyl, aryl group and heteroaryl group are those which do not substantially diminish the potassium ion channel activity of the compound. Examples include halogen, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>S)Rc<annotation encoding="application / x-tex">S)R^{c}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NRc(C=O)ORc<annotation encoding="application / x-tex">-NR^{c}(C=O)OR^{c}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−O(C=O)NRdRe<annotation encoding="application / x-tex">-O(C=O)NR^{d}R^{e}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NRc(C=S)ORc<annotation encoding="application / x-tex">-NR^{c}(C=S)OR^{c}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−O(C=S)NRdRe<annotation encoding="application / x-tex">-O(C=S)NR^{d}R^{e}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NRc(C=O)NRdRe<annotation encoding="application / x-tex">-NR^{c}(C=O)NR^{d}R^{e}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−<annotation encoding="application / x-tex">-< / annotation>< / semantics>< / com:Math> <com:Math><semantics>NRc(C=S)NRdRe<annotation encoding="application / x-tex">NR^{c}(C=S)NR^{d}R^{e}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(=S)Rc<annotation encoding="application / x-tex">-C(=S)R^{c}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(=O)Rc<annotation encoding="application / x-tex">-C(=O)R^{c}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_{1}-C_{6})< / annotation>< / semantics>< / com:Math>alkyl, cycloalkyl, <com:Math><semantics>−(CH2)1−4<annotation encoding="application / x-tex">-(CH_{2})_{1-4}< / annotation>< / semantics>< / com:Math>-cycloalkyl, heterocyclyl, -(CH<com:Sub>2< / com:Sub>)<com:Sub>1-4< / com:Sub>-heterocyclyl, aryl, -NHC(=O)-heterocyclyl, -NHC(=O)-cycloalkyl, - <com:Math><semantics>(CH2)1−4<annotation encoding="application / x-tex">(CH_2)_{1-4}< / annotation>< / semantics>< / com:Math>-aryl, heteroaryl or <com:Math><semantics>−(CH2)1−4<annotation encoding="application / x-tex">-(CH_2)_{1-4}< / annotation>< / semantics>< / com:Math>-heteroaryl, wherein each of said <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkyl, cycloalkyl, -(CH<com:Sub>2< / com:Sub>)<com:Sub>1-4< / com:Sub>-cycloalkyl, heterocyclyl, -(CH<com:Sub>2< / com:Sub>)<com:Sub>1-4< / com:Sub>-heterocyclyl, aryl, -(CH<com:Sub>2< / com:Sub>)<com:Sub>1-4< / com:Sub>-aryl, heteroaryl and <com:Math><semantics>−(CH2)1−4<annotation encoding="application / x-tex">-(CH_2)_{1-4}< / annotation>< / semantics>< / com:Math>-heteroaryl are optionally substituted with halogen, [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>(C1−C3)<annotation encoding="application / x-tex">(C_1-C_3)< / annotation>< / semantics>< / com:Math>alkyl, halo<com:Math><semantics>(C1−C3)<annotation encoding="application / x-tex">(C_1-C_3)< / annotation>< / semantics>< / com:Math>alkyl, <com:Math><semantics>(C1−C3)<annotation encoding="application / x-tex">(C_1-C_3)< / annotation>< / semantics>< / com:Math>alkoxy<com:Math><semantics>(C1−C3)<annotation encoding="application / x-tex">(C_1-C_3)< / annotation>< / semantics>< / com:Math>alkyl, <com:Math><semantics>(C1−C3)<annotation encoding="application / x-tex">(C_1-C_3)< / annotation>< / semantics>< / com:Math>alkoxy, and halo<com:Math><semantics>(C1−C3)<annotation encoding="application / x-tex">(C_1-C_3)< / annotation>< / semantics>< / com:Math>alkyl, halo<com:Math><semantics>(C1−C3)<annotation encoding="application / x-tex">(C_1-C_3)< / annotation>< / semantics>< / com:Math>alkyl, halo<com:Math><semantics>(C1−C3)<annotation encoding="application / x-tex">(C_1-C_3)< / annotation>< / semantics>< / com:Math>alkyl, halo<com:Math><semantics>(C1−C3)<annotation encoding="application / x-tex">(C_1-C_3)< / annotation>< / semantics>< / com:Math>alkyl, halo<com:Math><semantics>(C1−C3)<annotation encoding="application / x-tex">(C_1-C_3)< / annotation>< / semantics>< / com:Math>alkyl, halo<com:Math><semantics>(C1−C3<annotation encoding="application / x-tex">(C_1-C_3< / annotation>< / semantics>< / com:Math> <com:Math><semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics>< / com:Math>)alkoxy, wherein <com:Math><semantics>Rc<annotation encoding="application / x-tex">R^c< / annotation>< / semantics>< / com:Math> is hydrogen or <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math>alkyl optionally substituted with 1 to 3 halogen; R<com:Sup>d< / com:Sup> and R<com:Sup>e< / com:Sup> are each independently selected from hydrogen and (C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkyl; and k is 0, 1 or 2. Suitable substituents for optionally substituted alkyl, carbocyclyl, and heterocyclyl also include <com:Math><semantics>=0<annotation encoding="application / x-tex">=0< / annotation>< / semantics>< / com:Math>.

[0023] In another embodiment, suitables substituents are selected from halo, - <com:Math><semantics>NHC(=O)O(C1−C4 alkyl)<annotation encoding="application / x-tex">NHC(=O)O(C_1-C_4 \text{ alkyl})< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NHC(=O)−C1−C4 alkyl<annotation encoding="application / x-tex">-NHC(=O)-C_1-C_4 \text{ alkyl}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−CN<annotation encoding="application / x-tex">-CN< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NHC(=O)−cyclobutyl<annotation encoding="application / x-tex">-NHC(=O)-cyclobutyl< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NHC(=O)−cyclobutyl<annotation encoding="application / x-tex">-NHC(=O)-cyclobutyl< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NHC(=O)−cyclobutyl<annotation encoding="application / x-tex">-NHC(=O)-cyclobutyl< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NHC(=O)−cyclobutyl<annotation encoding="application / x-tex">-NHC(=O)-cyclobutyl< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NHC(=O)−cyclobutyl<annotation encoding="application / x-tex">-NHC(=O)-cyclobutyl< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NHC(=O)−cyclobutyl<annotation encoding="application / x-tex">-NHC(=O)-cyclobutyl< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NHC(=O)−cyclo<annotation encoding="application / x-tex">-NHC(=O)-cyclo< / annotation>< / semantics>< / com:Math> oxetanyl, C=O, <com:Math><semantics>−C(=O)NRdRe<annotation encoding="application / x-tex">-C(=O)NR^dR^e< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(=O)Rc<annotation encoding="application / x-tex">-C(=O)R^c< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>ORc<annotation encoding="application / x-tex">OR^c< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(=O)ORc<annotation encoding="application / x-tex">-C(=O)OR^c< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NRdRe<annotation encoding="application / x-tex">-NR^dR^e< / annotation>< / semantics>< / com:Math>, or <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkyl optionally substituted with <com:Math><semantics>−C(=O)ORc<annotation encoding="application / x-tex">-C(=O)OR^c< / annotation>< / semantics>< / com:Math> or <com:Math><semantics>ORc<annotation encoding="application / x-tex">OR^c< / annotation>< / semantics>< / com:Math>, wherein <com:Math><semantics>Rc<annotation encoding="application / x-tex">R^c< / annotation>< / semantics>< / com:Math> is hydrogen or <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkyl optionally substituted with 1 to 3 halogen; and R<com:Sup>d< / com:Sup> and R<com:Sup>e< / com:Sup> are each independently selected from hydrogen and <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math>alkyl.

[0024] As used herein the terms "subject" and "patient" may be used interchangeably, and means a mammal in need of treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like). Typically, the subject is a human in need of treatment.

[0025] The terms "treatment," "treat," and "treating" refer to reversing, alleviating, reducing the likelihood of developing, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed, i.e., therapeutic treatment. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors), i.e., prophylactic treatment. Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

[0026] The term "effective amount" or "therapeutically effective amount" includes an amount of a compound described herein that will elicit a biological or medical response of a subject.

[0027] Certain of the disclosed compounds may exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center. "Enantiomer" means one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that contain two or more asymmetrically substituted carbon atoms. "Geometric isomer" are stereoisomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a carbocyclyl ring, or to a bridged bicyclic system.

[0028] "Racemate" or "racemic mixture" means a compound of equimolar quantities of two enantiomers, wherein such mixtures exhibit no optical activity, i.e., they do not rotate the plane of polarized light.

[0029] The compounds of the invention may be prepared as individual enantiomers by either enantio-specific synthesis or resolved from an enantiomerically enriched mixture. Conventional resolution techniques include forming the salt of a free base of each isomer of an enantiomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each enantiomer of an enantiomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the enantiomers of an enantiomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an enantiomeric mixture of either a starting material or a final product using various well known chromatographic methods.

[0030] When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight pure relative to all of the other stereoisomers. Percent by weight pure relative to all of the other stereoisomers is the ratio of the weight of one stereoisiomer over the weight of the the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight optically pure. Percent optical purity by weight is the ratio of the weight of the enantiomer over the weight of the enantiomer plus the weight of its optical isomer.

[0031] When the stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereomeric pair), it is to be understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers are included. It is to be further understood that the stereoisomeric purity of the named or depicted stereoisomers at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight pure relative to all of the other stereoisomers. The stereoisomeric purity in this case is determined by dividing the total weight in the mixture of the stereoisomers encompassed by the name or structure by the total weight in the mixture of all of the stereoisomers.

[0032] When a disclosed compound is named or depicted by structure without indicating the stereochemistry, and the compound has one chiral center, it is to be understood that the name or structure encompasses one enantiomer of compound free from the corresponding optical and geometric isomer, a racemic mixture of the compound, and mixtures enriched in one enantiomer relative to its corresponding optical isomer.

[0033] When a disclosed compound is named or depicted by structure without indicating the stereochemistry and e.g, the compound has at least two chiral centers, it is to be understood that the name or structure encompasses one stereoisomer free of other stereoisomers, mixtures of stereoisomers, and mixtures of stereoisomers in which one or more stereoisomers is enriched relative to the other stereoisomer(s). For example, the name or structure may encompass one stereoisomer free of other diastereomers, mixtures of stereoisomers, and mixtures of stereoisomers in which one or more diastereomers is enriched relative to the other diastereomer(s).

[0034] With respect to the generic Formula I, Ia, II, III, IV, V, VI, and VII, unless otherwise specified, one or more hydrogens can be replaced by deuterium. Isotopic enrichments include e.g., at least 10%, 25%, 50%, 75%, 80%, 85%, 90&, 95%, 87%, 98%, 99.0%, 99.5% and 99.8%". In one embodiment, all hydrogen atoms represented in Formula I, Ia, II, III, IV, V, VI, and VII are present in natural abundance. With respect to specific compounds disclosed herein, such as those in Table 1 and in the Exemplification section, all hydrogen atoms are present in natural abundance unless otherwise specified.

[0035] The compounds described herein may be present in the form of pharmaceutically acceptable salts. For use in medicines, the salts of the compounds of the invention refer to non-toxic "pharmaceutically acceptable salts." Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic / anionic or basic / cationic salts. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include e.g., salts of inorganic acids (such as hydrochloric acid, hydrobromic, phosphoric, nitric, and sulfuric acids) and of organic acids (such as, acetic acid, benzenesulfonic, benzoic, methanesulfonic, and p-toluenesulfonic acids). Compounds of the present teachings with acidic groups such as carboxylic acids can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s). Suitable pharmaceutically acceptable basic salts include e.g., ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts). Compounds with a quaternary ammonium group also contain a counteranion such as chloride, bromide, iodide, acetate, perchlorate and the like. Other examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, benzoates and salts with amino acids such as glutamic acid. 3. Description of Exemplary Compounds

[0036] In a first embodiment, the present disclosure provides a compound of Formula I: [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>(𝑰);<annotation encoding="application / x-tex">(\mathbf{I});< / annotation>< / semantics>< / com:Math> or a pharmaceutically acceptable salt thereof, wherein the variables are as described above.

[0037] In a second embodiment, the compound of Formula I is of the Formula Ia: [Image disponible dans le document PDF, Image available in the PDF document] , or a pharmaceutically acceptable salt thereof, wherein the variables in Formula Ia are as described in Formula I.

[0038] In a third embodiment, the compound of Formula I or Formula Ia is of the Formula II or III: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 3 (II); or (III); or a pharmaceutically acceptable salt thereof, wherein the variables in Formula II and III are as described in Formula I. In one alternative to the second embodiment, the optional substituents for each occurrence of an optionally group for the compounds of Formulas I, Ia, II, or III are 1 to 3 groups independently selected from R<com:Sup>7< / com:Sup> as defined in the sixth embodiment.

[0039] In a fourth embodiment, R<com:Sup>3< / com:Sup> in Formulas I, Ia, II, or III is selected from - <com:Math><semantics>C(=O)NH2<annotation encoding="application / x-tex">C(=O)NH_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−(C0−C4)<annotation encoding="application / x-tex">-(C_0-C_4)< / annotation>< / semantics>< / com:Math> alkylene)-heteroaryl, <com:Math><semantics>−(C0−C4)<annotation encoding="application / x-tex">-(C_0-C_4)< / annotation>< / semantics>< / com:Math> alkylene)-aryl, <com:Math><semantics>−N(R6)<annotation encoding="application / x-tex">-N(R^6)< / annotation>< / semantics>< / com:Math>-carbocyclyl, <com:Math><semantics>−N(R6)<annotation encoding="application / x-tex">-N(R^6)< / annotation>< / semantics>< / com:Math>- heterocyclyl, <com:Math><semantics>−N(R6)<annotation encoding="application / x-tex">-N(R^6)< / annotation>< / semantics>< / com:Math>-heteroaryl, <com:Math><semantics>−N(R6)<annotation encoding="application / x-tex">-N(R^6)< / annotation>< / semantics>< / com:Math>-aryl, <com:Math><semantics>−O(C0−C4)<annotation encoding="application / x-tex">-O(C_0-C_4)< / annotation>< / semantics>< / com:Math> alkylene)carbocyclyl, <com:Math><semantics>−O(C0−C4)<annotation encoding="application / x-tex">-O(C_0-C_4)< / annotation>< / semantics>< / com:Math> alkylene)heterocyclyl, <com:Math><semantics>−O(C0−C4<annotation encoding="application / x-tex">-O(C_0-C_4< / annotation>< / semantics>< / com:Math> alkylene)heteroaryl, <com:Math><semantics>−O(C0−C4<annotation encoding="application / x-tex">-O(C_0-C_4< / annotation>< / semantics>< / com:Math> alkylene)aryl, <com:Math><semantics>−S(C0−C4<annotation encoding="application / x-tex">-S(C_0-C_4< / annotation>< / semantics>< / com:Math> alkylene)carbocyclyl, <com:Math><semantics>−S(C0−C4<annotation encoding="application / x-tex">-S(C_0-C_4< / annotation>< / semantics>< / com:Math> alkylene)heterocyclyl, <com:Math><semantics>−S(C0−C4<annotation encoding="application / x-tex">-S(C_0-C_4< / annotation>< / semantics>< / com:Math> alkylene)heteroaryl, <com:Math><semantics>−S(C0−C4<annotation encoding="application / x-tex">-S(C_0-C_4< / annotation>< / semantics>< / com:Math> alkylene)aryl, <com:Math><semantics>−S(O)(C0−C4<annotation encoding="application / x-tex">-S(O)(C_0-C_4< / annotation>< / semantics>< / com:Math> alkylene)carbocyclyl, <com:Math><semantics>−S(O)(C0−C4<annotation encoding="application / x-tex">-S(O)(C_0-C_4< / annotation>< / semantics>< / com:Math> alkylene)heterocyclyl, <com:Math><semantics>−<annotation encoding="application / x-tex">-< / annotation>< / semantics>< / com:Math> <com:Math><semantics>S(O)(C0−C4)<annotation encoding="application / x-tex">S(O)(C_0-C_4)< / annotation>< / semantics>< / com:Math> alkylene)heteroaryl, <com:Math><semantics>−S(O)(C0−C4)<annotation encoding="application / x-tex">-S(O)(C_0-C_4)< / annotation>< / semantics>< / com:Math> alkylene)aryl, <com:Math><semantics>−S(O)2(C0−C4)<annotation encoding="application / x-tex">-S(O)_2(C_0-C_4)< / annotation>< / semantics>< / com:Math> alkylene)carbocyclyl, <com:Math><semantics>−S(O)2(C0−C4<annotation encoding="application / x-tex">-S(O)_2(C_0-C_4< / annotation>< / semantics>< / com:Math> alkylene)heterocyclyl, <com:Math><semantics>−S(O)2(C0−C4<annotation encoding="application / x-tex">-S(O)_2(C_0-C_4< / annotation>< / semantics>< / com:Math> alkylene)heteroaryl, <com:Math><semantics>−S(O)2(C0−C4 alkylene)<annotation encoding="application / x-tex">-S(O)_2(C_0-C_4 \text{ alkylene})< / annotation>< / semantics>< / com:Math>aryl, <com:Math><semantics>−NH(C1−C4 alkyl)<annotation encoding="application / x-tex">-NH(C_1-C_4 \text{ alkyl})< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S−(C1−C4 alkyl)<annotation encoding="application / x-tex">-S-(C_1-C_4 \text{ alkyl})< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(O)−(C1−C4 alkyl)<annotation encoding="application / x-tex">-S(O)-(C_1-C_4 \text{ alkyl})< / annotation>< / semantics>< / com:Math> alkyl), -S(O)2-(C1-C4 alkyl), and -C1-C6 alkyl, wherein each instance of said heterocyclyl, carbocyclyl, heteroaryl, aryl, <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C4<annotation encoding="application / x-tex">C_4< / annotation>< / semantics>< / com:Math> alkylene, and <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C4<annotation encoding="application / x-tex">C_4< / annotation>< / semantics>< / com:Math> alkyl are optionally substituted, and wherein said <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkyl is substituted with <com:Math><semantics>−NH2<annotation encoding="application / x-tex">-NH_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(C1−C4)<annotation encoding="application / x-tex">-N(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkyl)<com:Sub>2< / com:Sub>, <com:Math><semantics>−NHC(=O)−O−(C1−C4)<annotation encoding="application / x-tex">-NHC(=O)-O-(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkyl), -NHC(=O)-(C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub> alkyl), -CN, -NHC(=O)-cycloalkyl, -NHC(=O)-heterocyclyl, -OH, or -O(C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub> alkyl); or R<com:Sup>3< / com:Sup> and R<com:Sup>a< / com:Sup> or R<com:Sup>3< / com:Sup> and R<com:Sup>b< / com:Sup> taken together with the atoms they are attached form an optionally substituted 5-6 membered heterocyclyl or carbocyclyl, wherein the remaining variables are as described in Formula I or the second or third embodiment.

[0040] In a fifth embodiment, R<com:Sup>3< / com:Sup> in Formulas I, Ia, II, or III is selected from - <com:Math><semantics>C(=O)NH2<annotation encoding="application / x-tex">C(=O)NH_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−(C0−C4 alkylene)<annotation encoding="application / x-tex">-(C_0-C_4 \text{ alkylene})< / annotation>< / semantics>< / com:Math>-heteroaryl, <com:Math><semantics>−(C0−C4 alkylene)<annotation encoding="application / x-tex">-(C_0-C_4 \text{ alkylene})< / annotation>< / semantics>< / com:Math>-aryl, <com:Math><semantics>−O(C0−C4 alkylene)<annotation encoding="application / x-tex">-O(C_0-C_4 \text{ alkylene})< / annotation>< / semantics>< / com:Math> alkylene)carbocyclyl, <com:Math><semantics>−O(C0−C4<annotation encoding="application / x-tex">-O(C_0-C_4< / annotation>< / semantics>< / com:Math> alkylene)heterocyclyl, <com:Math><semantics>−O(C0−C4<annotation encoding="application / x-tex">-O(C_0-C_4< / annotation>< / semantics>< / com:Math> alkylene)heteroaryl, <com:Math><semantics>−O(C0−C4)<annotation encoding="application / x-tex">-O(C_0-C_4)< / annotation>< / semantics>< / com:Math> <com:Math><semantics>C4<annotation encoding="application / x-tex">C_4< / annotation>< / semantics>< / com:Math> alkylene)aryl, <com:Math><semantics>−S(C0−C4<annotation encoding="application / x-tex">-S(C_0-C_4< / annotation>< / semantics>< / com:Math> alkylene)carbocyclyl, <com:Math><semantics>−S(C0−C4<annotation encoding="application / x-tex">-S(C_0-C_4< / annotation>< / semantics>< / com:Math> alkylene)heterocyclyl, <com:Math><semantics>−S(C0−C4<annotation encoding="application / x-tex">-S(C_0-C_4< / annotation>< / semantics>< / com:Math> alkylene)heteroaryl, <com:Math><semantics>−S(C0−C4<annotation encoding="application / x-tex">-S(C_0-C_4< / annotation>< / semantics>< / com:Math> alkylene)aryl, <com:Math><semantics>−S(O)(C0−C4<annotation encoding="application / x-tex">-S(O)(C_0-C_4< / annotation>< / semantics>< / com:Math> alkylene)carbocyclyl, <com:Math><semantics>−S(O)(C0−C4<annotation encoding="application / x-tex">-S(O)(C_0-C_4< / annotation>< / semantics>< / com:Math> alkylene)heterocyclyl, <com:Math><semantics>−S(O)(C0−C4<annotation encoding="application / x-tex">-S(O)(C_0-C_4< / annotation>< / semantics>< / com:Math> alkylene)heteroaryl, <com:Math><semantics>−S(O)(C0−C4<annotation encoding="application / x-tex">-S(O)(C_0-C_4< / annotation>< / semantics>< / com:Math> alkylene)aryl, <com:Math><semantics>−<annotation encoding="application / x-tex">-< / annotation>< / semantics>< / com:Math> <com:Math><semantics>S(O)2(C0−C4)<annotation encoding="application / x-tex">S(O)_2(C_0-C_4)< / annotation>< / semantics>< / com:Math> alkylene)carbocyclyl, <com:Math><semantics>−S(O)2(C0−C4)<annotation encoding="application / x-tex">-S(O)_2(C_0-C_4)< / annotation>< / semantics>< / com:Math> alkylene)heterocyclyl, <com:Math><semantics>−S(O)2(C0−C4)<annotation encoding="application / x-tex">-S(O)_2(C_0-C_4)< / annotation>< / semantics>< / com:Math> alkylene)heteroaryl, <com:Math><semantics>−S(O)2(C0−C4<annotation encoding="application / x-tex">-S(O)_2(C_0-C_4< / annotation>< / semantics>< / com:Math> alkylene)aryl, <com:Math><semantics>−S−(C1−C4<annotation encoding="application / x-tex">-S-(C_1-C_4< / annotation>< / semantics>< / com:Math> alkyl), <com:Math><semantics>−S(O)−(C1−C4<annotation encoding="application / x-tex">-S(O)-(C_1-C_4< / annotation>< / semantics>< / com:Math> alkyl), <com:Math><semantics>−S(O)2−(C1−C4)<annotation encoding="application / x-tex">-S(O)_2-(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkyl), and <com:Math><semantics>−C1−C6<annotation encoding="application / x-tex">-C_1-C_6< / annotation>< / semantics>< / com:Math> alkyl, wherein each of said heterocyclyl, carbocyclyl, heteroaryl, aryl, C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub> alkylene, and C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub> alkyl are optionally substituted, and wherein said <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math>alkyl is substituted with <com:Math><semantics>−NH2<annotation encoding="application / x-tex">-NH_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(C1−C4)<annotation encoding="application / x-tex">-N(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkyl), <com:Math><semantics>−NHC(=O)−O−(C1−C4)<annotation encoding="application / x-tex">-NHC(=O)-O-(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkyl), NHC(=O)-(C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub> alkyl), -CN, -NHC(=O)-cycloalkyl, -NHC(=O)-heterocyclyl, -OH, or - <com:Math><semantics>O(C1−C4 alkyl)<annotation encoding="application / x-tex">O(C_1-C_4 \text{ alkyl})< / annotation>< / semantics>< / com:Math>; or <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>Ra<annotation encoding="application / x-tex">R^a< / annotation>< / semantics>< / com:Math> or <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>Rb<annotation encoding="application / x-tex">R^b< / annotation>< / semantics>< / com:Math> taken together with the atoms they are attached form an optionally substituted 5-6 membered heterocyclyl or carbocyclyl, wherein the remaining variables are as described in Formula I or the second, third or fourth embodiment.

[0041] In a sixth embodiment, each of said heterocyclyl, heteroaryl, carbocyclyl, aryl, C<com:Sub>1< / com:Sub>- <com:Math><semantics>C4<annotation encoding="application / x-tex">C_4< / annotation>< / semantics>< / com:Math> alkylene, and <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C4<annotation encoding="application / x-tex">C_4< / annotation>< / semantics>< / com:Math> alkyl for <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> in the first, second, third, or fourth embodiment are optionally substituted with 1 to 3 groups independently selected from R<com:Sup>7< / com:Sup>, where R<com:Sup>7< / com:Sup> is halogen, [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>OC(=O)Rc<annotation encoding="application / x-tex">OC(=O)R^{c}< / annotation>< / semantics>< / com:Math>, - OC(=S)OR<com:Sup>c< / com:Sup>, -C(=S)OR<com:Sup>c< / com:Sup>, -O(C=S)R<com:Sup>c< / com:Sup>, -C(=O)NR<com:Sup>d< / com:Sup>R<com:Sup>e< / com:Sup>, -NR<com:Sup>c< / com:Sup>C(=O)R<com:Sup>c< / com:Sup>, -C(=S)NR<com:Sup>d< / com:Sup>R<com:Sup>e< / com:Sup>, -NR<com:Sup>c< / com:Sup>C(= <com:Math><semantics>S)Rc<annotation encoding="application / x-tex">S)R^{c}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NRc(C=O)ORc<annotation encoding="application / x-tex">-NR^{c}(C=O)OR^{c}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−O(C=O)NRdRe<annotation encoding="application / x-tex">-O(C=O)NR^{d}R^{e}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NRc(C=S)ORc<annotation encoding="application / x-tex">-NR^{c}(C=S)OR^{c}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−O(C=S)NRdRe<annotation encoding="application / x-tex">-O(C=S)NR^{d}R^{e}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NRc(C=O)NRdRe<annotation encoding="application / x-tex">-NR^{c}(C=O)NR^{d}R^{e}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−<annotation encoding="application / x-tex">-< / annotation>< / semantics>< / com:Math> <com:Math><semantics>NRc(C=S)NRdRe<annotation encoding="application / x-tex">NR^{c}(C=S)NR^{d}R^{e}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(=S)Rc<annotation encoding="application / x-tex">-C(=S)R^{c}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(=O)Rc<annotation encoding="application / x-tex">-C(=O)R^{c}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_{1}-C_{6})< / annotation>< / semantics>< / com:Math>alkyl, cycloalkyl, <com:Math><semantics>−(CH2)1−4<annotation encoding="application / x-tex">-(CH_{2})_{1-4}< / annotation>< / semantics>< / com:Math>-cycloalkyl, heterocyclyl, <com:Math><semantics>−(CH2)1−4<annotation encoding="application / x-tex">-(CH_2)_{1-4}< / annotation>< / semantics>< / com:Math>-heterocyclyl, aryl, <com:Math><semantics>−(CH2)1−4<annotation encoding="application / x-tex">-(CH_2)_{1-4}< / annotation>< / semantics>< / com:Math>-aryl, heteroaryl or <com:Math><semantics>−(CH2)1−4<annotation encoding="application / x-tex">-(CH_2)_{1-4}< / annotation>< / semantics>< / com:Math>-heteroaryl, wherein each of said (<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math>)alkyl, cycloalkyl, -(<com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math>)<com:Sub>1-4< / com:Sub>-cycloalkyl, heterocyclyl, -(<com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math>)<com:Sub>1-4< / com:Sub>- heterocyclyl, aryl, <com:Math><semantics>−(CH2)1−4<annotation encoding="application / x-tex">-(CH_2)_{1-4}< / annotation>< / semantics>< / com:Math>-aryl, heteroaryl and <com:Math><semantics>−(CH2)1−4<annotation encoding="application / x-tex">-(CH_2)_{1-4}< / annotation>< / semantics>< / com:Math>-heteroaryl for <com:Math><semantics>ℝ7<annotation encoding="application / x-tex">\mathbb{R}^7< / annotation>< / semantics>< / com:Math> are optionally substituted with halogen, <com:Math><semantics>ORc<annotation encoding="application / x-tex">OR^{c}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NO2<annotation encoding="application / x-tex">-NO_{2}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−CN<annotation encoding="application / x-tex">-CN< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NRcC(=O)Rc<annotation encoding="application / x-tex">-NR^{c}C(=O)R^{c}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NRdRe<annotation encoding="application / x-tex">-NR^{d}R^{e}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(O)kRc<annotation encoding="application / x-tex">-S(O)_{k}R^{c}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(=O)ORc<annotation encoding="application / x-tex">-C(=O)OR^{c}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(=O)NRdRe<annotation encoding="application / x-tex">-C(=O)NR^{d}R^{e}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(=O)Rc<annotation encoding="application / x-tex">-C(=O)R^{c}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>(C1−C3)<annotation encoding="application / x-tex">(C_1-C_3)< / annotation>< / semantics>< / com:Math>alkyl, halo<com:Math><semantics>(C1−C3)<annotation encoding="application / x-tex">(C_1-C_3)< / annotation>< / semantics>< / com:Math>alkyl, <com:Math><semantics>(C1−C3)<annotation encoding="application / x-tex">(C_1-C_3)< / annotation>< / semantics>< / com:Math>alkoxy<com:Math><semantics>(C1−C3)<annotation encoding="application / x-tex">(C_1-C_3)< / annotation>< / semantics>< / com:Math>alkyl, <com:Math><semantics>(C1−C3)<annotation encoding="application / x-tex">(C_1-C_3)< / annotation>< / semantics>< / com:Math>alkoxy, and halo<com:Math><semantics>(C1−C3)<annotation encoding="application / x-tex">(C_1-C_3)< / annotation>< / semantics>< / com:Math>alkyl, halo<com:Math><semantics>(C1−C3)<annotation encoding="application / x-tex">(C_1-C_3)< / annotation>< / semantics>< / com:Math>alkyl, halo<com:Math><semantics>(C1−C3)<annotation encoding="application / x-tex">(C_1-C_3)< / annotation>< / semantics>< / com:Math>alkyl, halo<com:Math><semantics>(C1−C3)<annotation encoding="application / x-tex">(C_1-C_3)< / annotation>< / semantics>< / com:Math>alkyl, halo<com:Math><semantics>(C1−C3)<annotation encoding="application / x-tex">(C_1-C_3)< / annotation>< / semantics>< / com:Math>alkyl, halo<com:Math><semantics>(C1−C3<annotation encoding="application / x-tex">(C_1-C_3< / annotation>< / semantics>< / com:Math> <com:Math><semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics>< / com:Math>)alkoxy; or two instances of <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> are taken together on the same atom to form =O; <com:Math><semantics>Rc<annotation encoding="application / x-tex">R^c< / annotation>< / semantics>< / com:Math> is hydrogen or (C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkyl optionally substituted with 1 to 3 halogen; R<com:Sup>d< / com:Sup> and R<com:Sup>e< / com:Sup> are each independently selected from hydrogen and (C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkyl; and k is 0, 1 or 2, wherein the remaining variables are as described in Formula I or the second, third, fourth, or fifth embodiment.

[0042] In a seventh embodiment, R<com:Sup>3< / com:Sup> in Formulas I, Ia, II, or III is selected from 1) piperizinyl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, morpholinyl, azetidinyl, pyrazolyl, 4,5- dihydro-1,2,4-oxadiazolyl, 1,2,4-oxadiazolyl, tetrahydropyranyl, 2,5- diazabicyclo[2.2.1]heptanyl, and 3-azabicyclo[3.1.0]hexanyl, each of which is optionally substituted with 1 to 3 groups selected from R<com:Sup>7< / com:Sup>; 2) -S-(C<com:Sub>1< / com:Sub>-C<com:Sub>2< / com:Sub> alkyl), -O-(C<com:Sub>1< / com:Sub>-C<com:Sub>2< / com:Sub> haloalkyl), - <com:Math><semantics>C(=O)NH2<annotation encoding="application / x-tex">C(=O)NH_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−(C1−C2 alkylene)<annotation encoding="application / x-tex">-(C_1-C_2 \text{ alkylene})< / annotation>< / semantics>< / com:Math>-morpholinyl, <com:Math><semantics>−(C1−C2 alkylene)<annotation encoding="application / x-tex">-(C_1-C_2 \text{ alkylene})< / annotation>< / semantics>< / com:Math>-piperazinyl, <com:Math><semantics>−O(C1−C2 alkylene)<annotation encoding="application / x-tex">-O(C_1-C_2 \text{ alkylene})< / annotation>< / semantics>< / com:Math> alkylene)azetidinyl, -O(C<com:Sub>1< / com:Sub>-C<com:Sub>2< / com:Sub> alkylene)triazolyl, -O(C<com:Sub>1< / com:Sub>-C<com:Sub>2< / com:Sub> alkylene)pyrrolidinyl, -O(C<com:Sub>1< / com:Sub>-C<com:Sub>2< / com:Sub> alkylene)oxadiazole, <com:Math><semantics>−O(C1−C2)<annotation encoding="application / x-tex">-O(C_1-C_2)< / annotation>< / semantics>< / com:Math> alkylene)thiomorpholinyl, <com:Math><semantics>−O(C1−C2)<annotation encoding="application / x-tex">-O(C_1-C_2)< / annotation>< / semantics>< / com:Math> alkylene)thiomorpholinyl-1,1-dioxide, <com:Math><semantics>−O(C1−C2)<annotation encoding="application / x-tex">-O(C_1-C_2)< / annotation>< / semantics>< / com:Math> alkylene)oxazolyl, <com:Math><semantics>−O(C1−C2)<annotation encoding="application / x-tex">-O(C_1-C_2)< / annotation>< / semantics>< / com:Math> hydroxyalkylene)oxazolyl, <com:Math><semantics>−O(C1−C2)<annotation encoding="application / x-tex">-O(C_1-C_2)< / annotation>< / semantics>< / com:Math> alkylene)phenyl, and <com:Math><semantics>−O(C1−C2)<annotation encoding="application / x-tex">-O(C_1-C_2)< / annotation>< / semantics>< / com:Math> alkylene)cyclobutyl each of said morpholinyl, piperazinyl, azetidinyl, triazolyl, pyrrolidinyl, oxadiazole, thiomorpholinyl, thiomorpholinyl-1,1-dioxide, oxazolyl, phenyl, and cyclobutyl being optionally substituted with 1 to 3 groups selected from <com:Math><semantics>ℝ7<annotation encoding="application / x-tex">\mathbb{R}^7< / annotation>< / semantics>< / com:Math>; and 3) (C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub>)alkyl substituted with <com:Math><semantics>−NH2<annotation encoding="application / x-tex">-NH_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(C1−C4 alkyl)2<annotation encoding="application / x-tex">-N(C_1-C_4 \text{ alkyl})_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NHC(=O)O(C1−C4 alkyl)<annotation encoding="application / x-tex">-NHC(=O)O(C_1-C_4 \text{ alkyl})< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NHC(=O)−C1−C4 alkyl<annotation encoding="application / x-tex">-NHC(=O)-C_1-C_4 \text{ alkyl}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NHC(=O)−C1−C4 alkyl<annotation encoding="application / x-tex">-NHC(=O)-C_1-C_4 \text{ alkyl}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NHC(=O)−C1−C4 alkyl<annotation encoding="application / x-tex">-NHC(=O)-C_1-C_4 \text{ alkyl}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NHC(=O)−C1−C4 alkyl<annotation encoding="application / x-tex">-NHC(=O)-C_1-C_4 \text{ alkyl}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NHC(=O)−C1−C4 alkyl<annotation encoding="application / x-tex">-NHC(=O)-C_1-C_4 \text{ alkyl}< / annotation>< / semantics>< / com:Math> CN, -NHC(=O)-cyclobutyl, -NHC(=O)-oxetanyl, -OH, or -O(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C4<annotation encoding="application / x-tex">C_4< / annotation>< / semantics>< / com:Math> alkyl); <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> is halo, -C(=O)NR<com:Sup>d< / com:Sup>R<com:Sup>e< / com:Sup>, -C(=O)R<com:Sup>c< / com:Sup>, OR<com:Sup>c< / com:Sup>, -C(=O)OR<com:Sup>c< / com:Sup>, -NR<com:Sup>d< / com:Sup>R<com:Sup>e< / com:Sup>, or (C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub>)alkyl optionally substituted with -C(=O)OR<com:Sup>c< / com:Sup> or OR<com:Sup>c< / com:Sup>; or two instances of R<com:Sup>7< / com:Sup> are taken together on the same atom to form =0; <com:Math><semantics>Rc<annotation encoding="application / x-tex">R^c< / annotation>< / semantics>< / com:Math> is hydrogen or <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkyl optionally substituted with 1 to 3 halogen; R<com:Sup>d< / com:Sup> and R<com:Sup>e< / com:Sup> are each independently selected from hydrogen and (C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub>)alkyl, wherein the remaining variables are as described in Formula I or the second, third, fourth, fifth, or sixth embodiment.

[0043] In an eighth embodiment, R<com:Sup>3< / com:Sup> in Formulas I, Ia, II, or III is selected from 1) piperizinyl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, morpholinyl, azetidinyl, pyrazolyl, 4,5- dihydro-1,2,4-oxadiazolyl, 1,2,4-oxadiazolyl, tetrahydropyranyl, 2,5- diazabicyclo[2.2.1]heptanyl, and 3-azabicyclo[3.1.0]hexanyl, each of which is optionally substituted with 1 to 2 groups selected from R<com:Sup>7< / com:Sup>; 2) -S-(C<com:Sub>1< / com:Sub>-C<com:Sub>2< / com:Sub> alkyl), -O-(C<com:Sub>1< / com:Sub>-C<com:Sub>2< / com:Sub> haloalkyl), - <com:Math><semantics>C(=O)NH2<annotation encoding="application / x-tex">C(=O)NH_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−(C1−C2 alkylene)<annotation encoding="application / x-tex">-(C_1-C_2 \text{ alkylene})< / annotation>< / semantics>< / com:Math>-morpholinyl, <com:Math><semantics>−(C1−C2 alkylene)<annotation encoding="application / x-tex">-(C_1-C_2 \text{ alkylene})< / annotation>< / semantics>< / com:Math>-piperazinyl, <com:Math><semantics>−O(C1−C2 alkylene)<annotation encoding="application / x-tex">-O(C_1-C_2 \text{ alkylene})< / annotation>< / semantics>< / com:Math> alkylene)azetidinyl, -O(C<com:Sub>1< / com:Sub>-C<com:Sub>2< / com:Sub> alkylene)triazolyl, -O(C<com:Sub>1< / com:Sub>-C<com:Sub>2< / com:Sub> alkylene)pyrrolidinyl, -O(C<com:Sub>1< / com:Sub>-C<com:Sub>2< / com:Sub> alkylene)oxadiazole, <com:Math><semantics>−O(C1−C2)<annotation encoding="application / x-tex">-O(C_1-C_2)< / annotation>< / semantics>< / com:Math> alkylene)thiomorpholinyl, <com:Math><semantics>−O(C1−C2)<annotation encoding="application / x-tex">-O(C_1-C_2)< / annotation>< / semantics>< / com:Math> alkylene)thiomorpholinyl-1,1-dioxide, <com:Math><semantics>−O(C1−C2)<annotation encoding="application / x-tex">-O(C_1-C_2)< / annotation>< / semantics>< / com:Math> alkylene)oxazolyl, <com:Math><semantics>−O(C1−C2)<annotation encoding="application / x-tex">-O(C_1-C_2)< / annotation>< / semantics>< / com:Math> hydroxyalkylene)oxazolyl, <com:Math><semantics>−O(C1−C2)<annotation encoding="application / x-tex">-O(C_1-C_2)< / annotation>< / semantics>< / com:Math> alkylene)phenyl, and <com:Math><semantics>−O(C1−C2)<annotation encoding="application / x-tex">-O(C_1-C_2)< / annotation>< / semantics>< / com:Math> alkylene)cyclobutyl, each of said azetidinyl, triazolyl, pyrrolidinyl, oxadiazole, phenyl, and cyclobutyl being optionally substituted with 1 to 2 groups selected from <com:Math><semantics>ℝ7<annotation encoding="application / x-tex">\mathbb{R}^7< / annotation>< / semantics>< / com:Math>; and 3) (C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub>)alkyl substituted with <com:Math><semantics>−NH2<annotation encoding="application / x-tex">-NH_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(C1−C4 alkyl)2<annotation encoding="application / x-tex">-N(C_1-C_4 \text{ alkyl})_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NHC(=O)O−C1−C4 alkyl<annotation encoding="application / x-tex">-NHC(=O)O-C_1-C_4 \text{ alkyl}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NHC(=O)−C1−C4 alkyl<annotation encoding="application / x-tex">-NHC(=O)-C_1-C_4 \text{ alkyl}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−<annotation encoding="application / x-tex">-< / annotation>< / semantics>< / com:Math> CN, -NHC(=O)-cyclobutyl, -NHC(=O)-oxetanyl, -OH, or -O(C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub> alkyl), wherein the remaining variables are as described in Formula I or the second, third, fourth, fifth, sixth, or seventh embodiment.

[0044] In a ninth embodiment, R<com:Sup>2< / com:Sup> in Formulas I, Ia, II, or III is independently selected from halo, -CN, -O(C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub> alkyl), C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub> alkyl, C<com:Sub>3< / com:Sub>-C<com:Sub>4< / com:Sub> cycloalkyl, cyanoC<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub> alkyl, haloC<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub> alkyl, and hydroxyC<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub> alkyl, wherein the remaining variables are as described in Formula I or Formula Ia, or the second, third, fourth, fifth, sixth, seventh, or eighth embodiment. Alternatively, R<com:Sup>2< / com:Sup> in Formulas I, Ia, II, or III is independently selected from chloro, bromo, fluoro, -CN, -CH<com:Sub>3< / com:Sub>, -CH<com:Sub>2< / com:Sub>F, -CHF<com:Sub>2< / com:Sub>, -CF<com:Sub>3< / com:Sub>, -CH<com:Sub>2< / com:Sub>OH, -CH<com:Sub>2< / com:Sub>CH<com:Sub>3< / com:Sub>, - CH<com:Sub>2< / com:Sub>CN, -CH(CH<com:Sub>3< / com:Sub>)CH<com:Sub>3< / com:Sub>, -CH(CH<com:Sub>3< / com:Sub>)OH, -C((CH<com:Sub>3< / com:Sub>)<com:Sub>2< / com:Sub>)OH, -OCH<com:Sub>3< / com:Sub>, and cyclopropyl, wherein the remaining variables are as described in Formula I or the second, third, fourth, fifth, sixth, seventh, or eighth embodiment.

[0045] In a tenth embodiment, each of n, o, and p in Formulas I, Ia, II, or III is 1 or 2, wherein the remaining variables are as described in Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment.

[0046] In an eleventh embodiment, each of R<com:Sup>a< / com:Sup> and R<com:Sup>b< / com:Sup> in Formula I or Formula Ia is independently selected from hydrogen and C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub> alkyl, or wherein R<com:Sup>3< / com:Sup> and R<com:Sup>a< / com:Sup> or R<com:Sup>3< / com:Sup> and R<com:Sup>b< / com:Sup> taken together with the atoms they are attached form an optionally substituted 5-6 membered, nitrogen-containing heterocyclyl, wherein the remaining variables are as described in Formula I or the fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment.

[0047] In a twelfth embodiment, R<com:Sup>a< / com:Sup> in Formula I or Formula Ia is selected from hydrogen, methyl, and ethyl; or R<com:Sup>a< / com:Sup> and R<com:Sup>3< / com:Sup> are taken together with the atoms they are attached form an optionally substituted piperidinyl or an optionally substituted 1H-imidazolyl, wherein the remaining variables are as described in Formula I or Formula Ia, or the fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment. In one alternative, the piperidinyl or 1H-imidazolyl in the eleventh embodiment is optionally substituted at a ring nitrogen, wherein the remaining variables are as described in Formula I or Formula Ia, or the fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment.

[0048] In a thirteenth embodiment, R<com:Sup>3< / com:Sup> in Formulas I, Ia, II, or III is selected from halo, -CN, alkyl, -NH-(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl), alkyl-NH(R<com:Sup>7< / com:Sup>), -C(O)NH(R<com:Sup>7< / com:Sup>), carbocyclyl, heterocyclyl, -O-heterocyclyl, -NH-heterocyclyl, -O-alkylene-heterocyclyl, -O-alkylene- carbocyclyl, -NH-alkylene-carbocyclyl, and -NH-alkylene-heterocyclyl, or R<com:Sup>3< / com:Sup> is taken together with R<com:Sup>a< / com:Sup> to form an optionally substituted heterocyclyl, wherein R<com:Sup>7< / com:Sup> is selected from hydrogen and C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub> alkyl; and any alkyl, alkylene, carbocyclyl, or heterocyclyl portion of R<com:Sup>3< / com:Sup> is optionally substituted, wherein the remaining variables are as described in Formula I or the second, third, ninth, tenth, eleventh, or twelfth embodiment. Alternatively, R<com:Sup>3< / com:Sup> in Formulas I, Ia, II, or III is selected from: [Image disponible dans le document PDF, Image available in the PDF document] remaining variables are as described in Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth embodiment.

[0049] In a fourteenth embodiment, R<com:Sup>5< / com:Sup> in Formulas I, Ia, II, or III is selected from hydrogen, methyl and ethyl, wherein the remaining variables are as described in Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth embodiment.

[0050] In a fifteenth embodiment, R<com:Sup>4a< / com:Sup> and R<com:Sup>4b< / com:Sup> in Formulas I, Ia, II, or III are simultaneously fluoro, wherein the remaining variables are as described in Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth embodiment. Alternatively, R<com:Sup>4a< / com:Sup> is -CF<com:Sub>3< / com:Sub> and R<com:Sup>4b< / com:Sup> hydrogen in Formulas I, Ia, II, or III are simultaneously fluoro, wherein the remaining variables are as described in Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth embodiment.

[0051] In a sixteenth embodiment, m in Formulas I, Ia, II, or III is 0, wherein the remaining variables are as described in Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, or fifteenth embodiment.

[0052] In a seventeenth embodiment, R<com:Sup>3< / com:Sup> in Formulas I, Ia, II, or III is selected from: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 19 -SO<com:Sub>2< / com:Sub>Me, CH<com:Sub>2< / com:Sub>NH<com:Sub>2< / com:Sub>, and -CH<com:Sub>2< / com:Sub>NMe<com:Sub>2< / com:Sub>, wherein the remaining variables are as described in Formula I or the second, third, fourth, fifth, sixth, seventh, or eighth embodiment. [Image disponible dans le document PDF, Image available in the PDF document] Alternatively, R<com:Sup>3< / com:Sup> in Formulas I, Ia, II, or III is selected from: , [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] and , wherein the remaining variables are as described in Formula <Formule mathématique disponible dans le document PDF, Math available in the PDF document>${\bf I}$ or the second, third, fourth, fifth, sixth, seventh, or eighth embodiment. In another alternative, R<com:Sup>3< / com:Sup> in Formulas I, Ia, II, or III is selected from: [Image disponible dans le document PDF, Image available in the PDF document] and ables are as described in Formula I or the second, third, fourth, fifth, sixth, seventh, or eighth embodiment. In yet another alternative, R<com:Sup>3< / com:Sup> in Formulas I, Ia, II, or III is [Image disponible dans le document PDF, Image available in the PDF document] , wherein the remaining variables are as described in Formula I or the second, third, fourth, fifth, sixth, seventh, or eighth embodiment.

[0053] In an eighteenth embodiment, the compound of Formula I, Ia, II, or III, is of the Formula IV or V: [Image disponible dans le document PDF, Image available in the PDF document] , ٠ or a pharmaceutically acceptable salt thereof, wherein the remaining variables are as described in Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, or seventeenth embodiment.

[0054] In a ninteenth embodiment, the compound of Formula I, Ia, II, or III, is of the Formula VI or VII: [Image disponible dans le document PDF, Image available in the PDF document] (VII); . . . . or a pharmaceutically acceptable salt thereof, wherein the remaining variables are as described in Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, or sixteenth embodiment.

[0055] In a twentieth embodiment, ring A in Formulas I, Ia, II, III, IV, V, VI, or VII is [Image disponible dans le document PDF, Image available in the PDF document] , wherein the remaining variables are as described in Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, seventeenth, eighteenth, or nineteenth embodiment. Alternatively, ring A in Formulas I, Ia, II, III, IV, V, VI, or VII is [Image disponible dans le document PDF, Image available in the PDF document] , wherein the remaining variables are as described in Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, seventeenth, eighteenth, or nineteenth embodiment.

[0056] In a twenty-first embodiment, R<com:Sup>2< / com:Sup> in Formulas I, Ia, II, III, IV, V, VI, or VII is independently selected from <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C4<annotation encoding="application / x-tex">C_4< / annotation>< / semantics>< / com:Math> alkyl, halo <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C4<annotation encoding="application / x-tex">C_4< / annotation>< / semantics>< / com:Math> alkyl, and hydroxy <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C4<annotation encoding="application / x-tex">C_4< / annotation>< / semantics>< / com:Math> alkyl, wherein the remaining variables are as described in Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, seventeenth, eighteenth, nineteenth, or twentieth embodiment. Alternatively, R<com:Sup>2< / com:Sup> in Formulas I, Ia, II, III, IV, V, VI, or VII is independently selected from CH<com:Sub>3< / com:Sub>, CHF<com:Sub>2< / com:Sub>, CH<com:Sub>2< / com:Sub>F, -CH(CH<com:Sub>3< / com:Sub>)OH, and -CH<com:Sub>2< / com:Sub>OH, wherein the remaining variables are as described in Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, seventeenth, eighteenth, nineteenth, or twentieth embodiment.

[0057] In a twenty-second embodiment, R<com:Sup>5< / com:Sup> in Formulas I, Ia, II, III, IV, V, VI, or VII is hydrogen or <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C4<annotation encoding="application / x-tex">C_4< / annotation>< / semantics>< / com:Math> alkyl, wherein the remaining variables are as described in Formula I or or the second, third, fourth, fifth, sixth, seventh, eighth, seventeenth, eighteenth, nineteenth, twentieth, or twenty-first embodiment. Alternatively, R<com:Sup>5< / com:Sup> in Formulas I, Ia, II, III, IV, V, VI, or VII is hydrogen, wherein the remaining variables are as described in Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, seventeenth, eighteenth, nineteenth, twentieth, or twenty-first embodiment.

[0058] Specific examples of compounds are provided in Table 1 and Table 2 as well as the EXEMPLIFICATION section and are included as part of a twenty-third embodiment herein. Pharmaceutically acceptable salts as well as the neutral forms of the compounds in Table 1 and the EXEMPLIFICATION are also included. Table 1 [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] Table 2 [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] Table 2 - Continued [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] Table 2 - Continued [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] Table 2 - Continued [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] Table 2 - Continued [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] Table 2 - Continued [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] Table 2 - Continued [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 4. Uses, Formulation and Administration Pharmaceutically acceptable compositions

[0059] According to another embodiment, this disclosure provides a composition comprising a compound described herein or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in compositions is such that is effective to measurably modulate potassium channels in a biological sample or in a patient.

[0060] In certain embodiments, a composition described herein is formulated for administration to a patient in need of such composition. In some embodiments, a composition described herein is formulated for oral administration to a patient.

[0061] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose- based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0062] Pharmaceutically acceptable compositions described herein may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

[0063] Pharmaceutically acceptable compositions described herein may also be prepared in injectable form. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0064] Pharmaceutically acceptable compositions described herein may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs. Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically- transdermal patches may also be used.

[0065] The amount of compounds described herein that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated and the particular mode of administration. In some embodiments, provided compositions should be formulated so that a dosage of between 0.01 - 100 mg / kg body weight / day of the inhibitor, such as e.g., <com:Math><semantics>0.1−100<annotation encoding="application / x-tex">0.1 - 100< / annotation>< / semantics>< / com:Math> mg / kg body weight / day, can be administered to a patient receiving these compositions.

[0066] It should also be understood that a specific dosage and treatment regimen for any particular patient 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, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound described herein in the composition will also depend upon the particular compound in the composition. Uses of Compounds and Pharmaceutically Acceptable Compositions

[0067] In some embodiments, compounds and compositions described herein are useful in treating diseases and / or disorders associated with the activity of potassium channels. Such diseases and / or disorders include e.g., neurodegenerative and neurological conditions (e.g., Parkinson's disease, tremors, Alzheimer's disease, dementia, amyotrophic lateral sclerosis (ALS) ataxia, anxiety, depression, mood disorders, memory and attention deficits, bipolar disorder, psychosis, schizophrenia, traumatic brain injury, and narcolepsy), heart disease and realted conditions (e.g., ischaemic heart disease, coronary heart disease, angina pectoris, and coronary artery spasms), metabolic disease and bladder diseases (e.g., bladder spasms, urinary incontinence, bladder outflow obstruction, gastrointestinal dysfunction, irritable bowel syndrome, and diabetes), withdrawal symptoms associated with termination of addiction, and other conditions associated with the modulation of potassium channels such as e.g., respiratory diseases, epilepsy, convulsions, seizures, absence seizures, vascular spasms, renal disorders (e.g., polycystic kidney disease), erectile dysfunction, secretory diarrhoea, ischaemia, cerebral ischaemia, dysmenorrhea, Reynaud's disease, intermittent claudication, Sjorgren's syndrome, arrhythmia, hypertension, myotonic muscle dystrophia, spasticity, xerostomi, hyperinsulinemia, premature labour, baldness, cancer, immune suppression, migraine and pain.

[0068] In one, the present disclosure provides a method of modulating the activity of a potassium channel in a subject comprising the step of administering a compound of Formula I, or a composition comprising any of the compounds herein. In another embodiment, the present disclosure provides a method of positively modulating a SK2 channel in a cell comprising the step of contacting the cell with a compound of Formula I, or a composition comprising any of the compounds herein.

[0069] The present disclosure further provides a method of treating essential tremor in a subject comprising the step of administering a compound or pharmaceutically acceptable salt or composition described herein.

[0070] In some embodiments, the present disclosure provides a method of treating a disease or condition selected from a neurodegenerative disease, dementia, heart disease, withdrawal symptoms associated with termination of addiction, metabolic disease, and bladder disease. In other embodiments, the present disclosure provides a method of treating a disease or condition selected from ataxia, dystonia, Parkinson's disease, ischemia, traumatic brain injury, amyotrophic lateral sclerosis, hypertension, atherosclerosis, diabetes, arrhythmia, over-active bladder, and withdrawal symptoms caused by the termination of abuse of alcohol and other drugs of abuse.

[0071] Certain exemplary provided compounds, e.g., having structural formula I are set forth in the EXEMPLIFICATION section below. In some embodiments, a provided compound is one or more compounds selected from those exemplified in the EXEMPLIFICATION section below, or a pharmaceutically acceptable salt thereof. EXEMPLIFICATION

[0072] The representative examples that follow are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including the examples that follow and the references to the scientific and patent literature cited herein.

[0073] As depicted in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the synthetic methods and Schemes depict the synthesis of certain compounds of the present invention, the following methods and other methods known to one of ordinary skill in the art can be applied to all compounds and subclasses and species of each of these compounds, as described herein.

[0074] General Synthetic Scheme: Scheme 1. [Image disponible dans le document PDF, Image available in the PDF document]

[0075] In one aspect, compounds of Formula I can be prepared according to Scheme 1, where the variables R<com:Sup>1< / com:Sup>, R<com:Sup>3< / com:Sup>, R<com:Sup>5< / com:Sup>, R<com:Sup>4a< / com:Sup>, R<com:Sup>4b< / com:Sup>, X<com:Sup>1< / com:Sup>, X<com:Sup>2< / com:Sup>, and A are defined for Formula I. For example, compounds of Formula I can be prepared by reacting a compound of Formula 600 with a compound of Formula 601 in the presence of base, such as, e.g., diisopropylethylamine to form intermediate 602. Reduction with e.g., a reducing agent such as lithium aluminum hydride forms a compound of Formula 603. Reaction with a nitrogen atom on ring A affords 604 followed by halogenation with e.g., phosphorous tribromide gives 605. Treatment with amine reagent having the formula R<com:Sup>3< / com:Sup>-N in the presence of base, such as e.g., sodium t-butoxide gives 606. Scheme 1 is in no way limiting and represents only one method by which certain compounds described herein can be made. Other methods of making compounds of Formula I would be apparent to one of skill in the art. PREPARATION OF COMPOUNDS OF FORMULA I

[0076] Compounds of Formula I were prepared according to the general procedures outlined below.

[0077] Example 1 [Image disponible dans le document PDF, Image available in the PDF document]

[0078] Step 1

[0003] : To a stirred solution of methyl 2,4-dichloropyrimidine-6- carboxylate

[0001] (5 g, 24.16 mmol) in acetonitrile (50 mL) was added 4,4- difluorocyclohexylamine hydrochloride

[0002] (4.1 g, 24.158 mmol) and N,N-diisopropyl ethylamine (8.8 mL, 50.72 mmol) at rt and the mixture was stirred for 2 h. The reaction mixture was concentrated under reduced pressure. To the residue water (25 mL) was added, the solid thus formed was filtered and dried by suction to afford 4 g of crude which was purified by column chromatography using 15% ethyl acetate in pet ether as eluent to afford 2.8 g of methyl 2-chloro-6-((4,4-difluorocyclohexyl)amino)pyrimidine-4-carboxylate

[0003] as a white solid. <com:Math><semantics>MS(M+1)+=306.0<annotation encoding="application / x-tex">MS(M+1)^{+}=306.0< / annotation>< / semantics>< / com:Math>.

[0079] Step 2

[0004] : To a stirred solution of methyl 2-chloro-6-((4, 4- difluorocyclohexyl) amino) pyrimidine-4-carboxylate

[0003] (0.5 g, 1.635 mmol) in tetrahydrofuran (10 mL) was added a solution of lithium aluminum hydride in tetrahydrofuran (2 M, 1.63 mL, 3.27 mmol) at 0 °C. The reaction mixture was stirred at rt for 2 h. The reaction mixture was cooled to 0 °C, quenched with saturated ammonium chloride solution (2 mL) and extracted with ethyl acetate (2x25 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 0.4 g of crude (2-chloro-6-((4,4-difluorocyclohexyl)amino)pyrimidin-4-yl)methanol

[0004] as a brown gum. <com:Math><semantics>MS(M+1 / M+3)+=278.2 / 280.2<annotation encoding="application / x-tex">MS(M+1 / M+3)^{+}=278.2 / 280.2< / annotation>< / semantics>< / com:Math>.

[0800] Step 3[0006 and 0007]: To a stirred solution of (2-chloro-6-((4,4- difluorocyclohexyl)amino)pyrimidin-4-yl)methanol

[0004] (1.7 g, 6.12 mmol) in acetonitrile (20 mL) were added ethyl-1H-pyrazole-3-carboxylate

[0005] (0.87 g, 6.12 mmol) and cesium carbonate (2.99 g, 9.18 mmol). The reaction mixture was irradiated in microwave at 100 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was quenched with water (15 mL), acidified with 4 N HCl solutions (25 mL) and extracted with ethyl acetate (2x25 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 1.5 g as a mixture of 1-(4- ((4,4-difluorocyclohexyl)amino)-6-(hydroxymethyl)pyrimidin-2-yl)-1H-pyrazole-3- carboxylic acid

[0006] <com:Math><semantics>MS(M+1)+=354.1<annotation encoding="application / x-tex">MS(M+1)^{+}=354.1< / annotation>< / semantics>< / com:Math> and its ethyl ester

[0007] <com:Math><semantics>MS(M+1)+=382.2<annotation encoding="application / x-tex">MS(M+1)^{+}=382.2< / annotation>< / semantics>< / com:Math>.

[0081] Step 4

[0007] : To a stirred solution of a mixture of <com:Math><semantics>1−(4−(4.4−4.4))<annotation encoding="application / x-tex">1-(4-(4.4-4.4))< / annotation>< / semantics>< / com:Math> difluorocyclohexyl)amino)-6-(hydroxymethyl)pyrimidin-2-yl)-1H-pyrazole-3-carboxylic acid

[0006] and its ester

[0007] (3 g, 8.4 mmol) in ethanol (30 mL) was added conc. sulfuric acid (0.923 mL, 16.98 mmol). The reaction mixture was refluxed at 85 °C for 5 h and concentrated under reduced pressure. The residue was quenched with water (15 mL), neutralized with saturated aqueous sodium bicarbonate solution (20 mL), extracted with ethyl acetate (2x100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 3.3 g of crude which was purified by column chromatography using 65% ethyl acetate in pet ether as eluent to afford 2 g of ethyl 1-(4-((4,4-difluorocyclohexyl)amino)-6-(hydroxymethyl)pyrimidin-2-yl)-1H-pyrazole- 3-carboxylate

[0007] as an off-white solid. <com:Math><semantics>MS(M+1)+=381.8<annotation encoding="application / x-tex">MS(M+1)^{+}=381.8< / annotation>< / semantics>< / com:Math>.

[0082] Step 5

[0008] : To a stirred solution of ethyl 1-(4-((4,4-difluorocyclohexyl)amino)- 6-(hydroxymethyl)pyrimidin-2-yl)-1H-pyrazole-3-carboxylate

[0007] (2 g, 5.24 mmol) in dichloromethane (10 mL) was added phosphorus tribromide (1.41 g, 5.24 mmol) at 0 °C. The reaction mixture was stirred at rt for 1 h. The reaction mixture was quenched with ice cold water (50 mL) and extracted with dichloromethane (2x50 mL). The combined organic extracts was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using 35% ethyl acetate in pet ether as eluent to afford 0.7 g of ethyl 1-(4-(bromomethyl)-6-((4,4- difluorocyclohexyl)amino)pyrimidin-2-yl)-1H-pyrazole-3-carboxylate

[0008] as a white solid. <com:Math><semantics>MS(M+1 / M+3)+=444.2 / 446.1<annotation encoding="application / x-tex">MS(M+1 / M+3)^{+} = 444.2 / 446.1< / annotation>< / semantics>< / com:Math>.

[0083] Example 2 [Image disponible dans le document PDF, Image available in the PDF document]

[0084] Step 1

[0010] : To a stirred solution of ethyl 1-(4-(bromomethyl)-6-((4,4- difluorocyclohexyl)amino)pyrimidin-2-yl)-1H-pyrazole-3-carboxylate

[0008] (0.45 g, 1.01 mmol) in tetrahydrofuran (10 mL) were added 4-isopropyl-2-azetidinone

[0009] (0.126 g,) and sodium tert-butoxide (0.146 g, 1.52 mmol) at 0 °C. The reaction mixture was stirred at same temperature for 30 min. The reaction mixture was quenched with water (15 mL) and extracted with ethyl acetate (2x50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using 28% ethyl acetate in pet ether as eluent to afford ethyl 1-(4-((4,4- difluorocyclohexyl)amino)-6-((2-isopropyl-4-oxoazetidin-1-yl)methyl)pyrimidin-2-yl)-1H- pyrazole-3-carboxylate

[0010] as an off-white solid (0.28 g). <com:Math><semantics>MS(M+1)+=476.8<annotation encoding="application / x-tex">MS(M+1)^{+}=476.8< / annotation>< / semantics>< / com:Math>.

[0085] Step 2

[0011] : To a stirred solution of ethyl 1-(4-((4,4-difluorocyclohexyl)amino)- 6-((2-isopropyl-4-oxoazetidin-1-yl)methyl)pyrimidin-2-yl)-1H-pyrazole-3-carboxylate

[0010] (0.28 g, 0.58 mmol) in tetrahydrofuran (5 mL) was added lithium borohydride (0.038 g, 1.76 mmol) at 0 °C. The reaction mixture was stirred at rt for 1.5 h, quenched with ice and extracted with ethyl acetate (2x15 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 1-((6-((4,4-difluorocyclohexyl)amino)-2-(3-(hydroxymethyl)-1H-pyrazol- 1-yl)pyrimidin-4-yl)methyl)-4-isopropylazetidin-2-one

[0011] as a white solid (0.220 g). <com:Math><semantics>MS(M+1)+=434.9.<annotation encoding="application / x-tex">MS(M+1)^+ = 434.9.< / annotation>< / semantics>< / com:Math>

[0086] Step 3

[0012] : To a stirred solution of 1-((6-((4,4-difluorocyclohexyl)amino)-2-(3- (hydroxymethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)methyl)-4-isopropylazetidin-2-one

[0011] (0.22 g, 0.506 mmol) in dichloromethane (5 mL) was added diethylaminosulfur trifluoride (0.133 mL, 1.01 mmol) at 0 °C. The reaction mixture was stirred at rt for 15 min, quenched with 10% sodium bicarbonate solution (10 mL) and extracted with dichloromethane (2x20) mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude which was purified by column chromatography using 32% ethyl acetate in pet ether as eluent to obtain <com:Math><semantics>1−((6−((4,4−<annotation encoding="application / x-tex">1-((6-((4,4-< / annotation>< / semantics>< / com:Math> difluorocyclohexyl)amino)-2-(3-(fluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)methyl)-4- isopropylazetidin-2-one

[0012] , Compound 325 as a white solid (0.037 g). <com:Math><semantics>MS(M+1)+=437.2<annotation encoding="application / x-tex">MS(M+1)^{+}=437.2< / annotation>< / semantics>< / com:Math>, <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.52 (d, J = 2.4 Hz, 1H), 7.63 (d, J = <com:Math><semantics>6.4 Hz<annotation encoding="application / x-tex">6.4 \text{ Hz}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>1H<annotation encoding="application / x-tex">1\text{H}< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>6.60 (s, 1H)<annotation encoding="application / x-tex">6.60 \text{ (s, 1H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>6.40 (s, 1H)<annotation encoding="application / x-tex">6.40 \text{ (s, 1H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>5.45 (d, JF=48 Hz, 2H)<annotation encoding="application / x-tex">5.45 \text{ (d, JF} = 48 \text{ Hz, 2H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>4.35 (d, J=16.8 Hz, 1H)<annotation encoding="application / x-tex">4.35 \text{ (d, J} = 16.8 \text{ Hz, 1H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>4.11 (d, J = 16.1 Hz, 2H),3.59 (s, 1H),3.55 (m, 1H),2.92 (dd, J = 14.8, 5.2 Hz, 1H),2.65 (m, 1H)<annotation encoding="application / x-tex">4.11 \text{ (d, J = 16.1 Hz, 2H)}, 3.59 \text{ (s, 1H)}, 3.55 \text{ (m, 1H)}, 2.92 \text{ (dd, J = 14.8, 5.2 Hz, 1H)}, 2.65 \text{ (m, 1H)}< / annotation>< / semantics>< / com:Math> 1H), <com:Math><semantics>2.18−1.90<annotation encoding="application / x-tex">2.18 - 1.90< / annotation>< / semantics>< / com:Math> (m, <com:Math><semantics>6H<annotation encoding="application / x-tex">6H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>1.70−1.60<annotation encoding="application / x-tex">1.70 - 1.60< / annotation>< / semantics>< / com:Math> (m, <com:Math><semantics>2H<annotation encoding="application / x-tex">2H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>0.88<annotation encoding="application / x-tex">0.88< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=24<annotation encoding="application / x-tex">J = 24< / annotation>< / semantics>< / com:Math> Hz, <com:Math><semantics>6.8<annotation encoding="application / x-tex">6.8< / annotation>< / semantics>< / com:Math> Hz, <com:Math><semantics>6H<annotation encoding="application / x-tex">6H< / annotation>< / semantics>< / com:Math>).

[0087] Example 3 [Image disponible dans le document PDF, Image available in the PDF document]

[0088] Step 1

[0014] : To a stirred solution of ethyl 1-(4-(bromomethyl)-6-((4,4- difluorocyclohexyl)amino)pyrimidin-2-yl)-1H-pyrazole-3-carboxylate

[0008] (0.5 g, 1.012) mmol) in tetrahydrofuran (5 mL) was added 2-pyrrolidone

[0013] (0.478 g, 5.63 mmol) and potassium tert-butoxide (0.151 g, 1.351 mmol) at 0 °C. The reaction mixture was stirred at same temperature for 15 min. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2x25 mL). The combined organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue of was purified by column chromatography using 65% ethyl acetate in pet ether as eluent to afford ethyl 1-(4-((4,4-difluorocyclohexyl)amino)-6-((2-oxopyrrolidin-1- yl)methyl)pyrimidin-2-yl)-1H-pyrazole-3-carboxylate

[0014] as a white solid (0.25 g). <com:Math><semantics>MS(M+1)+=449.3.<annotation encoding="application / x-tex">MS(M+1)^+=449.3.< / annotation>< / semantics>< / com:Math>

[0089] Step 2

[0015] : The procedure is similar to step 2

[0011] in example 2. 0.25 g of ethyl 1-(4-((4,4-difluorocyclohexyl)amino)-6-((2-oxopyrrolidin-1-yl)methyl)pyrimidin-2-yl)- 1H-pyrazole-3-carboxylate

[0014] gave 0.2 g of 1-((6-((4, 4-difluorocyclohexyl) amino)-2- (3-(hydroxymethyl)-1H-pyrazol-1-yl) pyrimidin-4-yl) methyl) pyrrolidin-2-one

[0015] as a brown solid. <com:Math><semantics>MS(M+1)+=407.4<annotation encoding="application / x-tex">MS(M+1)^{+}=407.4< / annotation>< / semantics>< / com:Math>.

[0090] Step 3

[0016] : The procedure is similar to step 3

[0012] in example 2. 0.2 g of 1- ((6-((4, 4-difluorocyclohexyl) amino)-2-(3-(hydroxymethyl)-1H-pyrazol-1-yl) pyrimidin-4- yl) methyl) pyrrolidin-2-one

[0015] gave 0.035 g of 1-((6-((4,4-difluorocyclohexyl)amino)-2- (3-(fluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)methyl)pyrrolidin-2-one

[0016] , Compound 321 as a white solid. <com:Math><semantics>MS(M+1)+=409.2<annotation encoding="application / x-tex">MS(M+1)^{+}=409.2< / annotation>< / semantics>< / com:Math>, <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.62 (s, 1H), <com:Math><semantics>7.78<annotation encoding="application / x-tex">7.78< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=7.2<annotation encoding="application / x-tex">J = 7.2< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>6.66<annotation encoding="application / x-tex">6.66< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=2.6<annotation encoding="application / x-tex">J = 2.6< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>1.3<annotation encoding="application / x-tex">1.3< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>6.20<annotation encoding="application / x-tex">6.20< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>5.45<annotation encoding="application / x-tex">5.45< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>JF=1.0<annotation encoding="application / x-tex">JF = 1.0< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>48.0 Hz,2H<annotation encoding="application / x-tex">48.0 \text{ Hz}, 2H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>4.27 (s, 2H)<annotation encoding="application / x-tex">4.27 \text{ (s, 2H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>4.18 (bs, 1H)<annotation encoding="application / x-tex">4.18 \text{ (bs, 1H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>3.42 (t, J=6.84 Hz, 2H)<annotation encoding="application / x-tex">3.42 \text{ (t, J} = 6.84 \text{ Hz, 2H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>2.33 (t, J=8.0 Hz, 2H)<annotation encoding="application / x-tex">2.33 \text{ (t, J} = 8.0 \text{ Hz, 2H)}< / annotation>< / semantics>< / com:Math>, 2.15 – 1.90 (m, 8H), 1.65-1.5 (m, 2H).

[0091] Example 4 [Image disponible dans le document PDF, Image available in the PDF document]

[0092] Step 1

[0018] : To a stirred solution of ethyl 1-(4-(bromomethyl)-6-((4,4- difluorocyclohexyl)amino)pyrimidin-2-yl)-1H-pyrazole-3-carboxylate

[0008] (0.5 g, 1.126 mmol) in acetonitrile (10 mL) were added 3,5-dimethyl pyrazole

[0017] (0.119 g, 1.23 mmol) and cesium carbonate (0.550 g, 1.69 mmol). The reaction mixture was irradiated in microwave at 100 °C for 1 h, added water (10 mL) and extracted with ethyl acetate (2x15) mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using 55% ethyl acetate in pet ether as eluent to afford 0.23 g of ethyl 1-(4-((4,4- difluorocyclohexyl)amino)-6-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)pyrimidin-2-yl)-1H- pyrazole-3-carboxylate

[0018] as an off-white solid. <com:Math><semantics>MS(M+1)+=460.2<annotation encoding="application / x-tex">MS(M+1)^{+} = 460.2< / annotation>< / semantics>< / com:Math>.

[0093] Step 2

[0019] : To a stirred solution of ethyl 1-(4-((4,4-difluorocyclohexyl)amino)- 6-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)pyrimidin-2-yl)-1H-pyrazole-3-carboxylate

[0018] (0.220 g, 0.478 mmol) in tetrahydrofuran (5 mL) was added a solution of lithium aluminium hydride in tetrahydrofuran (478 mL, 2 M, 0.957 mmol) at 0 °C. The reaction mixture was stirred at rt for 1 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (3 mL) and extracted with ethyl acetate (2x25 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to afford N-(4,4- difluorocyclohexyl)-6-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)-2-(3-(fluoromethyl)-1H- pyrazol-1-yl)pyrimidin-4-amine

[0019] as an off-white solid <com:Math><semantics>(0.2 g)<annotation encoding="application / x-tex">(0.2 \text{ g})< / annotation>< / semantics>< / com:Math>. <com:Math><semantics>MS(M+1)+=418.2<annotation encoding="application / x-tex">MS(M+1)^+=418.2< / annotation>< / semantics>< / com:Math>.

[0094] Step 3

[0020] : The procedure is similar to step 3

[0012] in example 2. 0.2 g of N- (4,4-difluorocyclohexyl)-6-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)-2-(3-(fluoromethyl)-1H- pyrazol-1-yl)pyrimidin-4-amine

[0019] gave 0.036 g of N-(4,4-difluorocyclohexyl)-6-((3,5- dimethyl-1H-pyrazol-1-yl)methyl)-2-(3-(fluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-amine

[0020] , Compound 300 as an off-white solid. <com:Math><semantics>MS(M+1)+=420.2 / 421.2<annotation encoding="application / x-tex">MS(M+1)^+=420.2 / 421.2< / annotation>< / semantics>< / com:Math>, <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.62 (s, 1H), 7.82 (d, J = 7.4 Hz, 1H), 6.67 (d, J = 2.6 Hz, 1H), 5.93 (s, 1H), <com:Math><semantics>5.66<annotation encoding="application / x-tex">5.66< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>5.52−5.40<annotation encoding="application / x-tex">5.52 - 5.40< / annotation>< / semantics>< / com:Math> (d, JF = 49.96 Hz, 2H), <com:Math><semantics>5.09<annotation encoding="application / x-tex">5.09< / annotation>< / semantics>< / com:Math> (s, 2H), <com:Math><semantics>4.16<annotation encoding="application / x-tex">4.16< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>2.21<annotation encoding="application / x-tex">2.21< / annotation>< / semantics>< / com:Math> (s, 3H), <com:Math><semantics>2.13<annotation encoding="application / x-tex">2.13< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(s,3H),2.04−1.92(m,6H),1.54−1.51(m,2H).<annotation encoding="application / x-tex">(s, 3H), 2.04 - 1.92 (m, 6H), 1.54-1.51 (m, 2H).< / annotation>< / semantics>< / com:Math>

[0095] Example 5 [Image disponible dans le document PDF, Image available in the PDF document]

[0096] Step 1

[0022] : 0.850 g of ethyl 1-(4-(bromomethyl)-6-((4,4- difluorocyclohexyl)amino)pyrimidin-2-yl)-1H-pyrazole-3-carboxylate

[0008] gave 0.830 g of ethyl 1-(4-(((1-(tert-butoxycarbonyl)azetidin-3-yl)oxy)methyl)-6-((4,4- difluorocyclohexyl)amino)pyrimidin-2-yl)-1H-pyrazole-3-carboxylate

[0022] as a white solid. (Potassium tert-butoxide in tetrahydrofuran at rt, 10 min) <com:Math><semantics>MS(M+1)+=537.9<annotation encoding="application / x-tex">MS(M+1)^{+}=537.9< / annotation>< / semantics>< / com:Math>.

[0097] Step 2

[0023] : The procedure is similar to step 2

[0019] in example 4. 0.830 g of ethyl 1-(4-(((1-(tert-butoxycarbonyl)azetidin-3-yl)oxy)methyl)-6-((4,4- difluorocyclohexyl)amino)pyrimidin-2-yl)-1H-pyrazole-3-carboxylate

[0022] gave 0.570 g of tert-butyl 3-((6-((4, 4-difluorocyclohexyl)amino)-2-(3-(hydroxymethyl)-1H-pyrazol-1- yl)pyrimidin-4-yl)methoxy)azetidine-1-carboxylate

[0023] as an off-white solid. <com:Math><semantics>MS(M+1)+=494.8.<annotation encoding="application / x-tex">MS(M+1)^{+}=494.8.< / annotation>< / semantics>< / com:Math>

[0098] Step 3

[0024] : The procedure is similar to step 3

[0012] in example 2. 0.560 g of tert-butyl 3-((6-((4, 4-difluorocyclohexyl)amino)-2-(3-(hydroxymethyl)-1H-pyrazol-1- yl)pyrimidin-4-yl)methoxy)azetidine-1-carboxylate

[0023] gave 0.225 g of tert-butyl 3-((6- ((4,4-difluorocyclohexyl)amino)-2-(3-(fluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4- yl)methoxy)azetidine-1-carboxylate

[0024] as a white solid. <com:Math><semantics>MS(M+1)+=496.9<annotation encoding="application / x-tex">MS(M+1)^{+}=496.9< / annotation>< / semantics>< / com:Math>.

[0099] Step 4

[0025] : To a stirred solution of tert-butyl 3-((6-((4,4- difluorocyclohexyl)amino)-2-(3-(fluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4- yl)methoxy)azetidine-1-carboxylate

[0024] (0.2 g, 0.402 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (0.468 mL, 6.042 mmol) at 0 °C and the mixture was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure to afford 0.180 g of 6-((azetidin-3-yloxy)methyl)-N-(4,4-difluorocyclohexyl)-2-(3-(fluoromethyl)-1H-pyrazol-1- yl)pyrimidin-4-amine

[0025] as an off-white solid. <com:Math><semantics>MS(M+1)+=397.3<annotation encoding="application / x-tex">MS(M+1)^+ = 397.3< / annotation>< / semantics>< / com:Math>

[00100] Step 5

[0027] : To a stirred solution of 6-((azetidin-3-yloxy)methyl)-N-(4,4- difluorocyclohexyl)-2-(3-(fluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-amine

[0025] (0.180 g, 0.454 mmol) in dichloromethane (5 mL) were added triethylamine (0.17 mL, 1.20 mmol) and methyl chloroformate (0.180 g, 0.81 mmol) at 0 °C. The reaction mixture was stirred at same temperature for 10 min., partitioned between dichloromethane (10 mL) and water (3 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude was purified by column chromatography using 75% ethyl acetate in pet ether as eluent to afford 0.125 g of methyl 3-((6-((4,4- difluorocyclohexyl)amino)-2-(3-(fluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4- yl)methoxy)azetidine-1-carboxylate

[0027] , Compound 335 as a white solid. <com:Math><semantics>MS(M+1)+=455.2<annotation encoding="application / x-tex">MS(M+1)^{+}=455.2< / annotation>< / semantics>< / com:Math>, 1H-NMR (400 MHz, DMSO-d6): <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.61 (s, 1H), 7.85 (d, J = 6.84 Hz, 1H), <com:Math><semantics>6.64<annotation encoding="application / x-tex">6.64< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>6.52<annotation encoding="application / x-tex">6.52< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>5.45<annotation encoding="application / x-tex">5.45< / annotation>< / semantics>< / com:Math> (d, JF = <com:Math><semantics>48.0<annotation encoding="application / x-tex">48.0< / annotation>< / semantics>< / com:Math> Hz, 2H), <com:Math><semantics>4.46<annotation encoding="application / x-tex">4.46< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>4.39<annotation encoding="application / x-tex">4.39< / annotation>< / semantics>< / com:Math> (s, 2H), <com:Math><semantics>4.16<annotation encoding="application / x-tex">4.16< / annotation>< / semantics>< / com:Math>- 4.14 (m, 3H), 3.82 (s, 2H), 3.56 (s, 3H) 2.15-1.88 (m, 6H), 1.65-1.5 (m, 2H).

[00101] Example 6 [Image disponible dans le document PDF, Image available in the PDF document]

[00102] Step 1

[0028] : To a stirred solution of methyl-2-chloro-6-((4, 4- difluorocyclohexyl) amino) pyrimidine-4-carboxylate

[0003] (6.6 g, 21.589 mmol) in methanol was added methanolic ammonia (60 mL) at rt. After 2 h the reaction mixture was purged with nitrogen to remove excess ammonia and then concentrated under reduced pressure. The residue was diluted with water (100 mL) and stirred for 10 min. The solid formed was filtered, washed with water (25 mL) and dried under vacuum to afford 2-chloro- 6-((4,4-difluorocyclohexyl)amino)pyrimidine-4-carboxamide

[0028] as a white solid (5.5 g <com:Math><semantics>MS(M+1)+=291.1<annotation encoding="application / x-tex">MS(M+1)+=291.1< / annotation>< / semantics>< / com:Math>) and was taken as such to next step.

[00103] Step 2

[0029] : To a suspension of 2-chloro-6-((4,4- difluorocyclohexyl)amino)pyrimidine-4-carboxamide

[0028] (5.5 g, 18.92 mmol) in dichloromethane was added triethylamine (9.57 g, 94.6 mmol) and phosphorus oxychloride (7.25 g, 47.3 mmol) at 0 °C and the reaction mixture was stirred at rt. After 1 h the reaction mixture was quenched with ice (100 g) and extracted with dichloromethane (2x100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford brown oil which was purified by column chromatography using 30% ethyl acetate in hexane as eluent to afford 2-chloro-6-((4,4- difluorocyclohexyl)amino)pyrimidine-4-carbonitrile

[0029] as a pale yellow solid (3.6 g, 70 % yield). <com:Math><semantics>MS(M+1)+=273.1<annotation encoding="application / x-tex">MS(M+1)^{+}=273.1< / annotation>< / semantics>< / com:Math>.

[00104] Step 3

[0030] : To a solution of 2-chloro-6-((4,4- difluorocyclohexyl)amino)pyrimidine-4-carbonitrile

[0029] (3.6 g, 13.302 mmol) in tetrahydrofuran was added a solution of lithium aluminium hydride in tetrahydrofuran (9.9 mL, 2M solution, 19.803 mmol) at -15 °C and the reaction mixture was stirred at same temperature. Reaction turned dark brown after LAH addition. After 10 min, the reaction mixture was quenched with saturated aqueous sodium sulfate solution at 0 °C and stirred at rt. The suspension was passed through celite<com:Sup>TM< / com:Sup> bed, washed with chloroform (50 mL). The filtrate was concentrated under reduced pressure to afford 6-(aminomethyl)-2-chloro-N-(4,4- difluorocyclohexyl)pyrimidin-4-amine

[0030] as red oil (4.2 g, MS(M+1)<com:Sup>+< / com:Sup>=277.2) and it was taken as such to next step.

[00105] Step 4

[0031] : To a solution of 6-(aminomethyl)-2-chloro-N-(4,4- difluorocyclohexyl)pyrimidin-4-amine

[0030] (4.2 g, 15.178 mmol) in dichloromethane were added triethylamine (2.3 g, 22.76 mmol) and boc-anhydride (3.9 g, 18.213 mmol) at 0 °C and the reaction mixture was stirred at same temperature. After 1 h, the reaction mixture was quenched with ice and extracted with dichloromethane (2x100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford as brown oil, which was purified by column chromatography using 30% ethyl acetate in hexane as eluent to afford tert-butyl ((2-chloro-6-((4,4- difluorocyclohexyl)amino)pyrimidin-4-yl)methyl)carbamate

[0031] as a pale yellow solid <com:Math><semantics>(2.3g).MS(M+1)+=377.2.<annotation encoding="application / x-tex">(2.3 g). MS(M+1)^{+}=377.2.< / annotation>< / semantics>< / com:Math>

[00106] Step 5

[0032] : To a solution of tert-butyl ((2-chloro-6-((4,4- difluorocyclohexyl)amino)pyrimidin-4-yl)methyl)carbamate

[0031] (4.2 g, 15.178 mmol) and ethyl-1H-pyrazole-3-carboxylate

[0005] (4.2 g, 15.178 mmol) in acetonitrile was added cesium carbonate (4.2 g, 15.178 mmol) and the reaction mixture was heated at 85 °C in sealed tube. After 2 h, the reaction mixture was filtered, washed with chloroform (50 mL). The combined filtrate was concentrated under reduced pressure to afford pale brown oil which was purified by column chromatography using 35% ethyl acetate in hexane as eluent to afford ethyl 1-(4-(((tert-butoxycarbonyl)amino)methyl)-6-((4,4- difluorocyclohexyl)amino)pyrimidin-2-yl)-1H-pyrazole-3-carboxylate

[0032] as a pale yellow solid <com:Math><semantics>(2.2 g)<annotation encoding="application / x-tex">(2.2 \text{ g})< / annotation>< / semantics>< / com:Math>. MS(M+1)+=481.3.

[00107] Step 6

[0033] : To a solution of ethyl 1-(4-(((tert-butoxycarbonyl)amino)methyl)-6- ((4,4-difluorocyclohexyl)amino)pyrimidin-2-yl)-1H-pyrazole-3-carboxylate

[0032] (2.2 g, 4.578 mmol) in tetrahydrofuran was added a solution of lithium aluminum hydride in tetrahydrofuran (3.43 mL, 2 M, 6.867 mmol) at -20 °C and the reaction mixture was stirred at rt. After 30 min, the reaction mixture was quenched with saturated aqueous sodium sulfate solution at 0 °C and stirred at rt for 10 min. The mixture was passed through celite bed, washed with ethyl acetate (50 mL). The combined filtrate was concentrated under reduced pressure to afford tert-butyl ((6-((4,4-difluorocyclohexyl)amino)-2-(3-(hydroxymethyl)-1H- pyrazol-1-yl)pyrimidin-4-yl)methyl)carbamate

[0033] as an off-white solid (1.9 g). <com:Math><semantics>MS(M+1)+=439.1.<annotation encoding="application / x-tex">MS(M+1)^{+}=439.1.< / annotation>< / semantics>< / com:Math>

[00108] Step 7

[0034] : To a solution of tert-butyl ((6-((4,4-difluorocyclohexyl)amino)-2- (3-(hydroxymethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)methyl)carbamate

[0033] (1.9 g, 4.333) mmol) in dichloromethane was added diethylaminosulfur trifluoride (1.0 g, 6.499 mmol) at - 20 °C and the reaction mixture was stirred at same temperature for 15 min, quenched with saturated aqueous sodium bicarbonate solution at 0 °C and extracted with dichloromethane (2x50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford a red solid which was purified by column chromatography using 35% ethyl acetate in hexane as eluent to afford tert-butyl ((6-((4,4- difluorocyclohexyl)amino)-2-(3-(fluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4- yl)methyl)carbamate

[0034] as off-white solid <com:Math><semantics>(0.75 g)<annotation encoding="application / x-tex">(0.75 \text{ g})< / annotation>< / semantics>< / com:Math>. <com:Math><semantics>MS(M+1)+=441.2<annotation encoding="application / x-tex">MS(M+1)^+=441.2< / annotation>< / semantics>< / com:Math>.

[00109] Step 8

[0036] : To a solution of tert-butyl ((6-((4,4-difluorocyclohexyl)amino)-2- (3-(fluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)methyl)carbamate

[0034] (0.15 g, 0.340 mmol) in dichloromethane was added dry hydrogen chloride in dioxane (4M) at 0 °C and the reaction mixture was stirred at rt for 1 h, concentrated under reduced pressure and the residue was diluted with dichloromethane (20 mL). To the solution was added triethylamine (~ 1.5 mL) at 0 °C followed by acetyl chloride (0.054 g, 0.68 mmol). After 10 min, the reaction mixture was quenched with water, extracted with dichloromethane, washed with water and brine solution. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford N-((6-((4,4-difluorocyclohexyl)amino)-2- (3-(fluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)methyl)acetamide

[0036] , Compound 327 as an off-white solid <com:Math><semantics>(0.055 g)<annotation encoding="application / x-tex">(0.055 \text{ g})< / annotation>< / semantics>< / com:Math>. MS(M+1)<com:Sup>+< / com:Sup>=383.2, <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.63 (s, 1H), <com:Math><semantics>8.49<annotation encoding="application / x-tex">8.49< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>7.81<annotation encoding="application / x-tex">7.81< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>6.65<annotation encoding="application / x-tex">6.65< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>6.28<annotation encoding="application / x-tex">6.28< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>5.42<annotation encoding="application / x-tex">5.42< / annotation>< / semantics>< / com:Math> (d, JF = <com:Math><semantics>48<annotation encoding="application / x-tex">48< / annotation>< / semantics>< / com:Math> Hz, 2H), <com:Math><semantics>4.13<annotation encoding="application / x-tex">4.13< / annotation>< / semantics>< / com:Math> (bs, 3H), 2.15 -1.90 (m, 9H), 1.62 - 1.45 (m, 2H).

[00110] Example 7: [Image disponible dans le document PDF, Image available in the PDF document]

[00111] Step 1

[0038] :To a solution of cyclobutanecarboxylic acid (0.3 g, 2.99 mmol) in dichloromethane was added oxalyl chloride (1.14 g, 8.98 mmol) and N,N-dimethylformamide (0.02 g, 0.3 mmol) at 0 °C and the reaction mixture was stirred rt. After 1 h, the reaction mixture was concentrated under reduced pressure to afford cyclobutanecarbonyl chloride

[0038] as brown oil (0.4 g). This was taken as such to next step.

[00112] Step 2

[0039] : The procedure is similar to Step 8

[0036] in example 6. 0.3 g of tert- butyl ((6-((4,4-difluorocyclohexyl)amino)-2-(3-(fluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4- yl)methyl)carbamate

[0034] gave 0.098 g of N-((6-((4,4-difluorocyclohexyl)amino)-2-(3- (fluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)methyl)cyclobutanecarboxamide

[0039] , Compound 328 as pale brown solid. <com:Math><semantics>MS(M+1)+=423.2<annotation encoding="application / x-tex">MS(M+1)^+=423.2< / annotation>< / semantics>< / com:Math>; <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> <com:Math><semantics>8.61<annotation encoding="application / x-tex">8.61< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>8.26<annotation encoding="application / x-tex">8.26< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>7.80<annotation encoding="application / x-tex">7.80< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>6.64<annotation encoding="application / x-tex">6.64< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>6.21<annotation encoding="application / x-tex">6.21< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>5.45<annotation encoding="application / x-tex">5.45< / annotation>< / semantics>< / com:Math> (d, JF = 48 Hz, 2H), 4.12 (bs, 3H), 3.19 – 3.07 (m, 1H), 2.25 - 2.13 (m, 2H), 2.12 – 1.85 (m, 9H), 1.85 - 1.75 (m, 1H), 1.65 - 1.50 (m, 2H).

[00113] Example 8: [Image disponible dans le document PDF, Image available in the PDF document]

[00114] Step 1

[0040] : To a solution of tert-butyl ((6-((4,4-difluorocyclohexyl)amino)-2- (3-(fluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)methyl)carbamate

[0034] (0.3 g, 0.68 mmol) in dichloromethane was added 4M HCl in dioxane (5 mL) at 0 °C and the reaction mixture was stirred at rt for 1 h, concentrated under reduced pressure to afford 6- (aminomethyl)-N-(4,4-difluorocyclohexyl)-2-(3-(fluoromethyl)-1H-pyrazol-1-yl)pyrimidin- 4-amine

[0040] as an off-white solid. This was taken as such to next step.

[00115] Step 2

[0042] : To a solution of 3-oxetanecarboxylic acid

[0041] (0.140 g, 1.38) mmol) in N,N-dimethylformamide was added 1-propanephosphonic acid cyclic anhydride ((1.317 g, 2.07 mmol), triethylamine (0.209 g, 2.07 mmol) at 0 °C and the reaction mixture was stirred at rt. After 15 min, 6-(aminomethyl)-N-(4,4-difluorocyclohexyl)-2-(3- (fluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-amine

[0040] (0.26 g, 0.69 mmol) was added to the reaction mixture at 0 °C and stirred at rt for 16 h. The reaction mixture was quenched with water, extracted with ethyl acetate, washed with water and brine. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford brown oil, which was purified in the Reveleris flash system using ethyl acetate in hexane followed by methanol in chloroform as eluents in 12 g column. The product was isolated at 07 % methanol in chloroform as eluent to afford N-((6-((4,4- difluorocyclohexyl)amino)-2-(3-(fluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4- yl)methyl)oxetane-3-carboxamide, Compound 333

[0042] as a white solid (0.05 g). <com:Math><semantics>MS(M+1)+=425.2<annotation encoding="application / x-tex">MS(M+1)^{+}=425.2< / annotation>< / semantics>< / com:Math>; <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.63 (bs, 1H), 8.54 (bs, 1H), 7.82 (s, 1H), <com:Math><semantics>6.66<annotation encoding="application / x-tex">6.66< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>6.24<annotation encoding="application / x-tex">6.24< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>5.45<annotation encoding="application / x-tex">5.45< / annotation>< / semantics>< / com:Math> (d, JF = 48 Hz, 1H), <com:Math><semantics>4.69<annotation encoding="application / x-tex">4.69< / annotation>< / semantics>< / com:Math> (d, J = 7.9 Hz, 4H), <com:Math><semantics>4.19<annotation encoding="application / x-tex">4.19< / annotation>< / semantics>< / com:Math> (s, 3H), 3.92 - 3.82 (m, 1H), 2.12 - 1.92 (m, 7H), 1.57 (bs, 2H).

[00116] Example 9: [Image disponible dans le document PDF, Image available in the PDF document]

[00117] Step 1

[0044] : The procedure is similar to step 1

[0003] in Example 1. 1 g of methyl-2,4-dichloropyrimidine-6-carboxylate

[0001] gave 1.1 g of methyl 2-chloro-6-((3,3- difluorocyclohexyl)amino)pyrimidine-4-carboxylate

[0044] as a white solid. <com:Math><semantics>MS(M+1)+=306.7.<annotation encoding="application / x-tex">MS(M+1)^{+}=306.7.< / annotation>< / semantics>< / com:Math>

[00118] Step 2

[0045] : The procedure is similar to step 3

[0004] in Example 1. 1.1 g of methyl 2-chloro-6-((3,3-difluorocyclohexyl)amino)pyrimidine-4-carboxylate

[0044] gave 2 g of 6-((3,3-difluoro cyclohexyl)amino)-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidine-4- carboxylic acid

[0045] as yellow solid. MS(M-1)=350.0. This was taken as such to next step.

[00119] Step 3

[0046] Compound 350: To a solution of 6-((3,3- difluorocyclohexyl)amino)-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidine-4-carboxylicacid

[0045] (1.9 g, 5.407 mmol) in dichloromethane (10 mL) was added oxalyl chloride (2.74 g, 21.63 mmol) and N,N-dimethylformamide (0.04 g, 0.54 mmol) drop wise at 0 °C. Then the reaction mixture was stirred at rt for 1 h. The reaction mixture was concentrated under reduced pressure under N2 atm to afford 2.2 g of 6-((3,3-difluorocyclohexyl)amino)-2-(3,5- dimethyl-1H-pyrazol-1-yl)pyrimidine-4-carbonyl chloride. 6-((3,3- difluorocyclopentyl)amino)-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidine-4-carbonyl chloride was dissolved in tetrahydrofuran (10 mL) and the reaction mixture was purged with ammonia gas at -10 °C for 15 min. The reaction mixture was concentrated under reduced pressure to afford crude was purified by column chromatography using 6% methanol in chloroform as a solvent to afford 0.4 g of 6-((3,3-difluorocyclohexyl)amino)-2-(3,5-dimethyl-1H-pyrazol-1- yl)pyrimidine-4-carboxamide (Compound 350)

[0046] as an off-white solid. <com:Math><semantics>MS(M+1)+=351.2<annotation encoding="application / x-tex">MS(M+1)^{+}=351.2< / annotation>< / semantics>< / com:Math>. <com:Sup>1< / com:Sup>H-NMR (400 MHz, DMSO-d6): <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.10 (d, J = 7.60 Hz, 1H), 7.80 (s, 1H), 7.73 (s, 1H), 6.97 (s, 1H), 6.09 (s, 1H), 4.09 (bs, 1H), 2.54 (s, 3H), 2.44 (bs, 1H), 2.18 (s, 3H), 2.12 - 1.70 (m, 5H), 1.55 - 1.30 (m, 2H).

[00120] Step 4

[0047] Compound 351: To a solution of 6-((3,3- difluorocyclohexyl)amino)-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidine-4-carboxamide

[0046] (0.35 g, 0.99 mmol) in dichloromethane was added triethylamine (0.50 g, 4.99 mmol) and trifluoromethanesulfonic anhydride (0.71 g, 2.49 mmol) at 0 °C and the reaction mixture was stirred at same temperature. After 1 h, the reaction mixture was quenched with ice and extracted with chloroform, washed with water and brine solution. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford a pale brown solid, was purified in the Reveleris flash system instrument using ethyl acetate in hexane as solvent in 24 g column to afford 0.24 g of 6-((3,3- difluorocyclo hexyl)amino)-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidine-4-carbonitrile (Compound 351)

[0047] as an off-white solid. <com:Math><semantics>MS(M+1)+=333.2<annotation encoding="application / x-tex">MS(M+1)^{+}=333.2< / annotation>< / semantics>< / com:Math>. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.42 (d, J = 7.5 Hz, 1H), 6.85 (s, 1H), 6.12 (s, 1H), 4.07 (bs, 1H), 2.54 (s, 3H), 2.42 - 2.32 (m, 1H), 2.17 (s, 3H), 2.03 – 1.70 (m, 5H), 1.50 - 1.32 (m, 2H).

[00121] Example 10: [Image disponible dans le document PDF, Image available in the PDF document]

[00122] Step 1

[0048] : To a solution of 6-((3,3-difluorocyclohexyl)amino)-2-(3,5- dimethyl-1H-pyrazol-1-yl)pyrimidine-4-carboxylic acid

[0045] (0.52 g, 1.48 mmol) in N,N- dimethylformamide (5 mL) was added N,N-diisopropyl ethylamine (1.28 mL, 7.4 mmol), followed by N,O-dimethylhydroxylamine (0.22 g, 2.22 mmol) hydrochloride and HBTU (0.67 g, 1.776). The reaction mixture was stirred at rt for 3 h. The reaction mixture was quenched with ice, extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with water (20 mL), followed by brine (20 mL), dried over anhydrous sodium sulfate to afford 6-((3,3-difluorocyclohexyl)amino)-2-(3,5-dimethyl-1H-pyrazol-1-yl)-N-methoxy- N-methylpyrimidine-4-carboxamide

[0048] as a yellow solid <com:Math><semantics>(0.6 g)<annotation encoding="application / x-tex">(0.6 \text{ g})< / annotation>< / semantics>< / com:Math>. <com:Math><semantics>MS(M+1)+=395.0<annotation encoding="application / x-tex">MS(M+1)^+ = 395.0< / annotation>< / semantics>< / com:Math>

[00123] Step 2

[0049] Compound 352:To a solution of 6-((3,3- difluorocyclohexyl)amino)-2-(3,5-dimethyl-1H-pyrazol-1-yl)-N-methoxy-N- methylpyrimidine-4-carboxamide

[0045] (0.33 g, 0.836 mmol) in tetrahydrofuran (7 mL) at - 70 °C was added methyl magnesium bromide ((3 M solution in tetrahydrofuran) 2.23 mL, 6.69 mmol) drop wise. The reaction mixture was stirred at rt for 10 min. The reaction mixture was quenched with saturated solution of ammonium chloride (5 mL), extracted with ethyl acetate (2x20 mL). The combined organic layer was washed with brine(10 mL) and dried over anhydrous sodium sulfate to afford 0.6 g of crude product which was purified by column chromatography using 56% ethyl acetate in pet ether as eluent to afford 1-(6-((3,3- difluorocyclohexyl)amino)-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidin-4-yl)ethan-1-one (Compound 352)

[0049] of as a white solid <com:Math><semantics>(0.150 g)<annotation encoding="application / x-tex">(0.150 \text{ g})< / annotation>< / semantics>< / com:Math>. MS(M+1)<com:Sup>+< / com:Sup>=350.2, <com:Sup>1< / com:Sup>H NMR (400) MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.12 (d, J = 7.6 Hz, 1H), 6.84 (s, 1H), 6.12 (s, 1H), 4.13 (s, 1H), 2.56 (d, <com:Math><semantics>J=9.1 Hz,6H<annotation encoding="application / x-tex">J = 9.1 \text{ Hz}, 6H< / annotation>< / semantics>< / com:Math>, 2.20 (s, 3H), 2.05 – 1.73 (m, 6H), 1.52 – 1.31 (m, 2H).

[00124] Step 3

[0050] Compound 353: To a cooled solution of 1-(6-((3,3- difluorocyclohexyl)amino)-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidin-4-yl)ethan-1-one

[0049] (0.17 g, 0.486 mmol) in methanol (3 mL) was added sodium borohydride (0.018 g, 0.486 mmol). The reaction mixture was stirred at rt for 10 min, concentrated under reduced pressure, dissolved in water (5 mL), neutralized with 1.5 N HCl solutions (10 mL) and extracted with ethyl acetate (2x20 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate to afford 1-(6-((3,3- difluorocyclohexyl)amino)-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidin-4-yl)ethan-1-ol (Compound 353)

[0050] as a white solid <com:Math><semantics>(0.160 g)<annotation encoding="application / x-tex">(0.160 \text{ g})< / annotation>< / semantics>< / com:Math>. MS(M+1)<com:Sup>+< / com:Sup>=352.2, <com:Sup>1< / com:Sup>H-NMR (400 MHz, DMSO-d6): δ 7.70 (s, 1H), 6.51 (s, 1H), 6.03 (s, 1H), 5.36 (s, 1H), 4.46 (s, 1H), 4.07 (s, 2H), 3.32 (m, 1H), 2.16 (s, 1H), 1.99 (s, 3H), 1.95-1.91 (m, 3H), 1.80-1.73 (m, 5H), 1.44-1.38 (m, 2H), 1.34-1.28 (m, 5H),

[00125] Step 4[0051 and 0052] Compound 354 and 355: The isomers were separated by Supercritical Fluid Chromatography (SFC) to afford <com:Math><semantics>0.040 g<annotation encoding="application / x-tex">0.040 \text{ g}< / annotation>< / semantics>< / com:Math> of <com:Math><semantics>(+)−1−(6−(((S)−3,3−((S+1)−3))))<annotation encoding="application / x-tex">(+)-1-(6-(((S)-3,3-((S+1)-3))))< / annotation>< / semantics>< / com:Math> difluorocyclohexyl)amino)-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidin-4-yl)ethan-1-ol (Compound 354)

[0051] as a yellow solid <com:Math><semantics>MS(M+1)+=352.2<annotation encoding="application / x-tex">MS(M+1)^{+}=352.2< / annotation>< / semantics>< / com:Math>, <com:Sup>1< / com:Sup>H-NMR (400 MHz, DMSO- d6): <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.70 (d, J = 6.76 Hz, 1H), 6.51 (s, 1H), 6.03 (s, 1H), 5.36 (d, J = 4.12 Hz, 1H), 4.46 (t, <com:Math><semantics>J=5.36 Hz<annotation encoding="application / x-tex">J = 5.36 \text{ Hz}< / annotation>< / semantics>< / com:Math>, 1H), 4.07 (bs, 1H), 2.56 (s, 2H), 2.49 - 2.48 (m, 1H), 2.16 (s, 3H), 2.10 - 1.56 (m, 6H), 1.50 -1.49 (m, 1H), 1.48 -1.35 (m, 4H). and (-)-1-(6-(((S)-3,3- difluorocyclohexyl)amino)-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidin-4-yl)ethan-1-ol (Compound 355)

[0052] as a yellow solid. MS(M+1)<com:Sup>+< / com:Sup>=352.2, <com:Sup>1< / com:Sup>H-NMR (400 MHz, DMSO- d6): δ 7.70 (bs, 1H), 6.51 (s, 1H), 6.03 (s, 1H), 5.36 (s, 1H), 4.46 (bs, 1H), 4.07 (bs, 2H), 3.32 (m, 1H), 2.48 - 2.47 (m, 1H), 2.16 (s, 2H), 2.01 - 1.99 (m, 3H), 1.99-1.56 (m, 4H), 1.56 -1.49 (m, 1H), 1.49 -1.30 (m, 4H).

[00126] Example 11: [Image disponible dans le document PDF, Image available in the PDF document]

[00127] Step 1

[0053] : Concentrated sulfuric acid (5 mL, 93.80 mmol) was added to a solution of 6-((3,3-difluorocyclohexyl)amino)-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidine- 4-carboxylicacid

[0045] (1.1 g, 3.130 mmol) in ethanol (20 mL), after addition the reaction mixture was heated at 75 °C for 5 h, concentrated under reduced pressure, diluted with water (20 mL), cooled to 5 °C, basified with solid sodium carbonate till pH~ 10 and extracted with ethyl acetate (2x100 mL). The combined organic layers were washed with brine (3 x 300 mL), dried over anhydrous sodium sulfate, filtered and concentrated to afford 1.2 g of ethyl 6-((3,3-difluorocyclohexyl)amino)-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidine-4- carboxylate. This was purified by column chromatography using 20% ethyl acetate in pet ether as eluent to afford ethyl 6-((3,3-difluorocyclohexyl)amino)-2-(3,5-dimethyl-1H- pyrazol-1-yl)pyrimidine-4-carboxylate

[0053] as a yellow solid <com:Math><semantics>(0.660 g)<annotation encoding="application / x-tex">(0.660 \text{ g})< / annotation>< / semantics>< / com:Math>. MS(M+1)<com:Sup>+< / com:Sup>=380.0

[00128] Step 2

[0054] Compound 356:To a solution of ethyl 6-((3,3- difluorocyclohexyl)amino)-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidine-4-carboxylate

[0053] (0.15 g, 0.395 mmol) in tetrahydrofuran (2 mL), was added methyl magnesium bromide (3 M solution in tetrahydrofuran) 0.32 mL, 0.988 mmol)) drop-wise at 0 °C after addition the reaction mixture was stirred at rt for 3 h. The reaction mixture was cooled to 0 °C and quenched with (1.5 N) HCl solutions (5 mL). It was then extracted with ethyl acetate (2 x 30 mL). The combined organic layer was washed with water (20 mL), followed by brine (20 mL) and dried over anhydrous sodium sulfate to afford crude product which was purified by preparative HPLC to afford 2-(6-((3,3-difluorocyclohexyl)amino)-2-(3,5-dimethyl-1H- pyrazol-1-yl)pyrimidin-4-yl)propan-2-ol (Compound 356)

[0054] as an off-white solid <com:Math><semantics>(0.070 g). MS(M+1)+=366.2,1H NMR(400 MHz,DMSO-d6)δ7.68(bs,1H),6.64(s,1H),<annotation encoding="application / x-tex">(0.070 \text{ g}). \text{ MS}(\text{M}+1)^{+}=366.2, ^{1}\text{H NMR} (400 \text{ MHz}, \text{DMSO-d6}) \delta 7.68 (bs, 1H), 6.64 (s, 1H),< / annotation>< / semantics>< / com:Math> 6.04 (s, 1H), 5.18 (s, 1H), 4.10 (bs, 1H), 2.48 (s, 3H), 2.58 - 2.45 (m, 1H), 2.17 (s, 3H), 2.08 - 1.89 (m, 2H), 1.89 - 1.65 (m, 3H), 1.55 - 1.43 (m, 1H), 1.37 (s, 6H), 1.33 - 1.29 (m, 1H).

[00129] Example 12: [Image disponible dans le document PDF, Image available in the PDF document]

[00130] Step 1

[0055] : Compound 357 To a solution of ethyl 6-((3,3- difluorocyclohexyl)amino)-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidine-4-carboxylate

[0053] (220 g, 0.579 mmol) in tetrahydrofuran (6 mL), was added lithium aluminium hydride (2 M solution in tetrahydrofuran, 0.579 mL, 1.159 mmol) drop-wise at -78 °C, after addition the reaction mixture was stirred at -78 °C for 3 h. The reaction mixture was quenched with saturated solution of ammonium chloride solution (10 mL). It was then extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with water (10 mL), followed by brine and dried over anhydrous sodium sulfate to afford (6-((3,3- difluorocyclohexyl)amino)-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidin-4-yl)methanol (Compound 357)

[0055] as an off- white solid (0.150 g). <com:Math><semantics>MS(M+1)+=338.2<annotation encoding="application / x-tex">MS(M+1)^{+}=338.2< / annotation>< / semantics>< / com:Math>, <com:Sup>1< / com:Sup>H NMR (400) MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.73 (d, J = 7.6 Hz, 1H), 6.50 (s, 1H), 6.04 (s, 1H), 5.45 (t, J = 5.8 Hz, 1H), <com:Math><semantics>4.35<annotation encoding="application / x-tex">4.35< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=5.6<annotation encoding="application / x-tex">J = 5.6< / annotation>< / semantics>< / com:Math> Hz, 2H), <com:Math><semantics>4.07<annotation encoding="application / x-tex">4.07< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>2.40<annotation encoding="application / x-tex">2.40< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>2.16<annotation encoding="application / x-tex">2.16< / annotation>< / semantics>< / com:Math> (s, 4H), <com:Math><semantics>2.04−1.91<annotation encoding="application / x-tex">2.04 - 1.91< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>1.88−1.69<annotation encoding="application / x-tex">1.88 - 1.69< / annotation>< / semantics>< / com:Math> (m, 3H), <com:Math><semantics>1.46<annotation encoding="application / x-tex">1.46< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=13.6<annotation encoding="application / x-tex">J = 13.6< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>1.35<annotation encoding="application / x-tex">1.35< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=7.7<annotation encoding="application / x-tex">J = 7.7< / annotation>< / semantics>< / com:Math> Hz, 1H).

[00131] Example 13: [Image disponible dans le document PDF, Image available in the PDF document]

[00132] Step 1

[0056] Compound 358: To a solution of (6-((3,3- difluorocyclohexyl)amino)-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidin-4-yl)methanol

[0055] (0.1 g, 0.296 mmol) in dichloromethane (10 mL) was added diethylaminosulfur trifluoride (0.095 g, 0.592 mmol) drop-wise at 0 °C, after addition the reaction mixture was stirred at rt for 18 h. The reaction mixture was diluted with dichloromethane (20 mL). The organic layer was washed with 10 % sodium bicarbonate solution (15 mL) to afford crude product which was purified by preparative HPLC to afford N-(3,3-difluorocyclohexyl)-2-(3,5-dimethyl-1H- pyrazol-1-yl)-6-(fluoromethyl)pyrimidin-4-amine (Compound 358)

[0056] as a yellow solid <com:Math><semantics>(0.050 g)<annotation encoding="application / x-tex">(0.050 \text{ g})< / annotation>< / semantics>< / com:Math>. MS(M+1)<com:Sup>+< / com:Sup>=340.2, <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.89 (d, J = 7.5 Hz, 1H), <com:Math><semantics>6.43<annotation encoding="application / x-tex">6.43< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>6.07<annotation encoding="application / x-tex">6.07< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>5.31<annotation encoding="application / x-tex">5.31< / annotation>< / semantics>< / com:Math> (d, JF = <com:Math><semantics>46.3<annotation encoding="application / x-tex">46.3< / annotation>< / semantics>< / com:Math> Hz, 2H), <com:Math><semantics>4.09<annotation encoding="application / x-tex">4.09< / annotation>< / semantics>< / com:Math> (bs, 1H), <com:Math><semantics>2.53<annotation encoding="application / x-tex">2.53< / annotation>< / semantics>< / com:Math> (s, 3H), <com:Math><semantics>2.49−2.40<annotation encoding="application / x-tex">2.49 - 2.40< / annotation>< / semantics>< / com:Math> (m, 1H), 2.16 (s, 3H), 2.08 – 1.92 (m, 2H), 1.92 - 1.65 (m, 3H), 1.55 - 1.25 (m, 2H).

[00133] Example 14: [Image disponible dans le document PDF, Image available in the PDF document]

[00134] Step 1

[0057] : The procedure is similar to step 3

[0006] in example 1. 2.2 g of methyl 2-chloro-6-((4,4-difluorocyclohexyl)amino)pyrimidine-4-carboxylate

[0003] gave 2.8 g of 6-((4,4-difluorocyclohexyl)amino)-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidine-4- carboxylic acid

[0057] as a yellowish solid. <com:Math><semantics>MS(M+1)+=352.0<annotation encoding="application / x-tex">MS(M+1)^{+}=352.0< / annotation>< / semantics>< / com:Math>.

[00135] Step 2

[0058] : The procedure is similar to step 4

[0007] in example 1, 0.9 g of 6- ((4,4-difluorocyclohexyl)amino)-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidine-4-carboxylic acid

[0057] gave 0.71 g of methyl 6-((4,4-difluorocyclohexyl)amino)-2-(3,5-dimethyl-1H- pyrazol-1-yl)pyrimidine-4-carboxylate

[0058] as an yellow solid. <com:Math><semantics>MS(M+1)+=366.2<annotation encoding="application / x-tex">MS(M+1)^{+}=366.2< / annotation>< / semantics>< / com:Math>.

[00136] Step 3

[0059] The procedure is similar to step 2

[0049] in example 10. 0.65 g of methyl 6-((4,4-difluorocyclohexyl)amino)-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidine-4- carboxylate

[0058] gave 0.13 g of 2-(6-((4,4-difluorocyclohexyl)amino)-2-(3,5-dimethyl-1H- pyrazol-1-yl)pyrimidin-4-yl)propan-2-ol

[0059] , Compound 152. MS(M+1)<com:Sup>+< / com:Sup>=366.2, <com:Sup>1< / com:Sup>H- NMR (400 MHz, DMSO-d6): δ 7.62 (s, 1H), 6.64 (s, 1H), 6.03 (s, 1H), 5.17 (s, 1H), 4.05 (bs, 1H), 2.56 (s, 3H), 2.15 (s, 3H), 2.07-1.94 (m, 6H), 1.58-1.55 (m, 2H), 1.37 (s, 6H).

[00137] Example 15: [Image disponible dans le document PDF, Image available in the PDF document]

[00138] Step 1[0060 and 0061] Lithium aluminum hydride (2M THF solution, 31.62) mmol) was added drop-wise at -78 °C to a solution of ethyl 6-((4,4- difluorocyclohexyl)amino)-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidine-4-carboxylate

[0058] (6 g, 15.814 mmol) in tetrahydrofuran (85 mL). After addition the reaction mixture was stirred at -78 °C for 3 h, quenched with water (25 mL) and extracted with ethyl acetate (3x500 mL). The combined organic layer was washed with brine (3x300 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford mixture an which was purified by column chromatography using 50% ethyl acetate in pet ether as eluent to afford of 6-((4,4-difluorocyclohexyl)amino)-2-(3,5-dimethyl-1H-pyrazol-1- yl)pyrimidine-4-carbaldehyde

[0060] as an yellow solid (1.2 g MS(M+1)<com:Sup>+< / com:Sup>=338.0) and (6- ((4,4-difluorocyclohexyl)amino)-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidin-4-yl)methanol

[0061] , Compound 137 as an yellow solid <com:Math><semantics>(2.1 g)<annotation encoding="application / x-tex">(2.1 \text{ g})< / annotation>< / semantics>< / com:Math>. MS(M+1)<com:Sup>+< / com:Sup>=336.2, <com:Sup>1< / com:Sup>H NMR <com:Math><semantics>(400 MHz)<annotation encoding="application / x-tex">(400 \text{ MHz})< / annotation>< / semantics>< / com:Math>, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.67 (d, J = 7.7 Hz, 1H), 6.52 (s, 1H), 6.04 (s, 1H), 5.44 (t, J = 5.9 Hz, 1H), <com:Math><semantics>4.35<annotation encoding="application / x-tex">4.35< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=5.6<annotation encoding="application / x-tex">J = 5.6< / annotation>< / semantics>< / com:Math> Hz, <com:Math><semantics>2H<annotation encoding="application / x-tex">2H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>4.04<annotation encoding="application / x-tex">4.04< / annotation>< / semantics>< / com:Math> (bs, <com:Math><semantics>1H<annotation encoding="application / x-tex">1H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>2.56<annotation encoding="application / x-tex">2.56< / annotation>< / semantics>< / com:Math> (s, <com:Math><semantics>3H<annotation encoding="application / x-tex">3H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>2.16<annotation encoding="application / x-tex">2.16< / annotation>< / semantics>< / com:Math> (s, <com:Math><semantics>3H<annotation encoding="application / x-tex">3H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>2.10−1.85<annotation encoding="application / x-tex">2.10 - 1.85< / annotation>< / semantics>< / com:Math> (m, <com:Math><semantics>6H<annotation encoding="application / x-tex">6H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>1.65−1.85<annotation encoding="application / x-tex">1.65 - 1.85< / annotation>< / semantics>< / com:Math> 1.56 (m, 2H).

[00139] Step 2

[0062] : The procedure is similar to step 3

[0012] in example 2. 0.25 g of (6- ((4,4-difluorocyclohexyl)amino)-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidin-4-yl)methanol

[0061] gave 0.05 g of N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)-6- (fluoromethyl)pyrimidin-4-amine

[0062] , Compound 165 as an off-white solid. <com:Math><semantics>MS(M+1)+=340.2<annotation encoding="application / x-tex">MS(M+1)^{+}=340.2< / annotation>< / semantics>< / com:Math>, <com:Sup>1< / com:Sup>H-NMR (400 MHz, DMSO-d6): <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.83 (d, J = 6.96 Hz, 1H), 6.41 (s, 1H), <com:Math><semantics>6.05<annotation encoding="application / x-tex">6.05< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>5.30<annotation encoding="application / x-tex">5.30< / annotation>< / semantics>< / com:Math> (d, JF = <com:Math><semantics>46.3<annotation encoding="application / x-tex">46.3< / annotation>< / semantics>< / com:Math> Hz, 2H), <com:Math><semantics>4.04<annotation encoding="application / x-tex">4.04< / annotation>< / semantics>< / com:Math> (bs, 1H), <com:Math><semantics>2.52<annotation encoding="application / x-tex">2.52< / annotation>< / semantics>< / com:Math> (s, 3H), <com:Math><semantics>2.14<annotation encoding="application / x-tex">2.14< / annotation>< / semantics>< / com:Math> (s, 3H), <com:Math><semantics>2.07<annotation encoding="application / x-tex">2.07< / annotation>< / semantics>< / com:Math>- 1.94 (m, 6H), 1.57-1.54 (m, 2H),

[00140] Example 16: [Image disponible dans le document PDF, Image available in the PDF document]

[00141] Step 1

[0063] : The procedure is similar to step 2

[0049] in example 10. 2.8 g of 6- ((4,4-difluorocyclohexyl)amino)-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidine-4- carbaldehyde

[0060] gave 0.48 g of racemate 1-(6-((4,4-difluorocyclohexyl)amino)-2-(3,5- dimethyl-1H-pyrazol-1-yl)pyrimidin-4-yl)ethan-1-ol

[0063] , as an off-white solid. MS(M+1)<com:Sup>+< / com:Sup>=352.2, <com:Sup>1< / com:Sup>H-NMR (400 MHz, DMSO-d6): <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.64 (d, J = 7.20 Hz, 1H), 6.53 (s, 1H), 6.03 (s, 1H), 5.37 (s, 1H), 4.34 (bs, 1H), 4.10 (bs, 1H), 2.13 (s, 3H), 2.06 - 1.85 (m, 6H), 1.65 - 1.49 (m, 2H), 1.39-1.22 (m, 6H).

[00142] Step 2[0064 and 0065]: 0.48 g of 1-(6-((4,4-difluorocyclohexyl)amino)-2-(3,5- dimethyl-1H-pyrazol-1-yl)pyrimidin-4-yl)ethan-1-ol

[63] was purified by chiral preparative HPLC to afford 0.12 g of (-)1-(6-((4,4-difluorocyclohexyl)amino)-2-(3,5-dimethyl-1H- pyrazol-1-yl)pyrimidin-4-yl)ethan-1-ol

[0064] , Compound 198 as an off-white solid. <com:Math><semantics>MS(M+1)+=352.2<annotation encoding="application / x-tex">MS(M+1)^{+}=352.2< / annotation>< / semantics>< / com:Math>. SOR: -9.5°, solvent-methanol, concentration = 0.2, Temp-27.5 °C. <com:Sup>1< / com:Sup>H- NMR (400 MHz, DMSO-d6): <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.67 (d, J = 7.48 Hz, 1H), 6.54 (s, 1H), 6.04 (s, 1H), 5.39 (s, 1H), 4.47 (s, 1H), 4.05 (bs, 1H), 2.52 (s, 3H), 2.16 (s, 3H), 2.06-1.94 (m, 6H), 1.58-1.55 (m, 2H), 1.31 (d, <com:Math><semantics>J=0.60<annotation encoding="application / x-tex">J = 0.60< / annotation>< / semantics>< / com:Math> Hz, 3H), and 0.12 g of (+)1-(6-((4,4-difluorocyclohexyl)amino)-2- (3,5-dimethyl-1H-pyrazol-1-yl)pyrimidin-4-yl)ethan-1-ol

[0065] , Compound 199 as an off- white solid. MS(M+1)<com:Sup>+< / com:Sup>=352.2. SOR: +2.5, Solvent-methanol, Concentration=0.200, Temp- 27.3 °C. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.67 (d, J = 7.4 Hz, 1H), 6.54 (s, 1H), 6.04 (s, 1H), 5.39 (s, 1H), 4.47 (bs, 1H), 4.05 (bs, 1H), 2.52 (s, 3H), 2.17 (s, 3H), 2.17 - 1.85 (m, 6H), <com:Math><semantics>1.65−1.57<annotation encoding="application / x-tex">1.65 - 1.57< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>1.33<annotation encoding="application / x-tex">1.33< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=6.6<annotation encoding="application / x-tex">J = 6.6< / annotation>< / semantics>< / com:Math> Hz, 3H).

[00143] Example 17: [Image disponible dans le document PDF, Image available in the PDF document]

[00144] Step 1

[0066] : The procedure is similar to step 3

[0012] in example 2. 0.21 g of 6- ((4,4-difluorocyclohexyl)amino)-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidine-4- carbaldehyde

[11] gave 0.06 g of N-(4,4-difluorocyclohexyl)-6-(difluoromethyl)-2-(3,5- dimethyl-1H-pyrazol-1-yl)pyrimidin-4-amine

[0066] , Compound 142 as an off-white solid. <com:Math><semantics>MS(M+1)+=358.2<annotation encoding="application / x-tex">MS(M+1)^{+}=358.2< / annotation>< / semantics>< / com:Math>, <com:Sup>1< / com:Sup>H-NMR (400 MHz, DMSO-d6): <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.10 (d, J = 7.04 Hz, 1H), 6.77 (t, JF <com:Math><semantics>=54.7 Hz,1H,6.60 (s, 1H),6.10 (s, 1H),4.08 (bs, 1H),2.56 (s, 3H),2.16 (s, 3H),2.12−<annotation encoding="application / x-tex">= 54.7 \text{ Hz}, 1\text{H}, 6.60 \text{ (s, 1H)}, 6.10 \text{ (s, 1H)}, 4.08 \text{ (bs, 1H)}, 2.56 \text{ (s, 3H)}, 2.16 \text{ (s, 3H)}, 2.12 -< / annotation>< / semantics>< / com:Math> 1.88 (m, 6H), 1.62-1.53 (m, 2H).

[00145] Example 18: [Image disponible dans le document PDF, Image available in the PDF document]

[00146] Step 1

[0068] : To a solution of 6-((4,4-difluorocyclohexyl)amino)-2-(3,5- dimethyl-1H-pyrazol-1-yl)pyrimidine-4-carbaldehyde

[0060] (0.35 g, 1.043 mmol) and morpholine

[0067] (0.09 g, 1.047 mmol) in tetrahydrofuran (15 mL), was added titanium(IV)isopropoxide (0.61 g, 2.08 mmol) at 0 °C. After addition the reaction mixture was stirred at rt for 4 h, cooled to 0°C, added ethanol (4 mL) and sodium borohydride in portions. After 16 h the reaction mixture was concentrated under reduced pressure and the residue was basified with sodium bicarbonate solution (25 mL) till pH~ 10, extracted with ethyl acetate (3x100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product which was purified by column chromatography using 2% methanol in chloroform as eluent to afford of N-(4,4- difluorocyclohexyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)-6-(morpholinomethyl)pyrimidin-4- amine

[0068] , Compound 176 as an off-white solid <com:Math><semantics>(0.042 g)<annotation encoding="application / x-tex">(0.042 \text{ g})< / annotation>< / semantics>< / com:Math>. MS(M+1)<com:Sup>+< / com:Sup>=407.2, <com:Sup>1< / com:Sup>H NMR <com:Math><semantics>(400 MHz,DMSO-d6)δ7.66 (d, J=7.4 Hz,1H),6.50 (s, 1H),6.04 (s, 1H),4.03 (bs, 1H),<annotation encoding="application / x-tex">(400 \text{ MHz}, \text{DMSO-d6}) \delta 7.66 \text{ (d, J} = 7.4 \text{ Hz}, 1\text{H}), 6.50 \text{ (s, 1H)}, 6.04 \text{ (s, 1H)}, 4.03 \text{ (bs, 1H)},< / annotation>< / semantics>< / com:Math> <com:Math><semantics>3.62<annotation encoding="application / x-tex">3.62< / annotation>< / semantics>< / com:Math> (t, <com:Math><semantics>J=4.7<annotation encoding="application / x-tex">J = 4.7< / annotation>< / semantics>< / com:Math> Hz, <com:Math><semantics>4H<annotation encoding="application / x-tex">4H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>3.38<annotation encoding="application / x-tex">3.38< / annotation>< / semantics>< / com:Math> (s, <com:Math><semantics>2H<annotation encoding="application / x-tex">2H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>2.48<annotation encoding="application / x-tex">2.48< / annotation>< / semantics>< / com:Math> (s, <com:Math><semantics>3H<annotation encoding="application / x-tex">3H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>2.45<annotation encoding="application / x-tex">2.45< / annotation>< / semantics>< / com:Math> (s, <com:Math><semantics>4H<annotation encoding="application / x-tex">4H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>2.16<annotation encoding="application / x-tex">2.16< / annotation>< / semantics>< / com:Math> (s, <com:Math><semantics>3H<annotation encoding="application / x-tex">3H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>2.15−1.88<annotation encoding="application / x-tex">2.15 - 1.88< / annotation>< / semantics>< / com:Math> (m, 6H), 1.65 - 1.56 (m, 2H).

[00147] Example 19: [Image disponible dans le document PDF, Image available in the PDF document]

[00148] Step 1

[0069] : To a solution of (6-((4,4-difluorocyclohexyl)amino)-2-(3,5- dimethyl-1H-pyrazol-1-yl)pyrimidin-4-yl)methanol

[0061] (1.4 g, 4.14 mmol) in dichloromethane (55 mL) was added carbon tetrabromide (1.5 g, 4.564 mmol). The reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with water (25 mL) and extracted with dichloromethane (2x300 mL). the combined organic layer was washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 6-(bromomethyl)-N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-1H-pyrazol- 1-yl)pyrimidin-4-amine

[0069] as a brownish gum (1.25 g). MS(M+1 and <com:Math><semantics>M+3<annotation encoding="application / x-tex">M+3< / annotation>< / semantics>< / com:Math>)<com:Sup>+< / com:Sup>=400.2 / 402.2

[00149] Step 2

[0071] NSSY5107.0001: 0.4 g of 6-(bromomethyl)-N-(4,4- difluorocyclohexyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidin-4-amine

[0069] and N,N- dimethylamine

[0070] (0.18 g, 3.99 mmol) in tetrahydrofuran was heated at 80 °C to afford 0.028 g of N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)-6- ((dimethylamino)methyl)pyrimidin-4-amine

[0071] , Compound 177 as an off-white solid. <com:Math><semantics>MS(M+1)+=365.2<annotation encoding="application / x-tex">MS(M+1)^{+}=365.2< / annotation>< / semantics>< / com:Math>, <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 6.44 (s, 1H), 5.99 (s, 1H), 5.21 (bs, 1H), <com:Math><semantics>3.89<annotation encoding="application / x-tex">3.89< / annotation>< / semantics>< / com:Math> (bs, 1H), <com:Math><semantics>3.54<annotation encoding="application / x-tex">3.54< / annotation>< / semantics>< / com:Math> (s, 2H), <com:Math><semantics>2.63<annotation encoding="application / x-tex">2.63< / annotation>< / semantics>< / com:Math> (s, 3H), <com:Math><semantics>2.36<annotation encoding="application / x-tex">2.36< / annotation>< / semantics>< / com:Math> (s, 6H), <com:Math><semantics>2.31<annotation encoding="application / x-tex">2.31< / annotation>< / semantics>< / com:Math> (s, 3H), <com:Math><semantics>2.15−2.07<annotation encoding="application / x-tex">2.15 - 2.07< / annotation>< / semantics>< / com:Math> (m, 4H), <com:Math><semantics>1.99−1.83<annotation encoding="application / x-tex">1.99 - 1.83< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>1.72−1.55<annotation encoding="application / x-tex">1.72 - 1.55< / annotation>< / semantics>< / com:Math> (m, 2H).

[00150] Example 20: [Image disponible dans le document PDF, Image available in the PDF document]

[00151] Step 1

[0073] : 0.35 g of 6-(bromomethyl)-N-(4,4-difluorocyclohexyl)-2-(3,5- dimethyl-1H-pyrazol-1-yl)pyrimidin-4-amine

[0069] and 1-methylpiperazine

[0072] (0.096 g, 0.9618 mmol) in acetonitrile was added triethylamine (2 eq) and stirred at rt to afford 0.04 g of N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)-6-((4-methylpiperazin-1- yl)methyl)pyrimidin-4-amine

[0073] , Compound 178 as an off-white solid. <com:Math><semantics>MS(M+1)+=420.1<annotation encoding="application / x-tex">MS(M+1)^{+}=420.1< / annotation>< / semantics>< / com:Math>, <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.65 (d, J = 7.5 Hz, 1H), 6.49 (s, 1H), 6.04 (s, 1H), 4.03 (s, 1H), 3.37 (s, 2H), 2.56 (s, 3H), 2.39 (bs, 8H), 2.19 (s, 3H), 2.16 (s, 3H), 2.11 – 1.88 (m, 6H), 1.65 - 1.56 (m, 2H).

[00152] Example 21: [Image disponible dans le document PDF, Image available in the PDF document]

[00153] Step 1

[0074] : Sodium methoxide (0.33 g, 6.24 mmol) was added to a solution of 6-(bromomethyl)-N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidin-4- amine

[0069] (1.25 g, 3.122 mmol) in methanol (60 mL). After addition the reaction mixture was stirred at rt for 48 h, concentrated under reduced pressure, added saturated ammonium chloride solution (25 mL) and extracted with ethyl acetate (3x300 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude and which was purified by preparative HPLC to afford N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)-6- (methoxymethyl)pyrimidin-4-amine

[0074] as an off-white solid (0.71 g). <com:Math><semantics>MS(M+1)†=352.0<annotation encoding="application / x-tex">MS(M+1)^{\dagger}=352.0< / annotation>< / semantics>< / com:Math>, <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.70 (d, J = 7.6 Hz, 1H), 6.43 (s, 1H), 6.05 (s, 1H), 4.30 (s, 2H), 4.04 (bs, 1H), 3.40 (s, 3H), 2.52 (s, 3H), 2.16 (s, 3H), 2.12 - 1.88 (m, 6H), 1.62 - 1.56 <com:Math><semantics>(m,2H)<annotation encoding="application / x-tex">(m, 2H)< / annotation>< / semantics>< / com:Math>.

[00154] Example 22. [Image disponible dans le document PDF, Image available in the PDF document]

[00155] Step 1

[0076] : The procedure is similar to step 1

[0003] in example 1. 2.0 g of methyl 2,6-dichloropyrimidine-4-carboxylate

[0001] gave 2.56 g of methyl 2-chloro-6-((3,3- difluorocyclopentyl)amino)pyrimidine-4-carboxylate

[0076] as a pale brown solid. <com:Math><semantics>MS(M+1)+=292.<annotation encoding="application / x-tex">MS(M+1)^{+}=292.< / annotation>< / semantics>< / com:Math>

[00156] Step 2

[0077] : The procedure is similar to step 3

[0006] in example 1. 2.0 g of methyl 2-chloro-6-((3,3-difluorocyclopentyl)amino)pyrimidine-4-carboxylate

[0076] gave 2.1 g of 6-((3,3-difluorocyclopentyl)amino)-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidine-4- carboxylic acid

[0077] as a yellow solid. <com:Math><semantics>MS(M+1)+=338<annotation encoding="application / x-tex">MS(M+1)^{+}=338< / annotation>< / semantics>< / com:Math>.

[00157] Step 3

[0078] : To a solution of 6-((3,3-difluorocyclopentyl)amino)-2-(3,5- dimethyl-1H-pyrazol-1-yl)pyrimidine-4-carboxylic acid

[0076] (0.5 g, 1.482 mmol) in dichloromethane (10 mL) was added oxalyl chloride (0.313 g, 3.70 mmol) and N,N- dimethylformamide (0.010 g, 0.148 mmol) drop wise at 0 °C. Then the reaction mixture was stirred at rt for 1 h and concentrated under reduced pressure under N2 atm to afford 0.56 g of 6-((3,3-difluorocyclopentyl)amino)-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidine-4-carbonyl chloride. 6-((3,3-difluorocyclopentyl)amino)-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidine-4- carbonyl chloride (0.51 g, 1.40 mmol) was dissolved in tetrahydrofuran (10 mL) and purged with ammonia gas at -10 °C for 15 min. The reaction mixture was then concentrated under reduced pressure to afford crude which was purified by column chromatography using 6% methanol in chloroform as a eluent to afford 6-((3,3-difluorocyclopentyl)amino)-2-(3,5- dimethyl-1H-pyrazol-1-yl)pyrimidine-4-carboxamide

[33] , Compound 183 as a pale brown solid (0.21 g). MS(M+1)<com:Sup>+< / com:Sup>=337, <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6): <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.27 (d, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = -6.80 Hz, 1H), 7.81 (s, 1H), 7.70 (s, 1H), 6.97 (s, 1H), 6.09 (s, 1H), 4.49-4.50 (m, 1H), 2.58-2.67 (m, 4H), 2.21-2.32 (m, 7H), 1.92-1.82 (m, 1H),

[00158] Step 4

[0079] : The procedure is similar to Step 4

[0047] in example 09. 0.18 g of 6- ((3,3-difluorocyclopentyl)amino)-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidine-4- carboxamide

[0078] gave 0.1 g of 6-((3,3-difluorocyclopentyl)amino)-2-(3,5-dimethyl-1H- pyrazol-1-yl)pyrimidine-4-carbonitrile

[0079] , Compound 184 as an off-white solid. <com:Math><semantics>MS(M+1)+=319<annotation encoding="application / x-tex">MS(M+1)^{+}=319< / annotation>< / semantics>< / com:Math>, <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.33 (d, J = 2.4 Hz, 1H), 6.90 (s, 1H), 6.09 (s, 1H), 4.46 (bs, 1H), 2.80-257 (m, 1H), 2.55(s, 3H), 2.35-2.28 (m 2H), 2.18(s, 3H), 2.11-2.20 (m, 2H), 1.87 – 1.70 (m, 1H).

[00159] Example 23: [Image disponible dans le document PDF, Image available in the PDF document]

[00160] Step 1

[0080] : The procedure is similar to step 4

[0007] in example 1. 2.1 g of 6- ((3,3-difluorocyclopentyl)amino)-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidine-4-carboxylic acid

[0077] gave 1.56 g of ethyl 6-((3,3-difluorocyclopentyl)amino)-2-(3,5-dimethyl-1H- pyrazol-1-yl)pyrimidine-4-carboxylate

[0080] as a yellow gummy solid. MS(M+1)<com:Sup>+< / com:Sup>=366.

[00161] Step 2

[0081] : The procedure is similar to step 2

[049] in example 10. 0.25 g of ethyl 6-((3,3-difluorocyclopentyl)amino)-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidine-4- carboxylate

[0080] gave 0.03 g of 2-(6-((3,3-difluorocyclopentyl)amino)-2-(3,5-dimethyl- 1H-pyrazol-1-yl)pyrimidin-4-yl)propan-2-ol

[0081] , Compound 214 as a yellow solid. <com:Math><semantics>MS(M+1)+=352<annotation encoding="application / x-tex">MS(M+1)^{+}=352< / annotation>< / semantics>< / com:Math>, <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.87 (bs, 1H), 6.64 (s, 1H), 6.05 (s, 1H), <com:Math><semantics>5.20<annotation encoding="application / x-tex">5.20< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>4.49<annotation encoding="application / x-tex">4.49< / annotation>< / semantics>< / com:Math> (bs, 1H), <com:Math><semantics>2.59<annotation encoding="application / x-tex">2.59< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>2.34−2.30<annotation encoding="application / x-tex">2.34 - 2.30< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>2.29<annotation encoding="application / x-tex">2.29< / annotation>< / semantics>< / com:Math> (s, 3H), <com:Math><semantics>2.28−2.00<annotation encoding="application / x-tex">2.28 - 2.00< / annotation>< / semantics>< / com:Math> (m, 3H) 1.75 (m, 1H), 1.38 (s, 3H), 1.37 (s, 3H), 1.23 (m, 2H).

[00162] Example 24: [Image disponible dans le document PDF, Image available in the PDF document]

[00163] Step 1

[0082] : The procedure is similar to step 2

[0019] in Example 4. 0.18 g of ethyl 6-((3,3-difluorocyclopentyl)amino)-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidine-4- carboxylate

[0080] gave 0.04 g of (6-((3,3-difluorocyclopentyl)amino)-2-(3,5-dimethyl-1H- pyrazol-1-yl)pyrimidin-4-yl)methanol

[0082] , Compound 192 as a white solid. <com:Math><semantics>MS(M+1)+=324<annotation encoding="application / x-tex">MS(M+1)^{+}=324< / annotation>< / semantics>< / com:Math>, <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.90 (d, J = 7.0 Hz, 1H), 6.51 (s, 1H), <com:Math><semantics>6.04<annotation encoding="application / x-tex">6.04< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>5.45<annotation encoding="application / x-tex">5.45< / annotation>< / semantics>< / com:Math> (t, <com:Math><semantics>J=5.8<annotation encoding="application / x-tex">J = 5.8< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>4.46<annotation encoding="application / x-tex">4.46< / annotation>< / semantics>< / com:Math> (bs, 1H), <com:Math><semantics>4.36<annotation encoding="application / x-tex">4.36< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=5.8<annotation encoding="application / x-tex">J = 5.8< / annotation>< / semantics>< / com:Math> Hz, 2H), <com:Math><semantics>2.58<annotation encoding="application / x-tex">2.58< / annotation>< / semantics>< / com:Math> (s, 3H), 2.37 – 2.19 (m, 2H), 2.16 (s, 3H), 2.35-1.98 (m, 3H), 1.75 (m, 1H).

[00164] Step 2

[0083] :0.3 g of (6-((3,3-difluorocyclopentyl)amino)-2-(3,5-dimethyl-1H- pyrazol-1-yl)pyrimidin-4-yl)methanol

[0082] gave 0.3 g of 6-((3,3- difluorocyclopentyl)amino)-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidine-4-carbaldehyde

[0083] as a yellow solid (using Dess-Martin periodinane (2 eq) in dichloromethane). <com:Math><semantics>MS(M+1)+=322.<annotation encoding="application / x-tex">MS(M+1)^{+}=322.< / annotation>< / semantics>< / com:Math>

[00165] Step 3

[0084] The procedure is similar to step 3

[0012] in example 2. 0.2 g of 6- ((3,3-difluorocyclopentyl)amino)-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidine-4- carbaldehyde

[0083] gave 0.02 g of N-(3,3-difluorocyclopentyl)-6-(difluoromethyl)-2-(3,5- dimethyl-1H-pyrazol-1-yl)pyrimidin-4-amine

[0084] , Compound 168 as a white solid. <com:Math><semantics>MS(M+1)+=344<annotation encoding="application / x-tex">MS(M+1)^{+}=344< / annotation>< / semantics>< / com:Math>, <com:Sup>1< / com:Sup>H-NMR (400 MHz, DMSO-d6): <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.33 (d, J = 6.80 Hz, 1H), 6.78 (t, JF = 54.40 Hz, 1H), 6.61 (s, 1H), 6.11 (s, 1H), 4.47-4.53 (m, 1H), 2.67-2.68 (m, 1H), 2.52 (s, 3H), 2.22-2.34 (m, 7H), 1.92-1.85 (m, 1H),

[00166] Example 25: [Image disponible dans le document PDF, Image available in the PDF document]

[00167] Step 1

[0085] : The procedure is similar to step 2

[049] in example 10. 0.22 g of 6- ((3,3-difluorocyclopentyl)amino)-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidine-4- carbaldehyde

[0083] gave 0.05 g of 1-(6-((3,3-difluorocyclopentyl)amino)-2-(3,5-dimethyl- 1H-pyrazol-1-yl)pyrimidin-4-yl)ethan-1-ol

[0085] , Compound 225 as a pale yellow solid. <com:Math><semantics>MS(M+1)+=338<annotation encoding="application / x-tex">MS(M+1)^{+}=338< / annotation>< / semantics>< / com:Math>, <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.89 (s, 1H), 6.54 (s, 1H), 6.05 (s, 1H), <com:Math><semantics>5.39<annotation encoding="application / x-tex">5.39< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=4.6<annotation encoding="application / x-tex">J = 4.6< / annotation>< / semantics>< / com:Math> Hz, <com:Math><semantics>1H<annotation encoding="application / x-tex">1H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>4.49<annotation encoding="application / x-tex">4.49< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=6.9<annotation encoding="application / x-tex">J = 6.9< / annotation>< / semantics>< / com:Math> Hz, <com:Math><semantics>2H<annotation encoding="application / x-tex">2H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>2.65−2.55<annotation encoding="application / x-tex">2.65 - 2.55< / annotation>< / semantics>< / com:Math> (m, <com:Math><semantics>2H<annotation encoding="application / x-tex">2H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>2.35−2.22<annotation encoding="application / x-tex">2.35 - 2.22< / annotation>< / semantics>< / com:Math> (m, <com:Math><semantics>2H<annotation encoding="application / x-tex">2H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>2.16<annotation encoding="application / x-tex">2.16< / annotation>< / semantics>< / com:Math> (s, <com:Math><semantics>3H<annotation encoding="application / x-tex">3H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>2.17<annotation encoding="application / x-tex">2.17< / annotation>< / semantics>< / com:Math> (s, <com:Math><semantics>3H<annotation encoding="application / x-tex">3H< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>1.75<annotation encoding="application / x-tex">1.75< / annotation>< / semantics>< / com:Math> (s, <com:Math><semantics>1H<annotation encoding="application / x-tex">1H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>1.33<annotation encoding="application / x-tex">1.33< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=6.7<annotation encoding="application / x-tex">J = 6.7< / annotation>< / semantics>< / com:Math> Hz, <com:Math><semantics>3H<annotation encoding="application / x-tex">3H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>1.23<annotation encoding="application / x-tex">1.23< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=3.8<annotation encoding="application / x-tex">J = 3.8< / annotation>< / semantics>< / com:Math> Hz, <com:Math><semantics>1H<annotation encoding="application / x-tex">1H< / annotation>< / semantics>< / com:Math>).

[00168] Example 26: [Image disponible dans le document PDF, Image available in the PDF document]

[00169] Step 1[0087A and 0087B]: To a solution of 2,4-dichloro-6-methylpyrimidine

[0086] (5 g, 30.67 mmol) in tetrahydrofuran (20 mL) was added 4,4- difluorocyclohexylamine hydrochloride

[0002] (5.26 g, 30.67 mmol) and cesium carbonate (19.9 g, 61.3 mmol), then the reaction mixture was heated at 60 °C for 16 h. the reaction mixture was filtered to remove cesium carbonate, the filtrate was concentrated under reduced pressure to afford as an yellow gum and which was purified by column chromatography silica gel (60-120 mesh) using 40% ethyl acetate in pet ether as a eluent to afford 3.5 g of 2-chloro- N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087A] as an off-white solid and 2.8 g of 4-chloro-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-2-amine <com:Math><semantics>[0087B]<annotation encoding="application / x-tex">[0087B]< / annotation>< / semantics>< / com:Math>. <com:Math><semantics>MS(M+1)+=262<annotation encoding="application / x-tex">MS(M+1)^+=262< / annotation>< / semantics>< / com:Math>.

[00170] Step 2

[0088] : The procedure is similar to Step3

[0515] in example 188. 2.5 g of 2-chloro-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087A] gave 1.5 g of 4- ((4,4-difluoro cyclohexyl)amino)-6-methylpyrimidine-2-carbonitrile

[0088] at 80 °C for 16 h using sodium cyanide (1.1 eq), DABCO (1.1 eq) in dimethylsulfoxide. <com:Math><semantics>MS(M+1)+=243<annotation encoding="application / x-tex">MS(M+1)^{+}=243< / annotation>< / semantics>< / com:Math>.

[00171] Step 3

[0089] : The procedure is similar to Step4

[0516] in example 188. 1.5 g of 4-((4,4-difluoro cyclohexyl)amino)-6-methylpyrimidine-2-carbonitrile

[0088] gave 1.5 g of 4-((4,4-difluoro cyclohexyl)amino)-6-methylpyrimidine-2-carbothioamide

[0089] using ammonium sulfide (3 eq), triethylamine (2 eq) in N,N-dimethylformamide. MS(M+1)<com:Sup>+< / com:Sup> =287.

[00172] Step 4

[0091] : To a solution of 4-((4,4-difluoro cyclohexyl)amino)-6- methylpyrimidine-2-carbothioamide

[0089] (1.5 g, 5.23 mmol) in ethanol (15 mL) was added bromoacetone (0.86 g, 6.28 mmol1.), then the reaction mixture was stirred at rt in a closed vial for 16 h. the reaction mixture was concentrated to afford as an brownish gum and which was purified by column of silica gel (60-120 mesh) using 3% methanol in chloroform as eluent to afford as an off-white solid 0.700 g, as an HBr salt, which was dissolved in saturated bicarbonate solution and extracted with ethyl acetate (2x70 mL), the combined organic layer was dried over anhydrous sodium sulfate and concentrated under high vacuum to afford 0.41 g of N-(4,4-difluorocyclohexyl)-6-methyl-2-(4-methylthiazol-2-yl)pyrimidin- 4-amine

[0091] , Compound 231 as an off-white solid. <com:Math><semantics>MS(M+1)+=325<annotation encoding="application / x-tex">MS(M+1)^+=325< / annotation>< / semantics>< / com:Math>, <com:Sup>1< / com:Sup>H NMR (400) MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.52 (bs, 1H), 7.39 (d, J = 1.1 Hz, 1H), 6.35 (bs, 1H), 4.01 (bs, 1H), 2.43 (s, 3H), 2.29 (s, 3H), 2.07-1.95 (m, 6H), 1.59-1.52 (m, 2H).

[00173] Example 27: [Image disponible dans le document PDF, Image available in the PDF document]

[00174] Step 1

[0092] : The procedure is similar to step 3

[0006] in Example 1. 4 g of 2- chloro-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087A] gave 2.6 g of N- (4,4-difluorocyclohexyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)-6-methylpyrimidin-4-amine

[0092] , Compound 247 as white solid. <com:Math><semantics>MS(M+1)+=322.2<annotation encoding="application / x-tex">MS(M+1)^{+}=322.2< / annotation>< / semantics>< / com:Math>, <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.53 (d, J = 7.7 Hz, 1H), 6.21 (s, 1H), 6.03 (s, 1H), 4.01 (bs, 1H), 2.48 (s, 3H), 2.23 (s, 3H), <com:Math><semantics>2.15<annotation encoding="application / x-tex">2.15< / annotation>< / semantics>< / com:Math> (s, 3H), <com:Math><semantics>2.13−1.85<annotation encoding="application / x-tex">2.13 - 1.85< / annotation>< / semantics>< / com:Math> (m, 6H), <com:Math><semantics>1.62−1.47<annotation encoding="application / x-tex">1.62 - 1.47< / annotation>< / semantics>< / com:Math> (m, 2H).

[00175] Example 28: [Image disponible dans le document PDF, Image available in the PDF document] 0087A 0094

[00176] Step 2

[0094] : The procedure is similar to step 3

[0006] in Example 1. 0.3 g of 2- chloro-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087A] gave 0.26 g of 1-(4- ((4,4-difluorocyclohexyl)amino)-6-methyl pyrimidin-2-yl)-1H-pyrazole-3-carbonitrile

[0094] , Compound 212 as white solid. <com:Math><semantics>MS(M+1)+=319.2<annotation encoding="application / x-tex">MS(M+1)^{+}=319.2< / annotation>< / semantics>< / com:Math>, <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 7.81 (s, 1H), 7.19 (s, 1H), 6.32 (s, 1H), 4.16 (bs, 1H), 2.28 (s, 3H), 2.19 – 1.86 (m, 6H), 1.60 - 1.45 (m, 2H).

[00177] Example 29: [Image disponible dans le document PDF, Image available in the PDF document]

[00178] Step 1

[0096] :. The procedure is step 3

[0006] in Example 1. 0.3 g of 2-chloro-N- (4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087A] gave 0.21 g of 2-(3- cyclopropyl-1H-pyrazol-1-yl)-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine

[0096] , Compound 203 as off-white solid. <com:Math><semantics>MS(M+1)+=334.4<annotation encoding="application / x-tex">MS(M+1)^{+}=334.4< / annotation>< / semantics>< / com:Math>, <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO- d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.42 (s, 1H), 7.55 (s, 1H), 6.19 (s, 2H), 4.13 (bs, 1H), 2.25 (s, 3H), 2.14 – 1.92 (m, 7H), <com:Math><semantics>1.65−1.45<annotation encoding="application / x-tex">1.65 - 1.45< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>1.01−0.87<annotation encoding="application / x-tex">1.01 - 0.87< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>0.79−0.63<annotation encoding="application / x-tex">0.79 - 0.63< / annotation>< / semantics>< / com:Math> (m, 2H).

[00179] Example 30: [Image disponible dans le document PDF, Image available in the PDF document]

[00180] Step 1

[0098] : The procedure is step 3

[0006] in Example 1. 0.3 g of 4-chloro-N- (4,4-difluorocyclohexyl)-6-methylpyrimidin-2-amine [0087B] gave 0.14 g of N-(4,4- difluorocyclohexyl)-4-methyl-6-(3-methyl-1H-pyrazol-1-yl)pyrimidin-2-amine

[0098] , Compound 120 as a white solid. <com:Math><semantics>MS(M+1)+=308<annotation encoding="application / x-tex">MS(M+1)^{+}=308< / annotation>< / semantics>< / com:Math>, <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.52 (bs, 1H), <com:Math><semantics>7.35<annotation encoding="application / x-tex">7.35< / annotation>< / semantics>< / com:Math> (bs, 1H), <com:Math><semantics>6.86<annotation encoding="application / x-tex">6.86< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>6.38<annotation encoding="application / x-tex">6.38< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=2.6<annotation encoding="application / x-tex">J = 2.6< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>3.99<annotation encoding="application / x-tex">3.99< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=9.8<annotation encoding="application / x-tex">J = 9.8< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>2.29<annotation encoding="application / x-tex">2.29< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(s,3H),2.26(s,3H),2.10−1.87(m,6H),1.68−1.50(m,2H).<annotation encoding="application / x-tex">(s, 3H), 2.26(s, 3H), 2.10 - 1.87 (m, 6H), 1.68-1.50 (m, 2H).< / annotation>< / semantics>< / com:Math>

[00181] Example 31: [Image disponible dans le document PDF, Image available in the PDF document]

[00182] Step 1

[0099] : To a stirred solution of 2,4-Dichloro-6-methylpyrimidine

[0086] (5 g, 30.674 mmol) in tetrahydrofuran (50 mL) was added sodium thiomethoxide (2.14 g, 30.67 mmol) in portions at -10 °C under nitrogen. The mixture was stirred at -10 °C for 3 h. The solid precipitate was filtered, washed with methanol (20 mL) and dried under vacuum to afford 2-chloro-4-methyl-6-(methylthio)pyrimidine

[0099] as an yellow solid (5 g). <com:Math><semantics>MS(M+1)+=175.<annotation encoding="application / x-tex">MS(M+1)^{+}=175.< / annotation>< / semantics>< / com:Math>

[00183] Step 2

[0100] : The procedure is step 3

[0006] in Example 1. 2.5 g of 2-chloro-4- methyl-6-(methylthio)pyrimidine

[0099] gave 3.0 g of 4-methyl-2-(3-methyl-1H-pyrazol-1- yl)-6-(methylthio) pyrimidine

[0100] as a yellow liquid. <com:Math><semantics>MS(M+1)+=221<annotation encoding="application / x-tex">MS(M+1)^{+}=221< / annotation>< / semantics>< / com:Math>.

[00184] Step 3

[0101] : The procedure is similar to step 2

[0378] in example 145. 3.0 g of 4- methyl-2-(3-methyl-1H-pyrazol-1-yl)-6-(methylthio) pyrimidine

[0100] gave 1.3 g of 4- methyl-2-(3-methyl-1H-pyrazol-1-yl)-6-(methylsulfonyl)pyrimidine

[0101] as a yellow solid using 3-chloroperbenzoic acid (3 eq) in dichloromethane. <com:Math><semantics>MS(M+1)+=253<annotation encoding="application / x-tex">MS(M+1)^{+}=253< / annotation>< / semantics>< / com:Math>.

[00185] Example 32: [Image disponible dans le document PDF, Image available in the PDF document]

[00186] Step 1

[0102] : To a solution of 4-methyl-2-(3-methyl-1H-pyrazol-1-yl)-6- (methylsulfonyl)pyrimidine

[0101] (0.1 g, 0.396 mmol) in dry tetrahydrofuran (8 mL) was added 3,3-difluoro-N-methylcyclopentan-1-amine

[0075] (0.096 g, 0.792 mmol) under N2 atm. The reaction mixture was heated at 100 °C in sealed tube for 16 h. The reaction mixture was concentrated under reduced pressure to afford crude and which was purified by column chromatography using 30% ethyl acetate in hexane as a eluent to afford N-(3,3- difluorocyclopentyl)-6-methyl-2-(3-methyl-1H-pyrazol-1-yl)pyrimidin-4-amine, Compound 150 as a white solid (0.04 g). <com:Math><semantics>MS(M+1)+=294<annotation encoding="application / x-tex">MS(M+1)^{+}=294< / annotation>< / semantics>< / com:Math>, <com:Sup>1< / com:Sup>H-NMR (400 MHz, DMSO-d6): <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.41 (s, 1H), 7.79 (bs, 1H), 6.28 (d, <com:Math><semantics>J=2.5Hz<annotation encoding="application / x-tex">J = 2.5 Hz< / annotation>< / semantics>< / com:Math>, 1H), 6.2 (bs, 1H), 4.51 (bs, 1H), 2.67-2.58 (m, 1H), 2.24 (s, 3H), 2.24 (s, 3H), 2.20 (m, 2H), 2.10-2.06 (m, 2H), 1.77-1.74 (m, 1H).

[00187] Example 35: [Image disponible dans le document PDF, Image available in the PDF document]

[00188] Step 1

[0108] : The procedure is similar to step 1

[0106] in example 34. 0.15 g of 4- methyl-2-(3-methyl-1H-pyrazol-1-yl)-6-(methylsulfonyl)pyrimidine

[0101] gave 0.08 g of N- ((1R,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)-6-methyl-2-(3-methyl-1H-pyrazol-1- yl)pyrimidin-4-amine

[0108] , Compound 245 as an off-white solid. MS(M+1)<com:Sup>+< / com:Sup>=306, <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.34 (s, 1H), 7.65 (bs, 1H), 6.30 (d, J = 2.6 Hz, 1H), 6.16 (bs, 1H), 4.36 (bs, 1H), 2.45-2.30 (m, 2H), 2.28 – 2.12 (m, 2H), 2.25 (s, 3H), 2.21 (s, 3H) 1.91 (bs, 2H).

[00189] Example 38: [Image disponible dans le document PDF, Image available in the PDF document] UIUI UTT4

[00190] Step 1

[0114] : The procedure is similar to step 1

[0102] in example 32. 0.12 g of 4- methyl-2-(3-methyl-1H-pyrazol-1-yl)-6-(methylsulfonyl)pyrimidine

[0101] gave 0.06 g of 6- methyl-2-(3-methyl-1H-pyrazol-1-yl)-N-(4-(trifluoromethyl)cyclohexyl)pyrimidin-4-amine

[0114] , Compound 144 as a yellow solid. <com:Math><semantics>MS(M+1)+=340<annotation encoding="application / x-tex">MS(M+1)^+=340< / annotation>< / semantics>< / com:Math>, <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.42 (bs, 1H), 7.50 (bs, 1H), 6.27 (d, J = 2.5 Hz, 1H), 6.15 (bs, 1H), 3.89 (bs, 1H), 2.58 (bs, 1H), 2.44 (s, 3H), 2.42 (s, 3H), 2.10-1.95 (m, 2H), 1.91 (d, <com:Math><semantics>J=12.2 Hz<annotation encoding="application / x-tex">J = 12.2 \text{ Hz}< / annotation>< / semantics>< / com:Math>, 2H), 1.50 – 1.37 (m, 2H), 1.36-1.20 (m, 2H).

[00191] Example 39: [Image disponible dans le document PDF, Image available in the PDF document]

[00192] Step 1

[0115] : The procedure is similar to step 3

[0006] in example 1. 2.0 g of 2- chloro-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087A] gave 0.9 g of N- (4,4-difluorocyclohexyl)-6-methyl-2-(3-methyl-1H-pyrazol-1-yl)pyrimidin-4-amine

[0115] , Compound 148 as an off-white solid. <com:Math><semantics>MS(M+1)+=308<annotation encoding="application / x-tex">MS(M+1)^+=308< / annotation>< / semantics>< / com:Math>, <com:Sup>1< / com:Sup>H-NMR (400 MHz, DMSO-d6): <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.44 (bs, 1H), 7.79 (bs, 1H), 6.29-6.19 (m, 2H), 4.13-4.08 (m, 1H), 2.25 (s, 3H), 2.24 (s, 3H), 2.05-1.95 (m, 6H), 1.60-1.54 (m, 2H).

[00193] Example 40: [Image disponible dans le document PDF, Image available in the PDF document]

[00194] Step 1

[0117] : The procedure is similar to step 3

[0006] in example 1. 0.2 g 2- chloro-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087A] gave 0.18 g of N- (4,4-difluorocyclohexyl)-6-methyl-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4- amine

[0117] , Compound 200 as an off-white solid. <com:Math><semantics>MS(M+1)+=362.0<annotation encoding="application / x-tex">MS(M+1)^{+}=362.0< / annotation>< / semantics>< / com:Math>, <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.70 (d, J = 2.5 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 6.90 (d, J = 2.7 Hz, 1H), 6.40 <com:Math><semantics>(s,1H),4.04(bs,1H),2.33(s,3H),2.13−1.94(m,6H),1.65(qd,J=12.2,11.3,4.3Hz,2H).<annotation encoding="application / x-tex">(s, 1H), 4.04 (bs, 1H), 2.33 (s, 3H), 2.13 - 1.94 (m, 6H), 1.65 (qd, J = 12.2, 11.3, 4.3 Hz, 2H).< / annotation>< / semantics>< / com:Math>

[00195] Example 41: [Image disponible dans le document PDF, Image available in the PDF document]

[00196] Step 1

[0119] : The procedure is similar to step 3

[0006] in example 1. 0.2 g 2- chloro-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087A] gave 0.12 g of N- (4,4-difluorocyclohexyl)-2-(4-fluoro-3,5-dimethyl-1H-pyrazol-1-yl)-6-methylpyrimidin-4- amine

[0119] , Compound 201 as a white solid. <com:Math><semantics>MS(M+1)+=340.2<annotation encoding="application / x-tex">MS(M+1)^{+}=340.2< / annotation>< / semantics>< / com:Math>, <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.59 (d, J = 7.6 Hz, 1H), 6.22 (s, 1H), 4.00 (s, 1H), 2.48 (s, 3H), 2.34 – 2.14 (m, 6H), <com:Math><semantics>2.12−1.88<annotation encoding="application / x-tex">2.12 - 1.88< / annotation>< / semantics>< / com:Math> (m, 6H), <com:Math><semantics>1.55<annotation encoding="application / x-tex">1.55< / annotation>< / semantics>< / com:Math> (t, <com:Math><semantics>J=11.5<annotation encoding="application / x-tex">J = 11.5< / annotation>< / semantics>< / com:Math> Hz, 2H).

[00197] Example 42: [Image disponible dans le document PDF, Image available in the PDF document]

[00198] Step 1

[0121] : The procedure is similar to The procedure is similar to step 3

[0006] in example 1. 0.300 g of 2-chloro-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087A] and 0.220 g of 3-ethyl pyrazole

[0120] gave 0.08 g of N-(4,4-difluorocyclohexyl)- 2-(3-ethyl-1H-pyrazol-1-yl)-6-methylpyrimidin-4-amine

[0121] , Compound 197 as an white solid, MS(M+1)<com:Sup>+< / com:Sup>=336. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) δ 8.46 (bs, 1H), 7.56 (bs, 1H), 6.34 <com:Math><semantics>(d,J=2.5Hz,1H),6.20(bs,1H),4.14(s,1H),2.63(q,J=7.6Hz,2H),2.26(s,3H),2.12−<annotation encoding="application / x-tex">(d, J = 2.5 Hz, 1H), 6.20 (bs, 1H), 4.14 (s, 1H), 2.63 (q, J = 7.6 Hz, 2H), 2.26 (s, 3H), 2.12 -< / annotation>< / semantics>< / com:Math> <com:Math><semantics>1.91 (m, 6H),1.60−1.52 (m, 2H),1.21 (t, J=7.7 Hz, 3H).<annotation encoding="application / x-tex">1.91 \text{ (m, 6H)}, 1.60-1.52 \text{ (m, 2H)}, 1.21 \text{ (t, J} = 7.7 \text{ Hz, 3H)}.< / annotation>< / semantics>< / com:Math>

[00199] Example 43: [Image disponible dans le document PDF, Image available in the PDF document]

[00200] Step 1

[0123] : The procedure is similar to step 3

[0006] in example 1. 0.300 g of 2- chloro-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087A] and 0.148 g of 4- fluoro pyrazole

[0122] gave 0.150 g of N-(4,4-difluorocyclohexyl)-2-(4-fluoro-1H-pyrazol-1- yl)-6-methylpyrimidin-4-amine

[0123] , Compound 196 as an light yellow solid, <com:Math><semantics>MS(M+1)+=312<annotation encoding="application / x-tex">MS(M+1)^{+}=312< / annotation>< / semantics>< / com:Math>. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.64 (bs, 1H), 7.84 (d, J = 4.4 Hz, 1H), 7.66 (bs, 1H), 6.23 (bs, 1H), 4.17 (bs, 1H), 2.26 (s, 3H), 2.10-1.95 (m, 6H), 1.60-1.52 (s, 2H).

[00201] Example 44: [Image disponible dans le document PDF, Image available in the PDF document]

[00202] Step 1

[0125] : The procedure is similar to step 3

[0006] in example 1. 0.15 g 2- chloro-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087A] gave 0.1 g of 2-(1- (4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-1H-pyrazol-3-yl)acetonitrile

[0125] , Compound 208 as a white solid. <com:Math><semantics>MS(M+1)+=333.1<annotation encoding="application / x-tex">MS(M+1)^+=333.1< / annotation>< / semantics>< / com:Math>, <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.59 (s, 1H), 7.68 (s, 1H), 6.50 (d, J = 2.6 Hz, 1H), 6.24 (s, 1H), 4.11 (s, 3H), 2.28 (s, 3H), <com:Math><semantics>2.01(d,J=42.1Hz,6H),1.56(s,2H).<annotation encoding="application / x-tex">2.01 (d, J = 42.1 Hz, 6H), 1.56 (s, 2H).< / annotation>< / semantics>< / com:Math>

[00203] Example 45: [Image disponible dans le document PDF, Image available in the PDF document]

[00204] Step 1

[0127] : To a mixture of 4,4-difluorocyclohexanone

[0126] (2 g, 14.911 mmol), ethylamine (1.34 g, 29.82 mmol) and acetic acid (2.68 g, 44.73 mmol) in 1,2- dichloroethane under N2 atmosphere was added sodium triacetoxyborohydride (6.32 g, 29.82) mmol) portion wise at 0°C. The resultant reaction mixture was slowly warmed to rt. After 16 h, the reaction mixture was basified with 1 N sodium hydroxide solution and extracted with 10% methanol in chloroform. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford N-ethyl- 4,4-difluorocyclohexan-1-amine

[0127] , as brown oil. (1.5 g, 63% yield), MS(M+1)+=164.2. This is taken as such to next step.

[00205] Step 2[0128A & 0128B]: The procedure is similar to step 1

[0106] in example 34 (75 °C, acetonitrile). 1.2 g of 2,4-dichloro-6-methylpyrimidine

[0127] gave 0.6 g of 2-chloro- N-(4,4-difluorocyclohexyl)-N-ethyl-6-methylpyrimidin-4-amine [0128A] as white solid and 0.28 g of 4-chloro-N-(4,4-difluorocyclohexyl)-N-ethyl-6-methylpyrimidin-2-amine [0128B] as yellow solid. <com:Math><semantics>MS(M+1)+=290.3<annotation encoding="application / x-tex">MS(M+1)+=290.3< / annotation>< / semantics>< / com:Math>.

[00206] Step 3

[0129] : The procedure is similar to step 3

[0006] in Example 1. 0.3 g of 2- chloro-N-(4,4-difluorocyclohexyl)-N-ethyl-6-methylpyrimidin-4-amine [0128A] gave 0.17 g of N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)-N-ethyl-6-methylpyrimidin- 4-amine

[0129] , Compound 161 as yellow gum. MS(M+1)<com:Sup>+< / com:Sup>=350.4. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 6.52 (bs, 1H), 6.05 (s, 1H), 4.58 (bs, 1H), 3.43 (bs, 2H), 2.53 (s, 3H), 2.32 (s, 3H), <com:Math><semantics>2.17<annotation encoding="application / x-tex">2.17< / annotation>< / semantics>< / com:Math> (s, 3H), <com:Math><semantics>2.15−1.85<annotation encoding="application / x-tex">2.15 - 1.85< / annotation>< / semantics>< / com:Math> (m, 4H), <com:Math><semantics>1.83−1.73<annotation encoding="application / x-tex">1.83 - 1.73< / annotation>< / semantics>< / com:Math> (m, 4H), <com:Math><semantics>1.14<annotation encoding="application / x-tex">1.14< / annotation>< / semantics>< / com:Math> (t, <com:Math><semantics>J=6.9<annotation encoding="application / x-tex">J = 6.9< / annotation>< / semantics>< / com:Math> Hz, 3H).

[00207] Step 4

[0130] :. The procedure is similar to step 3

[0006] in Example 1. 0.2 g 4- chloro-N-(4,4-difluorocyclohexyl)-N-ethyl-6-methylpyrimidin-2-amine [0128B] gave 0.08 g of N-(4,4-difluorocyclohexyl)-4-(3,5-dimethyl-1H-pyrazol-1-yl)-N-ethyl-6- methylpyrimidin-2-amine

[0130] , Compound 160 as yellow gum. MS(M+1)<com:Sup>+< / com:Sup>=350.4. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 6.95 (s, 1H), 6.14 (s, 1H), 4.64 (bs, 1H), 3.49 (q, J = 6.9 Hz, 2H), 2.66 (s, 3H), 2.33 (s, 3H), 2.19 (s, 3H), 2.12 (bs, 2H), 2.05 - 1.75(m, 6H), 1.14 (t, <com:Math><semantics>J=6.9<annotation encoding="application / x-tex">J = 6.9< / annotation>< / semantics>< / com:Math> Hz, 3H).

[00208] Example 46: [Image disponible dans le document PDF, Image available in the PDF document]

[00209] Step 1

[0132] : To a stirred solution of 2-chloro-N-(4,4-difluorocyclohexyl)-6- methylpyrimidin-4-amine [0087A] (0.3 g, 1.146 mmol) in acetonitrile (10 mL) was added 3- bromo-5-methyl-1h-pyrazole (0.276 g, 1.719 mmol) and cesium carbonate (0.74 g, 2.29 mmol). The reaction mixture was irradiated in microwave at 150 °C for 2 h. The reaction mixture was filtered to remove cesium carbonate. Filtrate was concentrated under reduced pressure to afford crude product which was purified by column chromatography using 20% ethyl acetate in pet ether as eluent to afford 0.400 g of 2-(3-bromo-5-methyl-1H-pyrazol-1- yl)-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine

[0132] , Compound 220 as an off-white solid. <com:Math><semantics>MS(M+1)+=386.0<annotation encoding="application / x-tex">MS(M+1)^{+}=386.0< / annotation>< / semantics>< / com:Math>. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.69 (d, J = 7.7 Hz, 1H), 6.41 (s, 1H), 6.28 (s, 1H), 4.04 (s, 1H), 2.55 (s, 3H), 2.24 (s, 3H), 2.07 – 1.92 (m, 6H), <com:Math><semantics>1.59−1.53<annotation encoding="application / x-tex">1.59 - 1.53< / annotation>< / semantics>< / com:Math> (m, 2H).

[00210] Example 47: [Image disponible dans le document PDF, Image available in the PDF document]

[00211] Step 1

[0134] : To a stirred solution of 2-(3-bromo-5-methyl-1H-pyrazol-1-yl)-N- (4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine

[0132] (0.25 g, 0.647 mmol) in dioxane (5 mL), was added cyclopropylboronic acid

[0133] (0.111 g, 1.29 mmol) and potassium phosphate tribasic (0.274 g, 1.29 mmol). The reaction mixture was degassed for 10 min, added 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.026 g, 0.032 mmol) and irradiated in microwave at 110 °C for 2 h. After completion the reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to afford crude product which was purified by preparative HPLC to afford 0.021 g of 2-(3-cyclopropyl-5-methyl-1H-pyrazol-1-yl)-N-(4,4-difluorocyclohexyl)-6- methylpyrimidin-4-amine

[0134] , Compound 221 as an off-white solid. <com:Math><semantics>MS(M+1)+=348.2<annotation encoding="application / x-tex">MS(M+1)^{+}=348.2< / annotation>< / semantics>< / com:Math>, <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6): <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.52 (d, J = 7.64 Hz, 1H), 6.20 (m, 1H), 5.90 (s, 1H), 3.98 <com:Math><semantics>(m,1H),2.30(s,3H),1.93(s,3H),1.84−1.91(m,6H),1.50−1.57(m,2H),0.88(t,J=6.40)<annotation encoding="application / x-tex">(m, 1H), 2.30 (s, 3H), 1.93 (s, 3H), 1.84-1.91 (m, 6H), 1.50-1.57 (m, 2H), 0.88 (t, J = 6.40)< / annotation>< / semantics>< / com:Math> Hz, 2H), <com:Math><semantics>0.85<annotation encoding="application / x-tex">0.85< / annotation>< / semantics>< / com:Math> (t, <com:Math><semantics>J=4.48<annotation encoding="application / x-tex">J = 4.48< / annotation>< / semantics>< / com:Math> Hz, 2H).

[00212] Example 48: [Image disponible dans le document PDF, Image available in the PDF document]

[00213] Step 1

[0064] : To a stirred solution of hexane-2, 4-dione

[0135] (1 g, 8.760 mmol) in ethanol (25 mL) was added hydrazine hydrate (0.526 g, 10.51 mmol) drop-wise. The reaction mixture was refluxed at 85 °C for 5 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (50 mL) washed with water (20 mL). The organic extracts was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 0.8 g of 3-ethyl-5-methyl-1H-pyrazole

[0136] as colorless liquid. <com:Math><semantics>MS(M+1)+=110.8<annotation encoding="application / x-tex">MS(M+1)+=110.8< / annotation>< / semantics>< / com:Math>.

[00214] Step 2

[0137] : To a stirred solution of 3-ethyl-5-methyl-1H-pyrazole

[0136] (0.5 g, 4.53 mmol) in acetonitrile (5 mL), was added 2-chloro-N-(4,4-difluorocyclohexyl)-6- methylpyrimidin-4-amine [0087A] (0.59 g, 2.269 mmol) and cesium carbonate (1.47 g, 4.53 mmol). The reaction mixture was irradiated in microwave at 140 °C for 2 h, filtered to remove cesium carbonate and washed several times with chloroform (3x20 mL). The solvent was concentrated under reduced pressure to afford crude product which was purified by preparative HPLC to afford 0.050 g of N-(4,4-difluorocyclohexyl)-2-(3-ethyl-5-methyl-1H- pyrazol-1-yl)-6-methyl pyrimidin-4-amine

[0137] , Compound 249 as an off-white solid <com:Math><semantics>[MS(M+1)+=336.0.1H−NMR(400MHz,DMSO−d6):δ7.55(d,J=7.20Hz,1H),6.22(s,J=7.20Hz,1H)]<annotation encoding="application / x-tex">[MS(M+1)^{+} = 336.0. 1H-NMR (400 MHz, DMSO-d6): \delta 7.55 (d, J = 7.20 Hz, 1H), 6.22 (s, J = 7.20 Hz, 1H)]< / annotation>< / semantics>< / com:Math> 1H), 6.08 (s, 1H), 4.02 (s, 1H), 2.56 - 2.54 (m, 2H), 2.56 (s, 3H), 2.33 (s, 3H), 2.17-1.88 (m, 6H), <com:Math><semantics>1.59−1.51<annotation encoding="application / x-tex">1.59-1.51< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>1.17−1.85<annotation encoding="application / x-tex">1.17-1.85< / annotation>< / semantics>< / com:Math> (t, <com:Math><semantics>J=7.20<annotation encoding="application / x-tex">J = 7.20< / annotation>< / semantics>< / com:Math> Hz, 3H) and <com:Math><semantics>0.065<annotation encoding="application / x-tex">0.065< / annotation>< / semantics>< / com:Math> g of N-(4,4- difluorocyclohexyl)-2-(5-ethyl-3-methyl-1H-pyrazol-1-yl)-6-methylpyrimidin-4-amine

[0138] , Compound 260 as an off-white solid <com:Math><semantics>MS(M+1)+=336.0 / 337.0<annotation encoding="application / x-tex">MS(M+1)^{+}=336.0 / 337.0< / annotation>< / semantics>< / com:Math>. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.55 (d, J = 7.7 Hz, 1H), 6.23 (s, 1H), 6.06 (s, 1H), 3.98 (s, 1H), 3.01 – 2.95 (q, <com:Math><semantics>J=7.44 Hz,2H<annotation encoding="application / x-tex">J = 7.44 \text{ Hz}, 2H< / annotation>< / semantics>< / com:Math>), 2.24 (s, 3H), 2.17 (s, 3H), 2.08 - 1.87 (m, 6H), 1.58 - 1.53 (m, 2H), 1.17 (t, <com:Math><semantics>J=7.4Hz,3H<annotation encoding="application / x-tex">J = 7.4 Hz, 3H< / annotation>< / semantics>< / com:Math>).

[00215] Example 50: [Image disponible dans le document PDF, Image available in the PDF document]

[00216] Step 1

[0143] : The procedure is similar to step 3

[0006] in example 1. 0.250 g of 2-chloro-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087A] and 0.210 g of 3- isopropyl-1H-pyrazole

[0142] gave 0.200 g of N-(4,4-difluorocyclohexyl)-2-(3-isopropyl- 1H-pyrazol-1-yl)-6-methylpyrimidin-4-amine

[0143] , Compound 218 as an off-white solid which was purified by prep HPLC. <com:Math><semantics>MS(M+1)+=336<annotation encoding="application / x-tex">MS(M+1)^{+}=336< / annotation>< / semantics>< / com:Math>, <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.48 <com:Math><semantics>(s,1H),7.66(s,1H),6.39(d,J=2.7Hz,1H),6.21(bs,1H),4.15(s,1H),3.00−2.95(m,1H),<annotation encoding="application / x-tex">(s, 1H), 7.66 (s, 1H), 6.39 (d, J = 2.7 Hz, 1H), 6.21 (bs, 1H), 4.15 (s, 1H), 3.00-2.95 (m, 1H),< / annotation>< / semantics>< / com:Math> <com:Math><semantics>2.27<annotation encoding="application / x-tex">2.27< / annotation>< / semantics>< / com:Math> (s, 3H), <com:Math><semantics>2.14−1.88<annotation encoding="application / x-tex">2.14 - 1.88< / annotation>< / semantics>< / com:Math> (m, 6H), <com:Math><semantics>1.60−1.52<annotation encoding="application / x-tex">1.60 - 1.52< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>1.24<annotation encoding="application / x-tex">1.24< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=6.9<annotation encoding="application / x-tex">J = 6.9< / annotation>< / semantics>< / com:Math> Hz, 6H).

[00217] Example 51: [Image disponible dans le document PDF, Image available in the PDF document] - - - -

[00218] Step 1

[0144] : The procedure is similar to step 1

[0003] in example 1. 0.3 g of 2,4- dichloro-6-methylpyrimidine

[0086] gave 0.2 g of 2-chloro-N-(3,3-difluorocyclopentyl)-6- methylpyrimidin-4-amine

[0144] as an off-white solid. <com:Math><semantics>MS(M+1)+=247.9<annotation encoding="application / x-tex">MS(M+1)^+=247.9< / annotation>< / semantics>< / com:Math>.

[00219] Step 2

[0145] : 0.25 g of 2-chloro-N-(3,3-difluorocyclopentyl)-6-methylpyrimidin- 4-amine

[0144] and 0.145 g of 3, 5-dimethyl pyrazole in acetonitrile was irradiated at 150 °C to afford 0.1 g of N-(3,3-difluorocyclopentyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)-6- methylpyrimidin-4-amine

[0145] as a white solid. MS(M+1)<com:Sup>+< / com:Sup>=308.2, <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 6.13 (s, 1H), 6.01 (s, 1H), 5.50 (s, 1H), 4.39 (s, 1H), 2.74 – 2.54 (m, 4H), <com:Math><semantics>2.44(d,J=0.6Hz,3H),2.33(s,4H),2.25−1.99(m,2H),1.84(dq,J=12.5,7.6Hz,2H).<annotation encoding="application / x-tex">2.44 (d, J = 0.6 Hz, 3H), 2.33 (s, 4H), 2.25 - 1.99 (m, 2H), 1.84 (dq, J = 12.5, 7.6 Hz, 2H).< / annotation>< / semantics>< / com:Math>

[00220] Example 52: [Image disponible dans le document PDF, Image available in the PDF document]

[00221] Step 1

[0146] : The procedure is similar to step 3

[0006] in example 1. 1 g of 2- chloro-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087A] gave 0.7 g of ethyl 1-(4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-1H-pyrazole-3-carboxylate

[0146] as a pale yellow solid. <com:Math><semantics>MS(M+1)+=366.1<annotation encoding="application / x-tex">MS(M+1)+=366.1< / annotation>< / semantics>< / com:Math>.

[00222] Step 2

[0147] : The procedure is similar to step 2

[049] in example 10. 0.15 g of ethyl 1-(4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-1H-pyrazole-3- carboxylate

[0146] gave 0.015 g of 2-(1-(4-((4,4-difluorocyclohexyl)amino)-6- methylpyrimidin-2-yl)-1H-pyrazol-3-yl)propan-2-ol

[0147] , Compound 215 as a white solid. <com:Math><semantics>MS(M+1)+=352.39<annotation encoding="application / x-tex">MS(M+1)^{+}=352.39< / annotation>< / semantics>< / com:Math>, <com:Sup>1< / com:Sup>H-NMR (400 MHz, DMSO-d6): <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.44 (s, 1H), 7.55 (s, 1H), 6.45 (t, J <com:Math><semantics>=2.60 Hz,1H,6.19 (s, 1H),5.03 (s, 1H),4.10−4.09 (m, 1H),2.26 (s, 3H),2.05−1.95 (m, 6H),<annotation encoding="application / x-tex">= 2.60 \text{ Hz}, 1\text{H}, 6.19 \text{ (s, 1H)}, 5.03 \text{ (s, 1H)}, 4.10-4.09 \text{ (m, 1H)}, 2.26 \text{ (s, 3H)}, 2.05-1.95 \text{ (m, 6H)},< / annotation>< / semantics>< / com:Math> 1.57-1.54 (m, 2H), 1.45 (s, 6H).

[00223] Example 53: [Image disponible dans le document PDF, Image available in the PDF document]

[00224] Step 1[0149 & 0150]: The procedure is similar to step 3

[0006] in Example 1. 2 g of 2-chloro-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087A] gave 1.7 g of methyl 1-(4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-4-methyl-1H- pyrazole-3-carboxylate

[0149] as an off-white solid MS(M+1)+=380.0 and 0.4 g of 1-(4- ((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-4-methyl-1H-pyrazole-3- carboxylicacid

[0150] as a brown solid. MS(M+1)+=352.3.

[00225] Step 2

[0151] : To a solution of 1-(4-((4,4-difluorocyclohexyl)amino)-6- methylpyrimidin-2-yl)-4-methyl-1H-pyrazole-3-carboxylic acid

[0149] (0.7 g, 1.99 mmol) in dichloromethane was added oxalyl chloride (1.0 g, 7.96 mmol) at 0 °C and the reaction mixture was stirred at rt. After 1 h, the reaction mixture was concentrated under reduced pressure in nitrogen atmosphere to afford 1 g of 1-(4-((4,4-difluorocyclohexyl)amino)-6- methylpyrimidin-2-yl)-4-methyl-1H-pyrazole-3-carbonyl chloride as a brown solid

[0151] . <com:Math><semantics>MS(M+1)+=366.6<annotation encoding="application / x-tex">MS(M+1)+=366.6< / annotation>< / semantics>< / com:Math> (methyl ester mass). This was taken as such to next step.

[00226] Step 3

[0152] : Ammonia gas was purged to a solution of 1-(4-((4,4- difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-4-methyl-1H-pyrazole-3-carbonyl chloride

[0151] (0.7 g, 1.99 mmol) in tetrahydrofuran at -10 °C for 15 min. After 0.5 h, the reaction mixture was brought to rt and purged with nitrogen for 10 min. The reaction mixture was concentrated under reduced pressure to afford a pale brown solid, which was purified in the Reveleris flash system instrument using methanol in chloroform as solvent in 24 g column. The product spot was isolated at 4 % Methanol in chloroform as solvent to afford 0.650 g of 1-(4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-4- methyl-1H-pyrazole-3-carboxamide

[0152] , as white solid. <com:Math><semantics>MS(M+1)+=351.2<annotation encoding="application / x-tex">MS(M+1)+=351.2< / annotation>< / semantics>< / com:Math>.

[00227] Step 4

[0153] :NSSY5282.0001. To a solution of 1-(4-((4,4- difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-4-methyl-1H-pyrazole-3-carboxamide

[0152] (0.35 g, 0.85 mmol) in dichloromethane was added triethylamine (0.43 g, 4.28 mmol) and trifluoromethanesulfonic anhydride (0.61 g, 2.14 mmol) at 0 °C and the reaction mixture was stirred at same temperature. After 1 h, the reaction mixture was quenched with ice and extracted with chloroform, washed with water and brine solution. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford a pale brown solid which was purified in the Reveleris flash system instrument using ethyl acetate in hexane as eluent in 24 g column to afford 0.21 g of 1-(4- ((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-4-methyl-1H-pyrazole-3- carbonitrile

[0153] , Compound 253 as white solid. <com:Math><semantics>MS(M+1)+=333.2<annotation encoding="application / x-tex">MS(M+1)^+ = 333.2< / annotation>< / semantics>< / com:Math>. <com:Sup>1< / com:Sup>H NMR (400) MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.53 (s, 1H), 7.52 (d, J = 7.2 Hz, 1H), 6.37 (s, 1H), 4.05 (bs, 1H), 2.30 (s, 3H), 2.22 (s, 3H), 2.11 – 1.87 (m, 6H), 1.72 - 1.56 (m, 2H).

[00228] Example 54: [Image disponible dans le document PDF, Image available in the PDF document]

[00229] Step 1

[0154] : To a solution of 2-chloro-N-(4,4-difluorocyclohexyl)-6- methylpyrimidin-4-amine

[0150] (1 g, 2.63 mmol) in tetrahydrofuran was added lithium aluminum hydride (0.2 g, 5.27 mmol) at -78 °C and the reaction mixture was stirred at same temperature. After 2 h, the reaction mixture was quenched with saturated aqueous ammonium chloride at -78 °C, brought to rt and stirred for 15 min. The white precipitate formed was filtered off through celite bed and washed with ethyl acetate. The filtrate was washed with water and brine solution. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford a pale yellow solid, which was purified in the Reveleris flash system instrument using ethyl acetate in hexane as solvent in 24 g column to afford 0.07 g of (1-(4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin- 2-yl)-4-methyl-1H-pyrazol-3-yl)methanol

[0154] , Compound 236 as a white solid <com:Math><semantics>[MS(M+1)+=338.0.<annotation encoding="application / x-tex">[MS(M+1)^{+}=338.0.< / annotation>< / semantics>< / com:Math> <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.22 (s, 1H), 7.24 (d, J = 7.6 Hz, 1H), <com:Math><semantics>6.23<annotation encoding="application / x-tex">6.23< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>4.68<annotation encoding="application / x-tex">4.68< / annotation>< / semantics>< / com:Math> (t, <com:Math><semantics>J=5.7<annotation encoding="application / x-tex">J = 5.7< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>4.48<annotation encoding="application / x-tex">4.48< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=5.7<annotation encoding="application / x-tex">J = 5.7< / annotation>< / semantics>< / com:Math> Hz, 2H), <com:Math><semantics>4.02<annotation encoding="application / x-tex">4.02< / annotation>< / semantics>< / com:Math> (bs, 1H), <com:Math><semantics>2.32<annotation encoding="application / x-tex">2.32< / annotation>< / semantics>< / com:Math> (s, 3H), 2.10 (s, 3H), 2.12 - 1.89 (m, 6H), 1.70 - 1.55 (m, 2H). and 0.4 g of 1-(4-((4,4- difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-4-methyl-1H-pyrazole-3-carbaldehyde

[0155] as a white solid. <com:Math><semantics>MS(M+1)+=336.0<annotation encoding="application / x-tex">MS(M+1)^+ = 336.0< / annotation>< / semantics>< / com:Math>.

[00230] Example 55: [Image disponible dans le document PDF, Image available in the PDF document]

[00231] Step 2

[0156] :NSSy5293.0001. The procedure is similar to step 3

[0012] in Example 2. 0.5 g of (1-(4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-4- methyl-1H-pyrazol-3-yl)methanol

[0154] gave 0.15 g of N-(4,4-difluorocyclohexyl)-2-(3- (fluoromethyl)-4-methyl-1H-pyrazol-1-yl)-6-methylpyrimidin-4-amine

[0156] , Compound 258 as white solid. <com:Math><semantics>MS(M+1)+=340.2<annotation encoding="application / x-tex">MS(M+1)^{+}=340.2< / annotation>< / semantics>< / com:Math>, <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.33 (s, 1H), 7.34 <com:Math><semantics>(d,J=7.6Hz,1H),6.28(s,1H),5.49(s,1H),5.37(s,1H),4.04(bs,1H),2.26(s,3H),2.13<annotation encoding="application / x-tex">(d, J = 7.6 Hz, 1H), 6.28 (s, 1H), 5.49 (s, 1H), 5.37 (s, 1H), 4.04 (bs, 1H), 2.26 (s, 3H), 2.13< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(s,3H),2.11−1.84(m,6H),1.72−1.58(m,2H).<annotation encoding="application / x-tex">(s, 3H), 2.11 - 1.84 (m, 6H), 1.72 - 1.58 (m, 2H).< / annotation>< / semantics>< / com:Math>

[00232] Example 56: [Image disponible dans le document PDF, Image available in the PDF document]

[00233] Step 3

[0157] : The procedure is similar to step 3

[0012] in Example 2. 0.4 g of 1- (4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-4-methyl-1H-pyrazole-3- carbaldehyde

[0155] , Compound 246 gave 0.175 g of N-(4,4-difluorocyclohexyl)-2-(3- (difluoromethyl)-4-methyl-1H-pyrazol-1-yl)-6-methylpyrimidin-4-amine

[0157] as white solid. <com:Math><semantics>MS(M+1)+=358.0<annotation encoding="application / x-tex">MS(M+1)^+=358.0< / annotation>< / semantics>< / com:Math>. <com:Sup>1< / com:Sup>H-NMR (400 MHz, DMSO-d6): <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.40 (s, 1H), 7.41 (d, J = 7.20 Hz, 1H), <com:Math><semantics>7.00<annotation encoding="application / x-tex">7.00< / annotation>< / semantics>< / com:Math> (t, JF = 53.60 Hz, 1H), <com:Math><semantics>6.32<annotation encoding="application / x-tex">6.32< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>4.01<annotation encoding="application / x-tex">4.01< / annotation>< / semantics>< / com:Math> (bs, 1H), <com:Math><semantics>2.29<annotation encoding="application / x-tex">2.29< / annotation>< / semantics>< / com:Math> (s, 3H), <com:Math><semantics>2.19<annotation encoding="application / x-tex">2.19< / annotation>< / semantics>< / com:Math> (s, 3H), 2.15 - 1.90 (m, 6H), 1.72 - 1.58 (m, 2H).

[00234] Example 57: [Image disponible dans le document PDF, Image available in the PDF document]

[00235] Step 1

[87] : The procedure is similar to step 3

[0006] in example 1. 0.5 g 2-chloro- N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087A] gave 0.3 g of 1-(1-(4-((4,4- difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-1H-pyrazol-3-yl)ethan-1-one

[0159] as a white solid. <com:Math><semantics>MS(M+1)+=336.0<annotation encoding="application / x-tex">MS(M+1)+=336.0< / annotation>< / semantics>< / com:Math>.

[00236] Step 2

[0160] : The procedure is similar to step 3

[0050] in example 10. 0.15 g of 1- (1-(4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-1H-pyrazol-3-yl)ethan-1-one

[0159] gave 0.1 g of 1-(1-(4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-1H- pyrazol-3-yl)ethan-1-ol

[0160] , Compound 202 as an off-white solid. <com:Math><semantics>MS(M+1)+=338.0<annotation encoding="application / x-tex">MS(M+1)^+=338.0< / annotation>< / semantics>< / com:Math>, <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.48 (s, 1H), 7.58 (s, 1H), 6.44 (d, J = 2.7 Hz, 1H), 6.21 (s, 1H), <com:Math><semantics>5.20(d,J=4.8Hz,1H)<annotation encoding="application / x-tex">5.20 (d, J = 4.8 Hz, 1H)< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>4.88−4.58(m,1H)<annotation encoding="application / x-tex">4.88 - 4.58 (m, 1H)< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>4.15(s,1H)<annotation encoding="application / x-tex">4.15 (s, 1H)< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>2.26(s,3H)<annotation encoding="application / x-tex">2.26 (s, 3H)< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>2.01(d,J=41.4)<annotation encoding="application / x-tex">2.01 (d, J = 41.4)< / annotation>< / semantics>< / com:Math> Hz, 6H), <com:Math><semantics>1.56<annotation encoding="application / x-tex">1.56< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=9.3<annotation encoding="application / x-tex">J = 9.3< / annotation>< / semantics>< / com:Math> Hz, 2H), <com:Math><semantics>1.39<annotation encoding="application / x-tex">1.39< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=6.5<annotation encoding="application / x-tex">J = 6.5< / annotation>< / semantics>< / com:Math> Hz, 3H).

[00237] Example 58: [Image disponible dans le document PDF, Image available in the PDF document]

[00238] Step 1

[0161] . The procedure is similar to step 2

[0019] in Example 4. 1.4 g of ethyl 1-(4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-1H-pyrazole-3- carboxylate

[0146] gave 0.98 g of (1-(4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin- 2-yl)-1H-pyrazol-3-yl)methanol

[0161] Compound 204 as an off-white solid. <com:Math><semantics>MS(M+1)+=324<annotation encoding="application / x-tex">MS(M+1)^{+}=324< / annotation>< / semantics>< / com:Math>, <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.50 (s, 1H), 7.59 (bs, 1H), 6.45 (s, 1H), 6.21 (bs, 1H), 5.20 (s, 1H), 4.49 (d, <com:Math><semantics>J=5.7Hz<annotation encoding="application / x-tex">J = 5.7 Hz< / annotation>< / semantics>< / com:Math>, 2H), 4.16 (bs, 1H), 2.26 (s, 3H), 2.15 - 1.88 (m, 6H), 1.65- 1.48 (m, 2H).

[00239] Step 2

[0162] :0.9 g of (1-(4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin- 2-yl)-1H-pyrazol-3-yl)methanol

[0161] gave 0.62 g of 1-(4-((4,4-difluorocyclohexyl)amino)- 6-methylpyrimidin-2-yl)-1H-pyrazole-3-carbaldehyde

[0162] as a white solid, using manganese dioxide (5 eq) in dichloromethane. <com:Math><semantics>MS(M+1)+=322.3<annotation encoding="application / x-tex">MS(M+1)+=322.3< / annotation>< / semantics>< / com:Math>.

[00240] Step 3

[0163] : The procedure is similar to step 3

[0012] in Example 2. 0.7 g of 1- (4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-1H-pyrazole-3-carbaldehyde

[0162] gave 0.075 g of N-(4,4-difluorocyclohexyl)-2-(3-(difluoromethyl)-1H-pyrazol-1-yl)- 6-methylpyrimidin-4-amine

[0163] as an off-white solid. MS(M+1)<com:Sup>+< / com:Sup>=344.2, <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.69 (bs, 1H), 7.72 (bs, 1H), 7.12 (t, JF = 54.16 Hz, 1H), 6.77 (s, 1H), 6.29 (bs, 1H), 4.18 (bs, 1H), 2.28 (s, 3H), 2.17 – 1.83 (m, 6H), 1.65 - 1.57 (m, 2H).

[00241] Example 59: [Image disponible dans le document PDF, Image available in the PDF document]

[00242] Step 1: Thionyl chloride (0.49 g, 4.17 mmol) was added to a solution of (1-(4- ((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-1H-pyrazol-3-yl)methanol

[0161] (0.45 g, 1.39 mmol) in dichloromethane and the reaction mixture was heated at 50°C. After 1 h, the reaction mixture was concentrated under reduced pressure and the residue was triturated with hexane and dried vacuum to afford 0.41 g of 2-(3-(chloromethyl)-1H-pyrazol- 1-yl)-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine

[0164] as off-white solid. <com:Math><semantics>MS(M+1)+=342.2<annotation encoding="application / x-tex">MS(M+1)+=342.2< / annotation>< / semantics>< / com:Math>. This was taken as such to next step.

[00243] Step 2

[0165] : A solution of Potassium fluoride (1.08 g, 18.72 mmol), 18-crown-6 (0.12 g, 0.46 mmol) and 2-(3-(chloromethyl)-1H-pyrazol-1-yl)-N-(4,4-difluorocyclohexyl)-6- methylpyrimidin-4-amine

[0164] (1.6 g, 4.68 mmol), in acetonitrile was heated at 100 °C in sealed tube. After 24 h, the reaction mixture was quenched with 10% sodium bicarbonate solution until the pH around~ 10 and extracted with dichloromethane (3x400 mL), combined organic layer was washed with brine (2x200 mL), dried with anhydrous sodium sulfate, filtrate was concentrated to afford a crude product, which was purified by column chromatography to afford 0.81 g of N-(4,4-difluorocyclohexyl)-2-(3-(fluoromethyl)-1H- pyrazol-1-yl)-6-methylpyrimidin-4-amine

[0165] , Compound 233 as off-white solid. <com:Math><semantics>MS(M+1)+=326.2<annotation encoding="application / x-tex">MS(M+1)^{+}=326.2< / annotation>< / semantics>< / com:Math>, <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.60 (s, 1H), 7.66 (bs, 1H), 6.64 (s, 1H), <com:Math><semantics>6.26<annotation encoding="application / x-tex">6.26< / annotation>< / semantics>< / com:Math> (bs, 1H), <com:Math><semantics>5.45<annotation encoding="application / x-tex">5.45< / annotation>< / semantics>< / com:Math>(d, JF = 48 Hz, 2H), <com:Math><semantics>4.17<annotation encoding="application / x-tex">4.17< / annotation>< / semantics>< / com:Math> (bs, 1H), <com:Math><semantics>2.27<annotation encoding="application / x-tex">2.27< / annotation>< / semantics>< / com:Math> (s, 3H), <com:Math><semantics>2.13−1.87<annotation encoding="application / x-tex">2.13 - 1.87< / annotation>< / semantics>< / com:Math> (m, 6H), 1.62 - 1.57 (m, 2H).

[00244] Example 60: [Image disponible dans le document PDF, Image available in the PDF document]

[00245] Step 1

[0167] : The procedure is similar to step 3

[0006] in example 1. 0.5 g 2- chloro-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087A] and ethyl 5-methyl- 1H-pyrazole-3-carboxylate

[0166] (0.35 g, 2.29 mmol) gave 0.7 g of ethyl 1-(4-((4,4- difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-5-methyl-1H-pyrazole-3-carboxylate

[0167] as a white solid. <com:Math><semantics>MS(M+1)+=348.2<annotation encoding="application / x-tex">MS(M+1)+=348.2< / annotation>< / semantics>< / com:Math>.

[00246] Step 2 [0168 and 0169]: The procedure is similar to step 2

[0019] in example 4. 0.7 g ethyl 1-(4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-5-methyl-1H- pyrazole-3-carboxylate

[0167] gave 0.1 g of 1-(4-((4,4-difluorocyclohexyl)amino)-6- methylpyrimidin-2-yl)-5-methyl-1H-pyrazole-3-carbaldehyde

[0168] as an off-white solid. <com:Math><semantics>MS(M+1)+=338.38<annotation encoding="application / x-tex">MS(M+1)+=338.38< / annotation>< / semantics>< / com:Math> and 0.035 g of <com:Math><semantics>(1−(4−((4,4−difluorocyclohexyl)amino)−6−<annotation encoding="application / x-tex">(1-(4-((4,4-difluorocyclohexyl)amino)-6-< / annotation>< / semantics>< / com:Math> methylpyrimidin-2-yl)-5-methyl-1H-pyrazol-3-yl)methanol

[0169] , Compound 241 as a white solid. <com:Math><semantics>MS(M+1)+=336.35<annotation encoding="application / x-tex">MS(M+1)^{+}=336.35< / annotation>< / semantics>< / com:Math>, <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.57 (d, J = 7.7 Hz, 1H), <com:Math><semantics>6.24<annotation encoding="application / x-tex">6.24< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>6.20<annotation encoding="application / x-tex">6.20< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>5.09<annotation encoding="application / x-tex">5.09< / annotation>< / semantics>< / com:Math> (t, <com:Math><semantics>J=5.9<annotation encoding="application / x-tex">J = 5.9< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>4.41<annotation encoding="application / x-tex">4.41< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=6.0<annotation encoding="application / x-tex">J = 6.0< / annotation>< / semantics>< / com:Math> Hz, 2H), <com:Math><semantics>4.02<annotation encoding="application / x-tex">4.02< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>2.54<annotation encoding="application / x-tex">2.54< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(s,3H),2.25(s,3H),2.12−2.02(m,2H),1.95(d,J=14.0Hz,4H),1.56(d,J=11.9Hz,4H)<annotation encoding="application / x-tex">(s, 3H), 2.25 (s, 3H), 2.12 - 2.02 (m, 2H), 1.95 (d, J = 14.0 Hz, 4H), 1.56 (d, J = 11.9 Hz, 4H)< / annotation>< / semantics>< / com:Math> 2H).

[00247] Step 3

[0170] : The procedure is similar to step 3

[0012] in example 2, 0.1 g 1-(4- ((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-5-methyl-1H-pyrazole-3- carbaldehyde

[0169] gave 0.018 g of N-(4,4-difluorocyclohexyl)-2-(3-(fluoromethyl)-5- methyl-1H-pyrazol-1-yl)-6-methylpyrimidin-4-amine

[0170] , Compound 256 as a grey solid. <com:Math><semantics>MS(M+1)+=340.4<annotation encoding="application / x-tex">MS(M+1)^{+}=340.4< / annotation>< / semantics>< / com:Math>, <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.37 (d, J = 7.8 Hz, 1H), 6.33 (s, 2H), <com:Math><semantics>5.33<annotation encoding="application / x-tex">5.33< / annotation>< / semantics>< / com:Math> (d, JF = 48 Hz, 2H), <com:Math><semantics>3.97<annotation encoding="application / x-tex">3.97< / annotation>< / semantics>< / com:Math> (bs, 1H), <com:Math><semantics>2.56<annotation encoding="application / x-tex">2.56< / annotation>< / semantics>< / com:Math> (s, 3H), <com:Math><semantics>2.28<annotation encoding="application / x-tex">2.28< / annotation>< / semantics>< / com:Math> (s, 3H), <com:Math><semantics>2.13−1.88<annotation encoding="application / x-tex">2.13 - 1.88< / annotation>< / semantics>< / com:Math> (m, 6H), <com:Math><semantics>1.62<annotation encoding="application / x-tex">1.62< / annotation>< / semantics>< / com:Math> (q, <com:Math><semantics>J=11.6<annotation encoding="application / x-tex">J = 11.6< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>9.6<annotation encoding="application / x-tex">9.6< / annotation>< / semantics>< / com:Math> Hz, <com:Math><semantics>2H<annotation encoding="application / x-tex">2H< / annotation>< / semantics>< / com:Math>).

[00248] Example 61: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document]

[00249] Step 1

[0171] : The procedure is similar to step 3

[0012] in example 2. 0.15 g of 1- (4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-5-methyl-1H-pyrazole-3- carbaldehyde

[0168] gave 0.075 g of N-(4,4-difluorocyclohexyl)-2-(3-(difluoromethyl)-5- methyl-1H-pyrazol-1-yl)-6-methylpyrimidin-4-amine

[0171] , Compound 237 as a white solid. <com:Math><semantics>MS(M+1)+=358.35<annotation encoding="application / x-tex">MS(M+1)^+=358.35< / annotation>< / semantics>< / com:Math>, <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.72 (d, J = 7.6 Hz, 1H), 7.02 <com:Math><semantics>(t,JF=54Hz,1H),6.52(s,1H),6.31(s,1H),2.58(s,3H),2.28(s,3H),2.09−1.89(m,6H),<annotation encoding="application / x-tex">(t, JF = 54 Hz, 1H), 6.52 (s, 1H), 6.31 (s, 1H), 2.58 (s, 3H), 2.28 (s, 3H), 2.09 - 1.89 (m, 6H),< / annotation>< / semantics>< / com:Math> <com:Math><semantics>1.56(d,J=12.0Hz,2H),1.25(d,J=6.2Hz,1H).<annotation encoding="application / x-tex">1.56 (d, J = 12.0 Hz, 2H), 1.25 (d, J = 6.2 Hz, 1H).< / annotation>< / semantics>< / com:Math>

[00250] Example 63: [Image disponible dans le document PDF, Image available in the PDF document]

[00251] Step 1

[0175] : The procedure is similar to step 2

[0177] in example 62. 0.2 g of 4- chloro-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidine

[0173] gave 0.1 g of N-(4,4- difluorocyclohexyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidin-4-amine

[0175] , Compound 163 as an off-white solid. <com:Math><semantics>MS(M+1)+=308.2<annotation encoding="application / x-tex">MS(M+1)^{+}=308.2< / annotation>< / semantics>< / com:Math>, <com:Sup>1< / com:Sup>H-NMR (400 MHz, CDCl3): <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.20 (d, J = <com:Math><semantics>5.60 Hz<annotation encoding="application / x-tex">5.60 \text{ Hz}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>1H<annotation encoding="application / x-tex">1\text{H}< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>6.29 (d, J=5.60 Hz<annotation encoding="application / x-tex">6.29 \text{ (d, J} = 5.60 \text{ Hz}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>1H<annotation encoding="application / x-tex">1\text{H}< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>6.02 (s, 1H)<annotation encoding="application / x-tex">6.02 \text{ (s, 1H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>5.53 (s, 1H)<annotation encoding="application / x-tex">5.53 \text{ (s, 1H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>3.88 (s, 1H)<annotation encoding="application / x-tex">3.88 \text{ (s, 1H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>3.22 (s, 3H)<annotation encoding="application / x-tex">3.22 \text{ (s, 3H)}< / annotation>< / semantics>< / com:Math>, 2.34 (s, 3H), 1.97-1.90 (m, 4H), 1.86-1.73 (m, 2H), 1.71-1.65 (m, 2H),

[00252] Example 64: [Image disponible dans le document PDF, Image available in the PDF document]

[00253] Step 1

[0177] : The procedure is similar to step 3

[0006] in Example 1. 0.5 g of 2,4- dichloro-5-ethylpyrimidine

[0176] gave 0.25 g of 2-chloro-N-(4,4-difluorocyclohexyl)-5- ethylpyrimidin-4-amine

[0177] as a light brown gum. <com:Math><semantics>MS(M+1)+=276<annotation encoding="application / x-tex">MS(M+1)+=276< / annotation>< / semantics>< / com:Math>.

[00254] Step 2

[0178] : The procedure is similar to step 2

[0174] in Example 62 (without base). 0.25 g of 2-chloro-N-(4,4-difluorocyclohexyl)-5-ethylpyrimidin-4-amine

[0177] gave 0.03 g of N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)-5-ethylpyrimidin-4- amine

[0178] , Compound 111 as an off-white solid. <com:Math><semantics>MS(M+1)+=336.1<annotation encoding="application / x-tex">MS(M+1)^{+}=336.1< / annotation>< / semantics>< / com:Math>, <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.09 (s, 1H), 6.01 (s, 1H), 4.70 (d, J = 7.4 Hz, 1H), 4.17 (d, J = 9.8 Hz, 1H), <com:Math><semantics>2.66<annotation encoding="application / x-tex">2.66< / annotation>< / semantics>< / com:Math> (s, 3H), <com:Math><semantics>2.42<annotation encoding="application / x-tex">2.42< / annotation>< / semantics>< / com:Math> (q, <com:Math><semantics>J=7.5<annotation encoding="application / x-tex">J = 7.5< / annotation>< / semantics>< / com:Math> Hz, 2H), <com:Math><semantics>2.33<annotation encoding="application / x-tex">2.33< / annotation>< / semantics>< / com:Math> (s, 3H), <com:Math><semantics>2.18<annotation encoding="application / x-tex">2.18< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=10.3<annotation encoding="application / x-tex">J = 10.3< / annotation>< / semantics>< / com:Math> Hz, 4H), <com:Math><semantics>2.01−1.80<annotation encoding="application / x-tex">2.01 - 1.80< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>1.75−1.60<annotation encoding="application / x-tex">1.75 - 1.60< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>1.27<annotation encoding="application / x-tex">1.27< / annotation>< / semantics>< / com:Math> (t, <com:Math><semantics>J=7.5<annotation encoding="application / x-tex">J = 7.5< / annotation>< / semantics>< / com:Math> Hz, 3H).

[00255] Example 65: [Image disponible dans le document PDF, Image available in the PDF document]

[00256] Step 1[0180A & 0180B]: To a solution of 2,4-Dichloro-6-ethylpyrimidine

[0179] (1 g, 5.64 mmol) and 4,4-Difluorocyclohexylamine Hydrochloride (0.96 g, 5.64 mmol) in acetonitrile was added cesium carbonate (3.68 g, 11.29 g) and the reaction mixture was heated at 65 °C in sealed tube. After 16 h, the reaction mixture was filtered and the filtrate was concentrated to afford a crude product, which was purified by column chromatography to afford 0.8 g of 2-chloro-N-(4,4-difluorocyclohexyl)-6-ethylpyrimidin-4-amine [0180A] as colorless oil and 0.5 g of 4-chloro-N-(4,4-difluorocyclohexyl)-6-ethylpyrimidin-2-amine [0180B] as colorless oil. <com:Math><semantics>MS(M+1)+=276.0<annotation encoding="application / x-tex">MS(M+1)+=276.0< / annotation>< / semantics>< / com:Math>.

[00257] Step 2

[0181] : The procedure is similar to step 3

[0006] in Example 1. 0.3 g of 2- chloro-N-(4,4-difluorocyclohexyl)-6-ethylpyrimidin-4-amine [0180A] gave 0.05 g of N-(4,4- difluorocyclohexyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)-6-ethylpyrimidin-4-amine

[0181] , Compound 171 as off-white solid. <com:Math><semantics>MS(M+1)+=336.4<annotation encoding="application / x-tex">MS(M+1)^+=336.4< / annotation>< / semantics>< / com:Math>. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> <com:Math><semantics>7.56<annotation encoding="application / x-tex">7.56< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=7.7<annotation encoding="application / x-tex">J = 7.7< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>6.23<annotation encoding="application / x-tex">6.23< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>6.04<annotation encoding="application / x-tex">6.04< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>4.03<annotation encoding="application / x-tex">4.03< / annotation>< / semantics>< / com:Math> (bs, 1H), <com:Math><semantics>3.28<annotation encoding="application / x-tex">3.28< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>2.48<annotation encoding="application / x-tex">2.48< / annotation>< / semantics>< / com:Math> (s, 3H), <com:Math><semantics>2.16<annotation encoding="application / x-tex">2.16< / annotation>< / semantics>< / com:Math> (s, 3H), <com:Math><semantics>2.15−1.85<annotation encoding="application / x-tex">2.15 - 1.85< / annotation>< / semantics>< / com:Math> (m, 6H), <com:Math><semantics>1.62−1.49<annotation encoding="application / x-tex">1.62 - 1.49< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>1.18<annotation encoding="application / x-tex">1.18< / annotation>< / semantics>< / com:Math> (t, <com:Math><semantics>J=7.5<annotation encoding="application / x-tex">J = 7.5< / annotation>< / semantics>< / com:Math> Hz, 3H).

[00258] Step 3

[0182] : The procedure is similar to step 3

[0006] in Example 1. 0.3 g of 4- chloro-N-(4,4-difluorocyclohexyl)-6-ethylpyrimidin-2-amine [0180B] gave 0.95 g of N-(4,4- difluorocyclohexyl)-4-(3,5-dimethyl-1H-pyrazol-1-yl)-6-ethylpyrimidin-2-amine

[0182] , Compound 169 as white solid. <com:Math><semantics>MS(M+1)+=336.4<annotation encoding="application / x-tex">MS(M+1)^+ = 336.4< / annotation>< / semantics>< / com:Math>. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.35 (bs, 1H), 6.88 (s, 1H), 6.12 (s, 1H), 3.84 (bs, 1H), 2.64 (s, 3H), 2.60 – 2.53 (m, 2H), 2.18 (s, 3H), <com:Math><semantics>2.10−1.75<annotation encoding="application / x-tex">2.10 - 1.75< / annotation>< / semantics>< / com:Math> (m, <com:Math><semantics>6H<annotation encoding="application / x-tex">6H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>1.64−1.52<annotation encoding="application / x-tex">1.64 - 1.52< / annotation>< / semantics>< / com:Math> (m, <com:Math><semantics>2H<annotation encoding="application / x-tex">2H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>1.18<annotation encoding="application / x-tex">1.18< / annotation>< / semantics>< / com:Math> (t, <com:Math><semantics>J=7.6<annotation encoding="application / x-tex">J = 7.6< / annotation>< / semantics>< / com:Math> Hz, <com:Math><semantics>3H<annotation encoding="application / x-tex">3H< / annotation>< / semantics>< / com:Math>).

[00259] Example 67: [Image disponible dans le document PDF, Image available in the PDF document]

[00260] Step 1[0187A and 0187B]: The procedure is similar to Step 1[0180A & 0180B] in example 66. 0.5 g of 2,4-dichloro-6-cyclopropyl pyrimidine

[0186] gave 0.3 g of 2-chloro- 6-cyclopropyl-N-(3,3-difluorocyclopentyl) pyrimidin-4-amine [0187A] and 0.125 g of 4- chloro-6-cyclopropyl-N-(3,3-difluorocyclopentyl)pyrimidin-2-amine [0187B] both as colorless gums. <com:Math><semantics>MS(M+1)+=274.0<annotation encoding="application / x-tex">MS(M+1)+=274.0< / annotation>< / semantics>< / com:Math>.

[00261] Step 2

[0188] : The procedure is similar to step 3

[0006] in Example 1.0.3 g of 2- chloro-6-cyclopropyl-N-(3,3-difluorocyclopentyl)pyrimidin-4-amine [0187A] gave 0.175 g of 6-cyclopropyl-N-(3,3-difluorocyclopentyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidin-4- amine

[0188] , Compound 217 as white solid. <com:Math><semantics>MS(M+1)+=334.2<annotation encoding="application / x-tex">MS(M+1)^{+}=334.2< / annotation>< / semantics>< / com:Math>, <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.71 (s, 1H), 6.31 (s, 1H), 6.03 (s, 1H), 4.45 (s, 1H), 2.58 (dt, J = 13.6, 6.5 Hz, 1H), <com:Math><semantics>2.45<annotation encoding="application / x-tex">2.45< / annotation>< / semantics>< / com:Math> (s, 3H), <com:Math><semantics>2.31−2.17<annotation encoding="application / x-tex">2.31 - 2.17< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>2.15<annotation encoding="application / x-tex">2.15< / annotation>< / semantics>< / com:Math> (s, 3H), <com:Math><semantics>2.06<annotation encoding="application / x-tex">2.06< / annotation>< / semantics>< / com:Math> (dq, <com:Math><semantics>J=16.2<annotation encoding="application / x-tex">J = 16.2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>9.1<annotation encoding="application / x-tex">9.1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>8.0<annotation encoding="application / x-tex">8.0< / annotation>< / semantics>< / com:Math> Hz, <com:Math><semantics>2H<annotation encoding="application / x-tex">2H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>1.93<annotation encoding="application / x-tex">1.93< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>1.72<annotation encoding="application / x-tex">1.72< / annotation>< / semantics>< / com:Math> (dq, <com:Math><semantics>J=12.2<annotation encoding="application / x-tex">J = 12.2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>8.5<annotation encoding="application / x-tex">8.5< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>0.98−0.90<annotation encoding="application / x-tex">0.98 - 0.90< / annotation>< / semantics>< / com:Math> (m, 3H).

[00262] Step 3

[0189] : The procedure is similar to step 3

[0006] in Example 1. 0.125 g of 4-chloro-6-cyclopropyl-N-(3,3-difluorocyclopentyl)pyrimidin-2-amine [0187B] gave 0.045 g 4-cyclopropyl-N-(3,3-difluorocyclopentyl)-6-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidin-2- amine

[0189] , Compound 222 as white solid, <com:Math><semantics>MS(M+1)+=334.2<annotation encoding="application / x-tex">MS(M+1)^{+}=334.2< / annotation>< / semantics>< / com:Math>. <com:Sup>1< / com:Sup>H-NMR (400 MHz, DMSO-d6): <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.39 (bs, 1H), 6.99 (s, 1H), 6.13 (s, 1H), 4.29 (q, J = 7.20 Hz, 1H), 2.64 (s, 3H), 2.35 - 2.25 (m, 2H), 2.20 (s, 3H), 2.15-1.98 (m, 4H), 1.85-1.73 (m, 1H), 1.12 - 0.90 (m, 4H).

[00263] Example 69: [Image disponible dans le document PDF, Image available in the PDF document]

[00264] Step 1

[0195] : To a solution of 4-chloro-2-(methylsulfanyl)-6-(trifluoromethyl) pyrimidine

[0194] (1 g, 4.374 mmol) in acetonitrile (10 mL) was added N,N-diisopropyl ethylamine (0.84 g, 6.56 mmol), followed by 4,4-difluorocyclohexylamine hydrochloride

[0002] (0.75 g, 4.374 mmol). The reaction mixture was stirred at rt for 36 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (50 mL). The organic layer was washed with water (10 mL), followed by brine (10 mL). The organic layer was dried over anhydrous sodium sulfate to afford 1.4 g of N-(4,4- difluorocyclohexyl)-2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-amine

[0195] as a yellow gum. <com:Math><semantics>MS(M+1)+=328.3<annotation encoding="application / x-tex">MS(M+1)+=328.3< / annotation>< / semantics>< / com:Math>

[00265] Step 2

[0196] : To a solution of N-(4,4-difluorocyclohexyl)-2-(methylthio)-6- (trifluoromethyl)pyrimidin-4-amine

[0195] (0.55 g, 1.68 mmol) in dichloromethane (10 mL), 3-chloroperbenzoic acid (0.86 g, 5.04 mmol) was added portion-wise at 0 °C. The reaction mixture was stirred at rt for 3 h. The reaction mixture was diluted with dichloromethane (50 mL). The organic layer was stirred with saturated solution of sodium thiosulfate solution (20) mL), followed by 10% sodium bicarbonate solution (10 mL), water (10 mL) and brine water (10 mL). The organic layer was dried over anhydrous sodium sulfate to afford 0.6 g of N- (4,4-difluorocyclohexyl)-2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-amine

[0196] as a yellow solid. <com:Math><semantics>MS(M+1)+=359.9<annotation encoding="application / x-tex">MS(M+1)+=359.9< / annotation>< / semantics>< / com:Math>

[00266] Step 3

[0197] : To a solution of N-(4,4-difluorocyclohexyl)-2-(methylsulfonyl)-6- (trifluoromethyl)pyrimidin-4-amine

[0196] (0.55 g, 1.53 mmol) in acetonitrile (6 mL), was added 3,5-dimethyl pyrazole

[0017] (0.22 g, 2.296 mmol) and cesium carbonate (0.748 g, 2.296 mmol). The reaction mixture was irradiated in microwave at 130 °C for 2 h and concentrated under reduced pressure to afford 0.55 g of N-(4,4-difluorocyclohexyl)-2-(3,5- dimethyl-1H-pyrazol-1-yl)-6-(trifluoromethyl)pyrimidin-4-amine. This was purified by column chromatography using 60% ethyl acetate in pet ether as solvent to afford 0.090 g of N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)-6-(trifluoromethyl) pyrimidin- 4-amine

[0197] , Compound 162 as a white solid. <com:Math><semantics>MS(M+1)+=376.6<annotation encoding="application / x-tex">MS(M+1)^+=376.6< / annotation>< / semantics>< / com:Math>. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.30 (d, J = 7.5 Hz, 1H), 6.74 (s, 1H), 6.13 (s, 1H), 4.09 (bs, 1H), 2.57 (s, 3H), <com:Math><semantics>2.19<annotation encoding="application / x-tex">2.19< / annotation>< / semantics>< / com:Math> (s, 3H), <com:Math><semantics>2.15−1.90<annotation encoding="application / x-tex">2.15 - 1.90< / annotation>< / semantics>< / com:Math> (m, 6H), <com:Math><semantics>1.65−1.52<annotation encoding="application / x-tex">1.65 - 1.52< / annotation>< / semantics>< / com:Math> (m, 2H).

[00267] Example 71: [Image disponible dans le document PDF, Image available in the PDF document]

[00268] Step 1

[0201] : The procedure is similar to Step 1

[0195] in example 69. 0.5 g of 4- chloro-2-(methylthio)-6-(trifluoromethyl)pyrimidine

[0194] gave 0.4 g of N-(3,3- difluorocyclopentyl)-2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-amine

[0201] as an off- white solid. <com:Math><semantics>MS(M+1)+=314.1<annotation encoding="application / x-tex">MS(M+1)+=314.1< / annotation>< / semantics>< / com:Math>.

[00269] Step 2

[0202] : The procedure is similar to Step 2

[0196] in example 69. 0.4 g N- (3,3-difluorocyclopentyl)-2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-amine

[0201] gave 0.35 g of N-(3,3-difluorocyclopentyl)-2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4- amine

[0202] as an off-white solid. <com:Math><semantics>MS(M+1)+=346.2<annotation encoding="application / x-tex">MS(M+1)+=346.2< / annotation>< / semantics>< / com:Math>.

[00270] Step 3

[0203] : The procedure is similar to Step 3

[0197] in example 69. 0.2 g N- (3,3-difluorocyclopentyl)-2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-amine

[0202] gave 0.07 g of N-(3,3-difluorocyclopentyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)-6- (trifluoromethyl)pyrimidin-4-amine

[0203] , Compound 167 as a white solid. <com:Math><semantics>MS(M+1)+=362.2<annotation encoding="application / x-tex">MS(M+1)+=362.2< / annotation>< / semantics>< / com:Math>, 1H NMR (400 MHz, CDCl3): <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 6.52 (s, 1H), 6.06-5.99 (m, 2H), 4.36 (m, 1H), 2.70-2.65 (m, 4H), 2.39-2.29 (m, 5H), 2.23-2.16 (m, 2H), 2.12-2.09 (m, 1H).

[00271] Example 72: [Image disponible dans le document PDF, Image available in the PDF document]

[00272] Step 1

[0204] : The procedure is similar to Step 1

[0195] in example 69. 1.0 g of 4- chloro-6-(difluoromethyl)-2-(methylthio)pyrimidine

[0190] gave 0.8 g 4-(difluoromethyl)-6- (3,5-dimethyl-1H-pyrazol-1-yl)-2-(methylthio)pyrimidine

[0204] as an off-white solid. <com:Math><semantics>MS(M+1)+=271.2.<annotation encoding="application / x-tex">MS(M+1)+=271.2.< / annotation>< / semantics>< / com:Math>

[00273] Step 2

[0205] : The procedure is similar to Step 2

[0196] in example 69. 1.0 g 4- (difluoromethyl)-6-(3,5-dimethyl-1H-pyrazol-1-yl)-2-(methylthio)pyrimidine

[0204] gave 0.7 g of 4-(difluoromethyl)-6-(3,5-dimethyl-1H-pyrazol-1-yl)-2-(methylsulfonyl)pyrimidine

[0205] as an off-white solid.<com:Math><semantics>MS(M+1)<annotation encoding="application / x-tex">MS(M+1)< / annotation>< / semantics>< / com:Math>+=303.1.

[00274] Step 3

[0206] : The procedure is similar to Step 3

[0197] in example 69 (DIPEA as base). 0.4 g of 4-(difluoromethyl)-6-(3,5-dimethyl-1H-pyrazol-1-yl)-2- (methylsulfonyl)pyrimidine

[0205] gave 0.2 g of N-(4,4-difluorocyclohexyl)-4- (difluoromethyl)-6-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidin-2-amine

[0206] as a white solid. <com:Math><semantics>MS(M+1)+=358.2<annotation encoding="application / x-tex">MS(M+1)^{+}=358.2< / annotation>< / semantics>< / com:Math>, <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.94 (d, J = 7.4 Hz, 1H), 7.19 (s, 1H), <com:Math><semantics>6.76<annotation encoding="application / x-tex">6.76< / annotation>< / semantics>< / com:Math> (t, JF = 54 Hz, 1H), <com:Math><semantics>6.21<annotation encoding="application / x-tex">6.21< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>2.68<annotation encoding="application / x-tex">2.68< / annotation>< / semantics>< / com:Math> (s, 3H), <com:Math><semantics>2.21<annotation encoding="application / x-tex">2.21< / annotation>< / semantics>< / com:Math> (s, 3H), <com:Math><semantics>2.12−1.89<annotation encoding="application / x-tex">2.12 - 1.89< / annotation>< / semantics>< / com:Math> (m, 6H), <com:Math><semantics>1.60(d,J=11.8Hz,3H).<annotation encoding="application / x-tex">1.60 (d, J = 11.8 Hz, 3H).< / annotation>< / semantics>< / com:Math>

[00275] Example 73: [Image disponible dans le document PDF, Image available in the PDF document]

[00276] Step 3

[0207] : The procedure is similar to Step 3

[0197] in example 69 (DIPEA as base). 0.25 g of 4-(difluoromethyl)-6-(3,5-dimethyl-1H-pyrazol-1-yl)-2- (methylsulfonyl)pyrimidine

[0205] gave 0.2 g N-(3,3-difluorocyclopentyl)-4- (difluoromethyl)-6-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidin-2-amine

[0207] , Compound 181 as a white solid. <com:Math><semantics>MS(M+1)+=344.4<annotation encoding="application / x-tex">MS(M+1)^{+}=344.4< / annotation>< / semantics>< / com:Math>, <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.25 – 7.72 (m, 1H), <com:Math><semantics>7.22<annotation encoding="application / x-tex">7.22< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>6.77<annotation encoding="application / x-tex">6.77< / annotation>< / semantics>< / com:Math> (t, JF = 54.5 Hz, 1H), <com:Math><semantics>6.20<annotation encoding="application / x-tex">6.20< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>4.35<annotation encoding="application / x-tex">4.35< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>2.67<annotation encoding="application / x-tex">2.67< / annotation>< / semantics>< / com:Math> (s, 3H), <com:Math><semantics>2.55<annotation encoding="application / x-tex">2.55< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=8.1 Hz,1H,2.42−1.90 (m, 7H),1.82 (q, J=9.0 Hz,1H).<annotation encoding="application / x-tex">J = 8.1 \text{ Hz}, 1\text{H}, 2.42 - 1.90 \text{ (m, 7H)}, 1.82 \text{ (q, } J = 9.0 \text{ Hz}, 1\text{H)}.< / annotation>< / semantics>< / com:Math>

[00277] Example 74: [Image disponible dans le document PDF, Image available in the PDF document]

[00278] Step 1

[0208] : The procedure is similar to Step 3

[0197] in example 69. 0.3 g 2,4- dichloro-6-cyclopropylpyrimidine

[0186] gave 0.2 g of 4-chloro-6-cyclopropyl-N-(4,4- difluorocyclohexyl)pyrimidin-2-amine

[0208] as an off-white solid. <com:Math><semantics>MS(M+1)+=288.2<annotation encoding="application / x-tex">MS(M+1)+=288.2< / annotation>< / semantics>< / com:Math>.

[00279] Step 2

[0209] : The procedure is similar to Step 3

[0197] in example 69. 0.2 g 4- chloro-6-cyclopropyl-N-(4,4-difluorocyclohexyl)pyrimidin-2-amine

[0208] gave 0.04 g of 4- cyclopropyl-N-(4,4-difluorocyclohexyl)-6-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidin-2-amine

[0209] , Compound 226 as a white solid. MS(M+1)+=348.2, 1H NMR (400 MHz, DMSO- d6): δ 7.91 (m, 1H), 7.60 (m, 1H), 5.82 (s, 1H), 5.06 (m, 1H), 3.55 (s, 2H), 2.57 (m, 1H), 2.43 (s, 3H), 1.51-1.46 (m, 6H), 1.31-1.32 (m, 2H), 1.29 (s, 6H).

[00280] Example 75: [Image disponible dans le document PDF, Image available in the PDF document]

[00281] Step 1

[0211] : To a solution of 2-Bromo-4-Hydroxymethylthiazole

[0210] (2 g, 10.30 mmol) in N,N-dimethylformamide (20 mL) was added tert-butyl dimethylsilyl chloride (3.2 g, 20.6 mmol) and imidazole (2.80 g, 41.2 mmol), then the reaction mixture was stirred at rt for 5h. After the completion of the reaction, to the reaction mixture was added ice cold water and extracted with ethyl acetate (2x75 mL), the combined organic layer was dried over anhydrous sodium sulfate and concentrated to afford as an colorless liquid and which was purified by column of silica gel (60-120 mesh) using 15% ethyl acetate in hexane as eluent to afford 3 g of 2-bromo-4-(((tert-butyl dimethylsilyl)oxy)methyl)thiazole

[0211] as an colorless liquid.

[00282] Step 2

[0212] : To a solution of 2-bromo-4-(((tert-butyl dimethylsilyl)oxy)methyl)thiazole

[0211] (0.3 g, 0.97 mmol) in tetrahydrofuran (10 mL) at - 78 °C under N2 was added n-BuLi (2.5 M in hexane) (0.06, 1.07, 1.) and the resulting brown solution was stirred for 30 min before adding tributyltin chloride (0.38 g, 1.16 mmol) and the reaction mixture was allowed to warm to rt and left overnight. After completion, the reaction mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate (2x25 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated to afford 0.7 g of 4-(((tert-butyldimethylsilyl)oxy)methyl)-2- (tributylstannyl)thiazole

[0212] as a light yellow liquid.

[00283] Step 3

[0213] : To a solution of 2-chloro-N-(4,4-difluorocyclohexyl)-6- methylpyrimidin-4-amine [0087A] (0.3g, 1.14 mmol) in toluene (10 mL) was added 4- (((tert-butyldimethylsilyl)oxy) methyl)-2-(tributylstannyl) thiazole

[00212] (0.71g, 1.37mmol1.) and purged nitrogen for 5 min, then added tetrakis(triphenylphosphine)palladium(0) (0.26g, 0.22mmol0.) to the reaction mixture and was irradiated in microwave at 130 °C for 2 h. the reaction mixture was filtered through celite bed and the filtrate was concentrated to afford as an brownish gum and which was purified by column of silica gel (60-120 mesh), using 50% ethyl acetate in hexane as eluent to afford 0.140 g of 2-(4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)-N-(4,4-difluoro cyclohexyl)-6-methylpyrimidin-4-amine

[0213] as an colorless gum. <com:Math><semantics>MS(M+1)+=455<annotation encoding="application / x-tex">MS(M+1)+=455< / annotation>< / semantics>< / com:Math>.

[00284] Step 4

[0214] : To an ice cooled solution of 2-(4-(((tert-butyldimethylsilyl) oxy)methyl)thiazol-2-yl)-N-(4,4-difluoro cyclohexyl)-6-methylpyrimidin-4-amine

[0213] (0.12g, 0.26mmol1.) in diethyl ether (10 mL) was added hydrogenchloride (gas) in dioxane, After the completion of the reaction, the solid was filtered and washed with hexane to afford as off-white solid and which was dissolved in saturated sodium bicarbonate solution and extracted with ethyl acetate (2x25 mL), the combined organic layer was dried over anhydrous sodium sulfate and concentrated to afford as an colorless gum and which was purified by column of silica gel (60-120 mesh), using ethyl acetate as eluent to afford 0.055 g of (2-(4- ((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)thiazol-4-yl)methanol

[0214] , Compound 270 as an white solid. <com:Math><semantics>MS(M+1)+=341<annotation encoding="application / x-tex">MS(M+1)^{+} = 341< / annotation>< / semantics>< / com:Math>, <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.53 <com:Math><semantics>(s,2H),6.35(s,1H),5.39(t,J=5.7Hz,1H),4.62(d,J=5.7Hz,2H),4.09(s,1H),2.29(s,2H),4.09(s,2H),4.09(s,2H),4.09(s,2H),4.09(s,2H),4.09(s,2H),4.09(s,2H),4.09(s,2H),4.09(s,2H),4.09<annotation encoding="application / x-tex">(s, 2H), 6.35 (s, 1H), 5.39 (t, J = 5.7 Hz, 1H), 4.62 (d, J = 5.7 Hz, 2H), 4.09 (s, 1H), 2.29 (s, 2H), 4.09 (s, 2H), 4.09 (s, 2H), 4.09 (s, 2H), 4.09 (s, 2H), 4.09 (s, 2H), 4.09 (s, 2H), 4.09 (s, 2H), 4.09 (s, 2H), 4.09< / annotation>< / semantics>< / com:Math> 3H), 2.07-1.95 (m, 6H), 1.59-1.52 (m, 2H).

[00285] Step 5

[0215] : The procedure is similar to step 3

[0012] in example 2. 0.32 g of (2- (4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)thiazol-4-yl)methanol

[0214] gave 0.18 g of N-(4,4-difluorocyclohexyl)-2-(4-(fluoromethyl)thiazol-2-yl)-6- methylpyrimidin-4-amine

[0215] , Compound 273 as an light yellow solid, MS(M+1)<com:Sup>+< / com:Sup>=343. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.96 (d, J = 3.4 Hz, 1H), 7.57 (bs, 1H), 6.38 (bs, 1H), 5.50 (d, JF = 48.5 Hz, 2H), 4.10 (bs, 1H), 2.30 (s, 3H), 2.02-1.95 (m, 6H), 1.61-152 (m, 2H).

[00286] Example 76: [Image disponible dans le document PDF, Image available in the PDF document] - - - -

[00287] Step 1

[0216] :0.080 g of (2-(4-((4,4-difluorocyclohexyl)amino)-6- methylpyrimidin-2-yl)thiazol-4-yl)methanol

[0214] gave 0.080 g of 2-(4-((4,4- difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)thiazole-4-carbaldehyde

[0216] as an light brownish gum, using Dess-Martin periodinane(2 eq) in dichloromethane. <com:Math><semantics>MS(M+1)+=338<annotation encoding="application / x-tex">MS(M+1)+=338< / annotation>< / semantics>< / com:Math> and it was taken as such for next step.

[00288] Step 2

[00217] : The procedure is similar to step 3

[0012] in example 2. 0.080 g of 2-(4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)thiazole-4-carbaldehyde

[0216] gave 0.032 g of N-(4,4-difluorocyclohexyl)-2-(4-(difluoromethyl)thiazol-2-yl)-6- methylpyrimidin-4-amine

[0217] , Compound 277 as an light yellow gummy solid. MS(M+1)<com:Sup>+< / com:Sup>=338. <com:Sup>1< / com:Sup>H-NMR (400 MHz, DMSO-d6): <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.22 (t, J = 1.40 Hz, 1H), 7.50 (s, 1H), <com:Math><semantics>7.14<annotation encoding="application / x-tex">7.14< / annotation>< / semantics>< / com:Math> (t, JF = <com:Math><semantics>54.52<annotation encoding="application / x-tex">54.52< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>6.41<annotation encoding="application / x-tex">6.41< / annotation>< / semantics>< / com:Math> (bs, 1H), <com:Math><semantics>4.05<annotation encoding="application / x-tex">4.05< / annotation>< / semantics>< / com:Math> (bs, 1H), <com:Math><semantics>2.32<annotation encoding="application / x-tex">2.32< / annotation>< / semantics>< / com:Math> (s, 3H), <com:Math><semantics>2.09−1.99−1.90<annotation encoding="application / x-tex">2.09-1.99-1.90< / annotation>< / semantics>< / com:Math> (m, 6H), 1.63-1.57 (m, 2H).

[00289] Example 77: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document]

[00290] Step1

[219] : To a solution of 2-bromo-4-(trifluoromethyl)thiazole in tetrahydrofuran (10 mL) at -78 °C under N2 atmosphere was added n-Butyl lithium (2.5 M in hexane) and the reaction mixture was stirred at same temperature. After 30 min, tributyltin chloride was added to the reaction mixture at -78 °C and stirred at rt. After 16 h, the reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (2*25 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated to afford 2-(tributylstannyl)-4-(Rs)-thiazole [219A to C] as a yellow liquid. LCMS inconclusive and it was taken as such for next step.

[00291] Example 78 [Image disponible dans le document PDF, Image available in the PDF document]

[00292] Step 1

[0220] : To a solution of 0.2 g of 2-chloro-N-(4,4-difluorocyclohexyl)-6- methylpyrimidin-4-amine [0087A] and 0.7 g of 2-(tributylstannyl)-4- (trifluoromethyl)thiazole in toluene (8 mL), was degassed with nitrogen for 10 min and tetrakis(triphenylphosphine)palladium(0) was added to the reaction mixture and irradiated in microwave at 130 °C. After 2 h, the reaction mixture was passed through celite bed and the filtrate was concentrated to afford a crude product, which was purified by column chromatography to afford 0.025 g of N-(4,4-difluoro cyclohexyl)-6-methyl-2-(4- (trifluoromethyl)thiazol-2-yl)pyrimidin-4-amine

[0220] , Compound 269 as an light yellow solid. <com:Math><semantics>MS(M+1)+=379<annotation encoding="application / x-tex">MS(M+1)^{+}=379< / annotation>< / semantics>< / com:Math>. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.61 (s, 1H), 7.67 (bs, 1H), 6.41 (bs, 1H), 3.88 (bs, 1H), 2.32 (s, 3H), 2.03-1.95 (d, 6H), 1.60-1.52 (m, 2H).

[00293] Example 79: [Image disponible dans le document PDF, Image available in the PDF document]

[00294] Step 1

[0221] : The procedure is similar to step 1

[0220] in example 78. 0.2 g of 2- chloro-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087A] gave 0.016 g of 2- (4-cyclopro pylthiazol-2-yl)-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine

[0221] , Compound 267 as an yellow solid which was purified by Prep HPLC, <com:Math><semantics>MS(M+1)+=351<annotation encoding="application / x-tex">MS(M+1)^+ = 351< / annotation>< / semantics>< / com:Math>. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) δ 7.52 (bs, 1H), 7.38 (s, 1H), 6.35 (bs, 1H), 4.04 (bs, 1H), 3.01 (bs, 1H), <com:Math><semantics>2.29<annotation encoding="application / x-tex">2.29< / annotation>< / semantics>< / com:Math> (s, 3H), <com:Math><semantics>2.13−1.91<annotation encoding="application / x-tex">2.13 - 1.91< / annotation>< / semantics>< / com:Math> (m, 6H), <com:Math><semantics>1.60−1.52<annotation encoding="application / x-tex">1.60 - 1.52< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>0.93<annotation encoding="application / x-tex">0.93< / annotation>< / semantics>< / com:Math> (dt, <com:Math><semantics>J=8.3<annotation encoding="application / x-tex">J = 8.3< / annotation>< / semantics>< / com:Math>, <com:Math>...

Claims

1. A compound having the structural Formula Ia: [Image disponible dans le document PDF, Image available in the PDF document] (Ia); or a pharmaceutically acceptable salt thereof, wherein: [Image disponible dans le document PDF, Image available in the PDF document] ring A is selected from [Image disponible dans le document PDF, Image available in the PDF document] X 1 X^1 is selected from C ( R a ) C(R^a) and N N ; X 2 X^2 is selected from C ( R b ) C(R^b) and N, wherein X 1 X^1 and X 2 X^2 are not simultaneously nitrogen; each of R a and R b is independently selected from hydrogen and C 1 -C 4 alkyl; each R 2 R^2 is independently selected from halo, CN, O(C 1 -C 4 alkyl), C 1 -C 4 alkyl, C 3 -C 4 cycloalkyl, cyanoC 1 -C 4 alkyl, haloC 1 -C 4 alkyl, and hydroxyC 1 -C 4 alkyl; R 3 is selected from -C(=O)NH 2 , heteroaryl, heterocyclyl, aryl, -O-carbocyclyl, -O- heterocyclyl, -O-heteroaryl, -O-aryl, -S-carbocyclyl, -S-heterocyclyl, -S-heteroaryl, -S-aryl, -S(O)-carbocyclyl, -S(O)-heterocyclyl, -S(O)-heteroaryl, -S(O)-aryl, -S(O) 2 -carbocyclyl, -S(O) 2 -heterocyclyl, -S(O) 2 -heteroaryl, -S(O) 2 -aryl, -O(C 1 -C 4 alkylene)carbocyclyl, -O(C 1 -C 4 alkylene)heterocyclyl, -O(C 1 -C 4 alkylene)heteroaryl, -O(C 1 -C 4 alkylene)aryl, -S(C 1 -C 4 alkylene)carbocyclyl, -S(C 1 -C 4 alkylene)heterocyclyl, -S(C 1 -C 4 alkylene)heteroaryl, -S(C 1 -C 4 alkylene)aryl, − S ( O ) ( C 1 − C 4 -S(O)(C_1-C_4 alkylene)carbocyclyl, − S ( O ) ( C 1 − C 4 -S(O)(C_1-C_4 alkylene)heterocyclyl, − S ( O ) ( C 1 − C 4 alkylene ) -S(O)(C_1-C_4 \text{ alkylene}) heteroaryl, − S ( O ) ( C 1 − C 4 alkylene ) -S(O)(C_1-C_4 \text{ alkylene}) aryl, − S ( O ) 2 ( C 1 − C 4 alkylene ) -S(O)_2(C_1-C_4 \text{ alkylene}) alkylene)carbocyclyl, -S(O) 2 (C 1 -C 4 alkylene)heterocyclyl, -S(O) 2 (C 1 -C 4 alkylene)heteroaryl, − S ( O ) 2 ( C 1 − C 4 alkylene ) -S(O)_2(C_1-C_4 \text{ alkylene}) aryl, S ( C 1 − C 4 alkyl ) S(C_1-C_4 \text{ alkyl}) , S ( O ) ( C 1 − C 4 alkyl ) S(O)(C_1-C_4 \text{ alkyl}) , and S ( O ) 2 ( C 1 − C 4 alkyl ) S(O)_2(C_1-C_4 \text{ alkyl}) , wherein each of said heterocyclyl, carbocyclyl, heteroaryl, aryl, and C 1 -C 4 alkylene are optionally substituted with 1 to 3 R 7 3 R^7 ; each R 7 is independently selected from halogen, CN, OR c , NR d R e , S(O) k R c , N R c S ( O ) 2 R c NR^{c}S(O)_{2}R^{c} , S ( O ) 2 N R d R e S(O)_{2}NR^{d}R^{e} , C ( = O ) O R c C(=O)OR^{c} , O C ( = O ) O R c OC(=O)OR^{c} , − O C ( = O ) R c -OC(=O)R^{c} , − O C ( = S ) O R c -OC(=S)OR^{c} , C ( = S ) O R c C(=S)OR^{c} , O ( C = S ) R c O(C=S)R^c , C ( = O ) N R d R e C(=O)NR^dR^e , N R c C ( = O ) R c NR^cC(=O)R^c , C ( = S ) N R d R e C(=S)NR^dR^e , N R c C ( = S ) R c NR^cC(=S)R^c , N R c ( C = O ) O R c NR^c(C=O)OR^c , O ( C = O ) N R d R e O(C=O)NR^dR^e , N R c ( C = S ) O R c NR^c(C=S)OR^c , O ( C = S ) N R d R e O(C=S)NR^dR^e , N R c ( C = O ) N R d R e NR^c(C=O)NR^dR^e , N R c ( C = S ) N R d R e NR^c(C=S)NR^dR^e , C(=S)R c , C(=O)R c , (C 1 -C 6 )alkyl, cycloalkyl, -(CH 2 )1-4-cycloalkyl, heterocyclyl, -(CH 2 )1-4- heterocyclyl, aryl, -(CH 2 )1-4-aryl, heteroaryl or -(CH 2 )1-4-heteroaryl, wherein each of said (C 1 -C 6 )alkyl, cycloalkyl, -(CH 2 )1-4-cycloalkyl, heterocyclyl, -(CH 2 )1-4-heterocyclyl, aryl, - (CH 2 )1-4-aryl, heteroaryl and -(CH 2 )1-4-heteroaryl for R 7 are optionally substituted with halogen, O R c OR^c , N O 2 NO_2 , C N CN , N R c C ( = O ) R c NR^cC(=O)R^c , N R d R e NR^dR^e , S ( O ) k R c S(O)_kR^c , C ( = O ) O R c C(=O)OR^c , C ( = O ) N R d R e C(=O)NR^dR^e , C ( = O ) R c C(=O)R^{c} , ( C 1 − C 3 ) a l k y l (C_1-C_3)alkyl , halo ( C 1 − C 3 ) a l k y l (C_1-C_3)alkyl , ( C 1 − C 3 ) a l k y l (C_1-C_3)alkyl , ( C 1 − C 3 ) a l k y l (C_1-C_3)alkyl , ( C 1 − C 3 ) a l k y l (C_1-C_3)alkyl , and halo( C 1 C_1 - C 3 C_3 )alkoxy; or two instances of ℝ 7 \mathbb{R}^7 are taken together on the same atom to form =O; R c is hydrogen or (C 1 -C 6 )alkyl optionally substituted with 1 to 3 halogen; R d and R e are each independently selected from hydrogen and (C 1 -C 6 )alkyl; and k is 0, 1 or 2; R 4a is selected from fluoro and -CF 3 ; R 4b is selected from hydrogen and fluoro; R 5 R^5 is selected from hydrogen and C 1 C_1 - C 4 C_4 alkyl; m is 0; n is 1, 2 or 3; o is 1 or 2; and p is 1, 2, 3 or 4.

2. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of the Formula II or III: [Image disponible dans le document PDF, Image available in the PDF document] (III); . . or a pharmaceutically acceptable salt thereof.

3. The compound of Claim 1 or 2, wherein R 3 is selected from: [Image disponible dans le document PDF, Image available in the PDF document]4. The compound of any one of Claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R 4a and R 4b are simultaneously fluoro.

5. The compound of Claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 3 R^3 is [Image disponible dans le document PDF, Image available in the PDF document]6. The compound of any one of Claims 1, 2 and 5, or a pharmaceutically acceptable salt thereof, wherein the compound is of the Formula VI or VII: [Image disponible dans le document PDF, Image available in the PDF document] or a pharmaceutically acceptable salt thereof.

7. The compound of any one of Claims 1, 2, 5 and 6, or a pharmaceutically acceptable salt, wherein ring A is [Image disponible dans le document PDF, Image available in the PDF document]8. The compound of any one of Claims 1, 2 and 5 to 7, or a pharmaceutically acceptable salt thereof, wherein R 2 is independently selected from C 1 -C 4 alkyl, haloC 1 -C 4 alkyl, and h y d r o x y C 1 hydroxyC_1 - C 4 C_4 alkyl.

9. The compound of any one of Claims 1, 2 and 5, wherein R 5 is hydrogen.

10. The compound of Claim 1, wherein the compound is selected from: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] F ΗŅ Ņ O. 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[Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] and [Image disponible dans le document PDF, Image available in the PDF document] or a pharmaceutically acceptable salt thereof.

11. The compound of Claim 1, wherein the compound is of the Formula: [Image disponible dans le document PDF, Image available in the PDF document] or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a compound of any one of Claims 1 to 11, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

13. Use of a compound of any one of Claims 1 to 11, or a pharmaceutically acceptable salt thereof, or a composition of Claim 12, for treating a disease or condition in a subject selected from ataxia, dystonia, tremors, Parkinson's disease, ischemia, traumatic brain injury, amyotrophic lateral sclerosis, hypertension, atherosclerosis, diabetes, arrhythmia, over-active bladder, anxiety, epilepsy, insomnia, and withdrawal symptoms caused by the termination of abuse of alcohol and other drugs of abuse.

14. Use of a compound of any one of Claims 1 to 11, or a pharmaceutically acceptable salt thereof, or a composition of Claim 12, for the preparation of a medicament for treating a disease or condition in a subject selected from ataxia, dystonia, tremors, Parkinson's disease, ischemia, traumatic brain injury, amyotrophic lateral sclerosis, hypertension, atherosclerosis, diabetes, arrhythmia, over-active bladder, anxiety, epilepsy, insomnia, and withdrawal symptoms caused by the termination of abuse of alcohol and other drugs of abuse.