NZ729138B2 - Optionally fused heterocyclyl-substituted derivatives of pyrimidine useful for the treatment of inflammatory, metabolic, oncologic and autoimmune diseases - Google Patents

Optionally fused heterocyclyl-substituted derivatives of pyrimidine useful for the treatment of inflammatory, metabolic, oncologic and autoimmune diseases Download PDF

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Publication number
NZ729138B2
NZ729138B2 NZ729138A NZ72913815A NZ729138B2 NZ 729138 B2 NZ729138 B2 NZ 729138B2 NZ 729138 A NZ729138 A NZ 729138A NZ 72913815 A NZ72913815 A NZ 72913815A NZ 729138 B2 NZ729138 B2 NZ 729138B2
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New Zealand
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group
substituted
alkyl
unsubstituted
hydrogen
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NZ729138A
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NZ729138A (en
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Jensen Kim Birkebaek
N N Rager Niels Gr
Gouliaev Alex Haahr
Ian Sarvary
Der Glad Sanne Schr
Luigi Piero Stasi
Lene Teuber
Mikkel Vestergaard
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Nuevolution A/S
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Priority claimed from PCT/EP2015/067713 external-priority patent/WO2016020295A1/en
Publication of NZ729138A publication Critical patent/NZ729138A/en
Publication of NZ729138B2 publication Critical patent/NZ729138B2/en

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    • C07D487/04—Ortho-condensed systems

Abstract

Disclosed are compounds of Formula (I) that are active towards nuclear receptors, specifically receptor-related orphan receptors (RORs), pharmaceutical compositions containing the compounds and use of the compounds in therapy.

Description

OPTIONALLY FUSED HETEROCYCLYL-SUBSTITUTED DERIVATIVES OF DINE USEFUL FOR THE TREATMENT OF INFLAMMATORY, METABOLIC, ONCOLOGIC AND AUTOIMMUNE ES Field Aspects and embodiments described herein relate to compounds active towards r receptors, pharmaceutical compositions comprising the compounds, and methods of treating inflammatory, metabolic, oncologic and autoimmune diseases or ers using the compounds.
Background Nuclear receptors are a family of transcription factors involved in the regulation of physiological flinctions, such as cell differentiation, nic development, and organ physiology. Nuclear receptors have also been identified as ant ogical regulators in diseases such as cancer, diabetes, and autoimmune disorders.
Examples of nuclear receptors include the nucelar ic acid receptor-related orphan receptors (RORs). RORs n four principal domains: an inal A/B domain, a DNA-binding domain, a hinge domain and a ligand binding domain. Binding of ligands to the ligand-binding domain is believed to cause conformational changes in the domain resulting in downstream actions. Different isoforms exist and these isoforms differ in their N—terminal A/B domain only.
RORs consist of three members, namely ROR alpha (ROROL), ROR beta (RORB) and ROR gamma (RORy or RORc).
RORu is expressed in many tissues such as cerebellar Purkinj e cells, the liver, thymus, skeletal muscle, skin, lung, adipose tissue and kidney.
RORy also has a broad expression pattern and was the most recently discovered of the three members. To date, five splice variants have been recorded for RORy coding for two different protein isoforms: RORyl and RORy2 (RORyZ is also known as RORyt). Generally RORy is used to describe RORyl and/or RORyt. RORyl is expressed in many tissues and is predominantly expressed in the kidneys, liver, and skeletal muscle. In contrast, expression of RORyt is restricted to lymphoid organs such as the thymus. RORyt has been identified as a key regulator of Thl7 cell differentiation.
Thl7 cells are a subset of T helper cells which entially produce the cytokines IL- 17A, IL-17F, lL-21 and IL-22. Thl7 cells and their products have been shown to be associated with the ogy ofmany human inflammatory and autoimmune disorders. 2015/067713 There is thus evidence that RORu and RORy play a role in the pathogenesis of many diseases.
It would be desirable to provide compounds that modulate the activity of ROROL and/or RORy for use in treating inflammatory, metabolic and autoimmune diseases.
Summary In one aspect provided herein are compounds of a (1) R1 R4a\\ (R4b)n i (/27? M M R6a N \N XR6b 1 / R5 Y Formula (I) or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and stereoisomers thereof, wherein: Y is NR or O; R is hydrogen or substituted or unsubstituted C1_4 alkyl; R1 is ed from the group consisting of hydrogen, -OH, halogen, substituted or tituted C1_4 alkyl, substituted or unsubstituted C1_4 alkoxy, and substituted or unsubstituted C24 l; R2 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1_4 alkyl, substituted or unsubstituted C1_4 alkoxy, -CN, and -OH ; or R and R2 are combined to form a substituted or tituted fused ring; R3 is selected from the group consisting of hydrogen, halogen, -OH, substituted or unsubstituted C1_4 alkyl, substituted or unsubstituted C1_4 alkoxy, oxo, -C(=O)R10; R4a is selected from the group ting of hydrogen, halogen, -OH, substituted or unsubstituted C1_6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1_6 alkenyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl-C1_6 alkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroaryl-C1_6 alkyl; R4b is selected from the group consisting of hydrogen, halogen, oxo, -OH, substituted or unsubstituted C1_4 alkyl, tuted or unsubstituted C1_4 alkoxy, and - C(ZO)R10; R5 is selected from the group consisting of -(CR8R9)pOR12, -(CR8R9)p- CR13R14R15, -(CR8R9)p-C(=O)OR7, and -(CR8R9)p-C(=O)NR8R9; n, m, and p are integers ndently selected from the group consisting of 0, l, 2, 3 and 4; R681, R6b are independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1_6 alkyl, substituted or unsubstituted C1_6 alkenyl, tuted or unsubstituted C2_6 alkynyl, substituted or unsubstituted C1_6 alkoxy, substituted or unsubstituted C1_6 heteroalkyl, substituted or unsubstituted C3_g cycloalkyl, substituted or unsubstituted C3_g cycloalkenyl, substituted or unsubstituted C2_9 heteroalicyclyl, substituted or tituted aryl, and substituted or unsubstituted aryl, or R6a and R6b are taken together to form an oxo group or a ring system selected from substituted or unsubstituted C3_6 cycloalkyl, and substituted or unsubstituted C2_9 alicyclyl, or R6a and R13 are taken together to form a ring system selected from substituted or unsubstituted C3_6 cycloalkyl, and substituted or tituted C25 heteroalicyclyl; R7, R8, R9, and R12, are independently selected from the group consisting of hydrogen, substituted or unsubstituted C1_6 alkyl, substituted or unsubstituted C3_6 cycloalkyl, and substituted or unsubstituted C2_9 heteroalicyclyl; R10 is selected from the group consisting of C1_6 alkyl, C1_6 alkoxy, -OH, -NH2, -NH(C1_6 alkyl), -N(C1_6 alkyl)2, and C3_7 cycloalkyl; R13 is absent, or ed from the group ting of hydrogen, -OH, -CN substituted or unsubstituted C1_6 alkyl, substituted or tituted C1_6 alkenyl, substituted or unsubstituted C1_6 alkoxy, substituted or unsubstituted C3_g cycloalkyl, substituted or unsubstituted C3_g cycloalkenyl, and -(CR8R9)p-C(=O)OR7, -(CR8R9)p- SOZR7 and -(CR8R9)p-C(=O)NR8R9; R14 and R15 are independently selected from the group ting of hydrogen, and substituted or unsubstituted C1_6 alkyl, substituted or unsubstituted C3_6 cyclo alkyl, and tuted or unsubstituted C2_9 heteroalicyclyl; or R14 and R15 are combined to form a ring system selected from the group consisting of substituted or unsubstituted C3_g cycloalkyl, tuted or unsubstituted C3-8 cycloalkenyl, substituted or unsubstituted C2-9 heteroalicyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; B is a ring system selected from the group consisting of aryl, heteroaryl, and bicyclic heteroalicyclyl, provided that it is not chloro-IH-benzo[d]imidazolyl when R1 and R2 both are en; C is a ring system selected from C2-9 heteroalicyclyl; wherein B is attached to a carbon atom adjacent the N atom of ring system C; with the proviso the compound is not: N N N N In another aspect, provided herein are compounds of Formula (I) R1 R4a (R4b)n R6a N N R5 Y N C (R3)m Formula (I) or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and stereoisomers thereof, wherein: Y is NR or O; R is hydrogen or C1-4 alkyl, C1-4 kyl, or C1-4 hydroxyalkyl; R1 is selected from the group consisting of hydrogen, -OH, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 , and C2-4 alkenyl; R2 is selected from the group consisting of hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, -CN, and -OH; or R and R2 are combined to form a fused ring; R3 is selected from the group consisting of hydrogen, halogen, -OH, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, C1-4 haloalkoxy, oxo, and R10; R4a is selected from the group consisting of hydrogen, halogen, -OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, -CN, C1-6 alkyl substituted with -C(=O)NR8R9, C1-C6 alkoxy, C1-6 haloalkoxy, C1-6 alkenyl, C3-C6 cycloalkyl, aryl, aryl-C1-6 alkyl, heteroaryl, and aryl-C1-6 alkyl; R4b is selected from the group consisting of hydrogen, halogen, oxo, -OH, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 , C1-4 haloalkoxy, and -C(=O)R10; R5 is selected from the group consisting of -(CR8R9)pOR12, -(CR8R9)p-CR13R14R15, - (CR8R9)p-C(=O)OR7, and 9)p-C(=O)NR8R9; n, m, and p are integers independently selected from the group consisting of 0, 1, 2, 3 and 4; R6a, R6b are independently selected from the group consisting of hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkoxy, lkoxy-C1alkyl, C1-6 heteroalkyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, C2-9 heteroalicyclyl, C2-9 heteroalicyclyl-C1-6 alkyl, aryl, 1-6 alkyl, and heteroaryl, wherein aryl, C2-9 alicyclyl, and heteroaryl may be substituted by one or more substituents selected from the group consisting of halogen, C1-4 alkyl, C1-4 kyl, C1-4 alkoxy, C3-5 cycloalkyl, -(CH2)q-CONR23R24, -(CH2)q-SO2R23, -(CH2)q-NR23SO2R24 and -(CH2)q- SO2NR23, R23, and R24 are independently selected from the group consisting of hydrogen, C1-6 alkyl, -CN, C3-6 cycloalkyl, and C2-6 heteroalicyclyl, or R6a and R6b are taken together to form an oxo group or a ring system selected from C3-6 cycloalkyl and C2-9 heteroalicyclyl, or R6a and R13 are taken together to form a ring system selected from C3-6 lkyl and C2-9 heteroalicyclyl; R7, R8, R9, and R12, are independently selected from the group consisting of en, C1-6 alkyl, C1-6 haloalkyl, C1-6 yalkyl, C1-4 aminoalkyl, aryl-C1-6 alkyl, heteroaryl-C1-6 alkyl, aryl, C3-6 cycloalkyl, and C2-9 heteroalicyclyl, or R8 and R9 are combined to form a C2-C6 heteroalicyclyl; R10 is selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, -OH, -NH2, - NH(C1-6 alkyl), -N(C1-6 alkyl)2, and C3-7 cycloalkyl; R13 is , or selected from the group consisting of hydrogen, -OH, -CN, fluorine, C1-6 alkyl, C1-6 hydroxyalkyl or C1-6 alkoxy, C1-6 alkenyl, C1-6 alkoxy, C3-8 cycloalkyl, C3-8 cycloalkenyl, and -(CR8R9)p-C(=O)OR7, 9)p-SO2R7 and -(CR8R9)p-C(=O)NR8R9; R14 and R15 are independently selected from the group consisting of hydrogen, and substituted or tituted C1-6 alkyl, substituted or unsubstituted C3-6 cycloalkyl, and substituted or unsubstituted C2-9 heteroalicyclyl; or R14 and R15 are combined to form a ring system selected from the group consisting of substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted C3-8 cycloalkenyl, substituted or unsubstituted C2-9 heteroalicyclyl, tuted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, wherein when the ring system formed by the combination of R14 and R15 is substituted, it is substituted with -(CH2)q(R5a) wherein R 5a is independently selected from the group consisting of -CH2COOR20, -CH2CONR21R22, -CN, -CH2-CN, C1-6 alkyl, -CH2-SO2R20, - CH2C(CH3)2(OR20), -OR20, -CH2-triazolyl, -CF3, dimethyl substituted-imidazolyl-2,4-dione, - 2NR21R22, morpholinyl, -C(=O)-morpholinyl, piperidinyl-CH2OR20, -OCH2- tetrahydrofuryl, piperazinonyl, piperidinyl-CONR21R22, -OH, -CONR21R22, cyclopentyl, pyrrolidonyl, -NR21SO2R20, tetrazolyl, -CH2-tetrazolyl, 20-SO3R20, -SO2R20, - SO2NR21R22, and halogen; R20, R21, and R22 are independently of each other ed from the group consisting of hydrogen, C1-6 alkyl, -CN, and C3-6 cycloalkyl; q is an integer selected from 0, 1 or 2; B is a ring system selected from the group ting of aryl, heteroaryl, and bicyclic heteroalicyclyl, provided that it is not 5,6-dichloro-1H-benzo[d]imidazolyl when R1 and R2 both are hydrogen; C is a ring system selected from C2-9 heteroalicyclyl; wherein B is attached to a carbon atom adjacent the N atom of ring system C; and with the o the compound is not: N N N N According to a further , R and R2 are combined to form a fused ring. In r aspect, R5 is -(CR8R9)p-C(=O)OR7, or -(CR8R9)p-C(=O)NR8R9. Alternatively, R5 is - (CR8R9)p-CR13R14R15 wherein R14 and R15 are combined to form a ring system.
According to another aspect, there is provided a pharmaceutical composition comprising a compound of the herein above bed type and at least one pharmaceutical acceptable excipient.
According to yet r aspect, the herein above described compound or pharmaceutical composition are for use in therapy.
According to another aspect, the herein above described compound or pharmaceutical composition are for use in the treatment and/or prevention of inflammatory, metabolic and autoimmune diseases or disorders.
In another aspect, the herein above described compound or pharmaceutical composition are for modulating the activity of a retinoic acid receptor-related orphan receptor (ROR).
According to another aspect, the herein above bed compound is used for the manufacture of a medicament for the ent and/or prevention of an inflammatory, metabolic or autoimmune disease or disorder.
In another aspect, the herein above described compound is used for the manufacture of a medicament for modulating the activity of a retinoic acid receptor-related orphan receptor (ROR).
According to a further aspect, there is a method of treatment and/or prevention of an matory, lic, or autoimmune disease or er in a non-human animal comprising administering a compound as herein above described.
Further, advantageous features of s embodiments are defined in the dependent claims and within the detailed description below.
[Followed by page 5] Detailed ption of preferred embodiments Definitions Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.
As used herein, any "R" group(s) such as, without tion, R1, R21R3, R4, R5, R8, R9, and R10, represent substituents that can be attached to the indicated atom. A non- limiting list of R groups includes but is not limited to hydrogen, alkyl, alkenyl, l, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and alicyclyl. If two "R" groups are covalently bonded to the same atom or to adjacent atoms, then they may be "taken together" or "combined" as defined herein to form a cycloalkyl, aryl, heteroaryl or heteroalicyclyl group. For example, without tion, if Ra and Rb of an NRaRb group are ted to be "taken together" or "combined", it means that they are covalently bonded to one another at their terminal atoms to form a ring that includes the nitrogen: -N:M gab As readily ized by the skilled person, any given group sed herein may comprise further hydrogen(s) than the one(s) provided by a R-group, being hydrogen, attached to the group.
Whenever a group is described as being "unsubstituted or substituted," if substituted, the substituent(s) (which may be present one or more times, such as l, 2, 3 or 4 times) are independently selected fiom alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, OX0, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amido, N—amido, S- WO 20295 sulfonamido, N—sulfonamido, nitro, silyl, sulfenyl, sulf1nyl, sulfonyl, haloalkyl, koxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof.
When a substituent on a group is deemed to be "substituted," the tutent itself is substituted with one or more of the indicated substitutents. When the referenced substituent is substituted, it is meant that one or more hydrogen atoms on the referenced substituent may be replaced with a group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amido, o, S-sulfonamido, N—sulfonamido, nitro, silyl, sulfenyl, l, sulfonyl, haloalkyl, haloalkoxy, omethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, and the protected tives thereof The ting groups that may form the protective derivatives of the above substituents are known to those of skill in the art and may be found in references Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, which is hereby incorporated by reference in its entirety.
As used herein, "Cm to C11," "Cm-CH" or "Cm," in which "m" and "n" are integers refers to the number of carbon atoms in the relevant group. That is, the group can contain from "m" to "11", inclusive, carbon atoms. Thus, for example, a "C1 to C6 alkyl" group refers to all alkyl groups having from 1 to 6 carbons, that is, CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, CH3CH(CH)3CH2- CH3CH(CH)3CH2- and C-. If no "m" and "n" are designated with regard to a group, the broadest range described in these definitions is to be assumed.
As used herein, "alkyl" refers to a ht or branched hydrocarbon chain group that is fillly saturated (no double or triple bonds). The alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a cal range such as "l to 20" refers to each integer in the given range; e.g., "l to 20 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, eta, up to and including carbon atoms, although the present definition also covers the occurrence of the term "alkyl" where no numerical range is designated). The alkyl group may also be a medium size alkyl having 1 to 10 carbon atoms, such as "C1_6’ 3 . The alkyl group could also be a lower alkyl having 1 to 4 carbon atoms. The alkyl group of the compounds may be designated as "C1-C4 " "C1_4 alkyl" or r designations. By way of example only, "C1-C4 alkyl" or "C1_4 alkyl" indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, , isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like. When substituted, the substituent group(s) is(are) one or more group(s) individually and independently ed from alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, to, alkylthio, arylthio, cyano, halogen, yl, thiocarbonyl, C-amido, N—amido, S-sulfonamido, N—sulfonamido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, kyl, haloalkoxy, omethanesulfonyl, trihalomethanesulfonamido, and amino, ing mono- and di-substituted amino groups, and the ted derivatives thereof.
As used herein, "alkenyl" refers to an alkyl group that contains in the straight or branched arbon chain one or more double bonds. If more than one double bond is present, the double bonds may be ated or not conjugated. The alkenyl group may have 2 to 20 carbon atoms (whenever it appears herein, a numerical range such as "2 to " refers to each integer in the given range; 6. g. "2 to 20 carbon atoms" means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, eta, up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term "alkenyl" where no numerical range is designated). When substituted, the substituent group(s) is(are) one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy, mercapto, alkylthio, cyano, halogen, nitro, kyl, haloalkoxy, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof.
As used herein, "alkynyl" refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds. The alkynyl group may have 2 to 20 carbon atoms (whenever it appears herein, a numerical range such as "2 to 20" refers to each r in the given range; e.g., "2 to 20 carbon atoms" means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, eta, up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term "alkynyl" where no numerical range is designated). An alkynyl group may be unsubstituted or substituted. When substituted, the substituent(s) may be selected from the same groups disclosed above with regard to alkenyl group substitution.
As used herein, "hetero" may be attached to a group and refers to one or more carbon atom(s) and the ated hydrogen atom(s) in the attached group have been independently replaced with the same or different heteroatoms selected from nitrogen, oxygen, phosphorus and sulfur.
As used herein, "heteroalkyl," by itself or in combination with another term, refers to a straight or branched alkyl group consisting of the stated number of carbon atoms, where one or more carbon atom(s), such as l, 2, 3 or 4 carbon atom(s), and the ated hydrogen atom(s) have been independently replaced with the same or different heteroatoms selected from nitrogen, oxygen and sulfur. The carbon atom(s) being replace may be in the middle or at the end of the alkyl group. Examples of alkyl include, but are not limited to, yl, -O-alkyl, -NH-alkyl, ene-O- alkyl, etc As used herein, "aryl" refers to a carbocyclic (all carbon) ring or two or more fused rings (rings that share two adjacent carbon atoms) that have a fully delocalized pi- electron system. Examples of aryl groups include, but are not limited to, e, naphthalene and azulene. An aryl group may be substituted. When substituted, hydrogen atoms are replaced by substituent group(s) that ) one or more group(s) independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, lkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amido, N—amido, S- sulfonamido, N—sulfonamido, nitro, silyl, sulfenyl, sulf1nyl, sulfonyl, kyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof. When tuted, substituents on an aryl group may form a non-aromatic ring fiased to the aryl group, including a cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl.
As used herein, oaryl" refers to a monocyclic or multicyclic aromatic ring system (a ring system with fillly delocalized pi-electron system), in which at least one of the atoms in the ring system is a heteroatom, that is, an element other than carbon, including but not limited to, en, oxygen and sulfur. Examples of monocyclic "heteroaryl" include, but are not limited to, filran, thiophene, phthalazine, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, triazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, tetrazole, and triazine. Examples of yclic "heteroaryl" include, but are not limited to, quinoline, isoquinoline, quinazoline, quinoxaline, indole, purines, benzofuran, benzothiophene, benzopyranones (e.g. coumarin, chromone, and isocoumarin). A aryl may be substituted. When substituted, hydrogen atoms are replaced by substituent group(s) that is(are) one or more group(s) independently selected from alkyl, alkenyl, alkynyl, lkyl, cycloalkenyl, cycloalkynyl, aryl, aryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, o, N—amido, S- sulfonamido, onamido, nitro, silyl, sulfenyl, sulf1nyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof. When substituted, substituents on a heteroayl group may form a non-aromatic ring fused to the aryl group, including a cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl.
An "aralkyl" or "arylalkyl" is an aryl group connected, as a tuent, via an alkylene group. The alkylene and aryl group of an aralkyl may be substituted. es include but are not d to benzyl, substituted benzyl, 2-phenylethyl, 3- phenylpropyl, and naphthylalkyl. In some cases, the alkylene group is a lower alkylene group.
A "heteroaralkyl" or "heteroarylalkyl" is heteroaryl group connected, as a tuent, Via an alkylene group. The alkylene and heteroaryl group of heteroaralkyl may be substituted. Examples include but are not limited to 2-thienylmethyl, 3- lmethyl, filrylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, pyrazolylalkyl and imidazolylalkyl, and their substituted as well as benzo-fused analogs. In some cases, the alkylene group is a lower alkylene group.
An "alkylene" is a straight-chained tethering group, forming bonds to connect molecular fragments Via their terminal carbon atoms. The alkylene may have 1 to 20 carbon atoms. The alkylene may also be a medium size alkylene having 1 to 10 carbon atoms, such as , The ne could also be a lower alkylene having 1 to 4 carbon atoms. The alkylene may be designated as "C1-C4 alkylene", "C1_4 ne" or similar designations. Non-limiting examples include, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), and butylene (-(CH2)4-) groups. In the case of methylene, the two connected fragments are connected to the same carbon atom. A lower ne group may be substituted.
As used herein, "heteroalkylene" by itself or in combination with another term refers to an alkylene group consisting of the stated number of carbon atoms in which one or more of the carbon atoms, such as l, 2, 3 or 4 carbon atom(s), are independently replaced with the same or different heteroatoms selected from oxygen, sulfur and nitrogen. Examples of heteroalkylene include, but not limited to -CH2-O-, -CH2-CH2- 0-, -CH2-CH2-CH2-O-, -CH2-NH-, H2-NH-, H2-CH2-NH-, -CH2-CH2- NH-CH2-, -O-CH2-CH2-O-CH2-CH2-O-, -O-CH2-CH2-O-CH2-CH2-, and the like.
As used , "alkylidene" refers to a nt group, such as =CR’R’ ’, which is attached to one carbon of another group, forming a double bond. Alkylidene groups include, but are not limited to, methylidene (=CH2) and ethylidene (=CHCH3). As used herein, lkylidene" refers to an alkylidene group in which either R’ or R’ ’ is an aryl group. An dene group may be substituted.
As used herein, "alkoxy" refers to the group —OR wherein R is an alkyl, e.g. methoxy, ethoxy, n-propoxy, cyclopropoxy, l-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, amoxy, moxy and the like. An alkoxy may be substituted.
As used herein, "alkylthio" refers to the formula —SR wherein R is an alkyl is defined as above, e. g. methylmercapto, ethylmercapto, n-propylmercapto, l- methylethylmercapto (isopropylmercapto), lmercapto, iso-butylmercapto, sec- butylmercapto, tert-butylmercapto, and the like. An alkylthio may be tuted.
As used herein, "aryloxy" and "arylthio" refers to R0- and RS-, in which R is an aryl as defined above, e.g., phenoxy, naphthalenyloxy, azulenyloxy, anthracenyloxy, naphthalenylthio, phenylthio and the like. Both an aryloxy and arylthio may be substituted.
As used herein, "alkenyloxy" refers to the formula —OR wherein R is an l as defined above, e. g., vinyloxy, propenyloxy, n-butenyloxy, iso-butenyloxy, sec- pentenyloxy, tert-pentenyloxy, and the like. The alkenyloxy may be substituted.
As used herein, "acyl" refers to a hydrogen, alkyl, alkenyl, alkynyl, or aryl ted, as substituents, via a carbonyl group. es include formyl, , propanoyl, benzoyl, and acryl. An acyl may be substituted.
As used herein, "cycloalkyl" refers to a completely saturated (no double bonds) mono- or multi- cyclic hydrocarbon ring system. When composed oftwo or more rings, the rings may be joined together in a fused, bridged or spiro-connected fashion.
Cycloalkyl groups may range from C3 to C10, such as from C3 to C6. A cycloalkyl group may be unsubstituted or tuted. Typical cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. If tuted, the substituent(s) may be an alkyl or selected from those indicated above with regard to substitution of an alkyl group unless otherwise indicated. When substituted, substituents on a cycloalkyl group may form an aromatic ring fiJsed to the cycloalkyl group, including an aryl and a heteroaryl.
As used herein, "cycloalkenyl" refers to a cycloalkyl group that contains one or more double bonds in the ring although, if there is more than one, they cannot form a fully delocalized ctron system in the ring (otherwise the group would be "aryl," as defined herein). When composed of two or more rings, the rings may be connetected together in a filSGd, bridged or connected fashion. Cycloalkenyl groups may range from C3 to C10, such as from C5 to C10. A cycloalkenyl group may be unsubstituted or substituted. When substituted, the substituent(s) may be an alkyl or selected from the groups disclosed above with regard to alkyl group substitution unless otherwise indicated. When tuted, substituents on a cycloalkenyl group may form an ic ring fiJsed to the lkenyl group, including an aryl and a heteroaryl.
As used herein, "cycloalkynyl" refers to a lkyl group that contains one or more triple bonds in the ring. When composed of two or more rings, the rings may be joined together in a filSGd, bridged or spiro-connected fashion. Cycloalkynyl groups may range from C8 to C12. A cycloalkynyl group may be unsubstituted or substituted.
When substituted, the substituent(s) may be an alkyl or selected from the groups disclosed above with regard to alkyl group tution unless otherwise indicated.
When substituted, tuents on a cycloalkynyl group may form an ic ring fused to the cycloalkynyl group, including an aryl and a heteroaryl.
As used herein, "heteroalicyclic" or "heteroalicyclyl" refers to a 3- to 18 membered ring which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. The heteroalicyclic or heteroalicyclyl groups may range from C2 to C10, in some embodiments it may range from C2 to C9, and in other embodiments it may range from C2 to Cg. The oalicyclic" or "heteroalicyclyl" may be monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be joined together in a fused, bridged or spiro- connected n; and the nitrogen, carbon and sulfur atoms in the "heteroalicyclic" or "heteroalicyclyl" may be oxidized; the nitrogen may be quatemized; and the rings may also contain one or more double bonds provided that they do not form a fiJlly delocalized pi-electron system throughout all the rings, examples are 2H- benzo [b] [ l ,4]oxazin—3(4H)-one, 3 ,4-dihydroquinolin-2( l H)-one, 1,2,3 ,4- tetrahydroquino line, 3 ,4-dihydro-2H-benzo [b] [ l zine, 2,3 - dihydrobenzo[d]oxazole, 2,3-dihydro-lH-benzo[d]imidazole, indoline, and l,3-dihydro- 2H-benzo[d]imidazolone, and benzo[d]oxazol-2(3H)-one. Heteroalicyclyl groups may be unsubstituted or substituted. When substituted, the substituent(s) may be one or more groups independently selected from the group consisting of alkyl, l, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, hio, arylthio, cyano, halogen, C-amido, N—amido, S- sulfonamido, N—sulfonamido, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino , and the protected derivatives thereof.
Examples of such "heteroalicyclic" or "heteroalicyclyl" include but are not limited to, azepinyl, dioxolanyl, imidazolinyl, morpholinyl, oxetanyl, oxiranyl, piperidinyl N- Oxide, piperidinyl, piperazinyl, pyrrolidinyl, l, ridonyl, pyrazolidinyl, 2- oxopyrrolidinyl, ydrofilranyl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinyl sulfoxide, and rpholinyl sulfone. When substituted, substituents on a heteroalicyclyl group may form an aromatic ring fiased to the heteroalicyclyl group, including an aryl and a heteroaryl.
A "(cycloalkyl)alkyl" is a cycloalkyl group connected, as a substituent, Via an alkylene group. The alkylene and cycloalkyl of a (cycloalkyl)alkyl may be substituted.
Examples e but are not limited cyclopropylmethyl, cyclobutylmethyl, ropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, and the like. In some cases, the alkylene group is a lower alkylene group.
A "(cycloalkenyl)alkyl" is a cycloalkenyl group connected, as a substituent, Via an alkylene group. The alkylene and cycloalkenyl of a (cycloalkenyl)alkyl may be substituted. In some cases, the alkylene group is a lower alkylene group.
A "(cycloalkynyl)alkyl" is a cycloalkynyl group connected, as a substituent, Via an alkylene group. The alkylene and cycloalkynyl of a (cycloalkynyl)alkyl may be tuted. In some cases, the alkylene group is a lower alkylene group.
As used , "halo" or "halogen" refers to F (fluoro), Cl (chloro), Br (bromo) or I (iodo).
As used herein, "haloalkyl" refers to an alkyl group in which one or more ofthe en atoms are replaced by halogen. Such groups include but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, romethyl and l-chloro fluoromethyl, 2-fluoroisobutyl. A haloalkyl may be substituted.
As used herein, "haloalkoxy" refers to a RO-group in which R is a haloalkyl group. Such groups include but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy and rofluoromethoxy, 2-fluoroisobutyoxy.
A haloalkoxy may be substituted.
An boxy" group refers to a "RC(=O)O-" group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or oalicyclyl)alkyl, as defined herein. An 0- carboxy may be substituted.
A "C-carboxy" group refers to a "-C(=O)OR" group in which R can be the same as defined with respect to oxy. A C-carboxy may be substituted.
A "trihalomethanesulfonyl" group refers to an z-" group" wherein X is a halogen.
A dashed bond, WWWWW an optional unsaturation between the atoms , represents forming the bond. This bond may be unsaturated (e. g. C=C, C=N, C=O) or saturated (e. g. C-C, C-N, C-O). When a dashed bond is present in a ring system it may form part of an aromatic ring system.
A "nitro" group refers to a "-NOZ" group A "cyano" group refers to a "-CN" group.
A "cyanato" group refers to an "-OCN" group.
An "isocyanato" group refers to a "-NCO" group.
A "thiocyanato" group refers to a "-SCN" group.
A "carbonyl" group refers to a )-" group.
A "thiocarbonyl" group refers to a "—C(=S)-" group.
An "oxo" group refers to a " =0 " group.
A "hydroxy" group or "hydroxyl" group refers to an "-OH" group.
An "isothiocyanato" group refers to an " -NCS" group.
A nyl" group refers to an "-S(=O)-R" group in which R can be the same as defined with respect to O-carboxy. A sulf1nyl may be substituted.
A "sulfonyl" group refers to an "SOZR" group in which R can be the same as defined with respect to O-carboxy. A sulfonyl may be substituted.
An "S-sulfonamido" group refers to a "-SOZNRARB" group in which RA and RB indendently of each other can be the same as defined with respect to the R group as defined for O-carboxy, or combined to form a ring system selected fiom the group consisting of substituted or unsubstituted C3_g cycloalkyl, substituted or unsubstituted C3_g cycloalkenyl, substituted or unsubstituted C3_g cycloalkyl, substituted or unsubstituted C3_g cycloalkenyl tuted or unsubstituted heteroalicyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. A S-sulfonamido may be substituted.
An "N—sulfonamido" group refers to a "RSOZN(RA)-" group in which R and RA indendently of each other can be the same as defined with respect to the R group as defined for O-carboxy. An N—sulfonamido may be substituted.
A "trihalomethanesulfonamido" group refers to an "X3CSOZN(R)-" group with X as halogen and R can be the same as defined with respect to O-carboxy. A trihalomethanesulfonamido may be substituted.
A "C-amido" group refers to a "-C(=O)NRARB" group in which RA and RB indendently of each other can be the same as defined with respect to the R group as defined for oxy, or combined to form a ring system selected fiom the group consisting of substituted or unsubstituted C3_g cycloalkyl, substituted or tituted C3_g cycloalkenyl, substituted or unsubstituted C3_g cycloalkyl, tuted or unsubstituted C3_g cycloalkenyl substituted or unsubstituted heteroalicyclyl, substituted or tituted aryl, and substituted or unsubstituted heteroaryl. A C-amido may be substituted.
An do" group refers to a "RC(=O)NRA-" group in which R and RA indendently of each other can be the same as defined with respect to the R group as defined for O-carboxy. An o may be substituted.
An " refers to a "—C(=O)OR" group in which R can be the same as defined with respect to O-carboxy. An ester may be substituted.
A lower alkoxyalkyl refers to an alkoxy group connected Via a lower ne group. A lower alkoxyalkyl may be substituted.
An " or "amino" refers to "RNHZ" (a primary amine), "R2NH" (a secondary amine), "R3N" (a tertiary amine). An amino group may be substituted.
WO 20295 A lower aminoalkyl refers to an amino group connected via a lower alkylene group. A lower aminoalkyl may be substituted.
Any unsubstituted or monosubstituted amine group on a compound herein can be converted to an amide, any hydroxyl group can be converted to an ester and any carboxyl group can be converted to either an amide or ester using techniques wellknown to those skilled in the art (see, for example, Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999).
As used herein, the abbreviations for any protective groups, amino acids and other compounds, are, unless ted otherwise, in accord with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (See, Biochem. 11:942-944 (1972)).
As employed herein, the following terms have their accepted meaning in the al literature.
CDC13 ated chloroform DCM dichloromethane or CH2C12 DIPEA N,N-diisopropylethylamine DMF N,N—dimethylformamide DMSO dimethyl ide EtOAc ethyl acetate h hour(s) MeOH methanol TFA trifluoroacetic acid It is understood that, in any compound disclosed herein having one or more chiral centers, if an te stereochemistry is not expressly indicated, then each center may independently be of 1guration or S-conf1guration or a mixture thereof. Thus, the compounds provided herein may be enatiomerically pure or be stereoisomeric es. Further, nds provided herein may be scalemic mixtures. In addition, it is understood that in any compound having one or more double bond(s) generating geometrical isomers that can be defined as E or Z each double bond may independently be E or Z or a mixture thereof. Likewise, all tautomeric forms are also intended to be included.
As used herein, "tautomer" and "tautomeric" refer to alternate forms of a compound disclosed herein that differ in the position of a . Non-limiting examples include enol-keto and enamine tautomers, or the tautomeric forms of heteroaryl groups containing a ring atom ed to both a ring -NH- moiety and a ring =N— moiety such as pyrazoles, imidazoles, benzimidazoles, triazoles, and oles.
It is understood that isotopes may be present in the compounds described herein.
Each chemical element as represented in a compound ure may include any e of said element. For example, in a compound described herein a hydrogen atom can be any isotope of en, including but not limited to hydrogen-l (protium) and hydrogen-2 (deuterium). Thus, reference herein to a compound encompasses all ial isotopic forms unless the context clearly dictates otherwise.
As used herein, "pharmaceutically able salt" refers to a salt of a nd that does not te the biological actiVity and properties of the compound. Pharmaceutical salts can be obtained by reaction of a compound disclosed herein with an acid or base. Base-formed salts include, without limitation, ammonium salt (NH4+); alkali metal, such as, without limitation, sodium or potassium, salts; alkaline earth, such as, without limitation, calcium or magnesium, salts; salts of organic bases such as, without limitation, dicyclohexylamine, piperidine, piperazine, methylpiperazine, N—methyl-D-glucamine, diethylamine, ethylenediamine, ydroxymethyl)methylamine; and salts with the amino group of amino acids such as, without limitation, ne and lysine. Useful acid-based salts include, without tion, acetates, adipates, aspartates, ascorbates, benzoates, butyrates, caparate, caproate, caprylate, camsylates, citrates, decanoates, formates, filmarates, gluconates, glutarate, glycolates, hexanoates, laurates, lactates, maleates, es, oleates, oxalates, octanoates, propanoates, palmitates, phosphates, sebacates, succinates, stearates, sulfates, sulfonates, such as methanesulfonates, ethanesulfonates, p-toluenesulfonates, salicylates, tartrates, and tosylates.
Pharmaceutically acceptable solvates and hydrates are complexes of a compound with one or more solvent of water molecules, or 1 to about 100, or 1 to about , or one to about 2, 3 or 4, solvent or water molecules.
As used herein, a "prodrug" refers to a compound that may not be pharmaceutically active but that is ted into an active drug upon in vivo administration. The prodrug may be ed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug. Prodrugs are often useful e they may be easier to administer than the parent drug. They may, for example, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have better solubility than the active parent drug in pharmaceutical compositions. An example, without limitation, of a prodrug would be a compound disclosed herein, which is administered as an ester (the "prodrug") to facilitate absorption through a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to a carboxylic acid (the active entity) once inside the cell where water-solubility is beneficial. A fiarther e of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized in vivo to e the active parent compound. By virtue of knowledge of codynamic ses and drug metabolism in vivo, those skilled in the art, once a pharmaceutically active compound is known, can design prodrugs of the compound (see, e. g. Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392).
"Anti-drug" refers to a compound or composition acting against or opposing illicit drugs or their use. Compounds of the present application may act as anti-drugs.
As used herein, to "modulate" the activity of a or means either to activate it, i.e., to increase its cellular fianction over the base level ed in the particular environment in which it is found, or deactivate it, i.e., decrease its cellular fianction to less than the measured base level in the environment in which it is found and/or render it unable to perform its cellular fianction at all, even in the presence of a natural binding partner. A natural binding partner is an endogenous le that is an agonist for the receptor.
An "agonist" is defined as a compound that ses the basal activity of a receptor (i.e. signal transduction ed by the receptor).
As used herein, "partial agonist" refers to a compound that has an affinity for a receptor but, unlike an agonist, when bound to the receptor it elicits only a fractional degree of the pharmacological response ly associated with the receptor even if a large number of receptors are occupied by the compound.
An "inverse agonist" is defined as a compound, which reduces, or suppresses the basal ty of a receptor, such that the nd is not technically an antagonist but, rather, is an agonist with ve intrinsic activity.
As used , "antagonist" refers to a compound that binds to a or to form a complex that does not give rise to any response, as if the receptor was pied. An antagonist attenuates the action of an agonist on a receptor. An antagonist may bind reversibly or irreversibly, effectively eliminating the activity of the receptor permanently or at least until the antagonist is metabolized or dissociates or is otherwise removed by a physical or biological process.
As used , a "subject" refers to an animal that is the object of treatment, observation or experiment. "Animal" includes cold- and warm-blooded vertebrates and ebrates such as birds, fish, shellfish, reptiles and, in particular, s.
"Mammal" includes, without limitation, mice; rats; rabbits; guinea pigs; dogs; cats; sheep; goats; cows; horses; es, such as monkeys, chimpanzees, and apes, and, in particular, humans.
As used herein, a "patient" refers to a subject that is being treated by a medical professional such as an MD. or a D.V.M. to attempt to cure, or at least ameliorate the effects of, a particular disease or disorder or to prevent the disease or disorder from ing in the first place.
As used herein, a "carrier" refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, without limitation, dimethyl sulfoxide (DMSO) is a commonly utilized carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject.
As used herein, a "diluent" refers to an ingredient in a pharmaceutical composition that lacks cological activity but may be pharmaceutically necessary or desirable. For example, a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ion or inhalation. A common form of diluent in the art is a buffered aqueous on such as, without limitation, phosphate buffered saline that mimics the composition of human blood.
As used herein, an ient" refers to an inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, g ability, lubrication, disintegrating ability etc., to the composition. A "diluent" is a type of excipient.
A "receptor" is ed to include any molecule present inside or on the surface of a cell that may affect cellular physiology when it is ted or stimulated by a ligand. Typically, a receptor comprises an ellular domain with ligand-binding properties, a transmembrane domain that anchors the receptor in the cell membrane, and a cytoplasmic domain that generates a cellular signal in response to ligand binding ("signal transduction"). A receptor also includes any intracellular molecule that in response to ligation generates a signal. A or also includes any molecule having the characteristic structure of a receptor, but with no identif1able ligand. In addition, a receptor includes a truncated, modif1ed, mutated receptor, or any molecule comprising partial or all of the sequences of a receptor.
"Ligand" is intended to include any substance that interacts with a receptor.
"Selective" or "selectivity" is defined as a compound's y to generate a desired response from a particular receptor type, subtype, class or subclass while generating less or little response from other receptor types. tive" or tivity" of one or more particular subtypes of a receptor means a compound's ability to se the activity of the subtypes while causing less, little or no se in the activity of other subtypes.
As used herein, "coadministration" of pharmacologically active compounds refers to the delivery of two or more separate chemical entities, whether in vitro or in vivo. Coadministration means the simultaneous delivery of te agents; the simultaneous delivery of a mixture of agents; as well as the delivery of one agent followed by delivery of a second agent or additional agents. Agents that are coadministered are typically intended to work in conjunction with each other.
The term "an effective amount" as used herein means an amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which es alleviation or tion of the symptoms of the disease being treated.
When used , "prevent/preventing" should not be construed to mean that a condition and/or a disease never might occur again after use of a nd or pharmaceutical composition according to ments disclosed herein to achieve tion. Further, the term should neither be construed to mean that a condition not might occur, at least to some extent, after such use to prevent said condition. Rather, "prevent/preventing" is intended to mean that the condition to be prevented, if occurring despite such use, will be less severe than Without such use.
Compounds According to one aspect compounds of Formula (1) R1 R4a WW (R4b)n k 7‘87 R6a N \N R6b l / ‘ Formula (I) or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and stereoisomers thereof, wherein: Y is NR or O; R is hydrogen or substituted or unsubstituted C1_4 alkyl; R1 is selected from the group consisting of hydrogen, -OH, halogen, substituted or tituted C1_4 alkyl, substituted or unsubstituted C1_4 alkoxy, and substituted or unsubstituted C24 alkenyl; R2 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1_4 alkyl, substituted or unsubstituted C1_4 alkoxy, -CN, and -OH ; or R and R2 are combined to form a substituted or unsubstituted fused ring; R3 is selected from the group consisting of en, halogen, -OH, substituted or unsubstituted C1_4 alkyl, substituted or unsubstituted C1_4 alkoxy, oxo, -C(=O)R10; R4a is selected from the group consisting of hydrogen, halogen, -OH, substituted or unsubstituted C1_6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1_6 alkenyl, substituted or unsubstituted C3-C6 cycloalkyl, tuted or unsubstituted aryl, substituted or unsubstituted aryl-C1_6 alkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroaryl-C1_6 alkyl; R4b is ed from the group consisting of hydrogen, halogen, oxo, -OH, substituted or unsubstituted C1_4 alkyl, substituted or unsubstituted C1_4 alkoxy, and - C(=O)R10; R5 is ed from the group consisting of -(CR8R9)pOR12, -(CR8R9)p- CR13R14R15, 9)p-C(=O)OR7, and 9)p-C(=O)NR8R9; n, m, and p are integers independently ed from the group consisting of 0, l, 2, 3 and 4; R681, R6b are independently selected from the group consisting of hydrogen, halogen, substituted or tituted C1_6 alkyl, substituted or unsubstituted C1_6 alkenyl, substituted or unsubstituted C2_6 alkynyl, substituted or unsubstituted C1_6 alkoxy, substituted or unsubstituted C1_6 heteroalkyl, substituted or unsubstituted C3_g cycloalkyl, substituted or unsubstituted C3_g cycloalkenyl, substituted or unsubstituted C2_9 alicyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, or R6a and R6b are taken together to form an oxo group or a ring system selected from substituted or unsubstituted C3_6 cycloalkyl, and substituted or tituted C2_9 heteroalicyclyl, or R6a and R13 are taken together to form a ring system selected from substituted or unsubstituted C3_6 cycloalkyl, and substituted or unsubstituted C2_5 heteroalicyclyl; R7, R8, R9, and R12, are independently selected from the group ting of en, substituted or unsubstituted C1_6 alkyl, substituted or unsubstituted C3_6 cycloalkyl, and tuted or unsubstituted C2_9 heteroalicyclyl; R10 is selected from the group consisting of C1_6 alkyl, C1_6 alkoxy, -OH, -NH2, -NH(C1_6 alkyl), -N(C1_6 alkyl)2, and C3_7 cycloalkyl; R13, if not to be taken together with R681, is absent, or selected from the group ting of hydrogen, -OH, -CN substituted or unsubstituted C1_6 alkyl, substituted or unsubstituted C1_6 alkenyl, substituted or unsubstituted C1_6 , substituted or unsubstituted C3_g cycloalkyl, substituted or unsubstituted C3_g cycloalkenyl, and - (CR8R9)p-C(=O)OR7, -(CR8R9)p-SOZR7 and -(CR8R9)p-C(=O)NR8R9; R14 and R15 are independently ed from the group consisting of en, and substituted or tituted C1_6 alkyl, substituted or unsubstituted C3_6 cyclo alkyl, and substituted or unsubstituted C2_9 heteroalicyclyl; or R14 and R15 are combined to form a ring system selected from the group consisting of substituted or unsubstituted C3_g cycloalkyl, tuted or unsubstituted C3_g cycloalkenyl, substituted or unsubstituted C2_9 heteroalicyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; B is a ring system selected from the group consisting of aryl, aryl, and bicyclic heteroalicyclyl, provided that it is not 5,6-dichloro-lH-benzo[d]imidazol—2—yl when R1 and R2 both are hydrogen; C is a ring system selected from C2_9 heteroalicyclyl ; wherein B is attached to a carbon atom nt the N atom of ring system C; and with the proviso the compound is not: "x M IZ Z / U are provided.
As with any group of structurally related compounds which possess a particular utility, certain embodiments of variables of the compounds of Formula (I) may be particularly useful in their end use application.
In some embodiments of the compounds of Formula (I), R and R2 in combination with the pyrimidine ring form a ring system selected from o[2,3- d]pyrimidine and 6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine. The ring system may be pyrrolo[2,3-d]pyrimidine.
In some embodiments according to Formula (I) B is a ring system selected from the group consisting of aryl, heteroaryl, and bicyclic alicyclyl, provided that it is not 5,6-dichloro-lH-benzo[d]imidazoleyl; i.e. 2015/067713 In some further embodiments according to a (I), B is a ring system selected from the group ting of aryl, monocyclic heteroaryl, and bicyclic heteroalicyclyl.In some embodiments of the compounds of Formula (I), R and R2 in combination with the pyrimidine ring form a pyrrolo[2,3-d]pyrimidine or 6,7-dihydro- SH-pyrrolo[2,3-d]pyrimidine. The compounds of Formula (I) may also have the Formula (Ila): Formula (Ila) wherein R4,, and KM are independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1_4 alkyl, substituted or tituted C1_4 alkoxy, and -OH. In preferred nds of Formula (IIa), R43 and R4d may be independently selected from the group consisting of hydrogen, methyl, and fluorine.
Embodiment disclosed herein below in relation to various groups, rings and substituents of compounds of a (I) are, as indicated, equally applicable to compounds of any one of the Formulae (IIa-IIe) provided below herein, provided that WO 20295 the relevant group, integer, ring and/or substituent is present in the Formula of concern, as readily appreciated by the skilled person.
According to another ment, the compounds of Formula (I), compounds of Formula (Ila), and compounds of any one of Formulae (IIb-IIe) as disclosed herein below, have R5 being -(CR8R9)p-C(=O)OR7 or -(CR8R9)p-C(=O)NR8R9, unless otherwise specified. In an alternative embodiment, the compounds of a (I), compounds of Formula (Ila), and compounds of any one of Formulae (IIb-IIe) have R5 being -(CR8R9)pOR12. In these embodiments, R7, R8, R9, and R12 are independently selected of each other from hydrogen, substituted or unsubstituted C1_6 alkyl, substituted or unsubstituted aryl—C1_6 alkyl and substituted or unsubstituted aryl. Preferred groups of R7, R8, R9, and R12 are selected from hydrogen, C1_6 alkyl, C1_6 haloalkyl, C1_6 hydroxyalkyl, and aryl, while even more preferred groups are selected from hydrogen, methyl, ethyl and tert—butyl. The integer p is preferably selected from 0, l or 2. In some embodiments, p is 0.
According to yet another embodiment, R5 is 9)p-CR13R14R15. In this embodiment it is preferred that R14 and R15 are combined to form a ring system. Further, the integer "p" may be 0 (zero), or 1. While it is not intended that the ring system be particular limited, preferred ring systems are selected from the group ting of substituted or unsubstituted C3_7 cycloalkyl, substituted or unsubstituted C3_7 cycloalkenyl, substituted or unsubstituted C2_6 heteroalicyclyl, substituted or unsubstituted aryl, and tuted or unsubstituted heteroaryl. For example, R14 and R15 may be combined to form a ring system selected from the group consisting of phenyl, yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, thietanyl, pyrrolyl, pyrazolyl imidazolyl, pyrrolidinyl, imidazolinyl, lidinyl, thiazolidinyl, isothiazolidinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, anyl, thiazolyl, isothiazolyl, l, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, anyl, dioxanyl, filryl, ofuranyl, furazanyl, tetrahydrofuryl, pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, dithiolanyl, dithianyl, thiopyranyl, thianyl, l, oxetanyl, quinolyl, isoquinolyl, indolyl, iso-indolyl, and tetrahydrothienyl, any of which may be substituted or unsubstituted. Preferably, R14 and R15 are combined to form a ring system selected from the group consisting of cycloheptyl, exyl, cyclopentyl, dioxanyl, furyl, imidazolyl, isothiazolyl, olyl, morpholinyl, oxazolyl, oxetanyl, oxathianyl, , piperidinyl, pyranyl, pyrazolidinyl, pyrazolyl, pyridyl, pyrimidyl, pyrrolidinyl, pyrrolyl, tetrahydrofilryl, ydropyranyl, tetrazolyl, thianyl, thiazolyl, thienyl, thiomorpholinyl, thiopyryl, and triazolyl, all of which may be tituted or substituted. Some embodiments relate to the ring system formed being phenyl, pyridyl, cyclopentyl, cyclohexyl, piperidyl, pyrrolidinyl, oxetanyl, and tetrahydropyranyl, all which may be substituted by (CH2)q(R5a) as defined herein. Some embodiments relate to the ring system being , pyridyl, piperidinyl yl, or cyclohexyl. In ments wherein R14 and R15 are combined to form an aromatic ring system, R13 is absent.
In a fiarther ment, the ring system formed by the combination of R14 and R15 is substituted with -(CH2)q(R5a) wherein R5a is independently selected from the group consisting of -CH2COOR20, -CH2CONR21R22, -CN, C1_6 alkyl, -CH2-imidazolyl, - CHz-SOZRZO, -CH2C(CH3)2(OR20), -OCH3, -CH2-triazolyl, -CF3, dimethyl substituted- imidazolyl-2,4-dione, -CH2-SOZNR21R22, morpholinyl, -C(=O)-morpholinyl, piperidyl- CHZORZO, -OCH2-tetrahydrofuryl, piperazinonyl, dinyl-CONR21R22, -OH, - CONR21R22, 20)CH3, -COOR20, -CH2-pyrrolidyl, C1_6 alkylene-OH, cyclopentyl, idonyl, tetrazolyl, -CH2- tetrazolyl, -CH20R20, acyl, -SOR20, -SOzR20, -COR20, - NR21SOZR20, -SOZNR21R22, and halogen; R20, R21, and R22 are independently of each other selected from the group consisting of hydrogen, substituted or unsubstituted C1_6 alkyl, -CN, tuted or tituted C3_6 cycloalkyl, substituted or unsubstituted C2_6 heteroalicyclyl; and q is an integer selected from 0, l or 2.
Of course the ring system formed by the combination of R14 and R15 may, in alternative embodiments, be substituted with groups other than -(CH2)q(R5a).
According to some embodiments, R13 is selected from the group consisting of hydrogen, -CN, CH3, fluorine, -OH, -CH20H, -OCH3, -CH2CH20H, -C02H, -COz-C1_4 alkyl, ZR20 and -CONR8R9 wherein R8 and R9 are independently of each other selected from hydrogen, C1_4 alkyl and C1_4 aminoalkyl or R8 and R9 are combined to form a C2-C6 heteroalicyclyl. Some ments relate to R13 taken together with R6a to form a ring system selected from the group consisting of substituted or unsubstituted C3_6 cycloalkyl and substituted or unsubstituted C25 heteroalicyclyl.
According to some embodiments, R13 is absent or hydrogen.
In some embodiments of the compounds of Formula (I), Y is NR. Further, while R may be selected from the group ting of hydrogen, C1_4 alkyl, C1_4 haloalkyl, and C1_4 hydroxyalkyl. In one embodiment R is hydrogen.
According to some embodiments, R1 is selected from the group consisting of hydrogen, n, substituted or unsubstituted C1_4 alkyl, and substituted or unsubstituted C1_4 alkoxy. R1 may thus include C1_4 kyl and C1_4 hydroxyalkyl groups. In some embodiments, R1 is hydrogen or CF3.
According to some embodiments, R2 is selected from the group consisting of hydrogen, halogen, C1_4 alkyl, C1_4 kyl, and C1_4 hydroxyalkyl. In some embdoiments, R2 is a halogen such as fluorine.
In some embodiments, the compounds of Formula (I), compounds of Formula (11a), and compounds of any one of Formulae (IIb-IIe), as sed herein may have an R3 group selected from hydrogen, halogen, C1_4 alkyl, C1_4 haloalkyl, C1_4 hydroxyalkyl, oxo, C1_4 alkoxy and C1_4 haloalkoxy, unless otherwise specified. ing to one embodiment R3 is selected from the group consisting of hydrogen, methyl, fluorine, chlorine and oxo. In some embodiments, R3 is hydrogen.
In some compounds of Formula (I), compounds of Formula (11a), and compounds of any one of Formulae (IIb-IIe), as disclosed herein the integer m is selected from 2, 3, or 4, and at least two of the R3 groups t are bound to the same atom of ring system C. This ment provides compounds with one or two geminally substituted atoms that are part of ring system C. In some embodiments, R3 is flouro, such as geminally arranged fluoro atoms.
According to some embodiments ofthe compounds of Formula (I), compounds of a (11a), and compounds of any one of Formulae (IIb-IIe), as disclosed herein, R4a is selected from the group consisting of hydrogen, halogen, C1_6 alkyl, C1_6 haloalkyl, C1_6 hydroxyalkyl, C1-C6 alkoxy, C1_6 haloalkoxy, heteroaryl and aryl. In some embdoiments R4a groups are selected from the group consisting of methyl, ethyl, propyl, opyl, tert—butyl, ne, bromine, fluorine, methoxy, ethoxy, C1_2 haloalkyl, C1_2 haloalkoxy and triazolyl. In some embodiments R4a groups are -CF3, - CF2CF3, -CHF2, -OCF3, -OCF2CF3, and -OCHF2. In some embodiments R4a is selected from the group ting of pyl, halogen, ethoxy, CF3, -OCF3.
In some embodiments, wherein the ring system B is 6-membered aryl or heteroaryl, R4a is arranged in the para- or meta-position, in relation to the the carbon carrying ring system C.
According to some embodiments, R4b is selected from hydrogen, oxo, halogen, C1_4 alkyl, C1_4 haloalkyl, C1_4 hydroxyalkyl, C1-C4 alkoxy, and C1_4 haloalkoxy. In this ment, R4b may be further selected from methyl, ethyl, propyl, iso-propyl, tert- butyl, chlorine, bromine, fluorine, methoxy, ethoxy, -OH, C1_2 haloalkyl, and C1_2 haloalkoxy. es of R4, groups comprise -CF3, and -OCHF2. In , -CHF2, -OCF3, , some embodiments R4b is hydrogen.
Some embodiments relate to R4a being selected from the group consisting of methyl, ethyl, propyl, iso-propyl, utyl, chlorine, bromine, e, methoxy, ethoxy, C1_2 haloalkyl, C1_2 haloalkoxy, and triazolyl arranged in the above mentioned para- or meta-position, and R4b being en.
In some embodiments of the nds of of a (1), compounds of Formula (Ila), and compounds of any one of Formulae (IIb-IIe), as disclosed herein, R6a is selected from the group ting of hydrogen, substituted or unsubstituted C1_6 alkyl, substituted or unsubstituted C1_6 alkoxy, and substituted or unsubstituted aryl, or R6a and R13 are taken together to form a ring system selected from substituted or unsubstituted C3_6 cycloalkyl, and substituted or unsubstituted C2_9 heteroalicyclyl.
Further es of R6a are selected from hydrogen, C1_6 alkyl, C1_6 haloalkyl, C1_6 hydroxyalkyl, C1-6 alkoxy, C1_6 koxy, and aryl. It is preferred however, that R6a is hydrogen.
According to some embodiments, R6b is selected from hydrogen, substituted or unsubstituted C1_6 alkyl, substituted or unsubstituted C1_6 alkoxy, substituted or unsubstituted aryl—C1_6 alkyl, substituted or unsubstituted C2_9 heteroalicyclyl—C1_6 alkyl, and substituted or unsubstituted aryl in the compounds of Formula (1). Thus, R6b may be hydrogen, C1_6 alkyl, C1_6 haloalkyl, C1_6 hydroxyalkyl, C1-C6 alkoxy, C1_6 haloalkoxy, C1_6-alkoxy-C1_6-alkyl-, aryl-C1_6 alkyl-, C2_9 heteroalicyclyl-C1_4 alkyl-, lkoxy- aryl-, haloaryl, and aryl. Particular examples of compounds of Formula (I) have an R6b group selected from hydrogen, -(CH2)C(CH3)3, -(CH2)CONH2, phenyl, phenyl substituted with l to 3 halogens, -CH(CH3)OC(CH3)3, -CH2-phenyl-OCH3, -phenyl- OCH3, -CH2-pyridyl, CHz-cyclohexyl-CHZCOZH, -CH2-cyclohexyl-CHZCONHZCHZ- exyl-CHg-tetrazolyl, -CH2-cyclohexyl-CH20H, -CH2-cyclohexyl-NHSOZCHg, _ clohexyl-NHSOZCHZCFg, _CH2-cyclohexyl-CH2CN, -CH2-phenyl-CH2C02H, - CHz-phenyl-CHZCONH; -CH2-phenyl-CH2CONH2CH3, -CH2-phenyl-CH2-tetrazolyl, - enyl-CONHZ, -CH2-phenyl-SOZNH-cyclopropyl, -CH2-phenyl-SOZCH3, -CH2- phenyl-NHSOZCF3, -CH2-phenyl-NHSOZCH3, -CH2-phenyl-NHSOZCHF2, -CH2-pyridyl- CH3, -CH2-pyridyl-SOZCH3, -CH2-pyridyl-CH2CONH2, -CH2-pyrimidyl-NHSOZCH3, - CHz-piperidyl-COCHg, -CH2-piperidyl-SOZCH3, -CH2-piperidyl-SOZCF3, -CH2-thienyl- CHZCOZH, -CH2-cyclobutyl-CH2C02H, -CH2-cyclobutyl-CHZCONHZ, -CH2-cyclobutyl- COZH, -CH2-cyclobutyl-CONH2, -CH2-tetrahydrothiopyryl, -CH2-cyclopentyl, -CH2- cyclohexyl, -CH2-tetrahydrofi1ranyl, -CH2-tetrahydropyranyl, -CH2-oxetanyl, and -CH2- pyranyl.
Some embodiments relate to R6a and R6b being taken together to form a ring system selected from tuted or unsubstituted C3_6 cycloalkyl, substituted or tituted C2_9 heteroalicyclyl.
Ring system B in compounds of of Formula (I), compounds of Formula (Ila), and nds of any one of ae (IIb-IIe), as disclosed herein is not intended to be particularly limited, unless otherwise indicated. In some embodiments, ring system B is a mono- or bicyclic aryl, a mono- or bicyclic aryl, or a bicyclic alicyclyl.
Further, ring system B may be a monocyclic heteroalicyclyl. Ring system B may, but need not, be tuted With at least one of R4a or R4, that is a non-hydrogen substituent. Compounds of of Formula (1), compounds of Formula (Ila), and compounds of any one of Formulae (IIb-IIe), as disclosed herein, may also have a ring system B that is a mono-cyclic, 6-membered aryl or heteroaryl substituted With R4a. In some embodiments ring system B is selected from the group consisting of phenyl, pyridyl, pyridazinyl, pyrimidinyl, naphthyl and filranyl, such as from the group consisting of , pyridyl, and pyrimidinyl. Some ments ring system B is selected from the group consisting of phenyl, and pyridyl. In some embodiments, n is an integer selected from 1, 2, 3 and 4. Alternatively, 11 may be 0 g that R4a will be the only substituent on ring system B.
In some embodiments, the ring B is a bicyclic ring system, such as bicyclic aryl, bicyclic heteroaryl, or bicyclic heteroalicyclyl ring systems, e.g. benzazepine, benzazocines, benzimidazole, benzimidazoline, benzodioxin, benzodioxole, benzofilran, benzoisothiazole, benzothiadiazine, benzothiadiazole, benzothiazepine, benzothiazine, benzothiazole, benzothiophene, benzotriazole, benzoxadiazole, benzoxathiole, benzoxazepine, benzoxazine, benzoxazole, benzisoxazole, benzodioxole, chromane, chromene, coumarin, cyclopentapyridine, cyclopentapyrimidine, diazanaphthalene, dioxolopyridine, dioxolopyrimidine, dihydrobenzodioxine, dihydrobenzooxathiine, furofuran, furopyridine, furopyridine, rimidine, imidazopyridine, imidazopyrimidines, indane, indazole, indene, indole, indoline, indolizines, isobenzofuran, omenes, isoindole, isoindoline, noline, naphthalene, naphthyridine, oxathiolopyridine, olopyrimidine, oxazolopyridine, oxazolopyrimidine, pteridine, purine, pyranopyridine, pyranopyrimidine, pyrazolodiazepines, pyrazolopyridine, pyrazolopyrimidine, pyridobenzthiazine, pyridodiazepene, pyridooxazine, pyridopyrazine, pyridopyrimidine, pyridothiazine, pyrimidooxazine, pyrimidopyrimidine, pyrimidothiazine, pyrrolizine, pyrroloimidazole, pyrrolopyrazine, pyrrolopyridine, pyrrolopyrimidine, quinazoline, quinoline, quinolone, quinolizidine, quinoxaline, tetralin, thiazolopyridine, thiazolopyrimidine, thienodiazepine, thienopyridine, pyrimidine, thiochromane, thiochromene, ranopyridine, thiopyranopyrimidine, triazolopyridazine, triazolopyridine or triazolopyrimidine, all of which may be unsubstituted or substituted.
Like ring system B, the ring system C in compounds of Formula (I), compounds of Formula (Ila), and compounds of any one of Formulae Ie), as disclosed herein, is not intended to be particularly limited in scope, unless otherwise specified. According to one embodiment, ring system C is a C2_9 heteroalicycllen some embodiments ring system C is a 4membered alicyclyl. For example, ring system C may be pyrrolidinyl or linyl.
The r values of n and m may take any ular combination. In one ment, m is l or 2. Further, m may be 0 (zero) meaning that the ring system C is unsubstituted. In another embodiment, n is an integer selected from 1, 2, 3 and 4.
Alternatively, 11 may be 0 meaning that R4a will be the only substituent on ring system B. Alternatively, 11 may be 0 and R4a hydrogen, i.e. the ring system B is unsubstituted.
According to yet another embodiment, the compounds of Formula (I), nds of Formula (11a), and compounds of any one of Formulae (IIb-IIe), as disclosed herein, have R5 being -(CR8R9)p-C(=O)NR8R9; R8 and R9 are independently of each other ed from H and substituted or unsubstituted C1_6 alkyl; p is 0; and R6b is hydrogen or -(CH2)C(CH3)3.
Compounds disclosed herein may also comprise compounds of Formula (IIb): WO 20295 (Ram Formula (IIb) C is a pyrrolidine ring or a morpholine ring; R1 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1_4 alkyl, and substituted or unsubstituted C1_4 alkoxy; some compounds of Formula (IIb) have an R1 that is hydrogen or -CF3; R3 is independently selected from the group consisting of hydrogen, substituted or unsubstituted C1_4 alkyl, and halogen; R4a is selected from the group consisting of hydrogen, halogen, -OH, substituted or unsubstituted C1_6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1_6 l, tuted or unsubstituted aryl, substituted or unsubstituted aryl—C1_6 alkyl, substituted or unsubstituted heteroaryl, tuted or tituted heteroaryl—C1_6 alkyl; some compounds of Formula (11b) have an R4a that is selected from the group consisting of n, -CF3, -OCF3, iso-propyl, tert—butyl, - C1_6 alkoxy, C1_6 alkoxy tuted with one or more halogens, and phenyl; R4b is independently selected from the group consisting of hydrogen, halogen, - OH, substituted or unsubstituted C1_4 alkyl, substituted or unsubstituted C1_4 alkoxy, - C(ZO)R10; R5 is selected from the group consisting of substituted or unsubstituted C3_7 cycloalkyl, substituted or unsubstituted C3_7 cycloalkenyl, substituted or unsubstituted C2_6 heteroalicyclyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; R6a are R6b are independently selected from the group consisting of hydrogen and substituted or unsubstituted C1_6 alkyl; and m is an r ndently selected from the group consisting of l, 2, and 3; n is an r independently selected from the group consisting of l, 2, 3, and In compounds of a (11b), R5 may be selected from the group consisting of substituted or unsubstituted C4_7 cycloalkyl, substituted or unsubstituted C642 membered aryl, substituted or tituted 4-membered heteroalicyclyl, substituted or unsubstituted 5-membered aryl, substituted or unsubstituted 5-membered alicyclyl, substituted or unsubstituted 6-membered heteroaryl, a substituted or unsubstituted 6-membered heteroalicyclyl, substituted or unsubstituted 7-membered heteroaryl, and a substituted or unsubstituted 7-membered heteroalicyclyl. Thus, R5 may be ed from the group consisting ofphenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, thietanyl, pyrrolyl, pyrazoleyl imidazolyl, pyrrolidinyl, imidazolinyl, pyrazolidinyl, thiazolidinyl, isothiazolidinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, oxathianyl thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, piperidinyl, zinyl, morpholinyl, thiomorpholinyl, dioxolanyl, dioxanyl, furyl, dihydrofuranyl, filrazanyl, tetrahydrofilryl, pyranyl, ydropyranyl, tetrahydrothiopyranyl, dithiolanyl, nyl, thiopyranyl, thianyl, thienyl, oxetanyl, quinolyl, isoquinolyl, indolyl, isoindolyl , and tetrahydrothienyl, any of which may be substituted or unsubstituted. ally, R5 may be selected from the group consisting of cycloheptyl, cyclohexyl, cyclopentyl, dioxanyl, furyl, imidazolyl, azolyl, isoxazolyl, morpholinyl, oxazolyl, oxetanyl, oxathianyl, phenyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazolyl, pyridyl, dyl, pyrrolidinyl, pyrrolyl, tetrahydrofilryl, tetrahydropyranyl, tetrazolyl, thianyl, thiazolyl, thienyl, thiomorpholinyl, thiopyryl, and triazolyl, any ofwhich may be substituted or unsubstituted.
If substituted, R5 may be substituted with -(CH2)q(R5a), wherein R5a is independently selected from the group consisting of -CH2COOR20, -CH2CONR21R22, oxo, -CN, N, C1_6 alkyl, -CH2-imidazolyl, -CH2-SOZR20, -CH2C(CH3)2(OR20), - ORZO, riazolyl, -CF3, dimethyl substituted-imidazolyl-2,4-dione, -CH2- SOzNR21R22, morpholinyl, -C(=O)-morpholinyl, piperidyl-CHZORZO, -OCH2- tetrahydrofilryl, zinonyl, piperidinyl-CONR21R22, -OH, -CONR21R22, - CH(OR20)CH3, -COOR20, -CH2-pyrrolidyl, C1_6 alkylene-OH, cyclopentyl, pyrrolidonyl, , -NR21802R20, olyl, -CH2-tetrazolyl, -CH20R20, acyl, -SOR20, -SOgR20, -SOzR20, -SOZNR21R22, and n; R20, R21, and R22 are ndently of each other selected from the group consisting of hydrogen, substituted or unsubstituted C1_6 alkyl, -CN, substituted or unsubstituted C3_6 cycloalkyl, tuted or unsubstituted C2_6 heteroalicyclyl; and q is an integer selected from 0, l or 2.
Further, R5 may be selected from the group consisting of unsubstituted aryl, unsubstituted heteroaryl, aryl substituted with one or more C1_6 alkoxy, aryl substituted with -CH2COOC1_6 alkyl, aryl substituted with -CH2CONH-(C1_6 alkyl), aryl tuted with (C1_6 alkyl)2, -(CH2)-C(=O)OR7, -C(=O)OR7, _(CH2)-C(=O)NR8R9 or - C(=O)NR8R9, aryl substituted with _(CH2)-C(=O)NR8R9 or SOZR7, and C2_9 heteroalicyclyl substituted with _(CH2)-C(=O)NR8R9 or SOZR7; R7, R8, and R9 are independently selected from the group consisting of hydrogen, unsubstituted C1_6 alkyl, and C1_6 ne substituted with fiaranyl.
Compounds disclosed herein may also comprise compounds of Formula (11c): R4a M, (R4b)n 7‘37 Formula (IIc) wherein: R3 is hydrogen, fluorine or methyl; R4a is selected from the group consisting of hydrogen, fluorine, chlorine, - C(CH3)3, -CH2(CH3)2, -CF3, -OCH3, -OC(CH3)3, and -OCF3; R4b is selected from the group consisting of hydrogen, fluorine, chlorine, and - OCH3; m and n are integers independently selected from 1 or 2; Y is 0R7 or NR8R9; R7, R8, and R9 are independently selected from H and C1_6 alkyl; and B is selected from the group consisting of phenyl, pyridyl, dinyl, 2- benzothiazolyl, quinolinyl, and l,4-benzodioxanyl; and C is pyrrolidinyl or morpholinyl. nds disclosed herein may also comprise nds of Formula (11d): Formula (IId) wherein: B is ed from , pyridyl and pyrimidyl; C is pyrrolidinyl or morpholinyl; R4a is a substituent arrange in para- or meta-position compared to the carbon atom in the ring system C, and selected from the group consisting of hydrogen, halogen, C1_4 alkyl, C1-4 alkoxy, C1_4 haloalkyl (for example —CF3), C1_4 haloalkoxy (for example —OCF3), and aryl; R5 is a ring selected from the group consisting of phenyl, pyrimidinyl, pyridyl, pyridinyl-N-oxide, cyclohexyl, pyrrolyl, pyrazolyl, furanyl, pyrrolidonyl, tetrahydrofuranyl, tetrahydropyranyl, benzopyrrolidonyl, cyclobutyl, oxetanyl, tetrahydrothiophenyl, ydro-2H—thiopyranyl, cyclopentyl, cycloheptanyl, tetrahydrothiophenyl- l , l -dioxide, tetrahydro-2H—thiopyranyl- l , l -dioxide, 1 ,4- oxathianyl-4,4-dioxide, and piperidinyl, any of which may be unsubstituted or substituted with (RSb)t; R5b, when present, is independently selected from the group consisting of - CHZCOORZO, -CH2CONR21R22, oxo, -CN, -CH2-CN, -C1_6 alkyl, -CH2-imidazolyl, - CH2-SO2R20, -CH2C(CH3)2(OR20), -OR20, -CH2-triazolyl, -CF3, dimethyl substituted- imidazolidinyl-2,4-dione, -CH2-SO2NR21R22, linyl, -C(=O)-morpholinyl, piperazinonyl, piperidinyl-CONR21R22, -OH, -COR20, -CONR21R22, -CH(OR20)CH3, - , -CH2-pyrrolidonyl, -C1_6-alkylene-OH, -cyclopentyl, -pyrrolidonyl, -tetrazolyl, -CH2-triazolyl, -CH2OR20, -acyl, -SOR20, -SO2R20, -SO2NR21R22, -NR21802R20, and halogen; R20, R21, and R22 are independently selected from H, -C1_6 alkyl, -C1_6 haloalkyl, -C3_6 cycloalkyl, and -C1_6 heteroalicyclyl; and t is an integer selected from 1 or 2.
Compounds disclosed herein may also comprise compounds of Formula (He): (R3)m (He), or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and stereoisomers thereof, wherein: n, p and V are an integer selected from 0,1 and 2; R is hydrogen or C1_4 alkyl; R1 is ed from the group consisting of hydrogen, -OH, halogen, substituted or unsubstituted C1_4 alkyl, and substituted or unsubstituted C1_4 alkoxy; R2 is selected from the group consisting of hydrogen, halogen, C1_4 alkyl, C1_4 haloalkyl, and C1_4 hydroxyalkyl; or R and R2 are combined to form a fused ring; R3 is selected from the group consisting of hydrogen, halogen, -OH, substituted or unsubstituted C1_4 alkyl, tuted or unsubstituted C1_4 , oxo, and -C(=O)R10; R4a is selected from the group consisting of hydrogen, halogen, -OH, substituted or unsubstituted C1_6 alkyl, substituted or unsubstituted C1-C6 alkoxy, tuted or unsubstituted C1_6 alkenyl, substituted or tituted aryl, substituted or unsubstituted aryl-C1_6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or tituted heteroaryl, and substituted or unsubstituted heteroaryl-C1_6 alkyl; R4b is ed from the group consisting of hydrogen, oxo, halogen, -OH, tuted or unsubstituted C1_4 alkyl, and substituted or unsubstituted C1_4 alkoxy, - C(ZO)R10; R5a is selected from the group consisting of hydrogen, halogen, oxo, -CN, -OH, substituted or unsubstituted C1_6 alkyl, substituted or tituted C1_6 alkenyl, substituted or unsubstituted C1_6 alkoxy, substituted or unsubstituted C3_g cycloalkyl, substituted or unsubstituted C3_g cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl-C1_6 alkyl, substituted or unsubstituted C2-C8 alicyclyl, substituted or unsubstituted C2-C8 heteroalicyclyl—C1_6 alkyl, tuted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryl—C1_6 alkyl, - (CH2)qCO2R20, q-CONR20R21, -(CH2)q-SOR20, -(CH2)q-SO2R20, -(CH2)q- SO2NR21R22, and -(CH2)qNR2lsO2R20; q is an integer selected from 0 or 1; R20, R21, and R22 are independently of each other selected from the group consisting of hydrogen, substituted or unsubstituted C1_6 alkyl, -CN, substituted or unsubstituted C3_6 lkyl, and substituted or unsubstituted C2_6 alicyclyl, or R21 and R22 are ed to form a C3_6 cycloalkyl; R681, R6b are independently selected from the group consisting of hydrogen, substituted or unsubstituted C1_6 alkyl, substituted or unsubstituted C1_6 alkenyl, substituted or unsubstituted C2_6 alkynyl, substituted or unsubstituted C1_6 alkoxy, substituted or unsubstituted C1_6 heteroalkyl, substituted or unsubstituted C3_g cycloalkyl, substituted or unsubstituted C3_g cycloalkenyl, substituted or unsubstituted C2_9 heteroalicyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, or R6a and R6b are taken together to form and oxo group or a ring system selected from substituted or unsubstituted C3_6 cycloalkyl, and substituted or unsubstituted C2_9 heteroalicyclyl, or R6a and R13 are taken together to form a ring system ed from substituted or unsubstituted C3_6 lkyl, and substituted or unsubstituted C2_5 heteroalicyclyl; R7, R8, and R9 are independently selected from the group ting of hydrogen, substituted or unsubstituted C1_6 alkyl, substituted or unsubstituted C3_6 cycloalkyl, and substituted or tituted C2_9 heteroalicyclyl; R10 is ed from the group consisting of C1_6 alkyl, C1_6 alkoxy, -OH, -NH2, -NH(C1_6 alkyl), -N(C1_6 alkyl)2, and C3_7 cycloalkyl; R13, if not to be taken together with R681, is absent, or selected from the group consisting of hydrogen, -CN, -OH, substituted or unsubstituted C1_6 alkyl, substituted or unsubstituted C1_6 l, substituted or unsubstituted C1_6 alkoxy, substituted or unsubstituted C3_g cycloalkyl, substituted or tituted C3_g cycloalkenyl, and - (CR8R9)p-C(=O)OR7, -(CR8R9)p-SOZR7 and -(CR8R9)p-C(=O)NR8R9; B is a ring system selected from the group consisting of aryl, heteroaryl, and, C2-C9 bicyclic heteroalicyclyl; D is a ring system selected from the group ting of aryl, heteroaryl, C3_g cycloalkyl and, C2-C9 heteroalicyclyl, C is a ring system selected from C2_9 heteroalicyclyl, and with the proviso the compound is not: IZ Z / U Some embodiments relates to the compound according to a (He) wherein R3 is selected from the group consisting of hydrogen, halogen, C1_4 alkyl, C1_4 haloalkyl, C1_4 hydroxyalkyl, oxo, C1_4 alkoxy and C1_4 haloalkoxy; R4a is selected from the group consisting of en, n, C1_4 alkyl, C1-4 alkoxy, C1_4 haloalkyl, C1_4 haloalkoxy, and aryl; R4b is selected from the group consisting of hydrogen, oxo, halogen, C1_4 alkyl, C1_4 haloalkyl, C1_4 hydroxyalkyl, C1_4 alkoxy, and C1_4 haloalkoxy; R6a is selected from the group consisting of hydrogen, halogen, C1_6 alkyl, C1_6 haloalkyl, C1_6 hydroxyalkyl, C1_6 alkoxy, and C1_6 haloalkoxy; R6b is selected from the group ting of hydrogen, C1_6 alkyl, C1_6 haloalkyl, C1_6 hydroxyalkyl, C1_6 alkoxy, C1_6 alkoxy-C1_6 alkyl, C1_6 haloalkoxy, aryl- C1_6 alkyl, substituted or unsubstituted C2_9 heteroalicyclyl-C1_6 alkyl, and substituted or unsubstituted aryl; or R6,, and R6,, are taken together to form and oxo group or a ring system selected from substituted or unsubstituted C3_6 cycloalkyl, and tuted or unsubstituted C2_9 heteroalicyclyl, or R6,, and R13 are taken together to form a ring system selected from substituted or unsubstituted C3_6 cycloalkyl, and substituted or unsubstituted C25 heteroalicyclyl; In some embodiments the compounds of Formula (I), compounds of a (Ila), and compounds of any one of Formulae (IIb-IIe), as sed herein, B is aryl or aryl, for example phenyl, pyridyl, pyrazolyl, zinyl, pyrimidinyl, naphthyl and furanyl, unless otherwise specified. Some embodiments relates to B being phenyl, pyrimidyl or pyridyl.
In some embodiments the compounds of Formula (I), compounds of Formula (11a), and compounds of any one of Formulae (IIb-IIe), as disclosed herein, B is a 6- ed aryl tuted with R4, in the para-position or meta-position, a 6- membered heteroaryl substituted with R4, in the para-position or meta-position, or a 5- membered heteroaryl substituted with R4, in 2- or 3-position, unless otherwise specified.
In some embodiments the 6-membered aryl is phenyl and the 6-membered heteroaryl is pyridyl or pyrimidinyl. Some embodiments relate to R4, being selected from the group consisting of halogen, -CN, C1_4 alkyl, C1_4 haloalkyl, C1-C4 alkoxy, C1_4 haloalkoxy and heteroaryl, for example isopropyl, -CN, ethoxy, CF3, and -OCF3. Some embodiments relate to R4,, being selected from the group consisting of hydrogen, oxo, halogen, C1_4 alkyl, C1_4 haloalkyl, C1_4 hydroxyalkyl, C1-C4 , C1_4 haloalkoxy, and heteroaryl.
Some embodiments relate to R4, being selected from the group consisting of halogen, - CN, C1_4 alkyl, C1_4 haloalkyl, C1-C4 alkoxy, and C1_4 haloalkoxy, for example isopropyl, ethoxy, -CF3, -CHF2, -OCF3, and -OCHF2 and R4,, being selected from the group consisting of hydrogen, halogen, and -OH.
In some embodiments the compounds of Formulae (IIe), D is selected from the group ting of aryl, such as phenyl; heteroaryl, such as pyridyl, and pyrimidyl; C3_g cycloalkyl, such as cyclohexyl; and C24; heteroalicyclyl, such as piperidyl, ydro- anyl, thiopyranyl, tetrahydro-2H-thiopyranyl, tetrahydro-2H-thiopyranyl- l , l - dioxide, idinyl, thianyl and oxetanyl, all which may be substituted with one or more R5,. Some embodiments relates to R5,, being selected from hydrogen, C1_6 alkyl, such as methyl and ethyl; C1_6 hydroxyalkyl, such as methanol and ethanol; -(CH2)q-CN; -(CH2)q-CO2R20; q-C1_6 alkoxy, such as methoxy and ethoxy and methoxyethyl; oxo, -(CH2)q-heteroaryl, such as —(CH2-)q-tetrazolyl, —(CH2-)q-imidazolyl, —(CH2-)q- triazolyl; —(CH2-)q-CONR20R21; —(CH2-)q-COR20; —(CH2-)q-SO2R20; —(CH2-)q- NR2180R20; and —(CH2-)q-SO2NR21R22; R20, R21, and R22 are independently of each other selected from the group consisting of hydrogen, -OH, substituted or unsubstituted C1_6 alkyl, -CN, substituted or unsubstituted C3_6 cycloalkyl, and substituted or unsubstituted C2_6 heteroalicyclyl, or R21 and R22 are combined to form a C3_6 cycloalkyl; and q is an integer selected from 0 or 1.
As for any given group disclosed herein,the ring system D may comprise further hydrogen(s) than the one(s) provided by R5a being hydrogen.
In some ments R20, R21, and R22 are independently of each other selected from the group consisting of hydrogen, methyl, ethyl, cyclopropyl, -CF3, and - CHF2, In some embodiments the compunds of Formula (1), compounds of Formula (Ila), and compounds of any one of ae (IIb-IIe), as disclosed herein, R13 is absent, or ed from the group consisting of hydrogen, -OH, -CN, C1_4 hydroxyalkyl, C1_6 haloalkyl, —(CH2-)qCO2H, —(CH2-)q-SO2R20, —(CH2-)q-NR21802R20 and C1_6 alkoxy, or R13 combined with the atom to which it is attached and an adjacent R5a to form a C3_5 cycloalkyl, or C2-4 heteroalicyclyl.
In some ments the compounds of Formula (1), compounds of Formula (11a), and compounds of any one of Formulae (IIb-IIe), as disclosed , R6a is hydrogen, or combined with Rsa, R6b or R13 to form ring system such as a C3_6 cycloalkyl or C2_5-heteroalicyclyl; R6b is hydrogen or absent. In some embodiments both R6a and R6b are hydrogen.
In some embodiments the compounds according to a (IIe) R is hydrogen; R2 is selected from Cl or F; or R and R2 are combined to form a pyrrolo[2,3-d]pyrimidine, hydro-5H-pyrrolo[2,3-d]pyrimidine; m is an r selected from 0,1 and 2; n is an integer selected from 0 and l; V is an integer selected from 0 and 1; R3 is hydrogen or fluoro B is aryl or aryl, for example phenyl, pyridyl, pyrazolyl, pyridazinyl, pyrimidinyl, naphthyl or filranyl; C is C2_9 heteroalicyclyl, for example pyrrolidinyl or morpholinyl; R4a is ed from the group consisting of halogen, C1_4 alkyl, C1_4 haloalkyl, C1-C4 alkoxy, C1_4 haloalkoxy and heteroaryl, for example -CF3, -CHF2, -OCF3, - OCHF2, and triazolyl; R4b is selected from the group consisting of hydrogen, -OH, oxo, halogen, C1_4 alkyl, C1_4 haloalkyl, C1_4 hydroxyalkyl, C1-C4 , C1_4 haloalkoxy, and heteroaryl.
D is selected from the group ting of aryl, such as phenyl; heteroaryl, such as pyridyl, and dyl; C3_g cycloalkyl, such as cyclopentyl and cyclohexyl; and C2_g heteroalicyclyl, such as a mono-cyclic or a bridged C2_g heteroalicyclyl, such as piperidyl, tetrahydro-2H-pyranyl , thiopyranyl, tetrahydro-2H-thiopyranyl, tetrahydro- 2H-thiopyranyl-l,l-dioxide, oxetanyl, tropanyl, and pyrrolidinyl, all which may be substituted with one or more Rsa; R5a is selected from halogen, C1_6 alkyl, such as methyl and ethyl; C1_6 hydroxyalkyl, such as methanol and ethanol; C1_6 haloalkyl, such as —CF3, -(CH2)q-CN; -(CH2)q-acyl; -(CH2)q-C1_6 alkoxy, such as methoxy and ethoxy and methoxyethyl; - -heteroaryl, such as —(CH2-)q-tetrazolyl, —(CH2-)q-imidazolyl, —(CH2-)q-triazolyl; —(CH2-)q-CONR20R21; —(CH2-)q-COR20; )q-SO2R20; —(CH2-)q-NR2180R20; — (CH2-)q-SO2NR21R22; R20, R21, and R22 are independently of each other selected from the group consisting of hydrogen, -OH, substituted or unsubstituted C1_6 alkyl, -CN, substituted or unsubstituted C3_6 cycloalkyl, and substituted or unsubstituted C2_6 heteroalicyclyl, or R21 and R22 are combined to form a C3_6 cycloalkyl; and q is an integer selected from 0 or 1; R13 is absent, or selected from the group consisting of hydrogen, -OH,—CN, C1- 4 hydroxyalkyl, C1_6 haloalkyl, —(CH2-)q-SOZR20, )q-NR21SOZR20 and C1_6 alkoxy, or R13 combined with the atom to which it is attached and an adjacent R5a to form a C3_5 cycloalkyl, or C2-4 heteroalicyclyl; In some ments R13 is absent or hydrogen.
R6a is hydrogen, or ed with Rsa, R6b or R13 to form ring system such as a C3_6 cycloalkyl or C2_5-heteroalicyclyl; R6b is en or absent; for example both R6a and R6b are hydrogen.
In such an embodiment, B may be phenyl or l. Further, B may be phenyl with R4a in the para-position or meta-position, or a 6-membered heteroaryl substituted with R4a in the para-position or meta-position, or a 5-membered heteroaryl substituted with R4a in 2- or 3-position, wherein R4a is selected from a group other than hydrogen.
According to one aspect disclosed herein are compounds of Formula (X) Formula (X) or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and stereoisomers thereof, wherein: Y1 is NR or 0; Y2 is N or C; R is hydrogen or substituted or unsubstituted C1_4 alkyl; R1 is selected from the group consisting of hydrogen, -OH, halogen, -CN, - N02, -NH2, alkylamino, amide, acyl, ester, O-carboxy, mercapto, alkylthio, io, carbonyl, thisocarbonyl, C amido, N amido, S-sulfonamido, N sulfonamide, silyl, sulfenyl, sulfinyl, sulfonyl, substituted or unsubstituted C1_6 alkyl, substituted or unsubstituted C1_6 ,substituted or tituted C1_6 alkenyl, substituted or unsubstituted C2_6 alkynyl, substituted or unsubstituted C1_6 heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3_9 cycloalkyl, tuted or unsubstituted C3_g cycloalkenyl, substituted or unsubstituted C2_9 heteroaliyclyl; R2 is selected from the group consisting of hydrogen, -OH, halogen, -CN, - N02, -NH2, alkylamino, amide, acyl, ester, oxy, mercapto, alkylthio, arylthio, carbonyl, thisocarbonyl, C amido, N amido, S-sulfonamido, N amide, silyl, sulfenyl, sulfinyl, sulfonyl, substituted or unsubstituted C1_6 alkyl, substituted or unsubstituted C1_6 ,substituted or unsubstituted C1_6 alkenyl, substituted or unsubstituted C2_6 alkynyl, tuted or unsubstituted C1_6 heteroalkyl, substituted or WO 20295 2015/067713 unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3_9 cycloalkyl, substituted or unsubstituted C3_g cycloalkenyl, substituted or unsubstituted C2_9 heteroaliyclyl; or R and R2 are combined to form a fused ring; R4a is selected from the group consisting of hydrogen, halogen, -OH, tuted or unsubstituted C1_6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1_6 alkenyl, tuted or unsubstituted aryl, substituted or unsubstituted aryl—C1_6 alkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl-C1_6 alkyl; R3 and R4, are independently selected from the group consisting of hydrogen, halogen, -OH, substituted or unsubstituted C1_4 alkyl, substituted or unsubstituted C1_4 alkoxy, -C(=O)R10; R5 is selected from the group consisting of -(CR8R9)pOR12, 9)p- CR13R14R15, -(CR8R9)p-C(=O)OR7, and -(CR8R9)p-C(=O)NR8R9; n, m, and p are integers independently selected from the group ting of 0, l, 2, 3 and 4; R681, R6b are independently selected from the group consisting of en, substituted or unsubstituted C1_6 alkyl, substituted or unsubstituted C1_6 alkenyl, substituted or unsubstituted C1_6 alkynyl, substituted or tituted C1_6 alkoxy, substituted or unsubstituted C1_6 heteroalkyl, substituted or unsubstituted C3_g cycloalkyl, substituted or unsubstituted C3_g cycloalkenyl, substituted or unsubstituted C2_9 alicyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R7, R8, R9, and R12, are independently selected from the group consisting of hydrogen, substituted or unsubstituted C1_6 alkyl, substituted or unsubstituted C3_6 cycloalkyl, and substituted or unsubstituted C2_9 heteroalicyclyl; R10 is selected from the group consisting of C1_6 alkyl, C1_6 alkoxy, -NH2, - 6 alkyl), -N(C1_6 all In yet a related embodiment A is selected from the group consisting ofphenyl, pyridyl, pyrimidinyl, and n R1 is arranged in on 1 of the 6 ed ring, R1 is arranged in position 4 of the 6 membered ring, Y1 arranged in position 3 of the 6 membered ring, Y2 arranged in on 5 of the 6 membered ring.In a d embodiment R1 is selected from the group consisting of hydrogen, -OH, halogen, substituted or unsubstituted C1_4 alkyl, substituted or unsubstituted C1_4 alkoxy, and tuted or unsubstituted C2_4 alkenyl; and R2 is selected from the group consisting ofhydrogen, n, substituted or unsubstituted C1_4 alkyl, substituted or unsubstituted C1_4 alkoxy, -CN, -OH and -NO2; or R and R2 are combined to form a fused ring; In yet a related embodiment B is a ring system selected from the group consisting of aryl, heteroaryl, and bicyclic heteroalicyclyl; C is a ring system selected from the group consisting of C2_9 heteroalicyclyl and heteroaryl; wherein B is attached to a carbon atom adjacent the N atom of ring system C.
In some embodiments whenever a halogen is specified as a substituent the n is selected from fluoro or chloro.
Briefdescription oft/w drawings Figure 1 illustrates the TAMRA-labelled probe.
Figure 2 illustrates the characterisation of the Fluorescence Polarization (FP) assay with the TAMRA-labelled probe used in the FP assay.
Figure 3 depicts the assay results of example no. 89 in (A) Fluorescence Polarization Assay, (B) RORy Reporter Assay (Gal4), and (C) Thl7 Assay.
Specific examples of compounds are disclosed in Table 1 below.
Table 1. Example nds by Structure and Name.
Ex. Structure Name 4 3-[[2-[4-[2-(4- phenylphenyl)pyrrolidin— l - yl]pyrrolo[2,3-d]pyrimidin yl]butanoylamino]methyl]furan—2- carboxamide ° (2R)-2—[[5-fluoro[(2R)—2-[4- "WWW .W NHZ (trifluorometbyl)phenlepyrrolidin- / g l-yl]pyr1m1d1nyl]am1no] -4,4- HNN. $791M yl-pentanamide or (2R) m. WM F [[5-fluoro[(2S)[4- F "WW 1451"» MAW/F (trifluoromethyl)phenyl]pyrrolidin- MN < 3]" NF 1 -yl]pyrimidinyl]amino] -4,4- \ lllll r dimethyl-pentanamide 6 ° (2R)-4,4-dimethyl[[6-[2-[4- MM NJL (trifluoromethyl)phenyl]pyrrolidinl-yl ]pyrimidin HNM EM?" yl]amino]pentanamide . r.31 FA w M F" Md7 Ex. Structure Name 9 "grim "qu MW" (2R)[[6-[2-(1,3-benz0thiazol—2- QM) 2Q QMIQ M yl)pyr}ro}idiny1]-.5-flu0r0- W //N pyr1rn1d1nyl]arn1no](2,4,5- Nah trifluorophenyl)propanamide (£1W2f" F 11 ° (2R)[[6-[2-(2,4- WWW/M kw dichloropheny1)pyrrolidiny1] i é fluoro-pyrimidinyl]arnino]-4,4- "m WMQQ yl—pentanamide M" (MMQQN F [Wiwmw MCI 13 O (2R)[[5-fluor0 M WMJLWNH (trifluoromethyl)[2-[4- 2 F HvamNgMF; MF (trifluorornethyl)phenyl]pyrrolidin- 1-y1]pyrirnidinyl]arnino]-4,4- JO F dimethyl—pentanarnide k‘wxyN F W'm‘m "WM/q "F QMMNMQjQw/pf F 14 O (2R)-4,4-dirnethy1—2-[[5-rnethy1—6- \ALQ W [2-[4- ; orornethyl)phenyl]pyrrolidin- j? WMflm 1-y1]pyrirnidin F yl]arnin0]pentanarnide WEWMLaN wNm MA y "F Ex. Structure Name (2R)[[2,5-dimethyl[2-[4- (trifluoromethyl)phenyl]pyrro lidiny1]pyrirnidiny1]arnino]-4,4- dimethyl—pentanarnide 16 5-fluoro-N—(3-rnethoxy-1 ,3 - dimethyl—butyl)[2-[4- (trifluoromethyl)phenyl]pyrro lidiny1]pyrimidinarnine 17 O (2R)[[5-flu0r0[2-[4- (trifluoromethyl)phenyl]pyrro lidin- 1-y1]pyrirnidiny1]arnino]-3 -(4- methoxypheny1)propanamide (2R)[[5-fluor0[4-rnethyl[4- oromethyl)phenyl]pyrro lidiny1]pyrirnidiny1]arnino]-4,4- HfiM N dimethyl—pentanarnide WO 20295 Ex. Structure Name 19 O -[[6-[2-(4-tert- "MNMLRNH >{ butylphenyl)pyrro lidiny1] -5 - g fluoro-pyrimidinyl]arnino]-4,4- HNM‘Mfi'imm dimethyl—pentanarnide Q jN F w; @a: E (2R)[[5-fluoro[3-[4- M WWW/r "NH (trifluorornethyl)phenyl]morpholin- M‘T 2 E 4-y1]pyrirnidinyl]amino]-4,4- HN MAM F dimethyl—pentanarnide T (NJ) [ "w" WW0/" 21 F FMXM"F N—(3,3-dirnethylbuty1)fluoro [2_[4_ «WW (trifluorornethyl)phenyl]pyrrolidin- < My 1-y1]pyrimidinamine NJ1 NWMN Q M "WWW "NM" M" N "RM/j F 23 W% WNW" (2R)-2—[[5-fluoro[2-(6- quinoly1‘)pyrrolidi1‘1y1]pyrirnidin- m M (WM/M Mu W7" W W 4-y1]am1n0]—4,4-d1rnethyl- XXV/NM pentanamide F" "ME/M2! waif/[WC Ex. Structure Name (2R)[[6-[2-(2,3-dihydro-1,4- benzodioxinyl)pyrrolidiny1] -5 - fluoro-pyrirnidinyl]arnino] -4,4- dimethyl—pentanamide 29 (2R)[[5-flu0r0[2-[4- (trifluoromethyl)phenyl]pyrro lidin- yrirnidiny1]arnino]-3 -(4- methoxyphenyl)propan— 1 -01 (2R)[[5-flu0r0[2-[4- (trifluoromethyl)phenyl]pyrro lidiny1]pyrirnidiny1]arnino]-4,4- dimethyl—pentan— 1 -01 31 (2R)[[5-flu0r0[2-[4- (trifluoromethyl)phenyl]pyrro lidiny1]pyrirnidinyl] y1— amino]-N,4,4-trirnethyl- pentanamide WO 20295 Ex. Structure Name 32 HOYTC/ )1 Wm F M 2-[4-[[[5-fluoro[2-[4- H L (trifluorornethyl)phenyl]pyrrolidin- *WV N \} M" WW""" 1-y1]pyrirnidin N "HZ A 1 fluorophenyl)propanamide < 32/ L12 FW7ZMWF 38 O MJN -[[5-fluor0[3-rnethyl[4- KM orornethyl)phenyl]pyrrolidin- ; 1 -y1]pyrirnidiny1]arnino]-4,4- HNTKEW dimethyl—pentanarnide M" "Md" F T ffkywwwgF 39 O (2R)[[3-fluoro[2-[4- "M "WA/[L (trifluorornethyl)phenyl]pyrrolidin- MT/ NHZ ; 1-y1]pyridyl]arnino]-4,4- HN1(/MW dimethyl—pentanamide F W: WA Ex. Structure Name 40 [[5-fluoro[2—[4- (trifluoromethyl)phenyl]pyrro lidiny1]pyrirnidin yl]amino]methyl]phenyl]acetamide 41 5 -flu0r0-N—(1-rnethyl tetrahydropyran—4-y1-ethy1)[2-[4- (trifluoromethyl)phenyl]pyrro lidiny1]pyrimidinarnine 42 E (2R)[[5-fluoro[2-[5- (trifluorornethyl) pyridyl]pyrrolidin- 1 rirnidin yl]amino] -4,4-dirnethyl— pentanamide 43 ° (2R)[[6-[2-(4-tertbutoxyphenyl )pyrrolidin— 1 -y1] -5 - fluoro-pyrimidinyl]arnino]-4,4- dimethyl—pentanarnide Ex. ure Name 4-[[[5-fluor0[2-[4- (trifluoromethyl)phenyl]pyrro lidiny1]pyrirnidin yl]amino]methy1]benzoic acid 45 3-[[4-[[[5-flu0ro[2-[4- M 0k w" /M~4M (trifluoromethyl)phenyl]pyrro lidiny1]pyrirnidin yl]amino]rnethy1]phenyl]rnethyl]- ,5-dimethyl-imidazolidine-2,4- dione 46 ° 5-fluoro[2-[4- (trifluoromethyl)phenyl]pyrro lidiny1]pyrirnidin yl] amino]rnethy1]phenyl]rnethanesul fonarnide 48FFfix" 5-fluoro-N—[[4- (trifluoromethyl)phenyl]methyl] [2-[4- (trifluoromethyl)phenyl]pyrro lidiny1]pyrimidinarnine NWMN Ex. Structure Name 1 \l XMLO -tert-butoxy[[5-fluoro [2-[4- 0 NHZ g (trifluorornethyl)phenyl]pyrrolidin- HNW Wm 1-y1]pyrirnidin (m >1 F yl]arnino]butanarnide MHZ? F "g @a: 52 XX; —[[5-flu0r0[2-[4- (trifluoromethyl)phenyl]pyrro lidin- 1-y1]pyrirnidiny1]arnino]-3 - tetrahydropyran—4-y1-pr0panarnide 53 "MoUW12: M F N—[(3,4-dimethoxyphenyl)rnethyl]- H \ 5-fluoro[2-[4- mo" M" Ww/NM (NWT/NM?" (trifluorornethyl)phenyl]pyrrolidin- NMN 1-y1]pyr1rn1d1narn1ne M?"L%\ 54 N—[(2 3-dirnethoxypheny1)rnethyl] - -fluoro[2-[4- (trifluoromethyl)phenyl]pyrro lidiny1]pyrimidinarnine Ex. ure Name 55 N—[l-(3,4-dihydro-2H-1,5- benzodioxepiny1)propyl] fluoro[2-[4- (trifluoromethyl)phenyl]pyrro lidiny1]pyrimidinarnine 56 5-fluoro-N—[(4- morpholinopheny1)rnethyl][2-[4- (trifluoromethyl)phenyl]pyrro lidiny1]pyrimidinarnine 57 [4-[[[5-flu0ro[2-[4- (trifluoromethyl)phenyl]pyrro lidiny1]pyrirnidin yl]amino]methyl]phenyl]- morpholino-rnethanone Ex. Structure Name 58 ("W MNOH [1-[5-[[[5-fluoro[2-[4- W" (trifluorornethyl)phenyl]pyrrolidin- < L j H ii: i 1-y1]p.yrimidinyl]amino]rnethyl]- "f" "w (ABM "w "W 2-pyr1dyl]p1per1dy1]methanol "M "as" N 59 5-flu0r0-N—[[4-(tetrahydrofi1ran—2- ylrnethoxy)pheny1]rnethy1][2-[4- (trifluoromethyl)phenyl]pyrro lidiny1]pyrimidinarnine 60 [[5-fluoro[2-[4- (trifluoromethyl)phenyl]pyrro lidiny1]pyrirnidin yl]amino]methy1]phenyl]pipcrazin- 2-one 61 1-[4-[[[5-fluoro[2-[4- oromethyl)phenyl]pyrro lidiny1]pyrirnidin yl]amino]rnethyl]phenyl]piperidine- 3-carboxarnide Ex. Structure Name 62 O —[[5-fluoro[(2R)—2-[4- MMMMJLNNH >{ (trifluorornethyl)phenyl]pyrrolidin- g 1 -y1]pyrirnidiny1]arnino]-4,4- HNM $12233 dimethyl—pentanarnide or (2R) Q ")N F [[5-flu0r0[(ZS)[4- F ‘Mm "A" orornethyl)phenyl]pyrrolidin- N Q)" NF 1-y1]pyrimidinyl]amino]-4,4- K: w dimethyl—pentanarnide 63 (2R)[[5-fluoro[2—[4- (trifluorornethyl)phenyl]pyrrolidin- 0% NH 1-y1]pyrirnidiny1]arnino]-3 -(2- I8"; oxopyrrolidiny1)pr0panarnide NAN : "Manly" MW" MN MW NH? (\‘g/1 W/ 64 F \\F N—[(1R)-3 ,3 -dirnethy1— 1 h01in- 2-y1—buty1]—5-flu0r0[2-[4- «WM fl (trifluoromethyl)phenyl]pyrro lidin- K :3\ L W 1-y1]pyrimidinamine Mum/My N ffiWN WM M" KRflflkMN/JSQWWTJMNAW)"MH‘ F 65 ° (2R)[[5-fluor0[2-[2-rnethoxy- W" 4- » : (trifluorornethyl)phenyl]pyrrolidin- 17flaw 1 -y1]pyrirnidiny1]arnino]-4,4- fl F dimethyl—pentanarnide "WNW/5’" Ex. Structure Name 66 fiwlww F Ww\ 3-fluoro-N—[(6-rnethy1—3- NCM M) H j M; l)rnethyl][2-[4- WW / WWW" W WWW (trifluorornethyl)phenyl]pyrrolidin- MK > L wvfi 1-y1]pyridin—2-arnine {ww\ FM" WWI: 67 / ‘B 1-[(3,4-dirnethoxyphenyl)rnethyl] « W‘Mfl [2-[4- L k") w \1(3:; (trifluorornethyl)phenyl]pyrrolidin- " F me% 1-y1]pyrrolo[2,3-b]pyridine WOMM/QJ 68 O -[[5-fluoro[3-[4- M NMNJ—LWNH (trifluorornethoxy)phenyl]morpho 1i /" 2 g n—4-y1]pyrimidinyl]amino]-4,4- » {/wa dimethyl—pentanarnide AC " 69 n 7-[(3,4-dirnethoxypheny1)rnethyl] (""3 [2-[4- J NWa wng (trifluorornethyl)phenyl]pyrrolidin- W F Wm "WM"; F 1-y1]pyrrolo[2,3-d]pyrimidine «:aWU WOMM/MEMKWWDJ Structure Name methyl 2-[4-[[[5-flu0r0[2—[4- (trifluoromethyl)phenyl]pyrro lidin- 1 rirnidin yl]amino]rnethyl]phenyl]acetate 71 1-[2-[(1R)[[5-fluoro[2-[4- (trifluoromethyl)phenyl]pyrro lidin- 1-y1]pyrirnidiny1]arnino]-3 ,3 - dimethyl—buty1]rnorpho 1in yl]ethanone 72 (2R)[[5-flu0ro[2-[3-flu0r0 oromethyl)phenyl]pyrro lidiny1]pyrirnidiny1]arnino]-4,4- dimethyl—pentanarnide 73 5-fluoro[2-[3-fluoro (trifluoromethyl)phenyl]pyrro lidin- 1-y1][(6-rnethyl pyridyl)methoxy]pyrirnidine Ex. Structure Name 74 ‘‘‘‘‘‘ 5-fluor0[(6-methy1—3- pyridyl)methoxy]—6-[2-[4_ (trifluoromethylmhenyflpyrrolidiny1]pyrirnidine 77 (2R)[5-fluoro[(2R)[4- (trifluorornethyl)phenyl]pyrrolidin- 1-y1]pyrimidiny1]0xyrnethy1— pentanamide or (2R)—2—[5-flu0r0 [(ZS)[4- (trifluorornethyl)phenyl]pyrrolidin- 1-y1]pyrimidiny1]0xyrnethy1— pentanamide 78 (2R)[5-fluoro[(2R)[4- (trifluorornethyl)phenyl]pyrrolidin- 1-y1]pyrimidiny1]0xyrnethy1— pentanamide or (2R)—2—[5-flu0r0 [(ZS)[4- orornethyl)phenyl]pyrrolidin- 1-y1]pyrimidiny1]0xyrnethy1— pentanamide 79 2-[4-[[5-fluoro[2-[4- (trifluoromethyl)phenyl]pyrro lidin- 1 rirnidin yl]0xymethyl]phenyl]acetic acid Ex. Structure Name (2R)[5-fluoro[5-[4- (trifluorornethyl)phenyl]pyraz0 1 yl]pyrirnidin—4-yl]oxyrnethy1- pentanamide ‘‘‘‘‘‘‘ 81 [[5-fluoro[(2R)[4- (trifluoromethyl)phenyl]pyrro lidiny1]pyrirnidin in0]methyl]phenyl]acetic acid 83 2-[4-[[5-fluoro[[4- (trifluoromethyl)phenyl]methylarnin o]pyrirnidin—4- yl]0xymethyl]phenyl]acetic acid 84 2-[4-[[5-fluoro[2-[6- (trifluorornethyl)-3 - pyridyl]pyrrolidiny1]pyrirnidin yl]0xymethyl]pheny1]acetamide ure Name 2-[4-[[4—[2-[4- (trifluoromethyl)phenyl]pyrro lidin- 1-y1]pyrrolo [2,3 -d]pyrirnidin y1]methyl]phenyl]acetic acid 86 2-[5-[[5-fluoro[2-[4- (trifluoromethyl)phenyl]pyrro lidiny1]pyrirnidin yl]0xymethyl]pyrirnidin y1]acetarnide 87 2-[5-[[[5-fluoro[2-[4- (trifluoromethyl)phenyl]pyrro lidiny1]pyrirnidin yl]amino]rnethy1]pyrimidin—2- tarnide 88 4-[[[5-fluor0[2-[4- (trifluoromethyl)phenyl]pyrro lidiny1]pyrirnidin yl]amino]methyl]benzonitrile Ex. ure Name 89 5-fluoro-N—[(6-rnethy1—3- pyridy1)methy1][2-[4_ (trifluoromethylmhenyflpyrrolidiny1]pyrimidinarnine 90 5-fluoro[2-(4- methoxyphenyl)pyrrolidin— 1 - [(6-rnethy1—3- pyridyl)rnethyl]pyrimidin—4-amine 91 2-[4-[[[5-flu0r0[3-[4- (trifluorornethoxy)phenyl]morpho 1i n—4-y1]pyrirnidin yl]arnin0]methyl]phenyl]acetic acid 93 5-fluoro-N—[(4- methylcyclohexyl)methyl][2-[4- (trifluoromethyl)phenyl]pyrro lidiny1]pyrimidinarnine Structure Name -fluoro-N— [ [4-(irnidazo 1 ylmethy1)phenyl]rnethyl][2-[4- (trifluoromethyl)phenyl]pyrro lidiny1]pyrimidinarnine 95 5-fluoro-N—[[4- (methylsulfonylrnethyl)phenyl]meth [2-[4- (trifluoromethyl)phenyl]pyrro lidiny1]pyrimidinarnine 96 o-N—[(6-rnethy1—3- pyridyl)rnethy1]—6-[5-[4- (trifluoromethyl)phenyl]triazo 1 yl]pyrirnidin—4-arnine 97 5-fluoro-N—[(6-rnethy1—3- pyridyl)rnethy1]—6-[2-[4- (trifluorornethoxy)phenyl]pyrrolidin y1]pyrimidinarnine Ex. Structure Name 98 WWW Wm k. M2 F 1-[4-[[[5-flu0r0[2-[4- H JM"M} (trifluorornethyl)phenyl]pyrrolidin- W" W Mflfim M { 1-y1]pyrirnidin NgWQN {MAW y1]arnino]methyl]phenyl]rnethy1— (L a propan—2-ol NM\\MWF 99 " \[Nam MON F 5-fluoro-N—[(2-methoxyrnethy1— X WAX» H F 33 3-pyridyl)rnethyl][2-[4- ‘ "mm/"NM Hi /N ,x 1&3?me (trifluorornethyl)phenyl]pyrrolidin- 1-y1]pyrimidinamine \QiMARX 100 OH < \\N F Q)?M 5-[[[5-flu0r0[2-[4- H (trifluorornethyl)phenyl]pyrrolidin- ,/ WTwzi—W / WWW" " NC" )3: 1-y1]pyrirnidin M yl]amino]methyl]pyridinol [‘77""‘"""M my 104 Haj 2-[1-[5-fluoro[(6-rnethyl FM! "M W pyridyl)methylamino]pyrimidin—4- Fwy? "OH "$ng yl]pyrr01idin—2-yl]—5- (trifluorornethyl)phenol 7/ ‘3» NgwaMLFflflmfiw/N MWMJW Ex. Structure Name -fluoro-N—[(1-rnethy1pyrrol—3 - thyl] [2- [4- (trifluoromethyl)phenyl]pyrro lidiny1]pyrimidinarnine 106 5 -fluoro-N—[(1-rnethy1pyrazol—4- FM"ka yl)rnethy1] [2- [4- fig" (trifluoromethyl)phenyl]pyrro lidiny1]pyrimidinarnine ")7 3/: 5-fluoro-N—[(5-rnethy1—2- fury1)rnethyl][2-[4- (trifluoromethyl)phenyl]pyrro lidiny1]pyrimidinarnine Ex. Structure Name 108 kaF 5-[[[5-flu0r0[2-[4- F (trifluoromethyl)phenyl]pyrrolidin- a") 1 -y1]pyrirnidin 8%" yl]amino]methyl]pyrrolidinone «<5 1 N Maw/fl M (""ka HNWm RMJNWXNH 109 Q\ 4-[[[5-flu0ro[2-[4- >‘Mm »»»»»\ F (trifluorornethyl)phenyl]pyrrolidin- z [ M} 1-y1]pyr1rn1d1nyl]am1no]rnethyl]-. . . .
Wm Amv/H W")WM l-methyl-pyrrolidin-Z-one ( (NM5hard» 110 if" 5-[[[5-flu0r0[2-[4- "W"‘W'Nm‘ F F W orornethyl)phenyl]pyrrolidin- )7 M H K :2) 1-y1]pyr1rn1d1nyl]am1no]rnethyl]-. . . . ff mo W" 4’;ng ,» O \W >( 1 N,N—dimethyl-tetrahydrofuran—Z- "W" (W% arnide M‘Myfl‘w 1 1 1 F x W 5-fluoro-N—[(4- of ><0 H IWWWMy methoxytetrahydropyran—4- "aw M" (W \\" yl)rnethyl][2-[4- "WWW" wWw (trifluoer-ethylmhepyl]pyrrolidin- \< \j\ 1 -y1]pyr1rn1d1narn1ne Ex. Structure Name 112 1-[6-[[[5-flu0r0[2-[4- (trifluorornethyl)phenyl]pyrrolidiny1]pyrirnidinyl]amino]methyl] - 2-methylpyridyl]ethan01 1 13 1 N WW 5-fluoro-N—[(2-rnethoxy <1 ,3 n F\ pyridyl)rnethyl][2-[4- M WW (trifluoromethyl)phenyl]pyrro lidiny1]pyrimidinarnine 114 MOW/"mm 5-fluoro-N—[(6-rnethoxy pyridyl)rnethy1]—6-[2-[4- (trifluoromethyl)phenyl]pyrro lidin- 1 rimidinarnine 115 m 5 -fluoro-N-[[4-(1,2,4-triaz01—1- ylmethy1)phenyl]rnethyl][2-[4- oromethyl)phenyl]pyrro lidiny1]pyrimidinarnine Ex. Structure Name 116 M"OW-NM F W 5-fluoro-N—[(6-rnethoxy .(H W NF \ l)rnethy1]-N-rnethy1—6-[2-[4- "My" MM WWrrrrrr X (trifluororncthyl)phcnyl]pyrrolidin— NW" 1-y1]pyr1rn1d1narn1ne \iimmm/*iwfi 117 HOYKWW 2-[4-[[[5-fluoro[(2R)[4- (trifluoromethyl)phenyl]pyrro lidiny1]pyrirnidin yl]arnin0]rnethyl]phenyl]acetic acid 118 w wax 2-[4-[[[5-fluoro[(ZS)[4- (trifluoromethyl)phenyl]pyrro lidiny1]pyrirnidin yl]arnin0]rnethyl]phenyl]acetic acid 1 19 "0m WW 2-[4-[[[5-fluoro[3-[4- (trifluoromethyl)phenyl]morpho lin- 4-y1]pyrirnidin yl]arnin0]rnethyl]phenyl]acetic acid Ex. Structure Name 120 F [5-fluoro[2—[4- (trifluoromethyl)phenyl]pyrro lidiny1]pyrirnidin yl]amino]ethy1]benzoic acid 121 [3-[[5-fluoro-6—[2-[4_ N H % / "M MW M, M W‘‘‘‘‘ (A? (trifluoromethyl)phenyl]pyrro lidin- ( f 1-y1]pyrirnidin N"W" LEN-w 4Q / Z m Wmmm y1]arnino]pyrrolidiny1] -(4- y mg #3 pyridyl)rnethanone "Wm/"WI MN; F WWW" 5-[[[5-fluoro[2-[4- N i o H 1 :3; (trifluorornethyl)phenyl]pyrrolidin- rWTWW/Nw WWW 1-y1]pyrirnidin < > yl]amino]rnethyl]indolin-Z-one [Wm WM F "NF 123 5-flu0r0-N—[3-rnethyl(1H- tetrazol—S-yl)butyl]_6-[2_[4_ oromethyl)phenyl]pyrro lidiny1]pyrimidinarnine 2015/067713 Ex. Structure Name F WW 1-[[4-[[[5-flu0ro[2-[4- H N[ > (trifluorornethyl)phenyl]pyrrolidin- ~/ "WM ~/ \X 1-y1]pyrirnidin $ng me yl]amino]methyl]pheny1]rnethyl]pyr V ( fl rolidin-Z-one MMNflf‘fl/fifl FM" "F 126 F F 5-fluoro[2-[4- (trifluorornethyl)phenyl]pyrrolidin- F Wm "NF {W H ( > N-[[6-(trifluoromethyl) wl/W" "WWW MW WW" pyridyl]rnethyl]pyrimidin—4-amine NK‘M M’N w/"WN "mwa E; M) [WM/m 128 "Om/W F ‘‘‘‘‘‘q 2-[4-[[[5-flu0r0[2—[4- (ME > H / \ (trifluorornethyl)phenyl]pyrrolidin- W MM Wm /"\< 1-y1]pyrirnidin "(fix)" yl]amino]methyl]phenyl]ethanol mo 4-[[[5-fluor0[2-[4- L H P (trifluorornethyl)phenyl]pyrrolidin- I" YW w" "M Ngwyfiyh 1-y1]pyrirnidin yl]amino]rnethyl]tetrahydropyran—4- [Mm< W j 01 [MI/WK}: Ex. Structure Name 130 1-cyc10penty1—4-[[[5-fluor0[2-[4- (trifluoromethyl)phenyl]pyrro lidiny1]pyrirnidin yl]amino]methyl]pyrrolidinone 131 5-fluoro-N—[(4-rnethoxy pyridyl)rnethy1]—6-[2-[4- (trifluoromethyl)phenyl]pyrro lidiny1]pyrimidinarnine 132 o-N—[(6-rnethy1—2- pyridyl)rnethy1]—6-[2-[4- (trifluoromethyl)phenyl]pyrro lidiny1]pyrimidinarnine 134 9-[5-fluoro[2-[4- (trifluoromethyl)phenyl]pyrro lidin- 1-y1]pyrirnidinyl]—3,9- diazaspiro[4.5]decan—2-one Ex. Structure Name 135 91 4-[[[5-fluoro[2-[4- (trifluoromethyl)phenyl]pyrro lidiny1]pyrirnidinyl] -rnethy1— amino]methy1] - 1 y1—pyrrolidin- 2-one 1 3 6 M aim N—[(5 -ethy1—2-pyridyl)methyl] -5 - 1 F QM) f/\, fluoro-N—rnethyl[2-[4- MN (m) \i (trifluoromethyl)phenyl]pyrro lidin- [1%%N 1-y1]pyr1rn1d1narn1ne V" "35 M ‘MF 137 W0 [[5-fluoro[2-[4- [ TM (trifluoromethyl)phenyl]pyrro lidin- "MM"Xi M ‘‘‘‘‘‘ F W 1-y1]pyrirnidin /H AW'[m > yl]amino]methyl]phenyl]pyrrolidin- W" "M W ‘ 2-one "mi/M M m Fwy/RM F 138 /'\"‘M?~?"N 5-flu0r0-N—[[4-(1H-tetraz01—5- M) W yl)phenyl]rnethy1][2-[4- H W (Hm? I fm‘k (trifluoromethyl)phenyl]pyrro lidin- "raw"! H MNw‘ M 1 -y1]pyrimidinarnine W "m Structure Name N—benzyl-S-flu0r0[2-[4- (trifluoromethyl)phenyl]pyrro lidiny1]pyrimidinarnine 140 o-N—(4-pyridy1rnethyl)[2- (trifluoromethyl)phenyl]pyrro lidiny1]pyrimidinarnine 141 5-fluoro-N—(3-pyridy1rnethyl)[2- (trifluoromethyl)phenyl]pyrro lidiny1]pyrimidinarnine Ex. Structure Name 142 N—[(3,5-dirnethoxypheny1)rnethy1]- -fluoro[2-[4- oromethy1)pheny1]pyrrolidiny1]pyrimidinarnine FM MF 143 WWW F WK 1-[3-[[[5-fluor0[2-[4- (trifluoromethy1)pheny1]pyrrolidin- H (mm 1 H N1 M» H" "MN MW "M M" ("H " 1-y1]pyrirnidin "1% NWN "fr/M" g1]02:1nelino]rnethy1]pheny1]pyrrolidin- 144 14% F \ 3-[[[5-fluoro[2-[4- H HF N (trifluoromethy1)pheny1]pyrrolidin- M YW"WAMM "1 WT "W 1-y1]pyTirnidinyl]amino]rnethyl]' o NQKMWMQN LN N—methyl—benzarnide b"‘1'")1 145 «£11me :1 KM) F 3-[[[5-fluoro[2-[4- H (trifluoromethy1)pheny1]pyrrolidin- N NF" /W "H" "W W N" W) / yrirnidiny1]amino]rnethy1]- 0 NW": N,N—d1methy1—benzam1de "(W/W" Ex. Structure Name fl-WN W F 5-fluoro-N— [ [3-(1 ,2,4-triaz01— 1 - NW A > ylmethy1)phenyl]rnethyl][2-[4- N C H IfWw\M) (v u (trifluorornethyl)phenyl]pyrrolidin- 3 L 1 -y1]pyrimidinarnine 147 %—~« F m 5-fluoro-N—[[3- om K (methoxymethyl)phenyl]methyl] M mm: M," N W M" / M" "W "Ry/"Mm / fl [2_ [4_ N%"‘W‘,¢,N WWW (trifluorornethyl)phenyl]pyrrolidin- w KM") 1 -y1]pyrimidinarnine F/v "M‘NF F /"MW MOH 2-[4-[[[5-fluor0[2-[4- 4:: \N L H J I (trifluorornethyl)phenyl]pyrrolidin- J/ W~‘%~fiwr" "NW/WM 1-y1]pyrirnidin ,ngym no]methyl]cyclohexyl]acetic2101 150 WWW 5-fluoro[2-(5 -rnethy1—2- ); furyl)pyrrolidiny1] -N- [(6-rnethy1— 3 -pyridyl)methyl]pyrimidin amine Ex. ure Name N—(cyclobutylmethy1)fluoro[2- (trifluoromethyl)phenyl]pyrro lidiny1]pyrimidinarnine 152 F a 5-fluoro-N— [( 1 - methylcyclobutyl)rnethyl] [2- [4- (trifluoromethyl)phenyl]pyrro lidiny1]pyrimidinarnine 154 5-fluor0-N-(tetrahydrofilran-3 - ylmethyl)[(2R)[4- (trifluoromethyl)phenyl]pyrro lidiny1]pyrimidinarnine «("1 N "mm/M ‘ WWW C W W QW/ 2015/067713 Ex. Structure Name 155 F M"F 5-fluoro-N-(tetrahydr0pyran—2- "VWJQQVM F ylrnethyl)[(2R)-2_[4_ gm; (trifluoromethyl)phenyl]pyrro lidiny1]pyrimidinarnine ‘WNN‘ N/W’WNJKE w (aw 159 5-fluor0-N-(tetrahydr0thiophen—2- ylmethyl)[(2R)[4- (trifluoromethyl)phenyl]pyrro lidiny1]pyrimidinarnine 161 5-fluoro-N—[(4- methyltetrahydropyran—4- yl)methyl][(2R)[4- (trifluoromethyl)phenyl]pyrro lidiny1]pyrimidinarnine Ex. Structure Name 1 64 F 5 -fluoro-N-(tetrahydrothiopyran—4- \1"F F hyl) [(2R) [4- (MSX (trifluoromethyl)phenyl]pyrro lidin- EM 1 -y1]pyrimidinarnine a/WM "w N N W "w 454%) F ""M/Kmmfl 165 F 34%WF 3-[[[5-fluoro[(2R)[4- (trifluorornethyl)phenyl]pyrrolidin- M‘W‘Mfif‘fWM 1 -y1]pyrirnidin WWW yl] amino]rnethyl]tetrahydrothiophen -3 -O 1 4xfiw ‘W/N"MM/"aw MW N—[(4,4- dimethylcyclohexy1)rnethy1] -5 - fluoro[(2R) [4- (trifluoromethyl)phenyl]pyrro lidiny1]pyrimidinarnine WO 20295 Ex. Structure Name 167 1-[[[5-fluoro[(2R)[4- (trifluoromethyl)phenyl]pyrro lidiny1]pyrirnidin yl]amino]rnethy1]cycloheptanol 168 5-fluoro-N—[(2- H methoxycyclohexy1)rnethy1] WNW WM ’" "w "{"W W" [(2R)[4- (trifluoromethyl)phenyl]pyrro lidin- g X 1 -y1]pyrimidinarnine 169 4-[[[5-fluoro[(2R)[4- oromethyl)phenyl]pyrro lidiny1]pyrirnidin yl] amino]rnethyl]tetrahydrothiopyra n—4-01 170 N—[(1 , 1-di0x0thi01an—2-y1)rnethyl]fluoro [(2R)[4- (trifluoromethyl)phenyl]pyrro lidiny1]pyrimidinarnine Ex. ure Name N—[(2-tert-buty1tetrahydr0pyran—3 - yl)rnethy1]fluoro[(2R)[4- (trifluoromethyl)phenyl]pyrro lidiny1]pyrimidinarnine 178 5-fluoro-N—[(4- "WWW" isopropylcyclohexy1)rnethyl] J F H M [(2R)[4- "M WWW/NM (WWWWF/Nwfl (trifluoromethyl)phenyl]pyrro lidiny1]pyrimidinarnine "WM «6%) FM’XMWF 181 F ,F 5-fluor0-N-(tetrahydrofiJran-Z- wwwww F ylmethyl)[(2R)[4- ">3{MWWM (trifluoromethyl)phenyl]pyrro lidiny1]pyrimidinarnine Ex. Structure Name M 4;? 4-[[[5-flu0r0[(2R)[4- "Lg/3‘ Kim MW F (trifluorornethyl)pheny1]pyrrolidin- o < J H [ \ 1-y1]pyrirnidin Elm" "WW/N" (MT/NW?" yl]amino]methy1]benzenesulfonami —— de NWWWN 1 83 N—[(6-ch10r0-3 -pyridy1)rnethy1] -5 - F W" { 1 i H [C1 fluoro[(2R)—2-[4- h" N" "MW/"Maw" "MAN (trifluorornethyl)pheny1]pyrrolidiny1]pyrimidinarnine w N <1." N /m WWW mfiwfij 184 fl" F """"""‘"""‘\:M o N—[(1,1-di0x0thi01an—3-y1)rnethy1]— a: Mfk/fif: 5-fluoro[(2R)[4- Mr K >1: W (trifluorgmgthyl)phe11y1]pyrrolidin- Kw»? W 1 r1rn1d1narn1ne 185 F L"F 5-flu0r0-N—(3-thieny1rnethy1) [(2R)[4- 27M>( (trifluorornethyl)pheny1]pyrrolidin- Afiww 1 -y1]pyrimidinarnine W M/meN M"LL14?!) Structure Name 186 EL"? 0-N-(tetrahydropyran—3 - ylmethyl)[(2R)[4- "M; (trifluoromethyl)phenyl]pyrro lidiny1]pyrimidinarnine 47"] W m (My M" "M17// N 188 5-fluoro-N—[[1- (methoxymethyl)cyclobutyl]methyl] [(2R)—2-[4- (trifluoromethyl)phenyl]pyrro lidiny1]pyrimidinarnine 189 2-[4-[[[5-fluoro[(2R)[4- F k; (trifluoromethyl)phenyl]pyrro lidiny1]pyrirnidin \fi‘~(’W:\2N yl]amino]rnethy1]phenyl] -N-rnethy1— acetamide IM" J "mm/)L"/4 m "N wm/ 190 5-fluoro-N— [ [4-( 1 H-tetrazol—S - F /ma? ylrnethyl)cyclohexy1]rnethy1] KMWMNMflfWL [(2R)[4- (J oromethyl)phenyl]pyrro lidin- \MJWW"5% 1 -y1]pyrimidinarnine Ex. Structure Name 191 O 1-[4-[[[5-fluoro[(2R)[4- "LR / &/ (trifluoromethy1)pheny1]pyrro lidin- H fa?) 1-y1]pyrimidiny1]amino]rnethy1]- w"MT¢%%/MNmy" m 1 -piperidy1] ne 192 HOYV/W Mm 2-[4-[[[5-fluoro[2—[4- H [/1 X; (trifluorornethoxy)phenyl]pyrrolidin 0 WM "MW/Nw N My 1/ \g y1]pyrirnidin N»ME y1]arnin0]rnethy1]pheny1]acetic acid ("mi")My" 193 Km F 5 -flu0r0-N—[(1-0Xid0pyridiniurn— NRA H L 1M»\ M nethy1][(2R)[4- 0/ W WWW Nyflwrw N""1:(‘uriflu01romethy1)pheny1]pyrlrolidin- N Mam/2N EM 1 -y1]pyrimidinamine "MN/M \i WWW X -fluoro-N—[(1-oxidopyridiniurn— F W%N+MO- g 1N x "w 4-y1)rnethy1]—6-[(2R)[4- 2/ "N f kw" (trifluoromethy1)pheny1]pyrro lidin- MW KWN 1-y1]pyrimidinamine 39%)] FWWXMF Structure Name 2-[4-[[4-[(2R)[4- (trifluoromethyl)phenyl]pyrro lidin- 1-y1]pyrrolo [2,3 -d]pyrirnidin hyl]phenyl]acetic acid 196 2-[4-[[4—[(2R)[4- (trifluoromethyl)phenyl]pyrro lidin- yrrolo [2,3 -d]pyrirnidin y1]rnethyl]phenyl]acetamide 197 5-fluoro-N- [( 1 -rnethylsulfony1 piperidyl)rnethy1]—6-[(2R)[4- (trifluoromethyl)phenyl]pyrro lidiny1]pyrimidinarnine 198 Fwy}: 5-fluoro-N—[(3-rnethyloxetan y1)rnethyl][2-[4- (trifluoromethyl)phenyl]pyrro lidiny1]pyrimidinarnine army," {(NW NMW \‘Wwflw Ex. Structure Name 199 F W 5-fluoro-N—[(2- "MW methyltetrahydrofixan—Z- KW)" yl)rnethy1]—6-[(2R)[4- %? (trifluorornethyl)phenyl]pyrrolidin- WW 1 -y1]pyrimidinarnine K :> M? F M/NH 200 H°~ W F -flu0r0[(2R)[4- /\\N H (trifluorornethyl)phenyl]pyrrolidin- r \KW) 1-y1]pyrirnidin W yl]am1no]methyl]cyclohexano1 [

Claims (66)

1. A compound of Formula (I) Formula (I) or pharmaceutically acceptable salts, hydrates, es, polymorphs, and isomers thereof, wherein: Y is NR or O; R is hydrogen or C1-4 alkyl, C1-4 haloalkyl, or C1-4 hydroxyalkyl; R1 is selected from the group consisting of hydrogen, -OH, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, and C2-4 alkenyl; R2 is selected from the group consisting of hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, -CN, and -OH; or R and R2 are combined to form a fused ring; R3 is selected from the group consisting of en, n, -OH, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, C1-4 koxy, oxo, and -C(=O)R10; R4a is selected from the group consisting of hydrogen, halogen, -OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, -CN, C1-6 alkyl substituted with -C(=O)NR8R9, C1-C6 alkoxy, C1-6 haloalkoxy, C1-6 alkenyl, C3-C6 cycloalkyl, aryl, aryl-C1-6 alkyl, heteroaryl, and heteroaryl-C1-6 alkyl; R4b is selected from the group consisting of hydrogen, halogen, oxo, -OH, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and -C(=O)R10; R5 is ed from the group consisting of -(CR8R9)pOR12, -(CR8R9)p-CR13R14R15, - (CR8R9)p-C(=O)OR7, and -(CR8R9)p-C(=O)NR8R9; n, m, and p are integers independently selected from the group consisting of 0, 1, 2, 3 and 4; R6a, R6b are independently selected from the group consisting of hydrogen, halogen, C1-6 alkyl, C1-6 kyl, C1-6 hydroxyalkyl, C1-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkoxy, C1alkoxy-C1alkyl, C1-6 heteroalkyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, C2-9 heteroalicyclyl, C2-9 heteroalicyclyl-C1-6 alkyl, aryl, aryl-C1-6 alkyl, and aryl, wherein aryl, C2-9 alicyclyl, and aryl may be substituted by one or more substituents selected from the group consisting of halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C3-5 cycloalkyl, -(CH2)q-CONR23R24, -(CH2)q-SO2R23, -(CH2)q-NR23SO2R24 and -(CH2)q- SO2NR23, R23, and R24 are independently selected from the group ting of hydrogen, C1-6 alkyl, -CN, C3-6 cycloalkyl, and C2-6 heteroalicyclyl, or R6a and R6b are taken together to form an oxo group or a ring system selected from C3-6 cycloalkyl and C2-9 heteroalicyclyl, or R6a and R13 are taken together to form a ring system selected from C3-6 cycloalkyl and C2-9 heteroalicyclyl; R7, R8, R9, and R12, are independently selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-4 aminoalkyl, aryl-C1-6 alkyl, heteroaryl-C1-6 alkyl, aryl, C3-6 cycloalkyl, and C2-9 alicyclyl, or R8 and R9 are combined to form a C2-C6 heteroalicyclyl; R10 is selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, -OH, -NH2, - 6 alkyl), -N(C1-6 alkyl)2, and C3-7 cycloalkyl; R13 is absent, or selected from the group consisting of hydrogen, -OH, -CN, fluorine, C1-6 alkyl, C1-6 hydroxyalkyl or C1-6 alkoxy, C1-6 alkenyl, C1-6 alkoxy, C3-8 cycloalkyl, C3-8 cycloalkenyl, and -(CR8R9)p-C(=O)OR7, -(CR8R9)p-SO2R7 and -(CR8R9)p-C(=O)NR8R9; R14 and R15 are independently selected from the group consisting of en, and substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C3-6 cycloalkyl, and substituted or unsubstituted C2-9 heteroalicyclyl; or R14 and R15 are combined to form a ring system selected from the group consisting of substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted C3-8 cycloalkenyl, substituted or unsubstituted C2-9 heteroalicyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted aryl, wherein when the ring system formed by the combination of R14 and R15 is substituted, it is substituted with -(CH2)q(R5a) wherein R 5a is independently selected from the group consisting of -CH2COOR20, -CH2CONR21R22, -CN, -CH2-CN, C1-6 alkyl, O2R20, - H3)2(OR20), -OR20, -CH2-triazolyl, -CF3, yl substituted-imidazolyl-2,4-dione, - CH2-SO2NR21R22, morpholinyl, -C(=O)-morpholinyl, piperidinyl-CH2OR20, -OCH2- tetrahydrofuryl, piperazinonyl, piperidinyl-CONR21R22, -OH, -CONR21R22, cyclopentyl, idonyl, -NR21SO2R20, tetrazolyl, -CH2-tetrazolyl, -CH2OR20-SO3R20, -SO2R20, - SO2NR21R22, and halogen; R20, R21, and R22 are independently of each other selected from the group consisting of hydrogen, C1-6 alkyl, -CN, and C3-6 cycloalkyl; q is an integer selected from 0, 1 or 2; B is a ring system selected from the group consisting of aryl, heteroaryl, and bicyclic heteroalicyclyl, provided that it is not 5,6-dichloro-1H-benzo[d]imidazolyl when R1 and R2 both are hydrogen; C is a ring system selected from C2-9 heteroalicyclyl; wherein B is attached to a carbon atom adjacent the N atom of ring system C; and with the proviso the compound is not:
2. The nd according to claim 1, wherein R and R2 in combination with the dine ring of formula (I) form a pyrrolo[2,3-d]pyrimidine or 6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidine.
3. The nd according to claim 1 or claim 2, having the Formula (IIa): Formula (IIa) R4e and R4d are independently selected from the group consisting of hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, and -OH.
4. The compound according to claim 3, wherein R4e and R4d are independently selected from the group consisting of hydrogen, methyl, and fluorine.
5. The compound according to any one of claims 1 to 4, wherein R5 is -(CR8R9)p- C(=O)OR7, or -(CR8R9)p-C(=O)NR8R9.
6. The compound according to any one of claims 1 to 4, wherein R5 is - (CR8R9)pOR12.
7. The compound according to any one of claims 1 to 4, wherein R5 is -(CR8R9)p- CR13R14R15.
8. The compound according to claim 7, wherein R14 and R15 are combined to form a ring system selected from the group consisting of substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted C3-7 cycloalkenyl, substituted or unsubstituted C2-6 heteroalicyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, wherein when the ring system formed by the combination of R14 and R15 is substituted, it is substituted with -(CH2)q(R5a) n R 5a is independently selected from the group consisting of OR20, NR21R22, -CN, -CH2-CN, C1-6 alkyl, O2R20, - CH2C(CH3)2(OR20), -OR20, -CH2-triazolyl, -CF3, dimethyl substituted-imidazolyl-2,4-dione, - CH2-SO2NR21R22, morpholinyl, -C(=O)-morpholinyl, piperidinyl-CH2OR20, -OCH2- tetrahydrofuryl, piperazinonyl, piperidinyl-CONR21R22, -OH, -CONR21R22, cyclopentyl, pyrrolidonyl, -NR21SO2R20, tetrazolyl, -CH2-tetrazolyl, -CH2OR20-SO3R20, -SO2R20, - SO2NR21R22, and halogen; R20, R21, and R22 are independently of each other selected from the group consisting of hydrogen, C1-6 alkyl, -CN, and C3-6 cycloalkyl; q is an integer selected from 0, 1 or 2.
9. The nd according to claim 7 or claim 8, wherein R14 and R15 are combined to form a ring system ed from the group consisting of tuted or unsubstituted C4-7 cycloalkyl, substituted or unsubstituted C6-12 membered aryl, substituted or unsubstituted 4- membered heteroalicyclyl, substituted or unsubstituted 5-membered heteroaryl, substituted or unsubstituted 5-membered heteroalicyclyl, substituted or unsubstituted ered heteroaryl, a substituted or unsubstituted 6-membered heteroalicyclyl, tuted or unsubstituted 7-membered aryl, and a tuted or unsubstituted 7-membered heteroalicyclyl, wherein when the ring system formed by the combination of R14 and R15 is substituted, it is substituted with -(CH2)q(R5a) wherein R 5a is independently selected from the group consisting of -CH2COOR20, -CH2CONR21R22, -CN, -CH2-CN, C1-6 alkyl, -CH2-SO2R20, - CH2C(CH3)2(OR20), -OR20, -CH2-triazolyl, -CF3, dimethyl substituted-imidazolyl-2,4-dione, - CH2-SO2NR21R22, morpholinyl, -morpholinyl, piperidinyl-CH2OR20, -OCH2- ydrofuryl, piperazinonyl, piperidinyl-CONR21R22, -OH, -CONR21R22, cyclopentyl, pyrrolidonyl, -NR21SO2R20, tetrazolyl, -CH2-tetrazolyl, -CH2OR20-SO3R20, 0, - SO2NR21R22, and halogen; R20, R21, and R22 are independently of each other selected from the group consisting of hydrogen, C1-6 alkyl, -CN, and C3-6 cycloalkyl; q is an integer selected from 0, 1 or 2.
10. The compound according to any one of claims 7 to 9, wherein R14 and R15 are combined to form a ring system selected from the group consisting of phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, thietanyl, pyrrolyl, pyrazoleyl imidazolyl, pyrrolidinyl, imidazolinyl, pyrazolidinyl, thiazolidinyl, isothiazolidinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, zolyl, oxathianyl thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, nyl, piperidinyl, piperazinyl, linyl, thiomorpholinyl, dioxolanyl, dioxanyl, furyl, dihydrofuranyl, nyl, tetrahydrofuryl, pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, dithiolanyl, dithianyl, thiopyranyl, thianyl, thienyl, oxetanyl, quinolyl, isoquinolyl, l, iso-indolyl, and tetrahydrothienyl, any of which may be tuted or unsubstituted, wherein when the ring system formed by the combination of R14 and R15 is substituted, it is tuted with -(CH2)q(R5a) n R 5a is independently selected from the group consisting of -CH2COOR20, -CH2CONR21R22, -CN, N, C1-6 alkyl, -CH2-SO2R20, - CH2C(CH3)2(OR20), -OR20, -CH2-triazolyl, -CF3, dimethyl substituted-imidazolyl-2,4-dione, - CH2-SO2NR21R22, morpholinyl, -C(=O)-morpholinyl, piperidinyl-CH2OR20, -OCH2- tetrahydrofuryl, zinonyl, piperidinyl-CONR21R22, -OH, -CONR21R22, entyl, pyrrolidonyl, -NR21SO2R20, tetrazolyl, -CH2-tetrazolyl, -CH2OR20-SO3R20, -SO2R20, - SO2NR21R22, and halogen; R20, R21, and R22 are independently of each other selected from the group ting of hydrogen, C1-6 alkyl, -CN, and C3-6 cycloalkyl; q is an integer selected from 0, 1 or 2.
11. The compounds according to claim 10, wherein the ring system is selected from the group consisting of cycloheptyl, cyclohexyl, cyclopentyl, dioxanyl, furyl, imidazolyl, isothiazolyl, isoxazolyl, morpholinyl, oxazolyl, oxetanyl, oxathianyl, phenyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazolyl, pyridyl, pyrimidyl, pyrrolidinyl, pyrrolyl, tetrahydrofuryl, tetrahydropyranyl, tetrazolyl, thianyl, thiazolyl, thienyl, rpholinyl, ryl, and triazolyl, any of which may be substituted or tituted, wherein when the ring system formed by the combination of R14 and R15 is substituted, it is substituted with -(CH2)q(R5a) wherein R 5a is independently selected from the group consisting of -CH2COOR20, -CH2CONR21R22, -CN, -CH2-CN, C1-6 alkyl, -CH2-SO2R20, - CH2C(CH3)2(OR20), -OR20, -CH2-triazolyl, -CF3, dimethyl substituted-imidazolyl-2,4-dione, - CH2-SO2NR21R22, morpholinyl, -C(=O)-morpholinyl, piperidinyl-CH2OR20, -OCH2- tetrahydrofuryl, piperazinonyl, piperidinyl-CONR21R22, -OH, -CONR21R22, cyclopentyl, pyrrolidonyl, -NR21SO2R20, tetrazolyl, -CH2-tetrazolyl, -CH2OR20-SO3R20, -SO2R20, - SO2NR21R22, and halogen; R20, R21, and R22 are independently of each other selected from the group ting of hydrogen, C1-6 alkyl, -CN, and C3-6 cycloalkyl; q is an integer selected from 0, 1 or 2.
12. The compound according to any one of claims 7 to 11, wherein R13 is absent or selected from the group ting of hydrogen, -CN, -CH3, fluorine, -OH, -CH2OH, -OCH3, -CH2CH2OH, -CO2H, -CO2-C1alkyl and -CONR8R9 wherein R8 and R9 are ndently selected from hydrogen, C1-4 alkyl, and C1-4 aminoalkyl, or R8 and R9 are combined to form a C2-C6 heteroalicyclyl.
13. The compound according to any one of claims 1 to 12, wherein Y is NR.
14. The compound according to any one of claims 1 to 13, wherein R is hydrogen.
15. The compound ing to any one of claims 1 to 14, n R1 is selected from the group consisting of hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, and C1-4 alkoxy.
16. The compound according to any one of claims 1 to 15, n R1 is selected from the group consisting of hydrogen, n, C1-4 alkyl, C1-4 haloalkyl, and C1-4 hydroxyalkyl.
17. The compound according to any one of claims 1 to 16, wherein R1 is hydrogen or -CF3.
18. The compound ing to any one of claims 1 to 17, wherein R2 is selected from the group consisting of hydrogen, n, C1-4 alkyl, C1-4 haloalkyl, and C1-4 yalkyl.
19. The compound according to any one of claims 1 to 18, wherein R2 is halogen.
20. The compound according to any one of claims 1 to 19, wherein R2 is fluorine.
21. The nd according to any one of claims 1 to 20, wherein R3 is selected from the group consisting of hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, oxo, C1-4 alkoxy and C1-4 haloalkoxy.
22. The nd according to any one of claims 1 to 21, wherein R3 is selected from the group consisting of hydrogen, methyl, fluorine, chlorine, and oxo.
23. The nd according to any one of claims 1 to 22, n whenever m is an integer selected from 2, 3, or 4, at least two of the R3 groups present are bound to the same atom of ring system C.
24. The nd according to any one of claims 1 to 23, wherein R4a is selected from the group consisting of hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, -CN, C1-C6 alkoxy, C1-6 haloalkoxy, C3-C5 cycloalkyl, heteroaryl, and aryl.
25. The compound according to any one of claims 1 to 24, wherein R4a is selected from the group consisting of halogen, C1-4 alkyl, C1-4 haloalkyl, C1-C4 , C1-4 haloalkoxy, and heteroaryl.
26. The compound according to any one of claims 1 to 25, wherein R4a is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, tert-butyl, chlorine, fluorine, methoxy, ethoxy, C1-2 haloalkyl, C1-2 haloalkoxy, and triazolyl.
27. The compound according to any one of claims 1 to 26, wherein R4a is selected from the group consisting of -CF3, -CHF2, -OCF3, and -OCHF2.
28. The compound according to any one of claims 1 to 27, wherein R4b is selected from the group consisting of hydrogen, oxo, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-C4 alkoxy, -OH, and C1-4 haloalkoxy.
29. The compound according to any one of claims 1 to 28, wherein R4b is ed from the group consisting of methyl, ethyl, propyl, iso-propyl, tert-butyl, chlorine, fluorine, methoxy, ethoxy, -OH, C1-2 haloalkyl, and C1-2 haloalkoxy.
30. The compound according to any one of claims 1 to 29, n R4b is selected from the group consisting of -CF3, -CF2CF3, -CHF2, -OCF3, -OCF2CF3, and -OCHF2.
31. The compound according to any one of claims 1 to 30, wherein R6a is selected from the group consisting of hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and aryl; or R6a and R13 are taken together to form a ring system selected from C3-6 cycloalkyl, and C2-9 heteroalicyclyl, or R6a and R6b are taken together to form a ring system selected from C3-6 cycloalkyl, and C2-9 heteroalicyclyl.
32. The compound according to any one of claims 1 to 31, wherein R6a is selected from the group consisting of hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and aryl.
33. The compound ing to any one of claims 1 to 32, wherein R6a is hydrogen.
34. The compound according to any one of claims 1 to 33, wherein R6b is selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1alkoxy-C1alkyl, aryl-C1-6 alkyl, C2-9 heteroalicyclyl-C1-6 alkyl, heteroaryl, and aryl.
35. The compound according to any one of claims 1 to 34, wherein R6b is selected from the group consisting of en, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-C6 alkoxy, C1-6 haloalkoxy, and C1alkoxy-C1alkyl; or R6b is selected from the group consisting of -(CH2)q-aryl, -(CH2)q-C2-9 heteroalicyclyl, and -(CH2)q-heteroaryl, which may be substituted by one or more tuents selected from the group consisting of halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C3-5 cycloalkyl, -(CH2)q-CONR23R24, -(CH2)q-SO2R23, - (CH2)q-NR23SO2R24 and -(CH2)q-SO2NR23, R23, and R24 are independently ed from the group consisting of hydrogen, C1-6 alkyl, -CN, C3-6 cycloalkyl, and C2-6 heteroalicyclyl; and q is an integer selected from 0, or 1.
36. The compound according to any one of claims 1 to 35, wherein R6b is selected from the group consisting of hydrogen, -(CH2)C(CH3)3, -(CH2)CONH2, phenyl, phenyl substituted with 1 to 3 halogens, 3)OC(CH3)3, henyl-OCH3, -phenyl-OCH3, - CH2-pyridyl, CH2-cyclohexyl-CH2CO2H, yclohexyl-CH2CONH2,CH2-cyclohexyl- CH2-tetrazolyl, -CH2-cyclohexyl-CH2OH, -CH2-cyclohexyl-NHSO2CH3, yclohexyl- NHSO2CH2CF3, -CH2-cyclohexyl-CH2CN, -CH2-phenyl-CH2CO2H, -CH2-phenyl- CH2CONH2, -CH2-phenyl-CH2CONH2CH3, -CH2-phenyl-CH2-tetrazolyl, -CH2-phenyl- CONH2, -CH2-phenyl-SO2NH-cyclopropyl, -CH2-phenyl-SO2CH3, -CH2-phenyl-NHSO2CF3, - CH2-phenyl-NHSO2CH3, -CH2-phenyl-NHSO2CHF2, -CH2-pyridyl-CH3, yridyl- SO2CH3, -CH2-pyridyl-CH2CONH2, -CH2-pyrimidyl-NHSO2CH3, -CH2-piperidyl-COCH3, - CH2-piperidyl-SO2CH3, -CH2-piperidyl-SO2CF3, -CH2-thienyl-CH2CO2H, -CH2-cyclobutyl- CH2CO2H, yclobutyl-CH2CONH2, -CH2-cyclobutyl-CO2H, -CH2-cyclobutyl-CONH2, - CH2-tetrahydrothiopyryl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2-tetrahydrofuranyl, -CH2- tetrahydropyranyl, -CH2-oxetanyl, and -CH2-pyranyl.
37. The nd according to any one of claims 1 to 36, wherein R6b is en or -(CH2)C(CH3)3.
38. The compound according to any one of claims 1 to 37, wherein R6b is hydrogen.
39. The compound according to any one of claims 1 to 38, wherein R7, R8, R9, and R12 are independently ed from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, aryl-C1-6 alkyl, heteroaryl-C1-6 alkyl and aryl.
40. The compound according to any one of claims 1 to 39, wherein R7, R8, R9, and R12 are independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, and aryl.
41. The compound according to any one of claims 1 to 40, wherein R7, R8, R9, and R12 are independently selected from hydrogen, C1-4 alkyl, C1-4 haloalkyl, and C1-4 hydroxyalkyl.
42. The compound according to any one of claims 1 to 41, wherein R7, R8, R9, and R12 are independently selected from en, methyl, ethyl and tert-butyl.
43. The compound according to any one of claims 1 to 42, wherein ring system B is aryl or heteroaryl.
44. The compound according to any one of claims 1 to 43, wherein ring system B has at least one of R4a or R4b present and other than hydrogen.
45. The compound ing to any one of claims 1 to 44, wherein ring system B is a 6-membered aryl having R4a in the para-position or osition to ring system C, 6- membered heteroaryl having R4a in the para-position or meta-position to ring system C, or 5- membered heteroaryl having R4a in 2- or 3-position.
46. The nd according to any one of claims 1 to 45, wherein ring system B is ed from the group consisting of phenyl, pyridyl, pyrazolyl, pyridazinyl, pyrimidinyl, naphthyl and furanyl.
47. The compound ing to any one of claims 1 to 42, wherein ring system B is a C2-C9 bicyclic alicyclyl.
48. The compound according to claim 47, wherein the C2-C9 bicyclic heteroalicyclyl is selected from the group consisting of 2H-benzo[b][1,4]oxazin-3(4H)-one, 3,4- dihydroquinolin-2(1H)-one, 1,2,3,4-tetrahydroquinoline, 3,4-dihydro-2H- benzo[b][1,4]oxazine, hydrobenzo[d]oxazole, 2,3-dihydro-1H-benzo[d]imidazole, indoline, and 1,3-dihydro-2H-benzo[d]imidazolone, and benzo[d]oxazol-2(3H)-one.
49. The compound according to any one of claims 1 to 48, wherein ring system C is a C2-9 heteroalicyclyl.
50. The compound according to any one of claims 1 to 49, wherein ring system C is a 4membered heteroalicyclyl.
51. The compound according to any one of claims 1 to 50, wherein ring system C is selected from the group ting of a ered heteroalicyclyl, and 6-membered heteroalicyclyl.
52. The compound ing to any one of claims 1 to 51, wherein ring system C is selected from the group consisting of pyrrolidinyl, piperidyl, azetidinyl and morpholinyl.
53. The compound according to any one of claims 1 to 52, wherein m is an integer selected from the group consisting of 1, 2, 3 and 4.
54. The compound according to any one of claims 1 to 53, wherein m is 1 or 2.
55. The compound according to any one of claims 1 to 54, wherein n is an integer selected from the group consisting of 1, 2, 3 and 4.
56. The compound according to any one of claims 1 to 55, wherein n is 0 and/or m is
57. The compound according to any one of claims 1 to 56, wherein p is an integer selected from 0, 1 or 2.
58. The compound according to any one of claims 1 to 57, wherein p is 0.
59. The compound ing to claim 1, selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and , or a pharmaceutically acceptable salt or stereoisomer thereof.
60. A pharmaceutical composition comprising a compound according to any one of claims 1 to 59 and at least one pharmaceutical acceptable excipient.
61. Use of a compound according to any one of claims 1-59 in the manufacture of a medicament for the treatment and/or prevention of an inflammatory, metabolic or autoimmune disease or disorder.
62. The use according to claim 61, wherein the disease or disorder is selected from the group consisting of asthma, chronic obstructive pulmonary disease (COPD), bronchitis, atherosclerosis, helicobacter pylori infection, allergic diseases including ic rhinitis, allergic conjunctivitis and uvetis, sprue and food y, atopic itis, cystic fibrosis, lung allograph rejection, multiple sclerosis, rheumatoid tis, juvenile toid arthritis, osteoarthritis, ankylosing litis, psoriasis, psoriatic arthritis, steatosis, steatohepatitis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic hepatitis (NASH), lupus erythematosus, Hashimoto's disease, pancreatisis, autoimmune diabetes, mune ocular disease, ulcerative colitis, colitis, Crohn's disease, inflammatory bowel disease (IBD), inflammatory bowel syndrome (IBS), Sjögren's syndrome, optic is, type I diabetes, neuromyelitis optica, Myastehnia Gravis, Guillain-Barre syndrome, Graves' disease, tis, obesity, obesity-induced insulin resistance and type II diabetes, and cancer.
63. Use of a nd according to any one of claims 1-59 in the manufacture of a medicament for modulating the activity of a retinoic acid receptor-related orphan or (ROR).
64. The use according to claim 63, wherein the receptor is a ROR& receptor.
65. The use according to claim 63, wherein the receptor is a ROR&1 or ROR&t receptor.
66. A method of treatment and/or prevention of an inflammatory, metabolic, or mune disease or disorder in a non-human animal comprising administering a compound according to any one of claims 1-59. NUEVOLUTION A/S By the Attorneys for the Applicant SPRUSON & FERGUSON Per:
NZ729138A 2014-08-04 2015-07-31 Optionally fused heterocyclyl-substituted derivatives of pyrimidine useful for the treatment of inflammatory, metabolic, oncologic and autoimmune diseases NZ729138B2 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
SE1450920 2014-08-04
SE1450920-2 2014-08-04
SE1451406 2014-11-21
SE1451406-1 2014-11-21
PCT/EP2015/067713 WO2016020295A1 (en) 2014-08-04 2015-07-31 Optionally fused heterocyclyl-substituted derivatives of pyrimidine useful for the treatment of inflammatory, metabolic, oncologic and autoimmune diseases

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NZ729138B2 true NZ729138B2 (en) 2021-06-29

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