MXPA01006148A - N-ureidoalkyl-piperidines as modulators of chemokine receptor activity - Google Patents
N-ureidoalkyl-piperidines as modulators of chemokine receptor activityInfo
- Publication number
- MXPA01006148A MXPA01006148A MXPA/A/2001/006148A MXPA01006148A MXPA01006148A MX PA01006148 A MXPA01006148 A MX PA01006148A MX PA01006148 A MXPA01006148 A MX PA01006148A MX PA01006148 A MXPA01006148 A MX PA01006148A
- Authority
- MX
- Mexico
- Prior art keywords
- methyl
- alkyl
- substituted
- case
- piperidinyl
- Prior art date
Links
- 230000000051 modifying Effects 0.000 title claims abstract description 25
- 102000009410 chemokine receptors Human genes 0.000 title claims description 26
- 108050000299 chemokine receptors Proteins 0.000 title claims description 26
- 230000000694 effects Effects 0.000 title claims description 21
- 150000003839 salts Chemical group 0.000 claims abstract description 26
- 230000002265 prevention Effects 0.000 claims abstract description 15
- 208000006673 Asthma Diseases 0.000 claims abstract description 13
- 101700070842 CCR3 Proteins 0.000 claims abstract description 6
- 102100005861 CCR3 Human genes 0.000 claims abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 819
- 125000003386 piperidinyl group Chemical group 0.000 claims description 430
- 239000004202 carbamide Substances 0.000 claims description 405
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 398
- -1 (CF2) rCF3 Inorganic materials 0.000 claims description 393
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 365
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 362
- 229910052799 carbon Inorganic materials 0.000 claims description 270
- 229910052739 hydrogen Inorganic materials 0.000 claims description 217
- 229910052801 chlorine Inorganic materials 0.000 claims description 211
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 208
- 229910052731 fluorine Inorganic materials 0.000 claims description 207
- 229910052794 bromium Inorganic materials 0.000 claims description 201
- 229910052740 iodine Inorganic materials 0.000 claims description 198
- 125000000304 alkynyl group Chemical group 0.000 claims description 188
- JCXJVPUVTGWSNB-UHFFFAOYSA-N nitrogen dioxide Inorganic materials O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims description 187
- 125000005842 heteroatoms Chemical group 0.000 claims description 184
- 125000003342 alkenyl group Chemical group 0.000 claims description 173
- 125000000623 heterocyclic group Chemical group 0.000 claims description 172
- 150000001875 compounds Chemical class 0.000 claims description 142
- 229910052717 sulfur Inorganic materials 0.000 claims description 130
- 125000002837 carbocyclic group Chemical group 0.000 claims description 128
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- 125000000753 cycloalkyl group Chemical group 0.000 claims description 71
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 53
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 52
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 48
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 48
- 125000004076 pyridyl group Chemical group 0.000 claims description 43
- 125000001544 thienyl group Chemical group 0.000 claims description 43
- 125000002541 furyl group Chemical group 0.000 claims description 42
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- 229910052736 halogen Inorganic materials 0.000 claims description 38
- 229910052757 nitrogen Inorganic materials 0.000 claims description 38
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 35
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- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 32
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 18
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 17
- NQRYJNQNLNOLGT-UHFFFAOYSA-O piperidinium(1+) Chemical compound C1CC[NH2+]CC1 NQRYJNQNLNOLGT-UHFFFAOYSA-O 0.000 claims description 17
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 16
- 125000005843 halogen group Chemical group 0.000 claims description 16
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- 239000011701 zinc Substances 0.000 description 1
- 125000004933 β-carbolinyl group Chemical group C1(=NC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- YEJRWHAVMIAJKC-UHFFFAOYSA-N γ-lactone 4-hydroxy-butyric acid Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 description 1
Abstract
The present application describes modulators of CCR3 of formula (I) or pharmaceutically acceptable salt forms thereof, useful for the prevention of asthma and other allergic diseases.
Description
N-UREIDOALQUIL-PIPERIDINAS AS MODULATORS OF THE ACTIVITY OF CHEMICAL RECEPTORS
FIELD OF THE INVENTION
This invention relates, in general, to modulators of chemokine receptor activity, to pharmaceutical compositions containing them, and to methods of using same as agents for the treatment and prevention of inflammatory diseases such as asthma and allergic diseases. , as well as immune pathologies such as rheumatoid arthritis and atherosclerosis.
BACKGROUND OF THE INVENTION
Quimicionas are chemotactic cytokines, of molecular weight of 6-15 kDa, that are released by a wide variety of cells, to attract and activate, among other cell types, macrophages, T and B lymphocytes, eosinophils, basophils and neutrophils (reviewed in Luster, New Eng. J
Med., 338, 436-445 (1998) and Rollins, Blood, 90, 909-928
(1997)). There are two main classes of chemokines, CXC and CC, depending on whether the first two cysteines, in the amino acid sequence, are separated by a single
REF .: 129050
amino acid (CXC) or are adjacent (CC). CXC chemokines, such as interleukin-8 (IL-8), neutrophil-activating protein-2 (NAP-2) and melanoma-growth-stimulating protein (MGSA) are chemotactic mainly for neutrophils and T-lymphocytes , whereas CC chimicols, such as RANTES, MlP-la, MlP-lß, monocytic chemotactic proteins (MCP-1, MCP-2, MCP-3, MCP-4, and MCP-5) and eotaxins (- 1, -2 and -3) are chemotactic for, among other cell types, macrophages, T lymphocytes, eosinophils, dendritic cells and basophils. There are also the chemokines lyfotactin-1, lyfotactin-2 (both chemokines C), and fractalcin (a chemokine CXXXC) that are not found in any of the two main subfamilies of chemokines. Chemokines bind to specific cell surface receptors, which belong to the seven transmembrane protein family of proteins coupled to the G protein (reviewed in Horuk, Trends Pharm. Sci., 15, 159-165 (1994)) they call "chemokine receptors". By binding their connate ligands, the chemokine receptors transduce an intracellular signal through the associated trimeric G proteins, resulting, among other responses, in a rapid increase in intracellular calcium concentration, changes in cell shape,
Increased expression of cell adhesion cells, degranulation and promotion of cell migration. There are at least ten human chemokine receptors that bind to or respond to CC chemokines with the following characteristic patterns: CCR-1 (or "CKR-1" or "CC-CKR-1") [MlP-la, MCP-3 , MCP-4, RANTES] (Ben-Barruch, et al.,) Cell, 72, 415-425 (1993), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-2A and CCR-2B (or "CKR-2A" / "CKR-2B" or "CC-CKR-2A" / "CC-CKR-2B") [MCP-1, MPC-2, MPC-3, MCP-4, MCP-5] (Charo et al., Proc. Nati. Acad. Sci. United States of
North America, 91, 2752-2756 (1994), Luster, New Eng. J.
Med., 338, 436-445 (1198)); CCR-3 (or "CKR-3" or "CC-CKR-3") [eotaxin-1, eotaxin-2, RANTES, MCP-3, MCP-4]
(Combadiere, et al., J. Biol. Chem., 270, 16491-16494 (1995), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-4 (or "CKR-4" or "CC-CKR-4") [TARC, MIP-la, RANTES, MCP-1] (Power et al., J. Biol. Chem., 270, 19495-19500 (1995), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-5 (or "CKR-5" or "CC-CKR-5") [MIP-la, RANTES, MCP-lβ] (Samson, et al., Biochemistry, 35, 3362-3367 (1996); 6 (or "CKR-6" or "CC-CKR-6") [LARC] (Baba et al., J. Biol. Chem., 272, 14893-14898 (1997)); CCR-7 (or "CKR -7"or" CC-CKR-7") [ELC] (Yoshie et al., J. Leukoc, Biol. 62, 634-644 (1997)); CCR-8 (or" CKR-8"or" CC -CKR-8") [1-309, TARC, MlP-lβ] [Napolitano et al., J. Immunol., 157, 2759-2763 (1996), Bernardini et al.,
Eur. J. Immunol., 28, 582-588 (1998)); and CCR-10 (or "CKR-10" or "CC-CKR-10") [MPC-1, MPC-3] (Bonini et al, DNA and Cell Biol., 16 1249-1256 (1997)). In addition to mammalian chemokine receptors, it has been shown that mammalian cytomegalovirus, herpesvirus and poxvirus express, in infected cells, proteins with chemokine receptor binding properties (reviewed by Wells and Schwartz, Curr, Opin Biotech., 8, 741-748 (1997)). Human CC chemokines, such as RANTES and MCP-3, can cause rapid mobilization of calcium through these virally encoded receptors. The expression of the receptors may be permissive for infection, leaving the subversion of the normal immune system's survival and response to infection. Additionally, human chemokine receptors such as CXCR4, CCR2, CCR3, CCR5 and CCR8, can act as co-receptors for the infection of mammalian cells by microbes, for example as with human immunodeficiency viruses (HIV). Quimiciona receptors have been implicated as important mediators of inflammatory, infectious and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and
Atherosclerosis For example, the CCR-3 chemokine receptor plays a pivotal role in attracting eosinophils to sites of allergic inflammation and subsequently active cells. The chemokine ligands for CCR-3 induce a rapid increase in intracellular calcium concentration, increased expression of cell adhesion molecules, cellular degranulation and the promotion of eosinophil migration. Therefore, agents that would modulate the chymic receptors would be useful in those disorders and diseases. In addition, agents that modulate chemokine receptors would also be useful in infectious diseases such as for example by blocking infection of cells expressing CCR3 by HIV or in preventing the manipulation of immune cellular responses by viruses such as cytomegalovirus. A substantial amount of techniques has accumulated over the past decades, with respect to piperidines and substituted pyrrolidines. These compounds have been implicated in the treatment of a variety of disorders. WO 98/25604 discloses spiro-substituted azacycles, which are useful as modulators of chemokine receptors:
wherein R1 is C6_6alkyl, optionally substituted with functional groups such as -NR6CONHR7, wherein R6 and R7 may be phenyl further substituted with hydroxy, alkyl, cyano, halo and haloalkyl. These spiro compounds are not considered part of the present invention. WO 95/13069 focuses on certain compounds of piperidine, pyrrolidine, and hexahydro-1H-azepine, of the general formula:
wherein A can be substituted alkyl or Z-substituted alkyl, with Z = NR6a or O. Compounds of these types are claimed to promote the release of growth hormone in humans and animals. WO 93/06108 discloses pyrrolobenzoxazine derivatives as agonists and antagonists of 5-hydroxytryptamine (5-HT):
wherein A is lower alkylene and R4 may be phenyl optionally substituted with halogen. U.S. Patent No. 5,668,151 discloses Neuropeptide Y (NPY) antagonists comprising 1,4-dihydropyridines with a piperidinyl or tetrahydropyridinyl-containing portion attached to the 3-position of the 4-phenyl ring:
wherein B can be NH, N R1, O, or a bond, and R7 can be substituted phenyl, benzyl, phenethyl, and the like. These reference compounds are easily structurally distinguished, either by the nature of the urea functionality, the binding chain or the possible substitution of the present invention. The prior art does not describe or suggest the unique combination of fragments
structural elements that incorporate these novel piperidines and pyrrolidines, due to their activity towards the chemokine receptors.
BRIEF DESCRIPTION OF THE INVENTION
Accordingly, an object of the present invention is to provide novel agonists or antagonists of CCR-3, or pharmaceutically acceptable salts or prodrugs thereof. Another object of the present invention is to provide pharmaceutical compositions containing a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof. Another object of the present invention is to provide a method for the treatment of inflammatory diseases and allergic disorders, comprising administering to a host in need of such treatment, a therapeutically effective amount of at least one of the compounds of the present invention, or a salt or pharmaceutically acceptable prodrug form thereof. Another object of the present invention is to provide new N-ureidoalkyl piperidines, for the use
in therapy. Another object of the present invention is to provide the use of novel N-ureidoalkyl piperidines, for the manufacture of a medicament for the treatment of allergic disorders. In another modality, the present invention provides novel N-ureidoalkyl piperidines, for use in therapy. In another embodiment, the present invention provides the use of novel N-ureidolalkyl piperidines, for the manufacture of a medicament for the treatment of allergic disorders. These and other objects, which will be apparent during the following detailed description, have been achieved by the inventors' discovery that the compounds of Formula (I):
(I)
or stereosomers or pharmaceutically acceptable salts thereof, wherein E, Z, M, J, K, L, Q, R1, R2, R3 and R4 are defined later, are effective modulators of the
activity of chemokines.
DETAILED DESCRIPTION OF THE INVENTION
. [1] In one embodiment, the present invention provides novel compounds of formula (I):
(I)
or stereoisomers or pharmaceutically acceptable salts thereof, wherein:
M is absent or selected from CH2, CHR5, CHR13, CR13R13, and CR5R13;
Q is selected from CH2, CHR3, CHR, CR1JR, and CR > 53Rt-, 13,, •
J and K are selected from CH2, CHR °, CHRb, CR ° Rb and CR5R6;
L is CHR - with the proviso that:
when M is absent, J is selected from CH2, CHR5, CHR13, and CR5R13; it is selected from 0 and S; is selected from:
ring A is a C3-6 carbocyclic residue, with the proviso that the C3_6 carbocyclic residue is not phenyl;
R1 and R2 are independently selected from H, Ci-e alkyl, C2_8 alkenyl, C2-8 alkynyl, (CH2) r-C3_6 cycloalkyl, and a (CH2) r- C3_? Carbocyclic residue or substituted with R of 0-5;
Ra, in each case, is selected from C6-alkyl, C2_8 alkenyl, C2-8 alkynyl, (CH2) C3_6 cycloalkyl, Cl, Br, I, F, (CF2) rCF3, N02, CN, (CH2) rNRbRb , (CH2) rOH, (CH2) rO c, (CH2) rSH, (CH2) rSRA (CH2) EC (0) Rb, (CH2) rC (O) NRbRb, (CH2) rNRbC (0) Rb, (CH2) ) rC (0) ORb, (CH2) rOC (O) Rc, (CH2) rOH (= NRb) NRbRb, (CH2) rNHC (= NRb) NRbRb, (CH2) rS (O) pRc,
(CH2) rS (0) 2NRbRb, (CH2) rNRbS (0) 2Rc, and (CH2) rphenyl;
R, in each case, is selected from H, C? _6 alkyl, C3-6 cycloalkyl, and phenyl;
Rc, in each case, is selected from C ± -e alkyl, cycloalkyl
C3-6, and phenyl;
alternatively, R2 and R3 together form a ring of 5, 6, or 7 elements substituted with Ra of 0-3;
R is selected from a (CR 'R ") r-carbocyclic residue C3-10 substituted with R15 of 0-5 and a heterocyclic system (CR3'R3 ,,) r of 5-10 elements containing 1-4 selected heteroatoms of N, 0 and S, substituted with R15 of 0-3;
R 'and R ", in each case, are selected from H, alkyl Ci-e, (CH2) r-cycloalkyl C3_e, and phenyl;
R is absent, taken together with the nitrogen to which it is attached to form an N-oxide, or is selected from C? _6 alkyl, C2_8 alkenyl, C2_? Alkynyl,
(CH2) C3-6 cycloalkyl, (CH2) qC (0) R "b
(CH2) qC (0) NRaR4a ', (CH2) qC (0) OR4b, and a (CH2) carbocyclic residue substituted with Rc of 0-3;
Ra and Ra ', in each case, are selected from H, C? _6 alkyl, (CH2) r C3_6 cycloalkyl, and phenyl;
R > 4b, in each case, is selected from C? _6 alkyl, alkenyl
C2-8, (CH2) r C3_6 cycloalkyl, C2_8 alkynyl, and phenyl;
R 4c in each case is selected from C 6 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-6 cycloalkyl, Cl, F, Br, I, CN, N 0 2, (CF 2) rCF 3, (CH 2) rOalkyl C? _ 5, (CH2) rOH, (CH2) rS C1-5 alkyl, (CH2) rNR4aR4a ', and (CH2) rphenyl;
alternatively, R4 binds with R7, R9, R11, or R14 to form a 5-, 6-, or 7-membered piperidinium spirocycle or pyrrolidinium spirocycle with Ra of 0-3;
R5 is selected from a (CR5'R5") t-carbocyclic residue C3_? 0 substituted with R16 of 0-5 and a (CR5'R5") t-heterocyclic system of 5-10 elements containing 1-4 heteroatoms selected from N, O and S, substituted with R16 of 0-3;
R5 'and R5", in each case, are selected from H, C? _6 alkyl, (CH2) C3_6 cycloalkyl, and phenyl;
R, in each case, is selected from C? _e alkyl, C 2-8 alkenyl, C 2-8 alkynyl, (CH 2) cycloalkyl C3_6, (CF2) rCF3, CN, (CH2) rNR6aR6a ', (CH2) rOH, (CH2) ) rOR6, (CH2) rSH,
(CH2) rSR6b, (CH2) rC (0) 0H, (CH2) rC (0) R 6 ° bD, (CH2) rNR 6DdarC (0) R, 6a (CH2) rC (0) OR 6b
(CH2) rOC (0) R, 6ObD, (CH2) rS (0) pR, 6ObD, (CH2) rS (0) 2NR6aR6a ',
(CH2) rNR6dS (0) 2R6b and (CH2) tphenyl substituted with R6c of
0-3;
Roa and R, 6a, in each case, are selected from H, C? _6 alkyl, C3_6 cycloalkyl, and phenyl substituted with R, 6c of 0-3;
R, in each case, is selected from C? -6 alkyl, cycloalkyl
C3-6 and phenyl substituted with R 6c of 0-3;
R, in each case, is selected from C? -6 alkyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) rCF3, (CH2) rOalkyl C? -5, (CH2) rOH , (CH2) rSalt d-5, and (CH2) rNR6dR6d;
R, 6d, in each case, is selected from H, C? _6 alkyl, and C3_6 cycloalkyl;
with the proviso that when either of J or K is CR6R6 and R6 is halogen, cyano, nitro, or bonded to the carbon to which it is attached by a heteroatom, the other R6 is not halogen, cyano, or is bonded to the carbon to which it is attached. is linked by a heteroatom;
R7 is selected from H, C? -6 alkyl, C2_8 alkenyl, alkynyl
c22_-8, (CH2) qOH, (CH2) qSH, (CH2) qOR7d, (CH2) qSR 7d
(CH2) qNR, 7'aaDR7'aa'A (CH2) rC (0) OH, (CH2) rC (O) R, 7'bD,
(CH2) rC (0) NR7aR7a ', (CH2) qNR7aC (0) R7, (CH2) qNR7aC (O) H,
(CH2) r (0) OR7b, (CH2) qOC (0) R7, (CH2) qS (O) pR7b,
(CH2) qS (0) 2NR j7aaRr, 7aa'A (CH2) qNR7aS (0) 2R, 7'bD, haloalkyl C? _6, a (CH2) r-carbocyclic residue C3-? Or substituted with R7c of 0-3 , and a heterocyclic 5-10 element (CH2) r-system containing 1-4 heteroatoms selected from N, 0, and S, substituted with R7c of 0-2;
R, 7a and R, 7a ', in each case, are selected from H, Cs alkyl, C2_8 alkenyl, C2_8 alkynyl, (CH2) r-C3_6 cycloalkyl, a (CH2) r C3_10 carbocyclic residue substituted with R7e of 0 -5, and a heterocyclic 5-10 element (CH2) r-system containing 1-4 heteroatoms selected from N, 0, and S, substituted with R7e from 0-3;
R7b, in each case, is selected from C? -6 alkyl, C2-8 alkenyl, C2_8 alkynyl, a (CH2) r C3-6 carbocyclic residue substituted with R7e of 0-2, and a (CH2) r heterocyclic 5-6 elements containing 1-4 heteroatoms selected from N, 0, and S, substituted with R7e from 0-3;
R 7c in each case is selected from C 1 -C 6 alkyl, C 2 al alkenyl, C 2-8 alkynyl, (CH 2) r C 3-6 cycloalkyl, Cl, Br, 1, F, (CF 2) rCF 3, N 0 2, CN, ( CH2) rNR7fR7f, (CH2) rOH,
(CH2) rOalkyl C? _4, (CH2) rSalt C? -4, (CH2) rC (O) OH,
(CH2) EC (0) R7b, (CH2) rC (0) NR7fR7f, (CH2; rNR7fC (0) R7a,
(CH2) rC (O) O-alkyl '1-4, (CH2) r0C (0) R 7'b
(CH2) rNHC (= NR7f) NR7fR7f, (CH2) rS (0) 2NR7fR7f,
(CH2) rNR, 7'frSc (0) 2R, and (CH2) r phenyl substituted with R7e of 0-3;
R, 7d, in each case, is selected from C? _6 alkyl substituted with R, 7e of 0-3, alkenyl, alkynyl, and a C3-? O-substituted carbocyclic residue with R7c of 0-3;
R, 7e, in each case, is selected from C? _6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3_6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) ECF3, (CH2) rOalkyl C? -5, OH, SH, (CH2) rSalt C? _5 (CH2) rNR7fR7f, and (CH2) rphenyl;
R7f, in each case, is selected from H, C? -6 alkyl, and C3_6 cycloalkyl;
R is selected from H, C? _6 alkyl, C3_6 cycloalkyl, and (CH2) tphenyl substituted with R8a of 0-3;
R, in each case, is selected from C? _6 alkyl, C2-alkenyl, C2-s alkynyl, C3_6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) rCF3, (CH2) EOalkyl C1- 5, OH, SH, (CH2) rC1-5alkyl, (CH2) rNR7fR7f, and (CH2) rphenyl;
alternatively, R7 and R8 join to form cycloalkyl
R 8b is selected from H, C? _6 alkyl, C3_6 cycloalkyl, OH, CN, and (CH2) r-phenyl;
R is selected from H, C? _6 alkyl, C2_8 alkenyl, alkynyl
C2-8, F, Cl, Br, I, N02, CN, (CH2) rOH, (CH2) rSH,
(CH2) rOR > 9sd / (rC-Hu2_y), ES ooRSJd, (CHu2 ^) r MNDR »9aaDR39aa- ', (CH2) rC (O) OH,
(CH2) rC (0) R 9sb (CH2) rC (0) NR9aR9a ', (CH2) rNR9aC (0) R9a /
(CH2) rNR 9aaC (0) H, (CH2) rNR9aC (0) NHR9, (CH2) rC (0) OR 9sb
(CH2) r0C (0) R 93bA (CH2) rOC (0) NHR9a, (CH2) rS (0) pR 93bD,
(CH2) rS (0) 2NR9aR9a '(CH2) rNR9aS (0) 2R9b, haloalkyl C6-6, a (CH2) E-carbocyclic residue C3-? Or substituted with R9c of 0-5, and a (CH2) r- 5-10 element heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with R9c of 0-3;
R9a and R9a ', in each case, are selected from H, C6_6 alkyl, C2_8 alkenyl, C2-8 alkynyl, a (CH2) r_residue
C3-10 carbocyclic substituted with R9e of 0-5, and a 5-10 element (CH) r heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with R9e of 0-3;
R9b, in each case, is selected from C6_6 alkyl, C2_8 alkenyl, C2_8 alkynyl, a (CH2) r-C3-6 carbocyclic residue, substituted with R9e of 0-2, and a (CH2) r- heterocyclic system of 5-6 elements selected from N, O, and S, substituted with R9e of 0-3;
R 9c in each case is selected from C 1-6 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, (CH 2) r C 3-6 cycloalkyl, Cl, Br, I, F, (CF 2) rCF 3, N 0 2, CN, (CH 2) ) NR9fR9f, (CH2) rOH, (CH2) rOalkyl C? -, (CH2) rS alkyl C? _, (CH2) rC (O) OH, (CH2) rC (0) R9b, (CH2) EC (0) NR9fR9f, (CH2) ENR9fC (O) R9a, (CH2) rC (0) 0 C alquilo4 alkyl, (CH2) rOC (O) R9b,
(CH- :) rC (= -NMRR39If)) NR9fR9f, (CH2) rS (0) pR 9ybD,
(CH2) rNR, 93frSr (0) 2R, 9abD, and (CH2) rphenyl substituted with R9e of 0-3;
R, 9d, in each case, is selected from C? _6 alkyl, C2-6 alkenyl, C2_6 alkynyl, a C3_10 carbocyclic residue substituted with R 9: c from 0-3, a system
heterocyclic 5-6 elements containing 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with R9c of 0-3;
R 9e in each case, is selected from C? _6 alkyl, alkenyl
C2-s, C2-8 alkynyl, (CH2) r C6 cycloalkyl, Cl, F,
Br, I, CN, N02, (CF2) rCF3, (CH2) r0 alkyl C? _5, OH, SH,
(CH2) rS alkyl d-5, (CH2) ENR9fR9f, and (CH2) rphenyl;
R, 9f, in each case, is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl;
R 10 is selected from H, C 1 -C 6 alkyl, C 2 alkynyl C 2 alkynyl, F, Cl, Br, I, N 2, CN, (CH 2) E 0 H
(CH2) rOR10d, (CH2) rSR 10d (CH2) rNR10aR10a '(CH2) rC (0) OH
(CH2) rC (0) R 10b (CH2) rC (O) NR10aR10a 'ICH2) rNR, 1x0uaaC. (0) R10a
(CH2) ENR10aC 0) H, (CH2) rC (O) OR10b, (CH2) rOC (O) R10 (CH2) rS (0) pR, 1lOubJ, (CH2) ES (0) 2NR, 1l0uaatR-, 1l0uaa ' A (CH2) rNR10aS (O) 2R10 C1-6 haloalkyl, a (CH2) r carbocyclic residue C3_? Or substituted with R10c of 0-5, and a (CH2) r heterocyclic system of 5-10 elements containing from 1- 4 heteroatoms selected from N, O, and S, substituted with R10c of 0-3;
R, 10a and R a, in each case, are selected from H, alkyl Ci-g,
C2-8 alkenyl, C2-8 alkynyl, a (CH2) r C3_? carbocyclic residue or substituted with R10e of 0-5, and a heterocyclic (CH2) r system of 5-10 elements containing from 1-4 heteroatoms selected from N, O, and S, substituted with R10e of 0-3;
R10, in each case, is selected from C? -6 alkyl, C2_8 alkenyl, C2_8 alkynyl, a (CH2) r C3_6 carbocyclic residue substituted with R10e of 0-2, and a (CH2) r-heterocyclic system of 5-6 elements containing 1-4 heteroatoms selected from N, O, and S, substituted with R10e of 0-3;
R 10c in each case is selected from C ?6 alkyl, C2_8 alkenyl, C2_8 alkynyl, (CH2) r C3_6 cycloalkyl, Cl, Br I, F, (CF2) rCF3, N02, CN, (CH2) rNR10fR10f, (CH2 ) EOH (CH2) rO C alquilo alkyl, (CH2) rS C? -4 alkyl, (CH2) rC (0) OH (CH2) rC (O) R10b, (CH2) rC (O) NR10fR10f, (CH2) rNR10fC (O) R10a
(CH2) rC (0) 0 C 1i-4 alkyl (CH 2) r 0 C (0) R 10b
(CH2) rC (= NR llOufr), NR jliOUftRnlOf (CH2) rS (0) R, 10b (CH2) rNCH (= NR10f) NR10fR10f, (CH2) ES (O) 2NR10fR10f
(CH2) ENR10fS (O) 2R10b, and (CH2) r phenyl substituted with R10e of 0-3;
R, 10d, in each case, is selected from C? -6 alkyl, alkenyl
C2_6, C2-6 alkynyl, a C3_? 0 carbocyclic residue substituted with R10c of 0-3, and a 5-6 element heterocyclic system containing 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with R10c of 0-3;
R, in each case, is selected from C? -6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2) r C3_6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) rCF3, alkyl (CH2) rO d5, OH, SH, (CH2) rS alkyl C5-5, (CH2) rNR10fR10f, and (CH2) rphenyl;
R, in each case, is selected from H, C? _5 alkyl, and C3_e cycloalkyl;
alternatively, R9 and R10 join to form C3_7 cycloalkyl, cyclic ketal of 5-6 elements or = 0;
with the proviso that when R10 is halogen, cyano, nitro, or is bonded to the carbon to which it is attached through a heteroatom, R9 is not halogen, cyano or is linked to the carbon to which it is attached through a heteroatom;
R, 11 is selected from H, C? _6 alkyl, C2_8 alkenyl, C2-8 alkynyl, (CH2) q0H, (CH2) qSH, (CH2) qORlld,
(CH2) qSRlld, (CH2) qNRllaRlla ', (CH2) EC (O) OH, (CH2) rC (O) Rllb, (CH2) rC (O) NRllaRlla', (CH2) qNRllaC (O) Rlla,
(CH2) qNRllaC (0) NHRlla, (CH2) rC (O) ORllb, (CH2) qOC (O) Rllb, (CH2) qS (0) pRllb, (CH2) qS (0) 2NRllaRlla ', (CH2) qNRllaS (O) 2Rll, haloalkyl Ci-e, a (CH2) r-carbocyclic residue C3_? 0 substituted with Rllc of 0-5, and a (CH2) r-heterocyclic system of 5-6 elements containing 1-4 heteroatoms selected of N, O, and S, substituted with Rllc of 0-3;
Rlia and Rlla ', in each case, are selected from H, C? -6 alkyl, C2_8 alkenyl, C2_8 alkynyl, a (CH2) r- C3-? 0 carbocyclic residue substituted with Rlle of 0-5, and a (CH2) E-heterocyclic 5-10 element system containing 1-4 heteroatoms selected from N, O, and S, substituted with Rlle of 0-3;
Rllb, in each case, is selected from C6_6 alkyl, C2_8 alkenyl, C2_8 alkynyl, a C3-6 carbocyclic (CH2) E substituted with Rlle of 0-2, and a (CH2) r- heterocyclic system of 5-6 elements containing 1-4 heteroatoms selected from N, O, and S, substituted with Rlle of 0-3;
R, in each case, is selected from C? _6 alkyl, alkenyl
C2-8, C2_8 alkynyl, (CH2) E C3-6 cycloalkyl / Cl, Br, I, F, (CF2) rCF3, N02 CN, (CH2) rNRllfRllf, (CH2) rOH, (CH2) rO alkyl d-4 , (CH2) rS alkyl C? -4, (CH2) rC (0) OH, (CH2) rC (0) Rllb, (CH2) rC (0) NRllfRllf, (CH2) ENRllfC (O) Rlla, alkyl (CH2) ) rC (0) 0 C? _4, (CH2) NROC (O) Rllb,
(CH2) rC (= NRllf) NRllfRllf, (CH2) rNCH (= NRllf) NRllfRllf,
(CH2) rS (0) pRll, (CH2) rS (0) 2NRllfRllf, (CH2) ENRllfS (0) 2Rllb, and (CH2) r phenyl substituted with Rlle of 0-3;
R, lld, in each case, is selected from C? _6 alkyl, substituted with R, l, 0-3, C2_6 alkenyl, C2_6 alkynyl, and a C3_? 0 carbocyclic residue substituted with Rlie of 0-3;
Rlle, in each case, is selected from C? _6 alkyl, C2-alkenyl, C2-8 alkynyl, C3_6 cycloalkyl, Cl, F, Br, I,
CN, N02, (CF2) rCF3, (CH2) E0 C1-5 alkyl, OH, SH, (CH2) rS alkyl C? _5, (CH2) ENRUfRllf, and (CH2) rphenyl;
R, llf, in each case, is selected from H, C? _6 alkyl, and C3_6 cycloalkyl;
R12 is selected from H, alkyl C? _6, (CH2) qqO-yjHíí ,,
r C3_6 cycloalkyl, and (CH2) tphenyl substituted with R12a of 0-3;
R12a, in each case, is selected from C6_6 alkyl, C2_8 alkenyl, C2_8 alkynyl, C3_6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) rCF3, (CH2) rO C 1 alkyl 5, OH, SH, (CH2) rS alkyl C? _5, (CH2) rNR9fT9f, and (CH2) rphenyl;
alternatively, R11 and R12 join to form cycloalkyl
C3-7 *
R 13 in each case, is selected from C?-6 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-6 cycloalkyl, (CF 2) WCF 3
(CH2) NR13aR13a ', (CH2) rOH, (CH2) rOR 13b (CH2) rSH
(CH2) rSR13b, (CH2) wC (0) 0H, [CH2) wC (0) R 13b
(CH2) wC (0) NR 113JaarR > 13a '(CH2) rNR13dC (0) R13a, (CH2) wC (0) OR 13b
(CH2) rOC (0) R 13b (CH2) wS (0) pR 13b (CH2 wS (0) 2NR13aR13i (CH2) rNR13dS (0) 2R13b, and; CH2) w-f enyl substituted with
R13c of 0-3;
R13a and R13a ', in each case, are selected from H, C? -6 alkyl, C3_6 cycloalkyl, and phenyl substituted with R13C of 0-3;
R 1'3b in each case is selected from C 1 -C 6 alkyl, C 3 6 cycloalkyl, and phenyl substituted with R 13c 0-3;
R13C in each case is selected from C6_6 alkyl, C3_6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) rCF3, alkyl (CH2) rO C6-6, (CH2) rOH, (CH2) rS C1-5 alkyl, and (CH2) rNR13dR13d;
R 13d in each case is selected from H, C? _6 alkyl, and C3_6 cycloalkyl;
R 14 in each case is selected from C 1 _6 alkyl, C 2-8 alkenyl, C 2 8 alkynyl, (CH 2) r C 3 6 cycloalkyl, Cl, Br, I, F, N 2, CN, (CHR ') rNR 1 a R 1 a', (CHR ') rOH,
(CHR ') rO (CHR') rR 14d CHR ') rSH, (CHR') rC (0) H (CHR ') rS (CHR') rRl4d (CHR ') EC (0) OH
(CHR ') rC (O) (CHR') rR 14b (CHR ') rC (0) NR14aR14a'
(CHR ') ENR14fC (O) (CHR') rR14b, (CHR ') EC (0) 0 (CHR') rR 14d (CHR ') rOC (O) (CHR') ER14b, (CHR ') rC (= NR14f) NR1 aR1 '(CHR') ENHC (= NR14f) NR14fR1 f, (CHR ') rS (0) p (CHR') rR 14b
(CHR ') ES (0) 2NR14aR14a', CHR ')
(O) 2 (CHR ') rR 14b haloalkyl -6, C2_s alkenyl substituted with R' of 0-3, C2_8 alkynyl substituted with R 'of 0-3, (CHR') rphenyl substituted with R14e of 0-3, and a (CH2) r heterocyclic system of 5-10 elements containing 1-4 heteroatoms selected from N, O, and S, substituted with R15e of 0-2, or two R14 substituted on adjacent atoms of ring A forming together a
-6 element heterocyclic system containing 1-3 heteroatoms selected from N, 0, and S substituted with R15e from 0-2;
R ', in each case, is selected from H, alkyl d_6, C2_8 alkenyl, C2_s alkynyl, (CH2) r C3_6 cycloalkyl, and (CH) rphenyl substituted with R1 e;
R1 a and R14a, in each case, are selected from H, C? -6 alkyl, C2_8 alkenyl, C2_8 alkynyl, a (CH2) r- C3_? Carbocyclic residue or substituted with R1 e of 0-5, and a (CH2) Heterocyclic system of 5-10 elements containing 1-4 heteroatoms selected from N, O, and S, substituted with R1 and 0-2;
R14b, in each case, is selected from C? -6 alkyl, C2_s alkenyl, C2_8 alkynyl, a (CH2) E-C3_8 carbocyclic residue substituted with R14e of 0-3, and a (CH2) r heterocyclic system of 5-6 elements containing 1-4 heteroatoms selected from N, 0 and S, substituted with R1 and 0-2;
R, 14d, in each case, is selected from C2_8 alkenyl, alkynyl
C2-8, alkyl C? _6 substituted with R of 0-3, a (CH2) r-carbocyclic residue C3_? 0 substituted with Rl e
from 0-3, and a 5-6 element heterocyclic E (CH2) E system containing from 1-4 heteroatoms selected from N, O, and S, substituted with R1 e from 0-3;
R, in each case, is selected from C? -6 alkyl, C2_8 alkenyl, C2-8 alkynyl, (CH2) r C3-6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) rCF3, ( CH2) rO C1-5 alkyl, OH, SH, (CH2) rS C1-5 alkyl, (CH2) rNR14fR1 f, and (CH2) E phenyl;
R14f, in each case, is selected from H, C? _6 alkyl, C3_e cycloalkyl, and phenyl;
alternatively, Ri4 together with R form a piperidinium spirocycle or pyrrolidinium spirocycle of 5, 6 or 7 elements attached to ring A, the spirocycle substituted with Ra of 0-3;
R 15 in each case is selected from C 1-6 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, (CH 2) E C3_6 cycloalkyl, Cl, Br I, F, N02, CN, (CHR ') rNR15aR15a', (CHR ' ) rOH
(CHR ') rO (CHR') rR 15d (CHR ') rSH, (CHR') rC (0) H (CHR ') rS (CHR') rR 15d (CHR ') C (0) OH
(CHR ') rC (O) (CHR') rR 15b (CHR ') rC (0) NR15aR15a'
(CHR ') rNR, 1i5ofr, C (O) (CHR') rR 15b (CHR ') rC (0) 0 (CHR') rR 15d
(CHR ') rOC (0) (CHR') rR 15b (CHR ') rC (= NR15f) NR15aR15a',
(CHR ') rNHC (= NR15f) NR15fR15f, (CHR') rS (0) p (CHR ') rR 15b
(CHR ') rS (0) 2NR15aR15a' (CHR ') rNR15fS (O) 2 (CHR') rR15b, haloalkyl C? -6, C2_8 alkenyl substituted with R 'of 0-3, alkynyl substituted with R' of 0- 3, (CHR ') rphenyl substituted with R15e of 0-3, and a (CH2) r 5-10 elements heterocyclic system containing from 1-4 heteroatoms selected from N, O, and S, substituted with R15e of 0- 2;
R 15a and R15a ', in each case, is selected from H, Ci-g alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2) r C3_? Carbocyclic residue or substituted with R15e of 0-5, and a (CH2) 5-10 elements heterocyclic r-system containing from 1-4 heteroatoms selected from N, O, and S, substituted with R15e from 0-2;
, 15b, in each case, is selected from C? -6 alkyl, C2-g alkenyl, C2_8 alkynyl, a (CH2) r C3-g carbocyclic residue substituted with R15e of 0-3, and a (CH2) r 5-heterocyclic system? -6 elements containing 1-4 heteroatoms selected from N, O, and S, substituted with R15e of 0-2;
R, 15d, in each case, is selected from C2_8 alkenyl, alkynyl
C2_8, C1_6alkyl substituted with R15e of 0-3, one (CH2) r_ C3_? 0 carbocyclic residue substituted with R15e of 0-3; and a (CH2) r_ heterocyclic system of 5-6 elements containing 1-4 heteroatoms selected from N, O, and S, substituted with R15β from 0-3;
R15e, in each case, is selected from C? -6 alkyl, C2-8 alkenyl C2-8 alkynyl, (CH2) r C3-6 cycloalkyl Cl, F, Br, I, CN, N02, (CF2) rCF3, ( CH2) rO alkyl d5, OH, SH, (CH2) rS alkyl C5-5, (CH2) ENR15fR15f, and (CH2) rphenyl;
R, 15f, in each case, is selected from H, C? _6 alkyl, C3_6 cycloalkyl, and phenyl;
R 16 in each case is C 6 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, (CH 2), C 1 6 alkyl, Cl, Br I, F, N 0 2, CN, AHR ') rNR 1 166 a R D 1166 a ", (CHR') ) rOH
(CHR ') E0 (CHR') rR16d, CHR ') rSH, (CHR') rC (0) H (CHR ') rS (CHR') rR16d, (CHR ') rC (0) OH (CHR') rC (O) (CHR ') rR16b, (CHR') rC (0) NR16aR16a '(CHR') rNR16fC (O) (CHR ') rR16b, CHR') rC (O) O (CHR ') rR16d (CHR') rOC (O) (CHR ') ER16b, (CHR') rC (= NR16f) NR16aR16a '
(CHR ')) rrN: HC (= NR16f) NR16fR16f, (CHR') rS (0) p (CHR ') rR 16b ((CCHHRR' ') rr, S (0) 2NR16aR16a' (CHR ') rNR16fS (O ) 2 (CHR ') rR 16b haloalkyl d-6 / C2 alkenyl substituted with R' of
0-3, C2-8 alkynyl substituted with R 'of 0-3, (CHR') rf enyl substituted with R 1-6bee of 0-3;
R 16a and R16a ', in each case, are selected from H, C? -6 alkyl, C2-alkenyl, C2-8 alkynyl, a (CH2) r- C3_? Carbocyclic residue or substituted with R16e from 0-5, and a (CH2) r_ heterocyclic system of 5-10 elements containing from 1-4 heteroatoms selected from N, O, and S, substituted with R16e from 0-2;
R, 16b, in each case, is selected from C? _6 alkyl, C2-alkenyl, C2_s alkynyl, a (CH2) r_ C3_6 carbocyclic residue substituted with R16e of 0-3, and a (CH2) r- heterocyclic 5-6 elements containing 1-4 heteroatoms selected from N, O, and S, substituted with R16e of 0-2;
R16d, in each case, is selected from C2_8 alkenyl, C2-8 alkynyl, C6_6 alkyl substituted with R16a from 0-3; a (CH2) r- C3-10 carbocyclic residue substituted with R16e of 0-3, and a (CH2) r- 5-6 element heterocyclic system consisting of 1-4 heteroatoms selected from N, O, and S, substituted with R16a of 0-3;
R16e, in each case, is selected from C? _6 alkyl, C2-8 alkenyl, C2_8 alkynyl, (CH2) r C3_6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) rCF3, (CH2) E0 alkyl C? _5, OH, SH, (CH2) rS C1-5 alkyl, (CH2) rNR16fR16f, and (CH2) rphenyl;
R, 16f, in each case, is selected from H, C? _6 alkyl, C3? -cycloalkyl, and phenyl;
g is selected from 0, 1, 2, 3 and 4;
t is selected from 1 and 2;
w is selected from 0 and 1;
r is selected from 0, 1, 2, 3, 4, and 5;
q is selected from 1, 2, 3, 4, and 5; Y
p is selected from 0, 1, 2, and 3.
[2] In a preferred embodiment, the present invention provides novel compounds of formula (I), wherein;
Z is selected from O and S;
E is selected from:
R4 is absent, taken with the nitrogen which is attached, forms an N-oxide, or is selected from Ci-s alkyl,
(CH2) r C3_6 cycloalkyl, and (CH2) r-phenyl substituted with Rc of 0-3;
R4c, in each case, is selected from C6_6 alkyl, C2_8 alkenyl, C2_8 alkynyl, C3_6 cycloalkyl, Cl, F, Br, I,
CN, N02, (CF2) rCF3, (CH2) rO alkyl C? -5, (CH2) rOH, (CH2) rS alkyl d-5, (CH2) ENRaR4a ', and (CH2) E phenyl;
alternatively, R4 together with R7 or R9 or R14 form a piperidinium spirocycle of 5, 6, or 7 elements
substituted with Ra of 0-3;
R1 and R2 are independently selected from H, C? _ Alkyl;
R6, in each case, is selected from C4-4 alkyl, C2_8 alkenyl, C2_8 alkynyl, (CH2) r C3_6 cycloalkyl, (CF2) rCF3, CN, (CH2) EOH, (CH2) rOR6b, (CH2) rC ( O) rOR6b,
(CH2) cC (0) R6b, (CH2) rC (0) NR6aR6a '(CH2 rNR6dC (0) R6a (CH2) t phenyl substituted with R of 0-3;
R6a and R6a ', in each case, is selected from H, C? -6 alkyl, C3_6 cycloalkyl, and phenyl substituted with R6c of 0-3;
R, in each case, is selected from C? _6 alkyl, cycloalkyl
C3_6, and phenyl substituted with R 6c of 0-3;
R6c, in each case, is selected from C1-6 alkyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) rCF3, (CH2) rO alkyl d-5, (CH2) EOH, (CH2) rS alkyl d-5 / y (CH2) rNR6dR6d;
R, 6d, in each case, is selected from H, Cx_6 alkyl, and C3_6 cycloalkyl;
R7 is selected from H, C? _3 alkyl, (CH2) r C3-6 cycloalkyl,
2) qOR7d, (CH2) qNR7aR7a '(CH2) rC (0) R, 7'b
(CH2) qOH, (CH (CH2) rC (0) NR 7'aap R, 7a 'CH2) qNR / aC (0) R' haloalkyl C? -6,
(CH2) E phenyl with R c 0-2;
R 7a and R7a ', in each case, is selected from H, C? -6 alkyl, (CH2) r C3_6 cycloalkyl, a (CH2) rphenyl substituted with R7e of 0-3,
R, in each case, is selected from alkyl d-6, C2_8 alkenyl, C2_8 alkynyl, (CH2) r C3_6 cycloalkyl,
(CH2) E-phenyl substituted with R7e of 0-3;
R 7c in each case is selected from C? -4 alkyl, C2-alkenyl, C2-s alkynyl, (CH2) E C3_6 cycloalkyl, Cl, Br, 1 / F, (CF2) rCF3, N02, CN, ( CH2) rNR7fR7f, (CH2) rOH,
(CH2) rO alkyl d_4, (CH2) rC (0) R 7'b (CH2) rC (0) NR, 7 / frtR-, 7'f
(CH2) rNR 7'fr, C (0) R, 7a (CH2) ES (0) pR 7'bA (CH2) rS (0) 2NR7fR7f,
(CH2) rNR > 7'frSc (0) 2R / D, and (H2) r-phenyl substituted with Re 0-2;
R7d, in each case, is selected from C6_6 alkyl, (CH2) r C3_6 cycloalkyl, (CH2) rphenyl substituted with R7e of 0-3;
R, 7e, in each case, is selected from C? _6 alkyl, alkenyl
C2-4, C2-alkynyl, C3_6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) ECF3, (CH2) rO C alquilo5 alkyl, OH, SH,
(CH2) ES C1-5 alkyl, (CH2) rNR 7fRr > 7f, and (CH2) r-phenyl;
R, in each case, is selected from H, C? _s alkyl, C3_6 cycloalkyl;
R8 is H or together with R7 they form C3_7 cycloalkyl or
R 11 is selected from H, C 1 -C 6 -alkyl (CH 2) r C 3-6 cycloalkyl, (CH 2) qOH, (CH 2) q 0 Rlld, (CH 2) q N R R R A R ', (CH 2) r C (O) R 1b, (CH 2) rC (0) NRllaRlla ', (CH2) qNRllaC (0) RUa, C1-6 haloalkyl, (CH2) rphenyl with Rllc of 0-2, a (CH2) r 5-10 element heterocyclic system containing 1-4 heteroatoms selected from N, 0, and S, substituted with R15 of 0-3;
Rlla and Rlla ', in each case, is selected from H, C 1-6 alkyl, (CH 2) r C 3-6 cycloalkyl, a (CH 2) Ephenyl substituted with Rlle of 0-3;
Rllb, in each case, is selected from C6_6 alkyl, C2-8 alkenyl, C2_8 alkynyl, (CH2) r C3-6 cycloalkyl, (CH2) rphenyl substituted with Rlle of 0-3;
R lie, in each case, is selected from C ?4 alkyl, C2_8 alkenyl, C2_e alkynyl, (CH2) r C3_6 cycloalkyl, Cl, Br, I, F, (CF2) rCF3, N02, CN, (CH2) rNRllfRllf, (CH2) rOH, (CH2) r0 C C4 alkyl, (CH2) rC (0) Rllb, (CH2) rC (O) NRllfRllf, (CH2) rNRllfC (0) Rlla, (CH2) rS (0) pRllb, (CH2) rS (O) 2NRllfRllf, (CH2) rNRllfS (0) 2Rllb, and (CH2) rf enyl substituted with Rlle of 0-2;
Rlid in each case is selected from alkyl C? _6, (CH2) r C3-6 cycloalkyl, (CH2) Ephenyl substituted with Rlle of 0-3;
Rlle, in each case, is selected from alkyl d-4, alkenyl C2_6, alkynyl C2_8, cycloalkyl C3-e, Cl, F, Br, I, CN, N02, (CF2) rCF3, (CH2) E0 alkyl d_5, OH , SH, (CH2) rS alkyl C? -5, (CH2) rNRllfRllf, and (CH2) rphenyl;
R,? If, in each case, is selected from H, C? _5 alkyl, and C3-e cycloalkyl;
R12 is H or together with R11 form C3_7 cycloalkyl;
R, 13, in each case, is selected from C? -4 alkyl, cycloalkyl
C3-6, (CH2) NR, 1i3jaapR1l3jaa ', (CH2) OH, (CH2) 0R 1i3JbD, (CH2) WC (0) R13b,
(CH2) wC (0) NR13aR13a '(CH2) NR13dC (0) R13a,
(CH2) wS (0) 2NR13aR13a ', (CH2) NR13dS (0) 2R13b, and (CH2) w-phenyl substituted with R13c of 0-3;
R13a and R13a ', in each case, is selected from H, C? -6 alkyl, C3_6 cycloalkyl, and phenyl substituted with R13c of 0-3;
R13b, in each case, is selected from C? -6 / C3_6 cycloalkyl, and phenyl substituted with R13c from 0-3;
R 13c in each case is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, Cl, F, Br, I, CN, N 2, (CF 2) ECF 3, (CH 2) rO C 1 -C 5 alkyl, (CH 2) rOH, and (CH2) rNR13dR13;
R, 13d, in each case, is selected from C? _6 alkyl, C3_6 cycloalkyl;
q is selected from 1, 2 and 3; Y
r is selected from 0, 1, 2 and 3,
[3] In a preferred embodiment, the present invention provides novel compounds of formula (I), wherein:
is selected from a (CR3?) r- substituted carbocyclic residue with R15 of 0-5, wherein the carbocyclic residue is selected from phenyl, C3_6 cycloalkyl, naphthyl, and adamantyl; and a system (CR3?) r- heterocyclic system substituted with R15 of 0-3, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl , imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; Y
R5 is selected from (CR5?) T-phenyl substituted with R16 of 0-5; and a (R5?) t-substituted heterocyclic system with R16 of 0-3, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1, 2,4-triazolyl, 1, 2,4-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl.
[4] In a more preferred embodiment, the present invention provides new compounds of formula (I-i), wherein the compound of formula (I-i) is:
(Ii) in each case, is selected from alkyl C? _8, (CH2) E C3_6 cycloalkyl, CF3, Cl, Br, I, F, (CH2) rNR16aR16a ', N02, CN, OH, (CH2) rOR16d, ( CH2) EC (O) R16b,
(CH2) E (C) NR 1-6baaR16a '(CH2) ENR brC (0) R, 16b (CH2) rS (0) pR 16b
(CH2) rS (0) 2NR16aR16a ', (CH2) rNR16fS (0) 2R16b, and (CH2) rphenyl substituted with R16e of 0-3;
R16 and R16a ', in each case, are selected from H, C? _6 alkyl, C3-6 cycloalkyl, and (CH2) rphenyl substituted with R16e of 0-3;
R, in each case, is selected from H, C? _6 alkyl, C3-6 cycloalkyl, and (CH2) rphenyl substituted with R 16e from 0-3;
R > 16d, in each case, is selected from C? -6 alkyl and phenyl;
R, 16e, in each case, is selected from alkyl C? _6, Cl, F, Br, I, CN, N02, (CF2) ECF3, OH, and (CH2) rO alkyl C? _5; Y
R, 16f, in each case, is selected from H, and alkyl C? _5.
[5] In another even more preferred embodiment, the present invention provides novel compounds of formula (I-ii), wherein (I-ii) is:
(I-ii)
R16, in each case, is selected from C? _8 alkyl, cycloalkyl (CH2) r C3-6, CF3, Cl, Br, I, F, (CH2) ENR16aR16a ', N02, CN, OH, (CH2) rOR16d, (CH2) rC (0) R16, (CH2) rC (0) NR16aR16a ', (CH2) ENR16fC (0) R16b, (CH2) ES (0) pR16b, (CH2) ES (0) 2NR16aR16a',
(CH2) rNR16fS (0) 2R16b, and (CH2) rphenyl substituted with R16e of 0-3;
R16a and R16a ', in each case, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2) rf enyl substituted with R16e of 0-3;
R16b, in each case, is selected from H, C? _6 alkyl, C3_6 cycloalkyl and (CH) rphenyl substituted with R16e of 0-3;
R, 16d, in each case, is selected from alkyl d6 and phenyl;
R, 16e, in each case, is selected from C1-6 alkyl / Cl, F, Br, I, CN, N02, (CF2) rCF3, OH, and (CH2) r0 alkyl d_5; Y
, 16f in each case, is selected from H, and C1-5 alkyl.
[6] In a preferred embodiment, the present invention provides novel compounds of formula (I-i), wherein:
R5 is CH2phenyl substituted with R16 of 0-3;
R9 is selected from H, C? -6 alkyl, (CH2) r C3_6 cycloalkyl, F, Cl, CN, (CH2) rOH, (CH2) r0R9d, (CH2) ENR9aR9a ', (CH2) rOC (0) NHR9a , (CH2) E phenyl substituted with R9e of 0-5, and a heterocyclic system substituted with R9e of 0-2, wherein the heterocyclic system is selected from pyridyl, thiophenyl, furanyl, oxazolyl, and thiazolyl;
R and R, in each case, are selected from H, C? _6 alkyl, C3_6 cycloalkyl, and (CH2) E phenyl substituted with R9e of 0-3;
R, 9d, in each case, is selected from C? -6 alkyl and phenyl;
R, 9e, in each case, is selected from alkyl C? _6, Cl, F, Br, I, CN, N02, (CF2) ECF3, OH, and (CH2) rO alkyl C? -5;
R, 10 is selected from H, C? -5 alkyl, OH, and CH2OH;
alternatively, R9 and R10 together form C3-7 cycloalkyl, cyclic ketal of 5-6 elements or = 0;
with the proviso that when R10 is halogen, cyano, nitro, or is bound to the carbon to which it is attached through a heteroatom, R9 is not halogen, cyano, or is bonded to the carbon which its bonds through a heteroatom;
R is selected from H, C? -8 alkyl, (CH2) Eppryl substituted with Rlle of 0-5, and a (CH2) r- substituted heterocyclic system with Rlle of 0-2; wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, isoindolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; Y
R, Ile, in each case, is selected from alkyl C? -6, Cl, F, Br, I, CN, N02, (CF2) rCF3, OH, and (CH2) rO alkyl d-5;
R12 is H;
alternatively, R11 and R1 together form C3_7 cycloalkyl;
R 14 in each case is selected from Ci-β alkyl, (CH 2) r C3_6 cycloalkyl, CF3, Cl, Br, I, F, (CH2) rNR14aR1 a ',
N02, CN, OH, (CH2) r0R1 d, (CH2) EC (0) R14b,
(CH2) rC (0) NR14aR14a ', (CH2) rNR1 fC (0) R1 b, (CH2) rS (0) pR14b,
(CH2) ES (0) 2NR14aR14a '(CH2) rNR1 fS (0) 2R14, (CH2) rphenyl substituted with R14e of 0-3; and a 5-10 element heterocyclic (CH2) E system containing 1-4 heteroatoms selected from N, O, and S, substituted with R15e of 0-2; and two R14 substituents on adjacent atoms on a ring A to together form a 5-6 element heterocyclic system containing 1-3 heteroatoms selected from N, O, and S with R15e of 0-2;
R 14a and R1 ', in each case, are selected from H, Ci-β alkyl, C3_6 cycloalkyl, and (CH2) rphenyl substituted with R14e from 0-3; and a (CH2) r-heterocyclic system of -5-6 elements containing 1-4 heteroatoms selected from N, O, and S, substituted with R15e of 0-2;
R 14b in each case is selected from H, C? _6 alkyl, C3_6 cycloalkyl, and (CH2) E phenyl substituted with R14e of 0-3;
R, in each case, is selected from C? _6 alkyl and phenyl;
R, 14e, in each case, is selected from alkyl d-.6, Cl, F, Br, I, CN, N02, (CF2) rCF3, OH, and (CH2) rO C1-5 alkyl, and
R, 14f, in each case, is selected from H, and C 1-5 alkyl; Y
r is selected from 0, 1, and 2.
[7] In a preferred embodiment, the present invention provides novel compounds of formula (I-ii), wherein:
R is CH 2 phenyl substituted with R 16 of 0-3;
R is selected from H, C? _6 alkyl, (CH2) r C3_6 cycloalkyl, F, Cl, CN, (CH2) rOH, (CH2) rOR9d, (CH2) rNR9aR9a ',
(CH2) r0C (0) NHR, 93aa, (CH2) E phenyl substituted with R 9aee of 0-5, and a heterocyclic system substituted with R9e of 0-2, wherein the heterocyclic system is selected from pyridyl, thiophenyl, furanyl, oxazolyl, and thiazolyl;
R 9a and R9a ', in each case, are selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, and (CH 2) rphenyl substituted with R 9e of 0-3;
R, in each case, is selected from alkyl d6 and phenyl;
R, in each case, is selected from alkyl C? _6, Cl, F, Br, I, CN, N02, (CF2) rCF3, OH, and alkyl (CH2) E0 d-5 / *
R is selected from H, alkyl Ci-s, OH, and CH2OH;
alternatively, R9 and R19 together form C3_7 cycloalkyl, cyclic ketal of 5-6 elements or = 0;
with the proviso that when R10 is halogen, cyano, nitro, or linked to the carbon to which it is attached through a heteroatom, Rg is not halogen, cyano, or bonded to the carbon to which it is bound through a heteroatom
R, 11 is selected from H, C? _8 alkyl, (CH2) Ephenyl substituted with Rlle of 0-5, and a (CH2) r- substituted heterocyclic system with Rlle of 0-2; wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolyl, isoquinolinyl, imidazolyl, indolyl, isoindolyl,
piperidinyl, pyrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; Y
R, lle, in each case, is selected from alkyl C? _6, Cl, F, Br, I, CN, N02, (CF2) rCF3, OH, and alkyl (CH2) rO d-5;
R12 is H;
alternatively, R, 11 and R, 12 together form C3_7 cycloalkyl;
R '14 in each case, is selected from alkyl C? -8, (CH2) C3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2) rNR14aR14a',
N02, CN, OH, (CH2) rOR14d, (CH2) EC (0) R14b,
(CH2) rC (0) NR14aR14a '(CH2) rNR14fS (0) 2R1, (CH2) rphenyl substituted with R14e of 0-3, and a (CH2) r- heterocyclic system of 5-6 elements containing from 1-4 selected heteroatoms of N, O, and S, substituted with R15e of 0-2; or two R14 substituents on adjacent ring A atoms together form a heterocyclic system of 5-6 elements containing 1-3 heteroatoms selected from N, O, and S substituted with R15e of 0-2;
R and R, 14aa, in each case, is selected from H, C? -6 alkyl,
C-6 cycloalkyl, and (CH2) rphenyl substituted with R14e
of 0-3;
R, in each case, is selected from H, C? -6 alkyl, C3-6 cycloalkyl, and (CH2) rphenyl substituted with R 14e of 0-3;
R, in each case, is selected from C? -6 alkyl and phenyl;
R, 14e, in each case, is selected from alkyl C6, Cl, F, Br, I, CN, N02, (CF2) rCF3, OH, and alkyl (CH2) r0 C? -5;
R, in each case, is selected from H, and C1-5 alkyl; Y
r is selected from 0, 1 and 2.
[8] In a more preferred embodiment, the present invention provides novel compounds of formula (I-i), wherein:
J is selected from CH2 and CHR5;
K is selected from CH2 and CHR5;
R3 is a C3_? 0 carbocyclic residue substituted with R15 of 0-3, wherein the carbocyclic residue is selected from
cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl and adamantyl, and a (CR3?) E- heterocyclic system substituted with R15 of 0-3, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; Y
R-15 in each case, is selected from Ci-s alkyl, (CH2) r- C3_6 cycloalkyl, CF3, Cl, Br, I, F, (CH2) rNR15aR15a ', N02, CN, OH, (CH2) E0R15, (CH2) rC (O) R15b,
(CH2) EC (0) NR15aR15a '(CH2) ENR15fC (0) R 15b (CH2) ES (0) pR 15b
(CH2) rS (0) 2NR15aR15a '(CH2) rNR15fS (0) 2R15b, ÍCH2) rphenyl substituted with R 15e of 0-3, and a (CH2) r 5-6 elements heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with R15e of 0-2;
R15a and R15a ', in each case, is selected from H, C? _6 alkyl, C3_6 cycloalkyl, and (CH2) Ephenyl substituted with R15e
of 0-3;
R, in each case, is selected from H, C? -6 alkyl / C3_6 cycloalkyl, and (CH2) E phenyl substituted with R15e of 0-3;
R, 15d, in each case, is selected from C? -6 alkyl and phenyl;
R, 15e, in each case, is selected from alkyl C? _6, Cl, F, Br, I, CN, N02, (CF2) ECF3, OH, and (CH2) E0 C? -5 alkyl; Y
R, 15f, in each case, is selected from H, and C1-.5 alkyl.
[9] In a more preferred embodiment, the present invention provides novel compounds of formula (I-ii), wherein:
K is selected from CH2 and CHR5;
R is a C3-10 carbocyclic residue, substituted with R15 of 0-3, wherein the carbocyclic residue is selected from cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl and adamantyl, and a (CR3?) R-heterocyclic system substituted with R15 from 0-3, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl,
benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, triadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; Y
R 15 in each case is selected from alkyl C? _8, (CH2) E- C3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2) ENR15aR15a ',
N02, CN, OH, (CH2) rOR 15d (CH2) rC (0) R 15b (CH2) rC (0) NR15aR15a ', (CH2) ENR15fC (0) R15b, (CH2) rS (0)
(CH2) rS (0) 2NR15aR15a ', (CH2) rNR15fS (0) 2R15b, and (CH2) rphenyl substituted with R15e of 0-3; and a (CH2) r- 5-6 element heterocyclic system containing from 1-4 heteroatoms selected from N, O, and S, substituted with R15e from 0-2;
R15a and R15a ', in each case, are selected from C? _6 alkyl, C3-6 cycloalkyl, and (CH2) rphenyl substituted with R15e of 0-3;
R15b, in each case, is selected from H, C? -6 alkyl, C3_6 cycloalkyl, and (CH2) rphenyl substituted with R15e of 0-3;
R, in each case, is selected from C? _6 alkyl and phenyl;
R, in each case, is selected from alkyl C? _6, Cl, F, Br, I, CN, N02, (CF2) rCF3, OH, and (CH2) rO alkyl C? _5; Y
R, 15f, in each case, is selected from H, alkyl C? -5-
[10] Furthermore, in a more preferred embodiment, the present invention provides new compounds of formula (I) and pharmaceutically acceptable salt forms thereof, wherein the compound of formula (I) is selected from:
N- (3-methoxyphenyl) -N '- [trans-2- [[(3R, S) -3- (phenyl) -methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3-cyanophenyl) -N '- [trans-2- [[(3R, S) -3- (phenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3-acetylphenyl) -N '- [trans-2- [[(3R, S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3-acetylphenyl) -N '- [trans-2- [[(3R, s) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3-cyanophenyl) -N '- [trans-2- [[(3R, S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3-methoxyphenyl) -N '- [trans-2- [[(3R, S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3-nitriphenyl) -N '- [trans-2- [[(3R, S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3-acetylphenyl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3-acetylphenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3-acetylphenyl) -N '- [(1 R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3-acetylphenyl) -N '- [(IR, 2S) -2- [[(3R) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3-acetylphenyl) -N '- [(1R, 2S) -2- [[(3R) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3-acetylphenyl) -N '- [(IR, 2R) -2- [[(3S) -3- (4-
fluorophenyl) methyl) piperidinyl] methyl] ciciohexyl] -urea,
N- (3-cyanophenyl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3-cyanophenyl) -N '- [(1R, 2S) -2- [[(3R) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3-methoxyphenyl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3-methoxyphenyl) -N '- [(1R, 2S) -2- [[(3R) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (4-fluorophenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (4-fluorophenyl) -N '- [(1R, 2S) -2 - [[(3R) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (phenyl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- ((1H) -indazol-5-yl) -N '- [(IR, 2S) -2- [[3 S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- ((1H) -indazol-6-yl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (benzthiazol-6-yl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- ((1H) -indol-5-yl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- ((1H) -indol-6-yl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- ((1H) -2,3-dimethylindol-5-yl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl ] -urea,
N- (benzimidazol-5-yl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (indolin-5-yl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidnyl] methyl] cyclohexyl] -urea,
N- (3-cyano-4-fluorophenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-
fluorophenyl) methyl) piperidinyl] methyl] ciciohexyl] -urea,
N- (3-acetyl-4-fluorophenyl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3, 5-diacetylphenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3- (1-hydroxyethyl) phenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (4-methyl-thiazol-2-yl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (4-methyl-5-acetyl-thiazol-2-yl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl ] -urea,
N- (1, 3,4-thiadiazol-2-yl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] - urea,
N- (4-chloro-benzimidazol-2-yl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (thiazol-2-yl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (5-Methyl-isoxazol-3-yl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (1-methyl-pyrazol-3-yl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (4- (1, 2,4-triazol-1-yl) phenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] ciciohexyl] -urea,
N- (4- (1, 2,4-triazol-1-yl) phenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] ciciohexyl] -urea,
N- ((1H) -3-chloro-indazol-5-yl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl ] -urea,
N- (4-fluorophenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (4-chlorophenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (4-bromophenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3-bromophenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3-fluorophenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3,4-difluorophenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3-chloro-4-fluorophenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3,5-dichlorophenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- ((1H) -5-amino-indazol-1-yl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl ] -urea,
N- (3-chlorophenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3-fluoro-4-methylphenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3-cyano-4- (l-pyrazolyl) phenyl) -N '- [(lR, 2S) -2- [[(3S) -3- (4-
fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (2-methylphenyl) -N '- [(1R2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (2-methylphenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (2,4-dimethylphenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (2,4-dimethoxyphenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (2, 5-dimethoxyphenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (2-methoxy-5-methylphenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (2-methyl-5-fluorophenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3,5-bis (l-methyltetrazol-5-yl) phenyl) -N '- [(lR, 2S) -2- [[(3S)
3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3- (1-metltetrazol-5-yl) phenyl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (4-carboethoxymethyl) thiazol-2-yl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (5-bromothiazol-2-yl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (4,5-di (4-fluorophenyl) thiazol-2-yl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl ] cyclohexyl] -urea, i N- (2-fluorophenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea ,
N- (2-chlorophenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (indanon-6-yl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (indanon-4-yl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (4- (isopropyl) phenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3-nitro-4-methylphenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (trans-2-phenylcycloprop-1-yl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (2,4-difluorophenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (2, 5-difluorophenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methylpiperidinyl] methyl] cyclohexyl] -urea,
N- (2,4-dichlorophenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (2,5-dichlorophenyl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (2-methoxyphenyl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-
fluorophenyl) methyl) piperidinyl] methyl] ciciohexyl] -urea,
N- (2,4-dimethoxyphenyl) -N '- [(1R, 2) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (2,5-dimethoxyphenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (2-trifluoromethylphenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methylcyclohexyl] -urea,
N- (2-methylphenyl) -N '- [(1R 2 S) -2 - [[(3 S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3-trifluoromethylphenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3-methylphenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (4-methoxyphenyl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (4-ethoxycarbonylphenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (4-trifluoromethylphenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) ethyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (4-methylphenyl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (2-fluorophenyl) -N '- [(1R, 2S) -2 - [[(3S) - (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (2-chlorophenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidnyl] methyl] cyclohexyl] -urea,
N- (2-nitrophenyl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (2, -dichlorodenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3-nitrophenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3,5-ditrifluoromethylphenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (2,4-dimethylphenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-
fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (2,4-dimethoxy-5-chlorophenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3,4,5-trimethoxyphenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3, 5-dimethylphenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3-trifluoromethyl-4-chlorophenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (4-phenoxyphenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (4-ethoxyphenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (4-thiomethylphenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (2-naphthyl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (4-acetyphenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (2,6-dichloropyridin-4-yl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (5-indan-4-yl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (4-chloronaphth-1-yl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3-fluoro-4-methoxyphenyl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (A- (methylsulfonyl) phenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3- (methylsulfonyl) phenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- [2- ((1 H) -pyrrol-1-yl) phenyl] -N '- [(1 R, 2 S) -2 - [[(3 S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (1,3-benzodioxol-5-ll) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (1-acetylindolin-6-yl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (4- (6-methylbenzothiazol-2-yl) phenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] - urea,
N- (4- ((2,2-dimethylpropanoyl) amino) phenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl ] -urea,
N- (A- (1-methyltetrazol-5-yl) phenyl) -N '- [(1R2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea ,
N- (- (1-morpholino) phenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (quinolin-8-yl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3-hydroxyphenyl) -N '- [(IR, 2S) -2 - [[(3R) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] trifluoroacetate] -
urea,
N- (4- (acetylamino) phenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (4-hydroxyphenyl) -N '- [(IR, 2S) -2- [[(3R) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3-hydroxy-4-methoxyphenyl) -N '- [(IR, 2S) -2- [[(3R) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3- (cetylamino) phenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (4-fluoro-3-methylphenyl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl) methyl] cyclohexyl] -urea,
N- (3-methoxy-4-methylphenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (4-chloro-3-methylphenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (4- (N-methylcarboxamide) phenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (1-adamantyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (quinolin-5-yl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (quinolin-6-yl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (1, 4-benzodioxan-6-yl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] - urea,
N- (isoquinolin-5-yl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (4- (sulfonamide) phenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (benzotriazol-5-yl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (2-hydroxy-4-methylphenyl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3-hydroxy-4-methylphenyl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-
fluorophenyl) methyl) piperidinyl] methyl] ciciohexyl] -urea,
N- (2-methyl-benzothiazol-5-yl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- ((4-methoxyphenyl) methyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- ((4-fluorophenyl) methyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) iperidinyl] methyl] cyclohexyl] -urea,
N- ((4-methylphenyl) methyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- [(IR) -1- (phenyl) ethyl] -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea ,
N- (1-acetylindolin-5-yl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (5,6,7,8-tetrahydronaphth-1-yl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl ] -urea,
N- (3-acetyl-4-hydroxyphenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (4- (piperidin-1-yl) phenyl-N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (cyclohexyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (2-methoxyphenyl) -N '- [(IR, 2S) -2- [[(3S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] - urea,
N- (2,6-dimethylphenyl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (2-ethylphenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (2, 4, 6-trimethylphenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (2, 5-dimethoxyphenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (t-butyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (i-propyl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-
fluorophenyl) methyl) piperidinyl] methyl] ciciohexyl] -urea,
N- (ethoxycarbonylmethyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (2-trifluoromethoxy-phenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- [(IR, S) -1- (methoxycarbonyl) -2-methyl-propyl] -N '- [(IR, 2S) -2- [[(3S) - (4-fluorophenyl) methyl) piperidinyl] methyl ] ciciohexyl] -urea,
N- [(1S) -1- (methoxycarbonyl) -2-phenylethyl] -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl ] -urea,
N- [2,4,4-trimethyl-2-pentyl] -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] - urea,
N- [2-phenylethyl] -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3-acetylphenyl) -N '- [(1 R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N (2-carbomethoxyphenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- [(1S) -1- (phenyl) ethyl] -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea ,
N (4-phenyl) phenyl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N (1-naphthyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
(2- (phenyl) phenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N (phenylmethoxy) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N (3,4-dimethoxyphenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N ((3 H) -2-ethylquinazolin-4-on-3-yl) -N '- [(1 R, 2 S) -2 - [[(3 S) -3- (4-fluorophenyl) methyl) piperidinyl] ethyl] cyclohexyl] - urea,
N- (3-pyridinyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (6-methoxy-3-pyridinyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (2-methylquinolin-8-yl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (2-methylnaphthyl-1-yl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N (4- ((ÍH) -l-propyl-tetrazol-5-yl) phenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl ] methyl] ciciohexyl] -urea,
N (3-aminophenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3- (acetylamino) phenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N (3- (N-methylcarboxamide) phenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N (2-nitro-4-methoxyphenyl) -N '- [' (IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (8-hydroxyquinolin-5-yl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3-methylpyridin-2-yl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (isoquinolin-1-yl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3-acetylphenyl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclopentyl] -urea,
N- (3-acetylphenyl) -N '- [(1R, 2S) -2- [[(3R) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclopentyl] -urea,
N- (3-acetylphenyl) -N '- [(1R 2 S) -2 - [[(3 S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclopentyl] urea,
N- (3-cyanophenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-
fluorophenyl) methyl) piperidinyl] ethyl] cyclopentyl] urea,
N- (3-cyanophenyl) -N '- [(1R, 2S) -2- [[(3R) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclopentyl] urea,
N- (3-cyanophenyl) -N '- [(1R, 2S) -2- [[(3R) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclopentyl] urea,
N- (3-cyanophenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclopentyl] urea,
N- (phenyl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclopentyl] urea,
N- (phenyl) -N '- [(1R, 2S) -2 - [[(3R) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclopentyl] urea, and
N- (phenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclopentyl]
urea.
[11] In another embodiment, the present invention provides novel compounds of formula (I):
(I)
or stereoisomers or pharmaceutically acceptable salts thereof, wherein:
M is absent or selected from CH2, CHR5, CHR13, CR13R13, and CR5R13;
Q is selected from CH2, CHRA CHR 13,
and CRbR
J and L are selected from CH2, CHR5, CHR6, CR6R6 and CR5R6;
K is CHR5;
with the condition of:
when M is absent, J is selected from CH2, CHR5,
CHR 13 CR5R13;
Z is selected from 0 and S;
E is
ring A is a C3_6 carbocyclic residue, with the proviso that the C3_6 carbocyclic residue is not phenyl;
R1 and R2 are independently selected from H, C6_6 alkyl, C2_8 alkenyl, C2_8 alkynyl, (CH2) r C3_6 cycloalkyl, and a (CH2) r- C3-? Carbocyclic residue or substituted with 0-5 Ra;
Ra, in each case, is selected from C? _6 alkyl, C2_8 alkenyl, C2-8 alkynyl, (CH2) E C3_6 cycloalkyl, Cl, Br, I, F, (CF2) rCF3, N02, CN, (CH2) ENRbRb , (CH2) EOH,
(CH2) E0Rc, (CH2) ESH, (CH2) rSRc, (CH2) rC (0) Rb, (CH2) EC (0) NRbR, (CH2) ENRbC (0) Rb, (CH2) rC (0) ORb ,
(CH2) rOC (0) Rc,
NR, br, b (CH2) ES (0) pRc, (CH2) ES (0) 2NRbRb, (CH2) rNRbS (O) 2RC, and (CH2) Ephenyl;
Rb, in each case, is selected from H, C ± -e alkyl, C3_6 cycloalkyl, and phenyl;
Rc, in each case, is selected from alkyl d-6, cycloalkyl C3_6, and phenyl;
alternatively, R2 and R3 together form a ring of 5, 6, or 7 elements substituted with Ra of 0-3;
R is selected from a (CR R) r-carbocyclic residue C3_? 0 substituted with R15 of 0-5 and a heterocyclic system (CR3'R3") E of 5-10 elements containing 1-4 heteroatoms selected from N, O , and S, substituted with R15 of 0-3;
R3 'and R3", in each case, is selected from H, C? _6 alkyl, (CH2) E C3_6 cycloalkyl, and phenyl;
R, is absent, together with the nitrogen which binds form an N-oxide, or is selected from C? _6 alkyl, C2_8 alkenyl, C2-8 alkynyl, (CH2) E C3_6 cycloalkyl,
(CH2) qC (0) R4b, (CH2) qC (0) NR aR4a ', (CH2) qC (O) OR b, and a (CH2) r- carbocyclic residue C3_? Or substituted with R4c of 0-3;
R '4a and R a, in each case, is selected from H, C? _6 alkyl, (CH2) r C3_? Cycloalkyl, and phenyl;
R, in each case, is selected from C? -6 alkyl, C-8 alkenyl, (CH2) r C3-6 cycloalkyl, C2_8 alkynyl, and phenyl;
R4c, in each case, is selected from C6-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3_6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) ECF3, (CH2) rO alkyl d -5, (CH2) rOH, (CH2) ES alkyl C? _5, (CH2) ENR4aR4a ', and (CH2) Ephenyl;
alternatively, R4 together with R7, R9, R11 or R14 form 5-, 6- or 7-membered piperidinium spirocycle or pyrrolidinium spirocycle substituted with Ra of 0-3;
R5 is selected from a (CR5'R5") t-carbocyclic residue C3-? Or substituted with R16 of 0-5 and a (CR5'R5") t- 5-10 elements heterocyclic system containing 1-4 selected heteroatoms of N, O, and S, substituted with R16 of 0-3;
R and R, in each case, are selected from H, C? -6 alkyl,
(CH2) r C3_6 cycloalkyl, and phenyl;
R6, in each case, is selected from C6-alkyl, C2-8 alkenyl, C2_8 alkynyl, (CH2) r C3_6 cycloalkyl, (CF2) rCF3, CN, (CH2) ENR6aR6a ', (CH2) EOH, (CH2) ) rOR6b, (CH2) ESH,
(CH2) rSRbb (CH2) EC (0) 0H, (CH2) EC (0) R 6bbb
(CH2) rC (0) NR6aR6a '(CH2) ENR6dC (0) R6a, (CH2) EC (0) OR6,
(CH2) EOC (0) R 6b (CH2) ES (0) pR 6b (CH2) ES (0) 2NR 6DaatR- > 6a '
(CH2) ENR6dS (0) 2R6b, and (CH2) tphenyl substituted with R6c of 0-3;
R6a and R6a ', in each case are selected from H, C? _6 alkyl, C3-6 cycloalkyl, and phenyl substituted with R6c from 0-3;
R, 6b, in each case, is selected from C? _6 alkyl, C3-6 cycloalkyl, and phenyl substituted with R6c of 0-3;
R6c, in each case, is selected from C? _6 alkyl, cycloalkyl
C3-6, Cl, F, Br, I, CN, N02, (CF2) rCF3, alkyl
(CH2) EOC? -5, (CH2) EOH, (CH2) ES alkyl d5, and (CH2) rNR6dR6d;
R, in each case, is selected from H, alkyl d_6,
C3_6 cycloalkyl;
with the proviso that when either of J or L is CR 6rR > 6 and
Rc is halogen, cyano, nitro, or they are bonded to the carbon to which they are bound through a heteroatom, the other R6 is not halogen, cyano, or is bound to the carbon to which they are bound through a heteroatom;
R7 is selected from H, alkyl d-e, C2-alkenyl, C2-8 alkynyl, (CH2) qOH, (CH2) qSH, (CH2) qOR7d, (CH2) qSR7d,
(CH2) -, NR7aR7a (CH2) EC (0) OH, (CH2) rC (0) R7b,
(CH2) rC (0) NR 7'aaRn7a '(CH2) qNR7aC (0) R7a, (CH2) qNR7aC (0) H,
(CH2) rC (0) 0R 7'b °, (CH2) q0C (0) R 7'b (CH2) qS (0) pR 7'b
(CH2) qS0) 2NR7aR7a '(CH2), NR7aS (0) 2R7b, haloalkyl C? -6, a (CH) r-carbocyclic residue C3-10 substituted with R7c of 0-3, and a (CH2) r 5-10 element heterocyclic system containing 1-4 heteroatoms selected from N, 0, and S, substituted with R7c of 0-2;
R7a and R7a ', in each case is selected from H, Ci-β alkyl, C2_8 alkenyl, C2-8 alkynyl, (CH2) E C3-6 cycloalkyl, a (CH2) E- C3-10 carbocyclic residue substituted with R7e of 0-5; and a (CH2) r- heterocyclic system of 5-10 elements containing from 1-4 heteroatoms selected from N, O, and S, substituted with R7e of
0-3;
R7b, in each case, is selected from C? -e alkyl, C2_8 alkenyl, C2_8 alkynyl, a (CH) r- C3-6 carbocyclic residue substituted with R7e of 0-2, and a (CH) E-heterocyclic 5-6 elements containing from 1-4 heteroatoms selected from N, O, and S, substituted with R7e from 0-3;
R7A in each case is selected from alkyl d-6, C2-8 alkenyl, C2-8 alkynyl, (CH2) r C3_6 cycloalkyl, Cl, Br, I, F, (CF2) rCF3, N02, CN, (CH2) rNR7fR7f, (CH2) EOH, (CH2) E0 C? -4 alkyl, (CH2) ES C? -4 alkyl, (CH2) rC (O) OH, (CH2) EC (O) R7b, (CH2) rC ( O) NR7fR7f, (CH2) rNR7fC (0) R7a, alkyl (CH2) EC (O) 0C? _4, (CH2) EOC (0) R 7'b
(CH2) ENCH (= NR 'NR, 7 / frRn7'fJ (CH2) cS (0) 2NR, rR'r,
(CH2) ENR A'trSe (0) 2R, 7'bA and (CH2) rphenyl substituted with R7e of 0-3;
R, 7d, in each case, is selected from C? _6 alkyl substituted with R7e of 0-3, alkenyl, alkynyl, and a C3_? 0 carbocyclic residue substituted with R7c 0-3;
R, in each case, is selected from C? _6 alkyl, alkenyl
C2-s, C2-8 alkynyl, C3_6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) rCF3, (CH2) rO alkyl C? _5, OH, SH,
(CH2) rS C1-5 alkyl, (CH2) ENR 7, frRr > 7f, and (CH2) Ephenyl;
R Af, in each case, is selected from H, C 1-6 alkyl, and C 3-6 cycloalkyl;
R is selected from H, C? _6 alkyl, C3-6 cycloalkyl, and (CH2) tphenyl substituted with R8a of 0-3;
R, 8a, in each case, is selected from d6 alkyl, C2-8 alkenyl, C2_8 alkynyl, C3_6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) rCF3, (CH2) rO C1-5 alkyl , OH, SH,
(CH2) rS C1-5 alkyl, (CH2) rNR 7'fERt- > 7'fA and (CH2) Ephenyl;
alternatively, R7 and R8 together form C3_7 cycloalkyl,
R 8h is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, OH, CN, and (CH 2) r-phenyl;
R, 1"3, in each case, is selected from C1-6 alkyl, C2_8 alkenyl, C2_8 alkynyl, C3_6 cycloalkyl, (CF2) WCF3,
(CH2) ENRX 1J3aaRD 13a '(CH2) rOH, (CH2) E0R 13b (CH2) rSH,
(CH2) rSR 13b (CH2) wC (0) OH, (CH2) wC (0) R13b,
(CH2) wC (0) NR13aR13a ', (CH2) rNR13dC (0) R13a, (CH2 wC (0) OR13,
(CH2 EOC (0) R13b, (CH2) wS (0) R13b (CH2) wS (0) 2NR13aR13a '
(CH2) ENR13S (0) 2R1 and (CH2) w-phenyl substituted with
R13c of 0-3;
R13a and R13 ', in each case, is selected from H, C? -6 alkyl, C3_6 cycloalkyl, and phenyl substituted with R13c of 0-3;
, 13b in each case, is selected from C? _6 alkyl, C3_6 cycloalkyl, and phenyl substituted with R13c from 0-3;
R 13c in each case is selected from C?-6 alkyl, C3_6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF) ECF3,
(CH2) r0 C1-5 alkyl, (CH2) r0H, (CH2) rS alkyl C? -5, and (CH2) rNR13dR13d;
R, 13d, in each case, is selected from H, C? _6 alkyl, and C3-6 cycloalkyl, *
R1, in each case, is selected from C6_6 alkyl, C2_8 alkenyl, C2_8 alkynyl, (CH2) r C3_6 cycloalkyl, Cl, Br, I, F, N02, CN, (CHR ') rNR14aR14a', (CHR ') r0H,
[CHR ') rO (CHR') ER 14d (CHR ') rSH, (CHR') rC (0) H,
(CHR ') ES (CHR') ER 14d (CHR ') rC (0) OH
(CHR ') rC (0) (CHR') ER 14b (CHR ') rC (0) NR1 aR14a' (CHR ') ENR14fC (O) (CHR') ER14b, (CHR ') rC (0) 0 (CHR ') ER 14d
(CHR ') EOC (O) (CHR') ER14b, (CHR ') EC (= NR 114, fr
(CHR ') rNHC (= NR14f) NR14fR14f, (CHR') rS (0) p (CHR ') rR 14b
(CHR ') rS (0) 2NR14aR1 a', (CHR ') rNR14fS (O) 2 (CHR') rR1b haloalkyl C? _6, alkenyl C2_8 substituted with R 'of 0-3, alkynyl substituted with R' 0- 3, (CHR ') rphenyl substituted with R14e 0-3, and a (CH2) r- heterocyclic system of 5-10 elements containing from 1-4 heteroatoms selected from N, O, and S, substituted with R15e, of 0 -2, or two substituents R14 on adjacent atoms in ring A, together form a heterocyclic system of 5-6 elements containing 1-3 heteroatoms selected from N, O, and S substituted with R15e of 0-2;
R ', in each case, is selected from H, alkyl d-6, C2_8 alkenyl, C2_8 alkynyl, (CH2) r C3_6 cycloalkyl, and (CH2) rphenyl substituted with R14e;
R1a and R14a ', in each case, is selected from H, C? -6 alkyl, C2_8 alkenyl, C2_8 alkynyl, a C3_? 0 carbocyclic (CH2) E substituted with R1 e of 0-5, and a (CH2) ) r-heterocyclic system of 5-10 elements that
they contain from 1-4 heteroatoms selected from N, 0, and S, substituted with R 14e from 0-2;
R14b, in each case, is selected from C? -6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2) r- C3-6 carbocyclic residue substituted with R14e of 0-3, and a (CH2) E - heterocyclic system of 5-6 elements containing 1-4 heteroatoms selected from N, 0, and S, substituted with R1 and 0-2;
R14d, in each case, is selected from C2-8 alkenyl, C2_8 alkynyl, C6_6 alkyl substituted with R1e of 0-3, a (CH2) r-carbocyclic residue C3_? Or substituted with R14e of 0-3, and a (CH2) E-heterocyclic system of 5-6 elements containing from 1-4 heteroatoms selected from N, O, and S, substituted with R14e from 0-3;
R e, in each case, is selected from C ?_6alkyl, C2-alkenyl, C2_ alkynyl, (CH2) r C3_6 cycloalkyl, Cl, F,
Br, I, CN, N02, (CF2) rCF3, (CH2) rO C1-5 alkyl, OH, SH, (CH2) ES C1-5 alkyl, (CH2) rNR14fR14f, and (CH2) rphenyl;
R, 14f, in each case, is selected from H, C? _6 alkyl, C3-6 cycloalkyl, and phenyl;
alternatively, R14 together with R4 form a 5-, 6- or 7-membered piperidinium spirocycle or pyrrolidinium spirocycle linked to ring A, the spirocycle substituted with Ra of 0-3, or two R14 substituents on adjacent ring-A atoms together form a heterocycle system of 5-6 elements containing 1- 3 heteroatoms selected from N, O, and S substituted with R15e of 0-2;
R 15 in each case is selected from C ?_6 alkyl, C2_8 alkenyl, C2_8 alkynyl, (CH2) r C3_6 cycloalkyl, Cl, Br I, F, N02, CN, (CHR ') ENR15aR15a', (CHR ') rOH
(CHR ') rO (CHR') rR 15d (CHR ') rSH, (CHR') EC (0) H
(CHR ') rS (CHR' AR, 115d (CHR ') rC (0) OH (CHR') EC (0) (CHR 'AR, 115b, (CHR') rC (0) NR15aR15a '(CHR') ENR15fC (O) (CHR ') rR15b, (CHR') rC (O) O (CHR ') rR15d (CHR') rOC (O) (CHR ') rR15b, (CHR') rC (= NR15f) NR15aR15a '
(CHR ') ENCH (= NR15f) NR15fR15f, (CHR') rS (O) p (CHR ') rR15b
(CHR ') cS (0) 2NR 1i5: > aaRn15a 'CHR') ENR15fS (O) 2 (CHR ') rR15b haloalkyl C? -6, alkenyl C2_8 substituted with R' of 0-3, alkynyl C2_8 substituted with R 'of 0-3, (CHR') rphenyl substituted with R15e of 0-3, and a heterocyclic (CH2) r system of 5-10 elements containing from 1-4 heteroatoms selected from N, O, and
S, substituted with Ri3e of 0-2;
R15a and R15a ', in each case, is selected from H, C? -6 alkyl, C2_8 alkenyl, C2_8 alkynyl, a C3-? Carbocyclic (CH2) E- or substituted with R15e of 0-5; and a (CH2) r-heterocyclic system of 5-10 elements containing 1-4 heteroatoms selected from N, O, and S, substituted with R15e of 0-2;
R15b, in each case, is selected from C? -6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2) E-C3_6 carbocyclic residue substituted with R15e of 0-3; and a (CH2) r-heterocyclic system of 5-6 elements containing from 1-4 heteroatoms selected from N, O, and S, substituted with R15e from 0-2;
R15d, in each case, is selected from C2-8 alkenyl, C2_8 alkynyl, C ?_6 alkyl substituted with R15e from 0-3, a (CH2) E-carbocyclic residue C3_? 0 substituted with R15e from 0-3, and a (CH2) r-heterocyclic system of 5-6 elements containing from 1-4 heteroatoms selected from N, O, and S, substituted with R 15e from 0-3;
R, 15e, in each case, is selected from C? _6 alkyl, alkenyl
C2_8, C2_8 alkynyl, (CH2) E C3-β cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) rCF3, (CH2) rO C1-5 alkyl, OH, SH, (CH2) rS alkyl C1 -5, (CH2) rNR15fR15f, and (CH2) Ephenyl;
R 15f in each case is selected from H, C? _6 alkyl, C3_6 cycloalkyl, and phenyl;
R 16 in each case is selected from alkyl d-6, C2_8 alkenyl, C2_8 alkynyl, (CH2) E C3_6 cycloalkyl, Cl, Br I, F, N02, CN, (CHR ') ENR16aR16a', (CHR ') EOH
(CHR ') rO (CHR') rR 16d (CHR ') rSH, (CHR') rC (0) H (CHR ') ES (CHR') rR 16d (CHR ') rC (0) OH
(CHR ') rC (0) (CHR') rR 1: 6b (CHR ') EC (0) NR16aR16a'
(CHR ') rNR16fC (0) (CHR') rR16b, (CHR ') EC (O) O (CHR') ER16d
(CHR ') EOC (0) (CHR') rR 16b (CHR ') EC (= NR16f) NR16aR16a')
(CHR ') ENCH (= NR16f) NR16fR16f, (CHR') rS (0) p (CHR ') ER16b
(CHR ') ES (0) 2NR 116BaaRr > 16a '(CHR') rNR16fS (O) 2 (CHR ') rR16b C6_6 haloalkyl, C2_8 alkenyl substituted with R' of 0-3, C2_8 alkynyl substituted with R 'of 0-3, and (CHR') substituted phenyl with R16e of 0-3;
R16a and R16a ', in each case, is selected from H, C? _6 alkyl, C2_8 alkenyl, C2-8 alkynyl, a (CH2) r- C3_? 0 carbocyclic residue substituted with R16e of 0-5, and a (CH2) ) r-heterocyclic system of 5-10 elements that
contains 1-4 heteroatoms selected from N, 0, and
S, replaced with R 16e of 0-2;
R16b, in each case, is selected from C6_6 alkyl, C2_8 alkenyl, C2_8 alkynyl, a C3-e carbocyclic (CH2) E-substituted with R16e of 0-3, and a (CH2) r-heterocyclic system of -6 elements containing from 1-4 heteroatoms selected from N, O, and S, substituted with R16e from 0-2;
R16d, in each case, is selected from C2-8 alkenyl, C2_s alkynyl, C6_6 alkyl substituted with R16e from 0-3, a (CH2) r-carbocyclic residue C3-? Or substituted with R16e from 0-3, and a (CH2) r-heterocyclic system of 5-6 elements containing from 1-4 heteroatoms selected from N, O, and S, substituted with R 16β from 0-3;
R1 e, in each case, is selected from C6-alkyl, C2_8 alkenyl, C2_8 alkynyl, (CH2) E C3-6 cycloalkyl, Cl, F,
Br, I, CN, N02, (CF2) ECF3, (CH2) E0 C1-5 alkyl, OH, SH, (CH2) ES alkyl d5, (CH2) rNR16fR16f, and (CH2) Ephenyl;
R, in each case, is selected from H, Ci-β alkyl, and C3_6 cycloalkyl, and phenyl;
g is selected from 0, 1, 2, 3 and 4;
t is selected from 1 and 2;
w is selected from 0 and 1;
r is selected from 0, 1, 2, 3, 4, and 5;
q is selected from 1, 2, 3, 4, and 5; Y
p is selected from 0, 1, 2 and 3.
[12] In a preferred embodiment, the present invention provides novel compounds of formula (I), wherein:
z is selected from O and S;
R is absent, together with the nitrogen to which it binds, form an N-oxide, or is selected from C? _8 alkyl,
(CH2) E-cycloalkyl C3_6, and (CH2) r-phenyl substituted with
Rc of 0-3;
R, 4c, in each case, is selected from C? _6 alkyl, C2_s alkenyl, C2_8 alkynyl, C3_6 cycloalkyl, Cl, F, Br, I,
CN, N02, (CF2) ECF3, (CH2) E0 C1-5 alkyl, (CH2) rOH, (CH2) rS C1-5 alkyl, (CH2) ENR4aR4a ', and (CH2) rphenyl;
alternatively, R4 together with R7, R9, or R14 form a piperidinium spirocycle of 5, 6 or 7 elements substituted with Ra of 0-3;
R1 and R2 are independently selected from H, and C ?4 alkyl;
R6, in each case, is selected from C? _4 alkyl, alkenyl
C2_8, alkynyl '2-8 (CH2) r-C3_6 cycloalkyl,
(CF2) ECF3, CN, (CH2) r0H, (CH2) rOR6b, (CH2) rC (0) R6b,
(CH2) rC (0) NR6aR6a '(CH2) rNR6C (0) R6a, (CH2) tphenyl substituted with R6c of 0-3;
R6a and R6a ', in each case, is selected from H, C' _6 alkyl, C3-6 cycloalkyl, and phenyl substituted with R6c of 0-3;
R6b, in each case, is selected from C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with R6c of 0-3;
R, 6c, in each case, is selected from C 1-6 alkyl / C 3-6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) rCF3, (CH2) rO alkyl
ßd ^ ßd, C1-5, (CH2) rOH, (CH2) rS C1-5 alkyl, and (CH2) rNR ° uRc
R, 6d, in each case, is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl;
R7 is selected from H, C? -3 alkyl, (CH2) r C3_6 cycloalkyl, (CH2) qOH, (CH2) q0R7d, (CH2) qNR7aR7a ', (CH2) rC (O) R7b,
(CH2) rC (0) NR7aR7a '(CH2) qNR'aC (0) R, 7'a haloalkyl C? _6,
(CH2) rphenyl with R 7cc of 0-2;
R and R, in each case, is selected from H, C? -6 alkyl, (CH2) r C3_6 cycloalkyl, a (CH2) rphenyl substituted with R7e of 0-3;
R, 7b, in each case, is selected from C? _6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2) r C3-6 cycloalkyl, (CH2) rphenyl substituted with R7e of 0-3;
R 7c in each case is selected from C? -4 alquiloalkyl, C2_8 alkenyl, C2_ alqu alkynyl, (CH 2) r C 3-6 cycloalkyl, Cl, Br, I, F, (CF 2) rCF 3, N 2, CN, (CH 2) ENR 7fR 7f, (CH2) E0H, alkyl (CH2) EOC? _4, (CH2) rC (O) R7b, (CH2) EC (O) NR7fR7f,
(CH2) rNR7fC 0) R7a, (CH2) rS (O) pR7b, (CH2) rS (O) 2NR7fR7f,
(CH2) ENR A'rtS (0) 2R, 7'Db, and (CH2) rf enyl substituted with R7e of 0-2;
R7d in each case is selected from C6-alkyl, (CH2) C3-6 cycloalkyl, (CH2) rphenyl substituted with R, 7e of 0-3;
R 7e in each case is selected from C 1 _6 alkyl, C 2-8 alkenyl, C 2 8 alkynyl, C 3 6 cycloalkyl, Cl, F, Br, I, CN, N 2, (CF 2) ECF 3, (CH 2) E 0 C 5 alkyl , OH, SH, (CH2) ES C1-5 alkyl, (CH2) ENR7fR7f, and (CH2) Ephenyl;
R, 7f, in each case, is selected from H, C1-5 alkyl, C3_e cycloalkyl;
R8 is H or together with R7 cycloalkyl form C3_7, or
R11 is selected from H, C1-6 alkyl / (CH2) r C3_6 cycloalkyl / (CH2) q0H, (CH2) qORlld, (CH2) qNRllaRlla ', (CH2) rC (O) Rllb, (CH2) rC (0 ) NRllaRlla ', (CH2) qNRllaC (0) Rlla, haloalkyl d-6 / (CH2) rphenyl with Rllc of 0-2, a (CH2) r 5-10 elements heterocyclic system containing from 1-4 selected heteroatoms of N, O, and S, substituted with R15 of 0-3;
Rlla and Rlla ', in each case, is selected from H, C? _6 alkyl, (CH2) r C3_6 cycloalkyl, a (CH2) Ephenyl substituted with Rlle of 0-3;
R, in each case, is selected from C? -6 alkyl, C2-8 alkenyl, C2_8 alkynyl, (CH2) E C3_6 cycloalkyl, (CH2) Eppryl substituted with Rlle of 0-3;
R lie in each case, is selected from C ?4 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2) r C3_6 cycloalkyl, Cl, Br, I, F, (CF2) ECF3, N02, CN, (CH2 ) rNRllfRllf, (CH2) rOH, alkyl '(CH2) EOC? -, (CH2) rC (O) Rllb, (CH2) EC (O) NRllfRllf,
(CE2) r ^ R, llf > (O) R, 111a (CH = ASOAR l1lb (CHzJ rS ÍOJ z R, l u1l1fr ^ rn) lilifr
(CH2) rNRiirS (0) 2RliD, and (CH2) Ef enyl substituted with R lie 0-2;
Rlld, in each case, is selected from alkyl C? _6, (CH2) r C3_6 cycloalkyl, (CH2) rphenyl substituted with Rlle of 0-3;
Rlle, in each case, is selected from alkyl C6-6, C2_8 alkenyl, C2_8 alkynyl, C3_6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) rCF3, (CH2) rO alkyl C? _5, OH, SH, (CH2) rS alkyl d_5, (CH2) ENRllfRllf, and (CH2) rphenyl;
R, Ilf, in each case, is selected from H, C? _5 alkyl, and C3-6 cycloalkyl;
R is H or together with R form C3_7 cycloalkyl;
R, in each case, is selected from C? -4 alkyl, C3-6 cycloalkyl, (CH2) NR13aR13a ', (CH2) OH, (CH2) OR13b, (CH2) "C (O) R13,
(CH2) wC (0) NR13aR13a '(CH2) NR13C (0) R13a,
(CH2) wS (0) 2NR13aR13a ', (CH2) NR13 S (0) 2R13b, and (CH2) "-f-enyl substituted with R13c of 0-3;
R13 and R13a ', in each case, is selected from H, C? 6 alkyl, C3-6 cycloalkyl, and phenyl substituted with R13c of 0-3;
R 13b in each case is selected from C 1-6 alkyl, C 3-6 cycloalkyl, and phenyl substituted with R 3c of 0-3;
R 13c in each case is selected from C? _6 alkyl, C3_6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) rCF3, (CH2) rO C1-5 alkyl, (CH2) EOH, and ( CH2) rNR13dR13;
R, 13d, in each case, is selected from H, C? -6 alkyl and C3-g cycloalkyl;
q is selected from 1, 2, and 3; Y
r is selected from 0, 1, 2 and 3.
[13] In a more preferred embodiment, the present invention provides novel compounds of formula (I), wherein:
Ring A is selected from:
RJ is selected from a (CR3?) Carbocyclic E-residue substituted with R15 of 0-5, wherein the carbocyclic residue is selected from phenyl, C3_6 cycloalkyl, naphthyl, and adamantyl; and a (R3?) r-substituted heterocyclic system with R15 of 0-3, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl,
pyrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; Y
R5 is selected from (CR5?) T-phenyl substituted with R16 of 0-5; and a (CR5?) t-heterocyclic system substituted with R16 of 0-3, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisaxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, isoindolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl.
[14] In a still more preferred embodiment, the present invention provides novel compounds of formula (I-i), wherein the compound of formula (I-i) is:
(i-i)
R, 16, in each case, is selected from Ci- 8 alkyl (CH 2)
C3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2) ENR16aR16a ', N02,
CN, OH, (CH2) rOR 16d (CH2) rC (0) R16b, (CH2) rC (0) NR16aR16a ',
(CH2) rNR16fC (0) R16b, (CH2) ES (0) pR 16b and (CH2) rphenyl substituted with R 16e of 0-3;
R 16a and R, in each case, is selected from H, C? -6 alkyl, C3_6 cycloalkyl, and (CH2) rphenyl substituted with R16e of 0-3;
R 16b in each case is selected from H, C? -6 alkyl, C3_6 cycloalkyl, and (CH2) rphenyl substituted with R16e of 0-3;
R, 16d, in each case, is selected from C? -6 alkyl, and phenyl;
R, 16e, in each case, is selected from alkyl C6, Cl, F, Br, I, CN, N02, (CF2) rCF3, OH, and (CH2) rO alkyl C5-5; Y
R16f, in each case, is selected from H, alkyl C? _5.
[15] In another even more preferred embodiment, the present invention provides novel compounds of formula (I-i), wherein (I-ii) is:
d-ii)
R16, in each case, is selected from alkyl C? -8, (CH2) r C3_6 cycloalkyl, CF3, Cl, Br, I, F, (CH2) ENR16aR16a ', N02, CN, OH, (CH2) rOR16d, ( CH2) EC (0) R16b, (CH2) rC (O) NR16aR16a ', (CH2) rNR16fC (0) R16b, (CH2) ES (0) pR16b, (CH2) rS (O) 2NR16aR16a',
(CH2) rNR16fS (0) 2R16b, and (CH2) rf enyl substituted with R16e of 0-3;
R16a and R16a ', in each case, is selected from H, alkyl d_6, cycloalkyl C3_6, and (CH2) E phenyl substituted with R16e of 0-3;
R16b, in each case, is selected from H, C? _6 alkyl, C3_6 cycloalkyl, and (CH2) Ephlyl substituted with R16e with
0-3;
R, 16d, in each case, is selected from C? _6 alkyl and phenyl;
R, in each case, is selected from alkyl C? -6, Cl, F, Br, I, CN, N02, (CF2) rCF3, OH, and (CH2) rO C1-5 alkyl; Y
R, 16f, in each case, is selected from H, and alkyl C? _5.
[16] In a preferred embodiment, the present invention provides novel compounds of formula (I-i), wherein:
R is CH2phenyl substituted with R of 0-3;
R is selected from H, C? -6 alkyl, (CH2) E C3_6 cycloalkyl, F, Cl, CN, (CH2) rOH, (CH2) rOR9d, (CH2) rNR9aR9a ', (CH2) EOC (0) NHR9a , (CH2) rphenyl substituted with R9e of 0-5, and a heterocyclic system substituted with R9e of 0-2, wherein the heterocyclic system is selected from pyridyl, thiophenyl, furanyl, oxazolyl, and thiazolyl;
R9a and R9a ', in each case, is selected from H, C? -6 alkyl, C3_6 cycloalkyl and (CH) rphenyl substituted with R9e of 0-3;
R, 9d, in each case, is selected from C? _6 alkyl and phenyl;
R, 9e, in each case, is selected from alkyl C? -6, Cl, F, Br, I, CN, N02, (CF2) ECF3, OH, and (CH2) rO alkyl d_5;
R, 10, is selected from H, C C _s alkyl, OH, and CH 2 OH;
alternatively, R9 and R10 together form C3-7 cycloalkyl, cyclic ketal of 5-6 elements or = 0;
provided that R10 is halogen, cyano, nitro, or is attached to the carbon to which it is attached through a heteroatom, R9 is not halogen, cyano or is attached to the carbon to which it is attached through a heteroatom;
R11 is selected from H, alkyl C? -8, (CH2) rphenyl substituted with Rlle of 0-5, and a (CH2) E-substituted heterocyclic system with Rlle of 0-2, wherein the heterocyclic system is selected from pyridinyl , thiophenyl, furanyl, incazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, isoindolyl, piperidinyl, pyrrazole, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl , thiazolyl, oxazolyl, pyrazinyl and pyrimidinyl; Y
Rlle, in each case, is selected from alkyl d_6, Cl, F, Br, I, CN, N02, (CF2) rCF3, OH, and (CH2) r0 alkyl d_5;
R12 is H;
alternatively, R and R, 12 together form C3_7 cycloalkyl;
R? in each case, it is selected from alkyl C? -8, (CH2) E C3_6 cycloalkyl, CF3, Cl, Br, I, F, (CH2) rNR14aR1 a ', N02,
CN, OH, (CH2) EOR l4d (CH2) EC (0) R 14b (CH2) rC (0) NR14aR14a '
(CH2) rS (0) pR14b, (CH2) rS (0) 2NR1 aR1 a '
(CH2) rNR14fS (0) 2R1 b, (CH2) E phenyl substituted with R1 e of
0-3, and a (CH2) E-5-10 elements heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with R15e from 0-2; or two R14 substituents on adjacent atoms in rings A together form a heterocyclic system of 5-6 elements containing 1-3 heteroatoms selected from N, O, and S substituted with R15e of 0-2;
R14a and R14a ', in each case, is selected from H, C? _6 alkyl, C3_6 cycloalkyl, and (CH2) Ephenyl substituted with R 14e of
0-3; and a (CH2) r-heterocyclic system of 5-6 elements containing from 1-4 heteroatoms selected from N, O, and S, substituted with R15e from 0-2;
R14b, in each case, is selected from H, C, C6 alkyl, C3-6 cycloalkyl, and (CH2) rphenyl substituted with R14e from 0-3;
R, in each case, is selected from C? _6 alkyl and phenyl;
R, in each case, is selected from alkyl d6, Cl, F, Br, I, CN, N02, (CF2) rCF3, OH, and (CH2) rO alkyl d-5; Y
R, in each case, is selected from H, C1-5 alkyl;
r is selected from 0, 1, and 2.
[17] In a preferred embodiment, the present invention provides novel compounds of formula (I-ii), wherein:
R3 is CH2phenyl substituted with Rlb of 0-3;
R is selected from H, C1-6 alkyl, (CH2) r C3_6 cycloalkyl, F, Cl, CN, (CH2) rOH, (CH2) rOR9d, (CH2) ENR9aR9a ', (CH2) rOC (0) NHR9a, (CH2) rPhenyl substituted with R9e of 0-5, and a heterocyclic system substituted with R9e of 0-2, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, oxazolyl, and thiazolyl;
R9a and R9a ', in each case, is selected from H, C? _6 alkyl, C3_6 cycloalkyl, and (CH2) rphenyl substituted with R9e of
0-3;
R, in each case, is selected from C? -6 alkyl and phenyl;
R, in each case, is selected from alkyl Ci-e, Cl, F, Br, I, CN, N02, (CF2) rCF3, OH, and (CH2) rO alkyl C? -5;
R is selected from H, alkyl Ci-a, OH, and CH 2 OH;
alternatively, R9 and R10 together form C3_7 cycloalkyl, cyclic ketal of 5-6 elements or = 0;
with the proviso that when R9 is halogen, cyano, nitro, or is linked to the carbon to which it is attached through a heteroatom, R9 is not halogen, cyano, or is bound to the carbon to which it is attached through a heteroatom;
R 11 is selected from H, alkyl Ci-s, (CH 2) Ephenyl substituted with Rlle of 0-5, and a (CH 2) r- substituted hetrocyclic system with Rlle of 0-2, wherein the heterocyclic system is selected from pyridinyl , thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophanyl, benzofuranyl, benzoxazolyl, benzisaxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, isoindolyl, piperidinyl,
pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; Y
RUA in each case is selected from alkyl C? -6, Cl, F, Br, I, CN, N02, (CF2) ECF3, OH, and (CH2) rO alkyl C? -5;
R12 is H;
alternatively, R and R, 12 together form C3_7 cycloalkyl;
R 14 in each case is selected from alkyl C? _8, (CH2) E C3.6 cycloalkyl, CF3, Cl, Br, I, F, (CH2) ENR14aR14aJ, N02,
CN, OH, (CH2) EOR 14d (CH2) rC (0) R1b, (CH2) rC (0) NR 1i4iaarR14ai,
(CH2) rNR1 fC (0) R14, (CH2) rS (0) pR1, 14aD14a '(CH2) ES (0) 2NR1, aR- [CH2) rNR l14"fSc (0) 2R, lb (CH2) substituted phenyl with 0-3 Rl ey (CH2) 5-6 Element heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with R15e from 0-2, or two R14 substituents in adjacent atoms in the ring A forming together a 5-6 element heterocyclic system containing 1-3 heteroatoms selected from N, O, and S substituted with R15e of 0-2;
R a and R, l aa, in each case, is selected from H, alkyl C? _6,
C3_6 cycloalkyl, and (CH2) E phenyl substituted with R, 14e of 0-3;
R, 14b, in each case, is selected from H, C? -6 alkyl, C3_6 cycloalkyl and (CH2) Ephenyl substituted with R1 e of 0-3;
R, 1 d, in each case, is selected from C 1-6 alkyl and phenyl;
R, 14e, in each case, is selected from alkyl d6, Cl, F, Br, I, CN, N02, (CF2) ECF3, OH, and (CH2) rO C1-5 alkyl;
R, 14f, in each case, is selected from H, and C C_5 alkyl;
r 'is selected from 0, 1 and 2.
[18] In a more preferred embodiment, the present invention provides novel compounds of formula (I-i), wherein:
J is selected from CH2 and CHR5;
L is selected from CH2 and CHR5;
R3 is a C3_? Carbocyclic residue or substituted with R15 of 0-3, wherein the carbocyclic residue is selected from cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl and adamantyl, and a (CR3?) Substituted heterocyclic system R15 of 0 -3, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisazololyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl , 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; Y
R15, in each case, is selected from alkyl d-8, cycloalkyl (CH2) EC3-6, CF3, Cl, Br, I, F, (CH2) rNR15aR15a ', N02, CN, OH,
(CH2) EOR 15d (CH2) rC (0) R 15b (CH2) rC (0) NR15aR15a '
(CH2) rNR15fC (0) R15, (CH2) rS (0) pR 15b (CH2) rS (0) 2NR15aR15a '
(CH2) rNR15fS (0) 2R15b, (CH2) E-phenyl substituted with R 15e of 0-3, and a (CH2) r-heterocyclic system of 5-6 elements containing from 1-4 heteroatoms selected from N, O, and S, substituted with R15e of 0-2;
R > 15a and R, 15a, in each case, is selected from H, alkyl C? _6,
C3_6 cycloalkyl, and (CH2) rphenyl substituted with R, 15e of 0-3;
R 15b in each case is selected from H, alkyl-d_6, cycloalkyl C3_6, and (CH2) rphenyl substituted with R, 15e from 0-3;
R, in each case, is selected from C? -6 alkyl and phenyl;
R, in each case, is selected from alkyl d-6 / Cl, F, Br, I, CN, N02, (CF2) rCF3, OH and (CH2) rO alkyl C? _5; Y
R, in each case, is selected from H, alkyl C? _s.
[19] In a more preferred embodiment, the present invention provides novel compounds of formula (I-ii), wherein:
L is selected from CH2 and CHR5;
R3 is a C3_? Carbocyclic residue or substituted with R15 of 0-3, wherein the carbocyclic residue is selected from cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl and adamantyl, and a (CR3'H) r-heterocyclic system substituted with R15 of 0-3; wherein the heterocyclic system is selected from pyridinyl, thiophenyl,
furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisazololyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolinyl, isothiadiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1, 2, 3 triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; Y
R, 15, in each case, is selected from alkyl C? _8, (CH2) r C3.6 cycloalkyl, CF3, Cl, Br, I, F, (CH2) rNR15aR15a ', N02,
CN, OH, (CH ^ rOR, 115d (CE2) IC (0) R, 115b (CH2) rC (0) NR 15oaaRn 15a '
(CH2) ENR15fC (0) R15b, (CH2) rS (0) pR15b, (CH2) rS (0) 2NR15aR15a '
(CH2) rNR15fS (0) 2R15b, and (CH2) rphenyl substituted with R15e of 0-3, and a (CH2) r 5-6 elements heterocyclic system containing from 1-4 heteroatoms selected from N, O, and S, replaced with R15e of 0-2;
R15a and R15a ', in each case, is selected from H, C? _6 alkyl, C3_6 cycloalkyl, and (CH2) Ephenyl substituted with R15e of 0-3;
R 15b in each case is selected from H, C? -6 alkyl, C3_6 cycloalkyl, and (CH2) rphenyl substituted with R15e from 0-3;
R, in each case, is selected from C? _6 alkyl and phenyl;
R, in each case, is selected from alkyl C? -6, Cl, F, Br, I, CN, N02, (CF2) rCF3, OH, and (CH2) rO alkyl d-5; Y
R, 15f, in each case, is selected from H, and C1-5 alkyl
[20] In a still more preferred embodiment, the present invention provides new compounds of the formula (I) and pharmaceutically acceptable salt forms thereof, wherein the compound of the formula (I) is selected from:
N- (3-acetylphenyl) -N '- [trans-2- [[4- (4-fluorophenylmethyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3-nitrophenyl) -N '- [trans-2- [[4- (4-fluorophenylmethyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (4-nitrophenyl) -N '- [trans-2- [[4- (4-fluorophenylmethyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (4-pyridinyl) -N '- [trans-2- [[4- (4-fluorophenylmethyl) piperidinyl] ethyl] cydohexyl] -urea,
N- (3-acetylphenyl) -N '- [trans-2- [[4- (4-
fluorophenylmethyl) piperidinyl] methyl] cyclohexyl] -urea,
N- ((ÍH) -indazol-5-yl) -N '- [trans-2- [[4- (4-fluorophenylmethyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3-methoxyphenyl) -N '- [trans-2- [[4- (phenylmethyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3-methoxyphenyl) -N '- [trans-2- [[4- (4-fluorophenylmethyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3-methoxyphenyl) -N '- [cis-2- [[4- (phenylmethyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3-cyanophenyl) -N '- [trans-2- [[4- (4-fluorophenylmethyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3-acetylphenyl) -N '- [(SS, 2R) -2- [[4- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3-cyanophenyl) -N '- [(1S, 2R) -2- [[4- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3-methoxyphenyl) -N '- [(1S, 2R) -2- [[4- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (phenyl) -N '- [(1S, 2R) -2 - [[4- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3-acetylphenyl) -N '- [(IR, 2S) -2- [[A- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3-cyanophenyl) -N '- [(IR, 2S) -2- [[4- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3-methoxyphenyl) -N '- [(IR, 2S) -2- [[4- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (phenyl) -N '- [(IR, 2S) -2- [[4- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (phenylmethyl) -N '- [(1S, 2R) -2- [[4- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- ((1H) -indazol-5-yl) -N '- [(IR, 2S) -2- [[A- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- ((1H) -indol-5-yl) -N '- [(IR, 2S) -2- [[4- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea,
N- (3-methoxyphenyl) -N '- [3- [[4- (4-fluorophenylmethyl) piperidinyl] methyl] cyclohexyl] -urea, and
N- (3-Acetylphenyl) -N '- [3- [[4- (4-fluorophenylmethyl) piperidinyl] methyl] cyclohexyl] -urea.
[21] In another embodiment, the present invention provides a pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the present invention.
[22] In another embodiment, the present invention provides a method for modulating the activity of chemokine receptors, comprising administering to a patient in need thereof, a therapeutically effective amount of the compound of the present invention.
[23] In a fifth embodiment, the present invention provides a method for the treatment or prevention of inflammatory conditions, comprising administering to a patient in need thereof, a therapeutically effective amount of a compound of the present invention.
[24] In a fifth embodiment, the present invention
provides a method for the treatment or prevention of asthma, comprising administering to a patient in need thereof, a therapeutically effective amount of a compound of the present invention.
[25] In another embodiment, the present invention provides a method for modulating the activity of chemokine receptors, comprising administering to a patient in need thereof, a therapeutically effective amount of the compounds of formula (I):
íl)
or stereoisomers or pharmaceutically acceptable salts thereof, wherein:
M is absent or is selected from CH2, CHR5, CHR, CR 133Rr > Ij CR5R13;
Q is selected from CH2, CHR5, CHR13, CR13R13, and CR5R13;
J and K are selected from CH2, CHR5, CHR6, CR6R6 and CR5R6;
L is CHR3;
with the condition of:
when M is absent, J is selected from CH2, CHR, CHR13, and CR5R13;
Z is selected from 0 and S;
E is - (CR7R8) - (CR9R10) v- (CRuR12) -;
v is 1 or 2
R1 and R2 are independently selected from Ci-β alkyl, C2_8 alkenyl, C2-8 alkynyl, (CH2) r C3-6 cycloalkyl, and a (CH) E- C3_? 0 carbocyclic residue substituted with Ra of 0-5;
Ra, in each case, is selected from C ?4 alkyl, C2-alkenyl, C2_8 alkynyl, (CH2) r C3_6 cycloalkyl, Cl, Br, I,
F, (CF2) rCF3, N02, CN, (CH2) rNR bDRpb1; CH2) EOH, (CH2) r0Rc,
(CH2) rSH, (CH2) rSRc, (CH2) EC (0) RD, (CH2) EC (0) NR Rb,
(CH2) rNRbC (0) Rb, (CH2) EC (0) ORD, (CH2) E0C (0) Rc,
(CH2) rCH (= NRb) NRbRb, (CH2) rNHC (= NRb) NRbRb, (CH2) rS (O) PRC,
(CH2) ES (0) 2NR Rb, (CH2) rNRbS (0) 2Rc, and (CH2) Ephenyl;
R, in each case, is selected from H, C? -6 alkyl / C3_6 cycloalkyl, and phenyl;
Rc, in each case, is selected from C? _6 alkyl, C3-6 cycloalkyl and phenyl;
alternatively, R2 and R3 together form a ring of 5, 6, or 7 elements, substituted with Ra of 0-3;
R is selected from a C3 carbocyclic (CR3'R) E-residue. 10 substituted with R15 of 0-5 and one (CR3'R3") r-5-10 elements heterocyclic system containing from 1-4 heteroatoms selected from N, 0, and S substituted with R15 from 0-3;
R3 'and R3", in each case, is selected from H, alkyl C? _6,
(CH2) r C3_6 cycloalkyl, and phenyl;
R is absent, taken with the nitrogen to which it is attached, forms an N-oxide, or is selected from C? _8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, (CH 2) E C 3-6 cycloalkyl, (CH 2) qC (0) R 4b , (CH2) qC (0) NR4aR4a ', (CH2) qC (0) OR4b, and a (CH2) E-carbocyclic residue C3_? 0 substituted with R4c of 0-3;
R a and R a '/ in each case, are selected from H, alkyl Ci-e, (CH 2) r C 3-6 cycloalkyl, and phenyl;
R, 4b, in each case, is selected from C? -6 alkyl, C2-8 alkenyl, (CH2) E C3_6 cycloalkyl, C2-8 alkynyl, and phenyl;
R 4c in each case is selected from C 1 _6 alkyl, C 2-8 alkenyl, C 2 8 alkynyl, C 3 6 cycloalkyl, Cl, F, Br, I, CN, N 2, (CF 2) ECF 3, (CH 2) rO alkyl d 5, ( CH2) rOH, (CH2) ES alkyl C? _5, (CH2) ENR4aR4a ', and (CH2) Ephenyl;
alternatively, R4 together with R7, R9, R11 or R14 form a piperidinium spirocycle or pyrrolidinium spirocycle of 5, 6 or 7 elements substituted with Ra of 0-3;
R is selected from a (CR5'R5 ') t-carbocyclic residue C3_? 0 substituted with R16 of 0-5 and a (CR5'R5") t-heterocyclic system of 5-10 elements containing 1-4 heteroatoms selected from N, O, and S, substituted with R16 of 0-3;
R5 'and R5", in each case, are selected from H, C? _6 alkyl, (CH2) E C3_e cycloalkyl, and phenyl;
R6, in each case, is selected from alkyl -6 / C2_8 alkenyl, C2_s alkynyl, (CH2) E C3_6 cycloalkyl, (CF2) rCF3, CN, (CH2) rNR6aR6a ', (CH2) EOH, (CH2) EOR6b, ( CH2) ESH,
(CH2) rSR6, (CH2) EC (0) OH, (CH2) rC (0) R6b (CH2) rC (0) NR6aR6a '
CH2) rNR, 6 ° daC (0) R 6 ° a (CH2) EC (0) OR 6cb (CH2) r0C (0) R 6ObD,
(CH2) rS (0) pR, 6DbD, (CH2) rS (0) 2NR, 6baaRr, 6'a '(CHj ENR6dS (0) 2R6b, (CH2) tphenyl substituted with R6c of 0-3;
R6a and R6a ', in each case, are selected from H, alkyl d-6 / cycloalkyl C3_6, and phenyl substituted with R6c from 0-3;
R, 6b, in each case, is selected from alkyl d_6, cycloalkyl C3-6 / and phenyl substituted with R6c from 0-3;
R > 6c, in each case, is selected from C? _6 alkyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) ECF3, (CH2) rO alkyl d- 5, (CH2) rOH, (CH2) rS alkyl C? -5, and (CH2) rNR6dR6;
R, 6d, in each case, is selected from H, C1-6 alkyl, and C3_6 cycloalkyl "
R7 is selected from H, C? _6 alkyl, C2_8 alkenyl, C2-8 alkynyl, (CH2) qOH, (CH2) qSH, (CH2) qOR7d, (CH2) qSR7d, (CH2) qNR7aR7a ', (CH2) rC (0) 0H, (CH2) EC (O) R7b,
(CH2) EC (O) NR7aR7a ', (CH2) qNR7aC (O) R7a, (CH2) qNR'aaC (0) H,
(CH2) rC (0) OR7'b (CH2) qOC (0) R7'b (CH2) qS (0) pR7'b
(CH2) qS (0) 2NR7aR7a ', (CH2) qNR7aS (0) 2R7b, haloalkyl C6-6, a (CH2) r- C3-10 carbocyclic residue substituted with R7c of 0-3, and a (CH2) r- 5-10 element heterocyclic system containing 1-4 heteroatoms selected from N, 0, and S, substituted with R7c from 0-2;
R7a and R7a ', in each case, are selected from H, C? _6 alkyl, C2_8 alkenyl, C2_8 alkynyl, a (CH2) r-C3_10 carbocyclic residue substituted with R7e of 0-5, and a (CH2) E-system heterocyclic of 5-10 elements containing from 1-4 heteroatoms selected from N, 0, and S, substituted with R7e of 0-3;
R7b, in each case, is selected from C? -6 alkyl, C2-8 alkenyl, C2_s alkynyl, a C3-6 carbocyclic (CH) E substituted with R7e of 0-2, and a (CH2) E-system heterocyclic 5-6 elements containing 1-4 heteroatoms selected from N, O, and S, substituted with R7e of 0-3;
R7c, in each case, is selected from C? -6 alkyl, C2_8 alkenyl, C2_8 alkynyl, (CH2) r C3_6 cycloalkyl Cl, Br, I, F, (CF2) ECF3, N02, CN, (CH2) ENR7fR7f, ( CH2) rOH, (CH2) rO alkyl
C? _4, alkyl (CH2) rSC1_4, (CH2) EC (O) OH, (CH2) EC (0) R 7b
(CH2) EC (0) NR / rR'J (CH2) rNR, 7frC (0) R 7a, (CH2) EC (0) 0 alkyl Ci
4, (CH2) E0C (0) R 7b (CH2) rC (= NR7f) NR7fR7f, (CH2) ES (0) pR 7'bA
(CH2) rNHC (= NR7f) NR7fR7f, (CH2) ES (0) 2NR7fR7f /
(CH2) ENR'rS (0) 2RD, and (CH2) E-phenyl substituted with Re of 0-3;
R7d, in each case, is selected from C? -6 alkyl substituted with R7e of 0-3, alkenyl, alkynyl, and a C3-? Carbocyclic residue or substituted with R7c of 0-3;
R7e, in each case, is selected from C? _g alkyl, C2_8 alkenyl, C2_8 alkynyl, C3_6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) ECF3, (CH2) rO alkyl C _ 5, OH, SH, (CH2) ES alkyl C _ _5 (CH2) rNR 7'frrR > 7'fr and (CH2) r-phenyl;
R? 7f, in each case, is selected from H, C? -6 alkyl, and C3_6 cycloalkyl;
R is selected from H, C? _6 alkyl, C3_6 cycloalkyl, and (CH2) tphenyl substituted with R8a of 0-3;
R8a, in each case, is selected from C6-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3_6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) ECF3, (CH2) rO alkyl C ? 5, OH, SH, (CH 2) r S C 1-5 alkyl, (CH 2) r NR 7 f R 7f, and (CH 2) E phenyl;
alternatively, R7 and R8 together form C3_7 cycloalkyl, or = NR8b;
R '8b is selected from H, C? -6 alkyl, C3-6 cycloalkyl, OH, CN, and (CH2) r-phenyl;
R9 is selected from H, C? -6 alkyl, C2-8 alkenyl, alkynyl
C2_8, F, Cl, Br, I, N02, CN, (CH2) rOH, (CH2) rSH, (CH2) r0R 93d
(CH2) ESR9d, (CH2) ENR9aR9a ', (CH2) rC (0) OH,; CH2) rC (0) R 9ab
(CH2) rC (0) NR9aR9a ', (CH2) rNR, 93aa, C (0) RJ (CH2) ENR 93aa, C (0) H, (CH2) rNR9aC (0) NHR9a, (CH2) EC (0) OR 9bb (CH2) r0C (0) R 93bD,
(CH2) r0C (0) NHR 9sa (CH2) rS (0) pR 93b (CH2) ES (0) 2NR9aR9a '
(CH2) ENR9aS (0) 2R9b, haloalkyl C6-6, a (CH2) r-carbocyclic residue C3-10 substituted with R9c of 0-5, and a (CH2) r-heterocyclic system of 5-10 elements containing 1 - 4 heteroatoms selected from N, O, and S, substituted with R9c of 0-3;
R! 9a and R9a ', in each case, are selected from H, C? _6 alkyl, C2_8 alkenyl, C2_8 alkynyl, a C3-? (CH2) E-carbocyclic residue or substituted with R9c of 0-5, and a ( CH2) r- heterocyclic system of 5-10 elements containing 1-4 heteroatoms selected from N, O, and S, substituted with R9e of 0-3;
R9b, in each case, is selected from Ci-β alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2) r-C3_6 carbocyclic residue substituted with R9e of 0-2, and a heterocyclic system containing 1-4 selected heteroatoms of N, O, and S, substituted with R9e of 0-3;
R9A in each case is selected from Ci-e alkyl, C2_8 alkenyl, C2_s alkynyl, (CH2) E- C3_6 cycloalkyl, Cl, Br, I,
F, (CF2) ECF3, N02, CN, (CH2) ENR9fR9f, (CH2) r0H, (CH2) r0 alkyl d4, (CH2) rS alkyl C? -, (CH2) EC (O) OH,
(CH2) rC (0) R9b, (CH2) rC (0) NR9fR9f, (CH2) rNR9fC (O) R9a, alkyl
(CH2) rC (0) 0d_4, (CH2) EOC (0) R9b, (CH2) EC (= NR9f) NR9fR9f,
(CH2) ES (0) pR9b, (CH2) ENCH (= NR9f) NR9fR9f, (CH2) rS (O) 2NR9fR9f,
(CH2) ENR, 93frSc (0) 2R, 93bD, and (CH2) rphenyl substituted with R 93ee of 0-3;
R9d, in each case, is selected from C? _6 alkyl, C2-6 alkenyl, C2_? Alkynyl, a C3-10 carbocyclic residue substituted with R9c of 0-3, and a heterocyclic system of 5-6 elements containing 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with R9 of 0-3;
R, 9e, in each case, is selected from C 1-6 alkyl, alkenyl
C2_8, C2_8 alkynyl, (CH2) E C3_6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) rCF3, (CH2) E0 C1-5 alkyl, OH, SH, (CH2) rS C1-5 alkyl , (CH2) ENR9fR9f, and (CH2) Ephenyl;
R, 9f, in each case, is selected from C? _6 alkyl, and C3_e cycloalkyl;
R 10 is selected from H, C? -6 alkyl, C2-alkenyl C2_? Alkynyl, F, Cl, Br, N02, CN, (CH2) EOH, (CH2) EOR 10d
(CH2) ESR 10d (CH2) ENR 1l0uaaRn 10a '(CH2) rC (0) OH, (CH2) EC (0) R 10b
(CH2) EC (O) NR10aR10a '(CH2) ENR10aC (O) R10a, (CH2) ENR10aC (O) H
(CH2) EC (O) OR10b, (CH2) EOC (O) R10b, (CH2) rS (0) pR 10b
(CH2) rS (O) 2NR10aR10a ', (CH2) rNR10aS (O) 2R10, haloalkyl C? _6 a (CH2) r-carbocyclic residue C3_? 0 substituted with R10c of 0-5, and a (CH2) r-system heterocyclic 5-10 elements containing 1-4 heteroatoms selected from N, O, and S, substituted with R10c from 0-3;
R10a and R10a ', in each case, is selected from H, C? _6 alkyl, C2_8 alkenyl, C2-8 alkynyl, a C3_? 0 carbocyclic (CH2) E substituted with R10e of 0-5, and a (CH2) ) 5-10 elements heterocyclic r-system containing 1-4 heteroatoms selected from N, O, and S, substituted with R10e of 0-3;
R10b, in each case, is selected from C6_6 alkyl, C2_8 alkenyl, C2_8 alkynyl, a (CH2) r-C3_6 carbocyclic residue substituted with R10e of 0-2, and a (CH2) r-heterocyclic system of -6 elements containing 1-4 heteroatoms selected from N, O, and S, substituted with R10e of 0-3;
R 10c in each case is selected from C 1 -C 6 alkyl, C 2 8 alkenyl, C 2 8 alkynyl, (CH 2) E C 3 β cycloalkyl, Cl, Br, I,
F, (CF2) rCF3, N02, CN, (CH2) rNR 1i0UfIRp 10f, (CH2) EOH, (CH2) rO alkyl C? _4, (CH) rS alkyl C? -4, (CH2) EC (0) OH ,
(CH2) EC (0) R10, (CH2) rC (O) NR10fR10f, (CH2) rNR10fC (O) R10a, alkyl (CH2) rC (0) OC? _4 (CH2) EOC (O) R10b,
(CH2) EC (= NR10f) NR10fR10f, (CH2) ES (O) pR10b,
(CH2 ENHC (= NR10f) NR10fR10, (CH2) ES (O) 2NR10fR10f,
(CH2) rNR .1i0U fXSr (0) 2R, 1X0UbD, and (CH2) E phenyl substituted with R10e of 0-3;
R10d, in each case, is selected from alkyl d-6, C2-6 alkenyl, C2-β alkynyl, a carbocyclic residue C3_? Or substituted with R10c of 0-3, and a heterocyclic system of 5-6 elements containing 1? - 4 heteroatoms selected from the group consisting of N, O, and S, substituted with R 10c of 0-3;
R10e, in each case, is selected from C? -6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2) r C3_6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) rCF3, ( CH2) rO C1-5 alkyl, OH, SH, (CH2) rS C1-5 alkyl, (CH2) ENR10fR10f, and (CH2) E phenyl;
R 10f in each case is selected from H, alkyl d_6, cycloalkyl C3-β;
alternatively, R9 and R10 together form C3_7 cycloalkyl, cyclic ketal of 5-6 elements, or = 0;
with the proviso that when R10 is -OH, R9 is not halogen, cyano, or binds to the carbon to which it is attached through a heteroatom;
R 11 is selected from H, C? _6 alkyl, C2-alkenyl C2_8 alkynyl, (CH2) q0H, (CH2) qSH, (CH2) qORlld
(CH2) qRSlld, (CH2) qNRllaRlla ', (CH2) EC (O) OH, (CH2) EC (O) Rll
: CH2) EC (0 NR lllaanRlla '(CH2) qNRllaC (0) Rlla
(CH2) qNR, 111 ± aa, C (0) NHR lia (CH2) rC (0) 0Rllb, (CH2) q0C (0) R, 11b (CH2) qS (0) pR, 1l1lbb, (CH2) qS ( 0) 2NRllaRlla ', (CH2) qNRLAS (0) 2R haloalkyl C? _6, a (CH2) E-carbocyclic residue C3_? Or substituted with Rllc of 0-5, and a (CH2) E-heterocyclic system of 5-10 Elements containing 1-4 heteroatoms selected from N, 0, and S, substituted
Rlla and Rlla ', in each case, are selected from H, C? _6 alkyl, C2_8 alkenyl, C2_8 alkynyl, a (CH2) r- C3_? Carbocyclic residue or substituted with Rlle of 0-5, and a (CH2) r 5-10 elements heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with Rlle of 0-3;
Rllb, in each case, is selected from C? _6 alkyl, C2-8 alkenyl, C2_8 alkynyl, a (CH2) E- C3-6 carbocyclic residue substituted with Rlle of 0-2, and a (CH2) E-heterocyclic system of 5-6 elements containing 1-4 heteroatoms selected from N, O, and S, substituted with Rlle of 0-3;
R, 11c, in each case, is selected from C? _6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2) E-C3_6 cycloalkyl, Cl, Br
1 / F, (CF2) rCF3, N02, CN, (CH2) rNR lilifrRrjllf (CH2) rOH
(CH2) rO alkyl d-4, (CH2) rS alkyl C? -4, (CH2) EC (0) OH
(CH2) rC (0 RUb, (CH2) EC (0) NRUfRllf, (CH2) ENRllfC (0) Rlla alkyl (CH2) EC (0) OC? -4, (CH2) EOC (0) R llb
(CH2) cC (= NRllf) NRllfRllf, (CH2) ENHC (= NRllf) NRllfRllf
(CH2) ES (0) pRllb, (CH2) ES (0) 2NRllfRllf, (CH2) ENRllfS (O) 2Rllb and (CH2) rphenyl substituted with Rlle of 0-3;
R, in each case, is selected from C ?_6alkyl substituted with R, ω-3, C 2-6 alkenyl, C 2-6 alkynyl, and a C3_? Carbocyclic residue or substituted with Rlie from 0-3;
Rlle, in each case, is selected from C? _6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) ECF3, (CH2) rO alkyl C? -5, OH, SH, (CH2) ES alkyl C? -5, (CH2) ENR? FlR? f, and (CH2) E phenyl;
Rllf, in each case, is selected from H, Ci-β alkyl, and C3_6 cycloalkyl;
R 12 is selected from H, alkyl C? _6, (CH2) q0H, cycloalkyl
(CH2) EC3-6, and (CH2) E-phenyl substituted with R-112aa from 0-3;
R12a, in each case, is selected from C6-alkyl, C2-8 alkenyl, C2_8 alkynyl, C3_6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) rCF3, (CH2) r0 alkyl d- 5, OH, SH, (CH2) ES alkyl C? _5, (CH2) ENR9fR9f, and (CH2) Ephenyl;
alternatively, R and R together form C3-7 cycloalkyl;
R, 13, in each case, is selected from C? _6 alkyl, C2_8 alkenyl, C2_8 alkynyl, C3_6 cycloalkyl / (CF2) WCF3,
(CH2 NR13aR13a '(CH2) 0H, (CH2) OR 13b (CH2) SH, (CH2) SR 13b
(CH2) wC (0) OH, (CH2) wC (0) R13b, (CH2) wC (0) NR13aR13a ', (CH2) NR13dC (0) R13a,; CH2) wC (0) OR 13b (CH2) OC (0) R13b,
(CHzJwSÍOpR, 113b (CH2) wS (0) 2NR1l3jaaDR13a '(CH2) NR13dS (0) 2R13, and (CH2) w-f enyl substituted with R 13c of 0-3;
R13a and R13a ', in each case, is selected from H, C? -6 alkyl, C3_6 cycloalkyl, and phenyl substituted with R13c of 0-3;
R 13b in each case is selected from alkyl d-6, cycloalkyl C3_6, and phenyl substituted with R 13c from 0-3;
R 13c in each case is selected from C?-Alkyl, C 3-6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) rCF3,
(CH2) r0 alkyl C? _5, (CH2) EOH, (CH2) rS alkyl C? _5, and (CH2) ENR13dR13d;
R, 13d, in each case, is selected from H, C? _6 alkyl, and C3_6 cycloalkyl;
, 15 R, in each case, is selected from C? _8 alkyl, cycloalkyl (CH2) rC3_6, Cl, Br, I, F, N02, CN, (CHR ') rNR15aR15a',
(CHR ') EOH, [CHR') rO (CHR ') rR 15d (CHR') ESH,
(CHR ') EC (0) H, (CHR') rS (CHR ') ER 15d (CHR') EC (0) OH
(CHR ') EC (0) (CHR') ER 15b (CHR ') EC (0) NR15aR15a'
(CHR ') ENR, 115DfrC (O) (CHR') rR 15b (CHR ') ENR15fC (O) NR15fR15f
(CHR ') EC (0) 0 (CHR') ER 15d (CHR ') EOC (O) (CHR') rR15b
(CHR ') rC (= NR15f) NR15aR15a', (CHR ') rNHC (= NR15f) NR15fR15f
(CHR ') rS (0) p (CHR') rR 15b (CHR ') ES (0) 2NR15aR15a'
(CHR ') ENR15fS (0) 2 (CHR') ER15, haloalkyl d_6, alkenyl C2_s substituted with R 'of 0-3, alkynyl C2-8 substituted with R' of 0-3, (CHR ') rphenyl substituted with R15e from 0-3, and a 5-10 element heterocyclic r (CH2) r-system containing 1-4 heteroatoms selected from N, O, and S, substituted with R15e from 0-2;
R ', in each case, is selected from H, C? _6 alkyl, C2-alkenyl, C2_8 alkynyl, (CH2) r C3_6 cycloalkyl, and (CH2) E phenyl substituted with R15e;
R 15a and R15a ', in each case, is selected from H, C? _6 alkyl, C2_8 alkenyl, C2_8 alkynyl, a C3_? 0 carbocyclic (CH2) E substituted with R15e of 0-5, and a (CH2) 5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with R15e of 0-2;
R15b, in each case, is selected from C6_6 alkyl, C2_8 alkenyl, C2_8 alkynyl, a C3_6 substituted (CH2) E carbocyclic residue with R15e of 0-3, and a (CH2) r-heterocyclic system of -6 elements containing from 1-4 heteroatoms selected from N, 0, and S, substituted with R15e from 0-2;
R15, in each case, is selected from C2_8 alkenyl, C2-alkynyl, C6_6 alkyl substituted with R15e of 0-3, a (CH2) r-C3_? 0 carbocyclic residue substituted with R15e of 0-3, and a (CH2) 5- to 6-membered heterocyclic system containing from 1-4 heteroatoms selected from N, O, and S, substituted with R15e from 0-3;
R15e, in each case, is selected from C? _6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2) E C3_6 cycloalkyl, Cl, - F, Bx, I, CN, N02, (CF2) ECF3, ( CH2) r0 alkyl C? _ OH, SH, (CH2) ES C1-5 alkyl, (CH2) ENR15fR15f, and (CH2) Ephenyl;
R, in each case, is selected from H, C? -alkyl, C3_6 cycloalkyl, and phenyl;
R, 16, in each case, is selected from C? -8 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2) r C3_6 cycloalkyl, Cl, Br,
I, F, N02, CN, (CHR ') rNR16aR16a', (CHR ') r0H
(CHR ') rO (CHR') rR 16d (CHR ') rSH, (CHR') rC (0) H
(CHR ') rS (CHR') rR 16d (CHR ') rC (0) OH
[CHR ') rC (0) (CHR') rR 16b (CHR ') rC (0) NR16aR16a'
(CHR ') .RNR16fC (O) (CHR') rR16b, (CHR ') EC (O) O (CHR') ER16d
(CHR ') EOC (0) (CHR') rR 16b (CHR ') rC (= NR16f) NR16aR16a'
(CHR ') rNHC (= NR16f) NR16fR16f, (CHR') rS (0) p (CHR ') rR16
(CHR ') ES (0) 2NR16aR16a', (CHR ') rNR > 1l6t > fxSc (O) 2 (CHR ') r R, 16b C 1-6 haloalkyl, C 2-8 alkenyl substituted with R' of 0-3, C2_8 alkynyl substituted with R 'of 0-3, and (CHR') E phenyl substituted with R16e of 0 -3;
R 16a and R16a ', in each case, is selected from H, C? -6 alkyl, C2_8 alkenyl, C2_8 alkynyl, a C3_? 0 carbocyclic (CH2) E substituted with R16e of 0-5, and a (CH2) E-heterocyclic 5-10 element system containing 1-4 heteroatoms selected from N, O, and S, substituted with R16e of 0-2;
R16b, in each case, is selected from C? _6 alkyl, C2_s alkenyl, C2_8 alkynyl, a (CH2) r-C3-6 carbocyclic residue substituted with R16e of 0-3, and a (CH2) E-heterocyclic system of 5? -6 elements containing from 1-4 heteroatoms selected from N, O, and S, substituted with R16e from 0-2;
R16d in each case is selected from C2-8 alkenyl, C2_8 alkynyl, C6_6 alkyl substituted with R16e of 0-3, a (CH2) r- C3_? 0 carbocyclic residue substituted with R16e of 0-3, and a ( CH2) E-heterocyclic system of. 5-6 elements containing from 1-4 heteroatoms selected from N, O, and S, substituted with R16e from 0-3;
R16e, in each case, is selected from C? -6 alkyl, C2_8 alkenyl, C2-s alkynyl, (CH2) E-C3-6 cycloalkyl, Cl, F,
Br, I, CN, N02, (CF2) rCF3, alkyl (CH2) EOC? _5, OH, SH, (CH2) ES alkyl C? _5, (CH2) ENR16fR16f, and (CH2) Ephenyl;
R16f, in each case, is selected from H, C ?5 alkyl, C3-β cycloalkyl, and phenyl;
t is selected from 1 and 2;
w is selected from 0 and 1;
r is selected from 0, 1, 2, 3, 4 and 5;
q is selected from 1, 2, 3, 4, and 5; Y
p is selected from 1, 2 and 3.
[26] In a preferred embodiment, the present invention provides a method for modulating the activity of chemokine receptors, comprising administering to a patient in need thereof, a therapeutically effective amount of compounds of the formula (I) , where:
Z is selected from O and S;
R is absent, taken with the nitrogen to which it binds, forms an N-oxide, or is selected from C? _8 alkyl, (CH2) E C3_6 cycloalkyl, and (CH2) r-phenyl substituted with R4c of 0-3;
R4c, in each case, is selected from C6-6 alkyl, C2-8 alkenyl, C2_8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) ECF3, (CH2) rO alkyl C ? _5, (CH2) EOH, (CH2) ES alkyl C? _5, (CH2) rNR4aR4a ', and (CH2) rphenyl;
alternatively, R4 together with R7, R9, R11 or R14 form a piperidinium spirocycle of 5, 6 or 7 elements or a pyrrolidinium spirocycle substituted with Ra of 0-3;
R1 and R2 are independently selected from H, C? -4 alkyl;
R6, in each case, is selected from C? _4 alkyl, alkenyl
C2-8, C2-8 alkynyl, (CH2) r-C3_6 cycloalkyl,
(CF2) rCF3, CN, (CH2) EOH, (CH2) E0R6b, (CH2) EC (0) R6b,
(CH2) EC (0) NR6aR6a ', (CH2) ENR6dC (0) R6a, and (CH2) rphenyl substituted with R6c of 0-3;
R6a and R, in each case, are selected from H, C? _6 alkyl, C3_6 cycloalkyl, and phenyl substituted with R, 6cc of 0-3;
R, 6b, in each case, is selected from d-e alkyl, cycloalkyl
C3-6, and phenyl substituted with R 6c of 0-3
R, 6c, in each case, is selected from C1-6 alkyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) ECF3, (CH2) rO alkyl ds, (CH2) rS alkyl d-5, and (CH2) ENR6dR6;
R, 6d, in each case, is selected from H, C 1-6 alkyl, and C3-β cycloalkyl;
R7 is selected from H, C3_3 alkyl, (CH2) r C3_6 cycloalkyl, (CH2) qOH, (CH2) qOR7d, (CH2) qNR7aR7a ', (CH2) rC (O) R7b,
(CH2) rC (0) NR, 7'aaR, -, 7'aa ', (CH2) qNRaC (0) R 7a, haloalkyl C? -6,
(CH2) Ephenyl with R7'cc of 0-2;
R7a and R7a ', in each case, are selected from H, C? _6 alkyl, (CH2) r C3_6 cycloalkyl, a (CH2) rphenyl substituted with R7e of 0-3;
R, 7b, in each case, is selected from C? -6 alkyl, C2_8 alkenyl, C2-8 alkynyl, (CH2) E C3_6 cycloalkyl,
[CH2) r-phenyl substituted with R7e of 0-3;
Rlc, in each case, is selected from alkyl d-4, alkenyl C2-s, alkynyl C2-β, (CH2) r cycloalkyl C3-6, Cl, Br, I, F, (CF2) ECF3, N02, CN, (CH2) ENR7fR7f, (CH2) EOH, (CH2) rO alkyl d4, (CH2) rC (0) R7b, (CH2) rC (0) NR7fR7f,
(CH2) ENR7fC (0) R7a, (CH2) ES (0) pR, 7'bD, (CH2) rS (0) 2NR7fR7f,
(CH2) ENR7fS (0) 2R7b, and (CH2) rphenyl substituted with R7 of 0-2;
R7d, in each case, is selected from C? _6 alkyl, (CH2) E- C3_6 cycloalkyl, (CH2) rphenyl substituted with R7e of
0-3;
R e, in each case, is selected from alkyl? -e, alkenyl
C2_8, C2_8 alkynyl, C3_6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) rCF3, (CH2) E0 C1-5 alkyl, OH, SH, (CH2) rS
alkyl C? _5, (CH2) ENRrR 'and (CH2) E phenyl;
R, in each case, is selected from H, C? _5 alkyl, C3_6 cycloalkyl;
R is H or together with R form C3_7 cycloalkyl or = = NHRR8t > .
R11 is selected from H, C6-6 alkyl, (CH2) r-C3-6 cycloalkyl, (CH2) qOH, (CH2) qORlld, (CH2) qNRllaRlla ', (CH2) EC (O) Rll, (CH2) ) rC (0) NRllaRlla ', (CH2) qNRllaC (0) Rlla, C1-6 haloalkyl, (CH2) Ephenyl with Rllc of 0-2, a (CH2) r 5-10 elements heterocyclic system containing 1- 4 heteroatoms selected from N, O, and S, substituted with R15 of 0-3;
Rlla and Rlla ', in each case, is selected from H, C? -6 alkyl, (CH2) E-C3_6 cycloalkyl, a (CH2) Ephenyl substituted with Rlle of 0-3;
Rllb, in each case, is selected from Ci-e alkyl, C2-alkenyl, C2_8 alkynyl, (CH2) r-C3-6 cycloalkyl, (CH2) rphenyl substituted with Rlle of 0-3;
R, 11c, in each case, is selected from C ?4 alkyl, C2_8 alkenyl, C2_8 alkynyl, (CH2) rC3-6 cycloalkyl, Cl, Br,
I, F, (CF2) rCF3, N02, CN, (CH2) rNRllfRllf # (CH2) r0H, alkyl (CH2) rOC? _4, (CH2) EC (0) R llb (CH2) EC (0) NRUfRllf,
(CH2) rNRUfC (O) Rlla, (CH2) rS (O) pRllb, (CH2) ES (0) 2NRUfRllf, (CH2) rNRllfS (0) 2Rllb, and (CH2) Ef enyl substituted with Rlle of 0-2;
Rlld, in each case, is selected from alkyl C? -6, (CH2) r- C3-β cycloalkyl, (CH2) Ephenyl substituted with Rlle of 0-3;
R e, in each case, is selected from C 1 -C 6 alkyl, C 2-8 alkenyl, C 2 8 alkynyl, C 3 6 cycloalkyl, Cl, F, Br, I, CN, N 2, (CF 2) ECF 3, (CH 2) rO alkyl C1 -5, OH, SH, (CH2) rS alkyl C? _5 (CH2) rNRllfRllf, and (CH2) Ephenyl;
Rllf in each case is selected from H, C1-5 alkyl and C3_6 cycloalkyl;
R12 is H or together with R11 form C3-7 cycloalkyl;
1"R, in each case, is selected from C? -4 alkyl, C3-6 cycloalkyl, (CH2) NR13aR13a ', (CH2) OH, (CH2) OR13, (CH2) WC (O) R13b,
(CH2) NR, 113Jda, C (0) R13a, (CH2) wS (0) 2NR13aR13a '(CH2) NRljaS (0) 2R1JO, and (CH2) w-phenyl substituted with R13c of 0-3;
R and R, in each case, is selected from H, C? -6 alkyl, C3_6 cycloalkyl, and phenyl substituted with R13c of 0-3;
R, in each case, is selected from C? -6 alkyl, C3_6 cycloalkyl, and phenyl substituted with R13c of 0-3;
R 13c in each case is selected from C 1 -C 6 alkyl, C 3 6 cycloalkyl, Cl, F, Br, I, CN, N 2, (CF 2) ECF 3, (CH 2) rO C 1-5 alkyl, (CH 2) EOH, and (CH2) ENR13 R13d;
R, 13d, in each case, is selected from H, C 1-6 alkyl, and C 3-6 cycloalkyl;
q is selected from 1, 2 and 3; Y
r is selected from 0, 1, 2, and 3.
[27] In a more preferred embodiment, the present invention provides a method for the modulation of chemokine receptor activity, comprising administering to a patient in need thereof, a therapeutically effective amount of the compounds of formula (I). ),
where :
R3 is selected from a (CR3?) R- carbocyclic residue substituted with R15 of 0-5, wherein the carbocyclic residue is selected from phenyl, C3_6 cycloalkyl, naphthyl, and adamantyl; and a (R3?) r-substituted heterocyclic system with R15 of 0-3, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadizolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; Y
R5 is selected from (CR5?) -phenyl substituted with R16 of 0-5; and a (CR5?) t-substituted heterocyclic system with R16 of 0-3, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, isoindolyl, piperidinyl,
pyrazolyl, 1, 2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl.
[28] In a still more preferred embodiment, the present invention provides a method for the modulation of chemokine receptor activity, comprising administering to a patient in need thereof a therapeutically effective amount of the compounds of formula (Ii) , wherein the compound of formula (Ii) is:
(I-i)
R16, in each case, is selected from alkyl C? -8, (CH2) E- C3_6 cycloalkyl, CF3, Cl, Br, I, F, (CH2) ENR16aR16a ', N02, CN, OH, (CH2) rOR16d, (CH2) rC (0) R16b, (CH2) EC (O) NR16aR16a ', (CH2) ENR16fC (0) R16b, (CH2) ES (0) pR16b, (CH2) ES (O) 2NR16aR16a',
(CH2) rNR16fS (0) 2R16b, and (CH2) rphenyl substituted with R16e of 0-3;
R16a and R16a ', in each case, are selected from H, C? _6 alkyl, C3_6 cycloalkyl, and (CH2) rphenyl substituted with R16e of 0-3;
R16b, in each case, is selected from H, C? _6 alkyl, C3-6 cycloalkyl, and (CH2) rphenyl substituted with R16e of 0-3;
R, 16d, in each case, is selected from Ci-β alkyl, and phenyl;
R, 16e, in each case, is selected from alkyl C? _6, Cl, F, Br, I, CN, N02, (CF2) rCF3, OH, and (CH2) E0 alkyl d_5; Y
R, 16f, in each case, is selected from H, and C1-5 alkyl.
[29] In another even more preferred embodiment, the present invention provides a method for the modulation of chemokine receptor activity, comprising administering to a patient, in need thereof, an effective amount of compounds of formula (I- ii), wherein the compound of formula (I-ii) is:
ÍI-ü)
R, 16, in each case, is selected from alkyl C? _8, (CH2) r- C3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2) ENR16aR16a ',
N02, CN, OH, (CH2) EOR16, (CH2) rC (0) R16b,
(CH2) EC (0) NR16aR16a ', (CH2) ENR16fC (0) R16b, (CH2) rS (O) pR, 116b, (CH2) rS (0) 2NR16aR16a', (CH2) ENR16fS (0) 2R16b, and (CH2) Ef enyl substituted with R16e of 0-3;
R, 16aa and R, 16a ', in each case, is selected from H, C? -6 alkyl, C3-6 cycloalkyl, and (CH2) Ephenyl substituted with R16e of 0-3;
R16b, in each case, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2) rphenyl substituted with R16e of 0-3;
R, 16d, in each case, is selected from C 1-6 alkyl and phenyl;
R, 16e, in each case, is selected from alkyl C? -6, Cl, F, Br, I, CN, N02, (CF2) ECF3, OH, and (CH2) rO alkyl d_5; Y
R, in each case, is selected from H, and alkyl C? _5.
[30] In a preferred embodiment, the present invention provides a method for the modulation of chemokine receptor activity, comprising administering to a patient in need thereof, a therapeutically effective amount of compounds of formula (Ii) in where :
R5 is CH2f enyl substituted with R16 of 0-3;
R9 is selected from H, C? -6 alkyl, (CH2) E C3-6 cycloalkyl. F, Cl, CN, (CH2) E0H, (CH2) EOR9, (CH2) ENR9aR9a ', (CH2) EOC (0) NHR9a, (CH2) rphenyl substituted with R9e of 0-5, and a heterocyclic system substituted with R9e from 0-2, wherein the heterocyclic system is selected from pyridyl, thiophenyl, furanyl, oxazolyl, and thiazolyl;
R, 9a and R, 9a, in each case, are selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, and (CH 2) rphenyl substituted with R 9e of 0-3;
R, 9d, in each case, is selected from C? _6 alkyl and phenyl;
R, in each case, is selected from alkyl Ci-ß, Cl, F, Br, I, CN, N02, (CF2) rCF3, OH, and alkyl (CH2) EOC? _5;
R, 10 is selected from H, C C5 alkyl, OH, and CH2OH;
alternatively, R9 and R10 together form C3_7 cycloalkyl, cyclic ketal of 5-6 elements or = 0;
with the proviso that when R10 is halogen, cyano, nitro, or is bonded to the carbon to which it is attached through a heteroatom, R9 is not halogen, cyano, or is bound to the carbon to which it is attached through a heteroatom;
R11 is selected from H, alkyl Ci-β, (CH2) Ephenyl substituted with Rlle of 0-5, and a (CH2) E- substituted heterocyclic system with Rlle of 0-2, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, isoindolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; Y
R e, in each case, is selected from alkyl C? -6, Cl, F, Br, I, CN, N02, (CF2) rCF3, OH, and alkyl (CH2) E0 C? -5, "
R12 is H;
alternatively, R and R, 12 together form C3_7 cycloalkyl;
r is selected from 0, 1, and 2
[31] In another preferred embodiment, the present invention provides a method for modulating the activity of chemokine receptors, comprising administering to a patient in need thereof, a therapeutically effective amount of compounds of formula (I-ii). ), where:
R3 is CH2phenyl substituted with Rlb of 0-3;
R is selected from H, C ?_6 alkyl, (CH2) r C3_6 cycloalkyl, F, Cl, CN, (CH2) EOH, (CH2) EOR9d, (CH2) ENR9aR9a ', (CH2) EOC (0) NHR9a, (CH2) rphenyl substituted with R9e of 0-5, and a heterocyclic system substituted with R9e of 0-2, wherein the heterocyclic system is
selects from pyridyl, thiophenyl, furanyl, oxazolyl, and thiazolyl;
R 9a and R, in each case, is selected from H, C? _6 alkyl, C3_6 cycloalkyl, and (CH2) rphenyl substituted with R 9e
of 0-3;
R, in each case, is selected from C? -6 alkyl and phenyl;
R, 9e, in each case, is selected from alkyl C? _6, Cl, F, Br, I, CN, N02, (CF2) rCF3, OH, and (CH2) rO alkyl C? _5;
R is selected from H, C? -8 alkyl, OH, and CH2OH;
alternatively, R9 and R10 together form C3_7 cycloalkyl, cyclic ketal of 5-6 elements or = 0;
with the proviso that when R10 is halogen, cyano, nitro, or is linked to the carbon to which it is attached through a heteroatom, R9 is not halogen, cyano, or is bound to the carbon to which it is attached through a heteroatom;
R is selected from H, C? _8 alkyl, (CH2) rphenyl substituted with Rlle of 0-5, and a (CH2) E-substituted heterocyclic system with Rlle of 0-2, wherein the
heterocyclic is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, isoindolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2, 3- triazolyl, tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; Y
R, lle, in each case, is selected from alkyl C? -6, Cl, F, Br, I, CN, N02, (CF2) rCF3, OH, and alkyl (CH2) EOd-5;
R12 is H;
alternatively, R and R, 12 together form C3_7 cycloalkyl; Y
r is selected from 0, 1, and 2
[32] In a more preferred embodiment, the present invention provides a method for the modulation of chemokine receptor activity, comprising administering to a patient in need thereof, a therapeutically effective amount of compounds of formula (Ii) , where :
J is selected from CH2 and CHR5;
K is selected from CH2 and CHR5;
R3 is a C3_? Carbocyclic residue or substituted with R15 of 0-3, wherein the carbocyclic residue is selected from cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, and adamantyl, and a (CR3?) R-heterocyclic system substituted with R15 from 0-3, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl , pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; Y
R 15 in each case, is selected from alkyl C? _8, (CH2) C3_6 cycloalkyl, CF3, Cl, Br, I, F, (CH2) rNR 15at-, 15a '
N02, CN, OH, (CH2) E0R15d, (CH2) EC (0) R 15b
(CH2) EC (0) NR1í3aaaRpisa- (CH2) rNR, 1-L5Dfr, C (0) R, 1i5b, CH2) ES (0) pR, 1153bD,
(CH2) rS (0) 2NR15aR15a (CH2) rNR 1i5ofrS / (Oy,
(CH2) Ef enyl substituted with R15e of 0-3, and a (CH2) E- system
heterocyclic 5-6 elements containing from 1-4 heteroatoms selected from N, O, and S, substituted with R15e from 0-2;
R 15a and R, in each case, is selected from H, C? _e alkyl, d-β cycloalkyl, and (CH 2) r-phenyl substituted with R 15e of 0-3;
R 15b in each case is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, and (CH 2) E phenyl substituted with R 15e of 0-3;
R, in each case, is selected from C 1-6 alkyl and phenyl;
R, 15e, in each case, is selected from alkyl Ci-e, Cl, F, Br, I, CN, N02, (CF2) ECF3, OH, and (CH2) rO alkyl C? _5; Y
R, 15f, in each case, is selected from H, and C 1-5 alkyl.
[33] In another more preferred embodiment, the present invention provides a method for modulating the activity of chemokine receptors, comprising administering to a patient in need thereof, a therapeutically effective amount of compounds of formula (I). ii), where:
K is selected from CH2 and CHR;
R3 is a carbocyclic residue C3_? Or substituted with R of 0-3, wherein the carbocyclic residue is selected from cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl and adamantyl, and a (CR3?) R- heterocyclic system substituted with R15 of 0-3, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; Y
R, 15, in each case, is selected from alkyl C? _s, (CH2) r C3_6 cycloalkyl, CF3, Cl, Br, I, F,
(CH2) rNR, 1153aRR, 15Daa, N02, CN, OH, (CH2) EOR1Da, (CH2) rC (O) RiSD, (CH2) rC (0) NR15aR15a ', (CH2) ENR15fC (0) R15b, (CH2) ) rS (O) pR15, (CH2) rS (0) 2NR15aR15a ', (CH2) ENR15fS (0) 2R15, (CH2) rphenyl substituted with R15e of 0-3, and a (CH2) E- 5- heterocyclic system 6 items it contains from 1-4
selected heteroatoms of N, 0 and S, substituted with R15e of 0-2;
R 15a R, in each case, is selected from H, C? -6 alkyl, C3_6 cycloalkyl, and (CH2) rphenyl substituted with R 15e of 0-3;
R15b, in each case, is selected from H, C? _6 alkyl, C3_6 cycloalkyl, and (CH2) Ephenyl substituted with R15e of 0-3;
R, in each case, is selected from C? -6 alkyl and phenyl;
R, 15e, in each case, is selected from alkyl C? _6, Cl, F, Br, I, CN, N02, (CF2) rCF3, OH, and (CH2) E0 C? -5 alkyl; Y
R, 15f, in each case, is selected from H, and C 1-5 alkyl.
In another embodiment, the present invention provides a pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the present invention. In another embodiment, the present invention provides a method for modulating the activity of
Chemokine receptors, comprising administering to a patient in need thereof, a therapeutically effective amount of a compound of the present invention. In a preferred embodiment, the present invention provides a method for modulating the activity of chemokine receptors, comprising contacting a CCR3 receptor with an effective inhibitory amount of a compound of the present invention. In another embodiment, the present invention provides a method for the treatment of inflammatory conditions, comprising administering to a patient in need thereof, a therapeutically effective amount of a compound of the present invention. In another embodiment, the present invention provides a method for the treatment or prevention of selected diseases of asthma, allergic rhinitis, atopic dermatitis, inflammatory bowel diseases, idiopathic pulmonary fibrosis, pemphigoid bolus, helminthic parasitic infections, allergic colitis, eczema, conjunctivitis, transplant, family eosinophilia, eosinophilic cellulitis, eosinophilic pneumonias, eosinophilic fasciitis, eosinophilic gastroenteritis, drug-induced eosinophilia, HIV infection, cystic fibrosis, Churg-Strauss syndrome, lymphoma, Hodgkin's disease,
and colonic carcinoma. In a preferred embodiment, the present invention provides a method for the treatment or prevention of disorders selected from asthma, allergic rhinitis, atopic dermatitis, and inflammatory bowel diseases. In a more preferred embodiment, the present invention provides a method for the treatment or prevention of conditions wherein the condition is asthma.
DEFINITIONS
The compounds described herein can have asymmetric centers. The compounds of the present invention containing an asymmetrically substituted atom can be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by separation of racemic forms or by synthesis of optically active starting materials. Many geometric isomers of olefins, C = N double bonds, and the like, can also be present in the compounds described herein, and all of these stable isomers are contemplated in the present invention. The cis and trans geometric isomers are described
of the compounds of the present invention and can be isolated as a mixture of isomers or as separate isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are proposed, unless the specific stereochemical or isomeric form is specifically indicated. The term "substituted", as used herein, means that any one or more hydrogens on the designated atom are replaced with a selection of the indicated group, with the proviso that the designated atoms of normal valence are not exceeded, and that the substitution of result a stable compound. When a substituent is keto (ie, = 0), then 2 hydrogens are replaced in the atom. When any variable (for example, Ra) occurs more than once in any constituent of the formula for a compound, its definition in each case depends on its definition in each other case. Thus, for example, if it is shown that a group is substituted with Ra of 0-2, then said group may be optionally substituted with up to two groups Ra, and Ra in each case is selected independently of the definition of Ra. Also, combinations of substituents and / or variables are permissible only if such combinations give
result stable compounds. When a bond to a substituent is shown through a bond containing two atoms of a ring, then such a substituent may be linked to any atom in the ring. When a substituent is listed without indication of the atom through which such a substituent is bonded to the rest of the compounds of the given formula, then said substituent may be linked via any atom in said substituent. The combination of substituents and / or variables are permissible only if such combinations result in stable compounds. As used herein, "C? _8 alkyl" is intended to include both straight or branched chain saturated aliphatic hydrocarbon groups having a specific number of carbon atoms, examples of which include, but are not limited to, methyl, ethyl , n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl. Alkyl C? _8, tries to include groups d, d, C3, C4, C5, C6, C7, and C8 alkyl. "Alkenyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur at any stable point along the chain, such as ethenyl, propenyl, and the like. "Alquinyl" tries to include hydrocarbon chains of either a chain or configuration
branched and one or more triple carbon-carbon, unsaturated bonds, which may occur at any stable point along the chain, such as ethynyl, propynyl, and the like. "C3-6 cycloalkyl" is intended to include unsaturated ring groups having the specific number of carbon atoms in the ring, including mono-, bi-, or polycyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl in the case of C7 cycloalkyl. C3-6 cycloalkyl, is intended to include C3, C, C5, and C5-cycloalkyl groups; "Halo" or "halogen" is used herein to refer to fluoro, chloro, bromo, and iodo; and "haloalkyl" is intended to include both groups of branched and straight chain saturated aliphatic hydrocarbons, for example CF3, having the specific number of carbon atoms, substituted with 1 or more halogens (for example -CVFW where V = 3 and = the (2v + l)). The compounds of the formula I can be quaternized by standard techniques such as the alkylation of the piperidine or pyrrolidine with an alkyl halide to give the quaternary piperidinium salt, products of the formula I. Said quaternary piperidinium salt may include a counter ion. As used herein, "counterion" is used to represent a small species of negative exchange such as chloride, bromide, hydroxide, acetate,
sulfate, and the like. As used herein, the term "piperidinium spirocycle or pyrrolidinium spirocycle" is intended to mean a stable spirocycle ring system, in which the two rings form a quaternary nitrogen at the ring junction. As used herein, the term "5-6 element cyclic ketal" is intended to mean 2,2-substituted-1,3-dioxolane or 2,2-disubstituted 1,3-dioxane and its derivatives. As used herein, "carbocycle" or "carbocyclic residue" is intended to mean any monocyclic or bicyclic 3, 4, 5, 6, or 7 element, or bicyclic or tricyclic residue of 7, 8, 9, 10, 11, 12 or 13 elements, stable, any of which can be saturated, partially unsaturated, or aromatic. Examples of such carbocyclic residues include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,; [3.3.0] bicyclooctane, [.3.0] biciclononane,
[4.4.0] bicyclodecane (decalin), [2.2.2] bicyclooctane, fluorophenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin). As used herein, the term "heterocycle" or "heterocyclic system" means a monocyclic ring or
bicyclic of 5, 6, or 7 elements, or a bicyclic or heroecyclic ring of 7, 8, 9 or 10 elements, stable, which is saturated, partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, NH, O, and S and including any bicyclic group in which any of the heterocyclic rings defined above is attached to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring can be attached to its complement group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle can optionally be quaternized. It is preferred that when the total number of S atoms and 0 in the heterocycle exceeds 1, then these heteroatoms are not adjacent to each other. As used herein, the term "aromatic heterocyclic system" means a 5- or 7-membered monocyclic or bicyclic aromatic ring, stable, or bicyclic heterocyclic of 7 to 10 elements, which consist of carbon atoms and from 1 to 4 selected heteroatoms independently of the group consisting of N, O and S.
Examples of heterocycles include, but are not limited to, lH-indozole, 2-pyrrolidinyl, 2H, 6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidyl, 4aH-carbazole, 4H-quinolicinyl , 6H-1, 2, 5-thiadiacinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, carbazolyl, 4aH-carbazolyl, β-carbolinyl, chromanyl, chromenyl , cinnolinyl, decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro [2, 3-b] tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazolyl, indolenyl, indolinyl, indolicinyl, indolyl, isobenzofuranyl , isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl
(benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxaziazolyl, 1, 2, 5-oxadiazolyl,
1, 3, 4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl, fenantridinyl, fentanilinyl, fenarsacinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxyanyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole,
pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinilinyl, 4H-quinolicinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiacinyl, 1, 2, 3 -tiadizolyl, 1, 2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thiantrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl , 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3-, 4-triazolyl, tetrazolyl, and xanthenyl. Preferred heterocycles include, but are not limited to, pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiaphenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, isoidolyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl , pyrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl. Also included are fused ring compounds and spiro compounds containing, for example, the above heterocycles. The phrase "pharmaceutically acceptable" is used herein to refer to these compounds, materials, compositions, and / or dosage forms which are within the scope of the healthy judgment of the physician, suitable for
used in contact with the tissues of humans and animals, without excessive toxicity, irritation, allergic response, or other problem or complication, in proportion to a reasonable benefit / risk ratio. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds, wherein the parent compound is modified by the preparation of acid salts or bases thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, salts of organic or mineral acids of basic residues such as amines; organic or alkali salts of acidic residues such as carboxylic acids; and similar. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the original compound formed, for example, of non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include those derivatives of inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts are prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroximic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic,
ethanedisulfonic, oxalic, isethionic, and the like. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, which contains an acid or base portion. by conventional chemical methods. Generally, such salts can be prepared by reaction of the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid, in water or in an organic solvent, or in a mixture of the two; Generally, a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, p. 1418, the description of which is incorporated herein by reference. Since prodrugs are known to improve numerous desirable qualities of pharmaceutical products (ie, solubility, bioavailability, manufacture, etc.), the compounds of the present invention may be available in the form of prodrugs. Thus, the present invention is intended to cover prodrugs of the compounds claimed herein, methods for delivering the same and compositions containing the same. The "prodrugs" are intended to include any of the covalently linked carriers, which release
an active original drug of the present invention in vivo when said prodrug is administered to a mammalian subject. The prodrugs of the present invention are prepared by modifying modified functional groups present in the compound, such that the modifications are split, either by routine manipulation or in vivo, to the original compound. Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is linked to any group which, when the prodrug of the present invention is administered to a mammalian subject, is split to form a free hydroxyl group, free amino , or free sulfhydryl, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate, alcohol derivatives and amine functional groups in the compounds of the present invention. "Stable compound" and "stable structure" indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity of a reaction mixture and formulation into a therapeutically effective agent.
SYNTHESIS
The compounds of formula I can be prepared
using the reactions and techniques described below. The reactions are carried out in a suitable solvent for the reagents and materials used and suitable for the transformations that are carried out. It will be understood by those skilled in the art of organic synthesis that the present functionality of the molecule may be consistent with the proposed transformation. This may sometimes require judgment to modify the order of the synthesis stages or to select a particular process scheme from another, in order to obtain a desired compound of the invention. It will also be recognized that another main consideration in the planning of any synthesis route in this field is the sensible choice of the protecting group used for the protection of reactive functional groups present in the compounds described in this invention. One authority that describes many alternatives to the experienced practitioner is Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991). Generally, the compounds described in the scope of this patent application can be synthesized by the route described in Scheme 1. Appropriately substituted pyrrolidine (n = O) or piperidine (n = 1) 1 is alkylated by an N-protected alkylhalide. (halide = Cl, Br, I), mesylate, tosylate or triflate, 2, (where E represents a bond described within the scope of this application in its form
elaborated total, with the appropriate protective groups as will be understood by one skilled in the art or in a precursor form which can then be elaborated in its final form by methods familiar to a person skilled in the art) with or without base eliminator or acid, to give the protective amine _3 of piperidinyl or pyrrolidinylalkyl. If the halide is not I, then Kl can also be added to facilitate the displacement, as long as the solvent is adequate, such as an alcohol, 2-butanone, DMF or DMSO, among others. The displacement can be performed from the ambient temperature to the reflux temperature of the solvent. The protecting group is subsequently removed to give the amine A_. Protecting groups include phthalimide which can be removed by hydrazine, a reaction familiar to one skilled in the art; the bis-BOC which can be removed, either by TFA or HCl dissolved in a suitable solvent, both procedures are familiar to one skilled in the art; a nitro group instead of an amine, which can be reduced to provide an amine by conditions familiar to one skilled in the art; 2, 4-dimethylpyrrole (S.P. Breukelman, et al., J. Chem. Soc. Perkin Trans. I, 1984, 2801); N-1, 4, -Tetramethyl-disilyllazacyclopentane (STABASE) (S. Djuric, J. Venit, and P. Magnus Tet.Lett 1981, 22, 1787) and other protecting groups. The reaction with an isocyanate or
isothiocyanate _5 (Z = O, S), provides urea or thiourea 6. The reaction with a chloroformate or chlorothioformate 1_ (Z = 0, S) such as o-, p-nitrophenyl-chloroformate or phenylchloroformate (or its thiocarbonyl equivalents) , followed by displacement with an amine _9, also provide the corresponding ureas or thioureas 6_. In the same way, the reaction of the carbamate 8 ^ (X = H, or 2- or 4-N02) with disubstituted amine 1_0, provides urea or trisubstituted thiourea 12_. The reaction of the amine A_ (or its thiocarbonyl equivalent) provides the N, N-disubstituted urea or thiourea 1_2. The amine A_ can also be reductively aminated to provide L3, by the conditions familiar to one skilled in the art and by the following conditions: Abdel-Magid, A.F., et a. Tet. Lett. 1990, 31, (39) 5595-5598. This secondary amine can subsequently be reacted with isocyanates or isothiocyanates to provide trisubstituted ureas 1 or 4 with carbamoyl chlorides to provide tetrasubstituted ureas 15.
REACTION SCHEME 1
E = Linker
The amine A_ can also be converted to an isocyanate, isothiocyanate, carbamoyl chloride or its thiocarbonyl equivalent (isocyanate: Nowakowski, J. J Prakt.Chem / Chem-Ztg 1996, 338 (7), 667-671; Knoelker, H. .J. et al., Angew. Chem. 1995, 107 (22), 2746-2749; Nowick, JS et al., J. Org. Chem. 1996, 61 (11), 3929-3934; Staab, HA; Benz, W .; Angew Chem 1961, 73; isothiocyanate: Strekowski L. et al., J. Heterocycl. Chem. 1996, 33 (6), 1685-1688; Kutschy, Pet al., Synlett., 1997, (3 ), 289-290), carbamoyl chloride: Hintze, F.; Hoppe, D.; Synthesis (1992) 12, 1216-1218; thiocarbamoyl chloride: Ried, W.; Hillenbrand, H .; Oertel, G .; Justus Liebigs Ann Chem 1954, 590) (these reactions are not shown in Scheme 1). These isocyanates, isothiocyanates, carbamoyl chlorides or thiocarbamoyl chlorides can then be reacted with R2R3NH to provide di- or trisubstituted ureas or thioureas 12. An additional urea formation reaction involves the reaction of carbonyldiimidazole (CDI) (Romine, JL Martin, SW, Meanwell, NA, Epperson, JR, Synthesis 1994 (8), 846-850) with 4 followed by the reaction of the intermediate imidazolide with __ or in the reverse sequence (__ + CDI, followed by 4_). Activation of the imidazole intermediates also facilitates the formation of urea (Bailey, R.A., et al., Tet. Lett., 1998,
39, 6267-6270). One can also use 13 and 10 with CDI. The urea formation reactions are done in an inert non-hydroxylic solvent such as THF, toluene, DMF, etc., from room temperature to the reflux temperature of the solvent, and may use the use of an acid or base scavenger when necessary, such as carbonate and bicarbonate salts, triethylamine, DBU, Hunigs base , DMAP, etc. The substituted pyrrolidines and piperidines 1 can be obtained, either commercially or can be prepared as shown in Scheme 2. Commercially available N-benzylpiperid-3-one _ 16 can be debenzylated and protected with a BOC group, using familiar reactions to one skilled in the art. The subsequent Witting reaction, followed by reduction and deprotection, provides piperidine 20_, employing reactions familiar to one skilled in the art. The substituted pyrrolidines can be made by a similar reaction sequence. Other isomers and analogs around the piperidine ring can also be made by a similar reaction sequence. Chiral pyrrolidines / piperidines can be synthesized via asymmetric hydrogenation of 18_ using chiral catalysts (see Parshall, G.W. Homogeneous Catalysis, John Wiley and Sons, New York: 1980, pp. 43-45; Coliman, J. P., Hegedus, L.S. Principles and
Applications of Organotransition Metal Chemistry, University Science Books, Mill Valley CA, 1980, pp. 341-348).
REACTION SCHEME 2
Cyanoguanidines (Z = N-CN) can be synthesized by the method of K.S. Atwal, et al. and references contained therein (J. Med. Chem. (1998) 41, 217-275). The nitroethylene analogue (Z = C-N02) can be synthesized by the method of F. Moimas, et al., (Synthesis 1985, 509-510) and references contained therein. The malononitrile analogue (Z = C (CN) 2) can be synthesized by the method of Sasho, et al. (J. Med. Chem. 1993, 36, 572-579). The guanidines (Z = NRla) can be synthesized by the methods summarized in Scheme 3. The compound 2_1 wherein Z = S, can be methylated to provide the
metilisotiourea 22_. Displacement of the SMe group with amines provides the substituted guanidines 23 (see H. King and I. M. Tonkin J. Chem. Soc. 1946, 1063 and references therein). Alternatively, the reaction of thiourea 2_1 with amines, in the presence of triethanolamine and "sulfur lacquer", which facilitates the removal of HS, provides substituted guanidines 23 (K. Ramadas, Lett 1996, 37, 5161 and references in it). Finally, the use of carbonimidoildichloride 24, or 2_5, followed by sequential displacement by amines, provides the corresponding substituted guanidine 23 (S. Nagarajan, et al., Syn. Comm. 1992, 22, 1191-8 and references therein) . In a similar manner, the carbonimido-di-chlorides, R2-N = C (C1) 2 (not shown in scheme 3) and R3-N = C (C1) 2 (not shown), can also be reacted sequentially with amines to provide di and trisubstituted guanidines 23.
REACTION SCHEME 3
and
R3
N
One method for the introduction of substituents on the E-link is that of A. Chesney et al. (Syn.Comm. 1990, 20 (20), 3167-3180) as shown in Scheme A. The Michael reaction of pyrrolidine or piperidine 1 with the Michael 2_6 acceptor, provides intermediate 27, which can be subjected to reactions subsequent in the
same graphic. For example, the reduction provides alcohol 28, which can be made to amine 2J9, by standard procedures familiar to one skilled in the art. Some of these include mesylation or tosylation followed by displacement with NaN3 followed by reduction to provide amine 29. Another route as shown in Scheme 4, involves reaction with diphenylphosphoryl azide, followed by reduction of azide to provide the amine 29.
REACTION SCHEME 4
The mesylate or tosylate can also be displaced by other nucleophiles such as NH3, BOC2N, potassium phthalimide, etc., with subsequent deprotection, where necessary, provides amines 2 ^ 9. Finally, 29_ can be converted to urea or thiourea 30_ by methods discussed for Scheme 1 or for the compounds of this invention by the methods discussed previously. Similarly, the aldehyde 27 can be reacted with a lithium or Grignard 31 reagent to provide the alcohol adduct 33. This, in turn, can be converted to the urea or thiourea _34_ in the same manner as discussed for the conversion of 2_8 to 30. Scheme 5 shows that intermediary _36 can be extended via a Witting reaction (A: Chesney, et al., Syn.Comm. 1990, 20 (20), 3167-3180), to provide 37. This adduct can catalytically reduce to provide 3 or by other procedures familiar to one skilled in the art. Alkylation provides 39, followed by saponification and rearrangement Curtius (TL Capson and CD Poulter, Tet. Lett., (1984) 25, 3515-3518) followed by reduction of the benzyl protecting group, provides the amine A0_, which can be further elaborated as described earlier in Scheme 1 and elsewhere in this application for making the compounds of the invention. He
dialquillitium cuprate, organocopper, or copper-catalyzed Grignard addition (for a review, see G. H. Posner "An Introduction to Synthesis Using Organocopper Reagents," J. Wiley, New York, 1980; Organic Reactions, 19, 1 (1972)), for the alpha, beta-unsaturated ester 37 provides 4_1, which can be subjected to just subsequent transformations discussed to provide the amine 4_3, which can be further elaborated for the compounds of this invention as It is described early. The intermediate enolate ion obtained after the addition of cuprate at 37, can also be trapped by an electrophile to provide 4_2 (for a review, see R. J. K. Taylor, Synthesis 1985, 364). Similarly, another 2-carbon homologation is reported by A. Chesney et al. (ibid) in intermediate 36, which involves reacting 3_6 with an enolate anion to provide the aldol condensation product 42, wherein R12 = 0H. The OH group can be subjected to synthetic transformations which are familiar to a person skilled in the art, and which will be discussed in much detail later or in the application. Chiral auxiliaries can also be used to introduce stereoselectivity and enantioselectivity in these aldol condensations, procedures which are familiar to one skilled in the art.
Examples of such methods are shown in D. A. Evans, et al., J. Am. Chem. Soc. 1981. 103, 2127; D. A. Evans, J.
Am. Chem. Soc. 1982, 104, 1737; D. A. Evans, J. Am. Chem.
Soc. 1986. 108, 2476; GIVES. Evans, et al., J. Am. Chem. Soc.
1986, 108, 6757; D. A. Evans, J. Am. Chem. Soc. 1986, 108, 6395; D. A. Evans, J. Am. Chem. Soc. 1985, 107, 4346; AG Myers, et al., J. Am. Chem. Soc. 1997, 119, 6496. One can also perform an enantioselective alkylation on esters 38 or 41 with R12X wherein X is a residual group as described in Scheme 1 , provided that the ester is first attached to a chiral auxiliary (see above references by Evans, Myers and Mauricio by L. Vanderlei, J. et al., Synth Commun. 1998, 28, 3047). The alpha, beta-unsaturated ester _37 (Scheme 6) can also be reacted with dimethyloxosulfonium methylide (EJ Corey and M. Chaykovsky, J. Am. Chem. Soc. 1965, 87, 1345) to form a cyclopropane, the which may be subject to curtis rearrangement eventual and subsequent elaboration for the compounds of this invention, wherein the carbon containing R9R10 is attached to a cyclopropane ring with the carbon containing R11R12. In addition, the compound 4_8 can also be subjected to analogous reactions just described to form the cyclopropylamine 50, which can be further elaborated into the compounds of this invention as previously described. Compound 4J3 can be synthesized by an alkylation reaction of pyrrolidine / piperidine _1 with 4_7 bromide in an inert solvent, using the conditions as described for the 2-in-1 alkylation in Scheme 1.
Another way to synthesize the compounds within the scope of this application is shown in Scheme 7. The Michael reaction of amine 1 with an acrylonitrile _51 (as described by I. Roufus in J. Med. Chem. 1996, 39, 1514-1520), followed by the hydrogenation of Raney-Nickel, provides the amine 5_3, which can be made for the compounds of this invention as previously described.
REACTION SCHEME 6
In Schemes 4, 5 and 6, it is observed that there is no gem substitution in the alpha carbon for the electron subtractor group that was used as the electron acceptor.
Michael. In other words, in Scheme 4, there is no gem R10 to R9; in Scheme 5, there is no gem R10 to one of R9s and in Scheme 7 there is no gem from R10 to R9. The gem substitution can be induced by reacting the pyrrolidine or piperidine 1, with the epoxide of the Michael acceptors 26_, 3 ^ 5 and 51, to provide the corresponding alcohols (for amines that react with epoxides of the Michael acceptors, see Charvillon , FB; Amouroux, R.; Tet. Lett., 1996, 37, 5103-5106; Chong, JM; Sharpless, KB; J Org. Chem 1985, 50, 1560). These alcohols can optionally also be prepared in R10 by a person skilled in the art, for example, by tosylation of the alcohol and displacement of cuprate (Hanessian, S .; Thavonekham, B .; DeHoff, B .; J Org. Chem. 1989, 54, 5831), etc., and other displacement reactions, which will be discussed in great detail later in this application. REACTION SCHEME 7
n = 0, l 51 52
to the compounds - * - by previously discussed methods
In addition, the use of epoxides to synthesize compounds of this invention is shown in Scheme 8. The reaction of pyrrole or piperidine 1 with epoxide 54 provides protected amino-alcohol 55. This reaction works exceptionally well when R7 and R8 are H, but they are not limited to this. The reaction is carried out in an inert solvent at room temperature at the reflux temperature of the solvent. Protecting groups on the nitrogen atom of 5_4, include BOC and CBZ but are not limited thereto. The hydroxyl group may be optionally protected by a variety of protecting groups familiar to one skilled in the art.
REACTION SCHEME 8
Deprotection of nitrogen by methods familiar to one skilled in the art provides 56, which can be worked up into the compounds of this invention, by the methods discussed previously. If R9 = H, then
oxidation, for example, by the use of PCC (Corey EJ and Suggs, JW, Tet.Lett. 1975, 31, 2647-2650) or with the Dess-Martin periodinane (Dess, DB and Martin, JC, J Org. Chem. 1983, 48, 4155-4156) provides the ketone 5_7, which can be subjected to the nucleophilic 1,2-addition with organometallic reagents such as alkyl or reactive aryllithium, the Grignard or zinc reagents, with or without CeCl 3 ( T. Imamoto, et al., Tet. Lett., 1985, 26, 4763-4766; T. Imamoto, et al., Tet. Lett., 1984, 25, 4233-4236) in aprotic solvents such as ether, dioxane or THF. to provide alcohol 5_8. The hydroxyl group may optionally be protected by a variety of protecting groups familiar to one skilled in the art. Deprotection of nitrogen provides 5_6, which can be finally made for the compounds of this invention as discussed previously. The epoxides described by structure 5_4 can be synthesized enantioselectively from amino acid starting materials, by the methods of Dellaria, et al. J. Med Chem 1987, 30 (11), 2137, and Luly, et al. J. Org. Chem 1987, 52 (8), 1487. The ketone carbonyl group 5_7, in Scheme 8, can be subjected to Wittig reactions, followed by reduction of the double bond to provide alkyl, arylalkyl, heterocyclic alkyl, cycloalkyl, cycloalkylalkyl, etc., substitution to such position,
reactions that are familiar to a person skilled in the art. Wittig reagents can also contain functional groups which after reduction of the double bond provide the following functionality: esters (Buddrus, J. Angew Chem., 1968, 80), nitriles (Cativiela, C. et a., Tetrahedron 1996, 52 (16), 5881-5888), ketone (Stork, G. et al., J Am Chem Soc 1996, 118 (43), 10660-10661), aldehyde and methoxymethyl (Bertram, G. et al., Tetrahedron Lett. 1996, 37 (44), 7955-7958), gamma-butyrolactone Vidari, G. et al., Tetrahedron: Asymmetry 1996, 7 (10), 3009-3020), carboxylic acids (Svoboda, J et al., Collect Czech Chem Commun 1996, 61 (10), 1509-1519), ethers (Hamada, Y. et al., Tetrahedron Lett 1984, 25 (47), 5413), alcohols (after hydrogenation and deprotection-Schonauer, K.; Zbiral, E., Tetrahderon Lett 1983, 24 (6), 573), amines (Marxer, A., Leutert, T. Helve Chim Acta, 1978, 61) etc., all of which can also undergo similar transformations for a skilled in the art to form a wide variety ad of functionality in this position. Scheme 9 summarizes the chemical shift and the subsequent elaborations that can be used to synthesize the R9 groups. In scheme 9 it is observed that alcohol _55 or 5_8 can be tosylated, mesylated, triflate or converted to a halogen by methods familiar to a person skilled in the art, to produce compound 59.
(Note that all the following reactions in this paragraph can also be performed on the compounds, in the so-called carbon homologues of 5_5 or 5_8 where OH can be (CH2) EOH and it is also understood that these carbon homologs can have substituents on the well-known methylene groups). For example, a hydroxyl group can be converted to a bromide by CBr4 and Ph3P (Takano, S. Heterocycles 1991, 32, 1587). By other methods of conversion into an alcohol to a bromide or to a chloride or to an iodide, see R.C. LarocK, Comprehensive Organic Transformations, VCH Publishers, New York, 1989, pp. 354-360. The compound 5_9 in turn may be for a wide variety of nucleophiles as shown in Scheme 9 which includes but is not limited to azide, cyano, malonate, cuprates, potassium thioacetate, thiols, amines, etc., all the reactions of Nucleophilic displacement are familiar to a person skilled in the art. The displacement by nitrile produces a product of homologation of a carbon. The nitrile 60_ can be reduced with DIBAL to produce aldehyde 6_1. This aldehyde can be subjected to reduction for alcohol j52 with, for example, NaBH 4, which in turn can be subjected to all of the mentioned SN 2 displacement reactions for alcohol 5 5 or 58 5. The alcohol 62_ is a homolog of a carbon of alcohol 55 or _58. So, you can imagine that by taking an alcohol 62, converting it to a
leaving group X as described below for compounds 55 or 5_8_, and reacting it with NaCN or KCN to form a nitrile, the subsequent reduction with DIBAL to the aldehyde and subsequently the reduction with NaBH4 for the resulting alcohol in a two-product homologation carbons. This alcohol can be subjected to activation followed by the same SN2 displacement reactions discussed previously, ad infinitum, to result in homologation products of 3, 4, 5 ... etc., carbons. The aldehyde 61. can also be reacted with lithium or Grignard reagent to form an alcohol 61a which can also be subjected to the above displacement reactions. Oxidation by familiar method to a person skilled in the art produces ketone 61b. Displacement by malonate produces 6__ malonic ester which can be saponified and decarboxylated to produce carboxylic acid 6A_, to the two carbon homologation product. The conversion to ester 65 (A. Hassner and V. Alexanian, Tet. Lett, 1978, 46, 4475-8) and reduction with LAH produces alcohol 68 ^ which can undergo all the displacement reactions discussed for alcohol 55_ or 5_8. The alcohols can be converted to the corresponding 1Q_ fluoride by DAST (diethylaminosulfur trifluoride) (Middleton, W.J.; Bingham, E.M .; Org Synth 1988, VI, page 835). Sulfides 7_1 can be converted to sulfoxides 72
corresponding (p = l) by oxidation with sodium metaperiodate (NJ Leonard, CR Johnson J. Org. Chem. 1962, 27, 282-4) and in sulfones 72 (p = 2) by Oxona® (A. Castro, TA Spencer J. Org. Chem. 1992, 57, 3495-9). The sulfones 72 can be converted to the corresponding sulfonamides 7_3, by the method of H.-C. Huang, E. et al., Tet. Lett. (1994) 35, 7201-7204 which first involves the base treatment followed by the reaction with a trialkylborane producing a salt of sulfinic acid which can be reacted with hydroxylamine-O-sulfonic acid to produce a sulfonamide. Another route for sulfonamides involves an amine reaction with a sulfonyl chloride (G. Hilgetag and A. Martini, Preparative Organic Chemistry, New York: John Wiley and Sons, 1972, page 679). This sulfonyl chloride (not shown in Scheme 9) can be obtained from the corresponding sulfide (7_1 where R9d = H in scheme 9, the product of hydrolysis after displacement of the thioacetate), disulfide, or isothiouronium salt by simple reaction with chloride in water. The isothiouronium salt can be synthesized from the corresponding halide, mesylate or tosylate 5_9 via the reaction with thiourea (for a discussion of the synthesis of sulfonyl chlorides, see G. Hilgetag and A. Martini, ibid., P.670). The carboxylic acid _6_4 can be converted to amides 66 by standard coupling procedures or via a chloride
of acid according to the Schotten-Baumann chemistry or to a Weinreb amide (_66: R9a = Ome, R9a '= Me in scheme 9) (S. Nahm and SM Weinreb, Tet.Lett., 1981, 22, 3815-3818 ) which can undergo reduction to an aldehyde 67 (R9b = H in Scheme 9) with LAH (S. Nahm and SM Weinreb, ibid.) or reactions with Grignard reagents to form ketones 61_ (S. Nahm and SM Weinreb , ibid). The aldehyde _67_ which is obtained from the reduction of the Weinreb amide can be reduced to the alcohol with NaBH. The aldehyde or ketone 67 (or _6L or 61b for the material) can be subjected to Wittig reactions as discussed previously followed by the optional catalytic hydrogenation of the olefin. This Wittig sequence is a method for synthesizing the substituted heterocyclic and carbocyclic systems in R9 using the appropriate heterocyclic or carbocyclic reagent (or Horner-Emmons) Wittig. Of course, the Wittig reaction can also be used to synthesize alkenes in R9 and other functionality as such. The j55 ester can also form 6_6 amides by the Weinreb method (A. Basha, M. Lipton, and SM Weinreb, Tet., Lett, 1977, 48, 4171-74) (JI Levin, E. Turos, SM Weinreb, Syn Comm. 1982, 12, 989-993). The alcohol 68_ can be converted to ether _69 by procedures familiar to one skilled in the art, for example, NaH, followed by an alkyl iodide or by the Mitsunobu chemistry (Mitsunobu, O. Synthesis, 1981, 1-28).
The alcohol 5_5 or 58_, 62, or ____, can be acylated by procedures familiar to one skilled in the art, for example, by Schotten-Baumann conditions with an acid chloride or by an anhydride with a base such as pyridine to give 7_8_ . The halide, mesylate, tosylate or triflate 5_9 can be subjected to displacement with azide followed by reduction to give the amine 1A_ a process familiar to a person skilled in the art. This amine may be subjected to optional reductive amination and acylation to give a 7_5 reaction with ethyl formate (usually ethyl formate refluxed) to give the formate 75_. The amine 74 may again undergo optional reductive amination followed by the reaction with a sulfonyl chloride to give 76, for example under Schotten-Baumann conditions as discussed previously. This same sequence can be used for the amine 60a, the reduction product of the nitrile 60. The tosylate 5_9 can be subjected to displacement with cuprates to give 7_7 (Hanessian, S .; Thavonekham, B .; DeHoff, B .; J Org. Chem. 1989, 54, 5831). The aldehyde 61 or its homologous extensions can be reacted with a carbon anion of an aryl (phenyl, naphthalene, etc.) or heterocyclic group to give an aryl alcohol or a heterocyclic alcohol. If necessary, CeCl3 can be added (T. Imamoto, et al., Tet Lett, 1985, 26, 4763-4766, T. Imamoto, et al., Tet. Lett, 1984, 25, 4233-4236). This alcohol can be reduced
with Et3SiH and TFA (J. Org. Chem. 1969, 34, 4; J. Org. Chem. 1987, 52, 2226) (see discussion of heterocyclic and aryl anions for Schemes 20-22). These heterocyclic and aryl anions can also be alkylated by 59 (or their carbon homolog) to give compounds wherein R9 contains a heterocyclic and aryl group. The compound 5_9 or its carbon homologs can be alkylated by an alkyne anion to produce alkynes in R9 (see R.C. Larock, Comprehensive Organic Transformations, New York, 1989, VCH Publishers, p 297). In addition, carboxaldehyde 61 or its carbon homologues can undergo 1,2-addition by an alkylene anion (Johnson, AW The Chemistry of Acetylenic Compounds, V. 1. "Acetylenic Alcohols." Edward Arnold and Co., London ( 1946)). Nitro groups can be introduced by displacement of bromide _59 (or its carbon counterparts) with sodium nitrite in DMF (JK Stille and ED Vessel J. Org. Chem. 1960, 25, 478-490) or by the action of nitrite of silver in iodide 5_9 or its carbon counterparts (Org Syntheses 34, 37-39).
REACTION SCHEME 9
If an anion is made of pyrrolidine / piperidine 1 with LDA or n-BuLi, etc., then that anion in a suitable non-hydroxylic solvent such as THF, either dioxane, etc., can react in a Michael-like form ( 1, 4-addition) with an alpha, beta-unsaturated ester, to give an intermediate enolate which can be rapidly cooled with an electrophile (R9X) (where x is as described in Scheme 1) (Uyehara, T .; Asao, N., Yamamoto, Y .; J Chem Soc. Chem. Common. 1987, 1410) as shown in Scheme 10.
REACTION SCHEME 9 (continued)
It is understood that R9 is either in its final form or in a suitable protected, precursor form. This electrophile can be a carbon-based electrophile, and some examples are formaldehyde to introduce a CH2OH group, an aldehyde or a ketone which is also introduced to a carbon-approved alcohol, ethylene oxide (or other epoxides) that it introduces 'a group -CH2CH2OH (a two-carbon homologated alcohol), an alkyl halide, etc., all of which can then be processed in R9. It can also be an oxygen-based electrophile such as MCPBA, Davis reagent (Davis, FA; Haque, MS; J Org Chem 1986, 51 (21), 4083; Davis, FA; Vishwaskarma, L. C; Billmers, JM; Finn, J.; J Org Chem 1984, 49, 3241) or Mo05 (Martin, T. et al., J Org Chem 1996, 61 (18), 6450-6453) which introduces an OH group. These OH groups can be subjected to the displacement of reactions previously discussed in Scheme 9 or protected by suitable protecting groups and deprotected in a last step when the displacement reactions, described in Scheme 9 can be performed. In addition, these OH groups may also undergo displacement reactions with heterocycles as described for Schemes 19-22 to introduce substituted C or N heterocycles in this position. The ester 80_ can be converted into its amide Weinreb 82 (S. Nahm and S.
M. Weinreb, Tet, Lett., 1981, 22, 3815-3818) or the Weinreb amide 8_2 can be synthesized via Michael type addition of 1 to the Weinreb alpha, beta-unsaturated amide. Subsequently the reaction with a Gringnard reagent forms the ketone 85_. This ketone can also be synthesized in a step directly from 1 and alpha-beta-unsaturated ketone 84, using the same procedure. This ketone can be reduced with LAH, NaBH4 or other reducing agent to form an alcohol 8_6. Or, otherwise, the ketone 85_ can be reacted with an organolithium or Grignard reagents to form tertiary alcohol 87_. Or, otherwise, the ester 80_ can be directly reduced with LiBH 4 or LAH to give a primary alcohol 88.
REACTION SCHEME 10
88
The alcohols J36, 87_, and 8 may also be tosylated, mesylated, triflate, or converted to a halogen by methods previously discussed and displaced with a nucleophilic amine such as azide, diphenylphosphoryl azide (with or without DEAD and Ph3P), phthalimide, etc. as described previously (and which are familiar to a person skilled in the art) and after reduction (azide) or deprotection with hydrazine (phthalimide), for example, gives the corresponding amines. These can then be made into the compounds of this invention as discussed previously. The ketone 85_ can also be converted to imine 8_9 which can be reacted with a Grignard reagent or lithium reagent, etc., to form a protected amine _90 which can be deprotected and made into the compounds of this invention as discuss previously. Some protecting groups include benzyl and substituted benzyl which can be removed by hydrogenation, and cyanoethyl, which can be removed with aqueous base, etc. It will be understood that R7"12 in scheme 10 may be in its final form or in the form of a precursor, which may be worked up in the final form by procedures familiar to a person skilled in the art. have used to add in a manner of type Michael to alpha esters,
beta-unsaturated, where the substituents in the beta position of the unsaturated ester are joined together to form a cyclopentane ring (for example, the compound 7_9 where R and R8 are taken together to be - (CH2) -) (Kobayashi, K et al., Bull Chem Soc Jpn, 1997, 70 (7), 1697-1699). Thus the reaction of pyrrolidine or piperidine 1 with esters of cycloalkylidin 7_9 as in Scheme 10 gives the esters 8_0 where R7 and R8 are taken together to form a cycloalkyl ring. The subsequent elaboration gives compounds of this invention where R7 and R8 are taken together to form a cycloalkyl ring. The compounds of structure 95a can also be synthesized from epoxyalcohols which are shown in Scheme 11. The allyl alcohol 9JL can be epoxidized either stereoselectively, using the catalyst V0 (acac) 2 (for a review, see Evans: Chem. Rev. 1993, 93, 1307) or enantioselectively (Sharpless: J. Am. Chem. Soc. 1987, 109, 5765) to the epoxyalcohol 92_. Displacement with SN2 of the alcohol, using zinc azide and triphenylphosphine (Yoshida, AJ Org Chem. 57, 1992, 1321-1322) or diphenylphosphoryl azide, DEAD, and triphenylphosphine (Saito, A. et al., Tet. 1997, 38 (22), 3955-3958) produces azidoalcohol 93. Hydrogenation over a Pd catalyst produces aminoalcohol _94. This can also be protected in situ or in a subsequent stage with BOC20 to put a protective group
BOC, or with CBZ-Cl and a base to put a CBZ group or other protective groups. Alternatively, the amino group can be reacted with an isocyanate, an isothiocyanate, a carbamoyl chloride, or any reagent described in scheme 1 to form _5_5 which can be alkylated with 1 to form the compounds of this invention.
REACTION SCHEME 11
c
Sometimes the amine 1 may have to be activated with Lewis acids in order to open the epoxide ring (Fujiwara, M.; Imada, M.; Baba, A., Matsuda, H., Tetrahedron Lett 1989, 30, 739; Carón, M.; Sharpless, KB;
J Org Chem 1985, 50, 1557) or 1_ has to be deprotonated and used as a metal amine, for example lithium amide (Gorzynski-Smith, J.; Synthesis 1984 (8), 629) or MgBr amide (Carre , M. C; Houmounou, JP; Caubere, P .; Tetrahedron Lett 1985, 26, 3107) or aluminum amide (Overman, LE; Flippin, LA; Tetrahedron Lett 1981, 22, 195). Quaternary salts (where R4 occurs as a substituent) of pyrrolidines and piperidines can be synthesized by simple reaction of the amide with an alkylating agent, such as methyl iodide, methyl bromide, ethyl iodide, ethyl bromide, bromoacetate. of methyl or ethyl, bromoacetonitrile, allyl iodide, allyl bromide, benzyl bromide, etc. in a suitable solvent such as THF, DMF, DMSO, etc. from room temperature to the reflux temperature of the solvent. The spiro-quaternary salts can be synthesized in a similar manner, the only difference being that the alkylating agent is localized intramolecularly as shown in Scheme 12. It will be understood, by a person skilled in the art, that the functional groups may not be in its final form to allow the cyclization to the quaternary ammonium salt and may be in the form of a precursor in a protective form to be elaborated to its final form at a later stage. For example, the group NR1 (C = Z) NR2R3 in the more straight phenyl ring of compound 104 may exist as a
precursor of the nitro group for ease of handling during the formation of quaternary salt. The subsequent reduction and formation of the group NR1 (C = Z) NR2R3 yields the product 105. The leaving groups represented by X in scheme 12 may be the same as those shown in Scheme 1, but are not limited thereto. The N-oxides of pyrrolidine and piperidines can be made by the process of L. W. Deady (Syn.Comm. 1997, 7, 509-514). This simply causes the pyrrolidine or piperidine to react with MCPBA, for example, in an inert solvent such as methylene chloride.
REACTION SCHEME 12
The pyrrolidines and the multisubstituted piperidines can be synthesized by the methods summarized in scheme 13. The monoalkylation of 106 via an enolate using LDA or potassium hexamethyldisilazane, either by first being converted to an enamine, or by the use of other bases, all which can be done in THF, ether, dioxane, benzene, or an appropriate non-hydroxylic solvent from -78 ° C to room temperature, with an alkylating agent such as methyl iodide, benzyl bromide, etc. where X is as defined in Scheme 1, it produces the product 107. This product may subsequently be subjected again to alkylation under kinetic or thermodynamic conditions and then, if needed, it may be subjected to alkylation two more times to produce tri and tetrasubstituted analogs of 107. Kinetic or thermodynamic conditions give regioselectively alkylated products (for a discussion of thermodynamic vs. kinetic alkylations, see H. House Modern Synthetic Reactions, WA Benjamin, Inc. (Menlo Park, CA: 1972) chapter 9).
REACTION SCHEME 13
n = 0, l x = leaving group R5P = precursor for R5 H2 / Pd or Pd (OH) 2
to compounds by previously described methods
109 cis and trans
REACTION SCHEME 14
Subsequently the Wittig olefination produces compounds
108. Hydrogenation (asymmetric hydrogenation here is an option: Parshall, GW Homogeneous Catalysis, John Wiley and Sons, New York: 1980, pp. 43-45; Coliman, JP, Hegedus, LS Principles and Applications of Organotransition Metal Chemistry, Science University Books, Mili Valley, CA, 1980, pp. 341-348) provides pyrrolidine or piperidinia 109 which can be separated into its absolute and / or relative isomers at this stage or later in the synthesis either by crystallization, chromatographic techniques, or other methods familiar to a person skilled in the art. The amine 109 can then be made into the compounds of this invention by previously discussed methods (Scheme 1). Intermediate 107 containing carbonyl in Scheme 13 can also be reduced to the methylene analog via a Wolff-Kishner reduction and modifications thereto, or by other methods familiar to a person skilled in the art. The carbonyl group can also be reduced to an OH group, which can completely undergo the reactions described in scheme 9 to synthesize the R6 groups. This piperidine or pyrrolidine can be deprotected and elaborated into the compounds of this invention by methods discussed more recently. Thus, piperidines or pyrrolidines containing mono, di, tri or tetraalkylated carbonyl can be synthesized, which in turn can be reduced to the corresponding analogs
-CH2- that employ the Wolff-Kishner reduction or other methods. Another method for synthesizing gem-substituted pyrrolidines and piperidines is shown in Scheme 14. It will be understood by a person skilled in the art that some of the steps in this scheme may be rearranged. It will also be understood that gem disubstitution is only shown at a position on the piperidine ring and that similar transformations can be made on other carbon atoms as well as both piperidine and pyrrolidine. Thus, 3-carboethoxypiperidine 110 can be BOC-protected and alkylated using a base such as LDA, KHMDS, LHDMS, etc., in THF, ether, dioxane, etc. at -78 ° C, at room temperature, and an alkylating agent R6X where X is a halide (halide = Cl, Br, I), mesylate, tosylate or triflate, to produce 112. Reduction using DIBAL, for example, and if necessary followed by oxidation such as an oxidation of Swern (SL Huang, K. Omura, D. Swern J. Org. Chem. 1976, 41, 3329-32) producing aldehyde 113. Wittig olefination (114) followed by deprotection produces 115 which can be worked up as previously described in the compounds of this invention. The reduction of the Wittig adduct 114 produces 116 which can be unprotected to produce 117 which can be further elaborated as previously described in the compounds of this invention. The reaction
of aldehyde 113 with a Grignard reagent or alkyllithium produces alcohol 118 which can be catalytically reduced or with Et3SiH / TFA (J. Org. Chem. 1969, 34, 4; J. Org. Chem. 1987, 52, 2226) if R5 * (R5 * = R5 or a precursor thereof) is aromatic to produce 119. If R5 * is not aromatic, then OH can be reduced by the Barton method (Barton, DHR; Jaszberenyi, JC Tet., Lett. , 30, 2619 and other references therein). Once tosylated, the alcohol can be displaced with dialquillitium cuprates (not shown) (Hanessian, S .; Thavonekham, B .; DeHoff, B .; J Org. Chem. 1989, 54, 5831). If deprotection is necessary it produces 120 which can be worked up as previously described in the compounds of "the invention.
REACTION SCHEME 15
123 1. s-BuLi TMEDA 2. R5- 0 R13_?
A method for the alkylation of alkyl groups, arylalkyl groups, allyl groups, propargyl groups, etc., and a variety of other electrophiles in the alpha carbons of pyrrolidine and / or piperidine (alpha to the ring nitrogen atom) is represented for the work of Peter Beak, et al. as shown in scheme 15. It will be understood by a person skilled in the art that groups R5 and R13 are either in their precursor, protected or final form. Only one group R5 is substituted in piperidine / pyrrolidine 121. However, it will be understood by a person skilled in the art that additional functionality may be present in the ring in any of the precursor, protected or final forms. Thus, treatment with lithium, with an alkyllithium reagent such as n-BuLi or s-BuLi as shown, followed by rapid cooling with an electrophilic species, such as R5X or R13X where X is as defined in Scheme 1 and R5 and R13 are in their precursor, protective, or final form, yields monoalkylated piperidine / pyrrolidine 122. This alkylation can occur either stereoselectively (P. Beak and WK Lee J. Org. Chem. 1990, 55, 2578-2580) or enantioselectively if espartein is included as a source of chirality (P. Beak, et al., J. Am. Chem. Soc. 1994, 116, 3231-3239). The alkylation process can be repeated up to three or more
times as shown in scheme 15 to result in the di, tri, and tetrasubstitution in the alpha positions. Compounds where R9 and R10 form a cyclic ring of 3, 4, 5, 6 or 7 elements can be synthesized by the methods described in Scheme 16. These same methods can also be used to synthesize gem-disubstituted compounds in which R9 may be different from R10 by step alkylation of the malonate derivative. Of course, this scheme can be used to synthesize compounds where also R10 = H. For example, a malonate bound to cyclohexyl can be synthesized by addition of Michael and alkylation of I (CH2) 4CH = C002Me with dimethyl malonate using NaH / DMF (Desmaele, D.; Louvet, J-M.; Tet Lett 1994, 35 (16), 2549-2552) or by a double addition Michael (Reddy, DB, et al., Org. Prep. Procedure, Int. 24 (1992) 1, 21-26) (Downes, AM Gili, N. S., Lions, F., J Am Chem or by an alkylation followed by a second intramolecular alkylation using an iodoaldehyde (Suami, T., Tadano, K.; Kameda, Y .; Iimura, Y .; Chem Lett 1984, 1919), or by an alkylation followed by a second alkylation using an alkyl dihalide (Kohnz, H., Dull, B., Mullen, K., Angew Chem 1989, 101 (10), 1375), etc. .
REACTION SCHEME 16
diethyl malonate
1 n = 0, l
The subsequent monosaponification (Pallai, PV, Richman, S., Struthers, RS, Goodman, M. Int. J. Peptide Protein Res. 1983, 21, 84-92; M. Goodman Int. J. Peptide Protein Res. 17, 72-88), the standard coupling with pyrrolidine / piperidine 1 produces 128. The reduction with borane produces 129 followed by reduction with the LAH
it produces 130 which can then be converted to amine 131 and then to the compounds of this invention by means of the processes as previously discussed. The ester 129 can also be converted to a Weinreb amine and made with the compounds of this invention as described in Scheme 10 by the ester 8_0 which could introduce substituents R11 and R12.
• Scheme 17 describes another method for the synthesis of compounds where R9 and R10 are taken together to form the cycloalkyl groups. The aminoalcohols 132 are found in the literature (CAS Registry Nos. For n = 0, 1, 2, 3, respectively: 45434-02-4, 2041-56-7, 2239-31-8, 2041-57-8) . These can easily be protected, as with a BOC group (or CBZ, or any other compatible protecting group) by means of familiar procedures known to one skilled in the art to produce the alcohols 133. The alcohols can then be activated either by means of the conversion to a halide or a mesylate, tosylate or triflate by means of methods familiar to one skilled in the art and as previously discussed, and then alkylated with pyrrolidine / piperidine 1 by the conditions described in
Scheme 1 to produce 135. Subsequent deprotection produces the amine 136 that can be made to the compounds of this invention as previously described. Of course, the alcohol 133 can be oxidized to the "7AP * 7 R aldehydes and then can react with the R MgBr or R Li with or without CeCl3 to produce the corresponding alcohol 133 where instead of -CH2OH, we could have -CH768OH This oxidation-1, 2-addition sequence can be repeated to produce a tertiary alcohol.The alcohol can then be tosylated, mesylated, triflate, or converted to Cl, Br, or I by means of procedures familiar to someone skilled in the art. to produce 134 and then be displaced with pyrrolidine / piperidine 1 to produce 135. Subsequent deprotection produces 136 which can undergo processing to the compounds of this invention as discussed previously.
REACTION SCHEME 17
to the compounds by the previously described methods
A method for introducing cycloalkyl groups to R11R12 is shown in Scheme 18. Nitrogen protection of compounds 137 which are commercially available yield 138 (the protecting group can be BOC, CBZ, or any other compatible protective group) by means of family procedures by someone skilled in the art. Esterification by any of a number of familiar procedures by one skilled in the art (for example A.
Hassner and V. Alexanian, Tet. Left, 1978, 46, 4475-8) followed by alcohol reduction with DIBAL (or alternatively reduction to alcohol, for example, with LiBH, followed by oxidation Swern (op.cit.)) Produces aldehyde 139. Homologation of the carbon via the Wittig reaction followed by the hydrolysis of the vinyl ether yields the aldehyde 141. The reductive amination (Abdel-Magid, AF, et al., Tet.Lett., 1990, 31 (39) 5595-5598) produces the 142 followed by the deprotection produced by the amine 143 which can be prepared to the compounds of this invention by means of the previously discussed methods. Of course, the aldehyde 139 can react with R9ol0MgBr or R9610Li with or without CeCl to produce an alcohol that can be oxidized to a ketone. The Wittig homologation of a carbon, in this ketone, as described above, followed by hydrolysis yields 141 where the -CH2CHO is replaced with a group R9610 (-CHR9010 CHO).
REACTION SCHEME 18) n
, 1,2,3 DMAP 138 139 137
nte
The aldehyde 141 (-CH2CHO) or its mono-substituted analog synthesized above (-CH9O10CHO) can undergo an alkylation with R9610X where X is as defined in Scheme 1 to produce compound 141 which contains one or both of the alpha substitutes R9 and R10 to the aldehyde group. The alkylation can be carried out using the LDA or lithium of bistrimethylsilamide among other bases, in an inert solvent such as ether, THF, etc., of -78 ° C at room temperature. Aldehyde 141 (-CH2CHO) or its analogues
substitutes synthesized above (e.g., -CHR9R10CHO) can undergo reductive amination with 1 and subsequent processing to the compounds of this invention. The aldehyde 141 (-CH2CHO) or its substituted analogues synthesized above (eg, -CHR9R10CHO) can also undergo 1,2-addition with the R MgBr or R, 768L-, i to produce the corresponding alcohol -CH2CHR7ó8OH or -CHR9R10CHR7Ó8OH . The alcohol can then be tosylated, mesylated, triflate, or converted to Cl, Br, or I by means of familiar procedures by one skilled in the art and displaced with pyrrolidine / piperidine 1 to produce, after deprotection and Subsequent elaboration, the compounds of this invention. Or, otherwise the alcohol -CH2CHR7o8OH or -CR9R10CHR7O8OH can be oxidized (eg, Swern, op.cit.) To the ketone, and reductively aminated with the 1 and subsequently made to the compounds of this invention. Or else the alcohol -CH2CHR7o8OH or -CR9R10CHR7Ó8OH can be oxidized (eg, Swern, op.cit.) To the ketone and reacted once more with the R7o8MgBr or R7ó8Li to produce the corresponding alcohol -CH2CR7R8OH or -CR9R10CR7R8OH. If the ketone is easily enolized, CeCl3 can be used together with the Grignard reagent or lithium. Alcohol can again be
tosylated, mesylated, triflate, or converted to Cl, Br, or I by means of procedures familiar to one skilled in the art and displaced with pyrrolidine / piperidine JL to produce, after deprotection and subsequent elaboration, the compounds of this invention. Thus each of the groups R7, R8, R9, and R10 can be introduced into the compounds 141, 142, 143, and, of course, into the compounds of this invention, by means of the methods discussed above.
A method for the synthesis of the N-substituted heterocycles in R5 is shown in Scheme 19. The heterocycle can be deprotonated with NaH or by other bases familiar to one skilled in the art, in a solvent such as DMF, THF, or another suitable non-hydroxylic solvent and that reacts with the piperidine or pyrrolidine 143 from room temperature to the reflux temperature of the solvent. Deprotection and work up, as described above, produces the compounds wherein R5 contains an N-substituted heterocycle. If the nitrogen atom of the heterocycle is sufficiently nucleophilic, then a cleaning or eliminating acid, such as K2C03, KHC03, NaHCO3, among others, can be used instead of the
NaH, using the THF, DMF, or the methylethyl ketone as solvents. In this case the hydroxyl solvents can also be used, such as methanol, ethanol, etc., from room temperature to the reflux temperature of the solvent. Compound 143 as well as its other positional isomers are available, for example, from 4-hydroxymethylpiperidine, 2-, 3-, and 4-carboethoxypiperidine, ethyl ester of L- or D-proline, or from Methyl-benzyl-5-oxo-3-pyrrolidinecarboxylate, commercially available, by methods familiar to one skilled in the art and as previously discussed in this application.
REACTION SCHEME 19
n = 0, l is protection x = leaving group to the compounds by previously described methods J
A method for the synthesis of the C-substituted heterocycles in R5 is shown in Scheme 20. To many heterocycles such as those shown in Scheme 20, but not limited to these, can be added metals with strong bases such as LDA, n-BuLi, sec-BuLi, t-BuLi, etc., to produce the corresponding anionic species. These anions can also be generated via halogen-metal exchange using n-BuLi, or other alkylithium reagents. These reactions can be carried out in THF, ether, dioxane, DME, benzene, etc., from -78 ° C to room temperature.
REACTION SCHEME 20
to the compounds by means of the CX- methods. cv (- > previously described
Z1 R = suitable protective group or group - C (-> functional
etc ,
For reviews of these reactions of metalations and halogen-metal exchange see Organometallics in Organic Synthesis, FMC Corp., Lithium Division, 1993, pp. 17-39; Lithium Link, FMC Corp., Spring 1993, pp. 2-17; n-Butyllithium in Organic Synthesis, Lithium Corp. of America, 1982, pp-8-16; G. Heinisch, T. Langer, P. Lukavsky, J. Het. Chem. 1997, 34, 17-19. The anions can then be turned off with the electrophile 143 or its positional isomers
to produce the corresponding C-alkylated heterocyclic pyrrolidine or piperidine 145.
REACTION SCHEME 21
by previously described methods
Another method for the synthesis of the methylpyrrolidines or piperidines, heterocyclic, C-substituted, is shown in Scheme 21. The protected aldehyde 146 reacts with the anion of the heterocycle (its generation as previously described) from -78 ° C to the
room temperature with or without CeCl3 in an inert solvent such as THF, ether, dioxane, DME, benzene, etc., to produce the carbinol 147. Catalytic hydrogenation of the alcohol produces the corresponding methylene compound 145. Other methods of reduction include Et3SiH / TFA (J. Org. Chem. 1969, 34, 4; J. Org. Chem. 1987, 52, 2226) among other relatives by one skilled in the art. It is understood by one skilled in the art that the aldehyde group can be located at other positions instead of, for example, the 4-position of the piperidine in the compound 146 as described in Scheme 21. It is understood that others heterocycles may also be used, the same ones shown in Schemes 20 and 21.
The anions of the methyl-substituted heterocycles can also react with the piperidine or the BOC-protected pyrrolidone, 148, to produce the alcohols 149 as shown in Scheme 22 (see meta-revision reviews for references above). These alcohols can be reduced using Pt02 and TFA (P.E. Peterson and C. Casey, J. Org. Chem. 1964, 29, 2325-9) to produce piperidines and pyrrolidines 150. These can be
subsequently taken from the compounds of this invention as previously described. It is understood by one skilled in the art that the carbonyl group may be located in other positions, instead of, for example, the 4-position of the piperidine in the compound 148 as described in Scheme 22. It is understood that others heterocycles can also be used in addition to the same shown in Scheme 22.
REACTION SCHEME 22
It is also possible to react aryl (phenyl, naphthyl, etc.) anions, generated either by means of halogen-metal exchange or by means of metalation in the ortho direction (Snieckus, V. Chem. Rev. 1990, 90, 879 -
933)) using n- or s- or t-BuLi in a non-hydrophilic solvent such as THF, ether, etc., with or without TMEDA and allowing them to react with compounds 143, 146, and 148 with subsequent processing to produce the compounds of this invention by means of the methods described in Schemes 19-22.
Another method for the preparation of C-substituted heterocycles is shown in Scheme 23. Piperidone 148 undergoes a Wittig reaction with heterocyclic phosphorous ylides to produce 151. Hydrogenation with a noble metal catalyst such as Pd in a solvent either alcoholic or with an optionally active transition metal catalyst (see references to the asymmetric hydrogenation of Parshall and Coleman, op.cit.) produces 152 which can be further elaborated with the compounds of this invention by means of the procedures previously described. . It should be appreciated by one skilled in the art that the carbonyl group may be located at other positions instead of, for example, the 4-position of the piperidine in the compound 148 as depicted in Scheme 23. It is understood that the others
heterocycles may also be used in addition to the same shown in Scheme 23.
REACTION SCHEME 23
heterocycle
to the compounds by the previously described methods
The synthesis of the amines 9_, 1_0, and the amines which are precursors for the isocyanates or isothiocyanates should now be discussed. For example, 3-nitrobenzanboronic acid (153: Scheme 24) is commercially available and may undergo Suzuki couplings (Suzuki, A. Puré Appl. Chem. 1991, 63, 419) with a wide variety of iodine- or bromine aryls. substituted (aryls such as phenyl, naphthalene, etc.), heterocycles,
alkyls, alkenyls (Moreno-manas, M., et al., J. Org. Chem., 1995, 60, 2396), or alkynes. This may also be coupled with the triflates or aryls, heterocycles, etc., (Fu., J.-Snieckus, V. Tet., Lett., 1990, 31, 1665-1668). Both of the above reactions can also undergo carbonyl insertion in the presence of a carbon monoxide atmosphere (Ishiyama, et al., Tet. Lett., 1993, 34, 7595). These nitro-containing compounds (155 and 157) can then be reduced to the corresponding amines either via catalytic hydrogenation, or via a number of chemical methods such as Zn / CaCl 2 (Sawicki, EJ Org. Chem., 1956, 21 ). The compounds (158) of the carbonyl insertion can also undergo reduction of the carbonyl group either to the CHOH or CH bonds by means of methods already discussed
(NaBH4 or Et3SiH, TFA, etc.). These amines can then be converted to the isocyanate via the following methods
(Nowakowski, JJ Prakt Chem / Chem-ztg 1996, 338 (7), 667-671; Knoelker, H.-J. Et al., Angew Chem 1995, 107 (22), 2746-2749; Nowick, JS et al. ., J. Org. Chem., 1996, 61
(11), 3929-3934; Staab, H. A .; Benz, W.; Angew Chem 1961, 73); to isothiocyanate 5_ via the following methods
(Strekowski L. et al., J. Heterocycl Chem., 1996, 33 (6),
1685-1688; Kutschy, Pet al., Synlett 1997, (3), 289-290); to the carbamoyl chloride JLJL (after 156 or 158 amines are reductively made with a group R2) (Hintze, F., Hoppe, D .; Syntesis (1992) 12, 1216-1218); to thiocarbamoyl chloride __1 (after 156 or 158 it is reductively aminated with a group R2) (Ried, W., Hillenbrand, H., Oertel G .; Justus Liebigs Ann Chem 1954, 590); or it is only used as the 9_ or the JO (after the 156 and the 158 are reduced reductively with a group R2), in the synthesis of the compounds of this invention by means of the methods described in Scheme 1.
REACTION SCHEME 24
makes the isocyanate or isothiocyanate 5, or carbamoyl chlorides 11, or is used as 9 or 10 to make the compounds of this invention as described by the compounds of Scheme 1
Likewise, the protected aminobromobenzenes or triflates, protected, or aminobromoheterocyclics or triflates, protected, 159 (Scheme 25) can undergo the Suzuki-type couplings with the arylboronic acids or the heterocyclic boronic acids (160). These same bromides or triflates 159 may also undergo a Stille coupling (Echavarren, A.M., Stille, J.K.
J. Am. Chem. Soc, 1987, 109, 5478-5486) with the aryl, vinyl, or heterocyclic stannas 163. The bromides or triflates 159 may also undergo Negishi-type coupling with another heterocyclic aryl or bromides.
(Negishi E. Accts, Chem. Res. 1982, 15, 340: M. Sletzinger, et al., Tet. Lett, 1985, 26, 2951). Deprotection of the amino group produces an amine that can be coupled to make a urea and other elastives containing Z as described above and for Scheme 1. Protective amino groups include phthalimide, 2,4-dimethyl pyrrole (SP Breukelman, et al., J. Org. Chem., Soc. Perkin Trans. I, 1984, 2801); N-1, 4, 4-Tetramethyldisilyl-azacyclopentane
(STABASE) (S. Djuric, J. Venit, and P. Magnus Tet. Lett 1981, 22, 1787) and other relatives for someone skilled in the art.
REACTION SCHEME 25
invention as described by the compounds of Scheme 1
The compounds wherein R7 and R8 are taken together to form = NR8b can be synthesized by means of the methods in Scheme 25a. The JL reaction with nitrile a with catalysis with cCuCl forms amidine b where R8b is H (Rousselet, G .; Capdevielle, P., Maumy, M.; Tetrahedron Lett., 1993, 34, (40), 6395- 6398). It is noted that the portion of the urea may be in the final form or in the form of the precursor (eg, a protected nitrogen atom, P = protective group such as STABASE, bis-BOC, etc., as discussed previously. ) that can be subsequently
made in the compounds of this invention. The compounds b can also be synthesized by reacting iminoyl chloride c with pyrrolidine / piperidine 1 to produce b where R 8b is not H (Povazanec, F., et al., JJ Heterocycl. Chem., 1992, 29 , 6, 1507-1512). Iminoyl chlorides are readily available from the corresponding amide via PC15 or CCl4 / PPh3) (Duncia, J.V. et al., J. Org. Chem., 1991, 56, 2395-2400). Again, the portion of the urea may be in the final form or in the form of the precursor.
REACTION SCHEME 25a
n = 0, l
Many of the amines are commercially available and can be used as the _9, JL0_, or used as precursors for the isocyanates or isothiocyanates 5_. There are numerous methods for the synthesis of amines that are not commercially available familiar to one skilled in the art. For example, aldehydes and ketones can be converted, either O-benzyl oximes and then reduced with LAH to form an amine (Yamazaki, S .; Ukaji, Y .; Navasaka, K .; Bull Chem Soc Jpn 1986, 59, 525). Ketones
and the trifluoromethyl ketones undergo reductive amination in the presence of TiCl followed by NaCNBH to produce amines (Barney, CL Huber, EW, McCarthy, JR Tet Lett, 1990, 31, 5547-5550) Aldehydes and ketones undergo reductive amination with Na (AcCO) 3BH as previously mentioned to produce amines (Abdel-Magid, AF et al., Tet Lett., 1990, 31, (39) 5595-5598). The amines can also be synthesized from the aromatic or heterocyclic OH groups (for example, the phenols) via the Smiles rearrangement (Weidner, J. J. Peet, N. P. J. Het, Chem. 1997, 34, 1857-1860). Azide and nitrile are displaced from halides, tosylates, mesylates, triflates, etc., followed by LAH or other types or reduction methods to produce amines. Sodium diformylamide (Yinglin, H., Hongwen, H. Syntesis 1989 122), potassium phthalimide, and the bis-BOC-amine anion can completely displace halides, tosylates, mesylates, etc., followed by standard de-protection methods for producing amines, procedures that are familiar to one skilled in the art. Other methods for synthesizing more elaborated amines involve the Pictet-Spengler reaction, the Diels-Alder imine / immonium ion reaction (Larsen, S.D., Grieco, P.A.J. Am. Chem. Soc. 1985, 107, 1768-69;
Grieco, P. A. et al., J. Org. Chem., 1988, 53, 3658-3662; Cabral, J. Laszlo, P. Tet. Lett. 1989, 30, 7237-7238; the reduction of the amide (with LAH or diborane, for example), the organometallic addition to the imines (Bocoum, A. et al., J. Org. Chem., Comm. 1993, 1542-4) and others, all of which are familiar to someone skilled in the art.
Compounds containing an alpha alcohol side chain relative to the nitrogen of the piperidine / pyrrolidine ring can be synthesized as shown in Scheme 25b. Only the case of piperidine was exemplified, and one skilled in the art understands that alpha-substituted pyrrolidines can be synthesized by a similar route. It is also understood that appropriate substituents may be present in the piperidine / pyrrolidine ring. A 4-benzylpiperidine 196 is protected with the BOC group. The BOC-piperidine 197 is then added with metals under conditions similar to those of Beak, et al. (P. Beak and W. -K. Lee, J. Org. Chem., 1990, 55, 2578-2580, and references thereof) and quenched with the aldehyde to produce the alcohol 198. Metalation can also be enantioselectively performed using esparteine (P. Beak, ST Kerrick, S. Wu, J. Chu, J. Am.
Chem. Soc. 1994, 116, 3231-3239). This alcohol can be deprotonated with NaH and cyclized to carbamate 198a which allows structural assignments of the erythro and threo isomers. Deprotection with the base yields aminoalcohol 199. Subsequent N-alkylation produces phthalimidoalkylpiperidine 201. It is understood that the alkyl chain does not necessarily have to be n-propyl, but that n-propyl was chosen only for demonstration purposes. The deprotection of the phthalimido group with the hydrazine produces the amine 202. Finally, the reaction with an isocyanate or under any of the conditions described previy described in Scheme 1 produces the urea 203. If an isocyanate is used, the isocyanate can be added two. times to produce urea 204 carbamate.
The compounds wherein Z = N-CN, CHN02, and C (CN) 2 can be synthesized by means of the methods shown in Scheme 25c. Thus the amine 208 reacts with the
malononitrile 207 pure or in an inert solvent from room temperature to the reflux temperature of the solvent, or at the melting point of the solid / solid mixture, to produce malononitrile 206. Thus in turn can react with the amine 205 under similar conditions set forth above to produce the molononitrile 209. Similarly, a similar reaction sequence can be used to make the 212 and the 215 [for Z = C (CN) 2], see for example P. Traxler, et al., J. Med. Chem., (1997), 40_, 3601-3616; for Z = N-CN, see K. S. Atwal, J. Med. (1998) 41, 271; for Z = CHN02, see J. M. Hoffman, et al., J. Med. Chem., (1983) 26, 140-144).
REACTION SCHEME 25c
207 208
211 208
213 208 EXAMPLES
The compounds of this invention and their preparation can be further understood by the following working examples. These examples are understood as illustrative of the present invention, and should not be taken as limiting thereof.
EXAMPLE 1
Part A: preparation of 4-benzyl-l- (3-N-phthalimido-n-prop-1-yl) piperidine
The 4-benzylpiperidine (8.0 g, 45.6 mmol), 1 eq), N- (3-bromopropyl) -phthalimide (13.5 q, 50.2 mmol, 1.1 eq), potassium iodide (7.6 g, 45.6 mmol, 1 eq) and Potassium carbonate (2.6 g, 91.3 mmol, 2 eq) were refluxed in 125 ml of 2-butanone. The reaction was worked after 5 hours by filtering the inorganic solids after adding EtOAc and rinsing the 2X organic phase with water. The organic phase is dried with magnesium sulfate then the solvent is removed in vacuo to obtain an amber oil. The oil was purified by flash chromatography in 100% EtOAc to remove the impurities then with chloroform / methanol 8: 2 to isolate 3.67 g of the product as a slightly amber oil. NMR (300 MHz, CDC13) d 8.00-7.80 (m, 2H); 7.80-7.60 (m, 2H); 7.35-7.10 (m, 3H); 7.08 (d, 2H, J = 7 Hz); 3.76 (t, 2H, J = Hz); 2.83 (d, 2H, J = 10 Hz); 2.45-2.30 (m, 4H); 1.95-1.30 (m, 7H); 1.20-0.90 (m, 2H).
part B: preparation of 4-benzyl-l- (3-amino-n-prop-l-yl) piperidine
axi
The 4-benzyl-l- (3-N-phthalimido-n-prop-1-yl) piperidine (13.72 g, 37.9 mmol, 1 eq) was dissolved in 200 ml of EtOH at 25 ° C under N2, hydrazine was added anhydr(2.38 ml, 75.7 mmol, 2 eq). The solution was then refluxed during the time the white precipitate formed. The reaction was worked after reflowing 4 hours by filtering the solids. The solvent was removed in vacuo to obtain an oil which was repeatedly subjected in a rotary evaporator with toluene to remove excess hydrazine. An oil is obtained, an oil which is stirred in Et20. The insoluble material is then filtered with the solvent removed in vacuo to obtain 5.55 g of an amber oil as the product. NMR (300 MHz, CDC13) d 7.40-7.21 (m, 2H); 7.21-7.05 (m, 3H); 2.92 (d, 2H, J = 10 Hz); 2.73 (t, 2H, J = 7 Hz); 2.53 (d, 2H, J = 7 Hz); 2.40-2.20 (m, 2H); 1.84 (t of t, 2H, J = 7.7 Hz); 1.75-1.10 (m, 9H).
Part C: N- (3-cyanophenyl) -N '- [3- [4- (phenylmethyl) -1-piperidinyl] propyl] -urea
4-Benzyl-1- (3-amino-n-prop-1-yl) piperidine
(300 mg, 1.29 mmol, 1 eq) was dissolved in THF at 25 ° C under N2 then 3-cyanophenyl isocyanate was added. (186 mg, 1.29 mmol, 1 eq). The TLC after 30 minutes showed the reaction complete. The solvent was removed in vacuo then the residue was purified with silica gel in 100% EtOAc in chloroform / methanol at 8: 2 to yield 437 mg of an amber oil as product. NMR (300 MHz, DMSO-d6) d 9.90-9.50
(my h); 6.32 (s, ÍH); 7.93 (s, ÍH); 7.59 (d, ÍH, J = 7 Hz); 7.43 (t, ÍH, J = 7 Hz); 7.40-7.24 (m, 3H); 7.24-7.10 (m,
3H); 6.68 (t, ÍH, J = 7 Hz); 3.50-3.25 (m, 2H); 3.25-3.07
(m, 2H); 3.07-2.90 (m, 2H); 2.90-2.60 (m, 2H); 2.60-2.40 (m
2H); 2.00-1.60 (m, 5H); 1.60-1.30 (m, 2H).
EXAMPLE 2
Part A: Preparation of 4-benzyl-1-carbamethoxymethyl-1- [3- (3-cyano-phenylaminocarbonylamino) prop-1-yl] piperidinium bromide
4-Benzyl-l- [3- (3-cyano-phenylaminocarbonylamino) prop-1-yl] piperidine (50 mg, 0.133 mmol, 1 eq) was dissolved in acetone at 25 ° C under N2 then the methyl bromoacetate was added ( 13μL, 0.133mmol, 1eq). After 16 hours, the solvent was removed in vacuo and the residue was purified with silica gel in 100% EtOAc / 8: 2 chloroform / MeOH to yield 50 mg of white solids as a product. NMR (300 MHz, CD3OD) d 8.00-7.80 (m, ÍH); 7.65-7.45 (m, ÍH); 7.45-7.33 (m, ÍH); 7.33-7.05 (m, 6H); 4.50-4.25 (m, 2H); 4.00-3.60 (m, 5H); 3.50-3.20 (m, 6H); 2.70-2.50 (m, 2H); 2.10-1.60 (m, 7H).
EXAMPLE 3
Part A: preparation of 1- (t-Butoxycarbonyl) -3-piperidone
To an intense yellow solution of l-benzyl-3-piperidone hydrochloride (3.00 g, 1.33 mmol, 1 eq) in methanol (100 ml) was added 10% by weight palladium (dry basis) in activated carbon (600 mg) under a stream of
nitrogen. The resulting black suspension is deoxygenated by alternate evacuation and is flooded with nitrogen (3x) immediately after alternate evacuation and flooded with hydrogen (3x). The reaction suspension is then shaken or shaken vigorously under a 55 psi hydrogen atmosphere. After 12 hours, filtration by gravity of the suspension and concentration of the resulting filtrate in vacuo yielded 3-piperidone as a slightly viscous green oil. The oil was treated immediately with tetrahydrofuran (150 ml) and di-t-butyldicarbonate (4.73 g, 21.7 mmol, 0.98 eq). In the addition of the saturated aqueous sodium bicarbonate (25 ml), the oil was completely dissolved to give a slightly yellow suspension. After stirring the suspension vigorously for 2 hours, the now white suspension was seen in the aqueous hydrogen chloride (IN, 100 ml), and the phases were separated. The aqueous phase was extracted with ethyl acetate (3 x 70 ml), and the combined organic phases were washed with saturated aqueous sodium chloride (50 ml), dried with sodium sulfate, and filtered. Concentration of the resulting filtrate in vacuo yielded 1- (t-butoxycarbonyl) -3-piperidone (3.79 g, 86%) as a white oily solid. 1 HOUR
NMR (300 MHz, CDC13) d: 3.94 (s, 2H); 3.53 (t, 2H, J = 6 Hz); 2.41 (t, 2H, J = 7 Hz); 1.92 (m, 2H); 1.41 (s, 9H).
Part B: preparation of 1 ', 3- (2H) -Dehydro-3-benzyl-l- (t-butoxycarbonyl) piperidine
To a flame-dried 100 ml flask loaded with sodium hydride (60% by weight of the dispersion in mineral oil, 601 mg, 15.0 mmol, 2.3 eq) and 1,2-dimethoxyethane (20 ml) was added diethylphosphite of benzyl (3.42 g, 3.13 ml, 15.0 mmol, 2.3 eq) dropwise over a period of 5 minutes. After 10 minutes, 1- (t-butoxycarbonyl) -3-piperidone, in one portion, was added to the pale yellow suspension. The bottle was adapted with a reflux condenser, and the resulting yellow-gray suspension was heated under reflux conditions for 2 hours. On cooling to 23 ° C, the reaction is seen in aqueous hydrogen chloride (0.20 N, 100 ml) and diethyl ether (75 ml). The phases separated and the phase
The aqueous phase was made basic with saturated aqueous sodium bicarbonate at pH 9. The aqueous phase was extracted with diethyl ether (4 x 75 ml), and the combined organic phases were dried with sodium sulfate. Filtration, concentration in vacuo, and purification of the resulting residue by flash column chromatography (5% ethyl acetate in hexanes) provide a desired olefin mixture (410 mg, 23%) and the corresponding ethoxycarbamate ( 550 mg, 34%) as a clear oil. The ethoxycarbamate was removed in the subsequent step by means of flash column chromatography. 1H NMR (300 MHz,
CDC13) d: 7.30 (m, 2H); 7.18 (m, 3H); 6.42 (s, 2H); 4.02 (s, 2H), 3.50 (t, 2H, J = 6 Hz); 2.51 (t, 5H, J = 5 Hz); 1.61
(m, 2H); 1.49 (s, 9H). MS (Cl), m + / z (M + H) * = 274, [(M + H) * - (-C (0) OC (CH 3) 3)] = 174.
Part C: preparation of 1- (t-Butoxycarbonyl) -3-benzylpiperidine
To a solution of the impure product (410 mg, 1.50 mmol) obtained in the previous step in methanol (100 ml) was added palladium (dry base) 10% by weight, in activated carbon (200 mg) under a stream of nitrogen. The resulting black suspension was deoxygenated by alternate evacuation and flooded with nitrogen (3x), followed by alternate evacuation and flooding with hydrogen (3x). The reaction suspension is then shaken or shaken vigorously under a 55 psi hydrogen atmosphere. After 12 hours, filtration by gravity of the suspension and concentration of the resulting filtrate in vacuo resulted in a pale yellow residue. Purification of this residue by means of flash column chromatography gives 1- (t-butoxycarbonyl) -3-benzyl-piperidine (407 mg, 99%) as a clear oil. 1 H NMR (300 MHz, CDC13) d: 7.23 (m, 2H); 7.14 (m, 3H); 3.86 (m, 2H); 2.75 (br m, ÍH); 2.51 (m, 3H); 1.70 (br m, 2H); 1.64 (br.m, ÍH), 1.41 (s, 9H), 1.34 (br.m, 1H), 1.09 (br m, ÍH); MS (Cl), m * / z: (M + + 1) 276, [(M + H) * - (-C (O) OC (CH 3) 3)] = 176.
Part D: 3-Benzylpiperidine hydrochloride
To a solution of 1- (t-butoxycarbonyl) -3-benzylpiperidine (400 mg, 1.45 mmol) in methanol (5 mL) was added hydrogen chloride in dioxane (4M, 15 mL). The resulting yellow solution was stirred for 1 hour, at which time the reaction was concentrated in vacuo to provide the 3-benzylpiperidine hydrochloride (308 mg, 100%) as an amorphous solid. XH NMR (300 MHz, CD3OD) d: 7.27 (m, 2H); 7.19 (m, 3H); 3.29 (br, d, ÍH, J = 12 Hz); 3.20 (br, d, ÍH, J = 12 Hz); 2.87 (br, t, ÍH, J = 12 Hz); 2.67 (m, 1H); 2.60 (d, 2H, J = 7 Hz); 2.08 (m, ÍH); 1.70-1.87 (m, 3H); 1.26 (m, ÍH); MS (Cl), m * / z: (M + H) * = 176.
Part E: preparation of N- (3-methoxyphenyl) -N "- [3- [3- [(phenyl) methyl-1-piperidinyl] propyl] -urea
The above compound was prepared by methods similar to those employed in Example a, part C.
E NMR (300 MHz, CD3OD) d: 7.29-7.13 (m, 4H); 7/07 (d, ÍH, J = 9 Hz); 7.02 (m, ÍH); 6.78 (d, ÍH, J = 9 Hz); 6.60 (d, ÍH, J = 9 Hz); 3.77 (s, 3H); 3.30 (m, 2H); 2.80 (m, 2H); 2.53-2.32 (m, 4H); 1.85-1.55 (m, 7H); 1.44-0.78 (m, 2H). MS (ESI), m * / z: (M + H) * = 382.
EXAMPLE 4
Part A: Preparation of a, a'-Dibromo-3-nitro-o-xylene
55
The 3-nitro-o-xylene (10.0 g, 66.14 mmol, 1.00 eq),
N-bromosuccinimide (24.14 g, 135.6 mmol, 2.05 eq), and benzoyl peroxide (0.8 g, 3.30 mmol, 0.5 eq) were refluxed under N2 in 200 ml of carbon tetrachloride. The reaction was managed after two days by washing with 3 x 100 ml of water. The organic phase was dried with sodium sulfate, then the solvent was removed in vacuo to obtain an amber oil. The oil was purified by flash chromatography on an 8 cm x 20 cm quartz column, eluted with 7.5% EtOAc / hexanes to yield 4.46 g of product as a sticky solid. NMR
(300 MHz, CDC13) d 7.88 (d, ÍH, J = 7 Hz); 7.64 (d, ÍH, J = 7
Hz); 7.48 (dd, ÍH, J = 8 Hz), 4.86 (s, 2H); 4.69 (s, 2H).
Part B: Preparation of 1, 3-Dihydro-4 '- [4-fluorophenylmethyl] -4-nitro-spiro [2H-isoindol-2, 1'-piperidinium bromide]
4-Fluorobenzylpiperidine (0.94 g, 4.86 mmol, 1.0 eq), a, a'-dibromo-3-nitro-o-xylene (1.50 g, 4.86 mmol,
1. 0 eq), and the sodium carbonate (2.57 g, 24.3 mmol, 5.0 eq) were combined in 20 ml of THF and stirred at 25 ° C under N2, during the time that a white solid precipitated from the reaction mixture. The reaction was worked after 22 hours by means of filtering the solids and rinsing with THF. The solids were dissolved in methanol and applied to a 3.5 cm x 5 cm quartz column via a silica plug. The product is eluted with 20% MeOH / CHCl3 to yield 1.04 g of a white foam. NMR (300 MHz, CD3OD) d 8.27 (d, ÍH, J = 8 Hz); 7.84-7.80 (m, ÍH); 7.75-7.69 (m, ÍH); 7.23 (m, 2H);
7. 01 (dd, 2H, J = 8 Hz, 8 Hz), 5.38-5.37 (m, 2H); 5.09 (s, ÍH); 5.04 (s, ÍH); 3.80-3.72 (m, 2H); 3.65-3.54 (m, 2H); 2.71-2.68 (m, 2H); 2.05-1.75 (m, 5H)
Part C: Preparation of 4-Amino-l, 3-dihydro-4 '- [4-fluorophenylmethyl] -spiro [2H-isoindol-2, 1'-piperidinium bromide]
1, 3-Dihydro-4 '- [4-fluorophenylmethyl] -nitro-spiro [2H-isoindol-2, 1'-piperidinium] bromide (1.03 g, 2.46 mmol, 1.0 eq), zinc (5.32 g, 81.5 mmo, 33.0 eq), and calcium chloride (0.18 g, 1.60 mmol, 0.65 eq) were refluxed under N2 in 25 ml of a 78% ethanol / water solution. The reaction was worked after 5 hours by filtering through Celite® and the cake was rinsed with methanol. The filtrate was concentrated in vacuo in a mixture of water and an amber oil. The mixture was dissolved in 50 ml of 2-propanol, and concentrated in vacuo to remove excess water. The resulting yellow foam was dissolved in methanol and applied to a 3.5 cm x 5 cm quartz column via a plug of silica. The product is eluted with 20% MeOH / CHCl3 to yield 0.81 g of a yellow foam. NMR (300 MHz, DMSO) d 7.27-7.05 (m, 5H); 6.61-6.53 (m, 2H); 5.43-5.41 (m, 2H); 4.80 (bs, ÍH); 4.74 (bs, 2H); 4.63 (bs, ÍH); 3.62-3.43 (m, 4H); 2.60 (bd, 2H, J = 7 Hz); 1.98-1.59 (m, 5H).
Part D: Preparation of N- [1, 3-Dihydro-4 '- [4-fluorophenyl-methyl] spiro [2H-isoindol-2, 1'-piperidinium-4-yl] -N'-4-fluorophenylurea bromide
4-amino-1,3-dihydro-4 '- [4-fluorophenylmethyl] spiro [2H-isoindol-2, 1'-piperidinium] bromide (0.33 g, 0.84 mmol, 1.0 eq) and the isocyanate of 4 Fluorophenyl (0.23 g, 1.69 mmol, 2.0 eq) were combined in 3 ml of DMF and added at 25 ° C under N2. The reaction was worked after 22 hours by removing the solvent in vacuo, dissolving the residue in methanol, and applying the mixture to a 3.5 cm x 15 cm quartz column via a plug of silica. The product is eluted with 10% MeOH / CHCl3 to yield 65 mg of a yellow foam. NMR (300 MHz, DMSO) d 9.18 (s, ÍH); 9.00 (s, ÍH); 7.49-7.43 (m, 2H); 7.41-7.34 (m, 2H); 7.26-7.21 (m, 2H); 7.17-7.10 (m, 5H); 4.94 (s, 2H); 4.80 (s, 2H); 3.63-3.45 (m, 4H); 2.61 (bd, J = 7 Hz); 1.91-1.62 (m, 5H).
EXAMPLE 5
Part A: preparation of 4-benzyl-1- (3-hydroxy-3-phenylprop-1-yl) piperidine
To a 3-neck flask, dried to the flame, under an atmosphere of N2, with a magnetic stir bar, 4-benzylpiperidine (5.00 ml, 28 mmol, 1 eq), DBU (42 μL, 0.28 mmol, 0.01 eq) , and THF (100 ml) were added, mixed, and cooled to -15 ° C using a CCl4 / C02 (s) bath. Then acrolein (1.87 ml, 28 mmol, 1 eq) was injected slowly for 10 minutes maintaining the temperature at -15 ° C. After 0.5 hours at -15 ° C, phenylmagnesium chloride (2.0 M, 14.0 ml, 28 mmol, 1 eq) was injected slowly and the contents allowed to slowly warm to room temperature and then stirred for 48 hours. The reaction was worked up by adding 0.1 N NaOH and EtOAc (200 ml of each). The viscous magnesium salts were filtered by suction through glass fiber filter paper. The phases were separated and the aqueous phase was extracted again with ethyl acetate (2 x 200 ml). The organic phases were combined, washed with brine (1 x 200 ml), dried (MgSO 4) and the solvent was removed in vacuo to yield 7.39.
g of an amber oil. Flash chromatography in 100% ethyl acetate yields 2.48 g of an orange oil. NMR (CDC13) d 7.40-7.10 (m, 10H); 4.93 (d of d., ÍH, J = 3, 7 Hz): 3.12-2.96 (m, 2H); 2.68-2.46 (m, 4H); 2.01 (t of d, ÍH, J = 2, 10 Hz); 1.86-1.26 (m, 8H). ESI MS that detect (M + H *) = 310.
Part B: preparation of 4-benzyl-1- (3-azido-3-phenylprop-1-yl) piperidine
The product of part A (209 mg, 0.675 mmol, 1 eq), DBU (123 mg, 0.810 mmol, 1.2 eq), diphenylphosphoryl azide (0.175 ml, 0.810 mmol, 1.2 eq.) And toluene (1.0 ml) were They were mixed and stirred overnight at room temperature under a nitrogen atmosphere. The reaction was then worked up by adding ethyl acetate (50 ml), washed with water (3 x 25 ml), followed by washing with brine (1 x 25 ml), drying (MgSO4) and removing the solvent in vacuo. to produce 277 mg of an amber oil. Instant chromatography in hexane / acetate
ethyl 1: 1 produced 84 mg of the product as an oil. NMR (CDC13) d 7.41-7.09 (m, 10H); 4.56 (t, ÍH, J = 7 Hz); 3.83 (m, 2H); 2.52 (d, 2H, J = 7 Hz); 2.32 (t, 2H, J = 7 Hz); 2.30-1.77 (m, 5H); 2.59 (m, 2H); 1.98 (m, ÍH); 1.39-1.26 (m, 4H); IR (pure) 2095 cm1.
Part C: preparation of 4-benzyl-1- (3-amino-3-phenylprop-1-yl) piperidine
The compound of part B (100 mg), 10% Pd in carbon (120 mg), and methanol (100 ml) were carefully combined in a flask under an N2 atmosphere. The contents were then subjected to 1 atmosphere of H2 were supplied via a spray tube for 0.5 hours at room temperature. Filtration of the contents through Celite® and extraction of the solvent in vacuo yielded 70 mg of the product. NMR (CDC13) (only the maximum key) d 3.94 (t, 1, J = 7 Hz). NH4-C1 MS detects (M + H) * = 309.
Part D: N- (3-cyanophenyl) -N "- [3- [4- (phenylmethyl) -1-piperidinyl] -1-phenylpropyl] -urea
The compound of part C (57 mg, 0.185 mmol, 1 eq) was mixed and stirred with 3-cyanophenylisocyanate (26.6 mg, 0.185 mmol, 1 eq) in THF (1 ml) overnight at room temperature under a N2 atmosphere. The solvent was removed in vacuo and the residue was flash chromatographed on silica gel in hexane / ethyl acetate from 3: 1 to 1: 1, to 100% ethyl acetate, to yield 44.3 mg of an ethyl acetate oil. yellow color. NMR (CDC13) d 7.58 (s, ÍH); 7.52 (d, ÍH, J = 9 Hz); 7.42 (s, ÍH); 7.30-7.17 (9m, 8H); 7.12 (m, 3H); 4.82 (m, ÍH); 2.97-2.80 (m, 3H); 2.52 (d, 2H, J = 7 Hz); 2.35 (m, 2H); 2.05-1.85 (m, 4H); 1.81-1.60 (m, 2H); 1.54 (m, ÍH); 1.25 (m, ÍH). ESI MS detects (M + H) * = 453.
EXAMPLE 6
Part A: Preparation of 2-benzyloxycarbonylamino-l-phenyl-3-butane.
To a stirred suspension of methyltriphenylphosphonium bromide (10.72 g, 0.03 mole) in 100 ml of dry tetrahydrofuran at -78 ° C was added dropwise 1.6 M n-butyl lithium (17.5 ml, 0.028 mole), and the mixture was added dropwise. stirred for 0.5 hours at -78 ° C - -20 ° C. Then a solution of N-Cbz-phenylalanine (5.67 g, 0.02 mol) in 50 ml of dry tetrahydrofuran was added, and the mixture was stirred for 16 hours at room temperature. After the addition of saturated NH 4 Cl (50 ml) the mixture was extracted with EtOAc, and the extract was washed with water and brine. This was dried with Na2SO4 and evaporated to give an oily residue. The crude product was purified by flash chromatography on silica gel with elution of EtOAc-hexane 5; 95 to give pure 2-benzyloxycarbonylamino-1-phenyl-3-butane.
Part B: preparation of 2-benzyloxycarbonylamino-1-phenyl-3, 4-epoxy-butane.
To a stirred solution of 2-benzyloxycarbonylamino-1-phenyl-3-butene (1.43 g, 5.08 mmol) in 20 ml of CH 2 C 12 was added 3-chloroperoxybenzoic acid (2.19 g, 60%, 7.62 mmol) in several portions, and the The mixture was stirred at room temperature for 30 hours. After the addition of EtOAc (60 ml), the mixture was washed with saturated NaHCO3 and brine, and the organic phase was dried with Na2SO4. Evaporation of the solvent provides an oily residue. The crude product was purified by column chromatography on silica gel with elution with EtOAc-hexane 2: 8 to give 2-benzyloxycarbonylamino-1-phenyl-3,4-epoxybutane.
Part C: preparation of 2-benzyloxycarbonylamino-4- [4- (4-fluorophenyl) methyl-1-piperidinyl] -1-phenyl-butan-3-ol.
A solution of 4- (4-fluorophenyl) methyl-piperidine (0.515 g, 2.314 mmol) and 2-benzyloxycarbonylamino-l-phenyl-3,4-epoxy-butane (0.688 g, 2.314 mmol) in 5 mL of DMF was stirred for 4 hours at 100 ° C and cooled to room temperature. After the addition of EtOAc (30 ml), the mixture was washed with water (2x) and brine. The organic solution was dried with Na 2 SO, and evaporated to give an oily residue. This was then purified by passing it through a plug of silica gel with elution with EtOAc to give a pure product.
Part D: preparation of 2-amino-4- [4- (4-fluorophenyl) methyl-1-piperidinyl] -l-phenyl-butan-3-ol.
The above product was dissolved in 10 ml of ethanol, and 0.1 g of 10% Pd in carbon was added. The mixture was stirred under nitrogen (1 atmosphere) for 8 hours, and filtered through Celite. Evaporation of the solvent gave the title product as a solid (0.662 g).
Part E: preparation of N- (3-cyanophenyl) -N '- [l-benzyl-2-hydroxy-3- [4- (4-fluorophenylmethyl) -1-piperidinyl] propyl] -urea
To a solution of 2-amino-4- [4- (4-fluorophenyl) methyl-1-piperidinyl] -1-phenyl-butan-3-ol (50 mg, 0.14 mmol) in 2.5 mL of dry THF was added 3 -cyanophenyl isocyanate (20.2 mg, 0.14 mmol) and the mixture was stirred for 15 minutes at room temperature. Then the solvent was evaporated to give an oily residue. This was purified by chromatography on a column with silica gel eluting with EtOAc to give the pure title compound as an amorphous solid.
MS (ES +) for C30H33FN4O2: 501,
The following examples were prepared by means of the procedures previously described in Schemes 1-25, Examples 1-6 and / or by procedures familiar to one skilled in the art.
TABLE 1
* All stereotypes are (+ / -) unless otherwise indicated TABLE 2 **
m
** All compounds are amorphous unless otherwise indicated TABLE 3 **
n
** All compounds are amorphous unless otherwise indicated
The compounds of the present invention in which E contains ring A can be prepared in a number of ways well known to one skilled in the art of organic synthesis. As shown in Scheme 26, the 4-benzylpiperidine is N-alkylated with the alkylating agent, such as 165 (2-nitro-benzyl bromide (X = Br, R14 = H), Scheme 26) to give the N-benzyl compound 166. The nitro group of 166 was then reduced using catalytic hydrogenation to give the
corresponding aniline 167. Aniline can be converted to carbamate 168 using chloro-phenyl formate. Carbamate 168 can then react with several amines to give urea 169. Alternatively, aniline 167 can react with the appropriate isocyanates to directly give urea 169. Analogs of the saturated ring can also be used. For example, 4-benzyl piperidine can be alkylated with urea mesylate 185 (Scheme 30) to give the corresponding cyclohexyl derivative 186.
As shown in Scheme 27, 4-benzyl piperidine can also be N-alkylated with phenacyl bromide 170 to give nitroketone 171. The nitro group of 171 is then reduced using catalytic hydrogenation to give the corresponding aniline 172. The aniline 172 can react with the appropriate isocyanates to give the ketone urea 173. The ketone of 173 can be reduced with NaBH to give the alcohol 174.
Alternatively, epoxide 175 (R14 = H) can be deblocked with 4-benzylpiperidine to give the nitrobenzyl alcohol which was hydrogenated to give the aniline
alcohol 176. The aniline 176 can be treated with several isocyanates to give the urea 174 alcohols.
The 4-benzylpiperidine can also be N-alkylated with 3-cyanobenzyl bromide (177, Scheme 28) to give the analog of cyano 178. The cyano group is reduced using Raney nickel to give the corresponding benzyl amine 179. The treatment of 179 with isocyanates gives urea 180.
As shown in Scheme 29, the treatment of 3-ci.anoaniline with phenyl isocyanate gives urea 182. The cyano group of 182 is converted to imidate 183 with
HCl / ethanol. The reaction with 4-benzylpiperidine is ethanol then gives the amidine 184.
Saturated ring analogs can also be synthesized using the analogous procedures as outlined in Schemes 30 and 31. For example, 4-benzylpiperidine can be alkylated with urea mesylate 185 (Scheme 29) to give the corresponding cyclohexyl derivative 186. Alternatively, the start with the corresponding pure amino alcohol 187 [J. Am. Chem. Soc. 1996, 118, 5502-5503 and references here] one or something can protect the nitrogen to give the alcohol N-Cbz
188. The Swern oxidation of the alcohol gives the aldehyde 189. The reductive amination with the piperidine analogs gives the cyclohexylmethyl-1-piperidinyl analogue 190. The Cbz group is removed by catalytic hydrogenation to give the free amine 191, which it is treated with a phenyl isocyanate to give the desired urea analogue 192. Several examples using these synthesis methods are listed in Table 3a and Table 3.1.
169
A: DMF / K2C03 / RT or THF / RT. B: 10% Pd / C, 50 psi
H2 C: THF / Et3N / chlorophenylformate. D: NHR / DMF / 50 ° C. E: R-N = C = 0 / THF
REACTION SCHEME 27
A: DMF / K2C03 / T.AMB. or DMF / 50 ° C. B: 10% Pd / C, 50 psi H2, C: R-N = C = 0 / THF. D: NaBH4 / MeOH / T.AMB.
REACTION SCHEME 28
A: DMF / K2C03 / T.AMB. B: Raney Nickel 50 psi H2. C: R-N = C = 0 / THF
REACTION SCHEME 29
A: R-N = C = 0 / THF. B: EtOH / HCl / T. amb C: 4-benzylpiperidine / EtOH / T.amb.
186
A: R-N = C = 0 / DMF. B: Ms-Cl / THF C: 4-benzylpiperidine / DMF / T.amb. REACTION SCHEME 31
192 a: Benzyl chloroformate / Na2C03 / CH2Cl2. b. Swern Ox. c: NaBH (OAc) 3 d: H2 / Pd / C at 10% e: R- N = C = 0 / THF.
REACTION SCHEME 31a
187 188
H 193
195 a: Benzylchloroformate / Na2C03 / CH2Cl2. b. Swern Ox. c: NaBH (OAc) 3 d: H2 / 10% Pd / C: R-N = C = 0 / THF The following examples were synthesized using the methods outlined in Schemes 26-31a. These examples are understood as illustrative of the present invention, and are not limiting thereof.
EXAMPLE 218
N- [1- (phenylmethyl) -piperidinyl] -N '- [2- [[4- (phenylmethyl) -1-piperidinyl] -methyl] phenyl] -urea
A solution of 4-benzylpiperidine (1.75 g, 10 mmol) in 25 mL of DMF was treated with 2-nitrobenzyl bromide (2.16 g, 10 mmol) and K2CO3 (1.38 g, 10 mmol) and the reaction mixture was stirred at the room temperature for 2 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic extracts were washed successively with water and brine, and the organic solvent was removed under vacuum in a rotary evaporator to give 166 (Scheme 26, R14 = H) as a yellow oil.
The oil was redissolved in ethyl acetate (50 mL) and treated with 10% Pd / C and hydrogenated at 50 psi of hydrogen at room temperature for 40 minutes. The solution was then filtered and the solvent removed under vacuum to give the aniline 167 as a white solid. The aniline was purified by chromatography (MPLC, 40% ethyl acetate / hexane, silica gel) to give 2.0 g of aniline 167 as a white solid.
A solution of aniline 167 (1.2 g, 4.3 mmol) in THF was treated with Et3N (1.0 g, 10 mmol) and cooled in an ice bath at 0 ° C. Chlorophenyl formate (0.71 g, 4.5 mmol) was added to the mixture and stirred for 1 hour. The
The mixture was diluted with water and extracted into ethyl acetate. The extracts were washed with water and brine, and the solvent was removed under vacuum to give the phenyl carbamate 168 as a whitish or white-cream solid. The crude product was used without further purification.
A solution of phenylcarbamate 168 (0.2 g, 0.5 mmol) in DMF was treated with 4-amino-1-benzylpiperidine (95 mg, 0.5 mmol) and K2CO3 (138 mg, 1 mmol) and the mixture was heated to 50 ° C. 2 hours. The mixture was diluted with water and extracted with ethyl acetate. The extracts were washed with water and brine, and the solvent was removed under vacuum. The residue was purified by chromatography (MPLC, MeOH / 0-25% ethyl acetate, silica gel) to give 200 mg of target compound as a white solid, esi ms: (M + H) + = 497 .
EXAMPLE 219
N- [2,5-difluorophenyl) -N '- [2- [[4- (phenylmethyl) -1-piperidinyl] -methyl] phenyl] -urea.
An aniline solution 167 (Scheme 26; (R > 14 * = H) (140 mg, 0.5 mmol) in THF was treated with 2,5-difluoro-isocyanate (80 mg, 0.5 mmol) at temperature
environment for 1 hour. The solvent was removed under vacuum and the residue was purified by chromatography (MPLC, EtOAc / 20% Hexane, silica gel) to give the desired urea as a white solid, esi ms: (M + H) + = 436
EXAMPLE 220
N- [2,5-difluorophenyl) -N '- [[3- [[4- (phenylmethyl) -1-piperidinyl] methyl] phenyl] methyl] -urea.
A solution of 4-benzylpiperidine (1.75 g, 10 mmol) in 25 mL of DMF was treated with 3-cyanobenzyl bromide 177 (1.96 g, 10 mmol) and K2CO3 (2.76 g, 20 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic extracts were washed successively with water and brine, and the organic solvent was removed under vacuum in a rotary evaporator to give 178 (Scheme 28) as a white oil.
To a suspension of Raney nickel (2.0 g) in EtOH (saturated with NH3 (gas)) 178 crude (Scheme 28) (1.45 g, 5 mmol) was added and hydrogenated at 50 psi for 3 days. The solution was then filtered and the solvent removed under vacuum to give the amine 179 as a yellow oil. A
Solution of amine 179 (200 mg, 0.68 mmol) is THF treated, with 2,5-difluoroisocyanate (115 mg, 0.74 mmol) at room temperature for 1 hour. The solvent was removed under vacuum and the residue was washed with 1 N NaOH and water to give the desired urea as a white solid, esi ms: (M + H) + = 450.
EXAMPLE 221
N- [2,5-difluorophenyl) -N '- [2- [[4- (phenylmethyl) -1-piperidinyl] acetyl] phenyl] -urea.
To an ice-cooled solution of 2-bromo-2'-nitro-acetophenone 170 (2.4 g, 10 mmol) in DMF was added 4-benzylpiperidine (1.75 g, 10 mmol) and stirred for 30 minutes. The solution was poured into a mixture of K2C03 (1.38 g, 10 mmol) in water / ice and extracted with ethyl acetate. The ethyl acetate extract was washed several times with water. The resulting solution of crude nitroketone ethyl acetate 171 was treated with 10% Pd / C and hydrogenated at 50 psi of hydrogen at room temperature for 40 minutes. The solution was then filtered, the solvent was removed under vacuum, and the residue was purified by chromatography (MPLC, 30% ethyl acetate / hexane;
silica gel) to give 1.8 g of aniline 172 as a brown / brown solid.
An aniline solution 172 (Scheme 27) (310 mg, 1.0 mmol) in THF was treated with 2,5-difluoroisocyanate (160 mg, 1.0 mmol) at room temperature for 1 hour. The solvent was removed under vacuum and the residue was purified by chromatography (MPLC, EtOAc / hexane 20%, silica gel) to give 420 mg of the desired urea-ketone 173 as a white solid, this is: + H) + = 464.
EXAMPLE 222
N- [2,5-difluorophenyl) -N '- [2- [2- [4- (phenylmethyl) -1-piperidinyl] -1-hydroxyethyl] phenyl] -urea.
A solution of urea-ketone 173 (260 mg, 0.56 mmol) in MeOH was treated with NaBH (400 mg, 11 mmol) at room temperature for 1 hour. The solvent was removed under vacuum and the residue was treated with 1 N NaOH and extracted with EtOAc. The extracts were washed with water, brine and the solvent was removed under vacuum to give the desired alcohol 174 as a white solid, esi ms: (M + H) + = 466.
EXAMPLE 223
N- [3- (imino- [4- (phenylmethyl) -1- piperidinyl] methyl] phenyl] -N'-phenylurea.
A solution of 3-cyanoaniline (3.54 g, 30 mmol) in THF was treated with phenyl isocyanate (3.58 g, 30 mmol) at room temperature for 1 hour. The solvent was removed under vacuum and the residue was titrated with hexane to give 7 grams of urea 182 (Scheme 29) as a white solid. Urea 182 (1.0 g, 4.2 mmol) was dissolved in EtOH, cooled in an ice bath while HCl bubbled for 20 minutes. The solution was left fixed at room temperature for 24 hours. The solvent was removed under vacuum to give 1.1 g of imidate 183 as a white solid. The crude imidate (0.5 g, 1.8 mmol) was dissolved in EtOH and treated with 4-benzyl-piperidine (1.8 g, 10 mmol) at room temperature for 2 days. The solvent was removed under vacuum and the residue was purified by chromatography (MPLC, 0 to 30% EtOAc / MeOH, silica gel) to give 200 mg of the desired amide 184 (Scheme 29) as a white solid, esi ms: (M + H) + = 413.
EXAMPLE 416
N- [3-methoxyphenyl) -N '- [(1 R, 2S) -2 - [[(4-phenylmethyl) piperidinyl] methyl] cyclohexyl] -urea.
Step a: To a solution of the aminoalcohol (R, R) 187 [J. Am. Chem. Soc. 1996. 118, 5502-5503 and references herein) (1.9 g, 14.7 mmol) in CH2C12 (50 mL) was added 50 mL of an aqueous solution of Na2CO3 (2.4 g, 28.9 mmol). While stirring, benzyl chloroformate (2.51 g, 14.7 mmol) was added and the mixture was stirred at room temperature for 1 hour. The organic phase was separated and washed with water and brine. The solution was concentrated on a rotary evaporator and the residue was chromatographed on silica gel (30% ethyl acetate / hexane) to give 3.1 g (12 mmol) of 1_88 as a white solid. H NMR (300 MHz, CDC13) d 7.40-7.29 (m, 5 H), 5.11 (s, 2 H), 4.71 (bd, 1 H), 3.76-3.71 (m, 1 H), 3.53-3.28 (m , 3H), 2.00-1.95 (m, 1 H), 1.90-1.09 (m, 8 H). MS AP + (M + H) + = 264.3 (100%).
Step b: A solution of DMSO (2.52 g, 30 mmol) in
CH2C12 (50 mL) was cooled to -78 ° C. To this solution, oxalyl chloride (1.81 g, 14 mmol) was added dropwise and the resulting solution was stirred for about 10 minutes.
additional Then a solution of alcohol JLÍ was added
(2.5 g, 9.5 mmol) in CH2C12 (70 mL) via an addition poured into a funnel and stirred for 10 minutes. Then Et3N (5.0 g, 50 mmol) was added and the solution was allowed to warm to room temperature. The solution was diluted with water and the organic phase was washed with water, 1N HCl, and brine. The organic phase was dried with Na 2 SO 4, filtered, and concentrated to give 2.5 g (9.5 mmol) of the aldehyde 189 as a white solid. XH NMR (300 MHz, CDC13) d 9.59 (d, 3.6 Hz, 1 H); 7.38-7.28 (m, 5H), 5.07 (m, 2 H), 4.69 (m, ÍH), 3.84 (m, 21 H), 2.19-2.11 (m, 1 H), 2.09-2.01 (m, 1H) , 1.86-1.75 (m, 3H), 1.54-1.17 (m, 4 H).
Step c: A solution of aldehyde 189 (2.0 g, 7.7 mmol), 4- (4-fluorophenylmethyl) piperidine hydrochloride (1.8 g, 7.8 mmol) in dichloroethane (80 mL) was treated with
(NaOAc) 3BH (3.23, 15 mmol) and 1 mL of AcOH and stirred overnight at room temperature. The resulting solution was diluted with methylene chloride and washed with
NaOH IN, water, and brine. The organic solvents were removed under vacuum and the residue was chromatographed on silica gel (50% EtOAc / 100% hexane) to give 3.0 g (6.8 mmol) of 190 as an oil.
Step d: A solution of 190 (3.0 g, 6.8 mmol) in MeOH was treated with 1.5 g of 10% Pd / C and hydrogenated at 50 psi overnight in a Parr apparatus. The mixture was filtered and the filtrate was concentrated in a rotary evaporator to give 1.8 g (5.9 mmol) of the amine 191 as an oil.
Step e: A solution of the amine 191 (200 mg, 0.67 mmol) in THF was treated with 3-methoxyphenyl isocyanate (110 mg, 0.75 mmol) and the mixture was stirred for 30 minutes. The solvent was removed on a rotary evaporator and the residue chromatographed on silica gel (50% EtOAc / 100% hexane) to give 250 mg of urea 192 as a solid. MS esi: (M + H) + = 454.4 (100%), HRMS (M + H) + = 454.2875.
EXAMPLE 415
N- [3-acetylphenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl] piperidinyl] methyl] cyclohexyl] -urea.
Step a: To a solution of amino alcohol 187 (R, R) [J. Org. Chem. 1996, 61, 5557-5563; J. Am. Chem. Soc. 1996, 118, 5502-5503] (9.5 g, 73.8 mmol) in CH2C12 (200 mL) was added 200 mL of an aqueous solution of Na2CO3 (15 g, 141 mmol). While stirring, benzyl was slowly added
chloroformate (12.6 g, 73.8 mmol) and the mixture was stirred at room temperature for 1 hour. The organic phase was separated and washed with water and brine. The organic solvent was stirred in a rotary evaporator to give a white solid. The solid was recrystallized from hexane to give 16.3 g (62 mmol) of alcohol 188 (Scheme 31a) as a white solid. XH NMR (300 MHz, CDC13) d 7.40-7.29 (m, 5 H), 5.11 (s, 2 H); 4.71 (bd, 1 H); 3.76-3.71 (m, 1 H), 3.53-3.28 (m, 3 H), 2.00-1.95 (m, 1 H), 1.90-1.09 (m, 8 H). MS AP + (M + H) + = 264.3 (100%).
Step b: A solution of DMSO (36 g, 430 mmol) in CH2C12 (200 mL) was cooled to -78 ° C. To this solution, oxalyl chloride (27.41 g, 216 mmol) was added dropwise and the resulting solution was stirred for an additional 10 minutes. A solution of alcohol 188 (38 g, 144 mmol) in CH2C12 (150 mL) was added via an addition with a funnel and stirred for 10 minutes. Then, Et3N was added
- (58 g, 570 mmol) and the solution was stirred for 20 minutes and the ice bath was stirred and stirred for an additional 30 minutes. The solution was diluted with water and the organic phase was separated and washed with water, 1N HCl, and brine. The organic phase was dried with Na 2 SO 4, filtered, and
concentrated to give 38 g of aldehyde 189 as a white solid in the form of needles. The solid was recrystallized from hexane to give 19.7 grams of a first culture of aldehyde 189 as white needles. A second crop gave an additional 11 grams. XH NMR (300 MHz, CDC13) d 9.59 (d, 3.6 Hz, 1 H); 7.38-7.28 (m, 5 H), 5.07 (m, 2 H), 4.69 (m, 1 H), 3.84 (m, 21 H), 2.19-2.11 (m, 1 H), 2.09-2.01 (m, 1 H), 1.86-1.75 (m, 3 H), 1.54-1.17 (m, 4 H).
Step c: A solution of aldehyde 189 (19.6 g, 75 mmol) and (3S) -3- (4-fluorophenylmethyl) piperidine (14.5 g, 75 mmol) in dichloromethane (400 mL) was treated with Na (0Ac) 3BH ( 32 g, 152 mmol) and stirred overnight at room temperature. The resulting solution was poured slowly into a stirred mixture of ice / water / 1N NaOH and stirred for 20 minutes. The organic phase was separated and washed with water, and brine. The solution was dried with MgSO4 and the organic solvent was removed under vacuum and the residue was chromatographed on basic alumina (EtOAc / 50% hexane) to give 32.1 g (73 mmol) of amine 193 as a mixture of the cis and trans isomers (fifteen%). XH NMR (300 MHz, CDC13) d 7.79 (bs, 1 H), 7.38-7.29 (m, 5 H), 6.95-6.84 (m, 4 H), 5.08 (m, 2 H), 3.71 (m, 1 H, cis isomer), 3.06 (m, 1 H, isomer
cis), 2.80 (m, 1 H), 2.55-2.36 (m, 2 H), 2.30 (dd, J = 9 Hz, J = 13 Hz, 1 H, trans isomer); 2.05 (dd, J = 2 Hz, J = 13 Hz, 1 H, trans isomer); 1.81-0.90 (m, 16 H).
Step d: A solution of 193 (32 g, 73 mmol) in MeOH was treated with 8 g of 10% Pd / C and hydrogenated at 50 psi overnight in a Parr apparatus. The mixture was filtered and the filtrate concentrated on a rotary evaporator to give 20 g (65 mmol) of the amine 194, which was used without further purification.
Step e: A solution of the amine 194 (10 g, 32.8 mmol) in THF was treated with 3-acetylphenyl isocyanate (5.3 g, 32.8 mmol) and the mixture was stirred for 30 minutes. The solvent was removed on a rotary evaporator and the residue was chromatographed on silica gel (NHOH / MeOH / CH2Cl2 0.5: 4.5: 95) to give 11 g of 195 urea (Example 415) as a solid. 2 g of the cis isomer are also obtained (Example 416a). The urea from Example 415 was again purified with a second chromatography on silica gel (EtAc / Hex / TEA at 40: 60: 1) and the final recrystallization of the ether gave a crystalline solid, mp. 115-117 ° C, [a] D25 = + 16.8 ° (CH30H, c = 0.23 g / dL), XH NMR (300 MHz, CDC13) d 7.86 (m, 1 H), 7. 78 (bs, 1 H ), 7.68-7.64 (m, 1 H), 7.62 -7.59 (m, 1 H), 7.38 (t, J =
8 Hz, 1 H), 6.95-6.90 (m, 2 H) ', 6.79-6.72 (m, 2 H), 6.25 (s, 1 H), 3.21 (dt, J = 3 Hz, 11 Hz, 1 H ), 3.00-2.97 (m, 1 H), 2.66-2.56 (m, ÍH), 2.61 (s, 3 H), 2.44-2.32 (m, 4 H), 2.06 (dd, J = 2 Hz, J = 13 Hz, 1 H), 1.80-0.86 (m, 15 H). MS esi: (M + H) + = 466.3 (100%). Anal. Cale, for C28H36N302F: C, 72.23; H 7.70; N, 9.02. Found: C, 72.33; H,
7. 91; N, 9.00
EXAMPLE 415a
N- (3-acetylphenyl) -Nf - [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl] piperdinyl] methyl] cyclohexyl] -urea hydrochloride
A solution of Example 415 (15 g, 32 mmol) in 300 mL THF was cooled in an ice bath and treated dropwise with 36 mL of 1 M HCl / ether solution. The resulting solution was stirred for 30 minutes and concentrated in vacuo. The resulting solid was titrated with ether and the resulting white solid was dried under high vacuum overnight to give 16 g of the hydrochloride salt. pf. 58-60 ° C, [a] D25 = + 20.0 ° (CH30H, c = 0.23 g / dL). XH NMR (400 MHz, DMSO-D6) d 9.61 (s, 1 H), 9.15 (s, ÍH), 8.00 (m, 1 H), 7.63-7.61 (m, 1 H), 7.51-7.49 (m, IH), 7.39-7.34 (m, 1H), 7.22-7.17 (m, 2H), 7.09-7.04 (m, 2H), 6.86 (d, J = 8 Hz,
1 H), 3.47-3.31 (m, 4 H), 3.11 (m, 1 H), 2.98-2.82 (m, 2 H), 2.67-2.62 (dd, J = 5 Hz, J = 13 Hz, 1 H ), 2.58-2.50 (m, 2 H), 2.52 (s, 3 H), 2.39 (dd, J = 8 Hz, J = 13 Hz, 1 H), 2.16-2.06 (m, 2 H), 1.84- 1556 (m, '7H), 1.30-1.00 (m, 4 H). Anal. Cale. for
C28H37N302FCl * H20"THFo.25: C, 64.73; H 7.68; N, 7.81. Found: C, 64.89; H, 7.41; N, 7.81.
EXAMPLE 415b
N- (3-acetylphenyl) -N "- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl] -piperdinyl] methyl] cyclohexyl] -urea bencensulfonate
The benzenesulfonic acid monohydrate (1.06 g, 6 mmol) was dried by azeotropy with water from a benzene solution (twice) and the dry acid solution was added to a solution of example 415 (2.81 g, 6 mmol) in toluene (40 mL). The solvents were removed in vacuo (twice) and the resulting residue was recrystallized twice with toluene and dried under high vacuum overnight to give 2.77 g of the benzenesulfonic acid salt as a white solid, mp. 157-159 ° C [a] D25 = + 16.9 ° (CH3OH, c = 0.23 g / dL). Anal.
Caled, for C34H2N305FS: C, 65.47; H 6.80; N, 6.75; S 5.14. Found C, 65.48; H, 6.80; N, 6.70; S, 5.35.
The compounds of Table 3a and Table 3.1 were prepared by means of the procedures described in Schemes 26-31A, other examples and methods taught herein, and procedures familiar to one skilled in the art.
TABLE 3a
TABLE 3.1
Part A: The preparation of 1-t-butyloxycarbonyl-4-benzylpiperidine
The 4-benzylpiperidine (10.0 g, 57.1 mmol, 1.0 eq.) Was dissolved in 100 mL of THF under N2 and substantially cooled to 0 ° C. Di-tert-butyldicarbonate (11.21 g, 51.3 mmol, 0.9 eq.) Was added dropwise to 50 mL of THF. The evolution of the gas was observed. Once the evolution of the gas stopped, the ice bath was removed. After 20 hours, the THF was removed in vacuo then the residue was dissolved in EtOAc and rinsed 3X with citric acid IN, IX with brine. The organic was dried with magnesium sulfate and stripped to produce 15.4 g of a colorless oil as a product. Performance = 97.9% NMR
(300 MHz, CDC13) d 7.35-7.17 (m, 3H), 7.14 (d, 2H, J = 7 Hz), 4.20-3.90 (m, 2H); 2.75-2.55 (m, 2H), 2.54 (d, 2H, J = 7 Hz); 1.70-1.50 (m, 3H), 1.46 (s, 9H), 1.20-1.00 (m, 2H).
I enter treo
Part B: The preparation of erythro- and threo-cis-4-benzyl-1-t-butoxycarbonyl-o-ethylpiperidinemethanol
l-t-Butyloxycarbonyl-4-benzylpiperidine (5.0 g, 18.2 mmol, 1.0 eq.) was dissolved in Et20 at 25 ° C under N2 and cooled to -78 ° C. N, N, NA N'-Tetramethylethylenediamine (TMEDA) (3.29 mL, 21.8 mmol, 1.2 eq.) Was added followed by the dropwise addition of sec-butyllithium (16.76 mL, 21.8 mmol, 1.2 eq.): reaction was allowed to warm up to be stirred at -30 ° C for 30 minutes then again cooled to -78 ° C. Once cold, propionaldehyde (1.31 mL, 20.0 mmol, 1.1 eq) was added pure. The reaction was allowed to warm to -30 ° C then immediately quenched with 10 mL of water and the organic phase was separated. The aqueous phase was extracted 2X more with Et20. The organic phases were combined, dried with magnesium sulfate and the solvent was removed in vacuo to yield a colorless oil which was purified by flash chromatography in hexane / EtOAc from 4: 1 to 1: 1. Obtaining 0.68 g of a colorless oil such as isomer A, yield 11.2% and 0.91 g of a colorless oil such as isomer B, yield = 15.0%.
Isomer A NMR (300 MHz, CDCl 3) d 7.40-7.25 (m, 2H); 7.21 (d, ÍH, J = 7 Hz); 7.16 (d, 2H, J = 7 Hz); 3.60-3.30 (m, 2H); 2.56 (d, 2H J = 7 Hz); 1.90-1.00 (m, 7H); 1.46 (s, 9H); 1.00-0.70 (m, 5H).
Isomer B NMR (300 MHz, CDC13) d 7.30-7.23 (m, 2H); 7.20 (d, 1H, J = 7 Hz); 7. 14 (d, 2H, J = 7 Hz. 3.60-3.20 (m, 2H) 2.60-2.40 (m, 2H), 1.90-1.00 (m, 9H), 1.44 (s, 9H), 0.96 (t, 3H, J = 7 Hz).
ßritro Part C: The structure of Isomer B was determined via cyclization 4oc, 6 < x, 7oc-4-benzyl-7-ethyl-8-oxa-l-azabicyclo [4.3.0] nonan-9-one
Isomer B (60 mg, 0.18 mmol, 1 eq) was dissolved in DMF at 25 ° C under N2 then NaH (7.9 g, 0.198 mmol, 1 eq.) Was added. After 20 hours, 2 mL of water was added followed by EtOAc. The phases separated. The aqueous phase was extracted 2X more with EtOAc. The organic phases were combined, dried with magnesium sulfate, and the solvent was removed in vacuo to yield an oil which was purified with silica gel in hexane / EtOAc from 9: 1 to 1: 1. Obtaining 30 mg. Performance = 64%. The structure of the product was confirmed by N. O. E. NMR (300 MHz, CDC13) d
7. 40-7.20 (m, 3H); 7. 16 (d, 2H, J = 7 Hz); 4.45-4.25 (m,
ÍH); 4.00-3.80 (m, ÍH); 3.65-3.45 (m, ÍH); 2.95-2.70 (m,
ÍH); 2.65-2.45 (, 2H); 1.85-1.40 (m, AE); 1.40-1.00 (m, 6H).
Part D: The preparation of erythro-cis-4-benzyl-oc-ethylpiperidinemethanol
The erythro-cis-4-benzyl-1-t-butoxycarbonyl-ce-ethylpiperidinemethanol (isomer B of part B) (815 mg, 2.44 mmol, 1 eq) was dissolved in 8 mL of ethanol at 25 ° C under
N2 NaOH (391 mg, 9.78 mmol, 4 eq.) Was added and the mixture was refluxed for 4 hours. The solvent was removed in vacuo to yield an oil. Water was added followed by
EtOAc. The phases separated. The aqueous phase was extracted 2X more with EtOAc. The organic phases were combined, dried with magnesium sulfate, and the solvent was removed in vacuo to yield 390 mg of an oil. Performance =
68%. NMR (300 MHz, CDC13) d 7.35-7.20 (m, 2H); 7.23-7.00
(m, 3H); 3.75-3.65 (m, ÍH); 3.20-3.00 (m, ÍH); 2.90-2.40
(m, 4H); 1.70-1.50 (m, 2H); 1.50-1.30 (m, ÍH); 1.20-0.80 (m, 5H).
Part E: The preparation of erythro-cis-4-benzyl-oc-ethyl-1- (3-N-naphthalimido-n-prop-1-yl) piperidinemethanol
Erythro-cis-4-benzyl-o-ethylpiperidinemethanol
(195 mg, 0.84 mmol, 1 eq.), N- (3-bromopropyl) phthalimide (224 mg, 0.84 mmol, 1 eq), potassium iodide (139 mg, 0.84 mmol,
1 eq.), And potassium carbonate (231 mg, 0.84 mmol, 1 eq.) Were refluxed in 10 mL of 2-butanone for 2 hours. The reaction was carried out by filtering the inorganic solids. The filtered solvent was removed in vacuo to yield an oil. Which was purified by flash chromatography in 100% EtOAc then with chloroform / MeOH 4: 1. Obtaining 200 mg. Yield = 57%. NMR (300 MHz, CDC13) d 7.95-7.80 (m, 2H); 7.80-7.65 (m, 2H); 7.35-7.00 (m, 5H); 3.90-3.60 (m, 3H); 3.20-2.90 (m, 2H); 2.65-2.30 (m, 3H); 2.20-2.00 (m,
2H); 2.00-1.75 (m, 2H); 1.70-1.40 (m, AE); 1.35-0.90 (m, 3H); 0.96 (t, 3H, J = 7 Hz).
Part F: The preparation of erythro-cis-1- (3-amino-n-prop-1-yl) -4-benzyl-o-ethylpiperidinemethanol
The erythro-cis-4-benzyl-a-ethyl-l- (3-N-phthalimido-n-prop-1-yl) piperidinmethanol (200 mg, 0.48 mmol, 1 eq.) Was dissolved in 5 mL of ethanol a 25 ° C under N2. The anhydrous hydrazine (0.03 mL, 0.95 mmol, 2 eq) was added and the reaction was refluxed for 3 hours during which time a white precipitate (phthalhydrazide) formed. Once it cooled, the solids filtered. The filtrate solvent was removed in vacuo to yield an oil which was stirred in Et20. The crushed solids were filtered and the filtrate solvent was removed in vacuo to yield 120 mg of an oil. Performance = 87%. NMR (300
MHz, CDC13) d 7.27 (t, 2H, J = 7 Hz); 7.17 (d, ÍH, J = 7 Hz); 7.13 (d, 2H, J = 7 Hz); 3.70-3.30 (m, 2H); 3.20-3.00 (m, 2H); 3.00-2.70 (m, 2H); 2.70-2.40 (m, 2H) 2.30-2.10 (m,
ÍH); 2.10-1.90 (m, 2H); 1.90-1.40 (m, 5H); 1.40-1.00 (m, 3H); 0.96 (t, 3H, J = 7 Hz)
Part G: The preparation of erythro-cis-1- [3- (3-acetylphenylaminocarbonylamino) -n-prop-1-yl] -4-benzyl-a-ethylpiperidinemethanol and erythro-cis-1- [3- (3 -acetylphenylaminocarbonylamino) -n-prop-1-yl] -2- [1- (3-acetylphenylaminocarbonyloxy) -n-prop-1-yl) -4-benzylpiperidine
Erythro-cis-1- (3-amino-n-prop-1-yl) -4-benzyl-cc-ethylpiperidinemethanol (120 mg, 0.41 mmol, 1 eq.) Was dissolved in 5 mL of THF at 25 ° C. under N2 then the pure 3-acetylphenyl isocyanate was added. After 1 hour the solvent was removed in vacuo to yield an oil. Which was purified by flash chromatography in 100% EtOAc to chloroform / MeOH 4: 1. The product with an isolated mono-addition (product A) together with a product with
an additional bis-addition. Product A produced 81 mg of an oil. Performance = 43%. Product B produced 43 mg of an oil. Product A NMR (300 MHz, CDC13) d 7.86 (bs, ÍH); 7.73
(d, 1H, J = 1 Hz); 7.60 (S, ÍH); 7.56 (d, ÍH, J = 7 Hz); 7.40-7.15 (m, A E); 7.12 (d, 2H, J = 7 Hz); 6.30-6.05 (m, ÍH); 4.00-3.80 (m, ÍH); 3.50-3.30 (m, ÍH); 3.30-2.90 (m, 5H); 2.60-2.40 (m, 2 H); 2.57 (s, 3H); 2.30-2.10 (m, ÍH); 2.10-1.90 (m, 2H); 1.80-1.40 (m, 5H); 1.30-1.05 (m, 2H); 0.94 (t, 3H, J = 7 Hz). Product B NMR (300 MHz, CDC13) d 10.80-10.60 (m, ÍH); 8.20-8.00 (m, ÍH); 7.91 (bs, ÍH); 7.80-7.18 (m, 9H); 7.11 (d, 2H, J = 7 Hz); 6.20-6.00 (m, ÍH); 5.20-5.00 (m, ÍH); 3.50-3.00 (m, 4H); 2.57 (s, 3H); 2.56
(s, 3H); 2.55-2.00 (m, 5H); 2.00-1.00 (m, 10H); 1.00-0.80 (m, 3H)
Product A was separated with its enantiomers using a Daicel Chiral Pack AD column, eluted with 0.1% diethylamine in methanol. (-) -isomer [° C] D25 (c = 0.300 g / dL, MeOH) = -14.9 ° C. (+) -isomer [oc] D25 (c = 0.290 g / dL, MeOH) = + 20.2 ° "
The following compounds can be synthesized by means of the previously discussed methods: TABLE 3b
Example 332
Part A. The preparation of the phenyl ether of N-cyano-N '-3-methoxyphenylcarbamimide
M-Anisidine (4.56 mL, 4.06 mmol, 1 eq.), And diphenylcyancarbonimidate (967 mg, 4.06 mmol, 1 eq.) Were mixed and refluxed in acetonitrile under N2 for 1 hour. The solids precipitated. The reaction was carried out by filtering the solids. 580 mg was obtained as a product. P.F. = 170.0 - 171.0 ° C. NMR (300 MHz, DMSO-d6) d 8.70-8.50 (m, 1H); 7.43 (t, 2H, J = 7 Hz); 7.40-7.20 (m, 2H); 7.14 (d, 2H, J = 7 Hz); 7.00 6.80 (m, 2H); 6.80 6.70 (m, 1H); 3.80 (s, 3H).
Part B. The preparation of N '* -ciano-N' - (3- [4- (4-fluorobenzyl) piperidin] propyl-N- (3-methoxyphenyl) guanidine
The 3- (4- (4-fluorophenylmethyl-piperidin-1-yl) propylamine, (synthesized in a manner similar to the des-fluoro compound previously described) (53 mg, 0.20 mmol, 1 eq.) And the product of the Part A (50 mg, 0.20 mmol, 1 eq.) Were mixed and refluxed in 2-propanol under N2 for 1 hour.The reaction was separated and the residue
purified on silica gel in 100% ethyl acetate followed by chloroform / methanol 8: 2. Obtaining 55 mg of whitish solids as a product. NMR (300 MHz, CDCl3) d 7.33 (t, ÍH, J = 1 Hz) 7.10-6.90 (m, 4H); 6.90-6.80 (m, 3H); 3.83 (s, 3H); 3.50 - 3.35 (m, 2H); 2.90 - 2.70 (m, 2H); 1.50-1.20 (m, 3H). The mass spectrum detects 424 (M + H).
Example 334
Part A: The preparation of [(Methylthio) (3-acetylphenylamino)] methylenepropanedinitrile
To [bis (methylthio) methylene] propandinitrile 3.00 g, 17.6 mmol, 1 eq. ), and 3 '-amino-acetophenone (2.38 g, 17.6 mmol, 1 eq), were mixed and refluxed under N2 in ethanol for 16 hours. The solids were precipitated while cooling to 25 ° C. The solids were filtered. Obtaining 1.86 g of solid color burned or roasted. P.F. = 165.0 - 166.5 ° C. NMR (300 MHz, DMSO-d6) d 10.66 (m,
ÍH); 7.90-7.80 (m, 2H); 7.60-7.50 (m, 2H); 2.60 (s, 3H); 2.54 (s, 3H).
Part B: The preparation of 2 - [(3-acetylanilino) (. {3- [4- (4-fluorobenzyl) -1- piperidinyl] propyllamino) methylene] malononitrile
3- [4- (4-Fluorophenylmethyl) -1-piperidin-1-yl] propylamine (49 mg, 0.194 mmol, 1 eq) and the product from Part A (50 mg, 0.194 mmol, 1 eq.) The mixture was then stirred under N2 overnight. The reaction was separated and the residue was purified with chloroform / methanol. Obtaining 17 mg of a white amorphous solid. NMR (300
MHz, CDC13) d 7.82 (d, ÍH, J = 7 Hz); 7.73 (s, ÍH); 7.51
(t, ÍH, J = 7 Hz); 7.34 (d, ÍH, J = 7Hz); 7.10-6.80 (m, 4H); 3.28 (m, 2H); 2.62 (s, 3H); 2.64-2.40 (m, 2H); 2.40-2.25
(m, 2H); 2.05-1.70 (m, 2H); 1.70-1.35 (m, 3H); 1.20-0.80
(m, 2H). The mass spectrum detects 460 (M + H).
Example 335
Part A: The preparation of N- [1-methylthio) -2-nitroetenyl) -3-acetylbenzenamine
To a pure mixture of 1, l-bismethylthio-2-nitroethylene (6.5 g, 38.5 mmol, 10 eq) and 3-aminoacetophenone (0.5 g, 3.85 mmol, 1 eq) were melted together and heated at 140 ° C for four hours. The mixture was cooled to room temperature then subjected to flash chromatography, eluted with 50% ethyl acetate / hexanes, to yield 0.63 g of a yellow powder as a product.
Yield = 65% NMR (300 MHz, CDC13) d 11.82 (bs, ÍH), 7.95-7.91 (m, 2H), 7.59-7.48 (m, 2H), 6.73 (s, ÍH), 2.65 (s, 3H) 2.41 (s, 3H).
Part B: The preparation of 1- (3- { [(E) -1- ( { - [4- (4-fluorobenzyl) -1-piperidinyl] propyl.} Amino) -2- nitroethylenyl ] amino.}. phenyl) ethanone
To a suspension of N- [1- (methylthio) -2-nitroethenyl] -3-acetylbenzenamine (0.30 g, 1.19 mmol, 1.00 eq) in 20 mL of methanol was added to the 3- (4-fluorobenzyl) piperidinyl-1 -yl) propylamine (0.31 q, 1.25 mmol, 1.05 eq), and the mixture was stirred at room temperature. After three days, a colorless solution was observed. The solvent was removed in vacuo, and the residue was subjected to flash chromatography, eluted with 10% methanol / chloroform, to yield 0.38 g of an orange colored glass as a product. Yield = 70%.
NMR (300 MHz, CDC13) d 10.51 (bs, ÍH), 7.92 (d, ÍH, j = 8
Hz), 7.72 (bs, ÍH), 7.54 (dd, ÍH, J = 8 Hz, 8 Hz), 7.35
(bd, ÍH), 6.90-6.88 (m, 5H), 6.17 (s, ÍH), 3.54 (bs, 2H),
2. 92-2.84 (m, 2H), 2.63 (s, 3H), 2.51 (m, 2H), 1.99-1.91
(m, 4H), 1.55-1.50 (m, 3H), 0.88-0.85 (m, 2H). MS (ESI) detects (M + H) + = 455.
The following compounds can be prepared by means of the previously described procedures:
Table 3c
The following tables contain the representative examples of the present invention, and can be prepared by the methods described above, or by methods familiar to someone skilled in the art. Each entry in each table is intended to go hand in hand with each formula at the beginning of the table. For example, Entry 1 in Table 4 is intended to go hand in hand with each of the formulas la-44.
TABLE 4 *
TABLE 6 *
580
40 41 42
Table 7
j ^
13b or
R1 = a) H, b) methyl, c) ethyl, d) n-propyl, e) allyl, f) n-butyl, g) n-pentyl, and h) n-hexyl.
Utility The utility of the compounds according to the present invention as modulators of chemokine receptor activity can be demonstrated by methodology known in the art, such as assays for ligand binding of CCR-2 and CCR-3, as is described by Ponath et al., J. Exp. Med., 183, 2437-2448 (1996) and 'Uguccioni et al., J. Clin. Invest., 100, 1137-1143 (1997). Cell lines to express the receptor of interest include those that naturally express the chemokine receptor, such as EOL-3 or THP-1, those induced to express the chemokine receptor by the addition of chemical or protein agents, such as HL-60 or AML14.3D10 cells treated with, for example, butyric acid with the interleukin-5 present, or a cell engineered to express a recombinant chemokine receptor, such as CHO or HEK-293. Finally, the cells of blood or tissue, for example the eosinophils of
peripheral blood, isolated using the methods described by Hansel et al., J. Immunol. Methods, can be used in such tests. In particular, the compound of the present invention has agglutination activity to the CCR-3 receptor in the aforementioned assays. As used herein, "activity" is intended to mean a compound demonstrating an IC50 of 10 μM or a lower concentration, when measured in the above mentioned assays, such result is indicative of the intrinsic activity of the compounds as modulators of the activity of the chemokine receptor. A general link protocol is described below.
CCR3 Receptor Binding Protocol
Millipore filter plates (# MABVN1250) are treated with 5 μg / ml protamine in phosphate buffered saline, pH 7.2, for ten minutes at room temperature. The plates are washed three times with phosphate buffered saline and incubated with phosphate buffered saline for thirty minutes at room temperature. For agglutination, 50 μl of binding buffer (bovine serum albumin) is combined
0.5%, 20 mM buffer of HEPES and 5 mM magnesium chloride in RPMI 1640 medium), with or without a test concentration of a compound present at a known concentration, with 50 μl of human eotaxin labeled with 125-1 ( to give a final concentration of radioligand at 150 pM) and 50 μl of cell suspension in agglutination buffer containing a total of 5xl05 cells. The cells used for such binding assays can include cell lines transfected with a gene expressing CCR3 such as that described by Daugherty et al. (1996), isolated human eosinophils, as described by Hansel et al. (1991) or the AML14.3D10 cell line after differentiation with butyric acid as described by Tiffany et al. (1998). The mixture of the compound, cells and radioligand, is incubated at room temperature for thirty minutes. The plates are placed in a vacuum nozzle, the vacuum is applied and the plates are washed three times with agglutination buffer with added 0.5 M NaCl. The plastic skirt is removed from the plate, the plate is allowed to air dry, the wells are drilled and counted by PCM. The percent inhibition of clumping is calculated using the total count obtained in the absence of any competitor compound or ligand of
chemokine and back-up agglutination is determined by the addition of 100 nM eotaxin in place of the test compound. The utility of the compounds according to the present invention, as inhibitors of the migration of eosinophils or cell lines expressing chemokine receptors, can be demonstrated by the methodology known in the art, such as the chemotaxis assay described by Bacon et al., Brit J. Pharmacol., 95, 966-974 (1988). In particular, the compound of the present invention has activity in the inhibition of the migration of eosinophils in the aforementioned assays. As used herein, "activity" is intended to indicate that a compound demonstrates an IC50 of 10 μM or a lower concentration when measured in the assays mentioned above. Such a result is indicative of the intrinsic activity of the compounds as modulators of chemokine receptor activity. A protocol of the human eosinophil chemotaxis assay is described below. Assay of the Chemotaxis of Human Eosinophils
Neuroprobe MBA96 96-well chemotaxis chambers with 5-micron PFD5 filters, polycarbonate, Neuroprobe polyvinylpyrrolidone-free on-site heats in an incubator at 37 ° C prior to assay. Freshly isolated human eosinophils, isolated according to a method such as that described by Hansel et al, (1991), are suspended in RPMI with bovine serum albumin 0.1% at 1 x 106 cells / ml and heated in an incubator at 37 ° C before assay. A 20 nM solution of human eotaxin in RPMI 1640 with 0.1% bovine serum albumin is heated in an incubator at 37 ° C before the assay the eosinophil suspension and the 20 nM solution of eotaxin are mixed 1 each: 1 with RPMI 1640 preheated with 0.1% bovine serum albumin with or without a dilution of a test compound that is twice the desired final concentration. These mixtures are heated in an incubator at 37 ° C before testing. The filter is separated from the pre-heated Neuroprobe chemotaxis chamber and the eotaxin / compound mixture, is placed in a 96-well Polifiltronic MPC plate that has been placed in the lower part of the Neuro Probé chemotaxis chamber. The approximate volume is 170 microliters and there must be a positive meniscus after the dispersion. The filter turns to
Place on the 96-well plate, the rubber gasket is secured to the bottom of the upper chamber, and the chamber is assembled. A volume of 200 μl of the cell suspension / compound mixture is added to the appropriate wells of the upper chamber. The upper chamber is covered with a plate sealer, and the assembled unit is placed in an incubator at 37 ° C for 45 minutes. After incubation, the plate sealer is removed and all the remaining cell suspension is aspirated. The chamber is disassembled and, while the filter is held by the sides at a 90 degree angle, the cells that did not migrate are washed using a gentle stream of phosphate buffered saline provided by a dispensing bottle and then the filter is tapped. lightly with a rubber-tipped brush. The filter is allowed to dry completely and completely immersed in Wright Giemsa dye for 30-45 seconds. The filter is rinsed with distilled water for 7 minutes, rinsed once with water briefly, and allowed to dry. The cells that migrate are enumerated by microscopy. The mammalian chemokine receptors provide an objective to interfere with or promote the function of immune cells in a mammal, such as a mammal.
human. Compounds that inhibit or promote the function of the chemokine receptor are particularly useful for modulating the function of cells. immune for therapeutic purposes. Accordingly, the present invention is directed to compounds, which are useful in the prevention and / or treatment of a wide variety of inflammatory, infectious and immunoregulatory disorders and diseases, including asthma and allergic diseases, infection by pathogenic microbes (which , by definition, include viruses), as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. For example, a present compound, which inhibits one or more functions of a mammalian chemokine receptor (e.g., a human chemokine receptor), can be administered to inhibit (i.e., reduce or prevent) inflammatory disease. or infectious. As a result, one or more inflammatory processes are inhibited, such as leukocyte migration, adhesion, chemotaxis, exocytosis (for example, enzymes, histamine) or the release of the inflammatory mediator. For example, eosinophilic infiltration to inflammatory sites (for example, in asthma or allergic rhinitis) can be inhibited
according to the present method. In particular, the compound of the following examples has activity in blocking the migration of cells expressing the CCR-3 receptor, using the appropriate chemokines in the assays mentioned above. As used herein, "activity" is intended to indicate that a compound demonstrates an IC50 of 10 μM or a lower concentration when measured in the assays mentioned above. Such a result is also indicative of the intrinsic activity of the compounds as modulators of chemokine receptor activity. Similarly, a present compound, which promotes one or more functions of the mammalian chemokine receptor (e.g., a human chemokine), when administered to stimulate (induce or ameliorate) an immune or inflammatory response, such as emigration of leukocytes, adhesion, chemotaxis, exocytosis (for example, of enzymes, histamines) or the release of the inflammatory mediator, results in the beneficial stimulation of inflammatory processes. For example, eosinophils can be used to fight parasitic infections. In addition, the treatment of the inflammatory, allergic and autoimmune diseases mentioned above can be
also be contemplated for a present compound, which promotes one or more functions of the mammalian chemokine receptor if one contemplates the administration of sufficient compound to cause the loss of the expression of the receptor on the cells, through the induction of the internalization of the chemokine receptor or the administration of a compound in a manner that results in the misdirection of cell migration. In addition to primates, such as humans, a variety of other mammals may be treated, in accordance with the method of the present invention. For example, mammals can be treated, including but not limited to cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species. However, the method can also be practiced in other species, such as bird species. The subject treated in the methods above, is a mammal, female or male, in which modulation of the chemokine receptor is desired. "Modulation", as used herein, is intended to encompass antagonism, agonism, partial antagonism and / or partial agonism. Diseases or conditions of humans or other species, which can be treated with inhibitors
of the function of the chemokine receptor, include, but are not limited to: inflammatory or allergic diseases and conditions, including allergic respiratory diseases, such as asthma, allergic rhinitis, hypersensitive lung diseases, hypersensitivity pneumonitis, eosinophilic cellulitis (e.g. , Well syndrome), eosinophilic pneumonias (eg, Loeffler syndrome, chronic eosinophilic pneumonia), eosinophilic fasciitis (eg, Shulman syndrome), delayed-type hypersensitivity, interstitial lung diseases (ILD) (eg, pulmonary fibrosis) idiopathic, or ILD associated with rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondiolitis, systemic sclerosis, Sjorgren's syndrome, polymyositis, or dermatomyositis); systemic anaphylaxis or hypersensitivity responses, drug allergies (eg, to penicillin, cephalosporin), eosinophilia-myalgia syndrome due to ingestion of contaminated tryptophan, allergies to insect bites; autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, systemic lupus erythematosus, myasthenia gravis, juvenile attack diabetes; glomerulonephritis, autoimmune thyroiditis, Behcet's disease; rejection of grafts (for example, transplants),
including allograft rejection or graft-versus-host disease; inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis; spondyloarthropathies; scleroderma, psoriasis (including psoriasis mediated by T cells) and inflammatory dermatosis such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria, vascularitis (eg, necrotization, cutaneous and hypersensitive vascularitis); eosinophilic myositis, eosinophilic fasciitis, cancers with infiltration of leukocytes from the skin or organs. Other diseases or conditions may be treated, in which undesirable inflammatory responses should be inhibited, including, but not limited to, reperfusion damage, atherosclerosis, haematological malignancies, cytokine-induced toxicity (e.g., septic shock, endotoxic shock) , polymyositis, dermatomyositis, diseases or infectious conditions of humans or other species, which can be treated with chemokine receptor inhibitors, include, but are not limited to, HIV. Diseases or conditions of humans or other species, which can be treated with the promoters of chemokine receptor function, include, but
are not limited to: Immunosuppression, such as that in individuals with immunosuppressive syndromes, such as AIDS or other viral infections, individuals undergoing radiation therapy, chemotherapy, therapy for autoimmune disease or drug therapy (eg, therapy for corticosteroids), which causes immunosuppression; immunosuppression due to congenital deficiencies in receptor function or other causes; and infectious diseases, such as parasitic diseases, including, but not limited to, helminth infections, such as nematodes (coiled worms); (Trichuriasis, Enterobiasis, Ascariasis, Ancylostomatidae,
Hookworm, strongyloidiasis, trichinosis, filariasis); trematodes (Schistosomiasis, Clonorchiasis), cestodes (flat worms) (Echinococcosis, Taeniasis saginata, Cysticercosis); visceral worms, migraines by visceral larvae (for example Toxocara), eosinophilic gastroenteritis (for example, Anisaki sp., Focanema sp.), migraines by cutaneous larvae (Ancylostoma braziliense, Ancylostoma caninum). The compounds of the present invention are therefore useful in the prevention and treatment of a wide variety of infectious and inflammatory disorders and diseases.
immunoregulatory. In addition, the treatment of the inflammatory, allergic and autoimmune diseases mentioned above, it can also be. completed by the promoters of the chemokine receptor function if one contemplates the administration of sufficient compound to cause the loss of receptor expression on the cells, through the induction of chemokine receptor internalization or the administration of the compound in a way that results in the wrong direction of cell migration. In another aspect, the present invention can be used to evaluate specific putative agonists or antagonists of a G protein coupled receptor. The present invention is directed to the use of these compounds in the preparation and execution of screening assays for compounds that modulate the activity of chemokine receptors. In addition, the compounds of this invention are useful in establishing or determining the binding site of other compounds for chemokine receptors, for example, by competitive inhibition or as a reference in an assay to compare their known activity for a compound with an unknown activity. When new trials are developed or
protocols, the compounds according to the present invention, could be used to prove their effectiveness. Specifically, such compounds can be provided in commercial equipment, for example, for use in pharmaceutical research involving the diseases mentioned above. The compounds of the present invention are also useful for the evaluation of putative modulators specific to chemokine receptors. In addition, one could use the compounds of this invention to examine the specificity of coupled G protein receptors that are not believed to be chemokine receptors, whether they serve as examples of compounds, which do not agglutinate or as structural variants of the active compounds on these receptors, which can help to define the specific sites of interaction. The combination therapy to prevent and treat inflammatory, infectious and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis, and those pathologies indicated above, is illustrated by the combination of the compounds of this invention and other compounds, which
they are known for such utilities. For example, in the treatment or prevention of inflammation, the present compounds can be used, in conjunction with an anti-inflammatory or analgesic agent, such as an opiate agonist, a lipoxygenase inhibitor, an inhibitor of cyclooxygenase-2, an interleukin inhibitor, such as an interleukin-1 inhibitor, an inhibitor of tumor necrosis factor, and an NMDA antagonist, an inhibitor or nitric oxide, or an inhibitor of nitric acid synthesis, an anti-inflammatory agent non-steroidal inflammatory, a phosphodiesterase inhibitor, or an anti-inflammatory cytokine suppressant agent, for example, with a compound such as acetaminophen, aspirin, codeine, fentanyl, ibuprofen, indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam , a steroidal analgesic, sufentanil, sunlidac, interferon alfa and the like. Similarly, the present compounds can be administered with a pain reliever; an enhancer such as caffeine, an H2 antagonist, simethicone, aluminum or magnesium hydroxide; a decongestant, such as phenylephrine, phenylpropanolamine, pseudoephedrine, oxymetazoline, epinephrine, naphazoline, xylometazoline, propylhexedrine, or levodeoxy-ephedrine; and such an antitussive
such as codeine, caramifen, carbetapentane, or dextramethorphan; a diuretic; and a sedative or non-sedating antihistamine. Likewise, the compounds of the present invention can be used in combination with other drugs that are used in the treatment / prevention / suppression or amelioration of the diseases or conditions for which the compounds of the present invention are useful. Such other drugs can be administered by a route and in an amount commonly used, therefore, contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs is preferred, in addition to the compound of the present invention, therefore, the pharmaceutical compositions of the present invention, include those which also contain one or more other active ingredients, in addition to a compound of the present invention. Examples of other active ingredients that may be in combination with a compound of the present invention, whether administered separately or in the same pharmaceutical compositions, include, but are not limited to: (a) integrin antagonists such as, those for
selectins, ICAMs and VLA-4; (b) steroids such as beclomethasone, methylprednisolone, betamethasone, prednisone, dexamethasone, and hydrocortisone; (c) immunosuppressants such as cyclosporin, tacrolimus, rapamycin and other immunosuppressants of the FK-506 type; (d) antihistamines (histamine Hl antagonists), such as bromopheniramine, chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, metdilazine, promethazine, trimeprazine, azatadine, cyproheptadine, antazoline, phenylamine, pyrilamine, astemizole , terfenadine, loratadine, cetirizine, fexofenadine, descarboethoxyloratadine, and the like; (e) anti non-steroidal asthmatics, such as b2 antagonists (terbutaline, metaproterenol, fenoterol, isoetarin, albuteral, bitolterol and pirbuterol), theophylline, cromolyn sodium, atropine, ipratropium bromide, leukotriene antagonists (zafirlukasta, montelucasta, pranlucasta, iralucasta, pobilucasta, SKB-102, 203), inhibitors of leukotriene biosynthesis (zileuton, BAY-1005); (f) nonsteroidal anti-inflammatory agents (NSAIDs), such as propionic acid derivatives (alminoprofen, benxaprofen, bucloxic acid, carprofen, fenbufen, fenprofen, fluprofen, flurbiprofen,
ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, thiaprofenic acid, and thioxaprofen), acetic acid derivatives (indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclonic acid, fentiazac, furofenac, ibufenac, isoxepac , oxypinaco, sulindaco, thiopinaco, tolmetin, zidometacin and zomepiraco), formic acid derivatives (flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid), biphenylcarboxylic acid derivatives (diflunisal and flufenisal), oxicams (isoxicam, piroxicam , sudoxicam and tenoxican), salicylates (acetylsalicylic acid, sulfasalazine) and pyrazolones (apazone, bezpiperilone, feprazone, mofebutazone, oxifenbutazone, phenylbutazone); (g) cyclooxygenase-2 (COX-2) inhibitors; (h) phosphodiesterase type IV inhibitors (PDE-IV); (I) other chemokine receptor antagonists; (j) cholesterol lowering agents, such as HMG-COA reductase inhibitors (lovastatin, simvastatin and pravastatin, fluvastatin, atorvastatin, and other statins), sequestrants (cholestyramine and colestipol), nicotonic acid, fenofibric acid derivatives (genfibrozil) , clofibrate, fenofibrate, and benzafibrate), and probucol; (k)
antidiabetic agents, such as insulin, sulfonylureas, biguanides (metformin), α-glucosidase (acarbose) inhibitors and glitazones (troglitazone and pioglitazone); (1) interferon preparations (interferon-alpha-2a, interferon-2B, interferon alpha-N3, interferon beta-la, interferon beta-Ib, interferon gamma-Ib); (m) antiviral compounds, such as efavirenzo, nevirapine, indinavir, ganciclovir, lamivudine, famciclovir, and zalcitabine; (o) other compounds such as 5-aminosalicylic acid and prodrugs thereof, antimetabolites such as azathioprine and 6-mercaptopurine, and cytotoxic chemotherapeutic agents for cancer. The weight ratio of the compound of the present invention to the second active ingredient can be varied and will depend on the effective doses of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with an NSAID, the weight ratio of the compound of the present invention to the NSAID will generally vary from about 1000: 1 to about 1: 1000, preferably of about 200: 1 to about 1: 200. Combinations of a compound of the present invention and other active ingredients will also generally be within the range
mentioned above, but in each case, an effective dose of each active ingredient should be used. The compounds are administered to a mammal in a therapeutically effective amount. By "therapeutically effective amount" is meant an amount of a compound of Formula I, which, when administered to a mammal, alone or in combination with an additional therapeutic agent, is effective in preventing or ameliorating thromboembolic disease or the progression of the disease.
Dosage and Formulation The compounds of this invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or controlled release formulations), pills, powders, granules, elixirs, dyes, suspensions, syrups , and emulsions. These can also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. These can be administered alone, but will generally be administered with a pharmaceutical carrier,
selected based on the selected administration route and the standard pharmaceutical practice. The dosage regimen for the compounds of the present invention will, of course, vary depending on known factors, such as, the pharmacodynamic characteristics of the particular agent, and its mode and route of administration.; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the type of current treatment; the frequency of treatment, the route of administration, the renal and hepatic function of the patient and the desired effect. A physician or veterinarian can determine and prescribe the effective amount of the drug, required to prevent, respond to or stop the progress of thromboembolic disorder. As a general guide, the daily oral dose of each active ingredient, when used for the indicated effects, will vary between about 0.001 to 1000 mg / kg of body weight, preferably between about 0.01 to 100 mg / kg of body weight per day and more preferably between about 1.0 to 20 mg / kg / day. Intravenously, the most preferred doses will vary from about 1 to about 10 mg / kg / minute, during a constant infusion rate. The compounds of this invention can
to be administered in a single daily dose, or the total daily dose can be administered in divided doses or two, three or four times daily. The compounds of this invention can be administered in intranasal form via the topical use of suitable intranasal vehicles, or through the transdermal routes, using patches on the skin. When administered in the form of a transdermal delivery system, the administration of the dose will, of course, be continuous rather than intermittent through the dosing regimen. The compounds are typically administered in a mixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and in consistency with conventional pharmaceutical practices. For example, for oral administration in the form of a tablet or capsule, the active component drug can be combined with an inert, non-toxic pharmaceutically acceptable oral carrier such as
lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for administration in liquid form, the components of the oral drug can be combined with any inert, oral, non-toxic, pharmaceutically acceptable carrier, such as ethanol, glycerol, water, and the like. In addition, when desired or needed, suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars, such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums, such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. The lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. The disintegrants include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. The compounds of the present invention can also be administered in the form of delivery systems in liposomes, such as small unilamellar vesicles,
large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines. The compounds of the present invention can also be coupled with soluble polymers as carriers of drugs capable of being objective. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. In addition, the compounds of the present invention can be coupled to a class of biodegradable polymers useful for achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, polylactic acid and polyglycolic acid copolymers, polyepsilon caprolactone, polyhydroxy butyric acid , polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and copolymers of crosslinked or unsympathetic block hydrogels. Dosage forms (pharmaceutical compositions), suitable for administration, may contain from about 1 milligram to about
100 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions, the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight, based on the total weight of the composition. Gelatin capsules can contain the active ingredient and powdered carriers, such as starch, cellulose derivatives, magnesium stearate, stearic acid and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide the continuous release of mediation over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or it can be enterically coated for selective disintegration in the gastrointestinal tract. The liquid dosage forms for oral administration may contain colorants and flavors to increase patient acceptance. In general, water, an acceptable oil, saline solution, dextrose (glucose) and solutions of sugars
Related and glycols such as propylene glycol or polyethylene glycol, are suitable carriers for parenteral solutions. Solutions for paranteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffering substances. Antioxidant agents such as sodium bisulfite, sodium sulfite or ascorbic acid, either alone or in combination, are suitable stabilizing agents. Also used here are citric acid and its salts and sodium EDTA. In addition, parenteral solutions may contain preservatives, such as benzalkonium chloride, methyl or propylparaben, and chlorobutanol. Acceptable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, to standard reference text in this field. Representative pharmaceutical dosage forms useful for the administration of the compounds of this invention can be illustrated as follows:
Capsules A large number of unit capsules can be prepared by standard two-piece hard gelatin capsules each filled with 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose and 6 milligrams of magnesium stearate. Soft Gelatin Capsules A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil can be prepared and injected by means of a gelatin-positive displacement pump to form soft gelatin capsules that They contain 100 milligrams of the active ingredient. The capsules should be washed and dried. Tablets Tablets can be prepared by conventional procedures so that the dosage unit is 100 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams
of lactose. Suitable coatings can be applied to increase the palatability or delay absorption. Injectables A parenteral composition suitable for administration by injection can be prepared by stirring 1.5% by weight of the active ingredient in 10% by volume propylene glycol and water. The solution should be made isotonic with sodium chloride and sterilized. Suspension An aqueous suspension can be prepared for oral administration, so that each 5 ml contains 100 mg of the finely divided active ingredient, 200 mg of sodium carboxymethylcellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P. and 0.025 ml of vanillin. Where the compounds of this invention are combined with other anticoagulant agents, for example, a daily dose may be from about 0.1 to 100 milligrams of the compound of formula I and about 1 to 7.5 milligrams of the second anticoagulant, per kilogram of patient's body weight. For a tablet dosage form, the compounds of this invention can generally be
present in the amount of about 5 to 10 milligrams per dosage unit, and the second anticoagulant in an amount of about 1 to 5 milligrams per dosage unit. Where two or more of the above second therapeutic agents are administered, with the compound of Formula I, generally the amount of each component in a typical daily dose and a typical dosage form can be reduced relative to the usual dose of the agent when administered alone, in view of the additive or synergistic effect of the therapeutic agents when administered in combination. Particularly when provided as unique dosage units, there is the potential for a chemical interaction between the combined active ingredients, for this reason, when the compound of Formula I and the second therapeutic agent are combined in a single dosage unit, they are formulated from such that although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized (ie, reduced). For example, an active ingredient may be enteric coated. Through the enteric coating of one of the ingredients, it is
It is possible not only to minimize the contact between the combined active ingredients, but it is also possible to control the release of one of these components in the gastrointestinal tract, such that one of these components is not released in the stomach but instead is released in the intestines. One of the active ingredients can also be coated with a material, which effects a sustained release through the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. In addition, the sustained release component can be additionally coated enterically so that the release of this component occurs only in the intestine. Yet, another approach would involve the formulation of a combination product in which component one is coated with a sustained release and / or enteric polymer, and the other component is also coated with a polymer which is hydroxypropyl methylcellulose (HPMC) a low viscosity grade other suitable materials as are known in the art, to further separate the active components. The coating polymer also serves to form an additional barrier to interaction with the other component.
These, as well as other ways of minimizing contact between the components of the combination products of the present invention, either. administered in a single dosage form or administered in separate forms but at the same time, in the same manner, will be readily apparent to those skilled in the art, once having the present disclosure. As will be appreciated by one skilled in the art, numerous modifications and variations of the present invention are possible, in light of the teachings above. It will be understood, therefore, that within the scope of the appended claims, the invention may be practiced in a different manner, than as specifically described herein.
It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.
Claims (34)
- CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. A compound characterized in that it has Formula (I): (I) or stereoisomers or pharmaceutically acceptable salts thereof, wherein: M is absent or selected from CH2, CHR5, CHR13, CR13R13, and CR5R13; is selected from CH2, CHR5, CHR13, CR13R13, and CR5R1 J and K are selected from CH2, CHR5, CHR6, CR6R6 and CR5R6; L is CHR5; on condition that: when M is absent, J is selected from CH2, CHR, CHR13, and CR5R13; it is selected from 0 and S; is selected from: 47 ring A is a C3_6 carbocyclic residue, with the proviso that the C3_6 carbocyclic residue is not phenyl; R1 and R2 are independently selected from H, C6-6alkyl, C2_8alkenyl, C2-8alkynyl, (CH2) r- C3_6 cycloalkyl, and a (CH2) r- C3-? Carbocyclic residue or substituted with 0-5 Ra; Ra, in each case, is selected from alkyl C? -β, C2-8 alkenyl, C2_8 alkynyl, (CH2) C3_6 cycloalkyl, Cl, Br, I, F, (CF2) rCF3, N02, CN, (CH2) rNRbR , (CH2) rOH, (CH2) rORc, (CH2) rSH, (CH2) rSRA (CH2) rC (0) R, (CH2) rC (O) NRbRb, (CH2) rNRbC (0) Rb, (CH2) rC (0) ORE (CH2) rOC (0) Rc (CH2) rOH (= NRb) NRbR, (CH2) rNHC (= NRb) NRbRb, (CH2) r S (0) pRc, (CH2) rS (0) 2NRDRD, (CH2) rNRDS (0) 2Rc, and (CH2) rphenyl; Rb, in each case, is selected from H, C? -6 alkyl, C3_6 cycloalkyl, and phenyl; Rc, in each case, is selected from C? -6 alkyl, C3_6 cycloalkyl, and phenyl; alternatively, R2 and R3 together form a ring of 5, 6, or 7 elements substituted with R of 0-3; is selected from a (CR3 R '') r-carbocyclic residue C3_? 0 substituted with R15 of 0-5 and a system (CR3'R3, ') r heterocyclic of 5-10 elements containing 1-4 heteroatoms selected from N , 0 and S, substituted with R15 of 0-3; R3 'and R3' ', in each case, are selected from H, C? -6 alkyl, (CH2) r-C3_6 cycloalkyl, and phenyl; R4 is absent, taken together with the nitrogen to which it is attached to form an N-oxide, or is selected from C? -6 alkyl, C2_8 alkenyl, C2-8 alkynyl, (CH2) C3_6 cycloalkyl, (CH2) qC (O ) R4b, (CH2) qC (0) NRaRa ', (CH2) qC (0) OR4b, and a (CH2) carbocyclic residue substituted with R 4c of 0-3; Ra and R4a ', in each case, are selected from H, C? -6 alkyl, (CH2) r C3_6 cycloalkyl, and phenyl; R, 4b, in each case, is selected from C? -6 alkyl, C2_8 alkenyl, (CH2) r C3-6 cycloalkyl, C2_8 alkynyl, and phenyl; R 4c in each case is selected from C ?6 alkyl, C2_8 alkenyl, C2_8 alkynyl, C3_6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) rCF3, (CH2) rC1-5 alkyl, (CH2) ) rOH, (CH2) rS alkyl C? _5, (CH2) rNR4aR4a ', and (CH2) rphenyl; alternatively, R4 binds with R7, R9, R11, or R14 to form a 5-, 6-, or 7-membered piperidinium spirocycle or pyrrolidinium spirocycle with Ra of 0-3; R5 is selected from a (CR5'R5") t-carbocyclic residue C3_? Or substituted with R16 of 0-5 and a (CR5'R5") t-heterocyclic system of 5-10 elements containing 1-4 heteroatoms selected from N, O and S, substituted with R16 of 0-3; R5 'and R5", in each case, are selected from H, C? _6 alkyl, (CH2) C3_6 cycloalkyl, and phenyl; R, in each case, is selected from C6_6 alkyl, C2_8 alkenyl, C2_8 alkynyl, (CH2) C3_6 cycloalkyl, (CF2) rCF3, CN, (CH2) rNR6aR6a ', (CH2) r0H, (CH2) r0R6b, ( CH2) rSH, (CH2) rSR6b, (CH2) rC (0) 0H, (CH2) rC (0) R6 (CH2) rC (0) NR6aR6a '(CH2) rNR6dC (0) R6a, (CH2) rC (0) 0R, 6cb, (CH2) r0C (0) RbD, (CH2) rS (0) pR > 6DbD, (CH2) rS (0) 2NR6aR6a ',, 6c (CH2) rNR6dS (0) 2R6b and (CH2) tf enyl substituted with Rec of 0-3; R and R, in each case, are selected from H, C? _6 alkyl, C3_6 cycloalkyl, and phenyl substituted with R6c of 0-3; R, in each case, is selected from C? _6 alkyl, cycloalkyl C3-6 and phenyl substituted with R of 0-3; R, in each case, is selected from C? _6 alkyl, C3_6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) rCF3, (CH2) r0alkyl C? -5, (CH2) r0H, (CH2 ) rSalt C? -5, and (CH2) rNR6dR6d; R "6d, in each case, is selected from H, C? _6 alkyl, and C3_s cycloalkyl; with the proviso that when either of J or K is CR6R6 and R6 is halogen, cyano, nitro, or bonded to the carbon to which it is attached by a heteroatom, the other R6 is not halogen, cyano, or is bonded to the carbon to which it is attached. united by a heteroatom; R7 is selected from H, Ci-β alkyl, C2-alkenyl, C2-8 alkynyl, (CH2) qOH, CH2) qSH, (CH2) qOR7d, (CH2) qSR7d, (CH2) qNR7aR7a ', (CH2) rC (0) OH, (CH2) rC (O) R7, (CH2) rC (0) NR7aR7a '(CH2) qNR7aC (O) R7a, (CH2) qNR7aC (O) H, (CH2) r (0) OR 7b (CH2) q0C (0) R7b, (CH2) qS (0) pR7b, (CH2) qS (0) 2NR7aR7a ', (CH2) qNR7aS (0) 2R7, haloalkyl C6-6, a (CH2) r- C3-10 carbocyclic residue substituted with R7c of 0-3, and a (CH2) r- heterocyclic system of 5-10 elements containing 1-4 heteroatoms selected from N, O, and S, substituted with R7c of 0-2; R7a and R7a ', in each case, are selected from H, C? -6 alkyl, C2_8 alkenyl, C2_8 alkynyl, (CH2) r-C3_6 cycloalkyl, a (CH2) r C3_? Carbocyclic residue or substituted with R7e of 0 -5, and a (CH2) r-heterocyclic system of 5-10 elements containing 1-4 heteroatoms selected from N, 0, and S, substituted with R7e from 0-3; R7b, in each case, is selected from C6-6alkyl, C2-8alkenyl, C2-8alkynyl, a (CH2) r C3-e carbocyclic residue substituted with R7e of 0-2, and a (CH2) r heterocyclic system of 5-6 elements containing 1-4 heteroatoms selected from N, O, and S, substituted with R7e of 0-3; R7c, in each case, is selected from C? -6 alkyl, C2-alkenyl, C2_8 alkynyl, (CH2) r C3-6 cycloalkyl, Cl, Br, I, F, (CF2) rCF3, N02, CN, ( CH2) rNR7fR7f, (CH2) r0H, (CH2) rOalkyl C? _4, (CH2) rSalt C? -4, (CH2) rC (O) OH, (CH2) rC (0) R / b (CH2) cC (0) NR7fR7f, (CH2) rNR7fC (0) R7 7aa, (CH2) EC (O) Oalkyl C? -4, (CH2) r0C (O) R7 7bb, (CH2) rC (= NR7f) NR7fR7f, (CH2) rS (0) pR 7 / bb, (CH2) rNHC (= NR7f) NR7fR7f, (CH2) rS (O) 2NR7fR7f, (CH2) rNR7fS (0) 2R7b, and (CH2) r phenyl substituted with R7e of 0-3; R 7d in each case is selected from C?-Βalkyl substituted with R 7e of 0-3, alkenyl, alkynyl, and a C3_? Carbocyclic residue or substituted with R7c of 0-3; R7A in each case is selected from C6_6 alkyl, C2_8 alkenyl, C2_8 alkynyl, C3_6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) rCF3, (CH2) rOalkyl C? _5, OH , SH, (CH2) rSalt C? _5f (CH2) rNR7fR7f, and (CH2) rphenyl; R7f, in each case, is selected from H, C? -6 alkyl, and C3-6 cycloalkyl; R is selected from H, C? _6 alkyl, C3_6 cycloalkyl, and (CH2) tphenyl substituted with R8a of 0-3; R, in each case, is selected from C? -6 alkyl, C2-8 alkenyl, C2_8 alkynyl, C3_6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) rCF3, (CH2) rOalkyl? C1-5, OH, SH, (CH2) rC1-5Salt, (CH2) rNR7fR7f, and (CH2) rphenyl; alternatively, R7 and R8 join to form cycloalkyl R B'b is selected from H, C? _6 alkyl, C3_6 cycloalkyl, OH, CN, and (CH2) r-phenyl; R9 is selected from H, C? _6 alkyl, C2_8 alkenyl, C2-8 alkynyl, F, Cl, Br, I, N02, CN, (CH2) rOH, (CH2) rSH, (CH2) rOR9d, (CH2) rSR9d, (CH2) rNR, 99aapR9a '(CH2) rC (0) OH, (CH2) rC (0) R-, 9SbD, (CH2) rC (0) NR 599aarR, 9-a '(CH2) rNR9aC (0) R9a, (CH2) rNR9aC (0) H, (CH2) rNR9aC ( 0) NHR9a, (CH2) rC (O) OR9, (CH2) r0C (0) R9b, (CH2) r0C (0) NHR9a, (CH2) rS (O) pR9b, (CH2) rS (0) 2NR9aR9 ', (CH2) rNR9aS (0) 2R9b, haloalkyl C? _6, a (CH2) r-carbocyclic residue C3_? 0 substituted with R9c of 0-5, and a (CH2) r-heterocyclic system of 5-10 elements containing 1 -4 heteroatoms selected from N, O, and S, substituted with R9c of 0-3; R9a and R9a ', in each case, are selected from H, C? -alkyl, C2_8 alkenyl, C2-8 alkynyl, a (CH2) r_residue carbocyclic C3_? or substituted with R9e of 0-5, and a (CH2) r-heterocyclic system of 5-10 elements containing 1-4 heteroatoms selected from N, O, and S, substituted with R9e of 0-3; R9b, in each case, is selected from C? _6 alkyl, C2_8 alkenyl, C2_8 alkynyl, a (CH2) r-C3-6 carbocyclic residue, substituted with R9e of 0-2, and a (CH2) r-heterocyclic system of 5-6 elements selected from N, O, and S, substituted with R9e of 0-3; R 9c in each case is selected from C 1 -C 6 alkyl, C 2-8 alkenyl, C 2 al alkynyl, (CH 2) r C 3 6 cycloalkyl, Cl, Br, I, F, (CF 2) ECF 3, N 2, CN, (CH 2) rNR9fR9f, (CH2) r0H, (CH2) rOalkyl C? _4, (CH2) rS alkyl C? _4, (CH2) rC (O) OH, (CH2) rC (0) R9b, (CH2) rC (0) NR9fR9f, (CH2) rNR9fC (0) R9a, (CH2) rC (0) 0 alkyl '1-4 / (CH2) rOC (0) R 9sb (CH2) rC (= NR9f) NR9fR9f, (CHzJrSÍOpR 99b0, (CH2) rNHC (= NR 9f \ NR9fR9f, (CH2) rS (0) 2NR9fR9f, (CH2) rNR9fS (0) 2R9, and (CH2) rphenyl substituted with R9e of 0-3; R, 9d, in each case, is selected from C? -6 alkyl, C2-6 alkenyl, C2_6 alkynyl, a C3_? Carbocyclic residue or substituted with R9c from 0-3, a 48 heterocyclic 5-6 elements containing 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with R9c of 0-3; R 9e in each case, is selected from C? -6 alkyl, alkenyl C2_a, C2_8 alkynyl, (CH2) r C3_6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) rCF3, (CH2) r0 alkyl C? _5, OH, SH, (CH2) rS alkyl C? _5, (CH2) rNR9fR9f, and (CH2) rphenyl; R, in each case, is selected from H, C? _6 alkyl, and C3_e cycloalkyl; R 10 is selected from H, C? -6 alkyl, C2_8 alkenyl C2_8 alkynyl, F, Cl, Br, I, N02, CN, (CH2) r0H (CH2) rOR10d, (CH2) rSR10d, (CH2) rNR10aR10 ', (CH2) rC (0) OH (CH2) rC (0) R10b, (CH2 rNR10aC (O) R10a [CH2) rNR10aC (0) H, (CH2) rC (0) OR10b,; CH2) r0C (0) R 10b (CH2) rS (O) pR10b, (CH2) rS (O) 2NR10aR10a ', (CH2) rNR10aS (O) 2R10b haloalkyl C6-6, a (CH2) r carbocyclic residue C3-? Or substituted with R10c of 0-5 , and a (CH2) r heterocyclic system of 5-10 elements containing from 1-4 heteroatoms selected from N, O, and S, substituted with R10c from 0-3; R10a and R10a ', in each case, are selected from H, C? -6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2) r C3_? carbocyclic residue or substituted with R10e of 0-5, and a heterocyclic (CH2) r system of 5-10 elements containing from 1-4 heteroatoms selected from N, O, and S, substituted with R10e of 0-3; R10b, in each case, is selected from C?-Βalkyl, C2_s alkenyl, C2_8alkynyl, a (CH2) r C3-6 carbocyclic residue substituted with R10e of 0-2, and a (CH2) r-heterocyclic system of -6 elements containing 1-4 heteroatoms selected from N, O, and S, substituted with R10e of 0-3; R 10c in each case, is selected from C ?_6 alkyl, C2_8 alkenyl, C2-8 alkynyl, (CH2) r C3-6 cycloalkyl, Cl, Br I, F, (CF2) rCF3, N02, CN, (CH2) rNR10fR10f, (CH2) r0H (CH2) r0 C? -4 alkyl, (CH2) rS alkyl C? _4, (CH2) rC (0) 0H (CH2) rC (0) R 10b (CH2) rC (0) NR10fR10f, (CH2) rNR10fC (O) R10a (CH2) rC (0) 0 Ci- 4 alkyl, (CH2) r0C (0) R 10b (CH2) rC (= NR10f) NR10fR10f, (CH2) rS (0) R 10b (CH2) rNCH (= NR10f) NR10fR1 (CH2) rS (O) 2NR10fR10f (CH2) rNR10fS (O) 2R10b, and (CH2) r phenyl substituted with R10e of 0-3; R, in each case, is selected from alkyl C? -β, alkenyl C2_e, C2_6 alkynyl, a C3_? Carbocyclic residue or substituted with R10c of 0-3, and a 5-6 element heterocyclic system containing 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with R10c of 0-3; R, in each case, is selected from C6-alkyl, C2_8 alkenyl, C2_8 alkynyl, (CH2) r C3-6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) rCF3, alkyl (CH2) ) r0 C? _5, OH, SH, (CH2) rS alkyl C? _5, (CH2) rNR10fR10f, and (CH2) rphenyl; R, in each case, is selected from H, C? _5 alkyl, and C3_6 cycloalkyl,? alternatively, R9 and R10 join to form C3_7 cycloalkyl, cyclic ketal of 5-6 elements or = 0; with the proviso that when R10 is halogen, cyano, nitro, or is bonded to the carbon to which it is attached through a heteroatom, R9 is not halogen, cyano or is linked to the carbon to which it is attached through a heteroatom; R is selected from H, C? _6 alkyl, C2-alkenyl C2_8 alkynyl, (CH2) q0H, (CH2) qSH, (CH2) q0R? A, (CH2) qSR lid (CH2) qNRllaRlla '(CH2) rC (0) 0H, (CH2) rC (0) Rllb (CH2) rC (0) NRllaRlla ', (CH2) qNR «l ± l? AC (0) R, 11a, (CH2) qNRllaC (0) NHRlla, (CH2) rC (O) 0Rllb, (CH2) q0C ( O) Rllb, (CH2) qS (0) pRllb, (CH2) qS (0) 2NRllaRlla ', (CH2) qNRllaS (O) 2Rllb, haloalkyl C? -6, a (CH2) r-carbocyclic residue C3_? Or substituted with Rllc of 0-5, and a heterocyclic 5-6 element (CH2) r-system containing 1-4 heteroatoms selected from N, O, and S, substituted with Rllc of 0-3; Rlia and Rlla ', in each case, are selected from H, C? -6 alkyl, C2_8 alkenyl, C2_8 alkynyl, a (CH2) r-C3_? 0 carbocyclic residue substituted with Rlle of 0-5, and a (CH2) 5-10 elements heterocyclic r-system containing 1-4 heteroatoms selected from N, O, and S, substituted with Rlle of 0-3; Rllb, in each case, is selected from C? -6 alkyl, C2-8 alkenyl, C2_8 alkynyl, a (CH2) r-C3-6 carbocyclic residue substituted with Rlle of 0-2, and a (CH2) r-system heterocyclic 5-6 elements containing 1-4 heteroatoms selected from N, O, and S, substituted with Rlle of 0-3; R c, in each case, is selected from C? -6 alkyl, alkenyl C2-8, C2_8 alkynyl, (CH2) r C3-6 cycloalkyl, Cl, Br I, F, (CF2) rCF3, N02 CN, (CH2) rNRllfRllf, (CH2) rOH (CH2) rO alkyl C? _, ( CH2) rS alkyl C? _4, (CH2) rC (0) OH (CHzírCÍOJR1 (CH2) rC IOJR, 11th alkyl (CH2) rC (0) 0 (0) R llb -l- CH2) NROC (CH2) rC (= NRllf) NRllfRllf, (CH2) rNCH (= NR lilifS,) M NpRlilifrpRllf (CH2) rS (0) pRllb, (CH2) rS (0) 2NRllfRllf, (CH2) rNRllfS (O) 2Rllb and (CH2) r phenyl substituted with Rlle of 0-3; Rlld, in each case, is selected from C? -6 alkyl, substituted with Rlle of 0-3, C2_6 alkenyl, C2-6 alkynyl, and a C3-? Carbocyclic residue or substituted with R lie of 0-3; R, in each case, is selected from C? -6 alkyl, C2-8 alkenyl, C2_8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) rCF3, (CH2) r0 C C5 alkyl, OH, SH, (CH2) rS C alquilo5 alkyl, (CH2) rNRllfRllf, and (CH2) rphenyl; R "llf, in each case, is selected from H, C? _6 alkyl, and C3_6 cycloalkyl; R12 is selected from H, C6_6 alkyl, (CH2) qOH, (CH2) r C3_6 cycloalkyl, and (CH2) tphenyl substituted with R12a from 0-3; R12a, in each case, is selected from C? -6 alkyl, C2_8 alkenyl, C2_8 alkynyl, C3_6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) rCF3, (CH2) rO alkyl C? _5, OH, SH, (CH2) rS C1-5 alkyl, (CH2) rNR9fT9f, and (CH2) rphenyl; alternatively, R11 and R12 join to form C3-7 cycloalkyl; R 13 in each case is selected from C ?_6 alkyl, C2_8 alkenyl, C2_8 alkynyl, C3_6 cycloalkyl, (CF2) WCF3 (CH2) NR13aR13a ', (CH2) rOH, (CH2) rOR13b, (CH2) rSH (CH2) rSR13b, (CH2) wC (0) OH, (CH2) wC (0) R 13b (CH2) wC (0) NR13aR13a '(CH2) rNR13dC (O) R13a, (CH2) WC (O) OR13b (CH2) rOC (0) R13b, CH2) WS (O) pR13b, (CH2) WS (O) 2NR13aR13a' (CH2) rNR13dS (0) 2R13b, and (CH2) w-f enyl substituted with R13c of 0-3; R13a and R13a ', in each case, are selected from H, C? _6 alkyl, C3-6 cycloalkyl, and phenyl substituted with R13c of 0-3; R 13b in each case is selected from C? -6 alkyl, C3_6 cycloalkyl, and phenyl substituted with R13c of 0-3; R13C in each case is selected from C6-alkyl, C3_6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) rCF3, alkyl (CH2) rO C6-6, (CH2) rOH, (CH2) ) rS alkyl C? _5, and (CH2) rNR13R13d; R, in each case, is selected from H, C? _6 alkyl, C3-6 cycloalkyl; R? in each case, it is selected from C? -6 alkyl, C2-8 alkenyl, C2_8 alkynyl, (CH2) r C3_6 cycloalkyl, Cl, Br I, F, N02, CN, (CHR ') rNR1 aR1 a', (CHR ') rOH (CHR ') rO (CHR') ER 14d [CHR ') rSH, (CHR') rC (0) H (CHR ') rS (CHR') rR 14d (CHR ') rC (0) OH (CHR ') EC (0) (CHR') rR 14b (CHR ') rC (0) NR1 aR14a' (CHR ') rNR ^ rC (O) (CHR') rR 14b (CHR ') rC (0) 0 (CHR') rR 14d (CHR ') rOC (0) (CHR') rR 14b (CHR ') rC (= NR14f) NR1 aR14a' (CHR ') rNHC (= NR14f) NR1 fR14f, (CHR') rS (0) p (CHR ') rR 14b (CHR ') rS (0) 2NR14aR14a', (CHR ') rNR1 fS (O) 2 (CHR') rR14b haloalkyl C? -6, alkenyl C2_8 substituted with R 'of 0-3, alkynyl C2_8 substituted with R' of 0-3, (CHR ') rphenyl substituted with R14e of 0-3, and a (CH2) r heterocyclic system of 5-10 elements containing 1-4 heteroatoms selected from N, O, and S, substituted with R15e of 0 -2, or two R14 substituted on adjacent atoms of ring A forming together a 5-6 element heterocyclic system containing 1-3 heteroatoms selected from N, 0, and S substituted with R 15e from 0-2; R ', in each case, is selected from H, C? _6 alkyl, C2-8 alkenyl, C2_8 alkynyl, (CH2) r C3_6 cycloalkyl, and (CH2) r phenyl substituted with R 14e, R14a and R14a ', in each case, are selected from H, C? _6 alkyl, C2-8 alkenyl, C2_8 alkynyl, a (CH2) r-C3_? 0 carbocyclic residue substituted with R1 e from 0-5, and a ( CH2) r heterocyclic system of 5-10 elements containing from 1-4 heteroatoms selected from N, 0, and S, substituted with R1 e from 0-2; R 14b in each case is selected from C ?6 alkyl, C2-8 alkenyl, C2_8 alkynyl, a (CH2) r-C3-8 carbocyclic residue substituted with R14e from 0-3, and a (CH2) r heterocyclic 5-6 elements containing from 1-4 heteroatoms selected from N, O and S, substituted with R14e from 0-2; R, 14d, in each case, is selected from C2-8 alkenyl, alkynyl C2-8, C? -6 alkyl substituted with R14e of 0-3, a (CH2) r-carbocyclic residue C3_? Or substituted with R14e from 0-3, and a heterocyclic 5-6 element (CH2) r-system containing from 1-4 heteroatoms selected from N, O, and S, substituted with R14e from 0-3; R, in each case, is selected from alkyl Ci-e, alkenyl C2-s, C2_8 alkynyl, (CH2) r C3_6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) rCF3, (CH2) rO alkyl C? _5, OH, SH, (CH2) rS alkyl C? _5, (CH2) rNR14fR14f, and (CH2) rphenyl; R 14f in each case is selected from H, C? -6 alkyl, C3_6 cycloalkyl, and phenyl; alternatively, R? together with R4 they form a piperidinium spirocycle or pyrrolidinium spirocycle of 5, 6 or 7 elements attached to ring A, the spirocycle substituted with Ra of 0-3; R 15 in each case, is selected from C? -6 alkyl, alkenyl C2-8, C2_8 alkynyl, (CH2) r C3_6 cycloalkyl, Cl, Br I, F, N02, CN, (CHR ') rNR15aR15a', (CHR ') r0H (CHR ') r0 (CHR') rR15, (CHR ') rSH, (CHR') rC (O) H (CHR ') rS (CHR') rR15d, (CHR ') C (O) OH (CHR ') rC (0) (CHR') rR 15b (CHR ') rC (0) NR15aR15a' (CHR ') rNR15fC (O) (CHR') rR15b, (CHR ') rC (0) 0 (CHR') rR 15d (CHR ') EOC (0) (CHR') rR 15b (CHR ') rC (= NR15f) NR15aR15a' (CHR ') rNHC (= NR15f) NR15fR15f, (CHR') rS (0) p (CHR ') rR 15b (CHR ') cS (0) 2NR15aR15a' (CHR ') rNR15fS (O) 2 (CHR') rR, 1150bD, haloalkyl C? -6, C2_8 alkenyl substituted with R 'of 0-3, alkynyl substituted with R' of 0-3, (CHR ') rphenyl substituted with R15e of 0-3, and a (CH2) r 5-10 elements heterocyclic system containing from 1-4 heteroatoms selected from N, O, and S, substituted with R15e of 0-2; R15a and R15a ', in each case, is selected from H, C? _6 alkyl, C2_8 alkenyl, C2_8 alkynyl, a (CH2) r C3_? 0 carbocyclic residue substituted with R15e of 0-5, and a (CH2) r- heterocyclic system of 5-10 elements containing from 1-4 heteroatoms selected from N, O, and S, substituted with R15e from 0-2; R15b, in each case, is selected from C? _6 alkyl, C2-alkenyl, C2_? Alkynyl, a (CH2) r C3-6 carbocyclic residue substituted with R15e of 0-3, and a (CH2) r-heterocyclic system of 5? -6 elements containing 1-4 heteroatoms selected from N, O, and S, substituted with R15e of 0-2; R, in each case, is selected from C2_8 alkenyl, alkynyl C2-8, C? -6 alkyl substituted with R15e of 0-3, a (CH2) r_ carbo3cyclic residue C3-? Or substituted with R15e of 0-3; and a (CH2) r_ heterocyclic system of 5-6 elements containing 1-4 heteroatoms selected from N, O, and S, substituted with R15e of 0-3; R 15e in each case, is selected from C? _6 alkyl, alkenyl C2_s, C2-8 alkynyl, (CH2) r C3_6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) rCF3, (CH2) rO C1-5 alkyl, OH, SH, (CH2) rS alkyl C? _5, (CH2) rNR15fR15f, and (CH2) rphenyl; R 15f in each case is selected from H, C? -6 alkyl ,. C3_6 cycloalkyl, and phenyl; R 16 in each case is selected from C ?_6 alkyl, C2_8 alkenyl, C2_8 alkynyl, (CH2) r C3_6 cycloalkyl, Cl, Br I, F, N02, CN, (CHR ') rNR16aR16a', (CHR ') rOH (CHR ') rO (CHR') rR 16d (CHR ') rSH, (CHR') rC (0) H (CHR ') rS (CHR') rR 16d (CHR ') rC (0) 0H (CHR') rC (0) (CHR ') rR 16b (CHR') rC (0) NR16aR16a ' (CHR ') rNR16fC (O) (CHR') rR16b, (CHR ') rC (O) O (CHR') rR16d (CHR ') r0C (O) (CHR') rR16b, (CHR ') rC (= NR16f ) NR16aR16a '(CHR') rNHC (= NR16f) NR16fR16f, (CHR ') rS (O) p (CHR') rR16b (CHR ') rS (0) 2NR16aR16a', (CHR ') rNR16fS (O) 2 (CHR ') rR16b haloalkyl C6-6, C2-8 alkenyl substituted with R' of 0-3, C2_8 alkynyl substituted with R 'of 0-3, and (CHR') rphenyl substituted with R16e of 0-3; R 16a and R16a ', in each case, are selected from H, C? _6 alkyl, C2_8 alkenyl, C2-8 alkynyl, a (CH2) r- C3_? Carbocyclic residue or substituted with R16e of 0-5, and a ( CH2) r_ heterocyclic system of 5-10 elements containing from 1-4 heteroatoms selected from N, O, and S, substituted with R16e from 0-2; R16b, in each case, is selected from C? _6 alkyl, C2_8 alkenyl, C2_s alkynyl, a (CH2) r- C3_6 carbocyclic residue substituted with R16e of 0-3, and a (CH2) r- 5-6 heterocyclic system elements containing 1-4 heteroatoms selected from N, O, and S, substituted with R16e of 0-2; R16d, in each case, is selected from C2_8 alkenyl, C2_8 alkynyl, C6_6 alkyl substituted with R16a from 0-3; a (CH2) r- carbocyclic residue C3_? 0 substituted with R16e of 0-3, and a (CH2) r- heterocyclic system of 5-6 elements consisting of 1-4 heteroatoms selected from N, O, and S, substituted with R16a of 0-3; R, in each case, is selected from C? _6 alkyl, C2-8 alkenyl, C2_8 alkynyl, (CH2) r C3_6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) rCF3, (CH2) rO C1-5 alkyl, OH, SH, (CH2) rS C1-5 alkyl, (CH2) rNR16fR16f, and (CH2) rphenyl; R, in each case, is selected from H, C1-6 alkyl, and C3-e cycloalkyl, and phenyl; g is selected from 0, 1, 2, 3 and 4, t is selected from 1 and 2; w is selected from 0 and 1; r is selected from 0, 1, 2, 3, 4, and 5; q is selected from 1, 2, 3, 4, and 5; Y p is selected from 0, 1, 2, and 3.
- 2. The compound according to claim 1, characterized in that: Z is selected from O and S; E is selected from: R4 is absent, taken with the nitrogen which is attached, forms an N-oxide, or is selected from C? _8 alkyl, (CH2) r C3_6 cycloalkyl, and (CH2) r-phenyl substituted with Rc of 0-3; Rc, in each case, is selected from Ci-β alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) rCF3, (CH2) rO alkyl C? _5 (CH2) rOH, (CH2) rS alkyl C? _5, (CH2) rNR4aR4a ', and (CH2) rphenyl; alternatively, R4 together with R7 or R9 or R14 form a piperidinium spirocycle of 5, 6, or 7 elements substituted with Ra of 0-3; R1 and R2 are independently selected from H, C? _4 alkyl; R6, in each case, is selected from alkyl C? _, Alkenyl C2-8, C2-8 alkynyl, (CH2) C3_6 cycloalkyl, (CF2) rCF3, CN, (CH2) rOH, (CHaRrOR *; CH2) rC (0) rOR, 6cb (CH2) rC (0) R 6b (CH2) rC (0) NR6aR6a '(CH2) rNR6dC (0) R6a # y ; CH2) t phenyl substituted with R 6c of 0-3; R6a and R6a ', in each case, is selected from H, C? -β alkyl, C3-6 cycloalkyl, and phenyl substituted with R6c of 0-3; R, in each case, is selected from C? -β alkyl, cycloalkyl C3-6 / and phenyl substituted with R 6c of 0-3; R, in each case, is selected from C? -β alkyl, C3.6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) rCF3, (CH2) r0 C? _5 alkyl, (CH2) r0H , (CH2) rS alkyl C? _5, and (CH2) rNR6dR6; R, 6d, in each case, is selected from H, C? _6 alkyl, and C3-6 cycloalkyl, * R7 is selected from H, C3_3 alkyl, (CH2) r C3_6 cycloalkyl, (CH2) q0H, (CH2) qOR 7d (CH2¡3NR7aR7a '(CH2) rC (0) R7, JCH2) rC (0) NR7aR7a ', (CH2) qNR7aC (0) R7a, haloalkyl Ci- 6 / (CH2) r phenyl with R 7, cc 0-2; R and R, in each case, is selected from H, C? -6 alkyl, (CH2) r C3_6 cycloalkyl, a (CH2) rphenyl substituted with R7e of 0-3, R, in each case, is selected from Ci-β alkyl, C 2-8 alkenyl, C 2-8 alkynyl, (CH 2) r C 3-6 cycloalkyl, (CH2) r-phenyl substituted with R7e of 0-3; R 7c in each case is selected from C? -4 alquiloalkyl, C2-8 al alkenyl, C2_8 alkynyl, (C22) r C3_6 cycloalkyl, Cl, Br, I, F, (CF2) rCF3, N02, CN, (CH2) rNR7fR7f, (CH2) rOH, (CH2) rO C? -4 alkyl, (CH2) rC (O) R7b, (CH2) rC (O) NR7fR7f, (CH2) rNR7fC (0) R7a, (CH2) rS (0) pR 7'bA (CH2) rS (0) 2NR7fRf, (CH2) rNR'rS (0) 2RD, and (H2) r-phenyl substituted with R e 0-2; R 7d in each case is selected from alkyl C? -6, (CH2) r C3-6 cycloalkyl, (CH2) rphenyl substituted with R7e of 0-3; R e, in each case, is selected from alkyl C? -6, alkenyl C2_4, C2-S alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) rCF3, (CH2) r0 C? _5 alkyl, OH, SH, (CH2) rS C1-5 alkyl, (CH2) rNR 7, f3: pR7f, and (CH2) rphenyl; R, in each case, is selected from H, C1-5 alkyl, C3_6 cycloalkyl; R8 is H or together with R7 form C3_7 cycloalkyl or = NR8b; R11 is selected from H, C? -6 alkyl, (CH2) r C3-6 cycloalkyl, (CH2) q0H, (CH2) qORlld, (CH2) qNRllaRlla ', (CH2) rC (O) Rll, (CH2) rC (0) NRllaRlla ', (CH2) qNRllaC (0) Rlla, C1-6 haloalkyl, (CH2) rphenyl with Rllc of 0-2, a (CH2) r 5-10 element heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with R15 of 0-3; R a and R, in each case, is selected from H, C 1-6 alkyl, (CH 2) r C 3-6 cycloalkyl, a (CH 2) rhenyl substituted with Rlle of 0-3; R, 11b, in each case, is selected from C? _6 alkyl, C2_8 alkenyl, C2_8 alkynyl, (CH2) r C3_6 cycloalkyl, (CH2) rphenyl substituted with Rlle of 0-3; R lie in each case, is selected from C? -4 alkyl, C2_8 alkenyl, C2_8 alkynyl, (CH2) r C3-6 cycloalkyl, Cl, Br, I, F, (CF2) rCF3, N02, CN, (CH2) rNRllfRllf, (CH2) rOH, (CH2) r0 alkyl C? _, (CH2) rC (O) Rllb, (CH2) rC (O) NRllfRllf, (CH2) rNRllfC (0) Rlla, (CH2) rS (0) pR, 11b (CH2) rS (0) 2NRllfRllf, (CH2) rNRllfS (0) 2Rllb, and (CH2) rphenyl substituted with R1 of 0-2; Rlid in each case is selected from alkyl C? _6, (CH2) C3_6 cycloalkyl «(CH2) rphenyl substituted with R, l, 0-3; Rlle, in each case, is selected from C alquilo_alkyl, C 2-6 alkenyl, C2-alkynyl, C3_6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) rCF3, (CH2) rO alkyl C? _5 , OH, SH, (CH2) rS alkyl C? _5, (CH2) rNRllfRllf, and (CH2) rphenyl; R,? If, in each case, is selected from H, C? _5 alkyl, and C3_6 cycloalkyl, " R "12 is H or together with R form C_7 cycloalkyl; R "13, in each case, is selected from C? _4 alkyl, C3-6 cycloalkyl, (CH2) NR13aR13a ', (CH2) 0H, (CH2) OR13b, (CH2) WC (O) R13b, (CH2) wC (0) NR13aR13a '(CH2) NRljaC (0) R, 13a (CH2) wS (0) 2NR13aR13a, (CH2) NR13aS (0) 2R, 1i3JbD, and (CH2) w-f enyl substituted with R 13c of 0-3; R13a and R13a ', in each case, is selected from H, C? -6 alkyl, C3_6 cycloalkyl, and phenyl substituted with R13c of 0-3; R 13b in each case is selected from C ?_6 alkyl, C3_e cycloalkyl, and phenyl substituted with R13c from 0-3; Rl3c in each case is selected from C? -6 alkyl, C3_6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) rCF3, (CH2) rO alkyl d-5, (CH2) r0H, and ( CH2) rNR13 R13d; R13d, in each case, is selected from C? _6 alkyl, and C3_e cycloalkyl; q is selected from 1, 2 and 3; Y r is selected from 0, 1, 2 and 3. The compound according to claim 2, characterized in that: Ring A is selected from: RJ is selected from a (CR H) carbocyclic residue substituted with R15 of 0-5, wherein the carbocyclic residue is selected from phenyl, C3-6 cycloalkyl, naphthyl, and adamantyl; and a system (CR3?) r- heterocyclic system substituted with R15 of 0-3, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl , imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; Y R5 is selected from (CR5?) T-phenyl substituted with R16 of 0-5; and a (CR5?) t-substituted heterocyclic system with R 16 of 0-3, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl , piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,4-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl. 4. The compound according to claim 3, characterized in that - the compound of Formula (I-i) is: R, in each case, is selected from C? _8 alkyl, (CH2) r C3_6 cycloalkyl, CF3, Cl, Br, I, F, (CH2) rNR16aR16a ', N02, CN, OH, (CH2) rOR16d, (CH2) rC (0) R16b, (CH2) r (C) NR16aR16a ', (CH2) rNR16fC (O) R16, (CH2) rS (0) pR 16b (CH2) rS (0) 2NR16aR16a'f (CH2) rNR16fS (0) 2R16b, and (CH2) rf enyl substituted with R16e of 0-3; R and R, in each case, are selected from H, Cx-6 alkyl, C3_6 cycloalkyl, and (CH2) rphenyl substituted with R16e from 0-3; R 16b in each case is selected from H, C? -6 alkyl, C3-6 cycloalkyl, and (CH2) rphenyl substituted with R 16e of 0-3; R, 16d, in each case, is selected from C? _6 alkyl and phenyl; R, 16e, in each case, is selected from alkyl C? _6, Cl, F, Br, I, CN, N02, (CF2) rCF3, OH, and (CH2) r0 C? -5 alkyl; Y R16f, in each case, is selected from H, and alkyl C? _5. 5. The compound according to claim 3, characterized in that the compound of Formula (I) is: R16, in each case, is selected from alkyl Ci-β, cycloalkyl (CH2) r C3-6, CF3, Cl, Br, I, F, (CH2) rNR16aR16a ', N02, CN, OH, (CH2) rOR16d, (CH2) rC (0) R16b, (CH2) rC (O) NR16aR16a ', (CH2) rNR16fC (0) R16b, (CHZASÍOAR, 116b (CH2) rS (0) 2NRl 1o6aaRn16a ' (CH2) rNR16fS (0) 2R16b, and (CH2) rf enyl substituted with R 16e of 0-3; R and R, in each case, is selected from H, C? _6 alkyl, C3_6 cycloalkyl, and (CH2) rphenyl substituted with R 16e of 0-3; R 16b in each case is selected from H, C 1-6 alkyl, C3-β cycloalkyl, and (CH 2) rphenyl substituted with R 16e of 0-3; R, 16d, in each case, is selected from alkyl Ci-e and phenyl; R, 16e, in each case, is selected from C1-6 alkyl, Cl, F, Br, I, CN, N02, (CF2) rCF3, OH, and (CH2) r0 C5 alkyl; Y R, in each case, is selected from H, and C1-5 alkyl. 6. The compound according to claim 4, characterized in that: R is CH2phenyl substituted with R 1i6b of 0-3; R9 is selected from H, C? _ Alkyl, (CH 2) r C3_6 cycloalkyl, F, Cl, CN, (CH 2) rOH, (CH 2) rOR 9d, (CH 2) rNR 9 aR 9a ', (CH 2) rOC (0) NHR 9a, (CH2) rPhenyl substituted with R9e of 0-5, and a heterocyclic system substituted with R9e of 0-2, wherein the heterocyclic system is selected from pyridyl, thiophenyl, furanyl, oxazolyl, and thiazolyl; R9a and R9 ', in each case, are selected from H, C? _6 alkyl, C3_e cycloalkyl, and (CH2) rphenyl substituted with R9e of 0-3; R "9d, in each case, is selected from C? -6 alkyl and phenyl; R '9e, in each case, is selected from C 1-6 alkyl, Cl, F, Br, I, CN, N02, (CF2) rCF3, OH, and (CH2) rO alkyl C? _5; R "10 is selected from H, C1-5 alkyl, OH, and CH20H; alternatively, R9 and R10 together form C3_7 cycloalkyl, cyclic ketal of 5-6 elements or = 0; with the proviso that when R10 is halogen, cyano, nitro, or is bound to the carbon to which it is attached through a heteroatom, R9 is not halogen, cyano, or is bonded to the carbon which its bonds through a heteroatom; R 11 is selected from H, C? _8 alkyl, (CH2) rphenyl substituted with Rlle of 0-5, and a (CH2) r- substituted heterocyclic system with Rlle of 0-2; wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, isoindolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; Y R, in each case, is selected from alkyl C? -6, Cl, F, Br, I, CN, N02, (CF2) rCF3, OH, and (CH2) r0 C? _5 alkyl; R1 is H; alternatively, R and R "12 together form C3-7 cycloalkyl; R 14 in each case is selected from alkyl C? _8, (CH2) C3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2) rNR14aR1 a ', N02, CN, OH, (CH2) r0R14d, (CH2) rC (0) R14b, (CH2) rC (0) NR14aR1 a ', (CH2) rNR1 fC (0) R1 b, (CH2) rS (0) pR14, (CH2) rNR14fS (0) 2R1 b, (CH2) rf enyl substituted with R1 e of 0-3; and a (CH2) r- 5-10 element heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with R15e of 0-2; and two R14 substituents on adjacent atoms on a ring A to together form a 5-6 element heterocyclic system containing 1-3 heteroatoms selected from N, O, and S with R15e of 0-2; R14a and R14a ', in each case, are selected from H, C? _6 alkyl, C3_6 cycloalkyl, and (CH2) rphenyl substituted with R14e from 0-3; and a (CH2) r- heterocyclic system of 5-6 elements containing 1-4 heteroatoms selected from N, O, and S, substituted with R15e of 0-2; R, in each case, is selected from H, alkyl C? _6, C3-β cycloalkyl, and (CH2) r-phenyl substituted with R14e of 0-3; R, in each case, is selected from C? -6 alkyl and phenyl; R "14e, in each case, is selected from alkyl C? _6, Cl, F, Br, I, CN, N02, (CF2) rCF3, OH, and (CH2) rO alkyl d-5, and R14f, in each case, is selected from H, and C1-5 alkyl; Y r is selected from 0, 1, and 2. The compound according to claim 5, characterized in that: R is CH 2 phenyl substituted with R 1ib 6 of 0-3; R is selected from H, C? -6 alkyl, (CH2) r C3-6 cycloalkyl, F, Cl, CN, (CH2) r0H, (CH2) r0R9d, (CH2) rNR9aR9a ', (CH2) rOC (0) NHR, 9a, (CH2) rphenyl substituted with R 93ee of 0-5, and a heterocyclic system substituted with R9e of 0-2, wherein the heterocyclic system is selected from pyridyl, thiophenyl, furanyl, oxazolyl, and thiazolyl; R a and R y, in each case, are selected from H, C 1-6 alkyl, C3-6 cycloalkyl, and (CH2) rphenyl substituted with R: 9e of 0-3; R, in each case, is selected from C? _6 alkyl and phenyl; R, in each case, is selected from alkyl C? -6, Cl, F, Br, I, CN, N02, (CF2) rCF3, OH, and alkyl (CH2) rO C? _5; R10 is selected from H, C? _8 alkyl, OH, and CH2OH; alternatively, R9 and R19 together form C3_7 cycloalkyl, cyclic ketal of 5-6 elements or = 0; with the proviso that when R10 is halogen, cyano, nitro, or linked to the carbon to which it is attached through a heteroatom, R9 is not halogen, cyano, or linked to the carbon to which it is attached through a heteroatom; R is selected from H, C? _8 alkyl, (CH2) rhenyl substituted with Rlie of 0-5, and a (CH2) r- substituted heterocyclic system with Rlle of 0-2; wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolyl, isoquinolinyl, imidazolyl, indolyl, isoindolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; Y R, in each case, is selected from alkyl C? -6, Cl, F, Br, I, CN, N02, (CF2) rCF3, OH, and alkyl (CH2) rO d_5; R ^ is H; alternatively, R and R > Together they form C3_7 cycloalkyl; R 14 in each case is selected from Ci-s alkyl, (CH2) r C3_6 cycloalkyl, CF3, Cl, Br, I, F, (CH2) rNR14aR14a ', N02, CN, OH, (CH2) rOR14d, (CH-pJrCÍOJR «114b (CH2) rC (0) NR1 aR1 a '(CH2) rNR14fS (0) 2R14b, (CH2) rphenyl substituted with R14e of 0-3, and a (CH2) r- heterocyclic system of 5-6 elements containing from 1 -4 heteroatoms selected from N, O, and S, substituted with R15e of 0-2; or two R14 substituents on adjacent ring A atoms together form a heterocyclic system of 5-6 elements containing 1-3 heteroatoms selected from N, O, and S substituted with R15e of 0-2; R14a and R14a ', in each case, is selected from H, C? _6 alkyl, C3_6 cycloalkyl, and (CH2) rphenyl substituted with R14e from 0-3; R, in each case, is selected from H, C? -6 alkyl, C3_6 cycloalkyl, and (CH2) rphenyl substituted with R 14e of 0-3; R, in each case, is selected from C? _6 alkyl and phenyl; R, in each case, is selected from alkyl C? -6, Cl, F, Br, I, CN, N02, (CF2) rCF3, OH, and alkyl (CH2) rO C? _5; R, in each case, is selected from H, and alkyl C? _5; Y r is selected from 0, 1 and 2. 8. The compound according to claim 6, characterized in that: J is selected from CH2 and CHR5; K is selected from CH2 and CHR; R is a C3_? 0 carbocyclic residue substituted with R of 0-3, wherein the carbocyclic residue is selected from cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl and adamantyl, and a (CR3?) r- heterocyclic system substituted with R15 of 0-3, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3- triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; Y R 15 in each case is selected from alkyl C? _8, (CH2) r- C3_6 cycloalkyl, CF3, Cl, Br, I, F, (CH2) rNR15aR15a ', N02, CN, OH, (CH2) rOR15, (CH2 rC (0) R15b, (CH2) rC (0 NR15aR15a '(CH2) rNR15fC (0) R1 b, (CH2) rS (0) pR 15b (CH2) rS (0) 2NR, 1l5oaarR-) 1x5oaa'A (CH2) rNR13rS (0) 2RI3D, (CH2) rphenyl substituted with R15e of 0-3, and a (CH2) r-heterocyclic system of 5-6 elements containing 1-4 heteroatoms selected from N, 0, and S, substituted with R15e of 0-2; R a and R a, in each case, is selected from H, alkyl C? _6, C3_6 cycloalkyl, and (CH2) rphenyl substituted with R 15e of 0-3; R 15b in each case is selected from H, C? -6 alkyl, C3_6 cycloalkyl, and (CH2) rphenyl substituted with R15e of 0-3; R, in each case, is selected from C? _6 alkyl and phenyl; R, in each case, is selected from alkyl C? _6, Cl, F, Br, I, CN, N02, (CF2) rCF3, OH, and (CH2) rO alkyl d-5; Y R15f, in each case, is selected from H, and alkyl C? _5. 9. The compound according to claim 7, characterized in that: K is selected from CH2 and CHR5; R is a C3_? Carbocyclic residue, substituted with R of 0-3, wherein the carbocyclic residue is selected from cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl and adamantyl, and a (CR3?) R-heterocyclic system substituted with R15 from 0-3, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, triadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; Y R 15 in each case is selected from alkyl C? -8, (CH2) r- C3_6 cycloalkyl, CF3, Cl, Br, I, F, (CH2) rNR15aR15a ', N02, CN, OH, (CH2) rOR15d, (CH2) rC (0) R15b, (CH2) rC (0) NR15aR15a ', (CH2) rNR15fC (0) R15b, (CH2) rS (0) pR15b, (CH2) rS (0) 2NR15aR15a', (CH2) rNR15fS (0) 2R15b, and (CH2) ) R-phenyl substituted with R15e of 0-3; and a (CH2) r- 5-6 element heterocyclic system containing from 1-4 heteroatoms selected from N, O, and S, substituted with R15e from 0-2; R 15a R, in each case, are selected from C 1-6 alkyl, C 3-6 cycloalkyl, and (CH 2) rphenyl substituted with R 15e of 0-3; R15b, in each case, is selected from H, C? -6 alkyl, C3_6 cycloalkyl, and (CH2) rphenyl substituted with R15e of 0-3; R, in each case, is selected from C? -6 alkyl and phenyl; R, in each case, is selected from alkyl C? _6, Cl, F, Br, I, CN, N02, (CF2) rCF3, OH, and (CH2) rO alkyl d_5; Y R15f, in each case, is selected from H, C1-5 alkyl. The compound according to claim 1 and pharmaceutically acceptable salt forms thereof, characterized in that the compound of Formula (I) is selected from: N- (3-methoxyphenyl) -N '- [trans-2- [[(3R, S) -3- (phenyl) -methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3-cyanophenyl) -N '- [trans-2- [[(3R, S) -3- (phenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3-acetylphenyl) -N '- [trans-2- [[(3R, S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3-acetylphenyl) -N '- [trans-2- [[(3R, s) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3-cyanophenyl) -N '- [trans-2- [[(3R, S) -3- (4- fluorophenyl) methyl) piperidinyl] methyl] ciciohexyl] -urea, N- (3-methoxyphenyl) -N '- [trans-2- [[(3R, S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3-nitriphenyl) -N '- [trans-2- [[(3R, S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3-acetylphenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3-acetylphenyl) -N '- [(1 R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3-acetylphenyl) -N '- [(1 R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3-acetylphenyl) -N '- [(1R, 2S) -2- [[(3R) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3-acetylphenyl) -N '- [(1R, 2S) -2- [[(3R) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3-acetylphenyl) -N '- [(1R, 2R) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3-cyanophenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3-cyanophenyl) -N '- [(1R, 2S) -2- [[(3R) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3-methoxyphenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3-methoxyphenyl) -N '- [(1R, 2S) -2- [[(3R) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (4-fluorophenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (4-fluorophenyl) -N '- [(IR, 2S) -2- [[(3R) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (phenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- ((1H) -indazol-5-yl) -N '- [(1R, 2S) -2- [[3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- ((1H) -indazol-6-yl) -N '- [(1R, 2S) -2- [[(3S) -3- (4- fluorophenyl) methyl) piperidinyl] methyl] ciciohexyl] -urea, N- (benzthiazol-6-yl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- ((1H) -indol-5-yl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- ((1H) -indol-6-yl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- ((1H) -2, 3-dimethylindol-5-yl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl ] -urea, N- (benzimidazol-5-yl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (indolin-5-yl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidnyl] methyl] cyclohexyl] -urea, N- (3-cyano-4-fluorophenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3-acetyl-4-fluorophenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4- fluorophenyl) methyl) piperidinyljmethyl] ciciohexyl] -urea, N- (3, 5-diacetylphenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) ethyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3- (1-hydroxyethyl) phenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (4-methyl-thiazol-2-yl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (4-methyl-5-acetyl-thiazol-2-yl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl ] -urea, N- (1, 3,4-thiadiazol-2-yl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] - urea, N- (4-chloro-benzimidazol-2-yl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (thiazol-2-yl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (5-Methyl-isoxazol-3-yl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (1-methyl-pyrazol-3-yl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (4- (1, 2,4-triazol-1-yl) phenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] ciciohexyl] -urea, N- (4- (1, 2,4-triazol-1-yl) phenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] ciciohexyl] -urea, N- ((1H) -3-chloro-indazol-5-yl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl ] -urea, N- (4-fluorophenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (4-chlorophenyl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (4-bromophenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3-bromophenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3-fluorophenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4- fluorophenyl) methyl) piperidinyl] methyl] ciciohexyl] -urea, N- (3,4-difluorophenyl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3-chloro-4-fluorophenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3,5-dichlorophenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- ((1H) -5-amino-indazol-1-yl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl ] -urea, N- (3-chlorophenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3-fluoro-4-methylphenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3-cyano-4- (l-pyrazolyl) phenyl) -N '- [(1 R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] - urea, N- (2-methylphenyl) -N '- [(1R2S) -2- [[(3S) -3- (4- fluorophenyl) methyl) piperidinyl] methyl] ciciohexyl] -urea, N- (2-methylphenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (2,4-dimethylphenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (2,4-dimethoxyphenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (2, 5-dimethoxyphenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (2-methoxy-5-methylphenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (2-methyl-5-fluorophenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3,5-bis (l-methyltetrazol-5-yl) phenyl) -N '- [(1 R, 2 S) -2 - [[(3 S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl ] ciciohexyl] - urea, N- (3- (1-metltetrazol-5-yl) phenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4- fluorophenyl) methyl) piperidinyl] methyl] ciciohexyl] -urea, N- (4-carboethoxymethyl) thiazol-2-yl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (5-bromothiazol-2-yl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (4,5-di (4-fluorophenyl) thiazol-2-yl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl ] ciciohexyl] - urea, N- (2-fluorophenyl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (2-chlorophenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (indanon-6-yl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (indanon-4-yl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (4- (isopropyl) phenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4- fluorophenyl) methyl) piperidinyl] methyl] ciciohexyl] -urea, N- (3-nitro-4-methylphenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (trans-2-phenylcycloprop-1-yl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (2,4-difluorophenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (2,5-difluorophenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methylpiperidinyl] methyl] cyclohexyl] -urea, N- (2,4-dichlorophenyl) -N '- [(LR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (2,5-dichlorophenyl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (2-methoxyphenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (2,4-dimethoxyphenyl) -N '- [(1R, 2) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (2,5-dimethoxyphenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (2-trifluoromethylphenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methylcyclohexyl] -urea, N- (2-methylphenyl) -N '- [(1R2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3-trifluoromethylphenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3-methylphenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (4-methoxyphenyl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (4-ethoxycarbonylphenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (4-trifluoromethylphenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (4-methylphenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4- 5 fluorophenyl) methyl) piperidinyl] methyl] ciciohexyl] -urea, N- (2-fluorophenyl) -N '- [(1R, 2S) -2 - [[(3S) - (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (2-chlorophenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidnyl] methyl] cyclohexyl] -urea, N- (2-nitrophenyl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (2,4-dichloro-nyl) -N '- [(1 R, 2S) -2 - [[(3 S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3-nitrophenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3, 5-ditrifluoromethylphenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (2,4-dimethylphenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (2,4-dimethoxy-5-chlorophenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3,4,5-trimethoxyphenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3,5-dimethylphenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3-trifluoromethyl-4-chlorophenyl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (4-phenoxyphenyl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (4-ethoxyphenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (4-thiomethylphenyl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (2-naphthyl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (4-acetyphenyl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (2,6-dichloropyridin-4-yl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (5-indan-4-yl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (4-chloronaphth-1-yl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3-fluoro-4-methoxyphenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (4- (methylsulfonyl) phenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3- (methylsulfonyl) phenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- [2- ((1 H) -pyrrol-1-yl) phenyl] -N '- [(1 R, 2 S) -2 - [[(3 S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (1, 3-benzodioxol-5-ll) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (1-acetylindolin-6-yl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4- fluorophenyl) methyl) piperidinyl] methyl] ciciohexyl] -urea, N- (4- (6-methylbenzothiazol-2-yl) phenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] ethyl] cyclohexyl] - urea, N- (4- ((2,2-dimethylpropanoyl) amino) phenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl ] -urea, N- (4- (l-methyltetrazol-5-yl) phenyl) -N '- [(1R2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea , N- (4- (1-morpholino) phenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (quinolin-8-yl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3-hydroxyphenyl) -N '- [(IR, 2S) -2 - [[(3R) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea trifluoroacetate. N- (4- (acetylamino) phenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (4-hydroxyphenyl) -N '- [(1R, 2S) -2- [[(3R) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3-hydroxy-4-methoxyphenyl) -N '- [(1R, 2S) -2 - [[(3R) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3- (cetylamino) phenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (4-fluoro-3-methylphenyl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl) methyl] cyclohexyl] -urea, N- (3-methoxy-4-methylphenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (4-chloro-3-methylphenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (4- (N-methylcarboxamide) phenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (1-adamantyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (quinolin-5-yl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (quinolin-6-yl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (1, 4-benzodioxan-6-yl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (isoquinolin-5-yl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (4- (sulfonamide) phenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (benzotriazol-5-yl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (2-hydroxy-4-methylphenyl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3-hydroxy-4-methylphenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (2-methyl-benzothiazol-5-yl) -N '- [(1R, 2S) -2- [[(3S) -3- (4- fluorophenyl) methyl) piperidinyl] methyl] ciciohexyl] -urea, N- ((4-methoxyphenyl) methyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- ((4-fluorophenyl) methyl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- ((4-methylphenyl) methyl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- [(IR) -l- (phenyl) ethyl] -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea , N- (1-acetylindolin-5-yl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (5,6,7,8-tetrahydronaphth-1-yl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl ] -urea, N- (3-acetyl-4-hydroxyphenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (4- (piperidin-1-yl) phenyl-N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (cyclohexyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (2-methoxyphenyl) -N '- [(IR, 2S) -2- [[(3S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] - urea, N- (2,6-dimethylphenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (2-ethylphenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (2,4,6-trimethylphenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (2,5-dimethoxyphenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (t-butyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (i-propyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (ethoxycarbonylmethyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4- 5 fluorophenyl) methyl) piperidinyl] methyl] ciciohexyl] -urea, N- (2-trifluoromethoxyphenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- [(IR, S) -1- (methoxycarbonyl) -2-methyl-propyl] -N '- [(IR, 2S) -2- [[(3S) - (4-fluorophenyl) methyl) piperidinyl] methyl ] ciciohexyl] -urea, N- [(1S) -1- (methoxycarbonyl) -2-phenylethyl] -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl ] -urea, N- [2,4,4-trimethyl-2-pentyl] -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] - urea, N- [2-phenylethyl] -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3-acetylphenyl) -N '- [(1 R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N (2-carbomethoxyphenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- [(1S) -l- (phenyl) ethyl] -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea , N (4-phenyl) phenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N (1-naphthyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N (2- (phenyl) phenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N (phenylmethoxy) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N (3,4-dimethoxyphenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N ((3 H) -2-ethylquinazolin-4-on-3-yl) -N '- [(1 R, 2 S) -2 - [[(3 S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] - urea, N- (3-pyridinyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (6-methoxy-3-pyridinyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (2-methylquinolin-8-yl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (2-methylnaphthyl-1-yl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N (4- ((1H) -l-propyl-tetrazol-5-yl) phenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl ] methyl] ciciohexyl] -urea, N (3-aminophenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3- (acetylamino) phenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N (3- (N-methylcarboxamide) phenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N (2-nitro-4-methoxyphenyl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, 5 N- (8-hydroxyquinolin-5-yl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3-methylpyridin-2-yl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (isoquinolin-1-yl) -N '- [(1R, 2S) -2 - [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3-acetylphenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclopentyl] -urea, N- (3-acetylphenyl) -N '- [(1R, 2S) -2- [[(3R) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclopentyl] -urea, N- (3-acetylphenyl) -N '- [(1R2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclopentyl] -urea, N- (3-cyanophenyl) -N '- [(1R, 2S) -2 - [[(3 S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclopentyl] urea. N- (3-cyanophenyl) -N '- [(1R, 2S) -2- [[(3R) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclopentyl] urea, N- (3-cyanophenyl) -N '- [(1R, 2S) -2- [[(3R) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclopentyl] urea, N- (3-cyanophenyl) -N '- [(IR, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclopentyl] urea, N- (phenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclopentyl] urea, N- (phenyl) -N '- [(1R, 2S) -2 - [[(3R) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclopentyl] urea, and N- (phenyl) -N '- [(1R, 2S) -2- [[(3S) -3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclopentyl] -urea. 11. A compound characterized in that it has the Formula (I) (I) or stereoisomers or pharmaceutically acceptable salts thereof, wherein: M is absent or selected from CH2, CHR5, CHR13, CR13R13, and CR5R13; Q is selected from CH2, CHRA CHR ", CR13R, and CR ° Ri-1, J and L are selected from CH2, CHR3, CHR6, CR «6b-Rr, 6 ° and CR > 53tR- > 6, K is CHR - with the proviso that: when M is absent, J is selected from CH2, CHR5, CHR13, and CR5R13; Z is selected from 0 and S; E is ring A is a C3_6 carbocyclic residue, with the proviso that the C3_6 carbocyclic residue is not phenyl; R1 and R2 are independently selected from H, C6-6alkyl, C2-8alkenyl, C2-8alkynyl, (CH2) r C3-6 cycloalkyl, and a (CH2) r- C3-? Carbocyclic residue or substituted with Ra 0-5; Ra, in each case, is selected from C ?6 alkyl, C2_8 alkenyl, C2-8 alkynyl, (CH2) r C3_6 cycloalkyl, Cl, Br, I, F, (CF2) rCF3, N02, CN, (CH2) rNRbDtR-, bD, (CH2) r0H, (CH2) r0RA (CH2) rSH, (CH2) rSRc (CH2) rC (0) Rb, (CH2) rC (0) NRbRb, (CH2) rNRbC (0) Rb, (CH2) rC (0) ORb, (CH2) r0C (0) Rc, NRDRD, (CH2) rS (0) pRc,; CH2) rS (0) 2NRbRb, (CH2) rNRbS (0) 2RA (CH2) r-phenyl; Rb, in each case, is selected from H, C?-C 6 alkylcycloalkyl, and phenyl; Rc, in each case, is selected from C? -6 alkyl, cycloalkyl C3-6 / and phenyl; alternatively, R2 and R3 together form a ring of 5, 6, or 7 elements substituted with Ra of 0-3; R3 is selected from a C3_? (CR3'R3") r-carbocyclic residue or substituted with R15 of 0-5 and a heterocyclic system (CR3'R3") r of 5-10 elements containing 1-4 heteroatoms selected from N , O, and S, substituted with R15 of 0-3; R3 'and R3", in each case, is selected from H, C1-6 alkyl, (CH2) r C3_6 cycloalkyl, and phenyl; R4 is absent, together with the nitrogen which binds form an N-oxide, or is selected from alkyl d-6, C2_8 alkenyl, C2_8 alkynyl, (CH2) r C3_g cycloalkyl, (CH2) qC (0) R4b, (CH2) qC (0) NR4aRa ', (CH2) qC (O) OR4b, and a (CH2) r- C3-10 carbocyclic residue substituted with R4c of 0-3; Ra and R 4a ', in each case, is selected from H, C ?_6 alkyl, (CH 2) r C 3-6 cycloalkyl, and phenyl; Rb, in each case, is selected from C? -6 alkyl, C2-8 alkenyl, (CH2) r C3_6 cycloalkyl, C2_8 alkynyl, and phenyl; R 4c in each case is selected from C 1 -C 6 alkyl, C 2 8 alkenyl, C 2 8 alkynyl, C 3 6 cycloalkyl, Cl, F, Br, I, CN, N 0 2, (CF 2) rCF 3, (CH 2) r 0 C 5 alkyl, (CH2) r0H, (CH2) rS alkyl C? _5, (CH2) rNR4aRa ', and (CH2) rphenyl; alternatively, R4 together with R7, R9, R11 or R14 form 5-, 6- or 7-membered piperidinium spirocycle or pyrrolidinium spirocycle substituted with Ra of 0-3; R is selected from a (CR R5") t-carbocyclic residue C3_? 0 substituted with R16 of 0-5 and a (CR5'R5") t- heterocyclic system of 5-10 elements containing 1-4 heteroatoms selected from N , O, and S, substituted with R16 of 0-3; R5 and R5", in each case, are selected from H, C? _6 alkyl, (CH2) r C3_6 cycloalkyl, and phenyl; R6, in each case, is selected from C? _e alkyl, C2_8 alkenyl, C2_8 alkynyl, (CH2) r C3_6 cycloalkyl, (CF) rCF3, CN, (CH2) rNR6aR6a ', (CH2) rOH, (CH2) rOR6b, (CH2) rSH, (CHzJrSR613, (CH2) rC (0) OH, (CH2) rC (0) R 6cb (CH2) rC (0) NR 6 ° aatRN6a '[CH2) rNR 6DdUCr (0 R6a, (CH2) rC (0) OR 6DbU, (CH2) rOC (0) R 6βb (CH2) rS (0) pR 6cb (CH2) cS (0) 2NR6aR6a ' (CH2) rNR5dS (0) 2R6b, and (CH2) tphenyl substituted with R ° of 0-3; R6a and R6a ', in each case are selected from H, C? _6 alkyl, C3_? Cycloalkyl, and phenyl substituted with R6c from 0-3; R, 6b, in each case, is selected from Ci-β alkyl, cycloalkyl C3-6? and phenyl substituted with R 6c of 0-3; R6c, in each case, is selected from C? -6 alkyl, cycloalkyl C3_6, Cl, F, Br, I, CN, N02, (CF2) rCF3, alkyl (CH2) r0C? _5, (CH2) r0H, (CH2) rS C1-5 alkyl, and (CH2) rNR6R6d; R, 6d, in each case, is selected from H, C? -6 alkyl, C3_6 cycloalkyl; 54 with the proviso that when either of J or L is CR6R6 and R6 is halogen, cyano, nitro, or is bonded to the carbon to which they are attached through a heteroatom, the other R6 is not halogen, cyano, or is bonded to carbon to which they unite through a heteroatom; R7 is selected from H, C? _6 alkyl, C2-8 alkenyl, alkynyl C2-8, (CH2) qOH, (CH2) qSH, (CH2) qOR «7'd (CH2) qSR 7'dA (CH2) qNR7aR7a ', (CH2) rC (0) OH, (CH2) rC (0) R «7'bA (CH2) rC (0) NR 7'aaDR7a '(CH2) qNR7aC (O) R7a, (CH2) qNR7aC (O) H, (CH2) rC (0) OR '(CH2) qOC (0) R 7'b (CH2) qS (0) pR 7'b (CH2) qS (0) 2NRaRa, (CH2) qNRaS (0) 2R, haloalkyl C? _6, a (CH2) r-carbocyclic residue C3-? Or substituted with R7c of 0-3, and a (CH2) r- 5-10 element heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with R7c of 0-2; R7a and R7a ', in each case is selected from H, C? _6 alkyl, C2-s alkenyl, C2_8 alkynyl, (CH2) r C3_6 cycloalkyl, a (CH2) r- C3-? Carbocyclic residue or substituted with R7e of 0-5; and a (CH2) r- heterocyclic system of 5-10 elements containing from 1-4 heteroatoms selected from N, O, and S, substituted with R7e of 0-3; 5 R, in each case, is selected from C? _ß alkyl, C2_8 alkenyl, C2_8 alkynyl, a (CH2) r-C3_6 carbocyclic residue substituted with R7e of 0-2, and a (CH2) r 5-6 heterocyclic system elements containing 1-4 heteroatoms selected from N, O, and S, substituted with R7e of 0-3; R7c, in each case, is selected from Ci-e alkyl, C2_8 alkenyl, C2_8 alkynyl, (CH2) r C3_6 cycloalkyl, Cl, Br, I, F, (CF2) rCF3, N02, CN, (CH2) rNR7fR7f, ( CH2) rOH, (CH2) rO C4-4 alkyl, (CH2) rS C1-4 alkyl, (CH2) rC (O) OH, (CH2) rC (0) R7b, (CH2) rC (0) NR7fR7f, (CH2) rNR7fC (O) R7a, alkyl (CH2) rC (O) OC? _4, (CH2) rOC (O) R7b, (CH2) rC (= NR7f) NR7fR7f, (CH2) rS (O) pR7b, (CH2) rNCH (= NR7f) NR7fR7f, (CH2) rS (O) 2NR7fR7f, (CH2) rNR7fS (0) 2R7b, and (CH2) rphenyl substituted with R7e of 0-3; R7d, in each case, is selected from C? _6 alkyl substituted with R7e of 0-3, alkenyl, alkynyl, and a C3_? 0 carbocyclic residue substituted with R7c 0-3; R e, in each case, is selected from C 1-6 alkyl, alkenyl C2_8, C2_8 alkynyl, C3_6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) rCF3, (CH2) rO C1-5 alkyl, OH, SH, (CH2) rS alkyl C? _5, (CH2) rNR 7frRr > 7f, and (CH2) r-phenyl; R7f, in each case, is selected from H, alkyl d-6, and C3-6 cycloalkyl, R8 is selected from H, C? _6 alkyl, C3-6 cycloalkyl, and (CH2) tphenyl substituted with R8a of 0-3; R 8a in each case is selected from C 1 -C 6 alkyl, C 2 al alkenyl, C 2 8 alkynyl, C 3 -C 6 cycloalkyl, Cl, F, Br, I, CN, NO 2, (CF 2) rCF 3, (CH 2) rO C 1-5 alkyl, OH, SH, (CH2) rS C1-5 alkyl, (CH2) rNR7fR7f, and (CH2) rphenyl; alternatively, R7 and R8 together form C3-7 cycloalkyl, R, 8b is selected from H, C? _6 alkyl, C3_6 cycloalkyl, OH, CN, and (CH2) r-phenyl; R13, in each case, is selected from C? _6 alkyl, C2_8 alkenyl, C2_8 alkynyl, C3-6 cycloalkyl, (CF2) WCF3 (CH2) rNR13aR13a ', (CH2) rOH, (CH2) rOR13b, (CH2) rSH (CH2) rSR13b, (CH2) wC (0) OH, (CH2) wC (0) R 13b (CH2) wC (0) NR13aR13a '(CH2) rNR13dC (0) R13a, (CH2) wC (0) OR 13b (CH2) r0C (0) R 13b (CH2) wS (0) pR13b, (CH2) wS (0) 2NR13aR13a ' (CH2) rNR1 aS (0) 2R, and (CH2) W- phenyl substituted with R13c of 0-3; R13a and R13a ', in each case, is selected from H, C? -6 alkyl, C3-b-cycloalkyl, and phenyl substituted with R13c of 0-3; R13b, in each case, is selected from C? -6 alkyl, C3_6 cycloalkyl, and phenyl substituted with R13c. of 0-3; R13A in each case, is selected from C? _6 alkyl, C3_6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) rCF3, (CH2) rO C5 alkyl, (CH2) rOH, (CH2) rS C1-5 alkyl, and (CH2) rNR13dR13d; R "13d, in each case, is selected from H, C1-6 alkyl, and C3_6 cycloalkyl, * R14, in each case, is selected from C6_6 alkyl, C2_8 alkenyl, C2_8 alkynyl, (CH2) r C3_e cycloalkyl, Cl, Br, I, F, N02, CN, (CHR ') rNR1 aR1 a', (CHR ') rOH, (CHR ') rO (CHR') rR l d (CHR ') rSH, (CHR') rC (0) H, (CHR ') rS (CHR') rR l d (CHR ') rC (0) OH, [CHR ') rC (0) (CHR') rR lx b (CHR ') rC (0) NR1 aR1 a', (CHR ') rNR14fC (O) (CHR') rR1 b, (CHR ') rC (0) 0 (CHR') rR 14d (CHR ') rOC (0) (CHR') ER 14b (CHR ') rC (= NR 14f NR14aR14a' (CHR ') rNHC (= NR1 f) NR1 fR1 f, (CHR') rS (0) p (CHR ') rR 14b (CHR ') rS (0) 2NR1 aR14a', (CHR ') rNR14fS (O) 2 (CHR') rR1b, haloalkyl C? -6, alkenyl C2_8 substituted with R 'of 0-3, alkynyl substituted with R' 0-3, (CHR ') rphenyl substituted with R14ß 0-3, and a (CH2) r- 5-10 element heterocyclic system containing from 1-4 heteroatoms selected from N, O, and S, substituted with R15e, of 0-2, or two R14 substituents on adjacent atoms on ring A, together form a heterocyclic system of 5-6 elements containing 1-3 heteroatoms selected from N, O, and S substituted with R15e of 0-2; R ', in each case, is selected from H, C? _6 alkyl, C2-8 alkenyl C2_s alkynyl, (CH2) r C3_6 cycloalkyl, and (CH2) r phenyl substituted with R 14e, R 1 a and R 14a ', in each case, is selected from H, C 1 -C 6 alkyl, C 2 8 alkenyl, C 2 8 alkynyl, a (CH 2) r C 3 0 substituted carbocyclic residue with R 14e from 0-5, and a (CH 2) ) r-heterocyclic system of 5-10 elements containing from 1-4 heteroatoms selected from N, O, and S, substituted with R14e from 0-2; R14b, in each case, is selected from C? _6 alkyl, C2-8 alkenyl, C2_8 alkynyl, a (CH2) r- C3-6 carbocyclic residue substituted with R14e of 0-3, and a (CH2) r-heterocyclic system of 5-6 elements containing from 1-4 heteroatoms selected from N, O, and S, substituted with R14e from 0-2; R14d, in each case, is selected from C2_8 alkenyl, C2_8 alkynyl, C6_6 alkyl substituted with R1 e of 0-3, a (CH2) r- C3-10 carbocyclic residue substituted with R14e of 0-3, and a (CH2) r-heterocyclic system of 5-6 elements containing from 1-4 heteroatoms selected from N, O, and S, substituted with R14e from 0-3; R1 e, in each case, is selected from C6_6 alkyl, C2_8 alkenyl, C2_8 alkynyl, (CH2) r C3_6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) rCF3, (CH2) rO alkyl d-5, OH, SH, (CH2) rS C1-5 alkyl, (CH2) rNR1 fR1 f, and (CH2) rphenyl; R, 14f, in each case, is selected from H, C? -6 alkyl, C3_6 cycloalkyl, and phenyl; alternatively, R together with R form a spirocycle of piperidinium of 5, 6 or 7 elements or pyrrolidinium spirocycle linked to ring A, the spirocycle substituted with Ra of 0-3; R 15 in each case is selected from C 1 _6 alkyl, C 2-8 alkenyl, C 2 8 alkynyl, (CH 2) r C 3-6 cycloalkyl, Cl, Br I, F, N 0 2, CN, (CHR ') rNR 15 aR 15 a', (CHR ' ) rOH (CHR ') rO (CHR') rR 15d (CHR ') rSH, (CHR') rC (0) H (CHR ') rS (CHR') rR 15d (CHR ') rC (0) 0H (CHR ') rC (0) (CHR') rR 15b (CHR ') rC (0) NR15aR15a' (CHR ') rNR15fC (O) (CHR') rR15b, (CHR ') rC (0) 0 (CHR') rR 15d (CHR ') r0C (0) (CHR') rR 15b (CHR ') rC (^ = NR15f) NR15aR15a' (CHR ') rNCH (= NR15f) NR15fR15f, (CHR') rS (0) p (CHR ') rR 15b (CHR ') rS (0) 2NR15aR15a', (CHR ') rNR15fS (O) 2 (CHR') rR «15b C? -6 haloalkyl, C2_8 alkenyl substituted with R 'of 0-3, C2-8 alkynyl substituted with R' of 0-3, (CHR ') rphenyl substituted with R15e of 0-3, and a heterocyclic system (CH2) r of 5-10 elements containing from 1-4 heteroatoms selected from N, O, and S, substituted with R15e from 0-2; R15 and R15a ', in each case, is selected from H, C? _6 alkyl, C2-8 alkenyl, C2_8 alkynyl, a (CH2) r- C3_? 0 carbocyclic residue substituted with R15e of 0-5; and a (CH2) r-heterocyclic system of 5-10 elements that they contain 1-4 heteroatoms selected from N, 0, and S, substituted with R15e from 0-2; R, in each case, is selected from C? _6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2) r- C3_6 carbocyclic residue substituted with R15e of 0-3; and a (CH2) r-heterocyclic system of 5-6 elements containing from 1-4 heteroatoms selected from N, 0, and S, substituted with R15e from 0-2; R, in each case, is selected from C2_8 alkenyl, C2_8 alkynyl, C6_6 alkyl substituted with R15e from 0-3, a (CH2) r-C3_? 0 carbocyclic residue substituted with R15e from 0-3, and a (CH2) r-heterocyclic system of 5-6 elements containing from 1-4 heteroatoms selected from N, 0, and S, substituted with R15e from 0-3; R15e, in each case, is selected from C? -6 alkyl, C2-8 alkenyl, C2_8 alkynyl, (CH2) r C3_6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) rCF3, (CH2) r0 alkyl C5-5, OH, SH, (CH2) rS alkyl C5-5, (CH2) rNR15fR15f, and (CH2) rphenyl; R 5f, in each case, is selected from H, Ci-e alkyl, C 3-6 cycloalkyl, and phenyl; R "16, in each case, is selected from C? _6 alkyl, alkenyl C2-8, C2_8 alkynyl, (CH2) r C3_6 cycloalkyl, Cl, Br I, F, N02, CN, (CHR ') rNR16aR16a', (CHR ') rOH (CHR ') rO (CHR') rR 16d [CHR ') rSH, (CHR') rC (0) H (CHR ') rS (CHR') rR 16d, (CHR ') rC (0) OH (CHR') rC (0) (CHR ') rR 16b (CHR' cC (0) NR16aR16a ' (CHR ') rNR16fC (O) (CHR') rR16, (CHR ') rC (0) 0 (CHR') rR 16d (CHR ') rOC (0) (CHR') rR 16b (CHR ') rC (= NR16f) NR16aR16a' (CHR ') rNCH (= NR16f) NR16fR16f, (CHR') rS (0) p (CHR ') rR 16b (CHR ') rS (0) 2NR16aR16a', (CHR ') rNR16fS (O) 2 (CHR') rR16b haloalkyl C? _6, alkenyl C2_8 substituted with R 'of 0-3, alkynyl C2-8 substituted with R' of 0-3, and (CHR ') rphenyl substituted with R16e of 0-3; R16a and R16a ', in each case, is selected from H, C? _6 alkyl, C2-8 alkenyl, C2_8 alkynyl, a (CH2) r-carbocyclic residue C3_? Or substituted with R16e from 0-5, and a (CH2) ) 5-10 elements heterocyclic r-system containing from 1-4 heteroatoms selected from N, O, and S, substituted with R16e from 0-2; R16, in each case, is selected from C? _6 alkyl, alkenyl C2_8, C2_s alkynyl, a (CH2) r-C3_6 carbocyclic residue substituted with R16e of 0-3, and a (CH2) r-system heterocyclic of 5-6 elements containing from 1-4 heteroatoms selected from N, 0, and S, substituted with R16e from 0-2; R16d, in each case, is selected from C2_s alkenyl, C2_8 alkynyl, C6_6 alkyl substituted with R16e of 0-3, a (CH2) r-carbocyclic residue C3-? Or substituted with R16e of 0-3, and a ( CH2) r-heterocyclic system of 5-6 elements containing from 1-4 heteroatoms selected from N, O, and S, substituted with R16e from 0-3; R16e, in each case, is selected from C? -6 alkyl, C2_8 alkenyl, C2_8 alkynyl, (CH2) r C3_6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) rCF3, (CH2) rO alkyl C? -5, OH, SH, (CH2) rS alkyl C? _5, (CH2) rNR16fR16f, and (CH2) rphenyl; R, 16f, in each case, is selected from H, C? -6 alkyl, and C3_6 cycloalkyl, and phenyl; g is selected from 0, 1, 2, 3 and 4; t is selected from 1 and 2; w is selected from 0 and 1; r is selected from 0, 1, 2, 3, 4, and 5; q is selected from 1, 2, 3, 4, and 5; Y p is selected from 0, 1, 2 and 3. The compound according to claim 11, characterized in that: z is selected from O and S; R4 is absent, together with the nitrogen to which it binds, form an N-oxide, or is selected from C? _8 alkyl, (CH2) r-C3_6 cycloalkyl, and (CH2) r-phenyl substituted with R3c from 0-3; R, in each case, is selected from C6_6 alkyl, C2_s alkenyl, C2_8 alkynyl, C3_6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) rCF3, (CH2) rO alkyl C? _5 , (CH2) rOH, (CH2) rS alkyl C? _5, (CH2) rNR4aR4a ', and (CH2) rphenyl; alternatively, R4 together with R7, R9, or R14 form a piperidinium spirocycle of 5, 6 or 7 elements substituted with Ra of 0-3; R and R are independently selected from H, and alkyl Ci- 4 ' R6, in each case, is selected from C? -4 alkyl, alkenyl C2_8, C2-8 alkynyl, (CH2) r-C3_6 cycloalkyl, (CF2) rCF3, CN, (CH2) rOH, (CH2) rOR 6b (CH2) rC (0) R6b, (CH2) rC (0) NR6aR6a '(CH2) rNR6dC (0) R6a, and (CH2) tphenyl substituted with R6c of 0-3; R6a and R6a ', in each case, is selected from H, C6-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with R6c of 0-3; R "6b, in each case, is selected from C 1 -C alkyl, C 3-6 cycloalkyl, and phenyl substituted with R 6c of 0-3; R, 6c, in each case, is selected from C1-6 alkyl, C3_6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) rCF3, (CH2) rO C1-5 alkyl, (CH2) r0H, (CH2) rS C1-5 alkyl, and (CH2) rNR6dR6d; , 6d in each case, is selected from H, C? _6 alkyl, C3_e cycloalkyl; R7 is selected from H, C1-3 alkyl, (CH2) r C3_6 cycloalkyl, (CH2) q0H, (CH2) qOR7d, (CH2) qNR7aR7a ', (CH2) rC (O) R7b, (CH2) rC (0) NR, 7'aapR7'aa ', (CH2) qNR'aC (0) R 7'aa, haloalkyl C? _6, (CH2) rphenyl with R7'cc of 0-2; R7a and R a, in each case, is selected from H, alkyl d_6, (CH2) r C3-6 cycloalkyl, a (CH2) substituted phenyl R, in each case, is selected from C? -6 alkyl, alkenyl C2-C C2 alkynyl. (CH2) C3_6 cycloalkyl, (CH2) rphenyl substituted with R le of 0-3; R7c, in each case, is selected from C alquilo_alkyl, C2_8alkenyl, C2_8alkynyl, (CH2) r C3_6 cycloalkyl, Cl, Br, I, F, (CF2) rCF3, N02, CN, (CH2) rNR7fR7f, ( CH2) r0H, alkyl (CH2) rOC? -4, (CH2) rC (O) R7, (CH2) rC (O) NR, 7'frR) 7'fA : CH2 rNR7fC (0) R 7a (CH2) rS (O) pR7, (CH2) rS (O) 2NR7fR7f, and (CH2) r-phenyl substituted with R7e of 0-2; R, 7'da, in each case, is selected from C6_6 alkyl, (CH2) r C3-6 cycloalkyl, (CH2) rphenyl substituted with R7e of 0-3; R7e, in each case, is selected from C? _6 alkyl, C2_8 alkenyl, C2_8 alkynyl, C3-cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) rCF3, (CH2) rO alkyl C ? 5, OH, SH, (CH2) rS alkyl C? _5, (CH2) rNR7fR7f, and (CH2) rphenyl; R, in each case, is selected from H, C? _5 alkyl, C3_6 cycloalkyl; R8 is H or together with R7 cycloalkyl form C3_7, or = NR 8b, R11 is selected from H, C? -6 alkyl, (CH2) E C3-6 cycloalkyl, (CH2) qOH, (CH2) qORll, (CH2) qNRUaRlla ', (CH2) rC (0) Rllb, (CH2) rC (0) NRllaRlla ', (CH2) qNRllaC (0) Rlla, haloalkyl C? -6, (CH2) rphenyl with Rllc of 0-2, a (CH2) r-heterocyclic system of 5-10 elements containing from 1 - 4 heteroatoms selected from N, 0, and S, substituted with R15 of 0-3; Rlla and Rlla ', in each case, is selected from H, C1-6 alkyl, (CH2) r C3_6 cycloalkyl, a (CH2) rphenyl substituted with Rlle of 0-3; R "11b, in each case, is selected from C 1-6 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, (CH 2) r C 3-6 cycloalkyl, (CH 2) rphenyl substituted with Rlle of 0-3; Rllc, in each case, is selected from C ?4 alkyl, C2_8 alkenyl, C2_8 alkynyl, (CH2) r C3_6 cycloalkyl, Cl, Br, I, F, (CF2) rCF3, N02, CN, (CH2) rNRllfRllf, ( CH2) rOH, alkyl (CH2) rOC? -4, (CH2) rC (O) Rll, (CH2) rC (O) NRllfRllf, (CH2) rNRllfC (0) Rlla, (CH2) rS (0) pRllb (CH2) rS (0) 2NRllfRllf, (CH2) rNR «lillfLSr (0) 2R, 1111bD, and (CH2) rphenyl substituted with Rlle of 0-2; R, in each case, is selected from alkyl C? _6, (CH2) C3_6 cycloalkyl, (CH2) rphenyl substituted with R, l, 0-3; R, in each case, is selected from C? -6 alkyl, C2_8 alkenyl, C2_8 alkynyl, C3_6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) rCF3, (CH2) rO C1-5 alkyl, OH, SH, (CH2) rS alkyl C5-5, (CH2) rNRllfRllf, and (CH2) rphenyl; R > ? if, in each case, it is selected from H, C1_5 alkyl, and C3_6 cycloalkyl; R12 is H or together with R11 forms C3_7 cycloalkyl; R, in each case, is selected from C ?4 alkyl, C3-6 cycloalkyl, (CH2) NR13aR13a ', (CH2) 0H, (CH2) OR13b, (CH2) WC (O) R13b, [CH2) "C (0) NR 113JaaR" - > 13a '(CH2) NR 1l3jdaC (0) R «13a : CH2) wS (CH2) NR 1l3jdaSc (0) 2R "13b and (CH2) w-f enyl substituted with R13c of 0-3; R13a and R13a ', in each case, is selected from H, C? _6 alkyl, C3_6 cycloalkyl, and phenyl substituted with R13c of 0-3; in each case, it is selected from C1.6.6 cycloalkyl alkyl, and phenyl substituted with R13c of 0-3; R 13c in each case is selected from Cl 6 alkyl, C3_6 cycloalkyl, Cl, F, Br, I, CN, N02, (CF2) rCF3, (CH2) rO alkyl d-5, (CH2) rOH, and ( CH2) rNR13dR13d; r > 13d, in each case, is selected from H, alkyl d_6, and C3_6 cycloalkyl; q is selected from 1, 2, and 3; r is selected from 0, 1, 2 and 3. The compound according to claim 12, characterized in that: ring A is selected from: (R e selects from a (CR3?) r-substituted carbocyclic residue with R15 of 0-5, wherein the carbocyclic residue is selected from phenyl, C3_6 cycloalkyl, naphthyl, and adamantyl; and a (R3?) r-substituted heterocyclic system with R15 of 0-3, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; Y R5 is selected from (CR5?) T-phenyl substituted with R16 of 0-5; and a (CR5?) t- substituted heterocyclic system with R16 of 0-3, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisaxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, isoindolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl. 14. The compound according to claim 13, characterized in that the compound Formula (I) is: R, in each case, is selected from Ci-s alkyl, (CH2)? C3_6 cycloalkyl, CF3, Cl, Br, I, F, (CH2) rNR16aR16a ', N02, CN, OH, (CH2) r0R 16d CH2) rC (0) R16b, (CH2 rC (0) NR16aR16a ' (CHzJ (CH2) rS (0) pR 16b (CH2) rphenyl substituted with R16e of 0-3; 16a and R16a ', in each case, is selected from H, C? _6 alkyl, C3_6 cycloalkyl, and (CH2) rphenyl substituted with R16e of 0-3; R, 16b, in each case, is selected from H, Ci- 6 alkyl, C3_6 cycloalkyl, and (CH2) rphenyl substituted with R, 16e from 0-3; R, in each case, is selected from C? -6 alkyl, and phenyl; R, 16e, in each case, is selected from alkyl C? -6, Cl, F, Br, I, CN, N02, (CF2) rCF3, OH, and (CH2) r0 alkyl d-5; Y R16f, in each case, is selected from H, C1-5 alkyl. 15. The compound according to claim 13, characterized in that the compound of Formula (I) is: R, in each case, is selected from alkyl C? _8, (CH2) C3_6 cycloalkyl, CF3, Cl, Br, I, F, (CH2) rNRibaRAba, N02 CN, OH, (CH2) rOR 16d (CH2) EC (0) R 16b (CH2) rC (0) NR16aR16a ', (CH2) rNR16fC (0) R16b, (CH2) rS (0) pR16b, (CH2) rS (0) 2NR16aR16a ' (CH2) rNR16fS (0) 2R16b, and (CH2) rf enyl substituted with R, 16oee of 0-3; R 16a and R a, in each case, is selected from H, C? -6 alkyl, C3_6 cycloalkyl, and (CH2) rphenyl substituted with R, 16e of 0-3; R 16b in each case is selected from H, C? -6 alkyl, C3_6 cycloalkyl, and (CH2) rphenyl substituted with R16e with 0-3; R, in each case, is selected from C? _6 alkyl and phenyl; R16e, in each case, is selected from alkyl C? -6, Cl, F, Br, I, CN, N02, (CF2) rCF3, OH, and (CH2) r0 alkyl d_5; and R16f, in each case, is selected from H, and alkyl C? _5. 16. The compound according to claim 14, characterized in that: R is CH2phenyl substituted with Ri 1-6 of 0-3; R is selected from H, C? _6 alkyl, (CH2) r C3_6 cycloalkyl, F, Cl, CN, (CH2) rOH, (CH2) rOR9d, (CH2) rNR9aR9a ', (CH2) rOC (0) NHR9a, (CH2) rphenyl substituted with R9e of 0-5, and a heterocyclic system substituted with R9e of 0-2, wherein the heterocyclic system is selected from pyridyl, thiophenyl, furanyl, oxazolyl, and thiazolyl; R 9a and R9a ', in each case, is selected from H, C? _6 alkyl, C3-6 cycloalkyl and (CH2) rphenyl substituted with R9e of 0-3; R, 9d, in each case, is selected from alkyl d-6 and phenyl; R, 9e, in each case, is selected from alkyl C? _6, Cl, F, Br, I, CN, N02, (CF2) rCF3, OH, and (CH2) rO alkyl C? -5; R10 is selected from H, C? _5 alkyl, OH, and CH2OH; alternatively, R9 and R10 together form C3-7 cycloalkyl, cyclic ketal of 5-6 elements or = 0; provided that R10 is halogen, cyano, nitro, or is attached to the carbon to which it is attached through a heteroatom, R9 is not halogen, cyano or is attached to the carbon to which it is attached through a heteroatom; R "11 is selected from H, C? -8 alkyl, (CH2) rphenyl substituted with R" lie of 0-5, and a (CH2) r-heterocyclic system substituted with Rlle of 0-2, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, incazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, isoindolyl, piperidinyl, pyrrazole, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl, pyrazinyl and pyrimidinyl; Y R, in each case, is selected from alkyl C? -6, Cl, F, Br, I, CN, N02, (CF2) rCF3, OH, and (CH2) rO alkyl C? _5; R12 is H; alternatively, R > n and R > Together they form C3_7 cycloalkyl; R14, in each case, is selected from C C _8 alkyl, (CH2) r C3.6 cycloalkyl, CF3, Cl, Br, I, F, (CH2) rNR1 aR14a ', N02, CN, OH, (CH2) r0R14d , (CH2) rC (0) R14b, (CH2) rC (0) NR14aR14a ', (CH2) rNR14fC (0) R1b, (CH2) rS (0) pR1b, (CH2) rS (O) 2NR14aR1 a' , (CH2) rNR14fS (0) 2R14b, (CH2) rphenyl substituted with R14e of 0-3, and a (CH2) r 5-10 elements heterocyclic system containing 1-4 heteroatoms selected from N, O, and S , substituted with R15e of 0-2; or two R14 substituents in adjacent atoms in rings A together form a heterocyclic system of 5-6 elements containing 1-3 heteroatoms selected from N, O, and S substituted with R14a and R14a ', in each case, is selected from H, C? _6 alkyl, C3_6 cycloalkyl, and (CH2) rphenyl substituted with R14e from 0-3; and a (CH2) r-heterocyclic system of 5-6 elements containing from 1-4 heteroatoms selected from N, O, and S, substituted with R15e from 0-2; R1 b, in each case, is selected from H, alkyl C? -6, cycloalkyl C3_e, and (CH2) rphenyl substituted with R1 e of 0-3; R14d, in each case, is selected from C? -6 alkyl and phenyl; R, 14e, in each case, is selected from alkyl C6-, Cl, F, Br, I, CN, N02, (CF2) rCF3, OH, and (CH2) rO alkyl d5; Y R "14f, in each case, is selected from H, alkyl C? _5; r is selected from 0, 1, and 2, 17. The compound according to claim 15, characterized in that: R3 is CH2phenyl substituted with R16 of 0-3; R is selected from H, alkyl d_6, (CH2) r C3-6 cycloalkyl, F, Cl, CN, (CH2) rOH, (CH2) rOR9d, (CH2) rNR9aR9a ', (CH2) rOC (0) NHR9a, (CH2) rphenyl substituted with R9e of 0-5, and a heterocyclic system substituted with R9e of 0-2,. wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, oxazolyl, and thiazolyl; R9a and R9a ', in each case, is selected from H, C6-6 alkyl, cycloalkyl Ca6, and (CH2) rphenyl substituted with R9e of 0-3; R, 9d, in each case, is selected from C? -6 alkyl and phenyl; R > 9e, in each case, is selected from alkyl C? -6, Cl, F, Br, I, CN, N02, (CF2) rCF3, OH, and (CH2) r0 C? _5 alkyl; R, 10 is selected from H, C? -8 alkyl, OH, and CH20H; alternatively, R9 and R10 together form C3_7 cycloalkyl, cyclic ketal of 5-6 elements or = 0; with the proviso that when R9 is halogen, cyano, nitro, or is linked to the carbon to which it is attached through a heteroatom, R9 is not halogen, cyano, or is bound to the carbon to which it is attached through a heteroatom; R11 is selected from H, alkyl C? S, (CH2) rphenyl substituted with Rlle of 0-5, and a (CH2) r- substituted hetrocyclic system with Rlle of 0-2, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophanyl, benzofuranyl, benzoxazolyl, benzisaxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, isoindolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; Y Rlle, in each case, is selected from alkyl C? _6, Cl, F, Br, I, CN, N02, (CF2) rCF3, OH, and (CH2) r0 C? _5 alkyl; R12 is H; alternatively, R11 and R12 together form C3_7 cycloalkyl; R, in each case, is selected from alkyl Ci-β, (CH 2) C3_6 cycloalkyl, CF3, Cl, Br, I, F, (CH2) rNR14aR14aJ, N02, CN, OH, (CH2) rOR14d, (CH2) rC (0) R14, (CH2) rC (O) NR14aR14a-, (CH2) ) rNR14fC (0) R14b, (CH2) rS (0) pR14b, (CH2) rS (O) 2NR1 aR1 a ', (CH2) rNR14fS (0) 2R1 b, (CH2) rphenyl substituted with 0-3 R14e, and (CH) 5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with R15e of 0-2, or two R14 substituents in adjacent atoms in ring A forming a system together heterocyclic 5-6 elements containing 1-3 heteroatoms selected from N, 0, and S substituted with R15e of 0-2; R a and R, in each case, is selected from H, C? _6 alkyl, C3_6 cycloalkyl, and (CH2) rphenyl substituted with R14e of 0-3; R1 b, in each case, is selected from H, C? _6 alkyl, C3_6 cycloalkyl, and (CH2) tphenyl substituted with R14e of 0-3; R1 d, in each case, is selected from C? -6 alkyl and phenyl; R, 14e, in each case, is selected from alkyl C6-6, Cl, F, Br, I, CN, N02, (CF2) rCF3, OH, and (CH2) r0 C C5 alkyl; R, in each case, is selected from H, and alkyl d_5; r is selected from 0, 1 and 2. 18. The compound according to claim 16, characterized in that: J is selected from CH2 and CHR; L is selected from CH2 and CHR; R3 is a carbocyclic residue C3_? Or substituted with R of 0-3, wherein the carbocyclic residue is selected from cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl and adamantyl, and a (CR3?) R-substituted heterocyclic system R15 of 0-3, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisazololyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; Y R 15 in each case is selected from C? _8 alkyl, cycloalkyl (CH2) rC3_6, CF3, Cl, Br, I, F, (CH2) rNR15 R15a ', N02, CN, OH, (CH2) rOR15d, (CH2) rC (0) R15b, (CH2) rC (0) NR15aR15a ' (CH2) rNR15fC (0) R15b, (CH2) rS (0) pR15b, (CH2 rS (0) 2NR15aR15a ', (CH2) rNR15fS (0) 2R15b, (CH2) rf enyl substituted with R 15e of 0-3, and a (CH2) r-heterocyclic system of 5-6 elements containing from 1-4 heteroatoms selected from N, O, and S, substituted with R15e of 0-2; R 15a and R, in each case, is selected from H, C? -6 alkyl, C3_6 cycloalkyl, and (CH2) rphenyl substituted with R, 15e of 0-3; R, in each case, is selected from H, C? -6 alkyl, C3_6 cycloalkyl, and (CH2) rphenyl substituted with R15e of 0-3; R, in each case, is selected from C? _6 alkyl and phenyl; R, 15e, in each case, is selected from alkyl C? -6, Cl, F, Br, I, CN, N02, (CF2) rCF3, OH and (CH2) rO alkyl C? _5; Y R, in each case, is selected from H, C? -5 alkyl. 19. The compound according to claim 17, characterized in that: L is selected from CH2 and CHR5; R3 is a C3_? 0 carbocyclic residue substituted with R15 of 0-3, wherein the carbocyclic residue is selected from cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl and adamantyl, and a (CR3'H) r-heterocyclic system substituted with R15 of 0-3; wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisaxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolinyl, isothiadiadiazolyl, isoxazolyl, piperidinyl, pyrazolyl, 1, 2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; Y R15, in each case, is selected from C? _8 alkyl, (CH2) r C3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2) rNR15aR15 ', N02, CN, OH, (CH2) rOR 15d (CH2) rC (0) R 15b (CH2) rC (0) NR1l5oaaRt-, 15a ' (CH2 rNR15fC (0) R15b, (CH2) rS (0) pR 15b (CH2) rS (0) 2NR 1155aaRp15a ' (CH2) rNR15fS (0) 2R15b, and (CH2) rphenyl substituted with R15e of 0-3, and a (CH2) r-heterocyclic system of 5-6 elements containing from 1-4 heteroatoms selected from N, 0, and S, substituted with R15e from 0-2; Ri5a and 15a'f in each case, is selected from H, C? _6 alkyl, C3-e cycloalkyl, and (CH2) rphenyl substituted with R15e of 0-3; R, in each case, is selected from H, C? -6 alkyl, C3_6 cycloalkyl, and (CH2) rphenyl substituted with R15e of 0-3; R15d, in each case, is selected from C? -6 alkyl and phenyl; R, in each case, is selected from alkyl C? _6, Cl, F, Br, -I, CN, N02, (CF2) rCF3, OH, and (CH2) rO alkyl d-5; Y R15f, in each case, is selected from H, and C1-5 alkyl. The compound according to claim 11, and pharmaceutically acceptable salt forms thereof, characterized in that the compound of formula (I) is selected from: N- (3-acetylphenyl) -N '- [trans-2- [[4- (4-fluorophenylmethyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3-nitrophenyl) -N '- [trans-2- [[4- (4- fluorophenylmethyl) piperidinyl] methyl] cyclohexyl] -urea, N- (4-nitrophenyl) -N '- [trans-2- [[4- (4-fluorophenylmethyl) piperidinyl] methyl] cyclohexyl] -urea, N- (4-pyridinyl) -N '- [trans-2- [[4- (4-fluorophenylmethyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3-acetylphenyl) -N '- [trans-2- [[4- (4-fluorophenylmethyl) piperidinyl] methyl] cyclohexyl] -urea, N- ((ÍH) -indazol-5-yl) -N '- [trans-2- [[4- (4-fluorophenylmethyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3-methoxyphenyl) -N '- [trans-2- [[4- (phenylmethyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3-methoxyphenyl) -N '- [trans-2- [[4- (4-fluorophenylmethyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3-methoxyphenyl) -N '- [cis-2- [[4- (phenylmethyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3-cyanophenyl) -N '- [trans-2- [[4- (4-fluorophenylmethyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3-acetylphenyl) -N '- [(1S, 2R) -2- [[4- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3-cyanophenyl) -N '- [(1S, 2R) -2- [[4- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3-methoxyphenyl) -N '- [(1S, 2R) -2- [[4- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (phenyl) -N '- [(1S, 2R) -2- [[4- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3-acetylphenyl) -N '- [(1R, 2S) -2- [[4- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3-cyanophenyl) -N '- [(IR, 2S) -2- [[4- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3-methoxyphenyl) -N '- [(1R, 2S) -2- [[4- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (phenyl) -N '- [(1R, 2S) -2- [[4- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (phenylmethyl) -N '- [(lS, 2R) -2- [[4- (4- fluorophenyl) methyl) piperidinyl] methyl] ciciohexyl] -urea, N- ((1H) -indazol-5-yl) -N '- [(1R, 2S) -2- [[4- (4-fluordophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- ((1H) -indol-5-yl) -N '- [(IR, 2S) -2- [[4- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl] -urea, N- (3-methoxyphenyl) -N '- [3- [[4- (4-fluorophenylmethyl) piperidinyl] methyl] cyclohexyl] -urea, and N- (3-Acetylphenyl) -N '- [3- [[4- (4-fluorophenylmethyl) piperidinyl] methyl] cyclohexyl] -urea. 21. A pharmaceutical composition characterized in that it comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of one of claims 11 to 20. 22. A method for modulating the activity of chemokine receptors, characterized in that it comprises administering to a patient in need thereof a therapeutically effective amount of a compound of one of claims 11 to 20. 23. A method for modulating the activity of chemokine receptors, characterized in that it comprises contacting a CCR3 receiver with a effective inhibitory amount, of a compound of one of claims 11 to 20. 24. A method for the treatment or prevention of inflammatory diseases, characterized in that it comprises administering to a patient in need thereof, a therapeutically effective amount of a compound of an of claims 11 to 20. 25. A method for the treatment or prevention of asthma, characterized in that it comprises administering to a patient in need thereof a therapeutically effective amount of a compound of one of the claims of claim 11. at 20. 26. A method for the treatment or prevention of an inflammatory disorder, characterized in that it comprises administering to a patient in need thereof, a therapeutically effective amount of a compound of one of claims 11 to 20, in where the inflammatory disorder is selected from asthma, allergic rhinitis, atopic dermatitis, inflammatory bowel diseases, pulmonary fibrosis idiopathic, bolus pemphigoid, helminthic parasitic infections, allergic colitis, eczema, conjunctivitis, transplantation, familial eosinophilia, eosinophilic cellulitis, eosinophilic pneumonias, eosinophilic fasciitis, eosinophilic gastroenteritis, drug-induced eosinophilia, HIV infection, cystic fibrosis, Churg-Strauss syndrome, lymphoma, Hodgkin's disease, and colonic carcinoma. 27. The method according to claim 26, for the treatment or prevention of disorders selected from asthma, allergic rhinitis, atopic dermatitis and inflammatory bowel diseases. 28. A pharmaceutical composition, characterized in that it comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of one of claims 1 to 10. 29. A method for modulating the activity of chymic receptors, characterized in that it comprises administering to a patient in need thereof a therapeutically effective amount of a compound of one of claims 1 to 10. 30. A method for modulating chymic receptor activity, characterized in that it comprises contacting a CCR3 receptor with an effective inhibitory amount of a compound of one of claims 1 to 10. 31. A method for the treatment or prevention of inflammatory diseases, characterized in that it comprises when administering to a patient in need thereof, a therapeutically effective amount of a compound of one of claims 1 to 10. 32. A method for the treatment or prevention of asthma, characterized in that it comprises, when administering to a patient in need thereof, a therapeutically effective amount of a compound of one of claims 1 to 10. 33. A method for the treatment or prevention of an inflammatory disorder, characterized in that it comprises administering to a patient in need thereof, a therapeutically effective amount of a compound of one of claims 1 to 10, wherein the inflammatory disorder is selected from asthma, allergic rhinitis, dermatitis atopic, inflammatory bowel diseases, idiopathic pulmonary fibrosis, pemphigoid bolus, helminthic parasitic infections, allergic colitis, eczema, conjunctivitis, transplantation, familial eosinophilia, eosinophilic cellulitis, eosinophilic pneumonias, eosinophilic fasciitis, eosinophilic gastroenteritis, drug-induced eosinophilia, HIV infection , cystic fibrosis, syndrome Churg-Strauss, lymphoma, Hodgkin's disease, and colonic carcinoma. 34. The method according to claim 33, characterized in that it is for the treatment or prevention of disorders selected from asthma, allergic rhinitis, atopic dermatitis and inflammatory bowel diseases.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US60/112,717 | 1998-12-18 | ||
| US60/161,221 | 1999-10-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA01006148A true MXPA01006148A (en) | 2001-12-13 |
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