HK1054930B - Pyrrolo[2,3-d]pyrimidine compounds as immunosuppressive agents - Google Patents
Pyrrolo[2,3-d]pyrimidine compounds as immunosuppressive agents Download PDFInfo
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Description
Background
The present invention relates to pyrrolo [2, 3-d ] pyrimidine compounds which are inhibitors of protein kinases such as the enzyme janus kinase 3 (hereinafter JAK3) and are therefore useful as immunosuppressive agents in the treatment of organ transplantation, transplant rejection, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I diabetes and diabetic complications, cancer, asthma, atopic skin diseases, autoimmune thyroid diseases, ulcerative colitis, Crohn's disease, alzheimer's disease, leukemia and other immunosuppressive indications.
The invention also relates to methods of using such compounds to treat the aforementioned conditions in mammals, particularly humans.
JAK3 is a member of the Janus family of the protein kinase family. While essentially all tissues express other members of the family, expression of JAK3 is limited to hematopoietic cells. This is consistent with the fundamental role in signaling through the receptors for IL-2, IL-4, IL-7, IL-9 and IL-15 by the non-covalent binding of JAK3 to the gamma chain common to these multi-chain receptors. It has now been tested that JAK3 protein levels in severely reduced or their common gamma chain gene defective in X-associated severely combined immunodeficiency (XSCID) populations, suggesting that the immunosuppressive effects are due to blocking signaling through the JAK3 pathway. Animal studies have shown that JAK3 not only plays a critical role in the maturation of B and T lymphocytes, but also constitutively requires JAK3 to maintain T cell function. Modulation of immune activity by this novel mechanism demonstrates utility in the treatment of T cell proliferative diseases such as transplant rejection and autoimmune diseases.
Summary of The Invention
The present invention relates to compounds of formula I
Or a pharmaceutically acceptable salt thereof, wherein
R1Is a radical of the formula
Wherein y is 0, 1 or 2;
R4is selected from hydrogen, (C)1-C6) Alkyl radical (C)1-C6) Alkylsulfonyl group (C)2-C6) Alkenyl (C)2-C6) Alkynyl, wherein alkyl, alkenyl and alkynyl are optionally substituted with: deuterium, hydroxy, amino, trifluoromethyl, (C)1-C4) Alkoxy group, (C)1-C6) Acyloxy, (C)1-C6) Alkylamino group, ((C)1-C6) Alkyl radical)2Amino, cyano, nitro, (C)2-C6) Alkenyl (C)2-C6) Alkynyl or (C)1-C6) An amido group; or R4Is (C)3-C10) Cycloalkyl, wherein the cycloalkyl is optionally substituted with: deuterium, hydroxy, amino, trifluoromethyl, (C)1-C6) Acyloxy, (C)1-C6) Amido (C)1-C6) Alkylamino group, ((C)1-C6) Alkyl radical)2Amino, cyano (C)1-C6) Alkyl, trifluoromethyl (C)1-C6) Alkyl, nitro (C)1-C6) Alkyl or (C)1-C6) An acylamino group;
R5is (C)2-C9) Heterocycloalkyl, wherein the heterocycloalkyl must be substituted with 1 to 5 of the following groups: carboxy, cyano, amino, deuterium, hydroxy, (C)1-C6) Alkyl radical (C)1-C6) Alkoxy, halogen, (C)1-C6) Acyl radical, (C)1-C6) Alkylamino, amino (C)1-C6) Alkyl radical (C)1-C6) alkoxy-CO-NH, (C)1-C6) alkylamino-CO-, (C)2-C6) Alkenyl (C)2-C6) Alkynyl (C)1-C6) Alkylamino, amino (C)1-C6) Alkyl, hydroxy (C)1-C6) Alkyl radical (C)1-C6) Alkoxy (C)1-C6) Alkyl radical (C)1-C6) Acyl oxygen (C)1-C6) Alkyl, nitro, cyano (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, nitro (C)1-C6) Alkyl, trifluoromethyl (C)1-C6) Alkyl radical (C)1-C6) Acylamino group, (C)1-C6) Acylamino group (C)1-C6) Alkyl radical (C)1-C6) Alkoxy (C)1-C6) (ii) an acylamino group,amino (C)1-C6) Acyl, amino (C)1-C6) Acyl radical (C)1-C6) Alkyl radical (C)1-C6) Alkylamino radical (C)1-C6) Acyl group, ((C)1-C6) Alkyl radical)2Amino (C)1-C6) Acyl radical, R15R16N-CO-O-，R15R16N-CO-(C1-C6) Alkyl radical (C)1-C6) alkyl-S (O)m，R15R16NS(O)m，R15R16NS(O)m(C1-C6) Alkyl radical, R15S(O)mR16N，R15S(O)mR16N(C1-C6) Alkyl, wherein m is 0, 1 or 2 and R15And R16Each independently selected from hydrogen or (C)1-C6) An alkyl group; and a group of the formula:
wherein
a is 0, 1, 2, 3 or 4;
b. c, e, f and g are each independently 0 or 1;
d is 0, 1, 2 or 3;
x is S (O)nWherein n is 0, 1 or 2; oxygen, carbonyl or-C (═ N-cyano) -;
y is S (O)nWherein n is 0, 1 or 2; or a carbonyl group; and
z is carbonyl, C (O) O-, C (O) NR-, wherein R is hydrogen or (C)1-C6) An alkyl group; or Z is S (O)nWherein n is 0, 1 or 2;
R6、R7、R8、R9、R10and R11Each independently selected from the group consisting of: hydrogen or (C)1-C6) Alkyl optionally substituted with: deuterium, hydroxy, amino, trifluoromethyl, (C)1-C6) Acyl oxygen, (C)1-C6) Acylamino group, (C)1-C6) Alkylamino group, ((C)1-C6) Alkyl radical)2Amino, cyano (C)1-C6) Alkyl, trifluoromethyl (C)1-C6) Alkyl, nitro (C)1-C6) Alkyl or (C)1-C6) An acylamino group;
R12is (C)6-C10) Aryl radical, (C)2-C9) Heteroaryl group, (C)3-C10) Cycloalkyl or (C)2-C9) Heterocycloalkyl, wherein aryl, heteroaryl, cycloalkyl and heterocycloalkyl may be optionally substituted with 1 to 4 of the following groups: hydrogen, deuterium, amino, halo, oxo, hydroxy, nitro, carboxy, (C)2-C6) Alkenyl (C)2-C6) Alkynyl, trifluoromethyl, trifluoromethoxy, (C)1-C6) Alkyl radical (C)1-C6) Alkoxy group, (C)3-C10) Cycloalkyl group, (C)1-C6) alkyl-CO-NH-, (C)1-C6) alkoxy-CO-NH-, (C)1-C6) alkyl-CO-NH- (C)1-C6) Alkyl radical (C)1-C6) alkoxy-CO-NH- (C)1-C6) Alkyl radical (C)1-C6) alkoxy-CO-NH- (C)1-C6) Alkoxy, carboxyl (C)1-C6) Alkyl, carboxyl (C)1-C6) Alkoxy, benzyloxycarbonyl (C)1-C6) Alkoxy group, (C)1-C6) Alkoxycarbonyl (C)1-C6) Alkoxy group, (C)6-C10) Aryl, amino (C)1-C6) Alkyl radical (C)1-C6) Alkoxycarbonylamino group, (C)6-C10) Aryl radical (C)1-C6) Alkoxycarbonylamino group, (C)1-C6) Alkylamino group, ((C)1-C6) Alkyl radical)2Amino group, (C)1-C6) Alkylamino radical (C)1-C6) Alkyl group, ((C)1-C6) Alkyl radical)2Amino (C)1-C6) Alkyl, hydroxy, (C)1-C6) Alkoxy, carboxyl (C)1-C6) Alkyl radical (C)1-C6) Alkoxycarbonyl group, (C)1-C6) Alkoxycarbonyl (C)1-C6) Alkyl radical (C)1-C6) alkoxy-CO-NH-, (C)1-C6) alkyl-CO-NH-, cyano, (C)5-C9) Heterocycloalkyl, amino-CO-NH-, (C)1-C6) alkylamino-CO-NH- ((C)1-C6) Alkyl radical)2amino-CO-NH-, (C)6-C10) arylamino-CO-NH-, (C)5-C9) heteroarylamino-CO-NH-, (C)1-C6) alkylamino-CO-NH- (C)1-C6) Alkyl group, ((C)1-C6) Alkyl radical)2amino-CO-NH- (C)1-C6) Alkyl radical (C)6-C10) arylamino-CO-NH- (C)1-C6) Alkyl radical (C)5-C9) Heteroarylamino-CO-NH- (C)1-C6) Alkyl radical (C)1-C6) Alkyl cyano group, (C)1-C6) Alkylcarboxy (C)1-C6) Alkoxy group, (C)1-C6) Alkylcarboxy, sulfonamido, aminosulfonyl, sulfonamido (C)1-C6) Alkyl, sulfonamido carboxyl (C)1-C6) Alkyl radical (C)1-C6) Alkylsulfonyl group (C)1-C6) Alkylsulfonylamino group (C)1-C6) Alkylsulfonamido (C)1-C6) Alkyl radical (C)6-C10) Arylsulfonyl (C)6-C10) Arylsulfonylamino group (C)6-C10) Arylsulfonylamino (C)1-C6) Alkyl radical (C)1-C6) Alkylsulfonylamino group (C)1-C6) Alkylsulfonamido (C)1-C6) Alkyl radical (C)3-C10) Cycloalkyl group, (C)3-C10) Cycloalkoxy, (C)1-C6) Alkylamino group, ((C)1-C6) Alkyl radical)2Amino group, (C)6-C10) Arylamino, (C)1-C6) Alkylthio (C)6-C10) Arylthio group, (C)1-C6) Alkylsulfinyl (C)6-C10) Arylsulfinyl (C)1-C6) Alkylsulfonyl group (C)6-C10) Arylsulfonyl (C)1-C6) Acyl radical, (C)1-C6) alkoxy-CO-NH-, (C)1-C6) alkylamino-CO-, (C)5-C9) Heteroaryl group, (C)2-C9) Heterocycloalkyl or (C)6-C10) Aryl, wherein is optionally substituted at R12The heteroaryl, heterocycloalkyl and aryl groups of (a) may also be substituted with 1 to 3 substituents selected from the group consisting of: halogen, (C)1-C6) Alkyl radical (C)1-C6) alkyl-CO-NH-, (C)1-C6) alkoxy-CO-NH-, (C)1-C6) alkyl-CO-NH- (C)1-C6) Alkyl radical (C)1-C6) alkoxy-CO-NH- (C)1-C6) Alkyl radical (C)1-C6) alkoxy-CO-NH- (C)1-C6) Alkoxy, carboxyl (C)1-C6) Alkyl, carboxyl (C)1-C6) Alkoxy, benzyloxycarbonyl (C)1-C6) Alkoxy group, (C)1-C6) Alkoxycarbonyl (C)1-C6) Alkoxy group, (C)6-C10) Aryl, amino (C)1-C6) Alkyl radical (C)1-C6) Alkoxycarbonylamino group, (C)6-C10) Aryl radical (C)1-C6) Alkoxycarbonylamino group, (C)1-C6) Alkylamino group, ((C)1-C6) Alkyl radical)2Amino group, (C)1-C6) Alkylamino radical (C)1-C6) Alkyl group, ((C)1-C6) Alkyl radical)2Amino (C)1-C6) Alkyl, hydroxy, (C)1-C6) Alkoxy, carboxyl (C)1-C6) Alkyl radical (C)1-C6) Alkoxycarbonyl group, (C)1-C6) Alkoxycarbonyl (C)1-C6) Alkyl radical (C)1-C6) alkoxy-CO-NH-, (C)1-C6) alkyl-CO-NH-, cyano, (C)5-C9) Heterocycloalkyl, amino-CO-NH-, (C)1-C6) alkylamino-CO-NH- ((C)1-C6) Alkyl radical)2amino-CO-NH-, (C)6-C10) arylamino-CO-NH-, (C)5-C9) heteroarylamino-CO-NH-, (C)1-C6) alkylamino-CO-NH- (C)1-C6) Alkyl group, ((C)1-C6) Alkyl radical)2amino-CO-NH- (C)1-C6) Alkyl radical (C)6-C10) arylamino-CO-NH- (C)1-C6) Alkyl radical (C)5-C9) Heteroarylamino-CO-NH- (C)1-C6) Alkyl radical (C)1-C6) Alkylsulfonyl group (C)1-C6) Alkylsulfonylamino group (C)1-C6) Alkylsulfonylamino (C)1-C6) Alkyl radical (C)6-C10) Arylsulfonyl (C)6-C10) Arylsulfonylamino group (C)6-C10) Arylsulfonylamino (C)1-C6) Alkyl radical (C)1-C6) Alkylsulfonylamino group (C)1-C6) Alkylsulfonylamino (C)1-C6) Alkyl radical (C)5-C9) Heteroaryl and (C)2-C9) A heterocycloalkyl group;
R2and R3Each independently selected from the group consisting of: hydrogen, deuterium, amino, halogen, hydroxy, nitro, carboxy, (C)2-C6) Alkenyl (C)2-C6) Alkynyl, trifluoromethyl, trifluoromethoxy, (C)1-C6) Alkyl radical (C)1-C6) Alkoxy group, (C)3-C10) Cycloalkyl, wherein alkyl, alkoxy or cycloalkyl may be optionally substituted with 1 to 3 groups selected from: halogen, hydroxy, carboxy, amino (C)1-C6) Alkylthio (C)1-C6) Alkylamino group, ((C)1-C6) Alkyl radical)2Amino group, (C)5-C9) Heteroaryl group, (C)2-C9) Heterocycloalkyl group, (C)3-C9) Cycloalkyl or (C)6-C10) An aryl group; or R2And R3Each independently is (C)3-C10) Cycloalkyl group, (C)3-C10) Cycloalkoxy, (C)1-C6) Alkylamino group, ((C)1-C6) Alkyl radical)2Amino group, (C)6-C10) Arylamino, (C)1-C6) Alkylthio (C)6-C10) Arylthio group, (C)1-C6) Alkylsulfinyl (C)6-C10) Arylsulfinyl (C)1-C6) Alkylsulfonyl group (C)6-C10) Arylsulfonyl (C)1-C6) Acyl radical, (C)1-C6) alkoxy-CO-NH-, (C)1-C6) alkylamino-CO-, (C)5-C9) Heteroaryl group, (C)2-C9) Heterocycloalkyl or (C)6-C10) Aryl, wherein heteroaryl, heterocycloalkyl and aryl may be optionally substituted with 1 to 3 of the following groups: halogen, (C)1-C6) Alkyl radical (C)1-C6) alkyl-CO-NH-, (C)1-C6) alkoxy-CO-NH-, (C)1-C6) alkyl-CO-NH- (C)1-C6) Alkyl radical (C)1-C6) alkoxy-CO-NH- (C)1-C6) Alkyl radical (C)1-C6) alkoxy-CO-NH- (C)1-C6) Alkoxy, carboxyl (C)1-C6) Alkyl, carboxyl (C)1-C6) Alkoxy, benzyloxycarbonyl (C)1-C6) Alkoxy group, (C)1-C6) Alkoxycarbonyl (C)1-C6) Alkoxy group, (C)6-C10) Aryl, amino (C)1-C6) Alkyl radical (C)1-C6) Alkoxycarbonylamino group, (C)6-C10) Aryl radical (C)1-C6) Alkoxycarbonylamino group, (C)1-C6) Alkylamino group, ((C)1-C6) Alkyl radical)2Amino group, (C)1-C6) Alkylamino radical (C)1-C6) Alkyl group, ((C)1-C6) Alkyl radical)2Amino (C)1-C6) Alkyl, hydroxy, (C)1-C6) Alkoxy, carboxyl (C)1-C6) Alkyl radical (C)1-C6) Alkoxycarbonyl group, (C)1-C6) Alkoxycarbonyl (C)1-C6) Alkyl radical (C)1-C6) alkoxy-CO-NH-, (C)1-C6) alkyl-CO-NH-, cyano, (C)5-C9) Heterocycloalkyl, amino-CO-NH-, (C)1-C6) alkylamino-CO-NH- ((C)1-C6) Alkyl radical)2amino-CO-NH-, (C)6-C10) arylamino-CO-NH-, (C)5-C9) heteroarylamino-CO-NH-, (C)1-C6) alkylamino-CO-NH- (C)1-C6) Alkyl group, ((C)1-C6) Alkyl radical)2amino-CO-NH- (C)1-C6) Alkyl radical (C)6-C10) arylamino-CO-NH- (C)1-C6) Alkyl radical (C)5-C9) Heteroarylamino-CO-NH- (C)1-C6) Alkyl radical (C)1-C6) Alkylsulfonyl group (C)1-C6) Alkylsulfonylamino group (C)1-C6) Alkylsulfonylamino (C)1-C6) Alkyl radical (C)6-C10) Arylsulfonyl (C)6-C10) Arylsulfonylamino group (C)6-C10) Arylsulfonylamino (C)1-C6) Alkyl radical (C)1-C6) Alkylsulfonylamino group (C)1-C6) Alkylsulfonylamino (C)1-C6) Alkyl radical (C)5-C9) Heteroaryl or (C)2-C9) A heterocycloalkyl group;
provided that R is5Must be substituted by a group of formula II.
The invention also relates to pharmaceutically acceptable acid addition salts of the compounds of formula I. The acids used to prepare the pharmaceutically acceptable acid addition salts of these base compounds described previously herein are those which form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, benzoate, mesylate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate salts [ i.e., 1' -methylene-bis- (2-hydroxy-3-naphthoate) ].
The invention also relates to base addition salts of formula I. Chemical bases which can be used as reagents for preparing pharmaceutically acceptable basic salts of those compounds of formula I which are acidic in nature are those which form non-toxic basic salts with such compounds. Such non-toxic basic salts include, but are not limited to, those derived from pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine- (meglumine), and basic salts of lower alkanolammonium and other pharmaceutically acceptable organic amines.
The term "Oxone®"is the name of the monopersulfate compound used in the present invention, and its chemical formula is 2KHSO5·KHSO4·K2SO4Commercially available from Aldrich Chemical Company, P.O. Box 2060, Milwaukee, WI 53201, USA.
As used herein, unless otherwise specified, "alkyl" includes saturated monovalent hydrocarbon radicals having straight or branched chains or combinations thereof.
"alkoxy" as used herein includes O-alkyl, wherein "alkyl" is as defined above.
"halo" as used herein, unless otherwise indicated, includes fluoro, chloro, bromo or iodo.
The compounds of the invention may contain double bonds. When such a bond is present, the compounds of the present invention exist as cis and trans isomers and mixtures thereof.
Unless otherwise indicated, alkyl and alkenyl groups as used herein, and alkyl moieties in other groups (e.g., alkoxy groups) as used herein, may be straight or branched chain, and they may also be cyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl) or straight or branched chain and contain cyclic moieties. Unless otherwise indicated, halogen includes fluorine, chlorine, bromine and iodine.
(C) as used herein2-C9) Heterocycloalkyl, meaning pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl (aziridinyl), oxiranyl (oxiranyl), methylenedioxy (methylenedioxy), benzopyranyl (chromenyl), isoxazolidinyl, 1, 3-oxazolidin-3-yl, isothiazolidinyl, 1, 3-thiazolidin-3-yl, 1, 2-pyrazolidin-2-yl, 1, 3-pyrazolidin-1-yl, piperidinyl, thiomorpholinyl, 1, 2-tetrahydrothiazin-2-yl, 1, 3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl, 1, 2-tetrahydrodiazin-2-yl, 1, 3-tetrahydrodiazin-1-yl, tetrahydroazepinyl (azepinyl), piperazinyl, chromanyl, and the like. Said (C)2-C9) The heterocycloalkyl ring being through a carbon atom or sp3The hybrid nitrogen heteroatom linkage, as would be understood by one of ordinary skill in the art.
(C) as used herein2-C9) Heteroaryl means furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1, 3, 5-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 3-oxadiazolyl, 1, 3, 5-thiadiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1, 2, 4-triazinyl, 1, 2, 3-triazinyl, 1, 3, 5-triazinyl, pyrazolo [3, 4-b ] pyrazole]Pyridyl, cinnolinyl, pteridinyl, purinyl, 6, 7-dihydro-5H- [1]Pyridyl, benzo [ b ]]Thiophenyl, 5, 6, 7, 8-tetrahydro-quinoline-3-yl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thioindenyl, isothioindenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazolyl, isoquinolyl, quinolinyl, 2, 3-diazanaphthyl, quinoxalinyl, quinazolinyl, benzoxazinyl, and the like. Said (C)2-C9) Heteroaryl being through a carbon atom or sp3The hybrid nitrogen heteroatom linkage, as would be understood by one of ordinary skill in the art.
(C) as used herein6-C10) Aryl means phenyl or naphthyl.
The compounds of formula (I) may be administered in pharmaceutically acceptable form alone or in combination with one or more additional agents that modulate the immune system of a mammal or with anti-inflammatory agents. Such agents include, but are not limited to, cyclosporin A (e.g., Sandimmune)®Or Neoral®) Rapamycin (rapamycin), FK-506(tacrolimus), leflunomide (leflunomide), deoxyspergualin (deoxyspergualin), mycophenolate mofetil (mycophenolate) (e.g. Cellcept)®) Azathioprine (e.g. Imuran ®), daclizumab (e.g. Zenapax)®) OKT3 (e.g. Orthoclone)®) AtGam, aspirin, acetaminophen, ibuprofen (ibuprofen), naproxen (naproxen), piroxicam (piroxicam), and anti-inflammatory steroids (such as prednisolone (prednisone) or dexamethasone (dexamethasone)). These agents may be administered according to standard modes of administration, in a portion of the same dosage form or in a different dosage form, by the same or different routes of administration, on the same or different schedules.
The compounds of the present invention include all configurational isomers (e.g., cis and trans isomers). The compounds of the invention have asymmetric centers and thus exist in different enantiomers and diastereomers. The present invention relates to the use of all of the optical isomers and stereoisomers of these compounds of the invention and mixtures thereof, as well as to all pharmaceutical compositions and methods of using or containing them. In this regard, the present invention includes both the E and Z configurations. The compounds of formula I may also exist in tautomeric forms. The invention also relates to the use of all these tautomers and mixtures thereof.
The invention also includes pharmaceutical compositions comprising prodrugs of compounds of formula I. The invention also includes methods of treating or preventing diseases that can be treated or prevented with a protein Kinase inhibitor, such as the enzyme Janus Kinase 3, comprising administering a prodrug of a compound of formula I. Compounds of formula I having a free amino, amido, hydroxy or carboxy group may be converted into prodrugs. Prodrugs include compounds in which an amino acid residue or a polypeptide chain of two or more (e.g., two, three, or four) amino acid residues is covalently bonded via a peptide bond to a free amino, hydroxyl, or carboxylic acid group of a compound of formula I. The amino acid residues include the 20 naturally occurring amino acids generally indicated by three characters and also include 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, valine (norvlin), β -alanine, γ -aminobutyric acid, carbamoylornithine (citruline), homocysteine, homoserine, ornithine (ornithine) and methionine sulfone. Prodrugs also include compounds in which carbonates, carbamates, amides and alkyl esters are all covalently bonded to the above substituents in the compound of formula I through the carbonyl carbon of the side chain of the prodrug.
Preferred compounds of formula I include those wherein R5Is optionally substituted with one to three groups selected from deuterium, hydroxy, (C)1-C6) Alkyl, halogen, (C)1-C6) Alkoxy and a radical of the formula II2-C9) Those of heterocycloalkyl.
Other preferred compounds of formula I include those wherein a is 0; b is 1; x is a carbonyl group; c is 0; d is 0; e is 0; f is 0; g is 0.
Other preferred compounds of formula I include those wherein a is 0; b is 1; x is a carbonyl group; c is 0; d is 1; e is 0; f is 0; g is 0.
Other preferred compounds of formula I include those wherein a is 0; b is 1; x is a carbonyl group; c is 1; d is 0; e is 0; f is 0; g is 0.
Other preferred compounds of formula I include those wherein a is 0; b is 1; x is-C (═ N ═ cyano) -; c is 1; d is 0; e is 0; f is 0; g is 0.
Other preferred compounds of formula I include those wherein a is 0; b is 0; c is 0; d is 0; e is 0; f is 0; g is 1; and Z is-C (O) -O-.
Other preferred compounds of formula I include those wherein a is 0; b is 1; x is S (O)n(ii) a n is 2; c is 0; d is 0; e is 0; f is 0; g is 0.
Other preferred compounds of formula I include those wherein a is 0; b is 1; x is S (O)n(ii) a n is 2; c is 0; d is 2; e is 0; f is 1; g is 1; a compound wherein Z is a carbonyl group.
Other preferred compounds of formula I include those wherein a is 0; b is 1; x is S (O)n(ii) a n is 2; c is 0; d is 2; e is 0; f is 1; g is 0.
Other preferred compounds of formula I include those wherein a is 0; b is 1; x is a carbonyl group; c is 1; d is 0; e is 1; y is S (O)n(ii) a n is 2; f is 0; g is 0.
Other preferred compounds of formula I include those wherein a is 0; b is 1; x is S (O)n(ii) a n is 2; c is 1; d is 0; e is 0; f is 0; g is 0.
Other preferred compounds of formula I include those wherein a is 1; b is 1; x is a carbonyl group; c is 1; d is 0; e is 0; f is 0; g is 0.
Other preferred compounds of formula I include those wherein a is 0; b is 1; x is S (O)n(ii) a c is 0; d is 1; e is 1; y is S (O)n(ii) a n is 2; f is 0; conversion of g to 0A compound (I) is provided.
Other preferred compounds of formula I include those wherein a is 0; b is 1; x is S (O)n(ii) a c is 0; d is 1; e is 1; y is S (O)n(ii) a n is 2; f is 1; g is 0 compound.
Other preferred compounds of formula I include those wherein a is 0; b is 1; x is oxygen; c is 0; d is 1; e is 1; y is S (O)n(ii) a n is 2; f is 1; g is 0.
Other preferred compounds of formula I include those wherein a is 0; b is 1; x is oxygen; c is 0; d is 1; e is 1; y is S (O)n(ii) a n is 2; f is 0; g is 0.
Other preferred compounds of formula I include those wherein a is 0; b is 1; x is a carbonyl group; c is 1; d is 1; e is 1; y is S (O)n(ii) a n is 2; f is 0; g is 0.
Other preferred compounds of formula I include those wherein a is 0; b is 1; x is a carbonyl group; c is 1; d is 1; e is 1; y is S (O)n(ii) a n is 2; f is 1; g is 0.
Other preferred compounds of formula I include those wherein R12Is (C)6-C10) Aryl or (C)2-C9) A heteroaryl compound, wherein the aryl or heteroaryl is optionally substituted with one to four groups selected from: hydrogen, halogen, hydroxy, carboxy, trifluoromethyl, (C)1-C6) Alkyl radical (C)1-C6) Alkoxy group, (C)1-C6) alkyl-CO-NH-, amino (C)1-C6) Alkyl radical (C)1-C6) Alkylamino group, ((C)1-C6) Alkyl radical)2Amino, cyano, amino-CO-NH-, (C)1-C6) alkylamino-CO-NH- ((C)1-C6) Alkyl radical)2amino-CO-NH-, (C)5-C9) heteroarylamino-CO-NH-, (C)1-C6) Alkylsulfonyl group (C)1-C6) Alkylsulfonylamino group (C)6-C10) Aryl sulfonic acidAcylamino group, (C)1-C6) Alkylsulfonylamino and (C)1-C6) alkoxy-CO-NH-.
Particularly preferred compounds of formula I include those selected from the group consisting of:
4- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-ylmethyl } -benzenesulfonamide;
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (4-sulfamoyl-phenyl) -amide;
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (4-nitro-phenyl) -amide;
1- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -2-tetrazol-1-yl-ethanone (ethanone);
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (4-methylsulfamoyl-phenyl) -amide;
(3-hydroxy-pyrrolidin-1-yl) - { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -methanone (methanone);
[2- ({ 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carbonyl } -amino) -thiazol-4-yl ] -acetic acid;
methyl- (4-methyl-5 '-nitro-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-3-yl) - (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amine;
5- (2- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -2-oxo-ethyl) -thiazolidine-2, 4-dione;
{ 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -thiazolidin-3-yl-methanone;
methyl- [ 4-methyl-1- (5-nitro-thiazol-2-yl) -piperidin-3-yl ] - (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amine;
ethyl [2- ({ 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carbonyl } -amino) -thiazol-4-yl ] -acetate;
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (4-methanesulfonyl-phenyl) -amide;
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid thiazol-2-ylamide;
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (4-cyano-phenyl) -amide;
{ 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -pyrrolidin-1-yl-methanone;
furan-2-carboxylic acid (2- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-sulfonyl } -ethyl) -amide;
{ 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } (tetrahydro-furan-3-yl) -methanone;
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid isoxazol-3-ylamide;
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (6-cyano-pyridin-3-yl) -amide;
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -3, 4, 5, 6-tetrahydro-2H- [1, 2 '] bipyridinyl-5' -carbonitrile
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (4-methyl-thiazol-2-yl) -amide;
2-cyclopropyl-1- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -ethanone;
cyclopentyl- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -methanone;
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (3-methyl-isoxazol-4-yl) -amide;
[4- ({ 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carbonyl } -amino) -phenyl ] -acetic acid;
[1- (5-amino-thiazol-2-yl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amine;
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (3-methyl-isothiazol-5-yl) -amide;
3- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carbonyl } -cyclopentanone;
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid benzyl-methyl-amide; and
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid dimethylamide.
The present invention also relates to a pharmaceutical composition for (a) treating or preventing the following diseases or conditions in mammals, including humans: selected from organ transplant rejection, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I diabetes and diabetic complications, cancer, asthma, atopic skin diseases, autoimmune thyroid diseases, ulcerative colitis, Crohn's disease, alzheimer's disease, leukemia and other autoimmune diseases, or (b) inhibition of protein kinases or Janus Kinase 3(JAK3) in mammals including humans, comprising an amount of a compound of formula I or a pharmaceutically acceptable salt thereof effective for said disease or condition and a pharmaceutically acceptable carrier.
The present invention also relates to a method of inhibiting protein tyrosine kinases or janus kinase 3(JAK3) in a mammal, including a human, comprising administering to said mammal an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
The present invention also relates to a method of treatment or prophylaxis of a disease or condition selected from organ transplant rejection, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I diabetes and diabetic complications, cancer, asthma, atopic skin diseases, autoimmune thyroid diseases, ulcerative colitis, Crohn's disease, alzheimer's disease, leukaemia and other autoimmune diseases in a mammal, including a human, which comprises administering to said mammal an amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, effective in the treatment of such diseases.
Detailed Description
The following reaction scheme illustrates the preparation of the compounds of the present invention. R in this reaction scheme and discussion that follows2、R3、R4And R5The definitions are as above unless otherwise indicated.
Preparation A
Preparation B
Preparation C
Reaction scheme 1
Reaction scheme 2
Reaction scheme 3
In reaction 1 of preparation A, a 4-chloro-5-halopyrrolo [2, 3-d ] pyrimidine compound of formula XX, wherein R is hydrogen or a protecting group such as phenylsulfonyl or tolyl, is converted to a 4-chloro-5-halopyrrolo [2, 3-d ] pyrimidine compound of formula XX, wherein Y is chloro, bromo, or iodo, by reacting the compound of formula XXI with N-chlorosuccinimide, N-bromosuccinimide, or N-iodosuccinimide. The reaction mixture is heated to reflux in chloroform for about 1 hour to about 3 hours, preferably about 1 hour. Alternatively, in reaction 1 for preparation of A, a 4-chloropyrrolo [2, 3-d ] pyrimidine compound of formula XXI, wherein R is hydrogen, is converted to the corresponding 4-chloro-5-of XX, wherein Y is nitro, by reacting the XXI compound with nitric acid; nitropyrrolo [2, 3-d ] pyrimidine, in sulfuric acid at a temperature of about-10 ℃ to about 10 ℃, preferably about 0 ℃, for a reaction time of about 5 minutes to about 15 minutes, preferably about 10 minutes. Conversion of a compound of formula XXI, wherein Y is nitro, to the corresponding 4-chloro-5-aminopyrrolo [2, 3-d ] pyrimidine compound of formula XX, wherein Y is amino, the conversion of XXI to XX is carried out under a variety of conditions known to those skilled in the art, for example palladium hydrogenolysis or by tin (IV) chloride and hydrochloric acid.
In reaction 2 for preparation A, 4-chloro-5-halopyrrolo [2, 3-d ] of formula XX, wherein R is hydrogen]Pyrimidine compounds prepared by treatment of XX with N-butyllithiumTo the corresponding in which R2Is (C)1-C6) An alkyl or benzyl XIX compound, the reaction being carried out at about-78 ℃, and the dianionic intermediate thus formed being reacted with an alkyl halide or benzyl halide at a temperature of about-78 ℃ to room temperature, preferably at room temperature. Alternatively, the dianionic compound thus formed reacts with molecular oxygen to form the corresponding R24-chloro-5-hydroxypyrrolo [2, 3-d ] of formula XIX as hydroxy group]A pyrimidine compound. A compound of formula XX, wherein Y is bromine or iodine and R is benzenesulfonate, is converted to a compound of formula XIX, wherein R is bromine or iodine, by treatment with N-butyllithium at about-78 deg.C, followed by addition of zinc chloride at about-78 deg.C2Is (C)6-C12) Aryl or vinyl. The corresponding organozinc intermediate thus formed is then reacted with aryl iodide or vinyl iodide in the presence of a catalytic amount of palladium. The reaction mixture is stirred at about 50 ℃ to about 80 ℃, preferably about 70 ℃, for about 1 to about 3 hours, preferably about 1 hour.
In reaction 3 of preparation A, the compound of formula XIX is converted to the corresponding compound of formula XVI by treatment with N-butyllithium, lithium diisopropylamine or sodium hydride in the presence of a polar aprotic solvent such as tetrahydrofuran at a temperature of about-78 ℃. The anionic intermediate thus formed is further subjected to the following (a), (b), and (c): (a) when R is3When alkyl or benzyl, with an alkyl halide or benzyl halide at a temperature of about-78 ℃ to room temperature, preferably-78 ℃; (b) when R is3When alkoxy, with an aldehyde or ketone at a temperature of about-78 ℃ to room temperature, preferably-78 ℃; and (c) reacting the corresponding organozinc intermediate formed by the reaction with zinc chloride at a temperature of about-78 ℃ to room temperature, preferably-78 ℃, and then reacting the corresponding organozinc intermediate with aryl iodide or vinyl iodide in the presence of a catalytic amount of palladium. The resulting reaction mixture is stirred at about 50 ℃ to about 80 ℃, preferably about 70 ℃, for about 1 to about 3 hours, preferably about 1 hour. Or, the anion thus formed is reacted with molecular oxygen to form the corresponding R3Is hydroxy, has the formula XVI 4-chloro-6-hydroxypyrrolo [2, 3-d]A pyrimidine compound.
In reaction 1 of preparation B, a 4-chloropyrrolo [2, 3-d ] pyrimidine compound of formula XXI is converted into the corresponding compound of formula XXII in a similar manner to that described above in reaction 3 of preparation A.
In reaction 2 of preparation B, the compound of formula XXII is converted to the corresponding compound of formula XVI in a manner analogous to reactions 1 and 2 of preparation A described above.
In reaction 1 of preparation C, a 4-methylpyridine compound of formula XXXI is converted to the corresponding compound of formula XXX by first alkylation with benzyl chloride in the presence of a polar aprotic solvent such as acetone. The reaction mixture is stirred at about 40 ℃ to about 80 ℃ for about 4 to about 24 hours. The pyridinium intermediate thus formed is then reduced by a reducing agent such as sodium borohydride in the presence of a polar protic solvent such as methanol, ethanol, water or a mixture thereof. The reaction is stirred at about 0 ℃ to about room temperature for about 18 to 24 hours.
In reaction 2 of preparation C, a compound of formula XXX is converted to the corresponding compound of formula XXIX by treating XXX with a boron trifluoride etherate in the presence of a reducing agent and an aprotic solvent such as tetrahydrofuran. The reaction mixture is stirred at about 0 ℃ to room temperature for about 1 to about 3 hours. The intermediate complex thus formed is then basified with aqueous sodium hydroxide at about 0 ℃ to room temperature and re-used with an oxidizing agent such as hydrogen peroxide or Oxone®The treatment is carried out for about 12 to 24 hours.
In reaction 3 of preparation C, the compound of formula XXIX is treated with an oxidizing agent, such as chromium oxide or dimethyl sulfone, oxalyl chloride or SO, at ambient temperature for about 1 to 3 hours3-pyridine complexes. The ketone intermediate thus formed is then reacted with an amine (R) in the presence of an acid such as acetic acid in an organic solvent such as methanol, ethanol or tetrahydrofuran at about room temperature4-NH2) The treatment is for about 2 to about 24 hours. The corresponding imine intermediate thus formed is then treated with a reducing agent such as sodium borohydride or sodium cyanoborohydride or sodium triacetoxyborohydride at ambient temperature for about 2 to about 24 hours.
In reaction 1 of reaction scheme 1, a 4-chloropyrrolo [2, 3-d ] pyrimidine compound of formula XVII, wherein R is phenylsulfonyl or benzyl, is converted to the corresponding compound of formula XVI by treating XVII with benzenesulfonyl chloride, benzylchloride or benzylbromide in the presence of a base such as sodium hydride or potassium carbonate and a polar aprotic solvent such as dimethylformamide or tetrahydrofuran. The reaction mixture is stirred at about 0 ℃ to about 70 ℃, preferably about 30 ℃ for about 1 to about 3 hours, preferably about 2 hours.
In reaction 2 of reaction scheme 1, 4-chloropyrrolo [2, 3-d ] of formula XVI]Pyrimidine compounds and compounds of formula HNR4R5To the corresponding 4-aminopyrrolo [2, 3-d of formula XV]A pyrimidine compound. The reaction is carried out in an alcoholic solvent such as t-butanol, methanol or ethanol or other high boiling organic solvent such as dimethylformamide, triethylamine, 1, 4-dioxane or 1, 2-dichloroethane at a temperature of from about 60 ℃ to about 120 ℃, preferably about 80 ℃, typically for a reaction time of from about 2 hours to about 48 hours, preferably about 16 hours. When R is5In the case of nitrogen-containing heterocycloalkyl, each nitrogen must be protected by a protecting group such as benzyl. R5The removal of the protecting group is carried out under conditions suitable for the particular protecting group, such that the R protecting group used does not react with pyrrolo [2, 3-d ]]The pyrimidine ring has an influence. When using benzyl group, R5The removal of the protecting group is carried out in the presence of hydrogen and a catalyst such as palladium hydroxide/carbon in a solvent such as ethanol. R thus produced5The nitrogen-containing heterocycloalkyl group can be further reacted with a variety of different electrophiles of formula II. For urea formation, electrophiles of formula II, such as isocyanates, carbamates and carbamoyl chlorides, are reacted with the R in a solvent, such as acetonitrile or dimethylformamide, in the presence of a base, such as sodium or potassium carbonate, at a temperature of about 20 ℃ to about 100 ℃5The nitrogen of the heterocycloalkyl group is reacted for a time period of about 24 hours to about 72 hours. For amide and sulfonamide formation, electrophiles of formula II, such as acid chlorides and sulfonyl chlorides, are reacted with the R in a solvent such as methylene chloride in the presence of a base such as pyridine at ambient temperature5Nitrogen reaction of heterocyclic alkyl for about 12 hours to aboutFor 24 hours. The amide can also be formed by reacting a carboxylic acid with the heteroalkyl group in a carbodiimide such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide in a solvent such as methylene chloride at ambient temperature for a reaction time of 12 to 24 hours. For the alkyl group formation process, electrophiles of formula II, such as α, β -unsaturated amides, acids, cyanides, esters and α -haloamides, are reacted with R in a solvent, such as methanol, at ambient temperature5The nitrogen of the heteroalkyl group is reacted for a time period of from about 12 hours to about 18 hours. Alkyl groups can also be formed by reacting an aldehyde with the heteroalkyl group in the presence of a reducing agent such as sodium cyanoborohydride in a solvent such as methanol at ambient temperature for a period of about 12 hours to about 18 hours.
In reaction 3 of reaction scheme 1, the removal of the protecting group from the compound of formula XV, wherein R is phenylsulfonyl, to give the corresponding compound of formula I is carried out by treating the compound of formula XV with a strong base (alkalibase) such as sodium hydroxide or potassium hydroxide in an alcohol solvent such as methanol or ethanol or a mixed solvent such as ethanol/tetrahydrofuran or ethanol/water. The reaction is carried out at room temperature for about 15 minutes to about 1 hour, preferably 30 minutes. Removal of the protecting group from a compound of formula XV, wherein R is benzyl, is carried out by treating the formula XV with sodium in aqueous ammonia at a temperature of about-78 ℃, for a time period of about 15 minutes to about 1 hour.
In reaction 1 of scheme 2, the 4-chloropyrrolo [2, 3-d ] pyrimidine compound of formula XX is converted to the corresponding 4-aminopyrrolo [2, 3-d ] pyrimidine compound of formula XXIV in a manner analogous to reaction 2 of scheme 1 above.
4-amino-5-chloropyrrolo [2, 3-d ] of formula XXIV, wherein R is phenylsulfonyl and Z is bromine or iodine in reaction 2 of reaction scheme 2]The pyrimidine compounds are converted to the corresponding compounds of formula XXIII by subjecting XXIV to the following reactions (a), (b) and (c): (a) when R is2When aryl, it is in a non-polar solvent such as tetrahydrofuran or dioxane, in the presence of a catalytic amount of palladium (0) at a temperature of about 50 ℃ to about 100 ℃, preferably about 70 ℃(ii) with an arylboronic acid for about 2 hours to about 48 hours, preferably about 12 hours; (b) when R is2(ii) alkynyl, by reacting with an alkyne in the presence of catalytic amounts of copper (I) iodide and palladium (0) and a polar solvent such as dimethylformamide at room temperature for about 1 to about 5 hours, preferably about 3 hours; and (c) when R is2In the case of vinyl or styryl, with an olefin or styrene in the presence of a catalytic amount of palladium in dimethylformamide, dioxane or tetrahydrofuran at a temperature of from about 80 ℃ to about 100 ℃, preferably about 100 ℃, for from about 2 hours to about 48 hours, preferably about 48 hours.
In reaction 3 of scheme 2, a compound of formula XXIII is converted to the corresponding compound of formula XV in a similar manner as described above in reaction 3 of preparation A.
In reaction 1 of reaction scheme 3, a compound of formula XXII is converted to the corresponding compound of formula I in a similar manner as in reaction 2 of reaction scheme 1 above.
The compounds of the present invention are basic in nature and can form a wide variety of different salts with a variety of inorganic and organic acids. These salts, while necessarily pharmaceutically acceptable for administration to animals, are always in practice obtained by initially isolating the compound of the invention from the reaction mixture as a pharmaceutically unacceptable salt, then simply converting the salt back to the free base compound state by treatment with an alkaline agent, and then converting the free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the basic compounds of the invention are readily prepared by treating the basic compound with a substantially equivalent amount of the selected inorganic or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol, and after careful evaporation of the solvent, the desired solid salt is readily obtained. The acid addition salt may also be precipitated from the solution by adding a corresponding mineral or organic acid to an organic solvent.
Those compounds of the present invention that are acidic in nature are capable of forming basic salts with a variety of pharmaceutically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly sodium and potassium salts. These salts can be prepared by conventional methods. Chemical bases of the reactants used to prepare the pharmaceutically acceptable basic salts of the present invention are those that form non-toxic basic salts with the acidic compounds of the present invention. Such non-toxic base salts include those derived from pharmaceutically acceptable cations such as sodium, potassium, calcium, magnesium, and the like. These salts can be readily prepared by treating the corresponding acidic compound with an aqueous solution containing the desired pharmaceutically acceptable cation and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they can be prepared by another method, namely: the solution of the lower alkanol of the acidic compound is mixed with the desired alkali metal alkoxide and the resulting solution is evaporated to dryness in the same manner as described above. In each case it is preferred to employ stoichiometric amounts of the reactants to ensure complete reaction and maximum yield of the desired end product.
The compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. The active compounds according to the invention can therefore be formulated for oral, buccal, intranasal, parenteral (e.g. intravenous, intramuscular or subcutaneous) or rectal administration or in a form suitable for administration by inhalation or insufflation. The active compounds of the present invention may also be formulated in sustained release form.
Pharmaceutical compositions for oral administration may be in the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binders (e.g., pregelatinized corn meal, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (such as magnesium stearate, talc or silica); disintegrating agents (such as potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). The tablets may be coated by methods well known in the art. Oral liquid preparations may take the form of solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives, such as suspending agents (e.g. sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia (acacia)); non-aqueous carriers (such as almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl parabens or sorbic acid).
Compositions for buccal administration may take the form of tablets or lozenges formulated in conventional manner.
The active compounds of the invention may be formulated for parenteral administration by injection, for example by conventional catheterization or infusion methods. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The pharmaceutical composition may take the form of suspensions, solutions, emulsions or the like in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active composition may be a powder which is reconstituted with a suitable carrier, such as sterilised water at elevated temperature, prior to use.
The active compounds of the invention may also be formulated in pharmaceutical compositions for rectal use, for example as suppositories or retention enemas, e.g., conventional suppository bases containing cocoa butter or other glycerides.
For intranasal administration or administration by inhalation, the solution or suspension dosage forms of the active compounds of the invention are generally pumped from a pump spray container, squeezed by the patient, or from a pressurized container or a nebulizer, as an aerosol spray, with a propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas, as appropriate. In the case of a pressurized aerosol, the dosage unit may be determined by the piston delivering a metered amount. Pressurized containers or nebulizers may contain solutions or suspensions of the active compounds of the invention. A powder mixture containing a compound of the invention and a suitable powder base such as lactose or starch may be formulated into capsules or cartridges (e.g., made from gelatin) for use in an inhaler or insufflator.
The recommended dose for oral, parenteral or buccal administration of the active compounds according to the invention for the treatment of the above-mentioned diseases (e.g. rheumatoid arthritis) in average adults is, for example, 0.1 to 1000mg of active ingredient per unit dose, which can be administered 1 to 4 times per day.
The dose range of the aerosol formulation used to treat average adult human above-mentioned diseases (e.g. asthma) is preferably from 20 μ g to 1000 μ g of a compound of the present invention per metered dose or per "puff" of the aerosol. The total daily dose of aerosol is in the range of 0.1mg to 1000 mg. It can be administered in several divided doses per day, e.g. 2, 3, 4 or 8 times, each time in 1, 2 or 3 doses.
The compounds of formula (I) may be administered in pharmaceutically acceptable forms alone or in combination with one or more other agents that modulate the immune system of a mammal or with anti-inflammatory agents. The agents described herein include, but are not limited to, cyclosporin A (e.g., Sandimmune)®Or Neoral®Rapamycin, FK-506(Tacrolimus), Leflunomide, deoxyperguerin, mycophenolate (e.g. Cellcept)®) Azathioprine (e.g. Imuran)®) Daclizumab (e.g. Zenapax)®) OKT3 (e.g. Orthocolone)®) AtGam, aspirin, acctamicphen, ibuprofen, naproxen, piroxicam and anti-inflammatory steroids (such as prednisolone or dexamethasone); and these agents may be administered via the same or different routes of administration and with the same or different regimens as part of the same dosage form or in different dosage forms in accordance with standard pharmaceutical practice.
FK506 (Tacrolimus) is administered orally at a dose of 0.10-0.15mg/Kg body weight every 12 hours within the first 48 hours after surgery. This must be monitored by the content of tacrolimus in the serum.
Cyclosporine A (oral or intravenous preparation of Sandimmune, or Neoral)®Oral solution or capsule) is administered at 5mg/Kg body weight every 12 hours within 48 hours after the operation. This must be monitored by the amount of cyclosporine A in the serum。
These active agents may be formulated into sustained release formulations according to methods known to those skilled in the art. Examples of such formulations can be found in US 3538214, 4060598, 4173626, 3119742 and 3492397.
The ability of compounds of formula (I) or their pharmaceutically acceptable salts to inhibit Janus Kinase 3 and thereby demonstrate their effectiveness in treating diseases characterized by Janus Kinase 3 is shown by the following in vitro assay.
Biological assay
Assay for JAK3(JH 1: GST) enzyme
The JAK3 kinase assay utilizes a protein expressed in baculovirus-infected SF9 cells (a fusion protein of GST and the catalytic domain of human JAK3) purified by glutathione-sepharose affinity chromatography. The substrate for this reaction was poly-glutamic acid-tyrosine (PGT (4: 1), Sigmacatalog # P0275), which was spread on Nunc Maxi Sorp plates at a concentration of 100. mu.g/ml overnight at 37 ℃. Plates were washed three times in the morning after coating and JAK3 was added to a solution containing 100. mu.l kinase buffer (50mM HEPES, pH 7.3, 125mM NaCl, 24mM MgCl)2+0.2 μ M ATP +1mM sodium orthovanadate). The reaction was carried out at room temperature for 30 minutes and the plate was washed three more times. The amount of phosphotyrosine in the indicated wells was quantified by standard ELISA analysis using an anti-phosphotyrosine antibody (ICN PY20, Cat. # 69-151-1).
Inhibition of human IL-2 dependent T cell embryo proliferation
This screen measures the inhibitory effect of compounds on IL-2 dependent T cell embryo proliferation in vitro. Since JAK-3 is required for signaling through the IL-2 receptor, inhibitors of cellular activity of JAK-3 should inhibit IL-2 dependent T cell embryo proliferation.
The cells used in this test were isolated from fresh human blood. After isolation of monocytes using accuping system-Histopaque-1077(Sigma # a7054), the monocytes were washed with Lympho-Kwik T (One Lambda,inc., Cat # LK-50T) were isolated by negative selection from primary human T-cells. T-cells at 1-2X 106The concentration of/ml was cultured in medium (RPMI + 10% heat-inactivated fetal bovine serum (Hyclone Cat # A-1111-L) + 1% penicillin/streptomycin (Gibco)) and proliferation was induced by the addition of 10. mu.g/ml PHA (Murex Diagnostics, Cat # HA 16). At 5% CO2After three days at 37 ℃ the cells were washed three times in culture medium and resuspended to a density of 1-2X 106Cells/ml culture medium and 100 units/ml human recombinant IL-2 (R)&D System, Cat # 202-IL). After one week, the cells became IL-2 dependent and were maintained for 3 weeks by adding two equal volumes of medium +100 units/ml IL-2 weekly.
To test the ability of test compounds to inhibit IL-2 dependent T cell proliferation, IL-2 dependent cells were washed 3 times, resuspended in culture medium, and plated in flat-bottomed 96-well microtiter plates (Falcon # 353075). The original test compound in DMSO was serially diluted 2-fold from 10mM and added to three wells starting at 10 μ M. After one hour, 10 units/ml of IL-2 were added to each test well. The plates were then incubated at 37 ℃ with 5% CO2And keeping the temperature for 72 hours. Then use3The plate was pulsed with H-thymidine (0.5. mu. Ci/well) (NEN Cat # NET-027A) and incubated for an additional 18 hours. The plates were then harvested using a 96-well plate harvester and added to proliferating cells as measured by counting on a Packard Top Count scintillation counter3Amount of H-thymidine. The% inhibition of proliferation was plotted against the concentration of test compound. Determining IC from the map50Value (. mu.M).
The following examples illustrate the preparation of the compounds of the invention, but the invention is not limited to the details of the examples. The industrially pure reagents used were not further purified. THF is tetrahydrofuran. DMF is N, N-dimethylformamide. Hewlett Packard 5989 using chemical ionization (ammonium)®Alternatively, low resolution mass spectra were recorded using an Ionization field Fisons (or MicroMass) Atmospheric Pressure Chemical Ionization (APCI) with an acetonitrile/water mixture of 50/50 and 0.1% formic acid as the ionizing agent. The room temperature or ambient temperature is 20-25 deg.C.
Example 1
Furan-2-yl- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -
Piperidin-1-yl } -methanones
Method A
1-benzyl-4-methyl-pyridinium chloride
To a stirred solution of 4-methylpyridine (26ml/0.268mol) in 70ml of acetone was added 31ml (0.286mol) of benzyl chloride. The resulting mixture was stirred at 50 ℃ for 18 hours. After cooling to room temperature, filtration, washing with acetone and drying under reduced pressure gave 38g of the title compound. The filtrate was concentrated under reduced pressure to yield an additional 5.6 g of the title compound (74% combined yield).
LRMS：184。
Method B
1-benzyl-4-methyl-1, 2, 3, 6-tetrahydro-pyridine
To a stirred solution of the product of Process A (38 g/0.171 mol) dissolved in 140mL 10: 1 ethanol/water at 0 deg.C was added 16 g (0.427mol) of sodium borohydride in portions over 25 minutes. The resulting mixture was stirred at room temperature for 18 hours, during which time the reaction was quenched by addition of 100mL of water. The reaction mixture was filtered, the filter cake washed with water and ethyl acetate, and the combined filtrates were concentrated under reduced pressure to remove organics. The residue was diluted with water (100mL) and extracted with 150mL ethyl acetate. Subjecting the extract to Na2SO4Dried and concentrated to dryness in vacuo to give 32g (100%) of the title compound as a yellow oil.
LRMS：188(M+1)。
Method C
1-benzyl-4-methyl-pyridin-3-ol
To method B dissolved in 240mL THF21.4g of NaBH was added to a solution of substance (72.45g/0.387mol)4The mixture was cooled to 0 ℃ and then a boron trifluoride etherate solution (109.4mL in 200mL THF) was added dropwise over 1.5 hours. Upon addition the reaction mixture reached room temperature and was stirred for 2 hours. The reaction was cooled to 0 ℃ and 29.3mL of water was added dropwise over 15 minutes, followed by 2N sodium hydroxide (97.5mL) over 20 minutes. The resulting mixture was stirred at 0 ℃ for 40 minutes and then allowed to reach room temperature. Hydrogen peroxide (30%) (97.5mL) was added dropwise (approximately 30 min) at a rate that did not cause the reaction mixture to exceed 50 ℃. When the addition was complete, the reaction mixture was stirred for 10 minutes and then cooled to 0 ℃. The reaction mixture was reduced in volume to one third of its original volume in 5 minutes by adding concentrated hydrochloric acid (97.5mL) and the pH was adjusted to 9-10 with 6N sodium hydroxide. The resulting mixture was extracted three times with ether, and the combined ether layers were MgSO4Drying and evaporation to dryness in vacuo gave 65.32g (79%) of the title compound as a yellow oil.
LRMS：206.1(M+1)
The other method comprises the following steps: to room temperature and N2Add NaBH to a solution of product of Process B (18.7g/0.1mol) in THF (150mL)4(6.5g/0.170 mol). The slurry was cooled to 0 ℃ and BF was slowly added via an addition funnel3-OEt2(15mL, 16.8g/0.118mol) in THF (25 mL). The rate of addition is sufficiently slow that the temperature of the reaction mixture remains below 0 ℃ at all times. After the addition was complete, the reaction mixture was stirred at 0 ℃ for 1 hour and at room temperature for 1.5 hours. The reaction was cooled to 0 ℃ again and water (50mL) was added slowly to destroy excess borane. The reaction was stirred at room temperature for 2 hours, followed by addition of Oxone at 0 deg.C®(110g/0.343mol) in water (500 mL). The reaction mixture was allowed to warm to room temperature and stirred overnight. Solid-reinforced NaHSO3The reaction was quenched until all excess oxidant was destroyed (KI/starch paper). The pH of the reaction mixture is 1-2. The reaction mixture was then extracted three times with 50mL of ethyl acetate, the pH of the aqueous layer was adjusted to 12 with 6N sodium hydroxide and extracted with ethyl acetate (4 times, 100 mL). The organic layer was washed with brine and MgSO4Drying and vacuumConcentration gave 19.0g (92%) of the title compound as an oil.
LRMS：206.1(M+1)。
Method D
1-benzyl-4-methyl-piperidin-3-ol-toluene-4-sulfonate
To a stirred solution of the product of Process C (65.32g/0.318mol) dissolved in 175mL of acetone and cooled to 0 deg.C, a solution of p-toluenesulfonic acid monohydrate in 350mL of acetone was added (dropwise) over a period of 2 hours, and the resulting mixture was stirred at 0 deg.C for 1.5 hours. The precipitate was filtered and the filter cake was washed with 90mL diisopropyl ether. The solid was then dried in vacuo to give the title compound 58.55g (100%) as a white solid.
LRMS：378.5(M+1)。
Method E
1-benzyl-4-methyl-piperidin-3-one
To a solution of the product of Process D (9.8g/0.026mol) dissolved in 250mL of dichloromethane and cooled to 0 ℃ and 31.7mL of diisopropylethylamine 12.4g of SO dissolved in 153mL of dimethyl sulfone was added dropwise over a period of 40 minutes3-a pyridine complex. Once added, the reaction mixture was stirred at room temperature for 1.5 hours, then 200mL of saturated NaHCO was added3(aqueous) quenching reaction. The dichloromethane was removed in vacuo and the remaining aqueous residue was extracted four times with diisopropyl ether (150 mL). The combined ether layers were washed four times with water (100ml) and Na2SO4Drying and concentration to dryness in vacuo gave 3.81g (72.97%) of the title compound as a yellow oil.
LRMS：204(M+1)。
Method F
(1-benzyl-4-methyl-piperidin-3-yl) -methyl-amine
To a stirred solution of product of method E (3.81g/0.019mol) and 38mL of 2.0M methylamine in THF was added 2.2mL of acetic acid and the resulting mixture was stirred at room temperature for 1.5 h.
Sodium boron trihydroxide (NaB (OAc))3H) (7.94g/0.038mol) of a solid and the new mixture was stirred at room temperature for 18 hours. The reaction was quenched with 2N hydrochloric acid and the pH was adjusted to 1. The reaction mixture was washed twice with ether, then the pH of the aqueous layer was adjusted to 12 with 6N sodium hydroxide (aq) and extracted three times with dichloromethane. The combined dichloromethane layers were washed with Na2SO4Drying, filtration and evaporation to dryness in vacuo gave 3.51g (87.75%) of the title compound as a dark yellow oil.
LRMS：219.1(M+1)。
Method G
(1-benzyl-4-methyl-piperidin-3-yl) -methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amine
A mixture of 4-chloropyrrolo [2, 3-d ] pyrimidine (2.4g, 15.9mmol), product of method F (1.7g, 7.95mmol) and 10mL triethylamine from Davoll (J.Am.chem.Soc., (1960), 82, 131) was heated in a sealed tube at 100 ℃ for 4 days. After cooling to room temperature and concentration under reduced pressure, the residue was purified by flash chromatography (silica gel, 3% methanol/dichloromethane) to yield 1.0g (38%) of the title compound as a colorless oil.
LRMS：336.1(M+1)。
Method H
Methyl- (4-methyl-piperidin-3-yl) - (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amine
To a solution of product of method G (0.7G, 2.19mmol) dissolved in 15mL of ethanol was added 0.5G of 20% palladium hydroxide on carbon (50% water) (Aldrich) and the resulting mixture was stirred at room temperature under hydrogen pressure (50psi) for two days (Parr-Shaker). The filtered reaction mixture of Celite was concentrated to dryness in vacuo and the residue was purified by flash chromatography (silica; 5% methanol/dichloromethane) to yield 0.48g (90%) of the title compound.
LRMS：246.1(M+1)。
Method I
[1- (4-methoxy-benzenesulfonyl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amine
To a stirred solution of 1mL pyridine and 9mL dichloromethane were added 40mg (0.163mmol) of the product of Process H and 20L 4-methoxy-benzenesulfonyl chloride, and the resulting mixture was stirred at room temperature for 18 hours. Then 200mL of saturated NaHCO was added3(aqueous) quenching reaction. The organic layer was removed and the aqueous layer was extracted with dichloromethane. The dichloromethane layer was washed with Na2SO4Dried and concentrated to dryness in vacuo. The residue was purified by PTLC (silica; 10: 1 dichloromethane/methanol) to give 22mg (32%) of the title compound as a pale yellow solid.
LRMS：416.5(M+1)。
The compounds of examples 2-297 were prepared as described in example 1.
Example 2
[1- (4-methoxy-benzenesulfonyl) -4-methyl-piperidin-3-yl ] -methyl- (7H-
Pyrrolo [2, 3-d ] pyrimidin-4-yl) -amines
LRMS：416.
Example 3
(1-benzenesulfonyl-4-methyl-piperidin-3-yl) -methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amine
LRMS：386.
Example 4
2- (2- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-sulfonyl } -ethanone
Yl) -isoindole-1, 3-diones
LRMS：483.
Example 5
Cyclohexanecarboxylic acid (2- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-one-
Sulfonyl } -ethyl) -amides
RMS：463.
Example 6
2-chloro-N- (2- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-ylamino ] -piperidine-1-sulfonyl amide
-ethyl-benzamide
LRMS：492.
Example 7
4-chloro-N- (2- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-sulfonyl
-ethyl-benzamide
LRMS：492.
Example 8
Furan-2-carboxylic acid (2- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid
Sulfonyl } -ethyl) -amides
LRMS：447.
Example 9
3-methoxy-N- (2- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid
Sulfonyl } -ethyl) -benzamides
LRMS：487.
Example 10
Isoxazole-5-carboxylic acid (2- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine
-1-sulfonyl } -ethyl) -amide
LRMS：448.
Example 11
2, 4-difluoro-N- (2- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid
Sulfonyl } -ethyl) -benzamides
LRMS：493.
Example 12
3-chloro-N- (2- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-sulfonyl
-ethyl-benzamide
LRMS：492.
Example 13
3-fluoro-N- (2- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-sulfonyl
-ethyl-benzamide
LRMS：475.
Example 14
2-fluoro-N- (2- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-sulfonyl
-ethyl-benzamide
LRMS：475.
Example 15
4-fluoro-N- (2- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-sulfonyl
-ethyl-benzamide
LRMS：475.
Example 16
N- (2- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-sulfonyl } -
Ethyl) -benzamides
LRMS：457.
Example 17
Cyclopropanecarboxylic acid (2- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-one-
Sulfonyl } -ethyl) -amides
LRMS：421.
Example 18
Cyclopentanecarboxylic acid (2- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-one-
Sulfonyl } -ethyl) -amides
LRMS：449.
Example 19
Cyclopentyl- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -methyl
Ketones
LRMS：342.
Example 20
Tetrahydro-furan-2-carboxylic acid (2- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperazine
Pyridine-1-sulfonyl } -ethyl) -amides
LRMS：451.
Example 21
Tetrahydro-furan-3-carboxylic acid (2- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperazine
Pyridine-1-sulfonyl } -ethyl) -amides
LRMS：451.
Example 22
{ 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } - (tetrahydro-furan)
-2-yl) -methanones
LRMS：344.
Example 23
{ 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } - (tetrahydro-furan)
-3-yl) -methanones
LRMS：344
Example 24
Cyclohexanecarboxylic acid (3- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-one-
3-oxo-propyl-amides
LRMS：427.
Example 25
2-cyclopropyl-1- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -
Ethanones
LRMS：328.
Example 26
2- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carbonyl } -pyrrolidine
-1-Carboxylic acid tert-butyl ester
LRMS：443.
Example 27
{ 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -pyrrolidin-2-one
Alkyl-ketones
LRMS：343.
Example 28
1- (2- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carbonyl } -pyrrole
Alk-1-yl) -ethanone hydrochloride
LRMS：385.
Example 29
Furan-3-yl- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -
Ketone
LRMS：340.
Example 30
{ 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -pyridin-2-yl-
Ketone
LRMS：351.
Example 31
{ 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -phenyl-methanone
LRMS：350.
Example 32
1- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -2-phenyl-ethane
Ketones
LRMS：364.
Example 33
2-cyclopropyl-1- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -
Ethanone hydrochloride
LRMS：364.
Example 34
2- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carbonyl } -pyrrolidine
-1-Carboxylic acid tert-butyl ester
LRMS：443.
Example 35
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid benzamide
LRMS：379.
Example 36
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid benzamide
LRMS：365.
Example 37
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid tetrahydro-furan
-3-yl ester
LRMS：360.
Example 38
1- (4- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carbonyl } -piperidine
-1-yl) -ethanones
LRMS：399.
Example 39
2-cyclopentyl-1- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -
Ethanones
LRMS：356.
Example 40
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid cyclohexanamide
LRMS：371.
EXAMPLE 41
Azetidin (azetidin) -3-yl- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino
Phenyl ] -piperidin-1-yl } -methanone trifluoroacetate
LRMS：443.
Example 42
{ 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -pyrrolidin-1-one
Alkyl-ketones
LRMS：343.
Example 43
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid methyl-phenyl-
Amides of carboxylic acids
LRMS：379.
Example 44
{ 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -morpholin-4-yl-
Ketone
LRMS：359.
Example 45
Methyl- (4-methyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-3-yl) - (7H-pyrrolo [2, 3-d ] pyrimidine
Pyridin-4-yl) -amines
LRMS：323.
Example 46
Methyl- (4-methyl-1-thiazol-2-yl-piperidin-3-yl) - (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amine
LRMS：329.
Example 47
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid pyridin-3-yl
Amides of carboxylic acids
LRMS：366.
Example 48
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (4-fluoro-benzene)
Acyl) -amides
LRMS：383.
Example 49
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (4-nitro-benzene)
Acyl) -amides
LRMS：410.
Example 50
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (4-methoxy-
Phenyl) -amides
LRMS：395.
Example 51
4- ({ 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carbonyl } -amino) -
Benzoic acid ethyl ester
LRMS：437.
Example 52
{ 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -piperidin-1-yl-
Ketone
LRMS：357.
Example 53
Methyl- (4-methyl-5 '-nitro-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-3-yl) - (7H-pyrrolo
[2, 3-d ] pyrimidin-4-yl) -amines
LRMS：368.
Example 54
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (3-fluoro-benzene)
Acyl) -amides
LRMS：383.
Example 55
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (2, 4-difluoro-
Phenyl) -amides
LRMS：401
Example 56
Methyl- [ 4-methyl-1- (pyrrolidine-1-sulfonyl) -piperidin-3-yl ] - (7H-pyrrolo [2, 3-d ] pyrimidine-4-
Radical) -amines
LRMS：379.
Example 57
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (3-methoxy-
Phenyl) -amides
LRMS：395.
Example 58
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (3-nitro-benzene)
Acyl) -amides
LRMS：410.
Example 59
1- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carbonyl } -pyrrolidine
-2-Carboxylic acid methyl ester
LRMS：401.
Example 60
Methyl- [ 4-methyl-1- (5-nitro-thiazol-2-yl) -piperidin-3-yl ] - (7H-pyrrolo [2, 3-d ] pyrimidine-4-
Radical) -amines
LRMS：374.
Example 61
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -3, 4, 5, 6-tetrahydro-2H- [1, 2' ]
Bipyridinyl-5' -carboxylic acid methyl ester
LRMS：381.
Example 62
{ 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -3, 4, 5, 6-tetrahydro-2H- [1, 2' ]
Bipyridinyl-5' -yl } -methanol
LRMS：353.
Example 63
Methyl- [ 4-methyl-1- (piperidine-1-sulfonyl) -piperidin-3-yl ] - (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -
Amine (amino)
LRMS：393.
Example 64
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (3-cyano-benzene)
Acyl) -amides
LRMS：390.
Example 65
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (3, 4-difluoro-
Phenyl) -amides
LRMS：401.
Example 66
Methyl- [ 4-methyl-1- (morpholine-4-sulfonyl) -piperidin-3-yl ] - (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -
Amines as pesticides
LRMS：395.
Example 67
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (4-chloro-benzene)
Acyl) -amides
LRMS：399.
Example 68
Methyl- [ 4-methyl-1- (6-methyl-pyridazin-3-yl) -piperidin-3-yl ] - (7H-pyrrolo [2, 3-d ] pyrimidine-4-
Radical) -amines
LRMS：338.
Example 69
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (4-cyano-benzene)
Acyl) -amides
LRMS：390.
Example 70
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid biphenyl-4-
Amides of carboxylic acids
LRMS：441
Example 71
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (4-trifluoromethyl)
Phenyl-amides
LRMS：433.
Example 72
Methyl- (2- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-sulfonyl
Phenyl-ethyl-carbamic acid benzyl ester
LRMS：501.
Example 73
Cyclopropyl- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -methyl
Ketones
LRMS：314.
Example 74
Cyclobutyl- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -methyl
Ketones
LRMS：328.
Example 75
Tetrahydro-furan-3-carboxylic acid methyl- (2- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino
Yl ] -piperidine-1-sulfonyl } -ethyl) -amide
LRMS：465.
Example 76
Cyclohexanecarboxylic acid methyl- (2- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperazine
Pyridine-1-sulfonyl } -ethyl) -amides
LRMS：477.
Example 77
(5, 7-dichloro-1H-indol-2-yl) - { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino
Phenyl ] -piperidin-1-yl } -methanones
LRMS：458.
Example 78
4- ({ 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carbonyl } -amino) -
Benzoic acid
LRMS：409.
Example 79
(1-benzoxazol-2-yl-4-methyl-piperidin-3-yl) -methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amine
LRMS：363.
Example 80
(1H-indol-2-yl) - { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine
-1-yl } -methanone
LRMS：389.
Example 81
(5-fluoro-1H-indol-2-yl) - { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -
Piperidin-1-yl } -methanones
LRMS：407.
Example 82
(5-methoxy-3-methyl-benzofuran-2-yl) - { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidine
-4-yl) -amino ] -piperidin-1-yl } -methanone
LRMS：434.
Example 83
(5-chloro-benzofuran-2-yl) - { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -
Piperidin-1-yl } -methanones
LRMS：424.
Example 84
{ 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } - (5-nitro-benzene
And furan-2-yl) -methanones
LRMS：435.
Example 85
(5-chloro-2, 3-dihydro-benzofuran-2-yl) - { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidine-4-)
Yl) -amino ] -piperidin-1-yl } -methanones
LRMS：426.
Example 86
(4-hydroxy-piperidin-1-yl) - { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperazine
Pyridin-1-yl } -methanones
LRMS：373.
Example 87
1-2- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carbonyl } -benzo
Furan-5-yl) -ethanones
LRMS：432.
Example 88
1- (3-methyl-2- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carbonyl
1H-indol-5-yl-ethanones
LRMS：445.
Example 89
[1- (5-chloro-benzothiazol-2-yl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrrolo [2, 3-d ] pyrimidine-4-
Radical) -amines
LRMS：413.
Example 90
(3- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carbonyl } -3-aza-ring
-bicyclo [3.1.0] hex-6-yl) -carbamic acid tert-butyl ester
LRMS：470.
Example 91
3- (4-chloro-phenoxy) -1- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine
-1-yl } -propan-1-one
LRMS：428.
Example 92
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid pyridin-2-yl
Amides of carboxylic acids
LRMS：366.
Example 93
1- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carbonyl } -piperidine-4-carboxylic acid
Carboxylic acid amide hydrochloride
LRMS：436
Example 94
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (5-chloro-pyridine)
-2-yl) -amides
LRMS：400.
Example 95
3- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carbonyl } -cyclopentanone
LRMS：356.
Example 96
(3-hydroxy-cyclopentyl) - { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine
-1-yl } -methanone
LRMS：358.
Example 97
4- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carbonyl } -cyclohexanone
LRMS：370.
Example 98
3- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carbonyl } -cyclohexanone
LRMS：370.
Example 99
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (5-nitro-pyri-dine
Pyridin-2-yl) -amides
LRMS：413.
Example 100
[4- ({ 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carbonyl } -amino
Phenyl-acetic acid
LRMS：423.
Example 101
(4-amino-piperidin-1-yl) - { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperazine
Pyridin-1-yl } -methanone hydrochloride
LRMS：408.
Example 102
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (6-methyl-pyri-dine
Pyridin-2-yl) -amides
LRMS：380.
Example 103
1-methyl-4- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carbonyl } -
Pyrrolidin-2-ones
LRMS：371.
Example 104
1-benzyl-3- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carbonyl } -
Pyrrolidin-2-ones
LRMS：447.
Example 105
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (5-trifluoromethyl)
Yl-pyridin-2-Yl) -amides
LRMS：434.
Example 106
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -cyclohexanecarboxylic acid (4-cyano-benzene
Acyl) -amides
LRMS：389.
Example 107
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (4-aminomethyl)
Acyl-phenyl) -amides
LRMS：408.
Example 108
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (4-aminosulfone)
Acyl-phenyl) -amides
LRMS：444.
Example 109
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (5-methyl-thia-ne
Azol-2-yl) -amides
LRMS：386.
Example 110
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (5, 6-dichloro-
Benzothiazol-2-yl) -amides
LRMS：491.
Example 111
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (4-methyl-thia-ne)
Azol-2-yl) -amides
LRMS：386.
Example 112
Azetidin-1-yl- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-
Phenyl } -methanone hydrochloride
LRMS：365.
Example 113
[2- ({ 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carbonyl } -amino
Yl) -Thiazol-4-Yl ] -acetic acid Ethyl ester
LRMS：458.
Example 114
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (4, 5-dimethyl
Yl-thiazol-2-yl) -amides
LRMS：400.
Example 115
[2- ({ 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carbonyl } -amino
Yl) -Thiazol-4-Yl ] -acetic acid
LRMS：430.
Example 116
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid benzothiazole
-2-ylamide
LRMS：422.
Example 117
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid thiazol-2-yl
Amides of carboxylic acids
LRMS：372.
Example 118
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid [6- (2-dimethyl)
Aminoethylamino) -pyridin-3-yl ] -amides
LRMS：452.
Example 119
N- (4-chloro-phenyl) -2- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine
-1-yl } -acetamide
LRMS：413.
Example 120
N, N-dimethyl-2- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid
Phenyl } -acetamide
LRMS：331.
Example 121
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid [6- (2-pyrrole)
Alk-1-yl-ethylamino) -pyridin-3-yl ] -amides
LRMS：478.
Example 122
{2- [5- ({ 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carbonyl } -ammonia
Yl) -pyridin-2-yloxy ] -ethyl } -carbamic acid tert-butyl ester
LRMS：525.
Example 123
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid [6- (2-amino-
Ethoxy) -pyridin-3-yl ] -amides
LRMS：425.
Example 124
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (4-methylaminoacetic acid)
Phenylsulfonyl-phenyl) -amides
LRMS：458.
Example 125
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (4-methanesulfonyl
Phenyl-amides
LRMS：443.
Example 126
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (5-methyl- [1, 3,
4] thiadiazol-2-yl) -amides
LRMS：387.
Example 127
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (4-methylaminoacetic acid)
Phenylsulfonyl-phenyl) -amide hydrochloride
LRMS：495.
Example 128
Methyl- [ 4-methyl-1- (1-phenyl-ethyl) -piperidin-3-yl ] - (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amine
LRMS：350.
Example 129
(3-hydroxy-pyrrolidin-1-yl) - { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -
Piperidin-1-yl } -methanones
LRMS：359.
Example 130
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid tert-butyl ester
LRMS：346.
Example 131
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid [4- (2-dimethyl)
Aminoethyl) -thiazol-2-yl ] -amide
LRMS：443.
Example 132
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid 4-methanesulfonyl
-benzamides
LRMS：457.
Example 133
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (4-acetyl
Aminosulfonyl-phenyl) -amides
LRMS：486.
Example 134
1- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -2-phenyl-ethane
-1, 2-diketones
LRMS：378.
Example 135
Methyl- [ 4-methyl-1- (6-methylamino-pyrimidin-4-yl) -piperidin-3-yl ] - (7H-pyrrolo [2, 3-d ] pyrimidine
-4-yl) -amines
LRMS：353.
Example 136
Methyl- [ 4-methyl-1- (6-pyrrolidin-1-yl-pyrimidin-4-yl) -piperidin-3-yl ] - (7H-pyrrolo [2, 3-d ] pyrimidine
Pyridin-4-yl) -amines
LRMS：393.
Example 137
[1- (6-benzylamino-pyrimidin-4-yl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrrolo [2, 3-d ] pyrimidine
-4-yl) -amines
LRMS：429.
Example 138
N, N-dimethyl-N' - (6- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperazine
Pyridin-1-yl } -pyrimidin-4-yl) -ethane-1, 2-diamine
LRMS：410.
Example 139
[1- (6-chloro-pyrimidin-4-yl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -
Amines as pesticides
LRMS：358.
Example 140
[1- (2-fluoro-benzyl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amine
LRMS：354
Example 141
[1- (2-chloro-pyrimidin-4-yl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -
Amines as pesticides
LRMS：359.
Example 142
[1- (4-chloro-pyrimidin-2-yl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -
Amines as pesticides
LRMS：359.
Example 143
Methyl- [ 4-methyl-1- (2-methylamino-pyrimidin-4-yl) -piperidin-3-yl ] - (7H-pyrrolo [2, 3-d ] pyrimidine
-4-yl) -amines
LRMS：353.
Example 144
Methyl- [ 4-methyl-1- (4-pyrrolidin-1-yl-pyrimidin-2-yl) -piperidin-3-yl ] - (7H-pyrrolo [2, 3-d ] pyrimidine
Pyridin-4-yl) -amines
LRMS：353.
Example 145
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (3-methyl-iso
Oxazol-5-yl) -amides
LRMS：370.
Example 146
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (3-methyl-iso
Oxazol-4-yl) -amides
LRMS：370.
Example 147
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (5-methyl-iso
Oxazol-3-yl) -amides
LRMS：370.
Example 148
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (5-tert-butyl-
Isoxazol-3-yl) -amides
LRMS：412.
Example 149
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid isoxazol-3-
Amides of carboxylic acids
LRMS：356.
Example 150
N-methyl-3- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -
Propionamide
LRMS：331.
Example 151
1- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -propan-2-one
LRMS：302.
Example 152
{ 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -oxy-acetic acid methyl ester
Esters
LRMS：332.
Example 153
(1-cyclohexylmethyl-4-methyl-piperidin-3-yl) -methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amine
LRMS：342.
Example 154
[1- (5-amino-thiazol-2-yl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrrolo [2, 3-d ] pyrimidine-4-
Radical) -amines
LRMS：344.
Example 155
Methyl- (4-methyl-piperidin-3-yl) - (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amine
LRMS：246.
Example 156
3- { 4-methyl-3- [ methyl- (7H-pyrrolo (2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -3-oxo-propionic acid
Methyl ester
LRMS：346.
Example 157
(1-Benzenesulfonylmethyl-4-methyl-piperidin-3-yl) -methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amine
LRMS：400.
Example 158
(3-hydroxy-pyrrolidin-1-yl) - { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -
Piperidin-1-yl } -methanones
LRMS：359.
Example 159
1- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -propane-1, 2-di
Ketones
LRMS：316.
Example 160
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (6-sulfamoyl)
Acyl-pyridin-3-yl) -amides
LRMS：445.
Example 161
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (6-acetamido)
Yl-pyridin-3-Yl) -amides
LRMS：423.
Example 162
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid [4- (2-di-methyl)
Aminoethylamino-ethylaminosulfonyl) -phenyl ] -amides
LRMS：515.
Example 163
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (6-cyano-pyri-dine
Pyridin-3-yl) -amides
LRMS：391.
Example 164
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -3, 4, 5, 6-tetrahydro-2H- [1, 2' ]
Bipyridinyl-5' -sulfonic acid pyridin-2-ylamides
LRMS：479.
Example 165
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid [6- (pyrrolidine)
-1-carbonyl) -pyridin-3-yl ] -amide
LRMS：463.
Example 166
2-imidazol-1-yl-1- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid
Alkyl-ethanone
LRMS：354.
Example 167
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -3, 4, 5, 6-tetrahydro-2H- [1, 2' ]
Bipyridinyl-5' -carboxylic acid methylamides
LRMS：380.
Example 168
{ 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -3, 4, 5, 6-tetrahydro-2H- [1, 2' ]
Bipyridinyl-5' -yl } -morpholin-4-yl-methanones
LRMS：436.
Example 169
5- ({ 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carbonyl } -amino) -
Pyridine-2-carboxylic acid propylamides
LRMS：451.
Example 170
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -3, 4, 5, 6-tetrahydro-2H- [1, 2' ]
Bipyridinyl-5' -carboxylic acid amides
LRMS：366.
Example 171
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -3, 4, 5, 6-tetrahydro-2H- [1, 2' ]
Bipyridinyl-5' -carbonitriles
LRMS：348.
Example 172
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid [4- (pyrrolidine)
-1-sulfonyl) -phenyl ] -amide
LRMS：498.
Example 173
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid [4- (morpholine-4-)
Sulfonyl) -phenyl ] -amides
LRMS：514.
Example 174
(3-hydroxy-pyrrolidin-1-yl) - { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -
Piperidin-1-yl } -methanones
LRMS：359.
Example 175
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid [6- (morpholine-4-)
Carbonyl) -pyridin-3-yl ] -amides
LRMS：479.
Example 176
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid [6- (morpholine-4-)
Carbonyl) -pyridin-3-yl ] -amides
LRMS：479.
Example 177
2-imidazol-1-yl-1- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid
Alkyl-ethanone
LRMS：354.
Example 178
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid isoxazol-3-
Amides of carboxylic acids
LRMS：356.
Example 179
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (2, 5-methyl)
-2H-pyrazol-3-yl) -amide
LRMS：383.
Example 180
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (5-cyclopropyl)
-2-methyl-2H-pyrazol-3-yl) -amide
LRMS：409.
Example 181
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (3-methyl-iso
Thiazol-5-yl) -amides
LRMS：386.
Example 182
4- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-ylmethyl } -benzyl
Acid(s)
LRMS：380.
Example 183
Methyl- [ 4-methyl-5 '- (pyrrolidine-1-sulfonyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-3-
- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amines
LRMS：456.
Example 184
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -3, 4, 5, 6-tetrahydro-2H- [1, 2' ]
Bipyridinyl-5' -sulfonic acid methylamides
LRMS：416.
Example 185
4- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-ylmethyl } -benzenesulfonic acid
Amides of carboxylic acids
LRMS：415.
Example 186
N-tert-butyl-4- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl
Methyl } -benzenesulfonamides
LRMS：472.
Example 187
1- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -2-pyrazole-1-carboxylic acid
Alkyl-ethanones
LRMS：354.
Example 188
Methyl- [ 4-methyl-1- (5-nitro-benzooxazol-2-yl) -piperidin-3-yl ] - (7H-pyrrolo [2, 3-d ] pyrimidine
-4-yl) -amines
LRMS：408.
Example 189
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -3, 4, 5, 6-tetrahydro-2H- [1, 2' ]
Bipyridinyl-5' -sulfonic acid (2-hydroxy-ethyl) -amide
LRMS：446.
Example 190
N-tert-butyl-4- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl
Methyl } -benzenesulfonamides
LRMS：471.
Example 191
N-methyl-2- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid
2-oxo-acetamide
.LRMS：331.
Example 192
[1- (5-Ethanesulfonyl-benzoxazol-2-yl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrrolo [2, 3-d ]
Pyrimidin-4-yl) -amines
LRMS：455.
Example 193
Methyl- [ 4-methyl-1- (5-methyl-benzoxazol-2-yl) -piperidin-3-yl ] - (7H-pyrrolo [2, 3-d ] pyrimidine
-4-yl) -amines
LRMS：377.
Example 194
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (6-chloro-pyridine)
-3-yl) -amides
LRMS：400.
Example 195
Methyl- (4-methyl-1-quinolin-2-yl-piperidin-3-yl) - (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amine
LRMS：373.
Example 196
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -3, 4, 5, 6-tetrahydro-2H- [1, 2' ]
Bipyridinyl-5' -sulfonic acid amides
LRMS：402.
Example 197
1- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -2-pyrrolidine
-1-yl-ethane-1, 2-dione
LRMS：371.
Example 198
Methyl- [ 4-methyl-1- (4-methyl-benzoxazol-2-yl) -piperidin-3-yl ] - (7H-pyrrolo [2, 3-d ] pyrimidine
-4-yl) -amines
LRMS：377.
Example 199
1- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -2-morpholin-4-one
1, 2-dione
LRMS：387.
Example 200
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (6-methanesulfonyl
Yl-pyridin-3-Yl) -amides
LRMS：444.
Example 201
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (6-methanesulfonyl
Yl-pyridin-3-Yl) -amides
LRMS：444.
Example 202
Methyl- [ 4-methyl-1- (6-nitro-benzoxazol-2-yl) -piperidin-3-yl ] - (7H-pyrrolo [2, 3-d ] pyrimidine
-4-yl) -amines
LRMS：408.
Example 203
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (6-methanesulfonyl
Yl-pyridin-3-Yl) -amides
LRMS：444.
Example 204
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (6-methanesulfonyl
Yl-pyridin-3-Yl) -amides
LRMS：444.
Example 205
Methyl- [ 4-methyl-1- (6-nitro-benzoxazol-2-yl) -piperidin-3-yl ] - (7H-pyrrolo [2, 3-d ] pyrimidine
-4-yl) -amines
LRMS：408.
Example 206
Methyl- [ 4-methyl-1- (toluene-3-sulfonyl) -piperidin-3-yl ] - (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -
Amines as pesticides
LRMS：400.
Example 207
Methyl- [ 4-methyl-1- (4-trifluoromethyl-benzenesulfonyl) -piperidin-3-yl ] - (7H-pyrrolo [2, 3-d ] pyrimidine
-4-yl) -amines
LRMS：454.
Example 208
(1-benzothiazol-2-yl-4-methyl-piperidin-3-yl) -methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amine
LRMS：379.
Example 209
[1- (5, 7-dimethyl-benzooxazol-2-yl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrrolo [2, 3-d ]
Pyrimidin-4-yl) -amines
LRMS：391.
Example 210
2- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -benzoxazole
-6-Carboxylic acid methyl ester
LRMS：421.
Example 211
Methyl- [ 4-methyl-1- (6-methyl-benzoxazol-2-yl) -piperidin-3-yl ] - (7H-pyrrolo [2, 3-d ] pyrimidine
-4-yl) -amines
LRMS：377.
Example 212
[1- (6-methoxy-benzoxazol-2-yl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrrolo [2, 3-d ] pyrimidine
Pyridin-4-yl) -amines
LRMS：393.
Example 213
Methyl- [ 4-methyl-1- (5-trifluoromethyl-benzothiazol-2-yl) -piperidin-3-yl ] - (7H-pyrrolo [2, 3-d ]
Pyrimidin-4-yl) -amines
LRMS：447.
Example 214
[1- (5, 7-dichloro-benzoxazol-2-yl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrrolo [2, 3-d ] pyrimidine
Pyridin-4-yl) -amines
LRMS：432.
Example 215
[1- (6-chloro-pyridine-3-sulfonyl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrrolo [2, 3-d ] pyrimidine-4-
Radical) -amines
LRMS：422.
Example 216
[1- (4-chloro-benzenesulfonyl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amine
LRMS：421.
Example 217
[1- (4-fluoro-benzenesulfonyl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -
Amines as pesticides
LRMS：404.
Example 218
4- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-sulfonyl } -benzonitrile
LRMS：411.
Example 219
4- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-sulfonyl } -benzenesulfonate
Acyl fluorides
LRMS：468.
Example 220
2- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-sulfonyl } -benzonitrile
LRMS：411.
Example 221
1- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -2-tetrazole-1-
Alkyl-ethanones
LRMS：356.
Example 222
Methyl- [ 4-methyl-1- (2, 2, 2-trifluoro-ethanesulfonyl) -piperidin-3-yl ] - (7H-pyrrolo [2, 3-d ] pyrimidine
-4-yl) -amines
LRMS：392.
Example 223
[1- (2, 6-difluoro-benzenesulfonyl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrrolo [2, 3-d ] pyrimidine-4-
Radical) -amines
LRMS：422.
Example 224
[1- (4-tert-butyl-benzenesulfonyl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrrolo [2, 3-d ] pyrimidine-4-
Radical) -amines
LRMS：442.
Example 225
[1- (2, 4-difluoro-benzenesulfonyl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrrolo [2, 3-d ] pyrimidine-4-
Radical) -amines
LRMS：422.
Example 226
Methyl- [ 4-methyl-1- (2-trifluoromethyl-benzenesulfonyl) -piperidin-3-yl ] - (7H-pyrrolo [2, 3-d ] pyrimidine
-4-yl) -amines
LRMS：454.
Example 227
[1- (3, 5-bis-trifluoromethyl-benzenesulfonyl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrrolo [2, 3-d ]
Pyrimidin-4-yl) -amines
LRMS：522.
Example 228
[1- (3, 5-dichloro-benzenesulfonyl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrrolo [2, 3-d ] pyrimidine-4-
Radical) -amines
LRMS：455.
Example 229
4- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-sulfonyl } -benzyl ester
Acid(s)
LRMS：431.
Example 230
[1- (6-chloro-pyridine-3-sulfonyl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrrolo [2, 3-d ] pyrimidine-4-
Radical) -amines
LRMS：422.
Example 231
[1- (4-chloro-benzenesulfonyl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -
Amines as pesticides
LRMS：421.
Example 232
[1- (4-fluoro-benzenesulfonyl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -
Amines as pesticides
LRMS：404.
Example 233
4- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-sulfonyl } -benzonitrile
LRMS：411.
Example 234
4- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-sulfonyl } -benzenesulfonate
Acyl fluorides
LRMS：468.
Example 235
2- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-sulfonyl } -benzonitrile
LRMS：411.
Example 236
1- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -2-tetrazole-1-
Alkyl-ethanones
LRMS：356.
Example 237
Methyl- [ 4-methyl-1- (2, 2, 2-trifluoro-ethanesulfonyl) -piperidin-3-yl ] - (7H-pyrrolo [2, 3-d ] pyrimidine
-4-yl) -amines
LRMS：392.
Example 238
[1- (2, 6-difluoro-benzenesulfonyl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrrolo [2, 3-d ] pyrimidine-4-
Radical) -amines
LRMS：422.
Example 239
[1- (4-tert-butyl-benzenesulfonyl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrrolo [2, 3-d ] pyrimidine-4-
Radical) -amines
LRMS：442.
Example 240
[1- (2, 4-difluoro-benzenesulfonyl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrrolo [2, 3-d ] pyrimidine-4-
Radical) -amines
LRMS：422.
Example 241
Methyl- [ 4-methyl-1- (2-trifluoromethyl-benzenesulfonyl) -piperidin-3-yl ] - (7H-pyrrolo [2, 3-d ] pyrimidine
-4-yl) -amines
LRMS：454.
Example 242
[1- (3, 5-bis-trifluoromethyl-benzenesulfonyl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrrolo [2, 3-d ]
Pyrimidin-4-yl) -amines
LRMS：522.
Example 243
[1- (3, 5-dichloro-benzenesulfonyl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrrolo [2, 3-d ] pyrimidine-4-
Radical) -amines
LRMS：455.
Example 244
4- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-sulfonyl } -benzyl ester
Acid(s)
LRMS：431.
Example 245
(3-fluoro-phenyl) - { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-one
Radical-ketone
LRMS：368.
Example 246
Isothiazol-4-yl- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-one
Radical-ketone
LRMS：357.
Example 247
{ 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -thiophen-3-yl-
Ketone
LRMS：356.
Example 248
{ 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } - (5-methyl)
-1H-pyrazol-3-yl) -methanone
LRMS：354.
Example 249
(5-methyl-isoxazol-3-yl) - { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -
Piperidin-1-yl } -methanone.
LRMS：355.
Example 250
{ 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } - (5-methyl-thia-ne
Phen-2-yl) -methanones
LRMS：371.
Example 251
(4-fluoro-phenyl) - { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-one
Radical-ketone
LRMS：368.
Example 252
Methyl- [ 4-methyl-1- (3-nitro-benzenesulfonyl) -piperidin-3-yl ] - (7H-pyrrolo [2, 3-d ] pyrimidine-4-
Radical) -amines
LRMS：431.
Example 253
[1- (3-fluoro-benzenesulfonyl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -
Amines as pesticides
LRMS：404.
Example 254
(2-fluoro-phenyl) - { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-one
Radical-ketone
LRMS：368.
Example 255
(1, 5-dimethyl-1H-pyrazol-3-yl) - { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -
Amino-piperidin-1-yl-methanones
LRMS：368.
Example 256
{ 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } - (2-methyl-thia-ne
Azol-4-yl) -methanones
LRMS：371.
Example 257
{ 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -thiazol-4-yl-
Ketone
LRMS：357.
Example 258
(4-methyl-isothiazol-5-yl) - { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -
Piperidin-1-yl } -methanones
LRMS：371.
Example 259
2, 2-dimethyl-5- (2- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine
-1-yl } -2-oxo-ethyl) - [1, 3] dioxolan-4-one
LRMS：403.
Example 260
2-cyclopropyl-N- (2- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid
Sulfonyl } -ethyl) -acetamide
LRMS：436.
Example 261
N- (2- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-sulfonyl } -
Ethyl) -methanesulfonamides
LRMS：432.
Example 262
(3-hydroxy-pyrrolidin-1-yl) - { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -
Piperidin-1-yl } -methanones
LRMS：359.
Example 263
4- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-ylmethyl } -benzonitrile
LRMS：362.
Example 264
3- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-sulfonyl } -benzenesulfonate
Acyl fluorides
LRMS：469.
Example 265
2, 2-dimethyl-5- (2- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine
-1-yl } -2-oxo-ethyl) - [1, 3] dioxolan-4-one
LRMS：402.
Example 266
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid benzoate
LRMS：381.
Example 267
4- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-ylmethyl } -benzenesulfonic acid
Amides of carboxylic acids
LRMS：416.
Example 268
[1- (1H-imidazol-2-ylmethyl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrrolo [2, 3-d ] pyrimidine-4-
Radical) -amines
LRMS：326.
Example 269
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid 2-chloro-benzyl
Esters
LRMS：415.
Example 270
Methyl- [ 4-methyl-1- (1-methyl-1H-imidazol-2-ylmethyl) -piperidin-3-yl ] - (7H-pyrrolo [2, 3-d ] pyrimidine
Pyridin-4-yl) -amines
LRMS：340.
Example 271
1- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -2-phenoxy-
Ethanones
LRMS：380.
Example 272
2- (4-fluoro-phenoxy) -1- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine
-1-yl } -ethanone
LRMS：381.
Example 273
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid 2, 2, 2-trichloro
-Ethyl ester
LRMS：420.
Example 274
2- (2-chloro-phenoxy) -1- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine
-1-yl } -ethanone
LRMS：415.
Example 275
2- (3-chloro-phenoxy) -1- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine
-1-yl } -ethanone
LRMS：415.
Example 276
2-methanesulfonyl-1- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid
Alkyl-ethanone
LRMS：367.
Example 277
2- (1, 1-dioxo-tetrahydro-thiophen-3-yl) -1- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidine-4-
Yl) -amino ] -piperidin-1-yl } -ethanones
LRMS：407.
Example 278
Methyl- [ 4-methyl-1- (1-phenyl-ethyl) -piperidin-3-yl ] - (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amine
LRMS：351.
Example 279
1- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -2- (toluene
-4-sulfonyl) -ethanones
LRMS：443.
Example 280
2-hydroxy-1- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -b-ethyl ester
Ketones
LRMS：304.
Example 281
1- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -3-nitro-propan-e
-1-ketones
LRMS：347.
Example 282
5- (2- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -2-oxo-
Ethyl) -thiazolidine-2, 4-dione
LRMS：404.
Example 283
3-hydroxy-1- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -propane
-1-ketones
LRMS：318.
Example 284
N- (4- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -4-oxo-
Butyl) -methanesulfonamides
LRMS：410.
Example 285
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid 2, 2-dimethyl
-propyl ester
LRMS：360.
Example 286
1- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -2- (thiazolidine)
-3-sulfonyl) -ethanones
LRMS：440.
Example 287
(3, 4-dihydroxy-pyrrolidin-1-yl) - { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino
Phenyl ] -piperidin-1-yl } -methanones
LRMS：376.
Example 288
4- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carbonyl } -thiazolidine
-2-ketones
LRMS：376
Example 289
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid prop-2-ynyl ester
LRMS：328.
Example 290
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (2-cyano-ethyl ester)
Acyl) -amides
LRMS：342.
Example 291
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (2-cyano-ethyl ester)
Acyl) -amides
LRMS：342.
Example 292
1- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -cyclohexyl } -ethanone oxime
LRMS：302.
Example 293
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid cyanomethyl-
Methyl-amides
LRMS：342.
Example 294
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid isopropyl ester
LRMS：332.
Example 295
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (2-cyano-ethyl ester)
Methyl-amides
LRMS：356.
Example 296
4- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-ylmethyl } -pyridine
-1-alcohols
LRMS：355.
Example 297
{ 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -acetonitrile
LRMS：285.
Example 298
[1- (2-fluoro-benzyl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amine
Method J
To a solution of the product of Process H (50mg, 0.204mmol) dissolved in 5mL of methanol was added 154ul of 2-fluoro-benzaldehyde. The resulting mixture was stirred at room temperature for 4 hours while x mg (y mmol) of sodium cyanoborohydride was added and the new mixture was stirred at room temperature for 18 hours. 2 drops of 1N NaOH (aq) were added and the methanol was removed under reduced pressure. The residue was dissolved in chloroform and washed with water. The aqueous layer was back-washed three times with chloroform, and the combined chloroform extracts were over MgSO4Dried and concentrated to dryness in vacuo. Purification by flash chromatography (silica; 2.5% methanol/chloroform) then gave 36mg (47.5%) of the title compound as a white solid.
LRMS：372.4(M+1)。
The compound of example 299-324 was prepared as described in example 298.
Example 299
(1-benzyl-4-methyl-piperidin-3-yl) -methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amine
LRMS：336.
Example 300
(1-furan-2-ylmethyl-4-methyl-piperidin-3-yl) -methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amine
LRMS：326.
Example 301
[1- (4-methoxy-benzyl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -
Amines as pesticides
LRMS：366.
Example 302
[1- (4-fluoro-benzyl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amine
LRMS：354.
Example 303
Methyl- (4-methyl-1-pyridin-3-ylmethyl-piperidin-3-yl) - (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amine
LRMS：337.
Example 304
Methyl- (4-methyl-1-thiazol-2-ylmethyl-piperidin-3-yl) - (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amine
LRMS：343.
Example 305
Methyl- (4-methyl-1-pyridin-2-ylmethyl-piperidin-3-yl) - (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amine
LRMS：337.
Example 306
Methyl- [ 4-methyl-1- (1-phenyl-ethyl) -piperidin-3-yl ] - (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amine
LRMS：350.
Example 307
(1-benzyl-4-methyl-piperidin-3-yl) -methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amine
LRMS：336.
Example 308
(1-benzyl-4-methyl-piperidin-3-yl) -methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amine
LRMS：336.
Example 309
3- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-ylmethyl } -benzonitrile
LRMS：361.
Example 310
[1- (3-fluoro-benzyl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrido [2, 3-d ] pyrimidin-4-yl) -amine
LRMS：354.
Example 311
[1- (3-methoxy-benzyl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -
Amines as pesticides
LRMS：366.
Example 312
3- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-ylmethyl } -benzyl
Acid(s)
LRMS：380.
Example 313
[1- (2-fluoro-benzyl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amine
LRMS：354.
Example 314
[1- (2, 6-difluoro-benzyl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -
Amines as pesticides
LRMS：372.
Example 315
Methyl- (4-methyl-1-phenethyl-piperidin-3-yl) - (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amine
LRMS：350.
Example 316
[1- (2, 3-difluoro-benzyl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amine
LRMS：372.
Example 317
[1- (3, 4-difluoro-benzyl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -
Amines as pesticides
LRMS：372.
Example 318
[1- (4-Methylsulfonyl-benzyl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrrolo [2, 3-d ] pyrimidine-4-
Radical) -amines
LRMS：414.
Example 319
Methyl- { 4-methyl-1- [4- (piperidine-1-sulfonyl) -benzyl ] -piperidin-3-yl } - (7H-pyrrolo [2, 3-d ] pyrimidine
Pyridin-4-yl) -amines
LRMS：483.
Example 320
[1- (3, 5-difluoro-benzyl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -
Amines as pesticides
LRMS：372.
Example 321
[1- (3-chloro-benzyl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amine
LRMS：371.
Example 322
[1- (3, 5-difluoro-benzyl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -
Amines as pesticides
LRMS：372.
Example 323
[1- (3-chloro-benzyl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amine
LRMS：371.
Example 324
[1- (3, 5-dichloro-benzyl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -
Amines as pesticides
LRMS：405.
Claims (23)
1. A compound of formula I
Or a pharmaceutically acceptable salt thereof, wherein
R1Is a radical of the formula
Wherein y is 0;
R4is (C)1-C6) An alkyl group;
R5is piperidinyl, which must be substituted with 1 to 5 of the following groups: (C)1-C6) Alkyl, cyano (C)1-C6) Alkyl, [ ((C)1-C6) Alkyl radical)2Amino group]Acyl radical (C)1-C6) Alkyl, and a group of formula II:
wherein
a is 0, 1, 2, 3 or 4;
b. c, e, f and g are each 0 or 1;
d is 0, 1, 2 or 3;
x is S (O)2Oxygen or carbonyl;
y is S (O)2Or a carbonyl group; and
z is carbonyl, C (O) O-, C (O) NR-, wherein R is hydrogen or (C)1-C6) An alkyl group; or Z is S (O)2；
R6、R7、R8、R9、R10And R11Each selected from the group consisting of: hydrogen or (C)1-C6) Alkyl, optionally substituted with: deuterium, hydroxy, amino, trifluoromethyl, (C)1-C6) Acyloxy, (C)1-C6) Alkylamino group, ((C)1-C6) Alkyl radical)2Amino, cyano (C)1-C6) Alkyl, trifluoromethyl (C)1-C6) Alkyl, nitro (C)1-C6) Alkyl or (C)1-C6) An acylamino group;
R12is (C)6-C10) Aryl radical, (C)2-C9) Heteroaryl group, (C)3-C10) Cycloalkyl or (C)2-C9) Heterocycloalkyl, wherein said aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with 1 to 4 of the following groups: (C)1-C6) Alkoxy, halogen, oxo, nitro, cyano, (C)1-C6) Alkyl, trifluoromethyl, carboxyl, hydroxyl, (C)1-C6) Alkoxyacyl HN-, carboxy (C)1-C6) Alkyl, amino, (C)1-C6) Alkyl group HN, ((C)1-C6) Alkyl radical)2N, aminosulfonyl, (C)1-C6) Alkoxyacyl (C)1-C6) Alkyl radical (C)1-C6) Alkoxyacyl radical HN (C)1-C6) Alkoxy group, (C)1-C6) Alkylsulfonyl group (C)2-C9) Heterocycloalkyl group, ((C)1-C6) Alkyl radical)2N(C1-C6) Alkyl group, ((C)1-C6) An alkylacylamino group, and (C)1-C6) An alkylaminoacyl group;
R2and R3Each is hydrogen;
provided that R is5Must be substituted by a group of the formula II.
2. The compound of claim 1, wherein a is 0; b is 1; x is a carbonyl group; c is 0; d is 0; e is 0; f is 0; g is 0.
3. The compound of claim 1, wherein a is 0; b is 1; x is a carbonyl group; c is 0; d is 1; e is 0; f is 0 and g is 0.
4. The compound of claim 1, wherein a is 0; b is 1; x is a carbonyl group; c is 1; d is 0; e is 0; f is 0; g is 0.
5. The compound of claim 1, wherein a is 0; b is 0; c is 0; d is 0; e is 0; f is 0; g is 1; z is-C (O) -O-.
6. The compound of claim 1, wherein a is 0; b is 1; x is S (O)n(ii) a n is 2; c is 0; d is 0; e is 0; f is 0; g is 0.
7. A compound according to claim 1, which is a pharmaceutically acceptable salt thereof,wherein a is 0; b is 1; x is S (O)n(ii) a n is 2; c is 0; d is 2; e is 0; f is 1; g is 1; z is a carbonyl group.
8. The compound of claim 1, wherein a is 0; b is 1; x is S (O)n(ii) a n is 2; c is 0; d is 2; e is 0; f is 1; g is 0.
9. The compound of claim 1, wherein a is 0; b is 1; x is a carbonyl group; c is 1; d is 0; e is 1; y is S (O)n(ii) a n is 2; f is 0; g is 0.
10. The compound of claim 1, wherein a is 0; b is 1; x is S (O)n(ii) a n is 2; c is 1; d is 0; e is 0; f is 0; g is 0.
11. The compound of claim 1, wherein a is 1; b is 1; x is a carbonyl group; c is 1; d is 0; e is 0; f is 0; g is 0.
12. The compound of claim 1, wherein a is 0; b is 1; x is S (O)n(ii) a c is 0; d is 1; e is 1; y is S (O)n(ii) a n is 2; f is 0; g is 0.
13. The compound of claim 1, wherein a is 0; b is 1; x is S (O)n(ii) a c is 0; d is 1; e is 1; y is S (O)n(ii) a n is 2; f is 1; g is 0.
14. The compound of claim 1, wherein a is 0; b is 1; x is oxygen; c is 0; d is 1; e is 1; y is S (O)n(ii) a n is 2; f is 1; g is 0.
15. The compound of claim 1, wherein a is 0; b is 1; x is oxygen; c is 0; d is 1; e is 1; y is S (O)n(ii) a n is 2; f is 0; g is 0.
16. The method of claim 1A compound wherein a is 0; b is 1; x is a carbonyl group; c is 1; d is 1; e is 1; y is S (O)n(ii) a n is 2; f is 0; g is 0.
17. The compound of claim 1, wherein a is 0; b is 1; x is a carbonyl group; c is 1; d is 1; e is 1; y is S (O)n(ii) a n is 2; f is 1; g is 0.
18. The compound of claim 1, wherein R12Is (C)6-C10) Aryl or (C)2-C9) Heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one to four groups selected from: halogen, hydroxy, carboxy, trifluoromethyl, (C)1-C6) Alkyl radical (C)1-C6) Alkoxy group, (C)1-C6) alkyl-CO-NH-, amino, (C)1-C6) Alkylamino group, ((C)1-C6) Alkyl radical)2Amino, cyano, (C)1-C6) An alkylsulfonyl group.
19. A compound, wherein said compound is selected from the group consisting of:
4- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-ylmethyl } -benzenesulfonamide;
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (4-sulfamoyl-phenyl) -amide;
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (4-nitro-phenyl) -amide;
1- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -2-tetrazol-1-yl-ethanone;
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (4-methylsulfamoyl-phenyl) -amide;
(3-hydroxy-pyrrolidin-1-yl) - { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -methanone;
[2- ({ 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carbonyl } -amino) -thiazol-4-yl ] -acetic acid;
5- (2- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -2-oxo-ethyl) -thiazolidine-2, 4-dione;
methyl- [ 4-methyl-1- (5-nitro-thiazol-2-yl) -piperidin-3-yl ] - (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amine;
ethyl [2- ({ 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carbonyl } -amino) -thiazol-4-yl ] -acetate;
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (4-methanesulfonyl-phenyl) -amide;
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid thiazol-2-ylamide;
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (4-cyano-phenyl) -amide;
{ 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -pyrrolidin-1-yl-methanone;
furan-2-carboxylic acid (2- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-sulfonyl } -ethyl) -amide;
{ 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } (tetrahydro-furan-3-yl) -methanone;
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid isoxazol-3-ylamide;
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (6-cyano-pyridin-3-yl) -amide;
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (4-methyl-thiazol-2-yl) -amide;
2-cyclopropyl-1- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -ethanone;
cyclopentyl- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -methanone;
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (3-methyl-isoxazol-4-yl) -amide;
[4- ({ 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carbonyl } -amino) -phenyl ] -acetic acid;
[1- (5-amino-thiazol-2-yl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amine;
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid (3-methyl-isothiazol-5-yl) -amide; and
3- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carbonyl } -cyclopentanone;
or a pharmaceutically acceptable salt thereof.
20. A pharmaceutical composition for use in (a) treating or preventing the following diseases or conditions in a mammal: organ transplant rejection, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I diabetes and diabetic complications, cancer, asthma, atopic skin diseases, autoimmune thyroid diseases, ulcerative colitis, crohn's disease, alzheimer's disease, leukemia, and other autoimmune diseases, or (b) inhibition of protein kinases or janus kinases in mammals, which comprises an amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, effective for said disease or condition, alone or in combination with one or more additional agents which modulate the immune system of a mammal or with anti-inflammatory agents, and a pharmaceutically acceptable carrier.
21. Use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for inhibiting a protein kinase or janus kinase in a mammal, wherein a compound of claim 1, or a pharmaceutically acceptable salt thereof, is contained alone or in combination with one or more additional agents that modulate the immune system of a mammal or in combination with an anti-inflammatory agent.
22. Use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for the treatment or prevention of a disease or condition selected from organ transplant rejection, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I diabetes and diabetic complications, cancer, asthma, atopic skin diseases, autoimmune thyroid diseases, ulcerative colitis, crohn's disease, alzheimer's disease, leukemia, and other autoimmune diseases in a mammal, either alone or in combination with one or more additional agents that modulate the immune system of the mammal or in combination with anti-inflammatory agents.
23. The use of any one of claims 21-22, wherein the mammal is a human.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US21428700P | 2000-06-26 | 2000-06-26 | |
| US60/214,287 | 2000-06-26 | ||
| PCT/IB2001/000975 WO2002000661A1 (en) | 2000-06-26 | 2001-06-05 | PYRROLO[2,3-d]PYRIMIDINE COMPOUNDS AS IMMUNOSUPPRESSIVE AGENTS |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1054930A1 HK1054930A1 (en) | 2003-12-19 |
| HK1054930B true HK1054930B (en) | 2008-06-06 |
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