- 2,5-DISUBSTITUTED 3-METHYL PYRAZINES AND 2,5,6-TRISUBSTITUTED 3-METHYL PYRAZINES AS ALLOSTERIC SHP2 INHIBITORS
-
The present disclosure is directed to inhibitors of SHP2 and their use in the treatment of disease. Also disclosed are pharmaceutical compositions comprising the same.
- -
-
Paragraph 0387
(2018/03/26)
-
- 1-(TRIAZIN-3-YL/PYRIDAZIN-3-YL)-PIPER(-AZINE)IDINE DERIVATIVES AND COMPOSITIONS THEREFOR FOR INHIBITING THE ACTIVITY OF SHP2
-
The present invention relates to compounds of formula I: in which Y1, Y2, Y3, R1, R2a, R2b, R3a, R3b, R4a, R4b, R5a, R5b are defined in the Summary of the Invention; capable of inhibiting the activity of SHP2. The invention further provides a process for the preparation of compounds of the invention, pharmaceutical preparations comprising such compounds and methods of using such compounds and compositions in the management of diseases or disorders associated with the aberrant activity of SHP2.
- -
-
Paragraph 0276; 0277
(2017/01/23)
-
- 1-PYRIDAZIN-/TRIAZIN-3-YL-PIPER(-AZINE)/IDINE/PYROLIDINE DERIVATIVES AND COMPOSITIONS THEREOF FOR INHIBITING THE ACTIVITY OF SHP2
-
The present invention relates to compounds of formula I: in which m, Y1, Y2, Y3, R1, R2a, R2b, R3a, R3b, R4a, R4b, R5a and R5b are defined in the Summary of the Invention; capable of inhibiting the activity of SHP2. The invention further provides a process for the preparation of compounds of the invention, pharmaceutical preparations comprising such compounds and methods of using such compounds and compositions in the management of diseases or disorders associated with the aberrant activity of SHP2.
- -
-
Paragraph 0268
(2017/08/07)
-
- 1 -(TRIAZIN-3-YI_/PYRIDAZIN-3-YL)-PIPER(-AZINE)IDINE DERIVATIVES AND COMPOSITIONS THEREOF FOR INHIBITING THE ACTIVITY OF SHP2
-
The present invention relates to compounds of formula I: in which Y1, Y2, Y3, R1, R2a, R2b, R3a, R3b, R4a, R4b, R5a, R5b are defined in the Summary of the Invention; capable of inhibiting the activity of SHP2. The invention further provides a process for the preparation of compounds of the invention, pharmaceutical preparations comprising such compounds and methods of using such compounds and compositions in the management of diseases or disorders associated with the aberrant activity of SHP2.
- -
-
Paragraph 00255
(2015/08/03)
-
- 1 -PYRIDAZIN-/TRIAZIN-3-YL-PIPER(-AZINE)/IDINE/PYROLIDINE DERIVATIVES AND AND COMPOSITIONS THEREOF FOR INHIBITING THE ACTIVITY OF SHP2
-
The present invention relates to compounds of formula (I): in which m, p,Y1 Y2, Y3, R1, R2a, R2b, R3a, R3b, R4a, R4b, R4a and R5b are defined in the claims; capable of inhibiting the activity of SHP2. The invention further provides a process for the preparation of compounds of the invention, pharmaceutical preparations comprising such compounds and methods of using such compounds and compositions in the management of diseases or disorders associated with the aberrant activity of SHP2.
- -
-
Paragraph 00247
(2015/08/03)
-
- Discovery of a selective allosteric M1 receptor modulator with suitable development properties based on a quinolizidinone carboxylic acid scaffold
-
One approach to ameliorate the cognitive decline in Alzheimer's disease (AD) has been to restore neuronal signaling from the basal forebrain cholinergic system via the activation of the M1 muscarinic receptor. A number of nonselective M1 muscarinic agonists have previously shown positive effects on cognitive behaviors in AD patients, but were limited due to cholinergic adverse events thought to be mediated by the activation of the M2 to M5 subtypes. One strategy to confer selectivity for M1 is the identification of positive allosteric modulators, which would target an allosteric site on the M1 receptor rather than the highly conserved orthosteric acetylcholine binding site. Quinoline carboxylic acids have been previously identified as highly selective M1 positive allosteric modulators with good pharmacokinetic and in vivo properties. Herein is described the optimization of a novel quinolizidinone carboxylic acid scaffold with 4-cyanopiperidines being a key discovery in terms of enhanced activity. In particular, modulator 4i gave high plasma free fractions, enhanced central nervous system (CNS) exposure, was efficacious in a rodent in vivo model of cognition, and afforded good physicochemical properties suitable for further preclinical evaluation.
- Kuduk, Scott D.,Chang, Ronald K.,Di Marco, Christina N.,Pitts, Daniel R.,Greshock, Thomas J.,Ma, Lei,Wittmann, Marion,Seager, Matthew A.,Koeplinger, Kenneth A.,Thompson, Charles D.,Hartman, George D.,Bilodeau, Mark T.,Ray, William J.
-
experimental part
p. 4773 - 4780
(2011/09/20)
-
- Preparation of 4-heteroaryl-4-cyanopiperidines via SNAr substitution reactions
-
The scope and limitations of SNAr substitution reactions of metalated 4-cyanopiperidines with heterocyclic halides were explored. These facile reactions provide rapid access to a wide range of 4-heteroaryl-4-cyanopiperidines and have resulted i
- Chang, Ronald K.,Di Marco, Christina N.,Pitts, Daniel R.,Greshock, Thomas J.,Kuduk, Scott D.
-
scheme or table
p. 6303 - 6306
(2010/01/18)
-
- Discovery of N-{[1-(propylsulfonyl)-4-pyridin-2-ylpiperidin-4-yl]methyl}benzamides as novel, selective and potent GlyT1 inhibitors
-
Employing an iterative analogue library approach, novel potent and selective glycine transporter 1 (GlyT1) inhibitors containing a 4-pyridin-2-ylpiperidine sulfonamide have been discovered. These inhibitors are devoid of time-dependent CYP inhibition activity and exhibit improved aqueous solubility versus the corresponding 4-phenylpiperidine analogues.
- Zhao, Zhijian,Leister, William H.,O'Brien, Julie A.,Lemaire, Wei,Williams Jr., David L.,Jacobson, Marlene A.,Sur, Cyrille,Kinney, Gene G.,Pettibone, Doug J.,Tiller, Philip R.,Smith, Sheri,Hartman, George D.,Lindsley, Craig W.,Wolkenberg, Scott E.
-
scheme or table
p. 1488 - 1491
(2009/11/30)
-
- SUBSTITUTED HETEROCYCLIC ETHERS AND THEIR USE IN CNS DISORDERS
-
The invention encompasses compounds of Formula I, including pharmaceutically acceptable salts, their pharmaceutical compositions, and their use in treating CNS disorders.
- -
-
Page/Page column 36-37
(2009/09/05)
-
- SUBSTITUTED HETEROCYCLIC ETHERS AND THEIR USE IN CNS DISORDERS
-
The invention encompasses compounds of Formula I, including pharmaceutically acceptable salts, their pharmaceutical compositions, and their use in treating CNS disorders.
- -
-
Page/Page column 30
(2008/06/13)
-
- NK-1 AND SEROTONIN TRANSPORTER INHIBITORS
-
The invention encompasses compounds of Formula I, including pharmaceutically acceptable salts, their pharmaceutical compositions, and their use in treating disorders associated with an excess or imbalance of tachykinins or serotonin or both.
- -
-
Page/Page column 91
(2010/11/28)
-
- SUBSTITUTED PYRROLIDIN-3-YL-ALKYL-PIPERIDINES
-
The present invention relates to substituted pyrrolidinyl-3-yl-alkyl-piperidines, their stereoisomers, and pharmaceutically acceptable salts thereof and processes for preparation of the same. The compounds of the present invention are useful in their pharmacological activities such as tachykinin antagonism, especially substance P and neurokinin A antagonism, and the like. Compounds having the property of tachykinin antagonism are indicated for conditions associated with neurogenic inflammation and other diseases described herein.
- -
-
-