US2016122358A1PendingUtilityA1
Novel substituted pyrazolo-piperazines as casein kinase 1 d/e inhibitors
Est. expiryNov 14, 2033(~7.3 yrs left)· nominal 20-yr term from priority
Inventors:Upender VelaparthiChetan Padmakar DarnePeiying LiuMark D. WittmanBradley C. PearceErika M. V. AraujoBireshwar DasguptaJalathi Surendran NairSakthi Kumaran JanakiramanChandrasekhar Reddy RachamreddyMallikarjuna Rao MettuArul Mozhi Subbiah KaruppiahSubba Reddy BandreddyNagalakshmi PulicharlaRajesh Onkardas BoraShilpa Maheshwarappa HolehattiSelvakumar KumaravelDibakar MullickRamesh Kumar Sistla
A61P 35/00A61P 35/02A61P 43/00A61P 19/02A61P 25/00C07D 487/20C07D 491/147C07D 491/20C07D 519/00C07D 487/10C07D 487/04
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Claims
Abstract
The invention provides compounds of Formula (I): and pharmaceutically acceptable salts thereof. The compounds of Formula (I) inhibit protein kinase activity thereby making them useful as anticancer agents.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound according to Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
X is independently selected from 0 and NH;
R 1 is independently selected from carbocyclyl substituted with 1-5 R 5 , and heterocyclyl comprising carbon atoms and 1 to 3 heteroatoms selected from N, NR 4 , O, S, and substituted with 1-5 R 5 ;
R 2 is independently selected from (i) alkyl optionally substituted with F, Cl, Br, OR b , CN, NR a R a , —C(═O)NR a R a , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , carbocyclyl substituted with 1-8 R 7 , and heterocyclyl comprising carbon atoms and 1 to 4 heteroatoms selected from N, NR 6 , O, S, and substituted with 1-8 R 7 , (ii) cycloalkyl substituted with 1-8 R 7 , and (iii) cycloheteroalkyl substituted with 1-8 R 7 ;
R 3a , R 3b , R 3c , R 3d , R 3e and R 3f are independently selected from H, CN, C 1-4 alkyl substituted with 1-3
R 8 , —C(═O)OR b , —C(═O)NR a R a , —C(═O)R b , —NR a C(═O)R b , —NR a C(═O)OR b , —(CH 2 ) r -carbocyclyl substituted with 1-3 R 8 , and —(CH 2 ) r -heterocyclyl substituted with 1-3 R 8 ;
alternatively, R 3a and R 3b , or R 3c and R 3d , or R 3e and R 3f , together with the carbon atom to which they are both attached form a spiral carbocyclic or heterocyclic ring comprising carbon atoms and 1 to 4 heteroatoms selected from N, O, S, each substituted with 1-5 R 8 ;
alternatively, R 3a and R 3c or R 3b and R 3d together form a heterocyclic ring comprising carbon atoms and 1 to 4 heteroatoms selected from N, O, S, and substituted with 1-5 R 8 ;
R 4 is independently selected from H, C 1-4 alkyl substituted with 0-3 R e , —(CH 2 ) r CN, —(CH 2 ) r OR b ,
(CH 2 ) r S(O) p R c , —(CH 2 ) r C(═O)R b , —(CH 2 ) r NR a R a , —(CH 2 ) r C(═O)NR a R a , —(CH 2 ) r NR a C(═O)R b , —(CH 2 ) r NR a C(═O)OR b , —(CH 2 ) r OC(═O)NR a R a , —(CH 2 ) r NR a C(═O)NR a R a , —(CH 2 ) r C(═O)OR b , —(CH 2 ) r S(O) 2 NR a R a , —(CH 2 ) r NR a S(O) 2 NR a R a , —(CH 2 ) r NR a S(O) 2 R c , (CH 2 ) r -carbocyclyl substituted with 0-3 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-3 R e ;
R 5 , at each occurrence, is independently selected from H, C 1-4 alkyl substituted with 0-3 R e , F, Cl, Br, ═O, CN, NO 2 , —OR b , —(CH 2 ) r CN, —(CH 2 ) r OR b ,
(CH 2 ) r S(O) p R c , —(CH 2 ) r C(═O)R b , —(CH 2 ) r NR a R a , —(CH 2 ) r C(═O)NR a R a , —(CH 2 ) r NR a C(═O)R b , —(CH 2 ) r NR a C(═O)OR b , —(CH 2 ) r OC(═O)NR a R a , —(CH 2 ) r NR a C(═O)NR a R a , —(CH 2 ) r C(═O)OR b , —(CH 2 ) r S(O) 2 NR a R a , —(CH 2 ) r NR a S(O) 2 NR a R a , —(CH 2 ) r NR a S(O) 2 R c , (CH 2 ) r -carbocyclyl substituted with 0-3 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-3 R e ;
R 6 is independently selected from H, —C(═O)R b , —CO(═O)R b , —S(O) p R c , C 1-6 alkyl substituted with 0-5 R e , —(CH 2 ) r —C 3-6 carbocyclyl substituted with 0-5 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-5 R e ;
R 7 , at each occurrence, is independently selected from H, F, Cl, Br, ═O, —(CR d R d ) r CN, NO 2 , —(CR d R d ) r OR b , —S(O) p R c , —C(═O)R b , —(CR d R d ) r NR a R a , —(CR d R d ) r C(═O)NR a R a , —NR a C(═O)R b , —NR a C(═O)OR b , —OC(═O)NR a R a , —NR a C(═O)NR a R a , —(CR d R d ) r C(═O)OR b , —S(O) 2 NR a R a , —NR a S(O) 2 NR a R a , —NR a S(O) 2 R c , C 1-6 alkyl substituted with 0-5 R e , —(CR d R d ) r —C 3-6 carbocyclyl substituted with 0-5 R e ,
and —(CR d R d ) r -heterocyclyl substituted with 0-5 R e ;
R 8 , at each occurrence, is independently selected from H, F, Cl, Br, CN, C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl, C 2-6 alkynyl, —(CH 2 ) r —C 3-6 cycloalkyl substituted with 0-5 R e , —(CH 2 ) r -aryl substituted with 0-5 R e , —(CH 2 ) r -heterocyclyl substituted with 0-5 R e , CO 2 H, —(CH 2 ) r OR b , and —(CH 2 ) r NR a R a ;
R a , at each occurrence, is independently selected from H, CN, C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , —(CH 2 ) r —C 3-10 carbocyclyl substituted with 0-5 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-5 R e ; or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 R e ;
R b , at each occurrence, is independently selected from H, C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , —(CH 2 ) r —C 3-10 carbocyclyl substituted with 0-5 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-5 R e ;
R c , at each occurrence, is independently selected from C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , C 3-6 carbocyclyl, and heterocyclyl;
R d , at each occurrence, is independently selected from H and C 1-4 alkyl substituted with 0-5 R e ;
R e , at each occurrence, is independently selected from F, Cl, Br, CN, NO 2 , ═O, C 1-6 alkyl substituted with 0-5 R f , C 2-6 alkenyl, C 2-6 alkynyl, —(CH 2 ) r —C 3-6 cycloalkyl, —(CH 2 ) r -aryl, —(CH 2 ) r -heterocyclyl, CO 2 H, —(CH 2 ) r OR f , SR f , and —(CH 2 ) r NR f R f ;
R f , at each occurrence, is independently selected from H, C 1-5 alkyl optionally substituted with F, Cl, Br, C 3-6 cycloalkyl, and phenyl, or R f and R f together with the nitrogen atom to which they are both attached form a heterocyclic ring optionally substituted with C 1-4 alkyl;
p, at each occurrence, is independently selected from zero, 1, and 2; and
r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4.
2 . The compound according to claim 1 , having Formula (II):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is independently selected from aryl substituted with 1-4 R 5 , and 5- to 12-membered heteroaryl comprising carbon atoms and 1 to 3 heteroatoms selected from N, NR 4 , O, S, and substituted with 1-4 R 5 ;
R 2 is independently selected from (i) alkyl optionally substituted with F, Cl, Br, OR b , CN, NR a R a , —C(═O)NR a R a , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , carbocyclyl substituted with 1-8 R 7 , and heterocyclyl comprising carbon atoms and 1 to 4 heteroatoms selected from N, NR 6 , O, S, and substituted with 1-8 R 7 , (ii) cycloalkyl substituted with 1-8 R 7 , and (iii) cycloheteroalkyl substituted with 1-8 R 7 ;
R 3a , R 3b , R 3c , and R 3d are independently selected from H, CN, C 1-4 alkyl substituted with 1-3
R 8 , —C(═O)OR b , —C(═O)NR a R a , —C(═O)R b , —NR a C(═O)R b , —NR a C(═O)OR b , —(CH 2 ) r -carbocyclyl substituted with 1-3 R 8 , and —(CH 2 ) r -heterocyclyl substituted with 1-3 R 8 ;
alternatively, R 3a and R 3b , or R 3c and R 3d , or R 3e and R 3f , together with the carbon atom to which they are both attached form a spiral carbocyclic or heterocyclic ring comprising carbon atoms and 1 to 4 heteroatoms selected from N, O, S, each substituted with 0-5 R e ;
alternatively, R 3a and R 3c or R 3b and R 3d together form a heterocyclic ring comprising carbon atoms and 1 to 4 heteroatoms selected from N, O, S, and substituted with 0-5 R e ;
R 4 is independently selected from H and C 1-4 alkyl substituted with 0-3 R e ;
R 5 , at each occurrence, is independently selected from H, C 1-4 alkyl substituted with 0-3 R e , F, Cl, Br, ═O, CN, NO 2 , —OR b , —(CH 2 ) r CN, —(CH 2 ) r OR b ,
(CH 2 ) r S(O) p R c , —(CH 2 ) r C(═O)R b , —(CH 2 ) r NR a R a , —(CH 2 ) r C(═O)NR a R a , —(CH 2 ) r NR a C(═O)R b , —(CH 2 ) r NR a C(═O)OR b , —(CH 2 ) r OC(═O)NR a R a , —(CH 2 ) r NR a C(═O)NR a R a , —(CH 2 ) r C(═O)OR b , —(CH 2 ) r S(O) 2 NR a R a , —(CH 2 ) r NR a S(O) 2 NR a R a , —(CH 2 ) r NR a S(O) 2 R c , (CH 2 ) r -carbocyclyl substituted with 0-3 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-3 R e ;
R 6 is independently selected from H, —C(═O)R b , —CO(═O)R b , —S(O) p R c , C 1-6 alkyl substituted with 0-5 R e , —(CH 2 ) r —C 3-6 carbocyclyl substituted with 0-5 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-5 R e ;
R 7 , at each occurrence, is independently selected from H, F, Cl, Br, ═O, —(CR d R d ) r CN, NO 2 , —(CR d R d ) r OR b , —S(O) p R c , —C(═O)R b , —(CR d R d ) r NR a R a , —(CR d R d ) r C(═O)NR a R a , —NR a C(═O)R b , —NR a C(═O)OR b , —OC(═O)NR a R a , —NR a C(═O)NR a R a , —(CR d R d ) r C(═O)OR b , —S(O) 2 NR a R a , —NR a S(O) 2 NR a R a , —NR a S(O) 2 R c , C 1-6 alkyl substituted with 0-5 R e , —(CR d R d ) r —C 3-6 carbocyclyl substituted with 0-5 R e ,
and —(CR d R d ) r -heterocyclyl substituted with 0-5 R e ;
R 8 , at each occurrence, is independently selected from H, F, Cl, Br, CN, C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl, C 2-6 alkynyl, —(CH 2 ) r —C 3-6 cycloalkyl substituted with 0-5 R e , —(CH 2 ) r -aryl substituted with 0-5 R e , —(CH 2 ) r -heterocyclyl substituted with 0-5 R e , CO 2 H, —(CH 2 ) r OR b , and —(CH 2 ) r NR a R a ;
R a , at each occurrence, is independently selected from H, CN, C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , —(CH 2 ) r —C 3-10 carbocyclyl substituted with 0-5 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-5 R e ; or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 R e ;
R b , at each occurrence, is independently selected from H, C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , —(CH 2 ) r —C 3-10 carbocyclyl substituted with 0-5 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-5 R e ;
R c , at each occurrence, is independently selected from C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , C 3-6 carbocyclyl, and heterocyclyl;
R d , at each occurrence, is independently selected from H and C 1-4 alkyl substituted with 0-5 R e ;
R e , at each occurrence, is independently selected from F, Cl, Br, CN, NO 2 , ═O, C 1-6 alkyl substituted with 0-5 R f , C 2-6 alkenyl, C 2-6 alkynyl, —(CH 2 ) r —C 3-6 cycloalkyl, CO 2 H, —(CH 2 ) r OR f , SR f , and —(CH 2 ) r NR f R f ;
R f , at each occurrence, is independently selected from H, C 1-5 alkyl, C 3-6 cycloalkyl, and phenyl, or R f and R f together with the nitrogen atom to which they are both attached form a heterocyclic ring optionally substituted with C 1-4 alkyl;
p, at each occurrence, is independently selected from zero, 1, and 2; and
r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4.
3 . The compound according to claim 2 , wherein:
R 1 is independently selected from aryl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, thienyl, imidazolyl, thiazolyl, indolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, quinolinyl, isoquinolinyl, each substituted with 1-4 R 4 and R 5 ; R 4 , at each occurrence, is independently selected from H and C 1-4 alkyl substituted with 0-3 R e ; R 5 , at each occurrence, is independently selected from H, C 1-4 alkyl substituted with 0-3 R e , F, Cl, Br, ═O, CN,
NO 2 , —OR b , —S(O) p R c , —CN, —OR b , —(CH 2 ) r C(═O)R b , —(CH 2 ) r NR a R a , —(CH 2 ) r C(═O)NR a R a , —(CH 2 ) r NHC(═O)R b , —(CH 2 ) r NHC(═O)OR b , —(CH 2 ) r OC(═O)NR a R a , —(CH 2 ) r NHC(═O)NR a R a , —(CH 2 ) r C(═O)OR b , —(CH 2 ) r S(O) 2 NR a R a , —(CH 2 ) r NHS(O) 2 NR a R a , —(CH 2 ) r NHS(O) 2 R c , (CH 2 ) r -carbocyclyl substituted with 0-3 R e ,
and —(CH 2 ) r -heterocyclyl substituted with 0-3 R e ;
R a , at each occurrence, is independently selected from H, CN, C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , —(CH 2 ) r —C 3-10 carbocyclyl substituted with 0-5 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-5 R e ; or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 R e ; R b , at each occurrence, is independently selected from H, C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , —(CH 2 ) r —C 3-10 carbocyclyl substituted with 0-5 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-5 R e ; R c , at each occurrence, is independently selected from C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , C 3-6 carbocyclyl, and heterocyclyl; R e , at each occurrence, is independently selected from F, Cl, Br, CN, NO 2 , ═O, C 1-6 alkyl substituted with 0-5 R f , C 2-6 alkenyl, C 2-6 alkynyl, —(CH 2 ) r —C 3-6 cycloalkyl, CO 2 H, —(CH 2 ) r OR f , SR f , and —(CH 2 ) r NR f R f ; R f , at each occurrence, is independently selected from H, C 1-5 alkyl, C 3-6 cycloalkyl, and phenyl, or R f and R f together with the nitrogen atom to which they are both attached form a heterocyclic ring optionally substituted with C 1-4 alkyl; p, at each occurrence, is independently selected from zero, 1, and 2; and r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4.
4 . The compound according to claim 3 , wherein:
R 1 is independently selected from
R 4 , at each occurrence, is independently selected from H, C 1-4 alkyl substituted with 0-3 R e ;
R 5 , at each occurrence, is independently selected from H, C 1-4 alkyl substituted with 0-3 R e , F, Cl, Br, ═O, CN,
NO 2 , —OR b , —S(O) p R c , —CN, —OR b , —(CH 2 ) r C(═O)R b , —(CH 2 ) r NR a R a , —(CH 2 ) r C(═O)NR a R a , —(CH 2 ) r NHC(═O)R b , —(CH 2 ) r NHC(═O)OR b , —(CH 2 ) r OC(═O)NR a R a , —(CH 2 ) r NHC(═O)NR a R a , —(CH 2 ) r C(═O)OR b , —(CH 2 ) r S(O) 2 NR a R a , —(CH 2 ) r NHS(O) 2 NR a R a , —(CH 2 ) r NHS(O) 2 R c , (CH 2 ) r —C 3-6 cycloalkyl, —(CH 2 ) r -aryl substituted with 0-3 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-3 R e ;
R a , at each occurrence, is independently selected from H, CN, C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , —(CH 2 ) r —C 3-10 carbocyclyl substituted with 0-5 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-5 R e ; or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 R e ;
R b , at each occurrence, is independently selected from H, C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , —(CH 2 ) r —C 3-10 carbocyclyl substituted with 0-5 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-5 R e ;
R c , at each occurrence, is independently selected from C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , C 3-6 carbocyclyl, and heterocyclyl;
R e , at each occurrence, is independently selected from F, Cl, Br, CN, NO 2 , ═O, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, —(CH 2 ) r —C 3-6 cycloalkyl, and CO 2 H;
p, at each occurrence, is independently selected from zero, 1, and 2; and
r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4.
5 . The compound according to claim 4 , having Formula (III),
or a pharmaceutically acceptable salt thereof, wherein:
R 2 is independently selected from (i) alkyl optionally substituted with F, Cl, Br, OR b , CN, NR a R a , —C(═O)NR a R a , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , carbocyclyl substituted with 1-8 R 7 , and heterocyclyl comprising carbon atoms and 1 to 4 heteroatoms selected from N, NR 6 , O, S, and substituted with 1-8 R 7 , (ii) cycloalkyl substituted with 1-8 R 7 , and (iii) cycloheteroalkyl substituted with 1-8 R 7 ;
R 3a , R 3b , R 3c , and R 3d are independently selected from H, CN, C 1-4 alkyl substituted with 1-3
R 8 , —C(═O)OR b , —C(═O)NR a R a , —C(═O)R b , —NR a C(═O)R b , —NR a C(═O)OR b , —(CH 2 ) r -carbocyclyl substituted with 1-3 R 8 , and —(CH 2 ) r -heterocyclyl substituted with 1-3 R 8 ;
alternatively, R 3a and R 3b , or R 3c and R 3d , together with the carbon atom to which they are both attached form a spiral carbocyclic or heterocyclic ring comprising carbon atoms and 1 to 4 heteroatoms selected from N, O, S, each substituted with 1-5 R 8 ;
alternatively, R 3a and R 3c or R 3b and R 3d together form a heterocyclic ring comprising carbon atoms and 1 to 4 heteroatoms selected from N, O, S, and substituted with 1-5 R 8 ;
R 5 , at each occurrence, is independently selected from H, C 1-4 alkyl substituted with 0-3 R e , F, Cl, Br, —S(O) p R c , —CN, —OR b , NR a R a , C 3-6 cycloalkyl, aryl substituted with 0-3 R e , and heterocyclyl substituted with 0-3 R e ;
R 6 is independently selected from H, —C(═O)R b , —CO(═O)R b , —S(O) p R c , C 1-6 alkyl substituted with 0-5 R e , —(CH 2 ) r —C 3-6 carbocyclyl substituted with 0-5 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-5 R e ;
R 7 , at each occurrence, is independently selected from H, F, Cl, Br, ═O, —(CR d R d ) r CN, NO 2 , —(CR d R d ) r OR b , —S(O) p R c , —C(═O)R b , —(CR d R d ) r NR a R a , —(CR d R d ) r C(═O)NR a R a , —NR a C(═O)R b , —NR a C(═O)OR b , —OC(═O)NR a R a , —NR a C(═O)NR a R a , —(CR d R d ) r C(═O)OR b , —S(O) 2 NR a R a , —NR a S(O) 2 NR a R a , —NR a S(O) 2 R c , C 1-6 alkyl substituted with 0-5 R e , —(CR d R d ) r —C 3-6 carbocyclyl substituted with 0-5 R e ,
and —(CR d R d ) r -heterocyclyl substituted with 0-5 R e ;
R 8 , at each occurrence, is independently selected from H, F, Cl, Br, CN, C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl, C 2-6 alkynyl, —(CH 2 ) r —C 3-6 cycloalkyl substituted with 0-5 R e , —(CH 2 ) r -aryl substituted with 0-5 R e , —(CH 2 ) r -heterocyclyl substituted with 0-5 R e , CO 2 H, —(CH 2 ) r OR b , and —(CH 2 ) r NR a R a ;
R a , at each occurrence, is independently selected from H, CN, C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , —(CH 2 ) r —C 3-10 carbocyclyl substituted with 0-5 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-5 R e ; or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 R e ;
R b , at each occurrence, is independently selected from H, C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , —(CH 2 ) r —C 3-10 carbocyclyl substituted with 0-5 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-5 R e ;
R c , at each occurrence, is independently selected from C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , C 3-6 carbocyclyl, and heterocyclyl;
R d , at each occurrence, is independently selected from H and C 1-4 alkyl substituted with 0-5 R e ;
R e , at each occurrence, is independently selected from F, Cl, Br, CN, NO 2 , ═O, CO 2 H, C 1-6 alkyl substituted with 0-5 R f , C 2-6 alkenyl, C 2-6 alkynyl, —(CH 2 ) r —C 3-6 cycloalkyl, —(CH 2 ) r OR f , SR f , and —(CH 2 ) r NR f R f ;
R f , at each occurrence, is independently selected from H, C 1-5 alkyl, C 3-6 cycloalkyl, and phenyl, or R f and R f together with the nitrogen atom to which they are both attached form a heterocyclic ring optionally substituted with C 1-4 alkyl;
p, at each occurrence, is independently selected from zero, 1, and 2; and
r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4.
6 . The compound according to claim 5 , wherein:
R 2 is independently selected from
R 3a and R 3b are independently selected from H, CH 2 CH 3 , CH 3 , CH 2 OH, CH 2 CH 2 OH, CH 2 CH 2 OC 1-4 alkyl, CH 2 F, CHF 2 , CH 2 CH 2 F, CF 3 , CH 2 OCHF 2 , CH 2 CN, CH 2 CH 2 CN, CH 2 OC 1-4 alkyl, C(CH 3 ) 3 , CH(CH 3 ) 2 , C(CH 3 ) 20 H, C(CH 3 ) 2 F, C(═O)NH—C 3-6 cycloalkyl, C(═O)NH-heterocyclyl, and —CH 2 -heterocyclyl, wherein the heterocyclyl is independently selected from
R 3c and R 3d are independently selected from H, CH 3 , CH(CH 3 ) 2 , CF 3 , and C 3-6 cycloalkyl;
R 5 , at each occurrence, is independently selected from H, C 1-4 alkyl substituted with 0-3 R e , F, Cl, Br, —S(O) p R c , —CN, —OR b , NR a R a , C 3-6 cycloalkyl, and aryl substituted with 0-3 R e ;
R 7 , at each occurrence, is independently selected from H, F, Cl, Br, ═O, —(CH 2 ) r CN, NO 2 , —(CH 2 ) r OR b , —S(O) p R c , —C(═O)R b , —NR a R a , —C(═O)NR a R a , —NHC(═O)R b , —NHC(═O)OR b , —OC(═O)NR a R a , —NHC(═O)NR a R a , —C(═O)OR b , —S(O) 2 NR a R a , —NHS(O) 2 NR a R a , —NHS(O) 2 R c , C 1-6 alkyl substituted with 0-5 R e , aryl substituted with 0-5 R e , and heterocyclyl substituted with 0-5 R e ;
R 8 , at each occurrence, is independently selected from H, F, Cl, Br, CN, C 1-6 alkyl substituted with 0-5 R e , —(CH 2 ) r —C 3-6 cycloalkyl substituted with 0-5 R e , —(CH 2 ) r -aryl substituted with 0-5 R e , —(CH 2 ) r -heterocyclyl substituted with 0-5 R e , CO 2 H, —(CH 2 ) r OR b , and —(CH 2 ) r NR a R a ;
R a , at each occurrence, is independently selected from H, CN, C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , —(CH 2 ) r —C 3-10 carbocyclyl substituted with 0-5 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-5 R e ; or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 R e ;
R b , at each occurrence, is independently selected from H, C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , aryl substituted with 0-5 R e , and heterocyclyl substituted with 0-5 R e ;
R c , at each occurrence, is independently selected from C 1-6 alkyl substituted with 0-5 R e , C 3-6 carbocyclyl, and heterocyclyl;
R e , at each occurrence, is independently selected from F, Cl, Br, CN, NO 2 , ═O, CO 2 H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and —(CH 2 ) r —C 3-6 cycloalkyl;
p, at each occurrence, is independently selected from zero, 1, and 2; and
r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4.
7 . The compound according to claim 6 , wherein:
R 2 is independently selected from
R 3a and R 3b are independently H;
R 3c and R 3d are independently H;
R 5 , at each occurrence, is independently selected from H, F, Cl, and Br.
8 . The compound according to claim 5 , wherein:
R 2 is independently selected from
R 3a and R 3b are independently selected from H, CH 2 CH 3 , CH 3 , CH 2 OH, CH 2 CH 2 OH, CH 2 CH 2 OC 1-4 alkyl, CH 2 F, CHF 2 , CH 2 CH 2 F, CF 3 , CH 2 OCHF 2 , CH 2 CN, CH 2 CH 2 CN, CH 2 OC 1-4 alkyl, C(CH 3 ) 3 , CH(CH 3 ) 2 , C(CH 3 ) 2 OH, C(CH 3 ) 2 F, C(═O)NH—C 3-6 cycloalkyl, C(═O)NH-heterocyclyl, and —CH 2 -heterocyclyl, wherein the heterocyclyl is independently selected from
R 3c and R 3d are independently selected from H, CH 3 , CH(CH 3 ) 2 , CF 3 , and C 3-6 cycloalkyl;
R 5 , at each occurrence, is independently selected from H, C 1-4 alkyl substituted with 0-3 R e , F, Cl, Br, —S(O) p R c , —CN, —OR b , NR a R a , C 3-6 cycloalkyl, and aryl substituted with 0-3 R e ;
R 7 , at each occurrence, is independently selected from H, F, Cl, Br, ═O, —(CH 2 ) r CN, NO 2 , —(CH 2 ) r OR b , —S(O) p R c , —C(═O)R b , —NR a R a , —C(═O)NR a R a , —NHC(═O)R b , —NHC(═O)OR b , —OC(═O)NR a R a , —NHC(═O)NR a R a , —C(═O)OR b , —S(O) 2 NR a R a , —NHS(O) 2 NR a R a , —NHS(O) 2 R c , C 1-6 alkyl substituted with 0-5 R e , aryl substituted with 0-5 R e , and heterocyclyl substituted with 0-5 R e ;
R 8 , at each occurrence, is independently selected from H, F, Cl, Br, CN, C 1-6 alkyl substituted with 0-5 R e , —(CH 2 ) r —C 3-6 cycloalkyl substituted with 0-5 R e , —(CH 2 ) r -aryl substituted with 0-5 R e , —(CH 2 ) r -heterocyclyl substituted with 0-5 R e , CO 2 H, —(CH 2 ) r OR b , and —(CH 2 ) r NR a R a ;
R a , at each occurrence, is independently selected from H, CN, C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , —(CH 2 ) r —C 3-10 carbocyclyl substituted with 0-5 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-5 R e ; or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 R e ;
R b , at each occurrence, is independently selected from H, C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , aryl substituted with 0-5 R e , and heterocyclyl substituted with 0-5 R e ;
R c , at each occurrence, is independently selected from C 1-6 alkyl substituted with 0-5 R e , C 3-6 carbocyclyl, and heterocyclyl;
R e , at each occurrence, is independently selected from F, Cl, Br, CN, NO 2 , ═O, CO 2 H C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and —(CH 2 ) r —C 3-6 cycloalkyl;
p, at each occurrence, is independently selected from zero, 1, and 2; and
r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4.
9 . The compound according to claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 3a and R 3b , or R 3c and R 3d , together with the carbon atom to which they are both attached form a spiral carbocyclic or heterocyclic ring comprising carbon atoms and 1 to 4 heteroatoms selected from N, O, S, each substituted with 1-5 R 8 .
10 . The compound according to claim 9 , having Formula (IV):
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is C 3-6 cycloalkyl or heterocyclyl;
R 2 is independently selected from
R 5 , at each occurrence, is independently selected from H, C 1-4 alkyl substituted with 0-3 R e , F, Cl, Br, —S(O) p R c , —CN, —OR b , NR a R a , C 3-6 cycloalkyl, aryl substituted with 0-3 R e , and heterocyclyl substituted with 0-3 R e ;
R 7 , at each occurrence, is independently selected from H, F, Cl, Br, CN, NO 2 , —OR b , —S(O) p R c , —C(═O)R b , —NR a R a , —C(═O)NR a R a , —NHC(═O)R b , —NHC(═O)OR b , —OC(═O)NR a R a , —NHC(═O)NR a R a , —C(═O)OR b , —S(O) 2 NR a R a , C 1-6 alkyl substituted with 0-5 R e , aryl substituted with 0-5 R e , and heterocyclyl substituted with 0-5 R e ;
R 8 , at each occurrence, is independently selected from H, F, Cl, Br, CN, C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl, C 2-6 alkynyl, —(CH 2 ) r —C 3-6 cycloalkyl substituted with 0-5 R e , —(CH 2 ) r -aryl substituted with 0-5 R e , —(CH 2 ) r -heterocyclyl substituted with 0-5 R e , CO 2 H, —(CH 2 ) r OR b , and —(CH 2 ) r NR a R a ;
R a , at each occurrence, is independently selected from H, CN, C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , —(CH 2 ) r —C 3-10 carbocyclyl substituted with 0-5 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-5 R e ; or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 R e ;
R b , at each occurrence, is independently selected from H, C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , aryl substituted with 0-5 R e , and heterocyclyl substituted with 0-5 R e ;
R c , at each occurrence, is independently selected from C 1-6 alkyl substituted with 0-5 R e , C 3-6 carbocyclyl, and heterocyclyl;
R e , at each occurrence, is independently selected from F, Cl, Br, CN, NO 2 , ═O, CO 2 H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and —(CH 2 ) r —C 3-6 cycloalkyl;
p, at each occurrence, is independently selected from zero, 1, and 2; and
r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4.
11 . The compound according to claim 5 , or a pharmaceutically acceptable salt thereof, wherein:
R 3a and R 3c together form a carbocyclic or heterocyclic ring comprising carbon atoms and 1 to 4 heteroatoms selected from N, O, S, wherein the carbocyclic or heterocyclic ring is substituted with 1-5 R 8 ; and R 3b and R 3d are independently selected from H and C 1-4 alkyl.
12 . The compound according to claim 11 , having Formula (V):
or a pharmaceutically acceptable salt thereof, wherein:
R 2 is independently selected from
R 5 , at each occurrence, is independently selected from H, C 1-4 alkyl substituted with 0-3 R e , F, Cl, Br, —S(O) p R c , —CN, —OR b , NR a R a , C 3-6 cycloalkyl, aryl substituted with 0-3 R e , and heterocyclyl substituted with 0-3 R e ;
R 7 , at each occurrence, is independently selected from H, F, Cl, Br, CN, NO 2 , —OR b , —S(O) p R c , —C(═O)R b , —NR a R a , —C(═O)NR a R a , —NHC(═O)R b , —NHC(═O)OR b , —OC(═O)NR a R a , —NHC(═O)NR a R a , —C(═O)OR b , —S(O) 2 NR a R a , C 1-6 alkyl substituted with 0-5 R e , aryl substituted with 0-5 R e , and heterocyclyl substituted with 0-5 R e ;
R a , at each occurrence, is independently selected from H, CN, C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , —(CH 2 ) r —C 3-10 carbocyclyl substituted with 0-5 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-5 R e ; or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 R e ;
R b , at each occurrence, is independently selected from H, C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , aryl substituted with 0-5 R e , and heterocyclyl substituted with 0-5 R e ;
R c , at each occurrence, is independently selected from C 1-6 alkyl substituted with 0-5 R e , C 3-6 carbocyclyl, and heterocyclyl;
R e , at each occurrence, is independently selected from F, Cl, Br, CN, NO 2 , ═O, CO 2 H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and —(CH 2 ) r —C 3-6 cycloalkyl;
p, at each occurrence, is independently selected from zero, 1, and 2; and
r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4.
13 . A pharmaceutical composition comprising one or more compounds of any one of claims 1 - 12 and a pharmaceutically acceptable carrier.
14 . A method of inhibiting casein kinase Iδ/ε activity in a patient, comprising administering to the patient in need thereof, a therapeutically effective amount of one or more compounds according to any one of claims 1 - 12 .
15 . A method for treating a disease, with the pathological conditions of which the activation of casein kinase Iδ/ε is associated, wherein the method comprises administering to a patient, a pharmaceutical composition comprising, as an active ingredient of one or more compounds according to any one of claims 1 - 12 , or the salt thereof, wherein the disease is selected from a circadian rhythm disorder, a neurodegenerative disease, and cancer.Join the waitlist — get patent alerts
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