WO2023283933A1 - Compounds useful as kras g12d inhibitors - Google Patents
Compounds useful as kras g12d inhibitors Download PDFInfo
- Publication number
- WO2023283933A1 WO2023283933A1 PCT/CN2021/106767 CN2021106767W WO2023283933A1 WO 2023283933 A1 WO2023283933 A1 WO 2023283933A1 CN 2021106767 W CN2021106767 W CN 2021106767W WO 2023283933 A1 WO2023283933 A1 WO 2023283933A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- octan
- diazabicyclo
- methyl
- pyrimidin
- hydroxynaphthalen
- Prior art date
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Definitions
- the invention relates to KRAS G12D inhibitors, herein are Formula (I 0 ) compounds, and pharmaceutical compositions comprising such compounds, useful in the treatment of variety disorders, such as cancer. Also described are methods of inhibiting KRAS G12D activity, as well as methods therewith for treating KRAS G12D-associated disorders, and methods for preparing the Formula (I 0 ) compounds.
- KRAS Zika virus rat sarcoma 2 viral oncogene homolog
- GTP guanosine triphosphate
- GDP guanosine diphosphate
- GTPase activating proteins facilitate hydrolysis of GTP by KRAS while guanine nucleotide exchange factors (GEFs) catalyze GDP dissociation (Vetter et al., Science 2001, 294: 1299-1304) (K. Scheffzek et al., Science, 1997, 277: 333-338) . Under physiological conditions, KRAS is predominantly GDP-bound.
- GEFs epidermal growth factor
- Active KRAS interacts with effector proteins and activates downstream cellular signal transduction pathways, including the RAFMEK-ERK, PI3K-AKT-mTOR, and RalGDS pathways, regulate a wide a range of essential cellular processes, including cell differentiation, growth, and proliferation (Rajalingam, K et al., Biochim. Biophys. Acta, Mol. Cell Res. 1773, 1177-1195) (McCormick et al., Curr. Opin. Biotechnol, 1996, 7, 449–456) . In a regulated KRAS cycle, signaling is turned off upon GTP hydrolysis.
- KRAS-GTP Activating mutations in KRAS, most commonly at codons 12, 13 and 61, impair its intrinsic or GAP-mediated GTPase function, resulting in the accumulation of KRAS-GTP that constitutively active and thereby cause uncontrolled cell growth/proliferation, leading to tumorigenesis and tumor development (Cox AD et al., Small GTPases, 2010, (1) : 2-27) (Prior IA et al., Cancer Res, 2012, 72 (10) : 2457-2467) . Approximately 15%of all human tumors harbor mutant KRAS.
- the G12D mutation in KRAS occurs most frequently and is found in ⁇ 45%of pancreatic ductal adenocarcinoma patients, 13%of colorectal carcinoma patients, 10%of rectal carcinoma patients, 4%of non-small cell lung carcinoma patients and 1.7%of all small cell lung carcinoma patients (A.G. Stephen et al., Cancer Cell, 2014, 25: 272-281) .
- the high frequency of KRAS G12D mutation makes it an ideal drug target but effective drugs targeting G12D-mutated KRAS have not been marketed.
- the present invention relates to compounds that bind directly to KRAS G12D and block its activity. These compounds are provided to be useful as pharmaceuticals with desirable stability, bioavailability, therapeutic index, and toxicity values that are important to their drugability.
- the present disclosure relates compounds of Formula (I 0 ) , Formula (I) or Formular (I′) , which are useful as modulators of KRAS G12D activity, including salts thereof.
- the present disclosure also relates pharmaceutical compositions comprising a compound of Formula (I 0 ) , Formula (I) , Formular (I′) , and/or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
- the present disclosure also relates a method of treating a disease or disorder associated with the activity of KRAS G12D, the method comprising: determining if the subject has a KRAS G12D mutation; and if the subject is determined to have the KRAS G12D mutation, then administering to the subject a therapeutically effective amount of a compound of Formula (I 0 ) , Formula (I) , Formular (I′) , and/or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
- the present disclosure also relates processes and intermediates for making the compounds of Formula (I 0 ) , Formula (I) , Formular (I′) , and/or salts thereof.
- the present disclosure also relates a compound of Formula (I 0 ) , Formula (I) , Formular (I′) , and/or a pharmaceutically acceptable salt thereof, for use in therapy.
- the present disclosure also relates the use of the compounds of Formula (I 0 ) , Formula (I) , Formular (I′) , and/or pharmaceutically acceptable salts thereof, in the manufacture of a medicament for the treatment or prophylaxis of KRAS G12D-associated disorder, such as cancer.
- a medicament for the treatment or prophylaxis of KRAS G12D-associated disorder such as cancer.
- the present disclosure relates at least one compound of Formula (I 0 ) :
- each of n1 or n2 is independently selected from 0 or 1;
- n 0, 1, 2, or 3;
- n 0, 1, or 2;
- X 1 is NH, O, or S
- X 5 is N or CR X5 ; and R X5 is independently selected from -CN or -CF 3 ;
- each of R 3 is independently selected from hydrogen, halogen, C 1-3 alkoxy, or C 1-3 alkyl; or two R 3 together with the C atom to which they are both attached form a 3-to 5-membered cycloalkyl, or 3-to 5- membered halocycloalkyl.
- R′ is H, halogen, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, or -CH 2 CN;
- ring A is a 6-to 10-membered aryl, or 5-to 10-membered heteroaryl, and each of which is independently optionally unsubstituted or substituted with one or more R 1 ; and R 1 is H, halogen, hydroxy, C 1-3 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 2-5 haloalkenyl, C 2-5 haloalkynyl, C 1-3 haloalkoxy, C 1-5 hydroxy alkyl, -NR 4 R 4’ , -NC (O) R 4 , -C (O) NR 4 R 4’ , 3-to 5-membered cycloalkyl, 3-to 5-membered halocycloalkyl, or 3-to 5-membered heterocycloalkyl; and each of R 4 or R 4’ is independently selected from H, -NH 2 , -C 1-3 alkyl, or
- R is:
- each of R 5 is independently selected from halogen, -OH, -NH 2 , -CN, C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkyl, (C 1-3 alkoxy) C 1-3 alkyl-, (C 1-3 alkoxy) C 1-3 alkoxy-, (C 1-3 hydroxyalkoxy) C 1-3 alkoxy-, -C 1-3 alkylene-OC (O) NH (C 1-3 alkyl) , -C 1-3 alkylene-OC (O) N (C 1-3 alkyl) 2 , or each of R 6 or R 7 is independently selected from H or C 1-3 alkyl;
- u is selected from 1, 2, 3, or 4;
- X 0 is H, -OH, -NH 2 , -C 1-3 alkyl, -C 1-3 alkoxy, -C 1-3 alkylene-OC (O) NHC 1-3 alkyl, -C 1-3 alkylene-OC (O) N (C 1-3 alkyl) 2 , -C 1-3 alkylene-N (C 1-3 alkyl) 2 , or -C 1-3 hydroxy alkyl; and each of which can be independently optionally unsubstituted or substituted by a 3-to 7-membered heterocycle with one or more hetero atom independently selected from N, O, or S, and at least one of the hetero atoms is N which is directly connected to one of the C atoms of the C 1-3 alky or C 1-3 hydroxy alkyl, and the 3-to 7-membered heterocycle can be further optionally unsubstituted or substituted by a NH 2 , -OH, halogen, C 1-3 alkyl, C 1-3 al
- Y is C (R N ) 2 or NR N ; each of R N is independently selected from H, halogen, -NH 2 , -CN, -OH, -NHC (O) NHC 1-3 alkyl , -NHC (O) N (C 1-3 alkyl) 2 , -OC (O) NHC 1-3 alkyl, -OC (O) N (C 1-3 alkyl) 2 , -C 1-3 alkylene-NHC (O) NHC 1-3 alkyl, -C 1-3 alkylene-NHC (O) N (C 1-3 alkyl) 2 , -C 1-3 alkylene-OC (O) NHC 1-3 alkyl, -C 1-3 alkylene-OC (O) N (C 1-3 alkyl) 2 , -C 1-3 alkyl, -C 1-3 alkoxy, or each of R 6 or R 7 is independently selected from H or C 1-3 alkyl; each of R 8 , R 9 ,
- R 5 is defined as supra; is a double bond or a single bond to make the 5-5 fused ring system as an 5-5 fused heteroaromatic ring;
- Z is O, S, SO, or SO 2 ;
- ring B is fused with pyridine or pyrimidine ring, and wherein:
- ring B is a saturated or unsaturated 5-or 6-membered heterocyclic amide (lactam) , and each of which is independently optionally unsubstituted or substituted with one or more R 2 ;
- ring B is a saturated or unsaturated 5-or 6-membered heterocyclyl, saturated or unsaturated 5-or 6- membered heterocyclic amide (lactam) , 6-membered aryl, or 5-or 6-membered heteroaryl; and each of ring B is independently optionally unsubstituted or substituted with one or more R 2 .
- each of R 2 is independently H, halogen, C 1-3 haloalkyl, C 1-3 alkyl, C 1-3 alkoxy, or C 3-5 cycloalkyl; or two R 2 together with the C atom to which both R 2 are attached form an oxo, a 3-to 5-membered cycloalkyl, or a 3-to 5-membered heterocyclyl.
- the compound of Formula (I 0 ) is represented by the Formula (I) :
- the compound of Formula (I 0 ) is represented by the Formula (II) :
- the compound of Formula (I 0 ) is represented by the Formula (II-1) :
- the compound of Formula (I 0 ) is represented by the Formula (II-2) :
- the compound of Formula (I 0 ) is represented by the Formula (II-3) :
- the compound of Formula (I 0 ) is represented by the Formula (II-4) :
- the compound of Formula (I 0 ) is represented by the Formula (II-5) :
- the compound of Formula (I 0 ) is represented by the Formula (II-6) :
- the compound of Formula (I 0 ) is represented by the Formula (III) :
- the compound of Formula (I 0 ) is represented by the Formula (III-1) :
- the compound of Formula (I 0 ) is represented by the Formula (III-2) :
- the compound of Formula (I 0 ) is represented by the Formula (III-3) :
- n is 1.
- n1 is 0; n2 is 1; and n is 1.
- n is 2.
- n1 is 0; n2 is 1; and n is 2.
- n1 is 1; n2 is 0; and n is 1.
- n1 is 1; n2 is 0; and n is 2.
- the compound of Formula (I 0 ) is represented by the Formula (I′) :
- the compound of Formula (I 0 ) is represented by the Formula (II′) :
- the compound of Formula (I 0 ) is represented by the Formula (II′-1) :
- the compound of Formula (I 0 ) is represented by the Formula (II′-2) :
- the compound of Formula (I 0 ) is represented by the Formula (II′-3) :
- the compound of Formula (I 0 ) is represented by the Formula (II′-4) :
- the compound of Formula (I 0 ) is represented by the Formula (II′-5) :
- the compound of Formula (I 0 ) is represented by the Formula (II′-6) :
- the compound of Formula (I 0 ) is represented by the Formula (III′) :
- X 2 or X 4 is independently N or CR 2 .
- the compound of Formula (I 0 ) is represented by the Formula (III′-1) :
- the compound of Formula (I 0 ) is represented by the Formula (III′-2) :
- the compound of Formula (I 0 ) is represented by the Formula (III′-3) :
- X 1 is NH.
- X 1 is O or S.
- ring A is a phenyl or benzyl, or 5-, 6-, 7-, 8-, 9-, or 10-membered heteroaryl; and each of which is independently optionally unsubstituted or substituted with 1R 1 , 2R 1 , 3R 1 , 4R 1 , or 5R 1 .
- ring A is a phenyl or benzyl, or 5-or 6-membered heteroaryl, and each of which is independently optionally unsubstituted or substituted with 1R 1 , 2R 1 , or 3R 1 .
- ring A is a phenyl or a benzyl, and each of which is independently optionally unsubstituted or substituted with 1R 1 , 2R 1 , or 3R 1 .
- ring A is a phenyl or a benzyl, and each of which is independently optionally unsubstituted or substituted with 2R 1 or 3R 1 .
- ring A is a phenyl or a benzyl, and each of which is independently optionally unsubstituted or substituted with 3R 1 .
- R 1 is: i) H, F, Cl, Br, hydroxy, methyl, ethyl, propyl, vinyl, ethynyl, propynyl, methoxy, ethoxy; methyl could be substituted with 1F, 2F or 3F; ethyl could be substituted with 1F, 2F or 3F; the methyl group of methoxy could be substituted with 1F, 2F or 3F; or the methyl or the methylene group of ethoxy could be substituted with 1F, 2F, or 3F; ii) -NR 4 R 4
- R 1 is:
- each of R 4 or R 4’ is independently selected from H, methyl, or methoxy.
- R 1 is H, F, Cl, hydroxy, ethyl, ethynyl, or CF 3 .
- Z is S, SO, or SO 2
- ring B is fused with pyridine or pyrimidine ring
- ring B is a saturated or unsaturated 5-or 6-membered heterocyclyl, saturated or unsaturated 5-or 6-membered heterocyclic amide (lactam) , 6-membered aryl, or 5-or 6-membered heteroaryl, and each of ring B is independently optionally unsubstituted or substituted with 1R 2 , 2R 2 , or 3R 2 .
- Z is S
- ring B is fused with pyridine or pyrimidine ring
- ring B is a unsaturated 5-or 6-membered heterocyclyl, saturated or unsaturated 5-or 6-membered heterocyclic amide (lactam) , 6-membered aryl, or 6-membered heteroaryl, and each of ring B is independently optionally unsubstituted or substituted with 1R 2 , 2R 2 , or 3R 2 .
- Z is S
- ring B is fused with pyridine or pyrimidine ring
- ring B is an unsaturated 6-membered heterocyclyl, or saturated or unsaturated 6-membered heterocyclic amide (lactam)
- each of ring B is independently optionally unsubstituted or substituted with 3R 2 .
- Z is S
- ring B is fused with pyridine or pyrimidine ring
- ring B is a unsaturated 6-membered heterocyclyl, or unsaturated 6-membered heterocyclic amide (lactam)
- each of ring B is independently optionally unsubstituted or substituted with 3R 2 .
- Z is S
- ring B is fused with pyridine or pyrimidine ring
- ring B is a unsaturated 6-membered heterocyclyl, or saturated 6-membered heterocyclic amide (lactam)
- each of ring B is independently optionally unsubstituted or substituted with 3R 2 .
- R is and ring B is fused with pyridine or pyrimidine ring, and ring B is a saturated or unsaturated 5-or 6-membered heterocyclyl, saturated or unsaturated 5-or 6-membered heterocyclic amide (lactam) , 6-membered aryl, or 5-or 6-membered heteroaryl, and each of ring B is independently optionally unsubstituted or substituted with 1R 2 , 2R 2 , or 3R 2 .
- R is and ring B is fused with pyridine or pyrimidine ring, and ring B is a unsaturated 5-or 6-membered heterocyclyl, saturated or unsaturated 5-or 6-membered heterocyclic amide (lactam) , 6-membered aryl, or 6-membered heteroaryl, and each of ring B is independently optionally unsubstituted or substituted with 1R 2 , 2R 2 , or 3R 2 .
- R is and ring B is fused with pyridine or pyrimidine ring, and ring B is an unsaturated 6-membered heterocyclyl, or saturated or unsaturated 6-membered heterocyclic amide (lactam) , and each of ring B is independently optionally unsubstituted or substituted with 3R 2 .
- R is and ring B is fused with pyridine or pyrimidine ring, and ring B is a unsaturated 6-membered heterocyclyl, or unsaturated 6-membered heterocyclic amide (lactam) , and each of ring B is independently optionally unsubstituted or substituted with 3R 2 .
- R is and ring B is fused with pyridine or pyrimidine ring, and ring B is a unsaturated 6-membered heterocyclyl, or saturated 6-membered heterocyclic amide (lactam) , and each of ring B is independently optionally unsubstituted or substituted with 3R 2 .
- R is and ring B is fused with pyridine or pyrimidine ring, and ring B is
- R 2 is independently H, F, Cl, methyl, ethyl, methoxy, or ethoxy; the methyl could be substituted with 1F, 2F, or 3F; ethyl could be substituted with 1F, 2F, or 3F;
- R 2 is independently H, F, methyl or methoxy; the methyl could be substituted with 1F, 2F, or 3F.
- R 2 is independently H, F, or -CF 3 .
- X 5 is N or CR X5 ; and R X5 is independently selected from -CN or CF 3 .
- X 5 is N.
- m is 1 or 2.
- each of R 3 is independently selected from hydrogen, methyl or ethyl; or two R 3 together with the C atom to which they are both attached form a 3-membered cycloalkyl, or 3-membered halocycloalkyl.
- each of R 3 is independently selected from hydrogen.
- ring A is a 6-membered aryl, 10-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, or 10-membered heteroaryl, and each of which is independently optionally unsubstituted or substituted with one or more R 1 .
- ring A is a 6-membered aryl, 10-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, or 10-membered heteroaryl, and each of which is independently optionally unsubstituted or substituted with 1R 1 , 2R 1 , or 3R 1 .
- ring A is a 6-membered aryl, 10-membered aryl, 6-membered heteroaryl, or 10-membered heteroaryl, and each of which is independently optionally unsubstituted or substituted with 1R 1 , 2R 1 , or 3R 1 .
- ring A is a phenyl, or benzyl, 6-membered heteroaryl, or 10-membered heteroaryl, and each of which is independently substituted with 1R 1 , 2R 1 , or 3R 1 .
- ring A is a phenyl, or benzyl, and each of which is independently substituted with 3R 1 .
- ring A is a benzyl, which is optionally substituted with up to 3R 1 .
- ring A is a phenyl, which is optionally substituted with up to 3R 1 .
- R 1 is H, F, Cl, hydroxy, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, -NR 4 R 4’ , -NC (O) R 4 , -C (O) NR 4 R 4’ , 3-to 5-membered cycloalkyl, 3-to 5-membered halocycloalkyl, or 3-to 5-membered heterocycloalkyl; and each of R 4 or R 4’ is independently selected from H, methyl, or ethyl; methyl could be substituted with 1F, 2F
- R 1 is H, F, Cl, hydroxy, ethyl, ethynyl, or -CF 3 .
- R is
- R is and v is 0, 1, or 2.
- R 5 is independently selected from F, Cl, -OH, -NH 2 , -CN, methyl, ethyl, methoxy, ethoxy, methoxymethyl-, methoxymethoxy-, -CH 2 OC (O) NH (CH 3 ) , -CH 2 OC (O) N (CH 3 ) 2 , -CH 2 OC (O) N (CH 2 CH 3 ) 2 , -CH 2 CH 2 OC (O) N (CH 3 ) 2 , or hydroxymethyl, hydroxyethyl halomethyl, or haloe
- R is
- R is and u is selected from 1, 2, or 3.
- R is and u is selected from 1.
- R is and u is selected from 2.
- R is and u is selected from 3.
- X 0 is H, -OH, -NH 2 , -C 1-3 alkyl, -C 1-3 alkoxy, -C 1-3 alkylene-OC (O) NHC 1-3 alkyl, -C 1-3 alkylene-OC (O) N (C 1-3 alkyl) 2 , -C 1-3 alkylene-N (C 1-3 alkyl) 2 , -C 1-3 alkoxy, or -C 1-3 hydroxyalkyl; and each of which can be independently optionally unsubstituted or substituted by a 3-to 7-membered heterocycle
- X 0 is H, -OH, -NH 2 , methyl, ethyl, methoxy, ethoxy, -CH 2 OC (O) NHCH 3 , -CH 2 CH 2 OC (O) NHCH 3 , -CH 2 OC (O) N (CH 3 ) 2 , -CH 2 CH 2 OC (O) N (CH 3 ) 2 , -CH 2 OC (O) N (CH 2 CH 3 ) CH 3 , -CH 2 OC (O) N (CH 2 CH 3 ) 2 , -CH 2 OC (O) N (CH 2 CH 3 ) 2 , -CH 2 OC (O) N (CH 2 CH 3 ) 2 , -CH 2 OC (O) N (CH 2 CH 3 ) 2 , -CH 2 OC (O) N (CH 2 CH 3 ) 2 , -CH 2 N (CH 2 CH 3 ) 2 , -CH 2 N (CH 2 CH 3 ) 2
- X 0 is H, -OH, -NH 2 , methyl, ethyl, methoxy, -CH 2 OC (O) NHCH 3 , -CH 2 OC (O) N (CH 3 ) 2 , -CH 2 OC (O) N (CH 2 CH 3 ) CH 3 , -CH 2 OC (O) N (CH 2 CH 3 ) 2 , CH 2 N (CH 3 ) 2 , -CH 2 N (CH 2 CH 3 ) 2 ; and each of which can be independently optionally unsubstituted or substituted by a 5-or
- X 0 is H, methyl, -CH 2 OC (O) N (CH 3 ) 2 , -CH 2 N (CH 3 ) 2 , -CH 2 OH; and each of which can be independently optionally unsubstituted or substituted by a 6-membered heterocycle with one or more hetero atom independently selected from N or O, and at least one of the hetero atoms is N which is directly connected to one of the C atoms of the methyl, ethyl, or hydroxymethyl; and the 6-membered heterocycle can be further optionally unsubstituted or substituted by
- the halogen is F or Cl;
- the C 1-3 alkyl is methyl, ethyl, or propyl;
- the C 1-3 alkoxy is methoxy, ethoxy, or propoxy;
- the C 1-3 alkylene is -CH 2 -, -CH 2 CH 2 -, or CH 2 CH 2 CH 2 -;
- -N (C 1-3 alkyl) 2 is -N(CH 3 ) 2 , -N (CH 2 CH 3 ) 2 , or -N (CH 2 CH 3 ) CH 3 ;
- the halogen is F, or Cl;
- the C 1-3 alkyl is methyl or ethyl;
- the C 1-3 alkoxy is methoxy or ethoxy;
- the C 1-3 alkylene is -CH 2 -or -CH 2 CH 2 -;
- -N (C 1-3 alkyl) 2 is -N (CH 3 ) 2 or -N (CH 2 CH 3 ) 2 ;
- the -C 1-3 alkylene-N (C 1-3 alkyl) 2 is -CH 2 N (CH 3 ) 2 , -CH 2 N (CH 2 CH 3 ) 2 ,
- the halogen is F; the C 1-3 alkyl is methyl; the C 1-3 alkoxy is methoxy; the C 1-3 alkylene is -CH 2 -; -N (C 1-3 alkyl) 2 is -N (CH 3 ) 2 ; and the -C 1-3 alkylene N (C 1-3 alkyl) 2 is -CH 2 N (CH 3 ) 2 .
- the Y is NR N .
- the Y is C (R N ) 2 .
- each of R N is independently selected from H, F, Cl, -NH 2 , -CN, -OH, -NHC(O) NHCH 3, -NHC (O) NHCH 2 CH 3 , -NHC (O) NHCH 3 , -NHC (O) NHCH 2 CH 3 , -NHC (O) N (CH 3 ) 2 , -NHC(O) N (CH 2 CH 3 ) 2 , -OC (O) NHCH 3 , -OC (O) NHCH 3 , -OC (O) NHCH 2 CH 3 , -OC (O) N (CH 3 , -OC (O) NHCH 3 , -OC (O) NHCH 2 CH 3 , -OC (O) N (CH 3 , -OC (O) NHCH 3 , -OC (O) NHCH 2 CH 3 , -OC (O) N (CH 3 , -OC (O) NHCH 2 CH 3
- each of R N is independently selected from H, F, Cl, -NH 2 , -CN, -OH, -NHC(O) NHCH 3, -NHC (O) NHCH 2 CH 3 , -NHC (O) NHCH 3 , -NHC (O) NHCH 2 CH 3 , -NHC (O) N (CH 3 ) 2 , -NHC(O) N (CH 2 CH 3 ) 2 , -OC (O) NHCH 3 , -OC (O) NHCH 3 , -OC (O) NHCH 2 CH 3 , -OC (O) N (CH 3 , -OC (O) NHCH 3 , -OC (O) NHCH 2 CH 3 , -OC (O) N (CH 3 , -OC (O) NHCH 3 , -OC (O) NHCH 2 CH 3 , -OC (O) N (CH 3 , -OC (O) NHCH 2 CH 3
- each of R N is independently selected from H, F, Cl, -NH 2 , -CN, -OH, -NHC(O) NHCH 3, -NHC (O) N (CH 3 ) 2 , -OC (O) NHCH 3 , -CH 2 NHC (O) NHCH 3 , -CH 3 NHC (O) N (CH 3 ) 2 , -CH 2 OH, methyl, ethyl, methoxy, or each of R 8 , R 9 or R 10 is independently selected from H, F, Cl, -NH 2 , -OH, or
- each of R N is independently selected from H, F, -NH 2 , -OH, -CH 2 OH, methyl, or ethyl.
- each of R N is independently selected from H or methyl.
- each of R 6 or R 7 is independently H, F, Cl, NH 2 , OH, or methyl; methyl can be substituted with F or Cl; methyl can be substituted with OH; and the methyl of methoxy can be substituted with F or Cl.
- each of R 6 or R 7 is independently H or methyl.
- the present invention furthermore disclosures a pharmaceutical composition, comprising a therapeutically effective amount of at least one of compound or a pharmaceutically acceptable salt thereof as defined above, and a pharmaceutically acceptable excipient.
- the pharmaceutical composition comprising a therapeutically effective amount of at least one of compound as defined above, or a pharmaceutically acceptable salt thereof as defined above, and a pharmaceutically acceptable excipient.
- the pharmaceutical composition comprising a therapeutically effective amount of at least one of compound as defined above, or a pharmaceutically acceptable salt thereof as defined above, and a pharmaceutically acceptable excipient.
- the pharmaceutical composition comprising a therapeutically effective amount of at least one of compound as defined above, or a pharmaceutically acceptable salt thereof as defined above, and a pharmaceutically acceptable excipient.
- the pharmaceutical composition comprising a therapeutically effective amount of at least one of compound as defined above, a pharmaceutically acceptable salt thereof as defined above, and a pharmaceutically acceptable excipient.
- the present invention furthermore disclosures a method for inhibiting KRAS Gl2D activity in a cell, comprising contacting the cell in which inhibition of KRAS Gl2D activity is desired with an effective amount of at least one of compound as defined above or a pharmaceutically acceptable salt thereof as defined above.
- the method for inhibiting KRAS Gl2D activity in a cell comprising contacting the cell in which inhibition of KRAS Gl2D activity is desired with an effective amount of at least one of compound as defined above, or a pharmaceutically acceptable salt thereof as defined above.
- the method for inhibiting KRAS Gl2D activity in a cell comprising contacting the cell in which inhibition of KRAS Gl2D activity is desired with an effective amount of at least one of compound as defined above, or a pharmaceutically acceptable salt thereof as defined above.
- the method for inhibiting KRAS Gl2D activity in a cell comprising contacting the cell in which inhibition of KRAS Gl2D activity is desired with an effective amount of at least one of compound as defined above, or a pharmaceutically acceptable salt thereof as defined above.
- the method for inhibiting KRAS G12D activity in a cell comprising contacting the cell in which inhibition of KRAS G12D activity is desired with the pharmaceutical composition as defined above.
- the present invention furthermore disclosures a method for treating a KRAS G12D-associated cancer comprising administering to a patient in need thereof a therapeutically effective amount of at least one of compound as defined above, or a pharmaceutically acceptable salt thereof as defined above.
- the method for treating a KRAS G12D-associated cancer comprising administering to a patient in need thereof a therapeutically effective amount of at least one of compound as defined above, or a pharmaceutically acceptable salt thereof as defined above.
- the therapeutically effective amount of the compound as defined above is between about 0.01 to 100 mg/kg per day.
- the therapeutically effective amount of the compound as defined above is between about 0.1 to 50 mg/kg per day.
- the KRAS G12D-associated cancer is selected from the group consisting of Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma) , myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma) , alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma) , stomach (carcinoma, lymphoma, leiomyosarcoma),
- the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer.
- the present invention furthermore disclosures a method for treating cancer in a patient in need thereof, the method comprising (a) determining that the cancer is associated with a KRAS Gl2D mutation (e.g., a KRAS Gl2D-associated cancer) ; and (b) administering to the patient a therapeutically effective amount of at least one of compound as defined above.
- a KRAS Gl2D mutation e.g., a KRAS Gl2D-associated cancer
- the administering is done via a route selected from the group consisting of parenteral, intraperitoneal, intradermal, intracardiac, intraventricular, intracranial, intracerebrospinal, intrasynovial, intrathecal administration, intramuscular injection, intravitreous injection, intravenous injection, intra-arterial injection, oral, buccal, sublingual, transdermal, topical, intratracheal, intrarectal, subcutaneous, and topical administration.
- the administering is done via an intravenous injection.
- the administering is done via an intramuscular injection.
- the administering is done via an intramuscular injection.
- the administepyridine or pyrimidine ringomprises utilizing a delivery device In some embodiments of method, the administepyridine or pyrimidine ringomprises utilizing a delivery device.
- the administering is done in a hospital setting.
- a dash "-" at the front or end of a chemical group is used, a matter of convenience, to indicate a point of attachment for a substituent.
- -OH is attached through the carbon atom; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning.
- a wavy line drawn through a line in a structure indicates a point of attachment of a group. Unless chemically or structurally required, no directionality is indicated or implied by the order in which a chemical group is written or named.
- a solid line coming out of the center of a ring indicates that the point of attachment for a substituent on the ring can be at any ring atom.
- R′in the below structure can be attached to any of the carbon ring atoms or X 1 , including the bridge carbon atom (s) :
- C m-n indicates that the following group has from m to n carbon atoms.
- C 1-8 alkyl indicates that the alkyl group has from 1 to 8 carbon atoms.
- m-n membered rings wherein m and n are numerical ranges, such as “3-12-membered heterocyclyl” , refers to a ring containing 3-12 atoms, of which up to 80%may be heteroatoms, such as N, O, S, P, and the remaining atoms are carbon.
- a divalent group such as a divalent "alkyl” group, a divalent “aryl” group, etc., may also be referred to as an "alkylene” group or an “alkylenyl” group, or alkylyl group, an "arylene” group or an “arylenyl” group, or arylyl group, respectively.
- a compound provided herein” or “a compound described herein” or “a compound disclosed herein” or “a compound of the present disclosure” refers to the compounds of Formula Formula (I 0 ) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-4) , which also applies to the specific compounds of Examples 1 to Example 5.
- the term “about” directed to that value or parameter per se, includes the indicated amount ⁇ 10%, ⁇ 5%, or ⁇ 1%. Also, the term “about X” includes description of "X” .
- “Adjoining atoms” refers to atoms that are in immediately next to each other. For instance, in “C1-C2-C3-C4" atom C1 is adjoining to atom C2, atom C2 is adjoining to atoms C1 and C3, so on and so forth.
- alkyl refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 6 carbon atoms (i.e., C 1-6 alkyl) , or 1 to 10 carbon atoms (i.e., C 1-10 alkyl) .
- Alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.
- butyl includes n-butyl (i.e. - (CH 2 ) 3 CH 3 ) , sec-butyl (i.e. - CH (CH 3 ) CH 2 CH 3 ) , isobutyl (i.e. -CH 2 CH (CH 3 ) 2 ) and tert-butyl (i.e.
- propyl includes n-propyl (i.e - (CH 2 ) 2 CH 3 ) and isopropyl (i.e. -CH (CH 3 ) 2 ) .
- alkenyl groups include ethenyl, propenyl, butadienyl (including 1, 2-butadienyl and 1, 3-butadienyl) .
- alkynyl refers to an aliphatic group containing at least one carbon-carbon triple bond (C ⁇ C) and having from 2 to 10 carbon atoms (i.e., C 2-10 alkynyl) , or 2 to 4 carbon atoms (i.e., C 2-4 alkynyl) , etc.
- alkynyl also includes those groups having one triple bond and one double bond.
- alkoxy refers to the group "-O-alkyl” , for example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1, 2-dimethylbutoxy.
- haloalkoxy refers to an alkoxy group as indicated above, wherein one or more hydrogen atoms are replaced by a halogen.
- R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, and each of which may be optionally substituted, as defined herein.
- Examples of acyl group include formyl, acetyl, cylcohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl, etc.
- Amino refers to the group -NR a R b , herein R a and R b are independently selected from groups consisting of hydrogen, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl; and each of which may be optionally substituted.
- aryl refers to an aromatic carbocyclic group having a single ring (e.g. monocyclic) or multiple rings (e.g. bicyclic or tricyclic) including fused systems.
- aryl has 6 to 20 ring carbon atoms (i.e., C 6-20 aryl) , 6 to 12 carbon ring atoms (i.e., C 6-12 aryl) , etc.
- Some examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl.
- aryl does not encompass or overlap in any way with heteroaryl as defined below. If one or more aryl groups are fused with a heteroaryl ring, the resulting ring system is heteroaryl.
- cycloalkyl refers to a saturated or partially saturated cyclic alkyl group having a single ring or multiple rings including fused, bridged, and spiro ring systems.
- cycloalkyl also includes cycloalkenyl groups (i.e. the cyclic group having at least one double bond) .
- cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C 3-20 cycloalkyl) , 3 to 8 ring carbon atoms (i.e., C 3-8 cycloalkyl) , or 3 to 5 ring carbon atoms (i.e., C 3-5 cycloalkyl) , etc. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
- bridged refers to a ring fusion wherein non-adjacent atoms on a ring are joined by a divalent substituent, such as alkylenyl group, an alkylenyl group containing one or two heteroatoms, or a single heteroatom.
- a divalent substituent such as alkylenyl group, an alkylenyl group containing one or two heteroatoms, or a single heteroatom.
- Examples of bridged ring systems include quinuclidinyl and admantanyl.
- fused refers to a ring which is bound to an adjacent ring.
- spiro refers to a ring substituent which is joined by two bonds at the same carbon atom.
- spiro groups include 1, 1-diethylcyclopentane, dimethyl-dioxolane, and 4-benzyl-4-methylpiperidine, wherein the cyclopentane and piperidine, respectively, are the spiro substituents.
- Halogen or “halo” includes fluoro (F) , chloro (Cl) , bromo (Br) , and iodo (I) .
- Haloalkyl includes an unbranched or branched alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen. If a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached.
- Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two ( "di” ) or three ( “tri” ) halo groups, which may be, but are not necessarily, the same halogen.
- Some examples of haloalkyl include difluoromethyl (-CHF 2 ) and trifluoromethyl (-CF 3 ) .
- heteroaryl refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from N, O, and S.
- heteroaryl includes 1 to 20 carbon ring atoms (i.e., C 1-20 heteroaryl) , 3 to 12 carbon ring atoms (i.e., C 3-12 heteroaryl) , etc., and the number of ring heteroatoms, as used wherein, independently selected from nitrogen, oxygen, and sulfur.
- heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl.
- heteroaryl does not encompass or overlap with “aryl” as defined above.
- heterocyclyl or “heterocyclic ring” refers to a non-aromatic cyclic alkyl group, with at least one ring heteroatoms independently selected from boron (B) , nitrogen (N) , oxygen (O) , phosphorus (P) and sulfur.
- heterocyclyl or “heterocyclic ring” refer to rings that are saturated or partially saturated unless otherwise indicated, for example, in some embodiments “heterocyclyl” or “heterocyclic ring” refers to rings that are partially saturated where specified.
- Heterocyclyl or “heterocyclic ring” includes heterocycloalkenyl groups (i.e., the heterocyclyl group having at least one double bond) .
- a heterocyclyl may be a single ring or multiple rings wherein the multiple rings may be fused, bridged, or spiro.
- heterocyclyl has 2 to 20 carbon ring atoms (i.e., C 2-20 heterocyclyl) , 3 to 8 carbon ring atoms (i.e., C 3-8 heterocyclyl) , or 3 to 6 carbon ring atoms (i.e., C 3-6 heterocyclyl) ; having 1 to 5 ring heteroatoms independently selected from B, N, O, P, or S.
- heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, and morpholinyl.
- bridged-heterocyclyl refers to a four-to ten-membered cyclic moiety connected at two non-adjacent atoms of the heterocyclyl with one or more (e.g., 1 or 2) four-to ten-membered cyclic moiety having at least one heteroatom where each heteroatom is independently selected from B, N, O, P and S.
- bridged-heterocyclyl includes bicyclic and tricyclic ring systems.
- spiro-heterocyclyl refers to a ring system in which a three-to ten-membered heterocyclyl has one or more additional ring, wherein the one or more additional ring is three-to ten-membered cycloalkyl or three-to ten-membered heterocyclyl, where a single atom of the one or more additional ring is also an atom of the three-to ten-membered heterocyclyl.
- heterocyclyl and “heterocyclic ring” are used interchangeably.
- a heterocyclyl is substituted with an oxo group.
- sulfonyl refers to the group -S (O) 2 R a , where R a is alkyl, haloalkyl, heterocyclyl, cycloalkyl, heteroaryl, or aryl.
- R a is alkyl, haloalkyl, heterocyclyl, cycloalkyl, heteroaryl, or aryl.
- Some Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.
- Substituted means that one or more hydrogen atoms on the designated atom or group is substituted with one or more substituents other than hydrogen, in the conditions that the designated atom's normal valence is not exceeded.
- the substituents include, but not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof.
- impermissible substitution patterns e.g., methyl substituted with 5 fluorines or heteroaryl groups having two adjacent oxygen ring atoms.
- impermissible substitution patterns are well known to the skilled artisan.
- substituted may describe other chemical groups defined herein.
- substituted aryl includes, but not limited to, “alkylaryl. " Unless specified otherwise, if a group is described as optionally substituted, any substituents of the group are themselves unsubstituted.
- substituted alkyl refers to an alkyl group having one or more substituents that include hydroxyl, halo, amino, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
- substituted cycloalkyl refers to a cycloalkyl group having one or more substituents including alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amino, alkoxy, halo, oxo, and hydroxyl; by “substituted heterocyclyl” , it refers to a heterocyclyl group having one or more substituents including alkyl, amino, haloalkyl, heterocyclyl, cycloalkyl, aryl, heteroaryl, alkoxy, halo, oxo, and hydroxyl; the term “substituted aryl” refers to an aryl group having one or more substituents including halo, alkyl, amino, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, alkoxy, and cyano; the term “substituted heteroaryl” refers to a cycloal
- the one or more substituents may be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted.
- the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.
- a substituted cycloalkyl, a substituted heterocyclyl, a substituted aryl, and/or a substituted heteroaryl includes a cycloalkyl, a heterocyclyl, an aryl, and/or a heteroaryl that has a substituent on the ring atom to which the cycloalkyl, heterocyclyl, aryl, and/or heteroaryl is attached to the rest of the compound.
- the phenyl ring is substituted with a meta-chloro group:
- the disclosed compounds herein, or their pharmaceutically acceptable salts may contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R) -or (S) -or, as (D) -or (L) -for amino acids.
- the current disclosure includes all such possible isomers, as well as their racemic and optically pure forms.
- Optically active (+) and (-) , (R) -and (S) -, or (D) -and (L) -isomers may be prepared using chiral synthons or chiral reagents, or resolved by conventional techniques, such as, chromatography and fractional crystallization.
- stereoisomer refers to a compound containing the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable.
- the current disclosure contemplates various stereoisomers and mixtures thereof and includes “enantiomers” , which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another.
- enantiomers represent a pair of stereoisomers that are non-superimposable mirror images of each other.
- a 1: 1 mixture of a pair of enantiomers is a "racemic” mixture.
- a mixture of enantiomers at a ratio other than 1: 1 is a "scalemic" mixture.
- diastereoisomers represent stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
- Tautomer refers to a proton shift from one atom of a molecule to another atom of the same molecule.
- the present disclosure includes tautomers of any compounds provided herein.
- Tautomeric isomers are in equilibrium with one another.
- amide containing compounds may exist in equilibrium with imidic acid tautomers. No matter which tautomer is shown, and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, the amide containing compounds are understood to include their imidic acid tautomers. As the same, the imidic acid containing compounds are understood to include their amide tautomers.
- solvates also include the solvates of salts of the compounds disclosed and the hydrates of the compounds provided herein.
- any formula or structure provided herein also represents unlabeled forms as well as isotopically labeled forms of the compounds.
- Isotopically labeled compounds have the same structures as depicted by the formulas given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
- isotopes include isotopes, such as, of carbon ( 11 C, 13 C, 14 C) , nitrogen ( 15 N) , oxygen ( 17 O, 18 O) , phosphorous ( 31 P, 32 P) , fluorine ( 18 F) , chlorine ( 36 Cl) , and iodine ( 125 I) .
- Isotopically labelled compounds may have usages in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) in drug or substrate tissue distribution assays or in radioactive treatment of patients.
- PET positron emission tomography
- SPECT single-photon emission computed tomography
- the current disclosed compounds are capable to form acid salts by virtue of the presence of amino and/or groups similar thereto.
- pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic acids.
- pharmaceutically acceptable non-toxic acids include inorganic and organic acids.
- the compounds of Formula (I 0 ) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-4) are intended for pharmaceutical use they are preferably provided in substantially pure form, for example at least 60%pure, more suitably at least 75%pure, especially at least 98%pure (%are on a weight for weight basis) .
- compositions of the present invention comprise a compound represented by Formula (I 0 ) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-4) , or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants.
- compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
- the pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
- the compounds represented by Formula (I 0 ) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-4) , or a prodrug or a metabolite or pharmaceutically acceptable salts thereof, of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
- the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g. oral or parenteral (including intravenous) .
- compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a water-in-oil liquid emulsion.
- the compound represented by Formula (I 0 ) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-4) , or a pharmaceutically acceptable salt thereof may also be administered by controlled release means and/or delivery devices.
- the compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.
- compositions of this invention may include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt, of Formula (I 0 ) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-4) .
- the compounds of Formula (I 0 ) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-4) , or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
- the pharmaceutical carrier employed can be, for example, a solid, liquid or gas.
- solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
- liquid carriers are sugar syrup, peanut oil, olive oil, and water.
- gaseous carriers include carbon dioxide and nitrogen.
- oral liquid preparations such as suspensions, elixirs and solutions
- carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets.
- oral solid preparations such as powders, capsules and tablets.
- tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed.
- tablets may be coated by standard aqueous or nonaqueous techniques.
- a tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.
- Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
- Each tablet preferably contains from about 0.05mg to about 5g of the active ingredient and each cachet or capsule preferably containing from about 0.05mg to about 5g of the active ingredient.
- a formulation intended for the oral administration to humans may contain from about 0.5mg to about 5g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 0.05 to about 95 percent of the total composition.
- Unit dosage forms will generally contain between from about 0.0lmg to about 2g of the active ingredient, typically 0.01mg, 0.02mg, 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 25mg, 50mg, l00mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg or l000mg.
- compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water.
- a suitable surfactant can be included such as, for example, hydroxypropylcellulose.
- Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
- compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions.
- the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions.
- the final injectable form must be sterile and must be effectively fluid for easy syringability.
- the pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
- the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol) , vegetable oils, and suitable mixtures thereof.
- compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a compound represented by Formula I of this invention or a pharmaceutically acceptable salt thereof, via conventional processing methods. As an example, a cream or ointment is prepared by admixing hydrophilic material and water, together with about 0.05wt%to about 10wt%of the compound, to produce a cream or ointment having a desired consistency.
- compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier (s) followed by chilling and shaping in molds.
- the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
- additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
- additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
- additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
- other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient.
Abstract
Disclosed are compounds of Formula (I0), or a salt thereof, useful as KRAS G12D inhibitors to modulate or inhibit the activity of KRAS G12D mutant protein, wherein m equals 1, 2, or 3; n1, n2 equals 0 or 1; ring A, ring B, X1, X5, R, R', R3, and Z are defined herein. These compounds and pharmaceutical compositions comprising such compounds are useful in the treatment of various diseases or disorders, such as cancer, mediated by KRAS G12D mutant protein.
Description
The invention relates to KRAS G12D inhibitors, herein are Formula (I
0) compounds, and pharmaceutical compositions comprising such compounds, useful in the treatment of variety disorders, such as cancer. Also described are methods of inhibiting KRAS G12D activity, as well as methods therewith for treating KRAS G12D-associated disorders, and methods for preparing the Formula (I
0) compounds.
Background Art
KRAS (Kirsten rat sarcoma 2 viral oncogene homolog) gene is a proto-oncogene that encodes a small GTPase transductor protein. KRAS protein switches between an active to an inactive form via binding to guanosine triphosphate (GTP) and guanosine diphosphate (GDP) , respectively (Alamgeer et al., Current Opin Pharmcol, 2013; 13: 394-401) . GTPase activating proteins (GAPs) facilitate hydrolysis of GTP by KRAS while guanine nucleotide exchange factors (GEFs) catalyze GDP dissociation (Vetter et al., Science 2001, 294: 1299-1304) (K. Scheffzek et al., Science, 1997, 277: 333-338) . Under physiological conditions, KRAS is predominantly GDP-bound. Upon activation by receptor tyrosine kinases such as epidermal growth factor (EGF) receptors, GEFs are recruited to KRAS and initiate exchange of GDP for GTP. Active KRAS interacts with effector proteins and activates downstream cellular signal transduction pathways, including the RAFMEK-ERK, PI3K-AKT-mTOR, and RalGDS pathways, regulate a wide a range of essential cellular processes, including cell differentiation, growth, and proliferation (Rajalingam, K et al., Biochim. Biophys. Acta, Mol. Cell Res. 1773, 1177-1195) (McCormick et al., Curr. Opin. Biotechnol, 1996, 7, 449–456) . In a regulated KRAS cycle, signaling is turned off upon GTP hydrolysis. Activating mutations in KRAS, most commonly at codons 12, 13 and 61, impair its intrinsic or GAP-mediated GTPase function, resulting in the accumulation of KRAS-GTP that constitutively active and thereby cause uncontrolled cell growth/proliferation, leading to tumorigenesis and tumor development (Cox AD et al., Small GTPases, 2010, (1) : 2-27) (Prior IA et al., Cancer Res, 2012, 72 (10) : 2457-2467) . Approximately 15%of all human tumors harbor mutant KRAS. Among them, the G12D mutation in KRAS occurs most frequently and is found in ~45%of pancreatic ductal adenocarcinoma patients, 13%of colorectal carcinoma patients, 10%of rectal carcinoma patients, 4%of non-small cell lung carcinoma patients and 1.7%of all small cell lung carcinoma patients (A.G. Stephen et al., Cancer Cell, 2014, 25: 272-281) .
The high frequency of KRAS G12D mutation makes it an ideal drug target but effective drugs targeting G12D-mutated KRAS have not been marketed. Thus, there is a need to develop new therapeutic agent targeting KRAS G12D with sufficient efficacy and safety profile for use in KRAS G12D-mediated cancer. The present invention relates to compounds that bind directly to KRAS G12D and block its activity. These compounds are provided to be useful as pharmaceuticals with desirable stability, bioavailability, therapeutic index, and toxicity values that are important to their drugability.
Summary of Invention
The present disclosure relates compounds of Formula (I
0) , Formula (I) or Formular (I′) , which are useful as modulators of KRAS G12D activity, including salts thereof.
The present disclosure also relates pharmaceutical compositions comprising a compound of Formula (I
0) , Formula (I) , Formular (I′) , and/or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
The present disclosure also relates a method of treating a disease or disorder associated with the activity of KRAS G12D, the method comprising: determining if the subject has a KRAS G12D mutation; and if the subject is determined to have the KRAS G12D mutation, then administering to the subject a therapeutically effective amount of a compound of Formula (I
0) , Formula (I) , Formular (I′) , and/or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
The present disclosure also relates processes and intermediates for making the compounds of Formula (I
0) , Formula (I) , Formular (I′) , and/or salts thereof.
The present disclosure also relates a compound of Formula (I
0) , Formula (I) , Formular (I′) , and/or a pharmaceutically acceptable salt thereof, for use in therapy.
The present disclosure also relates the use of the compounds of Formula (I
0) , Formula (I) , Formular (I′) , and/or pharmaceutically acceptable salts thereof, in the manufacture of a medicament for the treatment or prophylaxis of KRAS G12D-associated disorder, such as cancer. As a sole agent or in combination with other active ingredients.
The present disclosure relates at least one compound of Formula (I
0) :
or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, and isomer thereof, and
each of n1 or n2 is independently selected from 0 or 1;
m is 0, 1, 2, or 3;
n is 0, 1, or 2;
X
1 is NH, O, or S;
X
5 is N or CR
X5; and R
X5 is independently selected from -CN or -CF
3;
each of R
3 is independently selected from hydrogen, halogen, C
1-3 alkoxy, or C
1-3 alkyl; or two R
3 together with the C atom to which they are both attached form a 3-to 5-membered cycloalkyl, or 3-to 5- membered halocycloalkyl.
R′ is H, halogen, hydroxy, C
1-3 alkyl, C
1-3 alkoxy, C
1-3 haloalkyl, C
1-3 hydroxyalkyl, or -CH
2CN;
ring A is a 6-to 10-membered aryl, or 5-to 10-membered heteroaryl, and each of which is independently optionally unsubstituted or substituted with one or more R
1; and R
1 is H, halogen, hydroxy, C
1-3 alkyl, C
2-5 alkenyl, C
2-5 alkynyl, C
1-3 alkoxy, C
1-3 haloalkyl, C
2-5 haloalkenyl, C
2-5 haloalkynyl, C
1-3 haloalkoxy, C
1-5 hydroxy alkyl, -NR
4R
4’, -NC (O) R
4, -C (O) NR
4R
4’, 3-to 5-membered cycloalkyl, 3-to 5-membered halocycloalkyl, or 3-to 5-membered heterocycloalkyl; and each of R
4 or R
4’ is independently selected from H, -NH
2, -C
1-3 alkyl, or 5-or 6-membered heteroaryl, and each of which is independently optionally unsubstituted or substituted by deuterium, halogen, -NH
2, -CN, -OH, -C
1-3alkyl, or -C
1-3alkoxy;
R is:
i)
wherein v is 0, 1, 2, or 3; each of R
5 is independently selected from halogen, -OH, -NH
2, -CN, C
1-3 alkyl, C
1-3 hydroxyalkyl, C
1-3 alkoxy, C
1-3 haloalkyl, (C
1-3 alkoxy) C
1-3 alkyl-, (C
1-3 alkoxy) C
1-3 alkoxy-, (C
1-3 hydroxyalkoxy) C
1-3 alkoxy-, -C
1-3 alkylene-OC (O) NH (C
1-3 alkyl) , -C
1-3 alkylene-OC (O) N (C
1-3 alkyl)
2, or
each of R
6 or R
7 is independently selected from H or C
1-3 alkyl;
X
0 is H, -OH, -NH
2, -C
1-3 alkyl, -C
1-3 alkoxy, -C
1-3 alkylene-OC (O) NHC
1-3 alkyl, -C
1-3 alkylene-OC (O) N (C
1-3 alkyl)
2,
-C
1-3 alkylene-N (C
1-3alkyl)
2, or -C
1-3 hydroxy alkyl; and each of which can be independently optionally unsubstituted or substituted by a 3-to 7-membered heterocycle with one or more hetero atom independently selected from N, O, or S, and at least one of the hetero atoms is N which is directly connected to one of the C atoms of the C
1-3 alky or C
1-3 hydroxy alkyl, and the 3-to 7-membered heterocycle can be further optionally unsubstituted or substituted by a NH
2, -OH, halogen, C
1-3 alkyl, C
1-3 alkoxy, -C
1-3 alkylene-N (C
1-3 alkyl)
2, or -N (C
1-3 alkyl)
2;
Y is C (R
N)
2 or NR
N; each of R
N is independently selected from H, halogen, -NH
2, -CN, -OH, -NHC (O) NHC
1-3 alkyl
, -NHC (O) N (C
1-3 alkyl)
2, -OC (O) NHC
1-3 alkyl, -OC (O) N (C
1-3 alkyl)
2, -C
1-3 alkylene-NHC (O) NHC
1-3 alkyl, -C
1-3 alkylene-NHC (O) N (C
1-3 alkyl)
2, -C
1-3 alkylene-OC (O) NHC
1-3 alkyl, -C
1-3 alkylene-OC (O) N (C
1-3alkyl)
2,
-C
1-3 alkyl, -C
1-3 alkoxy, or
each of R
6 or R
7 is independently selected from H or C
1-3 alkyl; each of R
8, R
9, or R
10 is independently selected from H, halogen, -NH
2, -CN, -OH, -C
1-3alkyl, or -C
1-3 alkoxy, and each of which is independently optionally unsubstituted or substituted by deuterium, halogen, -NH
2, -CN, -OH, -C
1-3 alkyl, or -C
1-3 alkoxy;
iii)
wherein v is 0, 1, 2, or 3; R
5 is defined as supra;
is a double bond or a single bond to make the 5-5 fused ring system as an 5-5 fused heteroaromatic ring;
Z is O, S, SO, or SO
2;
ring B is fused with pyridine or pyrimidine ring, and wherein:
i) if R is
Z is O, X
5 is N, and n is 1 or 2, ring B is a saturated or unsaturated 5-or 6-membered heterocyclic amide (lactam) , and each of which is independently optionally unsubstituted or substituted with one or more R
2;
ring B is a saturated or unsaturated 5-or 6-membered heterocyclyl, saturated or unsaturated 5-or 6- membered heterocyclic amide (lactam) , 6-membered aryl, or 5-or 6-membered heteroaryl; and each of ring B is independently optionally unsubstituted or substituted with one or more R
2.
Wherein, each of R
2 is independently H, halogen, C
1-3 haloalkyl, C
1-3 alkyl, C
1-3 alkoxy, or C
3-5 cycloalkyl; or two R
2 together with the C atom to which both R
2 are attached form an oxo, a 3-to 5-membered cycloalkyl, or a 3-to 5-membered heterocyclyl.
In some embodiments, the compound of Formula (I
0) is represented by the Formula (I) :
In some embodiments, the compound of Formula (I
0) is represented by the Formula (II) :
wherein
is a double bond or a single bond; when X
2 is N, X
3 is CR
2, and X
2 together with X
4 forms a lactam,
is a double bond; when X
3 is NR
2 or C (R
2)
2,
is a single bond.
In some embodiments, the compound of Formula (I
0) is represented by the Formula (II-1) :
In some embodiments, the compound of Formula (I
0) is represented by the Formula (II-2) :
In some embodiments, the compound of Formula (I
0) is represented by the Formula (II-3) :
In some embodiments, the compound of Formula (I
0) is represented by the Formula (II-4) :
In some embodiments, the compound of Formula (I
0) is represented by the Formula (II-5) :
In some embodiments, the compound of Formula (I
0) is represented by the Formula (II-6) :
In another embodiment, the compound of Formula (I
0) is represented by the Formula (III) :
In some embodiments, the compound of Formula (I
0) is represented by the Formula (III-1) :
In some embodiments, the compound of Formula (I
0) is represented by the Formula (III-2) :
In some embodiments, the compound of Formula (I
0) is represented by the Formula (III-3) :
In some embodiments of Formula (I
0) , n is 1.
In some embodiments of Formula (I
0) , n1 is 0; n2 is 1; and n is 1.
In some embodiments of Formula (I
0) , n is 2.
In some embodiments of Formula (I
0) , n1 is 0; n2 is 1; and n is 2.
In some embodiments of Formula (I
0) , in n1 is 1; n2 is 0; and n is 1.
In some embodiments of Formula (I
0) , n1 is 1; n2 is 0; and n is 2.
In some embodiments, the compound of Formula (I
0) is represented by the Formula (I′) :
In some embodiments, the compound of Formula (I
0) is represented by the Formula (II′) :
In some embodiments, the compound of Formula (I
0) is represented by the Formula (II′-1) :
In some embodiments, the compound of Formula (I
0) is represented by the Formula (II′-2) :
In some embodiments, the compound of Formula (I
0) is represented by the Formula (II′-3) :
In some embodiments, the compound of Formula (I
0) is represented by the Formula (II′-4) :
In some embodiments, the compound of Formula (I
0) is represented by the Formula (II′-5) :
In some embodiments, the compound of Formula (I
0) is represented by the Formula (II′-6) :
In another embodiment, the compound of Formula (I
0) is represented by the Formula (III′) :
In some embodiments, the compound of Formula (I
0) is represented by the Formula (III′-1) :
In some embodiments, the compound of Formula (I
0) is represented by the Formula (III′-2) :
In some embodiments, the compound of Formula (I
0) is represented by the Formula (III′-3) :
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , X
1 is NH.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , X
1 is O or S.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , ring A is a phenyl or benzyl, or 5-, 6-, 7-, 8-, 9-, or 10-membered heteroaryl; and each of which is independently optionally unsubstituted or substituted with 1R
1, 2R
1, 3R
1, 4R
1, or 5R
1.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , ring A is a phenyl or benzyl, or 5-or 6-membered heteroaryl, and each of which is independently optionally unsubstituted or substituted with 1R
1, 2R
1, or 3R
1.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , ring A is a phenyl or a benzyl, and each of which is independently optionally unsubstituted or substituted with 1R
1, 2R
1, or 3R
1.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , ring A is a phenyl or a benzyl, and each of which is independently optionally unsubstituted or substituted with 2R
1 or 3R
1.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , ring A is a phenyl or a benzyl, and each of which is independently optionally unsubstituted or substituted with 3R
1.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , R
1 is: i) H, F, Cl, Br, hydroxy, methyl, ethyl, propyl, vinyl, ethynyl, propynyl, methoxy, ethoxy; methyl could be substituted with 1F, 2F or 3F; ethyl could be substituted with 1F, 2F or 3F; the methyl group of methoxy could be substituted with 1F, 2F or 3F; or the methyl or the methylene group of ethoxy could be substituted with 1F, 2F, or 3F; ii) -NR
4R
4’, -NC (O) R
4, or -C (O) NR
4R
4’; and each of R
4 or R
4’ is independently selected from H, methyl; iii) 5-membered cycloalkyl, 5-membered halocycloalkyl, or 5-membered heterocycloalkyl.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , R
1 is:
i) H, F, Cl, hydroxy, methyl, ethyl, ethynyl; the methyl group of methoxy is optionally substituted with 1F, 2F, or 3F;
ii) NR
4R
4’, and each of R
4 or R
4’ is independently selected from H, methyl, or methoxy.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , R
1 is H, F, Cl, hydroxy, ethyl, ethynyl, or CF
3.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , Z is O or S.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , Z is O.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , Z is O, and ring B is fused with pyridine or pyrimidine ring, and ring B is a saturated or unsaturated 5-or 6-membered heterocyclic amide (lactam) , and each of which is independently optionally unsubstituted or substituted with one or more R
2.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , Z is O, and ring B is fused with pyridine or pyrimidine ring, and ring B is a saturated or unsaturated 6-membered heterocyclic amide (lactam) , and each of which is independently optionally unsubstituted or substituted with 1R
2, 2R
2, or 3R
2.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , Z is O, and ring B is fused with pyridine or pyrimidine ring, and ring B is a saturated 6-membered heterocyclic amide (lactam) , and each of which is independently optionally unsubstituted or substituted with 1R
2, 2R
2, or 3R
2.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , Z is O, and ring B is fused with pyridine or pyrimidine ring, and ring B is a saturated 6-membered heterocyclic amide (lactam) , and each of which is independently optionally unsubstituted or substituted with 3R
2.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , Z is O, and ring B is fused with pyridine or pyrimidine ring, and ring B is a saturated or unsaturated 6-membered heterocyclic amide (lactam) , and each of which is independently optionally unsubstituted or substituted with 3R
2, and ring B is
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , Z is S, SO, or SO
2, and ring B is fused with pyridine or pyrimidine ring, and ring B is a saturated or unsaturated 5-or 6-membered heterocyclyl, saturated or unsaturated 5-or 6-membered heterocyclic amide (lactam) , 6-membered aryl, or 5-or 6-membered heteroaryl, and each of ring B is independently optionally unsubstituted or substituted with 1R
2, 2R
2, or 3R
2.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , Z is S, and ring B is fused with pyridine or pyrimidine ring, and ring B is a unsaturated 5-or 6-membered heterocyclyl, saturated or unsaturated 5-or 6-membered heterocyclic amide (lactam) , 6-membered aryl, or 6-membered heteroaryl, and each of ring B is independently optionally unsubstituted or substituted with 1R
2, 2R
2, or 3R
2.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , Z is S, and ring B is fused with pyridine or pyrimidine ring, and ring B is an unsaturated 6-membered heterocyclyl, or saturated or unsaturated 6-membered heterocyclic amide (lactam) , and each of ring B is independently optionally unsubstituted or substituted with 3R
2.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , Z is S, and ring B is fused with pyridine or pyrimidine ring, and ring B is a unsaturated 6-membered heterocyclyl, or unsaturated 6-membered heterocyclic amide (lactam) , and each of ring B is independently optionally unsubstituted or substituted with 3R
2.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , Z is S, and ring B is fused with pyridine or pyrimidine ring, and ring B is a unsaturated 6-membered heterocyclyl, or saturated 6-membered heterocyclic amide (lactam) , and each of ring B is independently optionally unsubstituted or substituted with 3R
2.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , Z is S, and ring B is fused with pyridine or pyrimidine ring, and ring B is
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , R is
and ring B is fused with pyridine or pyrimidine ring, and ring B is a saturated or unsaturated 5-or 6-membered heterocyclyl, saturated or unsaturated 5-or 6-membered heterocyclic amide (lactam) , 6-membered aryl, or 5-or 6-membered heteroaryl, and each of ring B is independently optionally unsubstituted or substituted with 1R
2, 2R
2, or 3R
2.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , R is
and ring B is fused with pyridine or pyrimidine ring, and ring B is a unsaturated 5-or 6-membered heterocyclyl, saturated or unsaturated 5-or 6-membered heterocyclic amide (lactam) , 6-membered aryl, or 6-membered heteroaryl, and each of ring B is independently optionally unsubstituted or substituted with 1R
2, 2R
2, or 3R
2.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , R is
and ring B is fused with pyridine or pyrimidine ring, and ring B is an unsaturated 6-membered heterocyclyl, or saturated or unsaturated 6-membered heterocyclic amide (lactam) , and each of ring B is independently optionally unsubstituted or substituted with 3R
2.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , R is
and ring B is fused with pyridine or pyrimidine ring, and ring B is a unsaturated 6-membered heterocyclyl, or unsaturated 6-membered heterocyclic amide (lactam) , and each of ring B is independently optionally unsubstituted or substituted with 3R
2.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , R is
and ring B is fused with pyridine or pyrimidine ring, and ring B is a unsaturated 6-membered heterocyclyl, or saturated 6-membered heterocyclic amide (lactam) , and each of ring B is independently optionally unsubstituted or substituted with 3R
2.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , R is
and ring B is fused with pyridine or pyrimidine ring, and ring B is
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , R
2 is independently H, F, Cl, methyl, ethyl, methoxy, or ethoxy; the methyl could be substituted with 1F, 2F, or 3F; ethyl could be substituted with 1F, 2F, or 3F;
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , R
2 is independently H, F, methyl or methoxy; the methyl could be substituted with 1F, 2F, or 3F.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , R
2 is independently H, F, or -CF
3.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , two R
2 together with the C atom to which both R
2 are attached form an oxo, 3-, 4-, or 5-membered cycloalkyl, or 3-, 4-, or 5-membered heterocyclyl.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , two R
2 together with the C atom to which both R
2 are attached form an oxo, 3-or 4-membered cycloalkyl, or 3-membered heterocyclyl.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , two R
2 together with the C atom to which both R
2 attached form an oxo, or 3-membered cycloalkyl.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , two R
2 together with the C atom to which both R
2 attached form an oxo.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , two R
2 together with the C atom to which both R
2 attached form a 3-membered cycloalkyl.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , X
5 is N or CR
X5; and R
X5 is independently selected from -CN or CF
3.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , X
5 is N.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , m is 1 or 2.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , m is 1.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , each of R
3 is independently selected from hydrogen, methyl or ethyl; or two R
3 together with the C atom to which they are both attached form a 3-membered cycloalkyl, or 3-membered halocycloalkyl.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , each of R
3 is independently selected from hydrogen.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , ring A is a 6-membered aryl, 10-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, or 10-membered heteroaryl, and each of which is independently optionally unsubstituted or substituted with one or more R
1.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , ring A is a 6-membered aryl, 10-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, or 10-membered heteroaryl, and each of which is independently optionally unsubstituted or substituted with 1R
1, 2R
1, or 3R
1.
In some embodiments of Formula (I
0) , (I) , (I′) , (III) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , ring A is a 6-membered aryl, 10-membered aryl, 6-membered heteroaryl, or 10-membered heteroaryl, and each of which is independently optionally unsubstituted or substituted with 1R
1, 2R
1, or 3R
1.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , ring A is a phenyl, or benzyl, 6-membered heteroaryl, or 10-membered heteroaryl, and each of which is independently substituted with 1R
1, 2R
1, or 3R
1.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , ring A is a phenyl, or benzyl, and each of which is independently substituted with 3R
1.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , ring A is a benzyl, which is optionally substituted with up to 3R
1.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , ring A is a phenyl, which is optionally substituted with up to 3R
1.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , and R
1 is H, F, Cl, hydroxy, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, -NR
4R
4’, -NC (O) R
4, -C (O) NR
4R
4’, 3-to 5-membered cycloalkyl, 3-to 5-membered halocycloalkyl, or 3-to 5-membered heterocycloalkyl; and each of R
4 or R
4’ is independently selected from H, methyl, or ethyl; methyl could be substituted with 1F, 2F, or 3F; ethyl could be substituted with 1F, 2F, or 3F; the methyl group of the methoxy could be substituted with 1F, 2F or 3F; the ethyl group of the ethoxy could be substituted with 1F, 2F, or 3F.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , and R
1 is H, F, Cl, hydroxy, ethyl, ethynyl, or -CF
3.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , R is
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , R is
and v is 0, 1, or 2.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , R is
and v is 0.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , R is
and v is 1.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , R
5 is independently selected from F, Cl, -OH, -NH
2, -CN, methyl, ethyl, methoxy, ethoxy, methoxymethyl-, methoxymethoxy-, -CH
2OC (O) NH (CH
3) , -CH
2 OC (O) N (CH
3)
2, -CH
2OC (O) N (CH
2CH
3)
2, -CH
2CH
2 OC (O) N (CH
3)
2, or
hydroxymethyl, hydroxyethyl halomethyl, or haloethyl.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , R is
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , R is
and u is selected from 1, 2, or 3.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , R is
and u is selected from 1.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , R is
and u is selected from 2.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , R is
and u is selected from 3.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , X
0 is H, -OH, -NH
2, -C
1-3 alkyl, -C
1-3 alkoxy, -C
1-3 alkylene-OC (O) NHC
1-3 alkyl, -C
1-3 alkylene-OC (O) N (C
1-3alkyl)
2,
-C
1-3 alkylene-N (C
1-3 alkyl)
2, -C
1-3 alkoxy, or -C
1-3 hydroxyalkyl; and each of which can be independently optionally unsubstituted or substituted by a 3-to 7-membered heterocycle with one or more hetero atom independently selected from N, O or S, and at least one of the hetero atoms is N which is directly connected to one of the C atoms of the C
1-3 alky or C
1-3 hydroxy alkyl, and the 3-to 7-membered heterocycle can be further optionally unsubstituted or substituted by a NH
2, -OH, halogen, C
1-3 alkyl, C
1-3 alkoxy, -C
1-3 alkylene N (C
1-3 alkyl)
2 or -N (C
1-3 alkyl)
2.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , X
0 is H, -OH, -NH
2, methyl, ethyl, methoxy, ethoxy, -CH
2OC (O) NHCH
3, -CH
2CH
2OC (O) NHCH
3, -CH
2OC (O) N (CH
3)
2, -CH
2CH
2OC (O) N (CH
3)
2, -CH
2OC (O) N (CH
2CH
3) CH
3, -CH
2OC (O) N (CH
2CH
3)
2,
-CH
2N (CH
3)
2, -CH
2CH
2N (CH
3)
2, -CH
2N (CH
2CH
3) CH
3, -CH
2N (CH
2CH
3)
2; methyl or ethyl could be substituted with OH; and each of which can be independently optionally unsubstituted or substituted by a 3-, 4-, 5-, 6-, or 7-membered heterocycle with one or more hetero atom independently selected from N, O or S, and at least one of the hetero atoms is N which is directly connected to one of the C atoms of the methyl, ethyl; and the 3-, 4-, 5-, 6-, or 7-membered heterocycle can be further optionally unsubstituted or substituted by a NH
2, -OH, halogen, C
1-3 alkyl, C
1-3 alkoxy, -C
1-3 alkylene
-N (C
1-3 alkyl)
2, or -N (C
1-3 alkyl)
2.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , X
0 is H, -OH, -NH
2, methyl, ethyl, methoxy, -CH
2OC (O) NHCH
3, -CH
2OC (O) N (CH
3)
2, -CH
2OC (O) N (CH
2CH
3) CH
3, -CH
2OC (O) N (CH
2CH
3)
2,
CH
2N (CH
3)
2, -CH
2N (CH
2CH
3)
2; and each of which can be independently optionally unsubstituted or substituted by a 5-or 6-membered heterocycle with one or more hetero atom independently selected from N or O, and at least one of the hetero atoms is N which is directly connected to one of the C atoms of the methyl or ethyl; and the 5-or 6-membered heterocycle can be further optionally unsubstituted or substituted by a NH
2, -OH, halogen, C
1-3 alkyl, C
1-3 alkoxy, -C
1-3 alkylene N (C
1-3 alkyl)
2 or -N (C
1-3 alkyl)
2; methyl or ethyl could be substituted with OH.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , X
0 is H, methyl, -CH
2OC (O) N (CH
3)
2,
-CH
2N (CH
3)
2, -CH
2OH; and each of which can be independently optionally unsubstituted or substituted by a 6-membered heterocycle with one or more hetero atom independently selected from N or O, and at least one of the hetero atoms is N which is directly connected to one of the C atoms of the methyl, ethyl, or hydroxymethyl; and the 6-membered heterocycle can be further optionally unsubstituted or substituted by a NH
2, -OH, halogen, C
1-3 alkyl, C
1-3 alkoxy, -C
1-3 alkylene-N (C
1-3 alkyl)
2, or -N (C
1-3 alkyl)
2.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , the halogen is F or Cl; the C
1-3 alkyl is methyl, ethyl, or propyl; the C
1-3 alkoxy is methoxy, ethoxy, or propoxy; the C
1-3 alkylene is -CH
2-, -CH
2CH
2-, or CH
2CH
2CH
2-; -N (C
1-3 alkyl)
2 is -N(CH
3)
2, -N (CH
2CH
3)
2, or -N (CH
2CH
3) CH
3; the -C
1-3 alkylene-N (C
1-3 alkyl)
2 is -CH
2N (CH
3)
2, -CH
2N (CH
2CH
3)
2, -CH
2N (CH
2CH
3) CH
3, -CH
2CH
2N (CH
3)
2, -CH
2CH
2N (CH
2CH
3)
2, or-CH
2CH
2N (CH
2CH
3) CH
3.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , the halogen is F, or Cl; the C
1-3 alkyl is methyl or ethyl; the C
1-3 alkoxy is methoxy or ethoxy; the C
1-3 alkylene is -CH
2-or -CH
2CH
2-; -N (C
1-3alkyl)
2 is -N (CH
3)
2 or -N (CH
2CH
3)
2; the -C
1-3 alkylene-N (C
1-3 alkyl)
2 is -CH
2N (CH
3)
2, -CH
2N (CH
2CH
3)
2, -CH
2CH
2N (CH
3)
2, or -CH
2CH
2N (CH
2CH
3)
2.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , the halogen is F; the C
1-3 alkyl is methyl; the C
1-3 alkoxy is methoxy; the C
1-3 alkylene is -CH
2-; -N (C
1-3alkyl)
2 is -N (CH
3)
2; and the -C
1-3 alkylene N (C
1-3 alkyl)
2 is -CH
2N (CH
3)
2.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , the Y is NR
N.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , the Y is C (R
N)
2.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , each of R
N is independently selected from H, F, Cl, -NH
2, -CN, -OH, -NHC(O) NHCH
3, -NHC (O) NHCH
2CH
3, -NHC (O) NHCH
3, -NHC (O) NHCH
2CH
3, -NHC (O) N (CH
3)
2, -NHC(O) N (CH
2CH
3)
2, -OC (O) NHCH
3, -OC (O) NHCH
2CH
3, -OC (O) N (CH
3)
2, -CH
2NHC (O) NHCH
3, -CH
3NHC (O) N (CH
3)
2, -CH
2OH, -CH
2OC (O) NHCH
3, -CH
2OC (O) N (CH
3)
2,
methyl, ethyl, propyl, methoxy, ethoxy, or
each of R
8, R
9, or R
10 is independently selected from H, F, Cl, -NH
2, -CN, -OH, methyl, ethyl, methoxy, or ethoxy; and each of which is independently optionally unsubstituted or substituted by deuterium, F, Cl, -NH
2, -CN, -OH, methyl, ethyl, methoxy, or ethoxy.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , each of R
N is independently selected from H, F, Cl, -NH
2, -CN, -OH, -NHC(O) NHCH
3, -NHC (O) NHCH
2CH
3, -NHC (O) NHCH
3, -NHC (O) NHCH
2CH
3, -NHC (O) N (CH
3)
2, -NHC(O) N (CH
2CH
3)
2, -OC (O) NHCH
3, -OC (O) NHCH
2CH
3, -OC (O) N (CH
3)
2, -CH
2NHC (O) NHCH
3, -CH
3NHC (O) N (CH
3)
2, -CH
2OH, -CH
2OC (O) NHCH
3, -CH
2OC (O) N (CH
3)
2,
methyl, ethyl, propyl, methoxy, ethoxy, or
each of R
8, R
9 or R
10 is independently selected from H, F, Cl, -NH
2, -CN, -OH, methyl, ethyl, methoxy, or ethoxy; and each of which is independently optionally unsubstituted or substituted by deuterium, F, Cl, -NH
2, -CN, -OH, methyl, ethyl, methoxy, or ethoxy.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , each of R
N is independently selected from H, F, Cl, -NH
2, -CN, -OH, -NHC(O) NHCH
3, -NHC (O) N (CH
3)
2, -OC (O) NHCH
3, -CH
2NHC (O) NHCH
3, -CH
3NHC (O) N (CH
3)
2, -CH
2OH, methyl, ethyl, methoxy, or
each of R
8, R
9 or R
10 is independently selected from H, F, Cl, -NH
2, -OH, or methyl; and each of which is independently optionally unsubstituted or substituted by deuterium, F, Cl, -NH
2, -OH, or methyl.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , each of R
N is independently selected from H, F, -NH
2, -OH, -CH
2OH, methyl, or ethyl.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , each of R
N is independently selected from H or methyl.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , each of R
6 or R
7 is independently H, F, Cl, NH
2, OH, or methyl; methyl can be substituted with F or Cl; methyl can be substituted with OH; and the methyl of methoxy can be substituted with F or Cl.
In some embodiments of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-3) , each of R
6 or R
7 is independently H or methyl.
Exemplary compounds of the current invention are set forth below:
3- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
3- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
( (7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
( (3R, 7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
( (3R, 7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
( (3R, 7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
( (7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
( (3R, 7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
( (3R, 7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
( (3R, 7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
3- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -8- fluoropyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
3- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
3- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
3- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
3- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
3- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
3- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( ( (7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
3- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( ( (7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (S) -1- methylpyrrolidin-2-yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
( (7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
( (3R, 7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
( (3R, 7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
( (3R, 7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
( (7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
( (3R, 7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
( (3R, 7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
( (3R, 7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( (4- methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
( (7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8-oxo-6- (trifluoromethyl) -7, 8-dihydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
( (3R, 7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-oxo-6- (trifluoromethyl) -7, 8-dihydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
( (3R, 7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-6- (trifluoromethyl) -7, 8-dihydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
( (3R, 7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-6- (trifluoromethyl) -7, 8-dihydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
( (7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8-oxo-6- (trifluoromethyl) -7, 8-dihydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
( (3R, 7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-oxo-6- (trifluoromethyl) -7, 8-dihydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
( (3R, 7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-6- (trifluoromethyl) -7, 8-dihydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
( (3R, 7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-6- (trifluoromethyl) -7, 8-dihydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -7- (8-ethyl-7- fluoro-3-hydroxynaphthalen-1-yl) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2- fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
( (7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
( (3R, 7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
( (3R, 7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
( (3R, 7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
( (7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
( (3R, 7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
( (3R, 7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
( (3R, 7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 7-dihydropyrido [3, 4- d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
( (7aR) -7a- ( ( (4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8'-oxo-7', 8'-dihydro-5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -2'-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
( (3R, 7aR) -7a- ( ( (4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8'-oxo-7', 8'-dihydro-5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -2'-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
( (3R, 7aR) -7a- ( ( (4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8'-oxo-7', 8'-dihydro-5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -2'-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
( (3R, 7aR) -7a- ( ( (4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8'-oxo-7', 8'-dihydro-5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -2'-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
( (7aR) -7a- ( ( (4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8'-oxo-7', 8'-dihydro-5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -2'-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
( (3R, 7aR) -7a- ( ( (4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8'-oxo-7', 8'-dihydro-5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -2'-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
( (3R, 7aR) -7a- ( ( (4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) - 8'-oxo-7', 8'-dihydro-5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -2'-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
( (3R, 7aR) -7a- ( ( (4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8'-oxo-7', 8'-dihydro-5'h-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -2'-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2'- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2'- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2'- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2'- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2'- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2'- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4- d] pyrimidin] -8' (7'H) -one;
4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2'- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2'- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2'- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2'- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2'- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4- d] pyrimidin] -8' (7'H) -one;
4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2'- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (S) - 1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
( (7aR) -7a- ( ( (4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8'-oxo-7', 8'-dihydro-5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -2'-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
( (3R, 7aR) -7a- ( ( (4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8'-oxo-7', 8'-dihydro-5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -2'-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
( (3R, 7aR) -7a- ( ( (4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8'-oxo-7', 8'-dihydro-5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -2'-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
( (3R, 7aR) -7a- ( ( (4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8'-oxo-7', 8'-dihydro-5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -2'-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
( (7aR) -7a- ( ( (4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8'-oxo-7', 8'-dihydro-5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -2'-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
( (3R, 7aR) -7a- ( ( (4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8'-oxo-7', 8'-dihydro-5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -2'-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
( (3R, 7aR) -7a- ( ( (4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8'-oxo-7', 8'-dihydro-5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -2'-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
( (3R, 7aR) -7a- ( ( (4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8'-oxo-7', 8'-dihydro-5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -2'-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2'- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2'- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2'- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2'- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2'- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2'- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2'- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2'- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2'- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2'- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2'- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (S) -1- methylpyrrolidin-2-yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
( (7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
( (7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
( (7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8-oxo-6- (trifluoromethyl) -7, 8-dihydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-oxo-6- (trifluoromethyl) -7, 8-dihydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-6- (trifluoromethyl) -7, 8-dihydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-6- (trifluoromethyl) -7, 8-dihydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
( (7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8-oxo-6- (trifluoromethyl) -7, 8-dihydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-oxo-6- (trifluoromethyl) -7, 8-dihydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl) -8-oxo-6- (trifluoromethyl) -7, 8-dihydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-6- (trifluoromethyl) -7, 8-dihydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
( (7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-2-yl) oxy) methyl) hexahydro-1H- pyrrolizin-3-yl) methyl dimethylcarbamate;
( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
( (7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( ( (R) -3- fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
3- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- ( (1R, 5; ) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
3- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( ( (S) -1-methylpyrrolidin-2-yl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( ( (S) -1-methylpyrrolidin-2-yl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( ( (S) -1-methylpyrrolidin-2-yl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( ( (S) -1-methylpyrrolidin-2-yl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
( (7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
( (7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
3- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( ( (1- ( (dimethylamino) methyl) cyclopropyl) methyl) thio) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( ( (1- ( (dimethylamino) methyl) cyclopropyl) methyl) thio) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( ( (1- ( (dimethylamino) methyl) cyclopropyl) methyl) thio) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( ( (1- ( (dimethylamino) methyl) cyclopropyl) methyl) thio) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
3- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1- (morpholinomethyl) cyclopropyl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1- (morpholinomethyl) cyclopropyl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1- (morpholinomethyl) cyclopropyl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1- (morpholinomethyl) cyclopropyl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
3- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
3- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2- ( ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
3- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
3- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1- ( (4-methylpiperazin-1- yl) methyl) cyclopropyl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
3- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( ( (7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
3- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( ( (7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( ( (S) -1-methylpyrrolidin-2-yl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (S) -1-methylpyrrolidin-2-yl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (S) -1-methylpyrrolidin-2-yl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (S) -1-methylpyrrolidin-2-yl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
( (7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
( (7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (1- ( (dimethylamino) methyl) cyclopropyl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- ( (dimethylamino) methyl) cyclopropyl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( ( (1- ( (dimethylamino) methyl) cyclopropyl) methyl) thio) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( ( (1- ( (dimethylamino) methyl) cyclopropyl) methyl) thio) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (1- (morpholinomethyl) cyclopropyl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- (morpholinomethyl) cyclopropyl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- (morpholinomethyl) cyclopropyl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- (morpholinomethyl) cyclopropyl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4- d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( ( (S) -1-methylpyrrolidin-2-yl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (S) -1-methylpyrrolidin-2-yl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (S) -1-methylpyrrolidin-2-yl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (S) -1-methylpyrrolidin-2-yl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
( (7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8-oxo-6- (trifluoromethyl) -7, 8-dihydropyrido [3, 4-d] pyrimidin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-oxo-6- (trifluoromethyl) -7, 8-dihydropyrido [3, 4-d] pyrimidin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-6- (trifluoromethyl) -7, 8-dihydropyrido [3, 4-d] pyrimidin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-6- (trifluoromethyl) -7, 8-dihydropyrido [3, 4-d] pyrimidin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
( (7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8-oxo-6- (trifluoromethyl) -7, 8-dihydropyrido [3, 4-d] pyrimidin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-oxo-6- (trifluoromethyl) -7, 8-dihydropyrido [3, 4-d] pyrimidin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-6- (trifluoromethyl) -7, 8-dihydropyrido [3, 4-d] pyrimidin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-6- (trifluoromethyl) -7, 8-dihydropyrido [3, 4-d] pyrimidin-2-yl) thio) methyl) hexahydro-1H- pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (1- ( (dimethylamino) methyl) cyclopropyl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- ( (dimethylamino) methyl) cyclopropyl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( ( (1- ( (dimethylamino) methyl) cyclopropyl) methyl) thio) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( ( (1- ( (dimethylamino) methyl) cyclopropyl) methyl) thio) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (1- (morpholinomethyl) cyclopropyl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- (morpholinomethyl) cyclopropyl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- (morpholinomethyl) cyclopropyl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- (morpholinomethyl) cyclopropyl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (3R, 7aR) - 3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( ( (S) -1-methylpyrrolidin-2-yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (S) -1-methylpyrrolidin-2-yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (S) -1-methylpyrrolidin-2-yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (S) -1-methylpyrrolidin-2-yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
( (7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-2-yl) thio) methyl) hexahydro-1H- pyrrolizin-3-yl) methyl dimethylcarbamate;
( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
( (7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (1- ( (dimethylamino) methyl) cyclopropyl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- ( (dimethylamino) methyl) cyclopropyl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( ( (1- ( (dimethylamino) methyl) cyclopropyl) methyl) thio) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (1- (morpholinomethyl) cyclopropyl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- (morpholinomethyl) cyclopropyl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- (morpholinomethyl) cyclopropyl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- (morpholinomethyl) cyclopropyl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2'- ( ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2'- ( ( ( (S) -1-methylpyrrolidin-2-yl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( ( (S) -1-methylpyrrolidin-2-yl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( ( (S) -1-methylpyrrolidin-2-yl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( ( (S) -1-methylpyrrolidin-2-yl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
( (7aR) -7a- ( ( (4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8'-oxo-7', 8'-dihydro-5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -2'-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
( (3R, 7aR) -7a- ( ( (4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8'-oxo-7', 8'-dihydro-5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -2'-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
( (3R, 7aR) -7a- ( ( (4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8'-oxo-7', 8'-dihydro-5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -2'-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
( (3R, 7aR) -7a- ( ( (4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8'-oxo-7', 8'-dihydro-5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -2'-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
( (7aR) -7a- ( ( (4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8'-oxo-7', 8'-dihydro-5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -2'-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
( (3R, 7aR) -7a- ( ( (4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8'-oxo-7', 8'-dihydro-5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -2'-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
( (3R, 7aR) -7a- ( ( (4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8'-oxo-7', 8'-dihydro-5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -2'-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
( (3R, 7aR) -7a- ( ( (4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8'-oxo-7', 8'-dihydro-5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -2'-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2'- ( ( (1- ( (dimethylamino) methyl) cyclopropyl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (1- ( (dimethylamino) methyl) cyclopropyl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2'- ( ( (1- ( (dimethylamino) methyl) cyclopropyl) methyl) thio) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2'- ( ( (1- ( (dimethylamino) methyl) cyclopropyl) methyl) thio) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2'- ( ( (1- (morpholinomethyl) cyclopropyl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (1- (morpholinomethyl) cyclopropyl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (1- (morpholinomethyl) cyclopropyl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (1- (morpholinomethyl) cyclopropyl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2'- ( ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2'- ( ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2'- ( ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2'- ( ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2'- ( ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2'- ( ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2'- ( ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'- pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;
4- (2- ( (4'H, 6'H-Spiro [cyclopropane-1, 5'-pyrrolo [1, 2-b] pyrazol] -3'-yl) methoxy) -4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (2-chloropyrrolo [2, 1-b] thiazol-6-yl) methoxy) -8- fluoropyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (2- ( (4'H, 6'H-Spiro [cyclopropane-1, 5'-pyrrolo [1, 2-b] pyrazol] -3'-yl) methoxy) -4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (2-chloropyrrolo [2, 1-b] thiazol-6-yl) methoxy) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
4- (2- ( (4'H, 6'H-Spiro [cyclopropane-1, 5'-pyrrolo [1, 2-b] pyrazol] -3'-yl) methoxy) -4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (2-chloropyrrolo [2, 1-b] thiazol-6-yl) methoxy) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
3- (2- ( (4'H, 6'H-Spiro [cyclopropane-1, 5'-pyrrolo [1, 2-b] pyrazol] -3'-yl) methoxy) -4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
3- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (2-chloropyrrolo [2, 1-b] thiazol-6-yl) methoxy) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
3'- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoronaphthalen-1-yl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) oxy) methyl) -4'H, 6'H-spiro [cyclopropane-1, 5'-pyrrolo [1, 2-b] pyrazole] ;
6- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoronaphthalen-1-yl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) oxy) methyl) -2-chloropyrrolo [2, 1-b] thiazole;
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( (1-methyl-1, 4-dihydropyrrolo [3, 2-c] pyrazol-5-yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( (2-methyl-2, 4-dihydropyrrolo [3, 2-c] pyrazol-5-yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( (1-methyl-1, 4-dihydropyrrolo [3, 2-c] pyrazol-5-yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( (2-methyl-2, 4-dihydropyrrolo [3, 2-c] pyrazol-5-yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( (1-methyl-1, 4-dihydropyrrolo [3, 2-c] pyrazol-5-yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( (2-methyl-2, 4-dihydropyrrolo [3, 2-c] pyrazol-5-yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
3- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( (1-methyl-1, 4-dihydropyrrolo [3, 2-c] pyrazol-5-yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
3- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( (2-methyl-2, 4-dihydropyrrolo [3, 2-c] pyrazol-5-yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoronaphthalen-1-yl) -8-fluoro-2- ( (1-methyl-1, 4-dihydropyrrolo [3, 2-c] pyrazol-5-yl) methoxy) pyrido [4, 3-d] pyrimidine;
4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoronaphthalen-1-yl) -8-fluoro-2- ( (2-methyl-2, 4-dihydropyrrolo [3, 2-c] pyrazol-5-yl) methoxy) pyrido [4, 3-d] pyrimidine;
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (2-chloro-4H-furo [3, 2-b] pyrrol-5-yl) methoxy) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (2-chloro-4H-furo [3, 2-b] pyrrol-5-yl) methoxy) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (2-chloro-4H-furo [3, 2-b] pyrrol-5-yl) methoxy) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (2-chloro-4H-furo [3, 2-b] pyrrol-5-yl) methoxy) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (2-chloro-4H-furo [3, 2-b] pyrrol-5-yl) methoxy) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (2-chloro-4H-furo [3, 2-b] pyrrol-5-yl) methoxy) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;
3- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (2-chloro-4H-furo [3, 2-b] pyrrol-5-yl) methoxy) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
3- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (2-chloro-4H-furo [3, 2-b] pyrrol-5-yl) methoxy) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;
5- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoronaphthalen-1-yl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) oxy) methyl) -2-chloro-4H-furo [3, 2-b] pyrrole;
5- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoronaphthalen-1-yl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) oxy) methyl) -2-chloro-4H-furo [3, 2-b] pyrrole.
The present invention furthermore disclosures a pharmaceutical composition, comprising a therapeutically effective amount of at least one of compound or a pharmaceutically acceptable salt thereof as defined above, and a pharmaceutically acceptable excipient.
In some embodiments of pharmaceutical composition, the pharmaceutical composition, comprising a therapeutically effective amount of at least one of compound as defined above, or a pharmaceutically acceptable salt thereof as defined above, and a pharmaceutically acceptable excipient.
In some embodiments of pharmaceutical composition, the pharmaceutical composition, comprising a therapeutically effective amount of at least one of compound as defined above, or a pharmaceutically acceptable salt thereof as defined above, and a pharmaceutically acceptable excipient.
In some embodiments of pharmaceutical composition, the pharmaceutical composition, comprising a therapeutically effective amount of at least one of compound as defined above, or a pharmaceutically acceptable salt thereof as defined above, and a pharmaceutically acceptable excipient.
In some embodiments of pharmaceutical composition, the pharmaceutical composition, comprising a therapeutically effective amount of at least one of compound as defined above, a pharmaceutically acceptable salt thereof as defined above, and a pharmaceutically acceptable excipient.
The present invention furthermore disclosures a method for inhibiting KRAS Gl2D activity in a cell, comprising contacting the cell in which inhibition of KRAS Gl2D activity is desired with an effective amount of at least one of compound as defined above or a pharmaceutically acceptable salt thereof as defined above.
In some embodiments of method, the method for inhibiting KRAS Gl2D activity in a cell, comprising contacting the cell in which inhibition of KRAS Gl2D activity is desired with an effective amount of at least one of compound as defined above, or a pharmaceutically acceptable salt thereof as defined above.
In some embodiments of method, the method for inhibiting KRAS Gl2D activity in a cell, comprising contacting the cell in which inhibition of KRAS Gl2D activity is desired with an effective amount of at least one of compound as defined above, or a pharmaceutically acceptable salt thereof as defined above.
In some embodiments of method, the method for inhibiting KRAS Gl2D activity in a cell, comprising contacting the cell in which inhibition of KRAS Gl2D activity is desired with an effective amount of at least one of compound as defined above, or a pharmaceutically acceptable salt thereof as defined above.
In some embodiments of method, the method for inhibiting KRAS G12D activity in a cell, comprising contacting the cell in which inhibition of KRAS G12D activity is desired with the pharmaceutical composition as defined above.
The present invention furthermore disclosures a method for treating a KRAS G12D-associated cancer comprising administering to a patient in need thereof a therapeutically effective amount of at least one of compound as defined above, or a pharmaceutically acceptable salt thereof as defined above.
In some embodiments of method, the method for treating a KRAS G12D-associated cancer comprising administering to a patient in need thereof a therapeutically effective amount of at least one of compound as defined above, or a pharmaceutically acceptable salt thereof as defined above.
In some embodiments of method, the therapeutically effective amount of the compound as defined above is between about 0.01 to 100 mg/kg per day.
In some embodiments of method, the therapeutically effective amount of the compound as defined above is between about 0.1 to 50 mg/kg per day.
In some embodiments of method, the KRAS G12D-associated cancer is selected from the group consisting of Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma) , myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma) , alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma) , stomach (carcinoma, lymphoma, leiomyosarcoma) , pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma) , small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma) , large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma) ; Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma) , lymphoma, leukemia) , bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma) , prostate (adenocarcinoma, sarcoma) , testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma) ; Liver hepatoma (hepatocellular carcinoma) , cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma) , fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma) , multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses) , benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans) , meninges (meningioma, meningiosarcoma, gliomatosis) , brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma) , glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors) , spinal cord neurofibroma, meningioma, glioma, sarcoma) ; Gynecological: uterus (endometrial 'carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma) , granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma) , vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma) , vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma) , fallopian tubes (carcinoma) ; Hematologic: blood (myeloid leukemia (acute and chronic) , acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome) , Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma) ; Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevI′lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma.
In some embodiments of method, the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer.
The present invention furthermore disclosures a method for treating cancer in a patient in need thereof, the method comprising (a) determining that the cancer is associated with a KRAS Gl2D mutation (e.g., a KRAS Gl2D-associated cancer) ; and (b) administering to the patient a therapeutically effective amount of at least one of compound as defined above.
In some embodiments of method, the the administering is done via a route selected from the group consisting of parenteral, intraperitoneal, intradermal, intracardiac, intraventricular, intracranial, intracerebrospinal, intrasynovial, intrathecal administration, intramuscular injection, intravitreous injection, intravenous injection, intra-arterial injection, oral, buccal, sublingual, transdermal, topical, intratracheal, intrarectal, subcutaneous, and topical administration.
In some embodiments of method, the administering is done via an intravenous injection.
In some embodiments of method, the administering is done via an intramuscular injection.
In some embodiments of method, the administering is done via an intramuscular injection.
In some embodiments of method, the administepyridine or pyrimidine ringomprises utilizing a delivery device.
In some embodiments of method, the administering is done in a hospital setting.
It is understood that the present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention encompasses all combinations of the aspects and/or embodiments of the invention noted herein. It is understood that any and all embodiments of the present indention may be taken in conjunction with any other embodiment or embodiments to describe additional embodiments. It is also to be understood that each individual element of the embodiments is meant to be combined with any and all other elements from any embodiment to describe an additional embodiment.
Definitions
The following description is made with the understanding that the present disclosure is to be considered as an exemplification of the claimed subject matter, and is not intended to limit the appended claims to the specific embodiments illustrated. The headings used in this disclosure are provided for convenience and are not to be considered to limit the claims in any way. Embodiments illustrated under any heading might be combined with any other illustrated heading embodiments.
All technical and scientific terms used herein, unless defined otherwise, have the same meaning as commonly understood by one of ordinary skill in the art. It must be noted that as used in this disclosure, the singular forms "a" , "and" , and "the" include plural referents unless the context clearly dictates otherwise. Thus, "the compound" includes a plurality of such compounds and "the assay" includes one or more assays, and so forth.
As used in the present disclosure, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.
A dash "-" at the front or end of a chemical group is used, a matter of convenience, to indicate a point of attachment for a substituent. For example, -OH is attached through the carbon atom; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line drawn through a line in a structure indicates a point of attachment of a group. Unless chemically or structurally required, no directionality is indicated or implied by the order in which a chemical group is written or named. A solid line coming out of the center of a ring indicates that the point of attachment for a substituent on the ring can be at any ring atom. For example, R′in the below structure can be attached to any of the carbon ring atoms or X
1, including the bridge carbon atom (s) :
The prefix "C
m-n" indicates that the following group has from m to n carbon atoms. For example, "C
1-8 alkyl" indicates that the alkyl group has from 1 to 8 carbon atoms. In similar manner, the term "m-n membered" rings, wherein m and n are numerical ranges, such as "3-12-membered heterocyclyl" , refers to a ring containing 3-12 atoms, of which up to 80%may be heteroatoms, such as N, O, S, P, and the remaining atoms are carbon.
Also, some commonly used alternative chemical names may or may not be used. For example, a divalent group such as a divalent "alkyl" group, a divalent "aryl" group, etc., may also be referred to as an "alkylene" group or an "alkylenyl" group, or alkylyl group, an "arylene" group or an "arylenyl" group, or arylyl group, respectively.
"A compound provided herein" or "a compound described herein" or "a compound disclosed herein" or "a compound of the present disclosure" refers to the compounds of Formula Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-4) , which also applies to the specific compounds of Examples 1 to Example 5.
In certain embodiments, the term "about" , directed to that value or parameter per se, includes the indicated amount ±10%, ±5%, or ±1%. Also, the term "about X" includes description of "X" .
"Adjoining atoms" , as used herein, refers to atoms that are in immediately next to each other. For instance, in "C1-C2-C3-C4" atom C1 is adjoining to atom C2, atom C2 is adjoining to atoms C1 and C3, so on and so forth.
The term "alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 6 carbon atoms (i.e., C
1-6 alkyl) , or 1 to 10 carbon atoms (i.e., C
1-10 alkyl) . Alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl group having a specific number of carbons is named by a chemical name or identified by molecular formula, all positional isomers having that number of carbons may be included; thus, as an example, "butyl" includes n-butyl (i.e. - (CH
2)
3 CH
3) , sec-butyl (i.e. - CH (CH
3) CH
2CH
3) , isobutyl (i.e. -CH
2CH (CH
3)
2) and tert-butyl (i.e. -C (CH
3)
3) , and "propyl" includes n-propyl (i.e - (CH
2)
2CH
3) and isopropyl (i.e. -CH (CH
3)
2) .
The term "alkenyl" refers to an aliphatic group containing at least one carbon-carbon double bond (C=C) and having from 2 to 15 carbon atoms (i.e., C
2-15 alkenyl) , or 2 to 4 carbon atoms (i.e., C
2-4 alkenyl) . Examples of alkenyl groups include ethenyl, propenyl, butadienyl (including 1, 2-butadienyl and 1, 3-butadienyl) .
The term "alkynyl" refers to an aliphatic group containing at least one carbon-carbon triple bond (C≡C) and having from 2 to 10 carbon atoms (i.e., C
2-10 alkynyl) , or 2 to 4 carbon atoms (i.e., C
2-4 alkynyl) , etc. The term "alkynyl" also includes those groups having one triple bond and one double bond.
The term "alkoxy" refers to the group "-O-alkyl" , for example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1, 2-dimethylbutoxy. The term "haloalkoxy" refers to an alkoxy group as indicated above, wherein one or more hydrogen atoms are replaced by a halogen.
The term "acyl" refers to a group -C (=O) R, herein R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, and each of which may be optionally substituted, as defined herein. Examples of acyl group include formyl, acetyl, cylcohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl, etc.
The term "amido" refers to both a "C-amido" group which refers to the group -C (=O) NR
aR
b and an "N-amido" group which refers to the group -NR
aC (=O) R
b, wherein R
a and R
b are independently selected from groups consisting of hydrogen, alkyl, aryl, haloalkyl, heteroaryl, cycloalkyl, and heterocyclyl; and each of which may be optionally substituted.
"Amino" refers to the group -NR
aR
b, herein R
a and R
b are independently selected from groups consisting of hydrogen, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl; and each of which may be optionally substituted.
The term "aryl" refers to an aromatic carbocyclic group having a single ring (e.g. monocyclic) or multiple rings (e.g. bicyclic or tricyclic) including fused systems. As examples used herein, aryl has 6 to 20 ring carbon atoms (i.e., C
6-20 aryl) , 6 to 12 carbon ring atoms (i.e., C
6-12 aryl) , etc. Some examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl. Herein, aryl does not encompass or overlap in any way with heteroaryl as defined below. If one or more aryl groups are fused with a heteroaryl ring, the resulting ring system is heteroaryl.
The term "cyano" or "carbonitrile" group represented by -CN
The term "cycloalkyl" refers to a saturated or partially saturated cyclic alkyl group having a single ring or multiple rings including fused, bridged, and spiro ring systems. The term "cycloalkyl" also includes cycloalkenyl groups (i.e. the cyclic group having at least one double bond) . As used wherein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C
3-20 cycloalkyl) , 3 to 8 ring carbon atoms (i.e., C
3-8 cycloalkyl) , or 3 to 5 ring carbon atoms (i.e., C
3-5 cycloalkyl) , etc. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
The term "bridged" refers to a ring fusion wherein non-adjacent atoms on a ring are joined by a divalent substituent, such as alkylenyl group, an alkylenyl group containing one or two heteroatoms, or a single heteroatom. Examples of bridged ring systems include quinuclidinyl and admantanyl.
The term "fused" refers to a ring which is bound to an adjacent ring.
The term "spiro" refers to a ring substituent which is joined by two bonds at the same carbon atom. Some examples of spiro groups include 1, 1-diethylcyclopentane, dimethyl-dioxolane, and 4-benzyl-4-methylpiperidine, wherein the cyclopentane and piperidine, respectively, are the spiro substituents.
"Halogen" or "halo" includes fluoro (F) , chloro (Cl) , bromo (Br) , and iodo (I) . "Haloalkyl" includes an unbranched or branched alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen. If a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two ( "di" ) or three ( "tri" ) halo groups, which may be, but are not necessarily, the same halogen. Some examples of haloalkyl include difluoromethyl (-CHF
2) and trifluoromethyl (-CF
3) .
The term "heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from N, O, and S. As examples used herein, heteroaryl includes 1 to 20 carbon ring atoms (i.e., C
1-20 heteroaryl) , 3 to 12 carbon ring atoms (i.e., C
3-12 heteroaryl) , etc., and the number of ring heteroatoms, as used wherein, independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. The term “heteroaryl” does not encompass or overlap with “aryl” as defined above.
The term "heterocyclyl" or "heterocyclic ring" refers to a non-aromatic cyclic alkyl group, with at least one ring heteroatoms independently selected from boron (B) , nitrogen (N) , oxygen (O) , phosphorus (P) and sulfur. As used wherein, "heterocyclyl" or "heterocyclic ring" refer to rings that are saturated or partially saturated unless otherwise indicated, for example, in some embodiments "heterocyclyl" or "heterocyclic ring" refers to rings that are partially saturated where specified. "Heterocyclyl" or "heterocyclic ring" includes heterocycloalkenyl groups (i.e., the heterocyclyl group having at least one double bond) . A heterocyclyl may be a single ring or multiple rings wherein the multiple rings may be fused, bridged, or spiro. As used herein, heterocyclyl has 2 to 20 carbon ring atoms (i.e., C
2-20 heterocyclyl) , 3 to 8 carbon ring atoms (i.e., C
3-8 heterocyclyl) , or 3 to 6 carbon ring atoms (i.e., C
3-6 heterocyclyl) ; having 1 to 5 ring heteroatoms independently selected from B, N, O, P, or S. Examples of heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, and morpholinyl. The term "bridged-heterocyclyl" refers to a four-to ten-membered cyclic moiety connected at two non-adjacent atoms of the heterocyclyl with one or more (e.g., 1 or 2) four-to ten-membered cyclic moiety having at least one heteroatom where each heteroatom is independently selected from B, N, O, P and S. As used herein, "bridged-heterocyclyl" includes bicyclic and tricyclic ring systems. Also as used herein, the term "spiro-heterocyclyl" refers to a ring system in which a three-to ten-membered heterocyclyl has one or more additional ring, wherein the one or more additional ring is three-to ten-membered cycloalkyl or three-to ten-membered heterocyclyl, where a single atom of the one or more additional ring is also an atom of the three-to ten-membered heterocyclyl. As used herein, the terms "heterocyclyl" , and "heterocyclic ring" are used interchangeably. In some embodiments, a heterocyclyl is substituted with an oxo group.
"Hydroxy" or "hydroxyl" refers to the group -OH.
"Oxo" refers to the group (=O) or (O) .
The term "sulfonyl" refers to the group -S (O)
2R
a, where R
a is alkyl, haloalkyl, heterocyclyl, cycloalkyl, heteroaryl, or aryl. Some Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.
Wherever a group terminates in a singly bonded nitrogen atom, that group represents an -NH group unless otherwise indicated. Similarly, unless otherwise expressed, hydrogen atom (s) are implied and deemed present where necessary in view of the knowledge of one of skill in the art to complete valency or provide stability.
"Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the said event or circumstance occurs and instances in which it does not. Also, the term "optionally substituted" means that any one or more hydrogen atoms on the designated atom or group may or may not be replaced by a moiety other than hydrogen.
"Substituted" means that one or more hydrogen atoms on the designated atom or group is substituted with one or more substituents other than hydrogen, in the conditions that the designated atom's normal valence is not exceeded. The substituents include, but not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof. Similar indefinite structures arrived at by defining substituents with further substituents appended to infinity (e.g., a substituted aryl having a substituted alkyl which is itself substituted with a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc. ) are not intended for inclusion herein. Unless otherwise noted, the maximum number of serial substitutions in compounds described herein is three. For example, serial substitutions of substituted aryl groups with two other substituted aryl groups are limited to ( (substituted aryl) substituted aryl) substituted aryl. Similarly, the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluorines or heteroaryl groups having two adjacent oxygen ring atoms) . Such impermissible substitution patterns are well known to the skilled artisan. Whenever used to modify a chemical group, "substituted" may describe other chemical groups defined herein. For example, the term "substituted aryl" includes, but not limited to, "alkylaryl. " Unless specified otherwise, if a group is described as optionally substituted, any substituents of the group are themselves unsubstituted.
In some instances, "substituted alkyl" refers to an alkyl group having one or more substituents that include hydroxyl, halo, amino, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In additional instances, "substituted cycloalkyl" refers to a cycloalkyl group having one or more substituents including alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amino, alkoxy, halo, oxo, and hydroxyl; by "substituted heterocyclyl" , it refers to a heterocyclyl group having one or more substituents including alkyl, amino, haloalkyl, heterocyclyl, cycloalkyl, aryl, heteroaryl, alkoxy, halo, oxo, and hydroxyl; the term "substituted aryl" refers to an aryl group having one or more substituents including halo, alkyl, amino, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, alkoxy, and cyano; the term "substituted heteroaryl" refers to an heteroaryl group having one or more substituents including halo, amino, alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkoxy, and cyano and the term "substituted sulfonyl" refers to a group -S (O)
2R, herein R is substituted with one or more substituents including alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In other instances, the one or more substituents may be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted. In other instances, the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.
In some embodiments, a substituted cycloalkyl, a substituted heterocyclyl, a substituted aryl, and/or a substituted heteroaryl includes a cycloalkyl, a heterocyclyl, an aryl, and/or a heteroaryl that has a substituent on the ring atom to which the cycloalkyl, heterocyclyl, aryl, and/or heteroaryl is attached to the rest of the compound. For example, in the below moiety, the phenyl ring is substituted with a meta-chloro group:
The disclosed compounds herein, or their pharmaceutically acceptable salts may contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R) -or (S) -or, as (D) -or (L) -for amino acids. The current disclosure includes all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-) , (R) -and (S) -, or (D) -and (L) -isomers may be prepared using chiral synthons or chiral reagents, or resolved by conventional techniques, such as, chromatography and fractional crystallization. Traditional techniques for the preparation, isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC) . When the compounds disclosed herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, these compounds include both E and Z geometric isomers. As the same, all tautomeric forms are also intended to be included. Wherever compounds are represented in their chiral form, it is understood that the embodiment includes, but is not limited to, the specific diastereomerically or enantiomerically enriched form. In situations that the chirality is not specified but is present, it is understood that the embodiment is intended to include either the specific diastereomerically or enantiomerically enriched form; or a racemic or scalemic mixture of such compound (s) . "Scalemic mixture" is a mixture of stereoisomers at a ratio other than 1: 1.
The term "stereoisomer" refers to a compound containing the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The current disclosure contemplates various stereoisomers and mixtures thereof and includes "enantiomers" , which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another.
The term "enantiomers" represent a pair of stereoisomers that are non-superimposable mirror images of each other. A 1: 1 mixture of a pair of enantiomers is a "racemic" mixture. A mixture of enantiomers at a ratio other than 1: 1 is a "scalemic" mixture.
The term "diastereoisomers" represent stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
"Tautomer" refers to a proton shift from one atom of a molecule to another atom of the same molecule. The present disclosure includes tautomers of any compounds provided herein.
Some disclosed compounds herein exist as tautomeric isomers. Tautomeric isomers are in equilibrium with one another. For example, amide containing compounds may exist in equilibrium with imidic acid tautomers. No matter which tautomer is shown, and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, the amide containing compounds are understood to include their imidic acid tautomers. As the same, the imidic acid containing compounds are understood to include their amide tautomers.
The interaction of a solvent and a compound forms a "solvate" . Herein, the solvates also include the solvates of salts of the compounds disclosed and the hydrates of the compounds provided herein.
Any formula or structure provided herein also represents unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have the same structures as depicted by the formulas given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes include isotopes, such as, of carbon (
11C,
13C,
14C) , nitrogen (
15N) , oxygen (
17O,
18O) , phosphorous (
31P,
32P) , fluorine (
18F) , chlorine (
36Cl) , and iodine (
125I) . Isotopically labelled compounds may have usages in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) in drug or substrate tissue distribution assays or in radioactive treatment of patients.
In many cases, the current disclosed compounds are capable to form acid salts by virtue of the presence of amino and/or groups similar thereto.
The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic acids. When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Since the compounds of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-4) are intended for pharmaceutical use they are preferably provided in substantially pure form, for example at least 60%pure, more suitably at least 75%pure, especially at least 98%pure (%are on a weight for weight basis) .
The pharmaceutical compositions of the present invention comprise a compound represented by Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-4) , or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants. The compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
In practice, the compounds represented by Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-4) , or a prodrug or a metabolite or pharmaceutically acceptable salts thereof, of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g. oral or parenteral (including intravenous) . Thus, the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the compound represented by Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-4) , or a pharmaceutically acceptable salt thereof, may also be administered by controlled release means and/or delivery devices. The compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.
Thus, the pharmaceutical compositions of this invention may include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt, of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-4) . The compounds of Formula (I
0) , (I) , (I′) , (II) , (II′) , (II-1) to (II-6) , (II′-1) to (II′-6) , (III) , (III′) , (III-1) to (III-4) , or (III′-1) to (III′-4) , or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
The pharmaceutical carrier employed can be, for example, a solid, liquid or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen. In preparing the compositions for oral dosage form, any convenient pharmaceutical media may be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like may be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets may be coated by standard aqueous or nonaqueous techniques.
A tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.05mg to about 5g of the active ingredient and each cachet or capsule preferably containing from about 0.05mg to about 5g of the active ingredient. For example, a formulation intended for the oral administration to humans may contain from about 0.5mg to about 5g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 0.05 to about 95 percent of the total composition. Unit dosage forms will generally contain between from about 0.0lmg to about 2g of the active ingredient, typically 0.01mg, 0.02mg, 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 25mg, 50mg, l00mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg or l000mg.
Pharmaceutical compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol) , vegetable oils, and suitable mixtures thereof.
Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a compound represented by Formula I of this invention or a pharmaceutically acceptable salt thereof, via conventional processing methods. As an example, a cream or ointment is prepared by admixing hydrophilic material and water, together with about 0.05wt%to about 10wt%of the compound, to produce a cream or ointment having a desired consistency.
Pharmaceutical compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier (s) followed by chilling and shaping in molds.
In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound described by Formula I or pharmaceutically acceptable salts thereof, may also be prepared in powder or liquid concentrate form.
Generally, dosage levels on the order of from about 0.001mg/kg to about 150mg/kg of body weight per day are useful in the treatment of the above-indicated conditions or alternatively about 0.05mg to about 7g per patient per day. For example, cancer, disease and conditions of the immune system, may be effectively treated by the administration of from about 0.001 to 50mg of the compound per kilogram of body weight per day or alternatively about 0.05mg to about 3.5g per patient per day.
It is understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
The term “KRAS G12D” mutant refers to a mutant form of mammal KRAS protein that contains an amino acid substitution of an aspartic acid for a glycine at amino acid position 12. The positioning of the amino acid codes and residues of human KRAS is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01116: Variant p. Gly12Asp.
The term “inhibition” refers to a decrease in the baseline activity of a biological activity or process. “Inhibition of activity of KRAS G12D” thereof refers to a decrease in KRAS G12D activity as compared to the activity of that enzyme in the absence of the compound of the present disclosure.
The present disclosure compounds can bind to KRAS G12D then inhibit or negatively modulate KRAS G12D activity by a wide variety of molecular mechanisms, non-limiting examples include a showing of (a) a decrease in GTPase activity of KRAS; (b) a decrease in GTP binding affinity or an increase in GDP binding affinity; (c) an increase in K
off of GTP or a decrease in K
off of GDP; (d) a decrease in binding of guanine nucleotide exchange factors (GEFs) including but not limed to SOS1; (e) a decrease in binding of effectors or downstream signaling molecules including but not limed to Raf.
By negatively modulating the activity of KRAS G12D, the subject matter disclosed herein can be utilized to inhibit undesired cellular proliferation and/or anchorage-independent cell growth.
The term “KRAS G12D-associated disease or disorder” refers to disease or disorder associated with or mediated by or having a KRAS G12D mutation. Examples including, but not limited to KRAS G12D-assocaited cancer.
The term "subject" , "individual" or "patient" is used interchangeably, and refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates and humans. In some embodiments, patient is a human. In some embodiments, subject has been accredited or has been diagnosed as having a KRAS G12D mutation positive cancer (e.g., the cancer is determined by measuring method ratified by management organizations, such as Food and Drug Administration (FDA) ) . In some embodiments, the subject is suspected of having a KRAS G12D gene-associated cancer.
The term “disease” refers to any disease, discomfort, illness, symptoms or indications, and can be interchangeable with the term “disorder” or “condition” .
The term “cancer” encompass all forms of cancers, including, but not limited to, all forms of carcinomas, melanomas, blastomas, sarcomas, lymphomas and leukemias. Examples include but are not limited to breast cancer, bladder cancer, bladder carcinoma, uterine cancer, brain tumors, cervical cancer, colorectal cancer, esophageal cancer, endometrial cancer, liver cancer (including HCC) , laryngeal cancer, lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, renal carcinoma, kidney cancer (including RCC) , thyroid cancer, acute lymphocytic leukemia, acute myeloid leukemia, ependymoma, Ewing’s sarcoma, glioblastoma, medulloblastoma, neuroblastoma, osteosarcoma, rhabdomyosarcoma, rhabdoid cancer, and nephroblastoma (Wilm’s tumor) .
In some such embodiment, the subject matter disclosed herein can be utilized to inhibit, block, reduce or decrease KRAS G12D activation for the reduction of tumor growth and/or tumor metastasis, wherein the method comprises administering to said subject an effective amount of a compound of Formula I or la or a pharmaceutical composition described herein.
In some such embodiment, a compound detailed herein or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof, can also be used in combination with an additional therapy. The additional therapy may be optionally includes one or more therapeutic agents, radiation therapy, surgery (e.g., lumpectomy and a mastectomy) , chemotherapy, gene therapy, DNA therapy, viral therapy, RNA therapy, immunotherapy, bone marrow transplantation, nanotherapy, monoclonal antibody therapy, or a combination of the foregoing.
METHODS OF PREPARATION
The compounds of the current invention may be synthesized by varieties of methods by those skilled in the art of organic chemistry, and general synthetic schemes for preparing compounds of the present invention are described herein. These schemes are illustrative and not meant to limit the possible methodologies one skilled in the art to prepare the compounds disclosed herein. Different methods preparing the current disclosed compounds will be evident to those skilled in the art. General schemes to prepare the compounds of the present invention are given in the Examples section set out hereinafter. Preparation of homochiral examples may be realized by techniques known to one skilled in the art. For example, homochiral compounds may be prepared by separation of racemic products or diastereomers by chiral phase preparative HPLC. Alternatively, the example compounds may be prepared by methods known to give enantiomerically or diastereomerically enriched products.
The following disclosed reactions and techniques in this section are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and work up procedures, are selected to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is also understood by one skilled in the art of organic synthesis that the functional groups present on various portions of the molecule must be compatible with the reagents and reactions chosen. The restrictions of the substituents that are compatible with the reaction conditions will be evident to one skilled in the art, with alternatives required should incompatible substituents are present. Sometimes a judgment to modify the order of the synthetic steps or to select one specific rout over another is required in order to obtain a desired compound of the invention. It will also be understood that the planning of any synthetic route in this field will encompass the judicious choice of a protecting group used for protection of reactive functional groups present in the compounds described in this invention (Wuts and Greene, Greene’s Protective Groups in Organic Synthesis, Fourth Edition, Wiley and Sons (2007) ) .
REACTION SCHEMES AND EXAMPLES
The disclosed compounds of the present invention may be prepared from commercially available reagents using the synthetic methods and reaction schemes described herein, or using other reagents and conventional methods well known to those skilled in the art. For example, compounds of the present invention may be prepared using the General Reaction Schemes I-VII. It is understood that the current disclosed final compound may need to de-protect a protection group wherein a protection group (s) exists.
GENERAL REACTION SCHEMES
Scheme I
Compounds of Formula (II-1a) , wherein X
5 is N; m, n, X
1, ring A, R, R′, R
2, and R
3 is aforementioned or defined in the first aspect, can be prepared according to Scheme I:
N-acylation of the amine (1) with the acylchloride (a) in the presence of a base, such as TEA, and a solvent, such as DCM, afford the compound (2) . Coupling reaction of the intermediate (2) with a commercially available reagent (b) , such as, (E) -4-ethoxy-1, 1, 1-trifluorobut-3-en-2-one, in the presence of an organic base, like DBU, and a solvent, such as THF provides the compound (3) . Reflux of the intermediate (3) in the presence of p-TsOH and toluene generates the intermediate (4) . Hydrolysis of the intermediate (4) in the presence of a base, such as, 1N aq. NaOH, and a solvent, like THF, provides the compound (5) . Subsequent treatment (Curtius Rearangement) of the intermediate (5) in the present of TEA, t-BuOH as a solvent, and a reagent, like diphenyl azidophosphate give the amine (6) . Bromination of (6) in the presence of NBS generates the bromide (7) . Reaction of the bromide (7) with CuCN in a proper solvent, such as NMP at an elevated temperature gives the cyanide intermediate (8) . Hydrolysis of the cyanide (8) in an acidic condition, such as, aq. H
2SO
4 (1M) , at an elevated temperature affords the compound (9) . Cyclization of the intermediate (9) in the presence of a reagent, such as CDI provides the compound (10) . Subsequent treatment of the intermediate (10) in the presence of POCl
3 at an elevated temperature affords the chloride (11) . Selective substitution of the chloride in the presence of the amine (12) , a base, such as TEA, and a solvent, like DCM generates the intermediate (13) . Subsequent treatment of the compound (13) in the presence of an alcohol (14) or thiol (14) , an organic base, such as DIEA, and a solvent, like 1, 4-dioxane at an elevated temperature provides (II-1a) .
Compounds of Formula (II-1b) , wherein X
5 is CR
x5; m, n, X
1, ring A, R, R′, R
2, and R
3 is aforementioned or defined in the first aspect, can be prepared according to Scheme II:
Scheme II
Hydrolysis of the nitrile (8) in a basic condition, such as aq. KOH, at an elevated temperature provides the intermediate (15) . Esterification of the acid (15) in the presence of an acidic condition, like H
2SO
4, and a solvent of MeOH generates the ester (16) . N-acylation of the amine (16) in the presence of an acylchloride (c) , a base, such as TEA, and a solvent like DCM affords the compound (17) . Subsequent treatment of the intermediate (17) in the presence of a base, such as NaH (60%in mineral oil) , and a solvent, like DMF at an appropriate temperature, provides the cyclized intermediate (18) . Chlorination of the intermediate (18) in the presence of POCl
3 generates the chloride (19) . Following the similar procedures, such as the synthesis of intermediate (13) and (II-1a) , provides the intermediate (20) and the respected compounds (II-1b) respectively.
Compounds of Formula (II-2) , wherein P is a protection group, such as -Boc or -Cbz; m, n, X
1, X
5, ring A, R, R′, R
2, and R
3 is aforementioned or defined in the first aspect, can be prepared according to Scheme III:
Scheme III
Selective substitution of the dichloride (21) in the presence of the amine (12) , a base, such as DIEA, and a solvent, like DMSO, at an elevated temperature, affords the intermediate (22) . Subsequent treatment of the intermediate (22) in the presence of the alcohol (14) or thiol (14) , t-BuONa, BINAP, a catalyst, such as Pd (OAc)
2, and a solvent, like toluene, at an elevated temperature generates the intermediate (23) . Deprotection of the protecting group -P under a propriate conditions, such as Pd/C, H
2 wherein P is Cbz; TFA/DCM, wherein P is Boc-, affords the intermediate (24) . Subsequent Buchwald coupling reaction of the intermediate (24) in the presence of aryl-or heteroaryl-halide, such as arylbromide or heteroarylbromide (d) , Buchwald coupling condition, such as RuPhos, Pd
2 (dba)
3, t-BuOna, and a solvent, like toluene, at an elevated temperature, provides the compound of Formular (II-2) .
Compounds of Formula (II-3a) , wherein m, n, X
1, ring A, R, R′, and R
3 is defined in the first aspect, can be prepared according to Scheme IV:
Scheme IV
Reaction of the compound (25) in the presence of the amine (12) , a base, such as DIEA, and a solvent, like DMSO, at an elevated temperature, affords the intermediate (26) . Cyclization of the intermediate (26) in the presence of the imidamide (27) , TEA and a solvent, such as MECN, affords the compound (28) . Oxidation of the thioether (28) in the presence of an oxidation reagent, such as, m-CPBA, and a solvent like DCM provides the methyl sulfonyl compound (29) . Treatment of the methyl sulfonyl compound (29) in the presence of the alcohol (14) or thiol (14) , a base, such as t-BuONa, and a solvent like THF, generates the compound of Formular (II-3a) .
Compounds of Formula (II-4a) , wherein m, n, X
1, ring A, R, R′, and R
3 is defined in the first aspect, can be prepared according to Scheme V:
Scheme V
Treatment of the aldehyde (30) in the presence of the hydrazine (31) , a base, such as, DIEA, and a solvent, like DMF, provides the hydrazineylidene (31) . Reaction of the hydrazineylidene (31) in the presence of the amine (12) , a base, such as TEA, and a solvent, like DMF, provides the compound (32) . Treatment of the intermediate (32) in the CO (gas) atmosphere, a base, such as TEA, Pd (dppf) Cl
2, and a solvent, like MeOH, at an elevated temperature, affords the methyl ester (33) . Cyclization of the intermediate (33) under an acidic condition, such as, glacial acidic acid at an elevated temperature provides the compound (34) . Oxidation of the thioether (34) at the presence of an oxidative reagent, such as m-CPBA in a solvent like DCM affords the sulfoxide (35) . Substitutive reaction of the sulfoxide (35) in the presence of the alcohol (14) or thiol (14) generates the compound of Formular (II-4a) .
Compounds of Formula (III-1-1a) , wherein m, n, X
1, ring A, R, R′, R
2, and R
3 is aforementioned or defined in the first aspect, can be prepared according to Scheme VI:
Scheme VI
Selective substitution of the heteroaryl trichloride (36) in the presence of the amine (12) , a base, such as DIEA, and a solvent, like DCM, affords the dichloride (37) . Second selective substitution of the dichloride (37) in the presence of the alcohol (14) or thiol (14) , a base, such as DIEA, a solvent, like 1, 4-dioxane, at an elevated temperature, generates the intermediate 38. Suzuki coupling of the chloride (38) in the presence aryl/heteroaryl boronic acid (E) /ester (F) under a Suzuki coupling conditions provides compounds of Formular (III-1-1a) .
Compounds of Formula (III-1-2) , wherein m, n, X
1, ring A, R, R′, R
2, and R
3 is aforementioned or defined in the first aspect, can be prepared using the similar procedure as described for the aforementioned synthesis of the compounds of Formular (III-1-1a) excepting replacing the heteroaryl trichloride (36) with the 7-bromo-2, 4-dichloro-pyrido [2, 3-d] pyrimidine (39) :
Scheme VII
Compounds of Formula (III-1-3a) , wherein m, n, X
1, ring A, R, R′, R
2, and R
3 is aforementioned or defined in the first aspect, can be prepared using the similar procedure as described for the aforementioned synthesis of the compounds of Formular (III-1-1a) excepting replacing the heteroaryl trichloride (36) with the 7-bromo-2, 4-dichloro-8-fluoroquinazoline (40) :
Scheme VIII
Compounds of Formula (III-2-1) , wherein m, n, X
1, ring A, R, R′, R
2, R
3, and R
5 is aforementioned or defined in the first aspect, can be prepared according to Scheme IX:
Scheme IX
Suzuki coupling of the chloride (41) in the presence aryl/heteroaryl boronic acid (E) /ester (F) under a Suzuki coupling conditions provides the compound (42) . N-acylation of the intermediate (42) in the presence of acid (C) or its acylchloride (G) affords the amide (43) . Cyclization of the intermediate (43) in the presence of a base, such as, NaH (60%in mineral oil) , and solvent like DMF at an appropriated temperature generates the compound (44) . Chlorination of the intermediate (44) is realized by heating the mixture of (44) and POCl
3 to provide the dichloride (45) . A selective substitution of the dichloride (45) in the presence of the amine (12) , a base, such as TEA, and solvent like DCM affords the compound (46) . Subsequent treatment of the chloride (46) by the alcohol (14) or thiol (14) in the presence of a base, such as DIEA, and a solvent like 1, 4-dioxane at an elevated temperature provides the compounds of Formular (III-2-1) .
Compounds of Formula (III-2-2) , wherein m, n, X
1, ring A, R, R′, R
2, R
3, and R
X5 is aforementioned or defined in the first aspect, can be prepared according to Scheme X, adopting the similar procedure as outlined for the synthesis of compounds of formular (III-2-1) excepting replacing the compound (41) with compound (47) :
Scheme X
Alternatively, compounds of Formula (III-2-2) can be prepared according to Scheme XI:
Scheme XI
Synthesis of the intermediate (56) from the compound (47) can be realized using the similar procedures as outlined for the conversion of the intermediate (15) to Formular (II-1b) . Subsequent Suzuki coupling of the chloro intermediate (56) to the aryl/heteroaryl boronic acid (E) or the boronic ester (F) under Suzuki coupling condition provides the compounds of Formular (III-2-2) .
Scheme XII describes that the conversion of the compound (57) to the compounds of Formula (III-2-3) , wherein m, n, X
1, ring A, R, R′, R
2, R
3, and R
X5 is aforementioned or defined in the first aspect, can be carried out using the similar procedure as outlined in Scheme X or Scheme XI for the aforementioned synthesis of the compounds of Formular (III-2-2) excepting replacing the ethyl 4-amino-6-chloronicotinate (47) , herein (47) is optionally substituted by one or two R
2 groups, with the ethyl 2-amino-6-chloronicotinate (57) , herein (57) is optionally substituted by one or two R
2 groups:
Scheme XII
Scheme XIII describes that the conversion of the compound (58) to the compounds of Formula (III-2-4) , wherein m, n, X
1, ring A, R, R′, R
2, R
3, and R
X5 is aforementioned or defined in the first aspect, can be carried out using the similar procedure as outlined in Scheme VI for the synthesis of the compounds of Formular (III-1-1a) excepting replacing the 2, 4, 7-trichloro-8-fluoropyrido [4, 3-d] pyrimidine (36) with the 7-bromo-2, 4-dichloroquinoline-3-carbonitrile (58) , herein (58) is optionally substituted by one or more R
2 groups:
Scheme XIII
Compounds of Formula (II-1-c) , wherein m, n, X
1, ring A, R, R′, and R
3 is defined in the first aspect, can be prepared according to Scheme XIV:
Scheme XIV
A selective substitution of the dichloride (57) in the presence of the amine (12) , a base, such as TEA, and solvent like DCM affords the compound (58) . Subsequent of the chloride (58) by the alcohol (14) or thiol (14) in the presence of a base, such as DIEA, and a solvent like 1, 4-dioxane at an elevated temperature provides the compound (59) . Deprotection of the Boc group in the presence of TFA and solvent DCM affords compound (60) . Coupling reaction of the compound (60) to aryl halide (D) provides compound of Formular (II-1-C) .
Compounds of Formula (II’-1) to Formular (II’-4) , and Formula (III’-1) to Formular (III’-4) , wherein m, X
1, X
5, ring A, R, R′, R
2, R
3, and Z are defined in the first aspect, can be prepared adopting the similar procedures as outlined in Scheme I to XIV, excepting replacing the amin (12) with the amine (H) :
Examples
The Examples provided herein describe the synthesis of compounds disclosed herein as well as intermediates used to prepare the compounds. It is to be understood that individual steps described herein may be combined. It is also to be understood that separate batches of a compound may be combined and then carried forth in the next synthetic step.
In the following description of the Examples, specific embodiments are described. These embodiments are described in sufficient detail to enable those skilled in the art to practice certain embodiments of the present disclosure. Other embodiments may be utilized and logical and other changes may be made without departing from the scope of the disclosure. The following description is, therefore, not intended to limit the scope of the present disclosure, but rather is specified by the claims appended hereto.
Table 1 shows the part abbreviations of the present invention:
Table 1
The following abbreviations have been used in the examples:
Example 1
4- (4- (3, 6-Diazabicyclo [3.1.1] heptan-3-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
Step 1: 7-Fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalene-1, 3-diol
To a mixture of 7-fluoronaphthalene-1, 3-diol (12 g, 67.3 mmol, 1 eq. ) , 2-bromoethynyl (triisopropyl) silane (18.5 g, 70.7 mmol, 1.05 eq. ) , and KOAc (13.2 g, 134 mmol, 2.0 eq. ) in 1, 4-dioxane (80 mL) was added dichlororuthenium and1-isopropyl-4-methyl-benzene dimer (4.13 g, 6.74 mmol, 0.1 eq. ) under N
2. The resulting mixture was warmed to 110 ℃ and stirred for 2 h under N
2. The conversion was completed based on LC/MS. The reaction mixture was cooled to rt and partitioned between brine and EtOAc. After separation, the aq. layer was extracted with EtOAc (2x) . The combined organic layers were dried over anhydrous Na
2SO
4, collected by filtration. The filtrate was concentrated to give a residue which was purified by column chromatography (SiO
2, PE/EtOAc = 1/0 to 5/1) to give the title compound (15.6 g, 65%yield) as a black oil. LC-MS [M-H]
-=357.2.
Step 2: 7-Fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-ol
To a mixture of 7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalene-l, 3-diol (37 g, 103.2 mmol) and DIEA (40 g, 309.6 mmol, 3 eq. ) in DCM (370 mL) was added MOMCl (10.8 g, 134 mmol) at 0 ℃ under N
2. The mixture was warmed to rt and stirred for 0.5 h. The reaction conversion was completed based on LC/MS. The reaction mixture was diluted with ice-water (200 mL) and extracted with EtOAc (100 mL x 3) . The combined organic layers were washed with brine (200 mL) , dried over anhydrous Na
2SO
4, collected by filtration, and concentrated to give a residue. The residue was purified by column chromatography (SiO
2, PE/EtOAc = 1/0 to 50/1) to give the title compound (29 g, 70%yield) as a yellow solid. LCMS [M+H]
+ = 403.2.
Step 3: 7-Fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl trifluoromethanesulfonate
To a solution of 7-fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-ol (29.0 g, 72 mmol) and DIEA (27.9 g, 10.4 mL, 129 mmol) in DCM (200 mL) was added Tf
2O (30.5 g, 108 mmol, 17.9 mL, 1.5 eq) at -40 ℃ under N
2. The reaction mixture was stirred for 0.5 h under N
2. The conversion was completed based on LC/MS. The reaction mixture was diluted with ice-water (200 mL) and extracted with DCM (400 mL) . The organic phase was washed with brine, dried over anhydrous Na
2SO
4, and collected by filtration. The filtrate was concentrated on a rotary evaporator. The residue was purified by column chromatography (SiO
2, PE/EtOAc= 1/0 to 60/1) to afford the title compound (38.0 g, 99%yield) as a yellow oil. LCMS [M+H]
+ = 535.1.
Step 4: ( (2-Fluoro-6- (methoxymethoxy) -8- (4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane
To a mixture of 7-fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl trifluoromethanesulfonate (8 g, 15.0 mmol, 1 eq. ) , 4, 4, 5, 5-tetramethyl-2- (4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) -l, 3, 2-dioxaborolane (16.0 g, 63.0 mmol, 4.2 eq. ) , and KOAc (4.80 g, 48.9 mmol, 3.26 eq. ) in a degassed toluene (200 mL) was added Pd (dppf) Cl
2 (1.20 g, 1.64 mmol, 0.11 eq. ) . The mixture was vacuumed, filled with N
2 , and equipped with condenser and a N
2 balloon. The resulting mixture was warmed in a 130 ℃ oil bath and stirred for 12 h under N
2. The conversion was completed based on LC/MS. The reaction mixture was cooled to rt, partitioned between water and EtOAc. After separation, the aq. layer was extracted with EtOAc (2x) . The combined organic layers were washed with brine, dried over anhydrous Na
2SO
4, and collected by filtration. The filtrate was concentrated on a rotary evaporator. The residue was purified by column chromatography (SiO
2, PE/EtOAc = 100/1 to 50/1) to give the title compound (1.0 g, 17%yield) as a light yellow solid. LCMS [M+H]
+ = 513.
1H NMR (400 MHz, CDCl
3) δ 7.68 (dd, J = 9.0, 5.8 Hz, 1H) , 7.52 (d, J = 2.6 Hz, 1H) , 7.39 (d, J = 2.6 Hz, 1H) , 7.24 (t, J = 8.8 Hz, 1H) , 5.29 (s, 2H) , 3.52 (s, 3H) , 1.45 (s, 12H) , 1.18 (d, J = 2.4 Hz, 21H) .
Step 5: tert-Butyl 3- (2, 7-dichloro-8-fluoropyrido [4, 3-d] pyrimidin-4-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carboxylate
To a solution of 2, 4, 7-trichloro-8-fluoropyrido [4, 3-d] pyrimidine (3.4 g, 13.55 mmol, 1 eq. ) in dry DCM (40.0 mL) was added DIEA (13.4 mL, 81.30 mmol, 6 eq. ) at rt. Then the mixture was cooled to -40 ℃ under N
2, a solution of tert-butyl 3, 6-diazabicyclo [3.1.1] heptane-6-carboxylate (2.68 g, 13.55 mmol, 1 eq. ) was added dropwise over 10 min and stirred for 0.5 h. The conversion was completed based on LC/MS. The reaction was quenched with water (30.0 mL) . The resulting reaction mixture was extracted with EtOAc (30.0 mL x 3) . The combined organic layers were washed with brine, dried over anhydrous Na
2SO
4, collected by filtration, and concentrated under a reduced pressure. The resulted residue was purified by flash chromatography on a silica gel column (PE/EtOAc =40/1 to 20/1) to afford tert-butyl 3- (2, 7-dichloro-8-fluoropyrido [4, 3-d] pyrimidin-4-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carboxylate as whiter solid (1.9 g, 34%yield, 4.6 mmol) . LC-MS [M+H]
+ = 414.1.
Step 6: tert-Butyl 3- (7-chloro-8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carboxylate
To a solution of tert-butyl 3- (2, 7-dichloro-8-fluoropyrido [4, 3-d] pyrimidin-4-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carboxylate (500 mg, 1.21 mol, 1 eq. ) in dry 1, 4-dioxane (4 mL) was added (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol (342 mg, 2.4 mmol) and DIEA (0.6 mL, 3.63 mmol, 3 eq. ) under N
2. The reaction was warmed to 80 ℃ and stirred overnight. The conversion was completed based on LC/MS. The reaction mixture was cooled to rt, diluted with water (50.0 mL) and followed by addition of EtOAc (50.0 mL) . The two layers were separated and the aq. layer was extracted with EtOAc (2x) . The combined organic layers were dried over anhydrous Na
2SO
4, collected by filtration, and concentrated under the reduced pressure. The resulted residue was purified by flash chromatography on a silica gel column (DCM/MeOH =20/1) to afford the expected tert-butyl 3- (7-chloro-8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carboxylate (530 mg, 84%yield, 1.0 mmol) . LC-MS [M+H]
+ = 519.2.
Step 7: tert-Butyl 3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carboxylate
To a solution of tert -butyl 3- (7-chloro-8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carboxylate (530 mg, 1.02 mmol) in a mixture degassed solvent of dioxane (3.0 mL) and H
2O (1.0 mL) was added ( (2-fluoro-6- (methoxymethoxy) -8- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (787.9 mg, 2.05 mmol, 2 eq. ) , Cs
2CO
3 (668 mg, 2.05 mmol) and Pd (dppf) Cl
2 (150 mg, 0.20 mmol) . The mixture was vacuumed, filled with N
2, and this procedure was repeated three times. The reaction vessel was sealed. The resulting mixture was warmed to 110 ℃ and stirred for 1 h. The conversion was completed based on LC/MS. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3) . The combined organic layer was dried by Na
2SO
4 and collected by filtration. The filtrate was concentrated under a reduced pressure. The resulted residue was purified through flash chromatography on a silica gel column (DCM/MeOH =10/1) to afford the title compound (217 mg, 26%yield, 0.25 mmol) . LC-MS [M+H]
+ = 869.4.
Step 9: tert-Butyl 3- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carboxylate
To a solution of tert-butyl 3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carboxylate (217 mg, 0.25 mmol) in DMF (2.0 mL) was added CsF (190 mg, 1.25 mmol) at rt. The resulting mixture was stirred for 1 h, diluted with water (20.0 mL) , and extracted with EtOAc (20.0 mL x 3) . The combined organic layers were dried over anhydrous Na
2SO
4, collected by filtration, and concentrated under the reduced pressure to give the expected title compound (300 mg, crude) as a yellow oil, which was used directly without further purification. LC-MS [M+H]
+ = 713.3.
Step 10: 4- (4- (3, 6-Diazabicyclo [3.1.1] heptan-3-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
To a solution of tert-butyl 3- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carboxylate (300 mg, 0.42 mmol) in MeCN (2.0 mL) was added 4N HCl/MeOH (2.0 mL) at rt. The reaction mixture was stirred for 1 h, adjusted to pH ~ 7 with a sat. NaHCO
3, diluted with water (20 mL) , and extracted with EtOAc (20 mL x 3) . The combined organic layers were washed with brine, dried over anhydrous Na
2SO
4, collected by filtration, and concentrated under a reduced pressure. The residue was purified by Prep-HPLC (Mobile Phase A: 0.1%FA; Mobile Phase B: MeCN; Gradient: 30%-70%B over 55 minutes; Flow: 70 mL/min) to give the title compound (8 mg, 0.14 mmol, 3%yield) as a white solid. LC-MS [M+H]
+=569.2.
Example 2
3- (4- (8-Oxa-3-azabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol
Step 1: 2- (3-Bromo-5-chloro-4- (trifluoromethyl) phenyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane
To a solution of 1-bromo-3-chloro-2- (trifluoromethyl) benzene (5.0 g, 19.3 mmol) and 4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (4.93 g, 38.5 mmol) in THF (60.0 mL) was added dtbbpy (621 mg, 2.31 mmol) and (Ir (OMe) (cod) )
2 (1.28 g, 1.93 mmol, 0.1 eq. ) under N
2. The resulting mixture was purged with a stream of N
2 for 1 min, sealed, warmed to 60 ℃, and for 2 hr. The conversion was completed based on TLC. The reaction mixture was cooled to rt, partitioned between brine and DCM. After separation, the organic phase was concentrated in vacuo to give the title intermediate (12.0 g, crude) as a black oil, which was used directly for the next step without further purification. LCMS [M+H]
+ = 385.0.
Step 2: 3-Bromo-5-chloro-4- (trifluoromethyl) phenol
To a solution of 5-chloro-4- (trifluoromethyl) phenyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (12.0 g, 31.1 mmol) in THF (100.0 mL) and H
2O (50.0 mL) was added AcOH (74.8 g, 1.25 mol) . Then H
2O
2 (70.6 g, 623 mmol, 30%) was drop-wise added into the mixture at 0 ℃ for 20 min. The mixture was stirred at 0℃ for 1 h. The reaction conversion was completed based on TLC. Water (200 mL) and EtOAc (200 mL) were added. The two phases were separated. The organic phase was washed with Na
2SO
3 solution (200.0 mL x 2) , the brine (100 mL x 2) , dried over anhydrous Na
2SO
4, collected by filtration, and concentrated on a rotary evaporator. The residue was purified on a silica gel column (PE/EtOAc = 40: 1 to5: 1) to give 3-bromo-5-chloro-4- (trifluoromethyl) phenol (5.2 g, 83%yield over two steps) as a light brown oil. LC-MS [M+H]
+ =275.
Step 3: 5- (Benzyloxy) -1-bromo-3-chloro-2- (trifluoromethyl) benzene
To a solution of 3-bromo-5-chloro-4- (trifluoromethyl) phenol (5 g, 18.15 mmol, 1.0 eq. ) in CH
3CN (125 mL) was added benzyl bromide (3.73 g, 21.78 mmol, 1.2 eq. ) and K
2CO
3 (7.53 g, 54.46 mmol, 3.0 eq. ) . The resulting mixture was stirred for 2 h. The conversion was completed based on LC/MS. The reaction mixture was filtered through celite and washed with CH
3CN (100 mL) . The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (PE/EtOAc=1: 0) , followed by reverse phase Prep-HPLC (Mobile Phase A: 0.1%FA; Mobile Phase B: ACN; Gradient: 60%-90%B over 55 minutes; Flow: 70 mL/min) to give 5- (benzyloxy) -1-bromo-3-chloro-2- (trifluoromethyl) benzene (4.5 g, 68%yield) as a light yellow liquid. LC-MS [M+H]
+ =366.
1H NMR (60 MHz, CDCl
3) : δ 7.67-6.84 (m, 7H) , 5.15 (s, 2H) .
Step 4: 2- (5- (Benzyloxy) -3-chloro-2- (trifluoromethyl) phenyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane
To the mixture of 5- (benzyloxy) -1-bromo-3-chloro-2- (trifluoromethyl) benzene (2.01 g, 5.47 mmol) , 4, 4, 5, 5-tetramethyl-2- (4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) -l, 3, 2-dioxaborolane (4.17 g, 16.4 mmol) , and KOAc (1.62 g, 16.4 mmol) in a degassed1, 4-dioxane (80.0 mL) was added Pd (dppf) Cl
2 (0.90 g, 1.10 mmol, 0.2 eq. ) under N
2. The mixture was purged with N
2 for 10 sec., equipped with a condenser and N
2 balloon. The resulting reaction mixture was stirred in a 110 ℃ oil bath for 12 h. The conversion was completed based on LC/MS. The reaction mixture was cooled to rt, filtered, and the filtrate was concentrated to give a residue, which was diluted with EtOAc (100 mL) and water (80 mL) . After separation, the aq. layer was extracted with EtOAc (2x) . The combined organic layers were washed with brine, dried over anhydrous Na
2SO
4, collected by filtration, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc = 100/1 to 20/1) to give the title intermediate, 2- (5- (benzyloxy) -3-chloro-2- (trifluoromethyl) phenyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (1.2 g, 53%yield) as white solid. LC-MS [M+H]
+ = 413.
1H NMR (60 MHz, CDCl
3) : δ 7.49-7.46 (m, 5H) , 7.15-7.03 (m, 2H) , 5.17 (s, 2H) 1.45 (s, 12H) .
Step 5: 3- (2, 7-Dichloro-8-fluoropyrido [4, 3-d] pyrimidin-4-yl) -8-oxa-3-azabicyclo [3.2.1] octane
To a solution of 2, 4, 7-trichloro-8-fluoropyrido [4, 3-d] pyrimidine (2 g, 7.9 mmol) in DCM (30 mL) was added DIEA (5.8 mL, 35.5 mmol) at rt. The mixture was purged with a stream of N
2 gas for 10 sec, then cooled to -40 ℃, followed by addition of 8-oxa-3-azabicyclo [3.2.1] octane (Intermediate 7, 0.81 g, 7.1 mmol, 1.0 eq) under N
2. The resulting reaction mixture was stirred for 1 h. The conversion was completed based on LC/MS. The reaction mixture was diluted with DCM (50 mL) and poured into water (20 mL) . After separation, the organic layer was washed with brine, dried over Na
2SO
4, collected by filtration, and concentrated on a rotary evaporator. The residue was purified by silica gel column chromatography (PE/EtOAc = 3: 1) to give the title compound (1.4 g, 54%yield) as a yellow solid. LC-MS [M+H]
+ = 329.0.
Step 6: 3- (7-Chloro-8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -8-oxa-3-azabicyclo [3.2.1] octane
To a solution of 3- {2, 7-dichloro-8-fluoropyrido [4, 3-d] pyrimidin-4-yl} -8-oxa-3-azabicyclo [3.2.1] octane (1.4 g, 4.2 mmol) in 1, 4-dioxane (20 mL) was added (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol (0.90 g, 6.4 mmol) and DIEA (2.1 mL, 12.7 mmol) sequentially. The reaction mixture was warmed to 80 ℃ and stirred for 12 h under N
2. The reaction mixture was cooled to rt, diluted with EtOAc (100 mL) and H
2O (50 mL) . After separation, the organic layer was washed with brine, dried over anhydrous Na
2SO
4, collected by filtration, and concentrated in vacuo. The residue was purified by a silica gel chromatography (PE/EtOAc=1: 1 to DCM/MeOH=10: 1 (0.1%Et
3N was contained) ) to give the title compound (1.40 g, 76%yield) as a yellow solid. LC-MS [M+H]
+ =434.2.
Step 7: 3- (7- (5- (Benzyloxy) -3-chloro-2- (trifluoromethyl) phenyl) -8-fluoro-2- ( (tetrahydro-1H- pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -8-oxa-3-azabicyclo [3.2.1] octane
To a suspension of 3- (7-chloro-8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -8-oxa-3-azabicyclo [3.2.1] octane (200 mg, 0.46 mmol) in a degassed 1, 4-dioxane (9.0 mL) and H
2O (3.0 mL) were added Cs
2CO
3 (300 mg, 0.92 mmol) , Pd (dppf) Cl
2 (33.7 mg, 0.0461 mmol) and 2- [5- (benzyloxy) -3-chloro-2- (trifluoromethyl) phenyl] -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (190 mg, 0.460 mmol) . The mixture was vacuumed, filled with N
2, and equipped with a condenser and a N
2 balloon. The resulting reaction mixture was warmed to 110 ℃ and stirred for 2 h. The conversion was completed based on LC/MS. The reaction mixture was cooled to rt and diluted with EtOAc (100 mL) and H
2O (50 mL) . The two layers were separated. The organic layer was washed with brine, dried over Na
2SO
4, collected by filtration, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc =1: 1 to EtOAc (0.1%Et
3N was contained) ) to give the title compound (110 mg, 35%yield) as a yellow solid. LC-MS [M+H]
+ =684.2.
Step 8: 3- (4- (8-Oxa-3-azabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol
To a solution of 3- (7- (5- (benzyloxy) -3-chloro-2- (trifluoromethyl) phenyl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -8-oxa-3-azabicyclo [3.2.1] octane (110 mg, 0.16 mmol) in CH
3OH (5 mL) were added Pd/C (11.0 mg, 10%wt) . The mixture was degassed in vacuo, filled with H
2, and this sequence was repeated three times. The mixture was stirred under H
2 atmosphere balloon for 1 h. The reaction conversion was completed based on LC/MS. The resulting reaction mixture was filtered through a thin pad of celite with EtOAc (30 mL) . The filtrate was concentrated in vacuo to give the crude product. The crude product was purified by Prep-HPLC (Mobile Phase A: 0.1%FA; Mobile Phase B: ACN; Gradient: 30%-80%B over 55 minutes; Flow: 70 mL/min) and lyophilized to give the title compound (14.3 mg, 5%yield over two steps) as a white solid. LC-MS [M+H]
+ = 594.2.
1H NMR (400 MHz, CD
3OD) δ 9.09 (s, 1H) , 8.55 (s, 1H) , 7.10 (d, J = 2.4 Hz, 1H) , 6.71 (d, J = 2.4 Hz, 1H) , 4.56-4.52 (m, 6H) , 3.83-3.79 (m, 2H) , 3.60-3.53 (m, 2H) , 3.21-3.16 (m, 2H) , 2.32-2.25 (m, 2H) , 2.21 –1.97 (m, 8H) , 1.87-1.84 (m, 2H) .
Example 3 and 4
3- (4- (3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 8-dihydropyrido [3, 4-d] pyrimidin-7 (6H) -yl) -5-chloro-4- (trifluoromethyl) phenol
and
3- (4- (3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 8-dihydropyrido [3, 4-d] pyrimidin-7 (6H) -yl) -4- (trifluoromethyl) phenol
Step 1: 1-Bromo-3-chloro-5- (methoxymethoxy) -2 (trifluoromethyl) benzene
To a solution of 3-bromo-5-chloro-4- (trifluoromethyl) phenol (from EX. 2, Step 2, 1.1 g, 3.99 mmol, 1.0 eq. ) in DCM (30.0 mL) were added DIEA (1.55 g, 129.24 mmol, 3.0 eq. ) and MOMBr (1.50 g, 124.69 mmol, 3.0 eq. ) . The mixture was stirred at r, t for 1h, TLC showed the a new main spot . The reaction was diluted with DCM (30.0 mL) and water (30.0 mL) . The organic layer was concentrated in vacuo, dried over Na
2SO
4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column (PE/EtOAc=1: 0) to afford 1-bromo-3-chloro-5- (methoxymethoxy) -2- (trifluoromethyl) benzene (0.92 g, 2.88 mmol, 72%yield) as a colorless oil. LC-MS [M+H]
+ = 318.9.
Step 2: 2, 4-Dichloro-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidine
To a solution of tert-butyl 2, 4-dichloro-5, 8-dihydropyrido [3, 4-d] pyrimidine-7 (6H) -carboxylate (2.0 g, 6.6 mmol) in DCM (20.0 mL) was added TFA (7.0 mL) , and the reaction was stirred at rt for 3 hr. The reaction was concentrated under a reduced pressure to afford 2, 4-dichloro-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidine (3.5 g, crude) as a yellow oil, which was used directly for the next step. LC-MS [M+H]
+ =204.0.
Step 3: Denzyl 2, 4-dichloro-5, 8-dihydropyrido [3, 4-d] pyrimidine-7 (6H) -carboxylate
To a solution of 2, 4-dichloro-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidine (3.50 g, 17.2 mmol, 1 eq. ) in THF (50.0 mL) at 0 ℃ were added DIEA (4.45 g, 34.5 mmol) and CbzCl (2.93 g, 17.24 mmol) . The reaction was stirred at rt for 1 h. The mixture was concentrated in vacuo. The residue was partitioned between EtOAc (100 mL) and H
2O (100 mL) . After separation, the organic layer was concentrated in vacuo. The residue was purified by column chromatography (PE/EtOAc = 5/1 to 3/1) to give the title intermediate (2.10 g, 6.23 mmol, 94%yield over two-steps) as a yellow oil. LC-MS [M+H]
+ = 338.0.
Step 4: Benzyl 4- (8- (tert-butoxycarbonyl) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -2-chloro-5, 8-dihydropyrido [3, 4-d] pyrimidine-7 (6H) -carboxylate
To a solution of benzyl 2, 4-dichloro-5, 8-dihydropyrido [3, 4-d] pyrimidine-7 (6H) -carboxylate (2.10 g, 6.23 mmol) in DMSO (30.0 mL) were added DIEA (2.01 g, 15.6 mmol) and tert-butyl 3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (1.32 g, 6.23 mmol, 1 eq. ) , and the reaction was stirred at 55 ℃ for 12 hrs. The reaction was cooled to rt, diluted with EtOAc (100 mL) and H
2O (50 mL) . After separation, the organic layer was washed with brine, dried over Na
2SO
4, filtered and concentrated in vacuo. The residue was purified by column chromatography (PE/EtOAc = 5/1 to 3/1) to give benzyl 4- (8- (tert-butoxycarbonyl) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -2-chloro-5, 8-dihydropyrido [3, 4-d] pyrimidine-7 (6H) -carboxylate (2.10 g, 65% yield, 4.09 mmol) as a yellow solid. LC-MS [M+H]
+ = 514.3.
Step 5: Benzyl 4- (8- (tert-butoxycarbonyl) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 8-dihydropyrido [3, 4-d] pyrimidine-7 (6H) -carboxylate
To a solution of benzyl 4- (8- (tert-butoxycarbonyl) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -2-chloro-5, 8-dihydropyrido [3, 4-d] pyrimidine-7 (6H) -carboxylate (1.40 g, 2.73 mmol) in degassed toluene (80 mL) was added (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol (770 mg, 5.4 mmol) , t-BuONa (656 mg, 6.83 mmol6) , Pa
2 (dba)
3 (2476 mg, 0.27 mmol6) and BINAP (3426 mg, 0.55 mmol6) . The mixture was degassed 6 with N
2 for 1 min. The mixture equipped with a condenser and N
2 balloon was stirred at 110 ℃ for 3 h. The reaction mixture was cooled to rt, diluted with EtOAc and H
2O. After separation, the organic layer was dried over anhydrous Na
2SO
4, filtered and concentrated. The residue was purified by Prep-HPLC (Mobile Phase A: 0.1%FA; Mobile Phase B: ACN; Gradient: 50%-90%B over 55 minutes; Flow: 70 mL/min) to give benzyl 4- (8- (tert-butoxycarbonyl) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 8-dihydropyrido [3, 4-d] pyrimidine-7 (6H) -carboxylate (0.62 g, 36%yield, 1.0 mmol) as a yellow solid. LC-MS [M+H]
+ = 619.3.
Step 6: tert-Butyl 3- (2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
To a solution of benzyl 4- (8- (tert-butoxycarbonyl) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 8-dihydropyrido [3, 4-d] pyrimidine-7 (6H) -carboxylate (0.62 g, 1.0 mmol, 1eq. ) in MeOH (20.0 mL) were added NH
3/MeOH solution (20 mL) and Pd/C (0.20 g) . The mixture was vacuumed and filled with H
2. The mixture was stirred at rt under H
2 atmosphere for 4 h. TLC showed the starting materials was consumed completely and the reaction was filtered. The filtrate was concentrated in vacuo to afford the title compound (470 mg, 60%yield, 0.6 mmol) as a yellow solid. LC-MS [M+H]
+ = 485.3.
Step 7: tert-Butyl 3- (7- (3-chloro-5- (methoxymethoxy) -2- (trifluoromethyl) phenyl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
To a solution of tert-butyl 3- (2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (230 mg, 0.48 mmol ) in degassed toluene (8.0 mL) were added RuPhos (46.6 mg, 0.10 mmol) , Cs
2CO
3 (469 mg, 1.44 mmol) , 1-bromo-3-chloro-5- (methoxymethoxy) -2- (trifluoromethyl) benzene (154 mg, 0.484 mmol) and Pd
2 (dba)
3 (45.8 mg, 0.050 mmol) at rt under N
2. The mixture was degassed in vacuo and filled with N
2. The mixture equipped with a condenser and a N
2 balloon was stirred at 110 ℃ for 8 hr. LCMS showed the starting materials was consumed completely, the reaction was cooled to rt, diluted with EtOAc (30.0 mL) and water (30.0 mL) . After separation, the organic layer was washed with brine (20.0 mL) , dried over anhydrous Na
2SO
4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH = 3/1 to 1/1) to give the title intermediate (340 mg, 71%yield) as a brown solid. LC-MS [M+H]
+ = 723.3. Dechlorinated compound, tert-butyl 3- (7- (5- (methoxymethoxy) -2- (trifluoromethyl) phenyl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8- carboxylate. LC-MS [M+H]
+ = 689.
Step 8: 3- (4- (3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 8-dihydropyrido [3, 4-d] pyrimidin-7 (6H) -yl) -5-chloro-4- (trifluoromethyl) phenol and 3- (4- (3, 8-diazabicyclo [3.2.1] octan-3-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 8-dihydropyrido [3, 4-d] pyrimidin-7 (6H) -yl) -4- (trifluoromethyl) phenol
To a solution of tert-butyl 3- (7- (3-chloro-5- (methoxymethoxy) -2- (trifluoromethyl) phenyl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (340 mg, 0.47 mmol) in MeOH (25.0 mL) was added 4N HCl (25.0 mL) in a pressure tube. The reaction was stirred at 70 ℃ for 8 hr. The mixture was cooled to rt, concentrated in vacuo. The residue was purified by Prep-HPLC (Mobile Phase A: 0.1%FA; Mobile Phase B: ACN; Gradient: 30%-80%B over 55 minutes; Flow: 70 mL/min) to afford:
Example 3, P1: 3- (4- (3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 8-dihydropyrido [3, 4-d] pyrimidin-7 (6H) -yl) -5-chloro-4- (trifluoromethyl) phenol (16.0 mg, 6%yield over two-steps) as a white solid. LC-MS [M+H]
+ = 579.3.
1H NMR (400 MHz, CD
3OD) δ 6.78 (d, J =4.0 Hz, 1H) , 6.73 (d, J = 4.0 Hz, 1H) , 4.49 (s, 2H) , 4.23-4.13 (m, 2H) , 4.07 (s, 2H) , 4.02 (s, 2H) , 3.71-3.62 (m, 2H) , 3.49-3.40 (m, 2H) , 3.31-3.24 (m, 2H) , 3.22-3.14 (m, 2H) , 2.85 (s, 2H) , 2.31-2.26 (m, 2H) . 2.23-2.15 (m, 4H) . 2.12-2.04 (m, 6H) ;
Example 4, P2: 3- (4- (3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 8-dihydropyrido [3, 4-d] pyrimidin-7 (6H) -yl) -4- (trifluoromethyl) phenol (8.0 mg, 3%yield) as a white solid. LC-MS [M+H]
+ = 545.3.
1H NMR (400 MHz, CD
3OD) δ 7.61 (d, J = 8.8 Hz, 1H) , 6.90 (d, J = 2.4 Hz, 1H) , 6.44 (dd, J = 8.8 Hz, 2.4 Hz, 1H) , 4.49 (s, 2H) , 4.19-4.14 (m, 2H) , 4.03 (s, 2H) , 4.00 (s, 2H) , 3.69-3.62 (m, 2H) , 3.43-3.40 (m, 2H) , 3.30-3.24 (m, 2H) , 3.16 (q, d, J = 5.6 Hz, 2H) , 3.16 (q, d, J = 5.6 Hz, 2H) , 2.85 (q, d, J = 5.2 Hz, 2H) , 2.33-2.25 (m, 2H) . 2.23-2.14 (m, 4H) . 2.10-2.03 (m, 6H) .
Example 5
3- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) pheno
Step 1: tert-Butyl 5- (2, 7-dichloro-8-fluoropyrido [4, 3-d] pyrimidin-4-yl) -2, 5-diazabicyclo [2.2.2] octane-2-carboxylate
To a solution of 2, 4, 7-trichloro-8-fluoropyrido [4, 3-d] pyrimidine (3.4 g, 13.55 mmol, 1 eq. ) in dry DCM (40.0 mL) was added DIEA (13.4 mL, 81.30 mmol, 6 eq. ) at rt. Then the mixture was cooled to -40 ℃ under N
2, a solution of tert-butyl 2, 5-diazabicyclo [2.2.2] octane-2-carboxylate (2.68 g, 13.55 mmol, 1 eq. ) was added dropwise over 10 min and stirred for 0.5 h. The conversion was completed based on LC/MS. The reaction was quenched with water (30.0 mL) . The resulting reaction mixture was extracted with EtOAc (30.0 mL x 3) . The combined organic layers were washed with brine, dried over anhydrous Na
2SO
4, collected by filtration, and concentrated under a reduced pressure. The resulted residue was purified by flash chromatography on a silica gel column (PE/EtOAc =40/1 to 20/1) to afford the title compound as whiter solid (1.81 g, 32%yield, 4.38 mmol) . LC-MS [M+H]
+ = 428.1.
Step 2: tert-Butyl 5- (7-chloro-8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -2, 5-diazabicyclo [2.2.2] octane-2-carboxylate
To a solution of tert-butyl 5- (2, 7-dichloro-8-fluoropyrido [4, 3-d] pyrimidin-4-yl) -2, 5-diazabicyclo [2.2.2] octane-2-carboxylate (500 mg, 1.21 mol, 1 eq. ) in dry 1, 4-dioxane (4 mL) was added (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol (342 mg, 2.4 mmol) and DIEA (0.6 mL, 3.63 mmol, 3 eq. ) under N
2. The reaction was warmed to 80 ℃ and stirred overnight. The conversion was completed based on LC/MS. The reaction mixture was cooled to rt, diluted with water (50.0 mL) and followed by addition of EtOAc (50.0 mL) . The two layers were separated and the aq. layer was extracted with EtOAc (2x) . The combined organic layers were dried over anhydrous Na
2SO
4, collected by filtration, and concentrated under the reduced pressure. The resulted residue was purified by flash chromatography on a silica gel column (DCM/MeOH =20/1) to afford the expected title compound (530 mg, 84%yield, 1.0 mmol) . LC-MS [M+H]
+= 534.1.
Step 3: tert-Butyl 5- (7- (3-chloro-5- (methoxymethoxy) -2- (trifluoromethyl) phenyl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -2, 5-diazabicyclo [2.2.2] octane-2-carboxylate
To a solution of tert-Butyl 5- (7-chloro-8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -2, 5-diazabicyclo [2.2.2] octane-2-carboxylate (530 mg, 0.994 mmol) in a mixture degassed solvent of dioxane (3.0 mL) and H
2O (1.0 mL) was added 2- (5- (benzyloxy) -3-chloro-2-(trifluoromethyl) phenyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (from Step 4 of EX. 2, 787.9 mg, 1.91 mmol) , Cs
2CO
3 (668 mg, 2.05 mmol) and Pd (dppf) Cl
2 (150 mg, 0.20 mmol) . The mixture was vacuumed, filled with N
2, and this procedure was repeated three times. The reaction vessel was sealed. The resulting mixture was warmed to 110 ℃ and stirred for 1 h. The conversion was completed based on LC/MS. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3) . The combined organic layer was dried by Na
2SO
4 and collected by filtration. The filtrate was concentrated under a reduced pressure. The resulted residue was purified through flash chromatography on a silica gel column (DCM/MeOH =10/1) to afford the title compound (217 mg, 30 %yield, 0.294 mmol) . LC-MS [M+H]
+ = 738.2
Step 4: 3- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol
To a solution of tert-butyl 5- (7- (3-chloro-5- (methoxymethoxy) -2- (trifluoromethyl) phenyl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -2, 5-diazabicyclo [2.2.2] octane-2-carboxylate (210 mg, 0.285 mmol) in MeCN (2.0 mL) was added 4N HCl/MeOH (2.0 mL) at rt. The reaction mixture was stirred for 1 h. The reaction was completed based on LC/MS. The reaction mixture was neutralized to pH ~ 7 with a sat. aq. NaHCO
3, diluted with water (20 mL) , and extracted with EtOAc (20 mL x 3) . The combined organic layers were washed with brine, dried over anhydrous Na
2SO
4, collected by filtration, and concentrated under a reduced pressure. The residue was purified by Prep-HPLC (Mobile Phase A: 0.1%FA; Mobile Phase B: MeCN; Gradient: 30%-70%B over 55 minutes; Flow: 70 mL/min) to give the title compound (36 mg, 0.0606 mmol, 21%yield) as a white solid. LC-MS [M+H]
+ = 594.0.
1H NMR (400 MHz, DMSO-d
6) : δ9.16 (s, 1H) , 8.27 (s, 2H) , 7.18 (d, J = 2.4 Hz, 1H) , 6.76 (d, J = 2.4 Hz, 1H) , 4.91 (s, 1H) , 4.23 (s, 1H) , 4.09 (s, 2H) , 3.35-3.29 (m, 2H) , 3.16-3.12 (m, 2H) , 3.00-2.96 (m, 2H) , 2.63-2.58 (m, 2H) , 1.95-1.87 (m, 4H) , 1.84-1.73 (m, 4H) , 1.64-1.57 (m, 2H) .
Biological Activity
Ⅰ. KRAS G12D activity assay
Compounds disclosed herein were tested for inhibition of KRAS G12D activity by transcreener GDP assay. Compounds bind to KRAS G12D and resulting in the inhibition of nucleotide exchange (GDP-GTP) reaction was monitored by detection of GDP production with fluorescence readouts. An increase in GDP production was indicative of the formation of the active KRAS G12D-GTP complex.
Recombinant GDP-bound KRAS G12D (BPS, Cat. No. 100623) were pre-incubated with various concentrations of each compound. Following compound pre-incubation, GTP were added to proceed nucleotide exchange (GDP-GTP) reaction. To determine the extent of inhibition of KRAS G12D activity, detection reagent (BellBrook, Cat. No. 3014-1K) were added to the assay wells, incubated for 2h. The assay plates were then read on SpectraMax Paradigm with excitation at 580nm and emission at 620nm. Inhibition %were calculated using equation (1) : Inhibition %= (Max-Signal) / (Max-Min) *100. The fluorescence signal form the reaction well without test compound and the fluorescence signal form the reaction well without KRAS G12D as 0%and 100%inhibition, respectively. IC50 values were calculated using equation (2) : Y=Bottom + (Top-Bottom) / (1+ (IC50/X) *HillSlope) , Y is %inhibition and X is compound concentration. Inhibition of KRAS G12D activity by exemplary compounds of Formula (I) are shown in Table 1. The ranges for the KRAS G12D activity assay are: A = IC50≤ 50 nM; B =IC50 >50 nM to 250 nM; C = IC50 >250 nM to 1 μΜ; and D = IC50 > 1 μΜ.
Table 1.
Inhibition of KRAS G12D Activity by Exemplary Compounds
Compound No. | IC 50 (nM) |
EX. 1 | C |
EX. 2 | C |
EX. 3 | B |
EX. 4 | C |
EX. 5 | A |
II. KRAS G12D-SOS1 interaction assay
SOS1 is a key guanine exchange factor (GEF) , promoting the active form of KRAS. The ability of test compounds bind to KRAS G12D and impair KRAS G12D-SOS1 interaction were measured by HTRF assay using Cisbio KRAS/SOS1 binding kit (Cat. No. 63ADK000CB21PEH) . The interaction between Tag1-KRAS G12D and Tag2-SOS1 was detected by energy transfer from Terbium cryptate (HTRF donor) labelled on anti-Tag2 and XL665 (HTRF acceptor) labelled on anti-Tag1. A reduction in HTRF signal was indicative of impaired KRAS G12D-SOS1 interaction.
The procedure was conducted according to the manufactureR′sinstructions, Tag1-KRAS G12D, Tag2-SOS1 were mixed with diluted compounds, incubated at 25℃ for 15 min. Anti-Tag1-Tb and anti-Tag2-XL665 were then added to the assay plate, the mixture were further incubated for 3h. The fluorescent signal was read on an Envision
TM Plate Reader. The IC50 was determined from non-linear regression equation by Graphpad Prism8. The results for exemplary compounds of Formula (I) are shown in Table 3. The ranges for the KRAS G12D-SOS1 HTRF assay are: A = IC50≤ 50 nM; B =IC50 >50 nM to 250 nM; C = IC50 >250 nM to 1 μΜ; and D = IC50 > 1 μΜ.
Table 2.
Inhibition of KRAS G12D-SOS1 Interaction by Exemplary Compounds
Compound No. | IC 50 (nM) |
EX. 1 | B |
EX. 2 | B |
EX. 3 | A |
EX. 4 | B |
EX. 5 | A |
Ⅳ. Cellular signaling activity assay
The compounds of the present invention were tested for inhibitory activity of KRAS G12D downstream signaling in tumor cells. pERK modulation in AGS cells (ATCC CRL-1739) was determined using the Phospho/Total ERK1/2 Whole Cell Lysate kits (Meso Sacle Discovery K121DWD. AGS cells were cultured in DMEM medium containing 10%fetal bovine serum and Penicillin/Streptomycin, seeded in 96-well cell culture plates and allowed to attach for 16h. Diluted compounds were added to cell culture plates and incubated for 3h. After compounds treatment, cells were washed and lysed in MSD TRIS Lysis Buffer. pERK levels were determined according to the recommendations of the manufacturer. Signal intensities were measured using a MESO SECTOR S 600 reader, and IC50 values were calculated using a 4-paramerer logistic model.
The results for exemplary compounds are shown in Table 4. The ranges for the cellular signaling activity assay are: A = IC50≤ 50 nM; B =IC50 >50 nM to 250 nM; C = IC50 >250 nM to 1 μΜ; and D = IC50 > 1 μΜ.
Table 3.
Inhibition of KRAS G12D-mediated Phosphorylation of ERK by Exemplary Compounds
Compound No. | IC 50 (nM) |
EX. 1 | N/A |
EX. 2 | D |
EX. 3 | D |
EX. 4 | N/A |
EX. 5 | D |
Claims (147)
- A compound represented by the Formula (I 0) :or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, and isomer thereof, wherein:each of n1 or n2 is independently selected from 0 or 1;m is 0, 1, 2, or 3;n is 0, 1, or 2;X 1 is NH, O, or S;X 5 is N or CR X5; and R X5 is independently selected from -CN or -CF 3;each of R 3 is independently selected from hydrogen, halogen, C 1-3 alkoxy, or C 1-3 alkyl; or two R 3 together with the C atom to which they are both attached form a 3-to 5-membered cycloalkyl, or 3-to 5-membered halocycloalkyl.R′ is H, halogen, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, -CH 2CN;ring A is a 6-to 10-membered aryl, or 5-to 10-membered heteroaryl, and each of which is independently optionally unsubstituted or substituted with one or more R 1; and R 1 is H, halogen, hydroxy, C 1-3 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 2-5 haloalkenyl, C 2-5 haloalkynyl, C 1-3 haloalkoxy, C 1-5 hydroxy alkyl, -NR 4R 4’, -NC (O) R 4, -C (O) NR 4R 4’, 3-to 5-membered cycloalkyl, 3-to 5-membered halocycloalkyl, or 3-to 5-membered heterocycloalkyl; and each of R 4 or R 4’ is independently selected from H, halogen, -NH 2, -CN, -OH, -C 1-3alkyl, -C 1-3alkoxy or 5-or 6-membered heteroaryl, and each of which is independently optionally unsubstituted or substituted by deuterium, halogen, -NH 2, -CN, -OH, -C 1-3alkyl, or -C 1-3alkoxy;R is:i) wherein v is 0, 1, 2, or 3; each of R 5 is independently selected from halogen, -OH, -NH 2, -CN, C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkyl, (C 1-3 alkoxy) C 1-3 alkyl-, (C 1-3 alkoxy) C 1-3 alkoxy-, (C 1-3 hydroxyalkoxy) C 1-3 alkoxy-, -C 1-3 alkylene- OC (O) NH (C 1-3 alkyl) , -C 1-3 alkylene-OC (O) N (C 1-3 alkyl) 2, orX 0 is H, -OH, -NH 2, -C 1-3 alkyl, -C 1-3 alkoxy, -C 1-3 alkylene-OC (O) NHC 1-3 alkyl, -C 1-3 alkylene-OC (O) N (C 1-3 alkyl) 2, -C 1-3 alkylene-N (C 1-3alkyl) 2, -C 1-3 alkoxy, or -C 1-3 hydroxy alkyl; and each of which can be independently optionally unsubstituted or substituted by a 3-to 7-membered heterocycle with one or more hetero atom independently selected from N, O or S, and at least one of the hetero atoms is N which is directly connected to one of the C atoms of the C 1-3 alky or C 1-3 hydroxy alkyl, and the 3-to 7-membered heterocycle can be further optionally unsubstituted or substituted by a NH 2, -OH, halogen, C 1-3 alkyl, C 1-3 alkoxy, -C 1-3 alkylene-N (C 1-3 alkyl) 2 or -N (C 1-3 alkyl) 2;Y is C (R N) 2 or NR N; each of R N is independently selected from H, halogen, -NH 2, -CN, -OH, -NHC (O) NHC 1-3 alkyl , -NHC (O) N (C 1-3 alkyl) 2, -OC (O) NHC 1-3 alkyl, -OC (O) N (C 1-3 alkyl) 2, -C 1-3 alkylene-NHC (O) NHC 1-3 alkyl, -C 1-3 alkylene-NHC (O) N (C 1-3 alkyl) 2, -C 1-3 alkyl, -C 1-3 alkylene-OC (O) NHC 1-3 alkyl, -C 1-3 alkylene-OC (O) N (C 1-3alkyl) 2, -C 1-3 alkyl, -C 1-3 alkoxy, oreach of R 8, R 9 , or R 10 is independently selected from H, halogen, -NH 2, -CN, -OH, -C 1- 3alkyl, or -C 1-3alkoxy, and each of which is independently optionally unsubstituted or substituted by deuterium, halogen, -NH 2, -CN, -OH, -C 1-3 alkyl, or -C 1-3 alkoxy;each of R 5 is independently selected from halogen, -OH, -NH 2, -CN, C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkyl, (C 1-3 alkoxy) C 1-3 alkyl-, (C 1-3 alkoxy) C 1-3 alkoxy-, (C 1-3 hydroxyalkoxy) C 1-3 alkoxy-, -C 1-3 alkylene-OC (O) NH (C 1-3 alkyl) , -C 1-3 alkylene-OC (O) N (C 1-3 alkyl) 2, oreach of R 6 or R 7 is independently selected from H, or C 1-3 alkyl;Z is O, S, SO, or SO 2;ring B is fused with pyridine or pyrimidine ring, and wherein:ring B is a saturated or unsaturated 5-or 6-membered heterocyclic amide (lactam) , and each of which is independently optionally unsubstituted or substituted with one or more R 2;ring B is a saturated or unsaturated 5-or 6-membered heterocyclyl, saturated or unsaturated 5-or 6-membered heterocyclic amide (lactam) , 6-membered aryl, or 5-or 6-membered heteroaryl; and each of ring B is independently optionally unsubstituted or substituted with one or more R 2.herein i) or ii) , each of R 2 is independently H, halogen, C 1-3 haloalkyl, C 1-3 alkyl, C 1-3 alkoxy, or C 3-5 cycloalkyl, or two R 2 together with the C atom to which both R 2 attached form an oxo, a 3-to 5-membered cycloalkyl, or a 3-to 5-membered heterocyclyl;
- The compound or pharmaceutically acceptable salt thereof of claim 1 or claim 2, wherein the compound represented by the Formula (II) : wherein is a double bond or a single bond; when X 2 is N; X 3 is CR 2; and X 2 together with X 4 forms a lactam, is a double bond; when X 3 is NR 2 or C (R 2) 2, is a single bond.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 13, wherein n is 1.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 14, wherein n1 is 0, n2 is 1, and n is 1.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 13, wherein n is 2.
- The compound or pharmaceutically acceptable salt thereof of claim 1 to claim 13, or claim 16, wherein n1 is 0, n2 is 1, and n is 2.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1, wherein n1 is 1, n2 is 0, and n is 1.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1, wherein n1 is 1, n2 is 0, and n is 2.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 or claim 19 to claim 20, wherein the compound represented by the Formula (II′) : wherein is a double bond or a single bond; when X 2 is N, X 3 is CR 2, and X 2 together with X 4 forms a lactam, is a double bond; when X 3 is NR 2 or C (R 2) 2, is a single bond.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 31, wherein R′ is H, F, Cl, hydroxy, methyl, ethyl, methoxy, methyl substituted with 1F, 2F or 3F, ethyl substituted with 1F, 2F or 3F, methoxy substituted with 1F, 2F or 3F, or ethoxy substituted with 1F, 2F or 3F.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 32, wherein R′ is H, F, methyl, ethyl, methoxy, methyl substituted with 1F or 3F, ethyl substituted with 1F or 3F.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 33, wherein X 1 is NH.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 31, wherein X 1 is O or S.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 35, wherein ring A is a phenyl or benzyl, or 5-, 6-, 7-, 8-, 9-, or 10-membered heteroaryl, and each of which is independently optionally unsubstituted or substituted with 1R 1, 2R 1, 3R 1, 4R 1, or 5R 1.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 36, wherein ring A is a phenyl or benzyl, or 5-or 6-membered heteroaryl, and each of which is independently optionally unsubstituted or substituted with 1R 1, 2R 1, or 3R 1.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 37, wherein ring A is a phenyl or benzyl, and each of which is independently optionally unsubstituted or substituted with 1R 1, 2R 1, or 3R 1.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 38, wherein ring A is a phenyl or benzyl, and each of which is independently optionally unsubstituted or substituted with 2R 1 or 3R 1.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 39, wherein ring A is a phenyl or benzyl, and each of which is independently optionally unsubstituted or substituted with 3R 1.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 40, wherein R 1 is: i) H, F, Cl, Br, hydroxy, methyl, ethyl, propyl, vinyl, ethynyl, propynyl, methoxy, ethoxy; methyl could be substituted with 1F, 2F or 3F; ethyl could be substituted with 1F, 2F or 3F; methoxy could be substituted with 1F, 2F or 3F; or ethoxy could be substituted with 1F, 2F or 3F; ii) -NR 4R 4’, -NC (O) R 4, -C (O) NR 4R 4’; and each of R 4 or R 4’ is independently selected from H, methyl; iii) 5-membered cycloalkyl; 5-membered halocycloalkyl; or 5-membered heterocycloalkyl;
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 41, wherein R 1 is i) H, F, Cl, hydroxy, methyl, ethyl, ethynyl; methyl substituted with 1F, 2F, or 3F; ii) NR 4R 4’, and each of R 4 or R 4’ is independently selected from H, methyl.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 42, wherein R 1 is R 1 is H, F, Cl, hydroxy, ethyl, ethynyl, or CF 3.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 43, wherein Z is O or S.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 44, wherein Z is O.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 45, wherein Z is O, and ring B is fused with pyridine or pyrimidine ring, and ring B is a saturated or unsaturated 5-or 6-membered heterocyclic amide (lactam) , and each of which is independently optionally unsubstituted or substituted with one or more R 2.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 46, wherein Z is O, and ring B is fused with pyridine or pyrimidine ring, and ring B is a saturated or unsaturated 6-membered heterocyclic amide (lactam) , and each of which is independently optionally unsubstituted or substituted with 1R 2, 2R 2, or 3R 2.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 47, wherein Z is O, and ring B is fused with pyridine or pyrimidine ring, and ring B is a saturated 6-membered heterocyclic amide (lactam) , and each of which is independently optionally unsubstituted or substituted with 1R 2, 2R 2, or 3R 2.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 48, wherein Z is O, and ring B is fused with pyridine or pyrimidine ring, and ring B is a saturated 6-membered heterocyclic amide (lactam) , and each of which is independently optionally unsubstituted or substituted with 3R 2.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 47, wherein Z is O, and ring B is fused with pyridine or pyrimidine ring, and ring B is an unsaturated 6-membered heterocyclic amide (lactam) , and each of which is independently optionally unsubstituted or substituted with 1R 2, 2R 2, or 3R 2.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 47, or claim 50, wherein Z is O, and ring B is fused with pyridine or pyrimidine ring, and ring B is a unsaturated 6-membered heterocyclic amide (lactam) , and each of which is independently optionally unsubstituted or substituted with 3R 2.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 44, wherein Z is S, SO, or SO 2, and ring B is fused with pyridine or pyrimidine ring, and ring B is a saturated or unsaturated 5-or 6-membered heterocyclyl, saturated or unsaturated 5-or 6-membered heterocyclic amide (lactam) , 6-membered aryl, or 5-or 6-membered heteroaryl, and each of ring B is independently optionally unsubstituted or substituted with 1R 2, 2R 2, or 3R 2.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 44, or claim 53, wherein Z is S, and ring B is fused with pyridine or pyrimidine ring, and ring B is a unsaturated 5-or 6-membered heterocyclyl, saturated or unsaturated 5-or 6-membered heterocyclic amide (lactam) , 6-membered aryl, or 6-membered heteroaryl, and each of ring B is independently optionally unsubstituted or substituted with 1R 2, 2R 2, or 3R 2.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 44, claim 53, or claim 54, wherein Z is S, and ring B is fused with pyridine or pyrimidine ring, and ring B is a unsaturated 6-membered heterocyclyl, or saturated or unsaturated 6-membered heterocyclic amide (lactam) , and each of ring B is independently optionally unsubstituted or substituted with 3R 2.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 44, or claim 53 to claim 55, wherein Z is S, and ring B is fused with pyridine or pyrimidine ring, and ring B is a unsaturated 6-membered heterocyclyl, or unsaturated 6-membered heterocyclic amide (lactam) , and each of ring B is independently optionally unsubstituted or substituted with 3R 2.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 44, claim 52, or claim 55, wherein Z is S, and ring B is fused with pyridine or pyrimidine ring, and ring B is a unsaturated 6-membered heterocyclyl, or saturated 6-membered heterocyclic amide (lactam) , and each of ring B is independently optionally unsubstituted or substituted with 3R 2.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 58, wherein, R 2 is independently H, F, Cl, methyl, ethyl, methoxy, or ethoxy; methyl could be substituted with 1F, 2F, or 3F; ethyl could be substituted with 1F, 2F, or 3F.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 59, wherein, R 2 independently H, F, methyl or methoxy; methyl could be substituted with 1F, 2F, or 3F.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 60, wherein, R 2 is independently H, F, or CF 3.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 58, wherein, two R 2 together with the C atom to which both R 2 attached form a oxo; 3-, 4-, or 5-membered cycloalkyl; or 3-, 4-, or 5-membered heterocyclyl.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 58 or claim 62, wherein, two R 2 together with the C atom to which both R 2 attached form a oxo, 3-or 4-membered cycloalkyl, or 3-membered heterocyclyl.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 58, claim 62, or claim 63, wherein, two R 2 together with the C atom to which both R 2 attached form a oxo, or 3-membered cycloalkyl.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 58, or claim 62 to claim 64, wherein, two R 2 together with the C atom to which both R 2 attached form an oxo.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 58, or claim 62 to claim 64, wherein, two R 2 together with the C atom to which both R 2 attached form a 3-membered cycloalkyl.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 66, wherein, X 5 is N or CR X5; and R X5 is independently selected from -CN or CF 3.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 67, wherein, X 5 is N.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 68, wherein, m is 1, or 2.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 69, wherein, m is 1.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 70, wherein, each of R 3 is independently selected from hydrogen, methyl or ethyl; or two R 3 together with the C atom to which they are both attached form a 3-membered cycloalkyl, or 3-membered halocycloalkyl.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 71, wherein, each of R 3 is independently selected from hydrogen.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 72, wherein, ring A is a 6-membered aryl, 10-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, or 10-membered heteroaryl, and each of which is independently optionally unsubstituted or substituted with one or more R 1.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 73, wherein, ring A is a 6-membered aryl, 10-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, or 10-membered heteroaryl, and each of which is independently optionally unsubstituted or substituted with 1R 1, 2R 1 or 3R 1.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 74, wherein, ring A is a 6-membered aryl, 10-membered aryl, 6-membered heteroaryl, or 10-membered heteroaryl, and each of which is independently optionally unsubstituted or substituted with 1R 1, 2R 1 or 3R 1.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 75, wherein, ring A is a phenyl, or benzyl, 6-membered heteroaryl, or 10-membered heteroaryl, and each of which is independently substituted with 1R 1, 2R 1 or 3R 1.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 76, wherein, ring A is a phenyl, or benzyl, and each of which is independently substituted with 3R 1.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 77, wherein, ring A is a benzyl, and each of which is independently substituted with 3R 1.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 78, wherein, ring A is a phenyl, and each of which is independently substituted with 3R 1.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 79, wherein, and R 1 is H, F, Cl, hydroxy, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, -NR 4R 4’, -NC (O) R 4, -C (O) NR 4R 4’, 3-to 5-membered cycloalkyl, 3-to 5-membered halocycloalkyl, or 3-to 5-membered heterocycloalkyl; each of which could be substituted with 1F, 2F, or 3F; and each of R 4 or R 4’ is independently selected from H or -NH 2.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 80, wherein R 1 is H, F, Cl, hydroxy, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, NR 4R 4’, -NC (O) R 4, -C (O) NR 4R 4; methyl could be substituted with 1F, 2F, or 3F; ethyl could be substituted with 1F, 2F, or 3F; the methyl group of the methoxy could be substituted with 1F, 2F or 3F; the ethyl group of the ethoxy could be substituted with 1F, 2F, or 3F; and each of R 4 or R 4’ is independently selected from H or -NH 2.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 81, wherein, and R 1 is H, F, Cl, hydroxy, methyl, ethyl, vinyl, ethynyl, methyl substituted with 3F, ethyl 3F, methoxy substituted with 3F; ethoxy substituted with 3F.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 82, wherein, and FR 1 is H, F, Cl, hydroxy, ethyl, ethynyl, or -CF 3.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 87, wherein, R 5 is independently selected from F, Cl, -OH, -NH 2, -CN, methyl, ethyl, methoxy, ethoxy, methoxymethyl-, methoxymethoxy-, -CH 2OC (O) NH (CH 3) , -CH 2 OC (O) N (CH 3) 2, -CH 2OC (O) N (CH 2CH 3) 2, -CH 2CH 2 OC (O) N (CH 3) 2, or and each of which of could be substituted with one or more OH or halogen.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 87, wherein, R 5 is independently selected from F, Cl, -OH, -NH 2, -CN, methyl, ethyl, methoxy, ethoxy, methoxymethyl-, methoxymethoxy-, -CH 2OC (O) NHmethyl, -CH 2 OC (O) N (CH 3) 2, -CH 2OC (O) N (CH 2CH 3) 2, -CH 2CH 2 OC (O) N (CH 3) 2, or and each of which could be with one or more OH, F, or Cl.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 86, wherein, R 5 is independently selected from F, Cl, methyl, ethyl, hydroxymethyl, ethyl substituted with 1OH, methoxy, methyl substituted with 1F or 3F, ethyl substituted with 1F or 3F, -CH 2OC (O) NH (CH 3) , -CH 2 OC (O) N (CH 3) 2, -CH 2OC (O) N (CH 2CH 3) 2, or
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 85, wherein, R 5 is independently selected from F, Cl, -OH, -NH 2, -CN, methyl, ethyl, methoxy, ethoxy, methoxymethyl-, methoxymethoxy-, -CH 2OC (O) NH (CH 3) , -CH 2 OC (O) N (CH 3) 2, -CH 2OC (O) N (CH 2CH 3) 2, -CH 2CH 2 OC (O) N (CH 3) 2, or and methyl or ethyl could be substituted with 1OH or 3F.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 83, or claim 92 to claim 95, wherein X 0 is H, -OH, -NH 2, -C 1-3alkyl, -C 1-3alkoxy, -C 1-3alkylene-OC (O) NHC 1-3alkyl, -C 1-3 alkylene-OC (O) N (C 1-3alkyl) 2, -C 1-3alkylene-N (C 1-3alkyl) 2, -C 1-3 alkoxy, or -C 1-3 hydroxy alkyl; and each of which can be independently optionally unsubstituted or substituted by a 3-to 7-membered heterocycle with one or more hetero atom independently selected from N, O or S, and at least one of the hetero atoms is N which is directly connected to one of the C atoms of the C 1-3 alky or C 1-3 hydroxy alkyl, and the 3-to 7-membered heterocycle can be further optionally unsubstituted or substituted by a NH 2, -OH, halogen, C 1-3 alkyl, C 1-3 alkoxy, -C 1-3 alkylene N (C 1-3 alkyl) 2 or -N (C 1-3 alkyl) 2.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 83, or claim 92 to claim 96, wherein, X 0 is H, -OH, -NH 2, methyl, ethyl, methoxy, ethoxy, -CH 2OC (O) NHCH 3, - CH 2CH 2OC (O) NHCH 3, -CH 2OC (O) N (CH 3) 2, -CH 2CH 2OC (O) N (CH 3) 2, -CH 2OC (O) N (CH 2CH 3) CH 3, -CH 2OC (O) N (CH 2CH 3) 2, -CH 2N (CH 3) 2, -CH 2CH 2N (CH 3) 2, -CH 2N (CH 2CH 3) CH 3, -CH 2N (CH 2CH 3) 2; -CH 2OH, ethyl substituted with 1OH or 2OH; and each of which can be independently optionally unsubstituted or substituted by a 3-, 4-, 5-, 6-, or 7-membered heterocycle with one or more hetero atom independently selected from N, O or S, and at least one of the hetero atoms is N which is directly connected to one of the C atoms of the methyl, ethyl, methyl substituted with 1OH, or ethyl substituted with 1OH; and the 3-, 4-, 5-, 6-, or 7-membered heterocycle can be further optionally unsubstituted or substituted by a NH 2, -OH, halogen, C 1-3 alkyl, C 1-3 alkoxy, -C 1-3 alkylene N (C 1-3 alkyl) 2 or -N (C 1-3 alkyl) 2.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 83, or claim 92 to claim 97, wherein, X 0 is H, -OH, -NH 2, methyl, ethyl, methoxy, -CH 2OC (O) NHCH 3, -CH 2OC (O) N (CH 3) 2, -CH 2OC (O) N (CH 2CH 3) CH 3, -CH 2OC (O) N (CH 2CH 3) 2, -CH 2N (CH 3) 2, -CH 2N (CH 2CH 3) 2, methyl substituted with 1OH, or ethyl substituted with 1OH; and each of which can be independently optionally unsubstituted or substituted by a 5-or 6-membered heterocycle with one or more hetero atom independently selected from N or O, and at least one of the hetero atoms is N which is directly connected to one of the C atoms of the methyl, ethyl, or methyl substituted with 1OH; and the 5-or 6-membered heterocycle can be further optionally unsubstituted or substituted by a NH 2, -OH, halogen, C 1-3 alkyl, C 1-3 alkoxy, -C 1-3 alkylene N (C 1-3 alkyl) 2 or -N (C 1-3 alkyl) 2.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 83, or claim 92 to claim 98, wherein, X 0 is H, methyl, -CH 2OC (O) N (CH 3) 2, -CH 2N (CH 3) 2, or methyl substituted with 1OH; and each of which can be independently optionally unsubstituted or substituted by a 6-membered heterocycle with one or more hetero atom independently selected from N or O, and at least one of the hetero atoms is N which is directly connected to one of the C atoms of the methyl, ethyl, or methyl substituted with 1OH; and the 6-membered heterocycle can be further optionally unsubstituted or substituted by a NH 2, -OH, halogen, C 1-3 alkyl, C 1-3 alkoxy, -C 1-3 alkylene N (C 1-3 alkyl) 2 or -N (C 1-3 alkyl) 2.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 96 to claim 99, wherein, the halogen is F, or Cl; the C 1-3 alkyl is methyl, ethyl, or propyl; the C 1-3 alkoxy is methoxy, ethoxy, or propoxy; the C 1-3 alkylene is -CH 2-, -CH 2CH 2-, or CH 2CH 2CH 2-; -N (C 1-3alkyl) 2 is -N (CH 3) 2, -N (CH 2CH 3) 2, or -N (CH 2CH 3) CH 3; the -C 1-3 alkylene N (C 1-3 alkyl) 2 is -CH 2N (CH 3) 2, -CH 2N (CH 2CH 3) 2, -CH 2N (CH 2CH 3) CH 3, -CH 2CH 2N (CH 3) 2, -CH 2CH 2N (CH 2CH 3) 2, or -CH 2CH 2N (CH 2CH 3) CH 3.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 96 to claim 100, wherein, the halogen is F, or Cl; the C 1-3 alkyl is methyl, or ethyl; the C 1-3 alkoxy is methoxy, or ethoxy; the C 1- 3 alkylene is -CH 2-, or -CH 2CH 2-; -N (C 1-3alkyl) 2 is -N (CH 3) 2, or -N (CH 2CH 3) 2; the -C 1-3 alkylene N (C 1-3 alkyl) 2 is -CH 2N (CH 3) 2, -CH 2N (CH 2CH 3) 2, -CH 2CH 2N (CH 3) 2, or -CH 2CH 2N (CH 2CH 3) 2.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 96 to claim 101, wherein, the halogen is F; the C 1-3 alkyl is methyl; the C 1-3 alkoxy is methoxy; the C 1-3 alkylene is -CH 2-; - N (C 1-3 alkyl) 2 is -N (CH 3) 2; the -C 1-3 alkylene-N (C 1-3 alkyl) 2 is -CH 2N (CH 3) 2.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 96 to claim 102, wherein, the Y is NR N.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 96 to claim 102, wherein, the Y is C (R N) 2.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 96 to claim 104, wherein, each of R N is independently selected from H, F, Cl, -NH 2, -CN, -OH, -NHC (O) NHCH 3, -NHC (O) NHCH 2CH 3, -NHC (O) NHCH 3, -NHC (O) NHCH 2CH 3, -NHC (O) N (CH 3) 2, -NHC (O) N (CH 2CH 3) 2, -OC (O) NHCH 3, -OC (O) NHCH 2CH 3, -OC (O) N (CH 3) 2, -CH 2NHC (O) NHCH 3, -CH 3NHC (O) N (CH 3) 2, -CH 2OH, -CH 2OC (O) NHCH 3, -CH 2OC (O) N (CH 3) 2, methyl, ethyl, propyl, methoxy, ethoxy, or each of R 8, R 9 or R 10 is independently selected from H, F, Cl, -NH 2, -CN, -OH, methyl, ethyl, methoxy, or ethoxy; and each of which is independently optionally unsubstituted or substituted by deuterium, F, Cl, -NH 2, -CN, -OH, methyl, ethyl, methoxy, or ethoxy.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 96 to claim 105, wherein, each of R N is independently selected from H, F, Cl, -NH 2, -CN, -OH, -NHC (O) NHCH 3, -NHC (O) NHCH 2CH 3, -NHC (O) NHCH 3, -NHC (O) NHCH 2CH 3, -NHC (O) N (CH 3) 2, -NHC (O) N (CH 2CH 3) 2, -OC (O) NHCH 3, -OC (O) NHCH 2CH 3, -OC (O) N (CH 3) 2, -CH 2NHC (O) NHCH 3, -CH 3NHC (O) N (CH 3) 2, -CH 2OH, -CH 2OC (O) NHCH 3, -CH 2OC (O) N (CH 3) 2, methyl, ethyl, propyl, methoxy, ethoxy, or each of R 8, R 9 or R 10 is independently selected from H, F, Cl, -NH 2, -CN, -OH, methyl, ethyl, methoxy, or ethoxy; and each of which is independently optionally unsubstituted or substituted by deuterium, F, Cl, -NH 2, -CN, -OH, methyl, ethyl, methoxy, or ethoxy.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 96 to claim 106 wherein, each of R N is independently selected from H, F, Cl, -NH 2, -CN, -OH, -NHC (O) NHCH 3, -NHC (O) N (CH 3) 2, -OC (O) NHCH 3, -CH 2NHC (O) NHCH 3, -CH 3NHC (O) N (CH 3) 2, -CH 2OH, methyl, ethyl, methoxy, or each of R 8, R 9, or R 10 is independently selected from H, F, Cl, -NH 2, -OH, or methyl; and each of which is independently optionally unsubstituted or substituted by deuterium, F, Cl, -NH 2, -OH, or methyl.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 96 to claim 107, wherein, each of R N is independently selected from H, F, -NH 2, -OH, -CH 2OH, methyl, or ethyl.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 96 to claim 108, wherein, each of R N is independently selected from H, or methyl.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 96 to claim 108, wherein, each of R 6 or R 7 is independently H, F, Cl, NH 2, OH, methyl, methyl substituted with F or Cl, methyl substituted with OH, methoxy substituted with F or Cl.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 96 to claim 108, wherein, each of R 6 or R 7 is independently H, or methyl.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 111, wherein, R is and ring B is fused with pyridine or pyrimidine ring, and ring B is a saturated or unsaturated 5-or 6-membered heterocyclyl, saturated or unsaturated 5-or 6-membered heterocyclic amide (lactam) , 6-membered aryl, or 5-or 6-membered heteroaryl, and each of ring B is independently optionally unsubstituted or substituted with 1R 2, 2R 2, or 3R 2.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 112, wherein, R is and ring B is fused with pyridine or pyrimidine ring, and ring B is a unsaturated 5-or 6-membered heterocyclyl, saturated or unsaturated 5-or 6-membered heterocyclic amide (lactam) , 6-membered aryl, or 6-membered heteroaryl, and each of ring B is independently optionally unsubstituted or substituted with 1R 2, 2R 2, or 3R 2.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 112, wherein, R is and ring B is fused with pyridine or pyrimidine ring, and ring B is an unsaturated 6-membered heterocyclyl, or saturated or unsaturated 6-membered heterocyclic amide (lactam) , and each of ring B is independently optionally unsubstituted or substituted with 3R 2.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 112, wherein, R is and ring B is fused with pyridine or pyrimidine ring, and ring B is a unsaturated 6-membered heterocyclyl, or unsaturated 6-membered heterocyclic amide (lactam) , and each of ring B is independently optionally unsubstituted or substituted with 3R 2.
- The compound or pharmaceutically acceptable salt thereof of any one of claim 1 to claim 112, wherein, R is and ring B is fused with pyridine or pyrimidine ring, and ring B is a unsaturated 6-membered heterocyclyl, or saturated 6-membered heterocyclic amide (lactam) , and each of ring B is independently optionally unsubstituted or substituted with 3R 2.
- The compound or pharmaceutically acceptable salt thereof is independently selected from:3- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;3- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;( (7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;( (3R, 7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;( (3R, 7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;( (3R, 7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;( (7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;( (3R, 7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;( (3R, 7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;( (3R, 7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;3- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -8- fluoropyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;3- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;3- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;3- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen- 2-ol;4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;3- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;3- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;3- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( ( (7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;3- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( ( (7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H- pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;( (7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;( (3R, 7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;( (3R, 7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;( (3R, 7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;( (7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;( (3R, 7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;( (3R, 7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;( (3R, 7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;( (7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8-oxo-6- (trifluoromethyl) -7, 8-dihydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;( (3R, 7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-oxo-6- (trifluoromethyl) -7, 8-dihydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;( (3R, 7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-6- (trifluoromethyl) -7, 8-dihydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;( (3R, 7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-6- (trifluoromethyl) -7, 8-dihydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;( (7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8-oxo-6- (trifluoromethyl) -7, 8-dihydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;( (3R, 7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-oxo-6- (trifluoromethyl) -7, 8-dihydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;( (3R, 7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-6- (trifluoromethyl) -7, 8-dihydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;( (3R, 7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-6- (trifluoromethyl) -7, 8-dihydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;( (7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;( (3R, 7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;( (3R, 7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;( (3R, 7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;( (7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;( (3R, 7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;( (3R, 7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;( (3R, 7aR) -7a- ( ( (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -7- (8- ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1- yl) methyl) cyclopropyl) methoxy) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (S) -1- methylpyrrolidin-2-yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;( (7aR) -7a- ( ( (4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8'-oxo-7', 8'-dihydro-5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -2'-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;( (3R, 7aR) -7a- ( ( (4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8'-oxo-7', 8'-dihydro-5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -2'-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;( (3R, 7aR) -7a- ( ( (4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8'-oxo-7', 8'-dihydro-5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -2'-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;( (3R, 7aR) -7a- ( ( (4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8'-oxo-7', 8'-dihydro-5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -2'-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;( (7aR) -7a- ( ( (4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8'-oxo-7', 8'-dihydro-5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -2'-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;( (3R, 7aR) -7a- ( ( (4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8'-oxo-7', 8'-dihydro-5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -2'-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;( (3R, 7aR) -7a- ( ( (4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8'-oxo-7', 8'-dihydro-5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -2'-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;( (3R, 7aR) -7a- ( ( (4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8'-oxo-7', 8'-dihydro-5'h-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -2'-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2'- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2'- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2'- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2'- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2'- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2'- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2'- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2'- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2'- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2'- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4- d] pyrimidin] -8' (7'H) -one;4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2'- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2'- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;( (7aR) -7a- ( ( (4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8'-oxo-7', 8'-dihydro-5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -2'-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;( (3R, 7aR) -7a- ( ( (4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8'-oxo-7', 8'-dihydro-5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -2'-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;( (3R, 7aR) -7a- ( ( (4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8'-oxo-7', 8'-dihydro-5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -2'-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;( (3R, 7aR) -7a- ( ( (4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8'-oxo-7', 8'-dihydro-5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -2'-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;( (7aR) -7a- ( ( (4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8'-oxo-7', 8'-dihydro-5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -2'-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;( (3R, 7aR) -7a- ( ( (4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8'-oxo-7', 8'-dihydro-5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -2'-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;( (3R, 7aR) -7a- ( ( (4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8'-oxo-7', 8'-dihydro-5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -2'-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;( (3R, 7aR) -7a- ( ( (4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8'-oxo-7', 8'-dihydro-5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -2'-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2'- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2'- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2'- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2'- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2'- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2'- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2'- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -5'H- spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2'- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2'- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2'- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2'- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2-( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;( (7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;( (7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) - 2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (S) - 1-methylpyrrolidin-2-yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;( (7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8-oxo-6- (trifluoromethyl) -7, 8-dihydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-oxo-6- (trifluoromethyl) -7, 8-dihydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-6- (trifluoromethyl) -7, 8-dihydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-6- (trifluoromethyl) -7, 8-dihydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;( (7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8-oxo-6- (trifluoromethyl) -7, 8-dihydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-oxo-6- (trifluoromethyl) -7, 8-dihydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-6- (trifluoromethyl) -7, 8-dihydropyrido [3, 4-d] pyrimidin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-6- (trifluoromethyl) -7, 8-dihydropyrido [3, 4-d] pyrimidin-2- yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4- d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) - 2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (S) -1-methylpyrrolidin-2-yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;( (7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;( (7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one;3- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (tetrahydro-1H-pyrrolizin-7a (5H) - yl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;4- (4- ( (1R, 5; ) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;3- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( ( (S) -1-methylpyrrolidin-2-yl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( ( (S) -1-methylpyrrolidin-2-yl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( ( (S) -1-methylpyrrolidin-2-yl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( ( (S) -1-methylpyrrolidin-2-yl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;( (7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;( (7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;3- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( ( (1- ( (dimethylamino) methyl) cyclopropyl) methyl) thio) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( ( (1- ( (dimethylamino) methyl) cyclopropyl) methyl) thio) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( ( (1- ( (dimethylamino) methyl) cyclopropyl) methyl) thio) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( ( (1- ( (dimethylamino) methyl) cyclopropyl) methyl) thio) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;3- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1- (morpholinomethyl) cyclopropyl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1- (morpholinomethyl) cyclopropyl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2- ol;4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1- (morpholinomethyl) cyclopropyl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1- (morpholinomethyl) cyclopropyl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;3- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -8-fluoro-2- ( ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;3- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;4- (4- (2, 5-Diazabicyclo [2.2.2] octan-2-yl) -2- ( ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;3- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1- (pyrrolidin-1- ylmethyl) cyclopropyl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;3- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;3- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( ( (7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;3- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( ( (7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( ( (S) -1-methylpyrrolidin-2-yl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (S) -1-methylpyrrolidin-2-yl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (S) -1-methylpyrrolidin-2-yl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (S) -1-methylpyrrolidin-2-yl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;( (7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;( (7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (1- ( (dimethylamino) methyl) cyclopropyl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- ( (dimethylamino) methyl) cyclopropyl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( ( (1- ( (dimethylamino) methyl) cyclopropyl) methyl) thio) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( ( (1- ( (dimethylamino) methyl) cyclopropyl) methyl) thio) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (1- (morpholinomethyl) cyclopropyl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- (morpholinomethyl) cyclopropyl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- (morpholinomethyl) cyclopropyl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- (morpholinomethyl) cyclopropyl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) pyrimido [4, 5-d] pyridazin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( ( (S) -1-methylpyrrolidin-2-yl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (S) -1-methylpyrrolidin-2-yl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (S) -1-methylpyrrolidin-2-yl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (S) -1-methylpyrrolidin-2-yl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;( (7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8-oxo-6- (trifluoromethyl) -7, 8-dihydropyrido [3, 4-d] pyrimidin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-oxo-6- (trifluoromethyl) -7, 8-dihydropyrido [3, 4-d] pyrimidin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-6- (trifluoromethyl) -7, 8-dihydropyrido [3, 4-d] pyrimidin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-6- (trifluoromethyl) -7, 8-dihydropyrido [3, 4-d] pyrimidin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;( (7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8-oxo-6- (trifluoromethyl) -7, 8-dihydropyrido [3, 4-d] pyrimidin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-oxo-6- (trifluoromethyl) -7, 8-dihydropyrido [3, 4-d] pyrimidin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-6- (trifluoromethyl) -7, 8-dihydropyrido [3, 4-d] pyrimidin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-6- (trifluoromethyl) -7, 8-dihydropyrido [3, 4-d] pyrimidin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (1- ( (dimethylamino) methyl) cyclopropyl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- ( (dimethylamino) methyl) cyclopropyl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( ( (1- ( (dimethylamino) methyl) cyclopropyl) methyl) thio) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( ( (1- ( (dimethylamino) methyl) cyclopropyl) methyl) thio) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (1- (morpholinomethyl) cyclopropyl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- (morpholinomethyl) cyclopropyl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- (morpholinomethyl) cyclopropyl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- (morpholinomethyl) cyclopropyl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4- d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6- (trifluoromethyl) pyrido [3, 4-d] pyrimidin-8 (7H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( ( (S) -1-methylpyrrolidin-2-yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (S) -1-methylpyrrolidin-2-yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (S) -1-methylpyrrolidin-2-yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (S) -1-methylpyrrolidin-2-yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;( (7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-2-yl) thio) methyl) hexahydro- 1H-pyrrolizin-3-yl) methyl dimethylcarbamate;( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;( (7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;( (3R, 7aR) -7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-2-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (1- ( (dimethylamino) methyl) cyclopropyl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- ( (dimethylamino) methyl) cyclopropyl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( ( (1- ( (dimethylamino) methyl) cyclopropyl) methyl) thio) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (1- ( (dimethylamino) methyl) cyclopropyl) methoxy) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) - 2- ( ( (1- (morpholinomethyl) cyclopropyl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- (morpholinomethyl) cyclopropyl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- (morpholinomethyl) cyclopropyl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- (morpholinomethyl) cyclopropyl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6, 7- dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2'- ( ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2'- ( ( ( (S) -1-methylpyrrolidin-2-yl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( ( (S) -1-methylpyrrolidin-2-yl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( ( (S) -1-methylpyrrolidin-2-yl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( ( (S) -1-methylpyrrolidin-2-yl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;( (7aR) -7a- ( ( (4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8'-oxo-7', 8'-dihydro-5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -2'-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;( (3R, 7aR) -7a- ( ( (4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -8'-oxo-7', 8'-dihydro-5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -2'-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;( (3R, 7aR) -7a- ( ( (4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8'-oxo-7', 8'-dihydro-5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -2'-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;( (3R, 7aR) -7a- ( ( (4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8'-oxo-7', 8'-dihydro-5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -2'-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;( (7aR) -7a- ( ( (4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -8'-oxo-7', 8'-dihydro-5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -2'-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;( (3R, 7aR) -7a- ( ( (4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (7, 8-difluoro-3- hydroxynaphthalen-1-yl) -8'-oxo-7', 8'-dihydro-5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -2'-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;( (3R, 7aR) -7a- ( ( (4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8'-oxo-7', 8'-dihydro-5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -2'-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;( (3R, 7aR) -7a- ( ( (4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8'-oxo-7', 8'-dihydro-5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -2'-yl) thio) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2'- ( ( (1- ( (dimethylamino) methyl) cyclopropyl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (1- ( (dimethylamino) methyl) cyclopropyl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2'- ( ( (1- ( (dimethylamino) methyl) cyclopropyl) methyl) thio) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2'- ( ( (1- ( (dimethylamino) methyl) cyclopropyl) methyl) thio) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2'- ( ( (1- (morpholinomethyl) cyclopropyl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (1- (morpholinomethyl) cyclopropyl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (1- (morpholinomethyl) cyclopropyl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (1- (morpholinomethyl) cyclopropyl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4- d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2'- ( ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2'- ( ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2'- ( ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2'- ( ( (1- ( ( (R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) cyclopropyl) methyl) thio) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2'- ( ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (1- (pyrrolidin-1-ylmethyl) cyclopropyl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2'- ( ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( (1- ( (4-methylpiperazin-1-yl) methyl) cyclopropyl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2'- ( ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4'- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7'- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2'- ( ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -5'H-spiro [cyclopropane-1, 6'-pyrido [3, 4-d] pyrimidin] -8' (7'H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) - 2- ( ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (3R, 7aR) -3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- ( ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( ( (3R, 7aR) -3- (fluoromethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methyl) thio) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one;4- (2- ( (4'H, 6'H-Spiro [cyclopropane-1, 5'-pyrrolo [1, 2-b] pyrazol] -3'-yl) methoxy) -4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (2-chloropyrrolo [2, 1-b] thiazol-6-yl) methoxy) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;4- (2- ( (4'H, 6'H-Spiro [cyclopropane-1, 5'-pyrrolo [1, 2-b] pyrazol] -3'-yl) methoxy) -4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (2-chloropyrrolo [2, 1-b] thiazol-6-yl) methoxy) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;4- (2- ( (4'H, 6'H-Spiro [cyclopropane-1, 5'-pyrrolo [1, 2-b] pyrazol] -3'-yl) methoxy) -4- ( (1R, 5S) -3, 8- diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (2-chloropyrrolo [2, 1-b] thiazol-6-yl) methoxy) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;3- (2- ( (4'H, 6'H-Spiro [cyclopropane-1, 5'-pyrrolo [1, 2-b] pyrazol] -3'-yl) methoxy) -4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;3- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (2-chloropyrrolo [2, 1-b] thiazol-6-yl) methoxy) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;3'- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoronaphthalen-1-yl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) oxy) methyl) -4'H, 6'H-spiro [cyclopropane-1, 5'-pyrrolo [1, 2-b] pyrazole] ;6- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoronaphthalen-1-yl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) oxy) methyl) -2-chloropyrrolo [2, 1-b] thiazole;4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( (1-methyl-1, 4-dihydropyrrolo [3, 2-c] pyrazol-5-yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( (2-methyl-2, 4-dihydropyrrolo [3, 2-c] pyrazol-5-yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( (1-methyl-1, 4-dihydropyrrolo [3, 2-c] pyrazol-5-yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( (2-methyl-2, 4-dihydropyrrolo [3, 2-c] pyrazol-5-yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( (1-methyl-1, 4-dihydropyrrolo [3, 2-c] pyrazol-5-yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( (2-methyl-2, 4-dihydropyrrolo [3, 2-c] pyrazol-5-yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;3- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( (1-methyl-1, 4-dihydropyrrolo [3, 2-c] pyrazol-5-yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;3- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( (2-methyl-2, 4-dihydropyrrolo [3, 2-c] pyrazol-5-yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoronaphthalen-1-yl) -8-fluoro-2- ( (1-methyl-1, 4-dihydropyrrolo [3, 2-c] pyrazol-5-yl) methoxy) pyrido [4, 3-d] pyrimidine;4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoronaphthalen-1-yl) -8-fluoro-2- ( (2-methyl-2, 4-dihydropyrrolo [3, 2-c] pyrazol-5-yl) methoxy) pyrido [4, 3-d] pyrimidine;4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (2-chloro-4H-furo [3, 2-b] pyrrol-5-yl) methoxy) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (2-chloro-4H-furo [3, 2-b] pyrrol-5-yl) methoxy) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol;4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (2-chloro-4H-furo [3, 2-b] pyrrol-5-yl) methoxy) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (2-chloro-4H-furo [3, 2-b] pyrrol-5-yl) methoxy) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol;4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (2-chloro-4H-furo [3, 2-b] pyrrol-5-yl) methoxy) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (2-chloro-4H-furo [3, 2-b] pyrrol-5-yl) methoxy) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5, 6-difluoronaphthalen-2-ol;3- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (2-chloro-4H-furo [3, 2-b] pyrrol-5-yl) methoxy) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;3- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (2-chloro-4H-furo [3, 2-b] pyrrol-5-yl) methoxy) -8-fluoropyrido [4, 3-d] pyrimidin-7-yl) -5-chloro-4- (trifluoromethyl) phenol;5- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoronaphthalen-1-yl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) oxy) methyl) -2-chloro-4H-furo [3, 2-b] pyrrole;5- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (7, 8-difluoronaphthalen-1-yl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) oxy) methyl) -2-chloro-4H-furo [3, 2-b] pyrrole.
- A pharmaceutical composition, comprising a therapeutically effective amount of at least one of compound of claim l or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
- A pharmaceutical composition, comprising a therapeutically effective amount of at least one of compound of any one of claim l to claim 19, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
- A pharmaceutical composition, comprising a therapeutically effective amount of at least one of compound of claim 1 or claim 20 to claim 31 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
- A pharmaceutical composition, comprising a therapeutically effective amount of at least one of compound of claim 119 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
- A pharmaceutical composition, comprising a therapeutically effective amount of at least one of compound of claim 1 to claim 119 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
- A method for inhibiting KRAS Gl2D activity in a cell, comprising contacting the cell in which inhibition of KRAS Gl2D activity is desired with an effective amount of at least one of compound of according to claim 1 or a pharmaceutically acceptable salt thereof.
- A method for inhibiting KRAS Gl2D activity in a cell, comprising contacting the cell in which inhibition of KRAS Gl2D activity is desired with an effective amount of at least one of compound of according to any one of claim 1, to claim 19 or a pharmaceutically acceptable salt thereof. I0
- A method for inhibiting KRAS Gl2D activity in a cell, comprising contacting the cell in which inhibition of KRAS Gl2D activity is desired with an effective amount of at least one of compound of according to any one of claim 1, or claim 20 to claim 31 or a pharmaceutically acceptable salt thereof.
- A method for inhibiting KRAS Gl2D activity in a cell, comprising contacting the cell in which inhibition of KRAS Gl2D activity is desired with an effective amount of at least one of compound of according to claim 119 or a pharmaceutically acceptable salt thereof.
- A method for inhibiting KRAS G12D activity in a cell, comprising contacting the cell in which inhibition of KRAS G12D activity is desired with the pharmaceutical composition of any one of claim 114 to claim 118.
- A method for treating a KRAS G12D-associated cancer comprising administering to a patient in need thereof a therapeutically effective amount of at least one of compound according to claim 1 or a pharmaceutically acceptable salt thereof.
- A method for treating a KRAS G12D-associated cancer comprising administering to a patient in need thereof a therapeutically effective amount of at least one of compound according to any one of claim 1 to claim 19 or claim 119, or a pharmaceutically acceptable salt thereof.
- A method for treating a KRAS G12D-associated cancer comprising administering to a patient in need thereof a therapeutically effective amount of at least one of compound according to any one of claim 1, or claim 20 to claim 31 or claim 119, or a pharmaceutically acceptable salt thereof.
- A method for treating a KRAS G12D-associated cancer comprising administering to a patient in need thereof a therapeutically effective amount of at least one of compound according to any one of claim 1 to claim 118 or a pharmaceutically acceptable salt thereof.
- A method for treating a KRAS G12D-associated cancer comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition of any one of claim 119 to claim 123 or a pharmaceutically acceptable salt thereof.
- The method of any one of claim 124 to claim 133, wherein the therapeutically effective amount of the compound is between about 0.01 to 100 mg/kg per day.
- The method of any one of claim 124 to claim 134, wherein the therapeutically effective amount of the compound is between about 0.1 to 50 mg/kg per day.
- The method of any one of claim 129 to claim 135, wherein the KRAS G12D-associated cancer is selected from the group consisting of Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma) , myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma) , alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma) , stomach (carcinoma, lymphoma, leiomyosarcoma) , pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma) , small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma) , large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma) ; Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma) , lymphoma, leukemia) , bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma) , prostate (adenocarcinoma, sarcoma) , testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma) ; Liver hepatoma (hepatocellular carcinoma) , cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma) , fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma) , multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses) , benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans) , meninges (meningioma, meningiosarcoma, gliomatosis) , brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma) , glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors) , spinal cord neurofibroma, meningioma, glioma, sarcoma) ; Gynecological: uterus (endometrial 'carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma) , granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma) , vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma) , vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma) , fallopian tubes (carcinoma) ; Hematologic: blood (myeloid leukemia (acute and chronic) , acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome) , Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma) ; Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevI′ lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma.
- The method of claim 136, wherein the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer.
- A method for treating cancer in a patient in need thereof, the method comprising (a) determining that the cancer is associated with a KRAS Gl2D mutation (e.g., a KRAS Gl2D-associated cancer) ; and (b) administering to the patient a therapeutically effective amount of at least one of compound according to claim 1 to claim 19.
- A method for treating cancer in a patient in need thereof, the method comprising (a) determining that the cancer is associated with a KRAS Gl2D mutation (e.g., a KRAS Gl2D-associated cancer) ; and (b) administering to the patient a therapeutically effective amount of at least one of compound according to claim 119.
- A method for treating cancer in a patient in need thereof, the method comprising (a) determining that the cancer is associated with a KRAS Gl2D mutation (e.g., a KRAS Gl2D-associated cancer) ; and (b) administering to the patient a therapeutically effective amount of at least one of compound according to any one of claim 1 to claim 118.
- A method for treating cancer in a patient in need thereof, the method comprising (a) determining that the cancer is associated with a KRAS Gl2D mutation (e.g., a KRAS Gl2D-associated cancer) ; and (b) administering to the patient a therapeutically effective amount of a pharmaceutical composition according to any one of claim 1, or claim 20 to claim 31.
- The method of any one of claim 138 to claim 141, wherein the administering is done via a route selected from the group consisting of parenteral, intraperitoneal, intradermal, intracardiac, intraventricular, intracranial, intracerebrospinal, intrasynovial, intrathecal administration, intramuscular injection, intravitreous injection, intravenous injection, intra-arterial injection, oral, buccal, sublingual, transdermal, topical, intratracheal, intrarectal, subcutaneous, and topical administration.
- The method of claim 142, wherein the administering is done via an intravenous injection.
- The method of claim 142, wherein the administering is done via an intramuscular injection.
- The method of claim 142, wherein the administering is done via an intramuscular injection.
- The method of claim 142, wherein the administepyridine or pyrimidine ringomprises utilizing a delivery device.
- The method of claim 142, wherein the administering is done in a hospital setting.
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